Journal Club

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Journal Club
Birkmeyer NJ, Dimick JB, Share D, Hawasli A,
English WJ, Genaw J, Finks JF, Carlin AM,
Birkmeyer JD Michigan Bariatric Surgery
Collaborative. Hospital complication rates with
bariatric surgery in Michigan. JAMA. 2010 Jul
28304(4)435-42. Topol EJ, Bousser MG, Fox KA,
Creager MA, Despres JP, Easton JD, Hamm CW,
Montalescot G, Steg PG, Pearson TA, Cohen E,
Gaudin C, Job B, Murphy JH, Bhatt DL CRESCENDO
Investigators. Rimonabant for prevention of
cardiovascular events (CRESCENDO) a randomised,
multicentre, placebo-controlled trial. Lancet.
2010 Aug 14376(9740)517-23.
2010?8?19? 830-855 8? ??

• ?????? ???????? ????????
• Department of Endocrinology and Diabetes,
• Saitama Medical Center, Saitama Medical
  University
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• Matsuda, Masafumi

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Bariatric Surgery
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a reduction in mortality of 23 from 40!
some obese young adults may lose up to 20 years
of life expectancy if they do not reduce their
weight
Department of Surgery, and Center for Healthcare
Outcomes and Policy (CHOP) (Drs N. Birkmeyer,
Dimick, Finks, and J. Birkmeyer), and Department
of Family Medicine (Dr Share), University of
Michigan, Ann Arbor Department of Surgery, St
John Hospital and Medical Center, Detroit,
Michigan (Dr Hawasli) Department of Surgery,
Marquette General Hospital, Marquette, Michigan
(Dr English) and Department of Surgery, Henry
Ford Hospital, Detroit, Michigan (Drs Genaw and
Carlin). Corresponding Author Nancy J. O.
Birkmeyer, PhD, Michigan Surgical Collaborative
for Outcomes Research and Evaluation (M-SCORE),
Department of Surgery, University of Michigan,
211 N Fourth Ave, Ste 2A and 2B, Ann Arbor, MI
48104 (nbirkmey_at_umich .edu).
JAMA. 2010304(4)435-442
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Background
Context Despite the growing popularity of
bariatric surgery, there remain concerns about
perioperative safety and variation in outcomes
across hospitals. Objective To assess
complication rates of different bariatric
procedures and variability in rates of serious
complications across hospitals and according to
procedure volume and center of excellence (COE)
status.
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Methods
Design, Setting, and Patients Involving 25
hospitals and 62 surgeons statewide, the Michigan
Bariatric Surgery Collaborative (MBSC)
administers an externally audited, prospective
clinical registry. We evaluated short-term
morbidity in 15 275 Michigan patients undergoing
1 of 3 common bariatric procedures between 2006
and 2009. We used multilevel regression models to
assess variation in risk-adjusted complication
rates across hospitals and the effects of
procedure volume and COE designation (by the
American College of Surgeons or American Society
for Metabolic and Bariatric Surgery) status.
Main Outcome Measure Complications occurring
within 30 days of surgery.
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Adjustable gastric banding
Biliopancreatic diversion
Roux-en-Y gastric bypass
Sleeve gastrectomy
Vertical banded gastroplasty
with duodenal switch
A meta-analysis from University of California,
Los Angeles reports the following weight loss at
36 months Biliopancreatic diversion -
53 kg Roux-en-Y gastric bypass (RYGB) - 41 kg
Open - 42 kg Laparoscopic - 38 kg Adjustable
gastric banding - 35 kg Vertical banded
gastroplasty - 32 kg Sleeve gastrectomy ?
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It is estimated that in 2005, the number of
procedures performed in the United States was
more than 10 times as great as the number
performed in 1994, an increase from approximately
16,200 procedures to 171,000, and the number is
still rising. (N Engl J Med 2009 361520-521)
The American College of Surgeons and the American
Society for Metabolic and Bariatric Surgery have
implemented programs for accrediting hospitals as
centers of excellence (COE) in bariatric surgery.
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The LABS writing group assumes responsibility for
the content of this article. Members of the LABS
writing group are listed in the Appendix. Address
reprint requests to Dr. David R. Flum at the
Surgical Outcomes Research Center, Department of
Surgery, University of Washington, Box 356410,
Seattle, WA 98195-6410
N Engl J Med 2009361445-54.
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Why COE accreditation by professional
organizations or payers might not necessarily
identify safer hospitals with bariatric surgery?

• First, although COE applications often ask
  hospitals for rates of specific outcomes ( eg,
  postoperative venous thromboembolism), such
  outcomes data are generally not audited for
  accuracy or completeness and are often loosely
  defined.
• Second, aside from minimum case loads, most
  requirements for bariatric COE accreditation,
  including the availability of specific protocols
  and resources form an aging morbidly obese
  patients, are easily met by most hospitals with
  bariatric programs and likely have little bearing
  on surgical complication rates.
• Finally, given the highly competitive market
  place for bariatric surgery, COE accreditation
  programs may be attracting hospitals motivated as
  much by marketing advantage as by the desire to
  demonstrate and improve their quality.

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Results
Results Overall,7.3of patients experienced
perioperative complications, most of which were
wound problems and other minor complications.
Serious complications were most common after
gastric bypass (3.695confidence interval CI,
3.2-4.0), followed by sleeve gastrectomy (2.2
95 CI, 1.2-3.2), and laparoscopic adjustable
gastric band (0.9 95 CI, 0.6-1.1) procedures
(Plt.001). Mortality occurred in 0.04 (95 CI,
0.001-0.13) of laparoscopic adjustable gastric
band, 0 sleeve gastrectomy, and 0.14 (95 CI,
0.08-0.25) of the gastric bypass patients.
After adjustment for patient characteristics and
procedure mix, rates of serious complications
varied from1.6 (95CI,1.3-2.0) to3.5(95CI,
2.4-5.0) (risk difference, 1.995CI, 0.08-3.7)
across hospitals. Average annual procedure volume
was inversely associated with rates of serious
complications at both the hospital level
(lt150cases, 4.195CI,3.0-5.1150- 299 cases,
2.795CI, 2.2-3.2 and ?300 cases, 2.395CI,
2.0-2.6P.003) and surgeon level (lt100 cases,
3.895CI, 3.2-4.5 100-249 cases, 2.495
CI, 2.1-2.8 ? 250 cases, 1.995CI,
1.4-2.3 P.001). Adjusted rates of serious
complications were similar in COE and non-COE
hospitals (COE,2.795CI,2.5- 3.1 non-COE,
2.0 95 CI, 1.5-2.4 P.41).
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Conclusion
Conclusions The frequency of serious
complications among patients undergoing bariatric
surgery in Michigan was relatively low. Rates of
serious complications are inversely associated
with hospital and surgeon procedure volume, but
unrelated to COE accreditation by professional
organizations.
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Message/Comments
FDA??????????????????????????! ??????????????????
???????????? ???????????...?
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On March 31st 2010, Orexigen submitted a New Drug
Application (NDA) to the U.S. Food and Drug
Administration (FDA) for Contrave.
www.thelancet.com Published online July 30, 2010
DOI10.1016/S0140-6736(10)60888-4
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Novo Nordisk now plans to re-initiate the global
phase 3 programme in the first half of 2011 in
clinical trials comprising approximately 5,000
patients (June 22, 2010)
www.thelancet.com Published online October 23,
2009 DOI10.1016/S0140-6736(09)61375-1
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Lancet 2005 365 138997
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rimonabant
In 2006, the European Medicines Agency approved
the marketing of rimonabant in Europe. In 2007,
however, new contraindications were formulated by
the Agency. Also in 2007, the US Food and Drug
Administration denied approval in the USA.
Reasons for concern were neuropsychiatric side
effects, including depression and suicide
attempts.
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Scripps Translational Science Institute, La
Jolla, CA, USA (Prof E J Topol MD) Hopital
Lariboisiere, Paris, France (Prof M-G Bousser
MD) University of Edinburgh, Edinburgh, UK (Prof
K A A Fox MBCh) Brigham and Womens Hospital and
Harvard University, Boston, MA, USA (M A Creager
MD) Centre de Recherche, Institut Universitaire
de Cardiologie et de Pneumologie de Quebec,
Quebec, Canada (Prof J-P Despres MD) Rhode
Island Hospital and Brown University, Providence,
RI, USA (Prof J D Easton MD) Kerckhoff Klinik,
Bad Nauheim, Germany (Prof C W Hamm MD) Centre
Hospitalier Universitaire Pitie-Salpetriere,
Paris, France (Prof G Montalescot MD) INSERM
U-698, Universite Paris 7 and Hopital Bichat,
AP-HP, Paris, France (Prof P G Steg MD)
University of Rochester, Rochester, NY, USA (Prof
T A Pearson MD) Sunnybrook Health Sciences
Centre, Toronto, ON, Canada (E Cohen MD) Sanofi
-Aventis, Paris, France (C Gaudin MD, B Job MD, J
H Murphy MD) and VA Boston Healthcare System,
Boston, MA, USA (D L Bhatt MD)
Lancet 2010 376 51723
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Background
Blockade of the endocannabinoid receptor reduces
obesity and improves metabolic abnormalities such
as triglycerides, HDL cholesterol, and fasting
blood glucose. We assessed whether rimonabant
would improve major vascular event-free survival
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Methods
This double-blind, placebo-controlled trial was
undertaken in 974 hospitals in 42 countries. 18
695 patients with previously manifest or
increased risk of vascular disease were randomly
assigned to receive either rimonabant 20 mg
(n9381) or matching placebo (n9314).
Randomisation was stratified by centre,
implemented with an independent interactive voice
response system, and all study personnel and
participants were masked to group assignment. The
primary endpoint was the composite of
cardiovascular death, myocardial infarction, or
stroke, as determined via central adjudication.
Analysis was by intention to treat. This study
is registered with ClinicalTrials.gov, number
NCT00263042.
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Follow-up in the trial was prematurely ended on
Nov 6, 2008, because of a request by the
regulatory agency for cessation of clinical
research of rimonabant in Ireland, France, and
Germany. At that time, the mean exposure to the
drug had been 138 months (95 CI 136140)
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The frequency of serious psychiatric side-effects
also differed significantly, occurring in 232
(25) of patients in the rimonabant group
compared with 120 (13) in the placebo group
(plt00001). There were four suicide events in the
rimonabant group versus one in the placebo group,
and nine versus five patients, respectively,
attempted suicide.
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A study showed that single nucleotide variants in
a tyrosine kinase receptor gene (NTRK2) involved
in neurotrophic signalling were associated with
more than four-fold increased risk of suicide.
Furthermore, the clinical benefit of
endocannabinoid-1 blockade could have been
manifest in patients with a particular gene
variant in the endocannabinoid-1 or related
pathways.
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Results
At a mean follow-up of 138 months (95 CI
136140), the trial was prematurely
discontinued because of concerns by health
regulatory authorities in three countries about
suicide in individuals receiving rimonabant. All
randomised participants were analysed. At the
close of the trial (Nov 6, 2008), the composite
primary endpoint of cardiovascular death,
myocardial infarction, or stroke occurred in 364
(39) patients assigned to rimonabant and 375
(40) assigned to placebo (hazard ratio 097,
95 CI 084112, p068). With rimonabant,
gastrointestinal (3038 33 vs 2084 22),
neuropsychiatric (3028 32 vs 1989 21), and
serious psychiatric side-effects (232 25 vs
120 13) were significantly increased compared
with placebo. Four patients in the rimonabant
group and one in the placebo group committed
suicide.
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Conclusion
The premature termination of this trial has
important lessons for drug development. A drug
that was being marketed for weight loss, but
being tested for improving cardiovascular
outcomes, induced a level of serious
neuropsychiatric effects that was deemed
unacceptable by regulatory authorities, and both
the drug and the trial were abruptly terminated.
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Message
Rimonabant????????????????????????????????????????
????????????????????????????????????????? ?????
???????????
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