Effects of diltiazem on serum lipids, exercise performance and blood pressure: Randomized, double-blind, placebo-controlled evaluation for systemic hypertension

Effects of Diltiazem on Serum Lipids, Exercise Performance and Blood Pressure: Randomized, Double-Blind, Placebo-Controlled Evaluation for Systemic Hypertension PETER E. POOL, MD, SHIRLEY C. SEAGREN, BA, and ANTONE F. SALEL, MD,

with the statistical assistance of M. LORIE SKALLAND,

MS

Treatment of hypertension with dkretks, @ blockers and (Y bkdcers may be associated wfth adverse effects on exercise performance, serum lipfds and bkod chemistries, as well as wfth orthostatic effects and fluke retentkn. A randomized, double-bltnd, placeboccxttrolled trial of a sustained-release preparation of dittiazem as safe therapy for moderate essential hypertension was conducted. Dtftiazem was administered 2 times a day (360 mg/day ) to 16 patients and placebo to 14 patients in a 12-week study. Average supine btood pressure with dtftiazem therapy fell from 161/100 to 144/67 mm Hg wtthout fluid retention or ortho&tk effects. In an open-label study, patients from the placebo and difttazem groups continued with diltiazem therapy. At an average of over 6 months, supine bfood pressure on dittfazem was 147166 mm Hg, and after withdrawal to single-blind placebo, average supine bfood pressure increased to 1731104 mm Hg. All changes were stgntficant compared wfth base-

line and placebo (p
The antihypertensive effects of calcium-channel blockers have been well known for years,l but until recently, their therapeutic role has been considered secondary.2 A growing realization of the potential adverse effects of the most common first-line agents-/3 blockers and diuretics2-and new knowledge of the role of calcium in hypertension3 have led to the consideration of calcium-channel blockers as first-line thera: py. As the stepped-care approach to hypertension is abandoned, the potential advantages of calcium-channel blockers over diuretics and /3 blockers should be considered.

This study investigated, in a prospective, randomized, double-blind, placebo-controlled parallel trial, the effects of diltiazem as sole therapy in the treatment of moderate essential hypertension.

Special at-

tention was given to diltiazem’s efficacy, both short and long term, its orthostatic effects and tolerability, its effects on blood chemistries, especially serum lipids, and its effects on exercise performance. Methods The protocol was approved by this institution’s

Human

Research Committee, and each patient consented in writing to participate in the study. Design: All patients entering the study were required to have essential hypertension-defined as a stable resting supine diastolic pressure between 95 and 110 mm Hg. All patients were withdrawn from any prior antihypertensive medication for at least 2 weeks and were placed on single-

From the North County Cardiology Research Laboratory, Encinitas, California. This work was supported in part by a grant from Marion Laboratories, Kansas City, Missouri. Address for reprints: Peter E. Pool, MD, North County Cardiology Research Laboratory, 1087 Devonshire Drive, No. 300, Encinitas, California 92024. 80H

December

blind placebo. After 7 to 10 days on placebo, the patients began a series of weekly visits, during which resting supine pressures were obtained; the average of 3 measurements was recorded as the pressure at each visit. For a subject to qualify, his or her resting supine diastolic pressure on 2 consecutive weekly visits had to be between 95 and 110 mm Hg and could not vary by more than 7 mm Hg between visits. The average of these 2 visits was used as baseline. Patients requiring more than 4 weeks for stabilization were considered labile and they were excluded. Patients were also excluded if they had other significant disease, sick sinus syndrome or greater than first-degree atrioventricular block. No patient was allowed to take any concomitant medication known to affect blood pressure, including oral contraceptives and psychotropics. After baseline was established, each patient underwent dose titration with 1 capsule 2 times a day for the first 2 weeks, then 2 capsules 2 times a day for the second 2 weeks and 3 capsules 2 times a day for the third 2 weeks, if required. For those patients randomized to diltiazem, this made the daily dose 120, 240 and 360 mg, respectively, of the sustained-release preparation. Dosing continued upward until a 10% or greater reduction in diastolic pressure was achieved or until the highest dosage was reached. After a further 4week administration period, a final evaluation was made (week 12). Electrocardiograms, routine hematologic studies, chemistry analysis and urinalysis were performed prestudy, at end of titration and at week 12. After week 12, patients on diltiazem were allowed to continue on open-label diltiazem for an additional IO-month period, while those on placebo were allowed to begin titration and maintenance of open-label diltiazem. At the end of 10 months, a single-blind placebo withdrawal period was used to evaluate continuing blood pressure control. Patients on placebo were observed at 2-week intervals until supine diastolic blood pressure was >95 mm Hg, and 1 week after this they had another follow-up visit. Measurements of blood pressure and heart rate: Patients were evaluated in the morning, 10 to 14 hours after their last dose of medication. They were asked to refrain from smoking or using caffeine-containing beverages before their visit and had been fasting for at least 2 hours. Measurements were made using the same arm and usually by the same person. Systolic and diastolic blood pressure were determined by phase I and V of the Korotkov sounds. Supine pressures were recorded after 10 minutes of rest with the arm positioned at the patient’s side. Standing pressures were measured with the arm horizontal at the level of the fourth intercostal space at the sternum. Both supine and &minute standing pressures were based on an average of 3 determinations taken at least 1 minute apart. Pulses were counted for 30 seconds after the final pressure determination of a set. Immediate standing pressure was a single determination. Exercise testing: Patients underwent exercise testing according to the Bruce protocol4 at the prestudy visit (a “training” test), at the end of the placebo run-in (baseline), at the end of the titration period and at the end of the study (week 12). Blood pressure, heart rate, double product and ST change (V, and aVF) were obtained during the last 30 seconds of each 3-minute stage, at end of exercise and twice during recovery. Maximal exercise measurements were determined at the end of exercise. Submaximal measurements were made at the end of the stage before the last stage of exercise during which more than 60 seconds of exercise occurred. If the patient failed to exercise 60 seconds into stage 2, the end of stage 1 was used as submaximal exercise. Measurement of serum lipids: Serum lipid fractions wereassessed by quantitating total cholesterol,5high-density lipoprotein (HDL) cholesterol,‘j low-density lipoprotein

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cholesterol,very low-density lipoprotein cholesterol,the total cholesterol:HDL cholesterolratio and total triglycerides7 at the prestudy visit, (baseline),at end of titration and at end of week 12. Additional assessments were madeat the end of long-term observation. All sampleswere drawn after a 14hour fast. Subjects: Fifty patients met the initial entry criteria and wereenrolled in the placeborun-in after randomization (Table I). Thirteen of these (8 placeboand 5 diltiazem) failed to qualify during run-in, 1 patient in the diltiazem group requestedwithdrawal during this stageand 2 (1 in eachgroup) weredropped for adversereactionsto placebo.Four patients (2 in eachgroup) completed the entire trial and were found in retrospect not to have met stability criteria. They are treated in a separateanalysis.The remaining 30 patients (14 placeboand 16 diltiazem) were analyzed in the parallel portion of the blood pressuredata. These patients, plus the 4 just mentioned who completed the entire trial, constitute the patients in the analyseson exercise and adverse reactions. The samegroup, less 1 placebo patient who was excluded becauseof familial hyperlipidemia, constitutes the patients in the short-term lipid analysis.After the 12-week trial, 14placebo patients beganto take diltiazem, and they, together with 12 of the original diltiazem patients, are those analyzed in the long-term blood pressuretrial. The longterm lipid analysisincluded the 33 patients from the shortterm trial (with someof those on placebobeginning to take diltiazem) minus 2 placebopatients, 1 of whom never took diltiazem and another of whom had no lipid determination on diltiazem. Statistical analysis: Demographic characteristics at baseline were compared using a x2 test for sex, race and smokingcharacteristics and Student’s t test for age,weight and duration of hypertension to validate the randomization process.8To determine whether the diltiazem group and the placebogroup werecomparableat baseline,Student’s t tests were performed for eachkey parameter usingonly the baseline data. No significant differences were found for any parameter, with the exception that the randomization produced a significantly higher systolic and diastolic blood pressurein the placebogroup both at submaximaland maximal exercise. To determine whether diltiazem and placebogroups differed significantly at other times during the study, split-plot analysesof variance were performed on the differencesfrom baseline.If the treatment by evaluation interaction wasnot statistically significant (i.e., the 2 treatments were similar for the responsefrom end of titration to end of the study), an overall statement about the treatment (diltiazem versusplacebo) could be made. For any parametersexhibiting treatment by evaluation interaction, Student’s t tests were performed on the differences from baselineat eachevaluation. To determine whether significant changesfrom baseline occurred at any evaluation for either treatment, 2-way analysesof variance were performed by treatment for eachparameter in eachposition usingthe actual data. If the overall F test for the evaluation effect was significant at the 0.05 level, Duncan’s multiple comparisonprocedure wasusedto determine which evaluations differed significantly from baseline. The significanceof diltiazem’s long-term effects on blood pressureand lipid levels wasdetermined by the paired t test, comparingthe last observation with the baselinedetermination for blood pressureand the prestudy value for lipids. Categorical analysis was performed by determining whether patients achievedthe goalblood pressurereduction of 10%of baselinesupinediastolic pressure.At eachevaluation, a l-tailed Fisher’sexact test wasperformed to compare the percentage of diltiazem and placebo patients reaching goa1.s

00H

A SYMPOSIUM:

TABLE I

ROLE OF CALCIUM

Summary

Height Weight

M F (lb f SE): M F duration

SE = standard

IN HYPERTENSION

TABLE III

(16)

Placebo

10 M, 6 F 60 f 2 15 white, 1 other 69f 1 64% 1 182 f 9 157 f 8 1 l’;‘i :” (-)

f SE)

(in f SE):

Smoker Hypertension

DRUGS

of Patient Demographics Diltiazem

Sex Age (year Race

ENTRY-BLOCKING

( 14)

10 M, 4 F 61 f3 14 white

Average Blood Pressure and Heart Rate (* SE) In the Long-Term Study-Average 34.4 Weeks (26 Patients) Baseline

Sy;;;$mm

66 f 1 63f 1 187 f 7 13456 v-y; t-1

W

Standina (5 min) Diastolic (mm Hg): Supine Standing (5 min) Heart Rate (beatslmin): Suoine St&dktg (5 min)

(years)

error.

NS = not significant;

TABLE

II

164f4 165f4

End of Titration

D

P

D

Systolic (mm Hg): Supine Standing (5 min)

165 f 2 164f5

167 f 6 168f6

145 f 4+ 143 f 4’

Diastolic (mm Hg): Supine Standing (5 min)

100f 103f

100f 102f2

Heart rate (beatsimin): Supine Standing (5 min)

1 1

64 f 2 69 f 3

1

69 f 3 77 f 3

P 169f6 166f

6 1

71 f3 76 f 3

p
<0.0001 <0.0001

88 f 2 88 f 2

<0.0001 <0.0001

67 f 2 74 f 2

66 f 2 70 f 2

NS =0.032

SE = standard

error.

12-Week

End of Week

99 f lOOf 62 f 2 68 f 2

147f3 145f3

P

100 f 2 102f2

Average Blood Pressure and Heart Rate (& SE) In the Controlled Study in 30 Patlents (16 Diltlazem [D], 14 Placebo [PI) Baseline

Last Observation

12

D

P

144 f 5+ 149 f 5’

171 f 7 171 f 6

87 f 2+ 88 f 2+

101 f 3 102f3

62 f 2 70 l 2

70 f 3 75 f 4

l

A final analysiswas made to include the 4 patients who failed eligibility criteria but who received the drug through the double-blind portion of the protocol. The analysisyielded the samequalitative results. Result6

w

Demographics: The results of randomization of patients to diltiazem or placebo did not indicate any significant differences owing to sex, age, race, size, smoking history, concomitant diseases or duration of hypertension (Table I). Baseline blood pressure values (f 1 standard error) in the group randomized to placebo averaged 167 f 6/100 f 1 mm Hg supine, and 168 f 6/102 f 2 mm Hg after standing for 5 minutes. These values did not differ from values of subjects randomized to diltiazem, which averaged 165 f 2/100 f 1 mm Hg supine and 164 f 5/103 f 1 mm Hg standing. Dosage: For each patient, dosage was titrated for best response. All patients reached a daily dosage of 360 mg of the sustained-release preparation of diltiazem, which was given 2 times a day. Effects on blood pressure: Both systolic and diastolic blood pressure values were significantly reduced in patients treated with diltiazem compared with those receiving placebo. This was true for blood pressure taken in both the supine (p
different from baseline, no heart rate is significantly

p

Average supine blood pressure at end of titration and at week 12 in the placebo group was 169199 and 171/101 mm Hg, respectively. In those patients treated with diltiazem, average supine blood pressure was 145186 at end of titration and 144187 mm Hg at week 12. Average standing blood pressure at end of titration and at week 12 was, in the placebo group, 166/100 and 171/102 mm Hg, respectively, whereas in the group

treated with diltiazem it was 143/89 and 149/88 mm Hg, respectively. Supine diastolic pressure was reduced 10% or more in 11 of 16 patients treated with diltiazem compared with 1 of 14 patients treated with placebo (p <0.0007) at end of titration. At week 12,lO of 16 patients treated with diltiazem showed a 10% or more reduction of blood pressure, compared with 1 of 14 treated with placebo (p = 0.002). Long-term effects of diltiazem on blood pressure were evaluated in 26 patients-those randomized to diltiazem who continued on treatment after the medium-term study and those who finished the mediumterm study on placebo and were then placed on openlabel diltiazem therapy. These subjects were followed for an average of 34.4 f 11.4 (standard deviation) weeks (Table III). At their last observation, these patients had an average supine blood pressure of 147/88 mm Hg, compared with their baseline value of 164/100 mm Hg (p
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TABLE IV

Exercise

Data in the Controlled Submaximal

Baseline Time (s) SBP (mm Hg)

D P D P

DBP (mm Hg) HR (beats/min) DP X 100 ST Vs (mm) ST aVF (mm)

F D P D P D P D P

193; 208 99f 104f 137f 143f 266 297 -0.3 -0.5 -0.5 -0.6

12-Week

Maximal 12

-

f

f f f f f f

5 6 3 2 5 3 13 10 0.2 0.3 0.2 0.4

179< 2iaf aaf 103f 120f 139f 222 304 -0.2 -0.4 -0.2 -0.3

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Study In Dlltlarem

Exercise End of Week

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Exercise

Baseline

f f f f f f

201f 674 21af aaf aaf i5af 164f 317 358 -0.6 -0.8 -0.7 -0.8

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(D)- and Placebo

692 191 220 73f 77f 145f 164f 279 358 -0.2 -0.5 -0.2 -0.5

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Patlents

End of week 12 Versus Baseline 12

Submaximal

657 f 58

f 475 6 a 7 5 3 f 12 f ii f 0.3 f 0.3 f 0.3 f 0.4

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(P)-Treated

(end)

End of Week

602 f 61 6 5 3 3 5 4 15 12 0.1 0.3 0.2 0.4

JOURNAL

f 445 f 6 7 9 5 4 % 11 f 9 f 0.2 f 0.3 f 0.2 f 0.5

Maximal

-


-&.I5

I2

<%l

E


<%l NS
2 NS
SBP = systolic blood pressure; DBP = diastolic blood pressure; HR = heart rate; DP X 100 = double product (SBP X HR) X 100; ST Vs = STsegment position in Vs; ST aVF = ST-segment position in aVF; NS = not significant. At maximal exercise, significant differences occurred between diltiazem and placebo in HR (p = 0.0004) and DP X 100 (p = 0.0004); at submaximal exercise, significant differences occurred between diltiazem and placebo in SBP (p
pared with a baseline value of 165/102 mm Hg (p <0.0001). To be certain that the amelioration in blood pressure observed long-term was not due to improvement in underlying disease, 12 patients were withdrawn to single-blind placebo after 10 months of open diltiazem administration. They were seen every 2 weeks until supine diastolic blood pressure was >95 mm Hg, and then observed again 1 week later. This blood pressure level was reached in 2 weeks by 7 patients, in 3 weeks by 1 (who was on vacation at 2 weeks), in 4 weeks by 2 and in 6 weeks by 1. Average baseline supine pressure in this group was 173/104 mm Hg; at last diltiazem observation, it was 144184 mm Hg; at an average of 2.6 weeks after withdrawal, it was 172/100 mm Hg; and 1 week later, it was 170/100. Standing pressure values followed a similar pattern. Effects on heart rate: No clinically significant changes in heart rate were produced by treatment with either placebo or diltiazem. A small, statistically significant (p = 0.032) decrease in heart rate was noted during the long-term study, in the standing position only, where the heart rate fell from an average of 74 to 70 beats/min (Tables II and III). Orthostatic effects: Orthostatic effects on heart rate and blood pressure in patients treated with diltiazem were compared with those in patients treated with placebo at the end of 12 weeks. A small and essentially identical drop in systolic pressure was noted in each group, with no change in diastolic pressure. In the placebo group, supine pressure fell from 171/101 to 167/102 mm Hg immediately upon standing, whereas with diltiazem patients, the pressure fell from 144/87 to 142/87 mm Hg. The reflex increase in heart rate was similar in both groups. Effects on exercise performance (Table IV): In the 12-week study, the maximum duration of exercise increased an average of 55 seconds in the diltiazem group (p
TABLE V

Average Serum Llpld Levels (f SE) In the Controlled 12-Week Study (33 Patients, 18 Dlltlazem [D], 15 Placebo [PI) Baseline

Cholesterol HDL (mg/dl) LDL (mg/dl)

(mg/dl)

P

231f 222 f

ifD

52f 49f 36 145f 9 159f 7 25% 3 25f 3 4.74 f 0.39 4.99 f 0.28 126 f 16 127 f 15

L VLDL (mg/dl) CholesterolIHDL

End of Week

Fl P D

Triglycerides L

107

225 245 f 54f 56f 146f 164f 24f 25f 4.43 4.62 it8 120

f f f f

12

D

89

E

4 6 6 3 3 0.33 0.33 ia 13


HDL = high-density lipoprotein; LDL = low-density lipoprotein; VLDL = very low-density lipoprotein; NS = not significant; SE = standard error. No significant differences between diltiazem and placebo were found.

However, the difference between the groups was not significant. Blood pressure, heart rate and double product (heart rate X blood pressure) were all significantly decreased by diltiazem at submaximal exercise, whereas only heart rate and double product were decreased at maximal exercise. The differences from baseline values at maximal exercise were smaller than those at submaximal exercise. These same parameters, which were significantly different from baseline, were also significantly different from placebo (see Table IV). There was significantly less ST-segment depression in lead aVF in the diltiazem group at end of week 12 compared with baseline, both at submaximal and maximal exercise, but this difference was not significant compared with placebo, and its clinical significance is uncertain. Effects on serum lipids and blood chemistries: In the medium-term 12-week study (Table V), the only significant change in serum lipids was an increase in HDL cholesterol in the diltiazem group from 49 f 3

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A SYMPOSIUM:

TABLE VI

ROLE OF CALCIUM

Average Serum Llplds (f Long-Term Study-Average (31 Patients) Baseline

Chloesterol (mg/dl) HDL (mg/dl) LDL (mg/dl) VLDL (mg/dl) CholesterolfHDL Triglycerides (mgldl) Abbreviations

DRUGS

233 60 146f 25 4.2 126f

f 7 f 3 7 f 2 f 0.2 11

IN HYF’ERTENSION

TABLE VII

SE) In the 29.5 Weeks

Last Observation

227 f 6 52f 3 150f 5 24f 2 4.7 f 0.2 120 f 12

as in Table

ENTRY-BLOCKING

Adverse Reactions During Controlled 12-Week Study (34 Patlents, 19 Dlltlazem [D], 16 Placebo [PI)

P <::06 NS <0”:5 IiS

V.

to 56 f 4 mg/dl (p <0.05) between baseline and week 12. Other changes that exceeded 5% in magnitude but that were not statistically significant were an increase in cholesterol from 231 to 245 mg/dl in the diltiazem group and a fall in cholesterol:HDL ratio and triglycerides in both groups. In the long-term study, which involved 31 patients for an average of 29.5 weeks, HDL cholesterol increased from 52 f 3 to 60 f 3 mg/dl (p
Dizziness Edema Asthenia Constipation Dyspnea Dyspepsia Nocturia Paresthesia Headache Nausea Insomnia Chest pain Other Total

D

P

3”

i

; 2

f 0 0 1

f :

s 2

8 : : 23

All adverse effects that occurred more than d/ltiazem or placebo group are listed, regardless occurring only once are listed under “other.”

2: once in either the of severity. Those

acceptable response to treatment, with a decrease in average supine blood pressure from 165/100 to 144/87 mm Hg over 12 weeks. At more than an average of 8 months of treatment, average pressure remained at 147/88 mm Hg, but when patients were withdrawn to single-blind placebo, average supine blood pressure rose from 144/84 to 170/100 mm Hg. Several studieslGzO of exercise tolerance in hypertensive patients who were treated with various agents (diuretics, methyldopa and /3 blockers) until normotension was achieved found no significant decrease in exercise tolerance after treatment. Invasive studies,16Jg however, show that patients receiving /3 blockers must compensate for decreased inotropy and chronotropy with an increase in stroke volume and arterial-mixed venous oxygen difference, an ability that decreases with age. Bruce et all6 also showed that the exercise response to treatment was related to the underlying integrity of the recipient’s circulatory system. The studies just mentioned were conducted in patients who were an average of 15 to 20 years younger than those in the present study. The diltiazem-treated group in our study significantly increased maximal exercise duration by 55 seconds (p 60 years indicates that inotropy was not depressed and that normalized peripheral resistance allowed a ready increase in the stroke volume. Thus, diltiazem appears to normalize the response to exercise (at least with regard to blood pressure) rather than impair it, and may tend to increase exercise tolerance in hypertensive patients as it does in those with angina.21 There were no adverse effects on serum glucose, potassium or uric acid levels such as those seen with diuretic administration.

December

When patients are enrolled in any study of cardiovascular disease, there are often subtle behavioral changes with regard to diet, exercise and other habits, which are difficult to control. However, it does appear that the use of diltiazem is associated with a significant increase in HDL cholesterol in this population. Whether this change is clinically beneficial remains to be seen. It is clear that the adverse lipid effects seen with diuretics and fl blockers are not seen with diltiazem. This may reflect a mechanism similar to that responsible for the potentially positive lipid effects of prazosin.22~23 Serious adverse reactions to diltiazem were not seen. In consonance with prior experience in the use of diltiazem for the treatment of angina,24 adverse reactions to diltiazem were quantitatively not very different from those to placebo. Reactions that have been recognized as possibly associated with diltiazem, such as dizziness, edema, constipation and dyspepsia, were neither common nor severe. When compared with standard therapies for hypertension, such as diuretics and p blockers, diltiazem’s major disadvantages are cost and the Z-times-a-day dosage regimen. There are, however, several major advantages: diltiazem shows both short- and long-term effectiveness and is well tolerated; it does not impair exercise performance; it has no adverse effects on blood chemistries; it does not have an adverse effect, and may even have a positive effect, on serum lipids; and it does not cause orthostatic effects, fluid retention or tachycardia. Thus, it can be concluded that diltiazem is an acceptable monotherapy in patients with moderate essential hypertension. References 1. Lederballe-Pedersen 0. Calcium blockade as a therapeutic principle in arterial hypertension. Acta Pharmacol Toxicol 1981;49:supp 2: 1-3 1. 2. Laragh JH, Buhler FR, deLeeuw PW, Fleckensteln A, Fleckensteln-Grun G, Frlrhman WH, Zanchetll A, Doyle AE. Calcium metabolism and calcium channel blockers for understanding and treating hypertension. Am J Med 1984;77:suppl6B: l-23.

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3. McCarron DA. Calcium in the pathogenesis and therapy of human hypertension. Am J Med 1985;78:suppl 28:27-34. 4. Bruce RA, Hornsten TR. Exercise stress testing in evaluation of patients with ischemic heart disease. Prog Cardiovasc Dis 1969;11:371-390. 5. Lie RF, Schmlls JM, Pierre KJ, Gochman N. Cholesterol oxklase-based determination by continuous-flow analysis of total and free cholesterol in serum. Clin Chem 1976;22:1627-1630. 6. Bursteln M. Scholnlck HR. Morfln R. Raoid method for isolation of lipoproteinsfrom human serum by precipitation by polyanions. J Lipid Res 1970:11:583-595. 7. Bucoio G, David H. Quantitative determination of serum triglycerides by use of enzymes. Clin Chem 1973;19:475-482. 8. Snedecor GW, Cochran WG. Statistical Methods. Ames, Iowa: Iowa State University Press, 1973. 9. Goldman Al, Steele BW, Schnaper HW, Fltr AE, Frohllch ED, Perry HM Jr. Serum lipoprotein levels during chlorthalidone therapy. JAMA 1980:244:1691-1695. 10. Multible Risk Factor Intervention Trial Research Grouo MRFIT-risk factor change and mortality results. JAMA 1982;248:1465-1477. 11. Eosteln SE. Roblnson BF. Kahler RL. Braunwald E. Effects of betaadrenergic blockade on the’cardiac response to maximal and submaximal exercise in man. J Clin Invest 1965;44:1745-1753. 12. Rosl R. Problems of physical activity during treatment with beta-blockers. In: Lana E. Sorael F. Bloha L, eds. Beta-Blockers in the Elderlv. New York: Springer-Verlag, 1982:71-81. 13. Leren P, Foss PO, Helgeland A, Hjermann I, Holme I, Lund-Larsen PG. Effect of orooranolol and orazosin on blood lioids. Lancet 1980:2:4-6. 14. Day JL, rineicalfe J, Slmdson CN. Adrenergic mechanisms in control of plasma lipid concentrations. Br Med J 1982;284:1145-1148. 15. Drayer JIM, Kelm HJ, Weber MAA, Case DB, Laragh JH. Unexpected pressor responses to propranolol in essential hypertension. Am J Med 1976;60:897-903. 16. Bruce RA, Eleady-Cole R, Bennett LJ, Kusuml F. Divergent effects of antihypertensive therapy on cardiovascular responses and left ventricular function during upright exercise. Am J Cardiol 1972;30:768-774. 17. Lee W, Fox LM, Slotkoff LM. Effects of antihypertensive therapy on cardiovascular response to exercise. Am J Cardiol 1979;44:325-328. 18. Franz I-W. Differential antihypertensive effect of acebutolol and hydrochlorothiazldelamiloride hydrochloride combination on elevated exercise !):,9,“” pressures in hypertensive patients. Am J Cardiol 1980;46:301-

---.

19. 20.

21. 22. 23.

24.

Reybrouck T, Amery A, Bllllet L. Hemodynamic response to graded exercise after chronic beta-adrenergic blockade. J Appl Physiol 1977;42:133-138. Yamakado T, Oonlshl N, Kondo S, Nozlrl A, Nakano T, Takezawa H. Effects of diltiazem on cardiovascular resoonses during exercise in svstemic hypertension and comparison within proprano&ll Am J Car&l 1983;52:1023-1027. Pool PE, Seagren SC, Bonanno JA, Sale1 AF, Dennlsh GW. The treatment of exercise-inducible chronic stable angina with diltiazem: effect on treadmill exercise. Chest 1980;78:suppl:234S-238s. Nlcholson JP, Resnlck LM, Plckerlng TG, Marlon R, Sullivan P, Laragh JH. Relationship of blood pressure response and the renin-angiotensin system to first-dose prazosin. Am J Med 1985;76:241-244. Lowensteln J. Effect of prazosin on serum lipids in patients with essential hypertension: a review of the findings presented at the satellite svmooskim of coronary heart disease, hypertension and other risk factors,-Mlian, 1983. Am J Cardiol 1984:53:suool:2lA-23A. Pool PE. Seagren SC. Ldno-te% efficacy of diltiazem in chronic stable angina associated withatherosclerosis: effect on treadmill exercise. Am J Cardiol 1982;49:573-577.