Why the FDA Approved Dabigatran 150 mg and Not 110 mg
Stroke is the third most common illness in the United States, after myocardial infarction and cancer. In quality of life surveys, many respond that they prefer death to a permanently disabling stroke. Hypertension is a major risk factor for stroke. But the majority of strokes are considered “cryptogenic” because no definitive cause can be assigned.
Nonvalvular atrial fibrillation (AF) causes about 1 in every 5 to 6 strokes in the United States. These are not ministrokes or transient ischemic attacks. They are anatomically large strokes often causing permanent neurological disability and occasionally death. Embolic strokes due to AF have worse outcomes than other types of strokes. These strokes occur mostly in those over 65 years of age and especially those older than 75 years. They can terminate a lifestyle of independent living and force victims to be placed in settings where they receive round the clock skilled nursing care. These strokes disrupt, decimate, and devastate the social fabric that families have weaved over a lifetime, and they suck away the carefully sequestered savings for a planned retirement of hobbies, volunteer work, and visiting grandchildren.
Only two decades ago did we learn that we can reduce the stroke rate from nonvalvular AF by about 25% with aspirin. And for only slightly longer than one decade have we realized that we can reduce the stroke rate in nonvalvular AF by about another 40% with warfarin rather than aspirin.(1) But warfarin is cumbersome and labor intensive to use properly. The requirement of adjusting the dose according to the International Normalized Ratio (INR) to target a range of 2.0 to 3.0 requires a detailed strategic plan that coordinates laboratory testing in a frequency that varies from twice weekly to once monthly, communicates INR results to the clinician who doses the warfarin, and then informs the patient of whether the dose of warfarin requires adjustment because of new INR results that are unacceptably above or below the targeted range. In addition, warfarin is affected by hundreds of interactions with other medications and with foods. However, despite this myriad of limitations, warfarin remains remarkably effective. Well-dosed warfarin cuts the stroke rate in at risk patients to about 1-2% per year. It has also been marketed in the United States since 1954. So there are no hidden surprises about possible adverse effects.
The monopoly of warfarin (and the family of vitamin K antagonists) as the sole oral anticoagulant has been shattered. A pipeline of novel oral anticoagulants is being developed. The major anticipated advance has been increased convenience to patients and clinicians. The new drugs, whether they are anti-factor Xa or antithrombin agents, are administered in fixed doses, without any laboratory coagulation monitoring. The new anticoagulants have minimal drug-drug and drug-food interactions. It was anticipated that they would be noninferior to warfarin for stroke prevention, and that their rate of bleeding complications would not exceed that of warfarin.
In October 2010, the Food and Drug Administration (FDA) approved the novel antithrombin agent, dabigatran, in a dose of 150 mg twice daily for stroke prevention in nonvalvular AF. The pivotal clinical trial was RE-LY, a megatrial of more than 18,000 patients randomized to dabigatran 150 mg (6,076 patients), dabigatran 110 mg (6,015 patients), or warfarin (6,022 patients). The dose of dabigatran was double-blinded, but the administration of warfarin was open label. Dabigatran 150 mg twice daily surprised virtually everyone involved because it was superior to warfarin and cut the stroke rate by 34% compared with warfarin. In most circumstances, when an anticoagulant is superior in efficacy, it is less safe than the comparator drug. However, in RE-LY, the major bleeding rate was 3.3% with dabigatran 150 mg and 3.6% with warfarin. With regard to life-threatening bleeding, the frequency was 1.5% with dabigatran 150 mg versus 1.9% with warfarin. The intracranial bleeding rate was 60% lower with dabigatran 150 mg than with warfarin.(2)
Dabigatran 110 mg was noninferior to warfarin for stroke prevention. However, dabigatran 110 mg was superior to warfarin for safety, with a major bleeding rate of 2.9% compared with 3.6% for warfarin. There was a significant treatment-by-age interaction, such that dabigatran 110 mg twice a day compared with warfarin was associated with a lower risk of major bleeding in patients aged <75 years (1.9% versus 3.0%) and a similar risk in those aged >75 years (4.4% versus 4.4%). In contrast, dabigatran 150 mg twice a day compared with warfarin was associated with a lower risk of major bleeding in those aged <75 years (2.1% versus 3.0%) and a higher risk of major bleeding (primarily gastrointestinal bleeding) in those aged >75 years (5.1% versus 4.4%).(3) Regardless of age, gastrointestinal bleeding occurred more often in the 150 mg than in the 110 mg group.
The FDA had to decide whether to approve dabigatran 110 mg in addition to dabigatran 150 mg. At first glance, this might seem like an easy decision. Approve dabigatran 150 mg for superior stroke prevention compared with warfarin, and target its use for patients unlikely to suffer major bleeding. And approve dabigatran 110 mg for noninferior stroke prevention compared with warfarin, and target its use for patients at high risk of gastrointestinal bleeding. If one were to choose this strategy, which was put into place in Canada, it would be important to identify subgroups in which use of the 110 mg dose would be advantageous. Among those 75 years of age or older, was it worth trading a lower stroke rate with 150 mg compared with 110 mg of dabigatran (1.4 versus 1.9 per 100 patient-years) for a higher rate of major, mostly extracranial, gastrointestinal bleeding (5.1 versus 4.4 per 100 patient-years)? The FDA didn’t think so, and neither do I.
How about dosing among patients with moderately severe chronic kidney disease, with a creatinine clearance between 30-50 ml per minute? This group is of special interest because dabigatran is metabolized primarily by the kidneys. Surprisingly, dabigatran 150 mg was especially effective in this population compared with dabigatran 110 mg, with stroke rates of 1.3 versus 2.4 per 100 patient-years, respectively. And the major bleeding rate was no greater with dabigatran 150 mg. Even patients who had major bleeding during the trial and who resumed the same dose of dabigatran did not have more major bleeding in the 150 mg group compared with dabigatran 110 mg.(4)
In a detailed investigation of major bleeding comparing dabigatran 150 mg versus 110 mg, multiple key subgroups were analyzed. These included age, gender, weight, renal function, and use of aspirin, amiodarone, or a proton pump inhibitor. The only subgroup in which dabigatran 150 mg had more bleeding than dabigatran 110 mg was among patients weighing more than 100 kg. I believe this is a biologically implausible finding and attribute it to the play of chance when multiple subgroups are undergoing exploratory analysis.(3)
The FDA does not adjudicate cost-effectiveness. This specialized area utilizes the expertise of those who study pharmacoepidemiology and pharmacoeconomics.(5) It is clear that dabigatran 150 mg is far more cost-effective than dabigatran 110 mg.(6)
Finally, we clinicians are by nature conservative. We are taught that our primary duty is to do no harm. Whereas the harm from gastrointestinal bleeding is obvious, the benefit from a stroke that is prevented and that never occurs is easily overlooked.
My initial reflexive reaction to the FDA’s not approving the dabigatran 110 mg dose was to bemoan the lack of incremental decision-making flexibility that I would have been afforded. Having the 110 mg dose would have allowed subtle texturing and molding of my day-to-day clinical practice. Would I have been tempted to opt for less gastrointestinal bleeding in some elderly patients with chronic kidney disease at the steep price of less stroke prevention? Certainly yes. Canadian physicians confront this dilemma every day. It will be interesting to track the proportion of dabigatran prescriptions in Canada that designate the noninferior 110 mg dose versus the superior 150 mg dose. Widespread use of dabigatran 150 mg holds the promise of altering the fundamental epidemiology of stroke and reducing stroke incidence in patients with nonvalvular AF. Prospective cohort studies should be undertaken in the U.S. and in Canada to track future trends over time.
Finally, let’s put the dabigatran dosing issue in perspective. The major problem with stroke prevention in AF is not whether dabigatran 150 mg should be used in preference to 110 mg. The key problem is that too many AF patients who should be treated with anticoagulants are treated with antiplatelet therapy or remain untreated. In an overview of studies since 2000, a median of 52% of AF patients received anticoagulants, 30% received antiplatelet therapy, and 18% were untreated.(7) Intensive educational updates, peer review, and patient advocacy will improve these metrics and should lead to a decrease in stroke incidence.
- Hart RG, Pearce LA, Aguilar MI. Meta-analysis: Antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med. 2007;146:857-867.
- Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139-1151.
- Eikelboom JW, Wallentin L, Connolly SJ, Ezekowitz M, Healey JS, Oldgren J, et al. Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: An analysis of the randomized evaluation of long-term anticoagulant therapy (RE-LY) trial. Circulation. 2011;123:2363-2372.
- Beasley BN, Unger EF, Temple R. Anticoagulant options--why the FDA approved a higher but not a lower dose of dabigatran. N Engl J Med.
- Avorn J. The relative cost-effectiveness of anticoagulants: Obvious, except for the cost and the effectiveness. Circulation. 2011;123:2519-2521.
- Shah SV, Gage BF. Cost-effectiveness of dabigatran for stroke prophylaxis in atrial fibrillation. Circulation. 2011;123:2562-2570.
- Ogilvie IM, Welner SA, Cowell W, Lip GY. Characterization of the proportion of untreated and antiplatelet therapy treated patients with atrial fibrillation. Am J Cardiol. 2011;108:151-161.
Keywords: Aged, Amiodarone, Anticoagulants, Aspirin, Atrial Fibrillation, Canada, Hypertension, International Normalized Ratio, Myocardial Infarction, Pharmacoepidemiology, Quality of Life, Stroke, United States, Warfarin
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