Download Heart rate management in coronary artery disease: the CLARIFY

European Heart Journal Supplements (2009) 11 (Supplement D), D13–D18
doi:10.1093/eurheartj/sup017
Heart rate management in coronary artery
disease: the CLARIFY registry
Philippe Gabriel Steg*
INSERM U-698, Université Paris 7 and Assistance Publique – Hôpitaux de Paris, Paris, France
KEYWORDS
Coronary artery disease;
Heart rate;
Epidemiology;
Prognosis;
Registry
Coronary artery disease (CAD) is and will remain the first cause of death worldwide.
With progress made in treatment, an increasing number of patients survive acute coronary syndromes and will live as outpatients with or without anginal symptoms. The
characteristics, management, and outcomes of patients with chronic stable CAD are
not well known, because most of the information available stems from the highly
selected patient populations enrolled in randomized clinical trials or from hospitalbased cohorts and was gathered almost exclusively in Europe and North America.
Finally, a large fraction of the information available relates to patients with anginal
symptoms. To better characterize these patients, a large international observational
registry will be launched: CLARIFY aims to enrol in more than 30 countries over four
continents 25 000 outpatients with stable CAD, defined as history of documented
myocardial infarction (of more than 3 months), prior coronary revascularization,
chest pain with documented myocardial ischaemia or coronary stenosis of .50%
proven by angiography. Patients will be followed up annually to 5 years, with collection of information regarding risk factors, medical history, anthropometric indices,
blood pressure, and heart rate, laboratory measurements, treatments and cardiovascular events and procedures. Establishing the determinants of prognosis and particularly the impact of resting heart rate is among the main goals. CLARIFY will provide
contemporary information regarding characteristics management and outcomes of
patients with stable CAD. This should help improve care and ultimately the outcomes
of these patients.
Coronary artery disease (CAD) remains the leading cause
of death worldwide.1 Despite a steady decline in industrialized countries, cardiovascular mortality has increased
in low- and middle-income countries, as these countries
are undergoing a rapid epidemiological transition to a
Western lifestyle and its attendant high rates of cardiovascular disease. Therefore, despite the tremendous
progress made in prevention and cure of cardiovascular
diseases, projections are that cardiovascular disease
will remain the leading cause of death in 2020–30.
* Corresponding author. Département de Cardiologie, Centre Hospitalier Bichat-Claude Bernard, 46 rue Henri Huchard, 75018 Paris, France.
Tel: þ33 (0) 1 40 25 86 68; fax: þ33 (0) 1 40 25 88 65.
E-mail address: [email protected]
Among cardiovascular causes, CAD was and will remain
the first cause of death and stroke the second.2 For
these reasons, any insight into how to improve care and
outcomes of patients with CAD is of tremendous value
to public health and to patients.
Current prognosis of coronary artery disease
It is now recognized that CAD is a chronic disease, which
remains silent for several decades, as atherosclerotic
plaque builds up in the coronary arteries but in which
acute coronary syndromes (i.e. acute myocardial infarction and unstable angina) are precipitated by plaque
rupture or erosion causing thrombosis. In the intervals
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2009.
For permissions please email: [email protected].
D14
between acute episodes, the disease may become silent
again or the patient may suffer from myocardial
ischaemia, generally triggered by exercise or emotions
and which may be (but not necessarily) associated with
anginal symptoms. These intervals between acute
exacerbations of the disease are generally designated
as chronic stable CAD. In the past 30 years, there has
been enormous progress in the diagnosis and management of acute coronary syndromes, which have translated into major reductions in the acute and chronic
mortality rates associated with these.3 In addition, secondary prevention of acute coronary syndromes has also
made giant strides, with a series of large randomized
clinical trials establishing the value of anti-platelet
therapy, statins, and angiotensin-converting enzyme
inhibitors in order to prevent adverse cardiac events in
these patients.4,5 Because of the major improvement in
the initial outcomes and the survival from acute episodes, the overall pool of patients with established CAD
has enlarged. This group of patients remains at high
risk of subsequent cardiovascular events. Their management is now rather well codified. Essentially, the lifestyle
interventions and drugs used for secondary prevention
are similar across all types of acute coronary syndromes
(with or without ST-segment elevation).
Prognostic factors in coronary artery disease
Starting with the Framingham study, there is a host of
data to compute the risk of ischaemic heart disease in
healthy individuals, using scores such as the Framingham
risk score, the European SCORE project,6 and similar
types of scores. Likewise, there have been many
studies of the determinants of prognosis in patients hospitalized for acute coronary syndromes (acute myocardial infarction or unstable angina).4,5 Using data from
the TIMI repository of randomized clinical trials, the
TIMI group has devised a series of TIMI scores to predict
outcomes in STEMI and in non-ST-segment elevation
ACS.7 Using data from the international Global Registry
of Acute Coronary Events (GRACE), the GRACE investigators designed several scores to compute the risk of
adverse outcomes for the whole spectrum of ACS.
There is one score to predict short-term outcomes,8
one score to predict post-discharge outcomes up to 6
months9 and one score to compute overall risk.10 These
scores have been shown to be robust11 and to retain validity over time despite changes in management and outcomes.12 For individuals with established cardiovascular
disease, there is much less data available on how to
compute prognosis in a ’secondary prevention setting’.
The Framingham study has created a score for predicting
the risk of subsequent cardiovascular event in patients
with established cardiovascular disease.13 Likewise, the
REACH registry analysed a large cohort of stable outpatients with established atherothrombosis (CAD, cerebrovascular disease or peripheral arterial disease) to
predict the subsequent probability of cardiovascular
death, non-fatal myocardial infarction and non-fatal
stroke.14
P. Gabriel Steg
The role of heart rate as a prognostic factor
Heart rate as a predictor for cardiovascular
disease in healthy individuals
Epidemiological studies have shown that resting heart
rate is a predictor of cardiovascular mortality in healthy
individuals15–21 and in hypertensive patients.22–24 In
addition, resting heart rate was also found to be a predictive factor for sudden death.25
Heart rate among patients with established
coronary artery disease
The prognostic importance of heart rate in acute coronary
syndrome has been underscored by the fact that it was
incorporated in prognostic scores such as the GRACE risk
score, to predict hospital and post-discharge mortality
across all types of acute coronary syndrome,8–10 or the
simplified TIMI index for ST-segment elevation myocardial
infarction.26–28
There has also been a large body of evidence to support
the association between resting heart rate and mortality
in patients with established stable CAD, starting with
observations from the trials of beta-blockade after
acute myocardial infarction29,30 to the fact that heart
rate was associated with the incidence of new coronary
events in patients undergoing Holter ECG monitoring31
and to subsequent strong evidence of the association
between heart rate and mortality in patients with
stable CAD.32,33 More recently, the placebo arm of the
randomized BEAUTIFUL trial allowed prospective study
of the prognostic role of resting heart rate in patients
with CAD and left ventricular systolic dysfunction and
showed that elevated heart rate was associated with an
increased risk of adverse fatal and non-fatal cardiac
events. More importantly, in that trial, ivabradine, a
pure heart rate-lowering agent, was associated with a
reduction in the risk of coronary events, particularly
fatal and non-fatal myocardial infarction, among patients
with a baseline heart rate above 70 b.p.m., providing
additional validation that elevated heart rate is indeed
in the causal pathway from CAD to cardiac events.
While many studies had demonstrated clinical benefits
using drugs which lowered heart rate, such as betablockers, these effects could not easily be separated
from the important benefits related to blockade of the
sympathetic nervous system34–38 Studies of ivabradine
test the concept that heart rate lowering per se is therapeutic. The mechanisms by which heart rate reduction
in general and by ivabradine in particular may play a
beneficial role in preventing cardiovascular death or
myocardial infarction are multiple and have been
reviewed elsewhere.39–46
The need for reliable registry data in stable
coronary artery disease
Most of the data pertaining to patients with stable CAD
come from randomized clinical trials of drugs used in
Heart rate management in CAD
the secondary prevention of cardiovascular events, such
as EUROPA,47 CHARISMA,48 TNT,49 etc. An important limitation of such datasets derived from randomized clinical
trials is the highly selective nature of randomized
trials, which are known to involve a selected patient
population, with more favourable baseline demographics, risk characteristics, and outcomes than the
general population. Typically, randomized clinical trials
also tend to underrepresent elderly patients (often due
to the co-morbidities frequently present), women or
patients with lower socioeconomic status. All of these
selection biases create issues regarding the generalization of the results of randomized clinical trials.50 In
addition, even patients from routine clinical practice
who mimic the characteristics of trial participants tend
to have better outcomes than actual trial participants.51
Therefore, it is important to complement the observations made in highly selected randomized clinical
trial populations with data from more representative
studies, such as large-scale registries.
Registries have attempted to capture the patient
population with stable CAD, but often focus on a
single country or geographic region, or on acute manifestations of the disease, or only on patients with
anginal symptoms. In addition, some studies are crosssectional and therefore do not allow us to establish
links between baseline characteristics, management,
and subsequent outcomes. Therefore, it would be
important to have longitudinal observation of a representative large cohort of patients with stable CAD, spanning several geographic regions, focussing on stable
outpatients (as opposed to patients hospitalized or
recently discharged from hospitals for acute manifestations of the disease), and including both symptomatic
and asymptomatic patients. It would also be important
that such a database captures all suspected important
determinants of outcomes in order to analyse not only
the baseline characteristics and management practices
but also outcomes and prognostic determinants, including heart rate. Finally, the measurement of heart rate is
not well standardized and can fluctuate substantially.
Therefore, using a dataset in which resting heart rate
is carefully and reliably measured will be critical when
trying to assess the precise role of heart rate in
prognosis.
D15
CLARIFY: the protocol
CLARIFY is an international, prospective, observational,
longitudinal registry in stable CAD outpatients, with
5-year follow-up. This observational registry is designed
to collect data on the current status of outpatients
with stable CAD, including their demographic characteristics, clinical profiles, therapeutic strategies, and outcomes. This is not an interventional study to assess the
impact of a predefined therapy. In this longitudinal
study, 25 000 subjects will be followed up for 5 years
and data will be collected prospectively at annual
visits. Because of substantial geographic variations in
the epidemiology of stable CAD, this registry will be
international, in order to generate reliable data on
several geographic regions of the world. This strategy
will enhance the value of the results and yield data on
international variability in disease presentation, management, and outcomes.
Subject selection
Inclusion criteria: the study will enrol outpatients with
stable CAD, proven by history of at least one of the following criteria (Table 1):
† Documented myocardial infarction (more than
3 months ago)
† Coronary stenosis of more than 50% proven by coronary
angiography
† Chest pain with myocardial ischaemia, proven by stress
ECG, stress echocardiography, or myocardial imaging
† Coronary artery bypass grafting (CABG) surgery or percutaneous coronary intervention (more than 3 months
ago).
The study will exclude:
† Patients hospitalized for cardiovascular disease within
last 3 months (including revascularization)
† Patients with planned revascularization
† Conditions hampering the participation or the 5-year
follow-up such as limited cooperation, limited legal
capacity, serious non-cardiovascular disease or conditions interfering with life expectancy (cancer, drug
Table 1 Selection criteria
Inclusion criteria: outpatients with stable CAD, proven by history of at least one of the following criteria
Documented myocardial infarction (more than 3 months ago)
Coronary stenosis of more than 50% proven by coronary angiography
Chest pain with myocardial ischaemia, proven by stress ECG, stress echocardiography, or myocardial imaging
Coronary artery bypass grafting (CABG) surgery or percutaneous coronary intervention (PCI) (more than 3 months ago)
Exclusion criteria
Patients hospitalized for cardiovascular disease within last 3 months (including revascularization)
Patients with planned revascularization
Conditions hampering the participation or the 5-year follow-up such as limited cooperation, limited legal capacity, serious
non-cardiovascular disease, or conditions interfering with life expectancy (cancer, drug abuse, etc.) or severe cardiovascular
disease (advanced heart failure, severe valve disease, history of valve repair/replacement, etc.)
D16
abuse, etc.), or severe cardiovascular disease
(advanced heart failure, severe valve disease, history
of valve repair/replacement, etc.).
Study setting and site selection
To ensure that the study population is representative of
the real-life community of stable CAD outpatients, the
recruitment of sites and subjects should be based on
two principles: predefined selection of physician types
and consecutive enrolment of subjects. Selection of participating sites will be ensured by a two-tiered process:
first, in each participating country, the types (primary
care, internists, cardiologists, or other specialties) and
practice settings (hospital-based as opposed to ambulatory practice) of physicians who are in charge of CAD
patients will be determined, using the best epidemiological sources as well as market research data. This will
allow targeting of an appropriate proportion of each of
these physician types and settings. Ultimately, site selection will be done, using this information, by the National
Coordinator in each country. Each physician will recruit a
maximum of 15 outpatients with stable CAD as defined by
the inclusion criteria. Patients will be enrolled in each
practice setting over a brief period of time, suggesting
near, if not consecutive, patient enrolment and limiting
‘cherry picking’. Enrolment will take place worldwide
between October 2009 and April 2010 (implying that
the last patient will end follow-up around April 2015).
Cardiologists as well as office-based primary care physicians, including general practitioners, internists, and
physicians based in hospitals with outpatient clinics will
be involved in the registry. Finally, to ensure that a
balanced representation of participating countries, a
general target enrolment for any participating country
is 25 patients per million inhabitants (range 12.5–50).
Data collection and evaluation
The data will be collected anonymously using electronic
forms at baseline and annually for 5 years to ascertain
clinical events, hospitalization, employment status, or
sick leave. Between annual visits, a 6-monthly phone
call will help maximize follow-up and retention rates.
Information collected at baseline will include demographics, medical history, risk factors, employment
status, physical examination, heart rate (determined by
both pulse palpation and 12-lead electrocardiography)
using the most recent ECG within 6 months in clinically
stable patients, laboratory values (if available), and
current chronic medical treatments.
Each annual follow-up visit will collect information
regarding clinical events occurring since the last visit,
hospitalizations, interventions, death, employment status,
physical examination, heart rate, laboratory values (if
available), and current medical therapy (cardiovascular
and non-cardiovascular). In addition, quality of life data
will be collected at baseline and at follow-up using the
simplified EQ-5D tool.
P. Gabriel Steg
Main outcomes to be collected
Five-year follow-up of patients will be undertaken to
collect morbidity/mortality data, particularly cardiovascular death [divided into fatal myocardial infarction,
sudden death, and other cardiovascular deaths (fatal
stroke, heart failure, ruptured aneurysm, pulmonary
embolism, cardiac investigation/procedure/operation)],
non-cardiovascular deaths, and cardiovascular morbidity
(i.e. hospitalization for non-fatal myocardial (re)infarction, unstable angina, new-onset or worsening heart
failure, coronary revascularization (PTCA or CABG), nonfatal stroke, and other vascular events or procedures).
Statistical considerations
The data will be collected and analysed by an independent statistics centre at the Robertson Centre for Biostatistics, University of Glasgow, UK. The main analyses are
designed to describe patient characteristics at baseline
(including resting heart rate, other risk factors, and
medical therapy) and to estimate the annual cardiovascular event rates, and the outcome event rates by
region and country. Finally, another goal for CLARIFY is
to develop predictive models based on resting heart
rate to estimate the risk of subsequent cardiovascular
events in patients with CAD.
Determination of sample size
CLARIFY is an observational registry, and the size of the
population is not based on treatment comparison. The
number of patients that must be included depends on
cardiovascular event rates, number of subjects lost to
follow-up, and study duration. It is assumed that
CLARIFY will screen and enrol 25 000 subjects and
follow them up for 5 years with a loss to follow-up rate
of no greater than 5% per annum. Taking a conservative
approach and assuming that 1500 cardiovascular deaths
occur, there is ample power (at least 80%) to identify a
20% increase in mortality when comparing highest to
lowest quartiles of heart rate, if it is studied as a
categorical variable. Treating heart rate as a continuous
variable, we would have 90% power with a 5% alpha
error to detect an underlying hazard ratio of 1.06 per
10 b.p.m. increase in heart rate.
Event rates will be estimated using the Kaplan–Meier
approach and using estimated cumulative incidence
functions. The relationship between baseline heart rate
(from the ECG) and cardiovascular outcomes will be
modelled using parametric and semi-parametric models
(Cox proportional hazard models). Assumptions and
goodness-of-fit will be assessed using appropriate
statistical methods. Heart rate will be modelled as a
continuous variable and after categorization. The
additional prognostic value of heart rate will be determined using statistical tests of nested models and using
the c-index.
Heart rate management in CAD
Data management and ethical considerations
All data will be entered into an electronic case report
form and sent electronically by each country to the
data management centre where checks for completeness, internal consistency, and accuracy will be run.
Each site will obtain written consent from subjects,
verify inclusion criteria, and collect baseline data prospectively by questioning the subject. Pulse palpation
and the data from the most recent ECG within 6
months in clinically stable patients will be used to
obtain resting heart rate.
Data quality control will be performed onsite in 5% of
sites chosen at random in each country. At these sites,
100% of case report forms for patients enrolled at that
site will be monitored for source documentation and
accuracy. Data quality control will be done at
face-to-face quality control visits and will involve
review of source documents supporting the adequacy
and accuracy of data collected on the case report forms.
The study will be approved by local institutional review
boards and all patients will give informed consent in
accordance with national and local guidelines. Patient confidentiality will be ensured by utilizing patient identification code numbers to correspond to the computer files.
Anticipated insights from CLARIFY
CLARIFY will constitute the first large-scale international
registry of outpatients with stable CAD and provide contemporary information about the characteristics, management, and outcomes of these patients across a
variety of geographic and practice settings. It will also
collect information regarding quality of life and its
changes over time. It will help identify gaps between
evidence-based guidelines and clinical practice and
avenues for potential improvement, and should help
clarify the prognostic indicators in this population.
Additionally, it will provide an opportunity to test prospectively the importance of carefully collected resting
heart rate as a predictor of future cardiac events in
that population. This information should help improve
the care and ultimately the clinical outcomes of this
large group of patients who continue to remain, despite
medical progress, at high risk of adverse clinical outcomes and death.
Conflict of interest: P.G.S. receiving research grant from sanofiaventis (1999–2008) (significant), speakers bureau (all modest)
in Boehringer-Ingelheim, BMS, GSK, Menarini, Medtronic,
Nycomed, Pierre Fabre, sanofi-aventis, Servier, The Medicines
Company, consulting/advisory board (all modest) in Astellas,
AstraZeneca, Bayer, Boehringer-Ingelheim, BMS, DaiichiSankyo, Endotis, GSK, Medtronic, MSD, Nycomed, sanofiaventis, Servier, The Medicines Company and stockholding
Aterovax.
References
1. Anderson GF, Chu E. Expanding priorities—confronting chronic disease
in countries with low income. N Engl J Med 2007;356:209–211.
D17
2. Murray CJL, Lopez AD. Alternative projections of mortality and
disability by cause 1990–2020: Global Burden of Disease Study.
Lancet 1997;349:1498–1504.
3. Fox KA, Steg PG, Eagle KA, Goodman SG, Anderson FA Jr, Granger CB,
Flather MD, Budaj A, Quill A, Gore JM, GRACE Investigators. Decline
in rates of death and heart failure in acute coronary syndromes,
1999–2006. J Am Med Assoc 2007;297:1892–1900.
4. Van de Werf F, Bax J, Betriu A, Blomstrom-Lundqvist C, Crea F, Falk V,
Filippatos G, Fox K, Huber K, Kastrati A, Rosengren A, Steg PG,
Tubaro M, Verheugt F, Weidinger F, Weis M, Vahanian A, Camm J,
De Caterina R, Dean V, Dickstein K, Filippatos G, Funck-Brentano C,
Hellemans I, Kristensen SD, McGregor K, Sechtem U, Silber S,
Tendera M, Widimsky P, Zamorano JL, Silber S, Aguirre FV,
Al-Attar N, Alegria E, Andreotti F, Benzer W, Breithardt O,
Danchin N, Di Mario C, Dudek D, Gulba D, Halvorsen S, Kaufmann P,
Kornowski R, Lip GY, Rutten F, ESC Committee for Practice Guidelines
(CPG). Management of acute myocardial infarction in patients presenting with persistent ST-segment elevation: the Task Force on the
Management of ST-Segment Elevation Acute Myocardial Infarction
of the European Society of Cardiology. Eur Heart J 2008;29:
2909–2945.
5. Bassand JP, Hamm CW, Ardissino D, Boersma E, Budaj A,
Fernández-Avilés F, Fox KA, Hasdai D, Ohman EM, Wallentin L,
Wijns W. Guidelines for the diagnosis and treatment of
non-ST-segment elevation acute coronary syndromes. Task Force for
Diagnosis and Treatment of Non-ST-Segment Elevation Acute Coronary Syndromes of European Society of Cardiology. Eur Heart J 2007;
28:1598–1660.
6. Conroy RM, Pyörälä K, Fitzgerald AP, Sans S, Menotti A, De Backer G,
De Bacquer D, Ducimetière P, Jousilahti P, Keil U, Njølstad I,
Oganov RG, Thomsen T, Tunstall-Pedoe H, Tverdal A, Wedel H,
Whincup P, Wilhelmsen L, Graham IM, SCORE project group. Estimation of ten-year risk of fatal cardiovascular disease in Europe:
the SCORE project. Eur Heart J 2003;24:987–1003.
7. Antman EM, Cohen M, Bernink PJ, McCabe CH, Horacek T, Papuchis G,
Mautner B, Corbalan R, Radley D, Braunwald E. The TIMI risk score for
unstable angina/non-ST elevation MI: a method for prognostication
and therapeutic decision making. J Am Med Assoc 2000;284:835–842.
8. Granger CB, Goldberg RJ, Dabbous O, Pieper KS, Eagle KA, Cannon CP,
Van De Werf F, Avezum A, Goodman SG, Flather MD, Fox KA. Global
Registry of Acute Coronary Events Investigators. Predictors of hospital
mortality in the global registry of acute coronary events. Arch Intern
Med 2003;163:2345–2353.
9. Eagle KA, Lim MJ, Dabbous OH, Pieper KS, Goldberg RJ, Van de Werf F,
Goodman SG, Granger CB, Steg PG, Gore JM, Budaj A, Avezum A,
Flather MD, Fox KA, GRACE Investigators. A validated prediction
model for all forms of acute coronary syndrome: estimating the risk
of 6-month postdischarge death in an international registry. J Am
Med Assoc 2004;291:2727–2733.
10. Fox KA, Dabbous OH, Goldberg RJ, Pieper KS, Eagle KA, Van de Werf F,
Avezum A, Goodman SG, Flather MD, Anderson FA Jr, Granger CB. Prediction of risk of death and myocardial infarction in the six months
after presentation with acute coronary syndrome: prospective multinational observational study (GRACE). BMJ 2006;333:1091.
11. de Araújo Gonçalves P, Ferreira J, Aguiar C, Seabra-Gomes R. TIMI,
PURSUIT, and GRACE risk scores: sustained prognostic value and interaction with revascularization in NSTE-ACS. Eur Heart J 2005;26:
865–872.
12. Pieper KS, Gore JM, FitzGerald G, Granger CB, Goldberg RJ, Steg G,
Eagle KA, Anderson FA, Budaj A, Fox KA, Global Registry of Acute Coronary Events (GRACE) Investigators. Validity of a risk-prediction tool
for hospital mortality: the Global Registry of Acute Coronary Events.
Am Heart J 2009;157:1097–1105.
13. Fox CS, Pencina MJ, Wilson PW, Paynter NP, Vasan RS, D’Agostino RB
Sr. Lifetime risk of cardiovascular disease among individuals with and
without diabetes stratified by obesity status in the Framingham heart
study. Diabetes Care 2008;31:1582–1584.
14. Wilson PWF, Bhatt DL, Dalongeville J, D’Agostino R, Eagle K, Goto S,
Greenland P, Hirsh AT, Liau C-S, Ohman EM, Rother J, Reid C, Mas J-J,
Steg PG, on behalf of the REACH registry Investigators. An International Risk Prediction Model for Recurrent Cardiovascular Ischemic
Events. In The REACH Registry. J Am Coll Cardiol 2007; 396A
Abstract ACC.
D18
15. Shaper AG, Wannamethee G, Macfarlane PW, Walker M. Heart rate,
ischaemic heart disease, and sudden cardiac death in middle-aged
British men. Br Heart J 1993;70:49–55.
16. Kannel WB, Kannel C, Paffenbarger RS Jr, Cupples LA. Heart rate and
cardiovascular mortality: the Framingham study. Am Heart J 1987;
113:1489–1494.
17. Filipovský J, Ducimetière P, Safar ME. Prognostic significance of exercise blood pressure and heart rate in middle-aged men. Hypertension
1992;20:333–339.
18. Palatini P, Casiglia E, Julius S, Pessina AC. High heart rate: a risk
factor for cardiovascular death in elderly men. Arch Intern Med
1999;159:585–592.
19. Greenland P, Daviglus ML, Dyer AR, Liu K, Huang CF, Goldberger JJ,
Stamler J. Resting heart rate is a risk factor for cardiovascular and
noncardiovascular mortality: the Chicago Heart Association Detection
Project in Industry. Am J Epidemiol 1999;149:853–862.
20. Hsia J, Larson JC, Ockene JK, Sarto GE, Allison MA, Hendrix SL,
Robinson JG, LaCroix AZ, Manson JE, Women’s Health Initiative
Research Group. Resting heart rate as a low tech predictor of coronary events in women: prospective cohort study. BMJ 2009;338:b219.
21. Jouven X, Empana JP, Escolano S, Buyck JF, Tafflet M, Desnos M,
Ducimetière P. Relation of heart rate at rest and long-term (.20
years) death rate in initially healthy middle-aged men. Am J
Cardiol 2009;103:279–283.
22. Benetos A, Rudnichi A, Thomas F, Safar M, Guize L. Influence of heart
rate on mortality in a French population: role of age, gender, and
blood pressure. Hypertension 1999;33:44–52.
23. Kolloch R, Legler UF, Champion A, Cooper-Dehoff RM, Handberg E,
Zhou Q, Pepine CJ. Impact of resting heart rate on outcomes in
hypertensive patients with coronary artery disease: findings from
the INternational VErapamil-SR/trandolapril STudy (INVEST). Eur
Heart J 2008;29:1327–1334.
24. Gillman MW, Kannel WB, Belanger A, D’Agostino RB. Influence of
heart rate on mortality among persons with hypertension: the Framingham study. Am Heart J 1993;125:1148–1154.
25. Jouven X, Zureik M, Desnos M, Guérot C, Ducimetière P. Resting heart
rate as a predictive risk factor for sudden death in middle-aged men.
Cardiovasc Res 2001;50:373–378.
26. Wiviott SD, Morrow DA, Frederick PD, Giugliano RP, Gibson CM,
McCabe CH, Cannon CP, Antman EM, Braunwald E. Performance of
the thrombolysis in myocardial infarction risk index in the National
Registry of Myocardial Infarction-3 and -4: a simple index that predicts mortality in ST-segment elevation myocardial infarction. J Am
Coll Cardiol 2004;44:783–789.
27. Morrow DA, Antman EM, Giugliano RP, Cairns R, Charlesworth A,
Murphy SA, de Lemos JA, McCabe CH, Braunwald E. A simple risk
index for rapid initial triage of patients with ST-elevation myocardial
infarction: an InTIME II substudy. Lancet 2001;358:1571–1575.
28. Morrow DA, Antman EM, Charlesworth A, Cairns R, Murphy SA, de
Lemos JA, Giugliano RP, McCabe CH, Braunwald E. TIMI risk score
for ST-elevation myocardial infarction: a convenient, bedside, clinical score for risk assessment at presentation. An Intravenous nPA
for Treatment of Infarcting Myocardium Early II Trial substudy. Circulation 2000;102:2031–2037.
29. Gundersen T, Grottum P, Pedersen T, Kjekshus JK. Effect of timolol on
mortality and reinfarction after acute myocardial infarction: prognostic importance of heart rate at rest. Am J Cardiol 1986;58:20–24.
30. Hjalmarson A, Gilpin EA, Kjekshus J, Schieman G, Nicod P, Henning H,
Ross J Jr. Influence of heart rate on mortality after acute myocardial
infarction. Am J Cardiol 1990;65:547–553.
31. Aronow WS, Ahn C, Mercando AD, Epstein S. Association of average
heart rate on 24 h ambulatory electrocardiograms with incidence of
new coronary events at 48-month follow-up in 1,311 patients
(mean age 81 years) with heart disease and sinus rhythm. Am J
Cardiol 1996;78:1175–1176.
32. Palatini P. Heart rate: a strong predictor of mortality in subjects with
coronary artery disease. Eur Heart J 2005;26:943–945.
33. Diaz A, Bourassa MG, Guertin MC, Tardif JC. Long-term prognostic
value of resting heart rate in patients with suspected or proven coronary artery disease. Eur Heart J 2005;26:967–974.
P. Gabriel Steg
34. Laperche T, Logeart D, Cohen-Solal A, Gourgon R. Potential interests
of heart rate lowering drugs. Heart 1999;81:336–341.
35. Hjalmarson A. Significance of reduction in heart rate in cardiovascular disease. Clin Cardiol 1998;21:II3–II7.
36. Lechat P, Hulot J-S, Escolano S, Mallet A, Leizorovicz A, WerhlenGrandjean M, Pochmalicki G, Dargie H. Heart rate and cardiac
rhythm relationships with bisoprolol benefit in chronic heart failure
in CIBIS II trial. Circulation 2001;103:1428–1433.
37. Cucherat M. Quantitative relationship between resting heart rate
reduction and magnitude of clinical benefits in post-myocardial
infarction: a meta-regression of randomized clinical trials. Eur
Heart J 2007;28:3012–3097.
38. Flannery G, Gehrig-Mills R, Billah B, Krum H. Analysis of randomized
controlled trials on the effect of magnitude of heart rate reduction
on clinical outcomes in patients with systolic chronic heart filure
receiving beta-blockers. Am J Cardiol 2008;101:865–869.
39. Fox K, Borer JS, Camm J, Danchin N, Ferrari R, Lopez Sendon JL,
Steg PG, Tardif JC, Tavazzi L, Tendera M, the Heart Rate Working
Group. J Am Coll Cardiol 2007;50:823–830.
40. Giannoglou GD, Chatzizisis YS, Zamboulis C, Parcharidis GE,
Mikhailidis DP, Louridas GE. Elevated heart rate and atherosclerosis:
an overview of the pathogenetic mechanisms. Int J Cardiol 2008;
126:302–312.
41. Custodis F, Baumhäkel M, Schlimmer N, List F, Gensch C, Böhm M,
Laufs U. Heart rate reduction by ivabradine reduces oxidative
stress, improves endothelial function, and prevents atherosclerosis
in apolipoprotein E-deficient mice. Circulation 2008;117:2377–2387.
42. Drouin A, Gendron ME, Thorin E, Gillis MA, Mahlberg-Gaudin F,
Tardif JC. Chronic heart rate reduction by ivabradine prevents endothelial dysfunction in dyslipidaemic mice. Br J Pharmacol 2008;154:
749–757.
43. Yamamoto E, Lai Z, Yamashita T, Tanaka T, Kataoka K. Enhancement
of cardiac oxidative stress by tachycardia and its critical role in
cardiac hypertrophy and fibrosis. J Hypertens 2006;24:2057–2069.
44. Rogowski O, Shapira I, Shirom A, Melamed S, Toker S, Berliner S.
Heart rate and microinflammation in men: a relevant atherothrombotic link. Heart 2007;93:940–944.
45. Heidland UE, Strauer BE. Left ventricular muscle mass and elevated
heart rate are associated with coronary plaque disruption. Circulation 2001;104:1477–1482.
46. Patel SR, Breall JA, Diver DJ, Gersh BJ, Levy APl. Bradycardia is
associated with development of coronary collateral vessels in
humans. Coron Artery Dis 2000;11:467–472.
47. Fox KM, EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease Investigators. Efficacy of perindopril in reduction of cardiovascular events among patients with
stable coronary artery disease: randomised, double-blind, placebocontrolled, multicentre trial (the EUROPA study). Lancet 2003;362:
782–788.
48. Bhatt DL, Fox KA, Hacke W, Berger PB, Black HR, Boden WE, Cacoub P,
Cohen EA, Creager MA, Easton JD, Flather MD, Haffner SM, Hamm CW,
Hankey GJ, Johnston SC, Mak KH, Mas JL, Montalescot G, Pearson TA,
Steg PG, Steinhubl SR, Weber MA, Brennan DM, Fabry-Ribaudo L,
Booth J, Topol EJ, CHARISMA Investigators. Clopidogrel and aspirin
versus aspirin alone for the prevention of atherothrombotic events.
N Engl J Med 2006;354:1706–1717.
49. LaRosa JC, Grundy SM, Waters DD, Shear C, Barter P, Fruchart JC,
Gotto AM, Greten H, Kastelein JJ, Shepherd J, Wenger NK, Treating
to New Targets (TNT) Investigators. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med 2005;
352:1425–1435.
50. Rothwell PM. External validity of randomised controlled trials: ‘to
whom do the results of this trial apply?’. Lancet 2005;365:82–93.
51. Steg PG, López-Sendón J, Lopez de Sa E, Goodman SG, Gore JM,
Anderson FA Jr, Himbert D, Allegrone J, Van de Werf F, GRACE Investigators. External validity of clinical trials in acute myocardial infarction. Arch Intern Med 2007;167:68–73.