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
THANK YOU
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