DITPA (3,5-Diiodothyropropionic Acid), a Thyroid Hormone Analog to Treat Heart Failure
Phase II Trial Veterans Affairs Cooperative Study
Background— In animal studies and a pilot trial in patients with congestive heart failure, the thyroid hormone analog 3,5 diiodothyropropionic acid (DITPA) had beneficial hemodynamic effects.
Methods and Results— This was a phase II multicenter, randomized, placebo-controlled, double-blind trial of New York Heart Association class II to IV congestive heart failure patients randomized (2:1) to DITPA or placebo and treated for 6 months. The study enrolled 86 patients (n=57 to DITPA, n=29 to placebo). The primary objective was to assess the effect of DITPA on a composite congestive heart failure end point that classifies patients as improved, worsened, or unchanged based on symptom changes and morbidity/mortality. DITPA was poorly tolerated, which obscured the interpretation of congestive heart failure-specific effects. Fatigue and gastrointestinal complaints, in particular, were more frequent in the DITPA group. DITPA increased cardiac index (by 18%) and decreased systemic vascular resistance (by 11%), serum cholesterol (−20%), low-density lipoprotein cholesterol (−30%), and body weight (−11 lb). Thyroid-stimulating hormone was suppressed in patients given DITPA, which reflects its thyromimetic effect; however, no symptoms or signs of potential hypothyroidism or thyrotoxicosis were seen.
Conclusions— DITPA improved some hemodynamic and metabolic parameters, but there was no evidence for symptomatic benefit in congestive heart failure.
Received November 14, 2008; accepted April 10, 2009.
Congestive heart failure (CHF) is the leading hospital discharge diagnosis in patients over 65 years old in the United States, with a prevalence of more than 5 million and an incidence of 550 000 patients per year.1 Heart failure causes more deaths than cancer, accidents, and strokes combined and generates healthcare costs of more than $23 billion annually.2 The prevalence and incidence of CHF will increase as the population ages. Despite the reduction in mortality and morbidity with the use of angiotensin-converting enzyme inhibition/angiotensin II receptor blockade, β-blockers, aldosterone antagonists, implanted cardiac defibrillators, and cardiac resynchronization therapy, the prognosis of CHF remains dismal.
Clinical Perspective on p 3100
In an effort to develop a new agent to treat heart failure, we previously examined the thyroid hormone analog 3,5-diiodothyropropionic acid (DITPA) in animal models of CHF3,4 and in a phase I study of 19 patients with CHF.5 Herein, we report the first randomized, placebo-controlled phase II trial designed to evaluate the safety of and provide preliminary data on the potential efficacy of DITPA in patients with stable CHF.
Veterans 18 years or older with stable CHF (New York Heart Association [NYHA] classification II to IV) with an ejection fraction ≤40% were eligible if their lipid levels were stable and they were undergoing standard therapy for heart failure (diuretic, carvedilol or long-acting metoprolol, and angiotensin-converting enzyme inhibition or angiotensin II receptor blockade). Exclusion criteria included clinically important renal, hepatic, or hematologic disorders or laboratory findings; thyroid disease; hematocrit <30%; chronic pulmonary disease; changes in heart failure or lipid medications within the last 30 days; hemodynamically significant pericardial disease; severe angina pectoris; myocardial infarction, cardiac surgery, or placement of a biventricular pacer within 3 months of screening; noncardiac surgery, placement of an implanted cardiac defibrillator, or percutaneous coronary intervention within 30 days of screening; inoperable aortic stenosis; symptomatic ventricular arrhythmias in a patient without an implanted cardiac defibrillator, or ventricular arrhythmia requiring pharmacological therapy; current use of amiodarone; previous noncompliance; taking any investigational drug during the previous 30 days; a medical condition that the investigator believed would make the patient ineligible for the study; allergy to iodine or shellfish; not in sinus rhythm; currently pregnant, lactating, or of childbearing potential; on a cardiac transplant list; and cardiac surgery anticipated within 6 months. The study was approved by each site’s institutional review board; informed consent was obtained from each patient before screening.
Patients were randomized to DITPA or placebo (2:1 ratio), stratified by site (n=7) and age group (>71 or ≤70 years). DITPA was dosed twice daily, uptitrated in 90-mg/d increments at each 2-week visit to a maximum of 360 mg/d or until the thyroid-stimulating hormone concentration was <0.02 mU/L. To maintain masking, the titration was managed centrally. On April 5, 2006, after 64 patients were enrolled, the maximum dose was lowered to 270 mg/d with slower titration to that dose (and patients already receiving 360 mg/d were downtitrated at the next visit) on the recommendation of the Data and Safety Monitoring Board. Throughout the study, titration was slowed for explicitly defined excessive weight loss or, at the site’s discretion, for adverse events (AEs). A masked Treatment Committee (chaired by PWL and MM) made titration decisions. Visits were at weeks 2, 4, 6, 8 (completion of titration), 16, and 24 (end of treatment) and 30 days after treatment. Patients who terminated treatment early were maintained in follow-up if they agreed to it. DITPA active pharmaceutical ingredient was manufactured by Sigma-Aldrich Corporation (St Louis, Mo). The study active and placebo capsules were formulated, manufactured, and packaged by VA CSP Clinical Research Pharmacy Coordinating Center (Albuquerque, NM).
The primary efficacy end point was the clinical composite CHF end point, assessed by a masked End-Points Committee that classified patients into 1 of 3 categories based on their status at permanent discontinuation from study medication: “Worsened” for those with CHF-associated morbidity (hospitalization or urgent care)/mortality/premature discontinuation, an increase in NYHA classification, or at least moderate worsening on the patient global assessment; “improved” for those not classified as “worsened” who had a decrease in NYHA classification, or at least moderate improvement on the patient global assessment; or “unchanged.”6
Secondary efficacy end points included all-cause mortality and hospitalizations; echocardiography-derived measurements of cardiac dimensions, systolic and diastolic function; 6-minute walk test; health status (using the Chronic Heart Disease Questionnaire)7; physician global assessment; Specific Activity Score; cardiac output determined by impedance cardiography; lipid and triglyceride levels (fasting); and plasma levels of epinephrine, norepinephrine, dopamine, brain natriuretic peptide, tumor necrosis factor-α, interleukin (IL)-6, IL-8, IL-10, soluble IL-2 receptor, and monocyte chemoattractant peptide-1 (all measured at LabCorp); thyroid function tests, including serum thyroid-stimulating hormone, thyroxine (T4 by LC/MS), and triiodothyronine (T3; by LC/MS); and clinical and other laboratory parameters that reflected excess or deficient thyromimetic actions (detailed results for weight, lipids, and other measures will be presented in another publication).
Patients were monitored at each clinic visit for possible AEs and serious AEs based on the broad International Conference on Harmonisation and Food and Drug Administration definition, ie, any untoward sign, symptom, or experience in a patient who is administered a product, which does not necessarily have to have a causal relationship with this treatment.8 Clinical research associates from the Veterans Affair’s Good Clinical Practice Monitoring Group monitored sites to ensure that the study was conducted in compliance with the Food and Drug Administration’s good clinical practices.
The aim of the present phase II study was to evaluate the safety profile of DITPA and to obtain efficacy data sufficient to warrant a phase III study. Consequently, in planning the present study, type I error (1-tailed) and type II error were both set at 0.1. We planned to enroll 50 participants to be given placebo and 100 to be given DITPA to detect a moderate effect size of 0.45×SD, where SD is the common SD of the composite score in the 2 groups. The planned sample size was not achieved during the scheduled enrollment period. The sponsor elected not to extend enrollment and curtailed follow-up. Because the sample size was smaller than planned, instead of testing hypotheses, we present the 90% confidence intervals (CIs) to indicate the range of possible effects that are not excluded by the study. The interpretation is based on the entire picture of emerging trends.9 Analyses are intention-to-treat and include all patients with data for the measure, according to their assigned group.
The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
Description of Study Population and Protocol Adherence
Eighty-six patients (DITPA 57, placebo 29) were enrolled between June 24, 2004, and October 10, 2006. A request was made for an extension owing to slow recruitment. The sponsor reviewed the deliberations of the Veterans Administration Review Board and the Data and Safety Monitoring Board, and in light of the safety concerns raised by both bodies, as well as the underrecruitment, the sponsor decided to terminate the study. Because of the termination, 11 patients could not complete the full follow-up (administratively censored). Figure 1 summarizes the flow and follow-up status for the 24-week treatment phase.
Tables 1 through 3⇓⇓ include the baseline characteristics; groups were similar for most characteristics, except for use of implanted cardiac defibrillators and current smoking status. For patients still taking DITPA, serum thyroid-stimulating hormone levels had dropped to 0.2±0.50 (n=35) at 8 weeks and 0.1±0.18 at 24 weeks (n=20), respectively. The thyroid-stimulating hormone level rebounded to baseline levels (1.8±0.96, n=48) within 30 days after treatment for all but 2 patients (who required 60 days).
Early discontinuation of study drug was not seen in placebo patients but was common in DITPA-treated patients and was associated with AEs. Among the 48 DITPA patients not terminated because of funding cessation, only 21 (44%) continued to take DITPA for the full 24 weeks, whereas no placebo patients discontinued the placebo. The AEs associated with discontinuation (n=23) included gastrointestinal problems (4), fatigue (3), laboratory abnormality (3), cardiac arrhythmia (3), cardiac chest pain (2), and “other” (8). Table 4 shows the dose distribution of DITPA at 8 weeks (the point at which titration to thyroid-stimulating hormone criterion would have been completed, per protocol) and at 24 weeks. The decrease in average dose over time was due to both the elimination of the highest dose (360 mg) and dose reductions in individual patients. Adherence to drug (as estimated by pill counts) was 95% in DITPA and 98% in placebo participants; overall, 97% of dosing blister cards were returned for this assessment.
Primary Outcome Components
In patients treated with DITPA, an adverse trend was seen in the primary composite CHF outcome. The combined rate of CHF-associated hospitalization/urgent care or death was 10% in each group (Table 5). For patients not experiencing a major morbidity or mortality end point, the determination of the primary outcome incorporated changes in NYHA classification and patient global assessment. There was no trend for change in NYHA class (DITPA versus placebo: improved 8% versus 7%, unchanged 74% versus 79%, worsened 19% versus 14%), but there was a worsening with DITPA in the patient global assessment (DITPA versus placebo: improved 15% versus 38%, unchanged 70% versus 55%, worsened 15% versus 7%). Hospitalizations not associated with worsening CHF were seen in 26% of DITPA patients and 14% of placebo patients. There were 2 deaths, both in the DITPA group (15 days after randomization [myocardial infarction] and 34 days after randomization [sudden death]).
DITPA was associated with an increased cardiac index that peaked at 8 weeks (Figure 2), along with a decrease in systemic vascular resistance (−232±393.4 versus −45±307.1 dyne · sec · cm−5). Figure 2 also shows that the average dose of DITPA decreased over time. At 30 days after treatment, the change in cardiac index had diminished to 0.18 (90% CI −0.02 to 0.35). Figure 3 illustrates the change in left ventricular end-systolic diameter over time, with a tendency for a decrease in the DITPA group that paralleled the change in cardiac index. At 30 days after treatment, the decrease was −1.7 mm (90% CI −4.73 to 1.25 mm). Left ventricular end-diastolic diameter did not change. The use of DITPA increased heart rate (based on the percentage of patients with an increase of ≥10 bpm); in those taking DITPA, 61% (90% CI=49%–72%) experienced an increase whereas in those taking placebo, 41% (90% CI=26%–58%) experienced an increase.
Other Clinical Changes
Serum lipoproteins and body weight decreased with DITPA, with changes in total cholesterol at 24 weeks of −18±31.6 mg/dL (DITPA) versus −7±34.9 mg/dL (placebo), changes in low-density lipoprotein of −11±23.8 mg/dL (DITPA) versus −4±27.1 mg/dL (placebo), and weight loss of 11±9.7 lb (DITPA) versus 0±7.1 lb (placebo). There were no trends with regard to 6-minute walk, diastolic function, ejection fraction, quality of life, physician global assessment, epinephrine, norepinephrine, dopamine, brain natriuretic peptide, IL-6, IL-8, IL-10, monocyte chemoattractant peptide-1, or tumor necrosis factor-α.
Reported by Sites
Table 6 shows 3 categories of AEs. Of the patients with arrhythmias, 3 DITPA patients (5% of those randomized) experienced ventricular tachycardia (1 with ventricular fibrillation, 1 with nonsustained idioventricular rhythm), 2 patients (4%) given DITPA and 1 (3%) given placebo had sinus tachycardia, and 1 patient given placebo had atrial fibrillation. For serious AEs and AEs other than arrhythmias, the overall rates are given for specific events with an incidence of at least 10% in either group and with at least a 2-fold difference between the groups. Complaints common in both groups included fatigue (DITPA 46%, placebo 38%) and diarrhea and related symptoms (DITPA 40%, placebo 21%).
Routinely Measured per Protocol
There were no changes in signs and symptoms of thyrotoxicosis.10,11 Adverse trends were seen for several safety measures, and the estimates represent the largest change seen during follow-up: Soluble IL-2 receptor (change in median of 102% in DITPA versus −6% in placebo patients), hemoglobin (change in median of −6.2% with DITPA versus −1.0% with placebo), and hematocrit (change in median of −4.8% with DITPA versus −1.8% with placebo). Alkaline phosphatase, creatinine, blood urea nitrogen, red blood cell counts, and platelet counts did not change.
Given their small sample sizes, response estimates in subgroups are unreliable. Estimates of the primary outcome and drug discontinuation rate in females (n=5), blacks (n=9), and Hispanics (n=8) were not inconsistent with those of the overall group.
The thyroid hormone analog DITPA increased cardiac index and decreased lipids and weight, but DITPA was not well tolerated at the doses given, with a trend toward worsening of the composite end point. Although weight loss was dose-limiting in a few patients, consistent with a thyromimetic effect, other AEs were not clearly attributable to excessive thyroid hormone action (eg, fatigue and gastrointestinal symptoms). These unexpected adverse effects may reflect effects of DITPA unrelated to its thyromimetic properties and/or possibly heightened vigilance for AEs in the DITPA group, because weight loss led to suspicion of treatment assignment.
The structural similarity of DITPA to T4 and other thyroid hormone agonists and its demonstrated binding to nuclear thyroid hormone receptors make it likely that DITPA works as a thyromimetic agent.12 Although DITPA does not bind with high selectivity to specific thyroid hormone receptor isoforms, it differs in structure from T3 in that it lacks an outer-ring iodide and the amine in the carboxylic acid side chain. These differences would be predicted to change the interactions of DITPA with amino acid side chains in the receptor binding pocket, thereby altering receptor conformation. Because receptor conformation affects the interactions of the bound receptor with tissue-specific cofactors, it could contribute to differences in relative tissue potencies. The increase in cardiac index and decrease in vascular resistance seen with DITPA are typical cardiovascular actions of thyroid hormone. At the same time, the minimal increase in heart rate implies a different pattern of tissue-specific thyromimetic potencies. Such differences in relative potencies of tissue thyroid hormone actions have been shown previously for other thyroid hormone analogs, such as triiodothyroacetic acid,13 GC-1,14 and KB-141.15 The lowering of serum total and low-density lipoprotein cholesterol concentrations is also consistent with significant hepatic thyromimetic activity of DITPA.
The rationale for potential use of a thyroid hormone analog in the treatment of heart failure involves the known properties of thyroid hormone with respect to the cardiovascular system, such as an increase in left ventricular systolic performance, improvement of diastolic function, and a decrease in peripheral vascular resistance.16 In addition to the potential beneficial cardiac effects of thyroid hormone, heart failure is associated with alterations in thyroid hormone metabolism when there is no intrinsic thyroid disease, ie, “the euthyroid sick syndrome.”17 This observation has led investigators to examine the effects of T3 in situations with acute cardiac decompensation. Intravenous T3 improves cardiac performance in severe heart failure,18,19 and exogenously administered thyroid hormone provides inotropic support in patients undergoing coronary artery bypass grafting surgery, but it does not reduce mortality.20,21 In general, the beneficial therapeutic effects of exogenously administered thyroid hormone have been overshadowed by increases in heart rate and altered body metabolism.
We and other investigators have recognized these limitations of thyroid hormone and have explored the development of analogs of thyroid hormone that have less positive chronotropic effects.22 Our efforts led to the discovery that DITPA improves left ventricular function both in animal models3,4 and in a preliminary study of patients with heart failure, with no change in heart rate.5 This led to the design of the present phase II safety and efficacy study of DITPA.
A key strategy pursued in a phase II study is maximization of the probability of seeing an effect by use of the presumed maximum tolerated dose.23 Clearly, we were successful in this respect. It remains unclear whether the profile of response to lower doses would have been more favorable. Because resources did not permit randomization to different doses, our only unbiased avenue for assessing lower doses in the present study is to look at the subset of effects that were measured at the earlier time points, as DITPA was being titrated. Effects at 2 weeks reflect the 90-mg dose initiated at time zero, whereas effects at 4 weeks reflect the 180-mg dose initiated at week 2 in most patients. We did observe an early increase in heart rate and cardiac index at 2 and 4 weeks, respectively; however, we also saw a tendency for the patient global assessment to be worsening compared with placebo at 4 weeks. These observations suggest that 90 mg/d might be an efficacious dosing strategy for increasing cardiac index, particularly if the effect on cardiac index builds gradually. A protracted time course is suggested by Figure 2, in which cardiac index was higher at 16 to 24 weeks than at 4 weeks despite lower average doses at the later time points. Because 89% of patients with an opportunity to progress beyond 90 mg did so, this may also be a tolerable dose.
The potential benefit of drugs that increase cardiac index in patients with CHF is very controversial. Most investigators believe that increasing cardiac index and myocardial oxygen consumption simultaneously is not beneficial in CHF. This conclusion is based on the results of several studies showing that although treatment with inotropic agents increases cardiac output, it also decreases survival.24 In contrast, there are data to show that there is no deleterious effect of prolonged intravenous inotropic support in patients with end-stage CHF awaiting cardiac transplantation.25 In the case of DITPA, the increase in cardiac index was not accompanied by an increase in myocardial oxygen consumption in animal models of heart failure.3 In the present trial, the tendency for a reduction in left ventricular systolic diameter that paralleled the increase in cardiac index is intriguing, suggesting a positive inotropic effect of DITPA. Nevertheless, it remains unclear whether a drug that increases cardiac index will be useful in the treatment of heart failure.
Most of the treatments currently used in heart failure have not been shown to improve symptoms; rather, they decrease mortality.26–28 Mortality is not a feasible end point in a phase II study. Unfortunately, with the possible exception of ventricular remodeling, there are no good surrogate measures for mortality improvements in heart failure trials.29 Our strategy was to use a clinical composite score that combined morbidity and mortality with NYHA class and patient global assessment; however, because there were so few clinical events and no change in NYHA class, the composite was driven by patient global assessment. Because this assessment was not specific for heart failure (“How do you feel today as compared with how you felt before you started taking your study medication?”), our composite may well have been influenced largely by the nonspecific complaints of fatigue, gastrointestinal symptoms, etc. Indeed, the heart failure clinical measures were inconsistent across treatment arms. Table 5 shows a 10% rate of CHF-associated death/hospitalization in each group, whereas the rates in Table 6 favor DITPA for CHF serious AEs and rales but favor placebo for dyspnea. Part of the discrepancy may be due to the broader definition used in the composite, in which events need only to have been associated with worsening CHF to qualify as end points, whereas CHF serious AE reports would only be filed if CHF was the precipitating event. The 7% rate of CHF-associated study drug discontinuation in DITPA versus 0% in placebo patients is difficult to interpret in terms of causality on CHF symptoms, because 1 of the criteria (discontinuation) only occurred with DITPA. Thus, exacerbations unassociated with hospitalization or death were eligible as end points only if they coincided with study drug discontinuation (30 days before or 15 days after). Given the small number of events, the present study does not help clarify whether there might be a relationship between cardiac index and clinical measures in CHF. Other limitations of the present study include the small sample size, the intervention discontinuation rate, and possible unmasking due to weight loss.
In conclusion, the present trial has demonstrated limited tolerability of DITPA at doses approaching 360 mg/d in patients with stable heart failure. Although a dose of 90 mg/d might conceivably strike a balance between efficacy in increasing cardiac index and tolerability, the therapeutic window appears to be narrow. In addition, if thyroid hormone analogs are to be pursued in the treatment of heart failure, a translation of the increase in cardiac index to clinical benefit needs to be demonstrated.
Source of Funding
This study was supported by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Clinical Science Research and Development Service, Cooperative Studies Program.
Drs Goldman and Morkin, in conjunction with Drs Gregory Pennock and Joseph Bahl, received a use patent for 3,5-diiodothyropropionic acid (DITPA) that was assigned to the University of Arizona: US patent No. 6,534,676 B2 UA #03-075. The Department of Veterans Affairs and the University of Arizona have an agreement on the management of co-owned inventions and intellectual property that enables the university to direct matters related to patenting, marketing, and licensing of co-owned inventions. The University of Arizona licensed DITPA to Titan Pharmaceutical, South San Francisco, Calif. Dr Goldman previously owned stock in Titan; Drs Goldman, Morkin, and Ladenson were consultants for Titan but no longer receive payments. Dr Ladenson has received grant support from Titan. In December 2008, Titan Pharmaceutical discontinued the development of DITPA, and the license reverted back to the University of Arizona. The first US patent application for DITPA was issued as US 6,534,676 on March 18, 2003; the Canadian counterpart is CA 2002243801, which was issued on March 22, 2007. A second US patent application for analogs of DITPA was issued as US 6,716,877 on April 6, 2004.
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Billewicz WZ, Chapman RS, Crooks J, Day ME, Gossage J, Wayne E. Statistical methods applied to the diagnosis of hypothyroidism. Q J Med. 1969; 38: 255–266.
Pennock GD, Raya TE, Bahl JJ, Goldman S, Morkin E. Cardiac effects of 3,5-diiodothyropropionic acid: a thyroid hormone analog with inotropic selectivity. J Pharmacol Exp Ther. 1992; 263: 163–169.
Grover GJ, Mellström K, Ye L, Malm J, Li YL, Bladh LG, Sleph PG, Smith MA, George R, Vennström B, Mookhtiar K, Horvath R, Speelman J, Egan D, Baxter JD. Selective thyroid hormone receptor-beta activation: a strategy for reduction of weight, cholesterol, and lipoprotein(a) with reduced cardiovascular liability. Proc Natl Acad Sci U S A. 2003; 100: 10067–10072.
Pennock GD, Raya TE, Bahl JJ, Goldman S, Morkin E. Cardiac effects of 3,5-diiodothyroproprionic acid, a thyroid analog with inotropic selectivity. J Pharmacol Exp Ther. 1992; 263: 163–169.
Cohn JN, Johnson G, Ziesche S, Cobb F, Francis G, Tristani F, Smith R, Dunkman WB, Loeb H, Wong M, Bhat G, Goldman S, Fletcher RD, Doherty J, Hughes CV, Carson P, Cintron G, Sharetai R, Haakenson C. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med. 1991; 325: 303–310.
Hjalmarson A, Goldstein S, Fagerberg B, Wedel H, Waagstein F, Kjekshus J, Wikstrand J, El Allaf D, Vítovec J, Aldershvile J, Halinen M, Dietz R, Neuhaus KL, Jánosi A, Thorgeirsson G, Dunselman PH, Gullestad L, Kuch J, Herlitz J, Rickenbacher P, Ball S, Gottlieb S, Deedwania P; for the MERIT-HF Study Group. Effects of controlled-release metoprolol on total mortality, hospitalizations, and well-being in patients with heart failure: the Metoprolol CR/XL Randomized Intervention Trial in congestive heart failure (MERIT-HF). JAMA. 2000; 283: 1295–1302.
This was a randomized, placebo-controlled, phase II trial designed to evaluate the safety of and provide preliminary data on the potential efficacy of 3,5-diiodothyropropionic acid in patients with stable congestive heart failure. Although the trial was stopped early because of increased side effects at the dose we chose, the data do show beneficial hemodynamic effects of a thyroid hormone analog in the treatment of congestive heart failure. The use of a thyroid hormone analog to treat congestive heart failure is a new and different conceptual approach to the treatment of heart failure because the presumed mechanism of action of the thyroid hormone analog is to alter the molecular composition of the heart and vasculature. If the outcome in patients with congestive heart failure is to be improved, different approaches must be examined that include structural and molecular targets as opposed to attempts to achieve more and more neurohormonal blockade.
↵*Drs Goldman and McCarren contributed equally to this article.
The contents of this article do not represent the views of the Department of Veterans Affairs or the US government.
The online-only Data Supplement is available with this article at http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.108.834424/DC1.
Clinical trial registration information—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00032643.