CIBIS-II

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CIBIS-II Writers. "The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial". The Lancet. 1999. 353(9146):9-13.
PubMedFull text


Clinical Question

In patients with symptomatic HFrEF (LVEF ≤35%, NYHA class III-IV), does the beta blocker bisoprolol reduce mortality compared to standard therapy including diuretics and ACE inhibitors?

Bottom Line

When added to standard therapy including diuretics and ACE inhibitors, bisoprolol results in a 34% reduction in all-cause mortality in patients with HFrEF (LVEF ≤35%) and NYHA III-IV symptoms.

Major Points

At the time of its publishing, only the combination of isosorbide dinitrate and hydralazine (V-HeFT) and ACE inhibitors (SOLVD) had high-quality evidence demonstrating a mortality benefit in patients with heart failure with reduced ejection fraction (HFrEF). The subsequent V-HeFT II study[1] demonstrated that ACE inhibitors were superior to isosorbide/hydralazine. Thus, ACE inhibitors quickly gained favor as first-line agents in HFrEF patients, but it remained unclear whether other drug classes added to ACE inhibitors could result in incremental benefit.

The 1999 Cardiac Insufficiency Bisoprolol Study II (CIBIS-II) demonstrated that in patients with HFrEF (defined as LVEF ≤35%) and NYHA class III-IV symptoms, the beta blocker bisoprolol results in a 34% relative risk reduction in all-cause mortality (5% absolute reduction) when added to standard therapy including ACE inhibitors and diuretics.

Prior to CIBIS-II, it was unclear whether beta blockers were safe in patients with chronic CHF due to their negative inotropic, or contractility-related properties. This study, along with the concomitant MERIT-HF and later COPERNICUS trials which both showed a similar benefit with the beta blockers metoprolol and carvedilol, demonstrate that these agents are not only safe, but strikingly beneficial in HFrEF. These findings have established beta blockers as standard therapy for all patients with symptomatic HFrEF.

Guidelines

AHA/ACCF Heart Failure Guidelines (2013, adapted)[2]

  • Use of bisoprolol, carvedilol, or metoprolol sustained release for all patients with current or prior symptomatic HFrEF unless contraindicated (class I, level A)

Design

  • Multicenter, double-blind, parallel-group, randomized, controlled trial
  • N=2647
    • Bisoprolol (n=1327)
    • Placebo (n=1320)
  • Setting: 247 hospitals in 18 countries in Europe
  • Mean follow-up: 1.3 years
  • Analysis: Intention-to-treat
  • Primary outcome: All-cause mortality
  • Secondary outcomes: All-cause admissions, CV mortality, CV mortality and CV admissions, permanent premature treatment withdrawals

Population

Inclusion Criteria

  • Ambulatory
  • Aged 18-80
  • LVEF ≤35%
  • NYHA Class III-IV
  • Chronic CHF diagnosed at least 3 months prior to randomization
  • On standard medical therapy
    • ACE inhibitor required unless intolerant
    • Vasodilator required if ACE inhibitor intolerant

Exclusion Criteria

  • Uncontrolled HTN
  • Clinical instability within the last 6 weeks for CHF or within the last 3 months for ACS
  • Medication change within the preceding 2 weeks
  • ACS within the last 3 months
  • PCI or CABG within the last 6 months
  • Previous or scheduled heart transplant
  • AVB greater than 1st degree without a pacemaker
  • SBP at rest < 100 mmHg
  • CKD (serum Cr >= 300umol/L)
  • Reversible obstructive lung disease
  • Pre-existing or planned therapy with beta blockers

Baseline Characteristics

From the placebo group:

  • Demographics: Mean age 61 years, 80% male
  • Heart Failure: NYHA III 83%, NYHA IV 17%, ischemic CM 50%, mean LVEF 28%, AF 20%
  • Medications: Diuretic 99%, ACE inhibitor 96%, CCB 2%, nitrates 58%, digoxin 51%, amiodarone 16%, anticoagulant 31%, antiplatelet 42%

Interventions

  • Randomized to bisoprolol or placebo
  • Bisoprolol started at 1.25MG QD and increased up to goal 10MG QD every 3 weeks according to tolerance
  • Follow-up every 3 months until study termination

Outcomes

Comparisons are bisoprolol vs. placebo:

Primary Outcomes

All-cause mortality
12% vs. 17% (HR 0.66; 95% CI 0.51-0.81; P<0.0001)

Secondary Outcomes

All-cause admission
33% vs. 39% (HR 0.80; 95% CI 0.51-0.81; P=0.0006)
Cardiovascular death
9% vs. 12% (HR 0.71; 95% CI 0.56-0.90; P=0.0049)
Permant treatment withdrawals
15% vs. 15% (HR 1.00; 95% CI 0.82-1.22; P=0.98)

Post-Hoc Analyses

Sudden death
4% vs. 6% (HR 0.56; 95% CI 0.39-0.80; P=0.0011)
Pump failure
3% vs. 4% (HR 0.74; 95% CI 0.48-1.14; P=0.17)
Hospitalization for heart failure
12% vs. 18% (HR 0.64; 95% CI 0.53-0.79; P=0.0001)

Subgroup Analyses

Subgroup analyses by cause of heart failure and severity of disease at baseline showed no significant variation in the effect of bisoprolol on mortality or admissions to the hospital.

Adverse Events

Hospitalization for stroke
31 vs. 16 (P=0.04)
Hospitalization for bradycardia
14 vs. 2 (P<0.004)

Criticisms

  • Results provide clear support for the use of bisoprolol in HFrEF but do not speak to the relative merits of other beta blockers.
  • Average patient age of 61 is about a decade younger than that seen in clinical practice, limiting generalizability to older individuals.
  • CIBIS-II only demonstrated beneficial effects of beta blockade in patients with severe symptoms (NYHA III-IV). MERIT-HF demonstrated the effectiveness of the beta blocker metoprolol in patients with NYHA II-IV.

Funding

  • Study was sponsored by E Merck. Role of study sponsor in design and conduct of the study not explicitly defined.

Further Reading

  1. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure New Engl J Med 1991325:303-310
  2. Yancy CW, et al. "2013 ACCF/AHA guideline for the management of heart failure." Circulation. 2013;128:e240-e327.