Risk of intracranial haemorrhage in antidepressant users with concurrent use of non-steroidal anti-inflammatory drugs: nationwide propensity score matched study
BMJ 2015; 351 doi: https://doi.org/10.1136/bmj.h3517 (Published 14 July 2015) Cite this as: BMJ 2015;351:h3517
All rapid responses
At the time of my spontaneous SAH, the connection between NSAIDS and SSRIs was not known to my brain surgeon. I was 61 yrs. old with no history of stroke, HBP, heart problems, etc. I spent 3 days in ICU and the doctors told my husband my chances were 50/50. I had used NSAIDS approximately every other day at the normal dose for many years due to chronic osteoarthritis. I was also on Lexapro and had been on one SSRI or another for many years also. Many CAT scans and MRIs did not find anything surgical (aneurysm or AV malformation) so my brain surgeon blamed the NSAIDS and told me to never take them again. The article tends to find that no extra caution should be necessary in patients taking both SSRIs and NSAIDS but I disagree. I am now 65 yrs. old. I have to admit I am not thrilled to be taking 1/2 Norco (5mg./325mg.) for pain these days but I have little choice. Other than getting headaches when I drink caffeine, I have no aftereffects from the SAH but I assume I am lucky.
I live in Southern California and was born here.
Thank You.
Competing interests: No competing interests
Serotonin enhances platelet aggregation and since platelets cannot synthesize serotonin, transporter-mediated uptake from blood is required for maintenance of normal intra-platelet serotonin concentrations. Inhibition of this uptake of serotonin, by antidepressants that have effect on serotonin concentration, is thought to lead to a gradual depletion of platelet serotonin and consequently, to impaired platelet aggregation.1
Only antidepressants that have effect on serotonin concentrations (TCA, SSRI, SNRI) were analyzed separately in this study. It would be interesting to see the analysis of antidepressants that do not have an effect on serotonin concentrations because all antidepressants were included in a study and the conclusion was drawn from antidepressants in general.
Results of this study should be interpreted with great caution in clinical practice. One of the reasons is a widespread use of NSAIDs in OTC setting that hasn’t been documented in a study. Many NSAIDs are OTC products that can be bought without prescription and could possibly have an impact on a study's results.
Also, some of the results of the analysis of subpopulations do not speak in favor of evidence of correlation between the increase of intracranial hemorrhage and concomitant use of antidepressant and NSAIDs. In a population where we can expect chronic use of NSAIDs (rheumatoid arthritis), the risk of intracranial hemorrhage was significantly statistically reduced (0,2 CI 95% 0.18 to 0.25, p-0.01). While in a population in which the use of NSAIDs should be avoided, or at least used minimally (heart failure), we have a tendency to an increase in risk of intracranial hemorrhage (9,9 CI 95% 8.30 to 11.68, p-0.071). Surprisingly, in populations where we could expect an increased risk of hemorrhage by synergistic effect of mechanism of action (effect on platelets), risk was significantly reduced (platelet aggregation inhibitors, 0.7 CI 95% 0.59 to 0.84, p- 0.0026) according to statistics.
Because of all of the above mentioned factors, in my opinion, more evidence is needed for establishing a clear connection, which could consequently have clinical implications, between the use of antidepressant concomitantly with NSAIDs and increased risk of intracranial hemorrhage.
References:
1 Turner MS, May DB, Arthur RR, Xiong GL. Clinical impact of selective serotonin reuptake inhibitors therapy with bleeding risks. J Intern Med. 2007;261(3):205-13
Competing interests: No competing interests
The study conducted by Shin JY et al. 1, in which the authors report an increased risk of intracranial haemorrhage associated to the combined use (within 30 days) of antidepressants and non-steroidal anti-inflammatory drugs (NSAIDS) makes an important contribution to clinical practice. The authors carefully identified the different classes of antidepressants and found no statistically significant differences in risk of intracranial haemorrhage between the antidepressant drug classes. The authors, however, did not look at the interaction with the different types of NSAIDS, which include nonselective inhibitor of cyclooxygenase 1 and 2 (COX-1 and 2) and selective inhibitor of cyclooxygenase 2 (COX-2).2 In a large retrospective cohort study conducted in Australia, Caughey et al. 3 found that the use of any NSAID almost doubled the risk of any stroke (adjusted sequence ratio (ASR) of 1.88 (95%CI, 1.70-2.08), increasing the risk of ischemic (ASR1.90; 95% CI, 1.65–2.18) and hemorrhagic stroke (ASR, 2.19, 95% CI, 1.74–2.77).3 All non-selective NSAIDs except ibuprofen were associated with an increased risk for hemorrhagic stroke, and the risk following the use of selective inhibitor COX-2 ranged from 1.81 times for celecoxib (95% CI, 1.34–2.45) to 2.40 times for rofecoxib (95% CI, 1.77–3.26).3 The COX-2 inhibitors were developed to reduce gastrointestinal adverse events, increasing tolerability. However, some COX-2 inhibitors, i.e. rofecoxib and valdecoxib, have not been commercialized worldwide due to increasing the risk of adverse cardiovascular events, but others such as celecoxib and etoricoxib are still available in several countries.4,5 We value the authors’ contribution and suggest that future well-designed and high-quality cohort studies and clinical trials targeting the effects of different NSAIDS in respect of COX selectivity on the risk of intracranial haemorrhage in antidepressant users are warranted in order to better understand the mechanisms and the associated risk of the concomitant use of these two classes of drugs.
References:
1. Shin JY, Park MJ, Lee SH, Choi SH, Kim MH, Choi NK, Lee J, Park BJ. Risk of intracranial haemorrhage in antidepressant users with concurrent use of non-steroidal anti-inflammatory drugs: nationwide propensity score matched study. BMJ. 2015;351:h3517.
2. Bruno A, Tacconelli S, Patrignani P. Variability in the response to non-steroidal anti-inflammatory drugs: mechanisms and perspectives. Basic Clin Pharmacol Toxicol. 2014 Jan;114(1):56-63.
3. Caughey GE, Roughead EE, Pratt N, Killer G, Gilbert AL. Stroke risk and
NSAIDs: an Australian population-based study. Med J Aust. 2011 Nov
7;195(9):525-9.
4. Drazen JM. COX-2 inhibitors--a lesson in unexpected problems. N Engl J Med. 2005;352(11):1131-2.
5. Miao XP, Li JS, Ouyang Q, Hu RW, Zhang Y, Li HY. Tolerability of selective cyclooxygenase 2 inhibitors used for the treatment of rheumatological manifestations of inflammatory bowel disease. Cochrane Database Syst Rev. 2014;10:CD007744.
Competing interests: No competing interests
Re: Risk of intracranial haemorrhage in antidepressant users with concurrent use of non-steroidal anti-inflammatory drugs: nationwide propensity score matched study
An extensive systematic review and meta-analysis of previous research studies from 1960 to 2017, totalling 4,844,090 patient-years of follow-up, found that selective serotonin reuptake inhibitors (SSRIs) increased haemorrhagic stroke. [1]
Even without concurrent use of non-steroidal anti-inflammatory drugs, administering second generation antidepressants could increase the risk of intracranial haemorrhage.
Reference
[1] https://journals.sagepub.com/doi/10.1177/2396987319827211
Competing interests: No competing interests