Class effects of statins in elderly patients with congestive heart failure: a population-based analysis.
ABSTRACT Long-term treatment with statins reduces mortality in patients with congestive heart failure (CHF). Whether statin agents exert a class effect is unknown.
We analyzed long-term mortality in Canadian patients aged > or = 65 years who were discharged from hospital with a diagnosis of CHF from January 1998 to December 2002. Administrative data from Quebec, Ontario, and British Columbia were merged. We compared patients prescribed with atorvastatin, simvastatin, pravastatin, and lovastatin.
A total of 15,368 patients hospitalized with a diagnosis of CHF fulfilled the inclusion criteria for this study. In this final dataset, 6670 (43.4%) filled a prescription for atorvastatin, 4261 (27.7%) for simvastatin, 3209 (20.9%) for pravastatin, and 1228 (8.0%) for lovastatin. Clinical characteristics and proportion of days covered with a statin prescription were similar across groups. Drug dosages were relatively low, with 82% of patients who received the agent at a dose of < or = 20 mg. Although controlling for time-dependent covariates representing current use and dosage, as well as for age, sex, coronary artery disease, and several other comorbidities, treatment with pravastatin (adjusted hazards ratio [HR] 0.94, 95% CI 0.83-1.07), lovastatin (adjusted HR 1.02, 95% CI 0.88-1.17), or simvastatin (adjusted HR 0.92, 95% CI 0.83-1.01) had a similar effectiveness to prevent mortality compared to atorvastatin (reference in this analysis) in this population with CHF. Time-dependent exposure to a statin was highly protective against mortality.
Statins exert a class effect in patients with CHF, when used at a relatively low dose. The favorable effects appear largely independent of drug dosage.
Article: Response to the letterAmerican Heart Journal 08/2008; 156(2):e9. · 4.56 Impact Factor
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ABSTRACT: This article contains a review of the main developments in the field of geriatric cardiology reported during 2008. The focus is on research concerning the specific characteristics of elderly patients with heart failure, arrhythmias, ischemic heart disease, and aortic valve disease.Revista Espa de Cardiologia 01/2009; 62:53-66. · 3.34 Impact Factor
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ABSTRACT: Statins are widely used in clinical treatment. However, an U.S. Food and Drug Administration issued health alert has raised concerns for the adverse effects of statin-associated confusion and memory loss in the elderly people. It is necessary to clarify the relationship between statin use and risk of incident dementia as well as whether class effects exist. In this population-based retrospective cohort study, total 33,398 patients aged≥60years were selected from a subset of the Taiwan National Health Insurance Research Databases and followed up for tracking the occurrence of any type of dementia from 2000 to 2010. The Cox proportional hazards models were used. Compared to nonusers, statin users had a significantly lower risk of incident dementia (hazard ratio [HR], 0.78; 95% CI, 0.72-0.85, p<0.001). The potency and the cumulative duration of statin utilized were associated with the reducing risk of dementia. After stratifying by gender, the risk of incident dementia was lower in female statin users (HR, 0.76; 95% CI, 0.68-0.85, p<0.001) than in male statin users (HR, 0.86; 95% CI, 0.75-0.98, p=0.024). Higher potency and longer cumulative duration of statin use were required for reducing the risk of incident dementia in male patients than in female patients. Statin use was associated with a significantly lower risk of dementia in the elderly patients in Taiwan. The potency and the cumulative duration of statin utilized played critical roles.International journal of cardiology 03/2014; · 6.18 Impact Factor
Congestive Heart Failure
Class effects of statins in elderly patients with
congestive heart failure: A population-based analysis
Ste ´phane Rinfret, MD, MSc,aHassan Behlouli, PhD,bMark J. Eisenberg, MD, MPH,c,dKarin Humphries, DSc,e
Jack V. Tu, MD, PhD,fand Louise Pilote, MD, MPH, PhDb,gVancouver, British Columbia, Toronto, Ontario, and
Montreal, Quebec, Canada
Background Long-term treatment with statins reduces mortality in patients with congestive heart failure (CHF). Whether
statin agents exert a class effect is unknown.
Methods We analyzed long-term mortality in Canadian patients aged ≥65 years who were discharged from hospital
with a diagnosis of CHF from January 1998 to December 2002. Administrative data from Quebec, Ontario, and British
Columbia were merged. We compared patients prescribed with atorvastatin, simvastatin, pravastatin, and lovastatin.
Results A total of 15368 patients hospitalized with a diagnosis of CHF fulfilled the inclusion criteria for this study. In this
final dataset, 6670 (43.4%) filled a prescription for atorvastatin, 4261 (27.7%) for simvastatin, 3209 (20.9%) for pravastatin,
and 1228 (8.0%) for lovastatin. Clinical characteristics and proportion of days covered with a statin prescription were similar
across groups. Drug dosages were relatively low, with 82% of patients who received the agent at a dose of ≤20 mg. Although
controlling for time-dependent covariates representing current use and dosage, as well as for age, sex, coronary artery
disease, and several other comorbidities, treatment with pravastatin (adjusted hazards ratio [HR] 0.94, 95% CI 0.83-1.07),
lovastatin (adjusted HR 1.02, 95% CI 0.88-1.17), or simvastatin (adjusted HR 0.92, 95% CI 0.83-1.01) had a similar
effectiveness to prevent mortality compared to atorvastatin (reference in this analysis) in this population with CHF. Time-
dependent exposure to a statin was highly protective against mortality.
Conclusions Statins exert a class effect in patients with CHF, when used at a relatively low dose. The favorable effects
appear largely independent of drug dosage. (Am Heart J 2008;155:316-23.)
There has been increasing evidence over the last few
years of the benefits of 3-hydroxy-3-methylglutaryl
coenzyme A reductase inhibitors, or statins, in patients
with congestive heart failure (CHF).1,2Although their
beneficial effects on the primary and secondary preven-
tion of cardiovascular events and mortality are explained
by their power to reduce low-density lipoprotein
cholesterol (LDL-C),3the favorable effects of statinin CHF
are believed to be independent of the power of statin
agents to reduce LDL-C.1Multiple pleiotropic effects of
statins or cholesterol-independent mechanisms have
been described,1,2,4,5including antithrombotic and anti-
proliferative effects in patients with CHF that may lead to
improvement of symptoms and clinical outcomes.2,6
Statin agents differ in multiple characteristics, including
liver and renal metabolism, half-life, effect on other serum
lipid components, bioavailability, and potency to reduce
LDL-C.7,8No randomized controlled trial (RCT) to date
has compared statin agents in a population with CHF.
Drugs in the same class are generally thought to be
therapeutically equivalent because of similar mechanisms
of action, which is also called the class effect. In patients
with CHF, the relative importance of the potency of the
drug to reduce LDL-C compared to those pleiotropic
effects, which might differ between agents, is unknown.
These differences could potentially influence the extent
to which one given statin drug is beneficial in patients
with CHF. We conducted a population-based study to
examine the relative effectiveness of different statins in
patients with CHF. The objective of the study was to
evaluate whether statins exert a class effect on long-term
l'Université de Montréal, University of Montreal, Montreal, Quebec, Canada,bDivision
of Clinical Epidemiology, McGill University Health Center, McGill University, Montreal,
Canada, Divisions of
Medicine, Jewish General Hospital, McGill University, Montreal, Canada,eDivision of
Cardiology, University of British Columbia and Centre for Health Evaluation and
Outcome Science, Vancouver, British Columbia,
Sciences, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Canada,
Supported by grants from the Canadian Institutes of Health Research (#MOP53181,
Submitted April 20, 2007; accepted September 13, 2007.
Reprint requests: Louise Pilote, MD, MPH, PhD, Division of Internal Medicine and Clinical
Epidemiology, Montreal General Hospital, 1650 Cedar Avenue, Montreal, Quebec,
Canada H3G 1A4.
0002-8703/$ - see front matter
© 2008, Mosby, Inc. All rights reserved.
aDivision of Cardiology, Department of Medicine, Centre Hospitalier de
dClinical Epidemiology, Department of
fInstitute for Clinical Evaluative
gDivision of Internal Medicine, McGill University Health Center, McGill University,
survival in elderly patients who were hospitalized with a
primary diagnosis of CHF in 3 Canadian provinces.
Data on the treatment and clinical outcomes of all patients
aged ≥65 years who were admitted for CHF in Quebec, Ontario,
and British Columbia (BC) (the 3 most populous provinces in
Canada) between January 1, 1998, and December 31, 2002,
were obtained from government administrative databases in
each province and merged for this analysis.
The hospital discharge summary databases used to identify
patients with CHF in Quebec, Ontario, and BC are respectively
called the following: Maintenance et Exploitation des Données
pour l'Étude de la Clientèle Hospitalière (Med-Echo), Canadian
Institute for Health Information (CIHI), and the BC Patient
Hospitalization Data Base. Using encrypted provincial health
insurance numbers, these databases were linked to the
provincial physician and drug claims databases, which contain
information on Quebec patients' in- and out-patient diagnostic
and therapeutic procedures, as well as drug prescriptions (Régie
de l'Assurance Maladie du Québec [RAMQ] in Quebec, Ontario
Drug Benefit Plan database in Ontario, and PharmaCare [N65
years] in BC).
Complete survival data were obtained for Quebec patients
by using data from both the Med-Echo and RAMQ databases.
The mortality variable is only recorded in the Med-Echo
database if a patient dies in the hospital, whereas the RAMQ
mortality variable is based on death certification that occurs
out of hospital. In Ontario, the Ontario Registered Persons
Database (RPDB) and CIHI database were used to obtain
mortality data, as it contains information on the vital status of
all residents covered under the health insurance plan. In BC,
linkage with Deaths Registry of the BC Vital Statistics Agency
provided data on mortality. Survival status was available up to
March 2004 for Quebec, December 2003 for Ontario, and
December 2002 for BC patients. The accuracy of survival data
after myocardial infarction (MI) has been confirmed for
patients with acute MI in Ontario and Québec.9,10Therefore,
we considered likely that similar estimates can be extrapolated
to patients with CHF.
For this analysis, we included all elderly patients, aged
≥65 years, who were admitted with presumed new onset
CHF. Given that the objective of the analysis was to assess
the class effect of statin agents in patients with CHF, and
given that there would have been major issues of selection
bias going into the comparison of users and nonusers as
well as issues of survival bias, we excluded patients not
exposed to any statin during follow-up. These patients were
admitted to hospital with a most responsible discharge
diagnosis of CHF (International Classification of Diseases–9th
revision, code 428.x).
Several exclusion criteria were applied to increase the
specificity of the new onset of CHF diagnosis, as follows: (1)
previous admission for CHF within the past 3 years (to
ensure that patients were as homogeneous as possible); (2)
admitted to a long-term care hospital; (3) residence outside
province; (4) invalid health care number; (5) CHF as a
complication; (6) transferred from another acute care hospital
(to avoid counting patients twice); (7) discharged to a long-
term care institution, a rehabilitation center, or moved out
of province (as information on out-patient medication use is
Outcome of interest, exposure variable, and covariates
The outcome of interest was all-cause mortality. Exposure
was the type of statin agent the patient filled after discharge.
Follow-up for each patient was from the time of the first
statin prescription (time 0) to death or the end of the study
period. On the basis of the first statin prescribed, 4 statin
groups were formed (atorvastatin, pravastatin, simvastatin,
lovastatin). Use of fluvastatin was too infrequent in this
population and was not included. Rosuvastatin was not
available at the time of administrative data collection. For
statin usage patterns, we recorded the number of patients
who switched or stopped the initially prescribed statin
treatment. Stopping treatment was defined as discontinuation
of the initial statin or the absence of a prescription for the
initial statin or more days after the end of the previous
prescription. To indicate patient adherence on the treatment,
we calculated the ratio of the total number of days supplied
for the initial statin divided by the total number of follow-up
days (proportion of days covered). To assess the impact of
statin dose, we adjusted for the initial daily dose of each
statin by creating a binary variable “at or above most
frequently used dose.” We determined this dose by referring
to the dose most frequently tested in the large-scale RCTs of
each statin for long-term cardiovascular prevention, which
was evaluated to be 10 mg for atorvastatin and 40 mg for the
other statins.11We also considered the relative strength of
each statin agents to reduce LDL cholesterol in sensitivity
analyses using Quebec data. Atorvastatin 10 mg, lovastatin
40 mg, and simvastatin 40 mg can all reduce LDL-C by 37%.12
Atorvastatin 20 mg, lovastatin 80 mg, and simvastatin 80 mg
can further reduce LDL-C by 42% to 45%. Pravastatin is
weaker and 80 mg will be required to reduce LDL by 33%,
similar to atorvastatin 10 mg.12Therefore, for this sensitivity
analysis, we considered equivalent dosages: 10 mg of
atorvastatin, 40 mg of simvastatin, 40 mg of lovastatin, and
80 mg of pravastatin.
Patient demographic characteristics and comorbidities at
discharge were determined from the hospital discharge
databases, including coexisting cardiovascular and lung dis-
eases, chronic kidney, or liver conditions (including renal and
liver failure), as well as diabetes mellitus, dementia, and
malignant disease. Concurrent use of major cardiac medications
was also recorded, like β-blockers, angiotensin-converting
enzyme inhibitors, calcium-channel blockers, digoxin, diuretics,
warfarin, and clopidogrel. Use of acetylsalicylic acid was not
available from BC and Ontario data (because of availability over
the counter) and thus ignored. Use of statins during the year
before the index hospitalization was included as a baseline
covariate. Information was obtained regarding the inhospital
procedure performed (catheterization, percutaneous coronary
intervention [PCI], or coronary artery bypass graft [CABG]),
length of hospital stay, time to first statin prescription, year of
the CHF hospitalization, specialty of the treating physician
(cardiologist, internist, general practitioner, or other specialist),
Rinfret et al 317
American Heart Journal
Volume 155, Number 2
type of hospital (teaching or not), hospital volume, hospital
location (urban or rural).
Descriptive statistics were used to compare baseline patient
characteristics between statin groups. Kaplan-Meier curves
were generated for each separate province and all-cause
mortality by the type of statin used compared using the log-rank
test. After pooling data from the 3 provinces, a multivariate Cox
proportional hazards model was used to assess the associations
between type of statin used and survival. The proportional
hazard assumption was assessed by a plot of log (−log(survival
function)). Adjusted hazard ratios (HRs) for each statin
compared with the reference statin (atorvastatin, the most
frequently used) and 95% CIs were reported, with adjustment
made for baseline characteristics and potential confounders. In
addition, we also used 2 binary time-dependent exposure
variables, one to identify periods of exposure and the other to
account for dosage. The variable for exposure indicated current
exposure by assigning a value of 1 to all periods during which
the patient had a filled prescription and 0 to other periods. The
variable for dose assigned the value of 1 to those periods when
the current dosage was at or above the most frequently used
dosage in randomized trials and the value of 0 to periods when
dosage was below that. In survival analyses, patients were
censored at the time of switching or stopping the initial statin.
We used time-dependent modeling, with a nonexposed period
considered default. Therefore, if a patient was not exposed for a
given period, a 0 was assigned to the exposure variable.
However, if the patient failed to fill the prescription for 7 days or
longer, the patient was censored. Forced-entry regression was
used to include all these variables in all multivariable models to
adjust the between-drug comparisons for potential confounders.
We performed sensitivity analyses on the Quebec sub-dataset.
Those analyses were performed (a) to account for using a
different method for the effect of dosing and also (b) to
subsequently restrict the analysis to patients without overt
evidence of coronary heart disease. In the first analysis, we
modeled dosage using the relative “atorvastatin-equivalent”
dosage. To do that, the lovastatin dose was divided by 4, the
simvastatin dose by 4, and the pravastatin dose by 8. This
“atorvastatin-equivalent” dosage, in milligrams, was used as a
Table I. Demographic and clinical characteristics of patients with CHF prescribed statins
Characteristic LovastatinPravastatin Simvastatin Atorvastatin
No. of patients (% of total)
Median follow-up (y)
Median age (y)
Baseline comorbidities (%)
Other prescriptions at discharge (%)
Specialty of treating physician (%)
Hospital characteristics (%)
Hospitalization for CHF volume
17 18 1920
ARB, Angiotensin receptor blocker; COPD, chronic obstructive pulmonary disease; GP, general practitioner.
318 Rinfret et al
American Heart Journal
continuous variable in the Cox model. Finally, to try to mitigate
the effect of coronary artery disease and confounding by
indication, we excluded in one final sensitivity analysis all
patients with previous MI, CABG, and PCI, to verify the stability
of our findings, again using similar time-dependent Cox models.
The sensitivity analyses were only performed in the Quebec
cohort because of data accessibility. All statistical analyses were
performed using the SAS version 8.2 statistical software (SAS
Institute Inc, Cary, NC).
The initial merged dataset was composed of 206423
patients hospitalized with newly diagnosed CHF. The
final sample of 15368 patients was selected after the
exclusion of 84396 patients with previous CHF admis-
sions, 19376 patients aged b65 or N105 years, 13758
who died in hospital, 4459 who were discharged to
long-term care hospitals, 3930 who transferred from
another hospital, 895 who were not admitted to an
acute care hospital, 896 who presented CHF as a
complication, 874 nonprovince residents, 717 patients
with invalid health card number, 503 duplicates, 53591
without any statin prescription during follow-up, and
7660 patients who filled their statin prescription
N90 days after discharge. In this final dataset, 6670
(43.4%) filled a prescription for atorvastatin, 4261
(27.7%) for simvastatin, 3209 (20.9%) for pravastatin,
and 1228 (8.0%) for lovastatin.
Patient, physician, and hospital characteristics
The study sample was composed of 15368 elderly
individuals, with a median age of 75 years and a median
follow-up of 2.1 years (Table I). Patients who filled a
prescription for one of the 4 study statin drugs shared
similar demographic and clinical characteristics, except
that patients prescribed atorvastatin were more likely to
be diabetics (42% vs 35%) and to be receiving β-
blockers (45% vs 40%) than the rest of the study
population treated with another statin. Patients receiv-
ing lovastatin were less likely to be male (50% vs 55%)
or to have been treated by a cardiologist (23% vs 31%)
than the rest of the study population treated with
another statin. Evidence of coronary artery disease
(prior MI, prior PCI, or CABG) was balanced between
groups. We did not observe a pattern of preferential
prescribing of a given statin to sicker or healthier
patients. Patient characteristics were similar across the
3 provinces (data not shown).
Prescription characteristics are presented in Table II.
Most patients were already treated with a statin when
Table II. Prescription characteristics for patients prescribed a statin at discharge
No. of patients (% of total)
Use of statin before index hospitalization (%)
Time delay to fill the statin prescription after discharge (median and IQR, in days)
Duration of statin use in the first year (median in days)
Adherence of filled prescriptions (%)
Mean adherence (PDC)⁎
High adherence (%)y
Statin switch (%)
During first year
Mean dosages (mg)
Median dosages (mg) (IQR)
Dose distribution (%)
Dose changed during follow-up (%)
Statin at-or-above most frequently used dosage§
IQR, Interquartile range (25th, 75th percentiles).
⁎Adherence is defined as the proportion of days for which a patient was covered (PDC or proportion of days covered) by prescriptions over the year after discharge or until death if
the patient died in the year after discharge.
yAdherence of 80% of days covered (0,80) or higher.
zPersistence is defined as being on any statin drug 1 year after initial drug prescription filling.
§10 mg for atorvastatin and 40 mg for the other statins, in most RCT.
Rinfret et al 319
American Heart Journal
Volume 155, Number 2
hospitalized for their first episode of CHF. Patients
discharged on atorvastatin were least likely to have
been on a statin before the index hospitalization.
Compliance was similar across statin groups. Patients
in our sample had 83% of days covered with their
statin drug during follow-up (until death or switch),
and 74% had a high adherence (N80% of days
covered) to their drug regimen. Persistence was also
high and similar across groups, with 83% of patients
filling a statin prescription within 60 days of the
1-year follow-up time point. Patients prescribed
atorvastatin were the least likely to be switched to
another statin during the follow-up period. Lovastatin
and pravastatin users were more likely to switch
Average dosage was relatively low in all groups, with
≤82% of patients receiving the agent at a dose of ≤20 mg.
Very few patients (≤1%) were prescribed the highest
dose (80 mg) of each statin. The proportion of patients
who changed doses during follow-up was similar
Survival after hospitalization for CHF
Figure 1 shows the cumulative probability of survival in
the different statin groups with unadjusted Kaplan-Meier
curves, by province. Mortality rates were similar across all
4 statin groups (all log-rank P values N .05).
We used a multivariate Cox model to adjust for the
baseline characteristics listed in Table I and account
for the relative dosage as “at or above most frequently
used dosage” and model statin agents as time-
dependent exposure variables. In this analysis, treat-
ment with pravastatin (adjusted HR 0.94, 95% CI 0.83-
1.07), lovastatin (adjusted HR 1.02, 95% CI 0.88-1.17),
or simvastatin (adjusted HR 0.92, 95% CI 0.83-1.01)
had a similar effectiveness to prevent mortality
compared to atorvastatin (reference in this analysis) in
this population with CHF (Table III). Time-dependent
exposure to a statin was highly protective against
mortality. However, a drug dosage N10 mg for
atorvastatin or 40 mg for all the others was not
associated with further protection. The province
variable was not predictive of adverse outcomes (data
Sensitivity analyses were done with the Quebec data,
which comprised 43% of the total population (Table IV).
After modeling the drug dosage as “atorvastatin-equiva-
lent” instead of “at or above most frequently used
dosage,” we observed again a similar effectiveness across
all 4 agents. Exposure to a statin was highly protective
(adjusted HR 0.16, 95% CI 0.14-0.19), whereas a higher
dosage (“atorvastatin-equivalent”) of the drug was not.
Each increase of 1 mg of the “atorvastatin-equivalent”
dose was associated with a borderline significant 1%
relative increase in the risk of mortality (adjusted HR 1.01,
95% CI 1.00-1.01) (Table IV, section A). Finally, excluding
Survival rates by statin agent used and by provinces.
320 Rinfret et al
American Heart Journal
patients with a previous MI, PCI, or CABG within the
3 years before or during the index hospitalization did not
have any impact on the direction of the findings
(Table IV, section B).
In this elderly population with newly diagnosed
CHF, we observed no difference in effectiveness
between 4 commonly used statin agents (atorvastatin,
simvastatin, lovastatin, pravastatin) in the prevention
of mortality. These observations were robust and
independent of the way the drug dosage variable
was used in models. We also observed no differential
effectiveness across all 4 statin agents when restrict-
ing the dataset to patients without definite evidence
of CAD (previous MI, PCI, or CABG), suggesting
some benefits in patients with nonischemic cardio-
myopathy. The favorable effects of statin in our
patients were found to be independent of drug
dosage in multivariable models. Time-dependent
exposure to a statin was associated with an
important and significant 65% relative risk reduction
The class effect of statin therapy in CHF had
never been studied before. Our analysis is the first
to investigate the relative role of commonly used
statin agent and dosages on mortality in patients
with CHF. Our findings suggest that, if a favorable
effect of statins exists in CHF, it is likely indepen-
dent of their lipid-lowering effects, and that statin
agents might exert a class effect for this indication.
Although we are still waiting evidence from ongoing
large RCTs,2observational data have shown that
statin therapy reduces the need for urgent cardiac
transplant13and is associated with improved survival
in patients with CHF, irrespective of its cause, at
least in the elderly.14Although further reduction in
the LDL-C levels are clearly associated with improved
outcomes in patients with established CAD,3the
favorable effect of statins on CHF appears to be
independent of their lipid-lowering power. In several
small RCTs conducted mostly in patients with
nonischemic cardiomyopathy, treatment with selected
statin agents was associated with short-term choles-
terol-independent effects, including improved
endothelial function,15-17reduced inflammation (levels
of TNF-α, IL-6, C-reactive protein),15,17,18reduced
prothrombotic agents (PAI-1, antithrombin III, protein
C, factor V),18,19but also improved symptoms, quality
of life, and ejection fraction compared to placebo.17,18
Also, patients who developed chronic CHF during the
Scandinavian Simvastatin Survival Study follow-up had
similar changes in their lipoprotein level during follow-
up compared to patients who did not present CHF.
Yet, a significant 2% absolute reduction in the
incidence of CHF after 1 year was observed with statin
therapy in this study.20Moreover, lower LDL-C can be
deleterious in patients with CHF, increasing mortal-
ity,21,22through the so-called lipoprotein-endotoxin
hypothesis.23Statins reduce lipopolysaccharide-binding
protein synthesis. This lipoprotein binds to lipopoly-
saccharide, a pro-inflammatory endotoxin, that trans-
locates in the circulation through the intestinal tract
reflecting the effect.23We also observed an unfavor-
able trend for the effect of higher doses of statin on
mortality in our population, although the type of data
we analyzed can only be used to generate hypotheses
and is certainly not definitive. Nevertheless, in the
multivariable model, every increase by 1 mg of the
“atorvastatin-equivalent” dose was associated with a 1%
relative increase in the risk of mortality (adjusted HR
Table III. Time-dependent multivariable⁎Cox model for all-
cause mortality: all patients
Time-dependent exposure to a statin
At-or-above most frequent dosagey
⁎Controlling for all variables listed in Table I.
y10 mg for atorvastatin and 40 mg for the other statins.
Table IV. Time-dependent multivariable⁎Cox model for
Section A. Modeling dosage as “atorvastatin-equivalent” dosage
(n = 6612)
Time-dependent exposure to a statin
Section B. Excluding patients with previous MI, CABG, or PCI
(n = 3044)
Time-dependent exposure to a statin
zAtorvastatin/1, Simvastatin/4, Pravastatin/8, Lovastasin/4.12
⁎Controlling for all variables in Table I.
⁎⁎Quebec data only.
y10 mg for atorvastatin and 40 mg for the other statins.11
Rinfret et al 321
American Heart Journal
Volume 155, Number 2
1.01, 95% CI 1.00-1.01) in the Quebec sub-dataset.
Although LDL-C levels are not available from the type
of data we analyzed, higher doses of statin are
expected to further reduce LDL-C.12
Our study has, however, several potential limitations.
The first limitation is the observational and adminis-
trative nature of the dataset, from which we cannot
distinguish precisely nonischemic to ischemic cardio-
myopathy. Therefore, we cannot rule out preferential
prescribing of a given statin, especially atorvastatin, for
some higher risk patients with ischemic cardiomyo-
pathy. However, no difference in baseline prevalence
of previous MI, PCI, or CABG was observed when
comparing patients treated with the different statin
agents. Moreover, those factors were controlled for in
the multivariable model. Also, restricting the popula-
tion to those patients without overt evidence of CAD
did not change the direction of our results. Second,
we have no ability with this type of administrative
data to assess whether patients were hospitalized for
systolic or diastolic heart failure. Third, the type of
data did not allow us to test whether lower LDL-C
serum levels were predictive of increased mortality.
Actually, an alternative explanation for the higher
mortality observed with higher atorvastatin-equivalent
dosage in the model is confounding by indication,
where the sicker patients with CAD would receive the
highest dosages. However, this association remained
after excluding patients with overt CAD. Fourth, this
study is really about the class effect of relatively low
dosages of statin in CHF. The percentage of patients
who received high dosages was very small (b1%
received 80 mg or higher doses). Fifth, although our
analysis suggests a time-dependent protective effect of
statin therapy, we cannot exclude potential con-
founding by indication (statin discontinued because of
terminally ill heart failure, for example) or misclassi-
fication biases (patients admitted to a nursing home,
thus considered nonusers and censored). Therefore,
conclusions cannot be drawn from this analysis about
the protective effect of statin agents in patients with
CHF. However, this would not affect our observations
about the class effect of the different agents in this
population. Finally, there is limited correlation
between administrative diagnostic codes and some
clinical disease, especially for some of the comorbid-
ities used in the model.
In conclusion, our study demonstrates that statins
exert a class effect in patients with CHF, at relatively
low dose. The favorable effects appear largely
independent of drug dosage. Our results suggest that
non–lipid-lowering effects of statins might be more
important than potency to reduce LDL-C in patients
with CHF. We believe such results, given the cost
differences among agents, have potential important
health policy implications. Moreover, to the best of
our knowledge, there are no head-to-head trials and
there may never be trials in patients with CHF, given
that most of the statin agents are going off patent
soon or have gone off patent. Therefore, observational
data may well remain the only evidence for a class
effect of statins for this indication.
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The list of authors for the article entitled “Rationale and Design of the Trial of Routine ANgioplasty and Stenting
After Fibrinolysis to Enhance Reperfusion in Acute Myocardial Infarction (TRANSFER-AMI)” that appeared in Am
Heart J 2008;155:19-25 is incorrect. The following author was omitted by mistake: John Ducas, MD, Department of
Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada. The correct order of authors is as follows:
Warren J. Cantor, MD; David Fitchett, MD; Bjug Borgundvaag, MD; Michael Hefferman, MD; Eric A. Cohen, MD;
Laurie J. Morrison, MD; John Ducas, MD; Anatoly Langer, MD; Shamir Mehta, MD; Charles Lazzam, MD; Brian
Schwartz, MD; Vladimir Dzavik, MD; and Shaun G. Goodman, MD.
Rinfret et al 323
American Heart Journal
Volume 155, Number 2