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International Archives of BioMedical and Clinical Research [128] April – June 2018 | Vol 4| Issue 2

Section Pharmacology Original Article

A Randomized Comparative Study on

Efficacy and Safety Profile of Ivabradine and Ranolazine, in Patients of Chronic Stable Angina Pectoris

Nusrat Nabi

1

, Nilam Nigam

2*

, Pankaj Pranjal

3

, Nasir Nabi Naikoo

4

, Himika Mukhopadhyay

5

1Tutor/SR, Department of Pharmacology, Hamdard Institute of Medical Sciences, New Delhi

2Professor & Head, Department of Pharmacology; 3Professor, Department of General Medicine, Rama Medical College, Kanpur

4Senior Resident, Department of Pathology, ESIC Medical College, Kolkatta.

5Senior Resident, Department of Pathology, Apollo Hospital, Kolkatta

Background:Ischemic heart disease is one of the leading causes of global disease burden. Despite treatment with standard therapy, many patients with chronic stable angina pectoris remain symptomatic making it an urgent necessity to introduce new strategies. Hence this study was planned to compare the efficacy and tolerability of Ivabradine and Ranolazine; the two novel antianginal drugs.

Methods: This was a single blind, randomised, controlled trial. Thirty patients each taking IVA 5 mg twice daily or RAN 500 mg twice daily were randomised into two groups. Patients filled a pretested questionnaire on frequency of angina attacks and adverse reactions experienced at baseline and 2, 4 and 8 weeks. The haemodynamic parameters, routine laboratory investigations were evaluated at the baseline and after intervention. Results:There was no significant difference in the frequency of angina attacks per week between the IVA and RAN study groups. There was a statistically significant difference (P < 0.01) in the number of patients reporting ADR from the IVA group as compared to RAN group. In the IVA group, the most common ADR was dizziness (36.6%); whereas nausea (30%) and dizziness (23.3%) was most common in RAN group. The routine haematological and biochemical evaluations did not show any significant difference between the baseline and post intervention.

However, IVA significantly decreased the resting heart rate after eight weeks of intervention..

Conclusion:Both IVA and RAN are comparable and efficacious antianginal agents. However, RAN had a better safety and tolerability profile than IVA.

Key words: Antianginal drug, dizziness, ischemic heart disease (IHD), nausea, randomised controlled trial, serum sickness like reaction (SSLR)

DOI:10.21276/iabcr.2018.4.2.37 Received: 27.04.18

Accepted: 25.05.18

Dr. Nilam Nigam

Email: drnilamnigam@gmail.com

Copyright: © the author(s) and publisher.

IABCR is an official publication of Ibn Sina Academy of Medieval Medicine & Sciences, registered in 2001 under Indian Trusts Act, 1882.

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY- NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non- commercial

INTRODUCTION_____________________

It has been anticipated that by 2020, ischemic heart diseases (IHD) will be the leading cause of global disease burden[1]. In the last few decades, its incidence has increased in the economically developing countries. Angina pectoris is caused by myocardial ischemia due to an imbalance between myocardial perfusion and oxygen demand. Despite treatment with standard therapy (ST) plus cardiac revascularization, many patients remain symptomatic. It is necessary to introduce new strategies to reduce angina episodes. The medicines currently used in the management of chronic stable angina pectoris (CSAP) are mainly b blockers, calcium channel blockers (CCBs) and nitrates.[2]

However, these have some side effects like negative ionotropic effect with b blockers and hypotensive effect with CCBs and nitrates, which could have serious consequences and jeopardize the management of IHD. Among the novel drugs recently introduced for the management of chronic stable angina, late sodium current modulator ranolazine (RAN) and sinus node inhibitor ivabradine (IVA) represent two most true innovations. Ranolazine is a unique anti- ischaemic drug that was initially thought to act purely through metabolic mechanisms. However, it has recently been shown to be capable of inhibiting the late sodium current [3],

Access this article online Website:

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Quick Response code

DOI: 10.21276/iabcr.2018.4.2.37

ABSTRACT

*Corresponding Author

How to cite this article: Nabi N, Nigam N, Pranjal P, Naikoo NN, Mukhopadhyay H.A Randomized Comparative Study on Efficacy and Safety Profile of Ivabradine and Ranolazine, in Patients of Chronic Stable Angina Pectoris. Int Arch BioMed Clin Res. 2018;4(2):128-132.

Source of Support: Nil, Conflict of Interest: None

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www.iabcr.org Nabi N, et al.: A study on efficacy and safety profile of ivabradine and ranolazine

International Archives of BioMedical and Clinical Research [129] April – June 2018 | Vol 4| Issue 2

decreasing the calcium overload and thereby diastolic stiffness. This in turn improves myocardial perfusion. The anti-ischaemic properties of ranolazine have been shown to be exerted without significant modifications in heart rate, blood pressure, and ionotropic state. IVA is a specific heart rate (HR) decreasing agent acting on the sino-atrial node by selectively inhibiting the pacemaker If current in a dose dependent manner and reducing HR at rest as well as during exercise with minimal effect on myocardial contractility, blood pressure (BP) and intra-cardiac conduction.[4,5]

In our knowledge very few studies have been conducted globally comparing the novel antianginal drugs IVA and RAN.

Hence, this study was planned to compare the efficacy and tolerability of IVA and RAN in CSAP patients to generate data in Indian population.

METHODS__________________________

This study was conducted as a single blind, randomised, controlled trial in the outpatient department of general medicine and cardiology, at a tertiary care hospital in Kanpur.

The study was conducted from September 2016 to December 2016. A total of 60 subjects of CSAP were included in the study after due approval from the Institutional Ethics Committee. The study was conducted in accordance with the International Conference on Harmonisation – Good Clinical Practice (ICH-GCP) guidelines.

The inclusion criteria comprised of patients of either gender,

>18 years and < 60 years of age, diagnosed by the concerned physician as suffering from CSAP for more than three months, attending the general medicine or cardiology outpatient department of the hospital regularly and taking IVA or RAN for at least 1 month prior to the trial entry and willing to provide informed and written consent for participating in the study. Patients with known high-grade left main CAD;

congestive heart failure stage III/IV NYHA; symptomatic hypotension or uncontrolled hypertension [resting systolic blood pressure (SBP) >180 mmHg or diastolic blood pressure (DBP) >100 mmHg], past history of myocardial infarction, cerebrovascular event, severe bradycardia (resting HR <50 bpm) or sick sinus syndrome, second to third degree AV block, arrhythmias, history of chronic diabetes mellitus, rheumatoid arthritis, renal or hepatic impairment, pregnancy, lactation or anemia (Hb < 7 g/dL) were excluded from the study. Concomitant treatment with CYP3A4 inducers and inhibitors, diltiazem, verapamil, medicines that prolong QT interval (quinidine, sotalol, disopyramide, amiodarone), rifampicin, barbiturates, phenytoin, tricyclic antidepressants, antipsychotics, mefloquine, b blockers, digoxin, simvastatin, paroxetine, MAO inhibitors and cyclosporine were excluded due to known drug interactions with the trial medicines.

After seeking permission from the attending cardiologist, randomisation of the subjects was done into two study groups of 30 subjects each by computer generated random number allocation. Group A subjects received IVA 5 mg twice daily (M/s Lupin Laboratories Ltd., Mumbai, India) and group B received RAN 500 mg (M/s Cipla Ltd., Mumbai, India) twice daily for 8 weeks with dosage of the trial medicines based on the previous studies.[6,7] Standard marketed brands of both the drugs were supplied free of cost and administered in a single blind manner, with medication identity not being revealed to the patients. Allocation concealment was achieved using the serially numbered, opaque, sealed envelope technique. The randomization process and the

code breaking authority was given to a senior pharmacologist not interacting with the subjects. The patients received the total medication in three instalments at 0, 2 and 4 weeks; and were followed up at 2, 4 and 8 weeks from the start of the treatment. Along with the trial medicines, patients were allowed to continue with other antiplatelet, statin, antihypertensive and antianginal therapy on which they were already stabilized.

The primary endpoint of the study was the evaluation of the antianginal efficacy of the trial medicines and secondary endpoint being their safety profile (ADR) was assessed through a pretested questionnaire at the baseline and after 2, 4 and 8 weeks of intervention. The questions were related to the frequency of angina attacks, frequency and duration of ADRs after taking the medicine and the treatment taken for the ADRs. The vital signs, haemodynamic parameters (BP, HR) and electrocardiogram (ECG) recording was done on each study visit. The subjects were asked to report back to the OPD or inform telephonically the study coordinator in case of any ADR experienced at home. The history of ADR was specifically taken at each visit. Routine haematological profile (Hb%, serum electrolytes) and biochemical profile (LFT, RFT, RBS) were done at the baseline and after the intervention.

Statistical analysis

Chi-square test was used to analyze the difference in the frequency of ADRs. Comparison of the frequency of angina attacks was analyzed using the unpaired “t” test. The pre and post comparison of the trial medicines was tested for significance by the paired “t” test, with P < 0.05 being significant.

RESULTS___________________________

A total of 60 patients were enrolled in the study; with 30 patients each in IVB and RAN arm.

Demographic profile and clinical characteristics

The baseline profile of the subjects is summarised in Table 1. It was observed that the mean age of the subjects was.

The general characteristics of both the groups were comparable and thus adequately matched.

Laboratory investigations

Table 2 shows that haemoglobin (Hb), LFT, RFT, serum electrolytes and RBS readings at baseline and after 8 weeks of intervention did not show any significant difference in both IVA and RAN group. (using the paired “t” test).

Assessment of antianginal efficacy (primary outcome) From our data in Table 3 it is reflected that there was a highly significant difference (P < 0.01) in the frequency of angina attacks at 2, 4 and 8 weeks of drug intervention in both IVA and RAN arms when compared with the baseline. There was no significant difference in the mean ± SE of frequency of angina attacks across both the groups at 0, 2, 4 and 8 weeks.

No patient from either of the IVA or RAN group complained of angina attack at the end of 8 weeks of intervention.

Safety analysis (secondary outcome)

As depicted in Table 4, both drugs were well tolerated and no serious adverse events were encountered. 19 out of 30 patients from the IVA group and 11 out of 30 patients from the RAN group reported ADR at some point of the study.

There was a statistically significant difference (P < 0.01) in the number of patients reporting ADR from the IVA group as compared to RAN group. In the IVA group, the most common ADR was dizziness (36.6%). There were occasional reports of blurred vision (13.3%), headache (16.6%), backache

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International Archives of BioMedical and Clinical Research [130] April – June 2018 | Vol 4| Issue 2

(20%) and vertigo (13.3%) in the IVA group. The most common ADRs in the RAN group were nausea (30%) and dizziness (23.3%). There was a statistically significant difference for the reporting of nausea and dizziness at 2 and 8 weeks as well as 4 and 8 weeks (P < 0.05) in RAN group.

Whereas, statistical difference for reporting headache at 2 and 8 weeks (P < 0.05), backache at 2 and 8 weeks (P <

0.05) and blurred vision at 2 and 8 weeks (P < 0.01) was found in IVA group.

Compliance was excellent in both the study groups and none of the patients discontinued the treatment.

Haemodynamic parameters and cost effectiveness From the results of Table 5 we find that statistically, there was no significant difference in systolic BP, diastolic BP and HR in the RAN group at 0 and 8 weeks of the trial; whereas, IVA significantly decreased the resting HR but did not have a significant effect on the systolic and diastolic BP.

Table 1 :- Demographic profile and clinical characteristics of the subjects in IVA and RAN study groups

Parameters (units) Ivabradine (5 mg twice

daily)

Ranolazine (500 mg twice

daily)

n = 30 n = 30

Mean age±SEM 61.3±1.34 60.2±2.42

Men (%) 89 85

Women (%) 11 15

Mean number of anginal attacks per week

± SD 1.72±0.12 1.86±0.23

Chief complaints (all in numbers) Number of patients with chest pain on

exertion 29 29

Number of patients with palpitations 10 9

Number of patients with dizziness and

weakness 7 8

Number of patients with sweating 2 1

Number of patients with dyspnea 4 2

Table 2: Comparison of laboratory investigation parameters in IVA and RAN study groups (mean + SEM)

Laboratory Investigations

(units)

Ivabradine

(5 mg twice daily) Ranolazine (500 mg twice daily)

n = 30 n = 30

Baseline 8 weeks Baseline 8 weeks

Hb (gm%) 13.13±0.

32 13.86+0.36 13.73+0.31 13.12+0.33 Liver Function

Tests

AST (IU) 36.51+2.

11 37.45+2.62 36.02+2.19 36.58+1.89 ALT (IU) 29.09+2.

67 30.01+1.76 28.77+2.73 35.62+2.09 Serum Electrolytes

Na (mmol/L) 138.23+

1.01 137.18+1.1

1 137.02+1.81 137.07+1.29 K (mmol/L) 4.11+0.1

1 4.19+0.24 4.17+0.13 4.13+0.36

Kidney Function Tests

BUN (mg/dl) 19.03+0.

42 20.09+0.86 21.19+1.33 21.29+1.09 Serum Creatinine

(mg%) 1.01+0.0

4 1.05+0.01 0.91+0.04 0.98+0.07

RBS (mg%) 120.07+

3.46 121.41+2.9

9 119.67+3.01 120.92+2.89 AST=Aspartate aminotransferase, ALT=Alanine aminotransferase, IU=International unit

Table 3: Frequency of angina attacks in IVA and RAN study groups (mean + SEM)

n = 30 Baseline 2 weeks 4 weeks 8

weeks p

value Ivabradine

(5 mg twice daily) 1.86+0.17 0.32+0.07 0.01+0.02 0 <0.01 Ranolazine

(500 mg twice daily) 1.98+0.18 0.41+0.02 0.02+0.04 0 <0.01 p value IVA vs RAN >0.5 >0.5 >0.5 0

Table 4: Percentage distribution of adverse events in IVA and RAN study groups

Adverse

Events

2 weeks 4 weeks 8 weeks

Ivabradi

ne Ranolazi

ne Ivabradi

ne Ranolazi

ne Ivabradi

ne Ranolazi

ne 5 mg

twice daily

500 mg twice daily

5 mg twice daily

500 mg twice daily

5 mg twice daily

500 mg twice daily

n = 30 n = 30 n = 30 n = 30 n = 30 n = 30

Nausea 3.3 (1) 13.3 (4) 3.3 (1) 16.6 (5) 3.3 (1) 30 (9)

Vomiting - - - 3.3 (1) - 3.3 (1)

Constipation - 3.3 (1) - 3.3 (1) - 3.3 (1)

Headache 3.3 (1) 3.3 (1) 13.3 (4) - 16.6 (5) -

Dizziness 23.3 (8) 13.3 (4) 33.3 (10) 16.6 (5) 36.6 (11) 23.3 (8) Blurred

vision - - - - 13.3 (4) -

Muscle

cramps 3.3 (1) - 10 (3) - 10 (3) -

Arthralgia - - 3.3 (1) - 6.6 (2) -

Backache 6.6 (2) - 16.6 (5) - 20 (6) -

Vertigo 6.6 (2) 3.3 (1) 13.3 (4) - 13.3 (4) 6.6 (2)

Hypersensitiv

ity rash - - - - 3.3 (1) -

Cough/

dysnea 6.6 (2) - 6.6 (2) - 6.6 (2) -

Fever - - 3.3 (1) 3.3 (1) 3.3 (1) -

Table 5: Comparison of hemodynamic parameters in IVA and RAN groups (mean + SEM)

Hemodynamic

parameters Ivabradine

(5 mg twice daily) Ranolazine (500 mg twice daily)

n = 30 n = 30

Baseline 8 weeks Baseline 8 weeks Systolic BP (mmHg) 129.45+1.77 130.61+1.83 130.92+1.91 130.96+1.87 Diastolic BP (mmHg) 82.35+1.52 83.07+1.63 82.38+1.75 82.21+1.68 Heart Rate (beats per

minute) 78.05+1.88 72.37+1.71 76.05+1.36 75.89+1.32

DISCUSSION________________________

As per our knowledge very few studies have been reported comparing the efficacy and safety of IVA and RAN, the recently introduced antianginal drugs. Hence, there is urgent need to generate data for comparison and analysis especially in the Indian population. The results of our study as in Table 3, reflect that both IVA and RAN are effective antianginal agents and have a statistically significant effect on reduction of the frequency of angina attacks (P < 0.01) as compared to the baseline. Both the drugs were equally efficacious after the 8 weeks of study period as there was no statistically significant difference in the decrease in the frequency of angina attacks between the two groups. In our study, there was no statistically significant difference in the laboratory investigations performed at baseline and after 8 weeks of intervention, indicating the comparable safety of both drugs (Table 2). It was also observed in our study (Table

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www.iabcr.org Nabi N, et al.: A study on efficacy and safety profile of ivabradine and ranolazine

International Archives of BioMedical and Clinical Research [131] April – June 2018 | Vol 4| Issue 2

5) that there was no significant change in systolic and diastolic BP and HR in the RAN group, indicating that 500 mg of RAN twice daily does not alter the hemodynamic parameters, which is in agreement with findings of other studies.[8,9] However, IVA significantly reduced the HR, which is in affirmation with the results of a study by Borer et. Al., reporting that the HR at rest, during peak exercise and during exercise tolerance test, is significantly decreased when compared with placebo (P < 0.05) in patients randomly assigned to receive 2.5, 5 or 10 mg twice daily doses of IVA for 2 weeks in a placebo controlled double blind trial.[7] Some studies have even reported raised uric acid, serum creatinine and eosinophils with IVA, which was not recorded in our study.[10]

From the safety analysis data of our study (Table 4) it is significantly evident that RAN is superior to IVA in its safety profile. All the adverse effects (AES) noted were mild and classified as treatment emergent adverse events (TEAEs) across both study arms. The maximum number of reported AES was in the system organ class of “central nervous system disorders”. The number of patients who reported ADRs was significantly higher (P < 0.05) in the IVA (19/30) group as compared with the RAN (11/30) group. The most frequent ADRs reported by the patients of the RAN group was nausea (23.3%), whereas dizziness (36.6%) was the most frequent ADR reported by the patients of the IVA group.

Nausea and dizziness were the only ADRs that had a significantly difference between the RAN and IVB group; with nausea higher in RAN group and dizziness higher in IVA group. The cause of nausea may have been due to CTZ stimulation, vestibular disturbance or GIT dysfunction which needs to be investigated further. Some studies have reported dizziness, nausea, asthenia and constipation as the frequent ADRs with RAN.[6] Yet another trial has reported that there was no significant safety concern with RAN, which supports our understanding that RAN is safer than IVA.[11] Once again, in our study 16.6% of the patients in the IVA group and none from the RAN group reported headache after 8 weeks of study. It is postulated that the headache may have been due to blurred vision, phosphenes, inflammatory mediators, dizziness, bradycardia or postural hypotension. As IVA does not cross the blood brain barrier, it rules out any direct action on brain.[12] Phosphenes on the other hand are luminous phenomena, described as a transient enhanced brightness in a limited area of the visual field. It has been hypothesized that IVA interacts with the visual system by inhibiting hyperpolarization activated current in retinal cells (Ih).[13] Few studies have also reported that IVA by interacting with the retinal current (Ih) participates in the temporal resolution of the visual system by curtailing the retinal response to bright light. This is further supported by the finding that 13.3% of the patients from our study complained of blurred vision along with headache. It is recommended that specially designed studies should be planned to evaluate the association and long term implications of these ADR.

However, all these ADRs are of mild category and do not affect the patient’s ability to carry out their normal activities.[14] The patients in our study similar to the study conducted by Chaturvedi et.al., in Indian population,[15]

complained of a constellation of symptoms like arthralgias (6.6%), muscle cramps (10%), rash (3.3%) and fever (3.3%), which could be due to serum sickness like reaction (SSLR).

It is also noteworthy that drug detail summary of IVA (PROCORALAN; Servier Laboratories Ltd., Suresens,

France) mentions that vertigo and muscle cramps are its uncommon side effects.[16] Contrary to SSLR symptoms, fever was not commonly reported in our study and most patients were normothermic in both the groups, with only one patient in the IVA and RAN group complaining of fever.

However, one of the case report on SSLR caused by amoxicillin has reported absence of fever and as such, IVA could also have caused SSLR without fever.[17] As our results are in affirmation with those of Chaturvedi et. Al.,[15] it is highly recommended that the adverse event of SSLR with IVA intervention needs “causality assessment”. It also needs to be evaluated whether it has any association with Indian genetic constitution.

As the number of patients in our study was less, extrapolation of our data needs a larger sample size to confirm and validate our findings. The major limitation of this study as with all single blinded trials was the possibility of bias in subjective assessment by the attending investigator. Also no arrangement to assess the persistence of adverse events beyond the study period was done.

CONCLUSION_______________________

Both antianginal agents IVA and RAN appeared comparable in their efficacy. Thus, the two drugs represent an adjunctive and powerful therapeutic modality for the treatment of chronic stable angina, especially when conventional antianginal drugs are insufficient or inadequate.

RAN was more cost effective with a better safety and tolerability profile than IVA. SSLR was the distinct adverse event noticed by our study in the IVA group, which needs causality establishment. Although no important safety concerns were raised by this study, the limited duration of observation and sample size suggests the need for longer follow-up and larger sample size study before firm conclusions about their safety in chronic use can be drawn.

Acknowledgments

We would like to thank Dr. Rishika Agarwal and Dr Sughanda Garg, post graduate trainee, department of pharmacology, for their assistance.

Ethical Committee Approval: Approved

REFERENCES_______________________

1. Murray CJL, Lopez AD. The global burden of disease: A comprehensive assessment of mortality and disability from diseases, injuries, and risk factors in 1990 and projected to 2020. Cambridge, Harvard School of Public Health on behalf of the World Health Organization and The World Bank, 1996 (Global Burden of Disease and Injury Series, Vol. I).

2. Gravel GM, Tardif JC. Ivabradine: The evidence of its therapeutic impact in angina. Core Evid 2008;3:1-12.

3. Belardinelli L, Shryock JC, Fraser H. 2006a. Inhibition of the late sodium current as a potential cardio protective principle: effects of the late sodium current inhibitor ranolazine. Heart, 92(Suppl IV):iv6–iv14.

4. Riccioni G. Ivabradine: From molecular basis to clinical effectiveness.

AdvTher 2010; 27:160-7.

5. Simon L, Ghaleh B, Puybasset L, Guidicelli JF, Berdeaux A. Coronary and haemodynamic effects of S16257, a new bradycardic agent, in resting and exercising conscious dogs. J Pharmacol Exp Ther 1995;275:659-66.

6. Chaitman BR, Skettino SL, Parker JO, Hanley P, Meluzin J, Kuch J, et al. Anti-ischemic effects and long-term survival during ranolazine monotherapy in patients with chronic severe angina. J Am Coll Cardiol 2004;43:1375-82.

7. Borer JS, Fox K, Jaillon P, Lerebours G.; Ivabradine investigators group. Antianginal and antiischemic effects of ivabradine, an If inhibitor, in stable angina: A randomized, double -blind, multi centered, placebo-controlled trial. Circulation 2003;107:817-23.

8. Belardinelli L, Antzelevitch C, Fraser H. Inhibition of late (sustained/

persistent) sodium current: A potential drug target to reduce intracellular sodium-dependent calcium overload and its detrimental effects on cardiomyocyte function. Eur Heart J 2004;6:I3-7.

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9. Ver Donck L, Borgers M, Verdonck F. Inhibition of sodium and calcium overload pathology in the myocardium: A new cytoprotective principle.

Cardiovasc Res 1993; 27:349-57.

10. Electronic Medicines Compendium (eMC). Procoralan™ (ivabradine hydrochloride) [summary of product characteristics]. Servier Laboratories Ltd. (last updated: 09/12/2010). Available from:

http://www.emc.medicines. Org.uk/medicine/17188/SPC/Procoralan [Last accessed on 19/5/2010].

11. Stone PH, Chaitman BR, Koren A, Crager M. Abstract 3362: Effects of Ranolazine as monotherapy and combination therapy on rate pressure product at rest and during exercise: Results from the MARISA and CARISA trials. Circulation 2006;114:715.

12. Ruzyllo W, Ford IF, Tendera MT. Anti-anginal efficacy and safety of ivabradine compared with amlodipine in patients with stable effort angina pectoris: A 3-month randomised, double blind, multicentre, non inferiority trial. Drugs 2007;67:393-405.

13. Cervetto L, Demontis GC, Gargini C. Cellular mechanisms underlying the pharmacological induction of phosphenes. Br J Pharmacol 2007;150:383-90.

14. Tardif JC, Ford I, Tendera M, Bourassa MG, Fox K. Efficacy of ivabradine, a new selective If inhibitor, compared with atenolol in patients with chronic stable angina. Eur Heart J 2005;26:2529-36.

15. Chaturvedi A, Singh Y, Chaturvedi H, Thawani V, Singla S, Parihar D.

Comparison of the efficacy and tolerability of ivabradine and ranolazine in patients of chronic stable angina pectoris. J Pharmacol Pharmacother 2013;4:33-8.

16. Drug Details PROCORALAN 5 mg and 7.5 mg coated tablets.

Available from:

http://www.epgonline.org/mobile/drug-details.cfm/id/DR004072/

page/atoz/ letter/ P/ language/

LG0001/startrow_drug/161/drugName/PROCORALAN-5-mg-and-7.5- mg -coated-tablets [Last accessed on 20/5/2011].

17. Mener DJ, Negrini C, Blatt A. Itching like mad. Am J Med 2009;8:732-4.

References

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