Two Cheers for FOR THE past 50 years, serious research has been done on hypertension. It has taken some of us at least 25 years to persuade physicians, the government, and the public that hypertension is important. We have also known of several reasonably good treatments for approximately 25 years, a brief history of which I have written.' And now for the last decade, there have been three cheers for a few investigators and government officials and two for the rest of us. I do not believe we have yet earned the last cheer. And why not? Because a few of us were reared in the old-fashioned school of skeptical science, tempered with cautious enthusiasm, that currently is unpopular with government, the media, and those in public relations. True enough, our stodgy, doubting, often contentious pattern tended to keep us on the straight and narrow without inhibiting the fruition of the Golden Age of medicine. Still, this was not enough to establish beyond doubt that there was a unitary, standardized, and effective treatment for hypertensions of all sorts. As was to be expected, now that hypertension is receiv¬ ing widespread attention, much conflicting evidence crowds the literature. And with the jostling has come a large measure of confusion in physicians' minds, as well as in those of government and the public. On the bright side, it seems fair to accept the evidence that the predictive values of blood pressure, smoking habits, relative weight, and ECG abnormalities are estab¬ lished.2 Let me illustrate my point, with the premise that many satisfactory ways of treating hypertension have been available since 1950.
Labile, Borderline Hypertension First, the problem of "labile" or "borderline" hyperten¬
sion has come to the fore. It assumes special importance because so many persons are lumped into this category. But borderline hypertension is difficult to diagnose and to From the Research Division, Cleveland Clinic, Cleveland. Reprint requests to Research Division, Cleveland Clinic, 9500 Euclid Cleveland, OH 44106 (Dr Page).
Ave,
Hypertension
define, and it is uncertain whether all such patients have
the same prognosis. Some would classify borderline hyper¬ tensive patients as all who at any time had an arterial pressure of 140/90 mm Hg or greater. Others believe that unless even higher pressures are repeatedly observed, so serious a diagnosis is not justified. As it now stands, we do not know whether labile hypertension is the prelude to more severe essential hypertension or is simply highly variable arterial pressure. In 1945, Page .and Corcoran3 categorized the early
primary hypertensions as (1) simple vasomotor lability, (2) prehypertension, (3) neurogenic hypertension, and (4) early essential hypertension. I regret to say that I do not know much more about the differential diagnosis than I did then. The confusion is such that without certainty of the long-term outcome, borderline hypertensive persons are either subjected to a lifetime of treatment or to "super¬ vised" neglect. I wish the problem were no more complex than this, but it is. The first stumbling block is the way in which blood pressure is taken. (We will not consider here the details of positioning of the arm, cuff width, time of day, pulse rate, bladder distension, skinfold thickness, arm circumference, observer preference, and obesity.) Instruments for self-measurement of blood pressure vary greatly in quality and price. Some are awkward to use; others are overly elaborate and far too expensive. And inexplicably, manufacturers seem reluctant to either improve their products or reduce the prices. There is clearly a need for an impartial comparison of these instru¬ ments, since millions of patients will be involved, and particularly since so much hangs on the correct measure¬ ment of blood pressure. What about some of the instru¬ ments used by physicians and nurses? Berenson et al4 thoroughly examined 714 children, 2 V2 to 5V2 years of age, searching for risk factors at preschool age. Mean blood pressure readings taken on each of three instruments showed different readings. The Infrasonde gave the lowest readings, while the Baumanometer gave
Downloaded From: http://jama.jamanetwork.com/ by a Florida International University Medical Library User on 05/29/2015
the highest. An age gradient was found only for the systolic pressure on the Infrasonde, with considerable difference noted for the other instruments. The mean readings differed significantly between each pair of instruments, both for systolic and diastolic pres¬ sures. On all of the devices, the diastolic pressure vari¬ ability increased with younger children. The Infrasonde diastolic pressure readings were somewhat affected by individual examiners. The authors believe that the Infra¬ sonde systolic figures, at least, may be closer to realistic values than those from the other instruments. Serious errors in indirect blood pressure measurements are especially prone to occur among those older than 62 years, according to Spence et al.s They compared intraarterial pressures with indirect readings and found the latter false by 30 mm Hg or more in 12 of 24 patients suspected of having hypertension and in four of 16 patients younger than 60 years. I should not have to repeat that it is essential to know the qualifications of the person who measured the blood pressure, and yet I continue to see no effort being made to correct egregious human errors. Are we still to allow human inadequacy to condemn normal people to a life of medication and restriction or, vice versa, miss an impor¬ tant risk factor? We need more studies such as that of Watson et al,6 in which intra-arterial pressure was recorded for a 24-hour period before and during treatment. Variability and the results of screening have been reported by the Hyperten¬ sion Detection Group.7 There is one more caveat, which has created far too little concern: the interpretation of systolic pressure.
Systolic Pressure It has recently become modish to proclaim that systolic pressure is a better guide to prognosis than the diastolic.
The former is also said, with confidence, to correlate more closely during treatment with a number of vascular disor¬ ders, especially stroke, than is the diastolic pressure. This may be true, but fully convincing evidence of cause and effect is not available. Based on the mechanisms of blood pressure, just the opposite had long been asserted, with little attention given to systolic pressure because it seemed to reflect only the stiffness of resistance vessels and was not a measure of the load on the myocardium. Now I suspect that because labile or borderline hyper¬ tension has come to be appreciated, styles are changing. Although it had been recognized by those who had studied hypertension carefully over the years that borderline systolic hypertension was not always innocuous, it appar¬ ently came as a surprise that not only is it treatable, but perhaps it should be treated. Here again, there is dis¬ agreement, some believing that early hypertension need only be monitored, especially in those older than 60 years. In my
own experience, systolic pressure is far more variable than even generally supposed. If blood pressure is measured consecutively in some persons at 30-s intervals, systolic pressure may fall progressively, eg, 156/92 followed by 148/88, 140/86, and 133/84 mm Hg. One may thereby move easily from a borderline to a normotensive
classification: A quick cure, indeed! As though this were not enough, circadian rhythms must be considered, as has been done by Millar Craig et al.8 The question is what pressure is the correct one for statistical and epidemiologic studies. This is an important problem and, fortunately, is being studied by Souchek et al,9 among others. Failure to appreciate the mercurial nature of blood pressure readings has, I believe, flawed most epidemio¬ logic studies. This, plus uncertainties introduced by inex¬ perienced persons measuring blood pressure, make me hesitate in accepting unconditionally the current vogue for
"systolic hypertension."
Lowering Diastolic Pressure—How Much? The current discussion is whether lowering diastolic blood pressure to 90 mm Hg or lower is overdrawn, when the claim is made that either underperfusion of tissue occurs, or the incidence of myocardial infarction is increased. Common experience shows the former to be untrue, and common sense suggests that proof has not been forthcoming for the latter. Having been reared on the concept that lowering blood pressure in hypertension is a dangerous thing—especially because at that time we did not know how to do it—I continue to be astonished at how well lowering blood pressure is tolerated. Perhaps the most valuable thing I have learned is how important methods of measuring blood pressure are to the integrity of statistical evidence. Have we so soon forgotten that during the sprouting of knowledge of hypertension, it needed to be shown that reduction in blood pressure did not reduce renal hlood flow until it reached wholly unphysiological levels? Also, that during the early days of resistance to the introduction of sodium nitroprusside to clinical medicine, arterial pres¬ sures were reduced quickly in hypertensive patients and dogs to normal levels without disturbance? Even in malig¬ nant hypertension, it was promptly shown that severe reduction in blood pressure was lifesaving, rather than
threatening, owing to underperfusion.
Diuretics and Treatment
/3-lipoprotein levels in a small number of hypertensive, patients was noted by Glück et normal, al10 following therapies of four to six weeks of chlorthalidone, furosemide, or mefruside. The a-lipoprotein levels either did not change or decreased. Values of serum triglycéride or cholesterol tended to increase, although the rise was small. The authors believe, with some others, that diuretic therapy may increase the risk of myocardial infarction. Much the same was found by Ames and Hill." The occurrence of myocardial infarction was found in greater numbers in elderly, mildly hypertensive persons treated with thiazide diuretics than in control subjects, according to Morgan et al.12 They wrote that it was unlikely that therapy would improve the prognosis of elderly, mildly hypertensive persons. This is an example of An increase in or
observers who doubt the current fashionable assurance that our large-scale efforts at treatment of hypertension are unquestionably valuable. The reduction in the incidence of stroke in the past few years is cited as proof of our belief in the righteousness of
Downloaded From: http://jama.jamanetwork.com/ by a Florida International University Medical Library User on 05/29/2015
current mass treatment. For example, Beevers et al13 found that the degree of reduction in arterial pressure achieved during treatment was more important than borderline pressure for predicting stroke, confirming the benefits of antihypertensive therapy. There was some evidence of prevention of myocardial infarction as a result of therapy, but none that treatment aided in preventing coronary heart disease. While systolic pressure achieved during treatment predicted stroke better than diastolic pressure, no consistent trends were found for coronary heart disease. We are garrulous people. After all is said and done, we feel impelled to say something more. Perry and Smith'4 said it well after 471 pages of "Mild Hypertension: To Treat or Not to Treat": "These presenters made it clear that there are insufficient data for a definitive consensus recommendation as to how to handle mild hypertension." I would point out only that consensus medicine is not always the best medicine. Because I am by nature an optimist, my instinct is to believe in early treatment, especially to reduce the inci¬ dence of stroke, without undermining the patient's sense of well-being. For the past two years, I have measured my own blood pressure often six or more times a day and night to determine the pattern. There have been periods when clear hypertension occurred and others when pres¬ sure was entirely normal for several days. Systolic hyper¬ tension has been much the more common. I classify myself as "borderline," but there have been many periods when this diagnosis could have been easily missed. I feel intellectually happier keeping my blood pressure within a normal range with treatment. Whether or not it is doing any good, the experience of one biased patient is hardly convincing. My concern is that enough carefully gathered evidence be obtained to provide a clear answer to the problem. I would like to be able to add the extra cheer to the "two cheers" for everybody. our
Is Treatment of Borderline Hypertension Good
or
Bad?
Clearly, this is the kind of question every thoughtful clinician wants answered. The literature is almost equally divided on whether early treatment reduces the incidence of myocardial infarction. It is weighted somewhat in favor of prevention of stroke. The published reports from
England
seem more
commonly
to oppose treatment than
in this country. Fortunately, several comprehensive stud¬ ies, which may provide a definite answer, are now in progress in both countries. The problem is a difficult one if only for the reasons I have already cited. For example, Hamer et al15 believe the cardiac effects of hypertension are more closely related to the casual and exercising blood pressure than to the basal pressure.
The Public Health Service Hospital Study found that hypertension did not alter the major end points—death, myocardial infarction, or stroke—but lowered the rate of complications, such as ECG hypervoltage, left ventricular hypertrophy, radiographie cardiotreatment of mild
megaly, and retinopathy. Other large studies are in progress, such as the "Hypertension Detection and Follow-up Program," "European Working Party on High
Blood Pressure in Elderly," "Veterans AdministrationNational Heart, Lung, and Blood Institute Study Group for Evaluating Treatment of Mild Hypertension," "Medi¬ cal Research Council Working Party on Mild to Moderate Hypertension," and "The North Karelia Project," as well as "The Mayo Three Community Hypertension Control Program" and that of Jouve et al.'6 I hope that some of these will be continued long enough to determine the outcome.
It has not been my purpose to review the rapidly growing literature on the subject of early treatment. Rather, I have wanted to indicate the problems involved in the diagnosis and treatment of hypertension on a mass scale. It is my hope that a modicum of skepticism at this time will help prepare the way for a victory without contingencies. Irvine H. Page, MD Cleveland Clinic Cleveland
Nonproprietary Chlorthalidone—Hygroton.
Name and Trademark of
Drug
1. Page IH: The drug treatment of arterial hypertension. Clin Pharmacol Ther 7:567-576,1966. 2. Relationship of blood pressure, serum cholesterol, smoking habit, relative weight and ECG abnormalities to incidence of major coronary events: Final report of the Pooling Project, Pooling Project Research Group. J Chronic Dis 31:201-306,1978. 3. Page IH, Corcoran AC: Arterial Hypertension: Its Diagnosis and Treatment. Chicago, Year Book Medical Publishers Inc, 1945. 4. Berenson GS, Foster TA, Frank GC, et al: Cardiovascular disease risk factor variables at the preschool age\p=m-\theBogalusa heart study. Circulation 57:603-612, 1978. 5. Spence JD, Sibbard WJ, Cape RD: Pseudohypertension in the elderly. Clin Sci Mol Med 55:3995-4025, 1978. 6. Watson RDS, Stallard TJ, Littler WA: Influence of once-daily administration of beta-adrenocaptone antagonists on arterial pressure and its variability. Lancet 1:1210-1213, 1979. 7. Variability of blood pressure and the results of screening in the Hypertension Detection and Follow-up Program, Hypertension Detection and Follow-up Program Cooperative Group. J Chronic Dis 31:651-667, 1978. 8. Millar Craig MW, Mann S, Balasubramanian V, et al: Clin Sci Mol Med 55(suppl):391-393, 1978. 9. Souchek J, Stamler J, Dyer AR, et al: The value of two or three versus a single reading of blood pressure at a first visit. J Chronic Dis 32:197-210, 1979. 10. Gl\l=u"\ckZ, Baumgartner G, Weidmann P, et al: Increased ratio between serum beta- and alpha-lipoproteins during diuretic therapy: An adverse effect? Clin Sci Mol Med 55(suppl):325,1978. 11. Ames RP, Hill P: Raised serum lipid concentrations during diuretic treatment of hypertension: A study of predictive indexes. Clin Sci Mol Med
55(suppl):311-314,1978. 12. Morgan T, Ada W, Gillies A, et al: Treatment of mild hypertension. Clin Sci Mol Med 55(suppl):305-306, 1978. 13. Beevers DG, Johnston J, Devine BL, et al: Relation between prognosis and the blood pressure before and during treatment of hypertensive patients. Clin Sci Mol Med 55(suppl):333-336, 1978. 14. Perry HM Jr, Smith WM (eds): Mild hypertension: To treat or not to
treat. Ann NY Acad Sci 304:1-475, 1978. 15. Hamer J, Fleming J, Shinebourne E: Effect of walking on blood pressure in systemic hypertension. Lancet 2:114-117, 1967. 16. Jouve A, Goldet L, Mathieu M: Results of a national therapeutic trial
conducted in 10,000 hypertensive patients by 2,000 Clin Sci Mol Med 55(suppl):353-354, 1978.
Downloaded From: http://jama.jamanetwork.com/ by a Florida International University Medical Library User on 05/29/2015
general practitioners.
Labile, Borderline Hypertension First, the problem of "labile" or "borderline" hyperten¬
sion has come to the fore. It assumes special importance because so many persons are lumped into this category. But borderline hypertension is difficult to diagnose and to From the Research Division, Cleveland Clinic, Cleveland. Reprint requests to Research Division, Cleveland Clinic, 9500 Euclid Cleveland, OH 44106 (Dr Page).
Ave,
Hypertension
define, and it is uncertain whether all such patients have
the same prognosis. Some would classify borderline hyper¬ tensive patients as all who at any time had an arterial pressure of 140/90 mm Hg or greater. Others believe that unless even higher pressures are repeatedly observed, so serious a diagnosis is not justified. As it now stands, we do not know whether labile hypertension is the prelude to more severe essential hypertension or is simply highly variable arterial pressure. In 1945, Page .and Corcoran3 categorized the early
primary hypertensions as (1) simple vasomotor lability, (2) prehypertension, (3) neurogenic hypertension, and (4) early essential hypertension. I regret to say that I do not know much more about the differential diagnosis than I did then. The confusion is such that without certainty of the long-term outcome, borderline hypertensive persons are either subjected to a lifetime of treatment or to "super¬ vised" neglect. I wish the problem were no more complex than this, but it is. The first stumbling block is the way in which blood pressure is taken. (We will not consider here the details of positioning of the arm, cuff width, time of day, pulse rate, bladder distension, skinfold thickness, arm circumference, observer preference, and obesity.) Instruments for self-measurement of blood pressure vary greatly in quality and price. Some are awkward to use; others are overly elaborate and far too expensive. And inexplicably, manufacturers seem reluctant to either improve their products or reduce the prices. There is clearly a need for an impartial comparison of these instru¬ ments, since millions of patients will be involved, and particularly since so much hangs on the correct measure¬ ment of blood pressure. What about some of the instru¬ ments used by physicians and nurses? Berenson et al4 thoroughly examined 714 children, 2 V2 to 5V2 years of age, searching for risk factors at preschool age. Mean blood pressure readings taken on each of three instruments showed different readings. The Infrasonde gave the lowest readings, while the Baumanometer gave
Downloaded From: http://jama.jamanetwork.com/ by a Florida International University Medical Library User on 05/29/2015
the highest. An age gradient was found only for the systolic pressure on the Infrasonde, with considerable difference noted for the other instruments. The mean readings differed significantly between each pair of instruments, both for systolic and diastolic pres¬ sures. On all of the devices, the diastolic pressure vari¬ ability increased with younger children. The Infrasonde diastolic pressure readings were somewhat affected by individual examiners. The authors believe that the Infra¬ sonde systolic figures, at least, may be closer to realistic values than those from the other instruments. Serious errors in indirect blood pressure measurements are especially prone to occur among those older than 62 years, according to Spence et al.s They compared intraarterial pressures with indirect readings and found the latter false by 30 mm Hg or more in 12 of 24 patients suspected of having hypertension and in four of 16 patients younger than 60 years. I should not have to repeat that it is essential to know the qualifications of the person who measured the blood pressure, and yet I continue to see no effort being made to correct egregious human errors. Are we still to allow human inadequacy to condemn normal people to a life of medication and restriction or, vice versa, miss an impor¬ tant risk factor? We need more studies such as that of Watson et al,6 in which intra-arterial pressure was recorded for a 24-hour period before and during treatment. Variability and the results of screening have been reported by the Hyperten¬ sion Detection Group.7 There is one more caveat, which has created far too little concern: the interpretation of systolic pressure.
Systolic Pressure It has recently become modish to proclaim that systolic pressure is a better guide to prognosis than the diastolic.
The former is also said, with confidence, to correlate more closely during treatment with a number of vascular disor¬ ders, especially stroke, than is the diastolic pressure. This may be true, but fully convincing evidence of cause and effect is not available. Based on the mechanisms of blood pressure, just the opposite had long been asserted, with little attention given to systolic pressure because it seemed to reflect only the stiffness of resistance vessels and was not a measure of the load on the myocardium. Now I suspect that because labile or borderline hyper¬ tension has come to be appreciated, styles are changing. Although it had been recognized by those who had studied hypertension carefully over the years that borderline systolic hypertension was not always innocuous, it appar¬ ently came as a surprise that not only is it treatable, but perhaps it should be treated. Here again, there is dis¬ agreement, some believing that early hypertension need only be monitored, especially in those older than 60 years. In my
own experience, systolic pressure is far more variable than even generally supposed. If blood pressure is measured consecutively in some persons at 30-s intervals, systolic pressure may fall progressively, eg, 156/92 followed by 148/88, 140/86, and 133/84 mm Hg. One may thereby move easily from a borderline to a normotensive
classification: A quick cure, indeed! As though this were not enough, circadian rhythms must be considered, as has been done by Millar Craig et al.8 The question is what pressure is the correct one for statistical and epidemiologic studies. This is an important problem and, fortunately, is being studied by Souchek et al,9 among others. Failure to appreciate the mercurial nature of blood pressure readings has, I believe, flawed most epidemio¬ logic studies. This, plus uncertainties introduced by inex¬ perienced persons measuring blood pressure, make me hesitate in accepting unconditionally the current vogue for
"systolic hypertension."
Lowering Diastolic Pressure—How Much? The current discussion is whether lowering diastolic blood pressure to 90 mm Hg or lower is overdrawn, when the claim is made that either underperfusion of tissue occurs, or the incidence of myocardial infarction is increased. Common experience shows the former to be untrue, and common sense suggests that proof has not been forthcoming for the latter. Having been reared on the concept that lowering blood pressure in hypertension is a dangerous thing—especially because at that time we did not know how to do it—I continue to be astonished at how well lowering blood pressure is tolerated. Perhaps the most valuable thing I have learned is how important methods of measuring blood pressure are to the integrity of statistical evidence. Have we so soon forgotten that during the sprouting of knowledge of hypertension, it needed to be shown that reduction in blood pressure did not reduce renal hlood flow until it reached wholly unphysiological levels? Also, that during the early days of resistance to the introduction of sodium nitroprusside to clinical medicine, arterial pres¬ sures were reduced quickly in hypertensive patients and dogs to normal levels without disturbance? Even in malig¬ nant hypertension, it was promptly shown that severe reduction in blood pressure was lifesaving, rather than
threatening, owing to underperfusion.
Diuretics and Treatment
/3-lipoprotein levels in a small number of hypertensive, patients was noted by Glück et normal, al10 following therapies of four to six weeks of chlorthalidone, furosemide, or mefruside. The a-lipoprotein levels either did not change or decreased. Values of serum triglycéride or cholesterol tended to increase, although the rise was small. The authors believe, with some others, that diuretic therapy may increase the risk of myocardial infarction. Much the same was found by Ames and Hill." The occurrence of myocardial infarction was found in greater numbers in elderly, mildly hypertensive persons treated with thiazide diuretics than in control subjects, according to Morgan et al.12 They wrote that it was unlikely that therapy would improve the prognosis of elderly, mildly hypertensive persons. This is an example of An increase in or
observers who doubt the current fashionable assurance that our large-scale efforts at treatment of hypertension are unquestionably valuable. The reduction in the incidence of stroke in the past few years is cited as proof of our belief in the righteousness of
Downloaded From: http://jama.jamanetwork.com/ by a Florida International University Medical Library User on 05/29/2015
current mass treatment. For example, Beevers et al13 found that the degree of reduction in arterial pressure achieved during treatment was more important than borderline pressure for predicting stroke, confirming the benefits of antihypertensive therapy. There was some evidence of prevention of myocardial infarction as a result of therapy, but none that treatment aided in preventing coronary heart disease. While systolic pressure achieved during treatment predicted stroke better than diastolic pressure, no consistent trends were found for coronary heart disease. We are garrulous people. After all is said and done, we feel impelled to say something more. Perry and Smith'4 said it well after 471 pages of "Mild Hypertension: To Treat or Not to Treat": "These presenters made it clear that there are insufficient data for a definitive consensus recommendation as to how to handle mild hypertension." I would point out only that consensus medicine is not always the best medicine. Because I am by nature an optimist, my instinct is to believe in early treatment, especially to reduce the inci¬ dence of stroke, without undermining the patient's sense of well-being. For the past two years, I have measured my own blood pressure often six or more times a day and night to determine the pattern. There have been periods when clear hypertension occurred and others when pres¬ sure was entirely normal for several days. Systolic hyper¬ tension has been much the more common. I classify myself as "borderline," but there have been many periods when this diagnosis could have been easily missed. I feel intellectually happier keeping my blood pressure within a normal range with treatment. Whether or not it is doing any good, the experience of one biased patient is hardly convincing. My concern is that enough carefully gathered evidence be obtained to provide a clear answer to the problem. I would like to be able to add the extra cheer to the "two cheers" for everybody. our
Is Treatment of Borderline Hypertension Good
or
Bad?
Clearly, this is the kind of question every thoughtful clinician wants answered. The literature is almost equally divided on whether early treatment reduces the incidence of myocardial infarction. It is weighted somewhat in favor of prevention of stroke. The published reports from
England
seem more
commonly
to oppose treatment than
in this country. Fortunately, several comprehensive stud¬ ies, which may provide a definite answer, are now in progress in both countries. The problem is a difficult one if only for the reasons I have already cited. For example, Hamer et al15 believe the cardiac effects of hypertension are more closely related to the casual and exercising blood pressure than to the basal pressure.
The Public Health Service Hospital Study found that hypertension did not alter the major end points—death, myocardial infarction, or stroke—but lowered the rate of complications, such as ECG hypervoltage, left ventricular hypertrophy, radiographie cardiotreatment of mild
megaly, and retinopathy. Other large studies are in progress, such as the "Hypertension Detection and Follow-up Program," "European Working Party on High
Blood Pressure in Elderly," "Veterans AdministrationNational Heart, Lung, and Blood Institute Study Group for Evaluating Treatment of Mild Hypertension," "Medi¬ cal Research Council Working Party on Mild to Moderate Hypertension," and "The North Karelia Project," as well as "The Mayo Three Community Hypertension Control Program" and that of Jouve et al.'6 I hope that some of these will be continued long enough to determine the outcome.
It has not been my purpose to review the rapidly growing literature on the subject of early treatment. Rather, I have wanted to indicate the problems involved in the diagnosis and treatment of hypertension on a mass scale. It is my hope that a modicum of skepticism at this time will help prepare the way for a victory without contingencies. Irvine H. Page, MD Cleveland Clinic Cleveland
Nonproprietary Chlorthalidone—Hygroton.
Name and Trademark of
Drug
1. Page IH: The drug treatment of arterial hypertension. Clin Pharmacol Ther 7:567-576,1966. 2. Relationship of blood pressure, serum cholesterol, smoking habit, relative weight and ECG abnormalities to incidence of major coronary events: Final report of the Pooling Project, Pooling Project Research Group. J Chronic Dis 31:201-306,1978. 3. Page IH, Corcoran AC: Arterial Hypertension: Its Diagnosis and Treatment. Chicago, Year Book Medical Publishers Inc, 1945. 4. Berenson GS, Foster TA, Frank GC, et al: Cardiovascular disease risk factor variables at the preschool age\p=m-\theBogalusa heart study. Circulation 57:603-612, 1978. 5. Spence JD, Sibbard WJ, Cape RD: Pseudohypertension in the elderly. Clin Sci Mol Med 55:3995-4025, 1978. 6. Watson RDS, Stallard TJ, Littler WA: Influence of once-daily administration of beta-adrenocaptone antagonists on arterial pressure and its variability. Lancet 1:1210-1213, 1979. 7. Variability of blood pressure and the results of screening in the Hypertension Detection and Follow-up Program, Hypertension Detection and Follow-up Program Cooperative Group. J Chronic Dis 31:651-667, 1978. 8. Millar Craig MW, Mann S, Balasubramanian V, et al: Clin Sci Mol Med 55(suppl):391-393, 1978. 9. Souchek J, Stamler J, Dyer AR, et al: The value of two or three versus a single reading of blood pressure at a first visit. J Chronic Dis 32:197-210, 1979. 10. Gl\l=u"\ckZ, Baumgartner G, Weidmann P, et al: Increased ratio between serum beta- and alpha-lipoproteins during diuretic therapy: An adverse effect? Clin Sci Mol Med 55(suppl):325,1978. 11. Ames RP, Hill P: Raised serum lipid concentrations during diuretic treatment of hypertension: A study of predictive indexes. Clin Sci Mol Med
55(suppl):311-314,1978. 12. Morgan T, Ada W, Gillies A, et al: Treatment of mild hypertension. Clin Sci Mol Med 55(suppl):305-306, 1978. 13. Beevers DG, Johnston J, Devine BL, et al: Relation between prognosis and the blood pressure before and during treatment of hypertensive patients. Clin Sci Mol Med 55(suppl):333-336, 1978. 14. Perry HM Jr, Smith WM (eds): Mild hypertension: To treat or not to
treat. Ann NY Acad Sci 304:1-475, 1978. 15. Hamer J, Fleming J, Shinebourne E: Effect of walking on blood pressure in systemic hypertension. Lancet 2:114-117, 1967. 16. Jouve A, Goldet L, Mathieu M: Results of a national therapeutic trial
conducted in 10,000 hypertensive patients by 2,000 Clin Sci Mol Med 55(suppl):353-354, 1978.
Downloaded From: http://jama.jamanetwork.com/ by a Florida International University Medical Library User on 05/29/2015
general practitioners.
