By Dr. Geoffrey Modest
A recent review compared the adverse effects of dabigatran and rivaroxaban, two of the NOACs (non-vitamin K antagonist oral anticoagulants) –see doi:10.1001/jamainternmed.2016.5954. This follows another report finding increased bleeding risks as well as MIs in post marketing case reports for dabigatran following its approval. This new report, funded by Medicare and the FDA, did find a significant increase in major bleeds from rivaroxaban over dabigatran.
Details:
- Retrospective new-user cohort study of 118,891 patients with nonvalvular atrial fibrillation who were 65 years or older and enrolled in Medicare from 2011 to 2014. Patients were included if they had a diagnosis of atrial fibrillation or flutter and filled a first prescription for either drug in this time period. Excluded if they had less than six months of enrollment in Medicare, were younger than 65, were in a skilled nursing facility or nursing home.
- 52,240 were on dabigatran and 66,651 were on rivaroxaban
- 50% were 65 to 74-year-old/40% were 75 to 84-year-old, 47% female, 91% white/4% black, 33% with diabetes, 40% hyperlipidemia, 86% hypertension, 15% obese, 19% smoking, 15% with heart failure, 33% with CHADS2 score of 0 to 1, 40% with score of 2, 19% with score of 3; 10% with HAS-BLED score of 1, 54% score of 2, 29% score of 3.
Results:
- 2537 had a primary outcome of thromboembolic stroke (n=306), intracranial hemorrhage (176), or major extracranial bleeding (1209) including major GI bleeding (1018) and mortality (846).
- Rivaroxaban vs. dabigatran was associated with:
- 19% reduction in thromboembolic stroke, HR= 0.81 (0.65 to 1.01). Nonsignificant. This translates to 1.8 fewer cases of thromboembolic stroke per 1000 person-years
- 65% increase in intracranial hemorrhage, HR 1.65 (1.20 to 2.26). AIRD (adjusted incidence rate difference): 2.3 excess cases per 1000 person-years
- 48% increase in major extracranial bleeding, HR 1.48 (1.32 to 1.67). AIRD = 13.0 excess cases per 1000 person-years; including 40% increase in major gastrointestinal bleeding, HR 1.40 (1.23 to 1.59). AIRD of 9.4 excess cases per 1000 person-years
- 15% increase in overall mortality, HR 1.15 (1.00 to 1.32), borderline significant at p=0.051, AIRD of 3.1 excess cases per 1000 person-years. In patients 75 years or older or with CHADS2 score greater than 2, the excess risk was significant (27% and 24% increases, respectively).
- The excess rate of intracranial hemorrhage exceeded the attributed reduced rate of thromboembolic stroke (the latter actually didn’t reach statistical significance)
Commentary:
- As I have mentioned in several prior blogs, I am very concerned about the widespread adoption and use of NOACs in non-valvular atrial fibrillation. I believe there was significant drug company malfeasance in both the design and presentation of the data. See blogs referenced at the end for more information. This is not to say that NOACs are decidedly bad, just that the studies on which their approval were based were seriously flawed, perhaps largely because of the drug company cover-ups.
- As a point of reference, in a large meta-analysis of warfarin in patients with a fib, intracranial hemorrhage occurred in 6 patients on warfarin vs. 3 on control, with n= 2900); and extracranial hemorrhage with warfarin was less than 0.3% per year(see Hart RG. Ann Intern Med 2007; 146:857).
- It was interesting that more cardiologists prescribed rivaroxaban than family practitioners. Not sure what this reflects. Sensitivity analysis did not show that the patients on rivaroxaban were sicker. Perhaps the cardiologists were aware of the post marketing studies on the harms of dabigatran. Perhaps they were more influenced by the ROCKET-AF study of rivaroxaban(which has been criticized for using defective INR machines, see blogs and NEWS FLASH below). It is important to note that there are no head-to-head comparisons of these different NOAC medications
- It is perhaps significant that the curves for intracranial hemorrhage, major GI bleeding, and mortality diverged during the follow-up period, though there was convergence on the event rate for thromboembolic strokes (i.e.: increasing problems without increasing benefits).
- One wonders if some of the increased incidence of bleeding with rivaroxaban is that it actually has the same half-life as dabigatran of about 12 hours, but is dosed at once a day, whereas dabigatran is dosed twice a day
- The study is limited by several factors. It is a retrospective analysis, and cannot have the rigor of the conclusions of a well conducted randomized trial. Also the mean duration of on treatment follow-up was only four months, though they did have a reasonable representation of those on meds at least 6 to 8 months.
- So, to me this huge acceptance of NOACs over warfarin (which certainly has its well-known drawbacks) seems more to reflect drug company shenanigans and heavy-duty marketing than clear benefit, and with attendant risks (though i have occasionally prescribed them, e.g. when patients were spending long periods of time in other countries without access to INR monitoring).
For blogs on NOACs, best to go to https://stg-blogs.bmj.com/bmjebmspotlight/category/vte/, which has blogs on the rivaroxaban study (ROCKET-AF) using defective INR machines in those patients on warfarin, a huge Swedish study showing safety and efficacy of warfarin when patients were mostly in the appropriate therapeutic range, and a slew of articles on drug company malfeasance in promoting dabigatran when internal drug company memos for example showed that they knew that drug levels actually should be monitored (though this went against their main selling point: that one would not have to monitor levels vs warfarin), as well as the study mentioned above about post-marketing serious adverse events of dabigatran, with the comment that “the Institute for Safe Medication Practices reported that dabigatran was responsible for more serious adverse events than 98.7% of all medications” [and it seems to be better than rivaroxaban, at least by the above study!!!!!]. I also continue to be concerned about the lack of easy access to reversal agents for the NOACs, especially in smaller hospitals outside of large academic centers.
*********NEWS FLASH********
- There was a new investigative report by Deborah Cohen in BMJ last week (she seems to have spear-headed many of the really great reports in BMJ about drug company malfeasance), stating that the drug company (Janssen) actually knew that the INR testing devices were faulty in the ROCKET AF study (which single-handedly propelled rivaroxaban into blockbuster status), yet withheld this information from the FDA. It turns out that the increased intracranial bleeding with warfarin might have been related to the fact that 33% of actual laboratory readings of INR were above 4, yet the defective point-of-care machines gave an INR on the same sample of between 2-3 (see doi: 10.1136/bmj.i5131)