INDICATIONS FOR OFF-LABEL DRUG-ELUTING STENTING: THE REAL WORLD Giuseppe Biondi Zoccai Divisione di Cardiologia, Università di Torino 69° Congresso Nazionale della Società Italiana di Cardiologia - Roma, 15/12/2008

The distinction between on and off-label use is nonsense! Introductory remarks

The distinction between on and off-label use is nonsense! Introductory remarks Only on-label use is lawful, any off- label use will be punished!

In medio stat virtus (et veritas) Aristotles Introductory remarks

Learning goals On vs off-label: scope of the problem What is the definition of off-label stenting? What are the advantages of off-label stenting? What are the disadvantages of off-label stenting? Practical recommendations

Learning goals On vs off-label: scope of the problem What is the definition of off-label stenting? What are the advantages of off-label stenting? What are the disadvantages of off-label stenting? Practical recommendations

Scope of the problem Restenosis risk Thrombosis risk

Scope of the problem Restenosis risk Thrombosis risk

Scope of the problem

The off-label issue: fact or hype-driven fiction? Hits from PubMed with the following query: off AND label AND stent* AND coronary (29/11/2008) G. Biondi Zoccai – Off-label uses in the real-world Hits

Off-label use: is it common? Qasim et al, Am J Cardiol 2007

Off-label use: is it common?

Qasim et al, Am J Cardiol 2007 Off-label use: is it common?

Off-label lesion: a different animal? OFF-LABEL pts and lesions are/have more: older age, HTN, dyslipidemia, DM, prior AMI, prior PCI, prior CABG, CHF, PVD, comorbi- dities, RF, bleeding diathesis, AMI/ACS, MVD, LAD lesion

Off-label lesion: a different animal? ON-LABEL pts and lesions are/have more: OFF-LABEL pts and lesions are/have more: older age, HTN, dyslipidemia, DM, prior AMI, prior PCI, prior CABG, CHF, PVD, comorbi- dities, RF, bleeding diathesis, AMI/ACS, MVD, LAD lesion just plain simpler

Off-label concept: rock-solid?

Off-label: why should you bother?

P=0.002 P=0.019 P=0.025 P=0.037 P=0.63P=0.39P=0.21 P=0.09 Sangiorgi et al for the RECIPE Investigators, Am Heart J 2008

Learning goals On vs off-label: scope of the problem What is the definition of off-label stenting? What are the advantages of off-label stenting? What are the disadvantages of off-label stenting? Practical recommendations

Off-label indication/use

Some expert definitions Use of drug-eluting stents for in-stent restenosis, coronary artery bypass grafting, chronic total occlusions, or AMI (Rao et al, Am J Cardiol 2006)

Some expert definitions Use of drug-eluting stents for in-stent restenosis, coronary artery bypass grafting, chronic total occlusions, or AMI (Rao et al, Am J Cardiol 2006) Use of drug-eluting stents for restenotic lesion, location in bypass graft, lesion length>28-30 mm, diameter mm, left main, ostial, chronic total occlusion, bifurcation, or AMI (Behoar et al, JAMA 2007)

Some expert definitions Use of drug-eluting stents for in-stent restenosis, coronary artery bypass grafting, chronic total occlusions, or AMI (Rao et al, Am J Cardiol 2006) Use of drug-eluting stents for restenotic lesion, location in bypass graft, lesion length>28-30 mm, diameter mm, left main, ostial, chronic total occlusion, bifurcation, or AMI (Behoar et al, JAMA 2007) Use of drug-eluting stents for restenotic lesion, internal mammary artery or saphenous vein graft, left main, ostial, chronic total occlusions, bifurcation, AMI, or left ventricular ejection fraction<30% (Qasim et al, Am J Cardiol 2007)

Some expert definitions Use of drug-eluting stents for in-stent restenosis, coronary artery bypass grafting, chronic total occlusions, or AMI (Rao et al, Am J Cardiol 2006) Use of drug-eluting stents for restenotic lesion, location in bypass graft, lesion length>28-30 mm, diameter mm, left main, ostial, chronic total occlusion, bifurcation, or AMI (Behoar et al, JAMA 2007) Use of drug-eluting stents for restenotic lesion, internal mammary artery or saphenous vein graft, left main, ostial, chronic total occlusions, bifurcation, AMI, or left ventricular ejection fraction<30% (Qasim et al, Am J Cardiol 2007) Use of an approved device for a purpose that is not included as an indication in the approved device labelling (Holzer et al, Catheter Cardiovasc Interv 2008)

Learning goals On vs off-label: scope of the problem What is the definition of off-label stenting? What are the advantages of off-label stenting? What are the disadvantages of off-label stenting? Practical recommendations

Advantages The main advantage of off-label use is: patients/lesions with off-label features are those most likely to benefit from the anti- restenotic effects of drug- eluting stents, given their inherently increased risk of restenosis/disease progression

Advantages are easily explained ON-LABEL pts and lesions are/have more: OFF-LABEL pts and lesions are/have more: older age, HTN, dyslipidemia, DM, prior AMI, prior PCI, prior CABG, CHF, PVD, comorbi- dities, RF, bleeding diathesis, AMI/ACS, MVD, LAD lesion just plain simpler with ensuing lower restenotic risk!

Learning goals On vs off-label: scope of the problem What is the definition of off-label stenting? What are the advantages of off-label stenting? What are the disadvantages of off-label stenting? Practical recommendations

Disadvantages 1.Off-label indications can be riskier (eg because of lower compliance to dual antiplatelet therapy or increased thrombotic risk) 2.Off-label indications can lack sound data 3.Off-label indications can be denied reimbursement 4.Off-label indications can be medico- legally perilous

Disadvantages for Italian cardiologists Legge n. 94 del 8 aprile "Conversione in legge, con modificazioni, del decreto-legge 17 febbraio 1998, n. 23, recante disposizioni urgenti in materia di sperimentazioni cliniche in campo oncologico e altre misure in materia sanitaria" (Gazzetta Ufficiale 14 aprile 1998) [sulla sperimentazione, privacy e preparazioni magistrali] Legge di conversione 94/98. Articolo Il decreto-legge 17 febbraio 1998, n. 23, recante disposizioni urgenti in materia di sperimentazioni cliniche in campo oncologico e altre misure in materia sanitaria, è convertito in legge con le modificazioni riportate in allegato alla presente legge. 2. Con i decreti legislativi di cui alla legge 31 dicembre 1996, n. 676, e sulla base dei principi contenuti nella medesima legge e nel decreto-legge 17 febbraio 1998, n. 23, come modificato dalla presente legge, è disciplinata l'intera materia della riservatezza dei dati personali connessi alle prescrizioni mediche. 3. La presente legge entra in vigore il giorno successivo a quello della sua pubblicazione nella Gazzetta Ufficiale della Repubblica italiana.

Disadvantages for Italian cardiologists Articolo 3. Osservanza delle indicazioni terapeutiche autorizzate 1. Fatto salvo il disposto dei commi 2 e 3, il medico, nel prescrivere una specialità medicinale o altro medicinale prodotto industrialmente, si attiene alle indicazioni terapeutiche, alle vie e alle modalità di somministrazione previste dall'autorizzazione all'immissione in commercio rilasciata dal Ministero della Sanità. 2. In singoli casi il medico puo', sotto la sua diretta responsabilità e previa informazione del paziente e acquisizione del consenso dello stesso, impiegare un medicinale prodotto industrialmente per un'indicazione o una via di somministrazione o una modalità di somministrazione o di utilizzazione diversa da quella autorizzata, ovvero riconosciuta agli effetti dell'applicazione dell'articolo 1, comma 4, del decreto-legge 21 ottobre 1996, n. 536, convertito dalla legge 23 dicembre 1996, n. 648, qualora il medico stesso ritenga, in base a dati documentabili, che il paziente non possa essere utilmente trattato con medicinali per i quali sia già approvata quella indicazione terapeutica o quella via o modalità di somministrazione e purchè tale impiego sia noto e conforme a lavori apparsi su pubblicazioni scientifiche accreditate in campo internazionale.

Disadvantages for US cardiologists Wilkes et al, PLoSMedicine 2008

Overwhelming complexity?

Learning goals On vs off-label: scope of the problem What is the definition of off-label stenting? What are the advantages of off-label stenting? What are the disadvantages of off-label stenting? Practical recommendations

Off-label DES use Off-label use is an ominous prognostic (and proxy) risk factor, but not that much if we adjust for well-known patient, lesion and procedural predictors

Off-label DES use Not adjusted for saphenous/arterial graft lesions, left main, ostial, chronic total occlusions, or bifurcation! Win et al, JAMA 2007

Off-label DES use Qasim et al, Am J Cardiol 2007 No longer significant after adjustment for other covariates

True prognostic factors after DES implantation modified from Sangiorgi et al for the RECIPE Investigators, Am Heart J 2008 Late loss Binary restenosis Target lesion revascularization MACCE Diabetes LVEF CTO RVD ACC/AHA lesion type Calcification Unsuitable for direct stenting Lesion length

Off-label DES use Off-label use is an ominous prognostic (and proxy) risk factor, but not that much if we adjust for well-known patient, lesion and procedural predictors Off-label use can be pursued as long as the risk-benefit balance is favorable, compliance (to dual antiplatelet therapy) is likely, and reimbursement possible

Off-label DES use Off-label use is an ominous prognostic (and proxy) risk factor, but not that much if we adjust for well-known patient, lesion and procedural predictors Off-label use can be pursued as long as the risk-benefit balance is favorable, compliance (to dual antiplatelet therapy) is likely, and reimbursement possible Paradoxically, in many cases on-label patients/lesions can be treated with BMS rather than DES, reserving DES for off-label

On-label: the case for BMS P=0.002 P=0.019 P=0.025 P=0.037 P=0.63P=0.39P=0.21 P=0.09 Sangiorgi et al for the RECIPE Investigators, Am Heart J 2008

Take home messages

1. Off-label use is acceptable as long as the risk-benefit balance is acceptable

2. Dont forget you are treating a coronary lesion for the whole benefit of a patient CORONARY LESION REST OF PATIENT

3. Explain alternatives, risks, benefits and prepare a consent form including off-label use Give it to me straight Doc. Is it off-label?

Thanks for your attention! For further slides on these topics please feel free to visit the metcardio.org website: