Reduction in stroke risk: no role of pleiotropic effects of cholesterol-lowering therapies

  • Salvatore T & al.
  • Am J Med
  • 10 Jul 2019

  • curated by Pavankumar Kamat
  • UK Clinical Digest
Access to the full content of this site is available only to registered healthcare professionals. Access to the full content of this site is available only to registered healthcare professionals.

Takeaway

  • A meta-regression of cholesterol-lowering trials (including PCSK9 inhibitors) showed that a decrease in total cholesterol corresponds to a log-linear relationship with stroke reduction.
  • Cholesterol lowering is associated with a proportional decrease in the risk for stroke, without the need of invoking 'pleiotropic' effects of the therapy.

Why this matters

  • The causal role of cholesterol in coronary heart disease has been well established; however, the relationship between cholesterol levels and stroke is not clearly understood.
  • Although trials with statin have demonstrated a reduced incidence of stroke in treated individuals, trials with non-statin drugs or therapies have not done so, thereby supporting the theory that such effects are attributable to the 'pleiotropic' properties of statins.
  • The ability of the PCSK9 inhibitors evolocumab, bococizumab and alirocumab to reduce total and low-density lipoprotein (LDL) cholesterol by a mechanism completely independent of the mevalonate pathway was assessed by the FOURIER, SPIRE-1/SPIRE-2 and ODYSSEY OUTCOMES trials, respectively.

Study design

  • A comprehensive meta-regression of all reported trials on cholesterol lowering (FOURIER, SPIRE-1/2 and ODYSSEY OUTCOMES).
  • Key outcomes included:
    • Establishing the relationship between cholesterol lowering and the risk for total stroke and
    • Presenting a revised equation to predict the extent of total stroke reduction per each definite change in total cholesterol.
  • Funding: None.

Key results

  • FOURIER
    • Observed relative risk [RR] for total stroke in the original study: 0.79.
    • Predicted RR for total stroke RR using the new meta-regression: 0.79.
  • SPIRE-1 and -2
    • Observed RR for total stroke in the original study: 0.60.
    • Predicted RR for total stroke RR using the new meta-regression: 0.79.
  • ODYSSEY OUTCOMES
    • Observed RR for total stroke in the original study: 0.79.
    • Predicted RR for total stroke RR using the new meta-regression: 0.84.
  • The revised equation for predicting the saving of strokes as a function of total cholesterol lowering is LnRR = -0.061–0.005*(% total cholesterol reduction).
  • Based on the equation, a RR of 0.851, 0.810 and 0.770 can be expected for a 20%, 30% and 40% reduction in total cholesterol, respectively.

Limitations

  • The analysis was based on total cholesterol and not LDL cholesterol; however, LDL cholesterol has a better correlation with stroke.
  • Total stroke was used as an endpoint without the distinction of ischaemic and haemorrhagic strokes; however, only ischaemic stroke has a positive relation with total or LDL cholesterol.

Please confirm your acceptance

To gain full access to GPnotebook please confirm:

By submitting here you confirm that you have accepted Terms of Use and Privacy Policy of GPnotebook.

Submit