不同於Rofecoxib,Celecoxib可能與心肌梗塞風險增加無關


  Dec. 8, 2004 - 一項發表於12月7日線上,且即將於2005年2月1日發表於內科學誌的病例控制試驗結果顯示,不同於rofecoxib,celecoxib顯然不會增加心肌梗塞(MI)的風險。
  
  主要作者賓州費城大學醫學中心Stephen E. Kimmel醫師在一則新聞中表示,我們的結果顯示,在心臟病發作風險上,rofecoxib與celecoxib有很明顯的差異,這需要進一步的試驗,最好是隨機分派試驗,來完全地瞭解cyclooxygenase-2(COX-2)抑制劑的作用範圍。
  
  根據之前的試驗,研究人員暗示,COX-2選擇性抑制劑透過許多機轉影響心臟血管風險,其中一些會增加風險,例如抑制前列腺素合成,而其他的則會降低風險,例如抑制發炎。
  
  這項試驗包含了1,718位病患,因為首次非致命的MI住進5個郡的36家醫院,以及從同樣區域隨機選出的6,800位控制組受試者,透過電話訪談來進行藥物使用的申報。
  
  相較於沒有使用非類固醇抗發炎藥物(NSAIDs)的人們,服用celecoxib發生MI校正後的勝算比為0.43(95%信賴區間為0.23-0.79),服用rofecoxib的為1.16(95%信賴區間為0.70-1.93);相較於使用celecoxib者,使用rofecoxib發生MI的可能性明顯較高(校正後的勝算比,rofecoxib相較於celecoxib為2.72;95%信賴區間為1.24-5.95;P=.01)。
  
  沒有使用非選擇性NSAIDs發生非致命性MI的風險較低,Rofecoxib相較於naproxen的勝算比為3.39(95%信賴區間為1.37-8.40),而celecoxib相較於ibuprofen或是diclofenac的勝算比為0.77(95%信賴區間為0.40-1.48)。
  
  該項試驗的限制,包括可能的記憶誤差、未經控制的影響因子、觀察型試驗設計限制、僅有大約一半的合格參加者完成電話訪談、以及celecoxib造成MI風險較低是偶然。
  
  研究人員表示,celecoxib與rofecoxib與MI發生的機率是不同的;Celecoxib或是其他有關的COX-2選擇性抑制劑,可保護預防MI的可能性被認為僅僅是項理論,仍需要進一步的研究加以證實。
  
  國家衛生研究院、仙靈葆雅(現在是輝瑞藥廠)以及默克藥廠贊助這項試驗;Kimmel醫師接受輝瑞藥廠的顧問職,但是與COX-2抑制劑無關。
  
  在隨後的主篇評論中,布萊根婦女醫院、貝絲以色列女執事醫院,與麻州波士頓哈佛大學的Axel Finckh醫師與Mark D. Aronson醫師,討論最近有關rofecoxib下架以及相關的課題;他們附帶表示,抑制COX-2在動脈瘤形成的角色是很複雜的,而且目前為止尚未完全瞭解;然而,COX-2抑制劑的的心臟毒性最可靠的證據是來自於大型隨機分派、雙盲試驗,例如Vioxx Gastrointestinal Outcomes Research(VIGOR)試驗。
  
  Finckh與Aronson醫師表示,我們相信已經有兩種這類COX-2抑制劑不同的藥物與心臟相關死亡率的增加有關(rofecoxib與valdecoxib),醫師們應該避免對有心臟血管危險因子,及腸胃道毒性因子的病患,使用這些藥物作為第一線的治療;面對是否所有的COX-2抑制劑都有這類心臟毒性的不確定性,對於腸胃道毒性的高危險群病患,我們建議使用一種傳統非選擇性、非阿斯匹靈的NSAID,同時併用腸胃道保護藥物,或是celecoxib(Celebrex);目前急迫地需要進一步的試驗來闡明COX-2抑制劑與非選擇性、非阿斯匹靈NSAIDs的安全性。
  
  類風濕性疾病Centocor健康成果(CHORD)獎學金、Krikland基金會、國家衛生研究院、Stoneman品質提昇中心、貝絲以色列女執事醫院贊助這項試驗;Finkch醫師表示,正在申請惠氏藥廠的研究經費。

Unlike Rofecoxib, Celecoxib No

By Laurie Barclay, MD
Medscape Medical News

Dec. 8, 2004 — Unlike rofecoxib, celecoxib does not appear to increase risk of myocardial infarction (MI), according to the results of a case-control study posted online Dec. 7 and published in the Feb. 1, 2005, print issue of the Annals of Internal Medicine.

"Our results suggest that there is a marked difference between rofecoxib and celecoxib relative to heart-attack risk," lead author Stephen E. Kimmel, MD, MSCE, from the University of Pennsylvania Medical Center in Philadelphia, says in a news release. "Further studies, preferably randomized trials, are needed to fully understand the spectrum of effects of [cyclooxygenase-2] (COX-2) inhibitors."

Based on earlier studies, the investigators suggest that COX-2 selective inhibitors affect cardiovascular risk through various mechanisms. Some of these, such as inhibition of prostacyclin production, could increase risk, and others, such as inhibition of inflammation, could decrease risk.

Cases consisted of 1,718 patients with a first, nonfatal MI admitted to 36 hospitals in a five-county area, and 6,800 control subjects were randomly selected from the same counties. Self-reported medication use was determined from telephone interviews.

Compared with persons who did not use nonaspirin nonsteroidal anti-inflammatory drugs (NSAIDs), the adjusted odds ratio for MI was 0.43 (95% confidence interval [CI], 0.23 - 0.79) for celecoxib users and 1.16 (95% CI, 0.70 - 1.93) for rofecoxib users. Compared with the use of celecoxib, the use of rofecoxib was associated with a statistically significant higher likelihood of MI (adjusted odds ratio for rofecoxib vs celecoxib, 2.72; 95% CI, 1.24 - 5.95; P = .01).

Nonselective NSAIDs were associated with reduced odds of nonfatal MI compared with nonusers. Odds ratios were 3.39 (95% CI, 1.37 - 8.40) for rofecoxib vs naproxen, and 0.77 (95% CI, 0.40 - 1.48) for celecoxib vs ibuprofen or diclofenac.

Study limitations include possible recall bias and uncontrolled confounding, observational study design, telephone interviews completed by only about half of eligible participants, and possible chance association of celecoxib with a lower risk of MI.

"Celecoxib and rofecoxib were associated with different odds of MI," the authors write. "The possibility that celecoxib or other relatively COX-2 selective inhibitors could protect against MI should also be considered only a hypothesis that deserves further study."

The National Institutes of Health, Searle Pharmaceuticals (now Pfizer, Inc.), and Merck & Co., Inc., supported this study. Dr. Kimmel has consulted for Pfizer on matters unrelated to COX-2 inhibitors.

In an accompanying editorial, Axel Finckh, MD, MS, and Mark D. Aronson, MD, from Brigham and Women's Hospital, Beth Israel Deaconess Medical Center, and Harvard Medical School, in Boston, Massachusetts, discuss the recent market withdrawal of rofecoxib and surrounding issues. They note that the role of COX-2 inhibition in atherogenesis is complex and not completely understood. However, the most reliable evidence of cardiovascular toxicity of the COX-2 inhibitors comes from large randomized, double-blind trials such as the Vioxx Gastrointestinal Outcomes Research (VIGOR) study.

"We believe that because two separate drugs in the class of COX-2 inhibitors have now been associated with increased cardiovascular morbidity (rofecoxib and valdecoxib), physicians should avoid COX-2 inhibitors as a first-line agent in patients with cardiovascular risk factors and average risk for gastrointestinal toxicity," Drs. Finckh and Aronson write. "In light of the current uncertainty about whether cardiotoxicity is a class effect of COX-2 inhibitors, we suggest using either a nonselective nonaspirin NSAID with a concomitant gastroprotective agent or celecoxib (Celebrex) for patients at high risk for gastrointestinal toxicity. Further study is urgently needed to document the safety of COX-2 inhibitors and nonselective nonaspirin NSAIDs."

The Centocor Health Outcomes in Rheumatic Diseases (CHORD) fellowship, the Kirkland Foundation, the National Institutes of Health, and the Stoneman Center for Quality Improvement, Beth Israel Deaconess Medical Center, supported this work. Dr. Finckh reports a pending grant from Wyeth.

Ann Intern Med. Published online Dec. 7, 2004.

Reviewed by Gary D. Vogin, MD

    
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