Antithrombotic Therapy in Patients With SIHD
Preventing subsequent ischemic events in patients with established stable ischemic heart disease (SIHD) is key to improving their prognoses. The role of platelets in arterial thrombosis has been long established, and antiplatelet drugs have been the cornerstones to treatment and prevention of ischemic events.1,2 According to the guidelines, single antiplatelet therapy with aspirin or clopidogrel is recommended as a first-line approach for most patients.3,4
However, ischemic and bleeding risks are widely heterogeneous among the different subsets of patients and are affected by various factors, such as a history of percutaneous coronary intervention (PCI), a history of diabetes, and the co-prescription of anticoagulation therapy for atrial fibrillation.5-8 In this regard, there is hardly a "one size fits all" strategy but rather a multitude of options.
Antithrombotic Therapy for Patients With Diabetes and SIHD
Diabetes carries a substantial additional ischemic risk for patients with established coronary artery disease despite single antiplatelet therapy with aspirin.1,2 Recently, two strategies have been evaluated to reverse this high ischemic risk: the addition of an antiplatelet drug, ticagrelor, and the addition of an oral anticoagulant, rivaroxaban.
THEMIS (The Effect of Ticagrelor on Health Outcomes in Diabetes Mellitus Patients Intervention Study) randomized 19,220 patients and tested the addition of ticagrelor versus placebo on top of aspirin in patients with diabetes and SIHD without prior myocardial infarction.9 The primary ischemic composite endpoint of cardiovascular death, myocardial infarction, or stroke was significantly lower in the ticagrelor group compared with placebo (7.7% vs. 8.5%, respectively; hazard ratio [HR] 0.90; 95% confidence interval [CI], 0.81-0.99; p = 0.04). However, there was also an increase in Thrombolysis in Myocardial Infarction (TIMI) major bleeding (2.2% vs. 1.0%, respectively; HR 2.32; 95% CI, 1.82-2.94; p < 0.001) as well as a small but statistically significant increase in intracranial bleeding (0.7% vs. 0.5%, respectively; HR 1.71; 95% CI, 1.18-2.48; p = 0.005). A prespecified endpoint designed to weigh the ischemic-hemorrhagic balance examined events causing irreversible harm (the composite of all-cause death including fatal bleeding, myocardial infarction, stroke, and intracranial hemorrhage) and was not significantly different between the 2 groups (10.1% in the ticagrelor group vs. 10.8% in the placebo group; HR 0.93; 95% CI, 0.86-1.02).
The COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) trial tested a rivaroxaban-based strategy with or without aspirin in high-risk patients with stable atherosclerotic vascular disease (coronary or peripheral).10 The addition of a dose of rivaroxaban (2.5 mg twice daily) to aspirin reduced the primary outcome, a composite of cardiovascular death, stroke, or myocardial infarction, compared with aspirin alone (4.1% vs. 5.4%, respectively; HR 0.76; 95% CI, 0.66-0.86; p < 0.001). The rate of major bleeding was higher with rivaroxaban plus aspirin (3.1% vs. 1.9%, respectively; HR 1.70; 95% CI, 1.40-2.05; p < 0.001) but without significantly increasing intracranial or fatal bleeding. The endpoint designed to assess net clinical benefit (cardiovascular death, stroke, myocardial infarction, fatal bleeding, or symptomatic bleeding into a critical organ) was lower in the rivaroxaban-plus-aspirin group compared with aspirin alone (4.7% vs. 5.9%, respectively; HR 0.80; 95% CI, 0.70-0.91; p < 0.001).
Importantly, the ischemic-bleeding balance in the COMPASS trial appears to be more favorable for rivaroxaban in patients with additional risk factors, including diabetes. In COMPASS, patients with diabetes represented 10,341 out of 27,395 participants (37.8%). In a prespecified analysis, the benefit of rivaroxaban plus aspirin on the primary endpoint was similar across patients with or without diabetes (p for interaction = 0.77). The excess of major bleeding was also not different between the groups (p for interaction = 0.97). However, the risk of the primary endpoint was higher in the subset of patients with diabetes (2.3% for patients with diabetes vs. 1.4% for patients without diabetes for the primary endpoint at 3 years), and the absolute bleeding risk was comparable. Therefore, patients with diabetes derived a numerically larger absolute risk reduction from the addition of rivaroxaban than patients without diabetes.11 Also, when the ischemic risk factors that determined eligibility into COMPASS were studied in the patients from the REACH (Reduction of Atherothrombosis for Continued Health) registry, a more favorable ischemic bleeding balance in COMPASS-eligible patients with multiple risk factors was observed.12,13 Indeed, the ischemic risk increased from 7.0% (95% CI, 5.6-8.7%) with one risk factor to 21.8% (95%CI, 19.9-23.9%) with ≥4 risk factors. Meanwhile, the risk of bleeding ranged, respectively, from 1.5% (95% CI, 0.9-2.1%) to 3.2% (95% CI, 2.6-3.9%).
Some insights can be drawn from the comparative analysis of the THEMIS and COMPASS trials. First, in patients with ischemic heart disease and diabetes, the high ischemic burden can be reduced by the intensification of antithrombotic therapy beyond aspirin alone. However, this strategy will come with an additional bleeding risk regardless of the drug used. However, ischemic risk tends to increase far more than the bleeding hazard with the addition of risk factors. Comparing studies with different designs and enrollment criteria is always tricky, and no definite conclusion can be made. THEMIS was a trial dedicated to patients with diabetes, whereas diabetes was a subgroup in the COMPASS trial.
Antithrombotic Therapy for Patients With Diabetes and a History of PCI
Patients with a history of PCI have a higher risk of ischemic events.7 The benefit-risk balance of antithrombotic treatments in this subgroup is, therefore, modified.
In THEMIS, 11,154 patients (58% of the overall trial population) had a history of PCI.14,15 The reduction of the primary ischemic endpoint was significant in the ticagrelor group compared with placebo in patients with previous PCI (7.3% vs. 8.6%, respectively; HR 0.85; 95% CI, 0.74-0.97; p = 0.013). This benefit appeared to persist even years after the time of the PCI. Meanwhile, TIMI major bleeding was higher in the ticagrelor group compared with placebo in both patients with and without previous PCI (p < 0.001 for both groups; p for interaction = 0.20). Importantly, the irreversible harm outcome was lower with ticagrelor compared with placebo only in patients with previous PCI (9.3% vs. 11.0%, respectively; HR 0.85; 95% CI, 0.75-0.95; p = 0.005; p for interaction = 0.012), indicating net clinical benefit of ticagrelor in that population.
In the COMPASS trial, 16,560 patients had SIHD, and 9,862 (59.6%) had a history of PCI. In patients with a history of PCI, the primary endpoint was lower for the patients receiving rivaroxaban plus aspirin versus aspirin alone (4.0% vs. 5.5%, respectively; HR 0.74; 95% CI, 0.61-0.88). The risk of major bleeding was higher in the group receiving the combination compared with aspirin alone (3.3% vs. 2.0%, respectively; HR 1.72; 95% CI, 1.34-2.21), but the risk for net clinical benefit was lower (4.6% vs. 5.9%; HR 0.78; 95% CI, 0.65-0.93). The results were consistent in patients with or without prior PCI for both the primary endpoint (p for interaction = 0.85), the bleeding risk (p for interaction = 0.68), and the net clinical benefit (p for interaction = 0.98). In this analysis, the benefit of the association appeared similar irrespective of time since previous PCI, as noted in the THEMIS-PCI (Ticagrelor in patients with diabetes and stable coronary artery disease with a history of previous percutaneous coronary intervention) analysis with ticagrelor as well.16
The two antithrombotic strategies tend to have a different benefit-risk ratio in patients with a history of PCI. In THEMIS, the strategy appeared more favorable in patients with a history of PCI, but the benefit-risk ratio was not modified by a history of PCI in the COMPASS trial. The risk assessment following PCI should, therefore, guide the choice of the antithrombotic strategy. A ticagrelor-based dual antiplatelet therapy (DAPT) strategy is valuable in the first months after PCI, and, in patients with a history of prior PCI who have tolerated DAPT without bleeding with an estimated high risk of ischemic complications in the long term, extended-duration therapy may be warranted. A rivaroxaban-based strategy may be most appropriate in patients not already on DAPT but who are judged to be at high ischemic risk and low bleeding risk.
Balancing Antiplatelet Therapy and Anticoagulation in Patients With SIHD and Atrial Fibrillation
The choice of antithrombotic strategy for patients with SIHD with atrial fibrillation is challenging, especially following PCI with stent implantation. The risk of ischemic cerebrovascular events related to cardiac embolism is not as effectively prevented by the use of antiplatelet drugs and therefore requires the use of an anticoagulant. The risk of stent thrombosis, even if low with newer-generation stents, requires the use of antiplatelet drugs. On the other hand, triple therapy (DAPT plus an anticoagulant) carries a high risk for bleeding. Multiple randomized trials have addressed this issue.17-20 These trials tested the safety of triple versus dual antithrombotic therapy and direct oral anticoagulants (DOAC) versus vitamin K antagonists (VKA).
In all the trials, triple therapy was associated with higher risk of bleeding without a reduction of ischemic events. These findings were confirmed in a meta-analysis of 4 randomized trials that showed a decrease of 47% in TIMI major and minor bleeding in double versus triple therapy (4.3% vs. 9.0%, respectively; HR 0.53; 95% CI, 0.36-0.85) with the same rates of trial-defined major cardiac events (10.4% vs. 10.0%, respectively; HR 0.85; 95% CI, 0.48-1.29).21
In a recent network meta-analysis that gathered the data from the three major trials, the VKA-based triple therapy strategy appeared to be the most harmful in terms of bleeding.22 In contrast, dual therapy with a DOAC and a P2Y12 receptor inhibitor, dropping aspirin therapy, seemed to be the safest option. The latter was superior in terms of TIMI major bleeding (odds ratio [OR] 0.49; 95% CI, 0.39-0.82), TIMI major and minor bleeding (OR 0.43; 95% CI, 0.25-0.76), and intracranial hemorrhage (OR 0.26; 95% CI, 0.08-0.79) compared with triple therapy with VKA. At the same time, there was no difference in terms of ischemic outcomes or all-cause death.
A subgroup analysis of REDUAL-PCI (Randomized Evaluation of Dual Antithrombotic Therapy With Dabigatran vs. Triple Therapy With Warfarin in Patients With Nonvalvular Atrial Fibrillation Undergoing Percutaneous Coronary Intervention) focused on patients with diabetes.23 In that analysis, there was no interaction between the presence of diabetes and treatments. Indeed, there was still no significant difference in terms of ischemic outcomes between the dual and triple therapy groups. On the other hand, the rates of major or clinically relevant bleeding were lower in the groups receiving dual therapy compared with triple therapy. The reduction was more notable with dabigatran 110 mg 15.2% for dual therapy versus 27.5% for triple therapy (HR 0.54; 95% CI, 0.42-0.70) but remained significant with dabigatran 150 mg (23.8% for dual therapy vs. 25.1% for triple therapy; HR 0.63; 95% CI, 0.48-0.83).
In this regard, data from the randomized trials support DOACs over VKAs, as well as avoiding triple therapy after the first month, and preferably stopping aspirin on hospital discharge, keeping a DOAC and a P2Y12 platelet inhibitor.
The choice of antithrombotic therapy in patients with SIHD is influenced by factors such as a history of diabetes, previous PCI, and atrial fibrillation. Data from recent randomized controlled trials suggest that adding 2.5 mg of rivaroxaban is a good option for patients with diabetes and SIHD. Ticagrelor is a valuable option in high-risk patients, such as those with diabetes, in the first months following a PCI and in patients with a history of prior PCI who have previously tolerated DAPT without bleeding and with an estimated high-risk of stent-related or coronary artery-related complications in the long term. In case of the need for simultaneous antiplatelet therapy and anticoagulation, dual therapy with early cessation of aspirin and combining therapeutic anticoagulation along with a P2Y12 receptor antagonist should be preferred to triple therapy, and a DOAC should be preferred over VKA antagonists.
- Haffner SM. Coronary heart disease in patients with diabetes. N Engl J Med 2000;342:1040-2.
- Emerging Risk Factors Collaboration, Sarwar N, Gao P, Seshasai SRK, et al. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet 2010;375:2215-22.
- Fihn SD, Gardin JM, Abrams J, et al. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease: executive summary: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. Circulation 2012;126:3097-137.
- Knuuti J, Wijns W, Saraste A, et al. 2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes. Eur Heart J. 2020;41:407-77.
- Bhatt DL, Steg PG, Ohman EM, et al. International prevalence, recognition, and treatment of cardiovascular risk factors in outpatients with atherothrombosis. JAMA 2006;295:180-9.
- Steg PG, Bhatt DL, Wilson PWF, et al. One-year cardiovascular event rates in outpatients with atherothrombosis. JAMA 2007;297:1197-206.
- Bhatt DL, Eagle KA, Ohman EM, et al. Comparative determinants of 4-year cardiovascular event rates in stable outpatients at risk of or with atherothrombosis. JAMA 2010;304:1350-7.
- Cavender MA, Steg PG, Smith SC Jr, et al. Impact of Diabetes Mellitus on Hospitalization for Heart Failure, Cardiovascular Events, and Death: Outcomes at 4 Years From the Reduction of Atherothrombosis for Continued Health (REACH) Registry. Circulation 2015;132:923-31.
- Steg PG, Bhatt DL, Simon T, et al. Ticagrelor in Patients with Stable Coronary Disease and Diabetes. N Engl J Med 2019;381:1309-20.
- Eikelboom JW, Connolly SJ, Bosch J, et al. Rivaroxaban with or without Aspirin in Stable Cardiovascular Disease. N Engl J Med 2017;377:1319-30.
- Bhatt DL, Eikelboom JW, Connolly SJ, et al. Role of Combination Antiplatelet and Anticoagulation Therapy in Diabetes Mellitus and Cardiovascular Disease: Insights From the COMPASS Trial. Circulation 2020;141:1841-54.
- Darmon A, Bhatt DL, Elbez Y, et al. External applicability of the COMPASS trial: an analysis of the reduction of atherothrombosis for continued health (REACH) registry. Eur Heart J 2018;39:750-757a.
- Darmon A, Sorbets E, Ducrocq G, et al. Association of Multiple Enrichment Criteria With Ischemic and Bleeding Risks Among COMPASS-Eligible Patients. J Am Coll Cardiol 2019;73:3281-91.
- Bhatt DL, Steg PG, Mehta SR, et al. Ticagrelor in patients with diabetes and stable coronary artery disease with a history of previous percutaneous coronary intervention (THEMIS-PCI): a phase 3, placebo-controlled, randomised trial. Lancet 2019;394:1169-80.
- Bhatt DL, Steg PG. THEMIS and THEMIS-PCI. Eur Heart J 2019;40:3378-81.
- Bainey KR, Welsh RC, Connolly SJ, et al. Rivaroxaban Plus Aspirin Versus Aspirin Alone in Patients With Prior Percutaneous Coronary Intervention (COMPASS-PCI). Circulation 2020;141:1141-51.
- Gibson CM, Mehran R, Bode C, et al. Prevention of Bleeding in Patients with Atrial Fibrillation Undergoing PCI. N Engl J Med 2016;375:2423-34.
- Cannon CP, Bhatt DL, Oldgren J, et al. Dual Antithrombotic Therapy with Dabigatran after PCI in Atrial Fibrillation. N Engl J Med 2017;377:1513-24.
- Lopes RD, Heizer G, Aronson R, et al. Antithrombotic Therapy after Acute Coronary Syndrome or PCI in Atrial Fibrillation. N Engl J Med 2019;380:1509-24.
- Fiedler KA, Maeng M, Mehilli J, et al. Duration of Triple Therapy in Patients Requiring Oral Anticoagulation After Drug-Eluting Stent Implantation: The ISAR-TRIPLE Trial. J Am Coll Cardiol 2015;65:1619-29.
- Golwala HB, Cannon CP, Steg PG, et al. Safety and efficacy of dual vs. triple antithrombotic therapy in patients with atrial fibrillation following percutaneous coronary intervention: a systematic review and meta-analysis of randomized clinical trials. Eur Heart J. 2018;39:1726-1735a.
- Lopes RD, Hong H, Harskamp RE, et al. Safety and Efficacy of Antithrombotic Strategies in Patients With Atrial Fibrillation Undergoing Percutaneous Coronary Intervention: A Network Meta-analysis of Randomized Controlled Trials. JAMA Cardiol 2019;4:747-55.
- Maeng M, Steg PG, Bhatt DL, et al. Dabigatran Dual Therapy Versus Warfarin Triple Therapy Post-PCI in Patients With Atrial Fibrillation and Diabetes. JACC Cardiovasc Interv 2019;12:2346-55.
Clinical Topics: Anticoagulation Management, Arrhythmias and Clinical EP, Invasive Cardiovascular Angiography and Intervention, Stable Ischemic Heart Disease, Atherosclerotic Disease (CAD/PAD), Anticoagulation Management and Atrial Fibrillation, Atrial Fibrillation/Supraventricular Arrhythmias, Interventions and Coronary Artery Disease, Chronic Angina
Keywords: Angina, Stable, Platelet Aggregation Inhibitors, Aspirin, Percutaneous Coronary Intervention, Coronary Artery Disease, Atrial Fibrillation, Fibrinolytic Agents, Blood Platelets, Confidence Intervals, Myocardial Infarction, Intracranial Hemorrhages, Hemorrhage, Risk Factors, Numbers Needed To Treat, Atherosclerosis, Stroke, Registries, Diabetes Mellitus, Purinergic P2Y Receptor Antagonists, Anticoagulants, Coronary Vessels, Thienopyridines, Stents
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