1. Harry Potter and the new oral anticoagulants
V. Malavasi
G. Biondi Zoccai

2. Background
Last published atrial fibrillation (AF) guidelines show as crucial point oral anticoagulants (OAC) Rx before rhythm management Aspirin and other antiplatelet Rx are simple to take but have lower efficacy in preventing stroke or systemic embolism (SE) than vitamin K antagonists (VKA)
1. ACC/AHA/ESC guidelines: Fuster V et al. Circulation 2006;114:e257–354

3. Background
Warfarin is very effective at preventing stroke in patients with AF. Warfarin has several limitations, including drug and food interactions, a narrow therapeutic range, need for anticoagulation monitoring, and bleeding. Due to those caveats many pts remain untreated with VKA. Pts in VKA live about half of their time out of optimal INR range.
Turpie AG. Eur Heart J 2008;29:155–65; Khoo CW et al. Int J Clin Pract 2009;63:630–41
Baker WL J Manag Care Pharm 2009;15:

4. Background

5. Background
Baker WL J Manag Care Pharm 2009;15:

6. Background

7. Background
It is unclear whether they do really represent a favorable breakthrough in the management of AF. In addition, the practicing physician remains uncertain about the relative strengths and weaknesses of each of these new treatment options as no direct comparison among them is available nor is foreseeable.

8. Endpoints Efficacy: Safety Tolerability Stroke or SE Death
Major bleeding
Tolerability
Drug discontinuation

9. Methods =

10. Systematic reviews and pair-wise meta-analyses
What is a systematic review?
A systematic appraisal of the methodological quality, clinical relevance and consistency of published evidence on a specific clinical topic in order to provide clear suggestions for a specific healthcare problem
What is a pair-wise meta-analysis?
A quantitative synthesis that, preserving the identity of individual studies comparing two treatments, tries to provide an estimate of the overall effect of an intervention in comparison to the other

11. Methods for pair-wise meta-analysis
OR (A vs C)
TREATMENT A
TREATMENT C
TREATMENT A
TREATMENT C
TREATMENT A
TREATMENT C
TREATMENT A
TREATMENT C
TREATMENT A
TREATMENT C
TREATMENT A
TREATMENT C
Difference in effect beween treatment A vs C is computed by means of a weighted average of differences stemming from individual studies

12. Methods for indirect meta-analysis
OR (A vs C)
TREATMENT A
TREATMENT C
Ln ORA-B = Ln ORA-C – Ln ORB-C OR
(A vs B)
Var (Ln ORA-B) = Var (Ln ORA-C) – Var (Ln ORB-C)
TREATMENT B
TREATMENT C
OR (B vs C)

13. Methods for network meta-analysis
TREATMENT A
TREATMENT C
OR (A vs C) OR
(A vs B)
TREATMENT B
TREATMENT D
OR (B vs D) OR
(B vs A)
TREATMENT A
TREATMENT D
OR (A vs D)

14. Assumption behind indirect and network meta-analyses

15. A notable example
Psaty BM. JAMA 2003;289:

16. A notable example
Psaty BM. JAMA 2003;289:

17. 7114 citations screened at the title/abstract level:
124 from CENTRAL
6528 from Google Scholar
100 from MEDLINE/PubMed
362 from Scopus
7103 citations excluded because patently not pertinent
13 citations retrieved in full and appraised according to the selection criteria
6 studies excluded because not fulfilling inclusion/exclusion criteria
7 randomized trials finally included in the systematic review and meta-analysis

18. Warfarin Apixaban Rivaroxaban HD dabigatran HD edoxaban LD dabigatran
ARISTOTLE
ARISTOTLE-J
ROCKET AF
Apixaban
Rivaroxaban
Petro
RELY
Chung 2011
Weitz 2010
Petro
RELY
Chung 2011
Weitz 2010
HD dabigatran
HD edoxaban
LD dabigatran
LD edoxaban

21. Main features of included studies
Acronym, year
Region
Drugs tested
Doses of new anticoagulant (mg)
Other antiaggregant drugs and doses (mg)
Petro, 2007
Europe,
North
America
Dabigatran vs warfarin
50, 150, 300; all twice daily
No aspirin, or 81 or 325 mg
Re-LY LD, 2009
Worldwide
110 mg twice
daily
Concomitant use of aspirin (at a dose of <100 mg per day) or other antiplatelet agents was permitted
Re-LY HW, 2009
150 mg twice
Daily
Weitz,
2010
Edoxaban vs
warfarin
30, 60, 120
No restriction about aspirin
ARISTOTLE J, 2011
Asia
Apixaban vs warfarin
2.5; 5; all twice daily
ARISTOTLE, 2011
5 twice daily
No restriction about aspirin lower than 165 mg. Aspirin and clopidogrel together use were exclusion criteria
Rocket AF,
2011
Rivaroxaban vs warfarin 20
Aspirin ≤100 mg monotherapy and thienopyridine monotherapy allowed.
Chung,
30, 60

22. Main features of included studies
Acronym, year
Inclusion criteria
Exclusion criteria
Petro, 2007
AF with CHADS>=1
mitral stenosis, prosthetic heart valves, planned cardioversion, recent (<1 month) myocardial infarction, recent stroke or transient ischemic attack, coronary stent placement within 6 months, any contraindication to or another indication for anticoagulant therapy, major hemorrhage in the past 6 months, glomerular filtration rate <30 ml/min, abnormal liver function, risk of pregnancy, investigational drug use within 30 days, or any other condition that would not allow participation in the study
Re-LY LD, 2009
severe heart-valve disorder, stroke within 14 days or severe stroke within 6 months before screening, a condition that increased the risk of hemorrhage, a creatinine clearance <30 ml per minute, active liver disease, and pregnancy.
Re-LY HW, 2009
Weitz,
2010
AF with CHADS>=2
Women must have been ≥2 years post-menopausal and/or have undergone bilateral oophorectomy. Patients were excluded if they had mitral valve disease, endocarditis, or a mechanical valve; contraindications to anticoagulation therapy, including a known bleeding disorder, recent major bleeding, uncontrolled hypertension, a haemoglobin less than 10.0 g/dl, a platelet count less than 100,000/μl or a white blood cell count less than 3,000/μl; a requirement for ongoing treatment with a thienopyridine; AF secondary to reversible disorders (e.g., thyrotoxicosis); left ventricular aneurysm or atrial myxoma; an estimated life expectancy < 12 months; planned surgery or intervention within the study period; a history of hepatitis B or C or HIV infection; creatinine clearance < 30 ml/minute (min); a cardiac pacemaker or implantable cardioverter-defibrillator; investigational drug treatment (including edoxaban) or device implantation in the last three months, or plan to receive such therapy dur-
ing the study period. impaired hepatic function
ARISTOTLE J, 2011
recent stroke or TIA, valvular heart disease; sick sinus syndrome or severe conduction disturbance; non-cardiogenic stroke requiring ASA >100 mg/day or concomitant ASA and antiplatelet agents; contraindications for warfarin use; severe or refractory hypertension; New York Heart Association class IV heart failure; current thrombocytopenia: alanine aminotransferase or aspartate aminotransferase ≥2 × upper limit of normal; creatinine clearance <25 ml/min by Cockcroft Gault calculation; known or suspected hereditary
bleeding tendencies; and scheduled electrical, pharmacological, or surgical cardioversion during the treatment period

23. Main features of included studies
Acronym, year
Inclusion criteria
Exclusion criteria
ARISTOTLE, 2011
AF with CHADS>=1
AF due to a reversible cause, moderate or severe mitral stenosis, conditions
other than atrial fibrillation that required anticoagulation (e.g., a prosthetic heart valve), stroke within the previous 7 days, a need for aspirin at a dose of >165 mg a day or for both aspirin and clopidogrel, calculated creatinine clearance of <25 ml per minute
Rocket AF,
2011
AF with CHADS>=2
Hemodynamically significant mitral valve stenosis, Prosthetic heart valve; Planned cardioversion (electrical or pharmacological); AF due to a reversible cause, Active endocarditis; Active internal bleeding; Platelet count <90,000/μL at the screening visit; Sustained uncontrolled hypertension; Severe, disabling stroke within 3 months or any stroke within 14 days before the randomization visit; Transient ischemic attack within 3 days before the randomization visit; Indication for anticoagulant therapy for a condition other than atrial fibrillation; Aspirin >100 mg daily; Aspirin in combination with thienopyridines within 5 days before randomization; Intravenous antiplatelets within 5 days before randomization; Fibrinolytics within 10 days before randomization; Systemic treatment with a strong inhibitor or inducer of cytochrome P450 3A4, such as ketoconazole or protease; hemoglobin <10 g/dL at the screening visit; pregnancy or breast-feeding: any other contraindication to warfarin; known HIV infection at time of screening; renal clearance <30 mL/min at the screening visit; known significant liver disease
Chung,
previous valve surgery, contraindication to anticoagulants, known bleeding disorder, conditions associated with high risk of bleeding (e.g. past history of major bleeding; uncontrolled hypertension; uncontrolled diabetes; haemorrhagic disorder; significant thrombocytopenia), ongoing treatment with an antiplatelet agent, AF second ary to other reversible disorders, acute coronary syndrome or revascularisation procedures, stroke, transient ischaemic attack, any major surgery within the previous 30 days, left ventricular aneurysm or atrial myxoma, impaired hepatic function, serum creatinine ≥1.5 mg/dl, women of child-bearing potential without adequate contraception, pregnancy or lactation.

24. Main features of patients
Acronym, year
N. of pts
Paroxysmal AF (%)
HF (%)
Hypertension
Diagnosis (%)
Age (yrs)*
Diabetes
Previous Stroke/TIA
ASA(%)
Petro, 2007
502
22.9
29.3 71
70±8.3 25
17.3 -
Re-LY LD, 2009
12037
32.1
32.2
78.7
71.4±8.6
23.4
19.9
21.1
Re-LY HW, 2009
12098
32.6
31.8
78.9
71.5±8.8
23.1
20.3
19.6
Weitz,
2010
1146
64.9±6.8
49.5
ARISTOTLE J, 2011
222
1.3
83.3 70
27.9
24.3
ARISTOTLE, 2011
18113
15.1
35.5
87.3
70 (63-76)
19.2 31
Rocket AF,
2011
14264
17.5
62.6
90.3
73 (65-78)
40.4
54.9
36.3
Chung,
253 28
65±9 30 24

25. Risk of stroke or systemic embolism Risk of death
Risk of major bleeding
Risk of drug discontinuation

26. Risk of stroke or systemic embolism

27. Risk of death

28. Risk of major bleedings

29. Risk of drug discontinuation

30. Risk of stroke or systemic embolism

31. Risk of death

32. Risk of major bleeding

33. Risk of drug discontinuation

34. Stroke or sistemic embolism
Rivaroxaban
Low-dose edoxaban
High-dose edoxaban
Low-dose dabigatran
High-dose dabigatran
Apixaban
Warfarin 1 2 3 4 5 6 7 8 9 10
2,99
1,91
0,74
3,12
2,28
2,69
3,42

35. Death % 1 2 3 4 5 6 7 8 9 10 Rivaroxaban Low-dose edoxaban
High-dose edoxaban
Low-dose dabigatran
High-dose dabigatran
Apixaban
Warfarin 1 2 3 4 5 6 7 8 9 10
5,21
4,91
2,07
5,68
5,51
5,56
6,21 %

36. Major bleeding % 1 2 3 4 5 6 7 8 9 10 Rivaroxaban Low-dose edoxaban
High-dose edoxaban
Low-dose dabigatran
High-dose dabigatran
Apixaban
Warfarin 1 2 3 4 5 6 7 8 9 10
7,48
4,32
8,61
5,96
6,86
5,11
7,34 %

37. Drug discontinuation % 10 20 30 40 50 60 Rivaroxaban Low-dose edoxaban
High-dose edoxaban
Low-dose dabigatran
High-dose dabigatran
Apixaban
Warfarin 10 20 30 40 50 60
23,51
30,15
59,87
27,72
28,45
20,25 22 %

38. stroke or sistemic embolism
NNT (or NNH) vs warfarin
drug
stroke or sistemic embolism
death
major bleeding
drug discontinuation
Rivaroxaban
232
100
-736 66
Low-dose edoxaban 77 33 12
High-dose edoxaban 37 24
-78 3
Low-dose dabigatran
335
190 72 17
High-dose dabigatran 88
142
209 15
Apixaban
137
155 45
-57

39. Discussion
Novel OAC are effective as or more than VKA in preventing stroke or SE. Novel OAC share a strong evidence to decrease mortality: thus, is it still ethically sound to use VKA? Tolerability is a key point, due to significantly differentheterogeneity: apixaban appears to be the best drug, as confirmed in several papers
Connolly SJ N Engl J Med 2011

40. Limitations
To be(lieve) or not to be(lieve): this is the question Limited choice of endpoints: e.g. AMI, reasons for discontinuation, type of bleeding not considered

41. Conclusions
Novel OAC are effective to prevent stroke or SE and death without serious concerns about safety when compared with warfarin. In a head-to-head comparison, apixaban and HD dabigatran are more effective than warfarin but apixaban is better tolerated. Rivaroxaban is a valid alternative to warfarin but appears less effective than HD dabigatran and apixaban.

42. Conclusions
Given the superiority in one or more aspects (efficacy, safety, ease-of-use) of novel OAC, warfarin should not remain first choice therapy for anticoagulation in patients with non-valvular atrial fibrillation and at least moderate thromboembolic risk.

43. Conclusions
Given the superiority in one or more aspects (efficacy, safety, ease-of-use) of novel OAC, warfarin should not remain first choice therapy for anticoagulation in patients with non-valvular atrial fibrillation and at least moderate thromboembolic risk.

44. Thank you for your attention For any correspondence: For these and further slides on these topics feel free to visit the metcardio.org website: