Gastrointestinal and Cardiovascular Risks of NSAIDs

Patient-Related Risk Factors

• Increasing age, especially over 70 years, is a risk factor for gastrointestinal events, with previous gastrointestinal events increasing the risk of future events 2.5-4 times 1
• Elderly patients (≥60 years), patients with cardiovascular disease or risk factors, and patients with compromised renal function are at higher risk of adverse effects from NSAIDs, according to the National Comprehensive Cancer Network and American Heart Association 2, 3, 4

Medication-Related Risk Factors

• Concomitant use of anticoagulants, corticosteroids, or low-dose aspirin increases the risk of GI bleeding or events 2-4 fold 1
• Concurrent use with low-dose aspirin may reduce the cardioprotective effects of aspirin, and planned surgical procedures may increase the risk of perioperative bleeding 4, 5

Cardiovascular Risks

• Both celecoxib and meloxicam carry cardiovascular risks, as do all NSAIDs, with the risk of celecoxib being dose-dependent, significant only at doses of 400mg twice daily 2, 6
• The American Heart Association and American College of Cardiology note that NSAIDs, such as diclofenac and ibuprofen, carry FDA black box warnings for increased risk of cardiovascular thrombotic events, with risk increasing with duration of use and higher in patients with existing cardiovascular disease or risk factors 2

Gastroprotection and Compliance

• Proton pump inhibitors (PPIs) reduce gastric acid and promote healing, with an efficacy of up to 90% in reducing endoscopic NSAID-related ulcers, while misoprostol and H2 receptor antagonists have lower efficacy 6, 7
• The following table summarizes the efficacy of different gastroprotective agents:

• Celecoxib reduces the risk of gastrointestinal clinical events by approximately 50% compared to traditional NSAIDs, and adding a PPI to a traditional NSAID reduces the risk of bleeding ulcers by 75-85% 1
• Poor compliance with gastroprotective agents increases the risk of NSAID-induced upper GI adverse events by 4-6 times, and focusing only on upper GI protection may overlook significant lower GI tract problems caused by NSAIDs 6

Contraindications and Precautions

• Active gastrointestinal bleeding, severe heart failure, cirrhotic liver disease, and third trimester of pregnancy are contraindications for NSAID use, as they can worsen the condition or increase the risk of adverse effects 2, 8, 5
• Regular assessment for GI toxicity, hypertension, heart failure, and drug interactions is recommended by the American Geriatrics Society, along with periodic laboratory monitoring including renal function, electrolytes, and complete blood count 9

Monitoring and Management

• Repeat laboratory tests every 3 months to ensure lack of toxicity, including blood pressure measurement, BUN and creatinine, liver function tests, complete blood count, and fecal occult blood test 3
• Consider annual comprehensive assessment, including review of continued need for therapy, evaluation of dose optimization, comprehensive cardiovascular risk assessment, and assessment for any cumulative toxicity, in patients on long-term NSAID therapy (>1 year) 10
• The American College of Gastroenterology strongly advises against NSAIDs in patients with active gastrointestinal conditions, and recommends non-NSAID analgesics, such as acetaminophen/paracetamol, as a first-line option, with dose adjustments recommended for patients with hepatic cirrhosis 6, 11, 12
• Low-dose tricyclic antidepressants, such as amitriptyline, are effective for visceral pain with minimal GI effects, starting at 10mg at night and titrating by 10mg weekly to a maximum of 30-50mg 13
• The National Comprehensive Cancer Network suggests considering acetaminophen instead of a second NSAID for pain management, and using the lowest effective dose for the shortest duration possible, and using either topical diclofenac or oral ibuprofen (not both) with acetaminophen may provide a better safety profile for more severe pain 4