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Macrovascular Residual Risk Studies

10 January 2018
COMPASS: targeting residual cardiovascular risk in stable atherosclerotic vascular disease
In the COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) trial in patients with stable atherosclerotic cardiovascular disease (ASCVD), the combination of rivaroxaban (a direct factor Xa inhibitor) and aspirin reduced major adverse cardiovascular events compared with aspirin alone but was also associated with a higher risk of major bleeding.
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.
Objective: To investigate whether rivaroxaban alone or in combination with aspirin would be more effective than aspirin alone for secondary cardiovascular prevention.
Study design: Double-blind, double-dummy, randomized trial using a 3-by-2 partial factorial design. In the completed randomized comparison reported here, rivaroxaban with or without aspirin was compared with aspirin alone. Eligible subjects (except those who underwent randomization 4 to 14 days after coronary-artery bypass graft [CABG] surgery) entered a run-in phase during which they received a rivaroxaban-matched placebo twice daily and aspirin 100 mg once daily. Subjects who did not experience adverse events, and those enrolled 4 to 14 days after CABG surgery, were randomly assigned (1:1:1) to treatment with rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg once daily), rivaroxaban (5 mg twice daily) with an aspirin-matched placebo once daily, or aspirin (100 mg once daily) with a rivaroxaban-matched placebo twice daily. Patients were stratified by centre and the use of proton-pump inhibitor therapy at the time of randomization.  
Study population: 27,395 patients (mean 68.2 years, 22% women) with stable ASCVD (coronary artery disease [CAD], peripheral arterial disease, or both) were randomized. CAD patients <65 years were also required to have documented atherosclerosis in ≥2 vascular beds or to have ≥2 additional risk factors (current smoking, diabetes mellitus, an estimated glomerular filtration rate <60 ml per minute, heart failure, or nonlacunar ischaemic stroke ≥1 month earlier). Patients were well-treated with evidence-based secondary prevention therapies; 89.9% were on a lipid-lowering treatment and 71.2% received an angiotensin-converting–enzyme inhibitor/angiotensin-receptor blocker.
Primary variable: The primary outcome was a composite of cardiovascular death, stroke, or myocardial infarction (MI).

There were 3 secondary efficacy outcomes:

·          1: composite of ischaemic stroke, MI, acute limb ischaemia, or death from coronary heart disease

·          2: composite of ischaemic stroke, MI, acute limb ischaemia, or cardiovascular death

·          death from any cause.

The main safety outcome was a modification of the International Society on Thrombosis and Haemostasis (ISTH) criteria for major bleeding and included fatal bleeding, symptomatic bleeding into a critical organ, bleeding into a surgical site requiring reoperation, and bleeding that led to hospitalization (including presentation to an acute care facility without an overnight stay).
Methods: This event-driven trial planned to enrol 27,400 subjects, and assumed that with an event rate in the control arm of 3.3 per 100 person-years, the trial would continue until at least 2200 participants had a confirmed primary efficacy outcome, providing 90% power to detect a 20% lower risk in each of the two comparisons of rivaroxaban versus aspirin.

The trial was analysed on an intention-to-treat basis. Comparison between each of the rivaroxaban-based groups and the common aspirin control group was made with two separate log-rank tests stratified according to treatment with a proton-pump inhibitor.

Cox proportional-hazards models were used to determine hazard ratios (HR) and 95% confidence intervals (CIs).
Main results:

The trial was terminated after the first formal interim analysis for efficacy (50% of planned events) on the recommendation of the Independent Data and Safety Monitoring Board. At this time, 27,395 patients had been randomized: 9,152 received rivaroxaban plus aspirin, 9,117 received rivaroxaban alone and 9,126 received aspirin alone. The mean duration of follow-up was 23 months.

Treatment with rivaroxaban plus aspirin significantly reduced the primary outcome but also significantly increased the risk of major bleeding. Although there was no difference in the primary outcome between rivaroxaban alone and aspirin alone, bleeding events were more frequent with rivaroxaban (Table). The difference in bleeding events was mainly due to differences in bleeding that led to presentation to an acute care facility or hospitalization. Most of the excess major bleeding was into the gastrointestinal tract; there was no significant between group difference in the rate of fatal bleeding, intracranial bleeding, or symptomatic bleeding into a critical organ.

Table. Key outcomes

Outcome,       n (%)

RIV + aspirin (n=9152)

RIV (n=9117)

Aspirin (n=9126)

RIV + aspirin vs. aspirin

HR (95% CI)

RIV vs. aspirin

HR (95% CI)


379 (4.1)

448 (4.9)

496 (5.4)





Secondary 1

329 (3.6)

397 (4.4)

450 (4.9)





Secondary 2

389 (4.3)

453 (5.0)

516 (5.7)





All-cause death

313 (3.4)

366 (4.0)

378 (4.1)











Major and minor bleeding

288 (3.1)

255 (2.8)

170 (1.9)





For secondary 1 and secondary 2 outcome definitions, see above

RIV rivaroxaban; * p<0.05; ** p=0.01; *** p<0.001
Authors’ conclusion: Among patients with stable ASCVD, those assigned to rivaroxaban (2.5 mg twice daily) plus aspirin had better cardiovascular outcomes and more major bleeding events than those assigned to aspirin alone. Rivaroxaban (5 mg twice daily) alone did not result in better cardiovascular outcomes than aspirin alone and resulted in more major bleeding events.


This month’s Landmark article focuses on strategies to address residual cardiovascular risk beyond lipid-lowering therapy. Notably, long-term aspirin has been shown to significantly improve both fatal and non-fatal vascular events in people with established ASCVD (1). While previous studies have highlighted additional benefit with combination anti-thrombotic therapy, this also comes with an added risk of bleeding events (2,3). Evidence that rivaroxaban reduced the risk of risk of cardiovascular death, stroke, or MI in acute coronary syndrome patients (4), provided a rationale for evaluating its potential for improving clinical outcome (with favourable safety) in a stable secondary prevention setting,

 While the study was stopped prematurely (after a mean follow-up of 23 months) due to the proven superiority of the combination of rivaroxaban plus aspirin vs. aspirin alone for improvement in clinical outcomes, including all-cause death, the risk of major bleeding remains problematic. Most of the excess major bleeding was into the gastrointestinal tract; whether this can be satisfactorily addressed by concomitant treatment with a proton-pump inhibitor remains the focus of an ongoing investigation part of the COMPASS trial. Undoubtedly the findings of the COMPASS trial are strengthened by the large sample size and statistical robustness, although early termination may have led to over-estimation of the treatment effect with the combination therapy.

 How do these findings compare with trials of other secondary prevention strategies for targeting residual cardiovascular risk, such as FOURIER (with the PCSK9 inhibitor evolocumab) (5) and CANTOS (with the anti-interleukin-1β monoclonal antibody canakinumab) (6)? While all three strategies have proven benefit in reducing major adverse cardiovascular events in patients with stable ASCVD, cost may be a major deterrent to the routine use of biologics in the clinic. Moreover, such strategies do not eliminate residual cardiovascular risk in these high-risk patients, leading some to suggest that a renewed focus on adherence with evidence-based lipid-lowering and anti-hypertensive treatments that have a proven safety profile should have a higher priority (7).


1. Patrono C, Morais J, Baigent C et al. Antiplatelet agents for the treatment and prevention of coronary atherothrombosis. J Am Coll Cardiol 2017;70:1760–76.

2. Morrow DA, Braunwald E, Bonaca MP et al for the TRA 2P–TIMI 50 Steering Committee and Investigators. Vorapaxar in the secondary prevention of atherothrombotic events. N Engl J Med 2012;366:1404–13.

3. Anand SS, Yusuf S. Oral anticoagulants in patients with coronary artery disease. J Am Coll Cardiol 2003;41 (Suppl. S):62S–69S.

4. Mega JL, Braunwald E, Wiviott SD et al. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med 2012;366: 9-19.

5. Sabatine MS, Giugliano RP, Keech AC et al, for the FOURIER Steering Committee and Investigators. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017;376:1713–22.

6. Ridker PM, Everett BM, Thuren T et al for the CANTOS Trial Group. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 2017;377:1119–3.

7. Patrono C. Fighting residual cardiovascular risk in stable patients with atherosclerotic vascular disease: COMPASS in context. Cardiovascular Res 2017;113:e61–e63.

Key words residual cardiovascular risk; stable atherosclerotic cardiovascular disease; COMPASS trial; rivaroxaban; major adverse cardiovascular events; major bleeding