By Coleen Curran

 hs-CRP may diagnose potential cardiac risk and be the tip of the “inflammatory response” iceberg
While heart disease is still the No. 1 killer of humans – male and female – an increasing number of us survive the kind of heart attacks and strokes that 20 years ago would have resulted in death. With more and better treatment options, well-insured Americans can look forward to 20-25 years of life post-heart attack. On the other hand, survivors often live with the debilitating effects of congestive heart failure and other chronic heart problems. In addition to a daily regimen of pharmaceuticals, many find themselves housing pacemakers, implantable cardiac defibrillators, stents, grafts and other high-tech devices that keep the heart working but come with their own list of life-complicating features.

Still the trade-off is obviously worth it. Physicians and researchers continue to look for new ways to detect and treat heart disease, and it’s always exciting news when they discover a new test or find a better application for an old one, as happened recently in the case of high-sensitivity Commit-Reactive Protein (CRP).

Although diagnostic tests for C-Reactive Protein have been around for more than a decade, the newest type, a high-sensitivity CRP assay that can help predict heart disease in asymptomatic patients, is garnering more headlines than a Hollywood star with Oscar potential.

The 10-year-old version of the CRP test, which was used mainly to diagnose inflammation associated with general infection, is not sensitive enough to predict future heart problems. In fact, if test results from a high-sensitivity CRP test are higher than 3 mg/L, the test is considered invalid and must be repeated a week later. The higher result could indicate anything from a cold to a broken leg. A result of 3 mg/L with the old CRP test is clinically insignificant while the same result with a high-sensitivity CRP test could be an indicator of coronary risk.

chartTwo years ago, in an interview with CLP, one of the leading researchers of hs-CRP, Nader Rifai, Ph.D., DABCC of Children’s Hospital and Harvard Medical School, predicted that the protein would become an important marker for cardiac inflammation and heart damage in the future. In the interim there have been numerous successful research studies, and on Jan. 28, 2003, Rifai’s prognostications were realized when the American Heart Association (AHA) and the Centers for Disease Control and Prevention (CDC) released a landmark joint scientific statement recommending CRP tests for patients with elevated cholesterol and blood-pressure levels, but not at severe risk of heart disease. The guidelines constitute a landmark because it is the first time in two decades that the AHA and CDC have recommended a new instrument for physicians to assess cardiac risk. The reason for excluding high-risk patients from hs-CRP testing is that they would be treated aggressively as a matter of course. It is those patients with borderline high cholesterol who may or may not be candidates for statin drugs. A high hs-CRP result might tip the balance in favor of a prescription since statins have been shown to lower CRP levels as well as cholesterol levels.

“Everybody accepts that inflammation is important, everybody accepts that CRP levels are a good predictor of heart disease,” Rifai said. “But if you’re a clinician and you find someone with high CRP, we still really don’t have firm ground on intervention. Moderate intervention such as lifestyle change is fine, but it becomes more problematic when you want to be aggressive and start using statin drugs. That’s where the data – although it is very suggestive and strong – is not enough to recommend putting a patient on statin drugs.”

Thus, in February was launched the JUPITER study with Paul Ridker as chair. The JUPITER study will randomize 15,000 people with high CRP and low LDL on either a statin drug or placebo and follow them for 4 years.

“There are people who will complain no matter what, and there are people who will be very receptive. If history is any indication, the clinicians are always ahead of the national guidelines,” Rifai added.

The 15-member panel that wrote “Markers of Inflammation and Cardiovascular Disease: Application to Clinical and Public Health Practice,” recommend that CRP tests be used to help physicians determine the best treatment and prevention strategy for patients showing a 10 percent or greater risk of heart attack over 10 years. CRP levels are not meant to replace traditional indicators of coronary risk such as cholesterol and blood pressure levels, age, smoking and diabetes status. Rather, it is designed for use in conjunction with them. CRP is not a stand-alone test to “screen the entire population to find those at risk of heart disease,” according to the guidelines.

One of several studies that helped secure hs-CRP’s role as a cardiac marker involved an eight-year study of 3,597 women with metabolic syndrome. Metabolic syndrome is a clustering of three or more of five conditions: abdominal obesity, high triglycerides, low levels of “good” HDL cholesterol, high blood pressure and high glucose. After eight years of follow up, the age-related rate for heart attacks, strokes and operations to restore blood flow for women with metabolic syndrome and hs-CRP levels above 3 mg/L was 5.9 per 1,000 women per year. For those with the metabolic syndrome but hs-CRP levels less than 3.0 mg/L, the event rate was 3.4 per 1,000.

An analysis of the women with metabolic syndrome showed that those with the highest CRP levels (greater than 3.0 mg/L) were 2.1 times more likely to have a cardiovascular event than those with the lowest CRP levels (less than 1.0 mg/L).

“We have previously shown that CRP predicts cardiovascular risk in healthy individuals. Now we have evidence that CRP also does a very good job distinguishing lower, moderate and higher risk, even among people with metabolic syndrome,” said lead author Paul M. Ridker, M.D., a professor of medicine at Harvard and director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital in Boston.

Although Ridker’s team studied only women, he believes these data are likely true for men because other studies have linked CRP to individual components of the metabolic syndrome. Ridker notes that they don’t yet have evidence that lowering CRP will necessarily lower cardiovascular risk, but adds, “Studies evaluating this idea are only starting now.” Ridker is listed as the lead author on 12 of the 89 studies referenced by the AHA/CDC Scientific Statement on hs-CRP.

Inflammation and cardiac damage
In the past, it was widely believed that coronary artery disease was caused by a build-up of lipids and plaque that consequently narrowed the vasculature, but many recent studies have found a relationship between cardiovascular disease and inflammation. CRP is one of several inflammatory markers in the body shown to indicate cardiovascular risk. Others include adhesion molecules, cytokines, acute-phase reactants, fibrinogen, SAA and white blood cell count. But not all inflammation biomarkers are created equal.

High-sensitivity CRP has the advantage in a clinical setting because it offers the stability, commercial availability, and standardization (allowing comparison of results and precision of the assays as measured by the coefficient of variation) that make an assay clinically viable. In addition to being highly stable, hs-CRP has a proficiency-testing program from the College of American Pathologists in place, and a program to standardize hs-CRP testing is underway at the CDC. Most of the acute-phase reactant assays have acceptable coefficients of variation. The acceptable hs-CRP formulations offer precision down to or below 0.3 mg/L because it is within these lower (previously normal) CRP ranges that hs-CRP levels seem to have predictive capabilities for CVD events.

So what does the widespread clinical acceptance of CRP testing mean for patients, clinicians, laboratorians and the companies that make the test?

For patients, the hs-CRP test means one more method to help assess where they fall in the risk profile for cardiovascular disease. Cholesterol levels are an important marker, but fully half those who suffer heart attacks do not have elevated cholesterol levels. “Patients with very low cholesterol or very high cholesterol levels will have no need for a CRP test because there already are viable treatment protocols for them,” said Bernard C. Cook, Ph.D., consultant for Beckman Coulter. “It’s patients with borderline high cholesterol who would benefit most from the test.”

For clinicians, hs-CRP is one more bullet in the arsenal with which to fight cardiovascular disease. “We now realize that this marker can identify people at high risk for death and myocardial infarction when they have acute coronary syndromes,” said Robert S. Rosenson, M.D. of the Preventive Cardiology Center, Northwestern University Medical School. “There’s also utility for C-reactive protein in identifying people at risk for their first heart attack or first stroke. So it expands our ability to identify high-risk individuals.”

It’s important to remember that a patient’s high-sensitivity CRP reading is one piece of a cardiac risk algorithm developed by Ridker to assess cardiac risk. Even though hs-CRP has been around for a few years, it was not widely used by physicians because there were no set protocols on whom to test, what constituted low, medium and high CRP levels and what treatment to prescribe for patients with high test results.

Cook believes the AHA/CDC guidelines will impact the clinical decision to test or not to test. “The AHA/CDC statement is going to stimulate more use because so many physicians in the past have wondered what to do with the results, how to interpret the results,” Cook said. “ The quintiles (developed by Ridker) that were originally suggested helped with that, but they were also a little bit confusing. This gives physicians some guidelines and recommendations on how to interpret results, whom to test, when to test and what to do with the results.”

For laboratorians, the new guidelines on hs-CRP present another opportunity to educate physicians. “Some physicians may question the lab on what the tests result mean,” said Linda Rogers, Ph.D., a consultant for Beckman Coulter. “That’s why we try to educate the lab so they understand and can pass that information on. This AHA/ CDC statement now is something that we can put in front of physicians and say, ‘Your colleagues suggest this.’”

Rifai believes it is important for laboratorians to get on board and play an active role — leadership role – in offering hs-CRP. “If laboratories are not offering the right CRP test or providing only old CRP assay detection limits, that can be extremely frustrating for clinicians,” Rifai said. “It would be very nice if laboratorians took a leadership role on this.”

Considering the millions of dollars spent on the treatment and prevention of cardiovascular disease, diagnostic manufacturers are looking forward to participating in a growth market for the new high-sensitivity CRP test. The worldwide market for inflammatory markers such as CRP is about $20 million but is growing at about 40 percent per year, according to “Trends in the Early Diagnosis of Cardiovascular Disease” by Kalorama. The worldwide market for lipid testing was $450 million in 2002 with an estimated annual growth rate of 10 percent per year.

The original hs-CRP test, developed by Ridker in conjunction with Dade Behring, runs on that company’s BN-II nephelometer and Dimension family of analyzers. Since Dade’s is the only test approved right now, any other diagnostic manufacturers that offer hs-CRP licenses the formula from Dade Behring to produce it for their own analyzers.

Together with the recommended cutoffs for risk levels, the new AHA/CDC guidelines state that measurement of hs-CRP should be expressed as mg/L only, and ought to be done twice (averaging results), optimally two weeks apart, fasting or non-fasting in metabolically stable patients. If hs-CRP levels are >10mg/L, the test should be repeated and the patient examined for other sources of infection or inflammation.

As a risk marker, hs-CRP was found to be independently associated with incident coronary events after adjusting for age, total cholesterol, HDL cholesterol, smoking, body mass index, diabetes, history of hypertension, exercise level, and family history of coronary disease. Data are limited, however, for persons of African, South Asian, or Native American descent, who may be at particularly high CVD risk.

The panel determined that hs-CRP is an appropriate testing option in primary prevention for patients without known CVD who demonstrate other major risk factors. They discouraged using hs-CRP as a population-based screening tool or as a replacement for major risk factors for risk assessment. They endorsed – subject to clinical judgment- using hs-CRP testing in higher risk individuals to guide physician considerations of further evaluation (imaging or exercise testing), or therapy (lipid-lowering, antiplatelet, or cardiovascular agents).

The complete recommendations appear in the January 28, 2003 issue of Circulation, the journal of the American Heart Association.

The French paradox and CRP
In another recent study appearing in the journal Circulation, researchers suggest that the protective effects of alcohol may be attributed to its anti-inflammatory effect on the vascular system. In a cross-sectional survey of 2,833 patients from the Prevastatin Inflammation/CRP Evaluation Study, Dr. Michelle A. Albright and colleagues from Brigham and Women’s Hospital divided participants into five groups: those that drank less than one drink monthly; those that drank one to three drinks monthly; those that drank one to four drinks monthly; five to seven drinks weekly and more than two drinks daily.

chartAlcohol’s effects persisted after adjusting for multiple risk factors including age, sex, diabetes, aspirin use, smoking status and blood pressure (p < 0.001 for trend). In addition, the association was independent of the effects of statin therapy on cholesterol levels.

Despite the excitement surrounding hs-CRP, many researchers believe it is just the tip of the body’s “inflammation response” iceberg. Numerous studies underway are examining the role inflammation plays in breast, prostate and colon cancer, strokes and even Alzheimer’s. Given those stakes, high-sensitivity C-reactive protein and similar inflammatory markers promise to keep clinical laboratories as busy and busier than always.

Coleen Curran, based in Charlotte, N.C., is a writer, healthcare consultant and former editor of CLP.