- Email: [email protected]
JNC VI: what’s new and why?
DIAGNOSIS AND MANAGEMENT
regimens were well tolerated in all groups, including those on hemodialysis.
indicate that (1) changes in glucose and cholesterol metabolism are minor, especially with the smaller doses now being used; (2) cardiovascular morbidity and mortality have been reduced in hypertensive patients, even in those with hyperlipidemia or diabetes, when diuretics are used; and (3) concerns about hypokalemia-induced arrhythmias have been overstated. While special indications exist for other medications in the treatment of hypertension, for example, use of an angiotensin-converting enzyme inhibitor (usually in addition to a diuretic) for a patient with heart failure or diabetic nephropathy, most patients, including those with hyperlipidemia or glucose intolerance, can be effectively treated with a diuretic as initial therapy or as part of a combination regimen. Diuretics should be used more not less frequently; use of diuretics would reduce the number of resistant hypertensive patients.
Hemodynamic and Metabolic Effects of Transdermal Clonidine in Patients with Hypertension and Non–Insulin-Dependent Diabetes Mellitus D. Giugliano, R. Acampora, R. Marfella, C. La Marca, M. Marfella, F. Nappo, F. D’Onofrio. Afragola, Italy. Am J Hypertens 1998;11:184–9. The aim of this study was to evaluate the effect of transdermal clonidine on hemodynamic and metabolic parameters in patients who have elevated blood pressure and non– insulin-dependent diabetes mellitus (NIDDM). After a 2-week run in placebo period, 20 NIDDM patients who had diastolic blood pressure in the range of 90 to 105 mm Hg underwent a randomized, single blind, placebo controlled, cross-over study of 4-week treatment with clonidine (transdermal patch 2.5 mg/week) or placebo (inactive patch). Compared with placebo, clonidine significantly reduced systolic (153 6 6 vs. 163 6 8) and diastolic (88 6 2 vs. 98 6 3.5 mm Hg, P 5 .001) blood pressure, left ventricular mass (94 6 11 vs. 99 6 12 g/m2, P , .01) and fasting glucose levels. Total glucose disposal (glucose clamp) was 6.5 6 1.5 with placebo and 7.1 6 1.6 mg/kg/min with clonidine (P , .01). Oxidative glucose disposal (indirect calorimetry) was also greater after clonidine. Plasma glucose, insulin, and C-peptide responses following oral glucose (75 g) were significantly lower after clonidine, as well as urinary albumin excretion. Transdermal clonidine is effective in reducing blood pressure in hypertensive NIDDM patients and is well tolerated. It may be useful to reduce the cardiovascular impact of hypertension in diabetes mellitus.
COMMENT
JNC VI: What’s New and Why? Myron H. Weinberger, MD, Professor of Medicine, Indiana University School of Medicine, Indianapolis, Indiana Background At intervals of approximately 3– 4 years, a committee sponsored by the National Heart Lung and Blood Institute, with representation from virtually all organizations concerned with cardiovascular disease and the practice of medicine, is convened to review new information related to blood pressure and to issue relevant practice guidelines. The sixth such report, The Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC VI) (1), recently has been issued. This review will present the new recommendations for the treatment of hypertension reflected in this document along with the rationale for them. It is important to recognize that the report represents the consensus of a large number of experts in this area and has the advantages and disadvantages of all such attempts at achieving a group opinion.
Why Are Physicians Not Prescribing Diuretics More Frequently in the Management of Hypertension? Marvin Moser. Yale University School of Medicine, New Haven, CT. JAMA 1998;279: 1813–6. Diuretics have again been recommended by the Sixth Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI) as one of the first-choice medications in the management of hypertension. This recommendation is based on the results of numerous randomized, diuretic-based, long-term controlled clinical trials that have demonstrated a reduction in both cerebrovascular and cardiovascular morbidity. Despite this and other national recommendations, the use of diuretics has steadily decreased over the past 15 years. Reasons include heavy promotion of other medications and the perception that diuretics produce adverse metabolic effects and do not reduce coronary heart disease events. Data, however,
Significant Changes The first important distinguishing characteristic is in the name of the report itself. For the first time prevention is included in the document and is placed in the front. This reflects the results of studies conducted since the committee’s last report, which added a new level of blood pressure category, “high-normal blood pressure,” used for individuals demonstrating readings from 130 to 139 systolic or 85 to 89 diastolic. This category was identified because of evidence that such individuals already may have evidence of vascular disease and are more likely to progress to fixed
ACC CURRENT JOURNAL REVIEW September/October 1998 © 1998 by the American College of Cardiology Published by Elsevier Science Inc.
31
1062-1458/98/$19.00 PII S1062-1458(98)00055-5
DIAGNOSIS AND MANAGEMENT
arterial disease or retinopathy. At first glance, this stratification effort appears imposing, but note that the presence of diabetes, TOD/CCD or two risk factors mandates initial drug therapy at any level of blood pressure. Although the finding of blood pressure $160/$100 also mandates initiation of antihypertensive drug treatment, in the absence of such conditions, lifestyle modification can be attempted initially (for up to 12 months) before starting drug therapy.
Table 1. RISK STRATIFICATION AND TREATMENT Blood Pressure Levels
Group A*
Group B†
Group C‡
High-Normal (130–139/85–89) Stage 1 (140–159/90–99) Stages 2 and 3 (.160/.100
Lifestyle
Lifestyle
Drug therapy
Lifestyle
Lifestyle
Drug therapy
Drug therapy
Drug therapy
Drug therapy
*Group A: No other risk factors, target organ disease or concomitant cardiovascular disease. †Group B: One or more risk factors (not diabetes-diabetes mellitus); no target organ disease, or concomitant cardiovascular disease. ‡Group C: Target organ disease, concomitant cardiovascular disease or diabetes mellitus with or without other risk factors. Data from JNC VI Arch Intern Med 1997;157:2413– 46.
Lifestyle Modifications What are the lifestyle modifications that have been shown to be effective in reducing blood pressure in a majority of patients? Among obese hypertensive patients, weight loss, often as little as 10 lbs, will lower blood pressure in about 50% of cases. Not every obese hypertensive patient will demonstrate a decrease in blood pressure with weight loss and recidivism is a major problem. In patients who habitually consume more than 1 oz of pure ethanol daily (3 beers, 2–3 glasses of wine, 2 oz 100-proof whiskey or 2.5 oz 80-proof spirits), reducing intake to optimal levels may help lower blood pressure. Moderate physical activity (30 – 45 minutes of brisk walking 5 or more days per week) aids in weight loss, improves cardiovascular fitness and may help lower blood pressure independently. Of all of the dietary constituents, sodium, in the form of the chloride salt, is most likely to influence blood pressure. Moreover, severe salt restriction generally is not required because decreasing usual intake to levels of 2–3 g/day is sufficient for reduction of blood pressure in salt-sensitive subjects. In addition to the blood pressure effects, salt reduction also may reduce diuretic-induced potassium loss, be associated with regression of left ventricular hypertrophy and a reduced risk of osteoporosis and kidney stones. Increasing potassium intake has been shown to decrease the risk of developing hypertension in those with high-normal blood pressure as well as reduce blood pressure in those with potassium deficiency resulting from diuretic administration or lower dietary intake. Data concerning the effect of increased dietary calcium intake are equivocal. Although calcium supplementation lowers blood pressure in some individuals, these patients primarily appear to be salt-sensitive. The DASH trial demonstrated that a diet reduced in sodium and increased in potassium and calcium (fresh fruits and vegetables and low-fat dairy products) was effective in reducing blood pressure (2). In addition to these factors that may lower blood pressure, cessation of smoking and reduction of intake of cholesterol and saturated fats is recommended because of their effects on cardiovascular disease risk.
hypertension (i.e., $140/90). Recent studies have demonstrated that individuals with high-normal blood pressure can be prevented from developing fixed hypertension by the institution of lifestyle modifications (to be detailed subsequently) (2). Another major contribution of the JNC VI report is the introduction of a stratification approach to therapeutic decision making that implies recognition that all patients are not alike. The components of this stratification also will be presented subsequently. The JNC VI report has expanded the options for initial treatment consistent with the recognition of striking differences among individuals and has identified conditions in which specific agents are indicated based on the results of recent studies. These options include low-dose combination therapy for the first time and indicate that a fixed therapeutic recipe is not appropriate for all hypertensive patients. Risk Stratification Authors of the JNC VI report recommend a two-tiered stratification based on blood pressure levels and the presence of target-organ disease (TOD), concomitant cardiovascular disease (CCD) and recognized risk factors for CCD (Table 1). The blood pressure criteria are as follows: highnormal blood pressure (130 –139 systolic or 85– 89 diastolic), stage I (140 –159/90 –99) and stages II and III ($160/ $100). Risk group A includes those with no known risk factors, TOD or CCD, whereas B is reserved for those with at least one risk factor (excluding diabetes mellitus) and no TOD or CCD. Risk group C includes those with diabetes (reflecting the synergistic effect of hypertension in diabetics to amplify cardiovascular risk) and the presence of TOD or CCD with or without other risk factors. These risk factors include dyslipidemia (including hypertriglyceridemia), smoking, male sex, postmenopausal status, age .60 years and family history of premature cardiovascular disease. Target organ disease and concomitant cardiovascular disease include left ventricular hypertrophy, angina or prior myocardial infarction, coronary revascularization, heart failure, stroke or transient ischemic attack, nephropathy, peripheral
Drug Therapy Considerations When drug therapy is indicated, the JNC VI document emphasizes that the basis for the choice of a specific medi-
ACC CURRENT JOURNAL REVIEW September/October 1998
32
DIAGNOSIS AND MANAGEMENT
lated systolic hypertension (systolic pressure $160, diastolic ,90), typically observed in the elderly, reducing systolic pressure to levels of ,140 with diuretic, b-blocker or long-acting dihydropyridine calcium channel entry blocker has been shown to significantly reduce cardiovascular events and death. In patients with angina, b blockers and long-acting calcium channel antagonists are beneficial. In subjects susceptible to supraventricular tachycardia, b-blockers and nondihydropyridine calcium channel entry blockers are useful. Calcium channel blockers also may be useful in the treatment of hypertension associated with cyclosporine administration (transplant patients). Peripheral a1-adrenergic receptor antagonists (doxazosin, prazosin, terazosin) may be useful in patients with dyslipidemia because the drugs improve the lipid profile. Doxazosin also has been reported to improve insulin sensitivity and glucose tolerance in diabetic hypertensive patients. In patients with benign essential tremor, non-cardioselective b adrenergic receptor blockers are useful in diminishing tremor and blood pressure. b-adrenergic receptor blockers also are helpful in reducing many of the cardiovascular symptoms associated with hyperthyroidism, which result from adrenergic stimulation. In patients with migraine headaches, noncardioselective b-blockers and nondihydropyridine calcium channel entry blockers have been found to be beneficial. Thiazide diuretics may reduce the risk of osteoporosis in women. Men with symptoms of benign prostatic hypertrophy have had marked reduction in symptomatology with a1-adrenergic receptor blockers (doxazosin, prazosin and terazosin).
cation is the individual patient, the presence of concomitant disease(s) and risk factors and demographic characteristics such as age and race, which may influence the response to drugs. Thus, the report has expanded the list of drugs available as initial antihypertensive therapy to include virtually all agents approved by The U.S. Food and Drug Administration for the treatment of hypertension, including combination products, with the exception of drugs such as direct vasodilators, (minoxidil, hydralazine) central a2-adrenergic receptor agonists (clonidine, guanabenz and guanfacine) and ganglionic blocking agents (guanethidine), which generally are reserved for adjunctive therapy in severe, resistant hypertension. The report stresses that diuretics and b-adrenergic blocking agents are generally recommended as initial therapy for uncomplicated hypertensives when not otherwise contraindicated. However, full doses of these agents may have an adverse effect on the lipid profile or the insulin sensitivity and carbohydrate tolerance, two risk factors often encountered in hypertensive subjects. Thus, low-dose diuretic therapy (25 mg/day or less of hydrochlorothiazide or equivalent doses of other diuretics) may be required to avoid the undesirable metabolic effects. Such doses may not be fully efficacious in reducing blood pressure unless combined with other agents. Similarly, effective doses of b-blockers can adversely influence triglycerides, low-density lipoproteins and high-density lipoproteins. The development of low-dose combination products offers the potential of blood pressure control by the potentiating action of agents from different pharmacologic classes, while avoiding many of the adverse effects that are dose-dependent. Other advantages of combination therapy are increased compliance due to reduction in the number of medications required and, often, reduced cost and fewer side effects.
Caveats Some antihypertensive drugs have adverse effect on a variety of concomitant disorders. b-blockers may worsen bronchospasm or precipitate asthma. Depression may be worsened with b-adrenergic blocking agents, central a2-receptor agonists (clonidine, guanabenz, guanfacine) or reserpine. b-adrenergic blocking agents and high-dose diuretics (.25 mg/ day hydrochlorothiazide or its equivalence) can worsen insulin sensitivity and diabetes as well as the lipid profile. Similar changes can be observed with non–intrinsic sympathomimetic activity b-adrenergic receptor blocking agents. Diuretics may precipitate gout. Second- or third-degree heart block can be precipitated or worsened by nondihydropyridine calcium channel entry blockers. In the presence of hepatic disease, labetalol and methyldopa should not be used because of their potential to cause or worsen liver dysfunction. b-blockers may cause worsening of peripheral vascular disease symptoms by reducing peripheral blood flow. Potassium-sparing agents should be used cautiously, if at all, in patients with impaired renal function because of the danger of hyperkalemia. In the presence of bilateral renal vascular disease or in a patient with a solitary functioning
Specific Drugs A variety of recent studies have examined the benefit of specific forms of antihypertensive drug therapy in patients with associated or complicated diseases. In diabetes mellitus, angiotensin converting enzyme (ACE) inhibitors have been shown to reduce proteinuria and the rate of progression of diabetic renal disease. Such agents now are indicated for such patients. Physicians should recognize that ACE inhibitors often may not control blood pressure alone, and the addition of small doses of diuretic or calcium channel entry blocking drugs may be required. In congestive heart failure, ACE inhibitors and diuretics have been shown to be effective and to extend life expectancy. Recent studies suggest that carvedilol and losartan also may be beneficial in heart failure. Following myocardial infarction, b-adrenergic blocking agents (excluding those with intrinsic sympathomimetic activity) and ACE inhibitors have been shown to be advantageous in reducing morbidity and mortality and preventing congestive heart failure and sudden death. In iso-
ACC CURRENT JOURNAL REVIEW September/October 1998
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DIAGNOSIS AND MANAGEMENT
the reduction of cardiovascular events and death. It was possible to achieve and maintain the assigned levels of diastolic pressure for the duration of the study and subjective reports indicated that the reductions in pressure were well-tolerated and were associated with improved quality of life scores. Thus, achieving levels of diastolic pressure below the traditional mark of 90 mm Hg appears to be feasible and desirable. The major unanswered question that is undergoing investigation is whether specific antihypertensive drugs convey different protections or risks for cardiovascular disease at the same level of blood pressure reduction; this is under study in several large multicenter trials and results should be available over the next few years, perhaps in time for the JNC VII report.
kidney and significant renal vascular disease in the remaining kidney, ACE inhibitors and angiotensin II receptor blockers may cause worsening of renal function and must be used with caution and frequent monitoring of blood urea nitrogen and creatinine. In pregnancy, ACE inhibitors and, presumably, angiotensin II receptor blockers should not be used because of deleterious effects on fetal development and viability. Therapeutic Goals The minimal goal of blood pressure therapy is the reduction of blood pressure to levels of ,140/90 in all hypertensive patients. In some individuals, even lower pressures are beneficial. In diabetics, blood pressure reduction to levels as low as 120/70 has provided renal protection. In congestive heart failure, reduction of pressure to levels lower than 140/90 is beneficial, and in patients with non-diabetic renal disease a lower pressure seems to be advantageous. A recent multicenter, multinational, 4-year study of more than 18,000 hypertensives, the HOT study, was designed to assess the ability to reduce diastolic pressure to randomly assigned levels of ,90, ,85 and ,80 using titrated doses of a dihydropyridine calcium channel entry blocker (felodipine), an ACE inhibitor (enalapril), hydrochlorothiazide and metoprolol (if needed), and to assess the tolerability and cardiovascular effects of such reduction (3). Although the results of the study only have been reported in general form and more extensive analyses are in progress, some general observations are available. First, progressive reduction in diastolic pressure was associated with increasing benefit in
REFERENCES 1. The Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure. The sixth report (JNC VI). Arch Intern Med 1997;157:2413– 46. 2. Appel LJ, Moore TJ, Obarzanek E, et al. A clinical trial of the effects of dietary patterns on blood pressure. N Engl J Med 1997;336:1117–24. 3. Hansson L, Zanchetti A, Caruthers SG, et al. Effects of intensive bloodpressure lowering and low-dose aspirin in patients with hypertension: Principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet 1998;351:1755– 62. Address correspondence and reprint requests to Myron H. Weinberger, MD, Director, Hypertension Research Center, Indiana University School of Medicine, 541 Clinical Drive, Room 423, Indianapolis, IN 46202.
ACC CURRENT JOURNAL REVIEW September/October 1998
34
regimens were well tolerated in all groups, including those on hemodialysis.
indicate that (1) changes in glucose and cholesterol metabolism are minor, especially with the smaller doses now being used; (2) cardiovascular morbidity and mortality have been reduced in hypertensive patients, even in those with hyperlipidemia or diabetes, when diuretics are used; and (3) concerns about hypokalemia-induced arrhythmias have been overstated. While special indications exist for other medications in the treatment of hypertension, for example, use of an angiotensin-converting enzyme inhibitor (usually in addition to a diuretic) for a patient with heart failure or diabetic nephropathy, most patients, including those with hyperlipidemia or glucose intolerance, can be effectively treated with a diuretic as initial therapy or as part of a combination regimen. Diuretics should be used more not less frequently; use of diuretics would reduce the number of resistant hypertensive patients.
Hemodynamic and Metabolic Effects of Transdermal Clonidine in Patients with Hypertension and Non–Insulin-Dependent Diabetes Mellitus D. Giugliano, R. Acampora, R. Marfella, C. La Marca, M. Marfella, F. Nappo, F. D’Onofrio. Afragola, Italy. Am J Hypertens 1998;11:184–9. The aim of this study was to evaluate the effect of transdermal clonidine on hemodynamic and metabolic parameters in patients who have elevated blood pressure and non– insulin-dependent diabetes mellitus (NIDDM). After a 2-week run in placebo period, 20 NIDDM patients who had diastolic blood pressure in the range of 90 to 105 mm Hg underwent a randomized, single blind, placebo controlled, cross-over study of 4-week treatment with clonidine (transdermal patch 2.5 mg/week) or placebo (inactive patch). Compared with placebo, clonidine significantly reduced systolic (153 6 6 vs. 163 6 8) and diastolic (88 6 2 vs. 98 6 3.5 mm Hg, P 5 .001) blood pressure, left ventricular mass (94 6 11 vs. 99 6 12 g/m2, P , .01) and fasting glucose levels. Total glucose disposal (glucose clamp) was 6.5 6 1.5 with placebo and 7.1 6 1.6 mg/kg/min with clonidine (P , .01). Oxidative glucose disposal (indirect calorimetry) was also greater after clonidine. Plasma glucose, insulin, and C-peptide responses following oral glucose (75 g) were significantly lower after clonidine, as well as urinary albumin excretion. Transdermal clonidine is effective in reducing blood pressure in hypertensive NIDDM patients and is well tolerated. It may be useful to reduce the cardiovascular impact of hypertension in diabetes mellitus.
COMMENT
JNC VI: What’s New and Why? Myron H. Weinberger, MD, Professor of Medicine, Indiana University School of Medicine, Indianapolis, Indiana Background At intervals of approximately 3– 4 years, a committee sponsored by the National Heart Lung and Blood Institute, with representation from virtually all organizations concerned with cardiovascular disease and the practice of medicine, is convened to review new information related to blood pressure and to issue relevant practice guidelines. The sixth such report, The Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC VI) (1), recently has been issued. This review will present the new recommendations for the treatment of hypertension reflected in this document along with the rationale for them. It is important to recognize that the report represents the consensus of a large number of experts in this area and has the advantages and disadvantages of all such attempts at achieving a group opinion.
Why Are Physicians Not Prescribing Diuretics More Frequently in the Management of Hypertension? Marvin Moser. Yale University School of Medicine, New Haven, CT. JAMA 1998;279: 1813–6. Diuretics have again been recommended by the Sixth Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI) as one of the first-choice medications in the management of hypertension. This recommendation is based on the results of numerous randomized, diuretic-based, long-term controlled clinical trials that have demonstrated a reduction in both cerebrovascular and cardiovascular morbidity. Despite this and other national recommendations, the use of diuretics has steadily decreased over the past 15 years. Reasons include heavy promotion of other medications and the perception that diuretics produce adverse metabolic effects and do not reduce coronary heart disease events. Data, however,
Significant Changes The first important distinguishing characteristic is in the name of the report itself. For the first time prevention is included in the document and is placed in the front. This reflects the results of studies conducted since the committee’s last report, which added a new level of blood pressure category, “high-normal blood pressure,” used for individuals demonstrating readings from 130 to 139 systolic or 85 to 89 diastolic. This category was identified because of evidence that such individuals already may have evidence of vascular disease and are more likely to progress to fixed
ACC CURRENT JOURNAL REVIEW September/October 1998 © 1998 by the American College of Cardiology Published by Elsevier Science Inc.
31
1062-1458/98/$19.00 PII S1062-1458(98)00055-5
DIAGNOSIS AND MANAGEMENT
arterial disease or retinopathy. At first glance, this stratification effort appears imposing, but note that the presence of diabetes, TOD/CCD or two risk factors mandates initial drug therapy at any level of blood pressure. Although the finding of blood pressure $160/$100 also mandates initiation of antihypertensive drug treatment, in the absence of such conditions, lifestyle modification can be attempted initially (for up to 12 months) before starting drug therapy.
Table 1. RISK STRATIFICATION AND TREATMENT Blood Pressure Levels
Group A*
Group B†
Group C‡
High-Normal (130–139/85–89) Stage 1 (140–159/90–99) Stages 2 and 3 (.160/.100
Lifestyle
Lifestyle
Drug therapy
Lifestyle
Lifestyle
Drug therapy
Drug therapy
Drug therapy
Drug therapy
*Group A: No other risk factors, target organ disease or concomitant cardiovascular disease. †Group B: One or more risk factors (not diabetes-diabetes mellitus); no target organ disease, or concomitant cardiovascular disease. ‡Group C: Target organ disease, concomitant cardiovascular disease or diabetes mellitus with or without other risk factors. Data from JNC VI Arch Intern Med 1997;157:2413– 46.
Lifestyle Modifications What are the lifestyle modifications that have been shown to be effective in reducing blood pressure in a majority of patients? Among obese hypertensive patients, weight loss, often as little as 10 lbs, will lower blood pressure in about 50% of cases. Not every obese hypertensive patient will demonstrate a decrease in blood pressure with weight loss and recidivism is a major problem. In patients who habitually consume more than 1 oz of pure ethanol daily (3 beers, 2–3 glasses of wine, 2 oz 100-proof whiskey or 2.5 oz 80-proof spirits), reducing intake to optimal levels may help lower blood pressure. Moderate physical activity (30 – 45 minutes of brisk walking 5 or more days per week) aids in weight loss, improves cardiovascular fitness and may help lower blood pressure independently. Of all of the dietary constituents, sodium, in the form of the chloride salt, is most likely to influence blood pressure. Moreover, severe salt restriction generally is not required because decreasing usual intake to levels of 2–3 g/day is sufficient for reduction of blood pressure in salt-sensitive subjects. In addition to the blood pressure effects, salt reduction also may reduce diuretic-induced potassium loss, be associated with regression of left ventricular hypertrophy and a reduced risk of osteoporosis and kidney stones. Increasing potassium intake has been shown to decrease the risk of developing hypertension in those with high-normal blood pressure as well as reduce blood pressure in those with potassium deficiency resulting from diuretic administration or lower dietary intake. Data concerning the effect of increased dietary calcium intake are equivocal. Although calcium supplementation lowers blood pressure in some individuals, these patients primarily appear to be salt-sensitive. The DASH trial demonstrated that a diet reduced in sodium and increased in potassium and calcium (fresh fruits and vegetables and low-fat dairy products) was effective in reducing blood pressure (2). In addition to these factors that may lower blood pressure, cessation of smoking and reduction of intake of cholesterol and saturated fats is recommended because of their effects on cardiovascular disease risk.
hypertension (i.e., $140/90). Recent studies have demonstrated that individuals with high-normal blood pressure can be prevented from developing fixed hypertension by the institution of lifestyle modifications (to be detailed subsequently) (2). Another major contribution of the JNC VI report is the introduction of a stratification approach to therapeutic decision making that implies recognition that all patients are not alike. The components of this stratification also will be presented subsequently. The JNC VI report has expanded the options for initial treatment consistent with the recognition of striking differences among individuals and has identified conditions in which specific agents are indicated based on the results of recent studies. These options include low-dose combination therapy for the first time and indicate that a fixed therapeutic recipe is not appropriate for all hypertensive patients. Risk Stratification Authors of the JNC VI report recommend a two-tiered stratification based on blood pressure levels and the presence of target-organ disease (TOD), concomitant cardiovascular disease (CCD) and recognized risk factors for CCD (Table 1). The blood pressure criteria are as follows: highnormal blood pressure (130 –139 systolic or 85– 89 diastolic), stage I (140 –159/90 –99) and stages II and III ($160/ $100). Risk group A includes those with no known risk factors, TOD or CCD, whereas B is reserved for those with at least one risk factor (excluding diabetes mellitus) and no TOD or CCD. Risk group C includes those with diabetes (reflecting the synergistic effect of hypertension in diabetics to amplify cardiovascular risk) and the presence of TOD or CCD with or without other risk factors. These risk factors include dyslipidemia (including hypertriglyceridemia), smoking, male sex, postmenopausal status, age .60 years and family history of premature cardiovascular disease. Target organ disease and concomitant cardiovascular disease include left ventricular hypertrophy, angina or prior myocardial infarction, coronary revascularization, heart failure, stroke or transient ischemic attack, nephropathy, peripheral
Drug Therapy Considerations When drug therapy is indicated, the JNC VI document emphasizes that the basis for the choice of a specific medi-
ACC CURRENT JOURNAL REVIEW September/October 1998
32
DIAGNOSIS AND MANAGEMENT
lated systolic hypertension (systolic pressure $160, diastolic ,90), typically observed in the elderly, reducing systolic pressure to levels of ,140 with diuretic, b-blocker or long-acting dihydropyridine calcium channel entry blocker has been shown to significantly reduce cardiovascular events and death. In patients with angina, b blockers and long-acting calcium channel antagonists are beneficial. In subjects susceptible to supraventricular tachycardia, b-blockers and nondihydropyridine calcium channel entry blockers are useful. Calcium channel blockers also may be useful in the treatment of hypertension associated with cyclosporine administration (transplant patients). Peripheral a1-adrenergic receptor antagonists (doxazosin, prazosin, terazosin) may be useful in patients with dyslipidemia because the drugs improve the lipid profile. Doxazosin also has been reported to improve insulin sensitivity and glucose tolerance in diabetic hypertensive patients. In patients with benign essential tremor, non-cardioselective b adrenergic receptor blockers are useful in diminishing tremor and blood pressure. b-adrenergic receptor blockers also are helpful in reducing many of the cardiovascular symptoms associated with hyperthyroidism, which result from adrenergic stimulation. In patients with migraine headaches, noncardioselective b-blockers and nondihydropyridine calcium channel entry blockers have been found to be beneficial. Thiazide diuretics may reduce the risk of osteoporosis in women. Men with symptoms of benign prostatic hypertrophy have had marked reduction in symptomatology with a1-adrenergic receptor blockers (doxazosin, prazosin and terazosin).
cation is the individual patient, the presence of concomitant disease(s) and risk factors and demographic characteristics such as age and race, which may influence the response to drugs. Thus, the report has expanded the list of drugs available as initial antihypertensive therapy to include virtually all agents approved by The U.S. Food and Drug Administration for the treatment of hypertension, including combination products, with the exception of drugs such as direct vasodilators, (minoxidil, hydralazine) central a2-adrenergic receptor agonists (clonidine, guanabenz and guanfacine) and ganglionic blocking agents (guanethidine), which generally are reserved for adjunctive therapy in severe, resistant hypertension. The report stresses that diuretics and b-adrenergic blocking agents are generally recommended as initial therapy for uncomplicated hypertensives when not otherwise contraindicated. However, full doses of these agents may have an adverse effect on the lipid profile or the insulin sensitivity and carbohydrate tolerance, two risk factors often encountered in hypertensive subjects. Thus, low-dose diuretic therapy (25 mg/day or less of hydrochlorothiazide or equivalent doses of other diuretics) may be required to avoid the undesirable metabolic effects. Such doses may not be fully efficacious in reducing blood pressure unless combined with other agents. Similarly, effective doses of b-blockers can adversely influence triglycerides, low-density lipoproteins and high-density lipoproteins. The development of low-dose combination products offers the potential of blood pressure control by the potentiating action of agents from different pharmacologic classes, while avoiding many of the adverse effects that are dose-dependent. Other advantages of combination therapy are increased compliance due to reduction in the number of medications required and, often, reduced cost and fewer side effects.
Caveats Some antihypertensive drugs have adverse effect on a variety of concomitant disorders. b-blockers may worsen bronchospasm or precipitate asthma. Depression may be worsened with b-adrenergic blocking agents, central a2-receptor agonists (clonidine, guanabenz, guanfacine) or reserpine. b-adrenergic blocking agents and high-dose diuretics (.25 mg/ day hydrochlorothiazide or its equivalence) can worsen insulin sensitivity and diabetes as well as the lipid profile. Similar changes can be observed with non–intrinsic sympathomimetic activity b-adrenergic receptor blocking agents. Diuretics may precipitate gout. Second- or third-degree heart block can be precipitated or worsened by nondihydropyridine calcium channel entry blockers. In the presence of hepatic disease, labetalol and methyldopa should not be used because of their potential to cause or worsen liver dysfunction. b-blockers may cause worsening of peripheral vascular disease symptoms by reducing peripheral blood flow. Potassium-sparing agents should be used cautiously, if at all, in patients with impaired renal function because of the danger of hyperkalemia. In the presence of bilateral renal vascular disease or in a patient with a solitary functioning
Specific Drugs A variety of recent studies have examined the benefit of specific forms of antihypertensive drug therapy in patients with associated or complicated diseases. In diabetes mellitus, angiotensin converting enzyme (ACE) inhibitors have been shown to reduce proteinuria and the rate of progression of diabetic renal disease. Such agents now are indicated for such patients. Physicians should recognize that ACE inhibitors often may not control blood pressure alone, and the addition of small doses of diuretic or calcium channel entry blocking drugs may be required. In congestive heart failure, ACE inhibitors and diuretics have been shown to be effective and to extend life expectancy. Recent studies suggest that carvedilol and losartan also may be beneficial in heart failure. Following myocardial infarction, b-adrenergic blocking agents (excluding those with intrinsic sympathomimetic activity) and ACE inhibitors have been shown to be advantageous in reducing morbidity and mortality and preventing congestive heart failure and sudden death. In iso-
ACC CURRENT JOURNAL REVIEW September/October 1998
33
DIAGNOSIS AND MANAGEMENT
the reduction of cardiovascular events and death. It was possible to achieve and maintain the assigned levels of diastolic pressure for the duration of the study and subjective reports indicated that the reductions in pressure were well-tolerated and were associated with improved quality of life scores. Thus, achieving levels of diastolic pressure below the traditional mark of 90 mm Hg appears to be feasible and desirable. The major unanswered question that is undergoing investigation is whether specific antihypertensive drugs convey different protections or risks for cardiovascular disease at the same level of blood pressure reduction; this is under study in several large multicenter trials and results should be available over the next few years, perhaps in time for the JNC VII report.
kidney and significant renal vascular disease in the remaining kidney, ACE inhibitors and angiotensin II receptor blockers may cause worsening of renal function and must be used with caution and frequent monitoring of blood urea nitrogen and creatinine. In pregnancy, ACE inhibitors and, presumably, angiotensin II receptor blockers should not be used because of deleterious effects on fetal development and viability. Therapeutic Goals The minimal goal of blood pressure therapy is the reduction of blood pressure to levels of ,140/90 in all hypertensive patients. In some individuals, even lower pressures are beneficial. In diabetics, blood pressure reduction to levels as low as 120/70 has provided renal protection. In congestive heart failure, reduction of pressure to levels lower than 140/90 is beneficial, and in patients with non-diabetic renal disease a lower pressure seems to be advantageous. A recent multicenter, multinational, 4-year study of more than 18,000 hypertensives, the HOT study, was designed to assess the ability to reduce diastolic pressure to randomly assigned levels of ,90, ,85 and ,80 using titrated doses of a dihydropyridine calcium channel entry blocker (felodipine), an ACE inhibitor (enalapril), hydrochlorothiazide and metoprolol (if needed), and to assess the tolerability and cardiovascular effects of such reduction (3). Although the results of the study only have been reported in general form and more extensive analyses are in progress, some general observations are available. First, progressive reduction in diastolic pressure was associated with increasing benefit in
REFERENCES 1. The Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure. The sixth report (JNC VI). Arch Intern Med 1997;157:2413– 46. 2. Appel LJ, Moore TJ, Obarzanek E, et al. A clinical trial of the effects of dietary patterns on blood pressure. N Engl J Med 1997;336:1117–24. 3. Hansson L, Zanchetti A, Caruthers SG, et al. Effects of intensive bloodpressure lowering and low-dose aspirin in patients with hypertension: Principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet 1998;351:1755– 62. Address correspondence and reprint requests to Myron H. Weinberger, MD, Director, Hypertension Research Center, Indiana University School of Medicine, 541 Clinical Drive, Room 423, Indianapolis, IN 46202.
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