Refining Terms in Afib: Moving Away from “Valvular” and “Nonvalvular”

Atrial fibrillation has long been subclassified as either “valvular” (or associated with concomitant valve disease) or “nonvalvular” (AF without the presence of underlying hemodynamically significant valvular disease). The classification is used to determine patient eligibility to receive treatment with a direct oral non-vitamin K antagonist  anticoagulant (DOAC). However, results of a study recently published in the Journal of the American College of Cardiolgoy by the TIMI group (and an accompanying editorial) highlight the need to hone this distinction a bit more--that is, to define more precisely whether there are AF patients with types of valvular heart disease (VHD) that may, in fact, benefit from treatment with a DOAC.

The goal of the study was to analyze those patients in ENGAGE-TIMI 48 (RCT comparing the DOAC edoxaban to warfarin) who have underlying evidence of valvular heart disease. This included 2,824 patients with at least moderate aortic or mitral regurgitation, aortic stenosis or prior valve surgery (bioprosthetic replacement, valve repair or valvuloplasty) and excluded moderate to severe mitral stenosis (mild mitral regurgitation was included) or those with mechanical heart valves. Those with increased risk of bleeding, severe renal failure, or need for dual antiplatelet therapy were also excluded.

Patients with valvular heart disease were more likely to: 

  -- Be older (71.8 vs 70.4 y)
  -- Be female (42.2% vs. 37.5%)
  -- Have a slightly higher CHA₂DS₂-Vasc score (4.56 vs. 4.30) 

and less likely to have paroxysmal AF (19.7% vs. 26.7%). The comparator arm was comprised of 18,222 patients without valvular heart disease. 

In a multivariate analysis with a median follow-up of 2.8 years, there was no difference in the rate of stroke and systemic embolism in patients with valvular pathology but an overall higher rate of death (HR 1.40, p<.001), major adverse cardiovascular events (HR 1.29, p<.001) and major bleeding (HR 1.21, p=0.02).  The relative efficacy and safety of high dose edoxaban was similar in patients with and without valvular pathology (p-int =0.26).  There was a trend (although not statistically significant) towards less major bleeding in both groups with high dose edoxaban.

Based on these results, an accompanying editorial² recommended subclassifying “nonvalvular” AF into 4 distinct subtypes:

1) AF without valve disease (majority) – definitely ok to use DOACs

2) AF with valve disease (other than #3 and #4) – probably ok to use DOACs based on current study

3) AF with MS or rheumatic heart disease – no available data for DOACs

4) AF with mechanical valves – data thus far with pradaxa suggests harm with increased thromboembolic and bleeding complications with dabigatran; warfarin strongly suggested.³

This pivotal study raises the important question of how to better define subtypes of AF with an eye toward less ambiguous clinical assessment when considering elibility for a DOAC.  It also demonstrates the safety and efficacy of a DOAC in AF subtype #2  (patients with valvular heart disease that is secondary to moderate to severe MS, rheumatic heart disease, or prosthestic valves). The study is a “game changer” in how we classify AF.

References:

1. De Caterina R, Renda G, Carnicelli AP, et al. Valvular heart disease patients on edoxaban or warfarin in the ENGAGE AF-TIMI 48 Trial. J Am Coll Cardiol. 2017;69 1372-1382; DOI: 10.1016/j.jacc.2016.12.031.

2. Breithardt G. NOACs for stroke prevention in atrial fibrillation with valve disease: filling the gaps. J Am Coll Cardiol. 2017;11:1383-1385; DOI: 10.1016/j.jacc.2017.01.012.

3. Eikelboom JW, Connolly SJ, Brueckmann, M, et al. Dabigatran versus warfarin in patients with mechanical heart valves. N Engl J Med. 2013; 369:1206-1214. DOI: 10.1056/NEJMoa1300615.