SSRIs and Bleeding Risk: What Does the Evidence Say?

James L. Levenson, M.D.

Virginia Commonwealth University

Last updated: August 17, 2018

 

  • Do SSRIs increase bleeding risk?
    • There appears to be a small increased risk, but the absolute risk seems to be very small and not clinically significant in most patients.
  • Special caution is warranted in patients who:
    • have thrombocytopenia or platelet disorders,
    • have a coagulopathy or,
    • are taking multiple antiplatelet drugs.

 

 

 

Our next topic, how much risk of bleeding do SSRIs pose?
A recent meta-analysis concluded that the overall bleeding risk  is increased at least a third but with a fairly wide range based on the review of a large number of studies. So we’re going to talk about four different types of bleeding risk and what we know to date regarding SSRIs. Do SSRIs increase the risk for gastrointestinal bleeding, perioperative bleeding, postpartum bleeding and cerebral bleeding or hemorrhagic stroke?

 


So taking first, do SSRIs increase the risk of GI bleeding? There have been many studies but they are all retrospective or cohort studies. They are not randomized controlled trials and the data are very mixed. There have been a number of studies showing a relatively large increase in relative risk, at least a doubling. There are an equal number of studies showing a small increase in relative risk, say 1.3 times the risk of gastrointestinal bleeding in patients not receiving SSRIs. And yet there are an equal number of studies showing no increase risk at all. Fortunately, none of the studies have demonstrated increased mortality from SSRI-associated gastrointestinal bleeds and that’s reassuring. Another conclusion that comes from a review of the literature is that  whatever the risk is with SSRIs for GI bleeding the risk does increase considerably if the patient is taking multiple anti-platelet drugs. So an example would be a patient who following myocardial infarction develops depression and is prescribed in SSRI but is already taking aspirin or another non-steroidal anti-inflammatory drug as well as the anti-platelet agent clopidogrel. The risk of GI bleeding with SSRIs is also increased in patients who are infected with Helicobacter pylori, the bacteria that pose a risk for peptic ulcer disease.

 


There have been a number of meta-analyses that have tried to merge all these data and draw some general conclusions. And what they generally concluded regarding gastrointestinal bleeding is that there probably is a relative increased risk, somewhere between 1 1/2 and double the risk in patients not on SSRIs, that this relative risk is even higher, probably four times, on the order of four times as much if the patient is taking a non-steroidal anti-inflammatory drug or an anti-platelet drug. The risk is not increased if the patient is prospectively treated with an acid suppressant like a PPI or proton pump inhibitor. But the absolute risk of harm from a gastrointestinal bleed is really quite small. The number needed to harm for upper GI bleeding with SSRIs in low-risk patients was 3177 and still as high as 881 in high-risk patients. And I’ll talk in a minute about who are high risk patients. There’s been much less study of SNRIs but the little information we have today suggest they may not increase the risk.

 


What about if SSRIs are given to a patient who is also taking the blood thinner warfarin? Does that increase the risk of GI bleeding? The reports are mixed. I’m reassured that the US Food and Drug Administration does not warn of this interaction. I would avoid prescribing fluvoxamine in a patient on warfarin because fluvoxamine does increase warfarin levels by inhibiting 2D9. But that’s a different mechanism than interfering with platelet function. There appears no increased risk with heparin or enoxaparin. And to date, I have been unable to find any information, any cases of SSRIs causing gastrointestinal bleeding with the newer anticoagulants like etexilate, dabigatran, rivaroxaban and apixaban. And given how often SSRIs are prescribed and the fact that these drugs don’t act via platelets, they probably are safe to administer together.

 


So key points with regard to the risk of gastrointestinal bleeding with SSRIs include there have been many studies, the data vary but there does seem to be a 1 1/2 to doubling increase in the relative risk but the absolute risk of a gastrointestinal hemorrhage remains small. The risk is increased with concomitant nonsteroidal anti-inflammatory drugs. Caution is advised in patients who are taking multiple drugs that have impaired platelets. And what I would call high risk patients are those patients with marked thrombocytopenia, for example, a platelet count under 25,000. Patients with that low a platelet count are at risk for spontaneous bleeding. And I would also urge caution in the prescription of SSRIs in patients who have a normal number of platelets but who have dysfunctional platelets like in the inherited disorder von Willebrand disease. And we should mention that there are rare cases of SSRIs themselves causing thrombocytopenia.

 


Next, let’s review, do SSRIs increase perioperative bleeding? Hereto, the studies are all retrospective. For cohort studies, there are not any randomized controlled trials. And on the slide, I’ve included some exemplary studies. The top half of the slide shows studies that demonstrated varying degrees of increased risk of perioperative bleeding. And the bottom half of the slide shows studies that found there was no increased risk at all. Across all these studies, serious bleeding was quite rare. And because these were not randomized controlled trials, there are many potential confounding factors that make it difficult to interpret. A systematic review of 13 studies concluded that serotonergic antidepressants increase the risk or perioperative bleeding with the odds ratios between 1.2 and 4. But again, the actual amount of blood loss was small. So the bottom line here for perioperative bleeding risk with SSRIs is that there probably is a small increased relative risk. The absolute risk is quite small and it’s unlikely clinically significant except in those high risk patients that I was talking about when we reviewed gastrointestinal bleeding, namely patients with thrombocytopenia, patients with platelet dysfunction or patients on multiple anti-platelet drugs.

 


What do we know about whether SSRIs increase the risk for postpartum bleeding? This has been much less studied. But the few data we have are mixed, both data showing an increased risk and data showing no increased risk. And the systematic review that tried to look at this systematically concluded the same thing that we’re not sure. But just as an illustration of how difficult it can be to interpret such studies, another recent systematic review found that antidepressants were associated with a small increased relative risk but it was unrelated to how much they influence serotonin which tends to suggest that the increased risk may have nothing to do with the antidepressants at all. So bottom line for postpartum bleeding: There are a few data. What data we have point to a small increased relative risk at most and very small absolute risk, unlikely that it’s clinically significant except in high risk patients. We generally do not recommend stopping an SSRI shortly before delivery or caesarean section  because this increases risk for the precipitation of a postpartum depression.

 


Do SSRIs cause central nervous system bleeding, in other words a hemorrhagic stroke? Hereto, the evidence for SSRIs increasing stroke risk is mixed and somewhat difficult to interpret. So one meta-analysis found a small increased risk, 1.4 times the risk in patients who are not taking antidepressants of both ischemic and hemorrhagic stroke. Well, if SSRIs cause hemorrhagic stroke by interfering with platelet function, one would not expect an increase in ischemic stroke. And if anything, one would expect a reduction. Another study found a more than doubling of stroke risk with SSRI. Finally, another study showed that after patients had an ischemic stroke and were started on an SSRI for post stroke depression, they had an increased risk of GI bleeding, no increased risk of intracranial hemorrhage and a reduction in cardiovascular events. One reason for the murkiness in this data, the difficulty interpreting it is that depression and anxiety themselves have been independently associated with risk for hypertension and risk for stroke. And so antidepressants appearing to be associated with an increased risk of stroke may really be a marker for depression and anxiety as the cause of increased risk. Finally, one study showed a very small, that tried a control for this effect of depression and anxiety found a very small relative increased risk with SSRIs versus tricyclics.

 


So to summarize, the overall question of “do SSRIs increase any type of bleeding risk?” there probably is some small increased risk. The absolute risk appears to be very small and not clinically significant in most patients. It’s rarely serious. But caution is warranted in high risk patients,  those with thrombocytopenia or platelet disorders, those with coagulopathy, those who are in the throes of  an acute intracerebral hemorrhage and patients on multiple antiplatelet drugs.

References

  1. Jiang, H. Y., Chen, H. Z., Hu, X. J., Yu, Z. H., Yang, W., Deng, M., … & Ruan, B. (2015). Use of selective serotonin reuptake inhibitors and risk of upper gastrointestinal bleeding: a systematic review and meta-analysis. Clinical Gastroenterology and Hepatology, 13(1), 42-50.
  2. Anglin, R., Yuan, Y., et al (2014). Risk of upper gastrointestinal bleeding with selective serotonin reuptake inhibitors with or without concurrent nonsteroidal anti-inflammatory use: a systematic review and meta-analysis. The American journal of gastroenterology, 109(6), 811-819.
  3. Oka, Y., Okamoto, K., Kawashita, N., Shirakuni, Y., & Takagi, T. (2014). Meta-analysis of the risk of upper gastrointestinal hemorrhage with combination therapy of selective serotonin reuptake inhibitors and non-steroidal anti-inflammatory drugs. Biological and Pharmaceutical Bulletin, 37(6), 947-953.
  4. Cheng, Y. L., et al (2015). Use of SSRI, but not SNRI, increased upper and lower gastrointestinal bleeding: a nationwide population-based cohort study in Taiwan. Medicine, 94(46).
  5. Quinn, G. R., Singer, D. E.,et al (2014). Effect of selective serotonin reuptake inhibitors on bleeding risk in patients with atrial fibrillation taking warfarin. The American journal of cardiology, 114(4), 583-586.
  6. Wallerstedt, S. M., Gleerup, H., et al (2009). Risk of clinically relevant bleeding in warfarin‐treated patients—influence of SSRI treatment. Pharmacoepidemiology and drug safety, 18(5), 412-416.
  7. Samuel, N. G., & Seifert, C. F. (2017). Risk of Bleeding in Patients on Full-Dose Enoxaparin With Venous Thromboembolism and Selective Serotonin Reuptake Inhibitors. Annals of Pharmacotherapy, 51(3), 226-231.

Also, you can access to the original version in Spanish: “ISRS y riesgo de sangrado ¿Qué dice la evidencia?”

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