Important Clinical Trials In Cardiology - An Overview 2016-17

IMPORTANT CLINICAL TRIALS IN
CARDIOLOGY – 2016-17
1

METHODS
• In a randomized, controlled trial, 556 patients with
symptomatic systolic heart failure (left ventricular ejection
fraction, ≤35%) not caused by coronary artery disease
were assigned to receive an ICD, and 560 patients were
assigned to receive usual clinical care (control group).
• In both groups, 58% of the patients received CRT. The
primary outcome of the trial was death from any cause.
The secondary outcomes were sudden cardiac death and
cardiovascular death.
4

RESULTS
• After a median follow-up period of 67.6 months, the
primary outcome had occurred in 120 patients (21.6%) in
the ICD group and in 131 patients (23.4%) in the control
group (hazard ratio, 0.87; 95% [CI], 0.68 to 1.12; P =
0.28).
• Sudden cardiac death occurred in 24 patients (4.3%) in the
ICD group and in 46 patients (8.2%) in the control group
(hazard ratio, 0.50; 95% CI, 0.31 to 0.82; P = 0.005).
• Device infection occurred in 27 patients (4.9%) in the ICD
group and in 20 patients (3.6%) in the control group (P =
0.29).
5

6The median follow up period was 67.6 months

CONCLUSION
• In this trial, prophylactic ICD implantation in
patients with symptomatic systolic heart failure
not caused by coronary artery disease was not
associated with a significantly lower long-term
rate of death from any cause than was usual
clinical care.
7

METHODS
• In this double-blind trial, investigators randomly assigned
2157 patients with acute heart failure to receive a
continuous intravenous infusion of either ularitide at a
dose of 15 ng per kilogram of body weight per minute or
matching placebo for 48 hours, in addition to accepted
therapy.
• Treatment was initiated a median of 6 hours after the
initial clinical evaluation.
• The coprimary outcomes were death from cardiovascular
causes during a median follow-up of 15 months and a
hierarchical composite end point that evaluated the initial
48-hour clinical course.
9

RESULTS
• Death from cardiovascular causes occurred in 236 patients
in the ularitide group and 225 patients in the placebo group
(21.7% vs. 21.0%; hazard ratio, 1.03; 96% confidence
interval, 0.85 to 1.25; P = 0.75).
• In the intention-to-treat analysis, there was no significant
between-group difference with respect to the hierarchical
composite outcome.
• The ularitide group had greater reductions in systolic
blood pressure and in levels of N-terminal pro–brain
natriuretic peptide than the placebo group.
• However, changes in cardiac troponin T levels during the
infusion did not differ between the two groups in the 55%
of patients with paired data. 10

12
The mean decrease in SBP in the ularitide group was greater by 6.8
mm Hg at 6 hours and by 3.9 mm Hg at 48 hours than in the placebo
group (P<0.001 for both comparisons); these between-group
differences dissipated over a period of 72 to 120 hours.

CONCLUSIONS
• In patients with acute heart failure, ularitide exerted
favorable physiological effects (without affecting cardiac
troponin levels), but short-term treatment did not affect a
clinical composite end point or reduce long-term
cardiovascular mortality.
13

METHODS
• To assess the effect of high-dose spironolactone(100mg)
and usual care(25mg) on N-terminal pro-B-type natriuretic
peptide (NT-proBNP) levels compared with usual care
alone.
• This double-blind and placebo (or low-dose)-controlled
randomized clinical trial was conducted in 22 US acute
care hospitals among patients with AHF who were
previously receiving no or low-dose (12.5mg or 25mg
daily) spironolactone and had NT-proBNP levels of 1000
pg/mL or more or B-type natriuretic peptide levels of 250
pg/mL or more, regardless of ejection fraction.
.
15

RESULTS
• A total of 360 patients were randomized, of whom the
median age was 65 years, 129 (36%) were women, 200
(55.5%) were white, 151 (42%) were black, 8 (2%) were
Hispanic or Latino, 9 (2.5%) were of other race/ethnicity,
and the median left ventricular ejection fraction was 34%.
• Baseline median (interquartile range) NT-proBNP levels
were 4601 (2697-9596) pg/mL among the group treated
with high-dose spironolactone and 3753 (1968-7633)
pg/mL among the group who received usual care.
16

• There was no significant difference in the log NT-proBNP
reduction between the 2 groups (−0.55 [95%CI, −0.92 to
−0.18] with high-dose spironolactone and −0.49 [95%CI,
−0.98 to −0.14] with usual care, P = .57). None of the
secondary end point or day-30 all-cause mortality or heart
failure hospitalization rate differed between the 2 groups.
• The changes in serum potassium and estimated glomerular
filtration rate at 24, 48, 72, and 96 hours were similar
between the 2 groups.
17

CONCLUSIONS
• Adding treatment with high-dose spironolactone
to usual care for patients with AHF for 96 hours
was well tolerated but did not improve the primary
or secondary efficacy end points.
20

• Investigators randomly assigned 1905 eligible patients
with left main coronary artery disease of low or
intermediate anatomical complexity to undergo either
percutaneous coronary intervention (PCI) with
fluoropolymer-based cobalt–chromium everolimus-eluting
stents (PCI group, 948 patients) or CABG (CABG group,
957 patients).
• Anatomic complexity was assessed at the sites and defined
by a Synergy between Percutaneous Coronary Intervention
with Taxus and Cardiac Surgery (SYNTAX) score of 32 or
lower.
23

• The primary end point was the rate of a composite of death
from any cause, stroke, or myocardial infarction at 3 years,
and the trial was powered for noninferiority testing of the
primary end point (noninferiority margin, 4.2 percentage
points).
• Major secondary end points included the rate of a
composite of death from any cause, stroke, or myocardial
infarction at 30 days and the rate of a composite of death,
stroke, myocardial infarction, or ischemia-driven
revascularization at 3 years.
• Event rates were based on Kaplan–Meier estimates in
time-to-first-event analyses.
24

RESULTS
• At 3 years, a primary end-point event had occurred in
15.4% of the patients in the PCI group and in 14.7% of the
patients in the CABG group (difference, 0.7 percentage
points; upper 97.5% confidence limit, 4.0 percentage
points; P = 0.02 for noninferiority; hazard ratio, 1.00; 95%
confidence interval, 0.79 to 1.26; P = 0.98 for superiority).
25

• The secondary end-point event of death, stroke, or
myocardial infarction at 30 days occurred in 4.9% of the
patients in the PCI group and in 7.9% in the CABG group
(P<0.001 for noninferiority, P = 0.008 for superiority).
• The secondary end-point event of death, stroke,
myocardial infarction, or ischemia-driven
revascularization at 3 years occurred in 23.1% of the
patients in the PCI group and in 19.1% in the CABG group
(P = 0.01 for noninferiority, P = 0.10 for superiority).
26

CONCLUSIONS
• In patients with left main coronary artery disease
and low or intermediate SYNTAX scores by site
assessment, PCI with everolimus-eluting stents
was noninferior to CABG with respect to the rate
of the composite end point of death, stroke, or
myocardial infarction at 3 years.
28

METHODS
• In this prospective, randomised, open-label, non-inferiority
trial, patients with left main coronary artery disease were
enrolled in 36 centres in northern Europe and randomised
1:1 to treatment with PCI or CABG.
• Eligible patients had stable angina pectoris, unstable
angina pectoris, or non-ST-elevation myocardial
infarction.
• Exclusion criteria were ST-elevation myocardial infarction
within 24 h, being considered too high risk for CABG or
PCI, or expected survival of less than 1 year.
30

• The primary endpoint was major adverse cardiac or
cerebrovascular events (MACCE), a composite of all-
cause mortality, non-procedural myocardial infarction, any
repeat coronary revascularisation, and stroke.
• Non-inferiority of PCI to CABG required the lower end of
the 95% CI not to exceed a hazard ratio (HR) of 1·35 after
up to 5 years of follow-up.
31

RESULTS
• Between Dec 9, 2008, and Jan 21, 2015, 1201 patients
were randomly assigned, 598 to PCI and 603 to CABG,
and 592 in each group entered analysis by intention to
treat.
• Kaplan-Meier 5 year estimates of MACCE were 29% for
PCI (121 events) and 19% for CABG (81 events), HR 1·48
(95% CI 1·11–1·96), exceeding the limit for non-
inferiority, and CABG was significantly better than PCI
(p=0·0066). As-treated estimates were 28% versus 19%
(1·55, 1·18–2·04, p=0·0015).
32

• Comparing PCI with CABG, 5 year estimates were 12%
versus 9% (1·07, 0·67–1·72, p=0·77) for all-cause
mortality, 7% versus 2% (2·88, 1·40–5·90, p=0·0040) for
non-procedural myocardial infarction, 16% versus 10%
(1·50, 1·04–2·17, p=0·032) for any revascularisation, and
5% versus 2% (2·25, 0·93–5·48, p=0·073) for stroke.
33

CONCLUSIONS
• The findings of this study suggest that CABG might be
better than PCI for treatment of left main stem coronary
artery disease.
35

METHODS
• Investigators undertook an open-label, randomised
controlled trial at two university hospitals in Denmark.
• Patients presenting with STEMI who had one or more
clinically significant coronary stenosis in addition to the
lesion in the infarct-related artery were included.
• After successful percutaneous coronary intervention (PCI)
of the infarct-related artery, patients were randomly
allocated (in a 1:1 ratio) either no further invasive
treatment or complete FFR-guided revascularisation before
discharge.
37

• Randomisation was done electronically via a web-based
system in permuted blocks of varying size by the clinician
who did the primary PCI. All patients received best
medical treatment.
• The primary endpoint was a composite of all-cause
mortality, non-fatal reinfarction, and ischaemia-driven
revascularisation of lesions in non-infarct-related arteries
and was assessed when the last enrolled patient had been
followed up for 1 year. Analysis was on an intention-to-
treat basis.
38

RESULTS
• From March, 2011, to February, 2014, investigators
enrolled 627 patients to the trial; 313 were allocated no
further invasive treatment after primary PCI of the infarct-
related artery only and 314 were assigned complete
revascularisation guided by FFR values.
• Median follow-up was 27 months (range 12–44 months).
• Events comprising the primary endpoint were recorded in
68 (22%) patients who had PCI of the infarct-related artery
only and in 40 (13%) patients who had complete
revascularisation (hazard ratio 0∙56, 95% CI 0∙38–0∙83;
p=0∙004).
39

CONCLUSIONS
• In patients with STEMI and multivessel disease, complete
revascularisation guided by FFR measurements significantly
reduces the risk of future events compared with no further
invasive intervention after primary PCI.
• This effect is driven by significantly fewer repeat
revascularisations, because all-cause mortality and non-fatal
reinfarction did not differ between groups.
• Thus, to avoid repeat revascularisation, patients can safely have
all their lesions treated during the index admission. Future
studies should clarify whether complete revascularisation should
be done acutely during the index procedure or at later time and
whether it has an effect on hard endpoints.
41

METHODS
• Investigators randomly assigned 885 patients with STEMI
and multivessel disease who had undergone primary PCI
of an infarct-related coronary artery in a 1:2 ratio to
undergo complete revascularization of non–infarct-related
coronary arteries guided by fractional flow reserve (FFR)
(295 patients) or to undergo no revascularization of non–
infarct-related coronary arteries (590 patients).
• The FFR procedure was performed in both groups, but in
the latter group, both the patients and their cardiologist
were unaware of the findings on FFR.
43

• The primary end point was a composite of death from any
cause, nonfatal myocardial infarction, revascularization,
and cerebrovascular events at 12 months.
• Clinically indicated elective revascularizations performed
within 45 days after primary PCI were not counted as
events in the group receiving PCI for an infarct-related
coronary artery only.
44

RESULTS
• The primary outcome occurred in 23 patients in the
complete-revascularization group and in 121 patients in
the infarct-artery-only group that did not receive complete
revascularization, a finding that translates to 8 and 21
events per 100 patients, respectively (hazard ratio, 0.35;
95% confidence interval [CI], 0.22 to 0.55; P<0.001).
45

• Death occurred in 4 patients in the complete-
revascularization group and in 10 patients in the infarct-
artery-only group (1.4% vs. 1.7%) (hazard ratio, 0.80; 95%
CI, 0.25 to 2.56), myocardial infarction in 7 and 28
patients, respectively (2.4% vs. 4.7%) (hazard ratio, 0.50;
95% CI, 0.22 to 1.13), revascularization in 18 and 103
patients (6.1% vs.17.5%) (hazard ratio, 0.32; 95% CI, 0.20
to 0.54), and cerebrovascular events in 0 and 4 patients (0
vs. 0.7%).
• An FFR-related serious adverse event occurred in 2
patients (both in the group receiving infarct-related
treatment only).
46

RESULTS
• In patients with STEMI and multivessel disease who
underwent primary PCI of an infarct-related artery, the
addition of FFR-guided complete revascularization of
non–infarct-related arteries in the acute setting resulted in
a risk of a composite cardiovascular outcome that was
lower than the risk among those who were treated for the
infarct-related artery only.
• This finding was mainly supported by a reduction in
subsequent revascularizations.
47

CONCLUSIONS
• In patients with STEMI and multivessel disease who
underwent primary PCI of an infarct-related artery, the
addition of FFR-guided complete revascularization of
non– infarct-related arteries in the acute setting resulted in
a risk of a composite cardiovascular outcome that was
lower than the risk among those who were treated for the
infarct-related artery only.
• This finding was mainly supported by a reduction in
subsequent revascularizations.
49

METHODS
• Investigators randomly assigned 1845 patients undergoing
PCI to receive either a bioresorbable vascular scaffold
(924 patients) or a metallic stent (921 patients).
• The primary end point was target-vessel failure (a
composite of cardiac death, target-vessel myocardial
infarction, or target-vessel revascularization).
• The data and safety monitoring board recommended early
reporting of the study results because of safety concerns.
This report provides descriptive information on end-point
events.
51

RESULTS
• The median follow-up was 707 days.
• Target-vessel failure occurred in 105 patients in the
scaffold group and in 94 patients in the stent group (2-year
cumulative event rates, 11.7% and 10.7%, respectively;
hazard ratio, 1.12; 95% confidence interval [CI], 0.85 to
1.48; P = 0.43); event rates were based on Kaplan–Meier
estimates in time-to-event analyses.
52

a. Cardiac death occurred in 18 patients in the scaffold
group and in 23 patients in the stent group (2-year
cumulative event rates, 2.0% and 2.7%, respectively),
b. Target-vessel myocardial infarction occurred in 48
patients in the scaffold group and in 30 patients in the
stent group (2-year cumulative event rates, 5.5% and
3.2%),
c. Target-vessel revascularization occurred in 76 patients in
the scaffold group and in 65 patients in the stent group (2-
year cumulative event rates, 8.7% and 7.5%).
53

• Definite or probable device thrombosis occurred in 31
patients in the scaffold group as compared with 8 patients
in the stent group (2-year cumulative event rates, 3.5%vs.
0.9%; hazard ratio, 3.87; 95% CI, 1.78 to 8.42; P<0.001).
54

CONCLUSIONS
• In this preliminary report of a trial involving patients
undergoing PCI, there was no significant difference in the
rate of target-vessel failure between the patients who
received a bioresorbable scaffold and the patients who
received a metallic stent.
• The bioresorbable scaffold was associated with a higher
incidence of device thrombosis than the metallic stent
through 2 years of follow-up.
56

METHODS
• Investigators randomly assigned 9013 patients who had
stable or unstable coronary artery disease to undergo
percutaneous coronary intervention (PCI) with the
implantation of either contemporary drug-eluting stents or
bare-metal stents.
• In the group receiving drug-eluting stents, 96% of the
patients received either everolimus- or zotarolimus-eluting
stents.
• The primary outcome was a composite of death from any
cause and nonfatal spontaneous myocardial infarction after a
median of 5 years of follow-up.
• Secondary outcomes included repeat revascularization, stent
thrombosis ,and quality of life.
58

RESULTS
• At 6 years, the rates of the primary outcome were 16.6% in
the group receiving drug-eluting stents and 17.1% in the
group receiving bare-metal stents (hazard ratio,0.98; [CI],
0.88 to 1.09; P = 0.66).
• There were no significant between-group differences in the
components of the primary outcome.
• The 6-year rates of any repeat revascularization were 16.5%
in the group receiving drug-eluting stents and 19.8% in the
group receiving bare-metal stents (P<0.001); the rates of
definite stent thrombosis were 0.8% and 1.2%, respectively
(P = 0.0498).
• Quality-of-life measures did not differ significantly between
the two groups. 59

• In patients undergoing PCI, there were no significant
differences between those receiving drug-eluting stents
and those receiving bare-metal stents in the composite
outcome of death from any cause and nonfatal spontaneous
myocardial infarction.
• Rates of repeat revascularization were lower in the group
receiving drug eluting stents.
61

METHODS
• Investigators conducted a multicenter, randomized,
controlled, open-label clinical trial using the Swedish
Coronary Angiography and Angioplasty Registry for
enrollment.
• A total of 2037 participants with stable angina or an acute
coronary syndrome who had an indication for physiologically
guided assessment of coronary-artery stenosis were randomly
assigned to undergo revascularization guided by either iFR or
FFR.
• The primary end point was the rate of a composite of death
from any cause, nonfatal myocardial infarction, or unplanned
revascularization within 12 months after the procedure.
63

RESULTS
• A primary end-point event occurred in 68 of 1012 patients
(6.7%) in the iFR group and in 61 of 1007 (6.1%) in the
FFR group (difference in event rates, 0.7 percentage
points; [CI], −1.5 to 2.8%; P = 0.007 for noninferiority;
hazard ratio, 1.12; 95% CI, 0.79 to 1.58; P = 0.53); the
upper limit of the 95% confidence interval for the
difference in event rates fell within the prespecified
noninferiority margin of 3.2 percentage points.
64

• The results were similar among major subgroups.
• The rates of myocardial infarction, target-lesion
revascularization, restenosis, and stent thrombosis did not
differ significantly between the two groups.
• A significantly higher proportion of patients in the FFR
group than in the iFR group reported chest discomfort
during the procedure.
65

CONCLUSIONS
• Among patients with stable angina or an acute coronary
syndrome, an iFR-guided revascularization strategy was
noninferior to an FFR-guided revascularization strategy
with respect to the rate of major adverse cardiac events at
12 months.
67

METHODS
• Investigators evaluated the clinical outcomes in
intermediate-risk patients with severe, symptomatic aortic
stenosis in a randomized trial comparing TAVR
(performed with the use of a self-expanding prosthesis)
with surgical aortic-valve replacement.
• The primary end point was a composite of death from any
cause or disabling stroke at 24 months in patients
undergoing attempted aortic-valve replacement.
• Investigators used Bayesian analytical methods (with a
margin of 0.07) to evaluate the noninferiority of TAVR as
compared with surgical valve replacement.
69

RESULTS
• A total of 1746 patients underwent randomization at 87
centers. Of these patients, 1660 underwent an attempted
TAVR or surgical procedure.
• The mean(±SD) age of the patients was 79.8±6.2 years,
and all were at intermediate risk for surgery (Society of
Thoracic Surgeons Predicted Risk of Mortality, 4.5±1.6%).
• At 24 months, the estimated incidence of the primary end
point was 12.6% in the TAVR group and 14.0% in the
surgery group (95% credible interval [Bayesian analysis]
for difference, −5.2 to 2.3%; posterior probability of
noninferiority, >0.999).
70

• Surgery was associated with higher rates of acute kidney
injury, atrial fibrillation, and transfusion requirements,
whereas TAVR had higher rates of residual aortic
regurgitation and need for pacemaker implantation.
• TAVR resulted in lower mean gradients and larger aortic-
valve areas than surgery.
• Structural valve deterioration at 24 months did not occur in
either group.
71

CONCLUSION
• TAVR was a noninferior alternative to surgery in patients
with severe aortic stenosis at intermediate surgical risk,
with a different pattern of adverse events associated with
each procedure.
73

METHODS
• In this randomized, double-blind, phase 3 study,
investigators assigned 3396 patients with venous
thromboembolism to receive either once-daily rivaroxaban
(at doses of 20 mg or 10 mg) or 100 mg of aspirin.
• All the study patients had completed 6 to 12 months of
anticoagulation therapy and were in equipoise regarding
the need for continued anticoagulation. Study drugs were
administered for up to 12 months.
• The primary efficacy outcome was symptomatic recurrent
fatal or nonfatal venous thromboembolism, and the
principal safety outcome was major bleeding.
76

RESULTS
• A total of 3365 patients were included in the intention-to-
treat analyses (median treatment duration, 351 days).
• The primary efficacy outcome occurred in 17 of 1107
patients (1.5%) receiving 20 mg of rivaroxaban and in 13
of 1127 patients (1.2%) receiving 10 mg of rivaroxaban, as
compared with 50 of 1131 patients (4.4%) receiving
aspirin (hazard ratio for 20 mg of rivaroxaban vs. aspirin,
0.34; [CI], 0.20 to 0.59; hazard ratio for 10 mg of
rivaroxaban vs. aspirin, 0.26; 95% CI, 0.14 to 0.47;
P<0.001 for both comparisons).
77

• Rates of major bleeding were 0.5% in the group receiving
20 mg of rivaroxaban, 0.4% in the group receiving 10 mg
of rivaroxaban, and 0.3% in the aspirin group; the rates of
clinically relevant nonmajor bleeding were 2.7%, 2.0%,
and 1.8%, respectively.
• The incidence of adverse events was similar in all three
groups.
78

CONCLUSIONS
• Among patients with venous thromboembolism in
equipoise for continued anticoagulation, the risk of a
recurrent event was significantly lower with rivaroxaban at
either a treatment dose (20 mg) or a prophylactic dose (10
mg) than with aspirin, without a significant increase in
bleeding rates.
80

PIONEER AF PCI
81
NOVEMBER 14,2016

METHODS
• Investigators randomly assigned 2124 participants with
nonvalvular atrial fibrillation who had undergone PCI with
stenting to receive, in a 1:1:1 ratio, low-dose rivaroxaban
(15 mg once daily) plus a P2Y12 inhibitor for 12 months
(group 1), very-low-dose rivaroxaban(2.5 mg twice daily)
plus DAPT for 1, 6, or 12 months (group 2), or standard
therapy with a dose-adjusted vitamin K antagonist (once
daily) plus DAPT for 1, 6, or 12 months (group 3).
• The primary safety outcome was clinically significant
bleeding (a composite of major bleeding or minor bleeding
according to Thrombolysis in Myocardial Infarction
[TIMI] criteria or bleeding requiring medical attention).
82

RESULTS
• The rates of clinically significant bleeding were lower in
the two groups receiving rivaroxaban than in the group
receiving standard therapy (16.8% in group 1, 18.0% in
group 2, and 26.7% in group 3; hazard ratio for group 1 vs.
group 3, 0.59; 95% [CI], 0.47 to 0.76; P<0.001; hazard
ratio for group 2 vs. group3, 0.63; 95% CI, 0.50 to 0.80;
P<0.001).
• The rates of death from cardiovascular causes, myocardial
infarction, or stroke were similar in the three groups
(Kaplan–Meier estimates, 6.5% in group 1, 5.6% in group
2, and 6.0% in group 3; P values for all comparisons were
nonsignificant).
83

CONCLUSIONS
• In participants with atrial fibrillation undergoing PCI with
placement of stents, the administration of either low-dose
rivaroxaban plus a P2Y12 inhibitor for 12 months or very-
low-dose rivaroxaban plus DAPT for 1, 6, or 12 months
was associated with a lower rate of clinically significant
bleeding than was standard therapy with a vitamin K
antagonist plus DAPT for 1, 6, or 12 months.
• The three groups had similar efficacy rates, although the
observed broad confidence intervals diminish the surety of
any conclusions regarding efficacy.
85

METHODS
• In this double-blind, event-driven trial, investigators
randomly assigned 13,885 patients with symptomatic
peripheral artery disease to receive monotherapy with
ticagrelor (90 mg twice daily) or clopidogrel (75 mg once
daily).
• Patients were eligible if they had an ankle–brachial index
(ABI) of 0.80 or less or had undergone previous
revascularization of the lower limbs.
• The primary efficacy end point was a composite of
adjudicated cardiovascular death, myocardial infarction, or
ischemic stroke. The primary safety end point was major
bleeding. The median follow-up was 30 months.
87

RESULTS
• The median age of the patients was 66 years, and 72% were
men; 43% were enrolled on the basis of the ABI and 57% on
the basis of previous revascularization.
• The mean baseline ABI in all patients was 0.71, 76.6% of the
patients had claudication, and 4.6% had critical limb
ischemia.
• The primary efficacy end point occurred in 751 of 6930
patients (10.8%) receiving ticagrelor and in 740 of 6955
(10.6%) receiving clopidogrel (hazard ratio, 1.02; 95%[CI],
0.92 to 1.13; P = 0.65).
• In each group, acute limb ischemia occurred in 1.7% of the
patients (hazard ratio, 1.03; 95% CI, 0.79 to 1.33; P = 0.85)
and major bleeding in 1.6% (hazard ratio, 1.10; 95% CI, 0.84
to 1.43; P = 0.49).
88

CONCLUSIONS
• In patients with symptomatic peripheral artery disease,
ticagrelor was not shown to be superior to clopidogrel for
the reduction of cardiovascular events.
• Major bleeding occurred at similar rates among the
patients in the two trial groups.
90

METHODS
• Investigators conducted a randomized, double-blind,
placebo-controlled trial involving 27,564 patients with
atherosclerotic cardiovascular disease and LDL cholesterol
levels of 70 mg per deciliter (1.8 mmol per liter) or higher
who were receiving statin therapy.
• Patients were randomly assigned to receive evolocumab
(either 140 mg every 2 weeks or 420 mg monthly) or
matching placebo as subcutaneous injections.
93

• The primary efficacy end point was the composite of
cardiovascular death, myocardial infarction, stroke,
hospitalization for unstable angina, or coronary
revascularization.
• The key secondary efficacy end point was the composite
of cardiovascular death, myocardial infarction, or stroke.
• The median duration of follow-up was 2.2 years.
94

RESULTS
• At 48 weeks, the least-squares mean percentage reduction
in LDL cholesterol levels with evolocumab, as compared
with placebo, was 59%, from a median baseline value of
92 mg per deciliter (2.4 mmol per liter) to 30 mg per
deciliter (0.78 mmol per liter) (P<0.001).
• Relative to placebo, evolocumab treatment significantly
reduced the risk of the primary end point (1344 patients
[9.8%] vs. 1563 patients [11.3%]; hazard ratio, 0.85; 95%
confidence interval [CI], 0.79 to 0.92; P<0.001) and the
key secondary end point (816 [5.9%] vs. 1013 [7.4%];
hazard ratio, 0.80; 95% CI, 0.73 to 0.88; P<0.001).
95

• The results were consistent across key subgroups,
including the subgroup of patients in the lowest quartile
for baseline LDL cholesterol levels (median, 74 mg per
deciliter [1.9 mmol per liter]).
• There was no significant difference between the study
groups with regard to adverse events (including new-onset
diabetes and neurocognitive events), with the exception of
injection-site reactions, which were more common with
evolocumab (2.1% vs. 1.6%).
96

CONCLUSIONS
• In this trial, inhibition of PCSK9 with evolocumab on a
background of statin therapy lowered LDL cholesterol
levels to a median of 30 mg per deciliter (0.78 mmol per
liter) and reduced the risk of cardiovascular events.
• These findings show that patients with atherosclerotic
cardiovascular disease benefit from lowering of LDL
cholesterol levels below current targets.
98

METHODS
• Investigators conducted a phase 2, multicenter, double-
blind, placebo-controlled, multiple ascending-dose trial of
inclisiran administered as a subcutaneous injection in
patients at high risk for cardiovascular disease who had
elevated LDL cholesterol levels.
• Patients were randomly assigned to receive a single dose
of placebo or 200, 300,or 500 mg of inclisiran or two doses
(at days 1 and 90) of placebo or 100, 200, or 300 mg of
inclisiran.
100

• The primary end point was the change from baseline in
LDL cholesterol level at 180 days.
• Safety data were available through day 210, and data on
LDL cholesterol and proprotein convertase subtilisin–
kexin type 9 (PCSK9) levels were available through day
240.
101

RESULTS
• A total of 501 patients underwent randomization. Patients
who received inclisiran had dose-dependent reductions in
PCSK9 and LDL cholesterol levels.
• At day 180, the least-squares mean reductions in LDL
cholesterol levels were 27.9 to 41.9% after a single dose of
inclisiran and 35.5 to 52.6% after two doses (P<0.001 for
all comparisons vs. placebo).
• The two-dose 300-mg inclisiran regimen produced the
greatest reduction in LDL cholesterol levels: 48% of the
patients who received the regimen had an LDL cholesterol
level below 50 mg per deciliter (1.3 mmol per liter) at day
180.
102

• At day 240, PCSK9 and LDL cholesterol levels remained
significantly lower than at baseline in association with all
inclisiran regimens.
• Serious adverse events occurred in 11% of the patients
who received inclisiran and in 8% of the patients who
received placebo.
• Injection-site reactions occurred in 5% of the patients who
received injections of inclisiran.
103

CONCLUSIONS
• In this trial, inclisiran was found to lower PCSK9 and LDL
cholesterol levels among patients at high cardiovascular
risk who had elevated LDL cholesterol levels
105

METHODS
• In a multicenter, randomized, double-blind, placebo-controlled
phase 3 trial, investigators enrolled 12,092 patients who had at
least one of the following conditions: an acute coronary
syndrome within the previous 30 to 365 days, cerebrovascular
atherosclerotic disease, peripheral vascular arterial disease, or
diabetes mellitus with coronary artery disease.
• Patients were randomly assigned to receive either evacetrapib at
a dose of 130 mg or matching placebo, administered daily, in
addition to standard medical therapy.
• The primary efficacy end point was the first occurrence of any
component of the composite of death from cardiovascular
causes, myocardial infarction, stroke, coronary
revascularization, or hospitalization for unstable angina.
107

RESULTS
• At 3 months, a 31.1% decrease in the mean LDL cholesterol
level was observed with evacetrapib versus a 6.0% increase with
placebo, and a 133.2% increase in the mean HDL cholesterol
level was seen with evacetrapib versus a 1.6% increase with
placebo.
• After 1363 of the planned 1670 primary end-point events had
occurred, the data and safety monitoring board recommended
that the trial be terminated early because of a lack of efficacy.
• After a median of 26 months of evacetrapib or placebo, a
primary end-point event occurred in 12.9% of the patients in the
evacetrapib group and in 12.8% of those in the placebo group
(hazard ratio, 1.01; 95% CI, 0.91 to 1.11; P = 0.91).
108

CONCLUSIONS
• Although the cholesteryl ester transfer protein inhibitor
evacetrapib had favorable effects on established lipid
biomarkers, treatment with evacetrapib did not result in a
lower rate of cardiovascular events than placebo among
patients with high-risk vascular disease.
110

METHODS
• 12,705 participants in 21 countries who did not have
cardiovascular disease and were at intermediate risk were
randomly assigned to receive candesartan at a dose of 16
mg per day plus hydrochlorothiazide at a dose of 12.5 mg
per day or placebo.
• The first coprimary outcome was the composite of death
from cardiovascular causes, nonfatal myocardial infarction,
or nonfatal stroke, and the second coprimary outcome
additionally included revascularization, heart failure, and
resuscitated cardiac arrest.
• The median follow-up was 5.6 years.
113

RESULTS
• The mean blood pressure of the participants at baseline was
138.1/81.9 mm Hg; the decrease in blood pressure was
6.0/3.0 mm Hg greater in the active-treatment group than in
the placebo group.
• The first coprimary outcome occurred in 260 participants
(4.1%) in the active-treatment group and in 279 (4.4%) in
the placebo group (p=0.40);
114

• The second coprimary outcome occurred in 312 participants
(4.9%) and 328 participants (5.2%), respectively (p=0.51).
• In one of the three prespecified hypothesis-based
subgroups, participants in the subgroup for the upper third
of systolic blood pressure (>143.5 mm Hg) who were in the
active-treatment group had significantly lower rates of the
first and second coprimary outcomes than those in the
placebo group; effects were neutral in the middle and lower
thirds (P=0.02 and P=0.009, respectively, for trend in the
two outcomes).
115

CONCLUSION
• Therapy with candesartan at a dose of 16 mg per day plus
hydrochlorothiazide at a dose of 12.5 mg per day was not
associated with a lower rate of major cardiovascular events
than placebo among persons at intermediate risk who did
not have cardiovascular disease.
116

METHODS
• 12,705 participants in 21 countries who did not have
cardiovascular disease and were at intermediate risk were
randomly assigned to receive rosuvastatin at a dose of 10
mg per day or placebo.
• The first coprimary outcome was the composite of death
from cardiovascular causes, nonfatal myocardial infarction,
or nonfatal stroke, and the second coprimary outcome
additionally included revascularization, heart failure, and
resuscitated cardiac arrest.
• The median follow-up was 5.6 years.
118

RESULTS
• The overall mean LDL level was 26.5% lower in the
rosuvastatin group than in the placebo group.
• The first coprimary outcome occurred in 235 participants
(3.7%) in the rosuvastatin group and in 304 participants
(4.8%) in the placebo group (p=0.002).
• The results for the second coprimary outcome were
consistent with the results for the first (occurring in 277
participants [4.4%] in the rosuvastatin group and in 363
participants [5.7%] in the placebo group; P<0.001).
119

• The results were also consistent in subgroups defined
according to cardiovascular risk at baseline, lipid level, C-
reactive protein level, blood pressure, and race or ethnic
group.
• In the rosuvastatin group, there was no excess of diabetes or
cancers, but there was an excess of cataract surgery (in
3.8% of the participants, vs. 3.1% in the placebo group;
P=0.02) and muscle symptoms (in 5.8% of the participants,
vs. 4.7% in the placebo group; P=0.005).
120

CONCLUSIONS
• Treatment with rosuvastatin at a dose of 10 mg per day
resulted in a significantly lower risk of cardiovascular
events than placebo in an intermediate-risk, ethnically
diverse population without cardiovascular disease.
121

METHODS
• 12,705 participants at intermediate risk who did not have
cardiovascular disease were randomly assigned to rosuvastatin
(10 mg per day) or placebo and to candesartan (16 mg per day)
plus hydrochlorothiazide (12.5 mg per day) or placebo. In the
analyses reported here, the 3180 participants assigned to
combined therapy (with rosuvastatin and the two antihypertensive
agents) with the 3168 participants assigned to dual placebo were
compared.
• The first coprimary outcome was the composite of death from
cardiovascular causes, nonfatal myocardial infarction, or nonfatal
stroke, and the second coprimary outcome additionally included
revascularization, heart failure, and resuscitated cardiac arrest.
• The median follow-up was 5.6 years. 123

RESULTS
• The decrease in the LDL cholesterol level was 33.7 mg per
deciliter (0.87 mmol per liter) greater in the combined-therapy
group than in the dual-placebo group, and the decrease in systolic
blood pressure was 6.2 mm Hg greater with combined therapy
than with dual placebo.
• The first coprimary outcome occurred in 113 participants (3.6%)
in the combined-therapy group and in 157 (5.0%) in the dual-
placebo group (p=0.005).
• The second coprimary outcome occurred in 136 participants
(4.3%) and 187 participants (5.9%), respectively (p=0.003).
• Muscle weakness and dizziness were more common in the
combined-therapy group than in the dual-placebo group, but the
overall rate of discontinuation of the trial regimen was similar in
the two groups. 124

CONCLUSION
• The combination of rosuvastatin (10 mg per day),
candesartan (16 mg per day), and hydrochlorothiazide
(12.5 mg per day) was associated with a significantly
lower rate of cardiovascular events than dual placebo
among persons at intermediate risk who did not have
cardiovascular disease.
125

METHODS
• In this randomized, open-label, multicenter, controlled trial
with blinded adjudicated end-point assessments,
investigators randomly assigned patients scheduled for
catheter ablation of paroxysmal or persistent atrial
fibrillation to receive either dabigatran (150 mg twice
daily) or warfarin (target international normalized ratio,
2.0 to 3.0).
• Ablation was performed after 4 to 8 weeks of
uninterrupted anticoagulation, which was continued during
and for 8 weeks after ablation.
• The primary end point was the incidence of major bleeding
events during and up to 8 weeks after ablation; secondary
end points included thromboembolic and other bleeding
events.
128

RESULTS
• The trial enrolled 704 patients across 104 sites; 635 patients
underwent ablation.
• Baseline characteristics were balanced between treatment
groups.
• The incidence of major bleeding events during and up to 8
weeks after ablation was lower with dabigatran than with
warfarin (5 patients [1.6%] vs. 22 patients [6.9%]; absolute risk
difference, −5.3 percentage points; 95% confidence interval,
−8.4 to −2.2; P<0.001).
• Dabigatran was associated with fewer periprocedural pericardial
tamponades and groin hematomas than warfarin.
• The two treatment groups had a similar incidence of minor
bleeding events. One thromboembolic event occurred in the
warfarin group. 129

CONCLUSIONS
• In patients undergoing ablation for atrial fibrillation,
anticoagulation with uninterrupted dabigatran was
associated with fewer bleeding complications than
uninterrupted warfarin.
131

METHODS AND RESULTS
• Patients were randomly assigned to receive intravenous
procainamide (10 mg/kg/20 min)or amiodarone
(5mg/kg/20min).
• The primary endpoint was the incidence of major
predefined cardiac adverse events within 40 min after
infusion initiation.
• Of 74 patients included, 62 could be analysed.
• The primary endpoint occurred in 3 of 33 (9%)
procainamide and 12 of 29 (41%) amiodarone patients
(odd ratio, OR ¼ 0.1; 95% confidence interval, CI 0.03–
0.6; P ¼ 0.006).
133

• Tachycardia terminated within 40 min in 22 (67%)
procainamide and 11 (38%) amiodarone patients (OR ¼
3.3; 95% CI 1.2–9.3; P ¼ 0.026).
• In the following 24 h, adverse events occurred in 18%
procainamide and 31% amiodarone patients (OR: 0.49;
95% CI: 0.15–1.61; P: 0.24).
• Among 49 patients with structural heart disease, the
primary endpoint was less common in procainamide
patients (3 [11%] vs. 10 [43%]; OR: 0.17; 95% CI: 0.04–
0.73, P ¼ 0.017)
134

CONCLUSIONS
• This study compares for the first time in a randomized
design intravenous procainamide and amiodarone for the
treatment of the acute episode of sustained monomorphic
well-tolerated (probably) ventricular tachycardia.
• Procainamide therapy was associated with less major
cardiac adverse events and a higher proportion of
tachycardia termination within 40 min.
137

METHODS
• 9361 persons with a systolic blood pressure of 130 mm Hg
or higher and an increased cardiovascular risk, but without
diabetes, were randomly assigned to a SBP target of less
than 120 mm Hg (intensive treatment) or a target of less
than 140 mm Hg (standard treatment).
• The primary composite outcome was myocardial infarction,
other acute coronary syndromes, stroke, heart failure, or
death from cardiovascular causes.
139

RESULTS
 At 1 year, the mean SBP was 121.4 mm Hg in the intensive
treatment group and 136.2 mm Hg in the standard-treatment
group.
The intervention was stopped early after a median follow-up of
3.26 years owing to a significantly lower rate of the primary
composite outcome in the intensive-treatment group than in the
standard-treatment group (1.65% per year vs. 2.19% per year;
P<0.001).
All-cause mortality was also significantly lower in the intensive
treatment group (P = 0.003).
Rates of serious adverse events of hypotension, syncope,
electrolyte abnormalities, and acute kidney injury or failure, but
not of injurious falls, were higher in the intensive treatment group
than in the standard-treatment group. 140

• Rates of serious adverse events of hypotension, syncope, electrolyte abnormalities, and
acute kidney injury or failure, but not of injurious falls, were higher in the intensive
treatment group than in the standard-treatment group.
142

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
143

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