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Blood Transfusion Thresholds in Medical Patients with Coronary Artery Disease Internal Medicine Resident Grand Rounds December 4, 2001 Alexander Hadley, MD Case Presentation Mr. C is a 56-year-old male who presented to the ED at WFUBMC with several days of severe sub-sternal chest pain.

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blood transfusion thresholds in medical patients with coronary artery disease

Blood Transfusion Thresholds in Medical Patients with Coronary Artery Disease

Internal Medicine

Resident Grand Rounds

December 4, 2001

Alexander Hadley, MD

case presentation
Case Presentation
  • Mr. C is a 56-year-old male who presented to the ED at WFUBMC with several days of severe sub-sternal chest pain.
  • His pain and associated symptoms were classic for unstable angina.
  • He had a past history of HTN, tobacco abuse and a family h/o CAD.
case presentation3
Case Presentation
  • ROS:
    • Three months of gross hematuria.
    • Slowly progressive weakness and short of breath.
    • Several episodes of exertional angina over the previous weeks.
case presentation4
Case Presentation
  • Physical Exam
    • BP 126/61 Pulse 77 R 16 T 98.8
    • Orthostatic vitals: negative
    • Oral: Mucosa moist
    • Gen: pallor, ill appearing
    • Cardiac: Reg, no murmurs
    • Lungs: CTA
    • Ext.: no edema
case presentation5
Case Presentation
  • Labs
    • Hemoglobin 5.6 g/dl
    • Cardiac enzymes normal.
  • EKG
    • Anterior Q-waves.
    • No acute ischemic changes.
case presentation6
Case Presentation
  • Mr. C Ruled out for an acute MI.
  • He received four units of packed red blood cells and his hemoglobin became stable at 8.9 g/dl.
  • He had no more chest pain but did have persistent hematuria.
case presentation7
Case Presentation
  • A DSE was performed which showed a small area of inducible ischemia in his anterior / lateral wall.
  • Ultrasound of the abdomen showed normal kidneys but a mass in the bladder worrisome for transitional cell carcinoma.
case presentation8
Case Presentation
  • It was suggested that we should transfuse him to keep his hemoglobin above 10 g/dl because of his known CAD.
  • Is that right?
clinical questions
Clinical Questions
  • Is there any evidence to support using specific hemoglobin or hematocrit targets as criteria to transfuse asymptomatic patients with anemia?
  • Should we use different transfusion thresholds for people with coronary artery disease or acute coronary syndromes?
introduction
Introduction
  • In 1997 11.4 million units of red blood cells were transfused in the United States.
  • This number is slightly down from a decade ago when 12.2 million units were transfused.
introduction11
Introduction
  • Several investigators have reviewed the transfusions practices at hospitals and concluded that many transfusions are done without proper indications.
  • They estimate 25% of transfusions were inappropriate.
introduction12
Introduction
  • Conventional Wisdom has taught that:
    • hemoglobin levels should be kept above some minimum value such as 7 or 8 g/dl
    • patients with coronary artery disease need higher values to maintain myocardial oxygen supply (such as 10 g/dl or hematocrit of 30%).
  • This has been called the 10 / 30 Rule.
why keep heart patients at higher hg hct values
Why keep heart patients at higher Hg. / Hct. Values?
  • Patients with anemia have decreased oxygen carrying capacity.
  • The body compensates in two ways:
    • Increased cardiac output.
    • Increased release of oxygen from hemoglobin.
why keep heart patients at higher hg hct values15
Why keep heart patients at higher Hg. / Hct. Values?
  • In anemia,  2,3-DPG shifts the curve to the right.
why keep heart patients at higher hg hct values16
Why keep heart patients at higher Hg. / Hct. Values?
  • Problem 1: The increased cardiac output in anemia leads to increased oxygen demand.
  • Problem 2: At baseline the myocardium extracts a very high percentage of oxygen. Therefore the heart must increase blood flow to increase oxygen supply.
  • Problem 3: Coronary stenosis may limit blood flow.
why keep heart patients at higher hg hct values17
Why keep heart patients at higher Hg. / Hct. Values?

Problem 1 + Problem 2 + Problem 3 =

Ischemia.

(Maybe)

why limit transfusions
Why limit transfusions?
  • Limited supply
    • Blood donation has dropped from 14 million units in 1986 to 12 million units in 1997.
    • The increasing proportion of elderly in the US. Is projected to lead to serious shortages.
  • Costs
    • $155 per unit on blood
    • 12 million transfusions per year
    • $1.86 billion per year
risks of transfusion
Risks of Transfusion
  • Infectious
    • Viral
      • CMV
      • Hepatitis A, B, and C
      • HIV
      • HTLV Types I and II
    • Bacterial Contamination
risks of transfusion20
Risks of Transfusion
  • Immunologic Reactions
    • Non-hemolytic reaction (fever, chills, urticaria)
    • Acute hemolysis
    • Delayed hemolysis
    • Transfusion related lung injury (ARDS)
    • Transfusion Related Immunomodulation (TRIM)
current guidelines
“Current” Guidelines
  • Most transfusion guidelines focus on what types of blood products to give and how to give them. Most do not give specific transfusion thresholds.
  • There has been little human data to guide transfusion thresholds in medical patients.
  • Guidelines are based on expert opinion.
current guidelines22
“Current” Guidelines

NIH Health Consensus Conference on Red Blood Cell Transfusion (1988)

American Society of Anesthesiology (1996)

Canadian Medical Association (1997)

  • All conclude there is no evidence to support using hemoglobin or hematocrit levels as transfusion thresholds.
  • They stress clinical judgment as a guide.
acp guidelines
ACP Guidelines
  • In 1992 the ACP formed a task force to look at indications for transfusion in medical patients.
  • They specifically looked for data to support transfusion threshold but found little.
  • They reviewed available data including studies of the natural history of anemia, animal models, and laboratory research to reach their expert opinions.
acp guidelines26
ACP Guidelines

1. Assess the patient’s intravascular volume status. All asymptomatic patients, with or without risk factors, should be normovolemic. Normovolemic anemia (hemoglobin 7-10 g/dl) can be well tolerated in asymptomatic patients.

acp guidelines27
ACP Guidelines

2. Intravascular volume should be restored with crystalloids.

3. In asymptomatic patients with anemia who are at risk, transfusion is NOT indicated unless a deterioration in vital signs is seen on the patients develop symptoms.

acp guidelines28
ACP Guidelines

4. In the absence of the above risks or symptoms, transfusion is not indicated, independent of hemoglobin level.

slide30
Johnson, RG et al. “Comparison of two transfusion strategies after elective operations for myocardial revascularization.” 1992.
  • This was a prospective, randomized trial comparing two different transfusion thresholds in patients who had undergone elective coronary artery bypass surgery.
  • First trial to prospectively test the assertion that these patients could be safely treated with a restrictive transfusion protocol.
johnson rg et al
Johnson, RG et al.
  • Patients:
    • Patients enrolled prior to CABG.
    • Inclusion Criteria
      • Patients undergoing CABG
      • Able to bank three units of autologous blood
    • Exclusion Criteria
      • Hct < 35%
      • Unable to bank enough blood in time for surgery.
    • Over 500 excluded, 38 consented for study.
johnson rg et al32
Johnson, RG et al.
  • Design:
    • Patients were randomized to two groups that would receive autologous blood transfusion after CABG to keep their hematocrit at, or above, either 32% (liberal group) or 25% (conservative group).
    • Care for each group was the same throughout the study except for the target hematocrit.
    • On post-op day five and six patients underwent an exercise treadmill test.
johnson rg et al33
Johnson, RG et al
  • Results
    • Blood Use: Significantly fewer units blood were transfused in the post-op period in the conservative group, 2.05  0.93 vs. 1.0  0.86 (p = 0.012).
    • There was no significant difference cardiac output between the two groups.
    • Exercise tolerance was not statistically different between the two groups.
johnson rg et al34
Johnson, RG et al
  • Conclusions
    • Using a hematocrit of 25% vs. 32% resulted in lower use of RBCs.
    • The lower transfusion threshold was as safe as the higher level in this small group of post-CABG patients.
    • Exercise tolerance was not statistically different between the two groups.
johnson rg et al35
Johnson, RG et al
  • Limitations
    • Small sample size.
    • A very large number of patients undergoing CABG at the same time were not included, which could introduce unrecognized bias.
    • The post-CABG patients in this study represent a specialized group and the results cannot be easily generalized to patients undergoing PCI or patients further out from revascularization.
hebert pc et al does transfusion practice affect mortality in critically ill patients 1997
Hebert PC et al. “Does transfusion practice affect mortality in critically ill patients?” 1997
  • Retrospective and prospective cohort study of critically ill patients looking at associations between transfusion practice and mortality rates.
  • Patients who died had lower hemoglobin values than those who lived (p < 0.0001)
  • In patients, with cardiac disease there was a trend toward higher mortality when Hg was < 9.5 as compared with anemic patients without cardiac disease (p = 0.09).
slide37
Hebert et al. “A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care.” 1999
  • Canadian Critical Care Trials Group
hebert et al 1999
Hebert et al. 1999

Hebert et al. NEJM 1999; 340:6

hebert et al 199939
Hebert et al. 1999
  • Design
    • The study was carried out at 22 centers and uniform transfusion protocols were developed and followed at each site.
    • Patients in the restrictive group received transfusions when their hemoglobin fell below 7 g/dl with a goal of keeping their hemoglobin between 7 and 9 g/dl.
    • The threshold in the liberal group was 10.0 g/dl with a goal of 10 to 12 g/dl.
    • All other aspects of care were dictated by each patient’s individual need.
hebert et al 199940
Hebert et al. 1999
  • Endpoints:
    • Primary outcome = 30-day mortality
    • Secondary endpoints
      • 60-day mortality
      • Hospital and ICU mortalities
      • Hospital and ICU lengths of stay
      • Multiple-organ-dysfunction score (MODS)
hebert et al 199941
Hebert et al. 1999
  • Results:
    • Average daily hemoglobin was 8.50.7 in the restrictive group vs. 10.70.7 in the liberal group (p<0.01).
hebert et al 199942
Hebert et al. 1999
  • The restrictive group used 54% fewer unit of packed red cells during their stay than the liberal group: 2.64.1 vs. 5.65.3 (p<0.01).
hebert et al 199943
Hebert et al. 1999
  • There was a trend toward decreased mortality at 30 and 60 days, in the restrictive transfusion groups, but this did not reach statistical significance.
hebert et al 199946
Hebert et al. 1999
  • Sub-group analysis was preformed looking at age and severity of illness (using APACHE II scores).
  • For patients > 55 and those with APACHE II score > 20 all outcomes were similar.
hebert et al 199947
Hebert et al. 1999
  • For APACHE <= 20, 30-day mortality was 8.6% in the restrictive group vs. 16.1% in the liberal group. P = 0.03
  • ARR = 7.5%
  • NNT = 13.
hebert et al 199948
Hebert et al. 1999
  • For age <= 55, 30-day mortality was 5.7% in the restrictive group percent vs. 13.0% in the liberal group. P = 0.02
  • ARR = 7.3%
  • NNT = 14
hebert et al 199949
Hebert et al. 1999

P<0.01

  • Patients in the restrictive group had fewer cardiac complications.

P < 0.01

P = 0.60

P < 0.01

P = 0.28

hebert et al 199950
Hebert et al. 1999
  • Conclusions
    • Good design, groups well matched.
    • In critically ill patients, it is safe to use a transfusion threshold of 7.0 g/dl.
    • The liberal transfusion group (threshold 10.0 g/dl) had a trend toward higher mortality and significantly higher rates of cardiac events.
hebert et al 199951
Hebert et al. 1999
  • Conclusions cont.
    • In patients who had lower APACHE II scores, and were younger (55 or less), mortality was significantly lower in the group treated with the restrictive regimen.
hebert et al 199952
Hebert et al. 1999
  • Limitations:
    • May not be applicable to non-ICU patients.
    • Less ill patients may not be as susceptible to harm from blood transfusions.
    • The large number of excluded patient may have introduced unrecognized bias.
slide53
Hebert, et al. “Is a low transfusion threshold safe in critically ill patients with cardiovascular disease?” 2001
  • This is another study by the Canadian Critical Care Trials Group.
  • It is a sub-group analysis of the same patients from the previous trial.
  • They tried to identify patients from that trial that would be at risk from anemia because of heart disease.
hebert et al 2001
Hebert et al. 2001
  • Inclusion Criteria: Prior diagnosis of any of the following.
    • Ischemic heart disease
    • rhythm disturbances
    • uncontrolled hypertension
    • history of heart surgery (including valves)
    • history of vascular surgery
hebert et al 200155
Hebert et al. 2001
  • 357 patients were identified (160 in the restrictive group and 197 in the liberal group).
  • Baseline characteristics were similar except for a higher rate of prior diuretic use in the restrictive group.
hebert et al 200156
Hebert et al. 2001
  • Results
    • Average hemoglobin (g/dl) was lower in the restrictive group: 8.50.62 vs. 10.30.67 (p < 0.01).
    • Units of red blood cells used were again lower in the restrictive group: 2.44.1 vs. 5.25.0 (p < 0.01).
    • There was no statistical difference in the primary and secondary outcomes between the restrictive and liberal groups.
hebert et al 200158
Hebert et al. 2001
  • The odds ratio (OR) for 30-day mortality comparing the restrictive to the liberal group was 1.14 (95% CI 0.66-1.96) p=0.94
  • Adjusting for age, APACHE II score, ischemic heart disease, comorbid illnesses, and cardiac meds, the OR was 1.26 (95% CI 0.70-2.24) p=0.68.
hebert et al 200159
Hebert et al. 2001
  • Complications were similar (p>0.05) including MI, unstable angina, and cardiac arrest.
  • Acute pulmonary edema was less common in the restrictive group (9% vs. 18%; p = 0.01).
  • Limiting patients to those with ischemic heart disease did not change the results.
hebert et al 200160
Hebert et al. 2001
  • Conclusions:
    • Critically ill patients with cardiovascular disease can be safely maintained at a hemoglobin concentration of 7.0 g/dl.
    • A more liberal transfusion practice may lead to more cases of acute pulmonary edema.
    • The authors caution against applying this to patients with ongoing ischemia or acute MI.
hebert et al 200161
Hebert et al. 2001
  • Limitations:
    • As in the original study it is difficult to know if these result can be applied to less ill patients.
    • Large numbers of patients were excluded, possibly introducing bias.
    • Sub-group analysis can hide unknown prognostic variables and biases that were not accounted for in randomization.
wu et al blood transfusions in elderly patients with acute myocardial infarctions 2001
Wu, et al. “Blood transfusions in elderly patients with acute myocardial infarctions.” 2001
  • Retrospective cohort study using data collected by the Cooperative Cardiovascular Project.
  • This is a database of 234,769 patients funded by Medicare.
  • These patients were admitted to study centers in the U.S., from Jan. 1994 to Feb. 1995 with a diagnosis of acute MI
wu et al 2001
Wu, et al. 2001
  • Goal:
    • Assess the risk of anemia and the effects of blood transfusion in patients with acute myocardial infarctions.
wu et al 200164
Wu, et al. 2001
  • Inclusion criteria
    • Over 65
    • Confirmed diagnosis of myocardial infarction.
  • Exclusion criteria
    • Hematocrit > normal on presentation.
    • Readmission for MI
    • CABG during hospitalization
    • Bleeding prior to admission
wu et al 200165
Wu, et al. 2001
  • Exclusion criteria (cont.)
    • Transfer to or from a study facility.
  • Of the 234,769 patients in the CCB database 66.4% were excluded leaving a cohort of 78,974.
wu et al 200166
Wu, et al. 2001
  • Design
    • Patients were divided into cohorts based on their presenting hematocrit.
    • The database was used to record multiple variables about treatments, hospital course, and follow-up.
wu et al 200167
Wu, et al. 2001
  • Endpoints
    • Primary endpoint was 30-day mortality
    • Secondary endpoints:
      • In-hospital mortality
      • Length of stay
wu et al 200168
Wu, et al. 2001
  • Results:
    • There was a statistically significant trend toward higher mortality in patients that had lower a hematocrit on admission.
    • 3,680 patients (4.7%) received transfusions during their stay in the hospital.
    • 71.3% of patients in the group with the lowest hematocrits were transfused at some point.
wu et al 200171
Wu, et al. 2001
  • Conclusions:
    • A lower hematocrit at presentation was associated with increased lengths of stay and mortality.
    • For those patients who presented with a hematocrit less than 33.1%, blood transfusion was associated with decreased 30-day mortality.
    • For those patients who presented with a hematocrit greater than 36%, getting a blood transfusion was associated with increased 30-day mortality.
wu et al 200172
Wu, et al. 2001
  • Limitations
    • As a retrospective cohort study, these result do not allow us to draw conclusions about cause and effect.
    • The limited data collected about each patient leaves the possibility that there are other factors that led to the observed trends.
    • The large number of patients excluded from the sample could introduce unrecognized biases.
conclusions
Conclusions
  • There is no data to support using red blood cell transfusions to maintain a hemoglobin concentration of 10.0 g/dl (or any other value) in all patients with coronary artery disease.
conclusions74
Conclusions
  • In critically ill patients a transfusion threshold of 7.0 g/dl appears to be safe.
    • Even in patients with cardiovascular disease.
    • As long is there is not active ischemia.
  • The two studies by Hebert and the one from Johnson help to validate the 1992 ACP guidelines.
conclusions75
Conclusions
  • Wu’s retrospective study of elderly patients with acute MI showed an association between anemia and increased mortality and improved survival in anemic patients that were transfused with RBCs.
  • In the absence of better data to the contrary, elderly patients with MI should be transfused to keep the hematocrit above 33%.
case summary
Case Summary
  • Based on this review it would be safe to maintain Mr. C with a hemoglobin of 7.0 g/dl as long as he continues to be asymptomatic and develops no further evidence of active ischemia.
  • If he did have further angina or rule in for a myocardial infarction, I would recommend red blood cell transfusions to keep his hematocrit above 33.0%.
thanks to
Thanks to
  • Dr. Jim Kimberly
  • Dr. Todd Greenwood
  • Dr. Mary Hadley