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CLINICAL TRIALS |
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).
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{at}med.miami.edu.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Key Words: Amlodipine • atorvastatin • Framingham coronary heart disease estimated risk • drug interaction
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-methylglutaryl-coenzyme 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 other's efficacy or tolerability.26
The Respond trial was conducted to evaluate the feasibility, effectiveness, and safety of the coad-ministration 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.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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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 run-in/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
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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 center's 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 once-daily 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 computer-generated 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.
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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 >10x upper limit of normal (ULN) were recorded; for SGPT/ALT, SGOT/AST, GGT, alkaline phosphatase, and total bilirubin levels, >3x 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 >10x ULN or SGOT/SGPT >3x 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 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 x 5 factorial analysis of covariance (ANCOVA), in 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 step-down 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.
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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.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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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 equivalent (groups I + II) and in those with CHD (group III) (Figure 2A).
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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 coad-ministered (Table IIID). However, when pooled across the 4 active atorvastatin doses, coadministration of amlodipine 5 mg significantly reduced LDL-C 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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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 placebo-treated patients were peripheral edema, abdominal pain, and hyperglycemia (enzyme elevations that were reported as AEs are described in further detail below). Combination-treated patients did not experience any increase in either all-causality or treatment-related AEs compared with amlodipine or atorvastatin monotherapy.
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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 in the amlodipine-only group had CPK levels >10x 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 >3x 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 >3x 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 >3x ULN, but none of these persisted at this level during the trial. There was no incidence of elevated total bilirubin >3x 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%).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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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 to lower blood pressure. Similarly, coadministration with amlodipine did not affect the overall lipid-lowering 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 open-label 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 10-year 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 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 pressure-lowering and lipid-lowering 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.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Supplementary data are available at http://jcp.sagepub.com/supplemental/.
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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