Dabigatran for Stroke Prevention in AF Passes Cost-Effectiveness Test

November 01, 2010

November 1, 2010 (Philadelphia, Pennsylvania) With dabigatran (Pradaxa, Boehringer Ingelheim) recently FDA-approved for stroke prevention in atrial fibrillation (AF) and its availability in pharmacies imminent, a speculative cost-effectiveness analysis suggests that the oral thrombin inhibitor holds up well against the drug that, for many patients, it will likely replace [1]. That was especially true for patients with AF who had other risk factors for ischemic stroke as defined by their CHADS2 score.

"There is a brand-new drug coming out that may change the paradigm of care. Before it hit the shelves, we wanted to know if it could be cost-effective," senior author Dr Mintu P Turakhia (Veterans Affairs Palo Alto Health Care System, CA) told heartwire . "Our analysis suggests that for the average elderly patient with a CHADS2 score of 1 or higher, [dabigatran has] very good potential to be a cost-effective alternative to warfarin, ultimately depending on pricing."

With dabigatran given at 150 mg twice daily, the approved dosage for most patients, the incremental cost compared with using warfarin came in under the conventional cost-effectiveness threshold of $50 000 per quality-adjusted life-year (QALY) gained.

The analysis was published online today in the Annals of Internal Medicine, with first author Dr James V Freeman (Stanford University School of Medicine, CA).

It worked from assumptions regarding rates of adverse events and complications and their costs to the healthcare system, using outcomes in the >18 000-patient international RE-LY trial and Medicare data as guides.

Importantly, the analysis was also based on what has turned out to be a big overestimation of what dabigatran is apparently going to cost in the US. It pegged the drug's daily cost at $9.50 for a 110-mg twice-daily "low dose" and $13.00 for the 150-mg twice-daily "high dose," which were the dosages tested in RE-LY, the trial on which dabigatran's approval by the FDA was almost entirely based.

Freeman et al based their dollar figures on the drug's daily cost in the UK, where it has been available for prevention of venous thrombosis, and adjusted it slightly upward for the US market. However, a number of physicians have expressed hopes to heartwire that dabigatran will be priced at a much lower level for the US AF/stroke-prevention market than it currently is anywhere for venous thrombosis, as it will have to be taken indefinitely in AF rather than temporarily as in the other indication.

Indeed, Boehringer Ingelheim has apparently set the US wholesale price of two 150-mg dabigatran capsules at $6.75, according to news reports from October 26 [2].

That daily price, even after the likely markup for actual sale, Turakhia observed, "puts it well within the bounds of cost-effectiveness."

As for the low dose, the FDA has for the time being ignored the 110-mg lower dose from RE-LY--which was comparable to warfarin in efficacy and cut the major bleeding risk vs warfarin (the 150-mg dosage was superior in efficacy and comparable to warfarin for major bleeding)--and unexpectedly approved it at 75-mg twice daily. That dose had performed favorably in a smaller dose-finding study and, according to Boehringer Ingelheim [3], the agency intends it for the minority of the target population that has severe renal dysfunction.

Turakhia pointed out that RE-LY had excluded patients with severe renal dysfunction and the cost-effectiveness analysis didn't account for that population.

It did, however, look at QALYs gained for dabigatran at the two RE-LY dosages for preventing ischemic stroke in hypothetical patients aged >65 with AF and no contraindications to anticoagulation but a CHADS2 score >1, which meant the patient had a history of hypertension, heart failure, diabetes, cerebrovascular events/thromboembolism or an age >75 or any combination of those features. They compared that with a warfarin regimen aimed at achieving an international normalized ratio (INR) of 2.0 to 3.0, allowing for at least 14 INR tests over 90 days and a year of medication.

The patient's quality-adjusted life-expectancy--which accounted for adverse events, including the increased MI risk seen with the high dose in RE-LY, whose clinical relevance remains controversial--was 10.70 QALY at the low dose, 10.84 QALY at the high dose, and 10.28 QALY with warfarin. That made high-dose dabigatran the "most effective" of the three regimens, according to Freeman et al.

Total costs figured out to $164 576 for the low-dose, $168 398 for the high-dose, and $143 193 for warfarin.

The incremental cost-effectiveness ratios for dabigatran compared with warfarin were $51 229 per QALY for the low dose and $45 372 per QALY for the high dose.

In sensitivity analyses, the high-dose cost-effectiveness ratio improved further among patients with an even greater increased ischemic stroke risk, such as those with a CHADS2 score >2.

The low-dose dabigatran cost-effectiveness ratio improved and, in fact, surpassed that for the high dose among patients with a CHADS2 score of 0–1 and an increased absolute risk of intracranial hemorrhage, but the benefit was particularly sensitive to variation in the drug's price.

The cost-effectiveness analysis didn't account for at least one potential benefit from dabigatran that might come from its increasing use. "There's been a significant healthcare infrastructural investment dedicated to specialized anticoagulation providers and clinics. That being said, there's still a lot of variation in how well providers manage warfarin anticoagulation."

If the outcomes seen so far with dabigatran therapy "pan out outside of clinical trials, it could level the playing field in quality and variation across facilities and providers, and that also would add significant value."

On October 27, Boehringer Ingelheim announced that Health Canada has approved dabigatran (Pradax) for the RE-LY indication [4], specifying the 150-mg twice-daily dosage for most patients and making the 110-mg twice-daily dosage available for patients aged >80 years or for those at high risk of bleeding.

As reported by heartwire the previous day, a new AF-treatment guidelines statement from the Canadian Cardiovascular Society (CCS), released recently at the Canadian Cardiovascular Congress 2010 but obviously finalized much earlier, included dabigatran management on the safe assumption the drug would soon be approved.

Turakhia noted that the CCS guidelines appear to give the 150-mg twice-daily dosage its blessing even for many patients at low risk for ischemic stroke. That's also the case with the Canadian approval. But he cautions against any rush to use the higher dosage in that group.

"It concerns me because we really need to see how this increased risk of MI [observed with the high dose in RE-LY] pans out in the real world," he said. "The potential liability of rapid adoption is that it can end up being higher than anticipated."

Funding came from the American Heart Association and US Department of Veterans Affairs. The authors had no disclosures.


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