聯(lián)用血管緊張素抑制劑可增加高鉀血癥、急性腎損傷風(fēng)險(xiǎn)

    Combined angiotensin inhibition raises hyperkalemia, acute kidney injury risks

    亞特蘭大--美國(guó)腎病學(xué)會(huì)主辦的2013年腎臟周會(huì)議上公布的VA NEPHRON-D研究結(jié)果顯示，在糖尿病性腎病患者中，聯(lián)用血管緊張素轉(zhuǎn)換酶抑制劑和血管緊張素受體阻滯劑與高鉀血癥和急性腎損傷風(fēng)險(xiǎn)增加相關(guān)。該研究因這些安全問(wèn)題被提前停止。

    這項(xiàng)隨機(jī)對(duì)照研究由匹茲堡大學(xué)醫(yī)學(xué)、流行病學(xué)、臨床與轉(zhuǎn)化科學(xué)教授Linda F. Fried醫(yī)生及其同事進(jìn)行，入組1,448例合并2型糖尿病和中度糖尿病性腎病的患者：尿白蛋白/肌酐比值≥300,估計(jì)腎小球?yàn)V過(guò)率（eGFR）為30.0--89.9 mL/min/ 1.73 m2或體表面積。復(fù)合主要終點(diǎn)包括首次出現(xiàn)eGFR改變、晚期腎病（ESRD）或死亡。eGFR改變定義為eGFR降低≥30 mL/min/1.73 m2（如果初始eGFR≥60 mL/min/1.73 m2）或降低≥50%（如果初始eGFR<60 mL/min/1.73 m2）。

    這些患者接受至少30天的血管緊張素受體阻滯劑（ARB）氯沙坦100 mg每日1次治療，此為糖尿病患者的標(biāo)準(zhǔn)治療方案。此為，患者還隨機(jī)接受血管緊張素轉(zhuǎn)化酶（ACE）抑制劑賴諾普利或安慰劑10--40 mg每日1次治療。

    在截至研究停止的中位隨訪2.2年時(shí)，聯(lián)合治療組和安慰劑組分別有152例患者和132例患者（21% vs. 18.2%）出現(xiàn)復(fù)合主要終點(diǎn)事件[聯(lián)合治療組風(fēng)險(xiǎn)比（HR） 0.88].組間差異無(wú)統(tǒng)計(jì)學(xué)顯著性。

    雖然聯(lián)合治療組觀察到早期獲益趨勢(shì)，但該趨勢(shì)隨時(shí)間推移而降低，因此兩組在首次出現(xiàn)eGFR降低或ESRD這一次要腎臟終點(diǎn)方面無(wú)顯著差異（HR 0.78）。此外，兩組在死亡這一安全終點(diǎn)方面無(wú)差異（死亡HR 1.04）。兩組的心血管事件發(fā)生率也相似。

    然而，聯(lián)合治療組的高鉀血癥風(fēng)險(xiǎn)是安慰劑組的2倍以上（6.3 vs. 2.6起事件/100 人-年），急性腎損傷風(fēng)險(xiǎn)是安慰劑組的近2倍（12.2 vs. 6.7起事件/100 人-年）。每隨訪100人1年，聯(lián)合治療組的入院例數(shù)就增加17例，獲益-風(fēng)險(xiǎn)比不支持聯(lián)合治療，因?yàn)椴话踩?/p>

    該研究結(jié)果也同時(shí)發(fā)表于《新英格蘭醫(yī)學(xué)雜志》（2013 Nov. 9 [doi10.1056/NEJMoa1303154]）。

    VA-Nephron-D研究獲美國(guó)退伍軍人事務(wù)部研究和發(fā)展辦公室的合作研究項(xiàng)目支持。研究藥物由默克公司的研究者發(fā)起研究項(xiàng)目提供。Fried醫(yī)生曾作為一項(xiàng)研究的現(xiàn)場(chǎng)研究者從Reata制藥公司獲得支持。其他作者從默克、賽諾菲安萬(wàn)特、Complex和/或CytoPherx公司獲得演講費(fèi)或顧問(wèn)費(fèi)。

    隨刊述評(píng)：研究結(jié)果標(biāo)志著雙重RAAS阻斷治療的終結(jié)--目前而言

    荷蘭格羅寧根大學(xué)醫(yī)學(xué)中心臨床藥理科的Dick de Zeeuw醫(yī)生表示，該研究在現(xiàn)有證據(jù)基礎(chǔ)上進(jìn)一步表明，雙重腎素-血管緊張素-醛固酮系統(tǒng)（RAAS）阻滯治療不能降低心血管和腎臟發(fā)病率，并且實(shí)際上可增加風(fēng)險(xiǎn)。

    目前而言，如果無(wú)法在界定的患者中證實(shí)雙重RAAS阻滯治療具有腎臟和心血管保護(hù)作用，無(wú)法在不增加高鉀血癥和其他副作用風(fēng)險(xiǎn)的情況下使患者獲得預(yù)期效果（血壓降低和/或蛋白尿減少）的話，那么就不應(yīng)恢復(fù)雙重RAAS阻滯治療的使用。de Zeeuw醫(yī)生聲明是AbbVie、Astellas、阿斯利康等多家公司的顧問(wèn)或指導(dǎo)委員會(huì)主席，這些公司均為其機(jī)構(gòu)支付費(fèi)用（N. Engl. J. Med. 2013 Nov. 9 [doi:10.1056/NEJMe1312412]）。

    By: SHARON WORCESTER, Cardiology News Digital Network

    ATLANTA - The combined use of an angiotensin-converting enzyme inhibitor and an angiotensin receptor blocker was associated with an increased risk of hyperkalemia and acute kidney injury in patients with diabetic nephropathy in a randomized, controlled trial that was halted early because of these safety concerns.

    “The risk-benefit ratio does not support the use of these medications - they're not safe,” noted Dr. Linda F. Fried, speaking at Kidney Week 2013.

    The VA NEPHRON-D （Veterans Affairs Nephropathy in Diabetes） study involved 1,448 patients with type 2 diabetes and moderate diabetic nephropathy who were treated for at least 30 days with 100 mg daily of the angiotensin-receptor blocker （ARB） losartan, as is standard practice in patients with diabetes. The patients were randomized to also receive 10-40 mg daily of the angiotensin-converting enzyme （ACE） inhibitor lisinopril or placebo.

    At a median follow-up of 2.2 years as of the time the study was stopped, 152 patients in the combination-therapy group and 132 in the placebo group （21% vs. 18.2%） experienced the composite primary endpoint of first occurrence of a predefined change in the estimated glomerular filtration rate （eGFR）， end-stage renal disease （ESRD）， or death （hazard ratio with combination therapy, 0.88）。 The difference between the groups was not statistically significant, said Dr. Fried, professor of medicine, epidemiology, and clinical and translational science at the University of Pittsburgh and chief of peritoneal dialysis at Veterans Affairs Pittsburgh Healthcare System.

    Despite an early trend toward benefit, this trend diminished over time so that no significant difference was seen between the groups in the secondary renal end point of a first occurrence of a decline in the eGFR or ESRD （hazard ratio, 0.78）。 Also, no difference was seen between the groups with respect to the safety outcome of mortality （HR for death, 1.04）。 The rate of cardiovascular events in the groups was also similar.

    However, there was a greater than twofold increase in the risk of hyperkalemia in the combination therapy group, compared with the placebo group （6.3 vs. 2.6 events/100 person-years）， and a nearly twofold increase in the risk of acute kidney injury in the combination therapy group （12.2 vs. 6.7 event/100 person-years）， Dr. Fried said at the conference, which was sponsored by the American Society of Nephrology.

    The findings were published concurrently in the New England Journal of Medicine （2013 Nov. 9 [doi10.1056/NEJMoa1303154]）。

    Patients in the study had type 2 diabetes, a urinary albumin-to-creatinine ratio of at least 300, and an eGFR of 30.0 to 89.9 mL/minute per 1.73 m2 or body-surface area. Change in eGFR as specified for the composite primary endpoint of the study was a decline of at least 30 mL/minute per 1.73 m2 in those with an initial eGFR of at least 60 mL/minute per 1.73 m2, or a decline of at least 50% if the initial eGFR was less than 60 mL/minute per 1.73 m2.

    Treatment with medications that block angiotensin are known to slow loss of kidney function in individuals with diabetes and proteinuria. This is true for both ACE inhibitors and ARBs, which have different mechanisms of action, but the percentage of patients who progress to dialysis despite treatment with one of these medications remains high, Dr. Fried said.

    “So we need more treatments. A question that comes up is, 'Would more intensive blockade of angiotensin - using two （drugs） together - slow decline?' … The thought was that treatments that lowered proteinuria should lower progression. We did see the lower proteinuria but without the benefit on the endpoints,” she said during a press briefing in advance of the presentation of the late-breaking abstract.

    Instead, it became clear that the treatment was associated with significantly more hyperkalemia and kidney injury, she said, noting that significantly more patients in the combination therapy group experienced acute kidney injury requiring hospitalization, indicating the problem was not just one of “lab abnormalities.”

    In fact, for every 100 persons followed for 1 year, there were 17 more admissions to the hospital, Dr. Fried said, noting that “these were not small differences in safety outcomes.”

    “The risk-benefit ratio does not support the use of these medications - they're not safe.” she concluded.

    The VA-Nephron-D study was supported by the cooperative studies program of the Department of Veterans Affairs Office of Research and Development. The Investigator-Initiated Studies Program of Merck provided the study drugs. Dr. Fried reported receiving support from Reata Pharmaceuticals as a site investigator for a study. Other studies authors reported receiving lecture or consulting fees from Merck, Sanofi-Aventis, Complex, and/or CytoPherx.

    View on the News

    Finding marks end of dual RAAS blockade - for now

    The VA Nephron-D study adds to existing evidence suggesting that dual renin-angiotensin-aldosterone system （RAAS） blockade does not decrease cardiovascular and renal morbidity, and actually carries increased risks, Dr. Dick de Zeeuw wrote in an editorial that accompanied the study by Fried, et al., in the New England Journal of Medicine.

    “The effect of these 'failed' trials goes beyond the decision about whether we should use dual RAAS blockade in order to better protect our patients with diabetes. The results suggest that improvement in surrogate markers - lower blood pressure or less albuminuria - does not translate into risk reduction,” he said （N. Engl. J. Med. 2013 Nov. 9 [doi:10.1056/NEJMe1312412]）。

    The findings make it clear that dual RAAS blockade for the treatment of patients with diabetes cannot currently be recommended, he said, adding that “we need to find ways to design trials that ultimately provide a better balance between efficacy and safety.

    ”An enrichment design, selecting patients with a defined albuminuria response without adverse events, is a first step and is currently being tested,“ he said.

    While future studies will likely ”measure and integrate multiple drug responses to predict the chance of obtaining positive hard outcomes,“ for now, dual RAAS blockade can only be resuscitated if it can be shown that renal and cardiovascular protection is possible in a defined group of patients in whom the desired effects （decreased blood pressure and/or albuminuria） can be achieved without increasing the risk of hyperkalemia and other side effects, he concluded.

    Dr. de Zeeuw reported serving as an adviser or steering committee chair for AbbVie, Astellas, AstraZeneca, Bristol-Myers Squibb, ChemoCentryx, Johnson & Johnson, and Novartis, all of which have paid fees to his institution.

    Dr. de Zeeuw is with the department of clinical pharmacology, University of Groningen, and University Medical Center Groningen, in the Netherlands.