1. Review the most recent guidelines for management of hypertension and definitions of stages of hypertension.

2. Describe appropriate drug therapy for hypertension in varying disease states, including combination therapy.

3. Identify the indications for β-blockers in the treatment of hypertension.

4. Determine a patient’s individualized global risk assessment.

5. Review the cardiac benefits of β-blockade.

How to Manage Hypertension
Michael J. Bloch, MD, Associate Professor of Medicine, Department of Internal Medicine, University of Nevada School of Medicine, Founder and Medical Director, Saint Mary’s Risk Reduction Center, Reno, NV

Introduction: hypertension (HTN) prevalent (aging population, obesity); inadequate treatment leads to high-risk outcomes (eg, stroke, heart failure); only 35% of patients with high blood pressure (BP) controlled at goal; patients often noncompliant with recommended treatments; physicians and staff not aggressive enough in identification and treatment

Joint National Committee (JNC) 7 guidelines, 2003: 4 clas--ses—normal BP <120/<80 mm Hg; pre-HTN 120 to 139/80 to 89 mm Hg; stage I HTN 140 to 159/90 to 99 mm Hg; stage II HTN 160/100 mm Hg; treat pre-HTN with lifestyle modifications, unless high risk factors present (eg, chronic kidney disease [CKD], type 2 diabetes); stage I, start treatment with one drug; stage II, start treatment with 2 drugs; titrate to goal

Since JNC 7: have learned to treat better and sooner, to prevent cardiovascular (CV) disease and stroke; within each stage, wide variety of CV risk; treat based on CV risk, not just BP numbers; new strategies proposed to guide whom to treat and when to treat, eg, American Society of Hypertension (ASH), American Heart Association (AHA); AHA guidelines— recom---mend expansion of high-risk group beyond those with diabetes and CKD; aggressive treatment to goal (<130/<80 mm Hg) recommended for patients with coronary artery disease (CAD), left ventricular dysfunction, any CAD risk equivalent (eg, peripheral artery disease [PAD], carotid artery disease, abdominal aortic aneurysm [AAA]), or 10-yr Framingham Risk Score (FRS) >10%

Global risk assessment: use JNC 7 and AHA as basic guidelines, then treat based on overall CV risk; determine global CV risk by reviewing demographics (age, sex, BP), established CV or renal disease (atherosclerosis, stroke, congestive heart failure [CHF], renal insufficiency), other risk factors (diabetes, impaired glucose tolerance, obesity, dyslipidemia, metabolic syndrome), and end organ damage (left ventricular hypertrophy [LVH], retinopathy, microalbuminuria); global risk determines when to treat and how aggressively to treat; goal based on individual global risk; adjust guidelines as clinically appropriate for each patient; individualized treatment goals must be effectively communicated to patient and staff

Prehypertension: in absence of other risk factors, treat with lifestyle modifications; give specific advice about caloric intake (weight reduction), Dietary Approaches to Stop Hyper-tension (DASH) diet, sodium restriction, increased physical activity, and decreased alcohol intake; Trial Of Preventing Hypertension (TROPHY) study (2006)—considered drug therapy for patients with pre-HTN; ≈750 participants randomized to 4 yr placebo, or 2 yr candesartan followed by 2 yr placebo; primary end point development of new HTN; in placebo group, high incidence of HTN at 4 yr; candesartan group had lower BP in first 2 yr, but, after next 2 yr on placebo, BP remained lower than 4-yr placebo group; data important first step showing benefit of treating high-risk patients before HTN develops; patients most likely to progress—highest body mass index (BMI), oldest, highest BP readings, women, smokers, and those with history of parental HTN; FRS algorithm for 4-yr risk of developing HTN accessible at www.annals.org; speaker recommends treating these patients most aggressively, including potential use of medications; treat all cases pre-HTN with lifestyle modification; medication option for higher-risk patients (diabetes, CKD, CAD); think of HTN as avoidable end point

Hypertension in the Very Elderly Trial (HYVET): participants >80 yr of age; entry criterion BP 160-199/<110 mm Hg; participants randomized to diuretic (indapamide) or placebo (could add perindopril if needed to reach goal); study goal BP <150/<80 mm Hg; primary end point fatal or nonfatal stroke; study stopped early at 2 yr (4 yr planned) because of 28% reduction in total mortality in treatment group; most patients achieved systolic BP 140 to low 150s mm Hg; stroke much more common than CV death in older patients with HTN; HYVET and other studies show that fairly healthy older patients treated modestly for HTN do not have increased side effects, and do have decreased stroke and CV event risk; all study participants stage II HTN; achieved BP in these studies was systolic BP 140 to low 150s mm Hg; if you can lower to that without increasing orthostasis, risk of falling, and side effects, reasonable to push BP lower than that; if you can only get to systolic BP 130 to 140s mm Hg, still considerable benefit, and data support that; conclusion—modest treatment of stage II HTN in elderly leads to greater reduction in absolute risk for events than seen in any other patient group; benefits of more aggressive treatment for stage II HTN, and treatment of stage I HTN, in elderly remains unproven

Treatment: no longer use monotherapy; now think of early therapies and add-on therapies; most patients need 2 to 3 medications to get to goal; recent studies look at what types of combinations most effective early on and which better as add-on therapy; β-blockers no longer considered first-line therapy for HTN (in absence of HF or established CAD); Avoiding Cardiovascular Events in Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH)—study looking at which combination to pick for high-risk patients (HTN plus >55 yr of age plus other CV risk factor); participants randomized to angiotensin-converting enzyme inhibitor (ACEI) plus thiazide-type diuretic or ACEI plus dihydropyridine calcium channel blocker (CCB; amlodipine); goals BP <140/90 mm Hg for most patients, <130/80 mm Hg for those with diabetes or CKD; composite end point myocardial infarction (MI), CV death, stroke, or HF requiring hospitalization; at start, ≈37% had controlled HTN, at finish ≈80% controlled; study concluded ACEI plus amlodipine combination resulted in significant decrease in end points, and trend toward decreased all-cause mortality; Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET)—study used angiotensin receptor blocker (ARB), ACEI, or combination; in patients with HTN plus one CV risk factor, no difference between ACEI, ARB, or combination in end point events; early combination therapy—between antineurohormonal agents (eg, ARB, ACEI, possibly β-blockers), and vasodilator- blood volume reducers (eg, CCB, thiazide-type diuretic), choose one of each type, based on individual risk; for add-on therapy—need more data to guide choice of third and fourth drugs; as more medications added, more diuretic needed (eg, increase dose of thiazide-type, possibly add spironolactone)

Final lessons: need better system for optimal treatment of chronic asymptomatic conditions such as HTN; address patient understanding and concerns (eg, side effects); barriers to compliance (eg, limited access to care, medication cost); physician must overcome therapeutic inertia and act on elevated BP

All About Beta-Blockers
Jan N. Basile, MD, Professor of Medicine, Division of Internal Medicine/Geriatrics, Medical University of South Carolina; Director of Primary Care, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC

Introduction: β-blockers most heterogeneous class of antihypertensive agents; inadequate HTN control in United States; combination therapy usually required for control of BP; ACCOMPLISH trial demonstrated control rate of 80% at 30 mo (from 37%), but at 6 mo, control rate already 74%; recent retrospective data suggest faster control equals better outcomes; those with increased comorbidities need to start more slowly; CV outcomes differ by β-blocker, patient population, and disease state; β-blockers cardioprotective in patients with HF with decreased ejection fraction (EF), after MI, and in diabetes; atenolol less effective in elderly and patients with HTN and decreasing heart rate (HR); vasodilating β-blockers, (eg, carvedilol, nebivolol) act on central aortic pressure (what brain and heart see as BP), by increasing cardiac output and decreasing peripheral resistance; both have favorable side effect profile, and decreased adverse metabolic profile; in elderly patients, increased peripheral resistance main etiology of systolic HTN

Stages of HTN: JNC 7 defined normal, pre-HTN, stage I HTN, and stage II HTN; AHA guidelines (not evidence-based) recommend BP <120/<80 mm Hg for patients with HF and decreased EF; only evidence-based guidelines are BP <140/ <90 mm Hg in HTN and <140/<80 mm Hg in diabetes; unknown whether <130/<80 mm Hg better than higher BP; also unknown whether increased medication cost worth decreasing BP below recommended levels

Who has HTN: 34% to 37% of HTN population at goal control; racial disparities seen in outpatient setting; 2005 study showed less racial disparity at Veterans Affairs (VA) sites, although still slightly present; difficult to control HTN in younger black men, older Hispanic men, younger obese Hispanic women, and elderly black women

Treatment: one drug not enough for most patients; rule of 10’s (current systolic BP minus 140) –:10equals number of medications required to achieve BP goal; speaker starts 80% of patients on 2-drug fixed-dose combination; Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)—at entry, 37% of patients at goal (<140/<90 mm Hg), at 5 yr patients required multiple drugs to achieve goal; JNC 7 algorithm recommends initiating combination therapy with 2 drugs when BP 20/10 mm Hg above goal or BP >160/>100 mm Hg

β-blockers: pharmacologically and hemodynamically heterogeneous; previously recommended as initial therapy in all stages of HTN; benefits of β-blockers—antiatherogenic (reduce inflammation, shear stress, endothelial dysfunction, and risk for plaque rupture); antiarrhythmic (decrease HR and sympathetic activity, and increase cardiac vagal tone); anti-ischemic (decrease HR and BP, and prolong diastole); associated with reversal of cardiac remodeling; British Hyper-tension Society 2006 Guidelines—recommend β-blockers not be routinely prescribed as first- or second-line drugs unless patient has HF or ischemic heart disease; recommend caution in combining β-blockers with diuretics in view of increased risk for adverse metabolic consequences; comment— β-blockers often “rode on coattails” of thiazide diuretics; JNC recommendation was for “thiazides with or without β-blockers”; on their own, β-blockers not shown as effective in evidence- based initial strategies for outcome improvement in HTN; JNC 7—re-com-mends β-blockers for compelling indications, ie, in patients who are post-MI, at high CAD risk, or who have HF or diabetes, consider β-blocker as part of treatment cocktail; evidence for use of β-blockers—improved post-MI outcomes; in HF with reduced EF, they reduced mortality ≈34%; in patients with diabetes, β-blockers associated with prolonged survival; post-MI risk reduction may outweigh potential adverse effects of β-blockers

β-blockers in elderly: diuretic decreases stroke, CAD, CV death, and total mortality with statistical significance (not true with β-blocker); caution using β-blocker as initial therapy in elderly (outcome data not good unless compelling indication present)

Atenolol: once-daily use increased risk for stroke more than other antihypertensive agents, and increased trend toward MI and all-cause mortality; speaker’s atenolol pledge—do not use atenolol once daily (too short-acting); if needed, use twice daily; Anglo Scandinavian Cardiac Outcomes Trial (ASCOT ) using atenolol, stopped due to increased CV mortality (early death); atenolol ineffective study comparator

Relation of β-blocker–induced Heart-Rate Lowering and Cardioprotection in Hypertension: recent meta-analysis of randomized trials from 1996 to 2008 that used β-blocker as first-line treatment for HTN; ≥1-yr follow-up and inclusion of HR response required; 9 studies; 34000 patients on β-blockers vs 30000 on other antihypertensive agents, and 4000 on placebo; 78% of patients on atenolol only; after 3.5-yr follow-up, HR reduction in patients with HTN (and no compelling reason for β-blocker) associated with increased risk for all-cause death, MI, stroke, or HF; the more HR reduced, greater the risk for CV events and death; possible atenolol-related phenomenon; non-atenolol β-blockers did not increase stroke, MI, or all-cause mortality

Conduit Artery Function Evaluation (CAFE) study (2003): subset analysis from ASCOT trial; looked at difference between peripheral BP measurement and central aortic pressure (exerted on heart and brain); amlodipine with or without ACEI vs atenolol with or without thiazide diuretic; found that for same peripheral BP measurement, atenolol/thiazide group had higher central aortic pressure

Choosing β-blockers: types include nonselective (first generation), selective, and vasodilatory (eg, carvedilol, labetalol, nebivolol); properties to consider—selectivity, vasodilation, side effect profile, metabolic profile (possible outcome improvement), and efficacy; consider if drug has intrinsic sympathetic activity, cardioselectivity, vasodilation (via alpha or beta blockade, or nitric oxide pathway), and dosing frequency; vasodilatory β-blockers work through either α-receptor antagonism or, as with nebivolol, by upregulating L-arginine and increasing nitric oxide levels (significance on outcome improvement still unclear); compared with nonvasodilating β-blockers, vasodilating β-blockers have favorable effect on central aortic BP, increase cardiac output and decrease peripheral resistance (possible benefit in elderly), are associated with favorable side effect profile, and decrease adverse metabolic consequences; Cockcroft study—compared vasodilating to nonvasodilating β-blockers; demonstrated that although no significant difference in peripheral BP measurement, central aortic pressure significantly lower with nebivo-lol; clinical trials needed; hemodynamic effects—study compared atenolol 100 mg once daily with nebivolol 5 mg once daily; in nebivolol group, cardiac output and stroke volume preserved, peripheral resistance decreased, and HR reduced (but not as much as with atenolol); side effects—metabolic concerns (eg, glucose metabolism)), tolerability (eg, erectile dysfunction), and concerns about effectiveness in special populations (eg, elderly, diabetics, blacks); meta-analysis—reviewed 11 randomized controlled trials (1966-2001); findings showed cardioselective β-blockers produced no significant change in forced expiratory volume in one second (FEV1) or respiratory symptoms, either as single dose or during longer treatment; erectile dysfunction—crossover study compared nebivolol (5 mg once daily) with metoprolol (long-acting 95 mg once daily); erectile function reduced with metoprolol, better with nebivolol; hemoglobin A1c—carve-dilol less detrimental over 5-mo study period than metoprolol; nebivolol—reductions in glucose, cholesterol, and triglyceride levels seen over 6 mo; nitric oxide—only nebivolol upregulates nitric oxide

Recommendations: speaker prefers to use renin angiotensin system blocker plus CCB or thiazide; impact of ACCOMPLISH to be seen once published; for third drug, consider adding either CCB or thiazide, whichever not already being used; speaker considers chlorthalidone superior to hydrochlorothiazide; newer-generation β-blockers best used in patients with diabetes, obesity, or cardiometabolic syndrome; all patients need lifestyle modifications