GATEWAY Trial. Bariatric Surgery versus Conventional Medical Treatment in Obese Patients with Hypertension

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1 GATEWAY Trial Bariatric Surgery versus Conventional Medical Treatment in Obese Patients with Hypertension Carlos Aurelio Schiavon, MD, FACS On behalf of the GATEWAY Executive Committee and Investigators DISCLOSURE Study Funding: Ethicon Inc.; Consulting and Lectures: Johnson & Johnson Medical Brasil

2 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.

3 BACKGROUND THE PROBLEM An increasing number of hypertension cases occur in the overweight and obese population. Adequate control of these patients is a challenge. THE EVIDENCE Observational and randomized trials (focused in T2DM) showed reduction or discontinuation of antihypertensive medications after Bariatric Surgery, but the effect of Bariatric Surgery in obese patients with hypertension remains uncertain. ONE POTENTIAL SOLUTION Bariatric Surgery represents a safe and effective way to treat obesity. Hypertension amelioration is a potential beneficial effect.

4 GATEWAY TRIAL Design: Single center, open-label, randomized clinical trial to evaluate the efficacy of Gastric Bypass in reducing the prescription of antihypertensive drugs and its effect on hypertension and other cardiovascular risk factors. Prevention of Bias: concealed allocation (central web-based randomization) + intention-to-treat analysis. Trial Size: 100 patients recruited between may 2013 and June This sample provides 90% power to detect an increase in the probability of the primary end point from 10% in the medical therapy group to 40% in the gastric bypass group, assuming a two-sided alpha of 5%. Quality Control: e-crf + data management

5 100 Patients with hypertension, aged 18 to 65 years, BMI between 30.0 and 39.9 Kg/m2, treated with at least two antihypertensive drugs at maximum doses or more than two at moderate doses. Key exclusion criteria: SBP 180 mm Hg or DBP 120 mm Hg; Cardiovascular diseases; Severe psychiatric disorders; Secondary hypertension, except due to OSA; T1DM or T2DM with HbA1c > 7.0%; Current smokers. Concealed Randomization 1:1 Gastric Bypass Plus Medical Therapy ITT Medical Therapy (Lifestyle intervention: visits with cardiologist, nutritionist and psychologist) ITT Primary Endpoint: Reduction of at least 30% of the total antihypertensive medications, while maintaining systolic and diastolic blood pressure lower than 140 mm Hg and 90 mm Hg, respectively, at 12 months. Secondary Endpoints: Number of antihypertensive drugs; SBP and DBP (office and 24h-ABPM); Weight, waist circumference and BMI; HOMA-IR; Lipid profile; High-sensitivity C-reactive protein levels; 10-year Framingham risk score; Adverse events.

6 MEDICAL THERAPY BP goal: SBP<140 and DBP<90 If the patient was controlled using his/her own regimen, our option was to maintain the regimen; If the patient was not controlled, our option was adapt the regimen to: ACE or ARB plus Calcium channel blocker; Associated a Thiazide diuretic, if not controlled; Associated Spironolactone or Clonidine, if not controlled.

7 DRUG REDUCTION PROTOCOL BP goal: SBP<140 and DBP<90 SBP<110 mm Hg and/or DBP<70 mm Hg; 110<SBP<130 mm Hg or 70<DBP<80 mm Hg with symptoms of orthostatic hypotension; For Gastric Bypass Patients: Reintroduction of medication was checked on a daily basis in the post-op period.

8 BASELINE Characteristics Gastric Bypass (n=50) Medical Therapy (n=50) Age - yr 43.1 ± ± 9.2 Female no.(%) 36 (72) 34 (68) Race, Caucasian no.(%) 31 (62) 34 (68) Afro-Brazilian no.(%) 19 (38) 16 (32) BMI Kg/m ± ± 2.9 Dylipidemia no.(%) 20 (40) 16 (32) Diabetes no.(%) 4 (8) 4 (8) Framingham median (IQR) 4.5 (2.9 to 7.3) 5 (2.8 to 7.1) Creatinine mg/dl 0.7 ± ± 0.2 Number of antihypertensive drugs median (IQR) 3 (2 to 3) 3 (3 to 3)

9 PRIMARY END POINT 30% reduction in no. of antihypertensive medications while maintaining controlled blood pressure (%) Rate ratio, 6.6; 95% CI, 3.1 to 14.0; P value < % (41/49) Gastric bypass 12.8% (6/47) Medical therapy 51% (25/49) Patients showed a remission of hypertension No Patient showed a remission of hypertension

10 SPRINT LEVELS 30% reduction in no. of antihypertensive medications while maintaining systolic blood pressure <120mmHg (%) Rate ratio, 3.8; 95% CI, 1.4 to 10.6; P value % (16/49) Gastric bypass 8.5% (4/47) Medical therapy 22.4% (11/49) Patients showed a remission of hypertension maintaining a SBP<120 mm Hg Reduction of at least 30% of the total antihypertensive medications, maintaining a SBP<120 mm Hg

11 WEIGHT LOSS 0 Change in BMI from Baseline (kg/m 2 ) -4-8 P<0.001 Gastric bypass Medical therapy -12 Month Gastric bypass Medical therapy

12 PRIMARY END POINT x WEIGHT CHANGE Group Gastric bypass Medical therapy The proportion of patients Change in Body weight from baseline (%) Month

13 SECONDARY END POINTS End Point Gastric Bypass Medical Therapy P Value Number of antihypertensive 0 (0 to 1) (n=49) 3 (2.5 to 4) (n=47) <0.001 SBP - mmhg 123.6±13.4 (n=49) 128.3±18.0 (n=47) 0.11 DBP - mmhg 77.0±9.4 (n=49) 80.6±12.2 (n=47) 0.07 Waist circumference - cm 86.9±8.5 (n=47) 109.8±9.6 (n=39) <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) < year Framingham risk score -% 4.5±4.0 (n=46) 6.8±5.3 (n=39) 0.04

14 ADVERSE EVENTS Event Gastric Bypass Medical Therapy P Value Rehospitalization - no./total no. (%) 6/49 (12) 0/47(0) 0.03 Hypertensive crisis - no./total no. (%) 0/49(0) 1/47(2) 0.49 Reoperation for abscess - no./total no. (%) 1/49 (2) 0/47(0) 1.00 Cholelithiasis requiring laparoscopic cholecystectomy - no./total no. (%) 4/49(8) 0/47(0) 0.12 Anastomotic ulcer - no./total no. (%) 1/49 (2) 0/47(0) 1.00 Vomiting and dehydratation 1/49 (2) 0/47(0) 1.00 Anemia - no./total no. (%) 9/46 (20) 4/40 (10) 0.23 Secondary hyperparathyroidism - no./total no. (%) 6/42 (14) - - Hypovitaminosis B12 - no./total no. (%) 12/43 (28) - -

15 CONCLUSIONS Bariatric surgery represents an effective strategy for reducing antihypertensive drugs in obese patients with hypertension; These results have implications in minimizing nonadherence to therapy and its related consequences; Taken together with the improved metabolic and inflammatory profile, such effects have, theoretically, the potential to reduce major cardiovascular events.