A Multicentre Randomised Comparative Study Assessing The Efficacy and Safety of Amlodipine Versus Isosorbide-Mononitrate in The Treatment of symptomatic Myocardial Ischaemia.

Hussein Rizk*, Soliman Gharib*, Mohamed Diaa Dardir**,

Hossam Kandil*, Magdi Adb El Hamid*,Maged Abd Alaah***,

Hassan Khaled****and  Ihab Attia*****

*The Cardiology Department, Faculty of Medicine, Cairo University

** National Heart Institute, *** Intensive Care Unit, Matarya Hospital, **** Intensive Care Unit, Faculty of Medicine, Cairo University, ***** The Cardiology Department, Faculty of Medicine, Ain Shams University

 
Abstract

            Aim: We examined, in an open label a multi-center study, the efficacy of amlodipine, a 3^rd generation dihydropyridine calcium channel blocker with negligible inotropic and chronotropic activity and high trough-to-peak ratio in relieving angina symptoms and prolonging treadmill exercise time in patients with stable effort angina as compared to long-acting iso-sorbide mono-nitrate [ISMN].

            Methods: One hundred and twenty-three patients were randomized to receive amlodipine 5 or 10 mg once daily [65 (52.8%) patients or ISMN 20 or 40 mg twice daily [58 (45.2%) patients]. After a baseline symptom evaluation and exercise testing, the lower dose of each drug was started for 2 weeks and then doubled if no satisfactory relief of angina was observed. All patients were maintained on the adjusted dose for 4 weeks and then symptom evaluation and exercise testing were repeated. The two treatment groups were comparable regarding age, gender, number of angina episodes/week, number of sublingual nitrate tablets consumed weekly, score of angina control, heart rate, systolic and diastolic blood pressure [BP], total treadmill exercise time, maximal heart rate and BP reached, time to angina onset and time to ST segment depression.

Results: Both treatment lines improved symptoms markedly. However, amlodipine-treated patients had significantly fewer angina episodes/week [ 1.5 ± 2.4 versus 3.6 ± 4.3, P< 0.01] and fewer sublingual nitrate pills consumed weekly [1.5 ± 2.4 versus 3.1 ± 2.8, P< 0.01] than those receiving ISMN. Both drugs prolonged total treadmill exercise time [ from 7.6 ± 3.0 min. to 9.4 ± 3.1 min. for amlodipine and from 8.1 ± 3.0 min. to 10.7 ± 10.4 min.for ISMN]. Neither treatment produced significant heart rate or blood pressure change. Severe adverse reactions leading to drug discontinuation were observed in 10.3 % of patients of ISMN.

Conclusion: Compared to ISMN, the treatment of patients with chronic stable angina with amlodipine resulted in fewer angina episodes, less sublingual nitrate consumption, comparable exercise tolerance, much less adverse reactions and no drug discontinuation.

Introduction

Amlodipine is a calcium channel blocker of the 1,4-dihydropyridine class. The chemical structure of amlodipine differs from the other calcium channel antagonists of the same class by the presence of an amine-containing group in position 2 of the dihydropyridine ring ¹. Consequently, amlodipine has a long plasma half-life (35-50 hours) and steady-state plasma concentrations reached within 7 days ^2,3.

Effective plasma levels of the drug are maintained for 24-hours on a once-daily dosage regimen. This is important in the treatment of patients suffering from angina pectoris as the peak incidence of myocardial ischaemia often occurs in the early morning hours when the plasma level of drugs with shorter half-lives may be below the therapeutic level. Furthermore, the smooth onset of action eliminates the problem of reflex tachycardia associated with drugs characterized by a rapid onset of action.⁴

The drug has specific coronary and peripheral vasodilatory properties. Clinical studies comparing amlodipine with placebo ^5,6,7,8., with diltiazem ⁹, and in combination with b-blockers ^10,11 support amlodipine’s safety and efficacy in the treatment of angina with once-daily dosing.

Nitrates have been used for more than 100 years sublingually to treat, and for more than 30 years ( in transdermal and oral preparations) to prevent angina ¹². Nitrates have proved to be highly effective both in terminating acute attacks of angina and also in prevention of angina episodes ^13,14. Nitrates provide an exogenous source of endothelial-derived relaxing factor (EDRF), now known to be nitric oxide, which causes preload reduction by potent venodilation. Isosorbide-5- mononitrate, an active metabolite of isosorbide dinitrate, has proved to be an effective anti-anginal drug and is known to reduce not only angina, but also the incidence of silent myocardial ischaemia. ¹⁴

To our knowledge, few or no studies have compared the efficacy of amlodipine to that of isosorbide-5-mononitrate in treating angina pectoris.

The aim of this work is to compare the efficacy and tolerability of amlodipine versus a widely prescribed effective nitrate [long acting isosorbide-5-mononitrate ] in the treatment of symptomatic myocardial ischaemia.

Patients and Methods

1.      Design:

The study is a multicentre (6 centres) comparative study conducted in an open label, parallel group design.The trial duration was 8 weeks in total. At study entry, baseline history and angina evaluation was undertaken for two weeks while the patient was off medication [except sublingual isosorbide dinitrate [Dinitra 5 mg] permitted as required to relieve angina attacks]. At the second visit , patients were randomly assigned to receive either amlodipine in a dose of 5 mg/day, or long-acting isosorbide-5- mononitrate in a dose of 20 mg/b.i.d.. Patients were asked to report any side effects starting from this visit. The third visit, ( 2 weeks later), was used to adjust the dose: Patients who were still symptomatic on 5 mg once daily amlodipine, received 10 mg as a single dose/day, , while those who even still symptomatic on ISMN 20 mg b.i.d. , received 40 mg b.i.d. This was followed by a 4-week stabilization period, on the study drug, after titration to the appropriate dose. At the end of this stabilisation period, the drug efficacy was assessed by means of exercise stress testing, also performed at week 2. Sublingual isosorbide dinitrate was permitted throughout the trial for the symptomatic relief of angina.

C. Subject Selection:

A total number of one hundred and twenty-three (123) patients were recruited into the study; of them 65 (52.8% ) patients on amlodipine 5-10 mg once daily and 58 ( 45.2% ) patients on ISMN 20-40 mg twice daily The patients were randomly assigned using a randomization list. There were loss of follow-up of 2 patients for amlodipine group and 2 patients for ISMN group. Prior to study enrollment, informed consent was obtained from each subject in accordance with the recommendation of the revised Declaration of Helsinki (South Africa, 1996).

A.                 Inclusion Criteria

       1.         Newly diagnosed or chronic stable exercise-induced angina pectoris on no anti-anginal prophylactic therapy for the preceding 2 weeks.

       2.         Age:  from 21 to 75 year of age

       3.         Documented proof of myocardial ischaemia on exercise stress testing, i.e. at least 1 mm ST segment depression, flat or downsloping, measured 80 msecs after the J point within 9 minutes of the start of a graded treadmill exercise test using the Bruce protocol.

       4.         An average of three (3) or more angina attacks per week during the 2 weeks preceding entry into the study.

B.                 Exclusion Criteria

1.       A previous history of hypersensitivity to dihydropyridine calcium antagonists and nitrates, specifically amlodipine and long-acting isosorbide-5-mononitrate.

2.      A history or presence of:

·        Serious arrhythmias [ ventricular tachycardia, ventricullar fibrillation or bradycardia < 50 bpm]

·        Any serious or symptomatic valvular disease

·        Patients less than 3 months post myocardial infarction, angioplasty, CABG.

·        Hypertrophied or dilated cardiomyopathy

·        Hypertension [ arterial systolic B.P. > 160 and/or Diastolic B.P. > 90 mmHg , supine].

·        Symptomatic postural hypotension, or a drop in blood pressure of > 20 mmHg, systolic or, > 10 mmHg diastolic when assuming an upright posture for 2 min.

·        Existing or previous history of unstable angina.

·        Patients with highly positive stress test at baseline evaluation indicating the need for coronary angiography and possible re-vascularization.

·        ECG abnormalities which preclude interpretation of ischaemia [ left bundle branch block (LBBB),  left ventricular hypertrophy (LVH),  Wolf-Parkinsonian White (WPW) syndrome and digitalis effect].

·        Patients with heart failure  > NYHA class I

 

3.      Pregnancy, lactation or failure to be on adequate contraception if female and of childbearing potential.

 4.      A history of alcoholism, drug abuse, psychosis, antagonistic personality, poor motivation or other emotional or intellectual problems that are likely to invalidate informed consent, or limit the ability of the subject to comply with the protocol requirements.

 5.      Participation in any other studies involving investigational or marketed products within one month prior to entry into this study or concomitantly with this study.

 Data analysis were done to compare the parameters of exercise stress Test (EST) using the Bruce protocol at baseline and at the end of the study duration by Student’s (t) test.

 

Results

We examined in an open label , multi-center study, the efficacy of amlodipine, a 3^rd generation dihydropyridine calcium channel blocker with negligible inotropic and chronotropic activity in relieving subjective and objective markers of myocardial ischaemia as compared to the best available long-acting nitrate [long-acting isosorbide-5-mononitrate, ISMN].

One hundred and twenty-three patients { a total of 119 evaluable patients while loss of follow-up of  4 patients }, were randomized to receive amlodipine 5-10 mg once daily [65/123 (52.8% ) patients] or ISMN 20-40 mg twice daily [58/123  ( 45.2 % ) patients] as described under methodology, above; There were 65/123 (54.6%) males and  68/123 (57.1%) females, their ages ranged between 27 and 68 years. For amlodipine, there were 27/65 (39.1%) males and 39/65 (60%) females and results showed that 60/65 ( 92.3%) patients completed the study without adverse events, 3/65 (4.6%) had tolerable adverse events and 2/65 (3.1%) patients were dropped-out of the study. Only 7/65 (10.8%) patients were on 10 mg/day. As regards ISMN, , there were 29/58 (50%) males and 29/58 (50%) females and results showed that 39/58 (67.2%) patients completed the study without adverse events, 11/58 (19%) had tolerable adverse events, 6/58 (10.3%) had permenantly discontinued from the study due to untolerable adverse events and 2/58 (3.5%) patients were dropped-out of the study. There were 12/58 (21%)  patients on 80 mg/day.

{ No concomitant therapy with b-blockers was used during the study period}.

            BASELINE CHARACTERISTICS [ TABLE 1]:

The two treatment groups were comparable regarding age, gender, number of angina episodes/week, number of sublingual nitrate tablets consumed weekly, score of angina control, heart rate, systolic and diastolic B.P., total treadmill exercise time, maximal heart rate and B.P. reached, time to angina onset and time to ST segment depression.

Table [1]: The baseline characteristics of patients enrolled in the study.

 

Efficacy of treatment [Table 2]

Both treatment lines improved symptoms markedly. However, amlodipine-treated patients had significantly fewer angina episodes and fewer sublingual nitrate pills consumed weekly than those receiving iso-sorbide mononitrate [Fig. 1 A&B]. Both drugs significantly prolonged total exercise time and time to angina onset [Fig. 1 C&D]. At exercise testing during final evaluation, the maximal systolic B.P. reached was not significantly different, but the maximal heart rate reached was significantly higher in the amlodipine group.

Table [2]: Comparison between the study groups regarding the efficacy of treatment.

 Tolerability and side effects [ tables 3 & 4]

More patients on amlodipine were totally free of adverse effects than patients on isosorbide-5-mononitrate. Moreover, 10.3% of patients on isosorbide-5-mononitrate had to discontinue treatment because of intolerable adverse effects while none of patients on amlodipine had to discontinue treatment for this reason [table 3].

 

Table [3]: Incidence and severity of adverse effects.

 

	Amlodipine	ISMN
No adverse reactions	87 %	67.2 %
Tolerated symptoms, drug continued	4.3 %	19 %
Severe symptoms, drug discontinued	0 %	10.3%

The incidence of different adverse reactions is shown in table 4. The most commonly encountered side effect of long acting nitrate therapy was headache, which was the cause of drug discontinuation in 37.5 % of those who suffered it.

Table [4]: Number of patients suffering individual adverse effects.

 

	Amlodipine	ISMN
Headache	0	16
Dizziness/drowsiness	2	1
Fatigue	1	0
Palpitation	1	0
Nausea	0	1

 

Discussion:

            PERSPECTIVE:

In chronic coronary heart disease, myocardial ischaemia is an important cause of a symptom-limited life style. Both symptomatic and silent myocardial ischaemia are deleterious to myocardial systolic and diastolic performance, electric stability and overall survival ⁽¹⁵⁾ . The control of myocardial ischaemia is- thus- an important therapeutic target in chronic coronary artery disease.

          LIMITATION OF NITRATE THERAPY:

While long-acting nitrates remain the standard of preventing angina episodes, these drugs have two problems: a prominent adverse effect profile, mainly relating to headache, and the development of nitrate tolerance which may develop in up to 68% of patients, calculated as the mean of the percentage loss of the peak effect achieved by nitrates ⁽¹⁶⁾.

Avoidance of nitrate tolerance requires the provision of a drug-free interval, which leaves the patient vulnerable to myocardial ischaemia. This is particularly so if nitrate-free time coincides with the morning catecholamine rise. This is often the case if long acting nitrate is prescribed on a 9 am and 4 pm basis as currently recommended ⁽¹⁷⁾ .

LIMITATIONS OF SHORT-ACTING CALCIUM ANTAGONISTS:

The use of agents with low trough-to-peak ratio is associated with a poor 24-hour anti-ischaemia coverage. Even worse, short-acting dihydropyridine use is associated with the activation of two adverse counter-regulatory mechanisms: the sympathetic nervous system and the renin-angiotensin system. The use of these agents was associated with an excess of coronary events in several studies ( ^18,19,20) .

THE PRESENT STUDY:

This study showed convincingly that, compared to the best available nitrate therapy, amlodipine, a long-acting dihydropyridine with high trough-to-peak ratio and negligible inotropic and chronotropic effects produced a drastic reduction of ischaemic symptoms and amelioration of exercise-induced myocardial ischaemia in a normotensive population with chronic stable angina pectoris. This was achieved with minimal side-effects and without any significant blood pressure reduction.

CONCLUSION:

          It may be concluded that, compared to iso-sorbide mono-nitrate, the treatment of patients with chronic stable angina with amlodipine resulted in fewer angina episodes, less sublingual nitrate consumption, comparable exercise tolerance, fewer significantly adverse reactions and n o drug discontinuation.

CLINICAL IMPLICATION:

          While long-acting nitrates remain the standard of angina prevention in chronic stable angina, amlodipine is a reasonable alternative either to complement oral nitrate during the nitrate-free interval of the day or to replace these agents if their side-effect profile is not acceptable.

 This research was supported by a grant of The Clinical Research Department- Pfizer-Egypt.

REFERENCES

1)    Arrowsmith, JE et al (1986): Long-acting dihydropyridine calcium antagonists. 1,2-albolmethyl derivatives in coporating basic substituents. J. Med. Chem. 29, 1696-1702.

2)      Faulkener, JK et al (1986): The pharmacokoinetics of amlodipine in healthy volunteers single intravenous and oral doses and after repeated oral doses given once daily. Br. J. Pharmacol. 22, 21-25.

3)      Williams, D.M. and Cubeddu, L. (1988): Amlodipine pharmacokinetics in healthy volunteers. J. Clin.Pharmacol. 20, 990-994.

4)      Abbernethy,DR (1989): The pharmacokinetic profile of amlodipine. Am. Hear. J., 118 (5), 1100-1103.

5)      Reid, JL et al (1988): Pharmacokinetics of calcium antagonnists. J. Cardiovasc. Pharmacol. 12, 522-26.

6)      Kinnard, D.R. et al. (1988): Endurance testing for evaluation of antianginal therapy with amlodipine, a calcium channel blocking agent. J. Am. Col. Cardiol., 12, 791-796.

7)      Thadani, U (1989): Amlodipine: A once-daily calcium antagonist in the treatment of angina pectoris-a parallel dose response, placebo-controlled study.  The amplodipine study group. Am. Heart J., 118: 1135.

8)      Thaylor, S.H. et al. (1991): A double-blind, placebo-controlled, parallel dose-resposne study of amlodipine in stable excertional angina fectoris. J. Cardiovasc./ Pharmacol. 17, s 46-49.

9)      Bernink, P.J. et al (1991):  An 8-week double-blind study of amlodipine and diltiazem in patients with stable exertional angina pectoris. J. Cardiovasc. Pharmacol., 17, s53-56.

10)    Klein, W et al (1991): A 6-week double-blind comparison of amlodypiene and placebo in patients with stable exertional angina pectous receving concomittant. B-blocker therapy./ J. Cardiovasc. Pharmacol, 17, s 50-52

11)         Singh S et al (1989): Amlodipine versus nadolol in patients with stable angina pectous. Am. Heart J., 118, 1137-38.

12)         Brown BG.; Bolson E.; Peterson RB.; Pierce CD.; and Dodge HT. (1981): The mechanism of nitroglycerin action: stenosis vasodilation action  as a major component of the drug response. Circulation, 64, 1089-1097.

13)         Parratt JR. (1979): Nitroglycerin- the first one hundred years- new facts about an old drug. J.Pharm. Pharmacol. ,31, 801-809

14)         Horwitz LD.; Gorlin R; Taylor WJ; and Kemp HG  (1971): Effects of nitroglycerin on regional myocardial blood flow in coronary artery disease. J.Clin. Invest., 50, 1578-1584

15)         Chatterjee K (1990): Ischaemic heart disease. In: Internal Medicine. Stein JH (editor). Little, Brown.

16)         Dakak N.; Makhoul N.; Flugelman MY.; et al (1990): Failure of captopril to prevent nitrate tolerance in congestive heart failure secondary to coronary artery disease. Am. J. Cardiol. 66(5): 608-13.

17)         Goodman and Gilman’s (1990): The pharmacological Basis of Therapeutics. Eighth Edition. In: Drugs Used for the Treatment of Angina. Chap. 32, pp. 767, 774.

18)         Gaviraghi G.; Micheli D.; Trist D (1995): Recent developments in the use of calcium antagonists in myocardial protection. Pharmacol. Res. 31(3-4) : 251-4.

19)         Buhler FR (1997): Cardiovascular care with the new T-type calcium channel antagonist: possible role of attendant sympathetic nervous system inhibition. J. Hypertens. Suppl. 15 (5): S3-7.

20)         Ruschitzka FT.; Noll G.; Luscher TF (1998): Combination of ACE inhibitors and calcium antagonists: a logical approach. J. Cadiovasc. Pharmacol. , 31 Suppl 2 : S5-16