Aldosterone Antagonists in Mild Heart Failure

Harsha NagarajaraoJune, 2012

Evidence Based Surgery - 2012Medicine

Objectives

• Learn Patho-physiology of RAS pathway in heart failure

• Analysis of EMPHASIS-HF trial

• Brief overview of other trials looking on aldosterone antagonism in heart failure

Myocardial DamageMyocardial DamageMyocardial DamageMyocardial DamageMyocardial Failure

Preload Afterload

Na+/H2O RetentionVenoconstriction Systemic Vascular

Resistance

ACE Inhibitors? Beta-blockersARBAldosterone Antag.

Arterial Dilators

Fluid RestrictionLow-sodium DietDiureticsVenodilators

Cardiac OutputVentricular Filling Pressures

Complementary Mechanisms Vasopressin Renin/angiotensin/aldosterone Sympathetic Activity

Inotropic Agents

Aldosterone

New Biology of Aldosterone

• Aldosterone synthesis is widespreadsynthesis is widespread in the body outside of the adrenal cortex

• Aldosterone receptors are widespread receptors are widespread in the body as well as traditional renal receptors

• Aldosterone produces endothelial vascular dysfunctionendothelial vascular dysfunction

• Aldosterone produces tissue injury and fibrosistissue injury and fibrosis—seen in the myocardium, kidney, myocardium, kidney, and cerebral tissuesand cerebral tissues

• Aldosterone produces baroreceptor dysfunctionbaroreceptor dysfunction

For a long time Adrenal Cortex was thought off as a single source of Aldosterone

Aldosterone Receptor• Stimulated equally both by gluco-corticoids and mineralo-corticoids

• But in-vivo only aldosterone can effectively activate the receptor

• This is due to proximity of 11ß hydrosterone dehydrogenase – which is juxta-posed to aldosterone receptor and rapidly inactivates cortisol

Genomic and Non-Genomic Actions

• Aldosterone acts via traditional genomic transcription pathway which takes about 1-2 hours to reach its peak stimulation

• But some actions are also immediate not involving transcription of new genes – what cause there immediate effects is still under debate

Aldosterone• In vitro studies showed first that aldosterone reduced nitric oxide

production in response in inflammatory stimuli.

• In experimental animals in vivo, aldosterone was then found to produce a vascular inflammatory response with increased expression of cytokines such as osteopontin

• Aldosterone blockade reduces both tissue injury and tissue fibrosis this protection is seen even when aldosterone blockade is given at a dose too low to alter blood pressure—that is, the tissue protective effect of aldosterone blockade in experimental models is not simply due to its antihypertensive effect.

Tissue Level Effect of Aldostorone

• Aldosterone may reduce NO bioactivity by increasing NADH oxidase induced free radical production which in turn degrades NO.

Aldosterone activates NFkB

Aldosterone Induced Myocardial Fibrosis

Aldosterone EscapeDefined in two different Contexts:

1.Escape from the sodium-retaining effects of excess aldosterone (or other mineralocorticoids) in primary hyperaldosteronism, manifested by volume and/or pressure natriuresis.

2.The inability of ACE inhibitor therapy to reliably suppress aldosterone release, for example, in patients with heart failure or diabetes, usually manifested by increased salt and water retention. This latter sense may rather be termed refractory hyperaldosteronismrefractory hyperaldosteronism.

Aldosterone Escape

• The importance of aldosterone in congestive heart failure has been overlooked in recent years because ACE-inhibitor–related reductions in angiotensin were thought to eliminate aldosterone production.

• Such suppression of circulating aldosterone, however, is transient, as exemplified by the term “escape” used to describe the phenomenon.

Aldosterone EscapeBrevity of Aldosterone suppression is explained by:

-Potent stimuli for Aldosterone suppression may counter-act ACEI due to often used low dosage of medications secondary to limitations like hypotension and renal failure.

•E.g.: upright posture, physical activity, and excessive restriction of dietary sodium (to less than 3 g per day).

Aldosterone Escape Contd..• Some aldosterone synthesis is also independent of angiotensin

concentration

• For example, potassium-dependent aldosterone secretion is independent of angiotensin concentrations and is integral to intravascular volume regulation.

• This mechanism comes into play when sodium intake is excessively restricted, the use of loop diuretics leads to substantial urinary sodium losses, and potassium supplementation is used to counteract kaliuresis related to the use of loop diuretics.

• Finally, the role of reduced metabolic clearance of aldosterone and the biologic activity of its metabolites cannot be overlooked.

Aldosterone Escape

CHF and Aldosterone

• In patients with congestive heart failure, plasma aldosterone concentrations may reach 20 times the normal level.

• Two pathophysiologic mechanisms contribute to the increased concentrations.

Aldosterone in CHF• The first is an increase in the rate of aldosterone production by the adrenal

glands due to activation of RAS.

• The second, and not widely recognized, mechanism is a decreased rate of hepatic aldosterone clearance = causes plasma aldosterone concentrations to triple or quadruple.

• The primary determinant of aldosterone metabolism is hepatic blood flow. In patients with congestive heart failure, the rate of aldosterone clearance by the liver falls to 25 to 50 percent of the normal rate.

Aldosterone Hypothesized to be Causing Myocardial Fibrosis

ACEI in Near Normal Hearts

EnalaprilEnalapril

EnalaprilEnalapril

Ramipril – Post MIRamipril – Post MI

Captopril – post MICaptopril – post MI

Trandalopirl Post MITrandalopirl Post MI

PerindoprilPerindopril

TrandalopirlTrandalopirl

RamiprilRamipril

All Cause MortalityAll Cause Mortality

Primary end point NOT met.Primary end point NOT met.

AREA-IN-CHF

AREA-IN-CHF

Background• Context

– CHF is the most common reason for hospital admission– ACEI/ARB and Mineralocorticoid antagonists improve

survival in:• NYHA Class III/IV patients with systolic HF (RALES trial)• Patients post acute-MI with LV dysfunction/CHF (EPHESUS

trial)– Current standard of care: add mineralocorticoid to

class III/IV systolic HF pt already on BB + ACEI– What about my clinic CHF patient with only mild

symptoms?

“EMPHASIS-HF Trial”

RALES TrialRALES Trial

EMPHASIS-HFEMPHASIS-HF

Clinical Question

• Population: patients with systolic heart failure (EF ≤ 35%) and mild sxs (NYHA Class

II)

• Intervention: eplerenone (up to 50mg daily) + standard therapy (ie BB, ACEI)

• Comparison: placebo + standard therapy

• Outcome: death, hospitalization rates

Study Oversight• The executive steering committee designed and

oversaw the conduct of the trial and data analysis in collaboration with representatives of the study study sponsor (Pfizer). sponsor (Pfizer).

• The trial was monitored by an independent data and safety monitoring committee.

• Data were collected, managed, and analyzed by the sponsor according to a predefined statistical analysis plan, and the analyses were replicated by an independent academic statistician.

Study Design• Setting: 278 centers, 29 countries• Participants :

– 2737 patients, age ≥55 – NYHA Class II, EF ≤30% or ≤35% if QRS>130– already on maximized ACE or ARB + BB– hospitalization within 6 months OR ↑BNP– Excluded: baseline K >5.0, GFR <30

• Placebo vs. 25mg eplerenone daily – Both placebo and eplerenone were uptitrated– Lab checks with any dose adjustment– Decrease/stopped study med for hyperK

Dose was lower for GFR between 30 and 49 (provided potassium levels were less than 5 - Started at 25 mg every other day and then went up to 25 mg daily

Procedures

• Follow up every 4 months• Investigators were asked to stop the drug if k

was > 6 and decrease the dose if between 5 to 5.9

• Potassium was re-measured with in 72 hours in those with k > 6 and only re-started if repeat levels were < 5

Outcomes

• The primary outcome was a composite of death from cardiovascular causes or a first hospitalization for heart failure.

• The pre specified secondary outcomes were hospitalization for heart failure or death from any cause, death from cardiovascular causes, hospitalization for any reason

Statistics

• The initial assumptions were that, with 2584 patients and an annual event rate of 18% in the placebo group (based on data from a subgroup analysis of the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity– Added trial [CHARM-Added])

• It was estimated that trial would require 813 patients with a primary outcome occurring within 48 months to achieve 80% power to detect an 18% relative reduction in the risk of the primary outcome in the eplerenone group as compared with the placebo

Statistics• The data and safety monitoring committee’s charter

specified interim analyses of the primary outcome after approximately 271 and 542 events had occurred, with a statistical stopping guideline for an overwhelming benefit (two-sided P<0.001 in favor of eplerenone).

• In May 6, 2010, after the second interim analysis, the data and safety monitoring committee reported that the prespecified stopping boundary for an overwhelming benefit had been crossed.

• The full executive committee was informed, decided to stop the trial

Statistics

• Two study groups was assessed by means of a two-sample t-test, for continuous variables, or Fisher’s exact test, for categorical variables.

• Primary and secondary outcomes were conducted on data from all patients who had undergone randomization, according to the intention-to-treatintention-to-treat principle, with the use of Kaplan–MeierKaplan–Meier estimates and Cox proportional-Cox proportional-hazardshazards models

Study Population

• A total of 45 patients (3.3%) in the eplerenone group and 51 patients (3.7%) in the placebo group were enrolled on the basis of a QRS duration > 130 msec. (with EF b/n 30-35%)

• 195 patients (14.3%) in the eplerenone group and 190 patients (13.8%) in the placebo group were enrolled on the basis of the BNP or N-terminal pro-BNP criterion (with no IP admission over past 180 days)

• About 50% had history of MI (all > 30 days prior)

Study Details

• Eight patients (four in each study group) did not start the study medication and were not included in the safety analysis

• After completion of the dose-adjustment phase, at 5 months, 60.2% of patients who had been assigned to receive eplerenone were taking the higher dose (50 mg daily)

• The corresponding proportion in the placebo was 60.5%

• The mean doses in each group was 39.1±13.8 mg and 40.8±12.9 mg respectively

Study Details

• At the trial cutoff date, the study drug had been discontinued in 222 patients (16.3%) receiving eplerenone and 228 patients (16.6%) receiving placebo.

• At the trial cutoff date, 17 patients (1.2%) in the eplerenone group and 15 patients (1.1%) in the placebo group were lost to follow-up.

• The median duration of follow-up among all patients was 21 months, with 4783 patient-years of follow-up.

Outcomes

Results

Results

NNT

• The estimated number of patients who would need to be treated to prevent one primary outcome from occurring, per year of follow-up, was 19 (95% CI, 15 to 27)

• The estimated number needed to treat to postpone one death, per year of follow-up, was 51 (95% CI, 32 to 180).

Safety

• During the course of the study, 188 patients (13.8%) receiving eplerenone and 222 patients (16.2%) receiving placebo discontinued the study drug because of an adverse event (P = 0.09) – Analyzed numbers are in the next table.

Adverse Events

Review of Terms• Event rate: # of people experiencing an event

as a fraction of the total at-risk population ex: 15% rate of MI in control group (CER)

5% rate of MI in experimental group (EER)

• Relative risk: likelihood of the event happening in the experimental group as compared to the control group (Ideally, experimental or therapy group should have lower risk of event than control, ie ratio <1.0)

ex: 5% therapy group/15% control group = 0.333 Therapy pts have 1/3 the risk of MI as control patients

• RRR: difference between control and experimental event rates in relative terms – ie what proportion of risk reduction does the therapy contribute as compared to baseline risk?

ex: 15%-5%/15% = 0.6666 therapy pts have a 66% reduction in baseline rate of MI

• ARR: subtracted difference between experimental and control event rates

ex: 15% - 5% = 10% absolute risk reduction

• NNT: How many pts need to receive the therapy to prevent one event? (ie not all pts that take the medication will benefit)

ex: 1/10% = 10 pts treated to prevent one MI

Review of Terms

One Caveat…In Population where Event Rate Is Low

RRR: 66% 66% ARR: 10% 1.33%NNT: 10 75

OUTCOMEControl event Rate (%)

ExperEvent Rate (%)

Relative RiskEER/CER

RRR(CER-EER)CER (95% CI)

ARRCER-EER

NNT1/ARR(95% CI)

Death by any cause

15.5% 12.5% 0.81 0.19 3% 33

Death by CV cause

13.5% 10.8% 0.80 0.20 2.7% 37

CHF cause hospitaliz

18.4% 12% 0.65 0.35 6.4% 16

HyperK 3.7% 8% n/a n/a 4.3% (increase)

23(NNH)

Number Needed to Harm!!!

Are the Results Meaningful?

• Very clinically relevant outcomes– Easily applicable, meaningful to patients

• AKI, hyperkalemia, hypotension considered & reported

Can I Apply the Results to Patient Care?

Are the study patients similar to my patients? YES

Is the intervention feasible in my practice setting? YES

Are the benefits worth the harms and costs? YES*

Cautions

• Composite primary outcome – confusing to apply clinically

• Pharma funded (Pfizer, maker of eplerenone)– Eplerenone: $113/month– Spironolactone: $14/month

• NNH for hyperkalemia lower than NNT for reducing death.. However no deaths from hyperkalemia, no difference in hyperK hospitalization rates

Bottom Line

• Addition of eplerenone to maximized CHF regimen (BB + ACEI/ARB) in Class II systolic HF patients reduced all-cause mortality and decreased CHF hospitalizations with a statistically significant, though probably acceptable, risk of hyperkalemia.

– Extrapolate to spironolactone?– Choose reliable patients (given hyperK issues)– Recommendation not yet incorporated into CHF guidelines

HFSA - 2012HFSA - 2012

Study ValidityCriteriaWere pts randomized? YES

Was randomization concealed? YES

Were pts similar on important variables? YES

Was “intention to treat” analysis done? YES**

Were pts aware of group allocation? YES

Were outcome assessors aware of allocation? ?

Complete and long enough follow-up? YES

Transplantation

Inotropes

Nitrates, hydralazine

Aldosterone Antagonists

Digoxin

Beta-blockers

ACE inhibitors or AII Blockers

Diuretics Combinations

Na+ restriction, alchohol abstinence, activity counseling, weight monitoring

NYHA IAsymptomatic

NYHA IIMildsymptoms

NYHA IIIModeratesymptoms

NYHA IVSeveresymptoms

Massie, B.M., Cardiology 2001;Section 5:p. 14.

Management of Systolic Heart Failure

EMPHASIS-HF

TOPCAT

TOPCAT is a multi-center, international, randomized, double blind placebo-controlled trial of the aldosterone antagonist, spironolactone, in 3,445 adult subjects with heart failure and left ventricular ejection fraction of at least 45%, recruited internationally from over 200 clinical centers in the US, Canada, Russia, Republic of Georgia, Argentina, and Brazil.

Thank You