PARAGON-HF: Sacubitril-valsartan in heart failure with ejection fraction >=45%

By Hans Haag with editorial support from Ricky Turgeon

PARAGON-HF. NEJM 2019;381:1609-20

Bottom line:

• In patients with heart failure (HF) with left ventricular ejection fraction (LVEF) ≥45%, sacubitril-valsartan did not reduce the composite total HF hospitalizations/cardiovascular (CV) death or death from any cause over ~3 years.

• Sacubitril-valsartan increased the risk of hypotension (+5%) and angioedema (+0.4%) compared with valsartan.

• In subgroup analyses (which often lead us astray) sacubitril-valsartan reduced HF hospitalizations in females by ~1.5%/year (but not males) with LVEF in the “lower” range (45-60%).

Patients (n=4822 randomized)

• Screened 10,359 -> 5746 entered valsartan run-in (~9% discontinued) -> 5205 entered sacubitril-valsartan run-in (7% discontinued) -> 4822 randomized

• Included:

  • Age 50+

  • NYHA 2-4

  • LVEF ≥45% measured in the last 6 months

  • At least one of the following:

    • HF hospitalization within 9 months prior + NT-proBNP >200 pg/mL (>600 pg/mL if AF)

    • NT-pro-BNP >300 pg/mL (>900 pg/mL if AF)

  • Echo evidence of LA enlargement (e.g. LAV ≥55 mL or LAVi ≥29 mL/m^2) or LVH (septal thickness ≥1.1 cm)

  • Symptomatic HF for at least 30 days prior to screening visit

  • Structural heart disease (LA enlargement or LVH)

• Key exclusions:

  • Any prior LVEF <40%, history of dilated cardiomyopathy, hemodynamically significant valvular heart disease

  • Uncontrolled/life-threatening dysrhythmia, including AF-RVR

  • History of angioedema

  • Alternate diagnosis to explain HF symptoms (e.g. anemia with Hb <100 g/L, severe COPD)

  • Uncontrolled hypertension

  • SBP <100 mm Hg or symptomatic hypotension

  • eGFR <30 mL/min/1.73m^2 or a reduction of >35% after run-in period

  • K >5.2 mmol/L

• Baseline:

  • Age 73, 52% female, 82% white, 12% Asian, 2% Black

  • NYHA 2 (77%) & 3 (20%), LVEF median 57%, NT-proBNP ~900 pg/mL, HF hospitalization in last 12 months ~23%

  • Comorbidities: HTN 96%, diabetes 43%, AF/AFlutter 33%

  • Meds: Diuretic 96%, ACEI/ARB 86%, beta-blocker 80%, MRA ~25%

  • SBP 130, eGFR 63

Interventions: Sacubitril-valsartan 97/103 mg BID vs valsartan 160 mg BID

• Intervention: Sacubitril-valsartan 97/103 mg BID (82% on target dose)

• Comparator: Valsartan 160 mg BID (85% on target dose)

• Co-intervention: MRA permitted, all other non-study RAAS inhibitors stopped

Outcomes @ median 35 months (2.9 years)

Internal validity: Low risk of bias selection, performance, detection & attrition bias

• Selection bias: Computer-generated random sequence; allocation concealment by interactive web-response system

• Performance & detection bias: Patients, clinicians & investigators blinded to study allocation via double-dummy placebo

• Attrition bias: ITT analysis, LTFU <0.1%

Other considerations

• Generalizability:

  • 16% excluded in single-blind run-in

    • Consisted of (1) Valsartan 40-80 mg BID x 1-2 weeks, then (2) sacubitril-valsartan 49/51 mg BID x2-4 weeks, then randomized

  • PARAGON-HF defined “preserved” ejection fraction as >45%, which differs from the (subsequent) 2021 universal definition and classification of HF’s classification of HF with preserved LVEF as ≥50% and HF with LVEF 41-49% as mildly-reduced

• Pre-specified subgroup analysis of the primary outcome based on baseline LVEF suggests greater benefit with ARNI in patients with LVEF below the study median (≤ 57%) and in females (but no reduction in death in any subgroup)

  • In females, (for the outcome of first HF hospitalization) this translates to a reduction from 7.2%/y with valsartan down to 5.5%/y with sacubitril-valsartan (-1.7%/y)

  • A secondary paper further elicited an interaction between sex*LVEF and ARNI response:

    • Consistently no benefit for the primary outcome in males, regardless of LVEF

    • Benefit in females with LVEF ≤60%, with greater relative efficacy as LVEF decreased

    • This interaction has also been seen with candesartan (ARB) and spironolactone (MRA)

• Are the results clinically important?

  • Yes for: Patients who place higher value on reducing HF hospitalizations and improving quality of life than they do the increase in hypotension, angioedema (and higher cost)

  • Not for:

    • Males

    • Female patients with LVEF ≥60%

    • Female patients who do not care about the benefits noted above, or who are more concerned about costs, pill burden, and the adverse effects noted

  • However, given the more robust evidence and greater certainty for SGLT2 inhibitors and MRAs in this setting (noted below), ARNI should generally be offered after exhausting those other options.

Context

• Pharmacotherapeutic options for HF with LVEF >40% (including HF with mildly-reduced [41-49%] and preserved [≥50%] LVEF) are limited, with strongest evidence for MRAs and SGLT2i (published after PARAGON-HF); these medications reduce HF hospitalizations, but not death.

• Sacubitril targets the natriuretic peptide pathway by inhibiting neprilysin

  • Neprilysin is an enzyme that degrades natriuretic peptide (as well as “off-target” hormones, most importantly bradykinin)

  • Natriuretic peptides directly induce natriuresis, diuresis, peripheral vasodilation, and inhibit cardiac remodeling, and suppress the renin-angiotensin system.

• Sacubitril-valsartan reduced death and HF hospitalizations compared to the ACE inhibitor enalapril (the previous “gold standard”) in HF with reduced LVEF (HFrEF).

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)