VII. Possible Adverse Effects Related to Epoetin Therapy


During the initial Epoetin clinical trials, most of which were uncontrolled, a number of adverse effects were reported. Some of these adverse effects have not been observed consistently in subsequent experience with Epoetin, suggesting that Epoetin is not the direct cause of these adverse effects. Moreover, these adverse effects have not been observed when Epoetin is used in the treatment of non-renal anemias. However, because there has been much discussion of these adverse effects in the past, these "possible" adverse effects are reviewed here.


Possible Adverse Effects Related to Epoetin Therapy: Hypertension

Blood pressure should be monitored in all patients with CKD, particularly during initiation of Epoetin therapy. Initiation of anti-hypertensive therapy or an increase in anti-hypertensive medication, and reduction in Epoetin dose if there has been a rapid rise in Hgb/Hct, may be required to control an increase in blood pressure related to Epoetin therapy. (Evidence)

Rationale In our review of 47 publications, 785 of a total of 3,428 patients (approximately 23%) developed hypertension or an increase in blood pressure during treatment with Epoetin.22,34,38,59,102,106,235,245,252,292,319-355 While many factors thought to enhance a pressor response to Epoetin have been proposed,356 no single factor has been consistently linked to this response in the minority of CKD patients in whom it occurs. Several recent studies, however, have studied the role of the endothelium and/or vascular smooth muscle cell in the hypertensive reaction, since EPO receptors are present on endothelial cells.357 One in vitro study showed that Epoetin (250 U/ml) inhibited IL-1βΡinduced apoptosis of vascular smooth muscle cells which might induce hypertension since nitric oxide production is inhibited.358 However, another study showed that relatively long-term exposure of human endothelial cells in culture with Epoetin (4 U/mL) for 1 to 6 days increased nitric oxide synthase mRNA levels, but not endothelin-1 levels, suggesting that Epoetin has a vasodilatory effect on the endothelium.359 These in vitro studies are then contrasted with recent in vivo studies suggesting that a single dose of 100 U/kg of Epoetin results in an increase in mean arterial pressure (MAP) when Epoetin is administered IV, but not when it is administered SC.360 The increase in MAP is associated with an increase in the ratio of plasma endothelin to proendothelin360 and may be associated with elevated cytosolic ionic calcium and nitric oxide resistance.361 The incidence of hypertension associated with Epoetin is not associated with either the dose of Epoetin or whether a normal Hct is achieved.80,129 The hypertensive response is not observed in anemic patients without renal disease who are treated with Epoetin.124 Therefore, the cause of the Epoetin associated clinical hypertension remains unresoved to date. New onset or worsening hypertension in association with Epoetin therapy is thought to be related to an increase in vascular wall reactivity, along with hemodynamic changes related to an increasing red blood cell mass. Initiation of anti-hypertensive therapy or an increase in the dose of anti-hypertensive medications, intensified ultrafiltration if there is evidence of extracellular volume expansion, and/or a reduction in Epoetin dose may be required to control an increase in blood pressure related to Epoetin therapy. It is not necessary to withhold or discontinue Epoetin therapy due to hypertension unless such hypertension is refractory to aggressive blood pressure management. There is no evidence that increased blood pressure associated with the use of Epoetin should be treated any differently than hypertension in dialysis patients who are not treated with Epoetin. However, if hypertensive encephalopathy occurs, with or without seizures, Epoetin should be discontinued until clinical stability is achieved.


Possible Adverse Effects Related to Epoetin Therapy: Seizures

There is no need to restrict patient activities due to a concern about new onset seizures or a change in seizure frequency in patients being treated with Epoetin. A prior history of seizures is not a contraindication for Epoetin use. (Evidence)

Rationale The initial and largest multicenter study with Epoetin in the United States65 noted a higher incidence of seizures during the first 3 months of the study compared to historical controls. Ten subsequent studies which analyzed the incidence of seizures among patients receiving Epoetin found the mean percentage of patients with seizures to be 3% (59 of 2,203 patients), with a range of 0% to 13%.22,322,329,342,348,352,362-365 None of these studies reported the presence or absence of seizure history prior to the use of Epoetin. There is only one controlled study which has examined the incidence of seizure activity in dialysis-dependent ESRD patients in the absence of Epoetin therapy. In this study, one out of 20 patients (5%) not on Epoetin had a seizure.364 Except in the case of patients with hypertensive encephalopathy, there appears to be no evidence of an increased risk of seizures in CKD patients treated with Epoetin when appropriate dosage and titration recommendations are followed. Use of Epoetin in the patient with a prior history of seizures is not contraindicated since there is no evidence of an increase in the risk of seizure in ESRD patients receiving Epoetin therapy.


Possible Adverse Effects Related to Epoetin Therapy: Increased Clotting Tendency

A. There is no need for increased surveillance of access thrombosis in hemodialysis patients with either native fistulae or synthetic grafts when patients are treated with Epoetin. (Evidence)

B. Epoetin-treated hemodialysis patients do not need more heparin than patients not treated with Epoetin. (Evidence)

Rationale In our review of 26 studies in which 4,110 hemodialysis patients were enrolled, the average incidence of thrombosis of any access in patients on Epoetin was 7.5%.22,34,38,39,65,74,228,245,299,322,347,348,352,362,366-376 The target Hcts in these studies were <36%, but the mean achieved Hcts were approximately 34%. In general, the fewer patients enrolled in a study, the higher was the reported incidence of access thrombosis. Most of these papers cited either historical controls, or used patients as their own controls, pre- and post-Epoetin use. No difference was reported in the rate of access thrombosis in one study that compared patients receiving and not receiving Epoetin.370

There is evidence that Epoetin therapy does not increase the risk of progressive stenosis in native fistulae.377 The evidence that Epoetin therapy increases the risk of PTFE graft thrombosis is equivocal (Endnote o). In the recent Amgen study of hemodialysis patients with heart disease (CHF and/or ischemic heart disease), there was a significant increase in thromboses of both native fistulae and synthetic arteriovenous grafts in patients randomized to a target Hct of 42% 3%, compared to a target Hct of 30% 3%. However, there was no correlation between the Hct level achieved, the dose of Epoetin, and the occurrence of access thrombosis.80

There are many studies indicating that clotting function improves as the Hct increases to above 30% in dialysis patients.378 However, there is no evidence from the large, North American multicenter studies65,73 that increasing the red blood cell mass with Epoetin increases dialyzer heparin requirements, although a 20% to 40% increase in heparin requirements was noted in one European study.374 A recent autopsy study found that, over a 10-year period in which the percentage of hemodialysis patients receiving Epoetin increased, there was no increase in the prevalence of preterminal pulmonary thromboembolism.379

One study of 85 diabetic patients on peritoneal dialysis reported that patients treated with Epoetin had an increased incidence of peripheral vascular disease and an increased risk of serious limb or digit ischemia.380 This study was small, retrospective and had many potential confounders. In addition, no clotting studies were performed. A larger prospective randomized study would need to confirm these findings before a caution regarding use of Epoetin in diabetic PD patients could be recommended.


Possible Adverse Effects Related to Epoetin Therapy: Hyperkalemia

Epoetin-treated dialysis patients do not need more intensive potassium monitoring than patients not treated with Epoetin. (Evidence)

Rationale While serious hyperkalemia was observed in the early experience with Epoetin,35 the more recent data indicate that the incidence of hyperkalemia is not significantly higher in Epoetin-treated patients. Our review of five papers with a cumulative total of 1,167 patients revealed only 12 cases of hyperkalemia. In the two series322,329 accounting for 1,000 patients, the incidence of hyperkalemia was less than 1%. When patients receiving Epoetin were compared to patients not receiving Epoetin,370,376 the incidence of hyperkalemia in Epoetin-treated patients was less than or equal to the incidence in non—Epoetin-treated patients in two of the three studies.





© 2001 National Kidney Foundation, Inc

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