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Angiotensin-converting enzyme inhibition: a landmark advance in treatment for cardiovascular diseases
Jeffrey S. Borer
Weill Medical College of Cornell University, 47 East 88th Street, New York, NY 10128-1151, USA
Corresponding author. Tel: +1 212 746 4646; fax: +1 212 426 4353. E-mail address: canadad45{at}aol.com
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Abstract
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Angiotensin-converting enzyme-inhibitors (ACE inhibitors) were
first introduced into clinical practice for the relief of hypertension
(HT) more than a quarter of a century ago. Since that time,
as the basic pathobiology of cardiovascular (CV) diseases has
been increasingly understood, new applications for ACE inhibitors
have been developed. Indeed, through their action on the renin–angiotensin
system (RAS) and their local actions, ACE inhibitors have substantially
improved the prognosis of patients with diseases over the entire
continuum of CV disease, including HT, stable coronary artery
disease, myocardial infarction (MI), and heart failure (HF),
and have been applied specifically to prevent stroke, although
also preventing diabetes and delaying or reducing renal dysfunction.
The strength of available clinical data is such that guidelines
developed for cardiologists by professional societies now recommend
the use of ACE inhibitors for the management of HT, coronary
and atherosclerotic vascular disease, MI, and HF. Newer ACE
inhibitors with pharmacological profiles differing from those
of older agents have added to the ease of application and relative
safety of these drugs both for reduction of symptoms and for
improvement of outcomes. Although other agents modulating RAS
can provide some overlapping pharmacological effects and important
clinical benefits, ACE inhibitors remain unique in the range
of their proven benefits, justifying their central role in the
armamentarium of the CV specialist.
Key Words: Angiotensin-converting enzyme inhibition • Cardiovascular disease • Renin–angiotensin system
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Introduction
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Angiotensin-converting enzyme-inhibitors (ACE inhibitors) were
first introduced into clinical practice for hypertension (HT)
relief more than a quarter of a century ago. Since that time,
as the basic pathobiology of cardiovascular (CV) diseases has
been increasingly better understood and the likely physiological
and pathophysiological roles of ACE have been more fully elucidated,
new applications regularly have been developed, including therapies
for heart failure (HF)/left ventricular (LV) dysfunction, renal
diseases of various aetiologies, myocardial infarction (MI),
and stable coronary artery disease (CAD). As a result, during
the ensuing decades, this group of drugs has been responsible
for substantial improvement in outcome of patients with various
CV and associated diseases. Indeed, ACE inhibitors have demonstrated
efficacy throughout the continuum of CV disease from underlying
risk factors such as HT prior to the development of overt CV
disease, through end-stage CAD and HF (
Figure 1), in addition
to retarding renal dysfunction and the appearance of diabetes
mellitus.
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Figure 1 Major studies of angiotensin-converting enzyme-inhibitors along the cardiovascular disease continuum. AIRE, Acute Infarction Ramipril Efficacy Study; ALLHAT, Antihypertensive and Lipid-lowering Treatment to Prevent Heart Attack Trial; ASCOT-BPLA, Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm; CAD, coronary artery disease; CAPPP, Captopril Prevention Project; CHF, congestive heart failure; CONSENSUS, Cooperative North Scandinavian Enalapril Survival Study; CVD, cerebrovascular disease; EUROPA, European Trial on Reduction of Cardiac Events with Perindopril among Patients with Stable Coronary Artery Disease; ESRD, end-stage renal disease; HOPE, Heart Outcomes Prevention Evaluation; MI, myocardial infarction; PEACE, Prevention of Events with ACE Inhibition; PEP-CHF, Perindopril in Elderly People with Chronic Heart Failure; PREAMI, Perindopril and Remodeling in Elderly with Acute Myocardial infarction; PROGRESS, Perindopril Protection against Recurrent Stroke Study; REIN, Ramipril Efficacy in Nephropathy; SAVE, Survival and Ventricular Enlargement study; SOLVD, Studies of Left Ventricular Dysfunction; STOP-H2, Swedish Trial in Old Patients with Hypertension; TRACE, Trandolapril Cardiac Evaluation Study; V-HeFT, Vasodilator-Heart Failure Trial.
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History
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The first clinically available ACE inhibitor, captopril, was
initially developed for the treatment of HT, focusing specifically
on patients believed to have a predominantly renin-dependent
pathophysiology.
1 It may be of interest, given the widespread
application of ACE inhibitors during the succeeding 25 years,
that initial approval by the US Food and Drug Administration
(FDA) was associated with intense debate and discussion. The
drug's developer had performed initial approvability trials
in a population including a relatively high proportion of patients
with ‘collagen-vascular’ diseases; drug-associated
renal dysfunction in this population was disturbingly frequent.
Indeed, after prolonged discussion, the FDA's Cardio-Renal Advisory
Committee (on which I was serving my first term at the time)
finally voted for approval, but required the label to carry
a warning and the admonition that the drug should only be used
after two other drugs had failed to achieve acceptable blood
pressure (BP) control! Four years later, the second ACE inhibitor
to come to the FDA, enalapril, was introduced with a dossier
including far fewer patients afflicted with collagen-vascular
diseases and, perhaps as a result, with very little evidence
of renal dysfunction. Enalapril was quickly recommended for
approval by the Cardio-Renal panel—but its consideration
sparked a debate about the importance of differences in the
molecular structures of different ACE inhibitors to account
for differences in adverse pharmacological effects. In this
case, the sulfhydril groups of captopril (not present in enalapril)
were putatively, although perhaps incorrectly, associated with
the adverse renal experiences. Differences in the pharmacological
effects of different ACE inhibitors remain an important theme
today—but the overwhelming benefits associated with these
drugs, as a group, have earned them an important place as first-line
agents throughout the CV continuum.
Following captopril, several more ACE inhibitors were developed, with somewhat different pharmacological characteristics (longer duration of action, different adverse profiles, more or less efficacy vs. risk for various outcomes, etc.). During this interval, considerable evidence accumulated to support the therapeutic effects of ACE inhibitor beyond BP lowering (vascular, cardiac, and renal), even in the absence of systemic hyperactivity of the renin–angiotensin system (RAS). Indeed, as is the case with all drugs, ACE inhibitors have multiple pharmacological effects; both the benefits and the risks of ACE inhibitors cannot be attributable solely to systemic ACE inhibition.
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Benefits at the early stage of the cardiovascular disease continuum—hypertension
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ACE inhibitors were first developed for the treatment of HT,
for which they remain mainstays of therapy. Indeed, multiple
studies have demonstrated the efficacy of ACE inhibitor for
chronic BP reduction, particularly among patients with renin-dependent
HT; systemic renin excess incontrovertibly heightens the adverse
outcome risks of HT.
2–6 However, BP reduction in patients
with HT is therapeutic for stroke, MI, and CV death; BP reduction
in such patients is a well-demonstrated surrogate for reduction
in the risks of these outcome events. Consistent with this concept,
morbidity–mortality trials in HT have demonstrated the
efficacy of ACE inhibitor. The first such trials, Swedish Trial
in Old Patients with Hypertension (STOP-H2) and Captopril Prevention
Project (CAPPP) (
Figure 2),
3,4 demonstrated equivalent
benefits of ACE inhibitor to those of earlier established antihypertensive
agents, diuretics, and beta-blockers. The later Antihypertensive
and Lipid-lowering Treatment to Prevent Heart Attack Trial (ALLHAT)
found a similar effect on major CV outcomes with the ACE inhibitor,
lisinopril, in comparison with a thiazide diuretic, despite
significantly greater BP reduction with the diuretic.
5 Indeed,
owing to the accumulated evidence of efficacy in minimizing
specific sequelae of HT as well as of other CV diseases, ACE
inhibitors have the broadest spectrum of indications for use,
as endorsed by peer-selected expert guidelines committees, among
all antihypertensive agents.
7 Finally, in the recently published
Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering
Arm (ASCOT-BPLA) in which ACE inhibitor perindopril was coupled
with calcium channel blockade by a dihydropyridine (amlodipine),
the newer combination strategy was convincingly demonstrated
to provide greater reduction in total mortality (11%), major
CV events and procedures (16%), and new-onset diabetes (30%),
than equivalent BP lowering with the combination of a beta-blocker
and thiazide diuretic.
2
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Figure 2 (A) Relative risk of cardiovascular mortality and morbidity for ACE inhibitor vs. conventional therapy in the STOP-H2 trial. Data are adjusted for age, sex, diabetes, diastolic blood pressure, and smoking. Adapted with permission from Figure 3.4 (B) Relative risk of cardiovascular mortality and morbidity for captopril vs. conventional therapy in the CAPPP trial. The primary endpoint was a composite of fatal and non-fatal myocardial infarction, stroke, and other cardiovascular deaths. ACE inhibitor, angiotensin-converting enzyme-inhibitors; CAPPP, Captopril Prevention Project; CI, confidence interval; STOP-H2, Swedish Trial in Old Patients with Hypertension. Adapted with permission from Table 4.3
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Heart failure
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Since 1987, several large, prospective, randomized, placebo-controlled
clinical trials have demonstrated that treatment with several
different ACE inhibitors reduces mortality rates in patients
who have HF associated with systolic dysfunction.
8–11 In Cooperative North Scandinavian Enalapril Survival Study I
(CONSENSUS I), substantial mortality benefit was conferred by
administration of enalapril when compared with placebo, when
administered to patients with severe HF (
Figure 3).
8 The
Studies of Left Ventricular Dysfunction (SOLVD) extended these
benefits to a broader range of patients, including not only
those with symptomatic HF but also those with LV dysfunction
who were asymptomatic (‘Functional Class 0’ HF).
9,10 Vasodilator-Heart Failure Trial II (V-HeFT II) compared enalapril
with hydralazine plus nitrates, a combination that improved
outcome vs. placebo in the earlier Vasodilator-Heart Failure
Trial I (V-HeFT I), and demonstrated significantly enhanced
survival with the ACE inhibitor.
11 As a result of these and
other parallel studies, ACE inhibitors have been recommended
for indefinite administration to patients with chronic HF and
systolic dysfunction, both to minimize symptoms and to prolong
survival.
12,13
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Figure 3 Cumulative probability of death in the placebo and enalapril groups: the Cooperative North Scandinavian Enalapril Survival Study I (CONSENSUS I) trial of patients with severe heart failure. Reproduced with permission from Figure 1.8
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Although, as of yet, less compellingly demonstrated, HF associated
primarily with diastolic dysfunction may respond to ACE inhibitor.
This putative benefit may result from drug-mediated cardiac
remodelling, with reduction of myocardial mass, fibrosis (possibly
a direct effect of ACE inhibitors, as discussed subsequently),
and stiffness. Consistent with this hypothesis, a meta-analysis
of studies of anti-HT drugs has found ACE inhibitors to be the
most effective of these agents in reversing LV hypertrophy.
14 More importantly, in a study of the ACE inhibitors, perindopril
[Perindopril in Elderly People with Chronic Heart Failure (PEP-CHF)],
among patients with HF and diastolic dysfunction, benefit was
suggested, although not conclusively proven.
15 Although the
study lost its randomization power after 1 year, relative risk
reduction was 31% for the primary outcome (all-cause mortality
or unplanned HF hospitalization) when perindopril was administered
rather than placebo (
P = 0.055). Symptomatic improvement, including
more normal functional class (
P = 0.030) and enhanced 6-min
walk distance (
P = 0.011), was also noted.
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Coronary artery disease: myocardial infarction and cardiac remodelling
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ACE inhibitors improve outcome in patients who have suffered
MI. Although Cooperative North Scandinavian Enalapril Survival
Study II (CONSENSUS II) failed to demonstrate a benefit,
16 a
meta-analysis including data from more than 98 000 patients
with acute MI entered into four ACE inhibitor trials showed
that early ACE inhibitor treatment (
36 h post-MI) is associated
with significantly lower mortality both in the first week and
in the first month after MI (
Figure 4).
17 Long-term studies
of ACE inhibitor in patients who have suffered MI [Acute Infarction
Ramipril Efficacy Study (AIRE), Trandolapril Cardiac Evaluation
Study (TRACE), Survival and Ventricular Enlargement study (SAVE)]
have confirmed maintenance of these benefits over years.
18–20 Consequently, ACE inhibitor have become an indispensable part
of post-MI treatment in patients with subnormal LV function.
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Figure 4 Effect of ACE inhibitor therapy started in the acute phase (0–36 h) of myocardial infarction and continued for a short time (4–6 weeks) on cumulative mortality during days 0–30 in all trials combined: systematic overview of individual data from 100 000 patients in randomized trials. ACE inhibitor, angiotensin-converting enzyme-inhibitor. Reproduced with permission from Figure 1.17
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ACE inhibitor prevent or delay the detrimental cardiac remodelling
after MI that appears to contribute to worsening prognosis after
MI. For example, the recent Perindopril and Remodeling in Elderly
with Acute Myocardial infarction (PREAMI) trial in 1252 elderly
patients with preserved LV function, which studied post-MI,
has shown that perindopril can prevent or delay cardiac remodelling
(
Figure 5).
21 After 1 year, perindopril reduced the composite
primary endpoint of death, HF hospitalization, and cardiac remodelling
by 38% (
P = 0.001) vs. placebo.
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Figure 5 Effect of perindopril treatment on left ventricular remodelling and clinical outcome: the Perindopril and Remodelling in Elderly with Acute Myocardial Infarction (PREAMI) study. The primary endpoint was combination of death, hospitalization for heart failure, or left ventricular remodelling. Size of squares is proportional to the number of patients in that group. Dashed line indicates overall relative risk. CI, confidence interval; HF, heart failure. Reproduced with permission from Figure 2.21
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Coronary artery disease: outcome in stable coronary artery disease
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Certain ACE inhibitors have been compellingly demonstrated to
decrease the frequency of ischaemic events. These benefits presumably
are based at least in part on drug-mediated effects that have
been demonstrated experimentally, including retardation of atherosclerosis
development, reversal of endothelial dysfunction, and favourable
alteration of fibrinolytic balance; effects that are presumed
to involve inhibiting both angiotensin II (Ang II) and bradykinin
(BK) pathways.
22–25
These pharmacological effects formed the basis for large trials of ACE inhibitor in atherosclerotic vascular disease. These include the HOPE trial, in patients at high risk of CV events, which showed that ramipril at a dose of 10 mg daily decreases the risk of stroke, MI, and death by 22% in comparison with placebo (P < 0.001).26 The European Trial on Reduction of Cardiac Events with Perindopril among Patients with Stable Coronary Artery Disease (EUROPA) trial,27 aimed at a population with stable CAD and somewhat less evidence of risk than the HOPE population, confirmed and extended the findings of HOPE (Figure 6). Treatment with perindopril 8 mg daily on a background of now-standard preventive therapy (antiplatelet drugs, lipid-lowering agents, and beta-blockers if MI had occurred) reduced risk of cardiac death, non-fatal MI, or resuscitated cardiac arrest by 20% in comparison with placebo (P = 0.0003).27
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Figure 6 Time to the first occurrence of the primary endpoint after perindopril treatment of patients with stable coronary artery disease: the European Trial on Reduction of Cardiac Events with Perindopril among Patients with Stable Coronary Artery Disease (EUROPA). The primary endpoint was a composite of cardiovascular death, MI, or cardiac arrest. Error bars depict standard error. MI, myocardial infarction. Reproduced with permission from Figure 2.27
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The Prevention of Events with ACE Inhibition (PEACE) trial failed
to show the benefit of trandolapril in patients with stable
CAD.
28 This finding may relate to the dose selected for study
(4 mg) or to intrinsic differences in the pharmacological profile
of this ACE inhibitor vs. ramipril and perindopril. Nonetheless,
the usefulness of ACE inhibitors, as a group, for secondary
prevention in patients with established, stable CAD has been
demonstrated by results of meta-analyses of all relevant trials.
29,30 These results have been recognized by the European Society of
Cardiology and the American College of Cardiology/American Heart
Association.
31,32
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Beyond cardiac protection and treatment: kidneys, diabetes, and brain
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The CV disease continuum can be understood to extend to target
organs beyond the heart, including the brain and kidneys.
33,34 Indeed, CV dysfunction is an important cause of renal dysfunction;
renal disease is also a risk factor for adverse outcomes in
patients with established CAD.
35 ACE inhibitors are plausible
therapies for renal disease as RAS is implicated in the progression
of renal dysfunction in patients with established renal disease.
Perhaps, as a consequence, ACE inhibitors have unique nephroprotective
properties in comparison with other anti-HT agents. Thus, in
patients with type I diabetes, the ACE inhibitor captopril reduced
the rate of the combined endpoint of dialysis, renal transplantation,
and death (
Figure 7).
36 These benefits were confirmed in
additional studies of diabetic patients
37,38 and have been extended
to non-diabetic renal disease.
39–41 In patients with end-stage
renal disease, treatment with the ACE inhibitor perindopril
significantly reduced both CV and total mortality.
40
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Figure 7 Cumulative percentage of patients with diabetic nephropathy in the captopril and placebo groups who died, or required dialysis or renal transplantation. The numbers at the bottom of the panel represent the numbers of patients in each group at risk for the event at baseline and after each 6-month period. Reproduced with permission from Figure 1.36
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A direct effect on diabetes may also exist. In a meta-analysis,
regardless of indication for use (HT or CAD), reductions in
new-onset type 2 diabetes were noted when ACE inhibitors were
administered.
42 In addition, certain ACE inhibitor may be particularly
effective in preventing CV events in diabetics (
Figure 2B).
In the Perindopril Protection against Recurrent Stroke Study (PROGRESS), the first study of ACE inhibitors in patients with cerebrovascular disease, 6105 patients were treated with a perindopril-based therapy (addition of indapamide was allowed) or placebo.43 After 3.9 years, perindopril-based treatment reduced the primary endpoint and recurrent fatal or non-fatal stroke by 28% (P vs. placebo < 0.0001). Active treatment also reduced the risk of major vascular events by 26%. Similar reductions in the risk of stroke in hypertensive and non-hypertensive subgroups were noted (P < 0.01).
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Mode of action: differentiation with other renin–angiotensin system inhibitors
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Like all drugs, ACE inhibitors have many pharmacological effects,
some of which have not yet been clarified.
44,45 However, most
of these effects have been extensively studied and, plausibly,
are at least in part responsible for the clinical benefits provided
by these drugs. ACE inhibitors regulate the balance between
RAS and the kallikrein–kinin system. RAS is centrally
involved in BP regulation. ACE regulates the balance between
the vasodilatory and natriuretic properties of BK and the vasoconstrictive
and salt-retentive properties of Ang II. ACE inhibitors alter
this balance by decreasing the formation of Ang II and the degradation
of BK (
Figure 8). Their effects on the BK pathway differentiate
ACE inhibitors from other agents modulating RAS [angiotensin
receptor blockers (ARBs) and renin inhibitors] and probably
contribute to the clinical benefits of ACE inhibitor, particularly
to the prevention of MI in patients with stable CAD.
46 Evidence
favouring such differentiation has been recently provided by
a series of meta-regression analyses using data from 26 large
trials (involving 146 838 patients and 22 666 events) comparing
an ACE inhibitor or an ARB with placebo or active drug, prepared
by the Blood Pressure Lowering Treatment Trialists Collaboration.
47 This analysis revealed that both types of drugs produce a BP-dependent
event reduction, but that ACE inhibitors, and not ARBs, provide
an additional 9% risk reduction, which is independent of BP
lowering effects. In addition, probably acting by impeding transforming
growth actor (TGF)-ß activity, which is modulated
by local Ang II concentrations, ACE inhibitor blocks collagen
synthesis,
48 potentially beneficial in patients with HF because
of cardiomyopathy or CAD (but possibly deleterious in regurgitant
valvular diseases in which this effect may impair necessary
LV structural support to resist dilatation).
49
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Figure 8 Schematic diagram of the renin–angiotensin system and kallikrein–kinin system. Angiotensin-converting enzyme is strategically poised to regulate the balance between Ang II and bradykinin. ACE, angiotensin-converting enzyme; Ang, angiotensin. Reproduced with permission from Figure 1.51
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Although much of this review has discussed the effects of ACE
inhibitors as a group, all ACE inhibitors are not equivalent.
45 Pharmacologically, different types of ACE inhibitors exist:
captopril-like compounds are administered in active form, but
are further metabolized, with potential modulation of effects
by metabolites; prodrugs such as enalapril, perindopril, ramipril,
and trandolapril must be converted to their active form, leading
to potential variability in activity based on individual metabolic
characteristics; lisinopril-like compounds are active as administered
and are not further metabolized.
50 Of course, together with
these structural differences, half-lives, plasma-levels, trough/peak
relations, absorption characteristics, intermediary metabolism,
and elimination vary among the compounds. Perhaps, as a result,
differences in clinical actions have also been observed. For
example, perindopril and ramipril reduced CV morbidity and mortality
in patients with CAD in the EUROPA and HOPE trials,
27,37 but
in PEACE, trandolapril did not.
28 Considerable work remains
to elucidate the links between the pharmacokinetic and pharmacodynamic
properties and clinical effects.
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Conclusion
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Almost three decades after their introduction into clinical
use, ACE inhibitors have become recognized therapeutic choices
throughout the entire spectrum of CV diseases. Newer ACE inhibitors
with pharmacological profiles differing from those of older
agents have added to the ease of application and relative safety
of these drugs both for reduction of symptoms and for improvement
of outcomes. Although other agents modulating RAS (ARBs and
renin inhibitors) can provide some overlapping pharmacological
effects and important clinical benefits, ACE inhibitors remain
unique in the range of their proven benefits, justifying their
central role in the armamentarium of the CV specialist.
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Acknowledgement
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J.S.B. is a consultant to Servier Laboratoires, Neuilly sur
Seine, France; the preparation of this manuscript was supported
in part by Servier.
Conflict of interest: none declared.
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M. Tendera
Introduction
Eur. Heart J. Suppl.,
September 1, 2007;
9(suppl_E):
E1 - E1.
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Abstract
Introduction