COMPASS: All Signs Point to Big Impact in CAD and PAD, Experts Predict
After digesting the trial results, cardiologists polled by TCTMD believe that FDA approval will likely follow, although some caveats remain.
Assuming the COMPASS results are enough to convince regulators to make the low dose of rivaroxaban used in the study available to clinicians, the trial should influence how patients with stable atherosclerotic vascular disease are treated going forward, according to cardiologists interviewed by TCTMD.
“My prediction is that guidelines will adopt this . . . and I think that clinicians will use this,” John Eikelboom, MBBS (Population Health Research Institute, Hamilton, Canada), co-principal investigator of the trial, told TCTMD, adding that forthcoming cost-benefit analyses will likely be favorable in high-risk patients.
COMPASS, reported late last month at the European Society of Cardiology Congress 2017 in Barcelona, Spain, and published simultaneously online in the New England Journal of Medicine, showed that using the combination of a 2.5-mg, twice-daily dose of rivaroxaban (Xarelto; Bayer/Janssen) and low-dose aspirin reduced the risk of a composite of cardiovascular death, MI, or stroke compared with aspirin alone in patients with stable CAD, PAD, or both (4.1% vs 5.4%; HR 0.76; 95% CI 0.66-0.86).
The dual approach also increased major bleeding (3.1% vs 1.9%; HR 1.70; 95% CI 1.40-2.05), although an analysis looking at the net clinical benefit—which incorporated risks of the most serious bleeds—found the combination to be superior.
This really is a groundbreaking trial that’s going to change practice. Erin Michos
Cardiologists contacted by TCTMD generally agreed with Eikelboom’s assessment, particularly in the context of the ATLAS ACS 2-TIMI 51 trial results, which demonstrated similar effects in patients with an ACS. Taken together, experts say, the two trials will likely be enough to convince regulators to clear low-dose rivaroxaban for use in patients with stable vascular disease. As with many new treatments, however, integrating the COMPASS approach into daily practice will inevitably face some obstacles, they predicted—clinical inertia, concerns about bleeding and cost, and a lack of awareness of the findings among physicians, for example.
COMPASS “is really important because stable outpatients who have a history of atherosclerosis [are] at very high risk for ischemic events, and definitely there is a need . . . for further mechanisms to reduce risk,” said Erin Michos, MD (Johns Hopkins Medicine, Baltimore, MD), who pointed out that rivaroxaban plus aspirin lowered rates of cardiovascular death, all-cause mortality, and stroke. “That’s why I think this really is a groundbreaking trial that’s going to change practice.”
‘We Can Still Make a Difference, and We Should’
Several cardiologists echoed Michos, citing an unmet need for additional therapies to reduce risk in patients with stable vascular disease despite substantial progress in recent decades.
Mark Creager, MD (Dartmouth-Hitchcock Heart and Vascular Center, Lebanon, NH), noted that mortality from cardiovascular disease declined markedly in the first part of this century, but said that the gains have been tailing off. “Although we have made great strides with existing therapies, including antiplatelet agents and statins in particular, [as well as] other risk factor-modifying therapies, there’s still a ways to go,” Creager told TCTMD.
He pointed out that the benefit of rivaroxaban plus aspirin observed in COMPASS was obtained on top of standard preventive therapies. “If you look at prevalence of atherosclerotic vascular disease throughout the United States and you recognize that with these millions and millions of people you can further impact their outcome by reducing it by 25%, that’s a lot of people who may benefit,” said Creager, a past president of the American Heart Association. “We can still make a difference and we should.”
Putting the COMPASS results into context, Eikelboom said the achieved reduction in MACE was comparable to the impact of other secondary preventive therapies like statins and antihypertensives.
I think the benefits in terms of the mortality reduction and the reduction in stroke outweigh the increase in bleeding. Shamir Mehta
Shamir Mehta, MD (McMaster University, Hamilton, Canada), who predicted that COMPASS is “going to have a large impact,” said the efficacy of combining rivaroxaban and aspirin is clear, acknowledging that that comes at the cost of more major bleeding.
But, he said, “from my perspective, I think the benefits in terms of the mortality reduction and the reduction in stroke outweigh the increase in bleeding.”
Not everyone was willing to accept the COMPASS results at face value. Steven Nissen, MD (Cleveland Clinic, OH), pointed to the fact that COMPASS was stopped early by the data and safety monitoring board; this raises some concerns about effect sizes, he said, both in terms of efficacy and safety.
“I think you can understand why, when there are real harms [bleeding], I want the study to go to completion so that we can have a full understanding over the course of longer-term treatment of what happens to those benefits and those harms,” he said.
In addition, Nissen differed from other cardiologists interviewed by TCTMD by not giving credit to the trial for showing a reduction in all-cause mortality. According to a prespecified threshold of P = 0.0025, the difference in mortality—3.4% with rivaroxaban plus aspirin and 4.1% with aspirin alone—did not make the cut for statistical significance (HR 0.82; 95% CI 0.71-0.96; P = 0.01).
“There was not a mortality reduction. It did not meet the prespecified boundaries. There was a multiplicity issue,” Nissen said.
Some physicians who believed the mortality reduction to be robust said the statistical discrepancy was a technicality and focusing on it was “nitpicky,” whereas others highlighted the consistency of the finding with the reductions in other outcomes in the trial.
“Statistics are there for a reason but from a practical, clinical side, the fact that you made the triple [primary] endpoint, the fact that there is concordance of the mortality reduction with the other clinical endpoints, gives me reassurance that what we’re seeing is a real finding,” David Schneider, MD (University of Vermont, Burlington), commented.
Nissen also brought up an issue regarding the patient population of COMPASS when discussing the potential impact of the trial. In particular, patients who required dual antiplatelet therapy, anticoagulation, or other antithrombotic therapy were excluded.
“There’s always an unmet need to reduce cardiovascular morbidity and mortality in patients with heart disease. That goes without saying,” Nissen stated. “But it’s important to understand that this is a subpopulation of those patients, and it’s those who are stable chronically, don’t have an indication for a thienopyridine drug like clopidogrel or ticagrelor, and [meet] a certain set of criteria, and that will be very important to review when the whole labeling discussion comes up.”
Waiting on the Regulators
Of course, any influence the COMPASS results will have on physician decision-making is dependent on the 2.5-mg dose of rivaroxaban getting approval from regulators. In the United States, the Food and Drug Administration (FDA) declined to approve that dose—for use in the type of post-ACS population evaluated in ATLAS ACS 2-TIMI 51—first in 2012 and once again in 2014.
Regulators in Europe, by contrast, elected to approve the 2.5 mg twice daily dose for this indication, in addition to a range of others also approved in the United States. Currently, rivaroxaban is approved for use in the United States at a dose of 10 mg once daily for the prevention of deep vein thrombosis (DVT) after hip or knee replacement surgery; at doses of 15 or 20 mg once daily for prevention of stroke and systemic embolism in nonvalvular A-fib; and at doses of 15 twice daily or 20 mg once daily for the treatment of DVT and pulmonary embolism or for a reduction in the recurrence risk of those two events, respectively.
This should not be interpreted as a slam dunk. Steven Nissen
Nissen, who served on that committee and voted against approval, said an important issue when interpreting the results of ATLAS ACS 2-TIMI 51—which, like COMPASS, showed efficacy at the cost of an increase in major bleeding—was that there was too much loss to follow-up. He added that he is being cautious in his expectations about the impact of the COMPASS results, because problems like those seen with ATLAS ACS 2-TIMI 51 are not always readily apparent before the FDA starts performing a deep dive on the data.
The results of COMPASS are stronger than those from the prior trial in terms of P values, Nissen said, but “this should not be interpreted as a slam dunk.”
The consensus among most of the other cardiologists contacted by TCTMD, however, was that COMPASS—especially when considering the similar results of ATLAS ACS 2-TIMI 51—likely provides enough support for the 2.5-mg rivaroxaban dose to be approved, and Eikelboom said he would be surprised if the FDA didn’t do just that.
Still, predicting FDA decisions can be a tricky endeavor.
“I don’t know what they’re going to do, but I view this as a very important trial that certainly adds to our knowledge base, and in doing so, raises a new option for us treating our patients,” Creager said.
Is a ‘COMPASS Score’ Needed for Implementation?
Even if the regulatory hurdle is cleared, integration of the approach studied in COMPASS into daily practice will likely be slowed by other potential barriers.
Christopher Cannon, MD (Baim Institute for Clinical Research, Boston, MA), who expressed certainty about the eventual approval of the 2.5-mg rivaroxaban dose, listed several: basic awareness of the trial findings, bleeding concerns, cost, selection of appropriate patients, and potential difficulties in finding a place for the new treatment among all of the other existing antithrombotic options and in getting busy clinicians to take the time to make the change.
He and others predicted implementation will be smoothest in patients with PAD—in whom rivaroxaban plus aspirin prevented both MACE and major adverse limb events, including amputation—because of the relative lack of effective treatment options compared with the CAD population.
Physicians would be hesitant to add a new treatment that increases bleeding risk—even if it also brings a benefit—to patients with stable CAD who are already well controlled with existing therapies, Cannon said. “But for PAD patients, we know that they are very high risk . . . and so to see them and want to do something more I think makes good sense,” he said. “I would see that that would likely be the group where this could be very well adopted.”
Michos said that developing a way to individualize treatment decisions will be important in terms of implementation, because there is a constant need to balance thrombotic and bleeding risks and clinical trial results only provide information on treatment effects averaged over a population.
She said that she hopes a tool like the DAPT score—which can help clinicians identify individual patients who might benefit from prolonged dual antiplatelet therapy after stenting—will be developed to aid in finding the best candidates for rivaroxaban plus aspirin among the larger pool of patients with stable vascular disease. With such a tool in hand, physicians could then speak with their patients about the appropriate course of action.
“If this is approved, I wouldn’t universally recommend it broadly in all secondary-prevention patients, but I would consider it in some after I sit down with my own individual patient and figure out if they’re more likely to have a thrombotic event or more likely to have a bleeding event,” Michos said. “We need a COMPASS score.”
Eikelboom said work is being done to develop a method that integrates both ischemic and bleeding risks to identify ideal candidates for the COMPASS approach, acknowledging that not everybody enrolled in the trial would be suitable for long-term treatment.
“This is clearly a substantial advance over existing treatments and the challenge now is to see who are the best people to apply this in,” he said.
Even though these issues with implementation could take some time to address, it is likely the COMPASS findings will have a lasting impact on the care of patients with stable vascular disease, most of the physicians interviewed by TCTMD agreed.
“It always takes time for new therapies to be adopted in clinical practice. We’ve seen that with virtually every major advance in cardiology,” Mehta said. “But eventually the evidence speaks for itself, and once the guidelines change and once people have had a chance to digest the results, then uptake follows.”
Eikelboom JW, Connolly SJ, Bosch J, et al. Rivaroxaban with or without aspirin in stable cardiovascular disease. N Engl J Med. 2017;Epub ahead of print.
Anand S. COMPASS PAD—Cardiovascular Outcomes for People Using Anticoagulation Strategies trial: results in patients with peripheral artery disease. Presented at: ESC Congress 2017. August 27, 2017. Barcelona, Spain.
- COMPASS was funded by Bayer.
- Eikelboom reports receiving grants and personal fees from Bayer during the conduct of the study and grants and personal fees not related to the trial from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Daiichi Sankyo, Janssen, AstraZeneca, Eli Lilly, GlaxoSmithKline, and Sanofi-Aventis.
- Cannon reports receiving grants and personal fees from Boehringer Ingelheim during the conduct of the study; grant support and personal fees from Arisaph Pharmaceuticals, Takeda, Bristol-Myers Squibb, Amgen, and Merck; grant support from Janssen and Daichii Sankyo; and personal fees from Lipimedix, Pfizer, Sanofi, Regeneron, Kowa, Alnylam, Amarin, GlaxoSmithKline, AstraZeneca, and Eisai.
- Mehta reports receiving research grant support from Boston Scientific and AstraZeneca and consulting for Bayer and AstraZeneca.
- Schneider reports consulting for and receiving a research grant from Janssen.
- Creager, Michos, and Nissen report no relevant conflicts of interest.