PERSPECTIVE
The Appropriate Goals of Antihypertensive Therapy: Neither Too Much Nor Too Little Norman M. Kaplan, MD
• Although the treatment of hypertension has increased markedly during the last decade, many patients have been left undertreated, including many of the disadvantaged, the elderly, and those at relatively high overall risk for cardiovascular disease. A rapidly growing number of patients, however, are being exposed to overtreatment with resultant interference with their quality of life and potential hazards to their health. These include patients who are diagnosed and treated without adequate documentation of the presence of persistent hypertension, patients who are not appropriately managed with nondrug therapies, and patients who are given inappropriate and overly aggressive drug therapies. Better recognition of the frequency and potential hazards of overtreatment is needed so that more appropriate goals of antihypertensive therapy can be established and maintained. Annals of Internal Medicine. 1992;116:686-690. From the University of Texas Southwestern Medical Center at Dallas, Dallas, Texas. For the current author address, see end of text.
I n the United States today, the treatment of hypertension has become the most common reason for patients to see a physician and to receive medications (1). With the perception that this massive increase in the numbers of patients identified and treated for hypertension has contributed to the decreases in cardiovascular mortality witnessed over the past 20 years, repeated admonitions to find and treat all with an elevated blood pressure continue to appear (2, 3). Moreover, it is widely realized that many patients remain at risk because they have hypertension that is unrecognized or inadequately treated—the undertreated portion. On the other hand, I believe that few physicians are aware that an increasing number of hypertensive patients are being placed at physical risk and made increasingly uncomfortable because of unbridled enthusiasm to "get the pressure down." With current practices in the United States, the number of overtreated patients will certainly grow and become an increasingly serious problem in clinical practice. Reasons for Undertreatment of Hypertension A major reason that as many as half of hypertensive patients in the United States are not being adequately treated is that hypertension is more common in the poor, particularly in blacks living in inner cities, who 686
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are not receiving adequate care, particularly for nonacute conditions (4). They will be adequately treated for hypertension only if and when major changes in our health care delivery system are made. As Ginsberg and Ostow have noted (5), however, even if one or more of the plans now being considered for covering the uninsured are adopted, barriers to access and utilization will remain. For those poor who have access to health care, much of that care is provided in understaffed, underfunded public hospitals in which many impediments exist to the provision of long-term management of chronic conditions. Unless unemployment, illiteracy, and deprivation are largely eliminated, many hypertensive patients will remain untreated or inadequately managed. For many of those who are able to obtain medical care, treatment of hypertension may be inadequate because of the characteristics of the disease and its treatment that place many barriers to long-term control. Most patients who have no symptoms are asked to spend considerable money and are often made symptomatic without any obvious short-term advantages to their health. Obviously, adherence to therapy is a major problem with any asymptomatic condition that poses no immediate threat. Relatively few hypertensive patients are resistant to what should be adequate therapy. Some of these patients are not truly resistant if their pressures are taken outside of the physician's office. In various surveys (6, 7), as many as half of those with office diastolic blood pressure above 95 mm Hg despite treatment with two or more drugs have pressures persistently below 95 or even 90 out of the office. This "white-coat" phenomenon can best be recognized by use of home monitoring with an inexpensive semiautomatic device (8). Those who are truly resistant most commonly have expanded volume because of a combination of sodium retention by kidneys that are either damaged or that are reacting to a blood pressure lowered by nondiuretic drugs by retaining additional sodium. Excessive dietary sodium intake and inadequate diuretic therapy further complicate the problem. A larger number of patients are being undertreated because physicians are hesitant to push blood pressure down to the level needed for maximal protection. In most surveys of the status of hypertensive patients in the United States, a greater number of patients are being treated inadequately (blood pressure > 140/90) than the number of patients whose blood pressure is being kept under good control (1). Uncertainty remains as to the proper goal of therapy, but some patients are being kept at levels above 160/100 mm Hg, which are clearly above the appropriate goal. Levels that are too high may be condoned because of the desire not to induce bothersome side effects, particularly with the
use of drugs that act on the central nervous system or when initially high levels of blood pressure are lowered very quickly, inducing hypoperfusion of vital organs. Some patients are being treated to presumably adequate levels that may, in fact, not be maximally protective. One large group of such patients are diabetic patients who have early nephropathy as reflected by microalbuminuria. Considerable experimental data and limited clinical evidence suggest that protection against progressive diabetic glomerulosclerosis may require even lower systemic blood pressure than the 130/80 to 140/90 mm Hg range that most physicians are now seeking (9). In addition to diabetics, many hypertensive patients have multiple cardiovascular risk factors that place them at high overall risk (Table 1). They need even more vigorous therapy of minimally elevated blood pressure than do those patients who have none or few of these other risk factors. Care must be taken, however, not to lower the diastolic pressure in patients with preexisting coronary disease below the critical level needed to maintain coronary blood flow, a level that appears to be about 85 mm Hg (10). The common coexistence of dyslipidemia and hypertension mandates a more vigorous and more carefully constructed antihypertensive regimen that will avoid further aggravation of the lipid abnormality (10). These patients need the benefits of proper diet, regular exercise, and moderation of alcohol intake on both the blood pressure and the other cardiovascular risk factors. Because of the publication of the positive results of the Systolic Hypertension in the Elderly Trial (11), more patients will certainly be treated. In the past, many physicians have shied away from treating them because they had no evidence that lowering the blood pressure was beneficial and because they were concerned about potential harm from antihypertensive treatment of fragile elderly patients (1). Caution is still in order, but elderly patients with significant systolic hypertension are largely undertreated. Reasons for Overtreatment As noted above, more attention should be directed toward disadvantaged, resistant, high-risk, and elderly patients, all of whom tend to be undertreated. However, current medical practice in the United States is also exposing a substantial number of people to the dangers and inconveniences of overtreatment. Physicians in the United States aggressively diagnose and treat hypertension. Most practitioners in the United States diagnose and treat hypertension soon after recognition of a diastolic pressure above 90 mm Hg (12). Elsewhere, as in Germany (13), most practitioners treat only at levels above 100 mm Hg. Because this 10 mm Hg difference accounts for more than half of the entire hypertensive population, it potentially translates into over 20 million Americans being treated who might not be treated in other countries. The Appropriate Level of Therapy Although U.S. physicians usually start therapy soon after they document a diastolic pressure above 90 mm
Table 1. Prevalence of Other Coronary Risk Factors in Patients with Hypertension Risk Factor Smoking Hypercholesterolemia > 6.21 mmol/L* (> 240 mg/dL) Decreased high-density lipoprotein cholesterol < 1.03 mmol/L* (< 40 mg/dL) Left ventricular hypertrophy Obesity Diabetes Hyperinsulinemia Sedentary lifestyle
35 40 25 30 40 15 -50 > 50
* To convert to mg/dL, divide by 0.02586.
Hg, an expert committee of the World Health Organization and the International Society of Hypertension has recommended institution of drug therapy only if the diastolic blood pressure is 95 mm Hg or higher after 3 to 6 months of repeated blood pressure readings and the use of appropriate nondrug therapies (14) (Figure 1). The need for multiple readings, preferably out of the physician's office, is increasingly recognized as essential to avoid overdiagnosis and overtreatment. As many as half of people initially found to have a diastolic blood pressure above 95 mm Hg will spontaneously have a fall below 90 mm Hg on no therapy over the next 4 to 6 months (15). About 20% of those with office readings persistently elevated for years will be found to be consistently normotensive when multiple readings are obtained outside of the physician's office (16). Because such transient or "white-coat" hypertensive patients may have many other metabolic and hemodynamic dysfunctions that place them at higher overall risk (17), they need closer surveillance and more intensive use of nondrug therapies, but they do not need antihypertensive drug therapy. Patients with borderline or minimally elevated blood pressures who are otherwise at low cardiovascular risk should not be given drug therapy for two main reasons. First, such therapy has not been found to reduce their cardiovascular risks: In multiple large placebo-controlled clinical trials, clear protection has been demonstrated only for those with an initial diastolic blood pressure of 95 mm Hg or higher (18). Second, treating such patients is preventive and, despite our overwhelming desire to prevent more severe hypertension and its complications, preventive therapy with drugs cannot be ethically defended. Among others (19, 20), Allan Brett (21) has stated the issue as follows: In medical practice, the duty to inflect no harm (nonmaleficence) continuously competes with the duty to benefit the patient (beneficience). It follows that equivocal data on interventional efficacy may be sufficient to justify a recommendation to change some habits, since the risk of doing harm is small. Conversely, reasonably certain data is necessary to justify pharmacologic interventions, since the risk of doing harm is relatively greater. This argument assumes importance for a medicalized society in which unbridled enthusiasm to medicate often precedes reasonable proof of efficacy.
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The Need for Nondrug Therapies As noted by Brett, the changing of harmful habits can be justified in the management of patients with borderline hypertension. Physicians often talk about nondrug therapies but use them minimally or ineffectually because they are more difficult to implement and are widely thought to be ineffectual. Recent evidence documents the practicality and effectiveness of weight reduction (22), moderate sodium restriction (23), regular aerobic exercise (24), and moderation of alcohol intake to no more than two usual portions (for example, two beers, two glasses of wine, or two mixed drinks) per day (25). When such therapies are used appropriately, they will lower blood pressure safely and should cause no loss of pleasure. Many who would be overtreated with drugs may be adequately treated without drugs. However, adequate compensation needs to be provided to those who counsel and follow patients with nondrug treatments so that these therapies will be used more widely. The Problems with Antihypertensive Drugs For several reasons, drugs are often used incorrectly. Two problems with current practice are the use of too large a starting dose and the rigid addition of multiple drugs that are not appropriate to the patient's needs if only office readings are taken. Too Large a Starting Dose As seen with drugs introduced long ago, such as diuretics (26) and beta-blockers (27), as well as those introduced recently, including angiotensin-converting enzyme (ACE) inhibitors (27) and calcium channel blockers (28), the initially recommended starting doses have turned out to be too high. As Andrew Herxheimer has stated (27):
For a new drug to penetrate the market quickly, it should be rapidly effective in a high proportion of patients and simple to use. To achieve this, the dosage of the first prescription is therefore commonly set at about the ED90 level—ie, the dose which the early clinical (phase II) studies have shown to be effective in 90% of the target population, provided that the unwanted effects at this dose are considered acceptable. In 25% of patients a smaller, perhaps much smaller, dose (the ED25) will be effective. The patients in this quartile are the most sensitive to the drug and are liable to receive far more than they need if they are given the ED90. They are also likely to be more sensitive to the dose-related side-effects of the drug. Herxheimer goes on to recommend a logical solution: Tablets containing less than the usual maximal effective dose should be marketed. For this to be effective, however, physicians must be willing to start most patients with a dose of medication that will not be fully effective. As he states, "The disadvantage from the marketing standpoint is that for the majority of patients the dose must be titrated. That is time-consuming for doctors and patients and more difficult to explain to them. A drug requiring dose titration cannot be presented as the quick fix, the instant good news that marketing departments love" (27). The "quick fix" is inappropriate for most hypertensive patients. To allow for autoregulation of blood flow to maintain perfusion to vital organs when perfusion pressure is lowered, the fall in pressure should be relatively small and gradual (29). More precipitous falls in pressure as frequently seen with larger starting doses may induce considerable hypoperfusion that results in symptoms that are at least bothersome (fatigue, impotence) and that may be potentially hazardous (postural hypotension, coronary ischemia). It is far better to "start low and go slow." An excellent example is the calcium channel blocker, verapamil (28). A 50% dose reduction eventually provides almost
Figure 1. Recommendations for the definition and management of mild hypertension. From the Third Mild Hypertension Conference of the World Health Organization and the International Society of Hypertension. (Reproduced with permission from reference 7.) BP = blood pressure. 688
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as much antihypertensive efficacy with fewer initial side effects. Because this class of drugs has been found to be particularly useful in elderly patients (30), verapamil will probably be given to many older patients. For them, even half of the lower dose 180-mg sustainedrelease tablet may be preferable initially. Even though few patients will respond adequately to such a small amount, those that do will be better managed and the remainder will have begun on a slow titration to gently reduce the pressure to the desired level. Rigid Compared with Individualized Choices Until recently, most practitioners started every patient with a diuretic, usually in high doses. Because problems with high-dose diuretic-based therapy have surfaced at the same time that many more attractive agents have become available, initial therapy has been broadened to include choices from multiple classes of drugs. The 1988 report of the Joint National Committee (31) recommended beta-blockers, ACE inhibitors, and calcium channel blockers as initial choices in addition to diuretics. The second generation of alpha-blockers are also appropriate (32). With the availability of more drugs, the appropriate matching of the type of drug to the individual patient's needs, based primarily on the presence of concomitant medical conditions, is at least theoretically feasible. Individualized therapy offers the promise of causing fewer adverse effects with less medication that is more suited to the patient's needs. Examples include use of an alpha-blocker in a hypertensive patient with hypercholesterolemia or a calcium channel blocker in a patient with angina. Even when careful matching is attempted, the choice may either not be effective or may cause bothersome side effects. Therefore, sequential use of drugs from the major classes has been suggested as a way to find the best possible selection (33). Guyatt and coworkers (34) have proposed a series of randomized controlled trials for each individual patient referred to as "n-of-1," involving a series of blinded comparisons of individual drugs against a placebo until the optimum choice is found. As attractive as the approach may be, most patients can be provided with effective and comfortable therapy by simply checking carefully for both efficacy and adverse effects after a drug is started and substituting a drug from another class if that choice is not suitable. In particular, patients should be carefully questioned about symptoms induced by overtreatment, such as postural dizziness, fatigue, and impotence. Because blood pressure readings obtained in the office are usually higher than those present at home, overtreatment may not be suspected if only office readings are taken. In the past, the goal of therapy was usually to bring the pressure down to a level close to normal, that is, 120/80, without inordinate side effects. However, more recently, an observation first made in 1979 (35) has been amply reconfirmed (36): When the diastolic blood pressure is lowered below 85 mm Hg, a greater number of coronary ischemic events are seen, particularly in hypertensive patients with preexisting coronary disease.
Although the number of coronary events falls progressively as diastolic pressure is lowered from high levels to below 90 mm Hg, when a nadir around 85 mm Hg is reached, the number of events starts to rise again, defining a J- or U-curve of coronary events relative to treated blood pressure levels. The heart in the hypertensive patient may be uniquely vulnerable to a fall in perfusion when systemic pressure is lowered so that such ischemia may not be seen in the brain, kidney, or other vital organs when the pressure is lowered to near "normal" levels. Nonetheless, many hypertensive patients have coronary disease—often silent—and therefore are susceptible to the J-curve. Although some investigators question the existence of the J-curve and decry the practice of limiting treatment so that diastolic pressures are not lowered below 85 mm Hg (37), I believe current knowledge mandates caution in treating most patients, particularly those with a high likelihood of underlying coronary disease. This advice seems particularly prudent because there are no data documenting a decrease in coronary events when the diastolic blood pressure is lowered below 85 mm Hg compared with the event rate at levels of 90 mm Hg or higher. Even though keeping the diastolic blood pressure above 85 mm Hg may expose some patients to greater risks for stroke and renal damage, the overwhelming predominance of morbidity and mortality from coronary disease in the hypertensive population justifies this more conservative approach. This does not preclude the purposeful reduction of pressure to lower levels in certain patients who probably need even lower pressures. As noted earlier, diabetic patients with microalbuminuria may be one such group because very low systemic pressures may be needed to keep intraglomerular pressure low enough to stop progressive glomerular sclerosis. Conclusion Both overtreatment and undertreatment remain problems in the management of hypertension. Many persons are not being treated at all because of personal and societal barriers to health care that will require major changes in our entire delivery system. Most of the remainder of the undertreated are simply not being provided the care that is now recognized to be appropriate. I hope that they will be more adequately treated as physicians gain confidence through publication of results of clinical trials and exposure to continuing education. The issues of overtreatment are less easily recognized because most patients whose pressures are too low or whose therapy is inappropriate do not suffer overt complications and, if they do, their overtreatment may not be thought to be responsible. However, they are being put at additional risk and made to suffer unnecessarily from side effects. Neither too much nor too little may be hard to achieve, but most hypertensive patients can be treated to achieve safer levels of blood pressure without bothersome side effects. The proper response to therapy should be attainable by gradual, gentle reduction of the blood pressure by lower initial doses of drugs that are
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slowly titrated to the desired effects. The choice of therapy should be individualized and changed if necessary. Current Author Address: Dr. Kaplan: University of Texas Southwestern Medical Center, C88-102, 5323 Harry Hines Boulevard, Dallas, TX 75235. References 1. Kaplan NM. Hypertension in the population at large. In: Kaplan NM; ed. Clinical Hypertension, 5th ed. Baltimore: Williams & Wilkins; 1990:1-25. 2. Littenberg B, Garber AM, Sox HC J r . Screening for hypertension. Ann Intern Med. 1990;112:192-202. 3. Progress toward achieving the 1990 high blood pressure objectives. MMWR Morbid Mortal Wkly Rep. 1990;39:704-7. 4. Blendon RJ, Aiken LH, Freeman HE, Corey CR. Access to medical care for black and white Americans. A matter of continuing concern. JAMA. 1989;261:278-81. 5. Ginzberg E, Ostow M. Beyond universal health insurance to effective health care. JAMA. 1991;265:2559-62. 6. Waeber B, Scherrer U, Petrillo A, Bidiville J, Nussberger J, Waeber G, et al. Are some hypertensive patients overtreated? A prospective study of ambulatory blood pressure recording. Lancet. 1987;2:732-4. 7. Mejia AD, Egan BM, Schork NJ, Zweifler AJ. Artefacts in measurement of blood pressure and lack of target organ involvement in the assessment of patients with treatment-resistant hypertension. Ann Intern Med. 1990;112:270-7. 8. Evans CE, Haynes RB, Goldsmith CH, Hewson SA. Home blood pressure-measuring devices: a comparative study of accuracy. J Hypertens. 1989;7:133-42. 9. Mogensen CE. Prevention and treatment of renal disease in insulindependent diabetes mellitus. Semin Nephrol. 1990;10:260-73. 10. Kaplan NM. Changing hypertension treatment to reduce the overall cardiovascular risk. J Hypertens. 1990;8(Suppl 7):S175-9. 11. SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). JAMA. 1991;265:3255-64. 12. Bostick RM, Luepker RV, Kofron PM, Pirie PL. Changes in physician practice for the prevention of cardiovascular disease. Arch Intern Med. 1991;151:478-84. 13. Weiland SK, Keil U, Spelsberg A, Hense HW, Hartel U, Gefeller O, et al. Diagnosis and management of hypertension by physicians in the Federal Republic of Germany. J Hypertens. 1991;9:131-4. 14. 1989 guidelines for the management of mild hypertension: memorandum from a WHO/ISH meeting. J Hypertens. 1989;7:689-93. 15. Management Committee of the Australian Therapeutic Trial in Mild Hypertension. Untreated mild hypertension. Lancet. 1982;1:185-91. 16. Pickering TG, James GD, Boddie C, Harshfield GA, Blank S, Laragh J H . How common is white coat hypertension? JAMA. 1989;259: 225-8. 17. Julius S, Mejia A, Jones K, Krause L, Schork N, van de Ven C, et al. "White coat" versus "sustained" borderline hypertension in Tecumseh, Michigan. Hypertension. 1990;16:617-23.
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18. Freis ED. Rationale against the drug treatment of marginal diastolic systemic hypertension. Am J Cardiol. 1990;66:368-71. 19. Guttmacher S, Teitelman M, Chapin G, Garbowski G, Schnall P. Ethics and preventive medicine: the case of borderline hypertension. Hastings Cent Rep. 1981;ll(l):12-20. 20. Rose G. Strategy of prevention: lessons from cardiovascular disease. Br Med J [Clin Res Ed]. 1981;282:1847-51. 21. Brett AS. Ethical issues in risk factor intervention. Am J Med. 1984;76:557-61. 22. Schotte DE, Stunkard AJ. The effects of weight reduction on blood pressure in 301 obese patients. Arch Intern Med. 1990;150:1701-4. 23. Law MR, Frost CD, Wald NJ. By how much does dietary salt reduction lower blood pressure? Ill—Analysis of data from trials of salt reduction. BMJ. 1991;302:819-24. 24. World Hypertension League. Physical exercise in the management of hypertension: a consensus statement by the World Hypertension League. J Hypertens. 1991;9:283-7. 25. Parker M, Puddey IB, Beilin LJ, Vandongen R. Two-way factorial study of alcohol and salt restriction in treated hypertensive men. Hypertension. 1990;16:398-406. 26. Carlsen JE, Kober L, Torp-Pedersen C, Johansen P. Relation between dose of bendrofluazide, antihypertensive effect, and adverse biochemical effects. BMJ. 1990;300:975-8. 27. Herxheimer A. How much drug in the tablet? Lancet. 1991 ;337: 346-8. 28. Holzgreve H, Distler A, Michaelis J, Philipp T, Wellek S. Verapamil versus hydrochlorothiazide in the treatment of hypertension: results of long term double blind comparative trial. BMJ. 1989;299:881-6. 29. Strandgaard S, Haunso S. Why does antihypertensive treatment prevent stroke but not myocardial infarction? Lancet. 1987;2:65861. 30. Cummings DM, Amadio P J r , Nelson L, Fitzgerald J M . The role of calcium channel blockers in the treatment of essential hypertension. Arch Intern Med. 1991;151:250-9. 31. The 1988 report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med. 1988;148:1023-38. 32. Khoury AF, Kaplan NM. Alpha-blocker therapy of hypertension. An unfulfilled promise. JAMA. 1991;266:394-8. 33. Brunner HR, Menard J, Waeber B, Burnier M, Biollaz J, Nussberger J, et al. Treating the individual hypertensive patient: considerations on dose, sequential monotherapy and drug combinations. J Hypertens. 1990;8:3-11. 34. Guyatt GH, Keller J L , Jaeschke R, Rosenbloom D, Adachi JD, Newhouse MT. The n-of-1 randomized controlled trial: clinical usefulness. Ann Intern Med. 1990;112:293-9. 35. Stewart IM. Relation of reduction in pressure to first myocardial infarction in patients receiving treatment for severe hypertension. Lancet. 1979;1:861-5. 36. Farnett L, Mulrow CD, Linn WD, Lucey CR, Tuley MR. The J-curve phenomenon and the treatment of hypertension. Is there a point beyond which pressure reduction is dangerous? JAMA. 1991; 165:489-95. 37. Hansson L. How far should blood pressure be lowered? What is the role of the J-curve? [Editorial]. Am J Hypertens. 1990;3:726-9.
15 April 1992 • Annals of Internal Medicine • Volume 116 • Number 8
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The Appropriate Goals of Antihypertensive Therapy: Neither Too Much Nor Too Little Norman M. Kaplan, MD
• Although the treatment of hypertension has increased markedly during the last decade, many patients have been left undertreated, including many of the disadvantaged, the elderly, and those at relatively high overall risk for cardiovascular disease. A rapidly growing number of patients, however, are being exposed to overtreatment with resultant interference with their quality of life and potential hazards to their health. These include patients who are diagnosed and treated without adequate documentation of the presence of persistent hypertension, patients who are not appropriately managed with nondrug therapies, and patients who are given inappropriate and overly aggressive drug therapies. Better recognition of the frequency and potential hazards of overtreatment is needed so that more appropriate goals of antihypertensive therapy can be established and maintained. Annals of Internal Medicine. 1992;116:686-690. From the University of Texas Southwestern Medical Center at Dallas, Dallas, Texas. For the current author address, see end of text.
I n the United States today, the treatment of hypertension has become the most common reason for patients to see a physician and to receive medications (1). With the perception that this massive increase in the numbers of patients identified and treated for hypertension has contributed to the decreases in cardiovascular mortality witnessed over the past 20 years, repeated admonitions to find and treat all with an elevated blood pressure continue to appear (2, 3). Moreover, it is widely realized that many patients remain at risk because they have hypertension that is unrecognized or inadequately treated—the undertreated portion. On the other hand, I believe that few physicians are aware that an increasing number of hypertensive patients are being placed at physical risk and made increasingly uncomfortable because of unbridled enthusiasm to "get the pressure down." With current practices in the United States, the number of overtreated patients will certainly grow and become an increasingly serious problem in clinical practice. Reasons for Undertreatment of Hypertension A major reason that as many as half of hypertensive patients in the United States are not being adequately treated is that hypertension is more common in the poor, particularly in blacks living in inner cities, who 686
© 1992 American College of Physicians
Downloaded from https://annals.org by Karolinska Institute user on 01/11/2019
are not receiving adequate care, particularly for nonacute conditions (4). They will be adequately treated for hypertension only if and when major changes in our health care delivery system are made. As Ginsberg and Ostow have noted (5), however, even if one or more of the plans now being considered for covering the uninsured are adopted, barriers to access and utilization will remain. For those poor who have access to health care, much of that care is provided in understaffed, underfunded public hospitals in which many impediments exist to the provision of long-term management of chronic conditions. Unless unemployment, illiteracy, and deprivation are largely eliminated, many hypertensive patients will remain untreated or inadequately managed. For many of those who are able to obtain medical care, treatment of hypertension may be inadequate because of the characteristics of the disease and its treatment that place many barriers to long-term control. Most patients who have no symptoms are asked to spend considerable money and are often made symptomatic without any obvious short-term advantages to their health. Obviously, adherence to therapy is a major problem with any asymptomatic condition that poses no immediate threat. Relatively few hypertensive patients are resistant to what should be adequate therapy. Some of these patients are not truly resistant if their pressures are taken outside of the physician's office. In various surveys (6, 7), as many as half of those with office diastolic blood pressure above 95 mm Hg despite treatment with two or more drugs have pressures persistently below 95 or even 90 out of the office. This "white-coat" phenomenon can best be recognized by use of home monitoring with an inexpensive semiautomatic device (8). Those who are truly resistant most commonly have expanded volume because of a combination of sodium retention by kidneys that are either damaged or that are reacting to a blood pressure lowered by nondiuretic drugs by retaining additional sodium. Excessive dietary sodium intake and inadequate diuretic therapy further complicate the problem. A larger number of patients are being undertreated because physicians are hesitant to push blood pressure down to the level needed for maximal protection. In most surveys of the status of hypertensive patients in the United States, a greater number of patients are being treated inadequately (blood pressure > 140/90) than the number of patients whose blood pressure is being kept under good control (1). Uncertainty remains as to the proper goal of therapy, but some patients are being kept at levels above 160/100 mm Hg, which are clearly above the appropriate goal. Levels that are too high may be condoned because of the desire not to induce bothersome side effects, particularly with the
use of drugs that act on the central nervous system or when initially high levels of blood pressure are lowered very quickly, inducing hypoperfusion of vital organs. Some patients are being treated to presumably adequate levels that may, in fact, not be maximally protective. One large group of such patients are diabetic patients who have early nephropathy as reflected by microalbuminuria. Considerable experimental data and limited clinical evidence suggest that protection against progressive diabetic glomerulosclerosis may require even lower systemic blood pressure than the 130/80 to 140/90 mm Hg range that most physicians are now seeking (9). In addition to diabetics, many hypertensive patients have multiple cardiovascular risk factors that place them at high overall risk (Table 1). They need even more vigorous therapy of minimally elevated blood pressure than do those patients who have none or few of these other risk factors. Care must be taken, however, not to lower the diastolic pressure in patients with preexisting coronary disease below the critical level needed to maintain coronary blood flow, a level that appears to be about 85 mm Hg (10). The common coexistence of dyslipidemia and hypertension mandates a more vigorous and more carefully constructed antihypertensive regimen that will avoid further aggravation of the lipid abnormality (10). These patients need the benefits of proper diet, regular exercise, and moderation of alcohol intake on both the blood pressure and the other cardiovascular risk factors. Because of the publication of the positive results of the Systolic Hypertension in the Elderly Trial (11), more patients will certainly be treated. In the past, many physicians have shied away from treating them because they had no evidence that lowering the blood pressure was beneficial and because they were concerned about potential harm from antihypertensive treatment of fragile elderly patients (1). Caution is still in order, but elderly patients with significant systolic hypertension are largely undertreated. Reasons for Overtreatment As noted above, more attention should be directed toward disadvantaged, resistant, high-risk, and elderly patients, all of whom tend to be undertreated. However, current medical practice in the United States is also exposing a substantial number of people to the dangers and inconveniences of overtreatment. Physicians in the United States aggressively diagnose and treat hypertension. Most practitioners in the United States diagnose and treat hypertension soon after recognition of a diastolic pressure above 90 mm Hg (12). Elsewhere, as in Germany (13), most practitioners treat only at levels above 100 mm Hg. Because this 10 mm Hg difference accounts for more than half of the entire hypertensive population, it potentially translates into over 20 million Americans being treated who might not be treated in other countries. The Appropriate Level of Therapy Although U.S. physicians usually start therapy soon after they document a diastolic pressure above 90 mm
Table 1. Prevalence of Other Coronary Risk Factors in Patients with Hypertension Risk Factor Smoking Hypercholesterolemia > 6.21 mmol/L* (> 240 mg/dL) Decreased high-density lipoprotein cholesterol < 1.03 mmol/L* (< 40 mg/dL) Left ventricular hypertrophy Obesity Diabetes Hyperinsulinemia Sedentary lifestyle
35 40 25 30 40 15 -50 > 50
* To convert to mg/dL, divide by 0.02586.
Hg, an expert committee of the World Health Organization and the International Society of Hypertension has recommended institution of drug therapy only if the diastolic blood pressure is 95 mm Hg or higher after 3 to 6 months of repeated blood pressure readings and the use of appropriate nondrug therapies (14) (Figure 1). The need for multiple readings, preferably out of the physician's office, is increasingly recognized as essential to avoid overdiagnosis and overtreatment. As many as half of people initially found to have a diastolic blood pressure above 95 mm Hg will spontaneously have a fall below 90 mm Hg on no therapy over the next 4 to 6 months (15). About 20% of those with office readings persistently elevated for years will be found to be consistently normotensive when multiple readings are obtained outside of the physician's office (16). Because such transient or "white-coat" hypertensive patients may have many other metabolic and hemodynamic dysfunctions that place them at higher overall risk (17), they need closer surveillance and more intensive use of nondrug therapies, but they do not need antihypertensive drug therapy. Patients with borderline or minimally elevated blood pressures who are otherwise at low cardiovascular risk should not be given drug therapy for two main reasons. First, such therapy has not been found to reduce their cardiovascular risks: In multiple large placebo-controlled clinical trials, clear protection has been demonstrated only for those with an initial diastolic blood pressure of 95 mm Hg or higher (18). Second, treating such patients is preventive and, despite our overwhelming desire to prevent more severe hypertension and its complications, preventive therapy with drugs cannot be ethically defended. Among others (19, 20), Allan Brett (21) has stated the issue as follows: In medical practice, the duty to inflect no harm (nonmaleficence) continuously competes with the duty to benefit the patient (beneficience). It follows that equivocal data on interventional efficacy may be sufficient to justify a recommendation to change some habits, since the risk of doing harm is small. Conversely, reasonably certain data is necessary to justify pharmacologic interventions, since the risk of doing harm is relatively greater. This argument assumes importance for a medicalized society in which unbridled enthusiasm to medicate often precedes reasonable proof of efficacy.
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Percent
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The Need for Nondrug Therapies As noted by Brett, the changing of harmful habits can be justified in the management of patients with borderline hypertension. Physicians often talk about nondrug therapies but use them minimally or ineffectually because they are more difficult to implement and are widely thought to be ineffectual. Recent evidence documents the practicality and effectiveness of weight reduction (22), moderate sodium restriction (23), regular aerobic exercise (24), and moderation of alcohol intake to no more than two usual portions (for example, two beers, two glasses of wine, or two mixed drinks) per day (25). When such therapies are used appropriately, they will lower blood pressure safely and should cause no loss of pleasure. Many who would be overtreated with drugs may be adequately treated without drugs. However, adequate compensation needs to be provided to those who counsel and follow patients with nondrug treatments so that these therapies will be used more widely. The Problems with Antihypertensive Drugs For several reasons, drugs are often used incorrectly. Two problems with current practice are the use of too large a starting dose and the rigid addition of multiple drugs that are not appropriate to the patient's needs if only office readings are taken. Too Large a Starting Dose As seen with drugs introduced long ago, such as diuretics (26) and beta-blockers (27), as well as those introduced recently, including angiotensin-converting enzyme (ACE) inhibitors (27) and calcium channel blockers (28), the initially recommended starting doses have turned out to be too high. As Andrew Herxheimer has stated (27):
For a new drug to penetrate the market quickly, it should be rapidly effective in a high proportion of patients and simple to use. To achieve this, the dosage of the first prescription is therefore commonly set at about the ED90 level—ie, the dose which the early clinical (phase II) studies have shown to be effective in 90% of the target population, provided that the unwanted effects at this dose are considered acceptable. In 25% of patients a smaller, perhaps much smaller, dose (the ED25) will be effective. The patients in this quartile are the most sensitive to the drug and are liable to receive far more than they need if they are given the ED90. They are also likely to be more sensitive to the dose-related side-effects of the drug. Herxheimer goes on to recommend a logical solution: Tablets containing less than the usual maximal effective dose should be marketed. For this to be effective, however, physicians must be willing to start most patients with a dose of medication that will not be fully effective. As he states, "The disadvantage from the marketing standpoint is that for the majority of patients the dose must be titrated. That is time-consuming for doctors and patients and more difficult to explain to them. A drug requiring dose titration cannot be presented as the quick fix, the instant good news that marketing departments love" (27). The "quick fix" is inappropriate for most hypertensive patients. To allow for autoregulation of blood flow to maintain perfusion to vital organs when perfusion pressure is lowered, the fall in pressure should be relatively small and gradual (29). More precipitous falls in pressure as frequently seen with larger starting doses may induce considerable hypoperfusion that results in symptoms that are at least bothersome (fatigue, impotence) and that may be potentially hazardous (postural hypotension, coronary ischemia). It is far better to "start low and go slow." An excellent example is the calcium channel blocker, verapamil (28). A 50% dose reduction eventually provides almost
Figure 1. Recommendations for the definition and management of mild hypertension. From the Third Mild Hypertension Conference of the World Health Organization and the International Society of Hypertension. (Reproduced with permission from reference 7.) BP = blood pressure. 688
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as much antihypertensive efficacy with fewer initial side effects. Because this class of drugs has been found to be particularly useful in elderly patients (30), verapamil will probably be given to many older patients. For them, even half of the lower dose 180-mg sustainedrelease tablet may be preferable initially. Even though few patients will respond adequately to such a small amount, those that do will be better managed and the remainder will have begun on a slow titration to gently reduce the pressure to the desired level. Rigid Compared with Individualized Choices Until recently, most practitioners started every patient with a diuretic, usually in high doses. Because problems with high-dose diuretic-based therapy have surfaced at the same time that many more attractive agents have become available, initial therapy has been broadened to include choices from multiple classes of drugs. The 1988 report of the Joint National Committee (31) recommended beta-blockers, ACE inhibitors, and calcium channel blockers as initial choices in addition to diuretics. The second generation of alpha-blockers are also appropriate (32). With the availability of more drugs, the appropriate matching of the type of drug to the individual patient's needs, based primarily on the presence of concomitant medical conditions, is at least theoretically feasible. Individualized therapy offers the promise of causing fewer adverse effects with less medication that is more suited to the patient's needs. Examples include use of an alpha-blocker in a hypertensive patient with hypercholesterolemia or a calcium channel blocker in a patient with angina. Even when careful matching is attempted, the choice may either not be effective or may cause bothersome side effects. Therefore, sequential use of drugs from the major classes has been suggested as a way to find the best possible selection (33). Guyatt and coworkers (34) have proposed a series of randomized controlled trials for each individual patient referred to as "n-of-1," involving a series of blinded comparisons of individual drugs against a placebo until the optimum choice is found. As attractive as the approach may be, most patients can be provided with effective and comfortable therapy by simply checking carefully for both efficacy and adverse effects after a drug is started and substituting a drug from another class if that choice is not suitable. In particular, patients should be carefully questioned about symptoms induced by overtreatment, such as postural dizziness, fatigue, and impotence. Because blood pressure readings obtained in the office are usually higher than those present at home, overtreatment may not be suspected if only office readings are taken. In the past, the goal of therapy was usually to bring the pressure down to a level close to normal, that is, 120/80, without inordinate side effects. However, more recently, an observation first made in 1979 (35) has been amply reconfirmed (36): When the diastolic blood pressure is lowered below 85 mm Hg, a greater number of coronary ischemic events are seen, particularly in hypertensive patients with preexisting coronary disease.
Although the number of coronary events falls progressively as diastolic pressure is lowered from high levels to below 90 mm Hg, when a nadir around 85 mm Hg is reached, the number of events starts to rise again, defining a J- or U-curve of coronary events relative to treated blood pressure levels. The heart in the hypertensive patient may be uniquely vulnerable to a fall in perfusion when systemic pressure is lowered so that such ischemia may not be seen in the brain, kidney, or other vital organs when the pressure is lowered to near "normal" levels. Nonetheless, many hypertensive patients have coronary disease—often silent—and therefore are susceptible to the J-curve. Although some investigators question the existence of the J-curve and decry the practice of limiting treatment so that diastolic pressures are not lowered below 85 mm Hg (37), I believe current knowledge mandates caution in treating most patients, particularly those with a high likelihood of underlying coronary disease. This advice seems particularly prudent because there are no data documenting a decrease in coronary events when the diastolic blood pressure is lowered below 85 mm Hg compared with the event rate at levels of 90 mm Hg or higher. Even though keeping the diastolic blood pressure above 85 mm Hg may expose some patients to greater risks for stroke and renal damage, the overwhelming predominance of morbidity and mortality from coronary disease in the hypertensive population justifies this more conservative approach. This does not preclude the purposeful reduction of pressure to lower levels in certain patients who probably need even lower pressures. As noted earlier, diabetic patients with microalbuminuria may be one such group because very low systemic pressures may be needed to keep intraglomerular pressure low enough to stop progressive glomerular sclerosis. Conclusion Both overtreatment and undertreatment remain problems in the management of hypertension. Many persons are not being treated at all because of personal and societal barriers to health care that will require major changes in our entire delivery system. Most of the remainder of the undertreated are simply not being provided the care that is now recognized to be appropriate. I hope that they will be more adequately treated as physicians gain confidence through publication of results of clinical trials and exposure to continuing education. The issues of overtreatment are less easily recognized because most patients whose pressures are too low or whose therapy is inappropriate do not suffer overt complications and, if they do, their overtreatment may not be thought to be responsible. However, they are being put at additional risk and made to suffer unnecessarily from side effects. Neither too much nor too little may be hard to achieve, but most hypertensive patients can be treated to achieve safer levels of blood pressure without bothersome side effects. The proper response to therapy should be attainable by gradual, gentle reduction of the blood pressure by lower initial doses of drugs that are
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slowly titrated to the desired effects. The choice of therapy should be individualized and changed if necessary. Current Author Address: Dr. Kaplan: University of Texas Southwestern Medical Center, C88-102, 5323 Harry Hines Boulevard, Dallas, TX 75235. References 1. Kaplan NM. Hypertension in the population at large. In: Kaplan NM; ed. Clinical Hypertension, 5th ed. Baltimore: Williams & Wilkins; 1990:1-25. 2. Littenberg B, Garber AM, Sox HC J r . Screening for hypertension. Ann Intern Med. 1990;112:192-202. 3. Progress toward achieving the 1990 high blood pressure objectives. MMWR Morbid Mortal Wkly Rep. 1990;39:704-7. 4. Blendon RJ, Aiken LH, Freeman HE, Corey CR. Access to medical care for black and white Americans. A matter of continuing concern. JAMA. 1989;261:278-81. 5. Ginzberg E, Ostow M. Beyond universal health insurance to effective health care. JAMA. 1991;265:2559-62. 6. Waeber B, Scherrer U, Petrillo A, Bidiville J, Nussberger J, Waeber G, et al. Are some hypertensive patients overtreated? A prospective study of ambulatory blood pressure recording. Lancet. 1987;2:732-4. 7. Mejia AD, Egan BM, Schork NJ, Zweifler AJ. Artefacts in measurement of blood pressure and lack of target organ involvement in the assessment of patients with treatment-resistant hypertension. Ann Intern Med. 1990;112:270-7. 8. Evans CE, Haynes RB, Goldsmith CH, Hewson SA. Home blood pressure-measuring devices: a comparative study of accuracy. J Hypertens. 1989;7:133-42. 9. Mogensen CE. Prevention and treatment of renal disease in insulindependent diabetes mellitus. Semin Nephrol. 1990;10:260-73. 10. Kaplan NM. Changing hypertension treatment to reduce the overall cardiovascular risk. J Hypertens. 1990;8(Suppl 7):S175-9. 11. SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). JAMA. 1991;265:3255-64. 12. Bostick RM, Luepker RV, Kofron PM, Pirie PL. Changes in physician practice for the prevention of cardiovascular disease. Arch Intern Med. 1991;151:478-84. 13. Weiland SK, Keil U, Spelsberg A, Hense HW, Hartel U, Gefeller O, et al. Diagnosis and management of hypertension by physicians in the Federal Republic of Germany. J Hypertens. 1991;9:131-4. 14. 1989 guidelines for the management of mild hypertension: memorandum from a WHO/ISH meeting. J Hypertens. 1989;7:689-93. 15. Management Committee of the Australian Therapeutic Trial in Mild Hypertension. Untreated mild hypertension. Lancet. 1982;1:185-91. 16. Pickering TG, James GD, Boddie C, Harshfield GA, Blank S, Laragh J H . How common is white coat hypertension? JAMA. 1989;259: 225-8. 17. Julius S, Mejia A, Jones K, Krause L, Schork N, van de Ven C, et al. "White coat" versus "sustained" borderline hypertension in Tecumseh, Michigan. Hypertension. 1990;16:617-23.
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18. Freis ED. Rationale against the drug treatment of marginal diastolic systemic hypertension. Am J Cardiol. 1990;66:368-71. 19. Guttmacher S, Teitelman M, Chapin G, Garbowski G, Schnall P. Ethics and preventive medicine: the case of borderline hypertension. Hastings Cent Rep. 1981;ll(l):12-20. 20. Rose G. Strategy of prevention: lessons from cardiovascular disease. Br Med J [Clin Res Ed]. 1981;282:1847-51. 21. Brett AS. Ethical issues in risk factor intervention. Am J Med. 1984;76:557-61. 22. Schotte DE, Stunkard AJ. The effects of weight reduction on blood pressure in 301 obese patients. Arch Intern Med. 1990;150:1701-4. 23. Law MR, Frost CD, Wald NJ. By how much does dietary salt reduction lower blood pressure? Ill—Analysis of data from trials of salt reduction. BMJ. 1991;302:819-24. 24. World Hypertension League. Physical exercise in the management of hypertension: a consensus statement by the World Hypertension League. J Hypertens. 1991;9:283-7. 25. Parker M, Puddey IB, Beilin LJ, Vandongen R. Two-way factorial study of alcohol and salt restriction in treated hypertensive men. Hypertension. 1990;16:398-406. 26. Carlsen JE, Kober L, Torp-Pedersen C, Johansen P. Relation between dose of bendrofluazide, antihypertensive effect, and adverse biochemical effects. BMJ. 1990;300:975-8. 27. Herxheimer A. How much drug in the tablet? Lancet. 1991 ;337: 346-8. 28. Holzgreve H, Distler A, Michaelis J, Philipp T, Wellek S. Verapamil versus hydrochlorothiazide in the treatment of hypertension: results of long term double blind comparative trial. BMJ. 1989;299:881-6. 29. Strandgaard S, Haunso S. Why does antihypertensive treatment prevent stroke but not myocardial infarction? Lancet. 1987;2:65861. 30. Cummings DM, Amadio P J r , Nelson L, Fitzgerald J M . The role of calcium channel blockers in the treatment of essential hypertension. Arch Intern Med. 1991;151:250-9. 31. The 1988 report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med. 1988;148:1023-38. 32. Khoury AF, Kaplan NM. Alpha-blocker therapy of hypertension. An unfulfilled promise. JAMA. 1991;266:394-8. 33. Brunner HR, Menard J, Waeber B, Burnier M, Biollaz J, Nussberger J, et al. Treating the individual hypertensive patient: considerations on dose, sequential monotherapy and drug combinations. J Hypertens. 1990;8:3-11. 34. Guyatt GH, Keller J L , Jaeschke R, Rosenbloom D, Adachi JD, Newhouse MT. The n-of-1 randomized controlled trial: clinical usefulness. Ann Intern Med. 1990;112:293-9. 35. Stewart IM. Relation of reduction in pressure to first myocardial infarction in patients receiving treatment for severe hypertension. Lancet. 1979;1:861-5. 36. Farnett L, Mulrow CD, Linn WD, Lucey CR, Tuley MR. The J-curve phenomenon and the treatment of hypertension. Is there a point beyond which pressure reduction is dangerous? JAMA. 1991; 165:489-95. 37. Hansson L. How far should blood pressure be lowered? What is the role of the J-curve? [Editorial]. Am J Hypertens. 1990;3:726-9.
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