- A study compared the effects of glibenclamide and gliclazide, two sulphonylureas, on ischemic preconditioning (IPC) and nicorandil-induced myocardial protection in rats. - Glibenclamide abolished the protective effects of both IPC and nicorandil, but gliclazide did not affect IPC or nicorandil-induced protection. - Nicorandil caused a partial depolarization of mitochondrial membrane potential, an effect blocked by glibenclamide but not gliclazide. These results suggest gliclazide may allow protective effects in diabetic patients at risk of acute coronary syndromes unlike

3. Historical View
• Nicorandil has been available in Japan since 1984 as
Sigmart®,
• where it was first developed by :
Chugai Pharmaceuticals.

4. HYPOTHESIS
EVIDENCE BASED MEDCINE
RECOMMENDATIONS
CONCLUSION

5. HYPOTHESIS

6. Combines Potassium channel opening & Nitrate effects
Potassium channel opening action
N O
HN
O NO2
Nitrate like action
IONA Study Group. Lancet. 2002;359:1269-75. Rahman N et al. AAPS J. 2004;6:e34.

7. Potassium channel opening action
Vascular Smooth muscle cell

8. Journal of Clinical & Basic Cardiology, 1999.

10. • Reducing the myocardial damage that may result
from prolonged ischemic attacks, as seen by:
– Reduced infarct size
– Reduced ultra-structural damage
– Higher ATP reserves
– Fewer arrhythmic events
– Better functional recovery

11. Anti-ischemic Cardioprotective
effects effects
Arterial & venous Pharmacological
dilatation Preconditioning
Reduction in angina Reduction in angina
symptoms outcomes
Combining Hemodynamic & Metabolic benefits

12. EVIDENCE BASED MEDCINE

14. Impact Of Nicorandil in Angina
IONA Study Group. Lancet. 2002;359:1269-75

15. - Double blind, randomized, controlled trial, on 5126
patients with chronic stable angina.
- Comparing Nicorandil versus placebo (when added
to existing anti-anginal treatment).
- With a follow up period of up to 3 years.

16. Baseline therapy (%)
•Anti-platelet 88
•-blocker 56
•Ca-antagonist 55
•Nitrate 86
•Statin 57
•ACE inhibitor 29
•Insulin 3.4
•Hypoglycaemic 2.1

17. • Primary End Point:
– Coronary Heart Disease Death.
– Non fatal Myocardial Infarction.
– Unplanned Hospitalization for Cardiac Chest Pain.

18. 1ry end point
The combination of CHD death, non-fatal MI or
unplanned hospitalization for cardiac chest pain.
(P = 0.014)
1
Proportion event free
0.95
Nicorandil Nicorandil
Placebo
0.9
Placebo
0.85
0.8
17%
0.75
0 0.5 1 1.5 2 2.5 3
Years

19. All CV events
1
(P = 0.027)
Proportion event free
0.95
Nicorandil
Nicorandil
0.9
Placebo Placebo
0.85
0.8
14.5%
0.75
0.7
0 0.5 1 1.5 2 2.5 3
Years

20. ACS
CHD death, non-fatal MI or Unstable angina.
1
(P = 0.028)
Proportion event free
0.98
Nicorandil Nicorandil
Placebo
0.96
Placebo
22%
0.94
0.92
0.9

24. The Japanese Coronary Artery
Disease (JCAD) study
HORINAKA S et al. Circulation Journal Vol.74,
March 2010.

25. JCAD study
• A multicenter collaborative prospective observational
study of a large cohort of coronary artery disease
patients (13,812).
Who underwent coronary angiography and were
diagnosed as having significant stenosis in at least 1
coronary artery, with:
• Stable angina in 8,808 patients (64%).
• Acute MI in 2,955 patients (21%).
• Unstable angina in 2,049 patients (15%).

26. JCAD study
Patients were followed up for an average of 2.7 years, on medical treatments •
of:
Beta blockers, Nitrates, CCB, Statins, ACEI, ARB and Nicorandil.
As part of the JCAD Study, the effect of Nicorandil on outcome was •
examined (2,558 on Nicorandil Vs 2,558 control).

27. JCAD study
Nicorandil group risk factors:
Hypertension (55%).
Hyperlipidemia (53%)
Impaired glucose tolerance (42%)
Smoker (38%)
Family history (16%)
Heart failure (11%)
75% males and 25% females.

28. JCAD study
Nicorandil group background medications:
Beta blockers (22%).
Statins (36%)
Diuretics (18%)
ACEI (29%)
ARB (15%)
Sulfonylureas (10%)

29. JCAD study
1ry endpoint:
- Death from all causes.
2ry endpoints:
- Cardiac death. - Fatal MI.
- Cerebral or vascular death. - Congestive heart failure.

30. 1ry endpoint: Death from all causes.
35%
HORINAKA S et al. Circulation Journal Vol.74, March 2010

31. 2ry endpoint: Cardiac deaths
56% RRR
N.B: Death due to fatal MI, unstable angina, CHF, CABG,
cardiac arrest or CPAOA.

32. JCAD study
Other 2ry endpoints:
• Cerebral or vascular death (71% RRR, p=0.029).
(Death due to cerebral hemorrhage, cerebral infarction, aortic
dissection or rupture of aortic aneurysm).
• Congestive heart failure (33% RRR, p=0.014).

33. RECOMMENDATIONS

36. CONCLUSION

37. Dosage and Administration
• Starting dose: 10 mg twice daily.
• Maintenance dose: 10 – 20 mg twice daily.
• Maximum dose: up to a maximum of 30 mg twice
daily.
• A lower starting dose: of 5 mg twice daily may be
used in patients particularly prone to headache.

38. Packing Quality
• High quality packing:
- Double Al strip, sealed in Al bag, with
moisture absorbent.
- 3 strips, each of 10 double scored tablets.
• Price: 36 L.E.

39. CAD patient
refractory to current
anti-anginal therapy
 Randil can be added to standard therapy improving angina
outcomes and reducing the rate of ACS.
Across a wide range of patients with different traditional risk
factors.
CCSF Age or
score Hypertension Diabetes MI PCI/CABG sex
IONA study, Lancet 2002.

40. Newly diagnosed
CAD patient
Nicorandil is recommended to improve symptoms and/or
reduce ischemia in patients with stable angina
• Class I: Monotherapy in the absence of a Beta blocker.
• Class IIa: In combination with a Beta blocker.
ESC 2006 guidelines for the management of stable angina.

41. Communicate With Us
• Adwia.com
• http://randilbrand.blogspot.com/
• http://www.facebook.com/Randil.Adwia

45. THANK YOU

46. Myocardial protection from either ischaemic preconditioning or
nicorandil is not blocked by gliclazide
• Both IPC and nicorandil- induced protection
are abolished by glibenclamide but not
gliclazide in-vivo.
• These results may have important clinical
implications in type II diabetic patients at risk
of acute coronary syndromes.
• http://discovery.ucl.ac.uk/75012/

47. Myocardial protection from either ischaemic preconditioning or
nicorandil is not blocked by gliclazide
• Maddock, HL and Siedlecka, SM and Yellon, DM (2004) Myocardial protection from either ischaemic preconditioning or
nicorandil is not blocked by gliclazide. CARDIOVASC DRUG THER , 18 (2) 113 - 119.
• Full text not available from this repository.
• Abstract
• Objective: We compared the effects of two sulphonylureas, glibenclamide and gliclazide, on ischaemic preconditioning (IPC)
and nicorandil- induced protection in the in-vivo rat. We also studied the effects of these agents on the membrane potential of
isolated rat mitochondria.Methods: Anaesthetised male Sprague-Dawley rats were used in an open chest model of myocardial
infarction. Animals were randomly assigned to receive one of the following drugs: ( 1) saline control, ( 2) glibenclamide, 0.3
mg/kg, or ( 3) gliclazide, 1 mg/kg i.v. bolus. Each was then further randomised to one of the following treatments: ( a)
control, (b) IPC ( consisting of 2 x 5 mins of regional ischaemia and 5 minutes reperfusion) or ( c) nicorandil ( 50 ug/kg/min
i.v). infusion. Each group then underwent 25 mins regional ischaemia and 2 hrs reperfusion. Infarct to risk zone ratio (%) was
calculated by computerised planimetry of tetrazolium stained heart slices. The membrane potential of mitochondria isolated
from rat ventricles was measured using flow cytometry. Comparisons were made between groups in control medium,
nicorandil alone, and nicorandil with either glibenclamide or gliclazide.Results: Infarct size was significantly reduced with
IPC (15.0 +/- 1.1%,) and nicorandil (25.5 +/- 4.2%), versus control (44.1 +/- 3.2%), p < 0.005. Glibenclamide abolished IPC
(40.8 +/- 4.6%) and nicorandil-induced protection completely (39.5 +/- 5.1%). Gliclazide had no adverse effect on IPC (20.4
+/- 1.9%) or nicorandil- induced protection (23.6 +/- 2.2%), p < 0.005. Nicorandil caused a partial depolarisation of the
mitochondrial membrane potential (- 14.92 +/- 2.34%), which was abolished by glibenclamide (+ 2.03 +/- 0.53%), but not
gliclazide (- 16.47 +/- 3.36%), p< 0.01.Conclusion: Both IPC and nicorandil- induced protection are abolished by
glibenclamide but not gliclazide in-vivo. These results may have important clinical implications in type II diabetic patients at
risk of acute coronary syndromes.