Patients were defined as having completed the trial when they completed
24 months of follow-up, were followed up through July 2003 (end of study),
or were followed up through a primary end point (ventricular tachycardia or
ventricular fibrillation) or death.
ICD indicates implantable cardioverter defibrillator; VT, ventricular
tachycardia; and VF, ventricular fibrillation.
ICD indicates implantable cardioverter defibrillator; VT, ventricular
tachycardia; and VF, ventricular fibrillation. Error bars indicate 95% confidence
intervals (CIs). The sizes of the data markers are proportional to the numbers
of patients in the analyses.
Raitt MH, Connor WE, Morris C, Kron J, Halperin B, Chugh SS, McClelland J, Cook J, MacMurdy K, Swenson R, Connor SL, Gerhard G, Kraemer DF, Oseran D, Marchant C, Calhoun D, Shnider R, McAnulty J. Fish Oil Supplementation and Risk of Ventricular Tachycardia and Ventricular Fibrillation in Patients With Implantable DefibrillatorsA Randomized Controlled Trial. JAMA. 2005;293(23):2884–2891. doi:10.1001/jama.293.23.2884
Author Affiliations: Oregon Health and Science
University, Portland (Drs Raitt, Connor, Morris, Kron, Chugh, MacMurdy, Gerhard,
Kraemer, and McAnulty, Mss Connor and Marchant, and Mr Calhoun), Portland
VA Medical Center (Drs Raitt and MacMurdy), St Vincent Medical Center (Drs
Halperin and Oseran), and Oregon State University (Dr Kraemer), Portland;
Sacred Heart Medical Center, Eugene, Ore (Dr McClelland); Southwest Medical
Center, Vancouver, Wash (Dr Swenson); and Baystate Medical Center, Springfield,
Mass (Drs Cook and Shnider).
Context Clinical studies of omega-3 polyunsaturated fatty acids (PUFAs) have
shown a reduction in sudden cardiac death, suggesting that omega-3 PUFAs may
have antiarrhythmic effects.
Objective To determine whether omega-3 PUFAs have beneficial antiarrhythmic effects
in patients with a history of sustained ventricular tachycardia (VT) or ventricular
Design and Setting Randomized, double-blind, placebo-controlled trial performed at 6 US
medical centers with enrollment from February 1999 until January 2003.
Patients Two hundred patients with an implantable cardioverter defibrillator
(ICD) and a recent episode of sustained VT or VF.
Intervention Patients were randomly assigned to receive fish oil, 1.8 g/d, 72% omega-3
PUFAs, or placebo and were followed up for a median of 718 days (range, 20-828
Main Outcome Measures Time to first episode of ICD treatment for VT/VF, changes in red blood
cell concentrations of omega-3 PUFAs, frequency of recurrent VT/VF events,
and predetermined subgroup analyses.
Results Patients randomized to receive fish oil had an increase in the mean
percentage of omega-3 PUFAs in red blood cell membranes from 4.7% to 8.3%
(P<.001), with no change observed in patients
receiving placebo. At 6, 12, and 24 months, 46% (SE, 5%), 51% (5%), and 65%
(5%) of patients randomized to receive fish oil had ICD therapy for VT/VF
compared with 36% (5%), 41% (5%), and 59% (5%) for patients randomized to
receive placebo (P = .19). In the subset
of 133 patients whose qualifying arrhythmia was VT, 61% (SE, 6%), 66% (6%),
and 79% (6%) of patients in the fish oil group had VT/VF at 6, 12, and 24
months compared with 37% (6%), 43% (6%), and 65% (6%) of patients in the control
group (P = .007). Recurrent VT/VF events
were more common in patients randomized to receive fish oil (P<.001).
Conclusion Among patients with a recent episode of sustained ventricular arrhythmia
and an ICD, fish oil supplementation does not reduce the risk of VT/VF and
may be proarrhythmic in some patients.
Since the original observations that Greenland Eskimos eating a diet
high in omega-3 polyunsaturated fats (PUFAs) from sea mammals and fish had
an unexpectedly low risk of cardiac death,1,2 multiple
lines of evidence have suggested that omega-3 PUFAs have antiarrhythmic properties.
Four randomized clinical trials3- 6 have
shown that dietary changes or supplements to increase omega-3 PUFA intake
result in a reduced risk of sudden death without a consistent change in risk
of myocardial infarction. To test the hypothesis that omega-3 PUFAs have antiarrhythmic
properties, we performed a prospective, double-blind, randomized, placebo-controlled
trial of fish oil supplementation in patients with a recent episode of sustained
Patients at 6 medical centers in the United States were eligible for
entry if they were receiving an implantable cardioverter defibrillator (ICD)
for an electrocardiogram-documented episode of sustained ventricular tachycardia
(VT) or ventricular fibrillation (VF) that was not the result of acute myocardial
infarction or a reversible cause or who had a preexisting ICD and had received
ICD therapy for an episode of electrogram-documented VT/VF within the previous
Patients taking class I or class III antiarrhythmic medications were
excluded to prevent the inclusion of proven antiarrhythmic nonresponders and
to prevent potential confounding problems related to antiarrhythmic drugs
acting through similar mechanisms as fish oil. Patients who ate more than
1 fatty fish (salmon, Chilean sea bass, sardine, herring, or mackerel) meal
per week or who had taken flaxseed oil, cod liver oil, or fish oil supplements
in the last month were also excluded. Patients provided written informed consent
to participate. The study conformed to the principles of the Declaration of
Helsinki, was approved by the institutional review board at each site, and
was monitored by an independent data and safety monitoring board.
Definition of race/ethnicity was required by the National Institutes
of Health to determine any possible interaction with the treatment effect
and to ascertain balance between the group assignments. Race/ethnicity was
determined by asking participants to classify themselves.
The computer-generated, blocked randomization scheme (in block sizes
of 6) was stratified by arrhythmia at entry (VT vs VF) and by enrollment at
the time of ICD implantation (yes vs no). Patients were randomly assigned
to receive a total dosage of 1.8 g/d of fish oil, consisting of 42% eicosapentaenoic
acid (EPA) and 30% docosahexaenoic acid (DHA), or placebo (olive oil: 73%
oleic acid, 12% palmitic acid, 0% EPA/DHA). Oils were provided by Hoffman-LaRoche
Inc (Nutley, NJ) as ethyl esters of the fatty acids. The dose of fish oil
was based on preliminary studies that showed that it would increase the percentage
of red blood cell membrane fatty acid made up of EPA and DHA to a level between
6% and 10%. Levels in this range have been shown to be associated with a low
relative risk of sudden death in case-control studies.7,8 All
patients received ongoing dietary counseling to not change their intake of
fish and to follow the American Heart Association step I low-fat diet.
After randomization, patients were followed up for as long as 2 years
with monthly clinic visits at the enrolling center for the first 3 months
and every 3 months thereafter. At each visit, participants were asked to report
anticipated, unanticipated, and serious adverse events. Figure 1 shows the flow of patients through the study. Implantable
cardioverter defibrillator programming was left to the discretion of the attending
cardiologist, and the slowest heart rate programmed to trigger ICD therapy
was tracked. At all visits, the ICD memory was checked for occurrence of episodes
of ICD therapy. Blood was drawn for lipid analysis at baseline and months
1, 2, 3, 6, 12, 18, and 24. Fatty acid levels in plasma and red blood cells
were analyzed by methods that have been previously published9 and
the results were expressed as percentage of total fatty acids.
A printout of each episode of ICD therapy was reviewed by the local
investigator and by a member of the electrogram committee, both of whom were
blinded to the treatment assignment of the patient. Episodes of ICD therapy
were classified as VT, VF, atrial fibrillation, supraventricular tachycardia,
oversensing, or unknown using methods previously reported.10,11 When
there was disagreement between the investigator and the committee member on
the interpretation of the tracings, the tracings were reviewed by the entire
committee and classified by consensus. Only episodes of ICD therapy determined
to be due to VT or VF are included as end points in this article.
Forty-nine patients at 2 participating centers who were enrolled at
the time of ICD implantation underwent electrophysiologic testing through
the ICD at implantation and again 3 months later. Testing consisted of (1)
effective refractory period determined at drive train cycle lengths of 400
milliseconds and 600 milliseconds using a single extra stimulus decremented
at 10-millisecond intervals at 2× threshold; (2) up to 3× extra
stimuli at both drive train cycle lengths; and (3) defibrillation threshold
measurement using the step-up, step-down method, starting with an initial
energy of 12 J and using 3-J steps, with defibrillation threshold defined
as the minimum energy leading to successful defibrillation.
The primary end point was the time to the first episode of VT/VF leading
to ICD therapy. Predetermined secondary analyses were performed in subgroups
of qualifying arrhythmia (VT vs VF), history of coronary artery disease, and
ejection fraction. Based on an estimated 75% incidence12 of
these arrhythmias in placebo patients during 2 years of follow-up and a 15%
dropout rate, we calculated that 100 patients per group or 200 total would
be required for 92% power to detect a 33% reduction in event rate with treatment
using a 2-tailed α level of .05. Predefined secondary end points were:
(1) time to days with recurrent episodes of VT/VF leading to ICD therapy;
(2) time to first use of antiarrhythmic medication; and (3) change in defibrillation
threshold, inducibility of VT or VF, and the ventricular effective refractory
period from baseline to 3 months.
All analyses were performed based on intention to treat. The baseline
characteristics of patients randomized to receive fish oil vs placebo were
compared using the t test and the χ2 test
as appropriate. Differences in percentage of total plasma and red blood cell
membrane fatty acids over time were determined using separate mixed-model
analysis of variance models. The initial value was used as a covariate to
control for any differences at baseline, with the most appropriate covariance
structure selected using the Akaike information criterion. Least square–adjusted
means were estimated and compared for all analysis of variance effects; a
Tukey adjustment was applied within analyses to account for multiple comparisons.
All analyses were performed with SAS software, versions 8 and 9 (SAS Institute
Inc, Cary, NC).
Actuarial analyses were performed using the Kaplan-Meier method, and
the statistical significance of observed differences was determined using
the log-rank test. Survival is presented as percentage (standard error). For
the primary analysis of time to first arrhythmia and the secondary analysis
of time to first VT/VF analysis in patients with VT at study entry, a plot
of the natural logarithm of the negative of the natural logarithm of survival
vs the natural logarithm of survival was reviewed to assess the proportional
As a secondary analysis, a Cox proportional hazards model was used to
assess the significance of the primary outcome controlling for other baseline
characteristics. Variable selection was performed with these baseline characteristics
using all possible regression models with the score statistic and stepwise
addition of variables. Treatment group was then added to the best model to
determine if it was a significant predictor after controlling for significant
baseline characteristics. To determine if compliance modified the primary
analysis, all repeated measurements of plasma and red blood cell membrane
omega-3 PUFA levels were analyzed as time-dependent covariates using the Cox
proportional hazards model. The Anderson-Gill application of the Cox proportional
hazards model13 was used to assess the effect
of treatment group on the number of days with recurrent VT/VF events. That
is, each day on which a patient had VT or VF was modeled as an event. For
example, if a patient experienced arrhythmias on days 1, 3, and 5, each of
these 3 arrhythmias was included in the model with the time measured from
the last recorded arrhythmia.
Patients were enrolled from February 1999 until January 2003. Follow-up
was completed July 2003, with a median follow-up duration of 718 days (range,
20-828 days). Patients assigned to receive fish oil were followed up for a
median of 720 days (range, 20-828 days) and patients assigned to receive placebo
were followed up for a median of 718 days (range, 60-815 days). The baseline
demographics of patients assigned to fish oil and those randomized to placebo
were well balanced (Table 1). There
were no significant differences in serious adverse events in patients assigned
to fish oil compared with those assigned to placebo, with the possible exception
of an excess of hospitalizations for neurologic events in patients assigned
to placebo (Table 2). Seventeen patients
assigned to fish oil and 26 assigned to placebo stopped study medication prior
to the end of the trial because of adverse effects or unrelated severe illness.
At baseline, there was no difference in plasma or red blood cell membrane
plasma omega-3 fatty acids (DHA plus EPA), expressed as a percentage of total
fatty acids, between patients assigned to placebo and fish oil. Baseline plasma
fatty acid levels were 1.9% in patients assigned to fish oil, rising significantly
to 4.4% by 1 month, with no significant change thereafter through 24 months.
Red blood cell membrane levels in patients assigned to fish oil rose significantly,
from 4.7% at baseline to 6.8% at 1 month, and continued to increase to 8.3%
at 3 months, with no significant change thereafter. Patients assigned to placebo
had no significant change in plasma or red blood cell omega-3 fatty acid levels
over 24 months of follow-up. Plasma and red blood cell membrane omega-3 fatty
acid levels in patients assigned to fish oil were higher than levels in patients
assigned to placebo at all follow-up time points (P<.001).
There was no difference over time or between groups in the plasma or red blood
cell membrane levels of the 2 primary components of the placebo, oleic acid
and palmitic acid.
During follow-up, patients received ICD therapy for a total of 45 VF
episodes and 901 VT episodes. Other episodes of ICD therapy included 47 for
atrial fibrillation, 124 for supraventricular tachycardia, 2 for oversensing,
and 31 that could not be classified. The results of the analysis of the primary
end point, time to first episode of ICD therapy for VT/VF after randomization,
are shown in Figure 2. At 6, 12, and
24 months after randomization, respectively, 46% (SE, 5%), 51% (5%), and 65%
(5%) of patients assigned to fish oil had ICD therapy for VT/VF compared with
36% (5%), 41% (5%), and 59% (5%) of patients assigned to placebo (P = .19). In the subset of 133 patients whose qualifying
arrhythmia at the time of study entry was VT, patients assigned to fish oil
had a 61% (SE, 6%), 66% (6%), and 79% (6%) incidence of VT/VF treated by the
ICD at 6, 12, and 24 months, respectively (Figure
2), compared with 37% (6%), 43% (6%), and 65% (6%) among those assigned
to placebo (P = .007).
Regardless of ejection fraction, the group assigned to fish oil tended
to have a shorter time to first episode of ICD therapy for VT/VF than those
assigned to placebo (Figure 3). Figure 4 shows the hazard ratios and confidence
intervals (CIs) for the analysis of time to first VT/VF episode for each of
the prespecified subgroups and for the study population as a whole. Given
the predictive value of presenting arrhythmia on the primary end point, a
post hoc analysis of time to first VT and first VF episode was performed.
There was a trend toward an increased risk of VT in patients assigned to fish
oil but no apparent effect on the risk of VF (Figure 5). In multivariate analysis, an ejection fraction less than
40% (hazard ratio, 1.7; 95% CI, 1.1-2.5) and VT as the qualifying arrhythmia
(hazard ratio, 2.0; 95% CI, 1.3-3.1) were the independent predictors of time
to ICD therapy for VT/VF. When treatment assignment was added to this model,
the fish oil group had a hazard ratio of 1.4 (95% CI, 0.96-2.0).
An actuarial analysis of the time to recurrent episodes of VT/VF (ie,
time to each day on which an arrhythmia occurred) showed a significant increase
in the incidence of days with episodes of ICD therapy for VT/VF in patients
assigned to fish oil (P<.001). Patients assigned
to fish oil had ICD therapy for VT/VF on a mean of 3.5 (SE, 0.6) days compared
with 2.2 (0.5) days for patients assigned to placebo over the 2-year study.
To investigate whether compliance may have affected the results, analyses
were performed of time to first episode of VT/VF using plasma or red blood
cell membrane omega-3 PUFA levels as time-dependent covariates. These analyses
showed no significant association between (P>.20)
omega-3 PUFA levels and time to first episode of VT/VF. During follow-up,
class I or class III antiarrhythmic medications were initiated for 12% (3%),
22% (4%), and 29% (5%) of patients assigned to fish oil at 6, 12, and 24 months,
respectively, compared with 13% (3%), 15% (4%), and 25% (5%) in patients assigned
to placebo (P = .45). There was no difference
in the results of electrophysiologic testing between patients assigned to
fish oil vs placebo (Table 3).
In this study, fish oil supplementation in patients with an ICD and
a history of VT or VF did not prevent episodes of VT or VF. It is unlikely
that the lack of demonstrable beneficial effect was due to inadequate power
given the overall trend toward an increased risk of VT/VF in the fish oil
group. In fact, the trend toward a higher incidence of VT/VF overall with
fish oil supplementation, the significant increase in VT/VF occurrence in
patients with VT as the qualifying entry rhythm (P = .007),
and the increased rate of recurrent episodes of VT/VF in patients assigned
to fish oil (P<.001) all suggest that fish oil
may be proarrhythmic in this population.
The finding that fish oil did not reduce the risk of VT or VF and may
be proarrhythmic in this population is unexpected given evidence suggesting
that omega-3 PUFAs reduce cardiovascular mortality via an antiarrhythmic effect.
Long-term feeding studies in rats have shown that a diet high in omega-3 PUFAs
significantly reduced risk of VF during acute ischemia compared with control
animals.14 In an ischemic VF model in dogs,
acute infusion of free omega-3 PUFAs reduced the risk of ischemic VF by 75%.15,16 In support of the concept that omega-3
PUFAs have direct antiarrhythmic effects are the findings that omega-3 PUFAs
change the spontaneous beating rate of cultured myocardial cells,17 prevent and terminate drug-induced arrhythmias in
cultured myocardial cells,17,18 and
can bind to and inactivate myocardial sodium channels,19 a
class I antiarrhythmic effect.
There is also evidence for antiarrhythmic effects of omega-3 PUFAs in
humans. A retrospective analysis of the Physician’s Health Study revealed
that eating at least 1 fish meal per week was associated with a reduced relative
risk of sudden cardiac death after correction for known risk factors.20 There was no association between fish intake and
the risk of myocardial infarction. When blood levels of omega-3 PUFAs were
studied in a nested case-control analysis in this same population, patients
in the highest quartile of omega-3 PUFA levels (6%-10% of whole blood fatty
acid) had the lowest relative risk of sudden cardiac death after correction
for known risk factors.7 Similarly, Siscovick
et al8 showed that cardiac arrest cases had
significantly lower intake of fish and lower levels of red blood cell omega-3
PUFAs than controls.
Four prospective randomized trials have shown that supplementation with
fish oil or other measures to increase the intake of omega-3 PUFAs is associated
with a decreased risk of sudden death without a consistent change in risk
of myocardial infarction.3- 6 The
largest of these studies was the GISSI-Prevenzione trial, in which 11 323
patients who had experienced a myocardial infarction in the prior 3 months
were randomized to receive 1 g of fish oil or placebo daily21 in
an open-label study. Total mortality and sudden death mortality were significantly
reduced in patients assigned to fish oil, with significant differences in
mortality apparent within 4 months.5 There
was no observed difference in the rate of myocardial infarction suggesting
that the reduced mortality was due to an antiarrhythmic effect of fish oil.
As a result of this evidence, the American Heart Association has recommended
2 fatty fish meals per week for the general population and 1 g of EPA/DHA
per day for patients with coronary artery disease.22 Similarly,
the US Food and Drug Administration has authorized a qualified health claim
of a reduction in the risk of coronary artery disease for food containing
EPA and DHA.23
Despite enthusiasm for the beneficial effects of omega-3 PUFAs, ours
is not the first study to suggest a potentially proarrhythmic effect of fish
oil. Burr et al24 randomized 3114 men with
coronary artery disease to a programmed intervention to either not change
their intake of fish or to eat 2 portions of fatty fish per week (patients
who could not follow the increased fish diet were given 3 g/d of fish oil
as an alternative). In this unblinded study, the risk of sudden death was
higher among the 1572 patients randomized to fish or fish oil (hazard ratio,
1.54; 95% CI, 1.06-2.23), with a more prominent effect in the subset of 462
patients given fish oil (hazard ratio, 1.84; 95% CI, 1.11-3.05). It is possible
that in that unblinded study,24 overall compliance
with cardiovascular health recommendations was poor because patients consuming
a fish diet or fish oil thought they were protected. However, this could not
have occurred in our double-blind study.
Another consideration is whether our placebo, olive oil, could have
been antiarrhythmic. This explanation seems unlikely given that animal studies
have shown that olive oil does not have antiarrhythmic properties.14 Furthermore, there was no significant difference
between the groups over time in the red blood cell and plasma levels of the
main constituents of the olive oil placebo, oleic acid and palmitic acid.
In contrast, red blood cell and plasma omega-3 PUFA levels, which have been
shown to correlate well with myocardial omega-3 PUFA levels,25 were
significantly elevated when first tested after 1 month of therapy, suggesting
that an adverse effect of fish oil was responsible for the prominent divergence
of the event curves observed over the first 90 days of therapy.
The discordance between our results and the antiarrhythmic properties
of omega-3 fatty acids in other studies may lie in the fact that experimental
models used ischemic VF as an end point and the cohort and clinical trials
showing benefit used sudden death as an end point, whereas in this study we
used ICD therapy for VT or VF as the primary end point. The end point of ICD
therapy for VT or VF certainly addresses the influence of fish oil on the
risk of ventricular arrhythmias but may not be an ideal surrogate for the
risk of sudden death. In addition, the prior clinical studies were performed
in patients with recent myocardial infarction and relatively well-preserved
ventricular function, in whom ischemic VF might be expected to be the primary
cause of sudden death. In contrast, the patients in our study were substantially
different in that they had not had a recent myocardial infarction, on average
had significantly reduced left ventricular function, and, perhaps most important,
had a history of sustained ventricular arrhythmia.
A hypothesis suggested by Leaf et al26 supports
the concept that fish oil may have its most profound antiarrhythmic effects
in the setting of acute ischemia and VF. They point out that by shifting the
voltage required to change sodium channels from inactive to activatable, fish
oil could effectively inactivate sodium channels in partially depolarized
ischemic myocardium, thereby preventing rapid spontaneous depolarizations
and reducing the risk of VF. Although the majority of patients in our study
had coronary artery disease, they all had experienced episodes of sustained
VT or VF outside of the setting of acute myocardial infarction. The mechanism
of arrhythmia in such patients, especially VT patients in whom we observed
the most clearly adverse response to fish oil, is unlikely to be ischemic
but, instead, in the majority was probably myocardial scar-based reentry.
Although sodium channel blockade of the sort produced by omega-3 PUFAs may
be antiarrhythmic in the setting of acute ischemia, sodium channel blockade
has been shown to be proarrhythmic in patients with premature ventricular
contractions after myocardial infarction.27
Our study has several limitations. Although we designed the study to
have a 92% chance of detecting a 33% reduction in event rate, the total event
rate in the placebo group and the difference between placebo and fish oil
were less than predicted. As a result, post hoc analysis revealed that the
study had only 70% power to detect a 33% reduction in event rate. This finding
suggests that the lack of a demonstration of statistically significant proarrhythmia
in the primary end point may be a function of inadequate power. However, we
cannot rule out the possibility that the observed differences are due to chance
or are the result of an imbalance in an unmeasured variable that affects the
risk of VT/VF.
This study was undertaken to better understand the previously observed
reduction in sudden death mortality after myocardial infarction associated
with fish oil supplementation. The fact that we were not able to demonstrate
an antiarrhythmic effect of fish oil does not call into question the potential
benefits of fish oil or dietary fish intake in patients who have had a myocardial
infarction.22 Instead, our results suggest
that the mechanism of benefit, if due to antiarrhythmic properties, may not
be due to the suppression of reentrant VT or VF. The lack of benefit and the
suggestion that fish oil supplementation may increase the risk of VT or VF
in some patients with ICDs can reasonably be interpreted as evidence that
the routine use of fish oil supplementation in patients with ICDs and recurrent
ventricular arrhythmias should be avoided.
Corresponding Author: Merritt H. Raitt,
MD, Portland VA Medical Center, P-3-CARD, 3710 SW US Veterans Rd, Portland,
OR 97239 (email@example.com).
Author Contributions: Drs Raitt, Morris, and
McAnulty had full access to all of the data in the study and take responsibility
for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Raitt, Connor, Morris,
Halperin, Chugh, Gerhard, Kraemer, Marchant, McAnulty.
Acquisition of data: Raitt, Connor, Morris,
Kron, Halperin, Chugh, McClelland, Cook, MacMurdy, Swenson, Connor, Gerhard,
Oseran, Marchant, Calhoun, Shnider, McAnulty.
Analysis and interpretation of data: Raitt,
Connor, Morris, Halperin, Chugh, MacMurdy, Connor, Kraemer, Marchant, McAnulty.
Drafting of the manuscript: Raitt, Morris,
Kron, Cook, Kraemer, McAnulty.
Critical revision of the manuscript for important
intellectual content: Raitt, Connor, Morris, Halperin, Chugh, McClelland,
MacMurdy, Swenson, Connor, Gerhard, Kraemer, Oseran, Marchant, Calhoun, Shnider,
Statistical analysis: Morris, Kraemer.
Obtained funding: Raitt, Connor, Gerhard, McAnulty.
Administrative, technical, or material support:
Raitt, Connor, Kron, Halperin, Chugh, MacMurdy, Connor, Marchant, Calhoun,
Study supervision: Raitt, Connor, Morris, Halperin,
Swenson, Connor, Calhoun, Shnider, McAnulty.
Financial Disclosures: None reported.
Funding/Support: This study was supported by
National Institutes of Health grant R01HL61682, Public Health Service grant
5 M01 RR00334, and Hoffman-LaRoche Inc.
Role of the Sponsors: The funding agencies
had no role in the design and conduct of the study, in the collection, analysis,
and interpretation of the data, or in the preparation, review, or approval
of the manuscript.