STATIN BENEFITS IRRESPECTIVE OF CRP LEVEL

January 28, 2011 (Oxford, United Kingdom) — The idea that C-reactive protein (CRP) levels can be used to guide statin therapy has taken another knock, with the publication of an analysis from the large-scale Heart Protection Study (HPS) showing that statin treatment was associated with a similar reduction in vascular events irrespective of baseline concentrations of CRP [1].
In the analysis, published online in the Lancet on January 27, 2011, the reduction in vascular events with statin therapy remained consistent even in individuals with low concentrations of both CRP and LDL cholesterol.
Fueling the CRP Debate
The authors conclude: "The results do not lend support to the suggestion that the beneficial effects of statin therapy are affected by baseline CRP concentration or, more generally, by inflammation status." They add that the results could be applicable to all statins and to a wide range of people with and without preexisting vascular disease.
However, CRP advocate Dr Paul Ridker (Brigham and Women's Hospital, Boston, MA) argues that the HPS trial was conducted in a mainly secondary-prevention population and so these data should not be used to pass judgment on the usefulness of CRP measurements in a primary-prevention population, where, he says, "CRP measurement has been shown to provide as much incremental information on vascular risk as does total or HDL cholesterol and where CRP evaluation is recommended as a method to detect patient groups who benefit from statin therapy but otherwise would not qualify for treatment based on levels of LDL cholesterol."
Asked for his opinion on the study,Dr Roger Blumenthal (Johns Hopkins Medical Institute, Baltimore, MD) told heartwire : "These results are disappointing, in that some of us felt that [high-sensitivity] hs-CRP may be useful in the secondary-prevention setting. It clearly is not, based on these data." But he pointed out that CRP levels were still a predictor of absolute risk in HPS. "For now, I will continue to use hs-CRP and coronary calcium measurements selectively in patients in whom the decision to treat with lifelong statin and aspirin is unclear or if the patient qualifies for treatment but is inclined not to take it," he added.
The HPS trial randomized 20 536 men and women at high risk of vascular events to simvastatin 40 mg daily or placebo for a mean of five years. Overall, allocation to simvastatin resulted in a significant 24% proportional reduction in the incidence of first major vascular event.
For the purposes of the current analysis, patients were categorized into six baseline CRP groups (<1.25, 1.25–1.99, 2.00–2.99, 3.00–4.99, 5.00–7.99, and >8.00 mg/L). Results showed no evidence that the proportional reduction in the primary end point (the composite of coronary death, MI, stroke, or revascularization) or its components varied with baseline CRP concentration. Even in participants with baseline CRP concentration less than 1.25 mg/L, major vascular events were significantly reduced by 29%. There was also no significant heterogeneity in the relative risk reduction between the four subgroups defined by the combination of low or high baseline concentrations of LDL cholesterol and CRP. In particular, there was clear evidence of benefit (27% reduction) in those with both low LDL cholesterol and low CRP.
Lead author of the current paper, Dr Jonathan Emberson (Clinical Trial Service Unit, University of Oxford, UK), explained to heartwire that there had been confusion in the past as to whether a patient's baseline CRP level would affect the benefits of statins, with the suggestion that statins may be more effective in patients with high levels of CRP. Such an observation has been seen in a couple of post hoc analyses of studies, including the AFCAPS/TEXCAPS and CORONA trials. But Emberson noted that these trials did not have enough events to reach definitive conclusions.
He added: "These studies raised a hypothesis that statins may not be so effective in patients with low CRP levels. We tested that hypothesis in the much larger HPS trial and found that it is not the case."
What About JUPITER?
Emberson said these latest results from HPS were not inconsistent with those from the JUPITER trial, which showed a reduction in cardiovascular event rate with rosuvastatin vs placebo in primary-prevention patients with raised levels of CRP. Emberson pointed out that in the JUPITER trial, there was also no differential effect of rosuvastatin in patients with different CRP levels, although in that study all patients had levels above 2 mg/L.
"In the HPS study, we've shown that the benefits of statins also extend to lower CRP levels, right down to patients with levels below 1 mg/L," he added.
Emberson agreed that the patient population in HPS was probably higher risk than that in JUPITER, but he pointed out that the recent primary-prevention meta-analysis conducted by the Oxford group showed that the benefit of statins continued right down to very low-risk populations.
Asked how the JUPITER trial and the current HPS analysis can be interpreted together in terms of clinical practice, Emberson said: "JUPITER has shown that measuring CRP might be one way of identifying primary-prevention patients who may benefit from a statin. We are not arguing with that. But our take is that patients should be assessed for statin treatment by their overall absolute risk of vascular disease, and while CRP may be one factor in identifying those at higher risk, there are also other, perhaps easier, ways to assess risk such as age, smoking status, blood pressure, etc."
CRP: A Shining Star or a Dimming Light?
In a comment accompanying the paper, Dr Jean-Pierre Després (Université Laval, Quebec, QC), points out that the drivers of CRP concentrations and the relative weight of CRP to the global risk of cardiovascular disease might differ in different populations [2]. He also notes that although all subgroups benefited from statin therapy in HPS, both LDL-cholesterol and CRP concentrations were clearly associated with absolute major vascular-event rates, adding: "CRP is a cheap and convenient marker of inflammation related to risk of cardiovascular disease."
He concludes: "As for other controversies in cardiovascular medicine, it is with robust experimental and clinical evidence together with constructive criticism that CRP will appropriately position itself in the galaxy of simple CVD risk markers--as a shining star or a dimming light."
More Arguments From Ridker
Other points made by Ridker included the observation that while baseline CRP did not modify the vascular benefits of statin therapy in HPS, neither did baseline LDL. He reiterated Despres's argument: "CRP levels track directly with absolute risk in HPS; thus, these data confirm the ability of CRP to predict high risk."
Ridker also says that the HPS investigators chose not to address the hypothesis that on-treatment levels of CRP associate with the risk reduction attributable to statins, which he says has been seen in many prior statin trials. "The authors make the claim that such an analysis should not be done as it is nonrandomized, yet they go on to conclude that the benefits of statin therapy accrue solely to on-treatment LDL, an analysis that suffers equally from the same nonrandomized limitations."
Kaul: An Evidence Vacuum
Commenting on the debate for heartwire , Dr Sanjay Kaul (Cedars Sinai Medical Center, Los Angeles, CA) said that while the HPS did have the advantage of size and a wide range of CRP values, it was still a post hoc analysis and as such could not be considered definitive. "This study doesn't change much for me. Yes, it provides more ammunition for the detractors of the CRP hypothesis to stake their claim, but we are stuck in an evidence vacuum in this debate, without the quality of data we need to progress the arguments," he added.
But this may change if Ridker gets his way. He notes that the only way to test the inflammatory hypothesis of atherosclerosis is to directly randomize patients to targeted anti-inflammatory therapies, and his group hopes to launch two such trials this year.