Study reference

Study characteristics

Patient characteristics

Intervention (I)

Comparison / control (C)

Follow-up

Outcome measures and effect size

Comments

Yannopoulos, D. 2020

Type of study: a phase 2, single centre, open -label, adaptive, safety and efficacy randomised controlled trial.

Setting and country: USA, University of Minnesota Medical Center

Funding and conflicts of interest:

Funding National Heart, Lung, and Blood Institute.

The funder had no role in study design.

Inclusion criteria:

-Adults aged 18-75 years

-Presenting to University of Minnesota Medical Center

-Out of Hospital Cardiac Arrest (OHCA)
- refractory ventricular fibrillation
-No return of spontaneous circulation after three shocks

- automated cardiopulmonary resuscitation with a Lund University Cardiac Arrest System (body morphology able to accommodate a Lund University Cardiopulmondary Assist System).
-estimated transfer time shorter than 30 min.

Exclusion criteria:

Exclusion criteria included valid do not resuscitate orders;

blunt, penetrating, or burn-related injury;

drowning;

known overdose; known pregnancy; being a prisoner; being a nursing home resident; presence of an opt-out study bracelet; unavailability of the catheterisation laboratory; terminal cancer; absolute contraindications to emergent angiography; contrast allergies; and active gastrointestinal or internal bleeding.

N total at baseline:

Intervention: 15

Control: 15

Important prognostic factors²:

age ± SD:

I: 59 (43-73)

C: 58 (36-71)

Sex:

I: %93 M

C: %73 M

Groups comparable at baseline?

Yes

Extracorporeal membrane oxygenation (ECMO)-facilitated resuscitation.

As described in the trial Yannopoulos D, Kalra R, Kosmopoulos M, et al. Rationale and methods of the Advanced

R2Eperfusion STrategies for refractory cardiac arrest (ARREST) trial. Am Heart J 2020; 229: 29–

39. [PubMed: 32911433]

Standard advanced cardiac life support (ACLS) treatment.

In patients without pulses, the protocol dictated that the emergency department team continued treatment for at least 15 min after arrival to the department or for at least 60 min after the 911 call.

Length of follow-up:

6 months

Loss-to-follow-up:

Intervention

N (%) 1/15 (percentage)

Reasons (describe)
withdrew consent for continuation of participation on day 3 after randomisation.

Control:

N (%) 0

Reasons (describe). NA

Incomplete outcome data:

Intervention:

N (%) 0

Reasons (describe) NA

Control:

N (%)15/15 (percentage)

Reasons (describe): All patients died before the third month.

Outcome measures and effect size (include 95%CI and p-value if available):

Crucial

Survival

Survival (in hospital)

n/N, % (RR, 95%CI)  

I 6/14, 43%
C.1/15, 7%

(RR 6.43; 95%CI 0.88 to 46.92)

Risk difference (RD, 95%CI)
0.36 (3.7 to 59.2)

ICU survival

Not reported

30 d survival
n/N % (RR, 95%CI)  
I 6/15 (40%)
C 1/15 (7%)

(RR: 6.00; 95%CI: 0.82-44.00)

All primary analysis were done  on an intention to treat basis.

1 year survival
Not reported

Important

Favourable neurological status -

Not reported

Quality of life (1 year)

Not reported

Days alive and out of hospital (1 year).
Not reported

**Safety not defined. However, serious adverse events were measured (table 3)

The study was terminated at

the first preplanned interim analysis after

unanimous recommendation from the Data Safety Monitoring Board after enrolling 30 patients

because the posterior probability of ECMO superiority exceeded the prespecified monitoring

boundary.

Intention to treat analysis was performed.

Higher number of male in intervention group compared to normal population.

Belohvlavek 2022

Type of study: Single-center randomized clinical trial

Setting and country: Czech Republic, Prague

Funding and conflicts of interest:

Inclusion criteria:

-Adults aged 18 to 65 years

-receiving ongoing resuscitation

- witnessed OHCA of presumed cardiac etiology
-They received

a minimum of 5 minutes of advanced cardiac life support

without ROSC
-ECPR team was available at the

cardiac center

Exclusion criteria:

Patients who had unwitnessed cardiac arrest

or presumed noncardiac cause, -had suspected or confirmed

pregnancy,

-attained ROSC within 5 minutes during initial

resuscitation,
-regained consciousness,
-had obvious lifelimiting

comorbidities,
-bleeding diathesis,
-known do-notresuscitate

order,
-known prearrest Cerebral Performance

Category (CPC) 3 or greater

N total at baseline:

Intervention: 124

Control: 132

Important prognostic factors²:

age (IQR)
I: 59 (48 – 66)
C: 57 (47-65)

Sex:

I: 82%M

C: 83%M

Groups comparable at baseline?

Yes

Patients received mechanical compression (using LUCAS, Lund University Cardiac Arrest System; Physio-Control Inc/Jolife AB,

Lund, Sweden)

followed by intra-arrest transport to a cardiac center for ECPR and immediate

invasive assessment and treatment.

As described in Belohlavek J, Kucera K, Jarkovsky J, et al.

Hyperinvasive approach to out-of-hospital cardiac

arrest using mechanical chest compression device,

prehospital intraarrest cooling, extracorporeal life

support and early invasive assessment compared to

standard of care: a randomized parallel groups

comparative study proposal. J Transl Med. 2012;10:

163. doi:10.1186/1479-5876-10-163

Patients received continued advanced cardiac life support on site. Drugs, further defibrillations, or other interventions followed

recommended guidelines. If ROSC was achieved, transport

to the hospital was initiated and an early invasive strategy

(ie, coronary angiography) was encouraged.

Mechanical chest compression was initially only for invasive use, however use was left to the descrection of emergency physician.

Length of follow-up:

180 days

Loss-to-follow-up:

Intervention:

N (%) 0

Reasons (describe) NA

Control:

N (%) 0

Reasons (describe) - NA

Incomplete outcome data:

Intervention: 0

N (%) NA

Reasons (describe)

Control:

N (%) 0

Reasons (describe) NA

Outcome measures and effect size (include 95%CI and p-value if available):

Crucial

Survival

In hospital survival
Not reported

ICU survival

Not reported

30 d survival
n/N (%; 95%CI) 
I: 52/124, 42%
C: 43/132, 33%
RR 1.29; (95%CI 0.93 to 1.77)

1 year survival
Not reported.

Important

Favourable neurological status
CPC (1;2) at 30 days
n/N, %(RR, 95%CI); risk difference OR [95%CI] and absolute difference %, [95%CI, p value].
I: 38/124, 31%
C: 24/132, 18%
(RR 1.69 (1.08 to 2.64))  

OR 1.99 [1.11- to 3.57]

RD 12.4% [1.9%-22.7%, P=0.02]

CPC (1;2) at 180 days
n/N, %(RR, 95%CI); risk difference OR [95%CI] and absolute difference %, [95%CI, p value].
I: 39/124, 32%
C: 29/132, 22%
(RR 1.43 (0.95 to 2.16))

OR 1.63 [0.93- to 2.85]

RD  9.5% [-1.3%-20.1%, P=0.09]

Study was not focussed on mortality data.

Study was terminated earlier because the standardized test statistics for results of

primary end point in the study intersected a prespecified stopping

rule for futility at n = 256.

Cross over of patients took place (total of n=20, 7.6%). However, in the main analysis patients were analysed according to the randomization group (intention to treat).

Data of baseline was requested later during patient care and might therefore not have been available during initial treatment. 

Suverein, 2023

Type of study: Multicenter randomized, controlled trial (with an adaptive design).

Setting and country: The Netherlands, Maastricht

Funding and conflicts of interest: Authors declare no conflict of interest

Inclusion criteria:

-between 18 and 70 years of age,

-witnessed and had received bystander CPR,

- refractory out-of-hospital car­diac arrest

-Had an initial ventricular arrhythmia

-and did not have a return of spontaneous circulation within 15 minutes after CPR had been initiated

Exclusion criteria:

-Return of spontaneous circulation with sustained hemodynamic recovery within 15 min­utes.
-Terminal heart failure (New York Heart Association class III or IV).     
-Severe pulmonary disease (grade III or IV on the Chronic Obstruc­tive Pulmonary Disease Global Initiative for Obstructive Lung Disease criteria).
-Disseminated oncologic disease, -Obvious or suspected preg­nancy
-Bilateral femoral bypass surgery,
-known contraindications for extracorporeal CPR,
-known advance health-care directive prohibiting resus­citation or invasive ventilation,
- and expected time interval of more than 60 minutes between the initial cardiac arrest to the initiation of the cannulation procedure.
- a known Cerebral Performance Category score of 3 or 4 (indicating severe neu­rologic disability or persistent vegetative state) before cardiac arrest
-multi-injury trauma (Injury Severity Score >15 on a scale of 0 to 75, with higher scores indicating more severe injury

N total at baseline:

Intervention: 70

Control: 64

Important prognostic factors²:

age (+SD)
I:  54 (+12)
C: 57 (+10)

Sex:

I: 90%M

C: 89%M

Groups comparable at baseline?

Yes

Extracorporeal CPR (eCPR)

eCPR was performed with the use of Cardiohelp System and HLS Set Advanced 7.0 and 5.0 (Getinge) according to local institu­tional protocols. Postresuscitation care including targeted temperature manage­ment and extracorporeal circulation manage­ment, was delivered according to current guide­lines and institutional protocols.

As described in Bol ME, Suverein MM, Lorusso R, et al. Early initiation of extracorporeal life support in refractory out-of-hospital cardiac arrest: design and rationale of the INCEPTION trial. Am Heart J 2019; 210: 58-68.

Conventional CPR (standard advanced cardiac life support). 

Length of follow-up:

12 months

Loss-to-follow-up:

Intervention

N (%) 0

Reasons (describe) NA

Control:

N (%) 2/64

Reasons (describe) One patient withdrew consent for the use of data before the 30 day follow-up. Other patient was not assessed by an independent neurologist at 30 days.

Incomplete outcome data:

Intervention:

N (%) 0

Reasons (describe) NA

Control:

N (%): 2

Reasons (describe): NA

Patient who withdrew and patient who was not assessed by an independent neurologist.

Outcome measures and effect size (include 95%CI and p-value if available):

Crucial

Survival
In hospital survival
n/N, %(RR, 95%CI) 
I: 14/70, 20%
C: 13/64, 20%

(RR 0.98; 95%CI 0.50 to 1.93).

ICU survival

I: 14/70, 20%

C: 15/64 (23%)
(RR 0.85; 95%CI 0.45 to 1.63).

30 d survival
Not reported

1 year survival

Not reported

Important

Favourable neurological status
CPC (1;2) at 30 days
n/N, %(RR, 95%CI) ; risk difference OR [95%CI, P value]; risk difference [95%CI]
I: 14/70, 20%

C: 10/62, 16%
(RR 1.24, 0.59-2.59)

OR: 1.4 [0.5 to 3.5, P=0.52];

RD 1.05 [0.97 to 1.13]

CPC (1;2) at 3 months
n/N, %(RR, 95%CI) ; risk difference OR [95%CI, P value]; risk difference [95%CI]

I: 12/68, 18%

C: 9/63, 14%
(RR 1.24, 0.56-2.73)

OR: 1.5 [0.6 to 3.8];

CPC (1;2) at 6 months
n/N ; risk difference OR [95%CI]

I: 14/70, 20%

C: 10/63, 16%
(RR 1.26 (0.60 to 2.63).)

OR: 1.3 [0.5 to 3.3];

Adaptive study design with interim analysis

Cross over of patients took place(n=3). Data was analysed according to intention to treat analysis.

Unclearified loss of patients (ECPR group has 68 (out of 70) patients at 3 months survival)

Higher number of male in intervention and control group compared to normal population.

Study reference

(first author, publication year)

Was the allocation sequence adequately generated?

Definitely yes

Probably yes

Probably no

Definitely no

Was the allocation adequately concealed?

Definitely yes

Probably yes

Probably no

Definitely no

Blinding: Was knowledge of the allocated

interventions adequately prevented?

Were patients blinded?

Were healthcare providers blinded?

Were data collectors blinded?

Were outcome assessors blinded?

Were data analysts blinded?

Definitely yes

Probably yes

Probably no

Definitely no

Was loss to follow-up (missing outcome data) infrequent?

Definitely yes

Probably yes

Probably no

Definitely no

Are reports of the study free of selective outcome reporting?

Definitely yes

Probably yes

Probably no

Definitely no

Was the study apparently free of other problems that could put it at a risk of bias?

Definitely yes

Probably yes

Probably no

Definitely no

Overall risk of bias

If applicable/necessary, per outcome measure

LOW

Some concerns

HIGH

Yannopoulos, 2020

Definitely yes;

Reason: schedule was generated by Statisctical Data and Coordinating Center, with use of standard random number generator in R, with random permutations in blocks of two, four and six.

Definitely yes;

Reason: physical layer with opaque layer to determine assignment. Researchers had no access to patients randomly assignment.

Probably no;

Reason: Patients not mentioned.

Health care providers and researchers: were masked for the randomization process. However, treatment by ECMO – facilitated resuscitation or standard ACLS treatment was not masked.

Outcomes assessors partly blinded: functional assessment was done by research nurses who were masked. Collection of survival data (primary outcome) not mentioned.

Data analysing: not mentioned.

Probably no;

Reason: One loss to follow-up – withdrew consent, 3 days after randomisation. 

Probably yes;

Reason: no selective reporting was found

Definitely no;

Reason: Early terminated study.

ITT was performed for primary analysis.

High number of male in intervention group compared to control.

In hospital survival
Some concerns
Because study was earlier terminated
 

30 d mortality
Some concerns
Because study was earlier terminated

Belohlavek, 2022

Probably yes;

Reason:  Schedule was generated by a web based secured randomization system from the Institute of Biostatistics and Analyses, Faculty of Medicine,

Masaryk University, Brno. Patients were randomly assigned in

4 strata with block size of 8. 

Probably yes;

Reason: A telephone connection was subsequently

established during the ongoing chest compressions

between the cardiac center coordinator and the physician

or paramedic on scene (randomization call).

Probably no;

Reason:

Health care personel : not mentioned, but probably not blinded (because of phone contact)

Patients: not mentioned, probably not blinded

Researchers: mentioned that they were blinded to  the randomization

Outcome assessors:

Was assessed by a neurologist in a blinded fashion

Data analyst: not mentioned.

A side note is however that: the team, including study coordinator, intensivist, perfusionist

(a specialist responsible for an ECLS), interventional

cardiologist, study data manager, and interventional and

intensive care unit nurses simultaneously prepared all the

necessary equipment

Probably yes;

Reason: No information was given on loss to follow up

Probably yes;

Reason:

No selective reporting was found

Definitely no;

Reason: Early terminated study.

Cross over was done (n=20, 7.5%), however analysis were performed according to randomization group.  

Some bassline characteristics were obtained later and were therefore not available during initial treatment. The study does not discuss further influence of this on the results.

Blinding was not further clearified.

30 d survival
Some concerns
Early, terminated study

Important

Favourable neurological status -

CPC at 30 days and 6 months
Some concern
Early terminated study,

Suverein, 2023

Definitely yes;

Reason: Stratifying was done by smartphone app

*stratiefied according to center with use of a smartphone application (Randomizer, Medical University of Graz, Austria). Patients underwent randomization in a 1:1

Probably no;

Reason: The authors state that masking of treatment assignments was impossible and that this lead to cross over of three patients.

Probably no;

Reason:
Were patients blinded?
Not mentioned

Were healthcare providers blinded?
EMS teams yes (similar prehospital treatment), however they were aware of the trial.  Others were not mentioned

Were data collectors blinded?
First author collected the data. Investigators were however blinded at interim analysis. Probably, no

Were outcome assessors blinded?
Probably yes, CPC was assessed by blinded neurologist.

Were data analysts blinded?
First author analyzed the data. Investigators were however blinded at interim analysis. Probably, no

Probably no?

Reason: Two loss to follow, one patient withdrew consent before 30-day outcome assessment. One patient was not assessed by neurologist for primary analysis. 

Probably yes:

Reason: survival measurements are not consistently used. Methods description mentions two times 30-day survival, and lacks 3 months survival. Number of death/survival after hospital discharge was not mentioned either.

Definitely no:

Cross over (n=3, from control to intervention) but intention to treat was performed.

Table 4 shows unclearified loss of patients (ECPR group has 68 (out of 70) patients at 3 months survival)

High numbers of male in control and intervention group, results might therefore not be generalizable.

In hospital survival
LOW

ICU survival

LOW

 

Important

Favourable neurological status -

CPC at 30 days, 3 months and 6 months
LOW