|
|
|
 |
The Advancement of Clinical Practice in Chronic Kidney Disease  RPA Satellite Symposium March 22, 2002 Anemia in Patients With Cardiovascular Disease and Concomitant Renal Insufficiency. |  |
|
00:00
Dr. Kline Bolton: Our next speaker is Dr. Al-Ahmad. We're pleased to have a cardiologist who will brave the nephrology audience. But Dr. Al-Ahmad is going to talk to us about anemia in patients with cardiovascular disease and concomitant renal insufficiency. Thank you.
00:00
Dr Amin Al-Ahmad: I'd like to thank Ortho Biotech for giving me the opportunity to talk about something I feel is important. As Dr. Parfrey just pointed out to all of us, anemia is an independent risk factor for mortality in patients with end stage renal disease. Anemia has also been independently associated with the development of heart failure in patients with end stage renal disease and to some degree patients with normal kidney function or chronic renal insufficiency.
00:00
Anemia in heart failure
I'd like to stay away from the end stage renal disease patients and talk a little bit about patients who have heart failure and chronic renal insufficiency. Some of the causes for anemia in this patient population include; circulating cytokines, particularly in those patients who are very sick with heart failure, Class III and IV heart failure, malnutrition, renal insufficiency and frequent phlebotomy. Also treatment with ACE inhibitors which is one of the mainstays of the treatment of heart failure can decrease the level of erythropoietin which we know from some animal studies may be elevated in patients who have heart failure.
00:00
Anemia and chronic kidney disease in patients with left ventricular dysfunction
To look at the relationship between anemia, heart failure and renal insufficiency in more depth we evaluated the Studies of Left Ventricular Dysfunction (SOLVD) database. This in close collaboration with some of the nephrologists at our center, Andy Levey and Mark Sarnak. This, as you may know, was the first major randomized controlled trial looking at any ACE inhibitor in a population of patients with LV dysfunction. It was a multicenter study that randomized 6,797 patients to receive either enalapril or placebo and further stratified these patients by whether they were symptomatic ... in other words, whether they had heart failure ... or whether they were asymptomatic. All patients had to have an ejection fraction less than 35 percent.
00:00
Results
Of note the patient population was primarily male, Caucasian. Twenty percent of these patients had diabetes. About 70 percent of these patients had coronary disease as the cause of their LV dysfunction. At baseline entry into the study both hematocrit and serum creatinine were measured. We calculated GFR based on an equation derived and validated from the MDRD study. Patients were followed for a mean of 33 months and there were approximately 1500 deaths. Of these, 88 percent were cardiovascular. So this for the most part represents cardiovascular mortality.
00:00
Distribution of hematocrit in SOLVD patients
If we look at the distribution of hematocrits in these patients you'll see that it's well-distributed with the lowest hematocrits being in the 25 percent range, the highest 55 percent range with a mean of about 42 percent and a standard deviation of four and a half.
00:00
Distribution of renal function in SOLVD patients
Also if you look at the kidney function as measured by serum creatinine or by predicted GFR, you'll see a very nice distribution with a mean serum creatinine of 1.2 corresponding roughly to a mean GFR of 70.4 ml/min. And one thing I'd like to note is that virtually all cardiology studies exclude patients with renal insufficiency with creatinines greater than 2.5 mg/dl and sometimes even 2.0 mg/dl and that's one of the reasons you don't see any points beyond there.
00:00
Unadjusted total mortality stratified by hematocrit
Now, looking at mortality in patients with left ventricular dysfunction stratified by the level of hematocrit you can see that patients who have higher hematocrit levels have improved survival as compared to those patients with lower hematocrit levels. Here hematocrits greater than 46 survived better than hematocrits less than 35 percent.
00:00
Unadjusted total mortality stratified by renal function
If you look at patients who have renal insufficiency you see also that as the kidney function worsens, the survival also worsens, either measured by serum creatinine or by predicted GFR. And it's worth noting here that the kidney function also worsened with increasing age, presence of hypertension and worsening New York Heart Association class.
00:00
Results
Before adjusting for other covariates and confounders we found that for every 3 percent decrease in hematocrit there was a 12 percent unadjusted increased risk for total mortality that was statistically significant. After adjustment there was an 8 percent increased risk again for every 3 percent decrease in hematocrit, also highly statistically significant. For every 0.1 mg/dl increase in the serum creatinine there was a 10 percent increase in mortality. And after adjustment a 6 percent increase in mortality, highly statistically significant. Similarly for predicted GFR a 16 percent increase in mortality was found for every 10 ml/min decrease in GFR; when adjusting for covariates this was a 7 percent increase in mortality, highly statistically significant.
00:00
Anemia's impact on cardiovascular outcomes
Based on these data as well, as some data that Dr. McClellan shared with me that will be published soon that have confirmed some of our findings, we can say that anemia and chronic renal disease are both risk factors for mortality in patients with congestive heart failure or left ventricular dysfunction. But the question is: "Does treating the anemia in this patient population confer any benefit?" I'm going to show you some of the data that's available on this and I have to tell you it's not a lot. But this is what's out there.
00:00
Use of r-HuEPO in patients with chronic kidney disease
Two small studies looking at the cardiovascular effects of treatment with erythropoietin in patients who have anemia and chronic renal insufficiency. These studies were small, uncontrolled and single center. But they did, however, both find a significant decrease in left ventricular mass index as measured by echocardiography in the treatment group. In other words, patients who received erythropoietin had improved left ventricular mass index as compared with the control group.
00:00
Anemia in heart failure
Some data that Donald Silverberg looked at. He reviewed 142 patient charts. These patients all presented to a specialized CHF clinic at his center. This was a fairly sick population of patients with about 74 percent of these patients having New York Heart Association Class III and IV heart failure. Fifty-six percent of all patients had hemoglobin less than 12 percent, 12 g/dl, and 70 percent of patients, of patients who were Class III or IV heart failure had hemoglobin levels less than 12 g/dl. If you look at this slide here, on the x-axis is New York Heart Association Class and on the y-axis is the hemoglobin level. You'll see that as New York Heart Association Class gets worse, between Class I, II, III and IV, there is a progressive decrease in the mean level of hemoglobin. And this is statistically significant.
00:00
Epoetin and iron supplementation in heart failure
Dr. Silverberg than took 26 patients, all with fairly bad heart failure, New York Heart Association Class III and IV, low ejection fractions and anemia and treated them with erythropoietin in order to achieve a target hemoglobin of 12 grams per deciliter. Now, I'll tell you, this is not controlled data but is interesting nonetheless. He found that there was a statistically significant decrease in New York Heart Association Class from 3.6 to 2.6. There was also an increase in left ventricular ejection fraction from 27 percent to 35 percent, also statistically significant. Hospitalizations decreased and there was a decrease in the use of oral and IV furosemide in these patients. So interesting data but there was no control group in this population.
00:00
Epoetin and iron supplementation in heart failure (cont..)
He followed up with a small study where he had a randomized controlled study of 32 patients, all with pretty severe heart failure, Class III and IV heart failure, on maximal doses of heart failure medications, including ACE inhibitors, in some case beta blockers, and spironolactone. All of the patients had low ejection fractions less than 40 percent and hemoglobin levels were between 10 and 11.5 g/dl
00:00
Half these patients were randomized to receive erythropoietin and iron supplementation. They were followed for 8.2 months. And what he found was a significant reduction in the dose of IV and oral furosemide as well as days in the hospital. Of interest he also found a significant difference in ejection fraction between the control and treatment group with the control group having ejection fraction at the end of the study of 23 percent and the treatment group 36 percent, highly statistically significant. He also found improvements in the New York Heart Association Class of these patients when treated with erythropoietin.
00:00
Conclusion
So in conclusion, the level of hemoglobin and hematocrit is an independent risk factor for mortality in patients with left ventricular dysfunction. The level of renal function as measured by serum creatinine or predicted GFR is also an independent risk factor for mortality in these patients.
00:00
Treatment of anemia is beneficial in patients with chronic renal disease and may have additional potential benefit in patients with congestive heart failure. However, randomized controlled trials are needed in order to further examine this therapeutic strategy in patients with heart failure. Thank you.
Discussion
Anton Schoolwerth: Thanks, Dr. Al-Ahmad. In the SOLVD analysis, maybe you said it but I missed it, did you analyze the relationship between anemia and renal function?
Dr. Amin Al-Ahmad: We did. Anemia and renal function were not related except for at the extremes.
Anton Schoolwerth: Is there a reason besides that the patients with heart failure should have anemia? Can you speculate?
Dr. Amin Al-Ahmad: Besides renal? There are many reasons. ACE inhibitors. Patients who have severe heart failure have circulating cytokine levels that are elevated, causing bone marrow suppression. I think it's multifactorial. But at least we may be able to impact on the anemia and perhaps that may lead to improvement in cardiovascular outcomes.
Anton Schoolwerth: Good. Well, thank you. Dr. McClellan, are you treating your heart failure patients now with erythropoietin if they're anemic?
Dr. William McClellan: No. I think that the data still is very premature and time will tell. I would say though if patients have concomitant renal insufficiency then treating them with erythropoietin may be useful just to improve quality of life but otherwise until there's more data I'm not.
References
1. Foley RN, Parfrey PS, Harnett JD, Kent GM, Murray DC, Barre PE. The impact of anemia on cardiomyopathy, morbidity, and mortality in end-stage renal disease. Am J Kidney Dis. 1996 Jul;28(1):53-61.
2. Harnett JD, Kent GM, Foley RN, Parfrey PS. Cardiac function and hematocrit level. Am J Kidney Dis. 1995 Apr;25(4 Suppl 1):S3-7.
3. Volpe M, Tritto C, Testa U, Rao MA, Martucci R, Mirante A, Enea I, Russo R, Rubattu S, Condorelli GL, et al. Blood levels of erythropoietin in congestive heart failure and correlation with clinical, hemodynamic, and hormonal profiles. Am J Cardiol. 1994 Sep 1;74(5):468-73.
4. Al-Ahmad A, Rand WM, Manjunath G, Konstam MA, Salem DN, Levey AS, Sarnak MJ. Reduced kidney function and anemia as risk factors for mortality in patients with left ventricular dysfunction. J Am Coll Cardiol. 2001 Oct;38(4):955-62.
5. Hayashi T, Suzuki A, Shoji T, Togawa M, Okada N, Tsubakihara Y, Imai E, Hori M. Cardiovascular effect of normalizing the hematocrit level during erythropoietin therapy in predialysis patients with chronic renal failure. Am J Kidney Dis. 2000 Feb;35(2):250-6.
6. Portoles J, Torralbo A, Martin P, Rodrigo J, Herrero JA, Barrientos A. Cardiovascular effects of recombinant human erythropoietin in predialysis patients. Am J Kidney Dis. 1997 Apr;29(4):541-8.
7. Silverberg DS, Wexler D, Blum M, Keren G, Sheps D, Leibovitch E, Brosh D, Laniado S, Schwartz D, Yachnin T, Shapira I, Gavish D, Baruch R, Koifman B, Kaplan C, Steinbruch S, Iaina A. The use of subcutaneous erythropoietin and intravenous iron for the treatment of the anemia of severe, resistant congestive heart failure improves cardiac and renal function and functional cardiac class, and markedly reduces hospitalizations. J Am Coll Cardiol. 2000 Jun;35(7):1737-44.
This educational activity is supported by an educational grant from Ortho Biotech Products, L.P. This activity has been planned and produced in accordance with the ACCME Essential Areas and Policies and with CE policies of the State of California Board of Registered Nursing. From a CME Symposium held on March 22, 2002 at the Renal Physicians Association (RPA) Annual Meeting in Washington, DC. This symposium was approved by the RPA. It was not part of the official RPA Annual Meeting as planned by the RPA Program Committee. |
 |  | ||||||||||||||
| |||||||||||||||
 |  |
Windows
Media Player
Real Audio
Player
Discuss the increased prevalence of chronic kidney disease in the United States; 
