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ACC UPDATE 2018

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ARTICLES ON ANTIPLATELET AGENTS AND ANTICOAGULANTS
NUECARDIN IN HEART FAILURE

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ACC UPDATE 2018

  1. 1. Dr. NAGULA PRAVEEN
  2. 2. ANTIPLATELET AGENTS
  3. 3. PHARMCLO trial ■ Hypothesis – Selecting antiplatelet therapy for patients with ACS on the basis of a combination of genetic and clinical characteristics would lead to better outcome in comparison with standard of care, which bases the selection on clinical characteristics alone. Ardissino D et al. Prospective,Randomized ,Multicentre study of A pharmacogenomic Approach To the selection of Antiplatelet therapy in ACS. ACC 2018
  4. 4. Pharmacogenomic approach to selection of Antiplatelet therapy in ACS – PHARMCLO trial ■ Genotyping of ABCB1,CYP2C19*2 and CYP2C19*17 – STQ3system. ■ Clopidogrel, Prasugrel, Ticagrelor were selected based on the algorithm – clinical data and genetic data – obtained within 70 minutes at each patient’s bedside. ■ Followed up for a median of one year. ■ Composite primary end point – – CV death, – Non fatal myocardial infarction, – Stroke, – BARC 3-5 major bleeding.
  5. 5. Standard arm Pharmacogenomic arm No.of patients 440 448 Clopidogrel 50.7% 43.3% Ticagrelor 42.6% 32.7% (P <0.05) Prasugrel 8.4% 7.6% P2Y12 receptor antagonist switch 5.6% 6.8% No P2Y12 receptor antagonist 8.2% 6.5% Primary end point 25.9% 15.8% HR 0.58 {95% CI 0.43-0.78} P < 0.001 A Personalised approach to selecting antiplatelet therapy leads to a clinically meaningful reduction in ischemic and bleeding events in ACS patients.
  6. 6. ■ Pharmacogenomics analyzes how the genetic makeup of an individual affects his/her response to drugs. ■ The branch of genetics concerned with determining the likely response of an individual to therapeutic drugs.
  7. 7. ABCB1 - (ATP-binding cassette, sub-family B, member 1, also called MDR1 or TAP1) gene encodes the intestinal efflux transporter P-glycoprotein, which modulates the absorption of clopidogrel. Rapid absorption from intestine. Absorbed through P glycoprotein – encoded by ABCB1 gene. Inactivated - 85% - intestinal esterases. Active metabolite – 15% - in liver – thiol derivative. CYP2C19 - involved in both oxidation steps CYP3A4 – involved in second oxidation step Irreversibly binds to the cysteine derivative of P2Y12 receptor.
  8. 8. Generally, with respect to CYP2C19, individuals are classified as • rapid metabolizers if they are homozygous for the CYP2C19*1 allele (ie they are CYP2C19*1/CYP2C19*1), • intermediate metabolizers if they have one CYP2C19*1 allele plus one variant allele (such as CYP2C19*2 or CYP2C19*3), and • poor metabolizers if they carry two copies of a variant. Effective doses are higher for individuals who are poor metabolizers and thus treatment success is higher as well.
  9. 9. ■ Ticagrelor inhibits cellular uptake of adenosine. ■ Adenosine associated pleiotropic effects of the two P2Y12RA on vascular function, systemic inflammation, and circulating endothelial progenitor cells. ■ 62 patients, Randomization 1:1 ratio ■ Treatment for 5 weeks – cross over - then 5 weeks – Brachial artery flow mediated dilation (BaFMD) – Inflammatory markers – Number of circulating EPCs were compared. Han Saem Jeong et al. J Am Coll Cardiol Intv 2017;10:1646–58 Comparison of Ticagrelor vs Prasugrel for in Diabetic Patients with NSTEACS requiring coronary stenting
  10. 10. After 10 weeks follow up Ticagrelor group Prasugrel group P value Ba FMD 0.15 ± 0.19 mm - 0.03 ± 0.18 mm < 0.001 Interleukin – 6 - 0.58 ± 0.43 pg/ml - 0.05 ± 0.24 pg/ml < 0.001 TNF alpha - 5.62 ± 4.40 pg/ml - 0.42 ± 2.64 pg/ml < 0.001 Adiponectin 2.31  2.00 g/ml 0.08  1.50 g/ml < 0.001 Hs CRP Decreased in both groups SVAM-1 Absolute numbers of circulating EPCs CD 34 + / KDR + 42.5 ± 37.8 per l - 28.2 ± 23.7 per l <0.001 CD 34 + / CD 117 + 51.9 ± 77.2 per l - 66.3 ± 45.2 per l <0.001 CD 34 + / CD 133 + 55.2 ± 69.2 per l - 28.0 ± 34.1 per l < 0.001
  11. 11. ■ Compared to prasugrel, ticagrelor significantly – decreased inflammatory cytokines such as IL – 6 and TNF and – increased circulating endothelial progenitor cells (EPC), ■ Improved arterial endothelial function in diabetic NSTEACS patients. ■ Data support that pleiotropic effects of ticagrelor beyond its potent antiplatelet effects could contribute to additional clinical benefits.
  12. 12. WHAT IS KNOWN? Both ticagrelor and prasugrel have potent antiplatelet effects and have been administrated in patients with ACS. However, only ticagrelor inhibits cellular uptake of adenosine. WHAT IS NEW? In the present study, administration of ticagrelor significantly improved arterial endothelial function evaluated as baFMD. Ticagrelor also meaningfully decreased circulating proinflammatory cytokines such as IL-6 and TNF-a, and increased adiponectin levels during the follow-up. Moreover, ticagrelor significantly increased absolute numbers of circulating endothelial progenitor cells. WHAT IS NEXT? Future studies are needed to examine who can show more beneficial effects with ticagrelor than prasugrel.
  13. 13. NOVEL ORAL ANTICOAGULANTS
  14. 14. PERIPHERAL ARTERY DISEASE ■ What is the prognosis of patients who suffer Major Adverse Limb Events (MALE) with PAD ? ■ What is the impact of treatment with low dose rivaroxaban and aspirin compared to aspirin alone on incidence of MALEs in patients with PAD?
  15. 15. ■ Lower extremity PAD patients are at increased risk of MACE and MALEs. ■ Patients with lower extremity PAD, those with MALEs vs without MALEs – A. Incidence of Hospitalisations, MACEs, amputation, deaths – B. Impact of low dose rivaroxaban and aspirin vs rivaroxaban alone vs aspirin alone on incidence of MACE, Peripheral vascular interventions, and all peripheral vascular outcomes ■ Randomized double blind placebo trial of 6391 patients, 21 months follow up. ■ MALE event – severe limb ischemia leading to an intervention or major vascular amputation. (COMPASS - Cardiovascular Outco M es for People Using Anticoagulation StrategieS).
  16. 16. Incidence of MALE events 128 patients (2%) After MALE the cumulative risk of a Subsequent hospitalization 95.4% Vascular amputations 22.9% Death 8.7% MACE 3.8% MALE index event significantly increased the risk to experience Subsequent hospitalizations HR 7.21 P < 0.0001 Subsequent amputations HR 197.5 P < 0.0001 Death HR 3.23 P < 0.001
  17. 17. Combination of rivaroxaban 2.5mg bid plus aspirin vs aspirin alone Lowered the incidence of MALE by 43% 0.01 P value Total vascular amputations by 58% 0.01 Peripheral Vascular interventions by 24% 0.03 All peripheral vascular outcomes by 24% 0.02 • Prevention of MALE is of utmost importance in patients with lower extremity PAD. • Combination of low dose rivaroxaban 2.5 mg bid and aspirin significantly lowers the incidence of MALE and it related complications. Conclusion
  18. 18. ATRIAL FIBRILLATION
  19. 19. New Biomarkers associated with CV death in patients with AF using Multimarker screening : Insights from ARISTOTLE trial ■ Proximity Extension Assay (PEA) – a new multiplex analytic technique enabling analysis of hundreds of plasma biomarkers. ■ A total of 255 CV and inflammatory biomarkers association with CV death in patients with AF on oral anticoagulation was assessed. ■ NT- Pro BNP, ■ cTnT - hs, ■ IL-6, ■ Transferrin Receptor protein (TfR1), ■ FGF 23 were statistically significant associated with CV death. * Random Forest and the adjusted Cox- regression analysis
  20. 20. HR (95% CI ) per interquartile range NT proBNP 1.58 (1.38 – 1.83) cTnT hs 1.56 (1.40 – 1.75) IL-6 1.28 (1.14 – 1.44) TfR1 1.27 (1.14 - 1.41) FGF 23 1.18 (1.09 – 1.28) Independent association with CV death in patients with AF. Association of TfR1 and FGF -23 are novel. Role of iron regulation TfR1 and phosphate metabolism (FGF-23) warrants further investigation. Adjusted Cox analysis
  21. 21. Components of Virchows triad for thrombogenesis in AF
  22. 22. Comparative effectiveness and safety of NOACS vs Warfarin for secondary stroke prevention in AF : A Nationwide Danish cohort study ■ Efficacy of NOACS vs Warfarin in AF patients with prevalent ischemic stroke. ■ Three nationwide Danish Registries – AF with ischemic stroke claiming a first OAC prescription. ■ 6492 patients ■ 46% females Nielsen PB et al. ACC 2018
  23. 23. Apixaban Rivaroxaban Dabigatran Warfarin Median Number of patients 1,358 1,199 953 2,982 Mean age 64.8 73.1 71.4 10.8 Rates of TE at 12 months follow up 3.1% 2.8% 3.1% 4.0% Relative Risk of TE NOACS vs Warfarin 0.82 0.70 0.69 Principal safety outcome, the Hazard Ratio is 0.89 0.86 0.42
  24. 24. ■ NOACS had nonsignificantly lower relative risk for TE in comparison with warfarin. ■ Hazard Ratios for bleeding were significantly lower for dabigatran, but non- significant different for apixaban, rivaroxaban.
  25. 25. NOACs vs Warfarin in Hemorrhagic stroke ■ AF patients who sustained a hemorrhagic stroke were excluded from RCTs comparing NOACs vs Warfarin. ■ Nationwide Danish registry ■ Nonvalvular AF who sustained a hemorrhagic stroke and subsequently received OAC. ■ Primary effectiveness outcome of ischemic stroke/systemic embolism ■ Principal safety outcome of recurrent hemorrhagic stroke. Nielsen PB et al.
  26. 26. NOACS Warfarin No. of patients 1,894 344 269 Mean age 76  9.2 Females 40% Scandinavian stroke scale Non severe 72% Moderately severe 17% Severe 11%
  27. 27. Warfarin NOACS During two years follow up Thromboembolism 6.0 4.3 100 person years Effectiveness outcome 0.69 {95% CI 0.38 to 1.28} Recurrent Intracranial Hemorrhage 0.80 {95% CI 0.43 to 1.49} Use of NOACs was associated with a trend towards lower rates of recurrent hemorrhagic stroke and thromboembolism
  28. 28. BNP in AF ■ Outcomes of AF ■ Progression and composite outcome of MACE ■ ORBIT –AF II trial. ■ AF progression was defined as either paroxysmal becoming persistent or permanent, or persistent becoming permanent at any follow up in patients without permanent AF at baseline. Inohara et al.
  29. 29. No. of patients 13,375 BNP values at baseline ( 2797 Pts) 238 pg /ml range of 102-502 Prior HF 42.3% Rates of Paroxysmal AF at baseline 33.0% Persistent AF at baseline 13.3% Likelihood of AF progression 1.11 for every 100 pg/ml (95% CI 1.03-1.19) MACNE 1.12 for every doubling of BNP values (1.02 -1.22)
  30. 30. Direct comparison of safety and effectiveness of the Three different NOACs in patients with NVAF. Dabigatran Rivaroxaban Apixaban Total Patients with AF 648 538 599 1787 Mean follow up 439 ± 409 days Higher CHA2DS2- VASc score 2.6 ± 1.7 3.3 ± 1.9 3.9 ± 1.8 <0.001 Lower creatinine clearance 75.5 ± 28.8 73.4 ± 30.4 59.6 ± 25.9 <0.001 Hazards for safety and effectiveness endpoints Major bleeding rates Sotomi Y et al. ACC 2018
  31. 31. ■ The adjusted results indicated that apixaban and rivaroxaban have comparable safety and effectiveness with dabigatran in real world practice. ■ Major bleeding occurred more frequently in patients with apixaban, rivaroxaban than dabigatran, whereas events rate of stroke or systemic embolism were similar. ■ Apixaban and rivaroxaban were more frequently prescribed for patients with higher risks for bleeding and thromboembolism.
  32. 32. Safe outcomes with NOACS in obese patients undergoing Electrical Cardioversion for atrial tachyarrhythmias ■ Volume of distribution is related to weight ■ The month following DCCV is a high risk period for stroke. ■ Safety of performing DCCV in obese patients on NOAC. ■ All patients who underwent DCCV after > 3 weeks of NOAC or therapeutic warfarin treatment without a prior TEE over a 3 week period were included. ■ Obesity – Normal or overweight – BMI <30,Class I is 30 to < 35,Class II obesity – 35 to < 40,Class III - >40 ■ Primary end point was stroke at 30 days. Kaplan R et al.
  33. 33. Stroke Total number of patients 761 Severely obese 73 No strokes Class 2 obese 78 1 Class 1 obese 197 Normal / Overweight 413 1 Average age 66.4  10.3 Females 32.5% CHA2DS2 - VASc 2.6  1.6 Patients on NOACs 78.9% NOAC use in severely obese patients undergoing DCCV appears safe even in the absence of TEE.
  34. 34. NOACs in dialysis patients with AF ■ Safety and efficacy in dialysis patients is not well known. NOACs Warfarin Patients with NVAF 2,858 2,858 Apixaban – 2,276 Rivaroxaban - 325 Dabigatran - 257 Mean follow up 3.3 months 5.6 months Risk of Stroke /Systemic embolism - No major difference Lower risk of major bleeding
  35. 35. Choice of anticoagulants – SPRINT AF Registry ■ Stroke Prevention and Rhythm INTervention in Atrial Fibrillation (SPRINT AF) Non Valvular AF patients 2,498 Family medicine 67% Specialists 33% NOACs 1,402 Rivaroxaban 45% Dabigatran 32% Apixaban 23%
  36. 36. ■ Dosing frequency was the most common reason for selection of rivaroxaban. ( 56% vs 15% vs 11% , p <0.01 ) ■ Superior efficacy was more frequently cited as a reason for selection of dabigatran or apixaban relative to rivaroxaban. ( 60% vs 57% vs 51% , p < 0.01) ■ Lower risk of bleeding for selecting apixaban. ( 30% vs 10% vs 11%,p <0.001) ■ Clinical profile of patients treated with NOACs are similar. Ha AC et al. SPRINT AF Registry ACC 2018.
  37. 37. Equation to predict stroke risk in AF ■ Shared decision making with patients is essential before prescribing anticoagulants (AC) in patients with AF. ■ The CHA2DS2VASc score is recommended for the prediction of stroke. – Underestimates SR with zero scores – Not easy to remember.
  38. 38. (AFIB) 2 +S 4 + PAF + 0.1 A Age >75 F Heart failure I Insulin deficiency or diabetes B Blood pressure or HTN S Prior stroke or TIA P Plaque of the aorta,prior MI,PAD A 65-74 F Female gender Each letter gets a value of 1 if present SR – 0.1% -14.1% SR for CHA2DS2VASc score (0-9) – 0-15.2%
  39. 39. HEART FAILURE
  40. 40. ■ Neucardin is a portion of a naturally occurring protein known as Neuregulin- 1β2α. ■ Neuregulin-1 is found in the heart and by binding to receptors known as ErbB4 and ErbB2 found on cardiac muscle cells,Neuregulin-1 activates downstream signaling pathways important for cardiac function and structure. ■ The presence of Neuregulin-1 and its receptors has also been shown to be critical for normal heart development.
  41. 41. ■ The reasons for the hearts inability to pump blood to the body are complex, but include structural abnormalities in the cell known as myofibril disarray (A). Once bound to ErbB4, Neucardin activates many key molecules that are involved in restoration of an ordered cardiac muscle cell structure and this includes strengthening of the connections between the cells by reorganization of the intercalated discs, thereby increasing contractile function (B)
  42. 42. Neucardin in CHF ■ Maintaining cardiomyocyte structure and cardiac pumping functionality and physiology. ■ Recombinant EGF- Like domain of human neuregulin -1. ■ Disease modifying therapy for CHF treatment. ■ Effect on survival benefit and safety. Gao R et al.
  43. 43. HF patients 1600 NYHA class II or III Neucardin dose 0.6 ug/kg/d along with standard therapies Duration 23 weeks Follow up period is 1 year Primary end point All – cause mortality at 52 weeks Secondary end point CV death Re hospitalisation rate LVEF 6MWD NYHA classification QOL
  44. 44. Neucardin group Placebo group P value CHF patients 679 Decreased mortality 8.3% 10% NS NT pro BNP <1600 fmol/ml - mortality 2.6% 6.3% 0.087 Pooled analysis 2.1% 6.4% 0.005
  45. 45. Take Home Message  1.  2.  3.  4.  5.  6.  7.  8.  9.  10.
  46. 46. ■ Thank you

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