Reviewing the triple A in cardiology: The role of amlodipine-atenolol in angina relief

Published On 2021-07-27 07:15 GMT   |   Update On 2021-09-04 09:23 GMT

Amlodipine, a charged dihydropyridine-type (DHP) calcium channel blocker (CCB), has been widely used to treat hypertension. (1) Amlodipine especially in combination with beta-blockers has been shown to be highly beneficial for angina relief in situations where angina relief is not satisfactory with monotherapy with beta-blockers. (2, 3)

The following review aims to explore the specific advantages of the amlodipine-atenolol combination in angina relief by discussing their additive mechanisms and better tolerability in a fixed-dose combination across the spectrum of angina syndromes.
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Why amlodipine and beta-blocker combination scores over other antianginals?
Many patients with angina require more than one agent to control their symptoms. (2) While the initial treatment may be a beta-blocker or a calcium channel blocker [CCB] (like verapamil or diltiazem), when the need for monotherapy arises the combination of above two classes may pose a risk of additive cardio depressant effect, prolong the AV nodal conduction and elevate the right and left ventricular filling pressures (4).
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In this regard, a calcium channel blocker with predominant vasodilatory action- nifedipine was initially evaluated for combination therapy with beta-blockers for angina relief. (4) However, the vasodilation induced an acute increase in heart rate and thus the combination could not be considered suitable.
From here, further research paved the way for use of amlodipine in combination with atenolol for angina relief. Being a third-generation CCB, it has a gradual onset of action and a prolonged half-life (5) that causes little or no reflex tachycardia.(6) These properties improve its efficacy in suppressing ischemia.
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Mechanism of synergistic efficacy and minimization of side-effects with this combination
Amlodipine reduces coronary tone, decreases coronary vasoreactivity and lowers cardiac oxygen demand by reducing afterload. (7,8) Atenolol belonging to the class of cardio-selective beta-blockers improves survival (9) and belong to the most effective drug class for angina relief. It does so by reducing both the double product at onset of ischemia during treadmill testing and heart rate at onset of ischemia during ambulatory monitoring. (2)
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When combined together, these two drugs improve time to ST-segment depression on exercise testing by 34% (improved only 3% by atenolol alone). (2) The frequency of ischemic episodes decreases by 72% (57% with atenolol alone) (2).
If we talk about the adverse effect profile, it has been shown that several of the individual side-effects are mitigated when the two drugs are combined. For example, the heart rate lowering effect of atenolol is offset by systemic vasodilatation induced reflex sympathetic activity by amlodipine (3). The coronary vasoconstrictor effect of atenolol is mitigated by coronary vasodilatation by amlodipine.(2) Thus, the combination of these two drugs with different mechanisms of action, not only has additive benefits for angina relief but offers a collateral advantage of mitigation of each other's adverse effects.
The evidence base for Amlodipine-atenolol combination in angina relief.
Back in 1998, Dunselman et al (10) showed that the addition of amlodipine to atenolol in the treatment of myocardial ischemia despite optimal beta-blockade was well tolerated and led to improvement in symptomatic angina. The time to 1 mm ST-segment depression, time to onset of chest pain and total exercise duration improved with the combination therapy. Most notable was the finding of the improved safety aspect. Only 1 patient had treatment-related withdrawal.
The CASIS study showed that ischemia during treadmill testing was more effectively suppressed by amlodipine, whereas ischemia during ambulatory monitoring was more effectively suppressed by atenolol. Their combination on the other hand was more effective than monotherapy with either drug. (2)
Woodmansey et al amlodipine is effective as an additional agent when angina is uncontrolled on atenolol. It did not adversely affect cardiac output nor did it cause a disturbance of cardiac rhythm.(3)
How amlodipine is better than other CCBs like verapamil/diltiazem for angina patients?
Both diltiazem and verapamil may produce significant bradycardia and worsening of cardiac function when prescribed with beta-blockers. (11) In contrast dihydropyridines like amlodipine are safe in such combinations. Amlodipine does not produce reflex tachycardia or a cardio depressant effect. (12)
Further, in CESAR study it was shown that once-daily amlodipine or twice daily diltiazem in addition to atenolol have similar efficacy in angina relief but diltiazem is associated with more serious adverse effects. (13) Amlodipine tended to reduce the frequency of painful ischemic episodes by 45% while diltiazem does not affect this parameter. (13)
Why single daily dosing ensures compliance?
Most currently available CCBs require twice or thrice daily dosing due to their short half-lives .(6) Amlodipine and atenolol combination has a long half-life which endows it with an attractive therapeutic potential with a once-daily dosing regimen. (5).
Special drug packs promote adherence.
The keystone in managing chronic conditions is ensuring compliance. Patients need behavioural skills to facilitate the adoption and integration of medication-taking into everyday life. These behavioural skills use self-monitoring of adherence example by using calendarized packaging. (14) Amlodipine –atenolol fixed-dose combination is available in special blister packaging that has "day" reminders printed on it. All the days of the week are printed in a sequential manner with an arrow guided sequence to ensure optimal dose adherence. Such simple measures help to achieve drug compliance goals in patients who are on polypharmacy or those in the elderly age group who are unlikely to keep a strict record of their daily medicine intake.
Conclusion:
Amlodipine-atenolol combination improves the anti-anginal efficacy over monotherapy and its extremely well-tolerated safety profile makes it an attractive candidate for angina management. Specifically, in situations like underlying rhythm disturbance or reduced ventricular systolic function, where a combination of beta-blocker with verapamil or diltiazem may be contraindicated, this combination offers multiple benefits. The fixed-dose combination packs are now available with tracking markers to ensure that "missed doses" do not hamper the angina relief provided by the combination.
References:
1. Seung-Ah Lee, Hong-Mi Choi, Hye-Jin Park, et al , Amlodipine and cardiovascular outcomes in hypertensive patients: a meta-analysis comparing amlodipine-based versus other antihypertensive therapy, Korean J Intern Med. 2014 May; 29(3): 315–324
2. Davies RF, Habibi H, Klinke WP, et al. Effect of amlodipine, atenolol and their combination on myocardial ischemia during treadmill exercise and ambulatory monitoring. Canadian Amlodipine/Atenolol in Silent Ischemia Study (CASIS) Investigators. J Am Coll Cardiol. 1995 Mar 1;25(3):619-25
3. Woodmansey PA, Stewart AG, Morice AH, Channer KS. Amlodipine in patients with angina uncontrolled by atenolol. A double-blind placebo-controlled cross over trial. Eur J Clin Pharmacol. 1993;45(2):107-11
4. Leon MB, Rosing DR, Bonow RO, Epstein SE. Combination therapy with calcium-channel blockers and beta-blockers for chronic stable angina pectoris. Am J Cardiol. 1985 Jan 25;55(3):69B-80B
5. Abernethy DR. The pharmacokinetic profile of amlodipine. Am Heart J. 1989 Nov;118(5 Pt 2):1100-3.
6. Burges RA, Dodd MG, Gardiner DG. Pharmacologic profile of amlodipine. Am J Cardiol. 1989 Nov 7;64(17):10I-18I; discussion 18I-20I.
7. Follath F. The role of calcium antagonists in the treatment of myocardial ischemia. Am Heart J. 1989 Nov;118(5 Pt 2):1093-6
8. Bache RJ. Effects of calcium entry blockade on myocardial blood flow. Circulation. 1989 Dec;80(6 Suppl):IV40-6
9. Åke Hjalmarson, International beta-blocker review in acute and postmyocardial infarction, The American Journal of Cardiology, Volume 61, Issue 3, 1988, Pages 26-29.
10. Dunselman PH, van Kempen LH, Bouwens LH, Holwerda KJ, Herweijer AH, Bernink PJ. Value of the addition of amlodipine to atenolol in patients with angina pectoris despite adequate beta blockade. Am J Cardiol. 1998 Jan 15;81(2):128-32.
11. Dargie HJ. Beta-blockers and calcium antagonists in angina pectoris. The potential role of combination therapy. Drugs. 1988;35 Suppl 4:44-50
12. Murdoch D, Heel RC. Amlodipine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in cardiovascular disease. Drugs. 1991 Mar;41(3):478-505.
13. Knight CJ, Fox KM. Amlodipine versus diltiazem as additional antianginal treatment to atenolol. Centralised European Studies in Angina Research (CESAR) Investigators. Am J Cardiol. 1998 Jan 15;81(2):133-6
14. Bosworth HB, Granger BB, Mendys P, et al. Medication adherence: a call for action. Am Heart J. 2011 Sep;162(3):412-24.
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