NOVEMBER/DECEMBER 2023 VOL 34 NO 5 • Efficacy of an originator versus a generic formulation of simvastatin • Ultrasound training for non-cardiologists in a resource-limited setting • Association of serum lipoprotein-associated phospholipase A2 level and ACS • Pre-operative monocyte count-HDL ratio and postoperative acute kidney injury • Pregnancy outcomes in women with pulmonary hypertension in KwaZulu-Natal • Mitral valve area and left atrial function in rheumatic mitral valve stenosis • Red blood cell distribution volume to predict atrial fibrillation after CABG • Hypertension treatment in sub-Saharan Africa: a systematic review CardioVascular Journal of Afr ica (off icial journal for PASCAR) www.cvja.co.za
Pharmaco Distribution (Pty) Ltd. 3 Sandown Valley Crescent, South Tower, 1st Floor Sandton, 2196. PO Box 786522, Sandton, 2146. South Africa Tel: +27 11 784 0077. Fax: +27 11 784 6994. www.pharmaco.co.za ISA _ 21 _ 01 References: 1. Ismo® South African SAHPRA aproved package insert. 2. Ismo 20 Product Monograph(2015). 3. Abshagen,U. 1992. Pharmacokinetics of isosorbide mononitrate. The American Journal of Cradiology, [online] 70 (17),pp.G61-G66 4. Thadani U, Maranda CR, Amsterdam E, et al. Lack of Pharmacological Tolerance and Rebound Angina Pectoris during Twice-daily Therapy with isosorbide-5-mononitrate. Annals of Internal Medicine. 1994.; 120: 353-359. ISMO®-20 R/7.1.4/136. Each Ismo®-20 Tablet contains Isosorbide-5-mononitrate 20mg. S3 For full prescribing information, please refer to the approved package insert R T S Q P R T S Q P P Long term prophylaxis and management of Angina Pectoris1 No first-pass metabolism. 100% bioavalability2,3 Twice-daily dosing regimen shown to avoid withdrawal and tolerance4 Trust the Original!
ISSN 1995-1892 (print) ISSN 1680-0745 (online) Cardiovascular Journal of Afr ica www.cvja.co.za CONTENTS INDEXED AT SCISEARCH (SCI), PUBMED, PUBMED CENTRAL AND SABINET Vol 34, No 5, NOVEMBER/DECEMBER 2023 EDITORS Editor-in-Chief (South Africa) PROF PAT COMMERFORD Assistant Editor PROF JAMES KER (JUN) Regional Editor DR A DZUDIE Regional Editor (Kenya) DR F BUKACHI Regional Editor (South Africa) PROF R DELPORT EDITORIAL BOARD PROF PA BRINK Experimental & Laboratory Cardiology PROF R DELPORT Chemical Pathology PROF MR ESSOP Haemodynamics, Heart Failure & Valvular Heart Disease DR OB FAMILONI Clinical Cardiology DR V GRIGOROV Invasive Cardiology & Heart Failure PROF J KER (SEN) Hypertension, Cardiomyopathy, Cardiovascular Physiology DR J LAWRENSON Paediatric Heart Disease PROF A LOCHNER Biochemistry/Laboratory Science DR MT MPE Cardiomyopathy PROF DP NAIDOO Echocardiography PROF B RAYNER Hypertension/Society PROF MM SATHEKGE Nuclear Medicine/Society PROF YK SEEDAT Diabetes & Hypertension PROF H DU T THERON Invasive Cardiology INTERNATIONAL ADVISORY BOARD PROF DAVID CELEMAJER Australia (Clinical Cardiology) PROF KEITH COPELIN FERDINAND USA (General Cardiology) DR SAMUEL KINGUE Cameroon (General Cardiology) DR GEORGE A MENSAH USA (General Cardiology) PROF WILLIAM NELSON USA (Electrocardiology) DR ULRICH VON OPPEL Wales (Cardiovascular Surgery) PROF PETER SCHWARTZ Italy (Dysrhythmias) PROF ERNST VON SCHWARZ USA (Interventional Cardiology) SUBJECT EDITORS Nuclear Medicine and Imaging DR MM SATHEKGE Heart Failure DR G VISAGIE Paediatric DR S BROWN Paediatric Surgery DR DARSHAN REDDY Renal Hypertension DR BRIAN RAYNER Surgical DR F AZIZ Adult Surgery DR J ROSSOUW Epidemiology and Preventionist DR AP KENGNE Pregnancy-associated Heart Disease PROF K SLIWA-HAHNLE 263 FROM THE EDITOR’S DESK P Comerford CARDIOVASCULAR TOPICS 264 A retrospective study: efficacy of an originator versus a generic formulation of simvastatin in patients who suffer from hyperlipidaemia JR Snyman • KR Snyman on behalf of Simvotin® study group 268 Feasibility of focused cardiac ultrasound training for non-cardiologists in a resourcelimited setting using a handheld ultrasound machine B Acheampong • JR Starnes • YA Awuku • D Parra • MH Aliyu • JH Soslow 273 Association between the serum lipoprotein-associated phospholipase A2 level and acute coronary syndrome L Dong • J Tong • S Fan 278 Is pre-operative monocyte count-high-density lipoprotein ratio associated with postoperative acute kidney injury in isolated coronary artery bypass grafting? H Şaşkın 285 A three-year audit of pregnancy outcomes in women with pulmonary hypertension admitted to the high-risk obstetric unit at Inkosi Albert Luthuli Central Hospital, KwaZulu-Natal, South Africa S Budhram • P Krishundutt 292 Correlation between mitral valve area and left atrial function in rheumatic mitral valve stenosis patients A Fareed • M Hamed • F Makaldy • O Saleh 299 A new biomarker to predict atrial fibrillation and its adverse events after coronary artery bypass surgery: red blood cell distribution volume H Şaşkın • DA Görür
CONTENTS Vol 34, No 5, NOVEMBER/DECEMBER 2023 FINANCIAL & PRODUCTION CO-ORDINATOR ELSABÉ BURMEISTER Tel: 021 976 8129 Fax: 086 664 4202 Cell: 082 775 6808 e-mail: elsabe@clinicscardive.com PRODUCTION EDITOR SHAUNA GERMISHUIZEN Tel: 021 785 7178 Cell: 083 460 8535 e-mail: shauna@clinicscardive.com CONTENT MANAGER MICHAEL MEADON (Design Connection) Tel: 021 976 8129 Fax: 0866 557 149 e-mail: michael@clinicscardive.com The Cardiovascular Journal of Africa, incorporating the Cardiovascular Journal of South Africa, is published 10 times a year, the publication date being the third week of the designated month. COPYRIGHT: Clinics Cardive Publishing (Pty) Ltd. LAYOUT: Jeanine Fourie – TextWrap PRINTER: Tandym Print/Castle Graphics ONLINE PUBLISHING & CODING SERVICES: Design Connection & Active-XML.com All submissions to CVJA are to be made online via www.cvja.co.za Electronic submission by means of an e-mail attachment may be considered under exceptional circumstances. Postal address: PO Box 1013, Durbanville, RSA, 7551 Tel: 021 976 8129 Fax: 0866 644 202 Int.: +27 21 976 8129 e-mail: info@clinicscardive.com Electronic abstracts available on Pubmed Audited circulation Full text articles available on: www.cvja. co.za or via www.sabinet.co.za; for access codes contact elsabe@clinicscardive.com Subscription: To subscribe to the online PDF version of the journal, e-mail elsabe@clinicscardive.com • R500 per issue (excl VAT) • R2 500 for 1-year subscription (excl VAT) The views and opinions expressed in the articles and reviews published are those of the authors and do not necessarily reflect those of the editors of the Journal or its sponsors. In all clinical instances, medical practitioners are referred to the product insert documentation as approved by the relevant control authorities. LETTER TO THE EDITOR 291 Outcomes of pregnancy with pulmonary hypertension: low risk or a false dawn? OJ Ilonze REVIEW ARTICLE 307 Hypertension treatment in sub-Saharan Africa: a systematic review P Cavagna • C Leplay • R N’Guetta • KE Kramoh • IB Diop • DM Balde • JB Mipinda • M Azizi • X Jouven • M Antignac CASE REPORTS 318 A case of spontaneous isolated superior mesenteric arterial dissection with coeliac axis stenosis K Ye • Y Wang • S Wan 321 Very rare malposition of central venous catheter in cardiac surgery patients N Tanrikulu • A Haspolat • AS Koprulu PUBLISHED ONLINE (Available on www.cvja.co.za and in PubMed)
CARDIOVASCULAR JOURNAL OF AFRICA • Volume 34, No 5, November/December 2023 AFRICA 263 From the Editor’s Desk It is often difficult to understand the reluctance of some medical practitioners to accept generic substitutes of the originator medicine. Of course, there are seldom large-scale randomised clinical trials to prove equivalence but most reputable regulatory authorities register generics only after careful evaluation. Given the cost-saving consequences of generic substitution, it is understandable that most publicly funded health services require generic substitution in an attempt to spread the benefit to a larger population. To my knowledge there has not been any solid scientific proof that such substitution is in any way harmful. In this final issue of 2023, Snyman and colleagues (page 264) describe a retrospective, chart-based review of the effects of switching patients with hyperlipdaemia from the originator statin to a generic. They concluded this real-world evidence should allay any fears of generic inferiority of this important medicine in the treatment and prevention of high cardiovascular risk in patients requiring lipid-lowering therapy. The study was retrospective and chart-based but given those limitations, the results should be reassuring to those practicing in resource-poor settings. In a similar vein, Acheampong and colleagues from Ghana, collaborating with those in the USA (page 268) describe the outcome of an important evaluation, not of treatment, but of the investigation of patients with cardiovascular disease by training non-cardiologists in echocardiography performance and interpretation. Internal medicine residents at a tertiarylevel hospital in Ghana were trained to perform limited echocardiographic studies. Interpretation was compared to expert interpretation. Agreement improved over time. At the final evaluation, there was high agreement across all aspects: left ventricular structure and function, right ventricular structure and function, and presence of effusion. This accords with general experience. From the very early days of M-mode echocardiography, non-cardiologists and clinical technologists have been trained to perform these relatively simple measures successfully and it is reassuring to have it quantified and confirmed in a formal investigation. Certainly, evaluations of more complex aspects will require much more extensive training. Many consider that management of hypertension in Africa leaves much to be desired. A systematic review of the subject by Cavagna and co-authors (page 307) confirms this opinion. Budhram and Krishundutt (page 285) report a three-year audit of pregnancy outcomes in women with pulmonary hypertension admitted to a high-risk obstetric unit in South Africa. An important letter to the editor by Ilonze (page 291) points out that the results may not necessarily be generalisable because of both the method of diagnosing pulmonary hypertension (echocardiography) and the characteristics of the patient population. Such detailed critique is welcomed and will always be published. Pat Commerford Editor-in-Chief Professor PJ Commerford
CARDIOVASCULAR JOURNAL OF AFRICA • Volume 34, No 5, November/December 2023 264 AFRICA Cardiovascular Topics A retrospective study: efficacy of an originator versus a generic formulation of simvastatin in patients who suffer from hyperlipidaemia JR Snyman, KR Snyman on behalf of Simvotin® study group Abstract Background: South Africa is home to a multi-ethnic society with a large range of cultures and lifestyles. Cardiovascular disease is a major cause of morbidity and mortality. South Africa is known to have one of the highest incidence rates of hypercholesterolaemia in the world, especially among the Caucasian population. Aim: The aim of this retrospective chart review was to establish whether a multisource simvastatin (Simvotin®, Ranbaxy, a Sun Pharma company) maintained the cholesterol-lowering effect after switching from the innovator brand Zocor® (MSD South Africa) in the public-sector hospitals. Since prescribers often doubt the registration requirements of multisource products based on bioequivalence alone, this research was done to confirm similar clinical outcomes in a real-world setting. Methods: More than 200 charts were identified from patients treated for hyperlipidaemia. Patients were treated for at least six months prior to and again six months after the switching of brands in order to meet criteria to be eligible for inclusion. The lipid values at initiation of therapy as well as before switching (visit 1 and 2) had to be available and again six months after treatment on the multisource product (visit 3). Results: No significant change was observed in the lipid control after switching, confirming similarity. Conclusion: This real-world evidence should allay any fears of generic inferiority of this important medicine in the treatment and prevention of high cardiovascular risk in patients requiring lipid-lowering therapy. Keywords: hyperlipidaemia, simvastatin, cholesterol, lipid, hypercholesterolaemia Submitted 26/9/21; accepted 10/10/22 Published online 8/12/22 Cardiovasc J Afr 2023; 34: 264–267 www.cvja.co.za DOI: 10.5830/CVJA-2022-053 This study investigated the originator and generic formulations of simvastatin to determine whether clinical equivalence exists in a real-world setting. This study was undertaken in order to investigate whether there was indeed clinical or therapeutic equivalence between the originator and generic formulations of simvastatin, researching treated patient data retrospectively, before and after switching between two branded versions of simvastatin, one the originator and the other a multisource equivalent. In practice, the most important and common form of dyslipidaemia is hypercholesterolaemia.1 Research from animal and laboratory investigations, epidemiology and genetic forms of hypercholesterolaemia indicate that an elevated low-density lipoprotein cholesterol (LDL-C) level is a major cause of coronary heart disease (CHD).2 The South African guidelines advocate that the use of drug therapy must balance the cost against the clinical efficacy and risk of CHD.1,3 The recommendations, when initiating drug therapy, are indicated as follows: lipid-lowering drugs should be recommended to patients with a 10-year risk of an overt CHD event of > 20%, projected to the age of 60 years.4 Although clinical judgement plays an important role in initiation of treatment, patients with familial hypercholesterolaemia or the presence of established CHD (including a previous acute myocardial infarction) should be candidates for lipid-lowering drugs. The response to medicinal interventions varies from person to person and the general consensus is that an ‘anti-coronary’ diet, weight loss as well as a regular exercise routine are able to enhance the effects of lipid-lowering agents significantly.1,3 One of the pharmacological interventions used to treat increased cholesterol levels is a class of drugs called the statins. Statins are by far the most prescribed treatment choice for LDL-C reduction, which demonstrably reduce cardiovascular mortality rate.5 Statins act by inhibiting hydroxy-methylglutaryl co-enzyme A reductase, a key enzyme in cholesterol synthesis, leading up to an increased LDL-C clearance. The statins reduce LDL-C levels by up to 60% and produce small increases in highdensity lipoprotein cholesterol (HDL-C) and triglycerides (TG). Statins also appear to decrease intra-arterial and/or systemic inflammation by stimulating production of endothelial nitric oxide.5 This class of drug may also decrease LDL-C deposition in endothelial macrophages as well as decrease cholesterol in inflammatory cell membranes. This anti-inflammatory effect is anti-atherogenic, even in the absence of elevated lipid levels.5 Clinical pharmacologist, Pretoria, South Africa JR Snyman, MB ChB, MPharm Med, MD, jacques@dermav.co.za Pharmaceutics, Cape Town, South Africa KR Snyman, BPharm, MSc
CARDIOVASCULAR JOURNAL OF AFRICA • Volume 34, No 5, November/December 2023 AFRICA 265 Evidence from large-scale, prospective, double-blind, randomised clinical trials clearly indicates a rate reduction in total and cardiovascular morbidity and mortality with statins, initially for pravastatin,6,7 and shortly followed by evidence for simvastatin.8,9 An average reduction in LDL-C of about 1 mmol/l, maintained for approximately five years, produced a reduction in non-fatal myocardial infarction and coronary death in about one-quarter of the study populations.9 Although the concept of aggressive treatment of raised LDL-C level is now well entrenched, the cost of long-term treatment is often seen as prohibitive by third-party funders, especially in lower-risk individuals, therefore the increase in entry threshold of treatment. The introduction of multisource generic products has however, eroded this objection but introduced yet another from the prescriber and that is distrust in the equivalence of products. In order to investigate whether the distrust is founded on evidence, it was decided to retrospectively investigate the impact of the introduction of a multisource product into public-sector (government funded) lipid clinics by evaluating LDL-C values over time, before and after introduction. The primary aim of this real-world study was, therefore, to assess the efficacy of a generic formulation of simvastatin (Simvotin®, Ranbaxy, a Sun Pharma company) compared to a non-generic (originator) formulation of simvastatin (Zocor®, MSD South Africa) in patients with hyperlipidaemia, by assessing the maintenance of lipid control after the switch of medication from Zocor® to Simvotin®. Methods The analysis was performed as a multi-centre, retrospective study at three sites in South Africa (one each in Gauteng, Free State and KwaZulu Natal provinces). A retrospective, short review of patient files was done with no administration of study treatment. Ethics committee approval was obtained for retrospective chart review at each centre prior to initiation of the study and data collection. Patients received their normal care and medication at these public lipid or cardiology clinics. The study focused on a time period from 2005 to 2007, during which the simvastatin dispensed to patients at these clinics changed from the original drug (Zocor®) to the generic drug (Simvotin®). The time points for data collection assessed is illustrated in Fig. 1. The patients included in this study were male and female between the ages of 18 and 80 years who had been on treatment with the originator drug (Zocor®) for at least six months on the same dosage, before being switched to the generic drug (Simvotin®), and where the dose had been unchanged for the period until the second evaluation, which was at least six months after the switch. Patients were excluded from the study if they had been taking any other lipid-lowering agents in addition to the simvastatin. Demographics of the patients are presented in Table 1. This study was a retrospective chart review of patients’ files and therefore required no study-related administration of treatment. The lipid-lowering agents in treatment that were evaluated were simvastatin oral tablets, namely Zocor® and Simvotin® tablets that were used in a once-daily dosing regimen. No formal sample size estimation was done. A sample of 205 patients from three sites was enrolled into the study. These individuals formed the total number of patients who fulfilled the stated criteria and had pathology reports on lipid profiles on file. Patient were excluded if the lipid profiles were not available, or if they were taking other lipid-lowering agents, or were non-compliant (missed more than one script fill in a six-month period). All patients had to switch from originator to generic multisource product to be included in the study. With a sample size of 205 patients switched from Zocor® to Simvotin®, a two-sided 95% confidence interval for the true proportion (percentage) of patients controlled (the control rate) after the switch, using the large sample normal approximation of the binomial distribution, will extend to approximately 0.03 (3%) from the observed proportion (percentage) to be calculated from the sample, if the expected proportion (percentage) of controlled patients (after the switch) is between 0.85 and 0.90 (85 to 90%). The primary outcome of the study was to assess the efficacy of the generic formulation Simvotin® tablets in controlling the total cholesterol level in patients in relation to baseline (visit 1) after being switched from Zocor® tablets. All lipid levels available were recorded and analysed as secondary outcomes. They are displayed in Table 2. Statistical analysis All statistical procedures were performed on SAS®, release 9.1, run under Microsoft® Windows® for a personal computer, and p-values ≤ 0.05 were considered significant. Results The charts of 205 patients who fulfilled the inclusion criteria were included for review in the study. Of the 205 patients enrolled, 118 patients had the same strength of simvastatin administered at all three data-collection points (visit 1, 2 and 3), which means they had been prescribed the same strength of statin even after the switch from Zocor® to Simvotin® tablets (Table 2). These 118 patients would then not have a dosedifferent effect on cholesterol levels, which will then be used to demonstrate similarity. Dose continuity was a requirement for therapeutic equivalence. Table 1. Patient demographics Parameters Number (%) of patients Male 87 (42.4) Female 118 (57.6) Total 205 (100) Non-smoker 156 (76.1) Smoker 39 (19.0) Ex-smoker 10 (4.9) Total 205 (100) Visit 1 Visit 2 Visit 3 Assessment of lipid profile before initiation of therapy with Zocor® Assess lipid control rate on Zocor® before switch from Zocor® to Simvotin® Assess lipid control rate on Simvotin® >6 months on treatment with Zocor® >6 months on treatment with Simvotin® Fig. 1. Data-collection time points.
CARDIOVASCULAR JOURNAL OF AFRICA • Volume 34, No 5, November/December 2023 266 AFRICA The data were collected at the three time points on case report forms with specified fields captured to determine the outcome of the study. Among the fields assessed were total cholesterol, HDL-C, LDL-C (mmol/l, fasting) and TG (mmol/l, fasting). The total cholesterol, HDL-C, LDL-C and TG levels are reflected in Table 2. The mean changes in these levels from visit 1 to visit 2 (the reference period) and from visit 2 to visit 3 (the maintenance period) are also shown. The results show that from visit 2 to visit 3 there was no significant change in total cholesterol levels and that Simvotin® tablets maintained lipid control in these patients, after the switch was made from Zocor® tablets. The switch between brands occurred between visit 2 and visit 3 and we allowed six months between these visits on the same drug dose to assess therapeutic similarity. Discussion In this study, the generic simvastatin (Simvotin®) has been shown to be clinically equivalent in maintaining the lowered lipid levels at the same level as the originator simvastatin, Zocor®, in this real-world study. Adequate risk-factor control in patients at high risk for cardiovascular disease is essential to improve long-term prognosis. The significant benefit of good risk-factor control has been well established in patients with hypercholesterolaemia. Statins or HMG-CoA (3-hydroxy-3-methylglutaryl co-enzyme A) reductase inhibitors still remain the backbone of the treatment of patients with hypercholesterolaemia and have been well proven to reduce mortality and morbidity rates.10 As the statin drugs, such as simvastatin, have come off-patent, multiple multisource products or so-called generic drugs have been introduced into the current market. Since clinical or therapeutic comparative studies have never been a prerequisite for registration of small-molecule oral generic drugs where the active product ingredient is identical and where bioequivalence alone is considered sufficient proof of equivalence by the relevant regulatory authorities, many clinicians have had doubts as to the clinical equivalence of these multisource generic medicines. In this study the multisource simvastatin (Simvotin®) has been shown to be therapeutically equivalent in maintaining the lowered lipid levels at the same level as the originator simvastatin (Zocor®). A multisource product is described as having the same active product ingredient at the same dose strength, the same route of administration and same manufacturing quality and rigour, with a presumed similar therapeutic outcome. This then constitutes a bioequivalent product, according to the USA Food and Drug Administration (FDA).11 This real-world study aimed to demonstrate that a multisource product retained the therapeutic effect achieved by the originator. Statins are reversible inhibitors of the HMG-CoA enzyme, which leads to improved cholesterol clearance due to upregulation of receptors on the hepatocytes (LDL-C receptors).12-14 The bioavailability of simvastatin is very low due to its extensive pre-systemic elimination (approximately 7%), which gives relevance to doing a therapeutic equivalence study ensuring real-world similarity, since a typical bioequivalence study may be impaired by low and variable bioavailability of simvastatin.15 With the appropriate evidence of clinical equivalence, this generic drug can be prescribed with confidence by the practitioner. A generic drug is referred to as a drug that is a copy of a brand-name drug that has equivalent dosage, intended use, effectivity, side-effect profile, route of administration, risks, safety, as well as strength as the original drug and would, after dosing, reach the receptor site in equivalent concentrations and time exposure. Therefore, the pharmacological action is identical to that of the brand-name counterpart.16 Clinicians often express concern regarding therapeutic equivalence of multisource products. However, the fact that these products are more affordable and therapeutically equivalent may save the funder significantly and may enhance access.17 Pharmaceutical regulators around the world, such as the South African Health Products Regulatory Agency (SAHPRA) and the USA FDA requirements of a generic drug is that it is as safe and effective as the brand-name innovator.16,18 The efficacy and source of any medicine, in this case simvastatin, must be reliable to produce the desired clinical surrogate outcome, lowering of cholesterol, to be able to assume the same clinical risk-reduction outcome. Lipid lowering and reduced progression to significant coronary artery disease are the markers for successful treatment of hypercholesterolaemia and coronary artery disease. Lifestyle changes may affect outcomes, which is often seen as a weakness of real-world studies. However, in this study no significant changes inmeanweight were seen for the study subjects over the three data-collection time points, implying no major lifestyle impacts on the observed results. Other weaknesses of the study include the paucity of long-term outcomes, especially as these patients also suffered from other co-morbidities. However, the aim of the study was simply to assess therapeutic equivalence related to reduction and maintenance of reduction of lipid levels on different brands of simvastatin over a short period of time. Table 2. Cholesterol values (mmol/l): patients were on a constant strength of simvastatin between the time points Visit Number Mean SD Mean change p-value Total cholesterol Visit 1 117 6.28 4.35 Visit 2 118 5.43 1.65 Visit 3 118 5.53 1.65 ∆V1→V2 117 –0.84 4.16 –0.84 0.030* ∆V2→V3 118 0.10 1.00 0.10 0.283 HDL-C Visit 1 117 1.16 0.37 Visit 2 118 1.18 0.41 Visit 3 117 1.15 0.44 ∆V1→V2 117 0.02 0.28 0.02 0.515 ∆V2→V3 117 –0.02 0.28 –0.02 0.426 LDL-C Visit 1 113 3.90 1.85 Visit 2 115 3.55 1.74 Visit 3 114 3.67 1.68 ∆V1→V2 111 –0.39 1.04 –0.39 < 0.001* ∆V2→V3 112 0.10 0.86 0.10 0.202 Triglycerides Visit 1 41 1.81 1.05 Visit 2 118 1.66 1.17 Visit 3 118 1.63 0.94 ∆V1→V2 41 –0.26 1.08 –0.26 0.127 ∆V2→V3 118 –0.03 1.05 –0.03 0.753 * Statistically significant. LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; ∆V1→V2, difference between visit 1 and visit 2.
CARDIOVASCULAR JOURNAL OF AFRICA • Volume 34, No 5, November/December 2023 AFRICA 267 Conclusions The importance of established data illustrating bioequivalence of generic products when compared to the innovator product has become increasingly scrutinised by the medical community at large, who view bioequivalence data merely as a requirement to register a medicine in South Africa and not a marker for efficacy of the medicine. However, data illustrating the effectiveness in patient populations carry more weight in determining the acceptance of a product in the prescriber market. This retrospective, real-world analysis showed the effectiveness of a generic form of simvastatin (Simvotin®) in controlling and maintaining lipid levels in those patients who were switched from the innovator brand (Zocor®). Consent was granted to publish all details of any images, videos, recordings, etc, and that the authors as well as Ranbaxy (Pty) Ltd, a Sun Pharma company, have been shown the article contents to be published. The authors and researchers do not wish to share their data supporting the results reported in the manuscript to protect the privacy of patients consulted. Protection of patient information is of utmost importance to the researchers and authors. Furthermore, due to historic data file format of source environment, the additional data were not captured in collection sheets. The study was funded by Ranbaxy (Pty) Ltd, a Sun Pharma company. The sponsors had no influence on the independent research and did not assist in manuscript writing. The authors collated the data and wrote the article on behalf of the Simvotin® study group. The Simvotin® real-world study group: Profs D Marx and HJ Vermaak, Drs C Rajput, S Singh and JR Snyman – a clinical research group that had no commercial interest in any of the products researched and also declares no affiliation with the sponsor. The group also acknowledges the contributions of Z Ramadas and S Badari, employed by the sponsor company Ranbaxy Laboratories (Ltd) South Africa, for co-ordinating the process. References 1. South African Medical Association and Lipid and Atherosclerosis Society of Southern Africa Working Group. Diagnosis, management and prevention of the common dyslipidaemias in South Africa – clinical guideline, 2000. Expert Rev S Afr Med J 2000; 90(2): 164–177. 2. National Cholesterol Education Program. Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) Executive Summary. NIH publication no. 01-3670 May 2001: 1–28. 3. Klug EQ, Raal FJ, Marais AD, Smuts CM, Schamroth C, Jankelow D, Blom DJ, Webb DA. South African Dyslipidaemia Guideline Consensus Statement 2018 Update. Expert Rev S Afr Med J 2018; 108(11). 4. Pyörälä K , De Backer G, Graham I, Poole-Wilson P, Wood D. Prevention of coronary heart disease in clinical practice. Recommendations of the task force of the European Society of Cardiology, European Artherosclerosis Society and European Society of Hypertension. Eur Heart J 1994; 15: 1300–1331. 5. Endocrine and metabolic disorders: dyslipidemia. www.merck.com 6. Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, McKillop JH, Packard CJ. Prevention of coronary heart disease with pravastatin in men with hypercholesterolaemia. New Eng J Med 2005: 344: 1301–1307. 7. Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. New Eng J Med 1996; 335: 1001–1009. 8. Scandinavian simvastatin survival group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994; 344: 1383–1389. 9. Heart Protection study collaborative group. Heart protection study of cholesterol lowering with simvastatin in 20536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002; 360: 7–22. 10. Ward NC, Watts GF, Eckel RH. Statin toxicity: mechanistic insights and clinical implications. Circ Res 2019; 124: 328–350. 11. FDA. Generic Drug Facts. 2021. Available at: https://www.fda.gov/ drugs/generic-drugs/generic-drug-facts 12. Dainis AM, Ashley EA. Cardiovascular precision medicine in the genomics era. J Am Coll Cardiol Basic Transl Sci 2018; 3(2): 313–326. 13. Sturm AC, Knowles JW, Gidding SS, Ahmad ZS, Ahmed CD, Ballantyne CM, et al. Convened by the Familial Hypercholesterolemia Foundation. Clinical genetic testing for familial hypercholesterolemia. J Am Coll Cardiol Scien Expert Panel 2018; 72(6): 662–680. 14. Mytilinaiou M, Kyrou I, Khan M, Grammatopoulos DK, Randeva HS. Familial hypercholesterolemia: new horizons for diagnosis and effective management. Front Pharmacol 2018; 9: 707. 15. Mauro VF. Clinical pharmacokinetics and practical applications of simvastatin. Clin Pharmacokinet 1993; 24: 195–202. 16. Stoppler M. Generic drugs, are they as good as brand names? Available at: https://www.medicinenet.com/generic_drugs_are_they_as_good_as_ brand-names/views.htm 17. Larmour I, Pignataro S, Barned KL, Mantas S, Korman MG. A therapeutic equivalence program: evidence-based promotion of more efficient use of medicines. Med J Aust 2011; 194(12): 631–634. 18. KennedA.Genericsvsoriginalmedication.2017.Availableat:https://fpm. co.za/2017/05/03/generic-vs-original-medication/#:~:text=Generic%20 medicines%3A%20These%20medicines%20are,is%20also%20exactly%20the%20same
CARDIOVASCULAR JOURNAL OF AFRICA • Volume 34, No 5, November/December 2023 268 AFRICA Feasibility of focused cardiac ultrasound training for non-cardiologists in a resource-limited setting using a handheld ultrasound machine Benjamin Acheampong, Joseph R Starnes, Yaw A Awuku, David Parra, Muktar H Aliyu, Jonathan H Soslow Abstract Background: Heart disease remains a leading cause of morbidity and mortality, particularly in low- and middle-income countries. Access to diagnostic modalities is limited in these settings. Limited echocardiographic studies performed by non-cardiologists can increase access, improve diagnosis and allow for earlier medical therapy. Methods: Two internal medicine residents at a tertiary-level hospital in Ghana were trained to perform limited echocardiographic studies. Each trainee performed 50 echocardiograms and interpreted 20 studies across three predetermined timepoints. Interpretation was compared to expert interpretation. Results: Agreement improved over time. At the final evaluation, there was high agreement across all aspects: left ventricular structure (70%, kappa 0.52, p = 0.01), left ventricular function (80%, kappa 0.65, p = 0.004), right ventricular structure (90%, kappa 0.71, p = 0.002), right ventricular function (100%, kappa 1.00, p < 0.001), and presence of effusion (100%, kappa 1.00, p < 0.001). Conclusion: Non-cardiologists can be trained in focused echocardiography using handheld machines. Such training can increase access to diagnostic capabilities in resource-limited settings. Keywords: echocardiography, Ghana, training programmes, healthcare access Submitted 10/11/21, accepted 17/10/22 Published online 14/12/22 Cardiovasc J Afr 2023; 34: 268–272 www.cvja.co.za DOI: 10.5830/CVJA-2022-057 Both congenital and acquired heart disease remain important sources of childhood morbidity and mortality around the world. Congenital heart disease (CHD) accounted for more than 260 000 deaths in 2017, more than 180 000 of which were in infants less than one year of age.1 Although high-income countries have seen improvement in CHD-related mortality of more than 50% since 1990, countries in the lowest quantile have improved by just 6%.1 Similarly, an estimated 319 400 deaths occurred due to rheumatic heart disease (RHD) in 2015.2 While RHD has essentially been eliminated in many high-income countries, rates remain as high as 10 per 1 000 in sub-Saharan Africa.2 There is a significant difference in reported prevalence of CHD between high- and low-income countries (LIMCs), likely secondary to differences in access to healthcare and diagnostics.3 Although sub-Saharan Africa has the highest prevalence of RHD, prevalence is likely underestimated for the same reasons.4 Ischaemic heart disease and stroke are the leading causes of the cardiovascular disease burden, but RHD, cardiomyopathy and acute myocarditis remain important causes of morbidity and mortality.5 Rates of cardiac death are higher in LMICs, suggesting that later diagnosis and reduced access to care play a role in higher mortality rates.6,7 Furthermore, rates of cardiac disease in LMICs are difficult to quantify due to lack of data5 and are likely underestimated due to poor availability of diagnostic technologies.8 Cardiovascular imaging in the developing world is limited by cost and expertise. Recent improvements in handheld ultrasound technology have the potential to reduce barriers to access and lead to better identification of paediatric and adult cardiac disease. Portable ultrasound, including for echocardiography, has shown promise in the triage, diagnosis and treatment of patients in LMICs.9 This technology has been used successfully by experts in LMICs in a variety of settings for adults10-14 and for RHD screening in children.15-19 As this technology has become more available, various efforts have aimed to train non-experts to perform focused handheld echocardiography. A number of studies have demonstrated acceptable accuracy of focused studies by non-echocardiographers in high-resource settings.20-28 In the LMIC setting, studies have included cardiologists,11,14-17 cardiology trainees,10,13 sonographers,12 and, more recently, nurses and other non-experts.18,29-33 These studies were performed only in adults,11-14 were performed by expert cardiologists,15-17 or were limited to the evaluation of RHD.18,29-33 We hypothesised that non-experts, specifically internal medicine trainees, could use focused handheld echocardiography to successfully evaluate both children and adults. To our knowledge, this is the first study in an LMIC setting in which non-experts applied focused handheld echocardiography to such a broad patient group. Department of Pediatrics, Division of Pediatric Cardiology, Vanderbilt University Medical Center, Nashville, Tennessee, USA Benjamin Acheampong, MD, bacheampong@childrensomaha.org Joseph R Starnes, MD, joseph.starnes@vumc.org David Parra, MD Jonathan H Soslow, MD Department of Pediatrics, Division of Pediatric Cardiology, University of Nebraska Medical Center, Omaha, Nebraska, USA Benjamin Acheampong, MD Department of Medicine and Therapeutics, University of Cape Coast, Cape Coast, Ghana Yaw A Awuku, MD Vanderbilt Institute for Global Health, Vanderbilt University Medical Center, Nashville, Tennessee, USA Muktar H Aliyu, MD
CARDIOVASCULAR JOURNAL OF AFRICA • Volume 34, No 5, November/December 2023 AFRICA 269 Non-echocardiographers acquiring echocardiographic images need to be trained adequately in acquisition and interpretation to meet consistently high standards. The American Society of Echocardiography (ASE) has published guidelines on focused cardiac ultrasound, including training.34 The ASE recommends that this training include didactic education, hands-on experience and interpretation experience. The aim of this study was to assess the feasibility of a training programme for non-echocardiographers based on the ASE recommendations in resource-limited settings with handheld echocardiographic machines. Methods Echocardiograms were performed on 100 patients, including children and adults, at the Cape Coast Teaching Hospital in Ghana between July and September 2018. The first 100 patients to consent were included, regardless of the reason for presentation to the hospital. Residents were selected for training based on their willingness to participate. The study was approved by the Cape Coast Teaching Hospital ethical review board. All patients who agreed to participate in the study were included. Participants gave appropriate consent and assent where applicable. The Lumify probe (Lumify, Philips, Amsterdam, the Netherlands) is a 1–4-MHz single-phased array cardiac transducer equipped with scanning software that is connected to an Android tablet interface. The transducer performs most of the beam forming, image acquisition and reconstruction processing. The smart device serves as the display screen and is connected to a cloud-based application. The touchscreen display allows users to tap to start functions, pinch and drag to zoom in and out, and swipe to expand the images. Images can also be wirelessly transferred to a picture-archiving and communication system. Two internal medicine residents at the Cape Coast Teaching Hospital in Cape Coast, Ghana were trained. The training consisted of a didactic component, which included instructional videos with a paediatric cardiologist available to answer questions, which was followed by proctored image acquisition, independent imaging, and interpretation of echocardiograms. Echocardiographic training focused on obtaining limited echocardiographic windows for qualitative assessment of left ventricular (LV) size and function, right ventricular (RV) size and function, and presence or absence of pericardial effusion. Colour flow, doppler and evaluation of valvular stenosis and regurgitation were also discussed, but were not the focus of the study and were therefore not included in the evaluation phase. This training model was based on ASE recommendations for focused cardiac imaging with handheld machines.34 The didactic component consisted of training lectures, including basic ultrasound principles, basic cardiac anatomy and physiology, orientation to the machine, and demonstration of scanning, standard scanning windows and steps in interpreting echocardiographic studies (Table 1). During the didactic section, trainees were able to observe imaging by ultrasound technicians. After the didactic and observation period, trainees began a 10-week practical training that included a minimum of 20 individual scans per trainee with interpretations (Table 2). Each scan included multiple grayscale images: two each from the parasternal long-axis, short-axis and apical four-chamber views over a preset two-second loop (Table 3). M-mode images from the parasternal short axis at the level of the papillary muscles and through the aortic root and left atrium were obtained over four beats. These training scans were performed under direct supervision by a third-year paediatric cardiology fellow. Immediate feedback was provided to help improve image quality and understanding for subsequent studies. After the first six-week proctored phase, each trainee performed additional training that included three weeks of proctored imaging and interpretations and a one-week period of independent imaging and interpretation. Trainees reviewed images immediately after scanning and recorded interpretation in a secured REDCap database.35 Interpretation included qualitative analyses of LV and RV structure and function as well as evaluation of pericardial effusion. Each scan was independently interpreted by a paediatric cardiology fellow for comparison. Eachtraineeperformed50echocardiogramsandindependently interpreted 20 randomly selected studies. Evaluations occurred at three predetermined timepoints. The first was following six weeks of proctored training (20 proctored studies performed and 10 interpreted studies per trainee), the second following an additional three weeks of proctored training (20 independent studies performed and five interpreted studies per trainee), and the last at the completion of the study (10 independent studies performed and five interpreted studies per trainee). Statistical analysis All statistics were performed using Stata version 14.2 (StataCorp LP, College Station, TX). Kappa coefficients were calculated to measure inter-rater reliability. Predetermined cut-offs of < 0.00, 0.00–0.20, 0.21–0.40, 0.41–0.60, 0.61–0.80 and 0.81– Table 1. Didactic content Basic principles of ultrasound/echocardiography Handling of portable echocardiogram machine Cardiac anatomy and physiology Imaging windows in echocardiography Subjective assessment of LV structure and function Subjective assessment of RV structure and function Subjective assessment of atrial structure Evaluation of pericardium Table 2. Elements of practical training Two-dimensional imaging Qualitative assessment of LV structure and function Qualitative assessment of RV structure and function Qualitative assessment of atrial structures Presence and severity of pericardial effusion M-mode LV shortening fraction (parasternal short axis) Table 3. Images obtained in protocol Imaging window View Parasternal long axis 2D Parasternal short axis 2D, M-mode Apical 4-chamber 2D
CARDIOVASCULAR JOURNAL OF AFRICA • Volume 34, No 5, November/December 2023 270 AFRICA 1.00 indicating no agreement, poor, fair, moderate, substantial and almost perfect agreement were used. Interpretation of LV structure, LV function, RV structure, RV function, and pericardial effusion was compared to expert interpretation by a paediatric cardiology fellow. Results Forty studies from patients aged seven to 75 years, of whom 72% were males, were interpreted and included in the analyses. Twentyeight echocardiograms (70%) had at least one abnormality in the five evaluated categories. LV abnormalities were more common than RV abnormalities (Table 4). Inter-rater reliability was generally moderate to strong and improved over successive evaluation periods, as measured by the kappa coefficient (Table 5). One notable exception was LV structure, for which kappa slightly decreased over successive timepoints, beginning at 0.67 during the first evaluation and ending at 0.52 during the final evaluation. Similarly, percentage agreement was high throughout the study period and reached perfect agreement for some measurements. Although 70% agreement was found for pericardial effusion at the second timepoint, kappa was negative because 74% agreement was expected. Of note, only trivial and small pericardial effusions were missed. In order to continue supporting the residents, a gateway for image uploading was provided. This process allowed the cardiology fellow to continue to observe echocardiograms obtained in Ghana and to help the imagers with any questions or concerns, particularly images that were out of their scope of practice. Discussion A short training course based on ASE recommendations was sufficient to adequately train non-cardiologist residents to perform focused limited echocardiography in a low-resource setting in Ghana over a 10-week period. There was generally high percentage agreement and inter-rater reliability compared to a paediatric cardiology fellow with echocardiographic experience. This study provides a potential model that could be expanded, both at the Cape Coast Teaching Hospital and in other similar settings. More than 90% of children with heart disease are born in parts of the world where adequate cardiac care is not available.36 The expansion of echocardiography beyond specialists can begin to bridge at least part of the gap across the continuum of cardiac care. This study adds to the growing literature that non-echocardiographers can demonstrate acceptable accuracy using focused cardiac ultrasound.20-28,34 Although studies in the global setting have traditionally utilised experienced cardiologists or sonographers, more recent studies have incorporated other providers, such as nurses and healthcare workers.18,29-33 However, these studies have been limited to the evaluation of RHD by increasingly limited protocols. To our knowledge, this is the first study, albeit in a very small group, to show that non-experts in LMIC settings can successfully perform and interpret general echocardiograms in both children and adults. This is an important expansion of studies conducted in high-income countries, as LMICs provide a specific set of logistics challenges, including new equipment, infrastructure and educational barriers. There were some notable exceptions to the generally high level of inter-rater reliability in the study. Most notably, kappa was 0.00 for RV function at the first timepoint and –0.15 for effusion at the second timepoint despite high percentage agreement. This is a known paradox for the kappa statistic when events, such as RV dysfunction or effusion, are rare in the data.37,38 The high percentage agreement shows that the trainees demonstrated sufficient accuracy despite the low kappa values in these isolated circumstances. As the application of handheld echocardiography evolves, the training of personnel not originally intended to perform focused cardiac studies is becoming increasingly important. Skills in acquiring and interpreting focused handheld cardiac images should be taught to novices via both didactic and proctored training prior to implementation in resource-limited settings. Expectations of trainees and subjects should be carefully managed, including the limitations of handheld echocardiogram. The curriculum developed for this study was created to quickly train providers in basic echocardiographic assessment, but this curriculum can be duplicated in other underserved regions and modified to emphasise other areas of focus (for example, more focused assessment of valve disease for RHD and more focused assessment of wall-motion abnormalities for myocardial infarction). The didactic lectures have been recorded and can be distributed. The hands-on training is relatively short when compared with the potential improvement in access to care. Table 4. Characteristics of echocardiograms read by paediatric cardiologist Variables Normal Mild dilation At least moderate dilation LV structure, n (%) 18 (45) 15 (37.5) 7 (17.5) RV structure, n (%) 36 (90) 1 (2.5) 3 (7.5) Normal Mild depression At least moderate depression LV function, n (%) 21 (52.5) 5 (12.5) 14 (35) RV function, n (%) 32 (80) 3 (7.5) 5 (12.5) Absent Present Pericardial effusion, n (%) 33 (82.5) 7 (17.5) Table 5. Agreement in interpretation Evaluation 1 (n = 20) Evaluation 2 (n = 10) Evaluation 3 (n = 10) Agreement (%) Kappa p-value Agreement (%) Kappa p-value Agreement (%) Kappa p-value LV structure 80.0 0.67 < 0.001 80.0 0.64 0.002 70.0 0.52 0.01 LV function 60.0 0.23 0.07 80.0 0.55 0.03 80.0 0.65 0.004 RV structure 75.0 0.22 0.06 90.0 0.47 < 0.001 90.0 0.71 0.002 RV function 75.0 0.00 – 80.0 0.41 0.04 100.0 1.00 < 0.001 Effusion 100.0 1.00 < 0.001 70.0 –0.15 0.70 100.0 1.00 < 0.001
CARDIOVASCULAR JOURNAL OF AFRICA • Volume 34, No 5, November/December 2023 AFRICA 271 Our study is primarily limited by the small sample size. While the training model may be generalisable, only two residents at a single teaching hospital participated in the study, making comment on generalisability impossible. This study serves as a proof of concept that a short, multimodal training course can lead to skill acquisition in echocardiography. Future work will focus on adapting this model to larger groups, other geographic contexts and other types of acquired and congenital heart disease. Additionally, evaluation of trainees took place during and immediately following the training period. This timeline does not allow us to comment on the maintenance of skills over time. We plan to evaluate this schedule in future studies to determine the frequency of needed refresher trainings. We also report only qualitative assessment of the ventricular structure and function, as quantitative evaluation may not be available in resource-limited settings. In this context, abnormalities detected by non-cardiologists can be categorised into levels of severity with relative confidence, given the moderate to strong agreement in our study. Conclusion Non-cardiologist residents can be trained in focused echocardiography in a low-resource setting using handheld echocardiographic machines. This capacity building could increase access to point-of-care focused cardiac ultrasound in resource-limited settings if successful in broader contexts. References 1. Zimmerman MS, Smith AGC, Sable CA, Echko MM, Wilner LB, Olsen HE, et al. Global, regional, and national burden of congenital heart disease, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Child Adolesc Health 2020; 4(3): 185–200. 2. Watkins DA, Johnson CO, Colquhoun SM, Karthikeyan G, Beaton A, Bukhman G, et al. Global, Regional, and National Burden of Rheumatic Heart Disease, 1990–2015. N Engl J Med 2017; 377(8): 713–722. 3. Van der Linde D, Konings EEM, Slager MA, Witsenburg M, Helbing WA, Takkenberg JJM, et al. Birth prevalence of congenital heart disease worldwide: a systematic review and meta-analysis. J Am Coll Cardiol 2011; 58(21): 2241–2247. 4. Zühlke L, Mirabel M, Marijon E. Congenital heart disease and rheumatic heart disease in Africa: recent advances and current priorities. Heart 2013; 99(21): 1554–1561. 5. Roth GA, Johnson C, Abajobir A, Abd-Allah F, Abera SF, Abyu G, et al. Global, regional, and national burden of cardiovascular diseases for 10 causes, 1990 to 2015. J Am Coll Cardiol 2017; 70(1): 1–25. 6. Yusuf S, Rangarajan S, Teo K, Islam S, Li W, Liu L, et al. Cardiovascular risk and events in 17 low-, middle-, and high-income countries. N Engl J Med 2014; 371(9): 818–827. 7. Dokainish H, Teo K, Zhu J, Roy A, AlHabib KF, ElSayed A, et al. Global mortality variations in patients with heart failure: results from the International Congestive Heart Failure (INTER-CHF) prospective cohort study. Lancet Glob Health 2017; 5(7): e665–672. 8. Joseph P, Leong D, McKee M, Anand SS, Schwalm J-D, Teo K, et al. Reducing the global burden of cardiovascular disease, Part 1: the epidemiology and risk factors. Circ Res 2017; 121(6): 677–694. 9. Becker DM, Tafoya CA, Becker SL, Kruger GH, Tafoya MJ, Becker TK. The use of portable ultrasound devices in low- and middle-income countries: a systematic review of the literature. Trop Med Int Health 2016; 21(3): 294–311. 10. Giusca S, Jurcut R, Ticulescu R, Dumitru D, Vladaia A, Savu O, et al. Accuracy of handheld echocardiography for bedside diagnostic evaluation in a tertiary cardiology center: comparison with standard echocardiography. Echocardiography 2011; 28(2): 136–141. 11. Kobal SL, Lee SS, Willner R, Aguilar Vargas FE, Luo H, Watanabe C, et al. Hand-carried cardiac ultrasound enhances healthcare delivery in developing countries. Am J Cardiol 2004; 94(4): 539–541. 12. Singh S, Bansal M, Maheshwari P, Adams D, Sengupta SP, Price R, et al. American Society of Echocardiography: Remote Echocardiography with Web-Based Assessments for Referrals at a Distance (ASE-REWARD) study. J Am Soc Echocardiogr 2013; 26(3): 221–233. 13. Siqueira VN, Mancuso FJN, Campos O, De Paola AA, Carvalho AC, Moises VA. Training program for cardiology residents to perform focused cardiac ultrasound examination with portable device. Echocardiography 2015; 32(10): 1455–1462. 14. Tsutsui JM, Maciel RR, Costa JM, Andrade JL, Ramires JF, Mathias W. Hand-carried ultrasound performed at bedside in cardiology inpatient setting – a comparative study with comprehensive echocardiography. Cardiovasc Ultrasound 2004; 2(1): 24. 15. Beaton A, Aliku T, Okello E, Lubega S, McCarter R, Lwabi P, et al. The utility of handheld echocardiography for early diagnosis of rheumatic heart disease. J Am Soc Echocardiogr 2014; 27(1): 42–49. 16. Beaton A, Lu JC, Aliku T, Dean P, Gaur L, Weinberg J, et al. The utility of handheld echocardiography for early rheumatic heart disease diagnosis: a field study. Eur Heart J Cardiovasc Imagin. 2015; 16(5): 475–482. 17. Godown J, Lu JC, Beaton A, Sable C, Mirembe G, Sanya R, et al. Handheld echocardiography versus auscultation for detection of rheumatic heart disease. Pediatrics 2015; 135(4): e939–944. 18. Ploutz M, Lu JC, Scheel J, Webb C, Ensing GJ, Aliku T, et al. Handheld echocardiographic screening for rheumatic heart disease by non-experts. Heart 2016; 102(1): 35–39. 19. Lu JC, Sable C, Ensing GJ, Webb C, Scheel J, Aliku T, et al. Simplified rheumatic heart disease screening criteria for handheld echocardiography. J Am Soc Echocardiogr 2015; 28(4): 463–469. 20. Galderisi M, Santoro A, Versiero M, Lomoriello VS, Esposito R, Raia R, et al. Improved cardiovascular diagnostic accuracy by pocket size imaging device in non-cardiologic outpatients: the NaUSiCa (Naples Ultrasound Stethoscope in Cardiology) study. Cardiovasc Ultrasound 2010; 8(1): 51. 21. Blair JE, Brennan JM, Goonewardena SN, Shah D, Vasaiwala S, Spencer KT. Usefulness of hand-carried ultrasound to predict elevated left ventricular filling pressure. Am J Cardiol 2009; 103(2): 246–247. 22. Brennan JM, Blair JE, Goonewardena S, Ronan A, Shah D, Vasaiwala S, et al. A comparison by medicine residents of physical examination versus hand-carried ultrasound for estimation of right atrial pressure. Am J Cardiol 2007; 99(11): 1614–1616. 23. Croft LB, Duvall WL, Goldman ME. A pilot study of the clinical impact of hand-carried cardiac ultrasound in the medical clinic. Echocardiography 2006; 23(6): 439–446. 24. DeCara JM, Lang RM, Koch R, Bala R, Penzotti J, Spencer KT. The use of small personal ultrasound devices by internists without formal training in echocardiography. Eur Heart J Cardiovasc Imaging 2003; 4(2): 141–147. 25. Kimura BJ, Amundson SA, Willis CL, Gilpin EA, DeMaria AN. Usefulness of a hand-held ultrasound device for bedside examination of left ventricular function. Am J Cardiol 2002; 90(9): 1038–1039. 26. Lucas BP, Candotti C, Margeta B, Evans AT, Mba B, Baru J, et al.
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