Peripheral Atherectomy and Thrombectomy Devices
Number: 0295
Table Of Contents
PolicyApplicable CPT / HCPCS / ICD-10 Codes
Background
References
Policy
Scope of Policy
This Clinical Policy Bulletin addresses peripheral atherectomy and thrombectomy devices.
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Medical Necessity
For medical necessity criteria for peripheral atherectomy, see eviCore Healthcare Peripheral Vascular Intervention Clinical Guidelines.
Note: eviCore guidelines undergo a formal review annually; however, eviCore reserves the right to change and update the guidelines without prior notice. Draft guidelines are posted 90 days prior to implementation. Additional clinical guidelines may be developed as needed or may be withdrawn from use.
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Experimental, Investigational, or Unproven
The following interventions are considered experimental, investigational, or unproven because the effectiveness of these approaches has not been established:
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Mechanical or laser peripheral atherectomy for the following indications:
- Peripheral atherectomy of the renal artery, visceral artery;
- Abdominal aorta, brachiocephalic trunk and branches;
- The DETOUR system for the treatment of peripheral arterial disease;
- Intravascular shockwave lithotripsy of the anterior tibial, common iliac, external iliac, internal iliac, popliteal, posterior tibial, peroneal arteries, and superficial femoral artery for the treatment of atherosclerosis / calcified peripheral arterial lesions / intermittent claudication;
- Intravascular shockwave lithotripsy for the treatment of celiac artery occlusion, and renal artery stenosis;
- Isolated segmental pharmaco-mechanical thrombolysis (Trellis Peripheral Infusion System) for treatment of deep venous thromboses, Paget-Schroetter syndrome (also known as venous thoracic outlet syndrome) and other indications because there is inadequate evidence in the peer-reviewed published clinical literature.
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Related Policies
Background
Atherectomy was introduced in 1985 to improve upon the limitations of balloon angioplasty, primarily, abrupt re-closure and restenosis. Atherectomy devices cut and remove atherosclerotic plaque from a vessel wall or grind the atheroma into small particles, allowing them to embolize distally. Elastic recoil is reduced after atherectomy because the lumen is widened without stretching of the arterial wall.
Several types of atherectomy devices have been cleared by the U.S. Food and Drug Administration for peripheral use and primary success rates have been favorable with various devices; however, the Simpson Peripheral Atherocath has been the most widely used. This device has a circular cutter that spins at 2,000 rpm inside a metal housing with a window. Balloon inflation on the opposite side of the housing forces the plaque through the window where it is cut by advancing the rotating cutter in the housing. This device is best suited for short, discrete, eccentric stenosis. The catheters are bulky and stiff to use in the tibial or tortuous vessels. Primary success rate have been 82 to 100 % with few complications.
Data support the use of atherectomy as effective in the peripheral vessels in patients who meet the following criteria: have symptomatic peripheral vascular disease (limb-threatening ischemia or functionally limiting claudication); and cannot be treated by standard angioplasty techniques alone, i.e., balloon angioplasty would be ineffective or is contraindicated; and have an eccentric lesion that does not dilate with conventional balloon angioplasty, or vein bypass graft stenosis.
Until the problem of restenosis can be solved, atherectomy is a reasonable treatment for symptomatic peripheral vascular disease (limb-threatening ischemia or functionally limiting claudication) only when balloon angioplasty may be ineffective or contraindicated.
Greater than 70 percent stenosis is widely accepted in the literature and current practice to represent a hemodynamically significant stenosis. It is commonly accepted that stenoses less than 70 percent are not considered critical or severe. Supporting data comes from the trials studying the benefit or impact of carotid endarterectomy on the natural history of carotid stenosis. The data from those trials found a higher incidence of cerebrovascular events at symptomatic stenosis greater than 70 percent. This led to the recommendation that carotid revascularization should be offered to good risk candidates with carotid stenosis greater than 70 percent. Similarly, from the coronary artery literature, studies have computed tomography arteriogram (CTA) as an alternative to arteriogram as a reliable modality to predict severe stenosis, identifying stenosis greater than 70 percent is often used as the endpoint as it is considered the threshold for intervention.
Zeller et al (2007) reported a safety and efficacy study of the first rotational aspiration atherectomy system (Pathway PV) for the treatment of arterial lesions below the femoral bifurcation. A total of 15 patients (9 men; mean age of 71 +/- 9 years) with Rutherford stage 2 to 5 lower limb ischemia were enrolled at 3 study sites. Target lesions were in the superficial femoral (n = 7, 47 %), popliteal (n = 7, 47 %), and posterior tibial (n = 1, 6 %) arteries. Mean diameter stenosis was 97 % +/- 10 %; mean lesion length was 61 +/- 62 mm (range of 5 to 250). The primary study endpoint was the 30-day serious adverse event (SAE) rate. Interventional success (residual stenosis les than 30 %) was achieved in all lesions (100 %). Stand alone atherectomy was performed in 6 (40 %) patients, adjunctive balloon angioplasty in 7 (47 %), and stenting/endo-grafting in 2 (13 %). The SAE rate at 30 days was 20 % (3/15), including 1 perforation due to an unrecognized displacement of the guidewire (sealed with an endograft), 1 false aneurysm at the puncture site (successful duplex-guided compression therapy), and 1 dissection in conjunction with a distal embolism (stent implantation and aspiration thrombectomy). Primary patency rates measured by duplex ultrasound at 1 and 6 months were 100 % and 73 %, respectively; the target lesion revascularization (TLR) rate was 0 % after 6 months. The ankle-brachial index increased significantly from 0.54 +/- 0.3 at baseline to 0.89 +/- 0.16, 0.88 +/- 0.19, and 0.81 +/- 0.20 (p < 0.05) at discharge, 1 month, and 6 months, respectively. Mean Rutherford categories were 2.92 +/- 1.19 (range of 1 to 5), 0.64 +/- 1.12 (range of 0 to 1), and 0.83 +/- 1.33 (range of 0 to 3) at the same time points (p < 0.05). The authors concluded that the application of this new atherectomy device was feasible in all cases. The serious adverse event rate was moderate; however, all events were solved during the index procedure. The 0 % 6-month TLR rate is promising.
Mahmud et al (2007) noted that over the past decade, percutaneous revascularization therapies for the treatment of patients with peripheral arterial disease (PAD) have evolved tremendously, and a great number of patients can now be offered treatment options that are less invasive than traditional surgical options. With the surgical approach, there is significant symptomatic improvement, but the associated morbidity and mortality preclude its routine use. Although newer percutaneous treatment options are associated with lower procedural complications, the technical advances have outpaced the evaluation of these treatments in adequately designed clinical studies, and therapeutic options are available that may not have been rigorously investigated.
Bunting and Garcia (2007) stated that atherectomy is experiencing increased interest from endovascular specialists as a therapeutic treatment in the peripheral arteries. Long studied in the coronary vasculature, atherectomy has several theoretical advantages that make it uniquely suited for the peripheral circulation. In particular, infra-inguinal PAD experiences physiological stresses and forces that have made traditional percutaneous coronary treatments such as angioplasty and stenting not as successful. Re-stenosis has been a major problem for angioplasty and stenting alone. The SilverHawk atherectomy device has favorable short-term data but important longer-term data are limited and need further study. Laser atherectomy also has favorable applications in niche patients but the number of studies is limited. Unfortunately, athero-ablative technologies for PAD require more definitive objective data regarding 12-month and longer-term outcomes in order to obtain widespread scientific acceptance.
Biskup et al (2008) noted that an atherectomy device (SilverHawk) had been approved by the Food and Drug Administration, but the results with its use are unclear. These investigators analyzed a series of consecutive patients undergoing atherectomy. They retrospectively reviewed the charts of 35 patients undergoing infra-inguinal (IF) atherectomy in 38 limbs. The Trans-Atlantic Inter-Society Consensus (TASC) classification and Society of Vascular Surgery run-off scores were calculated. Time to event analysis was performed using Kaplan-Meier estimates. Risk factors affecting patency were analyzed with a multi-variate Cox model. Mean patient age was 70 +/- 9.6 years. Indications for intervention were claudication (26 %), rest pain (21 %), and tissue loss (53 %). Femoro-popliteal (FP) atherectomy was performed in 68 % and tibial atherectomy in 32 %. For FP lesions, the TASC distribution was A, 42 %; B, 23 %; C, 4 %; and D, 15 %. The average lesion treatment length was 9.4 +/- 10.6 cm (range of 1 to 40), and the run-off score was 5.1 +/- 3.5. For tibial lesions, the TASC distribution was A, 0 %; B, 17 %; C, 8 %; and D, 75 %. The average lesion treatment length was 9.2 +/- 6.0 cm (range of 2 to 20), with a run-off score of 5.4 +/- 2.4. A total of 39 % of patients had prior IF interventions. Adjunctive angioplasty of the atherectomized lesion was performed in 55 % of cases, stenting in 0 %, and adjunctive therapy for tandem lesions in 39 %. The post-operative ankle-brachial index increased by 0.30 +/- 0.14 and toe pressures increased by 40 +/- 32.4 mm Hg. Mean follow-up was 10 +/- 8 months (range of 0.3 to 23). During the studied period, 7 patients required major limb amputation and 5 open surgical re-vascularization. Total primary and secondary patency rates were 66 % and 70 % at 1 year, respectively. Primary and secondary patency rates for FP atherectomy were 68 % and 73 % at 1 year, respectively. The limb salvage rate was 74 % at 6 months. Patients with prior interventions in the atherectomized segment had an almost 10-fold decrease in primary patency. Atherectomy produces acceptable results, similar to those in reported series of conventional balloon angioplasty/stenting. Patients with prior IF interventions had a nearly 10-fold decrease in primary patency. A greater than 6-fold decrease in patency rates was noted in patients who underwent simultaneous inflow or outflow procedures, but this finding did not reach statistical significance (p = 0.082). The authors stated that future studies should focus on cost comparisons with other treatments such as angioplasty and stenting, and prospective randomized trials should be performed to compare these treatment alternatives.
Garcia and Lyden (2009) noted that compared to conventional percutaneous transluminal angioplasty (PTA) and stent implantation for arterial occlusive diseases, atherectomy offers the theoretical advantages of eliminating stretch injury on arterial walls and reducing the, rate of restenosis. Historically, however, neither rotational nor directional atherectomy, whether used alone or with adjunctive PTA, has shown any significant long-term benefit over PTA alone in the coronary or peripheral arteries. However, the SilverHawk Plaque Excision System has produced positive results in single-center prospective registries of patients with FP and IF lesions, with reduced adjunctive PTA, minimal adjunctive stenting, and competitive 6-month and 12-month patency rates. In the observational non-randomized TALON (Treating Peripherals with SilverHawk: Outcomes Collection) registry, freedom from target lesion re-vascularization was 80 % for 87 patients at 12 months. Questions remaining for further research with this device include more accurate determination of an event rate for distal embolization, the appropriate use of distal protection, the value of and appropriate circumstances for adjunctive angioplasty, and definitive patency and clinical outcomes.
Indes et al (2010) evaluated the outcomes of atherectomy versus subintimal angioplasty (SIA) in patients with lower extremity arterial occlusive disease. From September 2005 through July 2006, 27 patients (17 women; mean age of 65 years, range of 37 to 85) underwent atherectomy of 46 lesions (11 TASC C/D occlusions) with the SilverHawk device. Results were compared to 67 patients (34 men; mean age of 69 years, range of 46 to 92) undergoing SIA for 67 lower extremity arterial occlusions from July 1999 through June 2004. Technical success in the atherectomy cohort was 100 %. In the 11 patients with occlusions, symptoms improved in 10 and worsened in 1, but 9 (82.0 %) of the 11 patients required re-intervention, and 8 (72.7 %) patients with occlusive lesions re-occluded. Endovascular re-intervention was required to maintain primary patency in only 2 (12.5 %) of 16 patients treated for stenotic lesions. At 1 year, the assisted primary patency was 37.7 % in the atherectomy group. In the 11 patients with occlusive lesions, the patency rates were 36.8 % and 12.3 % at 6 and 9 months, respectively, versus 100 % and 83.3 % at the same time intervals in patients with stenotic lesions. Subintimal angioplasty was technically successful in 56 (83.6 %) of 67 occlusions. The assisted primary patency and limb salvage rates of the entire group (intention-to-treat) at 12 and 24 months were 59.2 % and 45.0 %, respectively, while the assisted primary patency of the 56 technically successful SIAs at 12 and 24 months were 70.7 % and 53.8 %, respectively. Limb salvage for the entire group (intention-to-treat) was 90.6 % and 87.9 % at 12 and 24 months, respectively. The authors concluded that atherectomy may yield acceptable primary patency and limb salvage in patients with stenotic lesions. Many of the patients treated for occlusive lesions require re-intervention. Based on patency and limb salvage, SIA appears superior to atherectomy for the treatment of lower extremity occlusive disease.
Sixt and co-workers (2010) reported the acute and long-term outcome of Silverhawk- assisted atherectomy for femoro-popliteal lesions. In this prospective study, de novo and re-stenotic lesions of the femoro-popliteal segments were treated with the Silverhawk device. A total of 161 consecutive patients (164 lesions) with PAD Rutherford classes 2 to 5 were included from June 2002 to October 2004 and October 2006 to June 2007 (59 % male, mean age of 67 +/- 11 years, range of 40 to 88) and the outcome analyzed according to the TASC II classification. Directional atherectomy alone was performed successfully in 28 % (n = 46), adjunctive balloon angioplasty in 65 % (n = 107) and stenting in 7 % (n = 11). The overall technical success rate was 76 % (124/164) and the procedural success rate 95 % (154/164). At 12 months primary patency rate was 61 % (85/140) and the secondary patency rate was 75 % (105/140) in the entire cohort, being less favorable in TASC D compared to TASC A to C lesions (p = 0.034 and p < 0.001, respectively). Furthermore, the re-stenosis rate differed trend-wise (p = 0.06) between de-novo and re-stenotic lesions. Changes in the ankle-brachial index (ABI) and the Rutherford classes were significantly in favor of TASC A to C lesions compared to TASC D after 12 months (p = 0.004). The event free survival (myocardial infarction, transient ischemic attack, or re-stenosis) was 48 % at 12 months and 38.5 % at 24 months. Predictor for re-stenosis in the multi-variable analysis was only male gender (p = 0.04). The authors concluded that the results in TASC D lesions are inferior to those in the lesser stages. Directional atherectomy of femoro-popliteal arteries showed a trend to better long-term technical and clinical outcome in de novo lesions compared to re-stenotic lesions.
Mohand and colleagues (2018) stated that peripheral atherectomy has been shown to have technical success in single-arm studies, but clinical advantages over angioplasty and stenting have not been demonstrated, leaving its role unclear. These investigators described patterns of atherectomy use in a real-world U.S. cohort to understand how it is currently being applied. The Vascular Quality Initiative was queried to identify all patients who underwent peripheral vascular intervention from January 2010 to September 2016. Descriptive statistics were performed to analyze demographics of the patients, co-morbidities, indication, treatment modalities, and lesion characteristics. The intermittent claudication (IC) and critical limb ischemia (CLI) cohorts were analyzed separately. Of 85,605 limbs treated, treatment indication was IC in 51 % (n = 43,506) and CLI in 49 % (n = 42,099). Atherectomy was used in 15 % (n = 13,092) of cases, equivalently for IC (15 %; n = 6,674) and CLI (15 %; n = 6,418). There was regional variation in use of atherectomy, ranging from a low of 0 % in one region to a high of 32 % in another region. During the study period, there was a significant increase in the proportion of cases that used atherectomy (11 % in 2010 versus 18 % in 2016; p < 0.0001). Compared with non-atherectomy cases, those with atherectomy use had higher incidence of prior peripheral vascular intervention (IC, 55 % versus 43 % [p < 0.0001]; CLI, 47 % versus 41 % [p < 0.0001]), greater mean number of arteries treated (IC, 1.8 versus 1.6 [p < 0.0001]; CLI, 2.1 versus 1.7 [p < 0.0001]), and lower proportion of prior leg bypass (IC, 10 % versus 14 % [p < 0.0001]; CLI, 11 % versus 17 % [p < 0.0001]). There was lower incidence of failure to cross the lesion (IC, 1 % versus 4 % [p < 0.0001]; CLI, 4 % versus 7 % [p < 0.0001]); but higher incidence of distal embolization (IC, 1.9 % versus 0.8 % [p < 0.0001]; CLI, 3.0 % versus 1.4 % [p < 0.0001]) and, in the CLI cohort, arterial perforation (1.4 % versus 1.0 %; p = 0.01). The authors concluded that despite a lack of evidence for atherectomy over angioplasty and stenting, its use has increased across the U.S. from 2010 to 2016. It was applied equally to IC and CLI populations, with no identifiable pattern of co-morbidities or lesion characteristics, suggesting that indications were not clearly delineated or agreed on. This study placed impetus on further understanding of the optimal role for atherectomy and its long-term clinical benefit in the management of PAD.
In a retrospective, multi-center study, Loffroy and colleagues (2020) examined the safety and mid-term outcomes of Rotarex S rotational atherectomy plus thrombectomy device (Straub Medical AG, Vilters-Wangs, Switzerland) with or without adjunctive treatment (e.g., percutaneous transluminal angioplasty, PTA/drug-coated balloon, DCB/stenting) in patients with ISR or occlusion in the iliac and/or infra-inguinal arteries. This trial included patients treated by in-stent percutaneous mechanical debulking (PMD) of the lower limbs with Rotarex S device between January 2013 and November 2018. The cohort consisted of 128 patients (88 men and 40 women), aged 39 to 94 years (mean of 66.7 ± 12 years). All patients presented with cardio-vascular risk factors. Overall, 51.5 % of patients had CLI. The study demonstrated a technical success of 96.9 % in the population with PMD and adjunctive PTA (95/128, 74.2 %) or adjunctive DCB (16/128, 12.5 %) or both (13/128, 10.2 %). At 12-months follow-up, the primary clinical success/patency rate was 92.3 % and the secondary clinical success/patency rate was 91.4 %. Rate of limb salvage was 93.7 %. Overall 32 (25 %) re-interventions were reported with mean time from Rotarex S treatment to re-intervention of 7.1 ± 8.2 months; TLR was 19.5 % (25/128); 7 (5.5 %) patients developed distal embolism that responded to endovascular treatment. At mean follow-up, MAE observed were death (18/128, 14.1 %), MI (9/128, 7.0 %), stroke (2/128, 1.6 %) and renal failure (3/128, 2.3 %). The authors concluded that re-canalization with Rotarex S rotational atherectomy plus thrombectomy device was a practical choice for arterial ISR/occlusions of the iliac and/or infra-inguinal arteries, regardless of the age of the thrombus, with satisfying TLR. Only adjunctive PTA was often necessary to further improve the re-canalization. These researchers stated that these findings justified further research in the application of the therapy to determine cost/benefit.
The authors stated that this study had several drawbacks. First, this was a non-randomized, retrospective study with a modestly-sized cohort with absence of control group. Furthermore, these investigators had heterogeneous population with different target vessels (iliac versus SFA versus popliteal artery (PA) versus combined), different stent occlusions like re-stenosis versus occlusion, acute thrombosis versus chronic thrombosis versus combined and the use of different techniques (debulking alone versus debulking + PTA versus debulking + DCB versus combined). They stated that the outcomes need to be confirmed in a larger study or randomized controlled trial (RCT) with longer follow-up.
Jaff et al (2010) analyzed therapeutic strategies, outcomes, and medical cost of treatment among Medicare patients with PAD. Patients who underwent therapy for PAD were identified from a 5 % random sample of Medicare beneficiaries from Medicare Standard Analytic Files for the period 1999 to 2005. Clinical outcomes (death, amputation, new clinical symptoms related to PAD) and direct medical costs were examined by chosen re-vascularization options (endovascular, surgical, and combinations). One-year PAD prevalence increased steadily from 8.2 % in 1999 to 9.5 % in 2005. The risk-adjusted time to first post-treatment clinical outcome was lowest in those treated with PTA or atherectomy and stents (hazard ratio [HR], 0.829; 95 % confidence interval [CI]: 0.793 to 0.865; p < 0.001) and stents only (HR, 0.904; 95 % CI: 0.848 to 0.963; p = 0.002) compared with PTA alone. The lowest per patient risk-adjusted costs during the quarter of the first observed treatment were associated with "PTA and stents" ($15,197), and stents only ($15,867). Risk-adjusted costs for surgical procedures (bypass and endarterectomy) were $27,021 during the same period. Diabetes was present in 61.7 % of the PAD population and was associated with higher risks of clinical events and higher medical costs compared with PAD patients without diabetes. The authors concluded that clinical and economic burden of PAD in the Medicare population is substantial, and the interventions used to treat PAD are associated with differences in clinical and economic outcomes. They stated that prospective cost-effectiveness analyses should be included in future PAD therapy trials to inform payers and providers of the relative value of available treatment options.
Guidance from the National Institute for Health and Clinical Excellence (NICE, 2011) concluded that "current evidence on the efficacy of percutaneous atherectomy of femoro-popliteal arterial lesions with plaque excision devices is inadequate in quality. Evidence on safety is inadequate, specifically with regard to the risk of distal embolization. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research." The NICE guidance stated that further research into percutaneous atherectomy of femoro-popliteal arterial lesions with plaque excision devices should take the form of well-conducted trials, which should define patient selection, treatment protocols and location and types of arterial lesions treated, and report long-term patency outcomes.
An interventional procedure consultation document on percutaneous laser atherectomy for peripheral arterial disease from the National Institute for Health and Clinical Excellence (2011) concluded: "The evidence on percutaneous laser atherectomy for peripheral arterial disease raises no major safety concerns. Current evidence on its efficacy is inadequate in quantity and quality (in particular, the technical indications for the procedure are not well described in the published literature). Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research." The consultation document stated that further research should describe the criteria for selection of patients and report clearly whether percutaneous laser atherectomy was used instead of conventional balloon angioplasty (and the reasons for this) or whether balloon angioplasty was attempted but found not to be feasible. In addition, reports should specify whether the procedure was used alone to recanalize arteries or with adjunctive balloon angioplasty and/or stenting. When percutaneous laser atherectomy is used instead of balloon angioplasty, then studies should compare the outcomes of the two procedures. Reported outcomes should include objective evidence of arterial patency and blood flow in addition to clinical effects. The consultation documents noted that long-term follow-up (2 years and beyond) would be useful.
Guidance from the National Institute for Health and Clinical Excellence (NICE, 2012) on percutaneous laser angioplasty concluded: "Current evidence on the efficacy and safety of percutaneous laser atherectomy as an adjunct to balloon angioplasty (with or without stenting) for peripheral arterial disease is adequate to support the use of this procedure provided that normal arrangements are in place for clinical governance, consent and audit." The guidance stated that patient selection should be carried out by a vascular multidisciplinary team including a vascular surgeon and a vascular interventional radiologist. The guidance stated that the multidisciplinary team should consider carefully whether using percutaneous laser atherectomy as an adjunct to balloon angioplasty (with or without stenting) for peripheral arterial disease is likely to have any benefits over conventional recanalization by balloon angioplasty (with or without stenting) alone. The specialist advisers to NICE listed key efficacy outcomes as an increase in arterial diameter and blood flow, tissue healing, symptom relief, improvement in quality of life, amputation-free survival and reintervention rates. The NICE committee noted that much of the evidence on this procedure is not recent, and that a limited amount of the older evidence described using laser alone for atherectomy but more recent evidence focused on its use as an adjunct to balloon angioplasty (with or without stenting). This more recent evidence and the advice of specialists underpinned the decision to evaluate laser recanalization as an adjunctive procedure. The NICE guidance noted, while the committee considered the evidence adequate to recommend normal arrangements for the use of percutaneous laser atherectomy as an adjunct to balloon angioplasty (with or without stenting), it remained uncertain about whether its use confers any advantages over balloon angioplasty alone and, if so, in which patients.
The Trellis® Peripheral Infusion System has been developed as a percutaneous mechanical thrombectomy treatment for deep vein thrombosis (DVT) that does not respond adequately to anticoagulant and/or thrombolytic therapy. This system consists of a specially designed catheter that is connected to a handheld motorized control unit. Guided by ultra-sonographic images, the Trellis catheter is inserted into an appropriate vein and advanced to the thrombosis. A guidewire is threaded through the clot; next the catheter is advanced into the clot so that the distal end of the catheter passes completely through the clot but the proximal end of the catheter does not enter the clot. At this point in the procedure, balloons in the proximal and distal ends of the catheter are inflated to seal off the section of the vein containing the clot, a thrombolytic agent is injected through the catheter into the clot, and the motor is activated, which causes rotation of a sinusoidally shaped wire that lies between the inflated balloons. The combined action of the thrombolytic agent and rotating wire disrupt the clot, and the disrupted material can be aspirated through the catheter. After clot removal, the balloons are deflated and the catheter is removed. The procedure using the Trellis system has been referred to as isolated segmental pharmaco-mechanical thrombolysis.
The Trellis Infusion System received FDA 515(k) clearance (K013635) on December 11, 2002. According to the clearance summary, the Trellis Infusion System is intended for controlled and selective infusion of physician-specified fluids, including thrombolytics, into the peripheral vasculature.
The Trellis Plus Infusion System received 510(k) clearance (K021958) on July 3, 2002. The system is intended for controlled and selective infusion of physician-specified fluids, including thrombolytics, into the peripheral vasculature.
The Trellis Reserve Infusion System received 510(k) clearance (K023514) on December 2, 2002. The Trellis™ Reserve Infusion System is intended for controlled and selective infusion of physician-specified fluids, including thrombolytics, into the peripheral vasculature.
A “Modification to the Trellis Reserve Infusion System” received 510(k) clearance (K032261) on August 22, 2003. According to the clearance summary, the Trellis™ Reserve Infusion System is intended for controlled and selective infusion of physician-specified fluids, including thrombolytics, into the peripheral vasculature. The Trellis Reserve Infusion System is equivalent to the predicate product, the original Trellis Reserve Infusion System. The indications for use, function, methods of manufacturing, and materials used are substantially equivalent. Bacchus Vascular, Inc. believes the Trellis Reserve Infusion System is substantially equivalent to existing legally marketed devices.
The Trellis-8 Peripheral Infusion System received 510(k) clearance (K050147) on February 3, 2005. According to the clearance summary the Trellis™-8 Peripheral Infusion System is intended for controlled and selective infusion of physician specified fluids, including thrombolytics, into the peripheral vasculature.
The Trellis-6 Peripheral Infusion System received 510(k) clearance (K071664) on July 13, 2007. According to the clearance summary the Trellis™-6 Peripheral Infusion System is intended for controlled and selective infusion of physician specified fluids, including thrombolytics, into the peripheral vasculature. The system enables the physician to isolate a treatment region, infuse a physician-specified fluid, and disperse the fluid by means of oscillation of a Dispersion Wire. The Isolation/Infusion component is a multi-lumen catheter with two compliant balloons at the distal end and infusion holes located between these balloons. The device also has a central through-lumen that is compatible with a 0.035" guidewire. The Dispersion Wire provides oscillation when activated. The Dispersion Wire is connected to an integral Oscillation Drive Unit that oscillates the Dispersion Wire within the isolated region to further disperse the infused fluid. If desired by the physician, post procedure aspiration of the isolated area between the occluding balloons may be accomplished through the catheter by using the guidewire lumen.
Papantoniou et al (2013) stated that Paget-Schroetter syndrome (PSS) is a rare form of thoracic outlet syndrome caused by axillo-subclavian vein thrombosis that typically presents in healthy young adults. Prompt therapy, traditionally by means of catheter-directed thrombolysis (CDT) prior to definitive surgery, can prevent the subsequent onset of post-thrombotic syndrome (PTS) and considerable disability. As CDT is associated with major hemorrhage and high overall treatment cost, pharmaco-mechanical thrombectomy (PMT) seems to be an attractive alternative that combines pharmacological thrombolysis with mechanical clot disruption. The Trellis-8 peripheral infusion catheter is an example of such a treatment, which provides topical thrombolysis in an isolated zone. These investigators described the use of the Trellis-8 PMT system in the successful management of 3 patients with PSS.
In a Cochrane review, Wasiak and colleagues (2012) examined the effects of percutaneous transluminal coronary rotational atherectomy (PTCRA) for coronary artery disease in patients with non-complex and complex lesions (e.g., ostial, long or diffuse lesions or those arising from in-stent re-stenosis) of the coronary arteries. For the original review, these investigators searched the Heart Group Specialized Register; The Cochrane Library to Issue 2, 2001; and MEDLINE, CINAHL, EMBASE and Current Contents to December 2002 and reviewed reference lists for relevant articles. For the current review, they searched the same registries from 2002 to 2012 and reviewed reference lists for relevant articles. These researchers included randomized and quasi-randomized controlled trials of PTCRA compared with placebo, no treatment or another intervention and excluded cross-over trials. Two review authors independently extracted data and assessed the risk of bias of the studies identified. Data were extracted independently by 2 review authors. They asked authors of trials to provide information when missing data were encountered. Statistical summaries used risk ratios (RR) and weighted mean differences. These researchers included 12 trials enrolling 3,474 patients. The overall risk of bias was unclear for the majority of articles due to a lack of reported data; however, the authors determined that this would be unlikely to impact negatively as most data outcomes were objective (e.g., death versus no death). There was no evidence of the effectiveness in improving patient outcomes of PTCRA in non-complex lesions. In complex lesions, there were no statistically significant differences in re-stenosis rates at 6 months (RR 1.05; 95 % confidence interval (CI): 0.83 to 1.33) and at 1 year (RR 1.21; 95 % CI: 0.95 to 1.55) in those receiving PTCRA with adjunctive balloon angioplasty (PTCA) (PTCRA/PTCA) compared to those receiving PTCA alone. Morphological characteristics distinguishing complex lesions have not been examined in parallel-arm randomized controlled trials. The evidence for the effectiveness of PTCRA in in-stent re-stenosis was unclear. Compared to angioplasty alone, PTCRA/PTCA did not result in a statistically significant increase in the risk of major adverse cardiac events (myocardial infarction (MI), emergency cardiac surgery or death) during the in-hospital period (RR 1.27; 95 % CI: 0.86 to 1.90). Compared to angioplasty, PTCRA was associated with 9 times the risk of an angiographically detectable vascular spasm (RR 9.23; 95 % CI: 4.61 to 18.47), 4 times the risk of perforation (RR 4.28; 95 % CI: 0.92 to 19.83) and about twice the risk of transient vessel occlusions (RR 2.49; 95 % CI: 1.25 to 4.99) while angiographic dissections (RR 0.48; 95 % CI: 0.34 to 0.68) and stents used as a bailout procedure (RR 0.29; 95 % CI: 0.09 to 0.87) were less common. The authors concluded that when conventional PTCA is feasible, PTCRA appears to confer no additional benefits. There is limited published evidence and no long-term data to support the routine use of PTCRA in in-stent re-stenosis. Compared to angioplasty alone, PTCRA/PTCA did not result in a higher incidence of major adverse cardiac events, but patients were more likely to experience vascular spasm, perforation and transient vessel occlusion. In certain circumstances (e.g. patients ineligible for cardiac surgery, those with architecturally complex lesions, or those with lesions that fail PTCA), PTCRA may achieve satisfactory re-vascularization in subsequent procedures.
An UpToDate review on “Specialized revascularization devices in the management of coronary heart disease” (Cutlip, 2014) states that “Rotational atherectomy summary – The American College of Cardiology/American Heart Association/Society for Cardiovascular Angiography and Interventions (ACC/AHA/SCAI) guideline update for PCI concluded that there is no evidence that rotational atherectomy improves late outcomes in lesions that can be safely treated with stenting or angioplasty alone. When rotational atherectomy is being considered, the weight of evidence or opinion was in favor of the efficacy of IVUS for establishing the presence and distribution and coronary calcium. However, in our practices, IVUS is rarely used for this indication”.
In a meta-analysis, Yang and colleagues (2014) evaluated the clinical value of primary stenting for treating PADs in below-the-knee arteries by comparing to PTA. PubMed, ScienceDirect, Embase, and CBM databases were searched for relevant articles. Based on the different types of stents, these researchers divided the primary stent group into the bare metal stent (BMS) group and drug-eluting stent (DES) group. The outcome measures were immediate technical success, freedom from target vessel revascularization (TVR-free) rate and limb salvage. A total of 14 studies (published between 2001 and 2012) satisfying the inclusion criteria were identified; 3,278 patients and 3,699 limbs constituted the final study population. The technical success rate of PTA was 90.95 % (95 % CI: 86.25 % to 94.15 %). Only 1 study reported a technical failure of 4 % (5/118) in the primary stent group. There were no significant differences in the 1-year primary patency and TVR-free rates between the PTA group and BMS groups (p > 0.05 and p > 0.05), respectively. The pooled estimates of 1-year primary patency and TVR-free rate in DES group were 85.05 % (95 % CI: 79.95 % to 89.02 %) and 90.52 % (95 % CI: 83.68 % to 94.67 %), respectively, which were better than those of the BMS (p < 0.001) and PTA groups (p < 0.001). The pooled estimate of 1-year limb salvage in the PTA, BMS, and DES groups was 88.41 % (95 % CI: 84.53 % to 91.43 %), 94.41 % (95 % CI: 89.52 % to 97.1 %), and 96.81 % (95 % CI: 94.04 % to 98.32 %), respectively. The BMS and DES groups had higher limb salvage rates than the PTA group (p < 0.001 for both comparisons). The rates of severe complications were low both in the PTA and primary stent groups. Although the influence analysis showed rather robust results, the heterogeneity was quite high and they were not adjusted for confounding variables. The authors concluded that primary BMS implantation had no advantage over PTA in reducing restenosis or re-vascularization for infra-popliteal disease; primary DES implantation appeared to be a promising treatment for focal infra-popliteal lesions. (The MeSH terms of this article included balloon).
In a Cochrane review, Chowdhury et al (2014) determined the effect of percutaneous transluminal angioplasty (PTA) compared with PTA with bare metal stenting (BMS) for superficial femoral artery (SFA) stenoses on vessel patency in people with symptomatic (Rutherford categories1 to 6; Fontaine stages II to IV) lower limb peripheral vascular disease. In addition, these researchers assessed the efficacy of PTA and stenting in improving quality of life, ankle brachial index (ABI) and treadmill walking distance. For this update the Cochrane Peripheral Vascular Diseases Group Trials Search Coordinator searched the Specialized Register (last searched August 2013) and the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 6, 2013). Randomized trials of angioplasty alone versus angioplasty with BMS for the treatment of superficial femoral artery stenosis were selected for analysis. Two review authors independently selected suitable trials, assessed trial quality and extracted data. Furthermore, these 2 review authors performed assessments of methodological quality and wrote the final manuscript. The third review author (ADM) cross-checked all stages of the review process. These investigators included 3new studies in this update, making a total of 11 included trials with 1,387 participants. The average age was 69 years and all trials included men and women. Participants were followed for up to 2 years. There was an improvement in primary duplex patency at 6 and 12 months in participants treated with PTA plus stent over lesions treated with PTA alone (6 months: odds ratio (OR) 2.90, 95 % confidence interval (CI): 1.17 to 7.18, p = 0.02, 6 studies, 578 participants; 12 months: OR 1.78, 95 % CI: 1.02 to 3.10, p = 0.04, 9 studies, 858 participants). This was lost by 24 months (p = 0.06). There was a significant angiographic patency benefit at 6 months (OR 2.49, 95 % CI: 1.49 to 4.17, p = 0.0005, 4 studies, 329 participants) which was lost by 12 months (OR 1.30, 95 % CI: 0.84 to 2.00, p = 0.24, 5 studies, 384 participants); ABI and treadmill walking distance showed no improvement at 12 months (p = 0.49 and p = 0.57, respectively) between participants treated with PTA alone or PTA with stent insertion. Three trials (660 participants) reported quality of life, which showed no significant difference between participants treated with PTA alone or PTA with stent insertion at any time interval. Anti-platelet therapy protocols and inclusion criteria regarding affected arteries between trials showed marked heterogeneity. The authors concluded that although there was a short-term gain in primary patency there was no sustained benefit from primary stenting (PS) of lesions of the superficial femoral artery in addition to angioplasty. Moreover, they stated that future trials should focus on quality of life for claudication and limb salvage for critical ischemia.
Antoniou et al (2014) examined if treatment of infra-inguinal arterial occlusive disease with drug-eluting stents (DESs) provided improved outcomes compared with BMSs or PTA alone. Altogether, 136 papers were found using the reported searches, of which 5 provided the best evidence to answer the question. All papers represent either level 1 or 2 evidence. The authors, journal, date, country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. Main outcome measures varied among the studies, and included patency, in-stent restenosis, target lesion revascularization, major adverse events, clinical improvement and limb salvage. Evidence on the comparative efficacy of DESs in femoro-popliteal arterial disease is mainly based on 2 RCTs. Paclitaxel-eluting stents were evaluated in the Zilver PTX trial and demonstrated superior 2-year results to either BMSs or PTA, as indicated/shown by patency (DES versus PTA, 74.8 versus 26.5 %, p < 0.01), clinical benefit (DES versus PTA, P < 0.01) and event-free survival (DES vs PTA, 86.6 vs 77.9%, P = 0.02). However, the SIROCCO trial found that the sirolimus-eluting stent did not exhibit statistically significant differences in 2-year in-stent re-stenosis (22.9 versus 21.1 %) and target lesion re-vascularization (6 versus 13 %) compared with the BMS. Treatment of infra-popliteal arterial disease with DESs was related with superior outcomes to those of BMSs, as indicated/shown by patency, freedom from target lesion revascularization and freedom from major adverse events. Furthermore, the ACHILLES trial, the only published trial comparing the infra-popliteal DES with PTA, revealed lower angiographic restenosis (22.4 versus 41.9 %, p = 0.019) and greater vessel patency (75 versus 57.1 %, p = 0.025) in the DES group at 1 year. However, data related to clinical parameters in patients with critical limb ischemia secondary to infra-geniculate arterial disease, such as limb salvage and ulcer healing, are insufficient. The authors concluded that treatment of infra-inguinal arterial disease with DES was safe and appeared to be superior to treatment with PTA alone or BMS. They stated that the role of DES in sustained improvement in clinical outcome end-points, such as limb salvage, remains to be elucidated.
Drug-Eluting (Drug-Coated) Balloons for the Treatment of Primary Lesion / Occlusion of Peripheral Arteries
In a multi-center, randomized non-inferiority trial, Baan and colleagues (2018) evaluated the relative performance of a DEB and a DES in patients with any (bare-metal or drug-eluting stent) ISR. Patients with any ISR were randomly allocated in a 1:1 fashion to treatment with a DEB or a DES. The primary end-point was non-inferiority in terms of in-segment minimal lumen diameter (MLD) at 6-month angiographic follow-up. Secondary end-points included angiographic parameters at 6 months and clinical follow-up up to 12 months. A total of 278 patients, of whom 56 % had DES-ISR, were randomized at 8 sites to treatment with DEB (n = 141) or DES (n = 137). As compared with DEB, DES was associated with larger MLD and lower % stenosis immediately post-procedure (1.84 ± 0.46 versus 1.72 ± 0.35; p = 0.018; and 26 ± 10 % versus 30 ± 10%; p = 0.03). Angiographic follow-up was completed at 196 ± 53 days in 79 % of patients. With respect to the primary end-point of in-segment MLD at 6 months, DEB was non-inferior to DES (DEB 1.71 ± 0.51 mm versus DES 1.74 ± 0.61 mm; p for non-inferiority < 0.0001); TVR at 12-month follow-up was similar in both groups (DES 7.1 % versus DEB 8.8 %; p = 0.65). The authors concluded that in patients with ISR, treatment with DEB was non-inferior compared with DES in terms of 6-month MLD. There were no differences in clinical end-points, including TVR up to 12 months. Therefore, use of a DEB is an attractive therapeutic option for ISR, withholding the need for additional stent implantation. Longer follow-up data are needed to validate these findings.
Beschorner and Zeller (2014) stated that mechanical atherectomy for in-stent restenosis (ISR) appeared to be limited by a low patency rate. This might be due to the mechanical trauma that induces an inflammatory response leading to recurrent ISR. Addition of drug-eluting balloon (DEB) angioplasty could overcome these challenges while preserving the advantages of a better acute result. However, the authors concluded that due to lack of clinical data, combination of atherectomy and DEB remains an experimental procedure for ISR treatment.
The Australian Safety and Efficacy Registry of New Interventional Procedures’ Technology Brief on “Drug-eluting stents and balloons for the treatment of peripheral vascular disease” (2012) considered DEBs to be investigational.
There is Cochrane “protocol” to evaluate the effectiveness of DEBs compared with non-stenting balloon angioplasty in patients with symptomatic lower-limb PAD (Kayssi et al, 2014).
Limpijankit (2015) stated that “Over the past decade, drug-coated balloons (DCBs) have emerged as an exciting new therapeutic option to prevent restenosis in the treatment of peripheral vascular disease …. In this year, 3 major pivotal trials have confirmed the safety and efficacy of paclitaxel-coated balloons in the endovascular treatment of femoro-popliteal artery disease. These are the Drug-Coated Balloon Versus Standard Percutaneous Transluminal Angioplasty for the Treatment of Superficial Femoral and/or Popliteal Peripheral Artery Disease (IN.PACT SFA) trial, the Lutonix Paclitaxel-Coated Balloon for the Prevention of Femoro-popliteal Restenosis 2 (LEVANT 2) trial, and 5-year follow-up of the Local Taxan With Short Time Contact for Reduction of Restenosis in Distal Arteries (THUNDER) trial …. Although the initial findings are encouraging, long-term follow-up will be useful in determining whether the benefit of these new devices is sustained, increased, or attenuated over time. In the LEVANT 2 trial, the primary patency endpoint from the Kaplan-Meier curves seem to drop distinctly in the Lutonix arm after 12 months, while the control arm remained unchanged …. although DCBs are generally safe and superior to standard balloon angioplasty, there are many unanswered questions about DCB technology. The results of these trials cannot be generalized to patients not included in these trials. Future studies should be performed in longer lesions, densely calcified lesions, or in-stent restenosis, and consider comparison with bare metal stents and drug-eluting stents. Trials combining DCBs with atherectomy (Atherectomy Followed by a Drug Coated Balloon to Treat Peripheral Arterial Disease [DEFINITIVE AR] trial) are being conducted to clarify if there is an additive effect. Another inconclusive issue is the appropriateness use of these devices. Which patient should be a good candidate for using these DCBs as the first-line therapy instead of standard balloon? In order to justify their broad use, the DCBs must show reduction in repeat revascularization, cost benefit, and improving quality of life. Another concern is the learning curve of how to use the DCBs to ensure proper uptake of the drug and minimize downstream drug loss. This is important to maximize the results of treatment. Post-approval study is also suitable for longer-term follow-up, which is certainly needed to confirm the durability of the benefit”.
In a Cochrane review, Bekken et al (2015) examined the effects of PTA versus PS for stenotic and occlusive lesions of the iliac artery. The Cochrane Peripheral Vascular Diseases Group Trials Search Coordinator searched the Specialized Register (last searched April 2015) and Cochrane Register of Studies (CRS) (Issue 3, 2015). The TSC searched trial databases for details of ongoing and unpublished studies. These researchers included all RCTs comparing PTA and primary stenting for iliac artery occlusive disease. They excluded quasi-randomized trials, case reports, case-control or cohort studies. They excluded no studies based on the language of publication. Two authors independently selected suitable trials. JB and HJ independently performed data extraction and trial quality assessment. When there was disagreement, consensus would be reached first by discussion among both authors and, if still no consensus could be reached, through consultation with BF. These investigators identified 2 RCTs with a combined total of 397 participants as meeting the selection criteria. One study included mostly stenotic lesions (95 %), whereas the second study included only iliac artery occlusions. Both studies were of moderate methodological quality with some risk of bias relating to selective reporting and non-blinding of participants and personnel. The overall quality of evidence was low due to the small number of included studies, the differences in study populations and definitions of the outcome variables. Due to the heterogeneity among these 2 studies it was not possible to pool the data. Percutaneous transluminal angioplasty with selective stenting and primary stenting (PS) resulted in similar improvement in the stage of peripheral arterial occlusive disease according to Rutherford's criteria, resolution of symptoms and signs, improvement of quality of life, technical success of the procedure and patency of the treated vessel. Improvement in walking distance as reported by the patient, measured claudication distance, ulcer healing, major amputation-free survival and delayed complications (greater than 72 hours) were not reported in either of the studies. In 1 trial, PTA of iliac artery occlusions resulted in a significantly higher rate of major complications, especially distal embolization. The other trial showed a significantly higher mean ABI at 2 years in the PTA group (1.0) compared to the mean ABI in the PS group (0.91); mean difference (MD) 0.09 (95 % CI: 0.04 to 0.14; p value = 0.001, analysis performed by review authors). However, at other time-points there was no difference. These researchers considered it unlikely that this difference was attributable to the study procedure, and also believed this difference may not be clinically relevant. The authors concluded that there is insufficient evidence to assess the effects of PTA versus PS for stenotic and occlusive lesions of the iliac artery. From 1 study it appeared that PS in iliac artery occlusions may result in lower distal embolization rates. They stated that more studies are needed to come to a firm conclusion.
Furthermore, an UpToDate review on “Percutaneous interventional procedures in the patient with lower extremity claudication” (Zaetta et al, 2016) states that “Drug-eluting balloons – A number of medical therapies aimed at preventing restenosis after femoral PTA have been tried, but only local delivery of paclitaxel has been shown to improve outcomes. Local delivery of paclitaxel was initially studied in the coronary circulation, but subsequently drug-eluting balloons (e.g., Lutonix, IN.PACT Admiral) have been approved for use in the United States as a means to deliver paclitaxel and have been used in the femoro-popliteal segment. Whether the reduced number of interventions that results offsets the additional expense of the drug-coated balloon remains to be determined”.
- medical journals (i.e., Medline),
- international registers for clinical studies (i.e., www.clinicaltrials.gov), and
- abstracts of scientific sessions.
Several RCTs with follow-up periods of up to 5 years demonstrated the effectiveness of paclitaxel-DCB technology. However, calcified lesions appeared to affect the effectiveness of DCB. Combinations of pre-conditioning methods with DCBs showed promising results. Although the mechanical abrasion of calcium via atherectomy or laser ablation showed favorable peri-procedural results, the long-term impact on re-stenosis and clinical outcome has to be demonstrated. Major advantages of the DCBs are the rapid delivery of drug at uniform concentrations with a single dose, their effectiveness in areas wherein stents have been contraindicated until now (i.e., bifurcation, ostial lesions), and in leaving no stent scaffold behind. Re-interventions are easier to perform because DCBs leave no metal behind. The authors concluded that various combinations of DCBs with other treatment modalities may prove to be viable options in future; there is still a lack of respectable prospective long-term data to state the long-term superiority of one DCB technology.
Steiner et al (2016) examined patient outcomes following the use of the Lutonix DCB in patients undergoing endovascular intervention in below-the-knee (BTK) arteries. A retrospective chart review identified 248 patients who were treated for symptomatic PAD with the Lutonix DCB between May 2013 and October 2014. A total of 40 patients were lost to follow-up, leaving 208 patients (mean age of 74.1±9.7 years; 138 men) with evaluable data for outcome analysis. The patient cohort suffered from either severe claudication (38.6 %) or CLI (61.4 %) in 220 limbs. Almost 2/3 (140, 63.6 %) of the 220 target lesions were total occlusions, and 37 (17.8 %) of all patients had occlusion of all 3 BTK vessels before intervention. Over a median 9-month follow-up, TLR occurred in 15.9 % of patients with an average time to first re-intervention of 8 months. In total, 39 amputations were performed in 31 limbs. However, 17 of these amputations were pre-planned minor amputations below the ankle; only 9 (4.1 %) major amputations occurred corresponding to 6.6 % of the CLI cohort. Freedom from the composite of death or major amputation was estimated as 92 % and 85 % at 6 and 12 months, respectively, by Kaplan-Meier analysis. In the full cohort, improvement of at least 1 Rutherford category was seen in 130 (59.1 %) limbs after 1 year or at the last follow-up, with 104 (80.0 %) of those limbs showing an improvement of greater than or equal to2 categories. The authors concluded that from this single-center experience, the Lutonix DCB showed therapeutic promise in a disease state where new treatment options are needed.
In a prospective, single-center, non-randomized study, Werner et al (2016) evaluated the safety and effectiveness of the Igaki-Tamai biodegradable scaffold after DEB angioplasty in patients with occlusive SFA disease. A total of 20 patients (mean age 66.7 ± 11.6 years; 14 men) with symptomatic de-novo SFA lesions undergoing angioplasty with the paclitaxel-coated balloon and subsequent implantation of the Igaki-Tamai bio-resorbable scaffold were included in this study. All patients were claudicants. The average diameter stenosis was 89.7 %, and the mean length was 43.6 mm. Clinical examinations with duplex sonography were performed after 1, 6, 9, and 12 months. The main study outcomes were technical success, re-stenosis, TLR, ABI improvement, and changes in quality of life (QOL) evaluated with the walking impairment questionnaire. Safety was assessed by monitoring the occurrence of AEs. Angioplasty with a paclitaxel-coated balloon was performed in all patients, resulting in an average diameter stenosis of 24 %. Subsequent implantation of the Igaki-Tamai scaffold reduced the average diameter stenosis to 3.5 %. In the first 6 months, 2 cases of re-stenosis were reported, with no TLRs within that period. However, by the 12-month follow-up in 19 patients, 11 patients had lost in-stent patency. Among these patients, 8 had TLRs, which were the only AEs recorded that were referable to the procedure; QOL assessments showed improvement in the majority of patients. The authors concluded that the findings of the GAIA-DEB study showed that DEB treatment of the femoral artery prior to the implantation of the biodegradable Igaki-Tamai scaffold was safe; however, the anti-proliferative actions of paclitaxel in the vessel wall were not effective in preventing re-stenosis, which occurred predominantly after 6 months.
Grotti et al (2016) reported the 3-year safety and effectiveness outcomes from the prospective all-comers DEBATE-ISR study of symptomatic diabetic patients with femoro-popliteal ISR undergoing treatment with paclitaxel-eluting balloons compared with historical diabetic controls. From January 2010 to December 2011, a total of 44 consecutive diabetic patients (mean age of 74 ± 11 years; 32 men) were treated with DEBs and enrolled in the study. The control group comprised 42 consecutive diabetic patients (mean age 76 ± 7 years; 23 men) treated with conventional balloon angioplasty (BA) from 2008 to 2009. No significant differences in terms of clinical, angiographic, or procedural characteristics were observed between the study groups; CLI was present in the majority of patients. Tosaka class III ISR was observed in more than 50 % of the patients. Mean lesion length was 132 ± 86 and 137 ± 82 mm in the DEB and BA groups, respectively (p = 0.7). At 3-year follow-up, the rate of TLR was 40 % in the DEB group versus 43 % in the BA group (p = 0.8); Kaplan-Meier analysis showed no significant differences in terms of freedom from TLR. The presence of a Tosaka class III occlusion was associated with a worse outcome in both study groups (OR 3.96, 95 % CI: 1.55 to 10.1, p = 0.004). The authors concluded that using DEBs for femoro-popliteal ISR yielded similar results to BA in terms of TLR at 3-year follow-up. The treatment of more complex ISR lesions was associated with an increased rate of TLR, irrespective of the technology used.
In a Cochrane review, Kayssi et al (2016) evaluated the effectiveness of DEBs compared with uncoated, non-stenting balloon angioplasty in people with symptomatic lower-limb PAD. The authors concluded that based on a meta-analysis of 11 trials with 1,838 participants, there is evidence of an advantage for DEBs compared with uncoated balloon angioplasty in several anatomic end-points (e.g., primary vessel patency [high-quality evidence], binary restenosis rate [moderate-quality evidence], and target lesion revascularization [low-quality evidence] for up to 12 months). On the other hand, there is no evidence of an advantage for DEBs in clinical end-points (e.g., amputation, death, or change in ABI, or change in Rutherford category during 12 months' follow-up). They stated that well-designed randomized trials with long-term follow-up are needed to compare DEBs with uncoated balloon angioplasties adequately for both anatomic and clinical study end-points before the widespread use of this expensive technology can be justified. An editorial (Richards, 2017) noted: "Advances in technology continue relentlessly, but not necessarily for patient benefit? This meta-analysis highlights this problem; 11 trials compared drug eluting angioplasty technology compared to simple angioplasty. Radiological results were better in the short to mid-term but there with no effect on any patient outcomes. Therefore, should the NHS use these devices? On-going NIHR HTA BASIL 2 & BASIL 3 trials are running to compare angioplasty (with or without drug coated balloons to surgical bypass."
In a prospective, single-arm, multi-center study, Schroeder et al (2015) evaluated the safety and effectiveness of the Stellarex DCB to inhibit re-stenosis in the superficial femoral and/or popliteal artery. This trial enrolled 50 patients with 58 lesions in the first cohort that needed pre-dilatation with an uncoated angioplasty balloon prior to inflation of the DCB. The primary effectiveness end-point was 6-month late lumen loss (LLL). The major secondary end-point was major AE (MAE) rate at 6 months, defined as cardiovascular death, amputation, and/or ischemia-driven TLR. The mean lesion length was 7.2 cm and baseline stenosis was 75.1 %. Calcification was present in 62.1 % of lesions and 12.1 % were occluded. Both end-points met their pre-specified performance goals; at 6 months, the MAE rate was 4 % and the mean LLL was 0.54 mm. The primary patency rate was 89.5 % at 12 months and 80.3 % at 24 months. The freedom from clinically-driven TLR rate, per Kaplan-Meier estimate, was 90.0 % at 12 months and 85.8 % at 24 months. Additionally, there were no amputations or cardiovascular deaths reported through 24 months. The authors concluded that the Stellarex DCB provided safe and durable clinical outcomes for treatment of femoro-popliteal artery disease through 24 months.
The drawbacks of this study included the lack of randomization and small proportion of chronic total occlusions (CTOs; 12.1 %). However, all occluded lesions were patent through 24 months, which suggested adequate effectiveness of this DCB in CTOs. These researchers stated that further assessment in complex disease is needed. The study also lacked objective criteria for the exclusion criterion “prohibitive” calcification, which may have left room for investigator bias. They stated that larger studies with robust designs are currently enrolling patients, including 2 RCTs and 1 global registry.
In a prospective, randomized, multi-center, single-blinded trial, Schroeder et al (2017a) evaluated the safety and effectiveness of a next-generation low-dose (2-µg/mm2 surface dose of paclitaxel) DCB. Patients were randomized (3:1) to treatment with a low-dose DCB or an uncoated PTA balloon. The primary safety end-point was a composite of freedom from device- and procedure-related death through 30 days after the procedure and freedom from target limb major amputation and clinically driven TLR through 12 months after the procedure. The primary effectiveness end-point was primary patency at 12 months. Patients were randomized to treatment with a DCB (222 patients, 254 lesions) or uncoated PTA balloon (72 patients, 79 lesions) after successful pre-dilatation. Mean lesion length was 7.2 and 7.1 cm, and 19.2 % and 19.0 % of lesions represented total occlusions, respectively. The primary safety end-point was met, and superiority was demonstrated; freedom from a primary safety event was 94.1 % (193 of 205) with DCB and 83.3 % (50 of 60) with PTA, for a difference of 10.8 % (95 % CI: 0.9 % to 23.0 %). The primary effectiveness end-point was met, and superiority of DCB over PTA was achieved (83.9 % [188 of 224] versus 60.6 % [40 of 66]; p < 0.001). Outcomes with DCB were also superior to PTA per the Kaplan-Meier estimate for primary patency (89.0 % versus 65.0 % at 365 days; log-rank p < 0.001) and for rates of clinically driven TLR (5.9 % versus 16.7 %; p = 0.014). The authors concluded that superiority with a low-dose DCB for femoro-popliteal interventions was demonstrated over PTA for both the safety and effectiveness end-points.
This study had several drawbacks. First, although the Clinical Events Committee, Data Safety and Monitoring Board, and core laboratory personnel were blinded to treatment, physicians were not blinded because of the visible coating on the DCB catheter. Secondly, these data cannot be generalized to other DCBs because head-to-head comparative trials have not been completed, and lastly, patients were selected with the use of strict inclusion and exclusion criteria; therefore, generalizability of these data to real-world cases may be limited.
In a prospective, multi-center, pilot study, Schroeder and colleagues (2017b) compared 2-year outcomes in patients treated with or without pre-dilatation prior to DCB angioplasty for symptomatic femoro-popliteal lesions. This pilot study was conducted at 3 sites in Germany. It compared claudicants undergoing pre-dilatation with a bare PTA balloon before DCB (pre-dilatation group) with patients undergoing direct DCB (direct DCB group). Patients were followed for 2 years. Outcomes included late lumen loss at 6 months, and ABI, MAE, and primary patency at 2 years. A Clinical Events Committee and core laboratories analyzed AEs and angiographic/duplex images, respectively. Between December 2011 and November 2012, a total of 50 patients were enrolled to the pre-dilatation group (12 % total occlusions) and 28 to the direct DCB group (5 % total occlusions). Follow-up compliance at the 2 year visit was 88 % (n = 44) and 86 % (n = 24), respectively. Late lumen loss at 6 months was lower in the direct DCB group (0.03 ± 0.68 mm versus 0.54 ± 0.97 mm; p = .01); MAE over 2 years occurred in 7 (15 %) patients who underwent pre-dilatation and in 5 (19 %) after direct DCB. Mean ABI at 2 years was 0.94 ± 0.15 after pre-dilatation and 1.0 ± 0.12 after direct DCB. Over 2 years, primary patency (80.3 % versus 78.2 %; p = 0.55) was not statistically different between the groups. After propensity score adjustments, 2 year findings remained unchanged. The authors concluded that paclitaxel-coated PTA, with or without bare pre-dilatation, was effective over 2 years in symptomatic patients with femoro-popliteal stenotic lesions; these findings should be considered preliminary and hypothesis-generating. Moreover, they stated that adequately powered RCTs of direct DCB use with or without pre-dilatation are needed to confirm these preliminary findings.
A major drawback of this study was its non-randomized sequential treatment allocation. Despite the use of propensity score co-variate adjustment, potentially confounding unmeasured variables (e.g., balloon inflation time) may introduce bias. These results may not be generalizable to total occlusions, which represented less than 10 % of lesions. Another main drawback of this pilot study was a small sample size (n = 28 in the DCB group) that was not specifically powered to detect clinically important differences between groups.
Krishnan and associates (2017) noted that DCB are a predominant revascularization therapy for symptomatic femoro-popliteal artery disease. Due to differences in excipients, paclitaxel dose and coating morphologies, varying clinical outcomes have been observed with different DCBs. These investigators reported the findings of 2 studies investigating the pharmacokinetic (PK) and clinical outcomes of a new DCB in the treatment of femoro-popliteal disease. In the ILLUMENATE Pivotal Study, a total of 300 symptomatic patients (Rutherford class 2 to 4), were randomized to DCB (n = 200) or PTA (n = 100). The primary safety end-point was freedom from device- and procedure-related death through 30 days, and freedom from target limb major amputation and clinically-driven TLR (CD-TLR) through 12-months. The primary effectiveness end-point was primary patency through 12-months. In the ILLUMENATE PK study, paclitaxel plasma concentrations were measured after last DCB deployment and at pre-specified times (1, 4, 24 hours and at 7 and 14 days post-procedure) until no longer detectable. In the Pivotal study, baseline characteristics were similar between groups; 50 % had diabetes, 41 % were women, mean lesion length was 8.3 cm and 44 % were severely calcified. The primary safety end-point was met (92.1 % for DCB versus 83.2 % for PTA, p = 0.025 for superiority) and the primary patency rate was significantly higher with DCB (76.3 % for DCB versus 57.6 % for PTA, p = 0.003). Primary patency per Kaplan Meier estimates at day 365 was 82.3 % for DCB versus 70.9 % for PTA (p = 0.002). The rate of CD-TLR was significantly lower in the DCB cohort (7.9 % versus 16.8 %, p = 0.023). Improvements in ABI, Rutherford class, and QOL were comparable, but the PTA cohort needed twice as many revascularizations; PK outcomes showed all patients had detectable paclitaxel levels after DCB deployment that declined within the first hour (54.4 ± 116.9 ng/ml to 1.4 ± 1.0 ng/ml). The authors concluded that the Stellarex DCB demonstrated superior safety and effectiveness as compared to PTA, and plasma levels of paclitaxel fall to low levels within 1 hour.
These investigators noted that although occurring despite randomization, the higher prevalence of re-stenotic lesions in the PTA cohort may impact the study results. They stated that long-term follow-up is needed in determining the extended durability of the intervention. Moreover, they stated that outcomes from this trial cannot be generalized to patients not included in this trial or to other DCBs; future studies should encompass adjunctive therapeutic options as well as optimal medical therapy and exercise.
Wu et al (2017) noted that several prospective controlled studies have evaluated the safety and effectiveness of drug-coated balloon angioplasty (DCBA) versus standard plain old balloon angioplasty (POBA) for femoro-popliteal ISR. These researchers performed a meta-analysis of prospective controlled trials to pool the results of these trials and obtain more reliable conclusions. Prospective controlled trials comparing DCBA versus POBA were searched through PubMed, Embase, the Cochrane Central Register of Controlled Trials, ISI Web of Knowledge, and relevant websites without language or publication date restrictions. The keywords were "drug-eluting balloon", "angioplasty", "femoropopliteal" and "in-stent restenosis". They selected recurrent ISR, freedom from CD-TLR, clinical improvement, ABI, and MAEs as the outcomes of this meta-analysis. Based on the inclusion criteria, these investigators identified 3 prospective clinical trials. The 1-year outcomes of DCBA and POBA were as follows: recurrent ISR (34.8 % versus 73.1 %, respectively; OR, 0.18; 95 % CI: 0.10 to 0.32, Z = 5.56, p < 0.00001), freedom from CD-TLR (82.2 % versus 54.1 %, respectively; OR, 4.20; 95 % CI: 2.05 to 8.61, Z = 3.92, p < 0.0001), clinical improvement (76.2 % versus 55.7 %, respectively; OR, 2.58; 95 % CI: 1.41 to 4.72, Z = 3.07, p = 0.002), ABI (MD, -0.04; 95 % CI: -0.13 to 0.04, Z = 1.01, p = 0.31), and MAEs (11.0 % versus 18.3 %, respectively; OR, 0.54; 95 % CI: 0.25 to 1.15, Z = 1.60, p = 0.002). The authors concluded that for femoro-popliteal ISR, DCBA was associated with superior efficacy outcomes compared with POBA, with the same safety outcome after a 1-year follow-up. Moreover, they stated that multi-center and large-scale prospective controlled trials comparing DCBA with other endovascular strategies are needed to further evaluate the safety and effectiveness profiles of DCBA in the treatment of femoro-popliteal ISR.
Andrassy et al (2017) stated that despite a constantly expanding spectrum of therapeutic options for lower limb artery disease, there is not yet a well-defined consensus on the specific type of endovascular treatment that is best suited. Clinical data on patients with femoro-popliteal disease treated with DCBs have not been elaborated sufficiently, especially in the case of ISR. These researchers performed a systematic search of the medical databases (PubMed). Keywords such as "drug-coated balloons" (DCB), "drug-eluting balloons", "in-stent restenosis", "de novo stenosis", "angioplasty", "superficial femoral artery", "popliteal artery", "above the knee", "below the knee", "peripheral artery disease" (PAD) have been used. Furthermore, data from reviews, original contributions regarding RCTs, observational studies, registries and single-center experiences have been included. Many trials have shown superiority for DCB- over PTA-treatment alone in TASC IIA and TASC IIB femoro-popliteal lesions. However, the currently available DCB systems are different in terms of efficacy and long-term outcomes depending on their mechanical and pharmacological features. Moreover, angiographic characteristics of femoro-popliteal lesions classified by Tosaka seem to influence subsequent outcomes of DCB treatment. The authors concluded that t there is still lack of reliable prospective long-term data regarding DCB technology.
In a meta-analysis, Candy et al (2017) reviewed all available literature to evaluate outcome of patients treated with DEBs compared with PTA through measuring the rate of TLR. These researchers performed an electronic search of the Medline, Scopus, Embase, Web of Science, and Cochrane Library databases. Articles reporting RCTs that compared treatment with DEBs versus PTA were selected for inclusion. A meta-analysis was performed by pooling data on rates of TLR, binary restenosis (BR), and LLL. The 10 included articles comprised a sample size of 1,292 patients. Meta-analysis demonstrated the rate of TLR in DEB-treated patients was significantly lower compared with patients treated with PTA at 6 months (OR, 0.24; 95 % CI: 0.11 to 0.53; p = 0.0004), 12 months (OR, 0.28; 95 % CI: 0.13 to 0.62; p = 0.002), and 24 months (OR, 0.25; 95 % CI: 0.10 to 0.61; p = 0.002). Decreased LLL and BR was demonstrated at 6 months in patients treated with DEBs compared with patients treated with PTA (MD, -0.74; 95 % CI: -0.97 to -0.51; p = 0.00001; OR, 0.34; 95 % CI: 0.23 to 0.49; p = 0.00001). The authors concluded that the findings of this meta-analysis demonstrated that treatment with DEBs compared with PTA resulted in reduced rates of re-intervention in patients with PAD. Moreover, they stated that comparison of DEBs to other emerging treatments to determine which method results in the lowest re-intervention rates and in the greatest improvement in QOL should be the focus of future trials.
In a systematic review and meta-analysis, Zhang et al (2017) evaluated the current available studies investigating outcomes of DEB and DES in the treatment of infra-popliteal artery disease. Multiple databases were systematically searched to identify studies investigating the outcomes of DEB and DES in the treatment of patients with infra-popliteal artery disease. The quality of studies was assessed by Cochrane Collaboration method. The demographic data, risk factors, outcomes, and anti-platelet strategy were extracted. A total of 9 studies were identified with 707 and 606 patients in DEB/DES and standard PTA/BMS group, respectively. The risk of TLR (OR = 0.38, 95 % CI: 0.23 to 0.63, p < 0.01), re-stenosis rate (OR = 0.30, 95 % CI: 0.18 to 0.50, p < 0.01), and amputation rate (OR = 0.49, 95 % CI: 0.29 to 0.83, p < 0.01) significantly decreased in the DES group. The overall survival (OR = 0.86, 95% CI: 0.56-1.32, P = .50) was similar in DES and standard PTA/BMS group; TLR (OR = 0.59, 95% CI: 0.32-1.09, P = .09), restenosis rate (OR = 0.49, 95% CI: 0.11-2.14, P = .35), amputation rate (OR = 1.32, 95 % CI: 0.51 to 3.40, p = 0.57), and overall survival (OR = 1.40, 95 % CI: 0.72 to 2.71, p = 0.32) were similar in DEB and standard PTA group. The authors concluded that the findings of this meta-analysis suggested that compared with standard PTA/BMS, DES may decrease the risk of CD-TLR, re-stenosis rate, and amputation rate without any impact on mortality. However, DEB has no obvious advantage in the treatment of infra-popliteal disease. Moreover, they stated that due to the limitations of this study, more RCTs, especially those for DEB, are needed.
Jongsma et al (2017) evaluated the effects of DEB angioplasty versus uncoated balloon (UCB) angioplasty to rescue infra-inguinal autologous bypass grafts at risk (BAR). The study included all consecutive patients treated endovascularly for BAR from December 1, 2012, to July 31, 2015. As of April 1, 2014, the primary treatment of BAR was changed from UCBs to DEBs. Patients treated with DEBs were prospectively recorded in a database and retrospectively analyzed. Patients treated with UCBs were retrospectively collected from a historical cohort with a similar inclusion period length as the DEB cohort. The follow-up scheme did not differ between the 2 groups. The primary end-point was the combined end-point of freedom from recurrent stenosis or bypass occlusion; secondary end-points were primary assisted patency, secondary patency, technical success, major amputation, and mortality. A total of 21 patients were treated in the DEB group and 18 were treated in the UCB group. The 2 groups were evenly distributed in demographics, bypass, treatment, and lesion characteristics. No statistically significant differences were found in the combined end-point of freedom from recurrent stenosis and the occlusion rate after 1 year between the UCB group (77.8 %) and the DEB group (80.0 %; p = 0.76). After 1 year, the primary assisted patency rate was 88.2 % in the UCB group versus 95.2 % in the DEB group (p = 0.47), and the secondary patency rate was 94.1 % in the UCB group versus 95.2 % in the DEB group (p = 0.91). During follow-up, re-stenosis developed in 4 patients (22.2 %) in the UCB group and in 4 patients (19.0 %) in the DEB group (p = 9.80); 1 bypass (5.6 %) in the UCB group and 1 bypass (4.8 %) in the DEB group occluded during follow-up (p = 0.884). The authors concluded that DEBs and UCBs performed equally in the treatment of significant stenosis in infra-inguinal autologous bypasses with regard to freedom from re-stenosis or bypass occlusion, primary assisted patency, and secondary patency at 1 year. These investigators suggested using a less expensive UCB in the treatment of BAR.
The National Institute for Health and Care Excellence (NICE, 2016) evaluated the Lutonix drug-coated balloon for peripheral arterial disease. The Lutonix DCB is a paclitaxel-coated percutaneous transluminal angioplasty (PTA) catheter that is indicated for treating peripheral arterial disease (PAD). The briefing found that the key points from the evidence are from 2 randomized trials (citing LEVANT studies I and II; n=101 and 476) comparing the Lutonix DCB with standard angioplasty using non-coated balloons in patients with symptomatic femoro-popliteal PAD. The Lutonix DCB showed significantly lower late lumen loss rates at 6 months post-procedure with a similar complication rate to standard balloon angioplasty. Two non-comparative, retrospective case series (citing Steiner et al. 2016 and Micari et al. 2016) indicate that the Lutonix DCB is a potentially viable treatment for below-the-knee PAD, with acceptable outcomes and safety rates. The briefing noted, however, that key uncertainties around the evidence are that the primary outcome of the 2 randomized studies is late lumen loss. This is considered to be a technical outcome so its clinical impact is unclear. The additional clinical evidence comprises retrospective non-comparative case series (n = 246 and n = 55).
An earlier assessment of drug-eluting balloons and stents for peripheral arterial disease by the Swedish Regional Health Technology Assessment Centre (HTA-centrum) (Falkenberg, et al., 2015) reached the following conclusions: "Despite almost 3,000 studied patients, no positive effects on patient-related outcomes have consistently been observed with drug eluting stents or balloons in the treatment of atherosclerotic disease of the lower extremities, compared with uncoated stents or balloons. Mortality rate within 12 months was reported to be between zero and 18 %, probably mainly related to the underlying general atherosclerotic disease. Commonly encountered SAEs are mortality, amputations, pseudo aneurysms and thrombosis. For patients with intermittent claudication (P1) due to below the knee lesions, it is uncertain whether there is little or no difference regarding mortality, restenosis or symptom severity with DES (sirolimus) compared with BMS. Very low certainty of evidence (Grading of Recommendations Assessment, Development, and Evaluation [GRADE] +000). In patients with critical ischemia (P2) and lesions below the knee, DES (everolimus) may reduce restenosis compared with BMS. In the same patient group, DEB with paclitaxel compared with UCB may slightly reduce symptom severity (Rutherford score). Low certainty of evidence (GRADE ++00). Importantly, for patients with critical ischemia below the knee, in one RCT comparing DEB (paclitaxel) with UCB (ref), a significant increase in amputation rate (not reported in the RCT) was detected in the DEB group when all amputated patients from the study flowchart were included in the analysis. There was also a non-significant but numerically higher mortality in the DEB (paclitaxel) group compared with the UCB group. In a mixed population (P3) (i.e. intermittent claudication or critical ischemia patients) with lesions above the knee, DES (paclitaxel) compared with BMS may reduce restenosis. DES (sirolimus) compared with BMS in lesions below the knee, may reduce restenosis and may slightly reduce symptom severity. In the mixed population, with lesions above and/or below the knee, restenosis may be reduced with DEB (paclitaxel) compared with UCB. In all cases low certainty of evidence (GRADE ++00). In the studied patient populations (P1-P3), the effect estimates for all other studied outcomes were uncertain, non-significant or inconclusive. Very low-, or low certainty of evidence (GRADE +000 or ++00)."
Bajraktari and co-workers (2016) performed a meta-analysis to evaluate the clinical efficiency and safety of DEB compared with DES in patients with drug-eluting stent restenosis (DES-ISR). A systematic search was conducted and all RCTs and observational studies that compared DEB with DES in patients with DES-ISR were included. The primary outcome measure – major adverse cardiovascular events (MACE) – as well as individual events such as TLR, stent thrombosis (ST), MI, cardiac death (CD) and all-cause mortality, were analyzed. A total of 3 RCTs and 4 observational studies were included with a total of 2,052 patients. MACE (RR = 1.00, 95 % CI: 0.68 to 1.46, p = 0.99), TLR (RR = 1.15 [CI: 0.79 to 1.68], p = 0.44), ST (RR = 0.37[0.10 to 1.34], p = 0.13), MI (RR = 0.97 [0.49 to 1.91], p = 0.93) and CD (RR = 0.73 [0.22 to 2.45], p = 0.61) were not different between patients treated with DEB and with DES. However, all-cause mortality was lower in patients treated with DEB (RR = 0.45 [0.23 to 0.87, p = 0.019) and in particular when compared to only 1st generation DES (RR 0.33 [0.15 to 0.74], p = 0.007). There was no statistical evidence for publication bias. The authors concluded that the results of this meta-analysis showed that DEB and DES had similar efficacy and safety for the treatment of DES-ISR.
Basavarajaiah and colleagues (2016) compared DEBs versus 2nd-generation DES in the treatment of DES-ISR. These researchers evaluated all procedures between 2009 and 2011, involving DES-ISR that were treated either with DEB or 2nd-generation DES. The measured end-points during the follow-up period were CD, target-vessel MI, TLR, TVR, and MACE defined as composite of cardiac-death, TV-MI, and TVR. A total of 247 patients (302 lesions) with DES-ISR were treated with either DEB (81 patients; 104 lesions) or 2nd-generation DES (166 patients; 198 lesions). The mean age of patients was 66.1 ± 9.4 years. There were higher numbers of patients with diabetes in the DEB group (DEB 47 % versus DES 33 %; p = 0.03). The mean length of DEB was significantly longer than the DES (35.4 versus 19.8 mm; p < 0.001). During the 12-month follow-up, there were no significant differences in the MACE rates (12.3 % versus 8.4 %; p = 0.3) and TLR rates (9.9 % versus 7.8 %; p = 0.6) between DEB and DES, respectively. On the multivariate analysis, use of DEB or DES was not the predictor of MACE (HR: 0.84, 95 % CI: 0.46 to 1.85; p = 0.6). There were no cases of definite or probable stent thrombosis in either group. The authors concluded that there were no significant differences in the clinical outcomes between DEB and 2nd-generation DES in the treatment of DES-ISR. They stated that these results should encourage operators to consider DEB in the treatment of DES-ISR, which offers certain advantages over DES.
Wang and associates (2017) evaluated the efficacy of DEB with DES in patients with ISR. Electronic databases were searched for RCTs and observational cohort studies which reported the clinical outcomes of using DEB comparing with DES implantation in patients with ISR. Clinical endpoints such as MACE, death, and MI were assessed. A total of 5 RCTs and 5 observational cohort studies with 962 patients in the DEB group and 908 patients in the DES group met inclusion criteria. There was no significant difference between DEB and DES in major clinical outcomes, such as MACE (OR 1.01; 95 % CI: 0.64 to 1.58; p = 0.97; I2 = 0 %), all-cause death (OR 1.04; 95 % CI: 0.54 to 1.98; p = 0.91; I2 = 0 %), cardiovascular death (OR 1.44; 95 % CI: 0.57 to 3.65; p = 0.44; I2 = 0%), stent thrombosis (OR 0.61; 95 % CI: 0.16 to 2.33; p = 0.47; I2 = 0 %), and MI (OR 1.02; 95 % CI: 0.53 to 1.94; p=0.96; I2 = 0 %). DEB was associated with a significant increase in TLR (OR 1.54; 95 % CI: 1.10 to 2.15; p = 0.01; I2 = 57 %). The authors concluded that treatment of ISR using DEB led to comparable clinical outcomes with DES implantation.
Milnerowicz and colleagues (2019) analyzed the long-term outcomes of a hybrid therapeutic approach combining rotational atherectomy with drug-coated balloon (DCB) angioplasty in patients with total in-stent occlusion in the iliac and/or infra-inguinal arteries. Between April 2014 and June 2017, a total of 74 consecutive patients (mean age of 66.7 ± 9.7 years; 49 men) with total occlusion of a previously implanted stent underwent endovascular re-canalization using the Rotarex system and DCB angioplasty; 50 % (n = 37) of the patients had CLI, and 41 % (n = 30) of the procedures were performed in emergency. Mean lesion length was 22 ± 15 cm. Overall procedure success was achieved in 73 (98.6 %) patients; 6 (8.1 %) CLI patients developed distal embolism that responded to thrombolysis; 3 (4.1 %) dissections did not require treatment, while 1 (1.4 %) perforation necessitated stent-graft implantation. In all, 33 (44.6 %) patients had an additional stent implanted, mainly due to a sub-optimal outcome (n = 28) or complications (n = 5 including the stent-graft). The re-stenosis rate assessed by Duplex ultrasound (US) at 12 months was 20.5 % (15/73); 4 (5.5 %) patients underwent TLR. Recurrent re-stenosis was more frequent in patients with Rutherford category 5 ischemia (p = 0.005), in emergency procedures (p = 0.021), after extensive procedures involving 3 independent vessel segments (p = 0.016), and if a complication arose during the procedure (p < 0.001). In multi-variate analysis, only occurrence of a procedural complication was an independent predictor of recurrent restenosis at 1 year (OR 63.3, 95 % CI: 5.7 to 701.5). The authors concluded that these findings implied that rotational atherectomy and DCB angioplasty may provide satisfactory outcomes in the treatment of total in-stent occlusion, with a satisfactory recurrent re-stenosis rate at 12 months.
Scheinert and colleagues (2014) examined the safety and efficacy of the Lutonix drug-coated balloon (DCB) coated with 2 μg/mm(2) paclitaxel and a polysorbate/sorbitol carrier for treatment of femoro-popliteal lesions. Subjects at 9 centers with Rutherford class 2 to 5 femoro-popliteal lesions were randomized between June 2009 and December 2009 to treatment with Lutonix DCB (n = 49) versus uncoated balloons (control group [n = 52]), stratified by whether balloon-only treatment (n = 75) or stenting (n = 26) was intended. The primary end-point was angiographic late lumen loss at 6 months; secondary outcomes included adjudicated SAEs (death, amputation, target lesion thrombosis, re-intervention), functional outcomes, and pharmacokinetics. Demographic, peripheral vascular disease, and lesion characteristics were matched, with mean lesion length of 8.1 +/- 3.8 cm and 42 % total occlusions. At 6 months, late lumen loss was 58 % lower for the Lutonix DCB group (0.46 +/- 1.13 mm) than for the control group (1.09 +/- 1.07 mm; p = 0.016). Composite 24-month SAEs were 39 % for the DCB group, including 15 TLR, 1 amputation, and 4 deaths versus 46 % for uncoated balloon group, with 20 TLR, 1 thrombosis, and 5 deaths. Pharmacokinetics showed bi-exponential decay with peak concentration (Cmax) of 59 ng/ml and total observed exposure (AUC(all)) of 73 ng h/ml. For successful DCB deployment excluding 8 malfunctions, 6-month late lumen loss was 0.39 mm and the 24-month TLR rate was 24 %. The authors concluded that treatment of femoro-popliteal lesions with the low-dose Lutonix DCB reduced late lumen loss with safety comparable to that of control angioplasty.
The authors stated that this study had several drawbacks. LEVANT I was a single-blind study. Although angiographic entry and stratification criteria were operator-determined prior to randomization, potential post-randomization procedural and follow-up bias cannot be precluded for unblinded operators. Only limited balloon sizes were available, and the protocol-mandated angiograms at 6 months may have confounded clinical follow-up. The study was limited by small sample size for evaluating binary outcomes such as clinical events or patency. Runoff was not compared between the 2 study groups. An unexpected limitation to the study was the balloon deployment malfunctions, with poorer late outcomes in the subgroup with failed deployment that diluted the ITT analysis. Despite the clear failure of drug delivery in this subset of subjects, safety and primary end-point treatment effect were still evident on an intention-to-treat (ITT) basis.
Rosenfield and associates (2015) stated that the treatment of PAD with percutaneous transluminal angioplasty is limited by the occurrence of vessel recoil and restenosis. Drug-coated angioplasty balloons deliver anti-proliferative agents directly to the artery, potentially improving vessel patency by reducing restenosis. In a single-blind, randomized trial conducted at 54 sites, these researchers assigned, in a 2:1 ratio, 476 patients with symptomatic intermittent claudication or ischemic pain while at rest and angiographically significant atherosclerotic lesions to angioplasty with a paclitaxel-coated balloon or to standard angioplasty. The primary efficacy end-point was primary patency of the target lesion at 12 months (defined as freedom from binary restenosis or from the need for TLR). The primary safety end-point was a composite of freedom from peri-operative death from any cause and freedom at 12 months from limb-related death (i.e., death from a medical complication related to a limb), amputation, and re-intervention. The 2 groups were well matched at baseline; 42.9 % of the patients had diabetes, and 34.7 % were current smokers. At 12 months, the rate of primary patency among patients who had undergone angioplasty with the drug-coated balloon was superior to that among patients who had undergone conventional angioplasty (65.2 % versus 52.6 %, p = 0.02). The proportion of patients free from primary safety events was 83.9 % with the drug-coated balloon and 79. 0% with standard angioplasty (p = 0.005 for non-inferiority). There were no significant between-group differences in functional outcomes or in the rates of death, amputation, thrombosis, or re-intervention. The authors concluded that among patients with symptomatic femoro-popliteal PAD, percutaneous transluminal angioplasty with a paclitaxel-coated balloon resulted in a rate of primary patency at 12 months that was higher than the rate with angioplasty with a standard balloon. The drug-coated balloon was non-inferior to the standard balloon with respect to safety. Moreover, these researchers stated that this trial did not provide definitive guidance concerning the potential role of this paclitaxel-coated balloon in clinical practice. They stated that although the findings were encouraging, long-term follow-up studies are needed in examining if the benefit of this intervention is sustained, increased, or attenuated over time. In addition, further studies may compare the drug-coated balloon with other therapeutic options, such as atherectomy or stenting with bare-metal stents or drug-eluting stents.
The authors stated that this study had several drawbacks. Although the trial was designed to have the power to detect a difference in the primary end-point of patency at 12 months, it was not designed to have the power to assess differences in functional end-points or QOL measures. Determinants of these outcomes may not be specific to the study lesion; changes may be due to progression of PAD in other arterial segments or to co-existing conditions that are known to limit physical function rather than to a difference in the device used to treat a specific lesion. In addition, although the patients, core laboratory staff, and clinicians performing the follow-up assessments were unaware of the study-group assignments, the physicians performing the index procedures could not be unaware of the assignments because of the different characteristics of the 2 types of angioplasty balloons.
In a prospective, multi-center study, Thieme and co-workers (2017) examined the safety, clinical benefit, and outcomes of the Lutonix 035 DCB in a heterogeneous, real-world patient population at 12 and 24 months. This trial enrolled 691 patients in 38 centers from 10 countries treated with the Lutonix 035 DCB in femoro-popliteal lesions. The primary safety end-point was freedom from a composite of target vessel restenosis, major index limb amputation, and device- or procedure-related death at 30 days. The primary effectiveness end-point was freedom from target lesion restenosis at 12 months; secondary end-points were acute device and procedural success and clinically assessed primary patency. Freedom at 30 days from the composite safety end-point was 99.4 %. Freedom from target lesion restenosis was 93.4 %/89.3 % for the overall population, 93.2 %/88.2 % for long lesions up to 500 mm, and 90.7 %/84.6 % for ISR at 12/24 months. Clinically assessed primary patency by Kaplan-Meier estimates was 85.4 %/75.6 % at 12/24 months. More than 76 % of patients showed improvement of at least 1 Rutherford category. The authors concluded that the Global SFA Registry 24-month outcomes confirmed the Lutonix 035 DCB was a safe and effective long-term therapeutic option in real-world patients with PAD with superficial femoral artery lesions, also in long lesions and ISR.
The authors stated that this study had several drawbacks. The trial was a prospective, multi-center, single-arm registry, and did not include a comparison control group. Rather, reference to past clinical experience was used as a point of comparison. Physicians enrolled patients for whom they believed the therapy would be appropriate, and the decision to enroll was not based on randomization or sequential patient identification. The study included patients observed in typical real-world clinical practice with a commercially available product used consistent with established European instructions for use (IFU). The intent of this study was to evaluate the DCB outcomes in standard of care practice. Reporting the TLR outcomes were real-world results and were not adjusted by core laboratory review.
Casserly (2017) stated that percutaneous treatment of atherosclerotic disease in the femoro-popliteal (FP) segment remains one of the most challenging subsets for endovascular operators. The experience of unacceptably high restenosis rates with POBA and nitinol self-expanding stents (SES) generated considerable interest in a variety of atherectomy technologies as a complement or replacement for angioplasty/stenting over the past 10 years. However, it has become clear that these technologies suffer from the same problem of high restenosis rates. In addition, application of atherectomy technologies was generally expensive, introduced greater technical challenges in performing the procedure, leading to a greater degree of variability in outcome based on operator experience and skill level, and probably increased the risk of distal embolization during treatment, necessitating the use of embolic protection devices. More recently, the pendulum has swung back toward the use of angioplasty and stents with the availability of DCB and a DES system with proven superiority over POBA and non–drug-eluting SES, respectively. The author noted that currently, there are 2 FDA-approved DCB systems available for clinical use in the FP segment. Each system was tested in pivotal randomized trials (LEVANT II [Moxy Drug Coated Balloon versus Standard Balloon Angioplasty for the Treatment of Femoro-popliteal Arteries] and IN.PACT SFA [Randomized Trial of IN.PACT Admiral Drug Coated Balloon versus Standard PTA for the Treatment of SFA and Proximal Popliteal Arterial Disease] trials) comparing DEB with POBA. Moving forward, there is a need to perform a head-to-head comparison between the 2 DCB systems to examine if the superior patency rates reported for the DCB arm of the IN.PACT SFA trial (using the IN.PACT Admiral DCB [Medtronic, Santa Rosa, CA]) reflected a real difference or was due to differences in patient population and/or lesion type, or trial design. This may help to move the field forward by examining if the dose of paclitaxel and the excipient used can have a significant clinical impact on restenosis rates. The author concluded that it must be accepted that DCB therapy will always suffer from the major Achilles heel of not being able to deal with the issue of elastic recoil or development of flow-limiting dissections following angioplasty. In addition, it would be naive to think that DCB therapy will reliably prevent restenosis in the most severe lesion types that are encountered in the FP artery. Although DCB therapy is a welcome addition to the options for re-vascularization in the FP segment, there is a long way to go before endovascular therapy that includes DCB angioplasty can rival the patency rates of surgical bypass. It is hard not to feel that an inert biodegradable metal scaffold combined with an anti-proliferative agent still offers the best chance of achieving this goal. Unfortunately, the many failures to-date for non-biodegradable DES in the FP segment have hampered investment and investigation, and may continue to do so for some time.
Kayssi and colleagues (2019) noted that stents are placed in the femoro-popliteal arteries for numerous reasons, such as atherosclerotic disease, the need for dissection, and perforation of the arteries, and can become stenosed with the passage of time. When a stent develops a flow-limiting stenosis, this process is known as "ISR". It is thought that ISR is caused by a process known as "intimal hyperplasia" rather than by the progression of atherosclerotic disease. Management of ISR may include performing balloon angioplasty, deploying another stent within the stenosed stent to force it open, and creating a bypass to deliver blood around the stent. The role of drug-eluting technologies, such as DEBs, in the management of ISR is unclear. Drug-eluting balloons might function by coating the inside of stenosed stents with cytotoxic chemicals such as paclitaxel and by inhibiting the hyperplastic processes responsible for ISR. It is important to perform this systematic review to evaluate the efficacy of DEB because of the potential for increased expenses associated with DEBs over uncoated balloon angioplasty, also known as POBA. In a Cochrane review, these researchers examined the safety and efficacy of DEBs compared with uncoated balloon angioplasty in people with ISR of the femoro-popliteal arteries as assessed by criteria such as amputation-free survival, vessel patency, TLR, binary restenosis rate, and death. They defined "ISR" as 50 % or greater narrowing of a previously stented vessel by Duplex US or angiography. The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialized Register, CENTRAL, MEDLINE, Embase, and CINAHL databases and the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registers to November 28, 2017. Review authors also undertook reference checking to identify additional studies. These researchers included all RCTs that compared DEBs versus uncoated balloon angioplasty for treatment of ISR in the femoro-popliteal arteries. Two review authors independently selected appropriate trials and performed data extraction, assessment of trial quality, and data analysis. The senior review author adjudicated any disagreements A total of 3 trials that randomized a combined total of 263 participants met the review inclusion criteria. All 3 trials examined the treatment of symptomatic ISR within the femoro-popliteal arteries. These trials were performed in Germany and Austria and used paclitaxel as the agent in the DEBs; 2 of the 3 trials were industry-sponsored. Two companies manufactured the DEBs (Eurocor, Bonn, Germany; Medtronic, Fridley, MN). The trials examined both anatomical and clinical endpoints. These investigators noted heterogeneity in the frequency of bailout stenting deployment between studies as well as in the dosage of paclitaxel applied by the DEBs. Using GRADE assessment criteria, they determined that the certainty of evidence presented was very low for the outcomes of amputation, TLR, binary restenosis, death, and improvement of one or more Rutherford categories. Most participants were followed-up to 12 months, but 1 trial followed participants for up to 24 months. Trial results showed no difference in the incidence of amputation between DEBs and uncoated balloon angioplasty. DEBs showed better outcomes for up to 24 months for TLR (OR 0.05, 95 % CI: 0.00 to 0.92 at 6 months; OR 0.24, 95 % CI: 0.08 to 0.70 at 24 months) and at 6 and 12 months for binary restenosis (OR 0.28, 95 % CI: 0.14 to 0.56 at 6 months; OR 0.34, 95 % CI: 0.15 to 0.76 at 12 months). Participants treated with DEBs also showed improvement of one or more Rutherford categories at 6 and 12 months (OR 1.81, 95 % CI: 1.02 to 3.21 at 6 months; OR 2.08, 95 % CI: 1.13 to 3.83 at 12 months). Data showed no clear differences in death between DEBs and uncoated balloon angioplasty. Data were insufficient for subgroup or sensitivity analyses to be conducted. The authors concluded that based on a meta-analysis of 3 trials with 263 participants, evidence suggested an advantage for DEBs compared with uncoated balloon angioplasty for anatomical end-points such as TLR and binary restenosis, and for one clinical end-point - improvement in Rutherford category post-intervention for up to 24 months . However, the certainty of evidence for all these outcomes was very low due to the small number of included studies and participants and the high risk of bias in study design. These researchers stated that adequately powered and carefully constructed RCTs are needed to examine the role of drug-eluting technologies in the management of ISR.
Medicines and Healthcare products Regulatory Agency (MHRA, 2019) provided the following recommendations for ongoing use of paclitaxel DCBs and implantable DESs in the treatment of patients with PAD:
- Do not use paclitaxel DCBs or DESs in the routine treatment of patients with intermittent claudication until further notice, as the potential mortality risk generally out-weighs the benefits.
- In patients with critical limb ischemia, management should follow NICE guideline CG 147 (2018), which recommends angioplasty or bypass surgery, with consideration of bare metal stents only where there is complete aorto-iliac occlusion.
- Use of paclitaxel DCBs and DESs in patients with critical limb ischemia remains an appropriate option in selected cases, where the benefits may out-weigh the risks. This is because these patients generally have a higher risk of irreversible ischemic damage resulting from restenosis, such as limb loss, and a lower life expectancy.
Drug-Eluting Balloon for Vein Grafts and Dialysis / Vascular Accesses
Bjorkman and colleagues (2017) analyzed outcomes of the first experiences with DEBs in native arteries, vein grafts, and vascular accesses. The study was also a pilot for the authors’ future prospective, randomized, and controlled studies regarding the use of DEBs in the treatment of the stenosis in bypass vein graft and dialysis access. A total of 93 consecutive patients were retrospectively analyzed and 81 were included in the study. Inclusion criteria included at least 1 previous percutaneous angioplasty to the same lesion. Patients were divided into 3 groups according to the anatomical site of the lesion:
- native lower limb artery,
- vein bypass graft, or
- vascular access.
Time from the previous percutaneous angioplasty to the DEB was compared to the time from the DEB to end-point in the same patient. End-points included any new re-vascularization of the target lesion, major amputation, or new vascular access. The median time from the DEB to end-point was significantly longer than the median time from the preceding percutaneous angioplasty to DEB in all 3 groups. This difference was clearest in native arteries and vein grafts, whereas the difference was smaller from the beginning and disappeared over time in the vascular access group. No significant differences were seen between the groups with regard to smoking, antiplatelet regime, diabetes, Rutherford classification, or sex. The authors concluded that although the setup of this study had several limitations, the results suggested that there could be benefit from DEBs in peripheral lesions. Moreover, they stated that very little data have been published on the use of DEBs in vein grafts and vascular accesses, and randomized and controlled prospective studies are needed to further investigate this field.
Trerotola and colleagues (2018) noted that re-stenosis remains a problem in hemodialysis access interventions. Paclitaxel-coated balloons have shown promise in reducing access-related re-stenosis in small trials. The primary hypotheses for this multi-center trial were superior effectiveness at 180 days and non-inferior safety at 30 days of a drug-coated balloon compared with conventional angioplasty for treatment of dysfunctional arterio-venous (AV) fistulae. This randomized trial enrolled 285 patients with dysfunctional AV fistulae at 23 centers. Grafts, central venous stenoses, thrombosed fistulas, and immature fistulas were excluded. All patients received angioplasty of the lesion responsible for access dysfunction. After successful angioplasty (less than or equal to 30 % residual stenosis), lesions were treated with either a paclitaxel-coated balloon or an uncoated control balloon of similar design to the drug-coated balloon. Access function during follow-up was determined per centers' usual protocols; re-intervention was clinically driven. The primary efficacy outcome assessment was carried out at 6 months, and the safety assessment was done within 30 days of the procedure. Pre-specified secondary end-points included assessment of post-intervention target lesion primary patency and access circuit primary patency at 6 months. The 180-day end-point was not met with target lesion primary patency (71 % ± 4 % for the drug-coated balloon and 63 % ± 4 % for control; p = 0.06), representing a difference of 8 % ± 6 % (95 % CI: -3 % to 20 %). Access circuit primary patency did not differ between groups. Interventions to maintain target lesion patency were fewer for the drug-coated balloon at 6 months (0.31 versus 0.44 per patient; p = 0.03). The primary safety non-inferiority end-point was met and did not differ between groups (p = 0.002). The authors concluded paclitaxel-coated balloon used after successful angioplasty in AV fistulas stenosis was not shown to be superior to a standard balloon using a strict 180-day definition of the 6-month end-point. Fewer interventions were needed in the drug-coated balloon group to maintain target lesion patency. The drug-coated balloon was as safe as the standard balloon.
Trerotola and associates (2020) presented final, 2-year results of a randomized trial comparing paclitaxel-coated versus uncoated balloon angioplasty following vessel preparation with ultra-high-pressure PTA hemodialysis AV fistulae. Twenty-three sites enrolled 285 subjects with dysfunctional AV fistulae located in the arm. Before 1:1 randomization, successful vessel preparation was achieved (full waist effacement, less than 30 % residual stenosis). Follow-up was clinically driven except for a 6-month office visit; 96 of 141 subjects in the DCB-arm and 111 of 144 in the control-arm completed the study. Target lesion primary patency (TLPP) rates for the DCB and control groups were 58 % ± 4 versus 46 % ± 4 (p = 0.02) at 9 months, 44 % ± 5 versus 36 % ± 4 (p = 0.04) at 12 months, 34 % ± 5 versus 28 % ± 4 (p = 0.06) at 18 months, and 27 % ± 4 versus 24 % ± 4 (p = 0.09) at 24 months, respectively. Mean time to TLPP event for subjects with an event was longer for DCBs (322 versus 207 days; p < 0.0001). Fewer interventions were needed to maintain target lesion patency in the DCB group at 9 months (p = 0.02) but not at 12 (p = 0.08), 18 (p = 0.13), or 24 months (p = 0.19). The non-inferiority safety target was met at all intervals (p < 0.01). Mortality did not differ between groups (p = 0.27). Post-hoc analyses showed equivalent DCB effect in all subgroups. The authors concluded that the use of a DCB after adequate vessel preparation in patent, dysfunctional arm AV fistulae resulted in an improved patency trend over control at 9 months and not at other time-points over the 2-year study, as well as significantly reduced interventions to maintain TLP and a significant prolongation of time to next intervention at the target lesion. Subset analysis did not reveal any specific factors suggesting more targeted application of the DCB. These investigators believed that these findings are an important step forward in the development of novel therapies that improve the QOL of patients undergoing hemodialysis. They hope the further introduction of other such therapies, as well as the analysis of more patients treated with DCBs, will result in a future precision-based approach to AV fistulae stenosis.
The authors stated that this study had several drawbacks. The investigative team performing the PTA could not be blinded to device, which could theoretically have affected outcomes even though the rest of the study team, patients, dialysis unit, core laboratory, data safety monitoring board, and clinical events committee were all blinded. Performance of a second “sham” PTA in the control-arm was considered by the study designers to be necessary to match the treatment and control groups, but this may have improved results in the control-arm and biased the study against the DCB. Likewise, insisting on optimal PTA-based vessel preparation may have biased the study in favor of the control-arm. Access surveillance methodology and thresholds for fistula imaging were not study-directed, such that clinically driven repeat intervention thresholds may have varied between study centers. Certain factors such as antiplatelet use were not controlled for in the study, and flow measurement was not consistently performed (or required) as part of the study. The latter might have given more objective referrals for clinically driven repeat intervention. Duration of DCB inflation was lengthened during the study in light of emerging data from DCB studies in arterial disease, and, although the subset analysis did not show any significant differences between shorter and longer inflations, use of the longer inflation time throughout the study could conceivably have influenced the results. As with any large trial over a long period of time, the data were incomplete for some subjects.
Intravascular Shockwave Lithotripsy of the Peripheral Arteries for the Treatment of Atherosclerosis / Calcified Lower Extremity Arterial Lesions / Intermittent Claudication
Giannopoulos and Armstrong (2019) noted that femoro-popliteal lesions account for a significant proportion of endovascular interventions for peripheral artery disease (PAD). These investigators reviewed the literature on the application of newly approved devices in the treatment of atherosclerotic lesions at this segment. New drug-coating technologies provide sustained drug-eluting over time and better scaffolds are more resistant to the increased biomechanical stress at the femoro-popliteal segment. Thus, the newer drug-eluting stents (i.e., Eluvia), nitinol interwoven stents (i.e., Supera), and drug-coated balloons (i.e., Stellarex) are associated with improved pharmacokinetic profiles and promising primary patency rates. A major predictor of technical failure and re-stenosis is the calcification of the target vessel. Recently, intravascular lithotripsy of calcified lesions at the femoro-popliteal segment with the Shockwave balloon was introduced as a feasible therapeutic option for these complex lesions. The authors also described the Tack Endovascular System, the first-of-its-type, for the repair of post-angioplasty dissections. These researchers concluded that the use of innovative stent designs and novel drug-coating, the application of adjunctive intravascular lithotripsy and the combined use of new devices treating complications, might improve the overall outcomes of angioplasty, thereby promising favorable outcomes even for more complex lesions.
Furthermore, UpToDate reviews on “Overview of lower extremity peripheral artery disease” (Berger and Davies, 2020) and “Management of claudication due to peripheral artery disease” (Davies, 2020) do not mention intravascular shockwave lithotripsy as a therapeutic option.
Holden (2019) noted that the endovascular management of complex lower limb arterial occlusive disease is generally associated with poorer acute results, a higher incidence of provisional stenting and subsequent re-stenosis compared to more simple arterial lesions. Even more challenging results can be expected when 2 complex features are combined such as chronic total occlusion (CTO) and severe calcification. Intravascular lithotripsy (IVL) with the Shockwave system has recently been examined as a familiar angioplasty-balloon-based but effective technique for the management of arterial calcification. In the DISRUPT PAD clinical trials, excellent acute results were obtained in moderate-to-severely calcified femoro-popliteal lesions, including a group of patients with CTOs. The incidence of provisional stenting was very low, despite the lesion complexity. There was a high incidence of subsequent re-stenosis, suggesting an anti-restenotic therapy with drug-coated balloon (DCB) is a necessary adjunct. This is being currently evaluated in the DISRUPT PAD III randomized trial. There has also been positive experience in calcified tibial artery CTOs in the DISRUPT BTK trial and further clinical experience is currently being accumulated.
Price et al (2019) stated that endovascular treatment of arterial diseases has become 1st-line in most cases due to improved technology. However, until recently, excessive atherosclerotic calcification has been a major limiting factor in the endovascular management of PAD, as well as vascular access for endovascular aneurysm repair (EVAR) and transcatheter aortic valve replacement (TAVR). The Peripheral Intravascular Lithotripsy (IVL) System applies pulsatile mechanical energy under fluoroscopic guidance to disrupt calcified lesions. These investigators introduced IVL in the treatment of calcific access vessels in preparation for EVAR and TAVR, as well as PAD applications to enhance luminal gain. Using the IVL System, angioplasty can be performed with lower pressures, which may minimize arterial dissection. Furthermore, the lithotripsy effect on calcium will enhance vessel compliance. The authors described several cases where IVL was used successfully and presented additional cases that may have benefitted from the use of this technology.
Rosseel et al (2020) stated that thoracic EVAR (TEVAR) is performed with large-bore delivery systems. Small-size access vessels may be a contraindication for TEVAR, especially in case of severe calcifications. In this case report, these researchers described the 1st-in-man use of IVL to enable trans-femoral delivery of TEVAR stent grafts in a patient with severely calcified iliac arteries. A 69-year-old woman with multiple sclerosis and thoracic aortic aneurysm (TAA) was referred for percutaneous TEVAR. Both common iliac arteries were severely calcified with circumferential calcifications and a minimum diameter below 5.5 mm. In order to enable percutaneous delivery of 20 French Valiant Navion stent grafts (Medtronic), the circumferential calcified plaques were treated by use of a Shockwave Peripheral Intravascular Lithotripsy Balloon. Subsequently, the aortic stent grafts were safely and successfully passed through the ilio-femoral artery and the TAA was excluded by TEVAR. Final angiography showed normal flow in the ilio-femoral artery without any signs of perforation or overt dissection. The authors concluded that this case-report demonstrated successful application of IVL in calcified ilio-femoral arteries enabling percutaneous transfemoral TEVAR. These researchers stated that if confirmed in future cases and trials, indications for transfemoral TEVAR may further expand toward patients with severely calcified PAD.
Adams and colleagues (2020) examined the performance of peripheral IVL in a real-world setting during endovascular treatment of multi-level calcified PAD. The Disrupt PAD III Observational Study was a prospective, non-randomized, multi-center, single-arm, observational study evaluating the acute safety and effectiveness of the Shockwave Peripheral IVL System for the treatment of calcified, stenotic lower limb arteries. Patients were eligible if they had claudication or chronic limb-threatening ischemia and moderate or severe arterial calcification. Between November 2017 and August 2018, a total of 200 patients (mean age of 72.5 ± 8.7 years; 148 men) were enrolled across 18 sites and followed through hospital discharge. In the 220 target lesions, IVL was more commonly used in combination with other balloon-based technologies (53.8 %) and less often with concomitant atherectomy or stenting (19.8 % and 29.9 %, respectively). There was a 3.4-mm average acute gain at the end of procedure; the final mean residual stenosis was 23.6 %. Angiographic complications were rare, with only 2 type D dissections and a single perforation following DCB inflation (unrelated to the IVL procedure). There was no abrupt closure, distal embolization, no re-flow, or thrombotic event. The authors concluded that the use of peripheral IVL to treat severely calcified, stenotic PAD in a real-world study demonstrated low residual stenosis, high acute gain, and a low rate of complications despite the complexity of disease. It should be noted that this was industry-sponsored study.
The authors stated that this study had several drawbacks. First, the Disrupt PAD III Observational Study was a single-arm study without a control group, therefore, no definitive comparisons could be made to other interventions regarding safety and effectiveness. While the purpose of the observational study was to examine acute outcomes following IVL treatment in the real-world setting, the Disrupt PAD III RCT will directly assess safety and effectiveness outcomes in IVL plus DCB compared with balloon angioplasty (BA) plus DCB. Second, by design, only acute procedure results were reported in this study. The PAD III RCT will follow subjects through 2 years, which will provide data on the longer-term safety and effectiveness of IVL. Third, the infra-popliteal lesions treated in this cohort were too few to analyze. During early enrollment in the observational study, there was limited commercial availability of the S4 IVL catheter sized for use in infra-popliteal lesions. Thus, data availability was limited for this lesion subset. However, the PAD III Observational Study has recently been expanded to 1,500 subjects with a minimum of 200 patients treated with the S4 IVL catheter. This allowance should ensure a robust infra-popliteal lesion cohort for evaluation.
Armstrong et al (2020) examined the safety and efficacy of peripheral IVL during endovascular treatment of iliac arterial PAD. The Disrupt PAD III Observational Study was a prospective, non-randomized, multi-center, single-arm study that examined the “real-world” safety and effectiveness of the Shockwave Peripheral IVL System for the treatment of de-novo calcified lesions in the peripheral arteries, with a goal of treating 1,500 patients. This was an analysis of consecutive patients enrolled for treatment of an iliac artery, a specified sub-group, with at least moderate calcification and a minimum length of 20 mm. Between December 2017 and July 2019, a total of 118 patients with a total of 200 lesions were enrolled across 20 sites – 101 patients were treated primarily for claudication or CLI, while 17 patients were treated to optimize the iliac vasculature for large-bore access. All 118 patients had successful IVL catheter delivery. The average reference vessel diameter was 7.3 mm ± 1.9 mm, with an average diameter stenosis of 83.1 % ± 13.4 % and an average lesion length of 58.3 mm ± 57.6 mm. Severe calcification was present in 82.0 % of overall cases. Stent placement was performed in 72.9 % of the overall cases. As expected, the access group received less adjunctive therapies including stents (41.2 %, p < 0.001). Angiographic complications were minimal with no flow-limiting dissections and a final mean residual stenosis of 12.0 % ± 12.1 % with no differences between the groups. The authors concluded that acute results with IVL in calcified iliac lesions suggested that it is a safe and effective option for calcified, stenotic iliac disease.
Lazar and Morrissey (2020) stated that as associated co-morbidities have transformed over time, the evaluation and management of PAD have evolved as well. New classification systems have been created to better understand the severity of a patient's condition and the risk of amputation. These classifications include the Wound, Ischemia, and Foot Infection (WIfI) and Global Anatomic Staging System (GLASS) classification systems. Through the use of these systems, a patient's disease can be appropriately staged and managed with medical, endovascular, or surgical therapies or a combination of these. Endovascular therapies specifically have grown with the explosion of new technologies. There are numerous options for patients with disease amenable to endovascular therapy. Among other new technologies currently under investigation is the Shockwave Lithoplasty System (Shockwave Medical, Fremont, CA), which adapts technology used in the treatment of renal calculi. This technology uses a catheter-guided balloon that produces powerful acoustic shockwaves to disrupt plaque while reducing vessel wall injury. The technology is being studied in the DISRUPT PAD III clinical trial. The authors concluded that a number of available technologies have been discussed and many others are on the horizon. They stated that although some devices have demonstrated superiority, it is clear that significant research and clinical trials are needed to determine the specific utility and effectiveness of each device.
Madhavan and co-workers (2020) performed an individual patient-level data (IPD) pooled analysis of available studies to examine the safety and efficacy of IVL in the treatment of PAD. These researchers pooled IPD, including baseline and procedural variables, from 5 prospective studies that examined IVL in the treatment of patients with extensive peripheral artery calcification. Final post-procedural percent diameter stenosis (%DS) and procedural angiographic complications were evaluated by independent core laboratory. Efficacy end-points were analyzed using linear mixed effects models and safety end-points were tabulated overall and by vascular bed. Among 336 patients who underwent endovascular re-vascularization with use of IVL, there was a significant reduction between pre-procedural and final %DS of 55.1 % (95 % CI: 53.3 to 57.0 %, p < 0.0001). Core-laboratory assessed lesion-level complications, including flow-limiting dissections (Types D-F), vessel perforation, distal embolization, thrombus, abrupt closure, and no re-flow, occurred in 4/328 (1.22 %) of treated lesions. The authors concluded that the present IPD of 5 prospective studies, marking the largest analysis to date evaluating the use of IVL in significantly calcified PAD lesions, demonstrated this treatment strategy to be both safe and effective. Moreover, these researchers stated that these findings support the need for prospective, randomized trials comparing IVL to non‐IVL approaches for the treatment of PAD, such as the ongoing DISRUPT PAD III RCT; further studies are needed to determine optimal treatment strategies for PAD in this vulnerable patient population.
The authors stated that this study had several drawbacks. The trials included in this analysis were single‐arm studies with no comparators, and so these investigators were unable to effectively compare the safety and efficacy of IVL with other endovascular PAD treatment devices. It was also important to note that a proportion of patients received adjunctive device therapy (approximately 12 % received atherectomy), and so isolating the benefits of IVL in this specific patient subset was challenging. However, these researchers performed separate analyses to evaluate improvements in vascular dimensions and safety profiles in patients who received stand-alone IVL therapy with IVL and other adjunctive treatments and found no differences in final %DS or procedural complication rates between these groups. Given the varying dimensions of the vascular beds included in this analysis, there is a need for improved end-points and parameters that have applicability in these different therapeutic settings. The authors presented net gain index as one potential measure of efficacy, which may allow for assessment and comparison of procedural success across different vascular territories. To fully understand the comparative effectiveness of these therapies, head‐to‐head trials ideally with the use of intravascular imaging would need to be carried out to better understand mechanisms of action. Given the limited number of patients available to study in each of the described key clinical subgroups (including a limited number of patients with chronic limb-threatening ischemia), larger cohorts will need to be studied to verify these observations. Lastly, discharge and follow‐up clinical assessment and outcomes data were not systematically collected in several of the studies included in this analysis, making it challenging to draw robust conclusions regarding the long‐term risks and benefits of treatment with IVL, with or without other calcium modification therapies; future studies should aim to address these limitations.
Hering and Heuser (2020) stated that among adults, 12 % have PAD, with nearly 30 % older than 70 years with the disorder. With obesity, diabetes mellitus (DM), tobacco abuse, hypercholesterolemia, as well as poorly controlled hypertension, the incidence of PAD continues to rise. Endovascular treatment of FP disease has an alarmingly high rate of re-stenosis, even with new technology with TLR rates at 40 % to 60 % at 1 year. These investigators stated that IVL appeared to be safe and acutely effective; however, there is no long-term data on whether it has a role in effective treatment of PAD.
Furthermore, an UpToDate review on “Endovascular techniques for lower extremity revascularization” (Dosluoglu, 2020) does not mention intravascular shockwave lithotripsy as a management / therapeutic option.
Tepe et al (2021) compared short-term outcomes in patients with femoro-popliteal artery calcification receiving vessel preparation with IVL or PTA before DCB for symptomatic PAD. The Disrupt PAD III (Shockwave Medical Peripheral Lithoplasty System Study for PAD) randomized trial enrolled patients with moderate or severe calcification in a femoro-popliteal artery who underwent vessel preparation with IVL or PTA prior to DCB or stenting. The primary endpoint was core lab-adjudicated procedural success (residual stenosis of less than or equal to 30 % without flow-limiting dissection) before DCB or stenting. In patients receiving IVL (n = 153) or PTA (n = 153), procedural success was greater in the IVL group (65.8 % versus 50.4 %; p = 0.01) and the percentage of lesions with residual stenosis of less than or equal to 30 % (66.4 % versus 51.9 %; p = 0.02) was greater in the IVL group, while flow-limiting dissections occurred more frequently in the PTA group (1.4 % versus 6.8 %; p = 0.03). Post-dilatation (5.2 % versus 17.0 %; p = 0.001) and stent placement (4.6 % versus 18.3 %; p < 0.001) were also greater in the PTA group. The rates of major adverse events (AEs) (IVL: 0 % versus PTA: 1.3 %; p = 0.16) and clinically driven TLR (IVL: 0.7 % versus PTA: 0.7 %; p = 1.0) at 30 days were comparable between groups. The authors concluded that IVL was an effective vessel preparation strategy that facilitated definitive endovascular treatment in calcified femoro-popliteal arteries in patients with PAD.
The authors stated that this study had several drawbacks. First, IVL was compared with PTA for vessel preparation; thus, the comparative effectiveness of IVL versus other strategies such as atherectomy remains unclear. Meaningful cross-trial direct comparisons between the Disrupt PAD III Trial and studies involving other calcium modifying technologies is not possible given the differences in trial parameters. Randomized trials comparing IVL and atherectomy (rotational, orbital, or directional) are needed to define the relative safety and effectiveness of these devices. Furthermore, a formal cost analysis was beyond the scope of this study. These investigators stated that additional analyses are needed to examine the impact of vessel preparation strategy on procedural resource utilization. Second, interpretation of 30-day clinical outcomes was confounded by definitive treatment using DCB or stent placement in all patients. Potential sources of controversy with this methodology related to ascertaining whether longer-term outcomes may be attributable to vessel preparation strategy or to the choice of definitive treatment. Third, these results may not be generalizable to patients with CLI due to calcified, stenotic infra-popliteal lesions because of the pre-specified trial eligibility criteria. However, outcomes following IVL treatment of calcified infra-popliteal lesions have been reported in the Disrupt BTK (Disrupt Below-The-Knee) Trial and more recently from the Disrupt PAD III observational study using the current Shockwave S4 IVL catheter. Fourth, investigators and research staff were not blinded to treatment allocation, and outcomes requiring clinical judgment may have been influenced by expectation bias. Finally, while these short-term results are encouraging, longer-term follow-up (ongoing in this study through 2 years) are needed to evaluate treatment durability following IVL. The powered secondary endpoint of primary patency at 12 months will be analyzed following appropriate follow-ups for all enrolled patients.
Wong and colleagues (2022) noted that IVL is a novel technique for plaque modification during endovascular re-vascularization for PAD with severe calcification. These researchers carried out a systematic review and meta-analysis to examine the safety and effectiveness of IVL in lower extremity PAD. They conducted a systematic literature search with pre-defined search terms using PubMed, Web of Sciences, OvidSP, and Embase. A meta-analysis was carried out in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Patient characteristics, lesion calcification, pre-IVL and post-IVL diameter stenosis, complications, and stent rates were assessed. A total of 9 studies were included, entailing a total of 681 patients (769 lesions) with IVL performed for PAD, of which 75.53 % (95 % CI: 66.08 % to 83.03 %) of the lesions were reported to have severe calcification. Comparison between pre-IVL and post-IVL diameter stenosis demonstrated a diameter stenosis reduction of 59.3 % (95 % CI: 53.30 % to 65.31 %). Vascular complications were rare, with flow limiting or type D/E/F dissection occurring in only 1.25 % (95 % CI: 0.60 % to 2.61 %) of cases. The overall pooled event rate for stent placement was 15.89 % (95 % CI: 5.22 % to 39.34 %). The authors concluded that the findings of this meta-analysis supported IVL as a safe and effective approach for calcified plaque modification in lower extremity PAD, achieving a diameter stenosis reduction of 59.3 % with minimal vascular complications. Moreover, these researchers stated that routine use of this device is not recommended; further high-quality evidence is needed to elucidate the effectiveness of IVL with respect to different clinical characteristics (e.g., lesion location and length); and when compared with other treatment modalities (e.g., atherectomy).
Tepe et al (2022) noted that endovascular treatment of calcified peripheral artery lesions may be associated with sub-optimal vessel expansion, increased complication risk, and reduced long-term patency. The primary endpoint from the Disrupt PAD III RCT showed superior procedural success in patients treated with IVL versus PTA. These investigators examined primary patency after 1 and 2 years in this randomized population. The Disrupt PAD III RCT enrolled 306 patients with moderately-to-severely calcified FP arteries treated with IVL (n = 153) or PTA (n = 153) before DCB treatment or stenting. The powered secondary effectiveness endpoint was primary patency at 1 year, defined as freedom from clinically driven TLR plus freedom from re-stenosis determined by Duplex US. Acute PTA failure requiring stent placement during the index procedure was pre-specified as a loss of primary patency. Primary patency at 1 year was significantly greater in the IVL arm (80.5 % versus 68.0 %, p = 0.017). The requirement for provisional stenting was significantly lower in the IVL group (4.6 % versus 18.3 %, p < 0.0001). Freedom from clinically driven TLR (IVL: 95.7 % versus PTA: 98.3 %, p = 0.94) and re-stenosis rates (IVL: 90.0 % versus PTA: 88.8 %, p = 0.48) were similar between the 2 groups at 1 year. At 2 years, primary patency remained significantly greater in the IVL arm (70.3 % versus 51.3 %, p = 0.003). The authors concluded that the Disrupt PAD III RCT secondary endpoint of superior 1-year primary patency was achieved, confirming the consistent safety and effectiveness of IVL followed by DCB treatment to facilitate a durable approach for patients with heavily calcified FP arteries largely without stent requirement.
The authors stated that this study had several drawbacks. First, IVL was compared to PTA for vessel preparation; thus, the comparative effectiveness of IVL versus other calcium-modifying strategies such as atherectomy remains unclear. Meaningful cross-trial direct comparisons between Disrupt PAD III and studies entailing other calcium-modifying technologies are not possible given the differences in trial parameters. Randomized trials comparing IVL and atherectomy (rotational, orbital, or directional) are needed to define the relative safety and effectiveness of these devices. Second, these findings may not be generalizable to patients with chronic limb threatening ischemia due to calcified, stenotic infra-popliteal lesions owing to the pre-specified trial eligibility criteria. However, outcomes following IVL treatment of calcified infra-popliteal lesions have been reported in the Disrupt Below-the-Knee (BTK) Trial, and more recently from the PAD III Observational Study using the Shockwave S4 IVL catheter. The Disrupt BTK II study is currently enrolling and will examine up to 250 patients with calcified BTK lesions treated with IVL with follow-up through 2 years. In addition, a recent single-center study by Stavroulakis et al (2023) included a majority of patients with chronic limb threatening ischemia, which showed consistent 1-year primary patency outcomes following IVL treatment. Third, while IVL has showed consistent results across clinical trial and “real-world” settings, the results achieved in the PTA arm in Disrupt PAD III may not be generalizable to the “real-world” clinical setting. Poorer outcomes relative to those achieved in the present study have been previously reported following PTA and DCB treatment in calcified PAD. It remains to be seen if low rates of re-vascularization and re-stenosis could be achieved outside the clinical trial setting. Fourth, this trial was not designed to specifically assess calcium as a barrier to drug uptake following vessel preparation with IVL or PTA and definitive treatment with DCB. Specific studies designed to examine vascular micro-morphologic changes following vessel preparation with calcium-modifying technologies and associated drug absorption are needed to address this important question. Furthermore, while core laboratory angiographic assessment was used to examine calcium severity using the well-established Peripheral Academic Research Consortium (PARC) criteria, there are inherent limitations of angiography in determining specific calcium morphologies (i.e., concentric, eccentric, superficial, and deep). These researchers stated that intra-vascular imaging studies are needed for further evaluation of these calcific lesion subtypes.
Intravascular Shockwave Lithotripsy for the Treatment of Celiac Artery Occlusion
In a case-report, Cheng and colleagues (2021) presented the novel use of adjunctive IVL before definitive intravascular stenting of a heavily calcified celiac artery ostial occlusion. This case entailed a 79-year old woman who presented with chronic post-prandial abdominal pain and weight loss. Selective angiography revealed a sub-totally occluded celiac artery. Percutaneous endovascular intervention of the celiac artery was attempted but was unsuccessful because of heavy calcification. The patient returned for a repeat procedure. A guidewire was successfully advanced across the sub-totally occluded ostium. A Shockwave Lithotripsy BDC 7.0-mm/60-mm balloon catheter was successfully used to modify the calcified plaque. Next, a stent was deployed for definitive therapy. The final angiogram showed an excellent result. The patient tolerated the procedure well and was sent home on dual antiplatelet therapy. Nine months after the procedure, she had gained weight and denied any further post-prandial abdominal pain. The authors concluded that the use of IVL treatment modality to modify calcified lesions in the splanchnic circulation should be considered as a novel approach to patients in whom traditional endovascular treatment modalities are thought to be suboptimal. Moreover, these researchers stated that further controlled studies are needed to examine the safety, feasibility, and efficacy of the use of this novel technology in this vascular territory.
Intravascular Shockwave Lithotripsy for the Treatment of Renal Artery Stenosis
Schnupp and associates (2020) stated that the use of shockwave lithotripsy for the treatment of heavily calcified atherosclerotic plaques before stenting showed great results in terms of feasibility and safety with favorable initial success. Evidence suggested that it is a useful tool to treat calcified lesions in peripheral and coronary arteries. These researchers described the case of a patient with calcified renal artery stenosis (RAS) successfully treated with the shockwave lithotripsy system. They presented the case of a 76-year old man with a known significant atherosclerotic RAS and refractory hypertension. The patient received an angioplasty of the right renal artery in the 1st session and he was admitted for a 2nd session to intervene in the left renal artery. The lesion was successfully treated with the lithotripsy system. Final angiography demonstrated an excellent position of the stent and good wall apposition. The authors concluded that this case showed that lithotripsy is safe and effective for the treatment of the RAS. These preliminary findings from a single-case study need to be validated by well-designed studies.
Yousif and colleagues (2021) noted that calcified lesions represent a hard obstacle to overcome in renal arteries, especially when renal angioplasty represents the only feasible course of action in the setting of high-risk bilateral RAS with refractory systemic hypertension and recurrent flash pulmonary edema. These investigators reported a case of symptomatic bilateral severely calcified RAS, treated successfully with intravascular ultrasound (IVUS)-guided coronary and peripheral intravascular shockwave lithotripsy systems and stenting. The authors concluded that intravascular shockwave lithotripsy is an attractive modality for the treatment of challenging, heavily calcified renal arteries that combines the calcium-disrupting capability of lithotripsy with the familiarity of balloon catheters to facilitate proper stent deployment. Moreover, these researchers stated that future trials will enhance the discernment into the safety, effectiveness, and position of IVL in the algorithms for the management of heavily calcified symptomatic bilateral RAS.
Combined Atherectomy and Balloon Angioplasty for the Treatment of Femoro-Popliteal Arterial Diseases
Wu and colleagues (2021) stated that the efficacy and cost-effectiveness of atherectomy for FP arterial diseases have not been determined yet. These investigators carried out a systematic review and meta-analysis to compare the safety and effectiveness between atherectomy combined with BA and BA alone for patients with de-novo FP steno-occlusive lesions. The Cochrane Library, Medline, and Embase were used to search for studies examining outcomes of atherectomy combined with BA compared with BA alone in FP arterial diseases from inception to July 2020. The methodological quality of the included studies was evaluated with the Cochrane Risk of Bias Tool. The GRADE framework was used to evaluate the level of evidence for each outcome. The fixed effects model was chosen to combine the data when I2 was less than 50 %; otherwise, the random effects model was used. Subgroup and sensitivity analyses were performed to further analyze the results. A total of 4 RCTs were included. The meta-analysis showed that atherectomy combined with BA was associated with improved technical success rate (RR 0.22, 95 % CI: 0.13 to 0.38, p < 0.001; I2 = 0; high quality), reduced bailout stenting (RR 0.15, 95 % CI: 0.07 to 0.32, p < 0.001; I2 = 16 %; high quality), and flow limiting dissection (RR 0.24, 95 % CI: 0.13 to 0.47, p < 0.001; I2 = 0; high quality). No statistically significant difference was found in TLR, primary patency, mortality, MAE, or ABI after 1-year follow-up. The authors concluded that compared with BA alone, atherectomy combined with BA may not improve primary patency, TLR, mortality rate, or ABI, but may reduce the need for bail-out stenting and the incidence of flow limiting dissection and increase the technical success rate in FP arterial diseases. Moreover, these researchers stated that further investigations studies are needed to confirm these findings.
Combined Percutaneous Mechanical Atherectomy and Thrombectomy Followed by a Drug-Coated Balloon Angioplasty for the Treatment of Femoro-Popliteal Artery In-Stent Re-Stenosis
Liu and colleagues (2021) noted that studies examining debulking devices with drug-coated balloons (DCBs) in the treatment of FP artery ISR were limited. In a prospective. single-center, single-arm study, these researchers examined the safety and mid-term outcome of percutaneous mechanical atherectomy plus thrombectomy (MATH) using the Rotarex S catheter followed by a DCB in the treatment of FP-ISR. Patients with symptomatic (Rutherford category 2 to 5) de-novo re-stenosis lesions of FP-ISR were treated with MATH and subsequent DCB. From June 2016 to May 2018, a total of 59 patients with FP-ISR were enrolled. The primary endpoint was TLR and changes in the Rutherford category of the target limb at 12 months. Secondary endpoints included primary and secondary patency at 12 months, technical success rate, MAE, and ABI. Risk factors for TLR were analyzed using Cox proportional hazard model. The average follow-up time was 33 ± 8 months. The rate of technical success was 88.1 % (52/59); and 9 patients received bail-out stenting. The rate of freedom from TLR was 84.7 % (50/59) at 1 year, the Rutherford category changed at 12 months were significantly improved from baseline (p < 0.01). The primary patency rates and the secondary patency at the 12-month follow-ups were 82.5 % and 92.5 %, respectively. The ABI changed at 12 months were significantly improved from baseline (p < 0.01). GLASS classification III (HR 18.44, 95 % CI: 1.57 to 215.99, p = 0.020) and post-operative Rutherford classification of greater than or equal to 4 [HR 8.28, 95 % CI: 1.85 to 37.06), p = 0.006] were identified as independent predictors of TLR. The authors concluded that these preliminary data suggested that MATH using a Rotarex S catheter combined with DCB angioplasty is a safe, minimally invasive, and effective treatment for FP-ISR with favorable, immediate, and mid-term outcomes. Moreover, these researchers stated that large-scale RCTs are needed to examine the safety and effectiveness of this combined approach with different compositions of devices.
The authors stated that this study had several drawbacks. First, it was limited by the relatively small number of patients (n = 59) enrolled and the absence of a control group; thus, the comparisons were insufficiently made by this cohort and published data. Second, selection bias existed in this study because the included subjects were not randomly assigned. Patients were excluded because of several criteria. Third, this study determined that the MATH and DCB had a low-favorable outcome, however, these investigators did not examine if certain subgroups of the patients or lesions profited the most, given the small sample size available. Fourth, the combination of atherectomy (rotational or directional) with DCB was insufficiently examined. Several types of DCBs and mechanical thrombectomy devices are currently available in the market.
Atherectomy of Inguinal Arteries for the Treatment of Atherosclerotic Lesions
Usai et al (2022) noted that surgical endarterectomy represents the gold standard for the treatment of atherosclerotic lesions of the groin vessels. Endovascular treatment such as atherectomy with or without drug coated angioplasty (DCA) of the so called no stenting zones, i.e., inguinal and popliteal vessels, is gaining growing acceptance as alternative option to open surgery. In a systematic review, these investigators examined the evidence regarding atherectomy and DCA for the common femoral artery (CFA). They carried out a search in multiple platforms (Medline, PubMed, Cochrane, Google Scholar, Embase) on studies over atherectomy and angioplasty for inguinal atherosclerotic lesions published between 2000 and 2021. As search strategy these researchers used a wide list of MeSH items, words, synonyms. Bibliographies of review articles were checked for further relating studies regarding atherectomy of CFA. A qualitative and quantitative data analysis was carried out. A total of 15 studies were included in the qualitative review. Not all studies were focused only on atherectomy of inguinal vessels, despite including such treatment. Therefore, data regarding this treatment were not exhaustive. A fairly homogeneous data analysis was possible in 7 of 15 studies. The remaining 8 studies were qualitatively analyzed but not included in the statistical analysis. In all 7 included studies directional atherectomy and DCA under filter protection were performed. In this subgroup, overall, 497 patients were treated with atherectomy; 68 % of the patients were males. Rutherford class from 1 to 3 dominated against 4 to 6 (63 % versus 37%). Mean technical success rate was 96 %, with a primary and secondary patency rate of 92 % and 98 %, respectively at 1 year. Procedure related vascular complications ranged from 1 % to 6 %. The authors concluded that current literature on atherectomy for inguinal arteries is scant, data were inhomogeneous and so were treatment modalities. Nevertheless, the findings of this systematic review suggested that this endovascular strategy is feasible with good short- and mid-term results. Moreover, these researchers stated that prospective trials with larger patient cohorts are needed to confirm these preliminary findings.
Phoenix Catheter for Below the Knee Atherectomy
Kumarasamy et al (2022) stated that PAD contains a significant proportion of patients whose main pathology is located in the infra-genicular arteries. The treatment of these patients requires a deliberate consideration due to the threat of possible complications of an intervention. In a retrospective, pilot study, these researchers examined the feasibility of a below-the-knee atherectomy (BTKA) by means of a 1.5-mm Phoenix atherectomy catheter and the patient outcome over the course of 6 months. The data of patients suffering from PAD with an infra-genicular pathology treated with 1.5-mm Phoenix atherectomy catheter between March 2021 and February 2022 were analyzed. Before the intervention, after 2 weeks and 6 months, the PAD stages were graded and ABIs were measured. The study demonstrated a significant improvement of ABI, both after 2 weeks and 6 months. Furthermore, the number of stage-IV PAD patients decreased by 15.2 % over the course of 6 months, and 18.2 % of the patients improved to stage-IIa. Only 1 bleeding complication on the puncture side occurred over the study, and no other complications were observed. The authors concluded that the use of the Phoenix atherectomy catheter in the BTKA area appeared to be feasible and related to a favorable outcome in this retrospective study.
These researchers stated that even if these findings appeared promising, relevant drawbacks have to be considered while examining the impact of BTK atherectomy for PAD patients. This study was a retrospective data analysis from a routine intervention with a wide range of pre-existing conditions, PAD stages and age differences. Since the subjects were treated in a multi-professional context together with physical therapists, general practitioners, diabetologists, etc., there were different impact factors regarding the post-interventional outcome. On the other hand, this cohort represented a real-life variety of patients with symptomatic PAD. Despite the heterogeneity of the group, there was a clear narrowing of the standard deviation (SD) among the ABIs post-intervention, which could be interpreted as a direct effect of the intervention itself. This study was a first assessment of the feasibility of the Phoenix 1.5-mm atherectomy system, and a long-term re-assessment appeared to be urgently needed to examine the impact of this novel device. This study could not include information regarding long-term vascularization following intervention. Still, the ongoing wound healing process in the PAD stage-V patients is very promising. These findings were not similar to those published in the already mentioned meta-analysis. Here, a less favorable improvement of wound healing was observed. One explanation could reside in the difference regarding the performed therapy. In addition, it could underline the advantages of atherectomy over sole angioplasty in the BTK area, even though the literature showed no difference in the mortality and amputation rates. This study was carried out to examine the feasibility and patency of BTKA with the Phoenix atherectomy catheter in 1 center as a pilot study. This study added to already existing and promising outcomes of atherectomy systems in the above-the-knee arteries and could become an additional method for improving long-term patency. The impact of the high expertise of the performing interventionalist must be mentioned, while a relevant risk of a confounder as well as a lack of transferability may exist. Additional studies should examine the effectiveness of re-vascularization therapy compared to conservative treatment according to the current European Society for Vascular Surgery (ESVS) guidelines. However, this study supported the existing data on interventional success and safety in BTKA. Furthermore, not only did the mean ABIs increase significantly; there was also a remarkable shift toward lower PAD stages. In accordance with this, in this study, the most relevant clinical improvements could be observed in stage-V PAD patients. Although ABI and PAD stages are routinely used assessment tools for clinicians, other tools such as transcutaneous oxygen pressure or near-infrared (NIR) spectroscopy could also be helpful to gather more information to evaluate patient outcomes and therapeutic success. These could strengthen the described findings in future studies.
Drug-Coated Balloon Angioplasty for Dysfunctional Dialysis Arterio-Venous Fistula
The Society of Cardiovascular Angiography and Interventions (SCAI) performed an appropriate use review of common clinical presentations for peripheral artery disease (PAD) to determine the appropriateness for devices and strategies for re-vascularization (Klein et al, 2017). This document summarized new information updating the previous Appropriate Use Criteria (AUC) documents published for aorto-iliac, femoral-popliteal, infra-popliteal and renal arterial circulation. The intent was to improve clinical decision-making by practitioners, to improve patients' understanding of the potential risks and benefits of intervention, and to provide interventionalists with an updated review of the current literature regarding the most recent advances in the field of endovascular therapy (EVT). The following were noted:
- There have been significant technological advances and further development of the evidence base for the treatment of femoral-popliteal arterial lesions since the original SCAI appropriate use document was published.
- While drug-eluting stents (DES) and drug-coated balloons (DCB) have not been evaluated in iliac arteries, in highly selected cases, they may be useful in an appropriately sized vessel with in-stent re-stenosis
- The evidence supporting the use of DCB for infra-popliteal lesions is less certain.
Lookstein et al (2020) stated that standard PTA is the current recommended treatment for dysfunctional hemodialysis fistulas; however, long-term outcomes of this treatment are poor. Drug-coated balloons delivering the anti-restenotic agent paclitaxel may improve outcomes. In a prospective, single-blinded, 1:1 randomized trial, these researchers enrolled 330 participants at 29 international sites. Patients with new or re-stenotic lesions in native upper-extremity (UE) AVFs were eligible for participation. After successful high-pressure PTA (HP-PTA), participants were randomly assigned to receive treatment with a DCB or a standard balloon. The primary effectiveness end-point was TLPP, defined as freedom from clinically driven target-lesion re-vascularization (TLR) or access-circuit thrombosis during the 6 months after the index procedure. The primary safety end-point, serious adverse events (SAEs) involving the AV access circuit within 30 days, was assessed in a non-inferiority analysis (margin of non-inferiority, 7.5 percentage points). The primary analyses included all participants with available end-point data. Additional sensitivity analyses were carried out to evaluate the effect of missing data. A total of 330 participants underwent randomization; 170 were assigned to receive treatment with a DCB, and 160 were assigned to receive treatment with a standard balloon. During the 6 months after the index procedure, TLPP was maintained more often in participants who had been treated with a DCB than in those who had been treated with a standard balloon (82.2 % [125 of 152] versus 59.5 % [88 of 148]; difference in risk, 22.8 percentage points; 95 % confidence interval [CI]: 12.8 to 32.8; p < 0.001). DCBs were non-inferior to standard balloons with respect to the primary safety end-point (4.2 % [7 of 166] and 4.4 % [7 of 158], respectively; difference in risk, -0.2 percentage points; 95% CI: -5.5 to 5.0; p = 0.002 for non-inferiority). Sensitivity analyses confirmed the results of the primary analyses. The authors concluded that DCB angioplasty was superior to standard angioplasty for the treatment of stenotic lesions in dysfunctional hemodialysis AVFs during the 6 months after the procedure and was non-inferior with respect to access circuit-related SAEs within 30 days.
In a prospective, single-center, pilot study, Tan et al (2021) examined the use of a sirolimus DCB in the management of a thrombosed AV graft (AVG). This study was carried out between October 2018 and October 2019. A total of 20 patients (age of 67.0 years ± 10; male = 35 %; mean time on dialysis = 31 months) with thrombosed UE AVG were enrolled. After successful pharmaco-mechanical thrombectomy and adequate treatment of the graft vein junction, sirolimus DCB angioplasty was carried out at the graft vein junction. Subjects were followed-up for 6 months, and all AEs occurring during the study period were recorded. The primary circuit patency rates at 3 and 6 months were 76 % and 65 %, respectively, while the assisted-primary circuit patency rates at 3 and 6 months were 82 % and 65 %, respectively. The 3- and 6-month secondary circuit patency rates were 88 % and 76 %, respectively. Using Kaplan-Meier analyses, the estimated mean primary, assisted-primary, and secondary patencies were 285 days (95 % CI: 194 to 376 days), 319 days (95 % CI: 221 to 416 days), and 409 days (95 % C: 333 to 485 days). No AE directly related to sirolimus DCB use was observed. The authors concluded that the findings of this pilot study suggested that the use of sirolimus DCB at the graft vein junction after the successful thrombectomy of AVG may be a feasible option to improve patency outcomes.
These investigators stated that this study had several drawbacks. This was a single-center study with a small sample size (n = 20) that limited its power and generalizability. There may also have been a selection bias as only patients without no residual stenosis or thrombus after successful thrombectomy were treated with DCB. The use of a cutting balloon to treat elastic recoil in some patients may have confounded the final results as cutting balloon has been shown to statistically improve the 6-month assisted-primary patency of stenotic graft vein junction in a subgroup analysis of an RCT comparing cutting balloons and conventional balloons (86 % versus 56 %). However, in an RCT that included a thrombosed AVG, the use of a cutting balloon has been shown to provide an equivalent 6-month patency when compared to standard PBA (37.5 % versus 29.3 %). Nevertheless, the requirement for a cutting balloon in some of the patients has demonstrated the need to treat acute elastic recoils, which are often observed during the treatment of graft vein junction stenosis. This is crucial as the primary purpose of sirolimus is to retard neointimal hyperplasia and not elastic recoil. Hence, it is important to ensure that acute recoil is adequately treated to achieve an optimal luminal vessel diameter with either high pressure or a cutting balloon before the use of DCB to achieve the objective of maintaining the luminal diameter through retardation of neointimal hyperplasia. Furthermore, there was no control group to directly compare the benefits of DCB over plain balloon in thrombosed AVGs, and a comparison with historical data using other devices, such as a covered stent, would be difficult. Of note, the treatment of graft vein junction with stent grafts was convincingly superior to PBA in 3 large RCTs and should serve as the gold standard therapy for subsequent studies on AVG.
Holden et al (2022) presented the 12-month outcomes of the IN.PACT AV Access Study, a prospective, single-blind study enrolling participants with obstructive de-novo or re-stenotic native UE AV dialysis fistula lesions treated with a DCB or PTA. After successful high-pressure PTA, participants at 29 international sites were randomized 1:1 to treatment with an IN.PACT AV DCB (n = 170) or standard uncoated PTA (n = 160). Outcomes at 12 months include TLPP, defined as freedom from clinically driven TLR or access circuit thrombosis; access circuit primary patency; number of re-interventions; and AEs involving the access circuit. At 12 months, TLPP was 63.8 % (90/141) in the DCB group compared with 43.6 % (61/140) in the PTA group (p < 0.001). The total number of re-interventions required to maintain TLPP through 360 days was 93 in the DCB group and 144 in the PTA group, with a 35.4 % reduction in re-interventions when DCB was used. Access circuit thrombosis occurred in 2.9 % (4/138) of the participants in the DCB group and in 6.2 % (8/129) of those in the PTA group (p = 0.19). Time to TLPP was assessed using a multi-variable analysis to identify the factors associated with loss of patency. The treatment device was the independent predictor with the largest effect, with a HR of 0.42 (95 % CI: 0.29 to 0.60; p < 0.001). The authors concluded that TLPP was statistically significantly higher with DCBs than with standard PTA at 12 months, showing the sustained and superior effectiveness of this device for the treatment of dysfunctional AV dialysis fistulae. Level of Evidence = II.
The authors stated that the drawbacks of this trial included the small sample size and short-term outcome; these researchers stated that longer-term outcomes will continue to be reported. Target lesions with stents or access circuits with a history of or current thrombosis were excluded from the trial. Furthermore, subjects were not blinded to their treatment device after 6 months. This trial included no grafts or target lesions in the central veins. DCBs had a significantly higher rate of TLPP and ACPP at 12 months, as a result of having fewer re-interventions. These investigators noted that these is a need for studies to report long-term outcomes of re-interventions to treat dysfunctional fistulae, especially given that few studies have examined long-term assisted patency or reported outcomes during a fistula’s entire life cycle from creation to abandonment. Furthermore, additional investigations examining device-specific treatment characteristics and procedural techniques are needed to optimize patient outcomes during a given intervention to ensure translation to successful dialysis.
Zhuang et al (2023) stated that AV fistula (AVF) stenosis is a common problem leading to dialysis access dysfunction. The conventional balloon (CB) is the most commonly used device during angioplasty but suffers from poor durability of results due to neointimal hyperplasia-mediated recurrence. The DCB is an adjunct to balloon angioplasty that reduces neointimal hyperplasia; thus, improving post-angioplasty patency. Despite the heterogeneity of DCB clinical trials to-date, the evidence suggested that DCBs of different brands are not necessarily equal, and that patient selection, adequate lesion preparation as well as proper DCB procedural technique are important to realize the benefit of DCB angioplasty.
Zhang et al (2023) noted that DCBs have been used in dialysis patients with AVF stenosis; however, whether DCBs have advantages over CBs is still controversial. In a meta-analysis, these investigators examined the safety and effectiveness of DCBs and CBs in the treatment of AVF stenosis. They searched the PubMed, Embase, and China National Knowledge Internet (CNKI) databases for RCTs that compared the effectiveness of DCB angioplasty versus CB angioplasty for AVF stenosis in dialysis patients and reported at least 1 outcome of interest. The results showed that the DCB group had a higher 1st-stage patency rate of the target lesion at 6 months (OR = 2.31, 95 % CI: 1.69 to 3.15, p < 0.01) and at 12 months (OR = 2.09, 95 % CI: 1.50 to 2.91, p < 0.01) after surgery. There was no statistically significant difference in all-cause mortality between the 2 groups at 6 months (OR = 0.85, 95 % CI: 0.47 to 1.52, p = 0.58), and at 12 months (OR = 0.99, 9 5% CI: 0.60 to 1.64, p = 0.97). The authors concluded that compared with CB, DCB as a new endovascular treatment for AVF stenosis exhibited a higher primary patency rate of target lesions and could delay the occurrence of re-stenosis. These researchers noted that currently there is no evidence that DCB could increase the mortality of patients; however, further clinical studies are needed to determine its mid‐ and long‐term safety and effectiveness in the treatment of AVF stenosis. These investigators believed that future studies should optimize the application technology according to specific vascular access types or lesion characteristics and clarify the role of DCBs in hemodialysis vascular access management.
The authors stated that this meta‐analysis had several drawbacks. First, the true event rates of subjects lost to follow‐up were unpredictable, and unlikely to be at either extreme end of their assumptions. Second, the paclitaxel doses were variable in studies analyzed, which could have affected the conclusions. Third, the concomitant diseases of patients included in various institutes were different, which may have resulted in a risk of bias. Fourth, this meta‐analysis did not include a particularly large number of RCTs and could have affected the conclusions.
DePietro and Trerotola (2023) noted that DCBs seek to inhibit re-stenosis in treated hemodialysis access lesions by delivering an anti-proliferative agent (paclitaxel) into the vessel wall. While DCBs have proven effective in the coronary and peripheral arterial vasculature, the evidence for their use in AV access has been less robust. In part two of this review, these investigators carried out a comprehensive overview of DCB mechanisms, implementation, and design, followed by an examination of the evidence basis for their use in AV access stenosis. They carried out an electronic search was on PubMed and Embase to identify relevant RCTs comparing DCBs and plain balloon angioplasty from January 1, 2010 to June 30, 2022 published in English. Many DCBs have been developed, each with unique properties, although the degree to which these differences impact clinical outcomes is unclear. Target lesion preparation, achieved by pre-dilation, and balloon inflation time have proven important factors in achieving optimal DCB treatment. Many RCTs have been performed, but have suffered from significant heterogeneity, and have often reported contrasting clinical results, making it difficult to draw conclusions on how to implement DCBs in daily practice. On the whole, it is likely there is a population of patients who benefit from DCB use, but it is unclear which patients benefit most and what device, technical, and procedural factors lead to optimal outcomes. More importantly, the use of DCBs appeared safe in the ESKD population. The authors concluded that DCB implementation has been tempered by the lack of clear signal regarding the benefits of DCB use. As further evidence is obtained, it is possible that a precision-based approach to DCBs may shed light onto which patients will truly benefit from DCBs. Until that time, the available evidence may serve to guide interventionalists in their decision-making, knowing that DCBs appear safe when used in AV access and may provide some benefit in certain patients.
Lookstein et al (2023) presented the 36-month outcomes of the prospective randomized IN.PACT AV Access study of participants with obstructive de-novo or re-stenotic native UE AVFs lesions treated with DCBs or standard PTA following successful HP-PTA. (The earlier results of this trial were described by Lookstein et al (2020) described above.) Participants at 29 international sites were randomized 1:1 to receive an IN.PACT AV DCB (n = 170) or undergo PTA (n = 160). The outcomes through 36 months included TLPP and access circuit primary patency (ACPP) (composites of clinically driven target lesion or access circuit re-vascularization and/or access circuit thrombosis), number of re-interventions, and SAEs involving the access circuit. TLPP was 52.1 % in the DCB group compared with 36.7 % in the PTA group through 24 months, and 43.1 % in the DCB group compared with 28.6 % in the PTA group through 36 months (both log-rank p < 0.001). ACPP was 39.4 % in the DCB group compared with 25.3 % in the PTA group through 24 months, and 26.4 % in the DCB group compared with 16.6 % in the PTA group through 36 months (both log-rank p < 0.001). Cumulative incidence of access circuit thrombosis through 36 months was 8.2 % in the DCB group compared with 18.3 % in the PTA group (log-rank p = 0.040). Cumulative incidence of mortality through 36 months was 26.6 % in the DCB group compared with 30.8 % in the PTA group (log-rank p = 0.71). The authors concluded that In this study, the DCB cohort had significantly higher TLPP and ACPP rates than the PTA cohort through 36 months and at every previously reported time-point. Because the incidence of mortality was similar and increased access circuit thromboses were observed in the PTA group in the long-term, this DCB demonstrated durable and consistent safety and effectiveness outcomes in the 36-month period following index treatment. The body of evidence supporting the outcomes and economic feasibility of DCB treatment for dysfunctional fistulae is compelling and suggested the use of IN.PACT AV DCB as a suitable option for routine AVF maintenance in patients with end-stage kidney disease (ESKD). Level of Evidence = II. This study was sponsored by Medtronic.
The authors stated that the drawbacks of this study included: (i) patient attrition from 24- to 36-month outcomes; (ii) patients who had target lesions located in grafts or central veins or within a stent were excluded from the study; and (iii) a history of or current access circuit thrombosis was also an exclusion criterion.
Chen et al (2023) stated that balloon angioplasty could decrease re-stenosis of hemodialysis vascular access. These investigators compared the safety and effectiveness of commonly available balloon angioplasty techniques for treating patients with failing autogenous AVFs and AVGs stenosis. They carried out a comprehensive literature search, including an updated search of PubMed and Embase (via Ovid) and screening of published meta-analyses. Primary patency at 6 and 12 months was the primary outcome, and the incidence of complications was the secondary outcome. The random-effects model was used to conduct all statistical analyses, which were performed using RevMan 5.3 and ADDIS 1.16.8. A total of 20 eligible studies entailing 4 balloon angioplasty techniques were entered into the final analysis. Although the direct meta-analysis indicated that cutting balloon angioplasty (CtBA) significantly improved primary patency at 6 [odds ratio (OR), 1.91; 95 % CI: 1.27 to 2.86] and 12 (OR, 1.56; 95 % CI: 1.13 to 2.15) months compared with conventional balloon angioplasty (CBA), this was not supported by network meta-analysis, which suggested that CtBA was associated with a higher risk of complications compared with DCB angioplasty (DCBA) [OR, 0.05; 95 % credible interval (CrI): 0.00 to 0.83], high-pressure balloon angioplasty (HBA) (OR, 0.04; 95 % CrI: 0.00 to 0.69), and CBA (OR, 0.11; 95 % CrI: 0.02 to 0.59). Subgroup analysis of AVFs did not detect any significant differences. The authors concluded that in failing AVF and AVG stenosis, HBA might be a preferential option as it is related to a lower risk of complications and has numerically higher primary patency than DCBA and CBA. These researchers stated that further studies are needed to confirm these findings.
The authors stated that this network meta-analysis had several drawbacks. First, most eligible studies included in this network meta-analysis only enrolled a limited sample size, which might introduce a small sample bias. Second, doses of paclitaxel were different from one to another, and most eligible studies did not provide information on the dose; thus, performing subgroup analyses to examine the impact of dose on pooled results was not possible. Third, eligible studies included in this network meta-analysis comprised combinations of various AVF configurations and de-novo lesions with recurrent ones; however, subgroup analysis could not be designed due to limited data, which may impair the reliability of the pooled results. Fourth, the majority of eligible studies were judged with a high risk of bias, which may inevitably impair the robustness and reliability of these findings.
An UpToDate review on “Endovascular intervention for the treatment of stenosis in the arteriovenous access” (Beathard, 2023a) states that “Drug-eluting balloon angioplasty -- Drug-eluting (i.e., paclitaxel-coated) balloons have been used to prevent restenosis after arterial angioplasty with good results, and their use has been extended to the treatment of venous stenosis associated with hemodialysis AV access. The available data support drug-eluting angioplasty (DEA); however, other issues such as cost and potential long-term effects should be considered. Nevertheless, DEA for the treatment of rapidly recurring lesions appears warranted, particularly for those lesions occurring within the cannulation zone where stent use is avoided. Several trials have compared DEA balloons (paclitaxel) with standard high-pressure balloon angioplasty (HPA). In general, these have shown improved lesion patency with DEA at 6 months and 1 year, though there has been some variability … There has been some evidence to suggest that paclitaxel-coated devices may contribute to excess mortality in patients with peripheral artery disease, and caution is advised. In view of this information, a systematic review and meta-analysis compared mortality rates in hemodialysis patients treated with DEA versus HBA. Among 8 studies that included 327 DEA cases and 331 HBA cases, mortality was similar at a mean follow-up of 13.5 months (13.8 % versus 11.2 %, respectively)”.
Furthermore, an UpToDate review on “Primary failure of the hemodialysis arteriovenous fistula” (Beathard, 2023b) states that “Most endovascular treatment reports involve simple percutaneous angioplasty using a plain balloon; however, the use of drug-coated balloons and stents have also been reported. Reports often mix forearm and upper arm accesses, but a few reports have specifically evaluated juxta-anastomotic stenosis … Several small single-center studies have shown the feasibility of using a drug-coated balloon in treating venous stenosis lesions to improve the outcome as compared with standard balloon angioplasty. The results of the studies have been variable. One prospective, multicenter trial compared treatment with a paclitaxel-coated balloon with standard angioplasty. The results obtained with the drug-coated balloon were statistically superior, but it did not report results for the juxta-anastomotic stenosis lesion separately”.
The DETOUR System for the Treatment of Peripheral Arterial Disease
Krievins et al (2018) stated that long segment occlusive disease in the superficial femoral artery remains a treatment challenge despite advances in open surgical and endovascular approaches. These investigators reported initial clinical results of an entirely new procedure to carry out percutaneous FP bypass using the DETOUR System. First-in-human patients were conducted in New Zealand from December 2013 to June 2014. After modifications to the technique and devices had significantly refined the procedure, the Detour I Trial commenced. These researchers carried out a review of initial results in the first 5 patients treated at a single center enrolled in IRB-approved, prospective clinical study using the DETOUR System. All patients signed informed consent with planned 2-year follow-up. The DETOUR System was used to create a stent graft bypass which originates in the SFA, travels through the femoral vein, and ends in the popliteal artery, bypassing the diseased segment. A cohort of patients were treated in Latvia from January 2015 to October 2015. The initial 5 patients in this cohort (age of 67.2 ± 11.4 years) with long femoral artery occlusions (29.5 ± 14.1 cm) were treated at a single clinical site. TORUS stent grafts were successfully implanted in all 5 patients (100 %) using an 8F delivery system. There were no peri-operative 30-day MAEs (death, major bleeding, DVT, TVR, or major amputation) observed. At 24-month follow-up, the primary patency rate was 80 % (4/5) and primary assisted patency was 100 % (5/5). Significant improvement in ABI and Rutherford class were observed in all patients. There was a single secondary procedure performed in these patients (proximal stent edge stenosis at 24 months). The venous function has not been damaged or compromised in any patient. The authors concluded that early results suggested that properly-selected patients with long-segment occlusive disease above the knee could be safely treated using the DETOUR System for percutaneous bypass, with favorable clinical outcomes extending to 2 years. Moreover, these researchers stated that further investigations are needed to examine the role of this approach in the treatment of long femoral lesions.
Schneider et al (2021) noted that the DETOUR 1 Trial was carried out to examine the safety of the femoral vein as a "pass through" conduit for covered stent placement during fully percutaneous FP bypass, also known as the DETOUR procedure. At 8 participating centers in this prospective, single-arm, international trial, 78 patients (82 FP lesions) were enrolled. All patients had patent femoral veins measuring 10 or larger mm in diameter at baseline. The DETOUR procedure involved delivery of a series of TORUS stent grafts, deployed from contralateral common femoral artery access to the ipsilateral proximal superficial femoral artery, with entry into the femoral vein and re-entry into the arterial vasculature at the above-the-knee popliteal artery. The TORUS stent grafts were deployed in an overlapping configuration as an arterial-arterial conduit. Due to this novel trans-venous approach, these investigators examined specific considerations related to the venous system to analyze the risk of venous thrombo-embolic complications. Symptomatic DVT, non-occlusive material associated with the graft such as benign endovenous graft-associated material, pulmonary embolism, Venous Clinical Severity Score (VCSS) and Villalta scores, and luminal occupancy by the stent graft were assessed as the ratio of cross-sectional areas (CSAs) of the stent graft to the native vein at baseline and 1 year after the procedure. A duplicate femoral vein was present in 20.7 % of cases. The majority of patients (86.8 %) had a femoral vein luminal area preservation of 55 % or higher; 32 patients experienced an increase in the vein diameter over time after the procedure; however, this pattern of venous remodeling was not uniform. Subjects who had a compensatory increase in the vein diameter had a smaller average baseline vein diameter compared with subjects who did not have a compensatory increase in the diameter of the vein (p = 0.0414). Only 2 patients (2.4 %) developed ipsilateral symptomatic DVT through 1 year of follow-up. There were no pulmonary embolism in any patient in the series. The overall VCSS and Villata scores did not change during follow-up. Mean VCSS and Villata were 0.8 ± 1.4 and 0.5 ± 1.1 at 1 year, compared with 0.6 ± 1.0 and 0.4 ± 0.9 at baseline, respectively. The authors concluded that the 1-year safety and effectiveness data from the DETOUR I Trial showed a promising percutaneous alternative to FP surgical bypass and the associated venous outcomes data suggested the trans-venous route is a good choice for a percutaneous bypass with minimal adverse venous sequelae. Moreover, it should be noted that the study sponsor (PQ Bypass, Milpitas, CA), although not involved in the data analysis or interpretation, was involved in the study design and data acquisition.
In a prospective, single-arm, multi-center study, Halena et al (2022) examined the 2-year safety and effectiveness of the PQ Bypass DETOUR system as a percutaneous FP bypass. A total of 78 patients with 82 long-segment FP lesions were enrolled in this trial. The DETOUR system deployed Torus stent grafts directed via a trans-venous route. Eligible patients included those with lesions of greater than 10 cm and average of 371 ± 55 mm. Key safety endpoints included MAEs and symptomatic DVT in the target limb. Effectiveness endpoints included primary patency defined as freedom from 50 % or greater stenosis, occlusion, or clinically-driven TVR (CD-TVR), primary assisted, and secondary patency. Chronic total occlusions and severe calcium occurred in 96 % and 67 % of lesions, respectively. Core laboratory-assessed total lesion length averaged 371 ± 51 mm with a mean occlusion length of 159 ± 88 mm. The rates of technical and procedural success were 96 %, with satisfactory delivery and deployment of the device without in-hospital MAEs in 79/82 limbs. The MAE rate was 22.0 %, with 3 unrelated deaths (4 %), 12 CD-TVRs (16 %), and 1 major amputation (1 %). DVT developed in 2.8 % of target limbs, and there were no reported pulmonary emboli. Primary, assisted primary, and secondary patency rates by the Kaplan-Meier analysis were 79 ± 5 %, 79 ± 5 %, and 86 ± 4 %, respectively. The authors concluded that the 2-year data from the DETOUR study suggested that the technology offers a promising percutaneous option for patients with symptomatic long-segment FP occlusive disease. Mid-term patency rates were favorable, and complications including venous thromboembolic disease were relatively infrequent. These researchers noted that these mid-term results confirmed the safety and effectiveness of the system as a viable solution for patients with complex FP disease who would otherwise be poor candidates for open surgical re-vascularization.
The authors stated that the potential drawbacks of the DETOUR study included the inability to find a single, fair comparator device, since the DETOUR system is the 1st of its kind. Given the mechanics of the device, it was expected to carry a very different effectiveness profile as compared to standard endovascular therapy (EVT) such as plain balloon angioplasty or even arterial stents in the treatment of more complex lesions. Furthermore, noting the minimally invasive mechanism of deployment, it was difficult to compare safety outcomes of the DETOUR system to the highly invasive open bypass. Comparisons of the DETOUR system to alternative therapies were limited to literature-reported data generated from distinct patient groups. An additional drawback of the study was the inclusion of 4 patients with bilateral treatment; a design feature that might confound the analysis to the extent that outcome in the 2 sides was correlated. Finally, clinical considerations of how the device affected the venous circulation, including complications of the AV connection, symptomatic DVT versus non-occlusive venous material associated with the graft, and the venous luminal preservation will need more thorough assessment.
Mosarla et al (2022) stated that PAD is an increasingly prevalent condition with significant associated morbidity, mortality, and healthcare expenditure. Endovascular interventions are appropriate for most patients with either ongoing symptoms of intermittent claudication despite lifestyle and medical optimization or chronic limb-threatening ischemia (CLTI). The femoro-popliteal segment is the most common arterial culprit responsible for claudication and the most commonly re-vascularized segment. Endovascular approaches to re-vascularization of the femoro-popliteal segment are advancing with an evolving landscape of techniques for arterial access, device-based therapies, vessel preparation, and intra-procedural imaging. These advances have been marked by debate and controversy, notably related to the safety of paclitaxel-based devices and necessity of atherectomy. These investigators provided a critical overview of the current evidence, practice patterns, emerging evidence, and technological advances for endovascular intervention of the femoro-popliteal arterial segment. Moreover, these investigators stated that percutaneous femoro-popliteal bypass may become a viable option for treating complex femoro-popliteal artery disease, avoiding the need for surgical re-vascularization. The PQ Bypass PQ Bypass Systems for Femoro-popliteal Bypass (DETOUR) System entails the use of the ipsilateral femoral vein to placed covered stent grafts as a conduit bypassing the SFA lesion. The safety and effectiveness of this device has been demonstrated in the DETOUR I Trial, with rates of primary, assisted primary, and secondary patency rates of 81 % ± 4 %, 82 % ± 4 %, and 90 % ± 3 %, respectively, and low rates of adverse events (AEs) in complex lesions. These promising findings have prompted FDA approval as a break-through device, and the larger scale DETOUR II Clinical Study is ongoing.
Sarradon et al (2023) described the technique and early results of lower extremity re-vascularization with total percutaneous bypass using extra-vascular placement of a stent graft (percutaneous prosthetic bypass). Patients with severe CLTI for whom open or endoluminal repair was either not feasible and/or had failed were selected for a pilot study using percutaneous prosthetic bypass. The procedure requires placement of 3 introducer sheaths in the contralateral common femoral artery, and the ipsilateral proximal, and distal superficial femoral arteries (SFAs). A guide-wire was placed from the contralateral sheath to the ipsilateral popliteal artery via the 2 ipsilateral sheaths. Two self-expanding polytetrafluoroethylene-covered stents were then placed from the proximal SFA to the distal SFA. A total of 30 bypasses were performed in 28 patients aged 71 ± 3 years. Of the 28 patients, 16 had severe claudication (Rutherford class 3; 53 %) and 14 had critical ischemia (Rutherford class 4 to 6; 47 %). The early results were excellent, with no deaths and 1 occlusion successfully treated with thrombolysis. No other complications requiring re-intervention occurred. The mean follow-up was 25.4 months (range of 3 to 36 months). The 12- and 36-month Kaplan-Meier survival curve was 100 % and 81 %, respectively. The primary patency, secondary patency, and freedom from amputation rates were 75 % and 75 %, 78 % and 75 %, and 100 % and 91 %, respectively. The authors concluded that for patients with long lesions and/or failed endovascular treatment, the described technique offered the advantage of a total percutaneous procedure with acceptable early results. These researchers stated that if these favorable outcomes were confirmed in larger series with longer follow-up, percutaneous extravascular bypass of the SFA will represent a complementary tool for infra-inguinal arterial repair.
The authors stated that the technique they described in this study differs from those reported previously. The DETOUR System (Endologix), whose results have been reported by Krievins et al (2020) was composed of a PQ crossing device, a PQ snare, and a Torus stent graft, which is a self-expanding nitinol wire frame encapsulated in expanded polytetrafluoroethylene. The delivery catheter is an over-the-wire 8F system. The crossing system allows for passage from the stump of the SFA into the superficial femoral vein from the contralateral side. A 0.014-in wire was snared by the PQ snare introduced from the tibial vein. Next, re-entry from the vein to the artery below the occlusion was created, allowing for placement of the covered stent. However, these investigators believe that the DETOUR System, when available on the market, might be more expensive than other existing techniques. Furthermore, the use of the deep femoral artery as the donor site exposes the limb to the risk of severe ischemia in case of bypass occlusion. additionally, the reported patency and limb salvage rates were inferior to the findings of this study. These researchers also noted that considering the short- and mid-term results reported by previous studies with significant numbers of patients and follow-up duration, the DETOUR System showed 96 % technical success, a Kaplan-Meier primary patency of 81 % ± 4 % at 1 year, and 94 % ± 3 % for secondary patency, with improved clinical status and few vein-related complications. Di Primio et al (2019) reported a 13 % procedure-related complication rate, including 1 death and a rate of peri-procedural hemorrhage at puncture sites requiring transfusion of 13 %. The mean follow-up was 21 months, with amputation-free survival of 80 % at 1 year, and 53 % at the last visit. The 1-year cumulative primary and secondary patency rates were 30 % and 60 %, respectively. These comparisons should be considered with caution before drawing firm conclusions, given the differences in patient selection, comorbidities, Rutherford status, and lesion type.
Drug-Coated Balloon Alone or in Combination with Atherectomy for the Treatment of Femoro-Popliteal Lesions
Cai et al (2020) noted that the "leave nothing behind" strategies have been becoming a popular treatment for FP arteriosclerosis obliterans. Atherectomy before DCB angioplasty may have an advantage in improving the effectiveness of drug delivery into the blood vessel wall. In a prospective, single-center RCT, these researchers compared the therapeutic effects of directional atherectomy combined with DCB angioplasty with DCB angioplasty alone in the treatment of FP arteriosclerosis obliterans. Patients with FP arteriosclerosis obliterans who received endovascular therapy from June 2016 to June 2018 in the authors’ hospital and presented with life-limiting claudication or severe CLI comprised the study cohort. Subjects were randomized to receive directional atherectomy combined with DCB angioplasty (n = 45) or DCB alone (n = 49). A total of 94 patients were enrolled in this trial with 72 men, and the mean age was 67 ± 10 years. The mean lesion length was 112 ± 64 mm. There were no significant differences in the baseline characteristics of patients and lesions between the 2 randomized groups (p > 0.05). Flow-limiting dissections occurred more frequently in the DCB group (n = 12; 24.5 %) than in the DA-DCB group (n = 2; 4.4 %; p = 0.006). The technical success rate in the DA-DCB group was superior to that in the DCB group (95.6 % versus 75.5 %, p = 0.006). The mean follow-up duration was 16.7 ± 6.1 months in the DCB group and 15.3 ± 5.8 months in the DA-DCB group. No amputations were performed. The overall mortality in the DCB group was 4.1 % (2/49), while all patients survived in the DA-DCB group. The 12-month and 24-month primary patencies in the DA-DCB group were greater than those in the DCB group (80.5 % versus 75.7 %; and 67.1 % versus 55.1 %, respectively); however, using all available patency data, no significant differences over time were observed (p = 0.377). The authors concluded that in this study, directional atherectomy combined with DCB angioplasty could decrease the flow-limiting dissection rate in the treatment of FP arteriosclerosis obliterans compared with DCB angioplasty alone. There was no significant difference between the 2 groups in terms of primary patency rate, which needed to be further clarified. The authors stated that the principal drawback of this study was the small sample size, and some patients’ follow-up did not reach 24 months; thus, was necessary to expand the sample size and perform a long-term follow-up study.
Dukic et al (2023) stated that the presence of severe arterial calcification is associated with less favorable outcomes in terms of procedural and clinical success as well as higher rates of major adverse limb events (MALEs). Recent studies incorporating rotational atherectomy for effective preparation of severely calcified lesions showed beneficial procedural outcomes by obtaining maximal luminal gain and improved long-term outcomes. In a prospective, observational, single-center study, patients with severely calcified FP lesions with CLI Rutherford 1 to 5 between January 2017 and July 2019 underwent atherectomy using the Jetstream Atherectomy system, followed by DCB angioplasty. Lesion calcification was categorized by the Peripheral Arterial Calcium Scoring System (PACSS), whereas lesion complexity was classified by the TASC. Safety and effectiveness aspects in terms of vessel injury, thrombo-embolism, and clinical success were systematically analyzed up to 12 months of follow-up (FU). A total of 162 consecutive patients (210 non-stented and 22 stented lesions) were treated; 12 (7.4 %) patients received bail-out stenting. Mean lesion length was 24.2 ± 4.8 cm; 51 % were chronic total occlusions (mean occlusion length 18.2 ± 5.1 cm). TASC-C lesions were present in 38 patients (23.5 %) and TASC-D lesions in 124 patients (76.5 %). The mean PACCS score was 3.3 ± 0.9. Device success was achieved in 88 %; procedural success was noted in 99 % of the lesions. Embolic protection device was used in 11.7 %; no perforation or dissection was observed. Asymptomatic peripheral embolization was noted in 10 patients (6.2 %). Clinical FU at 12 months was available in 157 of 162 patients (96.9 %). At 12-month FU, mean Rutherford classification at baseline of 3.7 ± 0.6 significantly dropped to 1.0 ± 0.9 (p < 0.05); baseline mean ABI of 0.4 ± 0.1 significantly increased to 0.8 ± 0.2 (p < 0.05); 92.6 % were free from TLR, 95.1 % were free from TVR); and binary re-stenosis measured by Duplex US occurred in 22 patients (13.6 %). Multi-variate analyses showed lesion length as predictive of stent placement (p = 0.02), whereas both lesion length (p = 0.006) and PACCS score (p = 0.02) were predictive of clinical success. The authors concluded that Jetstream rotational atherectomy in combination with DCB could be safely performed in long, calcified (non-)occlusive lesions with a relatively low rate of bail-out stenting and favorable clinical mid-term results.
Koeckerling et al (2023) noted that optimal endovascular management of IC remains disputed. In a systematic review and meta-analysis, these investigators compared the safety and effectiveness of BA, BMS, DCB, DES, covered stents, and atherectomy. They searched electronic databases for RCTs from inception through November 2021. Effectiveness outcomes were primary patency, TLR, and QOL. Safety endpoints were all-cause mortality and major amputation. Outcomes were evaluated at short-term (less than 1 year), mid-term (1 to 2 years), and long-term (2 years or longer) follow-up. A total of 51 RCTs enrolling 8,430 patients/lesions were included. In FP disease of low-to-intermediate complexity, DCBs were associated with higher likelihood of primary patency (short-term: OR 3.21, 95 % CI: 2.44 to 4.24; long-term: OR 2.47, 95 % CI: 1.93 to 3.16), lower TLR (short-term: OR 0.33, 95% CI 0.22-0.49; long-term: OR 0.42, 95% CI 0.29-0.60) and similar all-cause mortality risk, compared with BA. Primary stenting using BMS was associated with improved short-to-mid-term patency and TLR, but similar long-term effectiveness compared with provisional stenting. Mid-term patency (OR 1.64, 95 % CI: 0.89 to 3.03) and TLR (OR 0.50, 95 % CI: 0.22 to 1.11) estimates were comparable for DES versus BMS. Atherectomy, used independently or adjunctively, was not associated with effectiveness benefits compared with drug-coated and uncoated angioplasty, or stenting approaches. Paucity and heterogeneity of data precluded pooled analysis for aorto-iliac disease and QOL endpoints. The authors concluded that certain devices may provide benefits in FP disease; however, comparative data in aorto-iliac arteries is lacking. These researchers stated that gaps in evidence quantity and quality impede identification of the optimal endovascular approach to IC.
In a retrospective, cohort study, Yang et al (2024) examined the outcomes of a BMS, DCB alone, atherectomy plus a DCB (AT + DCB) and AT alone for the treatment of FP artery occlusion. Four groups were included: 119 patients underwent the BMS procedure, 89 patients underwent DCB alone, 52 patients underwent AT + DCB, and 61 patients underwent AT alone. Patients were followed-up at 1, 6, 12 and 24 months after the procedure, the clinical outcomes and complications were assessed, and the primary outcomes were primary patency and re-stenosis. AT + DCB showed a lower bailout stent, and BMS displayed a higher retrograde puncture, flow-limiting dissection, and post-dilation (p < 0.05). For all procedures, the walking distance, ABI, and pain score post-procedure were significantly improved compared with the pre-procedure values (p < 0.001). The re-stenosis rate was higher in BMS (21.0 %) and AT alone (24.6 %) than in DCB (10.1 %) alone and AT + DCB (11.5 %) (p = 0.04); there was no difference in amputation or clinically driven TLR among procedures. The primary patency rates were 77.7 %, 89.4 %, 88.0 %, and 73.7 % in the BMS, DCB alone, AT + DCB and AT alone groups at 24 months, respectively (p = 0.03), while the secondary patency and main AEs (stroke, MI, and death) were similar. Proximal concavity, proximal target vessel diameter of 5 mm or greater, run-off number of 2 or higher, and DCB use were protective factors for primary patency. The authors concluded that the findings of this study suggested the DCB procedure (combined with/without AT) demonstrated higher primary patency and that the AT combined with DCB procedure exhibited a lower incidence of flow-limiting dissection and bailout stenting; therefore, DCB devices (combined with/without AT) should be the 1st therapeutic choice for patients with FP lesions. Moreover, these researchers believed that this study could provide some evidence for the debate on the best procedure for FP occlusion.
The authors stated that although this trial carried out a head-to-head comparison of the 4 procedures of BMS, DCB alone, AT + DCB, and AT alone on FP occlusion lesions, there were several drawbacks. First, this trial was not a prospective RCT, and its results may be affected by potential confounding factors. Second, this study was not a multi-center data analysis, and the selection bias of patients and devices used may affect the generalizability of the conclusions. Third, this study did not include all the devices being used; therefore, these findings need further verification. These investigators stated that their conclusions still need to be confirmed by prospective, large-sample, multi-center RCT in the future.
Laird et al (2019) observed that, while randomized trials have demonstrated the superiority of drug-coated balloon (DCB) angioplasty versus standard percutaneous transluminal angioplasty (PTA) in patients with femoro-popliteal peripheral artery disease, the long-term durability of DCB angioplasty remains uncertain. The investigators reported on IN.PACT SFA, a prospective, multicenter, randomized single-blinded trial (Randomized Trial of IN.PACT Admiral Paclitaxel-Coated Percutaneous Transluminal Angioplasty [PTA] Balloon Catheter vs Standard PTA for the Treatment of Atherosclerotic Lesions in the Superficial Femoral Artery [SFA] and/or Proximal Popliteal Artery [PPA]) that enrolled 331 subjects with symptomatic (Rutherford 2-4) femoro-popliteal lesions. Subjects were randomly assigned 2:1 to the IN.PACT Admiral DCB or PTA. Assessments through 5 years included freedom from clinically driven target lesion revascularization, the primary safety end point, and major adverse events. Through 5 years, patients treated with the IN.PACT Admiral DCB demonstrated a sustained treatment effect with superior freedom from clinically driven target lesion revascularization when compared with PTA (Kaplan-Meier estimate of 74.5% versus 65.3%; log-rank P=0.020). The primary safety composite was achieved in 70.7% of subjects in the DCB and 59.6% in the PTA groups ( P=0.068). The major adverse event rate was 42.9% for DCB and 48.1% for PTA ( P=0.459). There were no device- or procedure-related deaths in either group as adjudicated by an independent and blinded Clinical Events Committee. The investigators concluded that the IN.PACT SFA randomized trial demonstrates that the IN.PACT Admiral DCB continues to perform better than PTA through 5 years with higher freedom from clinically driven target lesion revascularization. They stated that the sustained safety and effectiveness profile of this DCB supports its use as a preferred treatment choice compared with PTA for femoro-popliteal lesions.
An accompanying editorial (Banerjee & Shishehbor, 2019) noted that the investigators reported the proportion rates for clinically driven target lesion revascularization and other outcomes; however, this method does not properly account for censoring or withdrawal, nor does it take into account the timing of events, and is consequently less powerful. The Kaplan-Meier estimates and accompanying log-rank test account for censoring, dropout, and the timing of events and is thus slightly more sensitive to differences between groups; hence, we see P=0.02 for the log-rank test while the simplistic comparison of proportion rates returns P=0.08 for what is essentially the same outcome. The editorialist noted that this is also an issue in the reporting of the primary safety composite end point (70.7% and 59.6% subjects in the DCB and PTA groups, respectively; P=0.068), and Kaplan-Meier estimates for the same end point of 70.9% for the DCB and 60.5% for the PTA groups (log-rank P=0.012). The editorialist also highlighted that five-year all-cause mortality rate was 15.8% in DCB, and 9.6% in PTA arms (P=0.156). The trial was principally designed based on the effect size of primary patency, and therefore, underpowered to detect a difference in all-cause death between the 2 treatment groups. Nevertheless, a transitory statistically significant increase in the year 2 and 3 mortality rate is observed with DCB versus PTA. The durable treatment effect demonstrated in this study may not most immediately translate into an incremental use of this DCB in clinical practice. The editorialist observed that patients at particularly high risk for restenosis are currently under-represented in the IN.PACT SFA RCT. The lack of a very favorable treatment effect in the subgroup of patients with diabetes mellitus may be viewed as an additional limitation.
Zeller, et al (2022) stated that numerous randomized controlled trials (RCTs) have demonstrated the superiority of paclitaxel drug-coated balloons (DCBs) over non-coated angioplasty balloons for treatment of femoropopliteal peripheral arterial disease (PAD). The investigators noted that there is a paucity of clinical evidence in more complex patients who are often excluded from RCTs and long-term data up to 5 years are very limited in PAD revascularization studies. The investigators reported on the 5-year outcomes from the prospective, single-arm, international IN.PACT Global Study. The IN.PACT Admiral DCB was evaluated for femoro-popliteal atherosclerotic disease treatment in a real-world patient population. The investigators reported that 1,535 patients were enrolled at 64 international sites. The prespecified clinical cohort included 1,406 patients with claudication or rest pain. Patients were evaluated up to 5 years for the occurrence of adverse events and clinically driven target lesion revascularizations (CD-TLR). The mean lesion length was 12.1±9.5 cm in 1,774 lesions, 18.0% had in-stent restenosis, 35.5% were total occlusions and 68.7% were calcified. Per independent clinical events committee adjudication, the Kaplan-Meier estimate of freedom from CD-TLR up to 5 years was 69.4%, and the restricted mean survival time to first CD-TLR was 1,470.1 days. Outcomes were similar for males and females; freedom from CD-TLR was 69.1% in females and 69.6% in males (p=0.602). The cumulative incidence of major adverse events for the clinical cohort was 45.9% and freedom from all-cause mortality with the vital status update was 78.9% up to 5 years. The authors concluded that the IN.PACT Admiral DCB demonstrated safe and durable outcomes in real-world participants with complex femoro-popliteal disease.
An accompanying commentary (Secemsky and Korjian, 2022) stated that some limitations of this study should be highlighted. Although complex calcified lesions may require the use of adjunctive atherectomy, this was not allowed in this study. Furthermore, provisional stenting was used in 1 out of 5 patients. Despite not being independently associated with clinically driven TLR, the inclusion of this subset of patients added a layer of complexity when interpreting the outcomes. The single-arm nature of the study also limited the ability to draw major conclusions. The authors referenced previous trials and historical controls to provide some insights; however, comparisons were limited due to the differences in populations studied, and conclusions regarding these differences were speculative. Furthermore, there was a significant proportion of missing data at 5 years (approximately 15 %), which was to be expected with a registry study, but may added bias to the reported findings.
Appendix
Stage | Clinical Description | Objective Criteria |
---|---|---|
0 | Asymptomatic (no hemodynamically significant occlusive disease) | Normal treadmill or reactive hyperemia test |
1 | Mild claudication | Completes treadmill exercise; ankle pressure (AP) after exercise >50 mmHg but at least 20 mmHg lower than resting value |
2 | Moderate claudication | Between categories 1 and 3 |
3 | Severe claudication | Cannot complete treadmill exercise and AP after exercise <50 mmHg |
4 | Ischemic rest pain | At rest AP <40 mmHg, flat or barely pulsatile ankle or metatarsal pulse volume recording (PVR); toe pressure (TP) <30 mmHg |
5 | Minor tissue loss, non-healing ulcer, focal gangrene with diffuse pedal ischemia | At rest AP <60 mmHg, ankle or metatarsal PVR flat or barely pulsatile; TP <40 mmHg |
6 | Major tissue loss, extending above transmetatarsal (TM) level, functional foot no longer salvageable | Same as category 5 |
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Trellis Peripheral Infusion System
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Drug-Coated Balloon Angioplasty for Dysfunctional Dialysis Arterio-Venous Fistula
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The DETOUR System
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Drug-Coated Balloon with or without Atherectomy for the Treatment of Femoro-Popliteal Lesions
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