Harry Potter and the Harry Potter and the new oral new oral

anticoagulantsanticoagulants

V. MalavasiV. MalavasiG. Biondi ZoccaiG. Biondi Zoccai

BackgroundBackground

1. ACC/AHA/ESC guidelines: Fuster V et al. Circulation 2006;114:e257–354

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)

BackgroundBackground

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;63:630–41Baker WL J Manag Care Pharm 2009;15:244-52.

BackgroundBackground

BackgroundBackground

Baker WL J Manag Care Pharm 2009;15:244-52.

BackgroundBackground

BackgroundBackground

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.

EndpointsEndpoints

Efficacy: Stroke or SE Death

Safety Major bleeding

Tolerability Drug discontinuation

MethodsMethods

=

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

TREATMENT CTREATMENT CTREATMENT CTREATMENT CTREATMENT ATREATMENT ATREATMENT CTREATMENT CTREATMENT ATREATMENT ATREATMENT ATREATMENT ATREATMENT ATREATMENT A

Methods for pair-wise meta-analysis

TREATMENT CTREATMENT CTREATMENT CTREATMENT CTREATMENT ATREATMENT ATREATMENT ATREATMENT A TREATMENT CTREATMENT C

OR (A vs C)OR (A vs C)

Difference in effect beween treatment A vs C is computed by means of a weighted average of differences stemming from individual studies

TREATMENT ATREATMENT A

TREATMENT BTREATMENT B

TREATMENT CTREATMENT C

TREATMENT CTREATMENT C

OR (A vs C)OR (A vs C)

OR (B vs C)OR (B vs C)

OROR (A vs B)(A vs B)

Ln ORA-B = Ln ORA-C – Ln ORB-C

Var (Ln ORA-B) = Var (Ln ORA-C) – Var (Ln ORB-C)

Methods for indirect meta-analysis

TREATMENT ATREATMENT A

TREATMENT BTREATMENT B

TREATMENT CTREATMENT C

TREATMENT DTREATMENT D

OR (A vs C)OR (A vs C)

OR (B vs D)OR (B vs D)

OROR (A vs B)(A vs B)

Methods for network meta-analysis

TREATMENT ATREATMENT A TREATMENT DTREATMENT DOR (A vs D)OR (A vs D)

OROR (B vs A)(B vs A)

Assumption behind indirect and network meta-analyses

A notable example

Psaty BM. JAMA 2003;289:2534-2544.

A notable example

Psaty BM. JAMA 2003;289:2534-2544.

7114 citations screened at the title/abstract level:124 from CENTRAL6528 from Google Scholar100 from MEDLINE/PubMed362 from Scopus

13 citations retrieved in full and appraised according to the selection criteria

7 randomized trials finally included in the systematic review and meta-analysis

7103 citations excluded because patently not pertinent

6 studies excluded because not fulfilling inclusion/exclusion criteria

Apixaban

LD edoxaban

HD edoxaban

LD dabigatran

HD dabigatran

Rivaroxaban

Warfarin

ARISTOTLE

ARISTOTLE-J ROCKET AF

Petro

RELY

Petr

o RE

LY

Chung 2011

Weitz 2010

Chung 2011

Weitz 2010

Main features of included studiesAcronym, 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 Dabigatran vs warfarin 110 mg twicedaily

Concomitant use of aspirin (at a dose of <100 mg per day) or other antiplatelet agents was permitted

Re-LY HW, 2009 Worldwide Dabigatran vs warfarin 150 mg twiceDaily

Concomitant use of aspirin (at a dose of <100 mg per day) or other antiplatelet agents was permitted

Weitz,2010

Worldwide Edoxaban vswarfarin

30, 60, 120 No restriction about aspirin

ARISTOTLE J, 2011 Asia Apixaban vs warfarin 2.5; 5; all twice daily No restriction about aspirin

ARISTOTLE, 2011 Worldwide Apixaban vs warfarin 5 twice daily No restriction about aspirin lower than 165 mg. Aspirin and clopidogrel together use were exclusion criteria

Rocket AF,2011

Worldwide Rivaroxaban vs warfarin

20 Aspirin ≤100 mg monotherapy and thienopyridine monotherapy allowed.

Chung,2011

Asia Edoxaban vswarfarin

30, 60 No restriction about aspirin

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 AF with CHADS>=1

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

AF with CHADS>=1

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.

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

AF with CHADS>=1

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

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,2011

AF with CHADS>=1

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 secondary 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.

Main features of included studies

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 23.4 27.9 24.3

ARISTOTLE, 2011

18113 15.1 35.5 87.3 70 (63-76) 25 19.2 31

Rocket AF,2011

14264 17.5 62.6 90.3 73 (65-78) 40.4 54.9 36.3

Chung,2011

253 - 28 71 65±9 30 19.2 24

Main features of patients

Risk of stroke or systemic embolism

Risk of death

Risk of major bleedings

Risk of drug discontinuation

Risk of stroke or systemic embolism

[1,2][1,3]

[1,4][1,5]

[1,6][1,7]

[2,3][2,4]

[2,5][2,6]

[2,7]

[3,4][3,5]

[3,6][3,7]

[4,5][4,6]

[4,7]

[5,6][5,7]

[6,7]

caterpillar plot: lor

-5.0 -2.5 0.0 2.5 5.0

Risk of death

[1,2][1,3][1,4]

[1,5][1,6]

[1,7]

[2,3][2,4]

[2,5][2,6]

[2,7]

[3,4][3,5]

[3,6][3,7]

[4,5][4,6]

[4,7]

[5,6][5,7]

[6,7]

caterpillar plot: lor

-4.0 -2.0 0.0 2.0 4.0

Risk of major bleeding

[1,2][1,3]

[1,4][1,5]

[1,6][1,7]

[2,3][2,4]

[2,5][2,6]

[2,7]

[3,4][3,5]

[3,6][3,7]

[4,5][4,6]

[4,7]

[5,6][5,7]

[6,7]

caterpillar plot: lor

-2.0 -1.0 0.0 1.0 2.0

Risk of drug discontinuation

[1,2][1,3]

[1,4][1,5]

[1,6][1,7]

[2,3][2,4]

[2,5][2,6]

[2,7]

[3,4][3,5]

[3,6][3,7]

[4,5][4,6]

[4,7]

[5,6][5,7]

[6,7]

caterpillar plot: lor

-4.0 -2.0 0.0 2.0 4.0

Stroke or sistemic embolism

Rivaroxaban

Low-dose edoxaban

High-dose edoxaban

Low-dose dabigatran

High-dose dabigatran

Apixaban

Warfarin

0 1 2 3 4 5 6 7 8 9 10

2,992,99

1,911,91

0,740,74

3,123,12

2,282,28

2,692,69

3,423,42

Death

Rivaroxaban

Low-dose edoxaban

High-dose edoxaban

Low-dose dabigatran

High-dose dabigatran

Apixaban

Warfarin

0 1 2 3 4 5 6 7 8 9 10

5,215,21

4,914,91

2,072,07

5,685,68

5,515,51

5,565,56

6,216,21

%

Major bleeding

Rivaroxaban

Low-dose edoxaban

High-dose edoxaban

Low-dose dabigatran

High-dose dabigatran

Apixaban

Warfarin

0 1 2 3 4 5 6 7 8 9 10

7,487,48

4,324,32

8,618,61

5,965,96

6,866,86

5,115,11

7,347,34

%

Rivaroxaban

Low-dose edoxaban

High-dose edoxaban

Low-dose dabigatran

High-dose dabigatran

Apixaban

Warfarin

0 10 20 30 40 50 60

23,5123,51

30,1530,15

59,8759,87

27,7227,72

28,4528,45

20,2520,25

2222

%

Drug discontinuation

drug stroke or sistemic embolism death major

bleedingdrug

discontinuation

RivaroxabanRivaroxaban 232232 100100 -736-736 6666

Low-dose edoxabanLow-dose edoxaban 6666 7777 3333 1212

High-dose edoxabanHigh-dose edoxaban 3737 2424 -78-78 33

Low-dose dabigatranLow-dose dabigatran 335335 190190 7272 1717

High-dose dabigatranHigh-dose dabigatran 8888 142142 209209 1515

ApixabanApixaban 137137 155155 4545 -57-57

NNT (or NNH) vs warfarin

DiscussionDiscussion

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

LimitationsLimitations

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

ConclusionsConclusions

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.

ConclusionsConclusions

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.

ConclusionsConclusions

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.

Thank you for your attention

For any correspondence: gbiondizoccai@gmail.com

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