Safety and Efficacy of Nicorandil in Chronic Stable Angina by elfphabet5


									                                        ORIGINAL ARTICLE                                                 JIACM 2003; 4(3): 205-9

Safety and Efficacy of Nicorandil in Chronic Stable Angina – A Double
 Blind Comparative Randomised Trial with Isosorbide Mononitrate
                         Padmaja Udaykumar*, Prabha Adhikari**, Prathibha Periera***

Objectives : To evaluate the safety and efficacy of nicorandil in chronic stable angina and compare it with ISMN.
Patients and methods : 20 patients were randomised to receive either nicorandil or ISMN after baseline investigations. Dose was
titrated over one week and the full dose given for next three weeks. After repeating the investigations on day 28, patients were
switched over to receive the other study medication.
Results : Anti-anginal effects were assessed by reduction in anginal episodes, and consumption of rescue medication; anti-ischaemic
effects assessed by stress test parameters showed that nicorandil has anti-anginal effect comparable to ISMN. Anti-ischaemic
effects of nicorandil are not very convincing. It improved maximum exercise duration, RPP and was superior to ISMN in the side
effect profile.
Conclusion : Nicorandil is a safe and effective anti-anginal comparable to ISMN. Anti-ischaemic effects need to be proved by further
clinical trials.

Key words : Angina, Anti-ischaemic effect, Potassium channel activators.

Introduction                                                         belonging to nitrate group7,8, beta-blockers9,10,11, and
                                                                     calcium channel blockers12,13. However, there is a paucity
The relief of chest discomfort remains one of the primary
                                                                     of Indian literature on the role of this drug in angina
objectives in the management of patients with angina
                                                                     pectoris. Hence, it was decided to study the safety and
pectoris. Beta-blockers, calcium antagonists, and nitrates
                                                                     efficacy of nicorandil in 20 South Indian patients and
are indicated and widely used for this purpose, but all
                                                                     compare the same with isosorbide mononitrate (ISMN)
these agents have limitations, and are therefore not a
                                                                     sustained release preparation in a double blind,
complete answer to the problem1. There is a need to
                                                                     randomised, crossover trial.
augment, and perhaps replace, the conventional anti-
anginal agents and a number of alternative compounds
are currently under clinical investigation. Nicorandil
                                                                     Patients and methods
belongs to the class of compounds known as potassium                 Study design : The study was planned as a randomised,
channel activators which are characterised by their arterio-         comparative, double-blind, crossover clinical trial.
dilating and veno-dilating properties, and represents a
                                                                     Inclusion criteria : 20 adult men/women aged between
novel type of compound for use in the treatment of angina
                                                                     21-65 years having coronary artery disease with:
pectoris. Several non-comparative 2-4 and placebo-
controlled studies5,6 in patients with stable effort angina          a) Chronic stable angina, or angina not responding to other
have indicated that 2 hours after a single oral dose of (5-             available drugs with definite ECG evidence of myocardial
60 mg) nicorandil, there is a significant improvement in                ischaemia (ST depression > 2 mm, 80 milliseconds after
anginal symptoms including an increase in total exercise                J-point) during tread mill exercise testing and/or
duration by 12-36%, time to onset of angina by 20-78%,
and time to ST segment depression by 25-94%. It has also             b) those who develop typical anginal pain during
been proved by Western studies that nicorandil has                      exercise testing with horizontal or down-sloping ST
produced an equivalent improvement in ischaemic and                     segment depression of 2 mm or more measured 80
effort angina symptoms compared with standard drugs                     miliseconds after J point.

* Professor and Head, Department of Pharmacology, Fr. Muller Medical College, Mangalore, ** Professor of Medicine,
KMC, Mangalore, *** Associate Professor of Medicine, KMC, Mangalore.
Exclusion criteria                                              predetermined randomised order. During the next four
1. Hypertension of > 170/100 mm of Hg or patients on            weeks, the patients received the other study medication,
   antihypertensive medication.                                 the dose of which was determined by titration as earlier.
                                                                On day 28 and 56, patients underwent treadmill test and
2. Valvular heart disease, cardiomyopathy.
                                                                complete laboratory investigations.Throughout the study
3. Myocardial infarction in < 6 months, unstable angina,
                                                                period, the patients were asked to record the number of
   congestive cardiac failure.
                                                                anginal attacks and were allowed to use sublingual
4. Anaemia (Hb < 7G/dl).                                        nitroglycerine as the rescue medication.
5. Cardiac arrhythmias or II or III degree AV block.
                                                                Table I : Titration of nicorandil and ISMN doses.
6. IDDM (Type-1 diabetes mellitus).
                                                                                          ISMN              Nicorandil
7. Significant liver dysfunction or renal dysfunction.                                    ( twice a day)    (twice a day)
8. Systolic blood pressure < 100 mm Hg.                         Initiation                10 mg             5 mg
9. Pregnant women and nursing mothers.                          Intermediate dose
10. Known hypersensitivity to nitrates.                         for maintenance           20 mg             10 mg
                                                                High dose for
Methods                                                         maintenance               40 mg             20 mg
After obtaining ethics committee approval and informed          Table II : Shows the demographic data of 20 patients.
consent, 20 qualified patients were enrolled for the study                                                   Mean ± SD
(Table I) after randomisation to receive either nicorandil
                                                                Male/Female                                  12/8
or ISMN sustained release capsules. Maximum symptom
                                                                Age (Years)                                  54.9 ± 12
limited graded treadmill exercise testing was done on day
                                                                Weight (Kg)                                  58.5 ± 8
0 and a detailed case history and clinical examination
                                                                Old MI                                       nil
findings were recorded alongwith baseline symptoms.
Routine baseline haematological profile such as                 Heart rate/min.                              77 ± 9
haemoglobin, total WBC count, differential count and            Supine BP (mmHg) Systolic                    133.8 ± 21
platelet count, biochemical evaluation such as blood urea,                          Diastolic                82.4 ± 6
serum creatinine, bilirubin, SGOT, SGPT, blood glucose and
                                                                Table III : Shows the no. of anginal attacks.
electrocardiogram were done in all patients. Titration for
                                                                                                           No. of attacks
the optimum dose was done as follows: the patients
received 1 tablet of single strength twice a day for the        Baseline                                   14.61 ± 15.6*
first three days, and then 2 tablets twice a day for the next   After nicorandil                           7.14 ± 2.07*
4 days. From the next week onwards (day 8), the patients        After ISMN                                 4.4 ± 2.9*
received double strength medication i.e., two tablets twice     * P value < 0.05
a day for the next three weeks. If the patients did not
tolerate 2 tablets of double strength medication, they          Statistical tests
were given 1 tablet twice a day of the double strength for
                                                                Comparison of medications data with baseline values and
the rest of the study period (Table II).
                                                                comparison among two medications were done using
The patients were requested to report on the same day           ‘Paired T’ test.
(as day zero) of every week when the clinical examination,
record of anginal symptoms, rescue medication
                                                                Efficacy analysis
consumed and side effects during the last week were             Antianginal effects were assessed by a reduction in
made. The total duration of the trial was eight weeks.          anginal episodes and consumption of rescue medication.
During the first four weeks, the patients received either       Anti-ischaemic effects were assessed by evaluation of
nicorandil or ISMN sustained release capsules as per            various stress test parameters.

 206                             Journal, Indian Academy of Clinical Medicine      Vol. 4, No. 3   July-September 2003
Results                                                          Discussion
Twenty patients were enrolled for the study, of which            The results of our study shows that nicorandil is an
eighteen could complete the trial. There were 2 drop-outs        effective antianginal agent and has statistically significant
because of poor compliance.                                      effect on reduction of anginal attacks P (< .001). ISMN
                                                                 appeared significantly better in reducing angina
Table III shows the number of anginal attacks before
                                                                 frequency when compared to nicorandil. This is not in
(baseline) and during study medication. Table IV
                                                                 agreement with the previous comparative studies 6.
shows stress test parameters before (baseline) and
                                                                 However, it was not possible to assess the decrease in
after the study medication. Table V shows percentage
                                                                 consumption of rescue medications as the patients were
increase of double product over pretest values. Table
                                                                 reluctant to take rescue medication for mild anginal
VI shows haemodynamics at maximum ST depression.
                                                                 attacks which were relieved by rest.
Table VII shows side effect profile of nicorandil and

Table IV : Showing baseline stress test parameters and stress test parameters after study medication.
                                                  Baseline                         Nicorandil                        ISMN
1.   Time to ST depression (min)                   7.23 ± 2                         8.2 ± 3.2                        7.3 ± 3
2.   Max. exercise duration (min)                  7.5 ± 2.8                        8.4 ± 2.5                       7.1 ± 2.3
3.   Max. work load (Mets)                        8.8 ± 3.05                        10 ± 2.9                         8.7 ± 3
4.   Duration of recovery (min)                    7.8 ± 2.5                         5.9 ± 2                        6.6± 1.1

Table V : Showing percentage increase of double product over pre-test values.
Stage of exercise                                  Baseline                        Nicorandil                      ISMN
Pre-test                                        13,927 ± 4,386                   13,062± 4,277                11,835± 2,421
Peak exercise                                   20,255 ± 4,983                   22,817± 7,007                20,716 ± 5,035
% rise                                               31%                              35%                          48%

Table VI : Showing haemodynamics at maximum ST depression.
                                                  Baseline                      Nicorandil                        ISMN
Max. ST depression (mm)                          1.68 ± 0.79                   1.74 ± 0.87                    1.88 ± 0.71
Time to max ST dep. (min)                          7.23 ± 2                     8.2 ± 3.2                       7.3 ± 3
HR at max ST dep. (beats/min)                     131 ± 22.4                    137 ± 21                       129 ± 22
Syst. BP at max ST dep. (mm/Hg)                    155 ± 22                     160 ± 30                       155 ± 21
Double product (beats/min x mmHg)               20255 ± 49.83                 22817 ± 70.07                  20716 ± 50.35
P <0.05

Table VII : Showing side-effect profile.                         Ideally a wash-out period was needed before crosssing
                        Nicorandil                ISMN           over, since possible additive effects of the combination of
Headache                      1                     7            these two agents may be found after crossover. However,
Gastritis                     1                                  the additive effect would have occured with both the
Giddiness                     1                     0            drugs since one group received nicorandil first and the
Constipation                  0                     1            second group received ISMN retard first. Moreover, since
                                                                 these patients were symptomatic, we did not have the
SGOT, SGPT ↑                  1                     1
                                                                 permission of the ethics committee to give placebo during
ALK. PHOS ↑                   1                     0
                                                                 the wash-out period.

 Journal, Indian Academy of Clinical Medicine       Vol. 4, No. 3    July-September 2003                                 207
The efficacy of nicorandil as an anti-ischaemic agent in         by improvement in stress test parameters are not very
improving stress test parameters appears to be                   convincing. Its antianginal effect and anti-ischaemic effect
convincing. Although it appeared as if time to ST                are comparable to that of ISMN. It is an effective alternative
depression improved with nicorandil compared to ISMN-            to the conventional antianginal drugs in the treatment of
retard, this was not statistically significant. However,         stable angina pectoris. However, further clinical studies
maximum exercise duration declined with ISMN retard              are essential to establish that the broad anti-ischaemic
while it improved with nicorandil. Similarly, maximum            profile is beneficial in the treatment of other types of
work load achieved also was better with nicorandil when          angina and/or the ischaemic myocardium. Its role as an
compared to ISMN. Nicorandil and ISMN failed to improve          adjuvant antianginal agent in combination therapy for
haemodynamic parameters compared to baseline. But                angina pectoris needs to be defined by further trials.
nicorandil improved RPP significantly when compared to
                                                                 Moreover, nicorandil needs to be stored in a refrigerator.
ISMN. These findings are contrary to the earlier
                                                                 This could pose a problem in the Indian set-up due to
comparative studies where both nitrates and nicorandil
                                                                 financial constraints.
were found to significantly improve stress test parameters
such as time to onset of angina, total exercise duration,
time to > 1 mm ST segment depression. They did not find
any significant difference in any of the parameters when         Dr. Malathi Prabhu and Dr. N. Chowta for their assistance
nicorandil was compared with nitrates. Nicorandil was            in carrying out stress tests. The authors also thank ‘Torrent
superior to ISMN in it’s side effect profile. Incidence of       Pharmaceuticals’, Ahmedabad, for supplying nicorandil
headache was lower in significantly lesser percentage of         samples and financial support.
people when compared to ISMN. There was no statistically
significant difference in other side effects. Other side         References
effects noted with nicorandil were giddiness in one              1.   Campbell RWF. The defiencies of current medical therapy
patient and elevated serum transaminases and alkaline                 for the management of angina pectoris. Postgrad Med J
phosphatase in another patient. However, this was not                 1991; S37.
                                                                 2.   Awata N, Azuma J, Sawamura A, Harada H, Hamaguchi T.
clinically significant. Nicorandil was found to be unstable
                                                                      Efficacy of nicorandil on exercise performance in patients
at room temperature as three patients complained of                   with stable effort angina. Current Therapeutic Research 1989;
powdering of the tablets when they were stored in room                45: 621-32.
temperature due to non-availability of refrigerator at           3.   Hiasa Y, Hamai K, Wada T, Aihara T, Bando M et al. Chronic
home. Headache as a side effect following nicorandil                  effects of nicorandil on exercise tolerance in patients with
                                                                      stable effort angina pectoris. Tokushima J Exptl Med 1989;
therapy was reported as 22-48% in previous studies, but               36: 65-70.
was found to be low in our study (5%). Similarly, incidence      4.   Kinoshita M, Saki K. Pharmacology and therapeutic effects
of headache was found to be comparable to nitrate                     of nicorandil. Cardiovasc Drug Ther 1990; 4: 1075.
therapy in the previous study contrary to our study.             5.   Camm AJ, Maltz MB. A controlled single-dose study of the
However, the number of patients in our trial was too small            efficacy, dose response and duration of action of nicorandil
                                                                      in angina pectoris. Am J Cardiol 1989; 63-61.
to draw a definite conclusion that nicorandil does not
                                                                 6.   Meany TB, Ricardson P, Camm AJ et al. Exercise capacity after
cause headache. Because of poor storage conditions the                single and twice-daily doses of nicorandil in chronic stable
drug could have partially lost its potency and its ability to         angina pectoris. Am J Cardiol 1989; 63-6.
produce vasodilation and headache. Dizziness was found           7.   Doring D. Antianginal and anti-ischaemic efficacy of
in only one patient and has been found in patients on a               nicorandil in comparison with isosorbide-5 monotrate and
                                                                      isosorbide dinitrate. Results from two multicentric, double-
single dose greater than 40 mg. Other side effects such as            blind, randomised studies with stable coronary heart
nausea, vomiting, gastralgia, and abdominal pain were not             disease patients. J cardiovasc Pharmacol 1992; 20 (Suppl 3):
reported in our series.                                               S74.
                                                                 8.   Meeter Kelder JC, Tipsen JGP et al. Efficacy of nicorandil
In conclusion, nicorandil is a safe and effective anti-anginal        versus propranolol in mild stable angina of effort -A long
agent. However, its anti-ischaemic properties as evidenced            term’ double-blind study. J Cardiovasc Pharmacol 1992; 20

 208                              Journal, Indian Academy of Clinical Medicine        Vol. 4, No. 3     July-September 2003
     (Suppl 3): S59.                                                          heart disease: A double-blind, randomised, multicenter
9.   Di Somma S, Liquori V, Erdecchia P et al. A double-blind                 study. J Cardiovasc Pharmacol 1992; 20: S67.
     comparision of nicorandil and metoprolol in patients with            12. Guermonprez JL, Blin P, Peterlongo F. A double-blind
     effort stable angina (abstract ). Eur Heart J 1990; 11 (suppl):          comparison of the long-term efficacy of a potassium
     80.                                                                      channel activator and a calcium antagonist in stable angina
10. Raftery EB, Lahiri A, Hughes LO et al. A double-blind                     pectoris. Eur Heart J 1993; 14 (Suppl B): 30.
    comparison of a beta-blocker and a potassium channel                  13. Roland E. Safety profile of an anti-anginal agent with
    opener in excercise induced angina. Eur Heart J 1993; 14                  potassium channel opening activity: An overview. Eur Heart
    (Suppl B): 35.                                                            J 1993; 14 (Suppl B): 48.
11. Ulvenstam G, Diderholm E, Frithz G et al. Antianginal and             14. Purcell H, Patel DJ, Mulcahy D, Fox K. Nicorandil in
    anti-ischaemic efficacy of nicorandil compared with                       Cardiovascular drug therapy. Eds. Messerli FH. Edn. 2nd 1996;
    nifedipine in patients with angina pectoris and coronary                  Chp.178 P.1638-45. W.B.Saunders, New York.

 Journal, Indian Academy of Clinical Medicine                 Vol. 4, No. 3   July-September 2003                                    209

To top