INVICTUS trial supports vitamin K antagonists for rheumatic heart disease-associated AF
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In patients with rheumatic heart disease-associated atrial fibrillation, vitamin K antagonist therapy was associated with a lower rate of ischemic stroke and mortality compared with rivaroxaban, without increasing risk for major bleeding.
“Vitamin K antagonists should remain the standard of care for rheumatic heart disease-associated atrial fibrillation,” Ganesan Karthikeyan, MD, DM, from the All India Institute of Medical Sciences in New Delhi, India, said while presenting the results in a press conference at the European Society of Cardiology Congress.
Main findings
The randomized, noninferiority INVICTUS trial assessed efficacy and safety of once-daily rivaroxaban (Xarelto, Janssen/Bayer) 20 mg or 15 mg based on renal function compared with a dose-adjusted vitamin K antagonist in patients with rheumatic heart disease-associated AF. Warfarin was the most-used vitamin K antagonist, in 79% to 85% of all patients, and acenocoumarol was used in the others.
Among 4,565 patients with rheumatic heart disease-associated AF followed for a mean duration of 3 years, a primary efficacy endpoint event — which included stroke, systemic embolism, MI, or death from vascular or unknown causes — occurred in 560 patients assigned rivaroxaban and 446 assigned vitamin K antagonist therapy (proportional HR = 1.25; 95% CI, 1.1-1.41; P < .001).
“Patients who received rivaroxaban had a 25% increase in the risk of having had the primary outcome. Most of this difference was because of the difference in mortality. In a sense, vitamin K antagonists reduced mortality in patients with rheumatic heart disease,” Karthikeyan said.
Restricted mean survival time was 1,599 days among those assigned rivaroxaban and 1,675 among those assigned a vitamin K antagonist (difference, –76 days; 95% CI, –121 to –31; P < .001 for superiority). Incidence of death was higher in the rivaroxaban group compared with the vitamin K antagonist group (restricted mean survival time: 1,608 days vs. 1,680 days; difference, –72 days; 95% CI, –117 to –28).
The difference in mortality was primarily due to lower rates of sudden cardiac death and death due to mechanical pump failure in the vitamin K antagonist group, according to the researchers.
More patients assigned rivaroxaban also had a stroke (90 vs. 65; proportional HR = 1.37; 95% CI, 1-1.89), primarily ischemic stroke.
The researchers reported no significant difference in the rate of International Society of Thrombosis and Hemostasis major bleeding between the two groups (rivaroxaban, 40 patients; vitamin K antagonists, 56 patients; proportional HR = 0.76; 95% CI, 0.51-1.15; P = .18). The rate of fatal bleeding was lower with vitamin K antagonist therapy (4 vs. 15 patients; proportional HR = 0.29; 95% CI, 0.1-0.88).
Permanent discontinuation of the study drug was more common in the rivaroxaban group (about 23%), with the most common reasons cited as hospitalization for valve surgery and patient decision.
The results were simultaneously published in The New England Journal of Medicine.
Largest randomized trial of rheumatic heart disease-associated AF
INVICTUS is the largest randomized trial conducted in rheumatic heart disease, Karthikeyan said at the press conference. The study was conducted at 138 sites in 24 countries where rheumatic heart disease is endemic, mostly in Africa, Asia and Latin America, Karthikeyan said.
Patients enrolled in INVICTUS had a CHA2DS2 VASc score of 2 or higher, a mitral valve area of 2 cm2 or less, left atrial spontaneous echo contrast or left atrial thrombus. The mean age was 50.5 years and nearly three-quarters were women.
“Rheumatic heart disease affects over 40 million people around the world, most in low- and middle-income countries. About 20% of those presenting to the hospital with symptomatic disease have AF and an elevated risk for stroke,” Karthikeyan said.
However, he noted, earlier anticoagulant trials performed in patients with AF excluded patients with rheumatic heart disease because it was believed they had a prohibitively high risk for stroke. Further, he said, less than half of patients with rheumatic heart disease are prescribed vitamin K antagonist therapy and only one-third achieve therapeutic INRs.
“We’ve never had any randomized controlled trials of anticoagulation in patients with rheumatic heart disease-associated AF,” Karthikeyan said. The evidence base for treating these patients is based generally on observational data and clinical experience in these countries, Karthikeyan said. “For the first time, we present evidence in support of a particular treatment for valvular AF, specifically rheumatic valvular AF.”
Reference:
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Robert A. Harrington, MD, FAHA
The main takeaway is that this is exactly why we need the evidence from randomized clinical trials. The investigators designed this trial with the hypothesis that rivaroxaban would be noninferior to the vitamin K antagonists, and then people could switch to the easier-to-monitor approach of rivaroxaban. In fact, the exact opposite proved true.
It’s an ongoing lesson that your intuition is great to establish hypotheses, but your hypotheses really need to be tested. I would have predicted that rivaroxaban would be noninferior. This was a surprise.
This was a well-done trial by very good investigators. This is a very important question for many parts of the world.
The vitamin K antagonists are not going away. If you have a patient with rheumatic heart disease and AF — which is more common outside the U.S., but there are pockets where we do see rheumatic heart disease with AF — and they are candidates for anticoagulation, these data would tell you that we should anticoagulate them with vitamin K antagonists, and there is a benefit to be gained over the direct oral anticoagulants.
And rheumatic heart disease is too common in many parts of the world. The American Heart Association is involved around the world with the reduction of rheumatic heart disease, so this study is relevant to the association’s global work.
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Karthikeyan G, et al. Hot Line 5. Presented at: European Society of Cardiology Congress; Aug. 26-29, 2022; Barcelona, Spain (hybrid meeting).
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