Rivaroxaban Offers Net Reduction in Fatal or Irreversible Events in ACS: ATLAS ACS-2 TIMI-51
Lumping efficacy and safety together, particularly reversible bleeding, to assess net clinical benefit doesn’t provide the whole story, say experts.
Use of rivaroxaban (Xarelto; Bayer/Janssen) on top of dual antiplatelet therapy in patients with acute coronary syndrome is associated with a significant reduction in fatal or irreversible harmful clinical outcomes, according to a new analysis of the ATLAS ACS-2 TIMI-51 trial.
For every 10,000 patient-years of exposure, individuals with ACS who were treated with rivaroxaban 2.5 mg twice per day had 115 fewer fatal or irreversible ischemic events (nonbleeding-related cardiovascular death, MI, or stroke) compared with those who received placebo, but at a cost of 10 additional fatal or intracranial bleeds. In a sensitivity analysis excluding MI from ischemic events, the addition of rivaroxaban would prevent 90 fatal or irreversible nonbleeding-related cardiovascular deaths and strokes.
The new analysis, which was published July 2, 2018, in the Journal of the American College of Cardiology, homes in on fatal or irreversible clinical outcomes. To TCTMD, lead researcher C. Michael Gibson, MD (Beth Israel Deaconess Medical Center, Boston, MA), said the purpose of doing so was to level the playing field where ischemic and bleeding events of similar clinical importance were compared.
“People will report NACE—net clinical adverse events—but it lumps together death, MI, and stroke with major bleeding, which may be reversible and not an irreversible harm,” said Gibson. “A survived gastrointestinal bleed, while not a pleasant experience, does not result in irreversible harm to tissue or result in the death of tissue. Ischemic stroke and a heart attack, though, have irreversible death to the tissue and [cause] harm to the patient. So, to balance events and weight things equally, we wanted to look at all the fatal and irreversible ischemic and bleeding events that happen.”
Gibson noted that when the US Food and Drug Administration (FDA) approved the P2Y12 inhibitor prasugrel (Effient; Eli Lilly), they took a similar tact in weighing the components of the primary endpoint. Although prasugrel was associated with an increased risk of bleeding, the FDA concluded that most bleeding had little clinical consequence and that fatal bleeding was rare.
In 2013, the European Medicines Agency approved rivaroxaban for reducing the risk of atherothrombotic events following ACS, but the agent is not approved for this use in the US. In fact, the FDA has denied the ACS indication three times, the latest in 2014.
“Although it’s not approved in the United States, it is approved in many other countries around the world for the ACS condition,” said Gibson. He stressed the analysis is not intended to promote the drug in an unapproved fashion in the US, but rather to provide clinicians outside the country with data to help guide their clinical decisions.
Absolute Risk Reductions
In the ATLAS ACS-2 TIMI-51 trial, which was published in 2012, investigators randomized 15,526 patients with a recent ACS to twice-daily rivaroxaban (2.5 mg or 5.0 mg) or placebo on top of background therapy with a thienopyridine and aspirin for a mean duration of 13 months. Use of rivaroxaban reduced the primary composite endpoint of cardiovascular death, MI, or stroke by 16% compared with placebo and the 2.5-mg dose significantly reduced the risk of cardiovascular and all-cause mortality. Rivaroxaban increased the risk of major bleeding, including intracranial hemorrhage, but did not increase the risk of fatal bleeding events.
In the latest risk-benefit analysis, which included 9,435 patients treated with the twice-daily 2.5 mg dose, researchers say rivaroxaban would prevent 11 fatal or irreversible fatal ischemic events for each fatal or irreversible bleed. The results were confirmed in several sensitivity analyses.
“We did see a mortality benefit [in ATLAS] so the results aren’t too surprising,” said Gibson. “It looks like the amount of irreversible harmful ischemic events we prevent greatly outnumber the number of irreversible harmful bleeding events. When you put things on a level playing field, things greatly favor rivaroxaban.”
Shamir Mehta, MD (McMaster University, Hamilton, Canada), who was not involved in the study, said that assessing net clinical benefit with antithrombotic therapy is a “tricky subject” and no analysis is perfect.
“Having said that, I find this analysis to be useful, as it focuses on the absolute, rather than relative, benefit-risk profile by including only fatal or irreversible events on both sides of the equation,” he told TCTMD. “On balance, there seems to be a considerable advantage of the rivaroxaban 2.5 mg dose in ACS. Even when they excluded MI entirely and only cardiovascular mortality was weighed against fatal intracranial bleeding, there was still an advantage. Some might legitimately wonder how mortality stacks up against less serious types of bleeding, but for me, weighing a death with a less serious reversible bleed is just not same thing.”
Likewise, Sanjay Kaul, MD (Cedars-Sinai Medical Center, Los Angeles, CA), said the assessment of risk and benefit is difficult given the relative importance and frequency of efficacy and safety endpoints. The asymmetry between endpoints is further complicated in that clinical trials are often powered sufficiently to detect differences in clinical efficacy, but underpowered for safety.
“Accordingly, methodologic approaches that are designed to bring clarity to benefit-risk assessment are highly desirable,” Kaul said in an email. “In general, I am supportive of the effort, but it is only half a step forward as the other two major limitations remain unaddressed. In fact, I would argue because of the asymmetry in the frequency of outcomes—efficacy outcomes being more frequent compared with the safety outcomes—the absolute risk difference approach used might suggest favorable benefit-risk leading to an inference that contradicts the regulatory decision of nonapproval.”
Kaul noted to TCTMD that the FDA’s benefit-risk assessment framework to guide drug regulatory decisions endorses separate assessments of benefit and risk, but says nothing about the concept of net clinical benefit. In one recent advisory committee meeting, panelists were informally asked about the optimal approach for assessing risk and benefit and the majority endorsed a separate assessment over a weighted or net-clinical benefit approach, said Kaul.
Rivaroxaban Not Available for ACS in US
Last year at the European Society of Cardiology Congress, the COMPASS investigators showed that combining rivaroxaban and aspirin reduced the risk of cardiovascular death, MI, or stroke when compared with aspirin alone in patients with stable atherosclerotic vascular disease. The COMPASS trial showed a strong trend toward reduced all-cause mortality with rivaroxaban.
In an editorial accompanying the new paper, Eugenia Nikolsky, MD (Rambam Health Care, Haifa, Israel), and Freek Verheugt, MD (Hartcentrum OLVG, Amsterdam, the Netherlands), call the latest ATLAS analysis an “interesting supplementary approach” for highlighting the magnitude of the treatment effect, one that helps physicians to decide whether to use rivaroxaban after ACS. Like the others, they note the risk-benefit assessment has limitations, and state that “the final word regarding use of low-dose rivaroxaban and other agents for secondary prevention of cardiovascular diseases has not yet been said.”
Gibson, for his part, believes the overall ATLAS ACS-2 trial supports the expanded ACS indication. “I strongly believe in the data and strongly believe in the mortality data, particularly since it’s now been shown in the COMPASS trial,” he said.
For Kaul, the favorable benefit-risk profile of rivaroxaban in the latest analysis in unlikely to change things with respect to an expanded indication for ACS. He noted that the FDA was concerned about missing patient data, particularly the vital status of patients, and said this “precludes reliable and valid information regarding benefit-risk.” Additionally, there were questions about why the higher 5-mg dose did not show greater efficacy compared with the 2.5-mg dose, as well as the impact of the different doses on different endpoints, such mortality and MI.
To TCTMD, Mehta said rivaroxaban is unlikely to be used in ACS without regulatory approval, but that a second ACS study, one testing the 2.5-mg dose, could help in this regard.
Gibson CM, Levitan B, Gibson WJ, et al. Fatal or irreversible bleeding and ischemic events with rivaroxaban in acute coronary syndrome. J Am Coll Cardiol. 2018;72:129-136.
Nikolsky E, Verheugt FW. Ischemia and bleeding on the horns of a dilemma: do only hard endpoints count? J Am Coll Cardiol. 2018;72:137-140.
- Gibson reports funding through his institution from Johnson & Johnson and Bayer. He also reports research grants and honoraria from Bayer, Johnson & Johnson, and Portola.
- Nikolsky reports receiving honoraria from AstraZeneca and Bayer HealthCare.
- Verheugt reports honoraria from Bayer HealthCare, Daiichi-Sankyo, AstraZeneca, and Eli Lilly.