Network Meta-analyses a novel way for synthetic reviews. 黃道民

Network Meta-analysesa novel way for synthetic

reviews.黃道民

Traditional Clinical Trials.

• Randomized controlled trial

• Y: outcome• X: randomized and placebo controlled

• High level of evidence if adequately powered.

Meta-analysis

• Combine the information from “similar” trials into a formal summary.

• Especially when clinical trials are conflicting

Example:

m

In some cases, we would like to know:

• What do we think about the relative benefits of the treatments before knowing the results from this trial?

• What information can be gained from the results of this trial?

• the relative benefits of the treatments?

Network Meta-analysis

• Mixed treatment comparison• 利用“貝氏定理 (條件機率 )”為橋，比較各種治療的強弱。

By this mean, we can

• Which method is the better• Which diagnostic methods are better

(sensitive or specific)• Comparisons between treatments

CONTRAST INDUCED ACUTE KIDNEY INJURY (CI-AKI)

CI-AKI

• 3rd leading cause of hospital acquired AKI(~10%)

• Adverse outcomes of CI-AKI– Prolonged hospital stay– Long term adverse effect– Cost.

Circulation 105: 2259-2264, 2002

Am J Kidney Dis 39: 930-936, 2002.

Many options for prevention of CI-AKI

• N-acetylcysteine• Sodium bicarbonate• Felodopam• Statin• Furosemide

Ann Intern Med. 2008 Feb 19;148(4):284-94

The good: N-acetylcysteine; the bad: furosemide

Ann Intern Med. 2008 Feb 19;148(4):284-94

But questions remains…

• ACT trial 2011 (the biggest trial to date)– Neutral effect of NAC in CI-AKI prevention

• How about high dose? • What is the most effective strategy?

Aim of current study

• To compare the efficacy of medical prevention for CI-AKI

Methods

• Conventional meta-analysis• Network meta-analysis

17

Search strategy

• Pubmed before 2011/11/13• Age > 18 y/o underwent non-ionized contrast

injection

18

Search strategy1. "Contrast Media” [MeSH] 14. nephropathy2. Contrast medium 15. nephrotoxic

3. Contrast media 16. (impair or damage or reduce) and (renal or kidney)

4. contrast dye 17. contrast-induced nephropathy5. radiographic contrast 18. contrast-associated nephropathy

6. radiocontrast media 19. #10 or #11 or #12 or #13 or #14 or #15 or #16 or #17 or #18 #9 and #19

7. radiocontrast medium 21. “Clinical Trial” [Publication Type]8. contrast agent 22. “Random Allocation” [MeSH]9. #1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 23. “Single-Blind Method” [MeSH]

10. “Renal Insufficiency” [MeSH] 24. “Double-Blind Method” [MeSH]11. “Diabetic Nephropathies” [MeSH] 25. #21 or #22 or #23 or #2412. “Nephritis” [MeSH] 26. #20 and #2513. nephritis

Statistics

• Conventional meta-analysis.– Random effect model– Software: STATA 11.0 SE.

• Network meta-analsis– Winbugs for multiple treatment comparison

RESULTS

PubMed till2011.12.31

Age (15)CKD (26)

Contrast Study (20)Diretics (4)

Dose Study (4)Hydrationa Scheme (16)

Incomplete (1)Ionic Contrast (11)

Not Human Study (13)Not RCT (87)

Other Medications (23)Endpoint Other Than CAN (285)

Seconary Analyses (3)Transplantation (8)

Treatment Arms (8)Citations 80

Identification of Treatment arms.Treatment ArmPlacebo

Low Dose IV ACT (>1000mg/single dose)

High Dose IV ACT (>1000mg/single dose)

Low Dose Oral ACT (>1000mg/single dose)

High Dose Oral ACT (>1000mg/single dose)

Statin

NaHCO3

Theophyllin

Felodopam

Results: to be presented on word doc.

NOTE: Weights are from random effects analysis

Overall (I-squared = 64.3%, p = 0.001)

Briguori (2002)

Shyu (2002)

Buyukhatipoglu (2010)

Vallero (2002)

ID

Marenzi (2006)

Allaqaband (2002)

Carbonell (2010)

Poletti (2007)

Study

Kotlyar (2005)

Carbonell (2007)

Boccalandro (2003)

Kay (2003)

Webb (2004)

0.58 (0.35, 0.98)

0.57 (0.20, 1.63)

0.11 (0.02, 0.49)

1.00 (0.06, 16.76)

20.20 (1.13, 360.28)

OR (95% CI)

0.36 (0.19, 0.68)

1.23 (0.39, 3.89)

0.17 (0.04, 0.85)

0.18 (0.04, 0.89)

(Excluded)

1.02 (0.42, 2.47)

1.01 (0.41, 2.49)

0.29 (0.09, 0.94)

1.15 (0.75, 1.76)

100.00

9.50

6.68

2.81

2.71

Weight

12.60

8.82

6.36

6.33

%

0.00

10.78

10.58

8.74

14.08

0.58 (0.35, 0.98)

0.57 (0.20, 1.63)

0.11 (0.02, 0.49)

1.00 (0.06, 16.76)

20.20 (1.13, 360.28)

OR (95% CI)

0.36 (0.19, 0.68)

1.23 (0.39, 3.89)

0.17 (0.04, 0.85)

0.18 (0.04, 0.89)

(Excluded)

1.02 (0.42, 2.47)

1.01 (0.41, 2.49)

0.29 (0.09, 0.94)

1.15 (0.75, 1.76)

100.00

9.50

6.68

2.81

2.71

Weight

12.60

8.82

6.36

6.33

%

0.00

10.78

10.58

8.74

14.08

1.1 1 10

Conventional Meta-analysisLow IV ACT vs. placebo

OR = 0.58 (0.36 – 0.98)I2= 64%



Burns (2010)

Marenzi (2006)

Study

Baker (2003)

Thiele (2010)

Rashid (2004)

Kefer (2003)

ID

0.42 (0.23, 0.77)

0.30 (0.03, 3.15)

0.19 (0.09, 0.40)

0.20 (0.04, 1.00)

0.67 (0.34, 1.30)

0.75 (0.33, 1.72)

0.63 (0.10, 3.92)

OR (95% CI)

100.00

5.65

24.99

%

10.33

27.35

23.12

8.55

Weight

0.42 (0.23, 0.77)

0.30 (0.03, 3.15)

0.19 (0.09, 0.40)

0.20 (0.04, 1.00)

0.67 (0.34, 1.30)

0.75 (0.33, 1.72)

0.63 (0.10, 3.92)

OR (95% CI)

100.00

5.65

24.99

%

10.33

27.35

23.12

8.55

Weight

1.1 1 10

Conventional Meta-analysisHigh IV ACT vs. placebo

OR = 0.42 (95%CI: 0.23-0.77)I2= 53%



Castini (2010)

Shyu (2002)

Goldenberg (2004)

Kim (2010)

Gulel (2005)

Coyle (2006)

Kinbara (2010)

Kay (2003)

Vallero (2002)

Efrati (2003)ACTInvestigators (2011)

Boccalandro (2003)

ID

Moore (2006)

Lawlor (2007)

Reinecke (2007)

Tepel (2000)

Study

Allaqaband (2002)

Gomes (2005)

Ozcan (2007)

Diaz-Sandoval (2002)

Kimmel (2008)

Fung (2004)Miner (2004)

ElMahmoud (2003)MacNeill (2003)

Baskurt (2009)

Awal (2011)

Seyon (2007)

Amini (2009)

Sandhu (2006)

Ferrario (2009)

Tanaka (2011)

Briguori (2002)

Azmus (2005)

0.77 (0.57, 1.02)

1.29 (0.44, 3.76)

0.11 (0.02, 0.49)

1.30 (0.27, 6.21)

0.44 (0.11, 1.76)

0.64 (0.10, 4.19)

6.58 (0.77, 56.20)

0.42 (0.06, 2.77)

0.29 (0.09, 0.94)

20.20 (1.13, 360.28)

(Excluded)1.08 (0.84, 1.38)

1.01 (0.41, 2.49)

OR (95% CI)

7.82 (0.35, 174.42)

1.00 (0.13, 7.72)

0.47 (0.14, 1.61)

0.09 (0.01, 0.76)

1.23 (0.39, 3.89)

1.01 (0.36, 2.85)

0.90 (0.38, 2.18)

0.23 (0.05, 1.08)

0.42 (0.03, 5.06)

1.41 (0.44, 4.44)0.36 (0.15, 0.86)

1.53 (0.25, 9.48)0.11 (0.01, 0.97)

1.42 (0.43, 4.70)

0.07 (0.00, 1.24)

0.18 (0.01, 4.01)

0.75 (0.21, 2.67)

7.42 (0.37, 147.18)

1.39 (0.46, 4.17)

0.37 (0.07, 2.02)

0.57 (0.20, 1.63)

1.27 (0.61, 2.65)

100.00

4.18

2.62

2.52

3.00

1.89

1.52

1.89

3.77

0.90

0.009.39

5.01

Weight

0.79

1.65

3.55

1.55

%

3.82

4.36

5.19

2.52

1.17

3.845.31

1.981.45

3.66

0.89

0.79

3.39

0.84

4.07

2.20

4.25

6.05

0.77 (0.57, 1.02)

1.29 (0.44, 3.76)

0.11 (0.02, 0.49)

1.30 (0.27, 6.21)

0.44 (0.11, 1.76)

0.64 (0.10, 4.19)

6.58 (0.77, 56.20)

0.42 (0.06, 2.77)

0.29 (0.09, 0.94)

20.20 (1.13, 360.28)

(Excluded)1.08 (0.84, 1.38)

1.01 (0.41, 2.49)

OR (95% CI)

7.82 (0.35, 174.42)

1.00 (0.13, 7.72)

0.47 (0.14, 1.61)

0.09 (0.01, 0.76)

1.23 (0.39, 3.89)

1.01 (0.36, 2.85)

0.90 (0.38, 2.18)

0.23 (0.05, 1.08)

0.42 (0.03, 5.06)

1.41 (0.44, 4.44)0.36 (0.15, 0.86)

1.53 (0.25, 9.48)0.11 (0.01, 0.97)

1.42 (0.43, 4.70)

0.07 (0.00, 1.24)

0.18 (0.01, 4.01)

0.75 (0.21, 2.67)

7.42 (0.37, 147.18)

1.39 (0.46, 4.17)

0.37 (0.07, 2.02)

0.57 (0.20, 1.63)

1.27 (0.61, 2.65)

100.00

4.18

2.62

2.52

3.00

1.89

1.52

1.89

3.77

0.90

0.009.39

5.01

Weight

0.79

1.65

3.55

1.55

%

3.82

4.36

5.19

2.52

1.17

3.845.31

1.981.45

3.66

0.89

0.79

3.39

0.84

4.07

2.20

4.25

6.05

1.1 1 10

Conventional Meta-analysisLow oral ACT vs. placebo

OR = 0.77 (95%CI: 0.57 – 1.02)I2= 40%



Balderramo (2004)

Sar (2010)

ID

Study

Oldemeyer (2003)

Durham (2002)

Ochoa (2004)

0.67 (0.30, 1.49)

0.41 (0.03, 4.73)

0.15 (0.01, 3.13)

OR (95% CI)

1.30 (0.28, 6.16)

1.27 (0.45, 3.57)

0.27 (0.07, 1.07)

100.00

9.50

6.51

Weight

%

20.86

37.61

25.52

0.67 (0.30, 1.49)

0.41 (0.03, 4.73)

0.15 (0.01, 3.13)

OR (95% CI)

1.30 (0.28, 6.16)

1.27 (0.45, 3.57)

0.27 (0.07, 1.07)

100.00

9.50

6.51

Weight

%

20.86

37.61

25.52

1.1 1 10

Conventional Meta-analysisHigh oral ACT vs. placebo

OR = 0.67 (95%CI: 0.3 – 1.49)I2= 18%

Conventional Meta-analysisStatin vs. placebo

OR = 0.55 (95%CI: 0.3 – 0.95)I2= 0.9%



Patti (2011)

Ozhan (2010)

ID

Toso (2010)

Jo (2008)

Study

0.55 (0.31, 0.97)

0.35 (0.13, 0.92)

0.26 (0.05, 1.32)

OR (95% CI)

0.90 (0.37, 2.19)

0.74 (0.16, 3.40)

100.00

33.45

12.40

Weight

40.26

13.89

%

0.55 (0.31, 0.97)

0.35 (0.13, 0.92)

0.26 (0.05, 1.32)

OR (95% CI)

0.90 (0.37, 2.19)

0.74 (0.16, 3.40)

100.00

33.45

12.40

Weight

40.26

13.89

%

1.1 1 10



Castini (2010)

Merten (2004)

Masuda (2007)

Briguori (2007)

Adolph (2008)

Pakfetrat (2009)

Tamura (2009)

Lee (2011)

Vasheghani-Farahani (2010)

Motohiro (2011)

Vasheghani-Farahani (2009)

Maioli (2008)

Ozcan (2007)

Brar (2008)

Ueda (2011)

ID

Study

0.50 (0.31, 0.80)

0.98 (0.32, 3.02)

0.11 (0.01, 0.89)

0.14 (0.03, 0.69)

0.17 (0.04, 0.79)

1.59 (0.26, 9.80)

0.22 (0.07, 0.68)

0.10 (0.01, 0.80)

1.76 (0.78, 3.95)

1.00 (0.13, 7.51)

0.18 (0.04, 0.83)

1.26 (0.45, 3.48)

0.85 (0.48, 1.50)

0.30 (0.09, 0.97)

0.83 (0.47, 1.47)

0.19 (0.04, 0.98)

OR (95% CI)

100.00

7.62

3.65

5.19

5.58

4.50

7.56

3.70

9.63

3.90

5.49

8.27

11.24

7.35

11.21

5.10

Weight

%

0.50 (0.31, 0.80)

0.98 (0.32, 3.02)

0.11 (0.01, 0.89)

0.14 (0.03, 0.69)

0.17 (0.04, 0.79)

1.59 (0.26, 9.80)

0.22 (0.07, 0.68)

0.10 (0.01, 0.80)

1.76 (0.78, 3.95)

1.00 (0.13, 7.51)

0.18 (0.04, 0.83)

1.26 (0.45, 3.48)

0.85 (0.48, 1.50)

0.30 (0.09, 0.97)

0.83 (0.47, 1.47)

0.19 (0.04, 0.98)

OR (95% CI)

100.00

7.62

3.65

5.19

5.58

4.50

7.56

3.70

9.63

3.90

5.49

8.27

11.24

7.35

11.21

5.10

Weight

%

1.1 1 10

Conventional Meta-analysisNaHCO3 vs. placebo

OR = 0.5 (95%CI: 0.3 1– 0.80)I2= 58%%

Conventional Meta-analysisTheophylline vs. placebo

OR = 1.07 (95%CI: 0.43 – 1.82)I2= 59%



Dussol (2006)

Erley (1999)

ID

Huber (2003)

Lee (2011)

Matejka (2010)

Huber (2002)

Abizaid (1999)

Study

1.07 (0.43, 2.62)

3.27 (1.01, 10.63)

1.70 (0.15, 19.72)

OR (95% CI)

0.17 (0.03, 0.81)

1.76 (0.78, 3.95)

6.26 (0.31, 127.19)

0.22 (0.04, 1.09)

1.26 (0.33, 4.73)

100.00

17.91

8.85

Weight

14.43

21.40

6.64

14.20

16.56

%

1.07 (0.43, 2.62)

3.27 (1.01, 10.63)

1.70 (0.15, 19.72)

OR (95% CI)

0.17 (0.03, 0.81)

1.76 (0.78, 3.95)

6.26 (0.31, 127.19)

0.22 (0.04, 1.09)

1.26 (0.33, 4.73)

100.00

17.91

8.85

Weight

14.43

21.40

6.64

14.20

16.56

%

1.1 1 10



ID

Stone (2003)

Lee (2011)

Study

Tumlin (2002)

1.11 (0.60, 2.06)

OR (95% CI)

1.17 (0.71, 1.93)

1.76 (0.78, 3.95)

0.40 (0.11, 1.48)

100.00

Weight

50.08

32.72

%

17.21

1.11 (0.60, 2.06)

OR (95% CI)

1.17 (0.71, 1.93)

1.76 (0.78, 3.95)

0.40 (0.11, 1.48)

100.00

Weight

50.08

32.72

%

17.21

1.1 1 10

Conventional Meta-analysisFelodopam vs. placebo

OR = 1.11 (95%CI: 0.61– 2.00)I2= 43.8%

Network Approach

Summary of Effects.

　　 OR( 　 95% CrI 　 ) RankPlacebo Referent 8ACT IV Low 0.54 ( 0.25 - 1.15 ) 5ACT IV high 0.40 ( 0.18 - 0.87 )* 1ACT Oral Low 0.72 ( 0.51 - 1.02 ) 6ACT Oral high 0.45 ( 0.19 - 1.07 ) 2Statin 0.50 ( 0.18 - 1.31 ) 4NaHCO3 0.46 ( 0.28 - 0.73 )* 3Theophyllin 0.96 ( 0.39 - 2.37 ) 7Felodopam 1.06 ( 0.41 - 2.70 ) 9

Conclusion

• For 8 arms of methods to prevent CI-AKI,– High dose IV ACT– High dose oral ACT– Statin– NaHCO3

Were superior to placebo in meta-analyses• Among treatments,

– High Dose IV ACT and NaHCO3 were significantly superior to other treatments.

Network meta-analyses

• A well established method for systemic review.

Lancet. 2012 Mar 22. [Epub ahead of print]

THANKS FOR YOUR ATTENTION.

Documents

Network Meta-analyses a novel way for synthetic reviews. 黃道民