A fixed-dose combination of a selective beta-blocker and a calcium channel blocker for hypertension
Hypertension is one of the most common conditions seen in primary care, and is recognized as a major risk factor for coronary, cerebral and renal vascular diseases. Despite the armamentarium of available treatment options, many patients who receive antihypertensive treatment in primary care do not achieve recommended blood pressure (BP) goals. In a recent webinar, two experts shared insights on optimal hypertension management, with an emphasis on improving patients’ adherence to medication and the use of a fixed-dose combination (FDC) of bisoprolol fumarate and amlodipine (Concor® AMLO, Merck).
Rationale for targeting heart rate in hypertension management
“High heart rate [HR] and high BP have long been recognized as predictors of hypertension,” said Professor Sverre E. Kjeldsen of University Hospital of Ullevaal, Norway.
In hypertensive patients, the Losartan LIFE (Intervention for End Point Reduction in Hypertension) study demonstrated that persistence or development of a HR of ≥84 bpm was associated with a 46 percent higher risk of developing atrial fibrillation (AF). [Circ Arrhythmia Electrophysiol 2008;1:337-43] Subsequent studies also showed that HR of ≥84 bpm during antihypertensive treatment predicted a greater risk of incident heart failure (HF) and was associated with higher cardiovascular (CV) and all-cause mortality. [Am J Cardiol 2012;109:699-704; Eur Heart J 2010;31:2271-2279]
BB/CCB combination to control BP and reduce HR
“In the VALUE [Valsartan Antihypertensive Long-term Use Evaluation] trial, the calcium channel blocker [CCB] amlodipine was chosen as the comparator as it was, and still is, the most used CV drug with a half-life of 37 hours, a well-tolerated safety profile, and powerful antihypertensive and anti-ischaemic properties,” said Kjeldsen. “Amlodipine lowered BP more than expected, resulting in an unintended early difference in systolic BP between the two treatment arms of VALUE.” [Lancet 2004;363:2022-2031]
According to the 2018 European Society of Cardiology/European Society of Hypertension (ESC/ESH) Clinical Practice Guidelines for the Management of Arterial Hypertension, beta-blockers (BBs) in combination treatment should be preferentially used when there is a specific clinical indication, such as in patients requiring HR control, post-MI patients, patients with HF or AF, or younger women with or planning pregnancy. [Eur Heart J 2018;39:3021-3104] “There is a long list of other indications where the use of BBs is preferred in patients with hypertension, including glaucoma, migraine and aortic aneurysm,” noted Kjeldsen.
Bisoprolol is a highly selective BB shown in vitro to have a 19.6-fold higher affinity for the beta1 receptor compared with the beta2 receptor. [Cardiovasc Drugs Ther 1999;13:123-126]
“The combination of a BB such as bisoprolol with a CCB such as amlodipine is an established option for BP management cited in the 2013 and 2018 ESC/ESH guidelines,” noted Kjeldsen. [Clin Drug Investig 2009;29:427-439; J Hypertens 2013;31:1281-1357; Eur Heart J 2018;39:3021-3104]
The combination of amlodipine (which selectively inhibits calcium ion influx across cell membranes) with the highly beta1-selective bisoprolol results in an additive effect due to the different but complementary modes of action to control BP and reduce HR. “Amlodipine lowers total peripheral resistance, whereas bisoprolol lowers HR and cardiac output,” Kjeldsen explained. [Cardiovasc Disord Med 2016, doi: 10.15761/CDM.1000118]
FDC for better BP lowering and treatment adherence
A study that investigated the BP-lowering effect of amlodipine, bisoprolol and the FDC of amlodipine plus bisoprolol in patients with stage 2 essential hypertension demonstrated that the amlodipine-bisoprolol FDC conferred significant BP control with an antihypertensive effect that was greater than that achieved with amlodipine alone. In patients who received the FDC, systolic BP decreased from 164.2 mm Hg to 136.0 mm Hg. (Figure) [Int J Med Res Health Sci 2012;1:13-19]
More recently, a large noninterventional study (n=10,532) investigated the effects of switching from a free-dose combination to a FDC of amlodipine plus bisoprolol on treatment adherence and BP control. After 6 months on the FDC, mean systolic BP dropped from 147.3 mm Hg to 130.9 mm Hg. “The investigators also observed a substantial reduction in HR, from an average of 75 bpm to 68.6 bpm [±10],” noted Kjeldsen. [Cardiol Ther 2015;4:179-190]
“The data demonstrate the benefits of prescribing a FDC of bisoprolol plus amlodipine in terms of excellent adherence and an associated improvement in control of previously elevated BP,” the investigators concluded. [Cardiol Ther 2015;4:179-190]
Practical management of resistant hypertension
“In evaluation of resistant hypertension, the first step is to confirm treatment resistance. This should be followed by exclusion of pseudoresistance, which is done by confirming adherence to antihypertensive therapy,” said Dr Andy Wai-Kwong Chan, Specialist in Cardiology in Hong Kong. [Hypertension 2018;72:e53-e90] “Nonadherence to therapy is one of the main reasons for resistant hypertension.”
Once pseudoresistance has been excluded, the ESC/ESH Guidelines for the Management of Arterial Hypertension recommends that physicians assess common causes of secondary hypertension, such as obstructive sleep apnoea, primary aldosteronism and other endocrine conditions. [Eur Heart J 2018;39:3021-3104]
“Optimal management of resistant hypertension involves reinforcement of lifestyle changes, such as diet modification [on top of a low-sodium diet], weight loss and exercise. A BB may be added to the treatment regimen as this class of drugs has been shown to reduce the risk of HF and major CV events in hypertensive patients,” noted Chan.