The First Brazilian Registry of Hypertension

Accepted Manuscript The first Brazilian registry of hypertension

Renato D. Lopes, Weimar Kunz Sebba Barroso, Andrea Araujo Brandao, Eduardo Costa Duarte Barbosa, Marcus Vinicius Bolivar Malachias, Marco Mota Gomes, Celso Amodeo, Rui Manoel dos Santos Povoa, Margaret Assad Cavalcante, Dalton Bertolim Précoma, Antônio Carlos Sobral Sousa, João Miguel Malta Dantas, Evandro José Cesarino, Paulo Cesar B. Veiga Jardim, on behalf of the RBH Investigators PII: DOI: Reference:

S0002-8703(18)30255-2 doi:10.1016/j.ahj.2018.08.012 YMHJ 5766

To appear in:

American Heart Journal

Received date: Accepted date:

15 February 2018 17 August 2018

Please cite this article as: Renato D. Lopes, Weimar Kunz Sebba Barroso, Andrea Araujo Brandao, Eduardo Costa Duarte Barbosa, Marcus Vinicius Bolivar Malachias, Marco Mota Gomes, Celso Amodeo, Rui Manoel dos Santos Povoa, Margaret Assad Cavalcante, Dalton Bertolim Précoma, Antônio Carlos Sobral Sousa, João Miguel Malta Dantas, Evandro José Cesarino, Paulo Cesar B. Veiga Jardim, on behalf of the RBH Investigators , The first Brazilian registry of hypertension. Ymhj (2018), doi:10.1016/j.ahj.2018.08.012

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ACCEPTED MANUSCRIPT Research Letter

The First Brazilian Registry of Hypertension

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Running title: Brazilian Registry of Hypertension

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Renato D. Lopes, MD, MHS, PhD1,2; Weimar Kunz Sebba Barroso MD, PhD3; Andrea Araujo Brandao, MD, PhD4; Eduardo Costa Duarte Barbosa, MD5; Marcus Vinicius Bolivar Malachias,

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MD, PhD6; Marco Mota Gomes, MD7; Celso Amodeo, MD, PhD8; Rui Manoel dos Santos Povoa, MD, PhD9; Margaret Assad Cavalcante, MD, MSc10; Dalton Bertolim Précoma, MD,

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PhD11; Antônio Carlos Sobral Sousa, MD, PhD12; João Miguel Malta Dantas, MD, PhD13; Evandro José Cesarino, MD, PhD14; Paulo Cesar B. Veiga Jardim, MD, PhD3; on behalf of the

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RBH Investigators

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Author affiliations: 1Brazilian Clinical Research Institute, Sao Paulo, Brazil. 2Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC. 3Hypertension League,

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Federal University of Goias, Brazil. 4State University of Rio de Janeiro, Brazil. 5Moinhos de Vento Hospital - Porto Alegre, Brazil. 6Medical Sciences School of Minas Gerais, Brazil. University Center Cesmac, Alagoas, Brazil. 8Dante Pazzanese Institute of Cardiology – São

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Paulo, Brazil. 9Federal University of São Paulo, Brazil. 10Medical Sciences School, Oeste

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Paulista University and Regional Hospital – Presidente Prudente, Brazil. 11Parana Catolic University, Brazil. 12Sergipe Federal University, Brazil. 13 Research Institute of São Bernardo,

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Brazil. 14Medical Sciences School – Ribeirão Preto, Brazil.

Corresponding author: Renato D. Lopes, MD, MHS, PhD, Duke Clinical Research Institute, Box 3850, 2400 Pratt Street, Durham, NC 27705. E-mail [email protected]. Phone: (919) 668-8241; Fax: (919) 668-7056.

Word count: 1502 (text); tables: 2, figures: 1; references: 12

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ACCEPTED MANUSCRIPT Abstract A systematic, nationwide assessment of care of patients with hypertension in Brazil is needed. The objective of the First National Registry of Patients with Hypertension in Brazil (RBH) is to evaluate the clinical profile, treatment patterns, and outcomes of diagnosed hypertensive patients

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Key words: Hypertension, Registry, Risk Factors, Blood Pressure

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in the country.

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ACCEPTED MANUSCRIPT Hypertension affects almost one third of the adult population worldwide and is the leading risk factor for death and disability globally.1-4 Registries indicate that almost half of hypertensive patients have blood pressure (BP) above the target level,1-6 but many regions are underrepresented in these studies, especially low- and middle-income countries.1-6

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Most of the data for low- to middle-income countries such as Brazil come from cross-

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sectional regional studies, not prospective national studies.1,7,8 We conducted the First National

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Registry of Patients with Hypertension in Brazil (RBH) to evaluate the clinical profile, treatment

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patterns, and outcomes of patients in the country who have a diagnosis of hypertension.

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METHODS

The methods of the RBH were published previously.9 Briefly, the RBH was a multicenter,

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prospective, and observational study of patients with a diagnosis of hypertension who were

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followed for 1 year.9 A total of 2,646 participants from 45 sites in all regions of Brazil were

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included from June 2013 through October 2015, and followed until December 2016. The study included patients who were seen at exclusively public (46.7%), exclusively private (31.1%), and

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Material.

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mixed (22.2%) healthcare facilities. Eligibility criteria are described in the Supplemental

At least one follow-up visit was planned between 6 months and 1 year from study inclusion. If more than one visit occurred during this time period, this additional visit was documented as an intermediate visit. Demographic data as well as information regarding lifestyle features, cardiovascular risk factors, comorbidities, treatments (including adherence using the Morisky scale), and clinical and laboratory measures were collected (see Supplemental Material). The Brazilian Clinical Research Institute was the academic coordinating center

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ACCEPTED MANUSCRIPT responsible for the clinical research operations and study conduct (see Supplemental Material for study team). BP was measured with any type of regulated sphygmomanometer used routinely at the center, with 2 measures performed with the subject seated with an interval of at least 1 minute

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between each. A subgroup analysis of central arterial pressure was conducted using a

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noninvasive assessment of central arterial pressure with a validated Mobil-O-Graph equipment

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(DINA MAP CARDIOS – I.E.M.GmbH, Stolberg, Germany) at baseline and at follow-up visits. Controlled BP was considered using 2 different cut-points: 1) systolic BP < 140 mmHg and

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diastolic < 90 mmHg; 2) systolic BP < 130 mmHg and diastolic < 80 mmHg. Patients without

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controlled BP using 3 antihypertensive medications or patients using at least 4 antihypertensive drugs regardless of BP were considered to have resistant hypertension.

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The clinical events of interest included death (cardiovascular or not), requirement of

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dialysis and hospital admission for at least 24 hours due to hypertensive crisis, acute coronary syndromes, stroke/transient ischemic attack, and heart failure. The variables included in

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multivariable analysis were assessed at baseline (e.g., blood pressure). A complete description of

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the statistical analysis is provided in the Supplemental Material.9 This study was funded by the Brazilian Society of Cardiology. The authors are solely

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responsible for the design and conduct of this study, all study analyses, and drafting and editing of the paper.

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ACCEPTED MANUSCRIPT RESULTS Patient characteristics From a total of 2,646 patients enrolled in the study from June 2013 through October 2015, 1-year follow-up information was not available for 242 (9.1%) (Supplementary Figure 1). Baseline

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characteristics are shown in Table I. The mean age was 61.6 ± 11.9 years, and 55.7% were

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female. The baseline characteristics of the study population according to completion of follow-

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up are presented in Supplementary Table I; there were notable differences between those who completed follow-up and those who did not for the following: time since hypertension diagnosis,

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dyslipidemia, smoking, race and blood pressure (mean and on target).

Treatment patterns

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At baseline and 1 year (Supplementary Figure 2), the most common antihypertensive drugs used

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were thiazides (48.1% and 47.8%, respectively). Overall, 21.4% of all patients were considered to have resistant hypertension. At baseline, 39.4% of patients reported missing some

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antihypertensive drugs on a daily basis, and this decreased to 33% at 1-year follow-up.

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Regarding compliance with lifestyle orientations provided by treating physicians, 70.6% (70.2% at baseline and 71.1% at 1 year) and 53.8% (52.8% at baseline and 55.3% at 1 year) of

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these patients reported adhering to diet and exercise guidelines, respectively.

BP control The mean baseline BP was 137.2/82.8 mmHg, with 53.6% of the patients within target BP levels. When including only the planned 1-year follow-up visit, mean BP changed to 133.5/80.9 mmHg, with 60.6% of patients within target levels (P< 0.01 for both). When considering all BP

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ACCEPTED MANUSCRIPT information from all visits, including extra visits, the mean BP was 134.0/81.1 mmHg, with 59.6% of patients within target levels (Figure 1; P< 0.01 for both). BP control among different subgroups is described in Supplementary Table II. Patients age 65 years or younger (vs. older patients) and patients with (vs. without) peripheral artery disease were more likely to have their

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BP controlled at 1 year.

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Using a lower cut-point for BP control (< 130 × 80 mmHg), 641/2643 (24.3%) of the

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overall population were controlled at baseline and 490/1982 (24.7%) at 1 year. When this stricter threshold was applied only to patients with higher risk (diabetes and/or cardiovascular disease),

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382/1328 (28.8%) were controlled at baseline and 284/978 (29.0%) at 1 year.

Central arterial pressure assessment

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Supplementary Table III shows data on the subgroup of 277 patients (10.5% of the total

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population) who were evaluated for central arterial pressure, augmentation index, and pulse wave velocity at baseline and at 1 year. Central BP was reduced at follow-up from 125.5 (±21.3)

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mmHg systolic and 82.5 (±16.1) mmHg diastolic to 122.4 (±21.0) and 79.7 (±15.1) mmHg,

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respectively (P < 0.01 for diastolic and 0.02 for systolic).

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Clinical outcomes

Rates of clinical outcomes at 1-year follow-up are presented in Table II. Overall mortality was 1.3%, 4.9% of patients were hospitalized, and only 3 patients (0.1%) initiated dialysis. Death or hospitalization from cardiovascular causes occurred in 71/1096 (6.5%) patients without control of baseline BP and 73/1306 (5.6%) patients with controlled BP (<140 × 90 mmHg) at baseline (P = 0.40). At 1 year, hospitalization from cardiovascular causes occurred in

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ACCEPTED MANUSCRIPT 41/800 (5.1%) patients without control of BP and 53/1182 (4.5%) patients with controlled BP (<140 × 90 mmHg) (P = 0.58). Supplementary Table IV shows all the variables tested in univariable analysis, and Supplementary Table V reports a full model including all the variables associated with death

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and/or hospitalization from cardiovascular causes in univariable analysis with P < 0.25.

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Supplementary Table VI shows variables associated with death and/or hospitalization from

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cardiovascular causes in multivariable analysis built using backward elimination with the Akaike information criterion: history of cardiac diseases (OR 4.27, 95% CI 2.93-6.23; P <0.01) and

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history of peripheral artery disease (OR 1.82, 95% CI 1.01-3.30; P = 0.04). A sensitivity

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multivariable analysis of clinical outcomes among the 5 commonly used antihypertensive classes is reported in Supplementary Table VII and did not identify any significant association between

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classes of antihypertensive medications and death and/or hospitalization from cardiovascular

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causes at 1 year.

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DISCUSSION

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The first Brazilian registry of hypertension included a prospective follow-up of a large representative population of hypertensive patients in Brazil. Almost half of the population was

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outside the target of BP control. In addition, when stricter targets of 130 × 80 mmHg were used according to recent guidelines,10 BP control was achieved in only around 25% of patients both at baseline and at 1 year. This finding illustrates a large gap in the treatment of hypertension in Brazil and creates opportunities to implement potential interventions to improve the care of these patients.

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ACCEPTED MANUSCRIPT Regarding clinical events, we found slightly higher rates of death and cardiovascular events at 1 year than the previous literature.11,12 This may be, in part, because most of our sites were tertiary health care facilities with large numbers of high-risk patients. Despite the relatively small number of events at 1 year, we did find that prior cardiac disease and peripheral arterial

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disease were significantly associated with the risk of mortality and cardiovascular events among

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patients with hypertension in Brazil.

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Finally, we performed a noninvasive assessment of central BP in a subgroup of patients. Considering the lack of information regarding these metrics in Brazilian patients with

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hypertension, the data reported will be useful as reference standards for this particular

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population. Also the findings may help future researchers to explore and correlate different

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regulating the central arterial control.

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classes of antihypertensive drugs in terms of action on peripheral BP levels and on variables

Study limitations

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Because our study was conducted by cardiology sites, the quality of care may be overestimated

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in comparison to settings with more limited resources; therefore, our findings might not reflect other clinical care settings such as primary care in rural regions. Also, the lack of a formal

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central adjudication of clinical outcomes is another limitation of the current analysis.

Conclusion The Brazilian registry of hypertension is the first step to a more comprehensive analysis of the burden of hypertension in countries like Brazil, highlighting important gaps in the treatment of

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ACCEPTED MANUSCRIPT patients with hypertension, and may help guide the implementation of future interventions to

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improve the care of these patients.

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ACCEPTED MANUSCRIPT Funding/Support This study was funded by the Brazilian Society of Cardiology and led by its Hypertension Department. The authors are solely responsible for the design and conduct of this study, all study

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analyses, and drafting and editing of the paper.

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Conflict of Interest Disclosures

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Disclosures for Dr. Lopes are available at https://dcri.org/about-us/conflict-of-interest/. The other

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authors report no disclosures.

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ACCEPTED MANUSCRIPT References 1.

Mills KT, Bundy JD, Kelly TN, et al. Global disparities of hypertension prevalence and control: a systematic analysis of population-based studies from 90 countries. Circulation. 2016;134:441–450. Kannel WB. Blood pressure as a cardiovascular risk factor: prevention and treatment.

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Lim SS, Vos T, Flaxman AD, et al. A comparative risk assessment of burden of disease

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JAMA 1996;275:1571-6.

and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990-2010: a

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systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380:2224–

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2260.

Yusuf S, Hawkins S, Ounpuu S, et al.; INTERHEART Study Investigators. Effect of

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potentially modifiable risk factors associated with myocardial infarction in 52 countries

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(the INTERHEART study): case-control study. Lancet. 2004;364:937–952. Mozaffarian D, Benjamin EJ, Go AS, et al.; American Heart Association Statistics

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Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics-2015

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update: a report from the American Heart Association. Circulation. 2015;131:e29–e322. Ong KL, Cheung BM, Man YB, Lau CP, Lam KS. Prevalence, awareness,treatment, and

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control of hypertension among United States adults 1999-2004. Hypertension. 2007;49:69–

Malachias MVB, Souza WKSB, Plavnik FL, et al. 7th Brazilian Guideline of Arterial Hypertension. Arq Bras Cardiol. 2016;107(3 Suppl.3):1-83.

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ACCEPTED MANUSCRIPT 8.

VI Diretrizes Brasileiras de Hipertensão Sociedade Brasileira de Cardiologia / Sociedade Brasileira de Hipertensão / Sociedade Brasileira de Nefrologia. VI Diretrizes Brasileiras de Hipertensão. Arq Bras Cardiol. 2010;95(1 Suppl.1):1-51.

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Jardim PC, Souza WK, Lopes RD, et al. I RBH - First Brazilian Hypertension Registry.

Whelton PK, Carey RM, Aronow WS, et al. 2017

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10.

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Arq Bras Cardiol. 2016;107:93-98.

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ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a

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Report of the American College of Cardiology/American Heart Association Task Force on

11.

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Clinical Practice Guidelines. J Am Coll Cardiol. 2018;71:e127–e248. Lewington S, Clarke R, Qizilbash N, Peto R, Collins R; Prospective Studies Collaboration.

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Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of

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individual data for one million adults in 61 prospective studies. Lancet. 2002;360:1903– 1913.

Lewington S, Lacey B, Clarke R, et al.; China Kadoorie Biobank Consortium. The Burden

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12.

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of Hypertension and Associated Risk for Cardiovascular Mortality in China. JAMA Intern

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Med. 2016;176:524–532.

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ACCEPTED MANUSCRIPT Figure legends Figure 1. Variation in blood pressure values in 1 year.

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SBP indicates systolic blood pressure; DBP, diastolic blood pressure.

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ACCEPTED MANUSCRIPT Table I. Baseline Characteristics Overall (n = 2646)

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Characteristics Age, y 61.6 ± 11.9 Time since hypertension diagnosis, y 13.0 ± 10.4 Female 1472 (55.7) Race White 1472 (55.7) Black 452 (17.1) Asian 40 (1.5) Others 679 (25.7) Diabetes 784 (29.7) Dyslipidemia 1240 (46.9) Cerebrovascular disease 158 (6.0) Cardiac disease 750 (28.4) Renal disease 82 (3.1) Peripheral artery disease 120 (4.9) Smoking 165 (6.2) Physical activity * 1060 (40.1) Alcohol dependence ** 197 (7.5) SBP, mmHg 137.2 ± 21.5 DBP, mmHg 82.8 ± 12.2 BP on target 1417 (53.6) Glucose, mg/dL 115.76±49.0 Total cholesterol, mg/dL 187.04±42.8 HDL-cholesterol, mg/dL 48.05±13.2 LDL-cholesterol, mg/dL 111.17±37.4 Triglycerides, mg/dL 153.80±92.3 Medications Aspirin 1012 (38.3) Clopidogrel 150 (5.7) Metformin 563 (21.3) Insulin 153 (5.8) Statins 1264 (47.9) Data are presented as n (%) or mean ± SD. BP indicates blood pressure; DBP, diastolic BP; HDL, high-density lipoprotein; LDL, low-density lipoprotein; SBP, systolic BP. *Patients were asked about regular aerobic physical activities via a yes/no question. **If male patient drank ≥30 g of alcohol ≥3 times a week or female patient drank ≥15 g of alcohol ≥3 times a week.

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ACCEPTED MANUSCRIPT Table II. Clinical Outcomes at 1-Year Follow-Up Clinical Outcomes

n/N (%)

Death

32/2404 (1.3) 14/32 (43.8)

Non-cardiovascular

7/32 (21.9)

Unknown

11/32 (34.4)

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Cardiovascular

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Hospitalization from cardiovascular causes

114/2347 (4.9) 28/114 (24.6)

Acute myocardial infarction

21/114 (18.4)

Angina

17/114 (14.9)

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Hypertensive crisis

Stroke

13/114 (11.4)

Transient ischemic attack

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2/114 (1.8)

Heart failure

7/114 (6.1)

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Others

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Initiation of dialysis

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25/114 (21.9) 3/2339 (0.1)

Figure 1