Oral AnticoagulantsOral Anticoagulants

Antonio Raviele, MD, FESC, FHRS Antonio Raviele, MD, FESC, FHRS

SOBRAC 2015, Sao Paulo - Brazil, 4-6 November 2015 SOBRAC 2015, Sao Paulo - Brazil, 4-6 November 2015

ALFA – Alliance to Fight Atrial fibrillation, Mestre – Venice, ItalyALFA – Alliance to Fight Atrial fibrillation, Mestre – Venice, Italy

• Rationale for the use of OACs in AF pts• Different types of OACs• Clinical results for the prevention of TE • Net clinical benefit of the different OACs• Indications to antithrombotic treatment• Which OAC to start?• Which NOAC to prefer?

Main IssuesMain Issues

Ischemic Areas

Cerebral embolism as complication of AF

AF 4,5%AF 4,5%

Controls 0,2% - 1,4%Controls 0,2% - 1,4%

Annual Incidence in pts with AFAnnual Incidence in pts with AF

AF & Stroke

(The SPAF Investigators. AIM 1992; 116: 1 – 5)(The SPAF Investigators. AIM 1992; 116: 1 – 5)

Strokes related to Afib are more severe

The European Community Stroke Project

Lamassa M et al. Stroke (2001) 32: 392-398

Multi-centre, multi-national hospital-based registry involving 4462 patients hospitalized for first stroke

AFib diagnosed in 803 stroke patients (18%)

At 3 months, 32.8% of stroke patients with AFib were dead vs 19.9% of stroke patients without AFib

AFib increased by approximately 50% the probability of remaining disabled

AFib is Associated with Progressive Risk of StrokeAFib is Associated with Progressive Risk of Stroke• Independent predictor of stroke recurrence and severityIndependent predictor of stroke recurrence and severity

Simons, LA et al. Stroke (1998) 29: 1341

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9080706050403020100

Months of follow-up

AF Present

AF Absent

• To teduce the risk of thromboembolic events

when this risk outweighs the risk of bleeding

associated with the use of OACs.

Rationale for OACs in AFRationale for OACs in AF

• Rationale for the use of OACs in AF pts• Different types of OACs• Clinical results for the prevention of TE • Net clinical benefit of the different OACs• Indications to antithrombotic treatment• Which OAC to start?• Which NOAC to prefer?

Main IssuesMain Issues

• Vitamin K Antagonists (VKA)

• No Vitamin K Antagonists OACs (NOACs) or

Direct OACs (DOACs)

Different types of OACsDifferent types of OACs

• Vitamin K Antagonists, such as warfarin, are the

traditional OACs and until 2009 have been the only

class of OACs available.

Vitamin K AntagonistsVitamin K Antagonists

Point of action of VKA in the coagulation cascade.

Steffel J , Braunwald E Eur Heart J 2011;32:1968-1976

• The Non-VKA OACs (NOACs) or Direct OACs

(DOACs) are new compounds developed in the recent

years.

NOACs or DOACsNOACs or DOACs

Point of action of novel oral anticoagulants in the coagulation cascade.

Steffel J , Braunwald E Eur Heart J 2011;32:1968-1976

• Rationale for the use of OACs in AF pts• Different types of OACs• Clinical results for the prevention of TE • Net clinical benefit of the different OACs• Indications to antithrombotic treatment• Which OAC to start?• Which NOAC to prefer?

Main IssuesMain Issues

Hart RG, et al. Ann Intern Med. 2007; 146: 857-867

- 64%

Adjusted-Dose Warfarin Compared with Placebo or No Treatment*

------

Hart RG, et al. Ann Intern Med. 2007; 146: 857-867

Safety Outcomes for Major Antithrombotic Comparisons*

Limitations of VKA therapyLimitations of VKA therapy

Ansell J, et al. Chest 2008;133;160S-198S. Umer Ushman MH, et al. J Interv Card Electrophysiol 2008;22:129-137.Nutescu EA, et al. Cardiol Clin 2008;26:169-187.

This explains

• the low use and the high discontinuation

rate of warfarin in the real world,

• the inadequate level of anticoagulation

reached in many patients

Underuse of warfarinUnderuse of warfarin

Management of AF in clinical practice: Management of AF in clinical practice: VKA prescriptionVKA prescription

N=11.409ATRIA Cohort, USA

Go AS, et al.JAMA 2003;290:2685

N=5.333EuroHeart SurveyNieuwlaat R, et al.

Eur Heart J 2005;26:2422

N=23.657Medicare Cohort, USABirman-Deych E, et al.Stroke 2006;37:1070

No OACs VKA

55%67%64% 55%67%64%

Mean % of Time spent in Therapeutic Range (TTR): INR 2.0-3.0

Hallgreen CE et al. Pharmacoepidemiol Drug Saf. 2014; ;23: :974-83

Wallentin L et al. The Lancet 2010; 376, 975-983

Mean % of TTR in RE-LYCountry- based variation in average TTR

Verheugt FWA et al. The Lancet 2015; 386, 303-310

The 4 large RCTs comparing NOACs with warfarin for stroke prevention in AF (71.683 pts)

Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a

meta-analysis of randomised trials 

Christian T Ruff, Robert P Giugliano, Eugene Braunwald, Elaine B Hoffman, Naveen Deenadayalu, Michael D Ezekowitz, A John Camm, Jeffrey I Weitz, Basil S Lewis, Alexander

Parkhomenko, Takeshi Yamashita, Elliott M Antman. 

The Lancet 2014; 383: 955-962

Ruff CT et al. The Lancet 2014; 383: 955-962

Stroke or Systemic Embolic Events

Secondary efficacy and safety outcomes

Ruff CT et al. The Lancet 2014; 383: 955-962

Advantages of therapy with NOACsAdvantages of therapy with NOACs

Ruff CT et al. The Lancet 2014; 383: 955-962

Ansell J Circulation 2012;125:165-170

• Rationale for the use of OACs in AF pts• Different types of OACs• Clinical results for the prevention of TE • Net clinical benefit of the different OACs• Indications to antithrombotic treatment• Which OAC to start?• Which NOAC to prefer?

Main IssuesMain Issues

Should this patient be treated with OACsShould this patient be treated with OACs

??

Critical questionCritical question

OAC / Net Clinical BenefitOAC / Net Clinical Benefit

Potential benefit of ischemic

stroke prevention

Potential risk of serious

bleeding, in particular ICH

OAC / Net Clinical BenefitOAC / Net Clinical Benefit

(Isoff OAC – Ison OAC) – 1.5 x (ICHon OAC –ICHon OAC)

number of IS avoided by OACs - number of ICH attributable to OACs x 1.5 number of IS avoided by OACs - number of ICH attributable to OACs x 1.5

to account for the generally more disastrous effects of an intracranial bleed compared with an ischemic stroke

Friberg L, et al. Circulation 2012; 125: 2298-2307

Circulation 2012; 125: 2298-2307

Thromb Haemost 2011; 106: 739-749

Thromb Haemost 2012; 107: 584-589

Net Clinical Benefit for Oral Anticoagulation, Aspirin, or No Therapy in Nonvalvular Atrial Fibrillation Patients With 1 Additional Risk Factor of the CHA2DS2-VASc Score (Beyond Sex).Lip GY, Skjøth F, Rasmussen LH, Nielsen PB, Larsen TB.

J Am Coll Cardiol. 2015 ; 66: 488-90.

Olesen JB et al. Thromb Haemost 2011; 106: 739-749

Net Clinical Benefit for Oral Anticoagulation, Aspirin, or No Therapy in Nonvalvular Atrial Fibrillation Patients With 1 Additional Risk Factor of the CHA2DS2-VASc Score (Beyond Sex)

Lip GYH et al. J Am Coll Cardiol. 2015; 66: 488-490.

Banerjie A et al. Thromb Haemost 2012; 107: 584-589

Stroke rate per yearStroke rate per year

Threshold for starting OAC therapyThreshold for starting OAC therapy

taking into account that NOACs reduce by 50% the

annual incidence of ICH compared to warfarin

Warfarin: 1.7%Warfarin: 1.7%NOACs: 0.9% NOACs: 0.9%

• Rationale for the use of OACs in AF pts• Different types of OACs• Clinical results for the prevention of TE • Net clinical benefit of the different OACs• Indications to antithrombotic treatment• Which OAC to start?• Which NOAC to prefer?

Main IssuesMain Issues

Lip GYH, Lane DA. JAMA 2015; 313:1950-1962

Algorithm for Risk Stratification and Selection of Anticoagulation Therapy for Stroke Prevention in AF

• Rationale for the use of OACs in AF pts• Different types of OACs• Clinical results for the prevention of TE • Net clinical benefit of the different OACs• Indications to antithrombotic treatment• Which OAC to start?• Which NOAC to prefer?

Main IssuesMain Issues

Figure 1. Percent of patients free from stroke over time, stratified by time spent in therapeutic range (INR 2.0–3.0).

FD Richard Hobbs et al. European Journal of Preventive Cardiology 2015;2047487315571890

Lip GYH, Lane DA. JAMA 2015; 313:1950-1962

Lip GYH, Lane DA. JAMA 2015; 313:1950-1962

Algorithm for Risk Stratification and Selection of Anticoagulation Therapy for Stroke Prevention in AF

• Rationale for the use of OACs in AF pts• Different types of OACs• Clinical results for the prevention of TE • Net clinical benefit of the different OACs• Indications to antithrombotic treatment• Which OAC to start?• Which NOAC to prefer?

Main IssuesMain Issues

Choice of the NOAC

No head-to-head comparisons exist between the different NOACs

So it is difficult to provide definitive recommendations on which

NOAC should be used in the single patient.

Indeed, NOACs are all individually noninferior to warfarin in terms

of efficacy for stroke prevention in patients with AF

However, some patient and drug characteristics may help in

decision making

Choosing the right drug to fit the patient when selecting oral anticoagulation for stroke prevention in atrial fibrillation

Shields AM, Lip GYH. Journal of Internal Medicine 2015; 278,:1-18

Conclusions (1)

• VKA are very effective drugs in preventing TEE in pts with AF.

• NOACs are at least as effective (if not more effective) than VKA,

and associated with significantly lower risk of serious bleeding, i.e

intracranial hemorrhages.

• The favorable net clinical benefit of the different OACs prompts

their use in the majority of pts with AF, with the only exception of

those at low risk of stroke, i.e males with CHA2DS2-VASc score = 0

and females with CHA2DS2-VASc score = 1.

Conclusions (2)

• The SAME-TT2R2 score system may be used to decide which OAC

(warfarin or NOACs) to start in newly diagnosed non anticoagulated

pts.

• Although no head-to-head comparisons exist between the different

NOACs, some patient and drug characteristics may help in selecting

which drug to use in single patients.