Why Statins?
Polly Rimtepathip
Pharm.D. Candidate
October 28, 2011
Preceptor: Dr. Rahimi, Ali R.
Background
• Coronary heart disease (CHD) is the leading
cause of death in the US, causing one in every six
deaths in the US.
• However, the death rates for cardiovascular
disease (CVD) and CHD have decreased
substantially from 1996-2006 by about 30%.
• Studies have suggested that the decrease in
CHD-related mortality rates is associated with
the reduction in modifiable risk factors and
improvements in evidence-based therapies.
Background
• An important factor contributing to this trend is
the lipid-lowering therapies, especially statins.
• The current National Cholesterol Education
Program Adult Treatment Panel III (ATP III)
guidelines recommend the use of statins for
primary prevention based on a patient’s
cardiovascular risk profile and low-density
lipoprotein cholesterol (LDL-C) level.
Statins
• Statins, also known as HMG-CoA reductase
inhibitors, are lipid-lowering drugs that works by
inhibiting the enzyme HMG-CoA reductase, a
rate-limiting step in cholesterol synthesis in the
liver.
• Therefore, the effects of statins are inhibition of
cholesterol synthesis and increase in LDL uptake.
• In addition, statins may also help reabsorb
cholesterol that has built up on the artery walls,
preventing further blockage in the blood vessels.
Brugts JJ, Yetgin T, Hoeks SE, et al.
BMJ 2009;338:b2376
Funding: None
Background
• The use of statins in patients without established
cardiovascular disease or the use of statins as a
primary prevention has an important public
health implications.
• The use of statins as a primary prevention is still
ambiguous because of inconsistent findings in
research.
Purpose/Design
• Meta-analysis of randomized trials that focused
on primary prevention to determine whether
statins reduce all cause mortality and the
incidence of major coronary and cerebrovascular
events in people without established
cardiovascular disease but with cardiovascular
risk factors
Methods
• Databases: Cochrane Central Register of Controlled
Trials, Medline, Embase, DARE, and the ACP
Journal
• Inclusion Criteria:
▫ randomized trials of statins versus controls (placebo,
active control, or usual care)
▫ Had a mean follow-up of at least a year
▫ Reported on mortality or cardiovascular disease events
as primary outcomes
▫ Included at least 80% of people without established
cardiovascular disease or reported data separately on a
sole primary prevention group with a specific numbers
of patients and events in that group reported
Methods
• 1230 studies was searched and 10 fulfilled the
inclusion criteria.
• In total, 70,388 participants were randomized.
35,138 were allocated to statin therapy and
35,250 to control.
• The mean age was 63 years, and the mean
follow-up was 4.1 years.
• The mean baseline LDL was 3.63 mmol/L.
Methods
• The Jadad scale was used to score study quality,
and the study quality was four or more for all
included randomized clinical trials.
• For each trial, the summary odds ratios and 95%
confidence intervals for the clinical outcomes
were calculated.
Outcomes
• Primary end point was all cause mortality.
• Secondary end points were the composite of
major coronary events, including death from
CHD and non-fatal myocardial infarction (MI),
and the composite of major cerebrovascular
events, defined as fatal and non-fatal stroke.
• Death from CHD, non-fatal MI,
revascularizations and cancer were also
assessed.
Results
• The mean reduction in levels of total cholesterol
was 17.1%, low density lipoprotein cholesterol
was 25.6%, and triglyceride was 9.3%. High
density lipoprotein cholesterol increased by a
mean 3.3%.
• 5.7% of participants died in the control group
compared with 5.1% in the statin group;
therefore, statin therapy was associated with a
12% risk reduction in all cause mortality
compared with the control.
Results
• 5.4% of participants in the control group had a
major coronary event compared with 4.1% in the
statin group, a 30% risk reduction.
• Overall, 2.3% of participants in the control
group had a major CV event compared with 1.9%
in the statin group, a 19% risk reduction.
• The association between statin therapy and risk
of cancer was not significant.
Discussion
• Statin therapy was associated with a significant
risk reduction in all cause mortality of 12%, in
major coronary events of 30%, and in major
cerebrovascular events of 19%.
• Statin use was not associated with an increased
risk of cancer.
• Side effects such as increase in creatinine kinase
levels and myopathy have been reported
relatively frequently, but rhabdomyolysis and
hepatotoxicity are rare.
Limitations
• 3 trials in the analyses had a small proportion of
patients with clinical CVD.
• The dose and type of statin differed between
included trials.
• The included trials represented participants with
a clinically heterogenous level of risk, although
statistical heterogeneity was low.
Conclusion
• In patients without established cardiovascular
disease but with cardiovascular risk factors,
statin use was associated with significantly
improved survival and large reductions in the
risk of major cardiovascular events.
Mills EJ, Wu P, Chong G, et al.
Q J Med 2011; 104:109-124
Funding: None
Background
• Statins have been extensively studied in a large
variety of patient populations including both
primary and secondary prevention of
cardiovascular disease (CVD).
• It is widely used because of its effectiveness and
relatively inexpensive costs now that three of
them are available in generic form (lovastatin,
simvastatin and pravastatin).
• 10mg simvastatin is currently available OTC in
the UK.
Purpose
• Large and up-to-date systematic reviews with
meta-analyses can help to provide clinicians
with the most reliable and precise estimates of
treatment effects and rare adverse events.
• The study assembled randomized controlled
trials (RCT) to date in order to quantify the
effects of statin therapy on a wide range of
clinical outcomes and populations
Methods
• Inclusion Criteria:
▫ RCT of atorvastatin, fluvastatin, lovastatin,
pitavastatin, pravastatin, rosuvastatin, and
simvastatin for CVD event prevention among both
primary and secondary prevention populations
▫ Studies had to compare a statin to placebo,
standard therapy, or no-treatment
▫ Studies had to report on important cardiovascular
outcomes: All-cause mortality, CVD mortality,
fatal myocardial infarction (MI), non-fatal MI, and
major CV events (stroke, revascularization).
Methods
• Exclusion Criteria:
▫ RCT of cerivastatin (removed from the market)
▫ Studies that only reported on surrogate outcomes
such as LDL and HDL
▫ Follow-up studies where randomization had been
subverted
▫ Head-head statin evaluations
Methods
• Search strategy
▫ 12 databases (from inception to August 2010):
MEDLINE, EMBASE, Cochrane CENTRAL,
AMED, Web of Science, etc.
▫ Original authors were contacted for clarifications
when needed.
▫ Two investigators worked independently, in
duplicate, scanned all the abstracts and collected
information.
Methods
• Relative Risk (RR) and 95% confidence intervals
were calculated according to the number of events
reported in the original studies or sub-studies
intent-to-treat analyses.
• For adverse events, Peto’s Odds Ratio (OR) was used
to calculate event rates
• Co-variates (absolute LDL change, proportion of
men in the studies, had a history of coronary heart
disease (CHD), had baseline diabetes, were
hypertensive or current studies) were examined for
impact by a multivariable meta-regression analysis.
Outcomes
• Primary outcome is CVD mortality.
Results
• 76 RCTs were included in the study.
• Data were available on 170,255 participants with
the average age of 59.6, ranging from 38-75.
• Trials used four distinct controls: placebo (52
RCTs), usual care (18 RCTs), no treatment (4
RCTs) and conventional therapy (2 RCTs).
• Trials follows patients for an average of 2.7
years, ranged from 0.5-6.1 years.
• Mean pre-treatment LDL cholesterol was 180
mg/dL, ranged from 95-195 mg/dL.
Results
• In all trials combined, there was a 8.1% death among
patients receiving statin therapy and 9.5% deaths
among patients with control intervention.
▫ 10% reduction in all-cause mortality
• Each 10% change in absolute LDL levels was
associated with a 1.1% risk reduction.
• The large risk reduction was mainly attributed to the
20% risk reduction in CVD deaths (4.1% vs. 5.1%)
• A consistent reduction in fatal MI with an 18% risk
reduction was also noted
Results
• Reduction of deaths from stroke and non-CVD
causes were found statistically insignificant.
• A highly significant effect of statins on
revascularization status was also noted (6.2% vs.
8.1%).
• Low incidence of hemorrhagic strokes was found
in the treatment of statins.
• The analysis did not find a significant difference
between any statins.
Results
• The incidence of cancer was not different
between the statin and the control groups.
• No significant difference was found for
rhabdomyolysis between groups.
• A significantly increased rate of diabetes and
elevated AST were found.
Discussion
• The meta-analysis demonstrated consistent
benefits from LDL-lowering effects with statin
therapy: reduces major CVD events and allcause mortality.
• Only trials evaluating statins with inert controls
were included because previous analysis of
head-to-head trials have demonstrated that
these trials evaluated dosing rather than the
effectiveness of individual statins.
Discussion
• There was an evidence of increased diabetes
incidence with statin therapy; however, this
seems to be poorly monitored in clinical trials.
• The authors believe that, based on available
evidence, generic of statins exert similar
therapeutic effects to brand-label statins across
populations.
• Meta-analyses are limited in assessing
continuous outcome changes because they do
not have the individual level data.
Conclusion
• Statins play an important role in reducing
clinically relevant cardiovascular outcomes
across broad populations, most likely by
reducing LDL-C levels.
• Current guidelines aim to establish target LDL-C
reductions to improve a patients long-term
reduction in clinical events.
Crouse III JR, Raichlen JS, Riley WA, et al.
JAMA 2007;297:1344-1353.
Funding: AstraZeneca
Purpose
• The METEOR study was designed to investigate
the effect of a 40-mg dose of rosuvastatin on
CIMT over 2 years in middle-aged individuals
with low Framingham risk scores but with
subclinical atherosclerosis.
Methods
• Study design
▫ 2-year, double-blind, placebo-controlled trial
comparing a 40mg dose of rosuvastatin
▫ Sample: middle-aged asymptomatic individuals with
moderately elevated cholesterol and low risk of CVD
according to ATP III guidelines.
• All participants were provided counseling regarding
therapeutic lifestyle changes.
• Participants had evidence of thickening of the walls
of the extracranial carotid arteries as measured by
B-mode ultrasound.
Methods
• Inclusion criteria (low-risk but with subclinical
atherosclerosis):
▫ Men age 45-70, Women age 55-70
▫ LDL-C level of 120 - < 190mg/dL for those with
only age as a coronary heart disease risk factor
▫ LDL-C level of 120 - < 160mg/dL for individuals
with 2 or more coronary heart disease risk factors
and a 10-year risk of < 10%
▫ HDL-C level of ≤ 60mg/dL
▫ Triglycerides < 500mg/dL
▫ Maximum CIMT measurements of 1.2 – 3.5mm
from 2 ultrasound examinations
Methods
• Exclusions:
▫ Use of lipid-lowering therapies in previous 12
months
▫ Clinical evidence of coronary artery disease or
other peripheral atherosclerotic disease
▫ Prior revascularization procedures
▫ 10-year coronary heart disease risk of ≥ 10%
▫ Diabetes Mellitus, uncontrolled hypertension or
familial hypercholesterolemia, or Scr > 2mg/dL
Methods
• Carotid ultrasound examinations were
performed twice before randomization and once
each at 6, 12, and 18 months after
randomization, and then twice at the end of 24
months of study treatment.
• Adverse events were reported every 3 months at
clinic visits or at interim periods when notified.
• Investigators checked for adherence but were
unaware of treatment allocations.
Outcomes
• Primary outcome was annualized rate of change in
maximum CIMT based on all scans performed
during the 2-year study from each of the 12 carotid
artery sites (near and far walls of the right and left
common carotid artery, carotid bulb, and internal
carotid artery).
• Secondary CIMT end points were annualized rate of
change in maximum CIMT derived from the near
and far walls of : the right and left common carotid
artery, the right and left carotid bulb, the right and
left internal carotid artery; and annualized rate of
change in mean CIMT for the near and far walls of
the right and left common carotid artery.
Statistics
• The study assumed statistically significant
regression at 2 years, assuming a 2-sided level of
statistical significant of 0.05, 80% power, and a
mean (SD) decrease in CIMT of -0.0008mm/yr.
• 415 individuals were required for the
rosuvastatin group.
• Sample size of 167 in the placebo group was
calculated to provide > 90% power for the
between-group comparison.
• 30% withdrawal rate was predicted.
Results
• 5751 individuals were screened and 984 were
randomized.
• Rosuvastatin treatment was associated with a
49% reduction in LDL-C, a 34% reduction in
total cholesterol, an 8% increase in HDL-C, and
a 16% reduction in level of triglycerides
• Compared with placebo, rosuvastatin
significantly slowed progression of the
maximum CIMT for the 12 carotid sites (-0.0014
vs. +0.0131mm/yr)
Results
• In the placebo, there was a significant progression
for the primary and secondary CIMT end points
• Significant progression was not observed in the
rosuvastatin group for either the primary or
secondary CIMT end points.
• The frequency of adverse events was similar
between the treatment groups.
▫ Myalgia was the most common event (12.7% vs. 12.1%)
• There was 1 death during the study but was not
considered related to the treatment.
Results
• There were no cases of hepatitis,
rhabdomyolysis, or renal failure.
• The frequency of proteinuria was low.
• Overall, the frequency of adverse renal effects
was low and similar in both groups.
Discussion
• 40mg of rosuvastatin significantly slowed progression of
atherosclerosis both overall and for individual carotid
segments as assessed by CIMT measurements.
• Rosuvastatin lowered LDL-C by 48.8% and raised HDLC by 8.0% compared to baseline.
• 40mg dose is not a starting dose but was chosen to
provide the maximum efficacy expected to slow or delay
progression of atherosclerosis
• The METEOR trial expands findings to asymptomatic
patients who do not have meet the requirement for statin
use but have evidence of subclinical carotid
atherosclerosis
Discussion
• Low-risk individuals with only mild
atherosclerosis were chosen to justify the use of
a placebo group.
• The results show that rosuvastatin can have an
effect on small increases of CIMT associated
with early abnormalities of arterial structure.
• 40mg dose was well tolerated and showed a
similar safety profile to that of placebo.
Conclusion
• In middle-aged adults with Framingham risk
scores < 10% and evidence of subclinical
atherosclerosis, rosuvastatin treatment results in
statistically significant reductions in the rate of
progression of maximum CIMT during a 2-year
period compared with placebo.
• Larger, longer-duration randomized trials
focused on clinical events are needed to
determine the practice implications of these
findings.
Comments
• Even though the study specifically looked at
rosuvastatin, other statins in the class should
possess the same effect but may be to a different
extent.
• The study should compare different doses of
rosuvastatin to help determine whether the
maximum dose or aggressive therapy of statin
will be needed to reduce the CIMT.
Seminarian’s Conclusion
• Statins are effective agents for primary and
secondary prevention of cardiovascular events.
• In addition, statins also show reduction in allcause mortality.
• Statins are relatively safe to use with low
incidence of major adverse events.