Heart-failure patients participating in a highly structured exercise
program in the HF-ACTION trial, reported here at the American Heart
Association (AHA) 2008 Scientific Sessions, saw no significant
reductions in all-cause mortality or all-cause hospitalization as
compared with patients getting "usual care," including
recommendations for daily exercise.

But in secondary analyses, where investigators adjusted for what
they called the "strongest prognostic factors," the structured-
exercise group did show significant reductions in the combined
primary end point, as well as in the secondary end point of
cardiovascular mortality and heart-failure hospitalization.

On these grounds, co-principal investigator for the study, Dr
Christopher O'Connor (Duke University Medical Center, Durham, NC),
concluded: "The HF-ACTION study results support a structured
exercise training program for patients with reduced LV function and
HF symptoms in addition to evidence-based therapy."

HF-ACTION randomized 2331 heart-failure patients (NYHA class 2-4,
ejection fraction <35%) to either an exercise program focused on
increasing workout intensity and duration or to usual care, in which
exercise was simply encouraged, but without specific advice. The
structured-exercise group began with 36 supervised training sessions
for 30 minutes of exercise three times per week. Halfway through
this period, patients were given a treadmill or stationary bicycle
to use at home along with a heart-rate monitor and were advised to
work out five times per week at moderate intensity for 40 minutes.
The usual-care group, by contrast, was told at the study outset to
try to exercise at moderate intensity, 30 minutes per day, as
recommended by the ACC/AHA, but were not supervised or encouraged
along the way

Taking Action

After a mean of 2.5 years, rates of all-cause mortality and all-
cause hospitalizations combined were not significantly different
between the two groups. In secondary analyses, however,
investigators used what they termed prespecified major prognostic
factors identified at the outset of the trial--heart-failure
etiology, exercise duration, left ventricular ejection fraction,
Beck depression inventory, and history of atrial
fibrillation/flutter. When the analysis was adjusted for these
prognostic factors, the composite primary end point was
significantly reduced by 11%, and a composite of cardiovascular
mortality/heart-failure hospitalization was reduced by 15%.

In a comparison of safety outcomes--such as rates of cardiovascular
events, ICD firing, hospitalization for physical activity, or
fracture of the hip/pelvis--event rates were very similar between
the two groups. "One of the most important findings was that
exercise at this level was safe," O'Connor said.

Despite missing its primary end point, said O'Connor, "The HF-ACTION
study results support a structured exercise training program for
patients with reduced LV function and HF symptoms in addition to
evidence-based therapy."

Compelling Results

Discussing the results following their presentation, Dr Philip Poole-
Wilson (Imperial College London, UK) also took the view that HF-
ACTION provides support for a more intense and structured exercise
programs.

"Some people would say, well, they missed their primary end point,
let's all go home. I think that would be very wrong," he said.

Instead, he said, the adjusted outcomes are "very compelling" and
consistent with the findings from exercise tests in the two
groups. "I think this trial does support the use of exercise, and it
will strengthen the guidelines," he said.

The problem with HF-ACTION, as with every other exercise trial, is
that convincing patients to adopt and stick with an intensive
exercise program is very difficult. O'Connor told the media that at
three years, the median minutes of exercise per week for people in
the intensive arm of the study was approximately 50 minutes and the
proportion of patients adhering to the recommended 120 minutes per
week was just 30%.

"The one thing this trial does not show is what type of exercise to
advocate, and I think we're going to see a lot of other studies in
that area," Poole-Wilson said. "Not just what sort of exercise, but
how do you persuade people with heart failure to exercise and to
continue to exercise, so that the effect does not fade simply
because the person ceases to exercise?"

Not the Old Silk Purse/Sow's Ear

Challenged during the press conference to explain how a trial that
missed its primary end point could be interpreted so positively,
O'Connor took pains to distinguish the HF-ACTION results from those
of a negative drug trial, where overemphasis on secondary end points
is roundly viewed as a no-no.

"This is not a drug, it's a lifestyle intervention, and we know that
lifestyle intervention trials are very, very difficult," O'Connor
said. "At the end of 2.5 years of a drug trial, you'd have 85% to
95% of the patients still on the drug. In a trial like this, the
amount of exercise that people were doing in the exercise-training
group after three years was in the order of 50 to 60 minutes; we
wanted them at 120 minutes. So adherence is extremely difficult."

Having said that, he continued, the hazard ratios for the primary
end point and cardiovascular mortality/heart-failure
hospitalizations were very similar for the main results and the
adjusted analysis. "In the context of this type of trial, and
because it was prespecified, it was a fair analysis," O'Connor
said. "It's probably closer to the truth when you compared patients
who were alike in risk and low risk and alike in risk and high risk."