NORMALIZATION OF HEMATOCRIT IN HEMODIALYSIS PATIENTS WITH CARDIAC DISEASE DOES NOT INCREASE BLOOD PRESSURE

Abstract

Since the earliest reports of the use of Epoetin alfa in hemodialysis patients, it has been described that Epoetin alfa may exacerbate preexisting hypertension or induce hypertension in End Stage Renal Disease (ESRD) patients not previously hypertensive. We undertook this study to determine if the correction of anemia in ESRD patients with cardiac disease from a hematocrit of 30 ± 3% to 42 ± 3% with the use of Epoetin alfa would result in increased blood pressure. This study was a substudy of the “Normal hematocrit Study”.

Methods	=	Thirty-one patients were randomized into one of two arms. Patients in Group A had their hematocrit increased with the use of slowly escalating doses of Epoetin alfa to 42 ± 3% and patients in Group B were maintained with a hematocrit of 30 ± 3% throughout the course of the study. All patients had their blood pressure recorded with a 24 hour ambulatory BP device at study entry and at 28 weeks following randomization when they had achieved their target hematocrit. Pre-dialysis systolic and diastolic BP was also recorded.
Results	=	The mean hematocrit increased in Group A from 29.1 ± 2.4% to 40.8 ± 5.2% after 30 weeks. The hematocrit in Group B remained stable at 30 ± 3% throughout the course of the study. There was no difference in mean daytime, mean nighttime or 24 hour systolic or diastolic blood pressure between Groups A and B at either baseline or follow-up. Neither was there a difference in mean pre-dialysis systolic or diastolic BP between Groups A or B at baseline or Follow-up. Four patients in Group A and 4 patients in Group B required an increase in their antihypertensive medication during the course of the study.
Conclusion	=	It is possible to increase hematocrit to normal levels in hemodialysis with the administration of Epoetin alfa. The increase in hematocrit from 30 ± 3% to 42 ± 3% is not associated with increased blood pressure.

• ESRD
• Hemodialysis
• Epoetin alfa
• Blood pressure

INTRODUCTION

Since the very earliest observations on the use of Epoetin alfa to ameliorate the anaemia of end stage renal failure, it has been apparent that increasing hematocrit from low levels to 30% can exacerbate preexisting hypertension or induce hypertension in those not previously hypertensive (Winearls et al., 1986[[17]]; Eschbach et al., 1987[[6]]; Conlon et al., 1993[[5]]). This presented with the alarming development of hypertensive encephalopathy and sometimes seizures. Nephrologists learned early that if hematocrit was increased slowly with the use of lower doses of Epoetin alfa, this was less of a clinical problem. Recently a trial has been undertaken to determine if hemodialysis patients with clinically-evident ischemic heart disease or congestive heart failure are maintained at a hematocrit of 42 ± 3% (with the use of Epoetin alfa) demonstrate increased survival when compared to patients maintained at a hematocrit of 30 ± 3% (The Normal hematocrit Investigators, 1997). We therefore took this opportunity to study the effects of increasing hematocrit to 42 ± 3% on systolic and diastolic blood pressure and 24 hour ambulatory blood pressure in these patients. Herein we report our findings.

METHODS

We recruited a total of 60 patients form our institution to participate in the normal hematocrit study sponsored by Amgen Inc. The results of this study on survival have previously been published (The Normal hematocrit Investigators, 1997). The protocol was approved by the Duke University Institutional Review Board. Patients with clinical evidence of congestive heart failure or ischemic heart disease were randomized to have their hematocrit maintained at 30 ± 3% or at 42 ± 3%. Patients had weekly drawing of their hematocrit and biweekly adjustment of Epoetin alfa dose in a slowly escalating manner aiming to achieve a hematocrit of 42% in Group A. The protocol allowed for frequent assessment of iron stores and the use of intravenous iron preparation in order to maintain adequate iron supply for effective hematopoiesis. In order to be enrolled in this Ambulatory Blood Pressure monitoring study, patients had to have a pre-dialysis systolic blood pressure below 160 mm/Hg and a pre-dialysis diastolic BP below 100 mm/Hg during the 4 weeks prior to enrollment. Adjustment of antihypertensive medications was performed according to individual patient needs. All patients were dialyzed with Cobe dialysis machines and prescription was adjusted to achieve a KT/V of at least 1.2.

Patient selection

Thirty-five hemodialysis patients were enrolled in this study. To be included, each patient had to have a stable hematocrit of 30 ± 3% for the 4 weeks prior to enrollment in the study. Twenty six patients were on antihypertensive medications at the time of this study, which included calcium channel blockers (n = 17), angiotensin converting enzyme inhibitors (n = 8), beta blockers (n = 9), and minoxidil (n = 4). Baseline demographics of patients are outlined in Table 1

Table 1. Demographic characteristics of patients at time of randomization

	Group A	Group B
	(N = 15)	(N = 16)
Age	53.1 ± 12	56.2 ± 13
Male	56%	53%
Black	85%	71%
Time on dialysis (months)	18 ± 3	14.6 ± 8

Blood Pressure Monitoring

Twenty-four hour ambulatory blood pressure was measured using the Stuart Medical ambulatory blood pressure machine (Baltimore, Maryland). We have previously demonstrated this device to conform to British Hypertension Society Grade A for accuracy of recordings (Conlon et al., 1996[[4]]). The device was fitted 15 minutes prior to the start of hemodialysis, and the device was programmed to measure blood pressure every 30 minutes for 24 hours. All patients were counseled to relax their arm on their side when the device was recording, and advised to take their routine antihypertensive medications on the day they wore the device. In order to be included in the study each patient had to have had greater than 80% successful BP readings. All BP readings were included in the final analysis. Daytime was defined as between 7 a.m. and 10 p.m. and nighttime between 10:01 p.m. and 6:59 a.m. The mean daytime and nighttime systolic and diastolic BP for the 24 hr period were calculated. The follow-up ambulatory blood pressure recordings in Group B were all performed when the hematocrit was at least 40%.

Pre-dialysis BP was recorded every 4 weeks for 28 weeks after 10 minutes of quiet resting while seated using a standard technique with a recently calibrated aneroid syphgmomanometer by non physician personnel who were known to the patients. Phase five was used to determine diastolic pressure.

RESULTS

Thirty-one patients were enrolled in this study. The baseline demographic features of the patients are outlined in Table 1. Fifty-two percent were male and 74% were black, reflecting the high proportion of African American patients dialyzed in our units. The changes in hematocrit in response to Epoetin alfa therapy in Groups A and B are outlined in Figure 1 and the mean dose of Epoetin alfa per dialysis treatment in each Group is outlined in Figure 2. At entry the hematocrit in Group A was 29.1 ± 2.4% and patients were receiving 4800 ± 1176 U of Epoetin alfa per dialysis, the hematocrit in Group B was 29.1 ± 2.1 g/dL and were receiving 3365 ± 2800 U of EPO per treatment. Niether the hematocrit nor EPO dose were significantly different between Groups. At 28 weeks the mean hematocrit in Group A was 40.8 ± 5.2% and patients were receiving a mean of 14,400 ± 5883 U of EPO per treatment, and patients in Group B had a mean hematocrit of 30 ± 4.3 and were receiving 6,100 ± 5000 U of EPO per treatment.

Figure 1. Changes in mean hematocrit throughout the course of the study.

Figure 2. Mean daytime and nighttime systolic BP (±standard deviation) for Groups A and B.

The clinic measured pre-dialysis blood pressure and mean daytime and nighttime systolic and diastolic ambulatory blood pressure are outlined in Table 2 and Figure 3. There was no significant difference between mean daytime systolic or diastolic BP and mean nighttime systolic or diastolic BP at either baseline or follow up (Figure 3 and 4). There was no significant difference in mean daytime or nighttime systolic or diastolic BP between Group A and Group B at either baseline or follow up. Neither was there a difference in clinic measured systolic or diastolic blood pressures at any time point during the first six months of the study between Group A or Group B (Figure 5).

Table 2. Changes in antihypertensive medication during the course of the study

Group	Increased	Decreased	No Change
A (n = 15)	4	1	10
B (n = 16)	4	1	11

Figure 3. Mean daytime and nighttime diastolic BP (±standard deviation) for Groups A and B.

Figure 4. Mean Pre-dialysis systolic BP (±standard deviation) for the 6 months of the study.

Figure 5. Mean pre-dialysis diastolic BP (±standard deviation) for the 6 months of the study.

Ten patients in Group A and eleven patients in Group B completed the study without changes in their antihypertensive medications. Four patients in each Group required increases in their antihypertensive regimen and 1 patient in each Group required decreases in their antihypertensive regimen (Table 3).

Table 3. Blood pressure readings (in mm HG) ±standard deviation at randomization and follow-up for patients in Group A and Group B

	Baseline	Follow-up
Group A
Mean daytime systolic BP	148 ± 28.1	145 ± 27.8
Mean daytime diastolic BP	76.3 ± 11.6	78 ± 12
Mean daytime heart rate	85.2 ± 20.3	85 ± 17
Mean nighttime systolic BP	149 ± 27	148 ± 28
Mean nighttime diastolic BP	73.4 ± 14.5	75 ± 12
Mean nighttime heart rate	78 ± 27	78.6 ± 27
Mean clinic systolic BP	153 ± 25	156 ± 25
Mean clinic diastolic BP	87.6 ± 15.6	82 ± 13
Group B
Mean daytime systolic BP	148.5 ± 25	138 ± 32
Mean daytime diastolic BP	73.6 ± 13.2	75.5 ± 13
Mean daytime heart rate	89 ± 12	85 ± 18
Mean nighttime systolic BP	144.9 ± 28	137 ± 31
Mean nighttime diastolic BP	70.5 ± 20.5	82.9 ± 18.9
Mean nighttime heart rate	88.3 ± 16	88.7 ± 18.9
Mean clinic systolic BP	151.1 ± 25.4	150 ± 34
Mean clinic diastolic BP	77.6 ± 13.7	80.6 ± 16.7

DISCUSSION

In this study, we have shown that with the administration of increased amounts of Epoetin alfa it is possible to increase hematocrit levels to near normal levels in hemodialysis patients (Besarab 1998[[15]]). This increased hematocrit level did not appear to be associated with any change in either systolic or diastolic blood pressure or in the requirement for antihypertensive medications.

The etiology of the hypertension associated with Epoetin alfa has been unclear. Correction of anemia results in an increase in systemic vascular resistance (Maschio, 1995[[11]]). This is due to a combination of increased blood viscosity and loss of hypoxic vasodilation. In addition to the increase in vascular resistance, cardiac output falls. In experimental models breathing oxygen reverses hypoxic vasodilation and increases forearm vascular resistance (Roger et al., 1992[[13]]). It is noteworthy however that increasing hematocrit with Epoietin alfa in non uremic conditions, including normal volunteers and patients with AIDS or rheumatoid arthritis does not result in increased blood pressure (Berglund, Ekblom, 1991[[1]]; Pincus et al., 1990[[12]]). It has been suggested that Epoetin alfa associated hypertension may be an effect of the Epoetin alfa itself rather than a secondary phenomena from the increased red cell mass, although this has been debated. While Epoetin alfa does not appear to have a direct vasoconstrictor effect on vascular endothelium (Takahashi et al., 1995[[14]]) it has been reported that Epoetin alfa increases vascular responsiveness to circulating norepinephrine (Hand et al., 1995[[7]]). It has also been reported that Epoetin alfa may increase levels of the circulating vasoconstrictor endothelin 1 (Lebel et al., 1994[[10]]; Carlini et al., 1993[[2]]). If Epoetin alfa exerts its hypertensive effect by way of direct action on vascular endothelium it would have been hypothesized that patients in Group A would have significantly higher blood pressures than Group B as they received more than twice the Epoetin alfa dose compared to Group B.

Ambulatory blood pressure monitoring has been used previously to study changes in blood pressure induced by Epoetin alfa therapy (Jones et al., 1995[[9]]; van de Borne et al., 1992[[16]]; Clinical and Imai et al., 1995[[3]]; Ishimitsu et al., 1993[[8]]). These studies were all performed to study the effect of increasing Epoetin alfa from low levels to hematocrits close to 30%. Imai, van de Borne and Lebel (Clinical and Imai et al., 1995[[3]]; van de Borne et al., 1992; Ishimitsu et al., 1993[[8]]) each noted a marked increase in mean 24 hour ambulatory blood pressure with increases in hematocrit. Jones could not demonstrate a rise in blood pressure but the patients in this study did have adjustments in their antihypertensive medication. The increase in blood pressure in the Van de Borne study was in daytime systolic BP while in Imai's study Epoetin alfa increased nocturnal BP more than daytime BP, in Lebel's study blood pressure was similarly increased during the day and the night. In this and our previous study (Conlon et al., 1996[[4]]) we were not able to demonstrate a nocturnal decline in BP.

Clearly as a result of the relatively small number of patients enrolled in this study, the study would not have been able to detect small differences in blood pressure between the Groups. We believe the study was, however, large enough to detect clinically significant differences in blood pressure between the Groups. From a design point of view it would also have been preferable if all patients in each Group had their antihypertensive medications held constant throughout the course of the study so at the end of the study we would only have had to compare blood pressure levels. Such a study design however was considered unacceptable on ethical grounds.

In summary, we have demonstrated that the administration of increased doses of Epoetin alfa can increase hematocrit levels to those of non uremic subjects. It does not appear that this increased hematocrit is associated with exacerbation of hypertension.