Effects of Treatment on Morbidity in Hypertension III. Influence of Age, Diastolic Pressure, and Prior Cardiovascular Disease ; Further Analysis of Side Effects VETERANS ADMINISTRATION COOPERATIVE STUDY GROUP ON ANTIHWERTENSIVE AGENTS SUMMARY Additional data are presented from the Veterans Administration Cooperative Study with respect to the 194 control and 186 treated male patients with initial diastolic blood pressures averaging 90-114 mm Hg. Attack rates and effectiveness of treatment were examined with respect to the following risk factors present at entry: (1) cardio- vascular-renal (CVR) abnormalities, the prevalence of which was higher than in the general population of hypertensive patients; (2) diastolic bldod pressure; and (3) age. Both attack rates and effectiveness of treatment increased directly with the number of these risk factors present at entry. Age and presence of CVR abnormalities at entr) appeared to strongly inffuence subsequent attack rates, whereas entry level of blood pressure had a relatively smaller effect on attack rates. On the other hand, "effective- ness of treatment" appeared to be most influenced by the initial level of blood pres- sure. Patients with prerandomization diastolic blood pressure in the range of 90 to 104 mm Hg derived relatively little benefit from treatment unless they had CVR ab- normalities at entry or were over 50 years of age. A longer period of follow-up would be needed to assess the value of treatment in the lower risk subgroups. With respect to side effects, the incidence of mild hypokalemia, hyperuricemia, and elevated fasting blood sugar was significantly higher in the treated group. These and other side effects should be weighed against the benefit to be expected from treating hypertensive patients at low risk. From the Veterans Administration Hospital, Wash- ington, D. C. Permanent Members of the Study Group: hassimo Calabresi, M.D., C. Hilmon Castle, M.D., Leo Elson, M.D., Edward D. Freis, M.D. (Chairman), Rudolph E. Fremont, M.D., Michael A. Harris, M.D., David Littman, M.D., Eli A. Ramirez, M.D., and J.R. Thomas, M.D. Other Members: Luis A. Arias, M.D., Mark L. Armstrong, M.D., Alston W. Blount, M.D., Thomas A. Bruce, M.D., Ovid B. Bush, Jr., M.D. (deceased), Eugene C. Clark, M.D., Annette Fitz, M.D., R. M. Freeman, M.D., Edward D. Frohlich, M.D., Arthur Gear, M.D., John D. Kyriacopoulos, M.D., Alan R. Lyon, M.D., Gloria D. Massaro, M.D., Donald McCaughan, M.D., Jean Morgan, M.D., Henry W. Overbeck, M.D:, Eliseo- C. Perez-Stable, M.D., Mitchell H. Perry, M.D., Roger Sutton, M.D., and James Taguchi, M.D. Circul&on, Volume XLV, May 1972 991 Biostatisticians: Russell B. Tewksbury, Sc.D. (deceased ), Paul D. Williams, MS., and Lawrence Shaw, A.M. Central Ofice Coordinator: Harold \\`. Schnaper, M.D. Participating Veterans Administration Hospitals: Allen Park, Michigan, Birmingham, Alabama, Brooklyn, New York, Dayton, Ohio, Iowa City, Iowa, Jackson, Mississippi, Memphis, Tennessee, h`ashville, Tennessee, Oklahoma City, Oklahoma, Pittsburgh, Pennsylvania, Richmond, Virginia, Salt Lake City, Utah, St. Louis, Missouri, San Juan, Puerto Rico, Washington, D. C., West Haven, Connecticut, and West Roxbury, Massachusetts. Address for reprints: Dr. Edward D. Freis, Veterans Administration Hospital, 50 Irving Street, N.W., Washington, D.C. 20422. Received September 28, 1971; revision accepted for publication December 21, 1971. VA STUDY GROUP T HE VETERANS Administration Coop- erative Study Group previously reported on the results of a randomized, double-blind clinical trial in 194 control and 186 treated male patients with initial diastolic blood pressures averaging 90 through 114 mm Hg followed prospectively for periods up to 5.5 years, average 3.3 years.' Treatment consisted of a combination of hydrochlorothiazide, reserpine, and hydralazine. There were 19 deaths related to cardiovascular disease in the control group and eight in the treated series. Life table analysis indicated that the risk of a morbid event, fatal or nonfatal, over a 5-year period was reduced from 55 to 18% by treatment. Congestive heart failure, stroke, and progressive renal damage were sharply reduced or eliminated in the treated patients. However, the incidence of myocardial infarc- tion and sudden death was essentially the same in the control and treated groups. In addition to assessable morbid events, 20 control patients versus none of the treated group developed persistent diastolic elevations of 125 mm Hg or higher. In the initial report the patients were incompletely characterized as to the preva- lence of cardiovascular abnormalities prior to randomization. The present report determines the relationship between prior cardiovascular damage and the effectiveness of treatment. The influences of age and blood pressure also are analyzed in more detail than in the original paper. The prerandomization blood pressures given in this and in the initial report1 represent the average of the readings taken by the physician during the last two outpatient visits preceding randomization. Finally, additional data with respect to side effect and dose modifications are presented. Influence of Age The median ages were given in the initial report1 as 49.2 years for the control group and 48.1 years for the treated series. Additional data are presented in table 1. Fifty-one percent of the control and 55% of the treated group were less than 50 years of age. Approximately one fourth of the patients were in the 50-59-year age group. The 60 and above age group included 22.1% of the control and 20.5% of the treated patients, the oldest patient being 75 years of age. The prerandomization blood pressures for the different age groups are shown in table 2. Systolic blood pressure was related directly to age, and averaged 154 mm Hg in the patients under 40 years of age and rose with age to 178 mm Hg in the 70-75-year age group. Mean diastolic blood pressures, however, were es- sentially the same at all ages. There were no significant differences in blood pressure in the control and treated patients. Information. on the duration of known hypertension indicated that 48% had recog- nized hypertension for 5 years or more, and 29% had hypertension for 9 years or more. The relatively high prevalence of hypertension of long duration may be explained in part by the age distribution and in part by the fact that the sample included only patients with "fixed hypertension, namely those with diastolic blood pressures averaging 90 mm Hg or more from the fourth through the sixth day of hospitalization. The incidence of morbid events during the study by age at randomization is listed in table 3. As would be expected, the incidence of major complications rose with age. In the control group, 15.2% of the patients under age 50 years developed morbid events following randomization as compared to 62.8% of the patients above age 59 years. In the treated patients, the percentage incidence of morbid events was 6.9 and 28.9%, respectively, in these two age groups. Treatment appeared to be effective in all age groups. The effectiveness of Table 1 Age Disfkibution of Patients Age Control Treated (years) No. % No. % Total NO. YO 24-39 22 11.3 32 17.2 54 14.2 40-49 77 39.7 70 37.6 147 38.7 .50-59 52 26.8 46 24.7 98 25.8 60-69 28 14.5 23 12.5 51 13.4 70-75 1.5 7.7 1.7 8.0 30 7.9 Total 194 1oo.o - 186 izii- 380 100.0 MORBIDITY IN HYPERTENSION 993 Table 2 Relationship betw>een Age and Blood Pressure prior fo Handomiza%n .4ge (years) Control group Systolic Diastolic Mean blood pressure (mm Hg)* Treated group Systolic Diastolic Total Systolic Diastolic 24-39 151.6 104.4 155.2 103.4 153.7 103.8 40-49 159.5 104.5 159.2 105.2 159.4 104.8 50-59 169.5 105.2 163.2 104.7 166.5 105.0 60-69 176.2 104.9 169.7 101.4 173.3 103.3 70-75 173.7 100.4 182.9 106.0 178.3 103.2 All ages 164.8 104.4 162.7 104.4 163.8 104.4 *Average of last two clinic visits prior to randomization. Table 3 Incidence of Morbid Events with Respect to Age at Randomization Age (Y-3) <50 50-59 CO+ Total No. rand 99 .;2 43 194 contra1 group With events NO. 70 15 15.2 14 26.9 27 62.8 - -%- 28.9 Treated group Effectiveness No. With events of treatment* rand NO. YO (%) 102 7 6.9 55 46 4 8.7 68 38 11 28.9 54 - - 186 22 11.8 zi- *Difference between percent incidence of events in control and treated groups divided by percent. incidence in control group. Table 4 incidence of Assessable Events by Age and Diagnostic Category Age (years) Total <50 50-59 60+ events Diagnostic category C T C T C T C T Cerebrovascular accident Congestive heart failure Accelerated hypertension or renal damage Coronary artery disease* Atria1 fibrillation Dissecting aneurysm Other? Total morbid events Diastolic > 124 mm Hg 3 1 5 1 10 3 20 5 1 0 1 0 9 0 11 0 P 0 2 0 0 0 7 0 4 4 2 .i 5 13 11 0 2 0 1 2 0 2 3 0 0 1 0 1 0 2 0 0 0 1 0 0 3 1 3 % -7 14 a 27 ii -iiT 2 15 0 3 0 2 0 20 0 Abbreviations: C = control group; T = t,reated group. *Myocardial infarction or sudden death. tIncludes in treated group one patient terminated because of hypotensive reactions, one death from ruptured atherosclerotic aneurysm, and one patient with second-degree heart block. In control group includes one patient with left, bundle-branch block. treatment in preventing morbid events was estimated from the difference in the percent- age incidence of major complications between Circwlation, Volume XLV, May 1972 control and treated patients divided by the percentage incidence in the control patients (table 3). Treatment was 55% effective in the 994 VA STUDY GROUP subsample below 50 years of age, 68% in the 50-59-year age group, and 54% in the patients aged 60 years and over. The relationship between age and type of morbid event is shown in table 4. In the control group the most frequent complications in the oldest age group were cerebrovascular accidents and congestive heart failure. The latter was uncommon below age 60 years. However, increasing hypertension or progres- sive renal damage occurred predominantly in the control patients below age 50 years. Coronary artery disease occurred in all age groups but its percentage incidence was more common in the patients aged 60 years or over (tables 1, 4). Unlike the other categories, the complications of coronary artery disease did not appear to be affected by treatment. ty and variability in differentiating grade 1 from normal, only the grade 2 changes are reported. Such changes occurred in 31% of the control and 25% of the treated patients. Grade 2 sclerotic as opposed to hypertensive changes were defined as scattered prominent A-V nicks or asymmetric irregularity of arteriolar seg- ments. Such changes were reported in 24X of patients. Influence of Prior Cardiovascular Abnormalities The prevalence of cardiovascular-renal ab- normalities found prior to randomization is summarized in table 5. In grading the optic fundi, "hypertensive" and "sclerotic" changes were evaluated separately. Grade 1 hyperten- sive changes were defined as a probable decrease in arteriolar caliber with an A-V ratio of approximately 1:2, while grade 2 changes indicated a definite decrease in arteriolar caliber ranging from an A-V ratio less than I:2 to threadlike arterioles. Because of the difficul- Backgound charactistics were analyzed to determine the presence of cardiac, central nervous system (CNS), or renal abnormal- ities. All patients with severity grades" greater than zero with respect to any of these target organ systems were included with the follow- ing exceptions: headache, if this was the only CNS abnormality, and dyspnea on heavy effort if it was the only cardiac abnormality; optic fundi scores also were not included. Patients with dyspnea on ordinary activity, angina, left ventricular enlargement ( LVE ), cardiomegaly by X-ray, neurologic symptoms other than headache, or renal score greater than zero were included, On the basis of these criteria, 55% of the control group and 60% of the treated patients exhibited one or more abnormalities in the major target organ systems ( table 5). Ungerleider criteria" were used for deter- mining cardiomegaly from the standard poste- rior-anterior X-ray of the chest. By these criteria, 22% of the control group and 28% of Table 5 Prevalence of Cardiova.scular-Renal Abnormalities prior to Randonzimtian Control group Treated group Total Abnormality NO. YO NO. 70 NO. YO Optic fundi-grade 2 60 31.0 46 24.8 106 27.9 (hypertensive changes)* Any cardiac, CNS, or renal abnormalit.y* Cardiomegaly (X-ray)* LVE (ECG)* Renal grade l* Renal grade 2* Myocardial infarct Congestive heart failure* Cerebral thrombosis Patients randomized 107 53.2 112 60.2 219 .57.6 42 21.7 :,I -3 28..5 93 25.0 32 16.5 30 16.1 62 16.3 23 11.9 23 12.4 46 12.1 4 2.1 4 2.1 8 2.1 14 7.2 13 7.0 27 7.1 12 6.2 17 9.1 29 7.6 10 5.2 9 4.8 19 5.0 194 100.0 186 100.0 380 100.0 *Defined in text,. Circularion, Volume XLV, May 197 \lORBID!TY IN HYPERTENSION 995 the treated patients were considered to exhibit cardiomegaly prior to randomization. " The el&tkocardiographic criteria for left \.entricular enlargement ( LVE ) required that the patient',exhibit both voltage changes -( S in VI or V, plus- R in V, or V,; > 35 mm) and flat, biphasic, or"negative T waves in leads I, aVr,, and Va or V,;. Sixteen percent of both the &n&o1 and, treated groups exhibited LVE by these criteria `,prior to randomizatiqp. Renal damage-was graded as follows. Grade 1 included any two of the following: specific gravity of 1.020 or less in all of three separate overnight urine collections, proteinuria of If or- more in any one of these specimens, and phenosulfonphthalein (P&?) excretion of less than 45% in a pooled 2-hour specimen. Grade 2 changes included any two of the following: specific gravity of 1.015 or less, proteinuria l+ or more in all of three daily specimens, and PSP excretion of 30% or less. Grade 3 indicated all three of the above changes. Grade 4 denoted the presence of azdtemia. The frequency of grades 1 and 2 renal changks was the same in control and treated groups with 12% exhibiting grade 1 and 2% exhibiting grade 2 changes (table 5). None of the patients exhibited grade 3 changes. There were four patients in the contr'ol group and three in the treated series in whom the blood urea nitrogen was reported as being in the range of 25 to 32 mg/lOO ml. However, the serum creatinine value was normal in four of these patients, and they did not develop, m&bid events following randomization. Of the remaining three patients, one died of a carcinoma of the urinary bladder, another developed congestive heart failure, while the third, who had chronic glomerulonephritis (GN) with serum creatinine of 2.4 mg/lOO ml initially, was' later removed from the trial because of elevated diastolic blood pressure. Five patients, two in the control and three in the treated group, were diagnosed as having primary renal disease. Chronic glomer- ulonephritis was diagnosed in four and bilateral medullary sppnge ,kidney in q?le. One of the two control patients with chronic GN was removed because of elevated diastolic CirLuldion, Volume XLV, Mny 1972 blood pressure (see above) while the other developed a cerebral thrombosis. In the three "actively treated patieilts with primary renal disease there were no morbid events. Included in the study were some patients who had previous major events. Seven percent of the 380 patients, equally divided between control and treated groups, had sustained a myocardial infarction prior to randomization. Six percent of the control group and 9% of the treated patients had a past history of cardiac decompensation but were not in congestive heart failure at the time of randomization. Five percent of patients in both the control and treated groups had a clinical diagnosis of cerebral thrombosis. Patients with a history of other major complications of hypertension such as cerebral or subarachnoid hemorrhage, persistent congestive heart failure requiring continuous diuretics, accelerated phase of hypertension, or acute hypertensive encepha- lopathy `were not admitted into the trial. Cardkovascular-renal abnormalities were more frequent in the older patients (table 6). In those under 50 years of age, 46% presehted with 01~ or more abnormalities as opposed to 65% of the 50-59-year age g&tip ana 7SX `of the patients above age 59 years. The presence of prior cardiovasc&r dam- age greatly increased the risk `of developing morbid events following randomization (tiblc 7). In the patients with either myocardial infarction, congestive heart failure, or cerebral thrombosis prior to randomization, subsequent majbr complications occurred in 53% of the control and 26% of the treated group during the postrandomization period. In those with evidence of cardiac, CNS, or renal damage but ,without a major complication preceding randomization, the incidence of silbsequent morbid events was 33% `in the cdntrol patients and 8% in the treated group. Effecti\-eness of treatment for the combined subsamples pre- sehting with prerandomization abnormalities was 64% ( table 7 ) . The incidence of l&bid events \vas much less in the control series of patients presenting without abnormalities. In this subsample, 16% of the control patients developed a major 996 VA STUDY CROUP Table 6 Relationship between Age and Presence of Cardiac, CNS, or Renal Abnormality prior to Raudornizafion Age (years) No. rand Control group \Vith ahnormatity NO. % NO. rand Treated group \Vith abnormality No. YO Total NO. \Vitll ntrwrmality GWld NO. % <40 22 9 40.9 3% 13 40.6 54 2'2 40.7 40-49 77 29 37.7 70 41 58.6 147 70 47.6 .iO-.i9 .i2 34 6.5.4 46 30 65.2 9x 64 65.3 Go+ 43 3.5 81.4 3X 23 73.7 81 63 77.8 Total %z 107 Yi.2 IRS 112 60.2 380 TiG 57.6 Table 7 incidence of Morbid Events tvith Respect to Prerandomization Cardiac, CNS, or Renal Abnormality Status prerandomization NO. rand Control group Treated group With events \Vith events Kn`ectivenees NO. 0i treatment NO. % rand NO. "0 (7%) With abnormality: Prior MI, CHF, CVA All other Subtotal ;i4 1x X0 38 10 26.4 .iO 73 24 x2.. 9 74 6 X.1 7.5 c - - 107 39.j: 112 16 14.3 64 No abnormalit,y x7 14 16.1 74 6 X.1 .iO - Total 194 56 2X.!) 186 22 11.8 59 complication as opposed to 8% of the treated. The difference is not statistically significant although the trend indicating 50% effectiveness of treatment is similar to that found in the group with preexisting abnormalities. It should be emphasized that 20 control patients were removed from the trial prior to any morbid event because of elevations of diastolic pressures to more than 124 mm Hg which persisted for 3 weeks or longer.' Seven of the 20 patients had a prerandomization clinic diastolic blood pressure lower than IO5 mm Hg. Fifteen of the 20 were less than 50 years of age; 10 of the 20 had no evidence of cardiac, CNS, or renal abnormality. Since at this level of diastolic blood pressure the risk of developing subsequent events without treat- ment is very high,J the removal of these patients prior to the development of a morbid event probably resulted in an underestimate of the effectiveness of treatment in all subgroups but especially in the subgroup under age 50 years and the group presenting without cardiac, CNS, or renal abnormalities. Among the 27 fatalities occurring during the randomized trial, 17 deaths were associated with myocardial infarction or occurred sud- denly; of these, 11 occurred in thr control group and six in the treated patients. With respect to other risk factors in these 17 patients, six of the control and two of the treated patients had prerandomization serum cholesterol levels greater than 260 mg/ 100 ml. Two control patients and one treated patient exhibited fasting blood sugar levels above 110 mg/lOO ml. There was no evidence of hypokalemia during the annual examinations in any of the patients who had sudden death. Congestive heart failure occurred in 11 of the control patients. In five it represented a recurrence, while in six the initial attack occurred following randomization. Although 17 of the treated patients had a history of congestive heart failure prior to randomiza- tion, none developed recurrences during the postrandomization period. Influences on Therapeutic Effectiveness Because of the separate effects of level of diastolic blood pressure,' age, and prior car- diovascular abnormalities on the incidence of Ciwlation, Volnme XLI.. MC,\ 1972 MORBIDITY IN HYPERTENSION 997 Table 8 Attack Rates and Effecticeness of Treatment in Rehtion to Any One or Two Risk Factors at Entry Risk factors at entr>- Control group No. Attack rand rate* Treated proup NO. .4ttsck rand rate* EffiXthf3WSP of t,reatment (%) IXastolic presstIre: 90-104 mm Kg 10.5-144 mm Hg Age: < .iO years .iO+ years CVII. abnormalities: Without abnorma1it.v With abnormality CVR abuormalit,ies and diast,olic B P: Without abnormality 90-104 mm Hg 10.5-114 mm Hg With abnormality 90-104 mm Hg 10.5-114 mm Hg CVR abnormalities and age: Without abnormalitq- 11.9 0 0 0 2 1 2 Total patienk 194 186 168 167 137 137 Abbreviations: C = control group; T = treated group. The prevalence of FBS values of 110 mg/lOO ml or higher was essentially the same in the control and treated groups prior to randomiza- tion (table 12). One year after randomization, however, the prevalence was 20.8% in the treated series as compared to 15.6% in the control, and 2 years after randomization it was 30.0% in the treated and 17.0% in the control patients. FBS levels of 120 mg/lOO ml were found in 7.0% of the treated patients prior to randomization, 12.5% at the first annual, and 14.6% at the second annual examination. Because of the difference in total patients available for examination at the end of the first and second year of follow-up (table 12)) the data also were analyzed using as denom- inators only the patients who completed both the first and second annual examinations, The results still indicated a greater percentage of patients with elevated FBS in the treated as compared to the control group of patients. There was no significant correlation be- tween reduction in serum K and the increase in FBS in the treated group of patients. Atter 1 year of treatment mean serum K was 3.91 SD 0.57 mEq/liter in 119 treated patients with FBS levels below 110 mg/lOO ml and 3.89 SD 0.57 mEq/liter in 40 treated patients with FBS levels of 110 mg/lOO ml or higher. After 2 years, the serum K levels were 4.04 SD 0.58 and 3.98 SD 0.91 mEq/liter, respectively, in the two groups. Changes in Doses of Protocol Drugs At the time of randomization a combination of hydrochlorothiazide 50 mg and reserpine 0.1 mg twice daily plus hydralazine 25 mg three times daily" were administered to all patients in the treated group.* Obviously, this therapeutic regimen will result in a higher incidence of side effects than the usual method of initiating treatment with a single antihyper- tensive agent. Therefore, provision was made "The special medications used in this study were prepared by Dr. William E. Wagner of Ciba Pharmaceutical Co., Summit, New Jersey. Table 12 Percent Distribution of Fasfing Blood Sugar Levels on the Initial and First and Second Annual Examinations Fasting blood sugar (mg/lOO ml) Initial (o/oo) First annual (`To) Second annual (%) C T C T C T 1972 MORBIDITY IN HYPERTENSION 1003 only one fifth of the patients were above 60 years of age such patients contributed half of the morbid events. The incidence of morbid events in the control group was greater in patients with initial levels of diastolic blood pressure averaging 105-114 mm Hg than in those with 90-104 mm Hg at entry. The effectiveness of treatment was much greater for those with the higher initial blood pressure levels. In the present communication it is shown that preexisting cardiovascular disease markedly increases the risk of developing events in the control group and that the effectiveness of treatment over the limited period of observa- tion was greater in those with such evidence of prior disease. Termination of the trial was necessitated by the clear-cut evidence of benefit in the treated group as compared to the controls. Since the patients without evidence of cardiovascular disease were at reduced risk, follow-up was of too brief duration for the occurrence of many events or to obtain a statistically significant difference between control and treated groups in this subsample. However, the observed 50% effectiveness of treatment in the "no abnor- mality" group, which was not substantially different from the 64% effectiveness found in the group with abnormalities, is consistent with a protective effect of treatment. The results of the present trial justify more intensive efforts to identify and maintain under adequate treatment patients with any signs of cardiovascular damage or with diastolic blood pressure averaging in excess of 104 mm Hg. Evidence from surveys carried out in representative population groups", r indicate that many of these patients are either unaware of their hypertension or are not receiving adequate treatment. Additional evidence will be required, how- ever, to determine whether the benefits of treatment outweigh its disadvantages in lower risk patients, such as in those with mild hypertension and no evidence of vascular disease, particularly in women, and in patients with labile hypertension. Toxic reactions may occur with any of the presently available Circulation, Volume XLV. May I972 antihypertensive agents, and side effect, par- ticularly biochemical changes associated with thiazides and related diuretics, are relatively common. Modifications of doses often are required because of other disturbing side effects. While the risk associated with these various side effects appears small, it must be considered in relation to the benefit to be expected in treating patients whose risk of developing complications due to hypertension also is relatively low. If patients are not treated, however, they should be followed periodically to determine whether the hyper- tension progresses to a more severe stage. Such follow-up appears to be particularly important in younger patients. In the present study, 15 of the 20 control patients whose diastolic blood pressures became severely elevated were below 50 years of age; seven had an initial diastolic blood pressure below 105 mm Hg. In the present sample of patients, antihy- pertensive treatment appeared to be effective in reducing the complications associated with hypertension except for myocardial infarction and sudden death. This result is not necessar- ily inconsistent with the statistical evidence that elevated blood pressure is one of the "risk factors" associated with an increased inci- dence of coronary heart disease. It is possible that a larger sample size or a longer period of follow-up might have revealed differences not apparent in the present study. Also, a greater degree of protection might have been afforded if treatment had been instituted at an earlier stage of hypertension. Therapeutic trials are needed in a different population of hyperten- sivre patients in order to resolve this question. Acknowledgments We wish to thank Drs. Jacques Genest, Ray W. Gifford, Jr., Walter M. Kirkendall, Louis Lasagna, David W. Richardson, and Robert W. Wilkins for valuable consultation and advice. References 1. VETERANS ADMINISTRATION COOPERATIVE STUDY GROUP ON ASTIHYPERTENSIVE AGENTS : Effects of treatment on morbidity in hyperten- sion. II: Results in patients with diastolic blood 1004 VA STUDY GROUP pressure averaging 90 through 114 mm Hg. JAMA 213: 1143,197O 2. VETERANS ADMINISTRATION COOPERATIVE STUDY GROUP ON ANTIHYPERTENSIVE AGENTS: A double-blind control study of antihyperten- sive agents. I: Comparative effectiveness of reserpine, reserpine and hydralazine, and three ganglionic blocking agents, chlorisondamine, mecamylamine and pentolinium tartrate. Arch Intern Med (Chicago) 106: 81, 1960 3. UNGERLEIDER HE, GUBNER R: Evaluation of heart size measurements. Amer Heart J 24: 494, 1942 4. VETERANS ADMINISTRATTON COOPERATIVE STUDY GROUP ON ANTJHYPERTENSIVE AGENTS : Effects of treatment on morbidity: Results in patients with diastolic blood pressures averaging 115 through 129 mm Hg. JAMA 202: 1028, 1967 5. VETERANS ADMINISTRATION COOPERATIVE STUDY GHOUP ON ANTIHYPERTENSIVE AGENTS : A double-blind control study on antihyperten- sive agents. III: Chlorothiazide alone and in combination with other agents. Arch Intern Med (Chicago) 110: 230, 1962 6. WILBER JA: Detection and control of hyperten- sive disease in Georgia, U.S.A. In The Epidemiology of Hypertension, edited by Stamler J, Stamler R, Pullman TN. New York, Grune & Stratton, 1967, p 439 7. STAMLER J, ET AL.: Detection of susceptibility to coronary disease. Bull NY Acad Med 45: 1306, 1969 Ckculation, Volume XLV, May 1972