Thrombotic cardiovascular event

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. 

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). 

Because most hot flashes resolve in 1 to 3 years, short-term use may be all that is needed, and can significantly improve quality of life. Short-term use, however, may increase the risk for cardiovascular events due to thrombogenesis and coronary heart disease, and should generally be avoided in women with preexisting cardiovascular disease, prior history of blood clots, or any condition that increases the risk for thrombotic events. With each year of use the risk for breast cancer and gallbladder disease increases. Long-term use decreases the risk for colon cancer and hip fracture. The side effects, contraindications, and drug interactions with HRT are similar to those for oral contraception (see Case 34). 

The toxicity of ephedrine is closely related to adverse cardiovascular events, since the clinical presentation of toxicity reflects the sympathomimetic activity of these agents. The adrenergic effects can shorten cardiac refractory periods, permitting the development of reentrant cardiac arrhythmias. The worst complication related to the use of ephedrine is thrombotic stroke, presumably resulting from vasoconstriction of large cerebral arteries that in turn leads to local thrombosis [71]. Other adverse effects include hypertension, diaphoresis, hypothermia, and agitation. The best treatment in an overdose is the rapid identification of the symptoms followed by supportive management. 

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]. 

Recent analyses have allowed a more precise estimation of the increased cardiovascular risk associated with regular use of coxibs or non-selective NSAIDs. The 5-year efficacy and safety analysis of the Adenoma Prevention with Celecoxib Trial (2035 patients receiving placebo, celecoxib 200 mg bd, or celecoxib 400 mg bd) showed that for cardiovascular and thrombotic adverse events, the RR compared with placebo was 1.6 (95% Cl = 1.0, 2.5) for patients taking celecoxib 200 mg bd and 1.9 (95% Cl = 1.2, 3.1) for patients taking celecoxib 400 mg bd [12 ]. 

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 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. 

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... 

The initial question must be whether the clinical data point to the emergence of complications of this type. The 1990 International Consensus Meeting found an increase in acute cardiovascular accidents during use of oral contraceptives, but not persisting after they had been discontinued. There is also a great deal of anecdotal evidence, although in view of the massive scale on which oral contraceptives have been used over 40 years, coincidence alone would lead to the accumulation of many reports of adverse events. Other evidence suggesting an increase in arterial thrombotic events has been noted incidentally in... 

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