ICH Risk With Concurrent Use of Antidepressants and NSAIDs
ICH Risk With Concurrent Use of Antidepressants and NSAIDs
In this population based cohort study, we evaluated the association between the combined use of antidepressants and NSAIDs, compared with the use of antidepressants alone, and the risk of intracranial haemorrhage. Compared with the use of antidepressants alone, the combined use of antidepressants and NSAIDs was associated with an increased risk of intracranial haemorrhage.
These results are in line with those of a nested case-control study of the risk of intracranial haemorrhage in users of selective serotonin reuptake inhibitors, which found a trend towards an increased risk of intracranial haemorrhage in people with current exposure to both selective serotonin reuptake inhibitors and NSAIDs. The odds ratio of intracranial haemorrhage for current use of selective serotonin reuptake inhibitors and never use of NSAIDs was 0.7 (95% confidence interval 0.3 to 1.7) and the odds ratio for current use of both drug types was 2.4 (0.9 to 6.2), compared with never use of either drug type. Our study included all the classes of antidepressants, and we found no difference between them.
Advancing age and antithrombotic agents are well known risk factors for intracranial haemorrhage, but the hazard ratio for intracranial haemorrhage associated with the combined use of antidepressants and NSAIDs did not differ significantly in the patients who used antithrombotic agents or in older patients. The combined use of antidepressants and NSAIDs seems not to have had a major effect on patients who already had risk factors for intracranial haemorrhage. However, male sex was the most common risk factor for a higher hazard ratio for intracranial haemorrhage with combined use of antidepressants and NSAIDs. We verified our study design by including myocardial infarction, which is not related to bleeding. The endpoint not related to bleeding did not increase the risk of intracranial haemorrhage compared with the endpoints related to bleeding (hazard ratio 0.9, 0.65 to 1.32). Our results showed that the study design was adequate to detect the increase in risk of bleeding with combined use of antidepressant and NSAIDs (data not shown).
Antidepressants, particularly selective serotonin reuptake inhibitors, block platelet uptake, and use of these agents results in bleeding complications. NSAIDs are also known to inhibit normal platelet function. However, a previous population based study did not find a significant association of use of each drug with intracranial haemorrhage. Our study found the additional effect according to the drug-drug interaction based on the population based data. Serotonin-norepinephrine reuptake inhibitors work by inhibiting the reuptake of not only serotonin but also norepinephrine. Elevation of norepinephrine concentrations may be associated with an increased risk of intracranial haemorrhage. A high risk with venlafaxine was reported by De Abajo and Garcia-Rodriguez, who estimated the risk of upper gastrointestinal tract bleeding. This may be because, as they noted, venlafaxine has a lower affinity for the serotonin receptor than do most selective serotonin reuptake inhibitors, but to compensate for its lower potency in vitro, a threefold to sevenfold greater daily dose is usually prescribed.
To the best of our knowledge, this is the first population based cohort study focusing on the risk of intracranial haemorrhage associated with the combined use of antidepressants and NSAIDs. Most existing studies have been case-control studies and have focused on abnormal bleeding risk from selective serotonin reuptake inhibitors. This study included all antidepressant prescriptions in Korea during a five year period. We focused on changes in risk due to addition of NSAIDs to antidepressants, which could provide information about drug interaction.
Our finding should be interpreted with caution. This study has potential inaccuracy of coding and incompleteness of records. The outcome measures were also limited to patients admitted to hospital with intracranial haemorrhage, which does not capture events outside hospital. However, patients with fatal events are likely to be in hospital, which minimises the possibility of us missing fatal cases. A validation study compared the diagnosis derived from the Health Insurance Review and Assessment Service database with the actual diagnosis in patients' medical records in Korea. The overall positive predictive value of the diagnoses was 83.4% in the case of patients admitted to hospital. Computed tomography and magnetic resonance imaging are routinely used in the diagnosis of intracranial haemorrhage, and a radiologist's reading is required for insurance claims in Korea. According to a nationwide survey of 152 representative hospitals, computed tomography or magnetic resonance imaging was used in 89% of hospital admissions for intracranial haemorrhage. Agreement on diagnosis of intracranial haemorrhage is generally high in Korea and in other countries. We defined death by ICD-10 codes (I46.1, I46.9, R96, R98, and R99) without further records after the date of coding.
Our findings are subject to selection bias and confounding with respect to the relative difference in the baseline for the risk of intracranial haemorrhage between the comparison groups. However, we used propensity score matching, which should eliminate a greater proportion of the baseline differences than would stratification or covariate adjustment. Although we used a propensity score matched design, this does not preclude findings being influenced by potential confounders. Hidden bias may remain because of the influence of unmeasured confounders.
The addition of NSAIDs to antidepressant treatment increased the risk of intracranial haemorrhage within 30 days of the combination starting, especially in men. This result adds to evidence confirming the increase of risk with combination use of antidepressants and NSAIDs. Special attention is needed when patients use both these drugs together.
Discussion
In this population based cohort study, we evaluated the association between the combined use of antidepressants and NSAIDs, compared with the use of antidepressants alone, and the risk of intracranial haemorrhage. Compared with the use of antidepressants alone, the combined use of antidepressants and NSAIDs was associated with an increased risk of intracranial haemorrhage.
Comparison With Other Studies
These results are in line with those of a nested case-control study of the risk of intracranial haemorrhage in users of selective serotonin reuptake inhibitors, which found a trend towards an increased risk of intracranial haemorrhage in people with current exposure to both selective serotonin reuptake inhibitors and NSAIDs. The odds ratio of intracranial haemorrhage for current use of selective serotonin reuptake inhibitors and never use of NSAIDs was 0.7 (95% confidence interval 0.3 to 1.7) and the odds ratio for current use of both drug types was 2.4 (0.9 to 6.2), compared with never use of either drug type. Our study included all the classes of antidepressants, and we found no difference between them.
Advancing age and antithrombotic agents are well known risk factors for intracranial haemorrhage, but the hazard ratio for intracranial haemorrhage associated with the combined use of antidepressants and NSAIDs did not differ significantly in the patients who used antithrombotic agents or in older patients. The combined use of antidepressants and NSAIDs seems not to have had a major effect on patients who already had risk factors for intracranial haemorrhage. However, male sex was the most common risk factor for a higher hazard ratio for intracranial haemorrhage with combined use of antidepressants and NSAIDs. We verified our study design by including myocardial infarction, which is not related to bleeding. The endpoint not related to bleeding did not increase the risk of intracranial haemorrhage compared with the endpoints related to bleeding (hazard ratio 0.9, 0.65 to 1.32). Our results showed that the study design was adequate to detect the increase in risk of bleeding with combined use of antidepressant and NSAIDs (data not shown).
Antidepressants, particularly selective serotonin reuptake inhibitors, block platelet uptake, and use of these agents results in bleeding complications. NSAIDs are also known to inhibit normal platelet function. However, a previous population based study did not find a significant association of use of each drug with intracranial haemorrhage. Our study found the additional effect according to the drug-drug interaction based on the population based data. Serotonin-norepinephrine reuptake inhibitors work by inhibiting the reuptake of not only serotonin but also norepinephrine. Elevation of norepinephrine concentrations may be associated with an increased risk of intracranial haemorrhage. A high risk with venlafaxine was reported by De Abajo and Garcia-Rodriguez, who estimated the risk of upper gastrointestinal tract bleeding. This may be because, as they noted, venlafaxine has a lower affinity for the serotonin receptor than do most selective serotonin reuptake inhibitors, but to compensate for its lower potency in vitro, a threefold to sevenfold greater daily dose is usually prescribed.
To the best of our knowledge, this is the first population based cohort study focusing on the risk of intracranial haemorrhage associated with the combined use of antidepressants and NSAIDs. Most existing studies have been case-control studies and have focused on abnormal bleeding risk from selective serotonin reuptake inhibitors. This study included all antidepressant prescriptions in Korea during a five year period. We focused on changes in risk due to addition of NSAIDs to antidepressants, which could provide information about drug interaction.
Strengths and Limitations of Study
Our finding should be interpreted with caution. This study has potential inaccuracy of coding and incompleteness of records. The outcome measures were also limited to patients admitted to hospital with intracranial haemorrhage, which does not capture events outside hospital. However, patients with fatal events are likely to be in hospital, which minimises the possibility of us missing fatal cases. A validation study compared the diagnosis derived from the Health Insurance Review and Assessment Service database with the actual diagnosis in patients' medical records in Korea. The overall positive predictive value of the diagnoses was 83.4% in the case of patients admitted to hospital. Computed tomography and magnetic resonance imaging are routinely used in the diagnosis of intracranial haemorrhage, and a radiologist's reading is required for insurance claims in Korea. According to a nationwide survey of 152 representative hospitals, computed tomography or magnetic resonance imaging was used in 89% of hospital admissions for intracranial haemorrhage. Agreement on diagnosis of intracranial haemorrhage is generally high in Korea and in other countries. We defined death by ICD-10 codes (I46.1, I46.9, R96, R98, and R99) without further records after the date of coding.
Our findings are subject to selection bias and confounding with respect to the relative difference in the baseline for the risk of intracranial haemorrhage between the comparison groups. However, we used propensity score matching, which should eliminate a greater proportion of the baseline differences than would stratification or covariate adjustment. Although we used a propensity score matched design, this does not preclude findings being influenced by potential confounders. Hidden bias may remain because of the influence of unmeasured confounders.
Conclusion
The addition of NSAIDs to antidepressant treatment increased the risk of intracranial haemorrhage within 30 days of the combination starting, especially in men. This result adds to evidence confirming the increase of risk with combination use of antidepressants and NSAIDs. Special attention is needed when patients use both these drugs together.
