October 18, 2017 — Results from the pivotal Phase 3 COMPASS study found that the Xarelto vascular dose plus aspirin 100 mg once daily significantly reduced the risk of major cardiovascular events by 24 percent in patients with stable coronary and/or peripheral artery disease (CAD/PAD) compared to aspirin alone. This finding was driven by a robust 42 percent reduction in any stroke and 22 percent reduction in cardiovascular (CV) death. The risk of major bleeding was significantly higher in patients taking the Xarelto/aspirin regimen compared to aspirin alone, with no significant increase in fatal or intracranial bleeds. Findings from this global, randomized, superiority study were announced by Janssen Research & Development LLC, presented during a Hot Line session at the European Society of Cardiology (ESC) ESC Congress 2017, Aug. 26-30 in Barcelona, Spain, and simultaneously published in The New England Journal of Medicine.
Both CAD and PAD occur when arteries become hardened or narrowed due to a buildup of cholesterol and plaque, limiting blood flow to parts of the body. CAD occurs in the blood vessels that feed the heart, and PAD occurs in other blood vessels in the body (most often the legs, but also the brain, arms and abdomen). People with CAD might experience symptoms such as shortness of breath and chest pressure, while those with PAD may have painful cramping and numbness or weakness in their legs. A public health burden, CAD and PAD affect 16.5 million[i] and 10 million Americans[ii], respectively, and can lead to serious health issues, like heart attack, stroke and even death.
Despite use of preventative medicines as directed by current guidelines, approximately 5 percent of people with CAD or PAD will experience a debilitating or fatal CV event each year.[iii] Part of the EXPLORER clinical research program, COMPASS is the only randomized clinical study to investigate a Factor Xa inhibitor, specifically Xarelto, in preventing major CV events in this population.
"The results of COMPASS represent a true breakthrough in CAD and PAD, as they confirm the combination regimen of Xarelto and aspirin is highly effective and well-tolerated in preventing the devastating and irreversible CV events that often occur in these patients," said COMPASS lead investigator John Eikelboom, MBBS, associate professor, Division of Hematology & Thromboembolism, Department of Medicine, McMaster University, Hamilton Health Sciences, Hamilton, Ontario. "In addition to achieving a positive balance of efficacy and safety, we observed a considerable reduction in stroke and CV death, which could have a profound effect on how physicians manage patients with stable CAD and PAD."
COMPASS, the largest clinical study of Xarelto to date, enrolled a total of 27,395 patients with stable CAD and/or PAD. Patients were randomized in a 1:1:1 ratio, with one group receiving the Xarelto 2.5 mg twice-daily vascular dose plus aspirin 100 mg once daily regimen, another group receiving Xarelto 5 mg twice daily, and the final group receiving aspirin 100 mg once daily. Earlier this year, Janssen and its development partner Bayer announced COMPASS was being stopped approximately one year ahead of schedule due to efficacy, which was based on the recommendation of the study’s independent Data Monitoring Committee.
COMPASS met its primary efficacy endpoint, with the Xarelto/aspirin regimen shown to be superior to aspirin alone, reducing major CV events by 24 percent. Specifically, 4.1 percent of patients receiving the Xarelto/aspirin regimen experienced a CV event compared to 5.4 percent of those receiving aspirin alone (HR=0.76; 95% CI, 0.66-0.86; p<0.001).
Researchers also made the following observations:
- Specifically, the Xarelto/aspirin regimen reduced the risk of any stroke by 42 percent (HR 0.58; 95% CI, 0.44-0.76; p<0.001), CV death by 22 percent (HR 0.78; 95% CI, 0.64-0.96; p=0.02) and heart attack by 14 percent (HR 0.86; 95% CI, 0.70-1.05; p=0.14);
- For composite secondary efficacy outcomes, the Xarelto/aspirin regimen was superior to aspirin alone. Notably, the combination regimen reduced the combined secondary endpoint of coronary heart disease death, heart attack, ischemic stroke and acute limb ischemia by 28 percent compared to aspirin alone (3.6 vs. 4.9 percent; HR=0.72; 95% CI, 0.63-0.83; p<0.001);
- The hazard ratio for all-cause mortality for the Xarelto/aspirin regimen compared to aspirin alone was 0.82 (95% CI, 0.71-0.96; p=0.01);
- Major bleeding was significantly higher in the combination regimen with 3.1 percent experiencing a major bleed compared to 1.9 percent of those receiving aspirin alone (HR=1.70; 95% CI, 1.40-2.05; p<0.001). This was mainly due to an increase in bleeding leading to hospitalization, with most bleeding occurring in the gastrointestinal (GI) tract. Importantly, there was no significant difference in fatal bleeds, intracranial bleeds, symptomatic bleeding into a critical organ or bleeding into the surgical site requiring reoperation between the two groups, though the study was underpowered to detect these differences and the hazard ratios were higher compared to aspirin alone; and
- The effects of the Xarelto/aspirin regimen compared to aspirin alone on the primary outcome and on major bleeding were consistent among subgroups that were defined according to age, sex, geographic region, race or ethnic group, body weight, renal function, and history of cardiovascular risk factors.
Researchers also presented results from the Xarelto 5 mg twice daily group. Of patients taking Xarelto 5 mg twice daily, 4.9 percent experienced a major CV event compared to 5.4 percent of those receiving aspirin alone (HR=0.90; 95% CI, 0.79-1.03; p=0.11). These results were not statistically significant. Major bleeding was increased in the Xarelto 5 mg twice daily group compared to aspirin alone (2.8 vs. 1.9 percent; HR=1.51; 95% CI, 1.25-1.84; p<0.001).
Presented during the same Hot Line session at the ESC Congress 2017, a separate subgroup analysis examined patients with PAD, comprising 27.3 percent of the total enrollment in COMPASS. In patients with PAD in COMPASS, the combination regimen of the Xarelto 2.5 mg twice-daily vascular dose and aspirin 100 mg once daily significantly reduced the combined risk of CV death, heart attack and stroke by 28 percent compared to aspirin alone (5.1 vs. 6.9 percent; HR=0.72; 95% CI, 0.57-0.90; p=0.005). Most notably, patients with PAD taking the combination regimen had significantly fewer major adverse limb events by 46 percent (1.2 vs. 2.2 percent; HR=0.54; 95% CI, 0.35-0.84; p=0.005), acute limb ischemia by 44 percent (0.8 vs. 1.4 percent; HR=0.56; 95% CI, 0.32-0.99; p=0.04) and major amputations by 70 percent (0.2 vs 0.7 percent; HR=0.30; 95% CI, 0.11-0.80; p=0.01) compared to those taking aspirin alone.
"People with PAD are generally at higher risk of CV events, including death, and have fewer medical options available than patients with CAD alone, making these results exceptionally meaningful," added Eikelboom.
For more information: www.escardio.org
February 16, 2024 
