Real-life data with dabigatran convincing

For the first time, real-life data are available for one of the new oral anticoagulants. These were presented in Zurich on October 2, 2013. They demonstrate a compelling safety and efficacy profile of dabigatran in stroke prevention in non-valvular atrial fibrillation (AF), confirming previous results from both the pivotal study and long-term observational data.

The epidemiological figures on atrial fibrillation (VHF) are impressive: In Switzerland, approximately 100,000 people have a fivefold increased risk of suffering a stroke due to VHF: Of the total 16,000 strokes occurring annually, about 4000 are related to VHF. In addition, the most frequent stroke triggered by VCF is the ischemic stroke, which has particularly severe consequences: In 60% of patients with a first-ever ischemic insult, permanent disability remains, and 20% even die [1].

Brain protection as the primary goal

The distinction between ischemic and hemorrhagic stroke is an important factor in anticoagulation: blockage of a vessel in the brain (ischemic stroke) is most common in VHF sufferers, accounting for 92%. In contrast, only 8% of strokes are hemorrhagic and occur as a result of the rupture of a vessel in the brain [2]. “When it comes to atrial fibrillation, I agree with Woody Allen, who calls the brain his second most important organ: The important thing is to protect the brain. Because it is precisely this goal that is at the forefront of anticoagulation,” says Prof. Bernhard Meier, MD, of the Inselspital Bern. Anticoagulant therapy balances two poles: preventing the most common, ischemic stroke and minimizing the risk for cerebral hemorrhage. The goal is to ensure optimal therapy that protects patients from both hazards.

Thus, although the mandate is clear, too little is still being done about it in Switzerland as well. A study from St. Gallen on the use of vitamin K antagonists (VKA) showed, based on randomized measurement time points, that 26.7% of patients were undertreated (INR<2.0) and 14.2% were overtreated [3]. “This illustrates that in practice 40% of patients are not adequately protected by their warfarin therapy,” Prof. Meier said. Additionally, in everyday life, treatment with VKA is complicated by interactions with food and other drugs. Even if the INR value is optimally adjusted, therapy with a VKA only achieves a stroke reduction of 64%.

NOAKs – a breakthrough in anticoagulant therapy

With the development of the new oral anticoagulants (NOAKs), specifically with ^Pradaxa®, a breakthrough in the prevention of ischemic stroke in VCF was achieved, which is also confirmed by their recommendations in the relevant guidelines [4]. When treated with NOAKs, stroke protection no longer has to be bought by a significantly increased risk of cerebral hemorrhage, as was the case for a long time with standard therapy with VKA, explained Prof. Stuart Connolly, MD, Hamilton, Canada. The result of RE-LY [5, 6], the pivotal study of dabigatran, confirmed this: A significantly reduced risk of stroke and systemic embolism was demonstrated with dabigatran 2×150 mg/day. The lower dosage (2×110 mg/day) had a risk comparable to VKA, and at the same time, the risk of intracranial hemorrhage decreased significantly under both dosages. Severe bleeding rates were comparable with VKA at the high dose (2×150 mg/day), and rates of major bleeding decreased significantly with 2×110 mg/day dabigatran.

The high efficacy and balanced safety profile of ^Pradaxa® were also confirmed by long-term data from the RELY-ABLE study [7], in which patients were followed up for an additional 2.3 years on average after completion of the RE-LY study.

Study data alone are not enough

“In practice, we notice time and again that everyday clinical practice differs from study conditions. It’s like buying clothes: only when you actually try on a pair of pants can you judge whether they fit or not. Just looking at them in the catalog tells you very little,” says Prof. Meier. Consequently, data from everyday clinical practice should not be underestimated in their importance, because this is where it becomes apparent whether the results of the large pivotal trials can also be transferred to routine care and whether the ‘anticoagulation garment’ fits. The complex context in which therapy is provided is characterized by comorbidities, different treatment steps, and difficult chains of care. “Consequently, what matters to patients is what the bottom line is for them in real-world care,” is Prof. Meier’s assessment.

Clinical practice confirms efficacy and safety of dabigatran

Prof. Connolly presented precisely these data from everyday clinical practice. In the USA, there are evaluations that do not yet exist for the EU and Switzerland due to the later market launch. “An FDA mini-sentinel study [8] of 54,000 VHF patients now shows for the first time that Pradaxa® can hold its own in practice without idealized study conditions,” Prof. Connolly announced. For the evaluation, the FDA used insurance data. Compared to study data, this database offers an unfiltered insight into clinical reality, since virtually all physician visits and thus all bleeding events are listed.

It is assumed that side effects occurring with newly introduced drugs are reported more frequently than with substances that have been on the market for decades and of which physicians have long been aware of the side effects and no longer classify them as reportable. The FDA estimates that this phenomenon also occurred after ^Pradaxa® was approved. “The evaluation of the insurance data makes it clear that ^Pradaxa® does not cause a bleeding problem in clinical practice and that the fears and increased reporting rates that initially arose can be debunked. On the contrary, we see similar bleeding rates as under study conditions, which is very good news,” was Prof. Connolly’s assessment in Zurich. The incidence rate under dabigatran for gastrointestinal bleeding was 1.6 (events/100,000 treatment days); under VKA, the rate was significantly higher at 3.5 (Table 1). With regard to intracranial hemorrhage, the bleeding rate in VKA patients was 2.4, three times higher than with dabigatran, where the rate was only 0.8.

Further data from Canada reinforce the good performance of dabigatran in practice. The Quebec Provincial Registry [9] includes the disease trajectories of approximately 13,000 patients with nonvalvular AF over a 2-year period who restarted therapy with either dabigatran or warfarin. “Again, under both doses of dabigatran, we see a significant reduction in the rates of stroke and systemic embolism, as was previously observed in the pivotal studies,” Prof. Connolly said in assessing the results (Table 2) . The importance of this protection against ischemic stroke should not be underestimated.

^Pradaxa® is now approved in more than 100 countries in patients with VCF for the prevention of stroke and systemic embolism, representing more than two million patient-years of experience. Calculating the probability of events based on event rates in trials and practice, treatment with dabigatran has already prevented up to 93,000 strokes worldwide, compared with no treatment [10]. For Prof. Meier, this great benefit also justifies the more expensive treatment with dabigatran compared to VKA: “If you want to improve patient protection, you have to and should also invest in it.”

Source: Press Event ^Pradaxa® “Stroke Prevention in Nonvalvular Atrial Fibrillation. Newly published clinical and “real-life” safety data with ^Pradaxa®. October 2, 2013, Zurich.

Literature:

1. Gladstone DJ, et al: Potentially Preventable Strokes in High-Risk Patients With Atrial Fibrillation Who Are Not Adequately Anticoagulated. Stroke 2009; 40: 235-240.
2. Andersen KK, et al: Hemorrhagic and Ischemic Strokes Compared Stroke Severity, Mortality, and Risk Factors. Stroke 2009; 40: 2068-2072.
3. Bogdanovic et al. Quality of oral anticoagulation using coumarins in Switzerland. Cardiovascular Medicine 2013 Supplementum 22.
4. Camm AJ, et al: 2012 focused update of the ESC Guidelines for the management of atrial fibrilation. European Heart Journal 2012; 33: 2719-2747.
5. Connolly SJ, et al: Dabigatran versus warfarin in patients with atrial fibrilation. N Engl J Med 2009; 361: 1139-1151.
6. Connolly SJ, et al: Newly identified events in the ^RE-LY® trial. N Engl J Med 2010; 363: 1875-1876.
7. Connolly SJ, et al: Randomized Comparison of the Effects of Two Doses of Dabigatran Etexilate on Clinical Outcomes Over 4.3 Years: results of the ^RELY-ABLE® Double-blind Randomized Trial. Presented at the American Heart Association Scientific Session 2012m November 7th, 2012.
8. Southworth MR, et al: Dabigatran and postmarketing reports of bleeding. N Engl J Med 2013; 368: 1272-1274.
9. Quebec Privincial Registry, presented at the INESSS meeting, December 18, 2012.
10. Boehringer Ingelheim Press Release: ^Pradaxa® (dabigatran etexilate) drives Boehringer Ingelheim’s innovation promise in cardiovascular diseases, September 03, 2013, Ingelheim www.boehringer-ingelheim.com/news/news_releases/press_releases/2013/03_september_2013dabigatranetexilate.html

CARDIOVASC 2013; 12(6): 35-38