May 18th, 2013 by AllisonDellinger

The ASTRONAUT Randomized Trial

While I'm not in school or working, I wanted to motivate myself to stay informed about new clinical trials, so starting today (Monday, 5/20/13) I am going to begin posting a weekly "journal club" on my website.

Today I will examine "Effect of Aliskiren on Postdischarge Mortality and Heart Failure Readmissions Among Patients Hospitalized for Heart Failure,' or "The ASTRONAUT Randomized Trial," by Gheorghiade, Böhm, Greene, Fonarow, Lewis, Zannad, Solomon, Baschiera, Botha, Hua, Gimpelewicz, Jaumont, Lesogor, and Maggioni. (1)

  • Background

The renin-angiotensin-aldosterone system (RAAS) helps to maintain blood pressure through vasoconstriction and increased reabsorption of water and sodium in the kidney. When the kidneys sense a decrease in blood pressure, they release the enzyme renin. This renin breaks angiotensinogen down into angiotensin I (AT1). Angiotensin-converting enzyme (ACE) transforms AT1 into angiotensin II (ATII), which increases vasoconstriction and sympathetic activity. ATII also causes the release of aldosterone, which increases water and sodium reabsorption, increasing blood volume and therefore blood pressure.

Several blood pressure medications attempt to target different steps in the RAAS. ACE inhibitors, for example, stop the transformation of ATI to ATII, while Angiotensin II Receptor Blockers (ARBs) stop angiotensin from causing vasoconstriction and aldosterone release. However, these drugs can cause the kidneys to attempt to override their effects by releasing more renin. (1)

Tekturna (aliskiren) is a direct renin inhibitor made by Novartis. It was FDA approved in March 2007 for treatment of hypertension, as monotherapy or in conjunction with other drugs. One study randomized patients with average sitting diastolic blood pressure (DBP) of 95-109 to receive one of three daily doses of aliskiren (150mg, 300mg or 600mg) or placebo as monotherapy for 8 weeks (with a 2 week washout period and a 2-4 week placebo lead-up period.) They found that all treatment groups significantly lowered both DBP and systolic blood pressure (SBP) vs. placebo. (2)

The ALOFT trial, a double-blind placebo-controlled study published in 2008, looked at the use of aliksiren in heart failure. They examined adults with New York Heart Association (NYHA) class II-IV heart failure for at least 1 month, a past or current diagnosis of essential hypertension, and with a stable dose of an ACE inhibitor, ARB, or β-blocker, and plasma brain natriuretic peptide (BNP) >100pg/ml. BNP reductions are thought to lead to improved outcomes, lower mortality and hospitalization risk in heart failure patients. After a two week placebo run-in period, patients took either placebo or aliksiren 150mg daily for 12 weeks. A significant decrease in BNP was found in the treatment group(average 61pg/ml from baseline 301pg/ml;) however, only standing DBP had a significant decrease vs. placebo. Seated SBP, DBP, and standing SBP had an nonsignificant greater average decrease than placebo. (4)

Why This Study?

Heart failure patients have high rates of postdischarge mortality and rehospitalization. The authors of the ASTRONAUT trial theorized that incomplete RAAS suppression may be partly to blame, and so a direct renin inhibitor might reduce these risks.

Funding

Novartis Pharma AG.

  • Design and Methods

Objectives

Primary: 1st occurrence of cardiovascular (CV) death or rehospitalization for HR at 6 months after randomization.

Key Secondary: 1st occurrence of CV death or rehospitalization for HF within 12 months of randomization.

Other Secondary: 1st CV event (CV death, HF hospitalization, nonfatal myocardial infarction [MI,] nonfatal stroke, resuscitated suddent death) within 12 months, all-cause mortality within 6 and 12 months, changes from baseline in NT-proBNP levels (1, 6 & 12 months,) and quality of life at 1, 6 & 12 months (per Kansas City Cardiomyopathy Questionnaire.)

Design

  • International, double-blind placebo-controlled study.
  • Recruited between May 2009 & December 2011; follow-up period ending July 2012.
  • Patients randomized to either aliskiren 150mg daily or placebo in addition to standard therapy before hospital discharge. After 1 week, patients were assessed for safety and tolerability. After week 2, aliksiren increased to 300mg daily. After week 4, patients were checked for tolerability and decreased back to 150mg aliskiren as needed.

Inclusion Criteria

  • History of chronic HF (requiring standard therapy >29 days before hospitalization
    • 18 years or older
    • LVEF <41%
    • BNP >399pg/mL or NT-proBNP >1599pg/mL.
    • Signs/symptoms of fluid overload requiring hospitalization
    • Hemodynamically stable (SBP>109mmHg for 6 hours, no use of IV vasodilators (except nitrates) or inotropes from hospital presentation to randomization)

Exclusion Criteria

  • MI, cardiac surgery of stroke in past 3 months
  • Ventricular assistance device or any type of mechanical support
  • History of cardiac transplant or listed for transplant
  • Hemodynamically significant uncorrected primary cardiac valvular disease
  • Right HF due to pulmonary disease
  • Estimated glomerular filtration rate (eGFR) < 40ml/min/1.73m2
  • Na < 130mEq/L
  • K < 5.0mEq/L
  • Comorbid conditions with expected survival < 3 years.

Assessment and Monitoring

  • Safety & tolerability at weeks 1, 2, 4, and months 2, 3, 6, 9 & 12
  • Electrolytes, renal function at every visit
  • Minimum follow-up of 6 months, maximum of 12 months

Statistics

  • Cox proportional hazard regression model with treatment and 7 prespecified covariates: NT-proBNP, region, age, baseline SBP, baseline LVEF, basline serum creatnine, and baseline sodium.

  • 1782 participants needed for 80% power, assuming 25% event rate in the placebo group at 6 months, a 25% reduction for superiority of aliksiren over placebo, a drop-out rate of 10%, and an alpha value of 0.0495.

  • Results *

Enrollment

  • 1639 patients were randomized, 821 to receive aliskiren and 818 to receive placebo.
  • 808 treatment group subjects and 807 placebo group subjects included in efficacy analysis.
  • Due to the ALTITUDE study's premature halt for safety, recruitment for ASTRONAUT was ended early; however, an independent blinded power analysis showed that because they had already seen the required incidence of the primary endpoint, 1639 was sufficient for power.

Baseline Characteristics

  • NYHA Classification at Randomization: I/II - 33.9%; III/IV - 64.5%; Missing - 1.6%.
  • Background Therapies: Diuretic - 95.9%; ACEi/ARB: 84.2%; β-blocker: 82.5%; Digoxin: 38.9%; ICD: 15.7%; Cardiac resynchonization therapy: 6.7%; Permanent pacemaker: 11.2%

Outcomes

  • 201 patients in the aliskiren group (24.9%) and 214 patients in the placebo group (26.5%) experienced CV death or HF rehospitalization in the first 6 months. This was a nonsignificant decrease. (HR 0.92, 95% CI 0.76-1.12, P=0.41.)

  • There was no difference in secondary endpoints (CV death/HF rehospitalization in 12 months, first CV event within 12 months, all-cause death within 6 and 12 months) between groups.

  • First CV events were numerically less frequent in aliskiren group, but there were not enough events for statistical significance.

  • Myocardial infarction was statistically less frequent in the aliskiren group (18 vs 38, P=0.009.)

  • NT-proBNP level was statistically significantly decreased in aliskiren patients from placebo at each time point tested.

  • Diabetes mellitus (DM) status at baseline showed a statistically increased rate of 12-month composite endpoint of CV death and rehospitalization, and all-cause death. Patients with DM on aliskiren had higher rates of adverse effects.

Author's Conclusions

  • Aliskiren administration had no effect on the primary endpoint.
  • The study does not support adding aliskiren to patients hospitalized for exacerbation of heart failure.
  • Patients with diabetes had poorer outcomes and more adverse effects. A study of aliksiren that excludes patients with diabetes may be called for.

Strengths and Weaknesses

Strengths

  • Double-blinded
  • International, multicenter study
  • Appropriate power to detect change
  • Accurate estimation of event rate in placebo group
  • Inclusion of various background treatments
  • Long follow-up

Weaknesses

  • Not powered to analyze DM subgroup
  • Possible bias from funding source
  • No discussion of adherence
  • No differentiation between 150mg and 300mg groups

Practice Conclusions

Heart failure readmission rate is remarkably high, and further treatments for chronic heart failure need to be explored. However, aliskiren does not seem to have any benefit for patients with chronic heart failure, and the risks are increased for diabetic patients. I would not recommend beginning this for heart failure control in hospitalized patients.

References:

1) Gheorghiade, M et al. Effect of Aliksiren on Postdischarge Mortality and Heart Failure Readmission Among Patients Hospitalized for Heart Failure: The ASTRONAUT Randomized Trial. JAMA, March 20, 2013. 309:11:1125-1135.

2) Oh, B. et al. Aliskiren, an Oral Renin Inhibitor, Provides Dose-Dependent Efficacy and Sustained 24-Hour Blood Pressure Control in Patients With Hypertension. Journal of the American College of Cardiology, 2007. 49:11:1157-1163.

3) McMurray, J et al. Effects of the Oral Direct Renin Inhibitor Aliskiren in Patients With Symptomatic Heart Failure. Circulation, 2008. 1;17-24.

Read more from Allison Dellinger