Beyond ATP III-Impact of recent clinical trials on future lipid management guidelines and therapeutic goals

Based on a presentation by Neil J. Stone, MD

NEW ORLEANS?Several recent cardiovascular (CV) clinical trials have shown the benefit of aggressive lipid-lowering therapy. They have also highlighted the inadequacy of statin monotherapy in clinical practice today, resulting in residual coronary heart disease (CHD) risk that might be alleviated with more aggressive application of current therapies.

In a poll of the symposium audience using an interactive response system, 60% of respondents said that no more than half their patients with CHD or diabetes achieve a low-density lipoprotein (LDL) cholesterol target goal of <100 mg/dL. Only 13% of audience members reported that 75% to 100% of their patients reached the goal.

ATP III guidelines

The National Cholesterol Education Program Adult Treatment Panel III (ATP III) guidelines, which were issued in May 2001 (JAMA. 2001;285:2486-2497), introduced new features that more accurately identify patients at risk. Whereas ATP I focused on primary prevention and getting patients to know their cholesterol levels, ATP II focused particularly on CHD patients at highest risk for a CHD event. ATP III extended the focus of ATP II to identify particularly those with multiple risk factors and recommended that for those at highest risk the LDL cholesterol goal be below 100 mg/dL instead of merely equal to or less than 100 mg/dL. Some of the new features of ATP III are:

• Introduction of the Framingham risk score for individuals with &#8805;2 risk factors to more precisely define "global risk" and hence more adequately determine goals of therapy.
• "Coronary risk equivalents" (eg, presence of diabetes, noncoronary forms of atherosclerosis, or a 10-year Framingham score of >20%), which are factors that are equivalent to having had a coronary event (with therefore the same lipid goals).
• Therapeutic lifestyle changes as initial therapy for metabolic syndrome; this encompasses diet, weight loss, and physical activity and is the appropriate starting place for those who have gained weight because of an atherogenic diet and sedentary lifestyle.
• A secondary goal for non?high-density lipoprotein (non-HDL) cholesterol if triglycerides are &#8805;200 mg/dL after the LDL cholesterol goal is achieved. The goal for non-HDL cholesterol can be established at 30 mg/dL higher than that for LDL cholesterol. This is perhaps the least utilized feature of ATP III in clinical practice despite the ease of calculating non-HDL cholesterol (total cholesterol minus HDL cholesterol) as non-HDL cholesterol represents the sum of the atherogenic particles that carry cholesterol.

At the 2004 American College of Cardiology meeting, the question "How low an LDL cholesterol is low enough?" was asked repeatedly.

In his presentation at the symposium, Neil J. Stone, MD, reviewed studies that support and extend the ATP III guidelines. He advised clinicians to calculate a Framingham score for patients with 2 or more risk factors to determine their risk of coronary events. For individuals at very high or very low risk, it is unnecessary, he said, since the calculation would not affect how they are treated. Dr Stone emphasized that calculating Framingham global risk with the calculator or a pen and pencil literally takes seconds and yet it provides the patient and physician with a much better estimate of overall risk and hence helps define the intensity of therapy.

Recent clinical trials

Since the ATP III guidelines were issued, results from at least 5 relevant major clinical trials have appeared: the Heart Protection Study (HPS), Prospective Study of Pravastatin in the Elderly at Risk (PROSPER), Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHATLLT), Anglo-Scandinavian Cardiac Outcomes Trial Lipid Lowering Arm (ASCOT-LLA), and Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL). Overall, the trials involved subjects with a wide range of cholesterol values.

HPS. HPS included men and women with diabetes, aged 40 to 80 years with average to low LDL cholesterol levels and coronary disease or coronary disease equivalents (Lancet. 2002;360:7-22). The researchers found that treatment with 40 mg/day of simvastatin caused a reduction in CHD, the incidence of all vascular events, and total mortality. This finding held over a wide range of LDL cholesterol levels (eg, <100, 100-130, or >130 mg/dL).

"This was the first inkling that knowing someone's risk was just as important as ATP III emphasized," Dr Stone said. "Indeed, for those with LDLs under 100, knowing they were high risk was beneficial to them." According to the ATP III guidelines, people at high risk, as determined by the Framingham score, need to be treated to an LDL cholesterol goal <100 mg/dL. In addition, if the triglyceride level is &#8805;200 mg/dL, the goal for non-HDL cholesterol is <130 mg/dL.

Simvastatin treatment in HPS reduced the rate of vascular events from 25.2% to 19.8% among this high-risk population?a reduction of 25% (Figure). But these patients were still at substantial risk, with 1 in 5 experiencing an event. In essence, a further 75% reduction in risk was needed, Dr Stone said.

The study involved almost 6000 patients with diabetes, "more than all the [other] studies combined," Dr Stone noted. The approximately 2000 patients with diabetes and coronary disease "derived tremendous benefit with a statin at any level of LDL," he said. The patients without coronary disease had a lower amount of risk reduction, but since ATP III considers all patients with diabetes as high risk, they should all receive intensive lipid-lowering therapy.

Dr Stone concluded that the HPS showed "that older patients, women, those with lower LDLs than we had been used to treating, and patients with diabetes all derived benefit, and particularly those who had vascular disease elsewhere."

PROSPER. The PROSPER study was designed to determine whether the benefits of statin therapy would extend to an elderly population (Lancet. 2002;360:1623-1630). Men and women aged 70 to 82 years who had a history of vascular disease or were at increased risk were randomized to pravastatin 40 mg/day or to placebo and followed for a mean of 3.2 years.

Among these 5804 individuals, pravastatin reduced the incidence of the primary composite end point of CHD, nonfatal myocardial infarction (MI), or nonfatal or fatal stroke by 14% compared with placebo (14.1% vs 16.2%; P = .014). Unlike in the HPS, in PROSPER, statin therapy did not significantly reduce the incidence of stroke, but Dr Stone noted, the placebo group had a lower incidence of stroke than was seen in HPS, so it would have been difficult to show benefit in this 3-year study.

ALLHAT-LLT. Dr Stone described the ALLHAT-LLT as an apparent add-on study, "where they took a very good hypertension study" and tried to add on a comparison of the effects of pravastatin 40 mg/day versus usual care in an open-label manner. The open-label aspect was a critical design flaw, he said. The subjects for ALLHAT were at least 55 years old with stage 1 or 2 hypertension and at least 1 other CHD risk factor (JAMA. 2002;288:2998-3007). Eligible fasting LDL cholesterol levels were 120 to 189 mg/dL for patients without known CHD and 100 to 129 mg/dL for those with CHD.

A problem with the study was that 23% (not the expected 15%) of patients in the pravastatin group had dropped out by 6 years, and a substantial proportion of the usual care group was started on a statin during that time (so-called "drop-ins"), Dr Stone noted. At 4 years, LDL cholesterol levels were lowered by 27.7% in the pravastatin group and 11.0% in the usual care group. The 2 groups showed no statistical difference in the outcomes of overall mortality, CV deaths, or CHD events.

ASCOT-LLA. Part of the ASCOT study was a primary prevention trial for coronary and stroke events in patients with hypertension (aged 40-79 years) with average or lower than average cholesterol levels and with &#8805;3 defined risk factors (Lancet. 2003;361:1149-1158). Patients were randomized to various antihypertensive regimens, and those with eligible lipid levels were randomized to atorvastatin 10 mg/day or to placebo.

Such patients have a 10% to 12% Framingham risk for a coronary event over 10 years. The study was stopped early after 3 years because atorvastatin treatment produced a 36% reduction in the combined end point of nonfatal MI or CHD death, as well as a significant (27%) reduction in fatal and nonfatal stroke. Similar to HPS, statin therapy lowered LDL cholesterol at least 1 mmol/L or 38.8 mg/dL.

Dr Stone said the results of HPS, PROSPER, and ASCOT reinforce the basic message of ATP III that "effective LDL reduction substantially reduces the risk for CHD and CHD risk equivalents?&shy; LDL reduction that is only modest, about 18%, didn't result in a significant difference in the ALLHAT lipid arm."

REVERSAL. The results of this randomized, active-control trial showed that intensive lipid lowering with 80 mg/day of atorvastatin for 18 months stopped the progression of atherosclerosis, as assessed by measurement of atheroma volume with intravascular ultrasound (IVUS) (JAMA. 2004;291:1071-1080). In comparison, the group that received pravastatin 40 mg/day had a 2.7% increase in atheroma volume over the course of the study (P = .02). Mean LDL cholesterol levels were reduced to 79 mg/dL in the atorvastatin group and to 110 mg/dL in the pravastatin group, from a baseline of 150 mg/dL in both.

This IVUS study of 502 evaluable patients again supports the ATP III recommendation to lower LDL cholesterol to <100 mg/dL, Dr Stone said. In addition, atorvastatin lowered triglycerides, apolipoprotein B (apo B), and C-reactive protein more than pravastatin did. "I might add that non-HDL cholesterol [the total cholesterol minus the HDL cholesterol], the secondary end point in the ATP III guidelines, tracks well in many instances with apo B," Dr Stone said, "so [it is] another reason to look not only at LDL but also at non-HDL cholesterol [particularly if after the LDL cholesterol goal is reached, the triglycerides are still 200 mg/dL or greater]."

Aggressive lipid lowering needed

Many patients who get to an initial LDL cholesterol goal of <100 mg/dL still have a high residual risk of CV events, Dr Stone noted. High-risk groups, such as patients with diabetes or metabolic syndrome (particularly if they have heart disease), would benefit from an even more intensive approach. They may have an elevated non-HDL cholesterol or apo B even when LDL cholesterol is at the <100 mg/dLgoal, so more intensive therapy would result in fewer atherogenic particles that carry cholesterol.

Dr Stone concluded that coronary risk equivalents need to be treated as aggressively as existing coronary disease. Statin doses need to be chosen to lower LDL cholesterol substantially. "A reduction of 30% or more was observed in the clinical trials that showed robust results," Dr Stone said. He noted that an optional goal of <80 or even <70 mg/dL might be recommended for those CHD patients at highest risk. But he reminded the audience that it may be a very difficult goal to reach if the patient is starting at an LDL around 190 mg/dL.