legacy effect of statin treatment

Last edited 05/2021 and last reviewed 05/2022

Heart Outcomes Prevention Evaluation (HOPE)-3 study

  • was designed to determine if a reduction in low-density lipoprotein cholesterol (LDL-C) or blood pressure (BP), either alone or in combination, would reduce CV events in those at intermediate risk with no prior overt clinical CV events

  • men aged >= 55 years and women aged >=65 years were enrolled if they had one CV risk factor; women who were between 60 and 65 years were eligible if they had two risk factors
    • risk factors included elevated waist-to-hip ratio (>=0.85 in women, >=0.90 in men), current smoking, impaired fasting glucose, impaired glucose tolerance, or diabetes requiring only diet control, estimated glomerular filtration rate between 45 and 60 mL/min/1.73 m2, or a family history of premature heart disease in first-degree relatives (<65 years in women or <55 years in men)
    • participants were excluded if in the opinion of the treating physician, they needed or had contraindications to study medications or had previous CVD
  • study results:
    • rosuvastatin (10 mg per day) compared with placebo reduced major adverse cardiovascular (CV) events by 24% in 12 705 participants at intermediate CV risk after 5.6 years.

Follow-up study of HOPE-3

  • after the randomized treatment period (5.6 years)
    • participants were invited to participate in 3.1 further years of observation (total 8.7 years)
    • first co-primary outcome for the entire length of follow-up was the composite of myocardial infarction, stroke, or CV death [major adverse cardiovascular event (MACE)-1], and the second was MACE-1 plus resuscitated cardiac arrest, heart failure, or coronary revascularization (MACE-2)
    • 9326 (78%) of 11 994 surviving Heart Outcomes Prevention Evaluation (HOPE)-3 subjects consented to participate in extended follow-up
    • during 3.1 years of post-trial observation (total follow-up of 8.7 years)
      • participants originally randomized to rosuvastatin compared with placebo had a 20% additional reduction in MACE-1 [95% confidence interval (CI), 0.64-0.99] and a 17% additional reduction in MACE-2 (95% CI 0.68-1.01)
      • therefore, over the 8.7 years of follow-up, there was a 21% reduction in MACE-1 (95% CI 0.69-0.90, P = 0.005) and 21% reduction in MACE-2 (95% CI 0.69-0.89, P = 0.002)
  • CV benefits of rosuvastatin compared with placebo continue to accrue for at least 3 years after cessation of randomized treatment in individuals without cardiovascular disease indicating a legacy effect

The legacy effect of statin treatment:

"This is a very significant study because this reveals a legacy effect of statin use compared to placebo. In the original HOPE-3 study rosuvastatin (10 mg per day) compared with placebo reduced major adverse cardiovascular (CV) events by 24% in 12 705 participants at intermediate CV risk after 5.6 years. However, during an additional 3.1 years of passive follow-up of HOPE-3 study participants without CVD but at intermediate risk for CV events, there were further reductions in CVD for those who had been originally allocated to receive rosuvastatin during the active phase.

During the passive follow-up phase, the use of statins was similar (37%) in those originally allocated to receive rosuvastatin or placebo.

Depite similar levels of statin use in both the original active (rosuvastatin 10mg arm) and placebo arm, in the 3.1 years follow-up, there was a continued reduction in risk of MACE-1 (composite of myocardial infarction, stroke, or CV death) and MACE-2 (MACE-1 plus resuscitated cardiac arrest, heart failure, or coronary revascularization) of 20% and 17% respectively in those participants originally in the rosuvastatin arm. Thus there was a continued reduction in risk of cardiovascular related morbidity and mortality that was benefitted to those participants who had been in the original rosuvastatin 10mg arm that was apparent 3.1 years after the original study had completed.

These results indicate a sustained and perhaps enhanced benefit (legacy effect) that lasts for at least 3.1years after the first 5.6 years of active therapy" (2)

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