Isradipine therapy in chronic stable angina pectoris - comparison with nifedipine

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1 European Heart Journal (1991) 12, sradipine therapy in chronic stable angina pectoris - comparison with nifedipine P. CURRE AND S. SALTSS Department ofcardiology, Royal Liverpool Hospital, Liverpool, U.K. KEY WORDS: sradipine, nifedipine, calcium channel blocker, angina pectoris. Current available calcium antagonists, although useful in angina pectoris, are often poorly tolerated. We therefore compared isradipine, a new calcium antagonist, with nifedipine in 18 patients with angina. Patients sequentially received incremental doses ofeither isradipine (S) 2,5-7,5 mg three times daily or nifedipine (NF) mg three times dailyfor 6 weeks each, in a randomizeddouble-blind crossover study. Both agents producedsimilar (P= 0,43) increases in maximum exercise duration (S + 30%,. N F+34%) and an equivalent (P = t):38) increase in time to onset of angina on exercise (S+53%; NF+62%). Both S and NFsignificantly reduced exercise-inducedstdepression (-40% and -45%) to a similar degree (P=0 48). NF significantly (P=0'019) reduced angina attacks (-3'0 attacks.week-; 26%) compared to S (-0'4; 4%) whilst a similar but non-significant trend in favour of NF was also apparent in the consumption of sublingual glyceryl trinitrate (-0-1 tablets.week:', 2% vs +1 3.week- 1 ; 23%; P=0 28). However, significantly (P < 0,03) more patients experiencedadverse events whilst taking NF than with S (36 events in 16/18 (89%) v 18 in 9/18 (50%). Thus, S and NF increased exercise tolerance and reduced exercise angina and STdepression equally well although NFuse was associated with fewer anginal episodes and S withfewer side effects. ntroduction Calcium channel antagonists can effectively replace or supplement beta-blockers in the treatment of chronic stable angina pectoris'!'. A number ofcalcium antagonists are currentlyavailablebutalthoughoftenefficacious their use may be limited by negative inotropism, reflex sympathetic tachycardia and/or unacceptable vasodilatory side effects. sradipine, (S, Ciba-Geigy Pharmaceuticals) is a new dihydropyridine calcium antagonist which has been shown to be both devoid ofcardiodepressant effects at therapeutic doses and to produce relatively selective vasodilatory effects without substantial reflex tachycardia[2,3j. Potentially beneficial anti-arteriosclerotic features have also been noted with S in animal studies'". Favourable anti-anginal effects have been demonstrated using S in comparison with placebo, nifedipine (NF) and isosorbide dinitrate but these results were reported on an interim analysis'". Other studies have also compared S with NF in angina pectoris but only small numbers ofpatients were studied'?', The aim of this study was to assess the clinical value of S in terms of its safety, tolerability and anti-anginal efficacy when compared with NF in patients with coronary artery disease and stable exercise-induced angina pectoris. t was not intended to assess myocardial ischaemia by objective means and hence a current positive exercise test was not required as an entry criterion. Nonetheless, the degree ofst segment change was analysed. Submitted for publication on 19May 1989and in final revised form 5 October Correspondence: Dr Peter Currie, Department of Cardiology,Western General Hospital, Crewe Road, Edinburgh EH4 lxv, Scotland. Methods ETHCAL CONSDERAnONS The protocol was reviewed by the hospital ethical committee and all patients gave informed written consent. The study was conducted according to the revised Declaration of Helsinki. PATENTS The intention was to recruit a minimum of 30 patients aged 18 years or over using very stringent criteria to try and ensure homogeneity. For inclusion, a history of at least 3 months' stable exercise-induced angina was necessary. Objective evidence of coronary artery disease was also required in the form ofat least one of the following: (1) Previous documented myocardial infarction; (2) Angiographic demonstration of a significant stenosis (> 60%) in at least one major coronary artery; (3) Clearly positive (at least -0,2 mv horizontal or downsloping ST depression) exercise tolerance test; (4) Diagnostically positive rest or exercise thallium-201 scan. Patients were excluded from entry to the study by any one of the following: (a) Women of child-bearing potential; (b) Non-cardiac causes of chest pain e.g hiatus hernia; (c) Myocardial infarction within 3 months; (d) CABG within 6 months; (e) Other disease limiting exertion; (f) Electrocardiographic conduction defect; (g) Uncontrolled hypertension; (h) ntolerance of sublingual glyceryl trinitrate (GTN); (i) Serum creatinine > 177 llmol.1- l ; U) Elevated serum liver transaminases. Furthermore, patients only progressed to the active treatment period if they had at least eight anginal attacks during the 2-week placebo run-in period and were restricted by angina pectoris inside 10 min on exercise testing at X/91/ $03.00/0 1991The European Society of Cardiology

2 808 P. Currie and S. Saltissi Weeks0 2(2a} r + S S S 7'5mg 7'5-15mg 7'5-22'5 mg caps 3-6 caps 3-9 caps NFplacebo NF placebo NFplacabo SpiKebo S placebo 3 caps 3 caps caps 3 caps NF placebo NF placebo.,, r NF NF NF 30mg 3O-6Omg»9Omg caps 3 caps 3 caps S placebo Spiacabo Spacabo NF NF NF S S S 30mg 3O-6Omg 3O-90mg Hmg 7'5-15mg 7'5-22'5mg ' ' caps 3 caps 3 caps 3 caps 3-6 caps 3-9 caps SplKebo Spiacabo S placebo NFpKebo NFplacabo NF p18cabo Placebo run-n First active phase Placebo wash-out Second active phase Figure 1 sradipinecompared with nifedipine in stable angina pectoris: drug dosage regimen. week 2. Entry to active therapy was also prohibited by poor drug compliance (>20% missed placebo capsules), or excessive weekly variation (> 75%) in anginal attacks, (although a third week on placebo (2a, Fig. 1)was allowed in order to achieve this). Prophylactic anti-anginal medication, other than the study drugs, was prohibited during the study as were vasodilators, digoxin, psychotropic drugs and any drug with an action on the sympathetic nervous system. STUDY DESGN t was a randomized, NF controlled, double-blind crossover study, incorporating a 2-week single-blind placebo run-in period and an intermediate -week placebo wash-outperiod(fig. 1).The trial drugs were administered using a double-dummy technique. nitially, patients were randomized to either S 2 5 mg tds plus placebo NF or NF 10mg tds plus placebos. Dosageswere increasedin three steps at 2-weekly intervals to a maximum of 7 5 mg tds (22'5 mg daily) for S and 30 mg tds (90 mg daily) for NF, depending on angina frequency and/or adverse reactions. After the placebo wash-out period (week 9), patients crossed over to the alternative treatment regimen for a further 6 weeks. CLNCAL EVALUATON At each visit, patient diaries were studied for angina frequency and sublingual GTN consumption. Drug compliance was also assessed by tablet count and any adverse reactions or changes in concomitant medication were noted. A full physical examination was made at the start and finish of each drug period when estimations of haematology, serum biochemistry and urinalysis were also performed. EXERCSE TOLERANCE TEST At all visits except week 1, a maximum, symptomlimited, treadmill exercise tolerance test (modified Bruce protocol) was performed using a Marquette Case computerized system. Whenever possible, stress-tests were performed by the same investigator, at the same time of day, 2 h after a light meal and between 2-3 h after the last dose of trial drug. Patients were asked to refrain from smoking or consuming GTN for 2 h before exercise. Total exercise duration and time to onset of angina were the principal variables but heart-rate, blood pressure and ST segment depression, (leads, avf and V5' 80 ms after the J point), were also measured at the end of each exercise stage, at the onset of angina and at maximum exercise. Both the maximum ST depression and the sum of ST depression in all the recording leads were recorded at these three points in the test. ADVERSE EVENTS At each visit patients were asked to volunteer any adverse reactions or new symptoms and were then specifically questioned about a predetermined list of symptoms. Positive responses from both types of questioning were summated for comparison of adverse events between drugs. STATSTCAL METHODS Background data were carefully inspected to identify any imbalances between patient groups which may have affected efficacy or safety analyses. However, a formal statistical comparison was not made on entry since patients had been randomly allocated to the treatment groups. Analyses of covariance for a crossover study design were used to assess comparative efficacy between treatment groups with regard to changes in exercise data and angina diary data, and in this analysis only patients who completed the entire protocol were included. The significance of within-treatment changes was examined using Student's paired t-test. The same techniques described for assessing efficacy were also used to evaluate changes in blood pressure and heart rate. All changes in laboratory values relative to the baseline were compared using the Sign test. The 'baseline' was the initial visit if the treatment was received first, or the end of

3 S therapy in chronic stable angina pectoris 809 Table J lsradipine compared with nifedipine: patient withdrawals Reason for leaving study Patients Drug phase at withdrawal NF S Protocol violators 4 1* 1* Headache Unstable increased angina 3 2 Myocardial infarction Miscellaneous 3 2 Total Two patients who violated protocol were withdrawn after completing the study. Table 2 sradipine compared with nifedipine: resting haemodynamics Change- in systolic BP Change in diastolic BP Change in heart rate S (P=O'02) -8 5 (P=O'OO4) -1 8 (PO'5) NF -14,0 (P=O'OO) -7'5 (P O'004) +4 1 (P=O') BTS (P=0'5) (P=0 8) (P-O') BTS=Significance of between treatment difference; Changes are relative to results on placebo; BP=blood pressure (mmhg). the first treatment period if the drug was received in the second treatment period. Fisher's Exact probability test was used to assess the significance of between-treatment laboratory abnormalities. When evaluating adverse reactions, all study patients were analysed regardless of whether they completed the entire protocol. The number of patients reporting adverse events during each treatment were compared using Fisher's Exact probability test. Results BACKGROUND DATA Thirty-four patients (mean age 57 years, range 40-73) entered the randomized phase of the study, but of these only 18 completed the entire protocol and efficacy analyses were restricted to this group. Ten of these 18 patients had previous myocardial infarction (nine patients) or diagnostic coronary angiography (three patients) but in 8;18 patients the diagnosis of coronary disease was based only on > 2 mm of significant ST depression on exercise'" or a positive thallium scan'". Details ofthe 16withdrawals are given in Table 1. RESTNG HAEMODYNAMCS Resting systolic and diastolic blood pressure were significantly reduced by both S and NF, with no significant difference between the treatments (Table 2). However, no significant change in resting heart rate from baseline (mean 74 b.min ) was noted with either drug. EXERCSE TESTNG Maximum exercise The maximum treadmill exercise duration (baseline on placebo 331± 30 s, mean ± SEM), increased to 432± 43 s Q> oj> 30 0 Q> '0 c g :; Moxirnurn exercise Angina onset Figure 2 Maximum exercise duration and time to onset ofangina in patients (n 018) undergoing treadmill exercise testing during treatment with isradipine (), nifedipine (1111) or placeco (L:); *P<O O. (+30% (P=0'002) with S and 4441:46 (+34% (P < » with NF and crossover analysis did not reveal a significant difference between the treatments (P = 0-43) (Fig. 2). Systolic blood pressure (BP) at the exercise end-point (baseline, mean 162 mmhg) fell during treatment with both S and NF (-15 and 10 mmhg respectively) with no significant difference in their hypotensive effects (P =O 39). A fall in diastolic BP (baseline mean 84 mmhg) was also noted with S and NF at maximum exercise ( - 7 mmhg and - 8 mmhg, respectively) and again these

4 810 P. Currie and S. Saltissi Table 3 sradipine compared with nifedipine: ST depression on exercise Placebo sradipine Nifedipine Maximum STD (mm) Sum ofstd (mm) 0 9± ± ±0 3 (P=0 23) 1 2±0 5 (P=O'O) 0 6±0 3 (P=0'13) 1 1±0-4 (P=O'O) STD = ST depression (mean +SEM) at the end of the same final stage of exercise completed on all three treatments. changes were equivalent (P= 0'79). The mean heart rate Table 4 Adverseevents with isradipine or nifedipine (n=34) at peak exercise (baseline 124 b.min -) showed little change with either S (- 1 b.min -) or NF (no change), S NF and small reductions in baseline double product (mean mmhg.min-) with the two agents (-1654mmHg.min- 1 ; 8% and -715 mml-lg.min" '; 3%, respectively) were of a similar order (P= 0,32). Angina onset The time to angina onset (baseline on placebo 204±33s) increased to 311±40s (+53% (P=0 003)) with S and 330±45 s (+62% (P=0'005)) with NF (Fig. 2). These changes were not significantly different from each other (P=0 38). Systolic BP at angina onset (mean baseline 157 mmhg) fell during treatment with both S (- 12mmHg) and NF (- 9 mmhg) and these effects were not significantly different (P=0 52). A fall in diastolic BP at angina onset (baseline mean 87 mmhg) was also noted with S and NF (both - 8 mmhg). Changes in baseline heart rate (mean 116 b.min") at angina onset with S and NF were also equivalent (-3 and + 3 b.min -, respectively; P = 0,12). STsegment change Since each patient achieved a different maximum exercise time in each phase of the trial, the degree of ST depression was compared at the same point in time on exercise during treatment with placebo, S and NF - the end of the same maximum stage ofexercise completed by each patienton all three treatments. n this analysis (Table 3), the sum of ST depression in leads, avf and V5 was significantly reduced when patients were taking S (-40%) or NF (-45%) with no between-treatment difference (P= 0,48) and the maximum ST depression at this point tended to be lower (NS). At the exercise end-point on placebo, S or NF, there was no difference in maximum ST depression (-'±0'6mm vs -1 1±0 8 vs -1 0±0 3; mean } SEM) or sum of ST depression (-2-4± 0 6 mm vs -2 4±0 7 vs -1 9±0 6 (P=0'14)) respectively. ANGNA DARES The crossover analysis showed that the mean weekly baseline anginal frequency (11,4 attacks.week" ') was reduced significantly more (P=0 019) by NF (8,4 attacks.week" ': -26%) than with S (11'0 attacks.week- ; -4%). Weekly GTN consumption (baseline mean 5 2 tablets. week-) during NF therapy also tended to be lower than with S (5,1 tablets.week":'; Central nervous system *Dizzy/light-headed 3 10 *Headache 4 16 Others 6 11 Cardiovascular system Unstable angina 2 Myocardial infarction 2 2 "Palpitations 3 3 "Peripheral oedema 2 2 Others Gastro-intestinal system Nausea/vomiting 2 4 Constipation 0 Others 0 3 Miscellaneous Musculoskeletal 3 3 *Flushing 2 3 Dyspnoea 0 Total *Presumed vasodilator effects. -2% vs 6 4 tablets.week- ; +23% respectively), although this difference did not reach significance (P=0 26). SAFETY AND ACCEPTABLTY Laboratory data There was a significant (12%) increase in blood urea compared to the baseline during NF administration in those patients receiving the drug in the first phase (P = 0,002). Although this was significantly more than during treatment with S (P=0'007) it was not considered clinically important. n fact, a 2% drop in blood urea (not significant) was noted during treatment with NF in the second phase. One patient had elevated serum alanine aminotransferase (47 U.l-, normal <45) and aspartate aminotransferase (78 U.l-, normal <41) during treatment with S which returned to normal after second-phase NF therapy. Adverse events n order to optimize symptom control, drug dosages used in this study were intentionally titrated where necessary to levels at the upper end ofthe recommended range.

5 S therapy in chronic stable angina pectoris 811 Table 5 (n=34) sradipine compared with nifedipine: relationship ofdrug-dose to incidence ofside effects This necessitated mean daily doses at the end of each active phase of 19 2 mg (S) and 63 9 mg (NF). Fifteen patients (68%) received the maximum allowable dose of S (22'5 mg daily) but only 12 (53%) would tolerate maximum NF drug dosage (90 mg daily). Significantly morepatients (P = 0,015) receiving at least one dose of either drug had adverse reactions whilst taking NF (26/29 patients; 90%) than when taking S (17/ 29; 59%) although withdrawals due to adverse events wereequal on the two drugs (Table 1). Similarly, in the 18 patients completing the drug trial, side effects were significantly (P < 0,03) commoner with NF (36 side effects in 16/ 18patients (89%) vs 18in 9/18 (50%) on S). n all, 29/34 patients (85%) reported an adverse drug reaction, NF therapy being associated with twice as many side effects as S (61 vs 30 vs 14 on placebo) (Table 4). Both gastrointestinal complaints (8 vs 2) and in particular, the vasodilatory side effects of headache and dizziness (26 vs 7) were more frequent on NF. Adverse events were more common whilst taking NF irrespective of the drug dose and often occurred with the lowest dose of each drug (Table 5). Four patients underwent acute myocardial infarction during the study (two each on NF and S) and three others had increased or unstable angina (two S; one NF). Discussion sradipine (S) is an interesting new dihydropyridine calcium channel antagonist which has recently been licensed for use in hypertension. n animal studies, it appears to behave somewhat differently from nifedipine (NF). S produces relatively selective blockade ofcalciuminduced vasoconstriction in the coronary, skeletal and cerebral vascular beds but with little accompanying reflex tachycardia due to simultaneous inhibition of the sinus node'". S also produces very little effect on the P-Q intervall'l and its use may not therefote be restricted by the presence of atrio-ventricular block or concomitant beta-blockade. S lowers myocardial oxygen consumption by reducing afterload and in contrast to currently popular calcium antagonists does not demonstrate negative-inotropic properties'" ndeed, there is haemodynamic evidence supporting a potential role for S in the treatment ofheart failure[81. n the present study S was compared to NF in 18 patients selected to have exercise limitation by typical angina pectoris. Only three of these patients had angiographic proof of underlying coronary artery disease, but all the others had at least one strict alternative diagnostic criterion making the diagnosis ofcoronary artery disease highly likely. n these patients, treatment with NF was associated with fewer episodes of angina than S, although the two drugs had similar effectiveness in prolonging exercise, delaying angina onset and reducing ST depression during exercise testing. S was better tolerated than NF and was associated with fewer side effects of all types, but particularly vasodilatory ones. This difference was apparent even in the lower dosage ranges which are of the order commonly used in clinical practice. The lesser efficacy of S compared to NF in reducing angina during daily activities (cf diaries) contrasts with the equal effectiveness of the two drugs in improving objective exercise test performance, and in particular in increasing objective time to onset of exercise-induced angina. This discrepancy is difficult to explain but may relate to the better tolerance by patients ofs. tis possible that side effects whilst on NF (which occurred in 90% of subjects) may have resulted in the patients being less active when on that drug so reducing the chance ofdeveloping angina whilst their relative sense ofwell being on S may have allowed them to exercise moreand hence induce a greater number ofangina attacks. AlthoughNFappearsto be a moreeffectiveanti-anginal drug, the superior toleranceofs suggests that it may find a place as an alternative agent in patients intolerant of NF. The occasional reversible elevation of liver transaminases during treatment with S requires that liver function tests should be monitored in patients taking the drug and S should probably be avoided in the presence of known hepatic damage. We wish to thank Y. Tsao for her excellent technical work and R. Eldon and M. Barber (Sandoz Pharmaceuticals) for their support throughout the study. We acknowledge D. J. Nelson (Data Analysis and Research Ltd) and P. C. Ruegg for their preparation and review respectively of the statistical report. References [1] Lynch P, Dargie H, Krikler S, Krikler D. Objective assessment of anti-anginal treatment: a double blind evaluation of'propranolol, nifedipine and their combination. Br Med J 1980;281:

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