This is another example of a drug "doing great things to the lab test" that did not translate into clinical benefit, he said. "What we’re learning is that manipulating risk factors is tricky business, and some drugs and strategies may change them but will not favorably change the risk."
He also referred to the development of another CETP inhibitor, dalcetrapib, which was halted after what the manufacturer, Roche, recently announced was a lack of clinically meaningful efficacy of the drug in a phase III trial of patients with stable coronary heart disease following an acute coronary syndrome.
The lack of evidence that the targeted approach improves patient outcomes, he cited, includes the AIM-HIGH study, which found no additional benefit of niacin when added to statin therapy in patients with atherosclerotic cardiovascular disease and LDL cholesterol levels less than 70 mg/dL, even though niacin was associated with significant improvements in HDL cholesterol and triglyceride levels (N. Engl. J. Med. 2011;365:2255-67).
Dr. Krumholz also cited the JUPITER study, which found that treatment with rosuvastatin was associated with a significant reduction in major cardiovascular events among people who had LDL cholesterol levels below 130 mg/dL and elevated C-reactive protein levels (N. Engl. J. Med. 2008;359:2195-2207).
"We want to know that the strategies we employ actually help people and not just their lab tests, and even though the science is elegant that underlies the lipid hypothesis and no one is disputing the relationships and studies that have been conducted, we are beginning to recognize these drugs have a lot of effects," he said. "We know in an open population that these factors will predict risk, but don’t know whether changing them and that different strategies of changing them all have same benefit associated with them."
Recent concerns about reports of hyperglycemia and cognitive effects associated with statins emphasize that, for patients with little to gain from treatment, there is "no reason" to be exposed to this risk, but for those who have a lot to benefit from treatment, the risk may be worth taking, he said. In February, the Food and Drug Administration announced that memory loss and confusion associated with statins reversed once the statin was stopped and that reports of hyperglycemia had been added to statin labels.
A patient’s choice should also be considered, and when discussing treatment with patients, Dr. Krumholz likes to give them a sense of how many people need to take a medication like a statin for one person to benefit. "Even for a number that seems small, like 25, which is good in medicine, a patient may choose not to take it," he said, adding that treatment "should be customized, both to the patient’s preferences and to their risk."
Individual Risk Matters
In an interview, Dr. Robert Vogel, clinical professor at the University of Colorado, Denver, said that he agrees that the "the basic concept of getting to an LDL goal is wrong," and while he would not abandon LDL cholesterol as a risk factor, "I would certainly throw it out as a target." He said that this view is shared by a majority of lipidologists but a minority of cardiologists overall.
Dr. Robert Vogel
He also cited the JUPITER study as well as the Treating to New Targets (TNT) study, which, he pointed out, compared two different atorvastatin doses, not two different LDL goals. This is representative of what is actually known – the effects of larger versus smaller treatment doses, or treatment versus placebo. "We never have tested treatment to specific goals," so those effects are unknown, but that "is how the ATP guidelines have been written," he noted.
In the TNT study of about 10,000 people with clinical evidence of CHD and LDL cholesterol levels below 130 mg/dL, intensive lipid lowering with 80 mg of atorvastatin was associated with a reduction in the risk of major coronary events that was significantly greater than that associated with 10 mg of atorvastatin daily (N. Engl. J. Med. 2005;352:1425-35).
Dr. Vogel said that he hoped that in ATP IV the concept of treating to goal will be changed to treating high-risk patients with high-dose effective statins, if tolerated, and matching treatment not to the LDL cholesterol, level but to an individual’s risk "or to the situation that has been demonstrated to be effective in prospective trials." This approach would be a substantial difference from previous guidelines and would be "changing more towards something that looks like treating heart failure," for which treatment is not based on particular parameters but on treatments that have been demonstrated to be effective.