Drug–drug interactions between antithrombotic medications and the risk of gastrointestinal bleedingJoseph

Drug–drug interactions between antithrombotic medications and the risk of gastrointestinal bleeding

Joseph A. Delaney, MSc, Lucie Opatrny, MD MSc, James M. Brophy, MD PhD and Samy Suissa, PhD

From the Division of Clinical Epidemiology (Delaney, Opatrny, Brophy, Suissa), the Department of Epidemiology, Biostatistics and Occupational Health (Delaney, Brophy, Suissa), and the Division of Internal Medicine (Opatrny), McGill University Health Centre, Montréal, Que.
Correspondence to: Dr. Samy Suissa, Division of Clinical Epidemiology, Ross 4.29, Royal Victoria Hospital, 687 Pine Ave. W, Montréal QC H3A 1A1; fax 514 843-1493; samy.suissa@clinepi.mcgill.ca

Background: Anticoagulants and antiplatelet drugs (e.g., warfarin, clopidogrel and acetylsalicylic acid) are key therapeutic agents in the treatment of cardiovascular diseases. However, drug–drug interactions may lead to a greatly increased risk of gastrointestinal bleeding when these drugs are combined. We assessed whether antithrombotic drug combinations increased the risk of such bleeding in a general practice population.

Methods: We conducted a population-based, retrospective case–control study using records in the United Kingdom General Practice Research Database from 2000 through 2005. Cases were identified as patients over 18 years of age with a first-ever diagnosis of gastrointestinal bleeding. They were matched with controls by physician practice, patient age and index date (date of diagnosis of bleeding). All eligible patients had to have at least 3 years of follow-up data in the database. Drug exposure was considered to be any prescription issued in the 90 days before the index date.

Results: There were 4028 cases with a diagnosis of gastrointestinal bleeding and 40 171 matched controls. The prescribing of acetylsalicylic acid with either clopidogrel (adjusted rate ratio [RR] 3.90, 95% confidence interval [CI] 2.78–5.47) or warfarin (adjusted RR 6.48, 95% CI 4.25–9.87) was associated with a greater risk of gastrointestinal bleeding than that observed with each drug alone. The same was true when a nonsteroidal anti-inflammatory drug was combined with either clopidogrel (adjusted RR 2.93, 95% CI 1.74–4.93) or warfarin (RR 4.60, 95% CI 2.77–7.64).

Interpretation: Drug combinations involving antiplatelets and anticoagulants are associated with a high risk of gastrointestinal bleeding beyond that associated with each drug used alone. Physicians should be aware of these risks to better assess their patients' therapeutic risk–benefit profiles.

LINK:

http://www.cmaj.ca/cgi/content/full/177/4/347

CMAJ • August 14, 2007; 177 (4).

Use of Nonsteroidal Antiinflammatory Drugs: An Update for Clinicians: A Scientific Statement From the American Heart Association

Title: Use of Nonsteroidal Antiinflammatory Drugs: An Update for Clinicians: A Scientific Statement From the American Heart

Citation: Circulation. 2007;115:1634-1642.Clinical Trial: No


Perspective: Ten points to remember about this update on the use of nonsteroidal anti-inflammatory drugs (NSAIDs) are:

1. For patients with musculoskeletal symptoms whose symptoms are not controlled by nonpharmacological approaches, pharmacological treatments should then be considered. When choosing any medication, both safety and efficacy should be considered.

2. From both the patient’s and the physician’s perspectives, one needs to balance the risks and benefits of medications for pain relief.

3. In general, the least risky medication should be tried first, with escalation only if the first medication is ineffective. In practice, this usually means starting with acetaminophen or aspirin at the lowest efficacious dose, especially for short-term needs. Despite the potential for abuse, a role remains for narcotic medications for short-term pain relief.

4. Current evidence indicates that selective cyclooxygenase (COX)-2 inhibitors have important adverse cardiovascular effects that include increased risk for myocardial infarction, stroke, heart failure, and hypertension.

5. The risk for these adverse effects is likely greatest in patients with a prior history of or at high risk for cardiovascular disease. In these patients, use of COX-2 inhibitors for pain relief should be limited to patients for whom there are no appropriate alternatives, and then, only in the lowest dose and for the shortest duration necessary.

6. More long-term data are needed to fully evaluate the extent to which these important adverse cardiovascular effects may potentially be offset by other beneficial effects of these medications.

7. More data are also needed on the cardiovascular safety of conventional NSAIDs. Until such data are available, the use of any COX inhibitor, including over-the-counter NSAIDs, for long periods of time should only be considered in consultation with a physician.

8. Evidence indicates that ibuprofen, but not rofecoxib (a COX-2 inhibitor), acetaminophen, or diclofenac, interferes with aspirin’s ability to irreversibly acetylate the platelet COX-1 enzyme. Patients taking immediate release low-dose aspirin (not enteric coated) and ibuprofen 400 mg should take the ibuprofen at least 30 minutes after aspirin ingestion, or at least 8 hours before aspirin ingestion to avoid any potential interaction.

9. The debate about the increased risk of cardiovascular events attributed to the selective COX-2 inhibitors and the nonselective NSAIDs is part of a broader national debate about drug safety.

10. Optimal safety evaluation of drugs requires timely and complete submission of scientific data from the manufacturers, as well as increased funding and authority granted to the Food and Drug Administration by Congress.

Debabrata Mukherjee, M.D., F.A.C.C.