BARCELONA — Rivaroxaban (Xarelto) appeared risky for treating atrial fibrillation in rheumatic cardiovascular disease, the INVICTUS trial showed.
Rivaroxaban increased the composite of stroke, systemic embolism, myocardial infarction, or death from vascular or unknown causes by way of a relative 25%, with an interest rate of 8.06% weighed against 6.33% each year in the vitamin K antagonist group (proportional HR 1.25, 95% CI 1.10-1.41).
Stroke was actually more prevalent with rivaroxaban (proportional HR 1.54, 95% CI 1.10-2.16), reported Ganesan Karthikeyan, MD, of the All India Institute of Medical Sciences in New Delhi, at the European Society of Cardiology (ESC) meeting. The outcomes were simultaneously published in the New England Journal of Medicine (NEJM).
Also, all-cause mortality arrived with a substantial disadvantage for rivaroxaban (proportional HR 1.23, 95% CI 1.08-1.40) that translated to a restricted mean survival time difference of 72 days on the mean 3.1 years of follow-up, that your researchers characterized as a big difference “unlikely to be because of chance.”
As the death risk had not been expected in line with the pivotal clinical trials in atrial fibrillation with nonvalvular cardiovascular disease, the findings increase a variable picture for the direct-acting oral anticoagulants (DOACs) beyond non-valvular atrial fibrillation.
Edoxaban (Savaysa) numerically lowered ischemic stroke and all-cause mortality with a substantial decrease in net adverse clinical events weighed against vitamin K antagonists in the ENVISAGE-TAVI AF trial of transcatheter aortic valve replacement patients, whereas apixaban (Eliquis) was no much better than antiplatelet therapy or warfarin in exactly the same population, and also increased ischemic events in the ATLANTIS trial.
“To boost outcomes in these patients, we therefore have to look beyond anticoagulation alone or beyond a kind of anticoagulation drug by itself,” argued Gregory Y.H. Lip, MD, of the University of Liverpool in England, within an accompanying NEJM editorial. “Indeed, a one-size-fits-all approach might not be appropriate.”
Simplified management with DOACs weighed against warfarin could have been advantageous for rheumatic cardiovascular disease, because so many cases occur in low- and middle-income countries, “where regular INR [international normalized ratio] monitoring and dose adjustment of vitamin K antagonists is usually a challenge, due to difficulties in travel also to limitations in healthcare resources,” the researchers noted.
The INVICTUS trial included 4,565 patients in Africa, Asia, and Latin America who had atrial fibrillation and echocardiographically documented rheumatic cardiovascular disease at elevated stroke risk because of a minumum of one of the next:
- CHA2DS2-VASc score of at the very least 2 (56%)
- Mitral-valve section of only 2 cm2 (82%)
- Left atrial spontaneous echo contrast (11%)
- Left atrial thrombus (7%)
These patients (mean age 50.5, 72.3% women) were randomly assigned to get standard doses of rivaroxaban or dose-adjusted vitamin K antagonist. These were enrolled from August 2016 through September 2019 and followed for typically 3.1 years.
The trial was originally made with a primary endpoint of the composite of total stroke or systemic embolism, but stroke rates were lower and mortality greater than expected therefore the protocol was changed while still blinded. It had been terminated early in 2022 “as the primary question addressed by the trial have been satisfactorily answered.”
No difference was seen between groups for major bleeding or for hospitalization for heart failure. Valve-replacement surgery and mitral valve procedures were equally common between groups.
“The difference in mortality was almost entirely because of lower rates of sudden cardiac death and of death because of mechanical or pump failure in the vitamin K antagonist group,” the researchers described.
Concerning potential known reasons for the unexpectedly negative findings, Karthikeyan’s group suggested several options. “Patients in the vitamin K antagonist group had more physician interactions than those in the rivaroxaban group due to the dependence on monthly tabs on INR control. This example could have led to better overall care and fewer strokes and deaths,” they stated.
“Also, it had been possible that adherence to rivaroxaban therapy had not been as effective as adherence to vitamin K antagonist therapy because patients in the rivaroxaban group knew they were not getting the INR monitored,” the researchers said. Finally, the difference in stroke rates between your two groups may be tied somewhat to the “higher incidence of discontinuation of rivaroxaban, despite the fact that most of the patients who discontinued rivaroxaban then received a vitamin K antagonist,” they stated.
Regardless of the reason, Lip suggested that vitamin K antagonists remain preferred since it has been for atrial fibrillation connected with rheumatic cardiovascular disease.
“Nonetheless, to get a major influence on clinical outcomes, holistic treatment of patients with rheumatic heart disease-associated atrial fibrillation is necessary in integrated care-management pathways that look beyond anticoagulation alone,” he concluded.
The trial was supported by Bayer/Population Health Research Institute.
Karthikeyan disclosed no relationships with industry.
Lip disclosed relationships with Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, and Pfizer.