What is the Impact of Bisoprolol on Plasma Concentrations of Dabigatran

Introduction

Anticoagulant therapy is a component of medication for many patients with non-valvular atrial fibrillation (AF) to prevent stroke (CVA) and systemic embolism. It is especially used in patients with one or more risk factors, such as age over 75 years, history of CVA or transient ischemic attack, heart failure (NYHA class ≥ II), diabetes, or hypertension. In these indications, bisoprolol, a highly cardioselective beta-blocker with antihypertensive, anti-ischemic, and cardioprotective effects, is also commonly used.

Drugs and P-Glycoprotein

Dabigatran is characterized by minimal food interactions and drug interactions via cytochrome P450, but it is a substrate of P-glycoprotein. This efflux pump ensures the transport of many drugs in various cells. In enterocytes, it pumps the drug back into the lumen of the intestine, thus reducing the absorption of the substance. In cells forming the blood-brain barrier, it ensures that many xenobiotics do not penetrate into the CNS. In hepatocytes, P-glycoprotein participates in the elimination of drugs and their metabolites into bile and in the proximal tubule into urine.

Bisoprolol is a significant inhibitor of P-glycoprotein. When used together with dabigatran, it can be assumed that the inhibition of P-glycoprotein in enterocytes caused by bisoprolol may increase plasma concentrations of dabigatran.

Pharmacokinetic Study

The study by Slovak authors aimed to investigate the effect of concomitant therapy with bisoprolol on plasma levels of dabigatran in patients with non-valvular AF. Hospitalized patients (n = 29) were enrolled and divided into two groups for analysis − one group took dabigatran and bisoprolol (n = 18), and the other group took only dabigatran (n = 11).

Dabigatran was administered twice daily at individual doses of 150 or 110 mg according to the physician's recommendation, and bisoprolol was given at a dose of 5 mg immediately after dabigatran. The recommended doses of both drugs were taken by patients for at least 2 months. ACE inhibitors, furosemide, amiodarone, proton pump inhibitors (PPIs), and digoxin treatments were allowed, taken each morning after bisoprolol. Blood samples for analysis were taken in the morning before dabigatran administration (trough level) and 2 hours after administration.

Results

There were no significant demographic differences between the two groups that would lead to result distortion. The groups already differed in trough levels of dabigatran: patients taking dabigatran with bisoprolol had 83.5% higher dabigatran exposure than those not taking bisoprolol. The exposure was also increased 2 hours after drug administration: patients with the combination of dabigatran and bisoprolol had 56.9% higher dabigatran exposure. All differences were statistically significant.

The increase in dabigatran levels could also be influenced by concurrent administration of PPIs and digoxin, which also interact with P-glycoprotein. After performing a sensitivity analysis and excluding patients using PPIs or digoxin, values were recalculated and it was found that the differences in dabigatran exposure became even more pronounced. After excluding patients using PPIs, dabigatran exposure in the bisoprolol group was increased by 103.9% (trough level) and by 73.2% (2 hours after drug administration) compared to the group without bisoprolol. After excluding patients using digoxin, differences measured were 115.0% (trough level) and 76.9% (2 hours after drug administration).

Conclusion

The cited study confirmed that bisoprolol may increase dabigatran exposure by inhibiting P-glycoprotein, which could result in a higher risk of bleeding. The results of the main analysis indicated higher plasma levels of dabigatran when administered with bisoprolol, both before the dose and 2 hours after drug administration. The sensitivity analysis excluding patients using PPIs or digoxin showed that these drugs reduce dabigatran absorption. The effect of bisoprolol on increasing dabigatran levels, isolated from the effects of PPIs or digoxin, was even more pronounced. In the future, it will be necessary to describe the clinical significance of this interaction.

(lexi)

Sources:  
1. Nehaj F., Sokol J., Ivanková J. et al. Effect of bisoprolol on the level of dabigatran. Am J Ther 2020; 27 (2): e159–e164, doi: 10.1097/MJT.0000000000000786. 
2. SPC Pradaxa. Available at: www.ema.europa.eu/en/documents/product-information/pradaxa-epar-product-information_cs.pdf