Land mark trials 2015

Land mark trials in 2015
Dr K. V. Siva krishna

Topic outline
• Recent trials on
• Hypertension
• Heart failure
• ACS
• Lipids
• PAH
• Miscellaneous

• The SPRINT trial
• A Randomized Trial of Intensive versus
Standard Blood-Pressure Control.

• Among persons 50 years of age or older,
isolated systolic hypertension is the most
common form of hypertension, and
systolic blood pressure becomes more
important than diastolic blood pressure as
an independent risk predictor for coronary
events, stroke, heart failure, and end-
stage renal disease.

• Clinical trials have shown that treatment of
hypertension reduces the risk of
cardiovascular disease outcomes,
including incident stroke (by 35 to 40%),
myocardial infarction (by 15 to 25%),and
heart failure (by up to 64%).
• The target for systolic blood-pressure
lowering is uncertain.

• The current trial Systolic Blood Pressure
Intervention Trial (SPRINT), compared the
benefit of treatment of systolic blood
pressure to a target of less than 120 mm
Hg with treatment to a target of less than
140 mm Hg.

Eligibility, Randomization, and Follow-up.
The SPRINT Research Group. N Engl J Med
2015;373:2103-2116
STUDY
DESIGN

• PRIMARY OUTCOMES:
• COMPOSITE of
myocardial infarction,
acute coronary syndrome
not resulting in myocardial
infarction, stroke, acute
decompensated heart
failure, or death from
cardiovascular causes.
• Secondary outcomes
• Included the individual
components of the primary
composite outcome, death
from any cause, and the
composite of the primary
outcome or death from any
cause
• Renal outcome
• With chronic kidney disease
decrease in the eGFR of 50%
or more or the development of
ESRD requiring long-term
dialysis or kidney
transplantation.
• decrease in the eGFR of 30%
or more to a value of less than
60 ml per minute per 1.73 m2

Characteristic Intensive Treatment
(N = 4678)
Standard Treatment
(N = 4683
Age ≥75 yr 1317 (28.2) 1319 (28.2)
Chronic kidney disease‡ 1330 (28.4) 1316 (28.1)
Cardiovascular disease 940 (20.1) 937 (20.0)
Female sex — no. (%) 1684 (36.0) 1648 (35.2)
Systolic bp 139.7±15.8 139.7±15.4
Diastolic 78.2±11.9 78.0±12.0
Statin use — no./total
no. (%)
1978/4645 (42.6) 2076/4640 (44.7)
Aspirin use — no./total
no. (%)
2406/4661 (51.6) 2350/4666 (50.4)
Criterion for increased cardiovascular risk — no.
Baseline Characteristics of the Study Participants.

Systolic Blood Pressure in the Two Treatment Groups over the Course of the Trial.
The SPRINT Research Group. N Engl J Med 2015;373:2103-2116

Primary Outcome and Death from Any Cause.
The SPRINT Research Group. N Engl J Med
2015;373:2103-2116
245
314
Total deaths
365(155 Vs
210 )
p=0.003.
155
210
P=<0.0001

Forest Plot of Primary Outcome According to Subgroups.

Primary and Secondary Outcomes and Renal Outcomes.

Serious Adverse Events, Conditions of Interest, and Monitored Clinical Events.

Conclusions
• Conclusion:
• Among patients at high risk for cardiovascular
events but without diabetes, targeting a
systolic blood pressure of less than 120 mm
Hg, as compared with less than 140 mm Hg,
resulted in lower rates of fatal and nonfatal
major cardiovascular events and death from
any cause, although significantly higher rates
of some adverse events were observed in the
intensive-treatment group.

Study Overview
• Ezetimibe targets the Niemann–Pick C1–like 1
(NPC1L1) protein, thereby reducing absorption of
cholesterol from the intestine.
• When added to statins, ezetimibe reduces LDL
cholesterol levels by an additional 23 to 24%, on
average.
• The Improved Reduction of Outcomes: Vytorin Efficacy
International Trial (IMPROVE-IT) evaluated the effect of
ezetimibe combined with simvastatin, as compared with
that of simvastatin alone, in stable patients who had had
an acute coronary syndrome and whose LDL cholesterol
values were within guideline recommendations.
• In this trial, patients with an acute coronary syndrome
within the previous 10 days were randomly assigned to
simvastatin plus either ezetimibe or placebo

• Primary end point:
composite of
cardiovascular death,
nonfatal myocardial
infarction, unstable
angina requiring
rehospitalization,
coronary
revascularization (≥30
days after
randomization), or
nonfatal stroke.
• The median follow-
up was 6 years

Baseline Characteristics.
Cannon CP et al. N Engl J Med
2015;372:2387-2397

Kaplan–Meier Curves for the Primary Efficacy End Point.
Cannon CP et al. N Engl J Med 2015;372:2387-2397

Plot of the IMPROVE-IT Trial Data and Statin Trials for Change in Low-Density Lipoprotein
(LDL) Cholesterol versus Clinical Benefit.

Primary, Secondary, and Individual End Points.

Prespecified Safety End Points.

Conclusions
• In conclusion, the addition of ezetimibe to statin therapy
in stable patients who had had an acute coronary
syndrome and who had LDL cholesterol levels within
guideline recommendations further lowered the risk of
cardiovascular events.
• The event reduction was consistent with the predicted
effects seen with statins, even in the range of low LDL
cholesterol levels in this trial, and no offsetting adverse
events or toxic effects were observed.
• When added to statin therapy, ezetimibe resulted in
incremental lowering of LDL cholesterol levels and
improved cardiovascular outcomes.
• Moreover, lowering LDL cholesterol to levels below
previous targets provided additional benefit.

• Two of the most commonly used
antithrombotic worldwide are
unfractionated heparin, an indirect
thrombin inhibitor, with or without the
concomitant use of a glycoprotein IIb/IIIa
inhibitor, and bivalirudin, a direct thrombin
inhibitor, with a glycoprotein IIb/IIIa
inhibitor added only for periprocedural
ischemic complications.

Time-to-Event Curves through 30 Days
Stone GW et al. N Engl J Med 2008;358:2218-2230
HORIZONS AMI TRIAL

Unfractionated heparin versus bivalirudin in primary
percutaneous coronary intervention (HEAT-PPCI): an
open-label, single centre, randomised controlled trial

Figure 2
The Lancet 2014 384, 1849-1858DOI: (10.1016/S0140-6736(14)60924-7)
Compared with bivalirudin,
heparin reduces the incidence
of major adverse ischaemic
events in the setting of PPCI,
with no increase in bleeding
complications. Systematic use
of heparin rather than
bivalirudin would reduce drug
costs substantially

• MATRIX Antithrombin was a randomized
comparison of bivalirudin and
unfractionated heparin involving 7213
patients with ST segment elevation
myocardial infarction (STEMI) or a non–
ST-segment elevation acute coronary
syndrome for whom PCI was planned

• MATRIX Treatment Duration was a
randomized comparison of prolonged
bivalirudin administration with a post-PCI
infusion with short-term bivalirudin
administration without a post-PCI infusion,

STUDY DESIGN
• Total patients(7213)
Bivaluridin group(3610) Unfractionated heparin
group(3603)
Post PCI
infusion
(1799)
No post PCI
infusion
(1811)

• Coprimary outcomes
• Major adverse cardiovascular
events,: a composite of death from
anyNcause, myocardial infarction,
or stroke, up to 30 days, and
• net adverse clinical
events,Bleeding Academic
Research Consortium [BARC]
type 3 or 5 or major adverse
cardiovascular events, up to 30
days.
• Primary outcome (MATRIX
Treatment Duration)
• composite of urgent target-vessel
revascularization, definite stent
thrombosis, or net adverse clinical
events up to 30 days
• Secondary outcomes
• Death from cardiovascular
• causes, and stent thrombosis.
• Bleeding was also assessed and
adjudicated on the basis of the
Thrombolysis in Myocardial
Infarction (TIMI) and
• Global Utilization of Streptokinase
and Tissue Plasminogen Activator
for Occluded Coronary Arteries
(GUSTO17) scales.

Characteristics of the Patients at Baseline.
Valgimigli M et al. N Engl J Med 2015;373:997-1009

Coprimary Composite Study Outcomes at 30 Days.

Primary Composite Outcome at 30 Days, According to Duration of Bivalirudin Infusion.

Clinical Presentation and Medications at Baseline.

Clinical Outcomes up to 30 Days.

Conclusions
• In patients with an acute coronary syndrome,
the rates of major adverse cardiovascular
events and net adverse clinical events were not
significantly lower with bivalirudin than with
unfractionated heparin.
• The rate of the composite of urgent target-
vessel revascularization, definite stent
thrombosis, or net adverse clinical events was
not significantly lower with a post-PCI bivalirudin
infusion than with no post-PCI infusion.

CONCLUSIONS
• In conclusion, among patients with acute coronary
syndromes undergoing invasive treatment, neither the
rate of major adverse cardiovascular events nor the rate
of net adverse clinical events was significantly lower with
bivalirudin than with unfractionated heparin and
discretionary use of glycoprotein IIb/IIIa inhibitors.
• The post-PCI infusion of bivalirudin for at least 4 hours
after the intervention did not result in a lower rate of the
composite outcome of ischemic and bleeding events,
including stent thrombosis, than the rate with no post-
PCI infusion.

Background
• Current therapies for pulmonary arterial hypertension
target abnormalities in one of three intracellular
pathways with signaling dysfunction:
• The prostacyclin, nitric oxide, or endothelin pathway.
However, no single class of drug is consistently effective
in treating all patients, which suggests that no single
pathway plays a dominant pathogenic role
• Data on the effect of initial combination therapy with
ambrisentan and tadalafil on long-term outcomes in
patients with pulmonary arterial hypertension are scarce.

Inclusion criteria
• 18 and 75 years of age
• Weight >40 kg
• WHO Functional Class II or III
i. mPAP of >25 mmHg
ii. PVR >240 dynes.sec/cm5
iii. PCWP/LVEDP of ≤15 mmHg
Exclusion criteria
• Received previous PAH therapy
(PDE5i, ERA, chronic prostanoid*)
within 4 weeks prior to the
Screening Visit
• Pregnant females
• Inotropes with in past 2 weeks
before enrollment
• Known hypersensitivity to drugs
Patient selection

Follow-up (at weeks 4, 8, 16, and 24 and
every 12 weeks thereafter)
Ambrsentan+Tadalafil
Ambrsentan ALONE
End of
the study
Study design
Tadalafil alone
Randomisation done in
2:1:1 ratio
0
253 patients
126 patients
121 patients
Mean follow up
610 days
Total of 500 patients

End points
• Components of the
Primary End Point
• Death from any cause
• Hospitalization for
worsening pulmonary
arterial hypertension
• Disease progression
• Unsatisfactory long-term
clinical response
• Secondary end
points
• Change from baseline to
week 24 in N-terminal
• Pro–brain natriuretic
peptide (NT-proBNP)
level
• 6-minute walk distance,
WHO functional class,
and Borg dyspnea index

Characteristic Combinat
ion-
Therapy
Group
(N = 253
Pooled-
Monoth
erapy
Group
(N = 247
Ambrisentan
-
Monotherapy
Group
(N = 126
Tadalafil-
Monotherapy
Group
(N = 121
Age 54.5±14.3 54.2±14.
9
53.9±14.7 54.5±15.2
Female sex — no. (%) 188 (74) 200 (81) 100 (79) 100 (83)
Hypertension 104 (41) 95 (38) 52 (41) 43 (36)
Diabetes 19 (8) 30 (12) 13 (10) 17 (14)
Coronary artery
disease
16 (6) 4 (2) 2 (2) 2 (2)
Idiopathic 127 (50) 138 (56) 72 (57) 66 (55)
Associated with
connective-tissue
disease
103 (41) 84 (34) 44 (35) 40 (33)
Classification of pulmonary arterial hypertension
— no. (%)
Demographic and base line characteristics

Disease Severity at Baseline.
Galiè N et al. N Engl J Med 2015;373:834-844

Results
• A total of 123 participants had a primary
endpoint event up to the time of the final-
assessment visit, including 46 (18%) in the
combination- therapy group and 77 (31%)
in the pooled monotherapy group (43
[34%] in the ambrisentan- monotherapy
group and 34 in the tadalafil-monotherapy
group.

Primary and Secondary Efficacy End Points.
Galiè N et al. N Engl J Med 2015;373:834-844

Kaplan–Meier Curves for the Probability of a First Adjudicated Primary End-Point Event.
Galiè N et al. N Engl J Med
2015;373:834-844

Safety
• Peripheral edema, headache, nasal congestion
and anemia were more common in the
combination- therapy group than in either
monotherapy group, dizziness was more
common in the combination-therapy group than
in the tadalafil monotherapy group, and syncope
was more common in the tadalafil-monotherapy
group than in the other groups; the incidence of
hypotension was similar in the three study
groups.

ConclusionsConclusion
• Among participants with pulmonary arterial
hypertension who had not received previous
treatment, the risk of the composite outcome of
clinical failure was significantly lower among
those who received initial combination therapy
with ambrisentan and tadalafil than among those
who received monotherapy with either
ambrisentan or tadalafil

Twelve vs 48 months of dual antiplatelet
therapy after drug-eluting stent placement
The OPTIDUAL randomized trial
09/12/2015 ESC JOURNAL

Background (1)
The long-term risk of very late
thrombosis after PCI does not
decrease over time
Nearly half of the recurrent MACE
after PCI for ACS are associated
with non-culprit lesions at the time
of PCI
Wenaweser P et al. JACC 2008;52 Stone G et al. N Engl J Med 2011;364

Background (2)
DAPT trial: showed a reduction in rates of MACCE and stent
thrombosis but an increase in bleeding
Mauri L et al. N Engl J Med 2014;371:2155

Hypothesis
• On a background of aspirin, continuing
clopidogrel for up to 48 months would be
superior to stopping clopidogrel at 12
months following drug-eluting stent (DES)
implantation in reducing net adverse clinical
events (composite of death, MI, stroke or major
ISTH bleeding)
– Randomized, multicentre, open-label study conducted in
58 sites in France (January 2009–January 2013)

Inclusion criteria
• Patients with stable
CAD or ACS
• With ≥1 lesion with
a significant
stenosis in an
artery ≥2.25 mm
• Implanted with ≥1
DES of any type
Exclusion criteria
• DES implantation in an
unprotected left main
coronary artery
• Requirement for oral
anticoagulation
• Malignancies or other
coexisting conditions
associated with a life
expectancy of <2 years
Patient selection

DES insertion
12 ± 3 months
ASPIRIN + CLOPIDOGREL
Randomization of patients free of
MACCE or
bleed
Follow-up (every 6 months between 12 and 48 months)
ASPIRIN + CLOPIDOGREL
ASPIRIN ALONE
End of
the study
0 12 months
48 months
Study design

Methods
• Primary endpoint
– Net adverse clinical events: composite of all-
cause death, non-fatal MI, stroke, or major
bleeding (ISTH classification)
• Secondary endpoints
– Individual components of the primary outcome
– Stent thrombosis (defined according to the
Academic Research Consortium [ARC])
– Repeat revascularization of the treated vessel
– Bleeding (ISTH, GUSTO, TIMI, BARC
classifications)

Superiority trial:
– 983 patients per arm
– 80% power, alpha type-I error of 5%
– Significant reduction in the primary composite
outcome at 3 years post-randomization from 7%
with aspirin alone to 4% with extended DAPT
Owing to lack of resources and slower enrolment than
anticipated, the executive committee and sponsor
recommended termination of follow-up at the end of
September 2014
Statistical analysis

EXTENDED DAPT GROUP
n=695
ASPIRIN GROUP
n=690
P value
Age (years), mean (SD) 64.1 (10.8) 64.2 (11.5) 0.88
Women 18.3% 20.7% 0.23
Diabetes mellitus 30.6% 32.2% 0.54
Hypertension 57% 60.4% 0.19
Current/recent smoker 61.2% 57.8% 0.21
Previous PCI 25.9% 27.0% 0.66
Previous MI 17.1% 17.7% 0.78
Previous CABG 5.3% 5.1% 0.83
Stroke or TIA 4.2% 3.6% 0.60
Peripheral artery
disease
4.9% 6.5% 0.19
Patient baseline characteristics

EXTENDED DAPT GROUP n=695 ASPIRIN GROUP n=690 P value
Indication for PCI
STEMI 10.7% 11.9% 0.47
Non-STEMI 14.2% 17.0% 0.39
Unstable angina 9.5% 9.1% 0.81
Stable angina 34.5% 30.0% 0.07
Silent ischaemia 19.9% 21.9% 0.35
Other 11.2% 10.1% 0.63
Type of DES
Sirolimus 19.9% 17.5% 0.17
Paclitaxel 15.2% 16.0% 0.65
Zotarolimus 8.3% 10.8% 0.05
Everolimus 50.2% 49.2% 0.66
Other 6.4% 6. 5% 0.93
Target vessel
Left main <1% >1% 0.69
LAD 58% 64% 0.007
LCX 33% 31% 0.59
RCA 41% 39% 0.58
Procedural characteristics
65.6%
34.4% 38.0
%
62.0
%
35.1% 33.5
%

EXTENDED DAPT
GROUP n=695
ASPIRIN GROUP
n=690
P value
Statin 94.4% 93.3% 0.41
ACE inhibitor 75.1% 74.2% 0.71
Proton-pump inhibitor 49.8% 46.8% 0.27
Beta-blocker 78.0% 81.6% 0.09
Calcium-channel
inhibitor
30.9% 29.0% 0.43
Aspirin 100% 99.6% 0.12
Daily dose of aspirin at
the time of
randomization (mg)
0.84
≤100 78.6% 78.2%
101–300 21.4% 21.8%
Treatment at randomization

R 0.75, 95% CI 0.50-1.28
P=0.17
5.8%
7.5%
Primary outcome:
Composite of death, MI, stroke, major bleed

Components of the primary
endpoint
HR 0.65, CI 0.34-1.22
P=0.18
HR 0.69, CI 0.22-2.18
P=0.53
HR 0.67, CI 0.31-1.44
P=0.31
HR 0.98, CI 0.47-2.05
P=0.95
Death Stroke
MI Major bleed

4.2%
6.4%
HR 0.64, 95% CI 0.40-1.02
P=0.06
Post-hoc analysis of ischaemic
outcomes: death, stroke, or MI

Bleeding events
Extended-DAPT
group
Aspirin group Difference
Percentage points
(95% CI)
P value
GUSTO moderate or
severe
1.9% 1.7% 0.1 (-1.3 to 1.5) 0.85
Moderate 1.6% 1.2% 0.4 (-0.8 to 1.7) 0.49
Severe 0.4% 0.6% -0.2 (-0.9 to 0.6) 0.72
BARC type 2.6% 2.9% - 0.3 (-2.0 to 1.4) 0.72
2 0.7% 1.0% -0.3 (-1.3 to 0.7) 0.85
3 1.9% 2.0% -0.1 (-1.6 to 1.3) 0.83
5 0.1% 0 0.1 (-0.1 to 0.4) 1.00
TIMI major or minor 2.6% 2.9% -0.3 (-1.4 to 2.0) 0.72
Major 0.6% 0.6% 0.0 (-0.8 to 0.8) 1.00
Minor 2.2% 2.3% -0.1 (-1.7 to 1.4) 0.84
ISTH major 2.0% 2.0% 0.0 (-1.5 to 1.5) 0.98
ISTH moderate 0.9% 1.0% -0.1 (-1.1 to 0.9) 0.77

Meta-analysis of RCTs testing
12 months vs longer DAPT after
DES: Death, stroke, MI

Study limitations
• Only powered to detect major differences in
ischaemic and bleeding events
• Termination of the trial before enrolment and
follow-up were completed reduced the trial
power
• Open-label trial, although all clinical
outcomes were adjudicated by an
independent clinical event committee blinded
to treatment assignment

Conclusions (1)
Extending DAPT duration for up to 48 months
did not achieve statistical superiority compared
with stopping clopidogrel at 12 months with
regards to net adverse clinical outcomes, in
patients free of MACCE and major bleed 12
months after stent implantation

Conclusions (2)
• Borderline but non-statistically significant
reduction in post-hoc analysis of
ischaemic outcomes with extended DAPT
• No apparent increase in bleeding and all-
cause mortality with extended DAPT

Results from TASTE(september 18, 2014)
NEJM
Routine thrombus aspiration before
PCI in patients with STEMI did not
reduce the rate of death from any
cause or the composite of death from
any cause, rehospitalization for
myocardial infarction, or stent
thrombosis at 1 year

INCLUSION CRITERIA
• Patients with
STEMI who were
referred for
primary PCI within
12 hours after the
onset of
symptoms were
eligible to
participate in the
trial.
EXCLUSION CRITERIA
• Patients who had
undergone
previous
coronaryartery
bypass grafting or
those who had
received
fibrinolytic therapy
were not eligible
TOTAL TRIAL

Follow-up
THROMBECTOMY+ PCI
End of
the study
Study design
PCI ALONE
1:1 ratio
0
Mean follow up
180 daysTotal of 10,732 patients
5372 patients
5360 PATIENTS

• Primary outcome
• composite of death from
cardiovascular causes,
recurrent myocardial
infarction, cardiogenic
shock, or New York Heart
Association (NYHA) class
IV heart failure within 180
days. The key
• Safety outcome was
stroke within 30 days

LIMITATIONS
• First: The treating interventional cardiologists
were aware of study group assignments. (BIAS)
• Second: study included pt with less thrombus
burden also
• Third: This trial evaluated a strategy of routine
upfront thrombectomy versus PCI alone with
thrombectomy reserved as bailout; it did not
study the effect of selective use of
thrombectomy versus no thrombectomy

• Conclusion:
• In patients with STEMI who were undergoing PCI, a
strategy of routine manual thrombectomy did not reduce
the risk of cardiovascular death, recurrent myocardial
infarction, cardiogenic shock, or class IV heart failure
within 180 days, as compared with a strategy of PCI
alone with only bailout thrombectomy.
• Routine thrombectomy was associated with an increased
rate of stroke within 30 days.

• The potential benefit of dual antiplatelet
therapy beyond 1 year after a myocardial
infarction has not been established

Inclusion criteria
• Men and women >50 years
• Documented history of presumed
spontaneous MI with their most
recent MI occurring 1 to 3 years
prior to randomization and have
at least 1 of the following risk
factors: − Age ≥65 years
• − Diabetes mellitus requiring
medication
• −Documented history of a second
prior presumed spontaneous MI
(>1 year ago)
• − Angiographic evidence of
multivessel coronary artery
disease (CAD)
• Chronic, non-end stage renal ds
• Able to take ASA 75-150 mg/d
Exclusion criteria
• Planned use of ADP receptor
blockers
• Planned coronary,
cerebrovascular, or peripheral
arterial revascularization
• Need for chronic oral anticoagulant
therapy or chronic LMWH
• Ischemic stroke <14 days
• Liver and renal failure on HD
• Pregnancy/lactation
• Life expectancy <1 yr
• CABG in last 5 yr
• h/o IC bleed or major Sx <30 day
or GI bleed <6 mnths
Patient selection

Primary outcomes
• Composite of
cardiovascular death,
myocardial infarction, or
• Stroke .
Secondary outcomes
• Cardiovascular death
and
• Death from any cause
• Primary safety end point
• Thrombolysis in
Myocardial Infarction
(TIMI) major bleeding
• Secondary safety
endpoint
• Intracranial hemorrhage
• Fatal bleeding

Protocol
Randomised in 1:1:1
fashion

Kaplan–Meier Rates of Cardiovascular Death, Myocardial Infarction, and Stroke through 3
Years, According to Study Group.
Bonaca MP et al. N Engl J Med 2015;372:1791-1800

Hazard Ratios and Rates of the Primary End Point and Individual Components for Each Dose
of Ticagrelor and for the Two Doses Pooled.

Safety End Points as 3-Year Kaplan–Meier Estimates.

Conclusions
• The rates of bleeding and dyspnea were numerically
lower with the 60-mg dose of ticagrelor than with the 90-
mg dose, resulting in a lower rate of discontinuation of
the study drug and a better safety profile with the 60-mg
dose.
• Thus, in general, the 60-mg dose may offer a more
attractive benefit–risk profile, although these differences
were not significant

• In conclusion, the addition of ticagrelor, at
a dose of 90 mg twice daily or 60 mg twice
daily, to low-dose aspirin reduced the risk
of cardiovascular death, myocardial
infarction, or stroke and increased in the
risk of TIMI major bleeding among patients
who had had a myocardial infarction 1 to 3
years earlier.

• Background
• Dual antiplatelet therapy is recommended
after coronary stenting to prevent
thrombotic
• complications, yet the benefits and risks of
treatment beyond 1 year are uncertain.

• Patients were enrolled after they had undergone a coronary stent
procedure in which a drug-eluting stent was placed. After 12 months
of treatment with a thienopyridine drug (clopidogrel or prasugrel) and
aspirin, patients were randomly assigned to continue receiving
thienopyridine treatment or to receive placebo for another 18
months; all patients continued receiving aspirin.

End points
• The coprimary
efficacy end points
were stent thrombosis
and major adverse
cardiovascular and
cerebrovascular
events (a composite
of death, myocardial
infarction, or stroke)
during the period from
12 to 30 months.
• The primary safety
end point was
moderate or
severe bleeding

• Conclusions
• Dual antiplatelet therapy beyond 1 year
after placement of a drug-eluting stent, as
compared with aspirin therapy alone,
significantly reduced the risks of stent
thrombosis and major adverse
cardiovascular and cerebrovascular
events but was associated with an
increased risk of bleeding.

Land mark trails of 2014
Valsartan/sacubitril (codenamed LCZ696) is an
investigational combination drug consisting of
two antihypertensives in a 1:1 mixture by molecule count

Eligibility requirements
an age of at least 18 years,
• (NYHA) class II, III, or IV
symptoms, EF< 40%
• BNP level of at least 150 pg/ml
(OR [NT-proBNP] level ≥600
pg/ml)or, if they had been
hospitalized for heart failure within
the previous 12 months, a BNP of
at least 100 pg/ml (or an NT-
proBNP≥400 pg/ml).
• Patients taking any dose of an
ACE inhibitor or ARB were
considered for participation, but
for at least 4 weeks before
screening, patients were required
to take a stable dose of a beta-
blocker and an ACE inhibitor (or
ARB) equivalent to at least 10 mg
of enalapril daily.
Exclusion criteria
• Symptomatic hypotensionSBP 100
mm Hg at screening or 95 mm Hg
at randomization,
• eGFR below 30 ml/min/1.73 of BSA
at screening or at randomization or
a decrease in the eGFR of more
than 25% (which was amended to
35%) between screening and
randomization,
• a serum potassium level of more
than 5.2 mmol/lat screening (or
above 5.4 mmol per liter at
randomization),
• history of angioedema or
unacceptable side effects during
receipt of ACE inhibitors or ARBs

conclusion
• In, angiotensin receptor–neprilysin inhibition with
LCZ696 was superior to ACE inhibition alone in reducing
the risks of death and of hospitalization for heart failure.
• The magnitude of the beneficial effect of LCZ696, as
compared with enalapril, on cardiovascular mortality
was at least as large as that of long-term treatment with
enalapril, as compared with placebo.
• This robust finding provides strong evidence that
combined inhibition of the angiotensin receptor and
neprilysin is superior to inhibition of the renin–
angiotensin system alone in patients with chronic heart
failure.

Estimating the Long-Term Treatment
Benefits of Sacubitril–Valsartan
• To estimate the long-term treatment effects
of sacubitril– valsartan versus enalapril,
they derived actuarial estimates of age-
specific event rates and expected survival
times using data regarding the age at
randomization and the age at the time of
an outcome event from the PARADIGM-
HF trial.

Claggett B et al. N Engl J Med 2015;373:2289-2290.
Probability of Death from Any Cause or the Primary End Point Extrapolated
from the PARADIGM-HF Trial, According to Age Group.

• The protective effects of sacubitril–valsartan
remain consistent with long-term use, the
available follow up data estimate that treatment
with sacubitril–valsartan would result in a
projected benefit of 1 to 2 years of increased life
expectancy and survival free from heart failure
for patients such as those in the PARADIGM-HF
trial.

• Evolocumab, a monoclonal antibody that
inhibits proprotein convertase subtilisin–
kexin type 9 (PCSK9), significantly
reduced low-density lipoprotein (LDL)
cholesterol levels in short-term studies.

Follow-up
Evalocumab group
End of
the studyStudy design
Standard therapy
2:1 ratio
0 Mean follow up
11.1 months.
Total of 4465 patients
2976 patients
1489 PATIENTS
Evalocumab
420mg s/c
once in a
month
Evalocumab
140mg s/c
every 2 weeks
or 420mg
/month

• In conclusion, patients who had previously participated in
12 shorter-term parent trials of the PCSK9 inhibitor
evolocumab underwent repeat randomization to receive
either evolocumab or standard therapy in the OSLER
program.
• Evolucumab reduced levels of LDL cholesterol by 61%
by 12 weeks, with sustained reduction through the
median 11-month follow- up.
• In a prespecified exploratory analysis, there was
evidence of a reduction in the rate of cardiovascular
events among patients receiving evolocumab

• Clinical Inclusion Criteria:
• Patient must have a diagnosis
of diabetes mellitus (Type 1 or
Type 2) defined according to
the American Diabetes
Association
• Symptomatic coronary artery
disease.
• Angiographic Inclusion
Criteria:
• Lesions 34 mm or less in
length and a reference-vessel
diameter between 2.25 mm
and 4.0 mm
• Clinical Exclusion Criteria
• LVEF <30%
• Acute or chronic Kidney
disease
• Serious medical illness with ife
expectancy <12 mnths
• Angiographic Exclusion
Criteria:
• LMCA stenting
• Venous graft stenting
• Bifurcation stenting
• ISR

• Primary end point
• Target-vessel failure was
defined as a
• composite of cardiac
death,
• target-vessel myocardial
infarction, or
• ischemia-driven target-
vessel revascularization
• Secondary end points
• ischemia-driven target-
lesion revascularization,
• target-vessel
revascularization, the
composite of cardiac
death or target-vessel
myocardial infarction,
major adverse cardiac
events.

Clinical Outcomes.
Kaul U et al. N Engl J Med 2015;373:1709-1719

Prespecified Subgroup Analyses of the Primary End Point.
Kaul U et al. N Engl J Med 2015;373:1709-1719

Conclusion
• Study did not show noninferiority of paclitaxel-
eluting stents to everolimus eluting stents in
patients with coronary artery disease and
diabetes mellitus. Everolimus-eluting stents were
superior to paclitaxel-eluting stents with regard
to several end points, including target-vessel
failure, myocardial infarction, and stent
thrombosis.

• Inclusion criteria
• 18 years of age or older with
myocardial ischemia who were
undergoing PCI for one or two
new native coronary artery
lesions in separate epicardial
coronary vessels were eligible
for enrollment.
• Each lesion was required to be
no more than 24 mm in length
with a reference-vessel
diameter of 2.5 to 3.75 mm on
visual assessment.
• Exclusion criteria
• Patients with acute
myocardial infarction and
specific complex lesion
features were excluded

• The primary end point
was target-lesion failure
(a composite of cardiac
death, target-vessel
myocardial infarction, or
ischemia-driven target-
lesion
revascularization) at 1
year.
were the 1-year rates of
angina (excluding
symptoms through the
time of hospital
discharge), all
revascularization, and
ischemia-driven target-
vessel revascularization

Target-Lesion Failure at 1 Year.
Ellis SG et al. N Engl J Med 2015;373:1905-1915

Subgroup Analyses of Target-Lesion Failure at 1 Year.
Ellis SG et al. N Engl J Med 2015;373:1905-1915

• The Absorb everolimus-eluting bioresorbable vascular
scaffold was within the prespecified noninferiority margin
in comparison with the Xience everolimus-eluting cobalt–
chromium stent for the primary end point of target lesion
failure at 1 year.
• Although 1-year thrombosis rates were not significantly
different between the Absorb scaffold and the Xience
stent, subacute thrombosis between 1 day and 30 days
was more common with the Absorb scaffold in the
intention-to-treat analysis

Conclusion
• In conclusion, in this large-scale
randomized trial, treatment of noncomplex
coronary lesions with the Absorb
everolimus-eluting bioresorbable vascular
scaffold was within the prespecified range
for noninferiority to the Xience everolimus-
eluting cobalt–chromium stent with regard
to target-lesion failure at 1 year.

An observational study
From New York University School of Medicine,
New York (S. Bangalore, Y.G., S.
Blecker, J.X.); and the School of Public
Health, State University of New York at
Albany, Albany (Z.S., E.L.H.). Address reprint
requests to Dr. Bangalore at the Cardiovascular
Clinical Research Center, New
York University School of Medicine, New
York, NY 10016, or at sripalbangalore@
gmail.com.
This article was published on March 16,
2015, at NEJM.org.

• Selexipag, an oral selective IP
prostacyclin-receptor agonist, was shown
to be beneficial in the treatment of
pulmonary arterial hypertension.

Inclusion criteria
• The study population included patients 18 to 75 years of age who
had idiopathic or heritable pulmonary arterial hypertension or
pulmonary arterial hypertension associated with human
immunodeficiency virus infection, drug use or toxin exposure,
connective tissue disease, or repaired congenital systemic-to-
pulmonary shunts.
• Confirmation of the diagnosis by means of right heart catheterization
was required before screening.
• Patients were required to have a pulmonary vascular resistance of
at least 5 Wood units (400 dyn · sec · cm−5) and a 6-minute walk
distance of 50 to 450 m.
• Patients who were not receiving treatment for pulmonary arterial
hypertension and those who were receiving an endothelin- receptor
antagonist, a phosphodiesterase type 5 inhibitor, or both at a dose
that had been stable for at least 3 months were eligible for
enrollment.

• Patients who were receiving prostacyclin
analogues were not eligible.

Enrollment, Randomization, and Follow-up.
Sitbon O et al. N Engl J Med 2015;373:2522-2533

• Primary endpoint
• Composite of death or
• PAH complications that
include
1. Disease progression
2. worsening PAH, req
hospitalisation
3. Initiation of parenteral
prostanoid therapy or
4. long-term oxygen
therapy, or
5. Need for lung
transplantation or BAS.
• in 6-minute walk
distance from baseline to
week 26.
• worsening NYHA class
• death due to PAH or
• Hospitalization due to
PAH worsening
• death from any cause up
to the end of the study

End Points Related to Pulmonary Arterial Hypertension and Death.

Most Frequent Adverse Events and Abnormal Laboratory Results.

• In conclusion, among patients with
pulmonary arterial hypertension, the risk of
the primary composite end point of death
or a complication related to pulmonary
arterial hypertension was significantly
lower among patients who received
selexipag than among those who received
placebo.
• There was no significant difference in
mortality between the two study groups.

• Bleeding is a complication of treatment
with factor Xa inhibitors, but there are no
specific agents for the reversal of the
effects of these drugs.
• Andexanet is designed to reverse the
anticoagulant effects of factor Xa
inhibitors.

ANNEXA-A and ANNEXA-Rland mark trials in 2015

• Bleeding is a complication of treatment
with factor Xa inhibitors, but there are no
specific agents for the reversal of the
effects of these drugs.
• Andexanet is designed to reverse the
anticoagulant effects of factor Xa
inhibitors.
land mark trials in 2015

Take home message
1. Intensive blood pressure control resulted in
lower rates of fatal and nonfatal major
cardiovascular events and death from any
cause.
2. When added to statin therapy, ezetimibe
resulted in incremental lowering of LDL
cholesterol levels and improved cardiovascular
outcomes.
3. The use of evolocumab or arilocumab plus
standard therapy, as compared with standard
therapy alone, significantly reduced LDL
cholesterol levels and reduced the incidence of
cardiovascular events

• The rates of major adverse cardiovascular
events and net adverse clinical events
were not significantly lower with bivalirudin
than with unfractionated heparin.
• Routine manual thrombectomy, as
compared with PCI alone, did not reduce
the risk of cardiovascular death, recurrent
myocardial infarction, cardiogenic shock,
or NYHA class IV heart failure within 180
days.

• Everolimus-eluting stents were superior to
paclitaxel-eluting stents with regard to
several end points, including target-vessel
failure, myocardial infarction, and stent
thrombosis.
• The addition of ticagrelor, at a dose of 90
mg twice daily or 60 mg twice daily, to low-
dose aspirin reduced the risk of
cardiovascular death, myocardial
infarction, or stroke and increased in the
risk of TIMI major bleedingland mark trials in 2015

• The addition of ticagrelor, at a dose of 90 mg twice daily
or 60 mg twice daily, to low-dose aspirin reduced the risk
of cardiovascular death, myocardial infarction, or stroke
and increased in the risk of TIMI major bleeding among
patients who had had a myocardial infarction 1 to 3
years earlier.
• The protective effects of sacubitril–valsartan remain
consistent with long-term use, the available follow up
data estimate that treatment with sacubitril–valsartan
would result in a projected benefit of 1 to 2 years of
increased life expectancy and survival free from heart
failure for patients such as those in the PARADIGM-HF
trial.

•Thank you

Land mark trials 2015

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Land mark trials 2015