Adv Ther DOI 10.1007/s12325-014-0141-9
REVIEW
Advances in Clinical Cardiology Andrew H. McNeice • Neil M. McAleavey • Ian B. A. Menown
To view enhanced content go to www.advancesintherapy.com Received: June 10, 2014 Ó Springer Healthcare 2014
ABSTRACT
on pump). Latest trials in trans-aortic valve
Multiple,
implantation, heart failure (eplerenone, aliskiren, spironolactone, sildenafil, dopamine,
cardiology
potentially
or
nesiritide, omecamtiv mecarbil, the algisyl left
published over the past year. In this paper, we summarize and place in clinical context, new
ventricular augmentation device, and echoguided cardiac resynchronization), atrial
data regarding management of acute coronary syndrome and ST-elevation myocardial
fibrillation ablation),
infarction (copeptin assessment, otamixaban,
LUCASTM mechanical chest compression), and
cangrelor, prasugrel, sodium nitrite, inclacumab, ranolazine, preventive coronary
cardiovascular prevention (vitamins, renal denervation for resistant hypertension, renal
intervention of non-culprit lesions, immediate thrombolytic therapy versus transfer for
artery stenting, saxagliptin, alogliptin, and gastric banding) are also discussed.
primary
trials
have
practice-changing
intervention),
been
presented
new
(edoxaban, dabigatran, and cardiac arrest (hypothermia,
coronary
intervention data (thrombectomy, radial access, pressure wire fractional flow reserve, antiplatelet therapy duration and geneguidance, permanent and biodegradable polymers, coronary bifurcation and strategies),
Keywords: Acute Anticoagulation;
coronary syndrome; Antiplatelet; Atrial
fibrillation; Cardiac resynchronisation; Drugeluting stent; Lipids; Renal denervation
and coronary artery bypass data (off pump vs. Electronic supplementary material The online version of this article (doi:10.1007/s12325-014-0141-9) contains supplementary material, which is available to authorized users. A. H. McNeice N. M. McAleavey I. B. A. Menown (&) Craigavon Cardiac Centre, Southern Trust, Northern Ireland BT63 5QQ, UK e-mail:
[email protected] INTRODUCTION Over the last year, key trials in clinical cardiology
trials
have
been
presented
at
international meetings, including the American College of Cardiology, European Association for Percutaneous Cardiovascular
Adv Ther
Interventions (EuroPCR), European Society of
standard care including serial troponin testing
Cardiology (ESC), Transcatheter Cardiovascular
(n = 451) [1]. In the investigational arm, those
Therapeutics (TCT), and the American Heart Association (AHA). In this paper, new data on
with copeptin \10 pmol/L had expedited discharge and outpatient follow-up at 72 h
acute coronary syndrome (ACS), interventional cardiology, heart failure, atrial fibrillation (AF),
while those with copeptin C10 pmol/L were admitted for further assessment. The copeptin
electrophysiology, and preventive cardiology
strategy
are described and placed in clinical context.
emergency department in 66% of patients compared with only 12% using a standard
METHODS
serial troponin strategy. At 30 days, there was no significant difference in rates of major
guided
early
discharge
from
the
major
adverse cardiac events (MACE; 5.46% vs. 5.5%;
cardiology conferences were reviewed by the authors. Search terms included ‘‘acute
P not significant) [1]. BIC-8 adds to the body of evidence supporting use of early ACS
coronary
biomarkers along with troponin in emergency department protocols.
Clinical
trial
results
presented
syndrome,’’
at
‘‘interventional
cardiology,’’ ‘‘heart failure,’’ ‘‘atrial fibrillation,’’ ‘‘electrophysiology,’’ and ‘‘coronary prevention.’’ Selection criteria were trials of broad relevance to the cardiology community,
Antiplatelets, Anticoagulants, and Thrombolytic Therapy in ACS
those with the potential to change current practice, and those with the potential to guide further phase 3 research of clinical efficacy and safety. The analysis in this article is based on previously conducted studies, and does not
The Treatment of Acute Coronary Syndromes with Otamixaban (TAO; Clinicaltrials.gov #NCT01076764) trial randomized 13,229
involve any new studies of human or animal
patients with moderate to high-risk non-ST elevation myocardial infarction (NSTEMI) and
subjects performed by any of the authors.
a planned early invasive strategy to the intravenous factor Xa inhibitor otamixaban (bolus and infusion) or unfractionated heparin
ACUTE CORONARY SYNDROME TRIALS
plus, at the time of percutaneous coronary intervention (PCI), eptifibatide. The primary efficacy outcome—the composite of all-cause
Biomarkers in Diagnosis of Acute Coronary Syndrome The Biomarkers Clinicaltrials.gov
in
Cardiology 8 #NCT01498731)
death or new myocardial infarction (MI) through day 7—was not significantly different (BIC-8; trial
between groups (5.5% vs. 5.7%; adjusted relative risk (RR) 0.99 [95% CI, 0.85–1.16]; P = 0.93). In addition, the primary safety
randomized 902 emergency department patients at low to intermediate risk of ACS and
outcome of thrombolysis in myocardial infarction (TIMI) major or minor bleeding
initially negative troponin to an investigational
through day 7 was increased with otamixaban (3.1% vs. 1.5%; RR 2.13 [95% CI, 1.63–2.78];
strategy with assessment of copeptin, a provasopressin fragment which is an early marker of severe hemodynamic stress (n = 451), or to
P\0.001) [2]. The role for otamixaban in ACS at current doses thus appears limited.
Adv Ther
A pooled analysis of patient-level data was
during primary PCI for STEMI. The Preventive
undertaken combining results from the three
Angioplasty in Acute Myocardial Infarction
double-blind, randomized controlled trials of cangrelor (a rapid-acting, reversible intravenous
(PRAMI; Isrctn.org #ISRCTN73028481) investigators randomized 465 patients after
platelet inhibitor) versus placebo in patients with ST-elevation myocardial infarction
primary PCI for STEMI to ‘preventive PCI’ of additional non-culprit lesions during the
(STEMI), NSTEMI, and stable coronary disease
index
undergoing PCI. Use of cangrelor was associated with a significant reduction in the primary
conservative strategy of no planned PCI of non-culprit lesions (n = 231). After a mean
efficacy outcome of death, MI, ischemia-driven revascularization, or stent thrombosis at 48 h
follow-up of 23 months, the trial was stopped early based on a recommendation from the
(absolute risk reduction 1.9%; RR reduction
data and safety monitoring committee. The
19%) and reduction in stent thrombosis as a single endpoint (absolute risk reduction 0.3%;
preventative PCI strategy (Fig. 1) was associated with significant reduction in the
RR reduction 41%). The primary safety outcome of non-coronary artery bypass graft-related
primary composite endpoint of death from cardiac causes, non-fatal MI, or refractory
GUSTO (Global Use of Strategies to Open
angina (21 vs. 53; hazard ratio [HR] 0.35;
Occluded Coronary Arteries) severe or lifethreatening bleeding at 48 h was similar
95% CI 0.21–0.58; P\0.001), reduced nonfatal MI (HR 0.32; 95% CI 0.13–0.75), reduced
although the rate of GUSTO mild bleeding was higher in the cangrelor-treated patients [3].
refractory angina (HR 0.35; 95% CI 0.1820.69), and a trend to reduced death (HR 0.34; 95%
These pooled results may support a role for cangrelor in clinical practice as bridging therapy
CI 0.11–1.08). PRAMI thus clearly supports treatment of non-culprit lesions although it
should there be a delay to revascularization.
does not guide as to whether this is best
Current European and American guidelines recommended treating only the culprit artery
undertaken immediately during the index PCI or via an early staged procedure [4].
procedure
(n = 234)
or
to
a
Fig. 1 The number of primary outcome event rates at 23 months in the preventative and non-preventative arms of the PRAMI study. Adapted with permission from Wald et al. [4]. PCI percutaneous coronary intervention
Adv Ther
ACCOAST (A Comparison of Prasugrel at
The STREAM (Strategic Reperfusion Early
NSTEMI;
After Myocardial Infarction; Clinicaltrials.gov
Clinicaltrials.gov #NCT01015287) randomized 4,033 patients after diagnosis of NSTEMI to a
#NCT00623623) trial enrolled 1,892 patients with STEMI who presented within 3 h of
pretreatment 30 mg then
symptom onset and who could not undergo primary PCI within 1 h of first medical contact.
PCI
or
Time
angiography
of
Diagnosis
of
group (immediate prasugrel a further 30 mg later after if
PCI
was
required)
or
to
Patients were randomized to a pharmaco-
standard treatment (initial placebo, then 60 mg after angiography if PCI was required).
invasive therapy
arm of immediate with tenecteplase
thrombolytic and early
The primary efficacy endpoint (a composite of cardiovascular [CV] death, MI, stroke, urgent
angiography with or without PCI within 6–24 h, or to transfer for primary PCI. The
revascularization,
IIb/IIIa
median time from symptom onset to the start of
bailout) was not significantly different between the two treatment groups at 7 or
reperfusion therapy was 100 min in patients randomized to the thrombolysis group versus
30 days. However, TIMI major bleeding (either related to coronary artery bypass grafting
178 min in the primary PCI group (Fig. 2). Rescue PCI was permitted in the pharmaco-
[CABG] or not) was significantly higher in the
invasive arm and undertaken in 36%. The
pretreatment group at both 7 or 30 days, as were rates of non-CABG TIMI major bleeding and
primary endpoint—a composite of death from any cause, shock, congestive heart failure, or re-
life-threatening bleeding. This important result challenges the frequent previous practice of
infarction at 30 days—occurred in 12.4% of patients in the early thrombolysis group versus
P2Y12 loading in emergency departments at the time of NSTEMI diagnosis, at least for prasugrel,
14.3% patients in the primary PCI group (RR 0.86; 95% CI 0.68–1.09; P = 0.24). Following an
and potentially for clopidogrel and ticagrelor
early
since previous studies with these agents did not formally address the question [5].
hemorrhage, a reduced tenecteplase dose was used for patients C75 years after which no
Fig. 2 Time differences between patients receiving fibrinolytic therapy and patients who underwent primary PCI within the STREAM study. Figure used with permission
from author. Presented at the American College of Cardiology 2013; March, 2013; San Francisco, California. PCI percutaneous coronary intervention
or
glycoprotein
observation
of
excess
intracranial
Adv Ther
intracranial
placebo. The primary endpoint, change in
hemorrhage was noted (0.54% vs. 0.26%;
troponin I from baseline to 16 h and 24 h post-
P = 0.45). The STREAM findings are reassuring for medical settings in which STEMI patients
PCI, among the 322/544 patients who underwent PCI was reduced by inclacumab
may not have ready access to primary PCI, showing that a pharmaco-invasive approach
20 mg/kg compared with placebo by 22.4% at 16 h (P = 0.07) and by 24.4% at 24 h (P = 0.05).
may be as effective as transfer for primary PCI
No significant reduction in troponin was seen
and may circumvent the need for an urgent procedure in about two-thirds of treated
with inclacumab 5 mg/kg. Given the encouraging preliminary results a large clinical
patients [6].
endpoint study with inclacumab is planned [8].
Reducing Myocardial Damage in ACS
Antianginal Therapy
The Nitrites in Acute Myocardial Infarction
The TERISA (Type 2 Diabetes Evaluation of
(NIAMI; Clinicaltrials.gov #NCT01388504) trial randomized 229 patients undergoing primary
Ranolazine in Subjects With Chronic Stable Angina; Clinicaltrials.gov #NCT01425359) trial
PCI for their first STEMI in double-blind fashion to infusion with 70 lmol of sodium nitrite in
randomized 949 patients with diabetes and chronic angina to 8 weeks of ranolazine (target
5-mL saline or to placebo immediately prior to
dose 1,000 mg twice daily) or placebo. The
stent deployment. There was no significant difference in the primary endpoint of infarct
primary outcome, the average weekly number of anginal episodes over the last 6 weeks of the
size defined by cardiac magnetic resonance imaging by day 6–8 (median infarct size 22%
study, showed only a small reduction with ranolazine (3.8 vs. 4.3; P = 0.008) as did the
vs. 20%; P = 0.31) or secondary endpoints of plasma troponin measured over 72 h, infarct size
weekly sublingual nitroglycerin use (1.7 doses vs. 2.1 doses; P = 0.003) although treatment
at 6 months or left ventricular (LV) ejection
benefits appeared more prominent in patients
fraction at 6 months. The authors concluded that while higher doses, particularly in a diabetic
with higher glycated hemoglobin levels. Of relevance to clinical practice given the
subgroup, might show benefit, there was no evidence of benefit of the studied dose in STEMI
relatively high target dose of ranolazine (which is limited to 750 mg twice daily in
patients [7].
Europe) there was no excess in serious adverse
Myocardial damage is common after PCI, due in part to inflammation and platelet activation.
events between groups [9].
P-selectin plays a critical role in leukocyte and platelet rolling. In the SELECT-ACS trial (Effects
REVASCULARISATION AND INTERVENTIONAL CARDIOLOGY
significant
difference
in
of the P-Selectin antagonist inclacumab on myocardial damage following PCI for NSTEMI; Clinicaltrials.gov #NCT01327183), 544 patients scheduled for coronary angiography with or without PCI were randomized to receive the
Clopidogrel Genotyping for Antiplatelet Guidance Post-PCI
recombinant monoclonal immunoglobulin G4
Given the mixed results from previous research,
antibody inclacumab 5 mg/kg or 20 mg/kg, or
platelet
function
or
genotype-guided
Adv Ther
antiplatelet
therapy
is
for
routine
not
currently
genotype and pharmodynamic response was
but
not strong with 60% of the LOF group
important research is ongoing. Patients being treated with clopidogrel post PCI, but who carry
unexpectedly showing favorable platelet response and 31% of the GOF group showing
a clopidogrel loss of function (LOF) gene, are considered to be at higher risk of future
poor platelet response. This discordance highlights that genotype is only one of several
ischemic
non-
factors affecting platelet response. The addition
randomized Genotyping Infarct Patients to Adjust and Normalize Thienopyridine
of genotyping to pharmacodynamics data obtained from the platelet function tests did
Treatment (GIANT; Clinicaltrials.gov #NCT01134380) trial enrolled 1,445 patients
not significantly improve their already poor accuracy (in the main ARTIC trial) for
who underwent PCI within 24 h following
predicting ischemic outcomes in the setting of
STEMI [10]. Those patients with LOF genotype (n = 316) and assigned, at clinician discretion,
PCI. However, as ARTIC-GENE was only an observational rather than interventional study,
to a higher intensity antiplatelet regimen (double-dose clopidogrel or prasugrel; n = 272)
it would be useful to undertake a larger study in patients pre-defined with LOF genotype and
were shown to have a lower incidence of the
randomized
primary endpoint (death, MI, or stent thrombosis) at 1 year compared with those
ticagrelor) versus routine antiplatelet therapy with clopidogrel 75 mg.
(n = 55) remaining on standard therapy (3.3% vs. 15.6%; P = 0.04)—a level of risk which was
Thrombus Aspiration During ST-Segment
recommended
events.
The
practice
prospective,
to
intensified
(prasugrel
or
similar to those without the LOF genotype (n = 1,118; 3.3% vs. 3.04%; P non-inferiority
Elevation Myocardial Infarction
\0.0001).
Thrombus aspiration before primary PCI has been widely encouraged in guidelines given the
A subset of Randomization of
the ARCTIC a Monitoring
(Double Adjusted
mortality
reduction
observed
a
small
Antiplatelet Treatment Versus a Common Antiplatelet Treatment for DES [drug-eluting
randomized previous Thrombus Aspiration
stent] Implantation, and Interruption Versus
Elevation Myocardial Infarction (TASTE; Clinicaltrials.gov #NCT01093404) trial
Continuation of Double Antiplatelet Therapy; Clinicaltrials.gov #NCT00827411) trial
study. during
in
The large ST-Segment
randomized 7,244 patients from the Swedish
population—ARCTIC-GENE [11], underwent genetic testing with 459 patients identified
Coronary Angiography and Angioplasty Register (SCAAR) to manual thrombus
with
aspiration followed by PCI versus PCI only [12]. Unexpectedly, the primary endpoint (all-
a
LOF
gene
(slow
metabolizer
of
clopidogrel) and 935 identified with a gain-offunction (GOF) gene (rapid metabolizer). As
cause mortality at 30 days) was not significantly
expected, the prevalence of high on-treatment platelet reactivity (poor clopidogrel response by
reduced by thrombus aspiration (2.8% vs. 3.0%; HR 0.94; 95% CI 0.72–1.22; P = 0.63) although
platelet function testing) was higher in LOF
there were non-significant trends to reduction in recurrent MI at 30 days (0.5% vs. 0.9%;
group (40.3% vs. 30.9%; P = 0.015 at time of PCI and 22.7% vs. 9.7%; P\0.0001 by day 14–30). However, the concordance between
P = 0.09) and stent thrombosis (0.2% vs. 0.5%; P = 0.06). Thus the mortality benefit with
Adv Ther
thrombus aspiration that was observed in earlier
complications (1.2% vs. 2.9%; P = 0.12) and
clinical trials may have been a chance finding. A
higher rate of crossover to the alternative
conclusion awaits analysis of outcomes at 12 month follow-up and results from the
approach (6.1% vs. 1.7%; P = 0.006). In summary, an initial strategy of radial access
ongoing Trial of Routine Aspiration Thrombectomy With Percutaneous Coronary
appears preferable in female patients but with the recognition that approximately 1 in 20 may
Intervention versus PCI Alone in Patients With
require crossover to femoral access. New radial
STEMI Undergoing Primary PCI Clinicaltrials.gov #NCT01149044).
sheath designs such as the 6 in 5 Terumo sheath (which allows passage of 6 French size
(TOTAL;
Safety and Efficacy of Radial Approach
instruments, but with a 5 French outer diameter) may help to reduce crossover rates
in Women
further.
Radial access during PCI has been associated
Routine Fractional Flow Reserve During
with improved outcomes. However, women often have smaller diameter arteries than men,
Diagnostic Coronary Angiography
which might increase risk of radial spasm and prompt operators to switch to femoral access.
The RIPCORD (Does RoutIne Pressure wire assessment influence management strategy at
The Study of Access site for Enhancement of PCI
CORonary angiography for Diagnosis of chest
for Women (SAFE-PCI for Women; Clinicaltrials.gov #NCT01406236) randomized
pain?; Clinicaltrials.gov #NCT01070771) trial assessed, in 200 patients, whether routine
1,787 female patients undergoing PCI or cardiac catheterization to radial or femoral access [13].
assessment of fractional flow reserve (FFR) in all main coronary branches would significantly
The incidence of endpoint—Bleeding
the primary efficacy Academic Research
change management strategy compared with a strategy based on diagnostic angiography alone
Consortium (BARC) type 2, 3, or 5 bleeding or
[14]. Patients initially underwent standard
vascular complications that needed intervention \72 h—was lower than expected
diagnostic angiography by a first cardiologist who defined a treatment plan (plan 1) then left
in the femoral arm prompting the data safety and monitoring board to stop the trial early on
the catheterization laboratory while a second cardiologist measured FFR in all patent vessels
futility grounds. Despite the consequent under
of stentable ([2.25 mm) diameter. The FFR
powering, in the overall cohort, those randomized to radial approach showed a
results were shown to the first cardiologist who defined a second treatment plan (plan 2).
significant 65% reduction in the primary endpoint of bleeding/vascular complications
Comparing plan 1 versus plan 2 showed that inclusion of FFR changed the judgment of
(0.6% vs. 1.7%; P = 0.03) although a higher
coronary lesion severity in 64/200 patients
rate of crossover to the alternative approach (6.7% vs. 1.9%; P\0.001). Radial artery spasm
(32%). Based on angiography alone (plan 1), cardiologists intended to send 72 patients for
accounted for 42.9% of the crossover to the femoral approach. In the PCI alone subgroup
medical therapy only, 90 for PCI, 23 for CABG, and 15 for additional testing but after reviewing
(n = 691), there was a similar although non-
the FFR (plan 2), 89 patients were sent for
significant
medical therapy, 80 for PCI, 30 for CABG, and
reduction
in
bleeding/vascular
Adv Ther
only one for further tests. RIPCORD thus
ElementTM-everolimus DES (Boston Scientific
supports increased use of pressure wire during
Corporation, Marlborough, MA, USA) [16]. At
diagnostic angiography.
1-year follow-up, there was no significant difference in the primary endpoint of target
Optimal Duration of Dual Antiplatelet Treatment Post-PCI with Drug-Eluting
vessel failure rate (6.1% vs. 5.2%; P noninferiority = 0.006), target vessel-related MI
Stents
(2.2% vs. 1.3%; P = 0.154) or definite/probable Clopidogrel
stent thrombosis (0.55% vs. 0.88%; P = 0.40). Longitudinal stent deformation was noted in no
Therapy Following Treatment with the Endeavor-Zotarolimus drug-Eluting stent (DES)
Resolute Integrity patients versus 9 Promus Element patients (P = 0.002) but the
in Real-World Clinical Practice (OPTIMIZE; Clinicaltrials.gov #NCT01113372) trial,
deformation was not associated with adverse
The
OPTIMIzed
randomized
Duration
3,119
patients
of
with
stable
clinical events. Thus clinical outcomes appeared similar with event rates being encouragingly
coronary artery disease or low-risk ACS (unstable angina or no MI within 30 days)
low for both stents.
undergoing PCI to a short 3-month versus long 12-month duration of dual antiplatelet
Head-to-Head Permanent versus Biodegradable Polymer DES
therapy (DAPT) [15]. The primary composite
Comparison
endpoint of death, MI, stroke, or major bleeding at 1 year occurred in 93 patients receiving short
The Biomatrix FlexTM (Biosensors International
and 90 patients receiving long duration therapy (6.0% vs. 5.8%; P = 0.002 for non-inferiority).
Group, Ltd., Singapore) biodegradable polymer DES has been associated with lower rates of late
There was no significant difference in sub-acute stent thrombosis between 91–360 days (0.3% vs.
stent thrombosis than first-generation permanent polymer DES. Given the improved
0.1%) suggesting that short-term DAPT may be
stent thrombosis data with newer permanent
reasonable in low coronary risk patients, particularly those at elevated bleeding risk,
polymer DES, SORT-OUT VI (Randomized Clinical Comparison of Biomatrix FlexÒ and
although further larger studies are awaited.
Resolute IntegrityÒ; Clinicaltrials.gov #NCT01956448) randomized 2,999 patients
Head-to-Head Permanent Polymer DES
with chronic stable coronary artery disease or
Comparison
ACS to PCI with the Resolute Integrity permanent polymer zotarolimus DES
DUTCH PEERS (DUrable Polymer-based STent CHallenge of Promus Element Versus ReSolute
(n = 1,502) or the biodegradable polymer
Integrity in an All Comers Population; Clinicaltrials.gov #NCT01331707) was the first
(n = 1,497) [17]. The primary endpoint—a
BioMatrix biolimus
Flex DES
randomized comparison, in 1,811 patients, of
composite of cardiac death, MI, and target lesion revascularization at 12 months—was
two contemporary permanent polymer DES with novel flexible platforms—the Resolute
similarly low in Resolute Integrity (5.3%) and BioMatrix Flex (5.1%) groups. However, since
IntegrityÒ-zotarolimus DES (Medtronic, Inc., Minneapolis, MN, USA) versus Promus
the benefit of a biodegradable polymer is most likely to emerge after 1 year (after cessation of
Adv Ther
DAPT), longer term follow-up, ideally up to
similar composite of cardiac death, non-
5 years, is required to assess if Resolute Integrity
procedure-related
remains non-inferior at this time. The BIOFLOW II (BIOTRONIK-Safety and
revascularization for provisional versus complex strategies (15.8% vs. 21.8%; P = 0.15)
Clinical PerFormance of the Drug-ELuting Orsiro Stent in the Treatment of Subjects With
supporting use of a provisional one-stent strategy in most bifurcation cases.
Single de Novo Coronary Artery Lesions;
However, concerns remained about the
Clinicaltrials.gov #NCT01356888) study randomized 452 PCI patients 2:1 to the Orsiro
optimal strategy in the side branch were large. The Nordic-Baltic Bifurcation Study IV
stent (Biotronik, Buelach, Switzerland; a thin 60-lm strut cobalt–chromium platform coated
(Clinicaltrials.gov #NCT01496638) randomized 450 patients with true coronary bifurcation
with biodegradable poly-L-lactide acid and
lesions
sirolimus) versus Xience Prime (Abbott Laboratories, Abbott Park, IL, USA; 81 lm with
C2.75 mm to a provisional strategy or complex planned two-stent strategy (including 65% with
permanent polymer) [18]. At 9 months, Orsiro was shown to be non-inferior to Xience Prime
a culotte technique) [20]. The complex strategy required longer procedural time and contrast
with respect to the primary angiographic
volume. At 6-month follow-up, event rates were
endpoint of in-stent late lumen loss (0.10 mm vs. 0.11 mm; P\0.0001). On optical coherence
low and similar in both arms although there was a non-significant trend to lower MACE with
tomography (OCT), Orsiro was associated with less neointimal hyperplasia (0.74 mm2 vs.
the complex strategy (4.6% vs. 1.8%; P = 0.09). Longer term follow-up is required to assess the
1.00 mm2; P = 0.024) yet a slightly higher percentage of covered struts (98.3% vs. 97.5%;
clinical importance or otherwise of this trend. A culotte technique is often encouraged if a
P = 0.042) suggesting that the thinner struts
two-stent strategy be deemed necessary, but one
might encourage a very thin but uniform stent coverage. However, as the OCT findings are
criticism of culotte is the ensuing double layer of proximal stent and slight risk of difficulty re-
only hypothesis generating and the study was not powered for clinical endpoints, larger
crossing into the main vessel. Tryton is a dedicated side branch stent which includes a
studies with long-term follow-up are awaited.
main vessel anchor with reduced metal to artery
Coronary Artery Bifurcation Stent Strategy
ratio, through which a standard DES can be placed into the ongoing main vessel (modified
The Nordic Bifurcation study (Clinicaltrials.gov
culotte). TRYTON (A prospective, randomized trial of a dedicated side branch stent vs. a
#NCT00376571) randomized 413 patients with a coronary bifurcation lesion to a provisional
including
MI,
a
and
large
target
side
vessel
branch
provisional stent strategy in true coronary
strategy of main vessel stenting with optional
bifurcation lesions; Clinicaltrials.gov #NCT01258972) randomized 704 patients to a
side branch stenting (kissing balloon dilatation if residual severe stenosis or TIMI flow reduction
Tryton-based (2 stent) strategy or standard provisional stenting [21]. The Tryton strategy
and stent if persisting TIMI flow reduction) versus a complex strategy with planned stenting
was associated with a non-significant excess of
of main vessel and side branch [19]. Five-year
the primary endpoint, target vessel failure, at 9 months (17.4% vs. 12.8%; P = 0.108) mainly
follow-up in 404 (98%) patients reported a
due to an excess of peri-procedural creatine
Adv Ther
kinase-MB elevation. Both groups had low rates
respiratory failure/infection (5.9% vs. 7.5%),
of
vessel
acute kidney injury (28.0% vs. 32.1%), need
revascularization (4.7% vs. 3.6%) and no late stent thrombosis occurred in either group. In
for blood transfusion (50.7% vs. 63.3%), or reoperation for perioperative bleeding (1.4% vs.
larger side branches (C2.25 mm) Tryton was associated with numerically less target vessel
2.4%). Thus,
failure (11.3 vs. 15.6%; P = 0.383) and reduced
techniques are similar, if surgically competent
diameter stenosis (30.4% vs. 40.6%; P = 0.004). Although deployment success was high for
in both, an individualized patient approach appears appropriate, depending on whether the
Tryton, the clinical advantage is unclear.
clinical priority is ensuring full revascularization or avoiding renal failure/
Coronary Artery Bypass Grafting (CABG): Off Pump vs. On Pump
bleeding
It has been suggested that off-pump CABG (beating heart procedure without heart lung
approach.
bypass) might reduce morbidity/mortality, particularly for high-risk patients but previous
Transcatheter Aortic Valve Implantation
small randomized trials and meta-analyses have
The CoreValveÒ (Medtronic, Inc., Minneapolis,
shown conflicting results. The large German Off-Pump CABG in Elderly
MN, USA) transcatheter aortic valve implantation (TAVI) system (Fig. 3), which is
Trial (GOPCABE) study randomized high-risk 2539 patients (mean age of 78.5 years and
already well established in Europe, underwent evaluation as part of FDA approval in the
EuroSCORE of 8) to off-pump versus on-pump surgery [22]. The primary composite endpoint
pivotal US Extreme Risk Iliofemoral study (Clinicaltrials.gov #NCT01240902) of 487
of death, stroke, MI, repeat revascularization, or
patients
new renal replacement therapy at 30 days and at 12 months was not significantly different nor
stenosis considered at too high a risk of death or irreversible morbidity to undergo standard
were individual endpoints except for an excess of repeat revascularization after off-pump CABG
open heart surgery [24]. Randomization to medical therapy was deemed unethical given
(1.3% vs. 0.4%; P = 0.04).
previous
The Coronary Artery Bypass Surgery Off or On Pump Revascularization Study
estimated 42.7% rate of all-cause mortality or major stroke at 12 months for medically treated
(CORONARY; #NCT00463294)
patients in previous studies, use of CoreValve was associated with an improved primary
4,752
clinically
patients
driven
study to
target
Clinicaltrials.gov which randomized
off-pump
or
on-pump
while
major
outcomes
complications.
of
Patients
the
with
a
calcified aorta (which is difficult to cannulate) may also benefit from an off-pump CABG
endpoint
with
TAVI
symptomatic
data.
(all-cause
severe
Compared
aortic
with
mortality/major
an
stroke
surgery CABG found no difference in the primary composite endpoint of death, stroke,
rates of 9.3% at 1 month and 25.5% at 12 months) in addition to improved all-cause
MI, or new renal replacement therapy at 30 days [23]. Off-pump patients were significantly more
mortality (7.9% at 1 month, 24% at 12 months) and improvement of at least 1 New York Heart
likely to require repeat revascularization (0.7%
Association (NYHA) class (90% at 12 months).
vs. 0.2%) but significantly less likely to have
Regarding safety, rates of major stroke were
Adv Ther
0.7 cm2 and the mean aortic gradient was 46.4 mmHg prior to intervention. Thirty-day all-cause mortality was the primary safety endpoint, and at 30 days, the mean aortic gradient decreased from 46.4 to 11.5 mmHg. The pre-specified goal was 18 mmHg (P\0.001). The 30-day mortality and disabling stroke rates were both low (4.2% and 1.7%, respectively). Aortic regurgitation was minimal at 30 days. Dabigatran versus Warfarin in Patients with Metallic Heart Valves Dabigatran was not as effective as warfarin for the prevention of thromboembolic complications in patients with mechanical heart valves and was associated with an Fig. 3 Medtronic core valve (used with permission from Medtronic)
increased risk of bleeding according to the RE-
2.4% at 1 month and 4.1% at 12 months. Major
randomized 252 patients either undergoing mitral and/or aortic valve replacement
vascular complications were noted in 8.3% at 1 month. Moderate paravalvular leak was present in 11.5% at 1 month but fell to 4.1% by 12 months. Permanent pacemaker was required in 27% at 1 month. Based on these data, the FDA approved the CoreValve for US use in January 2014. TM
Observational data for the Lotus (Boston Scientific Corporation, Marlborough, MA, USA) valve system for TAVI was presented as part of TCT 2013 in San Francisco. This device is a second generation system which is fully retrievable and repositionable—a highly practical feature of importance for clinical practice.
REPRISE
II
(Clinicaltrials.gov
#NCT01627691), was a 120-patient prospective registry evaluating the efficacy and safety of the Lotus valve system [25]. Mean patient age was 84.4 years and 75.8% of patients were in NYHA class III or IV. The mean aortic valve area was
ALIGN (Clinicaltrials.gov #NCT01452347) study [26]. This prospective open-label trial
(population A) or who had undergone implantation of a mitral and/or aortic valve mechanical
bileaflet
valve
replacement
[3 months before randomization (population B). Of the 252 patients, 168 were assigned to receive dabigatran and 84 were assigned to receive warfarin. Dabigatran dosing was dependent on creatinine clearance and ranged from 150 mg twice daily to 300 mg twice daily to achieve a target trough plasma level of 50 ng of dabigatran per milliliter. Target international normalized ratio range in the warfarin arm was 2.0–3.0 or 2.5–3.5 depending on additional risk factors for thrombosis or presence of mitral valve replacement. The primary outcome (trough dabigatran of 50 ng/mL) was achieved for an average of 86% of the time. The study was stopped
early
because
of
excess
thromboembolic and bleeding events among
Adv Ther
patients in the dabigatran group including
was a randomized, double-blinded, placebo-
stroke in 9 patients (5%) and MI in 3 patients
controlled trial of 1,012 patients presenting
(2%) compared with no strokes or MIs in the warfarin group. One patient in the dabigatran
with an acute STEMI, without previous or current signs of heart failure. Patients were
group and 2 patients in the warfarin group died. Valve thrombosis without clinical symptoms
randomized to receive eplerenone or placebo within 24 h of presentation. The primary
was detected in 5 patients with dabigatran
composite endpoint was time to first event:
group (3%) but none with warfarin. The composite of stroke, transient ischemic attack,
CV mortality, re-hospitalization or extended initial stay due to a diagnosis of heart failure,
systemic embolism, MI, or death occurred in 15 patients (9%) in the dabigatran group and 4
sustained ventricular tachycardia or fibrillation. The study showed a significant reduction in
patients (5%) in the warfarin group (HR 1.94;
composite primary endpoints in the eplerenone
95% CI 0.64–5.86; P = 0.24). A major bleeding episode occurred in 7 patients (4%) in the
group after a mean follow-up of 10.5 months (HR 0.57; 95% CI 0.44–0.74; P\0.0001).
dabigatran group and 2 patients (2%) in the warfarin group, and bleeding of any type
However, the only individual endpoint to show a significant difference was the
occurred in 45 patients (27%) and 10 patients
natriuretic
(12%), respectively (HR 2.45; 95% CI 1.23–4.86; P = 0.01). A consistent pattern of increased
Elevated natriuretic peptide levels may herald future LV dysfunction or heart failure but can be
bleeding events in the dabigatran group was evident in both population A and population B.
present in the absence of an overt clinical condition. Nevertheless, without clinical
However, all major bleeding occurred in patients who underwent randomization within
endpoint differences, the finding is hypothesis generating at present. A reassuring finding was
1 week after cardiac surgery (population A). All
the safety profile of eplerenone and that there
patients with major bleeding had pericardial bleeding, which occurred within 2 weeks after
was no significant difference in the prevalence of hyperkalemia [27].
surgery in 5 patients in the dabigatran group and 2 patients in the warfarin group. Warfarin
Aliskiren in Heart Failure
peptide
level
after
a
month.
thus remains the anticoagulant of choice in patients with mechanical valve replacement.
The Aliskiren Trial on Acute Heart Failure Outcomes
(ASTRONAUT;
Clinicaltrials.gov
ADVANCES IN TREATMENT OF HEART FAILURE
#NCT00894387) trial randomized 1,615 patients from 316 centers with stable heart
Eplerenone in ACS
failure, LV ejection fraction (LVEF) \40% (mean 28%) and elevated natriuretic peptides to either aliskiren (a direct renin inhibitor) at a
The aldosterone antagonist eplerenone may have a role in preventing LV systolic dysfunction in acute MI. The Reduction of Heart Failure Morbidity in Patients with Acute ST-Elevation Myocardial Infarction trial (REMINDER; Clinicaltrials.gov #NCT01176968)
dose of 150 mg once daily (titrated to 300 mg as tolerated) or placebo, in addition to other heart failure medication. Treatment with aliskiren was associated with a lower level of N-terminal proB-type natriuretic peptide (NT-proBNP) but higher rates of hyperkalemia, worsening renal
Adv Ther
function and hypotension, and there was no
Phosphodiesterase-5
significant difference in the primary composite
Clinical
endpoint of CV death or heart failure rehospitalization at 6 months (HR 0.92; 95% CI
Diastolic Heart Failure (RELAX; Clinicaltrials.gov #NCT00763867) trial
0.76–1.12) [28]. Thus ASTRONAUT does not support routine addition of aliskiren in acute
randomized 216 patients in a double-blinded fashion with a LVEF [50% and NYHA class 2–3
heart failure.
to receive sildenafil, initially 20 mg three times
Heart Failure with Preserved Systolic
daily for 3 months, followed by 60 mg three times daily for a further 3 months (n = 113),
Status
Inhibition
and
Exercise
to
Improve
Capacity
in
Function
versus placebo (n = 103) [30]. There was no significant difference in the primary endpoint
While there are well-established treatment regimens for heart failure with systolic
of change in peak oxygen consumption at
dysfunction, there is a lack of evidence-based
24 weeks or secondary endpoint of exercise capacity, as determined by peak oxygen
treatment for patients with heart failure with preserved ejection fraction (HFpEF).
uptake or walk distance at 12 weeks. Thus, based on the RELAX data, Phosphodiesterase-5
Spironolactone has been found to reduce hospitalization in patients with HFpEF. The
inhibition with sildenafil for 24 weeks does not
Treatment of Preserved Cardiac Function Heart
appear to confer any benefit over placebo to patients with HFpEF [31].
Failure with an Aldosterone Antagonist (TOPCAT; Clinicaltrials.gov #NCT00094302)
Inotropes in Acute Heart Failure
trial randomized 3,445 heart failure patients aged 50 and over, with an LVEF [45%, at 270
The Renal Optimization Strategies Evaluation in
sites in six countries, to receive spironolactone at a dose of up to 45 mg per day or placebo.
Acute Heart Clinicaltrials.gov
Patients were followed prospectively for a mean
evaluated the benefit of low-dose dopamine or
of 3.3 years. Treatment with spironolactone did not alter the primary endpoint; the composite
nesiritide in patients with acute heart failure and renal dysfunction. Smaller studies had
of CV death, hospitalization for heart failure, and resuscitated cardiac arrest, but did
suggested benefit from low-dose therapy; however, neither drug had been rigorously
significantly
Failure (ROSE #NCT01132846)
AHF; trial
of
tested. In the ROSE AHF trial, 360 patients
hospitalizations for heart failure on its own (HR 0.83; 95% Cl 0.69–0.99; P = 0.042). Rates
hospitalized with acute heart failure and renal dysfunction were randomized in a double-
of hyperkalemia were significantly higher in the spironolactone group versus placebo
blinded fashion into two cohorts; one to receive low-dose dopamine (n = 122) and the
(18.7% vs. 9.1%; P\0.001), while rates of
other
hypokalemia were lower (16.2% vs. 22.9%; P\0.001) [29].
placebo. This was in adjunct to standard treatment. When compared to placebo,
Observational data and small trials had previously suggested that sildenafil might have
neither low-dose dopamine nor low-dose nesiritide enhanced decongestion or improved
a role in improving exercise capacity and
renal function when added to diuretic therapy,
clinical outcomes in patients with HFpEF. The
as measured by cumulative 72 h urinary output
reduce
the
number
low-dose
nesiritide
(n = 119)
versus
Adv Ther
and change in cystatin-C levels (P = 0.59 and
Left Ventricular Augmentation for Heart
P = 0.36, respectively) [32].
Failure
Omecamtiv mecarbil (OM), a cardiac myosin activator, has shown some promise as a positive inotrope in patients with acute heart failure. Current inotropes act via cyclic adenosine monophosphate and intracellular calcium-handling mechanisms, which may cause increases in heart rate, myocardial oxygen consumption, induce arrhythmias, and cause ischemia. OM acts independent of these mechanisms. The Acute Treatment with OM to Acute Heart
Increase Failure
Contractility in (ATOMIC-AHF;
Clinicaltrials.gov #NCT01300013) trial was a multicenter trial which randomized 613 patients
with
acute
heart
failure,
LV
ejection fraction \40%, elevated natriuretic peptides, and resting dyspnea or dyspnea on minimal exertion, to either a 48-h infusion of OM at three doses (115, 230, or 310 ng/mL) or to placebo [33]. The primary clinical endpoint was of dyspnea symptom response on the 7-point Likert scale assessed at 6, 24, and 48 h. While there was no overall significant difference in the primary endpoint (P = 0.33), on a subgroup analysis the cohort receiving the 310 ng/mL dose saw greater relief in dyspnea compared with placebo (51% vs. 37%; P = 0.03). There was also a trend toward a reduction in episodes of worsening heart failure. There were troponin elevations noted in the OM group; however, there was no increase in reported ischemic events. The overall adverse effects profile was similar to placebo and there was no evidence of the drug being proarrhythmic. It therefore has the potential to be a safe and effective treatment for acute heart failure but more studies are required. An oral formulation for chronic heart failure is also being developed.
Early preliminary results of a randomized, controlled study to evaluate Algisyl-LVRTM as a Method of Left Ventricular Augmentation for Heart Failure (AUGMENT-HF; Clinicaltrials.gov #NCT01311791) look promising [34]. The study randomized 30 patients at 16 centers with dilated cardiomyopathy, an LVEF of \35%, mostly NYHA class 3, and a peak oxygen consumption of 9–14.5 mL/kg/min, to have a liquid alginate polymer material injected into the ventricular wall via a small anterior thoracotomy (Fig. 4). In the Algisyl-LVRTM (LoneStar Heart, Inc., Dallas, TX, USA) group there were significant improvements at 3 and 6 months vs baseline in mean 6-min walk distances (P = 0.008, P = 0.03) and NYHA class (P = 0.002, P B 0.001), while there were no significant improvements in the control groups. These results suggest that the procedure
may
partly
restore
functional
capacity and quality of life in patients who remain very symptomatic despite optimal medical and device therapy. Echocardiography-guided Cardiac Resynchronization Therapy An important study to emerge from the ESC congress 2013 was Echocardiography-Guided Cardiac Resynchronization Therapy (EchoCRT; Clinicaltrials.gov #NCT00683696). The benefit of CRT has been established in previous studies for patients with a QRS[120 ms and LVEF\35%, However, there were conflicting small randomized trials and observational studies which were less conclusive regarding patients
with
narrower
QRS
complexes.
EchoCRT blindly randomized 809 patients with stable NYHA class 3–4 heart failure, an
Adv Ther
Fig. 4 Algisyl-LVRTM (LoneStar Heart, Inc., Dallas, TX, USA), an implantable biopolymer injected to augment LV function in dilated cardiomyopathies. Used with permission
from lonestarheartinc.com. DCM dilated cardiomyopathy, LV left ventricular
LVEF\35%, a QRS duration \130 ms, mechanical dyssynchrony on echo, and an
mortality increase in the CRT group (HR 1.8, 95% CI 1.11–2.93; P = 0.02) and there was an
indication for an implantable cardioverter defibrillator (ICD) to receive either a CRT-
even greater increase in CV death (P = 0.004). There were no significant changes between
enabled ICD or CRT-disabled device. The primary efficacy outcome was the composite
NYHA classes. The key conclusions for clinical practice were that in patients with a
of death from any cause or first hospitalization
QRS\130 ms,
for worsening heart failure. The trial was terminated early as there was a significant
hospitalization from heart failure, possibly increased mortality, and that echo was not
CRT
did
not
reduce
Adv Ther
Fig. 5 Role of natriuretic peptide-based screening and collaborative care for heart failure: the STOP-HF randomized trial. Major adverse cardiovascular events were defined as arrhythmia, transient ischemic attack,
stroke, myocardial infarction, peripheral or pulmonary thrombosis/embolus or heart failure). Used with permission from Ledwidge et al. [36]
useful
dysfunction with or without heart failure (OR
tool
in
guiding
therapy in patients complexes [35].
resynchronization
with
narrow
QRS
0.55; 95% CI 0.37–0.82; P = 0.003; Fig. 5) and a lower rate of emergency hospitalization for major CV events (incidence rate ratio 0.60;
Brain-type Natriuretic Peptide-guided
95% CI 0.45–0.81; P = 0.002).
Primary Care Intervention Reduces Heart Failure Risk The 5-year St Vincent’s Screening to Prevent Heart Failure Study (STOP-HF; Clinicaltrials.gov #NCT00921960) enrolled 1,374 patients with CV risk factors and randomized them to receive
ADVANCES IN ARRHYTHMIAS AND RESUSCITATION Edoxaban Non-inferior to Warfarin in AF Stroke Prevention
usual primary care (n = 677) or screening with
The Effective Anticoagulation With Factor Xa
brain-type natriuretic peptide (BNP) levels (n = 697) [36]. The screening group with BNP
Next
levels over 50 pg/mL (n = 263) underwent echocardiography and collaborative care between their primary care physician and a cardiology service. Screened patients were more likely to have further CV investigation and to receive renin–angiotensin–aldosterone system therapy. After 5-year follow-up, the screened group was found to have significantly less LV
Generation
in
Atrial
Fibrillation-
Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48; Clinicaltrials.gov #NCT00781391) trial, compared edoxaban, an oral direct factor Xa inhibitor to warfarin in the treatment of AF [37]. In the randomized, double-blinded, placebo-controlled trial, 21,105 patients with moderate to high-risk AF were randomized to receive either edoxaban 30 mg daily, 60 mg daily, or warfarin. In the
Adv Ther
high-dose arm, edoxaban was found to be non-
but did at 12 months (P = 0.04 for non-
inferior and superior to warfarin for the primary
inferiority) and was associated with a lower
endpoint of stroke or systemic embolic events in the modified intention-to-treat population
incidence rate of serious adverse events. In the persistent AF cohort, high-frequency source
(HR 0.79; 95% CI 0.63–0.99; P\0.001 for noninferiority, P\0.02 for superiority). In the low-
ablation plus CPVI was not superior to CPVI alone at 6 or 12 months and was associated with
dose arm edoxaban was non-inferior but not
an increase in serious adverse events. The results
superior for the primary endpoint (HR 1.07, 95% CI 0.87–1.31, P = 0.005 for non-inferiority,
suggest source ablation may play a role in the clinical management of paroxysmal AF but not
P = 0.44 for superiority). The primary safety outcome of major bleeding was higher in the
persistent AF [38].
warfarin group compared to either edoxaban
Magnetic Resonance Imaging (MRI) as a Predictor of Ablation Success
dose (P\0.001 for each). Gastrointestinal bleeding was higher in the high-dose edoxaban arm compared to warfarin, but lower in the low-dose edoxaban arm. The
The Delayed Enhancement-MRI determinant of successful Catheter Ablation of Atrial
results were similar to those for apixaban,
Fibrillation (DECAAF) study undertook high resolution delayed enhancement magnetic
rivaroxaban, and dabigatran and are likely to lead to approval of the agent.
resonance imaging (MRI) scans in 331 AF
Ablation of Drivers versus Circumferential
patients up to 30 days before and 90 days after ablation. Success was defined as freedom from
Pulmonary Vein Isolation in Patients with AF
AF recurrence at day 325 (excluding the 90 day blanking period). The degree of atrial fibrosis on of
pre-ablation MRI was an independent predictor of successful ablation (P\0.001). Stage 1 (\10%
Drivers vs Circumferential Pulmonary Vein
fibrosis), stage 2 (10–20% fibrosis), stage 3
Isolation in Patients with AF (RADAR-AF; Clinicaltrials.gov #NCT00674401) trial,
(20–30% fibrosis), and stage 4 ([30% fibrosis) were associated with 86, 63, 55, and 31%
presented at the AHA Scientific Sessions 2013, evaluated treatment with high-frequency
success rates, respectively. Residual fibrosis post ablation was also a predictor of
source ablation compared with circumferential
reoccurrence, with each percentage of residual
pulmonary vein among patients
isolation ablation (CPVI) with symptomatic drug
fibrosis correlating with a 8.2% increase risk of recurrent symptoms (HR 1.082, P\0.001). Of
refractory AF. Patients with paroxysmal AF were randomized to either source ablation
interest, on post ablation MRI images, only 6.7% of patients had all four pulmonary veins
(n = 56) or CPVI (n = 59), while those with
completely encircled. However, absence of a
persistent AF were randomized to have source ablation and CPVI (n = 59) versus CPVI alone
complete circle around a pulmonary vein does not preclude electrical isolation and pulmonary
(n = 58). The primary endpoint was freedom from AF at 6 and 12 months. In the paroxysmal
vein encirclement did not serve as a predictor of post ablation recurrence [39]. Thus MRI may be
AF cohort, high-frequency source ablation did
beneficial pre-procedure but less so post-
not achieve non-inferiority to CPVI at 6 months
procedure.
The
Radiofrequency
Catheter
Ablation
Adv Ther
Temperature Management Post-Cardiac
X-ray imaging). However, while the practical
Arrest
advantages were noted, the study LINC did not
Previous evidence from small randomized clinical trials and observational studies has suggested that elevated body temperature post cardiac arrest is associated with worse outcomes
find any significant difference in survival rates after 4 h and at 6-month follow-up, suggesting that mechanical compressions were as effective, but not superior to, manual compressions during cardiac arrest resuscitation [41].
and that induced hypothermia may improve clinical outcomes. The Target Temperature Management trial (TTM; Clinicaltrials.gov
CARDIOVASCULAR PREVENTION
#NCT01020916) randomized 950 patients post cardiac arrest to receive target body temperature
Pay for Performance: Better Lipid Levels?
management at 33 °C for 24 h versus 36 °C for 24 h. At 180-day follow-up, there was no difference in survival in the 33 °C group (50% vs. 48%; P = 0.51) or the composite of death/ poor neurological function (54% vs. 52%; P = 0.78) but a trend toward more serious adverse advents (RR 1.03, 95% CI 1.00–1.08; P = 0.086), in particular a significant excess of hypokalemia (P = 0.02).14 The findings from TTM thus suggest there is no significant benefit in maintaining a temperature 33 °C vs 36 °C. However, outcomes were better in both 33 °C versus 36 °C groups compared with previous studies, suggesting that prevention of hyperthermia may be the key aspect of clinical importance [40]. Mechanical Cardiopulmonary Resuscitation In the LUCAS in Cardiac Arrest (LINC; Clinicaltrials.gov #NCT00609778) Study, first
Optimizing lipid control across member nations is an important objective of the ESC. The Dyslipidemia International Study (DYSIS) [42] compared on-treatment levels of lowdensity lipoprotein cholesterol (LDL-C) among 540 patients from the UK (which has a closely audited primary care pay-forperformance system) with 4,260 patients from Germany (which has a high standard of overall health care but operates a budget restrictive system). The mean achieved LDL-C level in UK patients was 82 mg/dL compared with 111 mg/ dL in German patients and more patients from the UK obtained an LDL-C target level of \100 mg/dL (79.8% vs. 42%, P\0.01) [43]. It was noted that UK patients tended to be taking more potent or higher dose statins. It has been hypothesized that a pay-for-performance system with clinical audit may be a useful mechanism to encourage tighter lipid control.
presented at ESC 2013, 2,586 patients with
High-Dose Oral Vitamins and Ischemic
cardiac arrest were randomized to ongoing manual chest compression or switching to
Heart Disease
mechanical compression using the LUCAS Chest Compression System (which offers the
Despite possible benefits via anti-oxidant and other mechanisms, several previous large
potential advantage of enabling uninterrupted
randomized studies have not demonstrated a
chest compressions despite delivery of defibrillation or catheterization laboratory
CV benefit for vitamin supplementation. In a second arm of the 2 9 2 factorial-design Trial to
Adv Ther
(TACT;
The VessixTM renal denervation catheter
double-
(Boston Scientific Corporation, Malborough,
blinded randomized trial, 1,708 patients with previous MI were randomized to receive high-
MA, USA) comprises a low pressure balloon with 2 pairs of bipolar low wattage electrodes
dose daily multivitamins and minerals or placebo [44]. At a median of 55 months, use of
arranged in helical fashion on the balloon surface providing a helical arrangement of 4
the active vitamin/mineral treatment compared
ablation points. The design enables a shorter
with placebo was associated with a statistically non-significant 11% relative reduction in the
ablation time (30 s per 4 electrode application) and potentially less patient discomfort. Interim
risk of death, MI, stroke, coronary revascularization, or hospitalization for angina
6-month results from 139 of 145 enrolled patients in the REDUCE-HTN (Treatment of
(HR 0.89; 95% CI 0.75–1.07). Adherence rates
Resistant Hypertension Using a Radiofrequency
were low, with 46% of patients discontinuing treatment during the study, limiting
Percutaneous Transluminal Angioplasty Catheter; Clinicaltrials.gov #NCT01541865)
conclusions from the study. In the treatment arm 76% of patients completed 1 year of
trial presented at TCT Oct 2013 reported an office blood pressure reduction of 24.6/
treatment and only 47% completed 3 years of
10.3 mmHg and ambulatory blood pressure
treatment.
reduction of 11.2/6.3 mmHg. Results appeared durable out to 12 months within the 41 patients
Renal Denervation Therapy for Hypertension
who had reached that time point [46]. Given previous remarkably consistent
Emerging data for renal denervation during
results using variety of catheters, results of the Symplicity HTN-3 (Cinicaltrials.gov
Assess
Chelation
Clinicaltrials.gov
Therapy
#NCT00044213)
2013 and early 2014 has generated significant interest. Given encouraging data with the first-
#NCT01418261) trial, which randomized 535
single-point ablation
patients (2:1) to the first-generation Medtronic Symplicity catheter versus a sham procedure,
catheter (Medtronic, Inc., Minneapolis, MN, USA), multiple devices have been developed
were surprising. At 6 months, the denervation procedure appeared safe. However, although
and tested. 1-year follow-up data from the first human
denervation was associated with a 14.1 mmHg
generation Symplicity
TM
study of the EnlighHTN multi-electrode renal
reduction from baseline in office systolic blood pressure, the sham arm reported a
denervation catheter (EnligHTN I; St Jude Medical, St. Paul, MN, USA; Clinicaltrials.gov
11.7 mmHg reduction, resulting in a small, between-group reduction of only 2.39 mmHg
#NCT01438229) were presented at EuroPCR 2013. In this study, 46 patients with drug-
(95 % CI -6.89 to 2.12; P = 0.26, superiority
renal
margin 5 mmHg). Similarly, the between-group reduction in ambulatory blood pressure was
denervation therapy with the EnlighHTN catheter. At 12 months, 80% of patients
only -1.96 mmHg (95% CI -4.97 to 1.06; P = 0.98, superiority margin 2 mmHg).
showed reduction of at least 10 mmHg in systolic blood pressure compared with
Proposed reasons for the lower than expected
resistant
hypertension
underwent
baseline. No significant changes were reported
efficacy included heterogeneity of benefit in different patient subgroups, centers/operators
in renal function [45].
with lower procedural experience (optimal
Adv Ther
denervation may be more difficult with a
amlodipine–atorvastatin,
single electrode device and the 14.1 mmHg
contraindicated.
reduction was lower than previous studies), better than usual results of medical therapy,
randomized to stenting plus medical therapy did not show any significant reduction in the
and a need for longer follow-up since a placebo effect, if present, would be expected
primary composite endpoint of death from CV or renal causes, MI, stroke, hospitalization for
to decline with time [47].
congestive
Of importance, data from the separate Global Symplicity registry reported that those
insufficiency, or need for renal replacement therapy (35.1% and 35.8%, respectively;
with a baseline systolic blood pressure C160 mmHg had a 21.4 mmHg reduction by
HR 0.94; 95% CI 0.76–1.17; P = 0.58), nor any significant reduction in individual
6 months following denervation, whereas those
components
of
with baseline systolic blood pressure C140–159 mmHg had only a 4.6 mmHg
There was in systolic
a very modest improvement blood pressure in the stent
reduction following denervation. Thus severe hypertension (C160 mmHg despite maximally
group versus (-2.3 mmHg;
tolerated doses C3 medications) still appears
P = 0.03). Thus, CORAL does not support
most appropriate indication at present for patient selection. Trials are also ongoing to
routine stenting, even of severe renal artery stenoses, in hypertensive or chronic kidney
evaluate the potential role for patients with resistant hypertension and other comorbidities
disease patients [49].
associated with increased sympathetic drive including heart failure, dysrhythmia and
Blood Glucose Control and Safety of Dipeptidyl Peptidase-4 Inhibitors
diabetes [48].
in Patients with Ischemic Heart Disease
Stenting versus Medical Management
While diabetes is associated with increased CV
in Renal Artery Stenosis
risk, and treatment reduces microvascular complications, the macrovascular CV benefits
Previous randomized studies of renal artery stenting have been criticized for including
of improved glycemic control remain less clear with some treatment strategies associated with
patients with only moderate stenosis. The
an excess of CV events.
Cardiovascular Atherosclerotic
Renal (CORAL;
The Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes
Clinicaltrials.gov #NCT00081731) study, presented at AHA 2013 randomized 947
Mellitus study (SAVOR-TIMI 53; Clinicaltrials.gov #NCT01107886) randomized
patients with hypertension or chronic kidney
in double-blind fashion 16,492 patients with
disease and one or more severe (greater than 60% stenosis) atherosclerotic renal artery
type 2 diabetes and at risk of, or with a history of, CV disease to the dipeptidyl peptidase-4
stenoses to renal artery stenting plus medical therapy or to medical therapy alone.
(DPP-4) inhibitor saxagliptin 5 mg daily or placebo [50]. At a median follow-up of 2 years,
Medical
candesartan,
patients receiving saxagliptin were more likely
hydrochlorothiazide, and combination agent
to achieve a glycated hemoglobin target level of
therapy
Outcomes Lesions
included
in
After
heart
failure,
the
unless 43 months,
those
progressive
composite
renal
endpoints.
the medical therapy 95% CI -4.4 to
group -0.2;
Adv Ther
less than 7% (36.2% vs. 27.9%; P\0.001). There
Cholesterol
was no significant difference in the primary
Treatment Panel III criteria for metabolic
composite endpoint of CV death, MI, or ischemic stroke between the two groups
syndrome. Use of laparoscopic gastric banding was associated with a reduction of body mass
(P\0.001 for non-inferiority) although patients receiving saxagliptin compared with
index from a mean baseline of 35.1 kg/m2 to a mean of 27.9 kg/m2 at 5 years (P = 0.003).
placebo were more likely to be hospitalized for
Resolution
heart failure (HR 1.27; 95% CI 1.07–1.51; P = 0.007).
approximately two-thirds of patients (43% presurgery vs. 15% post-surgery at 1 year;
The Examination of Cardiovascular Outcomes with Alogliptin versus Standard of
P\0.001), and the prevalence remained low throughout 5-year follow-up (P\0.001). By
Care in Patients with Type 2 Diabetes Mellitus
2 years, there were significant improvements
and Acute Coronary Syndrome study (EXAMINE; Clinicaltrials.gov #NCT00968708)
in LDL-C, triglycerides and high-density lipoprotein (HDL)-C levels, although only the
randomized 5,380 patients with type 2 diabetes and ACS within the previous
improvement in HDL-C was maintained at 5 years (mean baseline 56.9 mg/dL vs.
15–90 days to the DPP-4 inhibitor Alogliptin at
70.29 mg/dL at 5 years) [52].
a renal-specific dose or placebo in addition to existing diabetic and CV therapy [51]. Patients receiving alogliptin were more likely to achieve a glycated hemoglobin target level of less than 7% (36.2% vs. 27.9%; P\0.001). As in SAVORTIMI 53, there was no significant difference in the primary composite endpoint of CV death, MI, or ischemic stroke between the two groups (P\0.001 for non-inferiority). Although there was a small numerical excess of patients receiving Alogliptin being hospitalized for heart failure, this did not reach statistical significance (HR 1.19, P = 0.22). Thus DPP-4 inhibitors show satisfactory overall CV safety, with caution advisable in patients at risk of heart failure.
Education
of
Program
metabolic
Adult
syndrome
in
CONCLUSION Important advances in the understanding of cardiology diagnostics and treatment have been achieved over the past year regarding management of ACS/STEMI, pharmacological, procedural and device strategies during PCI, CABG techniques, TAVI devices, heart failure, atrial fibrillation, cardiac arrest, and CV prevention including resistant hypertension. To optimize patient benefit, such findings now require
discussion
appropriate, practice.
into
and
integration,
clinical
guidelines
where and
Gastric Banding and Metabolic Syndrome
ACKNOWLEDGMENTS
5-year follow-up data from 50 patients undergoing laparoscopic gastric banding who
No funding or sponsorship was received for this
had a body mass index of between 30 and 40 kg/ m2 and at least one obesity-related comorbidity. At baseline 43% of subjects met the National
study or publication of this article. No writing assistance was utilized in the production of this manuscript. All named authors meet the ICMJE criteria for authorship for this manuscript, take
Adv Ther
responsibility for the integrity of the work as a whole, and have given final approval for the
4.
Wald D, Morris J, Wald N, et al. Randomized trial of preventive angioplasty in myocardial infarction. N Engl J Med. 2013;369:1115–23.
5.
Montalescot G, Bolognese L, Dudek D, et al. Pretreatment with prasugrel in non-ST-segment elevation acute coronary syndromes. N Engl J Med. 2013;369:999–1010.
6.
Armstrong P, Gershlick, Van de Werf F, et al. Fibrinolysis or primary PCI in ST-segment elevation myocardial infarction. N Engl J Med 2013;368:1379–87.
7.
Siddiqi N. The nitrites in acute myocardial infarction (NIAMI) trial. In: Presented at the American Heart Association Scientific Sessions, 7th Nov 2013; Dallas, Texas, USA.
8.
Tardif J, Tanguay J, Wright SS, et al. Effects of the P-Selectin antagonist inclacumab on myocardial damage after percutaneous coronary intervention for non-ST-segment elevation myocardial infarction: results of the SELECT-ACS trial. J Am Coll Cardiol. 2013;61(20):2048–55.
9.
Kosiborod M, Arnold SV, Spertus JA, et al. Evaluation of ranolazine in patients with type 2 diabetes mellitus and chronic stable angina: results from the TERISA randomized clinical trial (type 2 diabetes evaluation of ranolazine in subjects with chronic stable angina). J Am Coll Cardiol. 2013;61(20):2038–45.
version to be published. Conflict
of
interest. AMcN
and
NMcA
declare no conflict of interest. IM has received grants to the institution, lecture/consultancy honorarium, and conference sponsorship from Boston Scientific, Randox, Sanofi Aventis, Servier, Menarini, Biosensors, Astra Zeneca, Bayer, Boehringer Ingelheim, Daichii Sankyo, Eli Lilly, Bristol Myers Squibb, and Pfizer. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Compliance with ethics guidelines. The analysis in this article is based on previously conducted studies, and does not involve any new studies of human or animal subjects performed by any of the authors.
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