GENTOFTE, DENMARK — Patients receiving antithrombotic therapy following an MI who take a nonsteroidal anti-inflammatory drug (NSAID) are at an increased risk of bleeding and an increased risk of cardiovascular death, nonfatal recurrent MI, and stroke, according to the results of a new Danish observational study[1].
The increased risk of bleeding and cardiovascular events was observed in all patients regardless of the type of NSAID taken—selective COX-2 inhibitors or nonselective COX inhibitors—and even among patients who took the NSAID for a short period of time, report investigators.
“Although it seems unlikely that physicians can completely avoid prescription of NSAIDs, even among high-risk patients, these results highlight the importance of considering the balance of benefits and risks before initiating any NSAID treatment,” write Dr Anne-Marie Schjerning Olsen (Copenhagen University Hospital, Gentofte, Denmark) and colleagues in their report, published in the February 24, 2015 issue of the Journal of the American Medical Association.
The American Heart Association (AHA) recommends not prescribing an NSAID to patients with established cardiovascular disease, as does the European Medicines Agency (EMA). The Medicines and Healthcare Products Regulatory Agency in the UK and Danish Society of Cardiology also discourage the use of NSAIDs in these patients. Despite the discouragement, use of NSAIDs is widespread, note the investigators.
In an editorial[2], Dr Charles Campbell (University of Tennessee, Chattanooga) and Dr David Moliterno (University of Kentucky, Lexington) say the results support prior reports as well as the guidelines recommending that NSAIDs not be used in conjunction with antithrombotic medications.
“The cumulative evidence available is an important reminder that the while NSAIDs can be helpful and at times necessary medications for satisfactory quality of life, use of these medications among patients with a history of a recent MI is likely to be associated with clinically meaningful bleeding and ischemic risks,” they write.
The editorialists even worry that risks observed in the present study might be higher in the US, where NSAIDs are widely available over the counter. In some instances, physicians might not even be aware their post-MI patients are taking the drugs.
Speaking with heartwire , Dr Deepak Bhatt (Brigham and Women’s Hospital, Boston, MA), who was not involved in the research, said it’s important for physicians to obtain a complete medication history from their patients, including the use of NSAIDs. However, it’s possible over-the-counter medications get overlooked because patients aren’t necessarily thinking about them as drugs.
“The other aspect of the issue is that if a patient has really bad arthritis, you have to do something about that, too,” said Bhatt. “You can’t just say ‘tough it out,’ because that’s not typically going to work. I don’t think we can be overly dogmatic and say NSAIDs should never be used, because they are very effective medications, especially for arthritis when inflammation is present. The goal should be to minimize the dose and the duration to the extent that is possible, while realizing it might not always be possible.”
For patients who are going to be on dual antiplatelet therapy (DAPT) and a chronic NSAID, physicians could consider starting a proton-pump inhibitor, because it can reduce the risk of gastrointestinal bleeding, which accounts for a large proportion of bleeding, said Bhatt. “Sometimes physical therapy can help with arthritis, or other types of medication like acetaminophen, can help,” he said. “There are other approaches, but nothing is a perfect solution.”
Currently ongoing is a large Pfizer-sponsored study known as the Prospective Randomized Evaluation of Celecoxib Integrated Safety vs Ibuprofen or Naproxen (PRECISION) trial in 24 000 patients with rheumatoid arthritis or osteoarthritis at high risk for cardiovascular disease. The patients are being randomized to one of the three NSAIDs, and the cardiovascular safety results are expected in 2016.
Large Danish Registry Tracking Patients Prescriptions
In the present study, the Danish researchers analyzed the association between the concomitant use of NSAIDs and various antithrombotic medications, including aspirin, clopidogrel, and oral anticoagulant therapy, and adverse cardiovascular outcomes and bleeding risks in 61 971 patients admitted with a first-time MI between 2002 and 2011. The median follow-up was 3.5 years. During the study period, ibuprofen, a nonselective COX inhibitor, was the only NSAID available without a prescription, but the analysis relied solely on prescription NSAID use, which included higher doses of ibuprofen.
Overall, 34% of the Danish MI patients filled a prescription for at least one NSAID. During follow-up, there were 5288 bleeding events, including 2157 gastrointestinal bleeds and 799 fatal bleeds. Among the entire cohort, 30% experienced a cardiovascular event, defined as cardiac death, nonfatal recurrent MI, or stroke.
After adjustment for multiple baseline variables, the overall risk of bleeding was more than twofold higher among post-MI patients who were concomitantly taking an NSAID compared with those who were not (hazard ratio [HR] 2.02; 95% CI 1.81–2.26). The crude incidence rate was 2.2 bleeds per 100 person-years among those on antithrombotic therapy without an NSAID compared with 4.2 bleeds per 100 person-years among those concomitantly taking an NSAID.
The bleeding risks depended on the antithrombotic regimen but were all significantly increased among those taking DAPT and an NSAID. The bleeding risks were also significantly increased among the DAPT- and anticoagulant-treated patients taking an NSAID.
Every type of NSAID, including the selective COX-2 inhibitors and nonselective COX inhibitors, was associated with an increased risk of bleeding. In addition, no time period appeared to be safe, with bleeding risks heightened even within the first 3 days of treatment. The risk of serious bleeding was most pronounced with celecoxib and diclofenac.
Bleeding and Cardiovascular Risk NSAID Use
| Treatment groups | Bleeding risk, adjusted hazard ratio (95% CI) | Cardiovascular risk, adjusted hazard ratio (95% CI) |
| Clopidogrel plus aspirin (reference) | 1.00 | 1.00 |
| Aspirin plus NSAID | 1.24 (1.05-1.47) | 1.46 (1.32-1.60) |
| Clopidogrel plus NSAID | 1.34 (0.74–2.24) | 1.75 (1.26–2.41) |
| Oral anticoagulant plus NSAID | 1.92 (0.91–4.03) | 0.67 (0.32–1.41) |
| Clopidogrel plus aspirin plus NSAID | 2.41 (1.93–3.01) | 1.30 (1.08–1.55) |
| Clopidogrel plus aspirin plus oral anticoagulant plus NSAID | 2.94 (0.73–11.78) | 1.44 (0.46–4.45) |
| Oral anticoagulant plus single antiplatelet plus NSAID | 4.15 (2.81–6.13) | 1.62 (1.13–2.33) |
Regarding cardiovascular complications, the crude incidence rate for the combined end point was 11.2 per 100 person-years for those who received NSAIDs with any antithrombotic combination and 8.3 per 100 person-years for those who did not.
Overall, taking an NSAID was associated with a significant 40% increased risk of a cardiovascular event compared with those taking antithrombotics alone. For those taking DAPT, the addition of an NSAID increased the risk of a cardiovascular event 159% (HR 2.59; 95% CI 1.16–5.80) while aspirin plus an NSAID increased the risk 58% (HR 1.58; 95% CI 1.33–1.88). Like the risk of bleeding, the risk of cardiovascular events was observed among all the different NSAIDs.
NSAIDs Helpful but Carry Risks
To heartwire , Bhatt said the guidelines recommend minimizing the use of NSAIDs in patients with prior MI given the existence of these and other data, most of which are consistent, showing there might be risks associated with their use. For example, in the Reduction of Atherothrombosis for Continued Heath (REACH) registry, which included nearly 45 000 patients with stable atherothrombosis, the use of NSAIDs was associated with an increased risk of MI, stroke, and hospitalization for ischemia and heart failure. Overall, the risk of MI was increased 37% and the risk of stroke 21% among NSAID users.
“I think some things are pretty certain,” said Bhatt. “If a patient has a high cardiovascular risk, such as the Danish population who just had a heart attack, and particularly if they are getting other antithrombotic drugs—and if they’ve had a heart attack they should be—adding an NSAID is almost certainly going to increase their risk of bleeding in general, and in particular gastrointestinal bleeding.”
For some patients who have a bleeding event, there is the possibility they might stop taking their antiplatelet or anticoagulant medication because they attribute the bleed to these medications, noted Bhatt. This, in turn, can increase the risk of cardiovascular events.
Regarding the risk of ischemic or cardiovascular events with NSAIDs, the association is a little more controversial, noted Bhatt. “Again, though, I would say that more observational analyses than not suggest there might be some sort of link,” he toldheartwire . “And if there’s a link, it’s probably more likely to be apparent in people who are at higher risk.”
He noted that older patients with more comorbidities, such as those with arthritis, are more likely to take NSAIDs than healthier patients, so the results, even though adjusted for baseline patient characteristics, might be confounded by such variables. However, there are mechanisms in which NSAIDs might increase the risk of ischemic events. One theory is that NSAIDs might increase blood pressure, while another is the drugs, particularly ibuprofen, might interfere with aspirin’s beneficial cardiovascular effect, said Bhatt.
Olsen reports no relevant financial relationships. Disclosures for the coauthors are listed in the article. The editorialists report no relevant financial relationships.
References
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Olsen AM, Gisalason GH, McGettigan P, et al. Association of NSAID use with risk of bleeding and cardiovascular events in patients receiving antithrombotic therapy after myocardial infarction. JAMA 2015; 313:805-814.
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Campbell CL Moliterno. Potential hazards of adding nonsteroidal anti-inflammatory drugs to antithrombotic therapy after myocardial infarction: time for more than a gut check. JAMA2015; 313:801-802.