What is new in hypertensi n? MARIA ROJAS, MD MPH Mount Baker Nephrology September

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1 What is new in hypertensi n? MARIA ROJAS, MD MPH Mount Baker Nephrology September

2 Nothing to disclose except.

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4 Topics for discussion Background info Hypertension in the elderly Rationale for new medications Maternal and perinatal outcomes of control of Hypertension in pregnancy Role of Invasive procedures

5 Our reality

6 For the audience 85 year old male with history of well controlled Diabetes, Hypertension and Chronic Kidney Disease stage III. On Lisinopril and HCTZ. Low fall risk, no orthostatic symptoms. 24 hour ambulatory blood pressure monitoring with average systolic blood pressure of 145, average diastolic blood pressure of 80. Dipping 15% You recommend: A. Adding a third antihypertensive B. No change in current medications

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8 Hazard ratios A HR Better Worse P Value Unadjusted Analysis (95% CI) Prognosis Prognosis SBP<130 mm Hg 0.83 ( ).42 2 Anti HTN drugs 0.97 ( ).83 SBP<130 mm Hg and 2 anti-htn drugs 2.13 ( ) Hazard ratio B HR Better Worse P Value Adjusted analysis (95% CI) Prognosis Prognosis SBP<130 mm Hg 0.75 ( ).25 2 Anti HTN drugs 1.16 ( ).41 SBP<130 mm Hg and 2 anti-htn drugs 2.09( ).01 Age, per 5 y 1.25 ( ) <.001 Male sex 1.63 ( ) <.001 BMI ( ).001 Charlson Comorbidity Index score, per 1- point 1.09 ( ) ADL Score, per 1-point increase 0.77 ( ) < Treatment with Multiple Blood Pressure Medications, Achieved Blood Pressure, and Mortality in Older Nursing Home Residents, The PARTAGE Study. JAMA ItnternMed. 2015;175(6); February 16, 2015

9 ONHR causes of death Distribution of the Causes of Deaths 2 P drugs/sbp <130 mm Hg. % Characteristics Yes/Yes All Others* No/yes No/No Yes/No Patients, No. (%) 227 (20.1) 900 (79.9) 149 (13.2) 328 (29.1) 423 (37.5) Stroke Heart Failure CHD and sudden death Other CV All CV deaths Cancer Infection Fracture Other non-cv deaths All non-cv deaths Total mortality *Includes the 3 columns to the right. Treatment with Multiple Blood Pressure Medications, Achieved Blood Pressure, and Mortality in Older Nursing Home Residents, The PARTAGE Study. JAMA Intern Med. 2015;175(6); February 16, 2015

10 Premature sprint to a finish line.

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13 Control of Hypertension in Pregnancy Primary and Other Perinatal Outcomes* Variable Less Tight Control (N=493) Tight Control (N=488) Adjusted Odds Ratio (95%CI)** Primary Outcome no. (%) 155 (31.4) 150 (30.7) 1.02 ( ) Pregnancy lass no. (%) 15 (3.0) 13 (2.7) 1.14 ( ) Miscarriage 0 1 (0.2) Ectopic pregnancy 0 0 Elective termination 1 (0.2) 1(0.2) Perinatal death 14 (2.8) 11(2.3) 1.25.( ) Stillbirth 12 (2.4) 7(1.4) Neonatal death 2(0.4) 4(0.8) High-level neonatal care for >48 hr no./total no. (%) 141/480 (29.4) 139/479 ( ( ) Gestational age at delivery --wk 36.8± ±3.1 Small-for-gestational-age newborns no./total no. (%) Birth weight <10 th percentile 79/491 (16.1) 96/488 (19.7) 0.78 ( ) Birth weight <3 rd percentile 23/491 (4.7) 26/488 (5.3) 0.92 ( ) Other perinatal outcomes of live born infants Respiratory complications no./total no. (%) Clinical respiratory problem 82/480 (17.1) 67/479 (14.0) 1.19 ( ) Administration of oxygen beyond the first 10 min 34/479 (7.3) 25/477 (5.2) 1.24 ( ) of life Ventilatory support (with or without intubation) 35/478 (7.3) 38/479 (7.9) 0.86 ( ) beyond the first 10 min of life Use of surfactant 28/480 (5.8) 26/479 (5.4) 0.97 ( ) At least one serious neonatal complication no./total no. (%) Ƴ 40/480 (8.3) 40/479 (8.4) 0.96 ( ) Control of Hypertension in Pregnancy. The New England Journal of Medicine. 372;5/ January 29, 2015

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16 Wiki Hemodynamic Actions of Insulin Compensatory Hyperinsulinemia + + Insulin Compensatory Hyperinsulinemia - Sodium Reabsorption Cation Pump Activation ET-1 SNS Activation NO Vasodilatation Plasma Volume Vasoconstriction Insulin Resistance and Endothelial Dysfunction. Kim et al. Circulation. April 18, 2006

17 Synergistic NEP - ACE Vasopeptidase inhibitors (dual NEP-ACE inhibitors) NEP inhibition ACE Inhibiton NEP ACE Metabolites Natriuretic peptides (ANP, BNP) Angiotensin 2 < Angiotensin 2 Angiotensin 1 Vasodilatation Sodium excretion Antihypertrophic effect Antifibrotic effect Vasoconstriction Sodium retention Pro-hypertrophic effect Pro-fibrotic effect Synergistic effect on blood-pressure lowering and reduction of target organ damage Risk of angio-oedema Metabolites Bradykinin Metabolites Aminopeptidase P Synergistic antihypertensive effect of dual NEP-ACE inhibitors Vol.380 August 11,2012

18 Metabolic Syndrome with HT PI-3K (NO) SHR MAPK (ET-1) Blood Pressure, Insulinemia, ET-1, NO, Adiponectin, Vasodilation to Insulin PI-3K (NO) ROSIGLITAZONE MAPK (ET-1) Blood Pressure, Insulinemia, ET-1, NO, Adiponectin, Vasodilation to Insulin Insulin Resistance and Endothelial Dysfunction. Kim et al. Circulation. April 18, 2006

19 New drugs for HT Drug Preclinical Stage Phase 1-3 Pharmaceutical Industry Dual vasopetidase inhibitor Dual neprilysin-ace inhibitor Ilepatril (AVE7688) - Phase 3 Sanofi-Aventis Dual neprilysin-ece inhibitor Daglutril (SLV306) - Phase 2 Solvay Pharmaceuticals Dual ARNI LCZ696 - Phase 3 Novartis Pharmaceuticals Aldosterone-synthase inhibitor LCI699 - Phase 2* Novartis Pharmaceuticals Endothelin antagonist Bosetan - Phase 2 Actelion Pharmaceuticals Darusentan Phase 3* Gilead Sciences Nitric oxide donor Nitric oxide- releasing drugs Nitrosyl-combinamide Yes - - Nitric oxide- releasing hybrids Nitric oxide-losartan Yes - Cayman Chemicals Nitric oxide-telmisartan Yes - Cayman Chemicals CINOD Naproxcinod - Phase 3 NicOx Renin-prorenin blocker - Yes - - ACE 2 activator - Yes - - Aminopeptidase-A inhibitor QGC001 Yes - Quantum Genomics Corp Vaccine Angiotensin 1 vaccine PND Phase 2 Protherics Inc. Angiotensin 2 vaccine Cyt006-AngQb - Phase 2 Cytos Biotechnology AG Dual AT1R/ETA antagonist PS Phase 2 Ligand Pharmaceuticals Novel dual ARB and partial PPAR-ƴ agonist - Yes - - AGE breaker Alagebrium (ALT-711) - Phase 2* Synvista Therapeutics We have only listed molecules described in the text. ACE=angiotensin-l converting enzyme. ARNI=dual-acting angiotensin receptor-neprilysin inhibitor. CINOD=cyclo-oxygenase-inhibiting nityric-oxide donator. ARB=angiotensin-receptor blocker. PPAR-ƴ=peroxisome prolifetator-activated receptor-ƴ. AGE=advance glycation end-product. *Development stopped. Table: New drugs for hypertension Vol380 August 11, 2012

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21 Renal Denervation

22 Change in blood pressure (mm Hg) Change from baseline Blood Pressure Change from baseline in blood pressure at 6 months in patients with previous renal dernervation Vol.385 April 25,2015

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25 Thank you