Bredenoord, Annelien L.

Chamuleau, Steven A.J.

Dib, Nabil

Doevendans, Pieter A.

Koudstaal, Stefan

Niemansburg, Sophie L.

Wallet, Justin

Elsevier - Publisher Connector 

Figure 1
Practice-Level Variation in Inappropriate Prasugrel
Prescribing
Percentage of patients in individual practices receiving prasugrel inappropriately
ranged from 0% to 90% (median: 4.4% [interquartile range: 2% to 10%]).
The median rate ratio was 2.89 (95% conﬁdence interval: 2.75 to 3.03), indicating
signiﬁcant practice-level variation.
JACC Vol. 63, No. 25, 2014 Correspondence
July 1, 2014:2876–86
2877motivated for quality improvement and, therefore, inappropriate
and nonrecommended rates may be higher in nonparticipating
practices. Data on the contraindications to clopidogrel, reason for
choosing prasugrel instead of clopidogrel, dosage of prasugrel
pertaining to patients weighing <60 kg, results of platelet function
studies, and ischemic and bleeding outcomes are not collected
in the PINNACLE registry, and analyses pertaining to these
variables, therefore, could not be performed.
Almost 1 in 5 patients receiving prasugrel had an inappropriate
or nonrecommended indication with signiﬁcant practice-level vari-
ation. Our ﬁndings suggest opportunities to improve evidence-based
prasugrel prescribing.*Ravi S. Hira, MDy
Kevin Kennedy, MSz
Hani Jneid, MDxy
Mahboob Alam, MDy
Sukhdeep S. Basra, MD, MPHy
Laura A. Petersen, MD, MPHxk{
Christie M. Ballantyne, MDy
Vijay Nambi, MD, PhDxy
Paul S. Chan, MD, MScz
Salim S. Virani, MD, PhDxyk
*Baylor College of Medicine
6620 Main Street, Suite 11D
Houston, Texas 77030
E-mail: hira@bcm.edu
http://dx.doi.org/10.1016/j.jacc.2014.04.011
From the ySection of Cardiology, Department of Medicine, Baylor
College of Medicine, Houston, Texas; zMid America Heart
Institute, Saint Luke’s Hospital, Kansas City, Missouri; xMichael
E. DeBakey VA Medical Center, Houston, Texas; kHealth Policy,Quality and Informatics Program, Michael E. DeBakey Veteran
Affairs Medical Center Health Services Research and Development
Center for Innovations, Houston, Texas; and the {Section of Health
Services Research, Department of Medicine, Baylor College of
Medicine, Houston, Texas.
Please note: Dr. Alam has been a member of the advisory board for AstraZeneca. Dr.
Petersen has received grant/research support from the National Institutes of Health
(R01 HL0791731) and the Houston VA HSR&D Center of Excellence (HFP9O-
020). Dr. Ballantyne has received grant/research support (all signiﬁcant [>$10,000]
and all paid to institution, not individual) from Abbott, Amarin, Amgen, Eli Lilly,
GlaxoSmithKline, Genentech, Merck, Novartis, Pﬁzer, Regeneron, Roche, Sanoﬁ-
Synthelabo, the National Institutes of Health, and the American Heart Association;
she has also served as a consultant for Abbott, Aegerion, Amarin, Amgen, Arena,
Cerenis, Esperion, Genentech, Genzyme, Kowa, Merck, Novartis, Pﬁzer, Resverlogix,
Regeneron, Roche, and Sanoﬁ-Synthelabo; and on the speakers’ bureau for Abbott.
Dr. Nambi was a national monitor for a study sponsored by Anthera Inc.; a co-
investigator on a provisional patent ﬁled by Baylor College of Medicine, Roche
Diagnostics, on the use of biomarkers in heart failure prediction; and involved in a
research collaboration with GE and Tomtec. Dr. Virani has received grant/research
support in the form of a Department of Veterans Affairs Health Services Research
and Development Career Development Award (09-028) and an American Diabetes
Association Clinical Science and Epidemiology Award (1-14-CE-44). All other
authors have reported that they have no relationships relevant to the contents of this
paper to disclose. The views expressed in this article are those of the authors and do not
necessarily represent the views of the Department of Veterans Affairs.REFERENCES
1. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopi-
dogrel in patients with acute coronary syndromes. N Engl J Med 2007;
357:2001–15.
2. Prasugrel [package insert]. Indianapolis, IN: Eli Lilly and Company,
2013.
3. O’Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA
guideline for the management of ST-elevation myocardial infarction: a
report of the American College of Cardiology Foundation/American
Heart Association Task Force on Practice Guidelines. Circulation 2013;
127:e362–425.
4. Jneid H, Anderson JL, Wright RS, et al. 2012 ACCF/AHA focused
update of the guideline for the management of patients with unstable
angina/non-ST-elevation myocardial infarction (updating the 2007
guideline and replacing the 2011 focused update): a report of the
American College of Cardiology Foundation/American Heart Associa-
tion Task Force on Practice Guidelines. J Am Coll Cardiol 2012;60:
645–81.
5. Sandhu A, Seth M, Dixon S, et al. Contemporary use of prasugrel in
clinical practice: insights from the Blue Cross Blue Shield of Michigan
Cardiovascular Consortium. Circ Cardiovasc Qual Outcomes 2013;6:
293–8.Placebo in Autologous
Cell-Based Interventions
Hard Pill to Swallow?To the Editor: Cell-based strategies are under intense investiga-
tion in the pursuit to develop new effective treatment protocols
for ischemic heart disease (IHD). These strategies have been
mainly based on the use of tissue-speciﬁc autologous stem/
progenitor cells such as cells from bone marrow, adipose tissue,
or the heart itself (1). Several of these cell types have reached the
Correspondence JACC Vol. 63, No. 25, 2014
July 1, 2014:2876–86
2878phase of clinical testing (2,3). Clinical trials, in particular
trials investigating cell-based interventions, entail inherent sci-
entiﬁc and ethical challenges. Due to the combination of the
relative lack of experience with cell-based interventions, the
complexity, the variability (especially when autologous cells are
used), and the invasive character, traditional ethical issues get a
new perspective. One of these issues is the choice for the
comparator (4).
Treatment effect is generally assessed in clinical trials by means
of superiority of the novel intervention over standard clinical care
or placebo. Placebo is used to conceal intervention allocation both
for the patient and investigator-physician (5). In pharmaceutical
clinical trials, the placebo is often a capsule or tablet indistin-
guishable from the investigational new drug. However, in clinical
trials assessing autologous cell interventions for heart disease,
proper blinding can only be achieved when participants allocated
to the placebo group undergo the identical harvesting procedure
(e.g., bone marrow aspiration in the case of bone marrow mono-
nuclear cells) as well as a sham delivery procedure to the heart
undistinguishable from the cell delivery procedure. If the inter-
ventional cardiologist is not involved in the follow-up and/or
outcome analysis, the sham procedure may not necessitate an
actual injection with a placebo solution identical to the cell sus-
pension. Either way, in contrast to placebo tablets, autologous cell
interventions expose the control group to risk and harm, raising
ethical concerns.
To date, little is known about the extent to which sham in-
terventions in cell-based trials are performed. To address this
question, we conducted a systematic review on published reports of
randomized clinical trials (RCTs) investigating efﬁcacy of autolo-
gous cell interventions in patients with IHD. We assessed how
RCTs were designed regarding cell harvesting and/or cardiac sham
delivery, whether this depended on the type and stage of cardiac
disease, and the adverse events rate in sham procedure patients. A
search syntax was developed based on relevant synonyms for
domain, which is patients with IHD, and determinant, which is
cell intervention delivered to the heart (i.e., intracoronary delivery
or intramyocardial injection). The outcomedefﬁcacy of cell
interventiondwas deliberately withheld from our search syntax to
avoid potential reporting and retrieval bias. A systematic literature
search was conducted in MEDLINE and EMBASE on the
13th of May 2013. Two reviewers (S.K., J.W.) independently
screened title and abstract of studies in accordance of in-/exclusion
criteria (see the Online Appendix). The selected articles were
crosschecked to identify relevant studies missed by the initial search
using ISI Web of Science.
A total of 56 RCTs were identiﬁed that were published between
2001 and 2013. In total 3,610 patients were included in these
studies, of which 2,189 (61%) received autologous cells, compared
to 1,421 (39%) controls. In 75% of studies, bone marrow mono-
nuclear cells were the investigational cell type. Diagnosis was
acute myocardial infarction (MI) in 2,463 patients (982 controls
[40%]), compared to 1,147 patients (439 controls [38%]) with
chronic IHD (i.e., refractory angina or post-MI heart failure).
Combined cell harvesting and sham cardiac delivery, thereby
ensuring patient and investigator blinding, was performed in 22
of the 56 studies (39%). Analysis divided for IHD type revealed
that 11 of 36 studies (31%) used sham delivery in acute MI and
11 of 20 studies (55%) in chronic IHD (chi-square; p ¼ 0.09).
Apparently, use of placebo is generally not preferred in the acute
setting of MI in contrast with an elective cell interventionprocedure for chronic IHD. Furthermore, in 1 study, participants
allocated to the control group underwent cell harvesting but no
sham cardiac injections, while the rest of the studies used usual care
as a comparator.
Out of 22 studies that used placebo, adverse events in controls
were reported in 5 studies (23%), all of which investigating bone
marrow cells. A combined endpoint analysis of major cardiovas-
cular events revealed that intracoronary infusion of a placebo so-
lution did not lead to heightened mortality or serious morbidity in
these 5 studies. With regard to the cell harvesting procedure no
adverse events were reported.
Three major conclusions emanate from our study: 1) 39% of
RCTs investigating efﬁcacy of autologous cell intervention used
a double-blind trial design based on a sham procedure; 2) trials
using sham delivery were less frequently observed in acute MI
compared to chronic IHD; and 3) 23% of these trials reported data
on (minor) adverse events. This report shows that the choice for
the control group for cell-based interventions in cardiology differs
among research groups, which could be related to diverging views
on scientiﬁc necessity and ethical acceptability of sham. The di-
versity in the choice of the comparator group, shown by this
empirical report, supports the need to clarify when and under what
conditions sham is scientiﬁcally necessary and ethically acceptable,
and when another comparator is more appropriate in clinical trials
investigating cell-based interventions for cardiology and other
medical ﬁelds. This will, among others, probably correlate with the
study population, and the risk proﬁle of the sham procedure.
Hence, this report can function as a starting point to formulate
guidelines for researchers that aim to set up a cell-based
randomized trial.Stefan Koudstaal, MD PhDyz
Sophie L. Niemansburg, MDx
Nabil Dib, MD PhDk
Justin Wallet{
Pieter A. Doevendans, MD PhDyz
Annelien L. Bredenoord, PhDx
*Steven A. J. Chamuleau, MD, PhDyz
*Department of Cardiology, Division Heart and Lungs
University Medical Center Utrecht, Room E03.511
P.O. Box 85500
3508 GA Utrecht
the Netherlands
E-mail: s.a.j.chamuleau@umcutrecht.nl
http://dx.doi.org/10.1016/j.jacc.2014.03.045
From the yDepartment of Cardiology, Division Heart and
Lungs, University Medical Center Utrecht, Utrecht, the
Netherlands; zInteruniversity Cardiology Institute of the
Netherlands (ICIN), Utrecht, the Netherlands; xDepartment of
Medical Humanities, Julius Center for Health Sciences and
Primary Care, University Medical Center Utrecht, Utrecht, the
Netherlands; kClinical Cardiovascular Cell Therapy, University
of California, San Diego, San Diego, California; and the
{Faculty of Medicine, University Medical Center Utrecht,
Utrecht, the Netherlands.
Please note: This work was supported by the HGG Group BV to Dr. Koudstaal
and the “Wijnand M. Pon Stichting” to Drs. Koudstaal and Chamuleau. Dr. Dib
has served as a consultant for Cephalon/TEVA, Cardiovascular Systems, Biologics
Delivery Systems/Biosense Webster/Johnson & Johnson, Stemedica, and the
University of California. All other authors have reported that they have no re-
lationships relevant to the contents of this paper to disclose.
JACC Vol. 63, No. 25, 2014 Correspondence
July 1, 2014:2876–86
2879REFERENCES
1. Dimmeler S, Burchﬁeld J, Zeiher AM. Cell-based therapy of myocardial
infarction. Arterioscler Thromb Vasc Biol 2008;28:208–16.
2. Jeevanantham V, Butler M, Saad A, Abdel-Latif A, Zuba-Surma EK,
Dawn B. Adult bone marrow cell therapy improves survival and induces
long-term improvement in cardiac parameters: a systematic review and
meta-analysis. Circulation 2012;126:551–68.
3. Schachinger V, Erbs S, Elsasser A, et al. Intracoronary bone marrow-
derived progenitor cells in acute myocardial infarction. N Engl J Med
2006;355:1210–21.
4. Niemansburg SL, van Delden JJ, Dhert WJ, Bredenoord AL. Regen-
erative medicine interventions for orthopedic disorders: ethical issues in
the translation into patients. Regen Med 2013;8:65–73.
5. Temple R, Ellenberg SS. Placebo-controlled trials and active-control
trials in the evaluation of new treatments. Part 1: ethical and scientiﬁc
issues. Ann Intern Med 2000;133:455–63.
APPENDIX
For supplemental references, a ﬁgure, and a table, please see the online
version of this article.Letters to the EditorApplication of the
Gompertz Method for
Evaluating Survival Gains
in Patients Receiving Cardiac
Resynchronization TherapyIn the paper by Finegold et al. (1), the methods used for the
survival analysis have been described with insufﬁcient detail. It
appears, however, that lifespan gains were calculated through
a separate analysis of each individual trial, were then “weighted
according to study size,” and ﬁnally were “averaged across all trials.”
This step of the survival analysis, which is described by Finegold
et al. (1) in their Results section and not in the Methods, needs to
be clariﬁed in at least 2 aspects. First, the weighting process is
essential to any meta-analysis, because in this way, between-trial
variations are explored and conﬁdence intervals for differences are
estimated. So, one question is why the results were presented
exclusively on the basis of the pooled (or “average”) survival gain,
without any information on the gains calculated for each individual
trial and without any measure of statistical variability. Second, in
the calculation of the trial-speciﬁc lifespan gains, the authors state
that they “used the Gompertz method for this.” However, ﬁtting a
Kaplan-Meier curve to the Gompertz equation is a complex task
from a mathematical and statistical viewpoint (2,3), and it is un-
fortunate that no details were provided on this point.
If these inconsistencies are clariﬁed, this paper can be viewed
as an important contribution in this ﬁeld, mainly for reasons
of cost-effectiveness. Given that the gain of 1 month can be
valued at approximately V5,000 according to common bench-
marks (4–7), this study shows that the clinical beneﬁt of
this procedure is not, as suggested by short-term data, onlyapproximately 1 month (equivalent to V5,000, which would not
even cover the device cost) but could be as high as 6.5 months
(equivalent to more than V30,000, which is much more than the
cost of the device).*Andrea Messori, PharmD
Valeria Fadda, PharmD
Dario Maratea, PharmD
Sabrina Trippoli, PharmD
*Health Technology Assessment Unit
Area Vasta Centro Toscana
Regional Health System
Via Guimaraes 9-11
59100 Prato
Italy
E-mail: andrea.messori.it@gmail.com or
andrea.messori@estav-centro.toscana.it
http://dx.doi.org/10.1016/j.jacc.2014.01.083
REFERENCES
1. Finegold JA, Raphael CE, Levy WC, Whinnett Z, Francis DP.
Quantiﬁcation of survival gain from cardiac resynchronization therapy:
nonlinear growth with time, and greater gain in low-risk patients, make
raw trial data an underestimate of real-world behavior. J Am Coll
Cardiol 2013;62:2406–13.
2. Messori A. Survival curve ﬁtting using the Gompertz function: a
methodology for conducting cost-effectiveness analyses on mortality
data. Comput Methods Programs Biomed 1997;52:157–64.
3. Messori A, Trippoli S, Becagli P, Tendi E. Pharmacoeconomic proﬁle
of paclitaxel as a ﬁrst-line treatment for patients with advanced ovarian
carcinoma: a lifetime cost-effectiveness analysis. Cancer 1996;78:
2366–73.
4. Cleemput I, Neyt M, Thiry N, De Laet C, Leys M. Using threshold
values for cost per quality-adjusted life-year gained in healthcare de-
cisions. Int J Technol Assess Health Care 2011;27:71–6.
5. Adrian Towse A, Pritchard C, Devlin NJ. Cost-Effectiveness Thresh-
olds: Economic and Ethical Issues. London, England: King’s Fund and
Ofﬁce of Health Economics; 2002:1–140.
6. DrummondMF. Economic Evaluation in Health Care: Merging Theory
with Practice. New York, NY: Oxford University Press; 2001:1–286.
7. Messori A, Santarlasci B, Trippoli S, Vaiani M. Controvalore eco-
nomico del farmaco e beneﬁcio clinico: stato dell’arte della metodologia
e applicazione di un algoritmo farmacoeconomico. Pharmacoecon Ital
Res Artic 2003;5:53–67.ReplyApplication of the
Gompertz Method for
Evaluating Survival Gains
in Patients Receiving Cardiac
Resynchronization TherapyWe thank Dr. Messori and colleagues for asking for clariﬁcation on
the Methods used in our recent paper.
We should clarify that our Figure 2 used an average weighted
solely by the sample size of the 5 trials, because this seemed
appropriate weighting for combining rates across trials. The reason


Placebo in Autologous Cell-Based Interventions Hard Pill to Swallow?

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