Statins lower C-reactive protein (CRP), a major new risk factor for heart disease marked by inflammation

For years, doctors have believed that statin therapy lowers the risk of heart disease solely by lowering levels of cholesterol.

Now, researchers at Brigham and Women’s Hospital (BWH) have found that in addition to statins ability to lower cholesterol, it is also just as important that they lower C-reactive protein (CRP), a major new risk factor for heart disease marked by inflammation, through an easy, inexpensive blood test. This finding has prompted researchers to recommend that in addition to regular cholesterol checks, monitoring and managing CRP needs to be an integral part of the health strategy for patients with heart disease. Details of this research and its implications for “dual target” therapy are published in the January 6, 2005 issue of the New England Journal of Medicine.

In early 2004, results from the multi-national Pravastatin or Atorvastatin Evaluation and Infection Therapy – Thrombolysis in Myocardial Infarction (PROVE IT – TIMI 22) trial demonstrated that lowering a patient’s LDL or “bad” cholesterol to less than 70 mg per deciliter helped prevent recurrent heart attack and death. Now, for the first time, a pre-specified analysis to assess if lowering CRP leads to clinical benefit revealed that it is not enough to lower LDL cholesterol; CRP also needs to be lowered to less than two mg per liter in order to achieve the greatest clinical benefit.

According to the BWH’s Eugene Braunwald, MD, Harvard Medical School professor and chairman of the TIMI Study Group, “We now have evidence that lowering CRP is as important as lowering LDL cholesterol for patients to reduce the risk of recurrent cardiovascular events. Physicians prescribing statin therapy need to monitor CRP levels as well as cholesterol levels if they want to get the best results for their patients.”

Based on data from 3,745 patients in the PROVE IT – TIMI 22 trial who were treated with statin therapy, clinical outcomes after heart attack were linked not only to lowering LDL cholesterol, but also to lowering CRP levels. In fact, patients who had low CRP levels after statin treatment did significantly better than those with high CRP levels, regardless of the level of LDL cholesterol attained.

“These new data confirm the crucial role inflammation plays in heart disease,” said lead author, Paul M Ridker, MD of BWH. “The data also provide the first hard evidence that lowering CRP levels is associated with clinical benefits for our patients.”

In this study, CRP and LDL cholesterol levels were measured 30 days after heart attack patients began statin therapy. Researchers found that patients who had achieved the dual targets of low CRP and low LDL had the lowest rates of recurrent heart attack or death. Specifically, the recurrent event rates during 2.5 years of follow-up were:

• 9.9 percent among patients with LDL cholesterol more than 70 mg per deciliter and a CRP more than two mg per liter;
• 7.1 percent among patients with LDL cholesterol less than 70 mg per deciliter and a CRP more than two mg per liter;
• 7.0 percent among patients with LDL cholesterol more than 70 mg per deciliter and a CRP of less than two mg per liter; and,
• 4.9 percent among patients with LDL cholesterol less than 70 mg per deciliter and a CRP less than two mg per liter.

Even lower event rates – four percent – were seen among those who were able to further reduce CRP levels to less than one mg per liter.

According to cardiologist, Christopher P. Cannon, MD of BWH, “Patients need to achieve the dual goals of lowering cholesterol and lowering CRP. Like cholesterol, physicians need to regularly check CRP levels and then work with their patients to lower high levels through a combination of diet, exercise, weight loss, smoking cessation and, if appropriate, a more aggressive statin regimen. Within the PROVE IT-TIMI 22 trial, those patients who received high doses of statins not only achieved greater cholesterol reductions, but also achieved greater CRP reductions.”

Also being published in the same issue of the New England Journal of Medicine is a study from The Cleveland Clinic demonstrating that the rate of progression of atherosclerosis is slowed among patients who receive the greatest CRP reduction after initiating statin therapy. The two studies together provide a strong message that it is necessary to reduce both cholesterol and CRP to achieve maximal patient benefits. “The emerging CRP data represents a paradigm shift that has the potential to save thousands of lives,” Braunwald noted. “Our challenge now is to educate physicians and patients about the importance of CRP measurement and reduction, just as we did with LDL measurement and reduction a decade ago.”

“We are on the threshold of viewing CRP not only as a marker for risk, but as a target for therapy,” Ridker added. “The message for patients is to reach for the ‘dual targets’ of a low cholesterol and a low CRP.”