Will ATP IV Spell the End of Cholesterol Targets?


With the long-awaited updated clinical guidelines for cholesterol testing and management in adults expected to be released this summer, some experts are hoping that the recommendations will abandon the central focus of previous guidelines: treating to low-density-lipoprotein cholesterol targets.

The Adult Treatment Panel IV (ATP IV) guidelines will be the first since ATP III was released in 2001, which, like ATP II, identified LDL cholesterol lowering as the primary goal of treatment and identified different targets for LDL-lowering drug treatment. An update of the ATP III guidelines released in 2004 also supported the ATP III treatment goal of LDL cholesterol below 100 mg/dL in people at high risk, but also recommended an LDL cholesterol goal of 70 mg/dL or lower for patients at very high CHD risk, based on clinical trial evidence that had become available.

No Evidence Base for Goals

As the release of the guidelines has gotten closer, there have been calls by some cardiologists that LDL targets be abandoned – most notably in an open letter to the ATP IV committee, published in January, in which Dr. Rodney Hayward of the University of Michigan and Dr. Harlan Krumholz of Yale University encouraged the committee to "abandon the paradigm of treating patients to LDL targets, a change that will better align ATP IV with current clinical evidence" (Circ. Cardiovasc. Qual. Outcomes 2012:2-5).

"The dogma that treating to target is based on clinical trial evidence belies the fact that no clinical trial has yet tested this strategy," they wrote, referring to evidence in clinical trials indicating "that the use of statins, and not treatment to target, can reduce risk."

A tailored treatment strategy with high-dose statins based on risk prevents more coronary events while treating fewer people, and will save more lives than approaches aimed at LDL targets, Dr. Krumholz said in an interview.

"What we know about statins is that they reliably reduce risk in populations regardless of their baseline cholesterol levels," and that the benefit of an intervention depends on a patient’s underlying risk and the degree to which that intervention can reduce the risk, said Dr. Krumholz, director of the Yale-New Haven (Conn.) Hospital Center for Outcomes Research and Evaluation. "They seem to be effective no matter what the baseline LDL level is. So you’re not necessarily treating high cholesterol levels. At any level of cholesterol, it appears that these drugs lower risk."

He emphasized that he was not debating whether cholesterol is an underlying mechanism of atherosclerotic coronary heart disease. Rather, he considers statins as more of "a risk reduction pill" than a cholesterol reduction pill "because it doesn’t depend on someone’s cholesterol for its relative reduction in risk, so the people who benefit the most are the highest-risk patients."

In addition, Dr. Krumholz said that there has never been a large clinical trial that has sought to titrate patients to targets and evaluate outcomes, "so when people are identifying targets that everyone should be treated to, they are extrapolating data from many trials and drawing lines, but those are based on speculation." He cited the ACCORD study, which evaluated outcomes of tight glycemic control and found that achieving hemoglobin A1c below 7% with an aggressive approach increased mortality.

By focusing on targets, he said, "you are agnostic to the strategy to get you to those targets." For example, recommending treatment to reduce cholesterol to below 70 mg/dL or 100 mg/dL implies using whatever means possible to achieve that goal and to use that metric to measure success.

Lab Results Aren’t Outcomes

The danger in that strategy is that there are drugs that reduce LDL or raise HDL that "don’t necessarily achieve outcomes that you would expect for patients," Dr. Krumholz said. For example, fenofibrate is promoted as lowering triglyceride levels and raising HDL levels, but two large trials of fenofibrate’s impact on patient outcomes have been negative and there have been no positive trials, he pointed out.

It is not yet known whether treatment with ezetimibe, an inhibitor of intestinal cholesterol absorption that reduces LDL cholesterol, improves patient outcomes – which is being studied in an ongoing trial – and this uncertainty is reflected in the drug’s label. "So the focus on the target often obscures the fact that not all drugs that can get you to target have been shown to improve outcomes," he added said. (The ezetimibe label includes the statement that the effect of the drug on cardiovascular morbidity and mortality "has not been determined.")

Then there are the recent examples of the once highly promising cholesteryl ester transfer protein (CETP) inhibitors. Torcetrapib, a potent CETP inhibitor, was associated with extremely favorable changes in HDL cholesterol levels as well as reductions in triglycerides and LDL cholesterol in a study that was terminated early because treatment was associated with an increase in mortality and cardiac events; the drug was never approved. If the manufacturer had not conducted this study, the degree of harm identified in the study would have been extremely difficult to detect once it was approved and used in clinical practice, said Dr. Krumholz, the Harold H. Hines Jr. Professor of Medicine and professor of investigative medicine and of public health at Yale University.


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