Cardiovascular Outcomes for People Using Anticoagulation Strategies - COMPASS

Contribution To Literature:

The COMPASS trial showed that rivaroxaban plus aspirin was associated with fewer adverse cardiovascular events, but more major bleeding events vs. aspirin alone.

Description:

The goal of the trial was to evaluate anticoagulation strategies with rivaroxaban among patients with stable atherosclerosis.

Study Design

  • Randomized
  • Parallel
  • Blinded

Patients with stable atherosclerosis were randomized to rivaroxaban 2.5 mg twice daily plus aspirin (n = 9,152) vs. rivaroxaban 5 mg twice daily alone (n = 9,117) vs. aspirin alone (n = 9,126).

  • Total number of enrollees: 27,395
  • Duration of follow-up: mean 23 months
  • Mean patient age: 68 years
  • Percentage female: 23%
  • Percentage with diabetes: 38%

Inclusion criteria:

  • Atherosclerosis in ≥2 vascular beds or two additional risk factors (current smoking, diabetes, renal insufficiency, heart failure, or nonlacunar ischemic stroke ≥1 month)

Exclusion criteria:

  • High bleeding risk
  • Recent stroke or previous hemorrhagic or lacunar stroke
  • Severe heart failure
  • Advanced kidney disease
  • Use of dual antiplatelet therapy or anticoagulation
  • Limited prognosis

Principal Findings:

The primary outcome, incidence of cardiovascular death, myocardial infarction, or stroke, occurred in 4.1% of the rivaroxaban plus aspirin group vs. 4.9% of the rivaroxaban alone group vs. 5.4% of the aspirin alone group (p < 0.001 for rivaroxaban plus aspirin vs. aspirin alone; p = 0.12 for rivaroxaban alone vs. aspirin alone). The primary efficacy outcome was the same in all tested subgroups.

Secondary outcomes:

  • All-cause mortality: 3.4% for rivaroxaban plus aspirin, 4.0% for rivaroxaban alone, vs. 4.1% for aspirin alone (p = 0.01 for rivaroxaban plus aspirin vs. aspirin alone; p = 0.67 for rivaroxaban alone vs. aspirin alone)
  • All stroke: 0.9% for rivaroxaban plus aspirin, 1.3% for rivaroxaban alone, vs. 1.6% for aspirin alone (p < 0.001 for rivaroxaban plus aspirin vs. aspirin alone; p = 0.12 for rivaroxaban alone vs. aspirin alone)
  • Ischemic stroke: 0.7% for rivaroxaban plus aspirin, 0.9% for rivaroxaban alone, vs. 1.4% for aspirin alone (p < 0.001 for rivaroxaban plus aspirin vs. aspirin alone; p = 0.004 for rivaroxaban alone vs. aspirin alone)
  • Hemorrhagic stroke: 0.2% for rivaroxaban plus aspirin, 0.3% for rivaroxaban alone, vs. 0.1% for aspirin alone (p = 0.33 for rivaroxaban plus aspirin vs. aspirin alone; p = 0.005 for rivaroxaban alone vs. aspirin alone)
  • Major bleeding: 3.1% for rivaroxaban plus aspirin, 2.8% for rivaroxaban alone, vs. 1.9% for aspirin alone (p < 0.001 for rivaroxaban plus aspirin vs. aspirin alone, p < 0.001 for rivaroxaban alone vs. aspirin alone)
  • Cancer diagnosis: 4.0% for rivaroxaban plus aspirin, 4.0% for rivaroxaban alone vs. 3.8% for aspirin alone. In 77.1%, the timing of gastrointestinal (GI) cancer was within 6 months of a GI bleeding event, while in 88.7%, the timing of genitourinary (GU) cancer was within 6 months of a GU bleeding event.

COMPASS PAD: Among 7,470 participants with peripheral arterial disease (PAD), 4,129 had symptomatic PAD, 1,919 had carotid disease, and 1,422 had coronary artery disease plus ankle-brachial index <0.9.

  • Major adverse cardiac events (MACE): 5.0% for rivaroxaban plus aspirin, 6.0% for rivaroxaban alone, vs. 7.0% for aspirin alone (p = 0.005 for rivaroxaban plus aspirin vs. aspirin alone; p = 0.19 for rivaroxaban alone vs. aspirin alone)
  • Major adverse limb events (MALE): 1.5% for rivaroxaban plus aspirin, 1.9% for rivaroxaban alone, vs. 2.6% for aspirin alone (p = 0.01 for rivaroxaban plus aspirin vs. aspirin alone; p = 0.07 for rivaroxaban alone vs. aspirin alone)
  • Major bleeding: 3.0% for rivaroxaban plus aspirin, 3.0% for rivaroxaban alone, vs. 2.0% for aspirin alone (p = 0.009 for rivaroxaban plus aspirin vs. aspirin alone; p = 0.004 for rivaroxaban alone vs. aspirin alone)

COMPASS CAD: There were 24,824 subjects with coronary artery disease (CAD).

  • MACE: 4.0% for rivaroxaban plus aspirin, 5.0% for rivaroxaban alone, vs. 6.0% for aspirin alone (p < 0.0001 for rivaroxaban plus aspirin vs. aspirin alone; p = 0.094 for rivaroxaban alone vs. aspirin alone)
  • Major bleeding: 3.0% for rivaroxaban plus aspirin, 3.0% for rivaroxaban alone, vs. 2.0% for aspirin alone (p < 0.0001 for rivaroxaban plus aspirin vs. aspirin alone; p < 0.0001 for rivaroxaban alone vs. aspirin alone)

COMPASS-CABG: This substudy examined 1,448 COMPASS trial patients 4-14 days after CABG.

  • Graft failure: 9.1% for rivaroxaban plus aspirin, 7.8% for rivaroxaban alone, vs. 8.0% for aspirin alone (p = 0.45 for rivaroxaban plus aspirin vs. aspirin alone; p = 0.75 for rivaroxaban alone vs. aspirin alone)

COMPASS-PCI: This substudy examined 9,862 COMPASS trial CAD patients with a history of percutaneous coronary intervention (PCI).

  • MACE: 4.0% for rivaroxaban plus aspirin vs. 5.5% for aspirin alone (p for interaction vs. no history of PCI = 0.85)

COMPASS Heart Failure: There were 5,902 subjects with a history of heart failure and CAD or PAD.

  • MACE: 5.5% for rivaroxaban plus aspirin, 6.3% for rivaroxaban alone, vs. 7.9% for aspirin alone; rivaroxaban plus aspirin vs. aspirin alone (hazard ratio [HR] 0.68, 95% confidence interval [CI] 0.53-0.86), rivaroxaban alone vs. aspirin alone (HR 0.80, 95% CI 0.63-1.01)
  • Hospitalization for heart failure: Rivaroxaban plus aspirin vs. aspirin alone was associated with greater benefit among those with heart failure vs. those without heart failure (p for interaction = 0.05)
  • All-cause mortality: Rivaroxaban plus aspirin vs. aspirin alone was associated with greater benefit among those with heart failure vs. those without heart failure (p for interaction = 0.05)

COMPASS Vascular Risk: In this analysis, subjects were classified as high-risk according to REACH scoring (2 or more vascular beds affected, history of heart failure, or renal insufficiency) or CART scoring (2 or more vascular beds affected, history of heart failure, or diabetes).

  • High-risk features-REACH, MACE, acute limb ischemia, or total vascular amputation: 5.8% with rivaroxaban plus aspirin vs. 8.0% with aspirin (events prevented per 1,000 patients treated [95% CI] = 36 [21-52])
  • High-risk features-CART, MACE, acute limb ischemia, or total vascular amputation: 5.6% with rivaroxaban plus aspirin vs. 7.5% with aspirin (events prevented per 1,000 patients treated [95% CI] = 33 [19-47])
  • High-risk features-REACH, severe bleeding: 1.1% with rivaroxaban plus aspirin vs. 0.8% with aspirin (events caused per 1,000 patients treated [95% CI] = 3 [-4 to 9])
  • High-risk features-CART, severe bleeding: 1.0% with rivaroxaban plus aspirin versus 0.8% with aspirin (events caused per 1,000 patients treated [95% CI] = 1 [-4 to 6])

COMPASS Sex Differences: 22% of subjects were women and 78% were men. For cardiovascular death, myocardial infarction, or stroke:

  • Hazard ratio for rivaroxaban plus aspirin vs. aspirin alone for women = 0.72
  • Hazard ratio for rivaroxaban plus aspirin vs. aspirin alone for men = 0.76 (p for interaction = 0.75)

Major Bleeding:

  • Hazard ratio for rivaroxaban plus aspirin vs. aspirin alone for women = 2.22
  • Hazard ratio for rivaroxaban plus aspirin vs. aspirin alone for men = 1.60 (p for interaction = 0.19)

Overall cost differences (MACE): Direct cost savings of event plus procedure costs with rivaroxaban 2.5 BID plus aspirin 100 mg daily vs. aspirin 100 mg daily: mean, $682; overall, $6,144,221. Cost savings were robust across the four enrolling countries – United States, Canada, France, and Germany.

Estimation of lifetime benefit and risk: There is a wide distribution of benefit from ischemia prevention and harm from excess bleeding from the addition of rivaroxaban to aspirin.

Interpretation:

Among patients with stable atherosclerosis, rivaroxaban plus aspirin was associated with fewer adverse cardiovascular events, but more major bleeding events compared with aspirin alone. Net clinical benefit appears favorable for high-risk patients. Rivaroxaban alone was not more effective than aspirin alone. Rivaroxaban plus aspirin compared with aspirin alone was associated with a reduction in all strokes and ischemic strokes. Rivaroxaban alone compared with aspirin alone was not associated with a reduction in all strokes. Hemorrhagic strokes were very low in all treatment groups; however, there was a nonsignificant increase in this outcome for rivaroxaban plus aspirin compared with aspirin alone, and a significant increase in this outcome for rivaroxaban alone compared with aspirin alone. Findings were the same among those with PAD, CAD, heart failure, and women.

Rivaroxaban plus aspirin was effective at preventing both MACE and MALE among those with PAD. Bleeding is an important outcome; therefore, net clinical benefit will need to be carefully considered with this strategy. GI and GU bleeding should stimulate a search for a new cancer diagnosis in the same organ. Rivaroxaban plus aspirin (or rivaroxaban alone) was ineffective at improving bypass graft patency rates.

Directs costs from events and procedures were reduced with low-dose rivaroxaban plus aspirin compared with aspirin alone. However, since the actual cost of this dose of the drug is yet unknown, overall cost savings and cost-effectiveness analyses are unavailable at this time. Lifetime risk models can be constructed to estimate the balance of benefit and harm from the addition of rivaroxaban to aspirin.

References:

Presented by Dr. Kevin R. Bainey at the American Heart Association Annual Scientific Sessions (AHA 2019), Philadelphia, PA, November 16, 2019.

de Vries TI, Eikelboom JW, Bosch J, et al. Estimating individual lifetime benefit and bleeding risk of adding rivaroxaban to aspirin for patients with stable cardiovascular disease: results from the COMPASS trial. Eur Heart J 2019;Sep 1:[Epub ahead of print].

Presented by Dr. Yan Liang at the European Society of Cardiology Congress, Paris, France, August 31, 2019.

Anand SS, Eikelboom JW, Dyal L, et al., on behalf of the COMPASS Trial Investigators. Rivaroxaban Plus Aspirin Versus Aspirin in Relation to Vascular Risk in the COMPASS Trial. J Am Coll Cardiol 2019;73:3271-80.

Editorial Comment: Hiatt WR, Hess CN, Bonaca MP. Heterogeneity of Risk and Benefit in Subgroups of COMPASS: Relatively Similar But Absolutely Different. J Am Coll Cardiol 2019;73:3292-4.

Branch KR, Probstfield JL, Eikelboom JW, et al. Rivaroxaban With or Without Aspirin in Patients With Heart Failure and Chronic Coronary or Peripheral Artery Disease: The COMPASS Trial. Circulation 2019;June 5:[Epub ahead of print].

Sharma M, Hart RG, Connolly SJ, et al. Stroke Outcomes in the Cardiovascular OutcoMes for People using Anticoagulation StrategieS (COMPASS) Trial. Circulation 2019;Jan 22:[Epub ahead of print].

Lamy A, Eikelboom J, Sheth T, et al. Rivaroxaban, Aspirin, or Both to Prevent Early Coronary Bypass Graft Occlusion: The COMPASS-CABG Study. J Am Coll Cardiol 2019;73:121-30.

Editorial Comment: Alexander JH. Antithrombotic Therapy Following CABG: For the Patient, Not the Bypass Graft. J Am Coll Cardiol 2019;73:131-3.

Presented by Dr. John W. Eikelboom at the European Society of Cardiology Congress, Munich, Germany, August 26, 2018.

Anand SS, Caron F, Eikelboom JW, et al. Major Adverse Limb Events and Mortality in Patients With Peripheral Artery Disease: The COMPASS Trial. J Am Coll Cardiol 2018;71:2306-15.

Editorial Comment: Bonaca MP, Creager MA. Antithrombotic Therapy and Major Adverse Limb Events in Peripheral Artery Disease: A Step Forward. J Am Coll Cardiol 2018;71:2316-8.

Presented by Dr. Sonia Anand at the American College of Cardiology Annual Scientific Session (ACC 2018), Orlando, FL, March 11, 2018.

Connolly SJ, Eikelboom JW, Bosch J, et al. Rivaroxaban with or without aspirin in patients with stable coronary artery disease: an international, randomised, double-blind, placebo-controlled trial. Lancet 2018;391:205-18.

Anand SS, Bosch J, Eikelboom JW, et al. Rivaroxaban with or without aspirin in patients with stable peripheral or carotid artery disease: an international, randomised, double-blind, placebo-controlled trial. Lancet 2018;391:219-29.

Presented by Dr. Andre Lamy at the American Heart Association Annual Scientific Sessions (AHA 2017), Anaheim, CA, November 14, 2017.

Eikelboom JW, Connolly SJ, Bosch J, et al., on behalf of the COMPASS Investigators. Rivaroxaban with or without aspirin in stable cardiovascular disease. N Engl J Med 2017;377:1319-30.

Editorial: Braunwald E. An Important Step for Thrombocardiology. N Engl J Med 2017;377:1387-8.

COMPASS: Presented by Dr. John William Eikelboom at the European Society of Cardiology Congress, Barcelona, Spain, August 27, 2017.

COMPASS PAD: Presented by Dr. Sonia Anand at the European Society of Cardiology Congress, Barcelona, Spain, August 27, 2017.

Clinical Topics: Anticoagulation Management, Cardio-Oncology, Heart Failure and Cardiomyopathies, Prevention, Stable Ischemic Heart Disease, Vascular Medicine, Atherosclerotic Disease (CAD/PAD), Acute Heart Failure, Smoking, Chronic Angina

Keywords: AHA Annual Scientific Sessions, AHA19, ESC 19, ESC18, ESC Congress, ACC18, ACC Annual Scientific Session, AHA17, Anticoagulants, Aspirin, Atherosclerosis, Blood Coagulation, Cardiotoxicity, Coronary Artery Disease, Diabetes Mellitus, ESC2017, Heart Failure, Hemorrhage, Ischemia, Neoplasms, Peripheral Arterial Disease, Renal Insufficiency, Risk Factors, Smoking, Vascular Diseases, Angina, Stable


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