Ebook Practical cardiology (2nd edition) Part 1

(BQ) Part 1 book Practical cardiology presentation of content: Coronary risk factors, hypertension, an overview of clinical electro­ cardiography, the patient with chest pain. (BQ) Part 1 book Practical cardiology presentation of content: Coronary risk factors, hypertension, an overview of clinical electro­ cardiography, the patient with chest pain.

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This publication has been carefully reviewed and checked to ensure that the content is as accurate and current as possible at the time of publication We would recommend, however, that the reader verify any procedures, treatments, drug dosages or legal content described in this book Neither the author, the contributors, nor the publisher assume any liability for injury and/or damage to persons or property arising from any error in or omission from this publication National Library of Australia Cataloguing-in-Publication Data

_

Baker, Tracey.

Practical cardiology : an approach to the management of problems in cardiology

Tracey Baker ; George Nikolic ́ ; Simon O’Connor.

Publisher: Sophie Kaliniecki

Developmental Editor: Sunalie Silva

Publishing Services Manager: Helena Klijn

Edited by Caroline Hunter, Burrumundi Pty Ltd

Proofread by Tim Learner

Cover and internal design by DiZign

Index by Michael Ferreira

Typeset by TnQ Books and Journals Pvt Ltd

Printed in Hong Kong by 1010 Printing International Ltd

1999 when the first edition of this book was published. This edition, with a new publisher and 

a third author (George Nikolić), aims to bring the subject right up to date. Much has changed. Some  previous  recommendations  such  as  hormone  replacement  therapy  to  reduce  cardio-vascular  risk  have  been  reversed,  and  important  new  concepts  such  as  total  cardiovascular  risk have been introduced

No medical specialty has been so affected by the results of randomised trials. Some of the more  important  trials  have  been  listed  and  their  results  summarised.  References  have  been provided  throughout  the  book  for  important  management  recommendations.  Students  and medical staff are now expected to be able to back up their practice with evidence. We hope this book will make that task easier

able for those beginning to learn about ECG interpretation. We have not tried to reproduce these but rather to provide a text for those with some basic knowledge that puts ECGs into their clinical context

There is a new chapter devoted to electrocardiography. There are many basic books avail-Other  cardiac  investigations  are  dealt  with  throughout  the  book  and  a  DVD  has  been  provided to enable readers to see them in the way they are interpreted—as video images.Case-based learning sections have been provided for each area of cardiology to help students 

to understand the principles of this teaching method

We  hope  this  modern  problem-  and  evidence-based  cardiology  text  will  be  helpful  to   doctors and students

Tracey BakerGeorge NikolićSimon O’ConnorCanberra, April 2008

ix

AFFIRM: Atrial Fibrillation Follow­up Investigation of Rhythm Management Olshansky B, 

Rosenfeld LE, Warner AL, et al. J Am Coll Cardiol 2004; 43:1201–1208. This trial assessed the efficacy of rate control for patients with AF, comparing beta-blockers and calcium channel blockers in 2027 patients. Beta-blockers were more effective

APSIS: Angina Prognosis Study in Stockholm Forslund  L,  Hjemdahl  P,  Held  C,  et  al.  

Eur Heart J 2000; 21:901–910. In this study patients with angina (n = 731) and a positive 

exercise  test  were  randomised  to  treatment  with  verapamil  or  a  beta-blocker  and  then performed another exercise test. The maximal ST depression and the exercise duration were independent predictors of outcome over the following 40 months. 

ARTS: Arterial Revascularisation Therapy Study Serruys P, et al. N Engl J Med 2001; 344: 

1117–1124. This trial studied the effectiveness of CABG compared with angioplasty and bare metal stenting for diabetics with multi-vessel coronary disease. Diabetics in the CABG arm had a better outcome than those having angioplasty

ASSENT-2:  Assessment of the Safety and Efficacy of a New Thrombolytic–2.  ASSENT-2 

investigators. Lancet 1999; 354:716–722. This trial compared tenectoplase and alteplase for 16,949  patients  with  acute  myocardial  infarction.  There  was  no  difference  in  mortality  at  

30 days and one year between the two groups

BAATAF: Boston Area Anticoagulation Trial for Atrial Fibrillation The  Boston  Area 

Anticoagulation Trial for AF Investigators. New Engl J Med 1990; 323:1505–1511. Warfarin with a target INR of 1.5–2.7 was effective in preventing stroke in 212 AF patients compared with 208 AF patients treated with aspirin or nothing. The risk reduction was 86%. 

CAPRIE: Clopidogrel vs Aspirin in Patients at Risk of Ischaemic Events CAPRIE Steering 

committee. Lancet 1996; 348:1329–1339. The combined risk of stroke, infarction or vascular death was compared for 19,185 patients with vascular disease on treatment with aspirin or clopidogrel. There was a reduction in combined risk for the clopidogrel group, who also had 

a lower risk of gastrointestinal side effects. 

CARE­HF: Cardiac Resynchronisation­Heart Failure Cleland JG, Daubert JC, Erdmann E, et al. 

Cardiac Resynchronisation-Heart Failure Investigators. The effect of cardiac resynchronisation 

on morbidity and mortality in heart failure. N Engl J Med 2005; 352:1539–1549. Patients with severe heart failure were randomised to optimal conventional heart failure treatment 

or  optimal  treatment  and  CRT.  CRT  improved  symptoms,  and  reduced  the  frequency  of hospital admissions and mortality. 

xi

CASS: Coronary Artery Surgery Study CASS Investigators. New Engl J Med 1984; 310:750–758. 

This  open  label  study  looked  at  780  randomised  patients  with  mild  angina  or  who  were asymptomatic  after  infarction  to  CABG  or  medical  treatment  for  six  years.  There  was  no difference in the survival rate. 

CHARM—Alternative: Candesartan in Heart Failure; Assessment of Reduction in Mortality and Morbidity—Alternative Granger CB, McMurray JJV, Yusef S, et al. Lancet 2003; 362: 

772–776.  This  angiotensin  receptor  antagonist  was  successful  in  reducing  morbidity  and cardiovascular mortality in patients with chronic heart failure who were intolerant of ACE inhibitors. 

CHARM—Added: Candesartan in Heart Failure; Assessment of Reduction in Mortality and Morbidity—Added McMurray JJV, Ostergren J, Swedberg J, et al. Lancet 2003; 362: 

CIBIS II: Cardiac Insufficiency Bisoprolol Study II. The CIBIS scientific committee. Lancet 

1999; 353:9–13. In this study of the treatment of heart failure with bisoprolol, 2647 patients were treated with the drug or a placebo for a period of one to three years. All-cause mortality 

was 11.8% in the treated group and 17% in the placebo group (P < 0.0006). 

CIBIS III:  Cardiac Insufficiency Bisoprolol Study III.  Willenheimer  R,  et  al.  Circulation 

2005;112:2426–2435.  In  this  heart  failure  trial,  initiation  of  treatment  with  bisoprolol followed by enalapril was compared with the opposite (conventional) sequence. There were  

505 patients in each group and outcomes were the same at 1.22 years. 

CLARITY–TIMI 28:  Clopidogrel as Adjunctive Reperfusion Therapy.  Sabatine  MS,  et  al.  

Am Heart J 2005; 149:222–233. In this trial, 3491 patients with an acute ST elevation myocardial infarction and having standard reperfusion treatment were given a 300 mg loading dose of clopidogrel and then 75 mg a day in addition to aspirin or a placebo and aspirin. At 30 days the clopidogrel group had a significantly lower risk of death or re-infarction (CI 0.21–0.65). 

CLARITY: Clopidogrel as Adjunctive Reperfusion Therapy­Thrombolysis in Myocardial Infarction Sabatine MS, Cannon CP, Gobson M, et al. N Engl J Med 2005; 352. In this study 

the addition of clopidogrel to aspirin and fibrinolytic therapy for patients with an acute ST elevation infarct improved the patency rate and reduced ischaemic complications

COBRA: Association Between Erectile Dysfunction and Coronary Artery Disease Role of Clinical Presentation and Extent of Coronary Vessels Involvement: The Cobra Trial

Montorosi  P,  Ravagnani  PM,  Galli  S,  et  al.  Eur  Heart  J  2006;  27:2632–2639.  Erectile dysfunction as assessed by a questionnaire was present some years before clinical coronary disease in these patients

COMPANION: Comparison of Medical Therapy, Pacing and Defibrillation in Chronic Heart Failure Bristow MR, Feldman AM, Saxon LA, et al. N Engl J Med 2004; 350:2140. This study 

looked  at  cardiac  resynchronisation  therapy  with  or  without  an  implantable  defibrillator  in advanced chronic heart failure. Resynchronisation treatment in these heart failure patients reduced mortality and the frequency of hospital admissions compared with normal pacing. Patients whose resynchronisation pacemaker was also a defibrillator had a lower mortality again

CONSENSUS: Cooperative North Scandinavian Enalapril Survival Study N  Engl  J  Med 

1987;  316:1429–1435;  Circulation  1990;  82:1730–1736;  Am  J  Cardiol  1990;  66:40D–45D; 

Am J Cardiol 1992; 69:103–107. This trial of enalapril in severe heart failure showed a 27% reduction in mortality at 12 months compared with the placebo. 

DASH: Dietary Approaches to Stop Hypertension Moore TJ, Volmer WM, Appel LJ, et al. 

fat dairy products significantly reduced blood pressure in hypertensive patients compared with a control diet low in fruit and vegetables and high in dairy fats

Hypertension 1999; 34:472–477. In this study a combination diet rich in vegetables and low-DAVITT II: Danish Verapamil Infarction Trial II The Danish Study Group on Myocardial 

Infarction.  Am  J  Cardiol  1990;  66:779–785.  This  study  showed  long-term  treatment  with verapamil reduced major ischaemic events after myocardial infarction

DIG: Digitalis Investigation Group Trial Rich MW, McSherry F, Williford WO, et al. J Am 

Coll Cardiol 2001; 38:806–813. This trial of heart failure randomised 7788 patients with heart failure to digoxin or a placebo and usual treatment. The treated group had a 27% reduction 

in admission for heart failure and a 7% overall reduction in hospital admission. There was 

no difference in mortality

EAFT: European Atrial Fibrillation Trial EAFT Study Group. Lancet 1993; 342:1255–1262. This 

study compared aspirin and warfarin for the prevention of recurrent stroke in patients with non-rheumatic AF. The risk of stroke was reduced from 12% to 4% per year with warfarin

EPHESUS: Eplerenone Post­AMI Heart Failure Efficacy and Survival Study Pitt B, Remme W,  

Zannad  F,  et  al.  Eplerenone,  a  selective  aldosterone  blocker,  in  patients’  left  ventricular dysfunction  after  myocardial  infarction.  N  Engl  J  Med  2003;  348:1309–1321.  This  study showed  improved  outcomes  for  patients  treated  with  eplerenone  shortly  after  extensive myocardial infarction

Four S: Scandinavian Simvastatin Survival Study Scandinavian  Simvastatin  Survival  Study 

Group. Lancet 1994; 344:1383–1389. This important trial with 4444 patients showed a survival advantage for patients with coronary artery disease who were treated with a statin

FRISC: I FRagmin and Fast Revascularisation During Instability in Coronary Artery Disease Study FRISC-I Investigators. Lancet 1999; 354:708–715. FRISC II 1 year: FRagmin and Fast Revascularisation During Instability in Coronary artery Disease Study FRISC Investigators. 

Lancet  2000;  356:9–16.  These  studies  showed  a  significant  reduction  in  death,  recurrent infarction and hospital readmission for patients with unstable angina when they were treated with early intervention

GUSTO V Global Utilisation of Streptokinase and t­Pa for Occluded coronary arteries V

Topol EJ. The GUSTO Investigators. Lancet 2001; 357:1905–1914. In this trial of ST elevation infarction patients, reduced dose fibrinolytic treatment combined with glycoprotein IIb/IIIa inhibition was compared with standard fibrinolytic treatment. There was no difference in 30-day mortality

Heart Protection Study Heart Protection Study Collaborative Group. Lancet 2002; 360:7–22. In 

this study high-risk patients (previous IHD or multiple risk factors) up to the age of 80 were treated with simvastatin. Patients with average cholesterol levels were included. There was a 25% reduction in events over five years regardless of initial cholesterol level, age or sex. 

HERS II Heart and Estrogen/progestogen Replacement Study Shlipak  MG,  Chaput  LA, 

Vittinghoff E, et al. Am Heart J 2003; 146:870–875. In this part of the HERS studies, changes 

in lipid levels associated with HRT were not predictive of cardiovascular outcome

HOT: Hypertension Optimal Treatment Study Zanchetti A, Hansson L, Menard J, et al. Risk 

assessment and treatment benefit in intensively treated hypertensive patients of the Hypertension Optimal Treatment (HOT) study for the HOT study group. J Hypertens 2001; 19:819–825. In this study, maximum reduction in cardiovascular mortality occurred at blood pressures of about 139/87. However, there was no increase in mortality at blood pressure levels below this. 

IONA: Impact of Nicorandil in Angina The IONA Study Group. Lancet 2002; 359:1269–1275. 

In this study of 5126 patients with stable angina, in the group treated with nicorandil there was a significant improvement in the composite endpoint of death, non-fatal infarction and hospital admission with angina

LIFE: Losartan Intervention for Endpoint Reduction Study Daholf  B,  Devereux  RB, 

Kjeildsen SE,  et  al.  Lancet  2002;  359:995–1003.  In  this  trial  more  than  9000  hypertensive patients with LVH were treated with losartan (an ARA) or atenolol (a beta-blocker). There was similar reduction in blood pressure but the losartan group had fewer non-fatal strokes and a 25% reduction in the new onset of diabetes. 

LIPID: Long­Term Intervention with Pravastatin in Ischaemic Disease Study LIPID 

Investigators.  Am  J  Cardiol  1995;  76:474–479;  N  Engl  J  Med  1998;  339:1349–1357.  In this study 9000 patients with recent infarction of an acute coronary syndrome and a total cholesterol  level  of  4–7  mmol/L  were  randomised  to  treatment  with  this  statin  or  dietary advice. There was a relative risk reduction in death of 24%, as well as a significant reduction 

in further ischaemic episodes, for those patients treated with the statin. 

MADIT II: Multi­centre Automatic Defibrillator Implantation Trial II Moss AJ, Zareba W, 

Hall WJ, et al. New Engl J Med 2002; 346:877–883. In this trial 1232 patients with previous infarction and an ejection fraction of less than 30% were randomised to medical treatment or 

a defibrillator. There was a 4.5% relative risk reduction in death for the defibrillator group at 

20 months. These were patients who had not had documented ventricular arrhythmias. 

MERIT-HF: Metoprolol CR/xL Randomised Intervention Trial in Heart

Failure. The MERIT-HF study group. JAMA 2000; 283:1295–1302. In this trial, 3991 patients with heart failure (NYHA class II–IV) were treated with slow-release metoprolol or a placebo in addition to conventional treatment. The trial was ended after one year because of a significant reduction 

in all-cause mortality (7.2% vs 11% per patient year). This was a relative risk reduction of 0.60

MUSTT: Multi­centre Unsustained Tachycardia Trial Buxton AE, Lee AL, Fisher JD, et al. 

A randomised  study  of  the  prevention  of  sudden  death  in  patients  with  coronary  artery disease. N Engl J Med 1999; 341:1883–1890. In this trial patients with inducible VT, coronary artery  disease  and  an  ejection  fraction  less  than  40%  were  randomised  to  EPS-guided drug treatment or no treatment. Patients who had inducible arrhythmias had a small but significantly different decrease in overall mortality and arrhythmic death when treated with anti-arrhythmic drugs guided by EPS

PEP­CHF: The Perindopril in Elderly People with Chronic Heart Failure PEP investigators. 

Eur Heart J 2006; 27:2338–2345. This trial of an ACE inhibitor in patients with heart failure and a preserved ejection fraction showed improved exercise tolerance and fewer admissions to hospital for treated patients, but was not sufficiently powered to show a mortality benefit

PROGRESS: Perindopril Protection Against Recurrent Stroke Study PROGRESS Collaborative 

Study  Group.  Lancet  2001;  358:1033–1041.  This  randomised  trial  of  a  perindopril-based blood pressure-lowering regimen among 6108 individuals with previous stroke or transient ischaemic attack showed a significant reduction in stroke recurrence in treated patients. 

SAVE: Survival and Ventricular Enlargement Study Rutherford JD, Pfeffer MA, Moye LA, et al. 

Circulation 1994; 90:1731–1738. In this study, patients with asymptomatic left ventricular dysfunction had a better prognosis when treated with captopril than the placebo. 

SCD­HeFT: Sudden Death in Heart Failure Trial Bardy GH, Lee KL, Mark DB, et al. New 

Engl J Med 2005; 352:225–237. This trial compared the anti-arrhythmic drug amiodarone, 

a placebo and an ICD for patients with an ejection fraction of less than 35%. Follow-up was for 45 months. ICD treatment reduced mortality by 23%; amiodarone was no different from the placebo. 

SOLVD: Studies of Left Ventricular Dysfunction SOLVD Investigators. N Engl J Med 1991; 

325:293–302. This study looked at the effect on survival of enalapril in patients with a reduced left ventricular ejection fraction (< 35%) and congestive heart failure. In the treatment arm 

of the trial there was a 16% relative risk reduction of death. 

SPAF I: Stroke Prevention in Atrial Fibrillation SPAF  Investigators.  Circulation  1991;  83: 

527–539.  This  study  compared  a  placebo,  aspirin  and  dose-adjusted  warfarin  for  primary prevention of stroke or thromboembolism in patients with non-rheumatic atrial fibrillation. Follow-up was for three years. Warfarin reduced the risk by 67% compared with the placebo, and aspirin reduced it by 42%. Annual event rates were 2.3%, 3.6% and 7%, respectively, for warfarin, aspirin and the placebo. 

SPAF II: Stroke Prevention in Atrial Fibrillation SPAF Investigators. Lancet 1994; 343:687–691. 

This trial compared aspirin and warfarin for the prevention of embolic events in patients with 

AF. Warfarin reduced the absolute event rate by 0.7% a year

SPORTIF V: Stroke Prevention Using an Oral Thrombin Inhibitor in Atrial Fibrillation V

SPORTIF Investigators. JAMA 2005; 293:690–698. The oral thrombin inhibitor ximelagatran was  compared  with  warfarin  in  this  high-risk  AF  group.  Ximelagatran  was  as  effective  as warfarin in preventing stroke. However, the drug has been withdrawn by the manufacturer because of concerns about hepato-toxicity

STAF: Strategies of Treatment of Atrial Fibrillation Carlson J, Miketic S, Windeler J, et al. 

J Am Coll Cardiol 2003; 41:1690–1696. This trial compared rate control with rhythm control for patients with AF. There was no difference between the groups in risk of death, stroke or embolic event

TIBET: Total Ischaemic Burden European Trial Fox KM, Mulcahy D, Findlay I, et al. Eur Heart J  

1996; 17:96–103. In this trial patients with mild chronic angina were treated with atenolol, nifedipine or both (c. 200 patients in each arm). Combination treatment was more effective than either drug alone in improving exercise capacity. 

TNT: Treating to New Targets Trial Waters  DD,  Guyton  JR,  Herrington  DM,  et  al.  Does 

lowering low density lipoprotein in cholesterol levels below currently recommended guidelines yield incremental clinical benefits? Am J Cardiol 2004; 183:154. This trial was positive for patients with a high risk of further cardiac events

UKPDS: UK Prospective Diabetes Study UKPDS  Group.  Lancet  1998;  352:837–853.  This 

important  trial  compared  macrovascular  and  microvascular  complications  of  diabetes  in patients  randomised  to  intensive  blood  glucose  control  and  those  with  usual  treatment. Those in the intensive group had a reduction in microvascular complications of 25% over 

10 years but there was not a significant reduction in macrovascular complications though the reduction in risk of myocardial infarction came close to being significant. 

ValHeFT: Valsartan Heart Failure Trial Cohn  JN,  Tognoni  G N  Engl  J  Med 2001;  345: 

1667–1675. In this trial valsartan, an ARA, was compared with usual treatment for heart failure 

in patients with NYHA class II–IV heart failure. There was no difference in mortality overall between the groups but when compared against those patients not on an ACE inhibitor or beta-blocker there was an improvement in the valsartan group. 

learning

Many medical schools have adopted an integrated approach to aspects of teaching, whereby a patient with an important medical problem is chosen as a way of teaching different aspects of a disease process and its effect on the patient and society. A single case can be used for the teaching 

of anatomy, pathophysiology, history taking, physical examination, appropriate investigations and management of the condition. Students are also expected to understand the epidemiology, 

as well as ethical implications of the disease and its management

The usual approach is for a student to be chosen to lead the discussion and prepare the topic. A tutor is present to help keep the discussion directed, but most of the questioning of the group is done by the nominated student. The whole group is given the topic in advance and should prepare for the tutorial

In the clinical years the tutorial is based on a patient who has been seen by the nominated student. The student takes a detailed history and examines the patient. Access to the patient’s test results is usually permitted and relevant results (e.g. blood tests, X-rays and reports) are brought to the tutorial for discussion. 

We  have  included  examples  of  case-based  learning  presentations  in  important  areas  of cardiology. The aspects of the condition that need discussion are outlined. Not all the answers are provided, but areas that need research are indicated. Our hope is that these sections will help both student presenters and the rest of the group to profit from this important learning exercise

xxi

Class IIa Weight of evidence/opinion is in favour of usefulness/efficacy.

Class IIb Usefulness/efficacy is less well established by evidence/opinion

Level III-1 (B) Well designed pseudo-randomised trials (e.g. alternate allocation)

Level III-2 (B) Comparative studies, cohort studies, case-controlled studies

Level III-3 (C) Comparative studies with historical control, two or more single arm 

studies

xxiii

of risk factors have the potential to prevent much of this mortality.

Although the precise cause of coronary artery disease is not known, researchers have identified a number of risk factors that increase a person’s chance of developing symptomatic ischaemic heart disease (IHD) These risk factors have been identified on the basis of epide-miological research and, in most cases, probable or definite mechanisms of action have been demonstrated for these effects The concept of risk factors did not exist until the 1960s when data from the Framingham study began to emerge

An assessment of a patient’s risk factors for coronary disease is an important part of the management of cardiac symptoms The presence of risk factors makes symptoms suggestive

of coronary disease more significant However, risk factors do not predict acute ischaemia.1

Furthermore, the classic risk factors accounted for only 50% of the overall risk in the original Framingham cohort.2 More recent evaluation using additional factors may have increased the predictive value of risk factors.3

Everyone should at some stage have his or her cardiac risk factors assessed Patients senting with or without cardiac symptoms need periodic re-evaluation of their risk factors Much of this can be done by brief history taking and some simple investigations This provides

pre-an opportunity to make a decision about the overall or total risk for the patient pre-and to give appropriate advice and treatment

The causes of coronary symptoms

The symptoms of coronary artery disease are caused by the reduction of myocardial perfusion that results from narrowing of the lumen of one or more of the coronary arteries This narrowing

is most often the result of atherosclerosis Other much less common causes include:

1 coronary artery spasm (p 146) (often in an already diseased segment of artery but sometimes

as a result of the use of cocaine)

2 thrombosis (usually on an already diseased, or occasionally aneurismal, segment)

3 embolism (e.g from an infected aortic valve)

4 congenital coronary abnormality

5 vasculitis.

Numerous other cardiac symptoms and problems can be the eventual result of atheromatous coronary disease These include myocardial infarction (Ch 4), cardiac failure (Ch 7), cardiac arrhythmias (Ch 6) and some cardiac valve problems

Risk factor mechanisms of action

Atherosclerosis is thought to result primarily from a disturbance of the vascular endothelium The final common pathway for the effects of endothelial dysfunction is largely through abnor-malities of nitric oxide (NO) production This chemical, released by a healthy endothelium, is

a potent vasodilator and has anti-inflammatory and other favourable actions on the arteries

Causes of this disturbance can be:

n mechanical (hypertension)

n chemical (oxidised lipids, components of cigarette smoke, hyperinsulinaemia) or

n due to immunological injury

The damaged endothelium attracts inflammatory mediators, platelets and circulating lipids and promotes fibroblast and smooth muscle proliferation This results in the formation of a plaque, which may narrow the arterial lumen

Plaques can remain stable (or sometimes regress), enlarge, rupture or erode (more common

in diabetics) Most acute ischaemic events (acute coronary syndromes or acute myocardial infarctions) are thought to be the result of further luminal narrowing caused by the formation

of partly or fully occlusive thrombus on a ruptured or eroded plaque Coronary risk factors may therefore operate because they are atherogenic or thrombogenic

Plaque rupture

Plaque rupture may be at least partly an inflammatory process involving inflammatory cells,

cytokines and even bacteria This may explain the association between inflammatory markers such as high-sensitivity C reactive protein (hsCRP) and a risk of acute coronary events Although this association seems well established, there is still uncertainty about its role in overall risk assessment (p 21).4

Plaques at risk of rupture are called vulnerable plaques They typically have a thin fibrous

cap The shoulder regions (Fig 1.2 on p 6) of these caps are at risk of rupturing and ing material from within the plaque to come in contact with the blood stream This material

allow-is intensely thrombogenic Stable fibrous plaques are much less likely to rupture in thallow-is way Efforts are underway to develop tests that can identify vulnerable plaques This is not yet pos-sible, but multi-slice CT scanning and possibly MRI angiography may increasingly be able to provide information about plaque composition

Fig 1.1 on p 4) or cardiac risk (systematic coronary risk evaluation system or SCORE charts) These charts can be very helpful in deciding when intervention to reduce risk is warranted; for example, when anti-hypertensive treatment should be commenced for a patient with mild blood pressure elevation

Risk factor reduction involves assessing the presence, severity and importance of risk factors for a patient, and modifying these where possible Because the risk factors have a multiplicative effect, modest reduction in a large number of factors may lower the risk more than aggressive lowering of one factor Put another way, someone with a number of mild risk factors may be

at more risk than someone with one moderate risk factor For example, a man with a systolic blood pressure of 180 mmHg, a cholesterol of 5 mmol/L and who smokes has a 10% 10-year mortality risk on the SCORE risk chart published by the European Society of Cardiology (ESC),5

whereas a non-smoking man with a blood pressure of 140 mmHg and a cholesterol of 7 mmol/L has a 5% 10-year mortality risk Such charts may help convince patients of the need to control multiple risk factors

It must be remembered that the strongest risk factor for ischaemic coronary events is known coronary disease Thus the absolute benefits of risk reduction are greatest for a patient with

coronary disease (secondary prevention) (Table 1.2) Asymptomatic individuals with risk factors

are the targets for attempts at primary prevention Some risk factors are unalterable, such as age,

sex and family history

The importance of risk factor control can be seen in the estimates of reduction in coronary events shown in Table 1.3

Existing vascular disease

A history of previous myocardial infarction, angina, cerebrovascular disease or peripheral rial (vascular) disease is the major risk factor for future coronary events Risk factor control is

arte-of the utmost importance for such patients who have, on average, a 20% risk arte-of further events

in the following 10 years

Age

Eighty per cent of fatal myocardial infarcts occur in patients over the age of 65 Age alone is therefore not a reason to ignore other risk factors, although obviously the patient’s likely life expectancy may influence treatment Not all interventional trials have included elderly patients, but those that do have shown benefit The prognosis for elderly patients who have a significant ischaemic event is worse than for younger patients and they therefore have more to gain from treatment that may reduce the incidence of these events

Family history

A family history of coronary heart disease (CHD) is an independent risk factor when other factors such as dyslipidaemia and hypertension are excluded Coronary heart disease in a first-degree

Table 1.1 Important coronary risk factors

1 Existing vascular disease (coronary, cerebral or peripheral)

17 Abnormal CT calcium score/coronary angiogram

18 Left ventricular hypertrophy (hypertensive patients)

19 Abnormal carotid intima-media thickness

Figure 1.1 NHF risk assessment chart

relative (sibling or parent) under the age of 65 for a female relative or 55 for a male relative confers

a 2.5 times relative risk It is important to find out what relatives were affected, their age and how definite the diagnosis was A possible stroke in a 90-year-old uncle is not especially important

Dyslipidaemia

Many trials have shown that the risk of coronary artery disease is proportional to the total serum cholesterol and low-density lipoprotein (LDL) levels and inversely proportional to the high-density lipoprotein (HDL) levels A raised triglyceride level is, on its own, only a modest risk factor but becomes more important when associated with high serum cholesterol

Table 1.2 Treatment priorities

1 People with established vascular disease

2 Asymptomatic people at high risk

(a) People with multiple risk factors: > 5% 10-year mortality risk

(b) People with severely abnormal single risk factors: cholesterol > 8 mmol/L, low-density lipoprotein > 6, blood pressure > 180/110 mmHg

(c) People with diabetes

3 People with adverse family history

4 All other patients seen in routine practice

In general, studies such as the 4S Trial have shown that a 10% reduction in total cholesterol over three years confers a 20% reduction in ischaemic events and that the benefit increases with the duration of treatment.12 This benefit occurs in both symptomatic (secondary prevention) and asymptomatic (primary prevention) patients The lipid trials show a greater reduction in ischaemic events when cholesterol is lowered than when hypertension is controlled The converse

is true for cerebrovascular disease

Cholesterol lowering slows the progression of atheroma and may be associated with regression

of atheromatous lesions However, the reduction in the occurrence of ischaemic events is greater and occurs earlier than would be expected from the relatively minor changes in the angiographic appearances of the coronary plaques of treated patients The most likely explanation of this benefit

is that a lower serum cholesterol changes the lipid content of atheromatous plaques and makes them more stable This means they are less likely to rupture and attract thrombus (Fig 1.2).Improvement in endothelial function and vascular reactivity has also been demonstrated after cholesterol lowering

Total cholesterol and LDL seem to have a weaker association with coronary artery disease

in women than in men, and even then only up to the age of 65 The benefit of treatment has been shown for patients at least to the age of 80 and includes men and women Patients in all age groups who have a high total risk (i.e other risk factors) benefit, even if they have not had

an ischaemic event (primary prevention).13

Some early trials conducted before the availability of statins appeared to show an association between treatment and increased mortality from non-cardiac causes, but this seems not to be caus-ative and the association has not been seen in the later very large cholesterol lowering trials

Table 1.3 Average reductions in coronary events (benefits are greatest in patients with highest total risk)

1 Smoking cessation: 50% reduction in coronary events 6

2 Low-dose aspirin in high-risk patients: 25% reduction in coronary events 7

3 20% reduction in total cholesterol with statin treatment: 30% reduction in coronary events 8

4 Treatment with pravastatin after acute coronary events: 22% reduction in mortality 9

5 5–6 mmHg reduction in blood pressure: 15% reduction in coronary events

(40% risk reduction for stroke) 10

6 30 minutes of moderate exercise a day: 18% reduction in coronary events 11

Thrombus projecting into the lumen Lipid core Large lipid core

Lipid-rich core

Shoulder region

Shoulder region Thin fibrous cap with

inflammatory cells

Thick fibrous cap composed of collagen and smooth muscle

Lumen Lumen Lumen

Rupture at the shoulder

of the thin fibrous cap

a

b

c

plaque and (c) plaque rupture

An overview of lipid metabolism

As shown in Figure 1.3, the function of serum lipoproteins is to transport dietary and enous triglycerides and cholesterol Dietary triglycerides and cholesterol are incorporated into chylomicrons in the intestinal epithelium From here, they are sent to peripheral tissues, are acted on by the enzyme lipoprotein lipase and the triglycerides are broken down to release fatty acids that are used by adipose and muscle cells The remaining lipoprotein fragment, the chylomicron, enters the circulation and contains mainly cholesterol It is delivered to the liver where the cholesterol is either converted to bile acids, excreted directly in bile or redistributed

endog-to other tissues

Endogenous lipid production

Excess carbohydrate is used to make triglycerides in the liver These are secreted as very density lipoproteins (VLDL) and are acted on by lipoprotein lipase in peripheral tissues to remove the triglycerides, leaving cholesterol-rich low-density lipoproteins LDL carries choles-terol to peripheral tissues where it is used for membrane synthesis, steroid synthesis and bile acid production in the liver itself As cell membranes and lipoproteins break down, the cholesterol

low-is released into plasma and carried on HDL

Low-density lipoproteins

Sixty to seventy per cent of total cholesterol is transported as LDL, and total cholesterol measurements usually reflect LDL levels In both males and females, coronary heart disease risk is proportional to LDL and total cholesterol As seen above, LDL supplies cholesterol to peripheral tissues High concentrations of LDL in the serum accelerate atheroma by interacting with damaged endothelium Oxidation of LDL accelerates this process

A total cholesterol of 5.5 mmol/L, or LDL of 3.5 mmol/L, is usually considered the upper limit of normal but even these levels seem to be responsible for an increased population risk of atheroma Populations with lower average levels than these have less coronary disease Lower levels are beneficial for patients with established coronary disease or multiple risk factors

It is not yet clear whether the lowering of total cholesterol to less than 4.0 (LDL 2.0) provides further benefit or whether a target level is indeed the correct approach Trials of more aggressive cholesterol lowering are underway.14 Although a reduced HDL level (< 1) is associated with increased risk, there is no evidence as yet that raising HDL has beneficial effects An elevation of triglyceride levels (> 1.7) is also considered a marker of increased risk, but there is no evidence

to what level they should be reduced

Endogenous Exogenous

Chylom.

(TG & Chol.)

LDL receptor tissues

HDL and FFA

Endogenous chol.

Endothelium (Lipoprotein lipase) Endothelium

(Lipoprotein lipase) FFA

to adipose tissue and muscles to adipose tissue and muscles

Chol = cholesterol; FFA = free fatty acids; HDL = high-density lipoprotein; IDL = intermediate-density lipoprotein; LCAT = lecithin cholesterol acyltransferase; monog = monoglyceride; TG = triglycerides; VLDL = very low-density lipoprotein.

Total cholesterol and LDL levels can be affected by many factors (Table 1.4).

Very high LDL and total cholesterol levels can be associated with clinical signs such as tendon xanthomas (often on the dorsum of the hands), eruptive xanthomata (on the elbows and knees) and xanthelasma (fatty deposits around the eyes) (Fig 1.4)

Acute illness, such as myocardial infarction or an intervention such as coronary artery bypass grafting, can be associated with reduced cholesterol levels for 1–2 months LDL and total cholesterol levels are not affected by fasting

LDL levels are calculated according to the following formula: LDL = total cholesterol – HDL – (0.45 × triglycerides) This formula is not accurate when triglycerides are greater than

4 mmol/L

Cholesterol levels are physiologically increased in pregnancy, and their measurement during pregnancy is not useful

Table 1.4 Factors that affect LDL levels

1 High intake of saturated fat

2 High intake of dietary cholesterol (less

important than saturated fat intake)

3 Diuretics

4 Cyclosporine

5 Some progestogens

6 Secondary causes: anorexia nervosa,

hypothyroidism, Cushing’s syndrome,

porphyria, primary biliary cirrhosis

1 High intake of omega-3 fatty acids (fish, olive oil, canola)

2 High intake of soluble dietary fibres (legumes)

3 High intake of dietary anti-oxidant nutrients (oxidation may make existing LDL more atherogenic)

4 Plant sterols

High-density lipoproteins

HDL levels have an inverse relationship to coronary events in both men and women Those patients with an HDL level less than 0.9 have an eightfold increase in coronary events over those patients with a level greater than 1.5 mmol/L, when other factors are controlled HDL levels reflect the breakdown of triglycerides and LDL, and HDL levels are usually inversely related to triglyceride levels

The ratio of total cholesterol to HDL is important, especially when total cholesterol is in the

‘equivocal’ range of 5.5–6.5 mmol/L Total cholesterol/HDL should be less than 5 This ratio has been incorporated into a number of risk assessment tables, such as SCORE

A low HDL suggests the need to lower LDL and correct those factors that lower HDL (Table 1.5)

Triglycerides

The independent effect of triglyceride levels is weak, and high triglyceride levels are often ated with other risk factors (e.g low HDLs) Secondary causes of high triglycerides (Table 1.6) are common and confuse the picture, as does the fact that serum levels can vary greatly with fasting and recent alcohol intake

associ-The combination of high triglycerides and elevated LDL (combined dyslipidaemia) is ciated with a marked increase in coronary disease risk Isolated extremely high triglycerides (greater than 15 mmol/L) are a risk factor for pancreatitis rather than vascular disease.Modest elevations of triglycerides can usually be managed by weight control, a reduction in alcohol consumption and changes in medication

asso-Table 1.5 Factors that affect HDL levels

1 Oestrogen

2 Exercise

3 Small amounts of alcohol (10–20 g

per day in men)

Patterns of dyslipidaemia

Dyslipidaemia can be:

n sporadic (the most common cause)

n inherited (Table 1.7)

n secondary (Table 1.8)

There are different patterns of dyslipidaemia classified according to the lipoprotein abnormality and which lipids are abnormal These are not as important for management as they once were, but the choice of treatment may still be influenced by the pattern of the abnormality (Table 1.7).Secondary causes of dyslipidaemia should be considered if the dyslipidaemia is severe and does not respond to dietary measures (Table 1.9)

Table 1.7 Patterns of dyslipidaemia

III Chylomicrons, IDL Trig., chol Very rare

Table 1.8 The genetic dyslipidaemias

Familial

chylomicronaemia

Lipoprotein lipase defect

Chylomicrons Eruptive

xanthomata Pancreatitis

Familial

chylomicronaemia

Apolipoprotein CII deficiency

Chylomicrons, VLDL

Pancreatitis I, V None Familial type III

(dysbetalipo-proteinaemia)

Apolipoprotein BIE receptor deficiency

Chylomicron remnants

Eruptive xanthomata Atherosclerosis

III IIa, IIb IV

Fibrates Statins Nicotinic acid Familial hyper-

cholestrolaemia

(AUTO DOM

1:1500)

Deficient LDL receptor

VLDL Xanthomata IV Fibrates

Nicotinic acid Multiple

lipoprotein

hyperlipidaemia

Defect unknown

LDL, VLDL Atherosclerosis IIa, IIb

IV

Fibrates Nicotinic acid Statins

AUTO DOM = autosomal dominant inheritance; LDL = low-density lipoproteins; VLDL = very low-density

lipoproteins.

Treatment of dyslipidaemia

The important components of a treatment program for dyslipidaemia are as follows:

1 calculate the patient’s total risk

2 reduce the patient’s weight (reduces triglycerides, cholesterol)

3 increase the patient’s exercise activity (increases HDL, aids weight management)

4 modify the patient’s diet, as follows:

• ensure maximum of 30% kJ from fat

• ensure maximum of 30% fat as saturated fat

• increase plant and fish sources of fat

• increase anti-oxidant nutrients from food

• reduce alcohol intake if triglyceride level or blood pressure is high

5 treat secondary causes (drugs, diabetes, hypothyroidism)

6 modify other risk factors (e.g smoking) to reduce overall risk

7 consider drug treatment.

By ranking patients according to their risk of future coronary events it is possible to tailor ment (especially drug treatment) appropriately This is the basis for the current recommendations for lipid management in the Pharmaceutical Benefits Schedule This rather complicated schedule tries to take into account the importance of combinations of risk factors (Table 1.10)

treat-Drug treatment should be delayed in most patients without existing coronary disease until after six weeks to three months of dietary and lifestyle intervention, with the possible exception of those

at very high risk At present, the following drugs are used in the treatment of dyslipidaemia:

n statins (HMGcoA reductase inhibitors)

n absorption inhibitors

n resins

Table 1.9 Secondary causes of dyslipidaemia

Glucocorticoids LDL, VLDL

Nephrotic syndrome LDL, VLDL Hepatic Primary biliary cirrhosis LDL

Acute hepatitis VLDL Immune Systemic lupus

erythematosus (SLE)

Chylomicrons Monoclonal gammopathy Chylomicrons, VLDL Injury Burns, acute myocardial

infarction (AMI)

LDL

of follow-up.15 The WOSCOPS Trial demonstrated reduced cardiovascular risk for men with raised cholesterol but without previous cardiac events who were treated with pravastatin.16 The AFCAPs/TexCAPS Trial showed a reduced risk of a first ischaemic event for men and women with average cholesterol levels.17

The currently available HMGcoA reductase-inhibitors are fluvastatin (20–40 mg per day), simvastatin (5–80 mg per day), lovastatin (10–80 mg per day), pravastatin (10–40 mg per day), artorvastatin (10–80 mg per day) and, the most potent, rosuvastatin (10–40 mg per day) Except for artorvastatin, these drugs should be taken at night

Table 1.10 Patient category criteria for drug treatment

1 Patients with existing vascular disease

Existing and symptomatic coronary artery

disease

Any cholesterol level Symptomatic peripheral vascular disease Any cholesterol level

Symptomatic cerebrovascular disease Any cholesterol level

2 Patients with diabetes

Microalbuminuria Any cholesterol level

Aboriginal or Torres Strait Islander descent Any cholesterol level

Other diabetics TC > 5.5 mmol/L

3 Patients with a family history of symptomatic coronary disease

Before age of 60 in one or more first-degree

relatives or before age of 50 in one or more

second-degree relatives

If < 18 yrs old – LDL > 4 mmol/L

Familial dyslipidaemia identified by DNA or

tendon xanthomata

If >18 yrs old – LDL > 5 or – TC 6.5 or

– TC >5.5 and HDL <1

4 Patients with low HDL

HDL < 1 mmol/L TC > 6.5

5 Patients with other risk factors

Aboriginal or Torres Strait Islander descent TC > 6.5 or

Hypertensive patients TC > 5.5 and HDL < 1

Action: These agents bind to hepatic HMGcoA reductase and thereby reduce

choles-terol synthesis

Use: Hypercholesterolaemia; combined dyslipidaemia

Effect: 30% or greater reduction in total cholesterol; 40% reduction in LDL; 10–15%

increase in HDL; 10–20% reduction in triglycerides

Side effects: Increase in transaminases and CK, usually in the first three months, and

generally asymptomatic; muscle pain in up to 5%; myositis in 0.2%, slightly more so in combination with nicotinic acid or fibrates

Combinations: Resins; use with caution with fibrates or nicotinic acid

Cholesterol absorption inhibitors

Ezetimibe is the only drug in this class available so far It is a selective cholesterol absorption inhibitor It binds to cholesterol in the small bowel and reduces cholesterol delivery to the liver It does not interfere with the absorption of fat-soluble vitamins and is well tolerated Cholesterol reduction of about 10% is obtained from a single daily dose of 10 mg It is very effective when used in combination with statins Fixed-dose combination tablets containing

10 mg of ezetimibe and 40 or 80 mg of simvastatin are available Trials have demonstrated effective lowering of cholesterol, but trials showing a reduction in mortality or coronary events are not yet available

Resins

Cholestyramine (8–24 g per day)/colestipol (10–30 g per day)

Action: Reduce reabsorption of bile acids in the gut, resulting in a compensatory

increase in bile acid synthesis, thus reducing serum LDL

Use: Hypercholesterolaemia

Effect: 10–20% reduction in total cholesterol

Side effects: Nausea; constipation; diarrhoea; flatulence

Fibrates

Gemfibrozil (600 mg bd)

Action: Activates lipoprotein lipase and increases biliary cholesterol secretion

Use: Hypertriglyceridaemia; mixed dyslipidaemia (especially in diabetics)

Effect: 50% reduction in triglycerides; reduces LDL; increases HDL

Side effects: Gallstones; rashes; leucopenia; impotence; potentiates warfarin; contraindicated

in severe renal disease

Combinations: Use with caution with statins (increased risk of myositis)

Fenofibrate (160 mg per day)

This drug is similar in its mode of action to gemfibrozil There is less risk of rhabdomyolysis when it is used with statins than for gemfibrozil but caution is still required The FIELD study

of diabetics with raised triglycerides and cholesterol did not show a significant reduction in the primary endpoint of coronary events in treated patients.18

Probucol

500 mg bd

Action: Reduces LDL, increases HDL, anti-oxidant

Side effects: Frequent diarrhoea; dyspepsia; ventricular ectopic beats

Nicotinic acid

0.5–2 g per day

Action: Reduces hepatic production of VLDL

Use: Hypercholesterolaemia, hypertriglyceridaemia, low HDL levels

Effect: 25% reduction in cholesterol levels; 50% reduction in triglyceride levels

Side effects: (Common and limiting) flushing (use aspirin, and a gradually increasing dose

may help); dyspepsia; increased BSL; increased uric acid; abnormal LFTs; sional hepatic failure; dry skin

occa-Combinations: Increased risk of myositis when combined with statins

Fish oils

2–4 g omega-3 fatty acids per day

Action: Reduces triglyceride production by the liver; can increase LDL

Use: Hypertriglyceridaemia

Effect: 50% reduction in triglycerides; equivocal effects on LDL

Side effects: Unpleasant taste; possibly prolonged bleeding time

Plant sterols

Plant sterols resemble cholesterol and may work by inhibiting the absorption of dietary and biliary cholesterol from the small bowel Sitostanol-ester margarine has been shown to reduce cholesterol levels by 10% when used in amounts from 1.8 to 2.6 g per day.19

Summary of treatment

n Hypercholesterolaemia: treat with statins, ezetimibe, sterols, cholestyramine, colestipol,

nicotinic acid The statins are clearly the most effective drugs for the treatment of cholesterolaemia They are well tolerated, safe and almost always the drug of first choice for these patients

hyper-n Combined dyslipidaemia: treat with cholestyramine, colestipol, gemfibrozil (especially if

triglycerides > 3), nicotinic acid The statins are moderately useful for reducing triglycerides The newer drugs (e.g artorvastatin) are quite potent and may be very suitable for patients with combined dyslipidaemia

n Hypertriglyceridaemia: treat with gemfibrozil, nicotinic acid (caution needed in diabetics),

Smoking cessation is associated with a rapid decline in death rates from coronary disease, probably because of smoking’s thrombogenic effects Smoking seems less important as a risk factor in populations with low LDL levels

Table 1.11 Some effects of smoking

1 Increased atherogenesis, probably by toxic injury to endothelial cells

2 Hypoxia, resulting in intimal proliferation

Nicotine replacement patches may be helpful and appear safe even for patients with ischaemic heart disease The drug bupropion, which is a non-tricyclic antidepressant, is now available for patients who wish to stop smoking This drug seems safe for patients with cardiac disease, at least for those without unstable symptoms It does not cause conduction abnor-malities or increase the risk of ventricular arrhythmias Patients should be advised to continue smoking when they first start the drug but plan to stop on a particular day after about a week of treatment The drug is usually continued for at least seven weeks The starting dose is 150 mg daily and then 150 mg twice a day.

It is important to discuss strategies for smoking cessation with the patient and to try to establish a treatment plan that suits the individual

Passive smoking

Evidence of an increased cardiovascular risk from environmental smoke has been available for some years.20 Legislation is gradually reducing the risk for people in occupations associated with smoking (e.g serving in bars and restaurants) but patients with existing ischaemic heart disease should be advised to avoid exposure

Diabetes

Type 1 and type 2 diabetes and impaired glucose tolerance (IGT) (Table 1.12) are associated with

an increased risk of coronary disease, peripheral vascular disease and cerebrovascular disease.21

Diabetics have a two- to threefold risk of coronary disease at all ages and those with IGT have a 1.5-fold risk Diabetes is a stronger risk factor for women (3.3 times) than for men (1.9 times) The excess risk for type 1 patients is largely confined to those with diabetic renal disease All type 2 patients are at increased risk.22

Diabetes is thought to increase coronary heart disease because:

n increased insulin levels result in increased hepatic synthesis of LDL and triglycerides, causing

a mixed dyslipidaemia

n insulin resistance, which is characteristic of type 2 diabetes, is associated with numerous other cardiovascular risk factors: dyslipidaemia, hypertension, endothelial dysfunction and microalbuminuria

n hyperglycaemia itself may cause endothelial damage

n glycosylated LDL may be more atherogenic than non-glycosylated LDL

Table 1.12 Glucose tolerance, current WHO definitions (venous plasma glucose)

Normal glucose regulation < 6.0 < 7.8

Impaired glucose tolerance < 7.0 7.8–11.0

Glycaemic control

The UKPDS Trial has shown a very significant reduction in the microvascular complications

of diabetes with improved glycaemic control but the improvement in macrovascular tions did not quite reach significance Nevertheless, the UKPDS trialists estimate that each 1% reduction in HbA1c leads to a 14% reduction in cardiovascular risk

complica-Diabetics tend to have more diffuse coronary disease Figure 1.5 shows a diffusely diseased right coronary artery from a type 2 diabetic patient before and after coronary stenting (Ch 4) Coronary artery surgery involves a higher risk for diabetics, and graft disease and progression

of native disease occur earlier in these patients Nevertheless, diabetics probably have a better prognosis after surgical revascularisation than after angioplasty because of their higher risk of restenosis following angioplasty (p 200)

n a reduction in blood pressure

n an improvement in glucose tolerance

n a reduction in plasma fibrinogen and homocysteine levels

The recommendations for reducing the risk of coronary heart disease are for at least 3–4 sessions of physical activity of 30–40 minutes duration per week with 20–30 minutes of aerobic activity at 60–70% of the maximum heart rate for the patient’s age (Table 1.13 on p 18) The activity should be to the point of producing breathlessness

Renal impairment

Once the glomerular filtration rate falls to below an eGFR of 60 mL/minute or albuminuria has occurred, renal insufficiency is said to be present Patients with renal insufficiency have an increased risk of cardiovascular disease Cardiovascular disease accounts for 50% of the deaths of patients with end-stage renal failure Diabetics with renal failure have a 40 times greater risk of dying of cardiovascular disease These increased risks are thought to be the result of a combina-tion of factors including hypertension, increased endothelin and angiotensin levels, damage to the microvasculature, left ventricular hypertrophy, hyperparathyroidism and an increased level

of transforming growth factor beta These act via oxidative stress and more direct mechanisms

to damage the endothelium

Hormonal factors

Gender

Symptoms of coronary heart disease have their onset on average 10 years earlier in men than

in women However, by the age of 75 the risk is equal for both sexes The relative importance

of risk factors may be different for men and women, although risk factors in women have not been studied as extensively as risk factors in men Diabetes is more important as a risk factor

in women Dyslipidaemia is more important as a risk factor in men, although HDL levels seem relatively more important in women Hypertension confers a greater risk of stroke in women than it does in men

Women are more likely than men to present with angina and are less likely to present with tion However, after acute myocardial infarction (AMI), their early mortality is equal to or greater than that of men Women have a higher incidence of vasospastic and microvascular angina, and their

b

had type 2 diabetes for 12 years (b) The same artery after coronary stenting

pain is more likely than men’s to be nocturnal, and to occur at rest or with anxiety (i.e their pain is more likely to be described as ‘atypical’) They also have a greater incidence of ST-T wave changes

on electrocardiogram (ECG) and false positive treadmill tests, making diagnosis more difficult

Postmenopausal changes

The lower incidence of coronary heart disease in women under 60 has been thought to be related to the protective effect of oestrogens This has led to trials of hormone replacement therapy (HRT) in postmenopausal women.23 The results of these trials were surprising to many of the investigators HRT provided no protection to postmenopausal women In some groups there was an increased risk of myocardial infarction, especially in the first year There was a definite increase in the risk of stroke and venous thromboembolism, and there was a probable increased risk of breast cancer At the moment HRT has no role in the prevention of cardiovascular disease

Oestrogen-containing contraceptive pills

The oestrogen in current oestrogen-containing contraceptive pills is ethinyl oestradiol, which has a thrombogenic effect There is a negligible increased risk for most patients, but this is magnified by age and smoking There is a significantly increased risk of myocardial infarction

in women over 35 who smoke, and in those with known risk factors or those not monitored for hypertension For women over 35 on the oestrogen pill, who smoke more than 10 cigarettes per day, the relative risk of infarction is 20, and for those with hypertension the relative risk of stroke is 10 Risk is not associated with duration of pill use, suggesting that the major factor is thrombogenesis

Obesity and the metabolic syndrome

Obesity (body mass index, or BMI, > 30) is associated with an increased risk of all-cause ity, largely due to an increase in cardiovascular mortality Central obesity (waist/hip ratio > 0.9

mortal-in men and 0.8 mortal-in women) confers most risk, probably because of its association with important risk factors Risk factors associated with obesity include:

1 increased LDL cholesterol and triglycerides

Appetite suppressants such as sibutramine, a serotonin and noradrenaline uptake tor, can be useful in selected patients It is contraindicated for patients with a history of stroke

inhibi-or with uncontrolled hypertension Patients must have a BMI > 30, inhibi-or other risk factinhibi-ors and

a BMI between 25 and 30 Orlistat, a gastrointestinal lipase inhibitor, causes fat malabsorption and diarrhoea when fat intake exceeds 30% of total dietary intake There are similar guidelines for its use

Table 1.13 Target heart rates

There is evidence that gastric banding or bypass can lead to sustained weight loss in very obese patients The operation can be performed laparoscopically and at much lower risk than for previous open operations Successful surgery appears to be associated with a reduction in blood pressure, lipid levels and cardiovascular events.

The metabolic syndrome

Obesity represents part of the definition of this syndrome It has recently been redefined by the World Health Organisation (WHO) and the US National Cholesterol Education Program (NCEP) Expert Panel The diagnosis of the metabolic syndrome does not include any estimation

of insulin resistance but requires three or more of the following:

1 central obesity (waist circumference > 102 cm in men, > 88 cm in women)

2 impaired glucose tolerance (fasting glucose > 6.1 mmol/L)

3 elevated triglycerides (> 1.7 mmol/L)

4 low HDL cholesterol (< 1.0 mmol/L in men, < 1.3 mmol/L in women)

5 increased blood pressure > 130/85 mmHg.

Patients with the metabolic syndrome have a three times greater risk of dying of coronary disease than the general population

n elevated fibrinogen (possibly)

n oestrogen-containing contraceptive pills

n polycythaemia

n increased von Willebrand factor (a marker of endothelial dysfunction)

The following factors are associated with reduced thrombotic tendency:

n low-dose aspirin

n other anti-platelet drugs (e.g clopidogrel)

n fish oils and mono-unsaturated fatty acids

Alcohol intake

Alcohol intake has a complex relationship with coronary heart disease, with moderate intake being associated with decreased risk, and nil or heavy intake being associated with increased risk Moderate intake is defined as 10–30 g per day for men; the optimal level for women is uncertain and alcohol may not have the same protective effect for women Moderate alcohol intake is thought to be protective by:

n increasing HDL levels

n having anti-platelet activity

n having an anti-oxidant effect—some components of alcoholic drinks, especially red wine and possibly beer

The evidence for the protective effect of alcohol is not strong and non-drinkers should never

be urged to take up drinking

Hypertension and cerebrovascular disease increase in a linear fashion with alcohol intake,

as do triglyceride levels Therefore the beneficial effects of alcohol intake on coronary disease occur only at moderate intakes, and for those patients with hypertension, hypertriglyceridaemia

or cerebrovascular disease, alcohol intake probably does not confer benefit

Other dietary factors

Oxidation of lipoproteins and endothelial cells contributes to atherosclerosis Pro-oxidant factors include cigarette smoke Anti-oxidant factors include vitamin E, vitamin C and beta-carotene Vitamin supplementation trials (GISSI-Prevenzione24, HOPE25) have failed to show

a reduction in cardiovascular events for high-risk patients given vitamin E supplements Diets rich in anti-oxidants (with a high intake of fresh fruits and vegetables) are associated with a 15% reduced risk of ischaemic heart disease between the lowest and highest consumption groups.26

Flavanoids, which are present in apples, onions, tea and red wine, seem to be associated with lower risks of stroke and coronary events.27

Homocysteinaemia

Elevated plasma levels of homocysteine (an intermediary in methionine metabolism) are associated with coronary disease, cerebrovascular disease and peripheral vascular disease The mechanism responsible is not completely understood but possibilities include direct injury to endothelial cells, platelet activation and a pro-thrombotic effect on the coagulation cascade.Levels are extremely high in patients with homocystinuria, a rare autosomal recessive disorder, but abnormal levels can be found in subjects without this disorder In these patients, lack of folic acid and vitamin B6 (pyridoxine) may be a factor in abnormally high levels of this amino acid.Testing for homocysteinaemia may be worthwhile where there is a strong family history

of premature heart disease without dyslipidaemia, diabetes or other familial factors However,

up to now studies evaluating the effect of vitamins B6 and B12 and folate supplementation for patients with raised homocysteine levels have failed to show any benefit of treatment

com-or, perhaps less likely, that it reflects an intrinsic thrombogenic tendency

Experimental treatment of raised levels with fibrates is underway For the present, routine measurement of levels is not indicated but awareness of its importance as a risk factor reinforces the importance of cessation of smoking and encouragement of exercise

Non-steroidal anti-inflammatory drugs

Non-steroidal anti-inflammatory drugs (NSAIDs) are in common use for arthritic and cular pain The traditional NSAIDs (and aspirin) inhibit both cyclo-oxygenase (COX) 1 and 2 iso-forms The specific COX-2 inhibitors that are associated with a lower risk of gastrointesti-nal bleeding than the non-selective inhibitors have been widely used since their introduction

mus-Reports of increased cardiovascular risk emerged first with rofecoxib, then with other COX-2

inhibitors, and then with the non-selective older drugs (but not aspirin) A large Finnish controlled study of admissions with first myocardial infarction showed an average increased risk

case-of 40% for users case-of these drugs.28 The study was complicated by its inability to track counter NSAIDs Further work is underway, but patients with known ischaemic heart disease

over-the-or at high risk should be discouraged from using these drugs

C reactive protein is an acute phase reactant that is a member of the pentraxin family As well as being a marker of inflammation it has direct effects on the endothelium These include reduc-ing nitric oxide production, enhancing expression of local adhesion molecules and changing the macrophage uptake of LDL New high-sensitivity assays are able to measure low levels accurately High measurements, in the absence of acute inflammatory disorders, are associated with an increased risk of vascular events independent of other risk factors (Table 1.14)

hsCRP testing is reliable and inexpensive It is likely to become increasingly used as part of

a patient’s total risk assessment At this stage treatment is aimed at reversing modifiable risk factors more aggressively when high readings are obtained It has been shown, however, that statins lower hsCRP independently of their effect on cholesterol, and that patients with high hsCRP benefit more from statin treatment than those with low levels

Detected vascular abnormalities

Calcium scoring

High-resolution CT scanners can measure calcium within the coronary arteries in a single

breath-hold scan The measured calcium is given a number, the Agatston score The presence of

calcium within a coronary artery is a marker of coronary disease but not of obstructive disease

It does not give any information about the presence of soft plaque, which is more likely to be associated with an acute coronary event but a 0 score predicts a very low coronary risk A high score has been shown to be an independent risk factor for future events.29 Prospective studies proving the value of calcium scoring have not been performed Calcium scoring is likely to be superseded by multi-slice CT coronary angiography (p 136), which can produce images of the coronary lumen and generate a calcium score An elevated calcium score in an asymptomatic patient is probably best treated as an indication for aggressive risk factor management; for example, instituting statin treatment for a marginally elevated cholesterol level

Intima-media thickness

High-frequency ultrasound transducers can measure accurately the thickness of the carotid intima up to its interface with the media An intima-media thickness (IMT) of > 1.3 mm is associated with an increased cardiovascular risk, which remains significant after allowing for other risk factors

Ankle brachial index

The ankle brachial index (ABI) is relatively easy to measure with a sphygmomanometer and a Doppler ultrasound device The systolic blood pressure in the arm and in the posterior tibial and dorsalis pedis arteries is compared An ABI of < 0.9 means a stenosis of at least 50% somewhere between the aorta and the foot The test is a reliable sign of peripheral arterial disease and thus also coronary disease

Erectile dysfunction

Erectile dysfunction is a marker of endothelial dysfunction Because the penile arteries are smaller (1–2 mm) than the carotids (5–7 mm) and coronary arteries (3 mm), plaque burden and endothelial dysfunction may cause symptoms earlier here than in the other territories

Table 1.14 hsCRP measurements and risk of vascular events (stroke, myocardial infarction, acute coronary syndrome)

hsCRP level < 1 mg/L 1–3 mg/L > 3 mg/L

Note: levels > 10 mg/L suggest acute inflammation and should be repeated after a few weeks.

In some studies erectile dysfunction has reliably preceded symptomatic coronary disease in thirds of patients by an average of three years.30 A history of this problem in men indicates an increased risk of vascular events It is strongly associated with other risk factors such as smoking and diabetes but remains significant after allowing for these.

two-Infectious agents

There is continuing mild interest in the role of infection in promoting atherosclerosis and

especially unstable coronary syndromes Chlamydia pneumoniae and Helicobacter pylori are

commonly found in atheromatous plaques It is possible one or more infectious agents could

be the stimulus that sets off the inflammatory process that changes plaque structure, weakens the fibrous cap and unleashes the coagulation cascade that occludes the vessel The ACADEMIC study was not associated with a reduction in early coronary events for patients treated with antibiotics.31 Further work is underway

Conclusions

The aim of assessment and management of risk factors for coronary disease is the reduction of premature coronary events Primary prevention involves reduction of these events in asymp-tomatic individuals, and secondary prevention focuses on those with established heart disease All the strategies discussed above will reduce the relative risk of coronary events; however, the absolute benefit to an individual patient will depend on his or her absolute risk, and this depends

on the number and severity of all risk factors present: the total risk Thus the patients most likely

to benefit from risk factor reduction are:

n those with established coronary heart disease or other manifestation of CVD

n asymptomatic individuals with multiple risk factors or target organ damage

n close relatives of those with early onset heart disease or populations at increased risk (e.g Aboriginal Australians)

Aggressive treatment of a solitary risk factor may provide less benefit than modest reduction

in several risk factors Drug treatment, which always involves cost and the possibility of side effects, may not be warranted in those with a single risk factor

Summary of recommendations for CHD

risk factor reduction

Assess the severity and presence of all risk factors:

Manage risk factors by:

n encouraging smoking cessation

n undertaking dietary modification:

• ensure dietary fat is less than 30% of total kJ intake and less than 30% of total saturated fat

• increase intake of fish and plant oils

• restrict kJ intake if patient is overweight

• reduce salt and alcohol intake in hypertensive patients

n controlling blood pressure with lifestyle and medication

n maintaining diabetic control

n encouraging regular physical activity

n using prophylactic drugs in high-risk patients

• aspirin

• statins

• beta-blockers or ACE inhibitors after AMI

• ACE inhibitors in left ventricular (LV) dysfunction

n screening relatives of high-risk patients

n regularly following up and reviewing new risk factors, compliance, complications of disease and side effects of treatment

Risk factors: points to remember

1 Everyone needs risk factor assessment and advice

2 Existing coronary or vascular disease is the strongest risk factor for further coronary disease

3 Risk factors do not operate in isolation and the effect of multiple factors must

be taken in to account: the total risk.

4 An understanding of the difference between absolute and relative risk helps in the understanding of the operation of risk factors and their treatment

5 It may be possible to avoid drug treatment for patients with mild hypertension

or dyslipidaemia, if they are keen to make changes to the way they live

Case-based learning: CardiovasCular risk

assessmenT

Mr RF is 60 years old and presents for a check-up because he is concerned he may be at risk

of heart disease

Objectives for the group to understand

How should this type of request be managed? What can be done to assess an individual’s future cardiac risk, and what can be done to improve the prognosis for those at increased risk?

Epidemiology and population health

The presenter should ask the group to consider the concept of risk factors for cardiovascular disease and the differences between population risk factors and those for an individual How did the concept of risk factors arise?

Presenting symptoms and clinical examination

What questions should be asked of Mr RF to begin the risk factor assessment?

1 Is there a history of ischaemic heart disease or symptoms of heart disease (e.g angina)?

2 Has his cholesterol level been checked in the past? What was it? Has it been treated with diet

or drugs, or both? Has the level improved?

3 Is he a diabetic, or has he had an abnormal blood sugar measurement?

4 Is there a history of high blood pressure? Has this been treated? If so, how?

5 Is there a history of heart disease in the family? If so, who has been affected and at what age?

6 Does he smoke? How many cigarettes a day? If he has ceased smoking, when did he stop?

7 Does he exercise regularly?

8 Have any cardiac investigations been performed before? What were the results?

9 Is there a history of peripheral arterial disease (claudication) or erectile dysfunction?The group should appreciate that considerable information about risk can be obtained by asking simple questions

What physical examination should be performed?

Review of pathophysiology

The presenter should ask the group to review the mechanisms or likely mechanisms of action

of the major risk factors Many risk factors have been established by epidemiological research and the way they affect risk (e.g by altering endothelial function) has been worked out afterwards

Evidence-based practice relevant to case

What is the evidence from controlled trials of the importance of risk factors? Why do risk factors operate differently in different countries?

Mr RF’s history and physical examination

Questioning of Mr RF reveals:

1 No symptoms suggestive of angina and no known ischaemic heart disease

2 His cholesterol level four years ago was ‘a little high’ at 6.7 mmol/L

3 His blood sugars have always been normal

4 He has had some high blood pressure readings; usually around 165/90 He has not been treated with drugs for this

5 His younger brother had a by-pass operation at the age of 55 There is no other family history.

6 He stopped smoking yesterday; until then, he smoked 25 cigarettes a day for 40 years

7 He walks to the shops three days a week (1 km return) but is otherwise sedentary

8 He has not had any cardiac investigations that he can remember

9 He has not had claudication He has not had normal erections for several years

His physical examination reveals: weight 112 kg; BMI 30 kg/m2; waist measurement 102 cm; blood pressure 165/105 The peripheral pulses are present There are no carotid bruits There are no signs of heart failure Breath sounds are reduced

Diagnostic pathology

What tests are indicated? The group should list the appropriate tests and explain their purpose How will the results affect management of the patient?

Mr RF’s test results

1 Fasting blood sugar 12 mmol/L (p 15)

2 Total cholesterol 6.9, HDL 0.8, LDL 4.3, triglycerides 2.8 (p 9)

3 Creatinine 100 μmol/L, eGFR normal

4 ECG voltage LVH (p 35)

5 Urinalysis normal

Personal and professional development

and medico-legal aspects

What would be the group’s approach to explaining these results to Mr RF? How fully should the concept of total risk be explained to him? What might be done to ensure compliance with treatment recommendations? To what extent are expensive investigations and treatment (e.g prescription of statin drugs) warranted if a patient is unwilling to make other changes to his or her risk factors (e.g smoking, lack of exercise and attempts at weight loss)? Should mild elevation of cholesterol be treated with drugs in a smoker but not in a non-smoker?

force-Imaging

Mr RF would like to have a calcium score measured Would the group recommend he do this? Should he have an echocardiogram to look for left ventricular hypertrophy (p 36)? Would the result affect his management?

Psychosocial aspects

How would this complicated risk factor treatment be followed up? How would the group persuade Mr RF to continue multiple medications? What are realistic risk factor reductions for a patient such as Mr RF?

Mr RF’s long-term management

Six months later Mr RF has lost 4 kg in weight, walks 3 km a day and smokes five cigarettes

a day His blood pressure is 150/85 on treatment and the HBA1c is 8 on dietary treatment His total cholesterol is 5.0 mmol/L on drug treatment What is his risk now? Is this treatment adequate?

Research

Which research demonstrates the benefits of risk factor modification? Can information about this help a patient to understand the importance of risk factor control? n

End notes

1 Patel H, Herbert ME Myth: identifying classic risk factors helps to predict the likelihood of acute

ischemia Wet J Med 2000; 173:423–424.

2 Levy D, Brink S A Change of Heart: How the people of Framingham, Massachusetts, helped unravel

the mysteries of cardiovascular disease Alfred Knopf, New York; 2005.

3 Yusuf S, Hawken S, Ounpuu S, on behalf of the INTERHEART study investigators Effect of

poten-tially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study) case-control study Lancet 2004; 364:937–952.

4 Folsom AR, Chambless LE, Ballantyne CM, et al An assessment of incremental coronary risk

predic-tion using c-reactive protein and other novel risk markers: The Atherosclerosis Risk in Communities Study Arch Intern Med 2006; 166:1368–1373.

5 De Backer G, Ambrosini E, Borch-Johnsen K, et al European guidelines on cardiovascular disease

prevention in clinical practice Europ J Cardiovasc Prev and Rehab 2003; 10(suppl 1):S1–S78.

6 Wilson K, Gibson M, Willan A, Cook D Effect of smoking cessation on mortality after myocardial

infarction: meta-analysis of cohort studies Arch Intern Med 2000; 160:939–944.

7 Collaborative meta-analysis of randomised trials of anti-platelet therapy for prevention of death,

myo-cardial infarction and stroke in high risk patients BMJ 2002; 324:71–86.

8 Larosa JC, He J, Vupputuri S Effect of statins on risk of coronary disease: a meta-analysis of

ran-domised controlled trials JAMA 1999; 282:2340–2346.

9 LIPID Trial.

10 Ogden LJ, He J, Lydick E, et al Long-term absolute benefit of lowering blood pressure in hypertensive

patients according to the JNC-VI risk stratification Hypertension 2000; 35:539–543.

11 Tanasescu M, Leitzmann MF, Rimm EB, et al Exercise type and intensity in relation to coronary heart

disease in men JAMA 2002; 288:1944.

12 Pedersen TR, Wilhelmsen L, Faegerman O, et al Scandinavian Simvastatin Survival Study: a 2-year

extended follow-up of the original 4S patients Am J Cardiol 2000; 86:257–262.

13 Heart Protection Study.

14 TNT: Treating To New Targets Trial.

15 Pedersen TR, Wilhelmsen L, Faegerman O, et al Scandinavian Simvastatin Survival Study: a 2-year

extended follow-up of the original 4S patients Am J Cardiol 2000; 86:257–262.

16 West of Scotland Coronary Prevention Study 6595 middle-aged men with raised cholesterol were

randomised to a placebo or 40 mg of pravastatin This primary prevention trial demonstrated cant reduction in hospital admissions with cardiovascular disease for treated men J Am Coll Cardiol 1999; 33:909–915.

signifi- 17 Air Force/Texas Coronary Atherosclerosis Prevention Study: 6605 patients with ‘normal’ cholesterol

levels and low to average risk of cardiovascular disease were randomised to lovastatin or placebo There was a significant reduction in the risk of a first ischaemic event in treated patients Downs JR, Clearfield M, Tyroler HA, et al Am J Cardiol 2001; 87:1074–7079.

18 Fenofibrate Intervention and Event Lowering in Diabetes study: this randomised trial of 9795

diabet-ics treated with fenofibrate or placebo did not show a significant reduction in the primary outcome of coronary events Lancet 2005; 366:1849–1861.

19 Miettinen T, Puska P, Gylling H, et al Reduction of serum cholesterol with sitostanol-ester margarine

in a mildly hypercholesterolaemic population N Engl J Med 1995; 333:1308–12.

20 Law MR, Morris JK, Wald MJ Environmental tobacco smoke exposure and ischaemic heart disease:

an evaluation of the evidence BMJ 1997; 315:973–980.