Blood Transfusion Thresholds in Medical Patients with Coronary Artery Disease

1. Blood Transfusion Thresholds in Medical Patients with Coronary Artery Disease Internal Medicine Resident Grand Rounds December 4, 2001 Alexander Hadley, MD

2. 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.

3. Case Presentation • ROS: • Three months of gross hematuria. • Slowly progressive weakness and short of breath. • Several episodes of exertional angina over the previous weeks.

4. 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

5. Case Presentation • Labs • Hemoglobin 5.6 g/dl • Cardiac enzymes normal. • EKG • Anterior Q-waves. • No acute ischemic changes.

6. 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.

7. 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.

8. 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?

9. 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?

10. 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.

11. 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.

12. 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.

13. 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.

14. Why keep heart patients at higher Hg. / Hct. Values?

15. Why keep heart patients at higher Hg. / Hct. Values? • In anemia,  2,3-DPG shifts the curve to the right.

16. 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.

17. Why keep heart patients at higher Hg. / Hct. Values? Problem 1 + Problem 2 + Problem 3 = Ischemia. (Maybe)

18. 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

19. Risks of Transfusion • Infectious • Viral • CMV • Hepatitis A, B, and C • HIV • HTLV Types I and II • Bacterial Contamination

20. Risks of Transfusion • Immunologic Reactions • Non-hemolytic reaction (fever, chills, urticaria) • Acute hemolysis • Delayed hemolysis • Transfusion related lung injury (ARDS) • Transfusion Related Immunomodulation (TRIM)

21. “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.

22. “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.

23. 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.

24. ACP Guidelines

25. ACP Guidelines

26. 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.

27. 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.

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

29. Clinical Trials of Transfusion Thresholds

30. 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.

31. 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.

32. 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.

33. 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.

34. 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.

35. 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.

36. 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).

37. Hebert et al. “A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care.” 1999 • Canadian Critical Care Trials Group

38. Hebert et al. 1999 Hebert et al. NEJM 1999; 340:6

39. 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.

40. 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)

41. 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).

42. 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).

43. 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.

44. Hebert et al. 1999

45. Hebert et al. 1999

46. 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.

47. 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.

48. 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

49. 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

50. 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.