PDF: COMPASS
(2020)Objective
To evaluate the net clinical benefit (NCB) of adding rivaroxaban 2.5 mg twice daily to aspirin in patients with chronic coronary syndrome or peripheral arterial disease (PAD), integrating both efficacy (stroke, MI, cardiovascular death) and severe bleeding outcomes.
Study Summary
Intervention
Rivaroxaban 2.5 mg BID plus ASA 100 mg daily versus ASA alone. The rivaroxaban-only arm (5 mg BID) was not included in the NCB analysis.
Inclusion Criteria
Patients with stable atherosclerotic vascular disease, including chronic coronary syndrome or PAD. High-risk subgroups included those with polyvascular disease, diabetes, renal dysfunction (eGFR <60), or heart failure. Patients at high bleeding risk were excluded.
Study Design
Arms: Rivaroxaban 2.5 mg BID + ASA (n=9152) vs ASA alone (n=9126)
Patients per Arm: Rivaroxaban + ASA: 9152, ASA alone: 9126
Outcome
Bottom Line
The combination of rivaroxaban 2.5 mg twice daily plus aspirin resulted in fewer net clinical benefit events primarily by preventing adverse efficacy events, particularly stroke and cardiovascular mortality, with acceptable bleeding risk.
Major Points
- COMPASS was a landmark trial that established low-dose rivaroxaban (2.5 mg BID) + aspirin as a superior antithrombotic strategy for stable atherosclerotic vascular disease (CAD/PAD) compared to aspirin alone.
- Largest dual-pathway inhibition trial: 27,395 patients randomized across 602 centers in 33 countries. Three arms: rivaroxaban 2.5 mg BID + aspirin, rivaroxaban 5 mg BID alone, or aspirin alone.
- Primary efficacy outcome (CV death, stroke, MI): rivaroxaban + aspirin 4.1% vs aspirin alone 5.4% (HR 0.76, 95% CI 0.66–0.86, p<0.001) — significant 24% RRR. NNT = 77 over mean 23 months.
- Stroke reduction was the most dramatic component: HR 0.58 (42% RRR), driven by reduction in ischemic stroke. This made COMPASS highly relevant to stroke neurologists.
- CV death was also significantly reduced: HR 0.78 (22% RRR, p=0.02). All-cause mortality showed a trend (HR 0.82, p=0.06).
- Major bleeding was increased: 3.1% vs 1.9% (HR 1.70, p<0.001), but with no significant increase in fatal bleeding (HR 1.49, p=0.32) or intracranial hemorrhage (HR 1.10, p=0.72) — the bleeding increase was primarily GI.
- Net clinical benefit analysis (this publication): rivaroxaban + aspirin was favored for the composite of efficacy + fatal/critical bleeding (HR 0.80, 95% CI 0.70–0.91, p=0.0005).
- Trial was stopped early by DSMB at mean 23-month follow-up due to overwhelming efficacy — a notable event for a cardiovascular outcomes trial.
- Rivaroxaban 5 mg BID alone (without aspirin) was NOT superior to aspirin alone for the primary outcome — demonstrating that the dual-pathway strategy was specifically effective, not just higher-dose anticoagulation.
- This net clinical benefit analysis showed that the benefit-risk balance became increasingly favorable with longer treatment, suggesting durable benefit of dual-pathway inhibition.
Study Design
- Study Type
- Prespecified analysis of randomized controlled trial
- Randomization
- Yes
- Blinding
- Double-blind
- Sample Size
- 18278
- Follow-up
- Mean 23 months
- Countries
- Multiple countries
Primary Outcome
Definition: Net clinical benefit composite of cardiovascular death, stroke, myocardial infarction, fatal bleeding, or symptomatic bleeding into a critical organ
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 534/9126 (5.9%), 3.1%/year | 431/9152 (4.7%), 2.5%/year | 0.8 (0.70-0.91) | 0.0005 |
Limitations & Criticisms
- Excluded patients at high bleeding risk — the real-world population includes patients with prior GI bleeding, elderly frail patients, and those on concomitant anticoagulation, who may have a less favorable risk-benefit ratio.
- Early termination at mean 23 months — while positive for efficacy, longer follow-up would better characterize chronic bleeding risk and durability of benefit.
- Industry-sponsored (Bayer) — rivaroxaban manufacturer funded the trial.
- The carotid stenosis/prior CEA subgroup was small — unclear if the stroke reduction extends to patients with predominantly large-vessel disease mechanism.
- Prior lacunar or hemorrhagic stroke was excluded — cannot extrapolate to small-vessel disease or patients with ICH history.
- Aspirin dose was fixed at 100 mg — unclear if results apply to patients taking higher aspirin doses (common in US practice).
- The net clinical benefit composite may weight different outcomes unequally — fatal bleeding and disabling stroke have very different clinical implications.
- The 2.5 mg BID dose is unique to the vascular indication — different from the 20 mg AF dose, creating potential for dose confusion in clinical practice.
- No head-to-head comparison with DAPT (aspirin + clopidogrel) — which is the standard for recent stroke/TIA in the first 21 days.
Citation
Circulation. 2020;142:40–48