RCT · 2018-02-05 · •May be by chance the first RCT picked a population with baseline SvO2 of...

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RCT 2018/01/09 ICU

Transcript of RCT · 2018-02-05 · •May be by chance the first RCT picked a population with baseline SvO2 of...

Page 1: RCT · 2018-02-05 · •May be by chance the first RCT picked a population with baseline SvO2 of 48 %. •The baseline SvO2 inthe remaining trials was already higher than 70 %,

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Page 2: RCT · 2018-02-05 · •May be by chance the first RCT picked a population with baseline SvO2 of 48 %. •The baseline SvO2 inthe remaining trials was already higher than 70 %,

•��RCT�• CONSORT����• CONSORT�� Introduction• CONSORT�� Method• RCT�•��

Page 3: RCT · 2018-02-05 · •May be by chance the first RCT picked a population with baseline SvO2 of 48 %. •The baseline SvO2 inthe remaining trials was already higher than 70 %,

•��RCT�• CONSORT����• CONSORT�� Introduction• CONSORT�� Method• RCT�•��

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• Intervention • Comparison

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• Intervention • Comparison

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Page 12: RCT · 2018-02-05 · •May be by chance the first RCT picked a population with baseline SvO2 of 48 %. •The baseline SvO2 inthe remaining trials was already higher than 70 %,

• Intervention • Comparison

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Page 14: RCT · 2018-02-05 · •May be by chance the first RCT picked a population with baseline SvO2 of 48 %. •The baseline SvO2 inthe remaining trials was already higher than 70 %,

N Engl J Med 2017;377:465-75.

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•��RCT�• CONSORT����• CONSORT�� Introduction• CONSORT�� Method• RCT�•��

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CONSORT (/�• 1996*�#6CONSORT(/�D7

Consolidated Standards of Reporting Trials: >+@I'%�F��<$&3

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•��RCT�• CONSORT����• CONSORT�� Introduction• CONSORT�� Method• RCT�•��

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����Introduction

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•���������rationale ����•���������hypothesis �

• Clinical Question↓

• Research Question�PICO �� ���↓

• Intervention vs. Comparison �� ����

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��RQFINER����

• Feasible �����• Interesting ����• Novel������• Ethical ���• Relevant�����

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������� ���OK ?• Feasible �����• Interesting ����• Novel������• Ethical����• Relevant���!

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• RCTs are one of the possible experiments.

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Premise��

Hypothesis��

Outcome

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• RCTs are one of the possible experiments.

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Outcome

Page 25: RCT · 2018-02-05 · •May be by chance the first RCT picked a population with baseline SvO2 of 48 %. •The baseline SvO2 inthe remaining trials was already higher than 70 %,

• RCTs are one of the possible experiments.

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Premise��

Hypothesis��

Outcome

Page 26: RCT · 2018-02-05 · •May be by chance the first RCT picked a population with baseline SvO2 of 48 %. •The baseline SvO2 inthe remaining trials was already higher than 70 %,

Many other trials, in our opinion,failed either because ,,,,

• Wrong premises

• Premises that were too vague and generic.If too generic, the heterogeneity of thepopulation is an unavoidable consequence.

Page 27: RCT · 2018-02-05 · •May be by chance the first RCT picked a population with baseline SvO2 of 48 %. •The baseline SvO2 inthe remaining trials was already higher than 70 %,

����� vs. �����• The trialists spent a lot of effort in improving their internal validity, by increasing the numberof rules and caveats to avoid possible biases in the conduct of the trials.

• This obviously makes the results valid only for the restricted patient population enrolled in the study and the generalization of the results(the external validity) is problematic.

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EGDT: 2001 → 2015

N Engl J Med 2001;345:1368-77.

Page 29: RCT · 2018-02-05 · •May be by chance the first RCT picked a population with baseline SvO2 of 48 %. •The baseline SvO2 inthe remaining trials was already higher than 70 %,
Page 30: RCT · 2018-02-05 · •May be by chance the first RCT picked a population with baseline SvO2 of 48 %. •The baseline SvO2 inthe remaining trials was already higher than 70 %,

�� Hypothesis

• Severe sepsis, septic shock

↓ ��CVP�ABP�SvO2

•���������� �����

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Outcome

N Engl J Med 2001;345:1368-77.

×××

Page 32: RCT · 2018-02-05 · •May be by chance the first RCT picked a population with baseline SvO2 of 48 %. •The baseline SvO2 inthe remaining trials was already higher than 70 %,

?

Page 33: RCT · 2018-02-05 · •May be by chance the first RCT picked a population with baseline SvO2 of 48 %. •The baseline SvO2 inthe remaining trials was already higher than 70 %,

Premise 1, 2 ○

• May be by chance the first RCT picked a population with baseline SvO2 of 48 %.

• The baseline SvO2 in the remaining trialswas already higher than 70 %, suggesting that oxygen imbalance was not the primary problem in the majority of the patients.

Page 34: RCT · 2018-02-05 · •May be by chance the first RCT picked a population with baseline SvO2 of 48 %. •The baseline SvO2 inthe remaining trials was already higher than 70 %,

?

Page 35: RCT · 2018-02-05 · •May be by chance the first RCT picked a population with baseline SvO2 of 48 %. •The baseline SvO2 inthe remaining trials was already higher than 70 %,

Premise 3 Too generic and wrong

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The pendulum effect• )�/����4��%�2�.0�!$����

• Single center→Multi center�&#��(���-+• EGDT65�.0����• %-�.0�������3�*,�'"����1)���� ��7����

Crit Care Med 2010; 38[Suppl.]:S534–S538

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• Truly negative trials are valuable because they prevent the use of interventions that are either costly but nonbeneficial or even harmful (e.g.,intensive insulin therapy and hydroxyethyl starch).

• Understanding an evidence base requires the ability to distinguish among these reasons so as to differentiate trials that are truly negative from those that may be falsely negative.

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• Studies published between January 2007 and May 2013

• Single center���������

Page 39: RCT · 2018-02-05 · •May be by chance the first RCT picked a population with baseline SvO2 of 48 %. •The baseline SvO2 inthe remaining trials was already higher than 70 %,

•��RCT�• CONSORT����• CONSORT�� Introduction• CONSORT�� Method• RCT�•��

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'- ���

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����Participant�

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Was the right group of patients not identified?• ���" �� ���$�AMI�����%• �! ������������ICU�� �#�

Why have so many RCTs “failed?”

Crit Care Med 2010; 38[Suppl.]:S534–S538

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• General ICU� ������sepsis�ALI� ������������

Page 45: RCT · 2018-02-05 · •May be by chance the first RCT picked a population with baseline SvO2 of 48 %. •The baseline SvO2 inthe remaining trials was already higher than 70 %,

High Exclusion Rates Lead to Limited Clinical Applicability

With such tight exclusion criteria limiting enrollment,,,,

• How can the patient population that is actually studied really be representative of the entire population initially considered eligible?

• How can the results be applicable to the general ICU population?

Crit Care Med 2010; 38[Suppl.]:S534–S538

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TRICC study• Just 13% of 6451

patients screened were randomized.

Page 47: RCT · 2018-02-05 · •May be by chance the first RCT picked a population with baseline SvO2 of 48 %. •The baseline SvO2 inthe remaining trials was already higher than 70 %,

VAAST study• 802 (12.9%) of the 6229

patients screened underwent randomization

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• 1679 (84%) of 2011 patients were randomized.

N Engl J Med 2010;362:779-89.

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�� Intervention!

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Were the interventions ineffective?�� �������� ��������

��

truly negative�������� ���������OK

Why have so many RCTs “failed?”

Crit Care Med 2010; 38[Suppl.]:S534–S538

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Was it a question of severity?• 2*"!/�1�)+�( U shape���5)+�3�������� or ���4�� ���6

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Why have so many RCTs “failed?”

Crit Care Med 2010; 38[Suppl.]:S534–S538

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G-;VSample sizeW

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Page 54: RCT · 2018-02-05 · •May be by chance the first RCT picked a population with baseline SvO2 of 48 %. •The baseline SvO2 inthe remaining trials was already higher than 70 %,

Were the end points wrong?

• )�: 3'&�*0$7��9=:,�� ����;

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Was the power inadequate?

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Why have so many RCTs “failed?”

Crit Care Med 2010; 38[Suppl.]:S534–S538

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���Implementation�

•�� ���������•�����������enrollment�•�������� ����assign�

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• 9��������

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Proper use of envelopes• Envelopes must be made opaque through use of a

cardboard or aluminium foil insert

• Envelopes must be numbered, opened sequentially

• Reporting the use of sequentially numbered opaque sealed envelopes (SNOSE) is accepted to be the minimum standard

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0/&:Blinding;�masking )1

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Unblinded RCTs can be a problem because there is a risk that patients will receive different treatment according to the physician’s own beliefs.

Crit Care Med 2010; 38[Suppl.]:S534–S538

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$(�#�!-Statistical method.•�&���#� ����%, *�"���$(�#�!�

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•��RCT�• CONSORT����• CONSORT�� Introduction• CONSORT�� Method• RCT�•��

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•����Critical Care����RCT

JAMA. 2017;317(13):1321-1328.

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?; Premise

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�" Hypothesis

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8$3 Investigator-initiatedChief investigator

• Yu Kawazoe (2003��) �)�-/�� #"�→'���

• Kyohei Miyamoto92006��:�)�-/�� #"�

Collaborater

• Takeshi Morimoto ���.� 2�+� �#!

• Hitoshi Yamamura �7�/� "�→��� �#!

• Akihiro Fuke �7�/� %1��,����

• Atsunori Hashimoto ���.� "�

• Makoto Ito ��-/1��,���� 86

• Nobuaki Shime 5�,���� "�

• Kohei Kato &��.� "�

• Kenji Yamauchi �(�

• Hiroyuki Koami 4�

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February 2013 ; January 201603�

Page 74: RCT · 2018-02-05 · •May be by chance the first RCT picked a population with baseline SvO2 of 48 %. •The baseline SvO2 inthe remaining trials was already higher than 70 %,

Inclusion

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Exclusion

•+��(,�(Child-Pugh�-B or C)•���&!���+�����(NYHA �)•)"��� �� ��•'%#��+�*$,�•��� ��• Dexmedetomidine����� ��• Attending physician's decision

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',#�!���

Attending physician�eligible ")�•',���',&*��%(

• Internet Data and Information Center for Medical Research (INDICE)�+-�����$

�INDICEUMIN��� ����������“electronic data capturing system”

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• ��������"(����� �@→46:�����)

• ' "A8*;)�=>79.13�COPD

• �46:�ID��������/• (?�+ �0<�8*;)�-$��!• ,:ID�����"�2#5&��%

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• "#%�(��)*� ���+����������)*��� ,����'�

• �����$!�)*&�

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���

•�$��JSICM������%��•����������•"#�&���"#�&��� ���%��•�!�JSICM������%��

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Primary Outcome0!Co - Primary Outcome• 28&)�*• 28&Ventilator Free Days (����.�)47+ &%�28&8-�"��(25

2015/5/2�Ventilator Free Days��'(Outcome data�������/1)• �"���(2���→)��#3���

�$,�5&�)�→�"���(2�5&�VFD�0&� ���26&$,�28&�)��6�4&$,�6&�)��4�-���VFD2&5

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Sample size28����%!• �" 80% ��" 60%�MENDS study ��-84% vs. 59% ↓ α 5% β 20%

• �"172�'!↓ 15%#$�

• �"200��'!

����� ����(25�'!����25×,�&×2�.400 *�)�3�����+

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$� �

28����(#• ��% 80%→80% ��% 60%→72%

↓ α 5% β 20%

• �%172 *#

↓ 15%�&'�

• �%200 �*#

����!"����+25 *#����25×/�)×2�0400 -�,�3�����.

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Masking, Blinding

Open label•'- �)* �"���!#�+����•�����/�-35)*-4�"���!#�+����

→)*�/���������&������%2 ($1���limitation�,��.0

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The main statistical analysis for efficacyComparison between groups of 28-day mortalityMeasure: Death until 28 days after the initiation of mechanical ventilation. Patients who were alive at 28 days were censored at 28 days. Aim: Comparison of the occurrence of the events between groupsTest: Log-rank test, Cox proportional hazard model Significance: Two-sided p values of less than 0.05 were considered statistically significant. Confidence interval: 95%confidence interval (CI) of the hazard ratio were calculated. Expression: The number of the occurrence of the events, Cumulative incidence, and hazard ratio.

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Negative !

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The secondary statistical analysis for efficacy28-day mortality Measure: Death during 28 days Aim: Comparison of the occurrence of the events between groups Test: Chi-square test or Fisher exact testSignificance: Two-sided p values of less than 0.05 wereconsidered statistically significant.Confidence interval: NA.Expression: The number of the occurrence of the events, the ratio of the occurrence of the events.

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Data and safety monitoring board (DSMB) and interim analysis• Dr. Sadao Kawasaki (Department of Emergency

Medicine Minami Wakayama Medical Center, Japan) →���

• Dr. Takahiro Ashikawa (Department of emergency medicine, Minami Wakayama Medical Center, Japan) →���

• Dr. Yasuhiro Iwasaki (Department of Emergency and Critical Care Medicine, Wakayama Medical University, Japan) →���

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The DSMB will independently perform����•�$ ����1����)%�•'+"#����&

• Emergent reporting system�������������*�����(!

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Discussion

• The study may have identified a clinically important benefit of dexmedetomidine—an 8% reduction in 28-day mortality—that did not demonstrate statistical significance.

• Physicians may consider an 8% difference in 28-day mortality to be clinically significant but this study was underpowered to detect this difference.

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Funding• Funding/Support: This study was supported in part by a noncontractual research grant to Wakayama Medical University provided by Hospira Japan.

• Role of the Funder/Sponsor: Hospira Japan participated in part of the design of this study;however, it had no role in the conduct of the study;collection, management, analysis, and interpretation of the data; preparation or approval of the manuscript; or decision to submit the manuscript for publication.

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��

• No earlier multicenter RCTs have investigated the effects of ANP infusion in patients with cardiac surgery–associated AKI.

��

• We therefore decided to evaluate the effects of ANP on renal function and medical costs in patients with cardiac surgery–associated AKI.

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• ��&"&�0+�/�0+�)#����ICU�!$��ICU��-��ICU

• (*���

• 11%.���• May 2012 - March 201511��,���2• '���� 90�������

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����

• Double-blind

• ANP 0.02 μg /kg/min (2 mL/h) •��� (5% glucose, 2 mL/h�

• Preoperative level�����

•��������������

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���������

•����Study coordinators�INDICE��• INDICE randomization system����

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Inclusion

• Age of ≥20 years

• Recent elective cardiac surgery, namely, CABG, valve surgery, thoracic aortic aneurysm surgery, or a combination thereof.

• AKI within 48 hours after cardiac surgery

��������ANP����

Exclusion

• Severe hypotension or cardiogenic shock

• Right ventricular infarction

• Dehydration

• End-stage renal disease

• Administration of nonsteroidal anti-inflammatory drugs,

angiotensin-converting enzyme(ACE) inhibitor, or angiotensin

receptor blocker (ARB) within 24 hours before the operation

• Administration of contrast agent within 3 days before the operation

• Extracorporeal membrane oxygenation.

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The primary end point

• Change in renal function over the 90-day follow-up measured by serum levels of creatinine and cystatin C, and creatinine clearance or eGFR.

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• ������→ a difference in means of 74.25 � ���

↓↓↓ α 5% β 20%

• ��87���↓ 10%����

• ��97���

����������������

Sample size and power calculation

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Reasons why,,,,• approval of ethics committees• difficulty in obtaining consent from patients• decisions by several hospitals to prioritize

patients with ventricular assist devices.

• many surgeons in trial sites insisted on using ANP in patients with high preoperative creatinine levels

→these patients were excluded before assessment for eligibility and were administered ANP during surgery.

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• �!���#(+ � �

• ������%'("� )�� “��$&”�������������*

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����������

Page 104: RCT · 2018-02-05 · •May be by chance the first RCT picked a population with baseline SvO2 of 48 %. •The baseline SvO2 inthe remaining trials was already higher than 70 %,

Funding

• This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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•��RCT�• CONSORT����• CONSORT�� Introduction• CONSORT�� Method• RCT�•��

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49#�+�7!�� ;

• 1�.*�"�� ;����positive �negative �-)6• �����.*��� ;/:��positive��-)6?

'�+�7!�� ;

• 1�.*�"�� ;����positive ��-)6?• �����.*��� ;/:��positive��-)6?=$�������?>

.*� ;�%8(��3�5&������#�?

,2<���0?