Large trials vs observational studies in assessing benefit and harm: the example of aprotinin

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1 Large trials vs observational studies in assessing benefit and harm: the example of aprotinin Dean A. Fergusson, MHA, PhD Senior Scientist and Associate Director, Clinical Epidemiology Program, Ottawa Hospital Research Institute Director, Ottawa Methods Centre Director, University of Ottawa Centre for Transfusion Research Assistant Professor, Departments of Medicine, Surgery and of Epidemiology & Community Medicine, University of Ottawa

2 Disclosure No grants or consultancy monies from manufacturers of aprotinin, tranexamic acid, or epsilon-aminocaproic acid Principal Investigator on BART trial Published systematic reviews and editorials on the use of antifibrinolytics in cardiac and orthopedic surgery

3 Cardiac Surgery and Blood Transfusion >1,000,000 cardiac surgeries worldwide High-risk cardiac procedures (repeat and combined procedures) account for 25% of total cardiac surgeries These procedures present a high risk of bleeding Cardiac procedures consume 16-20% of blood supply The HIV/HCV epidemic in the 1980 s fueled a search for transfusion alternatives and blood substitutes

4 Antifibrinolytic Agents in Cardiac Surgery Drugs act by inhibiting fibrinolysis (prevent the breakdown of clots) In turn, blood loss is reduced In turn, need for donated blood is reduced Administered peri-operatively Used since the 1960 s and trialed in late 1980 s Until 2006, aprotinin was the most often drug used for preventing blood loss in cardiac surgery Lysine analogues (TXA& EACA) seen as the cheaper and less effective cousin to aprotinin not by all, but by most

5 1987 to 2001

6 What did we know about the effectiveness of aprotinin and lysine analogues?

7 Effectiveness of Aprotinin in Cardiac Surgery Number of systematic reviews of RCTs since the first trial published Primary outcome: proportion transfused 1994, 16 trials: OR 0.23 (0.16 to 0.33) 1997, 45 trials: OR 0.31 (0.25 to 0.39) 2001, 54 trials: RR 0.70 (0.60 to 0.76) Fremes SE et al. Ann Thorac Surg Laupacis A et al. Anesth Analg Henry DA et al. Cochrane Library, Vol. 4, 2001

8 Proven Efficacy Redundant Trials?? 5000 additional pts Cumulative Meta-Analysis of all RCTs Ref # a 26b a 57b Year of Publication Dec -87 Mar -89 Apr -89 Sep -90 Oct -90 Dec -90 Jun -91 Sep -91 Dec -91 Apr -92 Jun -92 Jun -92 Jun -92 Nov -92 Dec -92 Jan -93 Jul -93 Aug -93 Dec -93 Jan -94 Feb -94 Feb -94 Feb -94 Apr -94 Jul -94 Aug -94 Aug -94 Oct -94 Oct -94 Dec -94 Dec -94 Feb -95 Feb -95 Feb -95 Apr -95 Jun -95 Jun -95 Sep -95 Oct -95 Oct -95 Oct -95 May -96 Jul -96 Aug -96 Aug -96 Oct -96 Dec -96 Jan -97 Jan -97 Aug -97 Sep -97 Dec -97 Oct -98 Oct -98 Nov -98 Aug -99 Sep -99 Mar -00 Dec -00 Dec -00 Jan -01 Sep -01 Sep -01 # Pts Odds Ratios with 95% Confidence Intervals Favours Aprotinin Favours Control (0.03, 0.38) 0.22 (0.09, 0.52) 0.28 (0.20, 0.38) 0.29 (0.23, 0.38) 0.30 (0.24, 0.38) 0.33 (0.26, 0.41) Jun (0.29, 0.41) 67 Fergusson, Journal of Clinical Trials, 2005

9 Tranexamic Acid (30 studies) Same Story: Many trials demonstrating effectiveness

10 What about safety of aprotinin?

11 SAEs/Harm Known Anaphylaxis Potential Renal failure? Aprotinin loves the kidneys Thrombotic risk? Aprotinin clots you up Mortality? Downstream effects of renal and thrombotic effects Also need to consider harm of not receiving aprotinin Re-op for bleeding Death due to bleeding

12 SAEs/Harm Aprotinin versus Placebo/No intervention: Pooled trial data (Smith et al., 1996) Stroke: 2.4% vs 1.0% in aprotinin patients (p=0.027) Cochrane Systematic Review (Henry et al., 2001) Mortality RR=0.87, 95% CI Stroke: RR=0.43, 95% CI Renal failure: RR=1.19, 95% CI Laupacis Systematic Review (Laupacis et al., 1997) MI: OR=1.15, 95% CI

13 Evidence of Renal Dysfunction and Failure Three trials (Lemmer 1995, Cosgrove 1992, Swart 1994) reported a trend of a mild to moderate increase in serum creatinine but NO increase in irreversible renal failure or need for dialysis Lemmer showed that the changes were transient at 4 to 6 weeks follow-up

14 Meta-analysis of Renal Failure + Renal Dysfunction : Aprotinin vs. Placebo *13 trials no events: Full Dose Aprotinin 0/367 and Placebo 0/366 Jeremiah, Birkmeyer,, O O Connor: NEJM May 4, 2006

15 Meta-analysis of Renal Dysfunction : Aprotinin vs. Placebo Jeremiah, Birkmeyer,, O O Connor: NEJM May 4, 2006

16 For aprotinin, this represents the state of evidence until 2001 Proventransfusion benefit (>8000 patients) For aprotinin, potential trend in benefit for mortality, re-op, and stroke potential trend for an increase in renal dysfunction (not failure) and MI all derived from RCT data, albeit serious morbidity/mortality not the primary focus of any trial rarer outcomes not measured/reported

17 As of 2001, what did we know? Head to head trials suggest TXA may be as effective at reducing transfusion and need for re-operation Analysis of mortality, MI and stroke were generally uninformative due to lack of data Data remain an uncertain basis for replacing aprotinin with the cheaper lysine analogues in clinical practice Sounds like the right time for a definitive comparator trial!

18

19 Our Primary Question: Does aprotinin decrease massive postoperative bleeding by 3% (from 6% to 3%) in the initial 24 hours as compared to epsilon-aminocaproic acid or tranexamic acid in patients undergoing high-risk cardiac surgery? Secondary Outcomes (2 categories) Fatal/life threatening (mortality, MI, stroke) Serious morbidity (organ failure: kidney, lung, heart) Study Design: Randomized, double-blind, multi-centre randomized trial 3000 high-risk cardiac surgery patients

20 Timeline Protocol written in 1999 Funded in 2001 Enrollment began in September of 2002 Trial ended in October 2007

21 DSMB Letter October 16, patients

22 What happened since DSMB letter in October 2007? October 16 : Received letter from BART DSMB to stop giving aprotinin October 16: Suspended trial immediately and notified all centres October 17: Site IRBs, Health Canada and FDA notified October 19: BART Executive met and terminated the trial

23

24 Primary Outcome: Massive Bleeding Aprotinin vs EACA: RR: 0.80 (95% CI, 0.59 to 1.07) Adjusted OR: 0.80 (95% CI, 0.58 to 1.11) Aprotinin vs TXA: RR: 0.79 (95% CI, 0.59 to 1.05) Adjusted OR: 0.78 (95% CI, 0.56 to 1.08)

25 30-day Mortality A total of 108 of 2331 patients (4.6%) died within 30 days after study randomization 47 (6.0%) in the aprotinin group 30 (4.0%) in tranexamic acid 31 (3.9%) in aminocaproic acid Aprotinin vs TXA: RR: 1.55, (95% CI, 0.99 to 2.42) Aprotinin vs EACA: RR: 1.52 (95% CI, 0.98 to 2.36) Aprotinin vs TXA or EACA: RR: 1.53 (95% CI, 1.06 to 2.22)

26

27 Back to 2006

28 The arrival of large observational studies A number of large observational studies were published from 2006 to 2008 Majority showed aprotinin was harmful in terms of serious morbidity and mortality Renal failure, stroke, and MI in particular Most studies compared aprotinin to nothing Only 2 compared aprotinin to aminocaproic acid Few presented evidence of effectiveness -transfusion, massive bleeding, etc.

29 The most influential observational study Mangano, NEJM 2006

30 What did they find? Aprotinin increased risk of renal failure (OR= 2.59, 95%CI 1.36 to 4.95) in complex surgery In primary surgery, increased risk of MI or Heart Failure by 55% (P<0.0001) Increased risk of stroke or encephalopathy (181%, p=0.0001) What about the RCT evidence? NO data on proportion transfused, re-op rates, longer term mortality, massive bleeding

31 Further studies after Mangano demonstrating harm with aprotinin Mangano, JAMA 2007 Mortality with aprotinin increased compared to no therapy Odds Ratio: 1.59 (0.76 to 3.34) Karkouti, Transfusion, 2006 Renal failure (50% increase in creatinine or need for dialysis) with aprotinin increased by an absolute 7% (24% vs 17%) Shaw, NEJM 2008 Mortality with aprotinin increased compared to no therapy or EACA Hazard Ratio 1.32 (1.12 to 1.55) Aprotinin associated with a larger risk-adjusted increase in the serum creatinine level (P<0.001) Schneiweiss, NEJM 2008 Mortality with aprotinin increased compared to EACA Odds Ratio 1.32 (1.08 to 1.63) All observational studies

32 Concerns with Observational Studies Potential for significant confounding by indication (apples & oranges) Outcomes confounded by patient prognosis, physician preference based on prognosis, and physician choices No amount of elaborate analysis can account for these factors Evaluating aprotinin versus nothing did not reflect the reality of practice (all 3 commonly used in high-risk surgery)

33 Table 1. Baseline Characteristics of the 4374 Patients Mangano, NEJM, 2006

34 Big picture, why we need to be concerned Regulators placed warnings or suspended marketing authorization of aprotinin Numerous lawsuits launched Aprotinin use decreased significantly (potential harm to those patients not offered alternative) Impact on BART recruitment All based on observational work!

35

36

37 Endless number of websites devoted to aprotinin (Trasylol) lawyers & lawsuits Majority of which base their claims on the observational evidence published in 2006

38 yet at the same time, another SR of RCTs Favours Antifib Favours Placebo Brown et al. Circulation, 2007

39 What BART can answer Effectiveness of aprotinin compared to TXA & EACA in terms of massive bleeding Safety of aprotinin compared to TXA & EACA in terms of mortality and serious morbidity Results applicable to a purposively chosen high-risk patient population What BART can not answer Safety of aprotinin compared to nothing Effectiveness (massive bleeding) of aprotinin compared to nothing Effectiveness and safety in low risk cardiac surgery (e.g. primary CABG) For the above, meta-analyses of RCTs remain the most robust estimates and NOT observational studies

40 Conclusions Results from observational studies can differ from RCTs Primary culprit is BIAS (types of patients, outcome measurement, type of analyses) So, why mislead ourselves? Let s go with the most robust study design if causality is our aim the question being asked determines the appropriate research architecture Choosing the best research design for each question Dave Sackett & John Wennberg, BMJ, 1997 In the absence of large trials, systematic reviews of trials provide our best estimates of benefit and harm

41 My final take We needed larger trials to determine with a reasonable amount of certainty whether aprotinin was more beneficial than harmful We did not pay the same attention to assessing harm as we did to assessing benefit We relied on post-marketing surveillance and accumulation of case-reports Clinically Important Outcomes + More treatment choices = Larger Trials The leap to incorporating harm as a co-primary or secondary outcomes was not that large

42 Thank you!

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