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Twilight zone for CVD risk markers?

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Karen Titus

February 2013—Times are tough all over. For the middle class, for newspapers, for François Hollande and his fellow French Socialists.

Consider adding cardiac risk markers to that list. Despite decades of research and clinical experience, the marker conversation—what to measure, how, in whom—has become more an endless loop than a solid lineup. Old standbys still turn up in studies of novel markers, and tests that have arguably outlasted their usefulness still adhere, like barnacles, to laboratory menus. Some observers are even questioning the tenets of risk assessment.

While no one is putting cardiac risk markers on the endangered species list, they might no longer be the trophies in cardiology’s big game hunt, either. In wide-ranging interviews with CAP TODAY, three cardiac experts offered their off-center views on the field.

If, as some suggest, the search for a magic bullet is languishing, what now? Philip Greenland, MD, predicts a novel approach to risk assessment.

He’s co-author of a study (Yeboah J, et al. JAMA. 2012;308:788–795) comparing novel markers for enhancing cardiovascular risk assessment in intermediate-risk individuals, a group that some feel is ripe for more-refined risk stratification. The study suggested that coronary artery calcium was the best marker for discriminating between higher- and lower-risk patients in that middle group. High-sensitivity C-reactive protein, like CAC, ankle-brachial index, and family history, also performed as an independent predictor of coronary heart disease/cardiovascular disease, though with less oomph—for incident CHD, it provided the least reclassification improvement when added to the Framingham Risk Score.

The real surprise for laboratories, however, might be the notion that hs-CRP was considered to be a novel marker. By now it should be as familiar in the mouths of physicians as the household names Henry V reels off in his St. Crispin’s Day speech.

CRP is not a newcomer, acknowledges Dr. Greenland, the Harry W. Dingman professor of cardiology, Departments of Preventive Medicine and Medicine, Northwestern University Feinberg School of Medicine, Chicago. Its status as an acute-phase reactant has been known for three or four decades, while its association with cardiovascular risk became apparent in the past 15 years or so. Enthusiasm for this marker was understandably high, as it seemed to confirm the hypothesis that the atherosclerotic process was an inflammatory one.

Dr. Stanley Hazen

Dr. Stanley Hazen and his colleagues at the Cleveland Clinic are exploring links between phospholipids, gut flora, and cardiovascular risk. “It’s almost as if the gut flora is an
endocrine organ,” he says, “making hormones or biologically active species that are acting at a distant site.” [Photo: Dale Dong]

Yet hs-CRP continues to be scrutinized. To what extent is it truly predictive of cardiovascular events, asks Dr. Greenland, especially when other markers—lipid markers, for example—are more available and easily treatable? Even in the JUPITER trial (Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin), the largest to use CRP as a test for sorting risk, the optimal treatment was a lipid-lowering drug, not a classic anti-inflammatory, he says.

“Lots of studies have shown the limited predictive capability of CRP,” says Dr. Greenland, including the aforementioned JAMA study.

No one’s picking on CRP. Other studies continue to scratch the same patches of dirt, assessing and re-assessing the likes of fibrinogen, apolipoprotein B, apolipoprotein A-I, lipoprotein(a), homocysteine, and various cytokines, as well as what they mean when added to warhorses such as total cholesterol and high-density lipoprotein cholesterol.

And these are just the laboratory markers. You’d be hard-pressed to find a cardiologist who isn’t equally (if not more) captivated by imaging studies, or a preventive medicine physician who’s willing to shun seemingly quaint lifestyle markers related to exercise, diet, weight, and smoking.

The table is full of markers, in short. If, after decades of looking for the ideal marker, no winner has emerged, maybe it’s because people are playing the wrong game.

The hunt for cardiac risk markers began in earnest some 15 years ago, motivated by honorable intentions. When researchers started getting excited about finding new predictive markers, says Dr. Greenland, it was in the context of clinical practice guidelines that were suggesting it was important to know where a person fell on the risk spectrum. The chase was on. “Everyone, including me, expected we would find the magic bullet.”

At the time it hadn’t been shown that statins could lower risk in intermediate- and lower-risk people, he says. That’s no longer the case. But even as recently as five years ago, there was plenty of enthusiasm for knowing as precisely as possible where people fell on the risk spectrum, given the questions about the cost and clinical effectiveness of statins.

That need may be fading, Dr. Greenland suggests, though he adds that his views are not reflected in current guidelines. “I’m talking about tomorrow’s medicine, not today’s,” he says. Statins are powerful, like having the president on speed dial. Clinical trials are now showing that for patients at fairly low levels of risk, statins lower that risk even more. The issue then becomes less about markers/stratification and more about statins’ cost (they’re cheap) and patient tolerance (it’s good).

If the quality of risk prediction is important, Dr. Greenland says, “Then it would matter if we could find the marker that was one size fits all—a test that we want to do in everybody, sort of like a mammogram for breast cancer risk.

“On the other hand, for cardiovascular risk, there are people who say the cardiovascular mammogram is the coronary CT,” he continues. Though not every finding is a high-risk lesion, “Pretty much everything you see on a mammogram means there’s something you need to be thinking about. Those who are advocates of coronary CT say the same thing.” A lesion may not necessarily lead to a heart attack, but an absence of lesions means a person is at low risk.

If coronary calcium is the closest thing providers have to a magic bullet for CAD, however, its cost and the risks of radiation exposure make its broader use a questionable strategy. Nor is Dr. Greenland convinced that the breast cancer–CAD comparison should be stretched much further, given that breast cancer occurs at about one-tenth the rate of coronary disease.

In fact, on the disease spectrum, he places CAD closer to cavities than cancer. Both tooth decay and CAD are widespread in the population. Both can be relatively easy to prevent with lifestyle changes. And both rarely are. Ideally, people would stop eating candy and brush thrice daily, as Dr. Greenland puts it. But since that doesn’t happen, the choice has become to treat the population at large by fluoridating the water. “Then everybody is covered.”

A similar approach might be worth considering in CAD. So many people are at risk for CAD, Dr. Greenland says, “I would predict that more people with a risk factor will go on statins, sort of like most people today who perceive any sort of risk go on a low-dose aspirin. And if all of what I’m saying is true, then the use of markers becomes much less critical.”

“What I see happening is that the fascination with markers is winding down a little bit,” he says, “as people start to realize that what matters most is getting people on a risk reduction strategy.”

If the magic bullet is a treatment and not a test, however, it’s a little strange to Dr. Greenland that third-party payers have not yet calculated the price at which statins could be used among a wider swath of the population. “The effectiveness of statin therapy in low-risk people is published. That’s not a secret.”

Perhaps health care reform will push matters in that direction; at the very least, he predicts, providers will spend less energy fine-tuning risk.

That sounds like a smaller role for laboratories. Per Dr. Greenland, however, the best labs will continue to offer more than testing. Some already take test results and calculate coronary risk, using, say, the Framingham Risk Score and combining that with clinical recommendations from national guidelines. Laboratories could also work with clinicians to formulate testing strategies for patients. “That could be useful, because a lot of times clinicians get information back and have difficulty integrating it themselves. They may not know what the next step is,” he says.

One other player has gone noticeably silent on the topic of cost savings, says Allan Jaffe, MD. That would be the makers of markers, who, quite reasonably, have to eye market share and profit. “Quite frankly, the companies are ignoring cost containment,” says Dr. Jaffe, a clinical cardiologist and professor of medicine and laboratory medicine and pathology, Mayo Clinic.

That’s cause for concern, especially as health care spending becomes yet again a focus of attention. But Dr. Jaffe, who’s also chair of the Division of Clinical Core Laboratory Services in Mayo’s Department of Laboratory Medicine and Pathology, says any discussion of new markers first needs to address a more primal question: Is the proposed marker any better than what’s currently available? If it isn’t, then the discussion can stop right there.

It’s a hard question to answer. As the hs-CRP discussion has shown, even longstanding markers undergo periodic inquisitions. Dr. Jaffe draws attention to LDL cholesterol testing methods. It’s been clear for years, he says, that the current method of calculating LDL, using the Friedewald equation, has problems because of its reliance on triglycerides. At Mayo, the lab won’t report LDL cholesterol if triglycerides are above 400 mg/dL, though Dr. Jaffe says there’s a reasonable argument to be made that LDL results are confounded when triglyceride levels are lower, perhaps even 200 mg/dL. “So you’re talking about a fairly substantial number of patients.”

In that group, advanced lipid testing might be preferable. Most data show a modest but statistically significant improvement in using LDL particle number or apo B over LDL cholesterol. But, practically speaking, LDL cholesterol is cheap and widely available on multiple platforms. “New testing will be substantially more expensive than prior testing,” Dr. Jaffe says. It’s a complicated tradeoff. What’s the incremental benefit versus the incremental cost of making the switch?

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