Twilight zone for CVD risk markers?

He’s happy to enumerate other questions. How valuable is it to parse out yet another subset of patients—those with high triglycerides—and perform additional tests? Is that subset so large that perhaps a new paradigm, rather than more testing, is in order? And what is the ideal cutoff for triglycerides? The generally accepted level of 70 mg/dL for LDLc is an extrapolation from studies that haven’t asked the question directly, he says. Moreover, most of these studies used calculated LDL—what’s the best way to extrapolate those findings to other methods of determining LDL?

“There are some substantial scientific issues that need to be addressed,” says Dr. Jaffe. “It’s fair to say that there are some patients in whom apo B or LDL-P is apt to be better. But is it enough that we ought to do it on everybody?”

Those who aren’t defeated by the scientific challenges face another foe: behavior. Laboratories have spent years educating physicians about how to measure LDL and how to respond to it. A new method would have to be dramatically better “to want to go through the pain and suffering of re-educating everyone,” Dr. Jaffe says.

Then there’s the patient versus government dialectic. Government is talking about cost because that’s what government wants to reduce. Patients are fine with that. Sort of. “They say, ‘You save money—on someone else,’” says Dr. Jaffe. There’s no shortage of patients who worry about their cardiovascular health, whether they need to or not, and who will demand a new test either because they think it will be of benefit to them personally, or that it’s better, and therefore preferable, in general.

To keep things in balance, laboratories can try removing rusty markers from the menus, although one lab’s castaway could be a clinician’s keepsake, he cautions. “Clinicians have gotten used to certain things over time.” In relationships, familiarity breeds contempt, but in medicine it breeds higher test volumes. Some years ago Mayo Clinic discontinued use of the bleeding test, a seemingly reasonable move “because there was absolutely no evidence it worked,” Dr. Jaffe says. The test did not go gentle into that good night. Recalls Dr. Jaffe: “It was a war.”

Rightly or wrongly, clinicians had relied on it. “And now we were taking it away.”

Dr. Jaffe is not placing blame. “Life’s busy. From the clinicians’ point of view, do they want to spend three hours with the lab talking about getting rid of a test they like, or would they rather see more patients?”

Nonetheless, any serious discussion about containing costs should include dropping unnecessary markers, and labs are the ones best able to start those discussions. His lab is now looking at dropping the erythrocyte sedimentation rate, but it won’t happen without talking to clinicians first. It’s not just to avoid angering clinical colleagues. Those same colleagues are the ones who can decide to send their patients to other hospitals if the laboratory doesn’t provide the tests they want. And even if the lab sees no value in a test, it doesn’t know how it’s used by every clinician. By dropping it, “You may be doing some harm,” Dr. Jaffe cautions.

Dr. Jaffe sees the world the way it actually works, which helps explain his view of the marker story. If markers are losing some of their luster, it’s for reasons that stretch beyond pure science, he says. The most basic risk markers—weight, exercise, family history, smoking—are the easiest and cheapest to assess, but, echoing Dr. Greenland, he notes that that’s no guarantee of success. “We are in a society where sexy wins,” says Dr. Jaffe.

That’s one reason why biomarkers also receive less attention than imaging studies, he continues. Medical testing may have the equivalent of an old-boy network as well: Imaging historically has been developed by cardiology, not the laboratory, and that’s where cardiology’s interests naturally turn. It’s also to cardiology that reimbursement goes. In short, “Lab testing isn’t fun for clinicians. They don’t understand it, and they don’t get any remuneration from it,” says Dr. Jaffe.

Like Dr. Greenland, Dr. Jaffe sees both pros and cons of using cardiac calcium. It’s expensive. It exposes patients to radiation. Cardiac calcium scores don’t necessarily provide a clear next step either, beyond the obvious—work on lowering a patient’s risk. If the “sexy wins” model is viable, though (and it probably is—look how many people follow the gospel of Dr. Oz versus the recommendations of their own boring GP), a cardiac calcium score might spur patients to comply.

As section head of preventive cardiology, Cleveland Clinic, Stanley Hazen, MD, PhD, is all too familiar with patient noncompliance. He says new biomarkers could help give patients an extra push, including those who are at high risk.

“Maybe you need other tests to energize the patient to be compliant with diet, exercise, medication,” he says. LDL cholesterol no longer packs a fear factor, but inflammation markers do—and that’s important, he says, because the average patient who’s prescribed a statin only takes about a third of a year’s worth of the medication. “It’s as low as a quarter to as high as 40 percent,” he says. (Men, he says in an aside, “are actually, believe it or not, a little better at filling their prescriptions than women.” More evidence, perhaps, that CVD is an unpredictable science.)

His clinical work goes hand-in-hand with research efforts—he’s also department chair of cellular and molecular medicine at the Cleveland Clinic’s Ler­ner Research Institute. His main focus has been on the mechanisms of atherosclerosis and plaque vulnerability. His research group was one of the first to focus on myeloperoxidase, an enzyme linked to both; MPO has become a marker for identifying CVD risk in patients who otherwise might not be identified by other laboratory tests.

More recently, they’ve begun looking at metabolomic studies. While cholesterol and triglycerides have dominated the CVD discussion, Dr. Hazen and his colleagues have been asking questions about another class of lipids—phospholipids. (Last summer they received a nearly $5 million grant from the National Heart, Lung, and Blood Institute to continue this work.)

A paper published in Nature (Wang Z, et al. 2011;472:57–65) looked at the promising relationship between the gut flora-dependent metabolism of dietary lipid phosphatidylcholine and CVD pathogenesis. Three metabolites—choline, TMAO, and betaine—were shown to predict CVD risk, which could open the door to new tests and therapies. “Trimethylamine N-oxide looks like it’s going to be a very strong and complementary diagnostic test that helps identify people at risk” who otherwise would go unrecognized, based on traditional markers and tests, Dr. Hazen says.

The notion is straightforward. What we eat is absorbed through the filter of our intestinal flora. Even the average grade-schooler knows what foods are healthful and which aren’t, in general, but there’s currently only limited testing to tailor diets to an individual. Those who generate significant amounts of TMAO might need to decrease their intake of animal products, Dr. Hazen says, noting that foods that have high phosphatidylcholine also tend to be the same ones that have high fat and high cholesterol.

He’s even more excited by the concept behind this work: that gut flora can generate compounds that are biologically active and contribute to disease processes. “It’s almost as if the gut flora is an endocrine organ, making hormones or biologically active species that are acting at a distant site.” And, perhaps, that are worth monitoring at the individual level to determine the pathway’s contribution to heart disease.

He’s aware that new markers face an uphill battle. Just look at hs-CRP, he says. Which, of course, we have. Dr. Hazen points to the “incredible data” supporting its use. “From a statistical standpoint, it’s as good as a cholesterol level,” even if it’s not mechanistically linked to CVD the way cholesterol is.

It takes time and money to prove something works in medicine, and even then, the cost-benefit discussions are subjective. It’s a gray line, he says, not a black-and-white one. These are hard questions, and there’s no one right or wrong answer. He too refers to the JUPITER trial. “Every pharmaceutical company CEO would give his right arm to have a trial be as positive as that was,” he says. Though the trial showed significant benefit of putting patients on a statin if they had a normal cholesterol and high CRP, plenty of clinicians still argue that the evidence is insufficient to change guidelines. “It’s all in the mindset of the physician.”

Dr. Hazen shares Dr. Greenland’s fondness for statins. He takes as an example a person in his or her early twenties with an LDL on the higher side—135–140 mg/dL. National treatment guidelines say it’s an option to treat that patient with medications, but such a patient, as well as the physician, will often prefer lifestyle changes over a prescription drug. “And then they disappear from physician’s view for the next quarter of a century,” he says. “The next time they show up is with their heart attack, or an angioplasty requirement.” One could argue that pregnant women will see their physicians in the interim, but rarely does that include preventive, cholesterol-related care, he says.

He’s not all that interested in further refining risk categories. Like Berlioz, he thinks big. In preventive cardiology, that means making risk a broad, lifetime category of sorts. So, in the above scenario, Dr. Hazen recommends that the young adult go on a statin. “That’s the very person who’s going to have the single most benefit. It’s your life exposure to cholesterol that counts.”

His concern for low-risk patients is essentially a call for expanded testing. That may be a tough sell in the current cost climate, but he notes that just as he and his preventive cardiology colleagues at Cleveland Clinic add new markers to their algorithms, they’ll also vote old ones off the menu.

Five years ago, that happened to homocysteine. It was part of an initial panel for new patients, and those with high levels were given folic acid and B-complex vitamins. Studies have since shown that while the supplements lowered homocysteine, they didn’t lower cardiovascular risk. “Homocysteine does predict risk,” he says. “But it came off our panel because it raised more questions about what to do next.”

No one marker, but not too many. Trying to get it right, one could sympathize with Henry V at Agincourt. There, too, it was a matter of numbers. Bedford and Exeter, Salisbury, Westmoreland—all calculated the size of the troops and felt the English army lacking. Henry, of course, famously wished for not one man more.

Henry and his band of brothers turned out to be enough. But that was fiction, and it was written by Shakespeare. No wonder it worked. In cardiology, it’s anyone’s guess what the right mix will be.

Karen Titus is CAP TODAY contributing editor and co-managing editor.