Can J Cardiol Vol 25 No 10 October 2009567
2009 Canadian Cardiovascular Society/Canadian
guidelines for the diagnosis and treatment of
dyslipidemia and prevention of cardiovascular disease
in the adult – 2009 recommendations
Jacques Genest MD1, Ruth McPherson MD PhD2, Jiri Frohlich MD3, Todd Anderson MD4, Norm Campbell MD4,
André Carpentier MD5, Patrick Couture MD6, Robert Dufour MD7, George Fodor MD2, Gordon A Francis MD3,
Steven Grover MD1, Milan Gupta MD8, Robert A Hegele MD9, David C Lau MD10, Lawrence Leiter MD11,
Gary F Lewis MD12, Eva Lonn MD13, GB John Mancini MD14, Dominic Ng MD PhD11, Glen J Pearson PharmD15,
Allan Sniderman MD16, James A Stone MD PhD10, Ehud Ur MD14
1McGill University Health Centre, Montreal, Quebec; 2University of Ottawa Heart Institute, Ottawa, Ontario; 3St Paul’s Hospital, Vancouver, British
Columbia; 4Libin Cardiovascular Institute of Alberta, Calgary, Alberta; 5Centre hospitalier universitaire de Sherbrooke, Sherbrooke; 6Centre Hospitalier
Universitaire de Québec, Quebec City; 7Institut de recherches cliniques de Montréal, Montreal, Quebec; 8Department of Medicine, McMaster
University, Hamilton; 9Robarts Research Institute, London, Ontario; 10University of Calgary, Calgary, Alberta; 11St Michael’s Hospital, University of
Toronto; 12University of Toronto, Toronto; 13Population Health Research Institute, McMaster University, Hamilton, Ontario; 14University of British
Columbia, Vancouver, British Columbia; 15University of Alberta, Edmonton, Alberta; 16Edwards Professor of Medicine and Cardiology, McGill
University, Montreal, Quebec
Correspondence: Dr Jacques Genest, Faculty of Medicine, McGill University, Division of Cardiology, McGill University Health Centre/Royal Victoria
Hospital, 687 Pine Avenue West, Montreal, Quebec H3A 1A1. Telephone 514-934-1934 ext 34642, fax 514-843-2813,
Received for publication August 2, 2009. Accepted August 12, 2009
CVD is expected to increase in Canada in the next decade, pre-
dominantly because of increasingly sedentary lifestyles and an atten-
dant increase in the prevalence of obesity and diabetes mellitus. The
economic cost of CVD represents approximately $22 billion in direct
and indirect health care costs and lost productivity annually.
However, mortality from coronary artery disease (CAD) in Canada
has decreased by nearly 40% in the past several decades (2).
Intensive secondary prevention has resulted in a marked decrease in
recurrent cardiovascular events in patients with established CAD, to
a level approaching that of age- and sex-matched individuals with-
out clinical CAD (at least in clinical trials). The decrease in cardiac
mortality has been attributed to improvements in the control of
CVD risk factors – especially cholesterol levels, smoking and blood
pressure – and to improved medical management of patients with
CVD. Despite these improvements, CVD still represents the major
burden of disease in our society.
The incorporation of new data from clinical studies into clinical
practice guidelines helps promote a standard of care that is current and
uniform across Canada. Frequent updates are required to take this new
information into account. The development of guidelines has under-
gone major changes to reduce bias by promoting a structured process
that assesses and grades evidence, and highlights potential conflicts of
ardiovascular disease (CVD) causes one-third of deaths in
Canada – more than any other illness (1,2). The prevalence of
interest among contributors. Duality of interest of participants of guide-
line development has been the focus of much attention and debate,
recognizing that individuals have many potential sources of bias. In
common with documents prepared in other therapeutic areas, the pres-
ent guidelines were developed by volunteer experts in lipid disorders and
CVD, with full and open disclosure of their relationships with the phar-
maceutical industry. There was no direct financial support for this guide-
line development from industry, nor was there any involvement by them
in the guideline writing process.
While the major principles of screening and risk stratification in the
2006 Canadian lipid guidelines (3) have been retained, the process by
which this updated version was developed took into account comments
and criticisms by many stakeholders. The process changes include work-
ing under the Canadian Cardiovascular Society (CCS) guidelines pro-
cess, and the establishment of primary and secondary review panels. In
addition, members of the Canadian Vascular Coalition have had input
in the guideline process. A systematic electronic PubMed search of
original research published in the medical literature between January 1,
2006, and February 1, 2009, was performed. The following key words
were used: lipid-lowering therapy (including generic names of medica-
tions), statins, fibrates, niacin, ezetimibe, diet, cardiovascular disease,
prevention and clinical trials. Only blinded randomized controlled trials
with cardiovascular outcome data were retained for evaluation. Meta-
analyses of studies of the efficacy and safety of lipid-lowering therapies
©2009 Pulsus Group Inc. All rights reserved
J Genest, R McPherson, J Frohlich, et al. 2009 Canadian
Cardiovascular Society/Canadian guidelines for the diagnosis and
treatment of dyslipidemia and prevention of cardiovascular disease
in the adult – 2009 recommendations. Can J Cardiol 2009;25(10):
The present article represents the 2009 update of the Canadian
Cardiovascular Society guidelines for the diagnosis and treatment of dys-
lipidemia and prevention of cardiovascular disease in the adult.
Key Words: Atherosclerosis; Cardiovascular risk factors; Cholesterol; Coronary
artery disease; Dyslipidemia; Lipids; Secondary prevention
Les lignes directrices canadiennes 2009 de la Société
canadienne de cardiologie pour le diagnostic et le
traitement de la dyslipidémie ainsi que pour la
prévention des maladies cardiovasculaires chez l’adulte –
Des recommandations pour 2009
Le présent article contient la mise à jour 2009 des lignes directrices de la
Société canadienne de cardiologie pour le diagnostic et le traitement de la
dyslipidémie et pour la prévention des maladies cardiovasculaires chez
Genest et al
Can J Cardiol Vol 25 No 10 October 2009 568
and on the predictive value of established and emerging risk factors were
also reviewed. Strict criteria have been implemented for the incorpora-
tion of biomarkers of risk. Novel biomarkers (4,5) must show improved
risk prediction over the previously accepted markers and improved
CVD risk stratification, and demonstrate that clinical decisions and
outcomes are influenced by their measurement.
The Canadian Vascular Coalition represents an informal group of
stakeholders involved in CVD prevention under the banner of the
Canadian Institutes of Health Research. Member organizations are
listed in Supplementary Table 1. (Supplementary information begins
on page 576.) The recommendations for the treatment of lipoprotein
disorders are harmonized with those of the major Canadian stakehold-
ers in CVD prevention. Areas of discordance between the various
stakeholders and opinion leaders are highlighted and discussed. The
CCS provided oversight and logistical support for the process. The
recently released recommendations of the Canadian Heart Health
Strategy and Action Plan (available at http://www.chhs-scsc.ca/web/)
were also influential in writing these guidelines. The writing group
used a widely accepted system to grade and assess the evidence behind
the recommendations, based on consensus (Supplementary Table 2).
Since the previous publication of the recommendations for the
management and treatment of dyslipidemia in 2006 (3), a number of
new clinical studies have been published. When assessing interven-
tions, the primary outcomes examined were cardiovascular death,
nonfatal myocardial infarction (MI) and stroke as a combined end
point, and total mortality as a secondary end point. Less emphasis was
placed on the effects of biomarkers on cardiovascular risk or surrogate
end points, such as invasive or noninvasive atherosclerosis assessment.
The major changes in our recommendations since the 2006 guidelines
are summarized in Supplementary Table 3. The high-risk population
has been better defined, including patients with end-stage cardiac or
renal disease (ie, severe heart failure or chronic kidney disease on
hemodialysis, respectively). Improved, validated CVD event risk-
stratification tools are provided. This is especially relevant in subjects
at intermediate CVD risk for whom the justification of treatment,
other than health behaviour interventions, is often extrapolated from
studies of high-risk patients.
The screening strategy is defined in Table 1. The importance of
genetic factors and family history of premature CVD is taken into
account in the determination of risk (6,7). The importance of obe-
sity (especially abdominal obesity) as a major modifiable CVD risk
factor (8,9) is emphasized by including the International Diabetes
Federation (IDF) classification of the metabolic syndrome (10)
(Table 2) and including overweight and obesity in the screening
strategy. We have included risk stratification for several inflamma-
tory diseases, including rheumatoid arthritis, psoriasis and systemic
lupus erythematosis (SLE) (11-13). Such patients require compre-
hensive assessment and treatment of the traditional cardiovascular
risk factors. The association between inflammatory bowel diseases
(which share many commonalities with other inflammatory dis-
eases) and CVD is less well established (14,15). The use of bio-
markers of inflammation is now included in the guidelines based, in
large part, on the epidemiology of high-sensitivity C-reactive pro-
tein (hs-CRP) and clinical trials of patients with high hs-CRP
levels (4,5). Similarly, recommendations for patients with chronic
HIV infection who are on highly active antiretroviral therapies are
We also provide simplified target lipid levels. The emphasis is once
again focused on atherogenic lipoproteins, as reflected by the serum (or
plasma) levels of low-density lipoprotein cholesterol (LDL-C) or apoli-
poprotein (apo) B. The evidence favouring LDL-C reduction for the
prevention and treatment of atherosclerosis is strong and compelling,
and is based on multiple randomized clinical trials (17). Whereas a spe-
cific target level for LDL-C will remain a matter of debate, the data
indicate that a lower level of LDL-C is associated with reduced CAD
risk (18). LDL-C therefore continues to constitute the primary target of
therapy; the alternate primary target is apoB. A summary is provided of
optional secondary therapeutic targets of potential relevance once the
LDL-C (or apoB) is at target, including (in alphabetical order) the apoB
to apoAI ratio, the total cholesterol (TC) to high-density lipoprotein
cholesterol (HDL-C) ratio, and the hs-CRP, non-HDL-C and serum (or
plasma) triglyceride levels. Increased levels of all these parameters have
been found to confer additional risk. However, clinical trial evidence is
lacking on the importance of intervening on these variables to further
reduce risk and thus, they are considered secondary and optional targets
(19). We also provide further consideration for the noninvasive assess-
ment of atherosclerosis in asymptomatic individuals, bearing in mind
that data on cost effectiveness and outcomes are lacking.
While there is general agreement on the need for sustained, aggres-
sive and multifactorial therapeutic interventions in the secondary pre-
vention of CVD (18,20,21), controversy remains about the cost
effectiveness and societal impact of primary prevention strategies.
However, most heart attacks occur in subjects with relatively ‘normal’
Patients whose plasma lipid profile should be screened
*Data on inflammatory bowel diseases are lacking. CAD Coronary artery dis-
ease; eGFR Estimated glomerular filtration rate
International Diabetes Federation classification of the
Plus two of the following factors:
Data from reference 10
2009 Canadian cholesterol guidelines
Can J Cardiol Vol 25 No 10 October 2009569
serum cholesterol levels (based on population distribution) but fre-
quently suboptimal levels of cardiometabolic fitness in association with
tobacco consumption. Many biomarkers, including levels of serum lip-
ids, lipoproteins, apolipoproteins and various derived ratios, predict
CVD risk (5). However, it is important to keep in mind that none of the
traditional CVD risk factors or biomarkers reflect the actual presence or
absence of atherosclerosis. They help to establish CVD event risk rather
than the risk or presence of CVD itself. The inflammatory biomarker
hs-CRP also predicts risk and identifies a population that responds par-
ticularly well to statin therapy. Importantly, however, our ability to pre-
dict CVD events does not always translate into our ability to prevent
subsequent events. For instance, homocysteine level predicts CVD risk,
but lowering an elevated homocysteine level with folic acid and other
B vitamins to prevent recurrent cardiovascular events has proven to be
unsuccessful (22). Therefore, we have focused on CVD risk factors
whose measurement influences clinical decision making and for which
there exists a proven effect on clinical outcomes.
CaRDioVaSCuLaR RiSK FaCtoRS
Multiple epidemiological studies (23,24) have confirmed that the fol-
lowing risk factors account for the majority of CAD cases:
Other variables conferring risk include poor nutrition, caloric
excess resulting in overweight and obesity, physical inactivity and
psychological stress. Because of the increase in prevalence of obesity in
our society, the features of the metabolic syndrome (cardiometabolic
risk) should be evaluated (Table 2), and should focus the physician’s
attention on anthropometric (ie, ‘toxic waist’) and metabolic abnor-
malities that can be improved or corrected by health behaviour inter-
ventions. Patients with chronic kidney disease (25,26), chronic
autoimmune inflammatory diseases (rheumatoid arthritis, SLE and
psoriasis) (11-13), as well as those with chronic HIV infection requir-
ing highly active antiretroviral therapy (16), should be screened for
the traditional CVD risk factors and treated according to their deter-
mined risk. Many novel and emerging risk factors have been demon-
strated to improve risk prediction over and above the major risk factors
considered in the Framingham risk score (FRS), albeit usually margin-
ally, but these ‘emerging’ risk factors have not been shown to positively
influence treatment outcomes. The measurement of hs-CRP, however,
is being recommended in men older than 50 years and women older
than 60 years of age who are at intermediate risk (10% to 19%)
according to their FRS score and who do not otherwise qualify for
lipid-lowering therapy (ie, if their LDL-C is less than 3.5 mmol/L).
The rationale for measuring hs-CRP specifically in these individu-
als is that we now have class I evidence (5) for the benefit of statin
therapy in such individuals, if their hs-CRP is greater than 2.0 mg/L.
Data from the Justification for the Use of Statins in Prevention: an
Intervention Trial Evaluating Rosuvastatin (JUPITER) (5) show that
statin therapy reduces cardiovascular events (hazard ratio 0.56
[95% CI 0.46 to 0.69]; P<0.00001). Importantly, because hs-CRP can
be elevated during acute illness, clinical judgment should be exercised
in the interpretation of any single measurement of hs-CRP.
Screening (table 1)
Screening of the plasma lipid profile is recommended in adult men
who are at least 40 years of age, and in women who are at least 50 years
of age or postmenopausal (class I, level C). In addition, all subjects
with evidence of atherosclerosis in any vascular bed, irrespective of
age, should be treated as being a high-risk patient (Table 3). Similarly,
all adults with diabetes should have a complete lipid profile. Most
adults with diabetes (men older than 45 years and women older than
50 years of age, as well as many younger patients who have diabetes
with at least one additional traditional CVD risk factor) are consid-
ered to be at high risk for CVD events. Individuals with a family his-
tory of premature CVD (younger than 60 years of age) deserve earlier
screening. Several medical conditions are associated with premature
CVD. For instance, patients with arterial hypertension should be care-
fully assessed for concomitant metabolic disorders and dyslipidemias.
Patients with abdominal obesity, as defined by an increased waist cir-
cumference or a body mass index (BMI) of greater than 27 kg/m2 to
30 kg/m2 (overweight), or greater than 30 kg/m2 (obese) should also be
screened. The metabolic syndrome classification recommended by the
IDF classification is advocated because it most accurately reflects the
diverse ethnic makeup of Canada (Table 2) (10). Autoimmune
chronic inflammatory conditions such as rheumatoid arthritis, SLE
and psoriasis are associated with increased CVD event risk. Patients
with chronic kidney disease (estimated glomerular filtration rate of less
than 60 mL/min/1.73 m2) are also at increased risk for CVD events.
Target lipid levels
Risk levelInitiate treatment if:
Class I, level a
Class I, level a
Class IIa, level a
Class IIa, level a
Grades and levels of evidence for each target are shown in bold. Clinicians
should exercise judgement when implementing lipid-lowering therapy. Lifestyle
modifications will have an important long-term impact on health and the long-
term effects of pharmacotherapy must be weighed against potential side
effects. Meta-analysis of statin trials show that for each 1.0 mmol/L decrease
in low-density lipoprotein cholesterol (LDL-C), there is a corresponding RR
reduction of 20% to 25%. Intensive LDL-C lowering therapy is associated with
decreased cardiovascular risk. Those whose 10-year risk for cardiovascular
disease (CVD) is estimated to be between 5% and 9% have been shown in
randomized clinical trials to achieve the same RR reduction from statin therapy
as those at a higher 10-year risk (25% to 50% reduction in events), but the
absolute benefit of therapy is estimated to be smaller (in the order of 1% to 5%
reduction in CVD), the numbers needed to treat to prevent one cardiac event
are higher and the cost/benefit ratio of therapy is less favourable than for those
at higher risk for CVD. For individuals in this category, the physician is advised
to discuss these issues with the patient and, taking into account the patient’s
desire to initiate long-term preventive cholesterol-lowering therapy, to individu-
alize the treatment decision. *Atherosclerosis in any vascular bed, including
carotid arteries. apoB Apolipoprotein B level; CAD Coronary artery disease;
FRS Framingham risk score; HDL-C High-density lipoprotein cholesterol;
hs-CRP High-sensitivity C-reactive protein; PVD Peripheral vascular disease;
RRS Reynolds Risk Score; TC Total cholesterol
Class IIa, level a
Genest et al
Can J Cardiol Vol 25 No 10 October 2009 570
Clinical manifestations of genetic hyperlipidemias, including xan-
thomas, xanthelasmas and premature arcus cornealis, should be sought
because they may signal the presence of a severe lipoprotein disorder,
especially familial hypercholesterolemia – the most frequent mono-
genic disorder associated with premature CVD. Survival of patients
with chronic HIV infection has improved, due largely to highly active
antiretroviral therapies, which may be associated with accelerated
atherosclerosis (27). The consensus of opinion is that HIV patients
should also be evaluated for CVD risk and should be treated
The screening of children must be based on sound clinical judg-
ment. Children of patients with severe dyslipidemia (familial hyper-
cholesterolemia or chylomicronemia) should be evaluated and followed
in specialized clinics if affected. Similarly, premature CVD in first-
degree relatives should prompt the screening of family members for
significant lipoprotein disorders.
The etiology of CVD can be explained by conventional risk factors
(24), which can have both genetic and environmental determinants.
Importantly, 10% to 15% of patients with CAD have no apparent
major CAD risk factors. However, CVD and CVD-related events
occur along a continuum of risk, and persons with no apparent expo-
sure to the traditional CVD risk factors may be exceptionally suscep-
tible to the presence of apparently physiological levels of those risk
factors. Family and twin studies suggest a strong genetic influence on
premature CAD in particular. Results from the Framingham Offspring
Study (6) demonstrate that, after correction for known risk factors,
parental CVD was associated with a 1.7- and 2.0-fold increased risk for
women and men, respectively.
the metabolic syndrome
The metabolic syndrome is defined as the association of several
metabolic abnormalities including visceral adipose tissue mass
(ie, toxic waist), dyslipidemia (elevated triglycerides and low
HDL-C), elevated blood pressure and elevated serum glucose.
Several classifications of the metabolic syndrome share common ele-
ments that emphasize the increase of cardiometabolic risk factors
(8). However, a uniform classification of the metabolic syndrome
remains elusive. The IDF classification (10) has more stringent waist
circumference criteria than the National Cholesterol Education
Program Adult Treatment Panel-III (NCEP ATP-III) definition (3)
and serves as the current diagnostic classification system recom-
mended by the writing group (Table 2). Individuals with the meta-
bolic syndrome are more likely to be at higher long-term CVD risk
than estimated by the FRS alone. Currently, there is a paucity of data
on the clinical usefulness of the new IDF definition of the metabolic
syndrome to identify subjects with an intermediate FRS who may be
at higher risk for cardiovascular events. A retrospective analysis of
data from the Air Force/Texas Coronary Atherosclerosis Prevention
Study (AFCAPS/TexCAPS) suggests that determining the presence
of the metabolic syndrome using the NCEP ATP-III definition iden-
tifies subjects with an FRS of less than 20% who have a similar risk
to those without the metabolic syndrome with an FRS of 20% or
greater. Results from meta-analyses (28) suggest that there is a
1.5-fold increase in risk when adjusted for other cardiovascular risk
factors and that the increase in risk was higher among women than
among men. Therefore, some subjects in the higher range of interme-
diate FRS with the metabolic syndrome may require lipid-lowering
therapy to reduce their cardiovascular risk (class IIb, level C).
However, no study has thus far demonstrated an improvement in
outcome when subjects at intermediate risk were selected for lipid-
lowering treatment on the basis of the metabolic syndrome. The
measurement of hs-CRP may provide further help in the risk stratifi-
cation of subjects with the metabolic syndrome (29). As a practical
rule, an adult with the metabolic syndrome is extremely unlikely to
truly be at low risk for CVD; most are either at intermediate or high
risk for CVD. The FRS is a good starting point for the global risk
assessment of patients with the metabolic syndrome, as well as for
those without the metabolic syndrome. We recommend that clinical
judgement be used in some cases to move a patient up an FRS-
determined risk score category based on his or her ‘load’ of metabolic
risk factors or the ‘severity’ of the metabolic syndrome.
other risk factors
Many other factors have been shown to be associated with increased
CVD risk. These include specific lipoprotein subclasses, including
lipoprotein(a) (30), inflammatory biomarkers such as lipoprotein-
associated phospholipase A2 (also called platelet-activating factor
acetyl hydrolase) (31), cell adhesion molecules, homocysteine, uric
acid, coagulation and a variety of thrombosis parameters, serum glyco-
proteins, and both anatomical and functional measures of vascular
health available through an explosion of new imaging techniques,
many of which are noninvasive (32). Despite an increasing number of
new potential markers of risk, the traditional CVD risk factors remain
the priorities for screening and treatment as appropriate. Unless a
novel risk factor or marker has been proven to both influence clinical
decision making and therapeutic approaches, and to change clinical
outcomes, its use should remain within the specialized clinical and
research setting (32).
Cardiovascular risk assessment remains imperfect. The FRS
(Supplementary Tables 4A and 4B for men, and Supplementary
Tables 5A and 5B for women) for total CVD is now recommended
(33). The FRS has been shown to underestimate risk in specific catego-
ries of patients, especially in youth and women, and possibly in those
with the metabolic syndrome (28). Arbitrarily, an FRS of 20% or
greater at 10 years is considered to identify subjects at high risk for
CVD events. The FRS has been validated in Canada with the
Cardiovascular Life Expectancy Model (www.chiprehab.com) (34),
and this model has been shown to increase adherence to therapeutic
measures. The Reynolds Risk Score (RRS) constitutes an optional risk
engine and includes the conventional CVD risk factors in addition to
family history and hs-CRP (35,36) (http://www.reynoldsriskscore.org).
It has been validated in men and women in an American population,
but not yet in Canada. The Internet-based version of the RRS is now
also available in mmol/L.
Short-term versus long-term risk
The FRS is applicable to a large percentage of the Canadian popula-
tion and provides a reasonable estimate of the 10-year risk of a major
CVD event. A family history of premature CAD is considered to
increase the risk by 1.7-fold in women and 2.0-fold in men. An ele-
vated hs-CRP level is also a modulator of risk, especially in the
moderate- risk category (6). Many subjects at low or moderate short-
term (10-year) risk are at a high risk over the long term due to the
cumulative effects of single but significant elevated risk factors
(eg, severe systemic hypertension), the exponentially interactive effects
of multiple but only moderately elevated CVD risk factors and/or
changes in risk factors over time (for example, the young person with
diabetes). In the Framingham study, men in the lowest FRS tertile at
50 years of age experienced a 10-year cumulative risk of one in 25, but
a lifetime risk of nearly one in two. Women in the lowest FRS tertile
of risk at 50 years of age had a 10-year cumulative risk of one in 50, but
a lifetime risk of one in four (37,38). CVD risk should be reassessed
every three years (class IIB, level C). European guidelines use a risk
score based on total mortality (39).
High risk: Subjects are considered to be at high CVD risk if they have
any of the following:
•? Evidence? of? atherosclerosis? –? vascular? bruits,? an? ankle-brachial?
index of less than 0.9, documented CAD by invasive or noninvasive
2009 Canadian cholesterol guidelines
Can J Cardiol Vol 25 No 10 October 2009 571
testing, coronary angiography, nuclear imaging, stress echo-
cardiography, previous MI, coronary revascularization (percutane-
ous coronary intervention, coronary artery bypass graft surgery)
and other arterial revascularization procedures, cerebrovascular
accident, including transient ischemic attack, evidence of carotid
disease by carotid ultrasonography or angiography, or peripheral
with diabetes, as well as some younger people with diabetes who
have an additional risk as per Canadian Diabetes Association
guidelines (40); or
These subjects should receive intensive lifestyle modification advice
and benefit from a pharmacological approach aimed at lowering
Moderate risk: Many middle-aged Canadians will be in the moderate-
risk category. The increase in obesity in the adult population, coupled
with an increase in the prevalence of the individual components of the
metabolic syndrome, has created a major health concern. This was
recently addressed at the federal level in the Canadian Heart Health
Strategy and Action Plan (http://www.chhs-scsc.ca/web/). Subjects are
considered to be at moderate risk when their FRS is 10% to 19% at
10 years (33). This risk is further modulated by a family history of prema-
ture CAD and high hs-CRP.
Alternatively, the RRS, which combines the Framingham risk fac-
tors, family history and hs-CRP, can be considered for use to stratify
risk (35,36). The indications for pharmacological interventions are
based on primary prevention studies including AFCAPS/TexCAPS
(41), the West of Scotland Coronary Prevention Study (WOSCOP)
(42), the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)
(43), the Heart Protection Study (HPS) (44) and JUPITER (5).
Following the initiation of health behaviour interventions, pharmaco-
logical therapy is indicated if:
(class IIa, level A);
in women older than 60 years of age, irrespective of LDL-C
(class IIa, level B).
The measurement of hs-CRP should not be performed on everyone.
Men older than 50 years and women older than 60 years of age who are
at moderate risk for CVD (determined by FRS) and whose level of
LDL-C is less than 3.5 mmol/L are candidates because such individuals
have been shown to benefit from statin therapy (5) (class IIa, level B).
Subjects should be free of acute illness and the lower of two values,
taken at least two weeks apart, should constitute the baseline value.
Although widespread pharmacological therapy for those at low risk is
not recommended, subjects whose 10-year risk for CVD is estimated to
be between 5% and 9% have been shown in randomized controlled trials
(5) to achieve the same RR reduction from statin therapy as those at a
higher 10-year risk (25% to 50% reduction in events). However, the
absolute benefit of therapy is estimated to be smaller (in the order of 1%
to 5% reduction of CVD), the numbers needed to treat to prevent one
cardiac event are higher and the cost/benefit ratio of therapy is less
favourable than for those at a higher risk for CVD events. For individuals
in this category, the physician is advised to discuss these issues with the
patient and integrate the patient’s beliefs regarding the benefits and risks
of long-term preventive cholesterol-lowering therapy into the final indi-
vidualized treatment decision.
Low risk: The low-risk category applies to individuals with an FRS of less
than 10%. Pharmacological lipid-lowering treatment is advised for low-
risk subjects with severe dyslipidemia (LDL-C of 5.0 mmol/L or greater),
usually reflecting a genetic lipoprotein disorder, especially familial hyper-
cholesterolemia (class 1, level C). Consideration for lipid-lowering ther-
apy may also be indicated in subjects at low risk with a TC/HDL-C ratio
of greater than 6.0 (class IIb, level C). This especially applies to patients
with severe hypertriglyceridemia, in whom treatment may be indicated to
reduce the risk of pancreatitis. The need for treatment of subjects with
isolated HDL-C is a subject of debate because evidence that pharmaco-
logical treatment will reduce cardiovascular risk is lacking and currently
available therapies may not increase HDL-C to a clinically significant
extent. Clinical judgment should be used concerning the proper timing
for the initiation of pharmacological therapy in these patients. A careful
family history should be taken and the presence of additional CVD risk
factors may indicate the need for intervention in selected individuals. The
RRS has the potential to reclassify low-risk patients according to the FRS
when there is a family history and elevated hs-CRP.
ethnic differences in CaD risk
CAD rates vary among ethnic groups in Canada, with the highest
incidence among individuals of South Asian ancestry and the lowest
among individuals of Chinese ancestry (45). The higher risk among
individuals of South Asian ancestry is partly explained by an increased
prevalence of abdominal obesity, glucose intolerance, hypertriglyceri-
demia and low HDL-C. Individuals of First Nations ancestry are also at
markedly increased risk for diabetes and CAD (46). For these reasons,
the risk stratification approach provides an opportunity for greater
focus on overweight and obese individuals, as well as patients with
other related metabolic features, which should help ensure identifica-
tion of modifiable CVD risks, even within those populations unique to
the Canadian sociocultural milieu.
Cholesterol treatment target levels are derived from clinical trials.
Nearly all studies have measured the serum (or plasma) level of LDL-C
as an indicator of response to therapy (Table 3). The Cholesterol
Treatment Trialists (CCT) meta-analysis (17) of 14 statin trials showed
a dose-dependent relative reduction in CVD with LDL-C lowering.
Every 1.0 mmol/L reduction in LDL-C is associated with a correspond-
ing 20% to 25% reduction in CVD mortality and nonfatal MI. Data
from the Pravastatin or Atorvastatin Evaluation and Infection Therapy
(PROVE-IT) (47), Treating to New Targets (TNT) (48), Aggrastat to
Zocor (A to Z) (49), Incremental Decrease in End Points Through
Aggressive Lipid Lowering (IDEAL) (50) and the Study of the
Effectiveness of Additional Reductions in Cholesterol and
Homocysteine (SEARCH) (18) trials have confirmed that lowering
LDL-C to a mean of 2.0 mmol/L or less is associated with the lowest risk
of recurrent CVD events in secondary prevention patient populations
(51). Extrapolating from the available data, a 2.0 mmol/L absolute
reduction or a 50% relative reduction in LDL-C provides optimal ben-
efit in terms of CVD reduction (52). Thus, for high-risk subjects, the
target levels should be an LDL-C of less than 2.0 mmol/L, or a 50% or
greater reduction from baseline LDL-C (class I, level A). In the major-
ity of patients, this is achievable with statin monotherapy. Furthermore,
because apoB levels have so frequently been measured in outcome stud-
ies in parallel with LDL-C, apoB can be substituted for LDL-C (53,54).
The present version of the guidelines recommends apoB as the primary
alternate target to LDL-C. Based on the available evidence, many
experts have concluded that apoB is a better marker than LDL-C for
the risk of vascular disease and a better index of the adequacy of LDL-
lowering therapy than LDL-C (53). Also, there now appears to be less
laboratory error in the determination of apoB than LDL-C, particularly
in patients with hypertriglyceridemia, and all clinical laboratories could
easily and inexpensively provide standardized measurements of apoB.
However, not all experts are fully convinced that apoB should be mea-
sured routinely and, in any case, apoB is not presently being measured
in most clinical laboratories. Consequently, a substantial educational
effort for patients and physicians would be required for the most effec-
tive introduction of apoB into widespread clinical practice. Nevertheless,
all would agree that physicians who wish to use apoB in their clinical
care should be encouraged to do so. Furthermore, the present compro-
mise approach represents a positive transitional phase in the assessment
of lipid parameters to improve the prevention of CVD through the
Genest et al
Can J Cardiol Vol 25 No 10 October 2009 572
clinical measurement of apoB. The apoB target for high-risk subjects is
less than 0.80 g/L (class I, level A).
targets other than LDL-C (or apoB)
Secondary targets have been determined in post hoc analyses or as part
of prespecified analyses in a number of clinical trials. These secondary
targets include a TC/HDL-C ratio of less than 4.0, a non-HDL-C level
of less than 3.5 mmol/L, an apoB/apoAI ratio of less than 0.80, a trig-
lyceride level of less than 1.7 mmol/L and an hs-CRP level of less than
2.0 mg/L. Adjusting lipid-lowering therapy to optimize one or more of
these secondary targets may be considered in the high-risk patient
after achieving a target LDL-C or apoB, but the clinical advantages of
this approach, with respect to patient outcomes, remain to be proven.
The specific target for non-HDL-C should be less than 3.5 mmol/L
(33). A TC/HDL-C ratio of less than 4.0 or an apoB/apoAI ratio of less
than 0.8 is inferred from clinical trials and epidemiological data to convey
reduced CVD event risk in high-risk subjects. To date, no specific targets
for HDL-C or triglyceride levels have been determined in clinical trials,
although increases in HDL-C predict atherosclerosis regression (55) and
low HDL-C is associated with excess events and mortality in CAD
patients, even when LDL-C is lower than 1.8 mmol/L (56). A specific
target for hs-CRP in secondary prevention is based on the predetermined
analysis (51) of the PROVE-IT and A to Z studies, which showed that
patients with CAD who have reached both an LDL-C level of less than
2.0 mmol/L and an hs-CRP level of less than 2.0 mg/L had the lowest
CVD event rate (class IIa, level B). Similarly, an analysis (57) of the
JUPITER trial showed that the lowest cardiovascular event rate was
achieved in subjects who attained both an LDL-C level of less than
2.0 mmol/L and an hs-CRP level of less than 2.0 mg/L. To date, no clinical
trial has addressed the issue of treating the secondary targets of therapy
more aggressively, including hs-CRP, once LDL-C (or apoB) is at target.
Presently, hs-CRP as a secondary target of therapy is not recommended
based on the lack of clinical trial evidence that targeting a particular
hs-CRP level results in clinical benefit. Thus, clinicians must exercise
expert judgment and caution when considering further treatment intensi-
fication in secondary prevention or in high-risk primary prevention.
Although several clinical trials are ongoing, to date, no statin-based com-
bination therapy has been shown to improve clinical outcomes.
The target level for subjects at moderate risk are extrapolated from
high-risk clinical studies, especially ASCOT (43), HPS (44),
AFCAPS/TexCAPS (41), WOSCOP (42) and JUPITER (5). The
2006 recommendations also focused on LDL-C as the primary target of
therapy in these patients, with a treatment trigger LDL-C level of
3.5 mmol/L and a recommended 40% reduction (as was obtained in
the ASCOT trial ), thus reaching a level close to 2.0 mmol/L.
Based in large part on the JUPITER trial (5), in which a 50% reduc-
tion in LDL-C was achieved, we recommend the same targets of an
LDL-C level of lower than 2.0 mmol/L (apoB lower than 0.80 g/L) or
a 50% reduction from baseline LDL-C (class IIa, level A) when the
baseline level is known. For the above reasons, secondary targets of
therapy in the moderate- risk category are based on data extrapolation
and therefore, clinical judgment is required before a final treatment
plan is implemented (class IIb, level C). These revised recommenda-
tions are more stringent than the previous set (3). Clinicians should
exercise judgement to avoid premature or unnecessary implementa-
tion of lipid-lowering therapy. Health behaviour interventions will
have an important long-term impact on health and the long-term
effects of pharmacotherapy must be weighed against potential side
effects. A meta-analysis of statin trials (17) has demonstrated that for
each 1.0 mmol/L decrease in LDL-C, there is a corresponding RR
reduction of 20% to 25%. Intensive LDL-C lowering therapy is associ-
ated with a decreased risk of CVD events (18).
Congestive heart failure due to systolic dysfunction or end-stage
Recent studies (Controlled Rosuvastatin Multinational Trial in Heart
Failure [CORONA]  and Gruppo Italiano per lo Studio della
Sopravvivenza nell’Infarto Miocardico Heart Failure [GISSI-HF] )
have addressed the issue of statin treatment in end-stage heart failure (left
ventricular ejection fraction of less than 30%). These studies suggest that
statin therapy does not reduce CVD morbidity or mortality in advanced
heart failure of ischemic or nonischemic etiology. Similarly, the Deutsche
Diabetes Dialyse Studie (4D) (60) and A study to evaluate the Use of
Rosuvastatin in subjects On Regular haemodialysis: an Assessment of
survival and cardiovascular events (AURORA) (61) trials examined sta-
tin treatment in hemodialysis subjects (who were not considered to be
candidates for statin therapy by their physicians) and found no effect on
CVD outcomes. Clinical judgement must be applied when considering
the modest baseline elevation of LDL-C in these trials (approximately
3.5 mmol/L) and also the observation that patients on dialysis awaiting
renal transplantation may still benefit from statins.
Surrogate markers of CVD risk – testing for atherosclerosis
The ankle-brachial index is the ratio of systolic blood pressure in the
dorsalis pedis or posterior tibial artery to the systolic blood pressure in
the brachial artery. An ankle-brachial index value of less than 0.90 is
a reliable index of peripheral arterial disease, with a sensitivity of 90%
and a specificity of 98% for detecting greater than 50% stenosis. Such
patients have a high likelihood of concomitant CVD (62).
Exercise stress testing in asymptomatic men older than 40 years of
age can also be useful in risk stratification (63). A positive stress test is
highly predictive of CAD and future cardiovascular events. However,
the likelihood of detecting asymptomatic CAD remains low when the
pretest probability is low. Furthermore, a negative stress test has a low
negative predictive value, particularly in patient populations with a
higher pretest probability of CVD.
Carotid B-mode ultrasonography is also useful in assessing preclini-
cal atherosclerosis. In asymptomatic individuals 50 years of age or
older, several studies have demonstrated up to a fivefold increase in
future risk of CAD events when the carotid intima-media thickness
(CIMT) is greater than 1 mm, although a better measurement would
be a CIMT of greater than the 75th percentile for age, sex and ethnic
background (64). A screening strategy, based on carotid ultrasonogra-
phy, was recently proposed (64). Although CIMT quantification is not
yet a standard measure, evidence of early carotid atherosclerosis (visi-
ble arterial wall plaques or IMT of 1.5 mm or greater) by routine
carotid ultrasonography is probably an indication for statin therapy.
Some believe that noninvasive imaging, especially in the moderate-
risk category, may be useful to identify patients with undiagnosed,
subclinical atherosclerosis. The presence of atherosclerosis places the
individual in the high-risk category (class IIa, level C).
Cardiac computed tomography (electron-beam computed tomog-
raphy) and multidetector computed tomography coronary angiography
quantify the burden of coronary artery calcium and can be useful in
risk prediction. Importantly, not all plaques are calcified and calcium
cannot be used to reliably identify plaques at risk for rupture (65).
Even so, the negative predictive value of a coronary artery calcium
score of 0 remains very high (greater than 98%) for ruling out signifi-
cant coronary atherosclerosis or the development of coronary events
(65). Noninvasive imaging of the coronary arteries requires computer-
ized gated images of the heart, frequently with pharmacologically
induced bradycardia to improve image quality. While not as sensitive
as coronary angiography (66), it may be useful for the differential diag-
nosis of chest pain in highly selected patients. It is not recommended
for screening in asymptomatic subjects.
Health behaviour interventions remain the cornerstone of chronic dis-
ease prevention, including CVD prevention. They should be universally
applied for the prevention of chronic diseases such as obesity, type 2
diabetes, atherosclerosis, cancer and neurodegenerative diseases. The
major recommended health behaviour interventions are:
2009 Canadian cholesterol guidelines
Can J Cardiol Vol 25 No 10 October 2009
•? A? diet? low? in? sodium? and? simple? sugars,? with? substitution? of?
unsaturated fats for saturated and trans fats, as well as increased
consumption of fruits and vegetables;
•? Moderate? to? vigorous? exercise? for? 30? min? to? 60? min? most?
(preferably all) days of the week;
are no metabolic or clinical contraindications (67).
Smoking cessation: Smoking cessation is probably the most important
health behaviour intervention for the prevention of CVD. There is a
linear and dose-dependent association between the number of ciga-
rettes smoked per day and CVD risk (24). Pharmacological therapy is
associated with an increased likelihood of smoking abstinence.
Diet: Recommendations regarding the type of diet favouring health
maintenance have been fraught with controversy. Most authorities
agree that reducing saturated fats and refined sugars in the diet, while
increasing fruits, vegetables and fibres, is associated with increased
health. For patients with hypertriglyceridemia, a reduction in the intake
of alcohol and refined carbohydrates, in conjunction with increased
consumption of omega-3 and omega-6 polyunsaturated fats, is indicated.
Most important is the restriction of caloric intake to achieve and main-
tain a healthy body weight. In Caucasians, a BMI of less than 25 kg/m2
is considered optimal, while in subjects of Asian, Chinese and Japanese
descent, a lower BMI (less than 23 kg/m2) may be indicated. The dietary
content (percentage of protein, carbohydrate and fat) required to main-
tain a healthy weight does not appear to matter as long as caloric intake
is reduced (68). A diet suited to the individual that provides adequate
nutrition with a balance between caloric intake and energy expenditure,
is best. Often, a professional dietician is of value to provide advice and
follow-up. Moderate alcohol intake is acceptable (one drink per day for
women and two drinks per day for men) if no metabolic or clinical con-
traindications are present (67).
exercise: Physical activity is another important component of preven-
tion. Many studies have shown the benefits of regular exercise in main-
taining health and preventing CVD. Regular exercise also has beneficial
effects on diabetes risk, hypertension and hypertriglyceridemia, and
improves plasma levels of HDL-C. In several studies, a lower frequency
of CVD was noted in physically active individuals independent of
known CVD risk factors. A general recommendation for healthy indi-
viduals is at least 30 min to 60 min of moderate to vigorous physical
activity on most, but preferably all, days of the week.
Psychological factors: The INTERHEART study (69) confirmed the
importance of stress as a CVD risk factor. Following MI, patients with
depression have a worse prognosis, but it remains unclear whether
pharmacological treatment reduces this risk (70).
Pharmacotherapy (table 4)
LDL-C: In high-risk individuals, treatment should be started immedi-
ately, concomitant with health behaviour interventions with respect to
appropriate diet, physical activity, weight management and the cessa-
tion of tobacco consumption. The primary target of therapy is to achieve
an LDL-C of less than 2.0 mmol/L, an apoB of less than 0.8 g/L or a 50%
reduction in LDL-C from baseline values (class I, level A).
The majority of patients will be able to achieve target LDL-C lev-
els on statin monotherapy. However, a significant minority of patients
may require combination therapy with an agent that inhibits choles-
terol absorption (ezetimibe) or bile acid reabsorption (cholestyramine,
colestipol), or the concomitant use of niacin. These combinations are
generally safe and can decrease LDL-C by an additional 10% to 15%
for bile acid resins and up to 20% for ezetimibe and niacin. Clinical
outcome data on the incremental benefit of combination therapy with
statin plus ezetimibe, niacin or fibrate, versus statin monotherapy are
lacking, although clinical trials are underway to examine this issue.
triglycerides: A specific target for triglyceride levels in high-risk sub-
jects or for the primary prevention of CAD has not been established.
Epidemiological studies show that lower triglyceride levels are associated
with decreased CVD risk, and drugs that lower triglycerides have dem-
onstrated a reduction of CVD events in the Helsinki Heart Study (71)
and the Veterans Administration HDL Intervention Trial (VA-HIT)
(72). In both cases, the drug used was the fibric acid derivative gemfibro-
zil. Gemfibrozil should not be used with a statin because of the increased
risk of rhabdomyolysis. The Fenofibrate Intervention and Event
Lowering in Diabetes (FIELD) study (73) in diabetic patients using
fenofibrate failed to meet its primary end point in terms of CAD preven-
tion. In patients with hypertriglyceridemia, dietary therapy, exercise and
weight loss, with a focus on restriction of refined carbohydrates and
reduced alcohol intake, in association with increased intake of omega-3
fatty acids, are first-line therapies. The use of fibrates as first-line agents
is warranted in patients with extreme hypertriglyceridemia (triglyceride
levels greater than 10 mmol/L) to prevent pancreatitis. For patients with
moderate hypertriglyceridemia (triglyceride levels of 5 mmol/L to
10 mmol/L), fibrates may be useful, but the impact on CAD prevention
is less clear. In high-risk patients already on a statin, elevated triglyceride
levels (2 mmol/L to 5 mmol/L) may be further treated with a fibrate or
niacin. However, it has not been established whether the addition of a
fibrate or niacin to a statin further reduces CAD events once the LDL-C
is at target (class IIb, level C).
HDL-C: Smoking cessation, weight loss, exercise and moderate alco-
hol intake all increase HDL-C. These favourable health behaviours
stand on their own merit in terms of benefit over the long term and
HDL-C may be a marker of cardiovascular health. There is consider-
able controversy regarding the treatment of a low HDL-C, in part
because there are many genetic forms of HDL-C deficiency that do not
increase (or increase only slightly) CVD risk (74). Furthermore, the
treatment of a genetic HDL-C deficiency is often difficult with cur-
rently available medications (75). Statins have little effect on HDL-C
and fibrates only modestly raise HDL-C (5% to 10%) in most cases.
Niacin can increase HDL-C by 15% to 25%.
Generic name Trade name (manufacturer)
dose range (daily)
bile acid and/or cholesterol absorption inhibitors
*Increased myopathy on 80 mg; †Reduce dose or avoid in renal impair-
ment; ‡Should not be used with a statin because of an increased risk of
Genest et al
Can J Cardiol Vol 25 No 10 October 2009
Novel approaches to raise HDL-C are being tested clinically.
Despite early disappointing results (76), the data indicate that raising
HDL-C may still prove to be a valuable therapeutic target (77).
Combination therapy: The combination of a statin with niacin is
effective in improving the lipid profile of patients with combined dys-
lipidemia and low HDL-C. Niacin is more effective than fibrates in
increasing HDL-C concentrations. Side effects are most manifest with
crystalline niacin, and include flushing, dry skin, gastritis and wors-
ened glycemic control in persons with diabetes mellitus. Crystalline
niacin should be taken two to three times daily after meals and the
dose should be increased slowly. Extended-release niacin (Niaspan;
Oryx Pharmaceuticals Inc, Canada) is taken once daily and is better
tolerated. The use of acetylsalicylic acid (325 mg) 30 min to 60 min
before niacin attenuates the flushing in most patients. There is a small
but significant risk of hepato toxicity with niacin monotherapy or nia-
cin plus statin combination treatment and therefore, serum transami-
nase levels should be followed. Until the results of the Atherothrombosis
Intervention in Metabolic Syndrome with low HDL/High Triglyceride
and Impact on Global Health Outcomes (AIM-HIGH) (78) and
Heart Protection Study 2 Treatment of HDL to Reduce the Incidence
of Vascular Events (HPS2-THRIVE) (79) trials using combined statin/
niacin in high-risk patients are available, the data supporting the use
of niacin are based on small studies not powered for major adverse
CVD end points. Gradual titration of niacin and the use of acetylsali-
cylic acid to decrease flushing symptoms are recommended.
The combination of a statin with a fibrate may be used with close
patient follow-up. Because fibrates may increase serum creatinine, the
dose must be adjusted in patients with kidney impairment. Fibrates may
also increase serum homocysteine levels. It should be noted that the
recent FIELD study (73) demonstrated that fenofibrate monotherapy
did not significantly reduce CVD events in patients with diabetes and
mild hypertriglyceridemia. Available data suggest that fenofibrate is
reasonably safe in combination with a statin. Studies are underway to
determine whether the addition of a fenofibrate to a statin regimen
alters CVD risk. Gemfibrozil is associated with a higher risk of myotox-
icity and should not be used in combination therapy. For patients with
moderate hypertriglyceridemia, the addition of omega-3 fatty acids (2 g
to 4 g three times daily) to statin therapy is safe, and may lower triglyc-
erides and help achieve the TC/HDL-C ratio target.
Safety and laboratory monitoring
Before initiation of pharmacological therapy for dyslipidemias, a base-
line lipoprotein profile should be obtained after a 10 h to 12 h fast,
preferably with the subject refraining from alcohol for 24 h to 48 h.
The lipoprotein profile should include TC, HDL-C and triglycerides.
The LDL-C is derived from the Friedewald formula and is considered
accurate for triglyceride levels of less than 5 mmol/L. A fasting glucose
level should also be obtained at baseline to identify the presence of
impaired fasting glucose or diabetes. ApoB and apoAI measurements
should be made at the discretion of the physician. Important issues for
these newer biochemical analytes include standardization of labora-
tory measurement proficiency and reimbursement, both of which, at
present, vary widely across Canada. ApoB measurement may also be
useful for differentiation between familial hypertriglyceridemia and
familial combined hyperlipidemia, and in subjects with a low HDL-C.
A baseline thyroid-stimulating hormone level helps uncover the occa-
sional hypothyroid- induced hyperlipidemia. Baseline transaminases
(alanine aminotransferase [ALT] and aspartate aminotransferase),
creatinine and creatine kinase (CK) are useful to monitor potential
side effects associated with therapy. The frequency of follow-up mea-
surements is debated but should probably be performed semiannually,
or with any changes in lipid-lowering therapy.
Statins are well tolerated by most individuals. Myalgias represent the
most common side effect of statins and may occur in approximately 5%
of patients, although similar rates are often seen in the placebo groups in
clinical trials. Statin-related myalgias are characterized by dull muscle
aches and can be made worse by exercise, although they may occur in
sedentary patients. Serum levels of CK may remain normal. The diagno-
sis should be based on drug cessation and re-challenge. Myositis is an
inflammation of skeletal muscles and the diagnosis is based on muscle
discomfort and elevation of CK to more than three times the upper limit
of normal. This is a potentially serious condition and may be caused by
strenuous exercise. Dose reduction and close monitoring of CK levels or
discontinuation of the statin are often required. Of note, a genetic pre-
disposition to myositis is thought to underlie a number of cases.
Rhabdomyolysis is a potentially life-threatening condition with a preva-
lence of less than 1:100,000 statin- treated patients. It is characterized by
severe muscle pains, myoglobinuria and possibly, acute renal failure and
a CK level of greater than 10,000 U/L. The discontinuation of statins
and prompt hospitalization for supportive treatment is required.
Significant increases in hepatic transaminase levels, defined as an ALT
level of greater than three times the upper limit of normal, occur in
0.3% to 2.0% of patients and are generally dose related.
Both crystalline niacin and extended-release niacin preparations
can result in persistent significant elevations in ALT in approximately
1% of patients. A general recommendation is to measure ALT at base-
line, and between one and three months after initiating niacin therapy.
Fasting blood glucose and glycosylated hemoglobin should be moni-
tored every six to 12 months in patients treated with niacin, in view of
its tendency to raise blood glucose levels. If these parameters deterio-
rate significantly in patients treated with niacin, consideration should
be given to dose reduction or withdrawal of niacin therapy. Uric acid
levels should be monitored in patients taking niacin.
Reversible increases in plasma creatinine of 15% to 20% are com-
mon in fibrate- treated patients and more significant increases can
occur in patients with underlying renal disease. In patients with
renal insufficiency (estimated glomerular filtration rate of less than
60 mL/min/1.73 m2), fibrates should be initiated at the lowest avail-
able dose and increased only after re-evaluation of renal function and
Referral to a specialty clinic, advanced laboratory tests and genetic
Physicians are often confronted with issues of drug intolerance, com-
plex diagnostic cases, lack of laboratory resources, seemingly unex-
plained atherosclerosis, extremes of lipoprotein disorders or a lack of
response to conventional therapies. In such cases, referral to a spe-
cialized centre may be warranted. Most academic centres across
Canada have specialized lipid clinics and the laboratory resources
required for more extensive testing. In extreme cases, therapeutic
modalities, such as extracorporeal LDL apheresis techniques, are
available. We recommend that lipoprotein disorder specialists be
available in each province to provide care for more difficult patients
referred from primary care physicians.
Genetic testing for severe lipoprotein disorders is available in a few
highly specialized centres. However, a molecular genetic diagnosis is
not necessary for the majority of patients with severe dyslipidemia; the
biochemical and clinical data usually suffice to make a diagnosis. As a
research tool, however, the molecular study of extreme lipoprotein
disorders has provided considerable scientific insight including the
identification of potential future therapeutic targets.
aCKNoWLeDGeMeNtS: The authors thank the external review-
ers, Dr Philip Barter, Sydney Heart Institute (Sydney, Australia) and
Dr David Waters, Professor Emeritus, University of California (San
Francisco, USA), for their criticisms and comments.
CoNFLiCtS oF iNteReSt: These guidelines were developed
without financial or logistical support from pharmaceutical companies.
Under no circumstances were funds requested or received for work
related to these recommendations by members of the writing group or
review panelists. A full disclosure of the conflicts of interest can be
found on the CCS Web site (www.ccs.ca).
2009 Canadian cholesterol guidelines
Can J Cardiol Vol 25 No 10 October 2009575
SCReeNiNG FaStiNG LiPiD PRoFiLe
•? Screen men who are at least 40 years of age, and women who are at
least 50 years of age or postmenopausal.
Obesity (body mass index greater than 27 kg/m2);
Family history of premature coronary artery disease;
Clinical signs of hyperlipidemia;
Evidence of atherosclerosis;
Rheumatoid arthritis, systemic lupus erythematosis, psoriasis;
HIV infection on highly active antiretroviral therapy;
Estimated glomerular filtration rate of less than
60 mL/min/1.73 m2; or
•? Screen? children? with? a? family? history? of? hypercholesterolemia? or?
CaRDioVaSCuLaR RiSK aSSeSSMeNt
Determine risk using the Framingham risk score modified for family history
(double the cardiovascular disease risk percentage if any cardiovascular dis-
ease is present in a first-degree relative before 60 years of age). In men older
than 50 years or women older than 60 years of age, of intermediate risk
whose low-density lipoprotein cholesterol does not already suggest treat-
ment, high-sensitivity C-reactive protein can be used for risk stratification.
taRGetS oF tHeRaPy
Risk levelPrimary target: lDl-C Class, level
*Clinicians should exercise judgement when implementing statin therapy. Meta-
analysis of statin trials show that for each 1.0 mmol/L decrease in low-density
lipoprotein cholesterol (LDL-C), there is a corresponding 20% to 25% RR reduc-
tion. Those whose 10-year risk for cardiovascular disease is 5% to 9% have been
shown in randomized clinical trials to achieve the same RR reduction from statin
therapy as those at higher 10-year risk, but the absolute benefit of therapy is esti-
mated to be smaller. apoB Apolipoprotein B; CAD Coronary artery disease; FRS
Framingham risk score; HDL-C High-density lipoprotein cholesterol; hs-CRP High-
sensitivity C-reactive protein; PVD Peripheral vascular disease; RRS Reynolds
Risk Score; TC Total cholesterol
Secondary (optional) targets (once low-density lipoprotein
cholesterol is at goal)
•? Total? cholesterol? to? high-density? lipoprotein? cholesterol? ratio? of?
less than 4.0;
Clinical trial evidence is lacking for secondary targets; clinical
judgements are warranted.
In high-risk patients, pharmacological therapy should be considered
concomitantly with lifestyle changes. In moderate-risk patients, lifestyle
changes should be implemented first, followed by medications if the
targets are not reached.
Generic nameTrade name (manufacturer) Dose range (daily)
bile acid and/or cholesterol absorption inhibitors
*Simvastatin 80 mg has a higher incidence of rhabdomyolysis; †Reduce dose
or avoid in renal impairment; ‡Should not be used with a statin because of an
increased risk of rhabdomyolysis
other risk factors/risk markers
The clinical usefulness of other risk factors or markers of risk has not
been evaluated in large-scale clinical trials.
Noninvasive assessment of atherosclerosis
The determination of the ankle-brachial index, carotid plaque, coro-
nary calcium score or multidetector computed tomography coronary
angiography will detect asymptomatic atherosclerosis not always pre-
dicted by the cardiovascular risk assessment algorithms.
Most lipid-lowering medications are well tolerated. Serum transami-
nases and creatine kinase should be followed regularly (every six to
12 months) or when symptoms develop. Follow-up is not required if
levels are consistently normal and the patient has no symptoms.
Referral to specialized clinics
Most Canadian universities have a specialized lipid clinic. Cases of unex-
plained atherosclerosis, severe dyslipidemias, genetic lipoprotein disorders
and patients refractory to pharmacological treatment should be referred.
Canadian CholeSterol GuidelineS 2009: Summary of reCommendationS
Genest et al
Can J Cardiol Vol 25 No 10 October 2009 576
SuPPlemeNTaRy Table 2
Criteria used for evaluation of evidence
level of evidence
SuPPlemeNTaRy Table 3
major changes since the 2006 recommendations
Treated Smoker Diabetic
120-129 <120 NO NO
35-39 <0.9 140-159 120-129
160+ 130-139 YES
Adapted from reference 33. HDL-C High-density lipoprotein cholesterol; SBP
Systolic blood pressure
120-129 NO NO
35-39 <0.9 140-149 120-129
40-44 150-159 YES
45-49 >160 140-149
SuPPlemeNTaRy Table 4b
Cardiovascular disease risk for men
Points Risk, %
SuPPlemeNTaRy Table 4a
estimation of 10-year risk of total cardiovascular disease in
men (Framingham Heart Study)
SuPPlemeNTaRy Table 5a
estimation of 10-year risk of total cardiovascular disease in
women (Framingham Heart Study)
SuPPlemeNTaRy Table 1
Stakeholders in the elaboration of the Canadian lipid guidelines
Adapted from reference 33. HDL-C High-density lipoprotein cholesterol; SBP
Systolic blood pressure
2009 Canadian cholesterol guidelines
Can J Cardiol Vol 25 No 10 October 2009 577
SuPPlemeNTaRy Table 5b
Cardiovascular disease risk for women
Points Risk, %
1. Heart and Stroke Foundation of Canada. The Growing
Burden of Heart Disease and Stroke in Canada 2003.
(Version current at August 13, 2009).
2. Statistics Canada. CANSIM. <http://cansim2.statcan.ca>
(Version current at August 13, 2009).
3. McPherson R, Frohlich J, Fodor G, Genest J; Canadian
Cardiovascular Society. Canadian Cardiovascular Society position
statement – recommendations for the diagnosis and treatment of
dyslipidemia and prevention of cardiovascular disease.
Can J Cardiol 2006;22:913-27.
4. Ridker PM, Rifai N, Cook NR, Bradwin G, Buring JE. Non-HDL
cholesterol, apolipoproteins A-I and B-100, standard lipid measures,
lipid ratios, and CRP as risk factors for cardiovascular disease in
women. JAMA 2005;294:326-33.
5. Ridker PM, Danielson E, Fonseca FA, et al; JUPITER Study
Group. Rosuvastatin to prevent vascular events in men and
women with elevated C-reactive protein. N Engl J Med
6. Lloyd-Jones DM, Nam BH, D’Agostino RB, et al. Parental
cardiovascular disease as a risk factor for cardiovascular disease in
middle-aged adults – a prospective study of parents and offspring.
7. Friedlander Y, Siscovick DS, Weinmann S, et al. Family history
as a risk factor for primary cardiac arrest. Circulation
8. Després JP, Lemieux I. Abdominal obesity and metabolic syndrome.
9. Katzmarzyk PT, Mason C. Prevalence of class I, II and III obesity in
Canada. CMAJ 2006;174:156-7.
10. Alberti KG, Zimmet P, Shaw J; IDF Epidemiology Task Force
Consensus Group. The metabolic syndrome – a new worldwide
definition. Lancet 2005;366:1059-62.
11. Ward MM. Premature morbidity from cardiovascular and
cerebrovascular diseases in women with systemic lupus
erythematosus. Arthritis Rheum 1999;42:338-46.
12. Gladman DD, Ang M, Su L, Tom BD, Schentag CT, Farewell VT.
Cardiovascular morbidity in psoriatic arthritis. Ann Rheum Dis
13. Thorburn CM, Ward MM. Hospitalizations for coronary artery
disease among patients with systemic lupus erythematosus. Arthritis
14. Dorn SD, Sandler RS. Inflammatory bowel disease is not a risk
factor for cardiovascular disease mortality: Results from a
systematic review and meta-analysis. Am J Gastroenterol
15. Bernstein CN, Wajda A, Blanchard JF. The incidence of arterial
thromboembolic diseases in inflammatory bowel disease:
A population-based study. Clin Gastroenterol Hepatol
16. DAD Study Group; Friis-Møller N, Reiss P, Sabin CA, et al. Class
of antiretroviral drugs and the risk of myocardial infarction.
N Engl J Med 2007;356:1723-35.
17. Baigent C, Keech A, Kearney PM, et al. Efficacy and safety of
cholesterol-lowering treatment: Prospective meta-analysis of data
from 90,056 participants in 14 randomised trials of statins. Lancet
18. The SEARCH Study. <http://www.ctsu.ox.ac.uk/~search/> (Version
current at August 13, 2009).
19. Fruchart JC, Sacks F, Hermans MP, et al. The residual risk
reduction initiative: A call to action to reduce residual
vascular risk in patients with dyslipidemia. Am J Cardiol
20. Johnson C, Waters DD, DeMicco DA, et al. Comparison of
effectiveness of atorvastatin 10 mg versus 80 mg in reducing major
cardiovascular events and repeat revascularization in patients with
previous percutaneous coronary intervention (post hoc analysis of
the Treating to New Targets [TNT] Study). Am J Cardiol
21. Ford ES, Ajani UA, Croft JB, et al. Explaining the decrease in U.S.
deaths from coronary disease, 1980-2000. N Engl J Med
22. Lonn E, Yusuf S, Arnold MJ, et al; Heart Outcomes Prevention
Evaluation (HOPE) 2 Investigators. Homocysteine lowering with
folic acid and B vitamins in vascular disease. N Engl J Med
23. Smith SC Jr, Allen J, Blair SN, et al; AHA/ACC; National
Heart, Lung, and Blood Institute. AHA/ACC guidelines for
secondary prevention for patients with coronary and other
atherosclerotic vascular disease: 2006 update: Endorsed by the
National Heart, Lung, and Blood Institute. Circulation
24. Yusuf S, Hawken S, Ounpuu S, et al; INTERHEART Study
Investigators. Effect of potentially modifiable risk factors
associated with myocardial infarction in 52 countries (the
INTERHEART study): Case-control study. Lancet
25. Go AS, Chertow GM, Fan DJ, McCulloch CE, Hsu CY.
Chronic kidney disease and the risks of death, cardiovascular
events, and hospitalization. N Engl J Med 2004;351:1296-305.
26. Sarnak MJ, Levey AS, Schoolwerth AC, et al. Kidney
disease as a risk factor for development of cardiovascular
disease – a statement from the American Heart Association
Councils on Kidney in Cardiovascular Disease,
High Blood Pressure Research, Clinical Cardiology,
and Epidemiology and Prevention. Circulation
27. Barbaro G, Iacobellis G. Metabolic syndrome associated with
HIV and highly active antiretroviral therapy. Curr Diab Rep
28. Galassi A, Reynolds K, He J. Metabolic syndrome and risk of
cardiovascular disease: A meta-analysis. Am J Med
29. Ridker PM, Buring JE, Cook NR, Rifai N. C-reactive protein, the
metabolic syndrome, and risk of incident cardiovascular events.
30. Danesh J, Collins R, Peto R. Lipoprotein(a) and coronary heart
disease – meta-analysis of prospective studies. Circulation
31. Davidson MH, Corson MA, Alberts MJ, et al. Consensus
panel recommendation for incorporating lipoprotein-
associated phospholipase A2 testing into cardiovascular
disease risk assessment guidelines. Am J Cardiol
32. NACB LMPG Committee Members; Myers GL, Christenson RH,
Cushman M, et al. National Academy of Clinical Biochemistry
Laboratory Medicine Practice Guidelines: Emerging biomarkers for
primary prevention of cardiovascular disease. Clin Chem
33. D’Agostino RB, Ramachandran SV, Pencina MJ, et al. General
cardiovascular risk profile for use in primary care. The Framingham
Heart Study. Circ 2008;117:743-53.
34. Grover SA, Lowensteyn I, Joseph L, et al; Cardiovascular
Health Evaluation to Improve Compliance and Knowledge
Among Uninformed Patients (CHECK-UP) Study Group.
Patient knowledge of coronary risk profile improves the
effectiveness of dyslipidemia therapy: The CHECK-UP study:
A randomized controlled trial. Arch Intern Med
35. Ridker PM, Buring JE, Rifai N, Cook NR. Development and
validation of improved algorithms for the assessment of global
cardiovascular risk in women: The Reynolds Risk Score. JAMA
Supplementary information – continued
Genest et al
Can J Cardiol Vol 25 No 10 October 2009578
36. Ridker PM, Paynter NP, Rifai N, Gaziano JM, Cook NR. C-reactive
protein and parental history improve global cardiovascular risk
prediction: The Reynolds Risk Score for men. Circulation
37. Michos ED, Blumenthal RS, Becker LC. Women with a
Framingham risk score < 10 and a family history of premature
CHD have a high prevalence of subclinical coronary
atherosclerosis. Circulation 2004;110:790.
38. Lloyd-Jones DM. Short-term versus long-term risk for coronary
artery disease: Implications for lipid guidelines. Curr Opin Lipidol
39. Graham I, Atar D, Borch-Johnsen K, et al. European guidelines on
cardiovascular disease prevention in clinical practice: Full text.
Fourth Joint Task Force of the European Society of Cardiology and
other societies on cardiovascular disease prevention in clinical
practice (constituted by representatives of nine societies and by
invited experts). Eur J Cardiovasc Prev Rehabil
40. Leiter L, Genest J, Harris SB, et al. Dyslipidemia. Canadian
Diabetes Association Clinical Practice Guidelines Expert
Committee. Can J Diabetes 2008;32(Suppl 1):S107-S114.
41. Downs JR, Clearfield M, Weis S, et al. Primary prevention of acute
coronary events with lovastatin in men and women with average
cholesterol levels – results of AFCAPS/TexCAPS. JAMA
42. Shepherd J, Cobbe SM, Ford I, et al. Prevention of coronary
heart-disease with pravastatin in men with hypercholesterolemia.
N Engl J Med 1995;333:1301-7.
43. Sever, PS, Dahlof B, Poulter NR, et al. Prevention of coronary and
stroke events with atorvastatin in hypertensive patients who have
average or lower-than-average cholesterol concentrations, in the
Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm
(ASCOT-LLA): A multicentre randomised controlled trial. Lancet
44. Heart Protection Study Collaborative Group. MRC/BHF Heart
Protection Study of cholesterol lowering with simvastatin in
20,536 high-risk individuals: A randomised placebo-controlled
trial. Lancet 2002;360:7-22.
45. Anand SS, Yusuf S, Vuksan V, et al. Differences in risk factors,
atherosclerosis, and cardiovascular disease between ethnic groups in
Canada: The Study of Health Assessment and Risk in Ethnic
Groups (SHARE). Lancet 2000;356:279-84.
46. Kaler SN, Ralph-Campbell K, Pohar S, King M, Laboucan CR,
Toth EL. High rates of the metabolic syndrome in a First
Nations Community in western Canada: Prevalence and
determinants in adults and children. Int J Circumpolar Health
47. Cannon CP, Braunwald E, Mccabe CH, et al. Intensive versus
moderate lipid lowering with statins after acute coronary syndromes.
N Engl J Med 2004;350:1495-504.
48. Larosa JC, Grundy SM, Waters DD, et al. Intensive lipid lowering
with atorvastatin in patients with stable coronary disease.
N Engl J Med 2005;352:1425-35.
49. Wiviott SD, de Lemos JA, Cannon CP, et al. A tale of two trials:
A comparison of the post-acute coronary syndrome lipid-lowering
trials A to Z and PROVE IT-TIMI 22. Circulation
50. Pedersen TR, Faergeman O, Kastelein JJP, et al. High-dose
atorvastatin vs usual-dose simvastatin for secondary prevention after
myocardial infarction: The IDEAL study: A randomized controlled
trial. JAMA 2005;294:2437-45.
51. Murphy SA, Cannon CP, Wiviott SD, et al. Effect of intensive
lipid-lowering therapy on mortality after acute coronary
syndrome (a patient-level analysis of the Aggrastat to Zocor and
Pravastatin or Atorvastatin Evaluation and Infection Therapy –
Thrombolysis in Myocardial Infarction 22 trials). Am J Cardiol
52. Thompson GR, Hollyer J, Waters DD. Percentage change rather
than plasma level of LDL-cholesterol determines therapeutic
response in coronary heart disease. Curr Opin Lipidol 1995;6:386-8.
53. Barter PJ, Ballantyne CM, Carmena R, et al. Apo B versus
cholesterol in estimating cardiovascular risk and in guiding therapy:
Report of the Thirty-Person/Ten-Country Panel. J Intern Med
54. van der Steeg WA, Boekholdt SM, Stein EA, et al. Role of the
apolipoprotein B-apolipoprotein A-I ratio in cardiovascular risk
assessment: A case-control analysis in EPIC-Norfolk.
Ann Intern Med 2007;146:640-8.
55. Nicholls SJ, Tuzcu EM, Sipahi I, et al. Statins, high-density
lipoprotein cholesterol, and regression of coronary atherosclerosis.
56. Kini AS, Muntner P, Moreno PR, et al. Relation of high-density
lipoprotein cholesterol to mortality after percutaneous coronary
interventions in patients with low-density lipoprotein <70 mg/dl.
Am J Cardiol 2009;103:350-4.
57. Ridker PM, Danielson E, Fonseca FA, et al; on behalf of the
JUPITER Trial Study Group. Reduction in C-reactive protein and
LDL cholesterol and cardiovascular event rates after initiation of
rosuvastatin: A prospective study of the JUPITER trial. Lancet
58. Kjekshus J, Apetrei E, Barrios V, et al; CORONA Group.
Rosuvastatin in older patients with systolic heart failure.
N Engl J Med 2007;357:2248-61.
59. Gissi-HF Investigators; Tavazzi L, Maggioni AP, Marchioli R, et al.
Effect of rosuvastatin in patients with chronic heart failure (the
GISSI-HF trial): A randomised, double-blind, placebo-controlled
trial. Lancet 2008;372:1231-9.
60. Wanner C, Krane V, März W, et al; German Diabetes and
Dialysis Study Investigators. Atorvastatin in patients with type 2
diabetes mellitus undergoing hemodialysis. N Engl J Med
61. Fellström BC, Jardine AG, Schmieder RE, et al; AURORA
Study Group. Rosuvastatin and cardiovascular events in
patients undergoing hemodialysis. N Engl J Med
62. Ankle Brachial Index Collaboration; Fowkes FG, Murray GD,
Butcher I, et al. Ankle brachial index combined with
Framingham Risk Score to predict cardiovascular events and
mortality: A meta-analysis. JAMA 2008;300:197-208.
63. Greenland P, Gaziano JM. Clinical practice. Selecting asymptomatic
patients for coronary computed tomography or electrocardiographic
exercise testing. N Engl J Med 2003;349:465-73.
64. Stein JH, Korcarz CE, Hurst RT, et al; American Society of
Echocardiography Carotid Intima-Media Thickness Task Force.
Use of carotid ultrasound to identify subclinical vascular disease
and evaluate cardiovascular disease risk: A consensus statement
from the American Society of Echocardiography Carotid
Intima-Media Thickness Task Force. Endorsed by the Society
for Vascular Medicine. J Am Soc Echocardiogr
65. Greenland P, Bonow RO, Brundage BH, et al. ACCF/AHA 2007
clinical expert consensus document on coronary artery calcium
scoring by computed tomography in global cardiovascular risk
assessment and in evaluation of patients with chest pain: A
report of the American College of Cardiology Foundation
Clinical Expert Consensus Task Force (ACCF/AHA Writing
Committee to Update the 2000 Expert Consensus Document on
Electron Beam Computed Tomography). Circulation
66. Miller JM, Rochitte CE, Dewey M, et al. Diagnostic performance
of coronary angiography by 64-row CT. N Engl J Med
67. Kloner RA, Rezkalla SH. To drink or not to drink? That is the
question. Circulation 2007;116:1306-17.
68. Sacks FM, Bray GA, Carey VJ, et al. Comparison of weight-loss
diets with different compositions of fat, protein, and carbohydrates.
N Engl J Med 2009;360:859-73.
69. Lichtman JH, Bigger JT Jr, Blumenthal JA, et al. Depression and
coronary heart disease: Recommendations for screening, referral,
and treatment: A science advisory from the American Heart
Association Prevention Committee of the Council on
Cardiovascular Nursing, Council on Clinical Cardiology,
Council on Epidemiology and Prevention, and Interdisciplinary
Council on Quality of Care and Outcomes Research: Endorsed
by the American Psychiatric Association. Circulation
70. Lespérance F, Frasure-Smith N, Koszycki D, et al; CREATE
Investigators. Effects of citalopram and interpersonal
psychotherapy on depression in patients with coronary artery
disease: The Canadian Cardiac Randomized Evaluation of
Antidepressant and Psychotherapy Efficacy (CREATE) trial.
2009 Canadian cholesterol guidelines
Can J Cardiol Vol 25 No 10 October 2009579
71. Frick MH, Elo O, Haapa K, et al. Helsinki Heart Study:
Primary-prevention trial with gemfibrozil in middle-aged men
with dyslipidemia. Safety of treatment, changes in risk factors,
and incidence of coronary heart disease. N Engl J Med
72. Rubins HB, Robins SJ, Collins D, et al. Gemfibrozil for the
secondary prevention of coronary heart disease in men with low
levels of high-density lipoprotein cholesterol. Veterans Affairs
High-Density Lipoprotein Cholesterol Intervention Trial Study
Group. N Engl J Med 1999;341:410-8.
73. Keech A, Simes RJ, Barter P, et al. Effects of long-term fenofibrate
therapy on cardiovascular events in 9795 people with type 2
diabetes mellitus (the FIELD study): Randomised controlled trial.
74. Frikke-Schmidt R, Nordestgaard BG, Stene MC, et al. Association
of loss-of-function mutations in the ABCA1 gene with high-density
lipoprotein cholesterol levels and risk of ischemic heart disease.
75. Alrasadi K, Awan K, Ruel I, et al. Comparison of treatment of
severe high-density lipoprotein cholesterol deficiency in men
with daily atorvastatin (20 mg) versus fenofibrate (200 mg)
versus extended-release niacin (2 g). Am J Cardiol
76. Barter PJ, Caulfield M, Eriksson M, et al; ILLUMINATE
Investigators. Effects of torcetrapib in patients at high risk for
coronary events. N Engl J Med 2007;357:2109-22.
77. Barter P, Gotto AM, LaRosa JC, et al; Treating to New Targets
Investigators. HDL cholesterol, very low levels of LDL
cholesterol, and cardiovascular events. N Engl J Med
78. Brown BG, Zhao XQ. Nicotinic acid, alone and in combinations,
for reduction of cardiovascular risk. Am J Cardiol
79. ClinicalTrials.gov. <http://clinicaltrials.gov/ct2/
results?term=NCT00461630> (Version current at August 13, 2009).