Therapeutic Time in Range (TTR) and Patient Safety

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1 Therapeutic Time in Range (TTR) and Patient Safety Presented by: Kong Ming Chai Senior Principal Clinical Pharmacist Department of Pharmacy Singapore General Hospital

2 Rosendaal Linear Interpolation 1 INR 2.5 Target INR /0.8 x 24 = % ΔINR = 0.5 Within Range Below RangeΔINR = /0.8 x 24 = % INR 1.7 Day 0 Day Rosendaal FR, Cannegieter SC, van der Meer FJ, et al. Thromb Haemost 1993; 69:

3 Audit of ACC - % time INR in Therapeutic Warfarin Range No. of Dose Visit Date < to 2.6 >2.6 Target 2.0 to 2.5 days Below Within Above (mg) Range Range Range +/- 8/26/03 1:22 PM /21/03 1:14 PM /16/03 1:23 PM /27/04 1:34 PM /9/04 2:05 PM /23/04 2:17 PM /20/04 2:36 PM /3/04 2:31 PM /1/04 3:08 PM /26/04 2:05 PM Average INR no of visit 10 Avg Warfarin Dose 11% 76% 12% 100% Warfarin dose1.75mg = 1.5mg alternate with 2mg Anticoagulation Symposium Title of Slides & Workshop

4 Anticoagulation Symposium Title of Slides & Workshop

5 Primary Outcome Anticoagulation Symposium Title of Slides & Workshop

6 Incidences of hospitalizations Secondary Outcome Anticoagulation Symposium Title of Slides & Workshop

7 Audit of ACC Bench Mark from oversea What are some of the the oversea bench mark for a good ACC, eg at Anticoagulation Clinic of North America (ACNA) Percentage Time Within range > 70% Rate of Hospitalization (bleeding / Thrombosis): less than 5% Anticoagulation Symposium Title of Slides & Workshop

8 ACC Dawn Bench Marking Report SGH : %TTR 66.76%. Average : 69.76% Lowest : 57.34% Highest : 77.84% Anticoagulation Symposium Title of Slides & Workshop

9 Anticoagulation Symposium Title of Slides & Workshop

10 Stroke and Systemic Emboli (SE) Outcomes by INR Control Category: Results from SPORTIF III and V* *White, HD et al. Arch Intern Med. 2007; 167: Title of Slides 10

11 Comparison of Outcomes Among Patients Randomized to Warfarin According to Anticoagulant Control Results From SPORTIF III and V TTR <60% TTR 60-75% TTR >75% Mortality 4.20% 1.84% 1.69% Major Bleed 3.85% 1.96% 1.58% *White, HD et al. Arch Intern Med. 2007; 167: Title of Slides 11

12 Warfarin treatment in patients with AF: Outcomes associated with INR control Morgan C, et al. Thromb Res 2009;124:

13 TTR and Stroke Gallagher AM et al. Thromb Haemost 2011;106:

14 ACTIVE W Trial: VKA vs. dual antiplatelet therapy Minimum threshold TTR necessary to realize Benefit of warfarin: 58 65% Connolly SJ for Active W Investigators. Circulation 2008;118: Title of Slides 14

15 6-month events stable INR group Witt D, et al. 15

10% increase in center algorithm-consistent dosing predicted a 6.12% increase in TTR (95% CI 5.65-6.

16 10% increase in center algorithm-consistent dosing predicted a 6.12% increase in TTR (95% CI %), and an 8% decrease in rate of the composite clinical outcome (HR 0.92, 95% CI ). Title of Slides 16

17 Patient with Low INR variability Hylek, EM. J Cardiovasc Med 2009;10:

18 Patient with High INR variability Hylek, EM. J Cardiovasc Med 2009;10:

19 Anticoagulation Symposium Title of Slides & Workshop

20 How good is the INR control? STUDY TTR (MEDIAN) TTR (MEAN) Randomized Trial ACTIVE-W 65% 63% RELY 67% 64% ROCKET-AF 58% 55% ARISTOTLE 66% 62% Community Practice VARIA* (VA) 61% US Community Practice 66.5% *J Thromb Haemost Oct;8(10): **J Thromb Haemost Oct;6(10):

21 Various Models of Anticoagulation Management 21

22 Anticoagulation Symposium Title of Slides & Workshop

23 Anticoagulation Symposium Title of Slides & Workshop

24 Anticoagulation Symposium Title of Slides & Workshop

Point-of-Care INR Testing : An Evaluation of the CoaguChek XS TM in a Tertiary Hospital setting Ming Chai Kong 1, Teong Guan Lim 1, Heng Joo Ng 2, Lai Heng Lee 2 (1) Department of Pharmacy (2)

hospital laboratory assays as well as patient s acceptance of this device. Methods: Patients attending our anticoagulation clinic and hospitalised patients receiving warfarin therapy were studied.

25 Point-of-Care INR Testing : An Evaluation of the CoaguChek XS TM in a Tertiary Hospital setting Ming Chai Kong 1, Teong Guan Lim 1, Heng Joo Ng 2, Lai Heng Lee 2 (1) Department of Pharmacy (2) Department of Haematology, Singapore General Hospital, Singapore Aims: To determine the correlation between International Normalised Ratio (INR) values obtained using CoaguChekXS TM and standard hospital laboratory assays as well as patient s acceptance of this device. Methods: Patients attending our anticoagulation clinic and hospitalised patients receiving warfarin therapy were studied. After informed consent, 3 mls of blood were drawn for testing with usual laboratory essays. Simultaneously, a drop of capillary blood was drawn for testing with the CoaguChekXS TM. Results from both methods were analysed for concordance. To achieve a better correlation plot, INR readings were analysed according to the following ranges: <1, 1-2, 2-3, 3-4, 4-5, >5. A patient satisfaction questionnaire was distributed to all participants Results: A total of 230 patients were recruited and 253 INR readings were collected. Four patient data were excluded because CoaguChek could not read for INR>8. There were 123 (54.4%) males and 103 (45.6%) females, with an average age of 58.4 and average warfarin dose of 3.44mg daily. The correlation of INRs obtained from CoaguChek (y) and Laboratory (x) were as follows: y=0.7634x , correlation r = From the Bland Altman plot of difference in INR (CoaguChek - Lab) versus INR values of CoaguChek (y), the deviation of y-x is widen at INR>4. Using a tolerance test of the deviation at y-x<0.5, all the data in the INR range of 0.9 to 1.99, had less than 0.5 deviation. At INR ranges of , , , , , >5, the percentage of data with less than 0.5 deviation were 97.2%, 89.3%, 88.9%, 66.7%, 30.8%, 9.1% respectively. There were 138 responses to the patient satisfaction questionnaires. Of these, 89.7% of patients preferred the finger-pricking test, 66.7% said it was less painful and 50.7% preferred the shorter waiting time. Some commented that this method is easier, faster, more efficient, and more convenient. 53.6% of the patient were willing to pay S$8 for the test. Conclusions: The CoaguChek XS TM point-of-care machine produced a high overall correlation (r) with laboratory measured INR of Close correlation was mainly demonstrated for INRs in the range of with increasing deviation in the small population of subjects with INRs>3.5. Results beyond this INR should be rechecked with normal laboratory testing. Point-of-care testing was well accepted by the majority of patients. y = INR from Coaguchek XS Comparing INR values from Coaguchek XS vs Lab y = x R 2 = rrr = x = INR from Lab Bland Altman Plot of Difference in INR for CoaguChek vs Lab (y-x) vs CoaguChek (y) Coaguchek INR range (y) Tolerance Test (y-x)>=0.5 No. of points Tolerance Test (y-x) < 0.5 No. of points Subtotal Tolerance Test (y-x)>=0.5 No. of points in % Tolerance Test (y-x)<0.5 No.of points in % 0.9 to % 100.0% 1.5 to % 100.0% 2 to % 97.2% 2.5 to % 89.3% 3 to % 88.9% 3.5 to % 66.7% 4 to % 30.8% > % 9.1% Total % 88.0%

26 Benefits of home monitering

27 Anticoagulation Symposium Title of Slides & Workshop

28 Anticoagulation Symposium Title of Slides & Workshop

29 STABLE Study: Retrospective analysis of real-world PST: comparable TTR Study TTR (%) Patient Self Testing (real world) - weekly testing 73.9% Patient Self Testing (real world) test / mth 68.7% RE-LY Trial (dabigatran) 64.0% ROCKET-AF Trial (rivaroxaban) 55.0% ARISTOTLE Trial (apixaban) 62.0% Bloomfield Meta-analysis (2011) 66.1% THINRS Trial (2010) 66.2% DeSantis et al. ACC 2012; abstract #12-A9012-ACC 29

30 Stroke and Systemic Emboli (SE) Outcomes by INR Control Category: Results from SPORTIF III and V* *White, HD et al. Arch Intern Med. 2007; 167: Title of Slides 30

31 Anticoagulation Symposium Title of Slides & Workshop

32 Anticoagulation Symposium Title of Slides & Workshop

33 Anticoagulation Symposium Title of Slides & Workshop

34 Anticoagulation Symposium Title of Slides & Workshop

35 Anticoagulation Symposium Title of Slides & Workshop

36 36

37 Anticoagulation Symposium Title of Slides & Workshop

38 Take Home Points.... Systematic anticoagulation management improves TTR and clinical outcomes Patient self-testing at home with or without self-dose adjustment is an effective and safe means of managing warfarin therapy. Meta-analyses indicate that PST and PSM are more effective and just as safe as standard management (mixture of ACC and UC). Analysis of a large data base of real world patients performing PST shows that those who test frequently (weekly) have a rate of TTR > 73% and the overall group, a rate of TTR of > 69%. Recent ACCP guidelines (2012) recommend PSM (2B). For patients treated with VKAs who are motivated and can demonstrate competency in self-management strategies, including the self-testing equipment, we suggest PSM rather than usual outpatient INR monitoring (2B). For all other patients, therapy should be performed in a systematic and coordinated fashion. Title of Slides 38

39 potential benefits of PST/PSM Anticoagulation Symposium Title of Slides & Workshop

40 40 Title of Slides

41 Safety Title of Slides 41

42 WILL THERE BE A CONTINUING ROLE FOR WARFARIN? 1. Mechanical heart valves 2. Cost 3. Pregnancy 4. Severe renal impairment 5. Drug Interactions 6. Lack of acceptance of no monitoring 7. Reversal? 8. Nonadherence 9. Intolerant of novel anticoagulant drug Title of Slides 42

43 Warfarin has a Narrow Therapeutic Window Title of Slides 43

44 Warfarin has a Narrow Therapeutic Window Efficacy : Thrombosis % Safety : Bleeding %, Death Quality : Time in Therapeutic Range, Compliance Title of Slides 44

45 Cause of Bleeding, Thrombosis, Labile INR Follow-up (Transition of care) Phase of care Title of Slides 45

46 Case 1, Newly initiated on warfarin 76 year old patient with PMH of: DM, HTN, CKD, Gout, PUD, TKR Newly diagnosed R LL DVT in Feb 12 started warfarin on 06/02/12 HAS-BLED score= 4 (high risk of bleeding)

47 Case 1: 76 year old patient with PMH of: DM, HTN, CKD, Gout, PUD, TKR Newly diagnosed R LL DVT in Feb 12 started warfarin on 06/02/12 HAS-BLED score= 4 (high risk of bleeding) Date INR Warfarin Dose (mg) 06/02/ /02/ /02/ /02/ /02/ (discharge) 11/02/ /02/ /02/ /02/ /02/ /02/ /02/ /02/ /02/ Anticoagulation Symposium 09/03/2012, & Workshop 9pm 2015 >10 20/02/ f/u at Outpatient Date INR Warfarin Dose (mg) 20/02/ ? 3 21/02/2012? 3 22/02/2012? 3 23/02/2012? 3 24/02/ /02/ /02/ /02/ /02/ /02/ /03/ /03/ /03/ /03/ /03/ /03/ /03/ /03/ /03/2012, 10pm > A&E 10/03/2012, 10am >10

76 year old patient with PMH of: DM, HTN, CKD, Gout, PUD, TKR Newly diagnosed R LL DVT in Feb 12 started warfarin on 06/02/12 HAS-BLED score= 4 (high risk of bleeding) Date INR Warfarin Dose (mg)

48 76 year old patient with PMH of: DM, HTN, CKD, Gout, PUD, TKR Newly diagnosed R LL DVT in Feb 12 started warfarin on 06/02/12 HAS-BLED score= 4 (high risk of bleeding) Date INR Warfarin Dose (mg) 06/02/ /02/ /02/ /02/ /02/ /02/ /02/ /02/ /02/ /02/ /02/ /02/ /02/ /02/ /02/ Relevant problems: Inappropriate warfarin initiation dose: Started on higher dose than suggested for patients age>70 Patient discharge on 10/02/12 with INR of 2.98 at upper therapeutic limit & given relatively long TCU date of 10 days (i.e. on 20/02/12)

49 76 year old patient with PMH of: DM, HTN, CKD, Gout, PUD, TKR Newly diagnosed R LL DVT in Feb 12 started warfarin on 06/02/12 HAS-BLED score= 4 (high risk of bleeding) Date INR Warfarin Dose (mg) 20/02/ ? 3 21/02/2012? 3 22/02/2012? 3 23/02/2012? 3 24/02/ /02/ /02/ % weekly dose reduction & TCU in a week?vit K given(wasn t documented on system) 27/02/ /02/ /02/ /03/ /03/ /03/ /03/ /03/ /03/ /03/ /03/ /03/2012 > A&E ~9.5% weekly dose reduction Note: Patient s INR always supra-therapeutic since started on warfarin

Patient admitted at A&E on 09/03/12 for cellulitis & over-anticoagulation Date INR 09/03/2012 >10 (10pm) 10/03/2012 >10 (10am) 10/03/2012 >10 (9pm) 76 year old patient with PMH of: DM, HTN, CKD,

50 Patient admitted at A&E on 09/03/12 for cellulitis & over-anticoagulation Date INR 09/03/2012 >10 (10pm) 10/03/2012 >10 (10am) 10/03/2012 >10 (9pm) 76 year old patient with PMH of: DM, HTN, CKD, Gout, PUD, TKR Newly diagnosed R LL DVT in Feb 12 started warfarin on 06/02/12 HAS-BLED score= 4 (high risk of Vit K given? No PO Vit K Patient INR still IV Vit K Patient passed away likely due to massive ICH Relevant problems: Vitamin K not given when INR>10 (First INR) PO 3mg Vitamin K given on (after 2 nd INR reading of >10) INR not checked at close interval, ie 6 hours after giving vitamin K

51 Case 2 70 year old patient with PMH of: HTN, HLD, TIA, IHD Admitted with R MCA infarct with LV thrombus HAS-BLED score= 5 (high risk of bleeding) Anticoagulation initially held off due to possible hemorrhagic conversion seen in CT brain on 19/04/12 kept patient on aspirin 100mg OM Repeat CT brain on 23/04/12 showed reduction in mass effect but increased gyral hyperintensity & possible pethichial haemorrhage); however patient showed clinical improvement s/p mannitol since admission

52 Case 2: 70 year old patient with PMH of: HTN, HLD, TIA, IHD Admitted with R MCA infarct with LV thrombus, HAS-BLED score= 5 (high risk of bleeding). Anticoagulation initially held off due to possible hemorrhagic conversion seen in CT brain on 19/04/12 kept patient on aspirin 100mg OM 23/4/ Repeat CT brain showed reduction in mass effect but increased gyral hyperintensity & possible pethichial haemorrhage; however patient showed clinical improvement s/p mannitol since admission. Started patient on Enoxaparin on 24/4/2012

53 70 year old patient with PMH of: HTN, HLD, TIA, IHD Admitted with R MCA infarct with LV thrombus, HAS-BLED score= 5 (high risk of bleeding) Anticoagulation initially held off due to possible hemorrhagic conversion seen in CT brain on 19/04/12 kept patient on aspirin 100mg OM Repeat CT brain on 23/04/12 showed reduction in mass effect but increased gyral hyperintensity & possible pethichial haemorrhage); however patient showed clinical improvement s/p mannitol since admission Relevant problems: Consider lower initial dose of enoxaparin in patients with high risk of bleeding Inappropriate antidote :- IV Vitamin K was given but patient was only started on warfarin 12hour prior to event, (warfarin onset of action is 24h, full anticoagulation effect in 72-96h, duration of single dose is 2-5 days), ie warfarin unlikely to have any effect yet. Protamine should be given instead to reverse effect of enoxaparin (onset 3-5 hour, duration of action 12 hour)

54 Case 3 52 y/o, 45-kg, Chinese male patient PMHx: None Admission for intracranial hemorrhage (ICH) (25/2/2012) MRI-brain (27/2/2012): Thrombosis of the superior sagittal sinus, with secondary venous congestion of the occipital lobes, and venous haemorrhage in the left parietal lobe. Refer Neurology to start anticoagulation

55 Case 3 : 52 y/o, 45-kg, Chinese male, 25/2/2012 : Admission for intracranial hemorrhage (ICH) 27/2/2012 : MRI-brain: Thrombosis of the superior sagittal sinus, with secondary venous congestion of the occipital lobes, and venous haemorrhage in the left parietal lobe.

the superior sagittal sinus, with secondary venous congestion of

56 Case3 : 52 y/o, 45-kg, Chinese male, admission for intracranial hemorrhage (ICH) (25/2/2012) MRI-brain (27/2/2012): Thrombosis of the superior sagittal sinus, with secondary venous congestion of the occipital lobes, and venous haemorrhage in the left parietal lobe.

57 Case 4: Major bleed 73 y/o, 93-kg male patient (from Batam) PMHx: COPD (Ex-smoker) Admission for cellulitis (3/5/2012) + left LL DVT (confirmed in Batam hospital) OP was performed to remove soft tissue on 5/5/2012, then enoxaparin 40 mg was given for DVT prophylaxis US confirmed with DVT on 8/5/2012, then gave enoxaparin 100 mg BD for treatment Lab (steady during admission) ALT/AST: 16/19 U/L; bilirubin: 15 umol/l

58 Date INR Enoxaparin Anti-Xa Warfarin Vita K Albumin(g/L) Fluconazole Hb Clcr(ml /min) 5/5 - Operation (Left LL cellulitis) /5-40 mg X /5-40 mg X /5-40 mg 100 mg US: DVT 9/5-100 mg 100mg / (11 am) 100 mg X 5 (6 am) 17 Fluconazole 600 mg PO (5 pm) /5 9.46/9.8 X X X IV Vit K 3mg mg IV /5 1.3 X X X mg IV Tinzaparin 13/ ,000 U (7:53 am) X / ,000 U (5 pm) 0.26 (12 pm ) X 26 Blood x1 (6 pm) 7.5 (2 pm) 15/ X X / X X 19 Blood x / ,000U (11:52 am) X / ,000U (8:12 am) 19/ DNR (back to Batam) :12 am X 16 hematemesis, malena 9 18 X Blood x2 5.5

59 Date INR Enoxaparin Anti-Xa Warfarin Vit K Albumin(g/L) Fluconazole Hb Clcr(ml /min) 5/5 - Operation (Left LL cellulitis) /5-40 mg X /5-40 mg X /5-40 mg 100 mg US: DVT 9/5-100 mg 100mg / (11 am) 100 mg X 5 (6 am) 17 Fluconazole 600 mg PO (5 pm) /5 9.46/9.8 X X X IV Vit K 3mg mg IV /5 1.3 X X X mg IV Tinzaparin 13/ ,000 U (7:53 am) X / ,000 U (5 pm) 0.26 (12 pm ) X 26 Blood x1 (6 pm) 7.5 (2 pm) 15/ X X / X X 19 Blood x / ,000U (11:52 am) X / ,000U (8:12 am) :12 am X hematemesis, malena 19/ DNR (back to Batam) X Blood x

60 Is this preventable? 73 y/o, 93-kg male patient (from Batam) PMHx: COPD (Ex-smoker), Admission for cellulitis (3/5/2012) + left LL DVT (confirmed in Batam hospital) OP was performed to remove soft tissue on 5/5/2012, then enoxaparin 40 mg was given for DVT prophylaxis US confirmed with DVT on 8/5/2012, then gave enoxaparin 100 mg BD for treatment Lab (steady during admission), ALT/AST: 16/19 U/L; bilirubin: 15 umol/l Warfarin Nomogram for initiation Warfarin Fluconazole interaction, Reaction: INR range, reduce dose by 30-40%, monitor INR within 3-4 days LMWH in CrCl < 30ml/ml, dosage reduction needed 50% for Enoxaparin, 20% reduction for Tinzaparin Anti-Xa (peak & trough monitoring) HASBLED score = 3 (73 yo, impair renal function, anticoagulant) Recent major bleed, should anticoagulation be restarted in 2 days?

Incident of Hospitalization Total of 141 patients started on warfarin during study period Dec 2011-May 2012,then follow up for 6 months The total rate of hospitalization during follow up period due

61 Incident of Hospitalization Total of 141 patients started on warfarin during study period Dec 2011-May 2012,then follow up for 6 months The total rate of hospitalization during follow up period due to complications of warfarin therapy was 16/141 ie 11.3% Major Bleeding Minor Bleeding 4.2% (6/141) 7.1%(10/141) 4 out of 6 patients with major bleeding passed away (66%) Incidence of hospitalization, All warfarin patient, new & old at baseline, 9/2010-8/2011: ALL (ACC & Non ACC) patients on warfarin from Sept 2010-Aug 2011: 3.8% ACC (SGH) only : 1.9%

62 Other Re-hospitalisation data 11.3 % 3.8% (Overall) 1.9% (ACC)

63 Anticoagulation Symposium Title of Slides & Workshop

64 Anticoagulation Symposium Title of Slides & Workshop

65 Anticoagulation Symposium Title of Slides & Workshop

66 Counseling Education Misunderstanding eg did not take any green vegetables at all after counseling not aware of the need for consistency and moderation of diet Do not understand well the counseling session Forgotten about the counseling points Could not read, could not understand PIL Did not realise the need to close followup Remarks : Take at least 5 years to optimise compliance and TTR Title of Slides 66

67 Inpatient to Outpatient Challenges Transition of Care Patients are admitted because they are ill with possibly various disease states Anticoagulation may need to be interrupted for invasive procedures There are many changes to the medication Anticoagulation administration is frequent source of error Title of Slides 67

Thank You! For more information, please visit: http://www.

68 Thank You! For more information, please visit: kong.ming.chai@sgh.com.sg Title of Slides 68

69 Current state of anticoagulation management (VKA Therapy) Warfarin and other vitamin K antagonists have been the only oral anticoagulants for over 70 years (until recently) Warfarin has limitations as an anticoagulant: Need for frequent monitoring Large dosing differences between patients Narrow therapeutic window Dietary and drug interactions Labour intensive monitoring High rate of adverse events Ansell et al. Chest 2004;126(Suppl):202S-231S. 69

70 Warfarin is one of the most common drugs associated with adverse events One of the 5 most common drug classes implicated in ADEs One of the 5 most common drugs implicated in hospitalizations due to ADEs Insulin and warfarin are implicated in 1 in every 7 estimated ADEs treated in EDs In patients > 65 yrs, insulin, warfarin and digoxin are implicated in 1 in every 3 estimated ADEs treated in EDs Insulin or warfarin is implicated in more than 25% of all estimated hospitalizations due to ADEs Budnitz et al. JAMA 2006;296:

71 Consequences of problems with oral anticoagulants? Non - treatment of some conditions e.g. Atrial Fib (~ 50% of AF population not treated) Inadequate treatment of many conditions e.g. Atrial Fib, Heart Valves, etc. (only % TTR) Increased complications Hemorrhage & Thrombosis (3% - 15% rate of major AEs) Increased costs Title of Slides 71

72 Anticoagulation Symposium Title of Slides & Workshop

73 Anticoagulation Symposium Title of Slides & Workshop

74 Anticoagulation Symposium Title of Slides & Workshop

Anticoagulation in Special populations. Ng Heng Joo Department of Haematology Singapore General Hospital

Anticoagulation in Special populations Ng Heng Joo Department of Haematology Singapore General Hospital roymatheson.com Objectives Safer anticoagulation for The elderly Chronic kidney disease Obese patients