HIGHLIGHTS :AHA 2016 NEW ORLEANSDR.SHATHISKUMAR GOVINDARAJU

PIONEER AF – PCI study▪ -Study exploring two strategies of rivaroxaban and one of oral

vitamin K antagonists in patients with atrial fibrillation who undergo percutaneous coronary intervention

▪ To evaluate the safety of two different rivaroxaban treatment strategies and one vitamin K antagonist treatment strategy in patients with paroxysmal, persistent, or permanent non-valvular AF who undergo PCI with stent placement

PIONEER AF – PCI

PIONEER AF – PCI

RESULTS - rivaroxaban-based strategy was associated with a lower

frequency of clinically significant bleeding - TIMI major bleeding was similar between the three

groups - Major adverse cardiac events including stent thrombosis

appeared to be similar between the three groups.- All-cause death or rehospitalization was lower with a

rivaroxaban-based strategy compared with a warfarin/DAPT strategy.

Kaplan-Meier Estimates of First Occurrence of Clinically Significant Bleeding Events

TIM

I Maj

or, T

IMI M

inor

, or B

leed

ing

Req

uirin

g M

edic

al A

ttent

ion

(%)

697

Days

593 555 521 461 426 329VKA + DAPTNo. at risk

VKA + DAPT

26.7%

Treatment-emergent period: period starting after the first study drug administration following randomization and ending 2 days after stop of study drug. Clinically significant bleeding is the composite of TIMI major, TIMI minor, and BRMA. Hazard ratios as compared to the VKA group are based on the (stratified, only for Overall, 2.5 mg BID/15 mg QD comparing VKA) Cox proportional hazards model. Log-Rank P-values as compared to VKA group are based on the (stratified, only for Overall, 2.5 mg BID/15 mg QD comparing VKA) two-sided log rank test. Gibson et al. AHA 2016

VKA + DAPT

Riva + DAPT

18.0%

p<0.00018

HR = 0.63 (95% CI 0.50-0.80)ARR = 8.7NNT = 12

706697

636593

600555

579521

543461

509426

409329

Riva + DAPTVKA + DAPT

VKA + DAPT

Riva + P2Y12

16.8%

p<0.000013

HR = 0.59 (95% CI 0.47-0.76)ARR = 9.9NNT = 11

696697

628593

606555

585521

543461

510426

383329

Riva + P2Y12

VKA + DAPT

Riva + P2Y12

VKA + DAPTRiva + DAPT

Riva + P2Y12 v. VKA + DAPTHR=0.59 (95% CI: 0.47-0.76)p <0.000013ARR=9.9NNT=11

Riva + DAPT v. VKA + DAPTHR=0.63 (95% CI: 0.50-0.80)p <0.00018ARR=8.7NNT=12

696706697

628636593

606600555

585579521

543543461

510509426

383409329

Riva + P2Y12

Riva + DAPTVKA + DAPT

Kaplan-Meier Estimates of First Occurrence of CV Death, MI or Stroke

Car

diov

ascu

lar D

eath

, Myo

card

ial

Infa

rctio

n, o

r Stro

ke (%

)

DaysRiva + P2Y12

Riva + DAPTVKA + DAPT

694704695

648662635

633640607

621628579

590596543

562570514

430457408

VKA + DAPT

Riva + DAPT

Riva + P2Y12

Riva + P2Y12 v. VKA + DAPTHR=1.08 (95% CI: 0.69-1.68)p=0.750

Riva + DAPT v. VKA + DAPTHR=0.93 (95% CI: 0.59-1.48)p=0.765

6.5%

5.6%6.0%

Treatment-emergent period: period starting after the first study drug administration following randomization and ending 2 days after stop of study drug. Composite of adverse CV events is composite of CV death, MI, and stroke. Hazard ratios as compared to VKA group are based on the (stratified, only for the Overall, 2.5 mg BID/15 mg QD comparing VKA) Cox proportional hazards model. Log-Rank P-values as compared to the VKA group are based on the (stratified, only for Overall, 2.5 mg BID/115 mg QD comparing VKA) two-sided log rank test.6 Subjects were excluded from all efficacy analyses because of violations in Good Clinical Practice guidelines

No. at risk

Gibson et al. AHA 2016

All

Cau

se R

ehos

pita

lizat

ion

(%)

696706697

Days609607592

582570540

559548490

496493422

437454369

322367272

Riva + P2Y12

Riva + DAPTVKA + DAPT

No. at risk

Riva + P2Y12VKA + DAPT

Riva + DAPT

34.1%31.2%

41.5%

Riva + P2Y12 v. VKA + DAPTHR=0.77 (95% CI: 0.65-0.92)p=0.005ARR=7.4NNT=14

Riva + DAPT v. VKA + DAPTHR=0.74 (95% CI: 0.61-0.88)p=0.001ARR=10.3NNT=10

Treatment-emergent period: period starting after the first study drug administration following randomization and ending 2 days after stop of study drug. Rehospitalizations do not include the index event and include the first rehospitalization after the index event. Hazard ratios as compared to the VKA group are based on the Cox proportional hazards model. Log-Rank P-values as compared to VKA group are based on the two-sided log rank test.

All Cause Hospitalization for an Adverse Event

Gibson et al. AHA 2016

PIONEER AF – PCI

▪ Among stented AF participants, administration of either rivaroxaban 15 mg daily plus P2Y12 monotherapy for one year or rivaroxaban 2.5 mg BID plus 1, 6, or 12 months of DAPT reduced the risk of clinically significant bleeding as compared with standard of care VKA plus 1, 6, or 12 months of DAPT and yielded comparable efficacy with broad confidence intervals

▪ .

EUCLID study

▪ A Study Comparing Cardiovascular Effects of Ticagrelor and Clopidogrel in Patients With Peripheral Artery Disease

▪ The primary outcome, incidence of cardiovascular death, myocardial infarction, or ischemic stroke, occurred in 10.8% of the ticagrelor group versus 10.6% of the clopidogrel group (p = 0.65). Lack of efficacy was also observed in the cohort with a history of lower extremity revascularization: 11.4% with ticagrelor versus 11.3% with clopidogrel (p = 0.90).

▪ Secondary outcomes:▪ Acute limb ischemia: 1.7% with ticagrelor versus 1.7% with clopidogrel▪ Major bleeding: 1.6% with ticagrelor versus 1.6% with clopidogrel▪ Dyspnea resulting in drug discontinuation: 4.8% with ticagrelor versus

0.8% with clopidogrel (p < 0.001)

EUCLID study

▪ The primary safety end point, TIMI major bleeding, occurred in 1.6% of the patients in both the ticagrelor group and the clopidogrel group

▪ The rates of fatal bleeding, intracranial bleeding, and TIMI minor bleeding were similar in the two groups

▪ There were numerically fewer fatal bleeding events in the ticagrelor group than in the clopidogrel group (10 vs. 20), but there were significantly more bleeding events leading to discontinuation with ticagrelor than with clopidogrel (168 vs. 112; P<0.001)

▪ Overall, the TIMI major bleeding events were few and generally consistent among subgroups

EUCLID study

Conclusion- In patients with symptomatic peripheral artery disease,

ticagrelor was not superior to clopidogrel for the reduction of cardiovascular events, and each drug was associated with similar rates of major bleeding.

- However, ticagrelor was discontinued more frequently than clopidogrel because of the occurrence of side effects (mainly dyspnea and minor bleeding).

- * clopidogrel – od dose, cheap and equal efficacy

PRECISION trial

▪ A Randomized Trial Comparing the Safety of Celecoxib vs Ibuprofen or Naproxen

▪ The study demonstrated that patients treated with prescription doses of celecoxib, ibuprofen or naproxen had similar rates of cardiovascular events and dispels the long held perception of excess cardiovascular risk associated with long term use of Celebrex.”

PRECISION trial

▪ Statistically strong evidence that cardiovascular risk with approved doses of celecoxib is not greater than that of prescription doses of ibuprofen and naproxen.

▪ A primary endpoint occurred in 2.3 percent of patients receiving celecoxib as compared to 2.5 percent for patients receiving naproxen and 2.7 percent for patients receiving ibuprofen.

▪ Significantly fewer GI events occurred among patients treated with celecoxib as compared with those receiving prescription doses of either ibuprofen or naproxen.

▪ * No comparison with placebo

GLAGOV study

▪ Global Assessment of Plaque Regression With a PCSK9 Antibody as Measured by Intravascular Ultrasound (GLAGOV)

▪ The primary outcome, nominal change in percent atheroma volume at 78 weeks, was -0.95% in the evolocumab group versus 0.05% in the placebo group (p < 0.001 for between-group comparison). Results were the same in multiple tested subgroups.

▪ Secondary outcomes:▪ Patients with plaque regression: 64.3% with evolocumab versus 47.3

% with placebo (p < 0.001)▪ Major adverse cardiac events: 12.2% with evolocumab versus 15.3%

with placebo▪ 35% of patients still had atheroma progression even on evolocumab,

suggesting factors other than LDL may be involved

GLAGOV study

▪ The study was not large enough to make any definitive statements about clinical events or safety

▪ cardiovascular events were trending in the right direction (15.3% on placebo vs 12.2% on evolocumab), and adverse events looked reassuring, with no excess of myalgia, neurocognitive events, or new onset diabetes.

ART Trial

▪ To determine if the use of both internal mammary arteries (IMA) during coronary artery bypass graft (CABG) surgery improves survival, and reduces the need for further intervention (including surgery) compared to using one mammary artery. Patients will be followed up for 10 years after surgery.

▪ No significant differences in major cardiovascular outcomes were found over 5 years of follow-up.

▪ However, the incidence of sternal wound complication and reconstruction was two- and three-fold higher, respectively, with bilateral IMA CABG, and all of these events occurred in the first year and mainly in diabetics and those with a high BMI.

ART Trial

▪  In summary, adding one more IMA graft to patients undergoing CABG with LIMA grafting does not add further clinical benefit but may increase the risk of sternal wound complication, especially in at-risk populations.

▪ But the trial is only half way and we need wait 5 more years to see the full results

FUTURE trial

▪ FFR-Guided Revascularization vs. Angioplasty in CAD Patients ▪ Fractional flow-reserve (FFR)-guided revascularization may

not be a safe treatment strategy decision tool in patients with multivessel coronary artery disease (CAD), according to the results of the FUTURE Trial

▪ Acute coronary syndrome and stable coronary artery disease consecutive patients were randomized to either FFR-guided management or traditional management.

▪ The primary end point was a composite of major adverse cardiovascular events, including all-cause death, non-fatal heart attack, stroke and repeat coronary revascularization at one year.

FUTURE trial

▪ In the trial, only FFR values that were found to be 0.80 or below (n=399) were considered significant and could be treated by coronary bypass or stenting. For the angiography group, that cutoff was 50% stenosis or more.

▪ The study’s independent data safety monitoring board recommended to stop study enrollment due to a significant greater mortality in the FFR-group after analysis of the first 836 randomized patients.

▪ The interim results for the 933 included patients show at least a non-significant excess of mortality trend in the FFR group and no clinical benefit of FFR in comparison with angioplasty.

▪ In high-risk patients, FFR may not help for treatment decisions and could be associated with a negative safety signal.

ORION 1 Trial -Dosage selection for Phase III

▪ assessed a range of doses of inclisiran, which could provide qualitatively similar reductions in LDL-C to current approaches, but through quarterly or bi-yearly injections (every three or six months)

▪ Primary endpoint▪ Percent change in LDL-C levels from baseline at day 180

▪ Secondary endpoint▪ LDL-C levels at day 90 and other lipid parameters▪ LDL-C and PCSK9 levels over time▪ Safety and tolerability

Efficacy of one dose of inclisiran up to day 90Other lipid parameters - change from baseline

Total=4941 InclisiranDay 90 Placebo 100 mg 200 mg 300 mg 500 mg

N=124 N=61 N=122 N=122 N=65

Total cholesterol mean (SD) -1% (16) -22% (12) -26% (14) -

28% (15) -30% (11)

Triglyceride median 3% 1% -11%

-10% 0%

HDL-C mean (SD) -2% (14) 5% (11) 8% (12) 9% (16) 8% (15)

Non-HDL-C mean (SD) 0% (20) -30% (13) -37% (18) -

40% (19) -42% (15)

Apo-B mean (SD) -2% (16) -28% (12) -34% (15) -

37% (16) -40% (13)

Lp(a) median -1% -18% -21%

-23% -22%1: Includes patients with baseline and day-90 measurement for all parameters

ORION 1 Trial

▪ Inclisiran inhibits PCSK9 synthesis by RNA interference and lowers LDL-C significantly▪ One dose of 300 mg achieves mean 51% LDL-C reduction

▪ Two doses of 300 mg achieve mean 57% LDL-C reduction

▪ Inclisiran is well tolerated with no material safety issues▪ Potential for biannual or triannual dosing affirmed▪ Results of ORION-1 support start of Phase III▪ The efficacy, safety and dosing profile of inclisiran are likely to

ensure significant and durable reductions in LDL-C and thus potentially impact cardiovascular outcomes

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