Summary

Part I: Adult Patients with CRF

1. Based on evidence from interventional studies, what are the outcomes of maintaining target Hct above 36 percent compared with maintaining target Hct in the 30 to <36 percent range or, more importantly, in the 33 to <36 percent range?
2. Based on evidence from associational studies, what are the outcomes of maintaining target Hct above 36 percent compared with maintaining target Hct in the 30 to <36 percent range or, more importantly, in the 33 to <36 percent range?

Part II: Pediatric Patients with CRF

What is the effect on outcomes of maintaining an Hct above 30 compared with 27 to < 30 percent or, maintaining Hct above 33 compared with 27 to <33 percent?

Part III: Subpopulations of Interest (with or without CRF)

What is the effect on outcomes of maintaining the Hct level >36 percent as compared with 30 to <36 percent in the following patient subgroups (regardless of the presence of renal failure):

(1) Patients who have coronary artery disease,
(2) Patients who have congestive heart failure,
(3) Patients who live at high altitude,
(4) Patients who have arterial occlusive disease,
(5) Patients who have cerebrovascular disorders,
(6) Patients who have obstructive lung disease,
(7) Patients who are in the adolescent age group?

It has been hypothesized that the presence of one of the conditions listed in subgroups 1 through 6 may justify maintaining Hct level above 36 percent to minimize the morbidity associated with the specified condition. For the adolescent subgroup, it is hypothesized that growth and developmental outcomes would be improved by maintaining Hct above 36 percent.

Mortality

Two interventional studies, both full reports, and four cross-sectional analyses, three full reports and one abstract, described mortality results. The first interventional study was an RCT of 1,233 hemodialysis patients with documented congestive heart failure or ischemic cardiac disease. This study analyzed and reported results of both an intention-to-treat analysis and a cross-sectional analysis of the data. The second interventional study was a nonrandomized controlled trial of 115 hemodialysis patients free of comorbidity. The three additional cross-sectional studies, two full reports and one abstract, analyzed large databases of patients on dialysis.

The evidence does not permit a conclusion regarding the effect on mortality of maintaining Hct above 36 percent. To date, a survival advantage has not been demonstrated.

• There was increased mortality among the patients with cardiac disease who were randomized to normal target Hct (42 percent) as compared with low target Hct (30 percent), with 31.6 percent mortality versus 26 percent mortality, respectively (statistical significance not reported). The relative risk for the combined endpoint of mortality and first nonfatal myocardial infarction was 1.3 (95 percent confidence interval [CI] = 0.9 to 1.9) for the normal target Hct group compared with the low target Hct group. This trial was halted even though these results did not achieve statistical significance. It was determined that, even if the trial was completed, the results could not demonstrate a statistically significant benefit for the higher target Hct for the primary endpoint, and there was concern over the potential harm associated with attempting to maintain higher Hct in such patients.
• No deaths were observed in a population of CRF patients free of associated comorbidity who were maintained at Hct above 36 percent. However, the 6-month duration of followup in this study was too short to assess a long-term benefit or adverse effect on mortality.
• Of three large database studies, one study (n=16,153) found a significantly higher mortality among those patients with Hct above 36 percent; one study (n=75,283) found no significant difference in mortality between Hct above 36 percent compared with Hct 30 to <33 percent; and a third study (n=82,879), available only as an abstract, found a significantly reduced mortality rate for Hct above 36 percent.
• A fourth cross-sectional analysis was performed on the data from an RCT of 1,233 patients comparing target Hct of 42 percent with target Hct of 30 percent in hemodialysis patients with documented cardiac disease. So few patients in the 30 percent target Hct group achieved average Hct above 36 percent that none was included in the analysis. The lowest mortality rate was noted among those who achieved an average Hct 39 to 41.9 percent. However, no difference was apparent in mortality between patients who achieve Hct 36 to 38.9 percent compared with those who achieve Hct >30 to <36 percent. Among patients with average achieved Hct in the 30 to 36 percent range, mortality is lower in those patients assigned to the 30 percent target Hct group than those assigned to the 42 percent target Hct group.

Quality of Life

Four interventional studies, one full report and three abstracts, and two cross-sectional studies, both full reports, described quality-of-life findings. All studies suffered from relatively weak design or methodologic flaws that might introduce biases that overestimate effect on quality of life. These data did not provide strong and consistent evidence of a benefit on quality of life of maintaining the Hct above 36 percent compared with Hct >30 to <36 percent.

Hospital Utilization

Two interventional studies, both full reports, and four cross-sectional studies -- two full reports and two abstracts -- described hospital utilization. Overall, these data did not provide strong or consistent evidence of reduced hospital utilization in patients whose Hct is maintained above 36 percent as compared with those maintained at Hct >30 to <36 percent.

• One RCT in 1,233 hemodialysis patients found no significant difference in hospital utilization between patients randomized to either the lower or higher target Hct arms. A pre/post comparison trial in 115 hemodialysis patients found a significant reduction in hospital utilization when Hct was maintained above 36 percent, but the results of this unmasked study using a comparison with historical data prior to study entry must be viewed with caution.
• Of the cross-sectional studies, one full report found that hospital utilization in the Hct 33 to <36 percent group was lower than in either the Hct 30 to <33 percent or the Hct 36 percent groups. Another full report found a slightly lower hospitalization rate among patients with Hct above 36 percent, but no analysis of statistical significance was performed. Finally, two abstracts described favorable findings for the Hct >36 percent group but without analysis of the statistical significance.

Transfusion

One RCT reported utilization of red blood cell transfusion. This trial of 1,233 hemodialysis patients with cardiac disease found a significant reduction in red blood cell transfusion in the normal target Hct group compared with the low target Hct group, 21 percent transfused versus 31 percent transfused, respectively (p<0.001). In this study, the need for transfusion was largely associated with acute blood loss (e.g., from gastrointestinal bleeding or as a result of surgery).

Cardiac Events and Related Intermediate Cardiac Outcomes

Four full reports and three abstracts discussed cardiac outcomes. Two full reports addressed cardiac clinical events, and the remainder addressed cardiac intermediate outcome measures, including left ventricular hypertrophy (LVH) (as assessed by left ventricular mass index) and left ventricular dilatation (LVD) (as assessed by left ventricular cavity volume index).

There is limited evidence on cardiac events, and the available studies are insufficient to draw conclusions. However the evidence available does not demonstrate a reduction in cardiac events when Hct is maintained above 36 percent as compared with 30 to <36 percent.

• One RCT studied 1,233 hemodialysis patients who had documented congestive heart failure or ischemic cardiac disease. In this group of patients, although overall mortality was greater in the higher target Hct arm, no significant difference between the two study arms was seen in fatal or nonfatal cardiac events. A cross-sectional analysis of a Phase IV surveillance study in 324 patients reported zero myocardial infarctions (MI) in the Hct above 36 percent group, one MI in the Hct 33.1 to 36 percent group, and four MIs in the Hct 30 to 33 percent group. However, the number of events is small, and, relative to the Hct above 36 percent group, the number of patient-months of observation is almost three times higher in the Hct 33.1 to 36 percent group and almost seven times higher in the Hct 30 to 33 group. No statistical analysis is reported for these data thus limiting interpretation of the results.

The evidence on cardiac intermediate outcome measures described possible relationships between Hct above 36 percent and reduced left ventricular mass and left ventricular cavity size. Two full-report cross-sectional analyses suggested an association between Hct and cardiac outcome measures. However, data were insufficient from well-designed intervention studies to determine whether raising Hct above 36 from Hct 30 to 36 percent will result in a clinically meaningful improvement in left ventricular hypertrophy.

• A cross-sectional analysis of an observational, longitudinal study in 246 evaluable chronic renal failure patients who were not yet on dialysis was conducted. Because CRF is a progressive condition, Hct decreases over time as renal function deteriorates. Over a 12-month observation period, this study compared the relative changes in mean Hct level between the group of 55 subjects who met the criteria for significant left ventricular growth with the group of 191 subjects who did not demonstrate significant left ventricular growth. A significantly greater drop in Hct was observed in the group that showed significant left ventricular growth. Furthermore, each 1.5 percent decrease in Hct was associated with a 32 percent increased odds of showing significant left ventricular growth (odds ratio [OR]=1.32, 95 percent CI=1.1 to 1.58).
• A separate report by the same first author also reported a significant association between a lower Hct level and the presence of left ventricular hypertrophy (LVH) in predialysis patients.
• An abstract of a Canadian multicenter RCT described results in 125 evaluable hemodialysis patients with asymptomatic LVH or left ventricular dilatation (LVD) who were targeted to either an Hct 39 to 42 percent or Hct 28.5 to 31.5 percent. Changes in left ventricular measurements were compared after 40 weeks. No significant differences were observable in left ventricular mass index. Only one of four analyses reported achieved statistically significant findings. Left ventricular cavity size decreased to a greater extent in patients with LVH who were maintained in the higher target Hct group compared with those maintained at Hct approximately 30 percent (p=0.05).
• An abstract from a crossover study in 11 patients demonstrated statistically significant reductions in left ventricular mass index (p<0.01), left ventricular end-diastolic diameter (p<0.01), but not left ventricular end-systolic diameter.
• An abstract using a pre/post design in 13 patients reported no significant change in left ventricular mass after Hct was maintained above 36 for 4 months.

Exercise Performance

Four small interventional studies, two full reports and two abstracts, presented findings on intermediate outcome measures related to exercise performance. The two full reports included selected patients who were free of significant cardiovascular or musculoskeletal disease; patient selection criteria were not well described in the two abstracts. No cross-sectional analyses addressed this outcome.

The available evidence is suggestive of an improvement on physiologic measures of exercise performance when Hct is maintained above 36 percent compared with Hct 30 to 36 percent. However, whether these improvements in physiologic measures are predictive of clinically significant benefits needs to be established. In addition, such findings would need to be reproduced in large studies or populations more representative of the general population of patients with CRF.

• A full report of a double-masked, crossover study in 14 hemodialysis patients and an abstract of a crossover RCT trial in 27 hemodialysis patients both showed a significant improvement in several physiologic measures of physical work. However, the abstract reported that, depending on the outcome being considered, approximately one-half to two-thirds of the improvement was a result of conditioning and training and one-half to one-third of the total improvement was a result of correction of anemia.
• The two remaining studies, one abstract and one full report, also described favorable results from maintaining Hct above 36 percent. However, the selection of cases in the full report, nonrandomized control comparison study appeared open to substantial bias; and details regarding actual numerical results were very limited in the abstract.

Cognitive Function, Sleep Pattern, and Nutrition

Two full reports -- one interventional study in 20 hemodialysis patients performing neurophysiologic testing and another interventional study in 10 selected hemodialysis patients evaluating sleep patterns -- described testing conducted before and after Hct was raised to approximately 42 percent. A relationship between nutritional status and Hct level was described in an abstract reporting a cross-sectional analysis comparing serum levels of 3 different amino acids among 75 hemodialysis patients on epoetin therapy grouped according to Hct ranges. The average amino acid levels for each Hct group were compared with each other and with healthy control subjects.

Favorable results on physiologic measures of cognitive function, sleep patterns, or nutrition were observed with Hct levels above 36 percent in each of these studies. However, whether these improvements in physiologic measures are predictive of clinically significant benefits needs to be established. In addition, such findings need to be reproduced in large studies or populations more representative of the general population of patients with CRF.

Treatment-Related Morbidity

Eight studies -- four full reports and four abstracts -- described adverse events associated with maintaining Hct above 36 percent compared with Hct >30 to <36 percent. Seven of these were interventional studies, and one full report was a cross-sectional analysis of a Phase IV surveillance study without statistical analysis of results. Three of the four abstracts included fewer than 15 patients.

Blood Pressure

The evidence, derived from four full reports and three abstracts, showed no significant difference in overall blood pressure measurements when Hct was maintained above 36 percent compared with Hct >30 to <36 percent. However, several studies suggested that some patients required intensified medical management to maintain blood pressure control at Hct above 36 percent, but these studies did not permit estimation of the magnitude of the frequency of this occurrence. An RCT in 1,233 hemodialysis patients employed well-designed concurrent controls and reported no significant differences between target Hct groups in the use of various cardiovascular medications. The listed classes of medications included several antihypertensive agents; however, the reported details of data and methods of analysis did not clarify whether medication dosage might have been increased differentially in the high target Hct group.

Vascular Access Thrombosis

Five studies -- two full reports and three abstracts -- reported on vascular access thrombosis with Hct above 36 percent compared with Hct >30 to <36 percent. Targeting Hct at 42 percent significantly increased the rate of vascular access thrombosis in a population of patients with documented cardiac disease compared with targeting Hct at 30 percent. There is insufficient evidence in other groups of hemodialysis patients to determine the effect of Hct above 36 on vascular access thrombosis.

• The best quality evidence was from an RCT that included hemodialysis patients with documented congestive heart failure or ischemic cardiac disease. There was a statistically significant increase in vascular access thrombosis in the normal target Hct group (42 percent) as compared with the low target group (30 percent), 39 versus 29 percent, p=0.001. This group of patients may have been at particularly high risk of vascular access thrombosis because of associated cardiovascular comorbidity.
• Abstracts of two small concurrent control studies in hemodialysis patients reported no significant difference in vascular access thrombosis with Hct of 42 percent as compared with Hct 30 to 31 percent.
• Two pre/post comparisons in hemodialysis patients -- one full report and one abstract -- reported the observed rate of vascular access; however, the lack of a comparison control group limits interpretation of these findings.

Other Treatment-Related Morbidity

The evidence describing other treatment-related morbidities is limited to two full reports and one abstract. Overall, these studies did not suggest any significant increase in other adverse events such as cerebrovascular accident, transient ischemic attack, peripheral gangrene, intestinal ischemia, or seizure with Hct above 36 percent.

3. The evidence is not sufficient to compare the outcomes of maintaining target Hct above 30 percent with outcomes from the 27 to 30 percent range in pediatric patients with CRF.

No studies of pediatric patients with CRF were identified that met the study selection criteria for inclusion in this systematic review. The primary reason for exclusion of most of the studies reviewed in full-text was that the baseline or control Hct with which the normalized group was being compared was below 27 percent. Thus, the available evidence does not address the key question as set out in this systematic review, particularly with regard to outcomes of treatment efficacy.

4. The evidence is not sufficient to determine whether target Hct above 36 percent is more beneficial than target Hct 30 to <36 percent for subpopulations of interest with clinical characteristics thought to warrant Hct above 36 percent.

Patients Who Have Cardiovascular Disease

The most robust evidence on CRF patients with cardiovascular disease was from an RCT of 1,233 hemodialysis patients who had documented ischemic cardiac disease or congestive heart failure. This trial was halted because of increased mortality in the group assigned to 42 percent target Hct when compared with a 30 percent target Hct group. Although the results for a combined Endpoint -- death or first nonfatal MI -- had not achieved statistical significance (relative risk=1.3, 95 percent CI 0.9 to 1.9), it was determined that a benefit could not be demonstrated even if the trial was completed.

A second study provided a cross-sectional analysis in patients without CRF and compared perioperative morbidity and mortality for those with or without cardiovascular disease. No statistically significant difference was seen between patients who have a preoperative Hct above 36 percent compared with those who had an Hct >33 to <36 percent.

Patients Who Have Cerebrovascular Disease

A single cross-sectional analysis in patients without CRF but with cerebrovascular disease reported that, compared with patients with Hct at 30 to 35 percent, cerebral oxygen delivery was greater in those patients who had Hct levels between 40 and 45 percent, but not in those whose Hct was between 35 and 40 percent. No intervention study meeting selection criteria reported outcomes of maintaining Hct above 36 percent in a population with CRF and cerebrovascular disease.

Patients With Other Clinical Characteristics Thought to Warrant Hct Above 36 Percent

There were no studies that met selection criteria for inclusion in this systematic review for patients who live at high altitude, who have obstructive lung disease, or who are in the adolescent age group.

Conclusions

The published literature does not provide strong or consistent support that maintaining Hct above 36 percent is beneficial to patients with CRF. Although limited evidence derived from physiologic measures of functional status or left ventricular mass index suggests improvements in some selected patients, the potential for benefit should be tested in well-designed intervention studies.