Assessing the optimal strategy for dual antiplatelet therapy

Abstract

Coronary artery disease remains a leading cause of morbidity and mortality worldwide. Each year, millions of patients undergo stent placement to treat coronary artery disease. As stents are prone to thrombosis, which can potentially be devastating, patients are treated with dual antiplatelet therapy with aspirin plus a thienopyridine for at least 6–12 months after stent placement. New evidence suggests that long-term dual antiplatelet therapy beyond 1 year prevents ischemic events but also leads to increased risk of bleeding. To determine the optimal strategy for dual antiplatelet therapy after stent placement, the benefits and risks must be carefully considered and individualized for each patient.

Keywords:

• bleeding
• dual antiplatelet therapy
• ischemia
• risk stratification
• stent thrombosis

Patients undergoing percutaneous coronary intervention (PCI) with stents are at risk for both stent thrombosis and myocardial infarction in non-stented coronary segments. These events can be potentially catastrophic [1–3]. Dual antiplatelet therapy (DAPT) with aspirin plus a P2Y12 receptor blocker has been shown to decrease ischemic events within the first year after stent placement, albeit at the expense of increased bleeding risk [4–6]. Current US guidelines recommend DAPT for at least 1 year following drug-eluting stent (DES) placement in stable ischemic heart disease and for at least 1 year after either DES or bare metal stent (BMS) placement in acute coronary syndrome [7]. While particularly deadly in the short term, stent thrombosis also occurs years after stent placement [8]. The DAPT trial was a large international, multicenter, randomized, placebo-controlled trial designed to assess the benefits and risks of DAPT therapy beyond 1 year after stent placement [9]. The primary analysis focused on the nearly 10,000 patients who had received DAPT for 12 months after undergoing DES placement, who were then randomized to receive either placebo plus aspirin or a thienopyridine plus aspirin for an additional 18 months.

Patients who continued to receive DAPT after 1 year had significantly lower rates of stent thrombosis (0.4 vs 1.4% respectively, hazard ratio 0.29) and major adverse cardiovascular and cerebrovascular events (4.3 vs 5.9% respectively, hazard ratio 0.71) compared to patients in the placebo arm. The lower rate of major adverse cardiovascular and cerebrovascular events was driven by a substantial reduction in the rate of myocardial infarction (MI). Notably, even after 30 months of DAPT, there was an increase in the risk of stent thrombosis (0.3 vs 0.1% cumulative incidence for treatment and placebo arms, respectively) and MI (1.0 vs 0.4%) during the 3-month period after discontinuation of thienopyridine therapy. Therefore, there may be a rebound effect after discontinuation of DAPT, which can occur even years after stent placement. This suggests that if DAPT is to be discontinued, patients should be carefully monitored and there should perhaps be a tapering regimen.

However, patients receiving DAPT beyond 1 year also had a higher rate of moderate or severe bleeding (2.5 vs 1.6% respectively) compared to controls. This difference was primarily due to moderate bleeding as defined by the GUSTO criteria [10]. Unexpectedly, the rate of all-cause mortality was higher for patients with long-term DAPT therapy. This difference appeared to be driven by noncardiovascular causes of death, and, in particular, cancer-related mortality. While there was no difference in the rates of new cancer diagnoses after randomization, more patients in the group randomized to long-term DAPT had a prior history of cancer compared with the placebo group. To further investigate this mortality finding, a meta-analysis was performed that found no significant difference in all-cause, cardiovascular, or non-cardiovascular mortality between extended duration (average follow-up time of 24 months) versus short term (<6 months) DAPT or aspirin alone [11].

Although the primary analysis in the DAPT trial focused on patients who had undergone DES placement, nearly 1700 receiving bare metal stent (BMS) were also randomized at 12 months after stent placement to receive either placebo plus aspirin or a thienopyridine plus aspirin for an additional 18 months. The primary efficacy and safety endpoints showed the same trends as for the DES population [12].

Other randomized trials have attempted to compare outcomes for various durations of DAPT [13–17]. Most recently, the ITALIC (Is There A Life for DES After Discontinuation of Clopidogrel) trial randomized 941 patients to 24 months of DAPT and 953 patients to 6 months of DAPT [18]. The primary endpoint of death, MI, urgent target vessel revascularization, stroke and major bleeding was assessed at 12 months post-stenting and the authors concluded that 6 months of DAPT is non-inferior to longer duration treatment. However, the trial, terminated prematurely due to problems with recruitment, was likely underpowered to detect clinically meaningful differences. By contrast, the DAPT trial was substantially larger than comparator studies and adequately powered to assess its primary efficacy and safety endpoints. Furthermore, subsequent meta-analyses have corroborated the findings of the DAPT trial [19].

For clinicians and patients, the decision to continue DAPT beyond 1 year after stent placement requires weighing the risks and benefits. In this context, decision analysis models can provide a theoretical framework for the average patient. In one such approach, a Markov model was used to estimate the threshold of benefit from longer-duration DAPT that would be required to outweigh the increased risk of bleeding [20]. Separate models were developed for patients with DES placed after stable ischemic heart disease and acute coronary syndrome (ACS). In both non-ACS and ACS populations, only small reductions in major adverse cardiovascular events were required (5 and 2% reductions, respectively) for the benefits to exceed the risk of bleeding. The benefits achieved by long-term DAPT, as observed in the DAPT trial, easily exceeded these thresholds.

Nonetheless, while the DAPT trial measures the average treatment effect across populations, individual patients may vary substantially in their risks of ischemic and bleeding events. Optimizing the DAPT strategy for each patient depends on accurately stratifying them according to their risk of ischemia and bleeding.

Recent investigation shows promise in addressing this issue of risk heterogeneity. In a subgroup analysis of the DAPT trial population, patients who had suffered an acute MI at presentation were at relatively higher risk for subsequent ischemic events and lower risk for major bleeding after PCI compared with patients without MI [21]. In addition to prior MI, a separate study found that ST elevation on presentation, male sex, BMI, prior coronary artery bypass graft surgery, stent length, type of drug-eluting stent, older age, smoking, diabetes mellitus, congestive heart failure and chronic kidney disease all significantly predicted the likelihood of ischemic events after PCI [22]. The study also showed that bleeding risk could be predicted. However, bleeding risk was positively correlated with ischemic risk, with many of the same variables, including older age, smoking, diabetes mellitus, congestive heart failure and chronic kidney disease, predicting both ischemic and bleeding complications.

Ideally, once patients are appropriately classified according to risk, those with high ischemic and low bleeding risk would receive long-term DAPT while patients with low ischemic and high bleeding risk would not. The management decision for the remainder of patients, while less straightforward, could be made by carefully weighing the risks, benefits and preferences for each individual. Efforts to create clinical tools to support applying individualized therapy in this framework are ongoing.

In summary, the results of the DAPT trial provide valuable lessons for determining the optimal strategy for antiplatelet therapy after DES placement. For the average patient, and likely the majority of patients, the benefits of long-term DAPT appear to outweigh the risk. However, the balance between benefit and risk must be struck for each individual. While recent work has improved our ability to assess this balance for each patient, further investigation is warranted.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.