BARCELONA, SPAIN – The combination of a new low dose of 2.5-mg twice-daily rivaroxaban (Xarelto, Bayer/Janssen Pharmaceuticals) plus 100-mg once-daily aspirin was associated with a reduction in ischemic events and mortality and a superior net clinical benefit, balancing ischemic benefit with severe bleeding, than aspirin alone for secondary prevention in patients with stable atherosclerotic vascular disease in the COMPASS trial[1].
The results were presented today at the European Society of Cardiology (ESC) 2017 Congress by Dr John Eikelboom (McMaster University, Hamilton, ON). They were simultaneously published online in the New England Journal of Medicine.
“While there have been several previous studies of various antithrombotic/antiplatelet regimens added to aspirin, these have mainly been done in earlier post-ACS or stenting patients,” Eikelboom commented to theheart.org | Medscape Cardiology. “COMPASS is unique in that it was conducted in a population with stable cardiovascular disease and has shown particularly robust results with reductions in stroke and in cardiovascular and total mortality. It is very unusual to see these benefits.”
While bleeding was increased with the combination vs aspirin alone, fatal or intracranial bleeding was not significantly increased.
“Bleeding is an inevitable consequence of more effective antithrombotic treatment, but you have to look at the overall benefit—the net clinical benefit and the reduction in mortality, and we have shown significant benefits in both these end points,” Eikelboom said.
“There are 300 million patients with stable cardiovascular disease worldwide,” he noted. “If just 10% of these patients received rivaroxaban in addition to aspirin, this could prevent 100,000 deaths per year and several hundred thousand cardiovascular events, so the potential benefits are staggering.”
He added: “It is not up to us to select the patients who will get this drug—that is up to guideline committees and regulatory agencies—but to use the drug most efficiently I would start with those who stand to gain the most, and those are the patients at the highest baseline absolute risk.”
For the study, 27,395 patients with stable atherosclerotic vascular disease (coronary artery disease or peripheral arterial disease [PAD]) were randomized to one of three groups: rivaroxaban 2.5 mg twice daily plus aspirin 100 mg daily; rivaroxaban 5 mg twice daily alone; or aspirin 100 mg daily alone. The primary end point was a composite of cardiovascular death, stroke, or MI. The trial was stopped for superiority of the rivaroxaban-plus-aspirin group at 23 months.
Final results show that the combination of rivaroxaban plus aspirin was associated with significantly fewer primary-outcome events than aspirin alone. While there was also an increase in major bleeding, the net clinical benefit still suggested a benefit with the combination.
COMPASS Results: Rivaroxaban Plus Aspirin vs Aspirin Alone
| Outcome | Rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg daily), % | Aspirin (100 mg once daily) alone, % | HR (95% CI) | P |
|---|---|---|---|---|
| Primary outcome: CV death/stroke/MI | 4.1 | 5.4 | 0.76 (0.66–0.86) | <0.001 |
| Major bleeding | 3.1 | 1.9 | 1.70 (1.40–2.05) | <0.001 |
| Net clinical benefit: CV death/stroke/MI/ fatal bleed/symptomatic bleed into a critical organ | 4.7 | 5.9 | 0.80 (0.70–0.91) | <0.001 |
The combination group also showed a significant reduction in cardiovascular death (1.7% vs 2.2%, HR 0.78; P=0.02) and death from any cause (3.4% vs 4.1%, HR 0.82; P=0.01).
The rivaroxaban-alone group was not associated with a significant reduction in the primary outcome but also increased bleeding compared with aspirin alone, with no significant improvement in net clinical benefit.
COMPASS Results: Rivaroxaban Alone vs Aspirin Alone
| Outcome | Rivaroxaban (5 mg twice daily) alone, % | Aspirin (100 mg once daily) alone, % | HR (95% CI) | P |
|---|---|---|---|---|
| Primary outcome: CV death/stroke/MI | 4.9 | 5.4 | 0.90 (0.79–1.03) | 0.12 |
| Major bleeding | 2.8 | 1.9 | 1.51 (1.25–1.84) | <0.001 |
| Net clinical benefit: CV death/stroke/MI/fatal bleed/symptomatic bleed into a critical organ | 5.5 | 5.9 | 0.94 (0.84–1.07) | 0.36 |
Change Clinical Practice?
In an accompanying editorial[2] in the New England Journal of Medicine, Dr Eugene Braunwald (Brigham & Women’s Hospital, Boston, MA) says the rivaroxaban-plus-aspirin regimen in COMPASS was “the clear winner.”
He says the COMPASS trial “represents an important step forward in thrombocardiology, and it is likely to change practice guidelines.”
Braunwald was involved in a previous trial of rivaroxaban in cardiovascular-disease patients—the ATLAS ACS2 trial—in which both doses of 2.5 mg and 5 mg twice dally on top of antiplatelet therapy reduced major cardiovascular events but increased bleeding in patients with a recent acute coronary syndrome, with the lower dose showing reduced cardiovascular and total mortality, findings consistent with the COMPASS results. However, the US FDA has not approved this indication for the drug.
The ATLAS and COMPASS trials differ in that ATLAS involved more acute patients, with a recent ACS, and therapy was given for a mean of 13.3 months, whereas COMPASS involved a more stable population, a mean 7.1 years after the acute event, and therapy was continued for a mean of 23 months.
“The FDA had concerns about some specifics of the ATLAS trial such as some incomplete data. Now with the COMPASS data showing similar benefits, I think they may reconsider,” Eikelboom commented. “The ATLAS and COMPASS studies have evaluated the same dose of rivaroxaban on top of antiplatelet therapy, ATLAS focusing on more acute ACS patients, whereas COMPASS looked at later stable atherosclerotic disease patients. It is very reassuring that we saw very similar benefits.”
Commenting on the COMPASS results for theheart.org | Medscape Cardiology, Dr Magnus Ohman (Duke University Medical Center, Durham, NC), who was not involved in the study, said: “These are great results in patients with stable ischemic heart disease or peripheral arterial disease—a population we have not studied outside the ACS realm very much. They suggest that combination antithrombotic therapy has great value in preventing cardiac events.”
In terms of how the results may be applied in clinical practice, Ohman said: “One challenge will be how a practitioner incorporates this in all patients with stable disease and in which order all the preventive therapies will be applied. Aspirin and a statin are a given, then preventive therapy for blood-pressure control, which should then be followed by this novel antithrombotic therapy. This will require a lot of education and practical approaches. In this regard, the PAD group of patients seem natural, as they have very high event rates, where treatment effects can clearly be justified.”
Dr John H Alexander (Duke University School of Medicine), who was not involved in the study, said the results of the rivaroxaban-alone arm were disappointing “as many clinicians are/were looking forward to getting rid of aspirin.”
He said the combination therapy showed “a meaningful reduction in ischemic events, but with the trade-off of an increase in bleeding. This has pretty much been a common challenge with most/all chronic antithrombotic therapies.”
He added: “These data support that slightly shaky benefits of rivaroxaban on ischemic events seen in ATLAS were probably real. They also support that very low-dose rivaroxaban can be used on top of aspirin with only a modest (2.2% absolute) increase in bleeding. This is less than what was seen with rivaroxaban on top of dual antiplatelet therapy after ACS in ATLAS.”
Alexander noted that rivaroxaban has never been approved for use after ACS based on the ATLAS studies in the US and, although it has this indication in Europe, it is not widely used.
He believes the COMPASS results may change clinical practice, “but modestly and slowly.” He elaborated: “The ischemic-event reduction/bleeding increase trade-off, competing antiplatelet drugs, cost, and concerns about polypharmacy will all slow uptake and adoption.”
In terms of competition from dual antiplatelet therapy, Eikelboom responded: “While dual antiplatelet therapy definitely has a role very early after an acute event, the benefit doesn’t seem to last long term, whereas the combination of rivaroxaban and aspirin showed impressive reductions in events in patients many years after an acute event.”
Also commenting for theheart.org | Medscape Cardiology, Dr Kausik Ray (Imperial College London, UK), said: “The study is a clear demonstration that low-dose Xa inhibition when added to aspirin is better than current standards of care. There is a significant reduction in mortality, which is always hard to ignore. To offset this is an increase in bleeding—which, although was not different with regard to fatal bleeds or intracranial bleeds, is always a challenge in routine clinical practice.”
He added: “It’s likely that these results will impact guidelines but further data on individual risk/benefits analogous to CHADS-VASc and HASBLED scores for AF will help personalize risk/benefits beyond the overall results, especially in older patients and people with renal disease, where bleeding risk is a specific concern.”
The COMPASS trial was supported by Bayer. Eikelboom receives support from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi, Janssen, Pfizer, Portola, and Sanofi. Braunwald reports grants from GlaxoSmithKline, Merck, Novartis, AstraZeneca, Johnson & Johnson, and Daiichi Sankyo and personal fees from the Medicines Company and Theravance. Ohman was the study chair of the GEMINI-ACS trial, also funded by Jansen and Bayer. Alexander has research funding from and serves as a consultant to Bristol-Myers Squibb/Pfizer on apixaban. He has also consulted for Janssen. Ray reports no conflicts or disclosures with regard to Bayer.
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