||MIRACL And PRINCESS Highlighted At The 73rd American Heart Association Meeting (AHA)
Pfizer Inc reported yesterday that a
new clinical study showed patients treated with LIPITOR(R) (atorvastatin
calcium) following an acute coronary syndrome (ACS) experienced fewer
subsequent events than those treated with placebo. Results of the Myocardial
Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study were
presented yesterday at the 73rd Scientific Sessions of the American Heart
The study involved 3,086 patients who received either atorvastatin
(80 mg daily) or placebo for 16 weeks, both with dietary education and
counseling, initiated between 24 to 96 hours of an ACS, also known as mild
heart attack or severe cardiac chest pain. Patients ordinarily experience a
high rate of death and secondary ischemic events within this early period.
Study participants treated with atorvastatin experienced a significant
reduction (16%; p=0.048) in the risk of the primary combined endpoint of
death, non-fatal acute MI (heart attack), cardiac arrest with resuscitation,
or recurrent symptomatic myocardial ischemia requiring emergency
rehospitalization. The reduction in the combined endpoint was primarily due
to a favorable effect of atorvastatin on recurrent symptomatic myocardial
ischemia, or oxygen deprivation to the heart resulting in chest tightness,
which was reduced by 26% (p=0.02). In addition, the incidence of stroke was
significantly reduced in the atorvastatin group compared with the placebo
Previous trials with other statins have established the benefit of
conventional lipid-lowering therapy in reducing death and non-fatal events in
patients with stable coronary heart disease over periods of years. However,
the previous trials excluded patients who had sustained a recent ACS, a group
that is at a high risk of having a subsequent event. MIRACL is the first
trial to demonstrate that the clinical benefit of aggressive lipid-lowering
therapy can be achieved within the critical months (16 weeks) following an
acute coronary event.
"MIRACL demonstrated that intensive treatment with atorvastatin, begun
immediately after an acute coronary event, produces beneficial effects that
are apparent within several weeks," said Gregory Schwartz, M.D., Ph.D., Chief
of Cardiology, Denver Veterans Affairs Medical Center, and a Principal
Investigator in MIRACL, "providing evidence that the addition of intensive
lipid-lowering therapy to the standard of care may help improve the outcomes
of these patients."
Study participants' LDL-cholesterol levels declined from an average of
123 mg/dL (3.2 mmol/L) at baseline to 72 mg/dL (1.9 mmol/L) during treatment
with atorvastatin. Therefore, treatment lowered LDL-cholesterol to levels
well below the current recommended guideline of 100 mg/dL (2.6 mmol/L).
Current hospital treatment practice in this patient population includes a
host of medications including combinations of aspirin, heparin, nitrates, and
beta blockers, intended to target various aspects of the acute coronary
condition. A hospital survey revealed that many coronary heart disease
patients admitted for events do not receive lipid-lowering medication.
Specifically, only 41% of patients received lipid-lowering medication during
hospitalization and only 39% received it at discharge.
"MIRACL found that high-risk patients benefited from receiving aggressive
treatment with atorvastatin within 24 to 96 hours following an acute coronary
syndrome," said Anders Olsson, M.D., Ph.D., Department of Internal Medicine,
Faculty of Health Sciences, University Hospital, Linkoping, Sweden, and a
MIRACL Principal Investigator. "Not only was high dose atorvastatin effective
in reducing cardiovascular events, but the treatment was safe and generally
Atorvastatin is the subject of a broad clinical program consisting of a
series of novel studies currently underway that attempt to investigate
unanswered questions in the field of lipid lowering. Nearly 400 clinical
trials have been designed for studies with atorvastatin-a large number of
which have already been completed. These clinical studies are exploring the
possible opportunities for new uses of atorvastatin in clinical practice.
Atorvastatin has been shown in clinical studies to produce reductions in
LDL-C of 39% to 60% across the dose range of 10 mg to 80 mg in patients with
elevated cholesterol. Reductions in triglycerides of 19% to 37% were reported
in clinical trials across the same dose range. Trials assessing the effect of
atorvastatin on cardiovascular morbidity and mortality are also underway.
Atorvastatin is indicated as an adjunct to diet to reduce elevated
total-C, LDL-C, Apo B, and TG and to increase HDL-C levels in patients with
primary hypercholesterolemia and mixed dyslipidemia. The recommended starting
dose of atorvastatin is 10 mg once daily. The dosage range is 10 mg to 80 mg
once daily. Atorvastatin is generally well tolerated. Adverse reactions
usually have been mild and transient, with fewer than 2% of patients being
discontinued from clinical trials due to side effects related to atorvastatin.
This rate of discontinuation was comparable to that of placebo. The most
frequent adverse effects of atorvastatin are constipation, flatulence,
dyspepsia, and abdominal pain. It is recommended that liver function tests be
performed prior to and at 12 weeks following both the initiation of therapy
and any elevation of dose, and periodically thereafter. Myopathy should be
considered in any patient with diffuse myalgias, muscle tenderness or
weakness, and/or marked elevation of creatine phosphokinase (CPK).
Yesterday the results of the MIRACL trial demonstrated a positive
effect of the early use of new generation statin therapy. Combined ischemic
events were significantly reduced in the total study population with unstable
angina or non-Q-wave myocardial infarction. While these results provide a
valuable addition to knowledge of the treatment of post-MI patients, they also
raise a number of unanswered questions, including the longer term impact of
aggressive third generation statin therapy on stroke. These points will be
addressed by the PRINCESS trial (Prevention of re-INfarction by early
treatment of CErivaStatin Study).
The total group of patients in MIRACL provided an overall positive result.
However, statistical significance was not reached in either of the individual
sub-groups of unstable angina and non-Q-wave MI patients which both showed
positive trends. This highlights the need for additional research. The
PRINCESS trial will investigate whether the use of cerivastatin immediately
post-MI will prevent a second event across the whole spectrum of post-MI
patients, both non-Q-wave and Q-wave.
Of the two distinct types of myocardial infarction; non-Q-wave acute MIs
are characterized by a smaller infarct and account for approximately 28% of
hospitalizations due to chest pain, these patients have less potential for
in-hospital mortality. Q-wave MIs occur as a result of a moderate to large
infarct and patients are at much greater risk of mortality at the time of the
event, and account for approximately 27% of hospital admissions due to chest
Principal investigator of PRINCESS, Professor Lablanche, Lille Cardiology
Hospital, France, commented, "We welcome the positive result provided by the
MIRACL trial, however there still remain a number of unanswered questions in
the distinct post-MI populations. This heightens the importance for PRINCESS,
we still need more evidence and we believe that the use of cerivastatin within
the PRINCESS trial will provide this evidence."
The results of MIRACL and the treatment rationale of cerivastatin in
PRINCESS have been attributed to a number of factors, primarily powerful and
rapid LDL lowering leading to plaque stabilization, reduction of inflammatory
markers and improvement of endothelial function. Cerivastatin has
demonstrated these effects by rapid LDL-C lowering(i), and improving
endothelial function after only two weeks of treatment.(ii) Cerivastatin
therapy has also shown a positive effect on stabilizing plaques, by thickening
the fibrous cap and reducing the macrophage content.(iii)
The PRINCESS trial will investigate whether the use of cerivastatin
immediately post-MI will prevent a second event across the whole spectrum of
post-MI patients, both non-Q-wave and Q-wave. Endpoints include the reduction
of cardiovascular morbidity and mortality at 3 months and at 2 years, the
effect on inflammation markers, change on lipid parameters and safety
parameters. Treatment will be initiated within 48 hours after an acute MI.
Patients will be randomized to receive either cerivastatin or placebo for
three months to be followed by open-label cerivastatin treatment for a minimum
of two years. PRINCESS is a multinational, multicenter, double-blind,
randomized, placebo-controlled, parallel-group study of cerivastatin 0.4 mg
versus placebo in the early treatment of approximately 3,000 patients with an
acute myocardial infarction. The study will be conducted at 250 centres in
Europe and North America.
Cerivastatin (Baycol/Lipobay(TM)) is a potent new generation statin. A
new study(iv) in mixed dyslipidemia has recently provided impressive data by
treating 95% of patients to NCEP targets for LDL-C and additionally reducing
triglycerides by 32%, illustrating the powerful lipid-lowering efficacy of