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Current Trends in the Treatment of Hypertension: A Mixed Picture
AJH
1997;10:300S–305S
Current Trends in the Treatment of Hypertension: A Mixed Picture Stevo Julius
It has been calculated that hypertension ranks as the fourth largest mortality risk factor in the world, predicting 6% of all deaths. Mild hypertension accounts for the largest proportion of cardiovascular deaths in the United States because of its high prevalence. Thus, mild hypertension should be the focus of treatment efforts. In addition, to achieve better results in the next century, we will have to refocus the treatment from the global goal of blood pressure lowering to exploration of specific effects of drugs on the diverse pathophysiologic aspects of hypertension including the complex metabolic and hemodynamic aberrations associated with human hypertension, as well as trophic factors. Another disconcerting feature of current hypertension management is the inadequate lowering of the blood pressure in those patients treated for
I
n the last four decades the achievements of antihypertensive treatment have been quite exceptional. Together with some malignancies, hypertension is on a rather short list of conditions in which treatment of the symptom, without knowledge of the causes, decreases the disease-specific mortality. In the United States, early trials that have demonstrated that antihypertensive treatment reduces morbidity/mortality1 stimulated massive efforts for pa-
From the Division of Hypertension, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan. Address correspondence and reprint requests to Stevo Julius, MD, ScD, Frederick G. L. Huetwell Professor of Hypertension, Division of Hypertension, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 481090356.
© 1997 by the American Journal of Hypertension, Ltd. Published by Elsevier Science, Inc.
hypertension. The National Health and Nutrition Examination Study (NHANES) survey in United States shows that patients treated for hypertension have blood pressure values that are only slightly lower than in untreated hypertensives and remain higher than in normotensive subjects. Patient compliance with treatment is one major problem. The development of better tolerated drugs ought to bring improvement. Overall, an educational effort aimed at physicians, the general public, and health care providers is necessary to improve the treatment of hypertension and reverse the negative trends in cardiovascular mortality. Am J Hypertens 1997;10:300S–305S © 1997 American Journal of Hypertension, Ltd. KEY WORDS:
Hypertension, drug therapy, morbidity, mortality, angiotensin II receptor antagonist.
tient detection and for education of health care providers. Results soon followed and, as shown in Figure 1, from 1972 until 1990, mortality from strokes and coronary heart disease in the United States has been steadily declining. A careful observer, however, will note that 1) the decline of coronary heart disease is less steep than that in strokes, and 2) the stroke curve seems to be more shallow since 1982. The less steep decline in coronary mortality in the general population mirrors the result from antihypertensive treatment trials that have also shown the treatment to be more efficacious in reducing strokes than heart attacks.2,3 Possible reasons for this discrepancy have been widely discussed. However, the blunting of the stroke curve seems to have eluded us all. A review of most recent data in the Vital Statistics of the United States 0895-7061/97/$17.00 PII S0895-7061(97)00389-0
AJH–DECEMBER 1997–VOL. 10, NO. 12, PART 2
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FIGURE 1. Decline in age-adjusted mortality since 1972. Data for 1990 are provisional. Adapted from the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med 1993; 153:154 –183.
shows that the trend continued, and since 1992 the rates of strokes have ceased to decline. This, combined with recent data from the National Health and Nutrition Examination Study survey (NHANES)4,5 showing that in only 29% of all hypertensives is the blood pressure below the goal of 140/90 mm Hg, illustrates beyond any doubt that we still have a long way to go in combating hypertension and its consequences. In fact, a new concentrated effort—similar to the National High Blood Pressure Education Program—will be needed to reverse these negative trends. This article reviews some factors that may be responsible for the recent negative trend in cardiovascular mortality. THE LACK OF INTEREST IN PATHOPHYSIOLOGY AND THE UNREALISTIC EXPECTATION THAT BLOOD PRESSURE LOWERING WILL REVERSE ALL HYPERTENSION-RELATED MORBIDITY In teaching us the essentials about cardiovascular risk, epidemiologic studies unwittingly delivered the wrong message. Numerous tables for risk assessment, mostly based on the Framingham data, permitted calculation of the additive risk of such factors as high cholesterol levels, obesity, and hypertension. This implied that these risk factors are independent when, in fact, they are intimately interrelated.6 Hyperinsulinemia in hypertension is so frequent7,8 that it has been named a ‘‘syndrome.’’9 In the Tecumseh Blood Pressure study (Table 1), as in other studies, high insulin levels are closely associated with dyslipidemia and overweight.10 Furthermore, in the Tecumseh Blood Pressure study, higher blood pressure levels in men are strongly associated with higher hematocrit levels.11 Elevated insulin levels, which are secondary to insulin resistance, are a strong predictor of future coronary mortality.12–14 Furthermore, dyslipidemia
and elevated hematocrit are also well known risk factors for coronary heart disease.15,16 In the Tecumseh Blood Pressure study of young subjects (average age, 32 years), the significant correlation between insulin, dyslipidemia, obesity, and hematocrit extends in a linear fashion into the normotensive range. This suggests a fundamental relationship; factors regulating the blood pressure levels appear also to govern metabolic variables. Whereas this is of pathophysiologic interest and prompted us to speculate about the mechanism of the association,17,18 the clinical importance lies in the fact that a hypertensive patient is likely to have not only hypertension, but also many of the other coronary risk factors. Plasma renin values19 and norepinephrine levels20 are frequently increased in hypertension. Both high renin21 and enhanced sympathetic tone22 are associated with a poor cardiovascular prognosis in hypertension. Part of this negative effect may reflect the vascular and cardiac ‘‘trophic’’ effects of angiotensin and norepinephrine.23–26 Left ventricular hypertrophy is one of the strongest known risk factors for cardio-
TABLE 1. RISK FACTORS—TECUMSEH BLOOD PRESSURE STUDY Normotensive (n 5 822)
Borderline (n 5 124)
P
176 43
190 40
, .0001 , .001
95 12 92 14
135 18 95 30
, .0001 , .0001 , .001 , .001
Cholesterol (mg/dL) HDL (mg/dL) Triglycerides mg/dL) Insulin (mU/mL) Glucose (mg/dL) Overweight (%) Data taken from Julius et al.10
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vascular mortality,27 and vascular hypertrophy contributes to acceleration of hypertension.28 Behind the facade of blood pressure elevation in hypertension, there are a large number of other abnormalities, many of which contribute to cardiovascular risk in hypertension. The list of coronary risk factors quoted above is deliberately abbreviated and detailed discussion can be found elsewhere,18 but the main point of this presentation is that hypertension is a complex disease. It is therefore naive to expect blood pressure lowering to be a panacea, particularly when many antihypertensive drugs aggravate dyslipidemia, worsen insulin resistance, activate the renin-angiotensin system, and elicit a compensatory increase of sympathetic activity. Hence, the question is not whether blood pressure lowering (regardless of which drug is used) is useful: it is. Hypertension is a very strong risk factor, and lowering blood pressure will always be superior to placebo or to not treating the disease. However, the recent decline in the reduction of cardiovascular mortality forces us to ask whether we can do better. Will ‘‘blood pressure lowering plus’’ yield better results? Will antitrophic effects of angiotensin converting enzyme (ACE) inhibitors and angiotensin II antagonists translate into better clinical results? Will modern calcium antagonists outperform the first generation dihydropyridines? How do they compare with b-blockers and diuretics? New and better tolerated sympatholytics are being evaluated; will they be helpful? Luckily, the field of antihypertensive treatment is not dormant. Massive trials are being launched and many of these questions are being prospectively evaluated. We already know that blood pressure lowering with ACE inhibitor captopril is superior to other forms of blood pressure reduction in juvenile diabetics with renal failure.29 The hope is that we are moving from empirical to rational treatment of hypertension and that new trials will teach us when and how to use a specific antihypertensive treatment in a specific patient. INADEQUATE BLOOD PRESSURE LOWERING NHANES4,5 is a survey of a population sample carefully selected to represent overall trends in the United States. In the recent survey,5 the average blood pressure in the hypertensive population not receiving treatment was 144/88 mg Hg, attesting to the well known fact that most hypertensive patients have only mild blood pressure elevation. In the segment of hypertensive patients who were receiving treatment at the time of the survey, the average blood pressure was 135/83 mm Hg, a 9/5 mm Hg difference from that of untreated hypertensives. At first glance, the overall values achieved in hypertensives who are on treatment appear to be reasonable; however, one receives a
AJH–DECEMBER 1997–VOL. 10, NO. 12, PART 2
very different picture when these values are compared with the average values in the normotensive population which, in the NHANES survey, was 117/71 mm Hg. Obviously, one cannot expect an average mortality in a group of hypertensive subjects whose blood pressure is maintained at a level that exceeds that of the normotensive population by 18/12 mm Hg. These disappointing figures can be explained by a number of factors. The national recommendation in the fifth report of the Joint National Committee (JNC V) on Detection, Evaluation, and Treatment of High Blood Pressure calls for blood pressure lowering below 140/90 mm Hg, but does not specify how low physicians should decrease the blood pressure.30 By and large, physicians agree with this recommendation and are content to maintain blood pressure just below the dividing line between normotension and hypertension. Probably the major reason for this attitude is fear of the J-curve effect. The current controversy about the J-curve is a mirror image of discussions in the early 1950s, when conservative physicians were reluctant to use antihypertensive drugs for fear of underperfusing vital organs. These fears were soon dispelled by the overwhelming evidence that treatment is useful. Similarly, we will not move forward until the reports that blood pressure lowering below 85 mm Hg may be deleterious are fully explored.31,32 The results of the only prospective randomized trial to specifically investigate the issue of safety of aggressive blood pressure lowering in high risk patients will be available in the beginning of 1998. Should this study (the Hypertension Optimal Treatment [HOT] Study) demonstrate that it is safe to decrease blood pressure to near normotensive levels, new and more ambitious blood pressure goals will be promulgated. It is reasonable to expect that this will have a major impact on morbidity and mortality trends in the population. From the 1960s until 1990, the proportion of patients who were aware that they had high blood pressure increased from 53% to 89%.5 During the same period of time the percentage of subjects receiving antihypertensive medication increased from 35% to 79%. However, the percentage of subjects whose blood pressure is under control increased only modestly, from 45% to 55%. Admittedly, this is in part due to more stringent criteria (in the 1960s, the goal was blood pressure , 160/95 mm Hg and in the 1990s it was , 140/90 mm Hg). But the fact remains that in the 1990s, a large number of patients have inadequate blood pressure control. One of the major reasons for this state of affairs is the lack of compliance with antihypertensive medication regimens. Whereas cost of medication, memory problems, and ease of obtaining refills may all affect the compliance rates, there is no doubt that adverse effects of antihypertensive drugs are the over-
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TABLE 2. HARD ENDPOINT TRIALS IN HYPERTENSION, 1997 Acronym
Age (years)
N (1000)
ALLHAT ANBP2 CAPPP CONVINCE HOT INSIGHT LIFE NORDIL PROGRESS SCOPE SHELL STOP2 SYST-EUR SYST-CHINA TOTAL
551 65–84 25–66 . 55 50–80 55–80 55–85 50–69 any . 65 . 60 70–84 . 60 60–79
40 6 7 15 19.2 6.6 9.2 12 6 4 4.8 6.6 3.7 2.3 142,400
Treatment CCB versus ACEI or a-blocker versus diuretic ACEI versus diuretic ACEI versus b-blocker/diuretic CCB versus b-blocker/diuretic CCB 1 others CCB versus diuretics AIIRA versus b-blocker CCB versus b-blocker/diuretic CCB versus diuretic AIIRA versus placebo CCB versus diuretic CCB versus b-blocker versus ACEI CCB versus ACEI versus placebo CCB versus placebo
ALLHAT, Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial; ANBP2, Second Australian National Blood Pressure Trial; CAPPP, Captopril Prevention Project; CONVINCE, Controlled Onset Verapamil Investigation for Cardiovascular Endpoints Trial; HOT, Hypertension Optimal Treatment Trial; INSIGHT, International Nifedipine-GITS Study: Intervention as a Goal in Hypertension Treatment; LIFE, Losartan Intervention for Endpoint Reduction Trial; NORDIL, Nordic Diltiazem Study; SCOPE, Surveillance and Control of Pathogens of Epidemiologic Importance Study; STOP2, Second Swedish Trial in Old Patients with Hypertension; SYST-EUR, Systolic Hypertension in the Elderly in Europe Trial; SYST-CHINA, Systolic Hypertension in Elderly Chinese Trial; CCB, calcium channel blocker; ACEI, angiotensin converting enzyme inhibitor; AIIRA, angiotensin II receptor antagonist.
whelming cause of poor compliance. The industry is aware of this reality, as lack of compliance translates into therapeutic failure and less drug usage. Consequently, even if a drug were superior in its efficacy, it is unlikely that it would be released if it elicited many adverse effects. ACE inhibitors, newer calcium antagonists, and recently the angiotensin II receptor antagonists all have a superior safety profile compared with b-blockers and diuretics. In the present climate of health care economics, and because of their price and the JNC V recommendations, the use of first generation antihypertensive agents is less restricted than that of the new drugs. There is no doubt that diuretics and b-blockers are well tolerated by many patients and should not be overlooked as therapy. However, at the first sign of even minor side effects, physicians should feel free to reach for the medication that is most acceptable to the patient. A judicious use of drug combinations is another way to decrease the adverse effects. The use of adverse effect-free drugs will become particularly important if it is proved that it safely lowers blood pressure closer to the normotensive range. Often, it is not appreciated that the closer a patient is to normotensive levels, the harder it is to further decrease the patient’s blood pressure. In the HOT study, a greater upward titration has been used for patients whose goal diastolic blood pressure was , 80 mm Hg than if the goal was less ambitious.33
SOME WORRISOME CLINICAL RESEARCH TRENDS As indicated above,4 most patients with hypertension have only a mild blood pressure elevation. It is erroneous to think that all patients will first undergo a phase of acceleration of hypertension, and only after that has taken place will patients suffer hypertension related morbidity/mortality. In fact, many patients sustain hypertension-related morbidity at very mild blood pressure levels.34,35 Although for an individual patient the absolute risk for having an event may not exceed 0.5%/year,36 this risk is 35% higher than in the normotensive population. This small excess of risk, because of the extensive prevalence of mild hypertension related mortality, accrues from patients with mild hypertension. The effect of treatment on mortality reduction in hypertension is one of the best evaluated fields in clinical medicine. We have learned to practice evidence based medicine, and when treating hypertension, we tend to concentrate only on what has been proven beyond doubt. This approach, although generally justified, is frequently coupled with a denial that a problem may exist in milder ranges of blood pressure elevation; the national and international recommendations are not explicit and our clinical practice ranges from total neglect to partial and inconsistent attention. And yet, on sheer statistical grounds, this is the area in which we could all have a major impact on public health. The situation is likely to
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worsen as health maintenance organizations and other prepaid schemes start to discourage use of drugs in ‘‘gray areas.’’ Unfortunately, the present direction of research will only aggravate this tendency. During the last few years, clinicians have witnessed an impressive growth of clinical research in hypertension and very important questions are being evaluated. However, none of the studies is in mild hypertension and none is placebo controlled. As Table 2 shows, all present studies are ‘‘positively controlled,’’ ie, they evaluate the efficacy of one antihypertensive compound as compared with another. As stated previously, we need such studies to improve our clinical practice, but we do not need them to the exclusion of investigations of mild hypertension. The results of the Australian Trial in Mild Hypertension were published in 198034; the results of the Hypertension Detection and Follow-up Program (HDFP)37 trial on mild hypertension results were reported in 1979; and, as far as I can see, since then, the worldwide research on mild hypertension has slowed down substantially. Coupled with this is the tendency to perform research only in very high risk populations: the elderly, patients with target organ damage, or patients with multiple risk factors. This is understandable from the supporter viewpoint; to prove better efficacy within a reasonable time, one must choose a population with an anticipated high rate of cardiovascular events. However, in the climate of evidence based medicine, there is real danger that the results of these studies will further distort our perceptions and, more importantly, the perception of insurers, as to those who need treatment. As we learn more about complicated hypertension, we should not forget what has already been proven in moderate but uncomplicated hypertension, and we must dare to treat ‘‘on faith’’ subjects with persistent, very mild hypertension after the nonpharmacologic means have failed to reduce the blood pressure. REFERENCES 1.
2.
3.
4.
Veterans Administration Cooperative Study Group on Antihypertensive Agents: Effects of treatment on morbidity in hypertension: results in patients with diastolic blood pressure averaging 90 through 114 mmHg. JAMA 1970;213:1143–1152. Mulrow CD, Cornell JA, Herrera CR, et al: Hypertension in the elderly. Implications and generalizability of randomized trials. JAMA 1994;272(24):1932–1938. Collins R, Peto R, MacMahon S, et al: Blood pressure, stroke, and coronary heart disease. Part 2. Short-term reduction in blood pressure: overview of randomised drug trials in their epidemiological context. Lancet 1990;335:827– 838. Burt VL, Whelton P, Rocella EJ, et al: Prevalence of hypertension in the US adult population. Results from the Third National Health and Nutrition Examination Study. Hypertension 1995;25:305–313.
5.
Burt VL, Cutler JA, Higgins M, et al: Trends in the prevalence, awareness, treatment and control of hypertension in the adult U.S. population. Data from the Health Examination Surveys, 1960 to 1961. Hypertension 1995;26:60 – 69.
6.
Williams RR, Hunt SC, Hopkins PN, et al: Familial dyslipidemic hypertension. JAMA 1988;259:3579 –3586.
7.
Modan M, Halkin H, Almog S, et al: Hyperinsulinemia. A link between hypertension obesity and glucose intolerance. J Clin Invest 1985;75:809 – 817.
8.
Berglund G, Larsson B, Andersson O, et al: Body composition and glucose metabolism in hypertensive middle-aged males. Acta Med Scand 1976;200:163–169.
9.
Reaven GM: Banting lecture 1988; role of insulin resistance in human disease. Diabetes 1988;37:1595–1607.
10.
Julius S, Jamerson K, Mejia A, et al: The association of borderline hypertension with target organ changes and higher coronary risk. Tecumseh Blood Pressure Study. JAMA 1990;264:354 –358.
11.
Smith SD, Julius S, Jamerson K, et al: Hematocrit levels and physiologic factors in relationship to cardiovascular risk in Tecumseh, Michigan. Hypertension 1994;12: 455– 462.
12.
Ducimetiere P, Eschwege E, Papoz L, et al: Relationship of plasma insulin levels to the incidence of myocardial infarction and coronary heart disease mortality in a middle-aged population. Diabetologia 1980;19:205–210.
13.
Welborn TA, Wearne K: Coronary heart disease incidence and cardiovascular mortality in Busselton with reference to glucose and insulin concentrations. Diabetes Care 1979;2:154 –160.
14.
Pyorala K, Savolainen E, Kaukola S, et al: Plasma insulin as a coronary heart disease risk factor: relationship to other risk factors and predictive value during 91⁄2 year follow-up of the Helsinki Policemen Study population. Acta Med Scand 1985;701(suppl):38 –52.
15.
Sorlie PD, Garcia-Palmieri MR, Costas R Jr., et al: Hematocrit and risk of coronary heart disease: the Puerto Rico Heart Health Program. Am Heart J 1981;101:456 – 461.
16.
Campbell MJ, Elwood PC, Mackean J, et al: Mortality, haemoglobin level and haematocrit in women. J Chronic Dis 1985;38:881– 889.
17.
Julius S, Gudbrandsson T, Jamerson K, et al: Hypothesis. The hemodynamic link between insulin resistance and hypertension. J Hypertens 1991;9:983–986.
18.
Julius S: Sympathetic hyperactivity and coronary risk in hypertension (Corcoran Lecture). Hypertension 1993;21:886 – 893.
19.
Esler M, Julius S, Sweifler A, et al: Mild high-renin essential hypertension: neurogenic human hypertension? N Engl J Med 1977;296:405– 411.
20.
Julius S, Krause L, Schork K, et al: Hyperkinetic borderline hypertension in Tecumseh, Michigan. J Hypertens 1991;9:77– 84.
21.
Alderman MH, Madhavan S, Oot WL, et al: Association of the renin-sodium profile with the risk of myocardial infarction in patients with hypertension. N Engl J Med 1991;324:1098 –1104.
22.
Palatini P, Julius S: Heart rate and the cardiovascular risk. J Hypertens 1997;15:1–15.
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23.
Dzau VJ: Short- and long-term determinants of cardiovascular function and therapy: contributions of circulating and tissue renin-antiotensin systems. J Cardiovasc Pharmacol 1989;14(suppl 4):S1–S5.
24.
Dzau VJ, Gibbons GH, Pratt RE: Molecular mechanisms of vascular renin-angiotensin system in myointimal hyperplasia. Hypertension 1991;18(suppl):II-100 –II-105.
25.
Simpson P: Norepinephrine-stimulated hypertrophy of cultured rat myocardial cells is an alpha-1 adrenergic response. J Clin Invest 1983;72:732–738.
26.
Hart MN, Heistad DD, Brody MJ: Effect of chronic hypertension and sympathetic denervation on wall/lumen ratio of cerebral vessels. Hypertension 1980;2:419–428.
27.
Levy D, Garrison RJ, Savage DD, et al: Prognostic implications of echocardiographically determined left ventricular mass in the Framingham heart study. N Engl J Med 1990;322:1561–1566.
28.
Folkow B: Role of vascular factors in hypertension. Contrib Nephrol 1977;8:81–94.
29.
Lewis EJ, Hunsicker LG, Bain RP, et al: The effect of angiotensin-converting enzyme inhibition on diabetic nephropathy. N Engl J Med 1993;329:1456 –1462.
30.
Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure: The fifth report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med 1993;153:159 –183.
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31.
Cruickshank JM, Thorp JM, Zacharias FJ: Benefits and potential harm of lowering high blood pressure. Lancet 1987;March:581–584.
32.
Alderman MH, Madhavan S, Cohen H: Antihypertensive drug therapy. The effect of JNC criteria on prescribing patterns and patient status through the first year. Am J Hypertens 1996;9:413– 418.
33.
Julius S: The evidence for a pathophysiology significance of the sympathetic overactivity in hypertension. Clin Exp Hypertens [A] 1996;18:305–321.
34.
Australian National Blood Pressure Study: The Australian therapeutic trial in mild hypertension. Lancet 1980; 1:1261–1267.
35.
A report by the management committee of the Australian therapeutic trial in mild hypertension. Untreated mild hypertension. Lancet 1982;i:185–191.
36.
Julius S, Schork MA: Predictors of hypertension, in Perry HM, Jr, Smith WM (eds): Mild Hypertension: To Treat or Not to Treat. Annals of the New York Academy of Sciences, Vol. 304. NY Academy of Sciences, New York, 1978, pp. 38 –52.
37.
Hypertension Detection and Follow-up Program Cooperative Group: Five-year findings of the hypertension detection and follow-up program. I. Reduction in mortality of persons with high blood pressure, including mild hypertension. JAMA 1979;242:2562–2571.
1997;10:300S–305S
Current Trends in the Treatment of Hypertension: A Mixed Picture Stevo Julius
It has been calculated that hypertension ranks as the fourth largest mortality risk factor in the world, predicting 6% of all deaths. Mild hypertension accounts for the largest proportion of cardiovascular deaths in the United States because of its high prevalence. Thus, mild hypertension should be the focus of treatment efforts. In addition, to achieve better results in the next century, we will have to refocus the treatment from the global goal of blood pressure lowering to exploration of specific effects of drugs on the diverse pathophysiologic aspects of hypertension including the complex metabolic and hemodynamic aberrations associated with human hypertension, as well as trophic factors. Another disconcerting feature of current hypertension management is the inadequate lowering of the blood pressure in those patients treated for
I
n the last four decades the achievements of antihypertensive treatment have been quite exceptional. Together with some malignancies, hypertension is on a rather short list of conditions in which treatment of the symptom, without knowledge of the causes, decreases the disease-specific mortality. In the United States, early trials that have demonstrated that antihypertensive treatment reduces morbidity/mortality1 stimulated massive efforts for pa-
From the Division of Hypertension, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan. Address correspondence and reprint requests to Stevo Julius, MD, ScD, Frederick G. L. Huetwell Professor of Hypertension, Division of Hypertension, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 481090356.
© 1997 by the American Journal of Hypertension, Ltd. Published by Elsevier Science, Inc.
hypertension. The National Health and Nutrition Examination Study (NHANES) survey in United States shows that patients treated for hypertension have blood pressure values that are only slightly lower than in untreated hypertensives and remain higher than in normotensive subjects. Patient compliance with treatment is one major problem. The development of better tolerated drugs ought to bring improvement. Overall, an educational effort aimed at physicians, the general public, and health care providers is necessary to improve the treatment of hypertension and reverse the negative trends in cardiovascular mortality. Am J Hypertens 1997;10:300S–305S © 1997 American Journal of Hypertension, Ltd. KEY WORDS:
Hypertension, drug therapy, morbidity, mortality, angiotensin II receptor antagonist.
tient detection and for education of health care providers. Results soon followed and, as shown in Figure 1, from 1972 until 1990, mortality from strokes and coronary heart disease in the United States has been steadily declining. A careful observer, however, will note that 1) the decline of coronary heart disease is less steep than that in strokes, and 2) the stroke curve seems to be more shallow since 1982. The less steep decline in coronary mortality in the general population mirrors the result from antihypertensive treatment trials that have also shown the treatment to be more efficacious in reducing strokes than heart attacks.2,3 Possible reasons for this discrepancy have been widely discussed. However, the blunting of the stroke curve seems to have eluded us all. A review of most recent data in the Vital Statistics of the United States 0895-7061/97/$17.00 PII S0895-7061(97)00389-0
AJH–DECEMBER 1997–VOL. 10, NO. 12, PART 2
CURRENT TRENDS IN THE TREATMENT OF HYPERTENSION
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FIGURE 1. Decline in age-adjusted mortality since 1972. Data for 1990 are provisional. Adapted from the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med 1993; 153:154 –183.
shows that the trend continued, and since 1992 the rates of strokes have ceased to decline. This, combined with recent data from the National Health and Nutrition Examination Study survey (NHANES)4,5 showing that in only 29% of all hypertensives is the blood pressure below the goal of 140/90 mm Hg, illustrates beyond any doubt that we still have a long way to go in combating hypertension and its consequences. In fact, a new concentrated effort—similar to the National High Blood Pressure Education Program—will be needed to reverse these negative trends. This article reviews some factors that may be responsible for the recent negative trend in cardiovascular mortality. THE LACK OF INTEREST IN PATHOPHYSIOLOGY AND THE UNREALISTIC EXPECTATION THAT BLOOD PRESSURE LOWERING WILL REVERSE ALL HYPERTENSION-RELATED MORBIDITY In teaching us the essentials about cardiovascular risk, epidemiologic studies unwittingly delivered the wrong message. Numerous tables for risk assessment, mostly based on the Framingham data, permitted calculation of the additive risk of such factors as high cholesterol levels, obesity, and hypertension. This implied that these risk factors are independent when, in fact, they are intimately interrelated.6 Hyperinsulinemia in hypertension is so frequent7,8 that it has been named a ‘‘syndrome.’’9 In the Tecumseh Blood Pressure study (Table 1), as in other studies, high insulin levels are closely associated with dyslipidemia and overweight.10 Furthermore, in the Tecumseh Blood Pressure study, higher blood pressure levels in men are strongly associated with higher hematocrit levels.11 Elevated insulin levels, which are secondary to insulin resistance, are a strong predictor of future coronary mortality.12–14 Furthermore, dyslipidemia
and elevated hematocrit are also well known risk factors for coronary heart disease.15,16 In the Tecumseh Blood Pressure study of young subjects (average age, 32 years), the significant correlation between insulin, dyslipidemia, obesity, and hematocrit extends in a linear fashion into the normotensive range. This suggests a fundamental relationship; factors regulating the blood pressure levels appear also to govern metabolic variables. Whereas this is of pathophysiologic interest and prompted us to speculate about the mechanism of the association,17,18 the clinical importance lies in the fact that a hypertensive patient is likely to have not only hypertension, but also many of the other coronary risk factors. Plasma renin values19 and norepinephrine levels20 are frequently increased in hypertension. Both high renin21 and enhanced sympathetic tone22 are associated with a poor cardiovascular prognosis in hypertension. Part of this negative effect may reflect the vascular and cardiac ‘‘trophic’’ effects of angiotensin and norepinephrine.23–26 Left ventricular hypertrophy is one of the strongest known risk factors for cardio-
TABLE 1. RISK FACTORS—TECUMSEH BLOOD PRESSURE STUDY Normotensive (n 5 822)
Borderline (n 5 124)
P
176 43
190 40
, .0001 , .001
95 12 92 14
135 18 95 30
, .0001 , .0001 , .001 , .001
Cholesterol (mg/dL) HDL (mg/dL) Triglycerides mg/dL) Insulin (mU/mL) Glucose (mg/dL) Overweight (%) Data taken from Julius et al.10
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vascular mortality,27 and vascular hypertrophy contributes to acceleration of hypertension.28 Behind the facade of blood pressure elevation in hypertension, there are a large number of other abnormalities, many of which contribute to cardiovascular risk in hypertension. The list of coronary risk factors quoted above is deliberately abbreviated and detailed discussion can be found elsewhere,18 but the main point of this presentation is that hypertension is a complex disease. It is therefore naive to expect blood pressure lowering to be a panacea, particularly when many antihypertensive drugs aggravate dyslipidemia, worsen insulin resistance, activate the renin-angiotensin system, and elicit a compensatory increase of sympathetic activity. Hence, the question is not whether blood pressure lowering (regardless of which drug is used) is useful: it is. Hypertension is a very strong risk factor, and lowering blood pressure will always be superior to placebo or to not treating the disease. However, the recent decline in the reduction of cardiovascular mortality forces us to ask whether we can do better. Will ‘‘blood pressure lowering plus’’ yield better results? Will antitrophic effects of angiotensin converting enzyme (ACE) inhibitors and angiotensin II antagonists translate into better clinical results? Will modern calcium antagonists outperform the first generation dihydropyridines? How do they compare with b-blockers and diuretics? New and better tolerated sympatholytics are being evaluated; will they be helpful? Luckily, the field of antihypertensive treatment is not dormant. Massive trials are being launched and many of these questions are being prospectively evaluated. We already know that blood pressure lowering with ACE inhibitor captopril is superior to other forms of blood pressure reduction in juvenile diabetics with renal failure.29 The hope is that we are moving from empirical to rational treatment of hypertension and that new trials will teach us when and how to use a specific antihypertensive treatment in a specific patient. INADEQUATE BLOOD PRESSURE LOWERING NHANES4,5 is a survey of a population sample carefully selected to represent overall trends in the United States. In the recent survey,5 the average blood pressure in the hypertensive population not receiving treatment was 144/88 mg Hg, attesting to the well known fact that most hypertensive patients have only mild blood pressure elevation. In the segment of hypertensive patients who were receiving treatment at the time of the survey, the average blood pressure was 135/83 mm Hg, a 9/5 mm Hg difference from that of untreated hypertensives. At first glance, the overall values achieved in hypertensives who are on treatment appear to be reasonable; however, one receives a
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very different picture when these values are compared with the average values in the normotensive population which, in the NHANES survey, was 117/71 mm Hg. Obviously, one cannot expect an average mortality in a group of hypertensive subjects whose blood pressure is maintained at a level that exceeds that of the normotensive population by 18/12 mm Hg. These disappointing figures can be explained by a number of factors. The national recommendation in the fifth report of the Joint National Committee (JNC V) on Detection, Evaluation, and Treatment of High Blood Pressure calls for blood pressure lowering below 140/90 mm Hg, but does not specify how low physicians should decrease the blood pressure.30 By and large, physicians agree with this recommendation and are content to maintain blood pressure just below the dividing line between normotension and hypertension. Probably the major reason for this attitude is fear of the J-curve effect. The current controversy about the J-curve is a mirror image of discussions in the early 1950s, when conservative physicians were reluctant to use antihypertensive drugs for fear of underperfusing vital organs. These fears were soon dispelled by the overwhelming evidence that treatment is useful. Similarly, we will not move forward until the reports that blood pressure lowering below 85 mm Hg may be deleterious are fully explored.31,32 The results of the only prospective randomized trial to specifically investigate the issue of safety of aggressive blood pressure lowering in high risk patients will be available in the beginning of 1998. Should this study (the Hypertension Optimal Treatment [HOT] Study) demonstrate that it is safe to decrease blood pressure to near normotensive levels, new and more ambitious blood pressure goals will be promulgated. It is reasonable to expect that this will have a major impact on morbidity and mortality trends in the population. From the 1960s until 1990, the proportion of patients who were aware that they had high blood pressure increased from 53% to 89%.5 During the same period of time the percentage of subjects receiving antihypertensive medication increased from 35% to 79%. However, the percentage of subjects whose blood pressure is under control increased only modestly, from 45% to 55%. Admittedly, this is in part due to more stringent criteria (in the 1960s, the goal was blood pressure , 160/95 mm Hg and in the 1990s it was , 140/90 mm Hg). But the fact remains that in the 1990s, a large number of patients have inadequate blood pressure control. One of the major reasons for this state of affairs is the lack of compliance with antihypertensive medication regimens. Whereas cost of medication, memory problems, and ease of obtaining refills may all affect the compliance rates, there is no doubt that adverse effects of antihypertensive drugs are the over-
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TABLE 2. HARD ENDPOINT TRIALS IN HYPERTENSION, 1997 Acronym
Age (years)
N (1000)
ALLHAT ANBP2 CAPPP CONVINCE HOT INSIGHT LIFE NORDIL PROGRESS SCOPE SHELL STOP2 SYST-EUR SYST-CHINA TOTAL
551 65–84 25–66 . 55 50–80 55–80 55–85 50–69 any . 65 . 60 70–84 . 60 60–79
40 6 7 15 19.2 6.6 9.2 12 6 4 4.8 6.6 3.7 2.3 142,400
Treatment CCB versus ACEI or a-blocker versus diuretic ACEI versus diuretic ACEI versus b-blocker/diuretic CCB versus b-blocker/diuretic CCB 1 others CCB versus diuretics AIIRA versus b-blocker CCB versus b-blocker/diuretic CCB versus diuretic AIIRA versus placebo CCB versus diuretic CCB versus b-blocker versus ACEI CCB versus ACEI versus placebo CCB versus placebo
ALLHAT, Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial; ANBP2, Second Australian National Blood Pressure Trial; CAPPP, Captopril Prevention Project; CONVINCE, Controlled Onset Verapamil Investigation for Cardiovascular Endpoints Trial; HOT, Hypertension Optimal Treatment Trial; INSIGHT, International Nifedipine-GITS Study: Intervention as a Goal in Hypertension Treatment; LIFE, Losartan Intervention for Endpoint Reduction Trial; NORDIL, Nordic Diltiazem Study; SCOPE, Surveillance and Control of Pathogens of Epidemiologic Importance Study; STOP2, Second Swedish Trial in Old Patients with Hypertension; SYST-EUR, Systolic Hypertension in the Elderly in Europe Trial; SYST-CHINA, Systolic Hypertension in Elderly Chinese Trial; CCB, calcium channel blocker; ACEI, angiotensin converting enzyme inhibitor; AIIRA, angiotensin II receptor antagonist.
whelming cause of poor compliance. The industry is aware of this reality, as lack of compliance translates into therapeutic failure and less drug usage. Consequently, even if a drug were superior in its efficacy, it is unlikely that it would be released if it elicited many adverse effects. ACE inhibitors, newer calcium antagonists, and recently the angiotensin II receptor antagonists all have a superior safety profile compared with b-blockers and diuretics. In the present climate of health care economics, and because of their price and the JNC V recommendations, the use of first generation antihypertensive agents is less restricted than that of the new drugs. There is no doubt that diuretics and b-blockers are well tolerated by many patients and should not be overlooked as therapy. However, at the first sign of even minor side effects, physicians should feel free to reach for the medication that is most acceptable to the patient. A judicious use of drug combinations is another way to decrease the adverse effects. The use of adverse effect-free drugs will become particularly important if it is proved that it safely lowers blood pressure closer to the normotensive range. Often, it is not appreciated that the closer a patient is to normotensive levels, the harder it is to further decrease the patient’s blood pressure. In the HOT study, a greater upward titration has been used for patients whose goal diastolic blood pressure was , 80 mm Hg than if the goal was less ambitious.33
SOME WORRISOME CLINICAL RESEARCH TRENDS As indicated above,4 most patients with hypertension have only a mild blood pressure elevation. It is erroneous to think that all patients will first undergo a phase of acceleration of hypertension, and only after that has taken place will patients suffer hypertension related morbidity/mortality. In fact, many patients sustain hypertension-related morbidity at very mild blood pressure levels.34,35 Although for an individual patient the absolute risk for having an event may not exceed 0.5%/year,36 this risk is 35% higher than in the normotensive population. This small excess of risk, because of the extensive prevalence of mild hypertension related mortality, accrues from patients with mild hypertension. The effect of treatment on mortality reduction in hypertension is one of the best evaluated fields in clinical medicine. We have learned to practice evidence based medicine, and when treating hypertension, we tend to concentrate only on what has been proven beyond doubt. This approach, although generally justified, is frequently coupled with a denial that a problem may exist in milder ranges of blood pressure elevation; the national and international recommendations are not explicit and our clinical practice ranges from total neglect to partial and inconsistent attention. And yet, on sheer statistical grounds, this is the area in which we could all have a major impact on public health. The situation is likely to
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worsen as health maintenance organizations and other prepaid schemes start to discourage use of drugs in ‘‘gray areas.’’ Unfortunately, the present direction of research will only aggravate this tendency. During the last few years, clinicians have witnessed an impressive growth of clinical research in hypertension and very important questions are being evaluated. However, none of the studies is in mild hypertension and none is placebo controlled. As Table 2 shows, all present studies are ‘‘positively controlled,’’ ie, they evaluate the efficacy of one antihypertensive compound as compared with another. As stated previously, we need such studies to improve our clinical practice, but we do not need them to the exclusion of investigations of mild hypertension. The results of the Australian Trial in Mild Hypertension were published in 198034; the results of the Hypertension Detection and Follow-up Program (HDFP)37 trial on mild hypertension results were reported in 1979; and, as far as I can see, since then, the worldwide research on mild hypertension has slowed down substantially. Coupled with this is the tendency to perform research only in very high risk populations: the elderly, patients with target organ damage, or patients with multiple risk factors. This is understandable from the supporter viewpoint; to prove better efficacy within a reasonable time, one must choose a population with an anticipated high rate of cardiovascular events. However, in the climate of evidence based medicine, there is real danger that the results of these studies will further distort our perceptions and, more importantly, the perception of insurers, as to those who need treatment. As we learn more about complicated hypertension, we should not forget what has already been proven in moderate but uncomplicated hypertension, and we must dare to treat ‘‘on faith’’ subjects with persistent, very mild hypertension after the nonpharmacologic means have failed to reduce the blood pressure. REFERENCES 1.
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