Cardiovascular Disease, Chronic Kidney Disease, Death
Conditions
Keywords
homocysteine, multi-vitamin, cardiovascular disease, renal transplant recipients
Brief summary
The purpose of this randomized clinical trial is to determine if lowering homocysteine levels in renal transplant recipients with a multivitamin will reduce the occurrence of cardiovascular disease outcomes.
Detailed description
The hypothesis of the trial is as follows: Treatment with a high dose combination of folic acid, vitamin B6, and vitamin B12 will reduce the rate of pooled arteriosclerotic cardiovascular disease outcomes (i.e., pooled occurrence of non-fatal and fatal arteriosclerotic outcomes, including coronary heart, cerebrovascular, and peripheral vascular disease events) relative to treatment with an identical multivitamin containing no folic acid, and Estimated Average Requirement amounts of vitamin B6, vitamin B12, among chronic, stable renal transplant recipients
Interventions
DRUGHigh Dose Multivitamin
Vitamin B6 (Pyridoxine HCl): 50 mg Folic acid: 5.0 mg Vitamin B12: 1.0 mg Vitamin B1 (Thiamine HNO3): 1.5 mg Vitamin B2 (Riboflavin): 1.5 mg Vitamin C (Ascorbic Acid): 60 mg d-Biotin: 300 mcg Niacinamide: 20 mg Pantothenic Acid Calcium Pantothenate): 10 mg
DEVICELow Dose Multivitamin
Vitamin B6 (Pyridoxine HCl): 1.4 mg Folic acid: 0.0 mg Vitamin B12: 2.0 mcg Vitamin B1 (Thiamine HNO3): 1.5 mg Vitamin B2 (Riboflavin): 1.5 mg Vitamin C (Ascorbic Acid): 60 mg d-Biotin: 300 mcg Niacinamide: 20 mg Pantothenic Acid Calcium Pantothenate): 10 mg
Sponsors
Office of Dietary Supplements (ODS)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
35 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* 35 - 75 years old * Had kidney transplant at least 6 months * Calculated Creatinine Clearance must be 25 mL/min or greater * Must be willing to stop supplements (B6, B12, folic acid) for 4-6 weeks prior to visit
Exclusion criteria
* If pregnant or lactating * If of child bearing potential and not on birth control * If any of the following will limit life expectancy to less than 2 yrs: * Cancer * Congestive heart failure (CHF) (end stage) * Liver disease (end stage) * Severe pulmonary disease * Progressive HIV * Any other chronic wasting illness * If patient had myocardial infarction (MI), stroke, lower extremity amputation above ankle or percutaneous revascularization procedure (coronary, cerebrovascular, lower extremity) in past 2months * If patient had coronary artery bypass graft (CABG) or abdominal aortic aneurysm (AAA) in past 5 months * If patient has conditions that prevent reliable study participation e.g., depression, alcohol or drug abuse, other cardiovascular disease (CVD) studies * If patient has had multi-organ transplant, except kidney/pancreas
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Recurrent or de Novo Arteriosclerotic Cardiovascular Disease (CVD) Defined as the Occurrence of Non-fatal or Fatal Arteriosclerotic Outcomes Including Coronary Heart, Cerebrovascular, and Peripheral Vascular Disease Events | Up to 6 years (mean 4 years) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Resuscitated Sudden Death (RSD) | Up to 6 years (mean 4 years) | censored at 3 months after return to dialysis |
| CVD Death | Up to 6 years (mean 4 years) | censored at 3 months after return to dialysis |
| Coronary Artery Revascularization | Up to 6 years (mean 4 years) | censored at 3 months after return to dialysis |
| Mortality (All-cause) | Up to 6 years (mean 4 years) | censored at 3 months after return to dialysis |
| Renal Graft Failure | Up to 6 years (mean 4 years) | — |
| Fatal/Non-fatal Stroke | Up to 6 years (mean 4 years) | censored at 3 months after return to dialysis |
| Lower Extremity Peripheral Arterial Disease (PAD) | Up to 6 years (mean 4 years) | censored at 3 months after return to dialysis |
| Carotid Endarterectomy or Angioplasty | Up to 6 years (mean 4 years) | censored at 3 months after return to dialysis |
| Abdominal Aortic Aneurysm Repair | Up to 6 years (mean 4 years) | censored at 3 months after return to dialysis |
| Renal Artery Revascularization | Up to 6 years (mean 4 years) | censored at 3 months after return to dialysis |
| Fatal/Non-fatal Myocardial Infarction (MI) | Up to 6 years (mean 4 years) | censored at 3 months after return to dialysis |
Countries
Brazil, Canada, United States
Participant flow
Recruitment details
Trial enrolled 4110 participants from August 2002 through January 2007 at 20 clinical sites in the US, Canada, and Brazil.
Participants by arm
| Arm | Count |
|---|---|
| High Dose Multivitamin Multivitamin with increased folic acid, vitamin B6 and vitamin B12
High Dose Multivitamin: Vitamin B6 (Pyridoxine HCl): 50 mg Folic acid: 5.0 mg Vitamin B12: 1.0 mg Vitamin B1 (Thiamine HNO3): 1.5 mg Vitamin B2 (Riboflavin): 1.5 mg Vitamin C (Ascorbic Acid): 60 mg d-Biotin: 300 mcg Niacinamide: 20 mg Pantothenic Acid Calcium Pantothenate): 10 mg | 2,056 |
| Low Dose Multivitamin Multivitamin devoid of folic acid and with EAR amounts of vitamin B6 and vitamin B12
Low Dose Multivitamin: Vitamin B6 (Pyridoxine HCl): 1.4 mg Folic acid: 0.0 mg Vitamin B12: 2.0 mcg Vitamin B1 (Thiamine HNO3): 1.5 mg Vitamin B2 (Riboflavin): 1.5 mg Vitamin C (Ascorbic Acid): 60 mg d-Biotin: 300 mcg Niacinamide: 20 mg Pantothenic Acid Calcium Pantothenate): 10 mg | 2,054 |
| Total | 4,110 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 251 | 242 |
| Overall Study | Lost to Follow-up | 225 | 235 |
| Overall Study | Withdrawal by Subject | 198 | 171 |
Baseline characteristics
| Characteristic | High Dose Multivitamin | Low Dose Multivitamin | Total |
|---|---|---|---|
| Age, Continuous | 52 years STANDARD_DEVIATION 9.4 | 52 years STANDARD_DEVIATION 9.5 | 52 years STANDARD_DEVIATION 9.4 |
| Body mass index | 29 kg/m^2 STANDARD_DEVIATION 6.2 | 29 kg/m^2 STANDARD_DEVIATION 6.3 | 29 kg/m^2 STANDARD_DEVIATION 6.2 |
| Calculated or direct low-density lipoprotein cholesterol | 2.6 mmol/L STANDARD_DEVIATION 0.9 | 2.6 mmol/L STANDARD_DEVIATION 0.9 | 2.6 mmol/L STANDARD_DEVIATION 0.9 |
| Current smoker Current smoker | 230 participants | 221 participants | 451 participants |
| Current smoker Not current smoker | 1826 participants | 1833 participants | 3659 participants |
| Graft vintage | 6 years STANDARD_DEVIATION 5.1 | 5 years STANDARD_DEVIATION 5 | 5 years STANDARD_DEVIATION 5 |
| High-density lipoprotein cholesterol | 1.2 mmol/L STANDARD_DEVIATION 0.4 | 1.2 mmol/L STANDARD_DEVIATION 0.4 | 1.2 mmol/L STANDARD_DEVIATION 0.4 |
| History of CVD History of CVD | 406 participants | 414 participants | 820 participants |
| History of CVD No History of CVD | 1650 participants | 1640 participants | 3290 participants |
| History of diabetes mellitus History of diabetes mellitus | 813 participants | 850 participants | 1663 participants |
| History of diabetes mellitus No history of diabetes mellitus | 1243 participants | 1204 participants | 2447 participants |
| Prevalent hypertension Non-prevalent hypertension | 177 participants | 155 participants | 332 participants |
| Prevalent hypertension Prevalent hypertension | 1879 participants | 1899 participants | 3778 participants |
| Region of Enrollment Brazil | 307 participants | 305 participants | 612 participants |
| Region of Enrollment Canada | 249 participants | 249 participants | 498 participants |
| Region of Enrollment United States | 1500 participants | 1500 participants | 3000 participants |
| Sex: Female, Male Female | 767 Participants | 761 Participants | 1528 Participants |
| Sex: Female, Male Male | 1289 Participants | 1293 Participants | 2582 Participants |
| Total cholesterol | 4.8 mmol/L STANDARD_DEVIATION 1.2 | 4.8 mmol/L STANDARD_DEVIATION 1.1 | 4.8 mmol/L STANDARD_DEVIATION 1.1 |
| Triglycerides levels | 2.3 mmol/L STANDARD_DEVIATION 2.5 | 2.2 mmol/L STANDARD_DEVIATION 1.6 | 2.2 mmol/L STANDARD_DEVIATION 2.1 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 121 / 2,056 | 114 / 2,054 |
| serious Total, serious adverse events | 0 / 2,056 | 0 / 2,054 |
Outcome results
Primary
Recurrent or de Novo Arteriosclerotic Cardiovascular Disease (CVD) Defined as the Occurrence of Non-fatal or Fatal Arteriosclerotic Outcomes Including Coronary Heart, Cerebrovascular, and Peripheral Vascular Disease Events
Time frame: Up to 6 years (mean 4 years)
Population: Censored at 3 months after return to dialysis
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| High Dose Multivitamin | Recurrent or de Novo Arteriosclerotic Cardiovascular Disease (CVD) Defined as the Occurrence of Non-fatal or Fatal Arteriosclerotic Outcomes Including Coronary Heart, Cerebrovascular, and Peripheral Vascular Disease Events | 269 participants |
| Low Dose Multivitamin | Recurrent or de Novo Arteriosclerotic Cardiovascular Disease (CVD) Defined as the Occurrence of Non-fatal or Fatal Arteriosclerotic Outcomes Including Coronary Heart, Cerebrovascular, and Peripheral Vascular Disease Events | 278 participants |
p-value: 0.9395% CI: [0.84, 1.17]Regression, Cox
Secondary
Abdominal Aortic Aneurysm Repair
censored at 3 months after return to dialysis
Time frame: Up to 6 years (mean 4 years)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| High Dose Multivitamin | Abdominal Aortic Aneurysm Repair | 3 participants |
| Low Dose Multivitamin | Abdominal Aortic Aneurysm Repair | 5 participants |
p-value: 0.595% CI: [0.15, 2.57]Regression, Cox
Secondary
Carotid Endarterectomy or Angioplasty
censored at 3 months after return to dialysis
Time frame: Up to 6 years (mean 4 years)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| High Dose Multivitamin | Carotid Endarterectomy or Angioplasty | 10 participants |
| Low Dose Multivitamin | Carotid Endarterectomy or Angioplasty | 9 participants |
p-value: 0.7895% CI: [0.46, 2.8]Regression, Cox
Secondary
Coronary Artery Revascularization
censored at 3 months after return to dialysis
Time frame: Up to 6 years (mean 4 years)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| High Dose Multivitamin | Coronary Artery Revascularization | 111 participants |
| Low Dose Multivitamin | Coronary Artery Revascularization | 120 participants |
p-value: 0.795% CI: [0.73, 1.23]Regression, Cox
Secondary
CVD Death
censored at 3 months after return to dialysis
Time frame: Up to 6 years (mean 4 years)
Population: P was calculated with stratified proportional hazards models stratified by country
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| High Dose Multivitamin | CVD Death | 75 participants |
| Low Dose Multivitamin | CVD Death | 91 participants |
p-value: 0.2895% CI: [0.62, 1.15]Regression, Cox
Secondary
Fatal/Non-fatal Myocardial Infarction (MI)
censored at 3 months after return to dialysis
Time frame: Up to 6 years (mean 4 years)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| High Dose Multivitamin | Fatal/Non-fatal Myocardial Infarction (MI) | 90 participants |
| Low Dose Multivitamin | Fatal/Non-fatal Myocardial Infarction (MI) | 86 participants |
p-value: 0.6195% CI: [0.8, 1.45]Regression, Cox
Secondary
Fatal/Non-fatal Stroke
censored at 3 months after return to dialysis
Time frame: Up to 6 years (mean 4 years)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| High Dose Multivitamin | Fatal/Non-fatal Stroke | 35 participants |
| Low Dose Multivitamin | Fatal/Non-fatal Stroke | 32 participants |
p-value: 0.6495% CI: [0.69, 1.81]Regression, Cox
Secondary
Lower Extremity Peripheral Arterial Disease (PAD)
censored at 3 months after return to dialysis
Time frame: Up to 6 years (mean 4 years)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| High Dose Multivitamin | Lower Extremity Peripheral Arterial Disease (PAD) | 59 participants |
| Low Dose Multivitamin | Lower Extremity Peripheral Arterial Disease (PAD) | 53 participants |
p-value: 0.4995% CI: [0.79, 1.65]Regression, Cox
Secondary
Mortality (All-cause)
censored at 3 months after return to dialysis
Time frame: Up to 6 years (mean 4 years)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| High Dose Multivitamin | Mortality (All-cause) | 217 participants |
| Low Dose Multivitamin | Mortality (All-cause) | 214 participants |
p-value: 0.6795% CI: [0.86, 1.26]Regression, Cox
Secondary
Renal Artery Revascularization
censored at 3 months after return to dialysis
Time frame: Up to 6 years (mean 4 years)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| High Dose Multivitamin | Renal Artery Revascularization | 9 participants |
| Low Dose Multivitamin | Renal Artery Revascularization | 7 participants |
p-value: 0.695% CI: [0.48, 3.5]Regression, Cox
Secondary
Renal Graft Failure
Time frame: Up to 6 years (mean 4 years)
Population: Intention-to-treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| High Dose Multivitamin | Renal Graft Failure | 181 participants |
| Low Dose Multivitamin | Renal Graft Failure | 162 participants |
p-value: 0.1995% CI: [0.93, 1.43]Regression, Cox
Secondary
Resuscitated Sudden Death (RSD)
censored at 3 months after return to dialysis
Time frame: Up to 6 years (mean 4 years)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| High Dose Multivitamin | Resuscitated Sudden Death (RSD) | 7 participants |
| Low Dose Multivitamin | Resuscitated Sudden Death (RSD) | 9 participants |
p-value: 0.6695% CI: [0.3, 2.15]Regression, Cox