CLINICAL RESEARCH
Effects of High-Dose Atorvastatin on Cerebrovascular Events in Patients With Stable Coronary Disease in the TNT (Treating to New Targets) Study
David D. Waters, MD, FACC*, , , ,||,¶,#,*,
John C. LaRosa, MD*,,,,||,¶,#,
Philip Barter, MD*,,,,||,¶,#,
Jean-Charles Fruchart, PhD*,,,,||,¶,#,
Antonio M. Gotto, Jr, MD, DPhil, FACC*,,,,||,¶,#,
Roddy Carter, MD*,,,,||,¶,#,
Andrei Breazna, PhD*,,,,||,¶,#,
John J.P. Kastelein, MD, PhD*,,,,||,¶,# and
Scott M. Grundy, MD, PhD*,,,,||,¶,#
* University of California, San Francisco, California
State University of New York Health Science Center, New York, New York
Heart Research Institute, Sydney, Australia
Institut Pasteur, Lille, France
|| Weil Medical College of Cornell University, New York, New York
¶ Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
# University of Texas Southwestern Medical Center, Dallas, Texas
Manuscript received February 16, 2006;
revised manuscript received June 29, 2006,
accepted July 3, 2006.
* Reprint requests and correspondence: Dr. David D. Waters, Division of Cardiology, Room 5G1, San Francisco General Hospital, 1001 Potrero Avenue, San Francisco, California 94110. (Email: dwaters{at}medsfgh.ucsf.edu).
OBJECTIVE: We sought to assess the effects on cerebrovascular events of treating patients with stable coronary disease with low-density lipoprotein cholesterol (LDL-C) levels substantially below 100 mg/dl.
BACKGROUND: Lowering LDL-C with statins has been shown to reduce the risk of stroke in patients with stable coronary disease. In observational studies, naturally low cholesterol levels have been associated with an increased risk of hemorrhagic stroke.
BACKGROUND: The cerebrovascular benefits of treating patients with stable coronary disease to LDL-C levels substantially below 100 mg/dl have not been previously investigated.
METHODS: We describe an analysis of cerebrovascular events in the Treating to New Targets study, a trial where 10,001 patients with documented coronary disease were randomized to treatment with atorvastatin at 10 mg/day or 80 mg/day and followed for a median of 4.9 years.
RESULTS: Mean LDL-C levels were 101 mg/dl on 10 mg atorvastatin and 77 mg/dl on 80 mg. In addition to the reduction in major cardiovascular events (hazard ratio 0.78, 95% confidence interval [CI] 0.69 to 0.89; p = 0.0002), the primary end point of the trial, patients in the 80-mg arm experienced a reduction in cerebrovascular events (hazard ratio 0.77, 95% CI 0.64 to 0.93; p = 0.007) and stroke (hazard ratio 0.75, 95% CI 0.59 to 0.96; p = 0.02). Each 1-mg/dl reduction in LDL-C with treatment was associated with a 0.6% relative risk reduction in cerebrovascular events (p = 0.002) and a 0.5% relative risk reduction in stroke (p = 0.041). The incidence of hemorrhagic stroke was similar in the 80-mg and 10-mg groups, 16 and 17 respectively, and the hemorrhagic strokes were distributed evenly across quintiles of achieved LDL-C during treatment.
CONCLUSIONS: Among patients with established coronary disease, treating to an LDL-cholesterol substantially below 100 mg/dl with 80 mg/day atorvastatin reduces both stroke and cerebrovascular events by an additional 20% to 25% compared with the 10 mg/day dose. An increase in hemorrhagic stroke was not seen at low LDL-C levels. (Treating to New Targets; http://www.clinicaltrials.gov; NCT00327691
[ClinicalTrials.gov]
).
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Abbreviations and Acronyms
| | LDL-C = low-density lipoprotein cholesterol | | MI = myocardial infarction | | TIA = transient ischemic attack | | TNT = Treating to New Targets |
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