Blockade of the renin–angiotensin system (RAS) is a core therapeutic strategy in systolic
heart failure.
1
The value of angiotensin-converting enzyme (ACE) inhibitors was proven in two pivotal
trials conducted >20 years ago. More recently, angiotensin receptor blockers (ARBs)
have also been shown to be beneficial in systolic heart failure both as an alternative
to and when added to an ACE inhibitor. Separately, mineralocorticoid receptor antagonists
(MRAs) reduce mortality and morbidity when added to an ACE inhibitor or ARB (MRAs
are not considered further here). The latest approach to RAS blockade to be tested
in clinical practice is renin inhibition. Currently the efficacy and safety of the
renin inhibitor aliskiren is being tested in two clinical trials in heart failure,
the Aliskiren Trial of Minimizing OutcomeS for Patients with HEart failure (ATMOSPHERE)
and the Aliskiren Trial on Acute Heart Failure Outcomes (ASTRONAUT), described previously
in this journal.
2,3
However, on 20 December 2011, treatment in another study, the Aliskiren Trial In Type
2 Diabetes Using Cardio-Renal Disease Endpoints (ALTITUDE), was stopped on the recommendation
of its Data Monitoring Committee (DMC).
2,3
ALTITUDE was comparing placebo or aliskiren 300 mg once daily, added to background
ACE inhibitor or ARB therapy in patients with diabetes and either (i) increased urinary
albumin excretion or (ii) both a reduced estimated glomerular filtration rate (eGFR
30–60 mL/min/1.73 m2) and established cardiovascular disease. The primary outcome
in ALTITUDE is a composite of cardiovascular death, resuscitated sudden death, non-fatal
myocardial infarction, non-fatal stroke, unplanned hospitalization for heart failure,
end-stage renal disease, renal death, or doubling of baseline serum creatinine concentration,
sustained for at least a month. As a result of the DMC recommendation, ALTITUDE is
currently being closed out in an orderly fashion. The basis of the DMC recommendation
was futility (i.e. no prospect of demonstrating the treatment benefit anticipated
in the protocol) as well as safety concerns. These concerns included renal dysfunction,
hyperkalaemia, and hypotension (which are unsurprising) as well as an excess of strokes.
In the publically released information, the number of patients experiencing a non-fatal
stroke in the placebo group was 85 (2.0%) and 112 (2.6%) in the aliskiren group (nominal,
unadjusted, P-value 0.04).
6
Although this unexpected finding has provoked concern and discussion, the reported
numbers do not represent the final number of events in ALTITUDE (at the time of the
DMC's recommendation it was estimated that approximately a third of events remained
to be collected and adjudicated). Consequently, while the apparent imbalance in strokes
may persist or increase, it may also attenuate. Furthermore, given all prior data
relating use of antihypertensive therapy to a reduced incidence of stroke in patients
with diabetes, it is also possible that the imbalance in strokes represents a chance
finding.
7–9
In response to these findings it has been recommended that dual aliskiren and ACE
inhibitor/ARB therapy not be used in patients with both hypertension (the current
indication for aliskiren) and diabetes or moderate to severe renal dysfunction (eGFR
<60 mL/min/1.73 m2).
10
This recommendation has led to questions about the use of dual aliskiren therapy in
patients with diabetes in the ongoing ATMOSPHERE trial (and, to a lesser extent, also
the ASTRONAUT trial which has almost finished recruitment and will complete follow-up
this year). In ATMOSPHERE, patients with systolic heart failure and an elevated B-type
natriuretic peptide (BNP) or N-terminal pro BNP ( NT-proBNP) concentration are randomized
in equal proportions to receive either enalapril 10 mg twice daily, aliskiren 300
mg once daily, or the combination of both drugs.
3
ATMOSPHERE is an event-driven trial with a primary composite outcome of cardiovascular
death or heart failure hospitalization. We believe that the preliminary results of
ALTITUDE should not lead to any alteration in the conduct of ATMOSPHERE. The reasons
for taking this view are discussed in detail below.
Different patient populations
The patients in ALTITUDE are quite different from those in ATMOSPHERE. Virtually all
patients in ALTITUDE had treated hypertension and the median systolic blood pressure
(SBP) was 135 (Q1 126, Q3 150) mmHg. In ATMOSPHERE, 59% of patients recruited to date
have a history of hypertension and the median SBP at baseline is 120 (Q1 110, Q3 135)
mmHg. Whereas all patients in ALTITUDE had diabetes, only 29% of the ∼5500 patients
already randomized in ATMOSPHERE have this co-morbidity (and only one-third of these
are receiving dual aliskiren and enalapril therapy). Patients with an eGFR <35 mL/min/1.73
m2 cannot be randomized in ATMOSPHERE. A much smaller proportion of patients in ATMOSPHERE
have a moderately (<60 mL/min/1.73 m2; currently 27%) or substantially (<45 mL/min/1.73
m2; currently 7%) reduced eGFR, compared with ALTITUDE (68% and 33%, respectively).
More importantly, only 11% of patients in ALTITUDE had heart failure at baseline and,
of those with a measurement of left ventricular ejection fraction (EF, n = 258), only
62 patients had an EF ≤35%.
Different study design: the importance of the active run-in periods
Recognizing that patients with heart failure may suffer hypotension, renal dysfunction,
and hyperkalaemia with dual RAS blockade, ATMOSPHERE was designed with enalapril,
followed by enalapril plus aliskiren ‘open-label’ active run-in periods. Patients
experiencing clinically important changes in blood pressure, creatinine/eGFR, and
potassium at the end of each of these periods were unable to progress to the next
treatment period/randomization (Table 1
).
3
It is expected that this design should protect against some of the adverse effects
seen in ALTITUDE which did not have this design feature.
Table 1
Safety monitoring criteria that need to be met at screening (before open-label active
run-in) and randomization (after open-label active run-in)
Parameter
Screening visit (V1)
Randomization visit (V4)
Hyperkalaemia
K+ <5.0 mmol/L
K+ <5.2 mmol/L
Renal dysfunction
eGFR ≥40 mL/min/1.73 m2
eGFR ≥35 mL/min/1.73 m2
No decrease of eGFR of >25% from visit 1
BP
No symptomatic hypotension
No symptomatic hypotension
SBP ≥95 mmHg
SBP ≥90 mmHg
AEs
No AEs that preclude continuation according to the investigator judgement
No AEs that preclude continuation according to the investigator judgement
From Krum et al.
3
AE, adverse event; BP, blood pressure; eGFR, estimated glomerular filtration rate;
SBP, systolic blood pressure.
Prior experience with dual renin–angiotensin system blockade in heart failure
As mentioned above, dual RAS blockade with agents other than aliskiren has been shown
to be of benefit in two separate trials. Importantly, this benefit appears unique
to heart failure, possibly because this syndrome is characterized by intense RAS activation.
Similar benefit is not seen after myocardial infarction or in patients with chronic
arterial disease. Moreover, the benefit of dual ACE inhibitor and ARB therapy in heart
failure was apparent in patients who had and did not have diabetes, without any evidence
of heterogeneity of treatment effect in relation to this co-morbidity (CHARM-Added,
unpublished; and Val-HeFT
11
). In addition, dual ACE inhibitor plus ARB treatment was similarly beneficial in
patients with, and in those without, renal dysfunction (eGFR < 60 mL/min/1.73m2) in
Val-HeFT.
12
Prior experience with aliskiren in heart failure
Before embarking on ATMOSPHERE, the safety of adding aliskiren to an ACE inhibitor
or ARB was tested in a pilot trial, ALOFT, in patients with a history of hypertension
and heart failure.
13–15
Over 3 months, the addition of aliskiren 150 mg daily was not associated with a clinically
important excess of elevations in potassium or creatinine, including in patients with
diabetes. ‘Efficacy’ was assessed by measurement of reduction in BNPs which was similarly
reduced with aliskiren vs. placebo in patients with and without diabetes.
16
Type of clinical events in ATMOSPHERE compared with ALTITUDE
The pattern of clinical events in patients with chronic systolic heart failure is
quite different from that of the type of patients enrolled in ALTITUDE. In heart failure,
cardiovascular death and heart failure hospitalization are much more common than stroke
(or myocardial infarction) and, consequently, ATMOSPHERE is testing the effect of
aliskiren on a different burden of disease (hence the different primary and secondary
endpoints in ALTITUDE and ATMOSPHERE).
17,18
Ensuring patient safety: the role of the Data Monitoring Committee
Lastly and most importantly, the safety of patients in ATMOSPHERE is ensured by the
group of independent physicians (and a statistician) on the DMC whose primary role
is to protect the safety of patients enrolled in this trial.
3
The DMC members are the only individuals during the course of the trial aware of treatment
allocation, and these members have vast experience in conducting and monitoring trials
in heart failure, especially trials with RAS blockers. The DMC have been informed
of the results of ALTITUDE and have reviewed the findings of ATMOSPHERE in the light
of this new information. Their recommendation is that ATMOSPHERE should continue as
planned (DMC communication to ATMOSPHERE co-chairs 20 December 2011).
Based on the above considerations, the authors (who are the academic members of the
Executive Committee of the trial) strongly believe that the ATMOSPHERE study should
continue unchanged (including continued recruitment of patients with any of a history
of hypertension, diabetes, or reduced renal function) with whatever scrutiny is deemed
appropriate by the DMC. We believe that this situation is analogous to a previous
example of a safety concern raised about a treatment in one condition but the same
treatment continuing to be tested in a trial in heart failure.
19–21
Of course, all patients are being informed of the results of ALTITUDE and will only
continue in ATMOSPHERE if they are willing to sign an updated consent form.
Conflict of interest: All authors are members of the Executive Committee for the ATMOSPHERE
trial and they or their institutions have received payment from Novartis for this
role. J.J.V.M. is also a member of the Executive Committee of the ALTITUDE trial.