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MEDCAC Meeting

Levocarnitine for End Stage Renal Disease (Drugs, Biologics, and Therapeutics Panel)

06/20/2001

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Issue

Carnitine is an endogenous molecule that serves as a carrier in the transport of long-chain fatty acids across the inner mitochrondrial membrane, facilitating oxidation and energy production. Dialytic losses, combined with reduced renal synthesis and reduced intake of meat and dairy products, can cause carnitine deficiency in end stage renal disease (ESRD) patients. Levocarnitine injection has been approved by the Food and Drug Administration (FDA) for the "prevention and treatment of carnitine deficiency in ESRD patients who are undergoing dialysis. Levocarnitine injection was first approved by the in FDA 1992. The FDA approved the drug's indication for ESRD patients on December 15, 1999. Given inconsistencies among the fiscal intermediaries' local coverage policies for this drug, the Centers for Medicare and Medicaid Services (CMS) believes a national review is appropriate. Among other issues, CMS plans to examine, in this review, the clinical significance of carnitine deficiency and the issue of intravenous administration of carnitine supplementation versus oral administration.

Actions Taken

Agenda

Minutes

Minutes of June 20, 2001 Meeting

OPEN SESSION

Baltimore Convention Center
Baltimore, Maryland

Attendees

Thomas V. Holohan, MA, MD, FACP
Chairperson

Kimberly Long
Executive Secretary

Voting Members
Kathy J. Helzlsouer, MD, MHS
Robert C. Johnson, MS
Ronald P. Jordan, RPh
Mitchell Sugarman, MBA, MS

Temporary Voting Member
Emil P. Paganini, MD, FACP, FRCP

Temporary Non-Voting Member
Paul Metzger, MD

Industry Representative
Cathleen M. Dooley, MA

Consumer Representative
Christine M. Grant, JD

CMS Representative
Sean R. Tunis, MD, MSc

Tuesday, June 20, 2001, 8:35 a.m.

The Drugs, Biologics, and Therapeutics Panel met on June 20, 2001, to discuss the use of levo-carnitine (carnitine) in end stage renal disease (ESRD) patients. The meeting began with a reading of the conflict of interest statement, and the call to order.

Clinical Background.  Dr. Glenn Chertow from the University of California, San Francisco (UCSF), presented the Panel with an overview of the clinical background of carnitine deficiency, how it is acquired, and when administration of carnitine affects asthenia, malaise, muscle weakness, intradialytic cramps and hypotension, cardiomyopathy, EPO resistant anemia, and quality of life. He also explained the history of K/DOQI. The DOQI work group concluded that although the totality of evidence was unimpressive, a therapeutic trial could be reasonable.

FDA Presentation.    The FDA representative was unable to attend the meeting, but Dr. Tunis read a letter from the Director, Division of Metabolic and Endocrine Drug Products, summarizing the basis for FDA's approval of intravenous carnitine for the prevention and treatment of carnitine deficiency associated with ESRD in patients undergoing chronic hemodialysis.

CMS Presentation.    John Whyte, MD, MPH, discussed the reasons why the questions were referred to the Medicare Coverage Advisory Committee (MCAC), primarily because different groups expressed widely variant opinions about the same data. Because of this, a literature review followed by an open meeting was believed to be the best way to address the issue. Dr. Preston Klassen, MD, MHS, summarized the literature review conducted by the MCAC, Dr. Whyte then stated the questions the Panel would be asked to consider.

Scheduled Public Comments.   The Panel heard from 12 scheduled speakers, including repesentatives of Sigma Tau, the manufacturer of Carnitor injection; medical directors of CMS fiscal intermediaries from Georgia and Pennsylvania; a nephrologist from Ochsner Clinic in New Orleans; president of the National Association for Rare Disorders; two dialysis patients with history of carnitine treatment; a clinical nephrologist from University of California at Los Angeles (UCLA); the executive director of American Association of Kidney Patients (AAKP); a former senior endocrinologist at the FDA; and the executive director of Renal Beginnings, who gave a presentation on behalf of the Georgia Society of Nephrology (GSN).

These individuals relayed their personal experience, as well as the policies of organizations they represented, concerning the topic under discussion.

Review of Evidence by Panel Members.   Dr. Holohan and Ms. Dooley presented a summary of the data provided by CMS. Dr. Holohan shared a series of tables summarizing results of studies for different indications. Ms. Dooley related the results of the various data to the specific questions posed by CMS.

Open Public Comments.    Five additional commenters of the general public gave presentations to the Panel.

Open Panel Deliberations.   The Panel held a lengthy discussion. At the outset, Dr. Tunis reminded the Panel that although the issue of cost had been brought up, it is not an issue for the Panel, which will make its recommendations based on the adequacy of the evidence. During the deliberations, several panelists expressed concern over the definition of carnitine deficiency since several of the presenters indicated that there should be criteria other than a simple percentage of serum carnitine before administering levo-carnitine. Panelists also noted that many of the issues presented were difficult to answer given the specific questions proposed by CMS. Several panelists commended Georgia on the guidelines they had developed and encouraged CMS to look at them when drafting any national coverage decision. Panelists specifically noted there was very little evidence presented showing the efficacy of one method of treatment compared to another.

Final Panel Recommendations.

After further discussion, the panel voted on the following three motions:

(1) CMS to establish a mechanism to define carnitine deficiency in the ESRD patient population because there is adequate evidence that such a condition exists. The Panel voted unanimously in favor of that motion.

(2) There is adequate evidence that indicates some patients benefit from levo-carnitine; upon establishment of rational guidelines that identify this patient population, Medicare coverage should be provided. The Panel voted unanimously in favor of that motion.

(3) There is insufficient evidence to conclude that the route of administration, be it intravenous, oral, or dialysis fluid, is an important factor in the clinical safety of L-carnitine therapy in patients with ESRD on hemodialysis. The motion carries three to one, that the evidence is insufficient.

Adjournment. The meeting adjourned at 4:20 p.m.
I certify that I attended the meeting
of the Drugs, Biologics, and Therapeutics Panel
on June 20, 2001, and that these minutes
accurately reflect what transpired.
_________________________________
Kimberly Long
Executive Secretary, CMS

I approve the minutes of this meeting
as recorded in this summary.
______________________________
Thomas V. Holohan, MA, MD, FACP
Chairperson

Panel Voting Questions

Contact Information

Other Material

Memorandum to Panel

To:			Members and Guests of the Drugs, Biologics, and Therapeutics Panel

From:		John Whyte, MD; Preston Klassen, MD; Michael Londner, MD

Subject:		Literature Review

Date:		June 5, 2001

Attached is a Literature Review relating to the use of levocarnitine in end-stage renal disease (ESRD patients).

The following search strategy was used:

MESH heading: CARNITINE (exploded)
AND
MESH heading: (KIDNEY FAILURE, CHRONIC OR RENAL DIALYSIS OR DIALYSIS)

This initial strategy resulted in 181 articles. The articles were sorted by study design:

10 Randomized Controlled Trials
51 Prospective Clinical Trials
30 Case Control or Cohort studies
23 Reviews or Editorials
23 Letters to the Editor
44 Excluded on first pass:
Non-English
Non-human
Case report
Not focused on carnitine
Acute renal failure

The title and abstract of each article was screened by two reviewers for inclusion/exclusion. Discrepancies between reviewers were resolved by a consensus panel of three physicians.

In order to be included for data abstraction, articles had to meet the following inclusion criteria:

Human ESRD subjects
Minimum 10 subjects
Published after 1980
Clinically-relevant outcome measures
These included the following subgroups:
Pharmacokinetics (carnitine levels, effect of supplementation on levels, effect of dialysis on levels, etc.)
Cardiac function
Lipids and coagulation
Hematology (anemia, erythropoetin, RBC and WBC measures)
Other metabolic (e.g. nutrition)
Muscle and exercise
Quality of life

Only original journal articles were considered for inclusion. Letters to the editor and topic reviews were not considered for data abstraction. Several topic review articles were utilized for content and for expanding the potential article pool. Articles focusing on the pediatric population were excluded. This screening process resulted in 36 Articles for full data abstraction.

Bibliography

Bibliography for Levocarnitine for End Stage Renal Disease

Ahmad S, Robertson T, Golper T, Wolfson M et al. Multicenter trial of l-carnitine in maintenance hemodialysis patients . II. Clinical and biochemical effects. Kidney International 1990; 38:912-918.

Bellinghieri G, Savica V, Mallamace A, DiStefano C, et al. Correlation between increased serum an tissue l-carnitine levels and improved muscle symptoms in hemodialyzed patients. American Journal of Clinical Nutrition 1983; 38:523-531.

Bertoli M, Battistella PA, Vergani L, Naso A, et al. Carnitine deficiency induced during hemodialysis and hyperlipidemia: effect of replacement therapy. American Journal of Clinical Nutrition 1981; 34:1496-1500.

Brass EP, Adler S, Sietsema KE, Hiatt WR, et al. Intravenous l-carnitine increases plasma carnitine, reduces fatigue, and may preserve exercise capacity in hemodialysis patients. American Journal of Kidney Diseases 2001; 37:1018-1028.

Caruso U, Cravotto E, Tisone G, Elli M, et al. Long-term treatment with l-carnitine in uremic patients undergoing chronic hemodialysis: effects on the lipid pattern. Current Therapeutic Research 1983; 33:1098-1104.

Caruso U, Leone L, Cravotto E, Nava D.. Effects of L-carnitine on anemia in aged hemodialysis patients treated with recombitant human erythropoietin: a pilot study.. Dialysis and Transplantation 1998; 27::498-506.

Casciani C, Caruso U, Votto E, Corsi M, et al. Beneficial effects of l-carnitine in post-dialysis syndrome. Current Therapeutic Research 1982; 32:116-127.

Chan MK, Persaud J, Varghese Z, Baillod R, et al. Response patterns to DL-carnitine in patients on maintenance hemodialysis. Nephron 1982; 30:240-243.

Elisaf M, Bairaktari E, Katopodis K, Pappas M, et al. Effect of L-carnitine supplementation on lipid parameters in hemodialysis patients. American Journal of Nephrology 1998; 18:416-421.

Fagher B, Cederblad G, Eriksson M, Monti M, et al. L-carnitine and haemodialysis: double blind study on muscle function and metabolism and peripheral nerve function. Scandinavian Journal of Clinical Laboratory Investigation 1985; 45:169-178.

Fagher B, Cederblad G, Monti M, Olsson L et al. Carnitine and left ventricular function in hemodialysis patients. Scandinavian Journal of Clinical Laboratory Investigation 1985; 45:193-198.

Giovenali P, Fenocchip D, Montanari G, Cancellotti C, et al. Selective trophic effect of l-carnitine in type I and II a skeletal muscle fibers.. Kidney International 1994; 46:1616-1619.

Golper TA, Wolfson M, Ahmad S, Hirschberg R, et al. Multicenter trial of l-carnitine in maintenance hemodialysis patients. I. Carnitine concentrations and lipid effects.. Kidney International 1990; 38:904-911.

Guarnieri GF, Ranieri F, Togio G, Vasile A, et al. Lipid-lowering effect of carnitine in chronically uremic patients treated with maintenance hemodialysis. American Journal of Clinical Nutrition 1980; 33:1489-1492.

Kletzmayr J, Mayer G, Legenstein E, Heinz-Peer G, et al. Anemia and carnitine supplementation in hemodialyzed patients. Kidney International 1999; 55:S93-S106.

Labonia WD. L-carnitine effects on anemia in hemodialyzed patients treated with erythropoietin. American Journal of Kidney Diseases 1995; 26:757-764.

Lacour B, Chanard J, Haguet M, Basile C, et al. Carnitine improves lipid anomalies in hemodialysis patients. Lancet 1980; :763-764.

Maebashi M, Imamura A, Yoshinaga K, Sato T, et al. Carnitine depletion as a probable cause of hyperlipidemia in uremic patients on maintenance hemodialysis. Tohoku Journal of Experimental Medicine 1983; 139:33-42.

Matsumura M, Hatakeyama S, Koni I, Mabuchi H, et al. Correlation between serum carnitine levels and erythrocyte osmotic fragility in hemodialysis patients. Nephron 1996; 72:574-578.

Nilsson-Ehle P, Cederblad G, Fagher B, Monti M, et al. Plasma lipoproteins, liver function and glucose metabolism in haemodialysis patients: lack of effect of l-carnitine supplementation. Scandinavian Journal of Clinical Laboratory Investigation 1985; 45:179-184.

Rocchi L, Feola I, Calvani M, D'Iddio S, et al. Effects of carnitine administration in patients with chronic renal failure undergoing periodic dialysis, evaluated by computerized electromyography. Drugs Experimental Clinical Research 1986; 12:707-711.

Sakurauchi Y, Matsumoto Y, Shinzato T, Takai I, et al. Effects of l-carnitine supplementation on muscular symptoms in hemodialyzed patients. American Journal of Kidney Disease 1998; 32:258-264.

Semeniuk J, Shalansky KF, Taylor N, Jastrzebski J, et al. Evaluation of the effect of intravenous l-carnitine on quality of life in chronic hemodialysis patients. Clinical Nephrology 2000; 54:470-477.

Siami G, Clinton ME, Mrak R, Griffis J, et al. Evaluation of the effect of intravenous l-carnitine therapy on function, structure, and fatty acid metabolism of skeletal muscle in patients receiving chronic hemodialysis. Nephron 1991; 57:306-313.

Sloan RS, Kastan B, Rice SI, Sallee CW, et al. Quality of life during and between hemodialysis treatments: role of l-carnitine supplementation. American Journal of Kidney Diseases 1998; 32:265-272.

Spagnoli LG, Palmieri G, Mauriello A, Vacha G, et al. Morphometric evidence of the trophic effect of l-carnitine on human skeletal muscle. Nephron 1990; 55:16-23.

Srivastava DK, Kumar S, Misra AP. Reversal of haemodialysis induced hypertriacylglycerolemia by l-carnitine. Indian Journal of Clinical Biochemistry 1992; 7:19-21.

Suzuki Y, Narita M, Yamazaki N.. Effects of l-carnitine on arrhythmias during hemodialysis. Japan Heart Journal 1982; 23:349-359.

Thomas S, Fischer FP, Mettang T, Pauli-Magnus C, et al. Effects of l-carnitine on leukocyte function and viability in hemodialysis patients: a double-blind randomized trial. American Journal of Kidney Disease 1999; 34:678-687.

Trovato G, Ginardi V, Di Marco V, Dell'aira A, et al. Long-term L-carnitine treatment of chronic anaemia of patients with end-stage renal failure. Current Therapeutic Research 1982; 31:1042-1049.

Vacha GM, Giorcelli G, DiIddio S, Valentini G, et al. L-carnitine addition to dialysis fluid: a therapeutic alternative to hemodialysis patients.. Nephron 1989; 51:237-242.

Vacha GM, Giorcelli G, Siliprandi N, Corsi M.. Favorable effects of l-carnitine treatment on hypertriglyceridemia in hemodialysis patients: decisive role of low levels of high-density lipoprotein-cholesterol. American Journal of Clinical Nutrition 1983; 38:532-540.

Van Es A, Henny FC, Kooistra MP, Lobatto S, et al. Amelioration of cardiac function by l-carnitine administration in patients on haemodialysis. Contributions Nephrology 1992; 98:28-35.

Wanner C, Forstner-Wanner S, Schaeffer G, Schollmeyer P, et al. Serum free carnitine, carnitine esters and lipids in patients on peritoneal dialysis and hemodialysis. American Journal of Nephrology 1986; 6:206-211.

Weschler A, Aviram M, Levin M, Better O, et al. High dose of l-carnitine increases platelet aggregation and plasma trigylceride levels in uremic patients in hemodialysis. Nephron 1984; 38:120-124.

Yderstraede KB, Pedersen FB, Dragsholt C, Trostmann A et al. The effect of l-carnitine on lipid metabolism in patients on chronic haemodialysis. Nephrology Dialysis Transplantation 1987; 1:238-241.

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