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Review The use of medications in the secondary prevention of coronary artery disease in the Asian region

Jamshed Dalal, Lip-Ping Low, Dang Van Phuoc, Abdul Rashid Abdul Rahman, Eugenio Reyes, Arieska Ann Soenarta, Brian Tomlinson doi: 10.1185/03007995.2015.1010035

Abstract

Background: Cardiovascular diseases, of which coronary artery disease

(CAD) is a significant contributor, are a leading cause of long-term morbidity and mortality worldwide In the years ahead, it is estimated that approximately half of the world’s cardiovascular burden will occur in the Asian region Currently there is a large gap in secondary prevention, with unrealised health gains resulting from underuse of evidence-based medications, including beta-blockers, angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), aspirin and other antiplatelet agents, and lipid-lowering drugs Despite the almost universal recommendation for these drugs in unstable CAD, their under-prescription

is well documented for patients with acute heart failure, non-obstructive CAD, and for secondary prevention of CAD

Objective: This article reviews the burden of CAD in Asian countries together with guidelines supporting

evidence-based medication use from a secondary prevention perspective

Methods: The MEDLINE database was searched from 2000 to 2013, inclusive, for country-specific data

related to CAD and supplemented with unpublished registry data

Results: In the post-discharge setting following hospital admission for acute coronary syndromes, medication

prescription rates were low Beta-blocker prescription rates ranged from 49% in China to 99% in Singapore, ACE-inhibitor/ARB prescription rates ranged from 28% in China to 96% in Singapore, and lipid-lowering therapy rates ranged from 47% in China to 97% in Singapore Aspirin/antiplatelet drug prescription rates ranged from 86% in Indonesia to 99.5% in Singapore Recommendations are provided to improve patient outcomes and reduce the disease burden in Asia

Conclusions: Despite recommendations issued in international and national guidelines, use of CAD

medications in Asia remains suboptimal In the absence of clear contraindications, all patients with unstable CAD should receive these agents as secondary prevention This averts the need to target drug use according

to risk, with high-risk features paradoxically associated with under-prescribing of such drugs

University of the Philippines – College of Medicine, Manila, The Philippines; 6National

Cardiovascular Center, Harapan Kita Hospital, Jakarta, Indonesia; 7Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR

Address for correspondence: Professor Brian Tomlinson, The Chinese University of Hong Kong,

Division of Clinical Pharmacology, Department of Medicine and Therapeutics, 9/F., Clinical Sciences Building, Prince of Wales Hospital, Shatin, N.T., Hong Kong, +852 2632 3139,

btomlinson@cuhk.edu.hk

[Short title: Use of medications in secondary prevention of CAD in Asia]

Key words: Angiotensin converting enzyme inhibitors, Asian countries, aspirin, beta-blockers,

coronary artery disease, secondary prevention, statins

Abstract

Background: Cardiovascular diseases, of which coronary artery disease (CAD) is a significant

contributor, are a leading cause of long-term morbidity and mortality worldwide In the years ahead, it is estimated that approximately half of the world’s cardiovascular burden will occur in the Asian region Currently there is a large gap in secondary prevention, with unrealised health gains resulting from underuse of evidence-based medications, including beta-blockers,

angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), aspirin and other antiplatelet agents, and lipid-lowering drugs Despite the almost universal

recommendation for these drugs in unstable CAD, their under-prescription is well documented for patients with acute heart failure, non-obstructive CAD, and for secondary prevention of CAD

Objective: This article reviews the burden of CAD in Asian countries together with guidelines

supporting evidence-based medication use from a secondary prevention perspective

Methods: The MEDLINE database was searched from 2000 to 2013, inclusive, for

country-specific data related to CAD and supplemented with unpublished registry data

Results: In the post-discharge setting following hospital admission for acute coronary

syndromes, medication prescription rates were low Beta-blocker prescription rates ranged from 49% in China to 99% in Singapore, ACE-inhibitor/ARB prescription rates ranged from 28% in China to 96% in Singapore, and lipid-lowering therapy rates ranged from 47% in China to 97%

in Singapore Aspirin/antiplatelet drug prescription rates ranged from 86% in Indonesia to 99.5%

in Singapore Recommendations are provided to improve patient outcomes and reduce the

disease burden in Asia

Conclusions: Despite recommendations issued in international and national guidelines, use of

CAD medications in Asia remains suboptimal In the absence of clear contraindications, all patients with unstable CAD should receive these agents as secondary prevention This averts the need to target drug use according to risk, with high-risk features paradoxically associated with

under-prescribing of such drugs

Introduction

Coronary artery disease (CAD) is a leading cause of long-term morbidity and mortality

worldwide.1 According to the World Health Organization (WHO) Global Burden of Disease estimates, heart disease is a leading contributor to years living with disability in elderly people in low- and middle-income countries.2 Of the 57 million deaths worldwide in 2008, an estimated 17.3 million were due to cardiovascular disease (CVD), with more than 80% of cardiovascular deaths occurring in low- and middle-income countries CVD is responsible for 151 million disability-adjusted life years, 62 million of which are due to CAD and 46 million due to

cerebrovascular disease.2 Of particular concern, cardiovascular morbidity and mortality are predicted to increase substantially by 2030,3 with an estimated half of the world’s cardiovascular burden expected to occur in the Asian-Pacific region.4 Monitoring and management of

cardiovascular risks as well as implementation of appropriate strategies to tackle the increase in CVD morbidity and mortality are essential.5,6

Based on the Framingham experience, the principal personal atherogenic risk attributes that independently predict CAD are blood lipids, blood pressure, glucose tolerance and fibrinogen.7

In addition, lifestyle factors including obesity, smoking, and diet and exercise habit can affect the level of atherogenic risk Findings of the global INTERHEART and INTERSTROKE studies suggest that approaches to CVD prevention, as well as control of cardiovascular risk factors, such as hypertension, abnormal lipid levels, tobacco use, obesity, diabetes mellitus, diets with low intake of fruits and vegetables, physical inactivity, excessive alcohol intake, and

psychosocial factors, may be based on similar principles worldwide and have the potential to prevent most premature cases of myocardial infarction (MI) and stroke.8,9 The Reduction of

Atherothrombosis for Continued Health (REACH) registry, which involved a total of 67,888 patients in 44 countries, confirmed that classic cardiovascular risk factors are consistent and common throughout the world.10 However, risk factors are largely undertreated and under-

controlled in many regions The Prospective Urban Rural Epidemiological (PURE) study further showed that there is a large gap in secondary prevention worldwide, highlighting the extremely low rates of effective therapy usage in low- and middle-income countries.11 This evidence

emphasises the need for systematic efforts to identify reasons for underuse of drugs, and

implement strategies for the long-term use of effective and inexpensive drugs for the prevention

of CVD

All patients with CAD require ongoing management, which includes medication, control of risk factors and lifestyle modification Acute coronary syndrome (ACS), which occurs in patients with unstable CAD and presents as unstable angina (UA), ST-elevation myocardial infarction (STEMI) and non-ST elevation myocardial infarction (non-STEMI), typically requires

aggressive medical management particularly in high-risk patients In this regard, most current treatment guidelines recommend the use of beta-adrenergic (ß)-blockers, angiotensin converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs), aspirin and other

antiplatelet agents, and lipid-lowering drugs as appropriate agents for the treatment and

secondary prevention of CAD.12-15 However, despite the almost universal recommendation for these drug classes in the long term management of patients presenting with unstable CAD, their under-prescription has been well documented in patients with acute myocardial infarction (MI),16acute heart failure,17,18 non-obstructive CAD (<50% stenosis in any epicardial coronary artery),19

andfor secondary prevention of CAD.20,21 Limited data indicate that these drugs are also prescribed in the Asian region.22-24

under-Herein we review the burden of disease and appropriate use of secondary prevention medications

in the Asian region Although it is anticipated that epidemiological data will provide a valuable reference for physicians and policymakers alike, the principal objective of this review is to highlight the suboptimal use of CAD medications in the region with a view to improving patient access to these agents Given that the majority of the world’s cardiovascular burden is projected

to occur in the Asian-Pacific region, any evidence-based action to address this burden can only help in alleviating the burden of disease

Search criteria

The MEDLINE database was searched from 2000 to 2013, inclusive, to identify the more recent studies, using the primary search terms “coronary artery disease”, “acute coronary syndrome”,

“secondary prevention” and “Asia” and the names of each of the countries covered in this

review Relevant articles were selected by the authors Additional articles or abstracts were identified from these articles and unpublished registry data were obtained by some authors from their respective countries

CAD epidemiology and drug treatment in Asia

Consistent data regarding the prevalence, incidence and mortality associated with CAD are

difficult to source for individual countries in the Asian region Figure 1 provides a

between-country comparison of CAD-associated mortality in the Asia-Pacific region based on 2002 WHO

data, with non-age-adjusted death rates per 100,000 population varying from 26.3 per 100,000 in Brunei Darussalam to 159.7 per 100,000 in New Zealand.25 These data are limited in that they are not age-adjusted and therefore do not take into consideration the disproportionately higher expected death rates in countries with a higher mean population age Data on the epidemiology

of ACS, including in-hospital mortality, were largely derived from ACS registries and are

summarized for some countries in Asia where available in Table 1.26-33 Table 2 summarizes the

rates of secondary prevention drug use in these countries,27,29-32,34-36 together with data from the REACH37 and PURE11 studies for comparison When considered together, these data show a predominance of STEMI cases, although non-STEMI cases were more common in the

Philippines and Singapore, and UA cases were more common in Indonesia Thirty-day

in-hospital mortality rates ranged from 4.1–6.9% Of note, use of evidence-based medical therapies at-discharge was consistently higher than usage reported in both the PURE11 and REACH37studies However, with the exception of Singapore, the use of evidence-based secondary

prevention in patients with stable CAD in Asia was unacceptably low

China

Epidemiological data from 1,433 unselected patients with ACS enrolled in the Global Registry Acute Coronary Events from China (Sino-GRACE) prospective, non-randomized study showed that the majority of ACS patients in China present with STEMI (46.2%) compared with 16.7% with non-STEMI and 37.1% with UA.26 During hospitalization, 19.2% of patients had recurrent angina of which the majority of cases (53.2%) were UA No mortality data were presented in this study In a separate study of 16,860 patients aged 50–80 years with an established history of CAD, CVD or peripheral artery disease (PAD) from 51 hospitals in 14 cities of China, 78% of

patients overall had documented CAD.34 At screening, use of evidence-based secondary

prevention medications was low for ß-blockers (49%), ACE inhibitors (28%) and statins (47%), although 83% of patients were prescribed antiplatelet agents

ß-received all and 2% ß-received none Six-month all-cause mortality was higher in patients who received none of the recommended therapies (77.2%) compared with those who received some (6.6%) and all recommended therapies (3.4%; P<0.001)

India

The Treatment Patterns and Outcomes of Acute Coronary Syndrome Patients (TRACE) study was a multicentre, retrospective study undertaken to understand anti-thrombotic management patterns and outcomes of ACS patients in India.27 Unpublished data of a pilot study of 500 patients from 10 centres across India show that STEMI cases predominate, accounting for 40%

of ACS-related admissions followed by 36% with UA and 24% with non-STEMI In-hospital ACS-related mortality and 30-day mortality rates were 4.2% and 6.7%, respectively The larger CREATE study of 20,468 patients with a confirmed ACS diagnosis was a prospective registry study conducted in 89 centres across 50 cities in India.28 This study confirmed the high rate of

STEMI cases (60.6%) in India, which were less likely than non-STEMI or UA cases to be treated with ß-blockers (58% vs 62%) and lipid-lowering drugs (51% vs 54%), and more likely to be treated with ACE inhibitors or ARBs (61% vs 51%) Furthermore, choice of pharmacological agents differed between high-income and low-income patients: thrombolytics, 61% vs 52%; ß-blockers, 59% vs 50%; lipid-lowering drugs, 61% vs 36%; and ACE inhibitors/ARBs, 63% vs 54% Mortality was higher for low-income compared with high-income patients (8.2% vs

5.5%).28 Previously unpublished data from the pilot study of 500 ACS patients show that hospital use of secondary preventative therapy is initially low for ß-blockers (43%), ACE

in-inhibitors/ARBs (32%) and lipid-lowering therapies (68%).27 However, prescription of these drugs was improved at discharge, although not to the same level as aspirin (90%) and other antiplatelet medications (88%) An audit of more than 2,900 prescriptions conducted in

Rajasthan state in patients with stable CAD confirmed the suboptimal use of secondary

prevention therapy in India.36

significantly higher among patients who did not receive reperfusion therapy compared with

patients who received acute reperfusion therapy, either by primary percutaneous coronary

intervention (PCI) or fibrinolytic therapy (13.3% vs 5.3% vs 6.2%, respectively; p<0.001) Despite established recommendations for the use of evidence-based medical therapy in

Indonesia, in-hospital and post-discharge usage remains suboptimal, particularly with respect to ß-blockers and ACE inhibitors/ARBs.29

Malaysia

Analysis of data from the Malaysian ACR Registry collected throughout 2006 from 3,422

patients with ACS admitted to 12 tertiary cardiac centres and general hospitals in nine states found that STEMI cases were predominant (42%) followed by non-STEMI (33%) and UA cases (25%).30 Overall in-hospital mortality was 6.7%, with 30-day mortality rates for STEMI, non-STEMI and UA of 11%, 8% and 4%, respectively Thrombolysis, which was used for STEMI cases only, reduced in-hospital and 30-day mortality by nearly 50% PCI also reduced 30-day mortality for patients with non-STEMI and UA However, fewer women than men received thrombolysis (men: 71%; women: 67%) or underwent PCI (men: 22%; women: 16%) despite making up 25% of the cohort Pharmacological therapy included aspirin and statins administered

in more than 90% of patients ß-blockers and ACE inhibitors/ARBs were administered in 66% and 65% of patients, respectively.30

Philippines

In the Philippines, a currently unpublished report of the Philippine Heart Association Acute Coronary Syndrome Registry of 1,044 ACS patients showed that non-STEMI cases (46%) are more prevalent than STEMI cases (42%) and UA (12%).31 The majority of patients were male

(67%), with a peak incidence of ACS occurring at 51–60 years of age In-hospital and 30-day mortality rates were 6.9% and 7.5%, respectively Thrombolytic therapy was administered to just 10.5% of STEMI patients, and primary PCI was conducted in only 10.3% of cases In-hospital drug utilization rates were low, with just 56% of patients given ß-blockers, 67% given aspirin, 72% given lipid-lowering drugs, and 52% given ACE inhibitors or ARBs At discharge,

evidence-based drug utilization rates increased, with at least 85% of patients prescribed such drugs in the post-hospital setting.31

Singapore

According to the Singapore Myocardial Infarction Registry, in 2010, ischaemic heart disease including acute MI was the second leading cause of death (18.7%) and the third leading cause of hospitalization (3.7%).32 In 2010, the number of patients with diagnosed ACS episodes was 7,189, with the number of non-STEMI cases approximately twice that of STEMI cases (65% vs 29%, respectively) The number of deaths among acute MI patients decreased from 1,557 in

2008 to 1,257 in 2010, with approximately twice as many deaths among patients with

non-STEMI compared with non-STEMI In 2010, ACS-related 30-day mortality was 12.7% Over the 2007-2010 surveillance period, the proportion of patients receiving evidence-based medications

on arrival to hospital and at discharge has increased, such that in 2010 the rates of medication uptake were at least 95% for ß-blockers, ACE inhibitors/ARBs, aspirin, other antiplatelet

medications, and lipid-lowering drugs.32

Thailand

The Thai Registry of Acute Coronary Syndrome (TRACS) registry is a multicentre, prospective, nationwide registry that includes 39 participating medical centres.33 During 2007-2008, 2,007 ACS patients were enrolled, including 55% with STEMI, 33% with non-STEMI and 12% with

UA Among patients with STEMI, 67% received reperfusion therapy, including 42.6% who received thrombolysis and 24.7% who received PCI In patients with non-STEMI ACS, 38.4% received coronary angiography and approximately 25% received revascularization either by PCI

or bypass surgery In-hospital mortality was 4.8% overall, and 5.3% for STEMI, 5.1% for STEMI, and 1.7% for UA During a 1-year follow-up, 12-month mortality rates were 14.1%, 25.0% and 13.8%, respectively This report did not include data relating to evidence-based pharmacological therapy.33

non-Current international and regional guidelines on the management of stable CAD

In stable CAD, dilative therapy was previously believed to offer superior efficacy to an initial pharmacologic approach based on the assumption that high-risk coronary anatomy or myocardial ischaemia increases the risk of myocardial infarction and death.38 The Clinical Outcomes

Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial showed that in patients with stable angina, evidence-based medical therapy alone was similarly effective as PCI

in preventing MI and death, thereby establishing these treatments as non-competing,

complementary therapies that are part of a comprehensive management approach.39 Furthermore, major advances in understanding of the pathophysiology of ACS, as well as increased insight into plaque and patient vulnerability has led to the more aggressive use of targeted

pharmacologic agents that constitute best practice in the management of stable CAD.38

Three drug classes are considered essential in this setting: lipid-lowering, antihypertensive and antiplatelet agents.40 Statins have demonstrated clear benefits in morbidity and mortality in the secondary prevention of CAD First-line antihypertensive therapy for patients with CAD should include both a ß-blocker and an ACE inhibitor, which have additional benefits beyond their antihypertensive effects Calcium channel blockers or ARBs are acceptable alternatives to ACE inhibitors if the latter is not tolerated As well as providing symptomatic relief as a result of reduced heart rate, blood pressure and contractility, ß-blockers prolong diastole resulting in increased coronary artery blood flow and myocardial perfusion Moreover, most ß-blockers have antiarrhythmic effects, and atenolol, bisoprolol, carvedilol, metoprolol and nebivolol additionally have antioxidant and antiproliferative properties, which are associated with the inhibition of apoptosis.39,41-46 However, the selectivity of the ß-blocker is an important determinant of

apoptosis, with adrenergic stimulation of β1-receptors increasing apoptosis whereas adrenergic stimulation of β2-receptors inhibits apoptosis Since the non-selective carvedilol blocks both β1- and β2-receptors, the β2-blockade may antagonize the beneficial antioxidant and antiproliferative effects Moreover, the majority of myocardial damage is ß1-receptor-mediated, with

noradrenaline having a much higher affinity for ß1- than for ß2- 1-receptors In either to-moderate or moderate-to-severe left ventricular dysfunction, the total adrenergic receptor occupancy consists of 88-90% of the ß1-subtype with values of 5-6% for the ß2- 1-receptors Thus, the selectivity of noradrenaline for ß1-receptors dictates that the vast majority of signalling traffic will be carried by ß1-receptor signal transduction pathways in the non-failing or failing human heart.47 Chronic stimulation of the ß1-receptor induces myocardial myocyte

mild-apoptosis/necrosis in adult rat myocytes via a cyclic adenosine monophosphate

(c-AMP)-dependent process, whereas chronic stimulation of the ß2-receptor inhibits myocardial

apoptosis/necrosis via a Gi-coupled pathway.48 Finally, aspirin alone is considered as a first-line antiplatelet agent except in patients with recent MI or stent placement, in which case the

combination with clopidogrel is recommended.40

Joint guidelines of the European Society of Cardiology and other European societies14 and guidelines of the American College of Physicians, American College of Cardiology Foundation, American Heart Association, American Association for Thoracic Surgery, Preventive

Cardiovascular Nurses Association, and the Society of Thoracic Surgeons12 recommend lowering therapy, ß-blockers, ACE inhibitors, and antiplatelet therapy with aspirin in patients

lipid-with stable CAD as secondary prevention (Table 3) Several countries considered in detail in this

review have also issued guidance on the use of these drugs in CAD, including the Chinese

Society of Cardiology,49 the Indonesian Heart Association,50 the Malaysian Clinical Practice Guidelines on the Management of Stable Angina Pectoris,51 and the Philippine Heart Association

Clinical Practice Guidelines for the Management of Coronary Artery Disease (Table 3).52 Not every country has its own national guidelines Indonesian guidelines on the management of stable CAD are based on European Society for Cardiology and American Heart Association Guidelines India also uses American guidelines,12 and the Association of Physicians of India has previously published an expert consensus document on management of ischaemic heart

disease.53 In Singapore where there are no national guidelines, each cardiac centre has its own protocol

Why are CAD medications under-prescribed?

Despite recommendations issued in both international and national guidelines, use of CAD

medications in Asia remains suboptimal (Table 2) A number of factors likely contribute to the

discrepancy between the recommendations in CAD guidelines and the limited application of these guidelines by a large number of physicians in Asia and elsewhere in the world Among these, the emphasis in recent years on anatomically-driven, mechanical revascularization of obstructive coronary arterial stenoses resulted in a departure from an initial pharmacologic approach, with the treatment paradigm yet to move back into alignment with the current

understanding of best practice.38 Second, the equally strong emphasis of some guidelines on the management of the acute phase of ACS during hospitalisation54-57 could limit physicians’

attention to the equally important post-discharge setting However, the emphasis of major

international guidelines12-15 on the role of aggressive secondary prevention in the management of stable CAD suggests that other factors, such as errors of omission or therapeutic paradox may also account for this discrepancy.58 Limited medical experience and funding have also been cited

as reasons for the low uptake of evidence-based therapies, such as ß-blocker usage in the setting

of heart failure in Malaysia.24 Drug affordability and socioeconomic status of the patient are potential issues In an analysis of ACS registry data from India, low-income patients had greater mortality than high-income patients and were less likely to receive evidence-based treatments.28

In this example, adjustment for treatments eliminated the difference in mortality rate suggesting that removal of obstacles that produce delays in access to hospitals and provision of affordable treatments could reduce morbidity and mortality in these patients

Perhaps most concerning is the observation that CAD medications appear to be under-prescribed

in patients with high-risk features In a Korean registry study of patients with acute MI, higher

Killip class at admission, and the presence of LV systolic dysfunction and higher blood

creatinine level were, in addition to advanced age, associated with less use of optimal based medical therapy.23 Similar observations have been made in European studies where non-revascularised patients were less likely than revascularised patients to receive guideline-based secondary prevention medical therapy.59,60 A Canadian ACS registry study in which physicians were asked to give reasons why guideline-indicated medications were not prescribed during hospitalisation reported that the commonest reasons were “not high enough risk” or “no

evidence-evidence/guidelines to support use”.61

Non-provision of evidence-based therapies may therefore

be due to subjective underestimation of patient risk and any likely treatment benefit Bagnall et

al (2010) further indicated that oversights in the delivery of medical care were apparent

Based on our review of country data from the Asian region, it is of particular concern that uptake

of ß-blocker and ACE inhibitor/ARB therapy is especially low even in the post-discharge setting

(Table 2) Other studies have similarly reported that ß-blocker and ACE inhibitor prescription

rates are lower than aspirin and statins in the secondary prevention setting.62-64 The poor uptake

of these two drug classes is at the expense of their potential benefits In patients with stable CAD, ACE inhibition has been shown to reduce the risk of total and cardiovascular mortality, fatal and nonfatal MI, heart failure, revascularization, and stroke through a mechanism that includes endothelial protection as well as blood pressure reduction.65 Furthermore, ACE

inhibition has been shown to decrease the risk of new onset diabetes that is elevated in patients with stable CAD taking ß-blockers without ACE inhibitors.66 Possible reasons for the low uptake

of ACE inhibitors include the potential for drug-drug interactions, which increase exponentially

with the number of drugs given to a patient,67 and hyperkalaemia, elevation in serum creatinine, hypotension and cough.68

Potential benefits of ß-blocker therapy include decreased oxygen demand due to reductions in heart rate, blood pressure, and contractility, and an increase in diastolic filling time, with the consequent relief of ischaemic chest pain,40,69 as well as a reduction in risk of cardiovascular events compared with all other antihypertensive agents,70 and a reduction in risk of death.71 Such benefits are conferred through ß-1 blockade and are not found in ß-blockers with intrinsic

sympathomimetic activity, which should be avoided.40,72 Of particular relevance to

understanding why ß-blockers are underused is the profile of those patients who are less likely to initiate therapy with ß-blockers In a cohort of more than 24,000 patients hospitalised with ACS

in Northern Italy between 2004–2007 and who were discharged from hospital without

contraindications for ß-blockers, just 67% initiated ß-blocker therapy.73 Independent predictors

of ß-blocker initiation included age and receipt of invasive procedures during hospitalisation, such as CABG, PCI and cardiac catheterisation, with older age and frailty associated with a lower likelihood of initiating ß-blocker therapy With respect to age, the finding that first-line ß-blockade with atenolol performed poorly in reducing cardiovascular risk in elderly patients with hypertension may have hidden in meta-analyses the positive secondary preventative effects observed in younger patients including those with diabetes.69

The adverse event profile of β-blockers may also limit their use.12 However, a recent systematic review of 13 double-blind, placebo-controlled studies of 15,383 CHF patients that investigated genuine versus spurious side-effects of β-blockers in heart failure refutes the myth that β-

blockers are not well tolerated by such patients: 28 of the 33 classically-described side-effects were not more common on β-blockade than placebo.74

However, this result was only clear for bradycardia and intermittent claudication Of 100 patients who developed dizziness on β-

blockers, 81 would have developed it on placebo For diarrhoea, this proportion was 82/100, and for hyperglycaemia 83/100 At least 6 side effects were less common for β-blockers compared with placebo, including depression (reduced by 35%, p<0.01) and insomnia (reduced by 27%, p=0.01) For most of the 33 classically-described side-effects for β-blockers, there was no

significant difference between β-blockers and placebo, including syncope, headache, impotence, weight increase, fatigue, and postural hypotension Severe side effects leading to discontinuation

of treatment by the patient were significantly more frequent on placebo.74

Severe bradycardia, pre-existing high degree of atrioventricular block, sick sinus syndrome and refractory heart failure are absolute contraindications to ß-blocker use Relative contraindications include bronchospastic disease or active peripheral arterial disease However, underuse of ß-blockers based on previously established relative contraindications of severe chronic obstructive pulmonary disease (COPD) and other reactive airway diseases (RAD) may no longer be justified, with evidence now showing that ß-blockers reduce mortality and the risk of exacerbations in patients with COPD and RAD.75,76 Despite such evidence, ß-blockers continue to be under-prescribed in patients hospitalised with acute heart failure and accompanying COPD/RAD.17,77

Recommendations for medication use in the management of stable CAD in Asia

Despite the availability of various guidelines on the management of stable CAD, secondary prevention practices that utilise evidence-based therapies, including ß-blockers, aspirin, ACE