Frailty and Co-Prescribing of Potentially Interacting Drugs in New Users of Warfarin

Abstract

Background Warfarin is underutilised in frail older people because of the fear of bleeding complications. Drug interactions are an independent bleeding risk factor. However, the extent to which potential drug interactions are taken into account at warfarin therapy initiation in frail patients is not known. Objective The objective of this study was to investigate the use of potentially interacting drugs increasing the bleeding risk before and after warfarin initiation in frail and non-frail patients. Methods We conducted an observational study including inpatients aged ≥ 60 years initiated on warfarin in a tertiary hospital in Adelaide, South Australia. Frailty status was assessed with the Reported Edmonton Frail Scale. Medication charts were reviewed before and after warfarin initiation. Results In total, 151 patients (102 non-frail and 49 frail) were included. Before warfarin initiation, the use of clopidogrel and acetaminophen was more common in frail patients compared with non-frail patients (25.5% vs 10.2%, p = 0.0135, 63.8% vs 35.7% p = 0.0014, respectively). The use of non-steroidal anti-inflammatory drugs, 9.2% in non-frail patients and 6.4% in frail patients before warfarin initiation, was completely stopped after warfarin initiation in both groups. The use of antiplatelet drugs decreased from 56.1% in non-frail patients and 66.0 % in frail patients to 12.2% and 14.9%, respectively. Instead, the use of drugs affecting the metabolism of warfarin or vitamin K increased in both groups. No statistically significant difference was seen in the exposure to interacting drugs between study groups after warfarin initiation. Acetaminophen, senna glycosides and cytochrome P450 2C9 inhibiting drugs were the most common interacting drugs at discharge used in 49.0%, 18.4% and 20.4% of non-frail patients and 53.2%, 29.8% and 19.1% of frail patients, respectively. Conclusions The overall frequency of potential drug interactions was moderate and frail patients were not exposed to warfarin drug interactions more often than non-frail patients. Further studies in larger study populations are required to verify these results.

U.S. FDA Approved Drugs from 2015–June 2020: A Perspective

“…One of the challenges with clinical DDI studies that are performed regularly during the new drug development is their inability to decipher all the potential DDIs because of polymorphism of drug-metabolizing enzymes, genetic variations among populations, patient-to-patient variability due to altered physiology, and so on. Terfenadine and cisapride are examples of victims that were withdrawn from the market postapproval due to significant DDIs. , The classical anticoagulant warfarin is another example of a victim, which is reported to have severe interactions with multiple marketed drugs …”

“…216,217 The classical anticoagulant warfarin is another example of a victim, which is reported to have severe interactions with multiple marketed drugs. 218…”

Drug Interactions Affecting Oral Anticoagulant Use

“…Many psychotropic drugs can interact with warfarin. 19,[63][64][65][66][67][68][69][70][71][72][73][74][75] Two older antiepileptic medications, carbamazepine and phenytoin, are known inducers of multiple CYP 450; carbamazepine decreased mean INR levels by 0.63 and, in a large retrospective cohort study, patients already taking warfarin required a 50% increase in warfarin maintenance dose after initiation of carbamazepine. 69,70 Phenytoin exerts a biphasic interaction with warfarin.…”

“…83 Nonsteroidal Anti-Inflammatory Drugs Nonsteroidal anti-inflammatory drugs (NSAID) potentiate the risk of bleeding with warfarin. 14,19,87,88 This increased risk of bleeding is present for nonselective COX (cyclooxygenase) as well as COX-2 selective inhibitor NSAIDs. 14,88 The nature of this interaction extends beyond purely a pharmacological interaction, but comprises a pharmacokinetic component as well, likely involving displacement of warfarin from plasma proteins.…”

“…When warfarin is initiated in the setting of a CYP2C9 inhibitor, as is estimated to occur 20% of the time, a patient may not develop a supratherapeutic international normalized ratio (INR) because monitoring is more frequent during the initiation phase of warfarin. 19,20 However, if the same precipitant drug is initiated in the setting of chronic and stable warfarin therapy, then the patient may develop an elevated INR if the interaction goes unrecognized and more frequent INR monitoring is not performed. Figure 2 depicts a simple algorithm clinicians can use to screen and manage drug interactions with warfarin use.…”