Clinical trial NCT00407641: Effects of Tinzaparin on Cardio-vascular Outcomes and on Blood Lipids in Diabetic Patients on Chronic Hemodialysis
Official title: Effects of Tinzaparin Sodium on Cardio-vascular OUtcomes and on Blood Lipids in Diabetic Patients on Chronic HEmodialysis: A Long-term, Prospective Study (The "Tinzaparin COULD HELP" Study).
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE4
Conditions: Diabetes Mellitus
Hemodialysis
Keywords: diabetes mellitus
chronic hemodialysis
anticoagulation
outcome
Lead sponsor: Anemia Working Group Romania
Sponsor class: OTHER
First posted: 2006-12-05
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: Low molecular weight heparin (LMWH) provides a safe and effective alternative to UFH for hemodialysis anticoagulation. While unfractionated (UF) heparin has been implicated in hyper-lipidemia, the effect of LMWHs on the lipid profile in non-diabetic patients on chronic hemodialysis remains controversial. The effect of LMWH in diabetic patients, a high risk group for developing hyper-lipidemia and cardio-vascular disease, has not been studied.

The study intends to examine the long-term effects of the replacement of UFH by LMWH (tinzaparin sodium) on cardio-vascular outcomes and on lipoprotein profiles in a large group of diabetic patients stable on HD.

Detailed description: Hemodialysed diabetic patients constitute a high-risk subset of patients for developing cardio-vascular disease, which accounts for nearly 50% of deaths. In those patients, mortality rates probably exceed 20% per year. After stratification for age, race and gender, cardio-vascular mortality is 10-20 times higher in these patients than in the general population. Thus cardio-vascular risk factors in these patients should be managed early, aggressively and in a multi-factorial manner in order to reduce their high cardio-vascular morbidity and mortality.

Low molecular weight heparin (LMWH) provides a safe and effective alternative to UFH for hemodialysis anticoagulation. While unfractionated (UF) heparin has been implicated in hyper-lipidemia, the effect of LMWHs on the lipid profile in non-diabetic patients on chronic hemodialysis remains controversial. The effect of LMWH in diabetic patients, a high risk group for developing hyper-lipidemia and cardio-vascular disease, has not been studied.

The study intends to examine the long-term effects of the replacement of UFH by LMWH (tinzaparin sodium) on cardio-vascular outcomes and on lipoprotein profiles in a large group of diabetic patients stable on HD.

Tinzaparin sodium is superior to UFH in terms of reducing cardio-vascular and cerebrovascular outcomes (primary end-point). Tinzaparin sodium is superior to UFH in terms of reducing the specified lipid parameters of stable diabetic patients on chronic hemodialysis.

A time-to-event analysis is the tool that will be used for recording events rate. Accordingly, the study will aim in enrolling 200 diabetic nephropathy patients, but allowing for a 10% drop-out rate, the number of evaluable patients in the study will be 180.

Therefore, for the primary triple end-point of death/MI/stroke (ischemic) with 180 evaluable patients, we will have an 80% power (at a two-sided alpha level of 0.05) to detect a statistical significant difference in the 2 groups if the rate of events in the UFH group is 30% and on tinzaparin is 13% or less.

For the secondary end-points in cardiovascular morbidity and mortality, if we assume that the event rate in the UFH group is 50%, then a statistical significance can be achieved if the rate in the tinzaparin group is at 30% or less.

For differences in average lipid values between the 2 groups, with 180 evaluable patients, a 2-sided alpha level at 0.05 and with 80% power, we can detect statistical significance if the difference is: for Total Cholesterol=19 mg/dL (SD of 46), for HDL-C = 4.6 mg/dL (SD=11), for TG = 30 mg/dL (SD=72), for LDL-C = 15 (SD=36) and for ApoB = 13 (SD=32).

Eligibility criteria: Inclusion Criteria:

* willingness to give written informed consent for participation in the study
* age 18-80 years old
* ability to understand and follow instructions and able to participate in the study for the entire period
* clinically stable (based on the investigator's judgment) within the three months prior to the screening visit
* written and signed agreement

Exclusion Criteria:

* antecedents of cerebrovascular accident, documented myocardial infarction, coronary angioplasty or bypass surgery within 6 months prior to the screening visit
* currently enrollment in any other investigational device or drug study, or participation in another clinical study within 30 days prior to the screening visit
* known or suspected drug or alcohol abuse
* known congenital or acquired bleeding disorders including hepatic failure and amyloidosis, present active major bleeding;
* increased risk of hemorrhage, due to: pericarditis or bacterial endocarditis, severe uncontrolled hypertension, active ulcerative and angiodysplastic gastrointestinal disease, hemorrhagic stroke, shortly after brain, spinal or ophthalmological surgery, concomitant treatment with platelet inhibitors, recent surgical procedures (especially with hemorrhagic complications or those in which hemorrhagic complications would be very severe - cardio-vascular, ophthalmological or neurological), planned surgical procedure within the next week, (history of) heparin-induced thrombocytopenia, with any other disease which, in the opinion of the investigator, makes unacceptable his/her inclusion in the study (known hypersensitivity to heparin, benzyl alcohol, or pork products that should not be treated with innohep®, severe psychiatric disorders, age \<18 years, malignant disorders and a life expectancy \<6 months, patients that were involved in another research study (studies) in the last month.

Primary outcomes:
measure: the composite event rate in death (any cause), myocardial infarction and stroke
Secondary outcomes:
measure: Cardio-vascular: the composite event rate of unstable angina, transient ischemic attacks, peripheral arterial disease, other, consequent to atherosclerosis
measure: Lipid profile
Other outcomes:
Locations:
city: Baia Mare
country: Romania
facility: Baia Mare County Hospital
city: Brasov
country: Romania
facility: "Sarah" Hemodialysis Centre
city: Bucharest
country: Romania
facility: "Dr Carol Davila" Teaching Hospital of Nephrology
city: Bucharest
country: Romania
facility: "N Paulescu" Institute
city: Bucharest
country: Romania
facility: Fundeni Clinical Hospital
city: Cluj
country: Romania
facility: Cluj University Hospital
city: Craiova
country: Romania
facility: Dolj County Hospital
city: Focsani
country: Romania
facility: Vrancea County Hospital
city: Iasi
country: Romania
facility: "CI Parhon" Clinical Hospital
city: Oradea
country: Romania
facility: Bihor County Hospital
city: Ploiesti
country: Romania
facility: Prahova County Hospital
city: Targoviste
country: Romania
facility: Dambovita County Hospital
city: Timisoara
country: Romania
facility: Timisoara County Hospital
Study officials:
affiliation: Dr Carol Davila Teaching Hospital of Nephrology
name: Gabriel Mircescu, Professor
role: STUDY_CHAIR
affiliation: "Dr Carol Davila" Teaching Hospital of Neprology
name: Constantin Verzan, MD, PhD
role: STUDY_DIRECTOR
affiliation: Dr Carol Davila Teaching Hospital of Nephrology
name: Cristina Capusa, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: