No reason to fear very low LDL

October 11, 2005

(BETHESDA, MD) - Very low LDL cholesterol levels appear to be safe for heart patients on statin therapies, according to a new study in the Oct. 18, 2005, issue of the Journal of the American College of Cardiology.

"There was no apparent safety concern for patients whose resultant LDL on intensive therapy was lower than current guidelines. There was a trend toward improved clinical outcomes in the lowest LDL groups," said Stephen D. Wiviott, M.D., from Brigham and Women's Hospital in Boston, Massachusetts.

The researchers used data from a large trial comparing two cholesterol-lowering statin drugs in patients following acute coronary syndromes, such as unstable angina or heart attacks, the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction 22 (PROVE IT-TIMI 22) study. This new analysis involved 1,825 heart patients who had received high doses (80 milligrams per day) of atorvastatin. More than 90 percent of the patients had LDL (low-density lipoprotein, the so-called "bad" cholesterol) levels below the target level of 100 milligrams per deciliter of blood after four months of therapy. Some patients saw their LDL levels drop below 40 mg/dl.

Dr. Wiviott said that they reviewed this data from PROVE IT because some studies have suggested an association between very low levels of cholesterol and higher rates of death, strokes caused by bleeding, and other health issues. Rather than assessing the safety of statin treatment itself, this analysis looked at the effects of various levels of LDL by comparing the results for patients who were all taking the same high doses of atorvastatin.

"While the main results of the trial demonstrated that intensive statin therapy is superior to moderate statin therapy in patients following acute coronary syndromes, there has been concern among the medical community about treating patients with very high doses of potent statins. This stems largely from the epidemiologic literature which shows that patients with very low cholesterol, not on treatment, have higher mortality," Dr. Wiviott said.

There was no significant difference in safety outcomes among the groups of patients, including rates of death, bleeding strokes, or muscle, liver or retinal abnormalities. What's more, the patients who achieved LDL levels of 60 mg/dl or lower had fewer major cardiac events, including death, heart attack, stroke, recurrent coronary artery blockages or treatment to reopen coronary arteries.

Dr. Wiviott said the results offer reassurance to patients and clinicians using high doses of statins following acute coronary syndromes.

"In order to achieve the greatest benefit following acute coronary syndromes, patients should be treated early with intensive statin therapy. There is no need to reduce the dose in follow-up just because LDL is well below targeted levels," he said.

Dr. Wiviott noted that the PROVE IT trial was not originally designed to answer questions about the safety of very low LDL levels.

"This type of analysis should be considered 'hypothesis generating' and needs to be confirmed in other studies," he said.

John J.P. Kastelein, M.D. from the Academic Medical Center at the University of Amsterdam, Netherlands, who was not connected with this study, but who is helping to lead two large long-term studies of intensive statin therapy, welcomed this first solid information about the safety of low LDL levels.

"What's very important for me is that this trial is the first indication that very low LDL levels are actually safe. Of course, the time frame is modest, but it is the first indication that we can sustain low LDL levels without any cost in terms of extra side effects," Dr. Kastelein said.
Disclosure Box

The PROVE IT-TIMI 22 study of pravastatin and atorvastatin was funded by Bristol-Myers Squibb, the manufacturer of pravastatin (brand name Pravachol). This article used data from only the atorvastatin arm of the PROVE IT-TIMI 22 trial. Atorvastatin (brand name Lipitor) is a Pfizer product.

Dr. Wiviott says the TIMI Study Group has received grant support from Bristol-Myers Squibb, Merck, and Pfizer. He adds that he has given educational lectures and received honoraria from Pfizer and Merck.

Other reports from the PROVE IT trial of statin therapy in patients following acute coronary syndromes:

  • The benefits of statin therapy may involve much more than just lowering cholesterol among patients following acute coronary syndromes. Statins counter inflammation and immune system activation that is linked to coronary artery disease. Statins also have beneficial effects on the functioning of the endothelium, the inner lining of blood vessels. Statins are associated with improvements in markers of blood coagulation. Further research is needed to understand what role these factors play in acute coronary syndromes and whether they are causal or coincidental. However, despite therapy, patients remain at high risk of recurrent events following acute coronary syndromes.

    State-of-the-Art Paper: The Potential Relevance of the Multiple Lipid-Independent (Pleiotropic) Effects of Statins in the Management of Acute Coronary Syndromes

  • Benefits of intensive statin therapy were apparent within 30 days and persisted for the duration of the trial among patients in the PROVE IT-TIMI 22 trial. A composite end point of death, heart attack or rehospitalization for recurrent acute coronary syndromes occurred in 3.0 percent of patients receiving high-dose (80 mg/day) atorvastatin treatment compared to 4.2 percent of patients receiving standard-dose (40 mg/day) pravastatin therapy. Among those patients who did not suffer a clinical event within six months, the benefits of high-dose atorvastatin persisted during the remainder of the follow-up period, with a composite event rate of 9.6 percent compared to 13.1 percent among patients who were receiving standard-dose pravastatin therapy.

    Early and Late Benefits of High-Dose Atorvastatin in Patients With Acute Coronary Syndromes

  • After four months of therapy, high-dose statin therapy was independently associated with lower C-reactive protein levels, regardless of other risk factors present in 2,885 patients participating in the PROVE IT-TIMI 22 trial. Among those patients receiving intensive statin therapy, having fewer cardiovascular risk factors was associated with a lower C-reactive protein level, suggesting that control of multiple risk factors may be a way to further lower C-reactive protein levels.

    Relationship Between Uncontrolled Risk Factors and C-Reactive Protein Levels in Patients Receiving Standard or Intensive Statin Therapy for Acute Coronary Syndromes in the PROVE IT-TIMI 22 Trial

    American College of Cardiology

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