With permission from: http://medstat.med.utah.edu/WebPath/TUTORIAL/MYOCARD/MI014.html

The publication by the CARE (Cholesterol and Recurrent Events) investigators of their observations regarding the role of inflammatory markers and coronary events ^1,2 has led some in the pharmaceutical industry to suggest their product has unique properties in these clinical scenarios. Is the observation of the CARE investigators unique to a specific statin or is it a class action?

The CARE investigators conducted a case control study of data collected as part of the double-blind randomized, placebo-controlled trial comparing 40mg of pravastatin to placebo in secondary prevention patients. Two serum markers of inflammation [serum amyloid A (SAA) and C-reactive protein (CRP)] were collected prior to randomization. A total of 4159 patients were then followed prospectively for coronary events. A total of 391 participants enrolled suffered a subsequent myocardial infarction or a coronary-related death during the observational period. Pre-randomization serum levels of SAA and CRP from these participants were then compared to age- and sex-matched controls who did not suffer an event. Several observations were made:

• Mean pre-randomization serum concentrations of SAA and CRP were significantly higher in those participants who suffered a coronary event than in those who did not.
• Participants with the highest levels of SAA and CRP who were randomized to placebo were at highest risk of a subsequent event.
• Participants with the highest levels of SAA and CRP who were randomized to treatment with pravastatin were at no greater risk than those with low serum levels of SAA and CRP.

The investigators then examined the effect of treatment with pravastatin in 477 randomly selected participants in CARE who remained free of a coronary event and for whom blood samples were available at baseline and at 5 years.² Of the 472 subjects included, 258 had been assigned to receive pravastatin and the remainder (214) were treated with placebo.

• Median serum CRP increased over baseline in those treated with placebo and decreased over time in those subjects assigned to the pravastatin arm. The median decrease in serum CRP was 21.6%.
• The magnitude of the decrease in CRP did not correlate with reduction in LDL-cholesterol.

Is the reduction in inflammatory markers a unique property of pravastatin or do the other statins possess similar capabilities?

Strandberg and colleagues³ have provided some preliminary information that suggests that pravastatin may not be unique in this regard. The effect of treatment with either 20mg of simvastatin or 20mg of atorvastatin was examined in 66 secondary prevention hyperlipidemic subjects. Serum CRP levels were determined at baseline prior to therapy and after 4 months of treatment.

• Overall, median serum CRP levels fell by 30% (1.58mg/L to 1.10mg/L).

While the studies are different in their eligibility, duration of follow-up and sample size, there is remarkable similarity in the degree of reduction in CRP in these secondary prevention hyperlipidemic patients. Based on this preliminary report, the ability to reduce inflammatory markers may be a class effect and not be unique to pravastatin. Furthermore, it seems likely that that an increase in inflammatory markers is a reflection of the activity of the atherosclerotic process in the vascular system. Improvement in the markers is likely a reflection of the favorable effect of the anti-atherosclerotic action of the drug. Drugs as diverse as the statins, aspirin and macrolide antibiotics have all been demonstrated in preliminary reports to alter serum CRP levels favorably.⁴

References:

1. Ridker PM, Rifai N, Pfeffer MA, et al. Inflammation, pravastatin and the risk of coronary events after myocardial infarction in patients with average cholesterol levels. Circulation 1998; 98(9):839-844.
2. Ridker PM, Rifai N, Pfeffer MA, et al.Long-term effects of pravastatin on plasma concentrations of C-reactive protein . Circulation 1999; 100(3):230-235.
3. Strandberg TE, Vanhanen H, Tikkanen MJ. Effect of statins on C-reactive protein in patients with coronaru artery disease. Lancet 1999; (353(9147):118-119.
4. Danesh J. Smoldering arteries? Low-grade inflammation and coronary heart disease JAMA. 1999; 282(22):2169-71.