What is the rationale for initial treatment with combination therapy?

264A

FACULTY ABSTRACTS

Wednesday, May 14, 10:00 AM-12:00 PM Achieving Blood Pressure Goals: Is Fixed-Dose Combination Therapy the Answer?* WHO SHOULD BE CONSIDERED FOR INITIAL THERAPY WITH COMBINATION ANTIHYPERTENSIVE AGENTS? George L Bakris. Rush-Presbyterian–St. Luke’s Medical Center, Rush Hypertension Clinical Research Center, Chicago, IL Recent trends in hypertension research and treatment guidelines have emphasized stratification of the hypertensive population by risk level to provide greater specification in therapeutic strategies. This increased focus on special populations reflects a greater recognition of the heterogeneous nature of hypertension; the strong correlations of high blood pressure (BP) with increased risks for cardiovascular (CV) and renal morbidity and mortality; and the need for hypertension treatment to help reduce these associated disease risks by providing target-organ protection beyond BP reduction. The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI) established 3 risk categories, the highest of which is Risk Group C, including patients with target-organ damage, clinical CV disease, and/or diabetes. The JNC VI report sets a BP goal of ⬍130/85 mm Hg for Risk Group C patients, a level lower than the ⬍140/90 mm Hg goal for patients with uncomplicated hypertension. This goal, however, is very difficult to attain in high-risk patients, whose BP is difficult to control due to their advanced disease and associated conditions. Angiotensin-converting enzyme (ACE) inhibitors are widely recommended as preferred antihypertensive therapy for patients with diabetes, especially type 1 diabetes. Along with diuretics, ACE inhibitors are also recommended for use in patients with heart failure. These recommendations are based on substantial research data demonstrating that ACE inhibitors can significantly retard the progression of renal disease and reduce the risk of CV events in high-risk patients. Major clinical outcome trials, including HOT (Hypertension Optimal Treatment), UKPDS (United Kingdom Prospective Diabetes Study), and ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial), have shown that 40% to 50% of patients require multiple agents to achieve BP control. Moreover, the SHIELD (Study of Hypertension and the Efficacy of Lotrel in Diabetes) study has demonstrated that starting with combination therapy will achieve goal BP faster, compared with the monotherapy approach. For these reasons, a fixed, low-dose combination agent that includes an ACE inhibitor may be appropriate initial therapy in high-risk patients. The combination of a calcium channel blocker (CCB) or diuretic with an ACE inhibitor can provide additive effects, thus lowering BP more quickly and effectively than would occur with monotherapy. The combination of an ACE inhibitor with either a CCB or diuretic would also help bring the benefits of target-organ protection provided by ACE inhibitors to African Americans, who are at disproportionately high risk for CV and renal morbidity and mortality. Data from AASK (African American Study of Kidney Disease and Hypertension) have clearly indicated that ACE inhibitors are associated with better renal outcomes, compared with conventional drugs, in African Americans with hypertension and mild renal insufficiency. The LOGIC (Lotrel: Gauging Improved Control) trial, a large, openlabel study (n⫽6000) of patients whose BP was uncontrolled with amlodipine monotherapy, found that switching patients to a combination of a CCB with an ACE inhibitor produced an additional mean reduction in BP of 15.6/11.5 mm Hg (P⬍0.001 vs amlodipine monotherapy) and a significant reduction of amlodipine-associated pedal edema. An analysis of the African-American cohort of this study (n⫽1423) found results similar to those in the overall group: with the switch from amlodipine monotherapy to combination therapy, adding the ACE inhibitor produced an additional mean reduction in BP of 13.9/10.4 mm Hg (P⬍0.001 vs amlodipine monotherapy). Therefore, fixed, low-dose combination ther0895-7061/03/$30.00

AJH–May 2003–VOL. 16, NO. 5, PART 2

apy may be considered for initial antihypertensive treatment in all highrisk patients, including African Americans. Key Words: Amlodipine, Benazepril, Combination Antihypertensive Therapy *This activity is supported by an unrestricted educational grant from Novartis Pharmaceuticals Corporation.

WHAT IS THE RATIONALE FOR INITIAL TREATMENT WITH COMBINATION THERAPY? Thomas D Giles. Louisiana State University School of Medicine, New Orleans, LA Hypertension is a complex disorder involving multiple, interrelated pathogenetic factors, including increased blood volume and vasoconstriction, and overactivity of the sympathetic nervous system and reninangiotensin-aldosterone system. Only about half of all patients generally respond to a given antihypertensive monotherapy, and major trials have shown that close to 50% of all patients need multiple antihypertensive drugs to reach their recommended blood pressure (BP) targets. Hence, a rational approach to hypertension treatment is the use of multiple therapies in combination, strategically integrated to address the several factors causing high BP. Combination therapies for hypertension have been used since the 1950s. Whereas the causes of hypertension are known to interactively exacerbate one another, combination therapy is theoretically designed for each component agent to potentiate and maximize the effects of the other, and, in some cases, to mutually counteract their adverse effects. The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI) recommends a stepped-care approach to antihypertensive treatment, involving titration of initial monotherapy and addition of agents with different, complementary mechanisms of action until goal BP is achieved. The JNC VI report also recommends the use of agents that provide protection against hypertension-related target-organ damage, independent of BP reduction. Furthermore, the report notes that fixed-dose combinations may be appropriate for use as initial antihypertensive therapy. The selection of initial antihypertensive monotherapy has been the object of considerable research and controversy. The long-anticipated results of ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) indicate that diuretics are effective antihypertensive drugs. The trial showed no difference in the primary endpoint, combined fatal coronary heart disease or nonfatal myocardial infarction (MI). Moreover, despite lower BP reduction, diuretics were unable to be statistically separated from the other drugs used in the trial. Epidemiologic survey data indicate that the rate of BP control among hypertensive patients in the United States is only 27%. This persistently poor rate of BP control, despite the availability of numerous effective antihypertensive therapies, suggests that a number of factors are hampering the effectiveness of hypertension treatment. Although titration of initial monotherapy is recommended and frequently practiced to achieve BP control in patients not responsive to the starting dose, increasing doses are positively correlated with a higher rate of adverse effects, with the exception of ACE inhibitors and angiotensin II receptor blockers (ARBs). In view of the above issues, using combination therapy for treatment of hypertension is a rational approach. Fixed-dose combination therapy may use lower doses of each component agent than would be necessary with titration of monotherapy, thereby reducing the risk of adverse effects and noncompliance. Furthermore, initial combination therapy may allow for the greater use of ACE inhibitors and ARBs, which appear to provide benefits in target-organ protection independent of BP lowering, as recommended by JNC VI. Angiotensin-converting enzyme inhibitors are © 2003 by the American Journal of Hypertension, Ltd. Published by Elsevier Inc.

AJH–May 2003–VOL. 16, NO. 5, PART 2

recommended as first-line agents in patients with type 1 diabetes or renal disease, patients who have had an MI, and patients with heart failure. Key Words: Hypertension, Combination Therapy, ACE Inhibitors, Diuretics *This activity is supported by an unrestricted educational grant from Novartis Pharmaceuticals Corporation.

ACCOMPLISH–THE FIRST CLINICAL TRIAL IN MORTALITY REDUCTION WITH ANTIHYPERTENSIVE COMBINATION THERAPY Kenneth Jamerson. Department of Internal Medicine, Division of Hypertension, University of Michigan Health System, Ann Arbor, MI The use of combination therapy is a superior strategy for controlling blood pressure when compared to monotherapy. The possibility that specific combination therapies could improve cardiovascular outcomes has not been previously studied. Angiotensin II may play an important role in promoting coronary atherosclerosis because of its effect on endothelial function and subsequent vasocontriction, abnormal smooth cell migration, macrophage activation, and promotion of platelet aggregation. There is also a potential role for calcium channel blockers (CCBs) in the atherosclerotic process. A review of scientific research provides support for several anti-atherosclerotic mechanisms for amlodipine: antioxidant activity and increased resistance of lipids to oxidative stress, remodeling of vascular smooth muscle cell membranes, inhibition of smooth muscle cell proliferation and migration, and enhancement of endothelial nitric oxide (NO) production. An additive increase in NO production is a possible pathway of synergy for angiotensin-converting enzyme (ACE)/CCB combination drug therapy. A recent study has evaluated the effects of an ACEinhibitor, amlodipine, and their combination on vasodilation and NO production in canine coronary microvessels. While both agents increased NO production, the combination had a synergistic effect and marked NO formation. The ACCOMPLISH trial is the first major hypertension outcomes trial that will randomize subjects to a specific fixed-dose combination drug as initial therapy. An exciting possibility is that specific drug combinations may confer target organ protection in addition to and independent of their blood pressure lowering effects. The ACCOMPLISH study will evaluate whether the fixed-dose combination of amlodipine/benazepril (Lotrel) provides added benefits in reducing morbidity and mortality from cardiovascular events in a high-risk hypertensive population when compared with an ACE-inhibitor (benazepril) diuretic combination. Key Words: clinical trials, combination therapy, event driven trials *This activity is supported by an unrestricted educational grant from Novartis Pharmaceuticals Corporation.

HOW SHOULD COMBINATION THERAPY BE STARTED? Michael A Weber. State University of New York Downstate College of Medicine, Brooklyn, NY The latest guidelines for the treatment of hypertension recommend stratification of blood pressure (BP) goals according to patient risk level. For example, the recommended BP goal for high-risk patients such as those with diabetes, cardiovascular (CV) disease, or renal insufficiency is ⬍130/85 mm Hg or ⬍130/80 mm Hg—lower than the ⬍140/90 mm Hg target for patients with uncomplicated hypertension. However, epidemiologic data show that only about 27% of hypertensive people in the United States have their BP controlled to ⬍140/90 mm Hg, indicating the need for improved antihypertensive treatment. Major trials show that 40% to 50% of all patients require multiple antihypertensive agents to achieve their BP goal. The failure of monotherapy to control BP in trials

FACULTY ABSTRACTS

265A

of stepped-care drug strategies has led to a renewed and growing interest in combination antihypertensive therapy. Combination therapy has been shown to address the multiple pathophysiologic factors that play a role in BP elevation, including blood volume, vasoconstriction, and the impact of sympathetic nervous system and renin-angiotensin system (RAS) activity, potentially resulting in both greater reduction in BP and in lowered risks for target-organ damage. The use of a fixed, low-dose combination agent also offers lower doses of each component than those that may be necessary with monotherapy, thus reducing the risks of dose-dependent adverse events (AEs) and associated compliance problems. These benefits may be enhanced when an angiotensin-converting enzyme (ACE) inhibitor is used as a component agent. While agents that block the RAS have been amply demonstrated to provide both renal and cardiac protection in hypertensive patients, independent of BP reduction, these effects may be amplified in combination with an agent with a complementary mechanism of action. For example, the ALERT (A Lotrel Evaluation of Hypertensive Patients with Arterial Stiffness and Left Ventricular Hypertrophy) trial compared the effects of amlodipine/benazepril combination therapy with those of monotherapy with the component drugs on arterial distensibility and left ventricular mass (LVM). Combined ACE inhibitor and calcium channel blocker (CCB) treatment was more efficacious than high doses of the individual agents in increasing arterial compliance and reducing LVM. Use of a combination agent may thus be appropriate as initial therapy in patients at high CV risk, such as those with diabetes, CV disease, renal insufficiency, or any combination of these risk factors. Furthermore, because multiple antihypertensive agents are necessary to achieve BP goals in close to half of all patients, use of combination therapy in addition to, or in replacement of, a failed monotherapy—in a stepwise manner—is also a rational option. ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial), for example, found that a diuretic-based regimen reduced CV risk to a similar extent as did CCB-based and ACE inhibitor– based regimens. However, after the 5-year treatment period of ALLHAT, 9.0% of subjects given a diuretic initially had switched to CCB or ACE inhibitor monotherapy, and an additional 13.2% were taking a CCB or ACE inhibitor with a diuretic; the average number of antihypertensive agents required by each subject was 1.8. Switching to, or adding, a fixed, low-dose ACE inhibitor/CCB combination therapy rather than monotherapy with either component may be significantly more effective and safer. An open-label study including more than 6000 patients with diastolic BP values between 90 and 110 mm Hg, despite amlodipine monotherapy, found that switching patients to amlodipine/benazepril combination therapy produced an additional mean reduction in BP of 15.6/11.5 mm Hg (P⬍0.001 vs amlodipine monotherapy). Furthermore, the incidence of pedal edema, a common AE associated with CCB therapy, was improved in 85% of patients experiencing the problem. Along with diuretics, ACE inhibitors and CCBs are 2 of the most effective and widely used antihypertensive agents available. Emerging evidence suggests the optimal use of these agents may be in fixed, low-dose combination therapy rather than as monotherapies. Key Words: Amlodipine, Benazepril, Antihypertensive Therapy *This activity is supported by an unrestricted educational grant from Novartis Pharmaceuticals Corporation.

Wednesday, May 14, 4:00 PM-6:00 PM Hypertension in the Obese Patient: Pathogenic Mechanisms, Cardiovascular Risk, and Treatment* THE OBESITY EPIDEMIC AND CV RISK William H Dietz. Centers for Disease Control and Prevention, Atlanta, GA Obesity is now epidemic in the United States. Children and adolescents appear to be at particularly high risk, and the increases in the prevalence of overweight children and adolescents doubled between NHANES III (1988-1994) and the current NHANES (1999-2000). Although over-