Background: Interaction between proton pump inhibitors (PPI) and warfarin is controversial. Previous clinical studies have only a short follow-up period. Methods and Results: All patients (n = 716) for whom warfarin was prescribed from November 1, 2010 to October 30, 2011 were extracted from electronic health records. In retrospective analysis for 1 year, PPI were prescribed to 404 patients. Among them, 108 patients were taking warfarin for more than 6 weeks before and after PPI. The profile of these patients was analyzed: 63 patients took lansoprazole; 15 patients took omeprazole; 30 patients took rabeprazole. No statistical difference was observed among 3 groups in age, body weight, concomitant use of other drugs, and comorbidity. Warfarin dose and INR did not change after PPI. Multivariate stepwise logistic regression analysis revealed that upper quartile of increment of INR was associated with the presence of atrial fibrillation (OR 3.77, 95% CI 1.16 - 12.27). The patients who had warfarin for shorter periods before PPI, or those who had PPI first (n = 141) had similar dose of warfarin and INR. In all patients analyzed (n = 404), including patients whose follow-up periods were shorter than 6 weeks (n = 155), a patient had cerebral bleeding, and 2 patients had cerebral infarction. Conclusions: Unfavorable interaction between warfarin and PPI was negligible in clinical use. Relatively higher INR was achieved after PPI in the presence of atrial fibrillation.
Atrial fibrillation is a major cause of systemic embolism, which often results in cerebral infarction with severe sequelae [
Drug interaction of warfarin and PPI is a very important issue, because warfarin inhibits competitively the metabolic enzymes of PPI for their degradation [
We studied the interaction of warfarin and 3 PPI by the retrospective observation for relatively long-term.
All patients who received warfarin and one of PPI from November 1, 2010 to October 30, 2011 were extracted from the electrical health records in our institution (n = 716).
Main analysis was performed using the data of the patients who received warfarin more than 6 weeks before the initial administration of a PPI. Information on demographic data, underlying disease, NSAIDS and/or anti- platelet drug use, time course of warfarin dose and prothrombin time (INR), complications were collected, dividing into 3 drug groups of PPI (lansoprazole, omeprazole, rabeprazole). The other PPI were not included because they were not available in Japan during the study period. A linear logistic regression analysis was done to find factors that affected the warfarin effects.
A supplementary analysis was also done for the patients who received warfarin first but equal to or less than 6 weeks prior to PPI administration, and the patients who received PPI first (n = 141). Mean warfarin dose and INR was calculated for these patients. Because warfarin dose could be adjusted along with the time course in the presence of PPI, they were excluded from a logistic regression analysis for the factors affecting warfarin dose and INR.
Only side effects were studied for the patients who received warfarin and PPI for less than 6 weeks (n = 155). The patients who did not receive warfarin and PPI simultaneously were excluded from the analysis (n = 312).
Data are shown as mean ± SD in the text, and median (the first and the third quartile) in some figures. Statistical analysis was performed using ANOVA for the difference of demographic data among 3 groups, Friedman test for the time-course of warfarin dose and INR within the same PPI group, Kruskal-Wallis test for the comparison among 3 groups during the time course. Chi-square test was performed when appropriate. Univariate and multivariate logistic regression analysis was performed for the main analysis to find out the factors that affected an anti-thrombotic effect of warfarin. P < 0.05 was considered statistically significant. Confidential intervals were shown in the presentation of odds ratio. The protocol of this study was approved by the ethics committee of our institution.
The subjects of this analysis were the patients who had a sufficient period of warfarin dose adjustment (>6 weeks) prior to the introduction of PPI (n = 108).
Time-course of prothrombin time (INR) before and after PPI introduction was shown in
. Comparison of patients’ characteristics
Lansoprazole | Omeprazole | Rabeprazole | P value* | |
---|---|---|---|---|
Patient number | 63 | 15 | 30 | |
Age (years old) | 71.2 ± 11.3 | 74.1 ± 8.9 | 71.0 ± 12.1 | 0.6420 |
Body weight (kg) | 60.0 ± 12.1 | 63.5 ± 15.4 | 60.5 ± 12.5 | 0.6310 |
Male [%] | 40 [63.5] | 10 [66.7] | 24 [80.0] | 0.2732 |
Atrial fibrillation [%] | 37 [58.7] | 8 [53.3] | 14 [6.7] | 0.5474 |
Ventricular tachycardia [%] | 11 [17.5] | 3 [20.0] | 6 [20.0] | 0.9454 |
Valvular heart disease [%] | 16 [25.4] | 4 [26.7] | 6 [20.0] | 0.8237 |
Cardiac valve replacement [%] | 8 [12.7] | 3 [20.0] | 5 [16.7] | 0.7317 |
Cardiomyopathy [%] | 7 [11.1] | 0 [0] | 2 [6.7] | 0.3484 |
Myocardial infarction [%] | 17 [27.0] | 5 [33.3] | 6 [20.0] | 0.6023 |
Angina pectoris [%] | 6 [9.5] | 0 [0] | 4 [13.3] | 0.3450 |
Amiodarone [%] | 3 [4.8] | 0 [0] | 2 [6.7] | 0.6027 |
Antiplatelet [%] | 11 [17.5] | 2 [13.3] | 7 [23.3] | 0.6788 |
Aspirin [%] | 27 [42.9] | 6 [40.0] | 11 [36.7] | 0.8494 |
NSAIDS [%] | 11 [17.5] | 2 [13.3] | 4 [13.3] | 0.8449 |
P-value*: Chi-square test or Kruskal-Wallis test.
Changes in INR before and after PPI: The average INR were plotted against time-course of each PPI group. At the week 0, PPI was introduced to the patient. No significant changes were observed in all groups
did not change INR during the treatment in 3 groups.
Dose adjustment of warfarin was shown in
Visit-to-visit changes of INR after the introduction of PPI are shown in
There was a tendency that the changes were greater in lansoprazole group, but the difference was less than 50%. There was no statistical difference among 3 groups.
Maximal change of INR in each patient after the introduction of PPI was shown in
Changes in warfarin dose before and after PPI: The average doses of warfarin were plotted against time-course of each PPI group, as shown in Figure 1. Dose was not changed after PPI introduction
Visit-to-visit INR variability: The range of INR variability of each patient was evaluated as standard deviation over mean INR. Variability was not different in all groups
Maximum change of INR after PPI introduction: The maximum change of INR during follow-up period after PPI introduction was compared among each PPI group. There was no significant difference among 3 groups
Percentage of the patients who was in the upper quartile of INR increase: Some patients showed relatively large increase of INR after the introduction of PPI. When the patients showed >0.690 increase of INR, they were in the upper-most quarter of all study population. The distribution of these patients in each PPI group is shown in the figure. INR of the patients in the labeprezole group tended to increase larger than INR in other groups, but it was not significant
Univariate logistic regression analysis was performed to find the conditions that could affect the INR increase (
Analysis was done for the patients for whom the add-on effects of PPI to warfarin could not be evaluated because of the short period (<6 weeks) before PPI introduction or the presence of PPI administration before warfarin. Eighty (80) patients for lansoprazole, 22 patients for opmeprazole and 39 patients for rabeprazole were identified for this analysis. The average INR was 1.84 ± 0.42 for lansoprazole group, 1.80 ± 0.36 for omeprazole
. Univariate logistic regression analysis
Variable | Odds ratio | 95% CI | P-value |
---|---|---|---|
Age | 1.0078 | 0.9605 - 1.0575 | 0.7511 |
Gender [male vs female] | 1.0000 | 0.3225 - 3.1006 | 0.9923 |
Atrial fibrillation | 3.7692 | 1.1579 - 12.2702 | 0.0227 |
Ventricular tachycardia | 0.7187 | 0.1447 - 3.5689 | 0.6863 |
Valvular heart disease | 1.0000 | 0.3109 - 3.2163 | 0.9943 |
Cardiac valve replacement | 2.0125 | 0.5130 - 7.8951 | 0.3159 |
Cardiomyopathy | 1.8182 | 0.3883 - 8.5140 | 0.4415 |
Myocardial infarction | 1.3068 | 0.3100 - 5.5095 | 0.7148 |
Angina pectoris | 1.0250 | 0.9611 - 1.0931 | 0.4522 |
Amiodarone | 0.4808 | 0.0410 - 5.6413 | 0.5599 |
Antiplatelet | 0.3520 | 0.0620 - 1.9996 | 0.2387 |
Aspirin | 1.3750 | 0.4537 - 4.1676 | 0.5735 |
NSAIDS | 1.0000 | 0.2228 - 4.4889 | 0.9921 |
Lansoprazole vs other PPI | 1.1875 | 0.3760 - 3.7506 | 0.7696 |
Dependent variable = upper quartile (75th) of INR increment >0.690.
. Multivarite logistic regression analysis
Variable | Odds ratio | 95% CI | P-value |
---|---|---|---|
Age | 0.9961 | 0.9305 - 1.0662 | 0.9095 |
Gender [male vs female] | 1.0915 | 0.2306 - 5.1675 | 0.9121 |
Atrial fibrillation | 15.1362 | 1.5243 - 150.3010 | 0.0202 |
Ventricular tachycardia | 6.7423 | 0.2719 - 167.1845 | 0.2440 |
Valvular heart disease | 0.4054 | 0.0174 - 9.4225 | 0.5738 |
Cardiac valve replacement | 8.5921 | 0.2555 - 288.9540 | 0.2305 |
Cardiomyopathy | 3.7666 | 0.3353 - 42.3062 | 0.2825 |
Myocardial infarction | 7.4395 | 0.4903 - 112.8927 | 0.1481 |
Angina pectoris | 6.3843 | 0.3530 - 115.4705 | 0.2095 |
Amiodarone | 0.1674 | 0.0065 - 4.3037 | 0.2806 |
Antiplatelet | 0.4582 | 0.0526 - 3.9959 | 0.4800 |
Aspirin | 1.2026 | 0.2372 - 6.0981 | 0.8237 |
NSAIDS | 2.6302 | 0.2860 - 24.1870 | 0.3929 |
Lansoprazole vs other PPI | 1.4527 | 0.2936 - 7.1884 | 0.6471 |
Dependent variable = upper quartile (75th) of INR increment >0.690.
group and 1.88 ± 0.52 for rabeprazole group, respectively. The average dose of warfarin was 2.57 ± 1.35 mg for lansoprazole group, 2.32 ± 0.63 mg for omeprazole group and 2.65 ± 1.54 mg for rabeprazole group, respectively. These numbers are not different from the patients of main analysis. There was no difference among 3 PPI groups.
All ischemic and major bleeding events were investigated in all patients who received warfarin and PPI simultaneously (n = 404). In addition to the patients for the analysis described above, 155 cases who received warfarin and PPI only for a short period (<6 weeks) were included. There were 2 cases of cerebral infarction. Warfarin and omeprazole were started simultaneously for them. Age/INR/warfarin dose were 59 years old/1.48/1.5 mg and 70 years old/1.76/2.75 mg, respectively. A patient had cerebral bleeding after warfarin and lansoprazole were started simultaneously. Age/INR/warfarin dose were 80 years old/2.51/3 mg. The conditions of these patients were not severe and they were treated conservatively.
Proton pump inhibitors (PPI) are metabolized by cytochrome P450. However, metabolic pathways for each PPI are slightly different. Lansoprazole and omeprazole are metabolized mainly by CYP2C19 and partly by CYP3A4 [
This study showed that the use of PPI on top of warfarin did not change anti-coagulation action of warfarin for more than 6 weeks. There was a tendency of slight increase of INR after the addition of PPI, but the difference was small. The fluctuation of anti-coagulation action was also small enough to require special attention in clinical situations. The difference among 3 PPIs were not discernible. These observations were the case when we looked at the patients who had PPI first. The average dose of warfarin and INR were not different from those of the patients who had warfarin first.
In some cases, the anti-coagulation effect of warfarin was fluctuated [
Cerebrovascular complications occurred in 3 cases among a total of 404 cases during 1 year period in this study. This is a relatively low percentage compared with the other studies [
Major limitation of this study is the fact that this is a retrospective observation. However, we included all patients for the analysis. If PPI had any discernible interactions with warfarin, it should be detected in this study. Indeed, INR was not changed after the introduction of PPI. Physicians could change warfarin dose, but it was not remarkable as shown in
In conclusion, concomitant use of PPI and warfarin is safe and no special attention is required. No dose-ad- justment of warfarin is necessary after the introduction of PPI.
No conflict of interest to be reported.