sacubitril/valsartan dec hosp and CV mortality vs enalapril

A recent research letter assessed a subset of patients in the PIONEER-HF trial of sacubitril/valsartan vs enalapril who were hospitalized  with symptomatic heart failure with reduced ejection fraction (see chf decomp sacub better than enal circ2019 in dropbox, or DOI: 10.1161/CIRCULATIONAHA.118.039331; and see chf angio-nepril inhib nejm 2014 in dropbox, or DOI: 10.1056/NEJMoa1409077 for the original trial). This new assessment is a post-hoc rigorous adjudication of hospitalized patients for rates of rehospitalization for heart failure and mortality by cause, according to standardized definitions, whereas the initial study relied on investigator-reported data.

 

Details:

-- in the original study, 8442 patients with class II, III, or IV heart failure and ejection fraction <40% were randomized to sacubitril/valsartan 200mg bid vs enalapril 10 mg bid. the study was terminated early because of evident benefit after 27 months, though the schedule was for an 8 week trial

-- patients were required also to have a plasma B-type natriuretic peptide (BNP) level >150 pg/ml, or N-terminal pro-BNP >600 pg/ml

-- median age 64, 22% female, 66% white/5% black/18% asian

-- at admission to the initial study: systolic BP 122 mmHg, creat 1.13 mg/dL, ischemic cardiomyop 60%, LVEF 30%, median BNP 253 pg/mL, median N-terminal pro-BNP 1615 pg/mL, NYHA class I in 5%/class II 70%/class III 24%/class IV 1%, 63% had prior admissions for heart failure, 43% MI, 9% stroke

    --78% had been on ACE-I/22% ARB/80% diuretic/30% digitalis/93% b-blocker/56% mineralocorticoid antagonist/15% implantable cardioverter-defibrillator/7% cardiac resynchronization therapy

-- in the initial study, the primary outcome of a composite of death from cardiovascular causes or hospitalization for heart failure occurred in 21.8% in sacubitril/valsartan vs 26.5% on enalapril, a 20% decrease

    -- 17.0% vs 19.8% died, 16% reduction

        -- of these people, 13.3% vs 16.5% died from cardiovascular causes, 20% reduction

    -- risk of hospitalization was also decreased by 21%

 

-- for this current study they analyzed a cohort of  881 pretty sick patients: they were admitted to the hospital with heart failure, mean age 62, 72% men, 36% black persons; all had symptomatic heart failure with LVEF <40% but quite elevated N-terminal pro-BNP of >1600 pg/mL or BNP >400 pg/mL

 

Results:

-- over 8 weeks, there were:

    -- 25 deaths (2.8%), 16 classified as cardiovascular

    -- 93 confirmed hospitalizations for heart failure (10.6%)

 

--through 8 weeks after randomization:

    -- composite endpoint of all-cause mortality, rehospitalization for heart failure, left ventricular assist device implantaton, or listing for cardiac translpant: 42% decrease with sacubitril/valsartan, HR 0.58 (0.40-0.85), p=0.005

    -- composite endpoint of cardiovascular death or rehospitalization for heart failure: 9.2% vs 15.2%, 42% decreased, HR 0.58 (0.39-0.87), p=0.007

    -- rehospitalization for heart failure: 8.5% vs 13.6%, 39% decreased, HR 0.61 (0.40-0.93), p=0.021

-- at 30 days:

    -- rate of CV death or rehospitalization for HF was 5.8% vs 8.6%, HR 0.67 (0.40-1.11)

    -- rate of rehospitalization for HF was 5.1% vs 7.0%, HR 0.72 (0.42-1.25)

--review of all of the curves for these outcomes: clear separation at about 14 days, increasingly splayed curves for the rest of the trial until followup terminated at 56 days

 

Commentary:

-- other relevant findings from the PARADIGM-HF study:

    -- there was less renal toxicity with sacubitril/valsartan vs enalapril, for details see http://gmodestmedblogs.blogspot.com/2018/05/heart-failure-less-renal-toxicity-with.html

    -- there is evidence that lower doses of ACE inhibitors are effective, and this is equally true for sacubitril/valsartan: see http://gmodestmedblogs.blogspot.com/2018/01/lower-enalapril-dose-effective-in-heart.htm

    -- another analysis of this PARDIGM-HF study found that N-terminal pro-BNP was significantly decreased in the sacubitril/valsartan group as early at one week after starting medications, see chf sacubitril PARADIGM dec BNP NEJM2019 in dropbox, or DOI: 10.1056/NEJMoa1812851

    -- and another one found that switching patients from enalapril to sacubitril/valsartan after the 8-week study ended found a more profound decrease in N-terminal pro-BNP, vs just continuing the sacubitril/valsartan (see see chf angio-nepril in acute HF jamacardiol2019 in dropbox, or doi:10.1001/jamacardio.2019.4665). ie, there was a larger benefit by switching from enalapril to sacubitril/valsartan (making up for the initially smaller benefit from enalapril)

 

-- one concern i have with the recommendations to start sacubitril/valsartan early (as is strongly suggested by the PIONEER-HF study and its various substudies) is that there is no study comparing adding a mineralocorticoid antagonist (MRA) first.  in PARADIGM-HF only 56% were on an MRA at the time of the study, and there is pretty impressive evidence of mortality benefit even in those with only mild heart failure symptoms (see the EMPHASIS-HF study: chr eplerenone mild sx NEJM2011 in dropbox, or DOI: 10.1056/NEJMoa1009492)

 

--cost of medications: per GoodRx, the cost sacubitril/valsartan is about $600 per month (a coupon will take off $50), vs enalapril at $25 per month, though lisinopril is significantly cheaper, in the $5-$10 range; and spironolactone is in the $5 range

 

--and, this current study was just a post-hoc analysis of an RCT, so it is liable to confounding and does not reach the level of statistical rigor of an RCT. But, it is notable and reasonably anticipated that if sacubitril/valsartan works for a more general population, its benefits are likely to be more profound in a study of much sicker patients (hospitalized, much higher N-terminal pro-BNP than in the larger study), as was found in this analysis

 

so, i bring up this study because it reinforces that especially in patients who were admitted to the hospital with decompensated heart failure, there is pretty strong evidence that there is a dramatic mortality and rehospitalization benefit by initiating sacubitril/valsartan right away in the hospital. And the benefit is pretty quick, within weeks. it is important to remember that sacubitril/valsartan should NOT be administered with an ACE-I (higher risk of angioedema), and the ACE-I should be discontinued at least 36 hours before starting the sacubitril/valsartan. Unfortunately, there are no studies comparing adding spironolactone vs sacubitril/valsartan: I suspect that the Novartis, the drug company that makes sacubitril/valsartan and that also sponsored the PARADIGM-HF study, would not see such a comparison as in their interests….

 

geoff​

 

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