Peter J Fitzgerald
Martin B Leon
Columbia University Medical Center
There has been growing concern about the safety and safety-related costs of drug-eluting stents (DES). Their rapid growth and wide market penetration already equals that of popular pharmaceutical drugs. Consequently, the significance of even a low incidence of side-effects becomes magnified by sheer volume. The safety profiles of the different drug-eluting stents represent just one aspect of the concern associated with the rapid adoption of these devices. The success and safety of stent placement depends on meticulous technique, thorough acute follow-up and 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 DES nor bare-metal stents have eliminated this safety concern.(1) Of patients who experience stent thrombosis, 60–70% suffer myocardial infarction 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 with calculations 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 $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 DES (0.4% for the sirolimus-eluting stent,(5) 0.6% for the paclitaxel-eluting stent).(6) 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<0.001),confirming the observations of several case reports.(4,7,8) 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 (HR, 1.09; p<0.001 for each 10% decrease).
The importance of patient adherence to combined antiplatelet therapy suggests that this can be a precarious link in the safety chain. Current standards call for four weeks of clopidogrel and aspirin following implantation of bare-metal stents.(9,10) But the optimal term for antiplatelet therapy following implantation of DES 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 stents,(5,11-13) 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 6–12 months (or even longer), 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 very 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 that the manufacturer of clopidogrel does not have an approval from the US Food and Drug Administration (FDA) to promote the use of the drug with DES. Therefore, the manufacturer cannot join the manufacturers of DES in emphasising the importance of strict adherence to the antiplatelet regimen.
However, even when patient adherence to antiplatelet therapy is excellent, the potential difficulty of patient variability in response to clopidogrel or aspirin remains. 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 DES in reducing restenosis has also created the unfortunate situation where the unconditional importance of optimal technique in stent deployment is no longer aggressively emphasised. The evidence for this trend is anecdotal, but improperly deployed DES 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 poststent 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 DES 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.
A lack of data
Yet another weak link in the safety chain is represented by the fact that current data for DES 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 DES, accurate assessment of the long-term safety of these devices is problematic.(7) An ongoing collaboration between manufacturers and the FDA to monitor the long-term safety of DES is urgently needed. Until such a programme is in place, the possibility of a major product disaster 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 DES – must be managed more diligently in the future. Practitioners should participate in the process of gathering data so that all adverse events are promptly reported and we can assess the short- and long-term risk to our patients. DES certainly represent a breakthrough medical technology, but the absence of meticulous care to avoid incremental device-related complications, such as stent thrombosis, threatens to offset the benefits
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