Effect of Intensive Lipid Lowering, With or Without Antioxidant Vitamins, Compared With Moderate Lipid Lowering on Myocardial Ischemia in Pa
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循环学杂志 2005年第4期
Brigham & Women’s Hospital (P.H.S., S.K., W.C., H.C., J.O., A.P.S., M.A.C.)
Massachusetts General Hospital, Boston, Mass (D.M.L.-J.)
Beth Israel Deaconess Medical Center, Boston, Mass (M.J.)
Newton Wellesley Hospital (J.R.), Newton, Mass
University of Texas Southwestern Medical Center, Dallas (T.C.A.)
Oregon State University, Corvallis (B.F.)
National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Md (G.S.).
Abstract
Background— Lipid lowering with statins prevents adverse cardiac events. Both lipid-lowering and antioxidant therapies may favorably affect vasomotor function and thereby improve ischemia.
Methods and Results— In a randomized, double-blind, placebo-controlled trial, 300 patients with stable coronary disease, a positive exercise treadmill test, 48-hour ambulatory ECG with 1 episode of ischemia, and fasting total cholesterol of 180 to 250 mg/dL were assigned to 1-year treatment with intensive atorvastatin to reduce LDL to <80 mg/dL (n=96), intensive atorvastatin to reduce LDL to <80 mg/dL plus antioxidant vitamins C (1000 mg/d) and E (800 mg/d) (n=101), or diet and low-dose lovastatin, if needed, to reduce LDL to <130 mg/dL (n=103; control group). Ischemia end points, including ambulatory ECG monitoring and exercise treadmill testing, and endothelial assessment using brachial artery flow-mediated dilation were obtained at baseline and at 6 and 12 months. Baseline characteristics were similar in all groups. LDL decreased from 153 mg/dL at baseline in the 2 atorvastatin groups to 83 mg/dL at 12 months (each P<0.0001) and from 147 to 120 mg/dL in the control group (P<0.0001). During ambulatory ECG monitoring, mean number of ischemic episodes per 48 hours decreased 31% to 61% in each group (each P<0.001; P=0.15 across groups), without a change in daily heart rate activity. Mean duration of ischemia for 48 hours decreased 26% to 62% in each group (each P<0.001; P=0.06 across groups). Mean exercise duration to 1-mm ST-segment depression significantly increased in each group, but total exercise duration and mean sum of maximum ST depression were unchanged. Angina frequency decreased in each group. There was no incremental effect of supplemental vitamins C and E on any ischemia outcome. Flow-mediated dilation studies indicated no meaningful changes.
Conclusions— Intensive lipid lowering with atorvastatin to an LDL level of 80 mg/dL, with or without antioxidant vitamins, does not provide any further benefits in ambulatory ischemia, exercise time to onset of ischemia, and angina frequency than moderate lipid lowering with diet and low-dose lovastatin to an LDL level of <120 mg/dL.
Key Words: antioxidants ; cholesterol ; coronary disease ; exercise ; vasoconstriction
Introduction
Low-density lipoprotein cholesterol, particularly oxidized LDL, affects atherosclerosis, endothelial function, and clinical cardiovascular outcomes. Statins are efficacious in improving atherosclerosis and endothelial function and in the primary and secondary prevention of adverse cardiovascular events1,2; however, it is unclear whether lipid-lowering or antioxidant therapy can reduce myocardial ischemia in patients with coronary artery disease (CAD). Ambulatory ECG (AECG) monitoring can detect myocardial ischemia in patients with CAD during routine daily activities that identifies patients at particularly high risk of cardiac events within 1 to 2 years of follow-up.3,4 Small or noncontrolled studies have suggested that LDL lowering reduces ambulatory ischemia compared with placebo,5,6 but it is uncertain whether more intensive lipid lowering, with or without antioxidant vitamins, offers greater prevention of ischemia.
Therefore, the purpose of the present study was to determine whether, compared with moderate LDL lowering with diet and low-dose lovastatin, intensive LDL lowering with atorvastatin, with or without supplemental antioxidant vitamins C and E, can reduce myocardial ischemia in patients with stable coronary disease as assessed by AECG monitoring during routine daily activities or by exercise treadmill testing. Ethical constraints now preclude the use of a control group with elevated LDL to study the effect of lipid lowering7; accordingly, the trial design addressed the effect of intensive compared with moderate lipid lowering.
Methods
The hypotheses, methods, and power/sample size calculations have previously been published.8 In brief, the inclusion criteria included age <85 years, fasting total cholesterol of 180 to 250 mg/dL, objective evidence of coronary disease, exercise-induced ST-segment depression 1.0 mm, and 1 episode of reversible ST depression of 1.0 mm during 48-hour AECG monitoring of routine activities. Exclusion criteria included an acute coronary syndrome within 1 month of study entry, coronary revascularization procedure within 6 months of study entry, congestive heart failure greater than NYHA class III, significant valvular heart disease, cigarette smoking within 2 months of study entry, and a resting 12-lead ECG that was not interpretable to detect the presence of ischemia. Patients were screened from outpatient cardiology practices in the participating hospitals.
Eligible patients were taken off all long-acting antianginal medications for 48 hours before baseline studies, which included an exercise treadmill test, flow-mediated dilation (FMD) assessment of the brachial artery, and 48-hour AECG monitoring during a weekday so that the usual physical and emotional stresses of the workplace could be monitored. Patients were encouraged to engage in their usual outpatient activities during AECG monitoring and to replicate that amount of activity in follow-up studies.
All patients were put on an NCEP step 2 diet and randomized to 1 of 3 groups for 1 year of treatment: intensive atorvastatin titrated to achieve an LDL of <80 mg/dL or a maximum dose of 80 mg/d, intensive atorvastatin as noted but with the addition of antioxidant vitamins C (1000 mg/d) and E (dl-alpha tocopheryl acetate, 800 mg/d), or a control group of diet plus low-dose lovastatin, if necessary, to achieve an LDL of <130 mg/dL. All medications were double blind and placebo controlled.
End Points
Once patients completed their baseline studies, they restarted their usual long-acting antianginal medication. Fasting lipids were reassessed every 4 weeks, and lipid-lowering medications were titrated as needed by a single unblinded research member to achieve the respective LDL goals in each group. Each titration of active lipid-lowering medication was matched by titration of placebo lipid-lowering medication in the placebo group. At 6 and 12 months after randomization, patients were again taken off their long-acting antianginal medications for 48 hours for follow-up studies of exercise testing, FMD, and AECG monitoring. Once the end-point assessments were completed, patients restarted their usual antianginal medications.
Exercise treadmill testing was performed with the Asymptomatic Cardiac Ischemia Pilot (ACIP) protocol9 and a Marquette CASE 3000 Treadmill system. Twelve-lead ECGs were recorded at the end of each minute of exercise and every 2 minutes of the recovery period until the ECG returned to baseline. The magnitude of ST-segment deviation from baseline was recorded in each lead during exercise. Ischemic ST-segment depression was defined as horizontal or downsloping ST-segment depression 1.0 mm compared with the baseline ST-segment value. Blinded rereadings were performed for quality control with excellent correlation (r=0.86 to 0.98 for exercise time to 1.0-mm ST depression from baseline to 6 or 12 months and average sum of ST depression across all leads).
FMD of the brachial artery, a measure of endothelium-dependent vasodilation, was assessed as previously described8 using diameter measurements based on the near and far walls of the intima at rest and in response to increased flow. Flow was induced by reactive hyperemia after inflation of a sphygmomanometer cuff on the forearm to suprasystolic pressure for 5 minutes. Images were acquired 1 minute after release of the cuff. Endothelium-independent vasodilation of the brachial artery was assessed 3 minutes after sublingual administration of nitroglycerin 0.4 mg. Blinded readings were compared for quality control with excellent correlation (r=0.80 to 0.85 for brachial artery diameter at rest and hyperemia and before and after nitroglycerin).
AECG monitoring for 48 hours, using 3 leads with the most marked ST-segment deviation during the qualifying exercise test, was performed with AM cassette recorders (Applied Cardiac Systems).8 Typically, a modified V5, aVF, and lead II were used. Recordings were made in the standing, supine, and left and right lateral decubitus positions to identify the presence of artifactual ST-segment deviation. Cassette recordings were analyzed on a Zymed playback system. An episode of ischemia was defined as 1-mm horizontal or downsloping ST-segment depression compared with the resting baseline lasting 1 minute separated by 5 minutes from other episodes. Blinded rereadings were performed for quality control with excellent correlation (r=0.95 to 0.98 for mean duration of ischemia and mean number of ischemic episodes).
Plasma samples for vitamins C, E, and F2-isoprostanes were collected, immediately frozen at –80°C, and shipped on dry ice to the core laboratory. For vitamin C, plasma was precipitated with metaphosphoric acid containing the metal chelator DTPA and analyzed by ion-paired, reversed-phase high-performance liquid chromatography with electrochemical detection. Then, - and -tocopherols were analyzed by reverse-phase high-performance liquid chromatography with electrochemical detection with tocol as the internal standard. Both assays have a coefficient of variation of <5%. F2-isoprostanes were quantified by an enzyme immunoassay (Cayman Chemical) with a coefficient of variation of <25%.
Anginal symptoms and nitroglycerin use for the 2-week period before each visit on the patient’s routine antianginal regimen was assessed from the patient’s diary and direct patient interview.
All clinical events were adjudicated (P.H.S.) by review of hospital records. The primary end points were (1) change in number and duration of ischemic episodes from the qualifying AECG to the 12-month AECG, (2) change in exercise time to 1.0-mm ST-segment depression from the qualifying exercise test to the 12-month exercise test, and (3) change in flow-mediated vasodilation of the brachial artery from baseline conditions to reactive hyperemia from the qualifying study to the 12-month study. Data are presented as mean±SD.
Statistical Analysis
Our sample size calculations8 estimated that 100 patients in a group would be sufficient to detect with 80% power a significant difference in AECG ischemia at the 5% level if up to 30% of control patients experienced resolution of ischemia during AECG monitoring and 50% of atorvastatin patients experienced resolution of ischemia.
Patient demographic and baseline clinical characteristics were compared between the 3 study arms through the use of the Fisher exact test for categorical measures and the Kruskal-Wallis 3-group nonparametric test for continuous measures.
Because most of our outcome measures were continuous but not normally distributed, we used the Kruskal-Wallis test to examine differences in outcome between the 3 groups at 6 and 12 months. If the Kruskal-Wallis test was significant, we performed pairwise comparisons between individual study arms using the Bonferroni correction. We looked for changes in outcomes within each treatment group using the baseline to 6-month change and the baseline to 12-month change as outcome variables in Wilcoxon sign-rank tests.
For one outcome, time to 1-mm ST depression on the exercise test, we used the log-rank test to compare outcomes between the study arms, treating patients who never reached 1-mm depression as censored at the end of their exercise tests. Changes between follow-up and baseline were analyzed within each treatment arm through Cox regression with repeated measures. For the incidence of clinical events, study arms were compared by use of the Fisher exact test. Two-sided values of P<0.05 were considered significant.
Results
Of the 597 patients screened, 300 were enrolled. Baseline characteristics were similar among the patients assigned to intensive atorvastatin alone (n=96), those assigned to intensive atorvastatin plus vitamins C and E (n=101), and those assigned to the control group (n=103) (Table 1). The median dose of atorvastatin in the 2 atorvastatin groups was 80 mg/d (P=0.93). In the control group, lovastatin was required in 91% of patients to lower LDL to <130 mg/dL; the median dose was 5 mg/d. Compliance by pill count was >95% at each follow-up visit. Of the 300 patients, baseline data were available for lipids in 100%, exercise tests in 100%, AECG in 97%, vitamins in 98%, and brachial artery in 77%; 254 patients (85%) completed the 12-month study. Participation was terminated early because of an adverse cardiac event in 17 patients (6%) (CABG in 8, myocardial infarction in 5, cardiovascular accident in 2, death in 1, and atrial fibrillation in 1), a drug-related adverse event in 7 patients (2%), and loss of interest or unwillingness to remain on blinded medication in 22 patients (7%).
Fasting Lipid and Vitamin C and E Values
By 6 months, LDL decreased in the 2 atorvastatin groups to 85.1±20 and 84.6±19 mg/dL, respectively. Seventy-nine patients (48%) did not achieve the LDL target value on atorvastatin either because their LDL value was at or below the target at the most recent visit and therefore the dose was not escalated (13% of patients) or because their LDL value remained high despite maximum dose of atorvastatin (35% of patients). The LDL in the control group decreased to 123.0±18 mg/dL. HDL cholesterol increased significantly only in the atorvastatin group at 6 and 12 months (Figure 1).
Only patients who received supplementation with vitamins C and E had significantly higher plasma levels of ascorbate and -tocopherol at 6 and 12 months of treatment (Figure 2). -Tocopherol levels decreased in the atorvastatin only group, reflecting a decrease in lipid levels. Plasma F2-isoprostanes, a reliable marker of lipid peroxidation, remained unchanged in all 3 treatment groups.
AECG Outcomes
The mean duration of AECG recording was 44 hours at each follow-up examination, and there were no differences among the 3 patient groups; 90% of all ischemic episodes were asymptomatic (Table 2). Patients in each of the 3 groups experienced a significant reduction in the frequency and duration of ischemia from baseline to 6 and 12 months. There was no correlation between the magnitude of LDL lowering and the reduction in ambulatory ischemia.
The reduction in the frequency and duration of ambulatory ischemia in each of the 3 groups occurred without a meaningful change in heart rate activity throughout the day. The mean heart rate was similar across the 3 groups at baseline (77±9, 78±11, and 78±11 bpm, respectively; P=0.42), at 6 months (76±9, 77±11, and 78±13 bpm, respectively; P=0.52), and at 12 months (76±9, 77±10, and 77±13 bpm, respectively; P=0.78). There were no significant differences in the change in mean heart rate from baseline to 6 months (P=0.23, 0.20, and 0.32, respectively) or from baseline to 12 months (P=0.35, 0.08, and 0.06, respectively). Similarly, there were no meaningful changes in the minimum or maximum heart rate across the 3 groups at any time point (data not shown).
Exercise Test Outcomes
There was a significant increase in the mean exercise duration to the onset of ischemia from baseline to 6 and 12 months in each group (Table 3). There was no association between the magnitude of LDL lowering and the increase in time to ischemic ST-segment depression (P=0.84 at 6 months; P=0.44 at 12-months). There was no improvement in the total exercise duration at 6 or 12 months or the sum of maximum ST-segment depression from baseline to 6 or 12 months.
Angina developed during the exercise test in 30% to 40% of patients and was the primary reason for discontinuing exercise in 10% to 20% of patients at each examination. There was no difference in the development of angina at the different examinations or across the 3 groups.
Endothelium-Dependent Vasodilation
There were no significant differences in brachial artery flow-mediated endothelium-dependent vasodilation at baseline or at 6 and 12 months (Table 4).
There were no meaningful differences in endothelium-independent vasodilation at baseline or at 6 and 12 months.
Angina Frequency and Nitroglycerin Consumption
Each lipid-lowering strategy was associated with a similar, significant reduction in angina frequency at 6 and 12 months (Table 5). There were similar reductions in nitroglycerin consumption, but these differences did not achieve statistical significance.
Clinical Events
The number of major clinical events during the study was small in each group. There were no significant differences across groups (Table 6).
Discussion
This is the first large, controlled study to investigate the effects of intensive compared with moderate lipid lowering on myocardial ischemia in stable coronary patients occurring during routine daily activities or during supervised exercise. We observed that ischemia end points of frequency and duration of ambulatory ischemia, time to the onset of myocardial ischemia during an exercise test, and angina frequency declined significantly during the 3 treatment strategies. Our control group required statin use in 91% of patients to achieve LDL levels consistent with current standards of care.7 The hypothesis that there would be differences in ischemia outcomes based on the magnitude of LDL lowering was null.
Lipid Lowering and Myocardial Ischemia
Episodes of myocardial ischemia occurring during routine daily activities are likely due to both the presence of fixed atherosclerotic obstructions and dynamic vasoconstriction resulting from abnormal vasomotor function. Elevated values of LDL cholesterol and oxidized LDL cause endothelial dysfunction and promote coronary vasoconstriction.10–14 LDL lowering and supraphysiological concentrations of antioxidant vitamins can improve endothelial function, prevent coronary vasoconstriction,2,15–18 and improve function of the resistance vessels.19,20 The marked reduction in the frequency and duration of ambulatory ischemia in this study occurring in the absence of changes in heart rate activity throughout the day suggests that the observed benefit was not due to decreased physical activity by the subjects. It is more likely that the threshold for myocardial ischemia was increased in association with LDL lowering, enabling the patients to do more physical activity without developing myocardial ischemia. Indeed, LDL lowering also significantly reduced angina frequency.
In a small study of patients treated with bezofibrate, lowering cholesterol improved exercise-induced coronary vasoconstriction,17 and in 2 small studies using dipyridamole21 or exercise stress testing,22 LDL lowering with pravastatin from 148 to 103 mg/dL was associated with significant improvement in the size of thallium perfusion defects. These benefits of lipid lowering may represent the effects of preventing the coronary vasoconstriction associated with exercise.17,23 In contrast, the lack of effect of lipid lowering on the maximum exercise duration or maximum ST-segment depression at peak exercise is consistent with the facts that maximum exercise capacity during the exercise test is related primarily to ischemia from a fixed atherosclerotic obstruction24 and that our therapies had little effect on fixed coronary stenoses over the 12 months of this study.
The observation that there was no difference in improvement of ambulatory or treadmill ischemia when LDL was lowered from 150 to 85 mg/dL compared with 120 mg/dL may be due to a variety of explanations. There may be a threshold effect of LDL lowering below which there is no incremental improvement in endothelial dysfunction and episodic coronary vasoconstriction, and all of our on-treatment LDL values may have been beneath this threshold. Investigations have generally indicated that a variety of lipid-lowering strategies such as statins and fibric acid derivatives administered either alone15–17 or in combination2 reduce LDL and improve coronary vasoconstriction. The pretreatment LDL values in these studies generally ranged from 148 to 195 mg/dL, and the on-treatment LDL values ranged from 77 to 120 mg/dL. In the 2 previous studies demonstrating the benefit of lipid lowering to improve ambulatory ischemia, LDL values were reduced from 165 mg/dL to values ranging from 115 to 125 mg/dL.5,6 The CARATS study did not demonstrate an improvement in coronary endothelial dysfunction from marked LDL lowering from 130 to 77 mg/dL by simvastatin,25 perhaps because the baseline LDL value was only mildly elevated.26 Our study is the first to specifically evaluate 2 levels of LDL goal (85 mg/dL in the atorvastatin groups, 120 mg/dL in the control group), and we found no difference in outcomes between the 2 groups.
Antioxidant Vitamins and Myocardial Ischemia
In this study, antioxidant vitamins C and E, in addition to atorvastatin, had no effect on any ischemia outcome compared with treatment with atorvastatin alone. Although antioxidant supplements have been suggested as a therapeutic approach for CAD patients, results from large, long-term clinical outcome trials and coronary endothelial function studies have not supported their clinical efficacy.27–29 Some have suggested that the inconsistent and generally negative results from antioxidant therapy are related to differences in vitamin formulation, dose, or timing of administration.27,30,31 The doses of vitamin C and E used in this study and the plasma levels of these vitamins, however, indicate that a therapeutic benefit should have been observed if the supplements were effective.31,32 The lack of an observed benefit does not support the use of antioxidant vitamins C and E for reducing myocardial ischemia.
Lipid Lowering and FMD of the Brachial Artery
Our observation that lipid lowering did not affect endothelial-dependent brachial artery FMD may suggest that such therapy does not improve endothelial dysfunction and that our observed reduction in ischemia was not related to amelioration of vasoconstriction. A recent study of FMD in elderly, hypercholesterolemic patients (mean age, 76 years) found that neither statins nor antioxidant vitamins, alone or in combination, improved FMD over a 6-month period.33 Furthermore, Kinlay and colleagues29 have shown that 6-month treatment with vitamins C and E did not improve FMD in patients with CAD. Although FMD is correlated to coronary endothelial function across a wide spectrum of clinical syndromes, it may not be sensitive enough to identify the changes in coronary endothelial function important for the myocardial ischemia threshold.
Cardiovascular Outcomes
The clinical event rate was remarkably low despite the high risk usually associated with the presence of ischemia during ambulatory monitoring and exercise treadmill testing.3,4,34 The decrease in ischemia end points in all 3 groups associated with the observed low clinical event rate at 1 year suggests that all 3 groups benefited from statins and LDL lowering.
Study Limitations
Some of the observed effects of the 3 lipid-lowering strategies may have been due to regression-to-the-mean phenomena or to a "therapeutic" effect associated with careful patient management in a well-supervised clinical trial. Regression-to-the-mean phenomena cannot be excluded as contributing to the observed reductions in ischemia. Studies of stable CAD patients using serial AECG monitoring to quantify the variability of episodes of ambulatory ischemia during routine daily activities, however, have not demonstrated regression-to-the-mean phenomena.35,36 The only way to evaluate the contribution of regression to the mean would be to use a sample of general patients not chosen on the basis of myocardial ischemia. Practical constraints precluded this approach.
Other reasons why the study was null may be that the magnitude of the difference in ischemia end points between the groups was so small that our power could not detect them or that our follow-up was too short.
Our ischemia end-point assessments were obtained while routine antianginal medications were withdrawn so that the effects of lipid-lowering strategies on endothelial function and ischemia could be most directly investigated. We do not know whether the antiischemia effects we observed would be maintained while patients are on antianginal medications.
Conclusions
This study randomized patients with coronary disease and active ischemia to LDL lowering with statins, with or without antioxidants, and to a control group. All 3 groups exhibited a very low cardiovascular event rate, along with reductions in AECG ischemia, exercise-induced ischemia, and angina. Higher doses of statins, greater LDL lowering, and antioxidant vitamins did not result in greater reduction in ischemia.
Our lack of a dose-response relationship between LDL lowering and ischemic end points in stable coronary patients contrasts with the recently reported relationship between LDL lowering and reduction in hard clinical end points in acute coronary syndrome patients.37 Differences in disease manifestations investigated and sample size may be responsible for the different relationships observed. PROVE IT-TIMI 2237 investigated acute coronary syndrome patients and was powered to evaluate clinical end points; our study investigated stable coronary patients and was powered to evaluate ischemia end points. Clinical end points in acute coronary syndrome patients are governed by highly unstable coronary plaques, whereas ischemia end points in stable coronary patients are governed by an advanced chronic obstruction and factors affecting myocardial O2 supply-demand balance. Different pathophysiological aspects of coronary disease may respond differently to LDL lowering.
Acknowledgments
This work was supported by NIH grant RO1-HL38780 and by an unrestricted grant from Pfizer, Inc. We are grateful to Marie Gerhard-Herman, MD, Shauna Hurley, and Wesley Knauft for analyses of brachial artery studies; to Gail MacCallum and Michelle Lucier for analyses of AECG studies; and to Deborah Hobbs for excellent technical assistance in the analysis of vitamins C and E and F2-isoprostanes.
Footnotes
Guest Editor for this article was Gregory L. Burke, MD, MSc.
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Massachusetts General Hospital, Boston, Mass (D.M.L.-J.)
Beth Israel Deaconess Medical Center, Boston, Mass (M.J.)
Newton Wellesley Hospital (J.R.), Newton, Mass
University of Texas Southwestern Medical Center, Dallas (T.C.A.)
Oregon State University, Corvallis (B.F.)
National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Md (G.S.).
Abstract
Background— Lipid lowering with statins prevents adverse cardiac events. Both lipid-lowering and antioxidant therapies may favorably affect vasomotor function and thereby improve ischemia.
Methods and Results— In a randomized, double-blind, placebo-controlled trial, 300 patients with stable coronary disease, a positive exercise treadmill test, 48-hour ambulatory ECG with 1 episode of ischemia, and fasting total cholesterol of 180 to 250 mg/dL were assigned to 1-year treatment with intensive atorvastatin to reduce LDL to <80 mg/dL (n=96), intensive atorvastatin to reduce LDL to <80 mg/dL plus antioxidant vitamins C (1000 mg/d) and E (800 mg/d) (n=101), or diet and low-dose lovastatin, if needed, to reduce LDL to <130 mg/dL (n=103; control group). Ischemia end points, including ambulatory ECG monitoring and exercise treadmill testing, and endothelial assessment using brachial artery flow-mediated dilation were obtained at baseline and at 6 and 12 months. Baseline characteristics were similar in all groups. LDL decreased from 153 mg/dL at baseline in the 2 atorvastatin groups to 83 mg/dL at 12 months (each P<0.0001) and from 147 to 120 mg/dL in the control group (P<0.0001). During ambulatory ECG monitoring, mean number of ischemic episodes per 48 hours decreased 31% to 61% in each group (each P<0.001; P=0.15 across groups), without a change in daily heart rate activity. Mean duration of ischemia for 48 hours decreased 26% to 62% in each group (each P<0.001; P=0.06 across groups). Mean exercise duration to 1-mm ST-segment depression significantly increased in each group, but total exercise duration and mean sum of maximum ST depression were unchanged. Angina frequency decreased in each group. There was no incremental effect of supplemental vitamins C and E on any ischemia outcome. Flow-mediated dilation studies indicated no meaningful changes.
Conclusions— Intensive lipid lowering with atorvastatin to an LDL level of 80 mg/dL, with or without antioxidant vitamins, does not provide any further benefits in ambulatory ischemia, exercise time to onset of ischemia, and angina frequency than moderate lipid lowering with diet and low-dose lovastatin to an LDL level of <120 mg/dL.
Key Words: antioxidants ; cholesterol ; coronary disease ; exercise ; vasoconstriction
Introduction
Low-density lipoprotein cholesterol, particularly oxidized LDL, affects atherosclerosis, endothelial function, and clinical cardiovascular outcomes. Statins are efficacious in improving atherosclerosis and endothelial function and in the primary and secondary prevention of adverse cardiovascular events1,2; however, it is unclear whether lipid-lowering or antioxidant therapy can reduce myocardial ischemia in patients with coronary artery disease (CAD). Ambulatory ECG (AECG) monitoring can detect myocardial ischemia in patients with CAD during routine daily activities that identifies patients at particularly high risk of cardiac events within 1 to 2 years of follow-up.3,4 Small or noncontrolled studies have suggested that LDL lowering reduces ambulatory ischemia compared with placebo,5,6 but it is uncertain whether more intensive lipid lowering, with or without antioxidant vitamins, offers greater prevention of ischemia.
Therefore, the purpose of the present study was to determine whether, compared with moderate LDL lowering with diet and low-dose lovastatin, intensive LDL lowering with atorvastatin, with or without supplemental antioxidant vitamins C and E, can reduce myocardial ischemia in patients with stable coronary disease as assessed by AECG monitoring during routine daily activities or by exercise treadmill testing. Ethical constraints now preclude the use of a control group with elevated LDL to study the effect of lipid lowering7; accordingly, the trial design addressed the effect of intensive compared with moderate lipid lowering.
Methods
The hypotheses, methods, and power/sample size calculations have previously been published.8 In brief, the inclusion criteria included age <85 years, fasting total cholesterol of 180 to 250 mg/dL, objective evidence of coronary disease, exercise-induced ST-segment depression 1.0 mm, and 1 episode of reversible ST depression of 1.0 mm during 48-hour AECG monitoring of routine activities. Exclusion criteria included an acute coronary syndrome within 1 month of study entry, coronary revascularization procedure within 6 months of study entry, congestive heart failure greater than NYHA class III, significant valvular heart disease, cigarette smoking within 2 months of study entry, and a resting 12-lead ECG that was not interpretable to detect the presence of ischemia. Patients were screened from outpatient cardiology practices in the participating hospitals.
Eligible patients were taken off all long-acting antianginal medications for 48 hours before baseline studies, which included an exercise treadmill test, flow-mediated dilation (FMD) assessment of the brachial artery, and 48-hour AECG monitoring during a weekday so that the usual physical and emotional stresses of the workplace could be monitored. Patients were encouraged to engage in their usual outpatient activities during AECG monitoring and to replicate that amount of activity in follow-up studies.
All patients were put on an NCEP step 2 diet and randomized to 1 of 3 groups for 1 year of treatment: intensive atorvastatin titrated to achieve an LDL of <80 mg/dL or a maximum dose of 80 mg/d, intensive atorvastatin as noted but with the addition of antioxidant vitamins C (1000 mg/d) and E (dl-alpha tocopheryl acetate, 800 mg/d), or a control group of diet plus low-dose lovastatin, if necessary, to achieve an LDL of <130 mg/dL. All medications were double blind and placebo controlled.
End Points
Once patients completed their baseline studies, they restarted their usual long-acting antianginal medication. Fasting lipids were reassessed every 4 weeks, and lipid-lowering medications were titrated as needed by a single unblinded research member to achieve the respective LDL goals in each group. Each titration of active lipid-lowering medication was matched by titration of placebo lipid-lowering medication in the placebo group. At 6 and 12 months after randomization, patients were again taken off their long-acting antianginal medications for 48 hours for follow-up studies of exercise testing, FMD, and AECG monitoring. Once the end-point assessments were completed, patients restarted their usual antianginal medications.
Exercise treadmill testing was performed with the Asymptomatic Cardiac Ischemia Pilot (ACIP) protocol9 and a Marquette CASE 3000 Treadmill system. Twelve-lead ECGs were recorded at the end of each minute of exercise and every 2 minutes of the recovery period until the ECG returned to baseline. The magnitude of ST-segment deviation from baseline was recorded in each lead during exercise. Ischemic ST-segment depression was defined as horizontal or downsloping ST-segment depression 1.0 mm compared with the baseline ST-segment value. Blinded rereadings were performed for quality control with excellent correlation (r=0.86 to 0.98 for exercise time to 1.0-mm ST depression from baseline to 6 or 12 months and average sum of ST depression across all leads).
FMD of the brachial artery, a measure of endothelium-dependent vasodilation, was assessed as previously described8 using diameter measurements based on the near and far walls of the intima at rest and in response to increased flow. Flow was induced by reactive hyperemia after inflation of a sphygmomanometer cuff on the forearm to suprasystolic pressure for 5 minutes. Images were acquired 1 minute after release of the cuff. Endothelium-independent vasodilation of the brachial artery was assessed 3 minutes after sublingual administration of nitroglycerin 0.4 mg. Blinded readings were compared for quality control with excellent correlation (r=0.80 to 0.85 for brachial artery diameter at rest and hyperemia and before and after nitroglycerin).
AECG monitoring for 48 hours, using 3 leads with the most marked ST-segment deviation during the qualifying exercise test, was performed with AM cassette recorders (Applied Cardiac Systems).8 Typically, a modified V5, aVF, and lead II were used. Recordings were made in the standing, supine, and left and right lateral decubitus positions to identify the presence of artifactual ST-segment deviation. Cassette recordings were analyzed on a Zymed playback system. An episode of ischemia was defined as 1-mm horizontal or downsloping ST-segment depression compared with the resting baseline lasting 1 minute separated by 5 minutes from other episodes. Blinded rereadings were performed for quality control with excellent correlation (r=0.95 to 0.98 for mean duration of ischemia and mean number of ischemic episodes).
Plasma samples for vitamins C, E, and F2-isoprostanes were collected, immediately frozen at –80°C, and shipped on dry ice to the core laboratory. For vitamin C, plasma was precipitated with metaphosphoric acid containing the metal chelator DTPA and analyzed by ion-paired, reversed-phase high-performance liquid chromatography with electrochemical detection. Then, - and -tocopherols were analyzed by reverse-phase high-performance liquid chromatography with electrochemical detection with tocol as the internal standard. Both assays have a coefficient of variation of <5%. F2-isoprostanes were quantified by an enzyme immunoassay (Cayman Chemical) with a coefficient of variation of <25%.
Anginal symptoms and nitroglycerin use for the 2-week period before each visit on the patient’s routine antianginal regimen was assessed from the patient’s diary and direct patient interview.
All clinical events were adjudicated (P.H.S.) by review of hospital records. The primary end points were (1) change in number and duration of ischemic episodes from the qualifying AECG to the 12-month AECG, (2) change in exercise time to 1.0-mm ST-segment depression from the qualifying exercise test to the 12-month exercise test, and (3) change in flow-mediated vasodilation of the brachial artery from baseline conditions to reactive hyperemia from the qualifying study to the 12-month study. Data are presented as mean±SD.
Statistical Analysis
Our sample size calculations8 estimated that 100 patients in a group would be sufficient to detect with 80% power a significant difference in AECG ischemia at the 5% level if up to 30% of control patients experienced resolution of ischemia during AECG monitoring and 50% of atorvastatin patients experienced resolution of ischemia.
Patient demographic and baseline clinical characteristics were compared between the 3 study arms through the use of the Fisher exact test for categorical measures and the Kruskal-Wallis 3-group nonparametric test for continuous measures.
Because most of our outcome measures were continuous but not normally distributed, we used the Kruskal-Wallis test to examine differences in outcome between the 3 groups at 6 and 12 months. If the Kruskal-Wallis test was significant, we performed pairwise comparisons between individual study arms using the Bonferroni correction. We looked for changes in outcomes within each treatment group using the baseline to 6-month change and the baseline to 12-month change as outcome variables in Wilcoxon sign-rank tests.
For one outcome, time to 1-mm ST depression on the exercise test, we used the log-rank test to compare outcomes between the study arms, treating patients who never reached 1-mm depression as censored at the end of their exercise tests. Changes between follow-up and baseline were analyzed within each treatment arm through Cox regression with repeated measures. For the incidence of clinical events, study arms were compared by use of the Fisher exact test. Two-sided values of P<0.05 were considered significant.
Results
Of the 597 patients screened, 300 were enrolled. Baseline characteristics were similar among the patients assigned to intensive atorvastatin alone (n=96), those assigned to intensive atorvastatin plus vitamins C and E (n=101), and those assigned to the control group (n=103) (Table 1). The median dose of atorvastatin in the 2 atorvastatin groups was 80 mg/d (P=0.93). In the control group, lovastatin was required in 91% of patients to lower LDL to <130 mg/dL; the median dose was 5 mg/d. Compliance by pill count was >95% at each follow-up visit. Of the 300 patients, baseline data were available for lipids in 100%, exercise tests in 100%, AECG in 97%, vitamins in 98%, and brachial artery in 77%; 254 patients (85%) completed the 12-month study. Participation was terminated early because of an adverse cardiac event in 17 patients (6%) (CABG in 8, myocardial infarction in 5, cardiovascular accident in 2, death in 1, and atrial fibrillation in 1), a drug-related adverse event in 7 patients (2%), and loss of interest or unwillingness to remain on blinded medication in 22 patients (7%).
Fasting Lipid and Vitamin C and E Values
By 6 months, LDL decreased in the 2 atorvastatin groups to 85.1±20 and 84.6±19 mg/dL, respectively. Seventy-nine patients (48%) did not achieve the LDL target value on atorvastatin either because their LDL value was at or below the target at the most recent visit and therefore the dose was not escalated (13% of patients) or because their LDL value remained high despite maximum dose of atorvastatin (35% of patients). The LDL in the control group decreased to 123.0±18 mg/dL. HDL cholesterol increased significantly only in the atorvastatin group at 6 and 12 months (Figure 1).
Only patients who received supplementation with vitamins C and E had significantly higher plasma levels of ascorbate and -tocopherol at 6 and 12 months of treatment (Figure 2). -Tocopherol levels decreased in the atorvastatin only group, reflecting a decrease in lipid levels. Plasma F2-isoprostanes, a reliable marker of lipid peroxidation, remained unchanged in all 3 treatment groups.
AECG Outcomes
The mean duration of AECG recording was 44 hours at each follow-up examination, and there were no differences among the 3 patient groups; 90% of all ischemic episodes were asymptomatic (Table 2). Patients in each of the 3 groups experienced a significant reduction in the frequency and duration of ischemia from baseline to 6 and 12 months. There was no correlation between the magnitude of LDL lowering and the reduction in ambulatory ischemia.
The reduction in the frequency and duration of ambulatory ischemia in each of the 3 groups occurred without a meaningful change in heart rate activity throughout the day. The mean heart rate was similar across the 3 groups at baseline (77±9, 78±11, and 78±11 bpm, respectively; P=0.42), at 6 months (76±9, 77±11, and 78±13 bpm, respectively; P=0.52), and at 12 months (76±9, 77±10, and 77±13 bpm, respectively; P=0.78). There were no significant differences in the change in mean heart rate from baseline to 6 months (P=0.23, 0.20, and 0.32, respectively) or from baseline to 12 months (P=0.35, 0.08, and 0.06, respectively). Similarly, there were no meaningful changes in the minimum or maximum heart rate across the 3 groups at any time point (data not shown).
Exercise Test Outcomes
There was a significant increase in the mean exercise duration to the onset of ischemia from baseline to 6 and 12 months in each group (Table 3). There was no association between the magnitude of LDL lowering and the increase in time to ischemic ST-segment depression (P=0.84 at 6 months; P=0.44 at 12-months). There was no improvement in the total exercise duration at 6 or 12 months or the sum of maximum ST-segment depression from baseline to 6 or 12 months.
Angina developed during the exercise test in 30% to 40% of patients and was the primary reason for discontinuing exercise in 10% to 20% of patients at each examination. There was no difference in the development of angina at the different examinations or across the 3 groups.
Endothelium-Dependent Vasodilation
There were no significant differences in brachial artery flow-mediated endothelium-dependent vasodilation at baseline or at 6 and 12 months (Table 4).
There were no meaningful differences in endothelium-independent vasodilation at baseline or at 6 and 12 months.
Angina Frequency and Nitroglycerin Consumption
Each lipid-lowering strategy was associated with a similar, significant reduction in angina frequency at 6 and 12 months (Table 5). There were similar reductions in nitroglycerin consumption, but these differences did not achieve statistical significance.
Clinical Events
The number of major clinical events during the study was small in each group. There were no significant differences across groups (Table 6).
Discussion
This is the first large, controlled study to investigate the effects of intensive compared with moderate lipid lowering on myocardial ischemia in stable coronary patients occurring during routine daily activities or during supervised exercise. We observed that ischemia end points of frequency and duration of ambulatory ischemia, time to the onset of myocardial ischemia during an exercise test, and angina frequency declined significantly during the 3 treatment strategies. Our control group required statin use in 91% of patients to achieve LDL levels consistent with current standards of care.7 The hypothesis that there would be differences in ischemia outcomes based on the magnitude of LDL lowering was null.
Lipid Lowering and Myocardial Ischemia
Episodes of myocardial ischemia occurring during routine daily activities are likely due to both the presence of fixed atherosclerotic obstructions and dynamic vasoconstriction resulting from abnormal vasomotor function. Elevated values of LDL cholesterol and oxidized LDL cause endothelial dysfunction and promote coronary vasoconstriction.10–14 LDL lowering and supraphysiological concentrations of antioxidant vitamins can improve endothelial function, prevent coronary vasoconstriction,2,15–18 and improve function of the resistance vessels.19,20 The marked reduction in the frequency and duration of ambulatory ischemia in this study occurring in the absence of changes in heart rate activity throughout the day suggests that the observed benefit was not due to decreased physical activity by the subjects. It is more likely that the threshold for myocardial ischemia was increased in association with LDL lowering, enabling the patients to do more physical activity without developing myocardial ischemia. Indeed, LDL lowering also significantly reduced angina frequency.
In a small study of patients treated with bezofibrate, lowering cholesterol improved exercise-induced coronary vasoconstriction,17 and in 2 small studies using dipyridamole21 or exercise stress testing,22 LDL lowering with pravastatin from 148 to 103 mg/dL was associated with significant improvement in the size of thallium perfusion defects. These benefits of lipid lowering may represent the effects of preventing the coronary vasoconstriction associated with exercise.17,23 In contrast, the lack of effect of lipid lowering on the maximum exercise duration or maximum ST-segment depression at peak exercise is consistent with the facts that maximum exercise capacity during the exercise test is related primarily to ischemia from a fixed atherosclerotic obstruction24 and that our therapies had little effect on fixed coronary stenoses over the 12 months of this study.
The observation that there was no difference in improvement of ambulatory or treadmill ischemia when LDL was lowered from 150 to 85 mg/dL compared with 120 mg/dL may be due to a variety of explanations. There may be a threshold effect of LDL lowering below which there is no incremental improvement in endothelial dysfunction and episodic coronary vasoconstriction, and all of our on-treatment LDL values may have been beneath this threshold. Investigations have generally indicated that a variety of lipid-lowering strategies such as statins and fibric acid derivatives administered either alone15–17 or in combination2 reduce LDL and improve coronary vasoconstriction. The pretreatment LDL values in these studies generally ranged from 148 to 195 mg/dL, and the on-treatment LDL values ranged from 77 to 120 mg/dL. In the 2 previous studies demonstrating the benefit of lipid lowering to improve ambulatory ischemia, LDL values were reduced from 165 mg/dL to values ranging from 115 to 125 mg/dL.5,6 The CARATS study did not demonstrate an improvement in coronary endothelial dysfunction from marked LDL lowering from 130 to 77 mg/dL by simvastatin,25 perhaps because the baseline LDL value was only mildly elevated.26 Our study is the first to specifically evaluate 2 levels of LDL goal (85 mg/dL in the atorvastatin groups, 120 mg/dL in the control group), and we found no difference in outcomes between the 2 groups.
Antioxidant Vitamins and Myocardial Ischemia
In this study, antioxidant vitamins C and E, in addition to atorvastatin, had no effect on any ischemia outcome compared with treatment with atorvastatin alone. Although antioxidant supplements have been suggested as a therapeutic approach for CAD patients, results from large, long-term clinical outcome trials and coronary endothelial function studies have not supported their clinical efficacy.27–29 Some have suggested that the inconsistent and generally negative results from antioxidant therapy are related to differences in vitamin formulation, dose, or timing of administration.27,30,31 The doses of vitamin C and E used in this study and the plasma levels of these vitamins, however, indicate that a therapeutic benefit should have been observed if the supplements were effective.31,32 The lack of an observed benefit does not support the use of antioxidant vitamins C and E for reducing myocardial ischemia.
Lipid Lowering and FMD of the Brachial Artery
Our observation that lipid lowering did not affect endothelial-dependent brachial artery FMD may suggest that such therapy does not improve endothelial dysfunction and that our observed reduction in ischemia was not related to amelioration of vasoconstriction. A recent study of FMD in elderly, hypercholesterolemic patients (mean age, 76 years) found that neither statins nor antioxidant vitamins, alone or in combination, improved FMD over a 6-month period.33 Furthermore, Kinlay and colleagues29 have shown that 6-month treatment with vitamins C and E did not improve FMD in patients with CAD. Although FMD is correlated to coronary endothelial function across a wide spectrum of clinical syndromes, it may not be sensitive enough to identify the changes in coronary endothelial function important for the myocardial ischemia threshold.
Cardiovascular Outcomes
The clinical event rate was remarkably low despite the high risk usually associated with the presence of ischemia during ambulatory monitoring and exercise treadmill testing.3,4,34 The decrease in ischemia end points in all 3 groups associated with the observed low clinical event rate at 1 year suggests that all 3 groups benefited from statins and LDL lowering.
Study Limitations
Some of the observed effects of the 3 lipid-lowering strategies may have been due to regression-to-the-mean phenomena or to a "therapeutic" effect associated with careful patient management in a well-supervised clinical trial. Regression-to-the-mean phenomena cannot be excluded as contributing to the observed reductions in ischemia. Studies of stable CAD patients using serial AECG monitoring to quantify the variability of episodes of ambulatory ischemia during routine daily activities, however, have not demonstrated regression-to-the-mean phenomena.35,36 The only way to evaluate the contribution of regression to the mean would be to use a sample of general patients not chosen on the basis of myocardial ischemia. Practical constraints precluded this approach.
Other reasons why the study was null may be that the magnitude of the difference in ischemia end points between the groups was so small that our power could not detect them or that our follow-up was too short.
Our ischemia end-point assessments were obtained while routine antianginal medications were withdrawn so that the effects of lipid-lowering strategies on endothelial function and ischemia could be most directly investigated. We do not know whether the antiischemia effects we observed would be maintained while patients are on antianginal medications.
Conclusions
This study randomized patients with coronary disease and active ischemia to LDL lowering with statins, with or without antioxidants, and to a control group. All 3 groups exhibited a very low cardiovascular event rate, along with reductions in AECG ischemia, exercise-induced ischemia, and angina. Higher doses of statins, greater LDL lowering, and antioxidant vitamins did not result in greater reduction in ischemia.
Our lack of a dose-response relationship between LDL lowering and ischemic end points in stable coronary patients contrasts with the recently reported relationship between LDL lowering and reduction in hard clinical end points in acute coronary syndrome patients.37 Differences in disease manifestations investigated and sample size may be responsible for the different relationships observed. PROVE IT-TIMI 2237 investigated acute coronary syndrome patients and was powered to evaluate clinical end points; our study investigated stable coronary patients and was powered to evaluate ischemia end points. Clinical end points in acute coronary syndrome patients are governed by highly unstable coronary plaques, whereas ischemia end points in stable coronary patients are governed by an advanced chronic obstruction and factors affecting myocardial O2 supply-demand balance. Different pathophysiological aspects of coronary disease may respond differently to LDL lowering.
Acknowledgments
This work was supported by NIH grant RO1-HL38780 and by an unrestricted grant from Pfizer, Inc. We are grateful to Marie Gerhard-Herman, MD, Shauna Hurley, and Wesley Knauft for analyses of brachial artery studies; to Gail MacCallum and Michelle Lucier for analyses of AECG studies; and to Deborah Hobbs for excellent technical assistance in the analysis of vitamins C and E and F2-isoprostanes.
Footnotes
Guest Editor for this article was Gregory L. Burke, MD, MSc.
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