Resistant Hypertension: A Practical Approach to the Guidelines Michael J Bloch, MD, FACP, FASH, FSVM, FNLA Department of Medicine, University of Nevada School of Medicine Vascular Care, Renown Institute for Vascular Health Reno, NV, USA

Disclosures Speakers Bureau Consultant Research Support Janssen, Amgen Amgen, Recor, Medtronic, Takeda International Research Support AstraZeneca, Recor, Vascular Dynamics

2008 AHA Scientific Statement Calhoun DA, et al. Circulation. 2008;117(25):e510-e26.

2017 ACC/AHA High Blood Pressure Guidelines Whelton et al, Hypertension 2017, Published online Nov 13, 2017

Outline: Diagnostic and Treatment Algorithm for Resistant HTN – 2017 Guidelines Confirm treatment resistance Exclude pseudoresistance Identify and reverse contributing lifestyle factors Discontinue or minimize interfering substances Screen for secondary cause of HTN Rationalize/Intensify pharmacologic treatment Refer to clinical HTN specialist Whelton et al, Hypertension 2017, Published online Nov 13, 2017 Calhoun DA, et al. Circulation. 2008;117(25):e510-e26. Calhoun et al, Circulation, 2008

Diagnostic and Treatment Algorithm for Resistant HTN – 2017 Guidelines Confirm treatment resistance Exclude pseudoresistance Identify and reverse contributing lifestyle factors Discontinue or minimize interfering substances Screen for secondary cause of HTN Rationalize/Intensify pharmacologic treatment Refer to clinical HTN specialist Whelton et al, Hypertension 2017, Published online Nov 13, 2017 Calhoun DA, et al. Circulation. 2008;117(25):e510-e26. Calhoun et al, Circulation, 2008

Does This Patient Have Resistant HTN? Definition from JNC7 and 2008 AHA Scientific Statement BP that remains above 140/90 mm Hg in patients who are adhering to an adequate and appropriate triple-drug regimen (including a diuretic) where all drugs are prescribed at near- maximum recommended doses Definition from ACC/AHA guidelines Uncontrolled BP (>130/80 mmHg in office) despite use of 3 medications Ideally one of which is a diuretic and all used at optimal doses BP controlled, but requiring at least 4 medications http://www.nhlbi.nih.gov/guidelines/hypertension/jnc7full.pdf. Accessed August 19, 2013. Whelton et al, Hypertension 2017, Published online Nov 13, 2017 Calhoun DA, et al. Circulation. 2008;117(25):e510-e26.

Poorly Controlled HTN in NHANES, 2005 to 2008 NHANES = National Health Awareness Nutrition Education Survey. Egan BM, et al. Circulation. 2011;124(9):1046-1058.

Diagnostic and Treatment Algorithm for Resistant HTN – 2017 Guidelines Confirm treatment resistance Exclude pseudoresistance Identify and reverse contributing lifestyle factors Discontinue or minimize interfering substances Screen for secondary cause of HTN Rationalize/Intensify pharmacologic treatment Refer to clinical HTN specialist Whelton et al, Hypertension 2017, Published online Nov 13, 2017 Calhoun DA, et al. Circulation. 2008;117(25):e510-e26. Calhoun et al, Circulation, 2008

Pseudoresistance Types of pseudoresistance Suspect when Inaccurate BP measurement Repeat BP measurement yourself, including standing BP and BP in both arms Poor adherence Look at pill bottles or call pharmacy White coat HTN Do out-of-office BP measurement with low threshold for 24 hour ABPM Suspect when Marked HTN without TOD BP therapy produces symptoms consistent with hypotension without much decrease in BP ABPM = ambulatory blood pressure monitoring; TOD = target organ damage. Calhoun DA, et al. Circulation. 2008;117(25):e510-e26.

“Resistant Hypertension” Classified by ABPM Spanish ABPM Registry of 8295 Patients De la Sierra A, et al. Hypertension. 2011;57(5):898-902.

Diagnostic and Treatment Algorithm for Resistant HTN – 2017 Guidelines Confirm treatment resistance Exclude pseudoresistance Identify and reverse contributing lifestyle factors Discontinue or minimize interfering substances Screen for secondary cause of HTN Rationalize/Intensify pharmacologic treatment Refer to clinical HTN specialist Whelton et al, Hypertension 2017, Published online Nov 13, 2017 Calhoun DA, et al. Circulation. 2008;117(25):e510-e26. Calhoun et al, Circulation, 2008

Resistant HTN: Reduction in BP When Changing from High to Low Salt Ingestion (Cross-over Study) Pimenta E, et al. Hypertension. 2009;54(3):475-481.

Diagnostic and Treatment Algorithm for Resistant HTN – 2017 Guidelines Confirm treatment resistance Exclude pseudoresistance Identify and reverse contributing lifestyle factors Discontinue or minimize interfering substances Screen for secondary cause of HTN Rationalize/Intensify pharmacologic treatment Refer to clinical HTN specialist Whelton et al, Hypertension 2017, Published online Nov 13, 2017 Calhoun DA, et al. Circulation. 2008;117(25):e510-e26. Calhoun et al, Circulation, 2008

Potential Interfering Substances Nonsteroidal anti-inflammatory drugs/Cox-2 inhibitors Alcohol Oral contraceptives Decongestants Stimulants Corticosteroids Anti-depressants (tricyclic) Cyclosporine Erythropoieten Natural licorice Certain herbal compounds (Ephedra, ma huang, ‘energy’ supplements) Illicit drugs Calhoun DA, et al. Circulation. 2008;117(25):e510-e526.

Diagnostic and Treatment Algorithm for Resistant HTN – 2017 Guidelines Confirm treatment resistance Exclude pseudoresistance Identify and reverse contributing lifestyle factors Discontinue or minimize interfering substances Screen for secondary cause of HTN Rationalize/Intensify pharmacologic treatment Refer to clinical HTN specialist Whelton et al, Hypertension 2017, Published online Nov 13, 2017 Calhoun DA, et al. Circulation. 2008;117(25):e510-e26. Calhoun et al, Circulation, 2008

Secondary (Contributing) Causes of Hypertension in Resistant HTN Common (consider in all patients) Obstructive sleep apnea – sleep study if symptoms Renal parenchymal disease – serum creatinine and urinalysis Primary aldosteronism – aldosterone/renin ratio Renal artery stenosis – non-invasive imaging* Thyroid disease Uncommon (consider in selected patients) Cushing’s disease Pheochromocytoma Aortic coarctation Hyperparathyroidism Intracranial tumor *May not be needed in all patients. Calhoun DA, et al. Circulation. 2008;117(25):e510-e526.

Diagnostic and Treatment Algorithm for Resistant HTN – 2017 Guidelines Confirm treatment resistance Exclude pseudoresistance Identify and reverse contributing lifestyle factors Discontinue or minimize interfering substances Screen for secondary cause of HTN Rationalize/Intensify pharmacologic treatment Refer to clinical HTN specialist Whelton et al, Hypertension 2017, Published online Nov 13, 2017 Calhoun DA, et al. Circulation. 2008;117(25):e510-e26. Calhoun et al, Circulation, 2008

Foundation of Initial Pharmacologic Therapy RAS Blocker Blood Volume Reducer or Vasodilator ACE-I or ARB Thiazide-Type Diuretic + CCB RAS = renin angiotensin system; ACE-I = angiotensin converting enzyme inhibitors; ARB = angiotensin II receptor blockers; CCB = calcium channel blocker.

What Next? Maximize diuretic therapy “Chlorthalidone should be preferentially used in patients with resistant HTN” “In patients with underlying CKD (creatinine clearance <30 mL/min) loop diuretics may be necessary Consider addition of mineralocorticoid receptor antagonist (spironolactone 25-50 mg, eplerenone >50 mg, amiloride 5-10 mg) Watch electrolytes and renal function!! CKD = chronic kidney disease. Calhoun DA, et al. Circulation. 2008;117(25):e510-e26.

BP Response with Spironolactone 25-50mg as 4th Drug: ASCOT Results (N=1411) 85.3 156.9 75.8 135.1 70 90 110 130 150 170 Mean BP (mm Hg) Systolic BP Diastolic BP  SBP = -21.9  DBP = -9.5 Pre Post 6% discontinuation rate due to adverse effects ASCOT = anglosaxon coronary outcomes study. Chapman N, et al. Hypertension. 2007;49(4):839-845.

Pathways-2 Study Spironolactone More Effective Than Comparators in Resistant Hypertension Williams B et al, Lancet 2015

Diagnostic and Treatment Algorithm for Resistant HTN – 2017 Guidelines Confirm treatment resistance Exclude pseudoresistance Identify and reverse contributing lifestyle factors Discontinue or minimize interfering substances Screen for secondary cause of HTN Rationalize/Intensify pharmacologic treatment Refer to clinical HTN specialist Whelton et al, Hypertension 2017, Published online Nov 13, 2017 Calhoun DA, et al. Circulation. 2008;117(25):e510-e26. Calhoun et al, Circulation, 2008

Choice of Additional Add-On Therapy Anti- Neurohormonal Agent Blood Volume Reducer or Vasodilator ARB or ACE-I, DRI, BB Thiazide/Loop, CCB, MRA, Other CCB, Peripheral Alpha Blocker, Direct Vasodilator, Central Acting Alpha1 Agonists Improved BP control Occurs if the BP-reducing effects of agents included in a combination are additive or synergistic Broader spectrum of response Increased response rate over a wider range of patient types Superior tolerability Reduced likelihood of dose-dependent side effects, clinical and metabolic, by combining smaller doses of two drugs vs high doses of a single agent Side effects associated with a particular drug are neutralized by the pharmacologic properties of the second drug High-Renin Drugs Low-Renin Drugs DRI = direct renin inhibitors; BB = beta blocker; CCB = calcium channel blocker; MRA = mineralocortidoid receptor antagonist.

Important Additional Points Consider bed-time dosing of one or more agents May be should “declare victory and go home” (ie: accept higher BP goals) SPRINT was not a trial of resistant hypertension Mean number of meds at study entry = 1.8 Mean number of meds in intensively treated group = 2.8 Limited data regarding risks and benefits of > 4 agents Ongoing device trials for resistant hypertension Arterial-Venous shunting Renal denervation therapy Baroreceptor strategies

Blood Pressure Hemodynamics Renal Volume Retention

Focused Protocols for Renal Denervation: ADD ON Therapy in Resistant Hypertension Patient Selection Randomization (Blinded to patients and observers) Primary BP Efficacy Endpoint Long-term BP Efficacy Endpoint ABPM ABPM ABPM Strictly-defined FIXED DOSE 3-drug regimen at baseline Renal Denervation Systematic addition of drugs needed to achieve BP control Patients with inclusion BP* confirmed by clinic and ABPM measurements Sham Procedure 4-Week Run-in Period 8-Week Initial Treatment Period† 4-Month Continuing Treatment Period * Clinic systolic BP 150-180 mmHg and ABPM systolic BP 140-170 mmHg † Can be extended with carful patient oversight From: Weber/ Kirtane/ Mauri/Townsend/Kandzari/Leon. CCI/ Clin Cardiol/JCH 2015; In press

Take Home Messages Resistant HTN Confirm treatment resistance Office BP >130/80 despite at least 3 meds at reasonable doses, one of which is diuretic Exclude pseudoresistance Including white coat resistance and poor adherence Incidence of white coat resistance likely increased with new BP goal Identify and reverse contributing lifestyle factors Including reduction in sodium consumption Discontinue or minimize interfering substances Screen for secondary cause of HTN Rationalize/Intensify pharmacologic treatment Consider chlorthalidone (or loop diuretic if CKD) Consider addition of a mineralocoticoid receptor antagonist (spironolactone) Consider using DHP and non-DHP CCB together Consider adding peripheral alpha blocker or beta-blocker (4th or 5th) Consider accepting a higher BP goal Consider bed-time dosing of at least 1 agent Watch for results of ongoing device therapy trials