A) Teaching Case

B) Telefonanfragen der Hausärzte

C) Dr House-Fälle

Solothurn 4.9.14

1440-1520

JH Beer, Baden

„Bruise Control I“

1) Mein Patient klagt über häufiges Nasenbluten mit

unterschiedlicher Heftigkeit, zuletzt und besonders lästig

während eines Flugs nach Mallorca.

Er steht unter NOAC (Rivaroxaban) wegen einer

unprovozierten TVT vor 3 Monaten. Er hat R deshalb selber

abgesetzt.

Frage: Mehr Blutungen unter NOACs?

Sind kleine Blutungen relevant?

Management von Blutungen?

Dauer der AK?

Risiko-Abwägungen?

Recurrent TE

NEJM 2013; 368: 709

2,486 pts

3m after VTE

and OAC: vs

2x150mg Dabigatran

vs placebo ctr

Major Bleeds: 0.3% vs 0.0%

MB orCR NMB: 5.3% vs 1,8%

RE-MEDY and RE-SONATE Extension Trials

3/681=0.4%

37/662=5.6%

Any bleeding 10.5%

5.9%

Bleeding

11% adherence <80%

30% missed some doses

from daily, to 2x in 6 years

20% bleedings, 2x major

1x stroke

33% some degree of

dyspepsia

Compliance

Impact of Poor Adherence: Efficacy and Safety Issues

11

Periodic loss of effectiveness

Occasional toxicity

Blaschke TF, Osterberg L, Vrijens B, Urquhart J. Adherence to Medications: Insights Arising from Studies on the Unreliable Link Between Prescribed and Actual Drug Dosing Histories. Annu Rev Pharmacol Toxicol. 2012;52:275-301.

BMJ,

14.09.13,

Vol. 347,

p.11

Major Bleeding

327 (2.13) 462 (3.09)

395 (3.6) 386 (3.4)

NOAC Warfarin

0.5 1.0

Favors NOAC Favors warfarin

HR 95% CI

0.60-0.80 0.69

0.90-1.20 1.04

342 (2.87) 421 (3.57) Dabi 110 0.70-0.93 0.80

1.5 0.0

Riva

Apixaban

399 (3.32) 421 (3.57) Dabi 150 0.81-1.07 0.93

No. of events (%/yr)

2.0

Not head to head comparison – For illustrative purpose only – adapted from references 1-4

1. Connolly et al. NEJM 2009; 361: 1139-51. 2. Connolly et al. NEJM 2010; 363: 1875-6.

3. Patel et al. NEJM 2011; 365: 883-91. 4. Granger et al. NEJM 2011; 365: 981-92.

Hemorrhagic Stroke

40 (0.24) 78 (0.47)

29 (0.26) 50 (0.44)

NOAC Warfarin

0.5 1.0

Favors NOAC Favors warfarin

HR 95%

CI

0.35-0.75 0.51

0.37-0.93 0.59

14 (0.12) 45 (0.38) Dabi 110

(ITT)

0.17-0.56 0.31

1.5 0.0

Riva (safety AT)

Apixaban

(ITT)

12 (0.10) 45 (0.38) Dabi 150

(ITT)

0.14-0.49 0.26

No. of events

(%/yr)

2.0

Not head to head comparison – For illustrative purpose only – adapted from references 1-4

1. Connolly et al. NEJM 2009; 361: 1139-51. 2. Connolly et al. NEJM 2010; 363: 1875-6.

3. Patel et al. NEJM 2011; 365: 883-91. 4. Granger et al. NEJM 2011; 365: 981-92.

ITT: Intention to Treat – AT: as treated.

Death From Any Cause

603 (3.52) 669 (3.94)

208 (1.87) 250 (2.21)

NOAC Warfarin

0.5 1.0

Favors NOAC Favors warfarin

HR 95% CI

0.80-0.99 0.89

0.70-1.02 0.85

446 (3.75) 487 (4.13) Dabi 110

(ITT)

0.80-1.03 0.91

1.5 0.0

Riva (safety AT)

Apixaban

(ITT)

438 (3.64) 487 (4.13) Dabi 150

(ITT)

0.77-1.00 0.88

No. of events (%/yr)

2.0

582 (4.5) 632 (4.9) 0.82-1.03 0.92 Riva (ITT)

Not head to head comparison – For illustrative purpose only – adapted from references 1-4

1. Connolly et al. NEJM 2009; 361: 1139-51. 2. Connolly et al. NEJM 2010; 363: 1875-6.

3. Patel et al. NEJM 2011; 365: 883-91. 4. Granger et al. NEJM 2011; 365: 981-92.

Bleeds

(GIT)

Circ 2011; 123: 2363 (mai 31)

Obere oder Untere GI-Blutungen mit Dabigatran

Stroke/systemic embolism: RE-LY® + RELY-ABLE®

BID = twice daily; D150 and D110 = dabigatran 150 and 110 mg BID, respectively; FU= follow -up; HR = hazard ratio

No. at risk

D110

D150

0 Years

1 2

0.04

0.06

0.08

0.10

0

0.02

D150: 1.25 %/yr

D110: 1.54 %/yr

HR: 0.81

95% CI: 0.66–0.96

All dabigatran patients 12 091 patients

3 4

6015 5709 4208 2740 1921

6076 5777 4298 2757 1943

Connolly SJ et al. AHA Scientific Sessions, 2012 / * data from RE-LY

Cum

ula

tive

ris

k

Dabigatran 150 mg BID

Dabigatran 110 mg BID

Warfarin (RE-LY only)*

covering 134’000 patients > 65 years has been completed and

2010-2012 Medicare Data USA

US-Postmarketing Mini Sentinel

NEJM 2013; March 13

0.5%/y 1.1%/y

0.25%/y 0.8%/y

TH 2008; 100:1047

Blood (may) 2008; 111: 4473

Bleeding Risk of the „Excluded“

1. How many of the patients with OAC admitted for bleeding had exclusion criteria

(How many of the patients with OAC admitted for infection had exclusion criteria)

23%

40%

Blood 2008; 111: 4473

Exclusion Criteria

•„not suitable for OAC (compliance, alcohol...)

•Cancer

•Comedication (eg plt inhibitors)

•Previous stroke

•Cardiac comorbidity

•Other comorbidity (renal)

Table 2 Drug – drug interactions and recommendations toward dosing according to EHRA practical guide [20]

Via Dabigatran Apixaban Rivaroxaban

Atorvastatin P-Gp competition and CYP 3A4 inhibition

+ 18 % (AUC) Minor increase No effect

Digoxin P-Gp competition No effect No effect No effect

Verapamil P-Gp competition (weak CYP3A4 inhibition)

+ 12 – 180 % Moderate increase Minor increase Cave if CrCl 15-50 ml/min

Diltiazem P-Gp competition und CYP3A4 inhibition

No effect + 40 % Minor increase Cave if CrCl 15-50 ml/min

Quinidine P-Gp competition + 50 % Moderate increase +50 %

Amiodarone P-Gp competition + 12 – 60 % Moderate increase Minor increase Cave if CrCl 15-50 ml/min

Dronedarone P-Gp and CYP3A4 inhibition + 70 – 100 % Moderate increase Moderate increase

Ketoconazole; itraconazole; voriconazole

P-Gp competition, CYP3A4 inhibition

+ 140 – 150 % + 100 % + 160 %

Fluconazole CYP3A4 inhibtion No data yet Moderate increase + 42 %

Cyclosporin P-Gp Kompetition Strong increase Moderate increase + 50 %

Clarithromycin; erythromycin P-Gp competition and CYP3A4 inhibition

+ 15 – 20 % Strong increase + 30 – 54 %

HIV protease inhibitors P-Gp competition and CYP3A4 inhibition

Strong increase Strong increase + 153 %

Rifampicin; St John’s wort; phenytoin; carbamazepine

P-Gp and CYP3A4/CYP2J2 inducers

- 66 % - 54 % - 50 %

Antacids (PPI, H2B) GI absorption - 12 – 30 % No effect No effect

Age ≥ 80 y. Increased plasma level

Age ≥ 75 y. Increased plasma level

Weight ≤ 60 kg Increased plasma level Red: Contraindicated/not recommended Orange: Reduce dose (dabigatran 2 x 110 mg; apixaban 2 x 2.5 mg; rivaroxaban 1 x 15 mg) Yellow: Consider dose reduction in presence of another „yellow“ factor

Lai A et al. Perioperative management of patients on new oral anticoagulants. Br J Surg. 2014 Jun;101(7):742-9.

BJS 2014

BJS 2014

Lai A et al. Perioperative management of patients on new oral anticoagulants. Br J Surg. 2014 Jun;101(7):742-9.

BJS 2014

Lai A et al. Perioperative management of patients on new oral anticoagulants. Br J Surg. 2014 Jun;101(7):742-9.

Perioperative Bridging Strategy Becomes Easier

Blood 2012; 120:2954

Bridging Strategy: Postop Restart

Blood 2012; 120:2954

TE - Risk Stratification perioperatively

Blood 2012; 120:2954

Stratification perioperatively: High Bleeding Risk

Blood 2012; 120:2954

Stratification perioperatively: Low Bleeding Risk

Blood 2012; 120:2954

38 Prandoni P et al. Haematologica. 2007;92:199-205.

0

10

20

30

40

50

60

Cu

mu

lati

ve I

ncid

en

ce o

f

VT

E R

ecu

rren

ce (

%)

0 1 8 5 9 10

Time After Discontinuation of Anticoagulation (years)

Unprovoked (n=864, 53%)

Provoked (n=762, 47%)

52.6%

22.5%

2 3 4 6 7

15.0%

6.6%

40.8%

16.1%

Higher Recurrence Rates in Unprovoked VTE

– After discontinuation of anticoagulation, VTE recurrence is more than

2-fold higher in patients with an unprovoked vs provoked VTE

Data from Italy

Approach to Long-Term and Extended Treatment of VTE

(After Acute Treatment Through 3 to 6 Months After Diagnosis)

Patient with PE or DVT*

stable on acute phase treatment

Etiology of VTE

Transient risk factor Malignancy

Treat with VKA or

approved NOAC

Discontinue treatment

after 3 mo. Consider extended treatment

(>6 mo.)

Consider extended treatment

(>6 mo.)

Bleeding risk? VTE recurrence risk

Continue treatment

indefinitely with VKA or

approved NOAC

Discontinue

treatment after

3 to 6 mo.

High VTE

recurrence risk

Low VTE recurrence risk

or high bleeding risk

Consider discontinuing treatment

in women at low risk of VTE

recurrence or if strong patient

preference to discontinue

Continue LWMH or

switch to approved

NOAC or a VKA

Discontinue AC or

continue LMWH, or

switch to approved

NOAC or VKA

Low to moderate High

Treat with VKA or

approved NOAC

Unprovoked VTE

Treat with

LMWH

* Upper or lower extremity.

AC=anticoagulation; LMWH=low molecular weight heparin; NOAC=novel oral anticoagulant; VKA=vitamin K antagonist.

Wells et al. JAMA. 2014;311(7):717-728.

39

Acute treatment

5-21 days*

Mid-term treatment

3-12 months* Extended treatment

LMWH

Rivaroxaban 15 mg b.i.d.

Apixaban 10 mg b.i.d.

Dabigatran 150 mg b.i.d.

Edoxaban 60 mg/d

Rivaroxaban 20 mg/d

Apixaban 5 mg b.i.d.

Dabigatran 150 mg b.i.d.

Edoxaban 60 mg/d

Rivaroxaban 20 mg/d

Apixaban 5 mg b.i.d.

or Apixaban 2.5 mg b.i.d.

Figure 2: acute and extended treatment of VTE with DOACs

* depending on study design

Holy, Beer Sem TH 2014

41

41

Bei Patienten mit schwerer Niereninsuffizienz (Kreatinin-Clearance 15-29 ml/min) ist Vorsicht geboten, da hier nur begrenzte klinische Daten vorliegen. Bei

diesen Patienten wurde eine signifikant erhöhte Rivaroxaban Plasmakonzentration (im Mittel 1,6 fach) gemessen. Sie müssen von Beginn der Behandlung an

sorgfältig auf Anzeichen und Symptome für Blutungskomplikationen und Anämie überwacht werden und die plasmatische Gerinnung sollte kontrolliert werden.

Bei jedem ungeklärten Hämoglobin- oder Blutdruckabfall sollte nach der Blutungsquelle gesucht werden.

60 ml/min

50 ml/min

40 ml/min

30 ml/min

15 ml/min

10 ml/min

Dabigatran

(Pradaxa®)

Rivaroxaban

(XARELTO®)

2x5 mg

GFR

20 mg

15 mg

15 mg

2x150 mg

Apixaban

(Eliquis®)

2x110 mg

2x2.5 mg (if in

comb.:

•- ≥ 80 J. or

•- ≤ 60 kg

GFR: Glomeruläre Filtrationsrate, TEP: Totalendoprothese, VHF: Vorhofflimmern, TVT: tiefe Beinvenenthrombose

Novel Anticoagulants – Dosing acc to renal function

Eliquis® (Apixaban) Swiss SmPC available at www.swissmedicinfo.ch

Pradaxa® (Dabigatran) Swiss SmPC available at www.swissmedicinfo.ch

Xarelto® (Rivaroxaban Swiss SmPC available at www.swissmedicinfo.ch