CSCS TRP:

Trials (and some Guidelines)

Aaron Spooner, FRCSC, MD, MEHP, MMgt

aaron.j.spooner@gmail.com
 OBJECTIVES

• Understand the scope of knowledge expected

of you for questions pertaining to important
trials
• Review important trials that are likely going to
show up on the exam
• Review the relationship between the
important trials and guidelines
• Lessen the uncertainty/fear associated with
this ill-defined topic
 IMPORTANT TRIALS

• Potentially dozens of papers you have to

know well
• Some fairly certainly going to be on the exam,
focus on these high yield papers
• Questions can come from trials in both
cardiac surgery and cardiology
• All big journals are fair game (Annals, Circ,
NEJM, Lancet, JTCVS…)
 HIGHEST YIELD

• Focus on papers addressing contemporary

issues in cardiac surgery
• Focus on trials/cohort studies comparing two
treatment modalities for the same
pathophysiology
• PCI vs CABG
• SAVR vs TAVI
• Repair vs replacement
• Clip vs MVr
 DON’T JUST LOOK AT THE ABSTRACT!!!

• Side effects of medications

• Ie. New hyperglycemic/cholesterol
• Indications for a procedure
• Ie. Infective endocarditis
• Technical considerations
• Ie. Mitraclip
• Inclusion/exclusion criteria
• Ie. TAVI
• How it affects guidelines
• Ie. All the CABG/PCI big trials
 TRIALS

DISCLAIMER!

• No published list of which trials you need to

know
• Everything you’re told is based on the best
guesses/experience of those who came
before you
• This is a text heavy presentation, sorry
 CABG VS PCI

• Syntax (NEJM 2009, Lancet 2013)

• CABG vs PCI in 3VD and LM
• Syntax 2 (EHJ 2017)
• Contemporary PCI vs historical control in
3VD
• Freedom (NEJM 2012)
• CABG vs PCI for MVD w/ diabetes
• EXCEL
• NOBLE
 SYNTAX

• 1 year = NEJM 2009, 5 year = Lancet 2013

• CABG v PCI in 3VD + LM
• 3VD 1095 pts
• LM 705 pts
• PCI w/ 1st gen stent (paclitaxel)
• Primary outcome @ 5 years
mortality/CVA/MI/repeat revasc.
• CABG superior (37 v 27%)
 SYNTAX

• 5 year results (Lancet 2013)

• Secondary outcomes
• MI – CABG superior (3.8 v 9.7%)
• Repeat revasc – CABG sup (13.7 v 25.9%)
• Death – no difference (11.4 v 13.9%)
• Stroke – no difference (3.7 v 2.4%)
• Of note: in patients with intermediate or high
SYNTAX scores, MACCE was significantly
increased with PCI (25.8 v 36% and 26.8 v 44%)
 SYNTAX

• Be able to answer:
• Define the SYNTAX score
• What are the different Syntax groups and how
does that affect the results of the original trial?
• How does this affect the guidelines?
• ACC/AHA 2011 CABG guidelines
• 2014 CSCS/CAIC position statement on MVD
• 2018 ESC/EACTS guidelines on myocardial
revascularization
 SYNTAX 2

• EHJ 2017
• Compares contemporary (2014-2015) PCI
group with historical Syntax cohort
• Utilized heart-team decision making,
bioresorbable DES, IVUS, modern guideline-
directed medical therapy, CTO techniques
• Primary outcome was MACCE
(death/CVA/MI/revasc) at 1 year
• Superior in modern cohort (10.6 v 17.4%)
 SYNTAX QUESTIONS

• What are 4 differences between the Syntax 1

and Syntax 2 PCI cohorts?
• What are two critiques of the Syntax 2 trial
 FREEDOM

• NEJM 2012
• CABG v PCI for MVD + DM
• Know inclusion criteria
• DM, CAD in > 2 arteries, suitable for PCI or
CABG, Sx. or objective evidence of
ischemia
• Know study population
• 60 y.o., 80% had 3VD, Syntax score 26, 33%
insulin dependent, LVEF >60%
 FREEDOM

• Primary endpoint – mortality/MI/CVA at 5

years
• Superior for CABG (27 v 19%)
• Secondary
• 5 year Mortality – CABG sup (16 v 11%)
• MI – CABG sup (14 v 6%)
• CVA – PCI sup (2 v 5%)
• Extended 7 year mortality – CABG sup (24
v 18%)
NOBLE

• Inclusion criteria:
• LM of >50% or FFR <0.8, no more than 3
additional non-complex lesions
• Different from Excel, where LM>70% or 50-
70% w/ FFR <0.8/IVUS
• Reached enrollment target of 1200 patients
• Different from Excel that had to stop early
due to poor enrollment (target 2600,
actual 1900)
 NOBLE

• 5 year primary outcome of

mortality/CVA/MI/repeat revasc
• CABG superior (28 v 19%)
• Secondary individual outcomes
• CABG superior in MI, repeat revasc, angina
• No difference in mortality, CVA
EXCEL

• 3 year results in 2016, 5 year results in

2019
• LM RCT where Syntax score <32
• Note LM lesion can yield Syntax score
anywhere from 12-25. Average in this
study 20.6
• Industry sponsored, designed, selected
sites
EXCEL

• Primary endpoint composite of death, CVA,

MI at 3 years (PCI non inferior)
• Secondary endpoints:
• Composite death/CVA/MI at 30 days
(PCI superior)
• Understand why
• Composite death/CVA/MI/revasc at 3
years (PCI non inferior)
 EXCEL

• 5 year primary outcome composite of

death/CVA/MI (no difference)
• Death worse in PCI (13 v 10%)
• Ischemia-driven revasc worse in PCI (17 v
10%)
• Cerebrovascular events (not CVA!) worse in
CABG (5 v 3%)
• Know critiques! (definition of MI,
downplaying of death, time to event curves)
 LM PCI POP QUIZ
NOBLE EXCEL

CABG PCI CABG PCI

Mortality

CVA

Revasc

MI

• List four reasons why the Noble and Excel

trials came to different conclusions
 ARTERIAL REVASCULARIZATION

• Rooby
• Coronary
• ARTS
• RAPS
• RAPCO
• Radial
 ROOBY

• 30 day/1 year results published in 2009

• 5 year outcomes in 2017
• Both in NEJM
• Short term primary outcomes:
• Death or complications (re-op, MCS,
cardiac arrest, coma, CVA, renal failure)
• Long term primary outcomes:
• Death, repeat revasc, MI
 ROOBY

• 30 day outcomes not different

• 1 year outcomes had higher composite rate
for off pump
• Off pump had fewer grafts used than planned
(~18 vs 11%)
• Patency was lower in off pump at 1 year (83
vs 88%)
 ROOBY

• Two 5 year primary outcomes

• Death
• Significantly different (15 vs 11%)
• Composite of death, MI, revasc
• Significantly different (31 vs 27%)

• Elective/stable CABG patients

• Surgeons needed to have done >20
• VA hospitals w/ trainees
• 65% radiographic follow up
 CORONARY

• 30 day (2012) and 5 year (2016) results both

published in NEJM
• 30 day publication demonstrates potential
benefits/risks of off pump:
• Less blood product transfusion, periop
bleeding, AKI, respiratory complications,
ventilation length
• Fewer grafts, more incomplete
revascularization, signal for early repeat
revasc needs
 CORONARY

• 5 year data
• Clinical primary outcome: composite of death, MI,
renal failure requiring dialysis, repeat revasc (23 vs
24%)
• Know differences to Rooby
• Surgeon had higher experience
requirements(>100 cases)
• Trainees excluded
• Randomized by surgeon experience
• Higher risk patients
 ART

• RCT of BIMA vs SITA

• 10 year results in NEJM 2019
• Primary outcome = death from any cause (20 v
21%, no difference)
• Understand the inclusion criteria
• Surgeon experience >50 BIMA operations
• What are the critiques/weaknesses
• Crossover (15% in BIMA arm)
• High radial use (20%)
 RAPS

• Canadian study!
• Understand primary outcome of functional
graft occlusions of RA vs SVG
• TIMI flow 0, 1, or 2
• Understand the relationship between worse
proximal stenosis and radial patency
 RAPCO

• RA vs RITA in <70 y.o. (or 60 in diabetics)

• RA vs SVG in >70
• 6 year mid term data
• Survival, event-free survival, and graft
patency similar at mid term follow up
• Why was the graft occlusion/patency different
from RAPS?
• Occlusion, 80% stenosis, string sign
 RADIAL

• NEJM article from 2018 – high yield

• 6 RCT combined analysis (includes RAPS and
RAPCO) of radial vs SVG @ 5 years
• Clinical primary composite outcome: death,
MI, repeat revascularization
• Graft patency secondary outcome
• Also know individual outcomes that make up
primary composite
 PCI + IMAGING

• Orbita
• FAME
• FAME II
• Pacific
 ORBITA

• PCI vs sham for angina relief in patients with

stable angina
• Primary endpoint – change in exercise time at
6 weeks. No difference between PCI and
sham
• No difference in Duke Treadmill Score or
Seattle Angina Questionnaire
• PCI better in improvements in stress echo and
complete freedom from angina
 FAME

• NEJM 2009
• RCT comparing FFR-guided PCI and
angiography-guided PCI
• Primary outcome composite of
death/MI/repeat revasc @ 1 year (13.2 v
18.3%, superior for FFR-guided)
• Solidified FFR threshold of <0.8 in literature
 FAME II

• NEJM 2012
• RCT comparing FFR-guided PCI to optimal
medical management in patients with stable
CAD
• Primary outcome composite of
death/MI/urgent revasc @ 1 year (4.3 v
12.7%, superior for PCI arm)
• Driven entirely by urgen revasc
 PACIFIC (NEJM 2017)

• Diagnostic differences between CTA, SPECT,

PET
• Control is FFR
• Hemodynamically significant if FFR <0.8
• CCTA most sensitive*
• SPECT most specific*
• PET overall had the highest diagnostic
accuracy*
 SHOCK + BLOOD

• Shock
• Shock 2 – IABP
• TRICS III
• TITRe 2
 SHOCK

• NEJM 2009
• 300 patients with shock due to MI
randomized to revasc vs medical stabilization
• Primary outcome mortality at 30 days – no
difference (47 v 56%)
• Mortality at 6 months superior in revasc
group (50 v 63%)
 SHOCK II - IABP

• NEJM 2012
• 600 patients with shock due to MI
randomized to get IABP or not
• Primary outcome mortality at 30 days – no
difference (40 v 41%)
• All secondary outcomes showed no difference
either
 QUESTIONS ON SHOCK

• How did the Shock II – IABP trial change the

guidelines on IABP usage in shock due to MI?
• AHA/ACC?
• EACTS/ECS?
• What are 4 clinical scenarios where a IABP
may be useful?
• What are 3 contraindications to IABP
placement?
 BLOOD TRIALS

• TRICS 3
• TITRe 2

• Restrictive vs liberal blood transfusion

• Understand cutoffs of how they defined these
groups
• Different endpoints/timelines
• Death/MI/CVA/dialysis at 6mo vs
infection/MI/major ischemia/gut ischemia @ 3
mo
 ANTICOAGULATION

• Proact – High risk

• Proact – Low risk
• Re-Align
 PROACT – HIGH RISK

• Lower dose v higher dose warfarin in high risk

mech AVR
• Inclusion:
• AF, LVEF<30%, LA>50mm, spontaneous contrast in LA,
history of neuro events within one year,
hypercoaguability, ventricular aneurysm, woman on
estrogen
• Primary endpoint: freedom from bleeding, TE,
valve thrombosis at 5 years – non inferior
 PROACT – LOW RISK

• DAPT v standard warfarin in low risk mechanical

AVR
• 3 months of Warfarin (INR 2-3) w/ ASA 81 then
randomized to:
• Warfarin (INR 2-3) w/ ASA 81 vs Clopidogrel 75
w/ ASA 81
• Freedom from bleeding, TE, valve thrombosis at 5
years – DAPT arm inferior, had excess TE cerebral
events and trial had to be terminated early
 RE-ALIGN

• Dabigatran vs warfarin in mechanical valve

• Inclusion:
• Mechanical AVR or MVR
• Starting drug within 7 days of surgery (population
A)
• Have to start the drug within 3 months post op
(population B)
• Terminated early due to excess bleeding/TE events
in dabigatran arm
• More stroke, more major bleeding
 BLOODY QUESTIONS

• 56 y.o. F w mechanical On-X AVR, EF 35%, LA

40mm. Can you use an alternative
anticoagulation strategy to warfarin with INR
target 2-3?
• What do the guidelines say regarding
alternative anticoagulation strategies for both
low-dose warfarin and alternative
anticoagulation strategies?
 MITRAL VALVE TRIALS

• CTSNet Moderate MR
• CTSNet Severe MR
• EVEREST I/II
• COAPT
• Mitra-FR
 ISCHEMIC MR

• CTSNet Moderate MR
• CTSNet Severe MR
• What to know:
• Mortality in each arm, Rate of recurrent MR, Rate
of hospitalizations, LVESVI, neurological events in
each arm, SVT in each arm
• What endpoints are significantly different, what
ones are not?
• How do these affect the ACC/AHA 2017 valve
guidelines?
 MITRACLIP

• Everest/Everest II
• Established criteria for Mitraclip
• (know anatomic indications/contraindications)
• COAPT vs Mitra-FR
• Primary endpoints for each (hospitalizations vs
death/hosp)
• How patient populations differed in each (ERO,
LVEDVI, med mgmt)
• Why the trials ended up with different results
(experience, follow up duration)
 VAD + ECMO TRIALS

• Rematch
• HEARTMATE II – DT
• HEARTMATE II – BTT
• ADVANCE – HVAD BTT
• ENDURANCE – HVAD vs HM2
• MOMENTUM 3 – HM3 vs HM2
• EOLIA
• CEASAR
 VAD + ECMO TRIALS
• Rematch
• DT: LVAD (w/ HM, pulsatile flow VAD) vs med
management
• Improved QOL @ 1 year, high burden of device
related morbidity at 2 years
• Heartmate II DT + BTT
• DT = HM2 vs HM
• Improved survival, stroke free survival, reop at 2
years
• BTT = non randomized HM2
• Survival/transplant = 80% at 18 mo
 VAD + ECMO TRIALS

• ADVANCE
• HVAD vs HM2
• HVAD non inferior to HM2 at 180 days in
survival/survival to transplant
 ENDURANCE

• HVAD vs HM2 in DT
• NYHA II-IV, LVEF <25%, Ineligible for transplant
• Primary = survival, freedom from disabling stroke or
reop for device failure at 2 years
• Same in both groups(55 v 59%)
• All stroke favours HM2 (30 v 12%)
• Note: supplemental trial shows strict BP control
reduces stroke risk
• Reop for failure favours HVAD (9 v 16%)
 MOMENTUM

• HM3 vs HM2 in DT or BTT

• Inclusion: advanced HF refractory to medical
therapy
• Primary = survival, freedom from disabling
stroke, reop for malfunctioning device at 2
years
• HM3 superior (80 v 60%)
• Driven by reoperation for device
malfunction (2 v 17%)
 EOLIA VS CESAR

• Two trials on VV ECMO vs medical

management in ARDS
• 60 day Mortality vs Mortality + severe
disability
• Understand why trials came to different
results
• Crossover in EOLIA
• Transfer to centers of excellence in CESAR
 MCS QUESTIONS

• What was the rate of pump thrombosis in the

both devices in MOMENTUM/ENDUR
• What are 4 design characteristics of HM3 that
improve pump thrombosis over HM2
• Centrifugal, wide blood-flow passages, no mechanical
bearings, programmed rapid changes in rotor speed (reduced
stasis in pump)
• How did the patients in the EOLIA trial have their
ventilation strategy optimized in the control arm?
• Low tidal volumes 5 mL/kg, Lower inspiratory pressures –
plateau pressure < 30 cm H20, Prone, Nitric oxide
 TAVI

• PARTNER 1A
• PARTNER 1B
• PARTNER 2
• PARTNER 3
• Corevalve Extreme risk
• Corevalve High risk
• SURTAVI Intermediate risk
• Corevalve (Evolut) Low risk
 PARTNER 1A + 1B

• PARTNER 1A
• TAVR v SAVR in high-risk
• NYHA II-IV, STS>10%, high risk prediction by surgeons
• Mortality the same (30 days, 1 year, 5y)
• Know which complications favoured SAVR (neuro,
leak, vascular issues)
• PARTNER 1B
• TAVR v med mgmt in inoperable pts
• Mortality superior at 1 (31 v 50%) and 5 (72 v 94%)
years
 PARTNER 2

• PARTNER 2
• TAVR vs SAVR in intermediate risk
• STS 4-8% or <4% when team thinks intermediate risk
• Primary endpoint = mortality or disabiling stroke at 2
years
• Overall same (19 v 21%) but just TF TAVR superior (17 v
20%)
• Know what favours TAVR and SAVR
• AKI, AF, Bleeding
• Vascular injury, leak, pacemaker
 PARTNER 3

• NEJM 2019
• STS score <4% (actual 1.9%)
• Primary outcome = death/CVA/rehospitalization @ 1
year
• Superior for TAVI (8.5 vs 15.1%)
• Important to know what favoured TAVI and what
favoured SAVR in secondary outcomes
• Critiques include drop out in SAVR arm, unblinded
outcome adjudication, highly selected patient cohort
 COREVALVE EXTREME + HIGH RISK

• Corevalve Extreme risk

• TAVR compared to Partner 1B
• Mortality/major stroke at 1year
• 26%, similar to Sapien results
• Corevalve High risk
• Estimated 30 day mortality 15-50%
• Primary outcome = 1 year mortality (14 v
19%, TAVI superior)
• 5 year results (JAMA 2019)
 SURTAVI INTERMEDIATE RISK

• TAVI vs SAVR in intermediate risk

• STS 3-15%, NYHA II-IV
• Primary endpoint = mortality or disabling
stroke at 2 years (13 v 14%, no difference)
• TAVI favoured = AKI, AF, transfusion
• SAVR favoured = moderate/severe AI, PPM,
vascular complications
• No difference = MACCE, mortality, stroke,
bleeding
 COREVALVE (EVOLUT) LOW RISK

• TAVI vs SAVR in low risk

• STS < 3%
• Primary endpoint = composite of death or
disabling CVA at 2 years (5.3% in TAVI v
6.7% in SAVR)
• TAVI favoured for CVA, bleeding
complications, AKI, a. fib
• SAVR favoured for paravalvular leak and
pacemaker implantation
 TAVI QUESTIONS

• According to the 2019 CCS position statement

on TAVI, what factors favour TAVI and what
favours SAVR?
• In the Partner 3 trial, what is the rate of CVA
in each arm at 1 year?
• In the Evolut low risk trial, what is the rate of
pacemaker in each arm?
 MISC TRIALS

• STICH (+ STICHES)
• Mechanical vs Biological valves by age
• Ross vs homograft
• ADSORB + INSTEAD XL
• SVR – RVPA vs MBTS
• EASE
 TRIALS

• STICH Trial (+ STICHES 10 year data)

• What are the two arms
• What are the inclusion/exclusion criteria
• What is the primary endpoint
• What is the mortality at 10 years? What about
prior to that?
• Note: understand that even though all cause
mortality wasn’t different prior to 10 years,
CV-related mortality and hospitalizations
superior at 5 years
 TRIALS

• California: Mechanical vs Biological Prosthesis for

AVR/MVR
• Not a RCT! Retrospective admin database
• 25k patients, largest database to publish this w/ 15
year mortality data
• Understand age stratifications and results in both
valves for each, where this comes up in guidelines
• Understand complications related to each type of
valve, trend to tissue usage
 TRIALS

• Ross
• RCT in Lancet in 2010
• Compared Ross vs homograft
• Survival difference at 10 years
• Understand how these survival numbers
relate to the California admin database
numbers
 TRIALS
• ADSORB
• Stenting in uncomplicated Type B
• Understand imaging endpoints (not clinical endpoints)
used and numbers that drove positive results
• Instead XL
• TEVAR vs OMT in uncomplicated Type B
• Clinical end point (mortality/aorta specific mortality) and
progression
• Note: stent graft induced false lumen thrombosis
associated with better survival and lower progression of
disease
 TRIALS

• Single Ventricle Reconstruction Trial – Sano vs BT

shunt
• HLHS kids
• RV-PA (aka Sano) vs MBT
• Understand transplant free survival rates at 1
year (74 vs 64%) and 6 years (64 vs 59%). Signif
@ 1 year, not at 6

• Understand drawbacks of RV-PA conduit

• Thrombotic events, strokes, seizures
 TRIALS

• EASE – Early vs conventional treatment for IE

• Inclusion: Dx of IE based on modified Duke,
Veggie >10mm, Severe MV or AV disease
• Exclusion: Mod-Severe CHF, Heart block,
abscess, fistula, PVE, hemorrhagic stroke
• Primary: in hospital mortality + clinical embolic
events within 6 weeks
• 3 v 23%, driven by embolic events (0 vs 21%)
 TRIALS I DIDN’T COVER

• Atrial fib trials

• ISCHEMIA trial
• POET trial
• Cardiology/medication focused trials
• COMPASS
• CANTOS
• FOURIER
• …