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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Advances in clinical cardiology.

Multiple, potentially practice-changing cardiology trials have been presented or published over the past year. In this paper, we summarize and place i...
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