DSpace at VNU: The use of medications in the secondary prevention of coronary artery disease in the Asian region

Just Accepted by Current Medical Research & Opinion
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

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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related to CAD and supplemented with unpublished registry data.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.

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1

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

Jamshed Dalal,1 Lip-Ping Low,2 Dang Van Phuoc,3 Abdul Rashid Abdul Rahman,4 Eugenio

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Reyes,5 Arieska Ann Soenarta,6 Brian Tomlinson7

1

Centre for Cardiac Sciences, Kokilaben Dhirubhai Ambani Hospital, Mumbai, India; 2Low

Cardiology Clinic, Mount Elizabeth Medical Centre, Singapore; 3Ho Chi Minh City University
Medical Centre, University of Medicine and Pharmacy, Ho Chi Minh City, Vietnam; 4Cyberjaya
University College of Medical Sciences, Cyberjaya, Malaysia; 5Department of Medicine,
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,


[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


2

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

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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 countryspecific 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.


3

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

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under-prescribing of such drugs.


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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

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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


5

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 undercontrolled 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

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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),16
acute heart failure,17,18 non-obstructive CAD (<50% stenosis in any epicardial coronary artery),19


6

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

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

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


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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

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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 inhospital 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 REACH37
studies. 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


8

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.

Hong Kong

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Epidemiological data from 975 consecutive patients presenting with STEMI/NSTEMI at a single
tertiary hospital in Hong Kong from September 2006 to May 2011 show that in the postdischarge setting, 90% of patients were prescribed antiplatelet therapy, 60% were prescribed ßblockers, 56% received ACE inhibitors/ARBs, and 70% were discharged on statin therapy.35 A
total of 916 patients (94%) received at least one of these recommended therapies, just 6%
received all and 2% 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


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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%; ßblockers, 59% vs. 50%; lipid-lowering drugs, 61% vs. 36%; and ACE inhibitors/ARBs, 63% vs.

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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 inhospital use of secondary preventative therapy is initially low for ß-blockers (43%), ACE
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

Indonesia
Data collected from the Jakarta Acute Coronary Syndrome (JAC) registry have shown that the
number of patients admitted to the emergency room with diagnosed ACS increased from 1,499
in 2005 to a peak of 3,402 in 2009, which represented 35% of all admissions.29 A recent report of
the JAC Registry involving 2,103 patients with ACS showed that most patients have UA (39%),
with equal numbers of STEMI (31%) and non-STEMI (30%) cases.29 In 2007, ACS-related inhospital mortality was 6.6%, but decreased to 4.1% in 2009 due to a more invasive treatment
approach being adopted in moderate- to high-risk ACS patients. In-hospital mortality was
significantly higher among patients who did not receive reperfusion therapy compared with

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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

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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, nonSTEMI 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

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(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,

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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 nonSTEMI compared with 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

12

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%

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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 nonSTEMI, 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

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

13

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

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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 β1and 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 mild-

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
apoptosis/necrosis in adult rat myocytes via a cyclic adenosine monophosphate (c-AMP)dependent process, whereas chronic stimulation of the ß2-receptor inhibits myocardial


14

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

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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 lipidlowering therapy, ß-blockers, ACE inhibitors, and antiplatelet therapy with aspirin in patients
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?


15

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

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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


16

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 evidencebased medical therapy.23 Similar observations have been made in European studies where nonrevascularised 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

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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/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


17

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

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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 ßblockade 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-


18

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 βblockers, 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

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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 ßblockers 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 underprescribed 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


19

inhibitors and statins, remain suboptimal in Asia. However, the exception of Singapore is noted
where the appropriate use of evidence-based therapy is primarily due to well-defined clinical
protocols within individual cardiac centres, and government indicators of performance. Regular
and random auditing of clinical practice in Singapore encourages the widespread use of
recommended treatments. This approach is supported by a significant increase in the appropriate

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use of evidence-based treatments in acute patients arriving at hospital, with relative ß-blocker use
alone increasing by more than 25% in the 4-year period between 2007 and 2010.32 Absolute
usage rates of evidence-based therapy during hospitalisation and discharge have been higher than
95% since 2007; it will be interesting to observe the impact of these levels of prescribing on the
CAD mortality burden in Singapore in the next few years.

Based on established guidelines, current evidence, and an understanding of the burden of CAD in
Asia, it is recommended that in the absence of clear contraindications, all patients should be
treated with the evidence-based therapies described herein. This averts the need to target
medication use according to risk, with physician risk stratification currently suboptimal
compared with objective measures of patient risk.78 To support the implementation of these
recommendations and to achieve the best possible outcomes for the patient, the following
additional recommendations are proposed:

Physicians should be supported in the goal of reducing CVD burden through the
availability of reliable and accurate information to assess the success of intervention

strategies on an ongoing basis; in this regard, it is proposed that all countries in Asia


20

should have a central ACS registry, with the goal of harmonising the activities of hospital
networks;
Such registries would ideally record the initial ACS event along with comorbidities, any
interventions and medical treatments during hospitalisation, post-discharge medications,
medication adherence, and secondary events during follow-up;

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Predictors of medication self-discontinuation include cost, increasing number of
medications, not using reminder tools and lower education;79 therefore, the use of oncedaily drugs is desirable;
Efforts to optimise utilisation of evidence-based treatment must be in place; this may be
in the form of periodic audits of drug utilisation or “snap shot” surveys conducted at
random intervals as part of the quality assurance process;
Evidence-based treatment should be made freely available, especially for secondary
prevention.

Conclusions
Cardiovascular disease continues to cause significant morbidity, mortality and impaired quality
of life in Asia, with unrealised health gains resulting from current underuse of evidence-based
medications. Despite a significant increase in the rate of coronary intervention, medical therapy
continues to retain a central role in the management of stable CAD. All patients with stable
CAD, in the absence of clear contraindications, should be treated with ß-blockers, ACE
inhibitors or ARBs, aspirin or other antiplatelet medications, and lipid-lowering drugs.

Transparency


21

Declaration of funding:
This study was funded by Merck, Pte Ltd.

Declaration of financial/other relationships:
All authors have acted as consultants to Merck Serono. The authors alone are responsible for the

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content and writing of this paper. CMRO Peer Reviewers 1 and 2 have no relevant financial or
other relationships to disclose. Peer Reviewer 3 is a consultant to and on the Speakers’ Bureau of
MSD.

Acknowledgments:
Editorial assistance was provided by Howard Christian of MIMS (Hong Kong) Limited.

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