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Dabigatran: current status
Attributes Of The Ideal Anticoagulant
Oral administration
Rapid onset of action/rapid offset of action
Wide therapeutic range
Predictable therapeutic effect with fixed or weight-
based dosing
No monitoring required (but the ability to monitor if
desired)
Well defined pharmacokinetics in presence of
renal or hepatic disease
Easily reversible
Cost effective
Oral Anticoagulants
 Vitamin K Antagonists ( Coumarins ) :
Warfarin, Acinocoumarol ( Acitrom )
 AntiThrombin Agents : Dabigatran,
Ximelagatran
 Anti Xa Agents : Rivaroxaban, Apixaban,
Edoxaban, Betrixaban,
Letaxaban,Darexaban (Discontinued
from September 2011), Eribaxaban
SPIL/Dr Borgharkar
Dabigatran2
Dabigatran2
Warfarin
 Most Commonly used oral anticoagulant.
 It is a water soluble Vitamin K antagonist.
 It interferes with the synthesis of Vitamin K
dependent clotting proteins which include
Factors II, VII, IX , X. It also impairs
synthesis of Vitamin K dependent
anticoagulant proteins C and S.
8. Efficacy is dependent upon infrastructure
 Time in therapeutic range (TTR) is associated with
improved safety and efficacy
 TTR is improved with AC management programs
 TTR is greater in countries with more sophisticated
health care infrastructure
How Often to Check INR
 In patients with stable Warfarin dosing INR should
be checked every 3 weeks.
 More frequent INR testing will be required with
addition of new drugs due to interactions.
 Self monitored and self guided therapy is better
for educated patients.
What's Wrong With Warfarin?
Narrow therapeutic range
Slow onset of action
Slow offset of action (long duration of action, long
elimination half life)
Multiple drug and dietary interactions
Monitoring required to maintain in therapeutic
range
Limitations of Vitamin K antagonist therapy
How Good Is Acenocumarol…?
 Warfarin is employed more frequently than
acenocoumarol because of its longer half-life (36
h), theoretically providing more stable
anticoagulation, and avoiding factor VII
fluctuations that potentially occur during
acenocoumarol treatment (half-life 10 h).
Acenocoumarol: A Review of Anticoagulant Efficacy and
Safety : JAPI Feb 2016
Overall Advantages Of
Acenocumarol
 Rapid onset of action
 The effect lasts for 15-20 hours.
 Less dependence on CYP2C9 for metabolism
compared to warfarin
 Better anticoagulation stability than warfarin
 Rapid reversal of anticoagulant action with relatively
small amounts of vitamin K17
Newer Direct Oral Anticoagulants
 Rapid onset of Action
 Half lives that permit once or twice daily action.
 Given in fixed doses without routine monitoring of
coagulation.
 Antidotes now available for Induced bleeding.
Dabigatran
 Competitive direct thrombin inhibitor.
 Inhibits both free and clot bound thrombin as
well as thrombin induced platelet aggregation.
 Substrate of P glycoprotein but no significant
drug interactions.
 Half life is 12 – 17 hours.
 Bioavailability is 6.5% and 80% of drug is
excreted by the kidneys.
 Pharmacokinetics:
 After oral administration, dabigatran etexilate is rapidly
absorbed.
 It get rapidly & completely converted to dabigatran
(active form in plasma)
 Peak plasma concentration reached in 0.5 – 2 hrs
 T1/2 is 15-17 hours
 90% of excreted unchanged in urine. So dose reduction
required in moderate renal impairment & is
contraindicated in severe renal impairment.
 Minimal metabolism of dabigatran by CYP3A4
enzymes is clinically insignificant
 No dose modification required in hepatic impairment
 Dabigatran is also a substrate for P- glycoprotein ( a
trans-membrane pump expelling drugs out of cell). So
P- glycoprotein inhibitors (e.g. amiodarone, verapamil
& clarithromycin) can increase whereas inducers (e.g.
rifampicin, st. john’s wort) may reduce dabigatran
level in plasma.
Dosing
 For prevention of Stroke in Non Valvular AF dose is
150 mg BD
 If Creatinine clearance is 15 – 30 ml/min, dose is
reduced to 75 mg BD.
 Now approved for VTE also: Patients should initially
receive a minimum of 5 day course of parenteral
anticoagulant before starting Dabigatran at 150 mg
BD.
 Qualitative assessment of anticoagulant activity is by
APTT.
 Quantitative assessment by Dilute Thrombin clotting
time.
Dabigatran2
Dabigatran2
SPIL/Dr Borgharkar
Valvular AF mainly refers to AF patients
that have either rheumatic valvular disease
(predominantly mitral stenosis) or
mechanical heart valves.
Dabigatran2
Dabigatran2
Dabigatran2
Dabigatran2
Dabigatran2
Dabigatran2
Dabigatran2
Dabigatran2
Dabigatran2
Dabigatran2
Dabigatran2
Dabigatran2
Stroke or Systemic Embolism
0.50 0.75 1.00 1.25 1.50
Dabigatran 110 vs. Warfarin
Dabigatran 150 vs. Warfarin
Non-inferiority
p-value
<0.001
<0.001
Superiority
p-value
0.34
<0.001
Margin = 1.46
HR (95% CI)
Warfarin betterDabigatran better
Ischemic/Unspecified Stroke
D 110 mg vs.
Warfarin
D 150 mg vs.
Warfarin
RR =1.11
95% CI = 0.89-1.40
P = 0.35
RR = 0.76
95% CI = 0.60-0.98
P = 0.03
Years of Follow-up
CumulativeHazardRates
0.00.020.040.060.08
0 0.5 1.0 1.5 2.0 2.5
Dabigatran110
Dabigatran150
Warfarin
Hemorrhagic Stroke
D 110 mg vs.
Warfarin
D 150 mg vs.
Warfarin
RR = 0.31
95% CI =0.17-0.56
P <0.001
RR =0.26
95% CI =0.14-0.49
P <0.001
Years of Follow-up
CumulativeHazardRates
0.00.010.020.030.04
0 0.5 1.0 1.5 2.0 2.5
Dabigatran110
Dabigatran150
Warfarin
Dabigatran2
Conclusions
 Dabigatran 150 mg significantly reduced stoke
compared to warfarin with similar risk of major
bleeding
 Dabigatran 110 mg had a similar rate of stroke as
warfarin with significantly reduced major bleeding
 Both doses markedly reduced intra-cerebral, life-
threatening and total bleeding
 Dabigatran had no major toxicity, but did increase
dyspepsia and GI bleeding
Conclusions
 Both Dabigatran doses offer advantages over
warfarin
 Dabigatran 150 is more effective and dabigatran
110 has a better safety profile
 There is potential to tailor therapy to individual
patient characteristics
Dabigatran2
Dabigatran2
Dabigatran2
Dabigatran2
Dabigatran2
Dabigatran2
Dabigatran2
Dabigatran2
Dabigatran2
Recent ACS: STEMI, NSTEMI, UA
No increased bleeding risk, No warfarin, No ICH, No
prior stroke if on ASA + Thienopyridine
Stabilized 1-7 Days Post-Index Event
PRIMARY ENDPOINT:
EFFICACY: CV Death, MI, Stroke* (Ischemic + Hemg.)
SAFETY: TIMI major bleeding not associated with CABG
Event driven trial of 1,002 events in 15,342 patients**
RIVAROXABAN
5.0 mg BID
N=5,176
ASA + Thieno, n=4,827
ASA, n=349
Stratified by Thienopyridine use at MD Discretion
+ ASA 75 to
100 mg/day
Placebo
N=5,176
ASA + Thieno, n=4,821
ASA, n=355
RIVAROXABAN
2.5 mg BID
n=5,174
ASA + Thieno, n=4,825
ASA, n=349
* Stroke includes ischemic stroke, hemorrhagic stroke, and uncertain stroke
** 184 subjects were excluded from the efficacy analyses prior to unblinding
SUMMARY-EFFICACY
• The primary efficacy endpoint of CV death, MI
and stroke was reduced when added to standard
therapy for both rivaroxaban doses combined,
and for the 2.5 and 5.0 mg BID doses separately
• CV and all cause death were reduced for both
rivaroxaban doses combined, and for the 2.5 mg
BID dose in both mITT and ITT analyses
SUMMARY-EFFICACY (cont.)
• When 2.5 mg PO BID of rivaroxaban was added
to ASA + thienopyridine, cardiovascular death
was reduced by 38% and all cause death by 36%
• One death prevented if 56 patients treated for two
years with 2.5 mg BID of Rivaroxaban
2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting
without persistent ST-segment elevation
RE-DUAL PCI: dual antithrombotic therapy
with dabigatran after percutaneous coronary
intervention in patients with atrial fibrillation
Christopher P. Cannon
Deepak L Bhatt, Jonas Oldgren, Gregory YH Lip, Stephen G Ellis, Takeshi
Kimura, Michael Maeng, Bela Merkely, Uwe Zeymer, Savion Gropper,
Matias Nordaby, Eva Kleine, Ruth Harper, Jenny Manassie, James L
Januzzi, Jurrien M ten Berg, Philippe Gabriel Steg and Stefan H
Hohnloser
On behalf of the steering committee and RE-DUAL PCI investigators
Study Design: Multicenter,
randomized, open-label trial
following a PROBE design
R
Randomiza
tion
≤120 hours
post-PCI*
6-month minimum treatment duration with visits every 3 months for
the first year, then visits and telephone contact alternating every
3 months and a 1-month post-treatment visit
Patients
with AF
undergoi
ng PCI
with
stenting
Dabigatran 150 mg BID +
P2Y12 inhibitor
Dabigatran 110 mg BID +
P2Y12 inhibitor
Warfarin (INR 2.0–3.0) + P2Y12
inhibitor + ASA
N=27
25
Mean
duration of
follow-up:
~14 months
Dabigatran (110 or 150 mg) P2Y12 inhibitor
Warfarin P2Y12 inhibitor
1 month of ASA (BMS) 3 months of ASA
(DES)
*Study drug should be administered 6 hours after
sheath removal and no later than ≤120 hrs post-
PCI (≤72 hrs is preferable). PROBE, prospective,
randomized, open, blinded end-point; R,
randomization; BMS, bare metal stent; DES, drug-
eluting stent. ClinicalTrials.gov: NCT02164864;
Full analysis set presented. HRs and Wald CIs from Cox proportional-hazard model. For the dabigatran 110 mg vs warfarin comparison, the
model is stratified by age, non-elderly vs elderly
(<70 or ≥70 in Japan and <80 or ≥80 years old elsewhere). For the dabigatran 150 mg vs warfarin comparison, an unstratified model is used,
elderly patients outside the USA are excluded. Non- inferiority P value is one sided (alpha=0.025). Wald two-sided P value from (stratified) Cox
Primary Endpoint: Time to first ISTH major
or clinically relevant non-major bleeding event
Probabilityofevent(%)
0
0 9
0
18
0
54
0
63
0
72
0
270 360
450
Time to first event
(days)
4
0
3
5
3
0
2
5
2
0
1
5
1
0
5
Warfarin
triple
therapy
Dabigatran
110 mg dual
therapy
HR: 0.52 (95% CI:
0.42–0.63)
Non-inferiority
P<0.0001 P<0.0001
0 9
0
18
0
54
0
63
0
72
0
270 360
450
Time to first event
(days)
4
0
3
5
3
0
2
5
2
0
1
5
1
0
5
0
Dabigatran
150 mg dual
therapy
Warfarin
triple
therapy
HR: 0.72 (95% CI:
0.58–0.88)
Non-inferiority
P<0.0001 P=0.002
Wald two-sided P value from (stratified) Cox proportional-hazard model (alpha=0.05).
ARR, absolute risk reduction
Primary endpoint: ISTH major or
clinically relevant non-major bleeding event
Dabigatran
110 mg dual
therapy
(n=981)
Warfarin triple
therapy
(n=981)
3
5
3
0
2
5
2
0
1
5
1
0
5
0
15.4
%
26.9
%
HR: 0.52 (95% CI:
0.42–0.63)
P<0.0001
Dabigatran
150 mg dual
therapy
(n=763)
Warfarin triple
therapy
(n=764)
20.2
%
25.7
%
HR: 0.72 (95% CI:
0.58–0.88)
P=0.002
Patientswithoutcomeevent(%)
ARR:
11.5%
ARR:
5.5%
Dabigatran2
RE-DUAL PCI results are now published
CONCLUSIONS
Among patients with atrial fibrillation who had undergone PCI, the risk of
bleeding was lower among those who received dual therapy with dabigatran
and a P2Y12 inhibitor than among those who received triple therapy with
warfarin, a P2Y12 inhibitor, and aspirin. Dual therapy was noninferior to triple
therapy with respect to the risk of thromboembolic events.
Oral dabigatran etexilate was as effective as enoxaparin in reducing the risk of venous
thromboembolism after total hip replacement surgery, with a similar safety profile.
Extended prophylaxis with oral dabigatran 220 mg once-daily was as effective as subcutaneous
enoxaparin 40 mg once-daily in reducing the risk of VTE after total hip arthroplasty, and
superior to enoxaparin for reducing the risk of major VTE. The risk of bleeding and safety
profiles were similar.
Dabigatran etexilate (220 mg or 150 mg) was at least as effective and with a similar safety profile
as enoxaparin for prevention of VTE after total knee-replacement surgery.
Dabigatran, effective compared to once-daily enoxaparin, showed inferior efficacy to the
twice-daily North American enoxaparin regimen, probably because of the latter's more intense
and prolonged dosing.
BACKGROUND
The direct oral thrombin inhibitor dabigatran has a predictable anticoagulant effect and may be an
alternative therapy to warfarin for patients who have acute venous thromboembolism.
RESULTS
A total of 30 of the 1274 patients randomly assigned to receive dabigatran (2.4%), as compared with
27 of the 1265 patients randomly assigned to warfarin (2.1%), had recurrent venous
thromboembolism; the difference in risk was 0.4 percentage points (95% confidence interval [CI],
−0.8 to 1.5; P<0.001 for the prespecified noninferiority margin). The hazard ratio with dabigatran
was 1.10 (95% CI, 0.65 to 1.84). Major bleeding episodes occurred in 20 patients assigned to
dabigatran (1.6%) and in 24 patients assigned to warfarin (1.9%) (hazard ratio with dabigatran, 0.82;
95% CI, 0.45 to 1.48), and episodes of any bleeding were observed in 205 patients assigned to
dabigatran (16.1%) and 277 patients assigned to warfarin (21.9%; hazard ratio with dabigatran, 0.71;
95% CI, 0.59 to 0.85). The numbers of deaths, acute coronary syndromes, and abnormal liver-
function tests were similar in the two groups. Adverse events leading to discontinuation of the
study drug occurred in 9.0% of patients assigned to dabigatran and in 6.8% of patients assigned to
warfarin (P=0.05).
CONCLUSIONS
For the treatment of acute venous thromboembolism, a fixed dose of dabigatran is as effective as
warfarin, has a safety profile that is similar to that of warfarin, and does not require laboratory
monitoring.
For the treatment of acute venous thromboembolism, a fixed dose of dabigatran is
as effective as warfarin, has a safety profile that is similar to that of warfarin, and
does not require laboratory monitoring.
Dabigatran has similar effects on VTE recurrence and a lower risk of bleeding
compared with warfarin for the treatment of acute VTE.
Dabigatran was effective in the extended treatment of venous
thromboembolism and carried a lower risk of major or clinically relevant
bleeding than warfarin but a higher risk than placebo.
Dabigatran2
Dabigatran2
Dabigatran2
• After an average follow-up of 16 months, 11.1 percent of patients
receiving dabigatran experienced one or more primary efficacy
endpoint events compared with 15.2 percent of patients on placebo,
for a 28 percent reduction in risk for patients on dabigatran.
• Analysis of the individual efficacy endpoints showed that patients
on dabigatran had a statistically significant 80 percent reduced risk
of nonhemorrhagic stroke than those receiving placebo although the
absolute event rates were low (2 vs. 10 strokes).
• Patients receiving dabigatran were 20 percent less likely to die from
a cardiovascular cause, 20 percent less likely to have an MI, 30
percent less likely to have an amputation and 53 percent less likely
to have a venous thromboembolism.
• However, none of these individual differences were statistically
significant.
• More patients receiving dabigatran experienced lower
gastrointestinal tract bleeding and minor bleeding compared with
patients receiving placebo.
• Most patients (98.9 percent) completed follow-up but 45.3 percent
of those on dabigatran discontinued the drug (14 percent because of
a major complication).
Assessing anticoagulant effect
No clearly defined mechanism by which to
determine if NOACs are working effectively in
individual patients making compliance difficult to
assess
For patients on warfarin, INR can be monitored to
ensure patient is within therapeutic range and
compliant with treatment
Monitoring anticoagulant effect of dabigatran
 Need not to assess regularly (ex. In the setting of
emergency surgery)
 In emergency most accessible tests are
1. TCT
2. aPTT
 If the TCT is normal, it is safe to assume that the level
of dabigatran is very low and that the patient’s risk of
bleeding development is similar to that of other
patients undergoing the procedure
Effects on coagulation tests
Dabigatran
• APTT and TT prolonged
NOT ACCURATE MEASURE OF
ANTICOAGULATION
• D-dimers lowered!
• Haemoclot Thrombin
Inhibition
• TIMING of test!
Rivaroxaban
• PT prolonged
(Do not use INR)
NOT ACCURATE MEASURE OF
ANTICOAGULATION
• D-dimers lowered!
• Anti-Xa specific for
Rivaroxaban
• TIMING of test!
Converting pts from or to Warfarin
 From warfarin to dabigatran
 Stop warfarin & start dabigatran once INR fall below 2
 From dabigatran to warfarin
 Adjust the starting time of warfarin based on creatinine clearance
CrCL (ml/min) Days before stopping
dabigatran
> 50 3 days
50 - 30 2 days
30 - 15 1 day
< 15 or dialysis not recommended
Converting pts from or to parenteral anticoagulants
From parenteral anticoagulants to dabigatran
 Intermittent parenteral anticoagulant
 Start dabigatran 0-2 hrs before next dose
 Continuous parenteral anticoagulant (e.g. UFH)
 Start dabigatran at the time of stopping parenteral
anticoagulant
 From dabigatran to parenteral anticoagulants
 Wait for 12 hrs (CrCl> 30 ml/min) or 24 hrs (CrCl< 30 ml/min)
after last dose of dabigatran before starting parenteral
anticoagulant
Invasive procedures-elective
• Discontinuation may be required depending
on bleeding risk/ type of procedure.
• Timing of discontinuation depends on CrCl
• SPCs provide specific information
Dabigatran in pts planned for elective surgery
 If possible, stop dabigatran 1-2 days before (CrCl> 50
ml/min) or 3-5 days before (CrCl< 50 ml/min)
invasive or surgical procedures.
 Longer periods may be considered if pt undergoing
1. Major surgery
2. Spinal puncture
3. Placement of spinal or epidural catheter or port
Unplanned surgery
Problems if patients on NOACs require
unplanned surgery or procedures; omit
dabigatran dose prior to the procedure;
stop rivaroxaban 24 hours prior to
intervention
Patients requiring emergency surgery can
have the anticoagulant effects of warfarin
reversed with dried prothrombin complex
and intravenous vitamin K1
Postoperative management
 It depends almost exclusively on the postoperative risk
of bleeding
 Procedures with with good hemostasis shortly after the
end of the procedure, resumption on same evening can
be done (i.e. minimum of 4 to 6 hours after surgery)
starting with a half dose (75 mg) for the first dose, and
thereafter the usual maintenance dose.
 For major abdominal surgery or urologic surgery with
incomplete hemostasis, resumption should be delayed
until there is no drainage or other evidence of active
bleeding
Cardioversion
Patients can stay on dabigatran and
warfarin while being cardioverted
No data on rivaroxaban in cardioversion
Drug interaction
 Concomitant use with P-glycoprotein inducers e.g.
rifampin, st. john’s wort reduces its anticoagulant
effect while inhibitors (e.g. amiodarone, verapamil &
clarithromycin) can increase its plasma level
 No other drug interactions are noted.
Contraindication
“Recently the FDA added a contraindication to the dabigatran
label against using the drug in patients with mechanical heart
valves” [12/19/2012 - Drug Safety Communication - FDA]
Based on
A clinical trial in Europe (the RE-ALIGN trial) was recently
stopped because dabigatran (Pradaxa) users were more likely to
experience strokes, heart attacks, and blood clots forming on the
mechanical heart valves than those were on warfarin. There was
also more bleeding after valve surgery in the Pradaxa users than
in the warfarin users.
• Risk of MI
The standard dose of dabigatran (150mg
twice a day) was associated with a small but
significant increase in MI; for every 476
people on dabigatran standard dose (150mg
twice daily), one additional MI was observed
No. needed to harm (NNH) 476
vs (NNT 172)
Avoid dabigatran if high risk of coronary
heart disease
Dabigatran2
Risk of bleeding
Dabigatran: less major bleeding on lower dose compared to warfarin
Rivaroxaban: more nose bleeds and haematuria, less intracranial
haemorrhage, less fatal bleeding compared to warfarin
Dabigatran2
Dabigatran2
Dabigatran2
Dabigatran2
Dabigatran2
Dabigatran2
Dabigatran2
Dabigatran2
Dabigatran2
Dabigatran2
Dabigatran2
Dabigatran2
Dabigatran2
Dabigatran2
Dabigatran2
Dabigatran2
THANK YOU

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Dabigatran2

  • 2. Attributes Of The Ideal Anticoagulant Oral administration Rapid onset of action/rapid offset of action Wide therapeutic range Predictable therapeutic effect with fixed or weight- based dosing
  • 3. No monitoring required (but the ability to monitor if desired) Well defined pharmacokinetics in presence of renal or hepatic disease Easily reversible Cost effective
  • 4. Oral Anticoagulants  Vitamin K Antagonists ( Coumarins ) : Warfarin, Acinocoumarol ( Acitrom )  AntiThrombin Agents : Dabigatran, Ximelagatran  Anti Xa Agents : Rivaroxaban, Apixaban, Edoxaban, Betrixaban, Letaxaban,Darexaban (Discontinued from September 2011), Eribaxaban
  • 8. Warfarin  Most Commonly used oral anticoagulant.  It is a water soluble Vitamin K antagonist.  It interferes with the synthesis of Vitamin K dependent clotting proteins which include Factors II, VII, IX , X. It also impairs synthesis of Vitamin K dependent anticoagulant proteins C and S.
  • 9. 8. Efficacy is dependent upon infrastructure  Time in therapeutic range (TTR) is associated with improved safety and efficacy  TTR is improved with AC management programs  TTR is greater in countries with more sophisticated health care infrastructure
  • 10. How Often to Check INR  In patients with stable Warfarin dosing INR should be checked every 3 weeks.  More frequent INR testing will be required with addition of new drugs due to interactions.  Self monitored and self guided therapy is better for educated patients.
  • 11. What's Wrong With Warfarin? Narrow therapeutic range Slow onset of action Slow offset of action (long duration of action, long elimination half life) Multiple drug and dietary interactions Monitoring required to maintain in therapeutic range
  • 12. Limitations of Vitamin K antagonist therapy
  • 13. How Good Is Acenocumarol…?  Warfarin is employed more frequently than acenocoumarol because of its longer half-life (36 h), theoretically providing more stable anticoagulation, and avoiding factor VII fluctuations that potentially occur during acenocoumarol treatment (half-life 10 h).
  • 14. Acenocoumarol: A Review of Anticoagulant Efficacy and Safety : JAPI Feb 2016
  • 15. Overall Advantages Of Acenocumarol  Rapid onset of action  The effect lasts for 15-20 hours.  Less dependence on CYP2C9 for metabolism compared to warfarin  Better anticoagulation stability than warfarin  Rapid reversal of anticoagulant action with relatively small amounts of vitamin K17
  • 16. Newer Direct Oral Anticoagulants  Rapid onset of Action  Half lives that permit once or twice daily action.  Given in fixed doses without routine monitoring of coagulation.  Antidotes now available for Induced bleeding.
  • 17. Dabigatran  Competitive direct thrombin inhibitor.  Inhibits both free and clot bound thrombin as well as thrombin induced platelet aggregation.  Substrate of P glycoprotein but no significant drug interactions.  Half life is 12 – 17 hours.  Bioavailability is 6.5% and 80% of drug is excreted by the kidneys.
  • 18.  Pharmacokinetics:  After oral administration, dabigatran etexilate is rapidly absorbed.  It get rapidly & completely converted to dabigatran (active form in plasma)  Peak plasma concentration reached in 0.5 – 2 hrs  T1/2 is 15-17 hours  90% of excreted unchanged in urine. So dose reduction required in moderate renal impairment & is contraindicated in severe renal impairment.
  • 19.  Minimal metabolism of dabigatran by CYP3A4 enzymes is clinically insignificant  No dose modification required in hepatic impairment  Dabigatran is also a substrate for P- glycoprotein ( a trans-membrane pump expelling drugs out of cell). So P- glycoprotein inhibitors (e.g. amiodarone, verapamil & clarithromycin) can increase whereas inducers (e.g. rifampicin, st. john’s wort) may reduce dabigatran level in plasma.
  • 20. Dosing  For prevention of Stroke in Non Valvular AF dose is 150 mg BD  If Creatinine clearance is 15 – 30 ml/min, dose is reduced to 75 mg BD.  Now approved for VTE also: Patients should initially receive a minimum of 5 day course of parenteral anticoagulant before starting Dabigatran at 150 mg BD.  Qualitative assessment of anticoagulant activity is by APTT.  Quantitative assessment by Dilute Thrombin clotting time.
  • 23. SPIL/Dr Borgharkar Valvular AF mainly refers to AF patients that have either rheumatic valvular disease (predominantly mitral stenosis) or mechanical heart valves.
  • 36. Stroke or Systemic Embolism 0.50 0.75 1.00 1.25 1.50 Dabigatran 110 vs. Warfarin Dabigatran 150 vs. Warfarin Non-inferiority p-value <0.001 <0.001 Superiority p-value 0.34 <0.001 Margin = 1.46 HR (95% CI) Warfarin betterDabigatran better
  • 37. Ischemic/Unspecified Stroke D 110 mg vs. Warfarin D 150 mg vs. Warfarin RR =1.11 95% CI = 0.89-1.40 P = 0.35 RR = 0.76 95% CI = 0.60-0.98 P = 0.03 Years of Follow-up CumulativeHazardRates 0.00.020.040.060.08 0 0.5 1.0 1.5 2.0 2.5 Dabigatran110 Dabigatran150 Warfarin
  • 38. Hemorrhagic Stroke D 110 mg vs. Warfarin D 150 mg vs. Warfarin RR = 0.31 95% CI =0.17-0.56 P <0.001 RR =0.26 95% CI =0.14-0.49 P <0.001 Years of Follow-up CumulativeHazardRates 0.00.010.020.030.04 0 0.5 1.0 1.5 2.0 2.5 Dabigatran110 Dabigatran150 Warfarin
  • 40. Conclusions  Dabigatran 150 mg significantly reduced stoke compared to warfarin with similar risk of major bleeding  Dabigatran 110 mg had a similar rate of stroke as warfarin with significantly reduced major bleeding  Both doses markedly reduced intra-cerebral, life- threatening and total bleeding  Dabigatran had no major toxicity, but did increase dyspepsia and GI bleeding
  • 41. Conclusions  Both Dabigatran doses offer advantages over warfarin  Dabigatran 150 is more effective and dabigatran 110 has a better safety profile  There is potential to tailor therapy to individual patient characteristics
  • 51. Recent ACS: STEMI, NSTEMI, UA No increased bleeding risk, No warfarin, No ICH, No prior stroke if on ASA + Thienopyridine Stabilized 1-7 Days Post-Index Event PRIMARY ENDPOINT: EFFICACY: CV Death, MI, Stroke* (Ischemic + Hemg.) SAFETY: TIMI major bleeding not associated with CABG Event driven trial of 1,002 events in 15,342 patients** RIVAROXABAN 5.0 mg BID N=5,176 ASA + Thieno, n=4,827 ASA, n=349 Stratified by Thienopyridine use at MD Discretion + ASA 75 to 100 mg/day Placebo N=5,176 ASA + Thieno, n=4,821 ASA, n=355 RIVAROXABAN 2.5 mg BID n=5,174 ASA + Thieno, n=4,825 ASA, n=349 * Stroke includes ischemic stroke, hemorrhagic stroke, and uncertain stroke ** 184 subjects were excluded from the efficacy analyses prior to unblinding
  • 52. SUMMARY-EFFICACY • The primary efficacy endpoint of CV death, MI and stroke was reduced when added to standard therapy for both rivaroxaban doses combined, and for the 2.5 and 5.0 mg BID doses separately • CV and all cause death were reduced for both rivaroxaban doses combined, and for the 2.5 mg BID dose in both mITT and ITT analyses
  • 53. SUMMARY-EFFICACY (cont.) • When 2.5 mg PO BID of rivaroxaban was added to ASA + thienopyridine, cardiovascular death was reduced by 38% and all cause death by 36% • One death prevented if 56 patients treated for two years with 2.5 mg BID of Rivaroxaban
  • 54. 2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation
  • 55. RE-DUAL PCI: dual antithrombotic therapy with dabigatran after percutaneous coronary intervention in patients with atrial fibrillation Christopher P. Cannon Deepak L Bhatt, Jonas Oldgren, Gregory YH Lip, Stephen G Ellis, Takeshi Kimura, Michael Maeng, Bela Merkely, Uwe Zeymer, Savion Gropper, Matias Nordaby, Eva Kleine, Ruth Harper, Jenny Manassie, James L Januzzi, Jurrien M ten Berg, Philippe Gabriel Steg and Stefan H Hohnloser On behalf of the steering committee and RE-DUAL PCI investigators
  • 56. Study Design: Multicenter, randomized, open-label trial following a PROBE design R Randomiza tion ≤120 hours post-PCI* 6-month minimum treatment duration with visits every 3 months for the first year, then visits and telephone contact alternating every 3 months and a 1-month post-treatment visit Patients with AF undergoi ng PCI with stenting Dabigatran 150 mg BID + P2Y12 inhibitor Dabigatran 110 mg BID + P2Y12 inhibitor Warfarin (INR 2.0–3.0) + P2Y12 inhibitor + ASA N=27 25 Mean duration of follow-up: ~14 months Dabigatran (110 or 150 mg) P2Y12 inhibitor Warfarin P2Y12 inhibitor 1 month of ASA (BMS) 3 months of ASA (DES) *Study drug should be administered 6 hours after sheath removal and no later than ≤120 hrs post- PCI (≤72 hrs is preferable). PROBE, prospective, randomized, open, blinded end-point; R, randomization; BMS, bare metal stent; DES, drug- eluting stent. ClinicalTrials.gov: NCT02164864;
  • 57. Full analysis set presented. HRs and Wald CIs from Cox proportional-hazard model. For the dabigatran 110 mg vs warfarin comparison, the model is stratified by age, non-elderly vs elderly (<70 or ≥70 in Japan and <80 or ≥80 years old elsewhere). For the dabigatran 150 mg vs warfarin comparison, an unstratified model is used, elderly patients outside the USA are excluded. Non- inferiority P value is one sided (alpha=0.025). Wald two-sided P value from (stratified) Cox Primary Endpoint: Time to first ISTH major or clinically relevant non-major bleeding event Probabilityofevent(%) 0 0 9 0 18 0 54 0 63 0 72 0 270 360 450 Time to first event (days) 4 0 3 5 3 0 2 5 2 0 1 5 1 0 5 Warfarin triple therapy Dabigatran 110 mg dual therapy HR: 0.52 (95% CI: 0.42–0.63) Non-inferiority P<0.0001 P<0.0001 0 9 0 18 0 54 0 63 0 72 0 270 360 450 Time to first event (days) 4 0 3 5 3 0 2 5 2 0 1 5 1 0 5 0 Dabigatran 150 mg dual therapy Warfarin triple therapy HR: 0.72 (95% CI: 0.58–0.88) Non-inferiority P<0.0001 P=0.002
  • 58. Wald two-sided P value from (stratified) Cox proportional-hazard model (alpha=0.05). ARR, absolute risk reduction Primary endpoint: ISTH major or clinically relevant non-major bleeding event Dabigatran 110 mg dual therapy (n=981) Warfarin triple therapy (n=981) 3 5 3 0 2 5 2 0 1 5 1 0 5 0 15.4 % 26.9 % HR: 0.52 (95% CI: 0.42–0.63) P<0.0001 Dabigatran 150 mg dual therapy (n=763) Warfarin triple therapy (n=764) 20.2 % 25.7 % HR: 0.72 (95% CI: 0.58–0.88) P=0.002 Patientswithoutcomeevent(%) ARR: 11.5% ARR: 5.5%
  • 60. RE-DUAL PCI results are now published CONCLUSIONS Among patients with atrial fibrillation who had undergone PCI, the risk of bleeding was lower among those who received dual therapy with dabigatran and a P2Y12 inhibitor than among those who received triple therapy with warfarin, a P2Y12 inhibitor, and aspirin. Dual therapy was noninferior to triple therapy with respect to the risk of thromboembolic events.
  • 61. Oral dabigatran etexilate was as effective as enoxaparin in reducing the risk of venous thromboembolism after total hip replacement surgery, with a similar safety profile.
  • 62. Extended prophylaxis with oral dabigatran 220 mg once-daily was as effective as subcutaneous enoxaparin 40 mg once-daily in reducing the risk of VTE after total hip arthroplasty, and superior to enoxaparin for reducing the risk of major VTE. The risk of bleeding and safety profiles were similar.
  • 63. Dabigatran etexilate (220 mg or 150 mg) was at least as effective and with a similar safety profile as enoxaparin for prevention of VTE after total knee-replacement surgery.
  • 64. Dabigatran, effective compared to once-daily enoxaparin, showed inferior efficacy to the twice-daily North American enoxaparin regimen, probably because of the latter's more intense and prolonged dosing.
  • 65. BACKGROUND The direct oral thrombin inhibitor dabigatran has a predictable anticoagulant effect and may be an alternative therapy to warfarin for patients who have acute venous thromboembolism. RESULTS A total of 30 of the 1274 patients randomly assigned to receive dabigatran (2.4%), as compared with 27 of the 1265 patients randomly assigned to warfarin (2.1%), had recurrent venous thromboembolism; the difference in risk was 0.4 percentage points (95% confidence interval [CI], −0.8 to 1.5; P<0.001 for the prespecified noninferiority margin). The hazard ratio with dabigatran was 1.10 (95% CI, 0.65 to 1.84). Major bleeding episodes occurred in 20 patients assigned to dabigatran (1.6%) and in 24 patients assigned to warfarin (1.9%) (hazard ratio with dabigatran, 0.82; 95% CI, 0.45 to 1.48), and episodes of any bleeding were observed in 205 patients assigned to dabigatran (16.1%) and 277 patients assigned to warfarin (21.9%; hazard ratio with dabigatran, 0.71; 95% CI, 0.59 to 0.85). The numbers of deaths, acute coronary syndromes, and abnormal liver- function tests were similar in the two groups. Adverse events leading to discontinuation of the study drug occurred in 9.0% of patients assigned to dabigatran and in 6.8% of patients assigned to warfarin (P=0.05). CONCLUSIONS For the treatment of acute venous thromboembolism, a fixed dose of dabigatran is as effective as warfarin, has a safety profile that is similar to that of warfarin, and does not require laboratory monitoring. For the treatment of acute venous thromboembolism, a fixed dose of dabigatran is as effective as warfarin, has a safety profile that is similar to that of warfarin, and does not require laboratory monitoring.
  • 66. Dabigatran has similar effects on VTE recurrence and a lower risk of bleeding compared with warfarin for the treatment of acute VTE.
  • 67. Dabigatran was effective in the extended treatment of venous thromboembolism and carried a lower risk of major or clinically relevant bleeding than warfarin but a higher risk than placebo.
  • 71. • After an average follow-up of 16 months, 11.1 percent of patients receiving dabigatran experienced one or more primary efficacy endpoint events compared with 15.2 percent of patients on placebo, for a 28 percent reduction in risk for patients on dabigatran. • Analysis of the individual efficacy endpoints showed that patients on dabigatran had a statistically significant 80 percent reduced risk of nonhemorrhagic stroke than those receiving placebo although the absolute event rates were low (2 vs. 10 strokes). • Patients receiving dabigatran were 20 percent less likely to die from a cardiovascular cause, 20 percent less likely to have an MI, 30 percent less likely to have an amputation and 53 percent less likely to have a venous thromboembolism. • However, none of these individual differences were statistically significant. • More patients receiving dabigatran experienced lower gastrointestinal tract bleeding and minor bleeding compared with patients receiving placebo. • Most patients (98.9 percent) completed follow-up but 45.3 percent of those on dabigatran discontinued the drug (14 percent because of a major complication).
  • 72. Assessing anticoagulant effect No clearly defined mechanism by which to determine if NOACs are working effectively in individual patients making compliance difficult to assess For patients on warfarin, INR can be monitored to ensure patient is within therapeutic range and compliant with treatment
  • 73. Monitoring anticoagulant effect of dabigatran  Need not to assess regularly (ex. In the setting of emergency surgery)  In emergency most accessible tests are 1. TCT 2. aPTT  If the TCT is normal, it is safe to assume that the level of dabigatran is very low and that the patient’s risk of bleeding development is similar to that of other patients undergoing the procedure
  • 74. Effects on coagulation tests Dabigatran • APTT and TT prolonged NOT ACCURATE MEASURE OF ANTICOAGULATION • D-dimers lowered! • Haemoclot Thrombin Inhibition • TIMING of test! Rivaroxaban • PT prolonged (Do not use INR) NOT ACCURATE MEASURE OF ANTICOAGULATION • D-dimers lowered! • Anti-Xa specific for Rivaroxaban • TIMING of test!
  • 75. Converting pts from or to Warfarin  From warfarin to dabigatran  Stop warfarin & start dabigatran once INR fall below 2  From dabigatran to warfarin  Adjust the starting time of warfarin based on creatinine clearance CrCL (ml/min) Days before stopping dabigatran > 50 3 days 50 - 30 2 days 30 - 15 1 day < 15 or dialysis not recommended
  • 76. Converting pts from or to parenteral anticoagulants From parenteral anticoagulants to dabigatran  Intermittent parenteral anticoagulant  Start dabigatran 0-2 hrs before next dose  Continuous parenteral anticoagulant (e.g. UFH)  Start dabigatran at the time of stopping parenteral anticoagulant  From dabigatran to parenteral anticoagulants  Wait for 12 hrs (CrCl> 30 ml/min) or 24 hrs (CrCl< 30 ml/min) after last dose of dabigatran before starting parenteral anticoagulant
  • 77. Invasive procedures-elective • Discontinuation may be required depending on bleeding risk/ type of procedure. • Timing of discontinuation depends on CrCl • SPCs provide specific information
  • 78. Dabigatran in pts planned for elective surgery  If possible, stop dabigatran 1-2 days before (CrCl> 50 ml/min) or 3-5 days before (CrCl< 50 ml/min) invasive or surgical procedures.  Longer periods may be considered if pt undergoing 1. Major surgery 2. Spinal puncture 3. Placement of spinal or epidural catheter or port
  • 79. Unplanned surgery Problems if patients on NOACs require unplanned surgery or procedures; omit dabigatran dose prior to the procedure; stop rivaroxaban 24 hours prior to intervention Patients requiring emergency surgery can have the anticoagulant effects of warfarin reversed with dried prothrombin complex and intravenous vitamin K1
  • 80. Postoperative management  It depends almost exclusively on the postoperative risk of bleeding  Procedures with with good hemostasis shortly after the end of the procedure, resumption on same evening can be done (i.e. minimum of 4 to 6 hours after surgery) starting with a half dose (75 mg) for the first dose, and thereafter the usual maintenance dose.  For major abdominal surgery or urologic surgery with incomplete hemostasis, resumption should be delayed until there is no drainage or other evidence of active bleeding
  • 81. Cardioversion Patients can stay on dabigatran and warfarin while being cardioverted No data on rivaroxaban in cardioversion
  • 82. Drug interaction  Concomitant use with P-glycoprotein inducers e.g. rifampin, st. john’s wort reduces its anticoagulant effect while inhibitors (e.g. amiodarone, verapamil & clarithromycin) can increase its plasma level  No other drug interactions are noted.
  • 83. Contraindication “Recently the FDA added a contraindication to the dabigatran label against using the drug in patients with mechanical heart valves” [12/19/2012 - Drug Safety Communication - FDA] Based on A clinical trial in Europe (the RE-ALIGN trial) was recently stopped because dabigatran (Pradaxa) users were more likely to experience strokes, heart attacks, and blood clots forming on the mechanical heart valves than those were on warfarin. There was also more bleeding after valve surgery in the Pradaxa users than in the warfarin users.
  • 84. • Risk of MI The standard dose of dabigatran (150mg twice a day) was associated with a small but significant increase in MI; for every 476 people on dabigatran standard dose (150mg twice daily), one additional MI was observed No. needed to harm (NNH) 476 vs (NNT 172) Avoid dabigatran if high risk of coronary heart disease
  • 86. Risk of bleeding Dabigatran: less major bleeding on lower dose compared to warfarin Rivaroxaban: more nose bleeds and haematuria, less intracranial haemorrhage, less fatal bleeding compared to warfarin