Dabigatran and myocardial ischemia: a pharmacologic perspective

In RE-LY, the landmark trial comparing dabigatran (Pradaxa^®) and warfarin in patients with atrial fibrillation, the investigators observed an increased risk of myocardial infarction (MI) among patients randomized to dabigatran [1].  Although the increased risk was only numerically different in patients randomized to the lower dose of dabigatran (110 mg), the higher dose (150 mg) group met the threshold for statistical significance (relative risk 1.38, CI 1.00 - 1.91, p = 0.048). Since the original publication of RE-LY, the subject of increased ischemic risk associated with dabigatran has been a topic of heated debate.  Two analyses published last month look at this issue in greater depth [2, 3].

In a sub-analysis of the original RE-LY trial [2], Hohnloser, et al found a numerical but not statistically significant difference in the annual risk of MI among patients randomized to dabigatran -- why this is different from the original trial is still a mystery to me, but I'll attribute it to how small the difference was in the original trial. Outcomes were similar among the subgroup of patients with a known history of coronary artery disease (CAD) and a pre-specified analysis of net clinical benefit -- a composite of ischemic, thrombotic, and hemorraghic events -- also favored dabigatran (p = 0.02).

However, in a meta-analysis of seven trials comparing dabigatran to standard therapy in atrial fibrillation, acute coronary syndromes, or venous thromboembolism [3], Uchino, et al observed a small but statistically significant risk of MI associated with dabigatran therapy (absolute risk 0.14% - 0.17%, p = 0.03). Results were similar when the revised data from RE-LY were included and when trials of shorter duration were excluded.

Most have contended that the increased risk attributed to dabigatran is due to the protective effects of warfarin rather than an adverse effect of dabigatran.  After all, warfarin improves outcomes post-MI and is more effective than aspirin for this indication [4].  However, given the difficulty of managing warfarin in such an extensive patient population, dual antiplatelet therapy has become the preferred standard of care in the majority of post-MI patients.

While the authors of these trials do not propose a pharmacologic basis for the potential risk of ischemic events associated with dabigatran therapy, I think a signal observed in an earlier trial may provide a few clues.  In PETRO [5], the first trial to evaluate dabigatran in patients with atrial fibrillation, patients were randomized to one of three doses of dabigatran (alone or in combination with aspirin) or adjusted-dose warfarin.  In the patients randomized to dabigatran, investigators observed an unexpected increase (17-31%) in the urinary excretion of 11-dehydrothromboxane B2 (DTB₂), a byproduct of thromboxane A₂ and a marker of platelet activation.  Thromboxane A₂ is a pro-inflammatory mediator responsible for platelet activation and aggregation and is implicated in the pathogenesis of acute coronary syndromes. The inhibition of thromboxane A₂ production is thought to be the mechanism by which aspirin exerts its beneficial effects in patients with ischemic heart disease.  Interestingly enough, the urinary excretion of DTB₂ in patients taking dabigatran was attenuated (by 40-57%) in those patients that were also on aspirin.

If the DTB₂ excretion observed in patients on dabigatran is responsible for the increased rates of ischemic events attributed to the drug, this could be responsible for the discrepancies observed between the RE-LY sub-analysis and the meta-analysis conducted by Uchino, et al.  Given the association between ischemic disease and atrial fibrillation, approximately 40% of the patients in RE-LY were also taking aspirin, a percentage that may have been sufficient enough to dilute the rates of ischemic disease that may have otherwise been observed.  If this is truly the case, it is not surprising that increased rates were not observed among patients with CAD, as the vast majority of them were likely on aspirin.

Although the incidence of CAD was not reported among patients enrolled in other trials included in the meta-analysis, I anticipate it was low given the heterogeneity of the patient population (with the exception of the single trial of patients with acute coronary syndromes). As a result, fewer of these patients would have been on concomitant aspirin therapy and would not have obtained a potential protective effect of aspirin.  Because more of these non-aspirin patients were included in the meta-analysis, it may have been enough to signal an increased risk of MI with dabigatran use.

Although this is entirely speculative, I do think it is important to at least recognize a plausible pharmacologic explanation for the increased risk of ischemic events attributed to dabigatran if such an effect actually exists. The issue is unlikely to be resolved without a prospective analysis -- a recommendation made by the authors of both publications. While I do not anticipate an investigation to be performed any time soon, I hope one will at least address the aspirin issue at some point in the future, as this could change how we manage patients on dabigatran therapy.  In other words, should we also be placing the majority of them on aspirin?

References

1. Connolly SJ, Ezekowitz MD, Wallentin L, et al; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009 Sep 17;361(12):1139-51.
2. Hohnloser SH, Oldgren J, Connolly SJ, et al. Myocardial Ischemic Events in Patients With Atrial Fibrillation Treated With Dabigatran or Warfarin in the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) Trial. Circulation. 2012 Feb 7;125(5):669-76.
3. Uchino K, Hernandez AV. Dabigatran Association With Higher Risk of Acute Coronary Events: Meta-analysis of Noninferiority Randomized Controlled Trials. Arch Intern Med. 2012 Jan 9.
4. Hurlen M, et al. Warfarin, aspirin, or both after myocardial infarction. N Engl J Med. 2002 Sep 26;347(13):969-74.
5. Ezekowitz MD, Reilly PA, Wallentin L, et al. Dabigatran with or without concomitant aspirin compared with warfarin alone in patients with nonvalvular atrial fibrillation (PETRO Study). Am J Cardiol. 2007 Nov 1;100(9):1419-26.

The value of a community pharmacist's intervention

Earlier this week, I was asked by a nurse practitioner from our electrophysiology group about alternative antibiotic therapy for a patient taking dofetilide (Tikosyn^®), an antiarrhythmic used for the maintenance of normal sinus rhythm in patients with atrial fibrillation or atrial flutter.  While dofetilide is an effective option for this condition -- about three-fourths of patients will remain in normal sinus rhythm at 12 months -- it is also associated with a small risk of torsades de pointes (or, simply torsades), a type of arrhythmia that can be fatal if not treated immediately.  Because of this risk, patients are admitted to the hospital and closely observed for their first five doses of dofetilide. Prior to discharge, patients are educated on things that might increase their risk for torsades, including interactions between dofetilide and several commonly prescribed medications. However, rather than asking patients to memorize all of the prescription medications that may interact with dofetilide, I provide them with the list and recommend that they obtain all of their medications at the same community pharmacy so that their pharmacist can screen for potentially dangerous drug-drug interactions.

One of our recently discharged patients saw his primary care physician (PCP) out of concern for worsening upper respiratory symptoms that were consistent with community-acquired pneumonia (CAP). The PCP prescribed two common antibiotics for CAP -- both of which have been associated with an increased risk of torsades when used in combination with dofetilide.  The patient went to his local community pharmacy to have the prescriptions filled, but the interaction was quickly identified by the pharmacist.  She contacted the PCP to alert him of the interaction but was told to disregard it and dispense the prescription anyway.  Out of concern for the patient's safety, the pharmacist called our clinic to confirm.

While both of the antibiotics in question were not absolutely contraindicated with dofetilide, our patient had already required a reduced dose of dofetilide during his initial hospitalization due to ECG changes that were concerning for potential torsades.  Moreover, the antibiotics selected were prescribed at doses that were too high for the patient's renal function, only  further increasing his risk for the dangerous arrhythmia. Given the potential danger associated with these drug interactions, the nurse practitioner called me and we developed an antibiotic regimen that would be equally efficacious but avoid an increased risk of torsades.

After hearing how the pharmacist had been so persistent in the best interest of the patient -- despite the heated response she received from his PCP -- I made it a point to call and thank her for her going out of her way to ensure the safety of this patient.  Given all of the pressures that are placed on community pharmacists, many would have proceeded with the prescription -- and rightfully so, given the prescriber's demands.

However, this pharmacist went above and beyond the call of duty to put her patient first... and may have prevented a potentially dangerous drug interaction in the process.  So thank you, M, for being such an advocate for your patients.

A hiatus of sorts

As some of you may have noticed, it has been a few weeks since I last posted here on the Unit. A lot has happened in the interim, the most significant of which was the death of my grandfather late last month. His passing was quite unexpected and I'm still not entirely sure that I've come to terms with the fact that I'll no longer see him walking his dogs down by the lake shore or hear his hilarious -- albeit mildly inappropriate -- jokes around the dinner table. He was born just a few years after the Greatest Generation but embodied many of its most endearing qualities -- dedication to faith, family, and country; appreciating the value of a hard day's work; doing things not for the recognition it might bring but simply because it was the right thing to do. He spent his last days on earth just as he had the previous 84 -- living life to its fullest.

Grandpa had a stroke in the early hours of January 24th. When I got the call from mom, he was already en route to Erlanger in Chattanooga, TN, so I was hopeful that he would be eligible for fibrinolytic therapy to dissolve the clot -- that is, until I got the second call to confirm that it had been a hemorrhagic rather than ischemic stroke. My heart sank. He had already been intubated and admitted to the intensive care unit (ICU) when I began my drive back to Tennessee. I spent the next six hours coming to terms with what I already knew was a grim prognosis based on my own experiences.  The burden of knowledge, as my uncle would later call it.

I was able to see him the following morning, although to me it wasn't really him -- at least not the person I had come to know over the last 28 years. His condition had rendered him a shell of his former self, an image I had hoped to be accustomed to based on my experiences in the ICU.  However, as any health care professional will tell you, it's never quite the same when it's your own. After the neurologist confirmed that the hemorrhage had progressed and his survival was unlikely, I helped my family make the decision to undergo comfort measures rather than further escalating his level of care, a decision I feel was consistent with my grandfather's wishes.  Within minutes he was gone.

As we prepared the arrangements for his memorial over the next several days, I reflected on my grandfather's life and the way he lived it.  I was again reminded of the brevity of life -- only a passing vapor -- and the importance of prioritizing those things that are the most important.  It helped reveal some areas where I'd lost focus and reminded me of many of those things that led me to where I am now. And while I still don't have it all figured out, I think the wisdom of my grandfather has brought me one step closer.  For that and all the many things he taught me along the way, I'll be forever grateful.

You'll be missed, Waldo.