The question addressed in the study was: Do people who have had a myocardial infarction and who are taking antithrombotics have an increased risk of serious bleeding, and of a new cardiovascular event if they also take non-steroidal anti-inflammatory drugs–painkiller and anti-inflammatory agents?

We found that taking NSAIDs, even for periods of under one week, was associated with increased risks of both bleeding and of myocardial infarction.

Describe for our readers what you found in your study

Aspirin, clopidogrel, and oral anticoagulants are widely used by patients with established cardiovascular disease to lower the risk of thromboembolic complications and mortality. Management guidelines advise that patients with myocardial infarction should be prescribed dual antithrombotic therapy (aspirin and clopidogrel) for up to 12 months and one agent thereafter, and a substantial proportion of patients also has an additional indication for oral anticoagulants (e.g. atrial fibrillation).

NSAIDs are used to treat pain and inflammation. They are effective and are among the most widely used drugs in the world. Some NSAIDs, for example, ibuprofen, can be bought without a prescription (i.e. over the counter) in many countries. Despite the easy availability, NSAIDs have side effects too. They increase the risk of bleeding, especially gastrointestinal bleeding arising from peptic ulcers, a serious event with high mortality rates. Co-prescription of proton pump inhibitor gastro-protection reduces but does not eliminate this risk. Some NSAIDs, for example diclofenac, are also associated with an increase in the risk of cardiovascular events including myocardial infarction. Though modest, the risk has substantial implications for persons with established cardiovascular disease who are already at risk of further events. As yet, there appears no means of mitigating NSAID-associated cardiovascular risk. Both risks are of considerable public health concern given the widespread use of NSAIDs. Aside from the use of aspirin (classified as an NSAID), the safety of antithrombotic-NSAID combinations after myocardial infarction has not been examined. We therefore conducted this study to investigate the association between concomitant use of NSAIDs and risk of bleeding and cardiovascular events in patients receiving antithrombotic treatment after myocardial infarction.

What this study did: This was an historical cohort study that included every resident in Denmark aged 30 years or older who had had a first myocardial infarction and who was taking antithrombotic drugs. Using hospital registries, we examined patients who suffered from serious bleeding or from a cardiovascular event (causing admission to hospital and/or death). Based on dispensed prescriptions, we were able to categorize patients as exposed or not to NSAIDs.

The study findings: Among over 60,000 Danish patients diagnosed with myocardial infarction between 2002 and 2011, one-third had at least one prescription for a NSAID, mostly ibuprofen and diclofenac, dispensed over a median follow-up of 3.5 years. Most treatment courses with NSAIDs were short (less than three weeks). In the same period, 8.5% (5,288 patients or 1 in 12 of the study group) had a gastrointestinal bleed (of whom 799 or 15% died) and 30% (18,568; 1 in 3) had a new cardiovascular risk, mostly myocardial infarction. We found that the risk of bleeding was doubled when patients were taking NSAIDs compared with not taking them (i.e. incidence rate of 4.2 and 2.2 events per 100 person-years, respectively [hazard ratio 2.02, 95% Confidence Interval 1.81-2.26]). Especially worrisome, an elevated bleeding risk was present even within three days of starting a NSAID. The risk of a cardiovascular event (mainly myocardial infarction) was also increased [hazard ratio 1.40, 95% Confidence Interval 1.30-1.49] when taking NSAIDs compared with not taking them and, similar to the bleeding hazard, an elevated risk was present within days of starting.

We believe our data raise two major clinical issues for physicians and patients. Firstly, NSAIDs substantially further increase bleeding risks already elevated owing to use of antithrombotic drugs. Secondly, NSAIDs appear to abolish the cardiac protection that antithrombotic drugs should provide.

Can you tell us about the Danish National Patient registry?

Each resident in Denmark has a unique and permanent identification number that enables individual-level linkage between nationwide registries. The Danish National Patient Register is a key Danish health register. The registry keeps records of all hospital admissions in Denmark since 1978. The register has been expanded over the years, from originally covering only somatic inpatients to now cover both in- and out-patients, a range of surgical procedures, and also some treatments provided by hospitals (e.g. cancer treatment including radiation). It is also used as a nationwide database for certain conditions with a mandatory registration of supplementary clinical information. Each hospital admission is registered with one main discharge coding diagnosis and, if appropriate, one or more supplementary diagnoses according to the International Classification of Diseases (ICD) codes (the 8th ICD revision until 1994 and the 10th revision [ICD-10] from 1994). Admission and discharge date as well as specific hospital and department is registered. The information is available for scientific purposes and all data are encrypted and anonymized. Data management is performed on secured servers with data only made available to the scientist to answer the specific questions asked. Access can be granted through contact with Statistics Denmark.

What advice do you give your patients when they ask about NSAID use and anti-thrombotic treatment?

If a patient asks about co-treatment with an NSAID and antithrombotic drug(s), we will strongly emphasize that this is high-risk treatment. In our practice, we always consider alternatives to NSAID therapy based on the individual patient. It may include analgesic alternatives such as paracetamol and/or non-pharmacological measures such as weight loss, physical therapy and exercise. Required use of NSAIDs in patients with known cardiovascular disease should be considered as an expert task – the prescribing physician should recognize this even though NSAIDs might be available as over-the-counter drugs. If an NSAID is the option chosen after consideration of risks and benefits, then we choose the 'least risky' in cardiovascular terms: ibuprofen or naproxen prescribed at the lowest effective dose for the shortest time possible. We also recommend that the patient is co-prescribed a proton pump inhibitor for gastro-protection.

Current recommendations from cardiac societies discourage the use of NSAIDs in patients with established or at increased risk of cardiovascular disease. However, pain is a common problem and very distressing; in practice, NSAIDs are used quite often by patients who have had a myocardial infarction. We are keen advocates of non-drug/lifestyle treatments for pain where possible. If NSAIDs are to be taken by patients with cardiovascular disease, it is important that both they and their doctors know the risks so that they can weigh up the benefits and downsides and make an informed decision. There has been a tendency to think that short-term use of NSAIDs is safe – our study suggests this in not the case and that even a few days of use is associated with increased risks of both bleeding and cardiovascular events. Notably, commonly used NSAIDs, such as diclofenac, which in some countries is available over-the-counter without any expert advice on potential side effects, were associated with increased risk that commenced at treatment onset – there was no window-period of 'safe' use. The easy availability of NSAIDs makes their risks a major public health matter especially where large vulnerable patient populations are concerned.

Reference

1. Schjerning Olsen MA, Gislason GH, McGettigan P, et al. NSAID Use With Risk of Bleeding and Cardiovascular Events in Patients Receiving Antithrombotic Therapy. JAMA. 2015;313(8):805-814.

Keywords: Acetaminophen, Analgesics, Anti-Inflammatory Agents, Non-Steroidal, Anticoagulants, Aspirin, Atrial Fibrillation, Cardiovascular Diseases, Cohort Studies, Confidence Intervals, Denmark, Diclofenac, Fibrinolytic Agents, Follow-Up Studies, Humans, Ibuprofen, Incidence, Inflammation, Inpatients, International Classification of Diseases, Life Style, Myocardial Infarction, Naproxen, Neoplasms, Nonprescription Drugs, Outpatients, Pain, Peptic Ulcer, Proton Pump Inhibitors, Public Health, Registries, Risk Assessment, Risk Factors, Ticlopidine, Weight Loss, Hypertension, Pulmonary

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