Effects of Bariatric Surgery in Obese Patients with

Effects of Bariatric Surgery in Obese Patients with Hypertension The GATEWAY Randomized Trial Carlos Aurelio Schiavon, MD, FACS On behalf of the GATEWAY Executive Committee and Investigators DISCLOSURE Study Funding: Ethicon Inc. Speaker Bureau and Honoraria: Johnson & Johnson Medical Brasil Embargo lifts Mon. , Nov. 13, 10: 45 a. m. to 12 noon PT

BACKGROUND THE PROBLEM ~40% of the American adults are Obese (~20% - Brazil). 60 -70% of hypertension in adults is attributable to adiposity. THE EVIDENCE Observational and randomized trials (mainly focused in T 2 DM) showed reduction or discontinuation of antihypertensive medications and overall reduction in CV events after Bariatric Surgery. However, RCT’s in a broad population of hypertensive obese patients had not been conducted. A PROMISSING SOLUTION Bariatric Surgery can provide a safe and effective auxiliary tool to BLOOD PRESSURE control in obese hypertensive patients. Reduction in antihypertensive medications can help in adherence to treatment.

100 Patients with hypertension, aged 18 to 65 years, BMI between 30. 0 and 39. 9 Kg/m 2, treated with at least two antihypertensive drugs at maximum doses or more than two at moderate doses. Single center, open-label, randomized clinical trial to evaluate Key exclusion criteria: Uncontrolled blood pressure; the efficacy of Gastric Bypass in reducing the prescription of Active Cardiovascular diseases; antihypertensive drugs and its effect on hypertension and Severe psychiatric disorders; Secondary hypertension, except due to OSA; other cardiovascular risk factors. T 1 DM or T 2 DM with Hb. A 1 c > 7. 0%; Current smokers. Concealed Randomization 1: 1 Gastric Bypass Plus Medical Therapy m. ITT 1 PATIENT LOST TO FOLLOW-UP Medical Therapy (Lifestyle intervention with visits to cardiologist, nutritionist and psychologist) 2 PATIENTS LOST TO FOLLOW-UP 1 PATIENT WITHDREW CONSENT m. ITT 47 PATIENTS WERE INCLUDED 49 PATIENTS WERE INCLUDED GATEWAY design details available at: Clinical. Trials. gov (NCT 1784848) Schiavon et al. BMJ Open. 2014; 4: e 005702.

GATEWAY TRIAL ⦿ Primary Endpoint: ⦿ Reduction of at least 30% of the total antihypertensive drugs, maintaining BP < 140/90 mm Hg, at 12 months. ⦿ Secondary Endpoints: ⦿ Remission of hypertension (BP < 140/90 mm. Hg without medications); ⦿ SPRINT Target (SBP<120 mm. Hg) ⦿ Number of Antihypertensive drugs; ⦿ SBP and DBP (office and 24 h-ABPM); ⦿ Weight, waist circumference and BMI; ⦿ HOMA-IR, Lipid profile, High-sensitivity C-reactive protein levels; ⦿ 10 -year Framingham risk score; ⦿ Adverse events.

MEDICAL THERAPY BP Target: SBP<140 and DBP<90 ⦿ if at target, patient current regimen was maintained; ⦿ if above target, patient current regimen was adapted to: ⦿ ACE inhibitors or ARB plus Calcium channel blocker; ⦿ As needed a Thiazide diuretic; ⦿ As needed Spironolactone or Clonidine. ⦿ Dose and/or number of antihypertensive drugs were reduced if: ⦿ SBP<110 mm Hg and/or DBP<70 mm Hg, or ⦿ Symptoms of orthostatic hypotension and 110<SBP<130 or 70>DBP<80, and ⦿ For Gastric Bypass Patients: Reintroduction of medication was checked on a daily basis in the post-op period.

BASELINE Characteristics Gastric Bypass (n=50) Medical Therapy (n=50) 43. 1 ± 9. 2 44. 6 ± 9. 2 Female – no. (%) 36 (72) 34 (68) Race, Caucasian – no. (%) 31 (62) 34 (68) Afro-Brazilian – no. (%) 19 (38) 16 (32) 37. 4 ± 2. 4 36. 4 ± 2. 9 20 (40) 16 (32) 4 (8) 4. 5 (2. 9 to 7. 3) 5 (2. 8 to 7. 1) 0. 7 ± 0. 1 0. 8 ± 0. 2 Office SBP – mm Hg 123. 0 ± 11. 6 122. 8 ± 12. 9 Office DBP – mm Hg 77. 6 ± 7. 0 78. 0 ± 9. 3 Number of antihypertensive drugs Median (IQR) 3 (2 to 3) 3 (3 to 3) Number of antihypertensive drugs 2. 8 ± 0. 6 3. 1 ± 0. 7 Age - yr BMI – Kg/m 2 Dylipidemia – no. (%) Diabetes – no. (%) Framingham – median (IQR) Creatinine – mg/d. L

≥ 30% reduction in no. of antihypertensive medications while maintaining controlled blood pressure (%) PRIMARY END POINT 100 Rate ratio, 6. 6; 95% CI, 3. 1 to 14. 0; P value <0. 001 75 83. 7% (41/49) 51% (25/49) Patients showed a remission of hypertension (Office) 50 51% 25 (25/49) 12. 8% No Patient showed a remission of hypertension (6/47) 0 Gastric bypass Medical therapy Consistent with these sensitivity analyses: complete-case analysis; per-protocol analysis, as-treated analysis, worst-case scenario, and multiple imputation analysis.

SPRINT TARGET ≥ 30% reduction in no. of antihypertensive medications while maintaining systolic blood pressure <120 mm. Hg (%) Reduction of at least 30% of the total antihypertensive medications, maintaining a SBP<120 mm Hg 100 Rate ratio, 3. 8; 95% CI, 1. 4 to 10. 6; P value 0. 005 75 22. 4% (11/49) Patients showed a remission of hypertension maintaining a SBP<120 mm Hg 50 25 32. 7% (16/49) 22. 4% (11/49) 8. 5% (4/47) 0 Gastric bypass Medical therapy

PRIMARY END POINT HAPPENED BEFORE WEIGHT CHANGE Group Gastric bypass Medical therapy 1. 0 0. 0 The proportion of patients 0. 8 -10 0. 7 -20 0. 6 0. 5 0. 4 -30 0. 3 0. 2 -40 0. 1 0. 0 -50 0 1 2 3 4 5 6 Month 7 8 9 10 11 12 Change in Body weight from baseline (%) 0. 9

SECONDARY END POINTS End Point Gastric Bypass Medical Therapy P Value Waist circumference - cm 86. 9± 8. 5 (n=47) 109. 8± 9. 6 (n=39) <0. 001 Fasting Plasma Glucose, mg/d. L 84. 0± 6. 8 (n=46) 98. 4± 19. 0 (n=40) <0. 001 HOMA-IR 1. 1 ± 0. 9 (n=46) 4. 8 ± 3. 3 (n=40) <0. 001 LDL-cholesterol - mg/dl 86. 9± 29. 2 (n=46) 116. 5± 35. 7 (n=40) <0. 001 HDL-cholesterol - mg/dl 56. 0± 12. 7 (n=46) 51. 2± 15. 1 (n=40) 0. 05 Triglycerides - mg/dl 85. 7± 46. 2 (n=46) 130. 0± 55. 0 (n=40) <0. 001 High-sensitivity C-reactive protein - mg/l 3. 1± 10. 4 (n=46) 8. 1± 9. 3 (n=40) <0. 001 10 -year Framingham risk score -% 4. 5± 4. 0 (n=46) 6. 8± 5. 3 (n=39) 0. 04

SECONDARY END POINTS 75% 1 or less 50% 3 or more Number of antihypertensive drugs Median (IQR) 0 (0 to 1) (n=49) 3 (2. 5 to 4) (n=47) Number of antihypertensive drugs 0. 7 ± 1. 0 3 ± 0. 9 SBP - mm. Hg 123. 6± 13. 4 (n=49) 128. 3± 18. 0 (n=47) 0. 11 DBP - mm. Hg 77. 0± 9. 4 (n=49) 80. 6± 12. 2 (n=47) 0. 07 <0. 001

ADVERSE EVENTS Event, no. /total no. (%) Nutritional deficiencies Anemia High PTH Hypovitaminosis B 12 Hypoalbuminemia Gastric Bypass P Value Base 12 m 13/50 (26) 23/46 (50) 3/50 (6) 9/46 (20) 6/45 (13) 6/42 (14) 4/46 (9) 12/43 (28) 1/46 (2) 0/43 (0) 0. 012 0. 01 1

ADVERSE EVENTS Gastric Bypass Medical Therapy 0 0 6/49 (12) 0/47(0) 0. 03 1/49 (2) 0/47(0) 1. 00 Vomiting and dehydratation Cholelithiasis requiring laparoscopy Hypertensive crisis (ER visit) 1/49 (2) 0/47(0) 1. 00 4/49(8) 0/47(0) 0. 12 0/49(0) 1/47(2) 0. 49 Anemia 9/46 (20) 4/40 (10) 0. 23 Event, no. /total no. (%) Deaths Rehospitalization Reoperation for abscess P Value

CONCLUSIONS ⦿Bariatric surgery represents an effective strategy in the treatment of obese patients with hypertension; ⦿These results have implications in minimizing non-adherence to therapy and its related consequences; ⦿Taken together with the improved metabolic and inflammatory profile, such effects have, in theory, the potential to reduce major cardiovascular events.

THANK YOU ⦿ COORDINATING CENTER: ⦿ RESEARCH INSTITUTE – Heart Hospital (HCor), Sao Paulo, Brazil. ⦿ Co-Chairs: Carlos Schiavon, Otavio Berwanger; ⦿ Executive Committee: Carlos Schiavon, Luciano Drager, Luiz Bortolotto, Celso Amodeo, Otavio Berwanger; ⦿ Project Office-Coordinating Center: Angela Bersch-Ferreira, Eliana Santucci, Camila Torreglosa, Dimas Ikeoka, Priscila Bueno; ⦿ Statisticians: Lucas Damiani, Renato Nakagawa Santos. ⦿ The Surgical and Multidisciplinary Team: Patrícia M. Noujaim, Hélio Halpern, Frederico L. J. Monteiro, Juliana D. Oliveira, Julia C. Frahya. ⦿ Ethicon Inc. that funded the study; ⦿ 100 Volunteers who agreed to participate in GATEWAY. Published online today at: