Phase 3 Randomized Controlled Trial Evaluating the Effect of Laparoscopic Roux-en-Y Gastric Bypass (LRYGB) on Hypertension Medication Reduction, Blood Pressure Levels and Others Cardiovascular Risk Factors.
Phase: NA
Conditions: Systemic Hypertension, Obesity
Sponsor: Hospital do Coracao

Page 1 of 51 
 
 
 
Version 6.1 – Dec 1st, 2014 
STUDY PROTOCOL 
 
 
 
 
 
Phase 3 Randomized Controlled Trial Evaluating the Effect of 
Laparoscopic 
Roux-en-Y 
Gastric 
Bypass 
(LRYGB) 
on 
Hypertension Medication Reduction, Blood Pressure Levels and 
Others Cardiovascular Risk Factors. 
 
 
GATEWAY (GAstric bypass surgery to TrEat patients With steAdy hYpertension) 
 
 
 
 
Version: 6.1 
 
Date: December 1st, 2014 
 
 
 
 
Coordinating Center:            Research Institute HCor 
  
 
  
 
Rua Abílio Soares, 250 – Paraíso 
  
 
  
 
ZIP CODE: 04005-000 São Paulo, SP – Brazil 
   
 
 
 
Phone: (11) 3053-6611 Extension: 8210 
  
 
Fax: (11) 3886-4695 
 
This is a confidential document. The acceptance of this document denotes 
agreement with the statement that any unpublished information contained herein 
can only be published or disclosed with express previous written approval. This 
document may exceptionally be disclosed to Research Ethics Committees 
provided that it remains confidential. 

Page 2 of 51 
 
 
 
Version 6.1 – Dec 1st, 2014 
TABLE OF CONTENTS 
 
1. INTRODUCTION ................................................................................................................ 7 
1.1 Burden of cardiovascular diseases in Brazil and worldwide ....................................... 7 
1.2 Bariatric surgery .............................................................................................................. 10 
1.3 Effect of bariatric surgery on reducing drug prescription .......................................... 12 
1.4 Effect of bariatric surgery on cardiovascular risk ....................................................... 13 
1.5 Effect of antihypertensive treatment ............................................................................. 14 
1.6 Rationale for Sphygmocor ............................................................................................. 15 
1.7 Study rationale ................................................................................................................. 15 
2. OBJECTIVES OF THE STUDY ...................................................................................... 17 
2.1 Primary objective ............................................................................................................. 17 
2.2 Secondary objectives ..................................................................................................... 17 
3. STUDY METHODS ........................................................................................................... 19 
3.1 Study design .................................................................................................................... 19 
3.2 Randomization ................................................................................................................. 19 
3.3 Blinding procedure .......................................................................................................... 19 
3.4 Video laparoscopic Roux-en-Y Gastric Bypass Description .................................... 19 
3.5 Antihypertensive Treatment ........................................................................................... 22 
3.6 Measurements of blood pressure and heart rate ....................................................... 23 
3.6.1 Ambulatory blood pressure monitoring (ABPM) ...................................................... 23 
3.6.2 Office blood pressure measurements ....................................................................... 23 
3.6.3. Central pressure and associated measures (SphygmoCor®) ............................. 24 
3.6.4 Polysomnography ........................................................................................................ 24 
3.7 Anthropometric measures .............................................................................................. 24 
3.8 Food intake data and Nutritional advice ...................................................................... 25 
3.9 Laboratory tests ............................................................................................................... 26 
3.10 Psychological assessment and follow-up ................................................................. 27 
3.11 Outcomes of interest ..................................................................................................... 27 
3.11.1 Primary outcome ........................................................................................................ 27 
3.11.2 Secondary outcomes ................................................................................................. 27 
3.12 Patients' identification ................................................................................................... 28 
3.13 Visits scheme ................................................................................................................. 28 
3.13.1 Screening visit ............................................................................................................ 28 
3.13.2 Randomization visit ................................................................................................... 29 
3.13.3 - Baseline visit ............................................................................................................ 30 
3.13.4 Follow-up visit 1 (week 1 after surgery) ................................................................. 30 
3.13.5 Follow-up visit 2 (week 4 after baseline visit) ........................................................ 31 
3.13.6 Follow-up visit 3 (month 3 after baseline visit) ...................................................... 31 
3.13.7 Follow-up visit 4 (month 6 after baseline visit) ...................................................... 31 
3.13.8 Follow-up visit 5 (month 12 after baseline visit) .................................................... 32 
3.13.9 Follow-up visit 6 (month 18 after baseline visit) .................................................... 32 
3.13.10 Follow-up visit 7 (month 24 after baseline visit) ................................................. 32 
3.13.11 Follow-up visits – 30, 42 and 54 months after baseline visit: ........................... 33 
3.13.12 Follow-up visits – 36, 48 and 60 months after baseline visit: ........................... 33 
3.14 Adverse event report .................................................................................................... 33 

Page 3 of 51 
 
 
 
Version 6.1 – Dec 1st, 2014 
3.14.1 Serious adverse event reporting ............................................................................. 34 
4. STUDY POPULATION ..................................................................................................... 35 
4.1 Inclusion criteria ............................................................................................................... 35 
4.2 Exclusion criteria ............................................................................................................. 35 
4.3 Recruitment ...................................................................................................................... 36 
4.4 Losses to follow-up ......................................................................................................... 36 
4.5 Consent withdrawal ......................................................................................................... 36 
5. STATISTICAL CONSIDERATIONS ............................................................................... 37 
5.1 Sample size calculation .................................................................................................. 37 
5.2 Statistical analysis ........................................................................................................... 37 
6. ADVERSE EVENTS ......................................................................................................... 39 
6.1 Adverse event definitions ............................................................................................... 39 
6.2 Unexpected adverse events .......................................................................................... 39 
6.3 Definition of serious adverse events ............................................................................ 39 
6.4 Evaluation of adverse event intensity .......................................................................... 40 
7. ADMINISTRATIVE PROCEDURES ............................................................................... 41 
7.1 Electronic case report forms (e-CRF) .......................................................................... 41 
7.2 Monitoring report ............................................................................................................. 41 
7.3 Filing of records ............................................................................................................... 41 
7.4 Publication ........................................................................................................................ 41 
7.5 Confidentiality .................................................................................................................. 42 
7.6 Data protection ................................................................................................................ 42 
7.7 Audits and inspections of regulatory agencies ........................................................... 42 
8. RESPONSIBILITIES ......................................................................................................... 43 
8.1 Investigator Responsibilities .......................................................................................... 43 
8.2 Sponsor responsibilities ................................................................................................. 44 
9. ETHICAL CONSIDERATIONS ....................................................................................... 46 
9.1 Approval from independent Research Ethics Committees (REC) ........................... 46 
9.2 Standards for conducting the study .............................................................................. 46 
9.2.1 Declaration of Helsinki ................................................................................................ 46 
9.2.2 Good Clinical Practices ............................................................................................... 46 
9.2.3 National clinical trials norms ....................................................................................... 46 
9.2.4 Obtainment of consent ................................................................................................ 46 
10. REFERENCES ................................................................................................................ 48 
 
 
 
 
 
 
 
 
 
 
 

Page 4 of 51 
 
 
 
Version 6.1 – Dec 1st, 2014 
SUMMARY 
 
  
 
TITLE 
Phase 3 Randomized Controlled Trial Evaluating the Effect of Laparoscopic 
Roux-en-Y Gastric Bypass (LRYGB) on hypertension Medication Reduction, 
Blood Pressure Levels and Others Cardiovascular Risk Factors. 
PRIMARY OBJECTIVE 
To assess the efficacy of Roux-en-Y gastric bypass plus medical treatment 
compared to medical treatment alone in reducing at least 30%of the total 
number of antihypertensive drugs, while maintaining controlled blood 
pressure (SBP<140 and DBP <90mmHg) at 12 months. 
SECONDARY 
OBJECTIVES 
 
To assess the efficacy of Roux-en-Y gastric bypass plus medical treatment 
compared to medical treatment alone, in obese hypertensive patients, on the 
following outcomes at 12 months: 
 
Number of antihypertensive drugs 
 
Systolic blood pressure. 
 
Diastolic blood pressure. 
 
Body weight and BMI. 
 
Waist circumference. 
 
Fasting glucose levels, HbA1c and insulin resistance  
 
LDL-cholesterol levels. 
 
HDL-cholesterol levels. 
 
Triglyceride levels. 
 
Uric acid levels. 
 
High-sensitivity C-reactive protein levels. 
 
Echocardiographic parameters  
 
Estimated risk for cardiovascular disease (Framingham Risk Score). 
 
Adverse events. 
 
Systolic and diastolic blood pressure measured by ABPM  
 
Central pressure, augmentation index, and pulse wave velocity 
measured by SphygmoCor®. 
 
Sleep quality as assessed by polysomnography. 
To assess the efficacy of Roux-en-Y gastric bypass plus medical treatment 
compared to medical treatment alone on all primary and secondary 
outcomes between 24 and 60 months of follow-up. 
STUDY DESIGN 
This is a randomized, single-center, phase III clinical trial, planned to be 
performed with concealed allocation of participants and intention-to-treat 
analyses, comparing gastric bypass plus medical therapy with medical 
therapy alone in patients with obesity and hypertension. 
RATIONALE 
 
Evidence from randomized clinical trials shows that patients undergoing 
bariatric surgery are able to reduce the number of drugs for the treatment of 
several cardiovascular risks factors after 12 months of surgery. However, a 
detailed analysis shows that this reduction was observed only in drugs for 
the treatment of type 2 diabetes mellitus. Additionally, results of meta-
analyses of studies, mostly observational, evaluating the effect of bariatric 
surgery on parameters other than weight loss suggest that bariatric surgery 
may reduce blood pressure. Thus, these findings should be confirmed by a 
study whose primary objective is to evaluate the effect of bariatric surgery on 
blood pressure levels in hypertensive patients. 

Page 5 of 51 
 
 
 
Version 6.1 – Dec 1st, 2014 
 
 
 
 
 
 
 
 
 
 
 
 
METHODOLOGICAL 
QUALITY 
Central web-based randomization with allocation concealment. Intention-to-
treat analysis 
INCLUSION CRITERIA 
 
Adults aged between 18 and 65 years. 
 
Patients with hypertension using at least 2 antihypertensive drugs at full 
doses or more than two drugs in moderate doses. 
 
Grade 1 and 2 obesity: BMI between 30.0 to 39.9Kg/m2. 
EXCLUSION CRITERIA 
 
 
Patients with blood pressure levels ≥ 180/120 mmHg; 
 
Cerebrovascular disease (stroke) in the past 6 months. 
 
Cardiac 
disease 
(myocardial 
infarction, 
angina, 
coronary 
revascularization, heart failure) that occurred or were diagnosed in the past 6 
months. 
 
Underlying psychiatric diseases: schizophrenia, bipolar disorder, severe 
depression, psychosis 
 
Kidney disease: diabetic nephropathy, creatinine clearance < 30 ml/min. 
 
Individuals with secondary hypertension, except due to sleep apnea. 
 
Advanced peripheral artery disease 
 
Patients with atrophic gastritis 
 
Type 1 diabetes; latent autoimmune diabetes of adults; type 2 diabetes 
mellitus with HbA1c >7.0% 
 
Alcoholism or use of illicit drugs  
 
Current tobacco smoking habit 
 
Previous abdominal surgery (except for MacBurney, Pfannenstiel, and 
video laparoscopic cholecystectomy) 
 
Severe hepatic disease 
 
Pregnant women or women at childbearing age not using effective 
contraceptive methods;  
 
Neoplasm occurring in the past 5 years 
 
Use of immunosuppressant drugs, chemotherapy or radiotherapy 
 
Inability to understand or to adhere to study procedures 
SAMPLE SIZE 
A total of 100 patients will be included. 
FOLLOW-UP  
Short term: 12 months 
Long term: 24, 36, 48 and 60 months 
TREATMENT 
REGIMENS 
Intervention group: Laparoscopic Roux-en-Y gastric bypass combined with 
medical treatment. 
Control group: medical treatment alone.  
COORDINATING 
CENTER 
Research Institute HCor 
Abílio Soares St, n° 250 – Paraíso – S.Paulo – SP – CEP 04005-000 – 
BRAZIL 
SPONSOR 
Ethicon Inc. represented in Brazil by Johnson & Johnson do Brasil Ind. e 
Com. de Prod. para Saúde Ltda – Grant #IIS2012 100238 

Page 6 of 51 
 
 
 
Version 6.1 – Dec 1st, 2014 
STUDY FLOW CHART 
 
 
 
 
                 WRITTEN INFORMED CONSENT 
 
 
 
 
 
 
 
Open Label 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility 
Adults of both sexes aged between 18 and 65 years; BMI between 30 to 30.9 Kg/m2. 
Systemic arterial hypertension requiring the use of two drugs in maximum dose or more than two 
drugs on moderate doses 
Pre-randomization 
6 weeks – 
standardization of 
anti-hypertensive 
medication 
Randomization 
Roux-en-Y Gastric Bypass +  
Medical Treatment 
 
Medical Treatment 
Clinical and postoperative (surgical patients) follow-up at 1, 3, 6, 12, 18, 24, 30, 36, 
42, 54 and 60 months 
•
Clinical assessment 
•
Anthropometric data 
•
Blood pressure measurements 
Follow-up tests: Baseline, 12, 24, 36, 48 e 60 months 
•
Blood pressure measurements (office-based and ABPM) 
•
Central pressure, augmentation index, and pulse wave velocity measured by 
SphygmoCor®  
•
Polysomnography (baseline, 12, 24 and 60 months) 
•
General tests (laboratory tests, echocardiogram, ECG) 

Page 7 of 51 
 
 
 
Version 6.1 – Dec 1st, 2014 
1. 
INTRODUCTION 
1.1 Burden of cardiovascular diseases in Brazil and worldwide 
 
Cardiovascular diseases (CVD), especially acute myocardial infarction 
(AMI) and stroke, are the main cause of mortality and disability in Brazil and 
Worldwide,(1,2,3) and the accelerated increase of the prevalence of these 
disease in developing countries is currently one of the most relevant public 
health issues. In 2020, it is projected that CVD will still be the leading cause of 
mortality and disability and that disability-adjusted life years (AVAIs) attributable 
to CVD will increase to nearly 140 to 160 million, with developing countries 
accounting for the highest incidence. 
Considering that the genesis of CVD is multifactorial, some of the most 
important factors in this process are systemic arterial hypertension and 
overweight. 
 
The association between hypertension with atherosclerotic disease is 
well established in the medical literature. Two systematic reviews of 
observational studies (involving more than 1.5 million individuals) provide 
enough evidence to confirm these findings.(4,5) This may be clearly inferred in 
the graph below which plots the risk of events on a logarithmic scale on the Y-
axis and the risk factor (expressed by blood pressure values) on a continuous 
arithmetic scale on the X-axis as shown in Figure 1.(4) Therefore, consistent 
evidence supports the idea that there is a log-linear association between blood 
pressure and the risk of CVD. 
 
 
 
 

Page 8 of 51 
 
 
 
Version 6.1 – Dec 1st, 2014 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fig. 1 - Association between pressure levels and coronary artery disease (A) 
and stroke (B) in a systematic review by the Prospective Studies Collaboration.4 
 
 
In addition to its independent association with CVD, hypertension is a 
highly prevalent condition. In this sense, a series of cross-sectional studies 
showed that the prevalence of hypertension in Brazil (in adult participants) is 
nearly 25%.(3) 

Page 9 of 51 
 
 
 
Version 6.1 – Dec 1st, 2014 
 
Equally important is the impact of obesity on cardiovascular risk. Obesity 
is currently considered a global epidemic. In the United States, one out of three 
individuals is obese. In Brazil, 49% of the adult population is overweight (BMI > 
25kg/m2) and 14.8% is obese (BMI > 30kg/m2), according to the 2008-2009 
Brazilian Household Budget survey conducted by the Brazilian Institute of 
Geography and Statistics (IBGE) (Table1). Increased obesity rates promote 
increased rates of several diseases, particularly those linked to metabolic 
syndrome, such as high blood pressure, type 2 diabetes, and dyslipidemias. 
If, on one hand, the incidence of obesity is rapidly increasing, on the other hand, 
the therapeutic possibilities have become increasingly limited. Recently, the 
Brazilian National Health Surveillance Agency (Agência Nacional de Vigilância 
Sanitária, ANVISA) decided to remove from the market most anti-obesity 
medications. The only medication currently available is sibutramine, which has 
a very limited indication, especially for patients with high blood pressure and 
CVD. 
 
Adherence to diet and physical activity is challenging in the middle and 
long terms. Therefore, therapeutic outcomes are poor, especially for grade II 
and III obesity, promoting a total weight loss of nearly 10%, which is far from 
ideal for these grades of obesity. 
 
 
 
 

Page 10 of 51 
 
 
 
Version 6.1 – Dec 1st, 2014 
Table 1.Prevalence of weight deficit, overweight and obesity in a 
population of individuals aged 20 years or more, based on criteria of the 
World Health Organization- OMS, by sex, according to age groups - 
Brazil – 2008-2009 period 
 
 
1.2 Bariatric surgery 
 
Considering the few therapeutic alternatives and the poor treatment 
outcomes, bariatric surgery is the best alternative for the treatment of patients 
with grade II obesity associated with comorbidities such as high blood pressure, 
diabetes, dyslipidemia, sleep apnea and with grade III obesity regardless of the 
presence of these comorbidities. 
Age Groups 
Prevalence of weight deficit, overweight and 
obesity in a population of individuals aged 20 
years or more, by sex (%) 
Total 
Men 
Women 
 
weight deficit 
Total 
2.7 
1.8 
3.6 
20-24 years old 
5.7 
3.3 
8.3 
25-29 years old 
3.2 
2.1 
4.3 
30-34 years old 
2.4 
1.2 
3.5 
35-44 years old 
1.4 
0.9 
1.9 
45-54 years old 
1.8 
1.3 
2.2 
55-64 years old 
2.1 
2.0 
2.2 
65-74 years old 
3.2 
2.5 
3.8 
75 years old or more 
4.4 
3.1 
5.4 
 
overweight 
Total 
49.0 
50.1 
48.0 
20-24 years old 
27.3 
30.2 
24.2 
25-29 years old 
38.2 
42.5 
33.9 
30-34 years old 
47.3 
52.7 
42.2 
35-44 years old 
52.8 
55.8 
50.0 
45-54 years old 
58.3 
58.7 
58.0 
55-64 years old 
60.7 
58.0 
63.0 
65-74 years old 
56.2 
52.2 
59.5 
75 years old or more 
48.6 
43.9 
51.9 
 
obesity 
Total 
14.8 
12.5 
16.9 
20-24 years old 
5.6 
5.1 
6.1 
25-29 years old 
9.7 
9.3 
10.0 
30-34 years old 
13.1 
12.9 
13.3 
35-44 years old 
15.6 
13.6 
17.4 
45-54 years old 
19.3 
16.8 
21.5 
55-64 years old 
21.3 
15.9 
26.0 
65-74 years old 
17.9 
12.4 
22.4 
75 years old or more 
15.8 
11.9 
18.6 

Page 11 of 51 
 
 
 
Version 6.1 – Dec 1st, 2014 
 
According to the Resolution No. 1,942/2010 of the Brazilian Federal 
Board of Medicine (Conselho Federal de Medicina, CFM), four bariatric surgery 
techniques are approved in Brazil: 
 Adjustable gastric band; 
 Sleeve gastrectomy;  
 Roux-en-Y gastric bypass; 
 Malabsorptive surgeries: Scopinaro and duodenal switch. 
 
All of these techniques are currently performed by video laparoscopy, 
due to better post-operative outcomes and to lower incidence of complications. 
Of these techniques, the most widely used in Brazil and worldwide is Roux-en-Y 
gastric bypass. 
 
Despite the benefits of surgery in the treatment of obesity and its 
comorbidities, this procedure is not exempt from risks. The Longitudinal 
Assessment of Bariatric Surgery (LABS) Consortium, which followed 2,975 
participants undergoing Roux-en-Y gastric bypass for 30 days after surgery, 
reported 6 deaths among 2,975 participants, i.e., mortality rate of 0.2%. Other 
complications observed in this study included deep vein thrombosis with 
possible pulmonary embolism. Twelve of the 2,975 (0.4%) participants 
developed either of these symptoms. The most frequently reported event in this 
study was the need for abdominal reoperation. Reasons for reoperation were 
not describe in this study, but the most common are fistulas, hemorrhage, and 
intestinal obstruction. Percutaneous drainage was required in 13 of the 2,975 
participants (0.4%), and reoperation was required in 94 of the participants 
(3.2%). In this study, 13 participants of the 2,975 (0.4%) remained hospitalized 
for more than 30 day..(11)  
 
In addition to postoperative complications, patients undergoing Roux-en-
Y gastric bypass may experience some nutritional deficiencies, especially of 
vitamin B12, iron (particularly in women of childbearing age), and calcium. 
Routine prophylaxes include multivitamin supplementation associated with 
parenteral complex B supplementation and specific supplementation regimens 
established according to clinical follow-up. Protein deficiency is extremely rare 
in this technique. 
 

Page 12 of 51 
 
 
 
Version 6.1 – Dec 1st, 2014 
1.3 Effect of bariatric surgery on reducing drug prescription 
 
Schauer et al.(12) conducted a randomized clinical trial that assessed the 
effect of two bariatric surgery techniques compared with intensive clinical 
treatment of obese patients with type 2 diabetes mellitus. In this study, the 
authors found that the two surgical techniques led to a statistically reduction in 
the number of antidiabetic drugs compared with clinical treatment after 12 
months. Additionally, there has also been a significant reduction in the use of 
lipid-lowering 
medications, 
anticoagulant, 
and 
antihypertensive 
agents, 
especially angiotensin-converting enzyme inhibitors (ACE), angiotensin receptor 
blockers, and diuretics. There was no statistically significant reduction in the use 
of beta-blockers and calcium-channel blockers, because few patients used 
these drugs at baseline. 
 
Reducing the number of prescribed medications is always a clinically 
relevant outcome, particularly when considering the issue of treatment 
adherence. This issue is even more relevant in the specific context of high 
blood pressure, due to the high prevalence of this condition (25% of the 
Brazilian population). However, nearly 50% of patients, regardless of clinical 
context, sex, age, or ethnicity, fail to adhere to prescribed drug regimen.(12-14) 
Several factors influence treatment adherence, the main factor is cost, 
especially that not covered in the household budget.(14)  
 
In the context of CVD, several comorbidities are associated, and 
therapeutic complexity has also an important impact on patient adherence. 
Choudhry e col.(15) found that only 67% of patients adhered to the treatment 
prescribed. They received 11.4 prescriptions with mean prescription of 6.3 
different medications in an intensive follow-up of 5 visits for only 3 months. 
 
Finally, dosage regimen is another factor that may influence adherence. 
Claxton et al.(16) observed a 10% loss of adherence in drugs administered once 
a day compared with those administered twice a day. 
 
In this sense, the impact of surgery on reducing drug prescription may be 
beneficial both for patient and for health systems, which often provide financial 
support to treatment. 
 

Page 13 of 51 
 
 
 
Version 6.1 – Dec 1st, 2014 
1.4 Effect of bariatric surgery on cardiovascular risk 
 
In a systematic review
(17) including 52 studies involving 16,867 
participants, the unweighted mean of relapse or resolution of hypertension was 
68% in participants with high blood pressure, 75% in those with diabetes 
mellitus, and 71% in those with dyslipidemias. These improvements occurred 
over a short-term (3 months) following and persisted in the long-term (greater 
than 155 months) follow-up. 
 
Moreover, pre and postoperative blood pressure measures, documented 
in 42% of the studies included, showed a reduction of mean systolic pressure 
from 139 to 124 mmHg and of mean diastolic pressure from 87 to 77 mmHg. 
The table 2 presents means for pre- and postoperative data for lipid profile, 
fasting glucose levels, glycated hemoglobin (reported in 42%, 27%, and 11.5% 
of studies, respectively), and other variables. 
 
Table 2. Effects of bariatric surgery on cardiovascular risk 
Variable 
Baseline 
Postoperative* 
Fasting glucose levels (mg/dl) 
126 
92 
HbA1c (%) 
7.5 
6.0 
Systolic pressure 
139 
124 
Diastolic pressure 
87 
77 
Total cholesterol 
205 
169 
LDL-cholesterol (mg/dL) 
118 
94 
HDL-cholesterol (mg/dL) 
49 
52 
Triglycerides 
169 
103 
RCP (mg/dL)** 
4.5 
1.7 
brachial artery (% of change)*** 
6% 
16% 
Adapted from systematic review by Heneghan et al.
(17)
 
* after a 34-month follow-up 
**based on 5 studies 
***based on 3 studies 
 
 
Overall mean weight loss, as assessed by percentage of excess weight 
loss, was 52% (ranging from 16% to 87%), including all types of surgical 
techniques. When stratified by surgical technique, the greatest losses were 
observed with Roux-en-Y gastric bypass and biliopancreatic diversion. 

Page 14 of 51 
 
 
 
Version 6.1 – Dec 1st, 2014 
1.5 Effect of antihypertensive treatment 
 
The benefit of pharmacological treatment with different agents in patients 
with hypertension has been established by a series of large randomized clinical 
trials and subsequent systematic reviews with meta-analysis of these trials.
(18)
 
The most recent and most cited reviews are those published by Psaty et al.
(19)
, 
Stassen et al.
(18) and Blood Pressure Lowering Trialists Collaboration
(20) (the 
latter of which was recently updated). In these reviews, no differences were 
observed between treatments and clinical events or between “new drugs” and 
“Conventional drugs”, even for the outcomes stroke and heart failure. 
 
Monotherapy is the standard initial treatment to reduce blood pressure in 
most patients with hypertension and changes to combined therapy (2 or more 
medications of different classes) when increased doses of antihypertensive fail 
to achieve the expected decrease in blood pressure.
(21-24)
 The effect of 
medication(s) on reducing blood pressure was summarized in a meta-analysis 
with 42 factorial studies (10,968 participants).(25) This meta-analysis 
summarized the results of studies that randomly allocated subjects to receive 
only 1 medication of different classes, a combination of different medications, or 
placebo. Results showed that thiazide alone reduced means for systolic 
pressure in 7.3 mmHg when used alone and in 14.6 mmHg when combined 
with a medication of other class. The corresponding reductions were 9.3 mmHg 
and 18.9 mmHg for the use of beta-blocker; 6.8 mmHg and 13.9 mmHg for the 
use of ACEI; and 8.4 mmHg and 14.3 mmHg for the use of calcium-channel 
blockers. These estimates show the synergic effect of antihypertensive 
medications of different classes. 
 
Conversely, most patients require combined treatment with two or more 
drugs as an initial treatment to achieve blood pressure control goals. A meta-
analysis summarizing 354 clinical trials that compared combined drug regimens 
found that the combination of two or more medications is associated with better 
rates of therapeutic success and fewer side effects compared with high doses 
of only one medication
(26)
 Such evidence justifies the frequent practice of using 
a combination of three or four drugs rather than administering the maximum 
dose of one drug to achieve adequate blood pressure control. 

Page 15 of 51 
 
 
 
Version 6.1 – Dec 1st, 2014 
1.6 Rationale for Sphygmocor 
 
Studies found that there is a higher correlation between central blood 
pressure and cardiovascular outcomes compared with peripheral blood 
pressure. In the Strong Heart Study,(27) central pulse pressure measured by the 
SphygmoCor was slightly more effective in predicting cardiovascular events 
than brachial pulse pressure in a population of American Indians, with a hazard 
ratio of 1.15 (95% confidence interval [95%CI] 1.07–1.24) versus 1.10 (95%CI 
1.03–1.18). 
 
Data are conflicting with regard to the clinical relevance of augmentation 
index. Some studies observed that augmentation index was correlated with 
coronary artery disease and cardiovascular events,(28,29) while other studies did 
not find this association(30). The use of augmentation index may be limited by 
the fact that it can only be measured in patients with normal ventricular function 
and controlled heart rate. Changes in pattern or duration of ventricular ejection 
reduce augmentation index regardless of arterial stiffness.(31) 
 
The Conduit Artery Function Evaluation (CAFE) showed that there was a 
greater reduction on systolic pressure measured by SphygmoCor with the 
amlodipine regimen compared with the atenolol regimen (mean 4.3 mmHg; 
95%CI 3.3–5.4 vs. mean 3.0; 95%CI 2.1–3.9 mmHg; P < 0.0001), although the 
reduction in peripheral blood pressure was similar in both regimens.(32) 
 
The effect of bariatric surgery on central pulse wave has not been 
investigated yet. Weight loss induced by bariatric surgery is expected to reduce 
peripheral vascular resistance, which may result in reduced central systolic 
pressure and augmentation index. In order to analyze these variables, we will 
measure central pulse wave using SphygmoCor at baseline 12, 24, 36, 48 and 
60 months after randomization. 
 
1.7 Study rationale 
 
In view of CVD burden and the difficulty in controlling risk factors, 
bariatric surgery appears to have promising effects. Although some randomized 
controlled trials investigated the effect of this surgery on the remission or 
improvement of type 2 diabetes mellitus, no randomized controlled trial was 

Page 16 of 51 
 
 
 
Version 6.1 – Dec 1st, 2014 
originally designed to assess the effect of bariatric surgery on high blood 
pressure. 
 
 

Page 17 of 51 
 
 
 
Version 6.1 – Dec 1st, 2014 
2. OBJECTIVES OF THE STUDY 
2.1 Primary objective 
 
To assess the efficacy of Roux-en-Y gastric bypass plus medical 
treatment compared to medical treatment alone in reducing at least 30%of the 
total number of antihypertensive drugs, while maintaining controlled blood 
pressure (SBP<140 and DBP <90mmHg) at 12 months.  
 
2.2 Secondary objectives 
 
To assess the efficacy of Roux-en-Y gastric bypass plus medical 
treatment compared to medical treatment alone, in obese hypertensive patients, 
on the following outcomes at 12 months: 
 
Number of antihypertensive drugs 
 
Systolic blood pressure. 
 
Diastolic blood pressure. 
 
Body weight and BMI. 
 
Waist circumference. 
 
Fasting glucose levels, HbA1c and insulin resistance  
 
LDL-cholesterol levels. 
 
HDL-cholesterol levels. 
 
Triglyceride levels. 
 
Uric acid levels. 
 
High-sensitivity C-reactive protein levels. 
 
Heart anatomy as evaluated by echocardiogram examination. 
 
Estimated risk for cardiovascular disease (Framingham Risk Score). 
 
Adverse events. 
 
Systolic and diastolic blood pressure measured by ABPM  
 
Central pressure, augmentation index, and pulse wave velocity 
measured by SphygmoCor®. 
 
Sleep quality as assessed by polysomnography. 
 

Page 18 of 51 
 
 
 
Version 6.1 – Dec 1st, 2014 
 
To assess the efficacy of Roux-en-Y gastric bypass plus medical 
treatment compared to medical treatment alone on all primary and secondary 
outcomes between 24 and 60 months of follow-up. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Page 19 of 51 
 
 
 
Version 6.1 – Dec 1st, 2014 
3. STUDY METHODS 
3.1 Study design 
 
Phase 3, single-center, randomized clinical trial, with allocation 
concealment, blinded outcome evaluators, and intention-to-treat analysis to 
evaluate the efficacy of video laparoscopic Roux-en-Y Gastric Bypass in the 
reduction of antihypertensive drugs prescription, systemic arterial blood 
pressure and other risk factors for cardiovascular events when compared to 
clinical treatment. 
 
3.2 Randomization 
 
Participants who fulfill all eligibility criteria and provide written informed 
consent will be allocated to either Roux-en-Y gastric bypass or medical 
treatment, in a 1:1 randomization ratio basis. The randomization list will be 
generated electronically using appropriate software, and it will be performed in 
blocks containing 10 patients to guarantee equal group sizes. Allocation 
concealment will be ensured using a web-based central, automated 
randomization system made available 24 hours a day by the System of Clinical 
Studies of HCor (Sistema de Estudos Clínicos do IEP HCor) Each investigator 
or study team will have access to the system through a specific username and 
password. 
 
3.3 Blinding procedure 
 
Because the study involves a surgical procedure, investigators and 
patients cannot be blinded in terms of treatment allocated to patients.  
 
3.4 Video laparoscopic Roux-en-Y Gastric Bypass Description 
 
Patients will be admitted to the Hospital do Coração (HCor)  at least 12 
hours before surgery. On the day before surgery, patients should follow a liquid 
diet and start fasting 10 hours before surgery. Current medications will be 
maintained, except otherwise recommended by attending physician. 
 
Patients will be assessed in a pre-anesthetic visit after admission and will 
receive relevant medication according to this evaluation. 

Page 20 of 51 
 
 
 
Version 6.1 – Dec 1st, 2014 
 
Patients will undergo general anesthesia and be placed in the horizontal 
dorsal recumbence with the right arm held close to the body. 
Deep vein thrombosis will be prevented with high compression elastic stockings 
and lower limb pneumatic compression. Cefazolin 2 g at the induction stage of 
anesthesia and 8h thereafter is used as a prophylactic antibiotic.  
 
Description of procedure (Fig. 3): 
 
Antisepsis with alcoholic chlorhexidine; 
 
Placement of surgical drapes; 
 
Performing pneumoperitoneum using a Veress needle, intra-abdominal 
pressure of 15 mm Hg; 
 
Performing five punctures – two measuring 12 mm and three measuring 5 
mm. 
 
Intestinal time: 
 
Identification of the angle of Treitz 
 
Measurement of the biliopancreatic limb – 100 cm; 
 
Sectioning using a white load stapler (Echelon flex 45); 
 
Measurement of the alimentary limb – 150 cm; 
 
Latero-lateral jejuno-jejununal anastomosis between the biliopancreatic 
limb and the alimentary limb at the point 150cm with a white load stapler 
(Echelon flex 45);  
 
Closing of stump with manual suture - Ethibond 2.0 suture; 
 
Closure of the mesenteric gap with Ethibond 2.0 suture; 
 
Measurement of common channel; 
 
Sectioning of the omentum near the border of the transverse colon. 
 
Gastric time: 
 
Creation of a 20-30mL gastric pouch using a blue load stapler (Echelon 
flex 45); 
 
First staple line between the first and second vessels of the lesser 
curvature; 
 
Second and/or third staple lines near the angle de His.  

Page 21 of 51 
 
 
 
Version 6.1 – Dec 1st, 2014 
 
Gastro-jejunal anastomosis (alimentary limb) using Echelon flex 45 stapler 
at 3-cm stapler ruler 
 
Insertion of nasogastric tube through anastomosis; 
 
Closure of stapler opening with manual suture – Ethibond 2.0 suture; 
 
Assessment of anastomosis integrity using the air test. 
 
In case of leakage - correction with manual suture; 
 
Closure of Petersen’s space; 
 
Review of abdominal cavity; 
 
Removal of trocars by direct view; 
 
Closure by planes; 
 
Dressing. 
 
Subjects 
preoperatively 
diagnosed 
with 
cholelithiasis 
will 
undergo 
cholecystectomy after gastric bypass: 
 
Dissection of cystic duct and artery 
 
Placement of LT-300 clips on cystic duct and artery; 
 
Sectioning of duct and artery; 
 
Electro cautery with cholecystectomy; 
 
Review of hemostasis; 
 
Removal of gallbladder by 12-mm puncture. 
 
 
 
 
 
 
 
 
 
 
 
Fig.2: Laparoscopic Roux-en-Y Gastric Bypass 
Immediate postoperative period: 

Page 22 of 51 
 
 
 
Version 6.1 – Dec 1st, 2014 
 
Total fasting; 
 
Maintenance fluid; 
 
Analgesia with 500mg dipyrone every 6 hours and nalbuphine if required; 
 
Gastric protector with 40mg pantoprazole every 12 hours; 
 
Antiemetics: bromopride 1ampoule every 8 hours and ondasentron 8 mg 
every 6 hours; 
 
Maintenance of compression stockings and pneumatic compressor; 
 
Walking allowed with aid; 
 
Antihypertensive medication: Sublingual 25mg Captopril if 
DBP>110mmHg 
 
First postoperative period: 
 
Start of liquid diet; 
 
Discontinuation of fluid maintenance therapy if food acceptance is good; 
 
Maintenance of analgesia, gastric protector, and antiemetics; 
 
Walking allowed; 
 
Reintroduction of antihypertensive medication according to blood 
pressure outcomes. 
 
Second postoperative 
 
Hospital discharge if food acceptance is good and there are no systemic 
changes. 
 
3.5 Antihypertensive Treatment 
 
Medical treatment will be standardized for all patients based on office BP 
levels. Patients will be preferably treated with angiotensin converting enzyme 
inhibitors or angiotensin receptor blockers and a calcium-channel blocker, 
except if these are contraindicated or if the patient has already controlled BP 
levels with their current regimen. If the above-mentioned association is already 
in use and the patient maintained systolic blood pressure (SBP) higher than 
130mmHg or diastolic blood pressure (DBP) higher than 80mmHg, the 
combination with a thiazide diuretic will be preferred. If a diuretic is 
contraindicated or if other medications are deemed necessary, spironolactone 

Page 23 of 51 
 
 
 
Version 6.1 – Dec 1st, 2014 
or clonidine will be used. Medications will be discontinued or reduced if patients 
presented with SBP lower than 130mmHg or DBP lower than 80mmHg 
associated with symptoms of orthostatic hypotension.33 In patients who achieve 
SBP lower than 110mmHg or DBP lower than 70mmHg, dose reduction of 
antihypertensive medications will eventually be attempted even in the absence 
of symptoms; reduced doses were maintained if SBP and DPB levels sustained 
below 140mmHg and 90mmHg. For patients submitted to bariatric surgery, the 
necessity of reintroducing antihypertensive medication will be initially checked 
on a daily basis in the immediate post-operative period, in the first visit one 
week after the procedure, as well as in the remaining follow-up visits according 
to the visit schedule. Patients will be treated for other associated co-morbidities 
according to national and international guidelines.34,36-38  Adherence to 
treatment will be based on patient self-report after hospital discharge. 
 
3.6 Measurements of blood pressure and heart rate 
 
The participants invited to attend screening visits will have a confirmed 
diagnosis of arterial hypertension requiring the use of at least 2 antihypertensive 
drugs at their full doses and will have their blood pressure measured according 
to the following tests described below. 
 
3.6.1 Ambulatory blood pressure monitoring (ABPM) 
 
Participants will have an Ambulatory Blood Pressure Monitoring test 
(ABPM) scheduled according to V Brazilian Guidelines for Ambulatory Blood 
Pressure Monitoring (ABPM)(39) on the day preceding the Initial visit, and after 
12, 24, 36, 48 and 60 months 
 
3.6.2 Office blood pressure measurements 
 
On every follow-up visit, study participants will have their blood pressure 
measured in the doctor’s office according to the protocol described below. 
Systolic (Korotkoff sound I; appearance of the first sound) and diastolic 
(Korotkoff sound V; disappearance of sounds) blood pressures will be 
measured using a standard mercury sphygmomanometer or a properly 
calibrated aneroid sphygmomanometer with the cuff size adjusted to the 

Page 24 of 51 
 
 
 
Version 6.1 – Dec 1st, 2014 
circumference of the arm, and patients should avoid consuming tobacco, 
alcohol, or caffeinated drink for at least 2 hours before examination. The same 
observer, using the same equipment, will take all measures and on the arm at 
the same level after patients remained sitting for 5 minutes with their arms 
positioned at the heart level. Measurements will be taken in triplicate and heart 
rate will be assessed at a 2-minute interval between two measurements. 
 
3.6.3. Central pressure and associated measures (SphygmoCor®) 
 
Central pressure and arterial stiffness will be assessed by SphygmoCor® 
(AtCor Medical). This device consists of a tonometer (pressure sensor) placed 
on the wrist directly above the radial artery, where the operator detects the 
strongest signal on pulse taking. A computer program accompanying the device 
allows for the calculation of central pressure and measures to assess arterial 
stiffness, such as pulse wave velocity and augmentation index. Patients should 
avoid consuming caffeine for at least 3 hours and alcohol for 10 hours before 
measurements. Measures should be taken preferably in the supine position. 
 
Tests with SphygmoCor® will be conducted at the Instituto Dante 
Pazzanese de Cardiologia. 
 
3.6.4 Polysomnography 
 
Patients will be referred for polysomnography at the Instituto do Coração 
(Instituto do Coração, School of Medicine, Universidade de São Paulo, 
FMUSP). This method will be used after randomization (baseline) visits after 12, 
24, 36, 48 and 60 
 
3.7 Anthropometric measures 
 
During clinical visits, a previously trained professional will measure 
weight, height, and waist circumference. 
 
Weight will be measured using a mechanical platform or digital scale with 
an accuracy of 100 g. Measures should be obtained twice and the mean of the 
two measurements will be considered the actual weight of the participant. If the 
difference between measures is greater than 1 cm, the procedure will have to 
be repeated until reaching an acceptable difference. 

Page 25 of 51 
 
 
 
Version 6.1 – Dec 1st, 2014 
 
Height will be measured using a stadiometer with an accuracy of 0.5 cm. 
Measures should be obtained twice and the mean of the two measurements will 
be considered the actual height of the participant If the difference between 
measures is greater than 1 cm, the procedure must be repeated until reaching 
an acceptable difference. 
 
Weight and height will be used to calculate the derived variable body 
mass index (BMI). BMI is calculated dividing current weight in kg by squared 
height in meters.  
 
Waist circumference will be measured using a non-stretch tape measure 
made of resistant material and accurate to 0.1 cm. Waist circumference will be 
measured at the midpoint between the last rib and the iliac crest in the 
midaxillary line. Measures should be obtained twice and the mean of the two 
measurements will be considered the actual waist circumference of the 
participant. If the difference between measures is greater than 1 cm, the 
procedure will have to be repeated until reaching an acceptable difference. 
Additionally, body composition (body fat percentage vs. lean mass percentage) 
will be measured by bioimpedance.
(40) 
 
3.8 Food intake data and Nutritional advice 
 
Dietary intake will be assessed using a 24-hour diet recall. This 
instrument investigates the type of food, preparations, portions, home 
measures, amounts, and times when meals are consumed 24 h before the visit. 
A photo book showing standard home measures will be used to assist the 
collection of the 24-hour diet recall. Nutritional composition in terms of energy 
and nutrients will be analyzed using a computerized system (Nutriquanti 
System). 
 
Patients from both groups will receive nutritional advice that is based on 
national statements for hypertension and obesity.34 A visit to a dietitian from the 
investigation team will follow each medical visit at the hospital to reinforce the 
nutritional recommendations previously indicated. Nutritional advices in the 
clinical group will be mainly directed at weight reduction and blood pressure 
control.34-36 Aiming at progressive weight loss over time, the total daily energy 
consumption calculated as 20 kcal/kg of ideal body weight per day will be 

Page 26 of 51 
 
 
 
Version 6.1 – Dec 1st, 2014 
stimulated among the patients. Similarly, for the improvement of blood pressure 
control, the ingestion of food with high sodium concentration, such as snacks, 
sausages and fast food, will be discouraged and the reduction of salt used for 
cooking at home or added to the already prepared food will be encouraged. 
Consuming fruits and vegetables will be stimulated also to increase potassium 
intake. 
 
3.9 Laboratory tests 
This protocol includes the following laboratory tests: 
LABORATORY TESTS 
Tests undertaken 
by the 2 study 
groups during visits 
 
 Fasting glucose levels 
 HbA1c 
 Insulin 
 High-sensitivity c-reactive protein 
 Complete blood count 
 Lipid profile 
 Hepatic enzymes (AST, ALT)  
 Uric acid 
 24-h urinary sodium and potassium  
 24-h urinary creatinine 
 Creatinine 
 Potassium 
 Urine analysis 
 Echocardiogram, Electrocardiogram, SphygmoCor® 
 ABPM  
 Polisomnography 
Tests undertaken 
only by the 
intervention group 
(bariatric surgery) 
 
 Iron, Ferritin 
 Vitamin B12 
 Total proteins and fractions 
 PTH 
 Parasitological stool test  
 Coagulogram 

Page 27 of 51 
 
 
 
Version 6.1 – Dec 1st, 2014 
LABORATORY TESTS 
 Full abdominal ultrasound  
 Upper abdomen ultrasound  
 Pelvic ultrasound 
 Upper digestive endoscopy with H.pilory search 
 
3.10 Psychological assessment and follow-up 
 
A psychological assessment will be performed at the baseline visit. This 
assessment will include scales to evaluate binge eating disorder, symptoms of 
anxiety and depression, and quality of life. Throughout the study, participants of 
both groups will receive psychological follow-up consisting of individual visits for 
participants of the surgical group and multidisciplinary group meetings for 
participants of the clinical group.  
 
3.11 Outcomes of interest 
3.11.1 Primary outcome 
 
Reduction on the total antihypertensive medications of at least 30% while 
maintaining controlled BP levels (SBP<140 and DBP <90mmHg) at 12 months. 
 
3.11.2 Secondary outcomes 
 
Reduction on the total antihypertensive medications of at least 30% while 
maintaining controlled BP levels (SBP<140 and DBP <90mmHg) at 24, 36, 48 
and 60 months. 
 
The following secondary outcomes (absolute change from baseline) will 
be assessed at 12, 24, 36, 48 and 60 months: 
 
Systemic blood pressure measured by ambulatory blood pressure 
monitoring (ABPM) 
 
Central pressure, augmentation index, and pulse wave velocity measured by 
SphygmoCor® 
 
Systolic blood pressure (measured at office visits) 
 
Diastolic blood pressure (measured at office visits)  
 
Body weight and BMI. 

Page 28 of 51 
 
 
 
Version 6.1 – Dec 1st, 2014 
 
Waist circumference. 
 
Fasting glucose levels, HbA1c and insulin resistance  
 
LDL-cholesterol levels. 
 
HDL-cholesterol levels. 
 
Triglyceride levels. 
 
Uric acid levels. 
 
High-sensitivity C-reactive protein levels. 
 
Estimated risk for cardiovascular disease (Framingham Risk Score). 
 
Echocardiographic parameters  
 
Sleep quality by polisomnography. 
 
Adverse events. 
 
3.12 Patients' identification 
 
Participants will be selected to participate in the study at HCor and may 
be referred from hypertension outpatient clinics of the Heart Institute (HC- 
FMUSP), from Instituto Dante Pazzanese de Cardiologia, from doctor's offices, 
or at patient's own initiative after being informed about the study through 
advertisement in print or digital media. Patients must have a previous diagnosis 
of hypertension and be taking maximum doses of at least two antihypertensive 
drugs or moderate doses of more than two antihypertensive drugs. Patients will 
be assessed by the study with regard to other eligibility criteria. Patients who 
met inclusion criteria in this outpatient phase will be invited to participate in the 
study and will be randomized to one of the treatment strategies. 
 
3.13 Visits scheme 
 
All visits will be scheduled according the date of inclusion of the patient in 
the study, with a time window of more or less 3 days. 
Follow-up visits are described in the sections below. 
 
3.13.1 Screening visit 
 
Participants will be fully informed about study methods and all the 
procedures they will be subjected to during the observation period, as well as 

Page 29 of 51 
 
 
 
Version 6.1 – Dec 1st, 2014 
the risks implicated in each procedure. Participants will be assessed for 
inclusion and exclusion criteria and for current hypertensive medication. When 
the candidate agrees to participate, and is in accordance with the eligibility 
criteria, he or she will be asked to sign the informed consent form. Then, 
antihypertensive treatment is adjusted as explained in session 3.5. 
 
3.13.2 Randomization visit 
 
This visit will be scheduled approximately 6 weeks after the screening 
visit. In this visit, a thorough medical history will be obtained and eligibility 
criteria confirmed. Participants meeting eligibility criteria will be randomized to 
undergo video laparoscopic Roux-en-Y gastric bypass or to receive medical 
treatment.  
 
After randomization, patients will receive an identification number code, 
which will be used in all documents from study subjects, including clinical 
records, mail, and any other elements requiring identification.  
 
Blood samples will be collected for baseline laboratory analysis (section 
3.9). 
 
Subjects allocated to the intervention group (video laparoscopic Roux-en-
Y gastric bypass) will undergo additional preoperative examinations to identify 
possible contraindications to surgery and assess adverse events associated 
with surgery. The following tests will be performed: full abdominal ultrasound, 
upper gastrointestinal endoscopy with search for H. pylori, coagulogram, and 
parasitological stool test. On this occasion, patients allocated to the surgical 
group will start multivitamin supplementation, which should be maintained up to 
the day before surgery. 
 
Office-based blood pressure will be measured. All the following exams 
are schedule close to the randomization visit: central pressure, pulse wave 
velocity, and augmentation index as measured by SphygmoCor®; ABPM; 
echocardiogram; electrocardiogram; bioimpedance; and polysomnography.  
 

Page 30 of 51 
 
 
 
Version 6.1 – Dec 1st, 2014 
3.13.3 - Baseline visit 
 
The baseline visit will be scheduled as soon as all the exams are ready. 
After this visit, patients of the gastric bypass group will undergo surgery. On this 
occasion, coagulation parameters should be normal. 
 
If cholelithiasis is identified on abdominal ultrasound, cholecystectomy 
will be simultaneously performed; H. Pylori positive patients will be treated with 
a triple regimen for 10 days – amoxicillin 2 g/day, clarithromycin 1 g/day, and 
pantoprazole 80 mg/day; subjects diagnosed with intestinal parasitosis will 
receive specific treatment. 
 
If test results contraindicate surgery, the patient will be excluded from the 
study and regarded as a randomization failure. 
 
A psychologist will see the participants of both groups. In the surgical 
group, psychological visits will focus on evaluating whether the patient is 
psychologically prepared to cope with changes resulting from surgery. In the 
clinical group, the focus will be on evaluating patient motivation to adhere to 
intervention. 
 
The participants of both groups will also be seen by a dietitian to assess 
baseline anthropometric measures, body composition by bioimpedance, a 24-
hour diet recall, and to receive nutritional counselling on weight control and salt 
intake. 
 
3.13.4 Follow-up visit 1 (week 1 after surgery) 
 
This will be a clinical visit involving the following procedures: 
 
Measurement of office-based systemic blood pressure and heart rate. 
 
Report if any adverse events, whether related or not with the study 
treatment. 
 
Dietitians visit to collect anthropometric measures and provide nutritional 
counselling (guidance on the use of protein supplements). 
 
Patients will provide information on treatment adherence. 
 
Multivitamin supplementation will be restarted. 
 
 

Page 31 of 51 
 
 
 
Version 6.1 – Dec 1st, 2014 
3.13.5 Follow-up visit 2 (week 4 after baseline visit) 
 
This will be a clinical visit involving the following procedures: 
 
Measurement of office-based systemic blood pressure and heart rate. 
 
Report if any adverse events, whether related or not with the study 
treatment. 
 
Dietitians visit to collect anthropometric measures and provide nutritional 
counselling (check on the use of protein supplements for postsurgical patients). 
 
Patients will provide information on treatment adherence. 
 
A psychologist will see patients in the surgical group, whereas those 
randomized to the clinical group were invited to group meetings. 
 
3.13.6 Follow-up visit 3 (month 3 after baseline visit) 
 
This will be a clinical visit involving the following procedures: 
 
Measurement of office-based systemic blood pressure and heart rate. 
 
Dietitians visit to collect anthropometric measures and provide nutritional 
counselling. 
 
Report if any adverse events, whether related or not with the study 
treatment. 
 
Patients will provide information on treatment adherence. 
 
A psychologist will see patients in the surgical group, whereas those 
randomized to the clinical group were invited to group meetings. 
 
Subjects in the surgical group will undergo ultrasound of liver and biliary 
structures for those who have not had their gallbladder removed. Participants 
with positive results for biliary calculus will undergo elective cholecystectomy. 
 
3.13.7 Follow-up visit 4 (month 6 after baseline visit) 
 
This will be a clinical visit involving the following procedures: 
 
Measurement of office-based systemic blood pressure and heart rate. 
 
Report if any adverse events, whether related or not with the study 
treatment. 
 
Dietitian visit to collect anthropometric measures, provide nutritional 
counselling, and obtain a 24-hour diet recall. 

Page 32 of 51 
 
 
 
Version 6.1 – Dec 1st, 2014 
 
Patients will provide information on treatment adherence. 
 
A psychologist will see patients in the surgical group, whereas those in 
the clinical group will be invited to group meetings. 
 
3.13.8 Follow-up visit 5 (month 12 after baseline visit) 
 
Before the scheduled visit, patients will undergo ABPM, Echocardiogram, 
Electrocardiogram, polysomnography, SphygmoCor®. 
This will be a clinical visit involving the following procedures: 
 
Measurement of office-based systemic blood pressure and heart rate. 
 
Dietitian visit to collect anthropometric measures, provide nutritional 
counselling, and obtain a 24-hour diet recall. 
 
Patients will provide information on treatment adherence 
 
Blood samples will be collected for laboratory analysis (section 3.9). 
 
A psychologist will see patients in the surgical group, whereas those 
randomized to the clinical group will be invited to group meetings.  
 
3.13.9 Follow-up visit 6 (month 18 after baseline visit) 
 
This will be a clinical visit involving the following procedures: 
 
Measurement of office-based systemic blood pressure and heart rate 
 
Dietitians visit to collect anthropometric measures, provide nutritional 
counselling, and obtain a 24-hour diet recall 
 
Collection of data on any adverse event, whether related or not with 
study treatments 
 
Patients will provide information on treatment adherence 
 
3.13.10 Follow-up visit 7 (month 24 after baseline visit) 
 
Before 
the 
scheduled 
visit, 
subjects 
will 
undergo 
ABPM, 
Echocardiogram, Electrocardiogram, polysomnography, SphygmoCor®. 
 
This will be a clinical visit involving the following procedures: 
 
Measurement of office-based systemic blood pressure and heart rate 
 
Dietitians visit to collect anthropometric measures, provide nutritional 
counselling, obtain a 24-hour diet recall, and measure body composition by 

Page 33 of 51 
 
 
 
Version 6.1 – Dec 1st, 2014 
bioimpedance. 
 
Report if any adverse events, whether related or not with the study 
treatment. 
 
Blood samples will be collected for laboratory analysis (section 3.9). 
 
Collection of information on treatment adherence 
 
Participants in the surgical group will be seen by a psychologist, whereas 
those in the will be invited to group meetings. 
 
3.13.11 Follow-up visits – 30, 42 and 54 months after baseline visit: 
 
These visits will include the same procedures conducted in the 18-
months follow-up visit. 
 
3.13.12 Follow-up visits – 36, 48 and 60 months after baseline visit: 
 
These visits will include the same procedures conducted in the 24-
months follow-up visit. Polysomnography will be done only at 60 months. 
 
3.14 Adverse event report 
 
The investigator will check for the occurrence of adverse events at all 
study visits. In case of an adverse event, complete and detailed information 
related to this event should be obtained and recorded on medical and clinical 
records with great detail, including treatment information. 
The following data should be provided when reporting an adverse event: 
 
Start and end date; 
 
Duration of the event in days; 
 
Intensity of the event (mild, moderate, or severe); 
 
Frequency of the event (unique, intermittent, or continuous); 
 
Severity; 
 
Nature of severity (fatal, life-threatening, permanent disability, need of 
hospitalization, congenital anomaly, or significant risk); 
 
Relationship between the events and study medication/procedure; 
 
Action taken; 
 
Event outcome (recovered, not recovered, with sequelae, or fatal). 

Page 34 of 51 
 
 
 
Version 6.1 – Dec 1st, 2014 
 
If the event is fatal, it will be necessary to record date of death, cause of 
death, and whether autopsy was performed. 
 
3.14.1 Serious adverse event reporting 
 
The investigator should record information about serious adverse events 
on medical and clinical records and complete the serious adverse event form. 
This form should be sent to the Research Ethics Committee within a maximum 
of 24 hours after being informed about the event. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Page 35 of 51 
 
 
 
Version 6.1 – Dec 1st, 2014 
4. STUDY POPULATION 
4.1 Inclusion criteria 
 
Adults aged between 18 and 65 years. 
 
Patients with hypertension using at least 2 antihypertensive drugs at full 
doses or more than two in moderate doses. 
 
Grade 1 and Obesity: BMI between 30.0 and 39.9. 
 
4.2 Exclusion criteria 
 
Patients with blood pressure levels ≥ 180/120 mmHg; 
 
Cerebrovascular disease (stroke) in the past 6 months. 
 
Cardiac 
disease 
(myocardial 
infarction, 
angina, 
coronary 
revascularization, heart failure) that occurred or were diagnosed in the past 6 
months. 
 
Underlying psychiatric diseases: schizophrenia, bipolar disorder, severe 
depression, psychosis 
 
Kidney disease: diabetic nephropathy, creatinine clearance < 30 ml/min. 
 
Individuals with secondary hypertension, except due to sleep apnea. 
 
Advanced peripheral artery disease 
 
Patients with atrophic gastritis 
 
Type 1 diabetes; latent autoimmune diabetes of adults; type 2 diabetes 
mellitus with HbA1c >7.0% 
 
Alcoholism or use of illicit drugs  
 
Current tobacco smoking habit 
 
Previous abdominal surgery (except for MacBurney, Pfannenstiel, and 
video laparoscopic cholecystectomy) 
 
Severe hepatic disease 
 
Pregnant women or women at childbearing age not using effective 
contraceptive methods;  
 
Neoplasm occurring in the past 5 years 
 
Use of immunosuppressant drugs, chemotherapy or radiotherapy 
 
Inability to understand or to adhere to study procedures 
 

Page 36 of 51 
 
 
 
Version 6.1 – Dec 1st, 2014 
4.3 Recruitment 
 
Participants will be selected from hypertension outpatient clinics or 
doctor's offices. At this time, all participants will be investigated for compliance 
with eligibility criteria and those meeting these criteria will be asked to provide 
written consent to participate in the study by signing the informed consent form.  
Medical history and baseline clinical characteristics will be obtained through 
history taking, and baseline data will be collected through medical tests.  
 
4.4 Losses to follow-up 
 
All efforts will be made to ensure complete follow-up of study 
participants, whether they adhere or not to the procedures described in this 
protocol. However, patients who, for any reason, do not return to the scheduled 
visits according to the protocol or refuse follow-up will be classified as lost to 
follow-up.  
 
4.5 Consent withdrawal 
 
Withdrawal of consent occurs when a patient spontaneously decides, for 
whatever reason, whether specified or not and at any time during the study, that 
he/she does not want to participate in the study anymore and that he/she does 
not allow for his/her follow-up data to be collected. 
 
 
 
 
 
 
 
 
 
 
 
 

Page 37 of 51 
 
 
 
Version 6.1 – Dec 1st, 2014 
5. STATISTICAL CONSIDERATIONS 
5.1 Sample size calculation 
 
The study was initially designed to enroll 60 patients. During the 
conduction of the trial, the Steering Committee decided to increase the sample 
size to 100 patients to improve precision around the effect estimate. This 
revised sample provides 90% power to detect an increase in the incidence of 
the primary end point from 10% in the medical therapy to 40% in the gastric 
bypass group, assuming a two-sided hypothesis test with a significance level of 
5%. 
 
5.2 Statistical analysis 
 
Baseline characteristics will be reported as counts and percentages, 
mean and standard deviation (SD), or median and interquartile range (IQR), 
whenever appropriate. 
 
Main analysis will be conducted according to the intention-to-treat 
principle; in case of missing values in 12-month visit we will use a simple carry-
over imputation procedure. We will assess the effect of the trial treatments on 
the primary outcome using Fisher exact test and presented rate ratios with 95% 
confidence intervals (CIs).  
 
We will conduct other five sensitivity analysis: complete-case analysis 
(without missing data imputation); per-protocol analysis (patients randomized 
from gastric bypass group who will not undergo surgery will be ignored), as-
treated analysis (patients randomized to gastric bypass group who will not 
undergo surgery will be analyzed in the medical therapy group), worst-case 
scenario imputation analysis (missing end point data will be imputed as a 
positive result in the medical therapy group and negative result in the gastric 
bypass group), and adjusted analysis for BMI, number of medications at 
baseline, Framingham Risk Score, serum insulin level at baseline and duration 
of hypertension using Poisson regression analysis with robust error variance.. In 
all cases, rate ratio will be presented with 95% CIs. 
 
Continuous secondary end points will be analyzed with adjustments for 
baseline values using repeated measure ANOVA models. Variables that do not 

Page 38 of 51 
 
 
 
Version 6.1 – Dec 1st, 2014 
hold normal distribution assumption will be analyzed using generalized 
estimating equation models with distribution that fit better the data. 
 
Analyses will be performed using R (R Core Team, 2016, Vienna, 
Austria) program. Results of diet recalls will be assessed using NutriQuanti®. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Page 39 of 51 
 
 
 
Version 6.1 – Dec 1st, 2014 
6. ADVERSE EVENTS 
 
Physicians will complete adverse event forms or serious adverse event 
forms with the information provided by patient either at clinical visits or by 
telephone. The Research Ethics Committee should be immediately informed in 
case of a serious adverse event. 
 
The physician must decide whether hospitalization, complementary tests, 
and early exclusion from the study are necessary. Medical care costs will be 
covered by the project. 
 
6.1 Adverse event definitions 
 
According to the Document of the Americas, adverse event is defined as 
any adverse medical occurrence in a patient or clinical research participant who 
underwent an intervention. This occurrence does not necessarily have a causal 
relationship with the treatment. Thus, an adverse event may be any unfavorable 
and unintentional sign, symptom, or disease (including abnormal laboratory 
findings), whether related or not to study interventions. 
 
6.2 Unexpected adverse events 
 
This is an adverse reaction whose nature, severity, or outcome is not 
consistent with information described in the package leaflet. It should be 
monitored according to guidelines for adverse reactions and, if applicable, 
according to guidelines for serious adverse reactions. 
 
6.3 Definition of serious adverse events 
 
A serious adverse event is any event that is fatal, life-threatening, 
debilitating or incapacitating or resulting in hospitalization (not relevant to the 
study), an event that causes longer hospital stay (relevant to the study and 
longer hospital stay than the length planned in the study protocol) or is 
associated with congenital abnormality. In addition, any event that the 
investigator considers serious or that may suggest any significant risk, 
contraindication, side effect, or prevention measure that may be associated with 
the use of the drug should be reported as a serious event. 

Page 40 of 51 
 
 
 
Version 6.1 – Dec 1st, 2014 
 
An event should be considered as life threatening if it poses the patient at 
immediate risk of death. An event should be considered as disabling or 
incapacitating if it causes significant and/or permanent impairment of the 
patient's ability to perform normal life activities. 
 
6.4 Evaluation of adverse event intensity 
 
Adverse events should be classified as to their severity into mild, 
moderate, or severe. The following table describes the definitions: 
Mild 
Adverse event easily tolerated by the patient, causing minimal 
discomfort, not interfering with his activities. 
Moderate 
Adverse event sufficiently discomforting to interfere with the 
patient's normal activities. 
Serious 
Any fatal, life-threatening, debilitating event, or an event leading 
to hospitalization, according to item 6.3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Page 41 of 51 
 
 
 
Version 6.1 – Dec 1st, 2014 
7. ADMINISTRATIVE PROCEDURES 
7.1 Electronic case report forms (e-CRF) 
 
Electronic reports forms will be accessed through the System of Clinical 
Studies of IEP-HCor (Sistema de Estudos Clínicos do IEP-HCor). They should 
be completed within a maximum of 5 days after visiting the patient. The 
electronic system for the development of informative reports on the completion 
status of forms and shows whether the completion of some of these forms is 
delayed and the duration of such delay, enabling the study team to manage 
participants in all research sites. 
 
All security recommendations set out by international guidelines for the 
use of e-CRFs are ensured by the system. In this sense, any changes of data 
made by the team and the reasons for the changes are recorded in the system, 
thus ensuring data accuracy and quality. 
 
7.2 Monitoring report 
 
The researcher must submit a study monitoring report every six months 
to Research Ethics Committee informing status of inclusion, safety data, and 
study schedule. 
 
7.3 Filing of records  
 
The Research Center will keep confidentiality of all study documentation, 
taking the appropriate measures to prevent premature or accidental destruction 
of such documents. The study documentation must be kept for at least 5 years 
after completion or discontinuation of the study. 
 
7.4 Publication 
 
We expect to publish at least four manuscripts related to this study: a 
design paper and main manuscripts describing study results at one, three and 
five years. 
 
Study findings will be published regardless of results. 
 

Page 42 of 51 
 
 
 
Version 6.1 – Dec 1st, 2014 
7.5 Confidentiality 
 
The investigator should ensure the privacy and confidentiality of study 
participants. In the e-CRFs and in any documents sent to the sponsor, only their 
identification number and name initials will identify participants. 
 
The investigator should provide direct access to patient records and 
source document for monitoring, audit, or inspection by the sponsor, authorized 
representatives of the sponsor, and regulatory authorities. 
 
7.6 Data protection 
 
Personal information of investigators and patients enrolled in the study 
that may be included in the database will be treated according to applicable 
laws and regulations. 
 
When filling or processing personal data from investigators and/or 
participants, all necessary measures will be taken to safeguard and prevent 
unauthorized third parties to have access to these data. 
 
7.7 Audits and inspections of regulatory agencies 
 
In order to ensure protocol compliance with good clinical practices and 
applicable legal requirements, investigators will be obliged to allow for audits 
and inspections of applicable regulatory agencies if necessary. The 
confidentiality of the obtained data and participant anonymity will be respected 
during these inspections. Any results and information from inspections of 
regulatory authorities will be immediately communicated by the investigation to 
the sponsor. 
 
Investigators should take all the required appropriate measures to 
implement corrective actions for all the issues raised during audits or 
inspections. 
 
 
 
 
 
 

Page 43 of 51 
 
 
 
Version 6.1 – Dec 1st, 2014 
8. RESPONSIBILITIES 
 
It is important to emphasize that all the procedures to be executed during 
the study period will be based on the guidelines described in Document of the 
Americas, Good Clinical Practice handbook, and related laws. 
 
8.1 Investigator Responsibilities 
 
The investigator should ensure the completion of all the procedures 
described in this protocol. The investigator is also responsible to report reliable 
data in an accurate and legible manner according to the provided instructions 
and provide study monitors with direct access to source documents if requested 
so. 
 
These are the responsibilities of the principal investigator: 
 
Submitting the trial project proposal to the REC of the study site and 
executing the study according to the Declaration of Helsinki, good clinical 
practices, and guidelines outlined in the Document of the Americas and in 
compliance with all laws and regulations applicable; 
 
Starting the study only after the protocol and the written informed 
consent are reviewed and approved by the REC where the study will be 
conducted and all local institutional requirements are complied; 
 
Ensuring that every patient and/or legal representative (or caregiver) 
reads, understands, and signs an informed consent form. 
Considering that Resolution No. 251 of the Brazilian National Health Council, 
dated of August 7, 1997, restates the non-transferable responsibility of 
investigators under the terms of Resolution No. 196/96, the principal researcher 
is responsible for: 
 
Submitting the complete research project to the REC under the terms of 
Resolutions No. 196/96 and 251/97. 
 
Filing clinical records of all research subjects for 5 years after study 
completion, respecting data confidentiality. 
 
If the investigator leaves the institution where the study was conducted, 
the documents should remain under the custody of the person who will occupy 
his/her position. 
 
Providing a detailed report, whenever requested or established by the 

Page 44 of 51 
 
 
 
Version 6.1 – Dec 1st, 2014 
REC, the National Research Ethics Committee (Comissão Nacional de Ética 
em Pesquisa, CONEP) or by the Brazilian Health Surveillance Agency 
(Secretaria de Vigilância Sanitária, SVS/MS). 
 
Communicating the occurrence of serious adverse events to the REC. 
 
Communicating proposals of possible changes in the project and/or 
justification for interruption and awaits for appraisal of the REC, except for 
urgent cases to safeguard the protection of study participants, when the REC 
should be informed a posteriori as soon as possible. 
 
Providing the REC, CONEP, and SVS/MS with all appropriately 
requested information. 
 
Proceeding with the continuous analysis of results throughout study 
execution, in order to detect as early as possible the benefits of one treatment 
over the other and to avoid adverse effects in study participants. 
 
Sending periodic reports within the deadlines established by the REC, 
providing at least a semi-annual report and a final report. 
 
Providing access to test and treatment results to patient's physician and 
to the patient whenever requested and/or indicated. 
 
Recommending that the same person will not participate in a new 
research project within the first year after participating in the previous research, 
unless the participant may directly benefit from the research. 
 
8.2 Sponsor responsibilities 
 
The sponsor of this study is obliged by the health authorities to 
implement all reasonable measures to ensure the adequate development of the 
study in terms of ethics and compliance with all items of the protocol. 
According to the Document of the Americas, sponsor responsibilities include: 
 
Quality assurance and control; 
 
Management of research, handling of data, keeping of records; Selection 
of a qualified team to conduct the study; 
 
Compensation of study participants and researchers; Research funding; 
 
Notification/submission of the research to regulatory authorities; Provide 
all information on research product(s); 
 
Manufacturing, packing, labeling, and promoting the coding of research 

Page 45 of 51 
 
 
 
Version 6.1 – Dec 1st, 2014 
product(s) according to good manufacturing practices; 
 
Provision and handling of research product(s); Providing of safety 
information;  
 
Ensuring that all drug adverse reactions are appropriately reported and 
reporting the notified events to the regulatory agency; 
 
Ensuring appropriate research monitoring. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Page 46 of 51 
 
 
 
Version 6.1 – Dec 1st, 2014 
9. ETHICAL CONSIDERATIONS 
9.1 Approval from independent Research Ethics Committees (REC) 
 
The study should be started only after being approved by the Research 
Ethics Committee of Hospital do Coração (HCor), which should grant the 
approval and provide one copy to the research investigator. 
 
9.2 Standards for conducting the study 
9.2.1 Declaration of Helsinki 
 
The present study will be conducted in full compliance with the current 
version of the Declaration of Helsinki. 
 
9.2.2 Good Clinical Practices 
 
The study will be conducted in accordance with the research protocol 
and to good clinical practices (GCP) guidelines. All study sites will be 
responsible for adhering to GCP principles and local study requirements. 
Institutions with no experienced in clinical research will receive specific training 
on GCP guidelines provided by the coordinating center. 
 
9.2.3 National clinical trials norms 
 
This study will be conducted in compliance with local regulations, 
Resolution RDC No. 196/96, Resolution RDC No. 251/97 and complementary 
resolutions from the Ministry of Health and National Health Council. 
 
9.2.4 Obtainment of consent 
 
According to the Document of the Americas, the administration of the 
informed consent form is a process through which the study participant 
voluntarily confirms his/her desire to participate in the study, particularly after 
being informed on all aspects relevant to his/her decision to participate. 
 
The informed consent form is a document that will be signed and dated 
by the research subject or his/her legal representative and the witness (if 
applicable) and will be used as documentary evidence that participants received 

Page 47 of 51 
 
 
 
Version 6.1 – Dec 1st, 2014 
enough information on the clinical trial, possible study intervention, and theirs 
rights as a research subjects, and that they voluntarily agreed to participate in 
the study. 
 
Before signing the Informed Consent form the investigator or his/her 
designated representative must provide all relevant information and give the 
participant or his/her legal representative enough time and opportunity to ask 
questions about the details of the study so that the patients can decide on their 
participation. 
 
The patients should also be informed that they can freely withdraw their 
consent and discontinue their participation in the study at any time, with the only 
responsibility of communicating this decision, without any damage to their 
treatment. 
 
If the participant or his/her legally authorized representative are unable to 
read or understand the study information, the participation of an impartial and 
independent witness is requested. This witness preferably should not be familiar 
with the clinical study. Fingerprints can be used if the subject or his/her legal 
representative is unable to sign the form. 
 
The research subject or his/her legal representative and the witness 
(when necessary) must sign and date two copies of the document. Similarly, the 
researcher who administers the Informed Consent form must also date and sign 
the two copies. One copy should be filed in the study center and the other copy 
should be provided to the participant. 
 
Note: All pages of the Informed Consent form must be initialed by the 
research subject, the legal representative and/or the witness (if applicable), and 
the researcher. 
 
 
 
 
 
 
 
 

Page 48 of 51 
 
 
 
Version 6.1 – Dec 1st, 2014 
10. REFERENCES 
1. Yusuf S, Reddy S, Ounpuu S, Anand S. Global burden of cardiovascular 
diseases: part I: general considerations, the epidemiologic transition, risk 
factors, and impact of urbanization. Circulation 2001;104:2746-53. 
2. Yusuf S, Reddy S, Ounpuu S, Anand S. Global burden of cardiovascular 
diseases: Part II: variations in cardiovascular disease by specific ethnic groups 
and geographic regions and prevention strategies. Circulation 2001;104:2855-
64. 
3. Duncan BB, Schmidt MI, Polanczyk CA, Mengue SS. [High mortality rates 
among 
Brazilian 
adult 
populations--an 
international 
comparison. 
Rev.Assoc.Med.Bras. 1992;38:138-44. 
4. Lewington S, Clarke R, Qizilbash N, Peto R, Collins R. Age-specific 
relevance of  usual blood pressure to vascular mortality: a meta-analysis of 
individual data for one million adults in 61 prospective studies. Lancet 
2002;360:1903-13. 
5. Lawes CM, Rodgers A, Bennett DA, Parag V, Suh I, Ueshima H et al. Blood 
pressure and cardiovascular disease in the Asia Pacific region. J.Hypertens. 
2003;21:707-16. 
6. Law MR, Wald NJ. Risk factor thresholds: their existence under scrutiny. BMJ 
2002;324:1570-6. 
7. Law MR, Wald NJ, Morris JK. The performance of blood pressure and other 
cardiovascular risk factors as screening tests for ischaemic heart disease and 
stroke. J.Med.Screen. 2004;11:3-7. 
8. Law MR, Wald NJ, Wu T, Hackshaw A, Bailey A. Systematic underestimation 
of association between serum cholesterol concentration and ischaemic heart 
disease in observational studies: data from the BUPA study. BMJ 
1994;308:363-6. 
9. Castelli WP. Cholesterol and lipids in the risk of coronary artery disease--the 
Framingham Heart Study. Can.J.Cardiol. 1988;4 Suppl A:5A-10A. 
10. MacMahon S, Peto R, Cutler J, Collins R, Sorlie P, Neaton J et al. Blood 
pressure, stroke, and coronary heart disease. Part 1, Prolonged differences in 
blood pressure: prospective observational studies corrected for the regression 
dilution bias. Lancet 1990;335:765-74. 

Page 49 of 51 
 
 
 
Version 6.1 – Dec 1st, 2014 
11. Longitudinal Assessment of Bariatric Surgery (LABS) Consortium, Flum DR, 
Belle SH, King WC, Wahed AS, Berk P, Chapman W, Pories W, Courcoulas A, 
McCloskey C, Mitchell J, Patterson E, Pomp A, Staten MA, Yanovski SZ, 
Thirlby R, Wolfe B. Perioperative safety in the longitudinal assessment of 
bariatric surgery. N Engl J Med. 2009 Jul 30;361(5):445-54. 
12. Schauer PR, Kashyap SR, Wolski K et al. Bariatric surgery versus intensive 
medical therapy in obese patients with diabetes. N Engl J Med 2012; 
366(17):1567-76. 
13. Dunbar-Jacob J, Erlen JA, Schlenk EA, Ryan CM, Sereika SM, Doswell 
WM. Adherence in chronic disease. Annu Rev Nurs Res 2000; 18:48-90. 
14. Cutler DM, Everett W. Thinking outside the pillbox--medication adherence 
as a priority for health care reform. N Engl J Med 2010; 362(17):1553-1555. 
15. Choudhry NK, Fischer MA, Avorn J, Liberman JN, Schneeweiss S, Pakes 
J, Brennan TA, Shrank WH. The implications of therapeutic complexity on 
adherence to cardiovascular medications. Arch Intern Med. 2011 May 
9;171(9):814-22. 
16. Claxton AJ, Cramer J, Pierce C. A systematic review of the associations 
between dose regimens and medication compliance. Clin Ther 2001; 
23(8):1296-1310. 
17. Heneghan H.M., MeronEldar S., Brethauer S.A., Schauer P.R., Young J.B. 
Effect of bariatric surgery on cardiovascular risk profile. Am J Cardiol 2011; 108 
(10):1499-1507 
18. Stassen JA, Fagard R, Thijs L, Celis H, Arabidze GG, Birkenhäger, et al. 
Randomised double-blind comparison of placebo and active treatment for older 
patients with isolated systolic hypertension. The Systolic hypertension in Europe 
(SYST–EUR). Lancet. 1997;350(9080):757-64. 
19. Psaty BM, Lumley T, Furberg CD, Schellenbaum G, Pahor M, Alderman MH 
et al. Health outcomes associated with various antihypertensive therapies used 
as first-line agents: a network meta-analysis. JAMA 2003;289:2534-44. 
20. Turnbull F, Neal B, Algert C, Chalmers J, Chapman N, Cutler J et al. Effects 
of different blood pressure-lowering regimens on major cardiovascular events in 
individuals with and without diabetes mellitus: results of prospectively designed 
overviews of randomized trials. Arch.Intern. Med. 2005;165:1410-9. 

Page 50 of 51 
 
 
 
Version 6.1 – Dec 1st, 2014 
21. Williams B, Poulter NR, Brown MJ, et al. Guidelines for the management of 
hypertension: report of the fourth working party of the British Hypertension 
Society, 2004 – BHSIV. J Hum Hypertens. 2004;18:139-85. 
22. CG18 Hypertension (persistently high blood pressure) in adults—NICE 
guideline. Available at: www.nice.org.uk. 
23. Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint 
National Committee on Prevention, Detection, Evaluation, and Treatment of 
High Blood Pressure. The JNC 7 Report. JAMA. 2003; 289:2560-73. 
24. The Taskforce for the management of Arterial Hypertension of the European 
Society of Hypertension (ESH) and of the European Society of Cardiology 
(ESC). Guidelines for the Management of Arterial Hypertension. J Hypertens. 
2007;25:1105-87. 
25. Wald DS, Law M, Morris JK, Bestwick JP, Wald NJ. Combination therapy 
versus monotherapy in reducing blood pressure: meta-analysis on 11,000 
participants from 42 trials. Am J Med 2009; 122(3):290-3. 
26. Law MR, Wald NJ, Morris JK, Jordan RE. Value of low dose combination 
treatment with blood pressure lowering drugs: analysis of 354 randomised trials. 
BMJ. 2003;326(7404):1427-35. 
27. Roman MJ, Devereux RB, Kizer JR, et al. Central Pressure More Strongly 
Relates to Vascular Disease  and Outcome Than Does Brachial Pressure: The 
Strong Heart Study. Hypertension. 2007;50:197-203. 
28. Weber T, Auer J, O’Rourke M, Kvas E, Lassnig E, et al. Arterial stiffness 
wave reflections, and the risk of coronary artery disease. Circulation. 
2004;109:184-9. 
29. Weber T, Auer J, O’Rourke MF, et al. Increased arterial wave reflections 
predict severe cardiovascular events in patients undergoing percutaneous 
coronary interventions. Eur Heart J. 2005;26:2657-63. 
30. Dart AM, Gatzka CD, Kingwell BA, et al. Brachial blood pressure but not 
carotid arterial waveforms predict cardiovascular events in elderly female 
hypertensives. Hypertension.2006;47:785-90. 
31. O’Rourke MF, Adji A. An updated clinical primer on large artery mechanics: 
implications of pulse waveform analysis and arterial tonometry. Curr Opin Cariol 
2005. 20 (4): 275-81. 

Page 51 of 51 
 
 
 
Version 6.1 – Dec 1st, 2014 
32. The CAFE Investigators, for the Anglo-Scandinavian Cardiac Outcomes 
Trial (ASCOT) Investigators. Differential Impact of Blood Pressure-Lowering 
Drugs on Central Aortic Pressure and Clinical Outcomes. Circulation. 
2006;113:1213-1225. 
33. Departamento de Hipertensão Arterial da Sociedade Brasileira de 
Cardiologia. I Posicionamento Brasileiro Sobre Hipertensão Arterial Resistente. 
Arq Bras Cardiol. 2012;99(1):576-85.  
34. Nobre F. Introduction: Brazilian guidelines on hypertension VI. Brazilian 
Society of Cardiology, Brazilian Society of Hypertension, Brazilian Society of 
Nephrology. J Bras Nefrol 2010;32(Suppl 1):III. 
35. ABESO ABpoEdOedSM-. Diretrizes Brasileiras e Obesidade. In: ABESO, 
ed. 3rd ed. Itapevi—SP—Brazil, 2009.  
36. Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint 
National Committee on Prevention, Detection, Evaluation, and Treatment of 
High Blood Pressure: the JNC 7 report. JAMA 2003;289:2560–72. 
37. American Diabetes A. Standards of medical care in diabetes—2013. 
Diabetes Care 2013;36(Suppl 1):S11–66.  
38. Sposito AC, Caramelli B, Fonseca FA, et al. IV Brazilian guideline for 
dyslipidemia and atherosclerosis prevention: department of Atherosclerosis of 
Brazilian Society of Cardiology. Arq Bras Cardiol 2007;88(Suppl 1):2–19. 
39. V Diretrizes Brasileiras de Monitorização Ambulatorial da Pressão Arterial 
(MAPA) e III Diretrizes Brasileiras de Monitorização Residencial da Pressão 
Arterial (MRPA). Rev Bras Hipertens 2011;18(1):7-17. 
40. Moissl UM, Wabel P, Chamney PW, Bosaeus I, Levin NW, Bosy-Westphal 
A, Korth O, Müller MJ, Ellegård L,Malmros V, Kaitwatcharachai C, Kuhlmann 
MK, Zhu F, Fuller NJ. Body fluid volume determination via body composition 
spectroscopy in health and disease. Physiol Meas. 2006;(9):921-33.