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Background
This policy is consistent with the Food and Drug Administration (FDA)-approved indications for sirolimus-eluting stents (Rx Velocity, Cordis, Johnson & Johnson) and paclitaxel-eluting stents (Taxus Express, Boston Scientific Corporation).
The use of stents has improved the results of percutaneous coronary re-vascularization. However, in-stent restenosis due to neointimal proliferation of connective tissue has been reported to occur in approximately 15 to 20 % of stent patients.
The macrolide anti-fungal agent sirolimus (rapamycin) has been shown to inhibit the proliferation of lymphocytes and smooth muscle cells and has been applied to the interior of balloon-expandable stents. The Rx Velocity consists of a stent coated with a mixture of synthetic polymers blended with sirolimus. The Rx Velocity is designed to release 80 % of the drug within 30 days after stent implantation. Only a small amount of the drug is required, and systemic side effects from the drug are avoided.
The FDA approved the stent based on a review of 2 clinical studies of safety and effectiveness of the sirolimus-eluting stent. In a multi-center, randomized, double-blind, controlled clinical trial conducted in the United States (the SIRIUS study), 1,058 patients were randomly assigned to receive either the sirolimus-eluting stent or an uncoated stainless steel stent. Patients in the SIRIUS study had blockages of 15 mm to 30 mm long in arteries that were 2.5 mm to 3.5 mm wide.
Results were similar for both types of stents in the weeks immediately following the procedure, but after 9 months the patients who received the drug-eluting stent had a significantly lower rate of repeat procedures than patients who received the uncoated stent (4.2 % versus 16.8 %). In addition, patients treated with the drug-eluting stent had a re-stenosis rate of 8.9 %, compared to 36.3 % of patients with the uncoated stent. The combined occurrence of repeat angioplasty, bypass surgery, myocardial infarction and death was 8.8 % for drug-eluting stent patients and 21 % for the uncoated stent patients. The types of adverse events seen with the drug-eluting stent were similar to those that occurred with the uncoated stent.
The FDA's approval of the sirolimus-eluting stent was also based on the results of a non-U.S. multi-center, randomized, double-blind, controlled clinical trial (the RAVEL study) comparing sirolimus-eluting stents with standard uncoated stents in 238 adults with stable or unstable angina pectoris or silent ischemia and single coronary lesions amenable to stenting. Lesions had to be between 2.5 mm and 3.5 mm in diameter, such that they could be covered by an 18 mm stent. Patients with complex coronary lesions, such as those containing substantial calcium or thrombus, were excluded from the study.
The investigators reported that use of a sirolimus-eluting stent resulted in the virtual elimination of angiographic evidence of neointimal hyperplasia and re-stenosis and greatly reduced the need for repeated re-vascularization procedures. At 6 months after stent placement, there was significantly less in-stent late luminal loss (a measure of neointimal proliferation) in patients receiving sirolimus-eluting stents than in patients receiving standard, uncoated stents. None of the patients receiving sirolimus-eluting stents had restenosis of 50 % or more of the luminal diameter, compared to 26.6 % of patients receiving standard stents. Within 1 year following stent placement, percutaneous re-vascularization had been performed in 22.9 % of recipients of standard, uncoated stents, and in none of the recipients of sirolimus-eluting stents. The investigators concluded that angina patients who received sirolimus-eluting stents had no angiographic evidence of late luminal loss or in-stent restenosis at 6 months after sirolimus-eluting stent placement and a very low rate of cardiovascular events within the year following stenting.
The safety and effectiveness of the Cypher stent in smaller diameter arteries or for longer blockage that required more than 2 stents was not studied in either trial. Also, the safety and effectiveness have not been studied in patients who are having a heart attack, patients who had previous intravascular radiation treatment, or patients who had their blockage in a bypass graft.
The FDA-approved labeling of the sirolimus-eluting stent warns that patients who are allergic to sirolimus or to stainless steel should not receive a Cypher stent. Caution is also recommended for people who have had recent cardiac surgery and for women who may be pregnant or who are nursing.
The FDA is requiring the manufacturer of the sirolimus-eluting stent to conduct a 2,000-patient post-approval study and continue to evaluate patients from ongoing clinical trials to assess the long-term safety and effectiveness of the sirolimus-eluting stent and to look for rare adverse events that may result from the use of this product.
The FDA has approved the paclitaxel-eluting stents (Taxus Express Paclitaxel-Eluting Coronary Stent System, Boston Scientific Corporation) for improving luminal diameter for the treatment of de novo lesions less than 28 mm in length in native coronary arteries greater than or equal to 2.5 to less than or equal to 3.75 mm in diameter. Paclitaxel (Taxol) is similar to sirolimus in that it has been shown to inhibit proliferation of connective tissues and smooth muscle.
Stone et al (2004) reported on the results of the Taxus-IV trial, a multi-center prospective, randomized, double-blind controlled clinical trial of a paclitaxel-eluting stent in 1,314 patients with angina or provokable ischemia who were receiving a stent in a single, previously untreated lesion in a native coronary artery. Patients in the Taxus-IV trial had vessel diameters between 2.5 and 3.75 mm, and had lesions between 10 to 28 mm in length that could be covered by a single stent. Patients with lesions of the left-main coronary artery were excluded. Patients were randomly assigned to receive either a bare-metal stent (BMS) or a paclitaxel-eluting stent (PES). At 9 months follow-up, the rate of target vessel re-vascularization due to ischemia was 12 % in patients who received the BMS, and 4.7 % in patients who received the PES (relative risk [RR] 0.39 (95 % confidence interval [CI]: 0.16 to 0.43). The rate of angiographic restenosis was 26.6 % in patients who received the BMS, and 7.9 % in patients who received the PES (RR 0.30 (95 % CI: 0.19 to 0.46). The rates of adverse events were similar between patients receiving the PES and the BMS.
The safety and effectiveness of the Taxus Express stent in smaller diameter arteries or for longer blockage that required more than 2 stents has not been studied. Also, the safety and effectiveness have not been studied in patients who are having a myocardial infarction, patients who had previous intravascular brachytherapy, or patients who had stenosis of a bypass graft.
The FDA-approved labeling of the PES warns that patients who are allergic to paclitaxel or to stainless steel should not receive a Taxus Express stent. Caution is also recommended for people who have had recent cardiac surgery and for women who may be pregnant or who are nursing.
The FDA is requiring the manufacturer of the PES to conduct a 2,000 patient post-approval study and continue to evaluate patients from ongoing clinical trials to assess the long-term safety and effectiveness of the PES and to look for rare adverse events that may result from the use of this product.
In a randomized controlled trial (n = 57), Duda et al (2005) examined the safety and effectiveness of the sirolimus-eluting S.M.A.R.T. Nitinol Self-expanding Stent by comparison with a bare stent in superficial femoral artery (SFA) obstructions. These investigators concluded that although there is a trend for greater efficacy in the sirolimus-eluting stent group, there were no statistically significant differences in any of the variables.
In a recent review on advances in the medical and surgical treatment of aorto-arteritis (also known as Takayasu arteritis), an inflammatory vascular disorder that produces arterial stenoses and aneurysms primarily involving the thoraco-abdominal aorta and its branches and the pulmonary arteries, Liang and Hoffman (2005) stated that new drugs that target intimal hyperplasia, as well as drug-eluting stents, deserve to be studied for possible utility as adjuncts to present treatments.
Dzavik (2005) stated that bifurcation lesions have been recognized as one of the most important challenges facing interventional cardiologists since the start of percutaneous coronary intervention (PCI). The potential of peri-procedural occlusion of the side branch (SB) was found to be significant, resulting in early attempts at protecting the SB with a 2nd guide wire and kissing balloon inflation in order to minimize this risk, and thus improve the procedural and short-term success of the procedure. The advent of stenting significantly improved the safety of the procedure, although, SB success continued to be a challenge. A variety of single- as well as double-stenting techniques were developed that improved the safety and short-term results of PCI involving SB. Long-term success, however, continued to elude, as a consequence of an increased need for target lesion revascularization (TLR) and higher major adverse cardiac event (MACE) rates following PCI of bifurcation lesions. The introduction of drug-eluting stents appears to have brought bifurcation PCI to a new level of long-term efficacy. Specialty bifurcation stents have been developed to provide easy access to the SB, however, these have to date had little impact on practice and have not been adopted widely. New techniques such as crush stenting and its several permutations, and simultaneous kissing stenting developed specifically for drug-eluting stents have been developed. Debate continues as to which the most effective technique is. True randomized comparisons are, however, lacking. It is likely that all of the currently utilized techniques have a place in interventional cardiologists’ quiver, and that each is appropriate in a particular anatomical scenario. Nonetheless, well-designed randomized studies assessing the various bifurcation techniques especially in complex bifurcation lesions are needed. Moreover, Iakovou et al (2005) reported that the cumulative incidence of stent thrombosis 9 months after successful drug-eluting stent implantation in consecutive "real-world" patients was substantially higher than the rate reported in clinical trials. Premature anti-platelet therapy discontinuation, renal failure, bifurcation lesions, diabetes, and low ejection fraction were identified as predictors of thrombotic events.
Shammas and Dippel (2005) stated that peripheral vascular disease (PVD) is very prevalent in the United States. Patients with PVD have a heightened inflammatory state and are at high-risk of death from acute cardiovascular problems rather than from progression of PVD. Modifiable risk factors for PVD include smoking, hypertension, diabetes, hyperlipidemia, elevated high sensitivity C-reactive protein, obesity, and the metabolic syndrome. Symptomatic treatment of claudication includes smoking cessation, exercise, cilostazol, statins, and re-vascularization with percutaneous or surgical therapy. Anti-thrombotic therapy with aspirin or clopidogrel is important to reduce cardiovascular events but does not affect symptoms of claudication. Patients with rest limb ischemia or ulceration should be re-vascularized to minimize the chance of limb loss. Percutaneous re-vascularization is not without significant complications, however, and future research needs to focus on inflammation, thrombosis, and restenosis in the PVD patient. Furthermore, new devices that tackle difficult lesions, drug-eluting stents, and pharmacological agents that reduce global atherosclerosis are on the horizon, and are likely to become critical components in the management of the PVD patient.
Owens et al (2011) stated that the endovascular management of symptomatic atherosclerotic SFA disease is challenging and requires consideration of unique anatomical, hemodynamic, and biomechanical factors. The current armamentarium of balloon catheters and flexible nitinol BMS have limited long-term effectiveness due to intimal hyperplasia resulting in re-stenosis. Unfortunately, the remarkably low re-stenosis rates achieved with drug-eluting stents (DES) placed in the coronary vasculature has not been replicated in the femoral artery. The reason for this is multi-factorial including delivery platforms, drug and dosage selection and trial design flaws. Currently, however, there are several novel therapies and delivery platforms in the development pipeline that have exhibited biologic effectiveness in pre-clinical and early clinical trials. While these offer promise in improving outcomes following lower extremity intervention, caution is warranted until the safety of these new technologies can be ensured.
Henry et al (2005) stated that percutaneous angioplasty and stent placement seem a useful technique for the treatment of vertebro-basilar insufficiency. This technique appears safe and effective for alleviating symptoms and improving blood flow to the cerebral circulation, with a low complications rate and good long-term results. However, this procedure needs experienced interventionists to choose the stent and have appropriate placement of the stent in the ostium of the vertebral artery (VA). The tortuosity of the VA may be technically challenging. The new coronary stents seem to be well-suited to treat atherosclerotic lesions of the origin and of the proximal VA. A large variability of restenosis risk has been reported. Drug-eluting stents may be the solution. The authors stated that prospective, randomized trials are needed to ascertain the clinical effectiveness of VA stenting in stroke prevention, its durability, and to define more clearly its indications.
Vermeersch and Agostoni (2005) noted that the percutaneous treatment of patients with obstructive atherosclerotic disease in degenerated coronary saphenous vein bypass grafts still remains one of the great challenges in interventional cardiology. These researchers discussed the actual evidence-based knowledge for the percutaneous management of this lesion subset, focusing in particular on the devices that are actually considered the "gold standard" for this treatment: BMS and distal protection devices. They commented on the negative results of the randomized trials regarding the promising polytetrafluoroethylene-covered stent-grafts, and offered insights into the currently available evidence for the use of DES in saphenous vein grafts. The authors stated that these devices are potentially the key promise for the long-term successful sealing of vein graft disease; however, clear and definitive data from controlled studies are needed.
Kolluri et al (2006) noted that renal artery stenosis (RAS) is a progressive manifestation of atherosclerosis. It is associated with hypertension and progressive renal failure. Non-invasive testing includes renal artery duplex, computed tomographic angiography and magnetic resonance angiography. Percutaneous transluminal renal angioplasty and stenting (PTRAS) is indicated for significant atherosclerotic RAS while percutaneous transluminal renal angioplasty is indicated for fibromuscular dysplasias associated with the proper clinical indications. PTRAS is associated with a high technical success rate and an acceptable adverse event and restenosis rate. Moreover, PTRAS appears to improve control of hypertension and renal preservation. All patients should be followed clinically and with periodic duplex ultrasonography. Re-stenosis is treated with repeat angioplasty and occasionally stenting. Current and future areas of investigation will involve distal protection and DES.
At the 2006 European Society/World Congress of Cardiology, results of 3 studies suggested that DES may lead to an increased risk of death and cardiac events compared with BMS. One study suggested an increase in death and Q-wave MI in subjects receiving a sirolimus-eluting stent, while the other indicated that this type of DES might increase non-cardiac mortality.
In the first study, Camenzind and associates performed a meta-analysis on randomized clinical studies comparing 1st-generation DES with BMS. Sirolimus-eluting stent trials entailed the RAVEL, SIRIUS, E-SIRIUS, and C-SIRIUS, and included 878 patients fitted with the novel stent and 870 who received BMS. The PES trials entailed TAXUS II, IV, V, and VI, and included information on 1,685 patients fitted with this stent and 1,675 who received BMS. The pooled incidence of death and Q-wave MI combined, analyzed from within the program by time points of follow-up, was significantly higher with the sirolimus-eluting stent than the BMS at 3 years, at 6 % versus 4 %, representing a 33 % relative increase in risk. In PES trials, the incidence of the combined endpoint at 3 years was 3.5 % with the DES compared with 3.1 % for the BMS. Pooling the latest follow-up data from each trial program revealed that the incidence all-cause death or MI was 2.4 % higher with the sirolimus-eluting stent than the BMS (6.3 % versus 3.9 %) and 0.3 % higher for PES than the BMS (2.6 % versus 2.3 %). Further analysis indicated that the rate of total mortality and Q-wave MI combined was a significant 38 % higher with the sirolimus-eluting stent versus the BMS (p = 0.03), while there was a trend towards a 16 % higher incidence with the PES. These researchers warned against indiscriminate use of 1st-generation DES and said that use of BMS may still be maintained, while awaiting safer 2nd-generation DES.
In the second study, Nordmann et al conducted a meta-analysis of randomized controlled trials that compared sirolimus-eluting stents and PES with BMS in their effect on total, cardiac, and non-cardiac mortality using last follow-up data. They found that although there was a trend to benefits with the DES for reducing total mortality at 1 year compared with BMS, there was a trend to increased mortality in years 2, 3, and 4 of follow-up. Furthermore, at 2 and 3 years' follow-up, there was increased non-cardiac mortality (cancer, lung disease, and stroke) with the sirolimus-eluting stent versus the BMS (odds ratio = 2.74 and 2.04, respectively), the majority of which related to cancer. These investigators concluded that preliminary evidence suggests that sirolimus-eluting stents but not PES may lead to increased non-cardiac mortality. Follow-up and assessment of cause-specific deaths in patients receiving DES are mandatory to determine the safety of these devices.
A third study tracked stent thrombosis rates in 8,000-plus patients enrolled in studies in Holland and Switzerland. Wenaweser reported that over 3 years, the cumulative rate of thrombosis was 2.9 %, but what was disturbing was that the rate was linear -- starting at 1.2 % at 30 days (similar to BMS) and then 0.6 % each year thereafter. Unlike BMS, thrombosis did not seem to wane with time, but continued to increase at the same rate, confirming concerns that DES suppress cell growth too much in some individuals, opening the door to thrombosis, which have serious consequences.
In the light of ongoing concerns over the safety of DES, the Society for Cardiovascular Angiography and Interventions (SCAI) has issued guidelines for use of the devices (Hodgson et al, 2007). The guidelines advise physicians to ensure that patients meet published guidelines' criteria for percutaneous coronary intervention before implantation of any stent. The guidelines also recommend that the physician decide on an individual-patient basis whether a DES, BMS, or surgical revascularization is most appropriate; discuss the risks and benefits with the patient; and document it in the medical record. The guidelines recommend that providers know which patients (those with diabetes, renal failure, etc.) and lesions (complex, long, small-diameter, etc.) carry high-risk for thrombosis with DES. Ideally, physicians should assess patients' likelihood of long-term compliance with dual antiplatelet therapy before implantation. Continuation for 1 year is strongly recommended in patients not at high risk for bleeding, and continuation beyond 1 year should be considered in patients at higher risk for stent thrombosis.
Tu and colleagues (2007) stated that the placement of DES decreases the frequency of repeat re-vascularization procedures in patients undergoing PCI in randomized clinical trials. However, there is uncertainty about the effectiveness of DES, and increasing concern about their safety, in routine clinical practice. From the Cardiac Care Network of Ontario's population-based clinical registry of all patients undergoing PCI in Ontario, Canada, these investigators identified a well-balanced cohort of 3,751 pairs of patients, matched on the basis of propensity score, who received either BMS alone or DES alone during an index PCI procedure between December 1, 2003, and March 31, 2005. The primary outcomes of the study were the rates of target-vessel re-vascularization, MI, and death. The 2-year rate of target-vessel re-vascularization was significantly lower among patients who received DES than among those who received BMS (7.4 % versus 10.7 %, p < 0.001). Drug-eluting stents were associated with significant reductions in the rate of target-vessel re-vascularization among patients with 2 or 3 risk factors for re-stenosis (i.e., presence of diabetes, small vessels [less than 3 mm in diameter], and long lesions [greater than or equal to 20 mm]) but not among lower-risk patients. The 3-year mortality rate was significantly higher in the BMS group than in the DES group (7.8 % versus 5.5 %, p < 0.001), whereas the 2-year rate of MI was similar in the 2 groups (5.2 % and 5.7 %, respectively; p = 0.95). The authors concluded that DES are effective in reducing the need for target-vessel re-vascularization in patients at highest risk for re-stenosis, without a significantly increased rate of death or MI.
In a meta-analysis, Stettler et al (2007) compared the safety and effectiveness of 2 DES (sirolimus-eluting stent and PES) and BMS. These investigators searched relevant sources from inception to March, 2007, and contacted investigators and manufacturers to identify randomized controlled trials in patients with coronary artery disease that compared DES with BMS, or that compared sirolimus-eluting stents head-to-head with PES. Safety outcomes included mortality, MI, and definite stent thrombosis; the effectiveness outcome was target lesion re-vascularization. These researchers included 38 trials (18,023 patients) with a follow-up of up to 4 years. Trialists and manufacturers provided additional data on clinical outcomes for 29 trials. A network meta-analysis with a mixed-treatment comparison method to combine direct within-trial comparisons between stents with indirect evidence from other trials while maintaining randomization was performed. Mortality was similar in the 3 groups: hazard ratios (HR) were 1.00 (95 % CI: 0.82 to 1.25) for sirolimus-eluting versus BMS, 1.03 (0.84 to 1.22) for PES versus BMS, and 0.96 (0.83 to 1.24) for sirolimus-eluting versus PES. Sirolimus-eluting stents were associated with the lowest risk of MI (HR 0.81, 95 % CI: 0.66 to 0.97, p = 0.030 versus BMS; 0.83, 0.71 to 1.00, p = 0.045 versus PES). There were no significant differences in the risk of definite stent thrombosis (0 days to 4 years). However, the risk of late definite stent thrombosis (greater than 30 days) was increased with PES (HR 2.11, 95 % CI: 1.19 to 4.23, p = 0.017 versus BMS; 1.85, 1.02 to 3.85, p = 0.041 versus sirolimus-eluting stents). The reduction in target lesion re-vascularization seen with DES compared with BMS was more pronounced with sirolimus-eluting stents than with PES (0.70, 0.56 to 0.84; p = 0.0021). The authors concluded that the risks of mortality associated with DES and BMS are similar. Sirolimus-eluting stents seem to be clinically better than BMS and PES.
In a meta-analysis, Schomig et al (2007) made a synthesis of the available evidence on the relative safety and effectiveness of 2 DES: (i) sirolimus-eluting stents (SES) and (ii) PES in patients with coronary artery disease. A total of 16 randomized trials of SES versus PES with a total number of 8,695 patients were included in this analysis. A full set of individual outcome data from 5,562 patients was also available. Mean follow-up period ranged from 9 to 37 months. The primary effectiveness end point was the need for re-intervention (target lesion re-vasculization). The primary safety end point was stent thrombosis. Secondary end points were death and recurrent MI. No significant heterogeneity was found across trials. Compared with PES, SES significantly reduced the risk of re-intervention (HR 0.74; 95 % CI: 0.63 to 0.87, p < 0.001) and stent thrombosis (HR 0.66; 95 % CI: 0.46 to 0.94, p = 0.02) without significantly impacting on the risk of death (HR 0.92; 95 % CI: 0.74 to 1.13, p = 0.43) or MI (HR 0.84; 95 % CI: 0.69 to 1.03, p = 0.10). The authors concluded that SES are superior to PES in terms of a significant reduction of the risk of re-intervention and stent thrombosis. The risk of death was not significantly different between the 2 DES, but there was a trend toward a higher risk of MI with PES, especially after the first year from the procedure. The observation that SES are superior to PES is in agreement with the analysis from Gurm et al (2008) who reported that patients treated with SES appear to have a significantly lower risk of re-stenosis and need for target vessel re-vascularization compared with those treated with PES.
The National Institute for Health and Clinical Excellence's (NICE, 2008) recommended the use of DES for the treatment of coronary artery disease only if the target artery to be treated has less than a 3-mm caliber or the lesion is longer than 15 mm, and the price difference between DES and BMS is no more than 300 pounds sterling.
Pfisterer et al (2009) evaluated the long-term benefit-risk ratio of DES versus BMS relative to stent size. All 826 consecutive BASKET (BAsel Stent Kosten-Effektivitäts Trial) patients randomized 2:1 to DES versus BMS were followed after 3 years. Data were analyzed separately for patients with small stents (less than 3.0 mm vessel/less than 4.0 mm bypass grafts, n = 268) versus only large stents (greater than or equal to 3.0 mm native vessels, n = 558). Clinical events were related to stent thrombosis. Three-year clinical TVR rates remained borderline reduced after DES [9.9 versus 13.9 % (BMS), p = 0.07], particularly in patients with small stents (10.7 versus 19.8 %, p = 0.03; large stents: 9.5 versus 11.5 %, p = 0.44). Cardiac death/MI rates (12.7 versus 10.0 %, p = 0.30) were similar, however, death/MI beyond 6 months was higher after DES [9.1 versus 3.8 % BMS, p = 0.009], mainly due to increased late death/MI in patients with large stents (9.7 versus 3.1 %, p = 0.006). The results paralleled findings for stent thrombosis. The authors concluded that the clinical benefit of DES was maintained at no overall increased risk of death or death/MI up to 3 years. However, death/MI rates were increased in DES versus BMS patients beyond 6 months, especially in patients with large stents, paralleling findings for stent thrombosis. Thus, stent size appears to influence the 3-year benefit-risk ratio after DES implantation.
Kirtane and colleagues (2009) performed a meta-analysis of DES studies to estimate the relative impact of DES versus BMS on safety and efficacy end points, particularly for non-FDA-labeled indications. Comparative DES versus BMS studies published or presented through February 2008 with greater than or equal to 100 total patients and reporting mortality data with cumulative follow-up of greater than or equal to 1 year were identified. Data were abstracted from studies comparing DES with BMS; original source data were used when available. Data from 9,470 patients in 22 randomized controlled trials (RCTs) and from 182,901 patients in 34 observational studies were included. Observational and RCT data were analyzed separately. In RCTs, DES (compared with BMS) were associated with no detectable differences in overall mortality (HR, 0.97; 95 % CI: 0.81 to 1.15; p = 0.72) or MI (HR, 0.95; 95 % CI: 0.79 to 1.13; p = 0.54), with a significant 55 % reduction in target vessel re-vascularization (HR, 0.45; 95 % CI: 0.37 to 0.54; p < 0.0001); point estimates were slightly lower in off-label compared with on-label analyses. In observational studies, DES were associated with significant reductions in mortality (HR, 0.78; 95 % CI: 0.71 to 0.86), MI (HR, 0.87; 95 % CI: 0.78 to 0.97), and TVR (HR, 0.54; 95 % CI: 0.48 to 0.61) compared with BMS. The authors concluded that in RCTs, no significant differences were observed in the long-term rates of death or MI after DES or BMS use for either off-label or on-label indications. In real-world non-randomized observational studies with greater numbers of patients but the admitted potential for selection bias and residual confounding, DES use was associated with reduced death and MI. Both RCTs and observational studies demonstrated marked and comparable reductions in target vessel re-vascularization with DES compared with BMS. These data in aggregate suggested that DES are safe and efficacious in both on-label and off-label use, but highlighted differences between RCT and observational data comparing DES and BMS.
In a systematic review and meta-analysis, Brar et al (2009) compared outcomes by stent type for death, MI, TVR, and stent thrombosis in RCTs of ST-segment elevation myocardial infarction (STEMI). A secondary analysis was performed among registry studies. These investigators searched Medline, Embase, the Cochrane Library, and Internet sources for articles comparing outcomes between DES and BMS among patients with STEMI between January 2000 and October 2008. Randomized controlled trials and registries including patients 18 years of age and older receiving a DES or BMS were included. These researchers extracted variables related to the study design, setting, participants, and clinical end points. A total of 13 RCTs were identified (n = 7,352). Compared with BMS, DES significantly reduced TVR (relative risk [RR]: 0.44; 95 % CI: 0.35 to 0.55), without increasing death (RR: 0.89; 95 % CI: 0.70 to 1.14), MI (RR: 0.82; 95 % CI: 0.64 to 1.05), or stent thrombosis (RR: 0.97; 95 % CI: 0.73 to 1.28). These observations were durable over 2 years. Among 18 registries (n = 26,521), DES significantly reduced TVR (RR: 0.54; 95 % CI: 0.40 to 0.74) without an increase in MI (RR: 0.87, 95 % CI: 0.62 to 1.23). Death was significantly lower in the DES group within 1 year of the index PCI, but there were no differences within 2 years (p = 0.45). The authors concluded that the use of DES appears safe and efficacious in RCTs and registries of patients with STEMI. The DES significantly reduce TVR compared with BMS, without an increase in death, MI, or stent thrombosis within 2 years of the index procedure.
Trikalinos and associates (2009) noted that over the past 2 decades, percutaneous transluminal balloon coronary angioplasty (PTCA), BMS, and DES succeeded each other as catheter-based treatments for coronary artery disease. These researchers carried out a systematic overview of RCTs comparing these interventions with each other and with medical therapy in patients with non-acute coronary artery disease. They searched Medline for trials contrasting at least 2 of the 4 interventions (PTCA, BMS, DES, and medical therapy). Eligible outcomes were death, MI, coronary artery bypass grafting, TLR/TVR, and any re-vascularisation. Random effects meta-analyses summarized head-to-head (direct) comparisons, and network meta-analyses integrated direct and indirect evidence. A total of 61 eligible trials (25,388 patients) investigated 4 of 6 possible comparisons between the 4 interventions; no trials directly compared DES with medical therapy or PTCA. In all direct or indirect comparisons, succeeding advancements in PCI did not produce detectable improvements in deaths or MI. The RR for indirect comparisons between DES and medical therapy was 0.96 (95 % CI: 0.60 to 1.52) for death and 1.15 (0.73 to 1.82) for MI. By contrast, these investigators recorded sequential significant reductions in target lesion or vessel re-vascularisation with BMS compared with PTCA (RR 0.68 [0.60 to 0.77]) and with DES compared with BMS (0.44 [0.35 to 0.56]). The RR for the indirect comparison between DES and PTCA for TLR/TVR was 0.30 (0.17 to 0.51). The authors concluded that sequential innovations in the catheter-based treatment of non-acute coronary artery disease showed no evidence of an effect on death or MI when compared with medical therapy. These results lend support to present recommendations to optimize medical therapy as an initial management strategy in patients with this disease.
Biondi-Zoccai et al (2008) conducted a systematic review of basic science and clinical evidence on the Xience V everolimus-eluting stents (EES), by thoroughly searching PubMed and online databases (updated September 2007). They also compared the clinical results of Xience V versus PES (Taxus) and SES (Cypher) by means of direct and indirect comparison meta-analysis. A total of 3 clinical studies has been retrieved focusing on Xience V, however both most recent and important trials were still unpublished. The first trial compared Xience V versus BMS, whereas the other 2 RCTs compared Xience V versus Taxus. Direct meta-analysis of Xience V versus Taxus showed that Xience V was significantly superior to Taxus in preventing binary angiographic re-stenosis and TVR (p < 0.05 for both). Indirect comparison between Xience V and Cypher, exploiting a recent 16-trial large meta-analysis, showed that Xience V was at least as effective as Cypher in preventing TVR (p = 0.12). The authors concluded that EES (Xience V) appear as a major breakthrough in coronary interventions, and superior efficacy has already been demonstrated in comparison to PES (Taxus). Data available to date also suggested that Xience V is at least as effective as SES (Cypher). Whether long-term results and direct comparison to Cypher will also be favorable remains to be established by future clinical trials.
Stone and colleagues (2009) reported the 2-year clinical follow-up data of EES in the treatment of patients with de novo native coronary artery lesions (SPIRIT) III trial. A total of 1,002 patients with up to 2 de novo native coronary artery lesions (reference vessel diameter, 2.5 to 3.75 mm; lesion length less than or equal to 28 mm) were randomized 2:1 to EES versus PES. Anti-platelet therapy consisted of aspirin indefinitely and a thienopyridine for greater than or equal to 6 months. Between 1 and 2 years, patients treated with EES compared with PES tended to have fewer episodes of protocol-defined stent thrombosis (0.2 % versus 1.0 %; p = 0.10) and MI (0.5 % versus 1.7 %; p = 0.12), with similar rates of cardiac death (0.3 % versus 0.3 %; p = 1.0) and TVR (2.9 % versus 3.0 %; p = 1.0). As a result, at the completion of the 2-year follow-up, treatment with EES compared with PES resulted in a significant 32 % reduction in target vessel failure (10.7 % versus 15.4 %; HR, 0.68; 95 % CI: 0.48 to 0.98; p = 0.04) and a 45 % reduction in major adverse cardiac events (cardiac death, MI, or target lesion revascularization; 7.3 % versus 12.8 %; hazard ratio, 0.55; 95 % CI: 0.36 to 0.83; p = 0.004). Among the 360 patients who discontinued clopidogrel or ticlopidine after 6 months, stent thrombosis subsequently developed in 0.4 % of EES patients versus 2.6 % of PES patients (p = 0.10). The authors concluded that patients treated with EES rather than PES experienced significantly improved event-free survival at a 2-year follow-up in the SPIRIT III trial, with continued divergence of the hazard curves for target vessel failure and major adverse cardiac events between 1 and 2 years evident. The encouraging trends toward fewer stent thrombosis episodes after 6 months in EES-treated patients who discontinued a thienopyridine and after 1 year in all patients treated with EES rather than PES deserve further study.
Chevalier and associates (2008) compared zotarolimus-eluting stents (ZES) with PES in a randomized trial of percutaneous intervention for de novo coronary artery stenosis. The primary end point was defined as non-inferiority of in-segment late lumen loss after 9 months. A total of 29 investigative sites in Europe, Australia, as well as New Zealand enrolled 401 patients, 396 of whom received a study stent. After 9 months, late lumen loss was significantly greater in the ZoMaxx group (in-stent 0.67 +/- 0.57 mm versus 0.45 +/- 0.48 mm; p < 0.001; in-segment 0.43 +/- 0.60 mm versus 0.25 +/- 0. 45 mm; p = 0.003), resulting in significantly higher rates of greater than 50 % angiographic re-stenosis (in-stent 12.9 % versus 5.7 %; p = 0.03; in-segment 16.5 % versus 6.9 %; p = 0.007). The upper bound of the 95 % CI on the difference in in-segment late lumen loss between the 2 treatment groups (0.27 mm) exceeded the 0.25 mm value pre-specified for non-inferiority. There were no significant differences between ZoMaxx and Taxus-treated groups with respect to TVR (8.0 % versus 4.1 %; p = 0.14), major adverse cardiac events (12.6 % versus 9.6 %; p = 0.43), or stent thrombosis (0.5 % in both groups). The authors concluded that after 9 months, ZES showed less neointimal inhibition than PES, as shown by higher in-stent late loss and re-stenosis by qualitative coronary angiography.
Waseda and colleagues (2009) compared the vessel response between ZES and PES using intra-vascular ultrasound (IVUS). Data were obtained from patients with serial (baseline and 8-months follow-up) IVUS analysis available (n = 198). Volumetric analysis was performed for vessel, lumen, plaque, stent, and neointima. Cross-sectional narrowing (given as percentage) was defined as neointimal area divided by stent area. Neointima-free frame ratio was calculated as the number of frames without IVUS-detectable neointima divided by the total number of frames within the stent. Subsegment analysis was performed at every matched 1-mm subsegment throughout the stent. At follow-up, the ZES group showed significantly greater percentage of neointimal obstruction (16.6 +/- 12.0 % versus 9.9 +/- 8.9 %, p < 0.01) and maximum cross-sectional narrowing (31.8 +/- 16.1 % versus 25.2 +/- 14.9 %, p < 0.01) with smaller minimum lumen area than the PES group did. However, the incidence of maximum cross-sectional narrowing greater than 50 % was similar in the 2 groups. Neointima-free frame ratio was significantly lower in the ZES group. In overall analysis, whereas the PES group showed positive remodeling during follow-up (13.7 +/- 4.2 mm(3)/mm to 14.3 +/- 4.3 mm(3)/mm), the ZES group showed no significant difference (12.7 +/- 3.6 mm(3)/mm to 12.9 +/- 3.5 mm(3)/mm). In subsegment analysis, significant focal positive vessel remodeling was observed in 5 % of ZES and 25 % of PES cases (p < 0.05). The authors concluded that there were different global and focal vessel responses for ZES and PES. Both DES showed a similar incidence of lesions with severe narrowing despite ZES having a moderate increase in neointimal hyperplasia compared with neointimal hyperplasia in PES. There was a relatively lower neointima-free frame ratio in ZES, suggesting a greater extent of neointimal coverage.
The Endeavor ZES from Medtronic received FDA approval on February 1, 2008, while Xience V EES from Abbott Vascular was approved by FDA on July 2, 2008 (Doostzadeh et al, 2010).
Machan (2006) reviewed the use of DES outside the coronary artery. The majority of research and clinical data on DES are from their use in coronary artery atherosclerosis; however, these devices can be used outside the coronary circulation in both vascular and non-vascular structures. In non-coronary arteries the principal indication for DES is the same as in the coronary circulation, prevention of re-stenosis. Human experience has been essentially limited to trials or compassionate use; 2 small controlled studies and a number of small observational single-center reports have been published, and there are trials in progress. To date, the data have not been as compelling as in the coronary circulation. The physical characteristics of each vascular bed such as external compressive forces, blood flow rates, wall thickness relative to lumen size, as well as vessel wall composition differ significantly from the coronary circulation and each presents unique challenges to local drug delivery. Outside the vascular bed, the principal expected use is the prevention of tissue ingrowth following stent insertion in tubular structures such as the trachea, esophagus or bile ducts. The authors concluded that considerable further study of DES is needed in each anatomical region to determine the ideal stent/drug combination and clinical appropriateness.
Lee (2009) noted that in unresectable malignant bile duct obstruction, endoscopic stent insertion is the treatment of choice. However, the current stent allows only mechanical palliation of the obstruction, and has no anti-tumor effect. Currently, in the vascular field, the DES is very highly favored. The requirements for a DES in a non-vascular tract, such as the bile duct, are far different from those of a DES to be used in the vascular tract. The non-vascular DES must suppress tumor proliferation and mucosal hyperplasia. For example, the non-vascular stent might be covered with a membrane that gradually releases a chemo-agent. Currently, there is not much experience with DES in the bile duct. Nevertheless, these researchers are continuously testing many anti-tumor agents in animal and human studies. The authors concluded that they expect and hope DES will work effectively for tumor cells in diverse ways and, more importantly, will prolong stent patency and the patients' survival periods. However, considerable investigation and a clinical study of DES will be required to achieve these goals.
In a meta-analysis, Joyal et al (2010) compared DES to BMS for the treatment of vein graft stenosis. PubMed and the Cochrane clinical trials database were systematically searched to identify all RCTs and observational studies examining DES for vein graft stenosis published in English between 2003 and 2009. Inclusion criteria included follow-up duration greater than or equal to 6 months. Data were stratified by study design and pooled using random effects models. A total of 20 studies were found to meet inclusion criteria; 18 studies were observational and 2 were RCTs. In observational studies, DES were associated with a reduction in MACE (odds ratio [OR] 0.50, 95 % CI: 0.35 to 0.72), death (OR 0.69, 95 % CI: 0.53 to 0.91), TVR (OR 0.54, 95 % CI: 0.37 to 0.79), and TLR (OR 0.54, 95 % CI: 0.37 to 0.78). The incidence of MI was similar between groups. In the RCTs, pooled results were inconclusive because of small sample sizes. The authors concluded that although data from observational studies suggest that the use of DES for vein graft stenosis has favorable effects on MACE, death, TVR, and TLR, these data should be interpreted with caution due to their observational nature. Corresponding RCT data are inconclusive. There remains a need for large multi-center RCTs to address the safety and effectiveness of DES for vein graft stenosis.
McLoughlin and Byrne (2008) stated that self expanding metal stents (SEMS) play an important role in the management of patients with malignant obstructing lesions in the gastrointestinal tract. Traditionally, they have been used for palliation in malignant gastric outlet and colonic obstruction as well as esophageal malignancy. The development of the polyflex stent, which is a removable self expanding plastic stent, allows temporary stent insertion for benign esophageal disease and possibly for patients undergoing neoadjuvant chemotherapy prior to esophagectomy. Potential complications of SEMS insertion include perforation, tumor overgrowth or ingrowth, and stent migration. Newer stents are being developed with the aim of increasing technical and clinical success rates, while reducing complication rates. Other areas of development include biodegradable stents for benign disease and radioactive or drug-eluting stents for malignant disease. It is hoped that, in the future, newer stents will improve our management of these difficult conditions and, possibly, provide prognostic as well as symptomatic benefit in the setting of malignant obstruction.
Katsanos et al (2010) noted that minimally invasive image-guided insertion of SEMS in the upper gastrointestinal tract is the current treatment of choice for palliation of malignant esophageal or gastro-duodenal outlet obstructions. These investigators presented a concise review of contemporary stenting practice of the upper gastrointestinal tract, and the procedures in terms of appropriate patient evaluation, indications, and contra-indications for treatment were analyzed, along with available stent designs, procedural steps, clinical outcomes, inadvertent complications, and future technology. Latest developments include biodegradable polymeric stents for benign disease and radioactive or drug-eluting stents for malignant obstructions.
Nakagawa (2011) stated that the effectiveness of the use of DES in the treatment of STEMI, a representative condition of acute coronary syndrome, is still unknown. In this article, data of registry, randomized, and meta-analyses studies were reviewed. Drug eluting stents showed a consistent trend toward decreasing the risk of repeat re-vascularization without increasing the incidence of death, recurrent MI, and stent thrombosis as compared to BMS. The findings concerning the use of DES in patients with STEMI are: (i) its short-term effect of reducing the re-stenosis and repeat re-vascularization rates is evident; (ii) no randomized studies have demonstrated the usefulness of DES in the prevention of death and recurrent MI; (iii) no randomized or meta-analyses studies have shown results sufficient to eliminate long-term safety concerns; and most importantly, and (iv) there are no data clearly indicating safety concerns.
Palmerini et al (2012) compared the risk of thrombosis between BMS and DES. For this network meta-analysis, RCTs comparing different DES, or DES with BMS currently approved in the United States were identified through Medline, Embase, Cochrane databases, and proceedings of international meetings. Information about study design, inclusion and exclusion criteria, sample characteristics, and clinical outcomes was extracted. A total of 49 trials including 50,844 patients randomly assigned to treatment groups were analysed. One-year definite stent thrombosis was significantly lower with cobalt-chromium everolimus eluting stents (CoCr-EES) than with BMS (odds ratio [OR] 0.23, 95 % CI: 0.13 to 0.41). The significant difference in stent thrombosis between CoCr-EES and BMS was evident as early as 30 days (OR 0.21, 95 % CI: 0.11 to 0.42) and was also significant between 31 days and 1 year (OR 0.27, 95 % CI: 0.08 to 0.74). CoCr-EES were also associated with significantly lower rates of 1-year definite stent thrombosis compared with paclitaxel-eluting stents (OR 0.28, 95 % CI: 0.16 to 0.48), permanent polymer-based sirolimus-eluting stents (OR 0.41, 95 % CI: 0.24 to 0.70), phosphorylcholine-based zotarolimus-eluting stents (OR 0.21, 95 % CI: 0.10 to 0.44), and Resolute zotarolimus-eluting stents (OR 0.14, 95 % CI: 0.03 to 0.47). At 2-year follow-up, CoCr-EES were still associated with significantly lower rates of definite stent thrombosis than were BMS (OR 0.35, 95 % CI: 0.17 to 0.69) and paclitaxel-eluting stents (OR 0.34, 95 % CI: 0.19 to 0.62). No other DES had lower definite thrombosis rates compared with BMS at 2-year follow-up. The authors concluded that in RCTs completed to date, CoCr-EES has the lowest rate of stent thrombosis within 2 years of implantation. The finding that CoCr-EES also reduced stent thrombosis compared with BMS, if confirmed in future RCTs, represents a paradigm shift.
De Luca and colleagues (2012) performed a meta-analysis using individual patient data to evaluate the long-term safety and effectiveness of DES compared with BMS in patients undergoing primary PCI for STEMI. Formal searches of electronic databases (MEDLINE and CENTRAL) and scientific session presentations from January 2000 to June 2011 were carried out. These investigators examined all completed randomized trials of DES for STEMI. Individual patient data were obtained from 11 of 13 trials identified, including a total of 6,298 patients (3,980 [63.2 %] randomized to DES [99 % sirolimus-eluting or paclitaxel-eluting stents] and 2,318 [36.8 %] randomized to BMS). At long-term follow-up (mean [SD], 1,201 [440] days), DES implantation significantly reduced the occurrence of TVR (12.7 % versus 20.1 %; hazard ratio [95 % CI], 0.57 [0.50 to 0.66]; p < 0.001, p value for heterogeneity, 0.20), without any significant difference in terms of mortality, re-infarction, and stent thrombosis. However, DES implantation was associated with an increased risk of very late stent thrombosis and re-infarction. The authors concluded that the present pooled patient-level meta-analysis demonstrated that among patients with STEMI undergoing primary PCI, sirolimus-eluting and paclitaxel-eluting stents compared with BMS are associated with a significant reduction in TVR at long-term follow-up. Although there were no differences in cumulative mortality, re-infarction, or stent thrombosis, the incidence of very late re-infarction and stent thrombosis was increased with these DES.
Werner et al (2012) presented the 5-year angiographical and clinical results of a retrospective registry assessing the performance of sirolimus-eluting stents (SES) in the treatment of infra-popliteal atherosclerotic disease. From 2004 to 2009, a total of 158 patients (95 men; mean age of 71.9 years) with chronic lower limb ischemia (Rutherford categories 3 to 6) underwent primary SES placement in focal infra-popliteal lesions. The angiographical endpoint was patency, defined as freedom from in-stent stenosis (ISS) greater than 50 %. Clinical endpoints were death, amputation, and bypass surgery. Results were correlated with patient and lesion characteristics and cumulative outcomes were assessed with Kaplan-Meier analysis. Technical success was achieved in all cases. The primary patency rates were 97.0 % after 6 months, 87.0 % after 12 months, and 83.8 % at 60 months. In-stent stenosis was predominantly observed in the first year after stent placement. Female gender was associated with a higher rate of ISS. During clinical follow-up of 144 (91 %) patients over a mean 31.1 +/- 20.3 months, there were 27 (18.8 %) deaths, 4 (2.8 %) amputations, and no bypass surgery. Clinical status improved in 92 % of the patients with critical limb ischemia (CLI) and 77 % of the patients suffering from claudication (p = 0.022). The authors concluded that treatment of focal infra-popliteal lesions with SES showed encouraging long-term angiographical results in this registry. Clinical improvement was evident, but more pronounced in CLI patients than in patients suffering from claudication. They stated that further studies are needed to evaluate the potential clinical benefit of SES as compared to balloon angioplasty or BMS in the treatment of infra-popliteal lesions.
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