clinical evaluation of antihypertensive drugs -...

CLINICAL PROGRESS

Clinical Evaluation of AntihypertensiveDrugs

By IRVINE H. PAGE, M.D., AND A. C. CORCORAN, M.D.

T HE evaluation of antihypertensive drugshas become a big business. Hundreds ofpeople who work in some aspect of clini-

cal investigation spend at least part of theirtime in this process. Their observations deter-mine the expenditure, first by the drug com-panies and then by the public, of some millionsof dollars a year. Even the law recognizes thefact that no accumulation of pharmacology,however sound, and no amount of promotioncan do anything for a drug which has not hada reasonably adequate clinical trial. Everyoneacknowledges that it is the crucial aspect deter-mining drug sale. But so far no one has paidmuch attention to the definition of the term,"adequate" or the characterization of theproper means of study of an antihypertensivedrug.

This is partly because it is a new field ofeffort. Less than 10 years ago we used to pleadwith manufacturers to turn their attention tothe field of antihypertensive medication. But,in a world in which the industrial emphasis wason antibacterials and vitamins, and with themedical profession apparently satisfied withgarlic and phenobarbital, we got very littleresponse. At long last, the commercial possi-bilities of a chronic and very common diseasehave been abundantly recognized and the damhas broken. The ensuing flood of drugs hastaken most investigators by surprise, findingthem without real agreement on technics andprocedures. As a result, there is a great deal ofrepetition and of waste effort, and the investi-gator too often deserts his legitimate field ofbasic scientific study to spend his time in a

From the Research Division of the ClevelandClinic Foundation, and the Frank E. Bunts Educa-tional Institute, Cleveland, Ohio.

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process in which he may eventually becomeenmeshed.The definition of what is a proper study of

an antihypertensive drug or procedure is by nomeans easy. Those of us who attempt thisprocess look with real envy on our colleagueswho deal with the clinical trial of antibacterialdrugs. They are concerned, for the most part,with diseases of brief duration and well-defined course and, above all, with such un-exceptionable measurements as those of feverand leukocytosis. We, on the other hand, dealwith a process usually of long and, very often,of unpredictable duration and with, as one ofour basic measurements, arterial pressure, anotoriously labile function. The field is, there-fore, very naturally vexed and confused.Claims and counterclaims are continuallymade. There is even some competition amonginvestigators for the latest drug, some naturaltendency to puff it at a scientific meeting. Asa result, the literature abounds with unimagi-native research and shows occasional lapses intoflagrant lauding of the latest product at hand.Our own studies in the treatment of hyper-

tension have nearly always been concernedwith patients who have severe or "malignant"hypertensive disease. There are two reasonsfor this choice. One is that the procedures wehave had available, first anterior nerve-rootsection, then lumbodorsal sympathectomy and,later, kidney extracts and pyrogens, were ad-mittedly somewhat heroic. Like the Mikado,we wished to let the punishment fit the crime.Next, the problem extends beyond the bloodpressure; people die, not of hypertension, butof hypertensive disease. In this selected groupof patients we had to deal with hypertensivedisease as well as with hypertension, with a

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EVALUATION OF ANTIHYPERTENSIVE DRUGS

serious indication for treatment, with a reason-ably certain prognosis, and with consistentlyand severely increased blood pressure.Most such patients are glad enough to enter

the hospital, so that this selection has directedus to technics of clinical trial in hospital. Webelieve that this has been a fortunate, if invol-untary, choice; we have no intention of decry-ing the efforts of those whom circumstancesforce into clinical study of milder hypertensivedisease in offices or out-patient departments.In fact we do this ourselves, since we quiteagree that the value of a drug can only beassessed finally in terms of its activity underthe normal circumstances of daily life. On theother hand, the concentration on severe hyper-tensive disease in the hospital has the realadvantage of a potentially well-controlledexperiment, and one that can yield reasonablyaccurate information from a small number ofpatients.

What Blood Pressure?If we dismiss as premature the speculations

that some of the available antihypertensivedrugs, with the specific exception of sympa-tholytic agents in pheochromocytoma, havedefinable points of attack on the basic mecha-nisms responsible for hypertension, then thebasic rationale of antihypertensive therapydepends on our recognition of the fact thatsevere and persistent high blood pressure isbad for the vessels. In this light, anything thatis reasonably safe and tolerable and that pro-duces by almost any means a persistent de-crease of blood pressure is a potentially usefulantihypertensive drug. Hence, much as wewould like to deal only with the basic problemof hypertensive disease as such, we are forcedto depend on measurements of blood pressure.The question is what pressure?The measurement we would like to have is

one that would be representative of the pa-tient's blood pressure as it is most of the time.The basal blood pressure, which is rathertediously secured, probably does not meet thisrequirement. Certainly the casual "resting"blood pressure does not, even when it is indefi-nitely multiplied. Casual readings are usuallyhigh. A minority of patients show waking, pre-

sumably basal pressure readings, consistentlyhigher than their casual, resting pressures asmeasured in the afternoon. Reliance on uncon-trolled, casual readings accounts for most ofthe vexatious claims in this field.We have arbitrarily resolved this difficulty by

dealing with weekly averages of supine, restingpressures. And, with the advent of drugs thatcause orthostatic drops in pressure, we haveadded averages of standing pressures. Others,using these drugs, have measured sitting pres-sures and, since most people with severe hyper-tension sit a good deal of the time, this is prob-ably also a representative datum. Our usualprocedure is to average the pressures weeklyof the readings made twice daily. The averageobliterates most of the peaks and the valleysand provides only a single datum for a week'seffort. But our experience indicates that this isa valid and representative datum.

The Control PeriodMost of the difficulty with the assessment of

drugs depends on the wide variety of opinionson what is a "reasonable" control period. Wehave reported our own experience elsewhere.'Briefly we have found that, in patients withsevere or malignant hypertensive disease, theaverage from the first week in hospital tendsto be higher by 8/5 mm. Hg for malignanthypertension and 10/5 mm. Hg for severeessential hypertension than the average ofthe second week. The averages of the secondand third weeks usually correspond closely,although a minority of patients, usually thosewith milder disease, continue to show somedecrease in pressure averages over three ormore weeks. These decreases represent adapta-tion to the ordered hospital routine, protectionfrom the onslaughts of the world outside, thepsychotherapeutic effects of close and sympa-thetic observation, and to these we often addthe effects, if any, of placebo medication.An extensive analysis2 of the effects of pro-

longed hospitalization on means of basal bloodpressures of patients with essential hyperten-sion yields data similar to our own, in that thelatter weeks of hospitalization usually demon-strate considerable stability of the means, whilethe mean of the first week's pressures and the

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CLINICAL PROGRESS

sequence of changes in pressure individuallytends to be somewhat variable. Undoubtedly,there is no substitute for prolonged controlobservations. On the other hand, particularlyin patients with demonstrably severe and ad-vancing hypertensive disease, the means of thesecond and third weeks of pressures formrepresentative indices of pressure level duringhospitalization and, as such, adequate baselinesfor therapeutic study.

There is no doubt that this is a tedious andexpensive process. But it has two large ad-vantages. First, it provided us with a bloodpressure datum that is truly significant. Sec-ondly, time is made available for detailedclinical study and for the investigation of du-bious points in the physical or laboratoryexamination. As a result, treatment beginsonly after the patient's status in terms of hy-pertensive disease is reasonably characterized.

The Estimate of Hypertensive Disease

This is made in terms of four panels, of whichthe diastolic blood pressure average is one. Theothers concern the cerebral and renal circula-tions and the heart. A large amount of datahas accumulated to suggest that it might alsobe desirable to evaluate other data, such asserum f3-globulin.The estimate of cerebral vascular disease is

either presumptive or objective; the presump-tive evidence, still very unsatisfactory, isgathered from history of headaches, encepha-lopathy, mild seizures and, probably best ofall, from a pooled estimate by several observersof the status of the fundi and retinal arterioles.The latter is made numerically in terms of con-striction, sclerosis, exudate, hemorrhage, andpapilledema, and this series of examinations iscontinued weekly.'

Fortunately, the renal panel, so importantin these patients, is much more accessible thanthe cerebral. This circulation is assessed interms of approximate filtration rate (from ureaclearance) or plasma creatinine, often bymeasurements of plasma para-aminohippurate(PAH) and mannitol clearances for betterdefinition, by measurements of maximum con-centrating power (Addis test) and by quanti-

tative determinations of urine protein andsediment.

Cardiac status is assessed in terms of func-tional capacity and, objectively, in terms ofcardiac enlargement as determined by theteleroentgenogram and the electrocardiogram.When, as commonly happens, there is evidenceof congestive heart failure, this is appropriatelytreated and brought to some optimum statusbefore the control period ends.The results of this study are plotted graphi-

cally in a "long chart" that has two large ad-vantages: It permits rapid visualization of thetrends of these significant functions duringcontrol and treatment periods and it is also aperpetual reminder to the investigator of exami-nations that may be inadvertently omitted.This chart (fig. 1), derived from one used byDr. D. D. Van Slyke in his study of Bright'sdisease, has saved untold time in record-search-ing, and is freely and wholeheartedly recom-NO |CLINICNO 570-525 SOYRS OHT 16025CM hT 64 KGDIAGNOSIS Eas..iIol Hype*rtenion

ARTERIAL 2XPRESSURE 200

180-a 160H9. 40

120

PITAIN 100

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FILTRATION 100RATE sop.t 73 30

F ILTRATION °'FRACTtON4

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PROTEINURIAGe. p. 24 0, 2.0

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TRANS CARDIAC ISOd.~ee 125% nol lo

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FIG. 1. A "long chart" showing how the data aregraphically ordered. The chart is used along with theclinical notes as a continuous record of the course ofthe patient's illness.

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mended as a tool in any prolonged therapeutictrial.The results of this study can also be lumped

together into a single numerical "severity in-dex,"3 4 in which a maximum score of 4 isassigned to each of the four panels.A maximum of four points each is assigned

to estimates of average supine diastolic pres-

sure and of the extent of hypertensive vasculardisease in the heart, kidneys and brain. Forexample, a patient with diastolic pressure

averaging more than 140 mm. Hg, grade IV,heart failure, uremia and grade IV retinop-athy, plus encephalopathy, would be graded16; improvement in any category reduces thegrade below 16.

Comparisons of pre- and post-treatmentseverity index in patients with like pretreat-ment indices is a useful way of summarizingthe experience with a drug. We are well aware

that the index we suggest is highly subjectivein its scoring and that a vast amount of studymight well be devoted to the compilation ofone more objectively based on the solid datumof mortality in untreated patients. Such pa-tients are now rare. Still, if there could be someagreement on this, or a like system of scoring,there would be less controversy about the valueof this or that experimental drug or procedurein any large group of patients. The history ofsympathectomy is a case in point and Dr.Smithwick's scoring is an attempt like ours, atsecuring comparability in the data.

Placebos and Blind Tests

We noted above that placebos are commonlygiven during the second and third weeks of the"control" period. Theoretically, there mightbe an advantage in starting the test period as

a blind or double-blind experiment. But thisprocedure has serious disadvantages and is, infact, impractical. We deal with highly vaso-

active drugs. Quite apart from their effects on

blood pressure, which most patients soon learnin one way or another, these all have side-effects that are definite and unmistakable. Asa result, a blind test loses its point because thepatient and the doctor very quickly recognizewhen a placebo is substituted for an activedrug. We still attempt such substitution when-

ever it seems practical, which is usually whenthe dosage of active drug has been reduced toa point at which side-effects are not easilydiscerned. As a routine procedure, however,we doubt its value, and use the placebo duringthe pretreatment period.

It may seem heresy in some eyes that webelieve it advantageous for the investigator tobe specifically interested in, and enthusiasticabout, the drug he is studying, and that there isa real scientific disadvantage in a dispassionateattitude. Two examples come to mind. Oneconcerns hexamethonium, which was used andstudied by Dr. F. H. Smirk with real devotion.As a result, his scrutiny was closer and histherapeutic results were better than ours orthose of most other workers. His estimate of thestatus of this agent was more accurate than theappraisals of those who desultorily gave it to afew people and, troubled by side-effects, moreor less sneeringly gave it up. The other con-cerns hydralazine; this has been widely de-spaired of as a useful medication; on the otherhand, because our colleague, Dr. RobertTaylor, and we were fascinated by its proper-ties, we used it in such a way that we havecome to regard it as a very useful and often alifesaving drug. This experience dependedlargely on our having enough enthusiasm for itto persuade ourselves and our patients that itwas to their advantage to accept and controlits common, initial, disagreeable side-effects.

The Out-Patient Study: Home PressuresWhen the time comes for discharge from the

hospital, there is no need to give up the experi-ment. As long as we relied on out-patient casualpressures we had few data from our out-patients that we would regard as convincing.Partly, this is because of the "break-through"of pressures under the emotional stimulus of acritical examination. Patients whose pressureaverages at home or in the hospital were rea-sonably normal, frequently showed high casualresting pressures as out-patients. In fact, someof the best responders to hydralazine wouldnot have been recognized as such had only thecasual pressures been available (fig. 2). Rather,they would have been categorized as showingimprovement in their hypertensive disease

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CLINICAL PROGRESS

MEANS OF HOSPITAL, CASUAL AND HOME PRESSURES

.-Ceeuoi-l 24X

Hos p italo l l blondsHrn-rp n II r -~~Horne

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FIG. 2. Open bars are means respectively of 4 and24 casual measurements of pressure; solid bars are

weekly means of hospital pressures and cross-hatchedbars are weekly means of home pressures. Hydrala-zine treatment was started on discharge from hospitaland showed no effect as judged from casual pressures.

Readmission to hospital established, by comparisonof hospital means, that pressure had actually de-creased, and this was confirmed by the subsequentmeans of home pressures. (Reproduced, with per-

mission, from the Annals of Internal Medicine.')

without corresponding changes in pressure, as

in the past, were so many sympathectomizedpatients. From such data as these, the errone-

ous conclusion has been drawn that, with thisor that agent or procedure, hypertension andhypertensive disease are dissociated phe-nomena. As far as we know this is a very rare

occurrence.

With the advent of the ganglion blockingagents, we embarked on a much wider program

of home-pressure readings than before. Datahave since accumulated to show that, in mostpatients, the home-pressure averages corre-

spond fairly well to hospital averages and that a

lack of such correspondence usually has a

clearly definable connotation that bears on thepatient's problem. We have also become im-pressed with the value of the datum providedby most of these patients as a basis for thera-peutic trial and, in many of them, with thepersonal therapeutic advantage of knowingtheir blood pressure and knowing that it isunder control. We would not recommend this

procedure to everyone. Those who use it area selected group. Only one out of some hun-dreds has demonstrated what might be inter-preted as significant psychologic stress fromthe procedure; this was a young man whomanifested the same psychologic stress to anyprocedure related to his hypertensive disease,which he was quite unwilling to accept.

The CocktailsEach of the presently available, antipressor

drugs has a limited field of usefulness. Somepatients respond to one, some to another andnot to the first. The dosage at which a responseis obtained varies from person to person and,in the same person, from time to time. As aresult, each drug has to be individually ad-justed or, to adhere to the current jargon,"titrated." Many drugs, notably the sympatho-lytic and ganglion-blocking agents, elicit astate of tolerance more or less rapidly. This isperhaps a good thing. We have a sardonicsuspicion that there would be a vast new field ofsignificant illnes if most of the ganglion-blocking agents, in the dosages administered,were not almost inert in most of the people whotake them.These considerations weigh heavily against

the dispensing of mixtures of hypotensivedrugs. They do not bear on the possibility thatsome patients may gain an advantage fromcombinations of such agents. Of course theymay. But they gain only when the dosage ofeach can be appropriately selected, which isnot the case when these agents are all packagedtogether in one pill. The use of these mixturesseems to us scientifically and professionallyindefensible unless it can be shown that theredoes exist some very unusual patient who hasno problems of tolerance or specific responsive-ness.

The CostHospitalization is costly; the investigator's

time and energy are costly; technicians arecostly; thus, the whole process of clinical trialis enormously expensive. Probably the greatestexpense is the time spent away from funda-mental investigation and contemplation of

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basic mechanisms, with all its attendant risksof ultimate intellectual sterilization of apotentially productive person. Very little ofthis cost is defrayed by those who receive thelargest financial advantage. Perhaps this is asit should be. It may be that the psychologicboost of being "first" and of reading a papereach year on the merits of some new drug isreward enough. To our minds, this is notenough. Certainly there are many who wouldlook with a jaundiced eye on a clinical trialthat was wholly and effectively supported bythe interested drug company. But the samecritics would not hesitate to accept a reportfrom the same investigator on an animal orchemical study, wholly subsidized and ofpotential commercial value. There must besome middle way between the present system,which inequitably distributes a large com-mercial cost on investigators, hospitals andpatients, and an equitable method, which

would not be open to the suspicion of commer-cial prejudice. The solution of this problemmight well be a specific aspect of the functionof the newly created Committee on the Investi-gation of Antihypertensive Agents, recentlyformed by the American Medical Association'sCouncil on Pharmacy.

REFERENCES1 CORCORAN, A. C., DUSTAN, H. P., AND PAGE, I. H.:

The evaluation of antihypertensive procedureswith particular reference to their effects on bloodpressure. Ann. Int. Med. 43: 1161, 1955.

2 WATKINS, D. M., FROEB, H. F., HATCH, F. T., ANDGUTMAN, A. B.: Effects of diet in essential hyper-tension. 1. Baseline study; effects in eighty-sixcases of prolonged hospitalization on regular hos-pital diet. Am. J. Med. 9, 428, 1950.

3 PAGE, I. H., AND CORCORAN, A. C.: ArterialHypertension: Its Diagnosis and Treatment.Ed. 2, Chicago, The Year Book Publishers, 1949.

4 CORCORAN, A. C., DUSTAN, H. P., TAYLOR, R. D.,AND PAGE, I. H.: Management of hypertensivedisease. Am. J. Med. 17, 383, 1954.

9rDisease in man is never exactly the same as disease in an experimental animal, for in man the

disease at once affects and is affected by what we call the emotional life. The physician who at-tempts to take care of a patient while he neglects this factor is as unscientific as the investigatorwho neglects to control all the conditions that may affect his experiment. The good physicianknows his patients through and through, and his knowledge is bought dearly. Time, sympathy,and understanding must be lavishly dispensed, but the reward is to be found in that personalbond which forms the greatest satisfaction of the practice of medicine. One of the essential quali-ties of the clinician is interest in humanity, for the secret of the care of the patient is in caring forthe patient.-FRANCIS WELD PEABODY. The Care of the Patient. Harvard University Press, 1927.

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IRVINE H. PAGE and A. C. CORCORANClinical Evaluation of Antihypertensive Drugs

Print ISSN: 0009-7322. Online ISSN: 1524-4539 Copyright © 1956 American Heart Association, Inc. All rights reserved.

75231is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TXCirculation

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