September 3, 2018
cardiovascular disease vs NSAIDS cover

NSAIDS and Cardiovascular Risk

Non-Steroidal Antiinflammatory Drugs (NSAIDS) are the most commonly used drugs in the US according to the CDC. NSAIDS address a wide range of maladies including pain, fever and inflammation. For this reason, they are commonly used by sports medicine physicians to treat orthopedic injuries and pain. NSAID use is increasing over time and meloxicam is now the 30th most prescribed drug in the US. Participants over 60 years of age, women, participants with high body mass index, increased waist circumference or heart disease were significantly more likely to be regular NSAID users [1].
Risks of long term NSAID use include cardiovascular disease, gastrointestinal ulceration and bleeding, kidney toxicity, and potential for hemorrhagic stroke. Aspirin is well accepted as an agent for the treatment and prevention of secondary cardiovascular effects events. Current guidelines also support the role of aspirin for prevention of primary cardiovascular disease, although this is more contentious. Other NSAIDS do not convey the same cardioprotective benefits. Non-aspirin NSAIDS have been linked to cardiovascular risk and higher doses of NSAIDS increases your risk of myocardial infarction.
Although sports medicine physicians are not treating many of the comorbidities of their patients, they need to be cognizant of the use of NSAIDS and individual cardiovascular risk. For a period of time COX-2 inhibitors were preferred due to their favorable GI profile. However, in 2004 Rofecoxib (Vioxx) was found to increase cardiovascular events and taken off the market. Providers have since been debating the cardiovascular safety of both COX-2 inhibitors and traditional NSAIDS.
nsaids and cardiovascular risk selectivity

Image 1. Table illustrating selectivity of various NSAIDS (courtesy of link.springer.com).

In 2016 the New England Journal of Medicine posted a review comparing cardiovascular safety in Celecoxib, Naproxen and Ibuprofen in patients who have osteoarthritis or rheumatoid arthritis. The primary outcome in the study was death from cardiovascular causes and a secondary outcome was major adverse cardiovascular events. They chose ibuprofen and naproxen because they are nonselective COX inhibitors verse celecoxib which is a selective COX-2 inhibitor and is thought to have higher cardiovascular risk. However, the PRECISION trial shows that the presumed elevated risk of celecoxib verse the nonselective COX inhibitors was not seen. In fact, celecoxib had the fewest number of cardiovascular events. The important thing to note with this study is to be careful with all NSAIDs. The risk of major cardiovascular events is elevated in celecoxib, naproxen, and ibuprofen [2].
Another drug that has become more popular due to a favorable GI profile and once daily dosing is Meloxicam. A study published in Rheumatology International in 2017 found that Meloxicam was associated with a 38% higher risk of MIs verse patients with remote use of NSAIDs [3]. The paper also looked at patients taking Diclofenac and found them to have 37% increased risk of having an MI compared to patients with a remote history of NSAID use.
table of nsaid safety, gastrointestinal risk, cardiovascular risk

Image 2. Table comparing the cardiovascular and gastrointestinal safety of commonly used NSAIDS (source unknown)

A systematic review published in PLOS Medicine in 2011 found ibuprofen and naproxen to be the safest while finding rofecoxib and diclofenac to have the highest risk [4]. A British Medical Journal study in 2011 found all drugs except naproxen showed some evidence for increased risk of cardiovascular death [5]. A follow up study in 2017 in the BMJ found that even naproxen increases risk of myocardial infarction [6]. In 2016, Pelletier et al. showed the celecoxib followed by nabumetone and acemetacin had the best cardiovascular risk profile [7].
The use of NSAIDS in patients treated by sports medicine physicians needs to be tailored to patients individual cardiovascular risk. The provider must consider concurrent use of aspirin, comorbidities including cardiovascular disease, chronic kidney disease, history of peptic ulcer disease and use of anticoagulation. When considering cardiovascular risk, there is no clear consensus on which drugs are the safest, although naproxen and ibuprofen may be the safest. This pharmacist letter from the therapeutic research center may help guide your decision making.

References

1. Davis JS, Lee HY, Kim J, et al Use of non-steroidal anti-inflammatory drugs in US adults: changes over time and by demographic Open Heart 2017;4:e000550. doi: 10.1136/openhrt-2016-000550
2. Nissen SE, Yeomans ND, et al; PRECISION Trial Investigators. Cardiovascular Safety of Celecoxib, Naproxen, or Ibuprofen for Arthritis. N Engl J Med. 2016 Dec 29;375(26):2519-29.
3. Dalal D, Dubreuil M, et al. Meloxicam and risk of myocardial infarction: a population-based nested case-control study. Rheumatol Int. 2017 Dec;37(12):2071-2078.
4. McGettigan P, Henry D. Cardiovascular risk with non-steroidal anti-inflammatory drugs: systematic review of population-based controlled observational studies. PLoS Med. 2011 Sep;8(9):e1001098.
5. Trelle S, Reichenbach S, et al. Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis. BMJ. 2011 Jan 11;342:c7086.
6. Bally M, Dendukuri N, et al. Risk of acute myocardial infarction with NSAIDs in real world use: bayesian meta-analysis of individual patient data. BMJ. 2017 May 9;357:j1909.
7. Pelletier JP, Martel-Pelletier J, Rannou F, Cooper C. Efficacy and safety of oral NSAIDs and analgesics in the management of osteoarthritis: Evidence from real-life setting trials and surveys. Semin Arthritis Rheum. 2016 Feb;45(4 Suppl):S22-7.