improved blood pressure control with isradipine in hypertensive patients treated with pindolol

Improved Blood Pressure Control with Isradipine in Hypertensive Patients Treated with Pindolol GORAN FRITHZ, M.D. fshktuna, Sweden BRAGE ASTROM, M.D. I/aste& Sweden BJORN DAHLOF, M.D., LENNART HANSSON, M.D. Gofeborg, Sweden CLAES TOLLIN, M.D. Jonkdping, Sweden PERTTI HIMANEN, M.D. Turku, Fin/and CARL-DAVID SUNDSTEDT, M.D. Base/, Switzerland

Isradipine is a new calcium antagonist of the dihydropyridine type with marked vasodilator activ- ity and minimal negative inotropic effects. It is a potent antihypertensive drug when given as monotherapy. This was a randomized double-blind crossover study of 16 weeks’ duration, including 80 hypertensive patients with diastolic blood pressures of at least 95 mm Hg who had shown clinically relevant antihypertensive responses, but no normalization of blood pressure during pindolol 10 to 15 mg once daily as monotherapy. Either isradipine or placebo was added to the beta- blocker at doses of either 2.5 mg or 5 mg twice daily, which was doubled after four weeks if the diastolic blood pressure remained more than 90 mm Hg. The addition of isradipine (in either dose regimen) caused a pronounced reduction of blood pressure with no changes in heart rate. Five patients were withdrawn from the study because of adverse events while receiving isradipine compared with three taking placebo. A further three patients withdrew from the study because of adverse events (one patient) or lack of efficacy (two patients) during placebo treatment. These results indicate that isradipine is an effective and well-tolerated adjunct to beta-blockers in hypertensive patients.

I t has long been recognized that the major hemody- namic characteristic of established hypertension is

increased peripheral resistance [l]; one of the ac- cepted principles in the treatment of hypertension, therefore, is vasodilatation. However, most of the vasodilating drugs available are short of ideal, causing reflex tachycardia, fluid retention, and orthostatic hypotension [2].

The antihypertensive action of calcium antagonists was noted more than 25 years ago, but the clinical implications have only recently been recognized. The calcium antagonists, especially those of the dihydropyridine type, have been investigated in detail and appear to lower blood pressure through reduction of the increased systemic vascular resistance. Moreover, this is achieved without the disadvantages usually as- sociated with vasodilator therapy [3].

Isradipine, a new calcium antagonist of dihydropyridine type, is structurally related to nifedipine, but has a benzofurazanyl group in position 4 of the pyridine ring instead of a nitrophenyl group. In animal experiments, it selectively inhibits the sinus node but has no effect on atrioventricular conduction, and its negative inotropic action is minimal compared with that of nifedipine or diltiazem [4].

Isradipine is a powerful coronary vasodilator and also dilatates cerebral and skeletal muscle vascular beds in animal models [5]. In studies in human hypertensive patients, it has also been shown to signifi- cantly decrease arterial pressure without clinically significant reflex tachycardia [6].

It has recently been demonstrated that calcium antagonists have antiatherogenic properties in animal models as well as in viva [7]. With isradipine, this effect has been observed in cholesterol-fed rabbits in doses relevant to human use. When other calcium antagonists were investigated in this model, higher doses were necessary to produce a similar effect [8].

Thus, as isradipine has been shown to be a potent antihypertensive agent with interesting clinical properties, it was logical to study further its effect in combination with other antihypertensive drugs. The present study was designed to evaluate the efficacy, toler- ability, and safety of isradipine in various doses when given to hypertensive patients who had not achieved adequate blood pressure control during monotherapy with the beta-blocker pindolol.

From the Departments of Medlclne at Eskilstuna, Vaster&, Ostra Hospital, Goteborg, Jbnkoplng, Sweden, and Turku, Finland; and Department of Cllnlcal Cardiovascular Research, Sandoz Ltd., Easel, Switzerland. Requests for reprints should be addressed to the Department of Clinical Cardiovascular Research, Sandoz, Ltd.. Bulldmg 386/ 816, CH-4002, Basel, Swttzerland.

MATERIALS AND METHODS Patients

Eighty patients, 51 men and 29 women, with a mean age 54 years (range, 33 to 721, were included in the study. All had mild-to-moderate essential hyperten-

April 17, 1989 The American Journal of Medicine Volume 86 (suppl 4A) 115

SYMPOSIUM ON ISRADIPINE / FRITHZ ET AL

Placebo Placebo Placebo

Placebo lsradipine lsradipine

Week 0 3 7 11 15 19

Blood pressure, heart rate X X X X X X

Clinical examination X X X X X X

Laboratory tests X X X X X X

sion according to the World Health Organization de& nition. The criterion for inclusion was a supine diastolic blood pressure of greater than or equal to 95 mm Hg despite a prolonged treatment with pindolol at doses of 10 to 15 mg daily.

Design The study was of a double-blind crossover design

(performed at five centers) with two parallel groups, one receiving a low-dose regimen and the other receiving high doses (Figure 1). During a single-blind run-in period of three weeks, the patients were given placebo as additional therapy. This was followed by the eight-week active-medication period (phase I).

Patients in the low-dose group were given 2.5 mg isradipine or placebo twice daily for four weeks. If the diastolic blood pressure was above 90 mm Hg after that time (Week 7), the dose was doubled for another four weeks. Thereafter (Week ll), the patients received the comparative drug (placebo or isradipine) according to the previous treatment. During this part of the study (phase II), the given dose was again 2.5 mg isradipine or placebo twice daily, which was doubled after four weeks if the diastolic blood pressure was not less than or equal to 90 mm Hg (Week 15). After a further four weeks, the study ended (Week 19).

In the high-dose group, similar titration was performed, starting with an initial dose of 5 mg isradipine or placebo twice daily for four weeks, which could be increased to 10 mg twice daily after four weeks. After eight weeks, the patients were given the comparative drug (placebo or isradipine) and the same titration procedure was followed as before.

In both high- and low-dose groups, a reduction of the dose was allowed if patients experienced adverse events at the double-dose level. Pindolol, however, was maintained at a constant dose throughout the study.

Blood pressure (the mean of three readings) was measured in the supine position after five minutes at rest and after one minute in standing position, using a mercury sphygmomanometer with a cuff 12 cm wide. The diastolic blood pressure was recorded at the point at which the Korotkoff sounds disappeared (onset of phase V).

Routine laboratory tests and electrocardiography were performed at regular intervals throughout the study. Patients were observed and questioned for adverse events experienced during the run-in period as well as during the double-blind phase.

Figure 1. Study design was ldentlcal for patients allocated to either the low- or hlgh.dose regl- mens.

STATISTICS For evaluation of the efficacy of isradipine as an an-

tihypertensive agent in pindolol-treated patients, the following statistical methods were used: l Wilcoxon’s signed-ranks test for paired data was

used to compare the blood pressures and heart rates recorded at Weeks 7, 11, 15, and 19 with the baseline data recorded at Week 3.

l A crossover evaluation was performed for each blood-pressure and heart-rate variable. The time period and sequence were examined for significance in addition to the form of treatment, using the valid data from Weeks 11 and 19. Subsequently the high- and low-dosage regimens were compared, using all four treatment-sequence groups.

l A qualitative assessment of response to treatment was made, using a reduction of diastolic blood pressure to less than or equal to 90 mm Hg or a decrease of at least 10 mm Hg compared with the baseline value as variables.

RESULTS Forty patients each were randomly assigned to ei-

ther a low- and a high-dose group, starting with 2.5 mg or 5.0 mg isradipine, or placebo twice daily, respectively. Eight patients discontinued the study because of adverse events, five during active treatment with isradipine, and three receiving placebo. Another four patients were excluded due to protocol violation or other technical reasons. However, the data from these patients were included in analyses when appropriate.

Clinically and statistically significant reductions in blood pressure compared with baseline were achieved with the addition of isradipine to pindolol therapy. The reductions were evident at four weeks after com- mencement of isradipine therapy and increased in magnitude at eight weeks. No statistically significant changes were seen in phase I for the placebo-treated patients but, in patients receiving isradipine, there was a statistically significant reduction of blood pressure compared with baseline that persisted in phase II (placebo treatment) (Table I).

Crossover analysis of the active treatment including all patients compared with placebo showed highly significant reductions of systolic and diastolic blood pressures compared with placebo, but no significant differences between the two treatment regimens (Table II).

Categorical assessment of the response to isradipine treatment in terms of diastolic blood pressure

116 April 17, 1989 The American Journal of Medune Volume 86 (suppl 4A)


TABLE I

Reductions of Blood Pressure Compared with Baseline (Week 3)

Treatment and Twice-Daily Dose

Systoltc BP (mm Hg) 2.5 mg Is-Placebo

5.0 mg

Is-Placebo 2.5 mg Placebo-Is 5.0 mg Placebo-Is

Dlastollc BP (mm Hg) 2.5 mg Is-Placebo 5.0 mg Is-Placebo

2.5 mg Placebo.ls 5.0 mg Placebo-is

P = blood pressure; Is = mdlplne 3 401. I <O.OOl. 1 <o 05.

Week 7 Week 11 Week 15 Week 19

Mean Significance Mean Significance Mean Significance Mean Significance

-9.3 * -14.2 * -13 NS -4.2 NS

-194 t -24.2 t -11.9 -6.0 -20 E.z -4.8 ii: -11.5 -21.2 “i” -14 1.9 -14.7

i -15.8 t

-82 1 -12.1 -2.9 NS -4.7 * -128 -19.8

1 -11.5 * -7.8 *

-04 -3.5 -8.6 -14.9 -14

ii: -0.9

E -10.2

: -13.3

TABLE II

Crossover Analyses of the Active-Treatment Period Compared with Placebo for All Patients (n = 68)

Systolic BP [mm Hg) Low-dose group (2.5-5.0 b.1.d.) mg High-dose group (5 O-10.0 mg b.1.d.)

Dlastolk BP [mm Hg) Low-dose group (2.5-5.0 b.1.d.) mg High-dose group (5 O-10.0 mg b.1.d.)

D - hln*A n*“rr,,*n. I? ,A *,,,,,.,. A*,,,,

Mean Mean Mean lsradipine Placebo Difference

144.2 157.9 -13.7 145.4 163.5 -18.1

903 1001 -9.8 89.2 101.7 -12.5

Number of Patients

i;

35 33

Significance

* *

* *

reduction showed that 78 percent of the patients in the low-dose group and 87 percent of the patients in the high-dose group attained a supine diastolic blood pressure of less than or equal to 90 mm Hg or had the diastolic blood pressure decreased by at least 10 mm Hg from the baseline. The mean isradipine dose was 4.2 mg twice daily in the low-dose group and 7.5 mg twice daily in the high-dose group.

There were no statistically significant changes in heart rate during the study.

SIDE EFFECTS AND EXCLUSIONS Five patients discontinued the study while receiv-

ing active treatment with isradipine. Two patients, who had histories of migraine and tension headache, respectively, withdrew because of severe headache and nausea after taking initial doses of isradipine. One patient was withdrawn from the study two days after starting 5 mg isradipine twice daily due to headache and nausea, and the other experienced itching erythema on the arms while taking 2.5 mg isradipine twice daily. The remaining patient discontinued treatment after developing soreness and ulcerations of the lips while taking 2.5 mg twice daily. This adverse effect disappeared on cessation of therapy and reap- peared when the patient was rechallenged with the drug. Otherwise, the most frequently reported adverse events while receiving active treatment were flushing and edema (four patients each), but these

events did not cause withdrawal. No orthostatic reac- tions were observed.

Two patients were withdrawn from the study while receiving placebo therapy due to an increase in blood pressure according to the study protocol, and one patient discontinued because of erythema of unknown origin on the arms.

The clinical laboratory tests showed no significant abnormalities, with the possible exception of one patient who had a slightly raised serum alanine transfer- ase (serum glutamic pyruvic transaminase) level, which normalized 12 days after the patient had com- pleted the study. No significant changes of body weight occurred during the study.

COMMENTS Recently, several large-scale studies have drawn

attention to the fact that many patients receiving hypertensive treatment are insufficiently controlled, in- creasing the risks of cardiovascular complications [9,10]. Thus, drugs of high efficacy as well as the pos- sibility of combined treatment are mandatory in the treatment of hypertension”

In the present study, patients not adequately controlled on a standard dose of the potent beta-blocker pindolol achieved a clinically relevant reduction of blood pressure after the addition of the calcium antagonist isradipine to their treatment. The mean isradipine dose in the low-dose group was 4.2 mg twice

April 17, 1989 The American Journal of Medlclne Volume 86 (suppl 4A) 117


daily and 7.5 mg twice daily in the high-dose group. Since the patients were homogeneous and the target blood pressures were the same for all patients, this finding is not unexpected. After the initial treatment period, the dose was doubled so that patients who were only, for example 2 to 3 mm Hg above the target blood pressure received the double dose even though a further reduction in blood pressure may have occurred on the lower dose. In effect, the design of the study was such that the mean dose administered was invariably higher than the optimal therapeutic dose for patients who responded to the drug.

Furthermore, it is also important to note that there were only minor differences between the antihypertensive effects of the low- and high-dose regimens. Thus, this study demonstrates that isradipine is effective at low doses in combination with pindolol and there is usually no need to increase the dose to over 5 mg twice daily.

No increase of body weight was observed, indicat- ing that there was no fluid retention, which is a com- mon adverse effect seen with vasodilators. This may be explained by the diureticlnatriuretic effect shown for isradipine as well as for several other calcium antagonists of the dihydropyridine type [ll]. It is worth mentioning that there was no ankle edema, sometimes seen in patients treated with calcium antagonists and caused by a generalized fluid and electrolyte retention.

The principal side effects, flushing and erythema, are not unexpected in treatment with a potent dihydropyridine calcium antagonist, and were moderate. Only five patients receiving isradipine were discontinued from the study because of adverse events versus three taking placebo.

In addition to demonstrating the efficacy of the

combination of isradipine and the beta-adrenoceptor antagonist pindolol, these findings are of importance in that they demonstrate that combined administra- tion of effective therapeutic doses of the two drugs produced the desired therapeutic response without adverse drug interactions, in particular, no car- diodepression. This confirms the results obtained in animal experiments where no additional negative inotropic or chronotropic effects were observed when isradipine was administered to animals pretreated with pindolol 1121.

REFERENCES 1. Frers ED: Haemodynamlcs rn hypertension Physrol Rev 1960: 40: 27-54. 2. Tararr RC, Dustan HP, Bravo EL, Nrarchos AP: Vasodllatlng drugs. contrastrng haemody- namrc effects Clan SCI Mel Med 1976: 5 ku~ul 31: 575S-5788 3. Gould DA, Hornung RS, Mann S, Balasubramanram V, Raftery EB, Slow channel rnhlbr- tons verapamil and nrfedrprne rn the management of hypertension. J Cardrovasc Pharmacol 1982; S269-S273. 4. Hof RP Comparrson of cardrodepressant and vasodllator effects of PN 200-110 (IS- radrprne), nifediprne and dlltlazem in anesthetized rabbrts. Am J Cardrol 1987; 59: 37B- 428. 5. Hof RP. Hof A. Scholtvsik G. Mennrnaer K: Effects of the new calcium antagonist PN ZOO.110 on the myocardrum and the regronal peripheral crrculatron rn anestheized cats and dogs. J Cardiovasc Pharmacol 1984; 6: 407-416 6. Hamrlton BP: Treatment of essential hypertension with PN 200-110 (rsradrpine) Am J Cardrol 1987: 59 141B-145B. 7. Parmley WW, Blumlern S, Lrevers R: Modrflcatron of experimental atherosclerosis by calcrum channel blockers. Am J Cardrol 1985; 55: 1658-1718 8. Habrb JB, Bossalle C, Wells S, Wrllrams C, Morrrssett JD, Henry PB Preservation of endothelrum dependent vascular relaxation rn cholesterol fed rabbrts by treatment wrth the calcium blocker PN 200-110. Circ Res 1986: 58: 305-309. 9. Lrndholm L: Hypertension and Its rusks. Eprdemrologrcal studies in Swedrsh prrmary health care (the%). Sweden: Unrversrty of Lund, 1984. 10. Isles CG, Walker LM. Beevers GD, et a/. Mortality in patrents of the blood pressure cl~nrc. J Hypertens 1986; 1, 141-156. 11. Krusell LR. Tang Jespersen L. Schmitz A, Thomsen K. Lederballe Pedersen 0: Repeth tive natriuresrs and blood pressure. Long-term calcium entry blockade with rsradrprne. Hypertension 1987; 10: 5U-581. 12. Hof RP: Interactjon between two calcium antagonrsts and two beta-blockers rn con- scrous rabbrts: hemodynamlc consequences of drfferrng cardrodepressant properties Am J Cardrol 1987: 59: 43B-51B

118 Aprrl 17. 1989 The Amerrcan Journal of Medicroe Volume 86 (suppl 4A)

improved blood pressure control with isradipine in hypertensive patients treated with pindolol

Documents