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Attending to links in the safety chain for drug-eluting stents

Peter J Fitzgerald
Stanford University

Martin B Leon
Columbia University Medical Center
New York

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.

Stent thrombosis
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).

Patient adherence
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)

Optimal technique
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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