Results of Hypertension Treatment With Low-Dose Combinations of a ?-Adrenergic Blocker and a Diuretic

The goal of drug therapy for hypertension, as with any pharmacologic intervention, is to achieve the desired therapeutic response without producing toxicity—maximizing efficacy yet minimizing untoward side effects. The recommended approach advocates beginning with a low dose of a single agent, which is then titrated upward as needed.1–5 However, monotherapy is successful in only 50% to 60% of instances6,7 because multiple mechanisms are involved in the pathogenesis of essential hypertension, and a single drug class may not interdict all offending pathways. Also, as higher doses of individual drugs are administered, there is an increased likelihood of producing untoward side effects and stimulating the body's compensatory mechanisms, which may partially attenuate the incremental gain in efficacy. Diuretics and β-adrenergic blocking drugs are the only two classes of antihypertensive drugs that have been tested and shown to reduce morbidity and mortality. They have been recommended as preferred initial therapy in patients with systemic hypertension.5 They are often combined to maximize blood pressure control either as separate agents or in single fixed-dose formulations.7,,,–11 The advantages of a single fixed-dose formulation are the simplicity and convenience of use, which lead to improved patient compliance and possible reduction in cost. The possible disadvantages include a reduced flexibility in dosage and the fact that the combination formulation may be too potent for initiating therapy. These problems may be more theoretic than real. In the last few years, low-dose fixed-dose combination formulations have been developed and have been approved for initial monotherapy.12,13 One of these, bisoprolol/hydrochlorothiazide, contains a low dose of a diuretic and a β-blocker. The combination is an effective antihypertensive drug; the low dose of each constituent minimizes the potential for adverse effects. Diuretics and β-blockers are appropriate agents to combine in hypertension treatment because they lower blood pressure more effectively in combination than when either is used as monotherapy. The β-blocker can counteract diuretic-induced rises in plasma renin activity14 and sympathetic nervous system outflow, while modifying diuretic-induced hypokalemia (Figure 1). A large number of fixed-dose diuretic/β-blocker formulations are commercially available using conventional doses of thiazides (hydrochlorothiazide [HCTZ], 25 to 50 mg daily) and various β-blockers (labetalol, metoprolol, propranolol, extended-release propranolol, and timolol), as well as 5 mg bendroflumethiazide with nadolol, and 25 mg chlorthalidone with atenolol (Table 1).15 Recent reports have suggested that these fixed-dose formulations can be used as initial therapy in hypertension treatment, but only after each individual component has been titrated to the appropriate level (the concept implies that a fixed-dose combination formulation will be available with the appropriate dosage determined with monotherapy titrations). Available Fixed-Dose Diuretic/β-Blocker Formulations Available Fixed-Dose Diuretic/β-Blocker Formulations It has been shown that diuretics and β-blockers used together are equally effective in lowering blood pressure in the young and elderly and in both black and white patients, a finding not observed when β-blockers are used as monotherapy in blacks, where they appear to be less effective.16 Like any other product, fixed-dose combinations must be shown to be effective (ie, superior to placebo) before US Food and Drug Administration (FDA) approval.17 In addition, each component of a combination product must be shown to be contributing to the therapeutic effect desired.17 Other requirements for approval deal with adverse drug reactions. There are adverse reactions that are dose-related and those that are dose-independent (within the therapeutic dose range). For example, hypokalemia may be an adverse reaction with thiazide use, and this effect is augmented as the dose is increased. It is therefore a dose-dependent side effect. In contrast, the cough observed with angiotensin converting enzyme (ACE) inhibition can be seen with subtherapeutic doses—a dose-independent side effect. The FDA has stated that approval is possible for initial monotherapy in hypertension treatment for a fixed-dose combination if the formulation contains agents that both have dose-dependent side effects (that will be minimized with smaller doses) or if the two agents cancel out each other's adverse reactions.18 At the same time, it must be demonstrated that the components of a fixed-dose combination are directly additive or synergistic in their blood pressure-lowering effects.18 This can be determined by the use of a factorial trial17–23 design, which involves administration of a range of two or more agents, both alone and in combination. This factorial design is also optimal for the identification of interactions as drugs can be compared simultaneously24–27 in the same trial. From a statistical point of view, these experiments are highly efficient for they permit precise characterization of dose-response and dose-toxicity relationships. Therefore, they also enable identification of an optimal dose ratio of the two agents in combination for purposes of both safety and effectiveness. There are new ACE inhibitor/calcium channel blocker (CCB) combinations available that employ low doses of both components (benazepril plus amlodipine, enalapril plus felodipine, enalapril plus diltiazem, and trandolapril plus verapamil) and cough is still observed—these combinations are not approved for initial monotherapy.28 A similar observation has been made with a very-low-dose combination of 6.25 mg HCTZ with benazepril. A combination of an ACE inhibitor (captopril) and hydrochlorothiazide has been approved as initial therapy primarily because the addition of the thiazide increases the duration of action of the ACE inhibitor so that once-a-day therapy is possible. First-line antihypertensive treatment approvals for a fixed-dose combination were granted to two diuretic/β-blocker formulations,18 low-dose chlorthalidone (12.5 mg) plus betaxolol (not commercially available) and low-dose HCTZ (6.25 mg) plus bisoprolol (commercially available). Both β-blockers are β1-selective. We evaluated the low dose HCTZ (diuretic)/bisoprolol (β-blocker) formulation in two studies.29,30 In the first study, which used a factorial design,29 512 patients with stage I and stage II hypertension were randomized in a 12-week placebo-controlled multicenter trial that assessed the antihypertensive effectiveness and safety of once-daily administration of 2.5, 10, or 40 mg of bisoprolol used alone or in combination with 6.25 or 25 mg of HCTZ. The effects of bisoprolol and HCTZ were additive with respect to reduction in diastolic and systolic blood pressures (Tables 2, 3), fulfilling the first requirement for first-line approval of a fixed-dose combination. The addition of HCTZ (or bisoprolol) to therapy with bisoprolol (or HCTZ) produced an incremental reduction in blood pressure. A HCTZ dosage of 6.25 mg daily produced significantly less hypokalemia and less of an increase in uric acid levels than a dosage of 25 mg daily. The low-dose combination of 2.5 mg daily bisoprolol and 6.25 mg HCTZ daily reduced diastolic blood pressure to <90 mm Hg in 61% of patients and demonstrated a safety profile that compared favorably with that of placebo, fulfilling the second criteria for first-line approval. Side effects were reduced with the combination compared to higher dose monotherapies and similar or better blood pressure control was achieved with a low-dose combination. Contribution of Bisoprolol and Hydrochlorothiazide to the Reduction from Baseline in Sitting Diastolic and Systolic Blood Pressures at Weeks 3 to 4, Based on an Additive Model Based on an additive model with factors bisoprolol dosage and hydrochlorothiazide dosage. Thus, for example, the estimated mean reduction in sitting diastolic blood pressure (BP) (10.9 mm Hg) for the combination of 2.5 mg/day bisoprolol and 6.25 mg/day hydrochlorothiazide is equal to the placebo effect (3.8 mm Hg) plus the effect of 2.5 mg/day bisoprolol (4.6 mm Hg) plus the effect of 6.25 mg/day hydrochlorothiazide (2.5 mm Hg). Reproduced from Frishman WH et al,29 with permission. Contribution of Bisoprolol and Hydrochlorothiazide to the Reduction from Baseline in Sitting Diastolic and Systolic Blood Pressures at Weeks 3 to 4, Based on an Additive Model Based on an additive model with factors bisoprolol dosage and hydrochlorothiazide dosage. Thus, for example, the estimated mean reduction in sitting diastolic blood pressure (BP) (10.9 mm Hg) for the combination of 2.5 mg/day bisoprolol and 6.25 mg/day hydrochlorothiazide is equal to the placebo effect (3.8 mm Hg) plus the effect of 2.5 mg/day bisoprolol (4.6 mm Hg) plus the effect of 6.25 mg/day hydrochlorothiazide (2.5 mm Hg). Reproduced from Frishman WH et al,29 with permission. Mean Reduction from Baseline in Sitting Diastolic and Systolic Blood Pressures and Response Rates by Treatment Group Based on an additive model with the factors bisoprolol and hydrochlorothiazide (HCTZ) dosage. Sitting diastolic blood pressure of 90 mm Hg or lower at week 12. Reproduced from Frishman WH et al,29 with permission. Mean Reduction from Baseline in Sitting Diastolic and Systolic Blood Pressures and Response Rates by Treatment Group Based on an additive model with the factors bisoprolol and hydrochlorothiazide (HCTZ) dosage. Sitting diastolic blood pressure of 90 mm Hg or lower at week 12. Reproduced from Frishman WH et al,29 with permission. The second study was a trial of 509 stage I and stage II hypertensive patients using a placebo-controlled, randomized, parallel therapy design,30 which assessed the antihypertensive effectiveness and safety of once-daily administration of 5 mg bisoprolol used alone or in combination with 6.25 mg thiazide and compared these treatments to placebo and 25 mg HCTZ. The combination produced greater blood pressure-lowering effects than 5 mg bisoprolol alone, placebo, or 25 mg HCTZ, with a side effect profile of the combination comparable to placebo. Less than 1% of subjects on the combination developed hypokalemia (< 3.4 mEq/L) compared to 6.5% taking 25 mg HCTZ once daily. The results of these studies reveal that a very-low-dose diuretic/β-blocker formulation can be used as initial monotherapy with therapeutic effects comparable to those observed with high-dose monotherapy with either component and with a side effect profile similar to placebo. Thus far, there are no long-term morbidity and mortality trials with the low-dose combination. Moderate or high-dose diuretics and β-blockers have been shown to reduce vascular events in patients with systolic and diastolic hypertension as well as in those with isolated systolic hypertension. The low-dose combination appears to be equally efficacious as an antihypertensive agent in black and white patients, young and old patients, and men and women.29,30 There are no published studies describing the additive effects of the low-dose combination formulation when added to other antihypertensive drugs (ACE inhibitors or calcium blockers). The very-low-dose HCTZ/β-blocker combination was also compared to standard doses of various monotherapies in two recent studies.31 In the first study, 218 patients with stage 1 and stage 2 hypertension were randomized into a placebo run-in, active-control, double-blind, dose-escalation trial comparing three once-daily doses of bisoprolol/HCTZ (2.5/6.25, 5/6.25, 10/6.25 mg) to amlodipine (2.5, 5, and 10 mg) and enalapril (5, 10, and 20 mg) titrated to achieve maximal blood pressure-reducing response. Blood pressure was measured for efficacy response 24 h after the drug dose. The study consisted of a 4- to 5-week placebo run-in phase, a 4-week dose escalation phase, and an 8-week maintenance phase. The study showed a comparable blood pressure reducing effect to maximally titrated bisoprolol/HCTZ and amlodipine (−13.4/−10.7 mm Hg and −12.8/−10.2 mm Hg respectively). Seventy-one percent of HCTZ/bisoprolol patients and 69% of amlodipine patients achieved goal blood pressure (diastolic blood pressure ≤ 90 mm Hg or a decrease in diastolic blood pressure ≥ 10 mm Hg). In contrast, only 45% of enalapril-treated patients achieved the blood pressure goal with a reduction of −7.3/−6.6 mm Hg, significantly less of a blood pressure response than with amlodipine or bisoprolol/HCTZ (enalapril effect might have been better if the drug had been used twice daily). There were 29 adverse experiences with the bisoprolol/HCTZ combination, 42 with amlodipine, and 47 with enalapril. One patient in the bisoprolol/HCTZ group dropped out because of adverse experiences compared to four in each of the other groups. Finally, in this study, while minor positive changes in quality-of-life scores were noted for bisoprolol/HCTZ and amlodipine the changes were not significant. Tables 4, 5, and 6 summarize the results of several comparative studies with bisoprolol/HCTZ and various other antihypertensive medications.31,34Table 5 compares a second study that evaluated the blood pressure lowering effects of a CCB, an ACE inhibitor, and a β-blocker/HCTZ combination with the first study quoted above.34 As noted, blood pressure response and response rates with the combination were as good or better than with the other antihypertensive agents, and adverse reactions were similar to placebo. Blood Pressure and Heart Rate Changes in Comparative Studies of Various Antihypertensive Medications Significant difference between this and other Study II groups. Significant difference between this and enalapril and placebo groups in Study II. Significant difference between this and enalapril group in Study I. Significant difference between this and enalapril group in Study I. Adapted from Prisant et al31 and Neutel et al,34 with permission. Blood Pressure and Heart Rate Changes in Comparative Studies of Various Antihypertensive Medications Significant difference between this and other Study II groups. Significant difference between this and enalapril and placebo groups in Study II. Significant difference between this and enalapril group in Study I. Significant difference between this and enalapril group in Study I. Adapted from Prisant et al31 and Neutel et al,34 with permission. Comparison of the Efficacy and Safety of Various Antihypertensive Agents and a Low-Dose Combination β-Blocker/Diuretic Comparison of the Efficacy and Safety of Various Antihypertensive Agents and a Low-Dose Combination β-Blocker/Diuretic Percent of Responders to Various Antihypertensive Reductions in Different Comparative Studies Responders are patients with DBP ≤ 90 mm Hg or with a mean reduction in DBP ≥ 10 mm Hg. Doses: 1, bisoprolol/HCTZ (2.5/6.25 mg), amlodipine (2.5 mg), enalapril (5 mg) daily; 2, bisoprolol/HCTZ (5/6.25 mg), amlodipine (5 mg), enalapril (10 mg) daily; 3, bisoprolol/HCTZ (10/6.25 mg), amlodipine (10 mg), enalapril (10 mg) twice daily; 4, enalapril (20 mg) twice daily. Significant difference between this group and other Study II groups. Significant difference between this group and placebo in Study II. Significant difference between this group and enalapril group in Study I. Adapted from Prisant et al31 and Neutel et al,34 with permission. Percent of Responders to Various Antihypertensive Reductions in Different Comparative Studies Responders are patients with DBP ≤ 90 mm Hg or with a mean reduction in DBP ≥ 10 mm Hg. Doses: 1, bisoprolol/HCTZ (2.5/6.25 mg), amlodipine (2.5 mg), enalapril (5 mg) daily; 2, bisoprolol/HCTZ (5/6.25 mg), amlodipine (5 mg), enalapril (10 mg) daily; 3, bisoprolol/HCTZ (10/6.25 mg), amlodipine (10 mg), enalapril (10 mg) twice daily; 4, enalapril (20 mg) twice daily. Significant difference between this group and other Study II groups. Significant difference between this group and placebo in Study II. Significant difference between this group and enalapril group in Study I. Adapted from Prisant et al31 and Neutel et al,34 with permission. In an open label trial, 13,700 patients with stage I and stage II hypertension were randomized to receive bisoprolol/HCTZ (2.5/6.25 mg and 5/6.25 mg) or one of several different ACE inhibitors (ramipril, quinapril, benazepril, enalapril, lisinopril, and others). Drugs were titrated to achieve blood pressure control over a 6-week treatment period. At the study's end, 72% of bisoprolol/HCTZ and 68% of ACE inhibitor treated patients achieved blood pressure control (diastolic blood pressure < 90 mm Hg or ≥ 10% reduction in diastolic blood pressure). The bisoprolol/HCTZ combination reduced blood pressure regardless of race, gender, or age and was well tolerated and associated with a low rate of patients who discontinued therapy. There are no studies where fixed-dose combination formulations have been used in morbidity and mortality outcomes. Several have included the use of diuretics with a β-blocker added if goal pressure was not achieved.32 In situations where patient compliance is an issue or where initial BP > 155 to 160/95 to 100 mm Hg, especially if target organ involvement is noted, it would seem appropriate to try a low-dose diuretic/β-blocker combination, followed by a higher-dose combination regimen if necessary. The available data indicate that such therapy may result in a better outcome. Diuretics and β-blockers have been used in combination as separate medications for many years and also as single fixed-dose formulations. A combination has the advantage of providing greater efficacy than single drugs as monotherapy, and negates some of the adverse reactions of the single drugs used alone (diuretics raise plasma renin activity and β-blockers reduce it).35β-Blockers have some mild antialdosterone, potassium-conserving effects that can negate the kaliuretic effects of thiazides. The diuretic could also prevent edema accumulation in patients with left ventricular dysfunction aggravated by β-blockers. Diuretics and β-blockers are also the two agents suggested by the JNC V as preferred initial monotherapy based on clinical outcome data.5 The combination of a β-blocker/diuretic also reduces blood pressure to a greater degree than β-blockers alone in blacks, where diuretics appear to be more effective; combinations of diuretics and β-blockers appear to control blood pressure equally well in blacks and whites. Combinations of diuretics and β-blockers have been used in the treatment of isolated systolic hypertension in the elderly with beneficial effects on stroke, myocardial infarction, and congestive heart failure incidences when compared to placebo therapy.33 Finally, combinations of diuretics and β-blockers have been used in very-low doses to achieve blood pressure effects comparable to or better than high-dose monotherapy with ACE inhibitors, calcium channel blockers, or diuretics with a side effect profile comparable to placebo and fewer adverse reactions than other medications tested. Based on these findings, the FDA has granted first-line treatment approvals in hypertension for two low-dose combination diuretic/β-blocker formulations (HCTZ/bisoprolol and chlorthalidone/betaxolol).