Cardiovascular NSAIDs

Recent data suggest that COX-2 inhibitors, including rofe-coxib, valdecoxib, and celecoxib, may increase the risk for MI and stroke.47 There is also some evidence that the non-selective NSAIDs may increase the risk for cardiovascular events.47,48 Rofecoxib was withdrawn from the market in late 2004 because of safety concerns. The FDA requested the withdrawal of valdecoxib from the market in 2005. The FDA also asked the manufacturers of celecoxib and non-selective NSAIDs (prescription and over-the-counter) to include information about the potential adverse cardiovascular effects of these drugs in their product labeling. The cardiovascular risk with COX-2 inhibitors and NSAIDs may be greatest in patients with a history of, or with risk factors for, cardiovascular disease. The American Heart Association recommends that the use of COX-2 inhibitors be limited to low-dose, short-term therapy in patients for whom there is no appropriate alternative.48 Patients with cardiovascular disease should consult a clinician before using over-the-counter NSAIDs. 

Previous peptic ulcer disease or upper gastrointestinal bleeding Cardiovascular disease and other comorbid conditions Multiple NSAID use (e.g., low-dose aspirin in conjunction with another NSAID)... 

With the availability of NSAIDs with COX-2 selectivity, clinicians postulated that these agents would avoid the need to add an additional prophylactic agent to therapy in patients with PUD risk factors. However, selective COX-2 inhibitors have not been shown to be any more effective than the combination of a PPI and a non-selective NSAID in reducing the incidence of ulcers, and questions remain regarding their long-term cardiovascular safety. 

Longer-term studies evaluating the cardiovascular risks associated with the use of COX-2 inhibitors have found a higher incidence of cardiovascular mortality with the use of these agents compared to traditional NSAIDs.29,33,34 This prompted the withdrawal of both rofecoxib and valdecoxib from the market and the inclusion of a black box warning in... 

NSAIDs may accentuate the increased risk of cardiovascular events inherent in patients with RA. Increases in blood pressure and fluid retention may exacerbate existing cardiovascular disease. With the evidence associating COX-2 inhibitors with cardiovascular disease, clinicians must carefully evaluate the potential risks of NSAID therapy against the potential benefits.2 See Chap. 55 for additional discussion of NSAID therapy. 

Cardiovascular Keep doses of NSAIDs and glucocorticoids low, consider initiation of folic acid to reduce homocysteine level elevations induced by methotrexate, consider initiation of low-dose aspirin and/or HMG-CoA reductase inhibitors (statins), and encourage smokers to discontinue tobacco use and assist with the development of a tobacco-cessation plan.11,12... 

NSAIDs are associated with gastrointestinal, renal, hepatic, and central nervous system toxicity and may increase blood pressure. NSAIDs that are selective for the cyclooxygenase-2 (COX-2) isozyme are less likely to cause gastrointestinal complications but may increase the risk of cardiovascular events. They are no more effective than nonselective NSAIDs. Selective agents should be reserved for patients at high risk of gastrointestinal complications and low risk for cardiovascular events. 

FIGURE 55-2. Treatment of osteoarthritis. OA, osteoarthritis COX-2, cyclooxygenase-2 CV, cardiovascular Gl, gastrointestinal, IA, intraarticular NSAID, nonsteroidal anti-inflammatory drug PPI, proton pump inhibitor. 

The advent of COX-2-selective inhibitors has led to unexpected results. By selectively inhibiting the COX-2 isoform, COX-2-selective NSAIDs increase the risk of cardiovascular events in certain patientsP COX-2 is responsible for the production of prostacyclin, a vasodilatory and antiplatelet substance. On the other hand, COX-1 controls the production of thromboxane A2, a vasoconstrictor and platelet aggregator. Selective inhibition of COX-2 results in decreased prostacyclin levels in the face of stable thromboxane A2 levels. An imbalance in the thromboxane A2 prostacyclin ratio ensues, which creates an environment that favors thrombosis. 

Cyclooxygenase-2 (COX-2)-selective inhibitors produce results comparable with those of traditional NSAIDs. However, cardiovascular safety concerns and the high cost of COX-2 inhibitors argue against their use for this disorder. 

The FDA approved this selective cyclooxigenase (COX)-2 inhibitor (Vioxx) for the treatment of pain and inflammation in 1999. This NSAID demonstrated to have a lower risk of side effects such as gastrointestinal ulcers and bleeding than nonse-lective COX inhibitors, for example, ibuprofen. In 2004, a long-term study of Vioxx in patients at increased risk of colon polyps was halted because of an increased cardiovascular risk (heart attack, stroke) in the rofecoxib group. Subsequently, Merck withdrew the drug from the world market at the end of September 2004 [46]. 

The devil you knew is safer than the one you ve just heard about. In the rofecoxib debate, for example, the media rarely attempted to quantify the number of life-threatening gastrointestinal bleeds caused by first generation NSAIDs but avoided by rofecoxib. Instead, the discussion focused entirely on the newly-identified cardiovascular risks. 

Cardiovascular (CV) risk NSAIDs may cause an increased risk of serious CV thrombotic events, myocardial infarction (Ml), and stroke, which can be fatal. This risk may increase with duration of use. Patients with CV disease or risk factors for CV disease may be at higher risk. 

Lactation Most NSAIDs are excreted in breast milk. In general, do not use in nursing mothers because of effects on infant s cardiovascular system. 

Gastrointestinal safety of COX selective inhibitors compared with non-selective NSAIDs the principle areas of concern are upper gastrointestinal and cardiovascular safety. 

Cardiovascular safety. Both drug types promote salt retention, can exacerbate heart failure and tend to raise blood pressure. COX-2 selective drugs also appear to raise the risks of thrombotic events, notably stroke and myocardial infarction, and recent evidence suggests that non-selective NSAIDs also raise these risks, though it is unclear whether to the same degree. For both drug types, dose and duration of treatment appear to affect risk. 

Some general principles for the treatment of Seronegative Spondylarthritis can be summarized as follows. Mild cases of SpA are controlled with physiotherapy and NSAIDs, paying attention to GI, renal, cardiovascular, hypertensive and hepatic risk... 

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