Dabigatran: New Data on MI and Ischemic Events

January 09, 2012

January 9, 2012 (Frankfurt, Germany and Cleveland, Ohio) — The question of MI risk with dabigatran (Pradaxa, Boehringer Ingelheim) is in the spotlight once again, with two new papers on the subject published within the last few days.

In one paper--published online on January 3, 2012 in Circulation--RE-LY investigators looked more closely at their data for any type of ischemic event and at the subgroup of patients with existing ischemic heart disease and found reassuring results for dabigatran [1]. "We have scrutinized the RE-LY data as much as we can, and I think these latest results alleviate the worry somewhat," lead author, Dr Stefan Hohnloser (J W Goethe University, Frankfurt, Germany), told heartwire .

But in the other paper, published online today in the Archives of Internal Medicine, a meta-analysis of seven trials of dabigatran appears to confirm an MI signal with the drug [2].

Data Not Conflicting?

However, lead authors of both papers agreed that they did not think the two new studies were conflicting. Hohnloser said: "There is a signal of MI with dabigatran in the RE-LY results, no question, and the same thing is seen in this new meta-analysis. We are not arguing about that. But when we look at the totality of all ischemic events in RE-LY there is no signal at all. We have also shown that the MI issue is not increased in patients with a history of ischemic heart disease, and there is a net clinical benefit of dabigatran over warfarin, regardless of whether patients have coronary heart disease or not."

Lead author of the meta-analysis, Dr Ken Uchino (Cleveland Clinic, OH) had a similar viewpoint. "Our paper shows an increase in MI when other studies are considered as well as RE-LY. And the Circulation paper looks into greater detail of those events in RE-LY and emphasizes the overall benefit of dabigatran. It is important to note that the increase in MI risk is small, and if used for AF, there is a net clinical benefit for dabigatran. When we wrote our paper, we weren't aware of this new data from RE-LY, and I think there was a concern about dabigatran in patients with ischemic heart disease. I think the Circulation paper has helped clarify that the risk of MI is not increased more in people who had a history of coronary heart disease, but the benefit of dabigatran is still there. It is reassuring on that point. On the basis of that data, I would not be concerned about using dabigatran in patients with ischemic heart disease."

However, he added: "The RE-LY data only deals with the AF population, and I think that if dabigatran is used in other indications, questions still remain and this needs more study. In the venous thromboembolism [VTE] population, the absolute risk of MI is very low, and I would doubt the benefit-risk ratio would be reversed, but I would like to see more data on this."

A Comprehensive Analysis of Ischemic Events

Hohnloser explained to heartwire that the Circulation paper was a much more comprehensive analysis of ischemic events in RE-LY. "We included all types of ischemic events--CABG, PCI, unstable angina, cardiac arrest, and cardiac death--as well as MI."

The MI numbers in RELY (previously reported) showed 80 such events in the 5983 patients in the dabigatran 110 mg group, 79 events in the 6059 patients in the dabigatran 150 mg group, and 63 events in the 5998 patients in the warfarin group. "Because the MI numbers were actually very low, we went back and added in every other type of ischemic event to give more statistical power," Hohnloser noted. Results showed no difference between the three groups.

"In addition, when you look at the totality of benefits with dabigatran--the reduction in hemorrhagic stroke, ischemic stroke, and bleeding vs the increased number of MI--there is clearly a net clinical benefit in favor of dabigatran over warfarin," Hohnloser said.

RE-LY: Cardiac Events and Net Clinical Benefit (Rate Per 100 Person-Years)

Events/benefit Dabigatran 110 mg Dabigatran 150 mg Warfarin
All ischemic events 3.38 3.53 3.60
Net clinical benefit 7.34 7.11 7.91

Net clinical benefit: composite of stroke, MI, CV death, pulmonary embolism, systemic embolism, or major bleeding.

The researchers examined the timeframe over which the ischemic events in RE-LY occurred and found that one-third of events happened well after the study drug was discontinued. "So they were probably completely unrelated to the medication," Hohnloser commented.

They also looked at just those patients who had a history of coronary disease, and this group showed the same benefit in terms of stroke prevention and bleeding reduction with dabigatran vs warfarin than in those without coronary heart disease. "The net clinical benefit is in favor of dabigatran in both patients with and without coronary artery disease," Hohnloser said.

On the possible reason for the numerical increase in MIs in the dabigatran group, Hohnloser suggested that this may have been because warfarin is more effective at preventing MI than dabigatran. "Other studies have shown that warfarin is very effective at preventing MIs. It is known to be better than aspirin in this regard, but aspirin is used in preference (in CAD patients) because of all the difficulties with warfarin."

Meta-Analysis of Seven Studies

In the meta-analysis, Uchino and his colleague Dr Adrian Hernandez, combined data from seven studies of dabigatran--the RELY and PETRO trials vs warfarin in AF patients; three studies of short-term prophylaxis of deep venous thrombosis with enoxaparin as control; one study in acute VTE with warfarin as control; and one study in ACS vs placebo.

Results showed dabigatran was significantly associated with a higher risk of MI or ACS than that seen with agents used in the control group.

Meta-Analysis: MI Risk With Dabigatran vs Control

End point Dabigatran Control HR (95% CI) p value
MI incidence 237/20 000 (1.19%) 83/10 514 (0.79%) 1.33 (1.03–1.71) 0.03

Commenting to heartwire , Hohnloser said: "I do believe this meta-analysis is helpful in that it is always good to have people raising safety issues so we get as much information as possible, but meta-analyses have their own problems. In this case, they have combined very different patient populations--those with AF and those with VTE. There are also different control groups--warfarin, enoxaparin, or placebo." He noted that Boehringer Ingelheim had conducted various meta-analyses and found that in trials comparing dabigatran to warfarin, there was a signal of increased MI, but in studies comparing dabigatran to enoxaparin or placebo, there was no difference in MI.

On this point, Uchino commented: "We can't say anything about MI risk in the studies which used enoxaparin and placebo as controls in isolation, as there were too few events. The increase seen in the meta-analysis could be due to a better preventative effect with warfarin, but we cannot conclude this for sure."

Hohnloser added: "The message from the meta-analysis is that there does appear to be an increased risk of MI with dabigatran vs warfarin. We would not argue with that. But if you compare all the bad things that can happen with both drugs, then dabigatran definitely has the advantage."

Editorialists Cautious

In an editorial accompanying the meta-analysis [3], Drs Jeremy Jacobs and Jochanan Stessman (Hadassah-Hebrew University Medical Center, Jerusalem, Israel) express concern about the "enthusiasm--nearly to the level of euphoria--to embrace the new, which must be restrained by the old aphorism: primum non nocere."

To heartwire , Jacobs added: "I think caution is needed with dabigatran, especially among patients with known active ischemic heart disease. High quality data from clinical use will be the way to clarify the as yet unresolved issues concerning its effect upon MI rates, and how significant this may or may not be in regard to its noninferiority for bleeding."

But Hohnloser argued: "There will always be people who are looking for reasons not to prescribe an expensive new drug, especially one like [dabigatran] that could be used in a huge amount of people, which has major cost issues. And these people will take ammunition from this meta-analysis. But they are forgetting about all the problems with warfarin and the fact that only half the patients with AF actually get it because it is so difficult to use. The Archives editorialists were not aware of our paper when they wrote their article, and if they were, I think they may have changed their conclusions somewhat."

After having seen the new data from RE-LY, Jacobs said it was "an interesting, albeit posthoc analysis, which successfully manages to smooth over the observed effect." He added: "The authors themselves suggest that a trial designed to compare cardiac outcomes might be necessary to resolve the issue."


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