ARTICLES ON ANTIPLATELET AGENTS AND ANTICOAGULANTS NUECARDIN IN HEART FAILURE

1. Dr. NAGULA PRAVEEN

2. ANTIPLATELET
AGENTS

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. 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. 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.

7. ■ 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.

8. 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.

13. 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.

15. ■ 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

16. 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

17. ■ 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.

18. 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.

21. NOVEL ORAL
ANTICOAGULANTS

22. 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?

23. ■ 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).

25. 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

26. 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

28. ATRIAL
FIBRILLATION

29. 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

30. 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

31. Components of Virchows triad for thrombogenesis
in AF

33. 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

34. 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

35. ■ 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.

36. 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.

37. 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%

38. 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

40. 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.

41. 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)

42. 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

43. ■ 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.

45. 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.

46. 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.

47. 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

48. 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%

49. ■ 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.

50. 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.

51. (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%

53. HEART FAILURE

54. ■ 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.

55. ■ 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)

57. 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.

58. 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

59. 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

62. Take Home Message
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63. ■ Thank you