HTA REPORT

Prostheses for primary total hip replacement in Italy

This report should be cited as "Age.na.s. HTA Report - Prostheses for primary total hip replace-ment in Italy, Rome, September 2008"

Contributions

Authors:Antonella Cavallo, Marina Cerbo, Dario Fella, Tom Jefferson, Antonio Migliore, Maria RosariaPerrini

Age.na.s., Agenzia Nazionale per i Servizi Sanitari Regionali Sezione ISS (Innovazione, Sperimentazione e Sviluppo), Rome (Italy)

Corresponding author:Maria Rosaria Perrini (perrini@agenas.it)

Experts:Emilio RomaniniConsultant (Orthopaedic)

GLOBE - Gruppo di Lavoro Ortopedia Basata sulle Prove di EfficaciaCasa di Cura San Feliciano, Rome (Italy)

External Reviewers:Peter Davidson

NCCHTA - National Coordinating Centre for HTA,NETS-CC - NIHR Evaluation, Trials and Studies Coordinating Centres,University of Southampton, Southampton (UK)

Claudia Giacomozzi

Dipartimento Tecnologie e Salute,ISS - Istituto Superiore di Sanità, Rome (Italy)

William J Gillespie

Hull York Medical SchoolUniversity of Hull, Hull (UK)

Mauro Grigioni

Dipartimento Tecnologie e Salute,ISS - Istituto Superiore di Sanità, Rome (Italy)

Michael A. Scott

NCCHTA - National Coordinating Centre for HTA,NETS-CC - NIHR Evaluation, Trials and Studies Coordinating Centres, School of Medicine, University of Southampton (UK)

Marina Torre

Ufficio di Statistica CNESPS - Centro Nazionale Epidemiologia, Sorveglianza e Promozione dellaSalute, ISS - Istituto Superiore di Sanità, Rome (Italy)

Peter Tugwell

Centre for Global Health, Institute of Population HealthUniversity of Ottawa, Ontario (Canada)

Gustavo Zanoli

GLOBE - Gruppo di Lavoro Ortopedia Basata sulle Prove di EfficaciaCasa di Cura S. M. Maddalena, Rovigo (Italy)

Editing and layoutDario Fella

Age.na.s. Agenzia Nazionale per i Servizi Sanitari Regionali

Acknowledgements:The Agenzia Nazionale per i Servizi Sanitari Regionali (age.na.s.) thanks all external reviewerswho kindly provided comments on an earlier draft of this report.

Age.na.s. also thanks those who contributed to the realisation of this report providing price data(Centrali di Acquisto Regionali), Henrik Bodén from the Division of Orthopaedics, KarolinskaInstitutet at Danderyd Hospital (Stockholm, Sweden) for his constructive comments and techni-cal details, Paolo Gazzaniga and Fernanda Gellona from the association of producers and distri-butors of medical devices (ASSOBIOMEDICA) for market details.

Age.na.s. also thanks Carlo Di Pietrantonj and Alessandro Rivetti from SEREMI (Servizio di riferi-mento Regionale di Epidemiologia, ASL 20, Alessandria, Italy), and Fabio Bernardini (age.na.s.)for their help in designing and carrying out the search strategy.

HTA REPORT

Prostheses for primary total hip replacement in Italy

Executive summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .9

Sintesi . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .11

1. Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .171.1 Indications for primary total hip replacement . . . . . . . . . . . . . . .171.2 Epidemiology: primary THR in Italy and worldwide . . . . . . . . .17

2. Technology, precedure and alternatives . . . . . . . . . . . . . . . . . . . . . . . . . . . .21

3. Report's objectives: policy and research questions . . . . . . . . . . . . . . . .23

4. Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .254.1 Methods of the systematic review . . . . . . . . . . . . . . . . . . . . . . . . . . . .25

4.1.1 Criteria for considering evidence . . . . . . . . . . . . . . . . . . . . . . . . . .254.1.2 Search methods for the identification of studies . . . . . . . . .26

4.2 National arthroplasty registries and methods for their analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .27

4.2.1 Searches in the arthroplasty registers . . . . . . . . . . . . . . . . . . . .284.2.2 Key variables in an arthroplasty register . . . . . . . . . . . . . . . . . .29

4.3 Cost-effectiveness analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .29

5. Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .315.1 Evidence from clinical studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .31

5.1.1 Description of review studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .335.1.2 Description of single studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .36

5.2 Analysis of evidence from arthroplasty registers . . . . . . . . . . . .375.3 Comparison between the evidence

from clinical studies and registers . . . . . . . . . . . . . . . . . . . . . . . . . . . .425.4 Cost-effectiveness analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .48

6. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .496.1 Limits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .51

7. Recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .53

8. Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .55

9. Competing interests declaration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .57

Bibliography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .59

Appendices1 - Technological characteristics of hip prostheses . . . . . . . . . . . . . . . .632 - Search strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .733 - Data extraction form for review studies . . . . . . . . . . . . . . . . . . . . . . . .774 - Data extraction form for single studies . . . . . . . . . . . . . . . . . . . . . . . . .835 - Minimum data set for an arthroplasty register . . . . . . . . . . . . . . . . .896 - List of included studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .917 - List of excluded studies with reasons for exclusion . . . . . . . . . . .938 - Instruments for outcome measurements . . . . . . . . . . . . . . . . . . . . . . .97

Glossary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .101

9

Executive summary

One-liner Patchy data and lack of knowledge of available hip systems in Italy prevented us from draf-

ting meaningful guidance on their use.

Background Total hip replacement (THR) is a global procedure with potentially high costs and benefits. The

wide array of available prostheses makes the issuing of evidence-based guidance on choice, apriority for the equitable and transparent use of resources in any health system. A previous reviewof the evidence from randomised controlled trials found limited poor quality evidence but did notinclude data from International and Regional registers and failed to identify a comprehensive listof prostheses available in Italy.

AimWe aimed to update the systematic review, include data from Regional and National registers

and construct a cost-effectiveness model to aid choice in people over 65 years.

Methods We assessed a minimum 5-year survival by prosthesis in people aged 65 or older who had

undergone an implant for non-traumatic indications. We identified the evidence by searching threedatabases and updating the existing review of effectiveness. We also assessed evidence from 3Italian regional registers and from the European Arthroplasty Register (EAR) which gathers datafrom 7 European and 3 non-European registers. We identified survival data for hip systems com-pared in at least one register plus studies, at least two registers and only in studies. To obtain anestimate of implant survival with data originating from different registers, we calculated an avera-ge survival weighted by number of implants so that the higher the number of implants reportedin each register, the more consistent was its contribution to the survival estimates.

ResultsWe included 5 primary studies and three reviews to update the dataset of 11 similar studies

from the existing review. We included data from the only 3 national and 1 Italian regional regi-sters reporting survival data by hip system. Although we were able to construct summary tablesfor a limited number of systems by availability of evidence, the systems with most evidence wereeither no longer available in Italy or their status was unknown. We were able to collect few andvery diverse cost estimates. Given the uncertainties on the availability and performance of hipsystems in Italy we did not carry out a cost-effectiveness analysis.

10

ConclusionsThe linking of reimbursement of hip systems with their performance is a priority issue for the

Italian NHS. Such a policy however cannot be carried out efficiently and equitably on current data.Countrywide comparable arthroplasty data from a register are required.

11

Sintesi

IntroduzioneL’intervento primario di sostituzione totale dell’anca (THR, Total Hip Replacement) è conside-

rato la soluzione migliore per trattare pazienti con osteoartrite severa dell’anca. L’osteoartrite col-pisce prevalentemente individui di età superiore ai 60 anni, ma la procedura di THR viene esegui-ta anche in giovani adulti affetti da artrite reumatoide. L’intervento primario consiste nella sostitu-zione totale dell’articolazione dell’anca con una protesi multicomponente.

Le protesi totali d’anca (chiamate comunemente protesi d’anca o hip system), recentementeclassificate come dispositivi di Classe III dalla Commissione Europea, sono costituite da 2 gruppidi componenti: la componente femorale, che generalmente comprende lo stelo e la testa, vieneinserita all’interno del canale femorale; la componente acetabolare, che generalmente comprendeun cotile (o coppa acetabolare) che viene impiantato nella pelvi e accoglie al suo interno uno opiù inserti. Il movimento relativo (scorrimento) della testa rispetto all’inserto permette il funziona-mento dell’articolazione e generalmente permette di condurre una vita normale, senza deficitmotori.

Una classificazione esaustiva di tutte le protesi d’anca adoperate nella pratica clinica è resacomplessa dal gran numero di dispositivi esistenti, dalla grande varietà di materiali, design, confi-gurazioni e dei rivestimenti superficiali e dalla continua e diversificata offerta delle aziende produt-trici. Una generica classificazione può essere fatta riguardo al metodo di fissaggio delle compo-nenti a contatto con l’osso. Stelo e coppa possono, infatti, essere cementati o non cementati. Nelprimo caso, viene impiegato del cemento per ossa (sostanza a base di polimetilmetacrilato, PMMA)avente funzione di riempitivo all’interfaccia con l’osso. Nel secondo caso le componenti vengonofissate direttamente sul tessuto osseo talvolta utilizzando viti, flange o spine. Si parla quindi di pro-tesi cementate quando entrambe le componenti sono cementate, protesi non cementate (o press-fit) quando nessuna componente è cementata, protesi ibride quando una componente è cemen-tata e l’altra è press-fit. Attualmente i dispositivi più impiegati presentano design modulare concombinazioni di componenti che soddisfano maggiormente le necessità del paziente e le preferen-ze del chirurgo.

L’impianto di una protesi totale d’anca non è però esente da complicazioni. A causa della com-plessa interazione con il tessuto osseo e della particolare biomeccanica dell’articolazione l’impian-to protesico può essere soggetto a dislocazione (nel breve termine), usura e mobilizzazione (nellungo termine). La complicazione più grave è la mobilizzazione che porta generalmente a re-inter-venire chirurgicamente. L’impianto viene quindi definito fallito e deve essere sottoposto a proce-dura di revisione (sostituzione o rimozione di una o più componenti della protesi). La revisione del-l’impianto presenta costi maggiori dell’intervento primario ed è tecnicamente più lunga e comples-sa, incidendo in modo rilevante sulla qualità di vita del paziente e dei suoi familiari oltre che sulServizio Sanitario Nazionale (SSN).

La procedura di THR è frequentemente eseguita negli ospedali di tutta Europa e il suo impat-to economico è assai rilevante. Inoltre, a causa dell’invecchiamento della popolazione e grazie alperfezionamento della tecnica chirurgica, i volumi sono in continua crescita. Con riferimento al

12

contesto Italiano, l’analisi della banca dati SDO (Schede di Dimissione Ospedaliera) ha mostratoun incremento del 32.4% nel numero di procedure di THR (codice ICD-9-CM 81.51) eseguite perqualsiasi indicazione nel periodo 1999-2005. Dall’analisi emerge anche che maggiormente sogget-ti alla procedura sono stati gli individui con età maggiore o uguale ai 65 anni, in prevalenza disesso femminile.

Per la valutazione delle performance di una determinata protesi, in termini di efficacia e sicu-rezza, è necessario tenere in considerazione una serie di variabili legate al paziente (ad es. età,indicazione, anatomia), legate alle caratteristiche del dispositivo (ad es. design, materiali, rivesti-menti superficiali) e alle modalità di intervento (ad es. metodo di fissaggio, tecnica chirurgica).L’osservazione di tali variabili può essere fatta all’interno di studi clinici opportunamente disegna-ti o attraverso la raccolta sistematica di tutti i dati all’interno di un registro di artroplastica. È impor-tante ricordare che l’analisi dovrebbe essere fatta tenendo in considerazione il singolo sistema pro-tesico (specificando coppa e stelo) in quanto le performance possono essere strettamente legatealle particolarità che contraddistinguono l’uno o l’altro dispositivo.

ObiettiviL’efficacia e la sicurezza delle protesi per la sostituzione totale dell’anca è sicuramente una

tematica importante per i sistemi sanitari di tutti i Paesi. I metodi concepiti da ciascuna nazioneper monitorare e regolare l’utilizzo e per gestire le politiche di rimborso dell’ampia varietà di dispo-sitivi esistenti sono abbastanza diversi e talvolta, come ad esempio nella pratica clinica Italiana,l’utilizzo e il rimborso non vengono,di fatto, posti in relazione all’efficacia dei dispositivi.

Obiettivo generale del report è stato quello di rendere più trasparente e chiara la situazioneattuale in merito all’utilizzo delle protesi totali d’anca in Italia, cercando di fornire informazioni utiliper i decisori nell’ottica dell’adozione di scelte orientate ad una politica di miglioramento dell’inter-vento sanitario con contestuale contenimento della spesa.

I quattro obiettivi elencati di seguito sono stati raggiunti in fasi successive del lavoro di asses-sment:

1. Aggiornamento dello studio condotto nell’ambito del Piano Nazionale delle Linee Guida (inparticolare il PNLG-8) “Revisione sistematica sulle protesi d’anca: affidabilità dell’impianto”risalente al 2003.

2. Analisi della struttura dei registri di artroplastica di nazioni europee ed extra-europee e deiregistri regionali italiani con raccolta ed analisi dei dati di efficacia in essi riportati.

3. Comparazione dei dati di efficacia ottenuti dagli studi clinici e dai registri individuati per cia-scun sistema protesico (hip system, cioè coppa e stelo, definito dal nome dei prodotti e deiproduttori), .

4. Rilevazione sul territorio italiano del prezzo di acquisto dei sistemi protesici individuati infunzione delle evidenze di efficacia disponibili.

13

MetodiPer il primo punto, aggiornamento della revisione sistematica del PNLG-8, sono state utilizza-

te metodiche di ricerca e analisi del evidenze riconosciute dalla communità scientifica internazio-nale. Sono stati considerati sistemi protesici impiantati per indicazioni non traumatiche in gruppidi pazienti con età media di 65 anni o superiore e con follow-up medio di 5 anni. Sono stati inclu-si trial randomizzati e studi osservazionali che comparavano differenti tipologie di sistemi protesi-ci o stesse tipologie con differenti caratteristiche (ad es. stessa coppa ma differenti steli, diversotrattamento superficiale). Sono stati considerati ed estratti anche studi di revisione che includeva-no studi randomizzati controllati o studi osservazionali. Le ricerche sono state effettuate su trebanche-dati (PubMed, EMBASE e Cochrane Library) e coprono il periodo 2004-2007, senza alcunarestrizione di lingua. L’estrazione dei dati e la valutazione della qualità metodologica degli studi èstata implementata da due autori indipendentemente.

Per il secondo punto, analisi e raccolta dei dati di efficacia dai registri, sono stati individuati edanalizzati 7 registri di nazioni europee, 3 registri di nazioni extra-europee e 3 registri regionali ita-liani. Le variabili maggiormente considerate sono state quelle che permettono di valutare l’effica-cia e la sicurezza dell’impianto e quindi quelle legate alla sopravvivenza dello stesso. L’impianto èconsiderato in sopravvivenza fin quando non si è verificato il suo fallimento, quindi fino a quandonon è stato sottoposto a revisione. In questo contesto è utile ricordare che il tasso di revisione (lapercentuale di impianti sottoposti a revisione ad un determinato periodo di tempo) può esserefacilmente collegato al tasso di sopravvivenza dell’impianto (percentuale di impianti ancora in sedead un determinato periodo di tempo) sottraendo quest’ultimo da 100.

Per il terzo punto, comparazione dei dati di efficacia ottenuti da studi e da registri, è stato defi-nito un criterio che permette di evidenziare in modo qualitativo e quantitativo le evidenze a sup-porto di ciascun sistema protesico. In particolare, i dati di sopravvivenza dei sistemi protesici sonostati raggruppati in 3 classi relativamente alla loro provenienza (da studi clinici e da almeno unregistro di artroplastica, soltanto da registri di artroplastica, soltanto da studi clinici).

Per il quarto punto, rilevazione del prezzo di acquisto dei sistemi protesici individuati, sonostate interrogate le centrali di acquisto delle Regioni e sono stati altresì consultati i listini prezzi deiproduttori.

RisultatiApplicando i criteri di inclusione agli studi individuati a seguito delle ricerche sulle tre banche

dati, 5 studi singoli e 3 studi di revisione sono stati sottoposti al processo di estrazione dei dati.

Dall’analisi degli studi singoli è emersa una qualità metodologica non ottimale, con gruppi dipazienti poco numerosi (il range di soggetti per studio era 20–204). Spesso si trattava di single-surgeon series (lo stesso chirurgo opera tutti i soggetti) condotti in istituti ortopedici specializzati.È da notare l’elevato numero di studi esclusi per carenze metodologiche o mancanza di dettaglirelativi ai dispositivi comparati. Tale fenomeno riflette il livello qualitativamente basso degli studiclinici, identificato già dallo studio del PNLG-8 e da altri autori.

Dall’analisi degli studi di revisione le problematiche emerse negli studi inclusi sono state leseguenti: i gruppi di pazienti erano poco numerosi; alcuni studi erano affetti da bias di attrito(pazienti persi al follow-up senza motivazione chiara); l’analisi della qualità della vita del paziente

14

veniva raramente effettuata; il follow-up degli studi era generalmente breve e mai superiore ai 10anni; alcuni studi erano privi di dichiarazione di conflitti di interesse degli autori e della fonte delfinanziamento dello studio.

In merito all’analisi e alla raccolta dei dati di efficacia dai registri di artroplastica è emersa unaeterogeneità notevole nella scelta delle variabili chiave e nel metodo di presentazione dei dati traregistri di diversa provenienza. Nell’ambito del presente studio, l’interesse principale è stato rivol-to ai dati di sopravvivenza degli impianti e questa scelta ha portato alla selezione di quei registriche riportavano tale dato. Tra i registri nazionali, soltanto quello Australiano, Danese e Svedeseriportavano la implant survival (sopravvivenza dell’impianto), riferita al singolo sistema protesicoed espressa in percentuale, a periodi di tempo diversi. Tra i registri regionali Italiani, essendo ispi-rato a quello Svedese, solo il registro protesico dell’Emilia-Romagna riportava dati di sopravviven-za dell’impianto.

La comparazione dei dati provenienti da fonti multiple (studi clinici e registri di artroplastica)è stata condotta adottando un criterio arbitrario relativo alla suddivisione su tre livelli di evidenzadei sistemi protesici individuati: sistemi protesici con evidenze provenienti da studi clinici e da regi-stri di artroplastica; sistemi protesici con evidenze provenienti soltanto da registri (almeno due,“vincolo dei due registri”); sistemi protesici con evidenze provenienti soltanto da studi clinici.Specifichiamo che il “vincolo dei due registri” è stato in questa sede definito per fornire maggioregeneralizzabilità alle stime di sopravvivenza dell’impianto. È noto infatti che le performance deidispositivi oggetto di analisi sono legate al contesto nazionale in quanto la familiarità dei chirurghicon un determinato sistema protesico varia da un Paese all’altro.

La rilevazione dei prezzi di acquisto dei sistemi protesici individuati, effettuata presso le cen-trali di acquisto delle Regioni si è conclusa con una copertura parziale. Tale risultato è sicuramen-te legato alla regionalizzazione del sistema che risulta in una alta variabilità inter-regionale delprezzo d’acquisto. Non avendo ottenuto dati di costo di qualità significativa per il contesto italia-no, non conoscendo il reale numero di diversi sistemi protesici utilizzati nella pratica clinica italia-na, non avendo stime di efficacia robuste nè un sistema di monitoraggio che segua il paziente pro-tesizzato durante tutto il ciclo della sua vita, non è stato ritenuto opportuno portare avanti un veromodello di costo-efficacia. I dati reali di efficacia in Italia sono, infatti, riportati soltanto nel rap-porto annuale del registro dell’Emilia-Romagna e, data l’alta specializzazione dei centri ortopedicipartecipanti a tale registro, tali dati non possono essere ritenuti generalizzabili a livello nazionale.

Attraverso i metodi precedentemente descritti è stato possibile identificare evidenze di effica-cia relative soltanto ad una piccola parte dei sistemi protesici utilizzati nella pratica clinica odier-na. La decisione di combinare dati provenienti da fonti molto diverse, studi clinici e registri di artro-plastica, può essere considerata uno dei principali punti di forza dell’approccio adottato.

In base a quanto emerge dai risultati del presente studio, soltanto 4 sistemi protesici sembra-no essere supportati da evidenze provenienti da fonti multiple (almeno uno studio e almeno unregistro): il sistema protesico Charnley (cementato), il sistema protesico Mallory-Head (noncementato), il sistema protesico composto da coppa Exeter e stelo Exeter Polished (cementato),e il sistema protesico PCA (non cementato). Dato che la scarsa performance di quest’ultimo è stataampiamente dimostrata, tale dispositivo è ormai desueto. Tuttavia, occorre specificare che a causadei criteri di selezione stringenti e della diversità delle fonti, i risultati mostrati nel presente rap-porto devono essere utilizzati con cautela e l’elenco di dispositivi appena descritto è riportato soloper illustrare le maggiori problematiche nel settore della valutazione delle protesi d’anca.

15

Vista l’inadeguatezza e la scarsa numerosità campionaria degli studi clinici, sembra consiglia-bile l’utilizzo di dati di efficacia provenienti dai registri di artroplastica per gestire le politiche di rim-borso. Infatti, come è emerso dal presente studio, tali dati sembrano essere statisticamente piùconsistenti poiché i gruppi di pazienti che ricevono lo stesso sistema protesico sono molto piùnumerosi all’interno di un registro piuttosto che in un trial clinico. Tuttavia, applicando il “vincolodei due registri”, mancano dati riferiti a 10 anni di follow-up (periodo ritenuto determinante perl’osservazione delle complicazioni legate all’impianto).

Inoltre, è da specificare che le variabili legate al sistema protesico non sono le uniche ad influi-re sulla sopravvivenza dell’impianto. Altri parametri, come l’età, il sesso, lo stato di salute, la qua-lità del tessuto osseo del paziente, assieme al numero di procedure di THR effettuate dal chirur-go e nella struttura ospedaliera dovrebbero altresì essere tenuti in considerazione per effettuareuna analisi bilanciata e realistica. Nessuno dei rapporti annuali dei registri di artroplastica analiz-zati effettuava una stratificazione per tutte queste variabili. Tale limite è sicuramente legato alladiversa natura dei registri nazionali, istituiti spesso per finalità differenti. Sono stati tuttavia indi-viduati diversi sforzi, da parte di associazioni internazionali, diretti ad uniformare le strutture deidiversi registri nazionali, in modo da ottenere in futuro dati dotati di maggiore generalizzabilità.

DiscussioneIn conclusione, quanto mostrato nel presente rapporto dovrebbe essere a sostegno di iniziati-

ve reali volte alla necessità di controllare l’utilizzo dei sistemi protesici per la sostituzione totaledell’anca e orientare di conseguenza le politiche di rimborso di tali dispositivi. Scopo principe di taliiniziative dovrebbe appunto essere quello di aiutare il chirurgo nella scelta dei sistemi con lemigliori performance, supportate dal più alto grado di evidenza, e guidare la scelta verso quelliche, a parità di performance, sono disponibili al prezzo più basso.

Occorre evidenziare che i limiti del presente studio sono legati alla qualità dei dati di origine enon sono di tipo metodologico, relativi alla ricerca e all’analisi delle informazioni. Ad esempio, inuna prospettiva di salute pubblica, gli studi clinici, così come sono stati condotti fino ad ora, sem-brano apportare un contributo minimo per la valutazione delle performance dei sistemi protesici.Infatti, problematiche legate alla scarsa numerosità dei gruppi e alla generalizzabilità dei risultati,ne inficiano notevolmente l’utilità. Anche la potenziale utilità dei dati di sopravvivenza degli impian-ti, estratti dai registri di artroplastica, è stata notevolmente attenuata dalla mancanza di stratifica-zione degli stessi all’interno dei rapporti annuali consultati. Inoltre, i diversi registri consultati sonocaratterizzati da diverse modalità di presentazione dei dati e anche la scelta delle variabili chiaverisulta essere non uniforme tra registri di diverse nazioni.

Nell’ambito della valutazione delle protesi per la sostituzione totale primaria dell’anca è quin-di ragionevole affermare che l’utilizzo del concetto di “best evidence” nel contesto Italiano è resoattualmente impossibile dalla mancanza di un sistema chiaro e validato per la raccolta e la gestio-ne dei dati reali di efficacia e di costo.

16

RaccomandazioniQuanto emerge da questo rapporto suggerisce un utilizzo più esplicito, da parte del SSN, delle

evidenze di efficacia per la gestione delle politiche di rimborso dei sistemi protesici per la sostitu-zione primaria totale dell’anca. Inoltre, rilevazioni continue dei dati di costo dovrebbero esserecondotte in maniera sistematica su tutto il territorio nazionale. Solo l’acquisizione diretta di dati diefficacia e costo reali può consentire una analisi costo-efficacia dettagliata in una prospettiva disalute pubblica orientata a politiche di contenimento della spesa.

Il metodo adatto per implementare questo tipo di approccio prevede innanzitutto l’istituzionedi un registro nazionale di artroplastica. Tale strumento permetterà, negli anni successivi alla suaintroduzione, di monitorare la pratica clinica, e in seconda misura il mercato, dei sistemi protesicinel contesto dell’artroplastica dell’anca. È auspicabile che il registro nazionale sia anche un fortestimolo per la collaborazione tra il SSN e le aziende produttrici.

Da quanto osservato, il rimborso dei sistemi protesici dovrebbe idealmente essere diretto versoquei dispositivi caratterizzati dai migliori dati di performance (efficacia e sicurezza) supportati daevidenze di alta qualità. Con questo criterio sarebbe possibile ottenere i vantaggi maggiori in ter-mini di interventi di revisione evitati e contenimento dei costi.

Per quanto riguarda i sistemi protesici di nuova o imminente introduzione, si raccomandanopolitiche di rimborso condizionato. Tali dispositivi dovrebbero essere inseriti in trial clinici rando-mizzati aventi adeguata potenza statistica e opportunamente disegnati e coordinati dalle autoritàcompetenti. In alternativa, i dispositivi di nuova o imminente introduzione dovrebbero essere rim-borsati solo se esistono prove di performance adeguata (efficacia e sicurezza) provenienti da regi-stri di artroplastica di altre nazioni. Con questi metodi verrebbe a crearsi un sistema di rimborsoorientato alla generazione di evidenza che premia l’utilizzo dei dispositivi con migliore evidenza diperformance e riduce i costi che il SSN sostiene per quei dispositivi non supportati da evidenze diefficacia clinica.

17

1. Background

1.1 Indications for primary total hip replacement

When other treatment options such as pharmacological therapy, weight loss, muscle-strengthe-ning exercises, and assistive devices have been exhausted, total hip replacement surgery is consi-dered to be the best approach to managing severe hip osteoarthritis and restoring mobility, provi-ded that the patient is otherwise in good health1. Rheumatoid arthritis also requires hip replace-ment. Whilst osteoarthritis is associated with advancing age, rheumatoid arthritis is more likely tooccur in young adults. Other diseases treated by the procedure of hip replacement include osteo-necrosis, congenital dislocation, Paget’s disease, ankylosing spondylitis and traumatic arthritis.

The procedure entails replacing the diseased hip joint with an artificial one. As part of the hipprosthesis, an artificial socket is implanted in the pelvis. The neck and head of the femur are repla-ced by a prosthesis that enables motion within the socket. The whole artificial joint is called “hipsystem” or simply “hip prosthesis” and the surgical procedure is defined total hip replacement(THR).

In this report the term “hip system” refers to all the components implanted in a THR proce-dure (stem, head, cup, liner and other components when required; see Appendix 1 for a moredetailed description). This term is used as synonymous of hip prosthesis.

The majority of patients are older than 60 years2 but the demand for hip replacement hasincreased over the past 10 years and is likely to continue to do so as a result of ageing popula-tions and because of the extension of the age range for this treatment2–4.

1.2 Epidemiology: primary THR in Italy and worldwide

Hip replacement is an elective surgery performed in a hospital setting with great frequency inmany European countries (e.g. about 170,000/year in Germany, about 65,000/year in England andWales, about 55,000/year in Italy) and thus has a significant budget impact5,6.

Data from the SDO database (Schede di Dimissione Ospedaliera, hospital discharge records)show an increase of 32.4% in the number of THR procedures (ICD-9-CM code 81.51) performedfor all reasons between 1999 and 2005 (Figure 1). The most frequent indication is osteoarthritiswith a prevalence of THR intervention in the age groups above 65 (Figure 2). Furthermore, thenumber of female hospitalisations for THR is greater than for males and this is closely linked togender-oriented degenerative pathologies such as osteoporosis7.

Arthritis is one of the most prevalent chronic conditions and is a leading cause of disability.However, the impact of arthritis is not restrained by national boundaries, affecting an estimated 3million Australians, 6 million Canadians, 8 million British, almost 43 million Americans, and 103 mil-lion in Europe. The hip being one of the most frequently affected joints. With the ageing of popu-lations, these numbers and the associated disabilities will quickly escalate8.

18

Figure 3 reports all the primary THRs performed in Italy per region. Among regions with thehighest number of THR procedures (Piemonte, Lombardia, Veneto, Emilia-Romagna, Toscana andLazio) only two (Lombardia and Emilia-Romagna) have instituted a regional arthroplasty registry.

Currently there are three Italian regional arthroplasty registries: Lombardia, Emilia-Romagnaand Puglia.

Figure 1: Trend for primary THR (ICD-9-CM code 81.51)performed in Italy from 1999 to 2005. Data from SDO database6.

19

Figure 2: Number of primary THR (ICD-9-CM code 81.51) per year and per age groups in Italy. Age groups for under 25 are not shown in the graph. Data from SDO datbase6.

Figure 3: Number of primary THR (ICD-9-CM code 81.51) performed in 2005 for all reasons inall the Italian regions. Regions are listed in geographical order (from north to south). Data from SDO database6.

Key: P.A. = autonomous province.

20

21

2. Technology, procedure and alternatives

Prostheses for THR consist of two groups of components: the femoral component (or stempart) that is fixed into a reamed medullary canal and the acetabular component (or socket part)that is inserted in place of the acetabular part of the joint.

The different components of the new joint can be implanted in the femur and acetabulum withor without bone cement. A first classification consists of cemented prostheses (all the componentsare fixed with cement), uncemented or cementless prostheses (all the component are press-fittedin the bone), and hybrid prostheses (one component is cemented and one is uncemented).

Nowadays a huge number of hip prostheses are commercially available, differing in configura-tions, designs, materials and surface treatments. Many models are available in modular designs,so that various combinations of features can be selected to best fit patient needs and surgeon pre-ferences (see Appendix 1 for the technical characteristics of hip prostheses).

Hip prostheses, as well as total joint prostheses, were classified as Class IIb devices (Class IIIwhen coated with hydroxyapatite) and regulated by the EU Directive 93/42/EEC9. Recently, inAugust 2005, after a request from France and the UK, hip, knee and shoulder prostheses havebeen reclassified as Class III devices. The Commission Directive 2005/50/CE states:

“(11) In order to achieve the optimal level of safety and health protection and to reduce the designrelated problems to the lowest level, the design dossier of hip, knee and shoulder replace-ments, including the clinical data used by the manufacturer to support the claimed perform-ance and the subsequent post-marketing design and manufacturing changes should be exam-ined in detail by the notified body before these devices are introduced in general clinical use.

(12) Consequently, the notified body should, under the full quality assurance system, effective-ly carry out an examination of the design dossier and of the changes to the approveddesign in accordance with point 4 of Annex II to Directive 93/42/EEC.

(13) For these reasons, it is necessary to proceed to the reclassification of hip, knee and shoul-der total joint replacements as class III medical devices.”

In this revision, the Commission stated that, as data concerning long-term performance are oftennot available, conclusions concerning clinical data reported by the manufacturers, and variationsin the design and realisation of the device have to be examined in detail before their generalisedclinical use. The main difference appears to be that the new directive puts more emphasis on pre-clinical evaluation9.

Several private Italian and International companies offer hip prostheses on the market. Eachmanufacturer’s prosthesis differs slightly from those of its competitors and a huge number ofmodels are used in the clinical practice (see the non-exhaustive lists reported in Appendix 1).

As far as the outcomes are concerned, a great variability in the performance of the prosthe-ses can be observed in all the published literature, including the 2003 systematic review on theeffects of THR (PNLG-810) carried out by the Italian National Guidelines Programme. As a resultof the complex interaction between the bone tissue and the prosthesis and considering the uni-que biomechanics of the joint, hip prostheses are potentially susceptible to complications both in

22

the short term (dislocation), and in the long term (wear and loosening). When loosening occurs,the successive step is revision of the failed implant (defined as the replacement or extraction ofone or more prosthesis components11). Revision operations are more expensive and time consu-ming than primary surgery, and besides being a burden to the National Health Service (NHS), theyhave a negative impact on the patient’s quality of life and on his/her family wellbeing.

A number of factors other than biomechanics can also affect the performance of the prosthe-sis and cause implant revision: fixation method (with or without bone cement); surface coatingsof the uncemented components (e.g. porous titanium or hydroxyapatite); wear of the bearing sur-faces; hospital and surgeon procedure volume.

23

3. Report's objectives: policy and research questions

We aimed to assess current evidence regarding the hip prostheses (or hip systems) used inItalian clinical practice, with the following objectives:

1. to update the PNLG-810 systematic review of the evidence, looking for comparativestudies assessing medium to long-term outcomes (mean follow-up of 5 years ormore) of surgery involving prostheses used in primary THR, and to assess the extentto which such outcomes vary between different devices;

2. to carry out a review of accessible data from national arthroplasty registries ofEuropean and non-European Countries, and from Italian regional arthroplasty regi-stries and assess their quality;

3. to compare data from comparative studies and registers for the same hip systems;

4. to report on hip systems using the available evidence of effectiveness and costs rele-vant to the Italian market, providing criteria to manage the reimbursement policy.

24

25

4. Methods

We were interested in assessing effectiveness and safety of prostheses used in primary THRsurgery with a minimum 5-year survival in gropus of patients with a mean age of 65 or more whohad undergone the procedure for non-traumatic indications.

We intended to synthesise the most recent evidence from published literature and from sear-ches in the arthroplasty registers. In particular, we were interested in performance data for eachhip system, i.e. survival rate. With this aim we performed a systematic review (see methods in para-graph 3.1) and considered evidence from arthroplasty registers (see methods in paragraph 3.2).

However, in view of the widely different outcomes used in literature identified by the PNLG-810 review and of the interlinked nature of the safety and effectiveness dimensions in THRstudies and arthroplasty registers, we decided to privilege the use of “implant failure” as an accep-table proxy to both patients and the health service12. The definition of failure in traditional survi-val statistics is “revision of one or more implant components or removal of the whole prosthesis”.Revision rate (the percent of implants revised at a time period) can be easily linked to implant sur-vival rate (percent of implants in place at a time period) subtracting from 100. Although the indi-cations for revision are known to be sensitive to local conditions, the general consensus appearsto favour revision as a blunt endpoint encompassing the two main dimensions of outcome. In ouranalysis, revision is defined as “replacement or extraction of one or more prosthesis component”.

4.1 Methods of the systematic review

4.1.1 Criteria for considering evidence

To update the PNLG-810 systematic review we considered two sources of evidence: reviews ofclinical studies and single clinical studies.

Types of studies

We included all randomised controlled trials (RCTs) and all observational studies comparing dif-ferent types of hip prostheses or the same prosthesis with different features (e.g. the same cupbut different stem, treated surface versus untreated surface, etc.). We included single studies witha mean follow-up of 5 years or more and review studies reporting evidence from RCTs and obser-vational studies.

Types of participants

Groups of patients with a mean age of 65 years or more affected by degenerative joint disea-ses (osteoarthritis and rheumatoid arthritis) who underwent primary THR.

26

Types of intervention

Primary THR, as described in the “Background” (Chapter 1). Only devices clearly identified bymanufacturer and model were considered.

Types of outcome measures

Data for the following outcomes were considered:

(1) Implant related complications

• dislocation of the prosthesis

• loosening of the prosthesis

• acetabular wear

• breakage of the implant

• disassembly of the implant

• peri-prosthetic fractures

• complications related to cement insertion

• other surgical complications of fixation (as detailed in each study)

• reintervention (or reoperation) and revision rate (within the follow-up period of thestudy)

• deep wound infection (infection around the implant)

(2) Final outcome measures

• mortality for implant-related causes (within the follow-up period of the study, bothearly and late)

• pain (persistent pain at the final follow-up assessment)

• mobility (use of walking aids, return to activity)

• other functional outcomes as listed in each study

• health related quality of life measures.

4.1.2 Search methods for the identification of studies

The same search strategy and databases used for the PNLG-810 review were used to includestudies published after June 2003 as follows:

• PubMed from June 2003 to July 2007;

• EMBASE from June 2003 to July 2007;

• The Cochrane Library from June 2003 to July 2007.

No language restrictions were applied. The general search strategy is shown in Appendix 2.

27

Two review authors independently extracted data for the outcomes listed above and themethodological quality of each study was assessed independently without masking the journalname and author details. The data extraction form for review studies is at Appendix 3, the dataextraction form for single studies is at Appendix 4. Differences were resolved by discussion bet-ween the reviewers. We assessed quality of the reviews and single studies separately and withinthese, we assessed quality of randomised and non-randomised studies separately.

Randomised studies were assessed according to the randomisation method, generation of theallocation sequence, allocation concealment, blinding, and follow up according to the criteria inthe Cochrane reviewers’ handbook13. Non-randomised studies were assessed for the presence ofpotential confounders using the appropriate Newcastle-Ottawa Scales (NOS) for cohort studies14.We assigned risk of bias categories to the studies on the basis of the number of items judged ina-dequate in each study: 1) low risk of bias: none or one inadequate item; 2) medium risk of bias:two or three inadequate items; and 3) high risk of bias: more than three inadequate items.

Review studies were assessed according to inclusion criteria, study design, search methodsand description of results.

4.2 National arthroplasty registries and methods for their analysis

Arthroplasty registries collect information regarding primary and revision operations performedin a defined geographical area, usually a single country. However, some regional registries alsoexist. Registries reflect the standards in surgical procedures of the reference health system. Datafrom registers are useful for assessing performances of hip systems as they could provide accep-table performances estimates. However, since each national register is an integral part of its healthsystem, its data are highly context specific. Differences between countries, such as experience incementing techniques, designs of implant, surgical approaches, regimes of rehabilitation, or gene-ral organisational and cultural features of the health system, may affect the outcome of the inter-vention15.

Open-access annual reports are usually available from the registries' web portal. Other disse-mination mechanisms consist in the publication of research activities in specialised peer-reviewedjournals.

In Europe, several arthroplasty registries are linked by the European Federation of NationalAssociations of Orthopaedics and Traumatology (EFORT)16. The European Arthroplasty Register(EAR) in cooperation with EFORT and the established European registers defined three aims of aregister16:

• registration in a central database of all primary and revision operations performed ina defined geographical area;

• follow-up of the implant until it has to be revised or the patient dies or emigrates;

• failure to be defined as a revision of at least one part of the implant.

A minimal data-set17 that have to be recorded in a register for primary and revisions procedu-res is suggested by EFORT and is reported in Appendix 5.

28

Italy does not have a National arthroplasty registry. The Italian NHS is regionalised and onlyfew regions decided to implement a registry. The three available regional prosthetic registries arein Emilia-Romagna, Lombardia and Puglia.

4.2.1 Searches in the arthroplasty registers

We searched the worldwide web for references to national arthroplasty registries. We alsoaccessed the EFORT portal16. We corresponded with several register workers to retrieve furtherinformation to aid our analysis. We identified arthroplasty registries for 7 European and 3 non-European countries. We considered all the 3 Italian regional arthroplasty registers currentlyimplemented (Table 1). In particular, we were interested in performance data for each hipsystem, i.e. survival rate expressed as a percent at a certain follow-up period (preferably at 10years).

Table 1: Arthroplasty registers consulted for analysis

Geographic

areaRegistry name Link to the website

European Countries

Denmark Danish Hip ArthroplastyRegister18 www.dhr.dk/ENGLISH.htm

England andWales

National Joint Registry forEngland and Wales 19 www.njrcentre.org.uk

Finland Finnish NationalArthroplasty Register 20 www.nam.fi/english/publications/

Norway Norwegian ArthroplastyRegister 21 www.haukeland.no/nrl/

Romania Romanian ArthroplastyRegister 22 www.rne.ro/site/Default.aspx

Slovakia Slovakian NationalArthroplasty Register 23 https://sar.mfn.sk/public/index.php?id=178

Sweden Swedish National HipArthroplasty Register 24 www.jru.orthop.gu.se/

Non-European Countries

Australia Australian OrthopaedicAssociation National JointReplacement Registry 25

www.aoa.org.au/jointregistry.asp

Canada Canadian JointReplacement Register 26 http://secure.cihi.ca/cihiweb/dispPage.jsp?cw_page=services_cjrr_e

New Zealand New Zealand JointRegister 27 www.cdhb.govt.nz/NJR/

Italy (Regional)

Emilia Romagna Registro Regionale diImplantologia ProtesicaOrtopedica 28

https://ripo.cineca.it/

Lombardia Registro OrtopedicoProtesico Lombardo 29 www.sanita.regione.lombardia.it/pubblicazionivarie/rapporto_registro_ortopedico.htm

Puglia Registro Regionale Protesid’Anca 30 www.cimedoc.uniba.it/prot_anca/

29

4.2.2 Key variables in an arthroplasty register

Data from arthroplasty registers may have higher generalisability than from formal studies withselected populations (i.e. higher likelihood that the types of patients, indications and proceduresreflected what actually happens in real everyday practice). In addition they are also likely to bemore powerful (numerous) and with a longer follow-up than data from formal studies such as cli-nical trials. Thus such data could successfully be used to enhance the evidence from formal stu-dies which had been found to be incomplete by previous reviews (PNLG-810). However, becauseof the potential differences between registers (e.g. different levels of description of prostheses andoutcome reporting)31 we also undertook a systematic comparison of the key variables in each regi-ster to assess the actual level of generalisability that each register offered and, as a consequen-ce, its capacity to contribute to our data set. We undertook this analysis on the basis of the mostrecent register reports that we could find and assumed that the data reported were in “so far” for-mat (i.e. cumulative from the inception of the register). Results of the survey are reported in para-graph 4.2.

We also tried to confine our analysis to data for primary THR for non-traumatic indications inthe age groups included in our review. Finally, we tabulated data from recognisable hip systemsby register and compared these data with those from single studies to construct a list of systemsfor which there is evidence from register and primary studies, and either from registers only andfrom studies only. Our assumption was that register and single-study evidence were probably ofhigher value given the diversity and larger denominator than data from registers or single studiesalone.

4.3 Cost-effectiveness analysis

We intended constructing a cost-effectiveness analysis comparing the costs and outcomes ofcompeting prostheses. Our aim was to guide decision-makers by calculating incremental cost-effectiveness ratios (ICERs). We attempted to develop a model which could allow comparison onthe basis of the available data, of the total costs of each device, with comparable technical andclinical features (fixation method, implant characteristics, articulating surfaces, etc.), with theireffectiveness. The outcome we considered was “years-free-of-revision”. We collected informationon the costs of those hip systems for which we had some clinical data. This was done by contac-ting regional purchasers and producers/distributors of prostheses. Our original intention was toproduce a cost per year-free-of-revision comparison by hip system. We also carried out a searchon our databases (Pubmed, Embase, Cochrane Library) for similar economic models that couldguide our methods. Several relevant studies2,32 were found but none from the Italian context,although we are aware of one ongoing study.

Using hospital discharge summaries we identified the specific surgical procedure of “primaryTHR”. We did not consider the “do nothing” alternative (no replacement) because of the impossi-bility of doing nothing at this stage in the acceptance and availability of the procedure.

We identified a reference population of both males and females older than 65 years, withdegenerative joint diseases. We planned to obtain implant survival data from our review of theevidence. We considered medium time of implanting necessary for primary THR (ICD-9-CM 81.51)and for total or partial revision (ICD-9-CM 81.53). In particular we calculated the time taken foreach type of intervention:

30

• Primary intervention: range 60-180 minutes;

• Partial revision: range 60-180 minutes (according to the component replaced);

• Total revision: 180 minutes or more.

The actors we considered for the intervention were: an orthopaedic surgeon, an assistant sur-geon and one or two assistants (surgical team), an anaesthetist, and two nurses.

Cost analysis was conducted on the purchasing price of the devices in Italy by differentRegions (Centralised purchasing system) or by medical facilities, and also from the manufacturersprice lists of referral for total implant systems.

We thought that the large variety of devices on the market, characterised by a wide range ofcosts, would need a sensitivity analysis to assess the robustness of results to the use of differentestimates of costs and effects.

As explained at paragraph 4.4 we were unable to complete a credible economic model.

31

5. Results

5.1. Evidence from clinical studies

We updated the PNLG-810 systematic review. The review presented evidence available to June2003 in an effort to provide guidance in the selection of hip systems. Literature searches werelimited to randomised controlled trials (RCTs) comparing outcomes of different hip systems withat least 5 years follow-up, without age restrictions in the patient population. One systematicreview and 57 single studies were identified for a more detailed evaluation. Among these, 11 RCTsfulfilled all the inclusion criteria and were extracted in detail33-43. In addition a partial list of devi-ces used in Italy was included. The authors of PNLG-810 concluded that the methodological qua-lity of the studies was poor and the gap between the systems used in Italy and those supportedby evidence was sizeable. The most notable limit of the study was its non-use of data from arthro-plasty registers. The authors of the PNLG-810 also noted the lack of association between deviceprice and scientific evidence supporting their use, but did not report price data. The evidence fromthe PNLG-810 review is presented in Table 2. This table is divided into 2 sections. The first sectionreports evidence from the PNLG-810 review without age restriction and the second section pre-sents evidence for groups of patients with a mean age of 65 or more from our 2007 update, asthis is the population with by far the highest burden of joint degenerative disease and primaryTHR (see paragraph 1.3 and Figure 2).

We identified 3,246 potentially relevant citations from all sources (Figure 4). After an initialscreening by title and abstract, 3,215 citations were excluded because of their lack of relevanceto our review. This left 31 full text articles which we retrieved for more detailed evaluation.Twenty-three studies were excluded: 3 were untraceable, 4 had an inappropriate endpoint, 6 dealtwith an irrelevant topic, 4 had an improper study design, 4 did not meet the inclusion criteria forage groups and/or follow-up length, 1 presented insufficient data and 1 presented inappropriatecomparators and confusing text (for the list of included studies see Appendix 6; for the list ofexcluded studies with reasons for exclusion, see Appendix 7).

This left 8 full text articles for data extraction. Three were review studies44-46 and five weresingle studies 47-51. Among the single studies, the study by von Schewelov et al.49 did not meetour inclusion criteria since the mean age of the groups of participants was below our limit of 65years. We decided to include it since the mean age differs only by one year (64 instead of 65years) and the study reported important evidence concerning the use of zirconium femoral heads.All extracted studies were in English.

32

Device

assessedAuthors

Device 1

(Manufacturer)

Device 2

(Manufacturer)

Num. of

patients

per

group

Mean fol-

low-up [y]

Quality

[risk of

bias]

Results Notes

Evidence from the PNLG review[6]

Cup Krismer et al.

199633RM (Mathys) PCA

(Howmedica)

60/60 8 High No differences - Not relevant (focused

on radiographic evalu-

ation of cup failure)

Stem Meding et al.

199734Bi-metric unc.

collarless

(Biomet)

Bi-metric unc.

collared

(Biomet)

100/103 3.75 High No differences - Stems coupled with

different cups;

- Too short follow-up

and unclear retired

from study

Hip system Thanner et al.

1999 35Harris-Galante I

unc. (Zimmer)

PCA unc.

(Howmedica)

87/84 9.4 High - 10-year survival:

PCA cup 58%, HG cup

99%; PCA stem 96%, HG

stem 86%

_

Hip system Garellick et al.

199936,37Spectron (S&N) Charnley

(DePuy)

204/206 10 Low No differences with HHS - Too much variables

for definitive judgment

Stem Yee et al.

199938Mallory-Head

HA (Biomet)

Mallory-Head

(Biomet)

33/27 4.5 High No differences _

Stem Meding et al.

199939Bi-metric cem.

collarless

(Biomet)

Bi-metric cem.

collared

(Biomet)

213/224 6.17 Medium Loss of cortical bone with

collarless stem

- No differences with

HHS

Hip System Sharp et al.

200040C-Fit unc.

porous coated

(Corin)

C-Fit unc. HA

(Corin)

78 (total) 5.17 Medium - No differences between

two groups;

- No relations between

Oxford Hip Score and

radiological evaluation;

- High revision rate

(27.5%) in a short fol-

low-up

Stem Settecerri et

al. 200241HD-II cem. col-

lared

(Howmedica)

HD-II cem. col-

larless

(Howmedica)

44/40 9.58 High - Mean HHS: 89 collared,

78 collarless (not sign. but

clinically relevant);

- Stem penetration: 1 mm

collared, 2.4 mm collar-

less;

- Stem failure: 7/24 col-

lared, 6/19 collarless (not

sign.)

_

Hip system Laupacis et

al. 200242Mallory-Head

unc.(Biomet)

Mallory-Head

cem. (Biomet)

124/126 6.3 Medium 12/77 cem. stem revised;

1/86 unc. stem revised

_

Hip system Palm et al.

200243Link Ribbed

Stem (Link)

Link Ribbed

Stem HA (Link)

8/12 8.75 Medium 7/8 non-HA revised;

1/12 HA revised

Non-coated Ribbed

Stem is - considered

not adequate and no

longer produced

Evidence from this review

Cup McCombe et

al. 200447Duraloc 100

(DePuy)

Exeter (Stryker) 52/63 8 Medium Mean wear rate: Duraloc

0.15 mm/y; Exeter 0.07

mm/y (p<0.0001)

_

Stem Rasquinha et

al. 200448Ranawat-

Burnstein

Interlock smooth

(Biomet)

Ranawat-

Burnstein

Interlock rough

(Biomet)

111/109 6.55 Medium - Durability of fixation is

similar between smooth

and rough femoral stems

- Too short follow-up (asep-

tic loosening is likely to

occur in 8-10 years)

Bearing

surfaces

Von

Schewelov et

al. 200549

Charnley Elite

Plus Stem

(DePuy) +

s-steel or zirco-

nium head +

Enduron cup

(DePuy)

Charnley Elite

Plus Stem

(DePuy) +

s-steel or zirco-

nium head +

Hylamer cup

(DePuy)

28/30/28

/28

5 Medium - High risk of fracture for zir-

conium oxide ceramic

head;

- High wear for Hylamer cup

- Mean age of 64

(below our inclusion

criteria);

- Four small groups

Liner Engh et al.

200650Marathon

(DePuy)

Enduron

(DePuy)

220 5.7 High Mean wear rates:

0.01 ± 0.07 mm/y for

Marathon

0.19 ± 0.12 mm/y for

Enduron

_

Stem Sherfey et al.

200651Exeter (Stryker) Endurance

(DePuy)

99/34 5.9 Medium High loosening rates for

Endurance stem

_

Table 2: Results of the PNLG-810 systematic review and our update to July 2007. Studies arereported in chronological order.

Key: unc. = uncemented; HA = hydroxyapatite; HHS = Harris Hip Score; cem. = cemented;

s-steel = stainless steel; y = years.

33

Figure 4: Flow diagram showing details of the literature search, including articles exclud-

ed at each phase of the review.

5.1.1 Description of review studies

Three review studies were included in this systematic review (Table 3). One of these, Aamodtet al.44 presented data on the clinical effectiveness of prostheses used for primary THR in Norway.Ni et al.45 compared cemented with uncemented femoral component whilst Morshed et al.46 com-pared cemented fixation with uncemented fixation in THR.

Aamodt et al.44 reported evidence from 132 studies between 1996 and 2000 updating sear-ches and results of two previous UK HTA programme reviews. The randomised controlled trialsincluded in the review had an average patient number of 340. The minimum follow-up of the inclu-ded studies was 5 years for clinical endpoint and 2 years for radiological analysis. The authors con-cluded that, among the THRs performed in Norway, the Charnley prosthesis had the best and mostcomprehensive evidence base with an implant survival better than 90% after 10 years follow-up.The authors noted that up to a third of prostheses used in Norway lacked any scientific evidenceand that the practice of conducting and publishing studies on self-produced prostheses withoutdeclaring a conflict of interest was widespread. The reviewers included 6 studies based on regi-ster data and commented that different registration procedures between-registers limited thecomparability of the data. Although the general quality of the review was good, this study focu-sed only on the THR performed in Norway and this could present a limit in the generalisation ofthe findings. Further, data were presented only as a synthetic narrative and tables didn’t reportsurvival rates of specific hip systems.

34

Ni et al.45 ran searches to October 2003 on a single database only (PubMed) which we consi-dered inadequate for the methodological quality of the review (although a manual search also sup-plemented the PubMed search). None of the 29 studies had a mean follow-up of more than 10years. There were 10 randomised controlled trials, 17 cohort studies and 4 controlled before-and-after studies. The study was focused only on the femoral component (stem) and authors conclu-ded that in the short-term, cemented femoral fixation present better clinical and functional outco-mes from than those from the uncemented. The results of the review are difficult to evaluatebecause no methodological quality assessment of included studies was undertaken.

Morshed et al.46 reported evidence from 20 studies without restriction on follow-up duration.Searches were carried out to the end of 2005. The authors reported that, in a large population,cement fixation has generally superior survival rates while for younger patients (aged 55 or less),uncemented fixation achieves lower revision rates. In addition the performance of cementedstems was correlated with the material (titanium stem vs. CoCr stem). The authors also noted thatcontrol groups in these studies had not always been assigned to the best available treatment. Thequality of the review appears impressive and the text includes numerous analyses (meta-analy-ses, meta regression and scatter plots). However, since no methodological quality assessment ismentioned in the text (apart from a description of some methodological weaknesses in theDiscussion section of the review), it is difficult to assess the reliability of the analyses and results.

The three identified reviews include studies across the same time period as the PNLG-810

review and our update. However, they rarely identify devices by name and manufacturer, thus limi-ting the utility of the information presented. While we checked the bibliography of included stu-dies for articles which we may have missed, we did not use the information other than to notesome of the generic conclusions.

Equally, we could not identify any Cochrane review assessing the effects of prostheses clear-ly identified by model. The content of the reviews were too general and mainly addressed que-stions such as type of surgical approach.

35

AuthorsYear of

Searches

Inclusion

criteria

Aims /

Comparison

N.

of studies

N.

of

patients

Mean

follow-up

[y]

Quality

[risk of

bias]

Results Notes

Aamodt etal., 200444

2000 -Primary THR;

-Hip prosthesesused in Norwayin 1996-2000(data from regi-ster);

-Follow-up 5 yearsminimum (for cli-nical endpoint);

-Follow-up 2 yearsfor otherendpoints (RSA,radiological ana-lysis, etc.);

-English, German,French, Swedish,Danish,Norwegian.

Clinicaleffectivenessof prosthe-ses used forprimary THRin Norway

132 340a 5b Low -The Charnley prosthe-sis had the best andmost comprehensiveevidence base (> 90%implant survival after10 years);

-The European marketis not well regulated(weakness of CEmark).

-The resultsare referredto THR inNorway.

Ni et al.,2005 45

2003 Studies with the-objectives tocompare cemen-ted and unce-mented THRaccording to theclinical and/orradiological out-come;

-Primary THR, notrevision THR norhemiarthroplasty;

-Original clinicalstudy, rather thana literature

Comparisonof cementedwith unce-mentedfemoralcomponent

29 _ < 10 High -Better short-term clini-cal and functional out-comes can be obtainedfrom cemented femoralfixation than thosefrom the uncemented;

-No studies has a meanfollow-up period ofmore than 10 years.

-Only 1 data-base;

-Quality con-sidered onlynarrative;

-Differentstudy design(impossibleextract con-clusion).

Morshed etal., 200746

2005 -THR performedfor any reasonother than fractu-re;

-Controlled com-parison ofcemented vs.uncemented fixa-tion;

-Outcome as mea-sured by survivalto time of revi-sion surgery forany reason.

Comparisonof cementedvs unce-mented fixa-tion in THR

20 _ Any Low -Cement fixation hassuperior survivalamong large popula-tion;-Uncemented fixationpresents lower revisionrate for young patients(younger than 55years);

-Cemented fixationresulted inferior whenTi stem is used ratherthan Co-Cr stem;

-Control groups havenot always selectedwith regard to the bestavailable treatment.

No quality

assessment.

a RCT averaged patient number;

b minimum follow-up;

Key: RSA = radiostereometric analysis; N. of studies = number of studies; N. of implants = number of

implants; y = years.

Table 3: Analysis of review studies. Studies are reported in chronological order.

36

5.1.2 Description of single studies

Five single studies were included in this systematic review (Table 2). Four studies were rando-mised: McCombe et al.47; Rasquinha et al.48; von Schewelov et al.49, and Engh et al.50. One study,by Sherfey et al.51, was a cohort study.

McCombe et al.47 presented 115 hip implants divided in two groups: uncemented cup (Duraloc100) and cemented cup (Exeter). Eight years of mean follow-up showed that the cemented cupused in the study wore less than the cementless cup. In particular, the mean rate of wear in thepatients with uncemented cup (Duraloc 100) was 0.15 mm/year (range from 0 to 0.4) whilst inpatients with cemented cup (Exeter) was 0.07 mm/year (range from 0 to 0.22) (p<0.0001).

Rasquinha et al.48 compared the performance of the same stem (Ranawat-Burnstein Interlock)with a 17 and 170 μinches of surface finish respectively. In 223 stems implanted and followed for6.55 years, no significant differences emerged between the two groups. In particular, using revi-sion for any cause as an end-point, the Kaplan-Meyer survivorship at 7 years was 99.1% ± 0.9%in the smooth cohort and 98.2% ± 1.7% in the rough cohort. The authors reported that follow-up had to be extended to 8-10 years since in the long-term aseptic loosening is likely to occur.

Von Schewelov et al.49 presented a population with a mean age of 64, that is just below ourinclusion criteria. This study reported evidence on zirconium heads and under-pressure re-heatedacetabular component (Hylamer). The authors presented 4 groups with different head-cup com-binations: stainless-steel femoral head combined with a standard UHMWPE acetabular component(Enduron); stainless-steel femoral head combined with a Hylamer acetabular component; zirco-nium-oxide ceramic femoral head combined with a standard UHMWPE acetabular component(Enduron); zirconium-oxide ceramic femoral head combined with a Hylamer acetabular compo-nent. The authors stated that the study had to be interrupted for ethical reasons, but this did notaffect its statistical power since the differences between groups were large. In particular, at 5-years follow-up, the mean annual wear measured was high in the groups with zirconium headif compared to the groups with stainless steel head (0.17 and 0.40 mm/y versus 0.11 and 0.34mm/y respectively). The authors suggest that, due to conflicting reports the concern about theirlong-term performance, these femoral heads should not be used in THR.

Engh et al.50 presented performance in terms of wear rate of 230 implants divided in cross-linked (Marathon) and standard poly-ethylene liners (Enduron). At 5.7 years mean follow-up, theauthors observed that the cross-linked poly-ethylene liner present a lower mean wear rate thanthe standard poly-ethylene liner. In particular, the mean wear rate was 0.01 ± 0.07 mm/year forthe cross-linked (Marathon) group and 0.19 ± 0.12 mm/year for the standard Poly-ethylene (PE)(Enduron) group.

Sherfey et al.51 conducted a study on collarless (Exeter) versus collared (Endurance) stem. Theauthors showed that in 152 implants after a 5.9 year follow-up period, performances of the col-larless stem were better than the collared in which high loosening rates had been registered. Inparticular the collarless stem (Exeter) presented revision rates comparable to those of theCharnley stem.

One of the important aspects of the included studies was the heterogeneity of outcomes andtheir definitions. Several other reviews6,45 have also mentioned heterogeneity of scales used tomeasure subjective domains such as pain and its role in functionality before and after THR. The

37

table in Appendix 7 summarises the important characteristics of the main instruments used in THRstudies. We found 2 studies used the same score (Harris Hip Score, HHS): Sherfey et al.51 and vonSchewelov et al.49, whereas the other three used different outcome measures. Although the focusof our analysis was not on the outcomes described in multidimensional scores, homogeneous dataof functionality following THR from studies and registers would have aided our analysis. We areaware of the OMERACT Initiative52 which is an effort to establish a core set of outcomes for jointreplacement studies. Such initiatives should be internationally supported.

In our analysis we noted that, unlike several authors10,46, the quality of clinical studies repor-ting evidence of clinical effectiveness of hip prostheses, was acceptable (Table 2) with four out ofthe five being classed with a medium risk of bias. However, in our update, we included only 5 pri-mary studies and the small number of studies did not allow us to make statements or draw con-clusions on the quality of published literature. Four of the included studies47-49,51 presentedmedium risk of bias whilst only one study50 had high risk of bias.

In the studies reporting effectiveness and safety of hip prostheses, concerns are often relatedto the declaration of conflicts of interest of authors or to the declaration of funding. All the inclu-ded studies reported a declaration of funding. In particular, 3 studies were unfunded47,48,51, 1 wasfunded by a private company50 and 1 had mixed private-public funding49. One of these studies48

was conducted in an orthopaedic centre owned by one of the authors, using prostheses patentedby one of the authors, but the text stated that no benefits or funds were received in support ofthe study.

Of the 3 review studies, one reported that no funder or sponsor participated in the design andconduction of the study46 whilst the other two did not report a declaration of funding or conflictof interests44,45.

Other common problems highlighted in the reviews were a poor description of the methods ofthe study, the frequent absence of description of attrition from the study and the fragmentarynature of the description of the study populations. Overarching problems were the heterogeneityin outcomes and their reporting and the piecemeal nature of the evaluation of the prostheses, i.e.those tested in clinical studies represent a proportion of what is available on the market.

5.2 Analysis of evidence from arthroplasty registers

From the systematic comparison of the key variables reported in the most recent registerreports (see methods in paragraph 4.2.2) we created Table 4. It presents a synopsis of content byarthroplasty register: for each register we reported the period covered (time range from the startof collecting data), the mean age of the patients implanted, the age stratification adopted for pre-senting data, the degree of compliance (percentage of departments involved in data-acquiring) inthe reference territory, the three most common primary diagnosis and whether if patient question-naires are available from the website. As can be seen there is considerable heterogeneity in datacollection and reporting. For example, when data are reported by age subgroups, no subgroupbreakdown is alike.

38

In addition not all registers report survival data per type of prosthesis (see Table 5) andimplant use can be very different between countries. Finally the survival time range in each regi-ster differ (e.g. 3 and 5 years or 3 and 6 years or 5 and 10 years) and some present implant sur-vival as Kaplan-Meier curves. These findings limit the possibility of using the data across nationalboundaries.

From the identified arthroplasty registries (see Table 1) we extracted only registers containingdata for our analysis. As stated in the methods (paragraph 4.2.1), we were interested in survivalrates per hip system, possibly with long-term follow-up (10 years). This criterion left only datafrom 5 registers which were appropriate for our analysis.

Among the registries from European countries, the Danish, Finnish, and Swedish presentedsurvival rates per type of prosthesis (hip system identified with product name of cup and stem) inthe form of a “cumulative survival rate” (the time from implant to revision). Among the registriesfrom non-European countries, only the Australian register presented such data and among theItalian regional registers only that of Emilia-Romagna. Other registries did not present survivaldata per hip system (see Table 5). Since data for the hip systems reported in the Finnish registerwere not reported in other registers or presented with a limited follow-up (2 years) we did notinclude its data in our analysis. This leaves only 4 registers for data extraction and reporting.

Although cumulative survival rates present the general view of the particular hip system per-formance, this could have clear limits since the survival rate at a certain period includes all thepatients that received a particular prosthesis. This population is unlikely to be homogeneous.Gender differences, age clusters, disease conditions cannot be evaluated and the estimated sur-vival rate could have a limited generalisability. For a more efficient analysis, the survival rate perhip system should be expressed by sex, age cluster, weight and indication. In fact, all these varia-bles affect implant survival12, 53-55.

The Danish, Finnish and Swedish registers are recognised worldwide for their high quality andare the only registers presenting several device-related variables. In particular, the Danish registerreports survival rate per type of prosthesis in patients with primary arthrosis at 3, 5 and 10 years.The Finnish register reports Kaplan-Meier survival curves per type of prosthesis per gender (maleand female) and per disease (primary osteoarthritis and rheumatoid arthritis). The Swedish regi-ster reports survival rate per type of prosthesis in patients with osteoarthritis at 5 and 10 years.However, no register reports survival rates per prostheses by age, sex, weight and diagnosis sepa-rately. The E-R register is inspired by the Swedish and therefore is well structured and the quali-ty of reporting is high. It reports survival data per hip system.

However to make the most of what we found, for each national register we extracted survivaldata for hip systems compared in at least two national registers (Table 6). We introduced this arbi-trary rule to increase power and to decrease the chance of inter-country variability (for exampledifferent surgical indications and practice). To obtain an estimate of implant survival with data ori-ginated from different registers, we calculated an average survival weighted by number ofimplants. In this way, the higher the implants reported in each register, the more consistent willbe its contribution to the survival estimates.

Due to the different structures of the registers, this analysis was sometimes very difficult andled to considerable loss of data (e.g. the hip systems reported in the Finnish Kaplan-Meier analy-

39

sis were not reported in other registers or presented a limited follow-up and all the devices repor-ted in the register of England and Wales have a maximum 3-years follow-up).

Register Period covered Mean age

[years]

Age clusters Compliance Principal primary

diagnosis

Patient

questionnaires

Australia25 1999-2006 69,9 0-54

55-64

65-74

75-84

>85

96% Osteoarthritis,

Avascular necrosis,

Fracture.

Data not reported

Canada26 2002-2005 68 <45

45-54

55-64

65-74

75-84

>85

- Degenerative

osteoarthritis,

Osteonecrosis,

Acute fracture.

Data not reported

England and

Wales192003-2006 68 - 45

45-54

55-64

65-74

75-84

>85

81.3%

(in 2006-2007)

Osteoarthritis,

Avascular necrosis.

Data not reported

Finland20 1990-2004 - 10-20

21-30

31-40

41-50

51-60

61-70

71-80

81-90

>91

100% Data not reported. Data not reported

New Zealand27 1999-2006 66,84 <55

55-64

65-74

>74

98%

(public hospitals)

Osteoarthritis,

Acute fracture,

Avascular necrosis.

Yes

Norway21 1987-2006 69,5 <40

40-49

50-59

60-69

70-79

>79

100% Primary osteoarthritis,

Fracture,

Congenital dysplasia,

Rheumatoid arthritis.

Data not reported

Sweden24 1979-2006 69 <50

50-59

60-75

>75

88% Primary osteoarthritis,

Fracture,

Inflammatory arthritis.

Yes (in Swedish)

TABLE 4: Some of the key variables reported in the arthroplasty registers. Nations are listed in alphabetical order.

Note: We identified a Swiss register, but it is in the implementation and roll-out phase, thus no useable

data are yet available. We were unable to obtain annual report from the Romanian22 and Slovakian23 regis-

ter sites. Additionally we are aware that three new arthroplasty registries are currently under construction

(the Italian National registry, the Scottish registry, and the Catalan Regional registry).

40

Table 5: Survival analysis in the annual reports of the arthroplasty registers

* patients implanted with osteoarthritis [%]; patients aged 60 and above [%]; Gender [%].

Key: × = reported in the annual report; K-M = Kaplan-Meier.

Register Survival-related

parameters

Hip system Single

components

Follow-up

[years]

Notes

European Countries

Denmark18 Cumulative survival X - 3-5-10 -

Systems implanted in

primary arthrosisX - 3-5-10 -

Finland20 K-M for men with pri-

mary osteoarthritisX - K-M curve -

K-M for women with pri-

mary osteoarthritisX - K-M curve -

K-M for women with

rheumatoid arthritisX - K-M curve -

Norway21 Does not report survival

data- - - -

Sweden24

Cumulative survival × - 5-10

Other details* are

referred to cumulative

survival per system

Systems implanted in

osteoarthritis × - 5-10 -

Non-European Countries

Australia25Cumulative survival X - 1-2-3-4-5

List of devices with

higher revision rate

Canada26 Does not report survival

data- - - -

New Zealand27 Does not report survival

data- - - -

Italy (Regional)

Emilia-Romagna28 Cumulative survival X X 3-6 -

Lombardia29 Does not report survival

data- - - -

Puglia30 Does not report survival

data- - - -

41

Table 6: Survival data per hip system (cup and stem) presented in at least two arthroplasty registries.

§ hip systems or devices which are certainly available in Italy.

* numbers implanted refer to cumulative estimates for all fixation methods (cemented and hybrid).

Key: N. Impl = number of implants performed using the hip system; CI = confidence interval;

E-R = Emilia-Romagna region.

Cup Stem Register Period N. Impl. 3

years

[%]

95%

CI

5

years

[%]

95%

CI

6

years

[%]

95%

CI

10

years

[%]

95%

CI

ABG II§

(uncemented)

ABG II§

(uncemented)

Australia 1999-2006 2,534 97.0 96.2 97.6 95.4 94.1 96.4 - - - - - -

Denmark - - - - - - - - - - - - - -

E-R 2000-2006 1,755 99.2 98.8 99.6 - - - 98.7 98.1 99.1 - - -

Sweden - - - - - - - - - - - - - -

Charnley

(cemented)

Charnley

(cemented)

Australia 1999-2006 406 98.2 96.0 99.2 95.9 92.1 97.9 - - - - - -

Denmark - - - - - - - - - - - - - -

E-R - - - - - - - - - - - - - -

Sweden 1992-2006 23,183 - - - 96.4 96.1 96.7 - - - 92.5 92.1 92.9

Charnley Ogee

(cemented)

Elite Plus

(cemented)

Australia 1999-2006 276 98.9 96.6 99.6 98.9 96.6 99.6 - - - - - -

Denmark 1995-2001 320 96.9 95.0 98.8 96.9 95.0 98.8 - - - 92.5 89.1 96.1

E-R - - - - - - - - - - - - - -

Sweden - - - - - - - - - - - - - -

CLS§

(uncemented)

CLS§

(uncemented)

Australia - - - - - - - - - - - - - -

Denmark - - - - - - - - - - - - - -

E-R 2000-2006 1,536 98.7 98.1 99.3 - - - 97.1 95.9 98.3 - - -

Sweden 1992-2006 823 - - - 98.7 97.7 99.7 - - - 97.0 95.0 99.0

Contemporary§

(cemented)

Exeter§

(cemented)

Australia 1999-2006 513 96.3 94.2 97.7 95.8 93.6 97.3 - - - - - -

Denmark 2001-2005 947 97.4 96.2 98.5 - - - - - - - - -

E-R 2000-2006 396 98.1 96.6 99.6 - - - 97.5 95.5 99.5 - - -

Sweden - - - - - - - - - - - - - -

Fitmor§

(uncemented)

CLS§

(uncemented)

Australia 1999-2006 446 96.0 93.4 97.6 96.0 93.4 97.6 - - - - - -

Denmark - - - - - - - - - - - - - -

E-R 2000-2006 739 98.3 97.3 99.3 - - - 97.8 96.5 99.1 - - -

Sweden - - - - - - - - - - - - - -

Mallory-Head§

(cemented or

uncemented)

Exeter§

(cemented)

Australia 1999-2006 341 99.0 97.0 99.7 98.5 96.0 99.5 - - - - - -

Denmark* 1995-2005 1,619 97.9 - - 97.4 - - - - - 94.7 - -

E-R - - - - - - - - - - - - - -

Sweden - - - - - - - - - - - - - -

Reflection§

(cemented or

uncemented)

Spectron EF§

(cemented)

Australia* 1999-2006 4,286 97.7 - - 96.6 - - - - - - - -

Denmark - - - - - - - - - - - - - -

E-R - - - - - - - - - - - - - -

Sweden 1992-2006 887 - - - 98.6 97.8 99.4 - - - 95.9 94.3 97.5

Secur-Fit

(cemented or

uncemented)

Omnifit

(cemented)

Australia* 1999-2006 768 96.1 - - 94.7 - - - - - - - -

Denmark - - - - - - - - - - - - - -

E-R - - - - - - - - - - - - - -

Sweden 1996-1999 104 - - - 89.1 83.0 95.2 - - - 73.1 64.2 82.0

Trident§

(uncemented)

ABG II§

(uncemented)

Australia 1999-2006 1,178 96.3 94.8 97.3 - - - - - - - - -

Denmark - - - - - - - - - - - - - -

E-R 2002-2006 392 98.0 96.5 99.5 - - - - - - - - -

Sweden - - - - - - - - - - - - - -

ZCA§

(cemented)

CPT§

(cemented)

Australia 1999-2006 398 97.6 95.2 98.8 96.6 93.7 98.2 - - - - - -

Denmark 1995-2005 3,061 98.3 97.8 98.8 98.0 97.4 98.5 - - - 94.7 91.8 97.8

E-R - - - - - - - - - - - - - -

Sweden 1993-2005 114 - - - 94.5 90.2 98.8 - - - - - -

42

5.3 Comparison between the evidence from clinical studies and registersWe approached the comparison of evidence from clinical studies and arthroplasty registers

assigning more credibility to consistent evidence from multiple sources. An important considera-tion already made by others2 concerns the reporting of sample size calculation and confidenceintervals56.

Single studies included in our analysis did not report either calculation of sample size or con-fidence intervals. The studies included in our analysis had sample sizes of between 20 to 204implants per arm. Faulkner et al.2 presented a sample size calculations for each type of studydesign. They stated that for RCTs and comparative studies, the detection of a difference of 4% inthe survival rates between two prosthesis designs, assuming an expected survival rate of 90% at20 years (with a 95% confidence interval) would require an achieved sample size of 1,085 hipsper arm. Allowing for death during follow-up, and assuming mean age at operation of 65 years,an initial sample size of 3,600 hips per arm might be required at this level of accuracy (fewer foryounger age groups). Alternatively, assuming a survival rate of 80%, to detect a relatively largedifference of 10% in prosthesis survival would require an achieved sample size of some 313 hipsper arm, or about 480-500 hips per arm if a total follow-up of 300 hips per arm was required for10 years. For cohort studies, a sample size of 600 hips is required to have a 95% confidence inter-val for an assumed 60% prosthesis survival rate at 20 years. Larger samples would be required tohave the same precision for higher percentage survival assumptions or for short period follow-up57. Thus all the single studies included in our review were probably underpowered to detect thedifferences stated in their objectives.

Table 7 reports our list of hip systems or component for which we identified (in descendingorder) data from arthroplasty registers and single studies, data from at least two registers anddata from single studies only. This list includes hip systems which are probably no longer availa-ble in Italy. As we could not identify with certainty all hip systems available in Italy, this furtherclassification should be seen as tentative and not definitive, with the exception of those prosthe-ses used in the Emilia-Romagna (E-R) region as reported in the regional register. These systemsare certainly in use in Italy, at least at the time of the latest report from the E-R registry. We can-not indicate which of the remaining hip systems in Table 7 and following tables are available inthe Italian market. This further “availability” classification is maintained in Table 8, 9 and 10 to aiddecision makers and readers.

From the 11 studies included in the PNLG-810 review, we included only the 5 assessing per-formance of total prostheses (hip system)35-37,40,42. Available evidence of performance of hipsystems appears plentiful, however there appear to be hundreds of different systems and variantsin the market (see at Appendix 1 the non-exhaustive list of systems in use in Italy). In this pro-spective, available evidence relates to the performance of a minority of systems as already shownby other authors10,44.

As can be seen from Table 7, evidence from both studies and registers is very sparse, relatingto only 4 hip systems.

We reported hip system by level of evidence: evidence from single studies and at least onenational register (Table 8), evidence from at least two arthroplasty registers (Table 9), and eviden-ce from single studies included in PNLG-810 and our review (Table 10). Our assumption was thatevidence from multiple sources should give us a more stable assessment of the performance ofhip systems.

43

Table 8 and Table 9 report, other than implant survival, the price range that we were able todetermine by interviewing Italian regional purchasers and providers. Our efforts were hamperedby the lack of a centralised inventory of hip systems available on the Italian market.

Table 7: List of hip systems with evidence from registers and studies (PNLG-810 and our upda-te), evidence from registers only, and evidence from studies only.

Note: this table contains data only on a minority of devices used in the Italian clinical practice.§ hip systems or devices which are certainly available in Italy;

Key: nr = not reported; R-B = Ranawat-Burstein; unc. = uncemented; cem. = cemented; HA = hydroxyapatite;

S-C-Z = Sulzer-Centerpulse-Zimmer; S&N = Smith & Nephew; E-R = Emilia-Romagna.

Hip system

(or cup + head + stem, when indicated)Manufacturer Registries Study

With evidence from registers and studies Charnley DePuy Australian, Swedish Garellick et al. 199936,37

PCA unc. Howmedica Swedish Thanner et al. 199935

Mallory-Head unc.§ Biomet Australian Laupacis et al. 200242

Exeter + Exeter Polished Stryker + Stryker Swedish McCombe et al. 200447

With evidence from two registers

ABG II§ Howmedica Australian, E-R -

Charnley Ogee + Elite Plus DePuy Australian, Danish -

CLS§ S-C-Z Swedish, E-R -

Contemporary§ + Exeter§ Howmedica + Stryker Australian, Danish, E-R -

Fitmore§ + CLS§ S-C-Z Australian, E-R -

Mallory-Head§ + Exeter§ Biomet + Stryker Australian, Danish -

Reflection§ + Spectron EF§ S&N + S&N Australian, Swedish -

Secur-Fit + Omnifit Osteonics + Stryker Australian, Swedish -

Trident§ + ABG II§ Stryker + Howmedica Australian, E-R -

ZCA§ + CPT§ Zimmer Australian, Danish -

With evidence from studies

Harris-Galante I unc. Zimmer - Thanner et al. 199935

Spectron S&N - Garellick et al. 199936,37

C-Fit unc. porous coated Corin - Sharp et al. 200040

C-Fit unc. HA coated Corin - Sharp et al. 200040

Mallory-Head cem. Biomet - Laupacis et al. 200242

Ribbed Stem Waldemar Link - Palm et al. 200243

Ribbed Stem HA coated Waldemar Link - Palm et al. 200243

Duraloc 100 + Exeter Polished DePuy + Stryker - McCombe et al., 200447

All-PE R-B + R-B Interlock smooth Biomet (all) - Rasquinha et al., 200448

R-B Ti Shell + Arcom liner + R-B Interlock rough Biomet (all) - Rasquinha et al., 200448

Enduron + s-steel head + Charnley Elite Plus DePuy (all) - Von Schewelov et al., 200549

Hylamer + s-steel head + Charnley Elite Plus DePuy (all) - Von Schewelov et al., 200549

Enduron + zirconia head + Charnley Elite Plus DePuy (all) - Von Schewelov et al., 200549

Hylamer + zirconia head + Charnley Elite Plus DePuy (all) - Von Schewelov et al., 200549

Duraloc 100 + Marathon liner + Prodigy DePuy (all) - Engh et al., 200650

Duraloc 100 + Enduron liner + Prodigy DePuy (all) - Engh et al., 200650

Duraloc + Exeter DePuy + Stryker - Sherfey et al., 200651

PCA + Exeter Howmedica + Stryker - Sherfey et al., 200651

Duraloc + Endurance DePuy + DePuy - Sherfey et al., 200651

44

Table 8: Survival at 5 and 10 years of hip systems with evidence from single studies and regi-sters. For these we were unable to find any price range. The devices are listed in alphabeticalorder.

Note: this table contains data only on a minority of devices used in the Italian clinical practice.

§ hip systems or devices which are certainly available in Italy;

a prostheses implanted at the start of the study

b implant survival at 6-years follow-up

c implant survival at 8-years follow-up

Key: unc. = uncemented; n. impl. = number of implants; NA = not available.

Table 9: Survival at 3, 5 and 10 years, and price range of hip systems with evidence from atleast two arthroplasty registers. The devices are ordered by number of implants.

Note: this table contains data only on a minority of devices used in the Italian clinical practice.

§ hip systems or devices which are certainly available in Italy;

a data from Emilia Romagna refer to 6-years implant survival

Key: A = Australia; D = Denmark; E-R = Emilia-Romagna; S = Sweden; NA = not available.

Cup Stem 5-years survival

from study

(n. impl.)

5-years survival

from register

(n. impl.)

10-years survival

from study

(n. impl.)

10-years survival

from register

(n. impl.)

Price range

(€)

Charnley Charnley - - 93.2% (206a) 92.5% (23,186) NA

PCA PCA - - 85% (84a) 84.7% (69) NA

Mallory-Head unc.§ Mallory-Head unc.§ 100%b (86) 96.7% (1,643) - - NA

Exeter Exeter Polished 100% c (63) 97% (6,374) - - NA

Cup Stem Countries Total

Implanted

3-years

survival [%]

5-years

survival [%]

10-years

survival [%]

Price range

(€)

Reflection§ Spectron EF§ 4,286 (A); 887 (S) 5,173 - 96.9 - NA

ABG II§ ABG II§ 2,534 (A); 1,755 (E-R) 4,289 97.9 96.8a - 2.500 - 3.300

ZCA§ CPT§ 398 (A); 3,061 (D); 114 (S) 3,573 - 97.7 - NA

CLS§ CLS§ 1,536 (E-R); 823 (S) 2,359 - 97.7a - 2.300 - 3.100

Mallory-Head§ Exeter§ 341 (A); 1,619 (D) 1,960 98.1 97.6 - NA

Contemporary§ Exeter§ 513 (A); 947 (D); 396 (E-R) 1,856 97.2 - - NA

Trident§ ABG II§ 1,178 (A); 392 (E-R) 1,570 96.7 - - 2.500 - 3.200

Fitmore§ CLS§ 446 (A); 739 (E-R) 1,185 97.4 97.1a - 2.300 - 2.700

Secur-fit Omnifit 768 (A); 104 (S) 872 - 94.0 - NA

Charnley Ogee Elite Plus 276 (A); 320 (D) 596 97.8 97.8 - NA

45

Table 10: Survival at 3, 5 and 10 years of hip systems with evidence from single studies.

The devices are listed in chronological order of publication of the relevant study

Note: this table contains data only on a minority of devices used in the Italian clinical practice.

a prostheses implanted at the start of the study

b implant survival is referred to 8-years follow-up

c implant survival is referred to 6.3-years follow-up

d implant survival is referred to 7-years follow-up

e implant survival is referred to 7.3-years follow-up

f implant survival is referred to 4.6-years follow-up

Key: uc = unclear.

Data from Tables 8 and 10 are of limited practical use: despite the fact that some of the pro-stheses might be no longer available, such a limited group represents a minimal sample of thesystems used in clinical practice and is supported by evidence from small studies (total denomi-nator is 1,228 implants with 16 different hip systems in Table 10).

Data from Table 9 are probably of greater practical use since they relate to widely used pro-stheses. However, as we were unable to define how many and what type of prostheses are avai-lable in Italy, the data from Table 9 may represent a very limited selection.

Our criteria for reporting evidence seems to be too optimistic when compared to the real qua-lity and quantity of data available. For example, in our analysis only 4 systems present survivaldata at 10 years and two of these show questionable performance1 (below 90% at 10 years).

1 The National Institute for Clinical Excellence (NICE), in its “Guidance on the Selection of Prostheses for

Primary Total Hip Replacement”58, states that a revision rate of 10% or less at ten years should be regarded

as the “benchmark” in the selection of prostheses for primary THR.

Cup Stem StudyTotal

Implanted

5-years

survival [%]

10-years

survival [%]

Harris-Galante I uncem. Harris-Galante I uncem. Thanner et al., 199935 87a - 86

Spectron Spectron Garellick et al., 199936,37 204a - 95.9

C-Fit uncem. (PC and HA) C-Fit uncem. (PC and HA) Sharp et al., 200040 uc 72.5b -

Mallory-Head cem. Mallory-Head cem. Laupacis et al., 200242 124a 89.5c -

Ribbed Stem (non-HA and HA) Ribbed Stem (non-HA and HA) Palm et al., 200243 20 - -

Duraloc 100 Exeter Polished McCombe et al., 200447 78 94.9b -

All-PE R-B R-B Interlock smooth Rasquinha et al., 200448 112 99.1d -

R-B Ti Shell + Arcom liner R-B Interlock rough Rasquinha et al., 200448 111 98.2d -

Enduron s-steel head + Charnley Elite Plus Von Schewelov et al., 200549 25 100 -

Hylamer s-steel head + Charnley Elite Plus Von Schewelov et al., 200549 29 79.3 -

Enduron zirconia head + Charnley Elite Plus Von Schewelov et al., 200549 28 96.4 -

Hylamer zirconia head + Charnley Elite Plus Von Schewelov et al., 200549 28 78.6 -

Duraloc 100 + Marathon Prodigy Engh et al., 200650 116 - -

Duraloc 100 + Enduron Prodigy Engh et al., 200650 114 - -

Duraloc (or PCA) Exeter Sherfey et al., 200651 118 95.8e -

Duraloc Endurance Sherfey et al., 200651 34f - -

46

Given the lack of relevant data we conducted an additional search in the four registers(Australian, Danish, Swedish and E-R) that report survival data per hip system. We were intere-sted in the 10 most common hip systems.

Tables 11 to 14 show performance evidence for the 10 most common hip systems reported inthe latest updated reports available on-line. The number of implants for each system is cumulati-ve and refers to the whole observation period (since the introduction of each system).

Data from the Australian register show that 103,848 primary THR procedures were performedduring the whole observation period. The procedures performed using the 10 most commonsystems were 40,039 representing 38.6% of the total number of primary THR procedures repor-ted by the register.

Data from the Danish register show that 55,415 primary THR procedures were performedduring the whole observation period. The procedures performed using the 10 most commonsystems were 33,347 representing 60.2% of the total number of primary THR procedures repor-ted by the register.

Data from the Swedish register show that 158,285 primary THR procedures were performedduring the whole observation period. The procedures performed using the 10 most commonsystems were 120,729 representing 76.3% of the total number of primary THR procedures repor-ted by the register.

Data from the E-R register show that 35,041 primary THR procedures were performed duringthe whole observation period. The procedures performed using the 10 most common systemswere 13,266 representing 37.9% of the total number of primary THR procedures reported by theregister.

As can be seen from the tables, the use of the devices is different in the various Countries.

Table 11: The 10 most common hip systems in Australia. Data from the latest

Australian arthroplasty register’s report25.

Key: N.Impl. = number of implants performed using the hip system.

Cup (Manufacturer) Stem (Manufacturer)N.

Impl.Period 3-yrs 4-yrs 5-yrs 6-yrs 10-yrs

TRIDENT (Stryker) EXETER V40 (Stryker) 10,354 1999-2006 97.8 97.5 - -

REFLECTION (Smith & Nephew) SYNERGY (Smith & Nephew) 5,551 1999-2006 97.6 97.4 96.6 - -

CONTEMPORARY (Stryker) EXETER V40 (Stryker) 3,963 1999-2006 97.7 97.4 97.4 - -

TRIDENT (Stryker) SECUR-FIT PLUS (Stryker) 3,291 1999-2006 98 97.8 97.6 - -

REFLECTION (Smith & Nephew) SPECTRON EF (Smith & Nephew) 3,166 1999-2006 97.5 97 96.2 - -

TRILOGY (Zimmer) VERSYS (Zimmer) 3,015 1999-2006 97.2 97 96.2 - -

TRIDENT (Stryker) ACCOLADE ((Stryker) 2,924 1999-2006 96.9 96.9 - - -

ALLOFIT (Zimmer) ALLOCLASSIC (Sulzer) 2,729 1999-2006 97.6 97.4 97.4 - -

ABG II (Stryker) ABG II (Stryker) 2,534 1999-2006 97 96.6 95.4 - -

TRIDENT (Stryker) SECUR-FIT (Stryker) 2,512 1999-2006 97.6 97.3 96.8 - -

47

Table 12: The 10 most common hip systems in Denmark. Data from the latest Danish arthro-plasty register’s report18.

Key: N.Impl. = number of implants performed using the hip system; u.k. = unknown.

Table 13: The 10 most common hip systems in Sweden. Data from the latest Swedish arthro-plasty register’s report 24.

Key: N.Impl. = number of implants performed using the hip system; u.k. = unknown.

Cup (Manufacturer) Stem (Manufacturer)N.

Impl.Period 3-yrs 4-yrs 5-yrs 6-yrs 10-yrs

LUBINUS ALL-POLY (Link) LUBINUS SP II (Link) 55,718 1992-2006 - - 98.3 - 96.3

CHARNLEY (Depuy) CHARNLEY (Depuy) 23,183 1992-2006 - - 96.4 - 92.5

EXETER DURATION (Stryker) EXETER POLISHED (Stryker) 10,282 1999-2006 - - 97.8 - -

REFLECTION (Smith & Nephew)SPECTRON EF PRIMARY

(Smith & Nephew)6,946 1996-2006 - - 97.6 - 93.3

CHARNLEY ELITE (Depuy) EXETER POLISHED (Stryker) 6,549 1996-2006 - - 98.8 - -

EXETER ALL-POLY (Stryker) EXETER POLISHED (Stryker) 6,374 1992-2006 - - 97 - 92.6

FAL (Link) LUBINUS SP II (Link) 4,059 1999-2006 - - 98.7 - -

SCAN HIP CUP (u.k.) SCAN HIP COLLAR (u.k.) 2,871 1992-2000 - - 97.8 - 91.9

CONTEMPORARY HOODED

DURATION (Stryker)EXETER POLISHED (Stryker) 2,545 2000-2006 - - 97.8 - -

CHARNLEY (Depuy) EXETER POLISHED (Stryker) 2,202 1992-2006 - - 98.3 - 97.3

Cup (Manufacturer) Stem (Manufacturer)N.

Impl.Period 3-yrs 4-yrs 5-yrs 6-yrs 10-yrs

LUBINUS (Link) LUBINUS SP II (Link) 6,990 1995-2005 98.1 - 97.5 - 94.9

TRILOGY HIGH (Zimmer) BI-METRIC TITANIUM (Biomet) 4,891 1995-2005 96.7 - 95.9 - 91.4

EXETER ALL PLAST (Stryker) EXETER (Stryker) 4,542 1995-2005 97.4 - 96.4 - 91.4

TRILOGY HIGH (Zimmer) BI-METRIC TITANIUM (Biomet) 3,799 1995-2005 96.6 - 94.9 - 87.5

ZCA (Zimmer) CPT (Zimmer) 3,061 1995-2005 98.3 - 98 - 94.7

MULLER (u.k.) BI-METRIC TITANIUM (Biomet) 2,487 1995-2005 97.3 - 95.4 - 92.4

UNIVERSAL (Biomet) BI-METRIC TITANIUM (Biomet) 2,346 1995-2005 96.8 - 94.1 - 84.9

EXETER DURATION (Stryker) EXETER (Stryker) 1,898 1995-2005 97.3 - 96.8 - 96.3

MALLORY-HEAD (Biomet) BI-METRIC TITANIUM (Biomet) 1,856 1995-2005 97.5 - 96.5 - 85.3

MALLORY-HEAD (Biomet) EXETER (Stryker) 1,477 1995-2005 98 - 97.7 - 94.7

48

Table 14: The 10 most common hip systems in Emilia-Romagna. Data from the last E-R

arthroplasty register’s report28.

Key: N.Impl. = number of implants performed using the hip system.

5.4 Cost-effectiveness analysis

On the basis of the data collected concerning costs and effectiveness of the devices, it has notbeen possible to design a cost-effectiveness model. There are some stringent data requirementsto undertake a meaningful cost-effectiveness analysis (in our case possibly a cost per year-free-of-revision). Firstly it is necessary to have a clear idea of the use of a system (i.e. howmany and which types of systems are used where). Secondly it is necessary to have meaningfuldata on their performance, ideally from large primary studies with the same randomisationsequence or registry data with similar adjustments for case-mix and other contextual factors whichwould allow us to compare the comparable. Thirdly we would need to have a credible estimate ofthe costs and their structure to estimate the societal opportunity costs of using one system com-pared to another in the Italian NHS.

None of these requirements were fulfilled by our analysis. Although this kind of analysis mayhave been theoretically possible with E-R data, its generalisation to the whole Italian NHS (whichis now regionalised) is of doubtful significance. In addition any attempt at introducing a cost-effectiveness hierarchy of hip systems based on such sparse data would be inequitable.

For example, the purchase price survey undertaken in different Italian regions demonstratedhow different variables can influence the final purchasing price of a device, in particular the regio-nal policy, the quantity and additional services purchased, and the presence on the market of localmanufacturers. These purchasing prices differ from the price list proposed by the manufacturers.

Cup (Manufacturer) Stem (Manufacturer)N.

Impl.Period 3-yrs 5-yrs 6-yrs 10-yrs

ANCA FIT (WRIGHT) ANCA FIT (WRIGHT) 4,086 2000-2006 97.8 - 96.8 -

FIXA (ADLER) APTA (ADLER) 1,885 2004-2006 - - - -

ABG II (STRYKER) ABG II (STRYKER) 1,755 2000-2006 99.2 - 98.7 -

CLS (ZIMMER) CLS (ZIMMER) 1,536 2000-2006 98.7 - 97.1 -

FITMORE (ZIMMER) CONUS (ZIMMER) 820 2000-2006 98.5 - 98.2 -

FITMORE (ZIMMER) CLS (ZIMMER) 739 2000-2006 98.3 - 97.8 -

FIXA (ADLER) RECTA (ADLER) 714 2004-2006 - - - -

BICON PLUS (ENDOPLUS) SL PLUS (ENDOPLUS) 586 2000-2006 98.1 - 98.1 -

CLS (ZIMMER) CONUS (ZIMMER) 584 2000-2006 98.3 - 97.2 -

TRILOGY (ZIMMER) VERSYS FIBER (ZIMMER) 561 2000-2006 97.6 - 97.6 -

49

6. Discussion

We identified evidence of reasonable quality on a tiny minority of devices used in the clinicalpractice. The recent reclassification of the hip prostheses (from Class IIb to Class III devices) ope-rated by the European Commission, should enhance the safety and effectiveness of the hip pro-stheses available on the market, but falls short of requiring clinical trials for each new device.

Our decision to include arthroplasty register data was motivated by the contribution that thesedata made to the evidence base. Equally, we believe that our decision to arrange evidence on thebasis of multiple sources provided greater stability of survival estimates of hip systems with thegreatest and most diverse evidence base. Given the diversity of data source and the differencebetween countries, we think that our results should be interpreted with caution.

The clinical use of four systems (Charnley hip system, PCA hip system, Mallory-Head unce-mented hip system, and Exeter cup with Exeter Polished stem) is backed by a wealth of data fromboth single studies and registers. However, one of these systems (PCA) is no longer used becau-se of its poor performance.

In terms of quantity, other devices (see Tables 9 and 10) have a more limited evidence basefrom either studies or two or more registers. However, Table 9 is characterised by large groups ofpatients and for this reason could guide use and reimbursement by the Italian NHS in approxima-tely the order of performance and cost. However, the partial nature of the data and lack of 10-year horizon (which appears to be standard follow-up time) may make its use inequitable.Equally a difference of 1 percentage point in survival over five years may seem trivial at a super-ficial glance. However considering the use on a population of thousands of recipients this wouldentail a significant additional number of re-intervention with consequent economic and personalimpacts. New devices or those under development, should be thoroughly tested in properly desi-gned and conducted clinical trials using standardised reporting methods. Alternatively, if clinicalevidence of the effects is lacking they should be enrolled in a program of evidence-generationwhich includes register reporting and larger trials.

We believe that the assessment of clinical effectiveness and safety of prostheses cannot bemade without an analysis of the specific implant (for example, general terms like “cemented” or“uncemented” include a vastly heterogeneous type of devices) since several characteristics aredevice-specific and may affect the performance of the implant. For this reason we included stu-dies that identified devices by product name and manufacturer. The vagueness of reporting of thetechnical details of the devices used in some primary studies was disconcerting.

In our opinion, clinical studies which focus on the performance of a single component are notsufficient to assess the complete performance and survival rate of a hip system, although theymay be useful in identifying safety problems. Such a complex joint system requires assessment ofall components and their performance as a system, not as single components, as primary THRtoday is mostly performed using modular devices. This approach is reflected in several of the con-sulted arthroplasty registers (Australian, Swedish, Finnish, Danish, E-R, see Table 1 for web links)in which implant performance is reported as hip system survival rate.

50

However, the variables related to the device are not the only ones affecting the effectivenessof the system. Several other variables, such as age of patient, sex, disease status, number of ope-rations undertaken annually by a consultant (surgeon volume), number of procedures carried outin an hospital (hospital volume), and other factors should be considered for a balanced analysis.In addition generalisability of data should be enhanced by reporting of register implant survivaldata stratified by these variables. No register achieves this in a systematic and comparable way,which may also be a reflection of the different history and objectives of the registers. Attempts atachieving a universal format such as those by the EFORT network17 should be commended andreceive due support.

Diversity of design and reporting was also common in the new studies that we identified. Noneof the 5 studies included in our 2007 update compared hip systems (acetabular and femoral com-ponent seen as a system). All comparisons were between two components differing for materials(e.g. highly cross-linked PE versus standard PE liner), design (e.g. collarless versus collared stem)and surface finish (e.g. smooth versus rough stem). Readers should bear in mind that several stu-dies were excluded from the PNLG-810 review and from our 2007 update because of methodolo-gical reasons (lack of comparison, lack of randomisation, short follow-up, different age groups)and lack of specificity of comparison description (i.e. inadequate hip system or device identifica-tion). As our objectives were to assist decision-makers by identifying specific systems, theserestrictions should have no impact on our conclusions.

Out of the three included reviews, only that by Aamodt et al.44 assessed prostheses by brandand name. The review by Ni et al.45 and Morshed et al.46 reported evidence on cemented anduncemented fixation without considering specific implants. Although the method of fixation is cru-cial and strictly related to patient age and others factors (e.g. bone quality), we think that classi-fication in cemented, uncemented and hybrid prostheses could be too generic and is not usefulfor decision-makers that need to consider the requirements of all patients.

The choice of fixation method (cemented, uncemented or hybrid implant) is a very controver-sial matter and no study has exhaustively established the dominance of a method over theothers59,45,46.

This is probably due to the influence of several confounding variables (e.g., patient age, sex,body weight and diagnosis) and to the different follow-up length (some cemented implants pre-sent 25-years follow-up). Both cemented and uncemented implants are heterogeneous groupswith many factors that can influence survivorship (e.g., geometry, materials, surface finishes, andbearings). Moreover, other factors including surgical approach, expertise of the surgeon, and studydesign may add to baseline differences between studies for assessing implants performances.

Despite the higher costs, uncemented implants present growing use in several countries, forexample USA60 and UK61. This contrasts with some European countries (e.g. Sweden) which haveadopted these newer uncemented technologies with more caution62.

The surgeon usually makes the final decision on the choice of fixation methods, thus his fami-liarity with the fixation method has to be taken into account. Results from Scandinavia may havelimited generalisability to the USA or other countries where cemented fixation is performed muchless frequently, where THR is performed at an earlier mean age62-65, or where the population isnot as socially or demographically uniform.

51

However, our findings should provide a basis for the development of evidence gathering ulti-mately culminating in a National Register. This would aid surgeons in choosing hip systems havingthe best performance covered by the higher degree of evidence, and decision-makers to reimbur-se the system that offers the best performance at the minimum price.

We have encountered difficulties in identifying cost data (given their large inter-regional varia-bility and patchy coverage), in finding data on the efficacy (available only in the Emilia-Romagnaregister and not generalisable to the national territory) and in the impossibility to track implantedpatients during their life. These findings precluded an equitable and realistic cost-effectivenessanalysis.

6.1 Limits

It is important to note that the available data, extracted from the latest open-access arthro-plasty register reports, do not allow stratification of evidence by case-mix (age, sex, indication,etc.). The play of confounding is inscrutable and the latest Swedish register’s report is the onlyone with a detailed analysis by case-mix. Further, all the registers' reports have different reportingand presentation formats. In addition some registries (e.g. Norway), prefer publication activity inspecialised peer-reviewed journals rather than detailed annual reporting.

Another potential limit is our arbitrary “2-registers rule” (see paragraph 5.3) which may havehad the effect of thinning evidence by discarding those data on prostheses reported in a singleregister. However, we believe this may have presented a more conservative (and perhaps moregeneralisable) estimate of effect of each prostheses.

We are conscious of the limits of our inclusion criteria and in constructing our evidence tablessome which may seem to lack realism, as they report data from a probable tiny minority of pro-stheses currently used. However we had no other way of identifying and guiding clinicians in theirchoice unless anecdotal evidence was included.

However, the lack of clarity as to the availability and performance of hip prostheses in Italy,makes the use of the concept of “best evidence” currently impossible.

52

53

7. Recommendations

We suggest that the Italian NHS must explicitly use performance evidence and cost data (andthus perform cost-effectiveness analysis) to manage the reimbursement policy of prostheses forprimary total hip replacement. The best tool to manage this approach in a credible and equitableway is the creation of a National arthroplasty registry that must be adopted in the whole Nationalterritory. Such a decision could be a robust method for monitoring clinical practice, and the mar-ket in the field of THR and could represent a strong stimulus to encourage manufacturers to col-laborate with our Health Service and provide the required information.

We conclude that ideally, reimbursement for hip systems should be primarily directed to thosesystems that have the greatest evidence base and provide the greatest benefits in terms of revi-sions avoided and cost containment. In general, we recommend that from now on, reimbursementshould be more closely tied to the effectiveness, safety and cost-effectiveness of devices. However,not to stifle progress we recommend that provisional reimbursement be given to those new ornewer hip systems that are being assessed as part of an adequately powered clinical trial or in anational or non-Italian registry, thus achieving coverage (or reimbursement) with evidence gene-ration.

Another approach could consist in providing conditional coverage for new and newer devicesto promote evidence-generation through coordinated clinical studies.

New technologies in the field of hip replacement are in an embryonic stage (see Appendix 1).For example, navigation technologies could improve the cup positioning as well as the resultinggeometry of the articulation; MIS (minimally invasive surgery) could lead to bleeding reduction,and faster rehabilitation; new bone-preserving implant designs could make revision proceduresless traumatic; new materials for the bearing surfaces could improve the resistance to wear.

Continuous innovation is necessary, but stakeholders have to remain critical, cautious andhonest as implanting the devices in patients is very different from developing and marketingthem66. The long-term results of all new implant concepts should to be evaluated before marketdistribution, and EU legislation should reflect this requirement.

54

55

8. Funding

Production of this report was made possible by financial contributions from the Italian Ministryof Labour, Health and Social Policies (CUD, Commissione Unica Dispositivi) and the age.na.s.

The age.na.s. takes sole responsibility for the final form and content of this report. The viewsexpressed herein do not necessarily represent the views of the Italian Ministry of Labour, Healthand Social Policies or any regional government.

56

57

9. Competing interests declaration

The authors declare that they will not receive either benefits or harms from the publication ofthis report. None of the authors have or have held shares, consultancies or personal relationshipswith any of the producers of the devices assessed in this document.

Two of the authors of this report (T. Jefferson and E. Romanini) and two of the external revie-wers (M. Torre and G. Zanoli) were co-authors in the systematic review cited as PNLG-810.

58

59

Bibliography

1. Nilsdotter A, Lohmander L. Age and waiting time as predictors of outcome after totalhip replacement for osteoarthritis. Rheumatology 2002;41:1261-67.

2. Faulkner A, Kennedy LG, Baxter K, et al. Effectiveness of hip prostheses in primarytotal hip replacement: a critical review of evidence and an economic model.HealthTechnol Assess 1998:2(6);1-133.

3. Sochart D, Porter M. Long-term results of total hip replacement in young patients whohad ankylosing spondylitis. Eighteen to thirty-year results with survivorship analysis.The Journal of Bone and Joint Surgery1997;79:1181-89.

4. Upshur R, Moineddin R, Crighton E et al. Seasonality of service provision in hip andknee surgery: a possible contributor to waiting times? A time series analysis. BMCHealth Services Research 2006;22:1-5.

5. Dreinhöfer K, Dieppe P, Stürmer T, et al. Indication for total hip replacement: com-parison of assessments of orthopaedic surgeons and referring physicians. Annals of the Rheumatic Diseases. 2006;65:1346-50.

6. Ministero della Salute, Banca dati SDO. Available on-line(http://www.ministerosalute.it/programmazione/sdo/bancaDati.jsp accessed on 5th

May 2008)

7. Mäkinen TJ, Alm JJ, Laine H, et al. The incidence of osteopenia and osteoporosis inwomen with hip osteoarthritis scheduled for cementless total joint replacement.Bone. 2007 ;40(4):1041-7.

8. Dunlop DD, Manheim LM, Yelin EH, et al. The costs of arthritis. Arthritis Rheum.2003;49(1):101-13.

9. “Dispositivi Medici - Aspetti regolatori e operativi” , CUD, Ministero della Salute, 2007.

10. PNLG-8, “Revisione sistematica sulle protesi d’anca: affidabilità dell’impianto”, 2004.

11. Annual report (2006) of the Swedish Hip Arthroplasty Register. Available on-line(http://www.jru.orthop.gu.se accessed on 7th April 2008).

12. Söderman P, Malchau H, Herberts P, et al. Outcome after total hip arthroplasty PartII. Disease specific follow-up and the Swedish National Total Hip ArthroplastyRegister. Acta Orthop Scand 2001;72 (2):113-19.

13. Deeks JJ, Higgins JPT, Altman DG, editors. Analysing and presenting results.Cochrane Reviewer’s Handbook 4.2.2; Section 8. The Cochrane Library, Issue 1,2004; Chichester, UK: John Wiley & Sons, Ltd.

14. Wells GA, Shea B, O’Connell D, et al. The Newcastle-Ottawa Scale (NOS) for assess-ing the quality of nonrandomised studies in meta-analyses.

15. Labek G, Stoica CI, Böhler N. Comparison of the information in arthroplasty registersfrom different countries. J Bone Joint Surg Br. 2008;90(3):288-91.

16. http://www.efort.org/ (accessed on 7th April 2008)

17. http://www.ear.efort.org/_documents/MinimalDataset_THA_primary.pdf (accessedon 7th April 2008)

60

18. Danish Hip Arthroplasty Register (www.dhr.dk/ENGLISH.htm, accessed on 7th April2008)

19. National Joint Registry for England and Wales (www.njrcentre.org.uk accessed on 7th

April 2008)

20. Finnish National Arthroplasty Register (www.nam.fi/english/publications/ accessed on7th April 2008)

21. Norwegian Arthroplasty Register (www.haukeland.no/nrl/ accessed on 7th April 2008)

22. Romanian Arthroplasty Register (www.rne.ro/site/Default.aspx accessed on 7th April2008)

23. Slovakian National Arthroplasty Register (https://sar.mfn.sk/public/index.php?id=178accessed on 7th April 2008)

24. Swedish National Hip Arthroplasty Register (www.jru.orthop.gu.se/ accessed on 7th

April 2008)

25. Australian Orthopaedic Association National Joint Replacement Registry(www.aoa.org.au/jointregistry.asp accessed on 7th April 2008)

26. Canadian Joint Replacement Register(http://secure.cihi.ca/cihiweb/dispPage.jsp?cw_page=services_cjrr_e accessed on7th April 2008)

27. New Zealand Joint Register (www.cdhb.govt.nz/NJR/ accessed on 7th April 2008)

28. Registro Regionale di Implantologia Protesica Ortopedica, Regione Emilia-Romagna(https://ripo.cineca.it/ accessed on 7th April 2008)

29. Registro Ortopedico Protesico Lombardo (www.sanita.regione.lombardia.it/pubbli-cazionivarie/rapporto_registro_ortopedico.htm accessed on 7th April 2008)

30. Registro Regionale Protesi d’Anca, Regione Puglia (www.cimedoc.uniba.it/prot_anca/accessed on 7th April 2008)

31. Kolling C, Simmen B R, Labek G et al. Key factors for a successful NationalArthroplasty Register. J Bone Joint Surg [Br] 2007;89-B:1567-73.

32. Barrack RL. Cost analysis of revision total hip replacement: a 5-year follow-up study.Clin Orthop Relat Res. 1999; 369:175-178.

33. Krismer M, Stockl B, Fischer M, et al. Early migration predicts late aseptic failure ofhip sockets. J Bone Joint Surg Br. 1996;78(3):422-6.

34. Meding JB, Ritter MA, Keating EM, Faris PM. Comparison of collared and collarlessfemoral components in primary uncemented total hip arthroplasty. J Arthroplasty.1997;12(3):273-80.

35. Thanner J, Kärrholm J, Malchau H, Herberts P. Poor outcome of the PCA and Harris-Galante hip prostheses. Randomized study of 171 arthroplasties with 9-year follow-up. Acta Orthop Scand. 1999;70(2):155-62.

36. Garellick G, Malchau H, Herberts P. The Charnley versus the Spectron hip prosthesis:clinical evaluation of a randomized, prospective study of 2 different hip implants. JArthroplasty. 1999;14(4):407-13.

37. Garellick G, Malchau H, Regner H, Herberts P. The Charnley versus the Spectron hipprosthesis: radiographic evaluation of a randomized, prospective study of 2 differenthip implants. J Arthroplasty. 1999;14(4):414-25.

61

38. Yee AJ, Kreder HK, Bookman I, Davey JR. A randomized trial of hydroxyapatite coat-ed prostheses in total hip arthroplasty. Clin Orthop. 1999;(366):120-32.

39. Meding JB, Ritter MA, Keating EM, Faris PM, Edmondson K. A comparison of collaredand collarless femoral components in primary cemented total hip arthroplasty: a ran-domized clinical trial. J Arthroplasty. 1999;14(2):123-30.

40. Sharp RJ, O’Leary ST, Falworth M, Cole A, Jones J, Marshall RW. Analysis of theresults of the C-Fit uncemented total hip arthroplasty in young patients with hydrox-yapatite or porous coating of components. J Arthroplasty. 2000;15(5):627-34.

41. Settecerri JJ, Kelley SS, Rand JA, Fitzgerald RH Jr. Collar versus collarless cementedHD-II femoral prostheses. Clin Orthop. 2002;(398):146-52.

42. Laupacis A, Bourne R, Rorabeck C, Feeny D, Tugwell P, Wong C. Comparison of totalhip arthroplasty performed with and without cement : a randomized trial. J Bone JointSurg Am. 2002;84-A(10):1823-8.

43. Palm L, Jacobsson SA, Ivarsson I. Hydroxyapatite coating improves 8- to 10-year per-formance of the link RS cementless femoral stem. J Arthroplasty. 2002;17(2):172-5.

44. Aamodt A, Nordsletten L, Havelin L, et al. Documentation of hip prostheses used in44.Norway: A critical review of the literature from 1996-2000. Acta Orthop. Scand.2004;75(6):663-76;

45. Ni GX, Lu WW, Chiu KY, et al. Cemented or uncemented femoral component in pri-mary total hip replacement? A review from a clinical and radiological perspective. J Orthop Surg (Hong Kong) 2005;13(1):96-105.

46. Morshed S, Bozic KJ, Ries MD, et al. Comparison of cemented and uncemented fixa-tion in total hip replacement: a meta-analysis. Acta Orthop. 2007;78(3):315-26.

47. McCombe P, Williams SA , A comparison of polyethylene wear rates between cement-ed and cementless cups. A prospective, randomised trial. J Bone Joint Surg Br2004;86(3):344-49.

48. Rasquinha V J, Ranawat C S, Dua V, et al. A prospective, randomized, double-blindstudy of smooth versus rough stems using cement fixation: minimum 5-year follow-up. J Arthroplasty 2004;19(7 Suppl 2):2-9.

49. von Schewelov T, Sanzen L, Onsten I, et al. Total hip replacement with a zirconiumoxide ceramic femoral head: a randomised roentgen stereophotogrammetric study. J Bone Joint Surg Br. 2005;87(12):1631-35.

50. Engh CA Jr, Stepniewski AS, Ginn SD, et al. A randomized prospective evaluation ofoutcomes after total hip arthroplasty using cross-linked marathon and non-cross-linked Enduron polyethylene liners. J Arthroplasty. 2006;21(6 Suppl 2):17-25.

51. Sherfey JJ, McCalden RW, et al. Mid-term results of Exeter vs Endurance cementedstems J Arthroplasty. 2006;21(8):1118-23.

52. Tugwell P, Boers M, Brooks P, Simon L, Strand V, Idzerda L. OMERACT: an interna-tional initiative to improve outcome measurement in rheumatology. Trials 2007; 8:38.

53. Bourne R, Mukhi S, Zhu, N, et al. Role of obesity on the risk for total hip or kneearthroplasty. Clin. Orthop. Relat. Res. 2007;465:185-88.

54. Flugsrud GB, Nordsletten L, Espehaug B, et al. The effect of middle-age body weightand physical activity on the risk of early revision hip arthroplasty: A cohort study of1,535 individuals. Acta Orthop. 2007;78(1):99-107.

62

55. Sarvilinna R, Huhtala HAS, Sovelius RT, et al. Factors predisposing to periprostheticfracture after hip arthroplasty: A case (n = 31)-control study. Acta Orthop. Scand.2004;75(1):16-20.

56. Goodman SN, Berlin JA. The use of predicted confidence intervals when planningexperiments and the misuse of power when interpreting results. Ann Intern Med.1994 Aug 1;121(3):200-6. Erratum in: Ann Intern Med 1995;122(6):478.

57. Gillespie WJ, Pekarsky B, O’Connell DL. Evaluation of new technologies for total hipreplacement. Economic modelling and clinical trials. J Bone Joint Surg Br.1995;77(4):528-33).

58. NICE, Guidance on the Selection of Prostheses for Primary Total Hip Replacement,Technology Appraisal Guidance, n. 2, UK,www.nice.org.uk

59. Parker MJ, Gurusamy K. Arthroplasties (with and without bone cement) for proximalfemoral fractures in adults. Cochrane Database Syst Rev. 2006;3:CD001706.

60. Kurtz S, Mowat F, Ong K, et al. Prevalence of primary and revision total hip and kneearthroplasty in the United States from 1990 through 2002. J Bone Joint Surg (Am)2005; 87 (7): 1487-97.

61. Roberts VI, Esler CN, Harper WM. What impact have NICE guidelines had on thetrends of hip arthroplasty since their publication? The results from the Trent RegionalArthroplasty Study between 1990 and 2005. J Bone Joint Surg Br. 2007;89(7):864-7.

62. Malchau H, Herberts P, Eisler T, et al. The Swedish Total Hip Replacement Register. JBone Joint Surg (Am) (Suppl 2) 2002; 84: 2-20.

63. Lucht U. The Danish Hip Arthroplasty Register. Acta Orthop Scand 2000; 71 (5): 433-9.

64. Puolakka R, Pitkanen M T, Rosenberg P H. Comparison of three catheter sets for con-tinuous spinal anesthesia in patients undergoing total hip or knee arthroplasty. RegAnesth Pain Med 2000; 25 (6): 584-90

65. CDC. National Hospital Discharge Survey, 1990-2002. United States Department ofHealth and Human Services, Centers For Disease Control, National Center for HealthStatistics 2002.

66. Eingartner C., “Current trends in total hip arthroplasty”, Ortopedia TraumatologiaRehabilitacja, 2007; 1(6); 8-14

63

Appendix 1

Technological characteristics of hip prostheses

Implantable medical devicesHip prostheses are classified as “implantable devices” since they solve their function inside the

body. As well as all implantable devices, that work inside the body for long or short periods, mate-rials assume a particular importance in the performance of the implant. Thus, implantable devicesmust be realised to work in a safe, reliable, economic, and physiologically acceptable manner.

With this aim a special class of materials has been created: biomaterials (Table A1.1). Froman historical definition, a biomaterial is a synthetic material used to replace part of a living systemor to function in intimate contact with living tissue (Pietrabissa, 1996). A primary requirement forany biomaterial is the biocompatibility defined as the acceptance of an artificial implant by the sur-rounding tissues and by the body as a whole.

The use of biomaterials did not become practical until the advent of an aseptic surgical techni-que developed in the 1860s. Earlier surgical procedures, whether they involved biomaterials ornot, were generally unsuccessful as a result of infection. Problems of infection tend to be intensi-fied in the presence of implantable devices, since the implant could be attacked by the immuno-logical defences of the body. The earliest successful implants, as well as a large part of modernones, were in the skeletal system. In time in order to enhance the biocompatibility of biomaterials,a wide range of chemical and physical properties have been developed and it is possible to defi-ne I, II and III generation biomaterials (Bronzino, 2002).

Table A1.1: Some of the materials used for medical devices (adapted from Bronzino 2002)

Key: PE = poly-ethylene; PTFE = poly-tetrafuoroethylene; Ti = titanium; Co = cobalt; Cr = chromium;

Au = gold; Ag = silver; Pt = platinum; s-steel = stainless steel.

Materials Examples

Polymers

(nylon, silicone, PE, PTFE, etc.)Sutures, blood vessels, hip socket, ear, nose, other soft tissues

Metals

(Ti and its alloys, Co-Cr alloys, Au, Ag, Pt, s-steels, etc.)

Joint replacements, bone plates and screws, dental root implants,

pacer and suture wires

Ceramics

(aluminium oxide, zirconium oxide, hydroxyapatite, carbon)

Dental implants, femoral head of hip replacement, coating of dental

and orthopaedic implants

Composites

(carbon-carbon, wire or fiber reinforced bone cement)Joint implants, heart valves

64

The bone tissue and the total joint implantsIn the past, implants to restore the function of traumatised or degenerated connective tissues

were designed with insufficient knowledge of biomechanics and thus, the clinical results were notvery encouraging. An increase of research activities into the mechanics of joints and biomaterialshas resulted in better designs with better in vivo performance. The improving long-term successof total joint replacements for the lower limbs is testimony to this. The reasons for the positiveoutcomes of joint implants have to be addressed to the particular properties of bone tissue. Boneis a hard tissue which is able to undergo continuous and spontaneous regeneration and to remo-del its micro and macrostructure through a balance between bone-forming processes (osteogene-sis) and bone-removing processes (osteoclasis). Changing the equilibrium between osteogenesisand osteoclasis bone can adapt its structure to a new mechanical environment.

These processes will respond to changes in the static and dynamic loads applied, i.e., if morethan the physiological load is applied, the equilibrium moves toward more bone-forming activity;conversely, the equilibrium moves toward more bone-removing activity if less load is applied (thisis known as Wolff ’s Law of bone remodeling).

One of the most common reasons for joint replacement is arthritis. Under this term we canfind more than a hundred rheumatic diseases affecting joints and connective tissues. The twomost common forms are osteoarthritis and rheumatoid arthritis. Osteoarthritis (also referred to asosteoarthrosis or degenerative joint disease) has a multifactorial origin and is the most commonform of arthritis. Rheumatoid arthritis is an autoimmune disease with a chronic and often progres-sive erosion of articular cartilage.

Joint degeneration is the end-stage of a destruction process of the articular cartilage, whichresults in severe pain, stiffness and loss of function. Unlike bone, cartilage has a very limited capa-city for repair, therefore when exposed to a severe mechanical, chemical, or metabolic injury, thedamage is permanent and often progressive.

Under normal conditions, the functions of the cartilage is to provide a congruent articulationbetween bones, to transmit load across the joint, to adsorb shock, and to allow low-friction move-ments between opposing joint surfaces.

Total joint replacements are permanent implants mimicking the natural biomechanics of thenatural joints. Since extensive bone and cartilage are removed during implantation, joint replace-ment is an irreversible procedure. Presently, joint implants are performed in the hip, knee, shoul-der, ankle, elbow, wrist and fingers.

Other than the materials and the shape of the devices, one of the most important elementsthat determines the long-term survival of joint implants is the method used for the implant fixa-tion. The fixation method is responsible for the load transfer characteristics (as mentioned above,bone responds to changes in load transfer).

For a “perfect” total joint implant, a number of issues must be considered (Bronzino, 2002):

• overloading and load-shielding of implant-bone interface may result in bone remod-elling with a consequent loosening of the implant;

• the articulating surfaces should work with minimum friction and should produce theleast amount of wear debris;

65

• the implant should be quickly and tightly fixed to the bone (ideally, immediately afterimplantation);

• removal of the implant (revision procedure) should not require the destruction of alarge amount of surrounding tissues.

Prostheses for primary total hip replacement The prosthesis for primary total hip replacement (THR) consists of two group of components:

the femoral component (or stem portion) that is fixed into the reamed medullary canal (by cemen-tation or press-fitting) and the acetabular component (or socket portion) that is inserted inside ofthe acetabular part of the joint (by cementation, press-fitting or screws).

Nowadays a huge number of devices are commercially available, differing for configurations,designs and materials.

The complete device is usually has 4 components (Figure A1.1):

• femoral stem;

• head;

• liner;

• acetabular cup.

Figure A1.1: Total hip prostheses and its different design: 1) femoral component; 2) head; 3) liner; 4) acetabular cup. A is the stem; A1 is the stem neck; A2 is an anatomical stem; A3 is astraight stem; B is the head; C is the monolithic cup; C1 is the liner; C2 is the insert; C3 is the cup

66

The prosthesis is defined monolithic if there is one part for each component and modular ifthere are more parts that require assembly during surgery. Monolithic prostheses were used in thepast while recent devices have modular designs that allow customization intra-operatively, andduring future revision surgeries. Thanks to modular designs various combinations of features canbe selected to best fit patient needs and clinician preferences.

Prostheses for THR can be divided in three wide classes:

• cemented prostheses: a layer of bone cement, poly-methylmetacrilate (PMMA), isused as a filler at the bone-implant interface;

• uncemented (or cementless) prostheses: the femoral and acetabular components arepress-fitted in the bone;

• hybrid prostheses: one component is cemented and the other uncemented, i.e.,cemented stem with uncemented cup (most common) or uncemented stem withcemented cup.

The stem may be “collared”, with a flange around the proximal part or “collarless“ when sucha flange is not present. Moreover, stem shape may be “straight” or “anatomical” and its surfacemay present different degrees of roughness. Designs with a modular neck also exists (see FigureA1.1).

The acetabular component may be monolithic, a cup that articulates with the head, or modu-lar, composed of two or three shields made of different materials (only one articulates with head,the others have a structural function). The cup may also present pins, flanges or screw holes.

The head is a spherical element with a conical hole. It is tightly fixed to the stem by a Morsetaper (cone-with-cone coupling) and it comes in specific diameters (usually 28, 32 and 36 mm).

The longevity of currently available implants, the rate at which surgical revisions are neededto replace failed implants, and the ease with which implants can be replaced, are primary con-cerns noted in the field of hip replacement.

Some general trends can be observed regarding the materials used, cemented stems areusually made of CoCr alloy and present a polished surface to facilitate stress exchange at themetal-cement interface; Press-fit stems are made of titanium alloy or CoCr alloy but are usuallycoated with porous titanium or hydroxyapatite (HA) to promote osseointegration; femoral headsmay be in stainless-steel, CoCr alloy, aluminium oxide, zirconium oxide or Oxinium (a new mate-rial resulting from the oxygen absorption into zirconium); the shell of the modular acetabular cupsare usually made of a titanium alloy with porous titanium or HA coatings whilst the liner may bemade of plastic (UHMWPE or XLPE), metal (Co-Cr alloy) or ceramic (aluminium oxide or zirconiumoxide).

Fixation methods In the early 1960's, the first cemented prosthesis was considered to be a great innovation

(AHRQ report, 2006). However, fragmentation of cement due to relative micro-movements at thebone-implant interface may result in loose particles namely debris. Such particles active themacrophages, which respond by releasing cytokines leading to a breakdown of the surroundingbone. This condition is defined “cement disease” and is one of the causes of the implant loosening.

67

To overcome this problem and to obtain more bone-preserving implants (that provide superiorbone stock in which to implant the revision prosthesis) research continues to develop uncemen-ted hip systems (also defined as press-fit components). One of the most important issues of thistechnology is the osseointegration, i.e. a firm fixation of the stem (or cup) achieved by variouscoatings or textures of the device’s surface that encourage bone growth onto the devices.

In general, the uncemented implants are contraindicated in patients with low bone quality andaltered bone remodelling, whilst seem to be the best choice for young and active patients.

Bearing surfacesThe choice of bearing surfaces, is crucial for the functionality and durability of the implant. As

stated above, the elements involved are the head and the liner.

Manufacturers have developed a number of different head-liner combination and have propo-sed on the market different classes of materials: plastics (ultra-high molecular weight poly-ethy-lene, UHMWPE, and highly cross-linked poly-ethylene, XLPE), metals (Cobalt-Chromium alloys),ceramics (aluminium oxide and zirconium oxide).

In general, the choice of bearing surfaces can be made between: metal-on-plastic, metal-on-metal, ceramic-on-ceramic. Table A1.1 reports some advantages and disadvantages of the diffe-rent combinations.

For a detailed description of all the combinations with several historical references readers canconsult the Horizon Scan report of the Agency for Health Research and Quality (AHRQ) on hipreplacement surgery, conducted by the ECRI Evidence-based Practice Center in December 2006(http://www.ahrq.gov/).

Table A1.1: Some of advantages and disadvantages of the principal bearing surfaces

Key: UHMWPE = ultra-high molecular weight poly-ethylene; XLPE = highly cross-linked poly-ethylene.

State of the ArtThe Italian Ministry of Labour, Health and Social Policies is creating a database containing all

the medical devices available on the Italian market (Repertorio dei Dispositivi Medici). Presently,it seems virtually impossible to know how many hip devices are available on the market.

We reported in Table A1.2 and Table A1.3 some of the devices identified in the PNLG-8 syste-matic review (2004) by searches in the regional arthroplasty registers. However, since not all theItalian Regions adopt an arthroplasty registry, the real number of devices used in Italy is proba-bly much higher than that reported in these tables.

Combinations Advantages Disadvantages

UHMWPE-on-Metal Decades of experience High wear rate

XLPE-on-Metal Less wear than UHMWPE Lack of long-term data

Metal-on-Metal Low wear Ion release

Ceramic-on-Ceramic Biocompatibility of wear particles Difficult positioning

68

Table A1.2: Some of the acetabular cups used in Italy listed in alphabetical order (table

adapted from the systematic review cited as PNLG-8, 2004)

Acetabular cups used in Italy: device name (manufacturer)

ABG (HOWMEDICA) EP FIT PLUS (ENDOPLUS) OSTEAL (CARAVER – ORTOPEDICAL)

ABGII (HOWMEDICA) EQUATEUR (AMPLITUDE) OSTEOLOCK (HOWMEDICA)

AC (HOWMEDICA) ETERNITY (BIOMET – MERCK) P.F.C. (JOHNSON & JOHNSON)

ACETABULAR CUP (BIRMINGHAM) EVOLUTION (HIT MEDICA) PBF (PERMEDICA – BIOMET)

ALBI (CREMASCOLI) EVORA SEM (DMO) PCA (HOWMEDICA)

ALBIPLUS (CREMASCOLI) EXCEED PC (BIOMET – MERCK) PE MULLER (PROTEK – SULZER)

ALLOCOR CUP (ALLOPRO) EXETER (HOWMEDICA) PINNACLE SECTOR II (DEPUY)

ALLOFIT S (ALLOPRO) EXPANSION (MATHYS) PLASMACUP (AESCULAP)

ANCA FIT (CREMASCOLI) FIN (BIOIMPIANTI) PLM (AMPLIMEDICAL)

ANTEGA (AESCULAP) FITEK (SULZER) PLUS FIT (ENDOPLUS)

ARMOR (ALLOPRO – SULZER) FITMORE (SULZER) PORO LOCK (HIT MEDICA)

ARTHOPOR II (JOHNSON & JOHNSON) FM (CITIEFFE) PRIMARY CUP METASUL (SULZER)

ARTIC (FII) FURLONG (JRI) PROTESI DA RIVESTIMENTO NATURALE (BIRMINGHAM)

ATLAS (FOURNITURES HOSPITALIERES) G3 (CITIEFFE) PROTESI DYSPLASIA DA RIVESTIMENTO (BIRMINGHAM)

AURA (BIOMET – MERCK) GAIA (DIDIENNE SANTE) RAC CEDIOR (SULZER)

AVANTAGE 3P (BIOMET – MERCK) HAC CERAFIT CUP (CERAVER – OSTEAL) REFLECTION (SMITH AND NEPHEW)

BICON PLUS (ENDOPLUS) HERMES (CITIEFFE) REFLECTION ALL POLY (SMITH AND NEPHEW)

BIOCERAMICA (SAMO) HERMES REV RIVESTITO (CITIEFFE) REVISION POROUS SHELL (SULZER)

CBF (MATHYS) HERMES RIVESTITO (CITIEFFE) RIPPEN (LINK)

CCB (MATHYS) HILOCK LINE (SYMBIOS) RM (MATHYS)

CFP (LINK) IDA (DEDIENNE SANTE) SCHALE CUP (INTRAPLANT)

CITATION (HOWMEDICA) INTERPLANTA (LINK) SECUR FIT (OSTEONICS)

CL (LIMA) INTERSEAL (WRIGHT) SII (LINK)

CLS (SULZER) JUMP (PERMEDICA) SL TITANIUM SHELL (PROTEK)

CLW (SULZER) JUMP DISPLASY (PERMEDICA) SP (LINK)

CONICAL SCREW CUP (PROTEK) LITHIA (SERF) SPH (LIMA)

CONSERVE PLUS (WRIGHT) LOR (ALLOPRO – SULZER) SPH BLIND (LIMA)

CONTEMPORARY (HOWMEDICA) MALLORY (BIOMET – MERCK) SPH CONTACT (LIMA)

CORAIL (DEPUY) MARBURG (ALLOPRO – SULZER) SPH PEG (LIMA)

CORRECTA (SULZER) MBA (GROUPE LEPINE) SPH REVISION (LIMA)

CSF FURLONG (JRI) McMINN (LINK) SPH ST (LIMA)

CUPULE AVANTAGE (BIOMET – MERCK) MEIJE (TORNIER) SPII SPECIALE PER DISPLASIA (LINK)

CUSTOM MADE (WRIGHT – CREMASCOLI) MEROS (BIOMPIANTI) STANDARD (AMPLITUDE)

DEFINITION (HOWMEDICA) METASUL STAR CUP (SULZER) STANDARD CUP (PROTEK – SULZER)

DELTA (BIOMECANIQUE INTEGREE) MONOBLOCK (ZIMMER) TEKNO (FIN)

DELTA PF (LIMA) MORPHOMETRIC (DEPUY) TIFLEX (PERMEDICA)

DUOFIT PDT (SAMO) MULLER (ALLOPRO – SULZER) TRANSCEND (WRIGHT)

DUOFIT PSF (SAMO) MULLER (BIOIMPIANTI) TRIDENT AD (HOWMEDICA)

DUOFIT PST (SAMO) MULLER (BIOMET – MERCK) TRIDENT (HOWMEDICA)

DURALOC 100 (DEPUY) MULLER (CITIEFFE) TRIDENT PSL (HOWMEDICA)

DURALOC 300 (DEPUY) MULLER (CREMASCOLI) TRILOC (DEPUY)

DURALOC 1200 (DEPUY) MULLER (DEPUY) TRILOGY (ZIMMER)

DURALOC (DEPUY) MULLER (GROUPE LÈPINE) TRILOGY AB (ZIMMER)

DURALOC BANTAM (DEPUY) MULLER (HIT MEDICA) ULTIMA (JOHNSON & JOHNSON)

DURALOC OPTION (DEPUY) MULLER (HOWMEDICA) VERSYS (ZIMMER)

DURALOC SECTOR (DEPUY) MULLER (LIMA) VERSYS CEMENTED PLUS (ZIMMER)

EASY (HIT MEDICA) MULLER (MATHYS) VERSYS FIBER METAL (ZIMMER)

ELATOS (LINK) MULLER (SAMO) VITALOCK CLUSTER (HOWMEDICA)

ELLIPTICAL CUP (STRATEC) MULLER (SMITH AND NEPHEW) VITALOCK SOLID (HOWMEDICA)

ELLIPTICAL CUP HEDROCEL (STRATEC) MULLER (SYMBIOS) VITALOCK TALON (HOWMEDICA)

ELLISTRA (STRATEC) MULLER TEKNO (FIN) WAGNER DA REVISIONE (ZIMMER)

ELLITTICA (SAMO) MULLER (ZIMMER) XP (CITIEFFE)

EPF PFANNE (ENDOPLUS) MULTINEK (LIMA) ZCA (ZIMMER)

EPF PLUS (ENDOPLUS) OPTICONTACT (CHIROPPO)

69

Table A1.3: Some of the femoral stems used in Italy listed in alphabetical order (table

adapted from the systematic review cited as PNLG-8, 2004)

Femoral stems used in Italy: device name (manufacturer)

AB (CITIEFFE) DUOFIT RKT (SAMO) PORO LOCK II (HIT MEDICA)

ABGII (HOWMEDICA) DUOFIT RTT (SAMO) PPF (BIOMET)

AC (HOWMEDICA) EASY (HIT MEDICA) PPF (STRATEC)

ACCOLADE (HOWMEDICA) EASY ANATOMIC (HIT MEDICA) PROFEMUR (CREMASCOLI )

ACCOLADE (OSTEONICS – HOWMEDICA) ELITE (DEPUY) PROFEMUR C (CREMASCOLI)

AD (SAMO) ELLITTICA (SAMO) PROFEMUR Z (WRIGHT – CREMASCOLI)

AHS (CREMASCOLI) EPOCH (ZIMMER) PROTESI DA RESEZIONE (LINK)

ALBI (CREMASCOLI) ESOP (FOURNITURES HOSPITALIERES) PROXILOCK FT (STRATEC)

ALBI PTC (CREMASCOLI) EUROPEAN HIP SYSTEM (CREMASCOLI) PTC (CREMASCOLI)

ALLOCLASSIC SL (ALLOPRO – SULZER) EXETER (HOWMEDICA) PTCR E (WRIGHT – CREMASCOLI)

ANATOMIQUE STEM (CEDIOR – SULZER) FIBER METAL TAPER (ZIMMER) PTF (CEDIOR – SULZER)

ANCA (CREMASCOLI) FIBER METAL (ZIMMER) RELIANCE (HOWMEDICA)

ANCA FIT (CREMASCOLI) FIN (BIOIMPIANTI) RESTORATION T3 (HOWMEDICA)

ANCA FIT CLU (CREMASCOLI) FIT STEM (LIMA) REVISION CON MODULO (LIMA)

ANTEGA (AESCULAP) FULLFIX (MATHYS) RIGHT (SMITH AND NEPHEW)

ARCAD (SYMBIOS) G2 (CITIEFFE) RIPPEN (LINK)

ARCAD CN (SYMBIOS) G2 (DEPUY) S ROM (JOHNSON & JOHNSON)

AURA (BIOMET – MERCK) G3 (CITIEFFE) S STEM (DEPUY)

AURA II (BIOMET – MERCK) GCA (LIMA) SAGITTA (SERF)

BASE MEIJE (TORNIER) H-AC STEM FURLONG (JRI) SELECTIV (FII)

BASIS (SMITH AND NEPHEW) HIPSTAR (HOWMEDICA) SEM III (DMO)

BEADED FULLCOAT PLUS (ZIMMER) IMAGE (SMITH AND NEPHEW) SL (AMPLIMEDICAL)

BHS (SMITH AND NEPHEW) ISOPHILE ANATOMIC (TORNIER) SL (BIOIMPIANTI)

BICONTACT (AESCULAP) JUMP (PERMEDICA) SL (HIT MEDICA)

BI METRIC (BIOMET – MERCK) JVC (CREMASCOLI) SL (LIMA)

BIOCERAMICA (SAMO) LC (SAMO) SL PLUS (ENDOPLUS)

BIODINAMICA (HOWMEDICA) LOGIC (AMPLITUDE) SL REVISION (SULZER)

C STEM (DEPUY) LOGICA (LIMA) SL STREAKES (HIT MEDICA)

C2 (LIMA) LUBINUS SP2 (LINK) SLR PLUS (ENDOPLUS)

CBC (MATHYS) LYDERIC (GROUPE LÉPINE) SPECTRON (SMITH AND NEPHEW)

CBH (MATHYS) MAINOSTREAM 30 (STRATEC) SPHERI SYSTEM II (HIT MEDICA)

CDH (SULZER) MAYO (ZIMMER) SPS (SYMBIOS)

CERES (DEDIENNE SANTE) MBA (GROUPE LÉPINE) STANDARD (TORNIER)

CF 30 (ALLOPRO) MERIDIAN (HOWMEDICA) STANDARD STRAIGHT (SULZER)

CFP (LINK) METABLOC (PROTEK – SULZER) STAR (PROTEK)

CHARNLEY MULLER (SAMO) MODULUS HYP SYSTEM (LIMA) STARFIT (STRATEC)

CITATION (HOWMEDICA) MP RECONSTRUCTION PROSTHESIS (LINK) STELCOR (PROTEK)

CL TRAUMA (LIMA) MRL (CREMASCOLI) STELO MODULARE NDS1 (CITIEFFE)

CLS (SULZER) MS 30 (PROTEK – SULZER) STEM (CREMASCOLI)

CLS VARUS (SULZER) MULLER AUTOBLOCCANTE (HIT MEDICA) SYNERGY (SMITH AND NEPHEW)

CONELOCK REVISION (STRATEC) MULLER AUTOBLOCCANTE (SULZER) T3 REVISION (HOWMEDICA)

CONSERVE PLUS (WRIGHT) OMNIFIT (OSTEONICS) TAPERLOC (BIOMET – MERCK)

CONUS (SULZER) OMNIFLEX (OSTEONICS) TOTAL COVER STEM (BIOMET – MERCK)

CORAIL (DEPUY) OMNIFLEX AD (OSTEONICS) ULTIMA (JOHNSON & JOHNSON)

CPS PLUS (ENDOPLUS) OMNIFLEX NORMALIZED (OSTEONICS) VECTRA 2 (VECTEUR ORTHOPEDIC)

CPT (ZIMMER) ORTHO FIT (ALLOPRO – SULZER) VECTRA 3 (STRATEC)

CUSTOM MADE (CREMASCOLI) P507 (SAMO) VERSYS CEMENTED LD (ZIMMER)

CUSTOM MK II (SYMBIOS) PBF (PERMEDICA) VERSYS CEMENTED (ZIMMER)

DEFINITION (HOWMEDICA) PBF/S (PERMEDICA) VERSYS ET (ZIMMER)

DEON (BIOIMPIANTI) PCA (HOWMEDICA) VERSYS FIBER METAL TAPER (ZIMMER)

DSP A DISCO DI COMPRESS. (ALLOPRO – SULZER) PCL (BIOIMPIANTI) VERSYS HERITAGE (ZIMMER)

DUOFIT CFS (SAMO) PERFECTA (WRIGHT) VERSYS REVISION CALCAR (ZIMMER)

DUOFIT CKA (SAMO) PERFECTA RA (WRIGHT) ZMR (ZIMMER)

DUOFIT CSF (SAMO) PORO LOCK (HIT MEDICA)

70

The FutureAt the present time 4 main “trends” can be identified in the field of THR: navigation techno-

logy, minimally/less invasive surgery, new bone-preserving implants, new material for bearing sur-faces (Eingartner 2007).

Navigation technology is an accepted and well studied surgical procedure in total knee arthro-plasty. In THR, many navigation systems offer navigated cup positioning or even workflows fornavigation of both the positions of cup and shaft as well as the resulting geometry of the articu-lation. Basically, there are two options for navigating the implant positioning in THR: image gui-ded procedures, consisting in pre- or intra-operative computer assisted tomography; and the mostrecent kinematic navigation, based on the registration of intra-operative landmarks and kinematicdata which are acquired and processed in real-time. These recent techniques address the indivi-dual anatomical situation of every patient.

New minimally or less invasive procedures often require an extended learning curve, especial-ly when using a very uncommon approach such as the double-incision techniques. Potential impro-vements (e.g. bleeding reduction, better and faster rehabilitation process, etc.) are not yet beshown in comparative reports. Limited visibility and exposure of anatomical landmarks mightincrease the risk of implant malpositioning, thus leading to an inferior long-term result in terms ofwear and durability. Navigation procedures, specific for minimally invasive surgery, could solve thisproblem but are still under development.

New implant concepts, mainly oriented to preserve the bone (e.g. metal-on-metal prosthesesfor hip resurfacing and short stem prostheses) have been introduced in several European coun-tries. These solutions could be suitable for younger patients. In fact, to perform THR in youngpatients means that a revision procedure will likely occurs and for this reason bone preserving isa key issue. Long-term results for these technologies, however, are still unavailable.

New materials for the bearing surfaces could improve the wear resistance since the propaga-tion of wear particles remains a main issue for long-term durability of THR. The actual trend inmaterial developments is strongly influenced by increased head diameters for improved hip fun-ction and dislocation stability. The preferred head diameter has changed from 32 mm in the 1980sto 28 mm in the 1990s and back to larger diameter up to 36 mm (and even larger in metal-on-metal prostheses).

71

Bibliography

Pietrabissa R, Biomateriali per protesi e organi artificiali, Patron Ed., 1996

Bronzino JD, “The Biomedical Engineering Handbook: Second edition”; 2000, CRC Press

AHRQ report: “Horizon Scan on Hip Replacement Surgery”, ECRI Evidence-based

Practice Center, December 22, 2006

PNLG-8, “Revisione sistematica sulle protesi d’anca: affidabilità dell’impianto”, 2004.

Eingartner C, “Current trends in total hip arthroplasty”, Ortopedia Traumatologia

Rehabilitacja, 2007; 1(6); 8-14

72

73

Appendix 2

Search strategy

PubMed search strategy

#1 Search (“Hip Prosthesis”[Mesh] OR “Arthroplasty, Replacement, Hip”[Mesh]

#2 Search hip[Title/Abstract] AND (replacement[Title/Abstract] OR

prosthesis[Title/Abstract] OR implantation*[Title/Abstract] OR

arthroplasty[Title/Abstract] OR hemiarthroplasty[Title/Abstract])

#3 Search (randomized controlled trial[Publication Type] OR controlled clinical

trial[Publication Type] OR randomized controlled trials[MeSH Terms] OR random

allocation[MeSH Terms] OR double-blind method[MeSH Terms] OR single-blind

method[MeSH Terms] OR clinical trial[Publication Type] OR clinical trials[MeSH

Terms]) OR (“clinical trial”[Text Word]) OR ((singl*[Text Word] OR doubl*[Text

Word] OR trebl*[Text Word] OR tripl*[Text Word]) AND (mask*[Text Word] OR

blind*[Text Word])) OR (placebos[MeSH Terms] OR placebo*[Text Word] OR ran-

dom*[Text Word] OR research design [mh:noexp]) NOT (animals[MeSH Terms]

NOT human[MeSH Terms])

#4 Search ((“Case-Control Studies”[MeSH]) OR (“case control studies”[Text Word]

OR “case control study”[Text Word]) OR (cases[Title/Abstract] AND

controls[Title/Abstract])) OR ((“Cross-Over Studies”[MeSH]) OR (cross over[Text

Word] OR crossover[Text Word])) OR ((“Cohort Studies”[MeSH]) OR (“cohort stud-

ies”[Text Word] OR “cohort study”[Text Word]) OR (cohort*[Title/Abstract])) OR

(“time series”[Text Word] OR “interrupted time series”[Text Word]) OR (“before

after”[Title/Abstract] OR “before-after”[Title/Abstract] OR

“before/after”[Title/Abstract] OR “before and after”[Title/Abstract])

#5 Search (“guideline” [pt] OR “practice guideline” [pt] OR “health planning guidelines”

[mh] OR “consensus development conference” [pt] OR “consensus development

conference, nih” [pt] OR “consensus development conferences” [mh] OR “consen-

sus development conferences, nih” [mh] OR “guidelines” [mh] OR “practice guide-

lines” [mh] OR (consensus [ti] AND statement [ti]))

#6 Search (“Technology Assessment, Biomedical”[Mesh] OR “United States Office of

Technology Assessment”[Mesh]) OR “technology assessment”[All Fields] OR

“health technology”

#7 Search #1 OR #2

#8 Search #7 AND systematic [sb]

#9 Search #3 OR #4 OR #5 OR #6

74

#10 Search #7 AND #9

#11 Search #8 OR #10

#12 Search #8 OR #10 Limits: Entrez Date from 2003/01/01

EMBASE search strategy

#1 ‘hip prosthesis’/syn OR ‘total hip prosthesis’/syn OR ‘hip arthroplasty’/syn

#12 hip AND (replacement OR prosthesis OR implantation* OR arthroplasty OR hemi-

arthroplasty)

#13 #1 OR #12

#16 ‘systematic review’/syn OR ‘meta analysis’/syn OR ‘sensitivity analysis’/syn

#18 ‘practice guideline’/exp OR guideline* OR ‘health planning guidelines’/exp OR

‘consensus development conference’/exp OR ((‘consensus’/exp) AND statement)

#28 ‘randomized controlled trial’/exp OR ‘clinical trial’/exp OR ‘randomization’/exp OR

‘double blind procedure’/exp OR ‘single blind procedure’/exp OR ((singl* OR

doubl* OR trebl* OR tripl*) AND (mask* OR blind*)) OR ‘placebo’/exp OR place-

bo* OR random* OR ‘case control study’/exp OR ‘cohort analysis’/exp OR ‘case

control study’:ti,ab OR ‘case control studies’:ti,ab OR (case* AND control*:ti,ab)

OR ‘cohort study’:ti,ab OR ‘cohort studies’:ti,ab OR ‘cross over study’:ti,ab OR

‘cross over studies’:ti,ab

#30 ‘biomedical technology assessment’/syn

#31 ‘technology assessment’:ab,ti,de OR ‘health technology’:ab,ti,de

#32 #16 OR #18 OR #28 OR #30 OR #31

#33 #13 AND #32

#34 #13 AND #32 AND [humans]/lim AND [embase]/lim

#35 #13 AND #32 AND [humans]/lim AND [embase]/lim AND [2003-2008]/py

Cochrane Library search strategy

#1 MeSH descriptor Hip Prosthesis explode all trees

#2 MeSH descriptor Arthroplasty, Replacement, Hip explode all trees

75

#3 (#1 or #2)

#4 (hip and (replacement or prosthesis or implantation* or arthroplasty or hemi-

arthroplasty))

#5 (#3 or #4)

#6 (#3 or #4) from 2003

76

77

Appendix 3

Data extraction form for review studies

General description

NB Do not leave blank spaces.

If there is no answer to the question write NR (not reported) or NA (not applica-

ble).

Study ID:

Published [Y/N]:

Date of publication:

Form of publication [abstract/full paper]:

Biblio ref:

Type of funder [government, mixed, private, industry, unfunded, undeclared/unknown]:

Pub Med abstract:

Date of last updated search:

78

Methods description

Rationale:

Objective:

Searches (list databases/sources):Electronic:Hand:

Strategy reported [Y/N]:

Inclusion criteria:

Types of studies:

Types of participants:

Types of intervention:

Types of outcome measures:

Number of included studies:

Included studies list [Y/N/Av from author]:

Excluded studies list [Y/N/Av from author]:

RCT average patient number:

Reasons for exclusion given [Y/N]:

Flow diagram [Y/N]:

Quality assessment [Y/N]:

If Y how [Score/Checklist/Other]:

How quality incorporated [Weighting/Sub group analysis/Narrative/Unclear]:

Meta-analysis included [Y/N]:

If Y brief statistical methods description:

Sub group analysis [Y/N]:

If Y was it mentioned in the protocol [Y/N]:

Heterogeneity analysed [Y/N]:

Heterogeneity discussed [Y/N]:

79

Results description

Synthesis of results:

Population Intervention Comparison OutcomeEstimate of effect

(95% CI) Notes

80

Conclusions description

Conclusions

Assessment of generalisability of results

Bottom line

81

Quality assessment

Y = yes

N = no

UC = unclear

Number ItemAnswer

Y/N/UCNotes

1 Is there an objective?

2 Is the objective clear?

3 Are the searches reported?

4 Were the searches done on at least 3 sources?

5 Do the searches appear thorough?

6 Were hand searches carried out?

7 Are the inclusion criteria explicit?

8 Are the inclusion criteria coherent with the objective?

9 Do the inclusion criteria include quality of primary studies as a criterion?

10 Was abstraction done in double?

11 Is the description of primary studies reported?

12 If there is a meta-analysis are interventions homogeneous?

13 If there is a meta-analysis are outcomes homogeneous?

14 If there is a meta-analysis are study designs homogeneous?

15 Is the statistical analysis appropriate?

16 Do conclusion flow logically from the results?

17 Is there a declaration of conflicts of interest?

82

83

Appendix 4

Data extraction form for single studies

General description

NB Do not leave blank spaces.

If there is no answer to the question write NR (not reported) or NA (not applica-

ble)

Study ID:

Published [Y/N]:

Date of publication:

Period of the study [from/to]:

Country of study:

Form of publication [abstract/full paper]:

Biblio ref.:

Type of funder [Government, mixed, private, industry, unfunded, undeclared/unknown]:

PubMed abstract:

84

Methods description

Rationale:

Objective:

Measured outcomes:

Groups of the studyGroup 1:Group 2:

Population:

Total number of patients enrolled in the study: ( hips)

Patient excluded from the study: ( hips)

Total number of participants: ( hips)

Number of participants for each groupGroup 1:Group 2:

Age at surgery (mean ± SD; (range)) [years]:Group 1:Group 2:

Gender [num. M / num. F]:Group 1:Group 2:

Clinical follow-up (mean ± SD; (range)) [months]:Group 1:Group 2:

Other follow-up (e.g. radiological):Mean ± SD; (range) [months]:Group 1:Group 2:

Type of implant [cemented, cementless, hybrid]Group 1:Group 2:

Name of device Group 1:Group 2:

85

Further characteristicsGroup 1:Group 2:

Common characteristics:

Manufacturer Group 1:Group 2:

Setting [general hospital/specialised institute]:

Quality of reporting (using the CONSORT statement): http://www.consort-statement.org

86

Results description

Synthesis of the results:

Device related complications:

Wear [ ] Revised [ ]

Loosening [ ] Revised [ ]

Dislocation [ ] Revised [ ]

Infection (sepsis) [ ] Revised [ ]

Osteolysis [ ] Revised [ ]

Other (to specify)

[ ] Revised [ ]

Number of implants subjected to revision during the study:

87

Conclusions description

Conclusions:

Assessment of generalisability of results:

Bottom line:

88

89

Appendix 5

Minimum data set for an arthroplasty register

This form is proposed by the European Artrhoplasty Register (EAR) - EFORT project(www.efort.org) as a minimum data set for an arthroplasty register.

Guidelines for EFORT Minimal datasets: • The patient has to be identified clearly to match primary and revision surgery. This

could be done by a unique personal code, which remains unaltered for lifetime of theperson (national or European medical codes) or an algorithm including personal datacreating this code.

• Bipolar and partial prosthesis are facultative, but recommended. It is recommendedto use a standardised documentation in these implants too. Parts of the forms refer-ring specifically to these implants can be recognised by smaller letters.

• Implants have to be tracked clearly, EAR is recommending a standardised way basedon recent technology

A standardised list covering the entire market should be set up including

• Article Number (EAN - Code)

• Lot number

• A description of the implant based on ISO-Norm 7206

The remark “databank” in the forms is referring to this system.

The technical procedures of implant tracking are defined by the National Arthroplasty Register.

Evaluations are done exclusively on request of the EARB, supported technically by the centralserver and evaluation unit located at IT-Campus in Halle/Saale, Germany.

Any publication is done by the EARB.

Owner of national datasets are exclusively the National Arthroplasty Registers.

The EARB is the only Board, which is authorised to give access to datasets.

Anyone who is interested in doing research based on EAR-aggregated datasets is invited tosend a proposal to the EARB.

Please contact the EAR-Coordinator for further information.

90

91

Appendix 6

List of included studies

Ref. Authors Design of the study Title

16 Aamodt et al., 2004 Review studyDocumentation of hip prostheses used in Norway: A critical review of

the literature from 1996-2000

17 Ni et al., 2005 Review studyCemented or uncemented femoral component in primary total hip

replacement? A review from a clinical and radiological perspective

18 Morshed et al., 2007 Review studyComparison of cemented and uncemented fixation in total hip

replacement: a meta-analysis

19 Von Schewelov et al., 2005 Randomised prospective studyTotal hip replacement with a zirconium oxide ceramic femoral head: a

randomised roentgen stereophotogrammetric study

20 McCombe et al., 2004 Randomised prospective studyA comparison of polyethylene wear rates between cemented and

cementless cups. A prospective, randomised trial

21 Rasquinha et al., 2004 Randomised prospective studyA prospective, randomised, double-blind study of smooth versus

rough stems using cement fixation: minimum 5-year follow-up

22 Engh et al., 2006 Randomised prospective study

A randomised prospective evaluation of outcomes after total hip

arthroplasty using cross-linked marathon and non-cross-linked

Enduron polyethylene liners

23 Sherfey et al., 2006 Prospective study (cohort) Mid-term results of Exeter vs Endurance cemented stems

92

Table A6.1: Single studies included and extracted in our review. Studies are reported in

chronological order.

Key: N. of impl. = number of implants; PE = poly-ethylene; UHMWPE = ultra-high molecular weight poly-

ethylene; y = years.

AuthorsDesign

of the studyQuestion

Device 1

(Manufacturer)

Device 2

(Manufacturer)

N. of

impl.

Mean

follow-up

[y]

Risk of

biasResults Notes

McCombe et al.,

200446Randomised

prospective

study

Uncemented

cup vs.

cemented

cup

Duraloc 100

(DePuy)

Exeter

(Stryker)

115 8 Medium Emerges

from the

study that

this all-PE

cup wears

less than the

cementless

cup used

-

Rasquinha et al.,

200447Randomised

prospective

study

Effect of sur-

face finish of

the cement-

ed stem

(17 vs. 170

μinches)

Ranawat-

Burnstein

Interlock

(Biomet)

Ranawat-

Burnstein

Interlock

(Biomet)

223 6.55 Medium Durability of

fixation is

similar

between

smooth and

rough

femoral

stems

Aseptic loos-

ening is like-

ly to occur in

8-10 years

von Schewelov et

al., 200548Randomised

prospective

study

4 groups:

- steel head

and UHMW-

PE cup;

- steel head

and Hylamer

cup;

- zirconium

head and

UHMWPE

cup;

- zirconium

head and

Hylamer cup

Steel head (or

zirconium

head) +

Enduron

(DePuy)

Steel head (or

zirconium

head) +

Hylamer

(DePuy)

114 5 Medium - High risk of

fracture for

zirconium

oxide

ceramic

head;

- High wear

for

Hylamer

cup

- Mean age

of 64 years

old;

- Small

groups of

patients

Engh et al., 200649 Randomised

prospective

study

Cross-linked

vs. non-

cross-linked

PE liners

Marathon

(DePuy)

Enduron

(DePuy)

230 5.7 ± 0.6;

(4.1-7.2)

High Marathon

mean wear

rate was

lower than

Enduron

mean wear

rate (0.01 ±

0.07 vs. 0.19

± 0.12

mm/y)

-

Sherfey et al.,

200650Prospective

study

(Cohort)

Collarless

stem vs.

collared

stem

Exeter

(Stryker)

Endurance

(DePuy)

152 5.9 Medium - The study

supports

the use of

Exeter;

- High loos-

ening rates

for

Endurance

-

93

Appendix 7

List of excluded studies with reasons for exclusion

Studies excluded for inappropriate end-point (n=4):Berend, M. E.; Smith, A.; Meding, J. B.; Ritter, M. A.; Lynch, T., and Davis, K. Long-term outcome and risk factors of proximal femoral fracture in uncemented and cemen-ted total hip arthroplasty in 2551 hips. J Arthroplasty. 2006; 21(6 Suppl 2):53-9.

Bordini, B.; Stea, S.; De Clerico, M.; Strazzari, S.; Sasdelli, A., and Toni, A. Factors affec-ting aseptic loosening of 4750 total hip arthroplasties: multivariate survival analysis. BMCMusculoskelet Disord. 2007; 869.

Keating, J. F.; Grant, A.; Masson, M.; Scott, N. W., and Forbes, J. F. Randomized compari-son of reduction and fixation, bipolar hemiarthroplasty, and total hip arthroplasty.Treatment of displaced intracapsular hip fractures in healthy older patients. J Bone JointSurg Am. 2006; 88(2):249-60.

Parker, M. J. and Gurusamy, K. Arthroplasties (with and without bone cement) for proximalfemoral fractures in adults. Cochrane Database Syst Rev. 2006; 3CD001706.

Studies excluded for irrelevant topic (n=6):Chang, W. R. and McLean, I. P. CUSUM: A tool for early feedback about performance? BMCMed. Res. Methodol. 2006; 6(-):5p

Kop, A. M. and Swarts, E. Selection of primary hip and knee arthroplasties for public hospi-tals in Western Australia: A clinical evidence approach. ANZ J. Surg. 2006; 76(12):1068-1074.

Mofidi, A.; Kapoor, H.; Kumar, R.; Rice, J.; Smyth, H.; Fenelon, G. C.; McElwain, J., Borton,D. Prospective randomized control trial comparing Biostop, a bioabsorbable cement restric-tor with the standard Hardinge cement plug. Eur. J. Orthop. Surg. Traumatol. 2004;14(2):99-103.

Schauss, S. M.; Hinz, M.; Mayr, E.; Bach, C. M.; Krismer, M., and Fischer, M. Inferior stabi-lity of a biodegradable cement plug. 122 total hip replacements randomized to degradableor non-degradable cement restrictor. Arch Orthop Trauma Surg. 2006; 126(5):324-9.

Toni, A.; Traina, F.; Stea, S.; Sudanese, A.; Visentin, M.; Bordini, B., and Squarzoni, S. Earlydiagnosis of ceramic liner fracture. Guidelines based on a twelve-year clinical experience. JBone Joint Surg Am. 2006; 88 Suppl 455-63.

Wembridge, K. R. and Hamer, A. J. A prospective comparison of cement restrictor migra-tion in primary total hip arthroplasty. J Arthroplasty. 2006; 21(1):92-6.

94

Studies excluded for inappropriate design (n=4):Daniel, J.; Pynsent, P. B., and McMinn, D. J. Metal-on-metal versus polyethylene in hip arthro-plasty: a randomized clinical trial. Clin Orthop Relat Res. 2004; (422):271; 271-2.

Fayard, J. P.; Chalencon, F.; Passot, J. P.; Dupre Latour, L., and Edorh, G. Ten-year resultsof ALIZE acetabular cup with hydroxyapatite coating and AURA hydroxyapatite-coated stemin total hip arthroplasty. J Arthroplasty. 2006; 21(7):1021-5.

Jones, D. L.; Westby, M. D.; Greidanus, N.; Johanson, N. A.; Krebs, D. E.; Robbins, L.;Rooks, D. S., and Brander, V. Update on hip and knee arthroplasty: current state of eviden-ce. Arthritis Rheum. 2005 15; 53(5):772-80.

Walton, N. P.; Darrah, C.; Shepstone, L.; Donell, S. T., and Phillips, H. The Elite Plus totalhip arthroplasty. J. Bone Jt. Surg. Ser. B. 2005; 87(4):458-462.

Studies excluded for follow-up and/or mean age out of inclusion criteria (n=4):

Hallan, G.; Aamodt, A.; Furnes, O.; Skredderstuen, A.; Haugan, K., and Havelin, L. I.Palamed G compared with Palacos R with gentamicin in Charnley total hip replacement. Arandomised, radiostereometric study of 60 hips. J Bone Joint Surg Br. 2006; 88(9):1143-8.

Hallan, G.; Lie, S. A., and Havelin, L. I. High wear rates and extensive osteolysis in 3 typesof uncemented total hip arthroplasty: a review of the PCA, the Harris Galante and theProfile/Tri-Lock Plus arthroplasties with a minimum of 12 years median follow-up in 96 hips.Acta Orthop. 2006; 77(4):575-84.

Landor, I.; Vavrik, P.; Sosna, A.; Jahoda, D.; Hahn, H., and Daniel, M. Hydroxyapatiteporous coating and the osteointegration of the total hip replacement. Arch Orthop TraumaSurg. 2007; 127(2):81-9.

Lombardi, A. V.; Mallory, T. H.; Cuckler, J. M.; Williams, J.; Berend, K. R., and Smith, T. M.Mid-term results of a polyethylene-free metal-on-metal articulation. The Journal ofArthroplasty. 2004; 19(7 Suppl 2):42-7.

Studies excluded for insufficient reporting and/or inappropriate comparators (n=2):

Barouk, P.; Maynou, C.; Hildebrand, H. F.; Aubertin, F.; Breme, J.; Cassagnaud, X., andMestdagh, H. [High incidence of total hip arthroplasty aseptic loosening with ion-coatedtitanium femoral heads] [Frequence elevee des descellements prothetiques aseptiquesapres utilisation d’un couple titane implante-polyethylene.]. Rev Chir Orthop ReparatriceAppar Mot. 2004; 90(1):26-32.

Qassem, D. M. and Smith, K. B. Effect of elevated-rim acetabular liner and 32-mm femoralhead on stability in total hip arthroplasty. Saudi Med J. 2004; 25(1):88-90.

95

Untraceable studies (n=3):Barden, B.; Seel, W.; Loer, F., and Konermann, H. The hollow prosthesis to reduce intrame-dullary pressure in cementless femoral hip arthroplasty: DIE ZEMENTFREIE HOHLSCHAFT-HUFTENDOPROTHESE ZUR REDUZIERUNG DES INTRAMEDULLAREN DRUCKES. Z. Orthop.Ihre Grenzgeb. 2004; 142(3):298-302.

Delaunay, C. [Can metal-on-metal bearings improve the longevity of total hip prostheses?][Un couple de frottement metal-metal peut-il ameliorer la longevite des protheses totalesde hanche?]. Rev Chir Orthop Reparatrice Appar Mot. 2005; 91(1):70-8.

Neuss, M.; Clemens, S.; Marx, R.; Weber, M.; Weisskopf, M., and Wirtz, D. C. [Is the implan-tation of titanium stems in hip prostheses really obsolete?] [Ist die Implantation von Titan-Schaften in der Huftendoprothetik wirklich obsolet?] Z Orthop Ihre Grenzgeb. 2005;143(3):337-42.

96

97

Appendix 8

Instruments for outcome measurements

Disease-Specific Questionnaires

1) WOMAC

The Western Ontario and McMaster Universities Osteoarthritis Index is a self administeredquestionnaire, validated for patients with osteoarthritis of the hip or knee, that measuresthe state of health of the patient, with a specific illness following an intervention for hip orknee replacement.

The different levels of the state of health are defined considering three areas with specificquestions for: pain, joint articulation and clinical functionality. The answers can be analy-sed singularly, or summed together in a total. Each reply is given a numeric score rangingfrom 0 to 4.

2) Oxford Hip Score

The Oxford Hip Score is a questionnaire that measures the state of health of an individualfollowing an intervention to implant a prosthesis or hip replacement. It is an instrumentthat has proved to be consistent reproducible, valid and sensitive to changing clinical con-ditions, above all for the evaluation of the state of health of patients who have undergonetotal hip replacement

It is composed of 12 questions divided into two macro categories, pain and joint articula-tion, valued in relation to different daily activities. A score, on a scale of 1-5, is attributedto each reply. The total score ranges from 12-60.

3) Harris Hip Score

The Harris Hip Score is a self administered questionnaire which evaluates the state ofhealth of a patient for a specific illness, in particular hip replacement. The evaluation isdone using a numerical score and considers 4 principal categories: pain, functionality,deformity and mobility. The functionality refers to daily activity and mobility. It is importantto specify that the categories of pain and function have an important weight in the scoringwith respect to the other two categories.

General-Health QuestionnairesAmongst the instruments of Health-Related Quality of Life (HRQoL) there are: SF-12 e SF-36,

EQ-5D, Health Utilities Index Mark 2 (HUI2) and Mark 3 (HUI3) e SF-6D.

1) Short-Form 36 and Short-form 12 items Health Survey

The SF-36 is a questionnaire that describes health as perceived by the patient both from a

98

physical and mental point of view. It is a questionnaire that in its initial form was very long,115 questions concentrated in 12 scales. Successively it has been reduced to 36 questionsin 8 scales. The information contained in the 8 scales are synthesised using two indexes,one concerning the physical state of health and the other the mental state of health.

With the identification of the two synthetic indexes a shorter questionnaire has been for-mulated, composed of 12 questions, SF-12, which gives a complete description of the stateof health of the patient. The SF-12 can be compiled in several minutes, and given its bre-vity can be given to the patient to be compiled with other more specific questionnaires forsingle morbidity.

In fact due to its brevity it is preferred in large-scale studies in which the differences in pre-cision are not particularly important. The evaluation is done describing the state of healthof the patient, both physical and mental, divided into two levels, very high and very low.

2) EQ-5D

The EQ-5D is a standardised instrument that measures the state of health of a patient givinga descriptive profile and a single value to indicate the state of health. It is widely recommen-ded in studies of cost-efficacy. It is suitable for self-compilation and can be used in the hospi-tal setting directly with the patient, in interviews or in a sample of postal surveys.

The questions are divided into five categories: mobility, self-care, usual activity, pain andanxiety/depression. Each level is evaluated using a scoring system that divides the judge-ment into three levels: no problem, some problems, and severe problems. The question-naire illustrates 243 “states of health” each one with its own weight that ranges from -0.594 to 1.

3) Health Utilities Index Mark 2 (HUI2) and Mark 3 (HUI3)

The two instruments represent two independent but complementary systems, whichdescribe the state of health of an individual.

They are composed by a classification system for the state of health and a general systemHealth-Related Quality of Life (HRQoL). They use an evaluation system which attributes anumeric score of judgement which for the HUI2 ranges from -0.03 (the worst) to 1 (per-fect), whilst for HUI3 ranges from -0.36 to 1.

99

Hip Score System

Key: X = variable considered.

Variables

Scoring Instrument Name

Harris Hip ScoreOxford Hip

ScoreWOMAC SF-12 SF-36 EQ-5D HUI2 and HUI3

Physical

FunctioningX X X X X

Role-Physical X X

Bodily Pain X X X X

Vitality X X X

General Health X X X

Social

FunctioningX X X X

Role-Emotional X X X X

Mental Health X X X

Pain X X X X X

Distance walked X X

Activities -

shoes, socksX X X

Public

TransportationX X X

Limp X X

Support / self-

sufficiencyX X X X

Stairs X X

Sitting X

Limb lenght dis-

crepancyX

Motions X

Stiffness X

Shooting, stab-

bing,spasmX

Work X

Bed at night X

Mehod of subministration

Interview X X

By phone X X

Face to face X X X

Questionnaire

Self adminis-

teredX X X X X X

To the relatives

Repeated in

time

Method of evaluation

Numeric X X X X X

Judgement X X X

100

Bibliography

M. Ostendorf, H.F. van Stel, E. Buskens. “Patient-reported outcome in total hip replacement.A comparison of five instruments of health status”, The Journal of bone & joint surgery, .86-B, No.6, 2004

Hwee-Lin Wee, David Machin, Wai-Chiong Loke. “Assessing differences in utility scores: acomparison of four widely used preferenced-based instruments”, International Society forPharmacoeconomics and Outcomes Research (ISPOR), 10, No. 4, 2007.

Peter Soderman, Henri Malchau, Peter Herberts. “Outcome after total hip arthroplasty: PartII. Disease-specific follow-up and the Swedish National Total Hip Arthroplasty Register”,Acta Orthop Scand 2001; 72 (2): 113-119.

Ware JE, Kosinski M, Bayliss MS. “Comparison of methods for scoring and statistical analy-sis of SF-36 health profiles and summary measures: summary of results from the MedicalOutcomes Study”. Medical Care 33, 1995.

Romanini E., Villani C., Torre M., “Qualità di vita e protesi di anca”, 2006, iii, 28 p. RapportoiISTISAN 06/4.

101

Glossary

Cochrane Library (CLIB)A collection of databases, published on disk, CD-ROM and the Internet and updated quarter-

ly, containing the Cochrane Database of Systematic Reviews, the Cochrane Controlled TrialsRegister, the Database of Abstracts of Reviews of Effectiveness, the Cochrane Review MethodologyDatabase, and information about the Cochrane Collaboration and other information.

Cochrane ReviewA Cochrane Review is a systematic, up-to-date summary of reliable evidence of the benefits

and risks of healthcare. Cochrane Reviews are intended to help people make practical decisions.For a review to be called a “Cochrane Review” it must be in the Parent Database maintained bythe Cochrane Collaboration. The Parent Database is composed of modules of reviews submittedby Collaborative Review Groups (CRGs) registered with the Cochrane Collaboration. The reviewscontributed to one of the modules making up the Parent Database are refereed by the editorialteam of the CRG, as described in the CRG module. Reviewers adhere to guidelines published inthe Cochrane Reviewers’ Handbook.

Comparative studiesA study where the effect of an intervention is assessed using comparison groups. This can be

a randomised controlled trial, a cohort study, a case-control study, etc.

CONSORTThe CONSORT Statement is intended to improve the reporting of a randomised controlled trial

(RCT), enabling readers to understand a trial’s design, conduct, analysis and interpretation, andto assess the validity of its results. It emphasises that this can only be achieved through comple-te transparency from authors. Investigators and editors developed and revised the CONSORT(CONsolidated Standards of Reporting Trials) Statement to help authors improve reporting byusing a checklist and flow diagram. The checklist items pertain to the content of the Title, Abstract,Introduction, Methods, Results and Discussion. The checklist includes the 22 items selected becau-se empirical evidence indicates that not reporting the information is associated with biased esti-mates of treatment effect, or because the information is essential to judge the reliability or rele-vance of the findings.

Observational studiesA comparative study in which the use of different interventions among participants is not allo-

cated by the researcher (it is merely observed). This could be cohort study, case-control study,cross-sectional study, etc.

102

Randomised controlled trialsA randomised controlled trial (RCT) is a scientific procedure commonly used in testing medi-

cines or medical procedures. RCTs are considered the most reliable form of scientific evidencebecause they eliminate all forms of spurious causality. RCTs are mainly used in clinical studies, butare also employed in other sectors such as judicial, educational and social research. Clinical RCTsinvolve allocating treatments to subjects at random. This ensures that the different treatmentgroups are ‘statistically equivalent’.

Newcastle Ottawa scale (NOS)A three-section checklist for assessing the methodological quality of non-randomised studies

such as cohort and case-control studies.

age.na.s. Agenzia Nazionale per i Servizi Sanitari Regionali

Sezione A.G.P. - Centro Stampa

Via Puglie 23, 00187 – Roma .

Tel. 06.427491 – fax. 06.42749488

www.agenas.it e-mail info@agenas.it