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The Choice

- 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

Physician and patient mean stroke threshold 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

The Choice

- 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?

Physician and patient mean bleeding threshold for 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

Values and Preferences

- 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

Issues for this Workshop

- 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)

Osteoporosis

- 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

Early treatment may be appropriate

- Baseline risk of fracture from alendronate RCTs over 2 year period
- non-osteoporotic NNTs
- vertebral 0.12% 1,790
- non-vertebral 2.54% 80
- osteoporotic
- vertebral 2.88% 72
- non-vertebral 6.85% 24

Benefits

- 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)

Values and Preferences

- 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

Grading Recommendations

- 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)

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