联用血管紧张素抑制剂可增加高钾血症、急性肾损伤风险

亚特兰大——美国肾病学会主办的2013年肾脏周会议上公布的VA NEPHRON-D研究结果显示，在糖尿病性肾病患者中，联用血管紧张素转换酶抑制剂和血管紧张素受体阻滞剂与高钾血症和急性肾损伤风险增加相关。该研究因这些安全问题被提前停止。

这项随机对照研究由匹兹堡大学医学、流行病学、临床与转化科学教授Linda F. Fried医生及其同事进行，入组1,448例合并2型糖尿病和中度糖尿病性肾病的患者：尿白蛋白/肌酐比值≥300，估计肾小球滤过率(eGFR)为30.0~89.9 mL/min/ 1.73 m2或体表面积。复合主要终点包括首次出现eGFR改变、晚期肾病(ESRD)或死亡。eGFR改变定义为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)。

这些患者接受至少30天的血管紧张素受体阻滞剂(ARB)氯沙坦100 mg每日1次治疗，此为糖尿病患者的标准治疗方案。此为，患者还随机接受血管紧张素转化酶(ACE)抑制剂赖诺普利或安慰剂10~40 mg每日1次治疗。

在截至研究停止的中位随访2.2年时，联合治疗组和安慰剂组分别有152例患者和132例患者(21% vs. 18.2%)出现复合主要终点事件[联合治疗组风险比(HR) 0.88]。组间差异无统计学显著性。

虽然联合治疗组观察到早期获益趋势，但该趋势随时间推移而降低，因此两组在首次出现eGFR降低或ESRD这一次要肾脏终点方面无显著差异(HR 0.78)。此外，两组在死亡这一安全终点方面无差异(死亡HR 1.04)。两组的心血管事件发生率也相似。

然而，联合治疗组的高钾血症风险是安慰剂组的2倍以上(6.3 vs. 2.6起事件/100 人-年)，急性肾损伤风险是安慰剂组的近2倍(12.2 vs. 6.7起事件/100 人-年)。每随访100人1年，联合治疗组的入院例数就增加17例，获益-风险比不支持联合治疗，因为不安全。

该研究结果也同时发表于《新英格兰医学杂志》(2013 Nov. 9 [doi10.1056/NEJMoa1303154])。

VA-Nephron-D研究获美国退伍军人事务部研究和发展办公室的合作研究项目支持。研究药物由默克公司的研究者发起研究项目提供。Fried医生曾作为一项研究的现场研究者从Reata制药公司获得支持。其他作者从默克、赛诺菲安万特、Complex和/或CytoPherx公司获得演讲费或顾问费。

随刊述评：研究结果标志着双重RAAS阻断治疗的终结——目前而言

荷兰格罗宁根大学医学中心临床药理科的Dick de Zeeuw医生表示，该研究在现有证据基础上进一步表明，双重肾素-血管紧张素-醛固酮系统(RAAS)阻滞治疗不能降低心血管和肾脏发病率，并且实际上可增加风险。

目前而言，如果无法在界定的患者中证实双重RAAS阻滞治疗具有肾脏和心血管保护作用，无法在不增加高钾血症和其他副作用风险的情况下使患者获得预期效果(血压降低和/或蛋白尿减少)的话，那么就不应恢复双重RAAS阻滞治疗的使用。de Zeeuw医生声明是AbbVie、Astellas、阿斯利康等多家公司的顾问或指导委员会主席，这些公司均为其机构支付费用(N. Engl. J. Med. 2013 Nov. 9 [doi:10.1056/NEJMe1312412])。

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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.

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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.