Table 1: Select baseline characteristics. The Population for Randomization included patients on hemodialysis as of April 1, 2013. The Trial Population included an open cohort of patients receiving in-center hemodialysis on April 1, 2014, or began receiving in-center hemodialysis during the trial period between April 1, 2014, and March 31, 2017.
Baseline characteristic
|
VALUE
|
Population for Randomization
|
Trial Population
|
Centers
|
Number of centers (n Patients)
|
72 (n=5,812)
|
72 (n=11,832)
|
Center Size 1
|
Mean ± Standard deviation
|
81 (69)
|
164 (137)
|
The composite outcome of CV-related death or major CV-related hospitalization 2
|
Historic rate per 100 person-years (cluster standard deviation)
|
10 (3.7)
|
11 (3.3)
|
Age (years)
|
Mean ± Standard deviation
|
67 (15)
|
66 (15)
|
Sex
|
Male
|
3373 (58%)
|
7069 (60%)
|
Living in a rural area
|
Yes
|
359 (6%)
|
809 (7%)
|
Etiology for End-stage kidney disease
|
Diabetes
|
2194 (38%)
|
4472 (38%)
|
Glomerulonephritis/autoimmune diseases
|
882 (15%)
|
1575 (13%)
|
Drug-induced nephropathy
|
83 (1%)
|
159 (1%)
|
Polycystic kidney disease
|
229 (4%)
|
426 (4%)
|
Renal vascular disease
|
1115 (19%)
|
1852 (16%)
|
Other
|
738 (13%)
|
2221 (19%)
|
Unknown
|
571 (10%)
|
1127 (10%)
|
Race
|
Asian
|
475 (8%)
|
854 (7%)
|
Black
|
562 (10%)
|
1022 (9%)
|
White
|
3698 (64%)
|
7598 (64%)
|
Other
|
1038 (18%)
|
2173 (18%)
|
Unknown
|
39 (1%)
|
185 (2%)
|
First dialysis modality
|
Home hemodialysis
|
33 (1%)
|
84 (1%)
|
In-center hemodialysis
|
5215 (90%)
|
10529 (89%)
|
Peritoneal dialysis
|
564 (10%)
|
1219 (10%)
|
First type of vascular access
|
Arteriovenous graft
|
103 (2%)
|
198 (2%)
|
Arteriovenous fistula
|
1044 (18%)
|
1999 (17%)
|
Central venous catheter
|
3927 (68%)
|
8157 (69%)
|
Peritoneal catheter
|
456 (8%)
|
1092 (9%)
|
Unknown
|
282 (5%)
|
386 (3%)
|
Last vascular access used before the index date
|
Arteriovenous graft
|
223 (4%)
|
376 (3%)
|
Arteriovenous fistula
|
2159 (37%)
|
3461 (29%)
|
Central venous catheter
|
3376 (58%)
|
7544 (64%)
|
Patient in the Ontario Drug Benefit in the six months before the index date
|
Yes 4
|
4494 (86%)
|
10196 (86%)
|
Number of unique hypertensive prescriptions in the six months before the index date
|
Mean ± Standard deviation
|
2 (2)
|
2 (2)
|
Prescribed hypertensive drugs 3
|
Angiotensin-converting enzyme (ACE) inhibitors
|
1157 (26%)
|
2199 (22%)
|
Angiotensin II Receptor Blocker
|
1258 (28%)
|
2413 (24%)
|
Beta-Blockers
|
2649 (59%)
|
5604 (55%)
|
Calcium Channel Blocker
|
2392 (53%)
|
5453 (53%)
|
Diuretics
|
1612 (36%)
|
4242 (42%)
|
Prior CABG/PCI
|
Yes
|
1234 (21%)
|
2612 (22%)
|
Coronary Artery Disease (with angina)
|
Yes
|
3541 (61%)
|
6861 (58%)
|
Heart failure
|
Yes
|
2862 (49%)
|
6177 (52%)
|
Diabetes mellitus
|
Yes
|
3402 (59%)
|
7244 (61%)
|
Depression
|
Yes
|
1528 (26%)
|
3161 (27%)
|
Ischemic Stroke
|
Yes
|
261 (4%)
|
551 (5%)
|
Lower extremity amputation
|
Yes
|
298 (5%)
|
554 (5%)
|
Lung disease (COPD)
|
Yes
|
2276 (39%)
|
4666 (39%)
|
Myocardial infarction
|
Yes
|
1454 (25%)
|
2909 (25%)
|
Major Cancer
|
Yes
|
841 (14%)
|
1803 (15%)
|
Peripheral vascular disease
|
Yes
|
1699 (29%)
|
3055 (26%)
|
Modified Charlson comorbidity score 5
|
Mean ± Standard deviation
|
4 (2)
|
4 (2)
|
2
|
1931 (33%)
|
3631 (31%)
|
3
|
519 (9%)
|
1028 (9%)
|
4
|
1382 (24%)
|
2883 (24%)
|
5+
|
1980 (34%)
|
4290 (36%)
|
Having a kidney transplant before the index date
|
Yes
|
71 (1%)
|
148 (1%)
|
Number of days spent in long-term care in the year before the index date
|
Mean ± Standard deviation
|
37 (164)
|
25 (133)
|
Number of days spent in the hospital in the year before the index date
|
Mean ± Standard deviation
|
11 (28)
|
17 (31)
|
Number of hospital admissions in the year before the index date
|
Mean ± Standard deviation
|
1 (1)
|
1 (1)
|
Time since starting dialysis (days)
|
Mean ± Standard deviation
|
1847 (1836)
|
1327 (1782)
|
1 Population for Randomization included patients that were on hemodialysis as of April 1, 2013 index date. The Trial Population included patients on hemodialysis as of April 1, 2014, and any patient who started in-center hemodialysis at one of the 72 participating centers during the three-year trial period. Follow-up ended March 31, 2017. The index date was the first date patients entered the respective cohort.
2 The composite outcome of cardiovascular-related death or hospitalization for myocardial infarction, ischemic stroke, congestive heart failure.
3 Percentages presented only for patients eligible to receive the Ontario Drug Benefit (ODB) plan in the six months before the index date (i.e., 4494 for Randomization Cohort and 10196 for the Trial cohort). CABG/PCI = Coronary artery bypass grafting / percutaneous coronary intervention.
4 Ontario residents are eligible for the Ontario Drug Benefit program include people 65 years or older, on social assistance, residing in homes for special care and long-term care homes, people receiving professional home care services, and registrants in the Trillium Drug Program.
5 This is an adapted version of the Charlson comorbidity index explicitly created for use in patients with ESRD. This version has a modified weighting scheme specific to dialysis patients.
Table 2: The percentage of times each of the baseline characteristics was balanced across each of the 1000 randomizations schemes in the Trial Population.
|
Baseline characteristic
|
Value
|
Constrained randomization method
|
|
Unrestricted / Simple
|
Prognostic baseline characteristics
|
Principal components
|
|
Center Size
|
Mean ± Standard deviation
|
32.9%
|
41.8%
|
38.7%
|
|
Composite outcome of CV-related death and major CV-related hospitalization
|
Rate (per 100 person-year)
|
32.5%
|
36.2%
|
33.5%
|
|
Age (years)
|
Mean ± Standard deviation
|
95.3%
|
99.8%
|
99.2%
|
|
< 65
|
97.8%
|
99.7%
|
99.9%
|
|
65 to 74
|
100.0%
|
100.0%
|
100.0%
|
|
75 to 84
|
100.0%
|
100.0%
|
100.0%
|
|
85 to 105
|
99.5%
|
100.0%
|
99.9%
|
|
Sex
|
Male
|
100.0%
|
100.0%
|
100.0%
|
|
Living in a rural area
|
Yes
|
63.0%
|
84.2%
|
65.8%
|
|
Etiology for End-stage kidney disease
|
Diabetes
|
93.0%
|
94.5%
|
95.0%
|
|
Glomerulonephritis/autoimmune diseases
|
96.3%
|
100.0%
|
99.5%
|
|
Drug-induced nephropathy
|
100.0%
|
99.9%
|
100.0%
|
|
Polycystic kidney disease
|
100.0%
|
100.0%
|
100.0%
|
|
Renal vascular disease
|
97.5%
|
97.6%
|
96.7%
|
|
Other
|
88.3%
|
91.9%
|
91.6%
|
|
Race
|
Asian
|
75.0%
|
81.3%
|
88.1%
|
|
Black
|
73.4%
|
95.9%
|
91.9%
|
|
White
|
45.6%
|
64.0%
|
90.2%
|
|
Other
|
56.6%
|
65.7%
|
77.5%
|
|
Unknown
|
93.2%
|
93.7%
|
93.6%
|
|
First dialysis modality
|
Home hemodialysis
|
100.0%
|
99.8%
|
99.9%
|
|
In-center hemodialysis
|
97.8%
|
98.6%
|
99.9%
|
|
Peritoneal dialysis
|
97.4%
|
98.7%
|
99.8%
|
|
First vascular access used at dialysis start
|
AV Graft
|
99.9%
|
100.0%
|
100.0%
|
|
Fistula
|
98.9%
|
99.1%
|
99.4%
|
|
Catheter
|
93.5%
|
96.2%
|
99.4%
|
|
PD Catheter
|
98.8%
|
99.0%
|
100.0%
|
|
Unknown
|
92.4%
|
93.8%
|
94.3%
|
|
Most recent vascular access before the index date
|
AV Graft
|
98.7%
|
99.8%
|
98.9%
|
|
Fistula
|
91.9%
|
94.8%
|
97.7%
|
|
Catheter
|
89.9%
|
94.0%
|
97.4%
|
|
Patients 65+ years in ODB in the 6 months prior to index date
|
Yes
|
97.5%
|
99.3%
|
99.4%
|
|
Unique hypertensive drugs six months before the index date
|
Mean ± Standard deviation
|
97.1%
|
99.9%
|
99.5%
|
|
Prescribed hypertensive drugs
|
Angiotensin-converting enzyme (ACE) inhibitors
|
99.4%
|
99.3%
|
99.5%
|
|
Angiotensin II Receptor Blocker
|
90.7%
|
96.1%
|
96.9%
|
|
Beta-Blockers
|
99.7%
|
100.0%
|
99.9%
|
|
Calcium Channel Blocker
|
98.1%
|
100.0%
|
99.6%
|
|
Diuretics
|
91.9%
|
97.0%
|
95.6%
|
|
CABG/PCI
|
Yes
|
99.4%
|
99.5%
|
100.0%
|
|
Heart failure
|
Yes
|
96.8%
|
100.0%
|
99.8%
|
|
Diabetes mellitus
|
Yes
|
99.0%
|
100.0%
|
100.0%
|
|
Ischemic Stroke
|
Yes
|
100.0%
|
100.0%
|
100.0%
|
|
Lower extremity amputation
|
Yes
|
99.9%
|
100.0%
|
100.0%
|
|
Lung disease (COPD)
|
Yes
|
99.0%
|
99.6%
|
100.0%
|
|
Myocardial infarction
|
Yes
|
99.2%
|
100.0%
|
100.0%
|
|
Major Cancer
|
Yes
|
100.0%
|
100.0%
|
100.0%
|
|
Peripheral vascular disease
|
Yes
|
90.7%
|
97.2%
|
91.4%
|
|
Modified Charlson comorbidity Score
|
Mean ± Standard deviation
|
96.8%
|
99.9%
|
100.0%
|
|
2
|
97.7%
|
100.0%
|
100.0%
|
|
3
|
100.0%
|
100.0%
|
100.0%
|
|
4
|
100.0%
|
100.0%
|
100.0%
|
|
5+
|
98.9%
|
100.0%
|
100.0%
|
|
Having a kidney transplant prior to index date.
|
Yes
|
100.0%
|
100.0%
|
100.0%
|
|
Number of hospital admissions in the year before the index date
|
Mean ± Standard deviation
|
93.9%
|
98.4%
|
98.4%
|
|
0
|
78.4%
|
76.4%
|
81.1%
|
|
1 to 3
|
99.5%
|
99.6%
|
99.9%
|
|
4 to 6
|
99.4%
|
99.6%
|
99.5%
|
|
7 to 9
|
100.0%
|
99.9%
|
100.0%
|
|
10+
|
92.1%
|
92.0%
|
94.6%
|
|
Long term care facility utilization in the year before the index date
|
Yes
|
81.3%
|
86.6%
|
86.1%
|
|
Time since the first date on dialysis (days)
|
Mean ± Standard deviation
|
88.1%
|
94.0%
|
94.4%
|
|
Table 3: Summary of the balanced baseline characteristics for the Trial Population.
Criteria
|
Constrained randomization method
|
|
Unconstrained / Simple
|
Prognostic baseline characteristics
|
Principal components
|
P-value**
|
|
11 prognostic characteristics ++
|
Number of constrained baseline characteristics that were balanced in all 1000 (100%) sampled allocations
|
0 of 11 (0%) ¥
|
2 of 11 (18%)
|
2 of 11 (18%)
|
<0.0001
|
|
Number of constrained baseline characteristics that were balanced in at least 950 (95%) sampled allocations
|
6 of 11 (55%)
|
10 of 11 (91%)
|
7 of 11 (64%)
|
|
Number of constrained baseline characteristics that were balanced in at least 900 (90%) sampled allocations
|
8 of 11 (73%)
|
10 of 11 (91%)
|
9 of 11 (82%)
|
|
Median (25th, 75th percentile) number of baseline characteristics that were balanced across the 1000 selected randomization schemes
|
10 (9, 11) *
|
11 (10, 11)
|
10 (10, 11)
|
|
|
29 baseline characteristics used in the principal component analysis**
|
Number of constrained baseline characteristics that were balanced in all 1000 (100%) sampled allocations
|
8 of 29 (28%)
|
12 of 29 (41%)
|
12 of 29 (41%)
|
<0.0001
|
|
Number of constrained baseline characteristics that were balanced in at least 950 (95%) sampled allocations
|
19 of 29 (66%)
|
23 of 29 (79%)
|
25 of 29 (86%)
|
|
Number of constrained baseline characteristics that were balanced in at least 900 (90%) sampled allocations
|
24 of 29 (83%)
|
25 of 29 (86%)
|
26 of 29 (90%)
|
|
Median (25th, 75th percentile) number of baseline characteristics that were balanced across the 1000 selected randomization schemes
|
27 (26, 28)
|
28 (27, 28)
|
28 (28, 29)
|
|
All 156 available baseline characteristics
|
Number of constrained baseline characteristics that were balanced in all 1000 (100%) sampled allocations
|
41 of 156 (26%)
|
46 of 156 (28%)
|
55 of 156 (35%)
|
<0.0001
|
|
Number of constrained baseline characteristics that were balanced in at least 950 (95%) sampled allocations
|
104 of 156 (67%)
|
115 of 156 (74%)
|
118 of 156 (76%)
|
|
Number of constrained baseline characteristics that were balanced in at least 900 (90%) sampled allocations
|
125 of 156 (80%)
|
132 of 156 (85%)
|
134 of 156 (86%)
|
|
Median (25th, 75th percentile) number of baseline characteristics that were balanced across the 1000 selected randomization schemes
|
147 (142, 150)
|
149 (146, 151)
|
150 (147, 151)
|
|
|
|
|
|
|
|
|
The Trial Population included patients on hemodialysis as of April 1, 2014, and new patients who started in-center hemodialysis during the three-year follow-up. We conducted simple randomization without any restrictions.
¥ For example, for simple randomization, 2 of the 11 chosen prognostic baseline characteristics were always balanced across 1000 randomly sampled allocation schemes.
*For example, for simple randomization, 500 of 1000 allocation schemes had at least ten balanced baseline characteristics out of the 11 prognostic baseline characteristics. As such, there is a 50% probability that a randomly selected allocation will have at least 10 of the 11 prognostic baseline characteristics balanced and a 75% probability that at least 9 of the 11 prognostic baseline characteristics will be balanced.
** We used the Kruskal-Wallis H Test to determine whether the three randomization techniques' median number of balanced characteristics was the same.
++ Prognostic baseline characteristics: Constraining on a set of baseline characteristics that thought to be important a priori and included the following patient-level information: age at index date, living in a rural area, Black race, Modified Charlson comorbidity index, number of hospital visits in the previous 12 months, number of unique drugs the patient was prescribed in the six months before the index date, as well as history in the last five years of diagnosis for peripheral vascular disease, congestive heart failure, coronary artery disease, myocardial infarction, number of nephrology consults in the previous 12 months before the index date.
** Results are shown for the 29 baseline characteristics included in the principal component analysis. We did not include any cluster-level baseline characteristics in the constraining process.
Table 4: Mean hazard ratio (2.5th, 97.5th percentile) for the composite outcome during a 3-year follow-up of patients on in-center hemodialysis.
Baseline characteristics adjusted in the analysis
|
Mean HR
|
Width of CI Ϫ
|
Type 1 error*
|
(2.5th, 97.5th percentile)
|
Unadjusted analyses
|
Simple (i.e., unconstrained) randomization
|
1.01 (0.87, 1.16)
|
0.280
|
5.9% ₳
|
Constrained on a minimal set of baseline characteristics ϒ
|
1.00 (0.89, 1.12)
|
0.233
|
3.2%
|
Constrained on a minimal set of baseline characteristics ϒ and historical rate of the primary outcome
|
1.00 (0.88, 1.13)
|
0.250
|
4.4% ₳
|
Constrained on a minimal set of baseline characteristics ϒ and cluster size at time of randomization
|
1.00 (0.88, 1.14)
|
0.260
|
5.2% ₳
|
Constrained on a minimal set of baseline characteristics ϒ, historical rate of the primary outcome, and cluster size at time of randomization
|
1.00 (0.88, 1.13)
|
0.247
|
4.5% ₳
|
Constrained on 10 principal components
|
1.01 (0.89, 1.12)
|
0.234
|
3.3%
|
Constrained on 10 principal components and historic rate of primary outcome
|
1.00 (0.88, 1.14)
|
0.261
|
5.2% ₳
|
Constrained on 10 principal components and cluster size at time of randomization
|
1.00 (0.87, 1.14)
|
0.264
|
4.1% ₳
|
Constrained on ten principal components, the historical rate of the primary outcome, and cluster size at time of randomization
|
1.00 (0.89, 1.13)
|
0.239
|
3.1%
|
Adjusted for constrained baseline characteristics**
|
Constrained on a minimal set of baseline characteristics ϒ
|
1.00 (0.89, 1.12)
|
0.232
|
8.6%
|
Constrained on a minimal set of baseline characteristics ϒ and historical rate of the primary outcome
|
1.00 (0.89, 1.12)
|
0.223
|
8.3%
|
Constrained on a minimal set of baseline characteristics ϒ and cluster size at time of randomization
|
1.00 (0.89, 1.11)
|
0.221
|
9.8%
|
Constrained on a minimal set of baseline characteristics ϒ, historical rate of the primary outcome, and cluster size at time of randomization
|
1.00 (0.90, 1.11)
|
0.216
|
9.6%
|
Constrained on 10 principal components
|
1.00 (0.90, 1.11)
|
0.203
|
5.2% ₳
|
Constrained on 10 principal components and historic rate of primary outcome
|
1.00 (0.90, 1.11)
|
0.201
|
6.0% ₳
|
Constrained on 10 principal components and cluster size at time of randomization
|
1.00 (0.90, 1.11)
|
0.203
|
6.3% ₳
|
Constrained on ten principal components, the historical rate of the primary outcome, and cluster size at time of randomization
|
1.00 (0.91, 1.11)
|
0.201
|
6.4% ₳
|
All randomization methods had 1000 randomization schemes. The cohort included patients on dialysis as of April 1, 2014, and any patient who started in-center hemodialysis at one of the 72 participating centers during the three-year follow-up.
HR= Hazard ratio; Width of CI = width of confidence interval (i.e., upper minus lower confidence limit).
Ϫ The confidence interval's width may not be equal to the difference between the lower and upper confidence limits because of rounding.
ϒ Included patient-level information: age, living in a rural area, Black race, Modified Charlson comorbidity index, number of hospital visits in the previous 12 months, number of unique drugs the patient was prescribed in the six months before the index date, as well as history in the last five years of diagnosis for peripheral vascular disease, congestive heart failure, coronary artery disease, myocardial infarction, number of nephrology consults in the previous 12 months before the index date.
* Type 1 error in the various constrained scenarios. Note: The nominal Type 1 error is 5%. The observed Type 1 error was within an "acceptable range" if it fell within the 95% confidence interval of the nominal value (i.e., between 3.6% and 6.4%).
** Adjusted analyses included baseline characteristics used in the constraining process.
₳ An acceptable Type 1 error was observed for this method (i.e., between 3.6% and 6.4%).