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Non-steroidal anti-inflammatory drugs, both non-selective and selective cyclooxygenase 2 inhibitors, are among the most widely used drugs, especially in the elderly, with multiple comorbidities. Exposition to a polypharmacy burden represents a favourable substrate for the onset of non-steroidal anti-inflammatory drug-induced deleterious effects. Cardiovascular and renal issues concerning the occurrence of myocardial infarction, atrial fibrillation, heart failure and arterial hypertension, as well as acute or chronic kidney damage, become critical for clinicians in their daily practice. 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