Dual anti-platelet therapy (DAPT) with aspirin and a P2Y12 antagonist is more effective than aspirin monotherapy in prevention of thrombosis, but at the cost of more bleeding. Patients at higher risk for thrombotic events, such as those with acute coronary syndromes (ACS) or a recent percutaneous coronary intervention (PCI), benefit from DAPT as its reduction in ischemic events outweighs its increase in bleeding risk.^1-3 However, the role of DAPT in patients at lower risk for thrombotic events, such as those with stable ischemic heart disease (SIHD), is less clear. A review of the current data on the utility of DAPT in SIHD patients can inform a clinical approach to its use and identify questions for future research.

Stable ischemic heart disease (SIHD) is defined as confirmed obstructive coronary artery disease without recent (<1 year) ACS or PCI.⁴ The 2012 American College of Cardiology and American Heart Association guidelines for SIHD management assign a class IIB recommendation for DAPT, which indicates that its benefit may outweigh risk, however, data for efficacy are less well established.⁴ This recommendation was based primarily on the Clopidogrel for High Atherothrombotic Risk Ischemic Stabilization, Management and Avoidance (CHARISMA) trial.⁵ CHARISMA randomized over 15,000 patients with either confirmed cardiovascular disease or at high risk for atherothrombotic events to treatment with DAPT (using clopidogrel) or aspirin monotherapy. After a median follow-up period of 28 months, the rates of myocardial infarction (MI), stroke or death were similar between treatment arms. However, a post-hoc analysis of SIHD patients with a history of MI indicated that DAPT therapy was more effective than aspirin in reducing ischemic events (7.3% DAPT patients vs. 8.8% aspirin patients, p=0.01), although at the cost of increased bleeding (2.0% DAPT patients vs. 1.3% aspirin patients, p=0.004).⁶

Other studies have analyzed prolonged use of DAPT in patients with ACS or elective PCI with support of its use in these populations. The Twelve or 30 Months After Dual Anti-Platelet Therapy After Drug-Eluting Stents (DAPT) trial compared 18 months of DAPT versus aspirin alone in over 9,000 patients who had tolerated 12 months of DAPT following PCI.⁷ Similar to the CHARISMA post-hoc analysis, DAPT patients benefited from a reduction in thrombotic events (4.3% DAPT patients vs. 5.9% aspirin patients, p<0.001) against an increase in bleeding (2.6% DAPT patients vs. 1.6% aspirin patients, p=0.001). In subgroup analyses, the beneficial effect of DAPT was similar by PCI indication (ACS or elective) and among patients who received a drug-eluting stent. However those who received a bare-metal stent did not see reduction in ischemic events, but did have higher rates of bleeding (4.6% DAPT patients vs. 1.8% aspirin patients, p=0.002), suggesting no net benefit of DAPT in this subgroup. Similar support for DAPT use in SIHD was seen in a meta-analysis pooling data from five randomized controlled trials totaling more than 79,000 patients with known ischemic heart disease. This study demonstrated a decrease in MI (2.7% DAPT patients vs. 3.3% aspirin patients, p<0.0001), particularly in patients with a history of ACS, at the cost of a increased risk of major bleeding (1.6% DAPT patients vs. 1.3% aspirin patients, p<0.0001).⁸ In contrast to these findings, an analysis of more than 3,000 SIHD patients in a prospective registry on treatment with aspirin plus clopidogrel or aspirin monotherapy showed no difference in a composite outcome of MI, stroke or cardiovascular death (5.5% DAPT patients vs. 5.7% aspirin patients, p=0.87) or major bleeding rate (1.0% DAPT patients vs. 0.7% aspirin patients, p=0.60).⁹ However, results from this non-randomized, prospective registry study were pooled from a heterogeneous group of SIHD patients and thus is unable to determine if particular subgroups of SIHD patients may benefit. Overall, the studies above indicate DAPT is of net benefit in certain SIHD patients, such as those with a history of MI or revascularized coronary disease.

The role of the newer P2Y12 antagonists, such as prasugrel and ticagrelor, in SIHD also remains unclear. Compared to clopidogrel, these medications confer a greater reduction in thrombotic risk but with higher rates of bleeding as shown in landmark trials studying newer DAPT regimens in ACS patients.^10,11 Yet the only study to evaluate newer P2Y12 agents in SIHD patients was the The Long Term Use of Ticagrelor in Patients with Prior Myocardial Infarction (PEGASUS-TIMI 54) trial.¹² In PEGASUS-TIMI 54, over 20,000 patients with an MI in the prior 1 to 3 years were randomized to DAPT with ticagrelor and aspirin or aspirin monotherapy. Results from the PEGASUS-TIMI 54 trial were analogous to DAPT studies with clopidogrel, finding a reduction in thrombotic endpoints with ticagrelor (7.8% DAPT patients vs. 9.0% aspirin patients, p<0.001) at the cost of increased bleeding (2.6% DAPT patients vs. 1.0% aspirin patients, p<0.001).

Translating these research findings to clinical practice is complex, in part due to the heterogeneity of SIHD. SIHD encompasses a diverse cohort of pathology, ranging from focal obstructive coronary plaque to diffuse, severe coronary atherosclerotic burden. Along this continuum of coronary disease and in conjunction with individual patient characteristics, clinicians must weigh employing DAPT against each individual's risk of thrombosis and potential for bleeding. This requires a rigorous evaluation within the thrombosis-bleeding framework when considering the risk-benefit ratio of DAPT. Most data from the trials and meta-analysis indicate the DAPT provides a net benefit in SIHD patients with prior MI. However, data is lacking in other high-risk SIHD populations, including those with unrevascularized, diffuse coronary disease or concurrent, pro-atherosclerotic comorbidities such as diabetes or chronic kidney disease. Risk prediction calculators may help weigh harm against benefit across these populations. Bleeding risk calculators^13-15 incorporate traditional risk factors associated with bleeding such as age, gender, diabetes and low body weight. These scores have shown excellent discriminatory capability in predicting bleeding risk and have been validated in large ACS populations. Bleeding scores can be evaluated against patient factors known to increase ischemic risk including age, multiple prior MIs, extensive CAD, history of diabetes or chronic kidney disease. Use of these risk scores, in conjunction with experienced clinical judgment, may help clinicians judge individual risk-benefit ratio with DAPT in SIHD populations.

Additional research is needed to understand the optimal use of DAPT in SIHD patients. One area of inquiry is translating trial data to individual patients. Data from randomized trials report the average benefit and risks of DAPT in study populations. Properly translating this average value to the individual patient's response to DAPT is crucial, but challenging. Methods to predict individual response to P2Y12 agents have the potential to further optimize patient selection for DAPT. In an example of a potential approach, Salisbury, et al retrospectively applied predictive thrombotic and bleeding models based on patient and procedural characteristics to individual patients in the TRITON-TIMI 38 trial.¹⁶ Among patients enrolled in the trial, there was marked variability in the predicted risk of ischemia (1.2-78% clopidogrel, 0.5-61% prasugrel) and bleeding (0.3-28.5% clopidogrel, 0.4-26.4% prasugrel), suggesting that individualized risk prediction is a potentially valuable strategy to determining the best balance of benefit and risk in patients. Application of this method to gauge the risk of thrombosis versus bleeding of DAPT in the SIHD population may be warranted.

Additional clinical trials and observational studies of DAPT in SIHD are also needed. Randomized controlled trials of SIHD patients with prior MI, stroke, or symptomatic peripheral arterial disease may identify populations where a net benefit with DAPT exists. Analyses of clinical registries can complement these trials by characterizing real-time practice patterns of DAPT use in SIHD and analyze underrepresented high-risk SIHD populations such as those with non-revascularized diffuse coronary disease, without an MI history, or on novel DAPT regimens composed of the newer P2Y12 agents. Furthermore, registries can evaluate, modify and validate risk prediction tools assessing the thrombosis-bleeding tradeoff of DAPT in the SIHD population.

Currently, available evidence suggests that DAPT use in SIHD patients is most beneficial in those with a history of MI. Clinicians should incorporate this evidence in their decisions for their patients, judiciously assessing the individual patient's benefit and risk for DAPT, and integrating further research findings in this population as it becomes available. The complex exercise of balancing DAPT risk and benefit in SIHD patients underscores the "art" inherent in medicine.

References

1. The CURE trial investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001; 345: 494-502.
2. Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 ACC/AHA guidelines for the management of patients with non-ST-elevation acute coronary syndromes. Circulation 2014; 130: e344-426.
3. O'Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction. J Am Coll Cardiol 2013; 61 (4): e78-e140.
4. Fihn SD, Blankenship JC, Alexander KP, et al. 2014 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS Focused update of the guideline for the diagnosis and management of patients with stable ischemic heart disease. J Am Coll Cardiol 2014;64(18):1929-1949.
5. Bhatt DL, Fox KA, Hacke W, et al. Clopidogrel and aspirin versus aspirin alone for prevention of atherothrombotic events. N Engl J Med 2006; 354: 1706-17.
6. Bhatt DL, Flather MD, Hacke W, et al. Patients with prior myocardial infarction, stroke or symptomatic peripheral arterial disease in the CHARISMA trial. J Am Coll Cardiol 2007; 49: 1982-8.
7. Mauri L, Kereiakes DJ, Yeh RW, et al. Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. N Engl J Med 2014; 371: 2155-66.
8. Helton TJ, Bavry AA, Kumbhani DJ, et al. Incremental effect of clopidogrel on important outcomes in patients with cardiovascular disease: a meta-analysis of randomized trials. Am J Cardiovasc Drugs 2007; 7: 289-97.
9. Lemesle G, Lamblin N, Meurice T, et al. Dual antiplatelet therapy in patients with stable coronary artery disease in modern practice: Prevalence, correlates and impact on prognosis. Am Heart J 2014; 168: 479-86.
10. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndrome. N Engl J Med 2007; 357: 2001-2015.
11. Bonaca MP, Bhatt DL, Cohen M, et al. Long-term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med 2015; 372: 1791-1800.
12. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009; 361: 1045-1057.
13. Subherwal S, Bach RG, Chen AY, et al. Baseline risk of major bleeding in non-ST-segment-elevation myocardial infarction: the CRUSADE bleeding score. Circulation 2009; 119: 1873-1882.
14. Mathews R, Peterson ED, Chen AY, et al. In-hospital major bleeding during ST-elevation and non-ST-elevation myocardial infarction care: derivation and validation of a model from the ACTION Registry(R)-GWTG. Am J Cardiol 2011; 107: 1136–1143.
15. Mehran R, Pocock SJ, Nikolsky E, et al. A risk score to predict bleeding in patients with acute coronary syndromes. J Am Coll Cardiol 2010; 55: 2556-2566.
16. Salisbury AC, Wang K, Cohen DJ, et al. Selecting anti-platelet therapy at time of percutaneous intervention for acute coronary syndrome. Circ Cardiovasc Qual Outcomes 2013; 6: 27-34.

Keywords: Acute Coronary Syndrome, Adenosine, American Heart Association, Aspirin, Blood Platelets, Body Weight, Comorbidity, Coronary Artery Disease, Diabetes Mellitus, Drug-Eluting Stents, Follow-Up Studies, Judgment, Metals, Myocardial Infarction, Percutaneous Coronary Intervention, Peripheral Arterial Disease, Peripheral Arterial Disease, Piperazines, Polyethylene Glycols, Prospective Studies, Randomized Controlled Trials as Topic, Registries, Renal Insufficiency, Chronic, Retrospective Studies, Risk Factors, Stroke, Thiophenes, Thrombosis, Ticlopidine, Angina, Stable

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