Reports

Concerns that drug-eluting stents (DES) may be associated with a greater risk of late stent thrombosis than bare-metal stents (BMS) continue to be allayed as new evidence consistently shows that DES in general, and sirolimus-eluting stents (SES) in particular, are at least as safe as BMS and are not more likely to cause early or late stent thrombosis. Moreover, evidence continues to support the superiority of DES over BMS in terms of the need to reintervene following stent placement, with target vessel revascularization rates being predictably and markedly lower following DES placement. Collectively, this new evidence will likely lead to a revision of earlier recommendations issued jointly by the Canadian Association of Interventional Cardiology (CAIC) and the Canadian Cardiovascular Society (CCS), as indicated by Dr. Érick Schampaert, Associate Clinical Professor of Medicine, Université de Montréal, and newly elected CAIC President.

A compelling argument in favour of the safety of SES comes from five-year follow-up data of C-SIRIUS (Canadian Study of the Sirolimus-eluting Stent in the Treatment of Patients with Long de novo Lesions in Small Native Coronary Arteries), presented by Dr. Schampaert. C-SIRIUS was designed to compare the safety and efficacy of SES and BMS in patients with lesions ranging from 15 to 32 mm in short vessels (2.5 to 3 mm in diameter). With only two months’ exposure to clopidogrel, eight-month angiographic data showed a 100% reduction of in-stent restenosis in SES recipients and a 95% reduction of in-lesion restenosis, again in favour of SES compared with BMS (P<0.001).

At five years, major adverse cardiac event rates were 34% in BMS patients compared with 14% in SES patients, while the need for target lesion revascularization was significantly lower among SES patients at 8% vs. 22% for their BMS counterparts (P=0.09). This meant that 89.8% of patients who had received a SES were free from target vessel failure at five years vs. 73.6% for BMS recipients—“highly statistically significant,” as Dr. Schampaert observed.

In the safety analysis, C-SIRIUS investigators identified two patients in each group who developed either a definite or a probable stent thrombosis at five years, a 4% event rate in each arm. “Aggressive secondary prevention is mandatory because 63% of the myocardial infarctions (MIs) that occurred in the study were not related to the target vessels, so secondary prevention is crucial to make sure that patients don’t sustain more events after receiving the stent,” Dr. Schampaert emphasized. “But SES are safe and effective to reduce target vessel failure at five years compared with BMS, and this benefit is maintained despite patients having had only two months of dual antiplatelet therapy post-stenting.”

Meta-analysis Data Review

Long-term findings from C-SIRIUS are reassuring but as a single study, they cannot unequivocally prove that DES are both safe and more effective than BMS. However, separate reviews of world-experience with SES vs. paclitaxel-eluting stents (PES) in one analysis, and SES or PES vs. BMS in another, strongly refute concerns that DES carry additional risks in stable coronary artery disease (CAD) patients. Again, their greater ability to reduce the need for target vessel revascularization compared with BMS was a salient and highly significant finding.

The first meta-analysis included 16 randomized trials involving a total of 8695 CAD patients who had received either a SES or a PES. As reported by Schömig et al. (J Am Coll Cardiol 2007;50(14):1373-80), there was a 26% reduction in the relative risk of SES patients having to undergo reintervention compared with PES patients (P<0.001). There was also a 34% relative risk reduction in stent thrombosis in favour of SES. Mortality rates were not different between the two groups, but there was a trend towards a higher MI risk with PES, especially after the first year post-stent (hazard ratio 0.84). Arguably, there are limitations to this particular meta-analysis, including the fact that all trials were open-label trials due to the impossibility of blinding completely different devices coming from two different manufacturers. As the authors pointed out, this could have had an impact on reintervention end points. Nevertheless, they still concluded that SES appear to reduce the risk of both reintervention and stent thrombosis to a greater extent than PES.

A second collaborative network meta-analysis (Lancet 2007;370(9591):937-48) involved 38 trials and included 18,023 patients who received either a DES (SES or PES) or a BMS. Patients were followed for up to four years. Trialists and manufacturers provided additional data on clinical outcomes for 29 trials. Overall, the incidence of death was similar in all three groups, as was the incidence of cardiac death.

In contrast, SES were associated with the lowest incidence of MI, whereas the incidence of MI was much the same between patients who received a PES and those who received a BMS.

Data on definite stent thrombosis according to Academic Research Consortium criteria were taken from 24 trials involving almost 13,000 patients. Based on this extensive data set, there was no significant difference in the cumulative incidence of definite stent thrombosis between the three types of stents. Nor was there any difference in the incidence of early stent thromboses between the three stent types. The main difference between groups was seen in the incidence of late stent thrombosis, occurring 30 days after stent placement and was roughly double for PES recipients vs. those who received either a SES or a BMS, where the incidence was the same.

The Ontario Experience

Most reflective of stent outcomes as they apply to real-world patients in Ontario are findings from Tu et al. (N Engl J Med 2007;357:1393-402). In this analysis, investigators identified a well-balanced cohort of 3751 pairs of patients, matched on the basis of propensity score, who received either a DES or a BMS during an index PCI procedure between December 1, 2000, and March 31, 2005. At two years’ follow-up, rates of target-vessel revascularization among DES patients were significantly lower at 7.4% than for BMS recipients at 10.7% (P<0.001).

Rates of target vessel revascularization among patients with several risk factors for restenosis were also significantly lower for DES compared with BMS patients. MI rates between the two groups were similar at 5.2% in DES patients and 5.7% in BMS patients, again at two-years’ follow-up.

Based on their experience with stents in Ontario, the authors concluded that DES are more effective than BMS in reducing the need for target-vessel revascularization in patients at highest risk for restenosis.

Summary

When the CAIC/CCS issued their joint position paper last February, the recommendations were based on the evidence that was available at that time. Since then, much new data have come to light. In particular, considerable effort has gone into reviewing the world experience with both SES and PES and to compare this experience with that of BMS. These comprehensive reviews, carried out by key opinion leaders in the field, have consistently supported the safety of DES in general, and SES in particular, compared with BMS. At the same time, they have consistently demonstrated DES use is associated with a significant reduction in the need to reintervene in target vessels, sparing patients both the morbidity and small mortality risk that any cardiac intervention has the potential to confer. As this new evidence is both compelling and reassuring, it is safe to assume that CAIC/CCS committee members may soon revise their joint position paper to reflect the new reality of DES vs. BMS, to help promote the best possible evidence-based care for the community at large.

Based on the following CCS/CCC-sanctioned sessions:

Oral Session: “Interventional Cardiology: Drug-Eluting Stents and ST Elevation Myocardial Infarction.” Sunday, October 21, 2007, 16:30-18:00, Room 202, Level 2. 17:15 – #232. Efficacy and Safety at 3 and 5 Years in the Canadian Multi-centre, Randomized, Double-blind Trial of the Sirolimus-eluting Stent in the Treatment of Patients with de novo Coronary Artery Lesions (C-SIRIUS). E Schampaert, EA Cohen, F Reeves, et al.

“Highlights of the 2007 CCS Recommendations on Heart Failure Update and the Joint CCS/CAIC Position Statement on Drug Eluting Stents and Antiplatelet Therapy.” Tuesday, October 23, 2007, 14:00-15:00, Room 2000A-B, Level 2.

This symposium is accredited and co-developed as an Accredited Group Learning Activity under Section 1 of the framework of Continuing Professional Development options as defined by the Maintenance of Certification Program of the Royal College of Physicians and Surgeons of Canada (RCPSC).