Gastrointestinal bleeding with warfarin

ADRs are certainly the most important form of iatrogenic (i.e. doctor-induced) disease. Many of the serious reactions that occur are well-recognised and potentially preventable - e.g. bleeding with warfarin, the upper gastrointestinal effects of NSAIDs. In public health terms, it is not newly introduced drugs that are responsible for most of the population burden of adverse drugs reactions but those whose safety profile is well-established (see below). 

Serotonin release by platelets plays an important role in hemostasis. Psychotropic drugs that interfere with serotonin reuptake may increase the occurrence of upper gastrointestinal bleeding with concurrent use of an NSAID or aspirin. Altered anticoagulant effects have been reported when either SSRIs or SNRIs are co-administered with warfarin. Hemostasis in warfarin therapy should be carefully monitored whenever duloxetine is initiated or discontinued. 

Aging is one of the major risk factors for developing gastric ulcers because of an increased incidence of Helicobacter pylori infections and a widely spread use of non-steroidal anti-inflammatory drugs (NSAID). Co-morbidity, with the need for prophylactic medication with antiplatelet therapy, warfarin and other anticoagulants, also increases the risk of gastrointestinal bleeding and ulcerations (Murakami et al. 1968). 

Morkunas A, Graeme K. Zafirlukast warfarin drug interaction with gastrointestinal bleeding. J Toxicol 1997 35 501. 

Although data from healthy subjects indicate no interaction of ketoprofen with warfarin, severe gastrointestinal bleeding and a prolonged prothrombin time have been attributed to this combination (SEDA-13, 81). 

A potentially dangerous interaction may occur between fluvoxamine and warfarin. There is a 65% increase in plasma warfarin concentration and a significant prolongation of prothrombin time. The selective serotonin reuptake inhibitors (SSRIs) increase the risk of upper gastrointestinal bleeding, and this effect is potentiated by the concurrent use of non-steroidal anti-inflammatory drugs (NSAIDs) or low-dose aspirin. There are anecdotal reports of bleeding disorder with the concomitant use of nicoumalone (a coumarin derivate), ibuprofen, and warfarin. 

Nizatidine 300 mg daily for 2 weeks had no significant effect on the prothrombin times, kaolin-cephalin clotting times, the activity of factors II, Vn, XI and X, or on steady-state semm warfarin levels in 7 healthy subjects taking warfarin. A lack of a pharmacokinetic interaction was also reported in the preliminary results of another study. An isolated case of gastrointestinal bleeding, associated with markedly prolonged prothrombin times, occurred after a 78-year-old took six doses of nizatidine 300 mg. ... 

Studies surest that diclofenac does not alter the anticoagulant effect of acenocoumarol, phenprocoumon or warfarin, su esting dose adjustments are unlikely to be needed. Isolated cases of raised INRs have been described. Note that all NSAIDs increase the risk of gastrointestinal bleeding, and an increased risk is seen when they are combined with anticoagulants. 

There is limited evidence to suggest that diflunisal might increase the anticoagulant effects of acenocoumarol and possibly warfarin, but probably not phenprocoumon. All NSAIDs increase the risk of gastrointestinal bleeding, and should be used with care in patients taking oral anticoagulants. 

Flessner MF, Knight H. Prolongation of prothrombin time and severe gastrointestinal bleeding associated with combined use of warfarin and ketoprofen. JAMA (1988) 259, 353. 

Ketorolac did not alter the pharmacokinetics of, or prothrombin time response to, warfarin. However, ketorolac has l en associated with serious gastrointestinal bleeding. 

However, a patient stabilised on warfarin, ferrous sulfate, phenobarbital and sulfasalazine had a marked increase in his prothrombin time ratio from about 3.2 to 10 after taking sulindac 100 mg twice daily for 5 days. There are 4 similar cases of this interaction on record. One of the patients had a gastrointestinal bleed after taking only three 100-mg doses of sulindac, although this patient was also taking flurbiprofen. Another patient was stabilised on about a 40% lower dose of warfarin with continuation of the sulindac. Another patient had a potassium-losing renal tubular defect, which was thought to contribute to the interaction. ... 

The possible interactions of warfarin or other antieoagulants with venlafaxine do not appear to have been studied, but, as of May 2000, the manufacturers had on record 6 case reports of increased prothrombin times, raised INRs and bleeding (haematuria, gastrointestinal bleeding, melaena, haemarthrosis) in patients taking warfarin with venlafaxine. ... 

Schelleman H, Bilker WB, Brensinger CM, Han X, Kimmel SE, Hennessy S. Warfarin with fluoroquinolones, sulfonamides, or azole antifungals interactions and the risk of hospitalization for gastrointestinal bleeding. Clin Pharmacol Ther 2008 84(5) 581-8. 

Plasma digoxin levels may decrease when the drug is administered with bleomycin. When bleomycin is used witii cisplatin, there is an increased risk of bleomycin toxicity Pulmonary toxicity may occur when bleomycin is administered with other antineoplastic drugs. Plicamycin, mitomycin, mitoxantrone, and dactino-mycin have an additive bone marrow depressant effect when administered with other antineoplastic drugs. In addition, mitomycin, mitoxantrone, and dactinomycin decrease antibody response to live virus vaccines. Dactinomycin potentiates or reactivates skin or gastrointestinal reactions of radiation therapy There is an increased risk of bleeding when plicamycin is administered witii aspirin, warfarin, heparin, and the NSAIDs. 

Patients at increased risk of NSAID-induced gastrointestinal adverse effects (e.g., dyspepsia, peptic ulcer formation, and bleeding) include the elderly, those with peptic ulcer disease, coagulopathy, and patients receiving high doses of concurrent corticosteroids. Nephrotoxicity is more common in the elderly, patients with creatinine clearance values less than 50 mL/minute, and those with volume depletion or on diuretic therapy. NSAIDs should be used with caution in patients with reduced cardiac output due to sodium retention and in patients receiving antihypertensives, warfarin, and lithium. 

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