Approximately 1.4 million Americans experience acute coronary syndromes (ACS) (ST-segment elevation myocardial infarction [STEMI], non-ST-segment elevation myocardial infarction [NSTEMI], or unstable angina) annually, of whom 800,000 are found to have myocardial infarction (MI).¹ Several randomized clinical trials have demonstrated that dual antiplatelet therapy (DAPT) reduces recurrent major adverse cardiovascular events (MACE) immediately following ACS.^2-4 The CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events) trial randomized approximately 12,000 patients with unstable angina or NSTEMI to aspirin (75-325 mg/day) plus clopidogrel (300 loading dose, followed by 75 mg /day) vs. aspirin alone and demonstrated a 20% relative risk reduction (RRR) (9.3% vs. 11.4% respectively, p < 0.001), in a composite of vascular death, MI, or stroke at a median 1.91 years of follow up in favor of clopidogrel.⁴ A step ahead, the TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel-Thrombolysis In Myocardial Infarction) trial demonstrated a 19% RRR (12.1% vs. 9.9% respectively, p < 0.001) in primary composite end point of cardiovascular death, non-fatal MI, or non-fatal stroke in favor of prasugrel when compared to clopidogrel among ACS patients undergoing invasive management over 14.5 months of follow-up.³ The PLATO (Study of Platelet Inhibition and Patient Outcomes) trial, which randomized approximately 18,000 patients with STEMI or NSTEMI to ticagrelor or clopidogrel, demonstrated a 16% RRR (9.8% vs. 11.7%, p < 0.001) in primary outcome (a composite of death from vascular, myocardial infarction, or stroke) at 1 year follow up.⁵ Based on the above data, the current ACC/AHA guidelines recommend continuation of DAPT up to 1 year following ACS.

The efficacy and safety of DAPT to reduce MACE beyond a year from ACS is at the center stage of discussion and has been evaluated in two major randomized controlled trials. The first, the DAPT trial, randomized approximately 10,000 patients with ACS who have undergone drug eluting stent placement and have tolerated DAPT for one year without any major complication.⁶ These patients were randomized to continue DAPT for another 18 months (total DAPT duration: 30 months after placement of drug-eluting stent [DES]) vs. standard of care 12 months of DAPT after DES. The primary outcome of the study, stent thrombosis (0.4% vs. 1.4%; hazard ratio, 0.29 [95% confidence interval {CI}, 0.17 to 0.48]; P < 0.001) and major adverse cardiovascular and cerebrovascular events (4.3% vs. 5.9%; hazard ratio, 0.71 [95% CI, 0.59 to 0.85]; P < 0.001), was lower in favor of continued DAPT. However, this came at an increased risk of bleeding, with rates of moderate to severe bleeding much higher (2.5% vs. 1.6%, p < 0.001) in the continued DAPT group. The second trial, the PEGASUS TIMI 54 (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) study, was designed with a strategy to evaluate DAPT in patients with prior MI and specific high-risk subgroups as discussed in detail below.⁷ The background for the trial was laid by findings of the CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance) trial.⁸ The CHARISMA trial tested the impact of DAPT with clopidogrel in patients with multiple atherothrombotic risk factors, documented coronary disease, documented cerebrovascular disease, or documented symptomatic peripheral arterial disease. While CHARISMA failed to show a reduction in the primary outcome of cardiovascular death, MI, or stroke in the overall study population, DAPT with clopidogrel demonstrated 12.3% reduction in relative risk of primary outcome (6.9% vs. 7.9%, p = 0.046), in a pre-specified subgroup analysis restricted to patients with established cardiovascular disease. The PEGASUS TIMI 54 trial randomized 21,162 patients with age ≥50 years and history of myocardial infarction 1-3 years prior to enrollment, and one additional risk factor (age ≥65 years, diabetes mellitus requiring medication, a second prior spontaneous MI, multi-vessel coronary artery disease, or chronic renal dysfunction) to one of the three groups: placebo, ticagrelor 60 mg twice daily, or ticagrelor 90 mg twice daily.⁷ The primary endpoint was similar to that in the CHARISMA trial, a composite of cardiovascular death, MI, or stroke at a median of 33 months. The primary outcome occurred in 7.85% (HR 0.85, p = 0.008) in the group that received 90 mg of ticagrelor twice daily, 7.77% (HR 0.84, p = 0.004) in the group that received 60 mg of ticagrelor twice daily, and 9.04% in the placebo group (number needed to treat: 84 for 90mg BID, 78 for 60mg BID). However, as widely observed, there is no free lunch in this world--reductions in MACE must be balanced with increased risk of bleeding with DAPT. In the CHARISMA trial, clopidogrel increased the rates of severe bleeding (2.1% vs. 1.3%, p < 0.001), but not moderate bleeding (1.7% vs. 1.3%, p = 0.09) or intracranial bleeding (0.3% vs. 0.3%, p = 0.89). In PEGASUS TIMI 54, the risk of bleeding observed at 3 years was 2.6% (HR 2.69, p < 0.001) in the group that received 90 mg of ticagrelor twice daily, 2.3% (HR 2.32, p < 0.001) in the group that received 60 mg of ticagrelor twice daily, and 1.06% in the placebo group (number needed to harm 64 with 90 mg BID, 80 for 60 mg BID). In this latest study, Bhatt et al. hypothesized that the balance between reduced MACE and risk of bleeding be further tipped in favor of reduced MACE by selecting those prior ACS patients at greatest risk for MACE – the diabetic subgroup.

The Diabetic Subgroup:

One-third of ACS occurs in diabetics, and diabetes is associated with more than two fold increase in recurrent major adverse cardiac event rate after index ACS compared to their non-diabetic counterparts.⁹ Pathobiologically, diabetes is associated with increased baseline platelet activation, enhanced platelet reactivity and aggregation as well as hypercoagulability, all of which increase the risk of atherothrombosis in this patient group.¹⁰ In trials of potent DAPT immediately following ACS (TRITON TIMI 38 and PLATO), the pre-specified diabetic subgroup demonstrated an equivalent or higher RRR from DAPT with similar rates of bleeding as compared to non-diabetics.^11,12 Given the greater event rates in diabetics, a greater absolute risk reduction (ARR) from DAPT was observed among diabetics. In the CURE trial however, reduction in MACE with clopidogrel did not reach statistical significance in the diabetic subgroup.

In their paper in the Journal of the American College of Cardiology, Bhatt et al. performed a subgroup analysis of PEGASUS TIMI 54 trial to examine the impact of DAPT among stable CAD patients with diabetes.¹³ Nearly 32% (6,806/21,162) of the patients in the PEGASUS TIMI 54 trial had diabetes, out of whom 87% (5,960/6,806) were treated with hypoglycemic pharmacological therapy. In diabetic patients, the absolute difference in primary outcome was 4% higher in the placebo arm as compared to non-diabetics at three-year follow up (11.6% vs. 7.84, p < 0.001). This alarmingly high event rate is consistent with prior studies of diabetics as compared to general ACS population. Event rates were even higher in diabetics treated with insulin, MACE 18.2%, and cardiovascular death was 8.1% in the placebo group over 3 years. Bhatt et al. demonstrated that similar to the results in overall ACS population, ticagrelor (both doses pooled) reduced the primary outcome, with similar relative risk reduction of 16% in diabetics as compared to non-diabetics but with greater levels of absolute risk reduction in the diabetic subgroup (1.6% ARR in primary outcome in diabetics as compared to non-diabetic population in which the ARR was 1.1%, NNT 67 for diabetics as compared to 91 for non-diabetics). The ARR was even greater (1.9%, NNT 53 at 3 years) in diabetics treated with pharmacological therapy. On the other hand, the risk of bleeding in diabetics treated with ticagrelor compared to placebo (2.56% vs. 0.98%, HR 2.56, 95% CI: 1.53 to 4.33, p = 0.0004) was similar to the non-diabetics treated with ticagrelor compared to placebo (2.39% vs. 1.09%, HR 2.47; 95% CI 1.73-3.53, p < 0.0001) without any significant interaction (p interaction = 0.89). Even more importantly, there was no difference in the rate of fatal or intracranial bleeding between the subgroups.

In conclusion, the results of this subgroup analysis demonstrate increased efficacy of ticagrelor for secondary prevention of cardiac events, 1-3 years after index ACS, in diabetics as compared to non-diabetic population with prior MI with a similar risk of bleeding (compared to non-diabetic counterparts). These positive findings are tempered by the residual risk demonstrated in the treated diabetics in this study with MACE of over 10% at 3 years, 16.9% for diabetics treated with insulin. Additional strategies are clearly needed to reduce remaining residual risk for this population. One such strategy, treatment of high-risk diabetics with DAPT prior to first MI is being tested in the THEMIS (Study Comparing Cardiovascular Effects of Ticagrelor Versus Placebo in Patients With Type 2 Diabetes Mellitus) trial.¹⁴

References

1. Mozaffarian D, Benjamin EJ, Go AS, et al. Executive summary: heart disease and stroke statistics--2016 update: a report from the American Heart Association. Circulation 2016;133:447-54.
2. Roe MT, Armstrong PW, Fox KA, et al. Prasugrel versus clopidogrel for acute coronary syndromes without revascularization. N Engl J Med 2012;367:1297-309.
3. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndrome. N Engl J Med 2007;357:2001-15.
4. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK. 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.
5. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndrome. N Engl J Med 2009;361:1045-57.
6. Mauri L, Kereiakes DJ, Yew RW, et al. Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. N Engl J Med 2014;371:2155-66.
7. Bonaca MP, Bhatt DL, Cohen M, et al. Long-term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med 2015;372:1791-800.
8. Bhatt DL, Fox KA, Hacke W, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med 2006;354:1706-17.
9. Nesto RW. Correlation between cardiovascular disease and diabetes mellitus: current concepts. Am J Med 2004;116;11S-22S.
10. Vinik AI, Erbas T, Park TS, Nolan R, Pittenger GL. Platelet dysfunction in type 2 diabetes. Diabetes Care 2001;24:1476-85.
11. James S, Angiolillo DJ, Cornel JH, et al. Ticagrelor vs. clopidogrel in patients with acute coronary syndromes and diabetes: a substudy from the PLATelet inhibition and patient Outcomes (PLATO) trial. Eur Heart J 2010;31:3006-16.
12. Wiviott SD, Braunwald E, Angiolillo DJ, et al. Greater clinical benefit of more intensive oral antiplatelet therapy with prasugrel in patients with diabetes mellitus in the trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with prasugrel-thrombolysis in myocardial infarction 38. Circulation 2008;118:1626-36.
13. Bhatt DL, Bonaca MP, Bansilal S, et al. Reduction in ischemic events with ticagrelor in diabetic patients with prior myocardial infarction in PEGASUS-TIMI 54. J Am Coll Cardiol 2016;67:2732-40.
14. https://clinicaltrials.gov/ct2/show/NCT01991795

Keywords: Acute Coronary Syndrome, Adenosine, Adenosine, Angina, Unstable, Blood Platelets, Cerebrovascular Disorders, Coronary Artery Disease, Diabetes Mellitus, Type 2, Drug-Eluting Stents, Hypoglycemic Agents, Insulin, Myocardial Infarction, Organoplatinum Compounds, Peripheral Arterial Disease, Platelet Activation, Platelet Aggregation Inhibitors, Polyethylene Glycols, Risk Factors, Secondary Prevention, Stroke, Thrombophilia, Thrombosis, Ticlopidine

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