Postgraduate Medicine
ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: http://www.tandfonline.com/loi/ipgm20
Antihypertensive therapy Karen J. Harper MS, PharmD & Alan D. Forker MD To cite this article: Karen J. Harper MS, PharmD & Alan D. Forker MD (1992) Antihypertensive therapy, Postgraduate Medicine, 91:6, 163-193, DOI: 10.1080/00325481.1992.11701321 To link to this article: http://dx.doi.org/10.1080/00325481.1992.11701321
Published online: 17 May 2016.
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~~CME credit article
Antihypertensive therapy Current issues and challenges
KarenJ. Harper, MS, PharmD Alan D. Forker, MD
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Preview How do antihypertensive agents affect overall cardiovascular health? Which ones affect lipid levels? Insulin sensitivity? Left ventricular hypertrophy? What is the agent of choice for treating systolic hypertension in elderly patients? The authors address these and other questions in this update on pharmacologic management of hypertension.
The treatment of hypertension remains a challenge for physicians-perhaps the ultimate challenge. Systemic hypertension is no longer regarded as simply a state of elevated blood pressure but rather as a syndrome of multiple abnormalities. This syndrome is characterized by (1) a link betw'een the circadian rhythm of blood pressure and the occurrence and timing of cardiovascular events, (2) lipid abnormalities, (3) insulin resistance and glucose intolerance, and (4) left ventricular hypertrophy (LVH). To meet the challenge of treating hypertension, the clinician must select drug therapy that treats all these aspects of the syndrome in addition to effectively lowering blood pressure, as will be discussed. One management issue is how antihypertensive therapy affects cardiovascular disease. Studies have shown that lowering blood pressure reduces the incidence of stroke by about 40% bur reduces the incidence of death secondary
to coronary artery disease (CAD) by only a small amount. This is of major concern, both because coronary events (particularly sudden death) are the major cause of death in patients with hypertension and because the use of thiazide diuretics (which have been the traditional cornerstone of drug therapy for hypertension) may actually place the patient at increased risk for CAD. Another concern of particular importance is systolic hypertension in elderly patients, which places them at high risk for cardiovascular events. As the prevalence of hypertension in the geriatric population increases, interest is focusing on treatment in this patient group, a subject we will also address. How antihypertensive agents affect a patient's quality of life is another key issue in management, as is compliance. Our final discussion is of new guidelines for designing a drug regimen that preserves quality of life and enhances patient compliance.
Circadian rhythm of blood pressure In both normotensive individuals and hypertensive patients, blood pressure follows a circadian pattern1 (figure 1). Blood pressure plateaus during the daytime hours and then begins to fall, reaching a nadir betw'een 8 PM and midnight. In the early morning hours, it rises sharply until a plateau is again reached betw'een 6 AM and 10 AM. This rapid rise in blood pressure parallels a rise in plasma concentrations of norepinephrine and epinephrine and is thought to be due to an increase in sympathetic nervous system activity during the arousal process. 2 A significant number of cardiovascular events have been noted to occur in the early to midmorning hours. 3 The therapeutic implication is that to be most effective in preventing coronary events, antihypertensive agents should prevent excessive fluctuations in daily blood pressure, especially in the early morning hours. Beta blockers, including atenolol (Tenormin), do not appear to control blood pressure during this time. 45 In contrast, the calcium channel blockers sustain their actions throughout the early morning hours. In particular, sustained-release formulations of both nifedipine6 (Procardia XL)
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163
To be most effective in preventing
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coronary events, antihypertensive agents should prevent excessive fluctuations in daily blood pressure, especially in the early morning hours.
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Figure 1. Circadian pattern of blood pressure measured on two separate occasions, 2 to 6 weeks apart, in 56 normal volunteers. Data were obtained using an automated portable blood pressure monitor. BP, blood pressure. Adapted, with permission, from Weber MA, Smith OH, Neutel JM, et al. Cardiovascular and metabolic characteristics of hypertension. Am J Med 1991;91(1A):4-10S.
164
First 24-hour study
e
and verapamil hydrochloride- 9 (Calan SR, Isoptin SR, Verelan) have been shown to maintain constant blood pressure control over 24 hours. Some antiadrenergic agents are also effective in this regard. Doxazosin mesylate (Cardura) maintains good 24-hour control, 10 and a new transdermal patch that delivers clonidine (Catapres-TTS) maintains blood pressure control for at least a week. 11 -14 An added benefit with long-acting formulations is that peak plasma concentrations, which occur with oral shortacting forms, are avoided, resulting in a lower incidence of side effects.
Second 24-hour study
and lipid metabolism Although clinical trials of antihypertensive therapy have shown a major reduction in the incidence of stroke, reduction in the incidence of death from CAD in these trials has been disappointing.15 A review of randomized controlled trials 16 found overall reductions in the incidence of fatal and nonfatal stroke of 38% and 43%, respectively, whereas the reduction in the incidence of fatal CAD and nonfatal myocardial infarction was only 8%. Several explanations have been proposed to account for the lower-than-expected reduction in
HYPERTENSION • VOL 91/NO 6/MAY 1, 1992/POSTGRADUATE MEDICINE
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Most thiazide-type diuretics have an unfavorable effect on lipid levels that may be more pronounced in patients with resting ECG abnormalities.
mortality from CAD. Inadequate sample size and inadequate statistical power to detect any significant effect of treatment on the incidence of fatal CAD are among these. When data are pooled to increase sample size and power, however, the results still show an only modest reduction in mortality from CAD in patients treated with diuretics and beta blockers. Another possible explanation is that the length of time over which a given study was conducted may have been too short to detect long-term effects of treatment on CAD. More important, any use of antihypertensive drugs by controls may have diluted the results, making any beneficial effects in the treatment group less apparent. A final, frequently cited explanation is that the antihypertensive agents used in these studies, mostly thiazide diuretics and beta blockers, have adverse effects on lipid metabolism and thereby increase susceptibility to CAD. Following is a discussion of various antihypertensive agents in terms of their effects on lipids (table 1). DIURETics--Most thiazidetype diuretics have adverse effects on lipid metabolism. In the Multiple Risk Factor Intervention Trial (MRFIT), 17 cholesterol levels were lowered 50% less in pa-
Table 1. The effects of selected antihypertensive agents on serum lipid profile Agent
Class
Factor
General effect (specific range)
Thiaz1des""
DiuretiC
Total cholesterol Triglycerides LDL
i (+5% to +8%) i (+ 15% to +25%) i (+5% to +8%)
Propranolol" (lnderal)
Beta blockert
Triglycendes HDL
l
Prazosin 3 ' 32 .l·l
Alpha 1 blockers
Total cholesterol Tnglycerides LDL HDL TC/HDL
(+8% to -9%) (+4% to -20%) (+1% to -17%) i (-4% to +20%) l (-3% to -19%)
Captopril" -' ' (Capoten)
ACE inhibitor
Total cholesterol Triglycerides HDL
l(-1%to-17%) l (-1% to -26%) i (+ 10% to +28%)
Diltiazem" (Cardizem)
Calcium channel blocker:j:
Total cholesterol Triglycerides LDL HDL TC/HDL
No change No change No change i(+15%) l(-11%)
(Minipress), doxazosin'·' (Cardura)
i (+ 15% to +50%) (-10% to -15%)
l l l
ACE, angiotensin-converting enzyme; HOL, high-density lipoprotein cholesterol; LDL, low-density lipoprotein cholesterol; TC/HDL, ratio of total cholesterol to HDL cholesterol; i, increased; l, decreased. 'In two studies of patients taking indapamide· ·' (Lozol), no change in lipid levels was observed. tStudies have shown that labetalol (Normodyne, Trandate), acebutolol (Sectral), pindolol (Visken), and the cardioselective beta blockers atenolol (Tenormin) and metoprolol (Lopressor) do not affect lipid levels. 2530 :j:ln two studies of patients taking n1fedipine' < (Adalat, Procardia), no change in lipid levels was observed.
tients treated with both dietary modification and either hydrochlorothiazide or the thiaziderelated diuretic chlorthalidone than in those treated only with dietary modification. Subgroup analyses of data from the MRFIT study suggested that the effect of diuretic treatment is less unfavorable in pa-
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tients without resting electrocardiographic (ECG) abnormalities than in those with such abnormalities. The long-term analysis of MRFIT' 8 showed that in men with resting ECG abnormalities present at baseline, the mortality rate from CAD was 18% higher in the treatment group than in the control group. Although this continued
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Alpha 1 blockers have beneficial cholesterol-
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lowering effects.
finding suggests that patients with baseline ECG abnormalities are at increased risk for death from CAD, the results must be interpreted with caution, as they are based on only a small number of events and make no adjustment for the multiple statistical tests used in subgroup analyses. In the Veterans Administration Mild Hypertension Trial, 19 ·2" patients treated with chlorthalidone were found to have elevated serum levels of total cholesterol, low-density lipoprotein (LDL), and very-low-density lipoprotein. These results were confirmed by another study/ 1which showed that hydrochlorothiazide and chlorthalidone increased plasma levels of total cholesterol by 6% and 8% and triglycerides by 17% and 15%, respectively; in addition, chlorthalidone significantly increased LDL levels. However, indapamide (Lozol), unlike other diuretics in the thiazide family, has been reported to be lipid-neutral when used in low doses 22-24 and thus may be a good choice for hypertensive patients requiring diuretic therapy. BETI\ BLOCKERS--Adverse effects on the lipid profile also occur with beta blockers. Overall, studies show that propranolol hydrochloride (lnderal) increases triglyceride levels by 25% to 100% and decreases high-density
lipoprotein (HO L) cholesterol levels by 10% to 20%. 25 When added to thiazides, both cardiaselective and noncardioselective beta blockers increase total triglyceride levels, decrease HO L levels, and increase the ratio of total cholesterol to HDL. When used as monotherapy, nonselective beta blockers have similar effects on serum cholesterol levels whereas selective beta blockers (atenolol and metoprolol tartrate [Lopressor]) appear not to affect HDL levels. Pindolol (Visken), a beta blocker with intrinsic sympathomimetic activity, may not significantly affect total cholesterol, HDL, or triglyceride levels and may even have a beneficial effect on the lipid profile, but further studies are needed to confirm this. 26 ·27 Labetalol hydrochloride (Normodyne, Trandate), a combined alpha and beta blocker, has been reported in two studies2829 to be lipid-neutral and in one studylo to reduce total cholesterol levels without changing HDL levels. OTIIER AGENTS--In contrast to the thiazide diuretics and beta blockers, the selective alpha blockers prazosin hydrochloride (Minipress), trimazosin (investigational), and doxazosin have been shown to decrease total cholesterol and triglyceride levels and to increase HDL levels. 31 -34
The beneficial cholesterollowering effects of the alpha1 blockers may be an important consideration in the treatment of hypertensive patients with abnormal lipid profiles. The angiotensin-convening enzyme (ACE) inhibitors and calcium channel blockers are lipid-neutral. 35 -39 In one study, 40 long-term antihypertensive treatment with the ACE inhibitor captopril significantly reduced total cholesterol and triglyceride levels and increased HDL levels. Results of the International Nifedipine Trial on Antiatherosclerotic Therapy (INTACT) 41 further demonstrate that the calcium channel blocker nifedipine possesses antiatherosclerotic effects in patients with CAD. IMPUCATIONS FOR lREAT-
MENT-Although the magnitude oflipid changes caused by diuretics and beta blockers may be small, an increase in LDL level may negate the beneficial reduction in risk for CAD associated with blood-pressure lowering. Data from the Framingham Heart Study suggest that patients with high blood pressure also have high serum cholesterol levels, 42 which puts them at increased risk for CAD. The close link between heart disease and cholesterol levels has been further demonstrated in several studies
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If a hypertensive patient has hypercholesterolemia and needs diuretic therapy, indapamide is a good choice.
of lipid-lowering regimens, in which the incidence of CAD was found to decrease by 2% to 3% for every 1% decrease in serum cholesterollevel. 4.l.44 In the post-myocardial infarction patient, however, beta blockers have been shown to decrease mortality. In addition, several studies have shown that beta blockers limit infarct size by 10% to 30% when therapy is begun within 4 to 6 hours of the onset of symptoms.' 1 The primary mechanisms of this beneficial effect are thought to be a reduction in myocardial oxygen consumption and a redistribution of blood flow from collateral vessels to areas of myocardial ischemia. Mortality may also be reduced through a reduction in arrhythmias. A beta blocker with no adverse effects on lipids, such as metoprolol or atenolol, should be a first-line agent in postmyocardial infarction patients with hypertension. Concern about the effects of various antihypertensive regimens on lipid levels has prompted a reassessment of the steppedcare approach to management. The Treatment of Mild Hypertension Study (TOMHS) 46 is an ongoing trial designed to resolve some of these issues. Until the results are known, a patient's serum cholesterol status should be as-
sessed prior to the initiation of drug therapy. If the patient has hypercholesterolemia, thiazide diuretics and propranolol should be avoided as first-line agents. Instead, an agent with either a lipid-neutral or a lipid-favorable effect should be chosen. Such a decision can be best made with knowledge of the patient's complete lipid profile. If diuretic therapy is necessary, as in the case of congestive heart failure or venous pooling, indapamide is the agent of choice. Indapamide is still a reasonable choice for black or obese patients, in whom hypertension is more salt-dependent. Loop diuretics should only be used for patients with high blood pressure and associated renal insufficiency, especially those whose serum creatinine level is greater than 2.0 mg/dL. The cost of a newer antihypertensive drug relative to the cost of thiazides is often of considerable concern to physicians. After all, patient compliance is directly proportional to the cost of medication and the frequency of dosing. Totalhealthcare costs, however, may be the more important consideration when comparing the cost-effectiveness of various antihypertensive agents. The potential secondary costs of disease outcomes resulting from
thiazide-associated lipid abnormalities could have a significant impact on overall healthcare costs. Although cost is an important consideration in choosing an appropriate antihypertensive regimen, greater thought should be given to the needs of the individual patient. Specifically, the agent(s) chosen should have the ability to adequately control a patient's blood pressure but not adversely affect his or her risk factors for coronary disease. Antihypertensive agents and insulin resistance Many hypertensive patients have glucose intolerance and insulin resistance, predisposing them to the development of non-insulindependent (type II) diabetes mellitus. Increased insulin resistance caused by antihypertensive therapy may further augment their risk for diabetes. Moreover, high insulin levels are associated with elevated triglyceride levels, hypercholesterolemia, and low HDL levels, which are independent risk factors for the development of CAD. Several prospective studies have evaluated the effect of various antihypertensive agents on insulin resistance. In one study, 47 thiazide diuretics were found to significantly reduce insulin sensitivity (11 %) and the insulin-
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Treatment of
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hypertension with thiazide diuretics and beta blockers may increase a patient's risk for diabetes.
sensitivity index (16%). (The insulin-sensitivity index is calculated by dividing the rate of glucose disposal by the mean insulin concentration during the euglycemic-hyperinsulinemic clamp technique. 4-) Beta blockers have also been shown to increase insulin resistance. In a trial comparing the two cardioselective beta blockers metoprolol and atenolol, 4s both drugs significantly reduced insulin sensitivity (20% and 13%, respectively). The insulinsensitivity index was reduced by 27% with metoprolol and 23% with atenolol. In a crossover study comparing propranolol (a nonselective beta blocker) to pindolol (a nonselective beta blocker with intrinsic sympathetic activity), a 30% reduction in the insulinsensitivity index was noted in the propranolol-treated group, compared with only a 17% reduction in the group receiving pindolol. 49 In contrast to the thiazide diuretics and beta blockers, the ACE inhibitor captopril (Capoten) and the alpha 1 blocker prazosin have been shown to have a positive effect on insulin resistance. In one study, 50 captopril was reported to significantly increase both insulin sensitivity (11 o/o) and the insulin-sensitivity index (18%). In another study, 51
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treatment of moderately obese hypertensive patients with prazosin significantly improved glucose uptake (14%) and the insulin-sensitivity index (33%). Preliminary data from an unpublished study of patients taking doxazosin suggest that its effect on insulin sensitivity is greater in patients with low insulin sensitivity than in those with high sensitivity. 49 The effect of calcium channel blockers on insulin sensitivity remains unclear, and the different types of calcium channel blockers may have different effects in this regard. In one study, 52 no significant alterations in insulin sensitivity were reported in patients taking diltiazem hydrochloride. Although the effects of various antihypertensive agents on glucose metabolism are not yet well defined, available data suggest that treatment of hypertension with thiazide diuretics and beta blockers may increase a patient's risk for diabetes. Until further studies are done with other pharmacologic agents, recommendations concerning this issue are difficult to make. For the treatment of a hypertensive patient who also has diabetes, however, the clinician may want to choose an agent known to enhance insulin sensitivity, such as an ACE inhibitor or alpha 1 blocker.
The effects of various antihypertensive agents on insulin resistance are summarized in table 2. Antihypertensive agents
andLVH The close relationship between hypertension and LVH has been demonstrated in several studies.5314 Of major concern is that the presence ofLVH is associated with a poor cardiovascular prognosis. 55 Data from the Framingham Heart Study clearly indicate that patients with LVH have a higher risk of sudden death, acute myocardial infarction, and cardiovascular morbidity. 56 One of the major contributory risk factors is an increased incidence of ventricular arrhythmias. Regression ofLVH by antihypertensive therapy could potentially reduce this risk. Several clinical studies have shown that LVH is reversible with certain antihypertensive drugs. In one study, 57 significant decreases in both left ventricular mass index and prevalence of premature ventricular contractions were noted in patients treated with calcium channel blockers but not in those treated with hydrochlorothiazide. The treatment ofLVH with antihypertensive therapy should take into account the mechanisms thought to contribute to
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In a patient with mild to moderate hypertension, sympathetic drive may cause left ventricular hypertrophy that can be relieved by a sympatholytic agent.
LVH. A close correlation exists between elevated systolic blood pressure and the development of LVH, most likely secondary to an increase in cardiac wall stress. The sympathetic nervous system and the renin-angiotensinaldosterone system also play major roles in the development ofLVH. The current thought is that antihypenensive agents that inhibit these mechanisms could produce regression of LVH. Therapy should thus be aimed ar the specific mechanism causing the hypenrophy. 58 For patients with severe hypenension, high blood pressure is the predominant force causing hypenrophic changes, and any agent having antihypenensive effects should produce LVH regression. In a patient with mild to moderate hypenension, sympathetic drive may be the dominant factor causing the hypenrophy, so a sympatholytic agent may be necessary to reduce left ventricular size. Studies in hypenensive patients59.60 have shown that the ACE inhibitors captopril and enalapril maleate (Vasotec) effectively cause regression ofLVH. These agents not only have an inhibitory effect on the reninangiotensin-aldosterone system but also secondarily inhibit the
T~ble 2 The effect of selecled .mt1hypertens1ve ~gents on u1suhn ;mcl qlucose metilbohsm. as measured by the •nsuhn-scns•l•v•ty 1ndcx·
Agentt
Dosage studied
Effect on ISI
2.5mgqd 25mg qd
No change .1.16%
200mg qd 50mgqd
.1.27% .1.23%
160 mg qd 10mgqd
.1.30% .1.17%
ACE Inhibitor Captopril"' (Capoten)
50-100 mg qd
i18%
Alphe1 blocker Prazosin'' (Minipress)
Smgqd
i33%
C8lclum chennel blocker Diltiazem" (Cardizem)
330 mg qd
No change
Dknttc8 lndapamide" (Lozol) Hydrochlorothiazide" (various)
Beta blockera Selective" Metoprolol (loplessor) Alenolol (Tenormin) Nonselective" Propranolol (lnderal) Pindolol (VtSken)
ACE. angiotensin-converting enzyme; ISI, insulin-sensitivity index; J., decreased; i, increased. 'Calculated by dividing rate of glucose disposal by mean insulin concentration during euglycemic-hyperinsulinemic clamp technique for measuring insulin sensitMty." tNo data available on effects of other groups, such as sympatholytics.
sympathetic nervous system. Both peripherally and centrally acting sympatholytic agents produce marked reductions in left ventricular mass. Clonidine hydrochloride61 (Catapres) and methyldopa62 (Aldomet) have been shown to be panicularly effective in this regard. Calcium channel blockers63 also effectively reduce left ventricular mass. In contrast, results of studies with beta blockers and diuretics have been inconsistent. Two
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studies of the effects of beta blockers in patients with LVH have shown a reduction in left ventricular mass64 '65 and two studies have shown no regression in mass. 60.66 In one study of patients with mild to moderate hypenension,67 treatment with hydrochlorothiazide resulted in no change in left ventricular muscle mass; LVH regression was observed, however, in another study conducted in patients with more severe hypenension. 68 Diuretics continued
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Isolated systolic hypertension is increasingly prevalent in older people, and puts them at increased risk for stroke.
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Table 3. The effect of vanous antohypertens1ve agents on left ventncular hypertrophy
Agent
Effect on LVH
Mechanism of action*
ACE inhibitors..,
.J.
Primary: Inhibit RAAS Secondary: Inhibit SNS
Sympatholyt1cs"'• Peripherally acting
.J. Decrease blooc pressure, decrease vascular resistance
Centrally acting
Decrease sympathetic outflow from CNS, also inhibit RAAS
Calcium channel blockers"•
.J.
Cause vasodilation
Beta blockerg001440
.1.-t
Decrease blooc pressure, decrease cardiac work, inhibit RAAS
Diuretics"'•
.1.-t
Inadvertently stimulate SNS and RAAS, increasing blood viscosity
Direct -acting vasodilators"
-t
Stimulate SNS and RAAS, work against LVH regression
ACE, angiotensin-converting enzyme; CNS, central nervous system; LVH, left ventricular hypertrophy; RAAS, renin-angiotensin-aldosterone system; SNS, sympathetic nervous system; .!., regression of LVH; .J. ->,results of studies have been inconsistent, some showing LVH regression, others reporting no change;->, no regression of LVH. "Mechanism by which agent produces regression of LVH, as measured by decrease in thickness of septum and posterior wall and decrease in left ventricular muscle mass.
stimulate both the sympathetic nervous system and the reninangiotensin-aldosterone system and may inadvertently worsen LVH, although this effect may be reversed by the addition of a sympatholytic drug. 69 '70 Direct-acting vasodilators such as hydralazine hydrochloride (Apresoline) and minoxidil (Loniten) have not been effective in producing LVH regression. 71 The effects of various antihyper-
tensive agents on LVH are summarized in table 3.
Systolic hypertension in the elderly Isolated systolic hypertension is increasingly prevalent in people 60 years of age and older, and epidemiologic studies72. 78 have shown that systolic blood pressure greater than 160 mm Hg is a major risk factor for stroke. Most of what we know about the treat-
ment of hypertension comes from studies focusing on elevated diastolic blood pressure. However, despite the paucity of data, two recent studies have shed some much-needed light on how to treat isolated systolic hypertension in the elderly population. The European Working Party on High Blood Pressure in the Elderly (EWPHE) study9 was a double-blind, placebo-controlled trial designed to assess the efficacy of antihypertensive therapy in patients over the age of 60. Eight hundred forty patients with elevated diastolic and systolic blood pressure were randomized either to a group receiving treatment with hydrochlorothiazide plus triamterene or to a placebo group. Methyldopa was added as a second drug in this trial when blood pressure remained elevated with diuretic therapy alone. A significant reduction in total cardiovascular mortality rate (38%, P= .023) was observed in the treated patients, due mostly to a reduction in the number of cardiac deaths (47%, P= .048) and a nonsignificant decrease in the rate of cerebrovascular death (43%, P= .15). The risk of nonfatal stroke was also significantly reduced (52%), although the risk of fatal stroke did not change. The Systolic Hypertension in
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Peripheral alpha blockers, although effective for treating hypertension, should be used with caution in elderly patients, who are more prone to orthostatic hypotension.
the Elderly Program (SHEP) 80 was designed to assess whether or not treatment of isolated systolic hypertension in elderly patients would reduce the incidence of both nonfatal and fatal stroke. For the SHEP study, isolated systolic hypertension was defined as systolic pressure greater than 160 mm Hg with diastolic pressure less than 90 mm Hg, when four readings taken during two patient visits were averaged. In the study, 4, 736 patients aged 60 years and above with isolated systolic hypertension were randomized either to a group treated with chlorthalidone (12.5 mg daily) or to a placebo group. Mter a 5-year follow-up period, the incidence of fatal and nonfatal stroke in the treatment group was significantly reduced (36%). Of interest is that the treatment benefit was apparent in all age-groups, including patients who were 80 years of age or older, a group not shown previously to benefit from hypertension treatment. Cardiovascular morbidity and coronary morbidity and mortality (secondary end points of the study) were also significantly reduced. Cardiovascular mortality and overall mortality (the remaining secondary end points) were not significantly affected, however. Two major differences in treat-
ment outcomes can be noted between the two trials and are most likely due to differences in study methodologies. The first is that treatment benefit in patients 80 years of age or older was observed in the SHEP study but not in the EWPHE study. This is probably because a greater number of subjects 80 years of age and older were included in the SHEP study (649, versus 155 in the EWPHE study). The second difference is that the reduction in total cardiovascular mortality observed in the EWPHE study was significant, whereas that in the SHEP study was not. The statistical power used in the study design of the SHEP protocol may not have been large enough to detect a difference in this end point. Other factors such as adverse metabolic effects of thiazide diuretics or a reduction of diastolic blood pressure below a patient's baseline reading may also account for this discrepancy. Despite the differences between the two studies in treatment outcomes, results have conclusively established that treatment of isolated systolic hypertension in elderly patients is beneficial. Is a thiazide-type diuretic such as chlorthalidone (Hygroton) the drug of choice for the treatment of isolated systolic hypertension
in elderly patients? Results of both the EWPHE trial and the SHEP study suggest that the answer to this question is yes, although a definitive answer will not be known until studies are conducted with newer antihypertensive agents. Unless an elderly patient has renal insufficiency or diabetes mellitus, a thiazide diuretic is preferable to a loop diuretic, because thiazides allow once-a-day dosing. Use of a thiazide-triamterene combination can minimize hypokalemia. Indapamide may also be a reasonable choice because of its benign metabolic effects. If it becomes necessary to add a second agent or use an alternative drug, good results have been obtained with various adrenergic blockers. Although we do not recommend combination therapy, a low-dose combination of 15 mg of chlorthalidone plus 0.1 mg of the central alpha agonist clonidine in a single daily dose has been reported to lower systolic blood pressure by at least 20 mm Hg in elderly patients. 81 Peripheral alpha blockers, although effective, should be used with caution in elderly patients, because this group is more prone to orthostatic hypotension. 52 Because LVH is prevalent in the elderly population, therapy with a sympatholytic, ACE inhibitor, or
continued
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The impact that treatment will have on a patient's quality of life must be considered in designing a treatment regimen.
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Table 4. Antihypertensive agents that require only once- or twice-a-day dosing Agent
Starting dosage
Side effects
Beta blockers Atenolol (Tenormin)
50 mg qd
Bronchospasm, fatigue, insomnia, depression, sexual dysfunction
Metoprolol (Lopressor)
100 mg qd or 50 mg bid
Similar to atenolol
Acebutolol (Sectral)
400 mg qd or 200 mg bid
Similar to atenolol, plus lupus (rare)
Labetalol (Trandate, Normodyne)
100mg bid
Orthostatic hypotension, fever, hepatotoxicity
Thiazide-type diuretics lndapamide (Lozol)
2.5 mg qd
Hyperuricemia, hypokalemia, hyponatremia, fatigue, sexual dysfunction
Hydrochlorothiazide (various)
12.5-50 mg qd
Hydrochlorothiazide (25 mg) plus triamterene (37.5-50 mg) (Dyazide, Maxzide)
1-2 tablets qd
Calcium channel blockers Sustained-release nifedipine (Procardia XL)
Sustained-release verapamil (Calan SR, lsoptin SR, Verelan)
}
Similar to indapamide, plus adverse effects on lipids
30 or 60 mg qd
Dizziness/flushing, headache, pedal edema, tachycardia
120-240 mg qd
Constipation, CHF, hypotension, AV block, bradycardia, edema, headache Similar to verapamil, but less likely to cause constipation
Sustained-release diltiazem Twice-a-day dosing (Cardizem SR) Once-a-day dosing (Cardizem CD)
60-120 mg bid 180mg qd
lsradipine (DynaCirc)
2.5 mg bid
Similar to nifedipine
ACE, angiotensin-converting enzyme; AV, atrioventricular; CHF, congestive heart failure.
calcium channel blocker should be considered, since all of these may produce regression ofLVH in addition to lowering blood pressure.
Designing a treatment regimen The impact that treatment will have on a patient's quality of life must be considered in designing a
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treatment regimen. Patient compliance is also an imponant consideration. Table 4lists antihypertensive drugs that only need to be taken once or twice a day, along with their starring dosage and most common side effects. Table 5 provides a summary of the advantages and disadvantages of various antihypenensive agents.
QUAUIY OF UFE-The treatment of hypenension can cenainly affect a patient's quality of life. The way a patient's lifestyle is affected by the illness is an imponant consideration. Antihypertensive agents have adverse effects, most prominently depression, sexual dysfunction, fatigue, and impairment of cognitive
HYNRTBNIIION • VOL 91/NO 6/MAY 1, 1992/POSTGRAOUATE MEDICINE
Table 4. Continued
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Agent
Starting dosage
Side effects
Captopril (Capoten)
25 mg bid
Cough. rash, angioedema, hyper\
ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: http://www.tandfonline.com/loi/ipgm20
Antihypertensive therapy Karen J. Harper MS, PharmD & Alan D. Forker MD To cite this article: Karen J. Harper MS, PharmD & Alan D. Forker MD (1992) Antihypertensive therapy, Postgraduate Medicine, 91:6, 163-193, DOI: 10.1080/00325481.1992.11701321 To link to this article: http://dx.doi.org/10.1080/00325481.1992.11701321
Published online: 17 May 2016.
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~~CME credit article
Antihypertensive therapy Current issues and challenges
KarenJ. Harper, MS, PharmD Alan D. Forker, MD
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Preview How do antihypertensive agents affect overall cardiovascular health? Which ones affect lipid levels? Insulin sensitivity? Left ventricular hypertrophy? What is the agent of choice for treating systolic hypertension in elderly patients? The authors address these and other questions in this update on pharmacologic management of hypertension.
The treatment of hypertension remains a challenge for physicians-perhaps the ultimate challenge. Systemic hypertension is no longer regarded as simply a state of elevated blood pressure but rather as a syndrome of multiple abnormalities. This syndrome is characterized by (1) a link betw'een the circadian rhythm of blood pressure and the occurrence and timing of cardiovascular events, (2) lipid abnormalities, (3) insulin resistance and glucose intolerance, and (4) left ventricular hypertrophy (LVH). To meet the challenge of treating hypertension, the clinician must select drug therapy that treats all these aspects of the syndrome in addition to effectively lowering blood pressure, as will be discussed. One management issue is how antihypertensive therapy affects cardiovascular disease. Studies have shown that lowering blood pressure reduces the incidence of stroke by about 40% bur reduces the incidence of death secondary
to coronary artery disease (CAD) by only a small amount. This is of major concern, both because coronary events (particularly sudden death) are the major cause of death in patients with hypertension and because the use of thiazide diuretics (which have been the traditional cornerstone of drug therapy for hypertension) may actually place the patient at increased risk for CAD. Another concern of particular importance is systolic hypertension in elderly patients, which places them at high risk for cardiovascular events. As the prevalence of hypertension in the geriatric population increases, interest is focusing on treatment in this patient group, a subject we will also address. How antihypertensive agents affect a patient's quality of life is another key issue in management, as is compliance. Our final discussion is of new guidelines for designing a drug regimen that preserves quality of life and enhances patient compliance.
Circadian rhythm of blood pressure In both normotensive individuals and hypertensive patients, blood pressure follows a circadian pattern1 (figure 1). Blood pressure plateaus during the daytime hours and then begins to fall, reaching a nadir betw'een 8 PM and midnight. In the early morning hours, it rises sharply until a plateau is again reached betw'een 6 AM and 10 AM. This rapid rise in blood pressure parallels a rise in plasma concentrations of norepinephrine and epinephrine and is thought to be due to an increase in sympathetic nervous system activity during the arousal process. 2 A significant number of cardiovascular events have been noted to occur in the early to midmorning hours. 3 The therapeutic implication is that to be most effective in preventing coronary events, antihypertensive agents should prevent excessive fluctuations in daily blood pressure, especially in the early morning hours. Beta blockers, including atenolol (Tenormin), do not appear to control blood pressure during this time. 45 In contrast, the calcium channel blockers sustain their actions throughout the early morning hours. In particular, sustained-release formulations of both nifedipine6 (Procardia XL)
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163
To be most effective in preventing
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coronary events, antihypertensive agents should prevent excessive fluctuations in daily blood pressure, especially in the early morning hours.
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Figure 1. Circadian pattern of blood pressure measured on two separate occasions, 2 to 6 weeks apart, in 56 normal volunteers. Data were obtained using an automated portable blood pressure monitor. BP, blood pressure. Adapted, with permission, from Weber MA, Smith OH, Neutel JM, et al. Cardiovascular and metabolic characteristics of hypertension. Am J Med 1991;91(1A):4-10S.
164
First 24-hour study
e
and verapamil hydrochloride- 9 (Calan SR, Isoptin SR, Verelan) have been shown to maintain constant blood pressure control over 24 hours. Some antiadrenergic agents are also effective in this regard. Doxazosin mesylate (Cardura) maintains good 24-hour control, 10 and a new transdermal patch that delivers clonidine (Catapres-TTS) maintains blood pressure control for at least a week. 11 -14 An added benefit with long-acting formulations is that peak plasma concentrations, which occur with oral shortacting forms, are avoided, resulting in a lower incidence of side effects.
Second 24-hour study
and lipid metabolism Although clinical trials of antihypertensive therapy have shown a major reduction in the incidence of stroke, reduction in the incidence of death from CAD in these trials has been disappointing.15 A review of randomized controlled trials 16 found overall reductions in the incidence of fatal and nonfatal stroke of 38% and 43%, respectively, whereas the reduction in the incidence of fatal CAD and nonfatal myocardial infarction was only 8%. Several explanations have been proposed to account for the lower-than-expected reduction in
HYPERTENSION • VOL 91/NO 6/MAY 1, 1992/POSTGRADUATE MEDICINE
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Most thiazide-type diuretics have an unfavorable effect on lipid levels that may be more pronounced in patients with resting ECG abnormalities.
mortality from CAD. Inadequate sample size and inadequate statistical power to detect any significant effect of treatment on the incidence of fatal CAD are among these. When data are pooled to increase sample size and power, however, the results still show an only modest reduction in mortality from CAD in patients treated with diuretics and beta blockers. Another possible explanation is that the length of time over which a given study was conducted may have been too short to detect long-term effects of treatment on CAD. More important, any use of antihypertensive drugs by controls may have diluted the results, making any beneficial effects in the treatment group less apparent. A final, frequently cited explanation is that the antihypertensive agents used in these studies, mostly thiazide diuretics and beta blockers, have adverse effects on lipid metabolism and thereby increase susceptibility to CAD. Following is a discussion of various antihypertensive agents in terms of their effects on lipids (table 1). DIURETics--Most thiazidetype diuretics have adverse effects on lipid metabolism. In the Multiple Risk Factor Intervention Trial (MRFIT), 17 cholesterol levels were lowered 50% less in pa-
Table 1. The effects of selected antihypertensive agents on serum lipid profile Agent
Class
Factor
General effect (specific range)
Thiaz1des""
DiuretiC
Total cholesterol Triglycerides LDL
i (+5% to +8%) i (+ 15% to +25%) i (+5% to +8%)
Propranolol" (lnderal)
Beta blockert
Triglycendes HDL
l
Prazosin 3 ' 32 .l·l
Alpha 1 blockers
Total cholesterol Tnglycerides LDL HDL TC/HDL
(+8% to -9%) (+4% to -20%) (+1% to -17%) i (-4% to +20%) l (-3% to -19%)
Captopril" -' ' (Capoten)
ACE inhibitor
Total cholesterol Triglycerides HDL
l(-1%to-17%) l (-1% to -26%) i (+ 10% to +28%)
Diltiazem" (Cardizem)
Calcium channel blocker:j:
Total cholesterol Triglycerides LDL HDL TC/HDL
No change No change No change i(+15%) l(-11%)
(Minipress), doxazosin'·' (Cardura)
i (+ 15% to +50%) (-10% to -15%)
l l l
ACE, angiotensin-converting enzyme; HOL, high-density lipoprotein cholesterol; LDL, low-density lipoprotein cholesterol; TC/HDL, ratio of total cholesterol to HDL cholesterol; i, increased; l, decreased. 'In two studies of patients taking indapamide· ·' (Lozol), no change in lipid levels was observed. tStudies have shown that labetalol (Normodyne, Trandate), acebutolol (Sectral), pindolol (Visken), and the cardioselective beta blockers atenolol (Tenormin) and metoprolol (Lopressor) do not affect lipid levels. 2530 :j:ln two studies of patients taking n1fedipine' < (Adalat, Procardia), no change in lipid levels was observed.
tients treated with both dietary modification and either hydrochlorothiazide or the thiaziderelated diuretic chlorthalidone than in those treated only with dietary modification. Subgroup analyses of data from the MRFIT study suggested that the effect of diuretic treatment is less unfavorable in pa-
VOL 91/NO 6/MAY 1, 1992/POSTGRADUATE MEDICINE • HYPERTENSION
tients without resting electrocardiographic (ECG) abnormalities than in those with such abnormalities. The long-term analysis of MRFIT' 8 showed that in men with resting ECG abnormalities present at baseline, the mortality rate from CAD was 18% higher in the treatment group than in the control group. Although this continued
165
Alpha 1 blockers have beneficial cholesterol-
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lowering effects.
finding suggests that patients with baseline ECG abnormalities are at increased risk for death from CAD, the results must be interpreted with caution, as they are based on only a small number of events and make no adjustment for the multiple statistical tests used in subgroup analyses. In the Veterans Administration Mild Hypertension Trial, 19 ·2" patients treated with chlorthalidone were found to have elevated serum levels of total cholesterol, low-density lipoprotein (LDL), and very-low-density lipoprotein. These results were confirmed by another study/ 1which showed that hydrochlorothiazide and chlorthalidone increased plasma levels of total cholesterol by 6% and 8% and triglycerides by 17% and 15%, respectively; in addition, chlorthalidone significantly increased LDL levels. However, indapamide (Lozol), unlike other diuretics in the thiazide family, has been reported to be lipid-neutral when used in low doses 22-24 and thus may be a good choice for hypertensive patients requiring diuretic therapy. BETI\ BLOCKERS--Adverse effects on the lipid profile also occur with beta blockers. Overall, studies show that propranolol hydrochloride (lnderal) increases triglyceride levels by 25% to 100% and decreases high-density
lipoprotein (HO L) cholesterol levels by 10% to 20%. 25 When added to thiazides, both cardiaselective and noncardioselective beta blockers increase total triglyceride levels, decrease HO L levels, and increase the ratio of total cholesterol to HDL. When used as monotherapy, nonselective beta blockers have similar effects on serum cholesterol levels whereas selective beta blockers (atenolol and metoprolol tartrate [Lopressor]) appear not to affect HDL levels. Pindolol (Visken), a beta blocker with intrinsic sympathomimetic activity, may not significantly affect total cholesterol, HDL, or triglyceride levels and may even have a beneficial effect on the lipid profile, but further studies are needed to confirm this. 26 ·27 Labetalol hydrochloride (Normodyne, Trandate), a combined alpha and beta blocker, has been reported in two studies2829 to be lipid-neutral and in one studylo to reduce total cholesterol levels without changing HDL levels. OTIIER AGENTS--In contrast to the thiazide diuretics and beta blockers, the selective alpha blockers prazosin hydrochloride (Minipress), trimazosin (investigational), and doxazosin have been shown to decrease total cholesterol and triglyceride levels and to increase HDL levels. 31 -34
The beneficial cholesterollowering effects of the alpha1 blockers may be an important consideration in the treatment of hypertensive patients with abnormal lipid profiles. The angiotensin-convening enzyme (ACE) inhibitors and calcium channel blockers are lipid-neutral. 35 -39 In one study, 40 long-term antihypertensive treatment with the ACE inhibitor captopril significantly reduced total cholesterol and triglyceride levels and increased HDL levels. Results of the International Nifedipine Trial on Antiatherosclerotic Therapy (INTACT) 41 further demonstrate that the calcium channel blocker nifedipine possesses antiatherosclerotic effects in patients with CAD. IMPUCATIONS FOR lREAT-
MENT-Although the magnitude oflipid changes caused by diuretics and beta blockers may be small, an increase in LDL level may negate the beneficial reduction in risk for CAD associated with blood-pressure lowering. Data from the Framingham Heart Study suggest that patients with high blood pressure also have high serum cholesterol levels, 42 which puts them at increased risk for CAD. The close link between heart disease and cholesterol levels has been further demonstrated in several studies
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If a hypertensive patient has hypercholesterolemia and needs diuretic therapy, indapamide is a good choice.
of lipid-lowering regimens, in which the incidence of CAD was found to decrease by 2% to 3% for every 1% decrease in serum cholesterollevel. 4.l.44 In the post-myocardial infarction patient, however, beta blockers have been shown to decrease mortality. In addition, several studies have shown that beta blockers limit infarct size by 10% to 30% when therapy is begun within 4 to 6 hours of the onset of symptoms.' 1 The primary mechanisms of this beneficial effect are thought to be a reduction in myocardial oxygen consumption and a redistribution of blood flow from collateral vessels to areas of myocardial ischemia. Mortality may also be reduced through a reduction in arrhythmias. A beta blocker with no adverse effects on lipids, such as metoprolol or atenolol, should be a first-line agent in postmyocardial infarction patients with hypertension. Concern about the effects of various antihypertensive regimens on lipid levels has prompted a reassessment of the steppedcare approach to management. The Treatment of Mild Hypertension Study (TOMHS) 46 is an ongoing trial designed to resolve some of these issues. Until the results are known, a patient's serum cholesterol status should be as-
sessed prior to the initiation of drug therapy. If the patient has hypercholesterolemia, thiazide diuretics and propranolol should be avoided as first-line agents. Instead, an agent with either a lipid-neutral or a lipid-favorable effect should be chosen. Such a decision can be best made with knowledge of the patient's complete lipid profile. If diuretic therapy is necessary, as in the case of congestive heart failure or venous pooling, indapamide is the agent of choice. Indapamide is still a reasonable choice for black or obese patients, in whom hypertension is more salt-dependent. Loop diuretics should only be used for patients with high blood pressure and associated renal insufficiency, especially those whose serum creatinine level is greater than 2.0 mg/dL. The cost of a newer antihypertensive drug relative to the cost of thiazides is often of considerable concern to physicians. After all, patient compliance is directly proportional to the cost of medication and the frequency of dosing. Totalhealthcare costs, however, may be the more important consideration when comparing the cost-effectiveness of various antihypertensive agents. The potential secondary costs of disease outcomes resulting from
thiazide-associated lipid abnormalities could have a significant impact on overall healthcare costs. Although cost is an important consideration in choosing an appropriate antihypertensive regimen, greater thought should be given to the needs of the individual patient. Specifically, the agent(s) chosen should have the ability to adequately control a patient's blood pressure but not adversely affect his or her risk factors for coronary disease. Antihypertensive agents and insulin resistance Many hypertensive patients have glucose intolerance and insulin resistance, predisposing them to the development of non-insulindependent (type II) diabetes mellitus. Increased insulin resistance caused by antihypertensive therapy may further augment their risk for diabetes. Moreover, high insulin levels are associated with elevated triglyceride levels, hypercholesterolemia, and low HDL levels, which are independent risk factors for the development of CAD. Several prospective studies have evaluated the effect of various antihypertensive agents on insulin resistance. In one study, 47 thiazide diuretics were found to significantly reduce insulin sensitivity (11 %) and the insulin-
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Treatment of
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hypertension with thiazide diuretics and beta blockers may increase a patient's risk for diabetes.
sensitivity index (16%). (The insulin-sensitivity index is calculated by dividing the rate of glucose disposal by the mean insulin concentration during the euglycemic-hyperinsulinemic clamp technique. 4-) Beta blockers have also been shown to increase insulin resistance. In a trial comparing the two cardioselective beta blockers metoprolol and atenolol, 4s both drugs significantly reduced insulin sensitivity (20% and 13%, respectively). The insulinsensitivity index was reduced by 27% with metoprolol and 23% with atenolol. In a crossover study comparing propranolol (a nonselective beta blocker) to pindolol (a nonselective beta blocker with intrinsic sympathetic activity), a 30% reduction in the insulinsensitivity index was noted in the propranolol-treated group, compared with only a 17% reduction in the group receiving pindolol. 49 In contrast to the thiazide diuretics and beta blockers, the ACE inhibitor captopril (Capoten) and the alpha 1 blocker prazosin have been shown to have a positive effect on insulin resistance. In one study, 50 captopril was reported to significantly increase both insulin sensitivity (11 o/o) and the insulin-sensitivity index (18%). In another study, 51
172
treatment of moderately obese hypertensive patients with prazosin significantly improved glucose uptake (14%) and the insulin-sensitivity index (33%). Preliminary data from an unpublished study of patients taking doxazosin suggest that its effect on insulin sensitivity is greater in patients with low insulin sensitivity than in those with high sensitivity. 49 The effect of calcium channel blockers on insulin sensitivity remains unclear, and the different types of calcium channel blockers may have different effects in this regard. In one study, 52 no significant alterations in insulin sensitivity were reported in patients taking diltiazem hydrochloride. Although the effects of various antihypertensive agents on glucose metabolism are not yet well defined, available data suggest that treatment of hypertension with thiazide diuretics and beta blockers may increase a patient's risk for diabetes. Until further studies are done with other pharmacologic agents, recommendations concerning this issue are difficult to make. For the treatment of a hypertensive patient who also has diabetes, however, the clinician may want to choose an agent known to enhance insulin sensitivity, such as an ACE inhibitor or alpha 1 blocker.
The effects of various antihypertensive agents on insulin resistance are summarized in table 2. Antihypertensive agents
andLVH The close relationship between hypertension and LVH has been demonstrated in several studies.5314 Of major concern is that the presence ofLVH is associated with a poor cardiovascular prognosis. 55 Data from the Framingham Heart Study clearly indicate that patients with LVH have a higher risk of sudden death, acute myocardial infarction, and cardiovascular morbidity. 56 One of the major contributory risk factors is an increased incidence of ventricular arrhythmias. Regression ofLVH by antihypertensive therapy could potentially reduce this risk. Several clinical studies have shown that LVH is reversible with certain antihypertensive drugs. In one study, 57 significant decreases in both left ventricular mass index and prevalence of premature ventricular contractions were noted in patients treated with calcium channel blockers but not in those treated with hydrochlorothiazide. The treatment ofLVH with antihypertensive therapy should take into account the mechanisms thought to contribute to
HYPERTENSION • VOL 91/NO 6/MAY 1, 1992/POSTGRADUATE MEDICINE
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In a patient with mild to moderate hypertension, sympathetic drive may cause left ventricular hypertrophy that can be relieved by a sympatholytic agent.
LVH. A close correlation exists between elevated systolic blood pressure and the development of LVH, most likely secondary to an increase in cardiac wall stress. The sympathetic nervous system and the renin-angiotensinaldosterone system also play major roles in the development ofLVH. The current thought is that antihypenensive agents that inhibit these mechanisms could produce regression of LVH. Therapy should thus be aimed ar the specific mechanism causing the hypenrophy. 58 For patients with severe hypenension, high blood pressure is the predominant force causing hypenrophic changes, and any agent having antihypenensive effects should produce LVH regression. In a patient with mild to moderate hypenension, sympathetic drive may be the dominant factor causing the hypenrophy, so a sympatholytic agent may be necessary to reduce left ventricular size. Studies in hypenensive patients59.60 have shown that the ACE inhibitors captopril and enalapril maleate (Vasotec) effectively cause regression ofLVH. These agents not only have an inhibitory effect on the reninangiotensin-aldosterone system but also secondarily inhibit the
T~ble 2 The effect of selecled .mt1hypertens1ve ~gents on u1suhn ;mcl qlucose metilbohsm. as measured by the •nsuhn-scns•l•v•ty 1ndcx·
Agentt
Dosage studied
Effect on ISI
2.5mgqd 25mg qd
No change .1.16%
200mg qd 50mgqd
.1.27% .1.23%
160 mg qd 10mgqd
.1.30% .1.17%
ACE Inhibitor Captopril"' (Capoten)
50-100 mg qd
i18%
Alphe1 blocker Prazosin'' (Minipress)
Smgqd
i33%
C8lclum chennel blocker Diltiazem" (Cardizem)
330 mg qd
No change
Dknttc8 lndapamide" (Lozol) Hydrochlorothiazide" (various)
Beta blockera Selective" Metoprolol (loplessor) Alenolol (Tenormin) Nonselective" Propranolol (lnderal) Pindolol (VtSken)
ACE. angiotensin-converting enzyme; ISI, insulin-sensitivity index; J., decreased; i, increased. 'Calculated by dividing rate of glucose disposal by mean insulin concentration during euglycemic-hyperinsulinemic clamp technique for measuring insulin sensitMty." tNo data available on effects of other groups, such as sympatholytics.
sympathetic nervous system. Both peripherally and centrally acting sympatholytic agents produce marked reductions in left ventricular mass. Clonidine hydrochloride61 (Catapres) and methyldopa62 (Aldomet) have been shown to be panicularly effective in this regard. Calcium channel blockers63 also effectively reduce left ventricular mass. In contrast, results of studies with beta blockers and diuretics have been inconsistent. Two
VOL 91/NO 6/MAY 1. 1992/POSTGRADUATE MEDICINE • HYPE~NSION
studies of the effects of beta blockers in patients with LVH have shown a reduction in left ventricular mass64 '65 and two studies have shown no regression in mass. 60.66 In one study of patients with mild to moderate hypenension,67 treatment with hydrochlorothiazide resulted in no change in left ventricular muscle mass; LVH regression was observed, however, in another study conducted in patients with more severe hypenension. 68 Diuretics continued
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Isolated systolic hypertension is increasingly prevalent in older people, and puts them at increased risk for stroke.
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Table 3. The effect of vanous antohypertens1ve agents on left ventncular hypertrophy
Agent
Effect on LVH
Mechanism of action*
ACE inhibitors..,
.J.
Primary: Inhibit RAAS Secondary: Inhibit SNS
Sympatholyt1cs"'• Peripherally acting
.J. Decrease blooc pressure, decrease vascular resistance
Centrally acting
Decrease sympathetic outflow from CNS, also inhibit RAAS
Calcium channel blockers"•
.J.
Cause vasodilation
Beta blockerg001440
.1.-t
Decrease blooc pressure, decrease cardiac work, inhibit RAAS
Diuretics"'•
.1.-t
Inadvertently stimulate SNS and RAAS, increasing blood viscosity
Direct -acting vasodilators"
-t
Stimulate SNS and RAAS, work against LVH regression
ACE, angiotensin-converting enzyme; CNS, central nervous system; LVH, left ventricular hypertrophy; RAAS, renin-angiotensin-aldosterone system; SNS, sympathetic nervous system; .!., regression of LVH; .J. ->,results of studies have been inconsistent, some showing LVH regression, others reporting no change;->, no regression of LVH. "Mechanism by which agent produces regression of LVH, as measured by decrease in thickness of septum and posterior wall and decrease in left ventricular muscle mass.
stimulate both the sympathetic nervous system and the reninangiotensin-aldosterone system and may inadvertently worsen LVH, although this effect may be reversed by the addition of a sympatholytic drug. 69 '70 Direct-acting vasodilators such as hydralazine hydrochloride (Apresoline) and minoxidil (Loniten) have not been effective in producing LVH regression. 71 The effects of various antihyper-
tensive agents on LVH are summarized in table 3.
Systolic hypertension in the elderly Isolated systolic hypertension is increasingly prevalent in people 60 years of age and older, and epidemiologic studies72. 78 have shown that systolic blood pressure greater than 160 mm Hg is a major risk factor for stroke. Most of what we know about the treat-
ment of hypertension comes from studies focusing on elevated diastolic blood pressure. However, despite the paucity of data, two recent studies have shed some much-needed light on how to treat isolated systolic hypertension in the elderly population. The European Working Party on High Blood Pressure in the Elderly (EWPHE) study9 was a double-blind, placebo-controlled trial designed to assess the efficacy of antihypertensive therapy in patients over the age of 60. Eight hundred forty patients with elevated diastolic and systolic blood pressure were randomized either to a group receiving treatment with hydrochlorothiazide plus triamterene or to a placebo group. Methyldopa was added as a second drug in this trial when blood pressure remained elevated with diuretic therapy alone. A significant reduction in total cardiovascular mortality rate (38%, P= .023) was observed in the treated patients, due mostly to a reduction in the number of cardiac deaths (47%, P= .048) and a nonsignificant decrease in the rate of cerebrovascular death (43%, P= .15). The risk of nonfatal stroke was also significantly reduced (52%), although the risk of fatal stroke did not change. The Systolic Hypertension in
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Peripheral alpha blockers, although effective for treating hypertension, should be used with caution in elderly patients, who are more prone to orthostatic hypotension.
the Elderly Program (SHEP) 80 was designed to assess whether or not treatment of isolated systolic hypertension in elderly patients would reduce the incidence of both nonfatal and fatal stroke. For the SHEP study, isolated systolic hypertension was defined as systolic pressure greater than 160 mm Hg with diastolic pressure less than 90 mm Hg, when four readings taken during two patient visits were averaged. In the study, 4, 736 patients aged 60 years and above with isolated systolic hypertension were randomized either to a group treated with chlorthalidone (12.5 mg daily) or to a placebo group. Mter a 5-year follow-up period, the incidence of fatal and nonfatal stroke in the treatment group was significantly reduced (36%). Of interest is that the treatment benefit was apparent in all age-groups, including patients who were 80 years of age or older, a group not shown previously to benefit from hypertension treatment. Cardiovascular morbidity and coronary morbidity and mortality (secondary end points of the study) were also significantly reduced. Cardiovascular mortality and overall mortality (the remaining secondary end points) were not significantly affected, however. Two major differences in treat-
ment outcomes can be noted between the two trials and are most likely due to differences in study methodologies. The first is that treatment benefit in patients 80 years of age or older was observed in the SHEP study but not in the EWPHE study. This is probably because a greater number of subjects 80 years of age and older were included in the SHEP study (649, versus 155 in the EWPHE study). The second difference is that the reduction in total cardiovascular mortality observed in the EWPHE study was significant, whereas that in the SHEP study was not. The statistical power used in the study design of the SHEP protocol may not have been large enough to detect a difference in this end point. Other factors such as adverse metabolic effects of thiazide diuretics or a reduction of diastolic blood pressure below a patient's baseline reading may also account for this discrepancy. Despite the differences between the two studies in treatment outcomes, results have conclusively established that treatment of isolated systolic hypertension in elderly patients is beneficial. Is a thiazide-type diuretic such as chlorthalidone (Hygroton) the drug of choice for the treatment of isolated systolic hypertension
in elderly patients? Results of both the EWPHE trial and the SHEP study suggest that the answer to this question is yes, although a definitive answer will not be known until studies are conducted with newer antihypertensive agents. Unless an elderly patient has renal insufficiency or diabetes mellitus, a thiazide diuretic is preferable to a loop diuretic, because thiazides allow once-a-day dosing. Use of a thiazide-triamterene combination can minimize hypokalemia. Indapamide may also be a reasonable choice because of its benign metabolic effects. If it becomes necessary to add a second agent or use an alternative drug, good results have been obtained with various adrenergic blockers. Although we do not recommend combination therapy, a low-dose combination of 15 mg of chlorthalidone plus 0.1 mg of the central alpha agonist clonidine in a single daily dose has been reported to lower systolic blood pressure by at least 20 mm Hg in elderly patients. 81 Peripheral alpha blockers, although effective, should be used with caution in elderly patients, because this group is more prone to orthostatic hypotension. 52 Because LVH is prevalent in the elderly population, therapy with a sympatholytic, ACE inhibitor, or
continued
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The impact that treatment will have on a patient's quality of life must be considered in designing a treatment regimen.
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Table 4. Antihypertensive agents that require only once- or twice-a-day dosing Agent
Starting dosage
Side effects
Beta blockers Atenolol (Tenormin)
50 mg qd
Bronchospasm, fatigue, insomnia, depression, sexual dysfunction
Metoprolol (Lopressor)
100 mg qd or 50 mg bid
Similar to atenolol
Acebutolol (Sectral)
400 mg qd or 200 mg bid
Similar to atenolol, plus lupus (rare)
Labetalol (Trandate, Normodyne)
100mg bid
Orthostatic hypotension, fever, hepatotoxicity
Thiazide-type diuretics lndapamide (Lozol)
2.5 mg qd
Hyperuricemia, hypokalemia, hyponatremia, fatigue, sexual dysfunction
Hydrochlorothiazide (various)
12.5-50 mg qd
Hydrochlorothiazide (25 mg) plus triamterene (37.5-50 mg) (Dyazide, Maxzide)
1-2 tablets qd
Calcium channel blockers Sustained-release nifedipine (Procardia XL)
Sustained-release verapamil (Calan SR, lsoptin SR, Verelan)
}
Similar to indapamide, plus adverse effects on lipids
30 or 60 mg qd
Dizziness/flushing, headache, pedal edema, tachycardia
120-240 mg qd
Constipation, CHF, hypotension, AV block, bradycardia, edema, headache Similar to verapamil, but less likely to cause constipation
Sustained-release diltiazem Twice-a-day dosing (Cardizem SR) Once-a-day dosing (Cardizem CD)
60-120 mg bid 180mg qd
lsradipine (DynaCirc)
2.5 mg bid
Similar to nifedipine
ACE, angiotensin-converting enzyme; AV, atrioventricular; CHF, congestive heart failure.
calcium channel blocker should be considered, since all of these may produce regression ofLVH in addition to lowering blood pressure.
Designing a treatment regimen The impact that treatment will have on a patient's quality of life must be considered in designing a
180
treatment regimen. Patient compliance is also an imponant consideration. Table 4lists antihypertensive drugs that only need to be taken once or twice a day, along with their starring dosage and most common side effects. Table 5 provides a summary of the advantages and disadvantages of various antihypenensive agents.
QUAUIY OF UFE-The treatment of hypenension can cenainly affect a patient's quality of life. The way a patient's lifestyle is affected by the illness is an imponant consideration. Antihypertensive agents have adverse effects, most prominently depression, sexual dysfunction, fatigue, and impairment of cognitive
HYNRTBNIIION • VOL 91/NO 6/MAY 1, 1992/POSTGRAOUATE MEDICINE
Table 4. Continued
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Agent
Starting dosage
Side effects
Captopril (Capoten)
25 mg bid
Cough. rash, angioedema, hyper\
