By Dr. Geoffrey Modest
Over the years, I have sent out several blogs about the drug company shenanigans/malfeasance in studies promoting NOACs (non-vitamin K antagonist oral anticoagulants) — See link at bottom. Here is a large study suggesting the benefits of warfarin (See doi:10.1001/jamacardio.2016.0199 ). The authors note that studies finding NOAC superiority were in comparison to warfarin where the times-in-therapeutic range (TTR) varied from 55.2% to 64.9%. In the current study researchers looked at the relative effectiveness of warfarin for patients with atrial fibrillation (AF) as it varied with TTR. Data are from a large Swedish registry.
Details:
- Retrospective, multicenter cohort study of 40,449 patients
- 40% women, mean age 73, mean CHA2DS2-VASc (see below) score 3.3, TTR<70% in 43%, hypertension 60%, heart failure 30%, renal failure 4%, excessive alcohol use 2%, history of falls 8%, prior major bleed 6%, MI 21%, diabetes 18%, stroke 19%, TIA 8%
- 4311 patients also on aspirin with the warfarin, with the concomitant diseases/risk factors about the same as the overall cohort except that 43% had a prior MI (vs 17% just on warfarin)
Results:
- Annual all-cause mortality 2.19% (2.07-2.31), intracranial bleed 0.44% (0.39-0.49)
- Comparing those with TTR <70% vs >70% (all are annual rates)
- All-cause mortality was 4.35% vs 1.29%
- Any major bleed was 3.81 vs 1.61%, with intracranial bleed 0.72 vs 0.34%; GI bleed 1.26 vs 0.56%
- Any thromboembolism was 4.41 vs 2.37%, MI 1.90 vs 0.98%, venous thromboembolism (VTE) 0.24 vs 0.09%, and arterial embolism 2.52 vs 1.41% [thromboembolism defined as: stroke, TIA, peripheral arterial emboli, venous thromboembolism, MI]
- The role of INR variability (dividing those around the median of higher vs lower variability in their cohort): comparing high vs low
- All-cause mortality was 2.94% vs 1.50%
- Any major bleed was 3.04 vs 1.47%, with intracranial bleed 0.51 vs 0.38%; GI bleed 1.05 vs 0.50%
- Any thromboembolism was 3.48 vs 2.46%, with MI 1.53 vs 0.96%, VTE 0.16 vs 0.11%, and arterial embolism 1.98 vs 1.51%
- For those with TTR >70%, INR variability did not matter
- For those on aspirin
- All-cause mortality was 2.57% vs 2.13%
- Any major bleed was 3.07 vs 2.04%, with intracranial bleed 0.62 vs 0.41%; GI bleed 1.16 vs 0.67%
- Any thromboembolism was 4.90 vs 2.12%, with MI 1.53 vs 0.96%, VTE 0.19 vs 0.12%, and arterial embolism 2.72 vs 1.54%
- For those with renal failure, intracranial bleed more than twice as common, with HR 2.25 (1.32-3.82)
- The strongest predictor of intracranial bleeding was renal failure
So, a few issues:
- These data, though not from a prospective, randomized study, do reflect more of a real-world community setting.
- The results for patients in good control (TTR>70%) is actually better than in the “pivotal NOAC studies”.
- In terms of the issue of using the combo of warfarin and aspirin:
- I am very concerned about the increased serious adverse events with this combination (see https://stg-blogs.bmj.com/bmjebmspotlight/2014/11/20/primary-care-corner-with-geoffrey-modest-md-aspirin-plus-warfarin-for-afib-and-cad/ , which looks at several observational studies on aspirin plus warfarin for patients with AF and CAD, all showing much higher risks (e.g., bleeding) without any clear benefit. The PREFER trial (see De Caterina, R. Heart 2014; 100: 1625) looked at a large European registry of patients with AF and found that 95% of those on dual antiplatelet and anticoagulation therapy did NOT have an “accepted indication” (i.e.: acute coronary syndrome or stenting –and, this is the current recommendation of the European Society of Cardiology guidelines in AF: anticoagulant therapy only except in these indications).
- In the above Swedish study, only 2.6% of those on additional aspirin had a clear indication for this therapy. And this study really supported NOT using aspirin, given the higher mortality, higher MI/VTE/arterial embolism, and much higher bleeding risk (though, as noted, this was not an RCT, had many more patients with prior MI, so it is not so surprising that there was an increase in these thrombotic events. But twice the level of major bleeds??? And 50% more thrombotic events??? Is aspirin really useful?? I personally have stopped aspirin in my patients on warfarin, based on the prior blog)
- So, my bottom line: this Swedish study confirms the utility of warfarin in patients with nonvalvular AF, though clearly differentiates its advantages in those in good control (INR in range >70% of the time) vs not. I do have trouble with the NOACs overall, given the noted drug company issues in my prior blogs and the lingering concern that if they are in an accident, reversal agents are not widely available. But I have occasionally used NOACs in patients who are leaving the country and cannot get their INR checked, or it is just too difficult to get the INR in range despite best efforts all around, often including home-based nursing care/checking the INR at home. That being said, the clear majority of my patients on warfarin are definitely in the >70% TTR category and seem to be doing just fine…. (though I do need to monitor them frequently, but, then again, most of them have significant cardiac and other morbidities, and my guess is that the increased monitoring/health system contact is actually a positive thing)
CHA2DS2-VASc (cardiac failure or dysfunction, hypertension, age 75 years [doubled], diabetes mellitus, stroke [doubled]–vascular disease, age 65-74 years, and sex category [female])
For older blogs, see: https://stg-blogs.bmj.com/bmjebmspotlight/2016/01/19/primary-care-corner-with-geoffrey-modest-md-antithrombotic-therapy-guidelines/ goes through the antithrombotic therapy guidelines but also reviews the history of drug company malfeasance with the NOACs, which really make me uneasy about using them…