![Page 1: Issues in clinical trials devices CRT · Core lab echo Long run in with OMT Followed by 3.Parallell RCT with hard endpoints 4. Moving to Mild HF RCT with hard endpoints. NYHA III-IV](https://reader033.vdocuments.net/reader033/viewer/2022060917/60aa6beba552cc78954eeac2/html5/thumbnails/1.jpg)
Issues in clinical trials devices
CRT
Cecilia Linde
Stockholm 13th december, 2019
![Page 2: Issues in clinical trials devices CRT · Core lab echo Long run in with OMT Followed by 3.Parallell RCT with hard endpoints 4. Moving to Mild HF RCT with hard endpoints. NYHA III-IV](https://reader033.vdocuments.net/reader033/viewer/2022060917/60aa6beba552cc78954eeac2/html5/thumbnails/2.jpg)
Disclosures
Cecilia Linde receives
Research grants to institution from Astra Zeneca, Swedish Heart-Lung-foundation and Stockholm County Council
Speaker honoraria from Medtronic, Abbot, Liva Nova, Novartis, Vifor , Microport, Boston Scientific, ImpulseDynamics, Bayer
![Page 3: Issues in clinical trials devices CRT · Core lab echo Long run in with OMT Followed by 3.Parallell RCT with hard endpoints 4. Moving to Mild HF RCT with hard endpoints. NYHA III-IV](https://reader033.vdocuments.net/reader033/viewer/2022060917/60aa6beba552cc78954eeac2/html5/thumbnails/3.jpg)
Prim prof ICDs are indicated in
50% of HF patients (HFrEF) and in
10% after myocardial infarction
But ony in HFrEF
CRTs are indicated in 30% of HF
patients (RiksSvikt registry)
NYHA class, LVEF, QRS width/LBBB
are the gate-keepers
But ony in HFrEF
Defibrillators and CRT save lives
![Page 4: Issues in clinical trials devices CRT · Core lab echo Long run in with OMT Followed by 3.Parallell RCT with hard endpoints 4. Moving to Mild HF RCT with hard endpoints. NYHA III-IV](https://reader033.vdocuments.net/reader033/viewer/2022060917/60aa6beba552cc78954eeac2/html5/thumbnails/4.jpg)
What the 2016 ESC HF guidelines say
Consider CRT+/-ICDIn symptomatic HFrEFProvided QRS > 130 ms
![Page 5: Issues in clinical trials devices CRT · Core lab echo Long run in with OMT Followed by 3.Parallell RCT with hard endpoints 4. Moving to Mild HF RCT with hard endpoints. NYHA III-IV](https://reader033.vdocuments.net/reader033/viewer/2022060917/60aa6beba552cc78954eeac2/html5/thumbnails/5.jpg)
Results from a case-based meta-analysis:5 RCT (NYHA II-III)
In pts on optimal medical treatment
34% Relative risk reduction in total mortality HR 0.66
35% Relative risk reduction in
Total mortality and heart failure hospitalizations HR 0.65
N=3872 pts
Cleland J et al Eur Heart J 2013: 46:3547
![Page 6: Issues in clinical trials devices CRT · Core lab echo Long run in with OMT Followed by 3.Parallell RCT with hard endpoints 4. Moving to Mild HF RCT with hard endpoints. NYHA III-IV](https://reader033.vdocuments.net/reader033/viewer/2022060917/60aa6beba552cc78954eeac2/html5/thumbnails/6.jpg)
CRT – a 20 year success story
![Page 7: Issues in clinical trials devices CRT · Core lab echo Long run in with OMT Followed by 3.Parallell RCT with hard endpoints 4. Moving to Mild HF RCT with hard endpoints. NYHA III-IV](https://reader033.vdocuments.net/reader033/viewer/2022060917/60aa6beba552cc78954eeac2/html5/thumbnails/7.jpg)
What is different about device studies
Patient safety / perioperative long term device related complicationsRisk benefit calculation
Expert implanter needed
High up front cost of therapy
Lack of reimbursement
Non belief from the medical society
Challenges
![Page 8: Issues in clinical trials devices CRT · Core lab echo Long run in with OMT Followed by 3.Parallell RCT with hard endpoints 4. Moving to Mild HF RCT with hard endpoints. NYHA III-IV](https://reader033.vdocuments.net/reader033/viewer/2022060917/60aa6beba552cc78954eeac2/html5/thumbnails/8.jpg)
Common order of device trials
Smaller studiesHighly specialized centersSicker patients
1. Observational studies2. Crossover RCT studies
Tight control of inclusion criteriaCore lab echoLong run in with OMT
Followed by3.Parallell RCT with hard endpoints
4. Moving to Mild HF RCT with hard endpoints
![Page 9: Issues in clinical trials devices CRT · Core lab echo Long run in with OMT Followed by 3.Parallell RCT with hard endpoints 4. Moving to Mild HF RCT with hard endpoints. NYHA III-IV](https://reader033.vdocuments.net/reader033/viewer/2022060917/60aa6beba552cc78954eeac2/html5/thumbnails/9.jpg)
NYHA III-IV patients
![Page 10: Issues in clinical trials devices CRT · Core lab echo Long run in with OMT Followed by 3.Parallell RCT with hard endpoints 4. Moving to Mild HF RCT with hard endpoints. NYHA III-IV](https://reader033.vdocuments.net/reader033/viewer/2022060917/60aa6beba552cc78954eeac2/html5/thumbnails/10.jpg)
Cardiac resynchronisation therapya French invention
PACE 1998;21:239-245
![Page 11: Issues in clinical trials devices CRT · Core lab echo Long run in with OMT Followed by 3.Parallell RCT with hard endpoints 4. Moving to Mild HF RCT with hard endpoints. NYHA III-IV](https://reader033.vdocuments.net/reader033/viewer/2022060917/60aa6beba552cc78954eeac2/html5/thumbnails/11.jpg)
•Randomised single blind comparison of
• * Biventricular VDD pacing with optimal AV delay
* Inactive VVI pacing (40 bpm)
Study design SR Group
2 weeks4 weeks
3 months 3 months
3 months3 months
no pacing (VVI40)
RV + LV VDD PACING
biventricular stimulation
no modification in drug treatment,
except for diuretics
MusticStudy
![Page 12: Issues in clinical trials devices CRT · Core lab echo Long run in with OMT Followed by 3.Parallell RCT with hard endpoints 4. Moving to Mild HF RCT with hard endpoints. NYHA III-IV](https://reader033.vdocuments.net/reader033/viewer/2022060917/60aa6beba552cc78954eeac2/html5/thumbnails/12.jpg)
MUSTIC study results : CRT vs VVI in severe HF sévere –
NYHA III et QRS > 150 ms
Cazeau S et al NEJM 2001
Six minute walk
Improved 23%
In BiV arm
Quality of life
Improved 32%
In BiV arm
![Page 13: Issues in clinical trials devices CRT · Core lab echo Long run in with OMT Followed by 3.Parallell RCT with hard endpoints 4. Moving to Mild HF RCT with hard endpoints. NYHA III-IV](https://reader033.vdocuments.net/reader033/viewer/2022060917/60aa6beba552cc78954eeac2/html5/thumbnails/13.jpg)
Mortality and CV Hosp
Mortality
![Page 14: Issues in clinical trials devices CRT · Core lab echo Long run in with OMT Followed by 3.Parallell RCT with hard endpoints 4. Moving to Mild HF RCT with hard endpoints. NYHA III-IV](https://reader033.vdocuments.net/reader033/viewer/2022060917/60aa6beba552cc78954eeac2/html5/thumbnails/14.jpg)
Long term outcome results in CARE-HF
HF mortality
SCD mortality
It took more than 2 years with CRT compared to optimal medical treatment to reduce
The risk of sudden cardiac death in the CARE HF trial
![Page 15: Issues in clinical trials devices CRT · Core lab echo Long run in with OMT Followed by 3.Parallell RCT with hard endpoints 4. Moving to Mild HF RCT with hard endpoints. NYHA III-IV](https://reader033.vdocuments.net/reader033/viewer/2022060917/60aa6beba552cc78954eeac2/html5/thumbnails/15.jpg)
![Page 16: Issues in clinical trials devices CRT · Core lab echo Long run in with OMT Followed by 3.Parallell RCT with hard endpoints 4. Moving to Mild HF RCT with hard endpoints. NYHA III-IV](https://reader033.vdocuments.net/reader033/viewer/2022060917/60aa6beba552cc78954eeac2/html5/thumbnails/16.jpg)
NYHA class II/I
![Page 17: Issues in clinical trials devices CRT · Core lab echo Long run in with OMT Followed by 3.Parallell RCT with hard endpoints 4. Moving to Mild HF RCT with hard endpoints. NYHA III-IV](https://reader033.vdocuments.net/reader033/viewer/2022060917/60aa6beba552cc78954eeac2/html5/thumbnails/17.jpg)
REVERSE: CRT in HF Classe NYHA I-II
91,688,8
94,5
69,7
92,5
93,9
69,2
73,676,8
96,6
60
70
80
90
100
110
0 6 12 18 24
Months Since Randomization
LV
ES
Vi
(ml/
m2 )
CRT OFF
CRT ON P<0.0001
0%
5%
10%
15%
20%
25%
30%
0 6 12 18 24
Months Since Randomization
Pe
rce
nta
ge
Ho
spit
ali
zed
fo
r H
F o
r
Die
d
CRT ON
CRT OFF
24.0%
11.7%
HR (95%CI): 0.38 (0.20-0.73)
P=0.003
C Daubert et Al, J Am Coll Cardiol 2009; 54: 1837-1846
Powered Secondary End Point: LVESVi
Time to First HF Hospitalization or Death
73 centres (EU et Etats Unis)
674 patients
![Page 18: Issues in clinical trials devices CRT · Core lab echo Long run in with OMT Followed by 3.Parallell RCT with hard endpoints 4. Moving to Mild HF RCT with hard endpoints. NYHA III-IV](https://reader033.vdocuments.net/reader033/viewer/2022060917/60aa6beba552cc78954eeac2/html5/thumbnails/18.jpg)
![Page 19: Issues in clinical trials devices CRT · Core lab echo Long run in with OMT Followed by 3.Parallell RCT with hard endpoints 4. Moving to Mild HF RCT with hard endpoints. NYHA III-IV](https://reader033.vdocuments.net/reader033/viewer/2022060917/60aa6beba552cc78954eeac2/html5/thumbnails/19.jpg)
Mechanism of action
19
![Page 20: Issues in clinical trials devices CRT · Core lab echo Long run in with OMT Followed by 3.Parallell RCT with hard endpoints 4. Moving to Mild HF RCT with hard endpoints. NYHA III-IV](https://reader033.vdocuments.net/reader033/viewer/2022060917/60aa6beba552cc78954eeac2/html5/thumbnails/20.jpg)
Time course of of reverse remodelingover 5 yrs in the REVERSE trial
Reverse remodeling developed in full over 2 years andWas thereafter maintained
![Page 21: Issues in clinical trials devices CRT · Core lab echo Long run in with OMT Followed by 3.Parallell RCT with hard endpoints 4. Moving to Mild HF RCT with hard endpoints. NYHA III-IV](https://reader033.vdocuments.net/reader033/viewer/2022060917/60aa6beba552cc78954eeac2/html5/thumbnails/21.jpg)
Reverse remodeling by drugs and CRT
Kramer DG JACC 2010;56:392
![Page 22: Issues in clinical trials devices CRT · Core lab echo Long run in with OMT Followed by 3.Parallell RCT with hard endpoints 4. Moving to Mild HF RCT with hard endpoints. NYHA III-IV](https://reader033.vdocuments.net/reader033/viewer/2022060917/60aa6beba552cc78954eeac2/html5/thumbnails/22.jpg)
Trial N Pts NYHA LVEF % SR/AF QRS ms
BBB Morb/
Mort
MUSTIC-SR 58 III 35% SR 150 NS no
MIRACLE 453 III,IV 35% SR 130 NS no
MUSTIC AF 43 III 35% AF 200 NS no
PATH CHF 41 III,IV 35% SR 120 NS no
MIRACLE ICD 369 III,IV 35% SR 130 NS no
CONTAK CD 227 II,IV 35% SR 120 NS no
MIRACLE ICD II 186 II 35% SR 130 NS no
PATH CHF II 89 III,IV 35% SR 120 NS no
COMPANION 1520 III,IV 35% SR 120 NS Yes
CARE HF 814 III,IV 35% SR 120 NS Yes
REVERSE 610 I,II <40% SR >120 NS no
MADIT CRT 1800 I,II <30% SR >130 NS Yes
RAFT 1800 II,III <30% SR/AF >120 NS yes
BLOCK HF 920/680 I-III <50% SR/AVB NA NS yes
ECHO CRT 810 III-IV <35% SR <130 NS yes
BIOPACE 1820 Any Any AVB NA NA Yes
12,000 pts included in >20 RCT
including six morbidity mortality trials
None had LBBB as inclusion criterium
Few (262) had AF as inclusion criterium
![Page 23: Issues in clinical trials devices CRT · Core lab echo Long run in with OMT Followed by 3.Parallell RCT with hard endpoints 4. Moving to Mild HF RCT with hard endpoints. NYHA III-IV](https://reader033.vdocuments.net/reader033/viewer/2022060917/60aa6beba552cc78954eeac2/html5/thumbnails/23.jpg)
How sub group analysis may leadto new research questions
• The QRS width and the morphology
• Aetiology
• Female sex
• Left ventricular ejection fraction
![Page 24: Issues in clinical trials devices CRT · Core lab echo Long run in with OMT Followed by 3.Parallell RCT with hard endpoints 4. Moving to Mild HF RCT with hard endpoints. NYHA III-IV](https://reader033.vdocuments.net/reader033/viewer/2022060917/60aa6beba552cc78954eeac2/html5/thumbnails/24.jpg)
Companion and CARE HF Sub group analysis
![Page 25: Issues in clinical trials devices CRT · Core lab echo Long run in with OMT Followed by 3.Parallell RCT with hard endpoints 4. Moving to Mild HF RCT with hard endpoints. NYHA III-IV](https://reader033.vdocuments.net/reader033/viewer/2022060917/60aa6beba552cc78954eeac2/html5/thumbnails/25.jpg)
Benefit from CRT in women and men by QRS widths in MADIT CRT inclusion criteria QRS > 130 ms
Zareba W et al Circulation 2011;123:1061
In this sub-study of MADIT CRT only LBBB pts benefited
![Page 26: Issues in clinical trials devices CRT · Core lab echo Long run in with OMT Followed by 3.Parallell RCT with hard endpoints 4. Moving to Mild HF RCT with hard endpoints. NYHA III-IV](https://reader033.vdocuments.net/reader033/viewer/2022060917/60aa6beba552cc78954eeac2/html5/thumbnails/26.jpg)
![Page 27: Issues in clinical trials devices CRT · Core lab echo Long run in with OMT Followed by 3.Parallell RCT with hard endpoints 4. Moving to Mild HF RCT with hard endpoints. NYHA III-IV](https://reader033.vdocuments.net/reader033/viewer/2022060917/60aa6beba552cc78954eeac2/html5/thumbnails/27.jpg)
Hazard ratios and 95% CI of benefit of CRT with regard to QRS width
Mortality
Mortality/HFH
Cleland J et al Eur Heart J 2013
N=3872 patients
+
-
-
+
![Page 28: Issues in clinical trials devices CRT · Core lab echo Long run in with OMT Followed by 3.Parallell RCT with hard endpoints 4. Moving to Mild HF RCT with hard endpoints. NYHA III-IV](https://reader033.vdocuments.net/reader033/viewer/2022060917/60aa6beba552cc78954eeac2/html5/thumbnails/28.jpg)
HF guidelines and CRT indication
in patients with LBBB
CRT is recommended in patients with LBBB
Level of evidence depends on QRS width
![Page 29: Issues in clinical trials devices CRT · Core lab echo Long run in with OMT Followed by 3.Parallell RCT with hard endpoints 4. Moving to Mild HF RCT with hard endpoints. NYHA III-IV](https://reader033.vdocuments.net/reader033/viewer/2022060917/60aa6beba552cc78954eeac2/html5/thumbnails/29.jpg)
HF guidelines and CRT indication in
patients with non-LBBB?
CRT should or may be considered in with non- LBBB
Level of evidence depends on QRS width
![Page 30: Issues in clinical trials devices CRT · Core lab echo Long run in with OMT Followed by 3.Parallell RCT with hard endpoints 4. Moving to Mild HF RCT with hard endpoints. NYHA III-IV](https://reader033.vdocuments.net/reader033/viewer/2022060917/60aa6beba552cc78954eeac2/html5/thumbnails/30.jpg)
As a consequence….
Results of the EchoCRT study
![Page 31: Issues in clinical trials devices CRT · Core lab echo Long run in with OMT Followed by 3.Parallell RCT with hard endpoints 4. Moving to Mild HF RCT with hard endpoints. NYHA III-IV](https://reader033.vdocuments.net/reader033/viewer/2022060917/60aa6beba552cc78954eeac2/html5/thumbnails/31.jpg)
How sub group analysis may leadto new research questions
• The QRS width and the morphology
• Aetiology
• Female sex
• Left ventricular ejection fraction
![Page 32: Issues in clinical trials devices CRT · Core lab echo Long run in with OMT Followed by 3.Parallell RCT with hard endpoints 4. Moving to Mild HF RCT with hard endpoints. NYHA III-IV](https://reader033.vdocuments.net/reader033/viewer/2022060917/60aa6beba552cc78954eeac2/html5/thumbnails/32.jpg)
Benefit from CRT in women and men by QRS widths in MADIT CRT inclusion criteria QRS > 130 ms
Zareba W et al Circulation 2011;123:1061
In this sub-study of MADIT CRT women benefited at lower QRS widths
![Page 33: Issues in clinical trials devices CRT · Core lab echo Long run in with OMT Followed by 3.Parallell RCT with hard endpoints 4. Moving to Mild HF RCT with hard endpoints. NYHA III-IV](https://reader033.vdocuments.net/reader033/viewer/2022060917/60aa6beba552cc78954eeac2/html5/thumbnails/33.jpg)
QRS width and LBBB (hatched) in women and men in Swedish heart failure registry RiksSvikt 13.782 pts
Linde et al Europace 2015;17:424
Women with heart failure have smaller QRS than men and women had LBBB at smaller widths
LBBB in HFpts27% in women24% in men
![Page 34: Issues in clinical trials devices CRT · Core lab echo Long run in with OMT Followed by 3.Parallell RCT with hard endpoints 4. Moving to Mild HF RCT with hard endpoints. NYHA III-IV](https://reader033.vdocuments.net/reader033/viewer/2022060917/60aa6beba552cc78954eeac2/html5/thumbnails/34.jpg)
![Page 35: Issues in clinical trials devices CRT · Core lab echo Long run in with OMT Followed by 3.Parallell RCT with hard endpoints 4. Moving to Mild HF RCT with hard endpoints. NYHA III-IV](https://reader033.vdocuments.net/reader033/viewer/2022060917/60aa6beba552cc78954eeac2/html5/thumbnails/35.jpg)
Women per se and men by terciles of height
![Page 36: Issues in clinical trials devices CRT · Core lab echo Long run in with OMT Followed by 3.Parallell RCT with hard endpoints 4. Moving to Mild HF RCT with hard endpoints. NYHA III-IV](https://reader033.vdocuments.net/reader033/viewer/2022060917/60aa6beba552cc78954eeac2/html5/thumbnails/36.jpg)
Height and response to CRT in women and men by height tertiles
Mortality and HFH
Mortality
_ _ _ _Shortest tertile of men
women
Female sex was not independent predictor of CRT benefit and short men (< 165 cm) benefited over a wide range of QRS widths
![Page 37: Issues in clinical trials devices CRT · Core lab echo Long run in with OMT Followed by 3.Parallell RCT with hard endpoints 4. Moving to Mild HF RCT with hard endpoints. NYHA III-IV](https://reader033.vdocuments.net/reader033/viewer/2022060917/60aa6beba552cc78954eeac2/html5/thumbnails/37.jpg)
How sub group analysis may leadto new research questions
• The QRS width and the morphology
• Aetiology
• Female sex
• Left ventricular ejection fraction
![Page 38: Issues in clinical trials devices CRT · Core lab echo Long run in with OMT Followed by 3.Parallell RCT with hard endpoints 4. Moving to Mild HF RCT with hard endpoints. NYHA III-IV](https://reader033.vdocuments.net/reader033/viewer/2022060917/60aa6beba552cc78954eeac2/html5/thumbnails/38.jpg)
Less women had HFrEF and more LVEF > 40%
Women
Men
LVEF and QRS width distribution by gender
in the Swedish HF registry in 25.171 ptsLund LH et al Eur Heart J 2013; 34:529
![Page 39: Issues in clinical trials devices CRT · Core lab echo Long run in with OMT Followed by 3.Parallell RCT with hard endpoints 4. Moving to Mild HF RCT with hard endpoints. NYHA III-IV](https://reader033.vdocuments.net/reader033/viewer/2022060917/60aa6beba552cc78954eeac2/html5/thumbnails/39.jpg)
REVERSE a RCT in NYHA I/II HF n=610distribof baseline LVEF (Inclusion criteria LVEF < 40%) mean LVEF 28%
LVEF by Center
39
LVEF by Core Lab
Linde C et al Circ HF 2013;6:1180-1189
24% had LVEF > 30%12% had LVEF > 35%
Reporting in 5%intervals
![Page 40: Issues in clinical trials devices CRT · Core lab echo Long run in with OMT Followed by 3.Parallell RCT with hard endpoints 4. Moving to Mild HF RCT with hard endpoints. NYHA III-IV](https://reader033.vdocuments.net/reader033/viewer/2022060917/60aa6beba552cc78954eeac2/html5/thumbnails/40.jpg)
Time to HF hosp or death in REVERSE patients
with LVEF < 30% or > 30%
Linde et al Circ HF 2013;6:1180
LVEF > 30% n=177LVEF < 30% n=431
P=0.012P=0.047
CRT-ON
CRT OFF
CRT ON
CRT OFF
Relative risk reduction 42% Relative risk reduction 74%
![Page 41: Issues in clinical trials devices CRT · Core lab echo Long run in with OMT Followed by 3.Parallell RCT with hard endpoints 4. Moving to Mild HF RCT with hard endpoints. NYHA III-IV](https://reader033.vdocuments.net/reader033/viewer/2022060917/60aa6beba552cc78954eeac2/html5/thumbnails/41.jpg)
Results of MADIT CRT in CRT vs controlas regards reverse remodeling by LVEF
Kutfyia V et al JACC 2013
![Page 42: Issues in clinical trials devices CRT · Core lab echo Long run in with OMT Followed by 3.Parallell RCT with hard endpoints 4. Moving to Mild HF RCT with hard endpoints. NYHA III-IV](https://reader033.vdocuments.net/reader033/viewer/2022060917/60aa6beba552cc78954eeac2/html5/thumbnails/42.jpg)
![Page 43: Issues in clinical trials devices CRT · Core lab echo Long run in with OMT Followed by 3.Parallell RCT with hard endpoints 4. Moving to Mild HF RCT with hard endpoints. NYHA III-IV](https://reader033.vdocuments.net/reader033/viewer/2022060917/60aa6beba552cc78954eeac2/html5/thumbnails/43.jpg)
Powered Study Objectives
• Primary Efficacy: Time to first event defined as:
• All-cause mortality, or
• HF Event, defined as either:
• Inpatient hospitalization for HF, or
• Outpatient event requiring invasive clinical intervention and management for HF (i.e. IV diuretics, ultrafiltration, or equivalent) and overnight stay
• Primary Safety: System-related Complication-free at 6 months > 80%
![Page 44: Issues in clinical trials devices CRT · Core lab echo Long run in with OMT Followed by 3.Parallell RCT with hard endpoints 4. Moving to Mild HF RCT with hard endpoints. NYHA III-IV](https://reader033.vdocuments.net/reader033/viewer/2022060917/60aa6beba552cc78954eeac2/html5/thumbnails/44.jpg)
MIRACLE EFterminated due toLow recruitment
![Page 45: Issues in clinical trials devices CRT · Core lab echo Long run in with OMT Followed by 3.Parallell RCT with hard endpoints 4. Moving to Mild HF RCT with hard endpoints. NYHA III-IV](https://reader033.vdocuments.net/reader033/viewer/2022060917/60aa6beba552cc78954eeac2/html5/thumbnails/45.jpg)
More benefit from CRT with LBBB and withlonger QRS duration but the two go togehter
Women may benefit more but reason unclearSize or sex?
CRT may be benefical across a wider range of low LVEFs in HFrFEF
Conclusion
![Page 46: Issues in clinical trials devices CRT · Core lab echo Long run in with OMT Followed by 3.Parallell RCT with hard endpoints 4. Moving to Mild HF RCT with hard endpoints. NYHA III-IV](https://reader033.vdocuments.net/reader033/viewer/2022060917/60aa6beba552cc78954eeac2/html5/thumbnails/46.jpg)
Conclusion
Sub group analysis never give the truth
Meta-analysis are helpful
But Randomised studies are s neededOr at least studies powered to answer the questione.g. women vs men