Population Impact of Drug Interactions with Warfarin: A Real-World Data Approach

Mar Martín-Pérez, David Gaist, Francisco J de Abajo, Luis A García Rodríguez

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

OBJECTIVE:  To investigate the population impact of previously reported interactions between warfarin and other drugs on international normalized ratio (INR) levels.

METHODS:  Using The Health Improvement Network (THIN), a United Kingdom primary care database, a cohort of warfarin users between 2005 and 2013 (N = 121,962) was followed until the first qualifying prescription for the potential interacting drugs was evaluated. Sixteen sub-cohorts, one for each study drug, and a control sub-cohort of warfarin were ascertained. Short-term changes in INR levels were assessed by comparing INR values measured before and after initiation of the interacting drug with paired Student's t-test. We also evaluated the proportion of patients with INR values outside the therapeutic range (INR: 2-3).

RESULTS:  Miconazole use was associated with the highest mean increase in INR (+3.35), followed by amiodarone (+1.28), fluconazole (+0.79), metronidazole (+0.75) and nystatin (+0.65). After subtracting the natural INR variation observed in the control sub-cohort, supra-therapeutic levels (INR > 3) were found in 53.2% (miconazole), 45.5% (amiodarone), 23.3% (metronidazole), 23.2% (fluconazole) and 17.6% (nystatin) of patients initiating treatment with these drugs. Carbamazepine use was associated with a mean INR decrease of -0.63 and infra-therapeutic levels (INR < 2) were observed in 46.2% of patients initiating carbamazepine. For all other drugs, the change was small to moderate, in absolute INR units (+0.23 to +0.55) and in the proportion of patients with INR levels out of therapeutic range (<16%).

CONCLUSIONS:  Clinically potentially important interactions were observed in several study drugs. The majority of them, although confirmed, had little impact after adjusting for standard INR variability in the general population of warfarin users.

Original languageEnglish
JournalThrombosis and Haemostasis
Volume118
Issue number3
Pages (from-to)461-470
ISSN0340-6245
DOIs
Publication statusPublished - Mar 2018

Fingerprint

International Normalized Ratio
Warfarin
Drug Interactions
Population
Pharmaceutical Preparations
Miconazole
Nystatin
Amiodarone
Fluconazole
Metronidazole
Drug and Narcotic Control
Prescriptions
Primary Health Care

Keywords

  • Journal Article
  • database
  • drug interactions
  • INR
  • anticoagulant drugs
  • warfarin
  • Fluconazole/administration & dosage
  • Follow-Up Studies
  • Humans
  • Middle Aged
  • Male
  • Nystatin/administration & dosage
  • Anticoagulants/administration & dosage
  • Young Adult
  • Drug Interactions
  • Aged, 80 and over
  • Adult
  • Female
  • Retrospective Studies
  • Databases, Factual
  • Miconazole/administration & dosage
  • Carbamazepine/administration & dosage
  • United Kingdom
  • International Normalized Ratio
  • Adolescent
  • Aged
  • Primary Health Care
  • Warfarin/therapeutic use
  • Amiodarone/administration & dosage

Cite this

Martín-Pérez, Mar ; Gaist, David ; de Abajo, Francisco J ; Rodríguez, Luis A García. / Population Impact of Drug Interactions with Warfarin : A Real-World Data Approach. In: Thrombosis and Haemostasis. 2018 ; Vol. 118, No. 3. pp. 461-470.
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title = "Population Impact of Drug Interactions with Warfarin: A Real-World Data Approach",
abstract = "OBJECTIVE:  To investigate the population impact of previously reported interactions between warfarin and other drugs on international normalized ratio (INR) levels.METHODS:  Using The Health Improvement Network (THIN), a United Kingdom primary care database, a cohort of warfarin users between 2005 and 2013 (N = 121,962) was followed until the first qualifying prescription for the potential interacting drugs was evaluated. Sixteen sub-cohorts, one for each study drug, and a control sub-cohort of warfarin were ascertained. Short-term changes in INR levels were assessed by comparing INR values measured before and after initiation of the interacting drug with paired Student's t-test. We also evaluated the proportion of patients with INR values outside the therapeutic range (INR: 2-3).RESULTS:  Miconazole use was associated with the highest mean increase in INR (+3.35), followed by amiodarone (+1.28), fluconazole (+0.79), metronidazole (+0.75) and nystatin (+0.65). After subtracting the natural INR variation observed in the control sub-cohort, supra-therapeutic levels (INR > 3) were found in 53.2{\%} (miconazole), 45.5{\%} (amiodarone), 23.3{\%} (metronidazole), 23.2{\%} (fluconazole) and 17.6{\%} (nystatin) of patients initiating treatment with these drugs. Carbamazepine use was associated with a mean INR decrease of -0.63 and infra-therapeutic levels (INR < 2) were observed in 46.2{\%} of patients initiating carbamazepine. For all other drugs, the change was small to moderate, in absolute INR units (+0.23 to +0.55) and in the proportion of patients with INR levels out of therapeutic range (<16{\%}).CONCLUSIONS:  Clinically potentially important interactions were observed in several study drugs. The majority of them, although confirmed, had little impact after adjusting for standard INR variability in the general population of warfarin users.",
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Population Impact of Drug Interactions with Warfarin : A Real-World Data Approach. / Martín-Pérez, Mar; Gaist, David; de Abajo, Francisco J; Rodríguez, Luis A García.

In: Thrombosis and Haemostasis, Vol. 118, No. 3, 03.2018, p. 461-470.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - Population Impact of Drug Interactions with Warfarin

T2 - A Real-World Data Approach

AU - Martín-Pérez, Mar

AU - Gaist, David

AU - de Abajo, Francisco J

AU - Rodríguez, Luis A García

N1 - Schattauer GmbH Stuttgart.

PY - 2018/3

Y1 - 2018/3

N2 - OBJECTIVE:  To investigate the population impact of previously reported interactions between warfarin and other drugs on international normalized ratio (INR) levels.METHODS:  Using The Health Improvement Network (THIN), a United Kingdom primary care database, a cohort of warfarin users between 2005 and 2013 (N = 121,962) was followed until the first qualifying prescription for the potential interacting drugs was evaluated. Sixteen sub-cohorts, one for each study drug, and a control sub-cohort of warfarin were ascertained. Short-term changes in INR levels were assessed by comparing INR values measured before and after initiation of the interacting drug with paired Student's t-test. We also evaluated the proportion of patients with INR values outside the therapeutic range (INR: 2-3).RESULTS:  Miconazole use was associated with the highest mean increase in INR (+3.35), followed by amiodarone (+1.28), fluconazole (+0.79), metronidazole (+0.75) and nystatin (+0.65). After subtracting the natural INR variation observed in the control sub-cohort, supra-therapeutic levels (INR > 3) were found in 53.2% (miconazole), 45.5% (amiodarone), 23.3% (metronidazole), 23.2% (fluconazole) and 17.6% (nystatin) of patients initiating treatment with these drugs. Carbamazepine use was associated with a mean INR decrease of -0.63 and infra-therapeutic levels (INR < 2) were observed in 46.2% of patients initiating carbamazepine. For all other drugs, the change was small to moderate, in absolute INR units (+0.23 to +0.55) and in the proportion of patients with INR levels out of therapeutic range (<16%).CONCLUSIONS:  Clinically potentially important interactions were observed in several study drugs. The majority of them, although confirmed, had little impact after adjusting for standard INR variability in the general population of warfarin users.

AB - OBJECTIVE:  To investigate the population impact of previously reported interactions between warfarin and other drugs on international normalized ratio (INR) levels.METHODS:  Using The Health Improvement Network (THIN), a United Kingdom primary care database, a cohort of warfarin users between 2005 and 2013 (N = 121,962) was followed until the first qualifying prescription for the potential interacting drugs was evaluated. Sixteen sub-cohorts, one for each study drug, and a control sub-cohort of warfarin were ascertained. Short-term changes in INR levels were assessed by comparing INR values measured before and after initiation of the interacting drug with paired Student's t-test. We also evaluated the proportion of patients with INR values outside the therapeutic range (INR: 2-3).RESULTS:  Miconazole use was associated with the highest mean increase in INR (+3.35), followed by amiodarone (+1.28), fluconazole (+0.79), metronidazole (+0.75) and nystatin (+0.65). After subtracting the natural INR variation observed in the control sub-cohort, supra-therapeutic levels (INR > 3) were found in 53.2% (miconazole), 45.5% (amiodarone), 23.3% (metronidazole), 23.2% (fluconazole) and 17.6% (nystatin) of patients initiating treatment with these drugs. Carbamazepine use was associated with a mean INR decrease of -0.63 and infra-therapeutic levels (INR < 2) were observed in 46.2% of patients initiating carbamazepine. For all other drugs, the change was small to moderate, in absolute INR units (+0.23 to +0.55) and in the proportion of patients with INR levels out of therapeutic range (<16%).CONCLUSIONS:  Clinically potentially important interactions were observed in several study drugs. The majority of them, although confirmed, had little impact after adjusting for standard INR variability in the general population of warfarin users.

KW - Journal Article

KW - database

KW - drug interactions

KW - INR

KW - anticoagulant drugs

KW - warfarin

KW - Fluconazole/administration & dosage

KW - Follow-Up Studies

KW - Humans

KW - Middle Aged

KW - Male

KW - Nystatin/administration & dosage

KW - Anticoagulants/administration & dosage

KW - Young Adult

KW - Drug Interactions

KW - Aged, 80 and over

KW - Adult

KW - Female

KW - Retrospective Studies

KW - Databases, Factual

KW - Miconazole/administration & dosage

KW - Carbamazepine/administration & dosage

KW - United Kingdom

KW - International Normalized Ratio

KW - Adolescent

KW - Aged

KW - Primary Health Care

KW - Warfarin/therapeutic use

KW - Amiodarone/administration & dosage

U2 - 10.1055/s-0038-1627100

DO - 10.1055/s-0038-1627100

M3 - Journal article

C2 - 29433149

VL - 118

SP - 461

EP - 470

JO - Thrombosis and Haemostasis

JF - Thrombosis and Haemostasis

SN - 0340-6245

IS - 3

ER -