鈣離子阻斷劑及ACE阻斷劑合併使用有助高血壓治療


  March 14, 2005 (奧蘭多) - 根據斯堪地那維亞心血管研究(Anglo-Scandinavian Cardiac Outcomes Trial,簡稱ASCOT)的血壓降低專案試驗(BPLA)研究結果顯示,鈣離子阻斷劑及血管張力素轉化酶抑制劑(ACE)合併使用,對高血壓的治療,效果比乙型阻斷劑及利尿劑還要好。
  
  來自英國倫敦皇家理工學院的Peter S. Severe醫師表示,相較於使用atenolol/bendroflumethiazide的患者,被隨機分配到amlodipine/perindopril的患者,有著較低的心血管疾病致死率,較少的中風機率,糖尿病的新發病例也比較少;對於高血壓的高危險群,與其探討單一用藥的效果,不如研究出一個最好的治療對策。
  
  治療的目標設定在140/90 mmHg以下;ASCOT-BPLA的試驗結果發表於美國心臟醫學學會(ACC)的2005年科學年會上。
  
  本項臨床試驗是最近一次的相關性研究,這項研究結果對美國國家聯席委員會高血壓的預防、檢查、評估及治療指引第7版(JNC-VII)所作出的建議提出質疑;JNC-VII的建議是,類似thiazide的利尿劑,應該用於大部分高血壓患者的初期治療。
  
  參與試驗的高血壓患者一共有19257位,年齡介於40到79歲之間,試驗者必須無心肌梗塞(MI)的現象,且無臨床上的冠狀動脈心臟病變(CHD);在2004年12月時,本項研究被提前終止,因為當時的數據顯示,Atenolol/bendroflumethiazide組較之amlodipine/perindopril組發生更多的試驗終點案例,因此數據監控人員及安全委員會作出停止的決定;Severe醫師表示,因為試驗提早結束的關係,導致ASCOT無法針對主要的試驗終點,判斷兩組之間是否有明顯的差異;試驗終點指的是非致命性的MI及致命性CHD症狀。
  
  該項試驗預測在1150個試驗終點案例發生後,即可在兩組之間看出明顯的差異,但實際上,只經過了5.4年及869個案例後,試驗即宣告結束;在試驗結束時,amlodipine/perindopril組的總合死亡相關風險,比另一組低了14%;非致命性MI及致命性CHD症狀,amlodipine/perindopril組也較之另一組低了10%;但就統計而言,這些並不構成明顯差異。
  
  在ACC的記者會上,Severe醫師表示,我們必須要為我們的研究結果抗辯,因為如果沒有提早結束,我們可以在統計上做到明顯的差異。
  
  ASCOT BPLA原先將本研究設計為階段性的治療試驗,患者在初期以隨機分配的方式接受鈣離子阻斷劑(必要時加入ACE阻斷劑),或乙型阻斷劑(必要時加入利尿劑);ASCOT來自瑞典的副發表員Bjorn Dahlof醫師表示,鈣離子阻斷劑試驗組中,只有14.3%的患者維持單藥治療,乙型阻斷劑組中只有8.6%。
  
  兩組之間,有一些二級試驗終點已經顯現了明顯的差異,項目如下:
  *糖尿病新發案例降低32% (P < .001)。
  *中風率降低23% (P < .001) 。
  *心血管病變致死率降低24% (P < .001)。
  *心血管病變案例及治療程序皆降低16% (P < .001)。
  *總冠狀動脈病變案例降低14% (P = .05)。
  
  紐約州康乃爾大學Weil醫學院的Richard Devereux醫師目前為該研究報告的評論員,他表示,很明顯的可以看出,如perindopril這一類的腎素系統抑制藥物,治療效果優於乙型阻斷劑及利尿劑。
  
  根據Devereux醫師,鈣離子阻斷劑的治療患者,不但糖尿病案例少了三分之一,也有較高的高密度脂蛋白膽固醇及三酸苷油脂的濃度;就這一點而言,鈣離子阻斷劑與ACE阻斷劑的結合,顯然優於乙型阻斷劑及利尿劑。
  
  有許多的與會人員皆預測,ASCOT-BPLA的試驗結果會對JNC造成壓力,可能因此去除JNC-VII中的thiazide使用建議。
  
  在ACC記者會中,Severe醫師指出,英國的治療準則建議將乙型阻斷劑納入第一線的治療,但是他認為英國的治療準則委員會應該會重新評估這項乙型阻斷劑的治療建議,這當然也是受到ASCOT-BPLA試驗結果的影響;Severe醫師進一步指出,ASCOT的數據會引發嚴重的質疑,也就是說,未來是否應該使用乙型阻斷劑來治療高血壓。
  
  本研究的贊助單位,含輝瑞藥廠及其在巴黎的Servier研究小組,瑞典哥本哈根的Leo Laboratories。

Calcium Channel Blocker and AC

By Peggy Peck
Medscape Medical News

March 14, 2005 (Orlando) — Calcium channel blockers and angiotensin-converting enzyme (ACE) inhibitors are a more effective combination for treating hypertension than beta-blockers and diuretics, according to results of the Anglo-Scandinavian Cardiac Outcomes in the Blood Pressure Lowering Arm (ASCOT-BPLA) trial.

Patients randomized to amlodipine/perindopril had significantly lower cardiovascular mortality, fewer strokes, and less new-onset diabetes than patients randomized to atenolol/bendroflumethiazide. Peter S. Severe, PhD, FRCC, professor of clinical pharmacology at Imperial College in London, U.K., said, "We were looking to see which treatment strategy worked best in high-risk hypertensive patients, rather than how well individual classes of drugs worked."

The patients were treated to a blood pressure goal of 140/90 mm Hg or less. The ASCOT-BPLA results were presented during a late-breaking clinical trials session here at the American College of Cardiology (ACC) 2005 Annual Scientific Session.

The trial is the latest hypertension study in which the findings raise questions about the recommendations of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure VII (JNC-VII) that “thiazide-like diuretics should be used as initial treatment for most patients with hypertension.”

The trial enrolled 19,257 hypertensive patients, aged 40 to 79 years, who had no previous myocardial infarction (MI) or clinical coronary heart disease (CHD). It was stopped early — November 2004 — when the trial's data monitoring and safety board determined that more end point events were occurring in the atenolol/bendroflumethiazide group than in the amlodipine/perindopril group. The early halt of the trial prevented the ASCOT results from reaching statistical significance for the primary end points of nonfatal MI and fatal CHD, Dr. Severe said. The study was powered to reach significance after 1,150 such events, but the trial was stopped after 5.4 years and 869 events. At the time the trial was halted, there was a 14% reduction in relative risk of all-cause mortality favoring the amlodipine/perindopril group (P < .001) There was also a 10% difference in the primary end point of nonfatal MI or fatal CHD — again favoring amlodipine/perindopril — but this did not reach significance.

"We defend our results because we believe it would have reached significance if the trial had not been prematurely halted," Dr. Severe said during an ACC press briefing.

ASCOT BPLA was designed as a step-therapy trial with patients initially randomized to either the calcium channel blocker or the beta-blocker with an ACE inhibitor added to the calcium channel blocker group and a diuretic to the beta-blocker group as needed, but only 14.3% of patients in the calcium channel blocker group and 8.6% in the beta-blocker group remained on monotherapy, said ASCOT copresenter Björn Dahlöf, MD, associate professor of medicine at Sahlgrenska University Hospital/Ostra in Goteborg, Sweden.

A number of prespecified secondary end points did, however, reach significance:

  • New-onset diabetes mellitus was decreased by 32% (P < .001).
  • Stroke was decreased by 23% (P < .001)
  • Cardiovascular death was decreased by 24% (P < .001).
  • Cardiovascular events and procedures were decreased by 16% (P < .001)
  • Total coronary events were reduced by 14% (P = .05).

Richard Devereux, MD, professor of medicine at Weill Medical College of Cornell University in New York, who served as discussant for the paper, said, “It is pretty clear that drugs which inhibit the renin system — such as perindopril — add much more of a benefit to the treatment regimen than does a beta-blocker and diuretic.”

Moreover, Dr. Devereux noted that patients in the calcium channel blocker group not only had about one third less diabetes, they also had better high-density lipoprotein cholesterol and triglyceride levels, which he said again favors the “newer” calcium channel blocker–ACE inhibitor combination over the older combination of beta blocker and diuretic.

Several attendees speculated that the ASCOT-BPLA results will increase pressure on the JNC to back away from the thiazide-first recommendations in JNC-VII.

At the ACC press conferences, Dr. Severe noted that the U.K. guidelines recommend beta-blockers as first-line treatment, but he and his colleagues expect the U.K. guideline committee to “reevaluate beta-blockers as first-line treatment” in light of the ASCOT BPLA results. Dr. Sever said the ASCOT data raise “serious questions about the future of beta-blockers in the management of hypertension.”

The study was funded by Pfizer, Inc., in New York, the Servier Research Group in Paris, France, and Leo Laboratories in Copenhagen, Denmark.

ACC 2005 Annual Scientific Session: Late-breaking clinical trials. Presented March 8, 2005.

Reviewed by Gary D. Vogin, MD

    
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