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IACC V01 . 19, No . ?
I.," r .1"- . 603
5%
Effect of Long-Terdn Enalapril Therapy on Cardiopulmonary Exercise
Performance in Men With Mild Heart Failure and Previous
Myocardial Infarction
KENNETH DICKSTEIN, MD. STALE B.ARVIK, MD, TORBJORN AARSLAND, RN
Stora"ge" Noro ..y
Forty-one men with documented myocardial infarction >6
months previously were randomized to long-term (48 weeksi
therapy with placebo or enalapril an a double-blind basis . All
.-king concurrent therapy with digitalis and a
patients were re
diuretic drug for symptomatic heart lettuce (fundional class tl yr
111). The mean age was 64 t 7 .3 years and no patient suffered
hum exerlional cheat pain. Patients underwent maximal.
-din
pulmonary exercise testing to exhaustion on an a gameler cycle
nine times over the course of 48 weeks. Gas exchange data were
rnlleeted no a heath by breach hails with use nr a ermtinumas
ramp protocol.
in the placebo group (n = 21), the mean It 50) peak oxygen
consumption IVO3) al baseline it, IRS t 5.1 versus 18.5 ae
5 .5 mtlkg per min at 48 waeks (-I od%, p = NS). In the enamprrl
group (n = 2u), the corresponding values were 18 .1 t 3.1 versus
18.3 ± 2 .6 mllkg per min (+2 .8%, p = NS) . The mean VOa at the
Vasodilator therapy with angiotensin-converting enzyme
inhibition has an established role in the management of
symplxnalic congestive heart failure (1,2). Improvement in
clinical status (3 .4), hemodynamics (5.61 and exercise performanm (7 .8) has been demonstrated . Therapy is associated with a reduction in the mortality rate associated with
piogressive congestive heart failure in patients in New York
Heart Association functional class IV (9) . However. the
effect of long-term therapy eat the functional capacity of
patients with mild heart failure has not been sufficiently
addressed . Most trials (10) have included patients in functional classes 11 to IV with heterogeneous causes of failure
and the sample size was usually too small to permit proper
analysis of the subset with mild heart failure . Few trials 111)
have included objective measurement of functional capacity .
Evaluation of the functional capacity in patients with
heart fail ire may be accomplished by assessment of perfor •
anaerobic threshold for The placebo group at baseline study was
13 .1 t 1.5 versus 12 .6 t 2.1 mV kit per min at 48 weeks i-2.2%,
p = N51 . The corresponding values for the enalapril group were
11 .8 t 23 versus 11 .8 ±2.4 mlkg per mini +1 .4% . p = NSt. The
mean tetnlexercise duration In the placebo group at baseline study
was 589 t 153 snout 620 ± 181 sat 48 weeks (+5.4%, p = NS).
The corresponding values for the enalepril group were 614 t 119
versus 632 ± 120 s (+3.599, p = N'S) .
There were no significant intergroup differences at any time
VISa, V0i at the anaernbk threshold err
eseecse duration. 1-snQ-term anginlensince nerting enzyme inhibition with enalapril in men with mild hart failure after
myocardial irfarelirn was not associated with signi8ant improvement in peak or submaximal rardiopatmanary exercse peefermartce.
(I Am Corl Cardiet 1991 ;18.. P1~6dA
with regard In peak
mane during exercise 112) . Cardiopulmonary exercise testing permits objective determination of peak oxygen consumption (V0,) (13) and VO 1 at the anaerobic threshold (14).
This technique provides a sensitive tool for evaluating the
effect of a therapeutic intervention on functional capacity
(15) . Therapy with diuretic drugs (16), inetropic agents (17).
vasodilators (18) and exercise training programs 119) has
demonstrated improvement in peak VO, in patients with
symptomatic heart failure.
We tested the hypothesis that chronic angiotensinconverting enzyme inhibition would improve the cardiopulmonary exercise performance of patients with mild heart
failure_ Forty-one men with documented myocardial infarction. requiring therapy with digitalis and a diuretic drug for
symptomatic heart failure. were randomized to concomitant
placebo or enalapril therapy . Patients underwent nine maximal cardiopulmonary exercise tests over the course of 48
weeks .
From the Tardioto;y llwmon. Medical Depanmeel . Central Hospital in
Roseland . Sta - anler. Norway . This study was supported by a grant tam.
Methods
Merck . Sharp A poame Research tabotatornes, west Point. Penrsylsania
and MSD-ono- en . Norvoy.
Manuscnpt received October 17 . 1990: revised nanmetipt received
January 21 . 1991, accepted February 10. 1991,
Add- for ,e vdols: Kenneth Dickstein, MD, Cardiology Division,
Medical Ikpmment . Central 8ospital in ttogabod . Stavanger.4011 Norvay .
0195, by
Studypalicnts. Forty-onemenwith deeumentedmyueardial infarction (>6 months before inclusion) and peak oxygen consumption (VO,) <25 mIkg per min were included in
the study . Myocardial infarction was confirmed by conven-
s nm.dco.,cv usg.nrCa<di5,1my
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r,Tlr'r09alYI ta .5ln
IACC Vat. Ix . No . 2
nun- ISNI - SW,_rA2
DICKSTEIN ET AL.
ENALA!'HII. AND EXERCISE IN CONGESTIVE HEART FAILURE
Cllrrical Chart tretrtlosaid Baseline Compamblhty of
41 P gents
Trenmemcrn1p
Tehk I .
hgr 11>
Syslalic BPI .. Hgl
Dmsmlic HI'Imm 14g1
Bell heart rare lb,S111.ifl
Plaeeh"
yr-7r
m . 17
79 14
Weight Ikgl
Prom n,a MI
Q .- Ml
Angrier MI
Peek CK Minn
Prak ^.SAT IUlIiler
Peak LDH NAiten
Redingmphie hoots sir tuna,
Echo UV ammeter IInml
>Ia1 PIC'day 0
24 h EEL[
Peek VQ Imikg per mint
AT V0, 1
.14g per mint
Learning dcralian Ia1
R IVCOJVO, I
19
la
35x
I aax
972
c
`
-
III)
194
907
129
EnelapnI
61, _ ,
115 c 17
xl_<
79 I e
xI
I1
F
Il
C
III • WK
291 e7 hi
I 'Ih t -A5
1_'5
re
n
nbII
13 1
549 ,
1,111 m
I
1 .5
753
a l4
,
Is
Ig .1 _ 1 I
II :-1s
1 • 119
12:1 = 11.10
Hale are rcprnted as
mete- ` SD . A S.AT - arpartare em
Iransrernae.AT VU, = osrgen onsepaon a, 1,e --b,, ih-Ud RP
blood pressoro: CKH = creative knee, ECG = ttrrIn dmgrarr Echo =
echocardiographic: LDH = lanalc dchydmgcnaac : LV = left rtinmalar.
MI = myocardial in6vetion : PVC= premanre •enoxular comyeser . R
rupiraory exchange ratio : VCO, = carbon dioxide elimvooion : VCI, _
oxygen consumpttan .
lional clinical, electrocardiographic IECG) and biochemical
criteria . The mean (s- SD) age was 64 - 7.3 years and re
patient suffered from exertional chest pain . All patients were
in sinus rhythm and concurrently treated with digitalis and a
diuretic drug for symptomatic heart failure . No patient was
receiving concurrent beta-adrenergic blacker therapy . Concurrent use of ant arrhythmic agents was permitted . : vc
patients received quinidine and four received disopyramide .
Fourteen patients were taking a long %cling %hole and fear
a calcium channel blacker . Thiriy-six patients were in New
York Heart Association functional class 11 and See were in
class III . Approximately 5g patients were screened and 41
note included in the study . The screening process was
selective in that patients with pvslinfarclian anpra or
marked symptoms of congestive heart failure were not
eligicle for screening . A detailed description of the clinical
characteristics of the study group is provided in Table I No
smtistically significant intergroup differences were found
Study pratnenl. The screening exercise protocol was
based on a conventional format with stepwise 25-W inerements at 3-min intervals . All further testing was based on a
continuous ramp protocol . Only candidates able to perform
exercise until exhaustion on the cycle ergometer were m .
eluded . Patients with exertional chest pain . >0 .2 mV ST
segment depression on the ECG or peak VO, >25 mltkg per
min were excluded . Before inclusion, patients underwent
routine spirometry to rule out clinically significant respira-
597
lore dysfunction . Informed consent was obtained from each
patient and the study protocol was approved by the Regional
Ethic% Committee at the University of Bergen and the
Norwegian State Drug Regulatory Agency in January 1987 .
Eligible patients were screened a minimum of 6 months
after myocardial rotor tiort and randomized I week later .
Uunng the run-in week, all patients underwent three maximal cardiopulmonary exercise tests (one screening and two
baseline), chest X-ray study, echocardiographic examination
and a 24-h ambulatory ECG . After randomization . patients
underwent exereinc testing at 4 . R . 12.
and 48 weeks.
Dosage schedule . During a 1-week run-in period . all patients received single-blind placebo therapy . At randomization . patients were assigned to either enalapril 110 mg once
daily) or matching placebo in a double-blind manner . After 4
weeks . in patients without symptomatic hypotensian or an
arterial systolic pressure <90 mm Hg, the dose of enalapril
was dtraIed to 20 mg once daily . Patients continued to
receive the dosage of digitalis and diuretic drug prescribed
bel'ore inclusion. Potassium supplementation was administerrxd according to the results of frequent biochemiaty
evaluation . Concurrent therapy with antiarrhythmic agents
was permitted .
Exercise testing prctocol- Testing occurred approximately 2 h after a light meal and always between 2 and 6 h
after ir-, ;ion of the test medication . The exact timing
interval was not standardized, Studies were performed using
an apriuril . electrically braked, cycle argameter (Mijnhardt
model KEM 111). After a 2-min rest on the cycle, patients
began pedaling at a rate of approximately (5 rpm at a work
rate that was programmed to increase smoothly by 15 W/min
according to a continuous ramp protocol .
Purirrltr Irrere instracted iv coercion maximally to syrnprnrnnrir, cuJ paints . A modified Burg scale was employed to
facihtatc communication with the patient with regard to
symptoms . A 12-lend FCC (Kane 620) was interfaced and
heart rate recorded continuously . Systolic blood pressure
was measured with a manometer cuff every 3 min .
Exrrrise and gas exchange data here collected continua
(Firth• with an automated breath by breath system manufactared by sledical Graphics Cmpomdon (System 201111) based
on methods previously described by Beaver et al . 1201 . In
this system . a clamp is placed on the hose and the patient
hreathes through a mouthpiece attached tea nonrebreathing
valve . Air is removed from the valve at a constant rate of
!75 mlimin and delivered to the oxygen and carbon dioxide
analyzers. The method utilizes a distributive processing
technique inv'olv'ing a waveform analyzer and a host eamputer . Expired flow, carbon dioxide and oxygen are measured with use of rapid responding discrete analyzers (a
prteu motachometer and a variable reluctance pressure transducer for flow, a dual-beam infrared absorption chamber for
carbon dioxide and a permanent zirconium oxide-based
electrochemical cel! for oxygen . These instruments were
caltbrated before every test with use of a standard 3-liter
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598
Al
FNALAPRII. AND I XI:RC'ISF IN CONGESTIVE HEART FAILURE
Nn . 2
Aupmt199159fi-fi )'
OI('85T FIN El
IACC V.I . I8.
Teble 2 . LaLorulory Results in 41 PJllenls
Treatment Group
Placeho
Hemoglobin IFIlurl
w'Iu 1111^'Incr/
PlAdd, I Ill' 1lerl
CreutimnelmmaVlnhl
ASAT ILTiterl
Al AT IL .28*1
(,t otr ImmoI hIeo
Chnlesteml found liter)
'Inglycerides ImmoPlherl
Grit ntid Immorinty
Salwmlmmolihlcn
n l',, jam Immnlnilcrl
Chlor & Immnhlnol
11a1o aw reported as ratan ,ohm,
mhrraShr*' jinn, gain Tahlc I
Endopril
W,;? ,
Bmelint
14.7 ] 1 .2
14 .5 t 0.5
49 a 1 .1
Bu.Seline
14.1 _ 0 .9
hR a 1 .1
48
'41
23G r 71
III 11
39 59
57 115
S 9 ± 1 .1
hI
a, e'-2
34 39
A1 -91
S .7 * I .^-
6,9 z 1 .5
_
405 m
its
1411
4 .1 2 0.4
IIMI_'_
SO. AI . AT
syringe and precision reference gases and were corrected for
barometric pressure, ambient temperature and humidity .
Exercise end points . Total exercise duration was recorded from the start of exercise to the point where the
patient was unable to maintain a constant pedaling rate . Peak
VO, was calculated as the average VO, value over the final
20-s period of exercise.
A eanrpurerized algaralan Iran developed to approximate
the manual modified V slope method of anaerobic threshold
detection (21 .22). With this algorithm . carbon dioxide elimination (VCO,) is plotted against VO, on equal axes . The
anaerobic threshold is located where the rate of rise of VCO,
is greater than the rate of rise of VO, . coinciding with an
increase in the slope of >1 . This increase in the slope results
from accelerating VCO, and indicates that bicarbonate buff.
ering of lactate is occurring (23). We (24) have demonstrated
that this technique is rrpruducible and corresponds well to
the lactate threshold .
The manual method employs a 45' triangle that is brought
in from the right, parallel to the VCO, versus VO, plot . This
facilitates detection of the inflection occurring with a slope
>1 . The computer program (22) automates this method and
analyzes the subset of the plot with a work rate >5 W and a
respiratory exchange ratio <I . This subset of data was
chosen to minimize the obscuring effects of the hvperventiIRIiun response at the onset of exercise and the respiratory
compensation that usually occmsjust before termination of
peak exercise. A line with a dupe of 1 (S I) is drawn through
the plot so that 5% of the data points lie below the line . The
ventilatory anaerobic threshold is detected at the last inflection of the VCO, versus VO, curve from S1 .
Statistical methods. Nonparametric statistical methods
were used to analyze continuous variables . Before treatment . the rank-sum lest was used to compare the treatment
groups and the signed-rank test was used to test intragroup
h .9 a L7
48
239 ` m
105 . 14
24 * 7
18 17
SS 1 .1
72 a I .]
M1.9 z 1 .7
23 . Lh
2.4 0 1 .9
424 ± 91
108 ± 1 :4
139U'_
41 *_ 0.1
4.9 `_ III
11x3
91) ' 3
olanine ommn Imn,rcmac' WRC = while hlnod
week,
14 .8 4 i .1
h .5 0 L4
229 2 45
106 x IS
24 r 6
'23 8
5 .5 1
7 .3 2 1 .1
2 .1 x L2
409 r. 128
141 _
4 .30.
'_ 4
99 '_ 3
cell mon1 ;
changes from pretreatment values . Differences between the
treatment groups with respect to changes from pretreatment
in continuous variables were tested by using nonparametric
analysis of covariance models . After rank transformation of
the dependent variable, ordinary parametric analysis of a
covariance model was employed .
Fisher's exact test was used to compare the treatment
groups with respect to dichotomous variables • such as the
presence or absence of a specific adverse experience or a
physical examination abnormality . The Wilcoxon rank-sum
test was used to compare treatment groups with respect to
ordinal variables . All values are reported as mean values
y SD.
Efficacy analyses for each time period were based on the
per-protocol approach . Only patients with data both at
baseline study and at the specified time were included . The
second of the two baseline tests was used for all analyses to
assure familiarity with the testing procedure and minimize
training effect . Although the data were analyzed for each
separate test during the trial, no formal adjustment to the
p values for these multiple comparisons was made . This fact
should be taken into account when interpreting the results
Results
Patient group characteristics and exercise performance
(Tables t and 2) . The groups were found to be comparable at
baseline study with regard to clinical characteristics and
exercise performance (Table 1) . The exercise variables were
reproducible . The mean peak oxygen consumption (V0) in
the first baseline test was 18 .4 '_ 4 .4 versus 18 .7 '_ 4 .6 mllkg
per min in the second baseline test. The mean difference of
the change between baseline tests was 0 .29 mllkg per min
with an SD of . 1 .65 and a Spearman correlation coefficient
of o.91 .
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1)ICKSTEIN ET AL .
I-Ski :AYnlLANI)I .ki .nitNEINCONGESTIVEHt'ARTFAILCRE
WC VA . IS. Nn
Aug-11 . : :WI, nit
Tahk 3- Exercnc Result, in
41
Polienls
11 v-k .
1
Yeak VU .Imrkp per min .
Ylacebn
Enalapril
Vu; w AT Iml kg no mini
INS - S'
IN I - I I
IN .lr1 .1
IN .I
I niRvcimv'
1 I A c
IIk • t 4
- 1 4
nutalion Il l
Ylncchu
Sd9 ' ft
1511 • iCl
.sI
ILrninpnl
hll - II'1
.I' - I_'ll
1
~Ic
FIr.IV I
nlncren«
•
,
repwred as m- vahc,
airnlnlrd
599
mom „~I~~mpnernl ~h.,E,, . trio
5i1) p - . vS In, .II s :si15
Ihnshold . Nlher athre5raauu, m in 1,hi,
A1
. nn,ern1
I
. Norm peak oxygen consumption NO .) (--SDI for 21
Ilacehu ( reated tupen drelesl and 20 enalapril-troatod Irlosod circles)
paticms over II weeks .
Swum
A1141 patients completed the study as per protocol. There
was one death due to recurrent myocardial infarction in the
placebo group ; no deaths occurred in the enalapril group .
The study was discontinued in three patients, all receiving
placebo . because of possible drug-related adverse experiences . The average dose of enalapril was 18 .75 mg . No
significant intergroup differences were observed during the
trial with regard to overall evaluation or functional class . At
baseline study . 36of the 41 patients were in New York Heart
Association functional class 11 and 5 were in class 111 . At 48
weeks, 37 patients were in class 11 and 3 were in clal' 111 .
There were no significant differences in body weight or
rest heart rate between the placebo and enalapril groups
during the study. Peak heart rate for the placebo group was
135 - 14 beatsanin at baseline compared with 132 x 14
bealstmin a148 weeks. In the enalapril group. peak heart rate
was 139 ± 16 at baseline versus 139 - 211 beats/min at 48
weeks. Systolic blood pressure increased by 7 .7- 15 mm Hg
in the placebo group and decreased by 3 .2 x 19 mm Hg in the
eaalaprrl group Ip : 0.011 . There were no significant differences between groups with regard to any of the laboratory'
variables measured during the course of the study . Specifically . serum creatinine and serum potassium showed no
significantintragroup change (Table 2tPrakandsubmavlmnlexerclceperformance Table 3i . Nu
statistically significant differences were Found between the
placebo and enalapril groups at any time with regard to peak
nr suhmaximal exercise performance variables . The peak
respiratory exchange ratioIVCQ/VQl was 1 .2 s 0.15 in the
placebo group and 12 - 0.08 in the enalapril group . This
confirms that effort was both adequate and comparable- In
the placebo group . the mean peak VO_ at baseline was 111 .8
± 5.2 compared with 18 .' 5 .5 mhkg per min at 48 weeks
I-1 .415 . p = NS) . In the enalapril group, the corresponding
values were 18 .1 . 3 .t compared with 18.3 - 2 .6 ml/kg per
min 102 .815 .p =NSI(Fig .II.
The mean VO, at the anaerobic threshold for the placebo
group at baseline was 13 .1 ` 3.5 versus 12 .8 ' 2 .1 mhkg per
min at 48 weeks p -= NSI . The eonespon''ing values
for the enalapril group were 11 .8 - 2
.3 versus 11 .8 -
'_A mhkg per mini-1 .49 . p - NS) IFig . 21. The mean total
exercise duration in the placebo group at baseline was 589 ±
153 census 620 - 181 sat 48 weeks 1+5 .49., p - NS) . The
currespundil .g values for the enalapril group were 614 ± 119
versus 632 - 120 s (r3 .5Y . P - NS) (Fig. 3) .
Discussion
Role of renin-angiolensin system in heart failure. Excessive vascular resistance is characteristic of patients with
reduced functional capacity due to inadequate delivery of
blood to exercising tissues (25) . The renin-angiotensin system is mar' wily activated during both moderate and strena s exercise in patients with mild heart failure 126) . This is
especially true fur patients on long-term diuretic therapy
1171 . Specifically . the angiotensin II response at peak escrow is particularly great in relation to the renin increase .
This response may be due to either increased production or
decreased degradation 1281 and may contribute substantially
Finite 1. Pleas csyur eoosaniplioim VI),) ai thu anaerobic thrush'
old Is5D1 Per 21 placebo-Ireated (open circles) and 20 enaletpriltrected 111 61 patients aver 48 weeks .
30 1
s
0
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Weeks
U[CKSTFIN FT AI.L
nNALAPRIL AND EXERCISE IN CONGESTIVE HEART FAILURE
000
840
reo
720
ado
ego
540
4t0
420
jag
300
0
4
a
12
24
as
48
WeBM.
csero iw durxr1nn (±Sn) for 21
20 enalapril-booted Nosed eiedesI
Figure 3 . Moon told
tapencirrkd and
weeks .
placebo-vealrd
patients aver46
to the attenuated vasudilatur reserve in skeletal muscle
observed to patients with heart failure (29,30) . Angiotensinconverting enzyme inhibition may partially correct this
pathophysiologic response (31) . improve vasodilator capacity (32) and increase muscle blood flow (331 . In addition,
long-term therapy has been shown to reduce the marked
increase in adrenergic tone that accompanies exercise in
these patients and further compromises tissue perfusion 1341 .
We therefore hypothesized that long-term angiotensinconvening enzyme inhibition might improve the ability of
skeletal muscle to extract oxygen at peak exercise and delay
the onset of anaerohinxis .
Effect of enalapril on exercise performance in mild versus
severe heart failure, We were unable to detect any dilfercnces between the effects of enalapril and placebo on the
peak or submarimal cardiopulmonary exercise performance
of men with mild heart failure after myocardial infarction .
This trial was not designed to evaluate the effects of longterm angiulensin-convening enzyme inhibition during the
acute or convalescent phase . We chose to limit the study
group to patients with confirmed myocardial infarction 6
months previously to obtain a relatively homogeneous group
of patients and minimize the contribution of deconditioning
to exercise impairment .
Appropriate interprekation of the results requires a careful
analysis of the study group . All patients were symptomatic
(functional class Il or 111) and in sinus rhythm . Patients were
judged to be clinically stable before inclusiu0 on their current
dosage of digitalis and a diuretic drug . No formal attempt to
withdraw these agents in order to establish their necessity was
included in the screening procedure. It is therefore likely that
some of the patients did not require diuretic therapy to prevent
symptoms of congestive heart failure .
The mean ecltocardiagraphic internal' dimensions indicate left venlrictdar dilation and imply systolic dss(unrrion .
However, information regarding ejection fraction was not
available . At the screening echocardiographic examination,
JACC Vol. 18, No. 2
August 1491 :596-d 2
28 patients were classified as having a moderate left ventricular wall motion abnormality and 13 patients were found to
have a severe wall motion abnormality .
Although patients had a peak oxygen consumption (VO,)
of < 25 mlikg per min on inclusion in the study, the baseline
mean peak VO, values (18 .8 . 1 2 mtlkg per min in the
placebo group and 18.1 t 3 .1 mllkg per min in the enalapril
group) indicate only mildly reduced exercise capacity. It is
likely that these ratients were well compensated hemodynamically with only mild left ventricular dysfunction . The
sample size did not permit prospective subset analysis
according to infarct type or location . Thirty-six of the 41
patients had a Q wave infarction and 24 had an anterior
infarction.
Convincing evidence (35.35) exists confirming symptomatic and functional improvement in patients with functional
class III or IV heart failure treated with angiotensinconvetting enzyme inhibi .ors . However, the evidence in
patients with mild heart failure is insufficient to permit
routine use of these agents. Several trials (3,16,37,38) have
demonstrated improved exercise performance in patients
with mild to moderate heart failure . A few studies (8,39)
have demonstrated improvement in patients with a peak VO,
comparable with values observed at baseline study in our
trial .
Maximal cardiopulmonary exercise testing . This method
is safe, noninvasive and has been shown to be a valuable tool
in the clinical assessment of functional capacity (II) and
prognosis (40) . It is our experience that peak effort can be
more readily achieved in male subjects and therefore only
men were included in this trial . We limited the study group to
patients with confirmed myocardial infarction to obtain a
homogeneous group of paskItts and to permit better definition of the clinical implications of the results . It has been
demonstrated that peak oxygen consumption can be reliably
achieved in patients with coronary artery disease (41) and we
(42) have shown that the results are highly reproducible in
such patients.
Ventricular function and exercise performance. Thu lvngterm hemodynamic response to angiotensim-converting enzyme inhibition cannot he reliably predicted `ron, the initial
short-term response (43) or from the baseline hemodyvem
[441 or neurohumoral status (45) . Noninvasive and angio.
graphic measurements of ventricular performance fail to
predict exercise performance (25) . Exercise capacity in the
presence of a low ejection fraction may be preserved by the
augmentation of stroke volume by elevated filling pressure,
preserved chronotroptc competence and increased oxygen
extraction by skeletal muscle (46). Objective measurement
of functional capacity requires assessment of the appropriate
physiologic variable, namely, oxygen uptake .
Although peak exercise results are readily determined,
controversy exists regarding the most appropriate method
for assessing submarimal exercise variables (47) . Progressive lactate accumulation reflects anaerobic glycolysis with
increased conversion of pyruvate to lactate (48). The deflec-
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Ia . No. 2
Aupu,t iv91 :5%-fiat
[ACC Vu1 .
E NArAPrtIL AND P
lions in the respiratory exchange ratio IVCO,dVO.l ]ureely
reflect the bicarbonate buffering of lactic acid (49) . The
method chosen for anaerobic threshold analysis in this trial
is based on the underlying physiology with detection of the
increase in carbon dioxide elimination (VCO,) as a function
of V0, 130) . This method has been validated against the
lactate threshold with use of conventional le :hniyues 1711 .
'[here was no significant intergoup difference in
exercise
performance observed at any rime during the course in this trial
in patien€% with mild but syruplomate congestive heart failure .
Despite repeated lestingand increa* - an familiarity with the test
procedure, neither placebo nor active therapy resulted in
increased peak VO,, increased 0, at the anaerobic threshold
or increased exercise duration compared with baseline values,
Not all trials 151 .521 of angioteasin-eoneerting enzyme inhibition in patients with mild congestive heart failure have demonstrated improved exercise performance . The clinical importance of apparently negative results is obvious 153) . Further
investigation is required to more correctly profile patients
likely to benefit from such intervention (541 .
Comparison with previous studies . Attention has recently
focused on this issue. In a study 1551 of asymptomatic
patients with an ejection fraction "'SS5 randomized to
eaptopril or placebo therapy in the early convalescent stage
after acute anterior myocardial infarction, a difference of
44% in total exercise duration was observed between patients treated with active drug versus placebo . This improvement on therapy was observed only in the subset of patients
with increased left ventricular volumes and severe wall
motion abnormalities . As expected . the degree of activation
of the renin-angiotensin-aldosterne system in these patients
was correlated with the presence of loop diuretic therapy .
However, this neurohurnoral activation was also correlated
with the presence of Killip class >2 . >30`1 left ventricular
wall akinesia and left ventricular aneurysm 156) .
Similarly . the baseline neurohumoral data from the Studies of Left Ventricular Dysfunction ISOLVDI 1571 indicate
that although neurohumoral activation occurs early in
asymptomatic patients with an ejection traction <35rir (prevention arm). this is primarily limited to activation of the
sympathetic nervous system and the release of atria) nairiuretic factor and arginine vasupressin . The renin-angintensin-aldosterone system becomes active at a later stage and
only when symptomatic heart failure is established . especially in the presence of diuretic therapy (Ireatment arm) .
Our data arc compatible with these recent findings . Only
13 of our patients had echocardiographic evidence of severe
left ventricular dysfunction . The mean peak VO, values at
baseline were only 2 miikg per min less than the mean peak
VO, values at baseline in the SOLVD prevention arm 15A t . It
is likely . therefore . that very few patients in our study had
substantial activation of the renin-angiotensin-aldosterone
system .
Clinical implications . Is a therapeutic trial with angiotensin-converting enzyme inhibition appropnatc in patients
with mild heart failure (591 1 Our trial addresses this issue .
v EXCISE
DICKSTEIN ET AL.
IN CONGESTIVE HFART FAILURE
601
All of uur patients had documented myocardial infarction
and were being treated for symptomatic heart failure . All
patients completed the trial per protocol . Nine tests over the
course of 48 weeks increased the power of detecting a
treatment effect . The high peak respiratory exchange ratios
confirmed peak effort . The gas exchange studies were perhuntedith rigorous detail 122 .24 .421. The mean peak VO,
values indicated mildly reduced exercise capacity compatible with functional class 11 (H)I .
J he results of this trial suggest that long-term angiotensin-converting enzyme inhibition will not improve peak or
suhmaximal exercise variables in men with mildly reduced
exercise capacity after myocardial inlirctian . Further attem
(lon should be directed toward evaluating the efficacy of
angiotensin-convr_ ;titlg enzyme inhibition in patients with
moderately reduced exercise performance in an attempt to
correctly profile patients likely to respond favorably .
we truthfully aeknnn9edge Steven Snapinn . PhD. Merck Sham & Dohme
Ro,cach Lahoratones . for expert a,sisance in data management and statisF,al ana]y,i,. The technical asstsumot of Kurt Tjclle, RN and the secretanal
e,,,,wau ~r Hdle Snares were essential .
I
2.
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