The Journal of Clinical Pharmacology

http://www.jclinpharm.org A Randomized, Placebo-Controlled Trial to Evaluate the Efficacy, Safety, and Pharmacodynamic Interaction of Coadministered Amlodipine and Atorvastatin in 1660 Patients With Concomitant Hypertension and Dyslipidemia: The Respond Trial
Richard A. Preston, Peter Harvey, Ottmar Herfert, Gary Dykstra, J. Wouter Jukema, Franklin Sun and David Gillen J. Clin. Pharmacol. 2007; 47; 1555 DOI: 10.1177/0091270007307879 The online version of this article can be found at: http://www.jclinpharm.org/cgi/content/abstract/47/12/1555

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CLINICAL TRIALS

A Randomized, Placebo-Controlled Trial to Evaluate the Efficacy, Safety, and Pharmacodynamic Interaction of Coadministered Amlodipine and Atorvastatin in 1660 Patients With Concomitant Hypertension and Dyslipidemia: The Respond Trial
Richard A. Preston, MD, Peter Harvey, MRCGP, Ottmar Herfert, MD, Gary Dykstra, DO, J. Wouter Jukema, MD, Franklin Sun, MPhil, MS, and David Gillen, MD

Guidelines stress the importance of the simultaneous management of multiple cardiovascular risk factors. This can in part be achieved by coadministration of lipid-lowering and antihypertensive treatments. Potential pharmacodynamic interaction between drugs should be investigated as part of developing single-pill combinations. The Respond trial assessed whether combining amlodipine to treat hypertension and atorvastatin to treat dyslipidemia affected the action of either monotherapy. A total of 1660 hypertensive patients with dyslipidemia received 1 of 15 combinations of amlodipine (placebo, 5, or 10 mg) and atorvastatin (placebo, 10, 20, 40, or 80 mg) in a 3 5 factorial randomized, placebo-controlled design. At 8 weeks, combinationtreated patients experienced dose-related and statistically

significant reductions in systolic blood pressure, low-density lipoprotein cholesterol, and Framingham risk score. Overall, coadministered atorvastatin and amlodipine was well tolerated and without adverse pharmacodynamic interaction; combination treatment did not affect the low-density lipoprotein cholesterollowering efficacy and safety of atorvastatin, or the systolic blood pressurelowering efficacy and safety of amlodipine. Keywords: Amlodipine; atorvastatin; Framingham coronary heart disease estimated risk; drug interaction Journal of Clinical Pharmacology, 2007;47:1555-1569 2007 the American College of Clinical Pharmacology

he profound benefits offered by antihypertensive and lipid-lowering pharmacotherapy have been well documented.1-4 Nevertheless, both hypertension and dyslipidemia are inadequately treated, or not treated at all, in the majority of patients.3,5,6 Furthermore, hypertension and dyslipidemia frequently coexist.7,8 Patients with concomitant hypertension and dyslipidemia often have existing cardiovascular disease
DOI: 10.1177/0091270007307879

or additional cardiovascular risk factors,7,8 markedly increasing their overall cardiovascular risk and mandating aggressive antihypertensive and lipidlowering therapy.1,2,4,9 Despite such high levels of risk, the percentage of patients who reach both their blood pressure and lipid targets is estimated to be less than 10% based on observational data.6 With the average population prevalence of concomitant hypertension and dyslipidemia estimated at 18% of men and 20% of women aged 20 years or older,6 the

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shortcomings of medical intervention result in an enormous excess burden of morbidity and mortality, as well as extensive utilization of costly health care resources.10 Therefore, innovative strategies designed to simultaneously lower blood pressure and lipid levels in patients at high cardiovascular risk are warranted. Typically, physicians treat patients with multiple cardiovascular risk factors by managing each risk factor separately, often sequentially rather than in parallel.11 This adds to pill burden and requires multiple physician visits to achieve appropriate drug titration for each risk factor. However, there have been repeated calls to abandon this stepwise approach.12-14 A single pill combining an antihypertensive and a lipid-lowering medication could streamline the prescribing process and provide an important step forward in managing cardiovascular risk. Such a combination ideally would be administered once daily with or without food. It should be free of clinically significant pharmacokinetic interaction (because multiple antihypertensive agents often are required to attain blood pressure goals,3,15 and patients at high risk of cardiovascular disease often receive other medications for concomitant conditions). Furthermore, it should be composed of medications with established safety, efficacy, and cardiovascular benefits. The combination of the dihydropyridine calcium channel blocker, amlodipine besylate, and the 3-hydroxy-3-methylglutarylcoenzyme A reductase inhibitor, atorvastatin calcium, satisfies these criteria; the safety and efficacy of both drugs have been demonstrated in several trials,16-24 and no significant pharmacokinetic interactions were observed between amlodipine 10 mg and atorvastatin 80 mg in a study involving healthy volunteers.25 In addition to assessing pharmacokinetic interaction between the component drugs, it is vital to test for pharmacodynamic interaction to be certain that the components are compatible for combining into a single pill. A single-pill therapy should be composed

of medications that do not have adverse effects on each others efficacy or tolerability.26 The Respond trial was conducted to evaluate the feasibility, effectiveness, and safety of the coadministration of amlodipine and atorvastatin for the treatment of patients with hypertension and dyslipidemia. This large-scale, placebo-controlled study was the first to examine the effects of amlodipine and atorvastatin combinations across their dose ranges. To date, it is the largest study conducted to assess the effects of the coadministration of 2 agents on 2 cardiovascular risk factors. Furthermore, it is designed to investigate potential unexpected or adverse pharmacodynamic interaction between amlodipine and atorvastatin, a step that is crucial for the development of the single pill. METHODS Study Design and Population Respond was a randomized, 3 5 factorial design, double-blind, double-dummy, placebo-controlled trial undertaken in 15 countries, across 4 continents. Participants were aged 18 to 75 years and had concomitant hypertension and dyslipidemia at screening, based on criteria set by the sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI)27 and the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) guidelines.1 Following the screening visit, participants underwent a taper/washout period (3 or 6 weeks for those receiving prior antihypertensive or lipid-lowering therapy, respectively). During the 2- to 3-visit runin/qualification period, baseline efficacy assessments were performed, and patients were allocated to 1 of 3 cardiovascular risk groups depending on the presence of risk factors and coronary heart disease (CHD) or risk equivalents (as defined by NCEP ATP III and JNC VI guidelines; Table I).1,27

From the Division of Clinical Pharmacology Clinical Research Center, Department of Medicine, Miller School of Medicine, University of Miami, Florida (Dr Preston); Crouch Oak Family Practice, Addlestone, Surrey, UK (Dr Harvey); General Practice, Linzer Strasse 4, 70469, Stuttgart, Germany (Dr Herfert); Bluestem Cardiology, Bartlesville, Oklahoma (Dr Dykstra); Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands (Dr Jukema); and Pfizer Inc, New York (Mr Sun, Dr Gillen). Submitted for publication April 30, 2007; revised version accepted August 4, 2007. Address for correspondence: Richard A. Preston, MD, Professor of Clinical Medicine, Director, Division of Clinical Pharmacology Clinical Research Center, Department of Medicine, Miller School of Medicine, University of Miami, 1500 NW 12th Avenue, 15th Floor West Tower, Miami, FL 33136; e-mail: rpreston@med.miami.edu. Supplementary data are available at http://jcp.sagepub.com/supplemental/.

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Table I
Group I Group II Group III All

Demographics and Baseline Characteristics by Cardiovascular Risk Group

Cardiovascular risk group criteria Fasting LDL-Ca 190-250 mg/dL (4.9-6.5 mmol/L) SBP 140-179 mm Hg and/or DBP 90-109 mm Hg 0 160-250 mg/dL (4.1-6.5 mmol/L) SBP 140-179 mm Hg and/or DBP 90-109 mm Hg 1 excluding CHD and DMc 809 (48.7) 413 (51.1) 65 (8.0) 545 (67.4) 199 (24.6) 57.7 (9.3) 744 27 12 26 28.6 (3.9) 29.1 (5.0) 7.4 (0.0-38.9) 5.3 (0.0-31.5) 188.7 (22.0) [4.88] [0.57] 150.8 (10.1) 93.7 (5.7) 10.0 (3.0) 17.9 (8.3) (92.0) (3.3) (1.5) (3.2) 740 20 23 16 (92.6) (2.5) (2.9) (2.0) 28.2 (4.4) 29.6 (5.4) 9.8 (0.0-47.9) 4.7 (0.0-36.1) 173.4 (26.3) [4.48] [0.68] 145.9 (8.2) 89.8 (5.1) 39 (4.9) 506 (63.3) 254 (31.8) 59.3 (8.6) 799 (48.1) 326 (40.8) 1660 (100.0) 776 (46.7) 117 (7.0) 1083 (65.2) 460 (27.7) 58.3 (9.1) 1532 (92.3) 48 (2.9) 35 (2.1) 45 (2.7) 28.4 (4.2) 29.3 (5.3) 8.5 (0.0-52.5) 5.0 (0.0-36.1) 181.8 (25.6) [4.70] [0.66] 148.4 (9.5) 91.8 (5.8) 130-250 mg/dL (3.4-6.5 mmol/L) SBP 130-159 mm Hg and/or DBP 85-99 mm Hg CHD, DM, or other atherosclerotic disease

Blood pressurea

52 (3.1) 37 (71.2) 13 (25.0) 32 (61.5) 7 (13.5) 52.0 (10.4) 48 (92.3) 1 (1.9) 0 3 (5.8) 29.9 (5.7) 29.4 (7.1) 6.6 (0.0-52.5) 3.9 (0.0-16.7) 203.1 (22.3) [5.25] [0.58] 149.4 (9.4) 93.7 (6.2) 8.2 (2.9) 11.1 (5.4)

Cardiovascular risk factors in addition to hypertension and dyslipidemiab Randomized patients, n (%) Sex, n (%) female Age 18-44 years, n (%) 45-64 years, n (%) 65 years, n (%) Mean, years (SD) Race White, n (%) Black, n (%) Asian, n (%) Other, n (%) Body mass index (kg/m2) Men, mean (SD) Women, mean (SD) Mean duration of primary diagnoses Hypertension, y (range) Dyslipidemia, y (range) Efficacy parameters LDL-C (mg/dL), mean (SD) [mmol/L] SBP (mm Hg), mean (SD) DBP (mm Hg), mean (SD) Framingham risk score, mean (SD) Framingham estimated 10-year CHD risk, mean (SD) Concurrent history of Diabetes mellitus, n (%) Ischemic heart disease, n (%) 0 1 (1.9) 0 4 (0.5) 244 (30.5) 465 (58.2)

244 (14.7) 470 (28.3)

CHD, coronary heart disease; DBP, diastolic blood pressure; DM, diabetes mellitus; LDL-C, low-density lipoprotein cholesterol; SBP, systolic blood pressure; SD, standard deviation. a. Average of measurements collected at 2 to 3 visits, 7 to 14 days apart. b. Includes age 45 years (men) or 55 years (women), history of CHD in a parent or sibling <55 years (men) or <65 years (women), smoking (current), and high-density lipoprotein cholesterol (HDL-C) <40 mg/dL (<1.03 mmol/L) (HDL-C 60 mg/dL [1.55 mmol/L] required 2 additional CHD risk factors). c. DM was permitted for patients enrolled prior to the National Cholesterol Education Program Adult Treatment Panel III amendment identifying DM as a CHD risk equivalent.

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Individuals were excluded if they had a previous history of intolerance to dihydropyridine calcium channel blockers and/or statins, or any serious disease or condition that could affect safety or study results. The study protocol was approved by each study centers institutional review board (all principal investigators and study centers are listed in an online appendix: http://jcp.sagepub.com/supplemental/). All participants provided written informed consent. Interventions Participants were randomized to 8 weeks of oncedaily treatment with 1 of 15 combinations of amlodipine, atorvastatin, and placebo (Figure 1). Placebo capsules were similar in size, color, smell, taste, and appearance to the corresponding active tablets. Randomization to double-blinded therapy (provided as coded study kits) was by a computergenerated randomization code obtained via telephone (ClinPhone, Inc, Princeton, New Jersey). The randomization schedule was protected, and the study remained blinded throughout. Treatment groups were balanced across all study sites. Patients were not permitted any additional antihypertensive or lipid-regulating therapies, nor could they receive any weight loss medications or drugs known or suspected to alter the absorption or metabolism of the study medications. Objectives and Outcome Measures The primary objective was to determine the effect of the coadministration of amlodipine and atorvastatin on the coprimary endpoints of the change from baseline to the endpoint in systolic blood pressure (SBP), as well as the percent change from baseline to the endpoint in low-density lipoprotein cholesterol (LDL-C). The main secondary objective was to determine whether atorvastatin, when coadministered with amlodipine, modifies the SBP-lowering efficacy of amlodipine and whether amlodipine, when coadministered with atorvastatin, modifies the LDLClowering efficacy of atorvastatin. A further secondary objective was to assess the effects of different coadministered dose combinations of amlodipine and atorvastatin on Framingham risk score. Framingham risk scores were calculated, at baseline and endpoint, and translated to estimates of 10-year CHD risk in accordance with the procedures defined by Wilson et al.28 Because group III patients had

CHD, or a CHD risk equivalent, at study entry, only group I and II patients were included in this analysis. A further objective was to compare the safety profile of coadministered atorvastatin and amlodipine with that of either compound alone and placebo. The severity, duration, date of onset, action taken, and suspected causal relationship to study drug of all adverse events (AEs) were recorded at each clinic visit. To determine abnormalities in muscle function, serum chemistry screens of creatine phosphokinase (CPK) were performed. Liver function tests (defined as tests for serum glutamic pyruvic transaminase/ alanine aminotransferase [SGPT/ALT], serum glutamic oxaloacetic transaminase/aspartate aminotransferase [SGOT/AST], gamma-glutamyl transpeptidase [GGT], alkaline phosphatase, and total bilirubin) were also undertaken. For CPK, enzyme levels >10 upper limit of normal (ULN) were recorded; for SGPT/ALT, SGOT/AST, GGT, alkaline phosphatase, and total bilirubin levels, >3 ULN were captured. Persistent elevations were also analyzed (in accordance with guidelines by the American College of Cardiology, the American Heart Association, and the National Heart, Lung, and Blood Institute).29 In this study, persistent elevations were defined as 2 consecutive measurements within a 14-day period. The normal range of CPK was defined as 18 to 198 U/L for men and 18 to 169 U/L for women. The normal range for the markers of liver function were defined as follows: SGPT/ALT, 6 to 34 U/L; SGOT/AST, 9 to 34 U/L; GGT, 4 to 49 U/L; alkaline phosphatase, 35 to 123 U/L; and total bilirubin, 0.2 to 1.2 mg/dL. Patients with CPK levels >10 ULN or SGOT/SGPT >3 ULN at any time during the treatment phase and confirmed by redraw were withdrawn from the trial. Statistical Methods The expected difference in LDL-C mean percentage change from baseline between amlodipine 5 mg and atorvastatin 10 mg and amlodipine 5 mg alone was 36.9% (standard deviation: 11.8%). The expected difference in SBP change from baseline between amlodipine 5 mg and atorvastatin 10 mg and atorvastatin 10 mg alone was 9.8 mm Hg (standard deviation: 10.9 mm Hg). Based on these assumptions, a sample size of 100 participants in each treatment arm was calculated to have 94% power (2-sided t test, = 0.05) to detect statistically significant treatment differences in SBP and LDL-C. Because greater treatment differences were expected for the higher

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AMLODIPINE AND ATORVASTATIN FOR HYPERTENSION AND DYSLIPIDEMIA

Randomized (n = 1660)

35 factorial design
(dotted line indicates the 8 active amlodipine and atorvastatin dose combinations) Atorvastatin Placebo Amlodipine Placebo 5 mg 10 mg P/P 5/P 10/P 10 mg P/10 5/10 10/10 20 mg P/20 5/20 10/20 40 mg P/40 5/40 10/40 80 mg P/80 5/80 10/80

Amlodipine

Placebo

5 mg

10 mg

Received intervention* Completed Discontinued Died Adverse event Lack of efficacy Lost to follow-up Other Included in efficacy analysis || Excluded from analysis Received intervention* Completed Discontinued Died Adverse event Lack of efficacy Lost to follow-up Other Included in efficacy analysis Excluded from analysis|| Received intervention* Completed Discontinued Died Adverse event Lack of efficacy Lost to follow-up Other Included in efficacy analysis Excluded from analysis||

Placebo 111 102 9 0 5 4 0 0 111 0 110 104 6 0 3 0 1 2 110 0 111 100 11 0 9 0 1 1 109 2

Atorvastatin 10 mg 20 mg 40 mg 111 111 111 99 103 96 12 8 15 0 1 0 8 1 6 2 1 2 0 3 4 2 2 3 111 111 111 0 0 0 111 111 110 102 106 101 9 5 9 0 0 0 5 2 7 1 0 0 0 2 1 3 1 1 110 111 109 1 0 1 110 110 111 101 99 103 9 11 8 0 0 0 7 10 5 0 0 1 2 0 2 0 1 0 108 110 111 2 0 0

80 mg 110 96 14 1 3 3 4 3 110 0 111 105 6 0 5 0 1 0 111 0 111 100 11 0 9 0 1 1 111 0

Figure 1.
*

Flow of participants through the Respond trial.

All randomized patients received allocated intervention, with the exception of 1 patient who was randomized to amlodipine 10 mg and atorvastatin 80 mg but received treatment with amlodipine 5 mg and atorvastatin placebo. Includes discontinuation due to laboratory abnormality. Includes patients who were unwilling to participate further in the study. Includes patients who were determined to have not met the study entry criteria or who deviated from the protocol. || Due to insufficient data for follow-up.

doses, the power to detect statistically significant results will be higher than for the lower dose comparisons. Assuming that 10% of randomized patients did not contribute to the primary efficacy assessment (for patients to be included in the primary efficacy analysis, the change from baseline for

either SBP or LDL-C was needed), the total number of patients required was approximately 1660. Differences between treatment groups in the coprimary efficacy parameters and Framingham risk scores at endpoint were analyzed according to a 3 5 factorial analysis of covariance (ANCOVA), in

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Table II
Primary

Coprimary and Secondary Efficacy Step-Down Analyses

Efficacy of Combined Treatment in Reducing LDL-C

Efficacy of Combined Treatment in Reducing SBP

Null hypotheses

No overall effect of amlodipine. If rejected then: No individual dose effect of amlodipine. If rejected then: Eight active combinations vs atorvastatin alone
Does Atorvastatin Modify the SBP-Lowering Effect of Amlodipine?

No overall effect of atorvastatin. If rejected then: No individual dose effect of atorvastatin. If rejected then: Eight active combinations vs amlodipine alone
Does Amlodipine Modify the LDL-C-Lowering Effect of Atorvastatin?

Secondary

Comparisons

The high atorvastatin doses (40 and 80 mg) combined across all amlodipine doses vs amlodipine alone The low atorvastatin doses (10 and 20 mg) combined across amlodipine doses vs amlodipine alone Eight active combinations vs amlodipine alone

Amlodipine 10 mg combined across all atorvastastin doses vs atorvastatin alone Amlodipine 5 mg combined across all atorvastastin doses vs atorvastatin alone Eight active combinations vs amlodipine alone

Secondary

Efficacy of Combined Treatment in Reducing Framingham Risk Score

Null hypotheses

No overall effect of amlodipine No individual dose effect of amlodipine Eight active combinations vs atorvastatin alone

No overall effect of atorvastatin No individual dose effect of atorvastatin Eight active combinations vs amlodipine alone

LDL-C, low-density lipoprotein cholesterol; SBP, systolic blood pressure. The tests were based on the ANCOVA model: Y = baseline + atorvastatin + amlodipine + atorvastatin amlodipine (3 5 factorial), where Y = change from baseline in SBP, LDL-C, or Framingham risk score.

which the independent variables were atorvastatin, amlodipine, and atorvastatin-by-amlodipine interaction, and the baseline measurement served as the covariate. Last observation carried forward was used for patients who did not complete the study or who had missing readings. To control for multiplicity and preserve overall type I error rate, comparisons were conducted in parallel using a step-down procedure.30 The stepdown approach has been recommended for the statistical assessment of a combination therapy when each component contributes to a different outcome.31 Statistical comparisons for the primary and secondary analyses are summarized in Table II. Data are presented as change in mean and in least squares (LS) mean from baseline to endpoint; P values are based on comparisons of LS means. RESULTS Patient Characteristics A total of 1660 patients (884 men and 776 women) were randomized, with similar numbers in each treatment group (Figure 1); 1517 patients (91.4%) completed the study; and 1654 patients were

included in the efficacy analysis. Participants were predominantly Caucasian (92.3%), over ideal body weight (mean body mass index: 28.4 kg/m2 for men and 29.3 kg/m2 for women), and with a mean age of 58 years (Table I). The mean baseline SBP was 148 mm Hg, and mean baseline LDL-C level was 182 mg/dL (4.7 mmol/L). Very few patients (3.1%) had only hypertension and dyslipidemia (group I); 48.7% had hypertension and dyslipidemia and additional cardiovascular risk factors, but no CHD or a risk equivalent (group II); and almost half (48.1%) had CHD, diabetes mellitus, or atherosclerotic disease (group III). During the 6 months before study entry, approximately one third of study participants had not received any antihypertensive or lipidlowering treatment. Effects on Blood Pressure Amlodipine at each dose reduced SBP compared with atorvastatin alone. All 8 active amlodipine + atorvastatin combination doses were superior to atorvastatin alone in reducing SBP (all P < .001; Table IIIA). When change in SBP was examined by cardiovascular risk group, reductions occurred in patients without CHD or risk

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AMLODIPINE AND ATORVASTATIN FOR HYPERTENSION AND DYSLIPIDEMIA

Table III

Primary Efficacy Analysis and Analysis of Effect Modification

(A) Efficacy of Combined Treatment in Reducing SBP Null Hypothesis LS Mean Difference, mm Hg (95% CI) P

1. No overall effect of amlodipine 2. No individual amlodipine dose effect Amlodipine dose vs atorvastatin only: 10 mg 5 mg 3. No individual combination treatment effect (Amlodipine + atorvastatin) vs atorvastatin only: (5 mg + 10 mg) vs 10 mg (5 mg + 20 mg) vs 20 mg (5 mg + 40 mg) vs 40 mg (5 mg + 80 mg) vs 80 mg (10 mg + 10 mg) vs 10 mg (10 mg + 20 mg) vs 20 mg (10 mg + 40 mg) vs 40 mg (10 mg + 80 mg) vs 80 mg
(B) Efficacy of Combined Treatment in Reducing LDL-C Null Hypothesis

<.001 11.3 8.2 (12.6, 9.9) (9.5, 6.8) <.001 <.001 <.001 <.001 <.001 <.001 <.001 <.001 <.001 <.001

9.3 9.2 6.6 6.0 11.6 9.9 10.3 11.0

(12.3, 6.3) (12.2, 6.2) (9.7, 3.6) (9.0, 3.0) (14.6, 8.5) (12.9, 6.8) (13.3, 7.2) (14.0, 7.9)

LS Mean Difference, % Points

(95% CI)

1. No overall effect of atorvastatin 2. No individual atorvastatin dose effect Atorvastatin dose vs amlodipine only: 80 mg 40 mg 20 mg 10 mg 3. No individual combination treatment effect (Amlodipine + atorvastatin) vs amlodipine only: (5 mg + 10 mg) vs 5 mg (5 mg + 20 mg) vs 5 mg (5 mg + 40 mg) vs 5 mg (5 mg + 80 mg) vs 5 mg (10 mg + 10 mg) vs 10 mg (10 mg + 20 mg) vs 10 mg (10 mg + 40 mg) vs 10 mg (10 mg + 80 mg) vs 10 mg
(C) Does Atorvastatin Modify the Effect of Amlodipine on SBP? Comparison

<.001 46.9 42.4 38.8 35.1 (49.2, (44.7, (41.1, (37.4, 44.6) 40.1) 36.5) 32.8) <.001 <.001 <.001 <.001 <.001 <.001 <.001 <.001 <.001 <.001 <.001 <.001

38.9 42.2 44.8 48.2 34.0 36.0 40.6 46.6

(42.9, (46.2, (48.8, (52.2, (38.1, (40.0, (44.6, (50.6,

34.9) 38.2) 40.8) 44.2) 30.0) 32.0) 36.7) 42.6)

LS Mean Difference, mm Hg

(95% CI)

1. Effect of the high and low atorvastatin doses Atorvastatin doses: 40 mg and 80 mg (high) 10 mg and 20 mg (low) 2. No individual combination treatment effect (Amlodipine + atorvastatin) vs amlodipine only: (5 mg + 10 mg) vs 5 mg (5 mg + 20 mg) vs 5 mg (5 mg + 40 mg) vs 5 mg (5 mg + 80 mg) vs 5 mg (10 mg + 10 mg) vs 10 mg

0.3 0.7

(2.2, 1.5) (2.5, 1.2)

.746 .490

1.0 2.7 0.2 0.1 0.6

(4.0, (5.7, (3.2, (3.0, (2.5,

2.0) 0.3) 2.8) 3.1) 3.6)

.522 .081 .892 .972 .703

(continued)

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Table III
(10 mg + 20 mg) vs 10 mg (10 mg + 40 mg) vs 10 mg (10 mg + 80 mg) vs 10 mg
(D) Does Amlodipine Modify the Effect of Atorvastatin on LDL-C? Comparison

(continued)
0.5 0.0 1.1 (2.6, 3.5) (3.0, 3.0) (4.1, 1.9) .761 .995 .485

LS Mean Difference, % Points

(95% CI)

1. Effect of the 10-mg and 5-mg amlodipine doses Amlodipine dose: 10 mg 5 mg 2. No individual combination treatment effect (Amlodipine + atorvastatin) vs atorvastatin only: (5 mg + 10 mg) vs 10 mg (5 mg + 20 mg) vs 20 mg (5 mg + 40 mg) vs 40 mg (5 mg + 80 mg) vs 80 mg (10 mg + 10 mg) vs 10 mg (10 mg + 20 mg) vs 20 mg (10 mg + 40 mg) vs 40 mg (10 mg + 80 mg) vs 80 mg

1.2 2.8

(3.2, 0.8) (4.8, 0.8)

.250 .006

5.5 2.8 1.8 1.2 3.2 0.9 0.2 2.2

(9.5, (6.7, (5.8, (5.2, (7.2, (3.1, (4.2, (6.2,

1.5) 1.2) 2.2) 2.8) 0.9) 4.9) 3.8) 1.8)

.007 .172 .372 .547 .126 .674 .927 .280

CI, confidence interval; LDLC, low-density lipoprotein cholesterol; LS, least squares; SBP, systolic blood pressure.

equivalent (groups I + II) and in those with CHD (group III) (Figure 2A). Atorvastatin did not modify the effect of amlodipine on SBP when the 2 drugs were coadministered (Table IIIC). Neither the high nor the low atorvastatin doses significantly affected the SBP-lowering efficacy of amlodipine. Comparisons of each combination dose versus amlodipine alone confirmed that atorvastatin did not affect the SBP-lowering efficacy of amlodipine (all P = NS). Effects on Low-Density Lipoprotein Cholesterol All 8 combination doses were significantly more effective than amlodipine alone in reducing LDL-C (all P < .001; Table IIIB). Reductions in LDL-C were similar among patients in groups I + II and in group III (Figure 2B). Overall, amlodipine did not alter the effect of atorvastatin on LDL-C when the 2 drugs were coadministered (Table IIID). However, when pooled across the 4 active atorvastatin doses, coadministration of amlodipine 5 mg significantly reduced LDLC more than the pooled atorvastatin monotherapy doses (LS mean change from baseline: 43.6% vs 40.8%; P = .006). Amlodipine 5 mg and atorvastatin 10 mg reduced LDL-C to a lower level than atorvastatin 10 mg alone (LS mean change from baseline:

39.0% vs 33.5%; P = .007). No other comparisons demonstrated a significant combination treatment effect (Table IIID). Effects on Framingham Risk Score and Estimated 10-Year Risk of Coronary Heart Disease Coadministered amlodipine and atorvastatin, among patients without existing CHD or a risk equivalent (ie, groups I + II), reduced Framingham risk scores, from baseline to endpoint. All planned comparisons demonstrated significant differences except amlodipine 10 mg and atorvastatin 10 mg versus atorvastatin 10 mg alone (P = .108). As a result of these reductions in Framingham risk score, the estimated 10-year risk of CHD was reduced to 7.3% to 10.7% at endpoint (mean baseline to endpoint reductions of 7.7 to 11.2 percentage points) from mean baseline levels of 15.8% to 18% in combination-treated patients. This represented mean baseline to endpoint reductions of 7.7 to 11.2 percentage points in estimated CHD risk or relative risk reductions of 44.2% to 62.3% (Figure 3). Maximal risk reduction was observed in patients coadministered amlodipine 5 mg and atorvastatin 80 mg and those receiving amlodipine 10 mg and atorvastatin 80 mg. No change in estimated 10-year CHD risk was observed in patients who received placebo only.

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Figure 2. (A) Effect of amlodipine, atorvastatin, and their combination on the mean change from baseline to endpoint in systolic blood pressure (SBP). (B) Effect of amlodipine, atorvastatin, and their combination on the mean change from baseline to endpoint in lowdensity lipoprotein cholesterol (LDL-C) levels.
*

Coronary heart disease risk groups as defined in Table I. Number of patients in each treatment group.

Safety Evaluation All 1660 randomized patients were included in the safety analysis. Overall, 85 patients (5.1%) discontinued due to AEs (Figure 1). Discontinuations due to AEs were similar in the combination (5.6%), amlodipine-alone (5.4%), atorvastatin-alone (4.1%), and placebo (4.5%) groups.

The majority of patients in each treatment group experienced AEs that were only mild to moderate in severity. Treatment-emergent all-causality AEs (Table IV) that occurred in combination-treated patients at more than twice the incidence of placebotreated patients were peripheral edema, abdominal pain, and hyperglycemia (enzyme elevations that were reported as AEs are described in further detail

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PRESTON ET AL Treatment-Emergent Adverse Events Occurring in 1% of All Combination-Treated Patients

Placebo (n = 111) Adverse Event, % All Cause Treatment Related Amlodipine Only (n = 221) All Cause Treatment Related Atorvastatin Only (n = 443) All Cause Treatment Related Amlodipine + Atorvastatin (n = 885) All Cause Treatment Related

Table IV

Peripheral edema Headache Respiratory tract infection Dizziness Abdominal pain Asthenia Vasodilatation Palpitation Diarrhea GGT increased Back pain Constipation SGPT (ALT) increased Rash Myalgia SGOT (AST) increased Alkaline phosphatase increased Hyperglycemia Arthralgia Nausea Pharyngitis Flu syndrome

2.7 9.9 4.5 2.7 0.0 2.7 2.7 1.8 1.8 0.0 0.9 0.9 0.0 0.9 1.8 0.9 0.0 0.0 3.6 2.7 0.9 0.9

2.7 5.4 0.9 1.8 0.0 1.8 2.7 1.8 0.0 0.0 0.9 0.0 0.0 0.0 1.8 0.9 0.0 0.0 0.0 1.8 0.0 0.0

12.2 5.0 3.2 3.2 0.9 1.8 0.9 1.8 0.9 0.5 1.8 1.4 0.5 0.5 1.4 0.5 0.0 0.5 1.4 1.4 0.5 0.0

10.9 4.1 0.0 2.7 0.0 1.8 0.9 1.8 0.9 0.5 0.5 0.9 0.5 0.5 1.4 0.5 0.0 0.5 0.5 0.9 0.0 0.0

1.1 7.7 3.8 1.1 2.3 1.8 0.7 0.9 1.1 1.4 1.1 0.5 1.1 0.7 1.8 0.7 0.5 0.9 0.9 1.6 0.7 1.8

0.9 4.5 0.7 1.1 1.8 1.1 0.7 0.7 0.5 1.4 0.2 0.5 1.1 0.5 1.1 0.7 0.5 0.2 0.0 1.4 0.2 0.2

9.9 5.3 4.9 2.4 2.3 2.1 2.0 1.9 1.9 1.8 1.7 1.7 1.7 1.7 1.6 1.5 1.1 1.1 1.1 1.0 1.0 1.0

9.4 3.6 0.3 2.1 1.6 1.5 1.9 1.6 0.7 1.8 0.8 1.2 1.5 1.5 1.0 1.5 1.0 0.3 0.5 0.7 0.0 0.0

Adverse events that occurred in combination-treated patients at more than twice the incidence of placebo-treated patients are italicized. GGT, gammaglutamyl transferase; SGOT (AST), serum glutamic oxaloacetic transaminase (aspartate aminotransferase); SGPT (ALT), serum glutamic pyruvic transaminase (alanine aminotransferase).

below). Combination-treated patients did not experience any increase in either all-causality or treatmentrelated AEs compared with amlodipine or atorvastatin monotherapy. The most common treatment-related AEs were peripheral edema (2.7% of placebo-treated and 9.4% of combination-treated patients), headache (5.4% placebo treated; 3.6% combination treated), and dizziness (1.8% placebo treated; 2.1% combination treated). These events were mild to moderate in severity. The incidence of treatment-related myalgia in combination-treated patients was low (1.0%) and similar to that in patients treated with amlodipine alone (1.4%), atorvastatin alone (1.1%), or placebo (1.8%). A total of 25 patients experienced serious AEs that began during the study or within 30 days of the last dose of double-blind study medication. Three of these events were deaths, all of which were considered by the investigators to be unrelated to study

medication. Only 1 serious AE (postural hypotension) was considered related to treatment (amlodipine 5 mg and atorvastatin 20 mg), and this AE was judged to be related to the amlodipine component of the treatment. No serious AEs were deemed related to coadministered amlodipine and atorvastatin. No increase in the incidence of AEs was observed at the higher versus lower amlodipine and atorvastatin doses. For example, 41% of patients coadministered amlodipine 10 mg and atorvastatin 80 mg experienced an AE versus 50% of those treated with amlodipine 10 mg and atorvastatin 20 mg and 45% of those receiving amlodipine 5 mg and atorvastatin 80 mg. Clinical Laboratory Test Abnormalities Among patients with at least 1 dose of study medication and 1 postbaseline safety assessment, the incidence of CPK elevation was low: only 1 patient

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AMLODIPINE AND ATORVASTATIN FOR HYPERTENSION AND DYSLIPIDEMIA

Figure 3. Mean change from baseline to endpoint in Framingham 10-year coronary heart disease (CHD) risk percentage in group I and II patients. Coronary heart disease risk groups as defined in Table I. CI, confidence interval.

in the amlodipine-only group had CPK levels >10 ULN. Increases in CPK were considered to be unrelated to study treatment. Among patients with at least 1 dose of study medication and 1 liver function reading, SGPT/ALT levels >3 ULN occurred in 18 patients; these elevations persisted at this level in 1 (0.5%) patient in the amlodipine-only group and 2 (0.2%) patients in the amlodipine + atorvastatin combination group. Elevations in SGOT/AST levels occurred in 10 patients but only persisted at this level in 1 patient in the amlodipine-only group. Gamma-glutamyl transpeptidase elevations >3 ULN occurred in 49 patients; these elevations persisted in 1 (0.2%) patient in the atorvastatin-only treatment group and 2 (0.2%) patients in the amlodipine + atorvastatin combination group. There were 4 patients with levels of alkaline phosphatase >3 ULN, but none of these persisted at this level during the trial. There was no incidence of elevated total bilirubin >3 ULN throughout the treatment period. Increases in SGPT/ALT, SGOT/AST, GGT, and alkaline phosphatase were reported as AEs (Table IV) and were considered to be treatment related by the investigator. The treatment-related enzyme elevations that occurred in at least 1% of combination-treated patients and had a numerically higher incidence rate than the rate in placebo-treated patients were

SGPT/ALT, GGT and alkaline phosphatase (SGPT/ALT, 0.0% vs 1.7%; GGT, 0.0% vs 1.8%; and alkaline phosphatase, 0.0% vs 1.0%). DISCUSSION This large placebo-controlled study establishes the safety, efficacy, and lack of pharmacodynamic or adverse interaction between coadministered amlodipine and atorvastatin in a clinically relevant population, consisting of patients with multiple cardiovascular risk factors. The majority of the study population had, in addition to hypertension and dyslipidemia, other concomitant cardiovascular risk factors or existing cardiovascular disease. Of clinical significance is the observation that considerable reductions in Framingham cardiovascular risk score were observed at 8 weeks in patients coadministered amlodipine and atorvastatin. Over 8 weeks, patients with hypertension and dyslipidemia, coadministered amlodipine and atorvastatin over a range of doses, had greater reductions in SBP compared with patients receiving atorvastatin alone and greater reductions in LDL-C versus patients receiving amlodipine alone. The LDL-C reduction observed was comparable with that in previous studies of atorvastatin.18,19,23 Coadministration with atorvastatin did not affect the ability of amlodipine

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to lower blood pressure. Similarly, coadministration with amlodipine did not affect the overall lipidlowering capacity of atorvastatin. However, when amlodipine 5 mg was coadministered with atorvastatin 10 mg, the LDL-C level was reduced to below that seen with atorvastatin 10 mg alone. No significant effect modification was observed for any other comparisons of individual doses of coadministered amlodipine and atorvastatin versus either agent alone. The results of the present study are comparable to the findings of the AVALON study.21 In AVALON, 847 hypertensive patients were randomized in an 8-week double-blind phase to receive amlodipine 5 mg and atorvastatin 10 mg, amlodipine 5 mg and placebo, atorvastatin 10 mg and placebo, or placebo alone. Coadministration of amlodipine 5 mg and atorvastatin 10 mg for 8 weeks achieved the greatest reductions in blood pressure and lipid levels, and interestingly, the LDL-C reductions were significantly greater compared with atorvastatin 10 mg alone (P = .007). There was no significant difference in blood pressure lowering when comparing coadministered amlodipine and atorvastatin and amlodipine alone. The 8-week double-blind phase of AVALON was followed by an 8-week single-blind phase, where all patients received amlodipine 5 mg and atorvastatin 10 mg, and then a 12-week openlabel phase, where coadministration continued and both drugs could be titrated to higher doses (amlodipine to 10 mg and atorvastatin to 80 mg). At 28 weeks, 67.3% of patients who had received both drugs throughout the study reached their blood pressure and LDL-C goals. Overall, coadministration of amlodipine and atorvastatin was effective and well tolerated, and there was no evidence of adverse pharmacodynamic interaction. Amlodipine/atorvastatin combination therapy is further supported by the favorable results of recent pharmacokinetic studies. Chung et al32 reported 2 randomized, 2-way crossover studies investigating whether single-pill amlodipine/atorvastatin was bioequivalent with coadministered amlodipine and atorvastatin; healthy volunteers received both drugs either as a single pill or by coadministration of separate pills, at the lowest (5/10 mg) or highest (10/80 mg) dose strengths. The 90% confidence intervals for the ratios of the geometric mean of maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) for the combination tablet/coadministered tablets were within 80% to 125%, demonstrating bioequivalence at both dose strengths. The authors also state that the pharmacokinetic properties observed for single-pill

amlodipine/atorvastatin were similar to those reported in the product labels of both commercially available amlodipine besylate33 and atorvastatin calcium.34 The lack of an adverse pharmacodynamic or pharmacokinetic interaction between amlodipine and atorvastatin is a key prerequisite for the coadministration of these 2 medications and their combination into a single pill.35 The reductions in SBP and LDL-C seen in the present study were apparent in individuals with varying levels of CHD risk. This is consistent with earlier studies of amlodipine and atorvastatin monotherapy.17,23 The results of the present study are also supported by those of the GEMINI study.36 This was a large (n = 1220) 14-week clinical trial, in which amlodipine and atorvastatin were coadministered as a single pill. Amlodipine/atorvastatin single-pill therapy was well tolerated across the dose range and enabled 57.7% of patients with hypertension and dyslipidemia to reach both their SBP and LDL-C goals. Subsequent open-label studies have confirmed the efficacy and safety of single-pill amlodipine/atorvastatin in African Americans37 and in patients with hypertension and dyslipidemia from Canada and Europe,38 as well as Africa, Asia, Australia, and Central/South America.39 Among patients without existing CHD or a risk equivalent who were coadministered amlodipine and atorvastatin, we observed significant reductions in Framingham risk score, resulting in a clear reduction of the estimated 10-year risk of CHD. This is consistent with the AVALON trial, where 28 weeks of amlodipine and atorvastatin coadministration was associated with a reduction in Framingham risk score from 15.1% at baseline to 6.9%.21 The Framingham-estimated 10-year risk of CHD has been adopted by recent treatment guidelines1,4 and provides a practical means of motivating patients toward healthy behaviors.40 Furthermore, Framingham 10year CHD risk estimates have been used to assess efficacy when interventions target cardiovascular risk factors.41-43 However, Framingham risk scores may overestimate the risk for CHD in some populations such as those in parts of Europe.44,45 Moreover, changes in CHD risk profile over time are best assessed using risk estimations derived from intervention trials rather than epidemiologic data.46 Nevertheless, the large reductions in Framingham risk score (relative risk reductions of 41.8%-62.3%) observed during the relatively short time course of the present study are of clinical relevance. The observed reductions in risk also highlight the importance of an integrated approach to reducing CHD

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risk. The lowering of blood pressure alone (amlodipine without atorvastatin) reduced estimated CHD risk by 3 to 5 percentage points, and LDL-C lowering alone (atorvastatin without amlodipine) reduced this risk by 6 to 7 percentage points. In comparison, combined blood pressure and LDL-C lowering reduced the estimated risk of CHD by 8 to 11 points. All treatments were well tolerated, and most AEs were mild or moderate in severity. The occurrence of AEs or laboratory abnormalities, or withdrawals due to AEs or laboratory abnormalities, was similar in patients coadministered amlodipine and atorvastatin compared with those in patients receiving either amlodipine or atorvastatin monotherapy. These results are consistent with those from the AVALON trial.21 Guidelines call for the simultaneous and aggressive treatment of multiple cardiovascular risk factors.1,2,4 However, many patients requiring antihypertensive or lipid-lowering therapy are undertreated.6,47,48 Indeed, one third of patients enrolled in this trial had not received antihypertensive or lipid-lowering treatment in the 6 months before the study. These data highlight the need for new methods to improve the management of overall cardiovascular risk. Evidence suggests that a combined approach using multifactorial interventions is associated with significant treatment benefits18,49,50 and that amlodipine and atorvastatin can have an important role in the management of cardiovascular risk.16,18,20,21 A recent analysis of the Anglo-Scandinavian Outcomes Trial Lipid-Lowering Arm (ASCOT-LLA) demonstrated that atorvastatin provided the greatest benefits when combined with amlodipine, reducing the relative risk of CHD events by 53%, compared with 16% when added to atenolol.51 Recent trials also have demonstrated that intensive lipid-lowering treatment provides significantly more protection against death or major cardiovascular events compared with standard lipid-lowering treatment.19,52 Similarly, the benefits of prompt, aggressive blood pressure control in hypertensive patients at high cardiovascular risk were demonstrated in the VALUE trial.20 One of the barriers to the effective treatment of multiple cardiovascular risk factors is the problem of adherence to therapy.53 Improvement is possible by initiating blood pressurelowering and lipidlowering therapy concomitantly or by reducing pill burden.53 A study conducted in patients newly initiated on a calcium channel blocker (CCB) or statin showed that the probability of achieving adherence with the single pill is almost twice that of amlodipine and atorvastatin taken separately (P < .0001).54

This study has demonstrated that the coadministration of amlodipine and atorvastatin across the dose ranges for both treatments is efficacious and safe in patients with hypertension and dyslipidemia. Importantly, this study has shown that there is no unexpected or adverse pharmacodynamic interaction between the 2 drugs. The Respond trial was therefore an important and necessary step in the successful development of amlodipine/atorvastatin single-pill therapy.
Financial disclosure: This study was funded by Pfizer, Inc. The first draft of this manuscript was written by the corresponding author (Dr Preston). Editorial/logistical support with the collation of author feedback and finalization of the manuscript was provided by Jon Edwards of Envision Pharma and funded by Pfizer, Inc, R. A. Preston has received research grants from Pfizer Inc, AstraZeneca, Wyeth, Berlex, Novartis, Schering-Plough, Ferring, Abbott, Optimer, Takeda, and Tap. P. Harvey has received research grants from Pfizer, Inc, for the conduct of the Respond and other studies and consultancy fees from Pfizer Inc, Dr Harvey has also received research grants from Merck, Sharp & Dohme, AstraZeneca, Procter & Gamble, Rotta, Alizyme, Eli Lilly, Novo Nordis, and Lundbeck. O. Herfert has received research grants from Pfizer. G. Dykstra holds stock options in Pfizer Inc in a pension plan. J. W. Jukema has received grants with regard to research protocols and lectures from Pfizer Inc, F. Sun and D. Gillen were employees of Pfizer, Inc when this study was conducted.

REFERENCES
1. Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults. Third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Circulation. 2002;106: 3143-3421. 2. De Backer G, Ambrosioni E, Borch-Johnsen K, et al. European guidelines on cardiovascular disease prevention in clinical practice. Third Joint Task Force of European and Other Societies on Cardiovascular Disease Prevention in Clinical Practice. Eur Heart J. 2003;24:1601-1610. 3. Chobanian AV, Bakris GL, Black HR, et al. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003;289:2560-2572. 4. Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004;110:227-239. 5. Wolf-Maier K, Cooper RS, Kramer H, et al. Hypertension treatment and control in five European countries, Canada, and the United States. Hypertension. 2004;43:10-17. 6. Wong ND, Lopez V, Tang S, Williams GR. Prevalence, treatment, and control of combined hypertension and hypercholesterolemia in the United States. Am J Cardiol. 2006;98:204-208. 7. Thomas F, Rudnichi A, Bacri AM, Bean K, Guize L, Benetos A. Cardiovascular mortality in hypertensive men according to presence of associated risk factors. Hypertension. 2001;37: 1256-1261.

CLINICAL TRIALS

1567

PRESTON ET AL

8. Johnson ML, Pietz K, Battleman DS, Beyth RJ. Prevalence of comorbid hypertension and dyslipidemia and associated cardiovascular disease. Am J Manag Care. 2004;10:926-932. 9. Mancia G. Total cardiovascular risk: a new treatment concept. J Hypertens Suppl. 2006;24:S17-S24. 10. Thom T, Haase N, Rosamond W, et al. Heart disease and stroke statistics2006 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2006;113:e85-e151. 11. Rosal MC, Ockene JK, Luckmann R, et al. Coronary heart disease multiple risk factor reduction: providers perspectives. Am J Prev Med. 2004;27:54-60. 12. Jackson R, Lawes CM, Bennett DA, Milne RJ, Rodgers A. Treatment with drugs to lower blood pressure and blood cholesterol based on an individuals absolute cardiovascular risk. Lancet. 2005;365:434-441. 13. Ansell BJ. Evidence for a combined approach to the management of hypertension and dyslipidemia. Am J Hypertens. 2005;18:1249-1257. 14. Nash DT. The clinical implications and management of concomitant hypertension and dyslipidemia. Postgrad Med. 2006;119:37-45. 15. 2003 European Society of HypertensionEuropean Society of Cardiology guidelines for the management of arterial hypertension. J Hypertens. 2003;21:1011-1053. 16. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group (The Antihypertensive and LipidLowering Treatment to Prevent Heart Attack Trial). Major outcomes in high-risk hypertensive patients randomized to angiotensinconverting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002;288:2981-2997. 17. Levine CB, Fahrbach KR, Frame D, et al. Effect of amlodipine on systolic blood pressure. Clin Ther. 2003;25:35-57. 18. Sever PS, Dahlof B, Poulter NR, et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes TrialLipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet. 2003;361:1149-1158. 19. Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350:1495-1504. 20. Julius S, Kjeldsen SE, Weber M, et al. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial. Lancet. 2004;363:2022-2031. 21. Messerli FH, Bakris GL, Ferrera D, et al. Efficacy and safety of coadministered amlodipine and atorvastatin in patients with hypertension and dyslipidemia: results of the AVALON trial. J Clin Hypertens (Greenwich). 2006;8:571-581. 22. Newman C, Tsai J, Szarek M, Luo D, Gibson E. Comparative safety of atorvastatin 80 mg versus 10 mg derived from analysis of 49 completed trials in 14,236 patients. Am J Cardiol. 2006;97:61-67. 23. Andrews T, Ballantyne C, Hsia J, Kramer J. Achieving and maintaining National Cholesterol Education Program low-density lipoprotein cholesterol goals with five statins. Am J Med. 2001;111:185-191.

24. Dahlf B, Sever PS, Poulter NR, et al. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes TrialBlood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet. 2005;366:895-906. 25. Caduet (amlodipine besylate atorvastatin calcium) [package insert]. New York: Pfizer, Inc; 2006. 26. Sleight P, Pouleur H, Zannad F. Benefits, challenges, and registerability of the polypill. Eur Heart J. 2006;27:1651-1656. 27. The sixth report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. Arch Intern Med. 1997;157:2413-2446. 28. Wilson PW, DAgostino RB, Levy D, Belanger AM, Silbershatz H, Kannel WB. Prediction of coronary heart disease using risk factor categories. Circulation. 1998;97:1837-1847. 29. Pasternak RC, Smith SC Jr, Bairey-Merz CN, Grundy SM, Cleeman JI, Lenfant C. ACC/AHA/NHLBI clinical advisory on the use and safety of statins. J Am Coll Cardiol. 2002;40:567-572. 30. Marcus R, Peritz E, Gabriel KR. On closed testing procedures with special reference to ordered analysis of variance. Biometrika. 1976;63:655-660. 31. Pledger G. The role of a placebo-treated control group in combination drug trials. Control Clin Trials. 1989;10:97-107. 32. Chung M, Calcagni A, Glue P, Bramson C. Bioavailability of amlodipine besylate/atorvastatin calcium combination tablet. J Clin Pharmacol. 2006;46:1030-1037. 33. Norvasc (amlodipine besylate) [package insert]. New York: Pfizer, Inc; 2005. 34. Lipitor (atorvastatin calcium) [package insert]. New York: Pfizer, Inc; 2007. 35. Blank R. A single-pill combination of amlodipine besylate and atorvastatin calcium. Drugs Today (Barc). 2006;42:157-175. 36. Blank R, Lasalle J, Reeves R, Maroni J, Tarasenko L, Sun F. Single-pill therapy in the treatment of concomitant hypertension and dyslipidemia (the Amlodipine/Atorvastatin Gemini Study). J Clin Hypertens (Greenwich). 2005;7:264-273. 37. Flack J, Victor R, Watson K, et al. Amlodipine/atorvastatin single-pill dual therapy improves goal attainment in the treatment of concomitant hypertension and dyslipidemia in AfricanAmericans: the CAPABLE trial. Mayo Clin Proc ; in press. 38. Feldman R, Hobbs F, Gensini G, et al. Multiple risk intervention with a single-pill combination (amlodipine/atorvastatin) helps patients to attain recommended target levels for blood pressure and lipids (the JEWEL Program). J Clin Hypertens. 2006;8:457. 39. Tse H, Ro Y, Howes L, et al. Multiple-risk intervention with single-pill amlodipine/atorvastatin therapy helps patients with diverse ethnicity attain recommended therapeutic goals for blood pressure and lipids (The GEMINI-AALA Study). J Hypertens. 2006;24(Suppl 6):S329. 40. Sullivan LM, Massaro JM, DAgostino RB. Presentation of multivariate data for clinical use: the Framingham Study risk score functions. Stat Med. 2004;23:1631-1660. 41. Hellenius ML, de Faire U, Berglund B, Hamsten A, Krakau I. Diet and exercise are equally effective in reducing risk for cardiovascular disease: results of a randomized controlled study in men with slightly to moderately raised cardiovascular risk factors. Atherosclerosis. 1993;103:81-91.

1568 J Clin Pharmacol 2007;47:1555-1569

AMLODIPINE AND ATORVASTATIN FOR HYPERTENSION AND DYSLIPIDEMIA

42. Lindholm LH, Ekbom T, Dash C, Isacsson A, Schersten B. Changes in cardiovascular risk factors by combined pharmacological and nonpharmacological strategies: the main results of the CELL Study. J Intern Med. 1996;240:13-22. 43. Ryan MJ Jr, Gibson J, Simmons P, Stanek E. Effectiveness of aggressive management of dyslipidemia in a collaborative-care practice model. Am J Cardiol. 2003;91:1427-1431. 44. Empana JP, Ducimetiere P, Arveiler D, et al. Are the Framingham and PROCAM coronary heart disease risk functions applicable to different European populations? The PRIME Study. Eur Heart J. 2003;24:1903-1911. 45. Brindle P, Emberson J, Lampe F, et al. Predictive accuracy of the Framingham coronary risk score in British men: prospective cohort study. BMJ. 2003;327:1267. 46. Thomsen TF, Davidsen M, Ibsen H, Jorgensen T, Jensen G, BorchJohnsen K. A new method for CHD prediction and prevention based on regional risk scores and randomized clinical trials; PRECARD and the Copenhagen Risk Score. J Cardiovasc Risk. 2001;8:291-297. 47. Johnson ML, Pietz K, Battleman DS, Beyth RJ. Therapeutic goal attainment in patients with hypertension and dyslipidemia. Med Care. 2006;44:39-46. 48. Cheung BM, Ong KL, Man YB, Lam KS, Lau CP. Prevalence, awareness, treatment, and control of hypertension: United States

National Health and Nutrition Examination Survey 2001-2002. J Clin Hypertens (Greenwich). 2006;8:93-98. 49. Gaede P, Vedel P, Larsen N, Jensen GVH, Parving H-H, Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med. 2003;348:383-393. 50. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360:7-22. 51. Sever P, Dahlf B, Poulter N, et al. Potential synergy between lipid-lowering and blood-pressure-lowering in the Anglo-Scandinavian Cardiac Outcomes Trial. Eur Heart J. 2006;27: 2982-2988. 52. LaRosa JC, Grundy SM, Waters DD, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005;352:1425-1435. 53. Chapman RH, Benner JS, Petrilla AA, et al. Predictors of adherence with antihypertensive and lipid-lowering therapy. Arch Intern Med. 2005;165:1147-1152. 54. Nichol M, Patel B, Thiebaud P, et al. A single pill combining antihypertensive and statin therapies improves patient adherence compared to multi-drug combinations: results from the Caduet Adherence Research Program and Education (CARPE)PBM Adherence Study. J Clin Hypertens. 2006;8:456.

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