Anemia Correction in Patients with CHF and CKD:
       Can Early Use Erythropoietin Reverse Cardiovascular Disease Morbidi...
In epidemiological reviews, a concurrent presence of both CVD and CKD leads to
a poorer outcome. The higher stage of CKD p...
III. Link between Cardiac Disease and Anemia.

       Multiple retrospective studies have shown the association of anemia ...
IV. Link between Anemia and Chronic Kidney Disease.

        Anemia has long been observed in patients with renal disease....
V. Mechanism of action.

A proposed mechanism of action linking cardiac disease, anemia, and chronic kidney
disease is sho...
VI. Outcomes with increases in Hemoglobin.

       To break this above cycle, various studies have challenged the hypothes...
Statistical Method

              Initial and final values were assessed by paired Student’s t-test,
       with p<0.05 be...
Study 2. Besarab A et al. The effects of Normal as Compared wit
Low Hematocrit Values in Patients with Cardiac Disease who...
relevant patients with typical demographics. Weakness were that it was
       open-label, there was an unexplained decline...
IX. References

1.    Levin A: Clinical Epidemiology of Cardiovacular Disease in Chronic Kidney
      Disease Prior to Dia...
11.   Besarab A, Bolton WK, Browne JK, Egrie JC, Nissenson AR, Okamoto DM,
      Schwab SJ, Goodkin DA: The Effects of Nor...
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Anemia Correction in Patients with CHF and CKD:

  1. 1. Anemia Correction in Patients with CHF and CKD: Can Early Use Erythropoietin Reverse Cardiovascular Disease Morbidity? Mike Speckhart, MD October 14, 2003 I. Introduction The incidences of kidney disease, cardiac disease and anemia are high and continue to grow. As internal medicine providers we can expect patients with any or all of these disease processes in our clinical practice. Anemia, cardiac disease and chronic kidney disease are physiologically linked, and research is showing that early correction of anemia with recombinant human erythropoietin can slow the development of heart failure and progression to end-stage renal disease. This paper will discuss the epidemiological association between anemia, cardiac disease, and chronic kidney disease. A proposed mechanism of action linking all three disease process will be detailed. Although no large clinical trials have been completed, the prospective studies where anemia management in patients with chronic kidney disease has affected cardiovascular outcomes will be discussed. II. Link between Cardiac Disease and Chronic Kidney Disease. The link between cardiac disease and kidney disease is largely epidemiological. Cardiovascular Disease (CVD) includes any of the following processes: coronary artery disease, heart failure, cerebrovascular disease, and peripheral artery disease. CVD is the leading cause of morbidity and mortality in patient with kidney disease, especially those on dialysis. The risk factors for CVD of left ventricular hypertrophy (LVH), congestive heart failure (CHF), and ischemic heart disease (IHD) are present in stages 1-4 of chronic kidney disease (CKD). Also, the more traditional risk factors in CVD of diabetes, hypertension, age, gender, dyslipidemia carry through as risk factors in CKD.[1]
  2. 2. In epidemiological reviews, a concurrent presence of both CVD and CKD leads to a poorer outcome. The higher stage of CKD portends a worse outcome as well. The National Kidney Foundation has classified different levels of kidney disease as follows: Table 1 summarizes the limited but consistent knowledge in linking CKD and CVD. Table 1. CVD and CKD links.[1] •The prevalence of hypertension is high in CKD, ranging from 87% to 90%. •At least 35% of CKD patients had evidence of IHD, angina, or myocardial infarction. •The prevalence of LVH increases with each stage of CKD. At stage 5, approximately 75% of patients have LVH. •Risk factors for LVH include elevated systolic blood pressure and anemia. •↑NYHA cardiac class associated with ↑LVH, ↓GFR,↓Hgb. •The presence of CVD predicts the faster decline in kidney function and need for dialysis. •The mortality rate after MI is at least 50% higher in those with impaired kidney function and on dialysis.
  3. 3. III. Link between Cardiac Disease and Anemia. Multiple retrospective studies have shown the association of anemia and worse outcomes in CVD specifically congestive heart failure (CHF). A less rigorous association can be established between anemia and ischemic heart disease. In a small review of 142 patients in a CHF clinic, 55% had Hgb < 12 g/dL. In NYHA class IV patients, 79% had Hgb < 12 g/dL, while only 9% of class I patients had Hgb < 12 g/dL. In a study of hospitalized patients, 66% of NYHA class IV patients had Hgb < 12 g/dL. In the Study of Left Ventricular Dysfunction (SOLVD), 6563 patients were retrospectively reviewed and survival rates were highest in patients with LV dysfunction (with or without CHF) who had a hematocrit >40%. Progressively poorer rates of survival were demonstrated in patients with lower hematocrit.[2,3] Thus an apparent association between higher hematocrit and survival was present. The largest study linking CKD, anemia and heart failure was the retrospective review of 1 million Medicare recipients age >65. In the study, 26% of CHF patients without anemia died over a two year period compared with 35% of CHF patients with anemia. Of the CKD patients, only 16% without anemia died over two years compared to 27% with anemia. Of the combined patients with both CHF and CKD, those without anemia had a 38% death rate compared to 46% of those with anemia.[3] The Atherosclerosis Risk in Communities (ARIC) Study was a prospective cohort study of 14410 patients. Of those patients, 1358 subjects were anemic (<13 g/dL males, <12 g/dL females). There were a total of 549 CVD events (MI, angioplasty, CABG, death secondary to heart disease) over the mean follow-up of 6.1 years in the entire cohort. Anemia was independently associated with an increased risk of CVD event of 1.41 (CI [1.01, 1.95], p<0.04) in the entire cohort. The following figure shows the presence of anemia as a risk factor for CVD survival in both men and women.[4]
  4. 4. IV. Link between Anemia and Chronic Kidney Disease. Anemia has long been observed in patients with renal disease. Richard Bright first made these observations in the 1830s. The etiology of this anemia has been primarily attributed to a reduction in the production (decreased kidney mass) and activity of erythropoietin. Other factors include deficiencies in substrates (iron, folate, B12, carnitine), erythropoietin inhibitors (inflammatory states, hyperparathyroidism), blood loss, and shortened red cell life span. The degree of anemia noted in individuals with CKD is dependent upon the type of kidney disease.[5] The National Kidney Foundation has produced the KDOQI guidelines after multiple reviews and a consensus opinion had determined the high level of evidence linking anemia to CKD. Clinicians should begin to follow and manage patients with anemia once the glomerular filtration rate < 60 ml/min. The parameters for anemia are as follows: Hgb <11 g/dL in premenopausal or pre-pubertal females, and Hgb <12 g/dL in adult males and post-menopausal females.[6] Figure 2. Anemia workup in chronic kidney disease regardless of cardiac status.[6]
  5. 5. V. Mechanism of action. A proposed mechanism of action linking cardiac disease, anemia, and chronic kidney disease is shown in figure 2. Figure 3.[3] Beginning with anemia as a starting point, tissue hypoxia results from abnormal levels of hemoglobin. Peripheral vasodilation occurs to compensate for locally low tissue oxygenation levels. Vasodilation induces lower blood pressure. The body responds by increasing sympathetic tone and thus decreasing renal blood flow. A low flow through the renal arteries decreases glomerular volume. The increased sympathetic tone independently induces the renin-angiotensin-aldosterone, which has been implicated in inducing cardiac cell apoptosis.[7] ADH is also released with resultant fluid retention. Plasma volume increases as fluid is retained and is implicated in LV dilation leading to LVH. Extreme LVH causes necrosis and apoptosis of myocardial cells resulting in CHF. Cytokine levels such as tumor-necrosis factor alpha (TNFα) are increased in CHF and have been implicated in development of anemia of chronic disease.
  6. 6. VI. Outcomes with increases in Hemoglobin. To break this above cycle, various studies have challenged the hypothesis that cardiovascular morbidity can be altered by increase hemoglobin levels using recombinant human erythropoietin. Endogenous levels of erythropoietin are low in chronic kidney disease patients. The studies reviewed have looked at cardiovascular outcomes in predialysis patients and those with ESRD. Most studies examining anemia therapy in predialysis kidney patients have been small and lacking controls. In the studies by Hayashi et al[8], and Portoles et al[9], a reversal of LVH was obtained by correcting anemia. Silverberg, et al., detailed below, in an uncontrolled trial of 179 diabetic (type II) and nondiabetics with severe resistant congestive heart failure demonstrated an improvement in cardiac and patient function (NYHA class), an association with less frequent hospitalizations, less renal impairment and less diuretic use in patients treated with EPO and Iron to maintain Hgb > 12.5 g/dL. [10] Study1. Silverberg et al. The effect of correction of anaemia in diabetics and nondiabetics with severe congestive heart failure and chronic renal failure by subcutaneous erythropoietin and intravenous iron. Nephrology Dialysis Transplantation (2003) 18: 141-146. Study Protocol In the Silverberg study, 95 patients without diabetes and 84 patients with diabetes were studied. All patients were treated by cardiologist for at least 3 months in CHF clinic and were maximally medicated with ACE inhibitors, beta-blockers, spironolactone, long acting nitrates, digoxin and oral and iv furosemide. All had severe CHF as judged by NYHA classes 3-4 despite medical management. All had levels of hemoglobin of 9.5-11.5 g/dL on at least three consecutive visits over 3 week period. Secondary causes of anemia such as hypothyroidism and deficiencies in B12 and folate were ruled out. All participants were given a starting dose of 4000-5000 IU/week with increases to 10,000 IU/week to maintain Hgb of 12.5 g/dL. IV Iron was given so that ferritin levels would reach 500micrograms/dL/week. All doses of medications except for furosemide were maintained. Patients were followed up weekly initially, then every 2-4 weeks depending on status. CBC, BMP, and Iron profile drawn each visit. HgbAIC was checked in diabetics every 3 months. Blood pressure was checked each visit. A MUGA scan was done initially and then at 4-6 month intervals. Rate of GFR change during anemia correction period was compared to rate of GFR change in the year preceding anemia correction. The number of hospitalizations during the anemia correction period were compared with a similar time period prior to the study. Finally, a Visual Analogue Scale (VAS) was implemented to assess the severity of the patients’ fatigue and/or shortness of breath at the beginning and end of the study. The duration of the study was 11.8 +/- 8.2 months (range 5 -27 months)
  7. 7. Statistical Method Initial and final values were assessed by paired Student’s t-test, with p<0.05 being considered significant. Analysis performed by SPSS program. Results Results are summarized in Table 2. Conclusions Increases in Hemoglobin to 12.5 g/dL in diabetics and nondiabetics with resistant CHF and mild to moderate CKD improved the NYHA class score, increased LVEF%, increased VAS score, decreased hospitalizations, slowed GFR decline. Strengths and Weakness This paper was prospective and had reasonable entry criteria, good follow-up and relevant endpoints. The number of patients was relatively large. The study was uncontrolled and included some subjective data (VAS score) in the analysis. Baseline GFRs were unknown. Studies looking at anemia correction in hemodialysis patients have shown mixed results. The Normalization of Hematocrit Trial was a prospective open label trial of 1233 hemodialysis patients with symptomatic heart disease or congestive heart failure randomized to a hematocrit of 42 % or 30% with primary end point of length of time to death or first nonfatal MI. The study was stopped early because of a 7% excess mortality in the higher hematocrit group using intention to treat analysis.[11,12]
  8. 8. Study 2. Besarab A et al. The effects of Normal as Compared wit Low Hematocrit Values in Patients with Cardiac Disease who are Receiving Hemodialysis and Epoetin. New England Journal of Medicine (1998) 339: 584-590. Methods This was a randomized, prospective, open-labeled trial of 1233 patients with congestive heart failure (need for hospitalization or nonroutine ultrafiltration in prior 2 years) or ischemic heart disease (angina, CAD documented by catheterization, or prior MI) who were undergoing hemodialysis at 51 centers. All had hematocrit levels of 27 to 33% and had been receiving epoetin for four weeks prior to enrollment. Protocol The patients were randomly assigned to one of two groups: a normal hematocrit group that received epoetin to achieve hematocrit values of 42%; the other group received epoetin to maintain hematocrit at 30%. Duration of enrollment was 3 years. Strict epoetin dosage applied. Results Conclusions After 29 months, the risk ratio for death in the high hematocrit group was 1.3 (CI[0.9, 1.9]), and the study was halted. Strengths and Weaknesses This paper is often quoted in review of this topic because of its significance in hemodialysis patients. Strengths were that the study was randomized, prospective, had power, had excellent follow-up, and had
  9. 9. relevant patients with typical demographics. Weakness were that it was open-label, there was an unexplained decline in dialysis clearance (Kt/V), access thrombosis, and iron requirement. Foley et al, investigated 146 hemodialysis patients with asymptomatic cardiomyopathy and randomized them to hemoglobin of 10 or 13.5 g/dL with the primary outcome being change of left ventricular mass index in those with LV hypertrophy and change of cavity index in those with LV dilation. The study showed no regression of established LV hypertrophy and dilation. Secondary outcomes that evaluated quality of life such as improvements in fatigue, depression and relationships were significant with higher hemoglobin levels.[13] Mancini et al, showed improvement in exercise capacity in patients with severe CHF after treatment with epoetin. [14] The largest study to date analyzing the effect of anemia correction on cardiovascular risk with patients not yet requiring renal replacement therapy is currently ongoing. The Cardiovascular risk Reduction by Early Anemia Treatment with Epoetin β (CREATE) trial is in the enrollment stage. In this study approximately 600 patients with moderate anemia (Hgb 11.0-12.5 g/dL) and CKD (GFR 15-35 ml/min) will be divided into two groups: one receiving Epo therapy early with a goal Hgb 13-15 g/dL, the other group receiving Epo only when Hgb <10.5 g/dL with a goal Hgb 10.5-11.5 g/dL. Left Ventricular Mass Index (LVMI) measured by echocardiography will be the primary efficacy variable. If there is significant difference after one year, the study will access time to first cardiovascular event (CHF, sudden death, arrhythmia, MI, CVA, angina, or PVD. Secondary objectives include progression of CKD and quality of life.[15] VII. Conclusion Studies showing association between anemia, heart failure, and chronic kidney disease are well established. A logical mechanism of action linking the three disease processes has been proposed. Trials with anemia normalization have shown wide ranging cardiovascular outcomes. The data by Hayashi, Portoles, and Silverberg have shown that correction of anemia early in kidney disease may provide improvement in cardiac status. Other studies have shown improvement in quality of life and exercise capacity. However, prolonged exposure to the uremic state present in advanced stages of kidney disease may cause irreversible cardiac structural changes and may not be favorable to anemia correction as seen in the Besarab study. More definitive studies, such as CREATE, will hopefully provide answers perhaps justifying the secondary prevention of cardiovascular disease by correction of anemia early in kidney disease.
  10. 10. IX. References 1. Levin A: Clinical Epidemiology of Cardiovacular Disease in Chronic Kidney Disease Prior to Dialyisis. Seminars in Dialysis 16(2): 101-105, 2003 2. Al-Ahmad A, Rand WM, Manjunath G, Konstam MA, Salem DM, Levey AS, Sarnak MJ: Reduced Kidney Function and Anemia as Risk Factors for Mortality in Patients With Left Ventricular Dysfunction. Journal of the American College of Cardiology 38(4): 955-962, 2001. 3. Silverberg D: Outcomes of anaemia management in renal insufficiency and cardiac disease. Nephrology Dialysis Transplantation 18(supp 2): ii7-ii12, 2003 4. Sarnak MJ, Tighiouart Hocine, Manjunath G, MacLeod B, Griffith J, Salem D, Levey AS: Anemia as a Risk Factor for Cardiovascular Disease in the Atherosclerosis Risk in Communities (ARIC) Study. Journal of the American College of Cardiology 40(1): 27-33, 2002. 5. Levin A: The role of anemia in the genesis of cardiac abnormalities in patients with chronic kidney disease. Nephrology Dialysis Transplantation 17: 207-210, 2002 6. http://www.kidney.org/professionals/kdoqi/guidelines_updates/ 7. Katz AM: The cardiomyopathy of Overload. Annals of Internal Medicine 121(5):363-371, 1994. 8. Hayayshi I, Suzuki A, Shoji T, Togawa M, Okada N, Tsubakihara Y, Ima E, Hori M: Cardiovascular effect of normalizing the hematocrit level during erythropoietin therapy in predialysis patients with chronic renal failure. American Journal of Kidney Diseae 35(2): 250-256, 2000. 9. Portoles J, Torralbo A, Martin P, Rodrigo J, Herrero JA, Barrientos A: Cardiovascular effects of recombinant human erythropoietin in predialysis patients. American Journal Kidney Disease 29(4): 541-548, 1997. 10. Silverberg DS, Wexler D, Blum M, Tchebiner JZ, Sheps D, Keren G, Schwartz D, Baruch R, Yachnin T, Shaked M, Schwartz I, Steinbruch S, Adrian I: The Effect of Correction of Anaemia in Diabetic and Non-diabetic with Severe Resistant Congestive Heart Failure and Chronic Renal Failure by Subcutaneous Erythropoietin and Intravenous Iron. Nephrology Dialysis Transplantation 18: 141-146, 2003.
  11. 11. 11. Besarab A, Bolton WK, Browne JK, Egrie JC, Nissenson AR, Okamoto DM, Schwab SJ, Goodkin DA: The Effects of Normal as Compared with Low Hematocrit Values in Patients with Cardiac Disease Who Are Receiving Hemodialysis and Epoetin. NEJM 339:584-590, 1998. 12. Stevens L, Stigant C, Levin A: Should Hemoglobin be Normalized in Patients with Chronic Kidney Disease? Seminars in Dialysis 15(1): 8-13, 2002. 13. Foley RN, Parfrey PS, Morgan J, Barre PE, Campbell P, Cartier P, Coyle D, Fine A, Handa P,et al: Effect of hemoglobin levels in hemodialyisis patients with asymptomatic cardiomyopathy. Kidney International 58, 1325-1335, 2000. 14. Mancini DM, Katz SD, Lang CC, LaManca J, Hudaihed A, Androne AS: Effect of erythropoietin on exercise capacity in patients with moderate to severe chronic heart failure. Circulation 107(2), 294-299, 2003. 15. Macdougall IC: CREATE: new strategies for early anaemia management in renal insufficiency. Nephrology Dialysis Transplantation 18(supp2): ii13-ii16, 2003.

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