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Aliskiren Alone or With Other Antihypertensives in the Elderly With Borderline and Stage 1 Hypertension: The APOLLO Trial
Study Questions:
Does lowering blood pressure (BP) reduce cardiovascular disease (CVD) among elderly adults with elevated BP?
Methods:
The APOLLO (Aliskiren Prevention of Later Life Outcomes) trial was a randomized, placebo-controlled, stratified 2 × 2 factorial clinical trial evaluating BP lowering among 11,000 elderly individuals. Individuals ages ≥65 years, with stable systolic BP (SBP) between 130 and 159 mm Hg, and in whom background BP therapy was unchanged for at least 1 month, were included. Patients were required to have either CVD (coronary heart disease, stroke or transient ischemic attack [TIA], peripheral artery disease) or one additional CV risk factor. Exclusion criteria included intolerance to study drugs, SBP >160 mm Hg or diastolic BP (DBP) >100 mm Hg, symptomatic heart failure, complex cardiac or valvular heart disease, stroke within the previous 3 months or TIA within the previous 7 days, acute coronary syndrome within the previous 1 month, cardiac surgery or percutaneous coronary intervention within the previous 3 months or planned in the next 3 months, estimated glomerular filtration rate (eGFR) <30 ml/min/ 1.73 m2, known renal artery stenosis, serum potassium >5.3 mmol/L, chronic liver disease, malignancy within the past 5 years, concurrent treatment with cyclosporine, quinidine or systemic conazoles, chronic use of non-steroidal anti-inflammatory drugs, or cyclooxygenase-2 inhibitors in subjects with eGFR <60 ml/min/1.73 m2. Following 5-week active run-in, participants were randomized to aliskiren (300 mg) or placebo, and to an additional antihypertensive (hydrochlorothiazide [25 mg] or amlodipine [5 mg]), or their respective placebos.
Results:
The sponsor terminated the study (in December 2011, closeout was May 2012) after 1,759 subjects (ages 72.1 ± 5.2 years, 88% receiving at least one antihypertensive) were randomized. The trial had started enrollment in January 2011, in 17 countries, involving 145 centers. The median follow-up time was 0.6 (interquartile range, 0.5-0.8) years, representing <2% of the expected 55,000 person-years of follow-up to be obtained within the APOLLO trial. Average age was 72.1 ± 5.2 years, 46.2% were women, 29.7% had a history of vascular disease, and 40.6% had diabetes. The study drugs were well tolerated with few serious adverse events during run-in and after randomization, with no significant differences between treatment groups. By design, three levels of BP reductions were achieved, adjusted mean BP reductions of 3.5/1.7 mm Hg (P, 0.001) by aliskiren, 6.8/3.3 mm Hg (p < 0.001) by hydrochlorothiazide or amlodipine, and 10.3/5.0 mm Hg (p < 0.001) by double therapy compared with placebo. Twenty-five major CVD events occurred. Nonsignificant trends toward fewer CVD events with greater BP reductions were evident: (hazard ratios [HRs], 0.82; 95% confidence interval [CI], 0.37-1.81 for 3.5 mm Hg SBP reduction; HR, 0.45; 95% CI, 0.19-1.04) for 6.8 mm Hg; and HR, 0.25; 95% CI, 0.05-1.18) for 10.3 mm Hg reduction for primary composite of CV death, MI, stroke, or significant heart failure.
Conclusions:
The investigators concluded that sizeable reductions in BP, with potential for substantial CVD reduction, can be safely achieved using combinations of BP drugs in the elderly with normal high and stage 1 hypertension.
Perspective:
These data represent an incomplete trial, and therefore, make it difficult to fully evaluate the long-term safety profile of the combinations used in this trial. Given the many exclusion criteria and the knowledge, the elderly hypertensive patients often have more comorbidities than younger patients; it is unclear how these limited results generalize to a real-world clinical geriatric population.
Keywords: Cyclosporine, Follow-Up Studies, Ischemic Attack, Transient, Quinidine, Comorbidity, Peripheral Arterial Disease, Risk Factors, Liver Diseases, Fumarates, Cardiovascular Diseases, Confidence Intervals, Hydrochlorothiazide, Hypertension, Stroke, Acute Coronary Syndrome, Cyclooxygenase 2 Inhibitors, Percutaneous Coronary Intervention, Potassium, Renal Artery Obstruction, Heart Failure, Heart Valve Diseases, Glomerular Filtration Rate, Amlodipine, Cardiac Surgical Procedures, Diabetes Mellitus
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