September 23, 2008
Steve Phurrough, MD
Director, Coverage & Analysis Group
Centers for Medicare and Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244-1850
Re: Potential topics for national coverage
determinations – use of levocarnitine in patients
on dialysis
Dear Dr. Phurrough,
On July 30, 2008, CMS published and requested
comment on a list of potential NCD topics for the
third quarter of 2008. Sigma-Tau Pharmaceuticals
has prepared this response to your request
related to the use of levocarnitine in dialysis.
On the list of potential NCD topics CMS wrote
that: Levocarnitine has unclear benefits in the
ESRD population. Recent revisions of K-DOQI
guidelines suggest a paucity of evidence to
support some uses.
We comment on the use of levocarnitine in the
ESRD population especially in regard to the use
of levocarnitine in the context of EPO resistant
anemia since it is this application that was the
subject of the recent recommendations by the K-
DOQI anemia working group cited by CMS in its
list of potential topics for review. We therefore
place particular emphasis on the additional data
supporting the application of levocarnitine in
the context of ESA therapy generated since the
adoption of the levocarnitine NCD in 2004 and the
significant flaws in the K-DOQI guidelines
concerning levocarnitine and ESA use that were
highlighted during the review period for that K-
DOQI and have become even more apparent since the
publication of that guideline.
As there have been no new clinical trials on the
use of levocarnitine for dialysis related
hypotension since the issuance of CAG-00077N, we
do not believe that there is a compelling basis
for modification of coverage for that indication.
Evidence for benefit of levocarnitine in the
context of ESA therapy for anemia in dialysis
patients
In crafting its NCD for levocarnitine in
dialysis, CMS performed an extensive review of
the literature concerning the effect of
levocarnitine therapy on parameters of the anemia
of chronic kidney disease including both an
independent effect on improvement of hemoglobin
and hematocrit levels as well as reduction of EPO
requirements for maintenance of specified anemia
treatment targets in the ESRD population. In
performing its analysis, CMS adhered to strictly
defined criteria for selection of appropriate
literature for review. Research qualified for
inclusion in the analysis only if it met the
following criteria:
• Clinical trial
• Human ESRD subjects
• Minimum of 10 subjects
• Published after 1980
• Clinically relevant outcome measures
The application of these criteria allowed
inclusion of eleven papers related to
levocarnitine and anemia treatment in dialysis
patients. Eight of these studies were randomized
control trials. Five of the eleven studies
examined the effect of levocarnitine therapy on
EPO requirements. In 3/5 studies the EPO
requirement decreased in association with
levocarnitine therapy; in an additional study,
the EPO requirement remained stable compared with
an increase in the control group. In only one
study was the change in EPO requirement similar
in both the carnitine treated and control group.
As a result of this analysis, CMS concluded:
“the evidence is adequate to conclude that the
use of levocarnitine to treat ESRD patients with
erythropoietin-resistant anemia (persistent
hematocrit < 30% with treatment) that has not
responded to standard erythropoietin dosage with
iron replacement, and for which other causes have
been investigated and adequately treated is
clinically effective, and, therefore, reasonable
and necessary.
This conclusion, based upon a systematic analysis
of the literature chosen according to clearly
specified selection criteria is thought to
represent an accurate interpretation of the
available data. Given the appropriateness of the
analytical strategy, it would seem that the sole
valid reason for questioning the conclusion of
the analysis would be the subsequent availability
of more recent data suggesting the lack of
efficacy of levocarnitine in reducing ESA
requirements in dialysis patients. In order to
judge whether such data provides the basis for a
reasonable challenge to the NCD, one must examine
the data that has emerged subsequent to the NCD
evaluation. As the most recent study included in
the CMS analysis of L-carnitine and anemia in
dialysis patients dated to May 2001(Brass et al),
it is worthwhile to review the results of studies
related to intravenous L-carnitine and renal
anemia published since the NCD deliberations that
satisfied the literature selection criteria used
by the MCAC.
1) Vesela E et al,July 2001
Twelve chronic hemodialysis patients were treated
with IV L-carnitine 15mg/kg after each
hemodialysis session for 6 months. The clinical
outcomes were compared with non-carnitine treated
patients. Whereas there was no significant change
in either hemoglobin level or EPO requirement in
the non-carnitine treated controls, six months
treatment with IV L-carnitine was associated with
an increase in hematocrit from 27 to 34 with a
concomitant reduction in rHuEPO dose from a mean
of 5500 units to 3500 units per week.
1
2) Savica 2005
48 chronic hemodialysis patients were treated
with IV L-carnitine 20mg/kg three times weekly
for six months. Outcomes were compared with 65
patients treated for 6 months with placebo
Carnitine treated patients had a mean increase in
HgB level from 9.6 to 10.7 as opposed to no
increase in HgB in the placebo treated patients
who started from a similar baseline HgB and
treated according to the same EPO regimen.
2
3) Kadiroglu AK et al (2005)
Seventeen maintenance hemodialysis patients were
treated with rHuEPO plus L-carnitine 1 gram IV
after each dialysis and compared over a sixteen
week treatment period with 17 patients treated
with rHuEPO without L-carnitine therapy. Iron
status was similar in both groups .Whereas the
target HgB was achieved in both groups, the
carnitine treated group had a 20% greater
reduction in EPO requirements in the course of
the study compared with non-carnitine treated
patients, (p<.05) 3
4) Steiber et al 2006
A double blind, randomized, placebo controlled
trial in which 50 hemodialysis patients were
treated with either 2 grams IV L-carnitine or
placebo for 24 weeks. For maintenance of HgB
within a desirable range, the erythropoietin dose
over the 24 week period was reduced from baseline
in the carnitine treated group relative to the
placebo group(-1.62 +/-.91 vs. 1.33 +/- .79 units
erythropoietin/dry weight/Hgb concentration
respectively<.05). 4
5) Arduini et al 2006
A double blind, placebo controlled study of 29
stable hemodialysis patients. Patients treated
either with L-carnitine IV 20mg/kg after each
dialysis or placebo (normal saline) for 24 weeks.
The primary endpoint was red blood cell (RBC)
survival. Baseline RBC survival was similar in
the carnitine and placebo groups (T1/2 40.2 +/-
8.9 days placebo,39.1+/- 7.5 days L
carnitine).RBC survival measured by Cr51
labeling increased by 3.6 days in the carnitine
treated group and decreased 4.8 days in the
placebo group. Estimate of the treatment related
difference was 8.5 days (95% CI .3, 17.2). Median
EPO dose decreased in the L-carnitine treated
patients and increased in the placebo treated
patients though the actual units of EPO for this
secondary endpoint are not shown in the paper. 5
It can therefore be seen that all studies
conducted subsequent to the levocarnitine
national coverage decision have confirmed the
efficacy of levocarnitine either in reducing EPO
requirements or independently increasing
hemoglobin or hematocrit.Since the data available
to the MCAC was said to support the use of L-
carnitine as adjunct treatment of dialysis
related anemia and studies since that time have
provided additional support for this application
of levocarnitine, there appears to be no
compelling reason to re-visit this indication for
levocarnitine use in dialysis patients.
As to the recent K-DOQI anemia recommendation
concerning the use of L-carnitine for EPO
resistance, the negative sentiment communicated
in the guidelines was the result of both an
incomplete data analysis and an incorrect reading
of the data cited. Sigma Tau commented
extensively on these errors during the open
response period following the issuance of the
preliminary guidelines.However, despite
endorsement of Sigma Tau’s corrections by several
members of the DOQI anemia committee, there was
no feedback to Sigma Tau by the committee
chairman, Dr.Van Wyck.The entire critique of the
DOQI guideline concerning L-carnitine and the
anemia of ESRD is attached to this document but
is briefly summarized as follows:
The DOQI committee had three principal criticisms
of the evidence supporting the use of L-carnitine
as adjunctive treatment for the anemia of ESRD:
The first criticism was the supposed lack of data
supporting specific mechanisms of action by which
L-carnitine could enhance the response to ESAs.
No less than five published studies were cited by
Sigma Tau which demonstrated improvement with the
use of L-carnitine in factors known to be
associated with resistance to ESAs. These
mechanisms included the following:
• Improvement in red blood cell
deformability6
• Stabilization of red cell osmotic
resistance7
• Reacylation of red cell membrane
phospholipids8
• Reduction in C-reactive protein levels 9
• Reduction in free oxygen radicals 1
Preservation of the integrity of the red cell
membrane by the various mechanisms cited above
results in an improved red cell life span as
demonstrated by Arduini et al (2006).Improvement
in red cell survival reduces the requirement for
red cell production stimulated by
ESAs .Furthermore, as chemical mediators of
vasospasm have been demonstrated to be released
by lysed red cells, improvement in red cell
membrane integrity and red cell survival would be
expected to reduce the release of those
vasoactive substances which might consequently
reduce the endothelial dysfunction documented in
dialysis patients. 10In omitting much of the
published literature on mechanisms of benefit on
anemia associated with L-carnitine, the DOQI
committee seems to have limited the scope of its
literature review to a significant degree.
The second criticism questioned the quality of
the data supporting the efficacy of L-carnitine
in reducing EPO requirements in dialysis
patients. Specific objection was raised to the
methodologies employed in the Labonia study
(1995).11 As part of its review of the K-DOQI
guidelines, Sigma Tau highlighted several
elements of the Labonia study that were
characteristic of an acceptable methodology.
These included random assignment to a control or
placebo group, clear characterization of
inclusion and exclusion criteria, clear
description of additional therapies for anemia
such as iron, B12, and folate, and employment of
a similar dialysis regimen for the placebo and
treatment groups. As to the K-DOQI criticism of
the size of the patient population, Sigma Tau
stated as follows:
“The Labonia study showed a reduction in EPO dose
of 38% - no reduction was demonstrated in the
placebo treated group. The reduction in dose was
significant for the carnitine treated patients at
a p value of <.02. The fact that this level of
significance for the reduction was achieved in a
small study group of 24 patients lends support to
the hypothesis of a reduction in EPO requirements
with carnitine use. The fact that the guideline
faults the study for being small ignores the
basic principles of study design where the number
of subjects necessary for a study is determined
by the effect size and standard deviation on the
measurement rather than some arbitrary
characterization and “large” or “small.”
The conclusion of benefit for L-carnitine in
improving the response to EPO has been supported
by the positive results of controlled clinical
trials conducted since the adoption of the most
recent K-DOQI guideline as summarized above.
The last criticism of the efficacy data concerned
the meta-analysis of carnitine and EPO response
authored by Hurot and published in JASN in
2002.12This meta-analysis clearly demonstrated
the efficacy of L-carnitine for reducing the
required dose of EPO for maintenance of a target
hemoglobin or hematocrit level. This study
included features indicative of a carefully done
meta-analysis. Prospective standards were adopted
for the selection of studies to be included in
the analysis. Retrospective trials as well as
nonrandomized and uncontrolled trials were
excluded from the analysis. These strict study
criteria restricted the included studies to 17
published trials of the 620 references initially
identified.
The effect measure analyzed in the carnitine-
anemia trials was that endorsed by the K-DOQI
anemia committee to be most significant is the
difference between carnitine and control in the
change in EPO dose from baseline. The conclusion
of the authors of this meta-analysis is as
follows:
“A reduction in EPO dose was achieved in the
carnitine treated groups in five of the six
studies while maintaining comparable target
hemoglobin in both the carnitine and control
groups. The EPO dose was significantly smaller as
compared with the control groups in four trials.
A common effect size of -.75 (random effect
model) was observed, with a statistically
significant level of heterogeneity (p
heterogeneity=.02). This indicates that a patient
in the 50th percentile of EPO dose distribution
in the placebo group would reduce his/her EPO
dose to the 23rd percentile if treated by L
carnitine.”
The strongest objection of the K-DOQI to this
meta-analysis concerned the heterogeneity of
response in the studies included in the Hurot
meta-analysis. This objection demonstrated an
incomplete grasp of the significance of the
random effects model used in the meta-analysis.
During its review of the K-DOQI reccomendations,
Sigma Tau answered the criticisms of the K-DOQI
in regard to heterogeneity as follows:
In regard to the heterogeneity cited by Hurot, et
al., the authors properly addressed these issues
by use of a random effects meta-analysis.
Heterogeneity among studies could invalidate the
meta-analysis only if the studies literally
contradicted one another, with an ambiguous
conclusion about whether the effect was
beneficial or not. As seen in the lower half of
Figure 3 from Hurot, et al., [2002, page 711],
there was no such ambiguity regarding the impact
of LC on EPO use. Only one study of seven had an
effect in the opposite, non-beneficial, direction
and its confidence interval included zero (no
effect). The other six studies were concordant in
direction (lower EPO dose with LC usage), five of
them significantly favoring LC. Among the seven
studies, heterogeneity of effect size was
discovered in stage 1 and appropriately addressed
in the stage 2 random effects meta-analysis.
Rather than making LC efficacy seem less
credible, a significant finding based on a
conservative
In summary, the negative conclusions of the most
recent K-DOQI in regard to the efficacy of L-
carnitine in the treatment of dialysis related
anemia are not supported by the primary
literature sources or the analytical procedures
employed in the cited studies. Sigma Tau sent
detailed comments to the K-DOQI anemia committee
during the period allowed for review but no
response was ever received to these comments.
CMS has an impressive record of basing coverage
decisions on data Any further restriction to the
coverage for levocarnitine in dialysis is
inconsistent with the data both prior to and
subsequent to the present levocarnitine NCD and
is likely to have negative consequences in regard
to outcomes in patient with ESRD.
Thank you for the opportunity to comment on this
important issue.
Sincerely,
Brian Schreiber, M.D.
Vice-President, Medical Affairs
Sigma Tau Pharmaceuticals
9841 Washingtonian Blvd., Suite 500
Gaithersburg, MD 20878
References
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2) Savica Vincenzo,MD,Santoro Domenico
MD,Mazzaglia Giampiero,MD et al L-Carnitine
Infuctions May Suppress Serum C-Reactive Protein
abd Improve Nutritional Status in Maintenance
Hemodialysis Patients Journal of Renal
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BI,Wellman GC Oxyhemoglobin-induced expressio of
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