PARADIGM-HF - Sacubitril/valsartan vs enalapril in HFrEF (short)

McMurray JJV, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014;371:993-1004.

Bottom-line: In patients with compensated HFrEF without symptomatic hypotension on an ACEI/ARB at a dose equivalent to enalapril 10 mg/d or greater, sacubitril-valsartan reduced the risk of death (NNT 36) and serious adverse events (NNT 23), including CV death or HF hospitalization (NNT 22) compared to enalapril at 2.3 years.

Context:

Medical therapy in heart failure focuses on blocking the compensatory mechanisms that eventually lead to morbidity and mortality, such as the renin-angiotensin-aldosterone system (RAAS)
- ACEIs, ARBs and mineralocorticoid antagonists reduce HF-related morbidity and mortality
The natriuretic peptide pathway is a newer molecular target for HF treatment that largely performs opposite functions to the RAAS
- Natriuretic peptides directly induce natriuresis, diuresis, peripheral vasodilation, inhibit cardiac remodelling, leading to decreased preload and afterload. Additionally, natriuretic peptides suppress the RAAS axis and adrenergic outflow
- Neprilysin is an enzyme that degrades natriuretic peptides, though it also degrades "off-target" hormones such as angiotensin II, bradykinin and vasopressin
The selection of combination of sacubitril/valsartan was based on lack of benefit with neprilysin inhibition alone, and harm with a neprilysin inhibition/ACEI combo
- Neprilysin inhibition alone: No effect on HF outcomes; postulated to result the effect of increased natriuretic peptides being offset by increased angiotensin II
- Neprilysin + ACE inhibition: Increased risk of angioedema, likely a result of the dual inhibition of bradykinin by neprilysin and ACE inhibition

Patients (n=8442)

Multicenter (1043 centres in 47 countries)
Inclusion:
- Adults with HFrEF
  - NYHA class II-IV
  - EF <40% (<35% after 2010 protocol change)
  - BNP 150+ pg/mL (NT-proBNP 600+ pg/mL) or hospitalized within 1 year + BNP 100+ pg/mL (NT-proBNP 400+ pg/mL)
- Stable dose of beta-blocker + ACEI/ARB dose equivalent to enalapril 10+ mg/day
Exclusion
- Current
  - Acutely decompensated HF
  - Symptomatic hypotension
  - Hemodynamically significant mitral or aortic valve disease (except MR 2o to LV dilatation)
  - SBP <100 mmHg at screening (SBP <95 mmHg at randomization)
  - GFR <30 or GFR decrease >25% (later amended to >35%) between screening & randomization visit
  - K >5.2 at screening (>5.4 at randomization)
- PMHx
  - ACS, stroke/TIA, major CV surgery or PCI within 3 months
  - Coronary or carotid artery disease likely to require surgical/percutaneous intervention within 6 months
  - Hx angioedema
10,521 underwent run-in phase -> 8442 randomized
Average patient
- Age 64, female (21%), white (66%), North America (7%)
- PMHx: AF (36%), MI (43%)
- HF characteristics
  - Ischemic CM 60%
  - Hospitalization for HF 63%
  - NYHA: 1 (4%), 2 (70%), 3 (24%), 4 (<1%)
  - Mean LVEF ~30%
  - Median BNP 255 (NT-proBNP 1631)
- HF tx: Diuretic (80%), beta-blocker (93%), mineralocorticoid antagonist (55%), ICD (15%), CRT (7%)
- SBP 122 mm Hg, HR 72 bpm, BMI 28
- SCr 100 umol/L

Interventions

I: Sacubitril-valsartan 200 mg PO BID
- Mean dose at last assessment: 375 mg/day
- 17.8% discontinued
C: Enalapril 10 mg PO BID
- Mean dose at last assessment: 18.9 mg/day
- 19.8% discontinued
Co-interventions common to both groups:
- Dose reduction if unacceptable side-effects at target doses

Results @ median 2.3 years

Lower risk of primary outcome (CV death or HF hospitalization) with sacubitril-valsartan: Sacubitril-valsartan 21.8%, enalapril 26.5% (NNT 22)
- Hazard ratio (HR) 0.80, 95% confidence interval (CI) 0.73-0.87
Improved secondary efficacy outcomes:
- Death: 17.0% vs 19.8% (NNT 36)
- Serious adverse events: 46.1% versus 50.6% (NNT 23)
- HF hospitalization: 12.8% vs 15.6% (NNT 36)
- Kansas City Cardiomyopathy Questionnaire (KCCQ) score difference: 1.64 (/100) better with sacubitril-valsartan (less than MCID)
Safety
- Increased:
  - Symptomatic hypotension: 14.0% vs 9.2% (NNH 22)
    - With SBP <90: 2.7% vs 1.4% (NNH 77)
- Reduced:
  - Cough: 11.3% vs 14.3% (NNT 34)
- No difference:
  - Angioedema: <0.05% in both groups
  - New-onset AF: 3.1% in both groups
  - Decline in renal function: 2.2% vs 2.6% (p=0.28)
    - Serum creatinine 221 umol/L or greater: 3.3% vs 4.5%
  - K >5.5: 16.1% vs 17.3% (>6.0 4.3% vs 5.6%)

Issue with internal validity?

No: Allocation-concealed, double-blind RCT with blinded outcome adjudication, with <1% loss-to-follow-up, analyzing the intention-to-treat population
- Low risk of allocation, performance, detection or attrition bias
- Trial stopped early after 3rd interim analysis. This may lead to an exaggerated estimate of benefit
- Active run-in period before randomization:
  1. Switched from previous ACEI/ARB to enalapril 10 mg BID x2 weeks
  2. Enalapril then D/Ced x1 day, then started on sacubitril-valsartan x4-6 weeks (started at 100 mg BID & increased to 200 mg BID)
  3. Leads to exclusion of patients who could not tolerate target-dose enalapril or sacubitril-valsartan in the short term

Additional publications of PARADIGM-HF

Relative risk reductions in primary outcome, CV death, HF hospitalization and death for sacubitril-valsartan versus enalapril are all consistent, regardless of EF
- Lower EF linearly associated with worse outcomes
In addition to lowering the risk of an initial HF hospitalization, sacubitril-valsartan reduces the risk of recurrent hospitalizations

Other RCTs of sacubitril-valsartan

PIONEER-HF
- Bottom line: Initiation of sacubitril-valsartan is feasible in patients hospitalized with decompensated HFrEF who are hemodynamically stable, & may reduce short-term HF re-hospitalization vs enalapril (NNT=18, though this is likely an overestimate of benefit). This study is underpowered for safety outcomes; the most significant adverse effect increased with sacubitril-valsartan over enalapril is symptomatic hypotension.
- Participants
  - Included 881 patients in US hospitalized for acutely decompensated HFrEF (EF=40% or less), hemodynamically stable (SBP >100 x6h, no IV inotrope >24h), BNP 400+ pg/mL or NT-proBNP 1600+ pg/mL
  - Baseline characteristics
    - 62 y/o; male (70-74%); white (58%), black (36%)
    - 1st HF dx in 34%
    - Time from hospital presentation median 68h
    - NYHA functional class: 2 (23-38%), 3 (61-64%), 4 (8-9%)
    - LVEF 25%
    - Vitals: SBP 118 mmHg, HR 80 bpm
    - Labs: NT-proBNP 2883 pg/mL, K 4.2 mmol/L, SCr 113 umol/L (eGFR 58)
    - Meds prior to admission: ACEI/ARB (48%), beta-blocker (60%), MRA (10%)
- Intervention: Sacubitril-valsartan to target dose 97/103 (“200”) mg PO BID (achieved in 55% at week 8)
  - Starting dose: 24/26 mg PO BID if SBP 100-119; 49/51 mg PO BID if SBP 120+
- Comparator: Enalapril to target dose 10 mg PO BID (achieved in 61% at week 8)
  - Starting dose: 2.5 mg PO BID if SBP 100-119; 5 mg PO BID if SBP 120+
- Both groups: Clinic follow-up with labs (CBC, SCr/lytes, etc) at week 1, 2 & then q2 weeks up to week 8
- Efficacy results @ 8 weeks
  - Improvement in surrogate outcome - primary outcome (change in NT-proBNP): Sacubitril/valsartan -47% vs enalapril -25%
    - Data missing at week 8 for 21% in both groups
    - Difference between groups emerged at week 1
  - No significant difference in underpowered exploratory clinical outcome (death; HF re-hospitalization; LVAD implantation; listed for heart transplant; unplanned outpatient visit for HF requiring IV diuretics; increase in PO diuretics >50%; addition of HF drugs): 56.6% vs 59.9%
    - Hazard ratio (HR) 0.93, 95% confidence interval (CI) 0.78-1.10
  - Reduction in HF re-hospitalization, in context of inconclusive findings on the composite clinical outcome: 8.0% vs 13.8% (HR 0.56, 0.37-0.84)
- Safety: No significant difference in symptomatic hypotension, worsening renal function, hyperkalemia or angioedema (though wide confidence intervals)
- Internal validity: Low risk of allocation, performance & detection bias; unclear risk of attrition bias for primary (surrogate outcome)