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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