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Original Investigation |

Effect of Aliskiren on Progression of Coronary Disease in Patients With Prehypertension:  The AQUARIUS Randomized Clinical Trial FREE

Stephen J. Nicholls, MBBS, PhD1; George L. Bakris, MD2; John J. P. Kastelein, MD, PhD3; Venu Menon, MD4,5; Bryan Williams, MD6; Juergen Armbrecht, MD7; Patrick Brunel, MD7; Maria Nicolaides, MD7; Amy Hsu, MS5; Bo Hu, PhD5; Hui Fang, PhD7; Rishi Puri, MBBS5; Kiyoko Uno, MD, PhD5; Yu Kataoka, MD, PhD1; Dianna Bash, RN5; Steven E. Nissen, MD4,5
[+] Author Affiliations
1South Australian Health and Medical Research Institute, Adelaide, Australia
2Department of Medicine, ASH Comprehensive Hypertension Center, University of Chicago Medicine, Chicago, Illinois
3Department of Vascular Medicine, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands
4Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio
5Cleveland Clinic Coordinating Center for Clinical Research, Cleveland, Ohio
6National Institute for Health Research, University College London Hospitals Biomedical Research Centre, London, England
7Novartis Pharmaceuticals, Basel, Switzerland
JAMA. 2013;310(11):1135-1144. doi:10.1001/jama.2013.277169.
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Published online

Importance  Blood pressure reduction and renin-angiotensin-aldosterone system inhibition are targets for treatment of atherosclerosis. The effect of renin inhibition on coronary disease progression has not been investigated.

Objective  To determine the effects of renin inhibition with aliskiren on progression of coronary atherosclerosis.

Design, Setting, and Participants  A double-blind, randomized, multicenter trial (Aliskiren Quantitative Atherosclerosis Regression Intravascular Ultrasound Study) comparing aliskiren with placebo in 613 participants with coronary artery disease, systolic blood pressure between 125 and 139 mm Hg (prehypertension range), and 2 additional cardiovascular risk factors conducted at 103 academic and community hospitals in Europe, Australia, and North and South America (enrollment from March 2009 to February 2011; end of follow-up: January 31, 2013).

Interventions  Participants underwent coronary intravascular ultrasound (IVUS) imaging and were randomized to receive 300 mg of aliskiren (n = 305) or placebo (n = 308) taken orally daily for 104 weeks. Disease progression was measured by repeat IVUS examination after at least 72 weeks of treatment.

Main Outcomes and Measures  The primary efficacy parameter was the change in percent atheroma volume (PAV) from baseline to study completion. Secondary efficacy parameters included the change in normalized total atheroma volume (TAV) and the percentage of participants with atheroma regression. Safety and tolerability were also assessed.

Results  Evaluable imaging data were available at baseline and follow-up for 458 participants (74.7%). The primary IVUS efficacy parameter, PAV, did not differ between participants treated with aliskiren (−0.33%; 95% CI, −0.68% to 0.02%) and placebo (0.11%; 95% CI, −0.24% to 0.45%) (between-group difference, −0.43% [95% CI, −0.92% to 0.05%]; P = .08). The secondary IVUS efficacy parameter, TAV, did not differ between participants treated with aliskiren (−4.1 mm3; 95% CI, −6.27 to −1.94 mm3) and placebo (−2.1 mm3; 95% CI, −4.21 to 0.07 mm3) (between-group difference, −2.04 mm3 [95% CI, −5.03 to 0.95 mm3]; P = .18). There were no significant differences in the proportion of participants who demonstrated regression of PAV (56.9% vs 48.9%; P = .08) and TAV (64.4% vs 57.5%; P = .13) in the aliskiren and placebo groups, respectively.

Conclusions and Relevance  Among participants with prehypertension and coronary artery disease, the use of aliskiren compared with placebo did not result in improvement or slowing of progression of coronary atherosclerosis. These findings do not support the use of aliskiren for regression or prevention of progression of coronary atherosclerosis.

Trial Registration  clinicaltrials.gov Identifier: NCT00853827.

Figures in this Article

Guidelines recommend blood pressure reduction in patients with hypertension with a treatment goal of 140 mm Hg for systolic and 90 mm Hg diastolic blood pressure for most individuals.1 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 patients with established coronary artery disease (CAD) who are in the prehypertension range.2,3

Preclinical data demonstrate that renin-angiotensin-aldosterone system (RAAS) activation plays an important role in atherosclerosis4 and that RAAS inhibition may have a direct beneficial effect on the artery wall.5 Conventional RAAS modulating agents result in a compensatory increase in circulating renin levels, which may counteract any vascular benefits.6 Direct renin inhibition enables RAAS modulation without increases in renin activity.7 A potential advantage is supported by evidence of an atheroprotective effect of renin inhibition in animal atherosclerosis models.810 However, enthusiasm for this approach decreased following the demonstration of potentially harmful clinical effects with the renin inhibitor, aliskiren, in patients with diabetes.11

The effect of renin inhibition on atherosclerotic plaque in humans has not been investigated. Measurement of coronary atherosclerotic plaque burden with intravascular ultrasound (IVUS) imaging enables examination of the effects of antiatherosclerotic therapies on progression of coronary disease.1214 Post hoc analyses of previous trials have demonstrated a direct relationship between achieved blood pressure levels and disease progression extending into the prehypertension range.15 Accordingly, we sought to determine if aliskiren would slow progression of coronary atherosclerosis in patients whose blood pressure was considered optimally controlled to current treatment targets.

Study Design

The Aliskiren Quantitative Atherosclerosis Regression Intravascular Ultrasound Study (AQUARIUS) was a prospective, randomized, multicenter, double-blind clinical trial. Randomization was stratified according to geographic region. The trial was designed by the Cleveland Clinic Coordinating Center for Clinical Research in collaboration with the trial sponsor, Novartis Pharmaceuticals. Institutional review boards at each site approved the protocol, and patients provided written informed consent.

Participants aged 35 years or older were eligible if they demonstrated at least one 20% stenosis on clinically indicated coronary angiography and a target vessel for imaging with less than 50% obstruction. Participants were required to have a systolic blood pressure between 125 and 139 mm Hg and a diastolic blood pressure less than 90 mm Hg at entry plus 2 cardiovascular risk factors from a list that included (1) history of myocardial infarction, acute coronary syndrome, or arterial revascularization, (2) no statin use in the preceding 3 months, (3) high-density lipoprotein cholesterol level lower than 40 mg/dL in men or 50 mg/dL in women or triglyceride level greater than 150 mg/dL, (4) ratio of urinary albumin to creatinine between 30 and 300 mg/g, (5) age older than 55 years, (6) type 2 diabetes, (7) current smoker, (8) left ventricular hypertrophy, and (9) high-sensitivity C-reactive protein level of 2 mg/L or greater. Participants were excluded if they were receiving at least 2 agents that target the RAAS, had uncontrolled hypertension (blood pressure ≥140/90 mm Hg) or heart failure, renal dysfunction, or liver disease.

Participants meeting the inclusion criteria underwent preliminary single-blinded treatment with 150 mg of aliskiren for 1 week to evaluate tolerability to the agent and then underwent 1:1 randomization via an interactive voice response system to treatment with 300 mg of aliskiren or placebo daily for 104 weeks. A clinical events committee blinded to treatment assignment centrally adjudicated cardiovascular events. In December 2011, following termination of a clinical trial of aliskiren treatment in patients with type 2 diabetes with background standard RAAS blocking therapy, the use of aliskiren in patients with diabetes treated with either an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) was contraindicated. Consequently, the participation of 91 patients with diabetes in the AQUARIUS study (43 in the aliskiren group and 48 in the placebo group) was prematurely discontinued from study treatment, 44 of them without having evaluable follow-up imaging.

Acquisition and Analysis of Ultrasound Images

Following coronary angiography, baseline IVUS imaging was performed. Previous reports have described the methods of image acquisition and analysis.3,1214,1620 Imaging was performed in a single artery and screened by a core laboratory. The target vessel was selected by the investigator as the longest and least angulated artery that contained no stenosis greater than 50%. Participants meeting prespecified requirements for image quality were eligible for randomization. After 104 weeks of treatment, patients underwent a second ultrasonographic examination in the same artery. Participants presenting for a clinically indicated coronary angiogram after taking study medication for more than 72 weeks were permitted to undergo early final study IVUS imaging. Using digitized images, personnel (unaware of the treatment status and time sequence of paired imaging) performed measurements of the lumen and external elastic membrane in images within a matched artery segment. The accuracy and reproducibility of this method have been reported previously.

The primary efficacy measure, percent atheroma volume (PAV), was calculated as follows:Graphic Jump LocationImage not available.where EEMarea is the cross-sectional area of the external elastic membrane and lumenarea is the cross-sectional area of the lumen. The change in PAV was calculated as the PAV at follow-up minus the PAV at baseline. A secondary measure of efficacy, normalized total atheroma volume (TAV), was calculated as follows:Graphic Jump LocationImage not available.where the average plaque area in each image was multiplied by the median number of images analyzed in the entire cohort to compensate for differences in segment length between participants. The efficacy measure of change in normalized TAV was calculated as the TAV at follow-up minus the TAV at baseline. An additional secondary efficacy measure included the percentage of participants that demonstrated any regression of PAV or TAV, defined as any decrease in the parameter from baseline. Exploratory end points included changes in blood pressure and biochemical measures, major adverse cardiovascular events, safety, and tolerability.

Statistical Analysis

For continuous variables with an approximately normal distribution, mean and standard deviation are reported. For variables not normally distributed, median and interquartile ranges (IQRs) are reported. Race was self-reported according to categories preselected by the investigators. The primary efficacy end point, biochemical measures, and blood pressure during treatment were analyzed by using analysis of covariance, after controlling for baseline value, region, and treatment, and reported as least squares means and 95% confidence intervals.

For the change in the primary efficacy parameter, PAV, a sample size of 222 patients in each treatment group was required to provide 80% power at a 2-sided α level of .05 to detect a nominal treatment difference of 0.80%, assuming a 3.0% standard deviation. This treatment difference exceeded previously reported differences in disease progression between those who did and did not experience a subsequent cardiovascular event.21 Assuming a withdrawal rate of 25%, 592 randomized study participants were required to ensure a final sample size of 444. All reported P values are 2-sided. The protocol and statistical analysis plan are available in the Supplement. All analyses were performed using SAS version 9.2 (SAS Institute Inc).

Participant Characteristics

The disposition of participants in the study is summarized in Figure 1. From March 2009 to February 2011, at 103 academic and community hospitals in Europe, Australia, and North and South America, 652 participants were treated with 150 mg of aliskiren for 1 week. Following this run-in period, 305 participants were randomized to 300 mg of aliskiren and 308 to placebo taken orally daily. There were 458 participants (74.7%) who remained in the study for more than 72 weeks and had IVUS imaging that permitted evaluation at both baseline and follow-up (end of follow-up: January 31, 2013). Of these participants, 225 were in the aliskiren group and 233 were in the placebo group. The 2 treatment groups had no significant differences in demographic characteristics, medication use, and laboratory values at baseline (Table 1). Similarly, baseline characteristics did not differ significantly between participants who completed the study and those who did not.

Place holder to copy figure label and caption
Figure 1.
Disposition of Patients in the AQUARIUS Study

ACE indicates angiotensin-converting enzyme; AQUARIUS, Aliskiren Quantitative Atherosclerosis Regression Intravascular Ultrasound Study; ARB, angiotensin receptor blocker.

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Table Graphic Jump LocationTable 1.  Patient Demographics and Concomitant Medication Use at Baseline
Blood Pressure and Biochemical Measurements

Table 2 summarizes exploratory outcomes of blood pressure and laboratory values at baseline and during treatment for the 458 participants who had completed IVUS imaging. During treatment, greater reductions were observed in the aliskiren group compared with the placebo group in time-weighted average systolic blood pressure (−2.9 mm Hg [95% CI, −4.1 to −1.7 mm Hg] vs −0.8 mm Hg [95% CI, −1.8 to 0.2 mm Hg], respectively; between-group difference, −2.09 mm Hg [95% CI, −3.60 to −0.60 mm Hg]; P = .007) and diastolic blood pressure (−2.0 mm Hg [95% CI, −2.7 to −1.2 mm Hg] vs −0.4 [95% CI, −1.1 to 0.3 mm Hg], respectively; between-group difference, −1.45 mm Hg [95% CI, −2.40 to −0.50 mm Hg]; P = .003).

Table Graphic Jump LocationTable 2.  Laboratory Values and Blood Pressure at Baseline and During Treatment for Patients With Evaluable Coronary Intravascular Ultrasound Imaging at Follow-up

Median levels of plasma renin activity during treatment were 0.2 ng/mL/h (IQR, 0.2 to 0.5 ng/mL/h) in the aliskiren group and 1.5 ng/mL/h (IQR, 0.6 to 6.3 ng/mL/h) in the placebo group (P< .001). Median levels of plasma renin concentration during treatment were 88.8 ng/L (IQR, 31.8 to 209.1 ng/L) in the aliskiren group and 19.8 ng/L (IQR, 9.9 to 63.0 ng/L) in the placebo group (P< .001).

IVUS and Clinical End Points

Table 3 summarizes the change in the IVUS imaging efficacy measures. There was no difference between the treatment groups with respect to measures of atheroma burden at baseline. The primary efficacy measure, PAV, decreased by 0.33% (95% CI, −0.68% to 0.02%) in the aliskiren group and increased by 0.11% (95% CI, −0.24% to 0.45%) in the placebo group (between-group difference, −0.43% [95% CI, −0.92% to 0.05%]; P = .08). A secondary outcome measure, TAV, decreased by 4.1 mm3 (95% CI, −6.3 to −1.9 mm3) in the aliskiren group and by 2.1 mm3 (95% CI, −4.2 to 0.1 mm3) in the placebo group (between group difference, −2.04 mm3 [95% CI, −5.03 to 0.95 mm3]; P = .18). Regression of PAV (defined as any decrease from baseline) was observed in 56.9% of patients in the aliskiren group and 48.9% of patients in the placebo group (P = .08). Total atheroma volume regressed in 64.4% of patients assigned to aliskiren and 57.5% of patients assigned to placebo (P = .13).

Table Graphic Jump LocationTable 3.  Intravascular Ultrasound Imaging Measures of Atheroma Burden

Sensitivity analysis was performed using multiple imputation to account for missing data in participants who did not have evaluable IVUS imaging at follow-up and demonstrated no differences with regard to the change in either PAV (−0.26% [95% CI, −0.62% to 0.09%] in the aliskiren group and 0.15% [95% CI, −0.20% to 0.48%] in the placebo group; between-group difference, −0.41 [95% CI, −0.90 to 0.09]; P = .11) or TAV (−4.05 mm3 [95% CI, −6.2 to −1.9 mm3] in the aliskiren group and −1.8 mm3 [95% CI, −3.9 to 0.3 mm3]; between-group difference, −2.3 mm3 [95% CI, to −5.3 to 0.7 mm3]; P = .14).

Prespecified exploratory analysis revealed that fewer centrally adjudicated major cardiovascular events were observed in the aliskiren group compared with the placebo group (26 [8.5%] vs 50 [16.2%], respectively; hazard ratio, 0.50 [95% CI, 0.31 to 0.81], P = .004), and fewer nonfatal myocardial infarctions (1 [0.3%] vs 8 [2.6%], respectively; hazard ratio, 0.13 [95% CI, 0.02 to 1.02], P = .02). The majority of cardiovascular events in the study were coronary revascularizations (Table 4 and Figure 2).

Table Graphic Jump LocationTable 4.  Clinical and Biochemical Adverse Events and Reasons for Discontinuation in the Safety Population (N = 613)
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Figure 2.
Incidence of Centrally Adjudicated Major Adverse Cardiovascular Events in Patients Treated With Aliskiren or Placebo
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Subgroup analyses (Figure 3) included outcomes in participants with and without diabetes. Percent atheroma volume was observed to decrease with aliskiren treatment in participants without diabetes (mean [SD], −0.53% [0.20%]; 95% CI, −0.93% to −0.13%), but not in those with diabetes (mean [SD], 0.15% [0.38%]; 95% CI, −0.61% to 0.90%). However, there was no significant difference between treatment groups in patients with or without diabetes (P = .55). There was no significant interaction found with heterogeneity testing for differences between treatment groups in any subgroup. There was no significant relationship between the change in PAV and achieved levels of either systolic (r = −0.05, P = .32) or diastolic (r = −0.003, P = .94) blood pressure in any subgroup.

Place holder to copy figure label and caption
Figure 3.
Subgroup Analysis of the Change in Percent Atheroma Volume

eGFR indicates estimated glomerular filtration. aCalculated as weight in kilograms divided by height in meters squared. bFour patients did not have valid results at baseline for this variable.

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Clinical and Laboratory Adverse Events

Table 4 shows reasons for study discontinuation, laboratory abnormalities, and centrally adjudicated clinical events. A greater number of discontinuations of participation due to adverse events was observed in the aliskiren group compared with the placebo group (8.2% vs 4.5%, respectively). A similar number of administrative discontinuations from study medications in participants with diabetes who were treated with another RAAS modifying agent was observed following the cessation of the Aliskiren Trial in Type 2 Diabetes Using Cardiorenal Endpoints (ALTITUDE) study. Investigator-reported incidence of hypotension (7.2% vs 3.9%; P = .04) and renal and urinary disorders (6.9% vs 4.9%; P = .38) were more likely to be observed in the aliskiren group compared with the placebo group. The incidence of hyperkalemia (≥5.5 mEq/L) was similar in both groups (10.7% in the aliskiren group vs 9.8% in the placebo group; P = .76).

The AQUARIUS study evaluated the effect of the renin inhibitor, aliskiren, on progression of coronary atherosclerosis in patients with prehypertension and established coronary disease whose blood pressure control was considered optimal by conventional guidelines. Aliskiren moderately reduced blood pressure, substantially reduced plasma renin activity, and produced a compensatory increase in plasma renin concentration. The primary and secondary IVUS end points failed to demonstrate a significant difference in disease progression between patients 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. 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 prespecifed as the primary end point.

Even though lowering blood pressure is a cornerstone of secondary prevention, the optimal level for patients with CAD remains uncertain. Current guidelines do not recommend drug treatment for patients with blood pressure levels below 140 mm Hg systolic and 90 mm Hg diastolic.1 Treatment targets are based on the findings of clinical trials of blood pressure lowering agents in patients with overt hypertension. Furthermore, these recommendations are derived from studies of heterogeneous populations that included patients with and without CAD. A prior placebo-controlled trial studied amlodipine and enalapril in patients with known coronary disease and a mean systolic and diastolic blood pressure of approximately 129 and 78 mm Hg, showing a statistically significant reduction in major adverse cardiovascular events.3 Large clinical trials are required to definitively determine whether there are disproportionate benefits from blood pressure lowering in patients with CAD, even when optimally controlled by current standards.

The role of the RAAS in cardiovascular disease has been extensively studied. Several lines of evidence suggest that renin may directly promote cardiovascular disease. Renin activates inflammatory and oxidative factors involved in atherosclerosis22 and measures of renin activity predict cardiovascular events in patients with hypertension.2327 Theoretically, compensatory increases in renin observed with conventional RAAS modulating agents may counterbalance potentially favorable effects on disease progression. In the AQUARIUS study, although greater blood pressure lowering was observed in the aliskiren treatment group, we did not observe a relationship between aliskiren and either achieved levels of blood pressure or slowing of disease progression. The mechanism underlying any potential benefit of aliskiren on atherosclerosis and cardiovascular events requires further investigation.

Renin inhibition as a therapeutic strategy has been controversial following the premature termination of a trial studying aliskiren in patients with diabetes; that study was stopped for a nonsignificant increase in cardiovascular events.11 A second trial studying the effects of renin inhibition in patients with heart failure also did not show a significant benefit.28 In contrast, an ambulatory blood pressure study evaluating the combination of aliskiren and valsartan in the setting of stage 2 chronic kidney disease showed no evidence of adverse effects, whereas overall 24-hour and nocturnal blood pressure was better controlled.29 In the current trial, we studied patients with coronary disease identified during cardiac catheterization; however, the mean estimated glomerular filtration rate was similar to the blood pressure study that showed benefit from the combination therapy.29

Patients with diabetes were withdrawn from our study after a change in the product label contraindicating concomitant use of aliskiren in patients with diabetes who were also treated with an ACE inhibitor or ARB. Nonetheless, some participants with diabetes completed the study, enabling analysis of differential effects in subpopulations of participants with diabetes and without diabetes. We did not observe a significant difference between treatment groups on subgroup analysis. Further study is required to determine whether aliskiren may exert different effects on the vasculature in patients with diabetes.

Although the current study focused primarily on measures of disease progression, all cardiovascular events were systematically collected and centrally adjudicated. Even though this investigation was not powered to investigate the effect of aliskiren on clinical outcomes, differences were observed between the 2 treatment groups for this exploratory outcome. Fewer cardiovascular events occurred in the aliskiren treatment group (26 [8.5%]) than in the placebo group (50 [16.2%]), including fewer numbers of deaths (1 vs 6, respectively), stroke (1 vs 4), and myocardial infarction (1 vs 8). However, these findings must be interpreted with caution because they represent a prespecified exploratory end point in a trial not formally powered to assess clinical outcomes and are based on small numbers of events; therefore, these findings should be considered hypothesis generating and require further investigation.

In this study, aliskiren was associated with a relatively low incidence of adverse events. Higher rates were observed in patients treated with aliskiren vs placebo for hypotension (7.2% vs 3.9%, respectively) and renal and urinary disorders (6.9% vs 4.9%). Despite considerable background use of other RAAS modulating agents, a low incidence of hyperkalemia was observed (10.7% vs 9.8%), consistent with the findings of studies of aliskiren in patients with better kidney function.29 These data, although based on exploratory analysis, suggest that a renin inhibitor may be able to be administered safely in patients with CAD without significant renal impairment and hyperkalemia.

A number of limitations should be noted. All patients presented for a clinically indicated coronary angiogram. Only 1 coronary artery was investigated in each participant; thus, the relevance of the findings to the remainder of the coronary vasculature is unknown. It is uncertain whether similar findings would have been demonstrated with aliskiren administration in the setting of primary prevention. The alteration of the trial to discontinue the participation of patients with diabetes and treated with an ACE inhibitor or ARB also represents a factor potentially confounding interpretation.

Among participants with prehypertension and CAD, the use of aliskiren compared with placebo did not result in improvement or slowing in the progression of coronary atherosclerosis. These findings do not support the use of aliskiren for regression or prevention of the progression of coronary atherosclerosis.

Corresponding Author: Stephen J. Nicholls, MBBS, PhD, South Australian Health and Medical Research Institute, PO Box 11060, Adelaide, SA 5001, Australia (stephen.nicholls@sahmri.com).

Published Online: September 3, 2013. doi:10.1001/jama.2013.277169.

AuthorContributions: Drs Nicholls and Nissen had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Nicholls, Menon, Williams, Armbrecht, Fang, Bash, Nissen.

Acquisition of data: Nicholls, Bakris, Armbrecht, Brunel, Nicolaides, Puri, Nissen.

Analysis and interpretation of data: Nicholls, Bakris, Kastelein, Menon, Williams, Armbrecht, Brunel, Nicolaides, Hsu, Hu, Fang, Puri, Uno, Kataoka, Nissen.

Drafting of the manuscript: Nicholls, Bakris, Menon, Armbrecht, Puri, Uno, Bash, Nissen.

Critical revision of the manuscript for important intellectual content: Bakris, Kastelein, Menon, Williams, Armbrecht, Brunel, Nicolaides, Hsu, Hu, Fang, Puri, Kataoka, Nissen.

Statistical analysis: Hsu, Hu, Fang, Nissen.

Obtained funding: Nicholls, Armbrecht, Nissen.

Administrative, technical, or material support: Nicholls, Bakris, Kastelein, Menon, Williams, Armbrecht, Brunel, Nicolaides, Uno, Bash, Nissen.

Study supervision: Nicholls, Kastelein, Menon, Williams, Armbrecht, Brunel, Nicolaides, Nissen.

Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. The 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. Dr Bakris reported serving as a consultant to Novartis, Daichi-Sankyo, Boehringer Ingelheim, Takeda, AbbVie, Medtronic, Relypsa, Gilead, Concert; receiving investigator-initiated grant funding from Takeda; and serving as the editor of the hypertension section of Up-To-Date and as editor of the American Journal of Nephrology. Dr Kastelein reported serving as a consultant to Novartis. Dr Menon reported receiving support for travel from Novartis for AQUARIUS trial meetings. Dr Williams reported receiving honoraria from Novartis, Boehringer Ingelheim, Pfizer, Servier, and Daichi Sankyo; and receiving support from the National Institute for Health Research University College London Hospitals Biomedical Research Centre. Drs Armbrecht, Brunel, Nicolaides, and Fang are employees of Novartis Pharma AG and are thus eligible for Novartis stock and stock options. Dr Nissen reported receiving research support from Amgen, AstraZeneca, Eli Lilly, Orexigen, Vivus, Novo Nordisk, Resverlogix, Novartis, Pfizer, Takeda, Sankyo, and sanofi-aventis; serving as a consultant for a number of pharmaceutical companies without financial compensation because all honoraria, consulting fees, or any other payments from any for-profit entity are paid directly to charity so that neither income nor any tax deduction is received. No other author reported disclosures.

Funding/Support: The study was funded by Novartis Pharmaceuticals.

Role of the Sponsor: Novartits Pharmaceuticals participated actively in designing the study, developing the protocol, and providing logistical support during the trial. Monitoring of the study was performed by the sponsor. The sponsor maintained the trial database. The results reported in this article are the results of the analyses performed by Ms Hsu and Dr Hu. The sponsor was permitted to review the manuscript and suggest changes, but the final decision on content was exclusively retained by the academic authors. Although the steering committee and coordinating center had confidentiality agreements with the sponsor, the study contract specified that a copy of the study database be provided to the coordinating center for independent analysis and granted the academic authors the unrestricted rights to publish the results.

Independent Statistical Analysis: After completion of the trial, as specified in the study contract, a complete copy of the database was transferred to the Cleveland Clinic Coordinating Center for Clinical Research, where analyses were verified by independent academic statisticians (Ms Hsu and Dr Hu).

Data and Safety Monitoring Board: Carl Pepine (chair), William Cushman, Peter Ganz, Kerry Lee, James Pool.

Intravascular Ultrasound Core Laboratory Staff: William Magyar, BS, Jordan Andrews, BS, Eva Balazs, BS, Anne Colagiovanni, BS, Teresa Fonk, BS, Karilane King, BS, Erin Mayock, BS, Roman Poliszczuk, BS, Rhiannon Regal, BS, Jill Rusticelli.

Investigators: Argentina: G. Migliaro and C. Majul (Hospital Britanico de Buenos Aires); A. Damonte (Instituto Cardiovascular de Rosario); P. Kantor (Sanatorio Dupuytren); E. Farias (Instituto de Cardiologia J. F. Cabral); A. Salvatierra Ruiz (Sanatorio Mitre); A. Pocovi (Instituto Alexander Fleming); A. Villamil (Instituto Cardiovascular de Buenos Aires). Australia: J. Cameron (Monash Medical Centre); S. Worthley (Royal Adelaide Hospital); N. Collins (John Hunter Hospital); C. Juergens (Liverpool Hospital). Belgium: J. Renkin (Cliniques Universitaires Saint-Luc); M. Vrolix (Ziekenhuis Oost Limburg); J. Lalmand (Centre Hospitaliere Universitaire); B. De Bruyne (OLV Zh); S. Vercauteren (Kliniek Sint-Jan); M. Goldstein (Clinique Sainte-Anne-Saint-Remi); J. Debrauwere (ASZ Aalst). Canada: J. Burton (University of Alberta Hospital); T. Cieza (CSSS de Chicoutimi); C. Constance (Hopital Maisonneuve-Rosemont); W. Hui (Royal Alexandra Hospitals); S. Lavi (London Health Sciences Center); J-C. Tardif (Montreal Heart Institute); J. Rodes Cabau (Quebec Heart Institute). France: C. Caussin (Hopital Marie Lannelongue); P. Coste (Hopital Cardiologique du Haut); E. Teiger (Hopital Henri Mondor); M. Elbaz (Hopital de Rangueil). Germany: R. Erbel (Universitaetsklinikum Essen); S. Baldus (Universitaetsklinikum Hamburg-Eppendorf); S. Moebius-Winkler (Herzzentrum Leipzig); H. Mudra (Stadtisches Klinikum Munchen GmbH); M. Bergmann (Asklepios Klinik St. Georg); J. Haase (Kardiocentrum Frankfurt an der Klinik). Hungary: R. Kiss (Magyar Honvedseg Honved Korhaz); B. Merkely (SOTE Kardiologiai Centrum); I. Ungi (Szegedi Tudomanyegeyetem Alt Orvo); I. Horvath (Pecsi Tudomanyegeyetem AOK); I. Edes (DEOEC). Italy: A. Colombo (Ospedale San Raffaele); G. Musumeci (Azienda Ospedaliera-Ospedali Riunit di Bergamo); M. Fineschi (A O Universitaria Senese); L. Viignali (Az Ospedaliero Universitaria di Parma); P. Presbitero (IRCCS Istituto Clinico Humanitas); S. Berti (Osperdale del Cuore); F. Prati (Azeienda Ospedaliera S. Giovanni-Addolorata); G. De Luca (Az. Osp. Univ. Maggiore della Carita); F. Airoldi (Policlinico Multimedica Universita degli Studi). Poland: J. Grzybowski (Insytut Kardiologii Im Prymasa); A. Lubinski (Uniwerstyecki Szpital Kliniczny); L. Bryniarski (Szpital Uniwersytecki w Krakowie); S. Dobrzycki (Uniwersytecki Szpital Kliniczny). Spain: F. Alfonso (Hospital Clinico San Carlos); J. Angel Ferrer (Hospital Vall D’Hebron); A. Cequier (H. Univesitari de Bellvitge); J. Zueco Gil (Hospital Universitario Marques de Valdecilla); J. Maria Hernandez (Hospital Virgen de la Victoria); A. Iniguez (Hospital Meixoeiro); C. Suarez (Hospital General de Asturias); R. Moreno (Hospital La Paz); J. Goicolea (Hospital Puerta de Hierro); A. Serra (Hospital del Mar); R. Rumoroso (Hospital de Galgakano). United States: J. Feldman (Katy Cardiology Associates); W. Herzog (Johns Hopkins University); M. Holland (Boulder Medical Center); V. Howard (VNH Heart Center Research); W. Jauch (Pasco Cardiology Center); M. Krolick (Heart and Vascular Center); G. Lasala (TCA Research); W. Leimbach (Hillcrest Healthcare System); M. Kumar Sharma (Parkway Cardiology Associates); R. Waksman (Washington Hospital Center); R. Webel (University of Missouri Health Care); S. Smith (Mountain States Health Alliance); J. Whitaker (Mountain States Health Alliance); R. Matthews (University of Southern California); M. Yasin (Integris Physician Services); W. Penny (San Diego Veterans Medical Center); K. Mavromatis (Atlanta VA Medical Center); S. Promisloff (Hillsboro Cardiology); M. Azrin (University of Connecticut Health Center); A-U-R. Zaki Masud (Buffalo Heart Group); J. Corbelli (Buffalo Cardiology and Pulmonary Associates); L. Kozlowski (Buffalo Cardiology and Pulmonary Associates); R. Vallabhan (HeartPlace/Baylor University Medical Center); J. Battaglia (Cardiology PC); M. Sheldon (University of New Mexico Health Sciences Center); M. Riccardi, V. Gupta (Borgess Heart Institute-Borgess Research Institute); W. Felten (Michigan Cardiovascular Institute); H. Colfer (Northern Michigan Hospital); F. D. Fortuin (Mayo Clinic Arizona); M. Feldman (University of Texas Health Sciences Center at San Antonio); L. Lancaster (Pima Research Foundation); H. Thai (Southern Arizona VA Healthcare System); K. Ziada (Gill Heart Institute); J. Mann (Wake Heart Research); M. Budoff (University of California Los Angeles); D. Westerhausen (Midwest Cardiovascular Research); K. Ramanathan (VA Medical Center Memphis); T. Haldis (Meritcare Medical Group); S. Kinlay (VA Boston Healthcare System).

Additional Contributions: We thank Craig Balog, BS, for research statistical support and Leslie Cho, MD, as well as all of the staff in the event adjudication group at the Cleveland Clinic Coordinating Center for Clinical Research. We also thank Beverley Smith, RN, Robin Roberts, MS, Satya Konkesa, MS, and Edna Cahill, MS, at Novartis for their role in study coordination. There was no additional compensation for their contributions beyond their usual compensation as employees.

Chobanian  AV, Bakris  GL, Black  HR,  et al; National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; National High Blood Pressure Education Program Coordinating Committee.  The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003;289(19):2560-2572.
PubMed   |  Link to Article
Cushman  WC, Evans  GW, Byington  RP,  et al; ACCORD Study Group.  Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med. 2010;362(17):1575-1585.
PubMed   |  Link to Article
Nissen  SE, Tuzcu  EM, Libby  P,  et al; CAMELOT Investigators.  Effect of antihypertensive agents on cardiovascular events in patients with coronary disease and normal blood pressure: the CAMELOT study: a randomized controlled trial. JAMA. 2004;292(18):2217-2225.
PubMed   |  Link to Article
Ferrario  CM, Strawn  WB.  Role of the renin-angiotensin-aldosterone system and proinflammatory mediators in cardiovascular disease. Am J Cardiol. 2006;98(1):121-128.
PubMed   |  Link to Article
Yusuf  S, Sleight  P, Pogue  J, Bosch  J, Davies  R, Dagenais  G; The Heart Outcomes Prevention Evaluation Study Investigators.  Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000;342(3):145-153.
PubMed   |  Link to Article
Sancho  J, Re  R, Burton  J, Barger  AC, Haber  E.  The role of the renin-angiotensin-aldosterone system in cardiovascular homeostasis in normal human subjects. Circulation. 1976;53(3):400-405.
PubMed   |  Link to Article
Nussberger  J, Wuerzner  G, Jensen  C, Brunner  HR.  Angiotensin II suppression in humans by the orally active renin inhibitor Aliskiren (SPP100): comparison with enalapril. Hypertension. 2002;39(1):E1-E8.
PubMed   |  Link to Article
Lu  H, Rateri  DL, Feldman  DL,  et al.  Renin inhibition reduces hypercholesterolemia-induced atherosclerosis in mice. J Clin Invest. 2008;118(3):984-993.
PubMed
Imanishi  T, Tsujioka  H, Ikejima  H,  et al.  Renin inhibitor aliskiren improves impaired nitric oxide bioavailability and protects against atherosclerotic changes. Hypertension. 2008;52(3):563-572.
PubMed   |  Link to Article
Kühnast  S, van der Hoorn  JW, van den Hoek  AM,  et al.  Aliskiren inhibits atherosclerosis development and improves plaque stability in APOE*3Leiden.CETP transgenic mice with or without treatment with atorvastatin. J Hypertens. 2012;30(1):107-116.
PubMed   |  Link to Article
Parving  HH, Brenner  BM, McMurray  JJ,  et al; ALTITUDE Investigators.  Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N Engl J Med. 2012;367(23):2204-2213.
PubMed   |  Link to Article
Nissen  SE, Nicholls  SJ, Wolski  K,  et al; PERISCOPE Investigators.  Comparison of pioglitazone vs glimepiride on progression of coronary atherosclerosis in patients with type 2 diabetes: the PERISCOPE randomized controlled trial. JAMA. 2008;299(13):1561-1573.
PubMed   |  Link to Article
Nissen  SE, Nicholls  SJ, Wolski  K,  et al; STRADIVARIUS Investigators.  Effect of rimonabant on progression of atherosclerosis in patients with abdominal obesity and coronary artery disease: the STRADIVARIUS randomized controlled trial. JAMA. 2008;299(13):1547-1560.
PubMed   |  Link to Article
Nicholls  SJ, Ballantyne  CM, Barter  PJ,  et al.  Effect of two intensive statin regimens on progression of coronary disease. N Engl J Med. 2011;365(22):2078-2087.
PubMed   |  Link to Article
Sipahi  I, Tuzcu  EM, Schoenhagen  P,  et al.  Effects of normal, pre-hypertensive, and hypertensive blood pressure levels on progression of coronary atherosclerosis. J Am Coll Cardiol. 2006;48(4):833-838.
PubMed   |  Link to Article
Nissen  SE, Tuzcu  EM, Schoenhagen  P,  et al; REVERSAL Investigators.  Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA. 2004;291(9):1071-1080.
PubMed   |  Link to Article
Nissen  SE, Nicholls  SJ, Sipahi  I,  et al; ASTEROID Investigators.  Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA. 2006;295(13):1556-1565.
PubMed   |  Link to Article
Nissen  SE, Tardif  JC, Nicholls  SJ,  et al; ILLUSTRATE Investigators.  Effect of torcetrapib on the progression of coronary atherosclerosis [published correction appears in N Engl J Med. 2007;357(8):835]. N Engl J Med. 2007;356(13):1304-1316.
PubMed   |  Link to Article
Nissen  SE, Tsunoda  T, Tuzcu  EM,  et al.  Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial. JAMA. 2003;290(17):2292-2300.
PubMed   |  Link to Article
Nissen  SE, Tuzcu  EM, Brewer  HB,  et al; ACAT Intravascular Atherosclerosis Treatment Evaluation (ACTIVATE) Investigators.  Effect of ACAT inhibition on the progression of coronary atherosclerosis. N Engl J Med. 2006;354(12):1253-1263.
PubMed   |  Link to Article
Nicholls  SJ, Hsu  A, Wolski  K,  et al.  Intravascular ultrasound-derived measures of coronary atherosclerotic plaque burden and clinical outcome. J Am Coll Cardiol. 2010;55(21):2399-2407.
PubMed   |  Link to Article
Durante  A, Peretto  G, Laricchia  A,  et al.  Role of the renin-angiotensin-aldosterone system in the pathogenesis of atherosclerosis. Curr Pharm Des. 2012;18(7):981-1004.
PubMed   |  Link to Article
Verma  S, Gupta  M, Holmes  DT,  et al.  Plasma renin activity predicts cardiovascular mortality in the Heart Outcomes Prevention Evaluation (HOPE) study. Eur Heart J. 2011;32(17):2135-2142.
PubMed   |  Link to Article
Wang  TJ, Gona  P, Larson  MG,  et al.  Multiple biomarkers for the prediction of first major cardiovascular events and death. N Engl J Med. 2006;355(25):2631-2639.
PubMed   |  Link to Article
Muhlestein  JB, May  HT, Bair  TL,  et al.  Relation of elevated plasma renin activity at baseline to cardiac events in patients with angiographically proven coronary artery disease. Am J Cardiol. 2010;106(6):764-769.
PubMed   |  Link to Article
Brunner  HR, Laragh  JH, Baer  L,  et al.  Essential hypertension: renin and aldosterone, heart attack and stroke. N Engl J Med. 1972;286(9):441-449.
PubMed   |  Link to Article
Alderman  MH, Madhavan  S, Ooi  WL, Cohen  H, Sealey  JE, Laragh  JH.  Association of the renin-sodium profile with the risk of myocardial infarction in patients with hypertension. N Engl J Med. 1991;324(16):1098-1104.
PubMed   |  Link to Article
Gheorghiade  M, Böhm  M, Greene  SJ,  et al; ASTRONAUT Investigators and Coordinators.  Effect of aliskiren on postdischarge mortality and heart failure readmissions among patients hospitalized for heart failure: the ASTRONAUT randomized trial. JAMA. 2013;309(11):1125-1135.
PubMed   |  Link to Article
Bakris  GL, Oparil  S, Purkayastha  D, Yadao  AM, Alessi  T, Sowers  JR.  Randomized study of antihypertensive efficacy and safety of combination aliskiren/valsartan vs valsartan monotherapy in hypertensive participants with type 2 diabetes mellitus. J Clin Hypertens (Greenwich). 2013;15(2):92-100.
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.
Disposition of Patients in the AQUARIUS Study

ACE indicates angiotensin-converting enzyme; AQUARIUS, Aliskiren Quantitative Atherosclerosis Regression Intravascular Ultrasound Study; ARB, angiotensin receptor blocker.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.
Incidence of Centrally Adjudicated Major Adverse Cardiovascular Events in Patients Treated With Aliskiren or Placebo
Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.
Subgroup Analysis of the Change in Percent Atheroma Volume

eGFR indicates estimated glomerular filtration. aCalculated as weight in kilograms divided by height in meters squared. bFour patients did not have valid results at baseline for this variable.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1.  Patient Demographics and Concomitant Medication Use at Baseline
Table Graphic Jump LocationTable 2.  Laboratory Values and Blood Pressure at Baseline and During Treatment for Patients With Evaluable Coronary Intravascular Ultrasound Imaging at Follow-up
Table Graphic Jump LocationTable 3.  Intravascular Ultrasound Imaging Measures of Atheroma Burden
Table Graphic Jump LocationTable 4.  Clinical and Biochemical Adverse Events and Reasons for Discontinuation in the Safety Population (N = 613)

References

Chobanian  AV, Bakris  GL, Black  HR,  et al; National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; National High Blood Pressure Education Program Coordinating Committee.  The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003;289(19):2560-2572.
PubMed   |  Link to Article
Cushman  WC, Evans  GW, Byington  RP,  et al; ACCORD Study Group.  Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med. 2010;362(17):1575-1585.
PubMed   |  Link to Article
Nissen  SE, Tuzcu  EM, Libby  P,  et al; CAMELOT Investigators.  Effect of antihypertensive agents on cardiovascular events in patients with coronary disease and normal blood pressure: the CAMELOT study: a randomized controlled trial. JAMA. 2004;292(18):2217-2225.
PubMed   |  Link to Article
Ferrario  CM, Strawn  WB.  Role of the renin-angiotensin-aldosterone system and proinflammatory mediators in cardiovascular disease. Am J Cardiol. 2006;98(1):121-128.
PubMed   |  Link to Article
Yusuf  S, Sleight  P, Pogue  J, Bosch  J, Davies  R, Dagenais  G; The Heart Outcomes Prevention Evaluation Study Investigators.  Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000;342(3):145-153.
PubMed   |  Link to Article
Sancho  J, Re  R, Burton  J, Barger  AC, Haber  E.  The role of the renin-angiotensin-aldosterone system in cardiovascular homeostasis in normal human subjects. Circulation. 1976;53(3):400-405.
PubMed   |  Link to Article
Nussberger  J, Wuerzner  G, Jensen  C, Brunner  HR.  Angiotensin II suppression in humans by the orally active renin inhibitor Aliskiren (SPP100): comparison with enalapril. Hypertension. 2002;39(1):E1-E8.
PubMed   |  Link to Article
Lu  H, Rateri  DL, Feldman  DL,  et al.  Renin inhibition reduces hypercholesterolemia-induced atherosclerosis in mice. J Clin Invest. 2008;118(3):984-993.
PubMed
Imanishi  T, Tsujioka  H, Ikejima  H,  et al.  Renin inhibitor aliskiren improves impaired nitric oxide bioavailability and protects against atherosclerotic changes. Hypertension. 2008;52(3):563-572.
PubMed   |  Link to Article
Kühnast  S, van der Hoorn  JW, van den Hoek  AM,  et al.  Aliskiren inhibits atherosclerosis development and improves plaque stability in APOE*3Leiden.CETP transgenic mice with or without treatment with atorvastatin. J Hypertens. 2012;30(1):107-116.
PubMed   |  Link to Article
Parving  HH, Brenner  BM, McMurray  JJ,  et al; ALTITUDE Investigators.  Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N Engl J Med. 2012;367(23):2204-2213.
PubMed   |  Link to Article
Nissen  SE, Nicholls  SJ, Wolski  K,  et al; PERISCOPE Investigators.  Comparison of pioglitazone vs glimepiride on progression of coronary atherosclerosis in patients with type 2 diabetes: the PERISCOPE randomized controlled trial. JAMA. 2008;299(13):1561-1573.
PubMed   |  Link to Article
Nissen  SE, Nicholls  SJ, Wolski  K,  et al; STRADIVARIUS Investigators.  Effect of rimonabant on progression of atherosclerosis in patients with abdominal obesity and coronary artery disease: the STRADIVARIUS randomized controlled trial. JAMA. 2008;299(13):1547-1560.
PubMed   |  Link to Article
Nicholls  SJ, Ballantyne  CM, Barter  PJ,  et al.  Effect of two intensive statin regimens on progression of coronary disease. N Engl J Med. 2011;365(22):2078-2087.
PubMed   |  Link to Article
Sipahi  I, Tuzcu  EM, Schoenhagen  P,  et al.  Effects of normal, pre-hypertensive, and hypertensive blood pressure levels on progression of coronary atherosclerosis. J Am Coll Cardiol. 2006;48(4):833-838.
PubMed   |  Link to Article
Nissen  SE, Tuzcu  EM, Schoenhagen  P,  et al; REVERSAL Investigators.  Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA. 2004;291(9):1071-1080.
PubMed   |  Link to Article
Nissen  SE, Nicholls  SJ, Sipahi  I,  et al; ASTEROID Investigators.  Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA. 2006;295(13):1556-1565.
PubMed   |  Link to Article
Nissen  SE, Tardif  JC, Nicholls  SJ,  et al; ILLUSTRATE Investigators.  Effect of torcetrapib on the progression of coronary atherosclerosis [published correction appears in N Engl J Med. 2007;357(8):835]. N Engl J Med. 2007;356(13):1304-1316.
PubMed   |  Link to Article
Nissen  SE, Tsunoda  T, Tuzcu  EM,  et al.  Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial. JAMA. 2003;290(17):2292-2300.
PubMed   |  Link to Article
Nissen  SE, Tuzcu  EM, Brewer  HB,  et al; ACAT Intravascular Atherosclerosis Treatment Evaluation (ACTIVATE) Investigators.  Effect of ACAT inhibition on the progression of coronary atherosclerosis. N Engl J Med. 2006;354(12):1253-1263.
PubMed   |  Link to Article
Nicholls  SJ, Hsu  A, Wolski  K,  et al.  Intravascular ultrasound-derived measures of coronary atherosclerotic plaque burden and clinical outcome. J Am Coll Cardiol. 2010;55(21):2399-2407.
PubMed   |  Link to Article
Durante  A, Peretto  G, Laricchia  A,  et al.  Role of the renin-angiotensin-aldosterone system in the pathogenesis of atherosclerosis. Curr Pharm Des. 2012;18(7):981-1004.
PubMed   |  Link to Article
Verma  S, Gupta  M, Holmes  DT,  et al.  Plasma renin activity predicts cardiovascular mortality in the Heart Outcomes Prevention Evaluation (HOPE) study. Eur Heart J. 2011;32(17):2135-2142.
PubMed   |  Link to Article
Wang  TJ, Gona  P, Larson  MG,  et al.  Multiple biomarkers for the prediction of first major cardiovascular events and death. N Engl J Med. 2006;355(25):2631-2639.
PubMed   |  Link to Article
Muhlestein  JB, May  HT, Bair  TL,  et al.  Relation of elevated plasma renin activity at baseline to cardiac events in patients with angiographically proven coronary artery disease. Am J Cardiol. 2010;106(6):764-769.
PubMed   |  Link to Article
Brunner  HR, Laragh  JH, Baer  L,  et al.  Essential hypertension: renin and aldosterone, heart attack and stroke. N Engl J Med. 1972;286(9):441-449.
PubMed   |  Link to Article
Alderman  MH, Madhavan  S, Ooi  WL, Cohen  H, Sealey  JE, Laragh  JH.  Association of the renin-sodium profile with the risk of myocardial infarction in patients with hypertension. N Engl J Med. 1991;324(16):1098-1104.
PubMed   |  Link to Article
Gheorghiade  M, Böhm  M, Greene  SJ,  et al; ASTRONAUT Investigators and Coordinators.  Effect of aliskiren on postdischarge mortality and heart failure readmissions among patients hospitalized for heart failure: the ASTRONAUT randomized trial. JAMA. 2013;309(11):1125-1135.
PubMed   |  Link to Article
Bakris  GL, Oparil  S, Purkayastha  D, Yadao  AM, Alessi  T, Sowers  JR.  Randomized study of antihypertensive efficacy and safety of combination aliskiren/valsartan vs valsartan monotherapy in hypertensive participants with type 2 diabetes mellitus. J Clin Hypertens (Greenwich). 2013;15(2):92-100.
PubMed   |  Link to Article

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