diuretics versus calcium-channel blockers in systemic hypertension: a preliminary multicenter...

Diuretics Versus Calcium-Channel Blockers in Systemic Hypertension: A Preliminary

Multicenter Experience with Hydrochlorothiazide and Sustained-Release Dlltiazem

WILLIAM H. FRISHMAN, MD, WALTER KIRKENDALL, MD, JOHN LUNN, MD,

DAVID McCARRON, MD, MARVIN MOSER, MD, HAROLD SCHNAPER, MD,

L. KENT SMITH, MD, JAMES SOWERS, MD, STEPHEN SWARTZ, MD,

and EDWARD ZAWADA, MD

The safety and effkacy of sustained-release diltiazem 120 to 180 mg, 2 times a day, were compared with hydrochkrothlazide 25 to 50 ng, 2 times a day, and the combination of diltiarem and hydrochlorothlazide in 58 psitients with mild to moderate hypertension (supine diastolic blood pressure between 95 and 114 mm H9) usi~ a placebo-controlled, paralleldedgn protocol. Data from an additional 21 patients were evaluated for safety only. The data reported herein represent the preliminary experience from a lar9er 200~patient multkenter study. All patients recehred placebo for 4 weeks, followed by either hydrochlom- thiazide or dlltiazem titrated to achieve a diastolic blood pressure reducWn’of1l0mmH9toreacha goal supine diastolic blood. pressure of <90 mm H9. Patients not achieving the treatment goal received hydrochlorothiazide plus diltiazem.

At week 14, on maintenance monotherslpy, dm- rem and hydrochlorothiazide produced comparable reductions in blood pressure from placebo-baseline (180.3 f 24.3/101.7 f 5.5 to 145.2 f 24.V89.8 f

7.4.mm Hg with diltlazem, 158.0 f 15.8/103.7 f 4.7 to 134.1 f 12.5189.2 f 9.5 nun Hg with hydrochk- rothiazide, p <O.OOl for both). Mltiazem and hycto- chtorothiazide achieved 9oal blood pressure In 42% and 45% of patients, respectively. The effects in reqondes were sustained for 8 months. In patients who did not achieve the treatment goal, 83% re- sponded to diltiazem plus hydrochlorothiazkle. No clinically significant postural hypotenskn was observed on any regimen. Heart rate was sl@htly lower with diltiazem than with hydrochkrothiazkie. Adverse effects were minimal with dittiazem, hydrochkrothia- zide and diltiazem plus hydrochl~iazide but more hypokakmia occurmd with hydrochlorothiazide.

Sustained-release diltlazem used twke daily pro- vided safe and effective therapy for mild to moderate hypertension when used alone or in combination with hydrochlorothiazide. As a monotherapy, sustained- release diltiazem is similar in efficacy to hydrochloro- thiazkie.

(Am J Cardioll985;58:92H-98H)

From the Division of Cardiology, Albert Einstein College of Medicine, Bronx, New York, General Medicine Division and Hypertension Unit, University of Texas Medical School at Houston, Houston, Texas, Department of Medicine, Princess Margaret Hospital, Nassau, the Bahamas, Nephrology Department, Health Sciences University, Port- land, Oregon, Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, Center of Aging, University of Alabama School of Medicine, Birmingham, Alabama, Department of Cardiology, Arizona Heart Institute, Phoenix, Arizona, Endocrine and Hypertension Division, Department of Medicine, Wayne State Univer- sity, Detroit Michigan, Department of Medicine, West Roxbury Veter- ans Administration Medical Center, Boston, Massachusetts and Division of Nephrology and Hypertension, Department of Internal Medicine, University of South Dakota, Sioux Falls, South Dakota.

Address for reprints: William H. Frishman, MD, Hospital of the Albert Einstein College of Medicine, 1825 Eastchester Road, Bronx, New York 10461.

Calcium-channel blockers are a distinct group of com- pounds that interfere with the normal transmembrane flux of extracellular calcium, on which vascular tissue depends for contraction and impulse generation.1 They reduce the contractile activity of the myocardi- urn and promote coronary and systemic arterial dilation.’ These hemodynamic effects provide the clinical rationale for the use of calcium-channel blockers in the management of ischemic heart disease1 and hypertrophic cardiomyopathy.2

Because systemic arterial dilation can be expected to reduce elevated arterial blood pressure, there has been considerable enthusiasm for the use of calcium- channel blockers in the medical management of sys-

92H

December 6, 1985 THE AMERICAN JOURNAL OF CARDIOLOGY Volume 56 93H

temic hypertension and hypertensive emergencies.3-s The effectiveness and safety of these drugs in the treatment of systemic hypertension have been clearly documented.a-e+la The efficacy of nifedipine and verapamil appears comparable to that of oral diuretics in hypertension.3J*gJ4J5 In this report, we describe a preliminary experience from a large multicenter trial designed to be the first well-controlled study comparing sustained-release diltiazem with hydrochlorothiazide in patients with systemic hypertension.

Methods

The data presented are based on a preliminary analysis of 77 patients who are part of a 200-patient multicenter study still in progress.

Patient selection: A total of 77 patients with mild to moderate systemic hypertension were enrolled after written and informed consent was obtained. Fifty-six patients were analyzed for safety and efficacy; 21 for safety only. The demographics of the 56-patient study group are listed in Table I.

All patients who were entered had essential hypertension with a stable resting supine diastolic pressure between 95 and 114 mm Hg while not taking medication. Potential patients were seen before the study, and were entered into a placebo run-in screening phase after all previously adminis- tered antihypertensive medication had been stopped for at least 2 weeks. For entry, stable resting supine diastolic pressures (each recorded pressure was the averge of 3 readings using Korotkov phase V) between 95 and 114 mm Hg and varying by < f7 mm Hg were required on 2 consecutive weekly visits starting with days 7 to 10 of the placebo run-in screening. If a patient needed more than 4 weeks to stabilize, he or she was considered labile and excluded from further study participation.

Patients with the following conditions were excluded from the study: significant cardiovascular disease other than essential hypertension, impaired renal function, greater than first-degree heart block, sick sinus syndrome, known abuse of alcohol or drugs, pregnancy and known hypersensitivity to thiazides or other sulfonamide-derived drugs.

Experimental design: The design of the multicenter trial is shown in Figure 1. A single-blind, placebo run-in screening of at least 2 weeks was used to establish baseline pressures. Eligible patients were then randomized to treatment with hydrochlorothiazide or sustained-release diltiazem in a double-blind, parallel fashion, using the double-dummy tech- nique. A titration period of up to 2 months then commenced;

TABLE I Demographlc Summary

Diltiazem Hydrochlorothiazide (n = 26) (n = 30)

Sex Men Women

21 :: 9

Age (years) Race

Black Other

Height (inches) Men Women

Weight (pounds) Men Women

Smokers Yes No

Duration of hypertension (years)

55f 10 56 f 10

:: :i

70 f 3 69 f 2 64 f 4 64 f 2

221 f 50 196 f 29 167 f 33 160 f 29

21 7

11 f8 :13*6

patients were given increasing doses of study medications (240 to 360 mglday diltiazem; 50 to 100 mglday hydrochlorothiazide, each in 2 divided doses) until optimal response was reached. Optimal response was either a reduction in supine diastolic blood pressure to <90 mm Hg or a reduction of at least 10 mm Hg for those patients with baseline pressures of 95 to 99 mm Hg. Upon achievement of the optimal response, patients entered an evaluation period for 4 weeks. Patients who achieved and maintained goal pressure reduction with the initial medication remained on that medication and were seen monthly for 3 months.

After the evaluation period, any patient who had not achieved and maintained the goal diastolic blood pressure received the other medication in unblinded fashion (titrated to optimum over a 2-month period) in addition to the initial medication. Upon reaching the optimal dose of the second medication, patients were followed for an additional 1 to 2 months to assess the safety and effectiveness of the combination therapy.

Methods of observation: Resting supine, immediate and 5-minute standing blood pressures were measured 10 to 12 hours after the last dose of medication and before the next dose. Safety was monitored during the placebo and active treatment phases with adverse-effect profiling, electrocar- diograms, complete blood counts and blood chemistries.

Statistical analysis: The experiment was designed with stratification by investigator to detect and adjust for any investigator differences in the treatment comparisons. How- ever, because of the imbalance of patient and treatment

I I

240 q/day1 j60 ngldayl

FIGURE 1. Study design for a multicenter comparison of hydrochlorothiazide (HCTZ) and sustained-release diltiazem (DTZ).

HCTZ

50 rug/day ) 100 mg/davf I I I

Monotherapy I

Titration Evaluation ’ Period Period ’

I I I I

weeks 1-2Cr.b) 1 vceks 3-10 1 veelrs 11-14 weeks 15-26 I

04H A SYMPOSIUM: ROLE OF CALCIUM ENTRY-BLOCKING DRUGS IN HYPERTENSION

TABLE II Mean ( f Standard Devlatlon) Supine Blood Pressure and Heart Rate on Monotherapy (All Patients) (p Values Versus Baseline)

End of Monotherapy Titration Baseline (Week 10) Week 14

Diltiazem HCTZ Diltiazem HCTZ Diltiazem HCTZ (n = 26) (n = 29) (n = 26) (n = 29) (n = 26) (n = 29)

SBP (mm Hg)’ 160f24 156f 16 145 f 23 136 f 13 145 f 24 134 f 13

DBP (mm Hg)’ 102f6 104f 5 p ==g02C$01 p ;102;Ol p ;o02;06 p = 0.0001

69f 10

MAP (mm Hg)’ 121 f 11 121 f 6 p1=70ir$1 p=60”~ol p1==60i;021 p = 0.0001

104 f 10

HR (beats/min)’ 76 f 9 73 f 7 p ;,02;01 p =$;“.OZl p ==gor”“l”ol p =7p~.O;l

p = 0.0069 NS p = 0.0066 NS

DBP = diastolic blood pressure; HCTZ = hydrochlorothiazide; HR = heart rate; MAP = mean arterial pressure; NS = not significant; SBP = systolic blood pressure.

TABLE Ill Mean (& Standard Devlatlon) Changes In Supine Blood Pressure and Heart Rate from Basallne on Monotherapy (All Patients) (p Values Versus TheraDles)

End Monotherapy Titration (Week 10) - Baseline

Dlltiazem HCTZ (n = 26) (n = 29)

Week 14 - Baseline

Diltiazem HCTZ (n = 26) (n = 29) Overall p Value*

SBP (mm Hg) -15 f 14 -21 f 17 -15 f 20 w (mm 4) -13f7 -13f7 -12f6 MAP (mm Hg) -14f6 -16 f 10 -13 f 11 HB (beats/min) -5f6 -0.3 f 9 -7f 12

Abbreviations as in Table II. l Overall differences between diltlazem and HCTZ therapies.

-22 f 16 NS -14f 11 -17 f 12 Ii:

-1f7 0.0346

groups among the various participating medical centers re- sulting from the interim data, we have simply pooled the sites for this analysis. We have avoided comparison of groups that achieved goal diastolic blood pressure on monotherapy with groups that did not achieve goal on combined therapy because of possible confusion in interpretation due to the different selection processes of these groups.

Baseline comparisons were made to test for differences in the treatment groups. For the parameters of sex, race, age, classification and smoking status, Fisher’s exact test for 2 X 2 tables was used, For the parameters of duration of hypertension, diastolic blood pressure, systolic blood pressure, mean arterial pressure and heart rate, a t test for indepen- dent samples was used.

Fisher’s exact test for independence using 2 X 2 tables was used to analyze diastolic blood pressure goal achievement by comparing (1) diltiazem with hydrochlorothiazide at week 14, (2) diltiazem blood pressure-goal achievers on monotherapy with hydrochlorothiazide-goal achievers on monotherapy at week 26 and (3) diltiazem-non-goal achievers on combined therapy with hydrochlorothiazide-non-goal achievers on combined therapy at week 26.

The t tests were then used to analyze the mean change by treatment in supine, immediate and 5-minute standing systolic and diastolic blood pressures, mean arterial pressure and heart rate. Analysis-of-variance methods, accounting for between- and within-patient variability, were used to compare (1) diltiazem with hydrochlorothiazide up to week 14, (2) diltiazem-goal achievers on monotherapy with hydrochlorothiazide-goal achievers on monotherapy over weeks 14, 18, 22 and 26 and (3) diltiazem-non-goal achievers on combined therapy with hydrochlorothiazide-non-goal achievers on combined therapy over weeks 14, 22 and 26.

Comparisons between hydrochlorothiazide and diltiazem were made dependent on a check for treatment-by-evaluation interaction. If the interaction was significant, comparisons were made and reported at each evaluation. If the interaction was not significant, an overall treatment main- effect comparison, which averages over evaluations, was reported. In addition, a covariance analysis on the week 14 data was used to check for response differences because of other identifiable factors, including age and race.

To evaluate the potential for postural hypotension, differences between immediate standing and resting supine systolic and diastolic blood pressures, mean arterial pressure and heart rate were examined. Analysis-of-variance tests of these differences were used to compare (1) diltiazem with hydrochlorothiazide over baseline and week 14, (2) diltiazem-goal achievers on monotherapy with hydrochlorothiazide-goal achievers on monotherapy over weeks 14 and 26 and (3) diltiazem-non-goal achievers on combined therapy over weeks 14 and 26. These evaluations were made for each group in total, as well as for subsets of each group based on age.

Results

A total of 77 patients were enrolled; 56 could be evaluated for both safety and efficacy. The other 21 patients could not be analyzed for the following reasons: inability to tolerate medications (7); noncompli- ance with dosing instructions (7); and withdrawals for other reasons, including protocol violations and other illness (7). The data from these patients are included in the safety analysis.

December 6, 1985 THE AMERICAN JOURNAL OF CARDIOLOGY Volume 56 95H

TABLE IV Mean (4~ Standard Devlatlon) Immediate Standing Blood Pressure and Heart Rate on Monotherapy (All Patlents) (p Values Versus Baseline)



SBP (mm Hg)’ 159f25 150f 12 141 f 15 129 f 17 136 f 23 127 fl6

DBP (mm Hg)’ 102 f 7 104f7 p ==60$o,01 p ;oO$;;l p ==60:;06 p ;oO$;;l

MAP (mm Hg)” 121fl3 119f7 p=60~~01 p=30$;;l p=30~;~l p=202”,“,’

HR (beats/min)* 81 f9 76 f 6 p = 0.0001 p = 0.0001 p ~60~~c$l p ;60$;021

78f 10 82 f 8 NS p = 0.0152 p = 0.0208 NS

Abbreviations as in Table II. l No statistical intergroup differences at baseline

TABLE V Mean (f Standard Devlatlon) 5-Mlnute Standing Blood Pressure and Heart Rate on Monotherapy (All Patients) (p Values Versus Basellne)



SBP (mm Hg)’ 157f23 157fl8 141 f 19 136 f 15 142 f 19 p = 0.0001 p = 0.0001 p DBP (mm Hg)’ 104f8 106f 8 92 f 8 94 f 9 ;802;01

p = 0.0001 p = 0.0001 MAP (mm Hg)’ 122 f 12 123 f 10 108 f 10 108 f 10 p==60~~c$

p = 0.0001 p = 0.0001 p = 0.0001 HR (beatsimin)’ 83 f 9 78 f 9 77 f 9 81 f7 75f 10

o = 0.0008 NS D = 0.0018

131 fl6 p ;,o~;;l

Pl==40;;021

p = 0.0001 79f 11

NS

Abbreviations as in Table II. l No statistical intergroup differences at baseline

Blood pressure and heart rate: Both diltiazem and hydrochlorothiazide caused a significant reduction in systolic and diastolic blood pressures at week 10 (end of titration) and at week 14 (end of maintenance). The data for supine, immediate and &minute standing systolic, diastolic and mean blood pressures and heart rate are shown in Tables II through V. At week 14, the mean daily dose of diltiazem was 326 mg; for hydrochlorothiazide it. was 79 mg.

at week 14 produced the goal pressure reduction in 10 of 14 patients who completed the study (71%).

The ability of diltiazem and hydrochlorothiazide to produce the goal reduction in supine and diastolic blood pressure was compared at week 14. Diltiazem produced the goal in 42% and hydrochlorothiazide in 45% of patients. In the patients maintained on diltiazem and hydrochlorothiazide monotherapy beyond week 14, the effects of therapy on blood pressure were maintained (observed at weeks l&22 and 26). At week 26, 91% of patients on diltiazem who achieved goal blood pressure at week 14 had maintained the goal pressure, while 73% of patients on hydrochlorothiazide maintained the goal blood pressure reduction.

Safety: Significant postural drops in blood pressures were not seen with either diltiazem or hydrochlorothiazide treatment. Significant adverse effects were minimal for diltiazem, hydrochlorothiazide and the combination. Four patients on diltiazem, 5 on hydrochlorothiazide and none on the combination discon- tinued participation because of adverse effects. No significant electrocardiographic abnormalities were noted. No significant alterations in laboratory values, other than those alterations in electrolytes consistent with thiazide therapy, were seen. Specifically, 7 patients became hypokalemic and 4 patients developed hyperuricemia on hydrochlorothiazide alone. On combination diltiazem and hydrochlorothiazide, the pat- tern was similar to that of hydrochlorothiazide alone: 8 patients developed hypokalemia and 7 patients developed hyperuricemia.

Discussion

The addition of hydrochlorothiazide to patients re- Many of the calcium-channel blockers have been ceiving diltiazem who did not achieve the goal pres- shown to be safe and effective for the treatment of sure reduction at week 14 produced the goal pressure systemic hypertension and hypertensive emergen- reduction in 6 of 11 patients (55%) at week 26. The cies.3-Q-13J6J7 In this preliminary report of a large addition of diltiazem to patients receiving hydrochlo- study of 200 patients, sustained-release diltiazem used rothiazide who did not achieve the goal blood pressure twice daily was shown to be as effective as hydrochlo-

86H A SYMPOSIW: ROLE OF CALCIUM ENTRY-BLOCKING DRUGS IN HYPERTENSION

TABLE VI Hemodynamic and Metabolic Comparison of Diltlazem and Hydrochlorothlaride (HCTZ)

Initial Chronic

HCTZ Diltiazem HCTZ Diltiazem

Vascular Volume 1 t- c+ t--e Total peripheral

vascular resistance 1 Heart rate c--e Y l1 Y t+ Cardiac output

I

t+ c+ 4-----*

Blood pressure Plasma renin activity Natriuresis

t tf-

Y

t t+

Potassium t--w Y t+

Lipids Uric acid ; z4 1 ::I Blood sugar

(type II diabetics) t c+ t t-

t = increase; +- - = no net change; 1 = decrease.

rothiazide used twice daily in reducing supine and standing blood pressure, both short and long term, in patients with mild to moderate systemic hypertension. Diltiazem was shown to cause a small but clinically insignificant reduction in heart rate compared with hydrochlorothiazide; whereas in the doses used, hydrochlorothiazide caused more hypokalemia. Both drugs were well tolerated.

Although diltiazem and hydrochlorothiazide are equally effective in the treatment of hypertension, they have different hemodynamic and metabolic effects (Table VI).16Js-20 Diltiazem reduces blood pressure predominantly through its vasodilator actions, without causing tachycardia.3pg Calcium entry blockers have also been shown to have natriuretic effects.16 They do not affect blood sugar, uric acid, lipids or potassium levels. Diuretics, such as hydrochlorothi- aside, work initially by reducing intravascular volume and cardiac output; later, with physiologic adapta- tions to therapy, vascular volume returns to baseline, vascular resistance is reduced and cardiac output is maintained. Diuretics raise plasma renin activity and, unlike diltiazem, can cause hyperglycemia in type II diabetic patients, raise plasma lipids and uric acid and reduce serum potassium.21*22

With long-acting, sustained-release preparations now available, diltiazem and some other calcium- channel blockers can be considered first-line therapy and alternative therapy to /3 blockers and diuretics because of their favorable hemodynamic and metabolic characteristics and low adverse-effect profiles. They may become the treatment of choice in patients with hypertension and angina pectoris, for which they have proven efficacy.23y24 Among the calcium-channel blockers, diltiazem has one of the lowest adverse effect frequencies5 and should play an important role in the treatment of hypertension in years to come.

Implications: These preliminary findings confirm that sustained-release diltiazem is an effective agent

in systemic hypertension with an antihypertensive po- tency similar to that of diuretics. Diltiazem has similar antihypertensive effects on other calcium-channel blockers. Because of the minimal adverse effects usu- ally encountered with diltiazem and its intrinsic nega- tive chronotropic action, it is likely to be useful as a single-drug treatment for hypertension. However, the higher cost of diltiazem and other calcium-channel blockers, compared with diuretic agents, may limit their use to patients in whom advantages in efficacy, adverse effect-profiles or compliance are shown.

1.

2.

3.

4.

5.

6.

7.

8.

8.

10.

11.

12.

13.

14.

16.

16.

17.

18.

18.

References Eraunwafd E. Mechanism of action of calcium-channel blocfdna aoents. - - N Engl J Med 1882:26:1618-1627. Borrow RO, Roslng DR, Bacharach SL, Green MV, Kent KM, Llpson LR, Maron BJ, Leon MB, Epstein SE. Effects of verapamll on left ventricular svstofic function and diastolic filling in patients wfth hypertrophic cardlo- myopathy. Circulation 1881;64:78ir-796. Splvack C, Ocken S, Frlshman WH. Calcium antagonists-cllnfcal use in the treatment of systemic hypertension. Drugs 1883;25:154-177. Guazd MD, Poless A, Florentlni MD, Bartorelll A, Moruzzl P. Treatment of hypertension with calcium antagonists. Review. Hypertension 1983;5:suppl ll:ll-85-k-90. Frlsffman WH, Ocken S, Splvack C, Charlap S, Packer M. Calcium channel antagonists in the treatment of systemic hypertension. In: Packer M. Frishman WH, eds. Calcium-Channel Antagonists In Cardiovascular Disease. Norwalk: AppletonCentury-Crofts, 1884:281. Klein WW. Treatment of hypertension with calcium-channel blockers: European data. Am J Med 1984;77:suppl4A:l43-146. Frlshman WH, Weinberg P, Peled HB, Klmmel B, Charlap S, Beer N. Calcium-entry blockers for the treatment of severe hypertension and hypertensive crisis. Am J Med 1984:77:suppf 28:35-45. Frlsffman WH, Charlap S, Dcken S. Splvack C. Calcium-channel t~boyrs~ and systemic hypertension. J Clln Hypertension 1985; 1:

fnouye IK, Massle BM, Benowftz N, Simpson P, Loge D. Antihypertensive therapy with diftiazem and comparison with hydrochlorothiazlde. Am J Cardiol 1984;53:1588-1592. Frlsffman WH, Charlap S, Klmmel B, .%tZbq S, Stroff J, Weinberg P, Momtszko E, Welzner J, Dorsa F, Pollack 8, Strom J. Twice-dally oral verapamil in essential hypertension. Arch Intern Med (in press). Charfap S, Kimmel 8, Lalter L, Weinberg P, Singer M, Lazar E, Saltzberg S, Dorsa F, Kafka K, Strom J, Frisffman W. Twice-daily nicardipine In tf?e treatment of essential hypertension. J Clin Hy Hornune RS, Gould EA. Jones RI, Sonecha B

erfension (in press). N, Raftery EB. Nifedloine

tablets for systemic hypertensioni a study usin intraarterial recordino. Am J Cardiof 1983:51:1 8

continuous ambulatory 23-1327.

And& L, Hansson L;Oro L, Ryman T. Experience with nltrendipine-a new calcium antagonist-in hypertension. J Cardiovasc Pharmacol 1883;5:55-61. Bfihfer FR, Hulthen UL, Klowskl W, Mifller FB, Boll1 P. The place of the calcium antagonist verapamil in hypertensive therapy. J Cardlovasc f%ar- macol 1982;4:suppl 35350-5357. Hatiln L, And&n L, Hansson L. Controlled trial of nifsdipine and bendroflu- methiazide in hypertension. J Cardiovasc Fharmacol1983;5:1083-1085. Laragh JH, Bfihler FR, DeLeeuw PW, Doyle AE, Fleckensteln A, Fleck- enstein-Grun 0. Frishman WH. Zanchettl A. Calcium metabolism and calciumchannel blockers for understanding and treating hypertension. Am J Med 1984;77:suppl88:1-23. Roblnson BF. Calcium-entry blockers in the treatment of systemic hypertension. Am J Cardiol 1985;55:suppl:lO2B-106B. Kfnosftito M, Kusakawa R, Sftlmano Y. Effects of diltiazem hydrochloride on renal hemodvnamics and urinarv efectrofvte excretion. JDII Circ J

McGraw BF, Walker SD, Hemfrerger JA, Gltomer SL, Nakama M. Clinf- c$e;;~ience with diftiazem In Japan. Pharmacotf-wrapy 1982; 2:

20. Johnson BF. The emerging problem of plasma lipid changes during antfhvoerfensfve theraov. J Cardiovasc Pharmacol 1982+suool 2: s213:221.

. _ . .

21. Laragh JH. Basic principles for the office evaluation and treatment of high blood oressure. Parf il. Laboratorv evaluation and treatment. Cardiovasc Rev Rep 1981;2:1318-1334. .

22. Ram CVS. Diuretics in the management of hypertension. Postgrad Med 1982;71:155-168.

23. Frlshman WH, Klein NA, Klein P, Strdm JA, Tawll, Stralr R, Wong B, Roth S, LeJemtef T, Poflack S, Sonnenbffck EH. A comparison of oral propran- ofof and verapamif in patients with hypertension and angina pectoris: a placebo-controlled double-blind randomized crossover trial. Am J Cardiol 1982;50:1164-1172.

24. Frisffman WH, Charlap S, Klmmel 8, Goldberger J, Phlllppldes 0, Klein N. Calcium-channel blockers in patients with combined angina pectoris and systemic hypertension. Am J Cardiof 1985;56:suppf:4lH-46H.

diuretics versus calcium-channel blockers in systemic hypertension: a preliminary multicenter...

Documents