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Primary hypertension
Primary
Hypertension
Survey of the Survival of Patients with Established Diastolic
Hypertension
Medical JOSEPH
H. HAFKENscnrEL,t
After Ten Years of
and Surgical Treatment*
M.D., JERRY E. SCHMITTHENNER, M.D. and EARL A. DAUGHERTY, M.D.
With the Technical
Assistance
Philadelphia,
of JOHN D. BENTLEY, hf.n. Pennsylvania
tension survived beyond five years (less than 5yc in the Keith, Wagener and Barker’series of 1939). Kinsey and co-workers8 have compared the survival of their surgical cases with the nonsurgical. Smithwick’s surgically treated patients had a survival rate that was higher at the end of a decade than that of the patients reported by Simpson and Smirk.9 The purpose of this report is to present evidence from one clinic’s experience suggesting that the estimate of 10 year survival of men treated medically (38ye) for established diastolic hypertension (Smithwick groups 3 and 4) is better than that of men treated surgically (307c surviving). This is encouraging and provocative. However, the estimates are based on the experience of too few patients to make the difference statistically reliable in favor of medical Perhaps a longer period of time and treatment. a larger series of patients in the same disease severity grouping will enable the clinician to decide whether the following statement is true or premature : “Persons who used to die in a year or two from rapidly progressing malignant hypertension are now being saved to lead active, productive lives for 5, 10 or more years.“‘” Our own experience leads us to believe that this is now possible but improbable. The only patient (with what we diagnosed as the accelerated form of hypertension) we have observed to survive 10 years and longer on medical management with depressor drug therapy was con-
ECENT advances in renal artery reconstruction’ and newer knowledge of quantitating the pathologic physiology of the adrenal gland in man2 have reduced the number of patients diagnosed as having primary hyperHowever, the majority of patients with tension. elevated arterial pressure seen in office and clinic practices have been shown to have primary hypertension. This remains a diagnosis established by exclusion, usually after a carefully designed hospital inpatient study program.3 Hopefully, as the group of patients with primary hypertension becomes more homogeneous, the natural history of the disturbance may be less Perera* has commented : “Even the uncertain. effect of primary hypertension on survival is open to question, for the mortality reported in different control groups of patients, followed for approximately 10 years, varies from 12 to 917c.” Clinical experience, generally, has indicated that the depressor drugs introduced since 1950 are potent agents. These compounds have made possible the moderation or normalization of severely elevated diastolic blood pressure levels. The medical approach rather than surgical management has been the major effort in the 1960’~.~,~ The precise assessment of the life-prolongation capacity of antihypertensive compounds requires some standard of comparison. Until now only a few patients considered in the “malignant” or accelerated phase of hyper-
R
* From the Cardiac Clinic and Medical Service “B” (Malcolm W. Miller, M.D., Chief), Lankenau Hospital, PhilaThis investigation was supported in part by research grants (H361 and H1817) from the National Heart delphia, Pa. Institute, Public Health Service; by grants from the Tobacco Industry Research Committee( QH17) and from the Committee on Problems of Alcohol of the National Academy of Sciences, National Research Council (UV25 j. t Address for reprints: Suite 304, 450 Sutter St., San Francisco, Calif. 94108. VOLUME
16,
JUL.Y
1965
61
Hafkenschiel,
Schmitthenner
and Daugherty TECHNIC OF ANALYZING DA.I-4
30
20
II Mean
Age 49.45
III Mean
Age 49.57
yrs.
IV Mean
Age 46.59
yrs.
t-age
at admission
yrs. ( 94 patients1
( 35patients1 ( 78 patents)
to study
Fig. 1. Ten year survival curues for ench Smithwick group (all sex and treatment groups combined). Correlation of survival rates with Smithwick grading at time of initial examination.
sidered port.”
so unusual
as to warrant
a case
re-
METHODS The case records of all patients with established diastolic hypertension of primary type seen in the Cardiac Clinic of Lankenau Hospital prior to May 1953, were reviewed and the following information transferred to “Info-Dex” heart-registry cards: Smithwick classification (1, 2, 3, 4), male or female, white or nonwhite, date first classified, age on entering the series, program of management (medical or surgical), date last seen or date of death. If postmortem examination had been possible or the death certificate was available and the death was due to the complications of hypertensive disease, the case was included in the series. Otherwise it was dropped from the series as of the year of death. A similar survey of the patient records of the private patients of the authors was also made. If there was no current follow-up information, a letter was addressed to the patient’s physician requesting the information about current status. In some instances when patients’ telephone numbers and addresses were available, the patient was contacted directly. Even though some were not optimally followed medically, no patient was dropped from the medically treated series for that reason. Thus, the inclusion of such patients tends to lower the survival rates. Eight patients studied before 1953 were lost to follow-up (as of June 1, 1962). Six of these were in the Smithwick 1 classification, and only 2 were group-4 patients. A similar follow-up search was also made for the patients seen in every year from May 1953, through May 31, 1962.
l’he patients who have been follo\ved 10 years or more were usually evaluated initiallv in the hospital during a week or so of study. we attempted to determine whether the outpatient’s diastolic pressure was fixed and whether the elevated blood pressure was secondary to some other cause that could be treated directly. In the course of such an observation, we employed the same criteria to assess the severity of the patient’s disease first used by Smithwick. The method of study has been much the same as that recently reported by Kinsey and Whitelaw.” A numerical value is assigned to different observation ofthe involvement of the various vascular beds. The individual factors are totaled, and if a patient has four or more points, he is automatically in Smith\+ick group 3 or 4 (see Table v12). However, he is in a group 3 classification only if he does not have any of the following : (1) cerebrovascular accident with residual signs; (2) frank congestive failure; (3) phenolsulfonphthalein (PSP) excretion below 15 per cent in 15 minutes plus poor response to amytal sedation. Such data were abstracted from the patient’s chart. The classifications were tabulated on a lvork sheet and
transferred to the individual cards. Having all the data on these individual cards for the Smithwick classifications in the years before 1950 through 1953 and the period up to May 31, 1962, the cards were analyzed statistically. Using the technics of Bradford Hi11,13we constructed survival curves for the 4 groups of patients. RESULTS Smithwick Groups 1 and 2: A total of 319 patients followed up for one year or more were used in the construction of the 10 year survival curves. These are shown in Figure 1 for each of the groups. The patients in group 1 (top curve, Fig. 1) have the best survival experience of any group. These patients have minimal evidence of vascular disease as indicated by Roman numeral one of the Smithwick grouping. However, at the end of 10 years of observation, only 90 per cent remain. An analysis of the 10 per cent who have died gives no clearunderstanding why they succumbed to one or more vascular This complications of the hypertensive state. group had the youngest mean age (average, 44.53 years) at the time of entering the study. Can adequate blood pressure control prevent the complications of hypertension in this group? We think this is possible and should be tested. The survival experience of patients of group 2 is not so good as the first group. Of the 107 patients of this series followed for 10 years or more, the largest number, 46 subjects, were classified in group 1; there were 40 in group 2 THE
AMERICAN
JOURNAL
OF
CARDIOLOGY
Primary
Hypertension-Survival
For the other 212 and 21 in groups 3 and 4. patients followed up for less than 10 years, entries on the curve show at 9, 8, 7, 6 etc., down to 1 y’ear survival. Snitlwi(k Groups 3 and 4: Because we have only- a small number of patients in our own series in groups 3 and 4 followed for 10 years or more, these patients have been grouped togethcr and are considered as to sex and type of treatment in Figure 2. The female patients on medical management have the best survival percentage over most of the period. However, those surgically managed (curve 2) do just about as well with approximately 60 per cent surviving at 10 \ears. It is of interest that after the first three years following the surgical procedure, no female patients were lost because of the of their hypertensive state. complications it is noteworthy that this female Further. surgical group was the youngest, having a mean age at the time they entered the series of 40 years. So surgically managed female or male patients entered the series in the last two years. The male medical patients are not very much different from the male surgical as to survival results at the end of the 10 year period. The men medically managed show 38 per cent survi\~al whereas those surgically managed are at 30 per cent. The medical male patients had a mean age at the beginning of the series five years old& than the mean age of the surgical group.
60 -
‘\
M
9
z
63
Experience
1 *\ ..---. \ =\
‘\
2
8
3
\
50 -
‘\
a-
\ \
,..F._ ._..
-.
.\
-.
20 IO -
-.
‘\ .-.*
30 1
FEMALE
MEDICAL
1
FEMALE
SURGICAL
3
MALE
MEDICAL
4 MALE
SURGICAL
0
I
2
(Mean [Mean (Mean
Age 51 87 yrs I Age 40.04 yrs)
Age 50.42 yis ,
(Mean Age 45 25 yrs 1
3
4
6
I
d
I IO
9
YEiRS
Fig. 2.
Ten ytw suroival GU~YXS for each sex and treatment (Smithwick groups 3 and 4 combined). More female patients survive than do male. The greater percentage of men medically treated is not statistically significant because of the small number in the groups.
COMMENT
Comnpar~son That
of Other
of
Current
Investigators:
Survival
Experience
with
To give some idea of
how the patients who are in Smithwick groups 3 and 4 medically managed might compare with patients medically managed in the series of other authors, we compared our group with the only group we are aware of with survivals of 10 years or more. The report of Simpson and Smirk9 (Fig. 3) describes the survival of patients classified as having malignant hypertension. The authors do not detail their criteria for the malignant state, but we assume that these individuals had papilledema (following the KeithWagener-Barker7 criteria) as the cardinal feature of the malignant hypertensive state. The female patients in groups 3 and 4 of our series are shown as curve 1 of Figure 3. This group has a more favorable survival experience, with almost 60 per cent surviving, whereas the female malignant series (curve 2) of Simpson and Smirk” shows less than 40 per cent. In the VOLUME
16.
JULY
1965
30 20 IO -
1
FEMALE
IIHV
2
FEMALE
MALIGNANT
3
MALE
4 MALE
III-IV
‘\ ‘\ ‘\
MALIGNANT
Fig. 3. Ten year survirxd cwucs for patients with malignant hypertension9 and Smithwick ,pmps 3-4, medico& treatrd. Simpson and Smirk use the Keith, Wagener and Barker classification, the presence of papilledema, as the criterion for grading hypertension as malignant. The survival rate of the male malignant group medically treated by Simpson and Smirk (curve 4) suggests a tenfold increase in survival, approximately 18 per cent, when compared with the 1939 report of Keith, Wagener and Barker. This study showed survival from five to nine years of only 1 patient in a series of 146 patients with malignant hypertension on a general medical regimen.
64
Hafkenschiel,
Schmitthenner
male patients there is a comparable, favorable survival curvealthoughit does not show so great a difference. The male patients of groups 3 and 4 (curve 3) have an approximate 38 per cent survival, whereas of the males with malignant hypertension treated by Simpson and Smirk medically (usually this means ganglionic blockers such as pentolinium), only 18 per cent are surviving at 10 years (curve 4, Fig. 3). So, based on the survival curves shown in this graph, we would have to conclude that there is something unfavorable about the presence of papilledema and the classification of “malignant” hypertension that leads to an adverse or shorter survival experience when compared with a group of patients in the Smithwick 3 and 4 using criteria mentioned earclassification, lier 8 I9,I2 Farmer and co-workerG reported from the Mayo Clinic 97 patients in group 3 (KeithWagener-Barker criteria) and 64 in group 4 who had been followed-up up to six years. This latter group would appear to be comparable to the 70 patients observed by Simpson and Smirk for 10 years. Only 23 per cent of the Mayo Clinic group 4 patients were still alive at six years. Farmer et al. concluded that medical treatment improves the prognosis in “malignant” hypertension and compares favorably with sympathectomy. In 1962, 251 patients with “malignant” hypertension were reported by Kinsey and coworkers8 as having been under observation up to 24 years, 160 having had surgical treatment. There were 28 male patients in the Smithwick group 4 classification and 21 female. The overall survival rate is given as 36 per cent at a 10 year follow-up level for all the Smithwick surgically treated patients. However, whether the per cent survival of group 4 (Smithwick classification) patients surgically treated would be as high as 36 per cent is uncertain inasmuch as Table III of that report shows only 7 patients in Smithwick classification group 4 surgically treated surviving 10 years or more. The most recent report of Smithwick and associates6 presents the survival rate of patients similarly grouped through only a seven year period. At the outset of this study in 1950, several questions were to be answered: (1) Which of the high blood pressure patients should be (2) Which should be treated medically treated? and which surgically? and (3) How would their survival rates compare with those untreated? The 10 per cent 10 year mortality for our
and
Daugherty
mildest group (curve I, Fig. 1) appears to be more favorable than the mortality reported by Smithwick in 1948 for his nonsurgical group 1 patients. At that time there was not a statistically significant, favorable, increased survival of his group 1 surgical patients. The more modern drug therapy used for our patients suggests that this does prolong life in the mildly hypertensive patient. After a two year study15 of the depressor drug hydralazine in a group of patients with established diastolic hypertension of mild to moderate elevations, we asked two more questions in 1953: Does hydralazine or any other depressor drug keep mildly hypertensive patients from getting worse and thus obviate surgical intervention? This is the most important question of all: Does medical or surgical treatment prevent patients from entering the accelerated phase of hypertension? The answer now is a qualified yes. Another question posed in 1953 was, “Does hydralazine or any other depressor drug or combination of drugs prolong the lives of those individuals with such severe hypertension that renal damage and azotemia preclude operation?“15 At that time, we suggested that a longer period of observation and a larger series of patients were needed before the latter question might be answered. Still more perspective is required before this second question can be answered, but now we are more optimistic than in 1953 but less so than Warren.l”,” Factors entering into framing an answer to the first question posed in 1953 are diverse. Some of the opinions expressed are summarized below. Possibility of Prevention of the Accelerated Form of Hypertension: Although some investigators question that the hypotension induced by depressor drugs is the important factor in arresting the progress of vascular complications, many physicians using antihypertensive drugs believe that normalization of elevated pressure is “very necessary” in all patients having only relatively minor insurance expressure elevations.r6 Life indicates an augmented mortality perience” in men (age 30-39) of five times the standard risk when the pressure is 150/100 or in the “high normal” range. Pagels has stated, “I think it has now been incontrovertibly shown that even slight elevations in blood pressure do significantly increase human mortality.” House1 et al.“’ and Beem, Corcoran,r9 Roland22 have been in favor of early treatment. Simpson and Smirk9 cite the decreasing THE AMERICAN
JOURNAL
OF
CARDIOLOGY
Primary
Hypertension-Survival
incidence of patients diagnosed as having “malignant” hypertension, particularly since the introduction of thiazide compounds in 1957, as evidence favoring the thesis of preventing the development of the accelerated phase by the early use of depressor drugs. Frcis? has emphasized the great need in clinical medicine for an office procedure that will detect renal damage at an early stage of Our experience suggests that hypertension. the intravenous phenolsulfonphthalein (PSP) test is a practical office or outpatient procedure in the attempt to detect a decrease in kidney function which might be related to a reduction in renal blood flo~.~~ The PSP excretion test helps to measure whether there is any deterioration in renal function and whether depressor drug therapy is not intensive enough to prevent Preservation of renal kidney vascular damage. function is, we believe, the most important guide to successful antihypertensive therapy. To conclude that the patient is being kept out of the accelerated phase when there is no evidence in the fundi of exudates, hemorrhages, or papilledema and without knowledge of the PSP excretion is inconsistent with the facts of insidious but relentless renal damage with only minimal elevations of diastolic pressure. Howeser, with the widespread use of the thiazidc congeners, PSP tests may be falsely low if the patient is not taken off such a drug for at least one week before the PSP test is used as a first approximation to the measurement of glomerular filtration rate, renal blood flow and A similar effect of uricotubular function.‘j suric agents on depressing the PSP test has been reported.“” Our own philosophy of prevention of the accelerated phase of hypertension was stated in 1957.2i Moreover, at that time there appeared to be a more favorable survival of the surgically Now at managed group 3 and group 4 patients. a 10 year follow-up period, survival of the medically treated patients in the same category is much the same. We are more radical now in initiating depressor drug therapy in patients with primary asymptomatic hypertension and without cardiovascular-renalcomplications (presumable Smithwick group 1 patients) than are some British physicians.28 Losing 10 per cent of patients in the Smithwick group 1 of our series in a decade is adequate reason for depressor drug therapy of most patients with fixed diastolic hypertension over 90 mm. Hg after three days of VOLUME
16,
JULY
1965
65
Experience
hospital bed rest. Waiting until the diastolic hypertension is 110 mm. Hg or higher, as Hamilton and co-workers”8 of Pickering’s group suggest, may be too late to prevent vascular damage in the brain, retina, heart or kidneys. SUMMARY
AND
CONCI.USION:,
All patients with blood pressure consistently over 15Oi90 mm. Hg should be studied carefully to determine whether they ha\c an established diastolic hypertension, and if so, whether this is secondary or primary hypertension. or the accelerated phase of “Malignant” hypertension might be prevented in most patients with fixed diastolic hypertension of 90 mm. Hg or higher after three days of hospital bed rest if the vascular complications, which are used to place patients in the categories denoted as Smithwick 3 and 4 probable prognosis groupings could be avoided by a careful general medical approach and early intensi1.e depressor drug therapy. Preservation of renal function is, we beiievc, the most important guide to successful antihypertensive therapy. Little of significance can be done to prolong life when renal functional deterioration and other vascular complications of the hrain and heart have progressed, usually insidiously, so that the patient presents with retinal hemorrhages, exudate and or papilledema. Usually renal blood flow is found to be markedly reduced when more precise testing of these patients is possible. Ten year survival curves of a small series of patients having the more serious cardio\rascularrenal complications (Smithwick 3 and 4 groups) suggest that medical treatment is as satisfactory in prolonging life as the surgical approaches that we have tested. Over-all survival varies from 30 to 90 per cent. More time and perspective appear to be necessary in order to validate the thesis: “The 1950’s coincide with the great improvement in the control of hypertension through drugs and other means. Modern drug therapy for this condition dates in this countrv from about 1950. Persons who used to die in a year or two from rapidly progressing malignant hypertension clre note’ being saved to lead active: /rod&w licrsfor 5, IO or more yenrs.“‘”
The assistance of Miss Zion of the Medical C&c History Bureau, New York, is greatly appreciated.
66
Hafkenschiel,
Schmitthenner
REFERENCES 1. DEBAKEY, M. E., MORRIS, G. C., JR.. MORGEN~ R. O., CRAWFORD, E. S. and COOLEY, D. A. Lesions of the renal artery. Surgical technic and results. Am. J. Surg., 107: 84, 1964. 2. JEFFERS, w. A., SELLERS,A. M., WOLFERTH, C. C., Ross, A. M. and BLAKEMORE.\V. S. Results of sympathectomy adrenalectomy. Am. J. and Surg., 107: 211, 1964. 3. BRUST, A. A., PERERA, G. A. and WILKINS, R. W. Classification of types of hypertension. Keport .J.A.M.A., 166: 640, to the Council on Drugs. 1958. 4. PERERA, G. A. Editorial: The unnatural history of (hypertensive) disease. Circulatzon, 21: 1, 1960. 5. HOLLANDER, W. and WILKINS, R. W. Present day management and indications for drug and surgical therapy. Am. J. Surg., 107: 204, 1964. 6. WHITELAW, G. P., KINSEY~D. and SMITHWICK, R. H. Factors influencing the choice of treatment rim. J. surg., 107: 220, in essential hypertension. 1964. 7. KEITH, N. M., WAGENER, H. P. and BARKER, N. W. Some different types of essential hypertension: Their course and prognosis. Am. J. M. SC., 197: 332,1939. 8. KINSEY, D., WHITELAW, G. P., WALTIIER, R. J., TWEOPHILIS,C. A. and SMITHWICK,R. H. The long-term follow-up of malignant hypertension. J.A.M.A.,181:571,1962. 9. SIMPSON, F. 0. and SMIRK, F. H. The treatment of malignant hypertension. Am. J. Cardiol., 9: 868,1962. C-V death rate drops for middle 10. WARREN, J. V. aged men. Am. Heart, 13: 1, 1963. 11. HAFKENSCHIEL,.J. H. Are malignant hypertension and benign hypertension different diseases? In : Hypertension-The First Hahnemann Symposium on Hypertensive Disease, p. 101. Edited by MOYER, J. H. Philadelphia, 1959. W. B. Saunders Company. 12. KINSEY, D. and WHITELAW, G. P. The hyperAm J. Method of study. tensive patient. S’urg., 107: 5, 1964.
and Daugherty
13. HILL? A. B. Principles of Medical Statistics, ed. 6, Chap. 14, Life table and survival after treatment. London, 1955. Lancet Ltd. 14. FARMER, R. G., GIFPORD, R. W., .JR. and HINES, E. A., JR. Drug therapy for severe hypertension. Ann. Znt. Med., 112: 118, 1963. 15. HAYKENSCHIEL,J. H. and LINDAUER, M. A. lHydrazinophthalazine (Apresoline) in the treatment of hypertension: A two-year study. Circulation, 7: 52, 1953. 16. PAGE, I. H. and DUSTAN, H. P. The changing outlook for hypertensives. J. Chron. Dis., 16: 115,1963. 17. Society of Actuaries. Build and Blood Pressure Study (two volumes). Chicago, 1959. Society of Actuaries. 18. PAGE, I. H. Newer antihypertensive drugs. Postgrad. Med., 27 : 448, 1960. 19. CORCORAN, A. C. Principles of chemotherapy in hypertension. J. Indiana M. A., 55 : 184, 1962. 20. BEEM, J. N. Causes of death due to hypertension: The effect of therapy. In Ref. 11, p. 106. 21. HOUSEL, E. L., KELLY, J. J. and DALY, J. W. The of hypertension. Angiology, 14: 28, diagnosis 1963. 22. ROLAND, F. P. First drug in essential hypertension. Am. Pratt., 12: 879, 1961. 23. FREIS, E. D. Office evaluation of the hypertensive patient (I and II). Mod. Concepts Cardiovas. Dis., 32: 822,1963. 24. HAFKENSCHIEL,J. H. Renal function studies in hypertension, with particular reference to the intravenous PSP test. Tr. Am. Coil. Cardiol., 5: 67,1955. Unpublished observations. 25. HAFKENSCHIEL,J. H. 26. NEWCOMBE, D. S. and COHEN, A. S. Effect of uricosuric agents on PSP test. Arch. Int. Med., 112: 738,1963. 27. HAFKENSCI~IEL,J. H. Modern concepts of hyperAm. J. Cardial., 2: tension and its treatment. 227,1958. 28. HAMILTON, M., THOMPSON,E. N. and WISNIEWSKI, T. K. M. The role of blood-pressure control in preventing complications of hypertension. Lnncet, 1: 235, 1964.
THE AMERICANJOURNAL OF CARDIOLOGY
Hypertension
Survey of the Survival of Patients with Established Diastolic
Hypertension
Medical JOSEPH
H. HAFKENscnrEL,t
After Ten Years of
and Surgical Treatment*
M.D., JERRY E. SCHMITTHENNER, M.D. and EARL A. DAUGHERTY, M.D.
With the Technical
Assistance
Philadelphia,
of JOHN D. BENTLEY, hf.n. Pennsylvania
tension survived beyond five years (less than 5yc in the Keith, Wagener and Barker’series of 1939). Kinsey and co-workers8 have compared the survival of their surgical cases with the nonsurgical. Smithwick’s surgically treated patients had a survival rate that was higher at the end of a decade than that of the patients reported by Simpson and Smirk.9 The purpose of this report is to present evidence from one clinic’s experience suggesting that the estimate of 10 year survival of men treated medically (38ye) for established diastolic hypertension (Smithwick groups 3 and 4) is better than that of men treated surgically (307c surviving). This is encouraging and provocative. However, the estimates are based on the experience of too few patients to make the difference statistically reliable in favor of medical Perhaps a longer period of time and treatment. a larger series of patients in the same disease severity grouping will enable the clinician to decide whether the following statement is true or premature : “Persons who used to die in a year or two from rapidly progressing malignant hypertension are now being saved to lead active, productive lives for 5, 10 or more years.“‘” Our own experience leads us to believe that this is now possible but improbable. The only patient (with what we diagnosed as the accelerated form of hypertension) we have observed to survive 10 years and longer on medical management with depressor drug therapy was con-
ECENT advances in renal artery reconstruction’ and newer knowledge of quantitating the pathologic physiology of the adrenal gland in man2 have reduced the number of patients diagnosed as having primary hyperHowever, the majority of patients with tension. elevated arterial pressure seen in office and clinic practices have been shown to have primary hypertension. This remains a diagnosis established by exclusion, usually after a carefully designed hospital inpatient study program.3 Hopefully, as the group of patients with primary hypertension becomes more homogeneous, the natural history of the disturbance may be less Perera* has commented : “Even the uncertain. effect of primary hypertension on survival is open to question, for the mortality reported in different control groups of patients, followed for approximately 10 years, varies from 12 to 917c.” Clinical experience, generally, has indicated that the depressor drugs introduced since 1950 are potent agents. These compounds have made possible the moderation or normalization of severely elevated diastolic blood pressure levels. The medical approach rather than surgical management has been the major effort in the 1960’~.~,~ The precise assessment of the life-prolongation capacity of antihypertensive compounds requires some standard of comparison. Until now only a few patients considered in the “malignant” or accelerated phase of hyper-
R
* From the Cardiac Clinic and Medical Service “B” (Malcolm W. Miller, M.D., Chief), Lankenau Hospital, PhilaThis investigation was supported in part by research grants (H361 and H1817) from the National Heart delphia, Pa. Institute, Public Health Service; by grants from the Tobacco Industry Research Committee( QH17) and from the Committee on Problems of Alcohol of the National Academy of Sciences, National Research Council (UV25 j. t Address for reprints: Suite 304, 450 Sutter St., San Francisco, Calif. 94108. VOLUME
16,
JUL.Y
1965
61
Hafkenschiel,
Schmitthenner
and Daugherty TECHNIC OF ANALYZING DA.I-4
30
20
II Mean
Age 49.45
III Mean
Age 49.57
yrs.
IV Mean
Age 46.59
yrs.
t-age
at admission
yrs. ( 94 patients1
( 35patients1 ( 78 patents)
to study
Fig. 1. Ten year survival curues for ench Smithwick group (all sex and treatment groups combined). Correlation of survival rates with Smithwick grading at time of initial examination.
sidered port.”
so unusual
as to warrant
a case
re-
METHODS The case records of all patients with established diastolic hypertension of primary type seen in the Cardiac Clinic of Lankenau Hospital prior to May 1953, were reviewed and the following information transferred to “Info-Dex” heart-registry cards: Smithwick classification (1, 2, 3, 4), male or female, white or nonwhite, date first classified, age on entering the series, program of management (medical or surgical), date last seen or date of death. If postmortem examination had been possible or the death certificate was available and the death was due to the complications of hypertensive disease, the case was included in the series. Otherwise it was dropped from the series as of the year of death. A similar survey of the patient records of the private patients of the authors was also made. If there was no current follow-up information, a letter was addressed to the patient’s physician requesting the information about current status. In some instances when patients’ telephone numbers and addresses were available, the patient was contacted directly. Even though some were not optimally followed medically, no patient was dropped from the medically treated series for that reason. Thus, the inclusion of such patients tends to lower the survival rates. Eight patients studied before 1953 were lost to follow-up (as of June 1, 1962). Six of these were in the Smithwick 1 classification, and only 2 were group-4 patients. A similar follow-up search was also made for the patients seen in every year from May 1953, through May 31, 1962.
l’he patients who have been follo\ved 10 years or more were usually evaluated initiallv in the hospital during a week or so of study. we attempted to determine whether the outpatient’s diastolic pressure was fixed and whether the elevated blood pressure was secondary to some other cause that could be treated directly. In the course of such an observation, we employed the same criteria to assess the severity of the patient’s disease first used by Smithwick. The method of study has been much the same as that recently reported by Kinsey and Whitelaw.” A numerical value is assigned to different observation ofthe involvement of the various vascular beds. The individual factors are totaled, and if a patient has four or more points, he is automatically in Smith\+ick group 3 or 4 (see Table v12). However, he is in a group 3 classification only if he does not have any of the following : (1) cerebrovascular accident with residual signs; (2) frank congestive failure; (3) phenolsulfonphthalein (PSP) excretion below 15 per cent in 15 minutes plus poor response to amytal sedation. Such data were abstracted from the patient’s chart. The classifications were tabulated on a lvork sheet and
transferred to the individual cards. Having all the data on these individual cards for the Smithwick classifications in the years before 1950 through 1953 and the period up to May 31, 1962, the cards were analyzed statistically. Using the technics of Bradford Hi11,13we constructed survival curves for the 4 groups of patients. RESULTS Smithwick Groups 1 and 2: A total of 319 patients followed up for one year or more were used in the construction of the 10 year survival curves. These are shown in Figure 1 for each of the groups. The patients in group 1 (top curve, Fig. 1) have the best survival experience of any group. These patients have minimal evidence of vascular disease as indicated by Roman numeral one of the Smithwick grouping. However, at the end of 10 years of observation, only 90 per cent remain. An analysis of the 10 per cent who have died gives no clearunderstanding why they succumbed to one or more vascular This complications of the hypertensive state. group had the youngest mean age (average, 44.53 years) at the time of entering the study. Can adequate blood pressure control prevent the complications of hypertension in this group? We think this is possible and should be tested. The survival experience of patients of group 2 is not so good as the first group. Of the 107 patients of this series followed for 10 years or more, the largest number, 46 subjects, were classified in group 1; there were 40 in group 2 THE
AMERICAN
JOURNAL
OF
CARDIOLOGY
Primary
Hypertension-Survival
For the other 212 and 21 in groups 3 and 4. patients followed up for less than 10 years, entries on the curve show at 9, 8, 7, 6 etc., down to 1 y’ear survival. Snitlwi(k Groups 3 and 4: Because we have only- a small number of patients in our own series in groups 3 and 4 followed for 10 years or more, these patients have been grouped togethcr and are considered as to sex and type of treatment in Figure 2. The female patients on medical management have the best survival percentage over most of the period. However, those surgically managed (curve 2) do just about as well with approximately 60 per cent surviving at 10 \ears. It is of interest that after the first three years following the surgical procedure, no female patients were lost because of the of their hypertensive state. complications it is noteworthy that this female Further. surgical group was the youngest, having a mean age at the time they entered the series of 40 years. So surgically managed female or male patients entered the series in the last two years. The male medical patients are not very much different from the male surgical as to survival results at the end of the 10 year period. The men medically managed show 38 per cent survi\~al whereas those surgically managed are at 30 per cent. The medical male patients had a mean age at the beginning of the series five years old& than the mean age of the surgical group.
60 -
‘\
M
9
z
63
Experience
1 *\ ..---. \ =\
‘\
2
8
3
\
50 -
‘\
a-
\ \
,..F._ ._..
-.
.\
-.
20 IO -
-.
‘\ .-.*
30 1
FEMALE
MEDICAL
1
FEMALE
SURGICAL
3
MALE
MEDICAL
4 MALE
SURGICAL
0
I
2
(Mean [Mean (Mean
Age 51 87 yrs I Age 40.04 yrs)
Age 50.42 yis ,
(Mean Age 45 25 yrs 1
3
4
6
I
d
I IO
9
YEiRS
Fig. 2.
Ten ytw suroival GU~YXS for each sex and treatment (Smithwick groups 3 and 4 combined). More female patients survive than do male. The greater percentage of men medically treated is not statistically significant because of the small number in the groups.
COMMENT
Comnpar~son That
of Other
of
Current
Investigators:
Survival
Experience
with
To give some idea of
how the patients who are in Smithwick groups 3 and 4 medically managed might compare with patients medically managed in the series of other authors, we compared our group with the only group we are aware of with survivals of 10 years or more. The report of Simpson and Smirk9 (Fig. 3) describes the survival of patients classified as having malignant hypertension. The authors do not detail their criteria for the malignant state, but we assume that these individuals had papilledema (following the KeithWagener-Barker7 criteria) as the cardinal feature of the malignant hypertensive state. The female patients in groups 3 and 4 of our series are shown as curve 1 of Figure 3. This group has a more favorable survival experience, with almost 60 per cent surviving, whereas the female malignant series (curve 2) of Simpson and Smirk” shows less than 40 per cent. In the VOLUME
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JULY
1965
30 20 IO -
1
FEMALE
IIHV
2
FEMALE
MALIGNANT
3
MALE
4 MALE
III-IV
‘\ ‘\ ‘\
MALIGNANT
Fig. 3. Ten year survirxd cwucs for patients with malignant hypertension9 and Smithwick ,pmps 3-4, medico& treatrd. Simpson and Smirk use the Keith, Wagener and Barker classification, the presence of papilledema, as the criterion for grading hypertension as malignant. The survival rate of the male malignant group medically treated by Simpson and Smirk (curve 4) suggests a tenfold increase in survival, approximately 18 per cent, when compared with the 1939 report of Keith, Wagener and Barker. This study showed survival from five to nine years of only 1 patient in a series of 146 patients with malignant hypertension on a general medical regimen.
64
Hafkenschiel,
Schmitthenner
male patients there is a comparable, favorable survival curvealthoughit does not show so great a difference. The male patients of groups 3 and 4 (curve 3) have an approximate 38 per cent survival, whereas of the males with malignant hypertension treated by Simpson and Smirk medically (usually this means ganglionic blockers such as pentolinium), only 18 per cent are surviving at 10 years (curve 4, Fig. 3). So, based on the survival curves shown in this graph, we would have to conclude that there is something unfavorable about the presence of papilledema and the classification of “malignant” hypertension that leads to an adverse or shorter survival experience when compared with a group of patients in the Smithwick 3 and 4 using criteria mentioned earclassification, lier 8 I9,I2 Farmer and co-workerG reported from the Mayo Clinic 97 patients in group 3 (KeithWagener-Barker criteria) and 64 in group 4 who had been followed-up up to six years. This latter group would appear to be comparable to the 70 patients observed by Simpson and Smirk for 10 years. Only 23 per cent of the Mayo Clinic group 4 patients were still alive at six years. Farmer et al. concluded that medical treatment improves the prognosis in “malignant” hypertension and compares favorably with sympathectomy. In 1962, 251 patients with “malignant” hypertension were reported by Kinsey and coworkers8 as having been under observation up to 24 years, 160 having had surgical treatment. There were 28 male patients in the Smithwick group 4 classification and 21 female. The overall survival rate is given as 36 per cent at a 10 year follow-up level for all the Smithwick surgically treated patients. However, whether the per cent survival of group 4 (Smithwick classification) patients surgically treated would be as high as 36 per cent is uncertain inasmuch as Table III of that report shows only 7 patients in Smithwick classification group 4 surgically treated surviving 10 years or more. The most recent report of Smithwick and associates6 presents the survival rate of patients similarly grouped through only a seven year period. At the outset of this study in 1950, several questions were to be answered: (1) Which of the high blood pressure patients should be (2) Which should be treated medically treated? and which surgically? and (3) How would their survival rates compare with those untreated? The 10 per cent 10 year mortality for our
and
Daugherty
mildest group (curve I, Fig. 1) appears to be more favorable than the mortality reported by Smithwick in 1948 for his nonsurgical group 1 patients. At that time there was not a statistically significant, favorable, increased survival of his group 1 surgical patients. The more modern drug therapy used for our patients suggests that this does prolong life in the mildly hypertensive patient. After a two year study15 of the depressor drug hydralazine in a group of patients with established diastolic hypertension of mild to moderate elevations, we asked two more questions in 1953: Does hydralazine or any other depressor drug keep mildly hypertensive patients from getting worse and thus obviate surgical intervention? This is the most important question of all: Does medical or surgical treatment prevent patients from entering the accelerated phase of hypertension? The answer now is a qualified yes. Another question posed in 1953 was, “Does hydralazine or any other depressor drug or combination of drugs prolong the lives of those individuals with such severe hypertension that renal damage and azotemia preclude operation?“15 At that time, we suggested that a longer period of observation and a larger series of patients were needed before the latter question might be answered. Still more perspective is required before this second question can be answered, but now we are more optimistic than in 1953 but less so than Warren.l”,” Factors entering into framing an answer to the first question posed in 1953 are diverse. Some of the opinions expressed are summarized below. Possibility of Prevention of the Accelerated Form of Hypertension: Although some investigators question that the hypotension induced by depressor drugs is the important factor in arresting the progress of vascular complications, many physicians using antihypertensive drugs believe that normalization of elevated pressure is “very necessary” in all patients having only relatively minor insurance expressure elevations.r6 Life indicates an augmented mortality perience” in men (age 30-39) of five times the standard risk when the pressure is 150/100 or in the “high normal” range. Pagels has stated, “I think it has now been incontrovertibly shown that even slight elevations in blood pressure do significantly increase human mortality.” House1 et al.“’ and Beem, Corcoran,r9 Roland22 have been in favor of early treatment. Simpson and Smirk9 cite the decreasing THE AMERICAN
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CARDIOLOGY
Primary
Hypertension-Survival
incidence of patients diagnosed as having “malignant” hypertension, particularly since the introduction of thiazide compounds in 1957, as evidence favoring the thesis of preventing the development of the accelerated phase by the early use of depressor drugs. Frcis? has emphasized the great need in clinical medicine for an office procedure that will detect renal damage at an early stage of Our experience suggests that hypertension. the intravenous phenolsulfonphthalein (PSP) test is a practical office or outpatient procedure in the attempt to detect a decrease in kidney function which might be related to a reduction in renal blood flo~.~~ The PSP excretion test helps to measure whether there is any deterioration in renal function and whether depressor drug therapy is not intensive enough to prevent Preservation of renal kidney vascular damage. function is, we believe, the most important guide to successful antihypertensive therapy. To conclude that the patient is being kept out of the accelerated phase when there is no evidence in the fundi of exudates, hemorrhages, or papilledema and without knowledge of the PSP excretion is inconsistent with the facts of insidious but relentless renal damage with only minimal elevations of diastolic pressure. Howeser, with the widespread use of the thiazidc congeners, PSP tests may be falsely low if the patient is not taken off such a drug for at least one week before the PSP test is used as a first approximation to the measurement of glomerular filtration rate, renal blood flow and A similar effect of uricotubular function.‘j suric agents on depressing the PSP test has been reported.“” Our own philosophy of prevention of the accelerated phase of hypertension was stated in 1957.2i Moreover, at that time there appeared to be a more favorable survival of the surgically Now at managed group 3 and group 4 patients. a 10 year follow-up period, survival of the medically treated patients in the same category is much the same. We are more radical now in initiating depressor drug therapy in patients with primary asymptomatic hypertension and without cardiovascular-renalcomplications (presumable Smithwick group 1 patients) than are some British physicians.28 Losing 10 per cent of patients in the Smithwick group 1 of our series in a decade is adequate reason for depressor drug therapy of most patients with fixed diastolic hypertension over 90 mm. Hg after three days of VOLUME
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1965
65
Experience
hospital bed rest. Waiting until the diastolic hypertension is 110 mm. Hg or higher, as Hamilton and co-workers”8 of Pickering’s group suggest, may be too late to prevent vascular damage in the brain, retina, heart or kidneys. SUMMARY
AND
CONCI.USION:,
All patients with blood pressure consistently over 15Oi90 mm. Hg should be studied carefully to determine whether they ha\c an established diastolic hypertension, and if so, whether this is secondary or primary hypertension. or the accelerated phase of “Malignant” hypertension might be prevented in most patients with fixed diastolic hypertension of 90 mm. Hg or higher after three days of hospital bed rest if the vascular complications, which are used to place patients in the categories denoted as Smithwick 3 and 4 probable prognosis groupings could be avoided by a careful general medical approach and early intensi1.e depressor drug therapy. Preservation of renal function is, we beiievc, the most important guide to successful antihypertensive therapy. Little of significance can be done to prolong life when renal functional deterioration and other vascular complications of the hrain and heart have progressed, usually insidiously, so that the patient presents with retinal hemorrhages, exudate and or papilledema. Usually renal blood flow is found to be markedly reduced when more precise testing of these patients is possible. Ten year survival curves of a small series of patients having the more serious cardio\rascularrenal complications (Smithwick 3 and 4 groups) suggest that medical treatment is as satisfactory in prolonging life as the surgical approaches that we have tested. Over-all survival varies from 30 to 90 per cent. More time and perspective appear to be necessary in order to validate the thesis: “The 1950’s coincide with the great improvement in the control of hypertension through drugs and other means. Modern drug therapy for this condition dates in this countrv from about 1950. Persons who used to die in a year or two from rapidly progressing malignant hypertension clre note’ being saved to lead active: /rod&w licrsfor 5, IO or more yenrs.“‘”
The assistance of Miss Zion of the Medical C&c History Bureau, New York, is greatly appreciated.
66
Hafkenschiel,
Schmitthenner
REFERENCES 1. DEBAKEY, M. E., MORRIS, G. C., JR.. MORGEN~ R. O., CRAWFORD, E. S. and COOLEY, D. A. Lesions of the renal artery. Surgical technic and results. Am. J. Surg., 107: 84, 1964. 2. JEFFERS, w. A., SELLERS,A. M., WOLFERTH, C. C., Ross, A. M. and BLAKEMORE.\V. S. Results of sympathectomy adrenalectomy. Am. J. and Surg., 107: 211, 1964. 3. BRUST, A. A., PERERA, G. A. and WILKINS, R. W. Classification of types of hypertension. Keport .J.A.M.A., 166: 640, to the Council on Drugs. 1958. 4. PERERA, G. A. Editorial: The unnatural history of (hypertensive) disease. Circulatzon, 21: 1, 1960. 5. HOLLANDER, W. and WILKINS, R. W. Present day management and indications for drug and surgical therapy. Am. J. Surg., 107: 204, 1964. 6. WHITELAW, G. P., KINSEY~D. and SMITHWICK, R. H. Factors influencing the choice of treatment rim. J. surg., 107: 220, in essential hypertension. 1964. 7. KEITH, N. M., WAGENER, H. P. and BARKER, N. W. Some different types of essential hypertension: Their course and prognosis. Am. J. M. SC., 197: 332,1939. 8. KINSEY, D., WHITELAW, G. P., WALTIIER, R. J., TWEOPHILIS,C. A. and SMITHWICK,R. H. The long-term follow-up of malignant hypertension. J.A.M.A.,181:571,1962. 9. SIMPSON, F. 0. and SMIRK, F. H. The treatment of malignant hypertension. Am. J. Cardiol., 9: 868,1962. C-V death rate drops for middle 10. WARREN, J. V. aged men. Am. Heart, 13: 1, 1963. 11. HAFKENSCHIEL,.J. H. Are malignant hypertension and benign hypertension different diseases? In : Hypertension-The First Hahnemann Symposium on Hypertensive Disease, p. 101. Edited by MOYER, J. H. Philadelphia, 1959. W. B. Saunders Company. 12. KINSEY, D. and WHITELAW, G. P. The hyperAm J. Method of study. tensive patient. S’urg., 107: 5, 1964.
and Daugherty
13. HILL? A. B. Principles of Medical Statistics, ed. 6, Chap. 14, Life table and survival after treatment. London, 1955. Lancet Ltd. 14. FARMER, R. G., GIFPORD, R. W., .JR. and HINES, E. A., JR. Drug therapy for severe hypertension. Ann. Znt. Med., 112: 118, 1963. 15. HAYKENSCHIEL,J. H. and LINDAUER, M. A. lHydrazinophthalazine (Apresoline) in the treatment of hypertension: A two-year study. Circulation, 7: 52, 1953. 16. PAGE, I. H. and DUSTAN, H. P. The changing outlook for hypertensives. J. Chron. Dis., 16: 115,1963. 17. Society of Actuaries. Build and Blood Pressure Study (two volumes). Chicago, 1959. Society of Actuaries. 18. PAGE, I. H. Newer antihypertensive drugs. Postgrad. Med., 27 : 448, 1960. 19. CORCORAN, A. C. Principles of chemotherapy in hypertension. J. Indiana M. A., 55 : 184, 1962. 20. BEEM, J. N. Causes of death due to hypertension: The effect of therapy. In Ref. 11, p. 106. 21. HOUSEL, E. L., KELLY, J. J. and DALY, J. W. The of hypertension. Angiology, 14: 28, diagnosis 1963. 22. ROLAND, F. P. First drug in essential hypertension. Am. Pratt., 12: 879, 1961. 23. FREIS, E. D. Office evaluation of the hypertensive patient (I and II). Mod. Concepts Cardiovas. Dis., 32: 822,1963. 24. HAFKENSCHIEL,J. H. Renal function studies in hypertension, with particular reference to the intravenous PSP test. Tr. Am. Coil. Cardiol., 5: 67,1955. Unpublished observations. 25. HAFKENSCHIEL,J. H. 26. NEWCOMBE, D. S. and COHEN, A. S. Effect of uricosuric agents on PSP test. Arch. Int. Med., 112: 738,1963. 27. HAFKENSCI~IEL,J. H. Modern concepts of hyperAm. J. Cardial., 2: tension and its treatment. 227,1958. 28. HAMILTON, M., THOMPSON,E. N. and WISNIEWSKI, T. K. M. The role of blood-pressure control in preventing complications of hypertension. Lnncet, 1: 235, 1964.
THE AMERICANJOURNAL OF CARDIOLOGY