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)

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)

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.

BRIDGE - Peri-procedure bridging of anticoagulation of AF patients on warfarin

Douketis JD, et al. Perioperative bridging anticoagulation in patients with atrial fibrillation. NEJM 2015;373:823-33.

Bottom line: In patients with AF & CHADS2 score <4 requiring interruption of warfarin, bridging with parenteral anticoagulation increases major bleeding (NNH 53 from bridging) without reducing thromboembolic events.

Patients (n=1884)

  • Randomized 1884, analyzed 1813

  • Included

    • Atrial fibrillation or flutter (paroxysmal or permanent) confirmed by EKG or pacemaker interrogation

    • Non-valvular or valvular AF both eligible

    • CHADS2 score 1 or higher

    • Receiving warfarin for 3+ months with INR 2.0-3.0

    • Undergoing elective invasive procedure felt to require interruption of warfarin

  • Excluded

    • Mechanical heart valve

    • Recent stroke, systemic embolism or TIA (in past 12 weeks) or major bleeding (in past 6 weeks)

    • CrCl <30 mL/min

    • Platelets <100

    • Planned cardiac, brain or spine surgery

  • Baseline characteristics

    • Age 72 y, male (73%), white (91%)

    • CHADS2 score

      • Mean score 2.3

      • 1 (23%), 2 (40%), 3 (24%), 4 (10%), 5 (3%), 6 (<1%)

      • HF/LV dysfunction ~33%

      • HTN 87%

      • Diabetes 41%

      • Prior stroke 8%

      • Prior TIA 8%

      • MI 15%

    • Undergoing procedure classified as having low bleeding risk 89%

    • Labs: INR 2.4, CrCl 88 mL/min

    • Concomitant ASA ~35%

Intervention & comparator

  • I: No bridging

    • Warfarin stopped 5 days before the procedure & restarted evening of surgery or POD 1, without bridging

  • C: Anticoagulant bridging

    • Warfarin stopped 5 days before the procedure & restarted POD0 evening or POD 1

    • Pre-op bridging: Dalteparin 100 units/kg subcut BID started 3 days before the procedure, last dose AM day before procedure (~24h before)

    • Post-op bridging: Dalteparin restarted 12-24h after low-bleeding-risk procedure & 48-72h after high-bleeding-risk procedure; continued x5-10 days until INR 2 or higher once

  • Adherence in both groups was ~86% pre-op & 96% post-op

Results @ day 30-37

  • Not bridging was non-inferior to bridging for the primary efficacy outcome (arterial thromboembolism; a composite of ischemic/hemorrhagic stroke, TIA, systemic embolism)

    • Intention-to-treat (ITT) population: No bridging 04.%, bridging 0.3% (difference 0.1%, 95% confidence interval [95%CI] -0.6% to +0.8%)

      • Stroke: 0.2% vs 0.3%

    • Per-protocol population: 0.3% vs 0.4% (difference 0.0%; 95% CI -0.7% to +0.7%)

  • Not bridging reduced the risk of major bleeding (ITT population): 1.3% vs 3.2% (NNT 53)

    • Minor bleeding: 12.0% vs 20.9% (NNT 12)

  • No difference in all-cause mortality: 0.5% vs 0.4%

Internal validity

  • Low risk of allocation, performance & detection bias

    • Interactive voice-response system

    • Dalteparin & matching placebo in identical vials

    • Blinded adjudication of all outcomes

  • Possible attrition bias due to moderate loss-to-follow-up (3.8%), which is higher than the rate of primary outcome events

  • Non-inferiority trial

    • Non-inferiority margin set as an absolute difference of 1.0% for arterial thromboembolism (wide);

    • Assumed ~1.0% absolute risk of arterial thromboembolism in both groups (actual event rate <1/2 expected);

    • Analysis of both ITT & per-protocol populations, which were nearly identical.

ATTR-ACT - Tafamidis for transthyretin amyloid cardiomyopathy

Maurer MS, et al. Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy. NEJM 2018;379:1007-16.

Bottom line:

  • In patients with transthyretin amyloid cardiomyopathy (ATTR-CM), tafamidis 20-80 mg/d reduced the risk of death (NNT 8) & cardiovascular hospitalization (NNT 13) over 30 months.

  • Based on subgroup analyses, tafamidis may increase CV hospitalizations in patients with NYHA functional class 3 HF at baseline.

  • Tafamidis did not increase overall or any specific adverse effects.

Patients (n=441)

  • Included

    • 18-90 y/o

    • ATTR, wild-type (ATTRwt) or due to a mutation (ATTRm), confirmed by cardiac or extra-cardiac biopsy

    • ATTR cardiomyopathy confirmed by

      • Echo - End-diastolic interventricular septal wall thickness >12 mm

      • Hx of heart failure (HF) with 1+ HF hospitalizations or clinical evidence of volume overload or NT-proBNP 600+ pg/mL

    • 6-minute walk-test (6MWT) distance >100 m

  • Excluded

    • NYHA functional class 4

    • Cause of HF other than ATTR CM, light-chain amyloidosis

    • Receiving other proven/potential therapy for ATTR

      • Hx of liver or heart transplant

      • Diflunisal, doxycycline, tauroursodeoxycholate

    • eGFR <25; ALT/AST >2x ULN; Severe malnutrition (quantified as serum albumin [g/L] * BMI <600)

    • Use of calcium-channel blockers or digoxin

  • Baseline characteristics

    • 74 y/o; male (90%); white (80%), black (14%)

    • ATTRwt (76%), ATTRm (24%)

    • NYHA functional class (FC): 1 (~8%), 2 (~59%), 3 (~33%)

    • Kansas City Cardiomyopathy Questionnaire (KCCQ) 66/100

    • 6MWT distance 350 m

    • BP 115/70 mm Hg (supine & standing)

    • Echo: LVEF 48%, interventricular wall thickness ~16 mm

    • NT-proBNP median ~3000

    • Meds: RAAS inhibitor (27%), beta-blocker (29%), diuretic (66-70%), antithrombotic (40%)

Interventions & control

  • I: Tafamidis 20 or 80 mg PO once daily

    • If adverse effect, those randomized to 80 mg/d could be reduced to 40 mg/d

  • C: Matching placebo

  • Adherence: 97% from each group took at least 80% of their doses (assessed by pill count at follow-up visits)

Results @ 30 months

  • Primary outcome of death or CV hospitalization: Win ratio: 1.70 (95% confidence interval [CI] 1.26-2.29)

    • “Win ratio” calculated using the Finkelstein-Schoenfeld method

      • Non-parametric test that compares every patient from the intervention group to every patient in the control group in pairwise fashion;

      • First, pairs are compared based on whether each is alive or dead at last common follow-up (e.g. if patient A followed for 2 years, but patient B dropped out at 1 year, then both are compared at year 1);

      • Second, if both are alive or both dead, then there is a draw, & they are compared based on the rate of CV hospitalizations;

      • The win ratio is a tally of all of these comparisons, where higher scores are better. Because this is a ratio, a confidence interval that does not include 1.00 is statistically significant

  • Death: Tafamidis 29.5%, placebo 42.9% (NNT 8)

    • Hazard ratio (HR) 0.70 (95%CI 0.51-0.96)

    • No significant subgroup difference based on TTR genotype or NYHA FC

  • CV hospitalizations: 52.3% vs 60.5% (NNT 13, relative risk 0.68, 95%CI 0.56-0.81)

    • Rate per patient/year: 0.30 vs 0.46

    • Subgroup based on NYHA class: p<0.001 for interaction; INCREASE with tafamidis in NYHA FC 3

    • Subgroup based on TTR genotype: p=0.11 for interaction

  • 6MWT distance vs placebo: +76 m

  • Quality of life (KCCQ) vs placebo: +13.6 points (range 0-100, higher scores are better)

  • No difference in overall, serious, or any individual adverse effects

Internal validity

  • Low risk of allocation, performance, detection & attrition bias

    • Computer-generated randomization stratified by TTR status (wild-type or mutant variant), baseline NYHA class

    • Allocation concealed: Allocation by using interactive web-response system

    • Blinding by use of matching placebo

    • Loss to follow-up <0.5% & modified intention-to-treat (mITT) analysis

REDUCE-IT - Icosapent ethyl (EPA) to reduce CV events

Bhatt DL, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. NEJM

Bottom line: In patients with existing ASCVD or diabetes + other CV risk factors, isocapent ethyl (esterified EPA) reduced the risk of CV events (NNT 21) versus placebo over 4.9 years. Conversely, icosapent increased the risk of AF (NNH 72), peripheral edema (NNH 67) and possibly serious bleeding (NNH 167) versus placebo.

It remains unclear how icosapent ethyl works to reduce CV events, or whether it benefits only patients with elevated triglycerides.

Patients (n=8179)

  • Enrolled in 11 countries from November 2011 to August 2016

  • 19,212 screened (10,429 did not meet inclusion criteria) -> 8179 randomized

  • Included

    • Either

      • Secondary prevention: 45+ y/o + established ASCVD, or

      • Primary prevention: 50+ y/o with diabetes + 1 other CV risk factor (male age 55+ y/o or female 65+ y/o; smoker; HTN; HDL-C <1 for men or <1.2 for women; hsCRP >3 mg/L; CrCl 30-60; retinopathy; albuminuria; ABI <0.9 without intermittent claudication)

    • Fasting triglyceride 1.7-5.6 mmol/L (amended in 2013 to 2.3-5.6)

    • LDL-C 1.0-2.6 mmol/L on a stable statin dose for at least 4 weeks

  • Key exclusion criteria

    • HF NYHA functional class 4; life-threatening condition other than CVD with expected prognosis <2y

    • BP >200/100 mm Hg; HbA1c >10.0%; CrCl <30 or need for peritoneal/hemodialysis

    • Planned PCI/CABG

    • Prior pancreatitis; ETOH abuse in past 6 months

    • Meds:

      • Lipid-lowering drugs other than statin +/- ezetimibe (niacin (>200 mg/d), fibrate, omega-3 supplements, bile acid sequestrants, PCSK9 inhibitors

      • Drugs that affect triglycerides & other lipids (tamoxifen, estrogen, progestins, thyroid replacement, systemic steroids.

    • Allergy to fish or shellfish

  • Typical baseline characteristics

    • 64 y/o, male (71%), white (90%)

    • Secondary prevention (71%), primary prevention (29%)

    • Type 2 diabetes (58%)

    • Labs

      • LDL-C 1.9 mmol/L, HDL-C 1.0 mmol/L, trigs 2.4 mmol/L

      • hsCRP 2.2 mg/L

    • Meds

      • Statin (100%): High-intensity (32%), moderate (62%), low (6%)

      • Ezetimibe 6%

Intervention & control

  • I: Icosapent ethyl 2 g PO BID

    • Purified formulation of eicosapentanoic acid (EPA), one of the main omega-3 fatty acids in fish oil;

    • Far exceeds doses found in over-the-counter (OTC) fish oil products, which are typically labeled to contain ~200 mg of EPA/capsule.

  • C: Matching “placebo” containing mineral oil

Results @ median 4.9 years

  • Reduction in primary CV outcome (composite of CV death, MI, stroke, PCI/CABG, or hospitalization for unstable angina [UA]): Icosapent ethyl 17.2% vs placebo 22.0% (NNT 21) & every individual component

    • Hazard ratio (HR) 0.75, 95% confidence interval (CI) 0.68-0.83

    • Reduction in 3-point MACE (CV death, MI, stroke): 11.2% vs 14.8% (NNT 28), HR 0.74, 95% CI 0.65-0.83

      • CV death: 4.3% vs 5.2% (HR 0.80, 95%CI 0.66-0.98)

      • Non-fatal or fatal MI: 6.1% vs 8.7% (HR 0.69, 95%CI 0.58-0.81)

      • Stroke: 2.4% vs 3.3% (HR 0.72, 95%CI 0.55-0.93)

    • Urgent/emergent PCI/CABG: 5.3% vs 7.8% (HR 0.65, 95%CI 0.55-0.78)

    • UA hospitalization: 2.6% vs 3.8% (HR 0.68, 95%CI 0.53-0.87)

  • Death from any cause: 6.7% vs 7.6% (HR 0.87, 95%CI 0.74-1.02 - inconclusive)

Safety

  • Increased:

    • Atrial fibrillation: 5.3% vs 3.9% (NNH 72)

    • Hospitalization for afib/flutter: 3.1% vs 2.1% (NNH 100)

    • Peripheral edema: 6.5% vs 5.0% (NNH 67)

  • Possible increased risk of serious bleeding: 2.7% vs 2.1% (NNH 167; p=0.06)

    • No difference in GI bleeds (1.5% vs 1.1%) or CNS bleeds (0.3% vs 0.2%)

Effect on surrogate outcomes

  • Trigs at year 1: -0.4 vs +0.05 mmol/L (-20% [-0.5 mmol/L] from baseline vs placebo

  • LDL-C at year 1: +0.05 vs 0.18 mmol/L (0.13 mmol/L lower vs placebo)

  • hsCRP at year 2: -0.2 vs +0.5 mg/L (-38% [0.8 mg/L] lower vs placebo

Internal validity

  • Low risk of allocation, performance and detection bias

    • Computer-generated randomization sequence stratified by CV risk group (2o or 1o prevention), use of ezetimibe & geographic region

    • Allocation concealment maintained by central allocation via interactive voice response system

    • Blinding of patients, investigators, clinicians maintained by use of mineral oil “placebo” in control group, which is similar in appearance to the intervention

  • Unclear (potentially high) risk of attrition bias

    • Low loss to follow-up (0.2%) for death

    • High loss to follow-up for non-fatal outcomes, with similar frequency between groups (icosapent ethyl 9.3%, placebo 10.0%)

    • Intention-to-treat analysis.

Other considerations

  • This is not a study of fish oil/omega-3 fatty acid supplements

    • High-quality evidence is exceptionally clear that fish oil/omega-3 fatty acid supplements, such as those sold at pharmacies, health food stores or over the Internet, do NOT reduce the risk of CV events in patients with or without CVD. This has been shown in a meta-analysis of 20 RCTs including 68,680 patients, as well as 2 other recent RCTs (ASCEND & VITAL).

  • The mechanism of action for CV event reduction with icosapent ethyl is unclear

    • Unlikely to be explained by triglyceride reduction

      • Identical CV relative risk reduction (RRR) regardless of baseline triglyceride concentration (<1.7 vs >1.7 or <2.3 vs >2.3 mmol/L);

      • Identical CV RRR regardless of whether achieved trigs <1.7 or 1.7+ mmol/L.

    • Not fully explained by LDL-C increase caused by mineral oil within placebo in comparator group

      • Identical RRR vs placebo patients who had LDL-C increase, decrease, or no change;

      • LDL-C difference of 0.13 mmol/L would only explain a ~3% RR difference based on estimates from the Cholesterol Treatment Trialists’ Collaboration meta-analysis of statins (where 1 mmol/L reduction in LDL-C associated with a ~25% RRR in CV events)

    • Other possible mechanisms include

      • Anti-inflammatory effect (or pro-inflammatory effect of mineral oil in placebo)?

      • Antiarrhythmic effect, or stabilization of cellular membranes?

        • Reduced tertiary outcomes of cardiac arrest (HR 0.52, 95% CI 0.31-0.86) & sudden cardiac death (HR 0.69, 95% CI 0.50-0.96)

      • Antithrombotic effect?

        • Reduced MI, stroke, as well as sudden cardiac events & likely increased risk of bleeding

  • Ongoing trials with EPA +/- DHA: STRENGTH (International) , RESPECT-EPA (Japan)