Long-Term Safety and Economic Impact of Drug-Eluting Stents

Drug-eluting stents (DES) were designed to prevent neointimal proliferation via the controlled release of antiproliferative agents. Two such DES have been approved for use in the United States. The sirolimus-eluting Cypher stent (SES, Cordis Corporation, Miami Lakes, Florida) and paclitaxel-eluting TAXUS stent (PES, Boston Scientific Corporation, Natick, Massachusetts) were approved for use after randomized controlled clinical trials demonstrated their superiority over bare-metal stents (BMS) at reducing restenosis rates and the need for repeat revascularization. Months after their approval by the U.S. Food and Drug Administration (FDA) in 2003, usage rates in the United States approached 90% for all percutaneous coronary interventions (PCI). However, several years after approval and widespread usage of DES, initial reports began to surface of a new late complication — stent thrombosis. Subsequently, the safety of DES has been debated and researched extensively. Issues of cost effectiveness have also been raised. The current data regarding the safety and efficacy of DES, as well as the long-term economic impact, will be reviewed.

The Stents

The two DES currently approved for use in the United States consist of a metallic stent backbone, a polymer covering, and the antiproliferative drug, which is mixed with the polymer. Sirolimus is an antibiotic with antiproliferative and immunosuppressive qualities. The efficacy of SES was first demonstrated in the RAndomized study with the sirolimus-coated Bx VELocity balloon expandable stent in the treatment of patients with de novo coronary artery lesion (RAVEL) and SIRolImus-coated stent in treatment of patients with de novo coronary arterial lesions (SIRIUS) trials. In the RAVEL trial, 238 patients were randomized to SES or BMS.¹ Angiographic follow up was performed six months after implantation. A significant reduction in late lumen loss, binary restenosis (i.e., the presence or absence of > 50% stenosis), and the amount of neointimal hyperplasia was significantly less in the patients who received a SES. At one-year clinical follow up, there was a significant reduction in adverse cardiac events (6 vs. 29%) driven solely by a reduction in target vessel revascularization.

In the SIRIUS trial, 1038 patients with stable or unstable angina were randomized to a SES or BMS.² At 9-month angiographic follow up, there was a significant reduction in late lumen loss, binary restenosis, and target lesion revascularization (TLR).

Paclitaxel is an antineoplastic agent which interferes with microtubule assembly. The polymer allows the antiproliferative drug to be slowly reduced from the stent over a period of days to months. The efficacy of the PES was first demonstrated in the TAXUS trials. In TAXUS II, 536 patients were randomly assigned to a PES or BMS.³ At 6 months, repeat angiography showed a significant reduction in in-stent restenosis (3.5% PES vs. 19.1% BMS). TLR was also significantly reduced (3.9 versus 13.3%).

In the larger TAXUS IV trial used for US regulatory approval, 1314 patients were randomized to PES or BMS.⁴ Angiographic follow-up was performed at nine months with a significant reduction in restenosis (8% PES vs. 27% BMS), late lumen loss (0.39 mm vs. 0.92 mm) and target lesion revascularization (3% vs. 11%). At one year, there was a significant reduction in major adverse cardiac events driven entirely by a reduction in ischemia-driven TVR.

Stent Thrombosis

Thrombotic occlusion of a stent (i.e., stent thrombosis) is an uncommon but potentially life-threatening complication of both BMS and DES. Stent thrombosis often presents with severe ischemia or acute myocardial infarction. Thirty-day mortality rates of patients who present with stent thrombosis are increased at approximately 7–15%.

Initial reports of late stent thrombosis occurring approximately one year after DES implantation began surfacing in 2004.5 In 2006, the Basel Stent Cost-effectiveness Trial — Late Thrombotic Events (BASKET-LATE) trial published results of 746 patients who had been randomized to BMS or DES. Patients were followed for 12 months after completing 6 months of dual antiplatelet therapy after stent implantation. In months 7–18 post-stent implantation, rates of death or myocardial infarction (MI) were 4.9% in the DES group versus 1.3% among patients receiving a BMS (adjusted hazard ratio 2.2, p = 0.03). Late stent thrombosis was confirmed in 2.6% in the DES group and 1.3% in the BMS group.⁶

Several etiologies of stent thrombosis occurring in DES have been proposed. Possible causes include delayed or incomplete endothelialization, polymer hypersensitivity or other late polymer reactions, stent malapposition, and insensitivity or allergy to aspirin or clopidogrel Premature cessation of dual antiplatelet therapy has been demonstrated to be the most significant risk factor for stent thrombosis. Other identified risk factors include failure of optimal stent placement, residual stenosis, long stent length, multivessel stenting, bifurcation stenting, diabetes mellitus, renal failure, low ejection fraction, and post-procedure TIMI flow grade less than 3.^7,8

At the World Cardiology Congress held in Barcelona in September 2006, conflicting data were released about the risk of late stent thrombosis with DES in the form of two group-level meta-analyses. Camenzind et al described a meta-analysis of the results of all published and presented trials comparing DES with BMS. This meta-analysis demonstrated increased rates of death or Q-wave MI with SES (HR 1.60, 95% CI 1.06 to 2.43), but not with PES (HR 1.15; 95% CI, 0.79 to 1.69).⁹ A separate meta-analysis of 4 randomized trials comparing SES to BMS showed no increased mortality with SES at 3 years of follow-up. Total mortality was 3.2% among BMS patients and 4.1% among SES patients (p = 0.37). Cardiac mortality was also similar (1.4 vs. 1.3%, p = 0.55).¹⁰

In order to standardize the definition of stent thrombosis among various researchers, a panel of investigators and representatives from major stent manufacturers and the FDA developed a consensus definition. The Academic Research Consortium delineated these consensus case definitions for stent thrombosis in 2006.¹¹ In addition to the case definition, stent thrombosis is also classified based on the time from stent implantation. Early stent thrombosis occurs < 30 days after PCI. Late occurs 30 days to one year post implantation, and very late stent thrombosis occurs greater than one year after PCI. Some investigators also differentiate acute (less than 24 hours after PCI) and subacute (one to 30 days after PCI) stent thrombosis.

As a result of the concerns raised at the World Cardiology Congress, the penetrance of DES use in the United States declined considerably late in 2006. The use of DES declined by nearly one-third from a peak of approximately 90%. In response to the safety concerns, the FDA convened a meeting of the Circulatory System Medical Devices Advisory Panel in December 2006 to make nonbinding recommendations to the FDA. Also, in response to the rising concerns about DES safety, the manufacturers of DES released patient-level data from pivotal trials and registries to clinical investigators. At the FDA panel meeting, long-term follow-up data from the DES manufacturers’ pivotal trials were reviewed.¹² Four-year rates of protocol-defined stent thrombosis were not significantly different in the SES versus BMS comparison (1.2 vs. 0.6%, respectively, p = 0.20) or in the PES versus BMS group (1.3% vs. 0.9%, respectively, p = 0.30). After one year, however, there were significantly more episodes of stent thrombosis in patients with SES versus BMS (p = 0.025) and in patients with PES vs. BMS (p = 0.028). Nevertheless, the rates of death or MI did not different significantly between the groups after four years. As expected, there were significant reductions in TLR with both types of DES. In these pivotal trials where DES was used for on-label indications, long-term follow-up, rates of death, or MI were not significantly different with DES than BMS. On-label indications for PES and SES include de novo lesions in native coronary arteries that are less than or equal to 28 mm in length, and with vessel diameters of 2.5 to 3.75 mm for PES and 30 mm in length and vessel diameter of 2.5 to 3.5 mm for SES. However, it is estimated that approximately 60% of DES use was for off-label indications. Off-label indications include complex lesions such as saphenous vein bypass grafts, bifurcation lesions, chronic total occlusions, smaller diameter vessels, or patients with multivessel disease. These off-label uses are not represented in the pivotal randomized controlled trials, which led to the approval of DES. Various “real-world” registry data were presented at the FDA meeting. One such registry was the Swedish Coronary Angiography and Angioplasty Registry (SCAAR), which included 19,771 patients who received BMS (n = 13,738) or DES (n = 6033) in Sweden in 2003 and 2004.¹³

During three years of follow-up, the two groups did not differ significantly in the composite of death and MI. In the initial 6 months post PCI, there was a trend toward a lower event rate in the DES group. In a separate “landmark analysis,” adjusted relative risks were determined from the time period 6 months after stent implantation. After six months, the event rate was significantly higher in the DES group (adjusted RR 1.20, 95% CI 1.05–1.37). There was also a significantly higher risk of death in the DES group from 6 months to 3 years (adjusted RR 1.32, 95% CI 1.11–1.57). However, these same investigators were urged to continue their long-term follow-up. In September 2007 at the European Society of Cardiology meeting, the investigators presented their 4-year follow-up data. After 4 years of follow-up involving patients receiving a BMS and patients receiving a DES, they found no overall significant different in mortality or MI. Although the event rate in the DES group was significantly higher after 6 months, this was compensated by a significantly lower event rate during the initial 6 months. At 4 years, they also found a significant reduction in restenosis and TVR favoring DES. They hypothesized that the results differed from 3 to 4 years because of increased awareness of the risks of late stent thrombosis. This perhaps led to a longer duration of dual antiplatelet therapy and improved stenting technique with higher balloon inflation pressure and more accurately sized stents.

Other recently published registry data support the long-term safety of DES. One such registry examined a matched cohort of 3751 pairs of patients who received either a BMS or DES in Ontario, Canada. The 3-year mortality rate was found to be significantly higher in the BMS group than in the DES group (7.8 vs. 5.5%, p < 0.001). The 2-year rate of MI was similar in the two groups (5.2 vs. 5.7%, p = 0.95), but in this same time period, target vessel revascularization was significantly lower in the DES group (7.4 vs. 10.7%, p < 0.001).

Overall data support the long-term safety of DES. There appears to be a small numerical increase in late stent thrombosis occurring in approximately 0.5% per year, but long-term data suggest there is no difference in the rates of death and MI. Due to the increased risk of late stent thrombosis, recent recommendations by the FDA, American College of Cardiology, American Heart Association, and Society for Cardiovascular Angiography and Interventions encourage continuing dual antiplatelet therapy for a minimum of 12 months after DES implantation.^15,16 Despite the risks of late events, DES have a clear advantage over BMS in regard to restenosis and TVR.

Modeling the Economic Impact

Despite concerns about long-term safety, DES have clear clinical benefits over BMS. However, given the small increased risk of late and very late stent thrombosis and the need for longer dual antiplatelet therapy with DES, the long-term economic impact of DES versus BMS is unclear. In order to compare costs, an analysis of the 4-year follow-up data from the TAXUS trials was performed. Follow-up data beyond 4 years are scarce. It is unclear if very late stent thrombosis rates continue or decrease over time beyond 4 years. While some 5-year evidence suggests that the very late stent thrombosis rates do not continue to increase, for purposes of economic comparison, it was assumed that the rates of very late stent thrombosis remain constant beyond the first 4 years. A modeling approach was used to estimate the direct medical costs up to 10 years after stent implantation. Cost analysis was performed from the payer perspective with hospitalization and physician visit costs based on the Medicare fee schedule for 2005. Clopidogrel was assumed to continue for 6 months after PES and 1 month after BMS implantation. The cost of clopidogrel was based on the actual wholesale price for 2005, and assumed 100% compliance for cost determination. Sensitivity analysis included 12 months of clopidogrel use after PES implantation and also used the ARC-defined stent thrombosis rates.

The cumulative medical costs over the first 4 years were $20,052 in the PES cohort and $21,371 in the BMS cohort. In years 5–10, the average annual costs were $199 ($163 due to TLR and $36 due to stent thrombosis) for PES and $160 ($154 for TLR and $6 due to stent thrombosis) for BMS, but overall costs remained lower with PES throughout the 10-year period. Using a 12-month clopidogrel scenario, the costs over the first 4 years were $20,935 in the PES cohort and $21,509 in the BMS cohort. When using the ARC definition of stent thrombosis, the costs over the first 4 years was $20,106 in the PES cohort and $21,496 in the BMS cohort.

In summary, this analysis demonstrated that the projected total medical costs over the first 4 years were lower with PES than BMS. Beyond the first 4 years, assuming that late stent thrombosis rates and TLR rates continued at the same rate, PES procedures continued to have lower costs throughout the 10-year period. The cumulative medical costs were still lower in the PES group, even if the duration of clopidogrel therapy was extended to 12 months in this cohort or if the ARC defined stent thrombosis definition was applied.

Cohen et al have performed multiple cost analyses of DES versus BMS. One such evaluation was done with patient-level data from the TAXUS-IV trial.¹⁷ In this cost-effectiveness analysis, the investigators found that over a 1-year follow-up period, PES use was associated with significant reductions in follow-up resource use and healthcare costs, driven primarily by the 60% reduction in TVR. Mean follow-up costs were $1,456 per patient lower in the PES group than the BMS group (p < 0.001). Aggregate 1-year costs, which included the cost of the initial stent implantation, were $572 higher in the PES group (p < 0.001), however, driven predominantly by the higher acquisition cost of the PES. Nevertheless, the authors concluded that PES from a cost-effectiveness perspective compared favorably with the cost effectiveness of other devices that had previously been shown to reduce coronary restenosis. In a previous analysis, a similar reduction in follow-up costs was seen with SES versus BMS.¹⁸

Future Technologies
The Taxus and Cypher stents were the first generation of DES approved for use in the United States. Next generation stents have been used widely in Europe and are expected to be available in the United States in the near future. Initial long-term safety data with the next generation of DES appear promising, while still maintaining low rates of restenosis and TVR.
The zotarolimus-eluting Endeavor stent (Medtronic Inc., Minneapolis, Minnesota) was recently approved by the FDA. Unlike first generation DES, the Endeavor stent is built upon a cobalt chromium alloy stent. This stent is coated with zotarolimus, a sirolimus analog, and a unique phosphorylcholine polymer. In the Endeavor II trial, 1197 patients were randomized to receive the zotarolimus-eluting stent or the same stent without the drug or polymer coating (Driver cobalt chromium stent). At 9 months, the primary endpoint of target vessel failure occurred in 15.1% with the bare-metal stent and 7.9% with the Endeavor (p = 0.0001). Stent thrombosis rates at one year did not differ significantly between the two groups (1.2% BMS vs. 0.5% DES). No documented stent thrombosis was observed beyond 30 days up to 24 months after implantation with the Endeavor stent.¹⁹

The everolimus-eluting Xience V stent (Abbott Vascular, Redwood City, California) is approved for use outside of the United States and is currently under evaluation by the FDA. Like the Endeavor stent, the Xience V stent is also built on a thin-strut cobalt chromium platform coated with another sirolimus analog, everolimus. Initial trials have demonstrated favorable clinical and angiographic outcomes.²⁰ In the SPIRIT III trial, 1002 patients in the United States were randomized to either the everolimus-eluting stent (n = 669) or PES (n = 333). The primary endpoint was angiographic in-segment late loss at 8 months in the first 564 patients enrolled in the study. Angiographic follow-up was performed in 77% of eligible patients (n = 436). In-segment late loss was significantly less in the everolimus-eluting stent group compared to PES (mean 0.14 mm vs. 0.28 mm, p ≤ 0.004). The everolimus-eluting stent was noninferior to PES for the major secondary end point of ischemia-driven target vessel failure (7.2% vs. 9.0%, respectively, p_{noninferiority} < 0.001, p_superiority = 0.31). At 1-year, there was a significant reduction in composite major adverse cardiac events in the everolimus-eluting stent group, compared to PES (6.0% vs 10.3%, p = 0.02), which was driven by decreased rates of MI and TLR.²¹

Summary

Since the introduction of DES in the United States, a period of widespread use culminated in over four million implantations. This enthusiasm has recently been tempered by concerns over long-term safety, especially regarding late and very late stent thrombosis. While earlier group-level analyses first highlighted this concern and the possible increased risk of death or MI, later patient-level meta analyses and multiple registry trials including thousands of patients followed for several years support the safety of DES with continued efficacy, particularly at reducing TVR. This reduction of TVR has led to a significant reduction in follow-up costs with DES compared to BMS. Meanwhile, the second generation of DES is nearing entry to widespread use in the United States. Initial data suggest these new platforms are safe and efficacious, although more long-term data will be needed to assess their safety and cost-effectiveness.