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PREVENTION, DETECTION, EVALUATION, AND MANAGEMENT OF HIGH BLOOD PRESSURE IN ADULTS

Thomas F. Whayne, Jr, MD, PhD, FACC, FAHA, FACP Professor of Medicine (Cardiology) University of Kentucky Gill Heart Institute NOVEMBER 2018 No conflicts to disclose Email: [email protected] (0 number zero) (0 is the number zero) Educational Need/Practice Gap Regarding hypertension, the major practice gap is failure to adequately control BP. Tight BP control as in JNC-7 is less with unofficial JNC-8 (2013) but nevertheless, the need for adequate treatment must still be emphasized. Now, the 2015 NIH study appears more like JNC-7, followed by additional guidelines, all adding to the confusion. Good judgment in clinical practice is still the order of the day. Objectives • Review the latest guidelines and evidence- based medicine for the treatment of hypertension. • Discuss specific mechanisms involved in the causation of hypertension and how this affects treatment. • Summarize specific invasive techniques for the difficult patient whose hypertension does not respond to medications. Expected Outcome

Approximately 75% of hypertensive patients are not adequately managed. This is in part the fault of many patients but also there is failure of clinicians to push for maximal beneficial results. Hopefully, a consideration of available information and medications will emphasize the possibilities for improved BP control. Hypertension pts. (50 million: 24% of US population): Treatment and Control

% of Hypertensives % on Rx Achieving taking Medications BP Control

24% Controlled on Rx Not 53% Not on Rx on Rx on Rx 29% Not Controlled on Rx

NHANES III, The Centers for Disease Control and Prevention, and the National Center for Health Statistics, Burt et. al., 1995 GOALS: HYPERTENSION Rx • HYPERTENSION AWARENESS. • 24 HR. BLOOD PRESS. CONTROL. – UNFORTUNATELY, 24 HR. AMBULATORY MONITORING IS DIFFICULT AND GENERALLY UNAVAILABLE. • MEDICATION TOLERANCE. • ABSENCE OF SIDE EFFECTS. • ABSENCE OF DETRIMENTAL METABOLIC EFFECTS. • AVOID TARGET ORGAN DAMAGE. MECHANISMS OF HYPERTENSION

• INCREASED CARDIAC OUTPUT. • INCREASED INTRAVASCULAR VOL. • INCREASED PERIPH. RESISTANCE. SO-CALLED“CURABLE” HYPERTENSION

• COARCTATION OF THE AORTA • CUSHING’S DISEASE • HYPERALDOSTERONISM • PHEOCHROMOCYTOMA • RENOVASCULAR RENOVASCULAR HYPERTENSION

• FIBROSIS IS MORE LIKELY ETIOLOGY AT YOUNGER AGE. • ATHEROSCLEROSIS IS MORE LIKELY ETIOLOGY AT AN OLDER AGE.

Renal Artery Duplex Study is Essential JNC 7 Classification of Hypertension (from 2006)*

*CME Connection Cardiology Edition 2006;2(6):7.

Chobanian AV, et al. NIH Publication 04-5230, 2004. “JNC” 8 (2013)* • JNC 8 is Eighth Joint National Commission. • The panel lost its NIH sponsorship and went ahead anyway with an unofficial guideline even though the NIH decided to turn guidelines over to the ACC/AHA. • Panel recommended liberalized BP goals of: – Age 60 and over. • BP less than 150/90. – Age 30 to 60 and under age 30. • BP less than 140/90. **James PA, et al. JAMA. doi:10.1001/jama.2013.274427 2015 Systolic Blood Pressure Intervention Trial (SPRINT): Adults ≥ 50 y with Hx CV Disease or at High CV Disease Risk*

2015 results: systolic BP <120 mmHg (intensive Rx [déjà vu JNC 7]) compared to systolic BP <140 mmHg (standard Rx). – Primary composite outcome (myocardial infarction, acute coronary syndrome, stroke, CHF, CV death) decreased 25% with intensive Rx. – All cause mortality significantly lower in intensive Rx group: HR 0.73%; 95% CI 0.60 to 0.90; P=0.003. – Hypotension, syncope, electrolyte abnormalities, and renal injury all higher in intensive Rx group (but not injurious falls). – Application of results dependent on clinical judgment, tolerance of Rx, avoidance of associated problems, probable limitation to 4 BP medications. – Fewer patients to meet SPRINT goals vs. 2014 but will have ↓ CV events.+ – Same benefit of intensive BP Rx for ↓ CV events in adults ≥75 years.#

*SPRINT Res. Group. N Engl J Med 2015;373: 2103-2016. +Ko MJ et al. J Am Coll Cardiol 2016;67:2821-2831. #Williamson JD et al. JAMA 2016;315:2673-2682. 2017 GLOBAL BURDEN OF HYPERTENSION & SYSTOLIC BP AT LEAST 110-115 mmHg.* • Data from multiple international surveys showed that rate of elevated systolic BP (defined as ≥110-115 mmHg systolic or defined as ≥140 mmHg systolic) increased significantly between 1990 and 2015. • Disability -Adjusted Life-Years (DALYs) and deaths associated with both definitions of elevated systolic BP, also increased.

*Forouzanfar MH, et al. JAMA 2017;317:165-182. 2017 BP CLINICAL PRACTICE GUIDELINE FROM AMERICAN COLLLEGE OF PHYSICIANS (ACP) AND AMERICAN ACADEMY OF FAMILY PRACTICE (AAFP)* • Recommendation 1: Adults ≥60 years with systolic BP ≥150 mmHg should be treated to achieve lesser level to reduce risk of mortality, stroke, and cardiac events. • Recommendation 2: Adults ≥60 years with Hx of stroke or TIA should be treated to systolic BP <140 mmHg to decrease risk of recurrent stroke. • Recommendation 3: For some adults ≥60 years at high CV risk, after individual assessment, consider target systolic BP <140 mmHg to decrease risk of stroke or cardiac events.

*Qaseem A, et al. Ann Intern Med 2017;166: 430-437. ACC/AHA HYPERTENSION GUIDELINE (2017)*# • NORMAL BP IS <120/80; HYPERTENSION STAGE 1: 130-139/80-89; STAGE 2: ≥140/90. • BENEFIT OF TREATMENT RELATED TO CV RISK. • TREATMENT RECOMMENDED FOR BP ≥130/80 WITH TARGET <130/80 FOR CVD OR ↑ CV RISK. • TREATMENT RECOMMENDED FOR BP ≥140/90 WITH TARGET <130/80 FOR 10-YR CV RISK <10%. • INITIAL TREATMENT FOR STAGE 1 HYPERTENSION: THIAZIDE (CHLORTHALIDONE), CCB, ACE, OR ARB. *Whelton PK, et al. J Am Coll Cardiol 2018;71:e127-e248. #Rubenfire M. CardioSource Plus. May 7, 2018. ESC/ESH HYPERTENSION GUIDELINES (2018) Classification of office blood pressure*

Systolic Category Diastolic (mmHg) (mmHg) Optimal <120 and <80 Normal 120–129 and/or 80–84 High normal 130–139 and/or 85–89 Grade 1 140–159 and/or 90–99 hypertension Grade 2 160–179 and/or 100–109 hypertension Grade 3 ≥180 and/or ≥110 hypertension Isolated systolic ≥140 and <90 hypertensionb

*Williams B, et al. Eur Heart J 2018;39:3021-3104. CV Mortality Risk Doubles with Each 20/10 mm Hg Increment in Blood Pressure*

8

6

4

2 CVMortalityRisk

0 115/75 135/85 155/95 175/105 SBP/DBP (mm Hg)

***Lewington S, et al. Lancet. 2002;360:1903-1913..

CME Connection Cardiology Edition 2006;2(6):2. Classification of HF: Comparison Between ACC/AHA HF Stage and NYHA Functional Class

ACC/AHA HF Stage1 NYHA Functional Class2

A At high risk for but without None structural heart disease or symptoms of heart failure (eg, patients with hypertension or coronary artery disease)

B Structural heart disease but without I Asymptomatic symptoms of heart failure

II Symptomatic with moderate exertion C Structural heart disease with prior or current symptoms of heart failure III Symptomatic with minimal exertion

D Refractory heart failure requiring IV Symptomatic at rest specialized interventions

1Hunt SA et al. J Am Coll Cardiol. 2001;38:2101–2113. 2New York Heart Association/Little Brown and Company, 1964. Adapted from: Farrell MH et al. JAMA. 2002;287:890–897. DIETARY APPROACH TO STOP HYPERTENSION (DASH): DASH Diet*, which is rich in vegetables, fruits and low-fat dairy products, is effective in lowering BP with high, intermediate and low sodium intake. DEVICE MANAGEMENT OF HYPERTENSION BY SLOWING AND REGULARIZING BREATHING: BIM (Breathe with Interactive Music)+. RESPeRATE®, InterCure Ltd., Lod, Israel#. Such devices can decrease hypertension. STORYTELLING TO Rx BLOOD PRESSURE: INTERVENTION: SIGNIF. IMPROVEMENT†.

*Sacks FM, et al. N Engl J Med 2001;344:3-10. +Schein MH, et al. J Human Hypertens 2001;15:271-278. #Viskoper R, et al. Am J Hypertens 2003;16:484-487. †Houston TK, et al. Ann Intern Med 2011;154:77-84. AVAILABLE Rx FOR HYPERTENSION • ALISKERIN. • ALPHAMETHYLDOPA*. • AMLODIPINE; DILTIAZEM, NIFEDIPINE, VERAPAMIL. • . • . • . • EPLERENONE; SPIRONOLACTONE. • HYDRALAZINE. • HYDROCHLOROTHIAZIDE. • *. • LISINOPRIL; CAPTOPRIL; ENALAPRIL, RAMIPRIL, ETC. • LOSARTAN; CANDESARTAN, VALSARTAN (NOTE GENERIC RECALL), ETC. • SUCCINATE; METOPROLOL TARTRATE*; . • MINOXIDIL. • . *SAFE FOR FETUS. DIURETICS

• THIAZIDES (HCTZ; CHLORTHALIDONE). • LOOP (eg Furosemide). • POTASSIUM SPARING. –AMILORIDE. –TRIAMTERENE. –SPIRONOLACTONE. BETA BLOCKERS • WITHOUT ISA: – (TENORMIN) – (KERLONE) – BISOPROLOL (ZEBETA) – CARVEDILOL (COREG) – METOPROLOL TARTRATE (LOPRESSOR) – METOPROLOL SUCCINATE (TOPROL XL) – (CORGARD) – NEBIVOLOL (BYSTOLIC) – (INDERAL) – (BLOCADREN) • WITH ISA: – (SECTRAL) – (CARTROL) – (LEVATOL) – (VISKEN) TOPROL-XL (Metoprolol Succinate)

AN EXCELLENT FOR TREATING HYPERTENSION AND CONGESTIVE HEART FAILURE CARVEDILOL DOSING

• GENERAL HYPERTENSION DOSE: 25 mg qAM after 2 days at 12.5 mg qAM. • MAXIMUM DOSE, HYPERTENSION, OR CHF: 25 mg bid if < 85 kg. 50 mg bid if > 85 kg. Bystolic™ - Nebivolol

Pharmacology: Bystolic is a Beta- blocking agent with high β-1 selectivity, no ISA or alpha-adrenergic blocking effects, and it has nitric oxide mediated vasodilatory effects. Bystolic™ - Nebivolol Summary

• Bystolic, nebivolol, is a highly cardioselective beta blocker with nitric oxide mediated vasodilating activity. This unique hemodynamic profile may provides benefit to a broader patient population. Unfortunately, limited head to head outcomes trials have not been published. • Convenient once daily (2.5 to 5 mg per day) dosing and few drug interactions. • Common adverse effects seen with beta blockers (fatigue, ED, bradycardia, depression) appear to be less common with nebivolol. ACE INHIBITORS AND ARBs ACE INHIBITORS: LISINOPRIL; CAPTOPRIL; ENALAPRIL; RAMIPRIL; PERINDOPRIL; BENAZEPRIL; FOSINOPRIL; MOEXIPRIL; AND QUINAPRIL. • ARBs: LOSARTAN; CANDESARTAN; VALSARTAN (NOTE GENERIC RECALL OF VALSARTAN FOR CARCINOGEN RISK); IRBESARTAN; AZILSARTAN; EPROSARTAN; TELMISARTAN; OLMESARTAN. Calcium Blockers: Role In Hypertension

• Relaxation of Vascular Smooth Muscle Results in Decreased Peripheral Vascular Resistance • All Calcium Channel blockers cause cardiac muscle depression Central Alpha-2 Agonists

• Clonidine (Catapres). – Still used frequently. • (Wytensin). • Guamfacine (Tenex). • Alphamethyldopa (Aldomet). – Of interest is the safety of alphamethyldopa for the fetus. DIRECT VASODILATOR

HYDRALAZINE (APRESOLINE®) Dose from 10 mg to 100 mg, 2-4 times/d. Especially excellent in renal insufficiency. ALPHA-1 BLOCKERS

• DOXAZOSIN (CARDURA). • (MINIPRESS). • (HYTRIN). PERIPHERAL ANTIADRENERGICS

Guanadrel (Hylorel) (Ismelin) (Serpasil)

POTASSIUM CHANNEL OPENER

Minoxidil COMBINED ALPHA-BETA BLOCKERS

• BUCINDOLOL (Thailand only) • CARVEDILOL • LABETALOL SELECTIVE ALDOSTERONE BLOCKER

EPLERENONE (INSPRA®): Of value in hypertension and CHF 25-50 mg once daily 50 mg bid max. in BP⇑ Must watch for hyperkalemia In EPHESUS*, there was ⇑ survival post acute MI with EF < 40 % and clinical evidence for CHF

*Pitt B. N Engl J Med. 2003;348:1309-1321. RENIN INHIBITOR (NEW CLASS)

GENERIC NAME: ALISKERIN. TRADE NAME: TEKTURNA® (NOVARTIS). Dose: 150 to 300 mg once a day.

Byung-Hee O, et al. J Am Coll Cardiol 2007;49:1157-1163. Isolated Systolic Hypertension

• Systolic BP > 140 mm Hg • Diastolic BP < 90 mm Hg • SHEP* (Thiaz. ± β Blocker) 36% Stroke ⇓ Other CV events ⇓ • Syst-EUR+ (Nitrendipine ± Enalapril/HCTZ) Stroke ⇓ 42% Other CV events ⇓

*Perry HM Jr, et al. JAMA. 2000;284:465-471. +Staessen JA, et al. J Hypertens. 2004;22:847-857. ACE Inhibitors In Diabetic Patients

• May decrease Proteinuria.

• May decrease deterioration of renal function. Racial Differences

African Americans: • African American study of Kidney Disease (AASK*) (AHA 2001) Showed Advantage for ACE Inhibitor (Ramipril) in Conserving Renal Function (composite of GFR, ESRD & death) • Better BP Response to Diuretics

*Wright JT Jr, et al. JAMA. 2002;288:2421-2431. DIABETES RISK AND BP Rx* • Probably ⇑ by HCTZ and β-blockers.

• Probably neutral with Ca channel blockers.

• Probably ⇓ by ACEI or ARB.

. *Williams B. J Am Coll Cardiol. 2005;45:813-827 Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack (ALLHAT) Trial Total of 33,357 Participants Randomized to Receive Chlorthalidone 12.5-25 mg, Amlodipine 2.5-10 mg or Lisinopril 10-40 mg

**ALLHAT Officers and Coordinators. JAMA. 2002;288:2981-2997.. ALLHAT Study Conclusions • Thiazide-Type Diuretics are Superior in Preventing One or More Major Forms or CV Disease and are Less Expensive for the Treatment or Hypertension than Rx such as Amlodipine or Lisinopril. • Thiazides Should be Preferred for First-Step Antihypertensive Therapy. • Compared to chlorthalidone, lisinopril significantly reduced cardiac conduction abnormalities, not seen with amlodipine or pravastatin (2016).*

*Dewland TA, et al. JAMA Intern Med. 2016;176:1085-1092. EVALUATION OF ALLHAT • Diuretics are Probably not Sufficiently Utilized • Must Consider the Individual Patient, eg.: – ACE or ARB for Diabetic – ACE and β-Blocker for Associated CHF – β-Blocker for Associated Angina and Post MI • Most patients will need More than One Medication to Control their Hypertension • The Interpretation by the News Media is that Physicians are not Using the Best and Least Expensive Medicine New-Onset Hypertension Reduced by Candesartan in TROPHY* [randomized untreated prehypertension patients (BP 120-139/80-89), age 30-65]

CME Connection Cardiology Edition 2006;2(4):8.

*Nesbitt SD, Julius S, et al. Am J Hypertens. 2005/18:980-985.. Carotid Blood Pressure Sensors The CVRx Rheos™ System

Programming System

Baroreflex Activation Leads

Implantable Pulse Generator SIMPLICITY STUDY: RENAL ARTERY DENERVATION TECHNIQUEOR SEVERE HYPERTENSION 2014 SYMPLICITY HTN-3 TRIAL* • A total of 535 patients with severe resistant hypertension underwent randomization in a 2:1 ratio to undergo renal-artery denervation or a sham procedure. • In this blinded trial, at 6 months following renal-artery denervation, there was no significant decrease of systolic blood pressure as compared to sham procedure. • Current status in 2017: in limbo/larger trials? *Bhatt DL, et al. N Engl J Med 2014;370: 1393-1401. CONCLUSIONS • There is much established benefit from the treatment of hypertension. • Selection of the optimal regimen requires experience, judgement, trial/error. • There is diminishing support for having to start with diuretic or β-blocker. • New device and invasive techniques for severe BP⇑ offer promise. • Direct renal artery surgery has not had good results.