진통소염제와 심혈관 위험, NSAIDs and cardiovascular risk

진통소염제는 nonselective NSAIDs이든 COX-2 inhibitors이든 심혈관 위험을 증가시킵니다. 다만 COX-2 inhibitors가 nonselective NSAIDs보다 위험이 크므로 심혈관 위험이 있는 환자에서는 COX-2 inhibitors를 피해야 합니다.

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즉, 심혈관위험이 있는 환자에서 진통소염제는 안 쓰면 좋겠지만 써야 할 상황이라면 nonselective NSAIDs를 사용하고, 위장관 보호가 필요하다면 PPI를 함께 사용합니다.

COX-2 Inhibitors (in Place of NSAIDs) ​ COX-2 inhibitors offer the hope of minimizing GI toxicity of NSAIDs while preserving their therapeutic effects. In a systematic review of randomized trials, when compared with nonselective NSAIDs the COX-2 inhibitors led to significantly fewer gastroduodenal ulcers (relative risk, 0.26; 95% CI, 0.23 to 0.30) and ulcer complications (relative risk, 0.39; 95% CI, 0.31 to 0.5), as well as fewer withdrawals caused by GI symptoms. However, the sparing effect of COX-2 inhibitors on ulcer development is negated by concomitant use of low-dose aspirin. ​ Current evidence indicates that COX-2 inhibitors are as effective as a combination of nonselective NSAIDs combined with a PPI in patients at risk for ulcers. In a randomized comparison of the NSAID diclofenac plus omeprazole versus celecoxib for secondary prevention of ulcer bleeding in patients who either were Hp negative or had undergone Hp eradication, a similar proportion of patients had recurrent bleeding in 6 months (6.4% in the diclofenac/omeprazole group and 4.9% of patients in the celecoxib group). Although the 2 treatments were comparable in terms of the incidence of ulcer bleeding, a subsequent follow-up endoscopic study showed that 20% to 25% of patients receiving either treatment developed recurrent endoscopic ulcers at 6 months. These findings suggest that neither treatment can eliminate the risk of recurrent bleeding in very high-risk patients. In a 13-month, double-blind randomized trial comparing celecoxib alone with celecoxib/esomeprazole in patients with a history of NSAID-associated ulcer bleeding, 8.9% of the celecoxib-alone group had recurrent ulcer bleeding compared with none of the combined therapy group (P = 0.0004). ​ Despite the improved gastric safety profile of COX-2 inhibitors, the cardiovascular risk associated with this new class of NSAIDs has been the subject of much concern. In the VIGOR study, the incidence of acute myocardial events, although low, was 4 times higher among patients receiving rofecoxib than among patients receiving naproxen. Whether this observed difference in myocardial infarction rates was related to an antiplatelet property of naproxen or to a prothrombotic effect of rofecoxib was hotly debated. Further data regarding the cardiovascular hazards of COX-2 inhibitors were derived from 2 long-term studies of colon polyp pre­vention, using either rofecoxib (the Adenomatous Polyp Prevention on Vioxx [APPROVE] study) and celecoxib (the Adenoma Prevention with Celecoxib [APC] study). In APPROVE, interim data at 18 months indicated that patients who had received 25 mg rofecoxib a day had twice the risk of serious cardiovascular events compared with patients who received placebo. In September 2004, rofecoxib was voluntarily withdrawn from worldwide markets in light of this unexpected finding. In the APC study, interim data at 33 months showed that serious cardiovascular events were significantly more frequent with celecoxib at the high dose of 400 mg twice a day (hazard ratio, 1.9; 95% CI, 1 to 3.3). In addition, in randomized placebo-controlled trials of 2 other COX-2 inhibitors, parecoxib and valdecoxib, in patients who had undergone coronary artery bypass surgery there was an almost 4-fold increased risk of myocardial infarction. ​ Thus, COX-2 inhibitors as a class increase the risk of myocardial infarction. However, both polyp prevention trials investigated (by design) supratherapeutic doses of rofecoxib and celecoxib used for extended time periods. In the TARGET study of the COX-2 inhibitor lumiracoxib, rates of myocardial infarction with lumiracoxib were lower than with ibuprofen but higher than with naproxen. Neither difference was statistically significant, because the trial was underpowered to detect a difference in cardiovascular outcomes between treatment groups. The MEDAL program was a prespecified pooled analysis of cardiothrombotic events from 3 trials in which patients with osteoarthritis or rheumatoid arthritis were randomly assigned to etoricoxib (60 mg or 90 mg daily) or diclofenac (150 mg daily). After an average treatment of 18 months, rates of cardiothrombotic events were similar between the 2 treatment groups. ​ Emerging evidence suggests that not only COX-2 inhibitors but also nonselective NSAIDs, with the exception of full-dose naproxen (1000 mg/day), increase cardiothrombotic risk. In a meta-analysis of randomized trials of COX-2 inhibitors (data mostly derived from rofecoxib and celecoxib), all COX-2 inhibitors increased the cardiothrombotic risk compared with placebo (risk ratio, 1.42; 95% CI, 1.13 to 1.78). This was largely attributable to an increased risk of myocardial infarction, with little difference in other vascular outcomes. A dose-dependent increase in cardiothrombotic events was observed with celecoxib. Importantly, there was no significant difference in cardiothrombotic risk between COX-2 inhibitors and nonselective NSAIDs, with naproxen (500 mg twice daily) the only exception. In a meta-analysis of observational studies, high-dose rofecoxib (≥25 mg a day), diclofenac, and indomethacin were associated with an increase in car­diothrombotic events, whereas celecoxib did not significantly increase the cardiothrombotic risk, though an increased risk could not be excluded with doses greater than 200 mg/day. A large-scale, randomized head-to-head comparison of COX-2 inhibitors and nonselective NSAIDs using predefined cardiothrombotic events as the primary endpoint is underway.

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Individuals who are not at risk for CV events do not use aspirin and are without risk for GI complications can receive nonselective NSAIDs without gastric protection. In those without CV risk factors but with a high potential risk (prior GI bleeding or multiple GI risk factors) for NSAID-induced GI toxicity, cautious use of a selective COX-2 inhibitor and co-therapy with misoprostol or high-dose PPI are recommended. Individuals at moderate GI risk without cardiac risk factors can be treated with a COX-2 inhibitor alone or with a nonselective NSAID with misoprostol or a PPI. Individuals with CV risk factors, who require low-dose aspirin and have low potential for NSAID-induced toxicity, should be considered for a non-NSAID agent or use of a traditional NSAID such as naproxen (lower CV side effects) in combination with gastric protection, if warranted. Finally, individuals with CV and GI risks who require aspirin must be considered for non-NSAID therapy, but if that is not an option, then gastric protection with any type of NSAID must be considered. Any patient, regardless of risk status, who is being considered for long-term traditional NSAID therapy, should also be considered for H. pylori testing and treatment if positive.

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REF. Harrison's Internal Medicine 20th edition

Sleisenger and Fordtran's Gastrointestinal and liver disease, 10th edition