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Drug Generally Well Tolerated
April 4, 2001 — For patients with certain cardiac events, such as a mild heart attack, lipid-lowering therapy with the drug atorvastatin at the highest approved dose reduces recurrent ischemic events (decrease in blood supply to the heart muscle) in the first 16 weeks, according to an article in the April 4 issue of The Journal of the American Medical Association.
Gregory G. Schwartz, M.D., Ph.D., of the Veterans Affairs Medical Center and University of Colorado Health Sciences Center, Denver, and colleagues investigated whether treatment with atorvastatin at a dosage of 80 milligrams per day, initiated 24 to 96 hours after certain acute coronary events, reduces death and nonfatal ischemic events. The Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Study was a randomized, double-blind trial conducted from May 1997 to September 1999, with follow-up through 16 weeks at 122 clinical centers in Europe, North America, South Africa, Australia and New Zealand.
According to background information cited in the article, blood cholesterol lowering with statin medications has been regarded as a long-term strategy to reduce death and ischemic cardiovascular events in patients with stable coronary heart disease, with significant effects evident after approximately two years of treatment. Previous trials excluded patients who had experienced recent unstable angina (chest pain occurring unpredictably or suddenly increasing in severity often without provocation) or acute myocardial infarction (MI) (heart attack). However, it is within the early period after certain acute coronary events that patients experience the highest rate of death and recurrent ischemic events. To date, it has not been determined whether initiation of treatment with a statin soon after these events can reduce the occurrence of these early events.
A total of 3,086 adults aged 18 years or older with unstable angina or non-Q-wave acute MI (a certain type of MI) took part in the MIRACL Study. The patients were stratified by center and randomly assigned to receive treatment with atorvastatin (80 milligrams per day) or matching placebo between 24 and 96 hours after hospital admission. The authors defined the primary end point as death, nonfatal acute MI, cardiac arrest with resuscitation, or recurrent symptomatic myocardial ischemia with objective evidence and requiring emergency re-hospitalization.
"During the 16-week study period, a primary end point event occurred in 228 patients (14.8 percent) in the atorvastatin group and 269 patients (17.4 percent) in the placebo group, an absolute difference of 2.6 percent. Atorvastatin treatment significantly reduced the risk of the primary combined end point [risk reduction of 16 percent]," the authors write.
"Likewise, there were no significant differences between the atorvastatin group and the placebo group in the incidence of secondary outcomes of coronary revascularization procedures, worsening heart failure, or worsening angina, although there were fewer strokes in the atorvastatin group than in the placebo group," they continue.
At the time of randomization, serum lipid levels were nearly identical in both groups, with mean LDL cholesterol level of 124 mg/dL. "At the end of the study, LDL cholesterol had increased by an adjusted mean of 12 percent to 135 mg/dL in the placebo group and decreased by an adjusted mean of 40 percent to 72 mg/dL in the atorvastatin group," the authors report.
No serious adverse event occurred with a frequency of more than 1 percent in either group. "Abnormal liver transaminases (greater than three times upper limit of normal) were more common in the atorvastatin group than in the placebo group (2.5 percent vs. 0.6 percent)," the authors write.
"In conclusion, the results of this trial indicate that treatment with 80 mg/per day of atorvastatin, initiated during the acute phase of unstable angina or non-Q-wave acute MI, reduces the risk of early, recurrent ischemic events, primarily recurrent symptomatic ischemia requiring hospitalization," the authors report.
Editorial: Study Results Encourage Lipid Treatment During Hospitalization for Patients With Certain Coronary Events
In an accompanying editorial, Frank M. Sacks, M.D., of the Harvard School of Public Health, Brigham and Women's Hospital and Harvard Medical School, Boston, writes that despite some limitations, results from the MIRACL trial are optimistic, encouraging lipid treatment of patients during hospitalization for acute coronary syndrome.
"The types of patients studied in MIRACL, those with acute coronary syndromes, comprise a sizable proportion of all coronary heart disease admissions, and are at high risk of additional events. If indeed recurrent unstable angina is reduced, then eventually, there should be fewer more serious events and less need for revascularization," he writes.
"Since no serious adverse effects of early treatment manifested, the positive results of MIRACL should be given the benefit of the doubt at this point," he continues. "It also is reasonable to include other types of patients with coronary heart disease not studied in this trial, such as those with Q-wave MI or those who undergo revascularization procedures, even though, as the authors surmised when they designed their trial, such patients are less likely to have early events that would be ameliorated by atorvastatin. Eventually, these patients most likely will benefit from statin therapy, as shown by previous trials."
"Given the potential short-term benefit, the definite longer-term benefit, and the apparent absence of harm, clinicians should be urged to include lipid therapy as an integral part of the treatment plan for patients before they are discharged from the hospital following an acute coronary event," he concludes.