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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. n a c se ers looking lu • 81 mg q.d. of acetylsalicylic acid (ASA), strials a u Clinical at specific therapies n o d s per encompassed the broader orisenot fusually r h • 25 mg q.d. of hydrochlorothiazide and o t have u y p d. A le co of related outcomes, such as: • 10 mg q.d. of atorvastatin. ibite singspectrum h o r a ep print d usthat ahis: • heart failure, e d John’s physical exam reveals s n i r w ho t e i u v a • atrial fibrillation, , his n is 76 bpm • HeartU rate yand ispla d • 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: F John’s Case n o i t u ib r t s i lD a i c r e t h g i r Copymm Co r o e r Sal o f t o N • 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