1. Pocket Guide to Anticoagulation in AF & Dual Antiplatelet Therapy in ACS Rumi Jaumdally 2015
This brief presentation will summarise the recently published NICE clinical guidelines on the management of atrial fibrillation. We will not go through the whole guideline since this would take too long , but rather focus on those elements that are relevant to the promotion of Xarelto.
Many of the recommendations in the 2006 guidelines are still there and those elements that are new for 2014 are highlighted in the guideline.
RJ 2015

2. HAS-BLED Bleeding Risk Score CHA2DS2VASc Stroke Risk Score
AF Risk vs Benefit
HAS-BLED Bleeding Risk Score
CHA2DS2VASc Stroke Risk Score
Notice that in line with all other recent guidelines, CHADSVASc is being recommended as the tool for stroke risk assessment and not CHADS.
This is irrespective of the type of AF and should also be applied to patients who are back in sinus rhythm after cardioversion.

3. Coagulation pathway: NOACX IX
IXa
Thrombin Xa
Fibrinogen
Fibrin
Prothrombin
VII TF
VIIa
VKA
VKA
Initiation
Inactive Factor
Active Factor
Transformation
Catalysis
Propagation
VKA II
Direct Factor Xa inhibition
Rivaroxaban/
Apixaban/
Edoxaban
Targets for anticoagulants
This slide shows a simplified model of the coagulation pathway
Different anticoagulants target different points in the coagulation pathway
Factor Xa inhibitors
Factor Xa is an attractive target for anticoagulation because it plays a key role in the coagulation process and no thrombin can be generated without Factor Xa
Several direct Factor Xa inhibitors are either licensed or in development. These include rivaroxaban, apixaban, edoxaban and betrixaban1
Direct thrombin inhibitors
Thrombin converts fibrinogen to fibrin and plays a key role in clot formation. It is also a potent activator of platelets
Direct thrombin inhibitors are able to inhibit free and clot-bound thrombin2 and block the final step of the coagulation cascade
The direct thrombin inhibitor ximelagatran (withdrawn from the market owing to concerns of severe liver toxicity during long-term use2) provided proof-of-principle for new oral anticoagulants without routine coagulation monitoring
Dabigatran is the only drug in this class to be available for clinical use for the prevention of thrombosis in hip and knee surgery and the prevention of stroke and systemic embolism in patients with AF3
VKAs
VKAs, such as warfarin, target multiple coagulation factors by inhibiting vitamin K-dependent carboxylation of Factors II, VII, IX and X, leading to reduced coagulant activity
Abbreviation
TF, tissue factor
References
Spyropoulos AC et al. Expert Opin Investig Drugs 2007;16:431–440
IIa
Direct Factor IIa inhibition
Dabigatran
Spyropoulos AC et al. Expert Opin Investig Drugs 2007;16:431–440 (adapted from)

4. Anticoagulation pathway

5. NOAC Pointers Specific Patient Characteristic High Risk of bleeding eg
HAS-BLED >3, Very old
Consider agent/Dose with lowest incidence of bleeding
Dabi 110, Edox, Apix
High Risk of Ischaemic Stroke, low Bleeding Risk
Consider agent/Dose with the best reduction of ischaemic stroke
Dabi 150
Previous Stroke (secondary prevention)
Consider Best Investigated Agent for greatest reduction of 2nd Stroke
Riva, Apix, Edox
CAD, Previous MI or High Risk for ACS-MI
Consider Agent least dependent on renal function
Apix, Edox 30,
Riva 15
Concomitant CYP Inhibitors
Consider Agents with no/little metabolism via CYP system
Dabi, Edox
Patient Preference
Consider once Daily Formulation
Riva, Edox

6. Platelet activation mechanisms
Storey RF. Lancet 2009;373:

7. The evolution of antiplatelet therapy
Aspirin
Ticlopidine
(not available in the UK)
Clopidogrel
Dual anti-platelet therapy
Prasugrel
1980s
1991
1998
2000’s
2009
2011
Treatment comparison
ASA vs Placebo
ISIS-21
ASA vs Clopidogrel
CAPRIE2
ASA + placebo vs Clopidogrel + ASA (UA/NSTEMI)
CURE3
ASA + placebo vs Clopidogrel + ASA (STEMI)
COMMIT4
CLARITY-TIMI 285
Clopidogrel + ASA vs Prasugrel + ASA (scheduled PCI)
TRITON-TIMI 386
RRR
(primary endpoint)
23% (vascular death)
8.7%
(vascular death,
stroke + MI)
20%
(CV death, non-fatal MI + stroke)
9.2% (death, reinfarction or stroke)
36%
(occluded infarct
related artery,
death, + recurrent MI)
19%
(CV death, non-fatal
MI + stroke)
ARR (primary endpoint)
2.4% (vascular death)
0.5% (vascular death,
2.1% (CV death, non-fatal MI + stroke)
0.9% (death, reinfarction or stroke)
6.7% (occluded infarct
2.2% (CV death, non-fatal
Speaker Notes
The slide illustrates the evolution of antiplatelet therapy and corresponding relative risk reduction (RRR) and absolute risk reduction (ARR) in primary endpoint in pivotal trials.
ISIS-2 (Second International Study of Infarct Survival) collaborative group: (n = 17,187) patients with suspected acute MI were randomised, with placebo control, between: a 1-hour intravenous infusion of streptokinase; one month of 160 mg/d aspirin; both active treatments; or neither.1
CAPRIE (Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events): (n = 19,185) patients were randomised to clopidogrel (75 mg/d) or aspirin (325 mg/d).2
CURE (Clopidogrel in Unstable angina to prevent Recurrent Events): (n = 12,562) patients with UA/NSTEMI randomised to clopidogrel (300 mg load, maintenance 75 mg/d) or placebo (6,303 patients) in addition to aspirin for 3-12 months.3
COMMIT (ClOpidogrel and Metoprolol in Myocardial Infarction Trial): (n = 45,852) patients with suspected acute MI were randomised to clopidogrel (75 mg/d) or placebo, in addition to aspirin 162 mg/d.4
CLARITY-TIMI (CLopidogrel as Adjunctive ReperfusIon TherapY – Thrombolysis In Myocardial Infarction): (n = 3,491) patients with STEMI were randomised to clopidogrel (300 mg load, maintenance 75 mg/d) or placebo. in addition to aspirin ( mg load, maintenance mg/d).5
TRITON-TIMI (TRial to assess Improvement in Therapeutic Outcomes by optimising platelet iNhibition with prasugrel – Thrombolysis In Myocardial Infarction): (n = 13,608) patients with moderate-to-high-risk ACS with scheduled PCI were randomised to prasugrel (60 mg load, maintenance 10 mg/d) or clopidogrel (300 mg load, maintenance 75 mg/d), in addition to aspirin ( mg/d).6
It is also important to note only two antiplatelet trials evaluating the above agents have demonstrated an absolute reduction in mortality, and both of these were against placebo:
ISIS-2 – performed nearly a quarter of a century ago, compared aspirin with placebo1
COMMIT – compared clopidogrel with placebo4
No mortality benefit was seen in the TRITON-TIMI 38 trial comparing prasugrel with clopidogrel6
Notes references
ISIS-2. Lancet 1998;2:
The CAPRIE Steering Committee. Lancet 1996; 348:
The CURE Investigators. N Engl J Med 2001;345:
Chen ZM, et al. Lancet 2005;366:
Sabatine MS, et al. N Engl J Med 2005;352:
Wiviott SD, et al. N Engl J Med 2007;357:
ARR = absolute risk reduction; RRR = relative risk reduction
ISIS-2. Lancet 1998;2:
The CAPRIE Steering Committee. Lancet 1996; 348:
The CURE Investigators. N Engl J Med 2001;345:
Chen ZM, et al. Lancet 2005;366:
Sabatine MS, et al. N Engl J Med 2005;352:
Wiviott SD, et al. N Engl J Med 2007;357:

8. Ticagrelor treatment also significantly reduced all-cause mortality
Incidence of all-cause mortality* in the PLATO study (secondary endpoint) 1,2 6
5.9
Ticagrelor significantly reduced the primary endpoint, a composite of cardiovascular death, myocardial infarction or stroke, at 1 year compared with clopidogrel (ARR 1.9%; RRR 16%; p<0.001)
All cause mortality was a secondary endpoint of the PLATO study (nominal p<0.001)1
Mortality benefit was seen consistently across subgroups, including those defined by management strategy (CABG, planned invasive or planned non-invasive)3-5
There was no difference in the incidence of stroke with ticagrelor vs clopidogrel (p=0.22) 1
Clopidogrel (n=9291)
4.5 4
Cumulative incidence (%)
Ticagrelor (n=9333) 2
ARR = 1.4%
RRR = 22%
Speaker Notes
In addition to the primary endpoint, the secondary endpoints of MI alone and CV death alone were significantly reduced.1 Total mortality achieved nominal significance.
To address the issue of multiple testing, a hierarchical test sequence was planned. The secondary composite efficacy end points were tested individually, until the first non-significant difference was found between the two treatment groups.1
It is important to note that the reduction in CV and total death is greater than that seen for the reduction in MI (16%), indicating that the reduction in mortality is not exclusively attributed to the reduction in MI.1
The non-significant effect on stroke is not surprising since both prasugrel and clopidogrel have previously had no significant effect on stroke.
There was a reduction in total mortality with ticagrelor compared with clopidogrel treatment; 22% RRR, 1.4% ARR, NNT 72.
The only other antiplatelet trials to demonstrate a mortality benefit have been ISIS-2 and COMMIT; both these benefits were against placebo.2,3
Notes references
Wallentin L, et al. N Engl J Med 2009; 361:
ISIS-2. Lancet 1998;2:
Chen ZM, et al. Lancet 2005;366:
nominal p<0.001 2 4 6 8 10 12
Months after randomisation
ARR = absolute risk reduction; RRR = re;lative risk reduction.
Wallentin L, et al. N Engl J Med 2009;361:
Data on file, AstraZeneca, BRIL/006/NOVA2010
Held C et al. J Am Coll Cardiol 2011; 57(6):762-84
Cannon CP et al. Lancet 2010; 375:283-93
James SK et al BMJ 2011;342:d3527