Medication use for acute coronary syndrome in Vietnam
Nguyen, Thang
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Acute Coronary Syndrome
in Vietnam
Thang Nguyen
Medication Use for Acute Coronary Syndrome in Vietnam
Thesis Groningen University – With summary in English, Dutch, and Vietnamese Cover design: Thang Nguyen, Hung V Le (Can Tho city, Vietnam)
Layout, typesetting and printing: Michał Sławiński, thesisprint.eu ISBN: (printed version) 978–94–034–0449–3
ISBN: (electronic version) 978–94–034–0448–6
Printing of this thesis was financially supported by the Graduate School for Health Research SHARE, the Graduate School of Science and Engineering (GSSE), the University of Groningen (RuG).
© 2018 Thang Nguyen
No part of this book may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or by any information
Acute Coronary Syndrome
in Vietnam
PhD thesis
to obtain the degree of PhD at the University of Groningen
on the authority of the Rector Magnificus Prof. E. Sterken
and in accordance with the decision by the College of Deans. This thesis will be defended in public on
Friday 16 March 2018 at 14.30 hours by
Thang Nguyen
born on 10 November 1985Prof. B. Wilffert Prof. T.T. Pham Co-supervisor Dr. T.H. Nguyen Assessment committee Prof. P. Denig Prof. V. Wirtz Prof. M. Bennie
Chapter 1
7 General introduction
Chapter 2
21 Physicians’ adherence to acute coronary syndrome prescribing guidelines in Vietnamese hospital practice: a cross‑sectional study
Chapter 3
41 Association between in‑hospital guideline adherence and postdischarge major adverse outcomes of patients with acute coronary syndrome in Vietnam: a prospective cohort study
Chapter 4
63 Enhancing prescribing of guideline‑recommended medications for
ischemic heart diseases: a systematic review and meta‑analysis of interventions targeted at health care professionals
Chapter 5
97 The Vietnamese version of the brief illness perception questionnaire,
the beliefs about medicines questionnaire and the eight‑item Morisky medication adherence scale: translation and cross‑cultural adaptation
Chapter 6
119 Patient adherence to treatment for acute coronary syndrome in Vietnam: a prospective observational study
Chapter 7
137 Pharmacist‑led intervention to enhance medication adherence in patients with acute coronary syndrome in Vietnam: a randomized controlled trial
Chapter 8
163 General discussion
Addendum
173Summary 175
Samenvatting (Dutch summary) 179
Tóm tắt (Vietnamese summary) 183
Acknowledgments 186
List of publications 188
Curriculum Vitae 193
One of the common CVDs is ischemic heart diseases (IHDs) or coronary artery diseases
including acute coronary syndrome and stable angina.1 There are two types of acute coronary
syndrome (ACS): (1) non‑ST‑elevation acute coronary syndrome (NSTEACS) comprising unstable angina and non‑ST‑elevation myocardial infarction, and (2) ST‑elevation acute coronary syndrome or myocardial infarction (STEACS/STEMI). Unstable angina is chest pain or discomfort that is accelerating in frequency or severity and may occur while at rest but does not result in myocardial necrosis. The discomfort may be more severe and prolonged than typical stable angina. Unstable angina, NSTEMI, and STEMI share common pathophysiological origins related to coronary plaque progression, instability, or rupture
with or without luminal thrombosis and vasospasm.2
CVDs are a major contributor to the growing public health epidemic in chronic diseases
or non‑communicable diseases (NCDs).3 CVDs are the number one cause of death globally:
more people die annually from CVDs than from any other cause.1,4 In 2015, CVD deaths were
17.9 million, rising by 12.5% since 2005.2 IHDs and stroke are the two main contributors to
CVD morbidity and mortality, accounting for 85.1% of all deaths due to CVDs and being the
two leading causes of disability‑adjusted life years (DALYs) worldwide in 2015.1,4,5 IHDs are the
world’s biggest killer, accounting for 8.9 million deaths in 2015.5,6 The estimated socioeconomic
burden of IHDs is reflected in the loss of 164 million DALYs in 2015.5
A significant proportion of CVD deaths is among 85% of the population residing
in low‑ and middle‑income countries (LMICs).7 According to the World Bank, LMICs comprise
of six geographic regions consisting of East Asia and the Pacific, Central and Eastern Europe and Central Asia, Latin America and the Caribbean, Middle East and North Africa, South Asia
Region, and Sub‑Saharan Africa.8 The Global Burden of Disease study showed that over the
past three decades, high‑income countries, Latin America, Western Europe and Central Europe have shown declines in the number of CVD deaths whereas the rest of the world has shown an
increase. East Asia (including Vietnam) registered a 47% increase over the same period.4
Survivors of ACS are at increased risk of recurrent infarctions and have an annual death
rate of up to six times that in people of the same age who do not have IHDs.9 Evidence‑based
interventions for secondary prevention include the use of antiplatelet agents, beta‑blockers, angiotensin‑converting enzyme inhibitors, and statins, as well as modifying lifestyle‑related
risk behaviors.1,9 The benefits of these medications are largely independent, but when used
together with smoking cessation, nearly 75% of recurrent vascular events may be prevented.1
Despite substantial benefits and generally low treatment costs, appropriate measures for secondary prevention after ACS are implemented in less than half of eligible patients, even in high‑income countries. Due to inequitable and inaccessible health care systems, inefficient use of limited resources and investing scarce resources in interventions that are not cost‑
Medicine use process
The purpose of pharmacotherapy management is to deliver the appropriate medicine to the patient who needs that medicine and to ensure the patient taking the medication as prescribed. To achieve the purpose, a physician should follow a standard process of
medicine use (Figure 1).10 The process starts with a diagnosis to determine the problem
that requires treatment. The therapeutic goal should be defined. The physician must decide which treatment is required, based on up‑to‑date clinical practice guidelines, to achieve the desired goal for an individual patient. The Institute of Medicine defines clinical practice guidelines as “statements that include recommendations, intended to optimize patient care, that are informed by a systematic review of evidence and an assessment of the benefits
and harms of alternative care options.”11 When the decision is made to treat the patient
with medications, the best medications for the patient are selected based on efficacy, safety, suitability, cost, and patient preferences. The dose, route of administration, and duration of treatment are determined, taking into account the condition of the patient. When receiving a medication, the patient should be provided proper information about both the medication and his or her condition. Next, the medication should be dispensed to the patient in a safe and hygienic manner, making sure that the patient understands the dosage and course of therapy. Then the patient decides whether or not to be adherent to taking the medication as prescribed. Finally, the physician should decide how to monitor the treatment, after consid‑ ering the probable therapeutic and adverse effects of the treatment during the follow‑up
period.10 This process is supported by the World Health Organization (WHO) by depicting
Physician adherence to prescribing guidelines
The first official guidelines for the diagnosis and management of ACS were published by the Agency for Health Care Policy and Research and the National Heart, Lung, and Blood
Institute in 1994.13 Recently, organizations such as the American Heart Association (AHA),
the American College of Cardiology (ACC), the European Society of Cardiology (ESC), and the Vietnam National Heart Association (VNHA) have developed and disseminated guidelines to facilitate the management of patients with ACS. In addition to percutaneous or surgical revascularization and cardiac rehabilitation programs, these guidelines strongly recommend the use of secondary prevention medications including antiplatelet agents (aspirin, P2Y12 receptor antagonists, or both), beta‑blockers, angiotensin‑converting
enzyme inhibitors or angiotensin II receptor blockers (ACEIs/ARBs), and statins.14–20
Prescribing of these guideline‑recommended medications has been shown to reduce
both in‑hospital and postdischarge morbidity and mortality.21–25 Perhaps a convincing
example of the magnitude of the effect of guideline adherence is an observational study of 65,000 patients with NSTEMI showing that every 10 percent increase in adherence to prescribing guideline‑recommended therapies was associated with a 10 percent reduction in in‑hospital mortality [adjusted odds ratio (OR) 0.90, 95% confidence interval (CI)
0.84–0.97].26 In‑hospital mortality was significantly lower in the hospitals with the highest
compared to the lowest adherence quartile (4.2% vs. 6.3%).26
A number of large registries [including the Global Registry of Acute Coronary
Events (GRACE),27 the Can Rapid Risk Stratification of Unstable Angina Patients Suppress
ADverse Outcomes with Early Implementation of the ACC/AHA Guidelines (CRUSADE),28
the Antiplatelet Therapy Observational Registry (ATPOR),29 and the Euro Heart Survey
(EHS)30] have shown variable adherence to guidelines for the management of patients
with ACS, though there have been improvements over the years.31 Adherence to guidelines
remains suboptimal in clinical practice,32–35 in particular, in LMICs.27,36 The ACCESS (Acute
Coronary Events – a Multinational Survey of Current Management Strategies) study,37
a prospective observational registry of patients hospitalized for ACS between 2007 and 2008 in 19 LMICs, found that aspirin and lipid‑lowering agents were each given to > 90% of patients, whereas uptake of beta‑blockers and ACEIs was at 78% and 68%, respectively.
Several large quality improvement programs have been implemented with the goal of increasing the use of guideline‑recommended medications for patients with ACS in the acute phase of the illness, at hospital discharge, and at long‑term follow‑up. The
notable programs including the Guidelines Applied in Practice (GAP),38 the Get With
The Guidelines (GWTG),39 and the European Quality Improvement Program for Acute
Coronary Syndromes (EQUIPACS)40 have demonstrated that it is possible to improve
quality of care. A systematic review by Murphy et al. (2015)41 showed that organizational
interventions were associated with approximately 20% reduced mortality in patients with IHDs [risk ratio (RR) 0.79; 95% CI 0.66–0.93).
Patient adherence to treatment
“Drugs don’t work in patients who don’t take them” (C. Everett Koop). Adherence is the key
mediator between medical practice and patient outcomes.42 Adherence to medications or
medication adherence was defined as the process by which patients take their medications
as prescribed, comprising initiation, implementation, and discontinuation.43 Patient compli‑
ance and medication adherence have been previously defined as synonymous.44 However,
in recent years, compliance has been viewed by many as having the negative connotation
that patients are subservient to physicians.45 The term “medication adherence” is now the
preferred terminology.43,45
Numerous studies on how to properly measure and quantify medication adherence
have been conducted but none of them can be counted as the gold standard.46 Different
tools have been designed and validated for different conditions, in different circumstances. Generally, measurements of medication adherence are categorized by the WHO as subjec‑
tive and objective measurements.46–48 Objective measures, including measurement of clinical
outcomes, dose counts, pharmacy records, electronic monitoring of medication administra‑ tion and drug concentrations, seemingly provide a good measure of a patient’s medication‑
taking behavior in many contexts,46–48 though most of these measures have drawbacks to
implement in resource‑limited settings.49 Subjective measures, including physician or
family reports, patient interviews and self‑report adherence scales, can be simple to use
and are less expensive.46–48 The most common drawback is that patients tend to underreport
non‑adherence to avoid disapproval from their healthcare providers. However, recently a number of well‑validated adherence scales have been strongly correlated with objective
measures of adherence in several different populations of patients.48
A substantial proportion of people do not adhere adequately to cardiovascular medications, and the prevalence of such suboptimal adherence is similar across all
individual CVD medications.50 A systematic review by Chen et al. (2015)51 showed that the
proportion of medication adherence ranged from 54% to 86% in patients discharged from
the hospital after an ACS. Notably, adherence to treatment is still suboptimal in LMICs.49,52
Poor medication adherence results in adverse health outcomes and increased healthcare costs. A large proportion of all CVD events may be attributed to poor adherence to cardio‑ vascular medications only, and the optimal adherence may confer a significant inverse
association with subsequent adverse outcomes.50,53 A systematic review by Bitton et al.
(2013)54 showed that medication adherence significantly improves health outcomes, and
reduced total annual IHD costs (between $294 and $868 per patient, equating to 10.1%‑ 17.8% cost reductions between high‑ and low‑adherence groups).
A systematic review by Santo et al. (2016)55 showed that many types of inter‑
lay health mentoring, and direct observation treatment. In terms of modes of delivery, the interventions were delivered by pharmacists, nurses, researchers, or other health
professionals.55 Pharmacists, in addition to medication dispensing, can provide medica‑
tion education and disease management for patients, to improve medication adherence to achieve the goals of desired therapeutic outcomes, and to improve safe medication
use.56 Previous systematic reviews conducted to measure the effect of pharmacists on the
care of patients with CVDs 57,58 and IHDs 56,59 have shown a positive impact on patient
outcomes. A recent study by Ho et al.60 evaluated a multifaceted intervention to improve
medication adherence involving pharmacist‑led medication reconciliation, education, and collaborative care between the pharmacists and physicians. Results of the study showed that patients randomized to the intervention were more likely to be adherent to cardio‑ vascular medications (clopidogrel, beta‑blockers, ACEIs, and statins) than those in the care as usual group (89.3% vs. 73.9%; p = 0.003).
Rationale and objectives of the thesis
Vietnam is a country located in Southeast Asia and borders Laos, Cambodia, and China.61
Economic reforms beginning in the late 1980s transformed Vietnam from one of the
poorest countries to a lower middle‑income country by 2009.62,63 From 1990 to 2015, the
trend of lower death rate and birth rate was associated with an increase in total population (66 to 93 million), life expectancy at birth (71 to 76 years), elderly population (8% to 10%),
and urban population (20% to 34%).64 The rapid economic growth, urbanization and aging
population in Vietnam have led to an increased burden of NCDs.66 NCDs are estimated to
account for 73% of total deaths.65 Cardiovascular diseases are a major contributor to the
NCD burden, accounting for 33% of total deaths.59 Notably, ACS is still one of the leading
causes of deaths in Vietnam.66 Vietnam has made some significant efforts to address NCDs
including the establishment of the NCD prevention and control program and advocating for its further prioritization, developing models for community‑based management of NCDs and initiating surveillance systems. Despite this progress, action to date has not been adequate to prevent the burden of NCDs from continuing to rise. Currently, health‑related challenges include a rising burden of CVDs, an ageing population, inequities in access to
healthcare services, and insufficient capacity of the healthcare system.67 There are concerns
about quality of medical care and patient outcomes and therefore there is a growing demand
for appropriate medicine use.68
The thesis has been inspired by the wish to gain more insight into the process of medicine use and contribute to the development of interventions to improve guideline and medication adherence in ACS in Vietnam. This thesis addresses two stages of the process of medicine use. The focus of the first part of the thesis is on physician adherence to prescribing guidelines. In Vietnam, prescribing guidelines for patients with ACS have
been introduced in clinical practice, but little is known about the extent and patterns of physicians’ prescribing according to guidelines and the association between the guideline
adherence and patient outcomes. The previous systematic review41 presented a significant
impact of organizational interventions on improved mortality of patients with IHDs, but the interventions involved both physician and patient adherence to recommendations on secondary prevention of IHDs (comprising lifestyle modification, prescribing medica‑ tions, or both). No work has been done focusing on types and the effect of interventions to enhance prescribing according to guidelines for patients with IHDs as far as we are aware. The second part of the thesis focuses on patient adherence to treatment. Although the importance of medication adherence in treatment for chronic diseases has been recognized, limited data indicate the extent of patient adherence to treatment for ACS and the role of pharmacists in improving the adherence in Vietnam. To measure medication adherence, standardized questionnaires have frequently been used because they are low in both cost and time expenditure. It is probably the most appropriate tool measuring medication adherence in LMICs like Vietnam where other inexpensive tools as pharmacy refill and pill counts cannot be used. Translation and cross‑cultural adaptation of these questionnaires are needed for studies on medication adherence in Vietnam. Therefore, the objectives of the thesis are:
1. To determine the extent of physician adherence to prescribing guideline‑recommended medications for patients with acute coronary in Vietnam.
2. To determine the association between in‑hospital guideline adherence and postdischarge major cardiovascular outcomes.
3. To determine types and the effect of interventions tested to improve prescribing and health outcomes in patients with ischemic heart diseases.
4. To translate and cross‑culturally adapt the Brief Illness Perception Questionnaire, the Beliefs about Medicines Questionnaire, and the Eight‑item Morisky Medication Adherence Scale into Vietnamese.
5. To determine the extent of patient adherence to treatment for acute coronary syndrome in Vietnam.
6. To assess whether a pharmacist‑led intervention enhances medication adherence in patients with acute coronary syndrome and reduces mortality and hospital readmission.
Outline of the thesis
Chapter 1 introduces the importance of guideline and medication adherence in cardiovas‑
cular diseases and acute coronary syndrome worldwide and in Vietnam.
Chapter 2 determines the extent of physician adherence to prescribing guideline‑recom‑
mended medications and identifies potential factors associated with the guideline adherence in treatment for patients with acute coronary syndrome in Vietnam.
Chapter 3 determines the association between in‑hospital guideline adherence and
postdischarge major cardiovascular outcomes of patients with acute coronary syndrome in Vietnam.
Chapter 4 systematically reviews randomized controlled trials of interventions to enhance
prescribing guideline‑recommended medications for patients with ischemic heart diseases in order to determine types and the effect of interventions tested to improve prescribing and health outcomes in patients with ischemic heart diseases.
Chapter 5 translates and cross‑culturally adapts the Brief Illness Perception Questionnaire,
the Beliefs about Medicines Questionnaire, and the Eight‑item Morisky Medication Adherence Scale into Vietnamese.
Chapter 6 determines the extent of patient adherence to treatment for acute coronary
syndrome postdischarge and identifies factors associated with the patient adherence.
Chapter 7 determines the effect of pharmacist‑delivered multifaceted interventions on
medication adherence and clinical outcomes of patients with acute coronary syndrome postdischarge in Vietnam.
Chapter 8 summarizes and discusses the main findings of the thesis as well as proposes
implications for clinical practice and future research in Vietnam and in other low‑income and middle‑income countries.
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adherence and secondary prevention measures after acute coronary syndrome hospital discharge: A randomized clinical trial. JAMA Intern Med. 2014;174(2):186–193.
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Physicians’ adherence to acute coronary
syndrome prescribing guidelines
in Vietnamese hospital practice:
a cross‑sectional study
Thang Nguyen, Thao H Nguyen, Hoa TK Pham, Thu TA Nguyen,
Khoa M Huynh, Phuong TB Vo, Tam T Pham, Katja Taxis
Tropical Medicine and International Health, 2015 May; 20(5):627–637
coronary syndrome (ACS) prescribing guidelines in Vietnamese hospital practice.
METHODS: A retrospective cross‑sectional study was performed collecting data from medical records of all patients with ACS admitted to two public hospitals in Ho Chi Minh city, Vietnam from January to December, 2013. Data were analyzed to determine the percentages of eligible patients receiving guideline‑recommended medications at hospital arrival and discharge and to identify factors associated with non‑adherence using multivariable logistic regression.
RESULTS: A total of 284 patients were included (mean age 64 years; 69.4% male). Of those patients eligible for treatment, aspirin was prescribed for 97.9% at arrival and 96.3% at discharge; dual antiplatelet therapy was prescribed for 92.3% at arrival and 91.7% at discharge; loading doses at arrival were prescribed for 79.5% (aspirin) and 55.8% (clopidogrel); beta blockers were prescribed for 58.7% at arrival and 76.7% at discharge; angiotensin converting enzyme inhibitors or angiotensin receptor blockers (ACEI/ARB) were prescribed for 89.1% at arrival and discharge; and statins were prescribed for 94.1% at arrival and 90.7% at discharge. Patients who underwent an invasive procedure were more likely to receive guideline‑ recommended medications at discharge: dual antiplatelet therapy (OR 3.77; 95% CI 1.23–11.52), beta blocker (OR 3.95; 95% CI 1.86–8.40), and ACEI/ ARB (OR 4.01; 95% CI 1.30–12.41).
CONCLUSIONS: In general, physicians closely adhered to ACS prescribing guidelines in Vietnamese hospital practice, but prescribing of beta blockers and clopidogrel loading doses was probably suboptimal.
7.3 million people died due to IHD (12.7% of total global mortality).1 Low‑and‑middle
income countries accounted for more than 80% of those.1 IHD comprises a spectrum of
diseases of the heart including acute coronary syndrome (ACS) which is the main cause
of IHD deaths.2 Patients with ACS suffer from myocardial ischemia. There are three types
of ACS: ST elevation (formerly Q‑wave) myocardial infarction (STEMI), non‑ST elevation
(formerly non‑Q wave) myocardial infarction (NSTEMI), and unstable angina (UA).3
International guidelines recommend using a combination of two antiplatelet agents (aspirin plus clopidogrel), a beta blocker, an angiotensin converting enzyme inhibitor or an angiotensin II receptor blocker (ACEI/ARB) and an HMG coenzyme A reductase inhibitor
(statin) to treat patients with ACS.3–7 This regimen has been shown to reduce in‑hospital
and postdischarge mortality rates in ACS patients.8,9 For example, an observational study of
almost 65,000 patients with NSTEMI showed that every 10 percent increase in adherence to prescribe guideline‑recommended treatment was associated with a 10 percent reduction in in‑hospital mortality (adjusted odds ratio 0.90, 95% CI 0.84–0.97). In‑hospital mortality was significantly lower in the hospitals with the highest compared to the lowest adherence
quartile (4.2% versus 6.3%).9 Despite such evidence, adherence to guidelines remains subop‑
timal,10–15 in particular, in low‑ and middle‑income countries.16–18 Shimony et al. (2014)17
showed that patients from high‑income countries (Canada and United States) were more likely to receive guideline‑recommended medications at discharge (OR 2.32, 95% CI 1.19–4.52, a combination of aspirin, clopidogrel, and a statin) than those in low‑ and middle‑ income countries (India, Iran, Pakistan, and Tunisia).
In Vietnam, ischemic heart disease was one of the major leading causes of death
across all ages in 2007.19 The Vietnam National Heart Association (VNHA) published the first
guidelines on management of ACS in 2006 with an update in 2008.20 VNHA guidelines are
in line with international guidelines in their recommendations of prescribing evidence‑based
medications.3–7,20 However, in contrast to some other Asian countries, little is known about
the prescribing patterns for patients with ACS during hospitalization and after discharge in Vietnamese hospitals. Therefore, we determined the extent of physician adherence to acute coronary syndrome (ACS) prescribing guidelines in Vietnamese hospital practice.
Methods
A retrospective cross‑sectional study was performed of all patients admitted with a diagnosis of ACS to the study hospitals between January and December 2013. The study was carried out in two public hospitals (provincial level), comprising 1200 beds (hospital A) and 700 beds (hospital B). Study wards were: Cardiology, Internal Medicine, Intensive Care Unit and Cardiac Intensive Care Unit. On the Cardiology wards, hospital A employed 26 physi‑ cians and had 52 beds; and hospital B employed 14 physicians and had 60 beds. Invasive procedures could be performed in both hospitals.
We included patients who survived during hospitalization with one of following discharge diagnoses according to coding of the International Classification of Diseases, 10th revision (ICD‑10): unstable angina (I20.0), acute myocardial infarction (I21), or subse‑ quent myocardial infarction (I22).21 For patients who were admitted several times during the study period, we only included the medical record of the first admission. We excluded patients (1) who had been admitted to another hospital initially and were transferred to the study site consequently; (2) who did not fully complete treatment therapy (i.e. patients who were transferred to another hospital for further treatment or patients who were discharged with or without permission of their physician when the therapy was incomplete); or (3) with missing data of arrival or discharge medications in their medical records.
All medical records of patients with a diagnosis of angina or ACS (I20, I21 and I22) were requested from the hospital record archives. Information from medical records was extracted by two researchers (KMH and PTBV) using a predefined data collection form. Data included: age, sex, health insurance, length of hospital stay, coronary artery disease risk factors, medical history of myocardial infarction, invasive procedures [including percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG)], comorbidities (peptic ulcer, asthma/COPD, renal failure, hepatic failure and heart failure), in‑hospital revascularization [invasive procedure (PCI or CABG) or non‑invasive procedure (with or without fibrinolysis)], Global Registry of Acute Coronary Events prediction score
for all‑cause mortality in the first 6 months after discharge (GRACE score),22 and labora‑
tory examinations. Details of all medications prescribed within the first 24 hours after hospital admission and at hospital discharge were collected (brand and generic name of the medication, dose, dosage form, administration route, and frequency of administra‑ tion). Information on contraindications to antiplatelet therapy, beta blockers, ACEI/ARBs or statins was also recorded.
Data were analyzed (1) to determine the percentages of eligible patients who were prescribed guideline‑recommended medications during the first 24 hours of hospitaliza‑ tion and at hospital discharge and (2) to identify factors associated with non‑adherence to prescribing guideline‑recommended medications.
Guidelines used in this study were the current version of the Vietnam National Heart Association (VNHA), the European Society of Cardiology (ESC) and the American College of Cardiology/American Heart Association (ACC/AHA). All three guidelines recommend use of two antiplatelet agents (aspirin and clopidogrel), a beta blocker, an ACEI/ARB and a statin within the first 24 hours after hospital admission (hereafter called “at arrival”) and at hospital discharge. This is a class I recommendation, i.e., the treatment should be given because of its benefit, usefulness or efficacy and supported by a high level of evidence (level A, data derived from multiple randomized clinical trials or meta‑analysis; or level B, data derived from a single randomized or large non‑randomized studies); with the exception of prescribing ACEI/ARB at arrival (not recommended in the ESC guidelines) or statin at arrival (not recommended in ACC/AHA guidelines and VNHA guideline for
STEMI) (Appendix 1).3–7,20
The percentage of eligible patients receiving a guideline‑recommended medication was calculated by dividing the number of eligible patients who were prescribed the medica‑ tion by the total number of eligible patients who should be prescribed the medication, multiplied by 100. Eligible patients for being prescribed aspirin, a loading dose of aspirin, dual antiplatelet therapy, a beta blocker or a statin were patients without contraindications to the medications. Eligible patients for being prescribed a loading dose of clopidogrel were patients younger than 75 years of age without contraindications to clopidogrel. Eligible patients for being prescribed an ACEI/ARB were patients with heart failure, a left ventricular ejection fraction (LVEF) < 40%, diabetes mellitus, or hypertension and without contraindi‑
cations to ACEI/ARBs. Contraindications were based on the current guidelines,4–7,20 AHFS
Drug Information (2012),23 Facts and Comparisons (2013)24 and the Vietnamese National
Formulary (2012)25 (Appendix 2). A patient with ACS and no relevant contraindications
was likely to be prescribed the following six discharge medications: two antiplatelet agents (aspirin and clopidogrel), a beta blocker, an ACEI/ARB, a statin and a proton pump inhibitor (protection against gastrointestinal side effects of antiplatelet therapy).
Data were analyzed using the Statistical Package for the Social Sciences, version 20th (SPSS 20). Multivariable logistic regression with forward stepwise method was performed to identify potential factors associated with guideline non‑adherence at arrival or discharge. The following variables were included in the multivariable model: age group (age ≥ 65 versus < 65 years); sex (male vs. female); diagnosis (NSTEMI vs. UA and STEMI vs. UA), health insurance; previously diagnosed diabetes mellitus, hypertension, dyslipidemia, myocardial infarction, heart failure; in‑hospital revascularization (invasive vs. non‑invasive procedure) (only for discharge recommendations); GRACE score (moderate vs. low risk and high vs. low risk) (only for discharge recommendations); number of discharge medications ( > 6 vs. ≤6 medications) (only for discharge recommendations). Patients with documented contraindications to the studied agents were excluded from this analysis.
Results
A total of 711 medical records of patients with a diagnosis of angina or ACS were identified and 284 patients were included in the study (Figure 1). The following medical records were excluded: 270 records of patients with a discharge diagnosis of unspecified angina or stable angina, and 7 records of second admissions; and 150 records because of exclusion criteria: 60 patients who had been admitted to another hospital initially and were transferred to the study site consequently, 90 patients who did not fully complete treatment therapy: 13 were transferred to another hospital for further treatment, 61 were discharged with permission of their physician when the therapy was incomplete, and 16 without physician permission.
The patients had a mean age of 64 years (range 30 to 105 years); 47% of the patients were over 65 years old (Table 1). The majority of patients were male (69.4%) and had hypertension (67%). Fifty five (18.7%) reported prior MI and 22 (7.7%) had prior PCI; 128 (45.1%) patients underwent PCI, 4 (1.4%) underwent CABG, and 152 (53.5%) had no invasive procedure and received pharmacological treatment with fibrinolysis (3 patients) or without fibrinolysis (149 patients); 191 (67.3%) patients had a moderate or high risk and 85 (29.9%) had a low risk of death within 6 months after hospital discharge. The risk of the remaining patients remained unknown because of missing data.
Aspirin was prescribed for 97.9% of eligible patients at arrival and 96.3% at discharge (Table 2). Fewer patients received an aspirin loading dose (79.5%) and a clopidogrel loading dose (55.8%). Documented contraindications for antiplatelet agents were intracranial hemorrhage, gastrointestinal (GI) bleeding, bleeding disorders, active GI ulcer, or asthma/ chronic obstructive pulmonary disease (COPD). Multivariable analysis showed that dual antiplatelet therapy at discharge was more frequently given to patients who underwent an invasive procedure during hospitalization or who received more than six discharge medications. STEMI patients were more likely than UA to receive an aspirin loading dose (Table 3). No factor was significantly associated with non‑adherence to prescribing a loading dose of clopidogrel.
Beta blockers were prescribed for 58.7% of eligible patients at arrival and 76.7% at discharge (Table 2). Documented contraindications to beta blockers were signs of heart failure, evidence of low output state, cardiogenic shock, second‑ or third‑degree heart block, or asthma. Patients with heart failure, STEMI (compared to UA), or female patients were less likely to receive a beta blocker at arrival. Patients were less frequently prescribed a beta blocker at discharge when they had no invasive procedure or when they had an NSTEMI (compared to UA) (Table 3).
- Unspecified angina or stable angina (n= 270) - Second admission
cases (n=7)
Medical records of ACS or angina patients of hospital A
in 2013 (N = 417)
Medical records of ACS or angina patients of hospital B
in 2013 (N = 294)
Number of patients reviewed N = 434
Number of patients included N = 284
Excluded (n=150)
- Transferred from the other hospitals (n=60) - Incomplete therapies (n= 90) - Missing data (n=0) NSTEMI N = 113 (39.8%) Unstable angina N = 55 (19.4%) N = 116 (40.8%) STEMI
Figure 1 Flowchart of the study population
Abbreviations: ACS, acute coronary syndrome; NSTEMI, non‑ST elevation myocardial infarction; STEMI, ST elevation myocardial
infarction; UA, unstable angina.
ACEI/ARBs were prescribed for 89.1% of eligible patients at arrival and at discharge (Table 2). Documented contraindications in patients not receiving ACEI/ARB were systolic blood pressure less than 100 mmHg, aortic valve stenosis, or glomerular filtration rate (GFR) less than 30 mL/min. Patients were less likely to receive an ACEI/ARB at hospital discharge when they had no invasive procedure (Table 3).
Statins were prescribed for 94.1% of eligible patients at arrival and 90.7% at discharge (Table 2). Documented contraindications to statins were elevations of hepatic transami‑ nases (3 times higher than the upper normal limits). No factor was significantly associated with non‑adherence to prescribing statins.
Table 1 Patient characteristics Patient characteristic (n = 284)Overall Type of ACS UA (n = 55) NSTEMI(n = 113) (n = 116)STEMI
Demographics and general characteristics
Mean age (±SD) 64.2 (±14.1) 63.6 (±11.5) 67.7 (±14.9) 61.0 (±13.6)
Age range 30–105 39–88 30–105 33–97
Male 197 (69.4) 37 (67.3) 64 (57.1) 94 (81.7) Insurance 176 (62) 46 (83.6) 71 (63.4) 58 (50.4) Length of hospital stay (days) 8 (1–41) 7 (2–38) 10 (1–41) 7 (2–40) Number of medications at discharge 6.9 (±1.5) 6.7 (±1.4) 7.4 (±1.6) 6.6 (±1.4) Number of discharge medications > 6 158 (55.6) 29 (52.7) 75 (66.4) 54 (46.6)
CAD risk factors
CAD family history 12 (4.2) 3 (5.5) 6 (5.3) 3 (2.6) Hypertension 193 (68) 42 (76.4) 84 (74.3) 67 (57.8) Diabetes 71 (25) 15 (27.3) 37 (32.7) 19 (16.4) Dyslipidemia 47 (16.5) 9 (16.4) 27 (23.9) 11 (9.5) Smoking 99 (34.9) 12 (21.8) 34 (30.1) 53 (45.7) CRP/fibrinogen increase 119 (41.9) 9 (16.4) 56 (49.6) 54 (46.6) Age ≥ 65 136 (47.9) 23 (41.8) 66 (58.4) 47 (40.5) Menopause 85 (29.9) 17 (30.9) 48 (42.5) 20 (17.2)
Medical history and comorbidities
Prior MI 55 (18.7) 20 (36.4) 28 (24.8) 5 (4.3) Prior undergone invasive procedure 24 (8.5) 7 (12.7) 9 (8) 9 (6.9) Peptic ulcer 28 (9.9) 3 (5.5) 10 (8.8) 15 (12.9) Asthma/COPD 20 (7) 4 (7.3) 12 (10.6) 4 (3.4) Renal failure 33 (11.6) 7 (12.7) 21 (18.6) 5 (4.3) Hepatic failure 5 (1.8) 0 2 (1.8) 3 (2.6) Heart failure 69 (24.3) 7 (12.7) 45 (39.8) 17 (14.7) In-hospital revascularization Invasive 1. (46.5) 14 (25.5) 37 (32.7) 81 (69.8) PCI 128 (45.1) 14 (25.5) 33 (29.2) 81 (69.8) CABG 4 (1.4) 0 4 (3.5) 0 Non‑invasive 152 (53.5) 41 (74.5) 76 (67.3) 35 (30.2) With fibrinolysis 3 (1.1) 0 0 3 (2.6) Without fibrinolysis 149 (52.5) 41 (74.5) 76 (67.3) 32 (27.6) GRACE score Low risk 85 (29.9) 17 (30.9) 21 (18.6) 47 (40.5) Moderate risk 74 (26.1) 21 (38.2) 22 (19.5) 31 (26.7) High risk 117 (41.2) 15 (27.3) 66 (58.4) 36 (31.0) Missing data 8 (2.8) 2 (3.6) 4 (3.5) 2 (1.7)
Abbreviations: ACS, acute coronary syndrome; CABG, coronary artery bypass grafting; CAD, coronary artery disease; COPD,
chronic obstructive pulmonary disease; CRP, C‑reactive protein; GRACE, global registry of acute coronary events; MI, myocardial infarction; NSTEMI, non‑ST elevation myocardial infarction; PCI, percutaneous coronary intervention; SD, standard deviation; STEMI, ST elevation myocardial infarction; UA, unstable angina.
Table 2 Utilization of guideline‑recommended medications Guideline recommendation Number of eligible patients receiving guideline-recommended
medication Number of eligible patients
Percentage of eligible patients receiving guideline-recommended medication At arrival Aspirin 191 195 97.9
Dual antiplatelet therapy 179 194 92.3
Aspirin loading dose 155 195 79.5
Clopidogrel loading dose 82 147 55.8
Beta blocker 84 143 58.7
ACEI/ARB 164 184 89.1
Statin 241 256 94.1
At discharge
Aspirin 208 216 96.3
Dual antiplatelet therapy 198 216 91.7
Beta blocker 168 219 76.7
ACEI/ARB 171 192 89.1
Statin 253 279 90.7
Abbreviations: ACEI/ARB, angiotensin converting enzyme inhibitor or angiotensin receptor blocker.
Table 3 Factors associated with guideline non‑adherence*
Guideline recommendation Factor Number of patients receiving guideline-recommended medication (%) Number of patients NOT receiving guideline-recommended medication (%) OR 95% CI p-value
Aspirin loading dose
at arrival ‑ STEMI** 76 (49.0) 7 (17.5) 6.1 2.2–17.0 0.001 Beta blocker at arrival ‑ Male 70 (83.3) 36 (61.0) 3.6 1.5–8.7 0.004 ‑ STEMI** 17 (28.8) 31 (52.5) 0.3 0.1–0.9 0.022 ‑ Heart failure 3 (3.6) 11 (18.6) 0.2 0.1–0.8 0.026 Dual antiplatelet at
discharge ‑ Invasive procedure 97 (49.0) 5 (27.8) 3.8 1.2–11.5 0.020 ‑ Discharge
medications >
6 110 (55.6) 5 (27.8) 4.6 1.5–14.0 0.007 Beta blocker at discharge ‑ NSTEMI** 54 (32.1) 28 (54.9) 0.3 0.1–0.7 0.007
‑ Invasive
procedure 96 (57.1) 14 (27.5) 4.0 1.9–8.4 < 0.001 ACEI/ARB at discharge ‑ Invasive
procedure 83 (48.5) 4 (19.0) 4.0 1.3–12.4 < 0.001
Abbreviations: ACEI/ARB, angiotensin converting enzyme inhibitor or angiotensin receptor blocker; CI, confidence interval;
NSTEMI, non‑ST elevation myocardial infarction; OR, odds ratio; STEMI, ST elevation myocardial infarction. (*) Using Multivariable Logistic Regression with Forward Stepwise Method
Discussion
Our study provides insight into pharmacological management of ACS at arrival and discharge from two Vietnamese hospitals. In line with previous studies, ACS patients in our study had a mean age above 60 years, were predominantly male and frequently had
chronic comorbidities (hypertension, dyslipidemia, and diabetes mellitus).16,26–28 In general,
physicians prescribed guideline‑recommended medications. Patients who underwent an invasive procedure were more likely to receive evidence‑based medications (aspirin plus clopidogrel, beta blocker, ACEI/ARB) at discharge. This was encouraging, but more eligible patients with ACS not undergoing an invasive procedure should receive the combination
treatment.3–7,20 When our results were compared to the figures of other low‑ and middle‑
income countries in several previous studies,16,17 adherence to guidelines seemed relatively
higher for antiplatelet therapy, ACEI/ARBs and statins, but lower for beta blockers.
Almost all eligible patients were prescribed aspirin at arrival and discharge and most patients received dual antiplatelet therapy. These findings are similar to many other studies
from around the world.27–31 Aspirin plays an essential role in ACS treatment.32,33 There is also
a lot of evidence to give a P2Y12 receptor blocker (e.g. clopidogrel) in addition to aspirin for
up to 1 year following an ACS,34–36 but physicians may have concerns about the benefit‑risk
ratio and extra cost of the second antiplatelet agent clopidogrel. We observed a considerable lower rate of prescribing aspirin and clopidogrel loading doses, especially in UA patients. Guidelines recommend to give a loading dose of aspirin as soon as possible to any patient thought to have an ACS (UA, NSTEMI or STEMI) and add a clopidogrel loading dose
in patients younger than 75 years of age.3–7,20,37–39 Further work needs to investigate reasons
for not following this advice.
The percentage of patients prescribed beta blockers at arrival was suboptimal and
lower than observed in some other studies (from 65 to 83%).40–42 Multivariable analysis showed
that patients with STEMI (compared to UA), heart failure, or female patients were less likely to receive beta blockers at arrival. Underutilization of beta blockers, especially at arrival, may be because of physicians’ concerns about adverse reactions of beta blockers in patients with comorbidities such as diabetes mellitus or heart failure. The initiation of oral beta blockers at arrival is recommended for all ACS patients without contraindications. Patients with contra‑ indications should be reevaluated during hospital stay for beta blocker candidacy because
of well‑established benefits of beta blockers for secondary prevention.4–7,20,43,44 Prescribing
beta blockers should be, therefore, improved focusing on female patients, and patients with heart failure or STEMI. Finally, we observed higher rates of using ACEI/ARBs and statins
than previous studies.28–31 This is encouraging as recommendations in guidelines are based
on several trials supporting the role of ACEI/ARBs (ISIS‑4, GISSI‑3 trial etc.) and statins
Especially failure to document contraindications may have led to misclassify some patients as being eligible for a certain treatment. Second, due to administrative reasons we had to exclude cases of patients who died during hospitalization so our results are not generaliz‑ able to this patient group. Third, we also had to exclude a large number of patients who were discharged home although their therapy was incomplete. We believe that patients with incomplete therapy were either of advanced age and/or severely ill, so physicians considered that treatment was no longer beneficial; or could not pay for further hospital treatment probably because of not being insured. There was insufficient information in the medical notes to identify reasons for incomplete therapy and because of the retrospective nature of our study we could not collect additional information about this. Furthermore, we excluded a group of patients whose discharge diagnosis was unspecified angina. A proportion of those patients may have had unstable angina. We excluded these patient groups because of predefined exclusion criteria. Further work is needed to investigate the quality of diagnosis and treatment in these patient groups, especially lack of access to treatment.
Are our results generalizable to other hospitals in Vietnam? To discuss this we need to explain some details of the Vietnamese healthcare system. Currently, the healthcare system in Vietnam consists of a public‑private mix. The public sector plays a leading role in providing inpatient health services, accounting for 93.9% of total inpatient admissions
in 2010.50 Care is provided at the following four levels in the public sector: community,
district, provincial and national level. About 50.8 million people were covered by social health
insurance in 2010, accounting for 60% of the population.50,51 People without insurance have
to cover cost of all treatment themselves. Insured patients receive treatment at their primary health facility which is specified by their insurance, e.g. a provincial hospital in the neigh‑ bourhood, but could be referred to higher level treatment if medically necessary. If patients
bypass their primary facility without a referral letter, they will have higher co‑payments.50
In Vietnam, life preserving treatment in the acute phase of an ACS can only be provided in hospitals at provincial and national level and in some private hospitals. It is not known which percentage of ACS patients are referred to this level of hospital treatment. Furthermore, there are differences between provincial hospitals; for example, not all hospitals at this level are equipped to undertake PCI procedures. Both study sites were provincial level hospitals. Therefore, our findings should be representative for ACS patients treated at provincial level hospitals with similar structure in Vietnam.
Conclusions
In general, physicians closely adhered to ACS prescribing guidelines in Vietnamese hospital practice, but prescribing of beta blockers and clopidogrel loading doses was probably suboptimal. There seems to be a large group of patients not completing hospital treatment and further work needs to investigate this issue.
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