Beta-blockers in HFrEF (CIBIS-II, COPERNICUS, US Carvedilol HF study, MERIT-HF)

November 24, 2016 by Ricky Turgeon in HFrEF

CIBIS-II: The cardiac insufficiency bisoprolol study II (CIBIS-II): A randomised trial. Lancet 1999;353:9-13.

US Carvedilol HF Study: Packer M, et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure: U.S. Carvedilol Heart Failure Study Group. N Engl J Med 1996;334:1349-55.

COPERNICUS: Packer M, et al. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 2001;344:1651-8.

MERIT-HF: Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL randomized intervention trial in congestive heart failure (MERIT-HF). Lancet 1999;353:2001-7.

Bottom line: Bisoprolol, carvedilol & extended-release metoprolol all reduced death in HFrEF (NNT ~10-20 @ 1 year). When evaluated, these beta-blockers also reduced hospitalizations to a similar degree.

Issues with internal validity?

No: All 4 were randomized, allocation-concealed, double-blind trials with <1% loss-to-follow-up analyzed using the intention-to-treat population
- All 4 RCTs were stopped early during interim analyses due to overwhelming evidence of a mortality benefit from the beta-blocker
2 trials had a run-in period:
- US carvedilol study: 2-week open-label run-in phase where all patients received carvedilol 6.25 mg PO BID. Those who could tolerate this dose (94% of patients) were randomized.
MERIT-HF: 2-week run-in period with placebo, after which those who took >75% of doses were randomized.

Patients

Interventions & co-interventions

I: Beta-blocker
- CIBIS 2: Bisoprolol started at 1.25 mg PO daily, increased weekly (-> 2.5 -> 5), then monthly (-> 7.5 -> 10) to a maximum tolerated dose of up to 10 mg PO daily
  - Achieved dose: 1.25-2.5 mg/d (33%), 5-7.5 mg/d (25%), 10 mg/d (42%)
- US Carvedilol HF Study: After the run-in where patients initially received carvedilol 6.25 mg PO BID, the dose was increased to 12.5 mg PO BID, then incrementally up to 50 mg PO BID as tolerated
  - Mean dose achieved during study 45 mg/d (80% achieved target dose)
- COPERNICUS: Carvedilol started at 3.125 mg PO BID x2 weeks, then doubled q2 weeks as tolerated to a target dose of 25 mg PO BID
  - As necessary, other drugs could be titrated or carvedilol titration frequency could be modified
  - Mean dose achieved @ 4 months: 37 mg/d
- MERIT-HF: Metoprolol extended-release 25 mg PO once daily (12.5 mg for NYHA III-IV at baseline), doubled q2 weeks as tolerated to a target dose of 200 mg PO daily
  - Mean dose achieved @ 6 months: 160 mg (64% achieved target dose)
C: Matching placebo

Results

Subroup analyses in the individual trials did not demonstrate any difference in relative benefit differences based on age, sex, HF etiology, NYHA functional class, or LVEF.
In all trials, the mortality benefit from beta-blockers stemmed from a reduction in both progression of HF & sudden cardiac death.

Other studies

The COMET trial is the largest RCT comparing different beta-blockers in HFrEF. It demonstrated a lower risk of death (NNT 17) over 4.8 years with carvedilol at a target dose of 25 mg PO BID versus metoprolol tartrate at a target dose of 50 mg PO BID
- The benefit of carvedilol in this trial may be a result of an unfair comparison rather than a true benefit. The short-acting metoprolol tartrate was used in this trial instead of the once-dialy long-acting succinate salt proven to reduce mortality in MERIT-HF. Additionally, the target metoprolol was half the target dose in MERIT-HF. The carvedilol dose and formulation were the same as in the landmark trials demonstrating benefit over placebo.

SWORD - d-sotalol in patients with previous MI & LV dysfunction

October 30, 2016 by Ricky Turgeon in Ventricular arrhythmias, HFrEF

Effect of d-sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction. Lancet 1996;348:7-12.

Bottom line: In patients with MI & LV dysfunction (the majority with moderately symptomatic HFrEF), d-sotalol (a pure potassium channel-blocking antiarrhythmic) increased the risk of death within 5 months of treatment.

Although there was no difference in arrhythmias captured on EKG, the majority of the deaths attributable to d-sotalol are presumed to be from induced polymorphic arrhythmias (TdP).

Patients

Inclusion
- Adults with either:
  - Recent MI (6-42 days), or
  - Remote MI (>42 days) + heart failure with NYHA functional class II or III
- LVEF <40%
Exclusion
- Unstable angina
- Heart failure NYHA IV
- PMHx
  - Life-threatening arrhythmia (sustained VT, VF, or cardiac arrest) unrelated to anMI
  - Sick sinus syndrome, 3rd degree AV block, 2nd degree AV block type 2 not treated with pacemaker
  - PCI or CABG within 14 days
  - QTc >460 msec
  - CrCl <50 mL/min
  - Serum K <4.0 mmol/L
  - Serum Mg <0.75 mmol/L
  - Use of concomitant class I or III antiarrhythmic
? screened -> 3121 randomized & analyzed
"Average" patient
- Age 60 y
- Female 14%
- White 93%
- Recent MI 29%
- Mean time from index MI - "recent" (3 weeks), "remote" (4 years)
- Heart failure NYHA class I (7%), II (72%), III (22%)
- LVEF 31%
- Baseline QTc 420 msec
- 24h Holter:
  - Mean 54 PVCs/hour
  - Patients with VT runs 36%

Interventions

I: d-sotalol
- Initial dose: 100 mg PO BID x1 week,
- If initial dose tolerated & QTc <520 msec: Dose increased to 200 mg PO BID x1 week
- If 200 mg PO BID tolerated & QTc <560 msec: Continued for rest of trial
- Throughout trial, dose reduced if >560 msec (d-sotalol discontinued if QTc >560 msec with 100 mg PO BID)
- Note: d-sotalol is the dextro enantiomer of sotalol, which has potassium-blocking activity, but minimal beta-blockade. Sotalol used in practice includes both the l & d enantiomers of sotalol.
C: Matching placebo

Results @ mean 5 months

Death (primary outcome): Relative risk 1.65 (95% confidence interval 1.15-2.36)
- d-sotalol 5.0% vs placebo 3.1% (number needed to harm = 53)
- Harmful effect consistent among all subgroup analyses
Arrhythmic events
- Deaths presumed to be due to arrhythmia: RR 1.77 (1.15-2.74)
  - 3.6% vs 2.0% (NNH 63)
- VF: 0.4% vs 0.2%
- Sustained VT: 0.2% vs 0.3%
- Torsade de pointes (TdP): 0.1% vs 0.1%
Discontinuation due to adverse events: 6.5% vs 5.2%

Issues with internal validity?

Unclear: Described as "randomized, double-blind trial", but no details provided on sequence generation, allocation concealment, blinding method, loss-to-follow-up, or use of intention-to-treat population;
- Despite the above, low risk of allocation, performance or detection bias as patients were quite similar at baseline, and the primary was as objective and unfalsifiable as it gets (all-cause mortality)
Trial stopped early (due to unexpected increased mortality in d-sotalol group)

SOLVD & SOLVD-Px - Enalapril in HFrEF & asymptomatic LV dysfunction

October 23, 2016 by Ricky Turgeon in HFrEF

The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991;325:293-302.

The SOLVD Investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med 1992;327:685-91.

Bottom line: In patients with HFrEF, enalapril reduced the risk of death and HF hospitalization (NNT 11) over 3-4 years. Patients with asymptomatic reduced EF did not experience a reduced risk of death with enalapril, but did have a reduced risk of progressing to HF (NNT 10) and HF hospitalization (NNT 24).

Patients (n=2569 in SOLVD, 4228 in SOLVD-Px)

Inclusion
- HF (SOLVD) or no "overt" HF (SOLVD-Px)
- EF 0.35 or less (mesaured by nuclear testing, angiography or echo)
Exclusion
- Age >80 y
- MI <1 month
- Hemodynamically serious valvular disease requiring surgery
- Unstable angina or angina severe enough to require revascularization
- Severe pulmonary disease
- SCr >177 umol/L
- "Any other disease that might substantially shorten survival"
"Average" patient
- SOLVD (overt HF)
  - Age 61 y
  - Female 20%
  - BP 125/77 mm Hg
  - HF characteristics
    - NYHA functional class I (11%), II (57%), III (30%), IV (<2%)
    - LVEF 25%
  - PMHx
    - CAD 70%, previous MI 66%
    - Dilated cardiomyopathy 18%
    - AF 10%
    - HTN 42%
  - Meds
    - Diuretics 85%
    - Digoxin 66%
    - Nitrate 40%
    - Beta-blocker 8%
- SOLVD-Px
  - Age 59 y
  - Female 11%
  - BP 125/78 mm Hg
  - NYHA functional class I (67%), II (33%)
  - LVEF 28%
  - PMHx
    - CAD 83%, MI 80%
    - Dilated cardiomyopathy 9%
    - AF 4%
    - HTN 37%
  - Meds
    - Diuretics 17%
    - Digoxin 12%
    - Nitrate 30%
    - Beta-blocker 24%

Interventions

I: Enalapril uptitrated up to maximum of 10 mg PO BID
- SOLVD: At end of study, ~33% had discontinued study drug & ~50% were taking 10 mg PO BID
- SOLVD-Px: 24% had discontinued study drug at end of study
C: Matching placebo

Results

SOLVD (overt HF) @ mean follow-up 3.4 y
- Death or HF hospitalization: 47.7% vs 57.3% (NNT 11)
  - Death (primary outcome): 35.2% vs 39.7% (NNT 23)
- All hospitalizations: 69% vs 74% (NNT 20)
- Safety
  - Any adverse event: 87% vs 82% (NNH 20)
    - Dizziness or fainting: 57% vs 50% (NNH 15)
    - Cough: 37% vs 31% (NNH 17)
    - SCr >177 umol/L: 10.7% vs 7.7% (NNH 34)
    - Serum K >5.5 mmol/L: 6.4% vs 2.5% (NNH 26)
SOLVD-Px @ mean follow-up 3.1 y
- Death or HF hospitalization: 2.7% vs 4.8% (NNT 48)
  - Death (primary outcome): 14.8% vs 15.8% (p=0.30)
  - HF hospitalization: 8.7% vs 12.9% (NNT 24)
- All hospitalizations: 41.5% vs 45.7% (NNT 23)
- Development of HF: 20.7% vs 30.2% (NNT 10)
- Safety
  - Any adverse event: 76% vs 72% (NNH 25)
  - Dizziness or fainting: 45.8% vs 39.2%
  - Cough: 33.8% vs 27.3%

Issues with internal validity?

No: Randomized, allocation-concealed, blinded trial with blinded outcome adjudication, low loss-to-follow-up (<0.5%) analyzed using the intention-to-treat population
Run-in phases:
- Patients received enalapril 2.5 mg PO BID x2-7 days to identify intolerant individuals (only 4% excluded during this phase)
- Then switched to placebo x14-17 days to identify patients who'd acutely decline off an ACEI (4% excluded during this phase)

Additional considerations

A subsequent systematic review and meta-analysis including CONSENSUS, SOLVD, as well as numerous smaller trials of ACE inhibitors in patients with HFrEF confirmed a consistent 23% relative risk reduction in death with ACE inhibitors in HFrEF
- Subgroup analyses suggested greatest relative mortality benefit in subgroups of individuals with NYHA class IV symptoms (dominated by CONSENSUS trial) and those with LVEF <25%

CONSENSUS - Enalapril in severe HF

October 23, 2016 by Ricky Turgeon in HFrEF

The Consensus Trial Study Goup. Effects of enalapril on mortality in severe congestive heart failure. N Engl J Med 1987;316:1429-35.

Bottom line: In patients with NYHA class IV HF (presumably with reduced EF), enalapril reduced the risk of death (NNT 6-7) & reduced symptom burden at 6 & 12 months.

Patients (n=253)

Inclusion
- Clinical diagosis of HF
  - Hx of heart disease
  - Symptoms of dyspnea and/or fatigue
  - Signs of fluid retention
- Symptomatic at rest (NYHA functional class IV)
- Cardiomegaly on CXR, defined as heart size
  - Men: >600 mL/m^2
  - Women: >550 mL/m^2
- No assessment of myocaridal function performed (? LVEF)
Exclusion
- NYHA <IV after optimization with diuretics & digoxin
- Hemodynamically important aortic/mitral stenosis
- MI <2 months
- Unstable angina
- Planned cardiac surgery
- 1o pulmonary disease or right HF due to pulmonary disease
- SCr >300 umol/L
"Average" patient
- Age 70
- Female 30%
- HF duration: <18 months (25%), 18 months to 4 y (~25%), >4 y (50%)
- PMHx
  - CAD 73%, previous MI 48%
  - Cardiomyopathy 15%
  - Valvular heart disease ~20%
  - AF ~50%
- BP 120/75 mm Hg
- SCr 130 umol/L
- K 4.0 mmol/L
- Meds
  - Furosemide 90% (mean dose 200 mg)
  - Spironolactone 55% (mean dose 80 mg)
  - Digoxin 93%
  - Nitrate 45%, hydralazine 2%
  - Anticoagulant 33%

Interventions & co-interventions

I: Enalapril
- Initial dose 5 mg PO BID (started in hospital)
- Then increased to 10 mg PO BID after 1 week
- Then the dose could be increased up to 20 mg PO BID
- Mean dose @ end of study: 18.4 mg/day (~10 mg PO BID)
C: Matching placebo
Co-interventions
- Optimized on diuretics +/- digoxin at start of trial
- Other non-ACEI vasodilators permitted, including nitrates, alpha-1 blockers, hydralazine

Results @ 6 months

Death, statistically significant reduction
- @ 6 months (primary outcome): 26% vs 44% (NNT 6 - relative risk reduction (RRR) 40%)
- @ 1 year: 36% vs 52% (NNT 7 - RRR 31%)
Improvement in NYHA functional class: 42% vs 22% (NNT 5)
Study drug discontinuation: 17% vs 14% (NSS)

Issues with internal validity?

Possible exaggeration of benefit due to early termination for mortality in enalapril group in unplanned interim analysis
Otherwise well-designed: Randomized, allocation-concealed, blinded trial with low loss-to-follow-up analyzed according to the intention-to-treat principle

CORONA & GISSI-HF - Statins in heart failure

September 29, 2016 by Ricky Turgeon in HFrEF, Dyslipidemia

Bottom line: Issues with generalizability strongly limit the applicability of CORONA and GISSI-HF to the real world.

CORONA selected an ischemic HFrEF population at lower risk of coronary events (>6 months from most recent MI), and was unable to rule out the 25-30% relative risk reduction in coronary events consistently demonstrated in statin RCTs.

GISSI-HF, on the other hand, may have washed out any effect in ischemic HFrEF by also enrolling patients with no CAD and at low risk for an atherosclerotic CV event. However, it is reasonable to conclude from GISSI-HF that patients with HF of non-ischemic origin likely will not benefit from statin therapy unless at high risk due to other coronary risk factors (i.e. traditional threshold of Framingham 10-year risk >20%).

(1) CORONA

Kjekshus J, et al. Rosuvastatin in older patients with systolic heart failure. N Engl J Med 2007;357:2248-61.

Patients

Inclusion
- 60+ y/o
- Chronic HFrEF with NYHA II-IV symptoms & LVEF <40% (<35% if NYHA II symptoms)
- HF of ischemic etiology, as reported by investigators
- Not already on statin & not thought to have absolute indication/contraindication by patient's physician
- Stable on optimal therapy x 2+ weeks
Exclusion
- Decompensated HF
- Need for inotropes
- MI in past 6 months
- PCI, CABG, ICD or biventricular pacemaker in past 3 months (or planned)
- Multifactorial HF
  - Clinically significant uncorrected primary valvular heart disease or malfunctioning prosthetic valve
  - HoCM
  - Acute endomyocarditis/myocarditis
  - Pericardia disease
  - Systemic disease (e.g. amyloidosis)
- Significant competing causes of morbidity & mortality
  - Liver disease or ALT >2x ULN
  - SCr >221 micromol/L
  - TSH >2x ULN
  - Chronic muscle disease or unexplained CK >2.5x ULN
  - "Any other condition that would substantially reduce life expectancy or limit compliance"
? screened -> 5459 entered placebo run-in -> 5011 randomized
"Average" patient
- 73 y
- Male 59%
- HF characteristics
  - NYHA class II (37%), III (62%)
  - EF 31%
- PMHx
  - MI 60%
  - Past/current angina 72%
  - CABG/PCI 26%
  - AFib 24%
  - ICD <3%
- Lipids: Total cholesterol 5.35, LDL 3.54, HDL 1.23 mmol/L
- Meds
  - Loop diuretic 75%
  - Digoxin 33%
  - ACEI or ARB 92%
  - Beta-blocker 75%

Issues with external validity (generalizability)?

Yes, multiple:
- Subjective inclusion criteria with unclear rationale (i.e. why the patients' physicians felt that they did not have an indication for a statin despite ischemic HFrEF)
- Extensive exclusion criteria ensured enrollment of patients without any significant comorbidities (& therefore fewer competing risks for death or hospitalization)

Interventions

I: Rosuvastatin 10 mg PO once daily
C: Matching placebo

Results @ median 2.75 y

LDL reduced by 44% from baseline with rosuvastatin
- @ baseline: 3.54 mmol/L
- @ 3 months: 1.96
No statistically significant difference in primary outcome (composite of CV death, MI or stroke): Hazard ratio 0.92 (95% CI 0.83-1.02)
- 11.4% vs 12.3% (p=0.12)
No statistically significant difference in secondary outcomes
- All-cause death: 11.6% vs 12.2% (p=0.31)
- Hospitalizations: 35.6% vs 38% (p=0.09)
  - Note: Statistically significant only when considering overall # of hospitalizations in each group
  - For worsening HF: 11.3% vs 12.3% (p=0.11)
- Any coronary event: 9.3% vs 10% (p=0.18)
  - MI: 1.9% vs 2.4% (HR 0.84, 0.70-1.00)
Safety:
- All-cause discontinuation & discontinuation due to adverse events statistically significantly LOWER with rosuvastatin vs placebo
- No statistically significant difference in myalgias, regardless of definition used (~9% in both groups)

Issues with internal validity?

No; Randomized (using minimization), allocation concealed, blinded (patients, clinicians, investigators) with unknown loss-to-follow-up, analyzed using intention-to-treat population.
Run-in phase of single-blind placebo x2-4 weeks to ensure adherence (excluded if took <80% of doses)

(2) GISSI-HF

Tavazzi L, et al. Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a raondomised, double-blind, placebo-controlled trial. Lancet 2008;372:1231-9.

Patients

Inclusion
- Adults with HF NYHA class II-IV
- Patients with HFpEF (LVEF >40%) had 1+ hospital admissions for HF in the last year
Exclusion
- Any non-cardiac comorbidity "unlikely to be compatible with a sufficiently long follow-up", including
  - Liver disease
  - SCr >221 micromol/L
  - ALT/AST >1.5x ULN
  - CK >1x ULN
- ACS within 1 month
- Planned cardiac surgery in next 3 months
7046 assessed for eligibility -> 4631 randomized -> 4574 analyzed
"Average" patient
- 68 y
- Male 76%
- HF characteristics
  - Ischemic 40%, dilated CM 34%, hypertensive 18%
  - NYHA class II (61%), III (36%)
  - On exam: S3 25%, MR murmur 64%, crackles 28%
  - EF 33%, >40% in 10%
- PMHx
  - MI 33%
  - CABG 13%, PCI 8%
  - AFib 20%
  - ICD 6.5%
- Lipids: LDL ~3.15, HDL 1.2 mmol/L
- Med
  - Diuretic 90%
  - Digoxin 40%
  - Nitrate 32%
  - ACEI or ARB 94%
  - Beta-blocker 62%

Issues with external validity?

Yes: Enrolled a broad range of patients with heart failure, with variable risk of atherosclerotic/statin-modifiable events
- Negative results here may not necessarily reflect lack of benefit in population of interest

Interventions

I: Rosuvastatin 10 mg PO once daily
C: Matching placebo

Results @ median 3.9 y

LDL reduced by ~30% in rosuvastatin group
- @ baseline: 3.16 mmol/L
- @ 1 y: 2.15 mmol/L
No statistically significant difference in either co-primary outcomes
- All-cause death: 28.8% vs 28.1%, HR 1.03 (95.5% CI 0.92-1.15)
- All-cause death or CV hospitalization: 57% vs 56%, HR 1.02 (99% CI 0.92-1.13)
Low rate of MI, with no statistically significant difference between groups: 2.7% vs 3.1%, R 0.88 (95% CI 0.63-1.24)
- Similar results for stroke: 3.6% vs 2.9% (HR 1.25, 0.91-1.73)

Issues with internal validity?

No: Randomized, allocation concealed, blinded (patients, clinicians & investigators) with low (<0.1%) loss-to-follow-up, analyzed using intention-to-treat population
No run-in phase