Abstract
Background
Differences between the updated versions of the Brazilian Guideline on Dyslipidemias and the American Heart Association (AHA)/American College of Cardiology (ACC) Cholesterol Guideline regarding cardiovascular risk stratification and statin eligibility are unknown.
Objectives
To compare cardiovascular risk categorization and statin eligibility based on the Brazilian guideline with those based on the AHA/ACC guideline in primary prevention patients.
Methods
We retrospectively analyzed individuals aged 40-74 years without high-risk conditions, with LDL-c 70 to < 190 mg/dL, not on lipid-lowering drugs, who underwent routine clinical assessment. Cardiovascular risk was stratified according to the Brazilian and the AHA/ACC guidelines. Subjects were considered eligible for statin therapy if LDL-c was at least 30 mg/dL above the target for the cardiovascular risk (Brazilian guideline) or the 10-year atherosclerotic cardiovascular disease risk was ≥7.5% (AHA/ACC guideline). A p-value < 0.05 was considered statistically significant.
Results
The study sample consisted of 18,525 subjects (69% male, age 48 ± 6 years). Among subjects considered at intermediate or high risk by the Brazilian guideline, over 80% would be in a lower risk category by the AHA/ACC guideline. Among men, 45% and 16% would be statin eligible by the Brazilian and the AHA/ACC guidelines criteria, respectively (p < 0.001). Among women, the respective proportions would be 16% and 1% (p < 0.001). Eighty-two percent of women and 57% of men eligible for statins based on the Brazilian guideline criterion would not be eligible according to the AHA/ACC guideline criterion.
Conclusions
Compared with the AHA/ACC guideline, the Brazilian guideline classifies a larger proportion of primary prevention patients into higher-risk categories and substantially increases statin eligibility. (Arq Bras Cardiol. 2020; 115(3):440-449)
Cardiovascular Diseases; Dyslipidemias; Atherosclerosis; Risk Factors; Prevention and Control; Primary Prevention; Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use
Resumo
Fundamento
Diferenças entre as versões atualizadas da Diretriz Brasileira de Dislipidemias e da Diretriz de Colesterol da American Heart Association (AHA)/American College of Cardiology (ACC) quanto à estratificação de risco cardiovascular e à elegibilidade para a terapia com estatina não são conhecidas.
Objetivos
Comparar a categorização de risco cardiovascular e a elegibilidade à terapia com estatina estabelecidas segundo a diretriz brasileira ou a diretriz da AHA/ACC em pacientes em prevenção primária.
Métodos
Nós avaliamos retrospectivamente indivíduos com idade entre 40 e 74 anos sem condições de alto risco, com LDL-c 70 -< 190 mg/dL, sem tratamento com agentes hipolipemiantes, e que passaram por avaliação clínica de rotina. O risco cardiovascular foi estratificado de acordo com a diretriz brasileira e a da AHA/ACC. Os indivíduos foram considerados elegíveis para estatina se os níveis de LDL-c estivessem no mínimo 30 mg/dL acima da meta para o risco cardiovascular (diretriz brasileira) ou se o risco em 10 anos para doença cardiovascular aterosclerótica fosse ≥ 7,5% (diretriz da AHA/ACC). Um valor de p < 0,05 foi considerado estatisticamente significativo.
Resultados
A amostra do estudo consistiu 18525 indivíduos (69% homens, idade 48 ± 6 anos). Entre os indivíduos considerados de risco intermediário ou alto segundo a diretriz brasileira, mais de 80% seriam classificados em uma categoria de risco mais baixo segundo a diretriz da AHA/ACC. Entre os homens, 45% e 16% seriam considerados elegíveis para a terapia com estatina segundo as diretrizes brasileira e da AHA/ACC, respectivamente (p < 0,001). Entre as mulheres, as respectivas proporções seriam 16% e 1% (p < 0,001). Oitenta e dois porcento das mulheres e 57% dos homens elegíveis para estatina com base no critério da diretriz brasileira não seriam considerados elegíveis para estatina segundo o critério da AHA/ACC.
Conclusões
Em comparação à diretriz da AHA/ACC, a diretriz brasileira classifica uma maior proporção dos pacientes em prevenção primária em categorias de risco mais alto e aumenta substancialmente a elegibilidade para estatina. (Arq Bras Cardiol. 2020; 115(3):440-449)
Doenças Cardiovasculares; Dislipidemias; Aterosclerose; Fatores de Risco; Prevenção e Controle; Prevenção Primária; Inibidores de Hidroximetilglutaril/uso terapêutico
Introduction
Although all guidelines on the management of blood cholesterol recommend cardiovascular risk stratification to guide the decision about statin initiation in primary prevention, different treatment decisions have been made depending on the guideline used.11. Xavier HT, Izar MC, Faria Neto JR, Assad MH, Rocha VZ, Sposito AC, et al. [V Brazilian Guidelines on Dyslipidemias and Prevention of Atherosclerosis]. Arq Bras Cardiol. 2013;101(4 Suppl 1):1-20.
2. Faludi AA, Izar MCO, Saraiva JFK, Chacra APM, Bianco HT, Afiune Neto A et al. Atualização da Diretriz Brasileira de Dislipidemias e Prevenção da Aterosclerose – 2017. Arq Bras Cardiol. 2017;109(2 Supl 1):1-76.
3. Goff DC, Lloyd-Jones DM, Bennett G, Coady S, D’Agostino RB, Gibbons R, et al. 2013 ACC/AHA Guideline on the Assessment of Cardiovascular Risk: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129(25_suppl_2):S49-S73.
4. Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol. Circulation.2019;139(25):e1082-e1143.-55. Mach F, Baigent C, Catapano AL, Koskinas KC, Casula M, Badimon L, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2019 Aug 31:pii:ehz455 (Epub ahead of print) In a previous study, we observed that a substantially higher proportion of the population in primary prevention was considered statin-eligible based on the recommendations of the V Brazilian Guideline on Dyslipidemias, than on the 2013 American College of Cardiology (ACC)/American Heart Association (AHA) Guideline on the management of blood cholesterol.66. Cesena FHY, Laurinavicius AG, Valente VA, Conceição RD, Santos RD, Bittencourt MS. Cardiovascular Risk Stratification and Statin Eligibility Based on the Brazilian vs. North American Guidelines on Blood Cholesterol Management. Arq Bras Cardiol. 2017;108(6):508-17. There was a clear discrepancy between the cardiovascular risk stratified by the Brazilian guideline11. Xavier HT, Izar MC, Faria Neto JR, Assad MH, Rocha VZ, Sposito AC, et al. [V Brazilian Guidelines on Dyslipidemias and Prevention of Atherosclerosis]. Arq Bras Cardiol. 2013;101(4 Suppl 1):1-20. and the risk calculated by the pooled cohort equations (PCE), as recommended by the ACC/AHA guideline.33. Goff DC, Lloyd-Jones DM, Bennett G, Coady S, D’Agostino RB, Gibbons R, et al. 2013 ACC/AHA Guideline on the Assessment of Cardiovascular Risk: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129(25_suppl_2):S49-S73.,77. Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;63(25 Pt B):2889-934.
The Brazilian Guideline of Dyslipidemias was updated in 2017. Some changes in the risk stratification process were made, and a target for low-density lipoprotein cholesterol (LDL-c) for low-risk patients was introduced.22. Faludi AA, Izar MCO, Saraiva JFK, Chacra APM, Bianco HT, Afiune Neto A et al. Atualização da Diretriz Brasileira de Dislipidemias e Prevenção da Aterosclerose – 2017. Arq Bras Cardiol. 2017;109(2 Supl 1):1-76. In 2018, a new AHA/ACC cholesterol guideline was published, proposing a new categorization of the cardiovascular risk.44. Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol. Circulation.2019;139(25):e1082-e1143. Differences between the current versions of the Brazilian and the AHA/ACC guidelines regarding risk stratification and statin eligibility in primary prevention are unknown and are of practical importance for the attending physician.
Therefore, the goals of this study were: (1) to compare the cardiovascular risk stratification as recommended by the 2017 Update of the Brazilian Guideline on Dyslipidemias with that recommended by the 2018 AHA/ACC Cholesterol Guideline in individuals in primary prevention without clinical manifestations of high cardiovascular risk; (2) to compare the proportion of statin-eligible individuals according to the Brazilian guideline and the 2018 AHA/ACC guideline criteria.
Methods
Study design and sample
This observational study was a retrospective analysis of individuals consecutively seen as part of a routine evaluation at the Department of Preventive Medicine of the Hospital Israelita Albert Einstein (São Paulo-SP, Brazil). The study population is the same sample included in our previous study66. Cesena FHY, Laurinavicius AG, Valente VA, Conceição RD, Santos RD, Bittencourt MS. Cardiovascular Risk Stratification and Statin Eligibility Based on the Brazilian vs. North American Guidelines on Blood Cholesterol Management. Arq Bras Cardiol. 2017;108(6):508-17. comparing the 2013 Brazilian Guideline on Dyslipidemias and the 2013 ACC/AHA Cholesterol Guideline (individuals who visited our service from 2009 to 2015), in addition to other individuals who underwent a health evaluation up to July 2018. Data were prospectively collected and gathered into a large database.
Our population of interest was individuals in primary prevention, without high-risk conditions, for whom guidelines recommend the use of risk scores to guide statin therapy.22. Faludi AA, Izar MCO, Saraiva JFK, Chacra APM, Bianco HT, Afiune Neto A et al. Atualização da Diretriz Brasileira de Dislipidemias e Prevenção da Aterosclerose – 2017. Arq Bras Cardiol. 2017;109(2 Supl 1):1-76.,44. Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol. Circulation.2019;139(25):e1082-e1143. Therefore, we excluded subjects with previous clinical atherosclerotic cardiovascular disease (ASCVD), subclinical ASCVD deemed relevant by the attending physician, aortic aneurysm, diabetes mellitus or chronic kidney disease (estimated glomerular filtration rate < 60 mL/min), patients with LDL-c ≥ 190 mg/dL, LDL-c < 70 mg/dL (not candidates for statins according to the AHA/ACC guideline44. Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol. Circulation.2019;139(25):e1082-e1143.) or taking lipid-lowering drugs. We also excluded subjects younger than 40 years or older than 74 years to restrict the sample to those whose age was appropriate for the calculation of the Framingham general cardiovascular risk score (general FRS) and the PCE.88. Lloyd-Jones DM, Braun LT, Ndumele CE, Smith SC, Sperling LS, Virani SS, et al. Use of Risk Assessment Tools to Guide Decision-Making in the Primary Prevention of Atherosclerotic Cardiovascular Disease: A Special Report From the American Heart Association and American College of Cardiology. J Am Coll Cardiol. 2019;73(24):3153-67.,99. D’Agostino RB, Vasan RS, Pencina MJ, Wolf PA, Cobain M, Massaro JM, et al. General cardiovascular risk profile for use in primary care: The Framingham heart study. Circulation. 2008;117(6):743-53.
Cardiovascular risk according to the 2017 Update of the Brazilian Guideline
We calculated the general FRS99. D’Agostino RB, Vasan RS, Pencina MJ, Wolf PA, Cobain M, Massaro JM, et al. General cardiovascular risk profile for use in primary care: The Framingham heart study. Circulation. 2008;117(6):743-53. as recommended by the 2017 Update of the Brazilian Guideline.22. Faludi AA, Izar MCO, Saraiva JFK, Chacra APM, Bianco HT, Afiune Neto A et al. Atualização da Diretriz Brasileira de Dislipidemias e Prevenção da Aterosclerose – 2017. Arq Bras Cardiol. 2017;109(2 Supl 1):1-76. The following variables are considered in this risk estimation: age, gender, systolic blood pressure, use of antihypertensive drugs, total cholesterol, high-density lipoprotein cholesterol (HDL-c), diabetes mellitus, and smoking. This score estimates the risk of coronary death, myocardial infarction, angina, ischemic or hemorrhagic stroke, transient ischemic attack, peripheral vascular disease, or heart failure in 10 years.
According to the Update of the Brazilian Guideline, the cardiovascular risk was stratified as follows:
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general FRS < 5%: low risk;
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general FRS between 5% and 10% (women) or between 5% and 20% (men): intermediate risk;
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general FRS > 10% (women) or > 20% (men): high risk.22. Faludi AA, Izar MCO, Saraiva JFK, Chacra APM, Bianco HT, Afiune Neto A et al. Atualização da Diretriz Brasileira de Dislipidemias e Prevenção da Aterosclerose – 2017. Arq Bras Cardiol. 2017;109(2 Supl 1):1-76.
ASCVD risk according to the 2018 AHA/ACC Guideline
We estimated the ASCVD risk by the PCE, as recommended by the 2018 AHA/ACC Guideline.44. Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol. Circulation.2019;139(25):e1082-e1143.,88. Lloyd-Jones DM, Braun LT, Ndumele CE, Smith SC, Sperling LS, Virani SS, et al. Use of Risk Assessment Tools to Guide Decision-Making in the Primary Prevention of Atherosclerotic Cardiovascular Disease: A Special Report From the American Heart Association and American College of Cardiology. J Am Coll Cardiol. 2019;73(24):3153-67. This score is derived from cohorts from the United States of America and considers the same traditional risk factors of the FRS, in addition to ethnicity. The PCE predict the 10-year risk of hard ASCVD events (coronary death, nonfatal myocardial infarction, fatal or nonfatal stroke).
According to the 2018 AHA/ACC Guideline, the ASCVD risk was stratified as follows:
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ASCVD risk < 5%: low risk;
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ASCVD risk between 5% and < 7.5%: borderline risk;
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ASCVD risk between 7.5% and < 20%: intermediate risk;
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ASCVD risk ≥ 20%: high risk.44. Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol. Circulation.2019;139(25):e1082-e1143.
Eligibility criteria for statin therapy
We categorized the study population into three categories of statin eligibility (non-eligible, potentially eligible and eligible), based on the recommendations of the 2017 Update of the Brazilian Guideline or the 2018 AHA/ACC Guideline.
The Brazilian guideline does not make clear recommendations on when to initiate statins in primary prevention, but establishes LDL-c targets based on the general FRS, as follows: LDL-c < 130 mg/dL, < 100 mg/dL, and < 70 mg/dL for low-risk, intermediate-risk, and high-risk individuals, respectively.22. Faludi AA, Izar MCO, Saraiva JFK, Chacra APM, Bianco HT, Afiune Neto A et al. Atualização da Diretriz Brasileira de Dislipidemias e Prevenção da Aterosclerose – 2017. Arq Bras Cardiol. 2017;109(2 Supl 1):1-76. Accordingly, we arbitrarily considered the following criteria for statin eligibility based on the Brazilian guideline:
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non-eligible: LDL-c below the target for the cardiovascular risk;
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potentially eligible: LDL-c between the target for the cardiovascular risk and < 30 mg/dL above the target;
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eligible: LDL-c 30 mg/dL or more above the target for the cardiovascular risk.
The 2018 AHA/ACC Guideline establishes that individuals at intermediate or high risk should be considered for statin initiation, whereas those at borderline risk may be considered under certain circumstances.44. Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol. Circulation.2019;139(25):e1082-e1143. Thus, we considered the following criteria for statin use:
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non-eligible: 10-year ASCVD risk < 5.0%;
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potentially eligible: 10-year ASCVD risk between 5.0% and < 7.5%;
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eligible: 10-year ASCVD risk ≥ 7.5%.
Statistical analysis
Data and analyses were stratified by sex, since our study population was composed of a higher proportion of men than women. Statin eligibility was also analyzed in pre-defined subgroups, according to age group and cardiovascular risk category.
Categorical variables were expressed as number of observations and proportions. Continuous variables were expressed as mean and standard deviation if normally distributed, or median and interquartile range if non-normally distributed. Normality was assessed by visual inspection of the distribution and calculation of the skewness (values between -1 and 1 were considered consistent with a normal distribution).
The chi-square test and the Fisher exact test, when appropriate, were used in the statistical analyses. A p-value < 0.05 was considered statistically significant. We calculated the Spearman's rank correlation coefficient to evaluate the relationship between the risk determined by the general FRS and the ASCVD risk estimated by the PCE. The R software and Microsoft Office Excel tools were used for data management and graph construction.
Ethical issues
This study was approved by the Ethics Research Committee of the Hospital Israelita Albert Einstein (CAAE 80925817.5.0000.0071). The Ethics Committee approved a waiver of the written informed consent based on the retrospective nature of the analyses.
Results
Population and baseline characteristics
From 45,146 subjects initially identified in the database, 26,621 (59%) were excluded, mainly because of age younger than 40 years (Figure 1). The final sample consisted of 18,525 subjects.
– Flowchart of subjects included in and excluded from the study. ASCVD: atherosclerotic cardiovascular disease; HDL-c: high-density lipoprotein cholesterol; LDL-c: low-density lipoprotein cholesterol; SBP: systolic blood pressure.
The study population was characterized by a predominance of middle-aged subjects, mostly (69%) men. Table 1 shows the baseline characteristics of the sample.
Cardiovascular risk
The 10-year cardiovascular risk determined by the general FRS and the 10-year ASCVD risk estimated by the PCE were shown to be highly correlated (Figure 2).
– Correlation between the 10-year general cardiovascular (CV) risk determined by the Framingham risk score (FRS) and the 10-year risk for atherosclerotic cardiovascular disease (ASCVD) estimated by the pooled cohort equations (PCE); and risk stratification according to the 2017 Update of the Brazilian Guideline on Dyslipidemias and the 2018 American Heart Association/American College of Cardiology (AHA/ACC) Cholesterol Guideline. rs: Spearman’s rank correlation coefficient.
A higher proportion of the study population would be categorized as high-risk by the Brazilian guideline, as compared to the AHA/ACC guideline (Table 1). Conversely, more subjects would be stratified as low-risk by the AHA/ACC guideline, in comparison with the Brazilian guideline (Table 1). All but three subjects considered at low risk by the Brazilian guideline would also be classified as low-risk individuals by the AHA/ACC guideline.
Among subjects at intermediate risk by the Brazilian guideline, a large proportion (5,932 [68%] men and 758 [92%] women) would be stratified as low risk by the AHA/ACC guideline. Only 1,140 (13%) men and 15 (2%) women at intermediate risk by the Brazilian guideline would have the same categorization by the AHA/ACC guideline.
Among high-risk men by the Brazilian guideline, a minority (154 [16%]) would also be in the high-risk stratum by the AHA/ACC guideline; most of them (822 [84%]) would be in the intermediate-risk category. Only 2 (1%) of high-risk women by the Brazilian guideline would be in the same risk category by the AHA/ACC guideline, whereas 45 (24%), 71 (38%), and 67 (36%) women would be in the low-, borderline-, and intermediate-risk categories, respectively.
The medians (quartiles) of the 10-year ASCVD risk by the PCE in the risk categories defined by the Brazilian guideline were as follows: 1.2% (0.9-1.5%) of men in the low-risk category, 3.7% (2.5-5.7%) in the intermediate-risk category, and 14.0% (11.6-17.6%) in the high-risk category; and 0.6% (0.4-1.0%) of women in the low-risk category, 2.7% (2.0-3.7%) in the intermediate-risk category, and 6.6% (5.1-9.5%) in the high-risk category.
Statin eligibility
The number of patients considered eligible for statin therapy would be 3 times higher according to the Brazilian guideline criterion, compared with the AHA/ACC criterion (Figure 3). This could be observed in most subgroups defined by sex, age, and risk category (Figures 3-5 ). Statin eligibility would be higher according to the AHA/ACC guideline only in older and high-risk men.
– Proportion of non-eligible, potentially eligible, and eligible subjects for statins, according to the 2017 Update of the Brazilian Guideline on Dyslipidemias (BR) or the 2018 American Heart Association/American College of Cardiology (AHA/ACC) Cholesterol Guideline (USA) in the total population and stratified by sex. p < 0.001 in the three groups.
– Proportion of non-eligible, potentially eligible, and eligible subjects for statins, according to criteria based on the 2017 Update of the Brazilian Guideline on Dyslipidemias (BR) or the 2018 American Heart Association/American College of Cardiology (AHA/ACC) Cholesterol Guideline (USA), by sex and age group. p < 0.001 in all subgroup analyses.
– Proportion of subjects non-eligible, potentially eligible, and eligible for statins, according to criteria based on the 2017 Update of the Brazilian Guideline on Dyslipidemias (BR) or the 2018 American Heart Association/American College of Cardiology (AHA/ACC) Cholesterol Guideline (USA), by sex and category of cardiovascular risk defined by the Update of the Brazilian Guideline on Dyslipidemias. p < 0.001 in all subgroup analyses.
Among 932 women considered eligible for statin therapy according to the Brazilian guideline, the vast majority (82%) would not be eligible according to the AHA/ACC criterion; only 7% would be eligible and 11% potentially eligible (Figure 6). Among 5,835 men eligible for statins by the Brazilian guideline, 27% would also be eligible by the AHA/ACC criterion, 16% would be potentially eligible and 57% non-eligible (Figure 6).
– Venn diagram showing the intersections of statin eligibility based on the 2017 Update of the Brazilian Guideline on Dyslipidemias or the 2018 American Heart Association/American College of Cardiology (AHA/ACC) Cholesterol Guideline, by sex.
Discussion
Our results reveal a clear discrepancy between the cardiovascular risk stratification proposed by the 2017 Update of the Brazilian Guideline on Dyslipidemias and that by the 2018 AHA/ACC Cholesterol Guideline. A large proportion of the population was classified as higher risk by the former than by the latter. As a consequence, once statin eligibility is based on risk stratification, more subjects would be eligible for statin therapy according to a criterion based on the Brazilian guideline (LDL-c at least 30 mg/dL over the recommended target), in comparison with the AHA/ACC criterion (10-year ASCVD risk by the PCE ≥ 7.5%). More than half of men and more than 80% of women eligible for statins based on the Brazilian guideline would not reach the 7.5% risk threshold to be eligible by the AHA/ACC criterion.
Different guidelines recommend different strategies to risk-stratify individuals and decide who should be considered for statin therapy (Table 2).22. Faludi AA, Izar MCO, Saraiva JFK, Chacra APM, Bianco HT, Afiune Neto A et al. Atualização da Diretriz Brasileira de Dislipidemias e Prevenção da Aterosclerose – 2017. Arq Bras Cardiol. 2017;109(2 Supl 1):1-76.,44. Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol. Circulation.2019;139(25):e1082-e1143.,55. Mach F, Baigent C, Catapano AL, Koskinas KC, Casula M, Badimon L, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2019 Aug 31:pii:ehz455 (Epub ahead of print) While the AHA/ACC guideline recommends a risk-based approach to guide statin initiation in primary prevention, the Brazilian and the European guidelines establish plasma LDL-c targets according to the cardiovascular risk. Moreover, while the PCE and the Systematic Coronary Risk Estimation (SCORE) recommended by the AHA/ACC and the European guidelines, respectively, predict the risk of hard endpoints, the general FRS recommended by the Brazilian guideline estimates the risk of hard and soft clinical events. Also noteworthy is the downgrade of aggravating factors (e.g., metabolic syndrome, elevated high-sensitivity C-reactive protein, family history of premature coronary artery disease) in the Update of the Brazilian Guideline, as well as the upgrade of the so-called risk-enhancing factors for treatment decisions in the 2018 AHA/ACC guideline (Table 2). Indeed, the well-established prognostic relevance of these factors supports their use in clinical practice.22. Faludi AA, Izar MCO, Saraiva JFK, Chacra APM, Bianco HT, Afiune Neto A et al. Atualização da Diretriz Brasileira de Dislipidemias e Prevenção da Aterosclerose – 2017. Arq Bras Cardiol. 2017;109(2 Supl 1):1-76.,44. Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol. Circulation.2019;139(25):e1082-e1143.,55. Mach F, Baigent C, Catapano AL, Koskinas KC, Casula M, Badimon L, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2019 Aug 31:pii:ehz455 (Epub ahead of print)
The present work updates and expands our previous report comparing the V Brazilian Guideline on Dyslipidemias and the 2013 ACC/AHA Cholesterol Guideline.66. Cesena FHY, Laurinavicius AG, Valente VA, Conceição RD, Santos RD, Bittencourt MS. Cardiovascular Risk Stratification and Statin Eligibility Based on the Brazilian vs. North American Guidelines on Blood Cholesterol Management. Arq Bras Cardiol. 2017;108(6):508-17. Seventy-five percent of the sample of the present analysis corresponds to the subjects included in the previous study; the remaining are subjects seen in the same setting more recently. Therefore, our results allow an evaluation of the impact of changes in the updated version of the Brazilian guideline on risk stratification and statin eligibility. In this regard, we observed a drastic reduction in the proportion of individuals categorized as high-risk (women: from 12% to 3% in the present study; men: from 41% to 8%). This finding may be explained by the abolishment, in the 2017 Update, of the reclassification of risk promoted by aggravating factors.22. Faludi AA, Izar MCO, Saraiva JFK, Chacra APM, Bianco HT, Afiune Neto A et al. Atualização da Diretriz Brasileira de Dislipidemias e Prevenção da Aterosclerose – 2017. Arq Bras Cardiol. 2017;109(2 Supl 1):1-76. Even so, among subjects considered at intermediate or high risk by the Brazilian guideline, over 80% would be in a lower-risk category by the AHA/ACC guideline.
The disagreement between the two stratification methods was already expected, since although both documents recommend similar thresholds to categorize the risk (e.g., low risk when below 5% in 10 years), the endpoints considered in the risk equations are different, as mentioned above.22. Faludi AA, Izar MCO, Saraiva JFK, Chacra APM, Bianco HT, Afiune Neto A et al. Atualização da Diretriz Brasileira de Dislipidemias e Prevenção da Aterosclerose – 2017. Arq Bras Cardiol. 2017;109(2 Supl 1):1-76.,44. Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol. Circulation.2019;139(25):e1082-e1143. Therefore, a person with 10-year ASCVD risk by the PCE of 5% has necessarily a higher 10-year risk estimated by the general FRS.
The lower proportion of subjects labeled as high-risk individuals by the 2017 Update of the Brazilian Guideline may explain the decrease in the rate of eligible subjects for statin therapy when we compare the present results with our previous study66. Cesena FHY, Laurinavicius AG, Valente VA, Conceição RD, Santos RD, Bittencourt MS. Cardiovascular Risk Stratification and Statin Eligibility Based on the Brazilian vs. North American Guidelines on Blood Cholesterol Management. Arq Bras Cardiol. 2017;108(6):508-17. (eligibility dropped from 58% to 45% in men and from 17% to 16% in women). Conversely, statin eligibility based on the AHA/ACC criterion, as expected, remained stable (17% in the previous study and 16% in the present study in men; and 2% in the previous study and 1% in the present study in women). Therefore, the difference between the Brazilian and the AHA/ACC guidelines narrowed, but remains very high.
Our findings regarding greater statin eligibility by the Brazilian criterion, compared to the AHA/ACC guideline, contrast with a contemporary study reporting statin eligibility by the 2013 ACC/AHA Guideline similar to that observed using the guidelines from the United Kingdom's National Institute for Health and Care Excellence (NICE, 2014) and the Canadian Cardiovascular Society (CCS, 2016).1010. Mortensen MB, Nordestgaard BG. Comparison of Five Major Guidelines for Statin Use in Primary Prevention in a Contemporary General Population. Ann Intern Med. 2018;168(2):85-92. Moreover, more individuals are statin candidates by the 2013 ACC/AHA Guideline when compared to the guidance from the U.S. Preventive Services Task Force (USPSTF, 2016) or the European Society of Cardiology/European Atherosclerosis Society (ESC/EAS, 2016).1010. Mortensen MB, Nordestgaard BG. Comparison of Five Major Guidelines for Statin Use in Primary Prevention in a Contemporary General Population. Ann Intern Med. 2018;168(2):85-92.,1111. Pagidipati NJ, Navar AM, Mulder H, Sniderman AD, Peterson ED, Pencina MJ. Comparison of Recommended Eligibility for Primary Prevention Statin Therapy Based on the US Preventive Services Task Force Recommendations vs the ACC/AHA Guidelines. JAMA. 2017;317(15):1563-7.
A larger proportion of the population in primary care treated with statins has the potential to prevent more cardiovascular events,1010. Mortensen MB, Nordestgaard BG. Comparison of Five Major Guidelines for Statin Use in Primary Prevention in a Contemporary General Population. Ann Intern Med. 2018;168(2):85-92. especially in the long term. Many younger individuals eligible for statins by the Brazilian criterion, but not by the AHA/ACC guideline (once age is the main driver of ASCVD risk), have relatively high LDL-c and a long-term benefit from statins comparable to the benefit seen in those currently recommended to the treatment by the AHA/ACC document.1212. Thanassoulis G, Sniderman AD, Pencina MJ. A Long-term Benefit Approach vs Standard Risk-Based Approaches for Statin Eligibility in Primary Prevention. JAMA Cardiol. 2018;3(11):1090-5.
Several factors may argue in favor of a more widespread use of statins in the general population: epidemiological and genetic data supporting “the lower the LDL-c, the better” hypothesis;1313. Ference BA, Ginsberg HN, Graham I, Ray KK, Packard CJ, Bruckert E, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J. 2017;38(32):2459-72 unequivocal evidence of benefits of statins from clinical trials, even in low-risk populations;1414. Cholesterol Treatment Trialists C, Mihaylova B, Emberson J, Blackwell L, Keech A, Simes J, et al. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet. 2012;380(9841):581-90. very good safety profile;1515. Collins R, Reith C, Emberson J, Armitage J, Baigent C, Blackwell L, et al. Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet. 2016;388(10059):2532-61. and low cost. Indeed, even a strategy of treating “everyone” with statins has been discussed.1616. Hadjiphilippou S, Ray KK. Cholesterol-Lowering Agents. Circ Res. 2019;124(3):354-63.
On the other hand, the benefit from lipid-lowering therapy depends on the baseline cardiovascular risk, and the 10-year absolute risk reduction may be negligible in some subsets of our sample which were statin eligible by the Brazilian guideline but not by the North American criterion. A widespread use of statin in the general population may not be justifiable based on a risk-benefit analysis. The strategy of avoiding statin for some years until the risk becomes higher may be preferable by some clinicians and patients.
Statin eligibility was higher by the Brazilian guideline criterion in all subgroups defined by age and sex, except for men over 60 years of age who almost always reached the 7.5% risk threshold for statin eligibility established by the AHA/ACC guideline. Therefore, the general recommendation for statin use in the elderly is a consequence of the risk-based nature of the AHA/ACC guideline and seems appropriate, since individuals at higher risk are those who benefit the most from statin therapy. Also, the event reduction promoted by statins can be seen even when baseline LDL-c levels are relatively low.1717. Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, Bhala N, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010;376(9753):1670-81. Moreover, statin use in older individuals is supported by a randomized clinical trial in which pravastatin reduced coronary events with no significant interaction with the baseline LDL-c level.1818. Shepherd J, Blauw GJ, Murphy MB, Bollen EL, Buckley BM, Cobbe SM, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet. 2002;360(9346):1623-30.
Special consideration should be made to treatment decisions in women. We detected a great disparity in statin eligibility between the two guidelines in women at intermediate and high risk, as categorized by the Brazilian document (Figure 5). This finding results from the huge discordance in risk stratification according to the guidelines, which relates to the lower risk threshold (>10% in 10 years) to categorize high-risk women in the Brazilian guideline. This decision made by the Brazilian document followed the 2011 AHA guideline recommendation for prevention of cardiovascular disease in women,1919. Mosca L, Benjamin EJ, Berra K, Bezanson JL, Dolor RJ, Lloyd-Jones DM, et al. Effectiveness-based guidelines for the prevention of cardiovascular disease in women--2011 update: a guideline from the american heart association. Circulation. 2011;123(11):1243-62. which was not adopted by other guidelines worldwide. A reappraisal of risk stratification among women in the Brazilian guideline may be suggested.
Our study has several limitations. The criterion for statin eligibility based on the Brazilian guidelines was arbitrarily chosen, once the document does not specify when statin therapy should be initiated. However, the assumption seems to be a reasonable approximation of routine clinical practice in Brazil and appropriate due to the known limitations of the efficacy of lifestyle changes (e.g., diet) on lowering blood LDL-c levels in the real world. Moreover, this criterion was the same used in our previous study,66. Cesena FHY, Laurinavicius AG, Valente VA, Conceição RD, Santos RD, Bittencourt MS. Cardiovascular Risk Stratification and Statin Eligibility Based on the Brazilian vs. North American Guidelines on Blood Cholesterol Management. Arq Bras Cardiol. 2017;108(6):508-17. which allowed a fair comparison of statin eligibility based on the V Brazilian Guideline or the 2017 Update. Our criteria for statin eligibility were solely based on the calculated risk; we acknowledge that conventional risk scores are imperfect and other non-traditional variables, such as the risk-enhancing factors and the coronary artery calcification, have an important role in the decision-making process, as noted above and in Table 2.44. Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol. Circulation.2019;139(25):e1082-e1143.,2020. Khambhati J, Allard-Ratick M, Dhindsa D, Lee S, Chen J, Sandesara PB, et al. The art of cardiovascular risk assessment. Clin Cardiol. 2018;41(5):677-84.,2121. De Filippis AP, Young R, Carrubba CJ, McEvoy JW, Budoff MJ, Blumenthal RS, et al. An analysis of calibration and discrimination among multiple cardiovascular risk scores in a modern multiethnic cohort. Ann Intern Med. 2015;162(4):266-75. Furthermore, as recent guidelines have emphasized, the use of statin in primary prevention should ideally follow a clinician-patient discussion on the benefits and risks of the therapy.44. Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol. Circulation.2019;139(25):e1082-e1143.Finally, the risk scores used in this study have not been validated or calibrated in the Brazilian population; this is especially relevant if we consider that socioeconomic markers, such as education, may influence cardiovascular endpoints independent of traditional risk factors.2222. Rosengren A, Smyth A, Rangarajan S, Ramasundarahettige C, Bangdiwala SI, Al Habib KF, et al. Socioeconomic status and risk of cardiovascular disease in 20 low-income, middle-income, and high-income countries: the Prospective Urban Rural Epidemiologic (PURE) study. Lancet Glob Health. 2019;7(6):e748-e60.
Conclusions
Compared with the 2018 AHA/ACC Cholesterol Guideline, the 2017 Update of the Brazilian Guideline on Dyslipidemias classifies a great proportion of the population in primary prevention into higher-risk categories. Consequently, statin eligibility is substantially higher according to a criterion based on the Brazilian guideline (LDL-c at least 30 mg/dL over the recommended target), in comparison with an approach based on the AHA/ACC guideline (10-year ASCVD risk by the PCE ≥7.5%). Patients and physicians should use critical judgment when deciding about statin initiation in primary prevention to optimize lifelong cardiovascular protection while avoiding overtreatment.
Acknowledgment
The authors thank Nea Miwa Kashiwagi, Nicolle Gomes Ferreira, and Susi da Silva Pereira de Lima for the organization and maintenance of the database used for this study.
Referências
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1Xavier HT, Izar MC, Faria Neto JR, Assad MH, Rocha VZ, Sposito AC, et al. [V Brazilian Guidelines on Dyslipidemias and Prevention of Atherosclerosis]. Arq Bras Cardiol. 2013;101(4 Suppl 1):1-20.
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2Faludi AA, Izar MCO, Saraiva JFK, Chacra APM, Bianco HT, Afiune Neto A et al. Atualização da Diretriz Brasileira de Dislipidemias e Prevenção da Aterosclerose – 2017. Arq Bras Cardiol. 2017;109(2 Supl 1):1-76.
-
3Goff DC, Lloyd-Jones DM, Bennett G, Coady S, D’Agostino RB, Gibbons R, et al. 2013 ACC/AHA Guideline on the Assessment of Cardiovascular Risk: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129(25_suppl_2):S49-S73.
-
4Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol. Circulation.2019;139(25):e1082-e1143.
-
5Mach F, Baigent C, Catapano AL, Koskinas KC, Casula M, Badimon L, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2019 Aug 31:pii:ehz455 (Epub ahead of print)
-
6Cesena FHY, Laurinavicius AG, Valente VA, Conceição RD, Santos RD, Bittencourt MS. Cardiovascular Risk Stratification and Statin Eligibility Based on the Brazilian vs. North American Guidelines on Blood Cholesterol Management. Arq Bras Cardiol. 2017;108(6):508-17.
-
7Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;63(25 Pt B):2889-934.
-
8Lloyd-Jones DM, Braun LT, Ndumele CE, Smith SC, Sperling LS, Virani SS, et al. Use of Risk Assessment Tools to Guide Decision-Making in the Primary Prevention of Atherosclerotic Cardiovascular Disease: A Special Report From the American Heart Association and American College of Cardiology. J Am Coll Cardiol. 2019;73(24):3153-67.
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9D’Agostino RB, Vasan RS, Pencina MJ, Wolf PA, Cobain M, Massaro JM, et al. General cardiovascular risk profile for use in primary care: The Framingham heart study. Circulation. 2008;117(6):743-53.
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10Mortensen MB, Nordestgaard BG. Comparison of Five Major Guidelines for Statin Use in Primary Prevention in a Contemporary General Population. Ann Intern Med. 2018;168(2):85-92.
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11Pagidipati NJ, Navar AM, Mulder H, Sniderman AD, Peterson ED, Pencina MJ. Comparison of Recommended Eligibility for Primary Prevention Statin Therapy Based on the US Preventive Services Task Force Recommendations vs the ACC/AHA Guidelines. JAMA. 2017;317(15):1563-7.
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12Thanassoulis G, Sniderman AD, Pencina MJ. A Long-term Benefit Approach vs Standard Risk-Based Approaches for Statin Eligibility in Primary Prevention. JAMA Cardiol. 2018;3(11):1090-5.
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13Ference BA, Ginsberg HN, Graham I, Ray KK, Packard CJ, Bruckert E, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J. 2017;38(32):2459-72
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14Cholesterol Treatment Trialists C, Mihaylova B, Emberson J, Blackwell L, Keech A, Simes J, et al. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet. 2012;380(9841):581-90.
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15Collins R, Reith C, Emberson J, Armitage J, Baigent C, Blackwell L, et al. Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet. 2016;388(10059):2532-61.
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16Hadjiphilippou S, Ray KK. Cholesterol-Lowering Agents. Circ Res. 2019;124(3):354-63.
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17Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, Bhala N, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010;376(9753):1670-81.
-
18Shepherd J, Blauw GJ, Murphy MB, Bollen EL, Buckley BM, Cobbe SM, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet. 2002;360(9346):1623-30.
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19Mosca L, Benjamin EJ, Berra K, Bezanson JL, Dolor RJ, Lloyd-Jones DM, et al. Effectiveness-based guidelines for the prevention of cardiovascular disease in women--2011 update: a guideline from the american heart association. Circulation. 2011;123(11):1243-62.
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20Khambhati J, Allard-Ratick M, Dhindsa D, Lee S, Chen J, Sandesara PB, et al. The art of cardiovascular risk assessment. Clin Cardiol. 2018;41(5):677-84.
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21De Filippis AP, Young R, Carrubba CJ, McEvoy JW, Budoff MJ, Blumenthal RS, et al. An analysis of calibration and discrimination among multiple cardiovascular risk scores in a modern multiethnic cohort. Ann Intern Med. 2015;162(4):266-75.
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22Rosengren A, Smyth A, Rangarajan S, Ramasundarahettige C, Bangdiwala SI, Al Habib KF, et al. Socioeconomic status and risk of cardiovascular disease in 20 low-income, middle-income, and high-income countries: the Prospective Urban Rural Epidemiologic (PURE) study. Lancet Glob Health. 2019;7(6):e748-e60.
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Study AssociationThis study is not associated with any thesis or dissertation work.
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Ethics approval and consent to participateThis study was approved by the Ethics Committee of the Hospital Israelita Albert Einstein under the protocol number 2.453.659. All the procedures in this study were in accordance with the 1975 Helsinki Declaration, updated in 2013.
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Sources of FundingThere were no external funding sources for this study.
Publication Dates
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Publication in this collection
28 Sept 2020 -
Date of issue
Sept 2020
History
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Received
07 Aug 2019 -
Reviewed
02 Oct 2019 -
Accepted
23 Oct 2019