Can NSAIDs increase Cardiovascular risk?

1.

Nonsteroidal Antiinflammatory Drugs (NSAIDs), Elsevier ClinicalKey Drug Class Overview

Content last updated: August 5, 2022.

Nonsteroidal antiinflammatory drugs (NSAIDs) are contraindicated in the setting of coronary artery bypass graft surgery (CABG). An increased incidence of myocardial infarction and stroke was found in clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10 to 14 days after CABG surgery. NSAIDs may cause an increased risk of serious cardiovascular thromboembolism, including myocardial infarction or stroke, which can be fatal. Some observational studies found that this increased risk of serious cardiovascular (CV) thrombotic events began as early as the first weeks of treatment; the increase in CV risk has been most consistently observed at higher doses. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, persons with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Current evidence is insufficient to determine if the risk of an event is higher or lower for any particular NSAID compared to other NSAIDs. There is no consistent evidence that concomitant use of aspirin mitigates the increased risk for cardiovascular thrombotic events[32122]. [56268][59937] Guidelines recommend against NSAID use in persons presenting with and hospitalized for ST-elevation myocardial infarction (STEMI) due to increased risk of mortality and CV complications associated with their use[55688]. Observational data from a national registry demonstrated that persons treated with NSAIDs in the post- MI period were at increased risk of reinfarction, cardiovascular-related death, and all-cause mortality beginning the first week of treatment. An increased relative risk of death in NSAID users continued during the follow-up period of 4 years. Data demonstrate that persons treated with NSAIDs were more likely to die in the first year after myocardial infarction compared to those not treated with NSAIDs[44130]. Avoid NSAID use in persons with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure.

Clinical trials of several cyclooxygenase-2 (COX-2) selective and nonselective nonsteroidal antiinflammatory drugs (NSAIDs) of up to 3 years duration have shown an increased risk of serious cardiovascular thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for cardiovascular thrombotic events is similar for all NSAIDs. Some observational studies found that this increased risk of serious cardiovascular thrombotic events began as early as the first weeks of treatment. In 2 large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10 to 14 days after coronary artery bypass graft (CABG) surgery, an increased incidence of myocardial infarction and stroke was noted. Observational studies conducted in the Danish National Registry have demonstrated that persons treated with NSAIDs in the post-MI period were at increased risk of reinfarction, cardiovascular-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated persons compared to 12 per 100 person years in non-NSAID exposed persons. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next 4 years of follow-up. The increase in cardiovascular thrombotic risk has been observed most consistently at higher doses. To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible[32122]. [56268]

not treated with NSAIDs[44130]. Avoid NSAID use in persons with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If an NSAID is used in persons with severe heart failure, monitor for signs of worsening heart failure. Blunting of the cardiovascular effects of several therapeutic agents used to treat fluid retention or edema has been observed with NSAID use. A meta-analysis of randomized, controlled trials demonstrated an approximately 2-fold increase in hospitalizations for heart failure among non-selective and COX-2 selective-treated subjects compared to placebo. Consider the sodium content of naproxen sodium in persons requiring severe sodium restriction. NSAIDs can lead to new onset of hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Persons taking NSAIDs may have impaired response to angiotensin-converting enzyme inhibitors, thiazide diuretics, or loop diuretics. Closely monitor blood pressure during NSAID receipt[32122]. [56268] A meta-analysis demonstrated that the effect of NSAIDs on blood pressure is the greatest in hypertensive individuals receiving antihypertensive medication. Normotensive subjects receiving antihypertensive therapy had higher increases in blood pressure than subjects with uncontrolled hypertension or normotensive subjects receiving no hypertensive therapy[27388]. Caution is recommended when administering NSAIDs to persons with cardiac disease, cardiomyopathy, cardiac arrhythmias (e.g., tachycardia), significant coronary artery disease (including acute myocardial infarction, angina, or history of myocardial infarction), peripheral vascular disease, cerebrovascular disease (e.g., stroke, transient ischemic attack), hypertension, pre-existing kidney disease, or fluid retention. Use the lowest effective dose for the shortest duration possible to minimize the potential risk for an adverse cardiovascular event[59937].

2.

Elsevier ClinicalKey Drug Monograph

Content last updated: May 2, 2024.

Adverse Reactions Like all NSAIDs, ibuprofen-induced increases in water retention and decreases in renal perfusion may exacerbate pre-existing cardiovascular complications, including hypertension (less than 1%) and congestive heart failure (specifically in patients with marginal cardiac function, less than 1%). Further, NSAIDs may increase the risk of serious cardiovascular thromboembolism, myocardial infarction, and stroke, which can be fatal. Estimates of increased relative risk range from 10% to 50% or more, based on the drug and dose studied. The risk may increase with increased exposure, as measured in dose or duration. Significant cardiovascular risk has been observed within days to weeks of NSAID initiation. The relative increase in cardiovascular thrombotic events over baseline appears to be similar in patients with or without cardiovascular disease or risk factors for cardiovascular disease; however, patients with known cardiovascular disease or risk factors may be at greater risk because of a higher baseline risk of events. While comprehensive data regarding relative cardiovascular safety of any particular NSAID compared to other NSAIDs is not available, celecoxib 100 mg twice daily was shown to be non-inferior to ibuprofen 600 to 800 mg 3 times daily or naproxen 375 to 500 mg twice daily for the composite endpoint of cardiovascular death, nonfatal MI, and nonfatal stroke in osteoarthritis or rheumatoid arthritis adult patients with or at high risk for cardiovascular disease. The intention-to-treat (ITT) analysis followed patients for 30 months, with 8,072 patients randomized to celecoxib, 8,040 randomized to ibuprofen, and 7,969 randomized to naproxen.

3.

Elsevier ClinicalKey Drug Monograph

Content last updated: March 4, 2024.

Contraindications And Precautions Lodine, like all nonsteroidal anti-inflammatory drugs (NSAIDs), may exacerbate hypertension and congestive heart failure and may cause an increased risk of serious cardiovascular thromboembolism, myocardial infarction, and stroke, which can be fatal. The FDA has warned that the risk of myocardial infarction or stroke can occur as early as the first weeks of using a NSAID, and risk may increase with higher doses and longer duration of use. Data demonstrate that patients treated with NSAIDs were more likely to die in the first year following a myocardial infarction compared to those not treated with NSAIDs. NSAIDs may increase the risk of a cardiovascular thrombotic event in patients with or without underlying heart disease or risk factors for heart disease. Patients with known heart disease or risk factors appear to have a greater likelihood of an event following NSAID use, likely due to a higher baseline risk. Current evidence is insufficient to determine if the risk of an event is higher or lower for any particular NSAID compared to other NSAIDs. There is an increased risk of heart failure with NSAID use. Caution is recommended when administering lodine to patients with cardiac disease, cardiomyopathy, cardiac arrhythmias (e.g., tachycardia), significant coronary artery disease (including acute myocardial infarction, angina, or history of myocardial infarction), peripheral vascular disease, cerebrovascular disease (e.g., stroke, transient ischemic attack), hypertension, pre-existing renal disease, or fluid retention. In addition, clinical practice guidelines state NSAIDs should not be administered to patients presenting with and hospitalized for ST-elevation myocardial infarction (STEMI) due to increased risk of mortality, reinfarction, hypertension, heart failure, and myocardial rupture associated with their use.

4.

Elsevier ClinicalKey Drug Monograph

Content last updated: March 4, 2024.

Adverse Reactions Clinical trials of several NSAIDs of up to 3 years duration have shown an increased risk of serious cardiovascular (CV) thromboembolism, including myocardial infarction (MI) and stroke, which can be fatal. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10 to 14 days after coronary artery bypass graft (CABG) surgery found an increased incidence of MI and stroke. The increase in CV thrombotic risk has been observed most consistently at higher doses. Observational studies conducted in the Danish National Registry have demonstrated that subjects treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated subjects compared to 12 per 100 person years in non-NSAID exposed subjects. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next 4 years of follow-up. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. There is no consistent evidence that concomitant use of aspirin mitigates the increased risk for cardiovascular thrombotic events. NSAIDs may also lead to onset of new hypertension or worsening of preexisting hypertension, which may contribute to the increased incidence of CV adverse events. Monitor blood pressure during the initiation of NSAID treatment and throughout the course of therapy. A meta-analysis of randomized, controlled trials demonstrated an approximately 2-fold increase in hospitalizations for heart failure in COX-2 selective-treated subjects and nonselective NSAID-treated subjects compared to placebo.

5.

Food and Drug Administration (DailyMed).

Publish date: February 1, 2022.

Boxed Warning WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS See full prescribing information for complete boxed warning. Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use ( 5.1 ) Indomethacin capsules are contraindicated in the setting of coronary artery bypass graft (CABG) surgery ( 4 , 5.1 ) NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events ( 5.2 ) Cardiovascular Thrombotic Events Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use [ see Warnings and Precautions (5.1) ]. Indomethacin capsules are contraindicated in the setting of coronary artery bypass graft (CABG) surgery [ see Contraindications (4) and Warnings and Precautions (5.1) ] . Gastrointestinal Bleeding, Ulceration, and Perforation NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events [ see Warnings and Precautions (5.2) ].

6.

Food and Drug Administration (DailyMed).

Publish date: May 6, 2021.

Boxed Warning Cardiovascular Thrombotic Events • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use (see WARNINGS and PRECAUTIONS ). • Meclofenamate sodium capsules are contraindicated in the setting of coronary artery bypass graft (CABG) surgery (see CONTRAINDICATIONS and WARNINGS ). Gastrointestinal Risk • NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events. (See WARNINGS ).

7.

Food and Drug Administration (DailyMed).

Publish date: May 4, 2024.

Boxed Warning WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS See full prescribing information for complete boxed warning. • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use ( 5.1 ) • Feldene (piroxicam) is contraindicated in the setting of coronary artery bypass graft (CABG) surgery ( 4, 5.1 ) • NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events ( 5.2 ) Cardiovascular Thrombotic Events • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use [see Warnings and Precautions (5.1) ]. • Feldene (piroxicam) is contraindicated in the setting of coronary artery bypass graft (CABG) surgery [see Contraindications (4) and Warnings and Precautions (5.1) ]. Gastrointestinal Bleeding, Ulceration, and Perforation • NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events [see Warnings and Precautions (5.2) ].