Frågedatum: 2019-04-11
RELIS database 2019; id.nr. 182, ULIC
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Sertralin och Eliquis interaktion



Fråga: Äldre patient med tid MS-diagnos (få restsymtom ev viss psykisk påverkan, ev vissa balansbesvär). Har urostomi + colostomi st p analcancer fistlar etc. Har spironolakton, metoprolol, enalapril för bt/hjärta. Pga värk oxycontin 20mg x3 + Alvedon 2x3. Pga sina psykiska besvär sertralin 100 mg + mirtazapin 30mg. Upplevs ofta labil i humöret. Har nu drabbats av förmaksflimmer för 2 år sen och har tidigare tackat bestämt nej till blodförtunning. Denna gång "låter hon mig bestämma". Rimligen borde hon ha Eliqius. Men då framkommer att sertralin intreragerar. Hjälper det att sänka setralin till 50 mg för att minska risken? (dvs är trombocytpåverkan dosberoende.) Att ge omeprazol hjälper väl bara magsäcken? Kanske kan jag ge reducerad eliquisdos (2½ mg x 2) för att minska blödningsrisken?

Svar: Sammanfattning
There are no studies on the safety of concomitant use of NOAC (non vitamin K oral anticoagulants) with serotonine re-uptake inhibitors (SSRIs).

No guidelines were found that recommend/suggest dose reduction for sertraline/SSRI or apixaban (Eliquis) to reduce the risk of bleeding due to the combined administration of both drugs.

Bleeding due to SSRI is probably mediated through serotonin reuptake inhibition in platelet. It is suggested that it might be dose-dependent like other side-effects with a similar mechanism.

PPIs reduce the rate of recurrent gastrointestinal bleeding in high-risk patients receiving aspirin. PPI co-therapy with anticoagulants, including apixaban, reduced the risk of upper gastrointestinal tract bleeding hospitalizations.

Svar
We have found no studies investigating the risk of bleeding with concomitant use of SSRIs and apixaban. (1, 2). The interaction between SSRI/SNRI/sertraline and apixaban (Eliquis) is a potential pharmacodynamic interaction, but concomitant use is not contraindicated. However, a post-hoc analysis of the ROCKET AF trial, where rivaroxaban was compared with warfarin in patients with atrial fibrillation, showed that concomitant use of SSRIs and rivaroxaban did not appear to increase the risk of bleeding, although the number of patients was limited (3).

It has been suggested that for patients who experience a hemorrhage and have a strong indication for SSRI therapy, it may be worth preferentially avoiding drugs with a particularly high affinity for the serotonin receptor, including sertraline, paroxetine, fluoxetine and clomipramine (4). Janusmed, The Swedish drug interaction database, suggests use of antidepressants other than SSRI/SNRI such as mirtazapine or reboxetine (2).

No guidelines were found that recommend/suggest dose reduction for sertraline/SSRI or NOAC to reduce the risk of bleeding due to the combined administration of both drugs (1).

SSRI/sertraline and bleeding risk The relationship between bleeding side-effects and the dosage of SSRIs has not been studied well (5). Bleeding due to SSRIs is probably mediated through serotonin reuptake inhibition in platelets. Therefore, it is suggested that it might be dose-dependent like other side-effects with a similar mechanism. Two case reports suggested that dose-adjustment could alleviate patients’ symptoms of bleeding.

Proton pump inhibitors (PPIs) Proton pump inhibitors (PPIs) are known to interact with key metabolic enzymes in the liver, such as CYP2C19 (omeprazole has high CYP2C19 inhibitory capacity) (6). The administration of PPIs to patients receiving oral selective, direct factor Xa inhibitors such as apixaban is unlikely to influence the pharmacokinetics of the drugs (6, 7). Only potent inhibitors and inducers of CYP3A4 and P-glycoprotein influence the pharmacokinetics of apixaban and thus not PPI (6). PPIs reduce the efficacy of drugs whose absorption depend on gastric pH, and this is likely a class effect since all PPIs affect gastric pH to approximately the same extent. Based on the physicochemical properties of apixaban, it is a compound that lacks ionizable groups in its molecular structure, and thus its aqueous solubility is not affected by changes in pH (8).

Randomized, controlled trials have shown that PPIs reduce the rate of recurrent gastrointestinal bleeding in high-risk patients receiving aspirin (9). In a retrospective cohort study, when anticoagulant treatment (including apixaban) with PPI co-therapy was compared with treatment without PPI co-therapy, the risk of upper gastrointestinal tract bleeding hospitalizations was found to be lower (10). In the ARISTOTLE study (11) 18.5% of patients received gastric antacid drugs, but no specific data are available for this subpopulation of patients. PPIs have no effect on other types of major bleedings.

According to an expert position paper on the use of PPI in patients with cardiovascular disease and antithrombotic therapy (6), administration of PPIs is warranted if an increased risk of GI bleeding is expected.

Referenser:
  1. PubMed. US National Library of Medicine/National Institutes of Health sökning gjord 2019-02-11 2019-02-22. http://www.ncbi.nlm.nih.gov/sites/entrez
  2. Janusmed interaktioner, Stockholms läns landsting; sökning gjord 2019-02-11 via www.janusinfo.se
  3. Quinn GR, Hellkamp AS, Hankey GJ, Becker RC, Berkowitz SD, Breithardt G, Fava M, Fox KAA, Halperin JL, Mahaffey KW, Nessel CC, Patel MR, Piccini JP, Singer DE. Selective Serotonin Reuptake Inhibitors and Bleeding Risk in Anticoagulated Patients With Atrial Fibrillation: An Analysis From the ROCKET AF Trial. J Am Heart Assoc. 2018 Aug 7;7(15):e008755
  4. Juurlink DN. Antidepressants, antiplatelets and bleeding: one more thing to worry about? CMAJ. 2011 Nov 8;183(16):1819-20.
  5. Mahin Eslami Shahrbabki, and Amir Eslami Shahrbabaki. Sertraline-Related Bleeding Tendency: Could It Be Dose-Dependent? Iran J Psychiatry Behav Sci. 2014 Autumn; 8(3): 81–83.
  6. Agewall S, Cattaneo M, Collet JP, Andreotti F, Lip GY, Verheugt FW, Huber K, Grove EL, Morais J, Husted S, Wassmann S, Rosano G, Atar D, Pathak A, Kjeldsen K, Storey RF; ESC Working Group on Cardiovascular Pharmacology and Drug Therapy and ESC Working Group on Thrombosis. Expert position paper on the use of proton pump inhibitors in patients with cardiovascular disease and antithrombotic therapy. Eur Heart J. 2013 Jun;34(23):1708-13, 1713a-1713b.
  7. Ward C, Conner G, Donnan G, Gallus A, McRae S. Practical management of patients on apixaban: a consensus guide. Thromb J. 2013 Dec 31;11(1):27.
  8. Upreti VV, Song Y, Wang J, Byon W, Boyd RA, Pursley JM, Lacreta F, Frost CE. Effect of famotidine on the pharmacokinetics of apixaban, an oral direct factor Xa inhibitor. Clin Pharmacol: Advances and Applications. 2013;11:59–66.
  9. Bhatt DL, Cryer BL, Contant CF, Cohen M, Lanas A, Schnitzer TJ, Shook TL, Lapuerta P, Goldsmith MA, Laine L, Scirica BM, Murphy SA, Cannon CP; COGENT Investigators. Clopidogrel with or without omeprazole in coronary artery disease. N Engl J Med. 2010 Nov 11;363(20):1909-17.
  10. Ray WA, Chung CP, Murray KT, Smalley WE, Daugherty JR, Dupont WD, Stein CM. Association of Oral Anticoagulants and Proton Pump Inhibitor Cotherapy With Hospitalization for Upper Gastrointestinal Tract Bleeding. JAMA. 2018 Dec 4;320(21):2221-2230.
  11. Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, Al-Khalidi HR, Ansell J, Atar D, Avezum A, Bahit MC, Diaz R, Easton JD, Ezekowitz JA, Flaker G, Garcia D, Geraldes M, Gersh BJ, Golitsyn S, Goto S, Hermosillo AG, Hohnloser SH, Horowitz J, Mohan P, Jansky P, Lewis BS, Lopez-Sendon JL, Pais P, Parkhomenko A, Verheugt FW, Zhu J, Wallentin L; ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011 Sep 15;365(11):981-92.