European Heart Journal (2015) 36, 1115–1122 CLINICAL RESEARCH

doi:10.1093/eurheartj/ehu449 Valvular heart disease

Characteristics, complications, and gaps in

evidence-based interventions in rheumatic heart
disease: the Global Rheumatic Heart Disease
Registry (the REMEDY study)

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Liesl Zühlke 1,2, Mark E. Engel 1, Ganesan Karthikeyan 3, Sumathy Rangarajan 4,
Pam Mackie 4, Blanche Cupido 1, Katya Mauff 5, Shofiqul Islam 4, Alexia Joachim 1,
Rezeen Daniels 1, Veronica Francis 1, Stephen Ogendo6, Bernard Gitura 7,
Charles Mondo 8, Emmy Okello 9, Peter Lwabi 9, Mohammed M. Al-Kebsi 10,
Christopher Hugo-Hamman 2,11, Sahar S. Sheta 12, Abraham Haileamlak 13,
Wandimu Daniel 13, Dejuma Y. Goshu 14, Senbeta G. Abdissa 14, Araya G. Desta 14,
Bekele A. Shasho 14, Dufera M. Begna 14, Ahmed ElSayed15, Ahmed S. Ibrahim 15,
John Musuku 16, Fidelia Bode-Thomas17, Basil N. Okeahialam 17, Olukemi Ige 17,
Christopher Sutton 18, Rajeev Misra19, Azza Abul Fadl 20, Neil Kennedy 21,
Albertino Damasceno22, Mahmoud Sani23, Okechukwu S. Ogah24,25,26, Taiwo Olunuga26,
Huda H.M. Elhassan27, Ana Olga Mocumbi28, Abiodun M. Adeoye24, Phindile Mntla29,
Dike Ojji30, Joseph Mucumbitsi31, Koon Teo4, Salim Yusuf4, and Bongani M. Mayosi1*
1
The Cardiac Clinic, Department of Medicine, Groote Schuur Hospital and University of Cape Town, J Floor Old Groote Schuur Hospital, Groote Schuur Drive, Observatory 7925, Cape
Town, South Africa; 2Division of Paediatric Cardiology, Department of Paediatrics and Child Health, Red Cross War Memorial Children’s Hospital and University of Cape Town, Cape
Town, South Africa; 3Department of Cardiology, All India Institute of Medical Sciences, New Delhi, India; 4Population Health Research Institute, Hamilton Health Sciences and McMaster
University, Hamilton, ON, Canada; 5Department of Statistical Sciences, University of Cape Town, Cape Town, South Africa; 6Department of Surgery, School of Medicine, College of
Health Sciences, University of Nairobi, Nairobi, Kenya; 7Cardiology Unit, Department of Medicine, Kenyatta National Teaching and Referral Hospital, Nairobi, Kenya; 8Cardiology Unit,
Department of Medicine, Mulago Hospital, Kampala, Uganda; 9Uganda Heart Institute, Kampala, Uganda; 10Faculty of Medicine and Surgery, University of Sana’a, Al-Thawrah Cardiac
Center, Sana’a, Yemen; 11Paediatric Cardiology Service, Windhoek Central Hospital, Windhoek, Namibia; 12Department of Paediatrics, Division of Paediatric Cardiology, Faculty of
Medicine, Cairo University Children’s Hospital, Cairo, Egypt; 13Department of Paediatrics and Child Health, Jimma University Hospital, Jimma, Ethiopia; 14Department of Internal Medicine,
Faculty of Medicine, Addis Ababa, Ethiopia; 15Department of Cardiothoracic Surgery, Al Shaab Teaching Hospital, Faculty of Medicine, Alzaiem Alazhari University, Khartoum, Sudan;
16
Department of Paediatrics and Child Health, University Teaching Hospital, University of Zambia, Lusaka, Zambia; 17Department of Paediatrics, Jos University Teaching Hospital, Jos,
Nigeria; 18Department of Paediatrics and Child Health, University of Limpopo, Polokwane, South Africa; 19Department of Internal Medicine, University of Limpopo, Polokwane, South
Africa; 20Faculty of Medicine, Benha University, Cairo, Egypt; 21Department of Paediatrics and Child Health, College of Medicine, University of Malawi, Blantyre, Malawi; 22Department of
Cardiology, Eduardo Mondlane University, Maputo, Mozambique; 23Department of Medicine, Bayero University and Aminu Kano Teaching Hospital, Kano, Nigeria; 24Division of
Cardiology, Department of Medicine, University College Hospital, Ibadan, Nigeria; 25Nigeria Ministry of Health, Umuahia, Abia State, Nigeria; 26Department of Medicine, Federal Medical
Centre, Abeokuta, Nigeria; 27Ahmed Gasim Teaching Hospital, Khartoum, Sudan; 28Instituto Nacional de Saúde and Eduardo Mondlane University, Maputo, Mozambique; 29Department
of Cardiology, Dr. George Mukhari Hospital and University of Limpopo (MEDUNSA Campus), Tshwane, South Africa; 30Cardiology Unit, Department of Medicine, University of Abuja
Teaching Hospital, Abuja, Nigeria; and 31Paediatric Cardiology Unit, Department of Paediatrics, King Faisal Hospital, Kigali, Rwanda

Received 17 August 2014; revised 19 October 2014; accepted 23 October 2014; online publish-ahead-of-print 26 November 2014

See page 1070 for the editorial comment on this article (doi:10.1093/eurheartj/ehu507)

Aims Rheumatic heart disease (RHD) accounts for over a million premature deaths annually; however, there is little contem-
porary information on presentation, complications, and treatment.
.....................................................................................................................................................................................
Methods This prospective registry enrolled 3343 patients (median age 28 years, 66.2% female) presenting with RHD at 25 hospitals
and results in 12 African countries, India, and Yemen between January 2010 and November 2012. The majority (63.9%) had
moderate-to-severe multivalvular disease complicated by congestive heart failure (33.4%), pulmonary hypertension
(28.8%), atrial fibrillation (AF) (21.8%), stroke (7.1%), infective endocarditis (4%), and major bleeding (2.7%).

* Corresponding author: Tel: +27 21 406 6200, Fax: +27 21 448 6815, Email: bongani.mayosi@uct.ac.za
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2014. For permissions please email: journals.permissions@oup.com.
1116 L. Zühlke et al.

One-quarter of adults and 5.3% of children had decreased left ventricular (LV) systolic function; 23% of adults and 14.1%
of children had dilated LVs. Fifty-five percent (n ¼ 1761) of patients were on secondary antibiotic prophylaxis. Oral anti-
coagulants were prescribed in 69.5% (n ¼ 946) of patients with mechanical valves (n ¼ 501), AF (n ¼ 397), and high-risk
mitral stenosis in sinus rhythm (n ¼ 48). However, only 28.3% (n ¼ 269) had a therapeutic international normalized ratio.
Among 1825 women of childbearing age (12 –51 years), only 3.6% (n ¼ 65) were on contraception. The utilization of
valvuloplasty and valve surgery was higher in upper-middle compared with lower-income countries.
.....................................................................................................................................................................................
Conclusion Rheumatic heart disease patients were young, predominantly female, and had high prevalence of major cardiovascular
complications. There is suboptimal utilization of secondary antibiotic prophylaxis, oral anti-coagulation, and contracep-
tion, and variations in the use of percutaneous and surgical interventions by country income level.
-----------------------------------------------------------------------------------------------------------------------------------------------------------
Keywords Rheumatic heart disease † Atrial fibrillation † Congestive heart failure † Stroke † Infective endocarditis †
Valvuloplasty † Valve surgery

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by a full study. The baseline characteristics of patients enrolled in
Introduction the pilot phase are reported here. Enrolled patients underwent assess-
Rheumatic heart disease (RHD) is one of the leading non- ment and treatment according to standard practices followed at each par-
communicable diseases in low- and middle-income countries and ticipating site. Patients were enrolled from 25 sites in 12 African
accounts for up to 1.4 million deaths per year.1,2 Patients with countries, Yemen, and India. Countries were grouped into three
income categories (2011 World Bank definitions): low-income countries
RHD also suffer from complications related to atrial fibrillation
(Ethiopia, Kenya, Malawi, Rwanda, Uganda, and Zambia), lower-middle-
(AF), infective endocarditis, and during pregnancy.3 – 5 Despite the
income countries (Egypt, India, Mozambique, Nigeria, Sudan, and
magnitude of the problem, there are few systematically collected Yemen), and upper-middle-income countries (Namibia and South
contemporary data on disease characteristics, treatments, complica- Africa).18 This study was approved by local ethics committees and
tions, and long-term outcomes in patients with RHD.6 The proposal written informed consent was obtained from the subjects (adults ≥ 18
of the World Health Organization to reduce mortality from RHD years) or their guardians (children , 18 years).
and other NCDs by 25% by the year 2025 requires an understanding The rationale, design, and objectives of the REMEDY study have been
of the contemporary characteristics and the use of proven interven- described previously.17
tions in patients living in endemic countries.7 We enrolled patients regardless of age with a primary diagnosis of
Much of the morbidity and mortality due to RHD can be prevented symptomatic RHD from outpatient clinics, emergency departments, or
by existing therapies.8,9 There is good evidence to suggest that sec- inpatient facilities, based on clinical and echocardiographic criteria.19
Patients with asymptomatic disease diagnosed through community
ondary prophylaxis with long-acting penicillin reduces the recur-
screening were not included. The AHA/ACC guidelines were used for as-
rence of episodes of acute rheumatic fever.10 Oral anti-coagulants
sessment of severity of valve lesions, left ventricular (LV) systolic dysfunc-
(OACs) in patients with rheumatic AF can reduce thromboembolic tion (i.e. left ventricular ejection fraction, LVEF , 54% in children and
complications, and percutaneous or surgical interventions can im- adults), and LV dilatation (i.e. LV end diastolic dimension , 50 mm in chil-
prove symptoms and prevent congestive heart failure (CHF).11,12 dren and , 55 mm in adults).11 Adherence to penicillin prophylaxis was
However, several older reports from developing countries have calculated based on percentage of prescriptions received over the 12
documented inadequate adherence to secondary prophylaxis and months preceding enrolment. Patients were excluded from the study if
poor control of OAC therapy,13 – 15 and it is not known whether the primary diagnosis of valvular disease was not RHD.
this has changed in recent times. In addition, rates of the use of per-
cutaneous and surgical interventions in developing countries may be Data collection
limited by the shortage of health facilities and trained staff.16 Demographic data, clinical findings, and details of electrocardiographic
The Global Rheumatic Heart Disease Registry (the REMEDY and echocardiographic findings were recorded on case report forms at
research sites and transmitted to the University of Cape Town Depart-
study) was designed to assemble a contemporary cohort of RHD
ment of Medicine Project Coordinating Office. These were relayed to
patients from developing countries to document patient characteris-
the Population Health Research Institute at Hamilton Health Sciences
tics and treatment patterns with particular reference to valvular and McMaster University, Hamilton, Ontario, Canada for further data
involvement, the prevalence of adverse cardiac events and the use checks and data storage.
of key treatments.17
Statistical considerations
Continuous variables were expressed as means with standard deviations
Methods or as medians with interquartile ranges as appropriate, and categorical
variables as frequencies and percentages. Comparisons between cat-
Study design egorical variables were assessed for statistical significance using the x 2
The Global Rheumatic Heart Disease Registry is a multi-centre, in- test, and the unpaired t-test was used to determine group differences
ternational hospital-based prospective registry of patients with RHD for continuous variables. Linear regression was utilized to explore rela-
which is conducted in two phases: a pilot phase which will be followed tionships between variables. Test results were adjusted by age and by
Evidence-based interventions in rheumatic heart disease 1117

specifying study centres as clusters. Statistical analyses were performed mode of administration, used by 1926 (89.5%) of patients with data
using STATA 11 (StataCorp, College Station, TX, USA). (n ¼ 2153); the remainder (227, 10.5%) were either on oral
penicillin or erythromycin. The use of secondary prophylaxis dif-
fered by country income group (Figure 4). Whereas oral and paren-
Results teral antibiotics were used in almost equal proportions in
upper-middle-income countries, nearly all participants in low- and
Clinical characteristics lower-middle-income countries received intramuscular penicillin.
A total of 3343 participants with RHD were enrolled between Overall, adherence to intramuscular penicillin and oral antibiotic
January 2010 and November 2012 (Supplementary material online, prophylaxis was similar (i.e. 78.6 + 32.3 and 78.0 + 32.9%, respect-
Table S1). Patients with RHD were young (median age 28 years), ively). However, adherence was higher in children compared with
mainly female (66.2%), and largely unemployed (75.3%) (Table 1 adults, for both intramuscular penicillin (81.8 + 30.8 vs. 76.9 +
and Figure 1). There were greater proportions of women in childbear- 33.1%, P , 0.001) and oral antibiotics (83.1 + 24.9 vs. 75.0 +

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ing age in low-income (86.5%) and lower-middle-income countries 36.6%; P , 0.001), respectively. Post-surgery patients were less
(90.3%) compared with upper-middle-income countries (66.9%) likely to be on secondary prophylaxis compared with those awaiting
(P , 0.01). surgery (31.1 compared with 61.5%, P , 0.001). Patients on a
Atrial fibrillation was documented in 586/2688 (21.8%) of patients 2-weekly intramuscular regime showed lower levels of adherence
with electrocardiograms performed at enrolment to the study (68.4%) than those on either a 3-weekly (76.0%) or 4-weekly
(Table 2). There were substantial variations in clinical features and regimen (82.8%) (P , 0.05).
the use of percutaneous and surgical interventions between the
different country income groups (Table 2). Stroke, peripheral embol-
ism, and the composite outcome of cardiovascular complications (i.e.
The use of oral anti-coagulants and other
stroke, systemic embolism, bleeding, or infective endocarditis) were medications
reported more frequently in patients living in upper-middle-income There were 1362 (40.7%) patients with indications for OACs in RHD
countries (14.5, 2.2, and 22.2%, respectively) compared with those (Table 3).11 Oral anti-coagulants were prescribed in 69.5% (946) of
from lower-middle-income (3,8, 0.2, and 10.1%, respectively) and such patients; the use of OACs was high in patients with mechanical
low-income countries (5.2, 0.3, and 8.7%, respectively) (P , 0.02). heart valves (91.6%) and AF (68.6%), but low in those with mitral
The proportion of children with decreased LVEF was lower in stenosis in sinus rhythm with either dilated left atrium or left atrial
upper-middle-income countries than in lower-middle- and low- thrombus (20.3%). Of the patients on OACs for the recognized indi-
income countries (P , 0.01). The use of valve replacement/repair cations, 12.2% (115) had had no international normalized ratio (INR)
and valvuloplasty positively correlated with rising country income monitoring, whereas 34.1% (323) had only one to three INR tests in
level (P ≤ 0.03) (Table 2 and Figure 2). the 6 months preceding enrolment. The INR at enrolment was sub-
therapeutic in 32.7% (309), therapeutic in 28.3% (268), and above the
Pattern and severity of native valve disease therapeutic range in 17.7% (167) (no INR testing on the remainder of
Figure 3 demonstrates the pattern of valve disease by age group in 21.4% (202)). Sixty percent of participants were unaware of the
patients without percutaneous or surgical intervention. Children in therapeutic range of INR values.
the first decade of life presented predominantly with pure mitral re- There was a high use of additional medication: 67.8% (2239/3296)
gurgitation, with mixed mitral and mixed aortic valve disease emer- of patients were on diuretics, 39.3% (1296/3296) on b-blockers,
ging as a dominant mitral valve lesion from the second decade of 34.7% (1144/3298) on digoxin, and 1.6% (52/3279) on other anti-
life. The frequency of pure mitral stenosis, isolated aortic valve arrhythmic drugs. Of those tested for human immune deficiency
disease (i.e. aortic stenosis or aortic regurgitation) and mixed virus (HIV) infection (1180, 35.3%), 56 (4.7%) were HIV positive;
aortic valve disease without mitral disease was low in early life, and the remainder (2163, 64.7%) were either unaware of their HIV
increased with age. status or declined to provide the information. In 1825, women of
The majority of cases of mitral stenosis (1119/1535, 72.9%), mitral childbearing age (12 –51 years), only 3.6% (65) were on contracep-
regurgitation (1479/2464, 60.4%), pulmonary stenosis (19/32, tive medication. A total of 73 women (3.6%) were pregnant at the
59.4%), tricuspid stenosis (58/107, 54.2%), and aortic stenosis time of enrolment, the youngest 14 years, and the oldest 51 years
(187/302, 61.9%) had moderate-to-severe disease, whereas the ma- of age. In total, 15 (20.6%) pregnant women were on warfarin.
jority of cases of aortic regurgitation (922/1671, 55.2%) were mild.
Patients with native valve disease had a dilated left ventricle (LV) in
23% (n ¼ 581) of adults and 16.4% (n ¼ 413) of children, and a Discussion
decreased ejection fraction in 18.3% (n ¼ 460) of adults and 5.6% This study has five main findings. First, the patients with RHD from
(n ¼ 140) of children. There was a gradient as patients increased in low- and middle-income countries were young (median age 28
age for dilated LV (P , 0.0001) and falling LVEF (P , 0.0001), years), largely female (66.2%), and had a high unemployment rate
which suggest disease progression. (75.3%). Second, the majority had moderate-to-severe valvular
heart disease that was associated with pulmonary hypertension
The use of secondary prophylaxis and up to a quarter of patients had LV dysfunction. Third, there
Overall, secondary penicillin prophylaxis was prescribed in 54.8% was an inadequate use of secondary antibiotic prophylaxis in devel-
(1761/3213) of patients. Intramuscular penicillin was the commonest oping countries, with lack of preventive treatment in nearly half of
1118 L. Zühlke et al.

Table 1 Demographic characteristics of 3343 children and adults with rheumatic heart disease

Low-income Lower-middle-income Upper-middle-income P Total

countries countries countries
...............................................................................................................................................................................
Participants, n (%) 1110 (33.2) 1370 (41.0) 863 (25.8) 3343
Age, median (IQR)a 24 (15–34) 28 (18–38) 39 (22– 52) 0.4 28 (18–40)
Women, n (%)b 728 (65.8) 867 (63) 616 (71.3) 0.33 2211 (66.2)
Women in childbearing age, n (%)c 630 (86.5) 783 (90.3) 412 (66.9) ,0.01 1825 (82.5)
Children, n (%)d 405 (36.6) 349 (25.5) 167 (19.4) 0.54 921 (27.6)
Adults with no formal schooling, n (%)e 66 (9.5) 354 (34.9) 38 (5.5) ,0.01 458 (19.1)
Completed primary level schooling 246 (35.2) 278 (27.4) 204 (29.6) 0.48 728 (30.3)

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Completed secondary level schooling 373 (53.4) 372 (36.7) 436 (63.3) 0.03 1181 (49.2)
Completed tertiary level education 13 (1.98) 10 (1.0) 11 (1.6) 0.5 34 (1.4)
Unemployed adults, n (%)f,g 529 (75.4) 766 (75.1) 520 (75.5) 0.98 1815 (75.3)

a
Data are available for 3339 participants.
b
Data are available for 3340 participants.
c
Defined as between the ages of 12 and 51.
d
Children are defined as younger than 19 years of age.
e
Data are available for 3317 participants.
f
Data are available for 2411 participants.
g
Adults are 19 years or older.

Figure 1 Age and gender distribution of 3339 children and adults with rheumatic heart disease.

patients. Fourth, whilst the overall use of OACs in patients with ap- Rheumatic heart disease is a chronic disease of the young that
propriate indications was relatively high (69.5%), it was low in patients accounts for the greatest cardiovascular related loss of disability-
with mitral stenosis in sinus rhythm at high risk for cardiac embolism. adjusted life years in children.20 Whilst female predominance is
The quality of anti-coagulation control at study enrolment was poor, well recognized,9 the prominence of women in the reproductive
with only a quarter of patients having INRs in the therapeutic age has major implications for the reproductive health of patients
range. Finally, there were variations between low-, lower-middle- living in developing countries.21 Rheumatic heart disease increases
and upper-middle-income countries in the ascertainment and preva- the risk of pregnancy and is one of the major non-obstetric causes
lence of cardiovascular complications, and the use of percutaneous of maternal death in Africa.3,22 The extremely low rate of the use
and surgical interventions for RHD. of contraception in this cohort is alarming, and reflects the poor
Evidence-based interventions in rheumatic heart disease 1119

Table 2 Clinical characteristics of 3343 children and adults with rheumatic heart disease

Low-income Lower-middle-income Upper-middle-income P

countries (N 1110) countries (N 1370) countries (N 863)
N (%) N (%) N (%)
...............................................................................................................................................................................
New York Heart Association Functional Class III & IV 306 (27.6) 384 (29.1) 119 (13.9) 0.24
...............................................................................................................................................................................
Medical history
Acute rheumatic fever 247 (22.3) 593 (44.3) 500 (59.0) 0.06
Congestive heart failure 476 (43.0) 285 (21.0) 349 (40.6) 0.06
Pulmonary hypertension 329 (29.9) 465 (34.2) 163 (19) 0.5
Stroke 58 (5.2) 52 (3.8) 125 (14.5) ,0.01

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Infective endocarditis 25 (2.3) 59 (4.36) 49 (5.7) 0.1
Major Bleeding 21 (1.9) 38 (2.8) 30 (3.5) 0.61
Peripheral embolism 3 (0.3) 3 (0.2) 19 (2.2) ,0.001
Cardiovascular complicationsa 96 (8.7) 137 (10.1) 191 (22.2) 0.02
Atrial fibrillation 163 (17.9) 241 (22.0) 182 (22.7) 0.49
...............................................................................................................................................................................
Echocardiography
Decreased LVEF in adults 223 (20.6) 262 (19.8) 176 (22.2) 0.58
Decreased LVEF in children 67 (6.2) 83 (6.3) 18 (2.3) ,0.01
Dilated LVEDD in adults 260 (23.9) 302 (22.7) 180 (22.3) 0.81
Dilated LVEDD in children 191 (17.6) 177 (13.3) 86 (10.7) 0.3
Left atrial thrombus 19 (1.8) 18 (1.4) 7 (0.8) 0.6
...............................................................................................................................................................................
Surgery
Valve replacement or repair 81 (11.3) 199 (27.8) 435 (60.8) ,0.01
Mechanical valve only 55 (93.2) 136 (86.6) 349 (93.8) 0.31
Bio-prosthetic valve only 4 (6.8) 18 (11.5) 19 (5.1)
Mechanical and biological prostheses 0 (0) 3 (1.9) 4 (1.1)
Percutaneous valvuloplasty 12 (1.1) 54 (4.0) 69 (8.0) 0.03

LVEF, left ventricular ejection fraction; LVEDD, left ventricular end diastolic dimension.
a
Cardiovascular complications include any of the following events: stroke, infective endocarditis, major bleeding, or peripheral embolism.

known teratogenicity of the agent. This calls for safer alternatives in

these women.
The pattern of rheumatic valve involvement that is characterized
by pure mitral regurgitation in the first two decades of life is similar
to what has been observed previously.24 – 27 This study additionally
found that the patients had moderate-to-severe rheumatic valve
disease that was associated with pulmonary hypertension and LV dys-
function in substantial proportions of cases. The enrolment of severe
cases probably reflects the referral patterns to the participating sites
which served as tertiary centres in their countries. These patients are
at high risk of developing CHF and infective endocarditis and will
require surgical intervention. In the Heart of Soweto study of 344
new cases of RHD seen at a tertiary centre, 22% required valve re-
placement/repair within a year, and 26% developed infective endo-
carditis within 30 months.24
Figure 2 Utilization of valve surgery and valvuloplasty in children
While the effectiveness of control programmes of RHD through
and adults from low-income, lower-middle-income, and
secondary prevention in the form of regular long-acting intramuscular
upper-middle-income countries.
benzathine penicillin injections is proven,28 implementation is difficult
and extremely variable both within and between countries.29 Low
provision of family planning and pre-pregnancy advice for women uptake has been highlighted in numerous countries.13,14,30,31 The
with heart disease in many regions of the world.21,23 We found that WHO recommends the life-long use of antibiotic prophylaxis to
20.6% of women who were pregnant were on warfarin despite the prevent rheumatic fever in patients with moderate-to-severe RHD,
1120 L. Zühlke et al.

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Figure 3 The pattern of native rheumatic valve disease in 2475 children and adults with no percutaneous or surgical interventions. AVD, aortic
valve disease; MAVD, mixed aortic valve disease; MMAVD, mixed aortic and mitral valve disease; MMVD, mixed mitral valve disease; MR, mitral
regurgitation; MS, mitral stenosis.

Figure 4 Adherence to secondary prophylaxis with penicillin in low-income, low-middle-income, and upper-middle-income countries.

such as those enrolled in this study.32 However, nearly half of partici- Oral anti-coagulants are recommended in RHD patients with
pants in this study were not on antibiotic prophylaxis at the time of en- mechanical heart valves, valvular heart disease associated with AF,
rolment. Thus, there is a need to identify barriers and enhance the or patients in sinus rhythm with mitral stenosis associated with a high-
delivery of secondary prophylaxis for RHD within the framework of risk factor such as previous stroke, left atrial thrombus, or dilated left
care for chronic diseases in low- and middle-income countries.33 atrium.11 In the present study, OACs were prescribed in 70% of
Evidence-based interventions in rheumatic heart disease 1121

Table 3 Use of anti-thrombotic medication and quality of anti-coagulation in patients with an indication for oral
anti-coagulant therapy

Indication Anti-thrombotic N (%) Details N (%)a

medication
...............................................................................................................................................................................
Mechanical valves Warfarin 501 (91.6) No INR tests done in 6 months prior to enrolment 28 (5.6)
1– 3 INR tests done 6 months prior to enrolment 155 (30.9)
Enrolment INR tests ,2.5 198 (39.5)
Enrolment INR tests in 2.5–3.5 range 168 (33.5)
Enrolment INR tests . 3.5 72 (14.4)
None 41 (7.5)
Aspirin 5 (0.9)
Total 547

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...............................................................................................................................................................................
Atrial fibrillation Warfarin 397 (67.8) No INR tests done in 6 months prior to enrolment 58 (14.6)
1– 3 INR tests done 6 months prior to enrolment 147 (37.0)
Enrolment INR tests ,2.0 94 (23.7)
Enrolment INR tests in 2.0–3.0 range 88 (22.2)
Enrolment INR . 3.0 85 (21.4)
None 126 (21.5)
Aspirin 55 (9.5)
Other (heparin) 8 (1.5)
Total 586
...............................................................................................................................................................................
Mitral stenosis in sinus rhythm Warfarin 48 (20.3) No INR tests done in 6 months prior to enrolment 29 (60.4)
and left atrial diameter ≥ 55 1– 3 INR tests done 6 months prior to enrolment 21 (43.8)
or left atrial thrombus Enrolment INR tests ,2.0 17 (35.4)
Enrolment INR tests in 2.0–3.0 range 12 (25.0)
Enrolment INR .3.0 10 (20.8)
None 169 (71.6)
Aspirin 19 (8.0)
Total 236

a
The denominator is the number of patients on warfarin for each indication; INR, international normalized ratio; target range for mechanical prosthetic valves, 2.5 –3.5; target range for
rheumatic atrial fibrillation or mitral stenosis in sinus rhythm with high-risk features, 2.0– 3.0.

patients with these indications, which is higher than the 58% use of Limitations: We report a hospital-based registry and cannot address
OACs found in a world-wide registry of non-rheumatic AF.15 Inter- the burden of disease in the community. Owing to the need for
national normalized ratio control was however poor, with only 1 availability of cardiology expertise and echocardiography facilities
in 4 patients on OACs having therapeutic INR levels at the time of for the diagnosis of RHD in the study, we have enrolled cases of
enrolment. Alternative strategies for improving anticoagulation in moderate-to-severe symptomatic RHD typically seen at referral
lower- and middle-income countries need to be considered, in- centres. But several of our participating sites (e.g. Namibia and
cluding the use of point-of-care INR testing and trials of new forms Zambia) were the sole (or one of few) referral centres in their re-
of oral anti-coagulants in RHD patients with native valves.34 – 36 spective countries, thereby providing a representative snapshot of
This study provides a basis for trials comparing different strategies symptomatic disease in these countries. Furthermore, past events
for anti-coagulation in RHD patients who have been excluded in vir- were self- or physician reported, and were not independently veri-
tually all randomized controlled trials of stroke prevention.15 fied. Similarly, adherence to secondary prophylaxis was not verified
We observed variations in the ascertainment of cardiovascular using pill counts or registers, as these were largely unavailable in
complications, echocardiographic LV dysfunction and the use of per- the countries involved. However, INR measurements were verified
cutaneous and surgical intervention by country income status. The in- from laboratory records. Finally, an additional limitation of the
creasing prevalence of cardiovascular sequelae with rising country REMEDY baseline study is that we report observations of a cross-
income status was independent of age, suggesting more effective de- sectional study. The interpretation of the findings of a cross-sectional
tection of such sequelae. The use of percutaneous and surgical inter- study are inherently limited. This particularly applies to comparisons
ventions was extremely low in low-income countries compared with across country income status as those are prone to ecological fallacy.
upper-middle-income countries, despite the greater prevalence of
patients with RHD and LV dysfunction who require these interven-
tions in low-income countries. These disparities in the ascertainment
Conclusions
of cardiovascular complications and the use of effective invasive inter- There are gaps in the implementation of medical and surgical inter-
ventions probably reflect differences in access to healthcare between ventions of proven effectiveness for RHD in low- and middle-income
countries. countries.7,19 These include the suboptimal use of penicillin for
1122 L. Zühlke et al.

secondary prophylaxis, inadequate monitoring and control of oral 8. Carapetis JR, Mayosi BM, Kaplan EL. Controlling rheumatic heart disease in develop-
ing countries. Cardiovasc J S Afr 2006;17:164 –165.
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9. Lawrence JG, Carapetis JR, Griffiths K, Edwards K, Condon JR. Acute rheumatic fever
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Braithwaite T, Brayne C, Bridgett L, Brooker S, Brooks P, Brugha TS,
International Clinical Research Fellowship, Thrasher Research Fund
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Early Career Award, Wellcome Trust Clinical Infectious Disease Re- Burney P, Burstein R, Calabria B, Campbell B, Canter CE, Carabin H, Carapetis J,
search Initiative (CIDRI) Research Officer Award, and the Hamilton Carmona L, Cella C, Charlson F, Chen H, Cheng AT-A, Chou D, Chugh SS,
Naki Clinical Scholarship. Coffeng LE, Colan SD, Colquhoun S, Colson KE, Condon J, Connor MD,
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Conflict of interest: A.E. has received a grant from Sheikan Insurance Criqui MH, Cross M, Dabhadkar KC, Dahiya M, Dahodwala N, Damsere-Derry J,
Danaei G, Davis A, Leo DD, Degenhardt L, Dellavalle R, Delossantos A,
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