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Rationale for combination therapy in hypertension management: focus on angiotensin receptor blockers and thiazide diuretics.

Abstract: Despite recognition that hypertension is a major risk factor for cardiovascular events and mortality, blood pressure control rates remain low in the US population. Reflecting clinical trial results, hypertension management guidelines assert the clinical benefit of achieving current blood pressure goals and indicate that most patients will require 2 or more drugs to reach goal. Well-designed drug combinations counter hypertension via complementary mechanisms that increase antihypertensive efficacy, potentially with lower rates of adverse events than higher dose monotherapy regimens. Lower adverse event rates, in turn, may contribute to greater adherence with treatment. The combination of a low-dose diuretic with agents that block the effects of the renin-angiotensin system (RAS), such as angiotensin receptor blockers, has been found in numerous clinical trials to be highly effective for lowering blood pressure in patients with uncomplicated as well as high-risk hypertension, with a comparable favorable side effect profile compared with monotherapy. Moreover, agents that block the RAS are associated with a lower risk of new-onset diabetes mellitus than other antihypertensive classes. Complementary combinations of antihypertensive agents provide an efficient and effective approach to hypertension management.

Key Words: angiotensin receptor blockers, cardiovascular disease, combination therapy, hypertension, thiazide diuretics, renin-angiotensin system

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More than 50 years ago, Franklin Roosevelt and Joseph Stalin, two powerful men with unlimited resources, died due to intracerebral hemorrhage as a direct result of uncontrolled hypertension. (1,2) An estimated 65 million Americans currently have hypertension, (3) and despite the availability of more than 100 antihypertensive agents, only 34% of all persons with hypertension and 56% of those treated reach the blood pressure (BP) goal of <140/90 mm Hg. (4) This holds true even for hypertensive patients with access to healthcare; in the third National Health and Nutrition Examination Survey (NHANES III), the vast majority of persons with uncontrolled hypertension had health insurance, reported a usual source of care, and visited their physician more than once in the prior year. (5) The problem of poor BP control is magnified by new definitions of hypertension (>140/90 mm Hg or > 130/80 mm Hg for patients with diabetes mellitus or chronic renal disease) and prehypertension (120-139/80-89 mm Hg), by increasing rates of overweight and obesity, and by an aging population. (6) Two thirds of Americans with hypertension are [greater than or equal to]60 years of age, (4) and by age [greater than or equal to]65 years, approximately 88% of persons with inadequate BP control have isolated systolic hypertension (7); this reflects both the age-related increase in systolic BP and the difficulty in treating systolic hypertension.

The clinical benefits of BP lowering are well established by numerous studies that show reductions in cardiovascular morbidity and mortality across a wide range of patient populations. (6) Meta-analyses of studies evaluating the effects of antihypertensive therapy on cardiovascular outcomes suggest that BP lowering largely drives the reduction in cardiovascular events across different classes of antihypertensive agents. (8,9) It is also evident based on clinical trial results that most persons with hypertension require therapy with a combination of 2 or more antihypertensive agents to achieve currently recommended BP targets. (6) Thus, the immediate focus of antihypertensive therapy should be reaching target BP with the ultimate aim of reducing cardiovascular morbidity and mortality. Because the pathophysiology of hypertension is multifactorial, well-designed combination regimens that target complementary BP-lowering mechanisms and associated compensatory responses provide an effective approach to achieving BP goals. (10) Whereas past guidelines identified specific BP thresholds above which treatment should be considered, (6) current recommendations focus on an individual patient's absolute or global risk as the basis for treatment decision making. (11) Rather than staging hypertension severity on the basis of BP values alone, more recently developed algorithms take into account a patient's BP level, cardiovascular risk factors, early disease markers, and clinical evidence of target organ damage. Thus, clinicians must be alert to a patient's overall cardiovascular risk and consider antihypertensive therapy even among normotensive patients at high risk.

Despite the clarity offered by treatment guidelines, which are based on clinical trial results achieved under optimal conditions, attaining and maintaining BP control is problematic in real-world settings, as evidenced by poor control rates and diminishing adherence with antihypertensive therapy over time. (12,13) Two issues fundamental to achieving BP control are sufficient therapy and patient adherence with therapy. Fixed-dose combinations of antihypertensive drugs with complementary mechanisms of action provide for greater efficacy often using lower doses of component agents than monotherapy, (14) a strategy which has the potential to reduce the risk of adverse events, increase adherence by simplifying the therapeutic regimen, and ultimately improve outcomes. (6) Several such combinations are available including: angiotensin-converting enzyme (ACE) inhibitor plus calcium channel blocker (CCB) or diuretic; beta blocker plus diuretic; or angiotensin receptor blocker (ARB) plus diuretic.

Combinations consisting of a low-dose thiazide diuretic with an ARB provide several advantages for the treatment of uncomplicated as well as high-risk hypertension. ARBs demonstrate BP-lowering efficacy comparable to ACE inhibitors and other antihypertensive drug classes, with an overall risk of adverse events comparable to placebo. (15) Treatment with ARBs is associated with a lower incidence of troublesome events commonly reported with other antihypertensive classes, such as cough with ACE inhibitors (16-18) and peripheral edema with CCBs. (19,20) In addition, ARBs have been shown to reduce the risk of cardiovascular events in a range of patients at high risk, (19) including those with prior myocardial infarction, (18) left ventricular dysfunction, (21) and heart failure. (22-24)

This review addresses current clinical guidelines for the use of combination antihypertensive therapy; the rationale for combining an ARB with a thiazide diuretic; clinical trial evidence supporting the ARB/diuretic combination in terms of BP-lowering efficacy and tolerability; and observational data regarding rates of adherence with different antihypertensive classes. To review clinical trials of ARB/diuretic combinations, a MEDLINE search was conducted using the terms "angiotensin receptor blocker," "angiotensin receptor antagonist," "diuretic," and "hydrochlorothiazide" with the limits of "clinical trial" and "randomized controlled trial." The terms "adherence," "compliance," and "persistence" were combined with "antihypertensive therapy" to retrieve studies on medication adherence.

Sufficient Therapy: Combination Regimens

Clinical Guidelines for the Use of Combination Therapy

Lifestyle modifications, including weight reduction, physical activity, and adopting Dietary Approaches to Stop Hypertension (DASH), remain the cornerstone of hypertension management, regardless of whether patients ultimately require pharmacologic therapy. (6) In a substantial proportion of patients, however, combination therapy will likely be necessary particularly for those at high risk for cardiovascular or renal disease in whom lower BP goals necessitate a more aggressive treatment plan (Fig. 1). (25) According to the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7), starting therapy with 2 drugs, separately or as fixed-dose combinations, may be considered when systolic BP is >20 mm Hg or diastolic BP is >10 mm Hg above the desired goal for the individual patient. (6) In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), which included patients with difficult-to-treat hypertension, 66% of patients reached BP goal by 5 years, with 63% of patients taking 2 or more medications. (26) JNC 7 recommends that physicians follow up monthly after initiating antihypertensive therapy to adjust medications until the BP goal is reached. (6) Once at goal, patients can be checked every 3 to 6 months.

[FIGURE 1 OMITTED]

In general, diuretics are recommended as one element of combination therapy to achieve BP control. (6) However, in high-risk patients, treatment with specific classes of antihypertensive agents has been shown to improve disease outcomes. (6,18) For example, RAS blockade is an important component of treatment for patients with diabetes and hypertension according to the JNC 7 guidelines, (6) a position that is in agreement with recommendations of the American Diabetes Association (ADA). (27) The ADA guidelines assert that all patients with diabetes and hypertension should be treated with an ACE inhibitor or ARB. If further BP reduction is needed, a diuretic should be added to the regimen. The ADA notes that in clinical trials of antihypertensive therapy for preventing vascular complications, many patients with diabetes needed 3 or more drugs to achieve the more stringent blood pressure targets. (27)

Additive effects of antihypertensive agents should be considered in other populations at high risk. The prevalence of hypertension among African Americans is substantially higher than in other racial/ethnic groups (41% versus 28% among white Americans), (28) as are rates of diabetes, heart failure, and end-stage renal disease, (29) which are all compelling indications for RAS blockade. (6) Guidelines from the Hypertension in African Americans Working Group of the International Society of Hypertension in Blacks (ISHIB) state that most African-American patients require at least 2 drugs to reach BP goals; in contrast to JNC 7, ISHIB suggests initiating combination therapy in African-American patients with BP [greater than or equal to]15/10 mm Hg above goal. (30) The ISHIB guidelines recommend 4 combination regimens for treatment of hypertension in African-American patients: a diuretic plus an ACE inhibitor, a diuretic plus an ARB, a diuretic plus a [beta]-blocker, or an ACE inhibitor plus a CCB. A summary of JNC-7, ADA, and ISHIB guidelines is shown in Table 1.

Rationale for Combining an ARB with Thiazide Diuretics

The mechanisms of action of agents that block the effects of the RAS augment the BP-lowering efficacy of diuretics. Thiazide diuretics lower BP through natriuresis (ie, sodium excretion), resulting in volume depletion and reduction of peripheral vascular resistance over time. (31,32) However, sodium depletion may result in RAS activation, increasing renin release and formation of angiotensin II, and potentially limiting the effect of the diuretic (Fig. 2). (32) Angiotensin II causes vasoconstriction, sodium retention, activation of the sympathetic nervous system, and other deleterious effects on the heart, kidney, and vasculature. Combining an ARB with a diuretic reduces sodium retention and vasoconstriction mediated by angiotensin II, at the same time reducing volume and enhancing the efficacy of both antihypertensive components. Several fixed-dose combinations of an ACE inhibitor or ARB plus hydrochlorothiazide (HCTZ) are currently available. (6)

[FIGURE 2 OMITTED]

In general, combination therapy may help patients attain BP control in a more timely manner and allow for lower doses of the component agents with fewer adverse events than higher-dose monotherapy. (14) An advantage of including an ARB in combination regimens is the low rate of adverse events associated with this class compared with other antihypertensive agents. (14,15) For example, ARBs have demonstrated greater tolerability than ACE inhibitors, as evidenced by a lower incidence of cough and angioedema. (33) ARB/HCTZ combinations are associated with a low rate of adverse events and treatment discontinuations comparable to that observed with ARB monotherapy. (34-37) Moreover, increasing the dose of diuretic in combination with an ARB only modestly increases the incidence of adverse events (statistical significance not reported). (35-37)

Clinical Trials of ARB/HCTZ Combination Therapy

Clinical trials evaluating ARB/HCTZ therapy consistently show significantly greater BP reductions with the combination versus component monotherapy in patients with mild-to-moderate hypertension, (36,37) stage 2 hypertension, (34,35,38) and systolic hypertension. (39) In addition, combination ARB/HCTZ therapy produced significant BP reductions in patients with uncomplicated hypertension who failed to respond to ARB monotherapy. (36,37) In two separate trials of valsartan (160 mg/d) (36) and eprosartan (600 mg/d), (37) patients with mild-to-moderate hypertension not controlled after 3 to 4 weeks on monotherapy were randomly assigned to 8 weeks of continued monotherapy or the addition of HCTZ. In both studies, the combination achieved a significantly greater reduction in diastolic BP, and significantly higher responder rates (percentage with <90 mm Hg or [greater than or equal to]10 mm Hg decrease) than monotherapy. (36,37) In the study of valsartan, systolic and diastolic BP reductions, as well as responder rates, were significantly (P [less than or equal to] 0.01) greater with a higher-versus lower-dose combination. (36)

ARB/HCTZ combination therapy also demonstrates BP-lowering efficacy comparable to amlodipine monotherapy, including in studies using 24-hour ambulatory BP monitoring. (40-44) In these studies, the ARB/HCTZ combination was associated with a lower rate of treatment discontinuations (ARB/HCTZ 2.5%-10.1%; amlodipine 11.3%-24.5%) and a lower incidence of peripheral edema (ARB/HCTZ 1.2%-8.9%; amlodipine 5.8%-44.6%). In a study of African Americans with mild-to-moderate hypertension, ARB/HCTZ combination therapy produced reductions in mean 24-hour BP similar to CCB monotherapy; however, peripheral edema and joint swelling were more common with the CCB than ARB/HCTZ, whereas rates of other adverse events were similar and low in both groups. (40) In a recent study, treatment of elderly patients with systolic hypertension with combination ARB/HCTZ resulted in greater reductions in 24-hour BP than CCB/HCTZ therapy, with lower rates of adverse events and treatment discontinuations in the ARB/HCTZ group (primarily due to a lower incidence of peripheral edema). (41)

A dose-dependent effect of ARB/HCTZ on BP reductions and control rates has been observed through the approved ARB dose range with losartan (up to 100 mg), valsartan (up to 320 mg), and olmesartan (up to 40 mg) in combination with HCTZ 12.5 to 25 mg. (38,39,45,46) A low incidence of adverse events with ARBs allows the use of these agents at higher doses, which may be advantageous for both lowering BP and improving clinical outcomes. Evidence from several clinical endpoint trials suggests that maximal ARB dosing produces the greatest reductions in cardiovascular and renal disease events (reviewed in Weir (47)). For example, in patients with type 2 diabetes and microalbuminuria, irbesartan 300 mg reduced the progression to nephropathy (relative risk 0.32; P < 0.001 versus placebo) to a greater degree than the 150 mg dose (0.56; P = 0.05 versus placebo). (48)

Diabetes and the RAS

RAS blockade is established therapy for patients with diabetes, who are at high risk for renal disease. (6,27) Treatment with ARBs has been shown to slow the progression of renal disease in patients with type 2 diabetes and microalbuminuria or nephropathy, the benefit of which appears to be maintained with combination ARB/HCTZ treatment. (20,48-50) Importantly, accumulated evidence indicates that RAS blockade also decreases the risk of new-onset diabetes among patients receiving antihypertensive therapy. A meta-analysis of hypertension trials involving approximately 116,000 patients, two thirds of whom did not have diabetes at baseline, found an overall 25% reduction (27% for ACE inhibitors; 23% for ARBs) in new-onset diabetes compared with other antihypertensive classes or placebo (Table 2). (51)

ALLHAT demonstrated a significantly higher risk of new-onset diabetes in those treated with a thiazide diuretic compared with a CCB or ACE inhibitor. (52) However, in the Losartan Intervention For Endpoint reduction in hypertension study, the ARB was associated with a 25% lower incidence of new-onset diabetes than [beta]-blocker therapy, even though the majority of patients in both groups were treated with a diuretic; this suggests a potentially mitigating effect of RAS blockade. (53) Supporting these findings, the Valsartan Antihypertensive Long-term Use Evaluation showed a 23% reduction in new-onset diabetes with valsartan-based versus amlodipine-based therapy that included HCTZ. (19) A potential mechanism for the protective effect is suggested by a recent analysis of hypertension trials indicating that RAS blockade improves insulin sensitivity and glucose metabolism. (54) Decreasing the risk of diabetes represents a crucial treatment advantage beyond BP reduction, as new-onset diabetes increases vascular risk comparably to preexisting diabetes and is associated with considerable morbidity and costs. (55,56)

Persistent Therapy

Clinical trial data demonstrate that effective antihypertensive regimens are available; however, no drug can be effective if the patient does not take it as prescribed. The choice of antihypertensive agent strongly determines patient persistence with therapy. (14) Treatment with ARBs has been associated with higher rates of adherence with therapy than other antihypertensive drug classes. (13,57-62) Although these studies used different designs, precluding comparison among them, the general order of antihypertensive drugs from most to least favorable long-term adherence was ARB > ACE inhibitor [greater than or equal to] CCB > diuretic. A study of adherence with antihypertensive therapy in usual-care settings analyzed a pharmacy claims database for new prescriptions of a CCB, an ACE inhibitor, and an ARB. (61) After 12 months, 63% of patients were still taking the ARB, 53% were still taking the CCB, and 50% were still on the ACE inhibitor (P < 0.001 for ARB versus both comparators).

Similarly, another clinic-based survey of more than 14,000 new users of antihypertensive agents found that patients initially prescribed an ARB had higher persistence rates than those prescribed agents from other classes. (62) Patients prescribed ACE inhibitors, CCBs, or diuretics discontinued therapy at rates that were higher by approximately 39%, 66%, and 85%, respectively, compared with ARBs (P < 0.0001). Moreover, switching, adding, or dropping a drug relative to the initial regimen also predicted low persistence: fewer than 10% of patients persisted with regimens that did not include the initial drug prescribed. (62) If patients are more likely to continue treatment with the first medication prescribed, tolerability and efficacy should figure heavily in that choice.

A Shifting Paradigm

Although physicians and patients have been concerned about the potential for adverse events due to rapid BP reduction, negative metabolic effects, and overall safety, these concerns have been allayed by the efficacy and tolerability profile of newer combination antihypertensive regimens. (63) In addition, the evidence that risk due to elevated BP is continuous and graded, with no lower threshold at least down to 115/75 mm Hg, (64) should give clinicians a sense of urgency to assess individual patients' absolute risk and treat to recommended targets. (6) Treatment of hypertension has come a long way in the past 50 years, yet much remains to be done. New and lower definitions of hypertension increase the difficulty of helping patients achieve BP control. Because a substantial proportion of patients require 2 or more antihypertensive medications to reach their BP goal, combinations of agents with complementary mechanisms offer the potential for greater efficacy without an increase in adverse events. Fixed-dose combination therapy offers an effective, well-tolerated, and convenient option for initiating therapy in a range of hypertensive patients who require greater BP reductions or those at higher risk. Combination therapy may help patients reach goal sooner and continue therapy longer. With the use of more effective and efficient treatment regimens, we can begin to relegate the risks of undertreated hypertension to history.

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David T. Nash, MD

From State University of New York Upstate Medical University, Syracuse Preventive Cardiology Center, Syracuse, NY.

Reprint requests to Dr. David T. Nash, Syracuse Preventive Cardiology, 600 East Genesee Street, Suite 204, Syracuse, NY 13202. E-mail: davidtnash@aol.com

Accepted November 29, 2006.

RELATED ARTICLE: Key Points

* Results of large-scale clinical trials indicate that most patients, particularly those at high risk for cardiovascular events require 2 or more antihypertensive agents to reach blood pressure goals recommended by current clinical guidelines.

* Because the pathophysiology of hypertension is multifactorial, well-designed combination regimens that target complementary blood pressure-lowering mechanisms provide an effective approach to achieving goals.

* The combination of an angiotensin receptor blocker with a thiazide diuretic provides several advantages for treating essential hypertension as well as patients at high risk for cardiovascular or renal disease events, based on their additive efficacy and lower rate of adverse effects and treatment discontinuations compared with higher dose component monotherapy or other antihypertensive regimens.

* Rates of patient adherence to antihypertensive therapy are higher with angiotensin receptor blockers than other antihypertensive classes in several observational studies.

* Agents that block the renin-angiotensin system also are associated with a lower incidence of new-onset diabetes than other antihypertensive classes or placebo.
Table 1. Clinical guidelines for hypertension management (6,26,29)

 JNC-7

Goals
Initiate drug therapy
 Monotherapy <20/10 mm Hg above goal
 Combination therapy [greater than or equal to]20/10 mm Hg above goal
Special considerations Treat with RAS blockade for patients with
 compelling indications (a)

 ADA

Goals Uncomplicated hypertension: 140/90 mm Hg
 Diabetes/renal disease: 130/80 mm Hg
Initiate drug therapy
 Monotherapy [greater than or equal to]10/10 mm Hg above goal
 Combination therapy Generally required to reach goal
Special considerations Treat all patients with diabetes and
 hypertension with RAS blockade; if greater BP
 reduction is needed, add a thiazide diuretic

 ISHIB

Goals
Initiate drug therapy
 Monotherapy <15/10 mm Hg above goal
 Combination therapy [greater than or equal to]15/10 mm Hg above goal
Special considerations Treat with RAS blockade for all patients with
 diabetes or renal disease

(a) Heart failure, postmyocardial infarction, high coronary disease
risk, diabetes, chronic kidney disease, recurrent stroke prevention. (6)
JNC, Joint National Committee on Prevention, Detection, Evaluation, and
Treatment of High Blood Pressure; ADA, American Diabetes Association;
ISHIB, International Society of Hypertension in Blacks; RAS,
renin-angiotensin system.

Table 2. Prevention of new-onset type 2 diabetes in clinical trials

 No. Risk Ratio
Trial patients Drugs (95% CI)

HOPE 9,297 ACE vs placebo 0.66 (0.51-0.85)
SOLVD 4,228 ACE vs placebo 0.26 (0.13-0.53)
PEACE 8,290 ACE vs placebo 0.83 (0.72-0.96)
CAPPP 10,985 ACE vs diuretic/BB 0.79 (0.67-0.94)
STOP-2 6,614 ACE vs diuretic/BB 0.96 (0.72-1.27)
ALLHAT 33,357 ACE vs diuretic 0.70 (0.56-0.86)
ANBP2 6,083 ACE vs diuretic 0.66 (0.54 0.85)
SCOPE 4,937 ARB vs placebo 0.81 (0.61-1.02)
CHARM 7,599 ARB vs placebo 0.78 (0.64-0.96)
LIFE 9,193 ARB vs BB 0.75 (0.63-0.88)
VALUE 15,245 ARB vs CCB 0.77 (0.69-0.86)
ALPINE 392 ARB [+ or -] CCB vs 0.13 (0.03-0.99)
 BB [+ or -] diuretic

ACE, angiotensin-converting enzyme inhibitor; ALLHAT, Antihypertensive
and Lipid-Lowering Treatment to Prevent Heart Attack Trial; ALPINE,
Antihypertensive Treatment and Lipid Profile in a North of Sweden
Efficacy Evaluation; ANBP2, The second Australian National Blood
Pressure study; ARB, angiotensin receptor blocker; BB, beta blocker;
CAPPP, Captopril Prevention Project; CCB, calcium channel blocker;
CHARM, Candesartan in Heart Failure Assessment of Reduction in Mortality
and Morbidity; HOPE, Heart Outcomes Prevention Evaluation; LIFE,
Losartan Intervention For Endpoint Reduction in hypertension study;
PEACE, Prevention of Events with Angiotensin Converting Enzyme
Inhibition Trial; SCOPE, The Study on Cognition and Prognosis in the
Elderly; SOLVD. Studies Of Left Ventricular Dysfunction; STOP-2, Second
Swedish Trial in Old Patients with hypertension; VALUE, Valsartan
Antihypertensive Long-term Use Evaluation.
Adapted from Abuissa H et al. J Am Coll Cardiol 2005;46:821-826.
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Title Annotation:Review Article
Author:Nash, David T.
Publication:Southern Medical Journal
Geographic Code:4EUUK
Date:Apr 1, 2007
Words:5705
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