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The Choice

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- atrial fibrillation patients increased risk of stroke
- can reduce with warfarin, but increased bleeding risk

- without treatment 100 patients will suffer:
- 12 strokes (6 major, six minor), 3 serious gi bleeds in 1 year

- warfarin would increase bleeds in 100 patients to 5 per year (2 additional bleeds)
- how many strokes must we prevent to make it worth taking warfarin with increased risk of bleeding?

PHYSICIAN AND PATIENT STROKE THRESHOLDS

FOR WARFARIN

- Baseline risk of 12 strokes and 3 major bleeds in 100 patients over 2 years
- Given warfarin would increase the risk of major bleeds to 5 in 100 patients, we then determined the minimum number of strokes that needed to be prevented for a participant to feel warfarin was justified

- without treatment 100 patients will suffer:
- 12 strokes (six major, six minor), 3 serious gi bleeds in 1 year

- warfarin would decrease strokes in 100 patients to 4 per year (8 fewer strokes, 4 major, minor)
- how many bleeds would you accept in 100 patients over a year, and still be willing to administer/take warfarin?

- Baseline risk of 12 strokes and 3 major bleeds in 100 patients over 2 years
- Given warfarin would decrease the risk of stroke to 4 in 100 patients, we then determined the maximum number of excess bleeds that participants were willing to accept

- every intervention has benefits, risks, inconvenience, costs
- decision a trade-off
- values and preferences differ
- Cochrane reviews particularly vulnerable because world-wide
- Cochrane reviews shouldn’t make recommendations

- should Cochrane reviews structure discussion?
- highlight tradeoffs and potential impact of values
- highlight implementation, applicability issues

- guideline developers using Cochrane reviews
- should they grade recommendations?
- should they use a uniform system (and if so, what should it look like)

- Common, serious morbidity
- vertebral and non-vertebral fractures

- Many agents available
- what should we offer women

- Evidence versus recommendations

Relative Risk with 95%CI of Vertebral Fracture After

Treatment with Calcium

Favours Calcium Favours Control

Prevention Trials

&

Chevalley 0.45 (0.11 to 1.88)

(n = 45)

&

Recker (w/fractures) 0.58 (0.35 to 0.97)

(n = 92)

&

(n = 99)

Recker (w/o fractures) 1.36 (0.70 to 2.62)

&

(n = 122)

Reid 0.45 (0.11 to 1.94)

&

(n = 177)

Riggs 0.90 (0.38 to 2.18)

&

Hansson 0.87 ( 0.10 to 7.71)

(n = 41)

&

Pooled Estimate 0.77 (0.54 to 1.09)

(n = 576)

0

0.5

1

1.5

2

2.5

3

Relative Risk, 95% CI

Relative Risk with 95% CI of Non-Vertebral Fracture after

Treatment with Calcium

Favours Calcium Favours Control

Prevention Trials

'

Chevally 0.48 ( 0.07 to 3.38)

(n = 45)

'

(n = 177)

Riggs 0.93 ( 0.44 to 1.96)

'

(n = 222)

Pooled Estimate 0.86 (0.43 to 1.72)

0

0.5

1

1.5

2

2.5

3

3.5

Relative Risk, 95% CI

Relative Risk with 95% CI for Vertebral Fractures

after Treatment with Vitamin D

Favours Vitamin D Favours Control

Standard Vitamin D (IU)

'

Baeksgaard(1998) 0.33(0.01 to 8.06)

(N =160)

Hydroxylated Vitamin D (ug)

'

Gallagher (1990) 0.90 (0.42 to 1.89)

(N =50)

'

Orimo (1994) 0.37 (0.09 to 1.44)

(N = 80)

'

Ott (1989) 1.46 ( 0.59 to 3.62)

(N = 86)

'

Tilyard (1992) 0.43 ( 0.31 to 0.61)

(N = 622)

'

(N =32)

Guesens (1986) 0.88 (0.43 to 1.80)

'

Orimo (1987) 0.46 (0.31 to 0.69)

(N = 86)

(N = 14)

'

Caniggia (1984) 0.20 (0.01 to 3.54)

Pooled Hydroxylated Vitamin D Estimate

'

0.61 ( 0.42 to 0.87)

(N = 970)

'

Pooled Estimate 0.60 (0.42 to 0.84)

(N =1130)

0

0.5

1

1.5

2

2.5

Relative Risk with 95% CI for Non-Vertebral Fractures

after Treatment with Vitamin D

Favours Vitamin D Favours Control

Standard Vitamin D (IU)

'

(N =3270)

Chapuy (1992) 0.75 ( 0.61 to 0.91)

'

Lips (1996) 1.04 (0.77 to 1.41)

(N =1916)

'

Dawson-Hughes* (1997) 0.45 (0.22 to 0.91)

(N =213)

Pooled Standard Vitamin D Estimate

'

(N = 5399)

0.78 (0.55 TO 1.09)

Hydroxylated Vitamin D (ug)

'

Ott (1989) 2.20 ( 0.52 to 9.24)

(N = 86)

'

Tilyard (1992) 0.50 ( 0.25 to 1.00)

(N =622)

'

Orimo (1994) 1.10 (0.02 to 2.0)

(N = 80)

Pooled Hydroxylated Vitamin D Estimate

'

0.87 (0.29 to 2.59)

(N =788)

'

(N = 6187)

Pooled Estimate 0.77 (0.57 to 1.04)

0

0.5

1

1.5

2

2.5

3

3.5

* Prevention Trial

RR of Vertebral Fracture after Treatment with HRT

Favours HRT Favours Control

'

(N = 75)

Lufkin 1992 0.63 (0.28, 1.43)

'

(N = 193)

Greenspan 1998 (0.70 (0.06, 7.55)

'

(N = 32)

Wilalawansa 1998 0.40 (0.09, 1.77)

'

(N = 2763)

Hulley 1998 0.74 (0.37, 1.47)

'

(N = 52)

Alexandersen 1999 2.78 ( 0.12, 65.09)

'

(N = 16608)

WHI 2002 0.65 (0.44, 0.97)

'

(N = 19723)

Pooled Estimate 0.66 (0.49, 0.90)

0.01

0.1

1

10

100

Relative Risk (95% CI)

RR of Non-Vertebral Fracture after Treatment with HRT

Favours HRT Favours Control

'

(N =193)

Greenspan 1998 (0.70 (0.22, 2.22)

'

(N =232)

Komulainen 1997 0.40 (0.16, 0.99)

'

(N =36)

Wilalawansa 1998 1.00 (0.07, 14.79)

'

(N =2763)

Hulley 1998 0.90 (0.69, 1.19)

'

(N =612)

Hosking 1998 0.98 ( 0.29, 3.34))

'

(N =50)

Alexandersen 1999 0.31 ( 0.03, 2.76)

'

(N =16608)

WHI 2002 0.68 ( 0.46, 0.99)

'

(N =20494)

Pooled Estimate 0.78 (0.64, 0.96)

0.01

0.1

1

10

100

Relative Risk (95% CI)

Relative Risk with 95% CI for Vertebral & Non-Vertebral

Fractures After Treatment with Raloxifene

Favours Raloxifene Favours Control

Vertebral Fractures

'

(N = 7705)

Ettinger 0.59 (0.50 to 0.70)

'

Lufkin 1.15 (0.75 to 1.75)

( N = 143)

Pooled Vertebral Fracture Estimate

'

0.64 ( 0.55 to 0.75)

(N = 7848)

Non-Vertebral Fractures

'

( N = 7705)

Ettinger 0.91 (0.79 to 1.06)

'

(N= 143)

Lufkin 0.51 ( 0.12 to 2.16)

Pooled Non Vertebral Fracture Estimate

'

0.91 ( 0.78 to 1.06)

(N = 7848)

Fixed Effects Model

0.1

1

10

* All Trials Secondary Treatment

Vertebral fracture results from Lufkin trial based on 15% cutoff in reduction of vertebrae

( baseline to 1 year)

Weighted Relative Risk for Vertebral Fractures after

Treatment with Etidronate

Favours Etidronate

Favours Control

Prevention Trials

&

(N = 209 )

Watts 0.52 (0.19 to 1.40)

&

(N =214)

Watts* 0.47 (0.14 to 1.61)

&

(N = 738)

Pooled Prevention Estimate 0.62 (0.30 to 1.27)

Treatment Trials

&

Montessori 0.14 (0.01 to 2.67)

(N = 80)

&

(N = 57)

Pacifici 1.10 (0.35 to 3.44)

&

(N = 66)

Storm 0.64 (0.35 to 1.17)

&

Wimalawansa 1998 0.67 (0.21 to 2.18)

(N = 35)

&

Lyritis 0.47 ( 0.17 to 1.36)

(N = 100)

&

(N = 338)

Pooled Treatment Estimate 0.68 (0.42 to 1.10)

&

Pooled Estimate 0.63 ( 0.44 to 0.99)

(N = 1076)

0.001

0.01

0.1

1

10

Relative Risk, 95% CI

Osteoporotic and Non-Osteoporotic Populations

(Primary Prevention Trials: Herd, Meunier, and Pouilles [n = 315] not included due to low incidence of

fractures)

* Treatment and Control Groups Received Phosphate

Weighted Relative Risk for Non-Vertebral Fractures

after Treatment with Etidronate

Favours Etidronate

Favours Control

Prevention Trials

&

(N = 209)

Watts 1.23 (0.68 to 2.22)

&

Watts** 1.16 (0.57 to 2.35)

(N = 214 )

&

Meunier 0.71 (0.15 to 3.32)

(N = 54 )

&

(N = 109 )

Pouilles 0.55 (0.16 to 1.9)

&

(N = 586 )

Pooled Prevention Trial Estimate: 1.06 (0.71 to 1.60)

Treatment Trials

&

(N = 66 )

Storm 0.85 (0.31 to 2.37)

(N = 35 )

&

Wimalawansa 1998 1.06 (0.12 to 9.24)

&

Lyritis 0.64 (0.18 to 2.30)

(N = 100)

&

Pooled Treatment Trial Estimate: 0.79 (0.38 to 1.67)

(N = 281)

&

Pooled Estimate 0.99 (0.69 to 1.42)

(N = 867)

0.1

1

10

Relative Risk, 95% CI

Osteoporotic and Non-Osteoporotic Populations

* Montessori Trial (N=80) not included in figure due to zero Non-Vertebral

Fractures occuring.

** Treatment and Control Groups Received phosphate

Relative Risk with 95% CI for Vertebral Fractures for Doses

of 5mg or Greater of Alendronate

Favours Alendronate Favours Control

Prevention Trials

'

McClung 0.34 (0.04 to 3.25)

(n = 355)

'

(n = 1355)

Pooled Prevention Estimate 0.45(0.06 to 3.15)

Treatment Trials

'

(n = 184)

Bone 0.68 ( 0.21 to 2.18)

'

(n = 157)

Chesnut 0.25 (0.03 to 2.34)

'

Liberman (USA) 0.52 ( 0.24 to 1.15)

(n = 478)

'

(n = 516)

Liberman (Int) 0.52 ( 0.20 to 1.34)

'

Black 0.53 (0.41 to 0.69)

(n = 2027)

'

Cummings 0.51 ( 0.31 to 0.84)

(n = 4432 )

'

Pooled Treatment Estimate 0.53 (0.43 to 0.65)

(n = 8005 )

'

(n = 9360)

Pooled Estimate 0.52 (0.43 to 0.65)

0.01

0.1

1

10

Adami and Hoskings trials not included in figure due to low vertebral fracture incidence.

Risk Ratios and Summary Estimates with 95% CI for

Non-Vertebral Fractures for Dose of 10mg or Greater of

Alendronate

Favours Alendronate Favours Control

Prevention Trials

'

(n =267)

McClung 0.79 (0.28 to 2.24)

Treatment Trials

'

(n = 211)

Adami 0.36 (0.07 to 1.80)

'

(n = 125)

Chesnut 0.43 (0.11 to 1.65)

'

(n = 380)

Liberman (USA) 0.55 (0.31 to 0.97)

'

(n =412)

Liberman (Int) 0.65 (0.32 to 1.34)

'

(n = 1908)

Pols 0.47 (0.26 to 0.83)

'

(n =419)

Rosen 0.35 (0.15 to 0.77)

'

(n = 3455)

Pooled Treatment Estimate 0.49 (0.36 to 0.67)

(n = 3722)

'

Pooled Estimate 0.51 (0.38 to 0.69)

0.01

0.1

1

10

Relative Risk with 95% CI for Non-Vertebral Fractures

after Treatment with Risedronate

(Final Year, All Doses)

Favours Risedronate Favours Control

Prevention Trials

'

Mortensen (1998) 0.49 (0.12 to 2.03)

(N = 111)

TreatmentTrials

'

Harris (1999) 0.64 (0.42 to 0.98)

(N = 1627 )

'

Clemensen (1997) 0.70 (0.45 to 1.09)

(N =132)

'

(N = 648)

McClung (Abstract) 0.71 (0.36 to 1.40)

'

Reginster (2000) 0.71 (0.47 to 1.06)

(N =812)

'

(N =3219 )

Pooled Treatment Estimate 0.69 (0.55 to 0.86)

'

Pooled Estimate 0.68 (0.54 to 0.85)

(N =3330 )

0

0.5

1

1.5

2

2.5

Relative Risk with 95% CI for Vertebral Fractures

after Treatment with Risedronate

(Final Year, All Doses)

Favours Risedronate Favours Control

Prevention Trials

'

(N = 111)

Mortensen (1998) 2.44 (0.12 to 49.43)

Treatment Trials

'

(N = 1278)

Harris 1- year (1999) 0.59 (0.36 to 0.97)

'

Harris - 3 year (1999) 0.64 (0.47 to 0.87)

(N =1374)

'

(N = 132)

Clemensen (1997) 1.52 (0.56 to 4.15)

'

(N = 541)

Fogelman (Abstract) 0.72 (0.45 to1.15)

'

Reginster 1 - year (2000) 0.55 (0.34 to 0.87)

(N = 663)

'

Reginster 3 - year (2000) 0.60 (0.44 to 0.81)

(N = 690)

'

Pooled Treatment Estimate 0.63 (0.54 to 0.75)

(N = 4687)

'

Pooled Estimate 0.64 (0.54 to 0.85)

(N =4789)

0.1

1

10

- Baseline risk of fracture from alendronate RCTs over 2 year period
- non-osteoporoticNNTs
- vertebral 0.12%1,790
- non-vertebral 2.54% 80

- osteoporotic
- vertebral 2.88% 72
- non-vertebral 6.85% 24

- Drugs that reduce vertebral fractures
- vitamin D, HRT, raloxifene, risedronate, alendronate

- Drugs that reduce non-vertebral fractures
- risedronate (1/3 RRR), alendronate (1/2 RRR)

- high value: reducing fractures, no uncertainty
- choose alendronate

- high value: reducing fractures, no inconvenience
- alendronate upright 30 minutes before meal
- choose residronate

- high value on “natural” treatment, low cost
- calcium and vitamin D

- high value on fracture reduction – early treatment
- high value living without medication – late treatment

- methodologic strength
- High (RCT), intermediate (quasi-RCTs), low (observational), insufficient (other)
- implementation, consistency, directness

- decision
- do it, don’t do, toss-up

- strength of decision
- strong (across range of values, most would choose
- weak (different choices across range of values)