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).

TRED-HF - Withdrawal of HF meds in patients with recovered (non-ischemic) dilated cardiomyopathy

Halliday BP, et al. Withdrawal of pharmacological treatment for heart failure in patients with recovered dilated cardiomyopathy (TRED-HF): an open-label, pilot, randomised trial. Lancet 2019 Jan 5;393(10166):61-73.

Bottom Line: In patients with recovered dilated cardiomyopathy (DCM), even careful withdrawal of HF medications will result in relapse of DCM (based on clinical signs, imaging or biomarkers) in approximately 4 out of 10 patients within 6 months, compared to no deterioration in this timeframe if these medications are continued.

These medications should be considered “lifelong” medications until we have tools that can reliably predict which patients can stop them without deteriorating.

Context

• In patients who initially have HF with reduced ejection fraction (HFrEF), recovery of ejection fraction >50% portends a more favorable prognosis

  • e.g. In one study, vs patients who had initial HFrEF followed by LVEF recovery to >50%, patients with non-recovered HFrEF had an increased risk of death, transplant or VAD placement (HR 3.4) & CV hospitalization (HR 1.8)

• The 2017 Canadian Cardiovascular Society (CCS) heart failure (HF) guidelines recommend consideration of monitored, sequential discontinuation of HF meds in certain subsets of patients with recovered non-ischemic cardiomyopathy

  • Including: chemotherapy-related, ETOH overuse-related, peripartum, tachycardia-related, or valvular cardiomyopathy

  • If: Asymptomatic (NYHA 1), LVEF and LV volumes normalized, trigger eliminated (e.g. ETOH abstinence, HR controlled, valve repaired/replaced)

• There is limited evidence for pharmacological treatment withdrawal in patients with HFrEF who get EF recovery

  • e.g. in an early observational study of 13 participants with DCM taking metoprolol for >2.5 years who weaned off metoprolol, 54% (7/13) experienced clinical deterioration (4 deaths & 3 patients who worsened by 1 NYHA functional class).

Design: Open-label RCT (pilot trial designed to plan larger trial)

Patients (n=51)

• Included if:

  • 16+ y/o

  • Previous dx of dilated cardiomyopathy (DCM) with LVEF 40% or lower

  • Currently:

    • NYHA functional class 1 (no current HF symptoms)

    • LVEF 50% or higher & left ventricular end diastolic volume indexed (LVEDVi) WNL (based on cardiac MRI, or 3D echo if MRI contraindicated)

    • NT-proBNP <250 ng/L

    • Treatment with 1+ of the following HF meds: Loop diuretic, ACEI, ARB, mineralocorticoid-receptor antagonist (MRA; spironolactone or eplerenone)

• Key exclusion criteria

  • Uncontrolled HTN (>160/100 mmHg in clinic)

  • Mod-severe valvular disease

  • Angina

  • Beta-blocker required for AF/flutter, VT, or SVT

  • GFR <30

  • Pregnant.

• Baseline characteristics (average of both groups unless specified)

  • Median age 55 y/o (IQR 45-64), male (67%)

  • Time since dx (4.9 y), median LVEF at dx 25%

  • Cause: Idiopathic (69%), familial (14%), trigger (excess ETOH, pregnancy, anthracycline, hyperthyroidism or myocarditis; 18%), pathogenic TTN truncation (22%)

  • Time since LVEF >50% (2 y)

  • CV symptom burden (0=none, 185=severe): 10-11

  • Quality of life using Kansas City Cardiomyopathy Questionnaire (KCCQ; 0=worst, 100=best)): 94-97

  • LVEF 60%, LVEDVi 83 mL/m^2, NT-proBNP 72 ng/L

    • Global longitudinal strain median 14% (values <16% considered abnormal)

  • Meds: ACEI/ARB (100%), beta-blocker (88%), MRA (47%), loop diuretic (12%)

Intervention & Comparator

• Intervention: Sequential discontinuation of HF meds over max 4 months, total 6 months follow-up

  • Order of drug dose reduction/discontinuation:

    • (1) Loop diuretic (reduced by 50% q2 weeks until furosemide 40 mg/d-equivalent, then D/Ced)

    • (2) MRA (reduced by 50% until equivalent to spiro 50 mg/d, then D/Ced)

    • (3) Beta-blocker (reduced by 50% until 25% target dose or lower, then D/Ced)

    • (4) ACEI/ARB (reduced by 50% until 25% target dose or lower, then D/Ced)

  • Follow-up schedule:

    • Baseline: Clinic visit, symptom & QoL questionnaire, exercise stress test, cardiac MRI, NT-proBNP

    • q4 weeks: Clinic visit & NT-proBNP

    • @ week 16: Repeat cardiac MRI

    • @ month 6: Same as baseline

• Comparator:

  • Phase 1 (randomized phase) x6 months: Continued all HF meds per baseline

    • @ baseline & month 6: Same as intervention group

    • @ weeks 8 & 16: Clinic visit, NT-proBNP

  • Phase 2: Then, non-randomized crossover to sequential discontinuation of HF meds as per intervention protocol

Results

Primary outcome: DCM relapse in 6-month randomized phase

• Defined as meeting 1+ of:

  • Clinical HF based on signs & symptoms

  • LVEF reduced by >10%, to <50%

  • LVEDVi increased by >10%, to above normal range

  • NT-proBNP doubled, to >400 ng/L

• Discontinuation group 44%, control group 0% (p=0.0001) - “number needed to harm” = 3 (rounded up from 2.3)

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Figure 3 from TRED-HF. Kaplan-Meier curve of time to relapsed DCM comparing discontinuation versus continuation of HF meds

Secondary outcomes:

• Composite safety outcome (CV death, major adverse CV events, unplanned CV hospitalization): 0 in both groups

• (Select) differences in means between groups from baseline to month 6:

  • KCCQ: -5.1 (95% CI -9.9 to -0.4; lower with discontinuation vs continuation of HF meds)

  • LVEF -9.5% (lower with discontinuation vs continuation)

  • LVEDVi +4.7 mL/m^2 (95% CI -1.5 to +11.0, p=0.14)

  • Vitals: HR +15 bpm, BP +7/+7 mmHg

  • Inconclusive: CV symptom burden, exercise time, peak VO2, log-transformed NT-proBNP

Secondary analyses including withdrawals from phase 1 + phase 2

• DCM relapse in control group phase 2: 36%

• Overall DCM relapse rate after HF med discontinuation: 40% (26% relapse <2 months of discontinuation)

Figure 4 from TRED-HF. Venn diagram breakdown of component of primary outcome met (includes all withdrawals from randomized phase + single-arm crossover phase)

Internal validity

• Allocation bias: Low risk

  • Computer-generated random sequence, 1:1 allocation in permuted blocks, stratified by baseline NT-proBNP

  • Centralized allocation via online system

• Performance bias: Low/unclear risk

  • Patients & their clinicians aware of treatment allocation; however, the study employed a standardized protocol to wean & D/C HF meds, as well as standardized monitoring

• Detection bias

  • Low risk of bias for objective outcomes (core lab MDs reading imaging unaware of study group allocation)

  • High risk of bias for QoL outcomes (patients completed the questionnaires aware of treatment allocation)

• Attrition bias: Low risk

  • Loss to follow-up 2% (1 participant in withdrawal group left trial after 7 days)

  • Analyzed intention-to-treat population

Other Considerations

• We can’t yet predict which stable, recovered DCM patients will deteriorate with D/C of HF meds

  • In this trial, predictors of DCM relapse after withdrawal of therapy included: greater age, use of >2 meds, use of MRA, higher NT-proBNP, lower global radial strain on cardiac MRI, & possibly lower peak VO2

    • However, based on univariable analysis only (no adjusting for other variables) & small n of events

  • DCM etiology did not clearly predict risk of deterioration with therapy withdrawal. Some patients with a seemingly reversible cause of DCM (e.g. ETOH use, pregnancy) did have DCM relapse upon D/Cing HF meds. Therefore, presence of a trigger does not indicate that D/Cing HF meds after HF remission will be safe.

RAAS inhibitor dose in HFrEF

Reference: Turgeon RD, et al. Higher versus lower doses of ACE inhibitors, angiotensin-2 receptor blockers and beta-blockers in heart failure with reduced ejection fraction: Systematic review and meta-analysis. PLoS ONE 14(2):e0212907

Bottom line:

The available evidence evaluating dose-response of medications in HFrEF have several caveats that require close scrutiny. With that said, pushing the dose of ACE inhibitors and ARBs appears to:

• Further reduces the risk of HF worsening or HF hospitalizations over 4-5 years;

• Increases the risk of side-effects such as lightheadedness, renal dysfunction & hyperkalemia. These are generally predictable, reversible, and manageable with holding or decreasing the ACEI/ARB dose.

The decision to aim for target ACEI/ARB doses must account for the consequences & severity of all of these events in an individual, rather than the relative size of the NNT versus NNHs. For example, HF hospitalizations impair patient quality of life, are costly to the healthcare system, & put patients at risk for numerous complications, such as hospital-acquired infections, VTE, & deconditioning. The severity of ACEI/ARB-related renal dysfunction can range from dialysis-dependent renal failure to a slight creatinine bump that's reversible upon decreasing the ACEI/ARB dose, & most often falls in the latter category.

 

Inclusion criteria from key trials

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Baseline patient characteristics from key trials

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Interventions in key trials

• ATLAS

  • I: High-dose lisinopril (32.5-35 mg PO once daily)

    • 91% achieved target dose

    • 27% discontinued study drug

  • C: Low-dose lisinopril (2.5-5 mg PO once daily)

    • 31% discontinued study drug

• High Enalapril Dose Study

  • I: High-dose enalapril (30 mg BID - 3x target dose in SOLVD)

    • ~45% achieved target dose by year 1

    • Mean achieved dose ~20 mg BID

  • C: Standard target-dose enalapril (10 mg BID)

    • ~80% achieved target dose by year 1

    • Mean achieved dose ~10 mg BID

  • Both groups started at 2.5 mg BID, uptitrated q1 week to target dose

• NETWORK

  • I-1: Standard target-dose enalapril (10 mg BID)

  • I-2: Half target-dose enalapril (5 mg BID)

  • C: Low-dose enalapril (2.5 mg BID)

  • All started at 2.5 mg BID; standard/half-dose groups doubled after 1 week; standard-dose further doubled 1 week later

• HEAAL

  • I: Losartan 150 mg once daily

    • Initial 50 mg daily, then uptitrated over 3 weeks

    • 94% achieved target dose

  • C: Losartan 50 mg once daily

Results (meta-analysis forest plots available in the open-access article)

Risk of bias

Other issues

• Inadequate follow-up duration

  • The High Enalapril Dose Study and NETWORK were both at substantial risk of a type 2 error, i.e. falsely concluding that higher doses did not result in additional benefits, as they had short follow-up periods of 6-12 months that may not adequately capture the potential benefits of targeting a higher ACEI dose

• Contamination bias: High risk

  • The ATLAS trial reported that ~20% of patients in each group started open-label ACEI therapy, which increased overall "ACEI dose" in the low-dose ACEI group and minimized potential differences in outcomes between the 2 treatment groups

• Run-in phases

  • ATLAS & HEAAL both had active run-in phases to exclude patients prior to randomization who would not tolerate a low-moderate dose of the study drug

    • Safety data from these studies will be lower than seen in an unselected real-world population

Generalizability

• Of the 4 key trials, ATLAS & HEAAL, which both included only HFrEF patients & used “high” doses that were attainable by >90% of patients in the trial, are the most generalizable to a real-world HFrEF population

• The High Enalapril Dose Study enrolled a population that is approximately 10 years younger than the usual mean age for HF trials. This is reflected in the higher proportion of patients who could achieve the 10 mg BID dose (80% versus 50% in SOLVD)

• Background HF medical therapy was seldom reported & none reported device therapy

ARBs vs ACEIs patients post-MI or at high risk of CVD

Dickstein K, et al. Effects of losartan and captopril on mortality and morbidity in high-risk patients after acute myocardial infarction: the OPTIMAAL randomised trial. Lancet 2002;360:752-60.

The ONTARGET Investigators. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008;358:1547-59.

VALIANT: Pfeffer MA, et al. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med 2003;349:1893-906.

Bottom line:

• In patients post-MI or at high risk of CVD, telmisartan & valsartan generally prevent CV events as well as ACE inhibitors with similar safety;

• The combination of ACEI+ARB is no better than monotherapy & increases the risk of adverse events (e.g. hypotension, hyperkalemia & renal impairment);

• Losartan is inferior to captopril for prevention of CV events.

 

Patients

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Interventions

• OPTIMAAL: ARB vs ACEI
  • ARB: Losartan started at 12.5 mg PO daily; increased to target 50 mg PO daily
    • 83% achieved target dose
  • ACEI: Captopril started at 12.5 mg PO TID; increased to target 50 mg PO TID
    • 81% achieved target dose
• ONTARGET: ARB, ACEI or combination of both
  • ARB: Telmisartan started at 20 mg PO daily; increased to target 80 mg PO daily
    • 87% achieved target dose
  • ACEI: Ramipril started at 2.5 mg PO daily; increased to target 10 mg PO daily (HOPE dose)
    • 82% achieved target dose
• VALIANT: ARB, ACEI or combination of both
  • ARB: Valsartan started at 20 mg PO BID; increased to target 160 mg PO BID
  • ACEI: Captopril started at 6.25 mg PO TID; increased to target 50 mg PO TID
  • 56% in each monotherapy group achieved target dose, 47% in combination group achieved target doses

Results @ 2-4.7 years

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Generalizability & internal validity

• Design of these trials essentially identical to the original 'ACEI vs placebo' trials that they mimic
  • I.e. high-quality allocation-concealed double-blind RCTs
• All 3 trials are non-inferiority trials with fair non-inferiority margins and analyses
  • Note: OPTIMAAL is the only of the 3 that does not demonstrate of the ARB (losartan) & in fact points towards significant inferiority to an ACEI
• As with the 'ACEI vs placebo' RCTs, results of these trials apply to patients that are post-MI, especially those with clinical HF & LV dysfunction, and those at high risk of CVD

ARBs in HFrEF (ELITE I & II, CHARM-Alternative, CHARM-Added & Val-HeFT)

ELITE: Pitt B, et al. Randomised trial of losartan versus captopril in patients over 65 with heart failure (Evaluation of Losartan in the Elderly Study, ELITE). Lancet 1997;349:747-52.

ELITE II: Pitt B, et al. Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: randomised trial-the Losartan Heart Failure Survival Study ELITE II. Lancet 2000;355:1582-7.

CHARM-Alternative: Granger CB, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial. Lancet 2003;362:772-6.

CHARM-Added: McMurray JJ, et al. Effects of candesartan in patients with chronic heart fialure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial. Lancet 2003;362:767-71.

Val-HeFT: Cohn JN, et al. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med 2001;345:1667-75.

Bottom-line: In patients with HFrEF with suboptimal beta-blocker use, ARBs reduce the risk of death or HF hospitalization (NNT 40-80/year; mainly from reduced HF hospitalizations), whether added to ACEI or used instead in ACEI-intolerant individuals. ARBs increase the risk of discontinuation due to adverse events when added to ACEI (NNH ~20-40), primarily from hypotension, renal dysfunction & hyperkalemia.

Results

Safety

• CHARM-Alternative
  • Any adverse event or lab abnormality: Candesartan 21.5% vs placebo 19.3% (p=0.23)
    • Hypotension leading to D/C: 3.7% vs 0.9% (NNH 36)
    • SCr increase leading to D/C: 6.1% vs 2.7% (NNH 30)
    • Hyperkalemia: 1.9% vs 0.3% (NNH 63)
• CHARM-Added
  • Any adverse event or lab abnormality: Candesartan 24.2% vs placebo 18.3% (NNH 17)
    • Hypotension leading to D/C: 4.5% vs 3.1%
    • SCr increase leading to D/C: 7.8% vs 4.1%
    • Hyperkalemia: 3.4% vs 0.7%
• Val-HeFT
  • Drug D/C: Valsartan 9.9% vs placebo 7.2% (NNH 37)
    • Dizziness 1.6% vs 0.4%
    • Hypotension: 1.3% vs 0.8%
    • Renal impairment: 1.1% vs 0.2%

Generalizability of trials adding ARB to ACEI

• CHARM-Alternative specifically enrolled patients intolerant of ACEI & therefore not receiving these agents, whereas 93% of patients enrolled in Val-HeFT received ACEI therapy
  • Results of CHARM-Added were similar to those of Val-HeFT (HR 0.85 for primary outcome & 0.83 for HF hospital admission)
• Patients in both trials had overall poor optimization of other HF meds (35-55% on beta-blockers, 5-25% on mineralocorticoid receptor antagonist) at baseline.

Internal validity

• Low risk of allocation, performance, detection and attrition bias, as all trials were randomized, allocation concealed, double-blind trials with blinded outcome adjudication, loss-to-follow-up <1% and intention-to-treat analysis.