Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT06084871 |
| Other study ID # |
I11-657-22 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
June 1, 2023 |
| Est. completion date |
June 1, 2025 |
Study information
| Verified date |
October 2023 |
| Source |
ERAS Turkey Association |
| Contact |
Onat Bermede, MD |
| Phone |
+905056374404 |
| Email |
onatbermede[@]gmail.com |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
- Rationale and background: Surgical patients' transfusions have changed from replacing
surgically lost blood with allogenic blood transfusions to implementing strategies that
reduce transfusion requirements. Patient Blood Management (PBM) is designed to maintain
hemoglobin concentration, optimize hemostasis, and minimize blood loss to improve
patient outcomes. There is mounting evidence that multimodal PBM programs can improve
postoperative outcomes and reduce perioperative blood transfusions and costs. The TULIP
study in Turkey showed higher uses of blood transfusions in major surgical patients,
including coronary artery surgeries in Turkey. The current studies also support the
preoperative use of intravenous iron and/or vitamin B12/folic acid in major surgical
patients. So, we aim to evaluate the efficacy of implantation of PBM in CABG surgeries
in Turkey.
- Research question and objectives: Is it possible to decrease the amount of perioperative
blood and blood products transfusions by implementing PBM in patients who underwent CABG
surgeries? The primary objective of the study is to demonstrate the reduction in
perioperative RBC units transfused, when PBM is implemented in cardiac surgery in
Turkey. The secondary objectives are to evaluate the concurrent reduction of FFP,
platelet and total blood products used as compared to a control group, length of
hospital and ICU stay following the surgery.
- Study design: A prospective, multicenter, non-interventional study with a
historical/retrospective control group.
- Population: Patients who are operated on for coronary artery bypass grafting.
- Variables: Demographic (age, sex), clinical (body mass index, comorbidities, ASA score,
P-POSSUM score, Charlson Comorbidity Index), operative (type and duration of
operations), laboratory (hemoglobin, platelet count, coagulation profile), laboratory
for anemia (transferrin saturation, ferritin, creatinine clearance), preoperative
treatment, transfusion data, and outcome (morbidity, mortality, lengths of hospital
stay).
- Exposures: Preoperative IV iron treatment of anemia.
- Data sources: Medical data of the patients are obtained after entering a prespecified
database (e-CRF) for the study subjects. For the control group, the medical data of the
patients will be obtained retrospectively from the database of the TULIP study.
- Study size: Study group: A total of 368 patients from five different centers across
Turkey. Control group: at least 368 patients from the same centers attending the TULIP
study. Finally, 736 patients will be included for the study.
Description:
Patient blood management (PBM) is defined as "the timely application of evidence-based
medical and surgical concepts designed to maintain hemoglobin concentration, optimize
haemostasis and minimize blood loss in an effort to improve patient's outcome" (1,2). Patient
blood management has recently been introduced in several areas where blood transfusions are
important, such as anaesthesiology, cardiac surgery, orthopedic surgery, or traumatology (3).
Its adoption has been recommended by the WHO since 2010, as well as by national health
regulation agencies, international professional societies, and the European Commission (4-7).
In literature, there is mounting evidence that multimodal PBM programs can be effective at
improving postoperative outcomes and reducing perioperative blood transfusions and costs (8).
Turkish Society of Anaesthesiology and Reanimation (TARD) PBM Task Force has been working on
this subject and studied transfusion practices in major surgery patients and the prevalence
of perioperative anemia (9). In the TULIP study, unfortunately, high usage of transfusions in
major surgical patients in Turkey was documented. As demonstrated in the TULIP study, one of
the surgeries that had high transfusion use, was cardiac surgery. Specific procedures with the
highest RBC use were also coronary artery bypass grafting (16.9% of all units). Low
hemoglobin concentration was the most common indication for intra-operative RBC transfusion
(57%).
Preoperative anemia is common in cardiac surgery, with a prevalence between 10% and 50%
(depending on the applied definition). Using the standard World Health Organization
definition, the prevalence of anemia in the adult cardiac surgery population seems to be
around 20% to 30% (10). Preoperative anemia is an independent risk factor for the transfusion
of RBC, postoperative morbidity, and mortality (11, 12). An analysis of 9,144 cardiac surgery
patients demonstrated that patients with low hematocrit values (<25%) during surgery who were
exposed to RBC transfusion had an increased morbidity (cardiac and renal) and hospital
mortality (13). Preoperative anemia is mostly the result of inadequate erythropoiesis owing
to iron deficiency, malnutrition, malabsorption, inflammation, bone marrow disorders, or
chronic blood loss. Importantly, anemic patients with iron deficiency need to be identified
as early as possible by the cardiologist, surgeon, or anesthesiologist. With the introduction
of a special PBM anemia walk-in clinic, anemia management can be initiated at an early stage.
This would allow for timely optimization of iron stores to compensate for iron deficiency
(14) or other treatable forms of anemia. Diagnosis and treatment of preoperative anemia are
currently not part of standard care but are a core element of PBM to increase Hb values in
cardiac surgery patients. In recent years, many studies investigated preoperative anemia and
its effects on the outcome of adult cardiac surgery patients (Table 1).
Table 1. Preoperative anemia and its effects on the outcome of adult cardiac surgery patients
Author Study Design Sample Size Primary Outcome
- Kulier et al. 2007 (14) Prospective, observational 5,065 Cardiac and noncardiac adverse
events ↑
- van Straten et al. 2009 (15) Prospective, observational 10,025 Early and late mortality
↑
- Carrascal et al. 2010 (16) Cohort study (retrospective) 1,388 Red cell transfusion ↑
Hospital stay ↑
- Piednoir et al. 2011 (17) Cohort study (retrospective) 100 Transfusion rate ↑
Postoperative fatigue ↑
- Hung et al. 2011 (18) Cohort study (retrospective) 2,688 Transfusion ↑ Death ↑ ICU stay
↑
- David et al. 2013 (19) Cohort study (retrospective) 943 Transfusion rate ↑
- Kim et al. 2015 (20) Cohort study (retrospective) 712 Transfusion rates ↑ Morbidity ↑
- Hallward et al. 2016 (21) Cohort study (retrospective) 1,972 Blood transfusion ↑ ICU
stay ↑ Hospital stay ↑
When the interventional studies investigating the effect of PBM in cardiac surgery patients
are examined, the studies showing visible differences are shown in Table 2.
Table 2. The effect of PBM in cardiac surgery patients
Author Study Design Sample Size Intervention Primary Outcome
- Karkouti et al. 2006 (22) Randomized, interventional 31 Iron ± EPO Hb level →
- Cladellas et al. 2012 (23) Cohort study (retrospective) 134 EPO + IV iron Renal failure
↓ Red blood cell transfusion ↓
- Garrido-Martin et al. 2012 (24) Randomized, interventional 159 Oral or IV iron IV iron
Hb level →
- Johansson et al. 2015 (25) Randomized, interventional 60 IV iron Hb level ↑
- Duce et al. 2017 (26) Cohort study retrospective 159 EPO vs. blood cell transfusion
Mortality → Thrombotic events →
- Spahn et al. 2019 (27) Randomized, interventional 1,006 IV iron, erythropoietin alpha,
vitamin B12 and folic acid Red blood cell transfusions ↓ Hb level ↑ Reticulocytes ↑
Reticulocyte Hb ↑
In literature, IV iron treatment is recommended for cardiac surgery patients. Examples of
these studies can be given as follows: Iron supplementation, especially in combination with
EPO is recommended when anemia of chronic disease is accompanied by iron deficiency with
complete depletion of iron stores (28).
The Hb concentration after iron supplementation rise approximately 1 to 2 g/dL within 2 to 4
weeks. Very recently, a trial investigating the effect of ultra-short-term treatment
(combination of iron, erythropoietin, vitamin B12, and folic acid administration) of 505
patients with iron deficiency or anemia undergoing cardiac surgery showed significantly
reduced RBC transfusions, higher Hb concentration, higher reticulocyte count, and a higher
reticulocytes Hb content during the first 7 days (27). This study suggests that an iron
supplementation even immediately before cardiac surgery has beneficial effects, however, an
early start to therapy could be more effective (29,30).
Whether different thresholds of Hb defining anemia in men and women lead to an undertreatment
of female patients has been investigated in many studies and is the subject of current
discussions. Most of these studies were conducted with cardiac surgery patients (31,32). The
latest data show that women have worse outcomes compared with men having anemia.
Although other factors have an impact on this result (e.g., higher age, higher incidence of
comorbidities, more acute and symptomatic stage in women), it is proposed that for all
patients, regardless of sex, a Hb threshold of 13 g/dL should be applied (33). This is
particularly important in those undergoing surgery with the use of cardiopulmonary bypass
where dependent on the system, in most cases, the same volume of fluid is added to the pump.
Perioperative bleeding has been shown to be an independent predictor of hospital mortality.
In a study including more than 9000 patients undergoing cardiac surgery with CPB, massive
blood loss (defined by the transfusion of at least five units of packed red blood cells on
the day of surgery) was associated with an 8-fold increase in mortality (34). Other studies
have also reported excess morbidity, particularly in terms of thromboembolic complications,
infections, and higher rates of surgical re-exploration (35). Notably, surgical
re-exploration and transfusion following bleeding are also associated with increased
infection, mortality, and a longer stay in ICU and hospital (36,37).
Excessive postoperative hemorrhage in cardiac surgery has a significant economic impact: a
retrospective German analysis of more than 1100 patients estimated its average additional
cost to be €6251 per patient (38).
Oral iron therapy is inexpensive and easy to administer, but its gastrointestinal side
effects limit the routine use of oral iron therapy (39). Several studies reported the good
efficacy of intravenous iron therapy (IVIT) in increasing hemoglobin levels and reducing
blood transfusions in patients with anemia (40-42). However, the recovery profiles according
to the status of the disease or condition of the patients are controversial regarding the
efficacy of IVIT in transfusion practices. While some elements of PBM have a strong evidence
base in cardiac surgery, such as the use of tranexamic acid (TXA) and reduced transfusion
thresholds (43,33), the evidence for preoperative anemia optimization with IVIT is less in
Turkiye. Sert et al. from Turkiye, evaluated retrospectively the data of patients who
underwent elective open-heart surgery. Their primary aim was to compare the patient outcomes,
the requirement for transfusion, and the cost of transfusion between two different periods
with and without PBM protocols. The authors found that the transfusion of unnecessary blood
and blood products was reduced, and the cost decreased with the PBM protocol, although blood
product usage did not affect 30-day mortality (44). It was observed that 37.1% of the
patients were anemic, 50.6% were using anticoagulant drugs, and 78% had at least an
additional disease. Although these factors were regarded as risk factors for transfusion, it
was determined that patients with anemia had more frequently required transfusions than those
without anemia.
In the general framework, five main risk factors for high risk of bleeding or transfusion are
very consistently identified independently of the country: pre-operative anemia, prior
cardiac surgery, clopidogrel 5 days or less before surgery, use of other P2Y12 inhibitors at
any point, and thrombocytopenia <100.000 platelets/mm3. In conclusion, more efforts are
needed to clarify and complement the currently available guidelines and to define a
homogenous landscape for PBM practices implementation (45).
Potential barriers to the implementation of PBM are lack of knowledge, under-representation
of anemia management in the education of young physicians, inadequate interpretation of
controversial evidence, errors in reasoning, oversimplification, wide variations in belief,
and lack of agreement of hospitals, self-efficiency, outcome expectancy, and stability of the
previous practice (46).
Therefore, we plan to perform a large-scale, prospective study in which a well-designed PBM
program is used to confirm the efficacy of perioperative IVIT in patients with CABG surgery.
As a second step, PABMiCS study is proposed to identify the benefits of PBM implementation,
including preoperative anemia management, in major cardiac surgeries in Turkiye.
