Thrombotic cardiovascular

Nonacidic drugs. COXIBs are associated with fewer gastrointestinal adverse effects, but otherwise the general profile of adverse reactions to NSAIDs applies. The possibility that COXIBs may be associated with increased risk of thrombotic cardiovascular events is the subject of pharmacovigilance studies. 

It has been suggested that the increase in thrombotic cardiovascular events in rofecoxib-treated patients probably represents the antiplatelet effect of naproxen (34,45,46). Naproxen has a long pharmacodynamic half-life and inhibits platelet aggregation by 88% for up to 8 hours (47). 

In VIGOR (30,33), the incidence of confirmed thrombotic cardiovascular events was 0.6% higher with rofecoxib than with naproxen (RR = 2.4 95% Cl = 3.9, 4.0). 

Cardiovascular risk increasing evidence is surfacing that NSAID use, but particularly the use of COX-2 selective NSAIDS, elevates the risk of cardiovascular morbidity and mortality. This is especially true in patients with preexisting cardiovascular disease. Thrombotic cardiovascular events are related to a relative increase in thromboxane and a relative diminution in prostacycline. Since most selective as well as nonselec-tive NSAIDS affect this relative imbalance of thromboxane over prostacycline they are all implicated in increasing the risk for thrombotic cardiovascular events [6]. However, naproxen appears to be risk-neutral with regard to cardiovascular events and may in fact be somewhat cardioprotective due to its nonselectivity [7j. 

However, some non-selective NSAIDs other than naproxen may also increase cardiovascular risk. Coxibs cause more cardiovascular adverse events than naproxen but do not seem to increase cardiovascular risk compared with some other non-selective NSAIDs [5, 9 7- For example, data from the MEDAL study (n = 23 504 patients, see above) showed that the thrombotic cardiovascular risk hazard ratio of etoricoxib versus diclofenac was 0.96 (95% Cl = 0.81, 1.15), suggesting that etoricoxib was not more dangerous than diclofenac [bF]. 

However, the mechanism for the increased incidence of cardiovascular disease in CHC users is believed to be thromboembolic and thrombotic changes, not atherosclerosis. 

Dysregulation of the vascular endothelium has emerged as a critical component of most thrombotic disorders [10, 21]. Often without any anatomical sign of atherosclerosis, many cardiovascular diseases express a vasomotor abnormality termed endothelial dysfunction, indexed clinically as impaired endothelium-dependent vasodilation [31]. Although its mechanism is multifactorial, endothelial dysfunction is characterized by diminished vascular NO production and/or bioavailability [32]. The... 

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. 

Cardiovascular- Palpitation tachycardia vascular thrombotic disease. 

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. 

Selectivity for COX-1 versus COX-2 is variable and incomplete for the older NSAIDs, but many selective COX-2 inhibitors have been synthesized. The selective COX-2 inhibitors do not affect platelet function at their usual doses. In testing using human whole blood, aspirin, ibuprofen, indomethacin, piroxicam, and sulindac are somewhat more effective in inhibiting COX-1. The efficacy of -2-selective drugs equals that of the older NSAIDs, while gastrointestinal safety may be improved. On the other hand, selective COX-2 inhibitors may increase the incidence of edema and hypertension. As of December 2008, celecoxib and the less selective meloxicam are the only COX-2 inhibitors marketed in the USA. Rofecoxib and valdecoxib, two previously marketed, selective COX-2 inhibitors, have been withdrawn from the market due to their association with increased cardiovascular thrombotic events. Celecoxib has an FDA-initiated "black box" warning concerning cardiovascular risks. It has been recommended that all NSAID product labels be revised to include cardiovascular risks. 

Effects of the cyclooxygenase-2 specific inhibitor valdecoxib versus nonsteroidal antiinflammatory agents and placebo on cardiovascular thrombotic events in patients with arthritis. Am] Ther. 2004 11 244-250. 

Fareed J, Hoppensteadt DA, Bick RL. Management of thrombotic and cardiovascular disorders in the new millennium. Clin Appl Thromb Hemost2003 9(2) 101-108. 

Limited data are available to link clopidogrel nonresponsiveness to the occurrence of thrombotic events. Matetzky et al. studied clopidogrel responsiveness in patients undergoing stenting for acute ST-elevation Ml. They found that patients who exhibited the highest quartile of ADP-induced aggregation had a 40% probability for a recurrent cardiovascular... 

ASA nonresponsiveness or resistance is reported in 5% to 60% of patients (39,40). There is emerging clinical evidence that ASA resistance is associated with an increased risk of major adverse cardiovascular events. Five studies in patients with coronary peripheral, and/or cerebrovascular disease have reported a 1.8- to 10-fold increased risk of thrombotic events (41,42). 

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