C-reactive protein could become target of therapy

Some clinicians are already tracking CRP in patients; others argue it is a risk marker and not a risk factor.

Patients with low C-reactive protein levels had better clinical outcomes regardless of their LDL levels in two studies recently reported.

“That C-reactive protein can be a prospective gauge of risk I think is settled beyond a doubt,” said Peter Libby, MD, chief of cardiovascular medicine at Brigham and Women’s Hospital.

“The second issue is target of therapy. Should we be checking C-reactive protein during therapy to see how we’re doing? Until these studies were published, I had been against that idea because we had no evidence. Today I have reason to believe that the lower the CRP, independent of LDL, the better the outcomes,” said Libby, section editor of Cardiology Today’s Vascular Biology section.

In commenting on the implications of the two trials, Steven Nissen, MD, said, “The fact that two groups did this from two different trial databases and got the same conclusion does add to the strength of the evidence.” Nissen is medical director of the Cleveland Clinic Cardiovascular Coordinating Center.

Peter Libby

One of the papers published in the New England Journal of Medicine by Nissen and colleagues analyzed data from the REVERSAL (Reversal of Atherosclerosis with Aggressive Lipid Lowering) trial, which randomized 502 patients to either 40 mg of pravastatin (Pravachol, Bristol-Myers Squibb) or 80 mg of atorvastatin (Lipitor, Pfizer).

CRP correlated to atherosclerosis

Researchers evaluated patients by ultrasonography at 18 months to measure the progression of atherosclerosis. Lipoprotein and CRP levels were also measured at baseline and follow-up.

After adjustment for the reduction in lipid levels, the decrease in CRP was independently and significantly correlated with the rate of progression of atherosclerosis, researchers wrote.

Nissen said that when the REVERSAL trial was first presented and showed a benefit with atorvastatin over pravastatin, most commentators said it was due to the LDL level.

“We suspected it wasn’t,” Nissen said, “because at any given level of LDL reduction, there was always less disease progression in the atorvastatin arm. It turns out that it was due to the fact that atorvastatin had a greater effect on CRP,” said Nissen, a member of Cardiology Today’s Noninvasive Imaging section.

Paul Ridker, MD, and colleagues evaluated the relationship between LDL cholesterol and CRP among the 3,745 patients in the PROVE IT-TIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy—Thrombolysis in Myocardial Infarction 22) trial, which randomized patients to 80 mg of atorvastatin or 40 mg of pravastatin.

PROVE IT-TIMI 22 investigators noted that patients who had achieved LDL cholesterol levels below 70 mg/dL had lower event rates than those at higher levels (2.7 events vs. 4 events per 100 person-years).

According to the research abstract, a nearly identical risk reduction was noted in those patients who had achieved CRP levels of less than 2 mg/dL, and this effect was found regardless of LDL levels.

“In these high-risk patients being treated with statin therapy, the CRP reductions that these patients get is as important for determining their clinical outcomes as the cholesterol reduction,” Ridker told Cardiology Today. “So the clinical message is we have a new way of thinking about statin therapy.” Ridker is director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital.

Eric Topol, MD, cardiology chairman at the Cleveland Clinic Foundation, agreed and said the papers moved the level of evidence on C-reactive protein from “acceptable” to “overwhelming.”

“For almost four years it has been my standard practice to track C-reactive protein,” Topol told Cardiology Today. “It’s really unfortunate that the overall cardiovascular community has not moved with the evidence. Maybe these latest two studies will be the tipping point.”

Role in secondary prevention

Nissen and Ridker said that more aggressive use of statins could lower CRP, but it can also be reduced by diet, exercise and smoking cessation.

Roger Blumenthal, MD, director of the Johns Hopkins Ciccarone Center for the Prevention of Heart Disease and a member of Cardiology Today’s Editorial Board on the Preventive Cardiology section, questioned the role that CRP should play in secondary prevention.

“These were very important, well-done studies, but I do not think serial CRPs are going to be useful because we aren’t going to be doing anything differently,” Blumenthal said. “We should be doing a comprehensive lifestyle and medical approach and not just draw another blood test and say, ‘Well, your CRP is 1 so I don’t think we need to do anything about your triglycerides, glucose or weight.’”

Topol said measurements of CRP could be a motivator for patients to make lifestyle changes. “There’s nothing better than weight loss or exercise or both to see the CRP plummet to less than 1, or even approach undetectable levels, which is very satisfying to patients,” he said.

Rita Redberg, MD, director of women’s cardiovascular services at the University of California San Francisco Medical Center and Editorial Board member of Cardiology Today’s Preventive Cardiology section, said CRP is more likely a risk marker than a risk factor.

“While there is clearly an association between CRP and events, these studies do not establish that this is a cause and effect,” she said. “Lower CRP has been shown to be associated with healthy diet, exercise and smoking cessation. If you do those things you lower your risk, but is it because you lowered your CRP or because doing those things would have lowered your risk anyway?”

Use in clinical practice

Redberg also highlighted an Archives of Internal Medicine paper, which concluded that relatively important fluctuations in CRP levels in patients with stable ischemic heart disease might be problematic for risk stratification and treatment monitoring.

Researchers examined 159 patients with stable ischemic heart disease and conducted two to eight CRP measurements at varying intervals from 15 days to six years. According to the research abstract, 40.3% of patients changed risk category between their first and second measurement, independent of BMI, smoking status, medication and clinical events.

“It may be problematic to use CRP as a routine risk marker in individual patients with stable ischemic heart disease given relatively important, apparently spontaneous fluctuations in the CRP values,” lead author Peter Bogaty, MD, Quebec Heart Institute, told Today in Cardiology. “I believe these findings raise a note of caution. They suggest it may be premature to incorporate CRP into routine clinical practice as a tool to guide management of patients.”

Ridker said that his data from PROVE-IT contrast with the data from the Quebec study. The PROVE-IT trial enrolled 3,745 patients, whereas the Quebec study enrolled 159. In PROVE-IT, CRP and LDL were measured at 30 days, four months and two years; 61.4% had no change in the CRP category over the follow-up period, which was similar to the 63.2% who had no change in LDL.

“The proportion who increased one or two categories of CRP over time — and thus might give a ‘false positive’ — was actually lower than the proportion who increased one or two LDL categories,” Ridker said. He said similar data were seen in other trials, including CARE, WHS and AFCAPS, which collectively included thousands of patients.

“In fact, the largest study to deal with this issue was the Danesh data from Iceland in which the decade to decade variability of CRP was again comparable to or superior to that of LDL,” Ridker said.

“I do not know why the data from Quebec look worse, but it may relate to the much smaller sample size or to the fact that the repeat CRP levels were not protocol driven but were repeated at varied and different time periods, perhaps in response to clinical change,” he said.

Further studies

Libby, who called the NEJM papers “groundbreaking,” said they open up several potential new avenues for research into the role of inflammation in heart disease.

“We’re on the threshold now of a very exciting era now that we know that inflammation is a target for therapy. We can ask the question: Do nonstatin medications also exert antiinflammatory effects that could correlate with clinical benefit in our patients at risk for cardiovascular disease?” Libby said.

“For example, is the interruption of the renin angiotensin aldosterone axis an antiinflammatory intervention? Are the insulin sensitizing thiazolidine drugs antiinflammatory? What about the other hypoglycemic agents such as metformin? We’re at a really exciting time.” – by Jeremy Moore

For more information:

• Bogaty P, Brophy JM, Boyer L, et al. Fluctuating inflammatory markers in patients with stable ischemic heart disease. Arch Intern Med. 2005;165:221-226.
• Nissen SE, Tuzcu EM, Schoenhagen P, et al. Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease. N Engl J Med. 2005;352:29-38.
• Ridker PM, Cannon CP, Morrow D, et al. C-reactive protein levels and outcomes after statin therapy. N Engl J Med. 2005;352:20-28.