Aspirin Worsens Exercise Performance and Pulmonary Gas Exchange in Patients
With Heart Failure Who Are Taking ACE Inhibitors

	September 4, 1999 - Poor lung function adds to exercise disability
in CHF patients. Impaired pulmonary gas transfer is one of these problems.
ACE inhibitors improve diffusion for carbon monoxide and exercise capacity,
an effect that seems to be mediated through prostaglandin activation since
it is inhibited by aspirin (cyclooxygenase blockade). This suggests that
aspirin may lower lung function and exercise ability in CHF in those patients
taking ACE inhibitors.
	A dose of 325mg aspirin was given daily for 8 weeks to 26 patients
with DCM (dilated cardiomyopathy) in class 2-3 CHF. Two groups were formed.
Group one (18 people) was patients who were taking an ACE inhibitor in
addition to digoxin and Lasix. Group 2 (8 people) was patients who were not
taking an ACE inhibitor with their digoxin and Lasix. During the study, group
1 took 10mg enalapril (Vasotec) twice a day.
	Results: Tests repeated at 8 weeks showed that aspirin was
deleterious in group 1. At rest carbon dioxide, peak exercise oxygen uptake
(VO2 max), and tidal volume levels were lower in this group. This was not
seen in group 2. However, once this part of the study was completed and
enalapril was included in their therapy, similar effects were seen in group
2.
	Conclusions: Aspirin does not affect lung function in CHF patients
NOT taking ACE inhibitors, but it lowers pulmonary diffusion for carbon
monoxide, VO2, and the ventilatory response to exercise in CHFers taking ACE
inhibitors. Whether the same may be true of smaller aspirin doses was not
tested.

Long version:

	Bradykinin-mediated prostaglandin manufacture is susceptible
to cyclooxygenase blockers such as aspirin. CHF is an example of
prostaglandin synthesis activation, and some of the benefits of ACE
inhibitors in CHF patients may be interfered with by cyclooxygenase blockers.
	Because difficulty breathing is a major cause of exercise disability
in CHF, we wondered if aspirin disturbs lung function in CHF patients taking
ACE inhibitors. We gave aspirin to CHF patients whose current therapy did
include an ACE inhibitor and to another group of CHF patients whose current
therapy did NOT include an ACE inhibitor.
	Patients - Patients with a history of smoking or who had received
aspirin in the previous 3 months were not included. Group 1 was 20 patients
with stable class 2-3 CHF caused by idiopathic cardiomyopathy, who were
taking an ACE inhibitor, with an average age of 61. Group 2 was 8 similar
patients, with an average age of 64, who had not taken an ACE inhibitor in
the previous 3 months. Two patients in each group were women.
	Lung Function Tests - Measurements of forced breathing out volume in
one second (FEV1), vital capacity (VC), maximal voluntary breathing (MVV),
and diffusing lung capacity for carbon monoxide (DLCO) were taken.
	Exercise Testing - Patients did a bicycle exercise test. Respiratory
gases were measured. A ramp test was used with the ramp rate aiming for a
test duration of 10 minutes. Exercise was stopped when the patient was unable
to go on due to shortness of breath or fatigue. Carbon dioxide, oxygen and
volume were measured at rest and during exercise. Oxygen consumption at peak
exercise (VO2 max) was measured.
	Hemodynamics - An echocardiogram measured right ventricular systolic
pressure and left ventricular EF.

Study

	50% of patients in groups 1 and 2 were in class 2 CHF. The remaining
patients in both groups were in class 3 CHF. Two patients in group one did
not complete the study for personal reasons and their data were not included
in the results. In the 2 week run-in period, each patient was twice tested
for lung function and maximum exercise; once at the beginning and once at the
end of run-in.
	Lasix and digoxin were continued in both groups. The ACE inhibitor
used in group one was 10mg enalapril twice a day. After run-in, 325mg
aspirin was given for 8 weeks. At the end of this period, lung function and
maximum exercise tests were repeated.
	After completion of this part of the study, 10mg enalapril twice a
day was added to group 2's therapy. These patients repeated lung and exercise
testing after 3-5 months, during which treatment was kept constant. Then
325mg aspirin was added and re-evaluation done in 4 weeks.

Results

	There were no group differences at baseline, and DLCO level in group
1 was the ONLY variable that worsened with the addition of aspirin. On this
basis, we decided that aspirin was deleterious when added in the presence of
enalapril and that aspirin was not deleterious when given in the absence of
enalapril.
	The effects of aspirin in group 1 were a decrease in exercise time,
peak exercise oxygen uptake and tidal volume; and an increase in the relation
of minute ventilation to carbon dioxide production. The variations were not
associated with changes in peak exercise heart rate, blood pressure, or
oxygen uptake per heart beat (oxygen pulse).

Discussion

	This study suggests that aspirin lowers ventilatory gas exchange and
exercise capacity in CHF patients taking ACE inhibitors.
	In chronic CHF, the extra production of vasodilating prostaglandins
attenuates neurohumoral activation and counteracts vasoconstriction induced
by angiotensin 2, norepinephrine, and endothelins (Jon's note: all 3 of these
natural vasoconstrictors are being countered by other CHF drugs either now
in use or now in trials). Cyclooxygenase inhibition causes a loss of these
counter-regulatory mechanisms. Although a prostaglandin-mediated activity
seems to be a common mechanism of action of some drugs, including diuretics
and nitrates, ACE inhibitors potentiate the cascade of this system.
	This study addresses the relevance of a potentiation of these
mediators through ACE inhibition, and of a counter-action such as may occur
when aspirin is added, in the presence of left ventricular dysfunction.
	The 2 groups had similar conditions, EFs, lung function, and right
ventricular systolic pressure. That inability to show an effect of aspirin in
patients not taking ACE inhibitors may have been caused by the small number
of patients studied is disproved by the occurrence of inhibition when aspirin
was reintroduced with enalapril.
	With inclusion of ACE inhibitor therapy, a decline in pulmonary
diffusion was seen with aspirin. When patients were taking ACE inhibitors,
lung gas exchange was also depressed by aspirin. Tidal volume during exercise
was reduced. It seems that in CHF patients taking ACE inhibitors, lung
prostaglandin production is enhanced and its inhibition with aspirin is
deleterious.
	Figuring out the practical significance of this effect of aspirin
on ACE inhibition is not easy. Aspirin IMPROVES outcome in the acute phase
of unstable angina or heart attack and is a cornerstone in prevention of
stroke. ACE inhibitors IMPROVE survival rate, quality of life, and exercise
performance in patients with left ventricular dysfunction. However, an
analysis of the CONSENSUS II trial supports the finding that emerged in the
SOLVD trial - that the survival rate curve was different when analysis was
done according to aspirin use or non-use in patients taking ACE inhibitors.
	Hall et al showed an attenuating action of aspirin on acute
hemodynamic changes with enalapril. Other studies, however, have pointed out
that the vasodilating effects of ACE inhibitors are related to blockade of
the angiotensin system and that a contrasting effect on vascular resistance
remains controversial. This exercise study shows that aspirin subtracts the
beneficial action of ACE inhibitors on peak VO2.

Limitations

	Our interpretation of findings in this study is weakened by lack of
measurements of plasma prostaglandins. These compounds have a half-life less
than 3 minutes and are not reliably measurable.

Conclusions

	This study indicates that cyclooxygenase prostaglandin blockade with
aspirin does not affect ventilation and oxygen consumption during exercise in
CHF patients NOT taking ACE inhibitors but worsens lung diffusion capacity
and makes breathing changes during exercise (tidal volume, ventilation to
carbon dioxide production) less effective in those who DO take ACE inhibitors.
Whether a lower dose of aspirin would show such an antagonism remains to be
seen.

Marco Guazzi MD, Gianluca Pontone MD, Piergiuseppe Agostoni MD

Am Heart J 138(2):254-260, 1999