PREVER STUDY. What we learned with the PREVER-PREVENTION Trial? Dr. Sandra C. Fuchs. Professor at Universidade Federal of Rio Grande do Sul, Brazil

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1 11 PREVER STUDY What we learned with the PREVER-PREVENTION Trial? Dr. Sandra C. Fuchs Professor at Universidade Federal of Rio Grande do Sul, Brazil

2 Financial Support: PREVER investigators: Sandra C. FUCHS, Carlos E Poli-de-Figueiredo, José A Figueiredo Neto, Luiz N Scala, Paul K WHELTON, Francisca Mosele, Renato B. de Mello, José F Vilela- Martin, Leila B. Moreira, Hilton Chaves, Marco M Gomes, Marcos R de Sousa, Ricardo P Silva, Iran Castro, Evandro J Cesarino, Paulo C Jardim, João G Alves, André A Steffens, Andréa A Brandão, Luiz A Bortolotto, Paulo R Alencastro, Abrahão Afiune Neto, Antônio C. Nóbrega, Roberto S Franco, Dario C Sobral Filho, Alexandro Bordignon, Fernando Nobre, Rosane Schlatter, Miguel Gus, Felipe C. Fuchs, Otávio Berwanger, Flávio D. FUCHS

3 Usual BP and CHD Mortality Título Floating absolute risk Age cohorts 1 million deaths Age Systolic BP (mm Hg) Diastolic BP (mm Hg) (Prospective Studies, Lancet 2002; 360:1903)

4 Prehypertension conveys three risks: Increases the incidence of hypertension Is a risk fator for target organ damage Increases mortality for CHD and Stroke

5 Incidence of Hypertension 1000 persons-year Moreira LB et al, J. of H Hypertension > 55 Idade 4 out of 5 prehypertensive 40 to 49 years-old in 10 years

6 Persistent prehypertension for ageing-related changes in LVM: the MONICA study Left ventricular mass (% change) 1005 adults from a population-based survey 1994/ / P= Normal BP Prehypertension Markus MR et al. J Hypertens 2008

7 Fukuhara M, et al. J Hypertens 2012 Incidence of Stroke and CHD: The Hisayama st. Population-based cohort (n=2634) 40 years-old adults, no CVD /85-89 mmhg /80-84 mmhg 305 Strokes 187 CHDs

8 Stevo Julius et al. TROPHY trial, NEJM 2006 Candesartan: 16 mg/d vs. placebo 2 years follow-up Participants: SBP: / DBP: mm Hg Baseline BP values: ~ 6 and 5 mm Hg higher Dose of candesartan: standard treatment RRR: 32% HPT

9 Lüders S. et al. PHARAO trial, J Hypertens Ramipril: 5 mg/d vs. no treatment 3 years follow-up of open-label treatment Participants: SBP: / DBP: mm Hg Baseline BP values: higher Ramipril: cough (4.8% versus 0.4%) RRR: 34% HPT

10 PREVER-PREVENTION aims: To assess the efficacy of a half dose of Chlorthalidone and Amiloride on incidence of hypertension among prehypertensive individuals To determine the safety of low dose of an association of diuretics and the reduction of target organ damage

11 PREVER-PREVENTION TRIAL Blood pressure / mmhg 21 health care centers from Brazil Men and women Aged 30 to 70 years

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13 Lifestyle intervention: lifestyle-focused semipersonalized Booklet Reinforcement at folow up visits Improve diet Salt-restricted Loose weight Reduce waist circumference Increase physical activity Smoking cessation

14 Office BP Office BP Pre RCT Office BP Office BP Lab Randomized clinical trial 12.5 Chlorthalidone Amiloride + Non-drug intervention Screening 1 3 R HPT Lifestyle modificatio n Placebo + Non-drug intervention

15 Primary endpoint Incidence of hypertension 140 / 90 mmhg (4 office BP) Coprimary endpoint Left ventricular mass Indexes of LVM; ECG

16 Secondary endpoints Adverse events Hypokalemia Hyperuricemia Diabetes mellitus Microalbuminuria Central laboratory

17 Study flow diagram of the PREVER-PREVENTION trial

18 Selected baseline characteristics [N (%) or mean ±SD] Intervention Placebo Males 186 (50.0) 179 (50.1) Age (years) 50.3 ± ± 10.5 White skin color* 195 (52.4) 206 (57.7) Body mass index (kg/m 2 ) 28.8 ± ± 5.3 Systolic BP (mm Hg) ± ± 7.2 Diastolic BP (mm Hg) 80.6 ± ± 6.2 Potassium (mg/dl) 4.6 ± ± 0.6 Creatinine (mg/dl) 0.80 ± ± 0.19 Microalbuminuria (µg/24h) 6.3 ± ± 6.3 Diabetes mellitus (%) 30 (8.1) 29 (8.1) Uric acid (mg/dl) 5.0 ± ± 1.0

19 Incidence of hypertension by treatment groups RRR=44%

20 Blood pressure according to treatment groups

21 Hazard ratio (95%CI) for hypertension stratified by clinical and demographic characteristics

22 Sokolow-Lyon voltage duration product (µvms) Change in left ventricular mass Placebo Intervention P = Baseline End of trial

23 Laboratorial outcomes (mean ± SD) at 18 m Chlorthalidone /Amiloride Placebo P value Fasting glucose (mg/dl) 97.3 ± ± Glycated hemoglobin (%) 5.7 ± ± New onset diabetes (%) 17 (5.5) 10 (3.3) 0.18 Potassium (mg/dl) 4.4 ± ± Creatinine (mg/dl) 0.90 ± ± Uric acid (mg/dl) 5.6 ± ± 1.3 <0.001 Microalbuminuria (µg/24h) 11.1 ± ±

24 Adverse events according to treatment group n(%) Adverse events Chlorth.+ amil. Placebo P Musculoskeletal compl. 32 (8.6) 30 (8.4) 0.9 Dizziness 33 (8.9) 25 (7.0) 0.4 Sleep complaints 13 (3.5) 13 (3.6) 0.9 Polyuria 16 (4.3) 8 (2.2) 0.12 Fatigue 9 (2.4) 14 (3.9) 0.3 Palpitations 6 (1.6) 10 (2.8) 0.3 Syncope 6 (1.6) 4 (1.1) 0.6 Sexual dysfunction 2 (0.5) 7 (2.0) 0.08 Cramps 7 (1.9) 2 (0.6) 0.11 Lithiasis 2 (0.5) 7 (2.0) 0.08 High BP 2 (0.5) 4 (1.1) 0.4 Low BP 3 (0.8) 2 (0.6) 0.7 Psychological compl. 4 (1.1) 9 (2.5) 0.14 At least 1 event 142 (38.2) 136 (38.1) 1.00

25 What we learned with the PREVER-PREVENTION Trial?

26 2 h glucose tolerance test (mmol/l) Pathway-3: 2h blood glucose concentrations Hydrochlorothiazide mg Amiloride 5-10 mg + Hydrochlorothiazide mg Amiloride mg weeks Baseline Brown M, et al. Lancet Endocrinolgy 2016

27 Systolic blood pressure in the two treatment groups over the course of the trial The SPRINT Research Group. N Engl J Med 2015;373:2103

28 Primary outcome: SPRINT MI CAD HF CV Death Stroke The SPRINT Research Group. N Engl J Med 2015;373:2103

29 Optimal Blood Pressure (<120/80 mmhg) % Chlorthalidone + Amiloride * **** ** ** *** Baseline Placebo * P<0.001 ** P=0.04 *** P=0.02 **** P=0.03 months

30 Overall results: PREVER-PREVENTION TRIAL Placebo Chlortalidone + amiloride Optimal blood pressure Prehypertension Hypertension P= %

31 ASCVD according to age Current age Sex Male Male Male Male Race White White White White Total cholesterol HDL cholesterol LDL cholesterol Personal history of diabetes No No No No On hypertension treatment No No No No Smoker No No No No On statin? Yes Yes Yes Yes On aspirin therapy? No No No No

32 ASCVD according to age and systolic blood pressure % Years

33 Classification of blood pressure* Normal BP Abnormal BP < 120/80 mmhg 120/80 mmhg. * For adults of all ages, with and without cardiovascular disease, renal disease or diabetes