Mul$ple Risk Factor Interven$on Trial (MRFIT) in Osteoarthri$s

Transcription

1 Mul$ple Risk Factor Interven$on Trial (MRFIT) in Osteoarthri$s Marc C. Hochberg, MD, MPH Professor of Medicine and Epidemiology and Public Health

2 Relevant Disclosures I have received consul$ng and speaking fees from Bioberica S.A. (Barcelona, Spain) and RoJapharm/Madaus (Monaz, Italy).

3 Why Prevent Osteoarthri$s? Most common form of arthri$s Important cause of ac$vity limita$on, physical disability, work loss and reduced health- related quality of life in older adults Most common indica$on for total joint arthroplasty Costs approach 1-2% of GNP in developed countries Associated with excess mortality Reduced physical ac$vity Comorbidi$es Use of medica$ons to treat symptoms of OA Current treatment unsa$sfactory in many pa$ents

4 From: The State of US Health, : Burden of Diseases, Injuries, and Risk Factors" JAMA. 2013;():-. doi: /jama " Number of Years Lived With Disability by Age for 20 Broad Groups of Diseases and Injuries in" the United States in 2010 for Both Sexes Combined" Date of download: 7/16/2013" Copyright 2012 American Medical Association. All rights reserved."

5 From: The Paradox of Disease Prevention: Celebrated in Principle, Resisted in Practice" JAMA. 2013;310(1): doi: /jama " Approaches to Curative and Preventive Medicine" Date of download: 7/2/2013" Copyright 2012 American Medical Association. All rights reserved."

6 Levels of Preven$on Reproduced from: Fletcher RH, Fletcher SW, Fletcher GS. Clinical Epidemiology: The Essen$als, 5th Edi$on, LippincoJ Williams & Wilkins, Philadelphia 2013.

7 OARSI- FDA Ini$a$ve: Types of Preven$on Trials Jordan JM, et al: Osteoarthritis Cart 2011;19:500-8.

8 Risk Factors for Knee OA Systema$c review of studies thru 1/3/2008 Included case- control and cohort studies Methodologic quality assessed Case defini$on Symptoma$c knee OA Radiographic knee OA Data extracted for strength of associa$on Blagojevic M et al: Osteoarthritis Cart 2010;18:24-33.

9 Risk Factors for Knee OA Variable No. studies OR (95% CI) Overweight (1.86, 2.55) Obese (2.28, 3.05) Prior knee injury (2.61, 5.70) Female gender (1.32, 2.55) Heberden s nodes (1.05, 2.10) Smoking (0.74, 0.95) Other factors associated with knee OA include increasing age; genetic predisposition, occupational activities (e.g., kneeling, squatting, climbing steps, standing > 2 hrs/day and lifting); higher BMD; and prior h/o meniscectomy. Blagojevic M et al: Osteoarthritis Cart 2010;18:24-33.

10 MRFIT- OA: Proposed Interven$ons Weight loss Nutri$onal counseling, reduced caloric intake and increased physical ac$vity (exericise) With or without pharmacologic agents Lorcaserin (Belviq, Arena Pharmaceu$cals GmbH) Phenterimine + Topiramate ER (Qsymia, Vivus Inc.) Orlistat (Alli, GlaxoSmithKline) Nutri$onal supplements Controversial efficacy but no safety signals in established disease

11 Weight Loss for OA History of weight loss was associated with reduced odds of symptoma$c radiographic knee OA Felson DT, et al: Ann Intern Med 1992;116: All professional socie$es recommend weight reduc$on for pa$ents with knee OA Pa$ents with knee OA who are overweight should be encouraged to lose weight and maintain their weight at a lower level.

12 Weight Loss for OA Systema$c review of 4 RCTs with data on 454 pa$ents with knee OA Mean weight loss of 6.1 kg (range: kg) Pooled es$mates for reduc$on in pain ES = 0.20 (95% CI ) Pooled es$mates for improvement in func$on ES = 0.23 (95% CI ) Christensen R, et al. Ann Rheum Dis 2007; 66:433-9

13 Figure 1 Flow of randomised controlled trials included in the systematic review. RCT, randomised controlled trial. Christensen, R. et al. Ann Rheum Dis 2007;66: Copyright 2007 BMJ Publishing Group Ltd.

14 Studies of Weight Loss Type 2 Diabetes Look AHEAD Intensive lifestyle interven$on (reduced caloric intake and increased physical ac$vity) Osteoarthri$s ADAPT IDEA The Look AHEAD Research Group. Control Clin Trials Oct;24(5): Miller GD et al: Control Clin Trials 2003; Aug;24(4): Messier SP et al: BMC Musculoskeletal Dis 2009 Jul 28;10:93. doi: /

15 ADAPT Factorial Design Miller GD et al: Control Clin Trials 2003; Aug;24(4):

16 ADAPT Results Variable Weight loss (kg) Improvement in WOMAC pain Decline in JSW (mm) Healthy Lifestyle 1.10 (- 3.00, 5.20) 1.23 (2.11, 0.35) (- 0.64, 0.14) Exercise alone 3.46 (- 0.77, 7.69) 0.40 (1.32, 0.52) (- 0.60, 0.22) *P < 0.05 compared to Healthy Lifestyle control group. Weight loss alone 4.61 (0.38, 8.84) 1.07 (1.95, 0.19) (- 0.53, 0.13) Exercise AND Weight loss 5.20 (0.85, 9.55) 2.20 (3.12, 1.28)* (- 0.71, 0.11) Messier SP et al: Arthri$s Rheum 2004;50:

17 Weight loss is associated with structure modifica$on in subjects with radiographic osteoarthri$s of the knee: Data from the Osteoarthri$s Ini$a$ve M.C. Hochberg 1,2, D. Bujak 1, K. Favors 1,2, J.D. Sorkin 1,2 and J. Duryea 3 1 University of Maryland School of Medicine and 2 VA Maryland Health Care System, Bal$more, MD; and 3 Brigham & Women s Hospital, Boston, MA.

18 Objec$ve To test the hypothesis that weight loss would be associated with a slower rate of decline in minimum joint space width (mjsw) in the medial $biofemoral compartment in subjects with radiographic knee OA enrolled in the OAI.

19 Results 1 Data from 2683 subjects with RKOA (KL > 2) were included in analysis. Mean (SD) age 62.1 (9.1) years Mean (SD) weight 83.9 (16.0) kg Mean (SD) BMI Mean (SD) WOMAC Pain Score 29.6 (4.8) 3.35 (3.56) kg/m 2 Nu Mean (SD) mjsw 3.97 (1.46) mm Mean (SE) annual rate of decline JSW mjsw JSW(0.225) Difference (95% CI) Mean (SD) JSW(0.25) 5.36 (1.54) mm (0.0052) mm (0.0051) mm (0.007, 0.036) mm

20 Results 2 Change in mjsw was significantly inversely related to weight change in mul$ple variable adjusted random effects models No significant difference in rate of decline in both mjsw and JSW(0.225) by per unit change in weight

21 mjsw: Results of Random Effects Model Effect B SE T value P value Intercept Weight < Time < V Age < WOMAC Pain < On pain meds Simultaneously adjusted for gender, race/ethnicity and site.

22 JSW(0.225): Results of Random Effects Model Effect B SE T value P value Intercept Weight < Time < V < Age < WOMAC Pain < On pain meds Simultaneously adjusted for gender, race/ethnicity and site.

23 Summary These data demonstrate an associa$on between weight loss and a reduc$on in the rate of decline in both mjsw and JSW(0.225) in subjects with radiographic knee OA enrolled in the OAI. These results suggest that clinically important weight loss (> 6 kg) may have structure modifying effects, in persons with radiographic knee OA.

24 Limita$ons Observa$onal study Rela$vely small amount of weight change observed over 48 months Most subjects had KL grade 2 at baseline Mean annual rate of decline in mjsw was < 0.10 mm. Did not analyze effect of weight change on car$lage thickness or volume as measured by MRI

25 Nutri$onal Supplements for OA Results of meta- analyses of RCTs for efficacy of glucosamine and chondroi$n sulfate alone or in combina$on on pain are controversial. Evidence of small significant effect on rate of decline in joint space width. Preliminary data suggest possible effect on rate of decline in car$lage volume.

26 Cochrane Review of glucosamine therapy for osteoarthri$s: 2009 update 25 randomised, double- blind, parallel- group, controlled trials (RCTs) iden$fied 4963 pa$ents (mean age 61 yrs, 69% females) 1905 randomized to glucosamine 3058 to comparators (placebo in 20 studies, NSAIDs in 5, and paracetamol in 1 study) Mainly oral route of administra$on, at variable dosage Majority of trials with glucosamine sulfate or hydrochloride Type and site of OA heterogenous, but 20/25 trials in knee. Towheed T, et al. Cochrane Database 2009; Issue 2

27 The Cochrane Review of glucosamine in OA: Glucosamine vs placebo - Pain - Towheed T, et al. Cochrane Database 2009; issue 2

28 Heterogeneity in Glucosamine RCTs Mainly due to 3 factors: Differences in study design and/or quality Was there adequate alloca$on concealment? Differences in the glucosamine salt, formula$on and/or dosage Differences in source of funding

29 Glucosamine Sulfate: Summary of Efficacy for Symptom Modifica$on Crystalline glucosamine sulfate is efficacious for reducing pain and improving func$on in pa$ents with symptoma$c knee OA Subjects who received crystalline glucosamine sulfate had a lower rate of adverse events compared with those who received NSAIDs Towheed T, et al. Cochrane Database 2009; issue 2

30 Structure Modifying Effects of Glucosamine SO 4 in Knee OA Two placebo- controlled RCTs demonstrated significant reduc$on in the average annual rate of decline in JSW among pa$ents receiving crystalline glucosamine sulfate 1500 mg per day Reginster J- Y et al. Lancet 2001;357: Pavelka, K. et al. Arch Intern Med 2002;162: Effect not modified by improvement in pain in post- hoc stra$fied analyses Pavelka K et al: Ostearthri$s Cart 2003;11:730-7

31 Glucosamine sulfate reduced Joint Space Narrowing (JSN) in two randomised, placebo- controlled, double- blind, 3- year trials in knee OA Reginster et al, Lancet 2001;357:251-6 JSW at enrolment, mm (mean±sd) 3-year JSN, mm (mean and 95% CI) Placebo (N=106) Glucosamine Sulfate (N=106) Difference 3.95± ± (-0.56 to -0.24) (-0.22 to 0.07) 0.33 (0.12 to 0.54) p Pavelka et al, Arch Intern Med 2002;162: Placebo (N=101) Glucosamine Sulfate (N=101) Difference p JSW at enrolment, mm (mean±sd) 3.63± ± year JSN, mm (mean and 95% CI) (-0.29 to -0.09) 0.04 (-0.06 to 0.14) 0.23 (0.09 to 0.37) 0.001

32 Crystalline glucosamine sulfate (RoJapharm) vs placebo - Minimum Joint Space Width 2009 Cochrane Update Towheed T, et al. Cochrane Database 2009; issue 2

33 Pooled incidence of TKR during a mean follow- up of 5 years ayer termina$on of the 3- year trials (Reginster 2001; Pavelka 2002) in pa$ents who had been in the studies for at least 12 months Placebo Glucosamine Sulfate Relative Risk P (N=131) (N=144) (95% CI) Patients with Total Knee Replacement 19 (14.5%) 9 (6.3%) 0.43 (0.20 to 0.92) Bruyere O, et al. Osteoarthri$s Cart 2008;16:

34 Time- to- event analysis of total knee replacement in the overall follow- up popula$on: P=0.026 (Log rank test) Bruyere O, et al. Osteoarthri$s Cart 2008;16:

35 Chondroi$n for Knee or Hip OA Searched Cochrane Registry, MEDLINE, EMBASE and CINAHL through 11/30/ RCTs with 3846 pa$ents contributed to meta- analysis for pain outcome Effect size = 0.75 (0.50, 0.99) Significant heterogeneity between trials Larger, more recently published and higher quality trials (i.e., those with alloca$on concealment and ITT analyses) showed smaller effects than smaller and older trials Subgroup analysis based on 3 large trials that included 40 percent of pa$ents showed an ES = 0.03 (- 0.07, 0.13) Reichenback S et al: Ann Intern Med 2007;146:

36 Chondroi$n for Knee or Hip OA Effects on radiologic joint space width 5 RCTs provided informa$on Difference of 0.16 mm (0.08, 0.24) for minimum JSW and 0.23 mm (0.09, 0.37) for mean JSW c/w placebo Small effect sizes (< 0.2 units) LiJle heterogeneity (I 2 = 8% and 21%) Reichenback S et al: Ann Intern Med 2007;146:

37 Meta- analysis: Objec$ves To update the prior meta- analysis with newly published data from studies of 2 years dura$on To determine the effects of orally administered chondroi$n sulfate on structure modifica$on, as measured by change in the rate of decline in minimum joint space width over 2 years, in pa$ents with symptoma$c knee OA. Hochberg MC: Osteoarthritis Cart 2010;18(Suppl 1):S28-31.

38 Results: Mean Decline (SD) in Minimum JSW (mm) Michel et al (2005) Sawitzke et al (2008) CS Placebo Difference (95% CI) (0.48) 0.07 (0.56) 0.12 (0.00, 0.23) 0.107* 0.166* 0.06 (-0.17, 0.28) Effect size (95% CI) 0.22 (0.01, 0.45) 0.09 (-0.24, 0.42) Kahan et al (2009) 0.07 (0.03) ** 0.31 (0.04) ** 0.14*** (0.06, 0.21) 0.26 (0.11, 0.42) *Adjusted for baseline JSW, sex, pain score, disease duration, weight, KL grade, site and weeks of treatment **SEM, ***Median difference as results were not normally distributed

39 Pooled Results No evidence of heterogeneity (I 2 = 0%) Pooled mean diff = 0.13 mm (0.06, 0.19) Z = 3.78, P = Pooled effect size = 0.23 (0.11, 0.35) Z = 3.70, P =

40 Limita$ons Methods of acquiring x- rays differed across individual trials Buckland- Wright MTP view (Sawitzke et al) Lyon- Schuss view No fluoroscopy (Michel et al) Fluoroscopy (Kahan et al) Es$mated standard devia$ons for rates of change using baseline values

41 Summary Results consistent with a small significant effect on reduc$on in rate of decline in minimum joint space width among pa$ents with knee OA assigned to chondroi$n sulfate compared to those assigned to placebo Results are robust even when data from GAIT are included in meta- analysis

42 Combina$on of Glucosamine and Chondroi$n Sulfate Chondroi$n sulfate (CS) and glucosamine (G) are widely prescribed as medicines in Europe and are available as over- the- counter (OTC) nutri$onal supplements in the U.S. There is ongoing debate about the efficacy of CS and G in the treatment of knee OA largely based on interpreta$on of results from meta- analyses. There are lijle data, however, on the efficacy of the combina$on of CS and G in the treatment of pa$ents with OA.

43 Pairwise Comparisons of the Overall Likelihood of a Response: GAIT p=0.008 p=0.04 p=0.002 p=0.02 p=0.007 p=0.001 p=0.03 Clegg DO, et al. N Engl J Med. 2006;354(8):

44 Methods Systema$c review conducted Searched Pubmed using Chondroi$n sulfate and Glucosamine and Osteoarthri$s Search conducted 6 April 2012 Search strategy Overall 197 Limit to English language and humans Limited to clinical trials, editorials, meta- analysis, RCTs, reviews and prac$ce guidelines Excluded review ar$cles Number of arvcles

45 Clinical Outcomes in Knee OA RCTs Study Pain FuncVon Global Lequesne ISK AEs Leffler et al (1999) Das & Hammad (2000) Y N Y - N N N N Y* N Rai et al (2004) Y - Clegg et al (2006) Messier et al (2007) N^ N^ N - N N # N *Sig only in KL2/3 stratum; ^Sig only in moderate- to- severe pain stratum; # Sig improvement in high adherent group

46 Summary Limited to moderate evidence for efficacy of the combina$on of G+CS in pa$ents with symptoma$c radiographic knee OA who have moderate- to- severe pain No evidence of adverse events c/w placebo Further well- designed studies need to be performed in order to support the use of the combina$on of G+CS in pa$ents with knee OA MOVES trial ( NCT )

47 PATIENTS" STUDY DESIGN" Ø Participants are from the OAI progression cohort." 1,390 participants from the OAI progression cohort" Ø Ø 24 consecutive-month follow-up with complete radiographic and MRI data for the most symptomatic knee, based on the highest WOMAC pain score, at the onset of the study (Time [T]0)." The participants were stratified into two main groups based on whether (+) or not (-) standard pharmacological treatment for OA (including analgesics and non-steroidal anti-inflammatory drugs [NSAIDs]) was taken for disease symptoms over a continuous period of 24 months. " Analgesic/NSAIDs n=300" 751 participants with follow-up for 24 consecutive months " (X-rays, MRI)" 600 participants included" 639 not followed for 24 consecutive months" 151 excluded for MRI related reasons (11: poor quality MRI, 96: missing one MRI, 39: did not have MRI of target knee) and 5: total knee replacement during the follow-up" +Analgesic/NSAIDs" n=300" Ø Moreover, these two groups were further stratified into subgroups based on whether or not subjects reported using a combination of Glu and CS." +Glu/CS" n=90" -Glu/CS" n=210" +Glu/CS" n=113" -Glu/CS" n=187" Martel- Pelle$er J, et al: EULAR 2013.

48 RESULTS and CONCLUSION Subjects who reported taking G+CS had significantly less loss of car$lage volume in the $bial plateau at both 12- and 24- months Significant in those with baseline mjsw > 3.6 mm but not in those with baseline mjsw < 3.6 mm. Data from this study provide support for the possible structure modifying effects of the G+CS combina$on in knee osteoarthri$s subjects. Subjects with milder structural changes would benefit more from the combina$on of G+CS than subjects with more advanced structural disease. Martel- Pelle$er J, et al: EULAR 2013.

49 MRFIT- OA: Poten$al Outcomes Primary preven$on Incident symptoma$c radiographic knee OA Secondary preven$on Non- acceptable symptom state (Virtual TJR) Total joint replacement

50 U.S. Department of Health and Human Services Supported By Na$onal Ins$tutes of Health Na$onal Ins$tute of Arthri$s and Musculoskeletal and Skin Diseases