Cardiovascular disease is the leading cause of death worldwide, and hypertension is a modifiable risk factor for cardiovascular disease. Risk increases with incremental increases in blood pressure, even within the normal range. Studies across different populations have now indicated that more than 70% of adults treated for primary hypertension will eventually require at least two antihypertensive agents(1)
When to switch from monotherapy to combination therapy?
Most of the guidelines including the 2017 AHA, 2018 ESC and JNC8 advocate the use of combination therapy in those patients where:
1. Target BP cannot be reached within few weeks of monotherapy.
2. At the time of diagnosis in patients with systolic blood pressures >160 mmHg and/or diastolic pressures >100 mmHg.
These constitute 10–15% of hypertensive populations and are at substantially greater risk of a future cardiovascular event. For every 20 mmHg increase in systolic blood pressure, there is an approximate doubling of cardiovascular risk.(5)
How is a CCB – Beta-blocker combination ideal in hypertension?
The combination therapy with amlodipine and atenolol for hypertension is suitable for two reasons: first, these two drugs act on different physiological systems. Amlodipine is a dihydropyridine calcium antagonist that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. Atenolol is a beta1-selective (cardio-selective) beta-adrenergic receptor blocking agent that has cardioinhibitory, central sympatholytic and renin-angiotensin axis inhibitory properties to ameliorate high BP.
Second, these drugs block the counterregulatory responses that are activated by the perturbation of the blood pressure regulatory mechanisms, for example reflex tachycardia induced by amlodipine mediated vasodilation is mitigated by negative chronotropic effects of atenolol. Similarly studies have shown that combining atenolol with amlodipine reduces the rate of constipation by up to 4 times as compared to amlodipine montherapy.(3)
Many of the side effects of these drugs are dose-dependent, for eg. the chances of developing pedal edema with amlodipine increase if the dose is increased from 5 mg to 10 mg. Thus when target BP is not achieved on 5mg daily dose, addition of a second drug like atenolol may be more rational than increasing the dose of montherapy.
Successful management of BP needs compliance with an ideal combination therapy
The basic principle for successful management of chronic conditions is medication compliance. Missed dose alone is not the only problem associated with drug compliance. Many patients especially of the elderly age group may often forget if they have taken their medicine or not. This may lead to double dosing of drugs. Suboptimal adherence, which includes failure to take medications as often as prescribed, and to persist on therapy long-term, is a well-recognized factor contributing to the poor control of blood pressure in hypertension (4) In addition, strict adherence to the timing of medicine intake is also very crucial most anti-hypertensives have a small half-life of 12-24 hours. In this regard, any skipped dose has the potential for a spike in BP and its clinical consequences.
In this regard, Fixed drug combinations (FDC) are formulated to simplify the medication regimens and thereby help in improving drug compliance. To help with this, some of them even have a day reminder on the packs. Such FDC pill is benefitted by a single day dosing which improves adherence, reduces cost, and eventually improve BP control.
Further improving the adherence is the launch of track-packs for this combination therapy, where patients can themselves monitor the daily intake of medicine and ensure that none of their doses are missed. The FDC therapy of amlodipine and atenolol is widely accepted for managing hypertension and chronic stable angina. It is now available in blister packaging that can help patients to keep a track of patient's daily intake. Days of the week are listed for each tablet in an arrow-guided sequence which ensures optimal dose adherence. Such measures help to a great extent in achieving BP goals in patients who are likely to miss their doses like elderly, or patients on multiple drugs for a condition like heart failure or coronary artery disease, etc.
Evidence base for amlodipine-atenolol combination:
Johnson BF et al. found that once-daily administration of amlodipine or atenolol was well-tolerated and provided adequate blood pressure control.(6) Pehrsson SK et al. found drug atenolol was more effective than amlodipine regarding total time and number of ST-depression episodes. They conclude that none of the drugs given alone is more effective than a combination of a beta-blocker with a calcium antagonist.(7)
A 12-week follow-up concluded that superior antihypertensive efficacy is offered by once-daily treatment with atenolol/amlodipine fixed-dose combination over atenolol monotherapy in patients.(8) Side-effects were found to be reduced by adding amlodipine to a beta-blocker which confirms the effectiveness of this combination.(9)
Why this combination is better than other fixed-dose combinations?
Other FDC combinations are also available for BP control, for eg. a combination of an ACE inhibitor(ACE-I) or an Angiotensin receptor blocker (ARB) with a beta-blocker or a thiazide diuretic or amlodipine itself. Such combinations have three important limitations (3): firstly, they pose the risk of hyperkalemia and worsening of renal function in patients with chronic kidney disease, secondly, they are unsafe for women of childbearing age group as any unplanned pregnancy while taking these drugs poses the risk of teratogenicity, and thirdly both ACE-I and ARBs lack any antianginal action. Another limitation is the high price of ACE-I or ARB-containing combinations.FDC of amlodipine and atenolol does not worsen renal function, is non-teratogenic, both drugs have antianginal action and is lower in cost.
Amlodipine-atenolol combination is available as amlodipine 5 mg with atenolol either 25mg or 50mg pack. Most adverse reactions reported during therapy with amlodipine and atenolol are of mild or moderate severity. Discontinuation of amlodipine due to adverse reactions was required in only about 1.5% of patients and was not significantly different from placebo (about 1%). The most commonly reported adverse reactions are headache and edema. Atenolol should be cautiously used in patients with history of peripheral artery disease, bronchial asthma, and bradyarrhythmias.(3)
The dosage of this combination should be reduced in patients with a creatinine clearance <35 ml/min/1.73 m(2).
Take home message for clinicians
Amlodipine proved to be highly effective for the treatment of hypertension and stable angina as evidenced by the fewer hospitalizations for unstable angina and revascularization in randomized controlled trials. It is effective for minimizing BP variability (BPV). Atenolol like beta-blockers are effective and safe antihypertensive drugs.
Fixed dose drug combination (FDC) of amlodipine and atenolol are being prescribed extensively for the management of hypertension and chronic stable angina. By combining two drugs with different mechanisms of action, an antihypertensive effect of two to five times greater than that obtained by monotherapy is possible.(10) Increasing the dose of monotherapy reduces coronary events by 29% and cerebrovascular events by 40%, while combining two antihypertensive agents with a different mechanism of action which help to reduces coronary events by 40% and cerebrovascular events by 54%. (11) Thus, the use of combination therapy provides greater protection to target organs and is particularly beneficial in patients with:
a) HTN associated with stable angina
b) HTN in the setting of mild to moderate renal dysfunction
c) Hypertensive females of child bearing age group
1. Cushman WC, Ford CE, Cutler JA, et al.; ALLHAT Collaborative Research Group. Success and predictors of blood pressure control in diverse North American settings: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). J Clin Hypertens (Greenwich). 2002; 4(6): 393-404.
2. Sever PS, Messerli FH. Hypertension management 2011: optimal combination therapy. Eur Heart J. 2011 Oct;32(20):2499-506. doi: 10.1093/eurheartj/ehr177. Epub 2011 Jun 22. PMID: 21697169.
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4. Burnier M, Egan BM. Adherence in Hypertension. Circ Res. 2019 Mar 29;124(7):1124-1140. doi: 10.1161/CIRCRESAHA.118.313220. PMID: 30920917.
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8. Mettimano M, Pichetti F. Combination therapy with beta-adrenergic blockade and amlodipine as second line treatment in essential hypertension. Int J Clin Pract 2000; 54:424-8.
9. Davies RF, Habibi H, Klinke WP, Dessain P, Nadeau C, Phaneuf DC, Lepage S, Raman S. Effect of amlodipine, atenolol and their combination on
10. Wald DS, Law M, Morris JK, Bestwick JP, Wald NJ. Combination therapy versus monotherapy in reducing blood pressure: meta-analysis on 11,000 participants from 42 trials. Am J Med 2009; 122:290-300.
11. Rubio-Guerra AF, Castro-Serna D, Elizalde-Barrera CI, Ramos-Brizuela LM. Current concepts in combination therapy for the treatment of hypertension: combined calcium channel blockers and raas inhibitors. Integr Blood Press Control 2009; 2:55-62
The above article has been published under the MD brand Connect Initiative