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7/25/2013

47th Annual Meeting ҉ August 2-4, 2013 ҉ Orlando, FL Presenter Disclosure Information

Financial Disclosure: I do not have a vested interest in or affiliation with any Pharmacology of corporate organization offering financial support or grant monies for this continuing education activity, or any affiliation with an organization whose Resistant Hypertension philosophy could potentially bias my presentation.

Other Disclosures: I have participated in the development of the “PRA and David Parra, Pharm.D., FCCP, BCPS HTN” app for the iPhone and Android smartphones. The app guides the user Clinical Pharmacy Specialist, Cardiology in the use of plasma renin activity to guide anti‐hypertensive therapy. I West Palm Beach VAMC received no compensation for its development or for its use which is available for download free of charge. Clinical Associate Professor Department of Experimental and Clinical Pharmacology College of Pharmacy, University of Minnesota The views expressed in this presentation reflect those of the author, and not necessarily those of the Department of Veterans Affairs.

Objectives Consequences of Uncontrolled Hypertension

•Describe the general approach to the drug management of resistant hypertension •Recognize commonly prescribed medications that may impede blood pressure control •Compare and contrast the pharmacokinetics/ancillary properties of antihypertensive agents to select the most appropriate agent when presented with a patient case • Apply the concept of plasma renin activity to help guide treatment decisions with antihypertensive agents

Messerli F. N Engl J Med 1995;332:1038-1039

Prevalence, Treatment, and Headlines of the St. Louis Post-Dispatch, April 13, 1945 Control of Hypertension 1999–2002 & 2005–2008 Percent of U.S. Adults Percent ofU.S.

Centers for Disease Control and Prevention. Vital signs: Prevalence, treatment, and control of hypertension—United States, 1999-2002 and 2005-2008. MMWR Morb Reprinted with permission Mortal Wkly Rep 2011; 60:1-6.

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Resistant Hypertension Prevalence of Resistant Hypertension

• Failure to achieve goal blood pressure in adherent •Observational estimates patients despite 3 antihypertensive agents from •NHANES 2005‐2008 – 20.7% different classes •Tertiary Hypertension Centers –11‐38% • Ideally one agent should be a diuretic •ASH (Carolinas, Florida, Georgia Chapter) 2007 – 16.2% •All should be at optimal doses • Clinical trial estimates • Includes patients whose blood pressure is • ALLHAT, ASCOT, ACCOMPLISH, LIFE, CONVINCE, and INVEST suggest up to 35% controlled but require 4 or more medications • Difficult to establish

Calhoun DA et al. Resistant hypertension: Diagnosis, evaluation, and treatment. A scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research. Hypertension. BMJ 2012;345:e7473. 2008;51:1403-19. Curr Opin Cardiol. 2012;27:386-91.

Early (1930) Antihypertensive Therapies

Animasa Mistletoe Benzyl benzoate “Natheim” bath Benzyl succinate Nitroscleran Calcium diuretin Potassium sulphocyanate Calcium Salts and low protein diet Radiation of the skull Corpus luteum Radium water Desecin Subtonin Diathermy Sodium sulphocyanate Irradiation of suprarenal region Theominal Liver extract Thyroid and potassium Lumbar sympathectomy permanganate Luminal Watermelon extract

Hypertension. 2011;57:1045-46. Curr Opin Cardiol. 2012;27:386-91 Ayman. JAMA 1930:95:246

Current Oral Antihypertensive Agents

•bumetanide • • lisinopril • isradipine •ethacrynic acid • • perindopril • nicardipine •furosemide • • azilsartan • nifedipine •torsemide The question remains: • hydrochlorothiazide • • candesartan • nimodipine • chlorothiazide • bucindolol • eprosartan • nitrendipine • indapamide • • irbesartan • diltiazem What approaches can be used to • chlorthalidone • • losartan • verapamil • metolazone •captopril • olmesartan • improve control, particularly in • amiloride •triamterene • enalapril • telmisartan • • eplerenone • fosinopril • valsartan • patients with resistant • spironolactone •moexipril • • • • quinapril • • minoxidil hypertension? • •ramipril • • hydralazine • • trandolapril • aliskiren • • • benazepril • amlodipine • • • felodipine

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Patient Characteristics Associated with Resistant Hypertension Lifestyle Factors Contributing to Resistant Hypertension •High baseline blood pressure •Older age • Obesity or overweight •Obesity • Excessive dietary salt ingestion •High salt diet •Chronic kidney disease •Physical inactivity •Diabetes •Left ventricular hypertrophy • Ingestion of low‐fiber, high‐fat diet •African American race •Female gender •Heavy alcohol ingestion • Residence in Southeastern United States

Hypertension. 2008;51:1403-1419 Hypertension. 2008;51:1403-1419

General Approach to Resistant Primary Cause of Resistant Hypertension Hypertension Cause of resistance found in 133/141 – 94% (83/91 – 91%) cases

Office Unknown • Confirm treatment resistance resistance 6% 6% Nonadherence Psychological 16% • Exclude pseudoresistance (24hr measurements) causes 9% • Address contributing lifestyle factors Secondary HTN • Discontinue or minimize interfering substances 5% • Screen for secondary causes of hypertension Interfering substances • Document target organ damage 1% Drug-related causes • Confirm appropriate treatment 58%

Hypertension. 2008;51:1403-1419 Garg JP, et al. Am J Hypertens 2005;18:619-26

Substances Impeding Blood Pressure Control: Mechanisms of Interference

•Sodium and water retention • Activation of the sympathetic nervous system • Activation of the renin–angiotensin system

Volpe M, Tocci G. Challenging Hypertension: How to Diagnose and Treat Resistant Garg JP, et al. Am J Hypertens 2005;18:619-626 Hypertension in Daily Clinical Practice Expert Rev Cardiovasc Ther. 2010;8(6):811-820.

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Commonly Recognized Substances Less‐Commonly Recognized Substances Impeding Impeding Blood Pressure Control Blood Pressure Control

• Non-steroidal anti-inflammatory agents •Neurologic and psychiatric agents • Sympathomimetic agents • Tricyclic , SNRIs (e.g. venlafaxine), • decongestants, diet pills, cocaine •Modafanil • methylphenidate, amphetamine salts •Herbal compounds • Alcohol •Ma huang (ephedra), bitter orange, blue cohosh, • Corticosteroids ginseng, guarana • Cyclosporine, tacrolimus •Vascular endothelial growth factor inhibitors • Erythropoietin stimulating agents • Bevacizumab • Estrogens (including oral contraceptives) •Sorafenib • Migraine medications • Sunitinib • Natural licorice

VEGF Inhibitors and Hypertension: Potential Mechanisms Treatment of Resistant Hypertension: 2008 AHA Statement

•Non‐Pharmacologic Recommendations • Pharmacologic Recommendations • Withdrawal or down titration of interfering substances •Use of a long‐acting thiazide diuretic (i.e. chlorthalidone) • Combine agents with different mechanisms of action •Triple regimen of ACE inhibitor or ARB, calcium channel blocker, and thiazide diuretic

Granger, J. P. Hypertension 2009;54:465-467 Hypertension. 2008;51:1403-1419

Diuretics and Their Treatment of Resistant Hypertension: 2008 Primary Sites of Action AHA Statement

• Addition of mineralocorticoid •Use of loop diuretic in patients with CKD (creatinine clearance <30 ml/min) •If blood pressure controlled consider adjustment of the treatment regimen to maintain control but with use of fewer medications and/or with use of a regimen that minimizes adverse effects • Need for additional knowledge (research) to identify and effectively treat these patients

Hypertension. 2008;51:1403-1419

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Thiazide Diuretics Common Thiazide Diuretics Effective when CrCl > 30ml/min (exception metolazone) • Excellent in combination with other agents t ½ Relative Elimination Anti-hypertensive dosing Absorption (hr) potency R=Renal H=Hepatic (typical) •Have been considered generally B=Biliary U=unknown

interchangeable 65% R Chlorthalidone ~65% ~47 1 12.5-25mg po once daily •Same pharmacologic effects 10% B, 25% U • Appropriate dose adjustment required HCTZ ~70% ~2.5 1 R 12.5-50mg po once daily

Indapamide • Equivalent clinical efficacy? ~93% ~14 20 >95% H 1.25-5 mg po once daily •Different pharmacokinetics and subsequent 80% R, 2.5-5mg po once daily Metolazone ~65% 4-5 10 pharmacodynamics 10%H, 10%B For Mykrox®: 0.5-1mg po QD

* Dose dependent, HCTZ= Hydrochlorothiazide Hardman JG, Limbird LE, Gilman AG. (Eds.). (2001) Goodman & Gilman's the pharmacological basis of therapeutics. (10th ed.). New York: McGraw-Hill. Lacy CF, Armstrong LL, Goldman MP, Lane LL (Eds.). (2005) Lexi-Comp’s Drug Information Handbook (13th ed.). Hudson Ohio: Lexi-Comp

Antihypertensive Effects of Hydrochlorothiazide Are All Thiazides Equal? versus Chlorthalidone on Blood Pressure

Chlorthalidone versus hydrochlorothiazide •Half‐life, duration of action •Less braking phenomenon? • ALLHAT, MRFIT versus ANBP2 •24‐hour ambulatory blood pressure comparison (Ernst et al. Hypertension. 2006;47:352‐358.)

Khosla N, Chua DY, Elliott, WJ, Bakris G. The Journal of Clinical Hypertension 2005;7(6): 354-346.

Antihypertensive Effects of Hydrochlorothiazide Antihypertensive Efficacy of versus Chlorthalidone on Blood Pressure HCTZ as Evaluated by ABPM

Mean change from week 0 to week 8 in average hourly ambulatory systolic BP.

p<0.001 for HCTZ 12.5-25mg vs. other antihypertensives

Ernst EE, Carter BL, et al. Comparative Antihypertensive Effects of Hydrochlorothiazide and Chlorthalidone on Ambulatory and Office Blood Pressure Hypertension. Messerli F, Makani H, Benjo A, et al. Antihypertensive efficacy of HCTZ as evaluated 2006;47:352-358. by ABPM. A meta-analysis of randomized trials. J Am Coll Cardiol 2011; 57:590-600.

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Dose Response Curve of Thiazide Diuretics HCTZ as Evaluated by ABPM •Hypokalemia •Dose related •May affect clinical outcome

p=0.0001 • SHEP subanalysis for systolic blood •Participants who had hypokalemia after 1 year pressure of treatment with a low‐dose diuretic did not with HCTZ experience the reduction in cardiovascular 50mg events achieved among those who did not have hypokalemia

J Am Coll Cardiol 2011; 57:590-600. Hypertension 2000;35:1025-1030

Thiazide Diuretics Inhibitors of Renal Epithelial Na+ Channels (K+ sparing diuretics) •Glucose intolerance (ALLHAT) •Triamterene and amiloride •Fasting glucose 3 to 5mg/dl higher with chlorthalidone • Employed for antikaluretic actions versus amlodipine and lisinopril • Generally poor antihypertensives when •New‐onset diabetes 11.6% versus 9.8% and 8.1% used alone (particularly triamterene) respectively •Secreted into proximal tubule blocking Na+ •No higher CV event rate in chlorthalidone group channels in late distal tubule and collecting •Similar findings in 14‐year SHEP follow‐up (Am J Cardiol 2005;95:29‐35) which differ from Verdechhia findings duct (Hypertension 2004;43:963‐969.)

Inhibitors of Na+/K+/2Cl‐ Symport (Loop Diuretics) Loop Diuretics

•Primary site of action: thick ascending limb • Antihypertensive mechanism: uncertain •Site of greatest Na+ capacity (25% of filtered Na+ load) •Do not have the demonstrated CV effects as the • Nephron segments past this site do not possess reabsorptive thiazide diuretics (studies not conducted) capacity to reabsorb this rejectate •Particularly useful in low GFR states where + ‐ • Mechanism of action: inhibitors of Na ‐K‐2Cl symporter thiazide diuretics may not be effective • Effective despite low GFRs • Generally need to be dosed twice daily (exception •Highly protein bound and not filtered into tubules torsemide) when used for hypertension • Efficiently secreted by organic acid transport system into proximal tubule gaining access to site of action

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Aldosterone Receptor Antagonists Aldosterone Receptor Antagonists

+ Absorption t ½ Relative Elimination Antihypertensive dosing •Aldosterone cause Na and water retention (hr) potency R=Renal (typical) and increase K+ and H+ excretion H=Hepatic Spironolactone ~65% ~1.6 H 25-100 mg/day in 1-2 •Aldosterone antagonists competitively divided doses Canrenone* ~16.5 H inhibit binding of aldosterone to these Eplerenone Unknown ~4-6 H 25-100mg/day in up to 2 receptors divided doses if > 50mg/day • Clinical efficacy is in part a function of * Active metabolite of spironolactone endogenous levels of aldosterone

Hardman JG, Limbird LE, Gilman AG. (Eds.). (2001) Goodman & Gilman's the pharmacological basis of therapeutics. (10th ed.). New York: McGraw-Hill. Lacy CF, Armstrong LL, Goldman MP, Lane LL (Eds.). (2005) Lexi-Comp’s Drug Information Handbook (13th ed.). Hudson Ohio: Lexi-Comp.

Spironolactone in True Aldosterone Receptor Antagonists Resistant Hypertension • Renewed interest in resistant hypertension Office 24hr • “Spironolactone: an old friend rediscovered” (Sica BP ABPM DA, Journ Clin HTN 2006;8:467‐69.) Baseline BP 169/92 149/86 N = 175

• Slow onset, but long duration of action Reduction 14/7 16/9 • 25‐50mg daily shown effective in resistant hypertension Associated with better response • Effective even when plasma aldosterone levels normal Higher waist circumference, lower aortic pulse pressure, • Strong additive effects with other agents and lower serum potassium Aldosterone:renin ratio not associated with BP response

Nishizaka MK, Amin Zaman M, Calhoun DA. Am J Hypertension 2003;16:925-930. Hypertension. 2010;55:147-152

Aldosterone Receptor Antagonists Aldosterone Receptor Antagonists Listed contraindications (eplerenone) Adverse Reactions • Serum potassium >5.5 mEq/l at initiation • Serious hyperkalemia (> 6.0mmol/L): 5% • Creatinine clearance <30 ml/min in any patient or < 50 • Renal insufficiency ml/min if being used for HTN • Gynecomastia/breast pain (10% spironolactone) • Concomitant use with the following potent CYP3A4 • Impotence, decreased libido, hirsutism, menstrual inhibitors: ketoconazole, itraconazole, , irregularities, breast cancer? (spironolactone) troleandomycin, clarithromycin, ritonavir, and nelfinavir • GI side effects (gastritis, ulcerations) • Type 2 diabetes with microalbuminuria • Rash • Serum creatinine >2.0 mg/dl (males) or >1.8 mg/dl (females)

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Other Pharmacologic Considerations Chronotherapy in Resistant Hypertension When Treating Resistant Hypertension N = 250 • Within class half‐lifes • Losartan versus others • Bisoprolol versus others • Ancillary properties of agents within a class • Beta‐blockers • Chronotherapy • Bedtime administration • Calcium channel blockers • Rebound effect of clonidine • Consider patches Hermida RC, Ayala DE, Fernandez JR, Calvo C. Chronotherapy improves blood pressure control and reverts the nondipper pattern in patients with resistant hypertension. Hypertension 2008; 51:69-76.

Prevalence, Treatment, and Less commonly used Agents Control of Hypertension 1999–2002 & 2005–2008 • Minoxidil • Need for concurrent diuretic and beta‐blocker • Reserpine • Well tolerated in low doses • Was often an add‐on therapy in older trials including ALLHAT • Hydralazine • Cochrane review concluded insufficient evidence to support any effects long‐term on systolic or diastolic blood pressure versus placebo Adults Percent ofU.S.

Centers for Disease Control and Prevention. Vital signs: Prevalence, treatment, and control of hypertension—United States, 1999-2002 and 2005-2008. MMWR Cochrane Database Syst Rev. 2010. Aug4;(8)CD004934 Morb Mortal Wkly Rep 2011; 60:1-6.

Are there other approaches that may be useful to guide antihypertensive therapy in uncontrolled hypertension?

• Noninvasive hemodynamic testing • Targeting of selected genetic polymorphisms • Age/race profiling • Plasma renin activity guided therapy

Hypertension. 2011;57:1045-46. Curr Opin Cardiol. 2012;27:386-91

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The Laragh Hypothesis I The Laragh Hypothesis I (continued)

Normal blood pressure is sustained by the close Conversely, if the body sodium‐volume interaction of two factors: falls, the kidneys reactively increase the (1) The body sodium‐volume content (V) plasma renin secretion. This results in (2) The plasma renin‐angiotensin system (R) increased arteriolar Under normal circumstances this interaction works well. The blood pressure will not rise when body sodium‐ which reduces the capacity of the volume increases, since it leads to a prompt suppression arterial tree and keeps the blood of renin release by the kidneys. This results in a pressure unchanged. vasodilation which accommodates for the volume increase and keeps the blood pressure unchanged.

Laragh JH, Am J Med 1973;55:261-274 Laragh JH, Am J Med 1973;55:261-274

The Laragh Hypothesis II The Laragh Hypothesis II (continued) 2. R hypertension According to this model, hypertension develops in three Renin dependent or R hypertension, occurs when the plasma situations: renin activity becomes too high for the existing body sodium‐ volume content (PRA ≥ 0.65 ng/ml/hr) 1. V hypertension 3. V + R hypertension Low renin or V hypertension occurs when the body The combination of sodium‐volume and renin dependent sodium‐volume content increases but cannot be offset hypertension occurs when the body sodium‐volume content by a concomitant fall in ambulatory plasma renin increases but ambulatory PRA cannot fall sufficiently (PRA ≥ activity (PRA), because PRA is maximally suppressed 0.65 ng/ml/hr) (PRA < 0.65 ng/ml/hr)

Laragh JH & Sealey JE, Am J Hypertens. 2011;24:1164-80 Laragh JH & Sealey JE, Am J Hypertens. 2011;24:1164-80

Categories of Antihypertensive Drugs Using Plasma Renin Activity (PRA) to Guide Treatment Decisions

THE ANTI‐V DRUGS THE ANTI‐R DRUGS • PRA < 0.65 ng/ml/hr (Natriuretic drugs) (Anti‐renin‐angiotensin system drugs) • Add or increase anti‐V drug, consider stopping anti‐R Reduce Body Sodium‐Volume Content Block or Suppress Plasma Renin‐Angiotensin drug Vasoconstrictor Activity • PRA > 0.65 ng/ml/hr ‐ < 6.5 ng/ml/hr • Aldosterone receptor blockers R1: Drugs that block the renin‐angiotensin system If on anti‐R drug, add anti‐V drug (if anti‐R drug Sulfonamide diuretics Converting enzyme inhibitors (ACEIs) maximized) Calcium channel blockers (CCBs) Angiotensin receptor blockers (ARBs) • If on anti‐V drug, add anti‐R drug Alpha blockers Direct renin inhibitors (DRIs) • PRA > 6.5 ng/ml/hr • Add or increase anti‐R drug, consider stopping anti‐V R2: Drugs that suppress renal renin secretion Beta adrenergic blockers drug Centrally acting alpha agonists Reserpine, methyl DOPA

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Prediction of Treatment Response to Beta‐ Prediction of Treatment Response to blocker and Thiazide Diuretic Beta‐blocker and Thiazide Diuretic

• Randomized clinical trial of 363 patients with untreated hypertension 1. Initial randomization (monotherapy) • 50‐100 mg atenolol (A), OR • 12.5‐25 mg hydrochlorothiazide (H) 2. Second phase (add‐on therapy) • H added to A patients, OR • A added to H patients

Turner et al, Am J Hypertens 2010; 23:1014-22

SBP Response to Atenolol and PRA Guided Treatment of Hydrochlorothiazide by Renin Percentile Uncontrolled Hypertension

• 73 outpatients with uncontrolled hypertension (SBP > 140, DBP > 90 on one or more drugs)

A+H H+A Baseline 1 Year SBP (mmHg) 163 ± 3 140 ±2 H A DBP (mmHg) 95 ±1 84 ±1 # Drugs 2.1 1.5

Turner et al, Am J Hypertens 2010; 23:1014-22 Blumenfeld JD, Laragh JH. Am J Hypertens 1998; 11:894-6

PRA Guided Treatment of PRA Guided Treatment of Resistant Hypertension Resistant Hypertension • Randomized evaluation of renin‐test guided or clinical hypertension specialist care (n=84 on average of 3 Baseline BP Last BP Change medications) (#meds) (#meds) • Renin‐test guided therapy involved: Renin Guided 157/87 127*/72* ‐29**/‐14 PRA (ng/mL/hr) Intervention (3.1) (3.1) < 0.65 Subtracting anti‐R drugs, and adding anti‐V drugs if necessary HTN Specialist 153/91 134*/79* ‐19/‐11 0.65‐6.5 Adding either an anti‐R or anti‐V (2.7) (3.0)

drug, whichever was missing * p<0.01 first vs. last; ** p<0.05 between groups > 6.5 Subtracting anti‐V drugs, and Greater rates of BP control (74% vs. 59%) adding anti‐R drugs if necessary

Egan BM et al, Am J Hypertens 2009; 22:792-801 Egan BM et al, Am J Hypertens 2009; 22:792-801

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Opportunity to Streamline Therapy Control Rates by Strategy

• Retrospective analysis of 1,096 patients from the Genetic Epidemiology of Responses to Antihypertensives (GERA) study – Thiazide diuretic for all – Age/race criteria – Plasma renin activity

Egan BM et al, Am J Hypertens 2009; 22:792-801 Am J Hypertens 2013 doi:10.1093/ajh/hpt047

Control Rates by Strategy Plasma Renin Determination Current Status

Blood pressure control rate No specific preparation needed Treatment Overall Black subjects White subjects • Regular dietary habits maintained strategy • Antihypertensive treatment not altered Thiazide 53.8 55.2 52.4 diuretic • Standard blood draw (EDTA Vacutainer) Age/race 61.3 55.2 67.1 • Centrifuged on the desk top Plasma renin 69.4* 62.1** 76.3* • Frozen samples sent to laboratory activity • Cost of $30 reimbursable (MediCare Clinical Laboratory Fee Schedule) *p< 0.001 vs. other strategies ** p< 0.02 vs. other strategies

Am J Hypertens 2013 doi:10.1093/ajh/hpt047

How to account for current ACEi or ARB Therapy Effective PRA (ePRA) Summary ACEi ARBs Renin (PRA)  Ang I  Ang II  BP Effects (ePRA) • All thiazide diuretics are not equal • All loop diuretics are not equal • Expanded role for mineralocorticoid receptor antagonists • Ancillary and within class differences of anti‐ hypertensive agents should be considered • Methods such as PRA guided therapy can enhance blood pressure control ePRA = PRA x 0.1 • Need for further research

Clin Pharmacol Ther 200:78:501-7. Hypertension. 2010;55:e16.

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