ADVANCES IN HYPERTENSION
From Interstate Postgraduate Medical Association Primary Care Update
Jan N. Basile, MD, Professor of Medicine, Medical University of South Carolina, Charleston
| Antihypertensive agents: in studies, significantly reduce cardiovascular morbidity and mortality, compared to
placebo; different classes of agents provide similar reductions in morbidity and mortality when compared head to
head; outcome differences observed in some trials may result from differences in central aortic pressure reduction
between agents or early differences in amount of blood pressure (BP) reduction; most of benefit results from BP reduction,
often requiring multiple agents
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| Importance of BP reduction: epidemiologic analysis of 61 studies that included 12.7 million individuals shows
increasing age and systolic and diastolic BP correlate with increase in risk for ischemic heart disease; Framingham
Heart Study—found BP correlates linearly with risk for coronary event; patients with prehypertension also at risk;
can prevent onset of hypertension with angiotension receptor blocker (ARB; eg, candesartan), but since no evidence
for improved outcome with BP <140/<90 mm Hg, prehypertension not treated, except in diabetic patients or
those with chronic kidney disease
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| Placebo-controlled trials: Veterans Affairs (VA) study— found diuretics as initial therapy significantly reduced
cardiovascular event rate; meta-analysis—of 14 trials using diuretics as initial therapy and 3 trials using β-blockers
as first therapy found significant event reduction in clinical heart failure (HF), stroke, left ventricular hypertrophy
(LVH), cardiovascular death, and coronary heart disease (CHD) events (fatal and nonfatal); BP reduction to <140/
<90 mm Hg prevents stroke, myocardial infarction (MI), and congestive heart failure (CHF)
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| Head-to-head trials: most comparative trials show different classes of agents provide similar reductions in morbidity
and mortality; several trials showed similar benefits associated with older drugs, including diuretics and β-
blockers, and newer agents, including calcium channel blockers (CCBs) and angiotensin-converting enzyme inhibitors
(ACEIs)
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| Event reduction: meta-analysis in Lancet by Blood Pressure Lowering Treatment Trialists Collaboration
(BPLTTC) compared event rates in relation to various classes of antihypertensives; ACEI vs diuretic or β-
blocker—no difference in rates of major cardiovascular events, cardiovascular mortality, or total mortality; CCB
vs diuretic or β-blocker—no difference in rates of major cardiovascular events, cardiovascular deaths, or total
mortality; ACEI vs CCB—no difference in rates of major cardiovascular events, cardiovascular mortality, or total
mortality; ACEI vs β-blocker or diuretic—no difference in rate of CHD, stroke, or HF; summary of meta-
analysis— β-blocker or diuretic therapy outperformed ACEI and CCB for all events; CCB superior to ACEI in reduction
of stroke; ACEI superior to CCB in HF reduction; ACEI, ARB, β-blockers, CCB, and diuretics all reduced
risk for major cardiovascular events; cardiovascular risk reduction depended on extent of BP lowering; except for
HF, cause-specific outcomes directly related to differences in BP reduction; conclusions of BPLTTC—BP reduction
associated with reduction in rate of stroke, major cardiovascular disease, total mortality, CHD, and cardiovascular
mortality; HF prevented by control of BP
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| Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack trial (ALLHAT): multi-
arm double-blind study compared long-acting thiazide diuretic to long-acting dihydropyridine CCB and long-acting
ACEI; study arm with α-blocker doxazosin—stopped early (2 yr before end of trial) because patients seemed
to worsen; concluded α-blocker should not be used as initial monotherapy in high-risk patients ≥55 yr of age;
findings—no difference in rate of fatal CHD or nonfatal MI (primary end points) in patients taking diuretic (chlorthalidone)
or ACEI (lisinopril), or CCB (amlodipine); recommend diuretic as initial therapy because of cost, availability,
and clinical outcomes; diuretic should always be included in therapeutic “cocktail”; ALLHAT data suggest
lowering BP with any of several classes of antihypertensive agents reduces complications from hypertension
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| Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT): compared short-acting β-blocker atenolol to long-
acting CCB amlodipine; if patient not at goal on atenolol monotherapy, thiazide diuretic added; perindopril added
to CCB in patients not at goal on monotherapy; trial stopped early because mortality rate higher in patients on
atenolol than in those on amlodipine; primary end point (nonfatal MI or fatal CHD) not met; several secondary end
points improved in patients on CCB and ACEI therapy, and fewer patients died on this regimen; concluded atenolol
should not be used as initial monotherapy for hypertension
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| Conduit Artery Function Evaluation (CAFE): substudy of ASCOT; looked at noninvasive mechanism for
central hemodynamic abnormalities in BP reduction; although no difference in brachial BP, further reduction in
central BP of 4 mm Hg in patients on amlodipine-based therapy compared to atenolol-based therapy; reduction in
central aortic BP may account for some differences seen in trial; finding provides plausible mechanism to explain
better clinical outcomes in patients treated with CCB/ACEI therapy in ASCOT; difference in central aortic BP
translates to 25% reduction in risk for stroke (similar to 27% reduction seen in ASCOT); central BP hypothesis
may explain differential effects of antihypertensive agents on cardiovascular structure seen in other recent trials
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| Importance of early BP control: Valsartan Antihypertensive Long-Term Evaluation (VALUE) trial—compared
ARB valsartan 80 mg to amlodipine 5 mg, then doubled dose at 1 mo, and added thiazide-type diuretic after 3 mo;
speaker recommends adding thiazide diuretic to initial dose of ARB and starting valsartan at 160 mg; 4 mm Hg
greater reduction of BP occurred in patients on amlodipine than on valsartan; conclusion that valsartan not better
than amlodipine as initial therapy; observational analysis suggests benefit with amlodipine due to early reduction in
BP; data suggest early reduction in BP better than later; speaker aims at getting patient to BP goal within first several
months of therapy
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| Compelling indications: concomitant conditions in which use of certain class of antihypertensive agents leads to
further outcome improvement, ie, beneficial effect on morbidity and mortality; these agents must be included in
cocktail of therapy; conditions include HF, post-MI ( β-blocker and ACEI), high-risk CHD, diabetes, diabetic nephropathy
(ACEI and ARB), stroke (ACEI and diuretic); diabetic nephropathy trials—Irbesartan Type 2 Diabetic
Nephropathy trial (IDNT) and Reduction of Endpoints in NIDDM with the Angiotensin 2 Antagonist Losartan
(RENAAL) study; target BP <130/80 mm Hg; 4 drugs used (first drug rarely final drug); recommend combination
therapy as initial strategy in many patients with hypertension, especially those with type 2 diabetes
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| National Institute of Clinical Excellence (NICE) 2007 guidelines: avoid β-blockers as initial strategy; consider
use of β-blockers as part of therapeutic cocktail in patients after MI, with HF with reduced ejection fraction,
or with angina; recommendations—younger patients should get ACEI or ARB as initial therapy; patients ≥55 yr of
age should get diuretic or CCB as initial strategy; black patients of any age should get diuretic or CCB as initial
therapy; speaker starts 80% of patients on combination therapy and recommends ACEI and diuretic or ARB and diuretic
as initial therapy in patients with stage 2 hypertension; consider combination of drugs in patients with stage 1
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Questions and Answers
| Prehypertension: defined as systolic BP 121 to 139 mm Hg with diastolic BP 81 to 89 mm Hg; includes stages 1a
and 1b; 130 to 139 mm Hg over 85 to 89 mm Hg associated with highest risk; risk increases continuously with
increasing BP, with ≥140/90 mm Hg defined as hypertension; no evidence for lowering BP in prehypertensive
range, except in patients with diabetes or chronic renal disease
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 | Trial of Preventing Hypertension (TROPHY)—4-yr double-blind trial in which patients with prehypertension randomized
to ARB (cansdesartan) or placebo; statistically significant reduction in new-onset hypertension in those
on candesartan (relative risk reduction ≈40%; absolute risk reduction ≈20%); starting BPs 134/84 mm Hg; candesartan
associated with 10 mm Hg reduction in systolic BP; however, lifestyle modification still recommended
to prevent onset of hypertension; currently, no evidence for improvement in outcome with treatment of prehypertension
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| Goals of therapy: defining patient’s risk most important; currently, no evidence that reducing BP to well under target
more beneficial; consider cost of treatment, incremental benefits, and medicines required; if patient on diuretic
and ACEI and has BP of 139/89 mm Hg, speaker would increase dosage to drive BP down further, but would probably
not add another drug
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| Lifestyle modifications: aerobic exercise, independent of weight loss, associated with BP reduction; weight
loss associated with BP reduction; salt restriction—consider in “salt-sensitive” patients (exaggerated increase
in BP in response to increased sodium level in blood); salt-sensitive patient populations include blacks, elderly,
and diabetics; consider restricting salt in these patients; speaker not against salt restriction in all patients
with hypertension
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| BP difference at home: patients should monitor BP at home; patient who monitors BP at home more likely to take
medicines regularly and have controlled BP; white coat hypertension—consider diagnosis if out–of-office BP
measurement differs by >5 mm Hg from in-office measurement; study suggested out-of-office BP may correlate
better with prognosis than in-office BP; have patients bring at-home monitor to office and take BP using same
method as at home; if BP same in office with their home monitor, respect their out of office reading; consider diagnosis
of white coat hypertension if 3 separate in-office readings higher than out-of-office readings in patient with
no target organ disease; consider 24-hr ambulatory monitoring for diagnosis
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| Brachial BP differences: take BP in same arm for each measurement; BP differences as high as 10 mm Hg can
occur between arms; take BP from arm with higher BP and document in chart which arm used to take BP; take BP
in both arms when making diagnosis of hypertension
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| Combination therapy: recommended as initial therapy in patient with 20/10 mm Hg burden of elevation; should
include thiazide diuretic; consider in stage 1 hypertension; suggested in patients with systolic pressures in 150 to
159 mm Hg range; avoid as initial therapy in oldest elderly patients; instead, start with single agent and titrate up
slowly, while monitoring carefully (elderly prone to orthostasis); most physicians do not titrate up or add another
agent to regimen; therapeutic inertia—occurs when practitioner fails to add another agent or titrate up to higher
dose of medication when patient’s BP not at or below target; study found therapeutic inertia present in 86% of patients
with uncontrolled BP; waiting 6 mo before adjusting therapy not acceptable; have patient monitor BP at
home for 2 wk, and if no change, increase dosage or add another drug; alternatively, make immediate regimen
change; speaker recommends that patients with uncontrolled stage 2 hypertension be seen or contacted weekly, and
patients with uncontrolled stage 1 disease be seen in 1 mo; once BP controlled, see patient every 3 to 6 mo
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| Unopposed α-blockade: based on ALLHAT trial, avoid in high-risk hypertensive patient (patient ≥55 yr of age
who has ≥1 cardiovascular risk factor); recommend adding thiazide diuretic, CCB, or ACEI to antihypertensive
therapy; consider adding α-blocker to another agent, but do not use as initial therapy or monotherapy in high-risk
patient
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| Dihydropyridine CCB-induced lower extremity edema: more common in women; direct dose response
(higher dose, higher risk); less edema when another drug (eg, ACEI, ARB) combined with CCB; newer agent that
combines CCB with AACEI produces less edema
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| Anxiety and hypertension: recommend longer-acting β-blocker or lozarepam (Ativan) in patient with anxiety attacks;
consider diagnosis of comorbid anxiety disorder
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| Calcium channel blockers: not associated with increased risk for cancer, suicide, or gastrointestinal bleeding;
effective initial therapy; improve outcome and associated with reduction in rate of stroke; however, speaker prefers
thiazide diuretic to CCB because of efficacy and cost; in ALLHAT, CCB prevented fatal CHD and nonfatal
MI, but not as effective for preventing HF as thiazide diuretic; can be used in blacks as initial therapy, although
speaker prefers diuretic because of superior efficacy in HF reduction; avoid in any patient with chronic renal disease;
dihydropyridine CCBs—cause arteriolar dilatation which causes fluid to seep into interstitium, resulting in
nonpitting edema; ACEI and ARBs cause postcapillary venular dilatation that allows fluid to be reabsorbed; add
ACEI or ARB to therapeutic regimen to ameliorate edema, starting with low dose, or decrease dose of CCB, depending
on requirement for BP control and for minimization of edema
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| β-blocker as initial therapy: not preferred as initial therapy in elderly; consider in younger patient; heterogeneous
group of compounds; avoid once-daily atenolol
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| Calcium supplementation: patient should keep using calcium supplements while taking CCB; thiazide diuretic
preferred as initial therapy in postmenopausal women; thiazide diuretics anticalciuric, increase bone mineral density,
and may decrease risk for fractures
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Suggested Reading
Alderman MH: JNC 7: brief summary and critique. Clin Exp Hypertens 26:753, 2004; Barzilay JI et al: Cardiovascular
outcomes using doxazosin vs. chlorthalidone for the treatment of hypertension in older adults with and without
glucose disorders: a report from the ALLHAT study. J Clin Hypertens 6:116, 2004; Basile JN: Fixed-dose
combination therapy in the treatment of hypertension: ready for prime time. South Med J 2007 100:343, 2007; Basile
JN et al: A historical look at hypertension: celebrating 100 years with the Southern Medical Association. South Med
J 99:1412, 2006; Basile JN et al: The importance of early antihypertensive efficacy: the role of angiotensin II receptor
blocker therapy. J Hum Hypertens 20:169, 2006; Basile JN: Optimizing antihypertensive treatment in clinical
practice. Am J Hypertens 16:13S, 2003; Basile JN: Most antihypertensives have similar efficacy and safety: a
meta-analysis. J Clin Hypertens 4:50, 2002; Cushman WC et al: Achieving blood pressure goals: why aren't we?
J Clin Hypertens 8:865, 2006; Leenen FH et al: Clinical events in high-risk hypertensive patients randomly assigned
to calcium channel blocker versus angiotensin-converting enzyme inhibitor in the antihypertensive and lipid-
lowering treatment to prevent heart attack trial. Hypertension 48:374, 2006; Neutel JM et al: Efficacy and safety of
irbesartan/HCTZ combination therapy as initial treatment for rapid control of severe hypertension. J Clin Hypertens
8:850, 2006; Sisson SD et al: Physician familiarity with diagnosis and management of hypertension according to
JNC 7 guidelines. J Clin Hypertens 8:344, 2006; Wexler R et al: Initiation of therapy for patients with essential hypertension
or comorbid conditions. Prim Care 33:887, 2006; Williams B et al: Differential impact of blood pressure-lowering
drugs on central aortic pressure and clinical outcomes: principal results of the Conduit Artery Function
Evaluation (CAFE) study. Circulation 113:1213, 2006.
Educational Objectives
| The goal of this program is to improve the treatment of patients with hypertension. After hearing and assimilating this
program, the clinician will be better able to:
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| 1. Discuss the use of specific agents to lower blood pressure and treat hypertension.
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| 2. Evaluate the data from clinical trials about the efficacy of antihypertensive agents in event reduction.
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| 3. Discuss the results of several large randomized controlled trials of antihypertensive agents.
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| 4. Describe the benefits of early blood pressure control.
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| 5. List the compelling indications for the use of specific antihypertensive agents.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty members to disclose
relevant financial relationships within the past 12 months that might create any personal conflicts of interest. Any
identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary
business or commercial interest. For this program, the following has been disclosed: Dr. Basile receives research
support from Boehringer Ingelheim, Novartis, and the National Heart, Lung, and Blood Institute, is a
consultant for AstraZeneca, Merck, and Novartis, and is on the Speakers’ Bureaus for Abbott, AstraZeneca, Boehringer
Ingelheim, Forest, GlaxoSmithKline, Merck, Novartis, Pfizer, and Sankyo.
Acknowledgements
Dr. Basile was recorded at the Interstate Postgraduate Medical Association’s Primary Care Update: Improving Patient
Care, in Newport Beach, CA, on November 5-8, 2006. The Audio-Digest Foundation thanks Dr. Basile and the
Interstate Postgraduate Medical Association for their cooperation in the production of this program.
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