Prescription of anti-coagulants and cholesterol-lowering drugs has been a common practice for the management of cardiac arrhythmia, specifically in atrial fibrillation (AF). However, cautions have to be taken since there would be a 40% surge in bleeding risk associated with the use of dabigatran, a renowned anticoagulant also known as Pradaxa, when the patients are treated with lovastatin or simvastatin, according to a recent study published in the Canadian Medical Association Journal.
Statins and dabigatran are commonly prescribed for the management of cardiovascular diseases. The pharmacokinetics of these drugs are well-known for a long time: Dabigatran etexilate is a prodrug whose absorption is opposed by intestinal P-glycoprotein and bio-activated by carboxylesterase, while lovastatin and simvastatin are inhibitors of intestinal P-glycoprotein and carboxylesterase.1-3 Yet little research has been done to investigate the potential interaction between statins and dabigatran, until recent data was published in the Canadian Medical Association Journal, which found that simvastatin and lovastatin were associated with 40% more bleeding risk when used in combination with dabigatran as compared to other statins.1 The increased risk of bleeding requiring hospital admission or emergency department visits were also seen compared with other statins. 1
“[This study] highlights a previously unrecognized drug interaction and indicates you could use other statins so patients could still derive the benefits of statins without getting the excess risk that might be imparted by lovastatin and simvastatin,” said Tony Antoniou, PhD, Associate Professor, Department of Family and Community Medicine, University of Toronto, the principle investigator of current study.4 He also pointed out that the elder patients aged at >65 were more vulnerable to the risk. 1
The findings were derived from two population-based, nested case–control studies involving Ontario residents with ≥ 66 years of age who started dabigatran etexilate between 1st May, 2012 and 31st Mar, 2014.1 The first study comprised patients with ischemic stroke; while the second study comprised patients with major hemorrhage. Each case was matched with up to 4 controls by age and sex. All cases and controls received a single statin in 60 days preceding the index date. The association between each outcome and the use of simvastatin or lovastatin, relative to other statins was investigated.
Among the 45,991 patients taking dabigatran etexilate, 397 cases with ischemic stroke and 1,117 cases with major hemorrhage were identified. It was found that the use of lovastatin and simvastatin, which is commonly used in local hospitals, were associated with the increased risk for major hemorrhage (adjusted OR=1.46; 95% Cl: 1.17-1.82) relative to atorvastatin, pravastatin, fluvastatin or rosuvastatin despite the low absolute risk of this event. Meanwhile, the use of lovastatin and simvastatin was not associated with an increased risk of stroke (adjusted OR=1.33; 95% CI: 0.88-2.0).
The author commented that the biggest strength of this study is the population-based feature. However, he agreed that the limitations are lacking laboratory data, such as markers of kidney function, and reliable data on non-prescription drugs that can influence bleeding. Besides, the findings may not be applicable to younger patients, who may have fewer risk factors for stroke or hemorrhage.
This finding is crucial as Kevin Marzo, MD, the chief of cardiology at Winthrop-University Hospital in Mineola, N.Y. noted “As many as 50% of patients on dabigatran (Pradaxa) also are taking a statin”.5 “The authors have identified a potentially serious problem,” said Dr. Andrew Rogove, medical director of stroke at Northwell Health’s Southside Hospital in Bay Shore, N.Y. “There are alternative statin drugs that do not have this effect on dabigatran,” he said.5 Rogove stressed, however, that “this study looked at older populations [age over 66] and may not hold true for younger patients.”
Meanwhile, Thomas Deering, MD, FACC, cardiologist from Piedmont Heart Institute, Altanta, commented that there was only one definitive study with publicized data on this controversial issue, so one should not overreact and should figure out how to identify patients at risk, who need closer monitoring on the occurrence of stroke or hemorrhage or even test for the blood level of dabigatran.4 He also proposed that “both statins and anticoagulants for strokes save lives and people should not jump to conclusions and stop their drugs based on a single observational analysis.” Further studies in other types of statins remain uncertain and more effort is required in basic investigation to determine the more accurate safety dose of statins and anticoagulants that fall into the therapeutic window.
Paul D Thompson, MD, Director of Cardiology at Hartford Hospital, pointed out that, “the study is interesting, but a major flaw is that neither researchers nor anyone else have actually measured dabigatran levels while on different statins and compared levels.” 4
It is recommended to extend the time between administration of dabigatran and lovastatin or simvastatin. In fact, the spacing of medication should attenuate any observed effect on the bleeding risk. And alternative statins not associated with increased bleeding risk should be used in patients instead of lovastatin and simvastatin.