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Higher Dose Regimen May Increase Risk for Muscle Problems
Sept. 1,
2004 — Statins initiated early after a patient experiences an acute coronary
syndrome (ACS) event at dosages above the typical starting dose may help reduce
subsequent cardiovascular events, but the high dose regimen used may increase
the risk for muscle-related complications, according to the results from the
Phase Z portion of the A to Z Trial recently released on the Journal of the
American Medical Association (JAMA) website.
According to background
information in the article, "Long-term therapy with statin drugs has been shown
to reduce the risk for death, myocardial infarction (MI) [heart attack], and
stroke among patients with established coronary artery disease, even when
low-density lipoproteins (LDL) cholesterol levels are not elevated." The authors
write that previous clinical trials evaluating statins enrolled patients who
were stable for several months following their coronary events. "Phase Z of the
A to Z trial was designed to evaluate a strategy of early initiation of
intensive treatment with simvastatin in ACS patients compared with a delayed,
less intensive strategy."
James A. de Lemos, M.D., from University of
Texas Southwestern Medical Center, Dallas, and colleagues from the A to Z trial,
enrolled 4, 497 patients with ACS between December 29, 1999 and January 6, 2003
at 322 centers in 41 countries. The average time from symptom onset to
randomization in phase Z was 3.7 days. The patients were randomized to either an
early intensive statin treatment strategy (40mg/per day of simvastatin for 30
days and then 80 mg/d of simvastatin thereafter) or to a less aggressive
strategy (placebo for four months and then 20 mg/d of simvastatin thereafter).
There were 2,265 patients in the early intensive treatment group and 2,232 in
the less aggressive treatment group. Clinical and laboratory assessments
(including, lipid levels, high sensitivity C-reactive protein serum chemistries,
and liver function tests) were performed prior to the study drug initiation and
at months one, four, eight and then every four months until the trial
completion. Patients were followed-up for at least six months and up to two
years.
"In the placebo plus simvastatin group, median LDL cholesterol
levels increased by 11 percent during the 4-month placebo period from 111mg/dL
to 124 mg/dL and then decreased to 77 mg/dL at month 8 after the initiation of
20 mg of simvastatin (31 percent change from baseline)," the researchers report.
"In the simvastatin only group, the median LDL cholesterol level decreased by 39
percent to 68 mg/dL over the first month during treatment with 40 mg/d of
simvastatin and then decreased an additional 6 percent to 62 mg/dL at month 4
following the increase to the 80 mg/d of simvastatin." The researchers continue,
"the primary end point of cardiovascular death, MI, readmission for ACS, and
stroke occurred in 343 patients (16.7 percent) in the placebo plus simvastatin
group compared with 309 (14.4 percent) in the simvastatin only group." The
researchers also note a high level of participants discontinued use of the study
drugs for various reasons, including a low number of muscle-related adverse
events.
"The traditional approach to lipid management following ACS has
been to begin with dietary management and then to initiate a statin agent at a
low dose and increase the dose stepwise to achieve target LDL cholesterol
levels. The findings from the A to Z trial, as well as from MIRACL and PROVE IT
[previous intensive statin therapy trials], support a strategy of aggressive LDL
cholesterol lowering following ACS to prevent death and major cardiovascular
events. Statins should be initiated early after ACS, with consideration of
dosages well above the typical starting dose, and they should be down-titrated
[decreased] or discontinued if important adverse effects, such as myopathy or
significant liver abnormalities develop."
Editor's Note: The trial was
funded by Merck & Company, Whitehouse Station, N.J. Please see JAMA study
for authors' financial disclosures.
Editorial: High Dose Statins in
Acute Coronary Syndromes
In an accompanying editorial, Steven E.
Nissen, M.D., from the Cleveland Clinic Foundation, writes, "Phase Z of the
Aggrastat to (A to Z) Zocor Trial published in this issue of JAMA, is to date
the largest trial testing the effects of aggressive statin therapy in ACS. ...
The high dose regimen failed to show a statistically significant benefit for
reducing the primary composite endpoint of cardiovascular death, myocardial
infarction, readmission for ACS, or stroke. In addition, the high-dose
simvastatin regimen was associated with an unusually high rate of
myopathy."
"It is important to reassure practicing physicians and
patients that the unfavorable risk-benefit relationship observed in the A to Z
trial does not in any way diminish the value of intensive statin treatment in
secondary prevention, including ACS patients. here was a trend toward reduced
events in the A to Z trial, a finding that supports the lower is better concept.
The increased myopathy rate applies only to a specific dose of a single agent
and should not tarnish this remarkable class of drugs. It must also be
emphasized that simvastatin in doses up to 40 mg/d has shown excellent safety
and efficacy in a series of clinical trials. or now, though, the 80 mg/d dose of
simvastatin should be used with caution, particularly because other effective
agents are available. Finally, in an era when criticism of selective reporting
of positive trial results is common, the A to Z investigators are to be
commended for their prompt and thorough reporting of a critically important
major trial that did not meet its original objectives."
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