JFP CV 4

Optimal Duration of Antiplatelet Therapy Following Acute Coronary Syndrome

Introduction

Acute coronary syndrome (ACS) comprises a range of clinical presentations most commonly caused by atherothrombosis, and include ST-segment elevation myocardial infarction (STEMI) and non-ST-segment elevation ACS (NSTE-ACS), the latter of which encompasses non-STEMI (NSTEMI) and unstable angina (UA). Family physicians play an important role in the management of ACS, particularly in identifying and addressing risk factors and postdischarge management.

ACS still represents a substantial morbidity and economic burden, despite the increased use of evidence-based pharmacological and interventional treatments leading to a reduction in death, cardiogenic shock, and recurrent ischemic events.¹ In 2010, there were an estimated 1.1 million unique hospital admissions for ACS in the United States,² and a study conducted from 2003 to 2006 estimated that the incremental annual direct costs of ACS were $40,671 per patient.³ Following an ACS, patients are also at a high risk of recurrent ischemic events and death, with ~30% of patients rehospitalized for suspected ACS within 5 years following the initial presentation.⁴

The benefits of dual antiplatelet therapy, with aspirin and a P2Y₁₂ inhibitor (clopidogrel, prasugrel, or ticagrelor), for the secondary prevention of thrombotic events in patients presenting with an ACS are well-established.^5-7 Guidelines recommend 12 months of dual antiplatelet therapy in the majority of patients.^8-10 Although residual ischemic risk is known to persist beyond 12 months following the initial ACS event,¹¹ clinical trials investigating prolonged dual antiplatelet therapy have produced inconsistent results.^12-18 However, the inclusion criteria for patient populations within these trials do vary; for example, some patients received a drug-eluting stent (DES) while others did not, influencing the baseline cardiovascular and bleeding risks. Therefore, the utilization of dual antiplatelet therapy beyond 12 months remains a challenging medical decision.

This newsletter will provide an overview of the available data pertaining to the optimal duration of dual antiplatelet therapy following an ACS, with a focus on individualized treatment plans to optimize patient outcomes.

Guidelines recommend that dual antiplatelet therapy with low-dose aspirin and a P2Y₁₂ inhibitor be initiated as soon as possible following an ACS, and be maintained for 12 months in the majority of cases (see below for exceptions).^8-10,19-21 Following the 12 months of dual antiplatelet therapy, it is recommended that aspirin monotherapy be administered indefinitely.^8-10,19,20

In patients with a very-high bleeding risk, such as those with prior intracranial hemorrhage, recent gastrointestinal bleeding, or concomitant anticoagulation therapy, the risk of morbidity from bleeding may outweigh the anticipated benefit of a 12-month dual antiplatelet therapy regimen. Therefore, earlier discontinuation of P2Y₁₂ inhibitor therapy may be considered.^10,21 However, dual antiplatelet therapy should be continued for a minimum of 1 month for patients receiving a bare-metal stent (BMS) or 6 months for patients receiving a DES.^8,20

Some guidelines also recognize that prolonged dual antiplatelet therapy (>12 months) may be beneficial under certain circumstances, particularly in patients with characteristics associated with high ischemic risk, such as prior myocardial infarction (MI), diabetes mellitus, or extensive coronary artery disease (CAD).^9,10,21 The "2016 American College of Cardiology (ACC)/American Heart Association (AHA) Guideline Focused Update on Duration of Dual Antiplatelet Therapy in Patients with Coronary Artery Disease" provides specific recommendations pertaining to the optimal duration of dual antiplatelet therapy in patients with ACS, taking into account ACS management strategy and individual bleeding risk. These recommendations are described in TABLE 1, and are summarized in the following algorithm: http://circ.ahajournals.org/content/circulationaha/134/10/e123/F5.large.jpg.²¹ However, the guideline emphasizes that decisions about the duration of dual antiplatelet therapy should be made on an individual basis using clinical judgment, assessment of the benefit-risk ratio, and patient preference.²¹

TABLE 1. Recommendations regarding the duration of dual antiplatelet therapy in patients with recent ACS (NSTE-ACS or STEMI) from the 2016 ACC/AHA Guideline Focused Update on Duration of Dual Antiplatelet Therapy in Patients with Coronary Artery Disease²¹

Abbreviations: ACC, American College of Cardiology; ACS, acute coronary syndrome; AHA, American Heart Association; BMS, bare metal stent; CABG, coronary artery bypass graft surgery; DES, drug-eluting stent; NSTE-ACS, non-ST-elevation acute coronary syndrome; PCI, percutaneous coronary intervention; STEMI, ST-elevation myocardial infarction.

^aHigh bleeding risk denotes those who have or develop a high risk of bleeding (eg, treatment with oral anticoagulant therapy) or are at increased risk of severe bleeding complication (eg, major intracranial surgery).

Ischemic risk is known to persist beyond 12 months following an ACS event. In a 5-year study of patients with ACS treated with percutaneous coronary intervention (PCI), although the stented target lesion was generally stable after the first 12 months, ischemic events unrelated to the target lesion continued to occur during years 2 to 5.²² Additionally, an analysis of patients with MI from the REduction of Atherothrombosis for Continued Health (REACH) registry demonstrated that 12 months after the initial event, the rate of residual ischemic risk continually increased by ~3.5% per year for the next 4 years.¹¹ However, studies investigating the efficacy and safety of prolonged (18–48 months) dual antiplatelet therapy compared with a standard 12-month regimen have produced variable results^{12-15,17,18,23-27} (TABLE 2).

TABLE 2. Summary of key studies investigating the optimal duration of dual antiplatelet therapy

Abbreviations: ACS, acute coronary syndromes; ARCTIC, Double Randomization of a Monitoring Adjusted Antiplatelet Treatment Versus a Common Antiplatelet Treatment for DES Implantation, and an Interruption Versus Continuation of Double Antiplatelet Therapy, One Year After Stenting; BARC, Bleeding Academic Research Consortium; BMS, bare-metal stent; CAD, coronary artery disease; CV, cardiovascular; DAPT, Dual Antiplatelet Therapy study; DES, drug-eluting stent; DES-LATE, Duration of Clopidogrel Therapy After Drug-Eluting Stent; EXCELLENT, Efficacy of Xience/Promus Versus Cypher in rEducing Late Loss After stENTing; GUSTO, Global Use of Strategies to Open Occluded Coronary Arteries; I-LOVE-IT, Evaluate Safety and Effectiveness of the Tivoli DES and the Firebird DES for Treatment of Coronary Revascularization; ISAR-SAFE, Randomized, Double-blind, Placebo-controlled Trial of 6 vs 12 Months Clopidogrel Therapy After Implantation of a Drug-Eluting Stent; ITALIC, Is There A LIfe for DES After Discontinuation of Clopidogrel; MI, myocardial infarction; NA, not available; OPTIDUAL, Optimal Duration of Dual Antiplatelet Therapy After Drug-Eluting Stent Implantation; OPTIMIZE, Optimized Duration of Clopidogrel Therapy Following Treatment With the Endeavor Zotarolimus-Eluting Stent in Real-World Clinical Practice; PCI, percutaneous coronary intervention; PRODIGY, PROlonging Dual Antiplatelet Treatment In Patients With Coronary Artery Disease After Graded Stent-Induced Intimal Hyperplasia study; REAL-LATE, Correlation of Clopidogrel Therapy Discontinuation in REAL-World Patients Treated With Drug-Eluting Stent Implantation and Late Coronary Arterial Thrombotic Events; SCAD, stable coronary artery disease; SECURITY, Second Generation Drug-Eluting Stents Implantation Followed by Six Versus Twelve-Month Dual Antiplatelet Therapy; STEEPLE, Safety and Efficacy of Enoxaparin in PCI Patients, an International Randomized Evaluation; TIMI, thrombolysis in myocardial infarction; TVR, target vessel revascularization; ZEST-LATE, Evaluation of the Long-term Safety After Zotarolimus-Eluting Stent, Sirolimus-Eluting Stent, or PacliTaxel-Eluting Stent Implantation for Coronary Lesions - Late Coronary Arterial Thrombotic Events.

A number of randomized controlled trials reported a significant reduction in the rate of ischemic events and a significant increase in the risk of bleeding with long-term dual antiplatelet therapy (>12 months), compared with a <12-month treatment period.^{12,15,17,23-26} However, some studies reported no significant difference in cardiovascular outcomes or the incidence of major bleeding between long- and short-term dual antiplatelet therapy.^{14,16,18,27,31,32}

In the largest of these randomized controlled trials, the Dual Antiplatelet Therapy (DAPT) study, 9961 patients who had undergone DES implantation and had been treated with dual antiplatelet therapy for 12 months without experiencing an ischemic or bleeding event were randomized to receive an additional 18 months of dual antiplatelet therapy or aspirin monotherapy. An additional 18 months of dual antiplatelet therapy was associated with a significant reduction in the rate of stent thrombosis (0.4% vs 1.4%; hazard ratio [HR], 0.29; 95% confidence interval [CI], 0.17–0.48; P<.001) and adverse cardiovascular and cerebrovascular events (4.3% vs 5.9%; HR, 0.71; 95% CI, 0.59–0.85; P<.001). However, this ischemic benefit was accompanied by a significant increase in the rate of moderate or severe bleeding, compared with aspirin monotherapy (2.5% vs 1.6%; P=.001).¹² A significant increase in the rate of all-cause mortality was also observed with extended dual antiplatelet therapy (2% vs 1.5%; HR, 1.36; 95% CI, 1–1.85; P=.05). However, there was no significant increase in cardiovascular death or fatal bleeding, and after excluding deaths occurring in patients diagnosed with cancer before enrollment, the difference in all-cause mortality between treatment groups was not significant.³³ A subgroup analysis from the DAPT study demonstrated that prolonged (30 months) dual antiplatelet therapy had a more favorable benefit-risk ratio in patients presenting with acute MI, compared with those without a history of MI.²⁶ This suggests that prolonged dual antiplatelet therapy may be beneficial in certain high-risk patient populations.

This is further supported by the results from the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance (CHARISMA) trial. This study evaluated dual antiplatelet therapy in 15,603 patients with established cardiovascular disease (CVD) or multiple CVD risk factors for a median follow-up of 28 months, and found no significant reduction in ischemic events, compared with aspirin monotherapy, over the same duration.²⁴ However, a post-hoc analysis of patients with prior MI, ischemic stroke, or symptomatic peripheral artery disease (n=9478) demonstrated that prolonged dual antiplatelet therapy resulted in a significant reduction in ischemic events compared with aspirin monotherapy in this patient population (7.3% vs 8.8%; HR, 0.83; 95% CI, 0.72–0.96; P=.01).²³

Finally, the Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin – Thrombolysis in Myocardial Infarction 54 (PEGASUS-TIMI 54) trial demonstrated that in patients who had experienced an MI 1 to 3 years previously, dual antiplatelet therapy significantly reduced the rate of the composite of cardiovascular death, MI, or stroke compared with aspirin monotherapy over a median follow-up of 33 months (7.9% in the group that received 90 mg ticagrelor twice daily vs 7.8% in the group that received 60 mg ticagrelor twice daily vs 9% in the placebo group (90 mg dose vs placebo [HR, 0.85; 95% CI, 0.75–0.96; P=.008]; 60 mg dose vs placebo [HR, 0.84; 95% CI, 0.74–0.95; P=.004]). However, significantly increased rates of Thrombosis In Myocardial Infarction (TIMI) major and minor bleeding were also observed with prolonged dual antiplatelet therapy compared with aspirin monotherapy (2.6% with 90 mg dose, 2.3% with 60 mg dose, and 1.1% with placebo; P<.001 for each dose vs placebo).²⁵

Conversely, several randomized clinical trials conducted in patients treated with DES found that shorter-duration dual antiplatelet therapy (3–6 months) was not associated with a significant increase in the risk of ischemic events and resulted in fewer bleeding complications compared with a 12-month regimen^28-32,34,35 (TABLE 2). However, the majority of patients included in these studies were not at high risk, with less than half presenting with an ACS and few instances of prior MI. Additionally, in the Efficacy of Xience/Promus Versus Cypher to Reduce Late Loss After Stenting (EXCELLENT) trial, a significant interaction between diabetes and outcomes was identified, with target vessel failure occurring more frequently in the 6-month dual antiplatelet therapy group than in the 12-month group in patients with diabetes.²⁹ Similar results were previously observed by Brar et al, who found that longer durations of clopidogrel treatment were associated with a lower incidence of death or MI following DES implantation in patients with diabetes.³⁶ This interaction may be due to the fact that diabetes is associated with poor outcomes and increased complications following ACS and PCI.^37-39 These results indicate that in patients at low ischemic risk and high bleeding risk treated with DES, 3 to 6 months of dual antiplatelet therapy may be reasonable. However, for high-risk patients, such as those with concomitant diabetes, the minimal necessary duration of dual antiplatelet therapy may be longer.

Taken together, these results suggest that there is a gradient of benefit for the use of prolonged dual antiplatelet therapy according to an individual patient's level of ischemic risk.

Among patients who receive 12 months of dual antiplatelet therapy without experiencing an ischemic or bleeding event, continued therapy decreases ischemic risk and increases the risk of bleeding events. A meta-analysis of 10 randomized clinical trials (n=32,287) found that the numbers needed to treat and to harm with prolonged (>12 month) dual antiplatelet therapy are similar for thrombotic (number needed to treat 152) and bleeding (number needed to harm 135) events.⁴⁰ This suggests that duration of dual antiplatelet therapy should be tailored to the individual patient, and highlights the importance of balancing a patient’s thrombotic profile against his/her bleeding risk.

Many factors associated with increased ischemic risk and increased bleeding risk have been identified and are outlined in the 2016 ACC/AHA guideline-focused update on the duration of dual antiplatelet therapy in patients with CAD (BOX 1). The presence of these factors should be carefully assessed when deciding on the optimal duration of dual antiplatelet therapy for an individual patient.²¹ Patients with characteristics associated with increased ischemic risk, particularly those with prior MI or concomitant diabetes, in whom dual antiplatelet therapy is well-tolerated in the first 12 months are most likely to benefit from prolonged dual antiplatelet therapy.^{21,23,25,26,29,36} Conversely, in patients at an increased risk of bleeding, such as those with a low body weight (<60 kg), renal dysfunction, or age >75 years, dual antiplatelet therapy beyond 12 months is not advisable.^21,41 Moreover, in patients at a very-high risk of bleeding events, such as those with prior intracranial hemorrhage, recent gastrointestinal bleeding, or concomitant anticoagulation use, early discontinuation of dual antiplatelet therapy (<12 months) should be considered.⁴¹ However, assessing the balance between ischemic and bleeding risk in an individual patient can be challenging, as patients can possess characteristics for both increased ischemic risk and increased bleeding risk, and factors relating to both can overlap.⁴² In an analysis of data from 2 large prospective cohorts of patients undergoing DES implantation (n=9727), multivariate predictors of bleeding were identified, and included older age (>75 years), smoking, diabetes, congestive heart failure, and chronic kidney disease. However, all significant predictors of long-term bleeding events were also associated with an increased risk of ischemic events. Further characteristics associated with ischemic risk were sex (male), increased body mass index, prior MI, prior coronary artery bypass graft (CABG), STEMI on presentation, stent length, and sirolimus-eluting stent use. The study also found that in most patients (>95%), long-term ischemic risk was greater than long-term bleeding risk.⁴²

Clinical prediction scores have been developed that may facilitate decisions surrounding the optimal duration of dual antiplatelet therapy. The DAPT score,⁴³ developed using data from the DAPT study, aims to help identify patients most likely to benefit from continuation of dual antiplatelet therapy beyond 12 months. The score ranges from –2 to 10, with weighted factors contributing to the score outlined in BOX 2.⁴³ In the derivation cohort (n=11,648), among patients with a high DAPT score (>2), continued dual antiplatelet therapy was shown to be associated with an absolute reduction in ischemic events that was 8 times greater than the absolute increase in moderate or severe bleeding. Conversely, among patients with a low DAPT score (<2), continued use of dual antiplatelet therapy was associated with an absolute increase in bleeding that was 2.4 times greater than the absolute reduction in ischemic events.⁴³ Risk scores derived using data from the Patterns of Non-Adherence to Anti-Platelet Regimen in Stented Patients (PARIS) registry also aim to predict the risk of coronary thrombotic events and major bleeding events following DES implantation, and show similar moderate levels of discrimination to the DAPT score.⁴⁴ These risk scores may be useful in identifying individual patients with discordant ischemic risks and bleeding risks; however, further external validation is required.

Conclusions

Despite the well-established benefits of dual antiplatelet therapy for the prevention of secondary ischemic events following an ACS, the optimal duration remains uncertain, with clinical studies reporting variable results. Guidelines recommend that dual antiplatelet therapy be initiated as soon as possible following an ACS, and maintained for 12 months in most cases. However, guidelines also recognize that shorter- or longer-duration dual antiplatelet therapy may be beneficial in certain cases. Thus, decisions surrounding the duration of dual antiplatelet therapy should be made on an individual basis using clinical judgment and an assessment of the individual patient’s bleeding risk and ischemic risk. Assessing the balance between ischemic and bleeding risk in an individual patient can be challenging, especially because of the substantial overlap of patient characteristics associated with ischemic risk and bleeding risk. Risk scores are available that aim to identify individual patients who may benefit from prolonged dual antiplatelet therapy. However, only moderate levels of discrimination have been observed with available risk scores, and further external validation is required. Further research is therefore required to develop and validate robust risk scores that can accurately predict whether an individual patient would benefit from longer- or shorter-duration dual antiplatelet therapy in a real-world setting.

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