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
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
Usual BP and CHD Mortality Título Floating absolute risk Age 256 80-89 128 70-79 64 60-69 32 50-59 16 8 4 2 1 61 cohorts 1 million 120 000 deaths Age 256 80-89 128 70-79 64 60-69 32 50-59 16 8 4 2 1 120 140 160 180 70 80 90 100 110 Systolic BP (mm Hg) Diastolic BP (mm Hg) (Prospective Studies, Lancet 2002; 360:1903)
Prehypertension conveys three risks: Increases the incidence of hypertension Is a risk fator for target organ damage Increases mortality for CHD and Stroke
Incidence of Hypertension 1000 persons-year Moreira LB et al, J. of H Hypertension 2008 100 80 68 66 60 40 42 20 22 0 35 36-45 46-55 > 55 Idade 4 out of 5 prehypertensive 40 to 49 years-old in 10 years
Persistent prehypertension for ageing-related changes in LVM: the MONICA study Left ventricular mass (% change) 1005 adults from a population-based survey 1994/95 2004/05 20 15.7 17 P=0.006 14 8.6 11 8 0 Normal BP Prehypertension Markus MR et al. J Hypertens 2008
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 130-139/85-89 mmhg 120-129/80-84 mmhg 305 Strokes 187 CHDs
Stevo Julius et al. TROPHY trial, NEJM 2006 Candesartan: 16 mg/d vs. placebo 2 years follow-up Participants: SBP: 130-139 / DBP: 85-89 mm Hg Baseline BP values: ~ 6 and 5 mm Hg higher Dose of candesartan: standard treatment RRR: 32% HPT
Lüders S. et al. PHARAO trial, J Hypertens. 2008 Ramipril: 5 mg/d vs. no treatment 3 years follow-up of open-label treatment Participants: SBP: 130-139 / DBP: 85-89 mm Hg Baseline BP values: higher Ramipril: cough (4.8% versus 0.4%) RRR: 34% HPT
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
PREVER-PREVENTION TRIAL Blood pressure 120-139 / 80-89 mmhg 21 health care centers from Brazil Men and women Aged 30 to 70 years
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
Office BP Office BP Pre RCT Office BP Office BP Lab Randomized clinical trial 12.5 Chlorthalidone + 2.5 Amiloride + Non-drug intervention Screening 1 3 R 1 3 6 9 12 15 18 HPT Lifestyle modificatio n Placebo + Non-drug intervention
Primary endpoint Incidence of hypertension 140 / 90 mmhg (4 office BP) Coprimary endpoint Left ventricular mass Indexes of LVM; ECG
Secondary endpoints Adverse events Hypokalemia Hyperuricemia Diabetes mellitus Microalbuminuria Central laboratory
Study flow diagram of the PREVER-PREVENTION trial
Selected baseline characteristics [N (%) or mean ±SD] Intervention Placebo Males 186 (50.0) 179 (50.1) Age (years) 50.3 ± 10.2 49.7 ± 10.5 White skin color* 195 (52.4) 206 (57.7) Body mass index (kg/m 2 ) 28.8 ± 4.8 28.7 ± 5.3 Systolic BP (mm Hg) 127.9 ± 7.3 127.8± 7.2 Diastolic BP (mm Hg) 80.6 ± 6.4 80.4 ± 6.2 Potassium (mg/dl) 4.6 ± 0.7 4.6 ± 0.6 Creatinine (mg/dl) 0.80 ± 0.19 0.79 ± 0.19 Microalbuminuria (µg/24h) 6.3 ± 5.9 7.0 ± 6.3 Diabetes mellitus (%) 30 (8.1) 29 (8.1) Uric acid (mg/dl) 5.0 ± 1.0 5.0 ± 1.0
Incidence of hypertension by treatment groups RRR=44%
Blood pressure according to treatment groups
Hazard ratio (95%CI) for hypertension stratified by clinical and demographic characteristics
Sokolow-Lyon voltage duration product (µvms) Change in left ventricular mass 230 225 220 215 210 229 223 224 213 Placebo Intervention P = 0.02 0 Baseline End of trial
Laboratorial outcomes (mean ± SD) at 18 m Chlorthalidone /Amiloride Placebo P value Fasting glucose (mg/dl) 97.3 ± 21.6 94.9 ± 22.9 0.17 Glycated hemoglobin (%) 5.7 ± 1.12 5.5 ± 0.94 0.11 New onset diabetes (%) 17 (5.5) 10 (3.3) 0.18 Potassium (mg/dl) 4.4 ± 0.5 4.5 ± 0.6 0.01 Creatinine (mg/dl) 0.90 ± 0.2 0.88± 0.4 0.6 Uric acid (mg/dl) 5.6 ± 1.4 5.3 ± 1.3 <0.001 Microalbuminuria (µg/24h) 11.1 ± 17.5 12.1 ± 24.2 0.5
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
What we learned with the PREVER-PREVENTION Trial?
2 h glucose tolerance test (mmol/l) Pathway-3: 2h blood glucose concentrations 8.0 7.5 Hydrochlorothiazide 25-50 mg Amiloride 5-10 mg + Hydrochlorothiazide 12.5-25 mg Amiloride 10-20 mg 7.0 6.5 6.0 0 12 24 weeks Baseline Brown M, et al. Lancet Endocrinolgy 2016
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
Primary outcome: SPRINT MI CAD HF CV Death Stroke The SPRINT Research Group. N Engl J Med 2015;373:2103
Optimal Blood Pressure (<120/80 mmhg) % 48 44 40 36 32 28 24 20 16 12 8 4 0 Chlorthalidone + Amiloride * **** ** ** *** Baseline 3 6 9 12 15 18 Placebo * P<0.001 ** P=0.04 *** P=0.02 **** P=0.03 months
Overall results: PREVER-PREVENTION TRIAL Placebo Chlortalidone + amiloride Optimal blood pressure 19.3 25.6 Prehypertension 61.2 62.8 Hypertension 11.7 19.5 P=0.002 0 20 40 60 80 100 %
ASCVD according to age Current age 40 50 60 70 Sex Male Male Male Male Race White White White White Total cholesterol 262 262 262 262 HDL cholesterol 40 40 40 40 LDL cholesterol 222 222 222 222 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
ASCVD according to age and systolic blood pressure % 26 25.9 22 18 14 10 6 2 14.9 10.8 7.4 3.1 5.3 2.2 40 50 60 70 19.1 115 125 130 135 140 Years
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