indications for off-label drug-eluting stenting: the real world giuseppe biondi zoccai divisione di...
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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 problemRestenosis riskRestenosis risk Thrombosis riskThrombosis risk
Scope of the problemRestenosis riskRestenosis risk Thrombosis riskThrombosis 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
Hit
s
Off-label use: is it common?
Qasim et al, Am J Cardiol 2007
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-LABELpts and lesionsare/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-LABELpts and lesionsare/have more:
OFF-LABELpts and lesionsare/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?
Off-label: why should you bother?
P=0.002
P=0.019
P=0.025
P=0.037
P=0.63P=0.39 P=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<2.5mm or >3.5-3.75 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<2.5mm or >3.5-3.75 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<2.5mm or >3.5-3.75 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-LABELpts and lesionsare/have more:
OFF-LABELpts and lesionsare/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 simplerwith 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 1998."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 1.1. 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 specialitàmedicinale o altro medicinale prodotto industrialmente, si attiene alleindicazioni terapeutiche, alle vie e alle modalità di somministrazione previstedall'autorizzazione all'immissione in commercio rilasciata dal Ministero dellaSanità.
2. In singoli casi il medico puo', sotto la sua diretta responsabilità e previainformazione del paziente e acquisizione del consenso dello stesso, impiegare unmedicinale prodotto industrialmente per un'indicazione o una via disomministrazione o una modalità di somministrazione o di utilizzazione diversada quella autorizzata, ovvero riconosciuta agli effetti dell'applicazionedell'articolo 1, comma 4, del decreto-legge 21 ottobre 1996, n. 536, convertito dallalegge 23 dicembre 1996, n. 648, qualora il medico stesso ritenga, in base a datidocumentabili, che il paziente non possa essere utilmente trattato con medicinaliper i quali sia già approvata quella indicazione terapeutica o quella via omodalità di somministrazione e purchè tale impiego sia noto e conforme a lavoriapparsi 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 Late loss loss
Binary Binary restenosisrestenosis
Target lesion Target lesion revascularizationrevascularization MACCEMACCE
Diabetes
LVEF
CTORVD
ACC/AHA lesion type
Calcification
Unsuitable for direct stenting
Lesionlength
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=0.39 P=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. Don’t 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:
http://www.metcardio.org/slides.html