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Vascular Protection:
Beyond Risk Reduction
Vascular protection typically involves the effort to reduce major adverse events in patients who
are at high risk. In this article, Dr. McDonald and Dr. Gyenes outline some of the more topical
cardiovascular protection strategies and the rationale for their use.
Michael McDonald, MD, FRCP; and Gabor Gyenes, MD, PhD
ocusing attention toward strategies for cardiovascular (CV) protection acknowledges
John, 56, presents to clinic for assessment of his
the vulnerability of the CV system which is
cardiovascular status. His medical history reveals:
exposed to a complex milieu of risk factors.
• percutaneous coronary intervention (PCI), with
While much has been written about CV protecangioplasty and stenting six months earlier
tion, it currently lacks precise definition.
following an episode of unstable angina,
Typically, it involves the effort to reduce major
• cardiac risk factors including hypertension and
adverse events in patients who are at high risk.
dyslipidemia,
These events include:
• he is a non-diabetic, non-smoker and
• death,
©
• a review of systems is negative for chest pain
• MI,
or any functional limitation.
• recurrent ischemia and load,
n
John’s medications include:
dow
• stroke.
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lu
• 81 mg q.d. of acetylsalicylic acid (ASA),
strials
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Clinical
at
specific therapies
n
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per encompassed the broader
orisenot fusually
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• 25 mg q.d. of hydrochlorothiazide and
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have
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le co of related outcomes, such as:
• 10 mg q.d. of atorvastatin.
ibite singspectrum
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d usthat ahis:
• heart failure,
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John’s physical exam
reveals
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• atrial fibrillation,
, his
n is 76 bpm
• HeartU
rate
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• deterioration of renal function, or even
• BP is 142/85 mmHg when seated.
• symptomatic peripheral vascular disease.
Arterial and central venous pulsations, precordial
evaluation and auscultatory findings all within
With this in mind, our review will outline
normal limits.
some of the more topical CV protection strategies and the rationale for their use.
Further investigations find:
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John’s Case
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•
Fasting glucose: 5.8 mmol/L
•
Fasting lipid profile:
- HDL-cholesterol 0.9 mmol/L
- LDL-cholesterol 2.4 mmol/L
•
Total cholesterol: HDL-cholesterol ratio 4.2
•
Serum creatinine: 88 micromol/L
•
Potassium: 4.1 mmol/L
•
Left ventriculogram: preserved left ventricular
systolic function (six months previously)
Is this patient adequately protected from
future cardiovascular events?
What further changes can be made to his
medication regime?
FAQ
Should all patients with diabetes
mellitus be taking an angiotensinconverting enzyme (ACE) inhibitor
for cardiovascular protection?
Diabetes is considered to be an equivalent to
coronary artery disease. Benefits regarding CV
and renal protection partly through BP lowering
in diabetic patients have been well established
and those with additional cardiac risk factors
should be on an ACE inhibitor.
For more on John, go to page 25
Perspectives in Cardiology / November/December 2006 23
Vascular Protection
Lifestyle modifications
In patients with diabetes in the post-MI setting
and those at high-risk for ischemic events, evidence is well established for the benefits of:
• smoking cessation,
• weight loss and
• tight glycemic control.
The American College of Cardiology
(ACC)/American Heart Association (AHA)
guidelines regarding ST elevation MI and stable angina contain a good overview of the available evidence supporting their recommendations for lifestyle interventions.
FAQ
Are ACE inhibitors and
angiotensin receptor blockers
(ARBs) equivalent and
interchangeable?
Evidence for CV protection with ACE
inhibitors is far more robust than for ARBs.
ARBs appear safe across a broad spectrum
from these early studies was the observed
reduction in MI and other CV events.
HOPE study
The idea that ACE inhibitors could have vascular
protective effects was prospectively evaluated in
the large-scale Heart Outcomes Prevention
Evaluation (HOPE) study.1 HOPE enrolled
patients who were at high-risk for, or who had
established vascular disease and found that
those taking ramipril experienced fewer CV
deaths, MIs or strokes compared to those taking
placebo (relative risk 0.78, 95% confidence
interval 0.70 to 0.86).
EUROPA study
Among patients with documented coronary
disease (but at lower overall baseline risk) in
the large-scale European trial on Reduction
Of cardiac events with Perindopril in
patients with stable coronary Artery disease
(EUROPA study), perindopril was associated
with a 20% reduction in CV death, MI or cardiac arrest compared to placebo.2
of high-risk patients and ongoing trials will
address their potential benefits for vascular
protection. At this time, ARBs remain good
alternative agents for patients intolerant to
ACE inhibitors.
Reducing BP and ACE
inhibitors
The concept of CV protection has largely
evolved from large-scale angiotensin-converting enzyme (ACE) inhibitor trials. Studies
looking at the role of ACE inhibitors in patients
with left ventricular dysfunction 15 years to
20 years ago demonstrated unequivocal morbidity and mortality benefits. An unexpected finding
24 Perspectives in Cardiology / November/December 2006
PEACE study
Of interest, the subsequently published Prevention
of Events with Angiotensin-Converting Enzyme
Inhibition (PEACE) trial did not demonstrate a
benefit of the ACE inhibitor trandolapril
vs placebo in stable coronary artery disease.3
The unexpected and contrary findings of this
About the Authors...
Dr. McDonald is a Cardiology Fellow at the
University of Alberta, Edmonton, Alberta.
Dr. Gyenes is an Assistant Professor at the Division
of Cardiology, at the University of Alberta, Edmonton,
Alberta. He is currently involved in a variety of
research topics dealing mainly with primary and
secondary prevention for coronary artery disease.
Vascular Protection
More on John
John has documented coronary disease with
persistent risk factors for future events.
While his BP is only slightly elevated on diuretic
monotherapy, he should be started on an
angiotensin-converting enzyme (ACE) inhibitor,
titrating to the recommended effective dose as
tolerated.
The benefits of ACE inhibitors for this patient are
well established and extend beyond their role as
effective antihypertensive agents, even in the
absence of left ventricular dysfunction.
Although the patient’s lipid profile approximates
recommended target values, his atorvastatin dose
should be increased to 80 mg q.d. to achieve an
LDL-cholesterol < 2 mmol/L.
Finally, he should remain on ASA indefinitely.
trial may be attributed to the lower risk profile
of the patients, the majority of whom were concomitantly treated with other protective therapies (Table 1).
ACE inhibitor benefits
Much debate has been centered on whether the
observed benefits of ACE inhibitors is simply
related to their efficacy as antihypertensive
agents. Indeed, data from large randomized controlled clinical trials and from meta-analyses
have shown that lowering BP with a variety of
agents including angiotensin receptor blockers
(ARBs), thiazide-type diuretics and calcium
channel blockers lowers the risk of major CV
events.
However, in patients with established cardiac
or vascular disease, many experts feel that ACE
inhibitors provide BP independent benefits
Table 1
Differences in baseline characteristics of patients enrolled in the HOPE,
EUROPA and PEACE trials.
Patient characteristics*
HOPE
EUROPA
PEACE
n = 9297
n = 12,218
n = 8290
Mean age
66
60
64
Prior MI
53
65
55
Diabetes mellitus
38
12
17
Prior CABG or PCI
40
55
72
Mean SBP/DBP (mmHg)
139/79
137/82
133/78
ASA/other antiplatelet
76
92
91
Lipid lowering therapy
29
58
70
ß-blockers
40
62
60
HOPE: Heart Outcomes Prevention Evaluation
EUROPA:The European trial on Reduction Of cardiac events with Perindopril in patients with stable coronary Artery disease
PEACE: Prevention of Events with Angiotensin-Converting Enzyme Inhibition
CABG: coronary artery bypass grafting
LVEF: left ventricular ejection fraction
SBP/DBP: systolic BP / diastolic BP
*
Numbers are percentages unless otherwise stated
Perspectives in Cardiology / November/December 2006 25
Vascular Protection
FAQ
Do I need to be concerned about
the adverse effects, such as
rhabdomyolysis and liver enzyme
elevation, with high dose statins?
Statins appear safe, even at higher doses.
For example, in the Pravastatin or
Atorvastatin Evaluation and Infection
Therapy—Thrombolysis in Myocardial
Infarction 22 (PROVE-IT) study evaluating
high dose (80 mg) atorvastatin, the
incidences of persistent liver enzyme
elevation and myalgia/CK elevation were
3.3% each, compared to 1.1% and 2.7%
respectively with conventional dose
regimes of pravastatin. There were no
cases of rhabdomyolysis over five years.
through their effects on vascular remodeling
and endothelial function. A recent update from
the Blood Pressure Lowering Treatment
Trialists’ Collaboration concluded that ACE
inhibitors may have a specific protective effect
in preventing coronary disease-related events.4
Evidence for CV protection with ARBs is weaker,
and ongoing trials will define the role of reninangiotensin-aldosterone inhibition with this
class of medications in high-risk populations.
ARBs have been shown to be safe across a spectrum of patients with respect to MI and they
remain effective alternatives to ACE inhibitors.5
Lipid Lowering
Lowering LDL-cholesterol (LDL-C) with statin
therapy has translated into unequivocal CV
morbidity and mortality benefits for a spectrum
of high-risk patients. Initial studies demonstrating
the efficacy of statins in patients with elevated
26 Perspectives in Cardiology / November/December 2006
cholesterol led to their evaluation in a broader
group of high-risk patients. The Heart Protection
Study (HPS) showed that irrespective of the
baseline lipid profile, patients with vascular disease (or vascular disease equivalents) who were
treated with 40 mg of simvastatin experienced
significantly fewer coronary-related deaths and
other major vascular events. There was approximately 20% risk reduction over five years.6
Subsequent landmark trials have explored
whether incremental benefits could still be
achieved with more aggressive lipid-lowering.
Results of the The Pravastatin or Atorvastatin
Evaluation and Infection Therapy—Thrombolysis
in Myocardial Infarction 22 (PROVE-IT) study
and Treating to New Targets (TNT) trials have
provided compelling evidence that high dose
statin regimes yield significant reductions in
major CV endpoints over conventional regimes,
with the magnitude of benefit reflecting the
degree of LDL-C lowering.7,8
A meta-analysis capturing > 90,000 patients
from 14 randomized trials of statin therapy has
shown that each 1 mmol/L reduction in LDL-C
corresponds to an approximate 20% reduction
in major vascular events, such as:
• MI,
• coronary death,
• revascularization and
• stroke.9
rials have provided
compelling evidence
that high dose statin
regimes yield significant
reductions in major CV
endpoints over
conventional regimes.
T
Vascular Protection
This benefit was noted at all levels of LDLC, leading authors of this analysis to conclude
that goals for statin treatment “should aim
chiefly to achieve substantial absolute reductions in LDL-C rather than to achieve particular
targets…” Moreover, a more aggressive lipidlowering approach appears to be well tolerated
and is not accomplished at the expense of
increased rates of serious adverse effects.
FAQ
Which patients need to be on
clopidogrel?
Clopidogrel is indicated for patients
who are ASA intolerant, or who have
had a high-risk acute coronary
syndrome presentation (with or without
revascularization) and for all patients
who have received angioplasty with
stenting. Patients with stents should
References
1. Yusuf S, Sleight P, Pogue J, et al: Effects of an angiotensin-convertingenzyme inhibitor, ramipril, on cardiovascular events in high-risk
patients. The Heart Outcomes Prevention Evaluation Study
Investigators. N Engl J Med 2000; 342(3):145-53.
2. Fox KM: Efficacy of perindopril in reduction of cardiovascular events
among patients with stable coronary artery disease: Randomized, double-blind, placebo-controlled, multicentre trial (the EUROPA study).
Lancet 2003; 362(9386):782-8.
3. Braunwald E, Domanski MJ, Fowler SE, et al: Angiotensin-convertingenzyme inhibition in stable coronary artery disease. N Engl J Med 2004;
351(20):2058-68.
4. Turnbull F: Blood pressure-independent effects for agents inhibiting the
renin-angiotensin system. Program and abstracts from the Fifteenth
European Meeting on Hypertension. June 17-21, 2005. Milan, Italy.
Plenary Session (http://www.medscape.com/viewarticle/507293).
5. McDonald MA, Simpson SH, Ezekowitz JA, et al: Angiotensin receptor
blockers and risk of myocardial infarction: Systematic review. BMJ
2005; 331(752):873.
6. Heart Protection Safety Collaborative Group: MRC/BHF Heart
Protection Study of cholesterol lowering with simvastatin in 20,536
high-risk individuals: A randomized placebo-controlled trial. Lancet
2002; 360(9326):7-22.
7. 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(15):1495-504.
8. 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(14):1483-4.
9. Cholesterol Treatment Trialists’ Collaborators. Efficacy and safety of
cholesterol-lowering treatment: Prospective meta-analysis of data from
90,056 participants in 14 randomised trials of statins. Lancet 2005;
366(9493):1267-78.
remain on clopidogrel as directed by
their cardiologist.
Antiplatelet protection
Finally, acetylsalicylic acid (ASA) should be
considered standard antithrombotic, vascular
protective therapy for anyone with:
• established CV disease,
• diabetes, or at
• moderate-to-high risk of vascular events.
Clopidogrel is an effective alternative therapy for
patients intolerant to ASA. The role of clopidogrel
in addition to ASA is currently limited to patients
who have had high-risk acute coronary syndrome
presentations or who have received percutaneous
coronary intervention with stenting.
Dr. Gyenes is also the author of a
recently published reference book
entitled 25 Landmark Trials in
Cardiology. The book details pivotal
trials that have had a significant
impact in the practice of cardiology,
with editorial comments to help put each trial
into perspective. The book is written with
attention to important clinical subtleties in order
to ensure that it is relevant to a broad range of
health professionals. For more information on
purchasing 25 Landmark Trials in Cardiology
please contact Dr. Gabor Gyenes at
[email protected].
PCard
Perspectives in Cardiology / November/December 2006 27