long-term systemic arterial blood pressure control with nicardipine

Long-Term Systemic Arterial Blood Pressure Control with Nicardipine

C. Hilmon Castle, MD, and Robert A. Wolbach, MD, PhD

Hlcadphbe was admini&red orally for up to 1 yearto25Opatkntswithessentialh~. Phase I, a 2- to 4-week placeho washout to estab- bll basehe SqJine dlastolii bleed pressure (BP), was folowed by 4 weeks of open-iabei nicardlplne doseWration(phaseII)toestabkhopthnaldosage ona3-kedailyre&nenforeachpatient.Atter nieonliphe adn&M&h, approximstely 79% of thepatkntshadst@nediastolicBP<90mmHgor 110mnlHgbeiowbasehe.Theredldoninsys- tOliCWddbtOilCBPSWdlS somewhat greater in patkntsolderthan6Oyears.Afterphaselll-an &week dedbbbd comparison of dosage regi- mens of 2- and 3-thnesdaily4 patkmts re- tumedtoa3-times&& reghnen at the& optimal yY--4e=uemenopentrubnrnt

Wdmentwithadiuretic ora~bkdcsrwasrequhwlby67patknts.Bythe endofphase!Iv,marethan1oopatientshadcom- pktedlY~ofnsewdips~ momtherapy (mean su- plncdiastolkBP=8SmmHg,approxbnaUy14 mm ttg bdow badne). Fhdy, paGents were ran- domly-t@-- onadouble- Mndbasisortakeamatchingplacebofor6weeics (phaseV,n= 101).Thedcard@inegrouphaddy adghtdungekr~diastokBP,whereas thoselTHxMlgplacebohadsta6snwilysignlfkant i- in supine diastok BP toward basstine values. Adverse experhws, attrlbuted to the va- sodlatoryeffectsofnicardipine,tededtooccurin theikstfewmonthsofthestudyandresultedin early withdrawai of 30 patients. Overal, thsse re- suits show that nicardiplm is a well-tokrated anti- hypededve agent with efficacy sustained dwsng 1 year of treatment.

(Am J Cardiol1989~35H41H)

From the University of Utah, Salt Lake City, Utah, and Syntex Labora- tories, Inc., Palo Alto, California.

Address for reprints: Robert A. Wolbach, MD, PhD, Syntex Labo- ratories, Inc., Lr2400, 3401 Hillview Avenue, Palo Alto, California 94303.

A lthough the etiology of essential hypertension is not fully understood, it is generally recognized that increased peripheral resistance is a fundamental

hemodynamic disturbance in hypertensive patients.1-3 Calcium antagonists are a diverse group of drugs used in the treatment of various cardiovascular and cerebrovas- cular disorders. In hypertension, calcium antagonists are thought to inhibit vascular smooth muscle contraction by decreasing intracellular calcium ion concentration, thus reducing both peripheral resistance and blood pressure (BP).3-5 Calcium antagonists have proved to be potent antihypertensive agents in clinical trials, with minimal effects on serum lipids, blood glucose levels or regional blood flo~.~-~

Nicardipine hydrochloride is a dihydropyridine calcium antagonist used for treatment of hypertension and angina. Clinical studies, mostly short-term (2 to 12 weeks), have shown that nicardipine reduces BP in hypertensive patients without many of the adverse effects associated with other antihypertensive therapies7-l4

Although numerous short-term nicardipine studies have been published, the chronic nature of hypertension requires that the long-term effects of nicardipine be assessed. This was a study of 1 year of nicardipine treatment in patients with mild or moderate hypertension. Antihypertensive efficacy, adverse effects, and the effects of age and race on responsiveness to nicardipine were evaluated. In addition, this study incorporated a design feature not included in previously reported long-term studies: a parallel double-blind withdrawal of patients from nicardipine treatment to confirm sustained efficacy after prolonged treatment.

MmHODS Patkntsz Ambulatory outpatients (n = 250) entered

this multicenter study and were treated with nicardipine for up to 60 weeks. Each of the 16 physician-investigators enrolled from 5 to 29 patients. The patients had stable mild or moderate essential hypertension, with a baseline supine diastolic BP of 95 to 115 mm Hg, inclusive. Pa- tients who were pregnant or who had angina pectoris, coronary artery disease or hypertensive retinopathy greater than grade II were excluded from the study. The study protocol was approved by institutional review com- mittees, and each patient gave informed consent before beginning nicardipine treatment.

Study de&n: This study consisted of 5 phases. Dur- ing phase I-the placebo run-in period of 2 to 4 weeks- patients received placebo 3 times daily. Baseline clinical and laboratory test values were established. Stable hypertension was confirmed by 2 supine diastolic BP measure-

THE AMERICAN JOURNAL OF CARDIOLOGY OCTOBER 17. 1989 3gH

A SYMPOSIUM: NICARMPINE-A VASDSELECTIVE CALCIUM ANTAGONIST

45 mg BID

SO mgl day

I

SO mgl day

Placebo

Phase I II Ill IV V

Baseline I

Titration I

TID vs Open Blinded BID I Treatment I Withdrawal

2 - 4 Weeks 4 Weeks 8 Weeks 40 Weeks 6 Weeks

FIGURE l.Shutyddgn. DID= 2timem~,TlD=3Umes daily.

ments obtained 1 week apart, within the range of 95 to 115 mm Hg and with a difference < 10 mm Hg between the 2 readings. The last measurement taken during phase I was used as the baseline supine diastolic BP. Phase II was a 4-week dose titration period. Initially, each subject received nicardipine, 20 mg, 3 times daily. If the patient did not respond adequately, i.e., supine diastolic BP remained >90 mm Hg or did not decrease 110 mm Hg, the dosage was increased to 30 mg 3 times daily. Phase III was an &week double-blind comparison of 2 dosage regi- mens. Patients continued with their optimal total daily dose as established in phase II, but it was administered as either a 2- or 3-times-daily regimen. Phase IV reestab- lished open-label, 3-times-daily use of nicardipine for 40 weeks, with the total daily dose used in phase III. Finally, patients who had tolerated open treatment well and agreed to participate in phase V received either nicardipine or matching placebo 3 times daily in a 6-week, ran-

domized, double-blind design that tested the persistence of the BP-reducing effect of nicardipine. Figure 1 presents the study design.

If deemed necessary for satisfactory BP control, investigators were free to add a supplemental antihypertensive medication (diuretic, fl blocker, or both) to the treatment regimen at any time during any phase of the study. Data collected after a patient received concomitant antihypertensive medication were excluded from efficacy analyses. Patients whose BP could not be controlled to the satisfac- tion of the investigators were withdrawn from the study.

safatydt3ffhC~- Nicardipine efficacy was assessed as the change in BP from baseline. BPS (supine and standing) were measured twice at each visit, and the mean of these 2 measurements was used for statistical analyses. Visits to the clinic were weekly in phases I, II and V; every 2 weeks during phase III; and every 2 months during phase IV. Patients receiving treat-

Systolic and Diastolic Blood Pressures k SEM W-W)

!EII 11

** 80 - **

Pre- Post- Pre- Post- Treatment Titration Treatment Titration 60 mgl day (n=106) 90 mgl day (n=128)

36H THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 64

rABLE I Patient Demographics

Dose Group

All 60 90 Patients w/day mg/W p Value

No. of patients 250 118 132 Age CVN 52.4 53.1 51.9 0.419 Weight (kg) 87.8 84.9 90.5 0.01* Body mass index+ 1.36 1.34 1.38 0.17; Men (%) 64 61 66 0.42* Women (%) 36 39 34 Smokers (%) 21 19 22 0.63* White (%) 69 69 70 Black (%) 24 25 22 0.w Other (%) 7 6 8

l One-way analysis of variance for dose group comparison (80 vs 90 Tg/day + Body mass index calculated as 31.81 ( y in poundsl/7height in Inches4 for

men; 34.13 (weigm in pounds/he@ in inches for women. * Likelihood ratio chiiuare test for group diirence (60 vs 90 mg/day). 5 Nonwhite groups combined; likelihood ratio chksquare test was used for compari-

so” of dosegroup.

ment throughout phase IV were considered to have com- pleted the study. Patients who withdrew during the placebo-controlled phase V were not considered early termina- tions; some withdrawals were expected and were encour- aged when BP increased.

Parametric analysis of variance was used for between- group comparisons; a 2-tailed paired t test was applied for within-group comparisons. Likewise, a 2-way analysis of variance was used to assess changes in BP by age and dose or by race and dose.

Patients underwent physical examination at entry and at study completion. Laboratory tests, including complete blood count, urinalysis and routine blood chemistry pan- els, were performed during the study. Electrocardio- grams were recorded during phase I and again at the end of nicardipine treatment.

Patient complaints, elicited by nondirective, open- ended questions, were recorded at each visit. Adverse changes observed in physical examination or laboratory tests were also recorded. Adverse events while patients were receiving nicardipine alone were evaluated separate- ly from those reported during treatment with concomitant antihypertensive medications.

RESULTS Nicardipine treatment was begun in 250 patients who

were included in the assessment of tolerability and safety. Supplemental antihypertensive medication (diuretic or 0 blocker) was required by 67 patients during some portion of the study. These patients did not differ from patients continuing to take monotherapy with respect to the proportion of patients younger than age 40 years, or the ratio of white to black patients. Because 6 patients began their use of diuretics or /3 blockers during phases I or II, their data were excluded from all efficacy analyses. Some of the remaining 244 patients were excluded from specific efficacy analyses because of invalid visits.

Of the 250 patients who started the study, 70 withdrew from the study early because of adverse experiences (30 patients, 12%), ineffectiveness of the study medica-

TABLE II Dose Titration for Nicardipine Treatment of Hypertension: Mean Systolic/Diastolic Blood Pressure (mm Hg) in Patients of Different Age Groups

43 Range (n)

End of Baseline* Titration

60 w/day

Mean Decrease?

20-39 (20) 44x59 (51) 60-79 (35)

WI/101 130/86 153/99 138/84 165/100 142/81

90 v/day

14.0/14.5 14.6/14.8 23.0/18.6

20-39 (22) 149/104 139/93 10.8/l 1 .O 40-59 (77) 155/103 MO/91 15.6/11.6 60-79 (29) 163/102 147/89 16.4/13.6

* Analysis of variance p values for systolic and diastolic pressure differences among age groups were a.m1 and 0.19, re.spectiiely.

t Analysis of variance p values for systolic and diastolic pressure differences among agegroups were 0.024 and 0.06?. respectively. Within each age group, mean change in Mood pressure was highly sign&ant at p <O.OOl.

n = number of patients/group.

tion (10 patients, 4%), loss to follow-up (10 patients, 4%), noncompliance (5 patients, 2%), medical problems unre- lated to nicardipine use (10 patients, 4%) and miscella- neous other reasons (5 patients, 2%).

Effe&onbbodp-: Because results for supine and standing BPS in patients were similar throughout the study, only supine BP results are presented.

Phase I-doa~mentatiot~ of hype&dom The de- mographic characteristics of the patients who were given nicardipine are shown in Table I. The patients ranged in age from 23 to 79 years (mean 52), 64% of the patients were men and 69% were white and 24% black. After placebo treatment, all patients had a diastolic BP >90 mm Hg.

Phase II-‘--- titration: During this phase, 106 patients continued to receive a total daily dose of nicardipine, 60 mg, and 128 patients were given the increased dosage of 90 mg/day. Not surprisingly, patients with dosages titrated up to 90 mg/day had statistically significantly higher mean supine diastolic BP at baseline than patients who required treatment with the lower dosage. At the end of phase II, supine diastolic BP was reduced to 90 mm Hg or at L 10 mm Hg below baseline for 179 of the 234 (76%) valid patients (92 patients treated with 60 mg/day and 87 treated with 90 mg/day). For both dose groups, BP was significantly reduced (Fig. 2). Nicardi- pine at 60 mg/day reduced mean supine BP from baseline by 17.3/16.0 mm Hg (p <O.Ol). Nicardipine at 90 mg/day reduced mean supine BP by 15.0/l 1.9 mm Hg (p <O.Ol).

Highly significant decreases in systolic and diastolic BP were evident in both dose groups in each of 3 age subgroups (20 to 39,40 to 59,60 to 79 years) as listed in Table II. However, the older patients had higher baseline systolic BP than the younger patients and the decrease in systolic BP was also greater in the older age group. Re- gression analyses confirmed that both systolic and diastolic BP changes increased with increasing age in the group of patients taking 60 mg/day (p = 0.018 and 0.036, respectively); the parallel trends in the patients

THE AMERICAN JOURNAL OF CARDIOLOGY OCTOBER 17, 1989 37H

A SYMPOSIUM: NICARDIPINE-A VASOSELECTIVE CALCIUM ANTAGONIST

TABLE 111 bse Titration for Nicardipine Treatment of Hypertension: Supine Diastolic Blood Pressure Changes in Black COmPared with White Patients

Daily Dose 60 mg Wm3 p Value* of Nicardipine Race Black White Black White

No. of pts. 29 70 29 89 0.44 Baseline mean SDBP lOOf 99&l 104fl 103fl 0.16 End of titration mean SDBP 8452 84fl 92f2 91 f 1 Mean change in SDBPt (mm Hg) -16f2 -15fl -11 f 1 -12fl 0.86

l For djtibwn of pa&n& between dose groups, p value is for likelihood ratio chIsquare test on race vs dose group. For blood presSUP data. P ValueS are for differences b&fw~~ race groups in Z-way analysis of variance.

t W&in each group. mean change in SDBP from baseline was highly significant at p <O.Ol SDBP = supine diastolic blood pressure

treated with 90 mg/day were not statistically significant. phase IV treatment than at baseline (p <O.Ol). The mean Although the calculation is not presented, the data in decrease from baseline in supine BP for the group taking Table II show that 22 of 42 patients in the youngest age 60 mg/day was 17.8/14.0 mm Hg. This represents a group (20 to 39 years) required titration from a dosage of small increase compared with the end of titration (2.9 60 to 90 mg/day. This was not significantly different mm Hg; p <0.05). For patients receiving 90 mg/day of from the proportion of patients in the older age groups nicardipine, the mean BP reductions achieved during who required the higher dosage (p = 0.74). phase II were maintained. For these patients, mean su-

Results comparing black and white patients are sum- pine BP was reduced at the end of phase IV by 15.2/ 13.1 marized in Table III. The higher dosage of nicardipine mm Hg compared with baseline. Figure 3 summarizes (90 mg/day) was required to control BP in 50% of the BP data collected at the end of treatment during phase black and in 56% of the white patients (p = 0.44). The IV. mean decrease in supine diastolic BP was not significant- Phase v-nleardlplne versus plaeebe tleaeulad ly different in the black and white patients. dnsg wlth&awd During this elective final phase of the

Phase Ill-sempaisea et damage reglmens: BP re- study, the results were similar in patients who had been ductions achieved during dose titration were maintained. treated with doses of 60 or 90 mg/day of nicardipine for 1 Analysis of BP changes from baseline to the end of phase year (Table IV). At the start of phase V, the patients III, and from the end of titration to the end of phase III, randomized to receive placebo or nicardipine had similar revealed no statistically significant differences between supine diastolic BPS. As this phase of the study pro the 2 dose groups (60 vs 90 mg/day) or between the 2 gressed, nicardipine-treated patients either maintained regimen groups (2 vs 3 times daily). This small study, their supine diastolic BP reductions or showed slight fur- although suggestive, is insufficient to warrant any recom- ther decreases. In contrast, placebotreated patients mendation of twice-daily use of nicardipine. showed statistically significant mean increases in supine

phua IV--term Mne treaM The diastolic BP. These increases constituted a return toward median duration of treatment for patients evaluated in baseline, and resulted in significant differences between phase IV was 1 year. BPS remained lower at the end of patients taking placebo and nicardipine in supine diastol-

160 150

Systolic and Diastolic

130

Blood 120 Pressures 110 -j 1 nr..

a0 -I Pre- Post- End of Pre- Post- End of

Treatment Titration Treatment Treatment Titration Treatment 60 mgl day (n=B6) 90 mgl day (n=74)

FlGuRE3.~RI:bng-temlbloodpresswe cdrdwlth -.-e-Pm=- atbueble,eftar4-week dosetlbBanmflaBerhalmenl tarrp~l~.*p<o.ogfor~rnen~franpoaaibrtkn;**p<o~ltortha meuachmgeframpMmabnd.-eshFSgus2.


TABLE IV Double-Blind Withdrawal from Nicardipine Treatment-Supine Diastolic Blood Pressure Changes: Nicardipine Versus Placebo

60 mg/W 90 m&?/day

Nicardipine Placebo

Mean change from baseline to start of phase V (mm Hg) -15 f 2* -17 f 2* No. of pts. 26 27 p value+ 0.28

Mean SDBP at start of phase V (mm Hg) 86f2 83fl No. of pts. 26 27 p value+ 0.12

Week 1 Mean change from start of phase V (mm Hg) 3f2 7f2* No. of ph. 23 26 p value+ 0.13

Week 3 Mean change from start of phase V (mm Hg) -1f2 5f2* No. of pts. 18 19 p value+ 0.02

Week 6 Mean change from start of phase V (mm Hg) -2f2 8f3* No. of pts. 13 15 p value+ 0.02 Mean change from start of phaseV to last valid visit (mm Hg) Of2 12f3* No of pts. 26 27 p value+ <O.ool

l p <O.OS for within-group cfmnges wing paired t test. + Compariin between nicardipine and pbcebo for each dose group using l-way analysis of variince. SDBP = supine diastolic blood pressure.

Nicardipine Placebo

-13 f 28 -15 f 2* 26 22

0.46 88f2 85f2 26 22

0.30

0*2 10f 1* 21 21

<O.ool

-1i2 11*3* 25 11

<O.ool

-1 f 1 14*3*- 20 11

<O.ool Oh1 14*2*

26 22 <O.ool

ic BP from weeks 3 through 6 of phase V (p <0.05 and p <O.Ol for the 60 and 90 mg/day patients, respectively). Figure 4 presents phase V results for patients in the high dosage group.

Tiderabillty anI utay: Most of the adverse effects that began or worsened during the study were attributed to the vasodilatory properties of nicardipine. The complaints reported at least once during the year of nicardipine monotherapy included headache (105 patients, 42%), pedal edema (48 patients, 19%), dizziness (46 patients, 18%), flushing (44 patients, 18%) and nausea (37

patients, 15%). In the 67 patients treated with concomitant antihypertensive medication, similar adverse experiences were reported before and after starting supplemental therapy: headache (8 patients, 12%), pedal edema (8 patients, 12%), dizziness (10 patients, 15%) and myalgia (10 patients, 15%). These patients who required combi- nation therapy reported the same types of adverse experiences with similar frequencies before and after they be.- gan supplemental use of diuretics or /3 blockers. Adverse experiences, in general, were first reported during the initial months of treatment, and resulted in early with-

n Nicardipine group

Baseline End of 1 yr 1 wk 2 wk 3 wk 4 wk 5 wk 6 wk Treatment - Nicardipine versus Placebo Treatment -

THE AMERICAN JOURNAL OF CARDIOLOGY OCTOBER 17, 1989 39ki

A SYMPOSIUM: NICARMPINE-A VASOSELECTIVE CALCIUM ANTAGONIST

drawal of 30 patients. Of these, 24 left the study within the first 12 weeks.

Changes in body weights and in electrocardiograms were minimal. Body weights were higher at baseline in patients treated with 90 mg/day of nicardipine, and tended to decrease slightly during the study. No statistically significant changes from baseline or differences between dose groups were found in PR interval or other electrocardiographic values.

During phase II, patients in both nicardipine dose groups demonstrated similar small increases in standing and supine pulse (means were 3 to 4 beats/mm). At the end of phase IV, heart rates remained slightly elevated compared with baseline values, although the increases seen in the group taking 90 mg/day were no longer statistically significant.

In general, nicardipine treatment was not associated with cliically important changes in mean laboratory values or in the values for individual patients. Although an increase was seen in mean blood glucose levels in patients treated with concomitant diuretics or fl blockers, careful review of individual patient data revealed the increases to be sporadic and of no clinical significance. Serum uric acid concentrations were minimally changed in patients treated with nicardipine alone, but patients given concomitant @ blockers or diuretics had a small mean increase in serum uric acid of approximately 0.5 mg/dL.

DISCUSSION Hypertensive patients often continue to receive treat-

ment for years. For this reason, it is critical that the long- term effects of new antihypertensive medications be assessed. In this study, the sustained efficacy of nicardipine monotherapy was confirmed. After dose titration, 40% of the 234 patients evaluated had adequate BP control with the lower nicardipine dosage (60 mg/day); an additional 39% of the patients required the higher dosage (90 mg/ day) to reduce supine diastolic BP <90 mm Hg or 210 mm Hg. During the year, 67 patients required supplemental antihypertensive medication to the treatment regimen and 5 patients withdrew for lack of BP response without use of supplemental medication.

No effects of race on patient responsiveness to nicardipine were detected. Black and white patients achieved similar reductions in BP, and similar proportions of patients required the higher dosage of the drug. In contrast, because @ blockers are reportedly less effective in black patients, their use as a first-line antihypertensive treatment in blacks is limited15~16

In this study, highly significant decreases in systolic and diastolic BP were demonstrated in each of 3 age groups (20 to 39,40 to 59 and 60 to 79 years). Although some reports suggest lesser efficacy of nicardipine in younger patients,13y17-19 our results show that nicardipine is quite an effective antihypertensive agent for the younger patients. In fact, our results generally favor the con- clusion of Massie et a120 that no marked effect of age on calcium antagonist efficacy has been established. It is possible, however, that nicardipine is more effective in the elderly but, if true, this age-dependent difference is modest.


Adverse events, mostly attributable to the vasodilatory effects of nicardipine tended to occur within the first 3 months of treatment. Those most often reported were headache, pedal edema, dizziness and flushing. No changes in body weight were observed, indicating that, as with other calcium antagonists, the pedal edema reported here did not result from fluid retention. An alternative explanation has been suggested: Precapillary vaso- dilation in the absence of venular dilation may result in elevated capillary pressure and increased capillary leaks3v4

In this study, nicardipine had little effect on laboratory test results. This contrasts with results from studies of other antihypertensive medications. For example, diuretic therapy has been associated with increases in uric acid, blood glucose and cholesterol concentrations, and decreases in serum potassium levels.3*21-23 Treatment with /3 blockers has been associated with changes in serum lip ids.24 Consequently, they are not recommended for patients with hyperlipidemia. l 8,20

As in short-term nicardipine studies,s*10*13y14 this l- year study revealed no consistent pattern of electrocardiographic changes. In contrast, both calcium antagonists diltiazem and verapamil have been associated with some electrocardiographic changes, such as a small increase in PR interval.25

Previous long-term nicardipine trials had results similar to those of the present study.11*17p26 All of those studies were open in design, and lacked parallel placebo control groups. Consequently, their conclusions were restricted It is accepted that ethical considerations prevent the use of a blinded placebo control group throughout long-term hypertension trials.

To circumvent these problems, a double-blind parallel withdrawal from treatment vs continuation of treatment concluded the present study. Patients receiving placebo during thii phase had statistically significant increases in BP, whereas patients continuing nicardipine treatment had no changes from the preceding open-label nicardipine treatment. These results provide a controlled study confirmation of nicardipine’s effectiveness in long-term treatment.

Overall, this study has shown nicardipine to be generally well-tolerated and highly effective at reducing BP in a demographically diverse study population. In conclu- sion, these results confirm the effectiveness and use of nicardipine as a first-line therapy for mild or moderate essential hypertension.

Achowledgmemt: We acknowledge with thanks the participation of the colleagues who treated patients in this study: Theodore B. Bemdt, MD, Reno, Nevada; Francis X. Burch, MD, San Antonio, Texas; Dennis Costello, MD, La Jolla, California; Robert C. Davidson, MD, Se attle, Washington; Raebum M. Evans, M.D., Indianapo- lis, Indiana; Morton H. Maxwell, MD, Los Angeles, Cal- ifornia; Nona F. Niland, MD, Austin, Texas; Daniel S. Prince, MD, Birmingham, Alabama; Paul H. Rogers, MD, Phoenixville, Pennsylvania; Joseph D. Sargent, MD, Topeka, Kansas; Harold W. Schnaper, MD, Bir- mingham, Alabama; Donald Sherrard, MD, Seattle,

Washington; Joseph S. Spindler, MD, Houston, Texas; David Wallack, MD, Littleton, Colorado; Peter Weiss, MD, Denver, Colorado. We also appreciate the help from Patricia Kasper, MS, and Nancy Szakacs, MBA, in study management, Ling-ling Tsao, MPH, and Deepa Rai, MS, in statistical analysis, and Sheila Jurik in prepa- ration of the manuscript.

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sive dose-response effects of nicardipine in stable essential hypertension. Br J Clin Pharmacoll985;20:135S-138s. 13. Asplund J. Nicardipine hydrochloride in essential hypertension-a controlled study. Br J Clin Pharmacol 1985;20:12OS-124s. 14. Forette F, Bellet M, Henry JF, Hervy MP, Poyard-Salmeron C, Bouchacowt P, Guerret M. Effect of nicardipine in elderly hypertensive patients. Br J Clin Pharmacol 1985:20:125S-129s. 15. Cubeddu LX, Aranda J, Singh B, Klein M, Brachfeld J, Freis E, Roman J, Eadea T. A comparison of verapamil and propranolol for the initial treatment of hypertension. Racial differences in response. JAMA 1986;256:2214-2221. 16. M’Buyamba-Kabangu JR, Lepira B, Fagard R, Lijnen P, Ditu M, Tshiani KA, Amery A. Relative potency of a beta-blocking and a calcium entry blocking agent as antihypertensive drugs in black patients. Eur J Clin Pharmacol 1986;29:523-527. 17. Murray TS, Langan J, Coxhead PF, Levinson N. Long-term effects of nicardipine in the treatment of essential hypertension. Br J Clin Pharmacol 1986;22:249S257S. 18. Frohlich ED. Initial therapy for hypertension. Hasp Pratt 1987;22:89-96. 19. Fagan TC, Conrad KA, Lessem JM. Nicardipine and hydrochlorothiazide: effects of age and pretreatment blood pressure. Eur Heart J 1988,9:78. 26. Massie BM, Rubau JF, Szlachcic J. Comparative studies of calcium channel blockers and beta-blockers in essential hypertension: clinical implications. Circu- lation 1987:75:suppl KV-163-V-169. 21. Amery A, Berthaux P, Bulpitt C, Deruyttere M, de Schaepdryver A, Dollery C, Fagard R, Forette F, Hellemans J, Lund-Johansen P, Mutsers A, Tuomilehto J. Glucose intolerance during diuretic therapy. Lancer 1978;1:681-683. 22. Grimm RH, Leon AS, Hunninghake DB, Lenz K, Hannan P, Blackburn H. Effects of thiazide diuretics on plasma lipids and lipoproteins in mildly hypertensive patients. Ann Intern Med 1981,94:7-l I. 23. Morgan DB, Davidson C. Hypokalaemia and diuretics: an analysis of publi- cations. Br Med J 1980;280:905-908. 24. Weinberger MH. Antihypertensive therapy and lipids. Arch Intern Med 1985;145:1102-1105. 25. Frishman WH, Sonnenblick EH. Calcium channel blockers. In: Hurst JW, ed. The Heart. New York: McGraw-Hill, 1986;1624-1639. 26. Dubois C, Blanchard D, Loria Y, Moreau M. Clinical trial of a new antihy pertensive drug, nicardipine: efficacy and tolerance in 29,104 patients. Curr Ther Res 1987;42:727-736. 27. West KM. Computing and expressing degree of fatness. JAMA 1980;243: 1421-1422.

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long-term systemic arterial blood pressure control with nicardipine

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