By Tim Drake, PharmD, MBA, BCPS

Assistant Professor of Pharmacy, College of Pharmacy, Roseman University of Health Sciences, South Jordan, UT

Dr. Drake reports no financial relationships relevant to this field of study.

SYNOPSIS: The addition of rivaroxaban to daily low-dose aspirin resulted in fewer cardiovascular outcomes and increased major bleeding compared to aspirin alone in patients with stable cardiovascular disease.

SOURCE: Eikelboom JW, Connolly SJ, Bosch J, et al. Rivaroxaban with or without aspirin in stable cardiovascular disease. N Engl J Med 2017;377:1319-1330.

Even with the use of highly effective secondary prevention medications such as statins, beta-blockers, renin angiotensin aldosterone system inhibitors, and aspirin, patients with cardiovascular disease continue to experience repeat events at a rate of 5-10% per year.1 The thrombotic nature of cardiovascular disease promotes study into anticoagulant and antiplatelet medications for primary and secondary prevention of cardiovascular disease. Anticoagulation with vitamin K antagonists in combination with aspirin has been proven to lower risk, but the increased rate of serious, life-threatening bleeding with the combination limited its use.2 Previous trials with factor Xa inhibitors have shown fewer severe bleeding events compared to warfarin when studied to prevent stroke and venous thromboembolism.

The COMPASS trial prospectively randomized 27,395 patients in a double-blind manner to either rivaroxaban 2.5 mg twice daily plus aspirin 100 mg daily, aspirin 100 mg daily, or rivaroxaban 5 mg twice daily. The primary endpoint was a composite of cardiovascular death, stroke, or myocardial infarction (MI). There were three secondary endpoints, which included: a composite of ischemic stroke, MI, acute limb ischemia, or death from coronary heart disease; a composite of ischemic stroke, MI, acute limb ischemia, or death from cardiovascular disease; or death from any cause. For safety, major bleeding was defined as fatal bleeding, symptomatic bleeding into a critical organ, bleeding into a surgical site requiring reoperation, and bleeding that led to hospitalization or admission to an acute care facility.4

The trial ended early because of benefit crossing the pre-determined threshold. The primary outcome occurred in 379 patients in the combined rivaroxaban/aspirin group compared to 496 patients in the aspirin-only group and 448 patients in the rivaroxaban-only group. This resulted in a 24% reduced risk (hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.66-0.86; P < 0.001) in patients taking both rivaroxaban and aspirin compared to aspirin alone. There was no significant difference between rivaroxaban alone and aspirin alone. For the secondary composite that included coronary heart disease death, the risk was reduced by 28% (HR, 0.72; 95% CI, 0.63-0.83; P < 0.001) in the rivaroxaban/aspirin group. The composite that included cardiovascular death resulted in a reduced risk of 26% (HR, 0.74; 95% CI, 0.65-0.85; P < 0.001). The rivaroxaban/aspirin group had 313 total deaths compared to 378 deaths in the aspirin-only group, which resulted in a HR of 0.82 (95% CI, 0.71-0.96; P = 0.01).4 Major bleeding occurred in 288 patients in the combined group compared to 170 patients in the aspirin-only group, resulting in a 70% increased risk (HR, 1.70; 95% CI, 1.40-2.05; P < 0.001). When looking at individual causes of bleeding, the biggest difference came from gastrointestinal bleeding (HR, 2.15; 95% CI, 1.60-2.89; P < 0.001), with no significant difference in fatal bleeding, nonfatal symptomatic intracranial hemorrhage, or nonfatal, symptomatic bleeding into a critical organ. When the primary outcome is combined with fatal bleeding or symptomatic bleeding into a critical organ, the HR was 0.80 (95% CI, 0.70-0.91; P < 0.001) in favor of the combination of rivaroxaban and aspirin compared to aspirin alone.4

COMMENTARY

The COMPASS trial adds evidence to show reduced cardiovascular events in patients with established cardiovascular disease who take an antithrombotic medication (rivaroxaban or warfarin) plus an antiplatelet agenet (aspirin). Previously, warfarin had not been recommended because of the increased risk of intracranial bleeding. The COMPASS trial showed increased rates of major bleeding with the combination of rivaroxaban and aspirin, but no significant difference in fatal bleeding or intracranial bleeding. The authors also gave a net clinical benefit outcome that supported the use of the combination, even with the risk of additional bleeds.

However, the benefit is not so clear when the number needed to treat (NNT) is compared with the number needed to harm (NNH). The NNT for the primary outcome is 77, and the NNH for major bleeds is 83. That means that 77 patients would need to be treated to prevent one event, but that for every 83 patients treated, one major bleed would occur. The advantage is that the rates of fatal and intracranial bleeds are very low, with no statistical difference compared to aspirin alone.

The conclusion might be that mortality and cardiovascular events can be reduced, with the side effect of clinically manageable nonfatal bleeding. Additionally, the part of the COMPASS trial that did not end early included randomizing patients to the proton pump inhibitor pantoprazole or placebo. It will be interesting to see if the addition of a proton pump inhibitor can prevent increased gastrointestinal bleeds. If this is the case, the balance between harm and efficacy would favor the addition of rivaroxaban to aspirin for secondary prevention.

REFERENCES

  1. 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;304:1350-1357.
  2. Anand SS, Yusuf S. Oral anticoagulants in patients with coronary artery disease. J Am Coll Cardiol 2003;41(Suppl S):62S-69S.
  3. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883-891.
  4. Eikelboom JW, Connolly SJ, Bosch J, et al. Rivaroxaban with or without aspirin in stable cardiovascular disease. N Engl J Med 2017;377:1319-1330.