A Fixed‐Dose Combination of Bisoprolol and Amlodipine for Hypertension: A Potential Benefit to Selected Patients

Hypertension is thought to affect approximately 1 billion people worldwide.1 It is a major risk factor for coronary artery disease, stroke, congestive heart failure and renal failure, and treatment reduces the incidence of these outcomes.2 In several large clinical trials, the majority of patients needed more than 1 drug to reach goal.3 Some hypertension guidelines suggest starting with 2 drugs in patients whose blood pressure is greater than 160/90 mm Hg.4, 5 The number of patients requiring at least 2 medications will likely increase dramatically if the 120/80 mm Hg goal of the SPRINT study becomes accepted practice.6 Where 2 drugs are not needed to achieve target blood pressure, combination therapy may still be useful by allowing use of lower doses of each agent, thereby reducing side effects.3 A number of pills with a combination of 2 antihypertensives are available. The article in this issue by Gottwald-Hostalek et al discusses the advantages of a fixed combination of amlodipine, a dihydropyridine calcium channel blocker, and bisoprolol, a beta 1 selective nonvasodilating beta-blocker that has been widely used in Europe, though less so in the United States.7 A combination pill containing these 2 classes of medicines has only recently become available. The most commonly recommended classes of antihypertensive medications are thiazides or thiazide-like diuretics, angiotensin-converting enzyme inhibitors (ACEs), angiotensin receptor blockers, calcium channel blockers (CCBs), and beta-blockers (BBs).8 A number of studies have compared drugs from different classes to see if some classes are more effective at preventing complications given the same level of blood pressure control. Most have not been able to show a difference among the classes in overall mortality,9 but some studies have shown a difference in various end points. For example, patients receiving amlodipine had a higher incidence of heart failure in the ALLHAT study,10 and patients on CCBs have experienced a greater reduction in the incidence of stroke.11 In some but not all of the studies showing differences in outcomes for a particular class, there was a small difference in mean blood pressure that could have explained the finding. There are a number of additional limitations to these studies. By comparing only mean blood pressures to determine comparability of blood pressure control between therapeutic groups, there is an implicit assumption that complications due to hypertension are linearly related to blood pressure. While some studies suggest this relationship is linear,12 several large studies indicate that the relationship is log-linear, so that interval increases in blood pressure on the higher end result in much larger increases in adverse events than the same magnitude interval increase on the lower end.13 So without presenting the distribution of blood pressures in the different treatment groups, one cannot conclude that the groups achieved comparable control. In addition, blood pressure fluctuates throughout the day. The blood pressures recorded in most studies are just values obtained during an office visit, with visits spaced several weeks apart. Typically there is an early-morning blood pressure surge. There is evidence that the degree of this surge is an independent risk factor for adverse events.14 Some blood pressure medications, though dosed once a day, may have a duration of action significantly less than 24 hours, thereby failing to block the early-morning surge. Further, in these studies a large percentage of patients were put on a second drug to achieve the blood pressure goal, and patients were often no longer on the initial drug by the end of the trial, so these were not clean head-to-head trials. Because of the limitations in these studies, it is generally stated that the degree of blood pressure control is the most important factor in preventing complications of hypertension.4 But while these studies are quite limited in their ability to indicate whether one class of medicine is superior to another beyond its ability to control blood pressure, they may provide important data regarding differences in outcomes using these medicines in practice. For that reason some guidelines no longer recommend BBs as first-line agents.15 Several meta-analyses have demonstrated that BBs provide less protection against stroke than other antihypertensives, particularly in patients older than 60.16 The Cochrane Collaborative reviewed the use of BBs to treat hypertension. They felt that there was suggestive evidence that BBs conferred less protection against stroke than other antihypertensives.17 They felt that the evidence for a class difference was weak, as most of the studies showing reduced protection against stroke by the BB used atenolol in once-a-day dosage. Because its half-life is only 6 to 9 hours,18 it may not be adequate for 24-hour coverage. Another explanation that has been offered for the apparent poorer outcomes with BBs is that the older nonvasodilating agents such as atenolol may not lower central blood pressure as much as other agents given the same level of peripheral blood pressure reduction.19 Elevated central blood pressure may be the more important factor that leads to vascular complications.20 In addition, BBs are discontinued due to side effects at a higher rate than other classes of antihypertensives.17 Combinations of antihypertensive drugs have not been studied as extensively. In the ACCOMPLISH trial the combination of a thiazide diuretic and an ACE was compared with the combination of amlodipine and ACE.21 Though in ALLHAT the diuretic was superior to amlodipine,10 the combination of amlodipine and ACE was superior to diuretic and ACE in the ACCOMPLISH trial. This suggests that the relative advantages of different agents when used as a single agent may not apply when used as a combination (though an alternative explanation is that the thiazide-like diuretic chlorthalidone used in ALLHAT is superior to thiazides22). As Gottwald-Hostalek et al discuss, there are a number of potential advantages to fixed-dose combinations. The European Society of Hypertension guideline expresses a preference for fixed combination pills when more than 1 agent is required.4 Fixed combinations may increase compliance, leading to better blood pressure control.23 There are potential cost advantages. Polypills with a fixed combination of antihypertensive, antiplatelet and cholesterol-lowering medications have been studied and are felt to provide advantages, particularly in poorer countries with less developed health care delivery systems.24 A downside to fixed combination pills is they offer less flexibility in choosing the dose of the individual agents. They also do not allow for one medicine to be given in the morning and the other in the evening. Blood pressure typically falls during the first hours of sleep, though some patients do not exhibit this fall, so-called nondippers.25 The incidence of nondipping is increased in patients on more than 1 antihypertensive. There is some evidence suggesting that moving one of the medicines to bedtime restores the normal dipping pattern and leads to better outcomes.26 A fundamental principle in choosing which medicines should be combined is that their mechanisms of action must be complementary. The combination of a BB and dihydropyridine CCB meets this criterion. Other factors to consider in choosing an agent are other underlying disease processes, age, and race. CCBs are among the preferred agents for treating hypertension in black patients and older patients. Even in the absence of hypertension, BBs (and nondihydropyridine CCBs) are used for rate control in atrial fibrillation as well as in other arrhythmias. BBs and CCBs are both used in treating angina. BBs have been shown to reduce the incidence of subsequent myocardial infarction for at least 1 year after the initial event.27 They also have been shown to prolong life in patients with ejection fraction less than 40%.28 Amlodipine has a half-life between 30 and 50 hours and is therefore suitable for once-a-day dosing.29 The half-life of bisoprolol is between 9 and 12 hours, only a little longer than that of atenolol.18 And like atenolol, it is a nonvasodilating beta-blocker, so there should be some concern about its use as a first line agent. Bisoprolol has not been used in hypertension outcomes studies, though it has been shown to prolong life in heart failure with reduced ejection fraction.30 The combination of bisoprolol and amlodipine is a reasonable combination for lowering blood pressure, but given the concerns about the use of beta-blockers in hypertension, it should be used particularly in patients with coronary artery disease, heart failure with reduced ejection fraction4,5 (or with other comorbidities for which a beta-blocker is helpful), in patients younger than 60,31 and in patients in whom other classes of antihypertensives are problematic. The availability of a fixed-dose combination will likely improve patient compliance.