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BARCELONA -- Rivaroxaban (Xarelto) appeared risky for treating atrial fibrillation in rheumatic heart disease, the INVICTUS trial showed.

Rivaroxaban increased the composite of stroke, systemic embolism, myocardial infarction, or death from vascular or unknown causes by a relative 25%, with a rate of 8.06% compared with 6.33% per year in the vitamin K antagonist group (proportional HR 1.25, 95% CI 1.10-1.41).

Stroke was actually more common 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 results were simultaneously published in the (NEJM).

Also, all-cause mortality came out with a significant 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 over the mean 3.1 years of follow-up, which the researchers characterized as a large difference "unlikely to be due to chance."

While the death risk was not expected based on the pivotal clinical trials in atrial fibrillation with nonvalvular heart disease, the findings add to a variable picture for the direct-acting oral anticoagulants (DOACs) outside of non-valvular atrial fibrillation.

Edoxaban (Savaysa) numerically lowered ischemic stroke and all-cause mortality with a significant reduction in net adverse clinical events compared with vitamin K antagonists in the ENVISAGE-TAVI AF trial of transcatheter aortic valve replacement patients, whereas apixaban (Eliquis) was no better than antiplatelet therapy or warfarin in the same population, and actually increased ischemic events in the ATLANTIS trial.

"To improve outcomes in these patients, we therefore need to look beyond anticoagulation alone or beyond a type of anticoagulation drug per se," argued Gregory Y.H. Lip, MD, of the University of Liverpool in England, in an accompanying NEJM . "Indeed, a one-size-fits-all approach may not be appropriate."

Simplified management with DOACs compared with warfarin would have been advantageous for rheumatic heart disease, as most cases occur in low- and middle-income countries, "where regular INR [international normalized ratio] monitoring and dose adjustment of vitamin K antagonists is often a challenge, owing to difficulties in travel and to limitations in health care 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 heart disease at elevated stroke risk due to at least one of the following:

• CHA₂DS₂-VASc score of at least 2 (56%)
• Mitral-valve area of no more than 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 receive standard doses of rivaroxaban or dose-adjusted vitamin K antagonist. They were enrolled from August 2016 through September 2019 and followed for an average of 3.1 years.

The trial was originally designed with a primary endpoint of the composite of total stroke or systemic embolism, but stroke rates were lower and mortality higher than expected so the protocol was changed while still blinded. It was terminated early in 2022 "because the primary question addressed by the trial had 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 due to lower rates of sudden cardiac death and of death due to mechanical or pump failure in the vitamin K antagonist group," the researchers pointed out.

As to potential reasons for the unexpectedly negative findings, Karthikeyan's group suggested a few options. "Patients in the vitamin K antagonist group had more physician interactions than those in the rivaroxaban group because of the need for monthly monitoring of INR control. This situation could have resulted in better overall care and fewer strokes and deaths," they stated.

"Also, it was possible that adherence to rivaroxaban therapy was not as good as adherence to vitamin K antagonist therapy because patients in the rivaroxaban group knew that they were not having the INR monitored," the researchers said. Finally, the difference in stroke rates between the two groups could also be tied somewhat to the "higher incidence of discontinuation of rivaroxaban, even though many of the patients who discontinued rivaroxaban then received a vitamin K antagonist," they stated.

Whatever the reason, Lip suggested that vitamin K antagonists remain preferred as it has been for atrial fibrillation associated with rheumatic heart disease.

"Nonetheless, to have a major effect on clinical outcomes, holistic treatment of patients with rheumatic heart disease-associated atrial fibrillation is needed in integrated care-management pathways that look beyond anticoagulation alone," he concluded.