Heart Failure, COPD Exacerbations Elevate Warfarin Sensitivity

Warfarin remains a cornerstone anticoagulant for a number of reasons that include its low cost at the pharmacy counter.

Research on warfarin’s drug-drug and food-drug interactions has been extensive, but a growing area of study is the influence disease states have on its pharmacokinetics.

One case-controlled, observational study published by pharmacists in the Annals of Pharmacotherapy indicated that patients with heart failure (HF) or chronic obstructive pulmonary disease (COPD) exacerbations have elevated sensitivity to warfarin.

The theory behind this is that warfarin is cleared through hepatic cytochrome P450 (CYP) enzymes, with the oxygen-dependent 3A4 and 2C9 isoenzymes being most significant. Oxygen is also critical for mitochondrial synthesis of high-energy bonds that are needed for drug transport and conjugation.

In HF and COPD, decreased oxygen levels may cause tissue hypoxia and deprive CYP enzymes and mitochondria of the building blocks they need to metabolize warfarin and other drugs.

For their study, the pharmacists compared 63 patients admitted for either HF or COPD exacerbations with a set of 60 controls subjects, which included HF and COPD patients who were stable, as well as those admitted for other reasons.

The researchers measured warfarin sensitivity as international normalized ratio (INR) per daily mg dose of warfarin at admission, and then compared it with periods of disease stability and also between the study groups.

HF patients experienced warfarin sensitivity most often, exhibiting a 94% increase in warfarin sensitivity at admission, the pharmacists found. In COPD patients, the increase at admission was 59%, and in control subjects, it was 24%, probably due to admission-related factors and stress.

As HF severity increased, so did warfarin sensitivity. In fact, patients with the most severe HF (New York Heart Association class 3 and 4) experienced 125% increases in warfarin sensitivity at admission. Additionally, 14% of HF patients required vitamin K rescue, while no controls needed it.

Increased warfarin sensitivity in HF and COPD patients during exacerbations can have profound clinical significance, the pharmacists noted.