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ONLINE APPENDIX
Figure 1. Consort Flow Diagram
Enrollment
Assessed for eligibility (n=436)
Excluded (n=16)
 Not meeting inclusion criteria (n=6)
 Declined to participate (n=6)
 Protocol deviation (n=4)
Randomized (n=420)
Allocation
Allocated to intervention (n=202)
 Received allocated intervention (n=202)
Allocated to placebo (n=218)
 Received allocated intervention (n=218)


Did not receive allocated intervention (n=0)
Did not receive allocated intervention (n=0)
Follow-Up
Lost to follow-up (unknown reasons) (n=4)
Lost to follow-up (unknown reasons) (n=4)
Discontinued intervention (n=18)
Non-compliance (n=6); stopped study-drug
(n=7); biventricular pacemaker implantation
(n=3); elective heart transplantation (n=2)
Discontinued intervention (n=10)
Non-compliance (n=5); stopped study-drug
(n=4); biventricular pacemaker implantation
(n=0); elective heart transplantation (n=1)
Analysis
Analysed (n=202)
 Excluded from analysis (n=0)
Analysed (n=218)
 Excluded from analysis (n=0)
Figure 2. Kaplan-Meier estimates of the time to cardiovascular death (A) and the time to
unplanned hospital stay for heart failure (B) in the placebo group (solid line) and CoQ10 group
(dashed line). CI = confidence interval; HR = hazard ratio.
Table 1. Trial Enrollment Criteria
Inclusion Criteria
Exclusion Criteria
•
NYHA functional class III or IV.
•
HF resulting from ischemic heart disease, dilated
percutaneous coronary intervention, cardiac
cardiomyopathy, or valvular heart disease.
resynchronization device, cardiac surgery, or
•
Typical symptoms and signs of HF.
stroke all within 6 weeks of enrollment.
•
Appropriate medical treatment of HF including a
•
HF from congenital heart disease.
diuretic, an angiotensin-converting enzyme
•
Uncorrected valvular heart disease or planned
•
inhibitor or an angiotensin-receptor blocker, a
beta-blocker, an aldosterone antagonist, and
valve surgery.
•
digoxin.
•
Doses of these agents must have been stable for
Planned other cardiac surgery or
resynchronization therapy.
•
at least 1 month before run-in.
•
Myocardial infarction, unstable angina pectoris,
On urgent waiting list for heart transplantation
(status 1 patients).
Beta-blocker dose must have been stable for at
•
Implanted mechanical assist device.
least 3 months.
•
On continuous inotropic support for HF.
•
>18 years of age.
•
Restrictive or hypertrophic cardiomyopathy.
•
Able to undertake a 6-minute walk test.
•
Alcoholic heart disease.
•
Acute inflammatory myocarditis.
•
Severe non-cardiac disease including malignancy
with life expectancy <1 year.
•
Psychosocial instability or anticipated problems
with compliance.
•
Women of childbearing potential and lactating
female patients.
•
Allergy to the constituents of the test medication.
•
Supplementary CoQ10 intake within the last
month before run-in.
•
6-minute walk distance >450 meters at run-in.
•
Participation in another controlled trial.
EF = ejection fraction; HF = heart failure; NYHA = New York Heart Association.
Table 2. Times and Periods of Effect Recording
Time of visit (week)
Variable
0
2
16
54
Symptom
Safety
106
Screening
Randomization
evaluation
monitoring
Final analysis
via VAS
+
+
+
-
-
Physician´s assessment
+
+
+
+
+
NYHA functional class
+
+
+
+
+
6MWT
+
+
+
-
Optional
Serum NT-proBNP
-
+
+
-
+
Heart rate, ECG, blood pressure
+
+
+
+
+
Optional
+
+
Optional
+
Serum CoQ10
-
+
+
-
+
Medications
+
+
+
+
+
Hospital stay for HF
-
-
+
+
+
Death
-
-
+
+
+
Safety, hospital stay not for HF
-
-
+
+
+
Compliance
-
+
+
+
+
Patient´s evaluation of symptoms
Echocardiography
ECG = 12 lead electrocardiogram; HF = heart failure; 6MWT = 6-minute walk test; NYHA = New York Heart
Association; NT-proBNP = N-terminal pro-B-type natriuretic peptide; VAS = visual analogue scale.
Table 3. Q-SYMBIO Power Calculations
Variables*
At entrance in study
After treatment
6MWT
300 meter ± 100 (normal distribution)
Difference in walk distance of ≥35 meter ± 125
(non-paired analysis)
NYHA functional class
NT-proBNP
NYHA class II: 10%
NYHA class III: 80%
Change of ≥20% of patients
NYHA class IV: 10%
Change of ≥20% of patients
650 pg/ml ±125 (normal distribution)
Difference in level of ≥ 60 pg/ml ±125
(non-paired analysis)
MACE†
Usual repeat hospital stay rate:
Difference in time to first admission ≥ 1 month.
2/year.
Median hospital stay-free period : 4
months
*Inclusion of 550 patients would provide a study power of >90% at a 5% level of significance to detect a difference
regarding the listed variables.
† Unplanned hospital stays for HF.
HF = heart failure; MACE = major adverse cardiovascular events; 6MWT = 6-minute walk test; NT-proBNP = Nterminal pro-B-type natriuretic peptide; NYHA = New York Heart Association.
Table 4. Clinical and Echocardiographic Assessments at Week 16
CoQ10
Placebo
N = 188
N = 197
Improvement
82* (44 %)
76 (39 %)
Unchanged
102 (54%)
118 (61%)
4 (2%)
1 (0.5%)
+ 37 ± 53
+ 37 ± 61
Dyspnea
−15 ± 22
−15 ± 24
Fatigue
−15 ± 22
−17 ± 22
General symptoms change
−11 ± 31
−11 ± 27
Heart rate, (beats/min ± SD)
−2 (79 ± 14)
−2 (80 ± 13)
Systolic blood pressure, (mm Hg ± SD)
0 ( 125 ± 18)
−1 (121 ± 15)
Diastolic blood pressure, (mm Hg ± SD)
−1 (76 ± 10)
0 (77 ± 10)
Left ventricular EF, (% ± SD)
+ 2 (33 ± 10)
+ 1 (32 ± 9)
Left ventricular EDD, (mm ± SD)
−1 (64 ± 8)
0 (64 ± 8)
Left ventricular ESD, (mm ± SD)
−1 (53 ± 10)
−1 (53 ± 11)
Change in values from baseline
NYHA classification, no. (%):
Deterioration
6MWT (m ± SD)
VAS, score (% ± SD)
*p = 0.200
EDD = end-diastolic diameter; EF = ejection fraction; ESD = end-systolic diameter; 6MWT = 6-minute walk test;
NYHA = New York Heart Association; VAS = visual analogue scale.
Table 5. Biochemical Assessments at Baseline at Week 16 and Week 106
Variable
CoQ10
Placebo
Week 16: n = 175
Week 16: n = 190
Week 106: n = 101
Week 106: n = 116
Serum CoQ10, µg/ml (mean ± SE)
Baseline
1.14 ± 0.08
0.91 ± 0.06
Week 16
3.01 ± 0.17 *
1.15 ± 0.09
2.01 ± 0.20
0.81 ± 0.06
Baseline
1,883 ± 271
1,692 ± 229
Week 16
1,499 ± 208
1,891 ± 312
Week 106
746 ± 171
811 ± 173
Week 106
Serum NT-proBNP†, pg/ml (mean ± SE)
*p < 0.001
†To convert values for NT-proBNP to picomoles per liter, divide by 8.457.
NT-proBNP = N-terminal pro-B-type natriuretic peptide.
Table 6. Clinical and Echocardiographic Assessments at Week 106
CoQ10
Placebo
(N = 148)
(N = 150)
Improvement
86* (58)
68(45)
Unchanged
61 (41)
79 (53)
1 (1)
3 (2)
Heart rate (beats/min ± SD)
−2 (78 ± 13)
−4 (79 ± 14)
Systolic blood pressure (mm Hg ± SD)
−2 (125 ± 18)
−1 (122 ± 16)
Diastolic blood pressure (mm Hg ± SD)
−2 (76 ± 8)
−1 (77 ± 9)
+ 2 (35 ± 10)
+ 2 (33 ± 11)
Left ventricular EDD (mm ± SD)
−1 (63 ± 8)
−1 (64 ± 8)
Left ventricular ESD (mm ± SD)
−2 (52 ± 11)
−1 (53 ± 11)
Change from baseline - Δ
NYHA classification – no. (%)
Deterioration
Left ventricular EF (% ± SD)
EDD end-diastolic diameter; EF = ejection fraction; ESD = end-systolic diameter; 6MWT = 6-minute walk test; NYHA
= New York Heart Association.
*p = 0.028.
Table 7. Cardiovascular Death
Outcome
CoQ10
Placebo
Total
N = 202
N = 218
N = 420
Death resulting from MI
2
3
5
Death resulting from HF
2
14
16
Sudden cardiac death
12
16
28
Pulmonary embolism
0
1
1
LVAD*
1
0
1
Urgent cardiac transplantation
1
0
1
18† (9 %)
34 (16 %)
52
Total
*According to the Protocol: Implantation of left ventricular assist device and urgent cardiac transplantation were
counted as deaths.
†p = 0.039.
HF = heart failure; LVAD = left ventricular assist device; MI = myocardial infarction.
Table 8. Death From Any Cause
Outcome
CoQ10
N = 202
Placebo
N = 218
Total
N = 420
Death resulting from MI
2
3
5
Death resulting from HF
2
14
16
Sudden cardiac death
12
16
28
LVAD*
1
0
1
Urgent cardiac transplantation
1
0
1
Pulmonary embolism
0
1
1
Cerebrovascular death
0
3
3
Non-CV or unknown causes of death
3
2
5
21† (10%)
39 (18%)
60
Total
*According to the Protocol: Implantation of left ventricular assist device and urgent cardiac transplantation were
counted as deaths.
†p = 0.036
CV = cardiovascular; HF = heart failure; LVAD = left ventricular assist device; MI = myocardial infarction.
Appendix 1
Visual analogue scale for symptoms (VAS): Symptoms were graded for dyspnea and fatigue, and
the score was calculated in percentages from scales with a position along a continuous line
between 2 endpoints.



For dyspnea as: 0% = no dyspnoea; 33.3% = dyspnoea at moderate activity; 66.6% =
dyspnea at slight activity; 100% = dyspnoea at rest.
For fatigue as: 0% = never; 33.3% = occasionally; 66.6% = often; 100% = always.
For symptoms change, a score compared to the previous visit as: 0% = deterioration; 50% =
no change; 100% = improvement.
Appendix 2
Study medication: 1 capsule 3 times daily together with a meal.
Verum: 1 gelatin capsule (Myoqinon, Pharma Nord ApS) contains the following:
Coenzyme CoQ10 (ubiquinone) 100 mg dissolved in a matrix of soybean oil; RRR-alpha-tocopherol
(antioxidant).The CoQ10 raw material (KanekaQ10) was provided by Kaneka Corp, Japan.
Placebo: 1 gelatin capsule contains the following: Soybean oil; RRR-alpha-tocopherol (antioxidant).