Download Coenzyme Q10 as an Adjunctive in the Treatment of Chronic

Journal of Cardiac Failure Vol. 1 No. 2 1995
Coenzyme Q10 as an Adjunctive in the Treatment of
Chronic Congestive Heart Failure
CLAES HOFMAN-BANG,
KARL SWEDBERG,
HANS ~STROM,
MD,* NINA REHNQVIST,
M D , PhD,~: I N G E L A W I K L U N D ,
M D , PhD,J"
M S c , PhD,~:
M D , P h D , * F O R T H E Ql0 S T U D Y G R O U P §
S~ockholrn, Danderydl, Gothenburg, Sweden
Abstract: Seventy-nine patients with stable chronic congestive heart failure were random-
ized into a double-blind, crossover placebo controlled study with 3-month treatment periods,
where either 100 mg coenzyme Qm (C°Q10) or placebo was added to conventional therapy.
Mean patient age was 61 -+ 10 years, ejection fraction at rest was 22% _+10%, and maximal
exercise tolerance was 91 + 30 W. The follow-up examinations included ejection fraction
(primary objective), exercise test, and quality of life questions. Ejection fraction at rest, during a slight volume load, and during a submaximal supine exercise increased slightly compared with placebo: 24% _+12% versus 23% _+12% (NS), 25% ___13% versus 23% _+12% (P
< .05), and 23% _+ 11% versus 22% _+11% (NS). Maximal exercise capacity increased from
94 _+31 W during the placebo period to 100 _+34 W during the CoQ10 period (P < .05). Total
score for the quality ef life assessment increased significantly from 107 _+ 23 during the
placebo period to 113 :._-22 during the CoQ~0 period (P < .05). The results indicate that oral
long-term treatment wkh 100 mg CoQ10 in patients with congestive heart failure only slightly improves maximal exercise capacity and the quality of life and that the clinical importance
of this needs to be further evaluated. Key words: heart failure, coenzyme Qx0, clinical trial.
It has been suggested that the remaining pool could serve
as a scavenger, protecting the cell from lipid peroxidation
caused by free oxygen radicals. Coenzyme Q10 protects
the ischemic myocardium 7 and acts as a membrane stabilizer, as well as an indirect stabilizer of the calcium channels of the membranes. 8
The myocardial content of C o Q I 0 is lower in patients
with severe heart failure than in those with mild heart
failure. 4 In hopes of avoiding any rate-limiting effects
from CoQ~0, there has been an interest in supplementing
CoQ10 in patients with heart failure. During the last 2-5
years, a few rather small placebo-controlled studies
revealed a beneficial effect on clinical symptoms and
ejection fraction; 9-11 however, a recent study with a double-blind crossover design was not able to confirm these
findings. 12 In an open, long-term follow-up study of 126
patients treated with CoQ10, ejection fraction improved
among 71% of the patients] 3
This investigation was designed to study the effects of
CoQ10 on myocardial function expressed as ejection fraction. Secondary objectives were used to explore changes
Coenzyme Qlo (C°Qlo) is an obligatory member of the
electron transport chain in the mitochondfia. ~ It is a fatsoluble quinone with characteristics common to vitamins? Normally present in high concentrations in cells
with high energy turnover (such as myocardial cells),
CoQto influences the rate of energy liberation from the
electron transport chain by regulation of certain key
enzymes. Therefore, CoQ10 plays an important role in the
bioenergetics of the cell. 3-5 Only a fraction of the total
pool of COQlo is necessary for an optimal electron flux. 6
From the *Department of Cardiology, Karolinska Hospital,
Stockholm, ?Divisionof Cardiology, Department qf Medicine, Danderyd
Hospital, Danderyd, and $Ostra Hospital, Gothenburg, Sweden.
Supported by grants from the Swedish Heart and Lung Foundation
and from Pharmacia, Sweden.
Manuscript received March 23, 1994; revised manuscript received
October 14, 1994; accepted October 20, 1994.
§See Appendix for a list of members.
Reprint requests: Claes Hofman-Bang, MD, Department of
Cardiology, Thoracic Clinics, Karolinska Hospital, S-104 01 Stockholm, Sweden.
101
102
Journal of Cardiac Failure Vol. 1 No. 2 March 1995
in maximal exercise capacity, quality of life, and the
safety profile of CoQ10.
Materials and M e t h o d s
Patients
Seventy-nine patients from seven Scandinavian hospitals were randomized into a double-blind crossover study
of COQl0 versus placebo. Informed consent was obtained
from each patient. To be entered in the study, a patien~
had to have symptomatic stable chronic congestive heart
failure (optimally treated but not with drugs other than
digitalis, diuretics, vasodilators, and/or angiotensinconverting enzyme [ACE] inhibitors for at least 2
months). Exclusion criteria were acute myocardial
infarction (within 2 months), valvular heart disease suitable for open heart surgery, symptom-limiting anginal
chest pain, poorly controlled hypertension, primary pulmonary disease, and renal dysfunction (serum creatinine
> 200 ~tmol/L).
The patients were stratified according to etiology of
cardiac disease and treatment with ACE inhibitors.
Baseline characteristics are presented in Table 1.
Protocol
The study protocol is outlined in Figure 1. Prior to randomization, all patients underwent a thorough evaluation
consisting of medical history, clinical examination, functional classification according to the New York Heart
Association (NYHA), and laboratory testing, including
CoQ10 in plasma, electrocardiography, chest radiograph,
bicycle ergometry, and determination of the ejection
fraction by nuclear angiography. The patients were
randomly assigned to double-blind therapy with CoQ10
or placebo. Coenzyme Qlo, 100 mg daily (Pharmacia,
Stock-holm, Sweden), or matching placebo was administered in capsule ~form once daily. Patients were followed
Plac~bo
Placebo
Run in
2-4 week*
CoOl0
CoQ10
Start
NYHA Class
3 months
NYHA Class
Exercise test
Exercise test
6 lnonths
NYHA Class
Exercise test
Ejection fraction
Quality of~life
Ejection fraction
Quality of life
Ejection fraction
Quality of life
Fig. 1. Study design. CoQ10,coenzyme Q10;NYHA, New York
Heart Association.
Table 1. Baseline Characteristics
Parameter
Mean _+SD or Number
Age (years)
Sex (male/female)
Etiology (iscbemic/nonischemic*)
Symptom duration (years)
NYHA class (II/III/1V)
Medication (%)
Digitalis
Diuretics
ACE inhibitors
Heart rate (beats/min)
Blood pressure (mmHg)
Systolic
Diastolic
Ejection fraction (%)
Rest
Legs up
Exercise
Maximal exercise tolerance (W)
Plasma level of CoQ10 (mg/mL)
61 _+ 10
69/10
33/46
4.2 _+4.0
13/60/6
75
96
60
82 _+ 16
125 _+21
80 _+9
22 + 10
21 _+ 10
20 _+9
91 _+30
1.01_+ 0.48
*Idiopathic cardiomyopathy, hypertensive heart disease, valvular
heart disease, and other miscellaneous forms. NYHA, New York
Heart Association; COQl0, coenzyme Q10; ACE, angiontensin-converting enzyme.
L
monthly at the outpatient clinic. The evaluation outlined
above and in Figure 1 was repeated after 3 and 6 months.
After 3 months, the patients were switched to the alternative treatment. The study protocol was approved by the
ethical review board of the Karolinska Institute.
Proced u res
All electrocardiograms were standard 12-lead recordings. Heart size was calculated from the chest radiograph
according to Jonsell, 14 with a normal limit of < 500
mL/m 2 body surface area for men and 450 mL/m 2 for
women.
Symptom-limited maximal exercise tests (WsL) were
performed in the sitting position on an electrically braked
bicycle ergometer. The workload was increased by 10 W
each minute. Perceived symptoms (anginal chest pain,
dyspnea) and exertion (leg fatigue) were scaled during
the last 15 seconds of every second workload and always
on the last workload; the 10-point scale was applied, as
described by Borg et al. 15
Left ventricular ejection fraction data were acquired at
rest, during a slight volume load induced by raising the
legs, and during supine exercise by means of a gammacamera (Maxicamera 400 T, General Electric,
Milwaukee, WI). Evaluation of acquisitions was performed with an automatic evaluation program (NUD/Yale
Nuclear Diagnostics, Stockholm, Sweden) using two ventricular regions of interest and a variable region of interest for background subtraction. Ejection fraction during
exercise was obtained after 6 minutes on a workload corresponding to 50% of the WSL.
Coenzyme Qlo in the Treatment of Heart Failure •
Quality of life was assessed using two self-administered questionnaires that had previously been well documented in terms of reliability and validity. A diseasespecific heart failure questionnaire was employed, which
was a slightly modified version of :.he questionnaire
developed for the Cooperative North Scandinavian
Enalapril Survival Study trial in severe heart failure. ~6In
its current form, the questionnaire has 26 items that, apart
from giving an overall score, combine into dimensions
depicting symptoms, physical activity restrictions, emotional distress, and life satisfaction. Additionally, the
sleep dysfunction scale was used to assess the degree of
sleep disturbance. 17 The sleep dysfunction scale uses six
graded Likert scales and includes four items. As a check,
the change in use of sleeping medication was also recorded. In an overall question, the patient rated whether
treatment had resulted in a clear improvement, some
improvement, no change, some deterioration, or a clear
deterioration. A similar question was used in the study by
Sharpe et al.18
The plasma levels of total CoQ10 were analyzed with a
high-performance liquid chromatographic method,
extensively described by Edlund. 19 The coefficient of
variation of the method is 2%.
Hofman-Bang et al.
103
Supine exercise
p =n.s.
%
605040302010-
Legs up
%
p =
0.025
60
'°1
50
40-
Statistical Methods
All statistical tests were based on data collected at
months 3 and 6. There was no washout period between
treatment periods. Efficacy data were analyzed using a
repeated measure analysis of variance to test for treatment, carryover, and strata effects (SAS Institute, Cary,
NC). A P value < .05 was considered significant. The
correlation between maximal exercise capacity (watts)
and the total score of quality of life was tested by the
Pearson correlation coefficient using differences from
baseline• A P value < .05 was considered significant.
Results
Sixty-nine patients completed the study according to
the protocol. Seven patients died, four during the placebo and three during the CoQ! 0 periods. Three patients
were withdrawn because of acute referral to heart transplantation, unassociated illness, and personal reasons,
respectively.
The primary endpoint of the study was the effect of
CoQ10 on ejection fraction. These resulls are presented in
Figure 2. In general, there was a sfight increase in ejection
fraction during the CoQ10 period. The only statistically significant difference was observed during volume load (legs
up), when ejection fraction increased from 22.6% _+ 12.1%
on placebo to 25.0% _+ 13% on CoQ10 (P < .05).
Symptom-limited maximal exercise tolerance (Fig. 3)
increased by 6%, from 94 _+31 W (placebo) to 100 _+34
3020.
10-
%
Rest
p = ILS.
°°t
50
40302010OPlacebo
CoQ10
Fig. 2. Results of ejection fraction measurements at rest,
during volume load, and during supine exercise shown as
individual data points. Means with standard deviations are
superimposed (thick shaded lines).
104
Journal of Cardiac Failure Vol, 1 No. 2 March 1995
Chest pain
p = l=.s.
109-
Heart rate
8-'
p = n~.
7-"
b.p.m.
220- I
6-
5-
200 ~
4-
~
180160-
32S
140-
1.~
120 100-
X
Leg fatigue
80-
6o-
p -- 0.04
10ip-
9-
40-
8765-
Exercise
4-
p = 0.016
3-
Watts
2-
200-
1180 -
0
160-
Dyspnea
140-
p -- 0.007
120-
0-
100-
98-
80-
7-
60-
640-
5-
20
4Placebo
COQlo
Fig. 3. Results of symptom-limited maximal exercise capacity
and heart rate at the highest comparable workload shown as
individual data points. Means with standard deviations are
superimposed (thick shaded lines).
321-
oJ
Placebo
CoQlo
Fig. 4. Results of Borg scaling at the highest comparable
workloads for dyspnea, leg fatigue, and chest pain shown as
individual data points. Means with standard deviations are
superimposed (thick shaded lines).
Coenzyme Qlo in the Treatment of Heart Failure •
Table 2. Means for Differences With 95% Confidence
Intervals Between CoQ10 and Placebo
Parameter
EF (rest) (%)
EF (legs up) (%)
EF (supine work) (%)
Exercise (W)
Heart rate (beats/rain)
Borg scaling
Dyspnea
Legs
Pain
95% Confidence
Interval
Mean Value
0.5
2.0
0.2
5.6
0.5
- 1.0-2.0
0.3-3.7
- 1.4-1.8
1.1-10.0
-2.7-3.6
-0.7
-0.6
-0.1
- 1.2--0.2
- 1.2-0
-0.6-0.3
W (CoQ10) (/9 < .05). Heart rate did not differ during exercise at comparable work loads. The most common reasons
to stop exercise were dyspnea and leg fatigue. Coenzyme
Q~0 caused a statistically significant decrease in the score
at the end of exercise for dyspnea and leg fatigue (Fig. 4).
Means for differences (with 95% contidence intervals)
between CoQ~0 and placebo are presented in Table 2.
The total score for the quality of life assessment
increased significantly from 107 during the placebo period to 113 during the CoQ10 period (P < .05), indicating
a general increase in the "feeling of well being." More
specifically, improved parameters by CoQ10 were those
related to life satisfaction and physical activity (Table 3).
There was a weak correlation between the total score on
the quality of life assessment and the maximal exercise
capacity using difference from baseline (r = .26; P =
.004). Coenzyme Q10 did not cause any significant changes
of the N Y H A functional classes.
There were no clinically or statistically significant
changes in the various blood specimens. Coenzyme Q10
in plasma was 1.01 __+.0.48 g g / m L duri:ag the ran-in period, 1.07 _+ 0.46 gg/mL during the placebo period, and
2.40 _+ 0.96 gg/mL during the CoQ10 period. The difference between the run-in and the placebo period and
CoQ1 o periods was significant (P < .00l). There were no
significant crossover effects or any strata effects in any of
the statistical tests.
Table 3. Results of the Quality of Life Questionnaire
Total score
Somatic symptoms
Emotions
Life satisfaction
Physical activity
Sleeping problem
Sleeping pills
Overall question*
Placebo
(mean _+SD)
CoQl0
(mean + SD)
P
107 4- 23
33 4- 9
34 _+7
20 4- 6
20 + 6
15 + 5
5+1
4 4- 1
113 _+22
35 + 7
364- 6
21 + 5
22 + 6
16 + 5
5+1
4 4- 1
.016
NS
NS
.014
.048
NS
NS
NS
CoQ10, coenzyme Qlo' *Patient's general well being.
105
Of the seven deaths during the study (4 occurred during
the placebo period), two patients died of progressive heart
failure, two patients died of myocardial infarction, and
three patients died suddenly. Only a few side effects were
noted (gastrointestinal disturbances during the placebo and
CoQt0 periods, 10 patients each; vertigo in 10 patients during the placebo and in 6 during the CoQ10 periods; and dry
skin in 4 patients during the placebo and in 6 during the
CoQ10 periods). All side effects were minor and none
could specifically be Mated to the CoQx0 period.
Discussion
CoQm, coenzyme Q10;EF, ejection fraction.
Parameter
Hofman-Bang et al.
The most important findings in this study were that
adjunctive treatment with 100 mg CoQ10 daily to patients
with heart failure caused an increase, however slight, in
maximal exercise capacity, improved symptoms related
to physical activity, and increased life satisfaction. Left
ventricular ejection fraction measured during a slight
volume load increased significantly. However, this
improvement was not sustained during submaximal exercise or at rest.
The rationale for using CoQ10 in the treatment of congestive heart failure was suggested in 1970 by Folkers et
al.,20 who described a myocardial deficiency of this substance. Folkers et al.4 analyzed endomyocardial biopsies
from 43 patients with congestive heart failure. Patients in
N Y H A classes III and IV had significantly lower levels
of CoQlo compared to those in N Y H A classes I and II.
Over the years, there have been several reports on clinical improvement by intravenous or oral CoQlo .3,9-a1,13,21-28
Many of these studies were uncontrolled and/or measured so-called "soft" endpoints (dyspnea at rest, ankle
edema, liver enlargement, pulmonary congestion, investigators' judgment, etc.). Doses varied between 30 and
100 mg/d. A few double-blind placebo controlled studies
have been performed, 9-11,27,2s where the main findings
were clinical improvement and improved indices of left
ventricular systolic function. However, in a recent study,
Permanetter and co-workers were unable to show any
improvement in cardiac performance or exercise tolerance. a2 They studied 25 patients with dilated cardiomyopathy and with less severe heart failure than our
patients. There was no significant improvement in any of
the subgroups in this study (nonischemic heart disease,
ischemic heart disease, ACE, and not-ACE). In patients
with angina pectoris, exercise time to limiting chest pain
was prolonged in two studies in which the dose of CoQt 0
ranged from 150 to 300 mg daily.29.3° A sustained positive
effect on ejection fraction and reduced mortality has been
reported. These observations were made over a period of
60 months in an open study lacking a control group. 13
This study differs from most previous studies in that it
was a conventional, controlled, crossover study with
106
Journal of Cardiac Failure Vol. 1 No. 2 March 1995
sufficient power to examine effects on myocardial function. It also differs from most studies as regards effects
on myocardial function. Except for a small increase during volume load, there was no obvious increase of the
ejection fraction. In our placebo-controlled study, this
finding was less clear than in previous studies. 9-n Earlier
investigations used systolic time intervals to measure
myocardial function. Radionuclide measurement of ejection fraction is a more established, direct, and accurate
method for the expression of left ventricular systolic
function than systolic time intervals. An important difference between our study and most previous investigations
is the current lack of significant improvement in subjective symptoms expressed as NYHA classes. However, a
significant but small improvement in quality of life was
noted in the CoQ10-treated group compared to the placebo-treated group. Differences in baseline plasma values
of CoQ10 (indicating a deficiency of the substance) can
be another explanation for different results. Langsjoen et
al. ~° reported on similar baseline levels of CoQ10
(0.77-1.04 pg/mL), while Folkers et al. 4 found substantially lower levels (0.60-0.77 pg/mL) in NYHA class
II-IV patients. A difference in methodology is the most
likely explanation; however, differences in dietary intake
may also influence the results.
The two important limitations of this study are duration of treatment and dosage. Three months might not be
enough time to evaluate the final outcome of CoQlo. In
particular, mortality, a major endpoint, could not be studied at all and was not included as an objective in this
study. Folkers et al. emphasized that CoQ10 in its active
form is bound to apoproteins. 13 The synthesis of these
compounds may span a fairly long time period (weeks to
months), which may delay the response to CoQ~0.
Current data suggest that 3 months should be long
enough for most patients to experience the possible benefit of CoQ10.9'10'13 Whether the dose of 100 mg CoQ10
daily is sufficient is unknown. Folkers et al. 4 explored
myocardial concentrations of CoQ10. The level of CoQ10
increased 19-86% in five patients who had been receiving 100 mg of the compound during 2-8 months. In a
substudy to this investigation, however, 11 patients did
not demonstrate any detectable increase in myocardial
CoQ10.31 The reason for this discrepancy remains to be
studied.
It may be concluded that CoQl0 in this study had a significant but minor adjuvant effect On exercise capacity
and symptoms measured as quality of life. The clinical
importance of these findings is not entirely clear. Before
recommending CoQao as supplementary therapy in heart
failure, it is desirable to improve the knowledge of its
pharmacodynamic properties
(dosage-myocardial
uptake-effect) and to compare the effects with those of
other adjuvant drugs.
Acknowledgments
The authors wish to express gratitude to Jerker
Ringstr6m and Eva Kelty for help with data management
and statistics, all the nurses involved in this project, and
Lars Ryd6n, Karolinska Hospital, Stockholm, for valuable criticisms.
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Appendix
The Q10 study group comprised the following investigators:
Karolinska Hospital, Stockholm, Sweden: Gunilla
Forssell, MD, Claes Hofman-Bang, MD, Hans Astr/3m, MD
Danderyd Hospital, Danderyd, Sweden: Nina
Rehnqvist, MD, Claes Held, MD, Lennart Forslund, MD,
Inge Bj6rkander, MD
S6dersjukhuset, Stockholm, Sweden: Johan Hulling, MD
Huddinge Hospital, Huddinge, Sweden: Karl-Erik
Karlberg, MD, Marten Rosenqvist, MD
Nacka Hospital, Nacka, Sweden: Andreas Sj6gren, MD,
Enno Loogna, MD
Falu Hospital, Falun, Sweden: Helge Saetre, MD,
Greger Ahlberg, MD
Rigshospitalet, Copenhagen, Denmark: Svend-Aage
Mortensen, MD
Steering Committee: Karl Swedberg MD, (chairman),
Ostra Hospital, Gothenburg, Nina Rehnqvist, MD,
Danderyd Hospital, Danderyd, Hans Astr6m, MD,
Karolinska Hospital, Stockholm
Safety Committee: Lars Wallentin, MD, Akademiska
Hospital, Uppsala, Sweden
Monitors Pharmacia: Gun Setterberg, Bernt Lund