Feb 14

Statins, coronary heart disease and abnormal LFTs

Journal reference: Athyros VG, Tziomalos K, Gossios TD, et al. Safety and efficacy of long-term statin treatment for cardiovascular events in patients with coronary heart disease and abnormal liver tests in the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) Study: a post-hoc analysis. Lancet 2010; 376: 1916–22 [1]

Link: http://dx.doi.org/10.1016/S0140-6736(10)61272-X

Published: 24 November 2010

Evidence cookie says...

Statin are effective and safe in patients with established coronary heart disease but with mild-to-moderate abnormal liver function tests.

In the study population, those who received statins had:

  • ↓ 68% relative risk of any cardiovascular event
  • improved liver function tests

Liver-related adverse events (ALT or ALT > 3x upper limit of normal) was rare.

Mild-to-moderate abnormal liver function tests should not preclude the use of statins in those who satisfy lipid lowering criteria.

More details:


Article details


Study design:

post-hoc analysis of randomised controlled trial


Study aim:

to assess whether statin therapy is safe and effective for patients with abnormal liver function tests (LFTs)


Methods summary:

  • The GREACE study:
    • prospective randomised study of patients with:
      • established coronary heart disease
      • younger than 75 years
      • serum LDL-cholesterol > 2.6 mmol/L
      • serum triglyceride < 4.5 mmol/L
    • all patients attended the atherosclerosis unit of Hippokration University Hospital, Thessaloniki, Greece
    • randomised to either:
      • structured care
        • followed up at the university clinic
        • started on atorvastatin with dose increased to a maximum of 80 mg
        • LDL-cholesterol goal was < 2.6 mmol/L
      • usual care
        • followed up by doctors of the patient’s choice outside of the hospital
        • treated according to their doctor’s usual standard of care
        • atorvastatin was not excluded from the usual care group
    • abnormal liver function tests were attributed to non-alcoholic fatty liver disease (NAFLD) by:
      • ultrasonographic diagnosis
      • exclusion of other causes (including alcohol misuse, chronic viral hepatitis, Wilson’s disease, and autoimmune hepatitis)
  • post-hoc analysis of the GREACE study
    • all original participants were included in the post-hoc analysis
    • primary endpoint:
      • first occurrence of any cardiovascular event
      • in patients with abnormal LFTs
      • comparing those treated with a statin to those without
    • secondary endpoints:
      • effect of statin treatment on LFTs and eGFR
      • in patients with abnormal LFTs
    • liver-related adverse effects of statin treatment was defined as raising serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) more than three times the upper limit of normal

Results summary:

  • primary endpoint (comparing patients with abnormal LFTs who received a statin to those who did not):
    • cardiovascular events of participants on statin = 22 (of 227), 9.7%
    • cardiovascular events of participants not on statin = 63 (of 210), 30.0%
    • 68% relative risk reduction, P < 0.0001
  • effect of statin treatment on LFTs
    • liver-related adverse effects:
      • 10 patients of 880 had raised ALT or AST concentrations more than three times the upper limit of normal
      • in 3 of these patients, LFTs normalised with reduction in atorvastatin dose
      • 7 patients of 880 (< 1%) were withdrawn from the study because of liver-related adverse effects
  • effect on LFTs comparing participants who received statins to those who did not:
    • ALT (IU/L), mean (SD):
      • on statin (baseline → study end):
        • 57 (8) → 37 (6)
        • -35% change, P < 0.0001
      • not on statin (baseline → study end):
        • 56 (9) → 63 (7)
        • +12% change, P = 0.003
    • AST (IU/L), mean(SD):
      • on statin (baseline → study end):
        • 49 (7) → 26 (4)
        • -47% change, P < 0.0001
      • not on statin (baseline → study end):
        • 49 (7) → 55 (8)
        • +12% change, P = 0.01
      • γ-glutamyl transpeptidase (GGT) (IU/L), mean(SD):
        • on statin (baseline → study end):
          • 70 (10) → 38 (6)
          • -46% change, P < 0.0001
        • not on statin (baseline → study end):
          • 68 (10) → 79 (12)
          • +16% change, P = 0.001
  • effect on eGFR (mL/min/1.73 m2) comparing participants who received statins to those who did not:
    • on statin (baseline → study end):
      • 59 (17) → 70 (10)
      • +19% change, P < 0.0001
    • not on statin (baseline → study end):
      • 68 (19) → 64 (18)
      • -6% change, P = 0.8

Study conclusion:

Statin treatment is safe and can improve liver tests and reduce cardiovascular morbidity in patients with mild-to-moderately abnormal liver tests that are potentially attributable to non-alcoholic fatty liver disease.


Participants:

  • participants had established coronary heart disease
  • any participants with LFT abnormalities had ALT and AST below three times the upper limit of normal at the start of the study
  • attended the atherosclerosis unit of Hippokration University Hospital in Greece
  • 1673 were assessed for eligibility of which, 1600 patients participated
  • mostly males (~ 80%)
  • no patients were lost to follow up
  • 313 (20%) had diabetes mellitus
  • 712 (45%) had metabolic syndrome
  • mean age approximately 60 years, with a standard deviation of 12 years
  • patients with abnormal liver function tests were:
    • on average overweight, mean BMI ~ 28
    • likely to have central obesity (90%)
    • likely to be hypertensive (85%)
    • likely to have diabetes mellitus (51%)
    • likely to have metabolic syndrome (90%)

Methodological weaknesses

  • care must always be taken with post-hoc analyses as the original study was not designed to measure these outcomes a priori
  • relatively small number of patients
  • LFT elevation in the participants with LFT abnormality at baseline was mild; mean ALT = 57 IU/L and mean AST = 49 IU/L
  • median statin doses in participants with LFT abnormalities was also in the low-moderate range; atorvastatin = 25 mg/d, simvastatin = 22 mg/d, pravastatin = 29 mg/d, fluvastatin = 40 mg/d
  • it is possible that the improvements in both the primary and secondary outcomes in the participants receiving statins are due to (or exaggerated by) confounding factors
    • participants receiving statins are more likely to have been randomised to the “structured care” arm that not only received statins but also received their care from the university clinic
    • participants receiving statins who were randomised to the “usual care” arm may have also received more intensive non-statin therapy from their usual doctors compared to those who did not receive statins

Methodological strengths

  • very similar baseline characteristics between participants who received statins and those who did not
  • no participant drop outs from the study

Biases and conflicts of interests

Nil obvious and nil declared.

Clinical relevance to primary health care

This study demonstrated that statin therapy in a population with mild-to-moderate liver function test (LFT) abnormality, who where otherwise indicated for treatment (established coronary heart disease, overweight, central obesity, hypertensive, metabolic syndrome), was safe and effective.

Those who received statins had:

  • 68% relative risk reduction in any cardiovascular event compared to those who did not receive statins
  • occurrence of elevation of serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) more than three times the upper limit of normal was uncommon in those receiving statins (approximately 1%)
  • serum ALT, AST and γ-glutamyl transpeptidase (GGT) improved during treatment; all three slightly worsened for those who did not receive statins

However, the post-hoc nature of this study limits the causal statements that can be made. Although benefits in cardiovascular events and LFTs are associated with the use of statins, there are significant confounding factors. It is probable that the use of statins in this study was also correlated with better/more intensive non-statin therapy. Furthermore, most patients with baseline LFT abnormalities had only mild elevations of ALT and AST and the average dose of statins used was relatively low.

Nevertheless, on balance of risks versus benefits, mild-to-moderate LFT abnormalities should not preclude the use of statins in those who satisfy lipid lowering criteria. Liver-related adverse effects are rare and statins may improve LFTs in non-alcholic fatty liver disease.

References

  1. Athyros VG, Tziomalos K, Gossios TD, et al. Safety and efficacy of long-term statin treatment for cardiovascular events in patients with coronary heart disease and abnormal liver tests in the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) Study: a post-hoc analysis. Lancet 2010; 376: 1916–22
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