Article

Attending to Links in the Safety Chain for Drug-Eluting Stents

Citation:European Cardiovascular Disease 2006;2(1):1–3

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An unintended consequence of the market success of drug-eluting stents has been a growing concern about their safety and safety-related costs. These devices have been so quickly and widely adopted that their market penetration already equals that of some of the most popular pharmaceutical drugs. Consequently, the absolute significance of even a low incidence of side effects becomes magnified by sheer volume.

The safety profiles of the different drug-eluting stents, however, represent just one aspect of the apprehension associated with the rapid adoption of these devices. The success and safety of stent placement depends on meticulous technique, thorough acute follow-up and then persistent long-term monitoring. Unfortunately, we have seen signs of weakness in each of these links in the safety chain.

The most catastrophic of the unwanted outcomes that have been associated with stenting is stent thrombosis. Neither drug-eluting stents nor bare metal stents have eliminated this safety concern.1 Of patients who experience stent thrombosis, 60-70% suffer myocardial infarction (MI) and 20-25% die.The overall incidence of stent thrombosis with bare metal stents is reported to be less than 1% and can be more frequent in high-risk patient/lesion subsets or multivessel procedures.2,3 Given that a total of 800,000 stents are implanted in the US annually and calculating based on a conservative stent-thrombosis rate of 0.9%, the additional economic burden in terms of healthcare costs directly associated with stent thrombosis can be estimated at more than US$80 million per year.1

A prospective study by Iakovou et al. of 2,229 consecutive real-world patients who received sirolimus-or paclitaxel-eluting stents found an overall nine-month incidence of stent thrombosis of 1.3%.4 This finding was substantially higher than the rates previously reported in the placebo-controlled randomised trials that led to the approval of drug-eluting stents (0.4% for the sirolimus-eluting stent,5 0.6% for the paclitaxel-eluting stent6).The fatality rate for patients experiencing stent thrombosis in the study by Iakovou and colleagues was 45%.Compared with patients in the pivotal placebo-controlled trials for these stents, the patients in this prospective study had a higher prevalence of diabetes, multivessel disease, small reference-vessel diameter and complex lesions.4

The single strongest independent predictor of stent thrombosis in this study was premature discontinuation of antiplatelet therapy (hazard ratio (HR) 89.78, p<0.0014), confirming the observations of several case reports.7,8 The other independent predictors of stent thrombosis were renal failure (HR 6.49, p<0.001), bifurcation lesions (HR 6.42, p<0.001), diabetes (HR 3.71, p=0.001) and a lower left ventricular ejection fraction (LVEF) (HR 1.09, p<0.001) for each 10% decrease.

The importance of patient adherence to combined anti-platelet therapy suggests that this can be a precarious link in the safety chain. Current standards call for four weeks of clopridrogel and aspirin following implantation of bare metal stents.9,10 However, the optimal term for anti-platelet therapy following implantation of drug-eluting stents remains unknown, with practices determined empirically. In the major clinical trials conducted to date, combined antiplatelet therapy has been recommended for two to three months following implantation of sirolimus-eluting stents5,11-13 and for three to six months following implantation of paclitaxel-eluting stents.6,14,15 Importantly, most physicians prefer to extend the dual antiplatelet regimen to at least six or 12 months, especially in patients with acute coronary syndromes or severe lesion complexity. Such prolonged obligatory dual antiplatelet therapy creates significant problems for patient compliance, especially in older patients with other co-morbid conditions. We do not know the accurate rates for patient adherence to dual antiplatelet therapy after stenting. Nevertheless, even a calculation based on the optimistic rate of 75% perfect adherence to antiplatelet agents suggests a substantial absolute number of patients at some increased risk.

The problem of patient adherence to antiplatelet therapy is further exacerbated by the fact the manufacturer of clopidogrel does not have approval from the US Food and Drug Administration (FDA) to promote the use of the drug with drug-eluting stents. Thus the manufacturer cannot join the manufacturers of drug-eluting stents in emphasising the importance of strict adherence to the antiplatelet regimen.

Even when patient adherence to antiplatelet therapy is excellent, there remains the potential difficulty of patient variability in response to clopidogrel or aspirin. It is estimated that 4-30% of patients treated with conventional doses of clopidogrel and 5-45% of patients treated with conventional doses of aspirin do not display adequate antiplatelet response.16,17 The phenomenon of impaired response to the combination of aspirin and clopidogrel has been associated with the pathophysiology of stent thrombosis in some patients.18

The success of drug-eluting stents in reducing restenosis has also created the unfortunate situation whereby the unconditional importance of optimal technique in stent deployment is no longer aggressively emphasised. The evidence for this trend is anecdotal, but improperly deployed drug-eluting stents are more frequently seen in our laboratories when patients return with follow-up problems. Intravascular ultrasound is routinely underutilised for stent deployment. Long stents are used more frequently with deployment across numerous side branches and without flush vessel wall apposition. Stent deployment pressures are lower, and the use of systematic post-stent high-pressure dilatations are less frequent.

Finally, exotic techniques such as stent 'crushing' and 'kissing' to treat bifurcations and other complex lesion scenarios are being used routinely in many catheterisation laboratories. Undoubtedly, as drug-eluting stents are being used in a wide variety of anatomic and clinical situations that have not been evaluated in randomised clinical trials, any deficit in deployment technique will increase the probability of a thrombotic event.

Yet another weak link in the safety chain is represented by the fact that current data for drug-eluting stents do not extend beyond two or three years of follow-up - not beyond nine months in most of the major clinical trials. Since there is a known risk of late thrombosis associated with drug-eluting stents,7 accurate assessment of the long-term safety of these devices is problematic. What is urgently needed is on-going collaboration between manufacturers and the FDA to monitor the long-term safety of drug-eluting stents. Until such a programme is in place, the possibility of a major product disaster, like that recently reported involving an implantable cardioverter defibrillator, will loom in the background.

Adherence to the prescribed antiplatelet therapy, optimal stent deployment techniques (especially in high-risk situations for thrombosis) and late monitoring for safety and efficacy - these links in the safety chain related to the use of drug-eluting stents must be managed more diligently in the future. Practitioners should participate in the process of data gathering so that all adverse events are promptly reported and we can assess the short- and long-term risks to our patients. Drug-eluting stents certainly represent a breakthrough medical technology, but the absence of meticulous attention to avoiding incremental device-related complications, such as stent thrombosis, threatens to offset the benefits.

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