Understanding ischemic heart disease and scope for amlodipine-atenolol combination.

Ischemic heart disease is one of the most common causes of mortality and morbidity worldwide. The medical management of this condition is targeted at reducing myocardial oxygen demand, improving flow toward ischemic regions, and countering the arrhythmogenicity induced by the ischemic substrate. (1) It is well established that amlodipine dihydropyridine-type (DHP)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). Next, we will review the scientific data and aim to answer a few important clinical queries.

The tale of the evolution of amlodipine- atenolol partnership.

Angina relief will often require more than one antianginal. In this scenario with multiple options available, how does a physician choose one drug (or combination) over the other?

While the initial treatment may be a beta-blocker or a calcium channel blocker (CCB) (like verapamil or diltiazem), when the need for combination therapy arises, the additive antianginal effect of two drug classes is surpassed by the additive adverse effects of this combination. The risk of additive cardio-depressant effect, prolonged AV nodal conduction, and elevating the right and left ventricular filling pressures are some of the important side effects that make this combination undesirable (4).

In this regard, a vasodilator calcium channel blocker like nifedipine was initially evaluated for combination therapy with beta-blockers for angina relief. (4) But 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 (5), it has a gradual onset of action and a prolonged half-life (5,6) that causes little or no reflex tachycardia (7). These properties improve its efficacy in suppressing ischemia (2)

Mechanism of synergistic efficacy

Amlodipine reduces coronary tone, decreases coronary vasoreactivity, and lowers cardiac oxygen demand by reducing afterload (8,9). Atenolol belongs to the class of cardio-selective beta-blockers that improve survival (10). 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)

When combined together, these two drugs improve time to ST-segment depression on exercise testing by 34% (improved only 3%) by atenolol alone. The frequency of ischemic episodes decreases by 72% (57% with atenolol alone). (2)

Actions beyond "just angina relief"

Amlodipine itself has been found to impact the progression of atherosclerosis at both coronary and carotid levels. In the PREVENT trial, patients treated with amlodipine reduced the progression of carotid atherosclerosis, as measured by the change in the intima-media thickness, compared with those treated with placebo. Moreover, amlodipine treatment was associated with fewer cases of unstable angina and coronary revascularization. (11) In the CAMELOT trial, amlodipine significantly reduced the rate of the primary end-point of cardiovascular events compared with placebo. (12) As for beta-blockers, studies have found a robust antiplatelet effect (13) and slowing of the rate of atherosclerosis (14).

Beating the odds in adverse effect profile:

It has been shown that several of the individual side effects of amlodipine and atenolol 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). This countering of each other's side effects further makes it one of the most ideal combinations.

The evidence base for Amlodipine-atenolol combination in angina relief.

Back in 1998, Dunselman et al (15) 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 0.1 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 improved safety aspects. 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 showed that this drug combination improved exercise time and time to onset of angina without significant change in heart rate or cardiac output. (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 (16). In contrast, dihydropyridines like amlodipine are safe in such combinations. Amlodipine does not produce reflex tachycardia or a cardio depressant effect. (17)

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. Amlodipine tended to reduce the frequency of painful myocardial ischemic episodes by 45% while diltiazem does not affect this parameter. (18)

Hypertensive patients with ischemic heart disease: an ideal indication.

Hypertension is one of the major risk factors for ischemic heart disease and appropriate control of blood pressure is the cornerstone of both primary and secondary ischemic heart disease prevention (19). Studies have shown that the cardiovascular protection provided by amlodipine in hypertensive patients is at par with any other antihypertensive agents. (20). Further addition of atenolol to amlodipine offers more robust BP control (21) and thus this "hypertensive IHD" class of patients form a near-perfect indication for this drug combination.

Why single daily dosing ensures compliance?

Most currently available CCBs require twice or thrice daily dosing due to their short half-lives (7). Amlodipine and atenolol combination has a long half-life which endows it an attractive therapeutic potential with a once-daily dosing regimen. (22).

How to ensure drug adherence?

The keystone in managing chronic conditions is ensuring compliance. Amlodipine –atenolol fixed-dose combination by virtue of its safe side-effect profile ensures good compliance. Further, this 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 (23).

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:

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19. Jindřich Špinar,Hypertension and ischemic heart disease, Cor et Vasa,2012 Volume 54, Issue 6, e433-e438

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22. Sharma Diksha, Mehta Dinesh Kumar, Bhatti Karun, Das Rina, Chidurala Ram Mohan. Amlodipine and Atenolol: Combination Therapy Versus Monotherapy in Reducing Blood Pressure – A focus on Safety and Efficacy. 2020. Research Journal of Pharmacy and Technology.

23. Enrica Menditto, Valentina Orlando, Giuseppe De Rosa, Paola Minghetti, Umberto Maria Musazzi, Caitriona Cahir, Marta Kurczewska-Michalak, Przemysław Kardas, Elísio Costa, José Manuel Sousa Lobo and Isabel F Almeida. Patient Centric Pharmaceutical Drug Product Design—The Impact on Medication Adherence. 2020. Pharmaceutics