Oral anticoagulants Sao Paulo
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Oral anticoagulants: state of the art
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Oral anticoagulants Sao Paulo
- 1. Oral AnticoagulantsOral Anticoagulants Antonio Raviele, MD, FESC, FHRSAntonio Raviele, MD, FESC, FHRS SOBRAC 2015, Sao Paulo - Brazil, 4-6 November 2015SOBRAC 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
- 2. • 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
- 3. Ischemic Areas Cerebral embolism as complication of AF
- 4. 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)
- 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
- 6. 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 Cumulativehazardoffatalstroke 100 0 0.01 0.02 0.04 0.050.05 0.03 9080706050403020100 Months of follow-up AF Present AF Absent
- 7. • 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
- 8. • 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
- 9. • Vitamin K Antagonists (VKA) • No Vitamin K Antagonists OACs (NOACs) or Direct OACs (DOACs) Different types of OACsDifferent types of OACs
- 10. • 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
- 11. Point of action of VKA in the coagulation cascade. Steffel J , Braunwald E Eur Heart J 2011;32:1968-1976
- 12. • The Non-VKA OACs (NOACs) or Direct OACs (DOACs) are new compounds developed in the recent years. NOACs or DOACsNOACs or DOACs
- 13. Point of action of novel oral anticoagulants in the coagulation cascade. Steffel J , Braunwald E Eur Heart J 2011;32:1968-1976
- 14. • 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
- 15. Hart RG, et al. Ann Intern Med. 2007; 146: 857-867 - 64% Adjusted-Dose Warfarin Compared with Placebo or No Treatment* - - - - - -
- 16. Hart RG, et al. Ann Intern Med. 2007; 146: 857-867 Safety Outcomes for Major Antithrombotic Comparisons*
- 17. 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.
- 18. 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
- 19. Management of AF in clinical practice:Management of AF in clinical practice: VKA prescriptionVKA prescription N=11.409 ATRIA Cohort, USA Go AS, et al. JAMA 2003;290:2685 N=5.333 EuroHeart Survey Nieuwlaat R, et al. Eur Heart J 2005;26:2422 N=23.657 Medicare Cohort, USA Birman-Deych E, et al. Stroke 2006;37:1070 No OACs VKA 55%67%64% 55%67%64%
- 20. Mean % of Time spent in Therapeutic Range (TTR): INR 2.0-3.0 Hallgreen CE et al. Pharmacoepidemiol Drug Saf. 2014; ;23: :974-83
- 21. Wallentin L et al. The Lancet 2010; 376, 975-983 Mean % of TTR in RE-LY Country- based variation in average TTR
- 22. 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)
- 23. 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
- 24. Ruff CT et al. The Lancet 2014; 383: 955-962 Stroke or Systemic Embolic Events
- 25. Secondary efficacy and safety outcomes Ruff CT et al. The Lancet 2014; 383: 955-962
- 26. Advantages of therapy with NOACsAdvantages of therapy with NOACs Ruff CT et al. The Lancet 2014; 383: 955-962
- 27. Ansell J Circulation 2012;125:165-170
- 28. • 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
- 29. Should this patient be treated with OACsShould this patient be treated with OACs ?? Critical questionCritical question
- 30. OAC / Net Clinical BenefitOAC / Net Clinical Benefit Potential benefit of ischemic stroke prevention Potential risk of serious bleeding, in particular ICH
- 31. 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 1.5number 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
- 32. 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.
- 33. Olesen JB et al. Thromb Haemost 2011; 106: 739-749
- 34. 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.
- 35. Banerjie A et al. Thromb Haemost 2012; 107: 584-589
- 36. 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%
- 37. • 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
- 38. Lip GYH, Lane DA. JAMA 2015; 313:1950-1962 Algorithm for Risk Stratification and Selection of Anticoagulation Therapy for Stroke Prevention in AF
- 39. • 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
- 40. 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
- 41. Lip GYH, Lane DA. JAMA 2015; 313:1950-1962
- 42. Lip GYH, Lane DA. JAMA 2015; 313:1950-1962 Algorithm for Risk Stratification and Selection of Anticoagulation Therapy for Stroke Prevention in AF
- 43. • 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
- 44. 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
- 45. 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
- 46. 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.
- 47. 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.
Editor's Notes
- Mister Chairmen, Ladies and Gentlemen, the topic of my presentation today concerns the use of oral anticoagulants for the prevention of thromboembolic events in patients with AF
- In doing this, I will deal with the following main issues: 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? Let me start with rationale for the use of OACs.
- We know that atrial fibrillation is associated with an increased risk of thromboembolic events, especially of ischemic stroke
- its mean annual incidence being, according to SPAF investigators, 4.5% in untreated patients, that is 5 times higher than in general population
- Interestingly, strokes related to AF are more severe, causing higher mortality, 33% at 3 months vs 20%, and higher disability, 50% more, than strokes unrelated to AF
- Moreover, they are associated with increased risk of stroke recurrence during the follow-up.
- Thus, the reason for giving OACs in patients with AF is to reduce the risk of thromboembolic events when this risk outweighs the risk of bleeding associated with OACs.
- Coming to the different types of OACs currently available
- We have essentially two categories: Vitamin K Inhibithors (VKA), and No Vitamin K Inhibithors OACs (NOACs) or Direct OACs (DOACs).
- Vitamin K Antagonists, such as warfarin, are the traditional OACs and until 2009 have been the only class of OACs available. These compounds block the vitamin k dependent liver production of the plasma coagulation factors II, VII, IX, and X.
- These compounds block the vitamin k dependent liver production of the plasma coagulation factors II, VII, IX, and X.
- The Non-VKA OACs (NOACs) or Direct OACs (DOACs) are new compounds developed in the recent years
- There are 4 NOACs currently licensed for use in nonvalvular AF: dabigatran that directly inhibits factor II (thrombin) inhibitor, and rivaroxaban, apixaban, and edoxaban that directly inhibit activated factor X (factor Xa).
- The clinical results of OACs for the prevention of thromboembolisms in pts with AF may be so summarized
- VKA are very effective drugs in preventing thromboembolic events in pts with AF. In the metanalysis of Hart and colleagues published in the Annals of Internal Medicine in 2007, adjusted-dose warfarin reduced the risk of stroke by 64%, when compared with placebo or no treatment.
- It also reduced the risk of all cause mortality by 26%, whereas doubled the risk of intracranial hemorraghes and major extranial hemorraghes.
- However, VKA therapy has several limitations, such as unpredictable response, narrow therapeutic window, slow onset/offset of action, numerous food-drug interactions, numerous drug-drug interactions, and warfarin resistance that make it difficult to use in clinical practice and that require routine coagulation monitoring and frequent dose adjustments resulting in substancial risk and inconvenience.
- This explains the low use and the high discontinuation rate of warfarin in the real world, as well as the inadequate level of anticoagulation reached in many patients
- For example, only 55 to 67% of patients who are good candidate to VKAs therapy, effectively receive these drugs
- Moreover, the percentage of time spent in therapeuic range (TTR), is about 60% also in patients enrolled in RCTs and is even lower in observational studies and in the real-word.
- Especially in less developed countries, as you can see in this RE-LY data
- The Non-Vitamin K Antagonists OACs have been evaluated in four large RCTs that have compared these drugs with warfarin for stroke prevention in AF, for a total of more than 71 thousands patients.
- A recent metanalysis of these trials published in Lancet last year
- has shown that NOACs compared with warfarin significantly reduced stroke or systemic embolic events by 19%
- mainly driven by a 51% reduction in hemorrhagic stroke, NOACs also significantly reduced all-cause mortality by 10% but increased gastrintestinal bleedings by 25%.
- NOACs have several advantages over warfarin, such as less intracranial hemorrahges, superiority versus warfarin in some cases, more predictable response, rapid onset/offset of action, no major food-drug interactions, fewer drug-drug interactions, these last properties enabling the administrations of fixed doses without the need for routine coagulation monitoring, thereby simplifying treatment
- However, NOACs have also some limitations, here reported: short half-live and no routine coagulation monitoring required with potential for increased risk of stroke or systemic embolism with poor drug compliance, no coagulation assay easily available to precisely measure anticoagulation effect, no specific antidotes till now even if this problem will be very soon overcome, or well-established procedure for reversing anticogulation in emergent situations, and finaaly the cost of these drugs that is surely high.
- And now the issue of the net clinical benefit of the different OACs
- Once the stroke and risk assessment has been performed, a critical question arises: should this patient be treated with OACs?
- To answer this question, on the most simplistic level, it is necessary to balance the potential benefit of ischemic stroke prevention with OAC against the potential risk of serious bleeding, in particular intracranial haemorrhages, the so-called net clinical benefit of OAC therapy.
- This is usually calculated by means of the following equation: number of ischemic strokes avoided by OAC minus number of ICH attributable to OACs weighted 1.5, to account for the generally more disastrous effects of an intracranial bleed compared with an ischemic stroke.
- Several studies have examined the net clinical benefit of OAC therapy in patients with atrial fibrillation
- According to Olesen and C., the net clinical benefit of warfarin is positive in patients with CHADS-VASc score of 2 or more, is negative in patients with CHADS-VASc score of 0, and is neutral or only marginally positive in patients with CHADS-VASc score of 1.
- In this more recent paper of Lip and C., regarding a Danish population, the net clinical benefit of warfarin is clearly positive also in patients with CHADS-VASc score of 1.
- For NOACs, the net clinical benefit appears to be better than that of warfarin, according to Banerjie and C. It is positive for all NOACs in patients with CHADS-VASc score of 2 or higher and is positive for dabigatran and apixaban in patients with CHADS-VASC score of 1. Interestingly, patients with a high HAS-BLED score seem to derive the highest net clinical benefit.
- Based on these data, the threshold for initiating OAC therapy has been calculated to be a stroke rate of 1.7% per year for warfarin, and 0.9% per year for NOACs, considering that NOACs reduce by 50% the annual incidence of ICH compared to warfarin
- and now, taking in mind these considerations, the indications to antithrombotic therapy.
- To this regard, we can use the flowchart recently proposed by Lip and Lane. The first step, in this flowchart, is to calculate the CHADS-VASc score to identify patients at low risk of stroke, who do not need any antithrombotic therapy. These are patients younger than 65 years with no stroke risk factors (CHADS-VASc score of 0 for male and 1 for female). Subsequently, all the other patients with at least 1 risk factor (male with CHADS-VASc score of 1 or higher and female with CHADS-VASc score of 2 or higher) can be offered OAC therapy.
- But which OAC to start, warfarin or NOACS?
- Warfarin is substantially equivalent to NOACs if the TTR (Time spent in Therapeutic range) is >65%, otherwise NOACs are more effective and safer. In this slide you can see how the freedom from stroke on warfarin is strictly related to TTR values.
- Thus, in order to help with decision making before starting OAC it would be important to predict which newly-diagnosed non-anticoagulated patients would do well on warfarin with high TTR. The SAME-TT2R2 score, reported in this slide, may be useful to this purpose. The score system assigns 1 point each to female sex, age less than 60 years, medical history of more than 2 comorbidities, and treatment with interacting drugs and 2 points each to tobacco use and nonwhite race.
- A score less than 3 suggests a good probability to achieve a TTR >65% and warfarin should be given as starting drug. In contrast, a score of 3 or higher suggests that patients are unlikely to achieve a good TTR, so a NOAC should be used initially.
- Finally, which NOAC to prefer?
- 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
- The considerations that may favour the use of a particular NOAC in different subgroups of patients are summarized in this slide. In elderly patients consider apiax… that are the agents with lower…; in patients with renal impairment, condider…
- In conclusion, Mister Chairmen, Ladies and Gentlemen, 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.
- 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.
- Especially in less developed countries, as you can see in this RE-LY data