Coronary Artery Brachytherapy and Other Adjuncts to Coronary Interventions
Number: 0491
Table Of Contents
PolicyApplicable CPT / HCPCS / ICD-10 Codes
Background
References
Policy
Scope of Policy
This Clinical Policy Bulletin addresses coronary artery brachytherapy and other adjuncts to coronary interventions.
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Medical Necessity
Aetna considers the following interventions medically necessary:
- Coronary artery brachytherapy (i.e., intra-coronary radiation) in native coronary arteries or coronary artery bypass grafts as adjunctive treatment during a second angioplasty/stent placement when blockage has re-occurred within the localized area of a previously placed bare metal stent (i.e., in-stent re-stenosis);
- Abciximab (ReoPro) as an adjunctive treatment for persons undergoing percutaneous angioplasty/stent placement.
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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:
- Coronary artery brachytherapy for use with drug-eluting stents, and for the primary prevention of re-stenosis and all other indications (except for those listed in policy section above) due to insufficient evidence in the peer-reviewed literature;
- The use of abciximab for the following indications (not an all-inclusive list) because there is currently insufficient evidence from randomized controlled trials regarding its safety or effectiveness for these indications:
- Acute ischemic stroke;
- Acute limb ischemia;
- Acute myocardial infarction without percutaneous intervention;
- Cardiac complications (e.g., coronary artery aneurysms) of Kawasaki disease;
- Saphenous vein graft interventions;
- Stenting of superficial femoral occlusive disease;
- Thromboembolic complications during cerebral aneurysm coiling;
- Thrombus resolution during intracranial bypass surgery.
- Abciximab/heparin therapy for left ventricular assist device implantation in individuals with heparin-induced thrombocytopenia;
- Intravascular shockwave lithotripsy for the treatment of coronary artery plaques.
Background
Intracoronary brachytherapy is used to prevent restenosis of an artery after angioplasty or stent placement by delivering a small amount of radiation to the treated area, which may reduce the need for additional angioplasty or bypass surgery. The radiation is intended to discourage the overgrowth of normal tissue as the healing process occurs.
When treating coronary artery disease with angioplasty or stents, the recurrence of coronary artery blockage at the site of treatment remains a significant risk. Recurrent coronary stenosis occurs in 20 to 30 % of patients in whom stents have been implanted for the treatment of obstructive lesions; when it occurs within the stent, it is referred to as in-stent re-stenosis. According to generally accepted guidelines, if re-stenosis occurs within a stent, it can usually be treated by pharmacotherapy and/or repeat angioplasty followed by brachytherapy.
A special catheter is used to radiate a localized area. The catheter is passed into the coronary arteries and across the target area. Once the targeted area of stenosis is "bracketed" by the catheter, the radiation is applied.
- gamma radiation and
- beta radiation.
In its FDA submission for the Checkmate System, the Cordis Corporation cited 6-month angiographic results of 3 landmark single- and multi-center randomized clinical trials (GAMMA-I with 252 patients, WRIST with 130 patients, and SCRIPPS-I with 60 patients). Results from these trials consistently showed a significant reduction in both angiographic and clinical in-stent re-stenosis versus placebo, as well as reduced major adverse clinical events. In the GAMMA-I trial, the rate of re-stenosis was reduced by 42 % by coronary artery radiation. I n the patients treated with gamma radiation, 24 % experienced re-stenosis, whereas in the control group not treated with radiation, 42 % had re-stenosis. The device is indicated for the delivery of therapeutic doses of gamma radiation for the purpose of reducing in-stent re-stenosis. The system is for use in the treatment of native coronary arteries (2.75 to 4.0 mm in diameter and lesions up to and including 45 mm in length) with in-stent re-stenosis following percutaneous re-vascularization using current interventional techniques.
The FDA approved product labeling for the Cordis Checkmate System states that the device should not be used in patients who are not good candidates for blood-thinning drugs or anti-platelet therapy.
In its FDA submission for the Novoste Beta-Cath System, the Novoste Corporation cited data from the START trial, a multi-center, randomized, placebo-controlled trial involving 476 patients. At 8 months, re-stenosis had occurred in 14 % of the stented segments in patients who had received radiation, as compared with 41 % of the controls. The device is indicated to deliver beta radiation to the site of successful percutaneous coronary intervention for the treatment of in-stent re-stenosis in native coronary arteries with discrete lesions (treatable with a 20 mm balloon) in a reference vessel diameter ranging from 2.7 mm to 4.0 mm.
The FDA-approved product labeling for the Beta-Cath System states that it should not be used for patients with unprotected left main coronary artery disease (50 % narrowing of the coronary artery) or for patients who are not candidates for blood-thinning drugs or anti-platelet therapy.
- total radiation cohort (those receiving either angioplasty or a stent);
- those receiving angioplasty and radiation; and
- those receiving angioplasty, stent and radiation.
In those patients receiving angioplasty and radiation, the rate of in-lesion re-stenosis was significantly reduced (21.4 % versus 34.3 % placebo control). In the group receiving angioplasty, stent and radiation, the radiation had a positive effect on preventing re-stenosis at the initial lesion site (21.1 % versus 33.0 % placebo control), but had a negative effect on the adjacent edges, leading to higher clinical re-stenosis compared with placebo (44.9 % versus 35.3 %).
Coronary artery brachytherapy has been shown to be effective in preventing re-stenosis in coronary artery bypass grafts. Waksman et al (2002) reported on the results of the SVC-WRIST Trial, a randomized controlled clinical trial of the effects of intra-coronary gamma brachytherapy in 120 patients with in-stent re-stenosis of saphenous vein grafts. After 6 months, the re-stenosis rate was lower in the 60 patients assigned to gamma brachytherapy than in the 60 assigned to placebo (21 % versus 44 %, p = 0.005). At 12 months, the rate of re-vascularization of the target lesion was 70 % lower in the gamma brachytherapy group than in the placebo group (17 % versus 57 %, p < 0.001), and the rate of major cardiac events was 49 % lower (32 % versus 63 %, p < 0.001). The investigators concluded that these results support the use of brachytherapy for the treatment of in-stent re-stenosis in patients with bypass grafts.
Castagna et al (2002) reported on the 6-month follow-up of 45 of 120 patients in the SVC-WRIST trial with restenotic lesions of saphenous vein grafts who were evaluated by intra-vascular ultrasound (IVUS). (Because the SVC-WRIST Trial protocol did not mandate IVUS, not all trial participants were evaluated with this procedure). The investigators reported a significant reduction in repeat stenosis in the patients randomized to gamma brachytherapy compared to placebo; they reported that the effectiveness of gamma brachytherapy in patients with re-stenosis of saphenous vein grafts was similar to that reported in other trials of gamma radiation therapy in patients with re-stenosis of native coronary lesions. The investigators concluded that intra-vascular brachytherapy effectively reduced intimal hyperplasia re-accumulation in vein graft in-stent re-stenosis with no deleterious effect on reference segments within 6 months.
Oliver and colleagues (2008) performed a meta-analysis of randomized trials assessing the outcome of vascular brachytherapy (VBT) or drug-eluting stents (DES) for the treatment of coronary artery in-stent restenosis (ISR). Studies utilising DES or VBT for ISR were identified by a systematic search. Data was pooled and combined overall effect measures were calculated for a random effect model in terms of deaths, myocardial infarctions, re-vascularization, binary restenosis, mean late luminal loss and major adverse cardiac events (MACE). A total of 14 eligible studies (3,103 patients) were included. Neither therapy had any effect on mortality or myocardial infarction rate. Vascular brachytherapy reduced the rate of re-vascularisation (risk ratio [RR] 0.59, 95 % confidence interval [CI]: 0.50 to 0.68), MACE (RR 0.58, 95 % CI: 0.51 to 0.67), binary re-stenosis (RR 0.51, 95 % CI: 0.44 to 0.59) and late loss (-0.73 mm, 95 % CI: -0.91 to -0.55 mm) compared to balloon angioplasty and selective bare metal stents (BMS) alone at intermediate follow-up and MACE (RR 0.72, 95 % CI: 0.61 to 0.85) at long-term follow-up. Drug-eluting stents reduced the rate of re-vascularisation (odds ratio [OR] 0.51, 95 % CI: 0.36 to 0.71), MACE (OR 0.55, 95 % CI: 0.39 to 0.79) and binary re-stenosis (OR 0.57, 95 % CI: 0.40 to 0.81) compared to VBT but follow-up was limited to 9 months. The authors concluded that VBT improves the long-term outcome of angioplasty compared with BMS alone in the treatment of ISR. Drug-eluting stents appear to provide similar results to that of VBT during short-term follow-up.
Beta-radiation is considered investigational in the prevention of de novo lesions in patients at a higher risk of re-stenosis undergoing angioplasty and/or stenting. While the initial data are promising in those patients receiving angioplasty and radiation, further randomized, multi-center, placebo-controlled trials to investigate the long-term effects of radiation and the risk of edge re-stenosis in the treatment of primary prevention of re-stenosis are needed.
Many questions concerning the safety (e.g., late thrombosis, re-stenosis at the proximal and distal edges of irradiated zones, myocardial infarction) of radiation for in-stented re-stenosis have been raised in the literature. Some authorities believe that, until these questions can be answered by additional randomized well-controlled clinical trials with larger numbers of patients, in different populations, and with long-term follow-up, physicians should remain cautious in their use of this technique.
Anti-Platelet Therapy
Intravenous platelet glycoprotein IIb/IIIa receptor inhibitors have been demonstrated to reduce the incidence of ischemic complications when used in conjunction with coronary interventions. ReoPro (abciximab) is a monoclonal antibody that forms a complex with glycoprotein IIb/IIIa receptors at the surface of blood platelets. Because ReoPro blocks these receptors it prevents the platelets from adhering to each other and from forming blood clots. According to the FDA-approved product labeling, ReoPro is indicated as an adjunct to percutaneous coronary interventions for the prevention of cardiac ischemic complications:
- In patients undergoing percutaneous coronary intervention;
- In patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours.
Use of abciximab in patients not undergoing percutaneous coronary intervention has not been studied. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting.
Stent implantation in the superficial femoral artery has been associated with suboptimal results while glycoprotein IIb/IIIa inhibitors have shown improved procedural results during coronary intervention. In a randomized, placebo-controlled trial, Ansel et al (2006) assessed the effect of abciximab during nitinol stenting of superficial femoral occlusive disease. Major outcome measures included 9-month re-stenosis defined as a decrease in ankle brachial index and in-stent duplex ultrasound restenosis, and adverse events defined as death (30 days) or repeat re-vascularization within 9 months. A total of 27 patients were randomized to abciximab and 24 patients to control (placebo). The primary end point of cumulative re-stenosis occurred in 15.4 % of patients given abciximab and in 12 % administered placebo (p = 0.873). The primary re-stenosis endpoint in diabetics and total occlusions were similar at 14.3 % and 15.4 %, respectively. The composite end point of 30-day mortality and 9-month re-vascularization occurred in 5.8 % abciximab and 0 % (p = 0.274) placebo with no 30-day deaths. Graded treadmill time and Rutherford class were all significantly improved in both groups, but the abciximab group did not appear to demonstrate any identifiable effect. The authors concluded that nitinol stenting of the superficial femoral artery was associated with favorable functional outcomes at 9 months. Adjunctive abciximab did not appear to demonstrate any identifiable effect.
In a Cochrane review on glycoprotein IIb/IIIa inhibitors for acute ischemic stroke (Ciccone et al, 2006), the authors concluded that there is currently insufficient evidence from randomized controlled trials regarding the safety or effectiveness of glycoprotein IIb/IIIa inhibitors therapy in the management of patients with acute ischemic stroke.
Seitz and Siebler (2008) reviewed the literature concerning the use of intravenously administered glycoprotein IIb/IIIa inhibitors (GPIs) abciximab, eptifibatide and tirofiban for the treatment of patients with acute ischemic brain infarction. In multi-center, prospective, randomized and placebo-controlled trials, abciximab had a higher cerebral bleeding risk, while tirofiban did not increase hemorrhage. When combined with fibrinolysis, abciximab and tirofiban were found to improve cerebral artery re-canalization and tissue re-perfusion resulting in reduced infarct volumes and improved neurological outcome. Thus, GPIIb/IIIa-receptor antagonists have a great potential for the treatment of acute stroke.
In a phase-III clinical trial, Adams and colleagues (2008) examined the relative safety and effectiveness of abciximab in patients with acute ischemic stroke with planned treatment within 5 hours since symptoms onset. The planned enrollment was 1,800 patients. The primary cohort enrolled those patients who could be treated within 5 hours of stroke onset. A companion cohort enrolled participants who were treated 5 to 6 hours after stroke as well as a smaller cohort of patients who could be treated within 3 hours of stroke present on awakening. The primary outcome measure was the dichotomous modified Rankin Scale score at 3 months as adjusted to the baseline severity of stroke among subjects in the primary cohort. The primary safety outcome was the rate of symptomatic or fatal intra-cranial hemorrhage that occurred within 5 days of stroke. The trial was terminated prematurely after 808 patients in all cohorts were enrolled by recommendation of an independent safety and effectiveness monitoring board due to an unfavorable benefit-risk profile. At 3 months, approximately 33 % of patients assigned placebo (72/218) and 32 % of patients assigned abciximab (71/221; p = 0.944) in the primary cohort were judged to have a favorable response to treatment. The distributions of outcomes on the modified Rankin Scale were similar between the treated and control groups. Within 5 days of enrollment, approximately 5.5 % of abciximab-treated and 0.5 % of placebo-treated patients in the primary cohort had symptomatic or fatal intra-cranial hemorrhage (p = 0.002). The trial also did not demonstrate an improvement in outcomes with abciximab among patients in the companion and wake-up cohorts. Although the number of patients was small, an increased rate of hemorrhage was noted within 5 days among patients in the wake-up population who received abciximab (13.6 % versus 5 % for placebo). The authors concluded that this trial did not demonstrate either safety or effectiveness of intravenous administration of abciximab for the treatment of patients with acute ischemic stroke regardless of end point or population studied. There was an increased rate of symptomatic or fatal intra-cranial hemorrhage in the primary and wake-up cohorts.
Schulz et al (2010) noted that the in the Bavarian Reperfusion Alternatives Evaluation (BRAVE)-3 study, up-stream administration of abciximab additional to 600 mg clopidogrel loading did not reduce the infarct size in patients with acute ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary interventions (PCI). The aim of this study was to investigate 1-year clinical outcomes in the BRAVE-3 study patients. A total of 800 patients with acute STEMI within 24 hrs from symptom onset, all treated with 600 mg of clopidogrel were randomized in a double-blind fashion to receive either abciximab (n = 401) or placebo (n = 399) in the intensive care unit before being sent to the catheterization laboratory. The main outcome of interest of the present study, the composite of death, recurrent myocardial infarction, stroke or re-vascularization of the infarct-related artery (IRA) at 1 year, was 23.0 % (92 patients) in the abciximab versus 25.7 % (102 patients) in the placebo group [RR = 0.90, 95 % CI: 0.67 to 1.20; p = 0.46]. The combined incidence of death, recurrent myocardial infarction or stroke was 9.3 % in the abciximab group versus 6.0 % in the placebo group (RR = 1.55, 95 % CI: 0.93 to 2.58; p = 0.09). There was a significant reduction of the IRA re-vascularization with abciximab compared to placebo (16.3 versus 22.3 %, RR = 0.71, 95 % CI: 0.52 to 0.98; p = 0.04). The authors concluded that in patients with STEMI, all receiving 600 mg clopidogrel, abciximab did not improve overall clinical outcomes at 1 year after PCI.
Dong et al (2010) performed a meta-analysis to evaluate the relative safety and efficacy of up-stream versus deferred administration of small-molecule GPIs (smGPIs) in STEMI patients. A total of 10 randomized clinical trials comparing up-stream versus deferred administration of smGPIs in 2,724 patients were located in the electronic databases of the published literature. Pre-procedural Thrombolysis In Myocardial Infarction Study (TIMI) grade 2 or 3 flow was present in 45.0 % of the up-stream group compared with 36.9 % in the deferred group (OR 1.40, p < 0.001). However, no difference in post-procedural TIMI 3 flow (OR 0.87, p = 0.25) was found between the groups. The 30-day mortality rate in the up-stream group did not differ from that of the deferred group (OR 1.04, p = 0.85). No significant difference was noted with respect to major bleeding complications (OR 1.25, p = 0.38). The authors concluded that in STEMI patients scheduled for primary PCI, although early smGPIs treatment improved initial epicardial patency, no beneficial effect on post-procedural angiographic or 30-day clinical outcome was found. Thus, the current available data do not support the routine utilization of up-stream smGPIs in STEMI patients treated with primary PCI.
Thiele and colleagues (2012) examined the safety and effectiveness of intra-coronary (IC) versus standard intravenous (IV) bolus application in patients with ST-elevation myocardial infarction (STEMI) undergoing this intervention. The AIDA STEMI trial was a randomized, open-label, multi-center trial. Patients presenting with STEMI in the previous 12 hrs with no contraindications for abciximab were randomly assigned in a 1:1 ratio by a central web-based randomization system to IC versus IV abciximab bolus (0.25 mg/kg bodyweight) during PCI with a subsequent 12 hrs IV infusion 0.125 μg/kg/min (maximum 10 μg/min). The primary endpoint was a composite of all-cause mortality, recurrent infarction, or new congestive heart failure within 90 days of randomization. Secondary endpoints were the time to occurrence of the primary endpoint, each individual component of that endpoint, early ST-segment resolution, TIMI flow grade, and enzymatic infarct size. A masked central committee adjudicated the primary outcome and its components. Treatment allocation was not concealed from patients and investigators. Between July, 2008 and April, 2011, a total of 2,065 patients were randomly assigned IC abciximab (n = 1032) or IV abciximab (n = 1033). Intra-coronary, as compared with IV abciximab, resulted in a similar rate of the primary composite clinical endpoint at 90 days in 1,876 analysable patients (7.0 % versus 7.6 %; OR 0.91; 95 % CI: 0.64 to 1.28; p = 0.58). The incidence of death (4.5 % versus 3.6 %; 1.24; 0.78 to 1.97; p = 0·36) and re-infarction (1.8 % versus 1.8 %; 1.0; 0.51 to 1.96; p = 0·99) did not differ between the treatment groups, whereas less patients in the IC group had new congestive heart failure (2.4 % versus 4.1 %; 0.57; 0.33 to 0.97; p = 0·04). None of the secondary endpoints or safety measures differed significantly between groups. The authors concluded that in patients with STEMI undergoing primary PCI, IC as compared to IV abciximab did not result in a difference in the combined endpoint of death, re-infarction, or congestive heart failure. Since IC abciximab bolus administration is safe and might be related to reduced rates of congestive heart failure the IC route might be preferred if abciximab is indicated in high-risk patients.
Stone and colleagues (2012) examined if bolus IC abciximab, manual aspiration thrombectomy, or both reduce infarct size in high-risk patients with STEMI. Between November 28, 2009, and December 2, 2011, a total of 452 patients presenting at 37 sites in 6 countries within 4 hrs of STEMI due to proximal or mid left anterior descending artery occlusion undergoing primary PCI with bivalirudin anti-coagulation were randomized in an open-label, 2:2 factorial design to bolus IC abciximab delivered locally at the infarct lesion site versus no abciximab and to manual aspiration thrombectomy versus no thrombectomy. A 0.25-mg/kg bolus of abciximab was administered at the site of the infarct lesion via a local drug delivery catheter. Manual aspiration thrombectomy was performed with a 6-F aspiration catheter. Primary end point were infarct size (percentage of total left ventricular mass) at 30 days assessed by cardiac magnetic resonance imaging (cMRI) in the abciximab versus no abciximab groups (pooled across the aspiration randomization); major secondary end point were 30-day infarct size in the aspiration versus no aspiration groups (pooled across the abciximab randomization). Evaluable cMRI results at 30 days were present in 181 and 172 patients randomized to IC abciximab versus no abciximab, respectively, and in 174 and 179 patients randomized to manual aspiration versus no aspiration, respectively. Patients randomized to IC abciximab compared with no abciximab had a significant reduction in 30-day infarct size (median, 15.1 %; interquartile range (IQR), 6.8 % to 22.7 %; n = 181, versus 17.9 % (IQR, 10.3 % to 25.4 %); n = 172; p = 0.03). Patients randomized to IC abciximab also had a significant reduction in absolute infarct mass (median, 18.7 g (IQR, 7.4 to 31.3 g); n = 184, versus 24.0 g (IQR, 12.1 to 34.2 g); n = 175; p = 0.03) but not abnormal wall motion score (median, 7.0 (IQR, 2.0 to 10.0); n = 188, versus 8.0 (IQR, 3.0 to 10.0); n = 184; p = 0.08). Patients randomized to aspiration thrombectomy versus no aspiration had no significant difference in infarct size at 30 days (median, 17.0 % (IQR, 9.0 % to 22.8 %); n = 174, versus 17.3 % (IQR, 7.1 % to 25.5 %); n = 179; p = 0.51), absolute infarct mass (median, 20.3 g (IQR, 9.7 to 31.7 g); n = 178, versus 21.0 g (IQR, 9.1 to 34.1 g); n = 181; p = 0.36), or abnormal wall motion score (median, 7.5 (IQR, 2.0 to 10.0); n = 186, versus 7.5 (IQR, 2.0 to 10.0); n = 186; p = 0.89). The authors concluded that in patients with large anterior STEMI presenting early after symptom onset and undergoing primary PCI with bivalirudin anti-coagulation, infarct size at 30 days was significantly reduced by bolus IC abciximab delivered to the infarct lesion site but not by manual aspiration thrombectomy. Moreover, the authors stated that larger trials are needed to examine if the degree of infarct size reduction at 30 days achieved with intra-coronary abciximab in the present study translate into improved late clinical outcomes without increasing bleeding.
De Luca et al (2012) performed a meta-analysis of randomized controlled trials (RCTs) to assess the safety and effectiveness of IC vs IV abciximab administration in STEMI patients undergoing primary angioplasty. These researchers obtained results from all RCTs enrolling STEMI patients undergoing primary PCI. The primary endpoint was mortality, while recurrent myocardial infarction, post-procedural epicardial (TIMI 3) and myocardial (MBG 2-3) perfusion were identified as secondary endpoints. The safety endpoint was the risk of major bleeding complications. A total of 8 RCTs were finally included in the meta-analysis, enrolling a total of 3,259 patients. As compared to IV route, IC abciximab was associated with a significant improvement in myocardial perfusion (OR (95 % CI) = 1.76 (1.28 to 2.42), p < 0.001), without significant benefits in terms of mortality (OR (95 % CI) = 0.85 (0.59 to 1.23), p = 0.39), re-infarction (OR (95 % CI) = 0.79 (0.46 to 1.33), p = 0.37), or major bleeding complications (OR (95 % CI) = 1.19 (0.76 to 1.87), p = 0.44). However, these investigators observed a significant relationship between patient's risk profile and mortality benefits from IC abciximab administration (p = 0.011). The authors concluded that the present updated meta-analysis showed that IC administration of abciximab is associated with significant benefits in myocardial perfusion, but not in clinical outcome at short-term follow-up as compared to IV abciximab administration, without any excess of major bleedings in STEMI patients undergoing primary PCI. However, a significant relationship was observed between patient's risk profile and mortality benefits from IC abciximab administration. Therefore, waiting for long-term follow-up results and additional randomized trials, IC abciximab administration can not be routinely recommended, but may be considered in high-risk patients.
Eitel et al (2013) noted that the aim of the AIDA STEMI (Abciximab IV versus IC. in ST-elevation Myocardial Infarction) cardiac magnetic resonance (CMR) substudy was to investigate potential benefits of IC versus IV abciximab bolus administration on infarct size and reperfusion injury in ST-segment elevation myocardial infarction. The AIDA STEMI trial randomized 2,065 patients to IC or IV abciximab and found similar rates of major adverse cardiac events at 90 days with significantly less congestive heart failure in the IC. abciximab group. Cardiac magnetic resonance can directly visualize myocardial damage and re-perfusion injury, thereby providing mechanistic and pathophysiological insights. These investigators enrolled 795 patients in the AIDA STEMI CMR substudy; CMR was completed within 1 week after ST-segment elevation myocardial infarction. Central core laboratory-masked analyses for quantified ventricular function, volumes, infarct size, microvascular obstruction, hemorrhage, and myocardial salvage were performed. The area at risk (p = 0.97) and final infarct size (16 % [interquartile range: 9 % to 25 %] versus 17 % [interquartile range: 8 % to 25 %], p = 0.52) did not differ significantly between the IC and the IV abciximab groups. Consequently, the myocardial salvage index was similar (52 [interquartile range: 35 to 69] versus 50 [interquartile range: 29 to 69], p = 0.25). There were also no differences in microvascular obstruction (p = 0.19), intra-myocardial hemorrhage (p = 0.19), or ejection fraction (p = 0.95) between both treatment groups. Patients in whom major adverse cardiac events occurred had significantly larger infarcts, less myocardial salvage, and more pronounced ventricular dysfunction. The authors concluded that this largest multi-center CMR study in ST-segment elevation myocardial infarction patients to date demonstrated no benefit of IC versus IV abciximab administration on myocardial damage and/or re-perfusion injury. Infarct size determined by CMR was significantly associated with major adverse cardiac events.
In a meta-analysis, Wang et al (2013) stated that abciximab is a widely used adjunctive therapy for acute coronary syndrome (ACS). However, the effect of IC administration of abciximab on cardiovascular events remains unclear when compared with IV therapy. These investigators systematically searched the Medline, Embase, and Cochrane Central Register of Controlled Trials databases and reference lists of articles and proceedings of major meetings for obtaining relevant literature. All eligible trials included ACS patients who received either IC administration of abciximab or IV. therapy. The primary outcome was major cardiovascular events, and secondary outcomes included total mortality, re-infarction, and any possible adverse events. Of 660 identified studies, these researchers included 9 trials reporting data on 3,916 ACS patients. Overall, IC administration of abciximab resulted in 45 % reduction in relative risk for major cardiovascular events (RR; 95 % CI: 24 to 60 %), 41 % reduction in RR for re-infarction (95 % CI: 7 to 63 %), and 44 % reduction in RR for congestive heart failure relative to IV therapy (95 % CI: 8 to 66 %); however, compared to IV therapy, IC administration of abciximab had no effect on total mortality (RR, 0.69; 95 % CI: 0.45 to 1.07). No other significant differences were identified between the effect of IC abciximab administration and IV therapy. The authors concluded that IC administration of abciximab can reduce the risk of major cardiovascular events, re-infarction, and congestive heart failure when compared with IV therapy.
Acute Limb Ischemia
Salzler et al (2016) stated that contemporary endovascular management of acute limb ischemia (ALI) generally consists of tissue plasminogen activator (tPA) based catheter-directed thrombolysis (CDT) with or without pharmaco-mechanical thrombectomy (PMT). Although abciximab is widely used in coronary re-vascularization, its safety and effectiveness in the treatment of ALI are unknown. These investigators reviewed their contemporary experience with the endovascular management of ALI and evaluated the safety and effectiveness of abciximab. A total of 49 consecutive patients with Rutherford class II (RII) ALI undergoing CDT for ALI from 2011 to 2014 was identified. Demographics, procedural details, and outcomes were assessed and reported. A total of 44 patients with RII ALI underwent tPA-based CDT in 49 discrete interventions. In 11 patients adjunctive abciximab infusion was also used. The majority (82 %) of patients treated with tPA ± PMT required over-night infusion and at least 1 subsequent procedure. Single-stage (on-table) thrombolysis was achieved in 91 % of cases with adjunctive abciximab use versus 18 % with tPA alone (p < 0.001). There was significantly less need for intensive care unit (ICU) monitoring, and there were no bleeding complications associated with adjunctive abciximab use. Overall length of stay and total operating room time favored the abciximab group; but did not reach statistical significance. Overall primary patency, secondary patency, and amputation-free survival were 46 ± 9.9 %, 79 ± 6.6 %, and 78 ± 9.2 %, respectively, at 1 year. The authors concluded that early results suggested adjunctive abciximab may safely facilitate on-table thrombolysis for RII ALI. This approach appeared to be associated with reduced resource utilization including fewer procedures, shorter operating room time, and less ICU admissions and 1-year outcomes compared favorably to a similar cohort of ALI patients treated with tPA-based therapy alone. These findings from a small study (only 11 subjects received abciximab) need to be validated in well-designed studies.
Saphenous Vein Graft Interventions
Harskamp et al (2016) noted that PCI of saphenous vein grafts (SVG) poses a high-risk for distal coronary thrombo-embolic events. Glycoprotein IIb/IIIa inhibitors are frequently used in hope of reducing the impact of this, although the safety and effectiveness of these drugs to improve outcomes in this setting are under-studied. In this study, patients were included if they had prior coronary artery bypass surgery and subsequently underwent PCI of greater than or equal to 1 SVG graft at a Dutch academic center between 1997 and 2008. These patients were matched 1:1 based on peri-procedural use of abciximab using a propensity-score matching algorithm based on 17 variables. Conditional logistic regression and Cox regression stratified on matched pairs were performed to evaluate the association between abciximab use and MACCE (the composite measure of mortality, myocardial infarction, stroke and repeat revascularization) at 30 days and up to 1 year. The composite of 30-day MACCE occurred in 18 patients (15.3 %) in the abciximab group and 16 patients (13.6 %) in the propensity matched control group (OR: 1.13, 95 % CI: 0.57 to 2.21, p = 0.73). At 1-year follow-up, MACCE rates were also similar (32.5 % versus 33.9 %, HR: 0.97, 95 % CI: 0.59 to 1.59). Major bleeding (BARC types 3a-c) was higher in the abciximab group (11.9 % versus 4.2 %, OR: 2.80, 95 % CI: 1.01 to 7.77). Ischemic outcomes did not differ among patients with ACS. The authors concluded that the use of intravenous abciximab was not associated with improved clinical outcomes up to 1-year among patients undergoing SVG PCI, but was related to more bleeding.
Acute Ischemic Stroke
Al-Mufti and colleagues (2017) retrospectively delineated the feasibility of the combined use of emergent carotid stenting and intra-arterial (IA) abciximab with intracranial re-vascularization in the setting of acute ischemic stroke and carotid occlusions. A total of 11 patients with complete cervical carotid occlusion with or without concomitant intracranial ICA and/or MCA occlusion were identified from a single center, retrospective review of patients admitted to the Stroke unit. These researchers evaluated all cases for complications of emergent cervical ICA recanalization employing carotid stenting and IA abciximab. All patients had complete cervical carotid occlusion with (n = 8) or without (n = 3) concomitant intracranial ICA and/or MCA occlusion. Successful emergent cervical ICA re-canalization was achieved in all cases. All patients were administered IA abciximab (dose range 6 to 17 mg, average of 11.4 mg) immediately following the cervical carotid stenting. There was complete re-canalization in all patients with no procedural morbidity or mortality. A single case (1/11, 9 %) developed asymptomatic hemorrhagic transformation. Upon discharge, 9 patients (9/11, 82 %) had a modified Rankin Scale (mRS) of 0 to 2, and 2 patients (2/11, 18 %) had a mRS of 3. The authors concluded that in acute ICA-MCA/distal ICA occlusions, extracranial stenting followed by intracranial IA abciximab and thrombectomy appeared feasible, safe, and effective. They stated that further evaluation of this treatment strategy is needed.
Cardiac Complications (e.g., Coronary Artery Aneurysms) of Kawasaki Disease
Bachlava and co-workers (2016) stated that there are limited data regarding the possible benefits of abciximab in children with Kawasaki disease (KD), who developed serious cardiac abnormalities non-responsive to standard treatment. These investigators retrospectively identified children with KD who were treated with abciximab from 2007 to 2015. Data regarding clinical course, treatment, echocardiographic data and follow-up at 1 and 6 months were retrieved. During the study period, a total of 15 children were identified who were diagnosed with KD and were given abciximab. The median age at onset of symptoms was 11 months (range of 2 months to 6 years). The median day of disease at admission was 10 days (range of 4 to 26 days) and the median day of administration of abciximab was 17 days (range of 9 to 40 days); 12 children were diagnosed with complete and 3 with incomplete KD. Aneurysms were found in 8 children: 2 had ectatic coronary arteries and 5 presented with both ectasia and aneurysms. At 1month follow-up, echocardiographic findings showed regression in the size of aneurysms in 11 children, resolution of the aneurysms or ectasia of coronary arteries in 3 children, while 1 child who could not take aspirin because of G6PD deficiency died. At 6 months of follow-up, echocardiographic findings showed resolution of coronary abnormalities in 12 (80 %) children, whereas 2 children (13.3 %) presented with significant regression of aneurysms. The authors concluded that abciximab may have an important role in the management of severe cardiac complications of KD, although prospective RCTs are needed to fully evaluate its role.
Thromboembolic Complications during Aneurysm Coiling
Martínez-Perez and associates (2017) evaluated the safety and effectiveness of abciximab for the treatment of thromboembolic complications during aneurysm coiling and determined the risk factors. From an aneurysm coiling database, patients treated with intra-arterial abciximab after having thrombotic complications during the coiling procedure were selected for analysis. Complications after using abciximab were categorized as hemorrhage, distal migration of the thrombus, and aneurysm re-canalization. A total of 14 coiling patients sustained a thromboembolic complication and were treated using intra-arterial infusion of abciximab and were subjected to further analysis. The age range was 48 to 76 years; 3 patients were male; 7 had subarachnoid hemorrhage. Only complete re-canalization was associated with clinical improvement, but this only occurred in 4 (28.5 %) cases. Partial or complete re-canalization occurred in 13 (93 %); 8 (57 %) patients had complications derived from the infusion; 3 had aneurysm re-canalization, 3 had distal migration of the thrombus and 1 had a hemorrhagic complication; 8 cases demonstrated acute infarcts related to the occluded vessel, while 7 made a good functional recovery. The authors concluded that successful re-canalization of a vessel occluded by thrombus formation during aneurysm coiling using abciximab infusion was less than optimal; there were risks related to abciximab, including bleeding and aneurysm re-canalization.
Lin and colleagues (2018) stated that flow diversion with the Pipeline embolization device (PED) is an effective neuro-endovascular method and increasingly accepted for the treatment of cerebral aneurysms. Acute in-situ thrombosis is a known complication of PED procedures. There is limited experience in the flow diversion literature on the use of abciximab for the management of acute thrombus formation in PED cases. In a retrospective study, data were collected on patients who received IA ReoPro with or without subsequent intravenous (IV) infusion during PED flow diversion treatment of intra-cranial aneurysms. A total of 30 cases in patients with a mean age of 56.7 years (range of 36 to 84) and a mean aneurysm size of 8.6 mm (range of 2 to 25) were identified to have intra-procedural thromboembolic complications during PED treatment. IA ReoPro was administered in all cases, with 20 cases receiving increments of 5-mg boluses and 10 cases receiving a 0.125 mg/kg IA bolus (half cardiac dosing). Complete or partial re-canalization was achieved in 100 % of the cases. IV ReoPro infusion at 0.125 μg/kg/min for 12 hours was administered post-procedurally in 22 cases with a residual thrombus. Post-procedurally, 18 patients were transitioned from clopidogrel (Plavix) to prasugrel (Effient). The majority of the cases (23/30; 77 %) were discharged home. Peri-procedural intra-cranial hemorrhage was noted in 2 cases (7 %) and radiographic infarct was noted in 4 cases (13 %), with an overall mortality of 0 % at the time of initial discharge. Clinical follow-up was available for 28/30 patients. The average duration of follow-up was 11.7 months, at which time 23/28 (82 %) of the patients had a mRS score of 0. The authors concluded that IA ReoPro administration was a safe and effective rescue strategy for the management of acute intra-procedural thromboembolic complications during PED treatment. Using a dosing strategy of either 5-mg increments or a 0.125 mg/kg IA bolus (half cardiac dosing) could provide high rates of re-canalization with low rates of hemorrhagic complications and long-term morbidity.
The authors stated that the drawbacks of this study were due to its retrospective, single-institution nature. Furthermore, there was heterogeneity in ReoPro dosing within this series. These researchers stated that prospective, randomized trials are needed to establish further protocols.
Intracoronary Brachytherapy for the Treatment of Recurrent Drug Eluting Stent In-Stent Restenosis
Meraj and colleagues (2021) stated that intracoronary brachytherapy (ICBT) is an effective treatment for ISR of BMS; however, its use has waned due to the advent of DES. In-stent restenosis following drug eluting stents (DES) occurs at a frequency of 8 % or greater. In a retrospective analysis, these investigators reported on the safety, short-term and long-term efficacy following ICBT for ISR in patients with DES. This analysis was carried out on patients treated on an institutional review board (IRB)-approved protocol using ICBT for DES ISR between January 2011 and October 2016. All subjects were followed for 24 months for procedural complications, mortality, clinical ISR/target lesion revascularization (TLR) and stroke. A total of 290 patients were identified with a mean age of 66.6 years. All subjects had high rates of typical coronary artery disease (CAD) risk factors. The primary outcome, composite of in-hospital mortality, myocardial infarction (MI), safety outcomes and procedural failure was noted in 1 (0.3 %) patient who had a MI. No other secondary outcome was noted in-hospital. At 1-year follow up, 12.4 % patients had ISR, 1.7 % patients died, and 1 (0.3 %) had ischemic stroke. At 2-year, 14.7 % had ISR, and a total 6 (2.1 %) patients had MI. The authors concluded that ICBT demonstrates excellent technical success rates for treatment, safety, and reasonable efficacy over 2-years to be free from recurrent clinical ISR. This study represented the largest ICBT data for DES ISR to-date among very complex lesion subsets, however, more prospective data are still needed to determine the optimal patient for treatment.
Abciximab for Thrombus Resolution During Intracranial Bypass Surgery
Buchanan and colleagues (2018) noted that abciximab is a glycoprotein IIb/IIIa receptor antagonist that functions to prevent platelet aggregation, thus reducing thrombus initiation and propagation. The use of abciximab in cardiac and neurosurgical procedures has been associated with a reduced incidence of ischemic complications and a decreased need for repeated intervention. In these settings, abciximab has been delivered trans-arterially via a micro-catheter or infused intravenously for systemic administration. In a case-report, these investigators described novel in-situ delivery of abciximab as an agent to dissolve "white clots", which are composed primarily of platelets, during an intracranial superficial temporal artery to middle cerebral artery bypass in a 28-year old woman with severe intracranial occlusive disease. Abciximab was able to resolve multiple platelet-based clots after unsuccessful attempts with conventional clot dispersal techniques, such as heparinized saline, tPA, mechanical passage of a wire through the vessel lumen, and multiple take-downs and re-anastomosis. After abciximab was administered, patency was demonstrated intra-operatively using indocyanine green (ICG) dye and confirmed post-operatively at 1 and 10 months via CT angiography. The authors concluded that the in-situ use of abciximab as an agent to disperse a thrombus during intracranial bypass surgery is novel and has not previously been described in the literature, and serves as an additional tool during intracranial vessel bypass surgery.
Abciximab / Heparin Therapy for Left Ventricular Assist Device Implantation in Patients with Heparin-Induced Thrombocytopenia
Lee and associates (2018) stated that optimal anti-coagulation strategy remains uncertain in patients with heparin-induced thrombocytopenia (HIT) and undergoing left ventricular assist device (LVAD) implantation. These researchers described their protocol of abciximab and heparin in these patients. The protocol was to administer abciximab, 0.25 mg/kg loading dose, followed by continuous infusion of 0.125 μg · kg-1 · min-1 throughout cardio-pulmonary bypass. Full-dose heparin was then given with subsequent additional doses to maintain an activated clotting time of 400 seconds or longer. The abciximab infusion was stopped 15 minutes after heparin reversal with protamine, and platelets were transfused. A total of 6 patients underwent LVAD implantation with this protocol in the authors’ program; HIT was confirmed in 4 patients; it was suspected in 2, which was negative after the operation; 1 patient received a HeartMate XVE and the others received HeartMate II. There were no thromboembolic complications; 1 patient required chest re-exploration for bleeding and temporary right VAD support. Post-operative anti-coagulation with argatroban was re-started on median post-operative day 3 (range of days 1 to 6) and warfarin was started on day 5 (range of days 3 to 12). Median post-operative ICU stay was 9 days (range of 5 to 76), and hospital stay was 22 days (range of 18 to 132). After the initial LVAD implantation, 1 patient required HeartMate XVE LVAD exchange to HeartMate II and subsequent heart transplant, both of which were performed with the abciximab/heparin protocol. A HeartMate II device was explanted in another patient after myocardial recovery. The remaining 4 patients were alive on device support. The authors concluded that this was the first report of a novel abciximab/heparin protocol for LVAD implantation in patients with HIT. They stated that these preliminary findings suggested the feasibility and safety of this protocol. They stated that further studies in the use of this protocol in HIT patients requiring cardiac operations are needed.
The authors stated that this study had several drawbacks. First, this is a retrospective study, and the sample number was limited (n = 6). Second, there was no control group to compare the peri-operative outcomes. Moreover, there were 2 patients without serotonin release assay testing albeit with strong clinical evidence supporting the diagnosis of HIT.
Adjuvant Abciximab in ST-elevation Myocardial Infarction
Caldeira and colleagues (2019) stated that the standard of care for acute STEMI includes the activation of a STEMI care network, the administration of adjuvant medical therapy, and re-perfusion through primary PCI. While primary PCI is nowadays the first option for the treatment of patients with STEMI, anti-thrombotic therapy, including anti-platelet and anti-coagulant agents, is the cornerstone of pharmacotherapies to optimize their clinical outcomes. These researchers described contemporaneous real-world patterns of use of anti-thrombotic treatments in Portugal for STEMI patients undergoing primary PCI. They carried out a retrospective, observational, cross-sectional study for the year 2016, based on data from 2 national registries: the Portuguese Registry on Acute Coronary Syndromes (ProACS) and the Portuguese Registry on Interventional Cardiology (PRIC). Data on oral anti-platelet and procedural IV anti-thrombotic drugs were retrieved. In 2016, the ProACS enrolled 534 STEMI patients treated with primary PCI, while the PRIC registry reported data on 2,625 STEMI patients. Of these, 99.6 % were treated with aspirin, 75.6 % with dual anti-platelet therapy (mostly clopidogrel), and GPIs (mostly abciximab) were used in 11.6 % of cases. Heparins were used in 80 % of cases (78 % un-fractionated heparin [UFH] and 2 % low molecular weight heparin [LMWH]). None of the patients included in the registry was treated with cangrelor, prasugrel or bivalirudin. Missing data were one of the main drawbacks of the registries. The authors concluded that in 2016, according to data from these national registries, almost all patients with STEMI were treated with aspirin and 76 % with dual anti-platelet agents, mostly clopidogrel; however, GP IIb/IIIa inhibitors (mostly abciximab) were used in few patients, and UFH was the most prevalent parenteral anti-coagulant drug.
Karathanos and associates (2019) examined the effectiveness of routine use of GPIs in STEMI treated with primary PCI. Online databases were searched for RCTs of routine GPIs versus control therapy in STEMI. Data from retrieved studies were abstracted and evaluated in a comprehensive meta-analysis. A total of 21 RCTs with 8,585 patients were included: 10 trials randomized tirofiban, 9 abciximab, 1 trial eptifibatide, and 1 trial used abciximab+tirofiban; only 1 trial used dual anti-platelet therapy with prasugrel/ticagrelor. Routine GPI use was associated with a significant reduction in all-cause mortality at 30 days (2.4 % [GPI] versus 3.2 %; RR, 0.72; p = 0.01) and 6 months (3.7 % versus 4.8 %; RR, 0.76; p = 0.02), and a reduction in recurrent MI (1.1 % versus 2.1 %; RR, 0.55; p = 0.0006), repeat re-vascularization (2.5 % versus 4.1 %; RR, 0.63; p = 0.0001), thrombolysis in MI flow less than 3 after PCI (5.4 % versus 8.2 %; RR, 0.61; p < 0.0001), and ischemic stroke (RR, 0.42; p = 0.04). Major (4.7 % versus 3.4 %; RR, 1.35; p = 0.005) and minor bleedings (7.2 % versus 5.1 %; RR, 1.39; p = 0.006) but not intra-cranial bleedings (0.1 % versus 0 %; RR, 2.7; p = 0.37) were significantly increased under routine GPI. The authors concluded that routine GPI administration in STEMI resulted in a reduction in mortality, driven by reductions in recurrent ischemic events; however predominantly in pre-prasugrel / ticagrelor trials. These researchers stated that studies with contemporary STEMI management are needed to confirm these findings.
Intravascular Shockwave Lithotripsy for the Treatment of Coronary Artery Plaques
In February 2021, the FDA approved the Shockwave Intravascular Lithotripsy (IVL) System with the Shockwave C2 coronary IVL catheter, which is indicated for lithotripsy-enabled, low-pressure balloon dilatation of severely calcified, stenotic de-novo coronary arteries before stenting. However, there is currently insufficient evidence to support the effectiveness of IVL for this indication.
Kereiakes et al (2020) stated that coronary calcification limits optimal stent expansion and apposition and worsens safety and effectiveness outcomes of percutaneous coronary intervention (PCI). Current ablative technologies that modify calcium to optimize stent deployment are limited by guide-wire bias and peri-procedural complications related to athero-embolization, coronary dissection, and perforation. Intravascular lithotripsy delivers pulsatile ultrasonic pressure waves via a fluid-filled balloon into the vessel wall to modify calcium and enhance vessel compliance, reduce fibro-elastic recoil, and reduce the need for high-pressure balloon (barotrauma) inflations. IVL has been used in peripheral arteries as stand-alone re-vascularization or as an adjunct to optimize stent deployment. The Disrupt CAD III is a prospective, multi-center, single-arm study designed to examine the safety and effectiveness of the Shockwave coronary IVL catheter to optimize coronary stent deployment in patients with de-novo calcified coronary stenoses. The primary safety endpoint was freedom from MACE (composite of cardiac death, MI, and target vessel re-vascularization [TVR]) at 30 days compared to a pre-specified performance goal. The primary effectiveness endpoint was procedural success without in-hospital MACE. Enrollment of this trial will complete early in 2020 with clinical follow-up ongoing for 2 years. The authors stated that the Disrupt CAD III will examine the safety and effectiveness of the Shockwave coronary IVL catheter to optimize coronary stent deployment in patients with calcified coronary stenoses.
Hill et al (2020) noted that coronary calcification hinders stent delivery and expansion and is associated with adverse outcomes. Intravascular lithotripsy (IVL) delivers acoustic pressure waves to modify calcium, enhancing vessel compliance and optimizing stent deployment. In a prospective, single-arm, multi-center study, these researchers examined the safety and effectiveness of IVL in severely calcified de-novo coronary lesions. This trial (Disrupt CAD III) was designed for regulatory approval of coronary IVL. The primary safety endpoint was freedom from MACE (cardiac death, MI, or target vessel re-vascularization) at 30 days. The primary effectiveness endpoint was procedural success. Both endpoints were compared with a pre-specified performance goal (PG). The mechanism of calcium modification was assessed in an optical coherence tomography (OCT) sub-study. A total of 431 patients were enrolled at 47 sites in 4 countries. The primary safety endpoint of the 30-day freedom from MACE was 92.2 %; the lower bound of the 95 % CI was 89.9 %, which exceeded the PG of 84.4 % (p < 0.0001). The primary effectiveness endpoint of procedural success was 92.4 %; the lower bound of the 95 % CI was 90.2 %, which exceeded the PG of 83.4 % (p < 0.0001). Mean calcified segment length was 47.9 ± 18.8 mm, calcium angle was 292.5 ± 76.5°, and calcium thickness was 0.96 ± 0.25 mm at the site of maximum calcification. OCT demonstrated multi-plane and longitudinal calcium fractures after IVL in 67.4 % of lesions. Minimum stent area was 6.5 ± 2.1 mm2 and was similar regardless of demonstrable fractures on OCT. The authors concluded that coronary IVL safely and effectively facilitated stent implantation in severely calcified lesions. Moreover, these researchers stated that longer-term clinical follow-up (ongoing in this study through 2 years) is needed to determine the durability of clinical benefit associated with IVL-optimized stent implantation. They stated that future studies should include more complex patient and angiographic lesion subsets to examine the generalizability of these observations, and clarify the relationships between measures of calcium fracture, stent expansion and long-term clinical outcomes.
The authors stated that this study had several drawbacks. First, the non-randomized study design lacked a concurrent control group. The comparison to an objective PG is an established pathway for investigational device exemption (IDE) approval and was derived in conjunction with the FDA. Orbital atherectomy was similarly approved in the U.S. based on a single-arm study that used an objective PG design. The high absolute procedural success rate and low absolute peri-procedural MACE rate (despite the severity of lesion calcification in the study population) coupled with its ease-of-use and rapid learning curve suggested that IVL may play an important role in the treatment of complex, high-risk calcified lesions. Second, the endpoint definitions for both peri-procedural MI and procedural success were chosen to match those used in the ORBIT II study for regulatory purposes and did not reflect current standards. Nevertheless, pre-specified sensitivity analyses using more contemporary definitions support and confirm the conclusions derived from the primary endpoint analyses. Third, OCT identified calcium fractures in 67.4 % of lesions after IVL; however, excellent minimum stent area (MSA), area stenosis, and stent expansion outcomes were observed regardless of calcium fracture visualization. This may represent a limitation of OCT to detect subtle morphological changes in calcified plaque that are beyond the resolution limits of current OCT technology. Fourth, protocol exclusion of adjunctive tools for plaque modification (atherectomy or cutting/scoring balloons) to facilitate IVL balloon crossing avoided confounding of the efficacy and the known complications associated with these devices and afforded an objective assessment of the mechanism of IVL plaque modification. Finally, although protocol exclusion of extremely tortuous vessels, true bifurcation lesions, and unprotected left main or ostial target lesions precluded generalizability of study findings to these subgroups, affording a cross-study comparison with the ORBIT II trial required enrollment of a similar study population. Future studies are needed to examine if there are any specific clinical or anatomic circumstances that are particularly suited to and are more safely or effectively treated with one or the other of these alternative lesion preparation strategies. Preliminary clinical experience suggested that atheroablative technologies may be required in specific situations to facilitate IVL-balloon placement and that these techniques may be complimentary.
Oksnes et al (2021) noted that IVL has been shown to be safe and effective for calcium modification in nonocclusive coronary artery disease (CAD); however, there were only case reports of its use in calcified chronic total occlusions (CTO). In a retrospective, observational, cohort study, these investigators reported data from an international multi-center registry of IVL use during CTO-PCI and provided provisional data regarding its safety and effectiveness. During the study period, IVL was used in 55 of 1,053 (5.2 %) CTO-PCI procedures. IVL was used within the occluded segment after successful CTO crossing in 53 procedures and during incomplete CTO crossing in 2 cases. The mean Japanese-CTO (J-CTO) score was 3.1. CTO-PCI technical and procedural success was achieved in 53 (96 %) and 51 (93 %) cases., respectively; 6 patients had a procedural complication, with 3 main vessel perforations (5 %); 2 had covered stent implantation, 1 required peri-cardiocentesis, and 1 was managed conservatively. All had combination therapy with another calcium modification device; 2 patients had a procedural MI (PMI) (4 %), and 2 others had a MACE (4 %) at a median follow-up of 13 (4 to 21) months. The authors concluded that IVL can effectively facilitate calcium modification during CTO-PCI. Moreover, these researchers stated that further investigation is needed to establish the safety and effectiveness of IVL and other calcium modification devices when used extra-plaque or in combination during CTO-PCI.
The authors stated that the main drawback of this study as that it was a retrospective, observational cohort study. Furthermore, it should be noted that IVL was used after CTO crossing in almost all cases; thus, introducing bias to procedural success rates. A period of novel technology adoption and impact of incremental device cost will have introduced some case selection bias, increasing the proportion of cases where an additional calcium modification device was used before IVL, where with improved access and more experience, IVL could be the 1st choice device when initial treatment with non-compliant balloon dilation or scoring/cutting balloon, or rotational atherectomy has failed. While IVL was used in 90 % of the procedures, quantitative data was not available for analysis.
Aksoy et al (2021) stated that data regarding the safety, effectiveness, and outcome of IVL in comparison to standard techniques are lacking. In a retrospective, single-center study, these researchers compared IVL with non-compliant high-pressure balloon percutaneous coronary angioplasty (PTCA). They carried out a retrospective, propensity-score-matched study to compare procedural success in 57 consecutive patients who received IVL-guided PCI in calcified coronary lesions (CCAD) with 171 matched patients who were treated with high-pressure PTCA with a non-compliant (NC)-balloon. The mean minimal lumen diameter (MLD) for the IVL group was 1.08 ± 0.51 mm, and the median percent diameter stenosis on quantitative angiography was 70.2 % (IQR, 60.2 % to 78.6 %). MLD in the high-pressure dilatation group was 0.97 ± 0.43 mm, and the median percent diameter stenosis was 71.5 % (IQR, 58.5 % to 77.0 %). IVL-guided PCI reduced median stenosis to 17.5 % (IQR, 9.3 % to 19.8 %) with an acute gain of 0.93 ± 0.7 mm. High-pressure dilatation resulted in a final median stenosis of 19.3 % (IQR, 13.33 % to 28.5 %). Procedural success was significantly higher (82.5 % versus 61.4 %; p: 0.0035) in the IVL group. MACE through 12 months occurred in 10.5 % of cases in the IVL group and in 11.1 % of the high-pressure group (p = 0.22). Angiographic complications (coronary dissection, slow or no reflow, new coronary thrombus formation, abrupt vessel closure) were very low (0.2 % versus 0.12 %). The authors concluded that IVL resulted in a significantly higher rate of procedural success compared to high- pressure NC-balloon dilatation in patients with CCAD. The rate of MACE through 12 months was similar to the standard therapy.
The authors stated that this study had several drawbacks. First, this was a retrospective, single-center study; a randomized study comparing IVL against conventional non-compliant balloon dilation or scoring/cutting balloon strategies would improve the knowledge of the safety and effectiveness of the technique. Second, patient inclusion into the study was based on the angiographic degree of calcification and not on intravascular imaging. Optical coherence tomography (OCT)/IVUS were performed in approximately 25 % of cases. This represented well the clinical routine in an all-comers cohort; however, for analyses of patients with an unsuccessful procedure (those with residual in-stent stenosis of greater than 20 %), pre-procedural intravascular imaging would have improved the failure analysis. Third, IVL may have limitations in asymmetrical calcifications. These clinical situations, as well as cost analyses, have not yet been performed.
In a retrospective, observational, single-arm study, Umapathy et al (2021) examined the clinical and angiographic outcomes of coronary IVL use in an all-comers population with moderate-to-severely CCAD. The primary endpoint was in-hospital MACE, which included cardiac death, MI, and TVR; and secondary endpoints were clinical success (stent expansion with less than 30 % in-stent residual stenosis and no in-hospital MACE) and angiographic success. Between August 2019 and December 2019, a total of 50 calcified lesions were treated in 45 patients using the Shockwave C2 IVL catheter. They were further studied in 3 treatment subgroups: primary IVL group with de-novo lesions (n = 23 lesions); secondary IVL group in which non-compliant balloon dilation failed (n = 15 lesions); and tertiary IVL group with IVL to under-expanded stents (n = 12 lesions). The mean diameter stenosis of calcified lesions was 63.2 ± 10.2 % at baseline; and decreased to 33.5 ± 10.9 % immediately following IVL (p < 0.001) and 15 ± 7.1 % following stenting (p < 0.001). Mean MLD was 1.1 ± 0.3 mm at baseline; and increased to 1.90 ± 0.5 mm following IVL (p < 0.001) and 2.80 ± 0.50 mm following stenting (p < 0.001). In-hospital and 30-day MACE occurred in 3 and 4 patients, respectively. Overall, clinical success and angiographic success were achieved in 90 % and 94 % of cases, respectively. The authors concluded that IVL appeared to be a safe, effective, and feasible strategy for calcium modification in an all-comers cohort with high success rate, minimal procedural complications, and low MACE rates. Moreover, these researchers stated that larger randomized studies of IVL with long-term follow-up are needed to confirm these initial findings.
The authors stated that the drawbacks of this study included that this was a retrospective, single-arm registry with short-term follow-up to 30 days. The small study cohort of 50 IVL-treated lesions had fewer patients in each treatment subgroup; therefore, results of the subgroup analyses should be considered exploratory and hypothesis-generating.
Liang and Gu (2021) stated that previous understanding holds that rotational atherectomy and modified balloons remain the default strategy for severely calcified coronary stenoses. In recent years, coronary IVL provides new ideas. These researchers examined the safety and effectiveness of IVL for the treatment of severely calcified coronary stenoses. The serial Disrupt CAD trials (Disrupt CAD I, Disrupt CAD II, Disrupt CAD III, and Disrupt CAD IV) were included in this study. The safety endpoint was freedom from MACE in hospital, at 30 days, and at 6 months following the index procedure. The effectiveness endpoints included procedural success and angiographic success. OCT was used to evaluate the mechanism of action of IVL quantifying the coronary artery calcification (CAC) characteristics and calcium plaque fracture. These investigators enrolled a total of 628 patients with a mean age of 71.8 years, 77.1 % men. In these patients, the left anterior descending artery and right coronary artery were the most vulnerable vessels. The diameter stenosis was 64.6 ± 11.6 % and the lesion length was 24.2 ± 11.4 mm. IVL had a favorable efficacy (93.0 % procedural success, 97.5 % angiographic success, and 100.0 % stent delivery). Among the 628 patients, 568, 568, and 60 reported MACE endpoints in hospital, at 30 days, and at 6 months, respectively. The results showed that 528, 514, and 55 patients were free from MACE in hospital, at 30 days, and at 6 months, respectively; and OCT measurements demonstrated that calcium fracture was the underlying mechanism of action for coronary IVL. The authors concluded that IVL is an efficient vessel preparation strategy in the presence of a heavy coronary calcium burden, and these findings appeared to be consistent regardless of ethnicity or geography. Moreover, calcium fracture facilitated increased vessel compliance and a favorable stent expansion. Furthermore, the impact of this technology on the long-term prognosis of patients with severe calcification is also the focus of attention and expectation. More importantly, the advantage of IVL over the other methods in this particular population is still unknown. Enhancing the comparison of IVL would aid in guiding the therapeutic decisions in these patients. These researchers hope that one day this technology can eventually replace the other coronary calcification treatment technologies currently used in clinical practice.
Kereiakes et al (2021) examined the cumulative safety and effectiveness of coronary intravascular lithotripsy (IVL). Patient data were pooled from the Disrupt CAD studies, which shared uniform study criteria, endpoint definitions and adjudication, and procedural follow-up. The primary safety endpoint was freedom from major adverse cardiovascular events (MACE, composite of cardiac death, all MI, or TVR) at 30 days. The primary effectiveness endpoint was procedural success, defined as stent delivery with a residual stenosis 30 % or less by quantitative coronary angiography without in-hospital MACE. Secondary outcomes included serious angiographic complications, target lesion failure, cardiac death, and stent thrombosis at 30 days. Between December 2015 and April 2020, a total of 628 patients were enrolled at 72 sites from 12 countries. Presence of severe calcification was confirmed in 97.0 % of target lesions with an average calcified segment length of 41.5 ± 20.0 mm. The primary safety and effectiveness endpoints were achieved in 92.7 % and 92.4 % of patients, respectively. At 30 days, the rates of target lesion failure, cardiac death, and stent thrombosis were 7.2 %, 0.5 %, and 0.8 %. Rates of post-IVL and final serious angiographic complications were 2.1 % and 0.3 %, with no IVL-associated perforations, abrupt closure, or episodes of no reflow. The authors concluded that in the largest cohort of patients treated with coronary IVL assessed to-date, coronary IVL safely facilitated successful stent implantation in severely calcified coronary lesions with a high rate of procedural success. Moreover, these researchers stated that ongoing clinical follow-up in the Disrupt CAD studies will determine whether the early results of IVL to facilitate stent implantation in severely calcified lesions would translate into high rates of long-term event-free survival.
The authors stated that this study had several drawbacks. First, although all 4 Disrupt CAD studies were carefully carried out with independent core laboratory and clinical events committee adjudication, they were all single-arm studies lacking a concurrent control population. The lack of a randomized comparator precludes definitive comparisons with balloon-based (scoring, cutting, non-compliant) or athero-ablative (rotational atherectomy [RA] or orbital atherectomy [OA], laser) techniques for PCI of severely calcified vessels. Second, sub-study data from intravascular imaging by OCT that provided insights to the proposed IVL mechanism of action were not provided in the present clinical report. Pooled analysis of this experience is ongoing and will be the focus of a future report. Nevertheless, adequate intravascular imaging data have been reported from the individual trials to support the premise of in-situ circumferential and longitudinal multi-plane calcium fracture with fracture expansion following stent implantation as the dominant mechanism of vascular calcium modification by IVL. These reports have documented high values for post-procedure percentage stent expansion and minimal stent area measured by OCT, which may favorably affect long-term TLF rates. Third, the safety and effectiveness of IVL shown in this analysis were applicable to the patient cohort studied and may not be generalizable to “all comers” with severe coronary calcification and did not apply to the routine treatment of moderately calcified lesions. Indeed, specific clinical (acute coronary syndromes) and angiographic target lesion subsets (ostial, left main, non-dilatable lesions, bypass graft, in-stent re-stenosis, lesion length of greater than 40 mm, etc.) were not included in this analysis. In addition, as the combined use of IVL with athero-ablative technologies was excluded from the Disrupt CAD studies, further investigation is needed to understand the potential complementary utility of these technologies. Data from the “real world” experience will be acquired with the forthcoming U.S. post-market study to address these study drawbacks.
Jattari et al (2022) noted that severe coronary artery calcification (CAC) can be an arduous obstacle in interventional cardiology, often leading to suboptimal results of PCI. Coronary IVL is a novel technique that modulates severe CAC; thus, facilitating stent implantation. In an observational, multi-center study, these researchers examined the feasibility, safety and effectiveness of coronary IVL in the treatment of severe CAC. Data from 134 IVL procedures in 5 Belgian hospitals were prospectively obtained. Successful delivery of the IVL catheter was achieved in all cases but 1 (99.3 %). The primary endpoint was final overall procedural success, which was obtained in 88.1 % of cases, an aggregate of 92.6 % in de-novo lesions and 77.5 % in stent under expansion ISR. IVL therapy effect was considered successful by the operators in 94 % of cases, with 68.7 % achieving optimal and 25.3 % achieving suboptimal results. The 1-month MACE rate was 3 %, including 2 cardiovascular deaths (1 in-stent thrombosis and 1 coronary artery perforation). The authors concluded that this real-world experience suggested that shockwave IVL is a feasible, safe and effective technique for the treatment of heavily calcified coronary lesions. Moreover, these researchers stated that further prospective and randomized studies are needed to confirm the added value when used upfront or after failure of the initially applied conventional techniques.
The authors stated that this study had several drawbacks. This was a real-life registry, including only a few procedures with intracoronary imaging, due to a lack of reimbursement in Belgium. Consequently, many parameters were evaluated angiographically, including severity of calcification and the assessment of the results (suboptimal versus optimal). Similar to all studies published thus far on IVL, the main limitations were that this study was not randomized; and that no long-term follow-up could be provided. Furthermore, no analysis was carried out for peri-procedural troponin rise/MI or acute cardiac injury.
Sattar et al (2022) noted that IVL can be used to aid deploying stent in severe CAC. In a meta-analysis, studies employing IVL for CAC lesions were included. The primary outcomes included clinical and angiographic success. The secondary outcomes, including lumen gain, maximum calcium thickness, and calcium angle at the final angiography site, minimal lumen area (MLA) site, and MSA site, were analyzed by the random-effects model to calculate the pooled standardized mean difference (SMD); tertiary outcomes included safety event ratios. A total of 7 studies (760 patients) were included. The primary outcomes: pooled clinical and angiographic success event ratio parentage of IVL was 94.4 % and 94.8 %, respectively. On a random effect model for standard inverse variance for secondary outcomes showed: minimal lumen diameter increase with IVL was 4.68 mm (p < 0.0001, 95 % CI: 1.69 to 5.32); diameter decrease in the stenotic area after IVL session was -5.23 mm (95 % CI: -22.6 to 12.8). At the MLA and final MSA sites, MLA gain was 1.42 mm2 (95 % CI: 1.06 to 1.63; p < 0.00001) and 1.34 mm2 (95 % CI: 0.71 to 1.43; p < 0.00001), respectively. IVL reduced calcium thickness at the MLA site (SMD -0.22; 95 % CI: -0.40 to 0.04; p = 0.02); calcium angle was not affected at the MLA site. The tertiary outcomes: most common complication was MACEs (n = 48/669), and least common complication was abrupt closure of the vessel (n = 1/669). The authors concluded that available evidence suggested that IVL safely and effectively facilitated stent deployment with high angiographic and clinical success rates in treating severely CCAD.
The authors stated that this meta-analysis had several drawbacks. Due to limited data, only single-arm observational studies were included; more studies, including randomized, double-blind studies, should be performed to study the safety and effectiveness in a head-to-head comparison with other calcium debulking procedures. Severe calcification definition was not uniform in included studies given lack of consistency of imaging use including intravascular ultrasounds and optical coherence tomography. The result of diameter stenosis had high heterogeneity, which could not be excluded given only 2 studies reported data. Furthermore, none of the included studies afforded adjunctive treatment with atherectomy or specialty cutting balloons. The post-procedural outcomes obtained therefore did account for any form of adjunctive treatment. This study predominantly discussed the angiographic comparison of lesion outcomes pre- and post-IVL. As such, the studies included did not allow adjunctive treatment with atherectomy or specialty cutting balloons. Currently, there is no head-to-head RCT comparing atherectomy (orbital or rotational) or cutting balloons with IVL.
Mhanna et al (2022) noted that IVL is a recently introduced therapeutic modality in the management of CCAD. These investigators carried out a comprehensive literature search for studies that examined the use of adjunctive IVL. The primary outcomes of this study were the clinical success, defined as the ability of IVL to produce residual diameter stenosis of less than 50 % (RDS < 50 %) after stenting with no evidence of in-hospital MACEs, and the angiographic success, defined as success in facilitating stent delivery with RDS < 50 % and without serious angiographic complications. The secondary outcomes included post-IVL and post-stenting changes in lumen area, calcium angle, and the maximum calcium thickness. Proportional analysis was used for binary data and mean difference was used for continuous data. All meta-analyses were conducted using a random-effect model and 95 % CIs were included. A total of 8 observational, single-arm studies, including 980 patients (1,011 lesions), were included; 48.8 % of the patients presented with ACS. Severe calcifications were present in 97 % of lesions. Clinical success was achieved in 95.4 % of patients (95 % CI: 92.9 % to 97.9 %). Angiographic success was achieved in 97 % of patients (95 % CI: 95 % to 99 %). There was an overall increase in post-procedural lumen area as well as significant reduction of calcium angle and maximum calcium thickness. The authors concluded that IVL appeared to have excellent safety and efficacy in the management of CCAD; however, adequately powered RCTs are needed to evaluate IVL compared to other calcium/plaque modifying techniques.
Honton and Monsegu (2022) stated that IVL is a novel approach to lesion preparation of severely calcified plaques in coronary and peripheral vessels. Lithotripsy is delivered by vaporizing fluid to create an expanding bubble that generates sonic pressure waves that interact with arterial calcification. Available data indicated that IVL led to increased vessel compliance before stent implantation with high efficacy and an excellent safety profile. Since it gained the CE mark in 2017, and with improved operator experience, the use of IVL has expanded into more complex clinical situations. The authors concluded that IVL is a promising therapy for complex calcified lesions with a short learning curve and a favorable safety profile; however, knowledge of the technical characteristics of the catheter and appropriate considerations in terms of preparation, use and specific conditions for IVL will improve daily results and outcomes in patients presenting with complex calcified coronary disease.
Sharma (2022) described a case of right coronary artery (RCA) calcifications successfully managed with shockwave intravascular lithotripsy (IVL)-assisted staged percutaneous coronary intervention (PCI). This case entailed a 74-year-old male patient presented with ST-segment elevation myocardial infarction (STEMI). At that time, coronary angiography demonstrated calcific thrombotic occlusion in the left anterior descending artery (LAD) and stenosis in proximal and mid tubular RCA. It was decided to proceed with immediate PCI of LAD followed by staged PCI of RCA. The patient presented with unstable angina at the time of the second repeat PCI of RCA and was managed with shock wave IVL-assisted staged PCI. The patient's condition was improved with good thrombolysis in myocardial infarction (TIMI) flow. The author stated that IVL is a relatively novel technique designed to overcome calcified stenosis in coronary arteries, with promising outcomes from several clinical trials.
Rola et al (2022) stated that the unprotected calcified left main disease represents a high-risk subset for PCI, and it is associated with a higher number of peri-procedural complications and an increased rate of in-stent thrombosis and re-stenosis. Adequate lesion preparation plays a crucial role in achieving a favorable PCI outcome. Rotational atherectomy (RA) is a well-established plaque-modifying method; nevertheless, the data regarding the effectiveness of RA in LM diseases is scarce. Recently, the novel ShockWave-Intravascular-Lithotripsy(S-IVL) device has been introduced to the PCI armamentarium in order to modify the calcified plaque. These researchers conducted a retrospective evaluation of 44 consecutive subjects who underwent the LM-PCI, and who were supported by either the RA or S-IVL. The Rota group consisted of 29 patients with a mean syntax score of 28.0 ± 7.5. The S-IVL group was composed of 15 subjects with a syntax score of 23.3 ± 13.0. There were no statistical differences regarding MACE between the RA and Shockwave arms of the in-hospital group (10.3 % versus 6.7 %), or in the 6-month (17.2 % versus 13.3 %) follow-up group. The authors concluded that RA and S-IVL could be safe and effective therapeutic strategies for calcified LM disease. Moreover, these researchers stated that further studies with a higher number of participants and longer follow-up times are needed to establish the potential benefits of RA and S-IVL for the management of LM stenosis. These investigators stated that this was a retrospective, observational, non-randomized, pilot study with a relatively short observation period (6 month follow-up). The study population was not large, and it was under-powered in terms of its ability to conduct a reliable assessment of events. Moreover, the rate of intravascular guidance for PCI procedures was comparatively low.
In a retrospective, single-center study, Rao et al (2022) examined safety and effectiveness of IVL in management of coronary artery calcification. Patients with hemodynamically stable acute coronary syndrome or symptomatic chronic coronary syndrome (CCS) and calcified coronaries on angiography and who underwent IVL were enrolled. Intravascular imaging was performed wherever feasible. The primary endpoint was procedural success. Furthermore, data regarding procedural complications were collected. A total of 29 patients underwent IVL with a majority being males and having co-morbidities such as hypertension and diabetes. A procedural success rate of 93.1 % was achieved with no patient having greater than 50 % residual stenosis. IVL catheter was successfully delivered in all patients. The mean catheter diameter was 3.3 ± 0.4 mm and mean number of delivered pulses was 70.3 ± 16.4. The arteries most commonly intervened were the left main coronary and the left anterior descending artery. Intracoronary imaging revealed a significant increase in minimum luminal cross-sectional area (MLA) post IVL (pre-MLA: 5.1 ± 2.5 mm2; post-MLA: 10.7 ± 2.9 mm2; p < 0.001). Two patients had in-hospital MACE in form of peri-procedural non Q-wave MI. No patient had arrhythmias, stent thrombosis, coronary perforation, or slow flow/no-reflow. Two patients had a rupture of IVL balloon while 4 had coronary artery dissection. The authors concluded that IVL was a safe and highly effective modality with high procedural success rate in management of calcified coronaries. The authors stated that the limitations of the study were the retrospective design, a small sample size, and the non-randomized nature with lack of a comparative control group. Furthermore, a lack of follow-up data and an absence of core laboratory analysis and intravascular imaging for the entire dataset were other limitations.
Kereiakes et al (2022) stated that coronary calcification impairs stent delivery and optimal expansion, a significant predictor of subsequent stent thrombosis and re-stenosis. Current calcium ablative technologies may be limited by guide-wire bias and peri-procedural complications. IVL delivers acoustic pressure waves to modify calcium, enhance vessel compliance, and optimize stent deployment. The Disrupt CAD III study demonstrated high (92.4 %) procedural success and low (7.8 %) 30-day MACE rates following IVL; however, longer term follow-up is needed to determine the durability of clinical benefit and the late impact of optimized stent implantation associated with IVL. This analysis evaluated 1-year outcomes from the Disrupt CAD III study. Disrupt CAD III was a prospective, single-arm approval study designed to assess the safety and effectiveness of IVL as an adjunct to coronary stenting in de-novo, severely calcified coronary lesions (n = 384). MACE was defined as the composite of cardiac death, MI, or ischemia-driven target vessel revascularization (TVR); target lesion failure was defined as cardiac death, MI, or ischemia-driven target lesion revascularization (ID-TLR). At 1 year, MACE occurred in 13.8 % of patients (cardiac death: 1.1 %, MI: 10.5 %, ischemia-driven TVR: 6.0 %) and target lesion failure occurred in 11.9 % (ID-TLR: 4.3 %), both driven by non-Q-wave MI (9.2 %). Stent thrombosis (definite or probable) occurred in 1.1 % of patients (including 1 event [0.3 %] beyond 30 days). The authors concluded that the Disrupt CAD III represented the largest long-term (1-year) analysis of coronary IVL to-date. IVL treatment prior to coronary stent implantation in severely calcified lesions was associated with low 1-year rates of MACE, ID-TLR, and stent thrombosis. Moreover, these researchers stated that further investigation is needed to examine if IVL can effectively reduce the longer term (beyond 1 year) annualized incidence of adverse stent device-related events in patients with severe target lesion calcification.
The authors stated that this study had several drawbacks. First, Disrupt CAD III was a single-arm study without a randomized comparator or concurrent control arm; as such, comparisons with ORBIT II or other trials should be considered hypothesis-generating. Furthermore, randomized studies would be needed to compare the impact of IVL treatment versus other calcium-modifying technologies on longer term outcomes. Second, multiple angiographic and patient demographic subsets were excluded per protocol which limited broader generalization of the observations to a “real-world” all-comers population. These groups included biomarker-positive acute coronary syndromes, severe renal insufficiency, extreme target vessel tortuosity, or unprotected left main, ostial, and saphenous vein bypass graft target lesions. Nevertheless, this study represented the largest clinical trial experience with coronary IVL in patients with severe lesion calcification who are often excluded from participation in most clinical trials. Similarly, patients with moderately calcified lesions were not included in the present study. The relative safety and effectiveness of IVL has not been examined in such lesions. Finally, the relationship between the intravascular imaging findings from the Disrupt III OCT sub-study and 1-year clinical outcomes has not yet been analyzed. A larger pooled analysis from the Disrupt CAD study is ongoing and will be better powered to assess these relationships.
Yap et al (2022) stated that coronary artery calcification can lead to suboptimal results when performing coronary angioplasty with conventional techniques. Shockwave intravascular lithotripsy (IVL) has recently been introduced as a new modality to treat heavily calcified coronary arteries. In a prospective, single-center study, these researchers examined the safety and procedural success of IVL in calcified lesions. Intra-vascular ultrasound (IVUS) was used in all cases to characterize the lesions pre-procedure and to assess procedural success post-procedure. The primary endpoint was procedural success, defined by IVL treatment and successful stent implantation. The secondary endpoint was in-hospital and 30-day MACE. A total of 5 patients with severely calcified lesions were successfully treated with IVL. The primary endpoint was achieved in all patients. All of the lesions were severely calcified with concentric calcium. Multiple calcium fractures were identified on IVUS after IVL in all cases. None of the patients suffered in-hospital or 30-day MACE. The average diameter stenosis at baseline was 1.8 ± 0.4 mm and the post PCI diameter stenosis was 2.9 ±0.1 mm, with significant acute luminal gain of 1.2 ± 0.3 mm (p < 0.01). There were no complications of coronary dissection, slow or no reflow, stent thrombosis, or vessel perforation. The authors concluded that their initial experience showed the feasibility and safety of IVL in the management of calcified coronary stenosis. The shockwave IVL is an effective treatment approach to disrupt coronary calcification, facilitating stent implantation with optimal results. It is a safe procedure with a good success rate and low rate of complications. Moreover, these researchers stated that this was a prospective, single-arm registry with a short-term follow-up period of 30 days. The study comprised a small study cohort (n = 5). They stated that larger randomized studies or clinical registries of IVL with long-term follow-up will be of significant clinical value.
Gardiner et al (2022) stated that coronary artery calcification (CAC) is commonly encountered by interventional cardiologists. Severe CAC may impair stent delivery or result in stent under-expansion, stent thrombosis and/or in-stent restenosis (ISR). Multiple tools have been developed to help overcome the challenges associated with CAC and improve outcomes for these patients. Intravascular shockwave lithotripsy (IVL) is a novel therapy that uses acoustic pressure waves for the modification of CAC. These researchers discussed the growing body of evidence to support the safety and effectiveness of IVL in the setting of de-novo severely calcified coronary arteries prior to stenting. They also discussed international real-world experience with the coronary IVL system. This included the use of IVL in the setting of acute coronary syndrome (ACS), ISR, and in combination with other tools for calcium modification. The authors concluded that IVL is a safe and effective therapy that results in the fracture of coronary calcium and facilitates optimal stent delivery and expansion. Moreover, these investigators stated that longer term follow-up is essential to shed light on the durability and late outcomes of an IVL strategy; RCTs are needed to compare IVL to alternative methods of calcium modification and to examine further the use of IVL for ACS.
The American College of Cardiology/American Heart Association practice guideline on “Coronary artery revascularization” (Lawton et al, 2022) stated that “Fibrotic or heavily calcified lesions can hinder stent expansion. The presence of calcium deposits thicker than 500 μm or calcium involving an arc of the vessel greater than 270° on intravascular imaging predicts the need for lesion modification to facilitate stent delivery. Lesions can be modified by using rotational atherectomy, orbital atherectomy, cutting balloon atherotomy, intracoronary lithotripsy, or excimer laser angioplasty. Despite promising results from hundreds of small mechanistic studies, dozens of large, randomized trials have shown that the routine use of athero-ablative devices does not improve clinical or angiographic outcomes”. The guideline rendered a IIb “may be considered” rating with the use of intracoronary lithotripsy for the treatment of fibrotic or heavily calcified lesions.
In a prospective, single-center registry, Yap et al (2023) examined he procedural success and safety of orbital atherectomy (OA) in calcified lesions. IVUS or optical coherence tomography (OCT) was used in all cases to characterize the severity of calcium pre-procedure, guide vessel sizing, and assess procedural success. The primary endpoint was procedural success, defined by successful stent implantation following OA treatment. The secondary endpoint was in-hospital and 30-day MACE. A total of 10 patients with severely calcified lesions were successfully treated with OA. The primary endpoint was achieved in all patients. All of the lesions were severely calcified with concentric calcium. None of the patients suffered in-hospital or 30-day MACE. The average minimal luminal diameter at baseline was 1.7 ± 0.3 mm and the post- PCI luminal diameter was 3.0 ± 0.3 mm, with a significant luminal gain of 1.3 ± 0.3 mm (p < 0.01). Slow flow during procedure occurred in 2 (20 %) cases, and dissection occurred in 1 (10 %) case during procedure. These were successfully treated with stent delivery to achieve TIMI III flow. There were no cases of stent thrombosis or vessel perforation. The authors concluded that their experience showed the feasibility and safety of OA in the management of calcified coronary stenosis. Intravascular imaging is an important adjunct to the use of OA to assess the severity of calcified coronary lesions, success of OA treatment, and to aid sizing of the vessel for stent implantation. OA is an effective treatment approach to disrupt coronary calcification, facilitating stent implantation with optimal results. It is a safe procedure with good success rate and low rate of complications. These researchers stated that this was a prospective, single-arm registry with short-term follow-up period of 30 days. They stated that larger, randomized studies or clinical registries of OA with long-term follow-up will be of significant clinical value.
Farhat et al (2023) stated that the use of rotational atherectomy (RA) and IVL in patients with ISR is still controversial. In a retrospective, single-center study, these researchers examined the safety and feasibility of RA and IVL in patients with calcified ISR. They also compared in-hospital and 1-year clinical outcomes between both groups. This trial included patients with calcified ISR treated with RA (between 2012 and 2021) and IVL (between 2019 and 2021). In-hospital and 1-year clinical outcomes were compared between IVL and RA patients. A total of 28 patients with ISR who underwent RA were compared with 24 ISR subjects after IVL. The procedural success rate was 100 % in both the groups. Quantitative coronary analysis revealed a similar degree of stenosis prior (66.4 ± 11.4 versus 68.8 ± 19.7, p = non-significant [NS]), and after the procedure (21.5 ± 20.5 versus 22.8 ± 12.1, p = NS) with no difference in acute luminal gain (1.34 ± 0.60 versus 1.38 ± 0.59, p = NS). There was 1 in-hospital MACE in the RA group. At 1-year follow-up, no difference was observed with respect to MACE rate (14.3 % versus 16.7 %, p = NS) and TLR (7.1 % versus 12.5 %, p = NS). The authors concluded that RA and IVL were safe and feasible techniques for calcified ISR yielding comparable results at 1-year follow-up. Moreover, these researchers stated that further clinical studies are needed to confirm these findings and shed more light on patient and lesion characteristics associated with the best outcomes.
In a retrospective, single-center study, Sandesara et al (2023) examined the safety and effectiveness of IVL for the treatment of calcified distal left main (LM) disease. These researchers analyzed the baseline clinical, angiographic, IVUS characteristics and procedural outcomes of 107 patients who underwent distal LM PCI with IVL (with or without adjunct atherectomy) versus RA alone for plaque modification before stenting. A total of 50 patients underwent calcium modification with IVL with or without adjunct atherectomy and 57 with RA only. The mean age was 73 years and with a high prevalence of diabetes (58.9 %), chronic kidney disease (42.1 %), prior re-vascularization (coronary artery bypass graft surgery [36.4 %] or prior PCI [32.7 %]). Acute coronary syndrome was the primary indication for PCI in over 50 % of the patients in both groups. Medina 1-1-1 LM bi-furcation disease was identified in 64 % and 60 % of the IVL and RA groups (p = 0.64), respectively. Final minimum stent area in distal LM (greater than 8.2 mm2 ), ostial LAD (greater than 6.3 mm2 ) and ostial LCX (greater than 5.0 mm2 ) were achieved in 96 %, 85 %, and 89 % of cases treated with IVL, respectively; and 93 %, 93 %, and 100 % of cases treated with RA, respectively (LM p = 1.00; LAD p = 0.62; LCX; p = 1.00 for difference between the 2 groups). Procedural success (technical success without in-hospital major AEs) was achieved in 98 % of the IVL group, and 86 % of the RA-only group (p = 0.04). There were 8 procedural complications (flow-limiting dissection, perforation, or slow/no-reflow) in the RA group compared to four4 in the IVL group (NS), and 1 patient in the RA required salvaged mechanical support compared to none in the IVL group. The authors concluded that plaque modification with coronary IVL appeared to be safe and effective for the treatment of severely calcified distal LM lesions compared to RA only. Moreover, these researchers stated that larger randomized studies are needed to confirm these findings.
In a retrospective study, Hesse et al (2023) examined the feasibility of IVL versus RA in unprotected calcified left main coronary artery (LMCA) disease. These researchers analyzed IVL and RA procedures carried out at a large tertiary hospital in the Northeast of England from January 1, 2019 to April 31, 2022. Major safety and effectiveness endpoints were procedural and angiographic success, defined by stent delivery with less than 50 % residual stenosis and without clinical or angiographic complications, respectively. Another important clinical endpoint was the composite of MACE at 1 year. From a total of 242 patients, 44 had LMCA IVL, 81 had LMCA RA, and 117 had non-LMCA IVL. Patients with LMCA disease were older and more likely to have aortic stenosis. IVL was a 2nd-line or bailout technique in 86.4 % LMCA, and 92.2 % non-LMCA cases. Procedural and angiographic success rates were 84 % or higher across all groups (p > 0.05). In 3 LMCA IVL, and 3 LMCA RA cases arrhythmias and cardiac tamponade complicated the procedures, respectively. At 1 year, MACE occurred in 10/44 (22.7 %) LMCA IVL, 16/81 (19.8 %) LMCA RA, and 25/117 (21.4 %) cases (p > 0.05). The authors concluded that IVL was feasible in unprotected calcified LMCA as a 2nd-line and 3rd-line adjuvant calcium modification technique. Moreover, these researchers stated that Its use in unprotected calcified LMCA disease should be formalized with the undertaking of large RCTs.
Rola et al (2023) stated that successful PCI in CTO improves the long-term outcome in patients with coronary artery disease (CAD). Heavy calcification remains one of the strongest predictors of an unfavorable outcome of PCI. In a case-series study, these researchers examined the effectiveness of shockwave IVL (S-IVL), a novel balloon-based coronary system, in facilitating modification of calcified coronary lesions. Participants entailed 5 patients with heavily calcified, un-dilatable CTOs lesions who were treated with S-IVL; they were selected out of all consecutive CTO-PCI patients performed at 2 high-volume cardiac centers. The registry included 5 patients successful CTO S-IVL procedures with an average J-CTO score of 2.6 points. In the short-term follow-up period, including the first 30 days, no cases of acute in-stent thrombosis, target lesion failure, or MACE and cerebrovascular events were noted. The authors concluded that these findings suggested that this approach can be safe and useful in the treatment of complex calcified CTO lesions.
Lv et al (2024) noted that severe coronary artery calcification is associated with low success rate of interventional operation, peri-operative adverse cardiac events, and poor prognosis, which is a major problem faced by operators. The existing therapy methods all have inherent limitations, such as unsatisfactory balloon cross-ability, inadequate balloon dilation, and so on. The emergence of IVL has brought the dawn of the treatment of calcified lesions by using unfocused acoustic pressure waves to fracture calcification in-situ; and IVL is the only technology capable of targeting deep calcification. These researchers hypothesized that IVL may have great clinical application values and potential prospects. Based on the existing clinical evidence of IVL and traditional treatment ways, these investigators discussed the safety and effectiveness of IVL. Combined with clinical practice, the precautions and coping strategies of IVL were analyzed. The authors concluded that any technology is constantly updated to achieve the best practical value, and IVL is no exception. Reducing the crossing profile of the balloon of IVL can optimize its cross-ability. Increasing the length and diameter of a single balloon of IVL or increasing the total pulse number of IVL can further reduce the time and cost of operation on the basis of expanding the application range. These researchers stated that the existing evidence shows that IVL has great application prospects and potential application value in valvular heart diseases accompanied by calcification. They noted that perhaps the emergence of IVL will set off a revolution in the treatment of coronary artery calcification.
In a prospective, multi-center, real-world registry, Rodriguez-Leor et al (2024) examined the performance of coronary IVL in calcified coronary lesions in a real-life, all comers, setting. The REPLICA-EPIC18 study prospectively enrolled consecutive patients treated with IVL in 26 centers in Spain. An independent core laboratory carried out the angiographic analysis and event adjudication. The primary effectiveness endpoint assessed procedural success (successful IVL delivery, final diameter stenosis of less than 20 %, and absence of in-hospital MACE). The primary safety endpoint measured freedom from MACE at 30 days. A pre-defined sub-study compared outcomes between ACS and chronic coronary syndrome (CCS) patients. A total of 426 patients (456 lesions) were included, 63 % of the patients presenting with ACS. IVL delivery was successful in 99 % of cases. Before IVL, 49 % of lesions were considered un-dilatable. The primary effectiveness endpoint was achieved in 66 % of patients, with similar rates among CCS patients (68 %) and ACS patients (65 %). Similarly, there were no significant differences in angiographic success after IVL between CCS and ACS patients. The rate of MACE at 30 days (primary safety endpoint) was 3 % (1 % in CCS, and 5 % in ACS patients; p = 0.073). The authors concluded that coronary IVL proved to be a feasible and safe procedure in a "real-life" setting, effectively facilitating stent implantation in severely calcified lesions. Patients with ACS on admission showed similar angiographic success rates but showed a trend toward higher 30-day MACE compared with patients with CCS. Moreover, these researchers stated that the impact of these good initial findings on long-term clinical outcomes has yet to be determined.
The authors stated that this study had several drawbacks. First, this non-randomized study design lacked a concurrent control group. Despite this drawback, the study showed a high procedural success rate and a remarkably low peri-procedural MACE rate, even considering the severity of lesion calcification and patient complexity in the study population. These positive outcomes, combined with the ease-of-use and rapid learning curve associated with IVL, strongly suggested that the technology may have a crucial role to play in the treatment of complex and high-risk calcified lesions. Second, there were certain lesions that were not appropriate for core laboratory analysis for various reasons. In 22 cases, the complexity of the lesions, such as overlapping branches or bi-furcation treatment with 2 stents, made them unsuitable for analysis. In 18 cases, the poor quality of the recordings, including the absence of a final result angiographic study or only fluoroscopy recording, prevented proper assessment. In addition, in 14 cases, the recordings were not sent to the core laboratory for analysis. Third, only 43 % of lesions were treated guided by intra-coronary imaging. Although the use of intra-coronary imaging is especially useful in the treatment of calcified lesions, these data represented real-life use outside the controlled context of clinical trials, and in fact, in the Disrupt CAD III Trial, only 100 patients out of 431 had intra-coronary OCT imaging.
Butala et al (2024) stated that calcified coronary lesions are a challenge for PCIs. Coronary IVL is a novel calcium modification technology approved for commercial use in February 2021; however, little is known regarding its uptake in U.S. clinical practice. These researchers described trends in use of calcium modification strategies, variation in use across hospitals, and predictors of calcium modification and IVL use in PCI. they included National Cardiovascular Data Registry CathPCI Registry patients who underwent PCI between April 1, 2018, and December 31, 2022. These investigators examined trends and hospital variation in calcium modification and IVL use. They used multi-variate hierarchical logistic regression to identify predictors of calcium modification and IVL use at hospitals in 2022. Of 2,733,494 PCIs across 1,676 hospitals over 4.75 years, 11.4 % were performed with calcium modification. Coronary IVL use increased rapidly from 0 % of PCIs in Q4 2020 to 7.8 % of PCIs in Q4 2022, which was accompanied by an overall increase in use of all calcium modification strategies (11.1 % to 16.0 %) during this period with a slight corresponding decrease in coronary atherectomy use (5.4 % to 4.4 %). In 2022, there was wide variation in IVL use across hospitals (median of 3.86 %; IQR, 0 % to 8.19 %), with IVL being the most common calcium modification strategy in 48 % of hospitals. The treating hospital was the strongest predictor of calcium modification (median odds ratio [OR], 2.49; 95 % CI: 2.40 to 2.57) and IVL use (median OR, 2.89; 95 % CI: 2.74 to 3.04). The authors concluded that the introduction of IVL has changed the landscape of calcium modification use for PCI. There was rapid uptake in use of coronary IVL after its commercial introduction in the U.S., which primarily resulted in an overall increase in use of calcium modification for PCI with some displacement of atherectomy. Furthermore, there remains wide variation in calcium modification and IVL use, and the strongest predictor of use was treating hospital site, which may reflect hospital price sensitivity to costly novel technologies or the selective rollout of IVL. These researchers found evidence of race and sex differences in the use of calcium modification for PCI and the initial use of IVL, which lends insight into the prevalence of calcified lesions in these demographic subgroups and has implications for the equitable rollout of novel technologies in interventional cardiology in the future.
The authors stated that these findings should be interpreted in the context of the following potential drawbacks. First, these results contained data only from hospitals participating in the CathPCI Registry and may not reflect non-participating hospitals; however, more than 90 % of hospitals participated in the CathPCI Registry, and it is thought to be nationally representative. Second, granular data on coronary calcification (arc of calcium, degree of calcification, and presence of nodules) or use of intravascular imaging was not available in the CathPCI database, and could affect use of calcium modification strategies. However, results were similar when repeated among the subset of patients with severely calcified lesions. Third, this study focused on patients who underwent PCI; however, the degree to which PCI was not attempted in patients with severe coronary calcification, or how the treatment rate of such lesions varied over time, could not be addressed.
Riley et al (2024) stated that the prevalence of calcification in obstructive coronary artery disease is on the rise; PCI of these calcified lesions is associated with increased short-term and long-term risks. To optimize PCI results, there is an expanding array of treatment modalities devoted toward calcium modification before stent implantation. The Society for Cardiovascular Angiography and Interventions put forth an expert consensus document regarding methods to identify types of calcified coronary lesions, a central algorithm to help guide use of the various calcium modification strategies, tips for when using each treatment modality, and a look at future studies and trials for treating this challenging lesion subset. This consensus document noted that IVL may be used in the presence of multiple guide-wires (e.g., bifurcation lesions) and may also be advantageous in aorto-ostial lesions. While hemodynamically vulnerable patients may not tolerate repeated or prolonged balloon obstruction of coronary flow during delivery of IVL therapy, recent data showed safety and feasibility of IVL in left main coronary artery PCI, and the rate of slow flow/no-reflow was lower with IVL than that with RA or OA. The off-label use of IVL has also been widely adopted in the treatment of stent under-expansion due to calcium, calcific neo-atherosclerosis within the stent, or nodular re-protrusion. The key limitation of the device, as with the other balloon-based technologies, is deliverability; however, this can be mitigated with increasing guide support via guide shape, guide extensions, buddy wires, or other techniques. Overall angiographic complication rates were less than 0.5 %. Moreover, these researchers stated that several RCTs evaluating IVL are underway. The Short-Cut (Shockwave Lithoplasty Compared to Cutting Balloon Treatment in Calcified Coronary Disease Trial; NCT06089135) trial aims to randomize 410 patients with calcified lesions to IVL versus cutting balloon (CB) in 2 cohorts -- those prepared with or without RA. The DECALCIFY (Prospective, Randomized, Controlled, Multicenter Study for the Treatment of Calcified Coronary Artery Lesions With Rotational Atherectomy versus Intravascular Lithotripsy; NCT04960319) Trial will randomize 100 patients to IVL versus RA and assess in-hospital MACE and stent expansion by OCT. The SONAR (Shockwave Balloon or Atherectomy with Rotablation in Calcified Coronary Artery Lesions; NCT05208749) multi-center RCT of 170 patients will randomize IVL or RA and assess post-procedural myocardial infarction. The BALI (Balloon Lithoplasty for Preparation of Severely Calcified Coronary Lesions Before Stent Implantation; NCT04253171) RCT will compare IVL with the standard of care (which can include plain balloon angioplasty, CB/scoring balloons, and RA) in 200 patients with the primary endpoint being strategy failure (failed stent delivery, residual stenosis of 20 % or greater, or TVF). Finally, the VICTORY (Value of IVL Compared to OPN Non-compliant Balloons for Treatment of Refractory Coronary Lesions; NCT05346068) Trial is a non-inferiority RCT to compare the impact of IVL with that of very high-pressure balloon on final stent expansion assessed by OCT in 280 patients with calcified lesions. Furthermore, several multi-center, observational IVL studies are underway. The Intravascular Balloon Lithotripsy in Left Main Stem Percutaneous Coronary Intervention Trial (NCT04319666) aims to follow 50 patients undergoing PCI for intravascular imaging–defined calcified left main disease. The EMPOWER CAD Trial (Equity in modifying plaque of women with under-treated calcified CAD; NCT05755711) is a post-market, multi-center, single-arm observational study to generate real-world clinical evidence associated with IVL in female patients. Other investigator-initiated, real-world registries examining the role of IVL in CAC are ongoing in various countries.
Polyzene-F Nanocoated Coronary Stent System
Cutlip et al (2022) stated that the Cobra Polyzene F nanocoated coronary stent system (PzF-coated stent) showed favorable clinical outcomes at 9 months; however, late results have not been reported. In a prospective, non-randomized study, these researchers examined the late safety and effectiveness of the PzF-coated stent for the treatment of de-novo coronary artery lesions. Patients with de-novo coronary artery lesions meeting eligibility criteria were enrolled in this trial and followed for 5 years. The primary endpoint was cardiac death, MI, target vessel failure (TVF), or clinically driven target vessel revascularization [TVR]) at 9 months. Secondary endpoints included MACE, cardiac death, MI, or clinically driven TLR, clinically driven TLR and definite or probable stent thrombosis (ST) during 5-year follow-up. Endpoints at 5 years were analyzed as cumulative incidence accounting for competing risk of death. Of 296 enrolled patients, 290 (98 %) were evaluable at 5 years. By 5 years, MACE had occurred in 61 (21.3 %), cardiac death in 11 (4.2 %), MI in 25 (8.6 %), and TLR in 34 (12.0 %) subjects. Between follow-up years 1 and 5, a 1st MACE occurred in 17 (6.2 %), including 10 (4.0 %) cardiac death, 4 (1.6 %) MI, and 7 (2.9 %) TLR events. There were no definite or probable ST. The authors concluded that the PzF-coated stent showed continued safety and effectiveness through 5 years with low-to-very low incident rates of MACE, MI, TLR and ST between 1 to 5 years following stent placement.
Bian et al (2023) noted that a stent for patients with coronary heart disease (CHD) provides a requirement for a long-term anti-platelet therapy because of the high possibility of the development of stent thrombosis. It was against this background that both Cobra and Catania PzF stents were designed to reduce the occurrence of ST. In a systematic review and single-arm meta-analysis, these investigators examined the safety and effectiveness of a PzF-nanocoated stent. The inclusion criteria entailed studies among patients with PzF-nanocoated coronary stents and reported target vessel failure (TVF) and ST as the outcomes, and the exclusion criteria entailed reported patients who could not receive the adjunctive medical therapies or without the necessary endpoints. Studies regarding PzF-nanocoated stents were searched in PubMed, Embase, and Web of Science and other sources. Because of the existence of few reports and a lack of comparison groups, a single-arm meta-analysis was carried out in R software (v3.6.2), using a random-effects model with the generic inverse variance method. After a heterogeneity test, assessment of evidence quality was performed by using Grading of Recommendations, Assessment, Development and Evaluation (GRADE) software. A funnel plot Egger's test was carried out to examine publication bias, and a sensitivity analysis was carried out to determine the robustness of the overall effects. A total of 6 studies of 1,768 subjects were included. The primary endpoint that pooled the TVF rate was 8.9 % (95 % CI: 7.5 % to 10.2 %), which comprised the pooled cardiac death (CD) rate (1.5 %, 95 % CI: 0 % to 3 %), MI rate (2.7 %, 95 % CI: 0.4 % to 5.1 %), TVR (4.8 %, 95 % CI: 2.4 % to 7.2 %), or TLR (5.2 %, 95 % CI: 4.2 % to 6.4 %), while the secondary endpoint ST was 0.4 % (95 % CI: 0.1 % to 0.9 %). The funnel plots of TVF, CD, TVR, and TLR did not show any serious publication bias, and TVF, TVR, and TLR showed evidence of moderate quality in GRADE assessment. The sensitivity analysis showed that TVF, TLR, and ST exhibited good stability (I2 = 26.9 %, 16.4 %, and 35.5 %, respectively), while the other endpoints demonstrated moderate instability. The authors concluded that these findings showed that the PzF-nanocoated coronary stents of the Cobra and Catania systems exhibited good safety and effectiveness in clinical application; however, the sample size of patients included in the reports was relatively small, and this meta-analysis will be updated if more studies in this field are published in the future.
The authors stated that as the amount of included reports and the total objective size were relatively small in this single-arm meta-analysis, publication bias analysis and sensitivity analysis were performed, which yielded relatively robust results. Moreover, there was a relatively obvious heterogeneity in some outcome parameters, and subgroup analysis showed that the main heterogeneity derived from the studies of COBRA stents. The principal drawback of this study was the lack of comparison studies such as an RCT clinical trial design, and the publication bias analysis may produce more accurate results when more studies are included.
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