Perspectives in Cardiology / November/December 2006 23
Michael McDonald, MD, FRCP; and Gabor Gyenes, MD, PhD
Vascular Protection:Beyond Risk ReductionVascular protection typically involves the effort to reduce major adverse events in patients whoare at high risk. In this article, Dr. McDonald and Dr. Gyenes outline some of the more topicalcardiovascular protection strategies and the rationale for their use.
Focusing attention toward strategies for car-diovascular (CV) protection acknowledges
the vulnerability of the CV system which isexposed to a complex milieu of risk factors.While much has been written about CV protec-tion, it currently lacks precise definition.Typically, it involves the effort to reduce majoradverse events in patients who are at high risk.These events include:• death,• MI,• recurrent ischemia and• stroke.Clinical trials looking at specific therapies
have not usually encompassed the broaderspectrum of related outcomes, such as:• heart failure,• atrial fibrillation,• deterioration of renal function, or even• symptomatic peripheral vascular disease.With this in mind, our review will outline
some of the more topical CV protection strate-gies and the rationale for their use.
John, 56, presents to clinic for assessment of hiscardiovascular status. His medical history reveals:
• percutaneous coronary intervention (PCI), with
angioplasty and stenting six months earlier
following an episode of unstable angina,
• cardiac risk factors including hypertension and
dyslipidemia,
• he is a non-diabetic, non-smoker and
• a review of systems is negative for chest pain
or any functional limitation.
John’s medications include:
• 81 mg q.d. of acetylsalicylic acid (ASA),
• 25 mg q.d. of hydrochlorothiazide and
• 10 mg q.d. of atorvastatin.
John’s physical exam reveals that his:
• Heart rate is 76 bpm and his
• BP is 142/85 mmHg when seated.
Arterial and central venous pulsations, precordialevaluation and auscultatory findings all withinnormal limits.
Further investigations find:
• 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 fromfuture cardiovascular events?
What further changes can be made to hismedication regime?
For more on John, go to page 25
Should all patients with diabetesmellitus be taking an angiotensin-converting enzyme (ACE) inhibitorfor 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.
FFAAQQ
John’s Case
24 Perspectives in Cardiology / November/December 2006
Vascular Protection
Lifestyle modifications
In patients with diabetes in the post-MI settingand those at high-risk for ischemic events, evi-dence 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 sta-ble angina contain a good overview of the avail-able evidence supporting their recommenda-tions for lifestyle interventions.
Reducing BP and ACEinhibitors
The concept of CV protection has largelyevolved from large-scale angiotensin-convert-ing enzyme (ACE) inhibitor trials. Studieslooking at the role of ACE inhibitors in patientswith left ventricular dysfunction 15 years to 20 years ago demonstrated unequivocal morbidi-ty and mortality benefits. An unexpected finding
from these early studies was the observedreduction in MI and other CV events.
HOPE study
The idea that ACE inhibitors could have vascularprotective effects was prospectively evaluated inthe large-scale Heart Outcomes PreventionEvaluation (HOPE) study.1 HOPE enrolledpatients who were at high-risk for, or who hadestablished vascular disease and found thatthose taking ramipril experienced fewer CVdeaths, MIs or strokes compared to those takingplacebo (relative risk 0.78, 95% confidenceinterval 0.70 to 0.86).
EUROPA study
Among patients with documented coronarydisease (but at lower overall baseline risk) inthe large-scale European trial on ReductionOf cardiac events with Perindopril inpatients with stable coronary Artery disease(EUROPA study), perindopril was associatedwith a 20% reduction in CV death, MI or car-diac arrest compared to placebo.2
PEACE study
Of interest, the subsequently published Preventionof Events with Angiotensin-Converting EnzymeInhibition (PEACE) trial did not demonstrate abenefit of the ACE inhibitor trandolaprilvs placebo in stable coronary artery disease.3
The unexpected and contrary findings of this
Dr. McDonald is a Cardiology Fellow at theUniversity of Alberta, Edmonton, Alberta.
Dr. Gyenes is an Assistant Professor at the Divisionof Cardiology, at the University of Alberta, Edmonton,Alberta. He is currently involved in a variety ofresearch topics dealing mainly with primary and secondary prevention for coronary artery disease.
About the Authors...
Are ACE inhibitors andangiotensin receptor blockers(ARBs) equivalent andinterchangeable?
Evidence for CV protection with ACE
inhibitors is far more robust than for ARBs.
ARBs appear safe across a broad spectrum
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.
FFAAQQ
Perspectives in Cardiology / November/December 2006 25
trial may be attributed to the lower risk profileof the patients, the majority of whom were con-comitantly treated with other protective thera-pies (Table 1).
ACE inhibitor benefits
Much debate has been centered on whether theobserved benefits of ACE inhibitors is simplyrelated to their efficacy as antihypertensiveagents. Indeed, data from large randomized con-trolled clinical trials and from meta-analyseshave shown that lowering BP with a variety ofagents including angiotensin receptor blockers(ARBs), thiazide-type diuretics and calciumchannel blockers lowers the risk of major CVevents. However, in patients with established cardiac
or vascular disease, many experts feel that ACEinhibitors provide BP independent benefits
John has documented coronary disease withpersistent risk factors for future events.
While his BP is only slightly elevated on diureticmonotherapy, he should be started on anangiotensin-converting enzyme (ACE) inhibitor,titrating to the recommended effective dose astolerated.
The benefits of ACE inhibitors for this patient arewell established and extend beyond their role aseffective antihypertensive agents, even in theabsence of left ventricular dysfunction.
Although the patient’s lipid profile approximatesrecommended target values, his atorvastatin doseshould be increased to 80 mg q.d. to achieve anLDL-cholesterol < 2 mmol/L.
Finally, he should remain on ASA indefinitely.
More on John
Table 1
Differences in baseline characteristics of patients enrolled in the HOPE,EUROPA and PEACE trials.
HOPE EUROPA PEACE
Patient characteristics* 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 EvaluationEUROPA:The European trial on Reduction Of cardiac events with Perindopril in patients with stable coronary Artery diseasePEACE: Prevention of Events with Angiotensin-Converting Enzyme InhibitionCABG: coronary artery bypass grafting LVEF: left ventricular ejection fractionSBP/DBP: systolic BP / diastolic BP
* Numbers are percentages unless otherwise stated
Vascular Protection
26 Perspectives in Cardiology / November/December 2006
Vascular Protection
through their effects on vascular remodelingand endothelial function. A recent update fromthe Blood Pressure Lowering TreatmentTrialists’ Collaboration concluded that ACEinhibitors may have a specific protective effectin preventing coronary disease-related events.4
Evidence for CV protection with ARBs is weaker,and ongoing trials will define the role of renin-angiotensin-aldosterone inhibition with thisclass of medications in high-risk populations.ARBs have been shown to be safe across a spec-trum of patients with respect to MI and theyremain effective alternatives to ACE inhibitors.5
Lipid LoweringLowering LDL-cholesterol (LDL-C) with statintherapy has translated into unequivocal CVmorbidity and mortality benefits for a spectrumof high-risk patients. Initial studies demonstratingthe efficacy of statins in patients with elevated
cholesterol led to their evaluation in a broadergroup of high-risk patients. The Heart ProtectionStudy (HPS) showed that irrespective of thebaseline lipid profile, patients with vascular dis-ease (or vascular disease equivalents) who weretreated with 40 mg of simvastatin experiencedsignificantly fewer coronary-related deaths andother major vascular events. There was approx-imately 20% risk reduction over five years.6
Subsequent landmark trials have exploredwhether incremental benefits could still beachieved with more aggressive lipid-lowering.Results of the The Pravastatin or AtorvastatinEvaluation and Infection Therapy—Thrombolysisin Myocardial Infarction 22 (PROVE-IT) studyand Treating to New Targets (TNT) trials haveprovided compelling evidence that high dosestatin regimes yield significant reductions inmajor CV endpoints over conventional regimes,with the magnitude of benefit reflecting thedegree of LDL-C lowering.7,8
A meta-analysis capturing > 90,000 patientsfrom 14 randomized trials of statin therapy hasshown that each 1 mmol/L reduction in LDL-Ccorresponds to an approximate 20% reductionin major vascular events, such as: • MI,• coronary death,• revascularization and • stroke.9
Do I need to be concerned aboutthe adverse effects, such asrhabdomyolysis and liver enzymeelevation, 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.
FFAAQQ
Trials have provided compelling evidence
that high dose statinregimes yield significantreductions in major CVendpoints over conventional regimes.
Perspectives in Cardiology / November/December 2006 27
This benefit was noted at all levels of LDL-C, leading authors of this analysis to concludethat goals for statin treatment “should aimchiefly to achieve substantial absolute reduc-tions in LDL-C rather than to achieve particulartargets…” Moreover, a more aggressive lipid-lowering approach appears to be well toleratedand is not accomplished at the expense ofincreased rates of serious adverse effects.
Antiplatelet protectionFinally, acetylsalicylic acid (ASA) should beconsidered standard antithrombotic, vascularprotective therapy for anyone with:• established CV disease,• diabetes, or at• moderate-to-high risk of vascular events. Clopidogrel is an effective alternative therapy forpatients intolerant to ASA. The role of clopidogrelin addition to ASA is currently limited to patientswho have had high-risk acute coronary syndromepresentations or who have received percutaneouscoronary intervention with stenting.
References1. Yusuf S, Sleight P, Pogue J, et al: Effects of an angiotensin-converting-
enzyme inhibitor, ramipril, on cardiovascular events in high-riskpatients. The Heart Outcomes Prevention Evaluation StudyInvestigators. N Engl J Med 2000; 342(3):145-53.
2. Fox KM: Efficacy of perindopril in reduction of cardiovascular eventsamong patients with stable coronary artery disease: Randomized, dou-ble-blind, placebo-controlled, multicentre trial (the EUROPA study).Lancet 2003; 362(9386):782-8.
3. Braunwald E, Domanski MJ, Fowler SE, et al: Angiotensin-converting-enzyme 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 therenin-angiotensin system. Program and abstracts from the FifteenthEuropean 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 receptorblockers and risk of myocardial infarction: Systematic review. BMJ2005; 331(752):873.
6. Heart Protection Safety Collaborative Group: MRC/BHF HeartProtection Study of cholesterol lowering with simvastatin in 20,536high-risk individuals: A randomized placebo-controlled trial. Lancet2002; 360(9326):7-22.
7. Cannon CP, Braunwald E, McCabe CH, et al: Intensive versus moderatelipid lowering with statins after acute coronary syndromes. N Engl JMed 2004; 350(15):1495-504.
8. LaRosa JC, Grundy SM, Waters DD, et al: Intensive lipid lowering withatorvastatin in patients with stable coronary disease. N Engl J Med2005; 352(14):1483-4.
9. Cholesterol Treatment Trialists’ Collaborators. Efficacy and safety ofcholesterol-lowering treatment: Prospective meta-analysis of data from90,056 participants in 14 randomised trials of statins. Lancet 2005;366(9493):1267-78.
Which patients need to be onclopidogrel?
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
remain on clopidogrel as directed by
their cardiologist.
FFAAQQ
PCard
Dr. Gyenes is also the author of arecently published reference bookentitled 25 Landmark Trials inCardiology. The book details pivotaltrials that have had a significantimpact in the practice of cardiology,
with editorial comments to help put each trialinto perspective. The book is written with attention to important clinical subtleties in orderto ensure that it is relevant to a broad range ofhealth professionals. For more information onpurchasing 25 Landmark Trials in Cardiologyplease contact Dr. Gabor Gyenes [email protected].
