THE HYPERTENSIVE PATIENT
From the 2007 Primary Care Update, sponsored by the Interstate Postgraduate Medical Association of North America
Jan N. Basile, MD, Professor of Medicine, Medical University of South Carolina, and Director of Primary Care Service
Line, Ralph H. Johnson Veterans Affairs Medical Center,Charleston, SC
| ROLE OF FIXED-DOSE COMBINATION THERAPY FOR HYPERTENSION
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| Key points: 1) to achieve recommended blood pressure (BP) goals, consider fixed-dose combination as initial strategy;
most patients require ≥2 antihypertensive agents (often in fixed-dose combination); 2) unclear whether thiazide-type diuretic
or calcium channel blocker more ideal as part of ideal combination therapy; 3) to improve clinical outcomes, necessary
to achieve effective BP control and, where evidence exists, to include specific antihypertensive agents as part of
ideal combination therapy; 2003-2004 National Health and Nutrition Examination Survey (NHANES) data—compared to
1999-2000 data, awareness of hypertension increased (still, 25% of hypertensives unaware of their condition); number of
patients on therapy increased; in United States, 37% to 57% of patients with hypertension controlled to <140/90 mm Hg
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| BP goals: minimum goal, <140/90 mm Hg; in patients with diabetes, chronic kidney disease, or coronary artery disease
(CAD), <130/80 mm Hg; monotherapy ineffective for reaching minimum goal in most patients; according to Seventh Report
of Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7),
if systolic BP >20 mm Hg above goal and diastolic BP >10 mm Hg above goal, initiating therapy with 2 drugs, as separate
prescriptions or in fixed-dose combinations, should be considered
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| Treatment algorithm: lifestyle modifications; determine BP goal; decide whether compelling indications for specific
drugs present; rule of 10s—need 1 additional drug for every 10-mm Hg elevation in systolic BP (5 mm Hg for diastolic
BP)
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| Combination therapy: β-blocker and diuretic; angiotensin-converting enzyme (ACE) inhibitor and diuretic; angiotensin-receptor
blocker (ARB) and diuretic; ACE inhibitor and dihydropyridine calcium channel blocker (DCCB; eg, amlodipine);
ACE inhibitor and nondihydropyridine calcium channel blocker (NCCB; eg, verapamil); ARB and DCCB;
reserpine, 0.05 to 0.10 mg at bedtime may be helpful in older patients with resistant elevated systolic BP; spironolactone
(Aldactone) also useful for resistant hypertension; clinical trials often show efficacy of drugs as initial strategy; combination
drugs used as final strategy shown to effectively control BP
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| Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT): chlorthalidone
as effective as amlodipine and lisinopril as initial therapy in high-risk hypertensives ≥55 yr of age; at inception of
trial, only 27% of patients controlled (66% at conclusion); 2 of 3 had BP <140/90 mm Hg; 1 of 3 not controlled; unclear
which combination of drugs most effective; 42,000 high-risk hypertensives initially randomized; found no difference in
primary and early secondary end points (including all-cause mortality) between thiazide diuretic (chlorthalidone) and
CCB; at time of study, thiazide recommended as initial therapy because of lower cost; thiazide diuretic unsurpassed at every
outcome; for coronary heart disease and stroke, thiazide diuretic better than ACE inhibitor; thiazide diuretic better
than ACE inhibitor and CCB for preventing first evidence of clinical heart failure (HF)
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| Chlorthalidone and hydrochlorothiazide (HCTZ): chlorthalidone used in many trials but found in only one
fixed-dose combination (with atenolol); duration of action of HCTZ, 16 to 24 hr (24-48 hr for chlorthalidone); chlorthalidone
≈2 times more potent than HCTZ and more prone to cause hypokalemia (speaker generally does not use doses >37.5
mg of HCTZ or >25.0 mg of chlorthalidone); meta-analysis concluded no statistical difference between chlorthalidone
and HCTZ; if using HCTZ in fixed-dose combination with, eg, atenolol, consider breaking tablet and using bid for longer
duration of action; atenolol largely ineffective for outcome improvement, so useful comparator in studies
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| Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial: amlodipine highly effective at lowering
BP; 80 mg of valsartan compared to 5 mg of amlodipine; after 1 mo, doses doubled; then, thiazide diuretic added;
during fourth month, dose of thiazide diuretic doubled; hypothesized equal BP reduction and that valsartan would improve
outcome more than amlodipine; findings—for first 3 mo, amlodipine more effective at reducing BP than valsartan;
early in study, amlodipine outperformed valsartan in primary end points of fatal and nonfatal myocardial infarction (MI);
at end of trial, no difference between valsartan and amlodipine as initial strategy
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| Avoiding Cardiovascular Events through COMbination therapy in Patients Living with Systolic Hypertension
(ACCOMPLISH) trial: directly compared fixed-dose combinations of amlodipine-benazepril (Lotrel)
to benazepril (Lotensin) and HCTZ as initial therapy; showed fixed-dose combination strategy reaches goal (<140/90
mm Hg) faster, with better BP control than step-care approach; after 6 mo on fixed-dose combination as initial therapy,
percentage of participants with BP <140/90 mm Hg increased from 37.6% to 73.0% (after 2.5 yr, 80%); fixed-dose combination
as initial therapy results in less up-titration and better BP control
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| Properties of fixed-dose combinations: sodium and water volume reduction and renin-angiotensin system
antagonism—diuretics and β-blockers; diuretics and ACE inhibitors; CCB and ACE inhibitor; CCB and ARB; amlodipine
more effective on high-sodium diet (reason no CCB-diuretic combination exists)
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| Initial combinations: ACE inhibitor or ARB recommended for younger patients; diuretic or CCB recommended for
older patients; diuretic or CCB recommended for black patients; consider risk factors; ACE inhibitor or ARB and β-
blocker combinations both work on renin-angiotensin-sympathetic nervous system axis and may not be as effective as
ACE inhibitor, β-blocker, or ARB and diuretic or ACE inhibitor or ARB and CCB combinations; for ACE inhibitors or
ARBs, better BP reduction achieved by adding thiazide diuretic or CCB to initial dose of ACE inhibitor or ARB than by
doubling dose of ACE inhibitor or ARB
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| Vasodilation: CCBs and ACE inhibitors or ARBs all vasodilators; CCBs reduce calcium-dependent vasoconstriction;
ACE inhibitors and ARBs reduce renin-angiotensin II vasoconstriction; combination results in greater BP reduction than
either drug alone; as dose of, eg, amlodipine increases, pedal edema not responsive to thiazide diuretics can occur (due to
arteriolar dilatation); ACE inhibitors and ARBs cause postcapillary venular dilatation and fluid reabsorption; ACE inhibitor
and CCB results in less edema than ARB and CCB combination
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| Compelling indications for specific antihypertensive agents: HF; post-MI; high coronary risk; diabetes; renal
disease; prevention of recurrent stroke
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| Advantages of fixed-dose combinations: better efficacy in BP reduction; fewer adverse effects than high-dose
monotherapy; lower cost; fewer physician visits
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| BLOOD PRESSURE CONTROL IN PATIENTS WITH METABOLIC SYNDROME
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| Metabolic syndrome: criteria for women—waist circumference >35 in; triglycerides ≥150 mg/dL; high-density lipoprotein
(HDL) <50 mg/dL; BP ≥130/85 mm Hg or patient on antihypertensive drug therapy; fasting blood glucose (FBG)
≥100 mg/dL; BP goal should be <130/80 mm Hg
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| JNC 7 compelling indications for diabetes: no differentiating factors to find one antihypertensive agent (independent
of BP-lowering effect) better for diabetes than another; in patients with clinical proteinuria or established chronic
kidney disease, use of ACE inhibitor or ARB preferred; 27% reduction of new-onset diabetes seen with ACE inhibitor
(23% with ARB); effectiveness seen with other pharmacologic agents; “nothing really surpasses” lifestyle modification
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| Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) trial: double-
blind randomization to ramipril (15 mg) or placebo; found therapy unable to prevent new-onset diabetes or death; Food
and Drug Administration (FDA) does not allow ACE inhibitors to claim prevention of new-onset diabetes as indication;
trial slightly over 3 yr; during follow-up, some suggestion “maybe that there would be separation; needs to taken with
grain of salt”; no statistical benefit of ramipril for new-onset diabetes or death as combined end point or new-onset diabetes
by itself
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| ALLHAT and diabetes: patients double-blindly randomized to long-acting thiazide diuretic (chlorthalidone), long-
acting CCB (amlodipine), or long-acting ACE inhibitor (lisinopril); found no favorability of CCB or ACE inhibitor over
chlorthalidone; no difference in primary outcome; in type 2 diabetics who had no known recognized proteinuria, mean
creatinine of 1 mg/dL, and assumed normal glomerular filtration rate (ie, no chronic kidney disease), thiazide diuretic led
to similarly favorable outcome in primary end point as with ACE inhibitor or CCB; in new-onset diabetes, ACE inhibitor
of statistically significantly greater benefit than diuretic in all patients; for new-onset diabetes (ie, becoming diabetic during
trial) ≈3.5% greater risk found with thiazide compared to lisinopril (≈1.8% increased risk compared to CCB); thiazide
diuretics diabetogenic in mean 5-yr follow-up, compared to initial therapy with CCB or ACE inhibitor; becoming diabetic
during trial affected some end points, eg, coronary heart disease, but not statistically significant; no difference for
combined cardiovascular disease or end-stage renal disease; conclusions— FBG levels increase in older adults with hypertension,
regardless of treatment type; development of diabetes associated with increased risk for CHD, regardless of
treatment type; risk of developing diabetes increased with chlorthalidone, compared to amlodipine and lisinopril, but no
conclusive or consistent evidence that diuretic-associated increase in diabetes risk increased risk for stroke, HF, end-
stage renal disease, or total mortality over follow-up period; diuretics have metabolic effects, but appear to improve outcome
in patients with hypertension
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| Recent article: study separated patients within ALLHAT who had metabolic syndrome but not diabetes; for primary end
point, no difference between diuretic and amlodipine or lisinopril; for secondary end points, no difference between diuretic
and amlodipine; diuretic appeared slightly better than ACE inhibitor in patients with metabolic syndrome within
ALLHAT; conclusion—treatment group comparison results similar in participants with and without metabolic syndrome
at baseline; for both metabolic syndrome and nonmetabolic syndrome participants, neither CCB nor ACE inhibitor superior
to diuretic; results similar with Adult Treatment Panel (ATP) III criteria for metabolic syndrome
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| Recommendations from American Diabetes Association: in patients with hypertension and frank diabetes,
ACE inhibitor or ARB (whichever tolerated) should be used; if BP not <130/80 mm Hg, diuretic should be added
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| Speaker’s approach to metabolic syndrome: ACE inhibitor or ARB; thiazide diuretic or CCB; if BP not <130/80
mm Hg, add another drug (eg, if initial therapy ACE inhibitor or ARB and diuretic combination, add CCB or newer-generation
β-blocker); diet and exercise; β-blockers cause weight gain and increase insulin resistance
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| β-blockers: propranolol; data on atenolol weak; vasodilating—newer-generation β-blockers, eg, carvedilol, nebivolol;
uncertain whether these should be used as first-line therapy; strong role as additive strategy; tend to pathophysiologically
improve insulin resistance and improve glucose control, or at least not detrimental; consensus guidelines— β-blockers
may still be considered option for initial and subsequent antihypertensive treatment strategies; because they cause weight
gain, dyslipidemia, insulin resistance, and increased incidence of new-onset diabetes, β-blockers not preferred in hypertensives
with multiple metabolic risk factors; this may not apply to vasodilator β-blockers (eg, nebivolol and carvedilol),
which have less or no dysmetabolic action; metabolic effects favorable (decreased glucose, cholesterol, and triglycerides)
with these drugs, eg, nebivolol
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| Conclusion: greater consideration should be given to initial treatment with ACE inhibitor or ARB for BP control; most
patients require thiazide-type diuretic in lower dose or CCB for BP control; newer-generation vasodilatory β-blockers,
eg, carvedilol and nebivolol (nebivolol not FDA-approved), may be preferred in patients with metabolic syndrome
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| Questions and answers: variance between BP readings—unusual to have later BP readings higher than initial reading;
take 3 readings and average last 2; speaker recommends averaging BP readings, disregarding highest and strikingly low
values; best time of day to take antihypertensive drugs—unknown; BP usually increases on awakening (taking medication
at night may be protective; measure BP right before taking medication to ensure BP controlled at end of dosing interval); if
BP not controlled, consider bid dosing; use of forearm cuff over radial artery for patients with short massive arm—no
good evidence; “cuff measurement artifact” results in higher-than-normal reading; use cuff 80% circumference of arm
(may need to use thigh cuff); indications for 24-hr BP monitoring—research purposes; drug studies; white coat hypertension
(3 separate readings, ≥1 wk apart, in which BP in office hypertensive and BP at home normal); monitor BP every 15
min while awake, every 30 min while asleep; look at diurnal pattern and burden of BP elevation (ie, how many values
above threshold for hypertension); ask patients to keep diary; some patients with alert reaction to BP may need to be
treated with rate-limiting CCB or β-blocker; masked hypertension—patients have prehypertension in office; systolic BP
usually 135 to 139 mm Hg, diastolic 85 to 89 mm Hg; when monitored outside of office, patients hypertensive (BP fluctuates;
eg, slightly above 140/90 mm Hg); advise patients to monitor BP at home and to call office if BP >140/90 mm Hg; aliskiren
(Tekturna)—potent direct renin inhibitor; FDA-approved; BP-reducing capacity similar to other monotherapies;
few recent studies about evidence-based improvement in outcome; recent study of type 2 diabetics with clinical proteinuria
showed that compared to placebo, adding Tekturna further improved reduction of proteinuria, with no deleterious effect on
renal function; role for selective serotonin reuptake inhibitors (SSRIs) in resistant hypertension—speaker thinks not; however,
low-dose lorazepam (Ativan) bid may be helpful in nervous patients with alert reactions to high BP
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Suggested Reading
ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group: The Antihypertensive
and Lipid-Lowering Treatment to Prevent Heart Attack Trial: Major outcomes in high-risk hypertensive patients
randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and
Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 288:2981, 2002; Barzilay JI et al: Fasting
glucose levels and incident diabetes mellitus in older nondiabetic adults randomized to receive 3 different classes of antihypertensive
treatment: a report from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).
Arch Intern Med 166:2191, 2006; Bloch MJ et al: Chlorthalidone reduces 24-hour ambulatory systolic blood
pressure more than hydrochlorothiazide. J Clin Hypertens (Greenwich) 8:452, 2006; Bloch MJ et al: Correction of thiazide-induced
hypokalemia prevents hyperglycemia and incident diabetes mellitus. J Clin Hypertens (Greenwich) 8:751,
2006; Chobanian AV et al: The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation,
and Treatment of High Blood Pressure: the JNC 7 report. JAMA 289:2560, 2003; Cushman WC et al: Achieving blood
pressure goals: why aren't we? J Clin Hypertens (Greenwich) 8:865, 2006; Davis BR et al: Role of diuretics in the prevention
of heart failure: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Circulation
113:2201, 2006; Jamerson KA et al: Rationale and design of avoiding cardiovascular events through combination therapy
in patients living with systolic hypertension (ACCOMPLISH) trial: the first randomized controlled trial to compare the
clinical outcome effects of first-line combination therapies in hypertension. Am J Hypertens 17:793, 2004; Julius S et al:
Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the
VALUE randomised trial. Lancet 363:2022, 2004; 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; Ong KL et al: Prevalence, awareness,
treatment, and control of hypertension among United States adults 1999-2004. Hypertension 49:69, 2007; Rahman M et
al: Renal outcomes in high-risk hypertensive patients treated with an angiotensin-converting enzyme inhibitor or a calcium
channel blocker vs a diuretic: a report from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack
Trial (ALLHAT). Arch Intern Med 165:936, 2005; Whelton PK et al: Clinical outcomes in antihypertensive treatment
of type 2 diabetes, impaired fasting glucose concentration, and normoglycemia: Antihypertensive and Lipid-Lowering
Treatment to Prevent Heart Attack Trial (ALLHAT). Arch Intern Med 165:1401, 2005.
Educational Objectives
| The goal of this program is to improve the management of hypertension in patients who are candidates for
fixed-dose combination therapy and/or have the metabolic syndrome. After hearing and assimilating this
program, the clinician will be better able to:
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 | 1. Establish appropriate blood pressure goals.
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| 2. Select treatment combinations based on clinical findings and trial data.
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| 3. List properties and advantages of fixed-dose combination therapy for hypertension.
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| 4. Discuss findings of clinical trials, such as the Antihypertensive and Lipid-Lowering treatment to prevent
Heart Attack Trial (ALLHAT).
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| 5. Describe newer antihypertensive agents, such as vasodilating β-blockers and direct renin inhibitors.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning
committee 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
has received grants and/or research support and/or is on the Speaker’s Bureau for Abbott Laboratories, AstraZeneca, Boehringer
Ingelheim, Daiichi Sankyo, Forest Laboratories, GlaxoSmithKline, Merck & Co, Novartis, Pfizer, and Wyeth. The
planning committee reported nothing to disclose.
Acknowledgements
Dr. Basile was recorded in Savannah, GA, at the 2007 Primary Care Update, presented November 4-7, 2007, by the Interstate
Postgraduate Medical Association. 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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