阿利吉仑未能成功治疗冠脉粥样硬化

根据前瞻性、随机、安慰剂对照的阿利吉仑定量动脉粥样硬化减轻血管内超声研究(AQUARIUS)的结果，对于高血压前期和冠心病(CAD)患者，肾素抑制剂阿利吉仑治疗未能改善冠脉粥样硬化或延缓冠脉粥样硬化的进展。


Stephen J. Nicholls博士

“对于已达到治疗目标的患者进一步追加抗高血压药物治疗的益处尚未明确。但少数试验评估了在已明确的高血压前期的CAD患者中进一步强化血压控制的效益和风险，”南澳大利亚健康与医学研究所的Stephen J. Nicholls博士及其同事说。因为已知肾素-血管紧张素-醛固酮系统(RAAS)活化在动脉粥样硬化中发挥重要作用，并且RAAS已知可能对于动脉壁具有直接的有益影响，研究者试图确定，在这些患者中，直接肾素抑制剂阿利吉仑能否延缓冠脉粥样硬化的进展。

纳入AQUARIUS研究的患者为35岁以上的成年CAD和高血压前期患者，收缩压为125~139 mmHg，舒张压低于90 mmHg，并伴有另外2项心血管危险因素。于2009年3月~2011年2月期间，从欧洲、澳大利亚、北美和南美的103家医院募集上述患者。基线时，患者在冠脉造影检查后接受冠脉血管内超声(IVUS)影像检查。共募集到613例受试者，这些患者在随机化之前的导入期接受150 mg 的阿利吉仑治疗1周。104周后，3/4（458例）患者接受相同血管的第二次IVUS检查(JAMA 2013 Sept. 3[doi:10.1001/jama.2013.277169])。主要疗效指标为基线至研究完成时的动脉粥样硬化斑块体积百分率(PAV)。次要疗效指标为标化总动脉粥样硬化斑块体积(TAV)较基线的变化。研究期间，在产品说明书变更中警告已接受一种ACE抑制剂或血管紧张素受体阻滞剂的糖尿病患者禁忌合并使用阿利吉仑之后，糖尿病患者退出研究，试验中的这一变化代表“一种可能混淆解释的因素，”研究者指出。尽管如此，该研究仍是首批评估肾素抑制对血压控制较理想的冠脉粥样硬化患者的动脉粥样硬化斑块影响的研究之一，他们说。

结果显示，“阿利吉仑有中度降压作用，显著降低血浆肾素活性，并且产生血浆肾素浓度的代偿性增高，”他们写道。但225例随机接受阿利吉仑300 mg治疗104周的受试者和233例随机接受安慰剂治疗的受试者的主要疗效指标变化无统计学差异（分别为–0.33%和0.11%）。阿利吉仑与安慰剂组的次要疗效指标也无统计学差异（分别为–4.1 mm³和–2.1 mm³），两组发生PAV（分别为56.9%和48.9%）和TAV（分别为64.4%和57.5%）减轻的患者比例也无统计学差异，研究者在欧洲心脏病学会年会上报告。这一结果同时在线发表于9月3日的JAMA杂志。“在预先设定的探索性分析中，我们发现，阿利吉仑组裁定的主要不良心血管事件较少（分别为26和50起）。尽管这些探索性分析结果支持对于已有CAD患者给予肾素抑制和血压治疗达标有潜在有益影响的假设，但当前的临床结果无法得出有效结论。明确证实临床结局获益需要一项更大规模、有充分统计学效能、将心血管事件预设为主要终点的临床试验，”他们说。

该研究结论为，未能证实肾素抑制剂阿利吉仑可减轻CAD患者的动脉粥样硬化或延缓动脉粥样硬化的进展。

该研究由诺华制药公司资助。Nicholls博士报告接受了阿斯利康、诺华、礼来、Anthera、LipoScience、罗氏和Resverlogix公司提供的研究资助；并接受了阿斯利康、罗氏、艾斯帕来恩、雅培、辉瑞、默克、武田、LipoScience、Omthera、诺和诺德、赛诺菲-安万特、Atheronova、Anthera、CSL Behring和勃林格-殷格翰公司提供的报酬或担任其顾问。其他作者也披露存在利益关系。详情见JAMA.com上的全文。

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By: Sharon Worcester, Cardiology News Digital Network

Treatment with the renin inhibitor aliskiren did not improve or slow the progression of coronary atherosclerosis in patients with prehypertension and coronary artery disease, according to the prospective, randomized, placebo-controlled Aliskiren Quantitative Atherosclerosis Regression Intravascular Ultrasound Study (AQUARIUS).

The change in the primary efficacy measure – percent atheroma volume (PAV) from baseline to completion – did not differ significantly in 225 subjects who were randomized to receive 300 mg of aliskiren for 104 weeks and 233 subjects who were randomized to receive a placebo (–0.33% vs. 0.11%, respectively), Dr. Stephen J. Nicholls of the South Australian Health and Medical Research Institute, Adelaide, Australia and his colleagues reported.

A secondary efficacy parameter – the change from baseline in normalized total atheroma volume (TAV) – also did not differ between the aliskiren and placebo groups (–4.1 mm3 vs. –2.1 mm3), and no significant differences were seen between the groups in the proportion of participants who experienced regression of PAV (56.9% vs. 48.9%) and TAV (64.4% vs. 57.5%), the investigators reported at the annual congress of the European Society of Cardiology.

The findings were simultaneously published online Sept. 3 in JAMA.

Patients included in AQUARIUS were adults over age 35 years with coronary artery disease and prehypertension, with systolic blood pressure of 125-139 mm Hg, and diastolic blood pressure less than 90 mm Hg, and with two additional cardiovascular risk factors. They were enrolled during March 2009–February 2011 at 103 participating academic and community hospitals in Europe, Australia, North America, and South America. At baseline, after coronary angiography, they underwent coronary intravascular ultrasound (IVUS) imaging.

A total of 613 participants were enrolled and treated with 150 mg of aliskiren for a 1-week run-in period before randomization. After 104 weeks, three-quarters of the patients, or 458, had a second IVUS on the same vessel (JAMA 2013 Sept. 3[doi:10.1001/jama.2013.277169]).

Patients with diabetes were withdrawn during the study period after a product label change warned that concomitant use of aliskiren in patients with diabetes who were treated with an ACE inhibitor or angiotensin receptor blocker was contraindicated; this alteration in the trial represents "a factor potentially confounding interpretation," the investigators noted.

Nonetheless, the study is among the first to evaluate the effect of renin inhibition on atherosclerotic plaque in patients with coronary atherosclerosis whose blood pressure was considered optimally controlled, they said.

"The benefit of additional blood pressure lowering agents in patients who have reached treatment goals has not been established. However, few trials have examined the benefits and risks of further intensifying blood pressure treatment in patient with established coronary artery disease (CAD) who are in the prehypertension range," they said.

Since renin-angiotensin-aldosterone system (RAAS) activation is known to play an important role in atherosclerosis, and since RAAS inhibition may have a direct beneficial effect on the artery wall, the investigators sought to determine if aliskiren, a direct renin inhibitor, would slow progression of coronary atherosclerosis in these patients.

"Aliskiren moderately reduced blood pressure, substantially reduced plasma renin activity, and produced a compensatory increase in plasma renin concentration," they wrote.

However, the primary and secondary IVUS endpoints failed to demonstrate a significant difference in disease progression between those who received aliskiren and those who received placebo.

"During the prespecified exploratory analysis, we observed fewer adjudicated major adverse cardiovascular events in the aliskiren group (26 vs. 50). Although these exploratory findings support the hypothesis of potential beneficial effects of renin inhibition in patients with preexisting CAD and blood pressure levels treated to goal, the current clinical findings are inconclusive. Definitive demonstration of a clinical outcome benefit will require a larger, adequately powered clinical trial with cardiovascular events prespecified as the primary end point," they said.

This study was sponsored by Novartis Pharmaceuticals. Dr. Nicholls reported receiving research support from AstraZeneca, Novartis, Eli Lilly, Anthera, LipoScience, Roche, and Resverlogix; and receiving honoraria from or serving as a consultant to AstraZeneca, Roche, Esperion, Abbott, Pfizer, Merck, Takeda, LipoScience, Omthera, Novo-Nordisk, sanofi-aventis, Atheronova, Anthera, CSL Behring, and Boehringer Ingelheim. Other authors also reported having disclosures. Details are available with the full text of the article at JAMA.com.

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Reserve aliskiren for limited group

Although the clinical findings of AQUARIUS should be interpreted with caution, as Dr. Nicholls and his colleagues note, the findings could be used to generate the hypothesis that aliskiren may have an effect on clinical outcomes in patients with coronary artery disease, but without diabetes or significant renal dysfunction, according to an accompanying editorial.

However, the large, adequately powered trial that would be required to test this concept is likely not feasible, wrote Dr. Jean-Claude Tardif and Dr. Jean Gregoire (JAMA 2013 Sept. 3[doi: 10.1001/jama.2013.277170]).

"In light of the efficacy of ACE inhibitors for secondary prevention, their established place in treatment guidelines, and the good tolerability profile of these agents and of angiotensin receptor blockers, it would appear difficult to displace these medications and justify the launch of another large aliskiren trial," they wrote.

ACE inhibitors, or angiotensin receptor blockers in those who can’t tolerate ACE inhibitors, should continue to be prescribed to improve outcomes in patients with coronary artery disease, and, barring additional evidence with respect to renin inhibition, its use should be limited, they said.

"Because aliskiren does reduce blood pressure, perhaps this agent could be reserved for use in patients with coronary disease and hypertension who cannot tolerate ACE inhibitors or angiotensin receptor blockers," they suggested.

Dr. Tardif and Dr. Gregoire are with the Montreal Heart Institute and the University of Montreal, Quebec. They both reported having disclosures. Details are available with the full text of the editorial at JAMA.com