Expert Answers to Three Key Questions · Randomised trial of cholesterol lowering in 4444 patients...

205

Dialogues in Cardiovascular Medicine - Vol 10 . No. 4 . 2005

Editorial R. Ferrari, D. J. Hearse 207

Lead Article The ABC of secondary cardiovascular prevention: the successes and what we need to obtain now - E. Lonn, J. Grewal 209

Expert Answers to Three Key Questions What is the best way to keep the renin-angiotensin system under control?A. S. Hall, N. Kilcullen 235How best to keep the sympathetic nervous system under control in coronary artery disease?C. Ceconi 244What is the best way to manage dyslipidemia? - J. Shepherd 249

Fascinoma Cardiologica Plants and the Heart: Windfalls from the opium poppy: the discovery of papaverine and verapamil - A. Hollman 259

Summaries of Ten Seminal Papers - M. Faircloth, M. Pedersen 265

Secondary Prevention

Collaborative meta-analysis of randomised trials of antiplatelettherapy for prevention of death, myocardial infarction, andstroke in high risk patients – Antithrombotic Trialists’ Collaboration

Effect of smoking cessation on mortality after myocardialinfarction: meta-analysis of cohort studies – K. Wilson and others

Secondary prevention of coronary heart disease in the elderlyC. J. Bulpitt

Beta blockade during and after myocardial infarction: an overview of the randomized trials – S. Yusuf and others

Effects of an angiotensin-converting-enzyme inhibitor,ramipril, on cardiovascular events in high-risk patients S. Yusuf and others

Efficacy of perindopril in reduction of cardiovascular eventsamong patients with stable coronary artery disease: randomised, double blind, placebo-controlled, multicentretrial (the EUROPA study) – K. Fox and EUROPA Investigators

Randomised trial of cholesterol lowering in 4444 patients withcoronary heart disease: the Scandinavian Simvastatin SurvivalStudy (4S) – Scandinavian Simvastatin Survival Study Group

The effect of pravastatin on coronary events after myocardialinfarction in patients with average cholesterol levels – F. M. Sacks

and others

MRC/BHF Heart Protection Study of cholesterol lowering withsimvastatin in 20,536 high-risk individuals: a randomisedplacebo-controlled trial – Heart Protection Study Collaborative Group

An overview of randomized trials of rehabilitation with exerciseafter myocardial infarction – G. T. O’Connor and others

Bibliography of One Hundred Key Papers 276


207

Roberto Ferrari, MD, PhD

David J. Hearse, BSC, PhD, DSc

he past 20 years have witnessed dramatic changes in our understanding and

treatment of ischemic heart disease. In terms of management, two major

trends, defining two categories of cardiologists, have emerged. The first is the

fast-growing predilection for the invasive approach to coronary artery disease,

epitomized by surgical or interventional reperfusion, both in the acute setting (primary

angioplasty) and in the stable phase. Those who embrace this strategy are known as

interventional cardiologists, and are engaged in what in effect is a sophisticated form

of "plumbing." They are unrepentant technophiles, always on the lookout for the most

up-to-date type of stent and the latest devices bristling with electronics. In stark

contrast to this first category is the preventive cardiology approach. This is based on

the rationale that intervention only takes care of a discrete manifestation of the disease,

but fails to address the possibility that atherosclerosis may progress to another vessel

or wreak havoc again in the same vessel that has been subjected to angioplasty or

bypass surgery. It has been said that the preventive cardiologists would dearly love to

ban their plumber colleagues from plying their trade. They are intent on understanding

the intimate mechanisms that lead to the initiation and progression of atherosclerosis

in the coronary arteries and on devising pathophysiologically based treatments. Not

only do these two categories of cardiologists differ in their therapeutic strategies,

they also differ in that the interventional cardiologist is seemingly more remote and

spends only minimal time with patients outside of the operating theater, whereas the

preventive cardiologist is more interactive and never tires of sharing advice and ideas

with his or her patients.

Much skepticism was harbored against preventive cardiology in the past. Any doubts

have now been cast aside thanks to the advent of evidence-based medicine, which has

provided ample proof of the efficacy of this approach. Skepticism has also receded as

drugs both old and new have been proven to prevent the progression and even the

onset of atherosclerosis. Thus, angiotensin-converting (ACE) enzyme inhibitors, statins,

antiplatelet agents, anticoagulants, and β-blockers have had their therapeutic profile

changed or enhanced by studies—some of them megatrials—proving their benefit in

secondary prevention. Some of these trials were especially rewarding in that they

Editorial

T

•••

provided findings that were totally unexpected. We have learned, for instance, that

statins play an important role even when low-density-lipoprotein (LDL) cholesterol

levels are normal. Likewise, some ACE inhibitors are of benefit even when the blood

pressure is normal. This in turn has given rise to a spate of questions and new concepts

concerning the mechanisms of action of these drugs: it is being increasingly hypothesized

that these recently recognized benefits stem not from the primary pharmacological

property of the drug (eg, reduction in blood pressure for the ACE inhibitors, reduction in

cholesterol levels for the statins, reduction in heart rate and blood pressure for the

β-blockers), but from secondary and possibly equally important mechanisms of action

converging on the vascular endothelium. This fascinating concept has breathed new

life into the curious term "pleiotropism." Although few appear to know the exact

meaning of the word and isolated voices even question its relevance, it denotes the

fact a single drug is endowed with several mechanisms of action—by analogy with the

genetic definition of the term. An intriguing conclusion drawn from the trials referred

to above is that, as far as secondary prevention is concerned, it is more important for

a drug to be included as part of the patient’s treatment program than to specify just

exactly how it should be used. As these drugs are to be used even when their primary

pharmacological target is normal, it follows that we cannot adjust the dose according

to their action. This has given rise to the controversial debate on the virtues of an

ideal polypill that would combine all the agents with proven benefit in secondary

prevention—which, in addition, would greatly enhance compliance.

In this issue of Dialogues devoted to secondary prevention, the authors have given pride

of place to the available pharmacological tools, but it is important to remember that

the first step in secondary prevention is to improve our patients' lifestyle. Although

this topic has been addressed in previous issues of Dialogues, let us be here once more

reminded how vital it is to spend time with our patients and explain the importance of

stopping smoking, eating a healthy diet, engaging in regular exercise, and controlling

diabetes and, of course, blood pressure.

Our final word will be to point out that for all the opposition between the interventional

approach and the preventive approach, it is not a matter of “one or the other” but of

“both together”: only when both approaches dovetail to form a single therapeutic

strategy will we be truly successful in our fight to curb the damage inflicted by coronary

disease.


Editorial - Hearse and Ferrari

208

•••

For most populations in the world, the last 100years have witnessed greater improvements in health status, compared with any other timein history. Globally, life expectancy increased

by about 25 years during the twentieth century, with agreater than 50% increase in longevity for most popu-lations. These improvements in health are likely a result of both improvements in disease prevention andhealth care as well as improvements in socioeconomicconditions in most societies.1 During this period, themajor causes of death and disability have shifted froma predominance of nutritional deficiencies and infec-tious diseases to chronic diseases such as cardiovas-cular diseases (CVD), cancers, and diabetes.2,3 MostWestern countries (such as those in North Americaand Western Europe) exhibited this epidemiologicaltransition in the first half of the twentieth century, resulting in marked increases in CVD during the first


The ABC of secondary cardiovascular prevention:the successes and what we need to obtain nowEva Lonn, MD, MSc, FRCPC, FACC; Jasmine Grewal, MD, FRCPC

Medicine, Division of Cardiology - McMaster University - Hamilton Health Sciences, General Site - Hamilton - Ontario - CANADA

Cardiovascular diseases (CVD) are the major causeof death and a significant cause of disability in theWestern world and are now threatening to impose an increasing health burden on developing nations.People with preexistent vascular disease are those athighest risk for adverse cardiovascular outcomes andrequire aggressive secondary preventive therapies. Largestrides have been made in the development of phar-macologic agents that target atherogenesis, thus offer-ing the ability to greatly impact on disease progressionand to prevent events. Compelling data from random-ized controlled trials have shown the benefits of aspirin(or antiplatelets) and angiotensin-converting enzyme(ACE) inhibitors (A), �-blockers and blood pressure–lowering agents (B), and cholesterol-lowering agents(C), particularly statins, in preventing recurrent eventsand improving survival. These data are the founda-tion for the advice for secondary prevention—theABCs. In addition, the evidence for the central roleof lifestyle factors as determinants of risk has led toincreased efforts toward developing interventionsaimed at modifying lifestyle patterns. Today’s biggestchallenge is one of implementation. Our focus shouldturn to educating physicians and patients alike aboutavailable therapies and their indications and poten-tial benefits. In addition, systematic, sustainable, andglobally applicable approaches to the secondary pre-vention of CVD need to be developed to truly realizethe vast benefits of existing therapies.

Keywords: cardiovascular disease; cardiovascular prevention; myocardialinfarction; stroke; statin; ACE inhibitor; angiotensin receptor blocker; antiplatelet agent; β-blocker; cardiac rehabilitationAddress for correspondence: Eva Lonn, MD, Professor of Medicineand Cardiology, Hamilton Health Sciences General Site, 237 Barton StreetEast, Hamilton, Ontario, Canada L8L 2X2, Canada(e-mail: [email protected])

Dialogues Cardiovasc Med. 2005;10:209-232

SELECTED ABBREVIATIONS

ARB angiotensin receptor blocker

CABG coronary artery bypass grafting

CHD coronary heart disease

COPD chronic obstructive pulmonary disease

COX cyclooxygenase

CRP C-reactive protein

CVD cardiovascular diseases

eNOS endothelial nitric oxide synthase

HRT hormone receptor therapy

MI myocardial infarction

NO nitric oxide

PCI percutaneous coronary intervention

PUFA polyunsaturated fatty acid

RAAS renin-angiotensin-aldosterone system

TIA transient ischemic attack

209Copyright © 2005 LLS SAS. All rights reserved www.dialogues-cvm.org

half of the century with rates peaking in the 1950s to1970s. Unprecedented research efforts both at the basic and clinical level have led to our understandingof many of the underlying pathophysiological mecha-nisms and epidemiological determinants of CVD andeffective therapies have been developed leading toextraordinary progress in reducing mortality and mor-bidity from CVD in these countries. However, many

challenges remain in spite of these advances and newchallenges such as increasing rates of obesity and diabetes are emerging, so that CVD remains the majorcause of death and disability in most Western countries.By contrast, with the later occurrence of industrializa-tion, urbanization, and economic development andalso due to increasing globalization, this epidemiologi-cal transition has occurred in the latter half of thetwentieth century in many of the developing countriesor is expected to occur in the near future in others,with continuing increases expected in most chronicdiseases, including CVD, over the next few decades.Thus, CVD, including coronary heart disease (CHD)and its equivalents, is no longer just an affliction ofthe sedentary Western world, but also of most otherregions, so that the epidemic of CVD imposes an on-going major global health and economic burden. There-fore, it is imperative that health care providers have a comprehensive understanding of available CVD pre-vention modalities, including primary and secondaryprevention strategies.

Increasing insight into vascular biology and the patho-genesis of atherosclerosis has had profound implica-tions in our understanding of CVD and its treatment.The development of pharmacologic agents that inter-vene on various pathways contributing to atherogenesisoffers the potential to have a great impact on haltingdisease and preventing events. In addition, the evi-dence for the central role of lifestyle factors as deter-minants of risk has led to increased efforts toward developing interventions aimed at modifying lifestylepatterns.

Most guidelines including those from Europe andNorth America recommend intensive secondary pre-vention in all patients with established CVD, whichhas been conclusively shown to confer a high risk ofsubsequent sudden death, myocardial infarction (MI),and stroke.4-9 Compelling data derived primarily fromrandomized controlled trials have shown the benefitsof aspirin (or antiplatelets) and angiotensin-convertingenzyme (ACE) inhibitors (A), β-blockers and bloodpressure–lowering (B), and cholesterol-lowering drugs(C), particularly statins, in preventing recurrent eventsand improving survival. Taken together, these data arethe foundation for the simple, but important advice forsecondary prevention—the ABCs. To incorporate life-style recommendations into this alphabetic mnemonic,D is for “diet” and “don’t smoke” and E for “exercise”.10

The ABCDEs have formed the basis for the guidelinesfor secondary prevention and have the potential tosubstantially reduce the burden of CVD. Great chal-


The ABC of secondary cardiovascular prevention - Lonn and Grewal

210

STUDY ACRONYMS

CAPRIE Clopidogrel versus Aspirin in Patientsat Risk of Ischemic Events

CURE Clopidrogel in Unstable angina to prevent Recurrent Events

EUROASPIRE EUROpean Action on Secondary Prevention by Intervention to Reduce Events

EUROPA EUropean trial on Reduction Of cardiac events with Perindopril in stable coronary Artery disease

GISSI Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico

HERS Heart and Estrogen/progestin Replace-ment Study

IST International Stroke Trial

MICRO-HOPE MIcroalbuminuria, Cardiovascular and Renal Outcomes–Heart Outcomes Prevention Evaluation

MIRACL Myocardial Ischemia Reduction with Acute Cholesterol Lowering

ONTARGET/ ONgoing Telmisartan Alone and in TRANSCEND combination with Ramipril Global

Endpoint Trial/Telmisartan random-ized Assessment Study in ACE Intolerant Subjects with Cardiovas-cular disease

PEACE Prevention of Events with Angiotensin-Converting Enzyme inhibition

PERSUADE PERindopril SUbstudy in coronary Artery disease and DiabEtes

PROVE-IT PRavastatin Or atorVastatin Evaluationand Infection Therapy

REVERSAL Reversal of Atherosclerosis with Aggressive Lipid Lowering

TNT Treating to New Targets

VA-HIT Veterans Affairs High-density lipopro-tein cholesterol Intervention Trial

WAVE Women’s Angiographic Vitamin and Estrogen [Trial]

lenges remain, however, in the implementation ofproven pharmacological interventions and in develop-ing efficacious, but also sustainable and widely appli-cable lifestyle interventions.

This review will summarize current evidence-basedapproaches to secondary prevention and some of theremaining questions and challenges in the manage-ment of patients with known CVD. It needs also to beemphasized, that in addition to aggressive preventivestrategies in people with preexistent vascular disease,population-based and individualized primary preven-tion approaches aimed at a wide range of people atrisk of developing CVD are essential.

LESSONS FROM VASCULAR BIOLOGYAND EPIDEMIOLOGY

Insights into the pathophysiology of atheroscleroticvascular disease have been essential in the develop-ment of effective treatment strategies. This review doesnot attempt to provide a comprehensive overview ofthe biology of atherosclerotic vascular diseases (ex-cellent reviews on this topic directed at a wide rangeof clinicians are available).11-22 However, a few briefpoints require special emphasis: (i) atherosclerosis isa complex, progressive disease caused by multiple,complementary pathophysiological mechanisms andtherefore the prevention of recurrent events in high-risk people with aggressive disease, which are thosetargeted in secondary prevention, necessarily requiresmultiple therapies; (ii) endothelial injury and dysfunc-tion is a critical component of vascular disease, it occursas a consequence of various CV risk factors and maybe modulated by endogenous endothelial repairmechanisms.23-26 Improvement in endothelial functionshould be regarded as a mechanistic target of therapy,although our ability to measure endothelial functionremains suboptimal and not yet suited for clinical use;and (iii) fundamental mechanisms involved in thegenesis and progression of atherosclerotic lesions andin rendering plaques vulnerable to rupture and conse-quent catastrophic events include lipid infiltration,oxidation, inflammation, and thrombosis, and shouldall be targeted by preventive therapies.11-22

Epidemiological data further guide our secondary pre-vention management. Several important principlesmerit particular consideration. • Atherosclerosis is a disease frequently resulting in death and disability and people with preexistent vascular disease are those at highest risk for adverseoutcomes. This is best illustrated by older studies

conducted prior to the widespread use of effectivepreventive therapies, which examined the natural history of CVD. Thus, a systematic overview of 23prospective studies completed prior to 1980 providesdata on 14 211 survivors of acute myocardial infarction(MI) and reveals that on average, in the absence ofpreventive treatment, a patient who “recovered” fromMI has a death rate of 10% for the first year followinghospital discharge and of 5% per year for each subse-quent year for at least 15 years and probably for therest of his or her life.27 Considering also, that in theabsence of modern therapies, about a third of patientssuffering a first acute MI and about half of those withrecurrent MI died before reaching the hospital or during hospital admission, these statistics are trulyastounding and justify the authors’ conclusion, thateffective preventive treatments (including aspirin,statins, β-adrenergic blocking agents, and ACE inhib-itors) are essential and should be maintained indefi-nitely in all survivors of acute MI. More recent statisticssuggest that in recent years, in spite of remarkabletherapeutic advances, patients with previous MI contin-ue to be at high risk for adverse outcomes, with 18%of men and 35% of women experiencing a recurrent MI,7% of men and 6% of women sudden death, and 8%of men and 11% of women sustaining a stroke within6 years after a first MI.28

• The major risk factors for CVD in all populations arecholesterol, blood pressure, diabetes (or abnormalitiesin glucose), tobacco exposure, obesity, insufficient dietary fruits and vegetables, and lack of regular exer-cise.29 There is ample evidence that clinicians shouldnot view these risk factors as being “present” or “ab-sent” because the relationship of most risk factors to CVD is continuous and extends over a wide range, including “normal” levels.30 Moreover, clinical trials ofcholesterol and blood pressure lowering suggest thatthe proportional (or relative) reduction in risk attaineddepends primarily on the magnitude of cholesterol andblood pressure lowering, irrespective of their startinglevel.31,32 For any proportional reduction in a risk factorlevel, the absolute benefit derived depends primarilyon an individual’s level of risk, and people with previ-ous CV events are at particularly high risk. Therefore,there is value in modifying risk factors in the majority ofpatients with established CVD, no matter what the levelof their risk factors.• People with diabetes have profound metabolic andvascular alterations and have been shown to be atvery high CV risk even in the absence of previous clin-ical manifestations of atherosclerosis.33 Therefore, aggressive CV prevention therapies need to be applied toall people with diabetes.



211

• The pathogenesis of acute MI, ischemic stroke, andperipheral arterial disease is attributed to atheroscle-rosis and thrombosis. Further, the determinants ofatherothrombosis in various vascular territories aresimilar and include all of the conventional risk factors.Interestingly, people with evidence of peripheral arte-rial disease represent the highest risk subset of allvascular patients and CHD is the major cause of deathin this population.34 Therefore, the need for CV preven-tion cannot be overlooked in these patients. In spiteof their different clinical presentation, the increasedrisk of future CV events is present in patients irrespec-tive of vascular territory (ie, cerebrovascular, peripheral,or coronary vasculature) in which the clinical mani-festation has occurred, and secondary prevention thera-pies should be applied consistently and aggressively in all vascular patients.

Table I lists categories of patients, who in addition tothose with CHD, are at high risk and require second-ary CV preventive therapies.

PHARMACOLOGIC INTERVENTIONS IN SECONDARY CVD PREVENTION

Aspirin, antiplatelets, and antithrombotic drugs

There is strong evidence that antiplatelet agents, inaddition to being effective in the setting of acute coro-nary syndromes and acute stroke (International StrokeTrial [IST]),35-37 reduce the risk of recurrent vascularevents in people with prior MI, occlusive stroke, tran-sient ischemic attack (TIA), stable angina, coronaryartery bypass grafting (CABG) and peripheral arterialdisease.38,39 The most plausible mechanism for thebenefit of aspirin in CVD relates to its ability to per-manently inhibit the platelet cyclooxygenase (COX)enzyme (primarily COX-1 in the low doses used in CVprevention), the enzyme required for the productionof thromboxane A2, a powerful promoter of plateletaggregation. More recently, it was suggested that the

anti-inflammatory actions of aspirin may contribute tovascular benefits, although the potential for low-doseaspirin to substantially reduce inflammation remainsunclear.39,40

The Antithrombotic Trialists' Collaboration, a compre-hensive systematic overview of 195 clinical trials in135 640 patients at high risk of occlusive arterial dis-ease, reported that 1 month or more of antiplatelettreatment reduced the odds of a vascular event (non-fatal MI, nonfatal stroke, or vascular death) by aboutone quarter compared with controls (odds reduction27%; 95% confidence interval [CI], 24%-30%; P<0.0001),of nonfatal MI by one third, nonfatal stroke by onequarter, and vascular mortality by one sixth. Absolutereductions in the risk of having a serious vascular eventwere 36 per 1000 treated for 2 years among patientswith previous MI, 38 per 1000 patients treated for 1 month among patients with acute MI, 36 per 1000treated for 2 years among those with previous strokeor transient ischemic attack, 9 per 1000 treated for 3 weeks among those with acute stroke, and 22 per1000 treated for 2 years among other high-risk patients,including those with stable angina, peripheral arterialdisease, and atrial fibrillation.38 In each of these high-risk categories, the absolute benefits substantiallyoutweighed the risks of major bleeding. Aspirin wasthe most widely studied antiplatelet drug, with dosesof 75-150 mg daily at least as effective as higher dailydoses (500-1500 mg daily), while the effects of doseslower than 75 mg daily were less certain (Figure 1).38

More recent trials suggest that thienopyridines suchas ticlopidine and clopidogrel may be as good as, oreven slightly more effective than aspirin in preventingrecurrent vascular events in patients with establishedCVD.39,41-43 These drugs selectively inhibit ADP-in-duced platelet aggregation, with no direct effect on themetabolism of arachidonic acid. Aspirin and clopido-grel both inhibit platelet aggregation, but act on dif-ferent pathways. Therefore, a potentially additive benefit can be envisioned.

The Antiplatelet Trialists’ Collaborative overview report-ed that, compared with aspirin, clopidogrel reducedthe risk of a vascular event by 10% (P=0.03). This resultis based primarily on the results of the Clopidogrelversus Aspirin in patients at Risk of Ischemic Events(CAPRIE) trial, a large randomized clinical trial of closeto 20 000 patients in which a relative risk reduction ofMI, stroke, and cardiovascular deaths of 8.7% (P=0.043)with clopidogrel 75 mg/day compared with aspirin wasobserved.41 Further, more recent evidence suggests that



212

Carotid artery disease

Peripheral arterial disease

Abdominal aortic aneurysm

10-year risk of coronary heart disease ≥20%*

Diabetes mellitus

Renal dysfunction

*ATP III modification of the Framingham risk tables.

Table I. Coronary heart disease equivalents.

combination of antiplatelet therapy with a thienopyri-dine derivative and aspirin in high-risk patients withunstable angina or non–ST-segment elevation MI ismore effective than aspirin alone.44 Ongoing trials willhelp evaluate whether the benefit noted in the Clopi-dogrel in Unstable Angina to prevent Recurrent Events(CURE) trial up to 1 year following non–ST-segmentelevation MI and more recently in the early phases ofacute ST-segment elevation MI,45 is also observed withchronic long-term therapy of patients with a variety of manifestations of coronary disease.46 In spite of theapparent small advantage of clopidogrel over aspirinin the CAPRIE trial and the potential, but yet to beproven, benefit of adding clopidogrel to aspirin, froma global perspective, considering the very significanteconomic implications of the widespread long-termuse of clopidogrel in a wide range of patients with vas-cular disease, aspirin remains at least for now the mostwidely recommended antiplatelet agent in secondaryprevention and should be the first-line therapy in themajority of cases.

Antiplatelet therapy is not without risk. Bleeding is themost important adverse effect of antiplatelet treatment.The Antithrombotic Trialists’ Collaboration reportedthat antiplatelet therapy is associated with an excessrisk of intracranial bleeding in trials of long-termtreatment. In addition, antiplatelet treatment is asso-ciated with a small, but significant excess of nonfatalmajor extracranial bleeds, but there is no clear excess

of fatal extracranial bleeds. Higher-dose antiplatelettherapy appears to be associated with more gastroin-testinal bleeding than lower doses.38 The thienopy-ridines appear to be associated with significantly lessgastrointestinal hemorrhage and upper gastrointestinalupset than aspirin. Clopidogrel is safer and bettertolerated than ticlopidine. In the CURE trial of morethan 12 000 patients with unstable angina or non–ST-segment elevation MI, the combination of clopidogreland aspirin is associated with a 38% increase in majorbleeding, P=0.001 (defined as intraocular, or requir-ing a transfusion of ≥2 units), but not life-threateningbleeds (P=0.13) (defined as a hemoglobin drop of ≥5 g/dL, hypotension needing IV inotropes, surgery tostop bleeding, symptomatic intracranial hemorrhage,or transfusion of ≥4 units of blood).44

The role of oral anticoagulant therapy in secondary CVprevention remains less well defined, with risks andobstacles related to the need for monitoring of levelsof anticoagulation probably outweighing benefits formost patients. High- and moderate-intensity oral an-ticoagulation are more effective than control and thanaspirin alone, but are associated with an increased riskof major bleeding and the need for very careful INR(international normalized ratio) monitoring.47 There-fore, the routine use of oral anticoagulation post my-ocardial infarction and in other patients with vasculardisease is currently not recommended. Anticoagulanttherapy should be considered in patients who do not



213

1345/ 9984

(13.5%)

1708/ 10 022(17.0%)

1007/ 9658

(10.4%)

1370/ 9644

(14.2%)

2045/ 11493(17.8%)

2464/ 11527

(21.4%)

1670/ 20 418(8.2%)

1858/ 20 403(9.1%)

1638/ 20 359(8.1%)

2102/ 20 543(10.2%)

Previousmyocardialinfarction

Acutemyocardialinfarction

Previousstroke/transient

ischaemic attack

Acutestroke

Otherhigh risk

Antiplatelet therapy

Control

Ad

just

ed

% o

fva

scula

r eve

nts

(+

1 S

E) 20

10

0

Benefit per 1000 patients (SE)

Mean monthsof treatment

P value

36 (5)

27

<0.0001

38 (5)

1

<0.0001

36 (6)

29

<0.0001

9 (3)

0.7

<0.0009

22 (3)

22

<0.0001

Figure 1. Absolute effectof antiplatelet therapy onvascular events (myocardialinfarction, stroke, or vascu-lar death) in main high-risk categories.

Modified from reference38: AntithromboticTrialists’ Collaboration.Collaborative meta-analy-sis of randomised trials ofantiplatelet therapy for pre-vention of death, myocar-dial infarction, and strokein high risk patients. BMJ.2002;324:71-86. Copyright© 2002, BMJ PublishingGroup Ltd.

tolerate aspirin or other antiplatelet agents and inthose with demonstrated left ventricular (LV) muralthrombus, or at high risk for developing mural throm-bus and subsequent embolic events, such as patientswith recent large anterior MI and major LV wall motionabnormalities.5 This indication is strengthened in thepresence of atrial fibrillation, congestive heart failure,LV aneurysm, or mural thrombosis detected on echo-cardiography.5 Oral anticoagulants require regularmonitoring for intensity of anticoagulant effects andshould be used carefully and judiciously due to theexcess risk of bleed. Novel oral antithrombotic that donot require the same degree of monitoring as coumarinanticoagulants are under investigation, but not yetavailable for clinical use.48

ß-Blockers

β-Blockers act by multiple mechanisms to improveoutcomes in patients with CHD, especially those withrecent acute MI. These include blood pressure lower-ing, improved balance of oxygen demand and supply,inhibition of sympathetic stimulation of the heart,and decreased ventricular irritability. β-Blockers haveproven benefits in the treatment of stable angina, in the post-MI setting, congestive heart failure, and arrhythmias.6,51

Several randomized controlled trials found benefitsassociated with the use of β-blockers post MI and alarge systematic overview of over 24 000 people report-ed that β-blockers improved survival in patients withprior MI by 23%, reduced the risk of sudden death by30%, and reduced the risk of nonfatal reinfarction by25%.52 While some studies suggested potential differ-ences in the clinical benefits of various β-blockers,later studies and systematic overviews did not identifyclear differences between β-blockers with and withoutcardioselectivity or membrane-stabilizing propertiesand between those with or without intrinsic sympath-omimetic activity. Subgroup analyses demonstratedcomparable benefits in men and women and foundthat β-blockers were particularly effective in subgroupswith highest baseline risk such as those over 50 yearsof age, those with a history of previous MI, hyperten-sion, or early heart failure symptoms post MI.53,54 Manyof the trials included in these classic meta-analysesare older and precede the common use of other moderntherapies. However, more recent studies confirm mor-tality benefits of β-blockers in the postthrombolyticera and in patients with LV dysfunction post MI.55-57

Adverse effects associated with β-blocker use such asbronchospasm, bradycardia, hypotension, heart block,fatigue, depression, nightmares, dizziness, hallucina-tions, and sexual dysfunction have been reported.51,58

However, serious adverse effects are uncommon when

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IMPORTANT UNANSWERED QUESTIONS

Unanswered questions regarding the use of anti-platelet and antithrombotic therapies in secondaryprevention include: (i) aspirin resistance may affect about 10% to 20% of patients with arterialthrombotic events. To date, there are no point-of-care, simple laboratory assays to identify indi-viduals who are likely to be resistant to aspirintherapy and correct treatment, if any, of aspirin“resistance” is unknown49,50; (ii) the use of com-

bined aspirin/clopidogrel therapy in chronic stablevascular disease holds promise, but requires further proof of efficacy, safety, and economic viability; and (iii) novel safe and easy-to-monitororal or subcutaneous anticoagulants may conferconsiderable benefit to very high-risk patient sub-sets. Such agents may become available in thenear future. These questions and others are underactive research.

SUMMARY AND RECOMMENDATIONS

All patients with CHD and CHD equivalents shouldbe treated with medium-dose aspirin (75-325 mgdaily) in the absence of clear contraindications.The recommendation is supported by variousguidelines and consensus documents.4-8,39 Theuse of combined antiplatelet therapy, includingaspirin and clopidogrel (75 mg daily) is mandatoryin patients who had a recent percutaneous coro-nary intervention (PCI) with stent(s) deploymentand should be considered in subsets of patients,such as those with recent non–ST-segment eleva-tion acute coronary syndromes or those who sus-tained a recurrent ischemic event while on aspirintherapy and in individual patients and societieswho can sustain the increased health care costsassociated with combined therapy. Chronic antico-agulants should be restricted to limited numbersof patients with specific indications, such as thosewith atrial fibrillation, LV mural thrombus, andrecent large anterior MI.

patients are appropriately selected for therapy. Forexample, a registry of 54 962 survivors of acute MI overthe age of 65 years reported a 15% lower 1-year mor-tality in patients with chronic obstructive pulmonarydisease (COPD) or asthma who were taking a β-blocker,but were not on β-agonist therapy, as compared withthose not on β-blocker therapy.59 However, β-blockersconferred no survival benefit to patients who were using a β-agonist or who had severe COPD or asthma.Similarly, although most clinicians are concerned aboutthe use of β-blockers in patients with intermittentclaudication, a meta-analysis found no adverse effectof β1-selective blockers on claudication symptoms.60

Cholesterol lowering with statins and the use of other drugs to treat dyslipidemias

Epidemiological studies demonstrate a strong andgraded association between elevated total and low-density lipoprotein (LDL) cholesterol and CV risk, both

in individuals without and those with establishedCVD.61-67 Low high-density lipoprotein (HDL) choles-terol is also an independent risk factor for atheroscle-rosis and is associated with poor outcomes in peoplewho already have CVD.63,68,69 Elevated triglycerideconcentration also confers an increased vascular risk,although this relationship has been more difficult toestablish and remains somewhat controversial.70,71

Lipid-altering agents include several classes of drugs:statins, bile acid sequestrants, nicotinic acid, choles-terol absorption inhibitors, and fibric acid derivatives.Statin drugs are the most effective drugs for loweringLDL cholesterol concentration, with reductions in therange of 20% to 60%, and also lower triglyceride levelsby 15% to 35% and raise HDL cholesterol concentra-tion by 5% to 15%.72 Statins are competitive inhibitorsof β-hydroxy-β-methylglutaryl coenzyme A (HMG-CoA)reductase, the rate-limiting step in cholesterol biosyn-thesis. The largest and most successful clinical trialsof lipid-modifying drugs have used statins. Their bene-ficial effects are likely not only a consequence of theireffect on lipids, but are thought to be mediated byadditional pleiotropic actions, the most importantbeing the increase in the bioavailability of nitric oxide(NO).73,74 Thus, statins have been shown to directlyupregulate endothelial nitric oxide synthase (eNOS)expression and activity, increasing NO availability, andto improve endothelial function. Statins have also po-tent anti-inflammatory properties and can favorablyalter plaque composition by reducing the accumulationof macrophages and decreasing the expression of ex-tracellular matrix-degrading enzymes, thus favoringplaque stability.75 Animal models of acute inflamma-tion have demonstrated the potent anti-inflammatoryproperties of statins and clinical trials have shown reductions in C-reactive protein (CRP) and other mark-ers of inflammation in human subjects treated withvarious statins.76 Other beneficial actions of statinsinclude inhibition of vascular smooth muscle cell pro-liferation, inhibition of leukocyte adhesion to the endo-thelium, and enhancement of fibrinolytic pathways.77

A number of large randomized placebo-controlledstatin trials conducted in patients with coronaryheart disease and diabetes (Table II, next page) 78-82

have clearly demonstrated that LDL-cholesterol low-ering of about 1.0 mmol/L in people at high risk of ischemic coronary events substantially reduces the riskof major vascular events by about 20%, with reductionsin all-cause mortality by about 12 %, coronary heartdisease and other vascular disease mortality by about20%, and nonfatal cardiovascular events, including MI



215


β-Blockers do not directly influence the athero-sclerotic process, ie, are not disease-modifyingagents. Benefits in very-low-risk post-MI patients,including those with early reperfusion, normalor near-normal LV function, and no ventriculararrhythmias, and in other secondary preventionsettings (in patients without previous MI), areless well established.


β-Blockers are recommended in all patients postMI who can tolerate this therapy.5,51 Treatmentshould be continued for at least 2 to 3 years andlikely indefinitely. Patients with high baseline risksuch as those with large infarcts, early heart fail-ure, impaired LV function, hypertension, and ven-tricular arrhythmias are likely to derive the mostbenefit. Although relative contraindications mayonce have been thought to preclude the use ofβ-blockers in some patients, evidence now sug-gests that, when administered with appropriatemonitoring, the benefits of β-blockers in reducingreinfarction and mortality actually outweigh therisks, even in patients with mild asthma or COPD,insulin-dependent diabetes mellitus, severe pe-ripheral arterial disease, first-degree heart block,and LV dysfunction or heart failure.

and stroke, by 26% and 17%, respectively (Figure 2).83

Clear benefits were shown in all subgroups evaluated,including various age groups, women and men, peo-ple with diabetes and those without, and those withcerebrovascular or peripheral arterial disease. The re-ductions in vascular events were additive to other effec-tive therapies, such as aspirin, β-blockers, and ACEinhibitors. Therefore, statin therapy should be usedwidely in patients with prior MI and in other vasculardisease patients, as well as in people with diabetesand no preexistent clinically manifest vascular disease.Recent evidence, such as the data provided by theHeart Protection Study, suggests that statin therapy isclearly beneficial even in those vascular disease patients

with levels of total cholesterol and LDL cholesterollower than 5.0 mmol/L and 2.5 mmol/L, respectively.81,83

These data support the notion that in patients withcoronary heart disease and other high-risk patient sub-sets, there is no clear cutoff value for LDL cholesterolbelow which there would be no benefit for furtherlowering it. While most current guidelines recommendLDL-cholesterol lowering to 2.5 mmol/L or lower inpost-MI patients, emerging data are challenging theserecommendations. A trial conducted in patients treat-ed by prior saphenous vein coronary artery bypassgraft surgery found that more aggressive reduction ofcholesterol aiming for target LDL cholesterol levels of1.6-2.2 mmol/L was more effective than a less aggres-



216

Table II. Large randomized controlled statin trials in people with coronary heart disease and diabetes.

Abbreviations: CHD, coronary heart disease; CVD, cardiovascular disease; RRR, relative risk reduction.

Trial acronyms: A to Z, Aggrastat to Zocor [trial]; CARDS, Collaborative Atorvastatin Diabetes Study; CARE, Cholesterol And Current Events [study],HPS, Heart Protection Study; LIPID, Long-term Intervention with Pravastatin in Ischemic Disease; PROVE-IT, PRavastatin Or atorVastatin Evaluationand Infection Therapy; 4S, Scandinavian Simvastatin Survival Study; TNT, Treating to New Targets.

Trial (No. of Study Treatments Follow-up Keypatients population (daily) (y) results

4 S Chronic stable CHD Simvastatin 20-40 mg 5.4 30% RRR in all-cause death (N=4444) Moderate-to-severe vs placebo and 34% RRR in major

hypercholesterolemia CHD events in the simvastatin group

CARE Stable post MI Pravastatin 40 mg 5 24% RRR in fatal CHD and (N=4159) Average cholesterol vs placebo nonfatal MI and

concentration 31% RRR in stroke in the pravastatin group

LIPID Chronic stable CHD Pravastatin 40 mg 61.5 22% RRR in all-cause death,(N=9014) Average cholesterol vs placebo 24% RRR in CHD death

concentration and 29% RRR in fatal and nonfatal MI

HPS CVD and/or diabetes Simvastatin 40 mg 5 13% RRR in all-cause death(N=20536) Average cholesterol vs placebo and 24% RRR in major

concentration CHD events in the simvastatin group

CARDS Type 2 diabetes Atorvastatin 80 mg 4 37% RRR in major CVD (N=2838) mellitus vs pravastatin 40 mg events in the atorvastatin

group

PROVE-IT Recent acute coronary Atorvastatin 80 mg 2 16% RRR in death and (N=4162) syndrome vs pravastatin 40 mg major CHD events in

Average cholesterol the atorvastatin group concentration

A to Z Recent acute coronary Simvastatin 80 mg 2 Trend towards fewer major (N=4497) syndrome vs simvastatin 40 mg CHD events in the high-

Average cholesterol dose simvastatin group concentration

TNT Chronic stable CHD Atorvastatin 80 mg 4.9 22% RRR in major CVD (N=10001) Average cholesterol vs atorvastatin 10 mg events in the atorvastatin

concentration 80 mg group

sive treatment regimen in retarding the progression ofcoronary artery disease.84 Similar enhanced benefitson retarding the anatomic progression of coronaryatherosclerosis were shown for a more aggressive lipid-lowering treatment strategy in the Reversal of Athero-sclerosis with Aggressive Lipid Lowering (REVERSAL)study85 and large randomized trials such as MyocardialIschemia Reduction with Acute Cholesterol Lowering(MIRACL), Pravastatin or Atorvastatin Evaluation andInfection Therapy (PROVE-IT), Aggrastat to Zocor (A toZ), and Treating to New Targets (TNT) indicate that ear-ly and more aggressive lipid-lowering statin therapyprovides more benefit than delayed and less aggressivestatin regimens, both in patients with recent acute MIand in those with chronic stable CHD.86-89 Based onresults of these trials some guidelines have been re-cently updated and suggest that more aggressive LDLcholesterol lowering (to levels <1.8 mmol/L) shouldbe achieved in secondary prevention.90

Statins are generally well tolerated and have few sideeffects. Large randomized trials have not substanti-ated earlier concerns about increased cancer risk and hazards related to accidental and violent death. Clinical trials and postmarketing surveillance datademonstrate that all currently available statins aregenerally well tolerated and that serious adverse ef-fects, such as rhabdomyolysis (<0.01%) and hepatitis(<0.01%) are exceedingly rare (even when using high-dose regimens).91

Other lipid-lowering agents studied in patients withcoronary heart disease including those with prior MIinclude fibrates, omega-3 fatty acids, resins, niacin,and estrogens. The recent Veterans Affairs High-Den-sity Lipoprotein Cholesterol Intervention Trial (VA-HIT)reported a 22% reduction in the risk of non-fatal MIand death from coronary causes in middle-aged menwith coronary heart disease and “normal” LDL choles-terol concentration treated with gemfibrozil.92 TheGruppo Italiano per lo Studio della Sopravvivenzanell’Infarto miocardico (GISSI)-Prevenzione trial foundbenefits associated with omega-3 polyunsaturated fattyacid (PUFA) therapy in patients post MI,93 althoughmost patients in this trial were not treated with a statinand it therefore remains uncertain if the benefits ob-served may extend to patients receiving statin therapy.Niacin and resins can be used as adjunctive therapyin addition to statins or in patients who do not toler-ate statin therapy and have also been associated with

improved outcomes in patients with CHD. Ezetimibeis the first in a new class of cholesterol absorption in-hibitors that impair cholesterol absorption at the brushborder of the intestine without affecting the absorp-tion of triglycerides or fat-soluble vitamins. It may beparticularly helpful in people who cannot toleratestatins in doses required to attain targets of therapy. Forexample, a randomized trial found that the reductionin LDL concentration was the same with atorvastatin10 mg/day and ezetimibe 10 mg/day, as with atorvas-



217

Events (%) RR & CIEnd point

Rate reduction(CI)Treatment Control (Treatment: Control)

Treatmentbetter

Controlbetter

Effect P<0.00001

0.5 1.0 1.5

Nonfatal MI

CHD death

Any major coronary event

CABG

PTCA

Unknown

Any coronary revascularization

Hemorrhagic stroke

Presumed ischemic stroke

Any stroke

Any major vascular event

Any death

2001 (4.4)

1548 (3.4)

3337 (7.4)

713 (3.3)

510 (2.4)

1397 (3.1)

2620 (5.8)

105 (0.2)

1235 (2.8)

1340 (3.0)

6354 (14.1)

3832 (8.5)

2769 (6.2)

1960 (4.4)

4420 (9.8)

1006 (4.7)

658 (3.1)

1770 (3.9)

3434 (7.6)

99 (0.2)

1518 (3.4)

1617 (3.7)

7994 (17.8)

4354 (9.7)

26% (21%, 30%)

19% (13%, 25%)

23% (20%, 26%)

25% (18%, 31%)

21% (11%, 31%)

24% (16%, 31%)

24% (20%, 27%)

–5% (–41%, 22%)

19% (11%, 26%)

17% (12%, 22%)

21% (19%, 23%)

12% (9%-16%)

Figure 2. Proportional effects on major vascularevents per mmol/L LDLcholesterol reduction.

Modified from reference83: Baigent C, Keech A,Kearney PM, et al; Choles-terol Treatment Trialists’(CTT) Collaborators. Choles-terol Treatment Trialists’(CTT) Collaboration Effica-cy and safety of cholesterol-lowering treatment in pros-pective meta-analyses ofindividual data from 90,056participants in randomisedtrials. Lancet. 2005;366:1267-1278. Copyright © 2005, Elsevier Ltd.

Abbreviations: CABG,coronary artery bypassgrafting; CHD, coronaryheart disease; MI, myocar-dial infarction; PTCA, percutaneous transluminalcoronary angioplasty.

tatin 80 mg alone.94 However, to date, no clinical out-come trials have demonstrated benefits with ezetimibe.Such trials are ongoing and will better define the roleof this lipid-modifying agent in secondary prevention.New agents, such as cholesterol ester transfer proteininhibitors95 and other agents that mobilize reversecholesterol transport from vascular cells are currentlyundergoing clinical trials and may further improveour management of high-risk patients.96

Angiotensin-converting enzyme (ACE) inhibitors and other drugs that modulate

the renin-angiotensin-aldosterone system (RAAS)

The renin-angiotensin-aldosterone system (RAAS) iscritically involved in the pathogenesis of vascular dis-ease and is an important therapeutic target.97-100 TheRAAS releases angiotensin II, a potent vasoconstrictor,which raises blood pressure and promotes atheroscle-rosis by increasing oxidative stress, inflammation, endothelial dysfunction, vascular growth, and by in-hibiting endogenous fibrinolysis (Figure 3). The RAASinteracts with the kallikrein-kinin system, which re-leases bradykinin. The effects of bradykinin in the vas-culature oppose many of the actions of angiotensin II;it stimulates synthesis of vasodilators, such as NO,hyperpolarizing factor, and prostacyclin, which improveendothelial function; it inhibits platelet adhesion andsmooth muscle cell proliferation and enhances thefibrinolytic balance by stimulating tissue plasminogenactivator (t-PA) synthesis. ACE inhibitors act by dualpathways to prevent angiotensin II formation and toblock the degradation of bradykinin into inactive pep-tides. By decreasing angiotensin II and increasingbradykinin, ACE inhibitors exert multiple effects thatprotect the coronary and peripheral vasculature(Table III).101-104

Earlier clinical trials have clearly demonstrated thebenefits of ACE inhibitors in hypertension,100 heartfailure,105,106 asymptomatic LV dysfunction,107 and inpatients with recent MI and low LV ejection fractionand/or heart failure.108-110 More recent trials have eval-uated the effects of ACE inhibitors in patients withCHD or arterial disease in other vascular territories inthe absence of heart failure and with preserved (normalor near-normal) LV systolic function. Surrogate endpoint trials have shown dose-dependent improvementin LV structure and function,111 endothelial function,112

and in slowing the atherosclerotic process (Figure 4).113

Large clinical end point trials confirm general reduc-tions in morbidity and mortality, although there aredifferences in the design and results of these trials(Table IV, page 220). The Heart Outcomes PreventionEvaluation (HOPE) study, demonstrated that 4 to 6years of treatment with 10 mg daily of ramipril reducedmajor vascular events, deaths, and new diabetes inpatients with preserved ventricular function and vas-cular disease or high-risk diabetes.114 The benefits ofACE inhibitors were also confirmed by the EUropeantrial on Reduction Of cardiac events with Perindoprilin stable coronary Artery disease (EUROPA),115 where-



218


The importance of pharmacological HDL-choles-terol raising requires further proof. Simplifiedapproaches to lipid lowering have been proposed,such as the treatment of all high-risk patientswith fixed medium- to high-dose statin therapyindependent of their cholesterol concentration.Similarly, simplified approaches to monitoringtreatment efficacy and safety have been suggested.Such approaches need to be further evaluated.


There is overwhelming evidence substantiating theuse of statin therapy in all patients with CHD,including those with recent or remote MI. Treat-ment should be initiated as soon as possible aftera diagnosis of vascular disease is made. The useof fibrates, omega-3 fatty acids, and niacin canbe considered in specific subsets of patients suchas those with low HDL cholesterol, elevated tri-glycerides and in patients who cannot toleratestatin therapy. Although most current guidelinessuggest to aim for LDL cholesterol levels ≤2.5mmol/L, HDL cholesterol ≥1 mmol/L, and triglyc-erides ≤2 mmol/L, these recommendations arelikely to be revised in light of recent data, whichsuggest that lowering of LDL cholesterol to aslow levels as possible is preferable. This view isreflected in the modified ATP III guidelines pub-lished in July 2004, which recommended an optional goal of LDL below 1.8 mmol/L for “high-risk” patients. It is probable that this recommen-dation and possibly even more aggressive ap-proaches will be widely suggested by guidelinesfrom various national and international societiesand organizations. Dietary therapy and exerciseneed to be recommended in conjunction withdrug therapy.

as the Prevention of Events withAngiotensin-Converting EnzymeInhibition (PEACE) trial reportedno reduction in CV in patientswith stable coronary artery dis-ease treated with trandolapril.116

Some have interpreted the PEACEtrial results as evidence for lackof benefit from ACE-inhibitortherapy in “low-risk” patients withCHD, or those who are receivingother effective therapies (espe-cially statins and revasculariza-tion). However, careful review ofthe totality of data provided fromthese three large trials showsthat ACE-inhibitor therapy doesindeed reduce all-cause death byabout 14% and major vascularevents by about 19% in a widerange of patients with vasculardisease and preserved LV systolicfunction, including those receiv-ing other cardiac and vascularprotective therapies (statins, aspirin, β-blockers), people ofvarious ages including the elder-ly, men, and women, and thosewith or without a history of hy-pertension, diabetes, and periph-eral arterial disease (Figure 5,page 220). Moreover, these ben-efits are maintained in the longterm.117 Based upon these find-ings, the 2004 task force of the

European Society of Cardiology (ESC) gave a class Irecommendation to the use of ACE inhibitors in pa-tients with vascular disease.104 The differences betweenthe results of the individual trials may be related tothe lower power of the PEACE trial, originally designedto randomize over 14 000 study participants, but witha much smaller final sample size, the choice of a lesssensitive primary end point, and the low complianceattained in this trial. However, differences in the ACEinhibitors used118,119 and the play of chance cannot befully excluded.

Patients with type 2 diabetes are particularly suitedfor ACE-inhibitor therapy, with substantial reductionsin macrovascular events, CV death, MI, and stroke, andin microvascular disease, particularly nephropathy, asshown in the MIcroalbuminuria, Cardiovascular andRenal Outcomes–Heart Outcomes Prevention Evalua-



219

Abnormalvasoconstriction

PAI-1/thrombosis

→

Collagen

Remodeling

→

Aldosterone→

Vasopressin→

Endothelin→

Activation ofthe SNS

Platelet aggregation

Superoxideproduction

Vascularsmooth muscle

growthCardiomyocyte

growth

Angiotensin II

Figure 3. Deleterious effects of angiotensin II.

Abbreviations: PAI-1, plasminogen activator inhibitor 1; SNS, sympathetic nervous system.

Vascular protective actions

Direct antiatherogenic effect Improved endothelial function Enhanced endogenous fibrinolysisInhibition of platelet aggregationAntiproliferative and antimigratory

for smooth muscle cells AntioxidantAnti-inflammatoryDecreased collagen matrix formation Protection from plaque ruptureImproved arterial compliance and tone

Table III. Beneficial effects of angiotensin-converting enzyme inhibitors in cardiovascular diseases.

Blood pressure lowering

Cardiac protective actions

Decrease in preload and afterloadDecrease in left ventricular massImproved myocardial remodelingDecrease in sympathetic

stimulation Reduction in reperfusion injury

Metabolic effects

Lipid-neutralImproved glucose metabolism

0.22

0.018

0.014

Placebo Ramipril2.5 mg

Ramipril10 mgN=732 patients with

vascular disease or diabetes

Change in m

ean m

axi

mu

m

caro

tid

IM

T (

mm

/y)

0.025

0.01

0.005

0.02

0.015

0

P=0.028

NS

Reduction (37%)

Figure 4. Dose-dependent slowing in the progression of carotidatherosclerosis in the Study to Evaluate Carotid Ultrasound changeswith Ramipril and vitamin E (SECURE).113

Abbreviations: IMT, intima-media thickness.

tion (MICRO-HOPE) substudy of HOPE120 and thePERindopril SUbstudy in coronary Artery disease andDiabEtes (PERSUADE) trial,121 a substudy of EUROPA,as well as in other studies. A particularly interestingand somewhat unexpected finding is the reduction innew diagnoses of diabetes in patients treated with ACEinhibitors,122 which was observed in retrospect in sev-eral trials and which is further explored in ongoingstudies.123

ACE inhibitors are generally well tolerated. The mostcommon side effects include cough, occurring in 5%to 10% of patients. Dizziness, hypotension, renal dys-function, and hyperkalemia are infrequent and cangenerally be avoided by careful drug titration and byavoiding the administration of ACE inhibitors in vol-ume-depleted patients and in those with bilateral re-nal artery stenosis.

Angiotensin-receptor blockers (ARBs) irreversibly in-hibit angiotensin II binding to the angiotensin receptorsubtype 1 (AT1), thought to account for most deleteri-ous actions of RAAS. The effect on AT1-mediated effectsof angiotensin II is more profound than that attainedwith ACE inhibitors, because angiotensin II can be

produced via alternate non–ACE-mediated pathways.However, ARBs do not directly affect bradykinin break-down (the interaction with the kallikrein-kinin systemvia AT2 receptor activation is less well understood andprobably less important), and the results of increasedavailability of angiotensin II associated with AT1 block-ade remain uncertain. To date, ARBs have been shownto: (i) effectively lower blood pressure with excellenttolerability in hypertensive patients124; (ii) reduce hos-pital admissions in patients with chronic heart fail-ure125; (iii) represent a viable option for the treatmentof patients with acute MI and significant LV systolicdysfunction126; and (iv) to halt the progression of renaldisease in patients with type 2 diabetes mellitus.127-129

Similar to ACE inhibitors, these agents seem to pre-vent or delay the onset of type 2 diabetes and are un-der investigation for this potentially important clinicalapplication. Benefits of ARBs alone or in combinationwith ACE inhibitors in the treatment of a wide rangeof patients with coronary and other vascular diseasehave been suggested, but remain still unproven. TheONgoing Telmisartan Alone and in combination withRamipril Global Endpoint Trial/Telmisartan Random-ized Assessment Study in ACE Intolerant Subjects withCardiovascular Disease (ONTARGET/TRANSCEND)



220

Study ACE inhibitor Key inclusion criteria Primary outcome

HOPE Ramipril 10 mg Vascular disease CV death, MI, N=9297 (80% had CAD) stroke (4.5 years) LVEF ≥40%

No heart failureAge ≥55 years

EUROPA Perindopril 8 mg CAD CV death, MI, N=12218 No heart failure cardiac arrest (4.2 years) Age ≥18 years

PEACE Trandolapril 4 mg CAD CV death, MI, N=8290 LVEF ≥40% coronary (4.8 years) Age ≥50 years revascularization

PFavors placeboFavors ACEI

Odds ratio

PlaceboACEI

Events rate (%)

0.5 1.25

All-cause death

MI

Stroke

Revascularization

7.5

6.4

2.1

15.5

8.9

7.7

2.7

16.3

<0.001

<0.001

<0.001

0.025

0.86

0.81

0.77

0.92

0.75 1

Figure 5. Pooled analysis of large angiotensin-converting enzyme inhibitor(ACEI) outcome trials in coronary heartdisease patients without heart failure(EUROPA, HOPE, PEACE). The totalityof evidence strongly favors a substantialbenefit for ACE-inhibitor therapy.

Trial acronyms: EUROPA, EUropeantrial on Reduction Of cardiac events with Perindopril in stable coronary Artery disease; HOPE, Heart OutcomesPrevention Evaluation; PEACE,Prevention of Events with Angiotensin-Converting Enzyme inhibition.

Table IV. Overview of large clinicaltrials of angiotensin-converting enzymeinhibitors in patients with stable coronary

heart disease and without heart failure.

Abbreviations: CAD, coronaryartery disease; CV, cardiovascular;LVEF, left ventricular ejection fraction;MI, myo-cardial infarction.

Trial acronyms: EUROPA, EUropeantrial on Reduction Of cardiac eventswith Perindopril in stable coronary

Artery disease; HOPE, Heart OutcomesPrevention Evaluation; PEACE,Prevention of Events with Angiotensin-

Converting Enzyme inhibition.

study in over 30 000 patients with preexistent CV dis-ease, but without heart failure or LV dysfunction, isexpected to provide further answers.130 For now, itseems reasonable to use ARBs in ACE-intolerant patients, although this approach remains unproven. Aldosterone blockade with drugs such as spironolac-tone and eplerenone has been shown to benefit pa-tients with hypertension, advanced heart failure, andthose with LV dysfunction post MI, but has not beentested in other settings.131-133

Drugs and supplements with no proven benefit and

potential for harm

Several drugs and supplements have been commonlyused in secondary prevention. However, recent evi-dence does not support the use of certain agents in-cluding: (i) vitamin E and other antioxidant vitamins;(ii) hormone replacement therapy (HRT) in post-menopausal women; and (iii) Class I antiarrhythmicagents (quinidine, procainamide, disopyramide, en-canide, flecainide, moricizine).

Oxidation was shown conclusively to play a majorrole in atherogenesis and large prospective epidemio-logical studies suggested that the use of antioxidantvitamins, particularly vitamin E supplements, may beprotective.134,135 However, a considerable number oflarge randomized clinical trials have failed to confirmbenefit. Antioxidant vitamins were shown to have aneutral effect in most settings,136 with a potential forharm in some patients, such as those at risk of devel-oping heart failure137 and when using high-dose prepa-rations.138 Importantly, the use of antioxidant vitaminsand that of other “natural” products often detractsfrom the focus and commitment needed to implementinterventions proven to reduce risk. It should be notedthat homocysteine-lowering B vitamins (folate and vitamins B6 and B12) are still under investigation inlarge clinical trials.139

The use of estrogen, alone or in combination withprogesterone, did also hold promise, based on find-ings derived from over 50 observational studies andfrom investigations indicating that HRT has favorableeffects on lipids, endothelial function, and arterial vasodilation.140,141 Unfortunately, clinical trials do notsubstantiate the use of HRT in CV prevention. In fact,the Women's Angiographic Vitamin and Estrogen(WAVE) trial found that angiographic progression ofcoronary disease worsened in women receiving HRT142

and the Heart and Estrogen/progestin ReplacementStudy (HERS) trial in 2763 women with CHD reportedno differences in CV outcomes between women ran-domized to 0.625 mg of conjugated equine estrogensplus 2.5 mg of medroxyprogesterone or placebo andan excess of venous thromboembolic events in thoseallocated to HRT.143 Similar disappointing results wereshown in primary prevention trials.144 Therefore, givencurrent information, HRT should not be used to re-duce the risk of CV events in postmenopausal women.

The data for Class I antiarrhythmic agents clearly in-dicate a substantial hazard related primarily to theproarrhythmogenic potential of these agents in pa-tients with structural heart disease.145



221


It remains uncertain whether all ACE inhibitorsshould be used in patients with stable coronaryand other vascular disease in the absence of heartfailure. The ACE-inhibitor preparations proven toreduce events are the high-tissue affinity, lipo-philic agents, specifically ramipril 10 mg/day andperindopril 8 mg/day. The role of ARBs in the ab-sence of heart failure and diabetic nephropathyrequires further exploration.


ACE inhibitors are recommended in all patientspost MI who can tolerate this therapy. Treatmentshould be initiated in the early phases of acute MIand continued indefinitely post MI. Other patientswith vascular disease, including those with pre-vious stroke and TIA, peripheral arterial disease,and type 2 diabetes with additional risk factorsshould also receive ACE-inhibitor therapy. ARBscan be used in heart failure patients already re-ceiving an ACE inhibitor, in patients with type 2diabetes with nephropathy, and may be consid-ered in other high-risk people who do not toler-ate ACE inhibitors.


There is no role for the use of antioxidant vitaminsupplements, HRT, and class I antiarrhythmicagents in secondary CV prevention. These inter-ventions have not been proven to benefit patients,can be associated with harm, and should beavoided.

CARDIAC REHABILITATION ANDLIFESTYLE MODIFICATIONS

Comprehensive cardiac rehabilitation programs includemedical evaluation, education, counseling, prescribedexercise, and CV risk factor modification, directed towards smoking cessation, the recognition and man-agement of psychosocial stressors, weight manage-ment, treatment of dyslipidemia, hypertension, anddiabetes, and using pharmacological, as well as non-pharmacological approaches. Goals of therapy in patients with established CV disease are outlined inTable V. Such comprehensive intensive approachescan achieve substantial success, as shown in peoplewith type 2 diabetes, where aggressive comprehensivemanagement of risk factors was shown to reduce CV events by over 50% compared with usual care.146

Comprehensive cardiac rehabilita-tion programs were shown to reducethe risk of cardiovascular deaths by 20% to 25% and reduce cardiacmorbidity.147

It needs to be strongly emphasizedthat lifestyle modifications are essential components of the man-agement of patients with coronaryheart disease and need to be an in-tegral component of secondary pre-vention strategies. This publicationdoes not aim to review in detail theevidence supporting the implemen-tation of lifestyle modifications. Suchevidence is available for smokingcessation, dietary modifications,regular exercise, and psychologicaland stress management, and is re-viewed in brief.

Smoking cessation

Many observational studies found that people withCHD who stopped smoking rapidly reduced the risk ofcardiac disease and MI (relative risk reduction about50% for recurrent coronary events or premature deathcompared with continuing smokers).148 About half ofthe benefits occur in the first year after smoking ces-sation, followed by a more gradual decrease in riskreaching the risk of never smokers after several yearsof abstinence. Among people with peripheral arterialdisease and stroke, smoking cessation has been shownin observational studies to be associated with im-proved exercise tolerance, decreased risk of amputa-tion, improved survival, and reduced risk of recurrentstroke. The interventions shown to be most effectiveto attain and sustain smoking cessation are referral toa smoking cessation program and the use of nicotinepatches or gum and bupropion.4,149,150

Dietary modifications and management of weight and

increased abdominal adiposity

Dietary intervention, such as a Mediterranean diet,rich in fish (particularly oily fish), fruit, vegetables,bread, pasta, potatoes, olive oil and rapeseed mar-garine can be highly effective in patients with estab-lished CHD.151 Other diets shown to be beneficial arelow-fat and high-fiber diets. Dietary recommenda-tions need to emphasize the need to limit energy in-take adjusted to maintain ideal body weight, intake of



222


It remains uncertain whether HRT preparationsother than conjugated equine estrogen alone orin combination with medroxyprogesterone mayhave some benefits in CV prevention. However, itis recommended that a conservative approach betaken in clinical practice, with avoidance of HRTin CV prevention, unless further research becomesavailable to support the use of other HRT prepa-rations. The role of homocysteine-lowering vita-mins remains under investigation.

Risk factor Goal of therapy

Vascular disease Aspirin, β-blocker, statin, and ACE-inhibitor in all patients who can tolerate these therapies independent of levels of risk factors

Blood pressure <130/80 mm Hg

Hyperglycemia HgA1C <7%

Dyslipidemia

LDL cholesterol<2.5 mmol/L (<1.8 mmol/L should be strongly

considered)

HDL cholesterol>1.1 mmol/L in men>1.3 mmol/L in women

Triglycerides <1.7 mmol/L

Excessive body weight Body mass index (BMI) <25 kg/m2

Sedentary lifestyle 30-45 minutes of moderate intensity exercise at least 5 days/week

Table V. Treatment goals in the secondary prevention of cardiovascular events.

saturated fats, not to exceed 30% of total lipids, ofcholesterol (<300 mg/day) and of complex carbohy-drates, as well as the need to ensure adequate intakeof micronutrients.

Regular exercise

Exercise is an important component of cardiac reha-bilitation programs that has been demonstrated toreduce by 20% to 25% the risk of cardiovascular deathin patients with previous MI.152 Current recommenda-tions suggest 30 to 45 minutes of moderate physicalactivity at least 5 days a week.

Phychological and stress management interventions

Depression and other forms of psychological stresswere shown to be associated with increased CV risk.153

A systematic overview in over 3000 people with CHDfound that psychosocial treatments significantly re-duced mortality and nonfatal events in the first 2 yearsof follow-up after MI (relative risk reduction of about40% for different CV end points).154

CHALLENGES AHEAD

Our biggest current challenge is to implement proveneffective therapies in all high-risk patients with CVD.A clear gap between physician knowledge of treatmentbenefits and clinical reality has been noted and needsto be narrowed. For example, the Second EUROpeanAction on Secondary Prevention by Intervention toReduce Events (EUROASPIRE II) survey, conducted innine European countries in 1999/2000, 5 years after theEUROASPIRE I survey of 1995/1996, found little changein smoking and hypertension rates among people withCHD, alarming increases in rates of obesity and dia-betes, while blood pressure control was achieved onlyin about half of the patients assessed and many werenot receiving life-saving medications.155 Similar data areavailable from the USA, Canada, and other regions.156-158

Initiatives directed at the systematic implementationof secondary prevention interventions are gaining in-creasing popularity159 and novel approaches such asthe “polypill” have been proposed.160 In addition, morephysician and patient education, as well as researchinto barriers in the implementation of CV prevention,are needed.

CONCLUSIONS

The potential gains associated with the consistent useof pharmacological secondary prevention interventionsare very large. Aspirin, β-blockers, ACE inhibitors, andlipid-lowering therapies lower the risk of future vascu-lar events by about 25% each in high-risk patients. Thebenefits of these interventions appear to be largelyindependent, so that when used together it is expectedthat two thirds to three quarters of future vascularevents could be prevented. When in addition to thesedrug therapies smoking cessation and aggressive blood-pressure lowering are attained, it may be possible tolower the risk of future vascular events by about fourfifths in high-risk people (Table VI).161,162

Given these tremendous potential gains, makingthese interventions available, affordable, accessible,and convenient, as well as understanding current bar-riers to the implementation of secondary CV preven-tion interventions, both in established marketeconomies and in developing countries, needs to bea priority and could lead to substantial individual andpublic health benefits.



223

Table VI. Potential cumulative impact of treatment with drugs provento improve outcomes in the secondary prevention of coronary heart dis-ease and in other high-risk patients.

Relative risk 2-Year reduction* event rate†

None … 8%

Aspirin 25% 6%

β-Blockers 25% 4-5%

Lipid-lowering 30% 3.0%(by 1.5 mmol/L)

ACE inhibitors 25% 2.3%

*Cumulative risk reduction if all drugs are used is about 75%.†“Events” designates cardiovascular death, myocardial infarction, or

strokes. A 4% annual event rate is assumed in the absence of secondary prevention therapies. Smoking cessation in current smokers, dietary modifications, regular exercise, and psychosocial counseling are likely to lead to substantial additional benefits.

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ight major randomized controlled trials, published between 1991 and 1995, directly studied the effect

of different angiotensin-convertingenzyme (ACE)-inhibitor regimenson survival immediately after acutemyocardial infarction (AMI). Thesewere all placebo controlled. Subse-quently, there have been two major

comparative studies assessing ad-ministration of angiotensin II type 1(AT1) receptor blockade either inconjunction with, or instead of, ACEinhibition with first-generationsulfhydryl-containing captopril. Inaddition, there has been one majorstudy of aldosterone receptor antag-onism used as an adjunct to ACEinhibition after myocardial infarc-

What is the best way to keep the renin-angiotensin system under control? Alistair S. Hall, MB, ChB, FRCP, PhD; Niamh Kilcullen, MB, BCh, MRCPI

Professor of Clinical Cardiology (A. S. Hall) and BHF Research Fellow (N. Kilcullen) BHF Heart Research Centre at Leeds - UK

E

Keywords: ACE inhibitor; angiotensin receptorblocker; myocardial infarction; acute coronarysyndromeAddress for correspondence:Alistair S. Hall, Professor of Clinical Cardiology;Consultant Cardiologist / Senior Lecturer, BHF Heart Research Centre at Leeds, G FloorJubilee Wing, Leeds General Infirmary, Leeds, LS1 3EX, UK.(e-mail: [email protected])



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Powerful evidence supports the long-term prescription of angiotensin-converting enzyme (ACE) inhibitorsin patients surviving an acute myo-cardial infarction (AMI) to enhancemorbidity and survival outcomes.Nevertheless, while physicians areprescribing ACE-inhibitor therapyto many patients at high-risk ofdeath, there continues to be a failureto prescribe appropriate ACE-inhi-bition regimens, resulting in an in-crease in subsequent patient death.Alternate use of an angiotensin receptor blocker (ARB) may beconsidered—though members ofthis class are also not readily inter-changeable with each other or withthe ACE inhibitors. The selectivealdosterone antagonist eplerenonemay represent a better alternativethan do the ARBs for ACE-intoler-ant patients, though whatever thestrategy, there is still the need toensure that appropriate treatmentdose and frequency are used.

SELECTED ABBREVIATIONS AND ACRONYMS

AIRE Acute Infarction Ramipril Efficacy

AMI acute myocardial infarction

ARB angiotensin receptor blocker

ELITE-2 Evaluation of Losartan In The Elderly–2

EMMACE Evaluation of Methods and Management of Acute Coronary Events

EPHESUS Eplerenone Post-acute myocardial infarction Heart failureEfficacy and SUrvival Study

EUROPA EUropean trial on Reduction Of cardiac events with Perindopril in stable coronary Artery disease

GISSI Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico

HOPE Heart Outcomes Prevention Evaluation

HR hazard ratio

ISIS Internatinal Study of Infarct Survival


OPTIMAAL OPtimal Trial In Myocardial infarction with Angiotensin II Antagonist Losartan

PEACE Prevention of Events with Angiotensin Converting Enzyme

RALES Randomized ALdactone Evaluation Study

RCT randomized controlled trial

SAVE Survival And Ventricular Enlargement

TRACE TRAndolapril Cardiac Evaluation

VALIANT VALsartan In Acute myocardial iNfarcTion

Copyright © 2005 LLS SAS. All rights reserved www.dialogues-cvm.org

tion. However, the definition of my-ocardial infarction has broadenedover the last few years and now encompasses patients previouslyconsidered to have a diagnosis ofunstable angina. This has left a gapin the evidence base that is bestaddressed by broadening the defi-nition of “secondary prevention” toinclude all patients with overt coro-nary artery disease, whether stableor unstable. In this setting, threelarge placebo-controlled studieshave been completed. Together withinformation obtained from acutecoronary syndrome registries andalso applied clinical common sense,this forms the basis for considera-tion of the question—“Secondaryprevention: what is the best way tokeep the renin-angiotensin systemunder control?”

DIRECT RCT EVIDENCEFOR ACE INHIBITION?

Four randomized controlled trials(RCTs) elected to treat individualswith suspected AMI starting withinthe first 36 hours after the onset ofsymptoms, of which two reportedno beneficial effect on survival.1,2

In contrast, both the InternationalStudy of Infarct Survival–4 (ISIS-4)and Gruppo Italiano per lo Studiodella Sopravvivenza nell’InfartoMiocardico–3 (GISSI-3) trials ob-served a small survival benefit at35 to 42 days, which was no longerstatistically significant on long-termfollow-up.3-5 In contrast, the Sur-vival And Ventricular Enlargement(SAVE) and TRAndolapril CardiacEvaluation (TRACE) investigatorsrandomized individuals with con-firmed AMI and evidence of systolicleft ventricular (LV) impairment;both studies observed a sustainedsurvival benefit with continued ACE-inhibitor therapy.6,7 Similarly, treat-ment of patients with clinical LVfailure after AMI resulted in majorand sustained survival benefits as

demonstrated by the Acute Infarc-tion Ramipril Efficacy (AIRE)8 andAIRE Extension (AIREX)9 studies.

Expert statements and guidelinespublished in 1996 and 1997 sum-marized and interpreted evidenceavailable at that time in differingways.10,11 However, despite alternateinterpretation as to the value ofACE-inhibitor therapy in secondaryprevention, there was agreementthat individuals with either clinicalLV failure or systolic LV impairmentshould be treated indefinitely. Fur-thermore, the recommendation thattrial treatment regimens be followedwhenever possible was widely en-dorsed.12 Importantly, potentialdifferences in the magnitude of sur-vival benefits resulting from differ-ent ACE-inhibitor regimens havebeen inadequately explored.

DIRECT RCT EVIDENCEFOR ANGIOTENSIN

RECEPTOR BLOCKADE

The OPtimal Trial In Myocardial in-farction with Angiotensin II Antag-onist Losartan (OPTIMAAL) andVALsartan In Acute myocardial iNfarcTion (VALIANT)13,14 studieshave compared angiotensin recep-tor blockers (ARBs), losartan, andvalsartan against the first-genera-tion, sulfhydryl-containing ACE in-hibitor captopril. The choice of thisparticular drug as comparator (alsoseen in many comparative heartfailure and hypertension trials) isan interesting one given captopril’slimitations as an ACE inhibitor.

Modeled on the terminal prolineamino acid of a peptide derivedfrom the venom of the Brazilian viperBothrops jararaca, captopril utilizeda sulfhydryl active moiety to pro-duce ACE inhibition. As this drugwas initially associated with a rangeof unacceptable side effects suchas proteinuria, skin rashes, altered

taste, other pharmaceutical compa-nies opted to replace the sulfhydrylgroup with a carboxyl moiety. Thepotency of the interactions withthe active site of the ACE of thecarboxyl group was seen to relateto the degree of lipophilicity of themolecule—a property that wouldlater prove to be an asset with re-gard to both: (i) access to a laterdiscovered second active site onACE molecule; and (ii) penetrationof the ACE inhibitor into normaland pathological tissues.

The OPTIMAAL study comparedlosartan 50 mg once daily with cap-topril 50 mg three times daily, in5477 patients with confirmed AMIand acute heart failure OR anteriorQ waves OR prior to MI. The all-cause mortality at a mean follow-uptime of 2.7 years was higher for thelosartan group (18%) than for thecaptopril group (16%) producing anincreased relative risk of 13% (95%confidence interval [CI], –1% to 28%;P=0.07) and an increased absoluterisk of 2% (20 extra deaths per 1000treated; number needed to harm[NNH] = 50). The secondary endpoint of cardiovascular death wasalso increased (hazard ratio [HR],1.17; 95% CI, 1.01 to 1.34; P=0.034).The authors concluded that ACEinhibitors should remain first-choice therapy.

As the Evaluation of Losartan In TheElderly–2 (ELITE-2)15 heart failurestudy also showed a strong trendtoward increased mortality withlosartan as compared with capto-pril, the FDA decided to withdrawthe drug’s heart failure license. Rea-sons for lack of efficacy have beendebated—predominantly to sug-gest that an inadequate dose wastested. However, as a prodrug de-pendent on first-pass metabolism inthe liver, losartan is converted intotwo different metabolites. The firstof these (EXP3174) is a potent


What is the best way to keep the RAS under control? - Hall and Kilcullen

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antagonist of the AT1 receptor andaccounts for 14% of the parentmolecule. A second metabolite(EXP3179) has a structure similarto indomethacin and accounts for86% of the parent molecule. Amongother actions, this second metabo-lite inhibits the COX-2 enzyme16,17

an effect that may be undesirablein patients with increased “global cardiovascular risk.”

This mechanism may also help toexplain why myocardial infarctionwas not reduced in the LosartanIntervention For Endpoint reductionin hypertension (LIFE) study,18

carried out in patients with hyper-tension and also left ventricularhypertrophy. This observation wasmore remarkable as it was at oddswith a significant reduction in stroke.This would suggest that losartanwas having more than one effect—as suggested also by the molecules’known pharmacokinetics.16,17 Whileit remains unclear to which extentother ARBs and their metabolitesmay also act as COX-2 inhibitors, afailure to prevent myocardial infarc-tion is consistently apparent.19,20

The VALIANT study had three armswith target doses as follows: (i) val-sartan 160 mg twice daily “V”; (ii)valsartan 80 mg twice daily plus cap-topril 50 mg three times daily “V&C”;and (iii) captopril 50 mg three timesdaily “C”. The primary outcome ofcardiovascular death up to a meanfollow-up of 24.7 months, wasidentical (“V”=16.8%; “V&C”=16.9%; “C”=16.9%; P=0.95). Patients re-cruited all had a confirmed AMIcomplicated by either asymptomaticLV dysfunction or overt heart failure.The authors conclude with the rec-ommendation that valsartan shouldbe considered to be a clinically ef-fective alternative to captopril. How-ever, it is interesting to considerthat if inert placebo “A” had beencompared with placebo “B” and also

the combination of “A + B,” the mor-tality outcomes would have beenidentical to each other as in thistrial. Consequently, the conclusionsof this study depend heavily on thebelief that captopril 150 mg daily isas effective an ACE-inhibitor regi-men as are the alternatives. As therehave been no conventional heartfailure studies performed with cap-topril, the premise of efficacy isbased entirely on the SAVE Study.

It is interesting to note that the 2-year placebo group mortality inSAVE was approximately 17% (ie,identical to VALIANT). However,comparisons are made difficult by:(i) the use of other concomitantmedicines; (ii) differing time fromMI to randomization; and (iii) percentage of patients with KillipClass >II. These and other differ-ences between the two studies serveto emphasize the inappropriatenessof extrapolating a survival benefitfrom SAVE to VALIANT.

DIRECT RCT EVIDENCEFOR ALDOSTERONE

ANTAGONISM

The Eplerenone Post-acute myo-cardial infarction Heart failure Effica-cy and SUrvival Study (EPHESUS)21

evaluation of the aldosterone an-tagonist eplerenone in 6632 patientswith heart failure or asymptomaticLV dysfunction after AMI was report-ed in 2005. Patients with an aver-age age of 64 y were randomized to placebo or eplerenone 50 mg/day and treated for a mean of 16 months. At that time there was a15% relative risk reduction (95% CI4% to 25%; P=0.008). These benefitswere in the presence of concomitanttreatment with ACE inhibitors/ARBs(86%; drugs and dosages not stated)and also β-blockers (75%). Baselineuse of statin therapy was surprising-ly low (47%). These benefits werein spite of the fact that serious hy-

perkalemia (>6 mmol/L) occurred in5.5% of patients given eplerenoneas compared with 3.9% given place-bo (P=0.002). Conversely, hypo-kalemia was lower for eplerenone.

These findings are supported byearlier observations for heart failurepatients given spironolactone aspart of the Randomized ALdactoneEvaluation Study (RALES).22 Hencethe repeated question of whether a“class effect” is being observed. Inessence, concern has been raisedthat the newer more selective aldo-sterone antagonist eplerenone maybe no better than the less selective,though much cheaper, drug spirono-lactone.

Importantly, neither drug hasdemonstrated the ability to preventmyocardial infarction—a commoncause of death in these patients.Consequently, this is unlikely to be the “best way to modulate therenin-angiotensin system” for themajority of patients in need of sec-ondary prevention.

EXTENDED RCT EVIDENCEFOR ACE INHIBITION

The HOPE study23 recruited 9297high-risk men and women, >55 yearsof age, with previous cardiovasculardisease or diabetes plus 1 risk fac-tor. These were randomly allocatedto receive either ramipril 10 mg/dayor matching placebo. During a meanfollow-up of 4.5 years there was a21% relative reduction in the risk ofclinical MI or cardiovascular death(95% CI, 11% to 30%; P=0.0003) withramipril treatment. There was also a highly significant reduction inall-cause mortality, stroke, and theneed for coronary revascularization.

Having already dramatically ex-tended the potential use of ACEinhibition in secondary prevention,there was still no conclusive evi-



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dence that ACE inhibition benefiteda broader, lower-risk group of pa-tients, who more accurately repre-sented the existing patient popula-tion with established coronary heartdisease. It was specifically to remedythis deficiency that the concept ofEUROPA (EUropean trial on Reduc-tion Of cardiac events with Perindo-pril in stable coronary Artery dis-ease)24 was developed. The studywas designed to assess the value ofACE inhibition in the prevention ofcardiac events in lower-risk patientswith stable coronary artery diseasealready on standard therapies. The ACE inhibitor perindopril was chosen for study on account of itslipophilic profile, sustained actionin lowering blood pressure (a singledose providing 24-hour control),additional documented anti-ischem-ic and antiatherogenic actions, aswell as its effect on cardiovascularremodeling: a multifactorial profile,which, in theory, might provide important benefit to the broad pa-tient population selected for study.

A total of 12 218 patients aged between 26 and 89 (mean age 60 y)were recruited from 24 Europeancountries. Patients were includedon the basis of established CAD(defined as a previous MI at least 6 months earlier, surgery or revas-cularization, abnormal coronaryangiography, or [in men] a positiveexercise test) without evidence ofheart failure. Over 80% of each groupwere male, 27% in each group werehypertensive, 12% were diabetic,15% were smokers, and 63% had hypercholesterolemia. In terms oftreatment, 92% were already takinga platelet inhibitor, 62% a β-blocker,58% a statin, 32% a calcium channelblocker, and 44% a nitrate. Follow-ing a 4-week run-in period, theywere randomized to receive eitherperindopril 8 mg/day (n=6110) ormatching placebo (n=6108) for anaverage of 4.2 years.

For the combined primary end point,event rates were 9.9% (603 of 6108patients) in the placebo group and8.0% (488 of 6110 patients) in theperindopril group: a 1.9% absoluterisk reduction and a 20% relativerisk reduction (P=0.0003). In addi-tion, perindopril reduced the sec-ondary end point of total mortality,cardiovascular death, unstable angi-na, or cardiac arrest (P=0.0009) andalso tertiary end points of fatal andnonfatal myocardial infarction (24%;P=0.001) and hospitalization forheart failure (39%; P=0.002). Benefitswere present across all subgroupsin men, women, older and youngerpatients, those with or without ahistory of prior MI, and those withor without diabetes, hypertension,or noncoronary vascular disease.Benefits were also seen regardlessof whether or not other therapiessuch as statins and β-blockers wereprescribed. All other tertiary endpoints showed a trend toward ben-efit, but did not achieve significancedue to low event numbers in bothtreatment arms.

The Prevention of Events with Angiotensin-Converting Enzyme(PEACE) Investigators reported anegative outcome when comparingtrandolapril 4 mg and placebo in pa-tients with coronary artery disease.25

However, they wrongly state thattheir failure to demonstrate clinicalbenefits relates to an event rate thatwas “lower than the event rates inthe ACE-inhibitor groups in (the)two previous trials.” Annualized all-cause mortality was similarly low inPEACE (1.6% per year) and EUROPA(1.5% per year) as compared withHOPE (2.3% per year). Furthermore,the annualized rate of occurrenceof the combined primary end pointfor PEACE was higher than for eitherof the other two trials: PEACE (4.6%per year); HOPE (3.2% per year), andEUROPA (2.1% per year). It is alsoapparent that the event rates for

cardiovascular death and nonfatalmyocardial infarction are similarlylow for PEACE (0.8% and 1.1% peryear) and EUROPA (0.9% and 1.3%per year) as compared with HOPE(1.4% and 2.2% per year). These sim-ilarities in event rates are presentdespite significantly different base-line rates of lipid lowering and revas-cularization (PEACE 72% and 70%;EUROPA 58% [70% at 3 years follow-up] and 57%; HOPE 28% and 44%)and must have been also influencedby the mean baseline age of pa-tients in the three trials (EUROPA60 y; PEACE 64 y, and HOPE 66 y).

REGISTRY EVIDENCE FOR ACE INHIBITION

In the Evaluation of Methods andManagement of Acute CoronaryEvents–1 (EMMACE-1) study per-formed in 1996, we sought to de-scribe the pattern of ACE-inhibitoruse for patients discharged fromhospital after AMI, assessing thepresence and magnitude of anydiscrepancies between actual andrecommended practice. Potentialcases of AMI were identified fromcoronary care unit (CCU) registers,biochemistry records of cardiac en-zyme assay requests, and hospitalmanagement systems.26 A full-timeresearch team then evaluated thehospital records of 3684 patients.The occurrence of AMI was con-firmed in 2196 cases, of whom 1656patients were discharged from hos-pital alive after a first event. Theoccurrence of either LV failure orsystolic LV impairment and alsodischarge prescriptions of ACE-inhibitor therapy were documentedand the survival status of all patientsto 1st January 1998 was ascertained.

Patient characteristics

The average of age of patients withLV dysfunction in this cohort of con-secutive patients discharged from



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adjacent hospitals over the sametime period was 72 years. This,coupled with the observation that40% of our cohort were female,makes us believe that we have ob-tained data on a sample that isrepresentative of routine clinicalcare. Attending physicians includedgeneralists as well as specialists:73% of patients were not cared forin a tertiary cardiac center and 27%were cared for outside of the CCU.While crude rates of thrombolysis(50%) and aspirin use at discharge(81%) were encouraging, statin (8%)and β-blocker (24%) use was low,reflecting prevailing beliefs over thetime period studied. Nonmeasure-ment of LV systolic function (55%)probably reflected UK practice,particularly in the light of studiessuch as AIRE in which clinical cri-teria were used to target patientsfor ACE-inhibitor therapy. A 1-yearmortality rate (from the time ofhospital discharge) of 19% for pa-

tients with LV dysfunction washigher than is seen in most clinicaltrials of unselected patients thoughit was consistent with other epi-demiological reports and the find-ings of studies such as AIRE thatrecruited patients with clinical heartfailure.

ACE-inhibitor use

Of 1656 patients with confirmedAMI surviving to hospital discharge,799 were categorized as having LVdysfunction based on documentedevidence of either clinical LV failureor systolic LV impairment. The AIREstudy entry criteria formed the basisof a diagnosis of LV failure, whilethe presence or absence of LV im-pairment was determined byechocardiography or radionuclear ventriculography. Patients withoutevidence of LV failure, in whom nomeasure of LV impairment had beenperformed, were considered to have

no documented LV dysfunction. Ofthe 799 (100%) patients with docu-mented LV dysfunction, 6 (0.8%) hadno record of discharge medication.ACE-inhibitor therapy was not prescribed to 315 (39%) patientsdespite documented evidence of LVdysfunction, potential contraindica-tions to ACE-inhibitor therapy be-ing present in 87 (11%) and absentin 227 (28%) cases.

Treatment regimens

Of the LV dysfunction patients re-ceiving ACE-inhibitor therapy atdischarge, only 24% were prescribeda trial-recommended dose. Thisproportion of patients varied signif-icantly with ACE-inhibitor subtype;captopril 4%, enalapril 16%, lisino-pril 36%, ramipril 31% (P<0.001).Frequency of administration alsovaried significantly between differentACE-inhibitor subtypes (P<0.001);(Table I).



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Table I. EMMACE-1 study angiotensin-converting enzyme (ACE)-inhibitor regimens and associated 1 year mortality. Ratios are derived from Cox pro-portional hazards multivariate models including: (i) ACE inhibitor versus ACE inhibitor at discharge; (ii) no ACE inhibitor versus ACE inhibitor at lessthan trial target dose and ACE inhibitor at trial target dose; (iii) no ACE inhibitor vs sulfhydryl ACE inhibitor (captopril) given less than 3 times daily; and(iv) no ACE inhibitor vs carboxyl ACE inhibitor (lisinopril, enalapril, or ramipril) given once daily and carboxyl ACE inhibitor given 2 times daily. Thehazard ratio for patients with evidence either of left ventricular failure or systolic left ventricular dysfunction prior to hospital discharge not given ACE-inhibitor therapy was 1.00 in all analyses; 95% confidence interval is shown in all cases. *P<0.05.

No ACE Multivariate modelinhibitor Captopril Lisinopril Enalapril Ramipril relative hazard(n=315) (n=84) (n=137) (n=141) (n=100) (95% CI)

No ACE inhibitor 100% (315) - - - - 1.00

Nontarget ACE - 96% (81) 64% (81) 84% (118) 69% (69) 0.73 (049 to 1.07)Target ACE - 4% (3) 36% (50) 16% (23) 31% (31) 0.54 (0.30 to 0.98)*

Sulfhydryl ACE inhibitor< 3 doses/day - 50% (42) - - - 0.80 (0.41 to 1.58)3 doses/day - 40% (34) - - - 0.65 (0.27 to 1.52)ALL 0.74 (0.41 to 1.34)

Carboxyl ACE inhibitor 1 dose/day - - 89% (122) 50% (70) 28% (28) 0.76 (0.50 to 1.16)2 doses/day - - 5% (7) 46% (65) 70% (70) 0.37 (0.20 to 0.70)*ALL 0.64 (0.43 to 0.95)*

Deaths 22% (70) 25% (21) 20% (28) 17% (24) 8% (8)

Multivariate model relative hazard 1.00 0.69 (0.47 to 0.99)*(95% CI)



“Real world” survival

Patients with LV dysfunction notprescribed an ACE inhibitor at dis-charge had a higher 1-year mortalitythan did those in whom an ACE inhibitor was prescribed (HR 1.32;95% CI 0.96 to 1.92; P=0.086). Thisassociation was even more markedfor patients with other traditionalACE-inhibitor selection criteria suchas anterior Q-wave MI (2.07; 1.24 to3.46; P=0.004) and the use of on-going diuretic therapy (1.64; 1.15 to2.43; P=0.005). Patients given anACE inhibitor at a suboptimal totaldaily dose were observed to have a1-year mortality rate (18.2%) thatwas higher than for patients receiv-ing trial recommended daily doses(15.0%) but lower than for those whoreceived no ACE inhibitor. One-yearmortality was 19.5% when contem-porary contraindications to ACEinhibition were present (includingno heart failure and preserved LVfunction), and 22.9% when no con-traindications were present.

Adjusted survival

Because a decision not to prescribean ACE inhibitor is likely to havebeen influenced by the presence ofother prognostic factors, confound-ing of univariate measurement ofsurvival is likely to have occurred.Consequently, we constructed a mul-tivariate model including 18 base-line variables. Once again, patientswith LV dysfunction not prescribedan ACE inhibitor at discharge had asignificantly higher 1-year mortalityrisk than did those in whom an ACE-inhibitor regimen was prescribed(Figure 1; HR 1.46; 95%, CI 1.00 to2.11; P=0.048). This association wasmore marked in patients with othertraditional selection criteria such asanterior Q-wave MI (2.19; 1.15 to4.16; P=0.017) and the use of ongo-ing diuretic therapy (1.56; 1.03 to2.38; P=0.038). As with univariate

analysis patients given an ACE in-hibitor at a suboptimal total dailydose were observed to have a 1-yearmortality risk that was more thanthat seen for patients treated witha trial recommended dose of ACEinhibitor though less than for thosereceiving no treatment. Failure toprescribe an ACE inhibitor at anydose was independently predictiveof a worse 1-year survival as com-pared with patients given a trialrecommended total daily dose (HR2.24; 95% CI 1.12 to 4.43; P=0.02).

ACE-inhibitor subtype and frequency

We extended our multivariate modelto assess additional aspects of thetherapeutic regimens prescribed.Sulfhydryl ACE inhibitor (captopril)as compared with no ACE inhibi-tion (HR 0.74; 95% CI 0.41 to 1.34;P=0.33) and carboxyl ACE inhibitoras compared with no ACE inhibitor(HR 0.64; 95% CI 0.43 to 0.95;P=0.03) were both associated with alower mortality though this achieved

statistical significance only for thecarboxyl subtype. We also evaluat-ed trial-recommended frequenciesof administration as compared tono ACE inhibition and also lowerfrequencies of administration ascompared with no ACE inhibitionfor both sulfhydryl and carboxylsubtypes (Table I). These data sup-port the belief that dose and fre-quency of administration, togetherwith selection of drug, are impor-tant in maximizing benefits.

“Class effect?”

Observing actual clinical practice ina time-window after the publicationof all key trials, we and others27-29

have noted therapeutic shortfallseven for those patients for whomtreatment indications are very clear.Importantly, few ACE inhibitorshave been prospectively evaluatedin patients after AMI with LV dys-function or in patients with chronicLV dysfunction when remote fromAMI. Consequently, equipotentregimens of ACE inhibitors in this

240

–2

Cum

ula

tive

haza

rd

1000

Adjusted hazard ratio for patients given ACE inhibitorat target dose as compared to no ACE inhibitor

0.54 (95% CI; 0.30 to 0.98; P =0.041)

200 350

Time after discharge (days)

No ACE inhibitor(96/315)

Nontarget ACE inhibitor (106/371)

Target ACE inhibitor (33/107)–1

0.015050 250 300

Figure 1. Adjusted cumulative hazard for the first Evaluation of Methods and Management ofAcute Coronary Events (EMMACE-1) study patients discharged after an acute myocardial infarctioncomplicated by left ventricular dysfunction based on angiotensin-converting enzyme (ACE)-inhibitortreatment given. Curves were derived from a Cox proportional hazards model. Hazard ratios with95% confidence intervals are reported in the text.



241

clinical situation are unclear. Forexample, the British National For-mulary advises that lisinopril be giv-en for prophylaxis after MI at a tar-get dose of 10 mg od based on theGISSI-3 trial. Yet the optimal doseof this well-studied agent in patientswith heart failure remains uncertain.It is widely assumed that all ACE in-hibitors are able to reduce the mor-tality of cardiac patients to a similardegree. This is referred to as a “classeffect.” However, such a belief as-sumes that equipotent regimens ofthese drugs are utilized. To date, no

randomized comparison of the effectof different ACE inhibitors on mor-tality has been performed. Neverthe-less, the belief that all ACE inhibitorsproduce similar effects on survival,regardless of how they are actuallyprescribed, is also untenable.

The PEACE and EUROPA trialsclosed recruitment in the year 2000being contemporary with regard to

the published evidence-base. Nev-ertheless, while EUROPA demon-strated a highly significant 20% relative risk reduction (95% CI 9 to29%; P<0.0003) PEACE observedonly 4% (95% CI –6% to 12%; P=0.43).Importantly, EUROPA studied 4000more patients than did PEACE alsoopting to use a higher dose of astructurally similar ACE-inhibitor(perindopril 8 mg vs trandolapril 4 mg). The stated reason for selec-tion of trandolapril 4 mg was thepositive outcome seen for theTRACE trial that assessed survival

effects in patients after myocardialinfarction that had an ejection frac-tion of less than 35%. Nevertheless,the likely target for treatment inPEACE was not circulating and ac-cessible plasma ACE, but rather thelarge amounts of ACE expressed by macrophages located within theshoulder of atheromatous plaques.While drug penetration will havebeen aided by the lipophilic profile

of trandolapril, HOPE patients mayhave also benefited from a higherdose of similar sized ACE-inhibitormolecule (ramipril 10 mg/day) andEUROPA patients from a higherdose of a smaller molecule (perindo-pril 8 mg/day).

CONCLUSIONS

Since the publication of the HOPEand EUROPA studies,21,22 many clinicians have opted to treat allpatients long-term after MI irrespec-tive of the presence or absence of

cardiac dysfunction. Although bothHOPE and EUROPA excluded pa-tients with recent myocardial infarc-tion, the consistent demonstrationof a clear benefit from ACE-inhib-itor therapy for patients with stablecoronary artery disease supports apolicy of routine use in patientswith all forms of acute coronarysyndrome (Figure 2). Nevertheless,contemporary, registry data30 indi-

Figure 2. Spectrum of disease states for which angiotensin-converting enzyme (ACE)-inhibitor therapy has been shown to produce majorsurvival benefits in randomized, placebo-controlled clinical trials.

Abbreviations: Angio, coronary angiogram; CABG, coronary artery bypass surgery; clin CCF, overt clinical congestive heart failure; DM,diabetes mellitus; ETT, exercise tolerance test; FH, family history of cardiovascular disease; LVEF, left ventricular ejection fraction; LVF, leftventricular failure; PCI, percutaneous coronary intervention; SBP, systolic blood pressure.

180

160

140

120

4 6 8 10

SBP

TC: HDL

Nonsmoker

Stableangina

Myocardialinfarction

Heartfailure

Global risk

ETTAngio

PCICABG

Lumen

Area ofdetail

DMHypertension

HyperlipidemiaSmoking

FH

Newdefinition

+/–LVF

LVEF<40%

Clin CCF+/–

EF<40%

SUDDEN DEATH

Lipid core

“Vulnerable” plaque

Fibrous cap

Media

➤

Lumen

Lumen

Area ofdetail

Lipid core

“Vulnerable” plaque

“Stable” plaque

Lumen

Lipid core

Lipid core

“Stable” plaque

Fibrous cap

Media

➤

cate the presence of multiple short-falls between routine care and rec-ommended practice based on thecombination of direct (after MI) andindirect (in presence of CAD) trialdata. Furthermore, the adverseconsequences of these shortfallsseem clear. Consequently, thereare a number of simple but impor-tant ways by which secondaryprevention by modulation of therenin-angiotensin system might beimproved. These include (i) widerroutine use of appropriate ACE-inhibitor regimens (ramipril 10 mgdaily; perindopril 8 mg daily)(ii) second-line use of the aldo-sterone antagonist eplerenone; and(iii) avoidance of ARBs (particularlylosartan) in this setting.

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Effects of the early administration ofenalapril on mortality in patients withacute myocardial infarction. Results of theCooperative New Scandinavian EnalaprilSurvival Study II (CONSENSUS II).

N Engl J Med. 1992;327:678-684.

2. Lisheng L, Liu LS, Wang W, et alfor the Chinese Cardiac Study Collaborative Group.

Oral captopril versus placebo among 13,634patients with suspected acute myocardialinfarction: interim report from the ChineseCardiac Study (CCS-1).

Lancet. 1995;345:686-687.

3. ISIS-4 Collaborative Group.

Fourth International Study of Infarct Sur-vival. A randomised factorial trial assessingearly oral captopril, oral mononitrate, andintravenous magnesium sulphate in 58,050patients with suspected acute myocardialinfarction.

Lancet. 1995;345:669-685.

4. GISSI-3 Investigators.

Six-month effects of early treatment withlisinopril and transdermal glyceryl trinitratesingly and together withdrawn six weeksafter acute myocardial infarction.


5. Pfeffer MA, Braunwald E, Moye LA,et al; the SAVE Investigators.

Effect of captopril on mortality and mor-bidity in patients with left ventricular dysfunction after myocardial infarction.Results of the survival and ventricular enlargement trial.

N Engl J Med. 1992;327:669-677.

6. Kober L, Torp-Pedersen C, CarlsenJE, et al; Trandolapril Cardiac Evalu-ation (TRACE) Study Group.

A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patientswith left ventricular dysfunction after myo-cardial infarction.

N Engl J Med. 1995;333:1670-1676.

7. The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators.

Effect of ramipril on mortality and morbidi-ty of survivors of acute myocardial infarctionwith clinical evidence of heart failure.

Lancet. 1993;342:821-828.

8. Hall AS, Murray GD, Ball SG.

Follow-up study of patients randomly allo-cated ramipril or placebo for heart failureafter myocardial infarction: AIRE Extension(AIREX) study.

Lancet. 1997;349:1493-1497.

9. Lindahl B, Diderholm E, LagerqvistB, et al.

Mechanisms behind the prognostic value of troponin T in unstable coronary arterydisease: a FRISC II substudy.

Lancet. 2001;38:979-986.

10. Latini R, Maggioni AP, Flather M,Sleight P, Tognoni G.

ACE inhibitor use in patients with myocar-dial infarction. Summary of evidence fromclinical trials.

Circulation. 1995;92:3132-3137.

11. Ryan TJ, Anderson JL, Antman JL,et al.

ACC/AHA guidelines for the managementof patients with acute myocardial infarction.A report of the American College of Cardiol-ogy/American Heart Association Task Forceon Practice Guidelines (Committee on Man-agement of Acute Myocardial Infarction).

J Am Coll Cardiol. 1996;28:1328-1428.

12. The Task Force of the WorkingGroup on Heart failure of the Euro-pean Society of Cardiology.

Guidelines: the treatment of heart failure.

Eur Heart J. 1997:18;736-753.

13. Dickstein K, Kfekshus J.

Effects of losartan and captopril on mortalityand morbidity in high-risk patients afteracute myocardial infarction: the OPTIMAALrandomised trial.

Lancet. 2002;360:752-760.

14. Pfeffer MA, McMurray JV, Velazquez EJ, et al.

Valsartan, captopril, or both in myocardialinfarction complicated by heart failure, leftventricular dysfunction, or both.

N Engl J Med. 2003;349:1893-1906.

15. Pitt B, Poole-Wilson PA, Segal R,et al.

Effect of losartan compared with captoprilon mortality in patients with symptomaticheart failure: randomised trial: the LosartanHeart Failure Survival Study ELITE II.

Lancet. 2000;355:1582-1587.

16. Kramer C, Sunkomat J, Witte J,et al.

Angiotensin II receptor-independent anti-inflammatory and antiaggregatory propertiesof losartan: role of the active metaboliteEXP3179.

Circ Res. 2002;90:770-776.

17. Sadoshima J.

Novel AT1 receptor-independent functions of losartan.

Circ Res. 2002 ;90:754-756.

18. LIFE Investigators.

Cardiovascular morbidity and mortality inthe Losartan Intervention For Endpoint re-duction in hypertension study (LIFE): arandomised trial against atenolol.

Lancet. 2002; 359: 995-1003.



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19. Verma S, Strauss M.

Angiotensin receptor blockers and myocar-dial infarction. These drugs may increasemyocardial infarction–and patients mayneed to be told.

BMJ. 2004;329:1248-1249.

20. Epstein BJ, Gums JG.

Angiotensin receptor blockers versus ACEinhibitors: prevention of death and myocar-dial infarction in high risk populations.

Ann Pharmacother. 2005;39:470-480.

21. The EPHESUS Investigators.

Eplerenone, a selective aldosterone blocker,in patients with left ventricular dysfunctionafter myocardial infarction.

N Engl J Med. 2003;348:1309-1321.

22. Pitt B, Zannad F, Remme WJ, etal; Randomized Aldactone EvaluationStudy Investigators.

The effect of spironolactone on morbidityand mortality in patients with severe heartfailure.

N Engl J Med. 1999;341:709-717.

23. HOPE Investigators.

Effects of an angiotensin-converting-enzymeinhibitor, ramipril, on cardiovascular eventsin high risk patients.

N Engl J Med. 2000;342:145-153.

24. EUROPA Investigators.

Efficacy of perindopril in reduction of cardio-vascular events among patients with stablecoronary disease: randomized, double-blind,placebo-controlled, multicentre trial (EUROPA study).

Lancet. 2003;362:782-788.

25. The PEACE Trial Investigators.

Angiotensin-converting–enzyme inhibitionin stable coronary artery disease.

N Engl J Med. 2004;351:2058-2052.

26. EMMACE-1 Investigators. Saps-ford R, Lawrance R, Dorsch M, et al.

Methods of identification of acute myocar-dial infarction cases; effects on treatment,mortality and implications for NationalService Framework audit.

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27. The ASPIRE Steering Group.

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28. The EUROASPIRE. SteeringGroup.

A European Society of Cardiology survey ofsecondary prevention of coronary heart dis-ease: principal results. European Action onSecondary Prevention through Interventionto Reduce Events.

Eur Heart J. 1997;18:1569-1582.

29. Krumholz HM, Vaccarino V,Ellerbeck EF, et al.

Determinants of appropriate use of angio-tensin-converting enzyme inhibitors afteracute myocardial infarction in persons > or = 65 years of age.

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30. The GRACE Investigators.

Implications of diabetes in patients withacute coronary syndromes. The Global Registry of Acute Coronary Events.

Arch Intern Med. 2004;164:1457-1463.



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244


nderstanding the mecha-nisms and pathophysiolo-gy of sympathetic nervoussystem (SNS) involvement

in the progression of coronary arterydisease (CAD) generally is essentialfor effective secondary prevention,in particular because the SNS hasattracted much less attention inthis setting than, for instance, afteracute myocardial infarction (MI),where β-blockers now have a well-recognized role.

SNS inhibition can influence pro-gression and outcome in CADthrough a variety of mechanisms:• Risk factor control, in particularby lowering blood pressure;• Decreased adrenergic burden onthe heart due to decreased sympa-thetic drive (catecholamines aretoxic to cardiomyocytes, even at theconcentrations commonly associ-

ated with environmental stress and heart disease)1;• Prevention of ventricular arrhyth-mias and sudden death2 throughmodulation of sympathetic/para-sympathetic balance and the cate-cholamine effect on intrinsic cardiacelectrophysiology;• Enhanced plaque stability andblood rheology, due to decreasedvessel wall stress from the nega-tive inotropism induced by the decreased sympathetic drive.

Despite such potential benefits inboth personal and public healthterms, the tools for controlling theSNS are relatively few. Pharmacolog-ic approaches have changed littlein their fundamentals for manydecades, in striking contrast withparadigm shifts in other therapeu-tic fields. This article reviews theavailable tools and current under-standing of SNS modulation insecondary CAD prevention.

PHARMACOLOGIC INHIBITION OF THE

SYMPATHETIC NERVOUS SYSTEM

ß-Blockers

β-Blockade has been a major ad-vance in the treatment of CAD because it prevents not only angina,but also new events. It does so bymechanisms that differ according tothe ischemic syndrome concerned,as explained below.

How best to keep the sympathetic nervous systemunder control in coronary artery disease? Claudio Ceconi, MD, FESC

Prof Claudio Ceconi - Cattedra di Cardiologia - Università degli Studi di Ferrara - Ferrara - ITALY

Keywords: acute coronary syndrome; β-blocker;cardiac rehabilitation; myocardial infarction;prevention; sympathetic nervous system Address for correspondence:Prof Claudio Ceconi, Unità Operativa di Cardiolo-gia, Arcispedale S. Anna, Corso della Giovecca,203, 44100 Ferrara, Italy(e-mail: [email protected])


UThere are clear pathophysiologicalgrounds for modulating the sympa-thetic nervous system in coronaryartery disease. The tools are pri-marily pharmacologic: �-blockershave been validated in multipleprospective controlled trials and arenow recommended on the basis ofthe best possible evidence by numer-ous cardiology societies in manysettings; their use benefits virtuallyall patients and has multiple tar-gets. Trials with newer agents, eg,ivabradine, are ongoing. The mainnonpharmacologic approach iscomprehensive cardiac rehabilita-tion: exercise programs directly im-pact major risk factors for cardiacdeath, such as heart rate variability.However, the quality of guidelineimplementation fails to match thequality of the supporting evidence:fewer than half of eligible patientsactually receive the recommendedtherapies. Closing this gap is nowthe main challenge for clinicians.

SELECTED ABBREVIATIONSAND ACRONYMS

ASIST Atenolol Silent Ischemia STudy

CAD coronary arterydisease

CAPRICORN Carvedilol PostInfarction SurvivalControl in Left Ventricular Dysfunction


SNS sympathetic nervoussystem


Myocardial infarctionYusuf et al appraised the efficacyof β-blockade during and after MIin a major overview of some 65randomized trials in 1985.3 Subse-quent evidence has only strength-ened this conclusion. Large long-term trials in a total of over 35 000 survivors of MI have shown that β-blockade improves survival by20% to 25% through decreases incardiac mortality, sudden death,and reinfarction.4-7

The effective β-blockers in this re-gard are propranolol, metoprolol,timolol, and acebutolol; no benefitversus placebo is shown by al-prenolol, oxprenolol, xamoterol, orpindolol.4,6 Although often used insecondary prevention, atenolol hasnot yet been adequately evaluatedin this setting, nor are any long-term trials in unselected patientsavailable for carvedilol. However,in the Carvedilol Post InfarctionSurvival Control in Left VentricularDysfunction (CAPRICORN) trial inpatients receiving angiotensin-con-verting enzyme (ACE) inhibitors,carvedilol reduced the frequency ofrecurrent nonfatal MI and all-causeand cardiovascular mortality.5

A recent meta-analysis of β-blockadein secondary prevention after MIincluded all 82 randomized studiesconducted between 1966 and 1999in a total of 54 234 patients (10.1%deaths).6 Follow-up was ≤6 months(“short-term”) in 51 of the studiesand >6 months (“long-term”) in theremainder. The short-term studiesshowed only a 4% reduction in theodds of death (95% confidence interval [CI]: –8% to 15%; Figure 1 ),equivalent to just 1 death per 250patients, which was not significant.The long-term studies, on the otherhand, showed a 23% reduction inthe odds of death (CI: 15% to 31%;Figure 2 ), meaning that 84 patientswould require treatment for 1 year

to prevent 1 death. This figure com-pares favorably with the mortalitybenefit conferred by antiplateletagents, warfarin, and statins afterMI. There was no evidence of addi-

tional benefit from an initial intra-venous dose. Meta regression inthe long-term studies identified a near significant trend towardsdecreased benefit from drugs with

245


How best to keep the sympathetic nervous system under control in CAD? - Ceconi

Weight (%)

Trial Odds ratio (95% CI)

Atenolol pooled

Labetalol pooled

Metoprolol pooled

Oxprenolol pooled

Pindolol pooled

Practolol pooled

Propranolol pooled

Timolol pooled

Fixed effects pooled

Full random effects pooled

Heterogeneity Q=21.0, df=50, P=1.0

74.2

0.4

11.2

2.4

0.1

2.0

8.7

1.0

100

100

0.93 (0.85 to 1.02)

1.84 (0.62 to 5.51)

0.88 (0.70 to 1.11)

1.30 (0.82 to 2.05)

1.00 (0.01 to 80.08)

1.23 (0.74 to 2.04)

1.00 (0.77 to 1.28)

0.72 (0.32 to 1.60)

0.95 (0.88 to 1.02)

0.96 (0.85 to 1.08)

0.01 1000.50.20.1 1 1052

Weight (%)

Trial Odds ratio (95% CI)

Acebutolol pooled

Alprenolol pooled

Atenolol pooled

Carvedilol pooled

Metoprolol pooled

Oxprenolol pooled

Pindolol pooled

Practolol pooled

Propranolol pooled

Sotalol pooled

Timolol pooled

Xamoterol pooled

Fixed effects pooled

Full random effects pooled

Heterogeneity Q=39.7, df=32, P=0.16

2.9

6.6

1.6

0.3

23.1

11.8

3.6

13.9

26.6

5.3

13.6

0.1

100

100

0.49 (0.25 to 0.93)

0.83 (0.59 to 1.17)

1.02 (0.52 to 1.99)

0.62 (0.05 to 5.61)

0.80 (0.66 to 0.96)

0.91 (0.71 to 1.17)

0.96 (0.60 to 1.55)

0.80 (0.63 to 1.02)

0.71 (0.59 to 0.85)

0.81 (0.54 to 1.21)

0.59 (0.46 to 0.77)

3.45 (0.25 to 188.83)

0.77 (0.70 to 0.84)

0.77 (0.69 to 0.85)

0.01 1000.50.20.1 1 1052

Figure 1. Pooled odds of death ratios in short-term trials with a single �-blocker (see text).

Adapted from reference 6: Freemantle N, Cleland J, Young P, Mason J, Harrison J. Beta blockadeafter myocardial infarction: systematic review and meta regression analysis. BMJ. 1999;318:1730-1737. Copyright © 1999, BMJ Publishing Group Ltd.

Figure 2. Pooled odds of death ratios in long-term trials with a single �-blocker (see text).

Adapted from reference 6: Freemantle N, Cleland J, Young P, Mason J, Harrison J. Beta blockadeafter myocardial infarction: systematic review and meta regression analysis. BMJ. 1999;318:1730-1737. Copyright © 1999, BMJ Publishing Group Ltd.

246

intrinsic sympathomimetic activity,which should therefore be avoided.The meta-analysis was also note-worthy for showing no evidence thatthe availability of new treatmentssuch as pharmacologic thrombolysisand aspirin decreases the benefitof β-blockade.

These results confirmed those of theCooperative Cardiovascular Projectin 201752 post-MI patients.7 Mor-tality was lower in every subgrouptreated with β-blockers, includingthose with comorbidities once con-sidered as contraindications, eg,chronic pulmonary disease, lowejection fraction and older age. Inparticular, β-blockade decreasedmortality in the lowest-risk sub-groups by 40%, suggesting that with-holding β-blockers from patientswith a favorable prognosis (youngage, intact left ventricular function,no residual ischemia or ventriculararrhythmia), as advocated by some,may be a misguided strategy. Ab-solute benefit may well be lower in these low-risk patients, but theirsurvival is indubitably increased.The subgroups with most to gainfrom β-blockade, on the other hand,include diabetics (in whom β-block-ers appear both safer and more effective than in nondiabetics8), theelderly,9,10 and patients with athero-sclerosis.7

Expert guidelines recommendingroutine long-term β-blockade afterMI are based on class I evidence,level A, of decreased mortality andmorbidity (Table I).4 Yet under halfof eligible patients actually receivethis treatment.11-13 Although there issome evidence that adverse eventsand side effects with β-blockers are more frequent than previouslythought, recent major systematicreviews show no increase in depres-sion and only a slight increase infatigue and sexual dysfunction,13,14

while asthma and chronic obstruc-

tive pulmonary disease are nolonger viewed as mandatory con-traindications.15

Non-ST-segment elevation ACS andchronic stable ischemic heart diseaseIn acute coronary syndromes (ACS),it is clearly difficult to differentiatethe early benefit of β-blockade dueto decreased ischemia and/or pre-vention of MI, from the long-termbenefit due to secondary prevention.Trials in this setting have been fewand sample sizes small. The evi-dence favoring β-blockade for pre-

venting MI and prolonging survivalis more conclusive in stable angina.The Beta-Blocker Pooling Projectreported a highly significant reduc-tion in mortality in post-MI stableangina, and it seems reasonable to assume that β-blockers preventdeath and MI even in the absence ofprior MI (Table I).9 In the AtenololSilent Ischemia STudy (ASIST), ate-nolol decreased ischemic episodesat 6 weeks and improved event-freesurvival at 1 year versus placebo.16

Sudden deathSympathetic overactivity is associ-ated with unstable angina and isparticularly intense after MI.17 Forreasons that remain disputed, theischemic heart is a powerful site oforigin of excitatory and/or inhibito-ry reflexes; indeed, it is likely thatboth sets of reflexes are usually activated simultaneously, althoughone eventually prevails. Sympa-thetic overactivity depresses baro-reflex function18 and can be a majordeterminant of cardiac accidents,including sudden death.2

Although the full complexity oftheir impact on autonomic andcardiovascular function is stilllargely unelucidated, β-blockers areeffective after acute MI in prevent-ing sudden death and, possibly, inpreventing/treating late ventriculararrhythmias (Table I).4,18

Their use should therefore be re-garded as mandatory in acute MI,the post-MI phase and also in congestive heart failure.



Table I. �-Blockade in secondary prevention: European Society of Cardiology guidelines.

Adapted from reference 4: Lopez-Sendon J, Swedberg K, McMurray J, et al; Task Force On Beta-Blockers of the European Society of Cardiology. Expert consensus document on beta-adrenergic receptorblockers. Eur Heart J. 2004;25:1341-1362. Copyright © 2004, European Society of Cardiology.

Setting/Indication Class Level

After acute myocardial infarctionAll patients without contraindications, indefinitely I A

To improve survival I ATo prevent reinfarction I APrimary prevention of sudden death I ATo prevent/treat late ventricular arrhythmias IIa B

In non-ST-segment elevation acute coronary syndromeLong-term secondary prevention I B

In chronic, stable ischemic heart diseaseeTo improve survival I ATo reduce reinfarction I A

Class of evidence: I: Evidence and/or general agreement that a given procedure/treatment is beneficial, useful and effective. IIa: Weight of evidence/opinion is in favor of usefulness/efficacy.

Level of evidence: A: Data derived from multiple randomized clinical trials or meta-analyses. B: Data derived from a single randomized clinical trial or nonrandomized studies.

Other pharmacologic treatments

Several other antiadrenergic classesof drugs are available, but nonehave been validated for use in sec-ondary prevention. Central antia-drenergic drugs (eg, clonidine) donot offer significant protection, norare they first-line treatments for hy-pertension, while other compoundssuch as reserpine and guanfacineare no longer used. No pilot studyis available to support the possibleuse of these agents, nor is there anypreclinical study to suggest theymay be useful in cardiovascularprevention.

An interesting approach to thetreatment of essential hypertensionis provided by imidazoline agonistagents such as rilmenidine. Thisagent binds to specific I1 imidazolinereceptors in the brain stem andkidney and reduces the sympatheticoveractivity associated with hyper-tension. Rilmenidine has a bettertolerance profile than α2 agonists(clonidine, α-methyldopa). In thepresence of metabolic disorders(dyslipidemia, metabolic syndrome,type 2 diabetes), in contrast to β-blockers, rilmenidine improveslipid parameters, insulin sensitivity,and plasma glucose concentra-tions.19 Rilmenidine has also beenshown to reduce left ventricular hypertrophy in patients with hyper-tension.20 Further trials are neces-sary to determine rilmenidine’svalue in secondary prevention.

Newer drugs promise greater poten-tial. Ivabradine, a specific blocker ofthe cardiac pacemaker (I f) current,is a novel selective heart rate–re-ducing agent with no negative ino-tropism and no effect on atrioven-tricular conduction or ventriculardepolarization. Developed as atreatment of stable angina, it lowersthe heart rate and double product,

thereby decreasing cardiac work-load and myocardial oxygen con-sumption. In mice, oral ivabradinereduces the heart rate without affecting ventricular performance.Ivabradine even continues to lowerthe heart rate in the face of condi-tions associated with significantSNS activation, including stress,cardiac-restricted overexpressionof β2-adrenergic receptors, and β-agonist administration.21 Clinicaltrials to determine its usefulness insecondary prevention are ongoing.

NONPHARMACOLOGIC INHIBITION OF THE SNS:

CARDIAC REHABILITATION

Environmental factors are critical to SNS balance. Stress control andenhanced psychological adjustmentto illness are major targets in car-diac rehabilitation strategy designedto modulate the SNS. Insofar as itsoverall aims are to optimize patientfunction, enhance quality of life,and minimize the risk of recurrence,cardiac rehabilitation is integral to,and overlaps with, secondary pre-vention. Its programs comprise ex-ercise training, behavioral changes,education, and psychological support. Some of the mechanismsinvolved directly impact the SNS:exercise training strengthens theparasympathetic component insympathovagal balance, resultingin increased heart rate variability,22

protection against malignant arrhythmia, lower myocardial wallstress, and long-term myocardialprotection. Exercise also affects thenatural history of atheroscleroticlesions by improving endothelialdysfunction23: nitric oxide directlyscavenges norepinephrine, a vaso-constrictor and an index of SNSoveractivity.24 A 2001 Cochrane review showed a 27% reduction inmortality with exercise alone or ex-ercise as part of a comprehensivecardiac rehabilitation strategy,25

while Hambrecht et al recently pub-lished the striking finding that aprogram of regular physical exercisein selected patients with stable CADproduced superior event-free sur-vival and exercise capacity thanpercutaneous coronary intervention,and at lower cost.26

REFERENCES

1. Mann DL, Kent RL, Parsons B,Cooper G.

Adrenergic effects on the biology of theadult mammalian cardiocyte.

Circulation. 1992;85:790-804.

2. Pitt B.

The role of beta-adrenergic blocking agentsin preventing sudden cardiac death.

Circulation. 1992;85(suppl I):I107-I111.

3. Yusuf S, Peto R, Lewis J, Collins R,Sleight P.

Beta blockade during and after myocardialinfarction: an overview of the randomizedtrials.


4. Lopez-Sendon J, Swedberg K, McMurray J, et al; Task Force OnBeta-Blockers of the European Society of Cardiology.

Expert consensus document on beta-adren-ergic receptor blockers.

Eur Heart J. 2004;25:1341-1362.

5. Dargie HJ.

Effect of carvedilol on outcome after myo-cardial infarction in patients with left-ventricular dysfunction: the CAPRICORNrandomised trial.

Lancet. 2001;357:1385-1390.

6. Freemantle N, Cleland J, Young P,Mason J, Harrison J.

Beta blockade after myocardial infarction:systematic review and meta regressionanalysis.

BMJ. 1999;318:1730-1737.

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7. Gottlieb SS, McCarter RJ, Vogel RA.

Effect of beta-blockade on mortality amonghigh-risk and low-risk patients after myo-cardial infarction.

N Engl J Med. 1998;339:489-497.

8. Malmberg K.

Prospective randomised study of intensiveinsulin treatment on long term survival afteracute myocardial infarction in patientswith diabetes mellitus. DIGAMI (DiabetesMellitus, Insulin Glucose Infusion in AcuteMyocardial Infarction) Study Group.

BMJ. 1997;314:1512-1515.

9. Beta-Blocker Pooling Project Research Group.

The Beta-Blocker Pooling Project (BBPP):subgroup findings from randomized trialsin post infarction patients.

Eur Heart J. 1988;9:8-16.

10. Priori SG, Aliot E, Blomström-Lundqvist C, et al.

Task Force on Sudden Cardiac Death of theEuropean Society of Cardiology.

Eur Heart J. 2001;22:1374-1450.

11. EUROASPIRE I and II Group.

Clinical reality of coronary preventionguidelines: a comparison of EUROASPIREI and II in nine countries. European Actionon Secondary Prevention by Intervention toReduce Events.

Lancet. 2001;357:995-1001.

12. Brady AJ, Oliver MA, Pittard JB.

Secondary prevention in 24,431 patients withcoronary heart disease: survey in primarycare.

BMJ. 2001;322:1463.

13. Dalal H, Evans PH, Campbell JL.

Recent developments in secondary preven-tion and cardiac rehabilitation after acutemyocardial infarction.

BMJ. 2004;328:693-697.

14. Ko DT, Hebert PR, Coffey CS,Sedrakyan A, Curtis JP, Krumholz HM.

Beta-blocker therapy and symptoms of depression, fatigue, and sexual dysfunction.

JAMA. 2002;288:351-357.

15. Salpeter S, Ormiston T, Salpeter E.

Cardioselective beta-blockers for reversibleairway disease.

Cochrane Database Syst Rev.2002;(1):CD002992.

16. Pepine CJ, Cohn PF, DeedwaniaPC, et al.

Effects of treatment on outcome in mildlysymptomatic patients with ischemia duringdaily life. The Atenolol Silent IschemiaStudy (ASIST).

Circulation. 1994;90:762-768.

17. Graham LN, Smith PA, Stoker JB,Mackintosh AF, Mary DA.

Sympathetic neural hyperactivity and itsnormalization following unstable anginaand acute myocardial infarction.

Clin Sci. 2004;106:605-611.

18. Malliani A, Montano N.

Sympathetic overactivity in ischaemic heartdisease.

Clin Sci. 2004;106:567-568.

19. Anichkov DA, Shostak NA,Schastnaya OV.

Comparison of rilmenidine and lisinoprilon ambulatory blood pressure and plasmalipid and glucose levels in hypertensivewomen with metabolic syndrome.

Curr Med Res Opin. 2005;21:113-119.

20. Farsang C, Lengyel M, Borbas S,Zorandi A, Dienes BS, on behalf ofthe VERITAS Investigators.

Value of rilmenidine therapy and its combi-nation with perindopril on blood pressureand left ventricular hypertrophy in patientswith essential hypertension (VERITAS).

Curr Res Med Opin. 2003;19:205-217.

21. Du XJ, Feng X, Gao XM, Tan TP,Kiriazis H, Dart AM.

If channel inhibitor ivabradine lowers heartrate in mice with enhanced sympathoad-renergic activities.

Br J Pharmacol. 2004;142:107-112.

22. Tygesen H, Wettervik C, Wennerblom B.

Intensive home-based exercise training incardiac rehabilitation increases exercise capacity and heart rate variability.

Int J Cardiol. 2001;79:175-182.

23. Niebauer J, Hambrecht R, Velich T, et al.

Attenuated progression of coronary arterydisease after 6 years of multifactorial riskintervention: role of physical exercise.

Circulation. 1997;96:2534-2541.

24. Tesfamariam B, Weisbrod RM,Cohen RA.

Endothelium inhibits responses of rabbitcarotid artery to adrenergic nerve stimulation.

Am J Physiol. 1987;253:H792-H798.

25. Jolliffe JA, Rees K, Taylor RS,Thompson D, Oldridge N, Ebrahim S.

Exercise-based rehabilitation for coronaryheart disease.

Cochrane Database Syst Rev.2001;(1):CD001800.

26. Hambrecht R, Walther C, Mobius-Winkler S, et al.

Percutaneous coronary angioplasty compared with exercise training in patientswith stable coronary artery disease: a randomized trial.

Circulation. 2004;109:1371-1378.

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What is the best way to manage dyslipidemia?Jim Shepherd, MD, PhD

Institute of Biochemistry - Royal Infirmary - Glasgow - UK

The processes involved in discov-ering, developing, and testing new drugs often focus on detailedrefinement of chemistry or engi-neering practice, which result insmall, albeit clinically valuable,improvements in the managementof a particular disease state. Butjust occasionally, either throughserendipity or insightful creativity,or both, a series of new compoundscomes to light whose uniqueness of action revolutionizes the man-agement of a hitherto intractableclinical problem. Such was thecase when pharmacology unveiledthe wide-ranging portfolio of lipid-lowering agents, which for thefirst time has allowed us to controlthe worst excesses of dyslipidemia inour patients. Here we consider thediscovery and review the clinicalmerits of the statins, ezetimibe, theperoxisome proliferator activatedreceptor (PPAR) agonists, andnicotinic acid.

Keywords: hypercholesterolemia; hyper-triglyceridemia; HDL cholesterol; statin; PPARα agonist; PPARγ agonist; nicotinic acidAddress for correspondence:Prof Jim Shepherd, Institute of Biochemistry,Royal Infirmary, Glasgow G4 0SF(e-mail: [email protected])


DISCOVERY OF THE ULTRACENTRIFUGE

heodor Svedberg (1884-1971)won the Nobel Prize forChemistry in 1926 for hisstudies of colloids.1 His early

research on these particles showedthat they were not only too small tobe seen by conventional light microscopy, but that jostling bysurrounding water molecules pre-vented their precipitation by gravity.High centrifugal forces were there-fore required to mimic the effectsof gravity on them. This realizationled to his construction of the firstultracentrifuge in 1924, a machinethat in its time was capable of gen-erating a force of up to 5000 timesthe force of gravity. Subsequent re-finements led to the development

of instruments that could applygravitational fields to colloids sothat discrimination could be madebetween them on the basis of theirmass. So, with the advent of theultracentrifuge, our ability to de-termine the molecular weights ofhighly complex particles like pro-teins became a reality.

IDENTIFICATION OFLIPOPROTEINS

The second ultracentrifuge that ap-peared in the United States (thefirst went to Melvin Calvin) was de-livered to the Donner Laboratoriesin Berkeley, California in the early1950s. John Gofman, Frank Lindgren,and their collaborators immediatelypressed it into service to look atserum proteins, despite the stric-tures of Kai Pedersen that serumprotein analysis might defeat them(“there’s some unstable moleculesin the serum and you can get anyresult you want from the ultracen-trifuge—don’t try to do it withblood”). Pedersen’s early predictionswere indeed vindicated by depress-ing findings. While most serum pro-teins (whose particle density wasapproximately 1.34 g/mL) were precipitated by ultracentrifugation,some seemed to float in the gravita-tional field. Frank Lindgren’s fertilemind ultimately resolved this dilem-ma. He conjectured that while mostproteins existed free in serum andso were sedimented by the ultracen-trifuge, some might be so intimatelyrelated to other molecules in solu-tion that, contrary to expectation,they actually float in high gravita-

T



SELECTED ABBREVIATIONSAND ACRONYMS

CETP cholesteryl ester transferprotein

HATS High-density lipoproteinAtherosclerosis Treat-ment Study

HHS Helsinki Heart Study

HPS Heart Protection Study

MMP-9 matrix metallopro-teinase 9

PPAR peroxisome proliferator activated receptor

TNT Treating to New Targets (study)

VA-HIT Veterans Affairs High-density lipoproteinIntervention Trial

250

tional fields. The concept of lipid-protein complexes or lipoproteinshad come of age.2 The logical exten-sion of these studies was not onlyto define lipid-protein complexesin the serum, but also to classifythem into particles of very low, low,and high density (now known asvery-low-density [VLDL], low-den-sity [LDL], and high-density [HDL]lipoproteins).

VASCULAR RISK FACTORS DEFINED

Epidemiological studies, pioneeredby the Framingham Project,3 capi-talized on the discovery of thelipoproteins to show that while in-creased concentrations of HDL inthe bloodstream led to protectionagainst coronary heart disease(CHD—the most important globalcause of death both then and now),circulating LDL predisposed to it.The teamwork of Joseph Goldsteinand Michael Brown in Dallas, Texas,and their intuitive concerns overthe relevance of an inherited formof hypercholesterolemia (definedby Carl Mueler in Oslo as an inher-ited disease caused by a defect inan autosomal gene and later identi-fied by Khachadurian in the Lebanonas occurring in a mild (heterozy-gous) and severe (homozygous)form of condition that we now knowas familial hypercholesterolemia)ultimately shed light on the role ofLDL in the pathogenesis of athero-sclerosis. Using cell culture tech-niques they showed that, whereascells from healthy individuals ex-pressed proteins on their surfacemembranes (LDL receptor proteins)that could recognize, bind, and as-similate LDL from the surroundingculture medium, individuals withfamilial hypercholesterolemia suf-fered from partial or complete ab-sence of functional LDL receptors.4

As a consequence, LDL cholesterollevels in their blood were signifi-

cantly higher than normal, and thusled to a substantial increase in theirrisk of developing atheromatousocclusion of their arterial tree, andof ultimately succumbing to coro-nary and peripheral arterial diseaseand stroke. So, the efficient opera-tion of these LDL receptors appearedto be a prerequisite to the avoid-ance of occlusive atherosclerosis.

PENICILLIN FOR THE HEART—

THE DEVELOPMENT OF THE STATINS

While Goldstein and Brown wereworking their way toward the NobelPrize in Physiology or Medicine in1985 “for their discoveries concern-ing the regulation of cholesterolmetabolism,” another researcher,Akira Endo, employed by the Sankyo

Pharmaceutical Company in Tokyo,put his mind to the identificationand manufacture of a fungal metab-olite capable of blocking cellularcholesterol production by inhibitingthe rate-limiting enzyme involvedin the cholesterol synthetic path-way, 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) reductase.His discovery, compactin, when giv-en to experimental animals, blockedcholesterol synthesis in their liverand led to upregulation of the ex-pression of LDL receptors on hepa-tocyte membranes. As a result, LDLwas extracted from their circulationand plasma cholesterol levels fellthrough activation of what was in effect a physiological pathway(Figure 1). Subsequent modifica-tion of this progenitor compoundresulted in the delivery to the clinicof a family of cholesterol-lowering


What is the best way to manage dyslipidemia? - Shepherd

SynthesisCholesterol

Bile acids

Statins

LDL inblood

LDL receptors

Figure 1. Mechanism of action of statins. By inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, the rate-limiting en-zyme for cholesterol synthesis in the liver, the statins deprive hepatocytes oftheir sterol source. This is restored by activation of low-density-lipoprotein(LDL) receptors on the hepatocyte membrane, which extract LDL from thecirculation and, in consequence, lower plasma LDL levels.

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molecules (the statins), which haverevolutionized our ability to decreaseplasma cholesterol levels and, as a result, have had a clinical impact,which some believe “is to athero-sclerosis what penicillin (the originalfungus-derived antibiotic) was toinfectious disease.”5 However, theprime lesson that emerged fromour use of antibiotics is that Natureis not as easy to tame as we mightimagine, and some are beginningto hint at the same conclusionsabout statins and CHD prevention.If these agents really lived up toexpectation, they say, surely coro-nary events would have been elimi-nated rather than “merely” reducedby 30% to 50%. But of course, despite the runaway successes ofstatin-based end point trials,6 noclinical study of this kind can trulyreflect the multifaceted biology ofreal life, and to eliminate a diseasewhose origins go back to childhoodwe no doubt will need to take ac-tion over a longer time frame thanthat dictated by the exigencies ofclinical trial design.

SPECIFIC INHIBITION OF CHOLESTEROL

ABSORPTION

Another important mechanistic issue needs also to be considered.Corporeal cholesterol homeostasisdepends on the balance betweenendogenous cholesterol production(principally in the liver) and intes-tinal absorption of the sterol fromthe diet and the enterohepatic circu-lation. Suppression of endogenouscholesterol production by statinsdoes nothing to inhibit the absorp-tion of exogenous sterol and cantherefore only be expected to bepartially effective in reducing plasmacholesterol levels. What we clearlyneed to do is simultaneously inhibitendogenous synthesis and exoge-nous absorption. Statins effectivelydeliver the former while the recentlyidentified drug, ezetimibe, is equallyable to provide the latter (Figure 2).

Ezetimibe7 was approved for clini-cal use in Europe and the USA inOctober 2002. It is virtually water

insoluble but, following ingestion, israpidly glucuronidated in the smallintestine and liver. The glucuronidesconstitute 90% of the drug found in the plasma and show greaterpotency than the native drug withregard to inhibition of cholesterolabsorption. Both the native and glu-curonidated compound are largelysequestered within and recyclethrough the enterohepatic circula-tion, thereby repeatedly deliveringactive agent to its therapeutic targetin the small intestine. Ezetimibebinds selectively to an as yet un-known structure (tentatively identi-fied as the Niemann-Pick C-1–like 1protein) on the villous brush bor-der of the upper jejunum, where itinhibits the absorption of choles-terol and related plant sterols. Because of its selective ability toinhibit intestinal cholesterol absorp-tion, it is an ideal partner for thestatins, which block hepatic sterolproduction. When these drugs arecombined,8-11 ezetimibe producesan additional 20% reduction in LDLcholesterol so that its coprescrip-



x

Cholesterolproduction

Hepaticcholesterolproduction

Cholesteroluptake

300 mg/d

1200 mg/d

900 mg/d

LDL

VLDL

HDLAcetyl CoA

Cholesterol

Cholesterol

Ezetimibe

Ezetimibe increasessterol excretion

Fecal sterols

Hepaticcholesterol

pool

Figure 2. Mechanism ofaction of ezetimibe. Eachday we ingest approxi-mately 300 mg of choles-terol in our diet, whichmixes in the small intes-tine with about 900 mg of endogenously producedsterol. Therefore, about1200 mg of sterol is losteach day into the feces.Ezetimibe increases this fecal loss by inhibitingcholesterol reabsorption in the small intestine.

Abbreviations: CoA,coenzyme A; HDL, high-density lipoprotein; LDL,low-density lipoprotein;VLDL, very-low-densitylipoprotein.

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tion with statins at their lowest doseresults in the same cholesterol re-duction as would be achieved bythe maximum dose of the statin inmonotherapy (Figure 3). Since in-tensive lipid-lowering therapy withstatins in patients with stablecoronary heart disease providessignificant clinical benefit beyondthat seen with moderate interven-tion,12,13 this low-dose statin/eze-timibe combination may therefore,in terms of safety, be an alternativeoption in situations where profoundcholesterol reduction is required.

STATINS AT THEIR ZENITH

Statins have revolutionized the man-agement of hypercholesterolemiaand rightly dominate the lipid-lowering drug field. However, therecent global launch of the “superstatin” rosuvastatin and the evidentsuccess of aggressive LDL choles-terol lowering with atorvastatin 80 mg in the Treating to New Targets(TNT) study means that the marketfor this new class of drugs is not

only becoming crowded, but mayalso have reached its maximal clin-ical potential. Alternative scenariosfor resetting the atherogenic profileof the circulating lipoproteins needto be addressed. Within this frame-work, raised triglyceride and lowHDL cholesterol are assuming in-creasing prominence, reawakeninginterest in well-established agentslike the fibrates and nicotinic acidand driving forward the enthusias-tic development of selective HDLcholesterol–enhancing compoundslike the cholesteryl ester transferprotein (CETP) inhibitors.

Low plasma concentrations of HDLcholesterol and elevated triglyceridecharacterize patients with diabetesor the metabolic syndrome, both ofwhich groups are at markedly in-creased risk of developing and dyingfrom cardiovascular disease.14,15

Although LDL cholesterol in insulin-resistant patients is commonlynormal or only modestly elevated,the characteristics of these choles-terol-containing particles are pro-foundly changed so that their size is

reduced, their density raised, andtheir atherogenicity accentuated.Simultaneous and similar changesappear to occur in HDL, which notonly becomes smaller and denser,but is also impaired in its ability toparticipate in reverse cholesteroltransport and to protect LDL againstendogenous oxidation.

Current treatment recommendationsfor the management of diabetic/metabolic syndrome dyslipidemiafocus on statins, even althoughplasma LDL cholesterol levels areusually only marginally (if at all)elevated in these patients. The driv-er behind this policy is the majorstatin trial outcomes, which demon-strated the benefits of reductaseinhibition in these populations,even although they were only a sub-set of the entire statin trial portfolio.But, while there is no doubt thatstatins significantly reduce the riskof coronary heart disease in insulin-resistant patients, subgroup analy-sis from the Heart Protection Study(HPS)16 showed that the residualrisk of a coronary event in diabeticpatients remained twice as high asthat in nondiabetics who got statins(Figure 4). So, although diabeticpatients gained as much propor-tionately as nondiabetics, in abso-lute terms, treatment did not reducetheir absolute risk to the same ex-tent as in nondiabetics. These find-ings were concordant in all statintrials, irrespective of the statin in-volved. So, clustering of risk factorsin insulin-resistant individuals in-creases their propensity to CHD andlimits their statin-derived benefit.

LDL cholesterol is the primary tar-get of statin therapy, whose effectson triglyceride-lowering (15% to25%) and HDL cholesterol raising(typically less than 10%) are consid-erably more modest. Even aggres-sive statin therapy with atorvastatinor rosuvastatin will improve little



–20

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Figure 3. Ezetimibe/statin combination therapy. Ezetimibe in monotherapy lowers low-density lipo-protein (LDL) cholesterol by approximately 18%, equivalent to the reductions seen with 10 mg of lovastatin or pravastatin. Each doubling of the dose of statin lowers LDL by only a further 6%, whilecombining statin and any dose with ezetimibe produces LDL reductions equivalent to the additive effectsof both drugs taken separately. Consequently, 10 mg of statin plus 10 mg of ezetimibe achieves thesame LDL reduction as that obtained by the highest statin dose prescribed as monotherapy.

253



on the above figures. Consequently,there is a growing realization that,despite the gold-standard status ofthe statins, additional therapy maybe required to deal with low HDLcholesterol and elevated triglyc-erides, both of which are not onlycommon, but also appear to sub-stantially increase the burden ofcardiovascular risk. Among all of thelipid risk factors, which influencecoronary heart disease, HDL choles-terol is preeminent and is clearlyestablished as independently predic-tive in both diabetic and nondia-betic individuals. Several trials havehelped to establish its importancein this regard, including the Veter-ans Affairs High-density lipoproteinIntervention Study (VA-HIT)17 andthe Helsinki Heart Study (HHS).18

In both, the individuals who gainedmost from gemfibrozil interventionwere those with initially low HDL,

raised triglyceride, and a predispo-sition to insulin resistance. Conse-quently, it seems logical to developthe concept of combining the LDL-lowering benefits of a statin withagents that specifically promoteHDL cholesterol elevation and tri-glyceride lowering.

STRATEGIES FOR RAISINGHDL CHOLESTEROL

AND LOWERING PLASMA TRIGLYCERIDE

Lifestyle modifications such asweight reduction coupled with ini-tiation of an exercise program andelimination of cigarette smokingwill all produce a significant, sus-tained improvement in plasmatriglyceride and circulating HDLcholesterol and should be part ofall CHD risk-reduction programs.However, in order to reach the re-

quired HDL targets, particularly inpatients with diabetes or the metab-olic syndrome, additional support-ive therapeutic strategies are oftenrequired. These include the pre-scription of peroxisome proliferatoractivated receptor (PPAR) agonists(α and γ) and nicotinic acid. Newerdrugs like the CETP inhibitors showa lot of promise, but have not yetbeen established in clinical practice.

PPARα AGONISTS

The fibrates, the progenitor PPARαagonists (the most popular of whichare fenofibrate, bezafibrate, andgemfibrozil) reduce triglyceride by20% to 50%, lower LDL cholesterolby 5% to 20%, and raise HDL choles-terol by 10% to 15%, depending onthe drug in question and the base-line lipid profile of the recipient.19

Several trials, the most recent of

7000 4000

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• Risk in diabetics with CHD was 68% higher• Statins reduced that risk by 12%• The residual risk remained twice as high as in statin-treated nondiabetics with CHD

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benefits seen in nondiabetic CHD sufferers

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SUBGROUP EVENT RATES

ANTICIPATED RECRUITMENT

CONCLUSIONSCHD +

diabetes

(a) Plac 1009 37.8

(b) Stat 972 33.4

1.68

1.48

Figure 4. Diabetics in the Heart Protection Study (HPS). The Heart Protection Study recruited approximately 20 000 participants,7000 of whom at baseline had CHD alone, while approximately 2000 were diabetics with CHD. Comparing how these two groupsfared in the study provides an indication of the seriousness of the pathology associated with diabetes. If we assign an arbitraryCHD risk value of 1 to the CHD group that received placebo, simvastatin treatment reduced that risk by 25% (to 0.75). However,the risk of the diabetics with CHD who were given placebo was 68% higher than those with CHD alone, and statin therapy wasonly capable of reducing that risk to 1.48. Consequently, the residual risk of CHD in the statin-treated diabetic CHD cohort remainedtwice as high as that seen in statin-treated nondiabetics with CHD.

Abbreviations: CHD, coronary heart disease; plac, placebo; Rx, prescription; stat, statin.

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which is VA-HIT, have establishedthe merit of such intervention inCHD prevention. Gemfibrozil admin-istration in VA-HIT reduced CHDdeath and nonfatal myocardial in-farction by 22% (P=0.006) over afive year treatment period.17 So, fibrate therapy seems to be a vi-able adjunct to statins20 (Table I),particularly in patients with raisedtriglyceride, low HDL cholesterol,and “average” LDL cholesterol, thekind of patient who commonly ap-pears with the metabolic syndromeor diabetes. As a consequence ofthis, cogent argument has beenraised for combining fibrates withstatins in individuals with combineddyslipidemia (raised triglycerideand LDL cholesterol and low HDLcholesterol). However, we do notknow enough about the relativemerits and risks of such a combina-tion to recommend it unreservedly

across the board. Certainly, the com-bination gives significantly greatertriglyceride and LDL cholesterolreduction than either agent alone,although its HDL cholesterol–rais-ing properties are perhaps not ideal;and there is serious concern aboutcombining gemfibrozil with anystatin following the unexpected and

catastrophic interactions observedbetween this fibrate and cerivas-tatin. Fenofibrate and bezafibratein combination with statins do notseem to carry this risk, and furtheranalysis of the Fenofibrate Interven-tion and Event Lowering in Diabetes(FIELD) trial20 may help reassureus on that score.

PPARγ AGONISTS

The PPARg agonists exemplified bythe thiazolidinediones like rosigli-tazone and pioglitazone, are activein the management of abnormali-ties of fat and carbohydrate metab-olism, and are indicated for thetreatment of diabetes mellitus(Figure 5). Of the two, pioglitazoneappears to be more potent as alipid-modulating agent, raising HDLcholesterol by about 10% and low-ering triglyceride by 18% to 20%.21

Both drugs also exhibit a range ofanti-inflammatory properties. Rosi-glitazone, for example, reduces theplasma level of the inflammatorymarker C-reactive protein (CRP),lowers the activity of matrix met-alloprotease 9 (MMP-9) in the

circulation, and suppresses theproduction of proinflammatory cytokines by adipose tissue. Theseeffects may help stabilize theatherosclerotic plaque,22 althoughthis yet remains to be established,as have the safety and efficacy ofthese agents in the long-termmanagement of vascular risk. Nolong-term studies of thiazolidine-diones/statin combinations havebeen published so far.

NICOTINIC ACID

Nicotinic acid is a long-standinglipid-lowering agent, which reducestriglyceride and LDL cholesterol byabout 50% and 25%, respectively,and raises HDL cholesterol by asmuch as 30% at the doses recom-mended in the clinic.23,24 Its power-ful effect on triglyceride (Figure 6)is also instrumental in increasingthe average size of LDL and HDLparticles in the circulation, therebysignificantly reducing the athero-genicity of the plasma lipoproteinprofile.24,25 It is therefore not sur-prising that in the Coronary DrugProject, an early investigation of

THIAZOLIDINEDIONES

FFA decreased

Improved glycemia

Improvedglucoseuptake

AdipogenesisIncreased fatty acid

uptake

Reducedgluconeogenesis

Increased lipogenesis

Increased glucoseuptakeSkeletal

muscle

Adipose tissue Liver

Figure 5. Some actions of thiazolidinediones. Thiazolidinediones, by their actions on hepatic,adipocyte, and skeletal muscle energy metabolism, reduce circulating lipids and lipoproteins, raisehigh-density lipoprotein (HDL) cholesterol, and improve glycemic control. FFA, free fatty acids.

Table I. Some actions of peroxisome prolifera-tor activated receptor–� (PPAR�) agonists.

Abbreviations: CRP, C-reactive protein; FFA,free fatty acids; TNF�, tumor necrosis factor–�.

Major impact on hepatocyte gene expressionTarget genes participate primarily in lipid catabolism

•FFA translocation into hepatocytes

•FFA oxidation in microsomes, peroxisomes, and mitochondria

•Lipoprotein assembly, secretion, and metabolism

May be anti-inflammatory• Inhibit cytokine (TNFα and

interleukin) production•Decrease CRP and fibrinogen

the potential of nicotinic acid, thedrug not only lowered the risk ofmyocardial infarction, but also, overthe long term, extended life.

Combining nicotinic acid with astatin is not only logical, but alsotherapeutically advantageous. Pro-

longed-release nicotinic acid coad-ministered with lovastatin (in dos-es of 1000 mg and 20 mg, respec-tively) lowered LDL cholesteroland raised HDL cholesterol by 32% and 17%, respectively26; and simi-lar changes induced by a nicotinicacid/simvastatin combination in

the High-density lipoproteinAtherosclerosis Treatment Study(HATS)27 drove a significant im-provement in coronary angiographyand a 90% fall in the frequency ofmajor coronary events comparedwith placebo (P=0.03) in patientswith established CHD. Currently,there is no clear consensus as to which is the most appropriatestatin for use with nicotinic acid,although it is noteworthy that afixed combination tablet of extend-ed-release nicotinic acid with lova-statin (Figure 7) has just becomeavailable in the United States.28

Nicotinic acid/simvastatin combi-nation may be more appropriate inEurope since this statin has nowlost patent protection (and lova-statin is not widely available) acrossthe Continent.

SUMMARY

• The wide-ranging portfolio ofbenefit that has been establishedfor the statins makes these agentsthe drugs of choice in patients withhypercholesterolemia and at risk of a first or repeat vascular event.

• Diabetics also benefit from suchintervention, although even ontreatment their vascular risk re-mains substantially elevated. Ad-dition of a fibrate or nicotinic acidmay improve the risk profile, al-though this remains to be estab-lished in the crucible of a clinicalend point trial.

• Patients with hypertriglyceridemiaand low HDL cholesterol merit in-tensive lifestyle advice and appro-priate intervention. Current evidencesuggests that fibrates or nicotinicacid may be of value in this situa-tion, based on a growing portfolioof clinical trial evidence.

Sheena Brownlie provided excellent secretarialsupport in the production of this manuscript.



255

0

–20

–10

–41

30

–47

0

LDL cholesterol

HDL cholesterol

TriglyceridesChan

ge f

rom

base

line (

%)

–40

–60

Figure 7. Combined effectsof nicotinicacid and lovastatin on plasma lipids.Findings from a study carried out in814 male+female patients, aged 21

and above, over 52 weeks. Duringmonth 1, patients were given 500 mg

niacin (Niaspan) and 10 mg lovastatin.Dosages were then increased to

1000 mg/ 20 mg (month 2), respectively;1500 mg/ 30 mg (month 3), respectively;2000 mg/40 mg (month 4), respectively.

The effects of the maximum dosage ofcombination therapy on low-densitylipoprotein (LDL) cholesterol, high-

density lipoprotein (HDL) cholesterol,and triglycerides are shown.

Based on data from reference 27.

Figure 6. Mechanism of action of nicotinic acid. Panel A: By binding to its receptor on adipocytemembrane, epinoephrine triggers the conversion of ATP to second messenger cyclic AMP (cAMP). Thisdrives the activation of intracellular lipase, which promotes lipolysis of triglyceride and stimulatesthe release of free fatty acids into the circulation. Panel B: Nicotinic acid reverses the above processby promoting the phosphodiesterase-driven degradation of cAMP to AMP. This shuts down triglyceridelipolysis and free fatty acid release.

Abbreviations: AMP, adenosine monophosphate; cAMP cyclic adenosine monophosphate; ATP,adenosine triphosphate; FFA, free fatty acids; Pi, inorganic phosphate; TG, triglycerides.

FFATG

Pi

A

ATP Adenyl cyclase

cAMP

AMP

Inactive lipase

Phospho- diesterasePhosphatase

Active lipase-P

Hormone eg,epinephrine

FFA

FFA FFATG

Pi

B

ATP Adenyl cyclase

cAMP

AMP

Inactive lipase

Phospho- diesterase

Nicotine acid

Phosphatase

Active lipase-P

Hormone eg,epinephrine

REFERENCES

1. No authors listed.

Theodor Svedberg; 1926 Nobel Laureate inChemistry.

http://www.nobdatafy.com/TS-bio.html.

2. Gofman JW, Glazier F, Tamplin A,Strisower B, de Lalla O.

Lipoproteins, coronary heart disease andatherosclerosis.

Physiol Rev. 1954;34:589-607.

3. Gordon T, Castelli WP, HjortlandMC, Kannel WB.

The prediction of coronary heart disease by high density and other lipoproteins: an historical perspective. In: Rifkind BM andLevy RI, eds.

Hyperlipidemia: Diagnosis and Therapy.New York, NY: Grune and Stratton Inc;1977:71-78.

4. Brown MS, Goldstein JL.

A receptor-mediated pathway for cholesterolhomeostasis. Nobel lecture, 9 December1985. In: Lindsten J, ed.

Nobel Lectures, Physiology or Medicine1981-1990. Singapore: World ScientificPublishing Co; 1993.

5. Roberts WC.

The underused miracle: the statin drugs areto atherosclerosis what penicillin was to in-fectious disease.

Am J Cardiol. 1996;78:377-378.

6. Gaw A, Packard CJ, Shepherd J.

Statins: The HMG-CoA Reductase Inhibitors in Perspective.

London, UK: Taylor & Francis Group; 2004.

7. Shepherd J.

Ezetimibe. In: Webb DJ, Paterson KR,Flockhart DA, eds.

The Year Book in Therapeutics.2005;1:269-291. Atlas Medical PublishingLtd; 2005.

8. Kerzner B, Corbelli J, Sharp S, et al.

Efficacy and safety of ezetimibe coadminis-tered with lovastatin in primary hypercholes-terolemia.

Am J Cardiol. 2003;91:418-424.

9. Melani L, Mills R, Hassman D, et al.

Efficacy and safety of ezetimibe coadminis-tered with pravastatin in primary hypercholes-terolemia: a prospective, randomized, dou-ble-blind trial.

Eur Heart J. 2003;24:717-728.

10. Davidson MH, McGarry T, Bettis R,et al.

Ezetimibe coadministered with simvastatinin patients with hypercholesterolemia.

J Am Coll Cardiol. 2002;40:2125-2134.

11. Betteridge CM, Houri J,Nortabartolo A, et al.

Effects of ezetimibe coadministered with atorvastatin in 628 patients with primary hypercholesterolemia.

Circulation. 2003;107:2409-2415.

12. Cannon CP, Braunwald E, McCabeCH, et al.

Comparison of intensive and moderate lipidlowering with statins after acute coronarysyndromes.

N Engl J Med. 2004;350:1495-1504.

13. LaRosa JC, Grundy SM, WatersDD, et al.

Intensive lipid lowering with atorvastatin inpatients with stable coronary disease.

N Engl J Med. 2005;352:1425-1435.

14. Haffner SM, Lehto S, RonnemaaT, et al.

Mortality from coronary heart disease insubjects with type 2 diabetes and in non-diabetic subjects with and without priormyocardial infarction.

N Engl J Med. 1998;339:229-234.

15. Malik S, Wong ND, Franklin SS,et al.

Impact of the metabolic syndrome on mortality from coronary heart disease, cardiovascular disease and all causes inthe United States.

Circulation. 2004;110:1245-1250.

16. Collins R, Armitage J, Parish S,et al.

MRC/BHF Heart Protection Study ofcholesterol lowering with simvastatin in5963 people with diabetes: a randomisedplacebo-controlled trial.

Lancet. 2003;361:2005-2016.

17. Rubins HB, Robins SJ, Collins Det al.

Gemfibrozil for the secondary prevention ofcoronary heart disease in men with low levelsof HDL cholesterol.

N Engl J Med. 1999:341:410-418.

18. Frick MH, Elo O, Haapa K, et al.

Helsinki Heart Study: primary preventiontrial with gemfibrozil in middle aged menwith dyslipidaemia.

N Engl J Med. 1987;317:1237-1245.

19. Chapman MJ.

Fibrates in 2003. Therapeutic action in athero-genic dyslipidaemia and future perspectives.

Atherosclerosis. 2003:171:1-13.

20. Keech A, Simes RJ, Barter P, etal; FIELD Study Investigators.

Effects of long-term fenofibrate therapy oncardiovascular events in 9795 people withtype 2 diabetes mellitus (the FIELD Study):randomized controlled trial.

Lancet. 2005;366:1829-1931.

21. Van Wyk JPH, de Koning EJP,Martens EP, Rabelink TJ.

Thiazolidinediones and blood lipids in type 2diabetes.

Atheroscler Thromb Vasc Biol.2003:23:1744-1749.

22. Haffner S, Greenberg AS, WestonWM, et al.

Effect of rosiglitazone treatment on non-traditional markers of cardiovascular disease in patients with type 2 diabetes.

Circulation. 2002;106:679-684.

23. Elam MB, Hunninghake DB,Davis KB, et al.

Effect of niacin on lipid and lipoprotein levelsand glycemic control in patients with diabetes and peripheral arterial disease.The ADMIT study.

JAMA. 2000;284:1263-1270.

24. Guyton JR, Blazing MA, Hagar J,et al.

Extended-release nicotinic acid versus gemfibrozil for the treatment of low levels of HDL cholesterol. Niaspan-GemfibrozilStudy Group.

Arch Int Med. 2000;160:1177-1184.



256

25. Superko HR, Krauss RM.

Differential effects of nicotinic acid in sub-jects with different LDL subclass patterns.

Atherosclerosis. 1992;95:69-76.

26. Insul W, McGovern ME, SchrottH, et al.

Efficacy of extended release niacin with lovastatin for hypercholesterolemia: assess-ing all reasonable doses with innovativesurface graph analysis.

Arch Intern Med. 2004;164:1121-1127.

27. Brown BG, Zhao XQ, Chait A, et al.

Simvastatin and niacin, antioxidant vita-mins, or the combination for the preventionof coronary disease.

N Engl J Med. 2001;345:1583-1592.

28. Kashyap ML, McGovern ME,Berra K et al.

Long-term safety and efficacy of a once-daily nicotinic acid/lovastatin formulationfor patients with dyslipidemia.

Am J Cardiol. 2002;89:672-678.



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259

he discovery and developmentof modern medicines fromplants is not usually a straight-forward process. Scientists

believe that the correct way to discovera new remedy is by knowing the mech-anism of action of a plant compoundand matching it with the biochemicalbasis of the disease process. However,it is not usually like that. Careful ob-servation by itself can yield dividends.For example, the antihypertensive ac-tion of reserpine was found when psy-chiatric patients, being treated withRauvolfia serpentina, had their bloodpressure measured as a routine. Aca-demic biochemical research led tothe discovery of lidocaine.1

Certainly no one could have predictedthat calcium channel blockers wouldbe discovered by way of a somewhatneglected compound found in theopium poppy, but that is exactly whathappened with verapamil.

THE OPIUM POPPY

Opium is produced by incising theunripe seed capsule of the opiumpoppy, Papaver somniferum L., anddrying the milky juice or latex thatruns out (Figure 1). The name comesfrom the Greek words for juice, sap of

trees “��,” and poppy juice “��,”which was Latinized to opium. TheSumerians in southern Mesopotamiacultivated opium and wrote about itas the “joy plant” in 3400 BC. It wasused medicinally in Egypt in 1500 BC,also in ancient Greece and Rome, andwas introduced into China by Arabiantraders. An account of how to getopium by slitting the capsule was writ-ten in 50 BC by Scribonius Largus,physician to Emperor Claudius.

One can only guess at the probablydangerous trial and error that led to itsdiscovery as an analgesic and narcoticdrug. Opium contains 25 different al-kaloids, which are separated into twoclasses. The important phenanthrenegroup has 10% morphine, 0.5% codeine,and 0.2% thebaine. The benzyliso-quinoline group has 1.0% papaverine,6.0% narcotine, and 0.3% narceine. The

concentrations are given as percent-ages of purified opium. The lattergroup has no analgesic or narcotic ef-fects and is not addictive. We are con-cerned here solely with papaverine.

PAPAVERINE

Pharmacological studies showed thatpapaverine (Figure 2) is a relaxant ofsmooth muscle especially when themuscle is in spasm, but that it doesnot paralyze the muscle cell that stillresponds to stimulation. It acts on themuscles of the bronchi, gastrointesti-nal tract, ureters, biliary system, andarteries. On the isolated heart it de-presses atrioventricular conduction andsuppresses ventricular premature beats.

In anesthetized dogs with coronaryartery ligation it decreases the thresh-old for ventricular fibrillation and astudy in conscious dogs showed thatit enhances the coronary blood flow.

In clinical medicine it was used, thoughwith only slight benefit, in childrenwith pyloric stenosis, and a trial done

Address for correspondence:Dr Arthur Hollman, “Sea Bank” Chick Hill Pett,East Sussex, TN35 4EQ, UK(e-mail: [email protected])

Dialogues Cardiovasc Med. 2005;10:259-263.

T

Plants and the Heart Windfalls from the opium poppy:

the discovery of papaverine and verapamilArthur Hollman, MD, FRCP, FLS

Department of Cardiology - Conquest Hospital - Hastings - East Sussex - TN37 7RD – UK


Figure 1. Photograph showing latex exuding from the incised unripe

seed capsule of an opium poppy. © Arthur Hollman.

Figure 2. Chemical structure of papaverine.

H3CO

H3CO

OCH3

HClOCH3

N

in 1940 was said to show that it re-duced the mortality of pulmonary em-bolism from 82% to 13%. It was usedin systemic arterial embolism, the ac-tion being by increase of collateralflow, but Dr Paul D White of Bostonreported in 1944 that it had little effectin angina pectoris or in hypertension.

WIDER USE OF PAPAVERINE

It was J. Pal in Germany in 1913 whohelped put papaverine on the widertherapeutic map. He found that itlowered intestinal tone without inter-fering with peristalsis and went on toadvise its use in gastric and intestinalspasms, in colics and in spastic con-stipation. We are reminded by thehistorian Christopher Lee not to judgepast events by the standards of thepresent day, so although “gastric andintestinal spasms” seem to be vagueentities, this was still an era of im-precise diagnosis. However, one caneasily understand that there was alarge market for this type of medicine,notably for constipation, which wasthen considered a cause of systemicillness. Indeed, the London surgeonW. Arbuthnot Lane was doing colecto-my and other operations on the colonin 1909 for “chronic intestinal stasis”in order to treat “auto intoxication”.He was parodied by George BernardShaw in The Doctor’s Dilemmaas the surgeon who operatedon the mythical nuciform sacto cure “chronic blood poisoning.”

PAPAVERINE AND ITS ANALOGS

Papaverine was isolated in 1848 andits synthesis in 1927 paved the wayfor the preparation of analogs, aimingfor better tolerance and greater speci-ficity of action. Two analogs were syn-thesized by Merck and Company inDarmstadt and the Chinoin Companyin Budapest: Eupaverin and Ethaverine.Walter Sneader comments that they

were widely prescribed as antispas-modics in the 1930s, even though theywere inferior in this respect to the atropine analogs then in use.2 Theother firm that became interested inthis line of enquiry was Knoll AG inGermany, and it was their chemist,Dr Ferdinand Dengel, who de-veloped verapamil.

VERAPAMIL IS SYNTHESIZED

Ferdinand Dengel studied chemistry inMunich, Marburg, and also in Frankfurtwhere he was an assistant to ProfessorWagner-Jauregg. He then joined Knolland went to Vienna where he workedwith Professor Ernst Spath. It was inVienna that he started work on pa-

paverine analogs at Knoll’s request,which he continued in 1938 in Knoll’sown department. After a delay due tothe war, his first compound was thespasmolytic Barbonin, but already hewas much more interested in findinga cardioactive substance using thehomoveratryl test as the guideline. InMay 1959, after years of work, he syn-thesized 75 grams of a viscous oilybase labelled D365 (D for Dengel). Itwas patented on April 28, 1961, withthe chemical name of iproveratril hy-drochloride and then given the genericname of verapamil (Figure 3).

THE PHARMACOLOGY OF VERAPAMIL

Dengel gave a watery solution of hiscompound to the Pharmacology

Department of Knoll whereProfessor Hans Haas and

Dr Gunther Hartfelder found in ani-mals that it had an impressive actionin dilating the coronary arteries, butunlike other vasodilators it had nega-tive inotropic and chronotropic effects.In 1964, a Canadian study in animalsby Melville et al showed that it im-paired atrioventricular conduction


Windfalls from the opium poppy: the discovery of papaverine and verapamil - Hollman

260

CH3O OCH3

OCH3•HCICH3O

CH3CN

C(CH2)3NCH2CH2

CH(CH3)2

Figure 4. Watercolor painting of an opium poppy plant by Dr Catharine E. Hollman. © Catharine Hollman.

Figure 3.Chemicalstructure ofverapamil.

261

and that it protected against chloro-form/epinephrine-induced ventricularfibrillation. They postulated that it hada “quinidine-like action,” while statingthat the actual antiarrhythmic mecha-nism was not known.3 But it was stillregarded as a β-blocking agent, albeitwith unusual features. However, in1968, after 5 years’ work, ProfessorAlbrecht Fleckenstein of Freiburgshowed that the negative inotropic effect resulted from inhibition of exci-tation-contraction coupling and thatthe mechanism involved reduction ofthe movement of Ca2+ into cardiacmyocytes. Thus was born the conceptof calcium channel blockade, a com-pletely new idea in the pharmacologyof cardiac muscle.4 A full account ofcalcium antagonists with useful refer-ences by J. Desmond Fitzgerald waspublished in this journal.5

CLINICAL STUDIES OF VERAPAMIL

In 1961, Dr Dengel, having faith in hiscompound, tested it on himself beforeit was given to volunteers and pa-tients. On September 1st, 1963, Knolllaunched the drug under the name of

Isoptin (an old trademark from 1942)and with the chemical name iprovera-tril. With the aim of treating anginapectoris, three clinics in Germany start-ed trials of the drug, reporting in 1964to 1966, and the patients in Munsterfound it so useful that they returnedto the clinic asking for further suppliesafter the trial had finished.

The first controlled double-blind studyof verapamil in angina pectoris wasdone by Sandler and his colleagues in 1968, and they commented that itwas still uncertain whether the modeof action was coronary vasodilatationor via myocardial depression. At adose of 120 mg three times a day they

found that exercise tolerance was improved, trinitrin consumption de-creased, and most importantly that ithad a significant effect on the amountand duration of ischemic ST-segmentdepression in the exercise electro-cardiogram.6

The antiarrhythmic action of verapamilhaving been shown in animals byMelville et al, it was natural to studythis effect clinically. An early paper bySchamroth, Krikler, and Garrett in 1972reported the results in 181 patients towhom it was given intravenously. Itwas invariably effective in paroxysmalsupraventricular tachycardia, while inatrial fibrillation it slowed the ventricu-lar response and often made it regular,the mechanism for this being uncer-tain. The drug was useful too in atrialflutter and in the preexcitation syn-drome. They wrote, “as a calcium ionantagonist and thus an antagonist ofelectromechanical coupling, it maybelong to a novel class of antiarrhyth-mic agents.”7 In vitro work in Oxford bySingh and Vaughan Williams showedthat verapamil’s mode of action re-quired that it be placed into the pre-viously unknown Class IV.8

A hypotensive effect of verapamil hadbeen noted in two studies of anginalpatients6,9 and, by 1970, reports of itsuse in hypertension started to be pub-lished. In 1978, Lewis and colleaguesin New Zealand did a careful double-blind crossover trial that confirmed itsvalue in hypertension. The responsewas dose-dependent and well seenwith 120 mg three times a day. Theyemphasized the virtual lack of side ef-fects at all dose levels, although, pre-dictably, this original optimism hadlater to be somewhat tempered, eg, inparticular due to the risk of congestiveheart failure in subjects with severeleft ventricular dysfunction, or the riskof hypotension.10



Figure 6. Production of opium in Afghanistan (2002), in metric tons. © UNOSAT. All rights reserved.

Figure 5. Photograph of an opium poppyflower. © Arthur Hollman.

Above 200150-200

100-15050-1001-50Considered poppy free

Opium Production, 2002District production (ton)

Following these early studies therehave been about 20 000 papers pub-lished that refer to verapamil. Thereare now at least 11 calcium channelblockers on the market and becausethey differ in their possible sites ofaction their therapeutic actions are dif-ferent. There are important differencesbetween verapamil and the dihydro-pyridine blockers such as amlodipine.Readers of this journal will be wellaware of the various compounds avail-able and the indications for their use.

We are taught a further lesson in thehistory of drug discovery when we learnthat the therapeutic scope of verapamilhas widened in an unforeseeable wayto become the first compound to beeffective against multidrug resistancein cancer.

BOTANY AND HORTICULTURE

Papaver was the original Latin name forpoppy. The poppy family, Papaveraceae,which has 23 genera and over 200

species is found in the northern hemi-sphere, mostly in temperate regions.The species are nearly all herbaceous,though occasionally there are smallshrubs. There are four subfamilies, oneof which, Eschscholziadeae, is foundonly in North America and containsthe California poppy (Escholzia orEschscholzia californica), the stateflower of California. The family wasnamed by the distinguished Frenchbotanist Antoine de Jussieu whoworked at the (still extant) Jardin desPlantes in Paris in the mid-1800s.French cardiologists will know thenearby Metro station Jussieu.

The opium poppy, Papaver somnifer-um L. is a handsome plant, up to onemeter high with large grey green pin-nately lobed leaves (Figure 4). Theunopened flower buds are noddingand the flower color varies from whiteto violet and red. The nonfleshy fruitis a capsule and when mature the seedis released through pores in the roofof the capsule. The seed is tiny andone plant will release many hundreds.

It is an annual. Although it is commonin the Middle East and Asia, it actuallyoriginated in the western part of theMediterranean region.

The flowers of the poppy family areusually single and often very beautiful(Figure 5). In my garden I grow the yel-low horned poppy Glaucium flavum,which is a feature of the nearby shinglebeach and also Argemone mexicana,the prickly poppy of Mexico, togetherwith the Oriental, Iceland, and Califor-nia poppies and of course the opiumpoppy, which seeds itself freely.

The poppy family has uses other thanthe medicinal ones of morphine,codeine, and papaverine, which occuronly in Papaver somniferum. Opiumpoppy seed contains no alkaloids andis used, for its nutty flavor, to sprinkleon cakes and bread. It also yields aculinary oil, olivette, and an artists’oil.Seeds of the prickly poppy and theyellow horned poppy contain oils thathave been used in the manufacture of soap.

One needs a warmer climate thanBritain to obtain a good yield of opium.Afghanistan is the source of 80% ofthe world’s opium and in 2004 it pro-duced 3400 metric tons, which couldyield 765 metric tons of heroin (Fig-ure 6). However it is interesting tofind that Tasmania with its mild cli-mate on the 41st parallel produces40% of the world’s legal supply of opi-ates (Figure 7). It also grows a genet-ically modified strain containing noopiates, but rich in the alkaloid the-baine, from which a painkiller, oxy-codone, is produced.

I would like warmly to thank my wife Dr Catharine Hollman for the painting of anopium poppy flower. Also I thank Dr Dennis

M Krikler for his advice, and the staff of the Rosewell Library, Conquest Hospital,

Hastings, for their valued assistance.

262



Figure 7.Opium poppyfield inTasmania. © Tom Holub/Unicyclist.com.All rightsreserved.

REFERENCES

1. Hollman A.

Coca,barley,and the giant reed: the discov-ery of local anesthetics and their use incardiology.

Dialogues Cardiovasc Med.2005;10:109-112.

2. Sneader W.

Drug Discovery. A History. Chichester,UK: John Wiley and Sons Ltd; 2005.

3. Melville KI, Shister HE, Huq S.

Iproveratril: experimental data on coronarydilatation and antiarrhythmic action.

CMAJ. 1964;90:761-770.

4. Fleckenstein A, Doring HJ,Kammermeir H.

Einfluss von Beta-Receptorenblockern undverwandten Substanzen auf Erregung,Kontraktion und Energiestoffwechsel der Myokardfaser [Influence of �-receptor blockers and related substances on the stim-ulation, contraction, and energy metabolismof myocardial cells].

Klin Wochenschr. 1968;46:343-351.

5. Fitzgerald JD.

Calcium antagonists and the importance ofpharmacological specificity of action.

Dialogues Cardiovasc Med. 2002;7:113-118.

6. Sandler G, Clayton GA,Thornicroft SG.

Clinical evaluation of verapamil in anginapectoris.

BMJ. 1968;3:224-227.

7. Schamroth L, Krikler DM, Garrett C.

Immediate effects of intravenous verapamilin cardiac arrhythmias.

BMJ. 1972;1:660-662.

8. Singh BN, Vaughan Williams EN.

A fourth class of anti-dysrhythmic action?Effect of verapamil on ouabain toxicity, onatrial and ventricular intracellular potentials,and on other features of cardiac function.

Cardiovasc Res. 1972;6:109-119.

9. Livesley B, Cattey PF, Campbell RC,Oram S.

Double blind evaluation of verapamil, propranolol and isosorbide dinitrate against a placebo in the treatment of angina pectoris.

BMJ. 1973;1:375-378.

10. Lewis GRJ, Morley KD, Lewis BM,Bones PJ.

The treatment of hypertension with verapamil.

N Z Med J. 1978;87:351-354.

263



any trials have been carried out with aspirin and other antiplatelet agents,demonstrating efficacy in the reduction ofserious vascular events in a wide varietyof patients at high risk of such events.

Indeed, the authors of this paper had previously publisheda meta-analysis of such studies in 1994. This was repeatedin 2002, in order to address some of the questions thatremained unanswered. For example, it was unclear whenantiplatelet agents should be initiated after ischemic stroke,and questions remained about the possible benefits fromaspirin therapy in patients with chronic atrial fibrillation,stable angina, and peripheral arterial disease (PAD).

Among 448 possibly suitable trials, 166 were excluded fora variety of reasons. The included studies were of patientsat high risk of a vascular event, randomized to aspirin orplacebo in 197 of the trials, and aspirin versus another an-tiplatelet regimen in the remaining 90 trials. Randomizedpatients had a likely annual incidence of an event of >3%due to a predisposing condition or previous event.

The numbers of included patients allowed the authors ofthis analysis to subcategorize results according to the con-dition that the trial was investigating, such as acute myo-cardial infarction (MI) or acute stroke, and also by the eventprevented, such as death, MI, or stroke. The death ratecombining all studies was 13.2% in the control group and10.7% in the aspirin group, though this was measuredover a variety of time periods according to design of individual trials. This reduction was highly significant, atP<0.0001. Benefits of similar magnitude and statisticalsignificance were seen in trials of aspirin in the treatmentof patients with acute myocardial infarction (MI), previousMI, previous stroke, or transient ischemic attack and othervascular events. The relative risk reduction for each wasapproximately 25%. This was less striking in acute strokeat 11%, though still highly significant (P=0.0009). In thiscondition, aspirin was associated with worsening hemor-rhagic stroke and hemorrhagic transformation of ischemicstroke, which partially cancelled the benefits of thrombo-embolic stroke reduction.

A summary of this length cannot hope to mention all theindividual analyses in this meta-analysis, since there were14 categories of disease for which patients were enrolled.However, for each of the main categories—coronary ar-tery disease, PAD, high risk of embolism (atrial fibrillationand valve replacement/surgery), and other high-risk con-ditions—aspirin demonstrated important and significantreductions in vascular events. The authors suggest thatthe failure to demonstrate benefit among diabetics is ex-plained by many of the analyses having confidence inter-vals that were as wide as the magnitude of benefit, thusincreasing the likelihood of false negatives findings.

There was no difference in the efficacy at doses from 75 to150 mg, 160 to 300 mg, and >500 mg, though toxicity wasgreater at the highest doses. Thus, 75 to 150 mg is recom-mended except when a rapid treatment effect is required,when a loading dose of 150 to 300 mg may be given.

This study showed that aspirin therapy is effective in pre-venting vascular events in patients with stable angina andintermittent claudication, and may be given in atrial fibrilla-tion if warfarin is unsuitable. Despite the issues mentionedabove, it is beneficial to initiate it promptly in acute stroke.When aspirin cannot be given, clopidogrel was found tobe an appropriate alternative.

266


Summaries of Ten Seminal Papers - Faircloth and Pedersen

Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients

Antithrombotic Trialists’ Collaboration

BMJ. 2002;324:71-86

M

The National Academy of Sciences opposes human reproductive cloning, but supports

therapeutic cloning; France returns to South Africa the remains of the “Hottentot Venus,”

aka Saartjie Baartman, born in 1789 and exploited as a circus freak; and a woman injured

by an exploding cappuccino machine in a Starbucks café is awarded $3.5 million

by a Manhattan jury

2002



267

his paper comprises a meta-analysis of 12 ar-ticles addressing the risk after myocardial in-farction, and the impact of smoking cessation.Smoking remains the leading cause of prevent-able death in the United States, with 400 000

people dying per year from smoking-related causes. Indi-viduals with ischemic heart disease who continue to smokehave been shown to be at particularly high risk, due to thewidespread effects of the cigarettes’ constituents, includ-ing adverse effects on coronary blood flow, myocardialoxygen demand, and the risk of thrombosis.

A thorough review of the medical literature databases wasconducted as well as searching through the citations ofrelevant articles, which revealed 12 useful papers that wereincluded in this meta-analysis. In these studies, nearly 12 000 patients had been enrolled between 1949 and 1988from across Europe and the USA. Smoking status was assessed at 1 to 12 months, and in two studies ongoingassessments were performed. Cessation rates of 29% to74% were recorded during follow up of 2 to 10 years.

Mortality rates ranged from 4% to 37% among the ex-smok-ers, and 8% to 54% among the ongoing smokers, with rela-tive risk reductions of 15% to 61%. The combined odds ratiofor death among the ex-smokers was 0.54 (95% confidenceinterval [CI], 0.46-0.62). This suggested that with an estimat-ed mortality rate among ongoing smokers of 20%, the num-ber needing to quit smoking in order to save one life is 13!Comparing all the papers, there were surprisingly few dif-ferences in methodology that might have been expectedto skew results. All except one study required self-certifica-tion of smoking status, which is a potential weakness,though one that would be likely to reduce the magnitudeof benefit seen. The benefits of smoking cessation wereobserved in all subgroups, and were independent of gender,country of study, timing of study (prior to or after 1980),and length of follow up.

It is striking to observe that the odds ratio of 0.54 in favorof smoking cessation compares extremely favorably withmeta-analyses of other interventions in the treatment of

myocardial infarction (MI). For thrombolysis, the equivalentfigure is 0.75 (95% CI, 0.71-0.79), for aspirin it is 0.77 (95%CI, 0.70-0.84), and for β-blockers, it is 0.88 (95% CI, 0.80-0.98). These analyses only included randomized controlledtrials, which have a higher validity than cohort studies,which made up all of the papers in this meta-analysis.

The limitations of this analysis include the inherent weak-nesses of cohort studies. In such studies, it is possible forunequal distribution of confounding variables to occur,though in the studies that controlled for infarct size and ageas possible confounders, this was not found to be the case.Although individuals who were motivated to stop smokingmight have made better use of medical services, and thusreceived more effective post-MI management, such an effectwould have caused a change in the odds ratios after 1980,after which many of the currently accepted therapies weremore widely introduced. Although publication bias is acommon concern in performing meta-analyses, the authorscalculated that it would require 241 null result studies tocause this analysis to produce a nonsignificant result.

The authors conclude by stating that this provides com-pelling evidence for the benefits of smoking cessationpost-MI, and that studies should now be directed at inter-ventions to increase the success of smoking cessation.

T

An urn containing the skull of Pope Benedict XIIIand worth more than £200 000 is stolen from a museum in Spain; paleontologists discover

a fossilized heart, the size of a grapefruit, in thechest cavity of fossilized skeleton uncovered in South Dakota; and British scientists head

for the South Atlantic in an attempt to disproveclaims that penguins fall over backwards

when aircraft fly overhead

2000

Effect of smoking cessation on mortality after myocardial infarction: meta-analysis of cohort studies

K. Wilson, N. Gibson, A. Willan, D. Cook

Arch Intern Med. 2000;160:939-944



Secondary prevention of coronary heart disease in the elderly

C. J. Bulpitt

Heart. 2005;91:396-400

ulpitt, in this paper, discusses strategies for sec-ondary prevention of established and stablecoronary artery disease in the elderly and thevery elderly (age 80 years or more). The authorpoints out that there is little evidence from

randomized controlled trials to guide our decisions in thevery elderly, as most major studies have few, if any, elderlyparticipants. The author argues that it is inappropriate tosimply extrapolate findings from younger age groups to theelderly since they vary in many ways from younger patients.For example, physiology changes with age, and this cohortis mainly female. Patients may have dementia or impairedrenal function, they may be on multiple-drug therapies for comorbidities, and they may have a perception of how,and how long, they wish to live, which is at variance withthat of younger patients

There is good evidence that, in the elderly, smoking cessa-tion reduces mortality. Being overweight is a good prognos-tic sign in the very elderly and advice to lose weight shouldpossibly be restricted to the obese. Exercise should be en-couraged. It is the author’s personal opinion that dietarychange is difficult to institute in the very elderly. Little isknown about alcohol consumption in the very elderly ex-cept that they tend to drink less than the young. However,moderate alcohol consumption is likely to confer somecardiac survival benefits.

Antiplatelet agents should be prescribed. There is evidencethat in the elderly (>65 years) aspirin causes an absolutereduction of 4.5% in vascular events. It is also possible thatthe incidence of both dementia and gastrointestinal can-cer is reduced. However, there is a 3% absolute increasein gastric bleeding, a 40% relative increase in hemorrhagicstroke, and a higher incidence of anemia.

β-Blockers result in a 6% reduction in total mortality at age65-75, but are underprescribed in this age group. Concernsregarding postural hypotension, bradycardia, bronchospasm,peripheral vascular disease, and masking of hypoglycemicevents warrant careful monitoring of these drugs in thisage group. There are no trials of β-blockers in subjects over

the age of 80 years. Angiotensin-converting enzyme (ACE)inhibition gives an absolute risk reduction of 3.5% in sub-jects over the age of 70. All patients should be prescribedthese, with the only limiting factors being hypotension andpostural hypotension. Lowering blood pressure is directlyrelated to a reduced incidence in vascular events, at leastuntil around 79 years. Recent trials in the very elderly(>80 years) showed that active treatment of hypertensionsignificantly reduces stroke, major coronary events, andheart failure. However, there was also a tendency towardincreased cardiovascular deaths and total mortality. For ev-ery stroke avoided, there was one excess nonstroke death.Trials on the subject are currently being undertaken.

The benefit of statins in reducing coronary events is wellestablished. Below age 80, the benefit of treatment greatlyoutweighs any disadvantage. Above this age, however, al-though coronary events are reduced (19%), no evidence ofa reduction in stroke incidence has been shown. In addi-tion, cancer incidence increased with pravastatin by 25%.

The author suggests that the minimum secondary preven-tion for the very elderly should be the institution of cardiacrehabilitation and antismoking advice, together with theprescription of antiplatelet and ACE-inhibitor treatment.

B

The New England Journal of Medicine reports that if obesity in children continues,

their life expectancy will be cut by 2 to 5 years;Pope Benedict XVI beatifies Charles de Foucauld

(1858-1916) soldier, explorer, Trappist monk, and hermit in the Algerian Sahara;

and Steve Fossett completes the first solo, nonstop round-the-world flight when his plane

GlobalFlyer lands in Kansas

2005

268



269

t the time this paper was published, 65 trialshad enrolled 50 000 patients to determinethe effects of β-blockers in the treatment ofmyocardial infarction (MI). The effect of earlyIV administration was assessed separately to

early oral and chronic oral administration, both in individ-ual studies and also by these authors. This is explained bythe variation in type of complication by time post-MI. Inthe early hours after MI, it is thought that 20% to 50% ofpatients die due to ventricular fibrillation (VF). In thosesurviving this early hazard, the short- and long-term deter-minant of morbidity and mortality is the volume of infarctedmyocardium. It is known that factors that increase oxygendemand, such as tachycardia, heighten the severity of in-jury, and there are also indirect influences on oxygen de-mand. Increased adrenergic activity increases circulatingfree fatty acids, which may lead to arrhythmias and alsoincrease myocardial oxygen consumption.

β-Blockers reduce cardiac work by lowering heart rate andblood pressure, hence reducing myocardial oxygen demand.Furthermore, lower effective adrenergic drive may resultin favorable redistribution of coronary blood flow, thusprotecting viable myocardium.

In the studies of early administration of β-blockers, it hadbeen expected that a limitation of infarct size would beseen, but the long duration (>12 hours) to effective block-ade with oral agents eclipsed the period of peak risk andmeant that no mortality benefit was seen. Early IV admin-istration was associated with a reduction in peak cardiacenzyme level by 20%, and improved R-wave preservationon the ECG, both of which indicate a reduction in infarctsize. A reduction in arrhythmias was seen and though thestudies did not reveal a mortality benefit, they were notpowered to do so.

This analysis demonstrated for the first time that long-termβ-blockade showed a reduction in mortality from 10.1% to8.0% (P<0.0001). Because of their relatively small size, only2 of 16 trials individually demonstrated a mortality benefit,and similarly, it was not possible to identify the likely

magnitude of benefit for specific subgroups. By combiningstudies, highly significant reductions in reinfarction (25%)and in sudden death (30%) were seen. Comparable bene-fits were seen across a range of different β-blockers exceptthose with intrinsic sympathomimetic activity, which offeredmuch lower protection.

Surprisingly, the level of side effects was only slightly higheramong patients given β-blockers than placebo, though nostatistical analysis of this could be performed. Concernshad been raised that β-blockade might cause excess ratesof bradycardia, heart block, significant hypotension, or car-diogenic shock, though surprisingly no significant increasewas observed. However, most trials excluded those withovert heart failure or at highest risk of these complications.

This study was one of the early meta-analyses, and theauthors provide a highly informative discussion of theprinciples and assumptions used in performing such anexercise. While such analyses are now widely accepted andfrequently used, this excellent summary remains highlyrelevant today.

In conclusion, early IV β-blockade seemed to limit infarctsize, and might reduce mortality. The authors indicatedthat the forthcoming International Study on Infarct Survival(ISIS) was likely to clarify this question. Long-term admin-istration certainly reduces mortality by approximately 20%,though the benefit is uncertain beyond 12 months.

A

Mikhail S. Gorbachev replaces KonstantinChernenko as Soviet leader;

Milos Formans’ film of the life of Mozart,“Amadeus,” wins the best film category

at the 57th Academy Awards;and India files suits against Union Carbide

over the Bhopal disaster

1985

Beta blockade during and after myocardial infarction: an overview of the randomized trials

S. Yusuf, R. Peto, J. Lewis, R. Collins, P. Sleight

Prog Cardiovasc Dis. 1985;27:335-371



270

OPE, (Heart Outcomes Prevention Evalua-tion) established evidence of benefit for an-giotensin-converting-enzyme (ACE) inhibitorsfor a new set of indications. It was previ-ously known that ACE inhibitors improved

the outcome in patients with left ventricular dysfunction,irrespective of the presence of symptomatic heart failure.

In HOPE, the ACE inhibitor ramipril was given to patientswith preserved left ventricular function, but who were athigh risk of cardiac and vascular events. Inclusion criteriawere an age of at least 55 years, and a history of coronaryartery disease, stroke, peripheral artery disease, or diabetes,with at least one cardiovascular risk factor (hypertension,elevated total cholesterol, depressed high-density lipopro-tein cholesterol, cigarette smoking, or microalbuminuria).Patients known to have heart failure or with an ejectionfraction (EF) below 40% were excluded. Although echocar-diography was not routinely performed, a subgroup of 496patients was investigated more intensively, in which theincidence of low EF was only 2.6%

Compliance with the therapy was good, with 87.4% of pa-tients assigned to the ramipril arm taking it at 1 year, and78.8% at the final follow up visit, at 5 years. The target dosewas 10 mg per day, and the proportions taking this dose at1 and 5 years were 82.9% and 75%, respectively. The mostcommon reason for discontinuing therapy in the ramiprilgroup was cough (7.3% versus 1.8% in the control group). Aslight drop in the blood pressure was observed in both theramipril and the placebo groups, but this was slightly moremarked in the ramipril group (mean reduction 3/2 mm Hg).

The primary outcome measure of the study was the com-posite outcome of myocardial infarction, stroke, or deathfrom cardiovascular causes. A significant difference betweenthe two groups was observed from 2 years and this wasmaintained until the end of the study, by which time 14.0%of the ramipril group had accrued one of the primary endpoints, compared with 17.8% of the control group (P<0.001;relative risk [RR], 0.78, 95% confidence interval [CI], 0.70-0.86). There were significant reductions in some of the

secondary outcome measures, including revascularizationand diabetes complications, though surprisingly not hos-pitalization due to either unstable angina or heart failure.Other benefits seen included a reduction in the risk of heartfailure, cardiac arrest, worsening angina, and a new diag-nosis of diabetes. These benefits were observed in thosetaking a variety of other agents known to be beneficial, including aspirin, β-blockers, and lipid-lowering agents.

The authors explain that the benefits seen were probablyonly partly due to blood pressure–lowering effects. Othermechanisms include direct effects on the heart or vascula-ture, including antagonism of the direct effects of angio-tensin II, which causes vasoconstriction, vascular smoothmuscle cell proliferation, and plaque rupture. In addition,ramipril improves vascular endothelial function, reducesleft ventricular hypertrophy, and enhances fibrinolysis. Thereduction in the incidence of diabetes and diabetes compli-cations is explained by a possible increase in insulin sen-sitivity, reduced insulin clearance, and mirrors findings fromthe Captopril Prevention Project and in subsequent trialsof ACE-inhibitors and angiotensin receptor blockers (ARBs).

This study increased the range of indications for ACE in-hibitors and predicts that treating 1000 patients for 4 yearswould prevent 150 events in 70 patients. The simplicityof the trial, its applicability to everyday practice, and themagnitude of benefit have had a profound impact on pre-scribing habits.

H

Effects of an angiotensin-converting-enzyme inhibitor, ramipril,on cardiovascular events in high-risk patients

S. Yusuf, P. Sleight, J. Pogue, J. Bosch, R. Davies, G. Dagenais; the Heart Outcomes Prevention Evaluation Study Investigators

N Engl J Med. 2000;342:145-153

An international team of surgeons performs the world’s first double hand–forearm transplant inLyon, France; a survey carried out for The Times

indicates that one third of people living in Englandnow see themselves as more English than British;

One million people rally in Madrid against theBasque separatist group ETA

2000



t is well established that angiotensin-convertingenzyme (ACE) inhibition effectively reduces mortali-ty and morbidity among patients with heart failure,left ventricular dysfunction, after myocardial infarc-tion (MI), with hypertension, and among other high-

risk patients. The beneficial effects of ACE inhibition appear to be due to many factors. In addition to loweringblood pressure, ACE inhibitors possess direct cardiovas-cular protective effects through angiotensin II reductionand increased bradykinin availability. Consequently, ACEinhibition may result in reduced neointimal formation,improved endothelial function, plaque stabilization, andfibrinolysis. This multifactorial antiatherosclerotic profileof ACE inhibition suggests that its application might beextended to all patients with established coronary heartdisease (CHD) and should not be restricted to patients withimpaired left ventricular function, heart failure, or thoseat high risk of atherosclerotic events.

This study aimed to assess the ability of the ACE inhibitorperindopril to reduce cardiovascular death, MI, and cardiacarrest in patients with stable CHD and without heart fail-ure or substantial hypertension. No patient had clinicalevidence of heart failure, but all had evidence of CHD;previous MI, angiographic evidence of coronary artery dis-ease, coronary revascularization or a positive stress testonly. A total of 12 218 patients were randomized to the drugor to placebo. Mean follow-up was 4.2 years. There wasgood compliance with the study medication and only 7%needed to reduce the perindopril dose from the full 8 mgto 4 mg (cough, hypotension, or abnormal creatinine).Most patients were taking concomitant medication: at ran-domization, 92% of the patients were taking platelet in-hibitors, 62% β-blockers, 58% lipid-lowering therapy.

The primary end point was a composite of cardiovasculardeath, nonfatal MI, and cardiac arrest with successful re-suscitation. Secondary end points were the composite oftotal mortality, nonfatal MI, hospital admission for unsta-ble angina, and cardiac arrest with successful resuscitation;also cardiovascular mortality and nonfatal MI, as well asthe individual components of these secondary outcomes

and revascularization (coronary artery bypass grafting orpercutaneous coronary intervention), stroke and admissionfor heart failure.

The primary end point occurred in 488 patients (8%) in thetreatment compared with 603 (10%) in the placebo group(P=0.0003). The benefit began to appear at 1 year (rela-tive risk reduction 10%, P=0.35) and gradually increasedthroughout the trial. The authors estimate that 50 patientsneed to be treated for a period of 4 years to prevent 1 ma-jor cardiovascular event.

The benefits reported for perindopril were in addition toother preventative measures, including aspirin, β-blockers,and lipid-lowering, and were consistent for all patientsand subgroups. The benefits were greater than might beexpected for the observed reduction in blood pressure(mean 5/2 mm Hg), and the effect was similar in those withtreated hypertension and those without hypertension. Thisimplies that the specific antiatherosclerotic effects of ACEinhibition should not be neglected.

The authors conclude that the results provide strong sup-port for consideration of perindopril in all patients withCHD irrespective of other preventative treatments, cardiacfunction, or risk factors.

I

Efficacy of perindopril in reduction of cardiovascular events amongpatients with stable coronary artery disease: randomised, doubleblind, placebo-controlled, multicentre trial (the EUROPA study)

K. M. Fox; EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease Investigators

Lancet. 2003;362:782-788

271

Palestinian Prime Minister Mahmoud Abbas stepsdown, claiming both Ariel Sharon and Yasir Arafat

have undermined his position; Sweden votes against adopting Europe’s single currency in

a referendum; and the New England Journal ofMedicine reports that injection of intestinal

hormone peptide YY (PYY) reduces appetite in both fat and thin individuals

2003



272

rior to 1994, when this study was published, therehad been several trials of cholesterol-loweringinterventions in primary and secondary preven-tion. Various methods and medications havebeen tried to lower lipid levels, including partial

ileal bypass surgery. However, no clinical trial had convinc-ingly showed that lowering of cholesterol prolongs life.Physicians were being conservative and cholesterol-loweringagents were not standard therapy in secondary preventionof coronary heart disease. The Scandinavian SimvastatinSurvival Study (4S) study showed that long-term treatmentwith simvastatin improved survival in CHD patients. Sim-vastatin is a hydroxyl-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor.

4S was a large study involving 94 clinical centers through-out Scandinavia, recruiting a total of 4444 patients. Patientswere aged 37 to 70 years with a history of angina or previ-ous myocardial infarction (MI) and a total cholesterol levelof 5.5 to 8.0 mmol/L Patients were excluded if they had ahistory of complicated MI with significant myocardial dys-function or required drug therapy for heart failure. The de-sign was double blind and patients were randomly assignedto simvastatin 20 mg or placebo. Dietary advice was givento all. At 6 months, patients with cholesterol levels stillout of range (>5.2) were given an increased dose of 40 mg(37%). Median follow up was 5.4 years.

Changes in baseline total, low-density lipoprotein (LDL),and high-density lipoprotein (HDL) cholesterol and serumtriglycerides were -25%, -35%, +8%, and –10%, respectivelyin the simvastatin group. The corresponding values in theplacebo group were +1%, +1%, +1%, and +7%.

The main end point, total mortality, was significantly re-duced by simvastatin, with a relative risk of 0.7. Lookingpurely at coronary deaths, the risk reduction was evengreater at 42% (relative risk 0.58) in the simvastatin group.Secondary end points also showed benefit from simvas-tatin. The relative risk of major coronary events (nonfatalMI, silent MI, resuscitated cardiac arrest) was 0.66. Tertiaryend points: any coronary event, any atherosclerotic event

(including cerebrovascular accident), percutaneous trans-luminal coronary angiography, coronary artery bypass graft-ing, and hospital admissions for non-MI coronary heartdisease, were also reduced in the simvastatin group.

In addition, the study showed that simvastatin was safe. Asingle case of rhabdomyolysis occurred in a woman taking20 mg once daily. Creatine kinase increased to 20 timesnormal in 1 placebo and 6 simvastatin patients, but noneexperienced muscle pain or weakness, the levels fell againwithout stopping any therapy. Aspartate aminotransferase(AST) increased similarly in both groups, alanine amino-transferase (ALT) also rose in both groups, but slightly morein the active group. Prior to this trial there had been someconcerns about a potential increase in violence and cancerwith lipid lowering. Although these end points were mea-sured, no such effect occurred.

The authors speculate as to how cholesterol lowering maymediate the observed effect—coronary lesions may stabi-lize as their lipid core shrinks or at least does not furtherenlarge, there is thus a drop in risk of plaque rupture, hencein intramural hemorrhage and intraluminal thrombosis,which in turn may cause coronary events. Stabilization ofcoronary lesions is the most likely mechanism underlyingthe improved survival observed in the trial. The authorscontinue and suggest that if simvastatin by lowering LDLcholesterol can lower mortality, then LDL cholesterolshould be an important factor in the pathogenesis of CHD.

P

Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian SimvastatinSurvival Study (4S)

Scandinavian Simvastatin Survival Study Group

Lancet. 1994;344:1383-1389

South Korea lifts the ban on business and economic links with the North;

King Hussein of Jordan makes his first official visit to Israel; and Microsoft founder

Bill Gates pays a record $30.8 million at Christie’s New York for an original treatise

written by Leonardo da Vinci

1994



273

The effect of pravastatin on coronary events after myocardialinfarction in patients with average cholesterol levels

F. M. Sacks, M. A. Pfeffer, L. A. Moye, J. L. Rouleau, J. D. Rutherford, T. G. Cole, L. Brown, J. W. Warnica, J. M. Arnold, C. C. Wun, et al; Cholesterol and Recurrent Events Trial investigators

N Engl J Med. 1996;335:1001-1009

ARE (Cholesterol And Recurrent Events) wasdesigned to answer the question of how totreat patients following myocardial infarction(MI), in whom cholesterol levels were withinthe accepted normal range. In this paper, Sacks

et al report that the relationship between cholesterol andcoronary events is stronger at higher levels of cholesterol.Aggressive treatment of cholesterol had been shown byangiography to reduce progression of coronary stenoses,or even cause regression. These benefits were shown torelate to the pretreatment cholesterol level. However, themajority of patients with MI have cholesterol levels closeto the population average and it remained unclear how totreat this group.

Four thousand patients were enrolled into this study at 3 to 20 months following MI. To be included, the totalcholesterol level had to be <6.2 mmol/L (240 mg/dL), withlow-density lipoprotein (LDL) cholesterol 3.0-4.5 mmol/L(115-174 mg/dL). Patients were randomized to receive ei-ther pravastatin 40 mg or placebo. Regular monitoring ofcholesterol was performed, and if LDL levels rose above4.5 mmol/L, patients were given advice, cholestyramine,or referred to their primary physician for further treatment.There was a significant reduction in cholesterol levels inthe pravastatin group, with the mean LDL falling by 32%from 3.6 to 2.5 mmol/L, which was 28% lower than in theplacebo group. The primary end point of fatal coronaryheart disease or MI was 24% lower in the pravastatin groupat 10.2% versus 13.2% in the control group (P =0.003). Inaddition, while the incidence of nonfatal MI was 6.5% and8.3%, respectively (P =0.02), the lower incidence of fatal MI(1.2% and 1.8%, respectively) was of only borderline signif-icance (P =0.07). There were significant reductions in therates of coronary artery bypass surgery, coronary angio-plasty, and stroke, and a borderline fall in rates of hospi-talization for unstable angina. However, there was a non-significant 9% reduction in the overall mortality.

These benefits were seen at all ages and were independ-ent of left ventricular ejection fraction. For all patients except a cohort with the lowest starting lipid levels (LDL

<3.2 mmol/L), benefits were seen, and the number in thislowest group was small. Consistent with previous studies,the benefits seen were more pronounced at higher startinglipid levels. There was no excess of side effects or abnormalbiochemical parameters in the treatment group. A slightlyhigher rate of breast cancer was observed in the treatmentgroup, though this was felt to be due a lower than expectedrate in the control group, and thus due to chance.

Thus this study proved that cholesterol lowering in patientswith average levels of cholesterol following MI loweredcoronary death rates and nonfatal MI, and it implied thatthe average cholesterol level was higher than ideal. Further-more, the reduction in stroke that had been found in post-hoc analyses of previous studies was confirmed as a pre-determined end point in this study. Although 4S producedgreater benefits, the authors suggest that this was moredue to a higher starting cholesterol level rather than sim-vastatin being more effective than pravastatin. The authorscalculate that prescribing pravastatin as in this study to1000 patients would prevent 150 cardiac events, including37 fatal or nonfatal MIs.

C

The New York Yankees beat the Atlanta Braves 3-2 to win the World Series for the first time in 18 years; research is published suggesting

that simple life forms may have appeared on Earthone billion years ago, twice as early as

previously thought; and Taliban forces capture the Afghan capital Kabul

1996

274



he correlation between low-density lipoprotein(LDL) cholesterol and ischemic heart disease(IHD) risk had been observed for some yearsprior to the inception of this trial. Althoughthere was still some controversy over the rela-

tionship, the authors explain that it is essentially linear,with no definite lower threshold in Western populationsbelow which risk tailed off. Studies of lipid-lowering medi-cations had shown that in high-risk patients a reduction inLDL was associated with a fall in mortality and morbidity.No such data were available in those without a prior diag-nosis of IHD, but considered to be at high risk by virtue ofother vascular disease or diabetes. Nor were data availablefor the elderly, females, and those with lower LDL levels,but with multiple risk factors. Approximately 20 500 pa-tients were entered into this study, which compared sim-vastatin 40 mg with placebo over 5 years, although 11 000more were excluded following a rigorous “run-in” phasedesigned to exclude those with poor compliance, a failureto respond to the medication, or with side effects. Thoseincluded were of both sexes, aged 40 to 80, and had a total cholesterol of at least 3.5 mmol/L. Patients were required to have a previous history of coronary or non-coronary vascular disease, diabetes, or if male over 65years, hypertension. In addition, a study of antioxidants(vitamins C and E, and β-carotene) was performed in the same population, though this failed to demonstrateany benefits.

Due to noncompliance in the statin group, and the prescrip-tion of open-label statins to those in the placebo group,the authors felt that observed differences represented only67% of the real difference between the groups. A mean re-duction in LDL of 1.0 mmol/L was seen. The total mortalitywas 12.9% in the treatment group and 14.7% in the con-trols, P =0.0003. A similarly significant reduction in coronarymortality was seen (5.7% v 6.9%). In addition, highly signifi-cant reductions were seen in the incidence of first nonfatalmyocardial infarction, first nonfatal stroke, as well as therates of angioplasty and coronary artery bypass surgery.These were summarized by the major vascular events ratebeing 19.8% and 25.2%, respectively, P<0.0001.

These benefits were observed at all ages, including 75 to80 years at time of randomization, and in both sexes, aswell as all other major subgroups (LDL <2.5 mmol/L, dia-betes and no vascular events, cerebrovascular disease,and peripheral arterial disease). In addition, despite thewidespread use of other effective therapies including aspirin, β-blockers and angiotensin-converting enzyme inhibitors, these benefits were maintained.

Concerns had previously been expressed that very low LDLlevels might be associated with an excess morbidity dueto other conditions. These were specifically sought, and noexcess of cancer, abnormal liver function tests, cognitivedecline, or respiratory impairment was observed. The rateof significantly abnormal creatine kinase levels was verylow, and although slightly higher in the statin group (7 vs1 cases), this was of borderline significance.

The authors conclude that prescribing should reflect futurerisk rather than be determined by the absolute LDL level.This is determined by the coexistent risk factors and pre-existing disease. Such treatment not only reduces the riskof coronary events, but other vascular events, and indeedthese benefits may be up to 30% greater than revealed bythe nature of the “intention-to-treat” analysis used.

T

MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial

Heart Protection Study Collaborative Group

Lancet. 2002;360:7-22

Scientists recreate poliovirus using the virus’ genomic sequence and DNA purchased by mail; Student Maxime Brunerie fires at Jacques Chirac

on the Champs-Élysées in an attempted assassination; and Paul Kagame and Joseph Kabila,

presidents of Rwanda and Congo, respectively,agree to end the 4-year-old war between their

countries that has claimed 3 million lives

2002

xercise training has been historically accepted asbeing of benefit following myocardial infarction(MI). Indeed, Heberden observed in 1772 that oneof his patients with presumed ischemic heartdisease was “nearly cured” after 6 months of daily

wood sawing for half an hour. Although exercise rehabilita-tion programs were widely available at the time this paperwas written, the only trials conducted failed to show anystatistical benefit due to being underpowered.

In this paper, studies of exercise alone, and exercise com-bined with advice on risk factor reduction, were reviewed.Due to the heterogeneous nature of the trials, and indeedof the exercise programs, each study is considered alone,and in combination with the others. The end points consid-ered were total mortality, cardiovascular mortality, suddendeath, and fatal and nonfatal MI. Although 36 trials werefound in the literature, 14 were excluded due either to thenature of randomization or short duration of follow-up.

In total, these studies had enrolled approximately 4500patients, among whom there had been 502 deaths. Therewere 412 cardiovascular deaths, and 202 sudden deaths.Of the 701 MIs that occurred, 312 were fatal. Individually,only two studies demonstrated a significant reduction indeath, though overall, the relative risk of death at 1 yearwas 0.77 (95% confidence interval [CI], 0.59-1.01); at 2 yearsthis risk was 0.74 (0.59-0.92) and 3 years 0.80 (0.66-0.96).The mortality was slightly lower in those who received riskfactor advice as well as exercise compared with exercisealone, though this difference was not significant. Death dueto MI or other cardiovascular causes demonstrated a simi-lar pattern to that described above. Rates of nonfatal MIwere slightly higher among those receiving rehabilitation,which implies either that exercise increases the risk of MIor, more likely, that it increases the likelihood of survivalfollowing MI. In addition, there was a significant reductionin sudden death among exercisers in the first year with anodds ratio of 0.63 (0.41-0.97) though, conversely, in the latteryears, there was a trend to an increase in death in this group.The highest rate of sudden death following MI is usuallyobserved during the first year, which may account for the

benefit at this time. The authors explain that the analysisis based on time from randomization, as data were notconsistently available on time from MI, which may thusdiminish the observed level of benefit derived from exercise.

By the nature of the studies reviewed, there are limitationsto the conclusions that may be drawn from this analysis.The authors explain that although additional advice on dietand smoking cessation tended to be beneficial, this wasnot statistically significant. Some end point data were miss-ing and it is not possible to predict whether this leads toan under- or overestimate of benefit. The authors state thatit is unlikely that there was a bias due to failure to publish“negative” trials. Few women were included, and most sub-jects were under 65 years of age, and thus conclusions arelimited to men under this age.

The benefits observed probably occur because exerciselowers heart rate and blood pressure, and is associatedwith lower circulating norepinephrine levels. Weight loss,improved metabolic efficiency of muscle, and increasedcoronary collateral formation may also contribute.

In conclusion, exercise programs, possibly combined withadvice relating to other secondary preventative measures,are of benefit following MI.

E

275



An overview of randomized trials of rehabilitation with exerciseafter myocardial infarction

G. T. O'Connor, J. E. Buring, S. Yusuf, S. Z. Goldhaber, E. M. Olmstead, R. S. Paffenbarger Jr, C. H. Hennekens

Circulation. 1989;80:234-244

The space probe Voyager 2 makes its closest approach to Neptune, discovering new moons

and a planetary ring system;Tadeusz Mazowiecki is elected first noncommunist president of Poland;and Roger Kingdom (USA) sets the

110-m hurdle record (12.92s) in Zurich

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