Warfarin preferred over DOAC for stroke prevention in RHD patients


By Michael Woodhead

1 Sep 2022

Surprising results from a major trial have indicated that warfarin is still the preferred oral anticoagulation strategy over DOACs for stroke prevention in patients with atrial fibrillation (AF) associated with rheumatic heart disease (RHD).

Findings from the INVICTUS study have shown that in patients with AF and RHD,  treatment with vitamin K antagonists reduced cardiovascular events and mortality without increasing major bleeding compared to rivaroxaban.

Presented at the ESC Congress 2022 in Barcelona, the results come from a multinational, randomised, open-label, non-inferiority trial that compared rivaroxaban 20 mg once daily to adjusted dose warfarin in 4,565 patients with echocardiographically-documented RHD, AF and an elevated risk of stroke (mitral stenosis with valve area ≤2 cm2, left atrial spontaneous echo contrast or thrombus, or CHA2DS2VASc score ≥2).

At a median follow up of 3.1 years, rivaroxaban treatment was associated with a significantly higher rate of the composite outcome of stroke, systemic embolism, myocardial infarction, or death from vascular or unknown causes, compared to warfarin (8.26% vs 6.46% per year).

More patients in the rivaroxaban group than in the warfarin group had a stroke, almost entirely due to a higher rate of ischaemic stroke in the rivaroxaban group. However the investigators noted that rates of stroke in both groups were lower than expected.

The risk of death was also significantly lower among patients on warfarin compared to rivaroxaban (restricted mean survival time 1,660 vs 1,587 days, difference -73 days).

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 warfarin group than in the rivaroxaban group.

There was no significant difference between the groups for the primary safety outcome of ISTH major bleeding, (0.67% vs 0.83% per year in the rivaroxaban and warfarin groups respectively), according to results published simultaneously in NEJM (linked here).

The study investigators said the ‘unexpected’ findings might be explained by patients in the warfarin group having more physician interactions — and better overall care — due to the need for monthly INR monitoring and dose adjustment. It was also possible that adherence to rivaroxaban therapy was worse than to vitamin K antagonist therapy because patients in the rivaroxaban group knew that they were not having the INR monitored.

Co-author Professor Ganesan Karthikeyan said patients with AF due to RHD tended to be younger and were more often female, than other AF patients, and often had advanced valvular disease.

It had been hoped that DOACs, which do not require regular INR monitoring and dose adjustment, would be a suitable alternative to warfarin for stroke prevention in this population, particularly in low-resource settings.

However the INVICTUS trial results “indicate that adjusted dose vitamin K antagonists should remain the standard of care for this patient population,” he concluded.

An accompanying commentary (linked here) said the treatment of RHD should be holistic and look beyond anticoagulation alone or beyond a type of anticoagulation drug per se.

“Perhaps the take-home message is that patients with atrial fibrillation may have a variety of ailments, and although stroke prevention is one of the pillars for managing atrial fibrillation, residual events are still common, despite anticoagulation,” wrote Professor Gregory Lip of the Liverpool Centre for Cardiovascular Science, University of Liverpool, UK.

“Hence, there has been a move toward a more holistic or integrated care approach to the management of atrial fibrillation, summed up as the ABC pathway: avoidance of stroke and the use of anticoagulation; better management of symptoms with patient-centred, symptom-directed decisions on rate or rhythm control; and cardiovascular and coexisting-condition risk management, including attention to lifestyle and psychological factors.”

He said strategies to improve outcomes in patients with AF and RHD should focus on early intervention in younger patients, with “integrated care-management pathways that look beyond anticoagulation alone”.

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