Comparison of Nicorandil and Atenolol in Stable Angina Pectoris

Liam 0. Hughes, MD, Edward L. Rose, MRCP, Avijit Lahiri, MSc, MBBS, and Edward 6. Raftery, MD

The efficacy of nicorandil was compared with aten- 0101 in 37 patients with chronic stable angina using a randomized, placebo-controlled, parallel study de- sign. After a single-blind placebo phase, patients were randomized to receive nicorandil or atenoloi using a double-dummy technique. Patients took ni- corandil 10 mg twice daily or atenoloi 50 mg once daily for the first 3 weeks, and if no adverse effects were encountered they took nicorandii 20 mg twice daily or atenolol 100 mg once daily, for the final 3- week phase. Treadmill exercise tests were per- formed at the end of each treatment phase immedi- ately before and 2 hours after the morning dose of medication. Groups were demographically similar. Placebo exercise times were 7.06 (0.60) minutes (mean f standard error of the mean) in the nicoran- dil group and 6.81 (0.47) minutes in the atenolol group. After 6 weeks, improvements in exercise time were before dosing: +1.47 (0.40) minutes with nicorandii (p <O.OOS) and +1.33 (0.29) min- utes with atenold (p <O.OOl). Improvements after therapy was administered were +2.45 (0.41) min- utes with nicorandil (p <O.OOl) and +2.37 (0.43) minutes with atenolol (p <O.OOOl). Whereas, the predose peak exercise double product (heart rate X

systolic blood pressure mm Hg/lOO) was reduced with atenolol (-43.6 units; p <O.OOl), an increase (+7.66 units; difference not significant) was noted with nieorandii. One patient taking atenolol and 5 taking nicorandil developed persistent headaches. One subject with severe 3-vessel coronary artery disease had fatal myocardial infarction within 3 days of starting nicorandfl, 10 mg twice daily. Ni- corandii and atenolol produce comparable improve- ment in exercise time in patients with stable angina but the former does not reduce myocardial oxygen demand. This new agent may be beneficial in pa- tients with angina in whom B blockers are contra- indicated, although headache may be a problem in a significant minority of patients.

(Am J Cardioi lSSO;66:679-662)

From the Department of Cardiology, Northwick Park Hospital & Clin- ical Research Centre, Watford Road, Harrow, Middlesex, United Kingdom. Manuscript received February 20, 1990; revised manuscript received and accepted May 8, 1990.

Address for reprints: Edward B. Raftery, MD, Northwick Park Hospital & Clinical Research Centre, Watford Road, Harrow, Middle- sex, United Kingdom.

icorandil N is a new antianginal drug that has been shown in animals and humans to have po- tent vasodilating and antispasmodic properties

which may be relatively selective to the coronary arter- ies.’ 3 The compound enhances potassium transport across cellular membranes415 and also contains a nitrate moiety. Despite the fact that nicorandil is a nitrate es- ter, its cardiovascular action differs from nitroglycerin in several respects. In particular, it has little effect on cardiac output, arterial blood pressure and pulse pres- sure.2 Early studies indicate that tolerance is less likely than with standard nitrate preparations.5,6 An increase in both cyclic guanosine monophosphate’ and released prostacyclin from vascular microsomes* have also been reported, which suggests other mechanisms of coronary vasodilation. The half-life of 6 to 8 hours permits twice- daily dosage, and total-daily dosages between 10 and 40 mg have been effective in patients with chronic stable angina.9-” To assess the clinical efficacy and the anti- ischemic properties of nicorandil, it was compared with the proven cardioselective p blocker atenolol’“-l4 in pa- tients with chronic stable angina.

METHODS Patients: Thirty-seven patients (35 men, 2 women)

with angiographically proven coronary artery disease (21 vessel with >70% luminal diameter stenosis) and stable angina1 symptoms for a minimum of 6 months were studied. Strict inclusion criteria were applied that required the development of reproducible angina dur- ing treadmill exercise, associated with a minimum of 1 mm ST-segment depression measured 80 ms after the J point. Patients with recent myocardial infarction (<3 months) labile ST/T-wave syndrome, hypertension (> 170/100 mm Hg) or those with angina due to valvu- lar disease were excluded as were women of childbear- ing age. All cardiovascular drugs (except sublingual ni- troglycerin) were withdrawn 14 days before trial entry.

Trial design: The trial consisted of 3 phases (Figure 1). An initial, single-blind placebo assessment was per- formed in all subjects. This comprised a baseline exer- cise test and 1 week of placebo (2 capsules twice daily in identical form to the later active medication) fol- lowed by 2 further tests: 1 before the trial morning dose of placebo and one 2 hours later. Patients exhibiting >20% variability in exercise time between these 3 tests were excluded. Those fulfilling the entry criteria were randomized into 2 groups to receive nicorandil (10 mg twice daily for 3 weeks followed by 20 mg twice daily for 3 weeks) or atenolol (50 mg/day for 3 weeks fol-

THE AMERICAN JOURNAL OF CARDIOLOGY SEPTEMBER 15, 1990 679

TABLE I Demographic and Anthropomorphic Details of the Two Patient Groups

Nicorandil (n = 19) Atenolol (n = 18)

Age (years) 61 (range 51-70) 61 (range 44-70) Male/female 19/o 16/2 Previous MI 7/19 7/18 Smoker 1 current 3 current

12ex 12ex Height (cm) mean f SD 173 (7.0) 170 (8.1) Weight (kg) mean f SD 77 (9.6) 72 (6.8) Duration of symptoms (mo) 79 (range 6-260) 41 (range 6-180)

ex = ex smoker, MI = myocardial Infarction; SD = standard deviation.

lowed by 100 mg/day for 3 weeks). Tests were per- formed at the end of each phase before and 2 hours after the morning dose.

Exercise testing: Exercise testing was performed at the same time each morning (0900 to 1100 hours) in a temperature-controlled laboratory according to Amer- ican Heart Association regulations.15 Patients were asked not to smoke or to take sublingual nitroglycerin on the morning of their tests. Maximum symptom-lim- ited graded treadmill exercise testing was performed on a motorized treadmill linked to an on-line computer analysis system (Case I-Marquette Electronics Inc.) us- ing continuous monitoring of bipolar leads CM5 and CC5. In each patient the lead showing the greatest ST change was identified and used in all subsequent tests to determine the time to 1 mm of ST depression. A modi- fied Chung protocol was used as previously described.i6 The computer provided digital measurement of the ST- segment level to an accuracy of 0.1 mm measured 80 ms after the J point or one-eighth of the RR interval, whichever was shorter. Systolic blood pressure was re- corded by sphygmomanometer every 3 minutes during exercise and the results entered into the computer.

Subjective improvement in symptoms was monitored by patient diary cards.

Statistical analysis: Treadmill test times to peak ex- ercise, time to angina and time to 1 mm ST depression

were analyzed by survival techniques with log rank sta- tistics to compare treatments. Heart rates and blood pressures were compared using t tests and differences from day 8 were used.

The study was approved by the hospital ethics com- mittee and all patients gave written consent.

RESULTS Thirty patients completed the trial. One patient with

severe 3-vessel coronary artery disease had fatal myo- cardial infarction on the third day of active treatment with nicorandil. An additional 6 patients withdrew be- cause of persistent severe headaches (5 nicorandil, 1 atenolol). In those who completed the study, all had their doses increased to the maximum without signifi- cant adverse effects, except 1 patient taking atenolol who developed a resting bradycardia <50 beats/minute with 50 mg. The demographic details of the 2 groups are listed in Table I.

Exercise time: Changes in exercise time, time to an- gina and time to 1 mm ST depression are shown in Fig- ure 2. Predose exercise time increased from 7.06 (0.60) (mean f standard error of the mean) minutes with pla- cebo to 8.53 (0.74) minutes with nicorandil 20 mg (difference 1.47 [0.40] minutes [p <O.OOS]). With aten- 0101 100 mg, the increase was from 6.81 (0.47) to 8.14 (0.57) minutes (difference 1.33 [0.29] minutes [p <O.OOl]). Postdose exercise time increased from 7.32 (0.59) to 9.77 (0.65) minutes with nicorandil (differ- ence 2.45 [0.41] minutes [p <O.OOOl]) and from 7.12 (0.46) to 9.49 (0.62) minutes with atenolol (difference 2.37 to.431 minutes [p <O.OOOl]). Time to 1 mm ST depression and time to angina increased both before and after administration of nicorandil and atenolol when compared with placebo times (Figure 1). There were no statistical differences between the magnitude of im- provement in the 2 treatment groups.

Heart rate and blood pressure: Differences in the change of heart rate and blood pressure between the 2 drug treatments are shown in Figure 3. Compared with placebo, predose resting heart rate decreased 1.42 (3.08) beats/min with nicorandil and 19.72 (2.77)

Dl D8 D29

I Nicorandil f 1 Omg bd

7

D50

I Nicorandil 20mg bd

i

Placebo

GkT (0900) (0900) \

Atenolol A 50mg bd ,

Atenolol 1 OOmg bd A

I I

- - ) = Final dose for each phase

I

FIGURE 1. Trial design showing parallel study after si*-blind placebo phase. D = day; GXT = graded ex- ercise testing.

660 THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 66

beats/min with atenolol-a highly significant difference between treatments (p <O.OOOl). Peak exercise heart rate increased 3.33 (2.25) beats/min with nicorandil and decreased 16.56 (4.08) beats/min with atenolol (p <O.OOOl). Predose resting systolic blood pressure de- creased 3.36 (4.67) mm Hg with nicorandil and 6.89 (3.62) mm Hg with atenolol (difference not significant). Relative to placebo, maximum systolic blood pressure increased 1.67 (5.23) mm Hg with nicorandil but de- creased 17.50 (4.23) mm Hg with atenolol (p <O.OOl). The predose peak exercise double product (maximum heart rate X systolic blood pressure mm Hg/lOO) in- creased by 7.56 units with nicorandil compared with a significant decrease of 43.6 units with atenolol (p <0.0001).

The incidence of severe headache was 5 of 19 in the nicorandil group, and an additional 6 patients had mild, transient headaches. The frequency of angina1 attacks decreased with both drugs, from 4 to 2/week with nico- randil and from 5 to 2/week with atenolol. Glyceryl trinitate consumption decreased from 4 to l/week with nicorandil and from 2 to l/week with atenolol.

DISCUSSION Despite the availability of numerous drugs to treat

patients with chronic stable angina, the negative inotro- pit and chronotropic effects of p blockers and some cal- cium antagonists and the problem of tolerance with

chronic nitrate therapy justifies the search for new ef- fective agents. Nicorandil is a new drug that augments potassium transport across cell membranes,h causing va- sodilatation, and also contains a nitrate moiety. The drug has been shown in animal and human studies to possess potent vasodilating properties.1-3 The efficacy of nicorandil was compared with the p blocker atenolol which has proven value in chronic stable angina.12-I4 The statistical power of the study was low and proving equivalence in the efficacy of the 2 treatments on the basis of our results was considered unlikely. However, the demographic similarity of the 2 patient groups en- abled comparisons of the mode of action of the 2 drugs to be made.

The principal aim was to examine the relative bene- fits of nicorandil (20 mg twice daily) with a commonly prescribed dose of atenolol (100 mg/day). However, a lower initial dose with an increase after 3 weeks of ther- apy was included in the protocol to minimize the inci- dence of adverse effects in the initial treatment phase. Exercise testing was performed at the same time of day (0900 to 1100 hours) for each patient and only those with reproducible angina were included. The double- dummy medication format ensured that both patient and investigator were blinded during the active treat- ment phases. By these means, observed changes were highly likely to be due to drug effect rather than spuri- ous influences.

FIGURE 2. Mean f standard error of the mean (bars) changes in exercise time, time to angina and time to 1 mm ST de- pression, before and 2 hours after nico- randil20 mg or atenolollO0 mg. Changes with respect to end placebo (day 8) are shown. No statistically significant (NS) dif- ference between the 2 drug treatments was found.

FIGURE 3. Mean f standard error of the mean (bars) changes in rest (R) and exer- cise (Ex) heart rate and systolic biood pressure (SBP). Changes with respect to end placebo (day 8) are shown. Statistical dims between the 2 treatment groups are shown. **p = <O.OOl; ***p = <0.0001; NS = not significant.

Pre-dose 0 Nicorandil

2 hours post dose

3.07 El Atenolol -t-T All NS

d -‘” Exercise Angina Imm ST Exercise Angina Imm ST

Change in heart rate Change in SBP @pm) @n-W)

*** Ex ***

Ex

O-

-10- 73 NS

-2o- R

17 Nicorandil q Atenolol

NS R

Pre dose 2 hrs post-dose

Pre dose 2 hrs post-dose

THE AMERICAN JOURNAL OF CARDIOLOGY SEPTEMBER 15. 1990 681

Both drugs produced comparable improvement in exercise time before and 2 hours after the final morning dosage, and the more objective index of ischemia (time to 1 mm ST depression) also showed significant and comparable improvement. The increase in exercise time with nicorandil, 20 mg, was similar to that described by Hayata et al9 in patients who exercised 30 minutes after receiving an identical oral dose. However, in our study patients were assessed at the end of a 6-week treatment period, which suggests that an attenuation of antiisch- emit effect may not be present with nicorandil. The im- provement in exercise time in the atenolol group was also comparable to those previously described in similar patients. The significant and comparable improvement in exercise time before the morning dose of medication with both drugs indicates that nicorandil, 20 mg twice daily, is as effective as atenolol, 100 mg once daily, in providing 24-hour antiischemic benefit to patients with stable angina.

However, the mechanism of action of the 2 drugs, inferred by the hemodynamic changes, were different. Atenolol improved exercise time by reducing the exer- cise heart rate and systolic blood pressure, thus reducing myocardial oxygen demand at all work loads. Nicoran- dil did not reduce the predose peak exercise double product, and peak oxygen demand was therefore not al- tered by the drug. Resting blood pressure was reduced, suggesting a peripheral vasodilatory action. The im- provement in exercise capacity with nicorandil was thus mediated through a reduction in afterload, and the small increase in peak exercise rate pressure product may reflect a degree of coronary vasodilation with sub- sequent alteration in coronary reserve.

Severe headaches were encountered by approximate- ly one-third of the patients taking nicorandil and caused 5 subjects to discontinue. In all these cases headaches remained without diminution during treatment, imply- ing a sustained vasodilating effect. The sustained hemo- dynamic changes in those who were assessed after 6 weeks of treatment with nicorandil also suggest that the well-described phenomenon of tachyphylaxis seen with many nitrate compoundsi7J8 may not occur with nico- randil.

Acknowledgment: We are grateful to Rhone-Pou- lent who supplied the trial medication,

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