Objectives and Designs of the Clinical Trials presented at the European Society of Cardiology Congress in Munich, 2018.

1. Objectives and Designs of the Clinical Trials
presented at the Hot Lines of the 2018 European
Society of Cardiology Congress in Munich, Germany

2. Clinical Trials – Hot Lines, ESC Congress 2018
Cardiovascular Research
presented at the Hot
Lines at ESC 2018

3. Sunday 26th of August, 2018 – Munich, Germany

4. MARINER trial in 8000 patients
Raskob et al. Thromb Haemost. 2016 Jun 2;115(6):1240-8 - NCT02111564
To assess the efficacy and safety of rivaroxaban compared with placebo for the prevention
of symptomatic venous thromboembolism (VTE) and VTE-related death post-hospital
discharge in high-risk, medically ill patient.
Study objective
Study design
Target population
Primary efficacy endpoint (adjudicated events)
Adults >40 years old, hospitalized for heart failure (with LVEF≤45%), acute respiratory
insufficiency or acute exacerbation of chronic obstructive pulmonary disease, acute
ischemic stroke, or acute infectious or acute inflammatory disease, including rheumatic
diseases. Suitable patients have an increased VTE risk and no other indication for
anticoagulation.
International, randomized (1:1), double-blind, placebo-controlled, event-driven, parallel
group trial. The study consists of a screening phase, a 45-day double-blind treatment phase
beginning at the time of hospital discharge and a 30-day safety follow-up period.
Composite of all symptomatic VTE events (lower extremity deep-vein thrombosis and non-
fatal pulmonary embolism) and VTE-related death (death adjudicated as either due to
pulmonary embolism or death in which pulmonary embolism cannot be ruled out).

5. CAMELLIA-TIMI 61 trial in 12000 patients
Bohula et al. Am Heart J. 2018 Aug;202:39-48 – NCT02019264
To evaluate the safety and efficacy of lorcaserin with regard to major adverse cardiovascular
events and progression to diabetes in overweight or obese patients at high cardiovascular
risk when compared with placebo.
Study objective
Study design
Target population
Primary endpoints (adjudicated events)
Obese or overweight adults with either established cardiovascular disease (and >40 years
old) with or without diabetes; or, diabetes (and >50 years old for men or >55 years old for
women) and at least one other cardiovascular risk factor: dyslipidemia, hypertension,
moderate renal insufficiency, an elevated high-sensitivity C-reactive protein, or micro-
or macroalbuminuria.
International, randomized, double-blind, placebo-controlled, event-driven trial. A 2-step
analysis is planned with noninferiority for MACE at an interim analysis (primary safety
outcome) continued by a superiority analysis for MACE+ (primary efficacy endpoint).
The primary safety endpoint of the trial is a composite of cardiovascular death, MI, or stroke
(MACE). The primary efficacy endpoint is a composite of cardiovascular death, MI, stroke,
hospitalization for unstable angina, heart failure, or any coronary revascularization (MACE+).

6. ARRIVE trial in 12546 patients
NCT00501059
To assess the efficacy (reduction of cardiovascular events) and safety of 100 mg enteric-
coated Acetylsalicylic Acid in patients at moderate risk of cardiovascular disease.
Study objective
Study design
Target population
Primary endpoint (adjudicated events)
Females >60 years old with >2 risk factors or males >55 years old with 2 to 4 risk factors.
Risk factors include: elevated cholesterol (TC>240 mg/dL or LDL>160 mg/dL for females, and
TC>200 mg/dL or LDL>130 mg/dL for males), current smoking (any cigarette in the past 12
months), low HDL cholesterol (HDL<40 mg/dL), elevated blood pressure (SBP>140 mmHg),
currently on any medication to treat high blood pressure, positive family history of early
coronary heart disease (a first-degree relative suffered a myocardial infarction <60 years).
Patients with previous vascular events or at a higher than moderate risk due to their
diabetes status are excluded.
International, randomized, double-blind, placebo-controlled, parallel group trial. Estimated
follow-up of 6 years.
Time to the first occurrence of the composite outcome of cardiovascular death, stroke or
transient ischemic attack, myocardial infarction, or unstable angina.

7. ASCEND trial in 15480 patients
Bowman et al. Am Heart J. 2018 Apr;198:135-144 - NCT00135226
To assess whether 100 mg daily Acetylsalicylic Acid safely prevents cardiovascular events
and cancer in patients with diabetes without known occlusive arterial disease, and to assess
whether supplementation with 1 g omega-3 fatty acids daily prevents cardiovascular events.
Study objectives
Study design
Target population
Primary efficacy endpoint (reviewed by the coordinating center)
Adults >40 years old, with clinical diagnosis of diabetes mellitus, no clear indication for
aspirin (no previous diagnosis of occlusive arterial disease: myocardial infarction, angina
pectoris, coronary or non-coronary revascularization procedure, stroke or transient ischemic
attack), no clear contra-indication to aspirin (i.e. not at high risk of bleeding due to
gastrointestinal hemorrhage or peptic ulcer within the previous 6 months, active hepatic
disease, or use of anti-coagulant therapy).
Multi-center (UK only), randomized, placebo-controlled, 2x2 factorial, blinded trial.
Recruitment was conducted by mail followed by a 2-month run-in period (to assure
compliance to medication). Follow-up included correspondence every 6 months.
Composite of serious vascular events (SVE) which include vascular death, non-fatal
myocardial infarction, non-fatal stroke or transient ischemic attack, excluding confirmed
intracranial hemorrhage.

8. ART trial in 3102 patients
Taggart et al. Eur Heart J. 2010 Oct;31(20):2470-81 - ISRCTN46552265
To assess whether the use of both internal mammary arteries (BIMA) during CABG improves
survival and reduces the need for further interventions when compared with a single IMA
(SIMA). For SIMA, a standard operation is performed using SIMA to LAD plus supplemental
vein or radial artery graft. For BIMA, both IMA are placed to left sided coronary arteries with
supplemental vein or radial artery. The IMA grafts can be used as composite grafts to each
other, as long as one remains in situ. IMA graft to the RCA is excluded.
Study objectives
Study design
Target population
Primary endpoint (flagged by offices of national statistics)
Patients with multi-vessel coronary artery disease undergoing coronary artery bypass
grafting (including urgent and off pump procedures). Patients with a single graft, re-do
procedure, evolving myocardial infarction, or concomitant valve surgery are excluded.
International, randomized, two-arm trial. The allocated procedure is performed by a trial
nominated surgeon approved by the steering committee as being sufficiently experienced
(i.e. performed >50 BIMA procedures). To reduce the possibility of clinical events occurring
after randomization and before revascularization, surgery is performed within 6 weeks of
randomization.
All-cause death at 10 years of follow-up.

9. Monday 27th of August, 2018 – Munich, Germany

10. ATTR-ACT trial in 400 patients
Maurer et al. Circ Heart Fail. 2017 Jun;10(6) - NCT01994889
To evaluate the efficacy, safety, and tolerability of tafamidis (a transthyretin [TTR] tetramer
stabilizer) in comparison with placebo for the treatment of TTR cardiomyopathy (a rare, life-
threatening disease characterized by the accumulation of amyloid fibrils of misfolded
transthyretin protein in the heart).
Study objective
Study design
Target population
Primary endpoint (adjudicated events)
Adults ≥18 to ≤90 years old, with a predominant cardiac phenotype of TTR amyloidosis with
either wild-type TTR or a variant TTR genotype, the presence of TTR amyloid deposits in
biopsy tissue, and a history of heart failure evidenced (e.g. prior hospitalization for heart
failure or clinical evidence of heart failure without hospitalization requiring diuretics). A 6-
minute walk test of >100 m and a plasma NT-proBNP ≥ 600 pg/mL are also required.
International, randomized, 3-arm, parallel, double-blind, placebo-controlled trial. The
duration of the double-blind treatment period (30 months) was based on the reported
median survival time from diagnosis for TTR-CM patients.
Hierarchical combination of all-cause death and frequency of cardiovascular-related
hospitalizations (defined as a non-elective admission to an acute care setting for medical
therapy for cardiovascular-related morbidity resulting in at least a 24-hour stay).

11. COMMANDER HF trial in 5000 patients
Zannad et al. Eur J Heart Fail. 2015 Jul;17(7):735-42 - NCT01877915
To demonstrate that rivaroxaban is superior to placebo in subjects with heart failure (HF)
and significant coronary artery disease (CAD), who are receiving standard care, in reducing
the risk of the composite of all-cause death, myocardial infarction or stroke following a
recent exacerbation of HF.
Study objective
Study design
Target population
Primary endpoint (investigator-reported events; no independent adjudication)
Adults >18 years old, clinically stable up to 30 days after a symptomatic index event, defined
as an exacerbation of HF symptoms requiring a hospitalization, emergency room or
observation unit admission or an unscheduled outpatient visit requiring parenteral therapy.
HF must be documented by a NT-proBNP ≥800 pg/mL or BNP ≥200 pg/mL, left ventricular
ejection fraction ≤40%, and documented significant CAD.
International, randomized (1:1), double-blind, placebo-controlled, event-driven, parallel
group trial. The study consists of a screening phase, a double-blind treatment phase, and
follow-up after the sponsor-announced global treatment end date (GTED).
Composite of all-cause death, myocardial infarction or stroke. The composite of fatal
bleeding or bleeding into a critical space with a potential for permanent disability is
assessed as a primary safety endpoint.

12. MITRA-FR trial in 288 patients
Obadia et al. EuroIntervention. 2015 Mar;10(11):1354-60 - NCT01920698
To demonstrate that percutaneous mitral valve repair using the MitraClip® system reduces
the occurrence of all-cause death or unplanned hospitalizations for heart failure (HF) at
12 months in comparison to optimal medical therapy alone.
Study objective
Study design
Target population
Primary efficacy endpoint (adjudicated events)
Adults >18 years old, with severe secondary mitral regurgitation and contraindication for
heart surgery as determined by a heart team, NYHA class > I, left ventricular ejection
fraction between 15-40%, hospitalization for HF in the last 12 months, and on optimal
medical therapy as defined by the investigator.
Multi-center (France only), randomized (1:1), open-label, controlled trial. Patients are
screened by the principal investigator at each site and presented to the local Heart Team.
Assessment includes transthoracic and trans-esophageal echocardiograms, vascular access
and anatomical conditions. Echo criteria are confirmed by an independent Core Lab before
randomization (Xavier Bichat Hospital, Paris, France).
Composite outcome of all-cause death and unplanned hospitalizations for HF, 12 months
after randomization.

13. GLOBAL LEADERS trial in 16000 patients
Vranckx et al. EuroIntervention. 2016 Nov 20;12(10):1239-1245 - NCT01813435
To determine the benefits and risks of an antithrombotic regimen using ticagrelor combined
with acetylsalicylic acid for one month and alone for 23 months, compared with
conventional dual antiplatelet therapy in patients undergoing stent implantation.
Study objective
Study design
Target population
Primary endpoint (investigator-reported clinical events plus Core Laboratory)
Adults >18 years old, with a clinical indication for percutaneous coronary intervention,
presence of one or more coronary artery stenosis of at least 50% in a native coronary artery
or in a saphenous venous or arterial bypass conduit suitable for coronary stent implantation
with a reference vessel diameter of at least 2.25 mm.
Multinational, randomized (1:1), open-label superiority trial. Coronary anatomy is to be
known in order to assess eligibility for percutaneous coronary intervention before
randomization in all patients.
Composite of investigator-reported all-cause death or non-fatal, new Q-wave myocardial
infarction identified by an independent ECG core laboratory (Cardialysis, Rotterdam, The
Netherlands) at two years post randomization.

14. Tuesday 28th of August, 2018 – Munich, Germany

15. PURE study in 218000 patients
Teo et al. Am Heart J. 2009 Jul;158(1):1-7.e1 - NCT03225586
To examine the relationship between societal influences (built environment, food and
nutrition policy, psychosocial/socioeconomic factors, and tobacco) and prevalence of risk
factors and chronic non-communicable diseases measured at baseline. And, to examine the
relationship between societal determinants and incidence of chronic non-communicable
disease events and on changes in rates of selected risk factors (e.g. smoking).
Study objectives
Study design
Target population
Primary outcomes (adjudicated events)
The selection of countries reflects a balance between involving a large number of
communities at different economic levels in countries with substantial heterogeneity in
social and economic circumstances and policies, and the feasibility of centers to successfully
achieve long-term follow-up. Communities are selected based on pre-defined criteria, and
sampling has been designed to achieve a broadly representative sample of adults aged
between 35 and 70 years.
International, large-scale, epidemiological study.
All-cause death and chronic non-communicable disease events are ascertained.

16. FREED trial in 1084 patients
Kojima et al. J Cardiol. 2017 Jan;69(1):169-175 – NCT01984749
To evaluate the effect of febuxostat on preventing cerebral or cardiorenovascular events in
elderly patients with hyperuricemia at risk for cerebral or cardiorenovascular disease
compared to conventional therapy. Febuxostat is a novel urate-lowering agent approved for
the treatment of gout and hyperuricemia.
Study objective
Study design
Target population
Primary endpoint (adjudicated events)
Adults >75 years old with confirmed hyperuricemia at risk for cerebral or cardiorenovascular
disease defined by the presence of hypertension, type 2 diabetes mellitus, renal disorder
(eGFR 30 to <60mL/min/1.73 m2), or cerebrocardiovascular disease occurring >3 months
prior to enrollment (i.e. stroke, coronary artery disease, vascular disease, or heart failure).
Multi-center (Japan only), randomized (1:1), open-label, blinded endpoint, two-arm parallel
trial.
Composite of all-cause death and the following non-fatal cerebral or cardiorenal vascular
events: stroke or transient ischemic attack, coronary artery disease (myocardial infarction,
unstable angina), heart failure hospitalization, arteriosclerotic disease requiring treatment
(aortic aneurysm, aortic dissection, and arteriosclerosis obliterans), renal impairment, and
new atrial fibrillation (including paroxysmal atrial fibrillation).

17. BASKET SMALL 2 trial in 758 patients
Gilgen et al. Clin Cardiol. 2018 May;41(5):569-575 – NCT01574534
To demonstrate the non-inferiority of paclitaxel‐coated balloons compared with drug eluting
stents in patients undergoing percutaneous coronary intervention (PCI) in small coronary
vessels (diameter <3 mm), irrespective of the indication with regard to the incidence of a
major adverse cardiac event at 12 months.
Study objectives
Study design
Target population
Primary outcomes (adjudicated events)
Patients with an indication for PCI in a small coronary vessel (diameter <3 mm), with either
an acute coronary syndrome, typical symptoms of coronary ischemia, or silent ischemia as
the reason for intervention. Patients with a concomitant large‐diameter PCI in the same
epicardial coronary artery or PCI of ISR as the culprit lesion, are excluded.
International (DACH), randomized (1:1), active-controlled, open-label trial.
Composite of cardiac death, non-fatal myocardial infarction, and target-vessel
revascularization.

18. VERDICT-EDI trial in 2500 patients
NCT02061891
To evaluate if acute invasive coronary evaluation and treatment conducted within 12 hours
of diagnosis improves clinical outcome compared to a deferred, sub-acute strategy in
patients with unstable angina pectoris or non-ST segment elevation myocardial infarction.
Furthermore, in an observational design the potential clinical benefit of coronary computed
tomography angiography to select patients for invasive investigation and treatment in the
two treatment arms (acute vs. deferred) is evaluated.
Study objectives
Study design
Target population
Primary outcomes
Adults > 18 years old, with unstable angina pectoris or non-ST segment elevation acute
coronary syndrome deemed suitable for invasive evaluation and treatment, with ECG
abnormalities suggestive of myocardial ischemia or elevated myocardial ischemia
biomarkers.
Multi-center (only Denmark), randomized (1:1), parallel-assignment, open-label trial.
Composite of all-cause death, non-fatal recurrent acute myocardial infarction,
hospitalization for refractory ischemia (acute coronary syndrome) or heart failure at 3 years.

19. High-STEACS trial in 48282 patients
NCT01852123
To evaluate whether use of a novel high-sensitivity troponin test to lower the threshold for
diagnosis of myocardial infarction is appropriate. If increased sensitivity does not reduce
specificity for the diagnosis, then this new test will improve patient outcome through better
targeting of therapies for coronary heart disease. However, if increased sensitivity leads to
poor specificity, then patients may be misdiagnosed and given inappropriate cardiac
medications with potentially detrimental outcomes.
Study objectives
Study design
Target population
Primary outcomes
Patients of all ages with suspected acute coronary syndrome and Troponin I measurement
as part of routine clinical care. No exclusion criteria are applied.
Multi-center (Scotland only), randomized, crossover assignment, single-blind trial.
Cardiovascular death or recurrent myocardial infarction at 1 year.

20. POET trial in 400 patients
NCT01375257
To show non-inferiority of partial oral treatment with antibiotics of endocarditis compared
to full parenteral treatment.
Study objectives
Study design
Target population
Primary endpoint
Adults > 18 years old with left-sided endocarditis based on the Duke criteria, infected with
Streptococci, Enterococcus faecalis, Staphylococcus aureus, or Coagulase-negative
staphylococci. Patients must receive at least 10 days of parenteral antibiotic treatment, and
at least 1 week of parenteral treatment after valve surgery. Need to be afebrile (T < 38.0) > 2
days, and show decreasing infection parameters (CRP dropped to less than 25% of peak
value or < 20 mg/l, and white blood cell count < 15 x 109/l) during antibiotic treatment. No
sign of abscess formation by echocardiography with transthoracic and trans-esophageal
echocardiography performed within 48 hours prior to randomization.
Multi-center (Denmark only), randomized, parallel assignment, open-label trial.
Composite of all cause mortality, unplanned cardiac surgery, embolic events and relapse of
positive blood cultures with the primary pathogen.

21. AIMS trial in 490 patients
Mullen et al. Trials. 2013 Dec 1;14:408 – ISRCTN90011794
To investigate whether the angiotensin II receptor antagonist irbesartan reduces the rate of
aortic dilatation in patients with Marfan syndrome compared to placebo.
Study objectives
Study design
Target population
Primary outcomes
Patients between 6 and 40 years old with clinically confirmed Marfan syndrome using the
revised Ghent diagnostic criteria (2010). Patients with previous cardiac or aortic surgery,
planned cardiac or aortic surgery at the time of randomization, aortic root Z-score ≤0, or
aortic diameter ≥4.5 cm, are excluded from the trial.
Multi-center (UK only), randomized, placebo-controlled, double-blind trial. The study
treatment will be in three phases, including a run-in phase with 75 mg once daily (OD) open-
label irbesartan for 4 weeks before randomization, followed by a low-dose treatment phase
with 150 mg (OD) active/placebo for 4 weeks, and a higher-dose phase with 300 mg (OD)
active/placebo maximum tolerated dose for remaining treatment period.
The primary outcome measure will be the absolute change in aortic root diameter per year
measured by echocardiography (John Radcliffe Hospital, Oxford, UK).

22. Ernest Spitzer, M.D.
The Netherlands
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