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

ACE inhibitors & ARBs in HFpEF

CHARM-Preserved: Yusuf S, et al. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved trial. Lancet 2003;362:777-81.

I-PRESERVE: Massie BM, et al. Irbesartan in patients with heart failure and preserved ejection fraction. N Engl J Med 2008;359:2456-67.

PEP-CHF: The perindopril in elderly people with chronic heart failure (PEP-CHF) study. Eur Heart J 2006;27:2338-45.

Bottom-line: In patients with HFpEF & well-controlled hypertension, ACE inhibitors and ARBs do not reduce the risk of hospitalization or death.

However, since uncontrolled hypertension is one of the predominant causes of HFpEF and an important risk factor for HF progression, most patients with HFpEF will end up receiving an ACEI/ARB anyway to control BP.

 

Patients & Generalizability

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These trials generally enrolled older individuals with clinical HF and a LVEF >40-45%. Notably, these trials excluded multiple conditions that may be classified as "HFpEF", namely valvular heart diseases such as aortic stenosis, pericardial disease and certain cardiomyopathies.

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Due to the exclusion criteria noted above, most of the cases of HFpEF in these trials were caused by hypertension (I-PRESERVE, PEP-CHF) or ischemia (CHARM-Preserved). it is thus worth mentioning that BP was well-controlled on average at baseline in all of these trials.

Interventions

• I: ACE inhibitor or ARB
  • CHARM-Preserved: Initially, candesartan 4-8 mg PO once daily, doubled q2 weeks to target 32 mg PO daily by week 6
    • At 6 months: 67% on target dose
  • I-PRESERVE: Initially, irbesartan 75 mg PO once daily, doubled q1-2 weeks to target 300 mg PO daily
    • 88% achieved target dose
  • PEP-CHF: Initially, perindopril 2 mg PO once daily, increased to 4 mg PO daily after 2 weeks
    • ~90% on 4 mg daily at 1 year
• C: Matching placebo

Results

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Internal validity

• All 3 trials are randomized, allocation-concealed, double-blind trials with loss-to-follow-up <2% and intention to treat analysis
• Other considerations:
  • I-PRESERVE employed 1 to 2-week single-blind placebo run-in phase. Patients that remained clinically stable in this phase were randomized
  • PEP-CHF: Trial recruitment stopped early due to expected futility

Other studies

• Meta-analysis of 13 RCTs of RAAS inhibition (including ACE inhibitors, ARBs and mineralocorticoid antagonists) in HFpEF (Herz 2016;41:76-86): When all pooled together,
  • No statistically significant difference in
    • Hospitalizations: HR 0.99 (0.96-1.03)
    • CV death: HR 0.98 (0.89-1.09)
    • Death: HR 0.99 (0.92-1.07)
    • 6-minute walk test distance
  • Statistically significant reduction in HF hospitalization (HR 0.89, 0.82-0.97), though this was driven by TOPCAT trial of mineralocorticoid antagonists. The lack of a reduction on death or all-cause hospitalization suggests that the reduction in HF-related hospitalization is offset by an increase in other events (e.g. syncope or falls from hypotension, hyperkalemia).

ACE inhibitors post-MI (CCS-1, CONSENSUS II, GISSI-3, ISIS-4, SMILE; AIRE, SAVE, TRACE)

Bottom line:

• Short-term use of ACE inhibitors reduces the risk of death post-MI regardless of HF signs/symptoms or LVEF at time of initiation (NNT 125-200).

  • Note: The previously-reviewed HOPE trial then supports continuing ACE inhibitors in patients without HF or LV dysfunction. 

• In patients with either clinical HF or reduced LVEF post-MI, long-term use of ACE inhibitors reduce the risk of death (NNT 14-20) and severe HF.

Short-term use of ACEI in MI all-comers:

• Oral captopril versus placebo among 13,634 patients with suspected acute myocardial infarction: Interim report from the Chinese Cardiac Study (CCS-1). Lancet 1995;345:686-7.
• ISIS-4 (Fourth International Study of Infarct Survival) Collaborative Group. ISIS-4: A randomised factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58,050 patients with suspected acute myocardial infarction. Lancet 1995;345:669-85.
• Swedberg K, et al. Effects of the early administration of enalapril on mortality in patients with acute myocardial infarction: Results of the Cooperative New Scandinavian Enalapril Survival Study II (CONSENSUS II). N Engl J Med 1992;327:678-84.
• Gruppo Italiano per lo Study della Sopravvivenza nell'infarcto Miocardico. GISSI-3: Effects of lisinopril and transdermal glyceryl trinitrate singly and together on 6-week mortality and ventricular function after myocardial infarction. Lancet 1994;343:1115-22.
• The Survival of Myocardial Infarction Long-Term Evaluation (SMILE) Study Investigators. The effect of the angiotensin-converting-enzyme inhibitor zofenopril on mortality and morbidity after anterior myocardial infarction. N Engl J Med 1995;332:80-5.

Long-term use of ACEI started shortly post-MI with LV dysfunction or clinical HF:

• Pfeffer MA, et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction: Results of the Survival and Ventricular Enlargement trial. N Engl J Med 1992;327:669-77.
• The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators. Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. Lancet 1993;342:821-8.
• Trandolapril Cardiac Evaluation (TRACE) Study Group. A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 1995;333:1670-6.

Issues with internal validity?

• No: All but 1 trial double-blind (GISSI-3) with measurement of objective outcome (all-cause mortality) and consistency between all trials.

Patients

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5 trials enrolled "all-comer" acute MI patients, regardless of the presence/absence of clinical HF or LVEF

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About 20% of patients in the "all comer" trials had clinical HF. LVEF was not routinely measured & is not reported in the original trial reports

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3 trials enrolled patients early after an MI if they had either clinical HF (AIRE) or reduced LVEF (SAVE, TRACE) for enrolment

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The majority of patients in the 2 trials of patients with LV dysfunction (SAVE, TRACE) did not have any clinical signs of HF at baseline despite an average LVEF ~30%

Generalizability: Who do these results apply to?

• Taken together, these 8 trials enrolled any patient within ~2 weeks of an MI with or without clinical HF or LV dysfunction in the fibrinolytic/pre-early invasive management era, as long as they did not have an absolute contraindication to ACEI such as SBP <90, AKI or hyperkalemia (exclusion criteria common to 2+ trials)
• Baseline use of concomitant medications (ASA, beta-blockers, etc) was variable, & overall suboptimal (ASA use ranged 55-94%)

Interventions

• Captopril studies
  • CCS-1: 6.25 mg PO test dose, followed by 12.5 mg PO TID x28 days
  • ISIS-4: 6.25 mg PO test dose, then 12.5 mg 2h later, then 25 mg 10h later, then 50 mg PO BID x28 days
    • 17% discontinued captopril before discharge
  • SAVE: Initial dose 6.25-12.5 mg PO TID, titrated up to 25 mg PO TID by hospital discharge, then increased to 50 mg PO TID & continued for trial duration (mean 3.3 y)
• Enalaprilat/enalapril (CONSENSUS II)
  • Enalaprilat 1 mg IV over 2h, then enalapril 2.5 mg PO BID, doubled daily as tolerated up to 20 mg PO BID on day 5 onward & continued for trial duration (41-180 days)
• Lisinopril (GISSI-3)
  • 5 mg PO daily x2 days, then 10 mg PO daily x6 weeks
  • 18% discontinued by week 6
• Ramipril (AIRE)
  • 2.5 mg PO BID x2 days, then 5 mg PO BID for trial duration (mean 1.25 y)
    • 86% discharged on 10 mg/d
• Trandolapril (TRACE)
  • 1 mg PO daily x2 days, then 2 mg PO daily x4 weeks, then 4 mg PO daily for trial duration (2-5.1 y)
• Zofenopril (SMILE)
  • 7.5 mg PO BID x1 day, doubled daily to target 30 mg PO BID, continued for total 6 weeks

Results

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The 5 all-comer trials all evaluated outcomes in the short term, & all but CONSENSUS II (which initiated ACEI therapy as IV) demonstrated a reduction in the incidence of death +/- HF with NNT ~125-200 for death at 4-6 weeks

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The trials of patients with clinical HF/LV dysfunction post-MI all evaluated outcomes beyond 1 year, with all trials demonstrating a mortality benefit that ranged from NNT 14-20 at ~1-5 y. Superficially, the greatest absolute benefit was seen in the AIRE trial, which enrolled only patients with clinical HF