Giuseppe Biondi Zoccai Interventional Cardiology, University of Turin, Italy Results of drug-eluting stent randomized trials: separating gold from fool’s gold with the statistician’s help DES e BMS: riflessioni e pensieri 23 febbraio 2007, San Donato Milanese

Consultant for Boston Scientific Italy and Cordis Italy either directly or through a Milan-based contract research organization No other conflicts of interest or funding to declare Disclosure

Previous euphoria from DES RCTs

Just DES it

Any doubt?

Nordmann, Eur Heart J 2006 Camenzind, WCC 2006 Bavry, Am J Med 2006 Mmmmm…

Scope of the problem Limits in internal validity Limits in external validity Limits in external validity Conflicts of interest

Incomplete masking Information bias Reliance on surrogate end-points Selection bias Systematic angiographic follow-up Threats to internal validity

An incomplete list of bias · Selection bias · Information bias · Confounders · Observation bias · Investigator’s bias (enthusiasm bias) · Patient’s background bias · Distribution of pathological changes bias · Selection bias · Small sample size bias · Reporting bias · Referral bias · Variation bias · Recall bias · Statistical bias · Selection bias · Confounding · Intervention bias · Measurement or information · Interpretation bias · Publication bias · Subject selection/sampling bias Sackett, J Chronic Dis 1979

Information bias

Selection bias

Ardissino, JAMA 2004

Incomplete masking of patients, physicians, adjudicators, statisticians…

Reliance on surrogate end-points

TVR MI DEATH TVF TVF?

Three coins – same value?

Inflation of adverse events by means of systematic angiographic follow-up

Fajadet, Circulation 2006

Inappropriate selection of highly compliant patients Inappropriate selection of low-risk patients Limited industry time-line Low overall statistical power Participation of high-volume centers Threats to external validity

Inappropriate selection of low-risk patients No previous or planned use of brachytherapy in the target vessel or of any drug-eluting stent No myocardial infarction within 72 hours before enrollment No LVEF <25% No hemorrhagic diatheses No history of anaphylaxis to contrast medium No serum creatinine level >2.0 mg/dL No leukocyte count <3500 per mm3 No platelet count <100,000 per mm3 No coexisting conditions that limited life expectancy to <24 months … Common selection criteria: Stone, NEJM 2004

Inappropriate selection of low-risk patients No left main or ostial target lesion No moderate or severe calcification of the target vessel or lesion No tortuosity or angulation No bifurcation of the target lesion No occluded target lesion No thrombus … Common selection criteria: Stone, NEJM 2004

Inappropriate selection of compliant patients Willingness to undergo clinical and angiographic follow-up Willingness to continue double antiplatelet therapy for >3-6 months Common inclusion criteria:

Limited industry time-line Market diffusion of 2nd gen. DES Preclinical studies of 1st gen. DES 1st gen. DES Clinical studies of 1st gen. DES 1st gen. DES Preclinical studies of 2nd gen. DES Clinical studies of 2nd gen. DES Market diffusion of 1st gen. DES 3rd gen. DES?

Detrimental conflicts of interest Ligthart, CMAJ 2007

Detrimental conflicts of interest

Making reason of complexity

Silber score for RCTs

Evidence-based medicine approach Appraising and using an article from the medical literature in 3 steps: Step 1 – Are the results of the study (internally) valid? Step 2 – What are the results? Step 3 – How can I apply these results to patient care (are they externally valid)? Guyatt, Users’ Guide to the Medical Literature, AMA Press 2002

EBM approach Are the results valid?Are the results valid? Did experimental and control groups begin the study with a similar prognosis? Were pts randomized?Were pts randomized? Was randomization concealed?Was randomization concealed? Were pts analyzed in the groups to which they were randomized?Were pts analyzed in the groups to which they were randomized? Were pts in the treatment and control groups similar with respect to known prognostic factors?Were pts in the treatment and control groups similar with respect to known prognostic factors? Did experimental and control groups retain a similar prognosis after the study started? Were pts aware of group allocation?Were pts aware of group allocation? Were clinicians aware of group allocation?Were clinicians aware of group allocation? Were outcome assessors aware of group allocation?Were outcome assessors aware of group allocation? Was follow-up complete?Was follow-up complete? Guyatt, Users’ Guide to the Medical Literature, AMA Press 2002

EBM approach Guyatt, Users’ Guide to the Medical Literature, AMA Press 2002 What are the results?What are the results? How large was the treatment effect?How large was the treatment effect? How precise was the estimate of the treatment effect?How precise was the estimate of the treatment effect? How can I apply the results to patient care?How can I apply the results to patient care? Were the study patients similar to my patient?Were the study patients similar to my patient? Were all clinically important outcomes considered?Were all clinically important outcomes considered? Are the likely treatment benefits worth the potential harm and costs?Are the likely treatment benefits worth the potential harm and costs?

Take home messages

Randomized clinical trials are the best tool available to appraise new treatmenta However, they are not immune from bias In addition, they applicability is limited in time and space Our goal should thus to combine the critical appraisal of the best available evidence with the individual patient characteristics and preferences, within the practical constraints of the surrounding health care system Take home messages

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