A Randomized Controlled Trial of Aliskiren in the Prevention of Major Cardiovascular Events in Elderly People Aliskiren Prevention Of Later Life Outcomes (APOLLO, CSPP100G2301)

Cardiovascular disease (CVD) remains the leading cause of death and is expected
to remain so in the foreseeable future. It is estimated that globally in 2005,
17.5 million people died from CVD (30% of all deaths), this is projected to
increase to 20 million by 2015. CVD and its risk factors, especially
hypertension, are important determinants of physical and cognitive disability
and dependence in the elderly, with resultant high mortality and morbidity.
Hypertension is highly prevalent and is a dominant cardiovascular (CV) risk
factor. It is especially common, and reaches epidemic proportions in the
elderly, contributing to high rates of major vascular events, including stroke,
myocardial infarction, heart failure and renal dysfunction. In elderly
individuals who have underlying coronary heart, cerebrovascular and/or
peripheral arterial diseases (PAD), hypertension increases their risk by three
fold or more. Effective treatment of hypertension, in primary and secondary
prevention, would be expected to substantially reduce this risk.
While hypertension is defined as a SBP > 140 mmHg or diastolic of > 90 mmHg,
most studies of blood pressure lowering in elderly people have enrolled those
with SBP > 160 mmHg and diastolic blood pressure (DBP) > 90 mmHg. In those
placebo-controlled studies, with entry BP > 160/90 mmHg and in which SBP was
reduced by at least 10 mmHg by active therapy compared to placebo, significant
reductions in CVD risk were clearly shown. In most studies of individuals with
lower levels of entry BP, BP lowering with active treatments vs. controls,
there were no clear reductions in major vascular events, although promising
differences were observed in some studies with the exception of special drugs
in special populations where specific BP reduction and non-hypertensive effects
of the drugs were being evaluated e.g. the HOPE or the EUROPA studies. At
present there are little convincing data as to whether BP lowering per se in
elderly individuals with SBP 159 mmHg or below is beneficial. Indeed this lack
of information has been highlighted in the most recent revision of the European
Society of Hypertension reappraisal of guidelines on hypertension management.
Despite the lack of data from clinical studies, some guidelines recommend
lowering BP in individuals with BP between 140 and 159 mmHg (SBP 130 mmHg in
diabetes), based on extrapolations from the epidemiologic data in people
without preexisting CVD. By contrast, in those with preexisting CVD, the
relationship between BP and events is not linear. Therefore, clarifying whether
BP lowering in elderly individuals with BP between 130 and 159 mmHg, especially
those with preexisting CVD, will lead to worthwhile reductions in major
clinical outcomes is important from three perspectives First, a clinical
perspective (as clear evidence will remove uncertainty and provide the evidence
to treat or not); second, a public health perspective (the population burden
from hypertension is greater from Stage 1 hypertension, than at higher levels),
and third, from an economic perspective (the largest expenditure for
antihypertensive medications and related visits is likely to be in stage 1
hypertension). If studies demonstrate a lack of a clinically important effect
of BP lowering in such populations, then prevention efforts can be redirected
to other measures. If clear benefit is demonstrated, then this should lead to
more widespread use of antihypertensive therapy. Often such therapy requires
the combination of multiple medications to reach target levels, with the
attendant increases in costs, greater complexity associated with drug
interactions leading to intolerance and poor adherence, particularly in the
elderly. Therefore it is important that the data justify the decision to treat
this level of BP.
The purpose of the APOLLO study is to evaluate the effects of a regimen that
uses as a foundation the direct renin inhibitor, aliskiren, in addition to
standard medical therapy, in individuals * 65 years of age, with SBP 130 to 159
mmHg, in a placebo-controlled clinical trial. No single BP lowering drug is
likely to produce the 10 mmHg or more reduction of SBP needed in order to see
clinical effect, in those with Stage 1 hypertension, and so combined therapy
will be necessary. The renin angiotensin aldosterone system (RAAS) modulating
effects of the direct renin inhibitor, aliskiren, would be expected to lead to
incremental clinical benefits in addition to its blood pressure lowering
effect.

Primary
1. To determine whether treatment with an aliskiren-based regimen (in part
combined with amlodipine or hydrochlorothiazide) compared to a non-aliskiren
based regimen, both on top of non-study BP lowering agents where applicable,
reduces the risks of major CV events (composite of CV death, non-fatal MI,
non-fatal stroke and significant heart failure)
2. To determine whether intensified therapy with aliskiren plus an additional
BP lowering drug (amlodipine or hydrochlorothiazide) compared to placebo, both
on top of non-study BP lowering agents where applicable, reduces the risk of
major CV events.
Secondary
To determine whether treatment with an aliskiren-based regimen compared to
non-aliskiren based regimen:
1. Prevents decline in the ability to perform everyday activities independently
(key secondary objective).
2. Prevents decline in renal function
3. Reduces total mortality.
Tertiary (exploratory)
To assess the effects of an aliskiren-based regimen on specific cardiovascular
outcomes (including components of the composite primary outcome; resuscitated
cardiac arrest, heart failure, coronary artery revascularization, atrial
fibrillation, unstable angina, worsening angina or new angina), diagnosis of
new diabetes, the components of health-related successful ageing, depression,
all cause hospitalizations, surgical procedures, non-CV death, development of
LVH by ECG criteria, microvascular complications of diabetes, malignancy, and
biomarkers.

Multicenter randomized double-blind phase IIIB study with 2x2 factorial design
and 2 strata.
3 study phases:
* Pre-run-in (1-4 weeks): Without study medication. Assessment of BP stability.
* Run-in (4-5 weeks): allocation to 1 of 2 treatments, base don existing
thiazide (HCT)/calciumantagonist (CA) treatment:
a. CA: HCT 12,5/25 mg plus alsikiren 150/300 mg per day (titration).
b. HCT: amlodipine 5 mg plus aliskiren 150/300 mg per day (titration).
c. No CA or HCT: Randomized allocation to group a or b.
* Double-blind treatment phase (estimated approx. 5 years): randomization to
a. Aliskiren 300 mg plus amlodipine 5 mg of HCT 25 mg per day (combination arm).
b. Aliskiren 300 mg (aliskiren monotherapy arm).
c. Amlodipine 5 mg or HCT 25 mg per day (amlodipine or HCT monotherapy arm).
d. Placebo.
Additional open-label blood lowering drugs if necessary.
Stratification for centre and background therapy.
There are 3 optional substudies: pharmacogetic research (blood), ambulatory BP
recording, MRI scans of the brain.
Annual follow-up of patients health after end of study (at least 5 years).
Ca 11.000 randomized patients.
Operations committee, steering committee, independent DSMB, event adjudication
committee.

Treatment with aliskiren plus amlodipine or HCT or aliskiren alone or
amlodipine or HCT alone or placebo.

Risk: Adverse events of study medication.
Burden:
Visits: 4 visits and 2 telephone calls in 1st 4,5 months. Thereafter 2 visits
and 1 telephone call with an interval of 3 months, thereafter visit every 6
months. Final visit 1 months after end of treatment phase. Therafter yearly
contact about health (may be by telephone) during at least 5 years.
Blood tests (safety, blood sugar, lipids, biomarkers): every visit, 400-500 ml
with study duration of 5 year.
In addition periodically: Physical examination and ECG.
Questionnaires and test, approx. yearly:
* Standard Assessment of Global-Activities in the Elderly (SAGE) with
components of 5-item Barthel Scale for BADL and the Lawton Scale for IADL
* Montreal Cognitive Assessment (MoCA)
* Timed Up and Go (TUG)
* Digit Symbol Substitution Test (DSS)
* Geriatric Depression Scale (short form)
* European Quality of Life-5 Dimensions (EQ-5D)
* Mini Mental State Examination (MMSE) in a subset of participants.
Optional: pharmacogenetic blood test (1x 10 ml). Results will not be
communicated, ambulatory 24h blood pressure recording (2x), MRI scan brain
(2x).