Haematology for GP s Part 2 Anticoagulation in DVT and PE Introduction NICE guidelines DVT and PE diagnosis and treatment Warfarin New anticoagulants Cases VTE VTE is an important cause of morbidity and mortality in the UK >64,000 patients diagnosed with VTE per year Managing VTE costs the NHS 640 million/year VTE in Bradford DVT Principles of diagnosis Other 19% Mechanical heart valves DVT 8% PE 8% Recurrent DVT 4% Recurrent PE 2% Wells score D-dimer USS 9% AF 50% DVT 150 new patients per year PE 150 cases per year 1
Wells Score Clinical diagnosis is difficult Risk Factors can predict Wells score >/=3 points: high risk (53%); 1 to 2 points: moderate risk (17%); <1 point: low risk (5%). Profesor Philip Wells The Ottawa Hospital The original 1997 DVT Wells score used a three-level risk stratification system. D-Dimer The negative predictive value of D-dimer Different quality of D-dimer tests Used in conjunction with Wells Score If Low risk If Moderate risk If High risk negative d-dimer 99% no DVT 96% no DVT 84% no DVT The 2003 version (which is referred to in the literature as updated, modified, revised or two-level ) uses two levels of risk stratification US legs Compressive US Three point compression Above knee only US Positive for DVT US vein - Colour Flow Compression 2
What about the calf veins? US calf veins is less sensitive for detection of below knee DVT NICE CG144 DVT diagnosis Three calf veins are not always seen Takes longer to do If negative, still need repeat in high risk Score 1 or less DVT unlikely Score 2 or more DVT likely Diagnostic Referral form Bradford GP Pathway PE diagnosis unlikely Wells 3
PE likely on wells score Treating VTE Duration of anticoagulation therapy NICE guidance Idiopathic or provoked Risks for bleeding Previous thrombosis Severity and type of thrombosis Post thrombotic syndrome On going risk factors D-Dimer / FVIII levels Investigating Unprovoked VTE All patients with unprovoked DVT or PE : Full physical examination as directed by history Chest X-ray Urinalysis FBC, Ca2+, LFTs If first VTE and >40 years old: CT abdomen/pelvis Mammogram Thrombophilia Testing Do not do routinely Do not test if continuing anticoagulation long term Do not test if provoked VTE Do not test relatives of patients with VTE routinely Consider testing if Unprovoked VTE and 1 st degree relative has had a VTE Consider Antiphospholipid antibody screen if Unprovoked VTE and stopping anticoagulation 4
Patient Verbal and Written information What is a VTE? What caused the VTE? How is it treated? Does the clot disappear? Can it cause long term damage? Will it happen again? How can I reduce the chance of another one? What about my family? What about pregnancy? What contraception is OK? Can I fly? Post thrombotic syndrome Diagnosis complications Prevention - Class 2 Below knee graduated compression stockings on affected leg for 2 years Risk for recurrence of DVT What is warfarin? Warfarin Haemorrhaging cows in 1920 s due to eating sweet clover in hay (not fresh) Coumarin derivative synthesised 1948 Vitamin K antagonist inhibits vitamin K epoxide reductase Inhibits carboxylation of FII, FVII, FIX, FX, PC, PS PIVKA (proteins induced in vitamin K absence) accumulate but no function (can be measured) Warfarin 2 isomers S and R Takes 2-3 days to work (while previously activated forms degrade) FII takes longest to reduce PC also reduced so initial pro-thrombotic phase covered by LMWH Six weeks v six months warfarin 1 st event 5
3 months or longer for unprovoked DVT Six months or Long term for 2 nd VTE Recurrence risk VTE (next 12 months) Provoked surgical event 0.5% Provoked non-surgical 1-2% Unprovoked 8-10% Unprovoked and positive antiphospholipid antibodies 20-40% Risk of bleeding whilst on oral anticoagulation INR Bleedingevents per 100 patient years 2 3 4.8 3 4.5 9.5 4.5 7 40.5 >7 200 ISCOAT study: Lancet 1996 Novel Oral Anticoagulants (NOAC) 6
1 Moderate to Severe bleeding: - reduction in Hb 2gd/L, transfusion of 2 units of red cells or symptomatic bleeding in critical area (i.e. requiring inotropic agents or bleeding requiring surgical intervention. Comparison Using Rivaroxaban what to watch out for Renal function CrCl<15 contraindicated CrCl 15-50 caution (consider reduce dose to 15mg daily after 3 weeks) Liver function Coagulopathy or Child Pugh B/C contraindicated Drug interactions- CYP3A4 inhibitors - Eg Azoles, HIV protease inhibitors, (clarithromycin) CYP3A4 inducers Rifampicin, some antiepileptics Currently only Rivaroxaban licensed for treatment of DVT and PE Stop Antiplatelet drugs Stop NSAIDs if possible Rivaroxaban prior to surgery / procedures Reversal of rivaroxaban Bradford Teaching Hospitals NHS Trust Guideline for management of bleeding (and urgent reversal in case of need for emergency surgery) in patients on rivaroxaban Rivaroxaban is an oral factor Xa inhibitor with a half life of 7-11 hours and mostly renal 66% excretion. There is no licensed reversal agent for rivaroxaban. Rivaroxaban-related bleeding Or requirement for urgent reversal in case of need for emergency surgery Rivaroxaban (Xarelto ): Patients should be given instructions on when to take their last dose, dependent on the type of procedure and their usual dose of rivaroxaban. Major surgery or high bleeding risk or spinal/epidural anaesthesia on 15mg/20mg rivaroxaban OD STOP rivaroxaban Assess clinical bleeding 1,2 and resuscitate patient as appropriate. May need to act before lab results are back in emergency. Check: FBC, G&S, U&E and Clotting screen, PT, APTT, TT, Fibrinogen, d-dimer Rivaroxaban prolongs PT if PT is normal rivaroxaban levels are low. Consider rivaroxaban plasma level Indicate time of last rivaroxaban dose when requesting test and considering management options. Mild bleeding Moderate-Severe bleeding Life-threatening or site critical bleeding Delay next dose or discontinue treatment as appropriate. Discuss with haematologist on call Discuss with haematologist on call Minor procedure and low bleeding risk on 15mg or 20mg rivaroxaban OD With normal renal function level of riavaroxaban reduces rapidly in 24 hours Monitor clotting screen and PT Activate massive haemorrhage pathway Symptomatic treatment Consider tranexamic acid (avoid in DIC) Mechanical compression Surgical intervention Activated charcoal (if rivaroxaban ingestion < 2 hours before Fluid replacement and haemodynamic support- ensure good diuresis Consider Prothrombin complex concentrate (Octaplex) (50 units/kg), max 3000 units, IV infusion at 10ml/min blood product support as indicated consider role for interventional vascular radiology Manage as for Moderate- Severe bleeding Give Prothrombin complex concentrate (Octaplex) (50 units/kg), max 3000 units, IV infusion at 10ml/min Reassess clinically Repeat FBC, U&E, Clotting. PT and rivaroxaban level to be monitored intraocular, intracranial, intraspinal, intramuscular with compartment syndrome, retroperitoneal, intraarticular or pericardial bleeding). 2 Life-threatening bleeding: symptomatic intracranial bleed, reduction in Hb 5gd/L, transfusion of 4 units of red cells, hypotension Case 1 Cases 33 year old obese man has a DVT following a cholecystectomy He is a smoker but otherwise well He comes to see you as he is worried about his 2 daughters who are teenagers and whether they may be at risk of thrombosis No one else in his family has had a thrombosis 7
Yes I would do thrombophilia testing 1. Would you do thrombophilia testing? 2. What advice would you give him? 3. What advice would you give his children about COCP? Thrombophilia testing shows FV leiden Heterozygous 4. Does this affect what you do? 5. Who would you test in the family? He has 8 sisters 2 brothers and 17 nieces. Case 1 - discussion 1. thrombophilia testing He has 3 risk factors for thrombosis Obesity, surgery, smoking. He is young this is a provoked DVT Thrombophilia testing is not recommended Case 1 2. What advice would you give him. Stop smoking lose weight Class II BK graduated compression stockings for 1 2 years Always try and reverse risk factors for VTE Case 1 3. What advice for his daughters. RCOG recommends that women with a 1 st degree relative <45 years with VTE should avoid COCP Thrombophilia testing does not change this advice Case 1 Does FV leiden heterozygous change what you would do? NO It is common 1 in 20 in UK Only weak risk factor for VTE 2-4x polulation risk No effect on duration of anticoagulation Very slight increased risk of recurrence 8
Case 1 5. Who would you test in the family No one Thrombophilia result would not alter advice as FHx is more important i.e. If negative test in relative still have increased risk due to FHx Case 2 A 27 year old teacher comes to see you. She had a DVT aged 19 whilst on the COCP. She is normal weight and a non-smoker. She has 2 sisters who both have had DVT in pregnancy and are known to have PS deficiency. She wishes to become pregnant and asks for a thrombophilia test. 1. Would you do thrombophilia testing? YES I would test her Results shows normal thrombophilia screen Free PS = 0.9 (normal) 2. What is your advice to her now regarding the pregnancy? 3. Does she need LMWH prophylaxis? Case 2 Discussion 1. Would you do a thrombophilia test? She has had a hormone provoked VTE in the past and is already at high risk in pregnancy. Thrombophilia screen would not affect management Case 2 2. What advice regarding pregnancy She is at high risk and would need to start prophylactic LMWH once positive pregnancy test until 6 weeks post partum. She should be referred to the combined Obstetrics/Haematology clinic once pregnant LMWH is safe in pregnancy and for breast feeding. Case 3 A 28 year old taxi driver had a massive PE while out shopping and collapsed in the street. He was admitted to A&E where he was thrombolysed and then started on warfarin. He is previously fit and well. A non-smoker. No recent flights, surgery or immobility. He has no significant symptoms. He has an extensive family but no FHx of VTE. His parents are first cousins. He comes to see you as he is due to complete his 6 months of warfarin soon and is a bit concerned about stopping it. 1. Would you do a thrombophilia test? 2. Would you do any other tests? 3. Would you stop his warfarin? 9
YES I would do a thrombophilia test Thrombophilia test normal Case 3 - discussion 1. Would you do a thrombophilia test? 4. Does this effect what you do now? 5. He has 3 young children can you reassure him that at least they wont be effected? He is aged <40. The VTE is unprovoked and there are no obvious risk factors. No FHx so not NICE recommended Would be difficult to test while on anticoagulation Case 3 2. Would you do any other tests? Case 3 3. Would you stop the warfarin It is an unprovoked event and you need to find a cause. Consider rare causes Need to assess risk of recurrence: d-dimer and factor VIII NO It is unprovoked event Massive PE Tend to have similar recurrences ie if DVT first time DVT at recurrence Low bleeding risk Thrombophilia screen result has no impact on duration of anticoagulation Things may change over time if INR difficult to control, alcohol / drug issues etc.. Case 3 4. Does the negative thrombophilia screen change anything? May make you look harder for another cause 5. What would you till the family Increased risk of VTE Avoid COCP Case 4 60 year old man has a DVT following his total hip replacement. He had a thrombophilia screen while in hospital and it shows antithrombin III deficiency (0.56 iu/ml) He has never had a DVT in the past and is otherwise very well, nonsmoker and keen walker. There is a history of VTE in his sister after her knee replacement. His brother has had 2 DVT and is on long term warfarin. He comes to see you because he is not keen on stopping warfarin after 6 months. 1. Are there any questions or tests you may want? 2. Would you stop the warfarin? 3. His daughter is currently in her first pregnancy what advice do you have for her? Would you test ATIII levels? 10
Case 4 - Discussion 1. Any questions or tests? Case 4 2. Would you stop the warfarin Would want to know if any on-going risk factors that can be modified eg. Smoking / obesity / post thrombotic syndrome Could test d-dimer and factor VIII level YES - despite Strong family history Strong thrombophilia ATIII deficiency But was provoked event No evidence that positive thrombophilia should effect duration of anticoagulation Case 4 3. Pregnant daughter advice ATIII high thrombophilia risk Can test ATIII in pregnancy (PS and APCR are reduced in pregnancy false positive) I think in her ATIII testing would be useful as such a strong family history. (this is against NICE guidance) However even if negative may need LMWH prophylaxis depending on other risk factors as strong FHx Case 5 A 55 year old business woman is due to fly to Australia. She had a DVT 3 years ago after a hysterectomy. She comes to you for advice about the travel and whether she should take aspirin to prevent clots. 1. What risk factors may effect your advice? 2. What would you advise? Aspirin? LMWH? Other? Case 5 - Discussion 1. Risk Factors Are there any reversible risks: HRT Smoking Obesity Recent surgery Case 5 2. Advice for flight Aisle seat Flight stockings Ankle exercises Try and reduce these risks if possible and avoid flight for 6 weeks post surgery if possible Risk of flights is in fact quite low: 1:4656 risk asymptomatic DVT >4 hour flight Severe PE very rare in flight <8 hours, 5: 1000000 flights >8 hours NO evidence alcohol / dehydration a risk factor Aspirin not recommended may be a role??? In very high risk consider LMWH (but in general this group on long term warfarin) 11
Case 6 40 year old crossword writer has an unprovoked DVT. He did smoke but has now stopped. There is no family history. He has no symptoms of disease and is well. Your colleague did a thrombophilia screen when he last came and he has come for the results prior to stopping his warfarin. Thrombophilia results: PT20210a - not detected FVL mutation not detected Chromogenic functional PC = 0.4 (0.8-1.2) Free PS = 0.37 (0.8-1.2) ATIII = 1.1 Lupus screen negative D-dimer <200 (normal) FVIII 97 iu/dl (55 150) Questions 1. What do you advise him about the results? 2. Should you stop the warfarin? Case 6 Discussion 1. The results PC and PS are vitamin K dependent so will be reduced on warfarin. As aged 40 and unprovoked CT to exclude malignancy Consider antiphospholipid antibody screen Case 6 2. Stop warfarin? VTE summary 1. History of thrombosis and risk factors most important YES He had a single unprovoked DVT but he did smoke and has now stopped. Risk recurrence provoked <1% v 5-8% unprovoked in 12 months It was not a life threatening event and was a DVT. His D-dimer is normal. Current advice is 6 months anticoagulation in unprovoked events 2. Reduce risk factors (like you would do in Ischemic heart disease) 3. Thrombophilia testing in general does not effect management (and can open a can of worms!) 4. Results of thrombophilia testing are difficult to interpret and can be effected by many factors 5. Provoked V Unprovoked 6. Role of NOAC in treatment 12