Most bleedings in COMPASS were GI bleeds and occurred in the first year
Major Bleeding in Patients With Coronary or Peripheral Artery Disease Treated With Rivaroxaban Plus Aspirin
Introduction and methods
The COMPASS trial demonstrated that the combination of rivaroxaban 2.5 mg twice daily plus aspirin 100 mg once daily compared with aspirin 100 mg once daily reduced the risk of the primary composite endpoint of CV death, stroke or myocardial infarction (MI) by 24% in patients with chronic coronary artery disease (CAD) or peripheral artery disease (PAD) [1-3]. The combination therapy was also associated with an increase in bleeding.
The COMPASS was a multicenter international trial that randomized 18,278 patients to the combination therapy of rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg once daily) vs aspirin alone (100 mg once daily) . The trial was stopped early after a mean follow-up of 23 months because the benefit of the combination therapy vs. aspirin alone was evident. The main safety outcome was major bleeding according to a modified ISTH definition, meaning that it includes fatal bleeding, symptomatic bleeding in a critical area or organ, surgical site requiring reoperation and bleeding leading to hospitalization or presentation to an acute care facility without overnight stay. This analysis aims to report the details of the sites, timing and investigator-reported severity of bleeding, and the medical management of bleeding in patients treated with the combination therapy as compared with aspirin only in the COMPASS trial.
- Combination therapy increased the risk of modified ISTH major bleeding as compared with aspirin alone (3.1% vs. 1.9%, HR: 1.70, 95%CI: 1.40-2.05, P<0.0001), and the risk according to the original ISTH definition (2.3% vs. 1.3%, HR: 1.78, 95%CI: 1.41-2.23), P<0.0001).
- Combination therapy did not significantly increase the risk of fatal bleeding (0.2% vs. 0.1%, HR: 1.49, 95%CI: 0.67-3.33, P=0.32), symptomatic critical organ bleeding (0.8% vs. 0.6%, HR: 1.37, 95%CI: 0.96-1.95, P=0.08) or bleeding into a surgical site leading to reoperation (0.2% vs. 0.1%, HR: 1.24, 95%CI: 0.58-2.65, P=0.58).
- Risk of major bleeding leading to hospitalization or presentation to acute care facility without overnight stay was higher with combination therapy (2.8% vs. 1.6%, HR: 1.76, 95%CI: 1.44-2.16, P<0.0001).
- The gastrointestinal (GI) tract (1.5% vs. 0.7%, HR: 2.15, P<0.0001) was the most common site of major bleeding in those randomized to combination therapy, followed by intracranial bleeding (0.3% vs. 0.3%, HR: 1.16, P=0.60), skin or injection site (0.3% vs. 0.1%, HR; 2.39, P=0.01), eye (0.2% s. 0.1%, 1.68, P=0.13), nasal (0.2% vs. 0.1%, HR: 1.25, P=0.57), urinary (0.1% vs. 0.2%, HR: 0.61, P=0.16), respiratory (0.1 vs. <0.1%, HR: 1.85, P=0.18) and genital tract (<0.1% vs. <0.1%, HR: 1.70, P=0.08).
- Minor bleedings were more common in the combination therapy group than in the aspirin alone group (9.2% vs. 5.5%, HR: 1.70, 95%CI: 1.52-1.90, P<0.0001).
- Most of the excess major and GI bleeding with the combination therapy occurred in the first year, while the benefit of the combination therapy in reducing the primary endpoint was consistent in years 1, 2, 3 and beyond.
- Similar significant increases in risk were seen for severe (HR:1.79), moderate (HR: 1.53) and mild (HR: 1.68) major bleedings with combination therapy vs. aspirin alone.
In the COMPASS trial, patients with chronic CAD or PAD randomized to the combination of rivaroxaban 2.5 mg twice daily and aspirin 100 mg once daily showed a 1.7-fold increase in both minor and major bleeding, compared to those taking aspirin only. Most bleedings were from the GI tracts and the increase in bleeding was mostly in the first year after randomization. It should be noted that people deemed at high bleeding risk were excluded from the COMPASS trial.
In their editorial comment, Bode et al. summarize the findings of the COMPASS trial, which suggest a net clinical benefit for secondary CV prevention with the combination therapy of low-dose rivaroxaban plus aspirin, vs aspirin alone, in those with stable CAD and PAD. Because regulatory agencies in many countries have already approved low-dose rivaroxaban in stable atherosclerotic disease, which makes a detailed description of bleeding side-effects important.
Bleeding is generally considered ‘bad’ and unwanted, but Bode and colleagues state that, in the absence of antithrombotic treatment without bleeding side effects, bleeding can also be considered as evidence of efficacy. Adverse outcomes associated with bleeding are often a consequence of stopping antithrombotic therapy rather than of the bleeding event itself. Moreover, not all bleedings are clinically significant, and certain types of bleeding can easily be managed, such as mild nose or upper GI bleedings. GI or urinary tract bleeding may even unmask tumors. Indeed, most bleedings in COMPASS were in the GI tract and could well be managed.
The fact that most bleedings events occurred during the first year, suggests that other therapeutic interventions may be explored that reduce bleeding risk, and de-escalation of antithrombotic therapy may be beneficial in selected patients.
Intracranial or fatal bleedings were not significantly increased with combination therapy, but the point estimates were consistent with the observed effects on other bleeding events. COMPASS is one of the largest randomized trials and symptomatic intracranial or fatal bleedings were rare with <0.5% incidence. This is important for the consideration of net clinical benefit; the risk of CV death, stroke, MI, fatal bleeding or symptomatic bleeding into a critical organ was reduced by 20% with the combination therapy. Phase IV trials and large registry data will have to confirm the safety of dual-pathway antithrombotic therapy. Bode et al. conclude that the bleeding analysis is reassuring and promises a true net clinical benefit for high-risk patients with stable atherosclerotic disease. They note: ‘Bleeding is never intended, but rarely is it prohibitive.’