Cardiovascular disease (CVD), principally myocardial infarction (MI) and stroke, is the leading clinical and public health problem in the United States and is rapidly becoming so worldwide. Their primary prevention is promising, in theory, but difficult to achieve in practice. The principal modalities that have demonstrated efficacy include therapeutic lifestyle changes (TLCs) and adjunctive drug therapies under the guidance of the health-care provider and tailored to the individual patient. The prevention and treatment of the pandemic of overweight and obesity and lack of regular physical activity, both of which are alarmingly common in the United States, prevention and treatment of hypertension, avoidance and cessation of cigarette smoking, adoption and maintenance of a healthy diet, and avoidance of heavy alcohol consumption all have proven benefits in decreasing the risks of a first MI and stroke as well as other clinical manifestations of CVD. Although adoption of TLCs would avoid the need for adjunctive drug therapies in many primary prevention subjects, this strategy is difficult to achieve or maintain for most and may be insufficient for many, especially those at high risk with metabolic syndrome. The criteria for metabolic syndrome, affecting over 40% of the adult population older than 40 in the United States, include overweight or obesity, dyslipidemia, hypertension, and insulin resistance, a precursor of diabetes. The adjunctive therapies of proven benefit in the primary prevention of MI and stroke include statins, blood pressure medications, aspirin, and drugs to treat insulin resistance and hyperglycemia. Fortunately, even for patients who prefer prescription of pills to proscription of harmful lifestyles, these drug therapies still have net benefits. The adoption and maintenance of TLCs and adjunctive drug therapies into clinical practice will reduce both the incidence of and mortality from a first MI and stroke as well as other major clinical manifestations of CVD.

Nonsteroidal anti-inflammatory drugs (NSAIDs) include traditional (tNSAIDs), such as ibuprofen, naproxen, and diclofenac, as well as selective cyclooxygenase-2 inhibitors (COXIBs), principally celecoxib. COXIBs were developed to decrease gastrointestinal side effects. Recently, the US Food and Drug Administration strengthened its warning about the risks of non-aspirin NSAIDs on myocardial infarction and stroke. The Cyclooxygenase 2 and Non-Steroidal Anti-Inflammatory Drug Trialist collaboration conducted a comprehensive worldwide meta-analysis using individual patient data exploring the risks of various COXIBs and NSAIDs on cardiovascular disease (CVD). Recently, the results of the Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen or Naproxen (PRECISION) trial were published that tested risks of COXIBs and NSAIDs on CVD. Generally, data from meta-analyses of trials not designed a priori to test hypotheses are less reliable than large-scale randomized trials to test small to moderate benefits or harm. When the sample size is large, randomization provides control of confounding not possible to achieve in any observational study. Further, observational studies, and especially claims data, have inherent confounding by indication larger than the effects being sought. Nonetheless, trials must be of sufficient size and duration and achieve high compliance and follow-up to avoid bias and confounding. In this regard, PRECISION has high rates of nonadherence and losses to follow-up that may have introduced bias and confounding. At present, therefore, it may be most prudent for clinicians to remain uncertain about benefits and risks of these drugs and make individual clinical judgments for each of their patients.