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American

College of
Cardiology
Annual Scientific Sessions

2016
Key Trials
MARCH 29-31, 2014
WASHINGTON, DC

CONTENT
1. Non-Statin Therapies only After Lifestyle Interventions and Statins,
Says ACC Consensus Statement on LDL-reduction
2. Low-dose Statin Therapy Alone and in Combination to BP Lowering
Reduces Long-term CV Events in Intermediate-risk Population: HOPE
3 Trial
3. STEMI Patients More Younger & Obese in Recent Years
4. Vitamin D Supplementation Improves Cardiac Function in Chronic
Heart Failure: VINDICATE Trial
5. Evolocumab Lowers LDL-C Levels in Statin Intolerant Patients:
GAUSS-3 Trial
6. Evacetrapib Fails to Reduce Major CV Events in High Risk Patients:
ACCELARATE Trial
7. Aliskiren Not Beneficial in Patients with CHF: ATMOSPHERE Trial
8. Losmapimod Fails to Show Benefit in AMI Patients: LATITUDE-TIMI 60
Trial
9. Rate and Rhythm Control Equally Beneficial in Atrial Fibrillation
Post-Cardiac Surgery
10.
Prognostic Value of the Cardiac Non-Invasive Tests Results
Varies by Test Type and Patient Gender: PROMISE Trial
11.
Plaque Morphology in Stable CAD Patients Similar Irrespective
of Gender
12.
Breast Arterial Calcification Strongly Associated with Coronary
Artery Calcification
13.
Mobile-health Intervention Associated with Improvement in
Physical Activity: The Stepathlon Cardiovascular Health Study
14.
Deferred Stent Implantation Not Superior to Conventional PCI
in STEMI Patients: DANAMI 3-DEFER Trial
15.
Ischemic Postconditioning Added No Clinical Benefit Over
Conventional Primary PCI in STEMI: DANAMI 3-iPOST Trial
16.
CABG added to Medical Therapy Improves Long-Term Survival
and Prognosis vs. Medical Therapy Alone in Patients with Ischemic
Cardiomyopathy: STICH Trial
17.
Cryoablation Noninferior to Radiofrequency Ablation in
Paroxysmal Atrial Fibrillation: FIRE AND ICE Trial
18.
Lung Impedance Guided Treatment Superior to Routine
Treatment in CHF: IMPEDANCE - HF Trial
19.
Vagal Nerve Stimulation not Beneficial in Chronic Heart Failure:
INOVATE-HF Trial
20.
TAVR Comparable to SAVR in Intermediate-Risk Patients with
Severe Aortic-Valve Stenosis: PARTNER 2A Trial
21.
TAVR with SAPIEN 3 Preferred over Surgery in Treatment of
Intermediate-Risk Patients with Severe Aortic Stenosis

22.
TAVR with CoreValve Noninferior to Surgical AVR in Improving
Survival in Severe Aortic Stenosis Patients: The CoreValve High-Risk
Study
23.
Superiority of Bariatric Surgery plus Medical Therapy vs
Medical Therapy Alone in Obese/ Overweight Diabetes Patients
Sustained for 5 Years: STAMPEDE Trial
24.
Cell Therapy with Ixmyelocel-T may Improve Outcomes in
Patients with Ischemic HF: ixCELL-DCM Tria
Non-Statin Therapies only After Lifestyle Interventions and Statins,
Says ACC Consensus Statement on LDL-reduction
A latest expert consensus statement issued by the American College
of Cardiology recommends the use of lifestyle modifications and
statins before choosing non-statin drugs for low density lipoprotein
cholesterol (LDL-C) reduction for prevention of cardiovascular (CV)
events.
The 2016 ACC Expert Consensus Decision Pathway on the Role of Non-Statin
Therapies for LDL-C Lowering in the Management of Atherosclerotic
Cardiovascular Disease (ASCVD) Risk was discussed at the American College
of Cardiology Scientific Sessions 2016. This statement is also endorsed by
the National Lipid Association (NLA).
This statement considered recently available trial evidence for non-statin
therapies such as ezetimibe, niacin and proprotein convertase
subtilisin/kexin
type
9
(PCSK-9)
inhibitors
for
formulating
the
recommendations. It provides response to 3 critical questions addressing the
following issues:
1. Patient populations in which non-statin therapies should be considered
2. Clinical situations in which non-statin therapies can be considered
(magnitude of LDL-reduction) and non-statin therapies to be considered for
statin intolerance
3. Particular non-statin agents and order of preference of these therapies

The recommendations advocate assuring adherence to healthy lifestyle in


patients before considering non-statin therapies. Few key recommendations
on non-statin therapies are enlisted as follows:
In patients with existing ASCVD or LDL-C >190 mg/dL, non-statin agents can
be considered if the maximally tolerated statin is unable to achieve LDL-C
reduction of >50% from baseline
Ezetimibe should be the first non-statin to be considered in most patient
scenarios due to its safety and tolerability and moderate CV risk reduction
shown when added to on-going statin therapy

Bile acid sequestrants (BAS) can be considered in ezetimibe intolerant


patients as second-line non-statin agents, although they should be avoided
in those with triglycerides (TGs) >300 mg/dL
The two currently approved PCSK-9 inhibitors, alirocumab and evolocumab
can be considered in patients failing to achieve therapy goals with maximum
tolerable dose of statin and ezetimibe in ASCVD patients at high-risk CV risk
and those with familial hypercholesterolemia. These drugs are currently not
recommended for primary prevention in patients other than familial
hypercholesterolemia.
The
non-statin
drugs
recommended
for
homozygous
familial
hypercholesterolemia include ezetimibe, BAS with consideration for use of
lomitapide, mipomerson, and LDL apheresis as necessary.
This consensus thus gives opportunity to consider non-statin therapies in
specific cases.
J
Am
Coll
Cardiol.
April
1st,
publication). doi:10.1016/j.jacc.2016.03.519

2016

(early

online

Low-dose Statin Therapy Alone and in Combination to BP Lowering


Reduces Long-term CV Events in Intermediate-risk Population:
HOPE - 3 Trial
According to The Heart Outcomes Prevention Evaluation3 (HOPE-3) trials,
presented at the American College of Cardiology Scientific Sessions 2016,
treatment with cholesterol-lowering therapy alone and in
combination with blood-pressure (BP) lowering treatment may
prevent cardiovascular (CV) events in patients without known
cardiovascular disease (CVD), and with an intermediate risk of
major CV events (~1% annually) but BP lowering alone doesn't offer
the same benefit unless BP was high.
The study randomized 12,705 patients in 2 x 2 factorial design to either (all
randomizations were done in a 1:1 fashion): 1) cholesterol lowering analysis:
rosuvastatin 10 mg (n = 6,361) or placebo (n = 6,344); 2) BP lowering
analysis: candesartan 16 mg/day + hydrochlorothiazide (HTCZ) 12.5 mg/day
(n = 6,356) or placebo (n = 6,349); or 3) cholesterol and BP lowering
analysis: rosuvastatin + candesartan + HCTZ (n = 3,180) or placebo (n =
3,168). The median follow-up is 5.6 years.
Results of the cholesterol lowering analysis showed significant reduction
in CV outcomes with rosuvastatin vs placebo (Table 1). Low density
lipoprotein (LDL) cholesterol too was significantly lowered by rosuvastatin at
the end of the study period (overall mean difference, 34.6 mg/ dL).
Table 1: Outcomes with cholesterol lowering group
Outcomes
Rosuvasta
tin
First co-primary outcome [composite of CV 3.7%
death/myocardial infarction (MI)/stroke]
Second co-primary outcome (composite of 4.4%
CV
death/MI/stroke/resuscitated
cardiac
arrest/heart failure/revascularization)
MI
0.7%
Coronary artery disease (CAD)
1.7%
Hospitalization for CV causes
4.4%
New-onset diabetes mellitus
3.9%

Placeb
o
4.8%

P value

5.7%

p < 0.001

1.1%
2.2%
5.8%
3.8%

p
p
p
p

p = 0.002

>
=
<
=

0.05
0.02
0.001
0.82

Thus, rosuvastatin was beneficial in a diverse population who did not have
CVD and who were at intermediate risk.
Results of the BP lowering analysis showed that the fixed-dose
combination of candesartan and HCTZ was not superior to placebo
in reducing CV events despite a 6/3 mmHg decrease in BP (Table 2)

Table 2: Outcomes with BP lowering group


Outcomes

Candesart
an + HCTZ
First co-primary outcome (composite of CV 4.1%
death/MI/stroke)
Second co-primary outcome (composite of 4.9%
CV
death/MI/stroke/resuscitated
cardiac
arrest/heart failure/revascularization)
Symptomatic hypotension
3.0%

Placeb
o
4.4%

P value

5.2%

p = 0.51

2.1%

p < 0.001

p = 0.40

Participants in the subgroup for the upper third of systolic BP (>143.5


mm Hg) who received candesartan+HCTZ had significantly lower
rates of the first and second coprimary outcomes than those in the
placebo group (hazard ratio: 0.76); while effects were neutral in the
subgroup who had middle (131.6 143.5 mmHg) and lower (<131.5 mmHg)
third of systolic BP.
Thus, candesartan+HCTZ was not associated with a lower rate of CV events
among persons at intermediate risk who did not have CVD. However, in
participants with uncomplicated mild hypertension, candesartan+HCTZ
significantly reduced the risk of cardiovascular events.
Results of the analysis that combined cholesterol and BP lowering data
showed significant reduction in CV outcomes with rosuvastatin +
candesartan + HCTZ vs placebo (Table 3).
Table 3: Outcomes with combined cholesterol and BP lowering group
Outcomes
Rosuvasta Placeb
tin
o
First co-primary outcome (composite of CV 3.6%
5.0%
death/myocardial infarction /stroke)
Second co-primary outcome (composite of 4.6%
6.5%
CV
death/MI/stroke/resuscitated
cardiac
arrest/heart failure/revascularization)
CV death
2.4%
2.9%
All strokes
1.0%
1.7%
MI
0.7%
1.2%
Hospitalization for CV causes
4.4%
6.0%

P value
p = 0.005
p = 0.001
p
p
p
p

>
<
<
=

0.05
0.05
0.05
0.005

Thus, fixed dose combination of rosuvastatin and two antihypertensive


agents was associated with a significantly lower risk of CV events among
intermediate-risk persons without previous CVD.

N
Engl
J
Med.
April
2nd,
2016
(early
online
publication).
doi:10.1056/NEJMoa1600176
N Engl J Med. April 2nd, 2016 (early online publication). doi:
10.1056/NEJMoa1600175
N Engl J Med. April 2nd, 2016 (early online publication). doi:
10.1056/NEJMoa1600177

STEMI Patients More Younger & Obese in Recent Years


According to a study presented at the American College of Cardiology
Scientific Session 2016, ST-segment elevation myocardial infarction
(STEMI) is occurring in younger patients, especially those who are
more obese and those who are more likely to have preventable risk
factors such as chronic obstructive pulmonary disease (COPD),
diabetes, hypertension and smoking.
This study analysed the heart disease risk factors among 3,912 consecutive
patients who were treated for STEMI at the Cleveland Clinic between 1995
and 2014. During the 20-year follow up period it was observed that the
mean age at STEMI presentation decreased from 65 years to 60
years and the prevalence of obesity increased from 31% to 40%. The
proportion of STEMI patients with diabetes increased from 24% to
31%, with hypertension grew from 55% to 77% and with COPD
increased from 5% to 12%; all these results were significant. The study
also revealed a significant increase (65% to 85%) in the proportion of
patients who have three or more major risk-factors. In addition,
there was also a rise in the number of STEMI patients who reported
smoking from 28% in 1995 to 46% in 2014. These trends were similar
across the entire cohort and in the CAD cohort.
Thus the study indicates that when patients present to clinic for routine
check-ups, it is critical to stress the importance of reducing risk factors
through weight reduction, eating a healthy diet and being physically active.
Poster 1248-002. STEMI: Pre-Hospital Care, Diagnosis and Treatment.

Vitamin D Supplementation Improves Cardiac Function in Chronic


Heart Failure: VINDICATE Trial
High-dose vitamin D supplementation for one year significantly
improves cardiac function in patients with chronic heart failure
(CHF) and vitamin D deficiency, according to results of the VitamIN D
treatIng patients with Chronic heArT failurE (VINDICATE) study presented at
the American College of Cardiology Scientific Sessions 2016.
This randomized, placebo-controlled double-blind trial enrolled a total of 299
patients with CHF secondary to left ventricular (LV) systolic dysfunction
(LVSD) and vitamin D deficiency [(25(OH) vitamin D3 <50nmol/L
(<20ng/mL)]. Patients already on optimal medical therapy were randomized
to receive vitamin D3 supplementation [4000IU (100g) 25(OH)D3] daily or
matching non-calcium-based placebo. The primary endpoint was change in
six-minute walk distance from baseline to 12 months, and the secondary
endpoint included the change in left ventricular ejection fraction at one year.
Although the results showed that one year of vitamin D supplementation had
no effect on 6-minute walk distance, it significantly improved cardiac
function on echocardiography resulting in an increase in LV ejection fraction
(LVEF) by 6.07%. It also caused a reversal of LV remodelling, by reducing LV
end diastolic (LVED) diameter by 2.49mm and LV end systolic diameter
(LVSD) by 2.09mm. (Table)
Table: Effect of 12 months of vitamin
secondary outcome variables
Endpoint
Randomiz
Mean
ed
change
treatment after 12
months
Primary Outcome
Six
minute Placebo
10.10
walk distance Vitamin D
-12.56
(m)
Secondary Outcome
LVEF (%)
Placebo
1.36
Vitamin D
7.65
LVED (mm)
Placebo
-0.08
Vitamin D
-2.45
LVSD (mm)
Placebo
-0.99
Vitamin D
-2.72

D supplementation on primary and


Difference in mean P-value
change

-24.11

0.255

6.07

<0.001

-2.49

0.002

-2.09

0.043

Thus, although one year of high-dose vitamin D supplementation did


not affect the 6-minute walk distance in patients with CHF, it

improved LV structure and function. These results potentiate the need


for further trials to establish the role of vitamin D in improving outcomes in
heart failure especially since vitamin D deficiency is common in patients with
CHF.
J Am Coll Cardiol. April 4th, 2016 (early online publication)
doi:10.1016/j.jacc.2016.03.508

Evolocumab Lowers LDL-C Levels in Statin Intolerant Patients:


GAUSS-3 Trial
The Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK-9) inhibitor,
evolocumab significantly reduced low density lipoprotein cholesterol
(LDL-C) levels after 6-months in statin intolerant patients with
uncontrolled LDL-C according to results of the Goal Achievement After
Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects
3 (GAUSS-3) trial presented at the American College of Cardiology Scientific
Sessions 2016 and published simultaneously in the Journal of American
Medical Association.
The GAUSS-3 was a two-stage trial with the initial phase A where-in a total of
491 participants were randomized to receive atorvastatin 20 mg or placebo
for 10 weeks followed by a 2-week washout period and treatment switching
for the next 10 weeks to determine true statin intolerance. Of these, 199
patients with confirmed statin intolerance entered Phase B along with 19
patients with elevated creatinine who directly entered phase B for a 2:1
randomization to subcutaneous evolocumab (420 mg monthly) or oral
ezetimibe (10 mg daily) for 24 weeks.
Patients randomized to evolocumab showed more than a 50%
reduction in LDL-C from baseline as compared to those on
ezetimibe. The between group difference in LDL-C for a mean of 22
and 24 weeks was -37.8% and for week 24 it was -36.1% in favour of
evolocumab. The muscle-related events reported were 21% and 29%
in the evolocumab and ezetimibe treated groups respectively (Table).
The active study drug was discontinued due to muscle-related
symptoms by 0.7% of patients on evolocumab and 7% of those
taking ezetimibe.
Table: Muscle-related adverse events reported in Phase B of the GAUSS-3
Trial
Adverse Events
Number (%) of patients
Ezetimibe (N = 73)
Evolocumab (N =
145)
Total muscle related 21 (28.8)
30 (20.7)
events
Myalgia
16 (21.9)
20 (13.8)
Creatine
kinase 1 (1.4)
4 (2.8)
increase
Musculoskeletal pain
1 (1.4)
5 (3.4)
Muscle weakness
0
3 (2.1)

Thus evolocumab resulted in significantly greater LDL-C reduction


as compared to ezetimibe after 24 weeks of treatment in patients
with statin intolerance due to muscle-related effects.
JAMA. April 3rd, 2016 (early online publication). doi:10.1001/jama.2016.3608

Evacetrapib Fails to Reduce Major CV Events in High Risk Patients:


ACCELARATE Trial
The cholesteryl ester transfer protein (CETP) inhibitor, evacetrapib joined
the ranks of other failed drugs of its class, torcetrapib and
dalcetrapib as it did not show reduction in major cardiovascular (CV)
events according to the results of the Assessment of Clinical Effects
of Cholesteryl Ester Transfer Protein Inhibition With Evacetrapib in
Patients at a High-Risk for Vascular Outcomes (ACCELARATE) trial
presented at the American College of Cardiology Scientific Sessions 2016.
This trial randomized 12,092 patients with high vascular risk (defined as ACS
between 30 and 365 days, peripheral artery disease, diabetes with coronary
artery disease or cerebrovascular disease) in a 1:1 ratio to receive
evacetrapib 130 mg or placebo. The mean age of the participants was 65
years with 23% females and 68% diabetics. The primary endpoint was a
composite of CV death, myocardial infarction (MI), stroke, coronary
revascularization or hospitalization for angina. The trial was scheduled to last
until 1,670 patients experienced the primary endpoint and 700 experienced
CV death, MI or stroke, with a minimum follow-up of 30 months.
The trial was terminated earlier as the preliminary analysis did not
show any impact of evacetrapib on the primary endpoint vs. placebo
(12.8% vs. 12.7%, p = 0.85 respectively). There was also no effect of
the drug as compared to placebo on the individual components of
the primary endpoint: CV death (7.2% vs.7.3%, p = 0.73); MI (7.2%
vs.7.3%, p = 0.73) and Stroke (1.5% vs. 1.6%, p = 0.82).
However, evacetrapib significantly raised high density lipoprotein
cholesterol (HDL-C) levels and reduced low density lipoprotein
cholesterol (LDL-C) from baseline. There was also a trend observed
towards reduction in all-cause mortality with evacetrapib vs placebo
(3.8% vs. 4.1%; HR = 0.84; 95% CI, 0.71-1.01), which was deemed to be a
chance finding according to the authors.
These results from the ACCELARATE trial indicated that although
evacetrapib resulted in a 130% rise in HDL-C and 37% decrease in
LDL-C from baseline, it was not lower CV risk in patients with high
vascular risk.

Aliskiren Not Beneficial in Patients with CHF: ATMOSPHERE Trial


According to the Aliskiren Trial to Minimize OutcomeS in Patients with HEart
failuRE (ATMOSPHERE) trial, presented at American College of Cardiology
Scientific Sessions 2016, aliskiren showed no benefit in reducing the
risk of death from cardiovascular (CV) causes or hospitalization due
to heart failure (HF) vs enalapril alone or in combination, in patients
with chronic heart failure (CHF) and reduced ejection fraction.
ATMOSPHERE, a 36.6 months follow-up trial, enrolled 7,012 CHF patients with
New York Heart Association class II-IV and mean left ventricular ejection
fraction 0.35, who were randomized in a 1:1:1 fashion to receive either
aliskiren 300 mg daily (n = 2,340), enalapril 5-10 mg daily (n = 2,336), or
enalapril 5-10 mg + aliskiren 300 mg daily (n = 2,340).
The primary outcome (composite of CV death or CHF hospitalization)
with aliskiren + enalapril was not significantly reduced vs. enalapril
(hazard ratio [HR] 0.93; p = 0.17 for superiority). The reduction with
aliskiren vs. enalapril was also not significant and the pre-specified
test for non-inferiority was not met. There were no significant
differences between the groups, in terms of secondary outcomes as
well as other prespecified exploratory outcomes (Table). Importantly,
the incidence of renal outcome (the composite of death from renal
causes, end-stage renal disease, or doubling of the serum creatinine
level) was significantly higher in the aliskiren + enalapril group vs.
enalapril (HR = 2.17, p = 0.007).
Table: Secondary outcomes and other outcomes:
Outcome
Combinatio
n Therapy
vs.
Enalapril
(HR)
Secondary outcomes: Change in
-0.03
the KCCQ clinical summary score
at 12 months*
Death from CV causes,
0.94
hospitalization for HF, nonfatal
myocardial infarction, nonfatal
stroke, or resuscitated cardiac
arrest
Fatal or nonfatal myocardial
0.87
infarction
Fatal or nonfatal stroke
0.93
First resuscitated cardiac arrest
0.96
Death from any cause
0.91

P
valu
e

Aliskiren
vs.
Enalapril
(HR)

P
valu
e

0.97

-1.02

0.20

0.23

1.01

0.80

0.36

0.85

0.28

0.65
0.86
0.12

1.12
1.10
1.04

0.42
0.69
0.46

*The Kansas City Cardiomyopathy Questionnaire (KCCQ) score was evaluated with the use of a repeated-measures
analysis with the baseline value as a covariate and treatment, dose stratum, NYHA class, and visit as factors and a
visit-by-treatment interaction; a score of 0 was used in patients who died. Scores were available at 12 months for
1811 patients in the combination-therapy group, for 1796 in the aliskiren group, and for 1804 in the enalapril group.

In terms of safety, the risk of hypotensive symptoms were significantly


greater in the aliskiren + enalapril group vs. enalapril group (13.8% vs.
11.0%, P = 0.005). The combination was also associated with higher risks of
elevated serum creatinine level (4.1% vs. 2.7%, P = 0.009) and elevated
potassium level (17.1% vs. 12.5%, P<0.001) vs enalapril alone group.
Thus aliskiren not only failed to show noninferiority, in reducing the risk of
death from CV causes or hospitalization due to heart failure, to enalapril
either as monotherapy or as combination therapy in patients with CHF, but
was also associated with higher incidence of side effects, including
hypotension and hyperkalemia.
Engl J Med; Apr 4:
10.1056/NEJMoa1514859

2016

(early

online

publication)

DOI:

Losmapimod Fails to Show Benefit in AMI Patients: LATITUDE-TIMI 60


Trial
Losmapimod, a p38 mitogen-activated protein kinase (MAPK)
inhibitor, is not superior to placebo in reducing adverse
cardiovascular (CV) events at 12 weeks in patients hospitalized with
an acute myocardial infarction (AMI) and on optimal medical
therapy, according to the results of LATITUDE-TIMI 60 study presented at the
American College of Cardiology Scientific Session 2016 and simultaneously
published online in Journal of American Medical Association.
Activation of p38 MAPK stimulates inflammation which, in turn, is implicated
in atherogenesis, plaque destabilization, and maladaptive processes in
myocardial infarction (MI). Losmapimod was therefore postulated to have
salutary beneficial effects in AMI by reducing inflammation. The LATITUDETIMI 60 was a randomized, placebo-controlled, double-blind, parallel-group
phase 3 trial conducted at 322 sites in 34 countries. It was designed to be
conducted in two phases: phase A to analyse initial safety and exploratory
efficacy and a larger phase B to evaluate the primary efficacy and was to be
conducted if phase A was positive. Patients hospitalized for AMI (non ST
elevated myocardial infarction within 24 hours of ischemic symptoms or ST
elevated myocardial infarction within 12 hours of onset) who had at least 1
additional predictor of cardiovascular risk were randomized to either twicedaily losmapimod (7.5 mg; n = 1738) or matching placebo (n = 1765) on a
background of guideline-recommended therapy. The patients were treated
for 12 weeks and were additionally followed for 12 weeks. The primary end
point was the composite of CV death, MI, or severe recurrent ischemia
requiring revascularization at 12 weeks.
Through week 12, the primary end point occurred in 8.1% of
patients on losmapimod and 7.0% on placebo (p = 0.24). CV death
(2.1% vs. 2.5%), fatal and non-fatal MI (5.3% vs. 4.3%) and severe recurrent
ischemia requiring revascularization (1.1 vs 0.9) were also similar in the
losmapimod and placebo groups. Secondary outcomes, including
incidence of stroke (0.8% vs 0.9%) and definite or probable stent
thrombosis, were also not significantly different between the two
groups (0.9% vs 1.5%). Similar results were observed at week 24 in
the overall cohort.
Losmapimod reduced serum hs-CRP levels, but it did not translate into a
clinical benefit at 12 weeks. Besides, the on-treatment rates of serious
adverse events were also higher with losmapimod vs. placebo (16% vs.
14.2%).
The trial was therefore terminated after phase A due to futility.
JAMA. April 4th, 2016 (early online publication). doi:10.1001/jama.2016.3609

Rate and Rhythm Control Equally Beneficial in Atrial Fibrillation


Post-Cardiac Surgery
Both rate control and rhythm control strategy were similarly
efficacious in patients who developed atrial fibrillation (AF) after
cardiac surgery, as per the results of a trial presented at the American
College of Cardiology Scientific Sessions 2016.
A total of 523 patients undergoing elective cardiac surgery [coronary artery
bypass grafting (CABG), valve surgery or both] who developed new-onset
post-operative AF that persisted for more than 60 minutes or recurrent
episodes of atrial fibrillation during the index hospitalization (7 days after
surgery), were randomized to undergo either rate control (n = 262) or
rhythm control (n = 261). The rate control strategy included drugs to reduce
heart rate with a target of achieving a resting heart rate of <100 beats per
minute, while the rhythm control group received amiodarone with or without
a rate-slowing agent. The primary end point was the total number of days of
hospitalization within 60 days after randomization, as evaluated by the
Wilcoxon rank-sum test.
Of the randomized patients, isolated CABG was performed in about 40%,
isolated valve surgery in about 40%, and combined CABG and valve surgery
in about 20%. The prevalence of postoperative AF was 28.1%, 33.7%, and
47.3% in these cases, respectively.
At study end, both rate control and rhythm control groups showed similar
results in the total number of hospital days (median, 5.1 days and 5.0 days,
respectively; P=0.76) with no statistically significant difference between the
two groups even for type of surgery (Table 1). ]
Table 1: Results (median) observed in the rate
groups
Variable
Rate
control
(n = 262)
No. of days in hospital from 5.1
randomization to 60 days
After isolated CABG
4.8
After isolated valve repair or 5.0
replacement
After CABG + valve repair or 5.3
replacement

control and rhythm control


Rhythm
control
(n = 261)
5.1

Pvalue
0.76

5.1
4.4

0.96
0.76

7.1

0.11

There were no significant differences in mortality as well as serious adverse


events between the two groups, including thromboembolic and bleeding
events. At study end, the percentage of patients with stable heart rhythm

without AF for the previous 30 days were 93.8% in the rate-control group and
97.9% for those in rhythm control group while 84.2% and 86.9% did not have
AF from discharge to 60 days.
Thus rate control and rhythm control fared equally in terms of
hospitalization for AF after cardiac surgery. In the light of these results,
choosing either of these strategies should depend on the individual patient
and physician preferences.
New Engl J Med. April 4th,
10.1056/NEJMoa1602002

2016

(early

online

publication)

doi:

Prognostic Value of the Cardiac Non-Invasive Tests Results Varies by


Test Type and Patient Gender: PROMISE Trial
According to the Prospective Multicenter Imaging Study for Evaluation of
Chest Pain (PROMISE) trial, presented at American College of Cardiology
Scientific Sessions 2016, women appear to derive more prognostic
information from coronary computed tomography angiography
(CTA), while men tend to derive similar prognostic information from
both CTA and stress test.
In the main PROMISE trial, low- to intermediate-risk patients with chest pain
were randomized to evaluation with an anatomical strategy (n = 4,996) or
functional strategy (n = 5,007). For anatomical strategy patients underwent
a 64-slice coronary CTA, while patients in functional strategy underwent
exercise electrocardiography (ECG), exercise imaging, or pharmacologic
imaging. This trial with the median follow-up of 25 months, showed that
though coronary CTA is not superior but it is an effective alternative to stress
testing among low- to intermediate-risk patients presenting with chest pain.
For this analysis of PROMISE, 8966 patients from the main trial were
assessed to understand the relationship between sex and cardiac noninvasive tests (NIT) tested as randomized (4500 CTA, 52% female; 4466
stress testing, 53% female).
There were 9.7% of total women population who had a positive test result,
with a significantly smaller proportion having positive CTAs
compared to positive stress tests (8% vs. 12%, p<0.001). The
significance of this difference persisted even after adjustment for clinical
factors [adjusted odds ratio (OR): 0.67; p<0.001]. In fact, CTA was less
likely to be positive compared to exercise ECG (OR: 0.39; p<0.001)
and nuclear stress testing (OR: 0.66; p<0.001) but not as compared
to stress echocardiography (OR: 0.90; p=0.58).
A total of 15.1% of total men in the study had a positive test result, with a
marginally greater proportion of CTAs being positive compared to
stress tests (16% vs. 14%, p=0.047). The significance of the difference
improved after adjustment for clinical factors (adjusted OR 1.23; p=0.019). In
fact, CTA was more likely to be positive compared to exercise ECG
(OR 1.79; p=0.01) and stress echocardiography (OR 2.10; p<0.001),
but not compared to nuclear stress testing (OR 1.03; p=0.75).
Overall, a positive NIT was strongly predictive of the composite endpoint of
all-cause death/myocardial infarction (MI)/hospitalization for unstable angina
compared with a negative NIT (HR 3.37). Among women, a positive CTA
was significantly associated with subsequent clinical events vs. a
negative CTA (hazard ratio [HR]: 5.9) than a positive stress test vs.
a negative stress test (HR 2.3). While among men, there was a non-

significant association between a positive CTA vs. a negative CTA


(HR 2.8), and a positive stress test vs. a negative stress test (HR
4.4). Negative CTA and stress tests were equally likely to predict an event in
both sexes (adjusted p-values=NS).
Thus the study indicates that there exists differences between stress testing
and anatomic testing in men and women with respect to positivity rates and
the prognostic information provided by each type.
J Am Coll Cardiol. Apr
doi:10.1016/j.jacc.2016.03.523

4th

2016

(early

online

publication).

Plaque Morphology in Stable CAD Patients Similar Irrespective of


Gender
Plaque characteristics assessed by multimodality imaging among
patients with stable coronary artery disease (CAD) were similar in
both men and women referred for coronary angiography, according to
a study presented at the American College of Cardiology Scientific Session
2016 and simultaneously published in JACC: Cardiovascular Imaging.
This study retrospectively analysed data from 383 patients (268 men and
115 women) with stable CAD who were referred for coronary angiography
and underwent optical coherence tomography (OCT). Among them 128 also
underwent intravascular ultrasound (IVUS)/ near infrared spectroscopy
(NIRS).
The OCT imaging data showed no significant difference in reference lumen
cross sectional area (CSA), minimum lumen CSA, or area stenosis. IVUS/NIRS
imaging data did not reveal any significant difference between external
elastic membrane CSA and lumen CSA in both reference and stenotic
segment. Plaque characteristics by IVUS were similar between both
the gender except for an increase in plaque burden in men
compared to women in the reference segment (44.4 vs. 39.3; p =
0.031). Maximal lipid core burden index at the 4-mm maximal segment as
seen on near infrared spectroscopy was similar in both groups. After
adjusting for age, body mass index, percutaneous coronary intervention
history, hypertension, insulin use, clinical risk factors, and total cholesterol,
gender was not found to be an independent predictor of severe
plaque burden by IVUS.
Thus results of this study suggest that equally aggressive primary and
secondary preventive measures irrespective of sex must be undertaken.
J Am Coll Cardiol Img. April
doi:10.1016/j.jcmg.2016.02.007

2nd,

2016

(early

online

publication).

Breast Arterial Calcification Strongly Associated with Coronary


Artery Calcification
A study presented at the American College of Cardiology Scientific Session
2016 and published simultaneously in JACC: Cardiovascular Imaging, for the
first time demonstrated a strong quantitative association of breast
arterial calcification (BAC) by digital mammography with coronary
artery calcification (CAC) in a large female cohort. It was observed that
BAC is superior to standard cardiovascular risk factors, while it was
equivalent to both Framingham risk score (FRS) and 2013 Cholesterol
Guidelines pooled Cohort Equations (PCE) for identification of high-risk
women.
The present study involving a total of 291 asymptomatic women with digital
mammography and nongated computed tomography evaluated if BAC
predicts CAC. The 4 main coronary arteries - left main, left anterior
descending, circumflex, and right- were identified on chest CT scans and the
extent of CAC in each artery was categorized as absent, mild (when <1/3 rd of
the length of the entire artery showed calcification), moderate (when 1/3 rd to
2/3rd of the artery showed calcification), or severe (when >2/3 rd of the artery
showed calcification) and scored as 0, 1, 2, or 3, respectively. When all the
four arteries were scored, each participant received a score from 0 to 12
which was divided into three categories on basis of increasing severity: 0, 1
to 3, and 4 to 12. Also, after performing digital mammography, for those
women with BAC, the number of vessels involved in each breast was
recorded and numerically coded as 1 to 6. If there were >6 BAC, then it was
coded as 6. Besides, the length of vessel involvement was recorded as none
(score - 0), less than one-third (score - 1), between one-third and two-thirds
(score - 2), and greater than two-thirds (score - 3). The density of calcium in
the most severely affected segment was recorded as: none (score - 0), mild
with clear visualization of the lumen and/or only 1 vessel wall involved (score
- 1), moderate with clouding of the lumen and calcification of both tangential
walls (score - 2), and severe with no visible lumen (score - 3). Thus after
summing up the three numbers for each breast, each woman received an
ordinal BAC score between 0 and 12 which was also divided into 3 categories
of increasing severity: 0, 1 to 3, and 4 to 12.
BAC was noted in 42.5% of study population while CAC was noted in 47.6%
of the total group. Women with positive BAC were significantly older, had
more hypertension and chronic kidney disease and smoked less often than
BAC negative women. On the other hand, women who were CAC positive
were significantly older, had more hypertension, chronic kidney disease and
diabetes than CAC negative women. The overall mean BAC score was 2.2
and mean CAC score was 1.6. The frequency of BAC > 0 was 27% for
women aged 39 -59 years, 47% for aged 60-69 years and 69% for
those aged 70-92 years (P <0.0001). Similarly, the frequency of CAC

> 0 increased from 28% to 55% to 79%, respectively, among the age
groups (P <0.0001). All BAC variables were significantly predictive
of the CAC score. In multivariable model, odds ratio for CAC >0 was
3.2 for BAC 4 to 12, 2.0 for age, and 2.2 for hypertension. The
sensitivity, specificity, positive and negative predictive values, and
accuracy of BAC >0 for CAC >0 were 63%, 76%, 70%, 69%, and 70%,
respectively.
The agreements of FRS risk categories with CAC and BAC risk categories
were 57% for CAC and 55% for BAC; the agreement was 47% for PCE risk
categories for CAC and 54% by BAC. BAC >0 had area under the curve of
0.73 for identification of women with CAC >0 which was equivalent
to both FRS (0.72) and PCE (0.71). BAC >0 increased the area under
the curve curves for FRS (0.72 to 0.77; p = 0.15) and PCE (0.71 to
0.76; p = 0.11) for the identification of high-risk (4 to 12) CAC. When
the analysis included 33 women with established CAD, BAC >0 was
significantly additive to both FRS (p = 0.02) and PCE (p = 0.04) for high-risk
CAC.
The study data thus indicates that it is reasonable to recommend further risk
assessment of BAC-positive women, preferably with a gated CAC scan, with
subsequent adjustment or institution of therapy as indicated by the CAC
score.
J Am Coll Cardiol Img. April 2nd,
doi:10.1016/j.jcmg.2015.10.022.

2016

(early

online

publication).

Mobile-health Intervention Associated with Improvement in Physical


Activity: The Stepathlon Cardiovascular Health Study
According to a The Stepathlon Cardiovascular Health Study presented at the
American College of Cardiology Scientific Sessions 2016, a low-cost
intervention through mobile health (mHealth) programs is
associated with large-scale improvement in physical activity, sitting
duration and weight.
This global analysis collected data from participants completing Stepathlon,
an annual 100-day global event in 2012, 2013, and 2014 via an interactive
multi-platform app available on mobile devices and the worldwide web. A
total of 69,219 adults participated from 481 employers in 1,481 cities (64
countries). The mean age of the group was 36 years, it consisted 23.9%
female and 92.0% were from lower-middle income countries. Participants
were organized in worksite-based teams, were issued pedometers, and were
encouraged to increase daily steps and physical activity.
On completion of Stepathlon participants showed significant
improvement in step count (+3,519 steps/day; p < 0.0001), exercise
days (+0.89 days; p < 0.0001), sitting duration (-0.74 hours; p <
0.0001), and weight (-1.45 kg; p < 0.0001). These improvements
occurred in both women and men, in all geographic regions, and in both high
and lower-middle income countries, and was also reproduced in 2012, 2013,
2014 cohorts. Besides, it was observed step increase, sitting duration
decrease, and increase in exercise days were predictors ofweight loss (all P
<0.0001).
Thus, mHealth lifestyle intervention showed a positive impact on targeting
physical inactivity and overweight/obesity, and could be implemented on
larger scale.
J Am Coll Cardiol. April
doi:10.1016/j.jacc.2016.03.472

3rd,

2016

(early

online

publication).

Deferred Stent Implantation Not Superior to Conventional PCI in


STEMI Patients: DANAMI 3-DEFER Trial
Deferred stenting at the time of primary percutaneous coronary
intervention (PCI) in ST-segment elevation myocardial infarction
(STEMI) patients is not superior in reducing the adverse
cardiovascular outcomes compared with conventional PCI according
to the DANAMI 3-DEFER study presented at the American College of
Cardiology Scientific Session 2016. The study was simultaneously published
in The Lancet.
In an open-labelled, randomised controlled trial involving 1215 STEMI
patients at four primary PCI centres in Denmark were randomly assigned to
receive either standard primary PCI with immediate stent implantation or
deferred stent implantation 48 h after the index procedure. The primary
endpoint was a composite of all-cause mortality, hospitalization for
congestive heart failure, recurrent infarction, and any unplanned of the
target vessel revascularisation (TVR) within 2 years follow-up.
After median follow-up of 42 months, primary endpoint occurred in 18%
of patients who had undergone standard PCI and in 17% of patients
who had deferred stent implantation (hazard ratio 0.99; p = 0.92).
Routine deferred stenting was associated with a higher risk of TVR
(7% with deferred stent group vs 4% in immediate stent group; p =
0.0345). Left ventricular ejection fraction (LVEF) at 18 months was
slightly higher with deferred stenting vs immediate stenting group
(60% for deferred vs. 57% immediate stenting; p = 0.04).
Procedure-related
myocardial
infarction,
bleeding
requiring
transfusion or surgery, contrast-induced nephropathy, or stroke
occurred in 5% of patients in the conventional PCI group vs 4% of
patients in the deferred stent implantation group, with no
significant differences between groups.
Thus, routine deferred stent implantation did not reduce the occurrence of
major adverse cardiovascular events when compared with conventional PCI
in STEMI patients.
Lancet
2016;
April
3rd,
2016
(early
online
DOI: http://dx.doi.org/10.1016/S0140-6736(16)30072-1

publication).

Ischemic Postconditioning Added No Clinical Benefit over


Conventional Primary PCI in STEMI: DANAMI 3-iPOST Trial
Ischemic postconditioning (with short bursts of balloon occlusion
immediately after establishing perfusion) is not superior to
conventional primary percutaneous coronary intervention (PCI) in
ST-segment elevation myocardial infarction (STEMI) patients. These
are the findings of the Third DANish Study of Optimal Acute Treatment of
Patients with ST-segment Elevation Myocardial Infarction (DANAMI 3-iPOST)
that was presented at the American College of Cardiology Scientific Sessions
2016. The findings clearly indicate a low clinical utility of ischemic
postconditioning during routine primary PCI.
This study was conducted to compare the utility of ischemic postconditioning in STEMI patients undergoing primary PCI. STEMI patients
undergoing primary PCI and having TIMI (thrombolysis in myocardial
infarction) 0-1 flow in the infarct-related artery (n = 1214, mean age = 62
years) were randomized in a 1:1 fashion to ischemic postconditioning or
conventional PCI. Amongst the patients randomized to the postconditioning
group, restoration of coronary flow was immediately followed by a balloon
angioplasty at the culprit lesion or stented segment. The balloon was inflated
4 times for 30 seconds (each instance of inflation separated by 30 seconds of
reflow). Patients were followed for a mean period of 37.5 months, during
which the incidence of primary endpoints that included major cardiovascular
events ([MACE], all-cause mortality, hospitalization for congestive heart
failure [CHF]) was recorded.
A total of 10.5% patients with ischemic postconditioning
experienced the primary outcomes vs. 11.2% patients in the
conventional group (hazard ratio [HR]; 0.93, p = 0.66). As per an indepth analysis, the incidence of all-cause mortality was slightly lower in the
postconditioning group vs. the conventional group (6.2% vs. 8.1%; p = 0.18).
The incidence of CHF hospitalization did not differ in both the study groups
(4.9% vs. 4.9%, p = 0.96). The results for secondary outcomes were also
comparable for both the study groups (recurrent MI: 5.4% vs. 4.7%, p = 0.64;
left ventricular ejection fraction (LVEF) at 18 months: 52.7% vs. 50.8%, p <
0.05; LVEF >45%: 80% vs. 72%, p = 0.015)
Although ischemic postconditioning was associated with improvement in
LVEF at 18 months, there was no reduction in CHF hospitalizations. This
perplexing finding needs further investigation through future in-depth
studies.

CABG added to Medical Therapy Improves Long-Term Survival and


Prognosis vs. Medical Therapy Alone in Patients with Ischemic
Cardiomyopathy: STICH Trial
Patients with ischemic cardiomyopathy who undergo a coronary
artery bypass grafting (CABG) while receiving standard medical
therapy have improved overall survival as well as lesser
hospitalization due to cardiovascular (CV) events over a period of 10
years when compared to patients receiving only medical therapy.
These are the findings of the Surgical Treatment for Ischemic Heart Failure
(STICH) study that was presented at the American College of Cardiology
Scientific Session, 2016 and simultaneously published online in the New
England Journal of Medicine.
It is unclear whether a strategy of CABG added to guideline-directed medical
therapy would provide added survival benefit over the medical therapy
alone, in patients with coronary artery disease (CAD), heart failure, and
severe left ventricular systolic dysfunction. This study was therefore
conducted to evaluate the long-term benefits of CABG in patients with
ischemic cardiomyopathy.
Patients with an ejection fraction 35% and CAD amenable to CABG (n =
1212) were randomized to either CABG group (CABG plus medical therapy, n
= 610) or medical-therapy group (medical therapy alone, n = 602 patients).
Patients were primarily followed for death from any cause. Death from CV
causes and death from any cause or hospitalization for CV events constituted
the major secondary outcomes of the study. The median duration of followup, including the current extended-follow-up study, was 9.8 years.
Death due to any cause was recorded in approximately 58.9%
patients in the CABG group and 66.1% in the medical-therapy group
(hazard ratio [HR] with CABG vs. medical therapy, 0.84; P=0.02).
Death specifically due to CV events was reported in 40.5% patients
in the CABG group vs. 49.3% patients in the medical-therapy group
(HR, 0.79; P=0.006). Death from any cause or hospitalization due to
CV events occurred in 76.6% patients in the CABG group vs. 87.0%
patients in the medical-therapy group (HR, 0.72; P<0.001).
New Engl J Med. April
10.1056/NEJMoa1602001

3rd,

2016

(early

online

publication).

DOI:

Cryoablation Noninferior to Radiofrequency Ablation in Paroxysmal


Atrial Fibrillation: FIRE AND ICE Trial
Cryoballoon ablation is as efficacious as radiofrequency ablation for
the treatment of patients with drug-refractory paroxysmal atrial
fibrillation according to the results of the FIRE AND ICE trial presented at
the American College of Cardiology Scientific Session 2016 and
simultaneously published online in The New England Journal of Medicine.
In a multicentric (16 centers in 8 countries), randomized trial, 762 patients
with drug-refractory paroxysmal atrial fibrillation underwent randomization to
pulmonary vein isolation by cryoballoon ablation (n = 378) or radiofrequency
current ablation (n = 384) and were followed for a mean duration of 1.5
years. The primary efficacy end point was recurrence of atrial fibrillation,
occurrence of atrial flutter or atrial tachycardia, use of antiarrhythmic drugs,
or repeat ablation, 90-day post index ablation. The primary safety end point
was a composite of death, cerebrovascular events, or serious treatmentrelated adverse events. The modified intention-to-treat cohort included all
patients who underwent randomization and their randomly assigned catheter
ablation procedure. The per-protocol cohort consisted of patients who were
treated and did not have a major protocol deviation (defined as a deviation
that confounded the efficacy end point; such deviations included amiodarone
use, undergoing an ablation with a nonstudy-specified catheter, and
undergoing an ablation with a catheter that was not in accordance with the
randomly assigned treatment group).
In the modified intention-to treat analysis, primary efficacy outcome
occurred in 34.6% of the cryoballoon ablation group vs 35.9% of the
radiofrequency current ablation group (hazard ratio [HR] = 0.96;
p<0.001 for noninferiority). In the per-protocol analysis, the primary
efficacy end point occurred in 31.9% of the cryoballoon group and in
35.05 of the radiofrequency group (HR: 0.91; p<0.001 for
noninferiority). The primary outcome was the same in all tested subgroups
and among different types of ablation catheters. The mean total
procedure time was significantly shorter in the cryoballoon group
than in the radiofrequency group (124 vs. 141 minutes; p<0.001).
Similarly, the left atrial dwell time (the length of time the catheter
was present in the left atrium during the procedure) was also
significantly shorter in cryoballoon group (92 vs. 109 minutes,
p<0.001). On the other hand, the mean total fluoroscopy time was
significantly shorter in the radiofrequency group than in the
cryoballoon group (17 vs. 22 minutes, p<0.001).
The primary safety outcome occurred in 10.2% of the cryoballoon
ablation group versus 12.8% of the radiofrequency current ablation
group (HR = 0.78; p=0.24). The commonly reported safety events were

groin-site complications (radiofrequency group: 16 vs cryoballoon group: 7)


and phrenic-nerve injury (radiofrequency group: 0 vs cryoballoon group: 10).
N Engl J Med. April
10.1056/NEJMoa1602014

4th,

2016

(early

online

publication)

DOI:

Lung Impedance Guided Treatment Superior to Routine Treatment in


CHF: IMPEDANCE - HF Trial
Noninvasive lung-impedance (LI) guided management is superior to
routine management in reducing hospitalizations for heart failure
and in offering improvement in survival at 1 year and beyond in
patients with chronic heart failure (CHF), according to the results of
IMPEDANCE-HF trial presented at the American College of Cardiology
Scientific Session 2016 and simultaneously published in the Journal of
Cardiac Failure.
This randomized, controlled, single-blind, two centre trial involved 256 CHF
patients with reduced ejection fraction (left ventricular ejection fraction
35%) and with New York Heart Association Class II-IV and who were
admitted for acute heart failure (AHF) within 12 months prior to recruitment.
These patients were randomized in a 1:1 fashion to either noninvasive LI
guided management (n = 128) or routine management (n = 128) and were
followed for at least 12 months. Noninvasive LI measurements were
performed with a new high-sensitive device, at each outpatient clinic visit.
The primary efficacy endpoint was AHF hospitalizations and secondary
endpoints were all-cause hospitalizations and mortality.
The results showed that, rate of hospitalization at 1 year for LI guided
arm vs. routine management, was 0.52 vs. 1.23 per patient-year (HR
= 0.51; p<0.001) (Number Needed to Treat=1.4). During the entire
study period (48 32 months -monitored patients, 39 26 months control patients), the benefit of LI guided treatment was maintained
(rate of hospitalizations for AHF: 0.41 vs. 0.94 per patient-year, HR
= 0.63; p<0.001) (Number Needed to Treat=1.9). The benefit of LI-guided
treatment was observed in all patients regardless of their functional NYHA
class. Besides, significant reductions were noted in all-cause (HR=
0.52, p=0.002) and cardiac mortality (HR= 0.41, p<0.001) with LI
guidance vs routine care. The incidence of non-cardiovascular death was
similar in both groups.
Thus, findings from this study for the first time indicate that noninvasive LI
guided management is superior as compared to routine management in
reducing heart failure hospitalizations.
J Cardiac Failure. April 4th,
10.1016/j.cardfail.2016.03.015.

2016

(early

online

publication):

doi:

Vagal Nerve Stimulation not Beneficial in Chronic Heart Failure:


INOVATE-HF Trial
The results of the INcrease Of VAgal TonE in Heart Failure (INOVATE-HF) trial,
presented at the American College of Cardiology Scientific Sessions 2016,
showed that vagal nerve stimulation (VNS) fails to reduce mortality
rate or heart failure (HF) events as compared to optimal medical
therapy in patients with chronic HF.
The INOVATE-HF was a multinational, randomized parallel group trial
conducted at 85 centres which enrolled a total of 707 chronic HF patients of
New York Heart Association (NYHA) class III symptoms and ejection fraction <
40%. Patients were randomized in a 3:2 ratio to either device implantation to
provide VNS (Active group) or continuation of medical therapy (Control
group). The primary endpoint of the trial was the composite of death from
any cause or first event for worsening HF.
The trial was terminated after a mean follow-up of 16 months due to futility
of results. The primary outcome (death or HF hospitalization) occurred in
30.3% of the patients in the VNS group vs. 25.8% of those in the control
group with no statistically significant difference between the two groups
[Hazard ratio (HR) 1.14, p = 0.37]. There was also no significant difference
between the VNS and the control group in annual death rate (9.3% and 7.1%,
p = 0.37).
Although the VNS group showed favourable improvements in quality of life,
6-minute walk test and NYHA class, there was no difference in the left
ventricular end-systolic volume index indicating that VNS does not reverse
cardiac modelling in patients with chronic HF.
J Am Coll Cardiol. April 4th,
doi:10.1016/j.jacc.2016.03.525

2016

(early

online

publication)

TAVR Comparable to SAVR in Intermediate-Risk Patients with Severe


Aortic-Valve Stenosis: PARTNER 2A Trial
Results of a latest randomized trial demonstrate that transcatheter aorticvalve replacement (TAVR) is similar to surgical aortic-valve
replacement (SAVR) in terms of reducing the primary endpoint of
all-cause mortality and disabling stroke at 2 years in intermediaterisk patients with severe aortic stenosis. Moreover, TAVR appeared to
be superior to SAVR when a transfemoral approach (used in about 75% of the
study population) was used. This landmark trial in the field of aortic valve
replacement was presented at the American College of Cardiology Scientific
Sessions 2016, and simultaneously published in The New England Journal of
Medicine.
Recent evidence suggests similar survival rates with TAVR and SAVR
amongst high-risk patients with aortic stenosis. This randomized study was
conducted to assess the safety and efficacy of balloon-expandable TAVR
compared with SAVR in intermediate-risk patients with aortic stenosis. A total
of 2032 intermediate-risk patients (mean age; 81.6 years) with severe aortic
stenosis from across 57 centers were enrolled in this study. Based on the
clinical and imaging findings, patients were categorized as transfemoralaccess cohort (76.3%) and transthoracic-access cohort (23.7%), before
randomization. Patients were then randomized to either TAVR or SAVR group.
The primary end point of the study was death from any cause or disabling
stroke at 2 years.
Both the study groups exhibited similar rates of mortality and
disabling stroke (P=0.001 for noninferiority, p = 0.33 for
superiority). As per the KaplanMeier analysis, event rates at 2
years were 19.3% in the TAVR group and 21.1% in the SAVR group
(hazard ratio [HR]; TAVR group, 0.89; P=0.25). The incidence of
primary outcome in the study groups is as per the following table.
Table: Outcomes in
Outcome
All-Cause Mortality
Cardiovascular
Mortality
Disabling Stroke

TAVR vs. SAVR group


TAVR Group
16.7%
10.1%
6.2%

at 2 years
SAVR Group
18.0%
11.3%

p Value
0.45
0.38

6.4%

0.83

Use of TAVR in the transfemoral-access cohort resulted in a lower


rate of death or disabling stroke vs. surgery (HR, 0.79; P=0.05). The
findings in the transthoracic-access cohort, were however similar in the two
groups. TAVR was associated with larger aortic-valve areas (1.54
cm2 vs. 1.4 cm2, p < 0.001) and lower incidence of life-threatening or
disabling bleeding at 30 days (10.4% vs. 43.4%, p < 0.0001), new-onset
atrial fibrillation at 30 days (9.1% vs. 26.4%, p < 0.001), and acute

kidney injury, as compared to SAVR. On the other hand, SAVR was


associated with fewer major vascular complications and less paravalvular
aortic regurgitation.
N Engl J Med. April
10.1056/NEJMoa1514616

2nd,

2016

(early

online

publication).

DOI:

TAVR with SAPIEN 3 Preferred over Surgery in Treatment of


Intermediate-Risk Patients with Severe Aortic Stenosis
As per the findings of a study presented at the American College of
Cardiology Scientific Sessions 2016, and simultaneously published in The
Lancet, Trans catheter aortic valve replacement (TAVR) using SAPIEN
3 valve is associated with a lower incidence of all-cause mortality,
stroke, and regurgitation at 1 year in intermediate-risk patients
with severe aortic stenosis. Furthermore, the clinical outcomes with
SAPIEN 3 TAVR were much more superior to those associated with
surgery, thus suggesting that TAVR might be the preferred treatment
alternative in such patient subgroup.
SAPIEN 3 is an observational study that enrolled 1,077 intermediate-risk
patients with severe aortic stenosis from over 51 centers in the United States
and Canada. Patients were assigned to receive TAVR with the SAPIEN 3 valve
(88% via transfemoral access). The incidence of all-cause mortality, strokes,
re-intervention, and aortic valve regurgitation at 1 year after implantation
was assessed. The following table gives the incidence of clinical outcomes at
1 year in the study subjects (Table).
Table: The outcomes in study subjects at 1 year
Outcome
Incidence
All-Cause Mortality
7.4%
(transfemoral
6.5%)
Disabling Stroke
2%
Aortic Valve Re-Intervention
1%
Moderate-Severe
Paravavular 2%
Regurgitation

sub-group:

The one year outcomes in this population were compared with those for
intermediate-risk patients treated with surgical valve replacement in the
PARTNER 2A trial using a prespecified propensity score analysis to account
for between-trial differences in baseline characteristics. In a propensity-score
analysis which included 963 patients treated with SAPIEN 3 TAVR and 747
with surgical valve replacement, TAVR appeared to be both, non-inferior
(pooled weighted proportion difference of 9.2%; p < 0.0001) and
superior (9.2%; p < 0.0001) to surgical valve replacement for the
primary composite outcome of mortality, stroke, and moderatesevere aortic regurgitation. TAVR was also superior to surgery for
individual outcomes of death (52%; p= 00003) and stroke (35%;
p=00038).
Further long-term, prospective randomized trials are warranted to confirm
these findings before they can be extended to intermediate- or low-risk
patient populations.

Lancet.
April
3rd,
2016
(early
online
DOI: http://dx.doi.org/10.1016/S0140-6736(16)30073-3

publication).

TAVR with CoreValve Noninferior to Surgical AVR in Improving


Survival in Severe Aortic Stenosis Patients: The CoreValve High-Risk
Study
The findings of the CoreValve High-Risk study presented at the American
College of Cardiology Scientific Sessions, 2016 and simultaneously published
in the Journal of the American College of Cardiology; demonstrate that
amongst patients with severe aortic stenosis, the clinical benefits
provided by transcatheter aortic-valve replacement (TAVR) with the
self-expanding CoreValve are non-inferior to those provided by
surgical valve replacement (SAVR) at 3 years.
The clinical benefits of TAVR in terms of improved survival at 2 years are
already well-established. The CoreValve High-Risk study was conducted to
determine if the clinical benefits of TAVR would extend up to 3 years.
A total of 747 patients with severe aortic stenosis deemed at increased risk
for surgery were enrolled in this study. Approximately 86% of the patients
had New York Heart Association (NYHA) class III or IV symptoms. Study
subjects were randomized 1:1 to TAVR (n = 390) or SAVR (n = 357). Clinical
data and detailed echocardiographic outcomes were obtained for all the
study subjects. All-cause mortality at 1, 2, and 3 years was the primary
endpoint of the study. In addition, the incidence of MACE or cerebrovascular
events during hospitalization, at 30 days, and during entire study period was
also assessed.
Patients randomized to TAVR had a significantly lower rates of 3-year allcause mortality or stroke vs. patients randomized to SAVR (37.3% vs. 46.7%;
p = 0.006). Also, all-cause mortality at each year was significantly
lower in the TVAR group as compared to the SAVR group (Table 1).
Table 1: All-cause mortality in the study groups
Year-Wise
All- TAVR
SAVR
Cause Mortality
1 Year
14.2%
19.1%
2 Years
22.2%
28.6%
3 Years
32.9%
39.1%

p Value
<0.0001
0.04
0.07

The incidence of stroke at 30 days and at 1 year was lower with TAVR vs.
SAVR (4.9% vs. 6.2% [at 30 days]; 8.8% vs. 12.6% [at 1 year]). The
incidence of stroke (including major stroke) and MACE at 3 years
was also lower with TAVR vs. SAVR (Table 2).
Table 2: Incidence of stroke and MACE in the study groups at 3 years
Outcome
TAVR
SAVR
p Value
Stroke
12.6%
19.0%
0.034

MACE

40.2%

47.9%

0.03

Further, TAVR patients exhibited better aortic valve hemodynamics


at 3 years (mean aortic valve gradient, 7.62 mmHg vs. 11.40 mmHg,
p < 0.001). Nevertheless 6.8% TAVR patients experienced moderate or
severe residual aortic regurgitation. There was no such incidence in SAVR
patients. There was no incidence of valve thrombosis in either study group.
J Am Coll Cardiol April 3rd,
doi:10.1016/j.jacc.2016.03.506

2016

(Early

Online

Publication).

Superiority of Bariatric Surgery plus Medical Therapy vs Medical


Therapy Alone in Obese/ Overweight Diabetes Patients Sustained for
5 Years: STAMPEDE Trial
The five year follow-up of the Surgical Therapy And Medications Potentially
Eradicate Diabetes Efficiently (STAMPEDE) trial presented at the American
College of Cardiology Scientific Sessions 2016 highlights that the
combination of intensive medical therapy and bariatric surgery is
superior to intensive medical therapy alone in achieving adequate
glycemic control in type 2 diabetes mellitus (DM) patients who are
obese or overweight, with results being sustained up to 5 years of
follow-up. Both gastric bypass and sleeve gastrectomy seem to achieve
similar results.
The STAMPEDE trial is the largest randomized trial comparing medical
therapy to bariatric surgery. The trial enrolled 150 DM patients with glycated
hemoglobin (HbA1c) >7% and body mass index (BMI) between 27-43 kg/m 2
(mean age: 49 years; females: 66%). The mean duration of DM was 8.3 years
and 53% were on 3 diabetes medications (47% of total used insulin). The
mean BMI was 36 kg/m2 (34% had BMI <35 kg/m2) and about 92% had
metabolic syndrome. Patients were randomized to either of the 3 arms: 1)
intensive medical therapy alone; 2) intensive medical therapy + Roux-en-Y
gastric bypass surgery; or 3) intensive medical therapy + sleeve
gastrectomy. The intensive medical therapy received by the patients was in
lines with the American Diabetes Association guidelines and included
lifestyle counseling and frequent home glucose monitoring. Patients were
followed-up and data was evaluated at 1 year, 3 years and 5 years. The key
outcome was to evaluate the percentage of patients who achieved HbA1c of
6%.
The 5 year follow-up data confirms the superiority of bariatric surgery over
medical therapy alone in obese or overweight DM patients as was earlier
shown in the 1-year and 3 year reports. The percentage of patients with
HbA1c 6% was higher in the gastric bypass (29%) and sleeve
gastrectomy arms (23%) as compared to the intensive medical
therapy alone arm (5%; p = 0.005 and p = 0.02, respectively). Mean
change in the body weight was also significantly higher, both in the
gastric bypass arm and the sleeve gastrectomy arm vs intensive
medical therapy alone arm (p < 0.001 for both groups). Besides, use
of
cardiovascular
and
glucose-lowering
medications
was
significantly reduced from baseline and was significantly lower in
both the gastric bypass arm and the sleeve gastrectomy arm vs
intensive medical therapy alone arm. Over 88% of surgically treated
patients had their glycemic control maintained without use of
insulin. It was observed that among the 2 surgery groups, gastric bypass

maintained greater weight loss than sleeve gastrecomy, while


requiring fewer medications.
The incidence of glycemic relapse i.e. patients who achieved HbA1c
of 6% at 1 year, but not at 5 years, was lowest in both the surgical
arms vs intensive medical therapy alone (40% vs. 50% vs. 80%, p =
0.16 and p = 0.34, respectively). However, change (from baseline) in
albumin/creatinine ratio was highest in the sleeve gastrectomy arm
group vs other groups (-16.7% vs. -59.5% vs. 7.1%, p < 0.001). In
both the surgical groups, achieving HBA1c < 6.0% was predicted both by
reduction in BMI and duration of diabetes of less than eight years.
At the end of 5 years, there were no late major complications of surgery
except for one reoperation which was done four years after randomization.
Besides, significant improvement in bodily pain and general health was
demonstrated in both surgery arms vs intensive medical group alone. Also,
several biomarkers associated with heightened cardiovascular risk were
reduced in both the surgical arms.

Cell Therapy with Ixmyelocel-T may Improve Outcomes in Patients


with Ischemic HF: ixCELL-DCM Trial
The findings of ixCELL-DCM, the largest cell therapy study done in patients
with heart failure (HF), demonstrate that transendocardial delivery of
ixmyelocel-T in HF patients with reduced ejection fraction due to
ischemic dilated cardiomyopathy results in a significant reduction in
adjudicated clinical cardiac events. The reduction in clinical events which
was significantly greater than that observed with placebo, was also
associated with improved patient outcomes. The study was presented
at American College of Cardiology Scientific Session, 2016 and also
published online in The Lancet.
Early-phase clinical trials with ixmyelocel-T (multicellular therapy produced
from a patients own bone marrow) have indicated that intra myocardial
delivery of ixmyelocel-T might improve clinical, functional, symptomatic, and
quality-of-life outcomes in HF patients with ischemic dilated cardiomyopathy.
This study was therefore conducted to assess the safety and efficacy of
catheter-based transendocardial injection of ixmyelocel-T cell therapy in HF
patients with reduced ejection fraction.
A total of 126 symptomatic ischemic dilated cardiomyopathy HF patients
from across 31 sites in North America were enrolled in this randomized,
double-blind, placebo-controlled phase 2B trial (ixCELL-DCM). All patients had
left ventricular ejection fraction (LVEF) 35%, an automatic implantable
cardioverter defibrillator fitted, and were ineligible for revascularization
procedures. Study subjects were randomly assigned (1:1) to receive
ixmyelocel-T (n= 60) or placebo (n = 66) at the time of bone marrow
aspiration, and followed for 12 months. The primary endpoint was a
composite of all-cause death, hospitalization due to cardiovascular events,
and unplanned clinic visits to treat acute decompensated HF.
The per-protocol primary efficacy analysis included 109 patients (58 in the
ixmyelocel-T group and 51 in the placebo group). The incidence of the
primary endpoint was higher in the placebo group (50 events in 25
[49%] of 51 patients) as compared to the ixmyelocel-T group (38
events in 22 [38%] of 58 patients). Thus, as compared to placebo,
ixmyelocel-T was associated with a 37% reduction in cardiac events
(risk ratio 063; p=00344). The incidence of serious adverse events
was higher in the placebo group vs. the ixmyelocel-T group (75% vs.
53%; p=00197).
Future in-depth studies are essential to confirm the promising results from
the ixCELL-DCM and to extend the benefits of cell therapy to HF patients.

Lancet.
April
4th,
2016
(Early
http://dx.doi.org/10.1016/S0140-6736(16)30137-4

Online

Publication).

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