Clinical trial NCT01259297: A Randomized Controlled Trial of Aliskiren in the Prevention of Major Cardiovascular Events in Elderly People
Official title: A Randomized Controlled Trial of Aliskiren in the Prevention of Major Cardiovascular Events in Elderly People
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Cardiovascular Events
Keywords: Aliskiren
Elderly
Major Cardiovascular Events
Effect of aliskiren-based regimen on major CV events (composite of CV death, non-fatal MI, non-fatal stroke and significant heart failure) in the elderly
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2010-12-14
Enrollment: 2336
Sex: ALL
Minimum age (years): 65
Standard ages: OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: TREATMENT

Brief summary: This study was planned to provide new information regarding the role of aliskiren (with or without additional therapy with a diuretic or a Calcium channel blockers (CCB)) in elderly individuals (≥ 65 years) with systolic blood pressure (SBP) 130 to 159 mmHg, in preventing major cardiovascular (CV) events and on global measures of physical, executive and cognitive function.

Detailed description: This was 2x2 factorial design study with 2 strata. As per protocol, the first co- Primary analysis as well as secondary analysis were aliskiren based regimen vs non-aliskiren based regimen. All aliskiren based arm were combined into the aliskiren based regimen and all non-aliskiren based arms were combined into non-aliskiren based regimen.

Eligibility criteria: Inclusion Criteria:

Systolic blood pressure 130 - 159 mmHg with any one of the following (1, 2 or 3):

1. Men and women aged ≥ 65 years if they have at least one of the following: (secondary prevention) Coronary heart disease

   * Previous myocardial infarction or
   * Stable angina or unstable angina with documented multi-vessel coronary artery disease, \> 50% stenosis in at least 2 major coronary arteries on coronary angiography, or positive stress test (ECG or nuclear perfusion scintogram), or
   * Multi-vessel PCI, or
   * Multi-vessel CABG surgery \> 4 years prior to informed consent, or with recurrent angina or ischemia following surgery Stroke/TIA Previous documented stroke or documented TIA \< 1 year before informed consent Peripheral artery disease
   * Previous limb bypass surgery or percutaneous transluminal angioplasty, or
   * Previous limb or foot amputation, or
   * History of intermittent claudication, with an ankle:arm BP ratio ≤ 0.80 on at least one side, or significant peripheral artery stenosis (\> 50%) documented by angiography or non-invasive testing
   * Diabetes mellitus: High-risk diabetics with evidence of end-organ damage
2. Men and women aged ≥ 65 years with no history of CVD, and with at least 1 CV risk factor (primary prevention):

   * History of dyslipidemia, defined as LDL cholesterol \> 3.5 mmol/L (135 mg/dL) or HDL\< 1.3 mmol/L (50 mg/dL) in women or \< 1.0 mmol/L (39 mg/dL) in men or total cholesterol/HDL ratio \> 5
   * History of current or recent smoking (regular tobacco use within 5 years)
   * Abdominal adiposity defined as waist/hip ratio ≥ 0.90 in women and ≥ 0.95 in men
   * History of dysglycemia defined as impaired fasting glucose (IFG - fasting plasma glucose 5.6 to 6.9 mmol/L \[101 to 124 mg/dL\]), or impaired glucose tolerance (IGT - fasting plasma glucose \< 7 mmol/L \[126 mg/dL\] but 2 hour glucose 7.8 to 11.0 mmol/L \[140 to 198 mg/dL\]) or type 2 diabetes
   * Renal dysfunction: eGFR\< 60 ml/min/1.73m2 but \> 30 ml/min/1.73m2 (MDRD formula) and/or microalbuminurea/macroalbuminurea
   * Clinical evidence of left ventricular hypertrophy
3. Men and women aged ≥ 70 years if they do not have any of the above (primary prevention)

Exclusion Criteria:

1. Current treatment with aliskiren, an ACE-inhibitor, an ARB or an aldosterone antagonist and unable to discontinue this therapy in those without clinical vascular disease. Individuals with CVD or type 2 diabetes and/or renal dysfunction may receive an ACE-inhibitor or an ARB, but not both, contraindications to Aliskiren, Amlodipine or Hydrochlorothiazide.
2. Use of both thiazide diuretic and amlodipine or another calcium channel blocker. Patients on only one of these two classes of drugs are eligible
3. Uncontrolled hypertension (systolic blood pressure ≥ 160 mmHg and/or diastolic blood pressure ≥ 100 mmHg)
4. Symptomatic heart failure, requiring the use of loop diuretics
5. Hemodynamically significant primary valvular or outflow tract obstruction (e.g. aortic or mitral valve stenosis, asymmetric septal hypertrophy, malfunctioning prosthetic valve). Constrictive pericarditis. Complex congenital heart disease.
6. Acute stroke \< 3 months or TIA ≤ 7 days before informed consent, acute coronary syndrome \< 1 months before informed consent
7. Planned cardiac surgery or angioplasty \< 3 months after informed consent or having had the procedure \< 3 months before informed consent
8. Severe renal impairment eGFR ≤ 30 ml/min/1.73m2 (MDRD formula); known renal artery stenosis ; serum potassium ≥ 5.3 mmol/L
9. Chronic liver disease (i.e. cirrhosis, esophageal varices, portocaval shunt or persistent hepatitis) or abnormal liver function, i.e., alanine transaminase (ALT) or AST \> 3x upper limit of normal (ULN)
10. Concurrent treatment with cyclosporine or quinidine; chronic use of non-steroidal anti-inflammatory drug (NSAIDs) or cyclooxygenase-2 (COX 2) inhibitors in patients with eGFR \< 60 ml/min/1.73m2 (MDRD formula)
11. History of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past 5 years regardless of whether there is evidence of local recurrence or metastases
12. Other serious condition(s) likely to interfere with study participation or with the ability to complete the study. Significant psychiatric illness, senility, dementia, alcohol or substance abuse, which could impair the ability to provide informed consent and to adhere to the study procedures

Primary outcomes:
measure: Number of Participants With Composite Cardiovascular Endpoints in Aliskiren Based Regimen Versus Non-Aliskiren Based Regimen
timeFrame: End of study (209 days (median))
measure: Number of Participants With Composite Cardiovascular Endpoints in Aliskiren+Amlodipine/HCTZ Group Versus All Placebo Group
timeFrame: End of study (209 days (median))
Secondary outcomes:
measure: Change From Baseline to End of Study in Standard Assessment of Global Activities in the Elderly (SAGE) Dimensions (Part I)
timeFrame: Baseline, End of study (209 days [median])
measure: Percentage of Participants With Standard Assessment of Global Activities in the Elderly (SAGE) Dimensions (Part II)
timeFrame: End of study (209 days [median])
measure: Number of Participants With Renal Dysfunction in Aliskiren Based Regimen Versus Non-Aliskiren Based Regimen
timeFrame: End of study (209 days (median))
measure: Number of Participants With Total Mortality in Aliskiren Based Regimen Versus Non-aliskiren Based Regimen
timeFrame: End of study (209 days (median))
Other outcomes:
measure: Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP)
timeFrame: Baseline (BL), 6 week, 6 month and 12 month
measure: Change From Baseline in Mean Sitting Diastolic Blood Pressure (msDBP)
timeFrame: Baseline (BL), 6 week, 6 month and 12 month
Locations:
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state: Alabama
city: Los Angeles
country: United States
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city: Northridge
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city: Jenin
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city: Merlo
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state: Rio Negro
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state: Santa Fe
city: Buenos Aires
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city: Buenos Aires
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state: Tamil Nadu
city: Lucknow
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state: Uttar Pradesh
city: Chennai
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city: Kota Bahru
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state: Kelantan
city: Kota Bharu
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state: Kelantan
city: Kuantan
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state: Pahang
city: Batu Caves
country: Malaysia
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state: Selangor
city: Kuala Lumpur
country: Malaysia
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city: Kuala Lumpur
country: Malaysia
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city: Breda
country: Netherlands
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city: Eindhoven
country: Netherlands
facility: Novartis Investigative Site
city: Groningen
country: Netherlands
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city: Leiderdorp
country: Netherlands
facility: Novartis Investigative Site
city: Rotterdam
country: Netherlands
facility: Novartis Investigative Site
city: Velp
country: Netherlands
facility: Novartis Investigative Site
city: Zoetermeer
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city: Dasmarinas
country: Philippines
facility: Novartis Investigative Site
state: Cavite
city: Laoag City
country: Philippines
facility: Novartis Investigative Site
state: Ilocos Norte
city: Quezon City
country: Philippines
facility: Novartis Investigative Site
state: Metro Manila
city: Binan City
country: Philippines
facility: Novartis Investigative Site
city: Manila
country: Philippines
facility: Novartis Investigative Site
city: Manila
country: Philippines
facility: Novartis Investigative Site
city: Pasig City
country: Philippines
facility: Novartis Investigative Site
city: Quezon City
country: Philippines
facility: Novartis Investigative Site
city: Paarl
country: South Africa
facility: Novartis Investigative Site
state: Western Province
city: Bloemfontein
country: South Africa
facility: Novartis Investigative Site
city: Durban
country: South Africa
facility: Novartis Investigative Site
city: Pretoria
country: South Africa
facility: Novartis Investigative Site
city: Valencia
country: Spain
facility: Novartis Investigative Site
state: Comunidad Valenciana
city: Ferrol
country: Spain
facility: Novartis Investigative Site
state: Galicia
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Puerto de Sagunto
country: Spain
facility: Novartis Investigative Site
city: Dalby
country: Sweden
facility: Novartis Investigative Site
city: Goteborg
country: Sweden
facility: Novartis Investigative Site
city: Göteborg
country: Sweden
facility: Novartis Investigative Site
city: Malmö
country: Sweden
facility: Novartis Investigative Site
city: Rättvik
country: Sweden
facility: Novartis Investigative Site
city: Stockholm
country: Sweden
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: Teo KK, Pfeffer M, Mancia G, O'Donnell M, Dagenais G, Diaz R, Dans A, Liu L, Bosch J, Joseph P, Copland I, Jung H, Pogue J, Yusuf S; Aliskiren Prevention of Later Life Outcomes trial Investigators. Aliskiren alone or with other antihypertensives in the elderly with borderline and stage 1 hypertension: the APOLLO trial. Eur Heart J. 2014 Jul;35(26):1743-51. doi: 10.1093/eurheartj/ehu079. Epub 2014 Mar 9.