the choice atrial fibrillation patients increased risk of strokeatrial fibrillation patients...
TRANSCRIPT
The ChoiceThe Choice• atrial fibrillation patients increased risk of strokeatrial fibrillation patients increased risk of stroke
– can reduce with warfarin, but increased bleeding riskcan reduce with warfarin, but increased bleeding risk
• without treatment 100 patients will suffer:without treatment 100 patients will suffer:– 12 strokes (6 major, six minor), 3 serious gi bleeds in 1 year12 strokes (6 major, six minor), 3 serious gi bleeds in 1 year
• warfarin would increase bleeds in 100 patients to 5 per warfarin would increase bleeds in 100 patients to 5 per year (2 additional bleeds)year (2 additional bleeds)
• how many strokes must we prevent to make it worth taking how many strokes must we prevent to make it worth taking warfarin with increased risk of bleeding?warfarin with increased risk of bleeding?
0
5
10
15
20
25
30
35
40
45
50
1 2 3 4 5 6 7 8 9 10 11
MINIMUM NUMBER OF STROKES PREVENTED
NU
MB
ER O
F PA
TIEN
TS/P
HYS
ICIA
NS
Physicians N=63
Patients N=61
PHYSICIAN AND PATIENT STROKE THRESHOLDS
FOR WARFARIN
Physician and patient mean Physician and patient mean stroke threshold for warfarinstroke threshold for warfarin
• Baseline risk of 12 strokes and 3 major bleeds in 100 Baseline risk of 12 strokes and 3 major bleeds in 100 patients over 2 yearspatients over 2 years
• Given warfarin would increase the risk of major bleeds to Given warfarin would increase the risk of major bleeds to 5 in 100 patients, we then determined the minimum 5 in 100 patients, we then determined the minimum number of strokes that needed to be prevented for a number of strokes that needed to be prevented for a participant to feel warfarin was justifiedparticipant to feel warfarin was justified
Physician meanthreshold
Patient meanthreshold
P value
Minimum strokereductionnecessary
2.5 1.8 <0.001
The ChoiceThe Choice
• without treatment 100 patients will suffer:without treatment 100 patients will suffer:– 12 strokes (six major, six minor), 3 serious gi bleeds in 1 12 strokes (six major, six minor), 3 serious gi bleeds in 1
yearyear
• warfarin would decrease strokes in 100 patients to 4 warfarin would decrease strokes in 100 patients to 4 per year (8 fewer strokes, 4 major, minor)per year (8 fewer strokes, 4 major, minor)
• how many bleeds would you accept in 100 patients how many bleeds would you accept in 100 patients over a year, and still be willing to administer/take over a year, and still be willing to administer/take warfarin?warfarin?
0
5
10
15
20
25
30
35
40
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22
MAXIMUM NUMBER OF ACCEPTABLE EXCESS BLEEDS
NU
MB
ER
OF
PH
YS
ICIA
NS
/PA
TIE
NT
S
Physicians N=63
Patients N=61
PHYSICIAN AND PATIENT BLEEDING THRESHOLDS FOR WARFARIN
Physician and patient mean Physician and patient mean bleeding threshold for warfarinbleeding threshold for warfarin
• Baseline risk of 12 strokes and 3 major bleeds in 100 Baseline risk of 12 strokes and 3 major bleeds in 100 patients over 2 yearspatients over 2 years
• Given warfarin would decrease the risk of stroke to 4 in Given warfarin would decrease the risk of stroke to 4 in 100 patients, we then determined the maximum number of 100 patients, we then determined the maximum number of excess bleeds that participants were willing to acceptexcess bleeds that participants were willing to accept
Physician meanthreshold
Patient meanthreshold
P value
Maximumincrease in
bleeding riskacceptable
10.3 17.4 <0.001
Values and PreferencesValues and Preferences
• every intervention has benefits, risks, inconvenience, costsevery intervention has benefits, risks, inconvenience, costs
• decision a trade-offdecision a trade-off
• values and preferences differvalues and preferences differ
• Cochrane reviews particularly vulnerable because world-Cochrane reviews particularly vulnerable because world-widewide
• Cochrane reviews shouldn’t make recommendationsCochrane reviews shouldn’t make recommendations
Issues for this WorkshopIssues for this Workshop
• should Cochrane reviews structure should Cochrane reviews structure discussion?discussion?– highlight tradeoffs and potential impact of valueshighlight tradeoffs and potential impact of values– highlight implementation, applicability issueshighlight implementation, applicability issues
• guideline developers using Cochrane reviewsguideline developers using Cochrane reviews– should they grade recommendations?should they grade recommendations?– should they use a uniform system (and if so, what should they use a uniform system (and if so, what
should it look like)should it look like)
OsteoporosisOsteoporosis
• Common, serious morbidityCommon, serious morbidity– vertebral and non-vertebral fracturesvertebral and non-vertebral fractures
• Many agents availableMany agents available– what should we offer womenwhat should we offer women
• Evidence versus recommendationsEvidence versus recommendations
Relative Risk with 95%CI of Vertebral Fracture After Treatment with Calcium
Favours Calcium Favours Control
Chevalley 0.45 (0.11 to 1.88)
Recker (w/fractures) 0.58 (0.35 to 0.97)
Recker (w/o fractures) 1.36 (0.70 to 2.62)
Reid 0.45 (0.11 to 1.94)
Riggs 0.90 (0.38 to 2.18)
Hansson 0.87 ( 0.10 to 7.71)
Pooled Estimate 0.77 (0.54 to 1.09)
0 0.5 1 1.5 2 2.5 3
Relative Risk, 95% CI
Prevention Trials
(n = 45)
(n = 92)
(n = 99)
(n = 122)
(n = 177)
(n = 41)
(n = 576)
Relative Risk with 95% CI of Non-Vertebral Fracture after Treatment with Calcium
Favours Calcium Favours Control
Chevally 0.48 ( 0.07 to 3.38)
Riggs 0.93 ( 0.44 to 1.96)
Pooled Estimate 0.86 (0.43 to 1.72)
0 0.5 1 1.5 2 2.5 3 3.5
Prevention Trials
Relative Risk, 95% CI
(n = 45)
(n = 177)
(n = 222)
Relative Risk with 95% CI for Vertebral Fractures after Treatment with Vitamin D
Favours Vitamin D Favours Control
Baeksgaard(1998) 0.33(0.01 to 8.06)
Gallagher (1990) 0.90 (0.42 to 1.89)Orimo (1994) 0.37 (0.09 to 1.44)
Ott (1989) 1.46 ( 0.59 to 3.62)Tilyard (1992) 0.43 ( 0.31 to 0.61)
Guesens (1986) 0.88 (0.43 to 1.80)Orimo (1987) 0.46 (0.31 to 0.69)
Caniggia (1984) 0.20 (0.01 to 3.54)
Pooled Hydroxylated Vitamin D Estimate 0.61 ( 0.42 to 0.87)
Pooled Estimate 0.60 (0.42 to 0.84)
0 0.5 1 1.5 2 2.5
Standard Vitamin D (IU)
Hydroxylated Vitamin D (ug)
(N =160)
(N =50)
(N = 80)
(N = 86)
(N = 622)(N =32)
(N = 86) (N = 14)
(N = 970)
(N =1130)
Relative Risk with 95% CI for Non-Vertebral Fractures after Treatment with Vitamin D
Chapuy (1992) 0.75 ( 0.61 to 0.91)Lips (1996) 1.04 (0.77 to 1.41)
Dawson-Hughes* (1997) 0.45 (0.22 to 0.91)
Pooled Standard Vitamin D Estimate 0.78 (0.55 TO 1.09)
Ott (1989) 2.20 ( 0.52 to 9.24)Tilyard (1992) 0.50 ( 0.25 to 1.00)Orimo (1994) 1.10 (0.02 to 2.0)
Pooled Hydroxylated Vitamin D Estimate 0.87 (0.29 to 2.59)
Pooled Estimate 0.77 (0.57 to 1.04)
0 0.5 1 1.5 2 2.5 3 3.5
Standard Vitamin D (IU)
Hydroxylated Vitamin D (ug)
* Prevention Trial
Favours Vitamin D Favours Control
(N =3270)
(N =1916)
(N =213)
(N = 5399)
(N = 86)
(N =622)
(N = 80)
(N =788)
(N = 6187)
RR of Vertebral Fracture after Treatment with HRT
Lufkin 1992 0.63 (0.28, 1.43)
Greenspan 1998 (0.70 (0.06, 7.55)
Wilalawansa 1998 0.40 (0.09, 1.77)
Hulley 1998 0.74 (0.37, 1.47)
Alexandersen 1999 2.78 ( 0.12, 65.09)
WHI 2002 0.65 (0.44, 0.97)
Pooled Estimate 0.66 (0.49, 0.90)
0.01 0.1 1 10 100
Relative Risk (95% CI)
Favours HRT Favours Control
(N = 75)
(N = 193)
(N = 32)
(N = 2763)
(N = 52)
(N = 16608)
(N = 19723)
RR of Non-Vertebral Fracture after Treatment with HRT
Greenspan 1998 (0.70 (0.22, 2.22)
Komulainen 1997 0.40 (0.16, 0.99)
Wilalawansa 1998 1.00 (0.07, 14.79)
Hulley 1998 0.90 (0.69, 1.19)
Hosking 1998 0.98 ( 0.29, 3.34))
Alexandersen 1999 0.31 ( 0.03, 2.76)
WHI 2002 0.68 ( 0.46, 0.99)
Pooled Estimate 0.78 (0.64, 0.96)
0.01 0.1 1 10 100
Relative Risk (95% CI)
Favours HRT Favours Control
(N =2763)
(N =193)
(N =612)
(N =36)
(N =232)
(N =50)
(N =16608)
(N =20494)
Relative Risk with 95% CI for Vertebral & Non-Vertebral Fractures After Treatment with Raloxifene
Ettinger 0.59 (0.50 to 0.70)Lufkin 1.15 (0.75 to 1.75)
Pooled Vertebral Fracture Estimate0.64 ( 0.55 to 0.75)
Ettinger 0.91 (0.79 to 1.06)Lufkin 0.51 ( 0.12 to 2.16)
Pooled Non Vertebral Fracture Estimate0.91 ( 0.78 to 1.06)
0.1 1 10* All Trials Secondary Treatment
(N = 7705)
( N = 143)
(N = 7848)
( N = 7705)(N= 143)
(N = 7848)
Vertebral Fractures
Non-Vertebral Fractures
Fixed Effects Model
Vertebral fracture results from Lufkin trial based on 15% cutoff in reduction of vertebrae ( baseline to 1 year)
Favours Raloxifene Favours Control
Weighted Relative Risk for Vertebral Fractures after Treatment with Etidronate
Favours Etidronate Favours Control
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
Watts 0.52 (0.19 to 1.40)
Watts* 0.47 (0.14 to 1.61)
Pooled Prevention Estimate 0.62 (0.30 to 1.27)
Montessori 0.14 (0.01 to 2.67)
Pacifici 1.10 (0.35 to 3.44)
Storm 0.64 (0.35 to 1.17)
Wimalawansa 1998 0.67 (0.21 to 2.18)
Lyritis 0.47 ( 0.17 to 1.36)
Pooled Treatment Estimate 0.68 (0.42 to 1.10)
Pooled Estimate 0.63 ( 0.44 to 0.99)
0.001 0.01 0.1 1 10
Relative Risk, 95% CI
(N = 80)
(N = 57)
(N = 66)
(N = 209 )
(N =214)
(N = 35)
(N = 1076)
Prevention Trials
Treatment Trials
(N = 738)
(N = 338)
(N = 100)
Weighted Relative Risk for Non-Vertebral Fractures after Treatment with Etidronate
Favours Etidronate Favours Control
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
Watts 1.23 (0.68 to 2.22)
Watts** 1.16 (0.57 to 2.35)
Meunier 0.71 (0.15 to 3.32)
Pouilles 0.55 (0.16 to 1.9)
Pooled Prevention Trial Estimate: 1.06 (0.71 to 1.60)
Storm 0.85 (0.31 to 2.37)
Wimalawansa 1998 1.06 (0.12 to 9.24)
Lyritis 0.64 (0.18 to 2.30)
Pooled Treatment Trial Estimate: 0.79 (0.38 to 1.67)
Pooled Estimate 0.99 (0.69 to 1.42)
0.1 1 10
Relative Risk, 95% CI
Prevention Trials
Treatment Trials
(N = 54 )
(N = 109 )
(N = 586 )
(N = 66 )
(N = 209)
(N = 214 )
(N = 35 )
(N = 281)
(N = 867)
(N = 100)
Relative Risk with 95% CI for Vertebral Fractures for Doses of 5mg or Greater of Alendronate
Adami and Hoskings trials not included in figure due to low vertebral fracture incidence.
McClung 0.34 (0.04 to 3.25)
Pooled Prevention Estimate 0.45(0.06 to 3.15)
Bone 0.68 ( 0.21 to 2.18)
Chesnut 0.25 (0.03 to 2.34)
Liberman (USA) 0.52 ( 0.24 to 1.15)
Liberman (Int) 0.52 ( 0.20 to 1.34)
Black 0.53 (0.41 to 0.69)
Cummings 0.51 ( 0.31 to 0.84)
Pooled Treatment Estimate 0.53 (0.43 to 0.65)
Pooled Estimate 0.52 (0.43 to 0.65)
0.01 0.1 1 10
Prevention Trials
Favours Alendronate Favours Control
(n = 355)
(n = 1355)
(n = 184)
(n = 157)
(n = 478)
(n = 516)
(n = 2027)
(n = 4432 )
(n = 8005 )
(n = 9360)
Treatment Trials
Risk Ratios and Summary Estimates with 95% CI for Non-Vertebral Fractures for Dose of 10mg or Greater of
Alendronate
McClung 0.79 (0.28 to 2.24)
Adami 0.36 (0.07 to 1.80)
Chesnut 0.43 (0.11 to 1.65)
Liberman (USA) 0.55 (0.31 to 0.97)
Liberman (Int) 0.65 (0.32 to 1.34)
Pols 0.47 (0.26 to 0.83)
Rosen 0.35 (0.15 to 0.77)
Pooled Treatment Estimate 0.49 (0.36 to 0.67)
Pooled Estimate 0.51 (0.38 to 0.69)
0.01 0.1 1 10
Prevention Trials
Treatment Trials
Favours Alendronate Favours Control
(n =267)
(n = 211)
(n = 125)
(n = 380)
(n =412)
(n = 1908)
(n =419)
(n = 3455)
(n = 3722)
Relative Risk with 95% CI for Non-Vertebral Fractures after Treatment with Risedronate
(Final Year, All Doses)
Mortensen (1998) 0.49 (0.12 to 2.03)
Harris (1999) 0.64 (0.42 to 0.98)
Clemensen (1997) 0.70 (0.45 to 1.09)
McClung (Abstract) 0.71 (0.36 to 1.40)
Reginster (2000) 0.71 (0.47 to 1.06)
Pooled Treatment Estimate 0.69 (0.55 to 0.86)
Pooled Estimate 0.68 (0.54 to 0.85)
0 0.5 1 1.5 2 2.5
Prevention Trials
Treatment Trials
Favours Risedronate Favours Control
(N = 111)
(N = 1627 )
(N =132)
(N = 648)
(N =812)
(N =3219 )
(N =3330 )
Relative Risk with 95% CI for Vertebral Fractures after Treatment with Risedronate
(Final Year, All Doses)
Favours Risedronate Favours Control
Mortensen (1998) 2.44 (0.12 to 49.43)
Harris 1- year (1999) 0.59 (0.36 to 0.97)
Harris - 3 year (1999) 0.64 (0.47 to 0.87)
Clemensen (1997) 1.52 (0.56 to 4.15)
Fogelman (Abstract) 0.72 (0.45 to1.15)
Reginster 1 - year (2000) 0.55 (0.34 to 0.87)
Reginster 3 - year (2000) 0.60 (0.44 to 0.81)
Pooled Treatment Estimate 0.63 (0.54 to 0.75)
Pooled Estimate 0.64 (0.54 to 0.85)
0.1 1 10
Prevention Trials
Treatment Trials
(N = 111)
(N = 1278)
(N =1374)
(N = 132)
(N = 541)
(N = 663)
(N = 690)
(N = 4687)
(N =4789)
Early treatment may be appropriateEarly treatment may be appropriate• Baseline risk of fracture from alendronate RCTs over 2 Baseline risk of fracture from alendronate RCTs over 2
year periodyear period
• non-osteoporoticnon-osteoporotic NNTsNNTs– vertebral 0.12%vertebral 0.12% 1,7901,790– non-vertebral 2.54%non-vertebral 2.54% 80 80
• osteoporoticosteoporotic– vertebral 2.88%vertebral 2.88% 72 72– non-vertebral 6.85%non-vertebral 6.85% 24 24
Benefits Benefits
• Drugs that reduce vertebral fracturesDrugs that reduce vertebral fractures– vitamin D, HRT, raloxifene, vitamin D, HRT, raloxifene, risedronate, alendronaterisedronate, alendronate
• Drugs that reduce non-vertebral fracturesDrugs that reduce non-vertebral fractures– risedronate (1/3 RRR), alendronate (1/2 RRR)risedronate (1/3 RRR), alendronate (1/2 RRR)
Values and PreferencesValues and Preferences• high value: reducing fractures, no uncertaintyhigh value: reducing fractures, no uncertainty
– choose alendronatechoose alendronate
• high value: reducing fractures, no inconveniencehigh value: reducing fractures, no inconvenience– alendronate upright 30 minutes before mealalendronate upright 30 minutes before meal– choose residronatechoose residronate
• high value on “natural” treatment, low costhigh value on “natural” treatment, low cost– calcium and vitamin Dcalcium and vitamin D
• high value on fracture reduction – early treatmenthigh value on fracture reduction – early treatment
• high value living without medication – late treatmenthigh value living without medication – late treatment
Grading RecommendationsGrading Recommendations
• methodologic strengthmethodologic strength– High (RCT), intermediate (quasi-RCTs), low (observational), High (RCT), intermediate (quasi-RCTs), low (observational),
insufficient (other)insufficient (other)– implementation, consistency, directnessimplementation, consistency, directness
• decisiondecision– do it, don’t do, toss-updo it, don’t do, toss-up
• strength of decisionstrength of decision– strong (across range of values, most would choosestrong (across range of values, most would choose– weak (different choices across range of values)weak (different choices across range of values)