CORONA & GISSI-HF - Statins in heart failure

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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