Study Says Higher Statin Doses = Lower Cholesterol

The risk of having a heart attack, and of dying from one, can be greatly reduced in patients with established heart disease when "bad" cholesterol is lowered well below levels currently recommended, according to a study published in the New England Journal of Medicine (April 8, 2004). Harvard Medical School researchers who conducted the study also affirmed that it is generally safe to prescribe higher doses of cholesterol-lowering statin drugs than is now the norm.

While the study was sponsored by the maker of the statin drug Pravachol to compare its impact to that of the statin drug Lipitor, many experts say that the conclusions about cholesterol levels and the relative safety of high statin doses should transform the treatment of heart patients regardless of the detailed outcomes of such statin-vs-statin competition.

"I don't think this study was a big surprise," said M. Ammar Hatahet, MD, MPH, FACP. "Previous studies have shown that at every level, lowering LDL further reduces the risk of heart attack and stroke." LDL, of course, refers to low-density lipoproteins, the "bad" cholesterol associated with heart disease.

"I think what's often missed in talking about this study is that it looked at secondary prevention (patients who already have established coronary artery disease), hence the results may not be generalizable for patients with mildly elevated cholesterol but no established heart disease," Dr. Hatahet noted. "What the study said that was more consistent with the previous ones was that in secondary prevention, the lower LDL the better."

More than 4,100 patients who had been hospitalized for sudden chest pain from heart disease were involved in the two-year study. According to national guidelines now used by most doctors, levels of LDL cholesterol should be below 100 milligrams (per deciliter of blood) in high-risk patients. Reducing cholesterol levels even more has significant benefits, the study found. The patients, in two groups, were given the highest doses of Pravachol (40 milligrams a day) and Lipitor (80 mg/day) available at the time.

Benefits Outweigh Risks
Patients in the study had cholesterol levels at or below the national guidelines when the study began. Later, those who took Pravachol had a median LDL level of 95 and those who took Lipitor had a median LDL level of 62. The Pravachol group had higher rates of heart attack, angioplasty, bypass surgery, and death after a month of statin treatment.

However, Dr. Hatahet cautioned, the study did not provide conclusive evidence on issues such as the impact of specific statin drugs on plaque stability and inflammation in coronary arteries. All patients in the study had plaque that had ruptured, causing severe chest pain from blood clots that stopped blood from getting to the heart. Plaque in coronary arteries is more likely to burst when it is inflamed. Conflicting results from the makers of various statin drugs mean that the jury is still out on how well each addresses this problem.

"Independent from lowering the LDL numbers, do different statins have additional benefits, such as reducing inflammation and stabilizing plaques? That question was not answered by this study," said Dr. Hatahet.

"The other point that was really important to take from the study is that, given the low rate of side effects in the study, it's pretty safe to prescribe a statin like Lipitor at its highest approved dose of 80mg/day, said Dr. Hatahet. "In the past, many doctors have shied away from using high dosages. They feared a resultant high rate of myopathy (a disorder of muscle tissue or muscles), but that didn't occur, so the highest approved dose of 80mg of Lipitor seems pretty safe.

"Because the dosages of the medicines were not comparable, I wouldn't say Lipitor did 'better' than Pravachol. Aside from bigger reductions of LDL at the same dose, I don't think Lipitor has any advantage over Pravachol, per se, as a statin drug. To get to the same LDL reduction, on average, you need to use twice as much of the Pravachol - milligram for milligram, Lipitor is twice as potent as Pravachol. I don't think it's an issue. The American Heart Association recommends using a statin to reach the goal LDL value, hence lowering LDL to the goal is much more important than which statin is used."

Side Effects Vary
Patients taking Lipitor in the study had more side effects than those taking Pravachol. In particular, liver enzymes were elevated in three times as many Lipitor patients as Pravachol patients. Dr. Hatahet noted that knowing how the body metabolizes particular statins is an important factor in determining which drug to use in order to minimize drug-drug and drug-disease interactions and side effects experienced by the individual patient.

"If you're on multiple drugs that are metabolized by the liver - particularly a group of enzymes call P-450 cytochrome 3A4 - the likelihood of liver complications are much higher. The clearance of Pravachol is primarily through the kidneys, not through the liver," said Dr. Hatahet, "so its interaction with other drugs is much less.

"Lipitor and the rest of the statins, Zocor included, are cleared through the liver, so the potential for drug-drug interaction is much higher. Sixty percent of all drugs metabolized by the liver are in fact metabolized by this particular enzyme, P-450 cytochrome 3A4, including many of the antibiotics, anti-seizure medications and anti-arrhythmia medications. So if you're on multiple drugs, particularly anti-fungal medications, then you probably want to be more careful when prescribed a statin that goes through the liver."

Dr. Hatahet said that the newest study is part of a growing body of evidence that will likely cause the guidelines for LDL levels to be lowered even further and speed doctors' acceptance of using higher doses of statin drugs to reach goal levels.

"Depending on how people read into the study, I think it will change some of the perception that a higher dose of Lipitor is not safe," said Dr. Hatahet. "It's been shown that it is safe. My own practice has been not to start with the smallest dose, starting with 10 milligrams and then trying 20 and then 40. I think you waste a whole lot of time doing it that way, so what I've done in the past depends on the goal for LDL reduction.

"Instead of trying a drug to see how much LDL reduction I get, I look to see how much LDL reduction the patient really needs at the outset. If the goal is less than 100, and you're at 160, then you need to get about a 60% reduction. If you need 60% reduction, Pravachol is unlikely to do it. Only Lipitor and Crestor at the higher doses may consistently get that much reduction. I think at least some clinicians probably will now be more comfortable, one, starting with a higher dose than they used to, and two, knowing that even the highest approved dosages are quite safe."

Dan Ullrich
HealthLink Contributing Writer

MCW Health News presents up-to-date information on patient care and medical research by the physicians of the Medical College of Wisconsin.