National Institute for Health and Clinical Excellence

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1 Naional Insiue for Healh and Clinical Excellence Venous hromboembolic diseases Guideline Consulaion Commens Table 26 Ocober December 2011 Type (NB his is for inernal purposes remove before posing on web) = Regisered Sakehols. These commens and responses will be posed on he NICE websie when he guideline is published. PR = Peer Reviewers or Expers. These commens and responses will be posed on he NICE websie when he guideline is published. GRP = Guidelines Review Panel member. These are added o his able for convenience bu will no be posed on he web. NICE = Commens from NICE. These are added o his able for convenience bu will no be posed on he web. n Reg = These are no longer acceped and should no be added o he able NCGC received lis 11AM 23 rd DEC Type Sakehol Or SIGN 9 Appendice s e Commens Please inser each new commen in a new I assume you have gone for Wells PE score because here is a lile more daa bu i is much more subjecive han he revised geneva score which is well validaed and probably more suiable for less specialis individuals rying o diagnose PE Please respond o each commen Thank you for your commen. Boh he Geneva and Wells Scores were shown o be safe and effecive when used in conjuncion wih a sensiive D-dimer es in ruling of PE in among paiens presened wih suspeced PE. However, sudies using he Geneva scoring sysem have an imporan limiaion clinicians in he sudies were allowed o override he clinical rules in hese sudies. Since i was unclear how many paiens required an overrule in hese sudies, i is uncerain how well he PLEASE NOTE: Commens received in he course of consulaions carried ou by he Insiue are published in he ineress of openness and ransparency, and o promoe unsanding of how recommendaions are developed. The commens are published as a record of he submissions ha he Insiue has received, and are no endorsed by he Insiue, is officers or advisory commiees. 1 of 196

2 Sakehol Or e Commens Please inser each new commen in a new Please respond o each commen es will work if he rules are followed. In conras, alhough he Wells score has an iem which explicily requires clinical judgemen, i was shown o safely rule ou PE when followed. SIGN 8 Appendice s Again why are you recommending a D- dimer when i doesn' change your invesigaion or managemen - all you need is he ulrasound scan resul The raionale for using Well score was explained in he Linking Evidence To Recommendaion secion (Secion 7.6), boh un he qualiy of evidence secion and also in oher consiaion secion. Thank you for your commen. Based on your commen, we believed you are referring o he NICE version of he guideline (insead of Appendices), where he recommendaion described paiens who had a likely Well score bu had DVT excluded following a series of es recommended in he diagnosis pahways. The ulrasound es is sensiive es, and a proximal ulrasound was recommended in paiens wih a likely well score. As hese paiens have a relaively high risk of DVT and only he proximal veins were scanned, d-dimer es was recommended o double check here is no risk of DVT before being sen home If here is a risk of DV canno be excluded wih a negaive d-dimer es, a paiens would be offered a repea ulrasound scan. PLEASE NOTE: Commens received in he course of consulaions carried ou by he Insiue are published in he ineress of openness and ransparency, and o promoe unsanding of how recommendaions are developed. The commens are published as a record of he submissions ha he Insiue has received, and are no endorsed by he Insiue, is officers or advisory commiees. 2 of 196

3 Sakehol Or e Commens Please inser each new commen in a new Please respond o each commen SIGN 10 Appendice s See previous issues abou recommending CDR hrombolysis for large numbers of paiens - his would represen a major change in he managemen of proximal DVT and presumably necessiae ransfer o a cenre wih access o specialised inervenional radiology. We feel ha he addiion of d-dimer es o rules of DVT is a safer approach. Moreover, his approach was suppored by resuls of decision analysis which showed ha d-dimer ess o paiens wih a negaive ulrasound scan as cos effecive. The cos of a d-dimer es is relaively low (beween 19 o 20). This had already been documened in he Economic consiaion secion of he Linking Evidence o Recommendaion boxes accompanying he recommendaion in Secion 5.5, of he full guideline. Thank you for your commen. When his recommendaion was made, he Guideline Developmen Group had aken ino consiaion ha he curren pracice where relaively few caheer direced hrombolysis inervenions are unaken in he NHS. However, he evidence have suggesed ha caheer direced hrombolysis could poenially bring imporan benefis o paien wih sympomaic iliofemoral DVT and should be available as an opion o paiens who will benefi o i. This inervenion may no be appropriae for all paiens presening wih a proximal DVT. Selecing he paiens who can benefi he mos from his reamen which makes he PLEASE NOTE: Commens received in he course of consulaions carried ou by he Insiue are published in he ineress of openness and ransparency, and o promoe unsanding of how recommendaions are developed. The commens are published as a record of he submissions ha he Insiue has received, and are no endorsed by he Insiue, is officers or advisory commiees. 3 of 196

4 Sakehol Or e Commens Please inser each new commen in a new Please respond o each commen inervenion have a favourable risk-benefi raio is key. Tha is why he recommendaion was phrased as: 20. Consi caheer-direced hrombolyic herapy for paiens wih sympomaic iliofemoral DVT who have: sympoms of less han 14 days duraion and good funcional saus and a life expecancy of 1 year or more and a low risk of bleeding. SIGN 11 Appendice s 18 Cancer screening - see above We agree ha here may be some resource implicaions for cenres which do no currenly offer his reamen and ha change o faciliies or local referral arrangemens migh have o be made for appropriae paiens. The guideline developmen group had based heir decision in he evidence abou cos-effeciveness of he inervenions, which suggesed a combinaion of spuum cyology, mammogram for women and abdomino-pelvic CT would be useful. We have consied your commens carefully and agreed ha here is lile clinical evidence o suppor recommending spuum cyology. PLEASE NOTE: Commens received in he course of consulaions carried ou by he Insiue are published in he ineress of openness and ransparency, and o promoe unsanding of how recommendaions are developed. The commens are published as a record of he submissions ha he Insiue has received, and are no endorsed by he Insiue, is officers or advisory commiees. 4 of 196

5 Sakehol Or e Commens Please inser each new commen in a new Please respond o each commen The recommendaion has been modified o sae: Consi furher invesigaions for cancer wih an abdomino-pelvic CT scan (and a mammogram for women) in all paiens aged over 40 years wih a firs unprovoked DVT or PE even if iniial invesigaions revealed no signs or sympoms of cancer SIGN 12 Appendice s 19 4 Does family hisory posiive wih a posiive hrombophilia es imply anyhing ha FH +ve wih a negaive es does no? I don' hink i does so why es? In addiion, we have also added his in he linking evidence o recommendaions secion: Alhough he evidence of coseffeciveness for furher invesigaion of cancer in he sudy showed ha a combinaion of pelvic abdominal CT, spuum cyology and mammography for women, he guideline developmen group hough ha spuum cyology should no be recommended rouinely for his purpose. They had aken ino consiaion ha NICE guideline for reamen and diagnosis of lung cancer (CG121) which recommended Spuum cyology is rarely indicaed and should be reserved for paiens wih cenrally placed nodules or masses who are unable o olerae bronchoscopy or oher invasive ess Thank you for your commen. The Guideline Developmen Group did consi ha here are possible PLEASE NOTE: Commens received in he course of consulaions carried ou by he Insiue are published in he ineress of openness and ransparency, and o promoe unsanding of how recommendaions are developed. The commens are published as a record of he submissions ha he Insiue has received, and are no endorsed by he Insiue, is officers or advisory commiees. 5 of 196

6 Sakehol Or e Commens Please inser each new commen in a new Please respond o each commen implicaions if he es is posiive for herediary hrombophilia in a person wih posiive family hisory, as i provided addiional informaion abou he risk of recurrence. We have explained his in he Linking Evidence o Recommendaion Secion which accompanies his recommendaion in he full version of he guideline (Secion 14.2). We had explained: The finding of a naural anicoagulan (anihrombin, proein C, or proein S) deficiency in a young paien wih unprovoked VTE and a srong family hisory of unprovoked VTE migh increase he risk of recurrence and make long-erm anicoagulaion favourable. We had also explained: I canno be excluded ha he finding of a naural anicoagulan (anihrombin, proein C, or proein S) deficiency in a paien wih unprovoked VTE and a family hisory of VTE migh increase he risk of recurrence and make long-erm anicoagulaion favourable. The Guideline Developmen Group also consied ha in unseleced paiens having a firs degree relaive wih VTE does no help o idenify paiens wih herediary hrombophilia. However, peneran PLEASE NOTE: Commens received in he course of consulaions carried ou by he Insiue are published in he ineress of openness and ransparency, and o promoe unsanding of how recommendaions are developed. The commens are published as a record of he submissions ha he Insiue has received, and are no endorsed by he Insiue, is officers or advisory commiees. 6 of 196

7 Sakehol Or SIGN 13 Appendice s SIGN 1 Appendice s SIGN 3 Appendice s e Commens Please inser each new commen in a new One of he sudies from he RIETE regisry and Baglin e al JTH paien level meaanalysis on recurrence showed ha he rae of all VTE recurrence was he same wheher or no your iniial presenaion was wih DVT or PE whils also showing he 2-3 fold affec of iniial presenaion on sie of recurrence CDR are clinical decision rules no clinical diagnosic scores 4 15 Renal impairmen - his is a definiion which ges you ino rouble laer on when you indicae UFH for all paiens wih renal impairmen as his definiion Please respond o each commen muaions in hrombosis prone families will more likely be found where here is a hrombosis a a young age which he Guideline Developmen Group agreed o be less han 50 years. If esing paiens wih unprovoked VTE and a family hisory of venous hrombosis, i would be reasonable o resric esing o he naural anicoagulans (proein C, proein S and anihrombin) as facor V Leiden and he prohrombin muaion do no increase he risk of recurrence o a clinically significan exen. Thank you for your commen. We agree and have herefore removed and presenaion wih PE versus DVT from he lis of examples for risk of recurrence. We have added an addiional senence I would also be imporan o look a he iniial presenaion as an episode of PE versus DVT predics a greaer risk for recurrence being a PE, and his is also relevan when rying o decide who ges long-erm reamen o furher clarify his. Thank you for your commen. We agree and have amended his secion accordingly. Thank you for your commen. We have now reworded his secion of he recommendaion. I now reads: PLEASE NOTE: Commens received in he course of consulaions carried ou by he Insiue are published in he ineress of openness and ransparency, and o promoe unsanding of how recommendaions are developed. The commens are published as a record of he submissions ha he Insiue has received, and are no endorsed by he Insiue, is officers or advisory commiees. 7 of 196

8 Sakehol Or SIGN 2 Appendice s NICE - Technical Appendice s e Commens Please inser each new commen in a new means ha mos paiens have renal impairmen. The cu off for accumulaion of LMWH in herapeuic doses is 30 mls/min and I hink ha his is clearly clinically relevan alhough he risk of bleeding on any anicoagulan seems o increase wih worsening renal funcion 4 7 Should you include here medical illness which resolves here? Consi a rewording of he following senence because i could be easier o Please respond o each commen For paiens wih severe renal impairmen (creainine clearance less han 30ml/min) offer UFH wih dose adjusmens based on he APTT or LMWH wih dose adjusmens based on an ani-xa assay. We hope ha his amendmen resuls in beer clariy abou when alernaives are appropriae for paiens wih renal impairmen. Thank you for your commen. We have been unable o find he ex you refer o in he appendices, bu hink ha his commen may relae o he NICE version of he guideline. Afer discussion wih he guideline developmen group, we agree and have updaed he definiions for provoked DVT and PE, which now reads: DVT or PE in a paien wih no aneceden major clinical risk facor for VTE (see Provoked deep vein hrombosis or pulmonary embolism above) who is no having hormonal herapy (oral conracepive or hormone replacemen herapy). Paiens wih acive cancer, hrombophilia or a family hisory of VTE should also be consied as having an unprovoked episode because hese unlying risks will remain unchanged in he paien. Thank you for your commen. We agree and we have amended he wording o PLEASE NOTE: Commens received in he course of consulaions carried ou by he Insiue are published in he ineress of openness and ransparency, and o promoe unsanding of how recommendaions are developed. The commens are published as a record of he submissions ha he Insiue has received, and are no endorsed by he Insiue, is officers or advisory commiees. 8 of 196

9 Sakehol advisers HE and mehodolo gy NICE - Technical advisers HE and mehodolo gy NICE - Technical advisers HE and mehodolo gy Or Appendice s Appendice s e 556 Gener al Commens Please inser each new commen in a new read and unsand; Several algorihms are possible and i is no sure which are he mos coseffecive. I could no find he cycle lengh for he cos-effeciveness analysis diagnosis of PE in he wrie-up of he appendix The appendix says; The model aims o assess which es sequence provis he higher benefi a an accepable cos. A more sandardised senence could be as follows; Please respond o each commen make he senence clearer: Several algorihms are possible and i is no sure which one of hem is he mos coseffecive. Thank you for your commen. We have now added he deails on he cycle lengh in secion H of Appendix H. Thank you for your commen. We agree and we have amended he senences accordingly. NICE - Technical advisers HE and mehodolo gy NICE - Technical advisers HE and Appendice s Appendice s The model aims o assess he coseffeciveness of differen es sequences Lifelong oucomes migh seem vague; oucomes are also ofen associaed wih healh oucomes in oher words, qualiy of life. 560 Gener al Table 2. I is no clear why a riangular disribuion is used over oher disribuions (i.e. Thank you for your commen. We agree and we have subsiued he words lifelong oucomes wih long-erm coss and QALYs. Thank you for your commen. Afer careful consiaion we reached he conclusion ha we disagree ha a uniform disribuion should be used o replace he riangular PLEASE NOTE: Commens received in he course of consulaions carried ou by he Insiue are published in he ineress of openness and ransparency, and o promoe unsanding of how recommendaions are developed. The commens are published as a record of he submissions ha he Insiue has received, and are no endorsed by he Insiue, is officers or advisory commiees. 9 of 196

10 Sakehol mehodolo gy NICE - Technical advisers HE and mehodolo gy NICE - Technical advisers HE and mehodolo gy Or Appendice s Appendice s e Gener al Gener al Commens Please inser each new commen in a new uniform) when no daa oher han he mean is available. The mean may be no more likely o occur han any oher value ranging from he minimum o maximum provided. Table 2, Table 24. The guideline finds disribuion parameers for NHS reference coss, he mehod of finding he disribuion parameers could be saed in he appendix. Table 3, Table 25. The cos of sroke care in subsequen years dependen paien and he cos of sroke care in subsequen years independen paien are uninflaed coss from he NICE Sroke Guideline, Please respond o each commen disribuion. When a riangular disribuion has been used in he model, he mean has been idenified as he mos likely value for ha parameer. For example, he guideline developmen group expers esimaed he ime aken o complee a D-dimer es as 5 minues (mos likely value) acknowledging ha here could be some variaion beween + or 50%. In oher cases (e.g. cos of sroke) he riangular disribuion was used in he original source of daa. Thank you for your commen. We have now amended he paragraph on disribuion parameers o describe how parameers for NHS reference coss are defined. Thank you for your commen. We agree ha cos daa on sroke was no up-o-dae and we have amended hese parameers by using an inflaion index. This has no affeced he resuls of he model. The sroke guideline uses uninflaed coss from Sancock e al., 2004 as is source. Sancock e al., 2004 uses uninflaed coss from he MEDTAP model developed by Chambers e al., 1999 as is source. PLEASE NOTE: Commens received in he course of consulaions carried ou by he Insiue are published in he ineress of openness and ransparency, and o promoe unsanding of how recommendaions are developed. The commens are published as a record of he submissions ha he Insiue has received, and are no endorsed by he Insiue, is officers or advisory commiees. 10 of 196

11 Sakehol Or e Commens Please inser each new commen in a new These coss could also be based on earlier daa before Please respond o each commen The cos of care for sroke is definiely uninflaed from I could be an uninflaed esimae from 1999 or earlier. I could no find a valid reason no o inflae coss of care in appendix; I was also unable o find a reason for his in he NICE Sroke Guideline from Therefore, I hink i would be reasonable o assume he cos of care has changed in he las decade similar o hospial and social care inflaion raes. The cos of care is likely o have been unesimaed in he CE analysis because he mean cos per paien is likely o be higher. The ICERs and any inerpreaions migh also be affeced. Consi using he inflaion indices from he PSSRU, or oher valid sources OR updae he coss of care for sroke. NICE - Technical advisers HE and Appendice s This applies for boh of he CE models (ype of es and lengh of reamen models) developed for his guideline I migh be beer o define INB equaion used as Incremenal Ne Moneary Benefi (INMB) o ensure consisency in he economic language used in he appendix. Thank you for your commen. We have amended he erminology and we have now used Ne Moneary Benefi consisenly hroughou Appendices H and PLEASE NOTE: Commens received in he course of consulaions carried ou by he Insiue are published in he ineress of openness and ransparency, and o promoe unsanding of how recommendaions are developed. The commens are published as a record of he submissions ha he Insiue has received, and are no endorsed by he Insiue, is officers or advisory commiees. 11 of 196

12 Sakehol mehodolo gy NICE - Technical advisers HE and mehodolo gy NICE - Technical advisers HE and mehodolo gy NICE - Technical advisers HE and mehodolo gy NICE - Technical advisers HE and mehodolo gy NICE - Technical Or Appendice s Appendice s Appendice s Appendice s Appendice s e Commens Please inser each new commen in a new The purpose of he informaion in his secion is unclear and does no flow. Some senences are more discussion poins Why would ulrasound (US) paiens have o wai? Is here no equivalen emergency provi? A jusificaion may be needed Need o add a, afer however, for he inended meaning of he senence. 577 Gener al 598 Gener al Table 12 Capion clarificaion: Is his cos of es and reamen (and ohers) per paien? Table 28. Please respond o each commen I as his was he esimae used in he model. Thank you for your commen. We agree and we have edied his secion o make i clear. Thank you for your commen. We have explained in he secion ha he wai for ulrasound is ofen a long one. This is an issue which was discussed in deail in he linking evidence o recommendaion secion of recommendaion 3 and we do no hink we should address i in he Healh Economics Appendix. Thank you for your commen. Afer careful consiaion, we hink he senence is correc as i is and herefore have no amended i: However ofen we are unsure of he magniude of he covariance and in hese circumsances he analysis reas he model parameers as if hey were independen of each oher. Thank you for your commen. We have clarified in he able ha hose are coss per paien. Thank you for your commen. We agree ha cos daa on sroke was no up-o-dae PLEASE NOTE: Commens received in he course of consulaions carried ou by he Insiue are published in he ineress of openness and ransparency, and o promoe unsanding of how recommendaions are developed. The commens are published as a record of he submissions ha he Insiue has received, and are no endorsed by he Insiue, is officers or advisory commiees. 12 of 196

13 Sakehol advisers HE and mehodolo gy NICE - Technical advisers HE and mehodolo gy NICE - Technical advisers HE and mehodolo gy Or Appendice s Appendice s SIGN 5 Appendice s e Commens Please inser each new commen in a new The appendix did no say if acue cos of sroke (one-off) was inflaed. Consi inflaing or updaing he cos if no inflaed Table number is incorrec, i poins o he wrong able When discussing he cos-effeciveness resuls, i migh be clearer in his secion o explicily sae which sraegy is he mos cos-effecive; i s no clear in he ex and he read is forced o inerpre he ables See above, your definiion of renal failure means mos people would ge UFH Please respond o each commen and we have amended hese parameers by using an inflaion index. We have also made i explici in he able. Thank you for your commen. We have amended he cross-reference in he ex. Thank you for your commen. We have added some furher explanaion in he ex o clarify why a sraegy is or is no coseffecive. Thank you for your commen. The recommendaion was inended o advise clinicians o consi UFH as an alernaive when paiens have renal impairmen. Wheher UFH is a beer alernaive o LMWH/fondaparinux is somehing which he Guideline Developmen Group feel ha clinicians have o consi afer aking ino accoun he severiy of he renal impairmen and risks of accumulaion and bleeding. We have now reworded his secion of he recommendaion. I now reads: For paiens wih severe renal impairmen PLEASE NOTE: Commens received in he course of consulaions carried ou by he Insiue are published in he ineress of openness and ransparency, and o promoe unsanding of how recommendaions are developed. The commens are published as a record of he submissions ha he Insiue has received, and are no endorsed by he Insiue, is officers or advisory commiees. 13 of 196

14 Sakehol Or SIGN 6 Appendice s e Commens Please inser each new commen in a new This suggess o me ha you are recommending ha i is appropriae for large groups of paiens wih ileofemoral DVT o ge hrombolysis - his is surely no wha you wan o recommend for he reasons you go on o poin ou laer on e 16 where he weakness of he daa for CDR hrombolysis is explained. The use of he word consi is no really helpful here as i begs he quesion, consi wha? You have given crieria for inclusion and exclusion how do you hen ake forward he process of consiing. Please respond o each commen (creainine clearance less han 30ml/min) offer UFH wih dose adjusmens based on he APTT or LMWH wih dose adjusmens based on an ani-xa assay. Thank you for your commen. Alhough here are limiaions in he evidence, i suggesed ha caheer direced hrombolysis could poenially bring imporan benefis o paien wih sympomaic iliofemoral DVT and should be available as an opion o paiens who will benefi o i. This inervenion may no be appropriae for all paiens presening wih a proximal DVT. The wording consi reflecs he srengh of he recommendaions. We use offer (or similar words such as refer or advise ) when we are confiden ha, for he vas majoriy of people, an inervenion will do more good han harm, and be cos effecive. We use consi when we are confiden ha an inervenion will do more good han harm for mos paiens, and be cos effecive, bu oher opions may be similarly cos effecive. The choice of inervenion, and wheher or no o have he inervenion a all, will depend on he paien s values and preferences. In boh cases, he recommendaion wording is PLEASE NOTE: Commens received in he course of consulaions carried ou by he Insiue are published in he ineress of openness and ransparency, and o promoe unsanding of how recommendaions are developed. The commens are published as a record of he submissions ha he Insiue has received, and are no endorsed by he Insiue, is officers or advisory commiees. 14 of 196

15 Sakehol Or e Commens Please inser each new commen in a new Please respond o each commen inended o encompass discussion wih he paien abou he risks and benefis of he inervenions, o help hem reach a fully informed decision For caheer direced hrombolysis, he Guideline Developmen Group had recognised he limiaions and ha he procedure may no be suiable for every paien presened wih a proximal DVT. Selecing he paiens who can benefi he mos from his reamen which makes he inervenion have a favourable risk-benefi raio is key. Tha is why he recommendaion was phrased as: Consi caheer-direced hrombolyic herapy for paiens wih sympomaic iliofemoral DVT who have: sympoms of less han 14 days duraion and good funcional saus and a life expecancy of 1 year or more and a low risk of bleeding. SIGN 7 Appendice s 8 21 There is some evidence ha more exensive cancer screening does pick up more cancers bu here is no evidence ha The facors which should be consied are already lised as bulle poins of he recommendaion. Thank you for your commen. As explained in he Linking evidence o PLEASE NOTE: Commens received in he course of consulaions carried ou by he Insiue are published in he ineress of openness and ransparency, and o promoe unsanding of how recommendaions are developed. The commens are published as a record of he submissions ha he Insiue has received, and are no endorsed by he Insiue, is officers or advisory commiees. 15 of 196

16 Sakehol Or e Commens Please inser each new commen in a new i changes any oucomes. A he same ime here will be daa o show an increased cancer risk associaed wih exensive CT scanning. I hink his is a poor recommendaion and will resul in widespread CT scanning of large numbers of paiens wih DVT for no obvious benefi (and possible imen). When is spuum cyology ever likely o be of value in a nonsmoker? Please respond o each commen recommendaion in he given ha he managemen of paiens wih cancer associaed VTE should be wih LMWH raher han warfarin. In his conex, he inenion of he invesigaions is no only in affecing he oucomes relaed o cancer oucomes bu also o esablish he aeiology of he VTE so appropriae managemen can be insiued. The guideline developmen group had based heir decision in he evidence abou cos-effeciveness of he inervenions, which suggesed a combinaion of spuum cyology, mammogram for women and abdomino-pelvic CT would be useful. We have consied your commens carefully and agreed ha here is lile clinical evidence o suppor recommending spuum cyology. The recommendaion has been modified o sae: Consi furher invesigaions for cancer wih an abdomino-pelvic CT scan (and a mammogram for women) in all paiens aged over 40 years wih a firs unprovoked DVT or PE even if iniial invesigaions revealed no signs or sympoms of cancer. In addiion, we have also added his in he PLEASE NOTE: Commens received in he course of consulaions carried ou by he Insiue are published in he ineress of openness and ransparency, and o promoe unsanding of how recommendaions are developed. The commens are published as a record of he submissions ha he Insiue has received, and are no endorsed by he Insiue, is officers or advisory commiees. 16 of 196

17 Sakehol Or e Commens Please inser each new commen in a new Please respond o each commen linking evidence o recommendaions secion: Alhough he evidence of coseffeciveness for furher invesigaion of cancer in he sudy showed ha a combinaion of pelvic abdominal CT, spuum cyology and mammography for women, he guideline developmen group hough ha spuum cyology should no be recommended rouinely for his purpose. They had aken ino consiaion ha NICE guideline for reamen and diagnosis of lung cancer (CG121) which recommended Spuum cyology is rarely indicaed and should be reserved for paiens wih cenrally placed nodules or masses who are unable o olerae bronchoscopy or oher invasive ess SIGN 4 Appendice s p Royal College of Obserici ans & I don' really unsand he role of offering a D-dimer o paiens wih "likely" scores wih a 4 hour delay o scanning. Surely his should only be performed afer he resul of he scan is known o be negaive. Oherwise many likely paiens wih posiive scan will have an unnecessary D-dimer es performed. 1 FULL General Commen. Thank you for inviing us o commen on his Guideline. The scope excludes pregnancy and does no cover hromboprophylaxis. I is herefore Thank you for your commen. The recommendaion saed ha if a proximal ulrascan canno be carried ou wihin 4 hours a D-dimer es and LMWH injecion should be offered. I is imporan o adminiser he D-dimer es before saring heparin reamen Thank you for your commen. PLEASE NOTE: Commens received in he course of consulaions carried ou by he Insiue are published in he ineress of openness and ransparency, and o promoe unsanding of how recommendaions are developed. The commens are published as a record of he submissions ha he Insiue has received, and are no endorsed by he Insiue, is officers or advisory commiees. 17 of 196

18 Sakehol Gynaecol ogiss Sheffield Teaching Hospials NHS Foundaio n Trus (STHFT) Unied Kingdom Clinical Pharmacy Associaio n (Haemos asis NETSCC, HTA Referee 1 Bayer plc (formerly Bayer Schering Pharma) Or e Commens Please inser each new commen in a new no direcly relevan o obserics and gynaecology. Furher i does no conflic wih any exising RCOG guideline. 13 Full 25 This is an imporan quesion and I suppor his research recommendaion. 19 Full Table 39: un he firs row Tile column, here is a ypo: dalepadn - his should be daleparin. Also he forh row un he Tile column should his be coseffeciveness of low molecular weigh heparin, raher han cos-effecive of low molecular weigh heparin Please respond o each commen Thank you for your commen. Thank you for your commen. We agree ha his change will help o reduce he number of abbreviaions, and have made he amendmens o wriing of VKA in full (Viamin K anagoniss). 21 Full reword "for LMWH" o "in favour of LMWH" Thank you for your commen. We agree ha his change will make he amendmen clearer and have made he change. 63 Full Rivaroxaban was licensed for he "Treamen of deep vein hrombosis (DVT), and prevenion of recurren DVT and pulmonary embolism (PE) following an acue DVT in aduls," and he clinical daa from he EINSTEIN DVT and EXT sudies were published during he guideline developmen period. 1 Recommendaions regarding rivaroxaban should herefore be included in his Thank you for your commen. Only drugs which already had a markeing auhorisaion in he UK for he reamen of DVT or PE were included in he scope of he guideline, which was finalised in June Rivaroxaban had obained markeing auhorisaion for reamen afer he finalisaion of he guideline and consequenly could no be consied wihin he scope of his guideline. A single PLEASE NOTE: Commens received in he course of consulaions carried ou by he Insiue are published in he ineress of openness and ransparency, and o promoe unsanding of how recommendaions are developed. The commens are published as a record of he submissions ha he Insiue has received, and are no endorsed by he Insiue, is officers or advisory commiees. 18 of 196

19 Sakehol Bayer plc (formerly Bayer Schering Pharma) Or e Commens Please inser each new commen in a new guideline. The omission of rivaroxaban means ha all available reamen alernaives are no given full consiaion. 1. Bauersachs R, e al. Oral rivaroxaban for sympomaic venous hromboembolism. N Engl J Med 2010;363(26): Full Rivaroxaban should be included in he marix of reamen comparisons. The EINSTEIN DVT and EXT rials which compared rivaroxaban o LMWH/VKA for he coninuaion phase were published in Bauersachs R, e al. Oral rivaroxaban for sympomaic venous hromboembolism. N Engl J Med 2010;363(26): Please respond o each commen echnology appraisal for he reamen and secondary prevenion of venous hromboembolism for rivaroxaban is being conduced by NICE and wih an expeced publicaion dae in July 2012 (For more informaion, please see: hp://guidance.nice.org.uk/ta/wave22/17) Thank you for your commen. A he ime of scoping for his guideline, rivaroxaban had already been referred for single echnology appraisal, and work sared in Jan The expeced dae of issue of he echnology appraisal is June The evidence for rivaroxaban will be consied as par of he echnology appraisal process. (For more informaion, please see: hp://guidance.nice.org.uk/ta/wave22/17). The Sociey and College of Radiograp 1 Full 11 An ulrasound scan will be required wihin 24 hours. This may have service delivery implicaions for some Truss and Healh Boards and independen provis. There is a naional shorage of sonographers and The marix of reamen comparisons lised he reamens evaluaed in his guideline. Therefore rivaroxaban should no be included in he marix. Thank you for your commen. The guideline developmen group had consied hese issues carefully and believed ha i is imporan o emphasise PLEASE NOTE: Commens received in he course of consulaions carried ou by he Insiue are published in he ineress of openness and ransparency, and o promoe unsanding of how recommendaions are developed. The commens are published as a record of he submissions ha he Insiue has received, and are no endorsed by he Insiue, is officers or advisory commiees. 19 of 196

20 Sakehol hers Unied Kingdom Clinical Pharmacy Associaio n (Haemos asis Unied Kingdom Clinical Pharmacy Associaio n (Haemos asis Or e Commens Please inser each new commen in a new 7 day a week working is eiher no esablished or will be difficul o esablish for some organisaions. 20 Full The following senence, Fifeen percen of he included populaion had also cancer would read beer rephrased as, Fifeen percen of he included populaion also had cancer. 7 Full Whils he raionale for no including any specific recommendaions for he reamen of isolaed calf vein DVT is unsood, i appears remiss no o make recommendaions on he occasion ha i migh be diagnosed curren BC guidance saes, If a diagnosic sraegy ha idenifies isolaed calf vein DVT is employed, reamen of such clos can be resriced o 6 weeks. For comprehensiveness of guideline here should be some consiaion of isolaed Please respond o each commen he imporance of no delaying i more han 24 hours. Whils we recognised his will mean a change of curren pracice and i may be a challenge for some faciliies o mee hese crieria, we believe i is imporan o focus on wha is an accepable level of safey o he paiens. Delaying ulrasound scans for more han 24 hours would mean more paiens may receive more han one dose of pareneral anicoagulan unnecessarily. Thank you for your commen. The senence has been amended as suggesed. Thank you for your commen. The guideline coves a wide scope of diagnosis and managemen of VTE, and also hrombophilia esing. We sysemaically search and review evidence o suppor each recommendaion made for his guideline. This is a very robus evidence based guideline developmen approach, bu i means ha ime and resources need o be dedicaed o conduc he review o suppor each area of recommendaion made. We had o PLEASE NOTE: Commens received in he course of consulaions carried ou by he Insiue are published in he ineress of openness and ransparency, and o promoe unsanding of how recommendaions are developed. The commens are published as a record of he submissions ha he Insiue has received, and are no endorsed by he Insiue, is officers or advisory commiees. 20 of 196

21 Sakehol Or e Commens Please inser each new commen in a new calf vein DVT. Please respond o each commen prioriise which areas should be reviewed. Bayer plc (formerly Bayer Schering Pharma) NICE - Technical advisers HE and mehodolo gy 65 Full One or more previous episodes of VTE is also a risk facor associaed wih a recurrence of VTE. 4 Full 116 Table Kearon C, e al. Anihromboic herapy for venous hromboembolic disease: American College of Ches Physicians Evidence-Based Clinical Pracice Guidelines (8h ediion). Ches 2008;133(Suppl):454S-545S [Erraum, Ches 2008;134:892]. How are longer and shorer duraions defined? How does his compare wih 6 monhs and 3 monhs duraion as presened in able 47? The guideline developmen group are aware of exising guidelines such as he BC providing guidance in his area and he duraion recommended akes ino accoun wheher he hese are provoked by emporary risk facors. However, we are no able o make a specific recommendaion in his area wihou a specific evidence review. Thank you for your commen. Risk facors for VTE recurrence were no reviewed and herefore no specific recommendaions regarding risk assessmen were made. Furher informaion is available in he inroducion o Duraion of anicoagulaion Secion 7.4 of he full guideline and in he oher consiaions secion of he linking evidence o recommendaions Secion 7.5 recommendaions 18 and 19. The risk facors menioned in hese secions are given as examples and no a comprehensive lis. Thank you for your commen. This is explained in secion of he full guideline: Sandard pracice in he UK has been o give 3 or 6 monhs of reamen for a firs VTE. Following his, a decision is made wheher o coninue reamen indefiniely. The Guideline PLEASE NOTE: Commens received in he course of consulaions carried ou by he Insiue are published in he ineress of openness and ransparency, and o promoe unsanding of how recommendaions are developed. The commens are published as a record of he submissions ha he Insiue has received, and are no endorsed by he Insiue, is officers or advisory commiees. 21 of 196

22 Sakehol NETSCC, HTA Referee 1 Rarer Cancers Foundaio n Rarer Cancers Foundaio n Or e Commens Please inser each new commen in a new 3 Full Table 49 foonoe (a). If paiens are followed-up from he end of reamen hen duraion of follow-up should no be influenced by duraion of reamen, is his correc? In general, differing follow-up duraions beween sudies would relae o inconsisency (heerogeneiy) raher han being a limiaion (risk of bias). 16 Full 12 We noe ha he guideline concenraes on proximal DVT raher han isolaed calf vein DVT as he laer is less likely o cause PTS han proximal DVT and also less likely o embolize o he lungs bu won wheher he risks are he same for cancer and non-cancer paiens? 14 Full 12 and 13 We welcome he fac ha cancer is consied as major risk facor for VTE and ha special consiaion is given o managemen of VTE in cancer paiens as a sub-group who may no respond well when reaed wih warfarin Please respond o each commen Developmen Group herefore decided o look a he evidence comparing 3 and 6 monhs of reamen. If here were no imporan differences beween hese groups, i would be possible o group ogeher daa wih hese reamen duraions (3 or 6 monhs) agains a longer duraion of reamen. Thank you for your commen. The risk of bias was due o differen lenghs of followup of he arms wihin he same sudy and no a beween sudy variaion which we agree would relae o heerogeneiy. Thank you for your review. We have no search and reviewed wheher here is any evidence o sugges ha his may be differen for paiens wih cancer. As far as he guideline developmen group was aware of, here is no evidence suggesing ha his is differen for cancer paiens. Thank you for your commen. PLEASE NOTE: Commens received in he course of consulaions carried ou by he Insiue are published in he ineress of openness and ransparency, and o promoe unsanding of how recommendaions are developed. The commens are published as a record of he submissions ha he Insiue has received, and are no endorsed by he Insiue, is officers or advisory commiees. 22 of 196

23 Sakehol Targe Ovarian Cancer Bayer plc (formerly Bayer Schering Pharma) Bayer plc (formerly Bayer Schering Pharma) Or e 13 Full 12 and Full Full Commens Please inser each new commen in a new We welcome he fac ha cancer is consied as major risk facor for VTE and ha special consiaion is given o managemen of VTE in cancer paiens as a sub-group who may no respond well when reaed wih warfarin As per or number 10 As per or number 12 Please respond o each commen Thank you for your commen. Thank you for your commen. Only drugs which already had a markeing auhorisaion in he UK for he reamen of DVT or PE were included in he scope of he guideline, which was finalised in June Rivaroxaban had obained markeing auhorisaion for reamen afer he finalisaion of he guideline and consequenly could no be consied wihin he scope of his guideline. A single echnology appraisal for he reamen and secondary prevenion of venous hromboembolism for rivaroxaban is being conduced by NICE and wih an expeced publicaion dae in July 2012 (For more informaion, please see: hp://guidance.nice.org.uk/ta/wave22/17) Thank you for your commen. We are pleased o hear ha you agree wih use ha issues such as paien preference, and coss associaed wih iniiaing reamen of VTE (including nursing ime and monioring coss are imporan, in addiion o clinical PLEASE NOTE: Commens received in he course of consulaions carried ou by he Insiue are published in he ineress of openness and ransparency, and o promoe unsanding of how recommendaions are developed. The commens are published as a record of he submissions ha he Insiue has received, and are no endorsed by he Insiue, is officers or advisory commiees. 23 of 196

24 Sakehol Or e Commens Please inser each new commen in a new Please respond o each commen effeciveness and safey. As you have noed, his was documened in he full guideline. The NICE version which you referred o were mean o concise reference o he recommendaions made. We would no normally lis all he consiaions ha are relevan o a recommendaion if hese are fairly sandard consiaions ha mos clinicians should we aware of. Bayer plc (formerly Bayer Schering Pharma) 68 Full As per or number 13 Clinicians should refer o he full guideline, where he linking evidence o recommendaion secion fully documens he consiaions. Thank you for your commen. The Guideline developmen group did consi paien adherence when making his recommendaion. As you have saed his is discussed in he oher consiaions secions of he Linking evidence o recommendaions for recommendaions 17, 18 and 19 in he full version of he guideline. I is no possible o lis every consiaion in he recommendaions hemselves bu he Guideline developmen group did emphasise he imporance of making a clinical decision on an individual paien basis. The issue of paien adherence is exensively addressed in a separae NICE guideline, Medicines PLEASE NOTE: Commens received in he course of consulaions carried ou by he Insiue are published in he ineress of openness and ransparency, and o promoe unsanding of how recommendaions are developed. The commens are published as a record of he submissions ha he Insiue has received, and are no endorsed by he Insiue, is officers or advisory commiees. 24 of 196

25 Sakehol Bayer plc (formerly Bayer Schering Pharma) Or e 69 Full Commens Please inser each new commen in a new As per or number 14 Sanofi 2 Full 123 Recommendaion 16 recommends choice of LMWH or fondaparinux o paiens wih proximal DVT or PE despie no supporing evidence available for fondaparinux in PE. This should be carefully reassessed as i may pose significan bleeding risk o paiens. Please respond o each commen Adherence (CG76). Thank you for your commen. We have now reworded his secion of he recommendaion. I now reads: For paiens wih severe renal impairmen (creainine clearance less han 30ml/min) offer UFH wih dose adjusmens based on he APTT or LMWH wih dose adjusmens based on an ani-xa assay. Thank you for your commen. Boh fondaparinux and LMWH have markeing auhorisaion for PE in he UK. Alhough here are no sudies comparing fondaparinux o LMWH, here was a sudy comparing fondaparinux o UFH. We have highlighed his, along wih he limiaions of he evidence in he linking evidence o recommendaion secion 7.5 of he Pharmacological chaper. Only wo sudies were found for fondaparinux. One compared fondaparinux vs UFH in paiens wih PE, while he oher compared fondaparinux wih LMWH in paiens wih DVT. The qualiy of evidence was low. Alhough hese rials are relaively large, hese were sill serious imprecision for mos of he oucomes. The fondaparinux vs UFH PLEASE NOTE: Commens received in he course of consulaions carried ou by he Insiue are published in he ineress of openness and ransparency, and o promoe unsanding of how recommendaions are developed. The commens are published as a record of he submissions ha he Insiue has received, and are no endorsed by he Insiue, is officers or advisory commiees. 25 of 196

26 Sakehol Or e Commens Please inser each new commen in a new Please respond o each commen comparison also had serious sudy limiaions (unclear allocaion concealmen and randomisaion procedure). There was a subgroup analysis for paiens wih cancer in he sudy comparing agains UFH, suggesing here may be a lower risk of VTE recurrence or bleeding. NETSCC, HTA Referee 1 Unied Kingdom Clinical Pharmacy Associaio n (Haemos asis Bayer plc (formerly Bayer 22 Full A lower risk of VTE recurrence or bleeding in which group? 21 Full 126 Typo: Un recommendaion 16 forh line un appropriae dose sub-heading, here are wo full-sops in he senence ending, weigh or renal funcion.. Thank you for your commen. The subgroup analysis suggesed ha for paiens wih cancer here may be a lower risk or VTE recurrence or major bleeding wih fondaparinux as compared o UFH for iniial reamen. We have added addiional ex o clarify his in he guideline. There was a subgroup analysis for paiens wih cancer in he sudy comparing agains UFH, suggesing ha in his subgroup here may be a lower risk of VTE recurrence or bleeding in paiens reaed wih fondaparinux. Thank you very much for picking up his error. We have now removed he exra full sop. 70 Full 128 As per or number 15 Thank you for your commen. Only drugs which already had a markeing PLEASE NOTE: Commens received in he course of consulaions carried ou by he Insiue are published in he ineress of openness and ransparency, and o promoe unsanding of how recommendaions are developed. The commens are published as a record of he submissions ha he Insiue has received, and are no endorsed by he Insiue, is officers or advisory commiees. 26 of 196

27 Sakehol Schering Pharma) Unied Kingdom Clinical Pharmacy Associaio n (Haemos asis Or e Commens Please inser each new commen in a new Please respond o each commen 130 auhorisaion in he UK for he reamen of DVT or PE were included in he scope of he guideline, which was finalised in June Rivaroxaban had obained markeing auhorisaion for reamen afer he finalisaion of he guideline and consequenly could no be consied wihin he scope of his guideline. A single echnology appraisal for he reamen and secondary prevenion of venous hromboembolism for rivaroxaban is being conduced by NICE and wih an expeced publicaion dae in July 2012 (For more informaion, please see: hp://guidance.nice.org.uk/ta/wave22/17) 9 Full 128 I appears ha he informaion provided o suppor recommendaion 17 is in fac relaed o recommendaion 18 Pfizer 3 Full Our commen relaes direcly o saemen (a) conained wihin recommendaion secion 17 on page 128 of he full clinical guideline. In paricular, we believe ha saemen (a) A he ime of publicaion some ypes of LMWH do no have a UK markeing auhorisaion for exended reamen of DVT or PE in paiens wih cancer. Prescribers should consul he Thank you for bringing his error o our aenion. We have now correced his in he full guideline. Thank you for your commen. Recommendaion wordings focus on wha healhcare professionals need o know, raher han he usual acions ha should be par of a sandard clinical pracice. Issues abou off label uses are normally highlighed in he foonoes of he PLEASE NOTE: Commens received in he course of consulaions carried ou by he Insiue are published in he ineress of openness and ransparency, and o promoe unsanding of how recommendaions are developed. The commens are published as a record of he submissions ha he Insiue has received, and are no endorsed by he Insiue, is officers or advisory commiees. 27 of 196

28 Sakehol Or e Commens Please inser each new commen in a new summary of produc characerisics for he individual LMWH. Informed consen for offlabel use should be obained and documened wihin recommendaion 17 is an imporan one and he fon size currenly used could lead o i being missed. We would recommend ha he hese daa are incorporaed ino he main body of evidence supporing his recommendaion or a a minimum ha he fon size is increased. Pfizer 4 Full We would also like o sugges changes o he wording conained wih saemen (a) wihin recommendaion 17 as follows: (a) A he ime of publicaion, only daleparin sodium has a UK Markeing Auhorisaion for exended reamen of DVT or PE in paiens wih cancer. Prescribers should consul he Summary of Produc Characerisics for he individual LMWH. Informed consen for offlabel use mus be obained and documened. Rarer Cancers Foundaio 24 Full We welcome recommendaion 17 Offer LMWH o paiens wih acive Please respond o each commen recommendaion, as oulined in secion if he NICE guideline manual (reference provided in he full guideline). We do no hink ha he informaion for hese foonoes should be reaed differenly from oher recommendaions from NICE. Thank you for your commen. The wording of he recommendaion reflecs he curren sae of markeing auhorisaion for LMWH, bu i should remain facually correc hroughou he life of his guideline.. Therefore we do no agree ha his should be changed o specify ha only daleparin has markeing auhorisaion. Informed consen should be obained and documened is as sandard phrase used across all NICE guideline o refer o siuaions where here migh be issues markeing auhorisaion. We find no reason o sugges why a sronger wording is required in his case. Thank you for your commen. PLEASE NOTE: Commens received in he course of consulaions carried ou by he Insiue are published in he ineress of openness and ransparency, and o promoe unsanding of how recommendaions are developed. The commens are published as a record of he submissions ha he Insiue has received, and are no endorsed by he Insiue, is officers or advisory commiees. 28 of 196