Aliskiren in Left Ventricular Hypertrophy - ALLAY

Jan 31, 2009
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Trial Sponsor:
Novartis Pharmaceuticals Corp, East Hanover, NJ
Date Presented:
01/01/2008
Date Published:
01/01/2009
Date Updated:
01/31/2009
Original Posted Date:
01/31/2009
References

Description:

The goal of this trial was to determine whether aliskiren, alone or in combination with losartan, was more effective than losartan alone on left ventricular hypertrophy (LVH) reduction in overweight hypertensive patients.

Hypothesis:

Aliskiren, alone or in combination with losartan, would be associated with a greater reduction in LVH, compared with losartan alone.

Study Design

Study Design:

Patients Screened: 1,104
Patients Enrolled: 460
Mean Follow Up: 36 weeks
Mean Patient Age: 58.8 years
Female: 22
Mean Ejection Fraction: 64.3%

Patient Populations:

  • Body mass index (BMI) >25 kg/m2
  • History of hypertension or newly diagnosed hypertension ≥140/90 mm Hg
  • Evidence of LVH by echocardiography (LV wall thickness ≥1.3 cm)

Exclusions:

  • LV ejection fraction <40%
  • Required continued treatment with ACEI or ARB
  • Mean systolic blood pressure >180 mm Hg or mean diastolic blood pressure >110 mm Hg during the study
  • BMI ≥42 kg/m2
  • Myocardial infarction, coronary artery bypass grafting, percutaneous coronary intervention, stroke, or transient ischemic attack within 6 months of study entry
  • Patients treated at entry with an ACEI or ARB who did not complete the 3-month washout period
  • Serum creatinine >1.7 mg/dl in men and >1.5 mg/dl in women
  • Serum K ≥5.2 mEq/L at first visit
  • Patients with pacemakers, implantable cardioverter defibrillators, or defibrillators

Primary Endpoints:

  • Change in LVMI, as assessed by cardiac magnetic resonance imaging from baseline to week 36

Secondary Endpoints:

  • Determine if aliskiren monotherapy is noninferior to losartan monotherapy in reducing LVMI
  • Safety and tolerability of study treatments

Drug/Procedures Used:

After a screening and washout period lasting 2-12 weeks, patients were randomized to three treatment arms: aliskiren 150 mg daily, losartan 50 mg daily, or a combination of the two medications. After 2 weeks, these medications were force-titrated to aliskiren 300 mg daily, losartan 100 mg daily, or the combination for 34 weeks. Other antihypertensives could be added as necessary, other than other renin-angiotensin system blockers and beta-blockers.

Concomitant Medications:

Diuretics (55.5%), calcium channel blockers (36%), alpha-blockers (5.3%), aldosterone receptor blocker (0.5%), beta-blocker (0.8%)

Principal Findings:

A total of 460 patients were randomized, 154 to the aliskiren arm, 152 to the losartan arm, and 154 to the combination arm. The mean systolic blood pressure ranged from 144.2 to 146.1 mm Hg. The mean baseline LV ejection fraction was normal. All patients had evidence of LVH, as evidenced by maximal LV wall thickness of 1.4 cm by echocardiography, and a mean baseline LV mass index (LVMI) of 123 g/m2.

Prior angiotensin-receptor blockers (ARBs) or angiotensin-converting enzyme inhibitors (ACEIs) were used in 50.6-52% of the patients. A large proportion of patients were on ≥2 concomitant antihypertensive agents at the end of the study (28.6% vs. 30.2% vs. 18.8% for aliskiren, losartan, and the combination, respectively).

The mean reductions in blood pressure were 6.5/3.8 mm Hg, 5.5/3.7 mm Hg, and 6.6/4.6 mm Hg for aliskiren, losartan, and the combination, respectively (p = 0.81). The primary endpoint of change in LVMI was 4.9 ± 1, 4.8 ± 1, and 5.8 ± 0.9 g/m2 with aliskiren, losartan, and the combination, respectively (all p < 0.0001 compared with baseline). Aliskiren was noninferior to losartan (p for inferiority < 0.0001), but the combination was not superior to losartan alone (p = 0.52).

Both end-systolic and end-diastolic volumes were significantly reduced in all three groups compared with baseline, but there was no difference between the groups themselves. Of note, the greatest reduction in LV mass was noted in patients who were not on an ACEI or ARB prior to the trial (p < 0.0001).

The incidence of any adverse event was similar (59.1% vs. 53.9% vs. 55.8%, respectively, p = 0.67), including the incidence of hyperkalemia (2.7% vs. 3.3% vs. 3.3%) and acute renal failure (0% vs. 0.7% vs. 0.7%). There were no deaths in any of the arms.

Interpretation:

The results of this surrogate endpoint study indicate that aliskiren is noninferior to losartan in reducing blood pressure and LVMI in obese hypertensive patients with LVH, but the reduction with the combination therapy was not superior to losartan alone. The incidence of serious side effects is low with both medications.

This study indicates that aliskiren could be used in lieu of losartan in patients with hypertension and LVH, based on patient and physician preferences, though cost considerations will also be important. Further studies adequately powered for clinical endpoints are needed to further elucidate differences in the two classes of medications.

References:

Solomon SD, Appelbaum E, Manning WJ, et al. on behalf of the Aliskiren in Left Ventricular Hypertrophy (ALLAY) Trial Investigators. Effect of the direct renin inhibitor aliskiren, the angiotensin receptor blocker losartan, or both on left ventricular mass in patients with hypertension and left ventricular hypertrophy. Circulation 2009;119:530-7.

Effect of the Direct Renin Inhibitor Aliskiren, Either Alone or in Combination With Losartan, Compared to Losartan, on Left Ventricular Mass in Patients With Hypertension and Left Ventricular Hypertrophy: The Aliskiren Left Ventricular Assessment of Hypertrophy (ALLAY) Trial. Presented by Dr. Scott Solomon at the SCAI-ACC i2 Summit/American College of Cardiology Annual Scientific Session, Chicago, IL, March/April 2008.

Keywords: Hypertrophy, Left Ventricular, Losartan, Angiotensin Receptor Antagonists, Overweight, Acute Kidney Injury, Renin-Angiotensin System, Blood Pressure, Hyperkalemia, Fumarates, Body Mass Index, Hypertension, Echocardiography


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