PROVE-IT and REVERSAL - the concept of the lower the better for cholesterol therapy in patients with coronary heart disease

Two head-to-head randomised trials comparing intensive treatment with atorvastatin 80 mg/day with moderate treatment with pravastatin 40 mg/day

• "Reversing Atherosclerosis with Aggressive Lipid Lowering" (REVERSAL) trial (1,2)
  • randomised 502 patients with stable coronary disease
    • 253 patients were randomized to atorvastatin 80 mg/day (intensive lipid lowering) and 249 patients were randomized to pravastatin 40 mg/day (moderate lipid lowering).
      • low-density lipoprotein (LDL) cholesterol levels decreased from a baseline mean of 150 mg/dL (3.9 mmol/L) in both groups to 79 mg/dL (2.0 mmol/L) in the atorvastatin group and 110 mg/dL (2.9 mmol/L) in the pravastatin group
      • high-sensitivity C-reactive protein (hs-CRP) levels decreased by 36.4% in the atorvastatin group versus 5.2% in the pravastatin group (P <0.001)
      • for the primary end point of percent change in total atheroma volume, a significantly lower rate of progression from baseline was observed with atorvastatin (-0.4%) than with pravastatin (2.7%) (P = 0.02)
      • results show that intensive lipid lowering with atorvastatin 80 mg/day for 18 months halted the progression of coronary atherosclerosis, whereas more moderate lipid lowering with pravastatin 40 mg/day was associated with progression (2)
• "Pravastatin or Atorvastatin Evaluation and Infection Therapy" (PROVE-IT) trial (3)
  • 4162 patients with acute coronary syndromes were randomised to either atorvastatin 80 mg or pravastatin 40 mg and followed for a mean of 24 months
    • atorvastatin (mean LDL of 62 mg/dl) was superior to pravastatin (mean LDL of 95 mg/dl), resulting in a 16% percent lower relative risk (22.4% versus 26.3%) of the primary end point (primary end point was a composite of death from any cause, myocardial infarction, documented unstable angina requiring rehospitalization, revascularization (performed at least 30 days after randomization), and stroke) (p = 0.005)
    • there was no significant difference in CRP in comparison between the two treatment groups
    • the study authors concluded that among patients who have recently had an acute coronary syndrome, an intensive lipid-lowering statin regimen provides greater protection against death or major cardiovascular events than does a standard regimen

Thus, both REVERSAL and PROVE-IT support the concept "the lower, the better". However, they do not allow to disentangle the independent and interdependent effects of statins on LDL cholesterol and the process of arterial inflammation.

Reference:

1. British Journal of Cardiology (2004), 11 (2), 99.
2. Nicholls SJ et al. Effect of atorvastatin (80 mg/day) versus pravastatin (40 mg/day) on arterial remodeling at coronary branch points (from the REVERSAL study). Am J Cardiol. 2005 Dec 15;96(12):1636-9. Epub 2005 Oct 28.
3. Cannon CP et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350(15):1495-504