SYSTEMATIC REVIEW AND INDIVIDUAL PATIENT LEVEL META-ANALYSIS OF STREAMLINERMULTILAYER FLOW MODULATOR IN THE

MANAGEMENT OF COMPLEX THORACOABDOMINAL

AORTIC PATHOLOGY

Niamh Hynes, Ala Elhelali, Edward B. Diethrich, Edel P.

Kavanagh, Liam Morris, Patrick Delassus, Sherif Sultan

THORACO ABDOMINAL AORTIC REPAIR: AN UNMET CLINICAL NEED

HAS ENDOVASCULAR REPAIR: THE SOLUTION?

MULTILAYER FLOW MODULATOR (MFM)

• Self-expandable mesh of cobalt alloy wires

• Interconnected in five layers

• Extremely flexible and compliant

• High kinking resistance

• High fatigue resistance

• Low total porosity

• CE marking: peripheral & aortic aneurysm repair

www.cardiatis.com

OBJECTIVE

• To assess pre-existing evidence relating to the feasibility of the MFM device in patients with a thoracoabdominal aortic aneurysm or dissection.

• Inform ongoing work for treating complicated thoracoabdominal aortic aneurysm and dissection cases.

Primary endpoint

• Establish aneurysm related deaths, renal impairment, spinal cord injury and stroke.

EMBASE, Cinhal, Cochrane Collection and Medline was preformed for accessible published articles between January 2008 and June 2014

The following keywords were using in all possible combinations: Multilayer flow modulator, MFM, Cardiatis, flow diverting stent, bare metal stent, flow diverter, thoracoabdominal aortic aneurysm, TAAA, abdominal aortic aneurysm, AAA, aortic aneurysm, dissection and multilayer stent

Inclusion Criteria: The availability of data on aneurysm anatomy, procedure and post-operative outcome

Exclusion criteria: Studies reporting on intracranial, visceral and peripheral aneurysms. Abstracts, Letters and comments were also excluded

STATISTICAL ANALYSIS

• Review Manager (Revman®) program version 5.3.3 (Cochrance

collaboration, Oxford UK)

• Heterogeneity was calculated using Revman I2 and Q statistic.

• A random effect model was assumed if heterogenicity existed

between the studies

• A p-value of less than 0.05 was considered statistically significant

• Funnel plots were constructed in order to assess publication bias

RESULTS

• 114 Identified through database search

• 7 identified through other sources

Database Search

• 121 Papers

Total Number of Studies Identified

•71 duplicate studies removed

•71 of studies screened

•56 studies excluded

•In total 15 studies included in qualitative analysis

Study selection

PAPERS INCLUDED IN REVIEW

Authors Year Study Type N Mean

Age

Sex

Angiletta et al.3 2014 Case Report 1 68 M

Chocron et al.4 2011 Case Report 1 69 M

Debing et al5 2014 Prospective Case Series 6 74 4M, 2F

Euringer et al6 2012 Case Report 1 45 M

Ferrero et al7 2013 Case Report 1 76 F

Flis et al8 2013 Case Report 1 50 M

Henry et al9 2014 Case Series 18 61 16M, 2F

Lazaris et al10 2012 Case Report 1 82 M

Natrella et al11 2012 Case Report 1 81 M

Pane et al12. 2013 Case Report 1 69 M

Polydorou et al13 2012 Case Series 22 67 22M

Sultan et al14 2013 Retrospective, Multicentre Review 55 65 41M, 14F

Sultan et al15 2014 Retrospective, Multicentre Review 38 71 30M, 8F

Tolva et al16 2012 Case Report 1 57 F

Vaislic et al17 2014 Prospective, Multicentre , Nonrandomised, Clinical Trial

(EudraCT registration: 2009-013678-42; Clinical trials.gov identifier NCT01756911)

23 76 19M, 4F

STUDY TYPES

• Three single centered prospective studies

(Debing et al, 2014; Henry et al, 2013; Polydorou et al, 2012)

• Nine case reports

(Angiletta et al, 2014; Chocron et al, 2011; Euringer et al, 2012; Ferrero et al, 2013; Flis et al, 2013; Lazaris et al, 2012; Natrella et al, 2012; Pane et al, 2013;Tolva et al, 2012)

• Two observational multi-centre reviews

(Sultan et al, 2013; Sultan et al 2014)

• One Prospective Multi-centre Non-randomised Clinical Trial

(Vaislic et al, 2014)

STUDY PARTICIPANTS

• A total of 171 study patients

• All patients were high risk for open surgical repair.

• 139 (81.3%) were male

• Mean age of 68.85years(+/-12.34years).

Characterization of Aortic Pathologies

• 8 (4.68%) Arch aneurysms,

• 1 (0.58%) Descending thoracic aneurysm,

• 101 (59.1%) TAAA (13 Type I, 24 Type II, 28 Type III, 17 type IV, 19 unclassified)

• 27 (22.2%) AAA (8 suprarenal, 10 juxtarenal, 9 AAA),

• 20 (11.7%) Type B dissections

• 14 (8.19%) Saccular aneurysms (8 mycotic)

TECHNICAL SUCCESS

• A total of 329 stents were implanted in 149 patients.

Polydorou et al did not report the number of stents used in 22 patients.

Technical success was achieved in 131 cases (76.6 %).

• Technical failure occurred in 38 cases which were used outside of indications for use

• In cases that were performed within IFU, technical success was 98.4%.

SURVIVAL

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

All Cause

Aneurysm-related

Months 0 1 6 12 18

All Cause Survival

Number at risk 171 171 139 86 16

% Survival

(+/- Standard Error)

100% 97.1%

(+/-1.26%)

85.0%

(+/-2.79%)

53.7%

(+/-3.94%)

37.4%

(+/-7.40%)

Aneurysm Related Survival

Number at risk 171 171 139 86 16

% Survival

(+/- Standard Error)

100% 97.1%

(+/-1.26%)

87.5%

(+/-2.62%)

78.7%

(+/-3.92%)

66.6%

(+/-9.62%)

OUTSIDE OF INDICATIONS FOR USEWithin

Indications

For Use

Outside

Indications

For Use

P

Number 132 39

Mean Age

(years)

67.8

+/-11.9

70.1

+/- 12.3

0.154

Male: Female

(%male)

108:24

(81.8%)

31:8

(79.5%)

0.741

Anatomy

Thoracoabdominal Aneurysm

Arch Aneurysm

Suprarenal Abdominal Aortic Aneurysm

Infrarenal Abdominal Aortic Aneurysm

Saccular/Mycotic Aneurysm

Stanford Type B Dissection

86 (65%)

8 (6%)

19 (14%)

9 (7%)

3 (2%)

7 (5%)

16 (41%)

0

0

0

10 (26%)

13 (33%)

0.007

0.116

0.012

0.095

<0.0001

<0.0001

Mean Diameter

(cm)

6.2

+/-1.37*

7.09

+/-1.59

0.0017

OUTSIDE OF INDICATIONS FOR USE

0

10

20

30

40

50

60

70

80

90

100

0 6 12 18 24

IFU

OIFU

OIFU IFU p-value Hazards Ratio 95% CI

30 Days 100% 96.2% (±1.63%) 0.224 0

1 Year 38.0% (±9.0%) 93.3% (±2.79%) <0.000001 10.65 4.51 to 25.18

18 Months 25.6% (±9.01%) 93.3% (±7.64%) <0.000001 10.65 2.72 to 23.57

FOREST PLOT: ALL-CAUSE MORTALITY

Risk Ratio Risk RatioStudy Weight M-H, Random, 95%CI M-H, Random, 95%CICase StudiesBenjelloun 2012 5.3% 3.00 [0.24, 37.67]Chocrom 2011 5.3% 3.00 [0.24, 37.67]Euringer 2012 5.3% 3.00 [0.24, 37.67]Ferero 2013 5.3% 0.33 [0.03, 4.19]Filis 2013 5.3% 3.00 [0.24, 37.67]Lazaris 2013 5.3% 0.33 [0.03, 4.19]Natrella 2012 5.3% 3.00 [0.24, 37.67]Pane 2013 5.3% 3.00 [0.24, 37.67]Pieper 2012 5.3% 3.00 [0.24, 37.67]Tolva 2012 5.3% 3.00 [0.24, 37.67]Subtotal (95%CI) 53.2% 1.93 [0.87, 4.30]Total eventsHeterogeneity: Tau2=0.00, Chi2 =4.64, df=9 (P=0.86); I2=0%Test for overall effect: Z=1.61 (P=0.11)

Prospective & Observational ReviewsChealtro 2014 5.1% 9.00 [0.64, 126.85]Debing 2014 6.5% 5.00 [0.81, 31.00]Henry 2012 7.3% 6.00 [1.63, 22.03]Polydorou 2012 7.3% 10.00 [2.65, 37.73]Sultan 2013 7.8% 12.75 [4.95, 32.85]Sultan 2014 7.8% 0.12 [0.05, 0.30]Vaisilic 2014 5.0% 47.00 [3.02, 730.37]Subtotal (95%CI) 46.8% 5.11 [0.89, 29.40]Total eventsHeterogeneity: Tau2=4.80, Chi2 =64.20, df=6(P<0.00001); I2=91%Test for overall effect: Z=1.83 (P=0.07)

Total (95% CI) 100.0% 2.97 [1.14, 7.75]Total events 0.001 0.1 10 1000Heterogeneity: Tau2=2.83, Chi2 =69.42, df=16(P<0.00001); I2=77% Favours RIP Favours SurvivedTest for overall effect: Z=2.23 (P=0.03)Test for subgroup differences: Chi2 =0.98, df=1(P=0.32); I2=0%

FOREST PLOT: ANEURYSM MORTALITY

Risk Ratio Risk RatioStudy Weight M-H, Random, 95%CI M-H, Random, 95%CICase StudiesBenjelloun 2012 2.9% 3.00 [0.24, 37.67]Chocrom 2011 2.9% 3.00 [0.24, 37.67]Euringer 2012 2.9% 3.00 [0.24, 37.67]Ferero 2013 8.8% 0.33 [0.03, 4.19]Filis 2013 2.9% 3.00 [0.24, 37.67]Lazaris 2013 8.8% 0.33 [0.03, 4.19]Natrella 2012 2.9% 3.00 [0.24, 37.67]Pane 2013 2.9% 3.00 [0.24, 37.67]Pieper 2012 2.9% 3.00 [0.24, 37.67]Tolva 2012 2.9% 3.00 [0.24, 37.67]Subtotal (95%CI) 41.2% 1.86 [0.90, 3.84]Total eventsHeterogeneity: Chi2 =4.64, df=9 (P=0.86); I2=0%Test for overall effect: Z=1.67 (P=0.09)

Prospective & Observational ReviewsChealtro 2014 2.9% 9.00 [0.64, 126.85]Debing 2014 5.9% 5.00 [0.81, 31.00]Henry 2012 11.8% 6.00 [1.63, 22.03]Polydorou 2012 11.8% 10.00 [2.65, 37.73]Sultan 2013 23.5% 12.75 [4.95, 32.85]Sultan 2014 0.0% 0.12 [0.05, 0.30]Vaisilic 2014 2.9% 47.00 [3.02, 730.37]Subtotal (95%CI) 58.8% 11.60 [6.38, 21.09]Total eventsHeterogeneity: Chi2 =2.92, df=5 (P=0.71); I2=0%Test for overall effect: Z=8.03 (P<0.00001)

Total (95% CI) 100.0% 7.59 [4.79, 12.01]Total events 0.001 0.1 10 1000Heterogeneity: Chi2 =19.21, df=15(P=0.20); I2=22% Favours RIP Favours SurvivedTest for overall effect: Z=8.65 (P<0.00001)Test for subgroup differences: Chi2 =14.56, df=1(P=0.0001); I2=93.1%

SECONDARY OUTCOMES• Paraplegia, spinal cord ischemia or renal insult: No reported cases

• Endovascular re-interventions: 22 (12.9%) were performed in 19 patients

• Conversion to open surgical repair: Two patients (1.17%), one within 30-days of the primary procedure

• Branch Patency: Of 449 branches covered there were 10 incidences of thrombosis, giving a patency rate of 97.8%.

Two studies did not report on the number of side branches covered. However patency rates of

100% were reported in both studies

• Mean length of hospital stay: 7.18 days (±5.23days).

Maximum length of stay was 21 days for a patient with a mycotic aneurysm who was treated

with intravenous antibiotics.

CHANGES IN SAC VOLUMEAuthors Number

of

Patients

Mean Follow-

up (months +/- SD)

Mean total

Volume

(cm3+/- SD)

Mean Volume at

Follow-up

(cm3+/- SD)

Aneurysm Sac Thrombosis

Debing (2014) 6 10.25

+/-

2.61

205.3

+/-

114.3

208.4

+/-

122.4

(2.2% increase)

At 6 months, sac volume:

Decreased in 2 patients,

Increased in 2 patients

Stable in 1 patient

(1 patient died post-operatively)

Natrella (2012)l 1 12 84.9 82.8 Partial thrombosis with reduction in diameter and volume

Sultan (2013) 55 8.2

+/-

5.3

309.84

+/-

259.62

355.39

+/-

328.56

(12months)

The ratio of thrombus to total volume stayed almost constant

at 0.48 over 12 months

The ratio of flow to total volume fell from 0.21 to 0.12 at 12

months

Vaislic (2014)l 23 12 At 12 months, 17 patients:

Change in ratio of sac to total lumen flow volume, -

28.9%

Change in ratio of thrombus volume to total lumen

volume, 21.3%

Complete or partial thrombosis was reported in 68 cases which were done within IFU.

In the 38 cases done outside of IFU Sultan et al reported sac expansion in all cases

with no stabilization or shrinkage

DISCUSSION

•Early results of endovascular repair using the MFM within indication for use

appears to be effective and safe for treatment of thoracoabdominal aneurysms &

dissections.

•The population treated using the MFM were a high risk surgical group

•30-day mortality rate was 2.9% (+/-1.26%)

•Overall survival at one year was 53.7% (+/-3.94%)

CONCLUSION• The results of these case reports and reviews are encouraging

for this technology ability to treat TAAA and dissection

• Adherence to well-defined IFU is essential

• Well-defined large clinical trials and long term follow-up are

necessary in order to accurately determine the efficacy and

safety of the Cardiatis MFM in treating complex

thoracoabdominal pathologies