RECENT IMPORTANT TRIALS

AND UPDATES-2019

Dr. AN Patnaik
What are the new guidelines announced in
2019?
AHA/ACC GUIDELINES,2019
• Arnett et al. 2019 ACC/AHA Guidelines on the Primary Prevention of
Cardiovascular Disease [ circulation Feb 2019]

• 2019 AHA/ACC/HRS Focused Update of the 2014 Guidelines for Management of

Patients with Atrial Fibrillation

• Cardiovascular Risk Reduction in High-Risk Pediatric Patients

• Novel CV Risk Reduction Therapies in Type 2 Diabetes and CVD: Consensus

Decision Pathways (ACC, 2019)
What are the updates in A.fib-guidelines?
Sarah D. de Ferranti. Circulation. Cardiovascular Risk Reduction in
High-Risk Pediatric Patients: A Scientific Statement From the
American Heart Association, Volume: 139, Issue: 13, Pages: e603-
e634, DOI: (10.1161/CIR.0000000000000618) © 2019 American Heart Association, Inc.
ESC GUIDELINES,2019
 2019 ESC/EAS Guidelines For The
Management Of Dyslipidaemias

2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular
risk (European Heart Journal 2019 -doi: 10.1093/eurheartj/ehz455) 8
Any one can tell some high-lights?
Chronic coronary syndromes
Six common scenarios at outpatient clinics

Patients with Patients withnew Patients with Patients >1year Patients with Asymptomatic
suspectedCAD onsetofHForLV stabilized after initial angina and subjects in
and ‘stable’ dysfunction and symptoms <1 diagnosis or suspected whom CAD is
anginal suspectedCAD year after an revascularization vasospastic or detected at
symptoms, ACS or patients microvascular screening
and/or with recent disease
dyspnoea revascularization

ESC Guidelines: Diagnosis And Management Of Chronic Coronary Syndromes

European Heart Journal 2019; 10.1093/eurheartj/ehz425)
2019 ESC Guidelines on chronic coronary syndromes last version
published in 2013

• The concept of ‘clinical likelihood of CAD’ is newly introduced, which refers to risk factors of
CAD

• The role of exercise ECG has been downgraded in the guidelines;

• Updated to use of dual antithrombotic therapy and specific guidance is given on which agent
may be added to aspirin in specific clinical scenarios.

• Recommendations also include use of other drugs for event prevention, including lipid-lowering
drugs (statins, ezetimibe, PCSK9 inhibitors) and antidiabetic drugs (SGLT2 inhibitors, GLP-1
receptor agonists).

• A decision tree for patients undergoing invasive coronary angiography,

Indian Guidelines
• 2019: API – guidelines on HTN
• 2019-Congenital Heart diseases: Timing of SX
Related specialities
• Guidelines on optimal management of anticoagulation therapy for venous
thromboembolism by the American Society of Hematology (ASH).Jan 31,
2019
• 2019 guidelines on CT IN TAVI by the Society of Cardiovascular Computed
Tomography (SCCT).Jan 30, 2019
• 2019 HRS Expert Consensus Statement on Evaluation, Risk Stratification,
and Management of Arrhythmogenic Cardiomyopathy
Name some popular trials published?
 ACS CCAD PCI/DAPT LIPIDS HTN DM- TAVI/mitra HF NOAC A.F MISC
CVD
ACC MRUSMI SCOT- SAFARI-STEMI REDUCE- INFINITY EVOLUT-LR Cardio- AUGUSTUS Apple- WRAP-IT
HEART SMART-CHOICE IT Alco-HTN PARTNERIII mems ANNEXA-4 Heart COACT
STOP-DAPT2 CLEAR- Creole TAVR- Optimizer study CABANA POET
TREAT WISDOM bicuspid Smart Low-carb- Hot-pe
DEFINE-PCI COAPT Momentum A.Fib TiCAGRE-
DECLARE-TIMI- -3 Alcohol-Af REVERSAL
58 PANACHE In-Hospital Flu
PIONEER- Shot
HF Hopeful heart
CODIACS-Qol
Glassy,Irac
ECS COMPLETE AFIRE THEMIS-PCI ORION- Radianc Caroli DANAMI- ENTRUST COACT
Historic SWED ISAR-react-5 11 e-2 na 16 yr -AF Agris
Australian HEART EMPA- Avert Popular age
RAPID-TnT ADVANCE Syntaxex Heart DAPA-HF Bio-stemi
study registry Syntax- PARAGON Chess
revolution HF Sassicassia
Popular-Genetics
TCT EXCEl-5yr TWILIGHT Partner-2A- PANORAMA Augustus-ACS
NOBEL-5Yr Ideal-LM 5yr -HF
ISAR-react-5

AHA COLCOT Ischemia- THEMIS-PCI Orion-9 Hygia DAPA- Recovery DAPA-HF Compass PATCH
Compass Twilight-ACS ORION- trial HF Galileo PARAGON VITAL
Evaporate Syntax-ex 10 HF Ischemia-CKD
EXCEL-5yr Fuel
Isch-CKD
Treat stroke to
target
FDA SSO₂) TAVR-FOR ARNI-Ped EPA-high
LOW RISK
1.ISCHEMIA TRIAL
ISCHEMIA TRIAL
• Over 8000 patients with stable (mild) symptoms suggestive of angina
• Stress test showing moderate to severe ischemia [stress imaging test
in 75% and stress ECG in 25%]

• Severe ischemia >10% on nuclear scan, >three segments on echo, or

greater than 12% on MRI

• Over 3000 screened out after a coronary CTA to exclude those with
left main stenosis or nonobstructive CAD..
International Study of Comparative Health Effectiveness With Medical and Invasive
Approaches (ISCHEMIA)
• Purpose: To evaluate clinical outcomes in
the comparison of an initial invasive approach (cardiac
catheterization and feasible revascularization) + OMT
to conservative, optimal medical therapy (OMT)
alone in patients with SIHD and moderate or severe
ischemia.
• Trial Design: N=5179, median age 64 years old; average
3.5 years follow-up. 320 sites; 37 countries.
• Primary Composite Endpoint: CV death, non-fatal MI,
resuscitated cardiac arrest, hospitalization for unstable
angina, or HF.
• Major Secondary Endpoint: CV death, MI.
An initial invasive approach compared
to conservative approach in SIHD patients with
moderate-severe ischemia did not reduce risk of
the primary endpoint or the secondary endpoint
of CV death or MI at a median of 3.3 years.

AHA Scientific Sessions 2019,

Philadelphia, Pennsylvania
Conclusion

Overall, an initial INV strategy as compared with an initial CON strategy

did not demonstrate a reduced risk over median 3.3 years for
 Primary endpoint - CV death, MI, hospitalization for UA, HF, RCA
 Major Secondary endpoint - CV death or MI

Cardiovascular Clinical Research Center

2.EXCEL/NOBEL-5 YRS
EXCEL-CONTROVERSY
• The EXCEL trial [2013] compared PCI to CABG in patients with left
main disease amendable to PCI.
• For patients with low Syntax score (0 to 22) left main lesions, the two
procedures produced similar results
• A class I recommendation in the European guidelines was added
The 5-year results-TCT 2019
NEJM on September 28, 2019
• The risk of death, stroke, or MI—the study’s primary endpoint—was
22.0% in the PCI arm and 19.2% in the CABG-treated patients, a
difference that was not statistically significant (P = 0.13).
• EXCEL investigators concluded there was no significant difference
between revascularization with PCI or CABG in patients with LMCAD
of low or intermediate anatomical complexity.
EXCEL Controversy
• The BBC's analysis of the unpublished secondary endpoint revealed an 80%
higher rate of MI in the PCI arm.
• An exploratory analysis of the primary endpoint with this definition of MI found a
44% higher rate of events in the PCI arm.
• European Association for Cardio-Thoracic Surgery removed their support for the
left-main recommendations in the European guidelines on myocardial
revascularization.
• The EXCEL investigators responded in a 3500-word rebuttal, in which they deny
wrongdoing and defend the results
• The BBC Newsnight producers say they have more information.
• EXCEL authors say they will publish more papers from the data.
• Surgeon David Taggart accused the EXCEL investigators stacking the deck in PCI’s
favour
EXCEL INTERPRETATION

1.The definition of MI and inclusion of periprocedural MI drove the

noninferiority of the composite endpoint of MI, stroke, and death.
2.Death rates were higher in the PCI arm
EXCEL authors did not report a secondary endpoint (MI as determined
with the universal definition) that was listed in the trial protocol.
NEJM editors and peer reviewers did not notice this omission
 Lancet, Dec,2019

• CABG was found to be superior to PCI for the primary composite endpoint (p=0·0002).
• All-cause mortality was estimated in 9% after PCI versus 9% after CABG (HR 1·08 [95% CI
0·74–1·59]; p=0·68);
• non-procedural myocardial infarction was estimated in 8% after PCI versus 3% after CABG
(HR 2·99 [95% CI 1·66–5·39]; p=0·0002);
• Revascularization was estimated in 17% after PCI versus 10% after CABG (HR 1·73 [95% CI
1·25–2·40]; p=0·0009).
In revascularization of left main coronary artery disease, PCI was associated with an inferior clinical outcome at 5
years compared with CABG.
Mortality was similar after the two procedures but patients treated with PCI had higher rates of non-procedural
myocardial infarction and repeat revascularization.
3.COMPLETE TRIAL?
***
N Engl J Med 2019; 381:1411-1421
4.SMART-CHOICE/STOP-DART/TWILIGHT
Shortened DAPT:TWILIGHT, SMART-CHOICE, and STOPDAPT-2

• TWILIGHT randomized 7100 patients deemed at high risk for bleeding and
ischemic events to either ticagrelor only or ticagrelor plus aspirin after an
initial 3 months without an event. Ticagrelor monotherapy was superior in
terms of bleeding and noninferior in terms of death, MI, and stroke.
• STOPDAPT-2 randomized 3000 patients who underwent PCI with a XIENCE
drug-eluting stent to either clopidogrel or clopidogrel plus aspirin after 1
month. Clopidogrel monotherapy was superior in terms of (major) bleeding
events and noninferior in terms of CV death, MI, definite stent thrombosis,
and stroke
• SMART-CHOICE randomized nearly 3000 patients undergoing PCI with
drug-eluting stents to either P2Y12 (77% clopidogrel) or P2Y12 plus aspirin
after an initial 3 months. P2Y12 monotherapy was superior in terms of
bleeding and noninferior in terms of death, MI, and stroke.
5.THEMIS/ PCI
6.ISAR-React-5
ISAR-REACT 5
• 4018 pt : P= 2006; T= 2012

• Prasugrel trounced ticagrelor for the reduction of death, MI, or stroke

at 1 year.
• Prasugrel achieved this superiority without an increase in major
bleeding.
7.IDEAL-LM
• Large vessel diameter and high flow conditions in the LMS might
favour a shorter-term post PCI DAPT duration.
• 818 all-comer LMS PCI patients to either the Synergy stent combined
with 4 months of DAPT or to the Xience stent with 12 months of
DAPT.
• The primary endpoint was the race of MACE (death, MI or ischaemia-
driven TVR) at 2 years.
• The primary endpoint at 2 years occurred in 14.6% of patients treated
with DAPT for 4 months following implantation with Synergy and
11.4% of patients treated with DAPT for 12 months following
implantation with Xience (P = 0.17).
8.REDUCE-IT
REDUCE-IT
• Highly purified form of eicosapentaenoic acid (EPA) has been shown
to reduce triglycerides.
• This study looked to see if the label could be expanded to include a
reduction in hard outcomes like death or MI.
• Earlier studies used over-the-counter fish oils, some nonpurified, and
with docosahexaenoic acid (DHA)
9.ORION
ORION trials with inclisiran
• Inclisiran is very exciting, not just
because it's a drug that lowers
LDL-C, but because it's in a
whole new class of drugs.
• It's a small interfering RNA
(siRNA)-based technology
downregulating the amount of
PCSK9 in your body.
Inclisiran for Participants With Atherosclerotic Cardiovascular Disease and Elevated Low-density
Lipoprotein Cholesterol (ORION-10)

• Purpose: to evaluate the safety and efficacy of

inclisiran, a drug in the siRNA class, in patients
with ASCVD and high LDL-C.
• Trial Design: 145 sites. N=1561. 18-month follow-
up. Phase 3, placebo-controlled, double-blinded
study; Patients randomized 1:1 to inclisiran 300
mg or placebo. Inclisiran dosed initially, then at 3
months, and then twice a year and maximally
tolerated statins.
• Co-primary Endpoints: % LDL-C change from Twice-yearly inclisiran safely reduced LDL-
baseline at day 510 and avg. % change from day
90 to day 540. C in ASCVD patients with continued high
LDL-C while on maximum tolerated statin
dose.

AHA Scientific Sessions 2019, Philadelphia, Pennsylvania

ORION-11 Inclisiran for subjects with ACSVD or ACSVD-risk equivalent and elevated low-density lipoprotein cholesterol

Study endpoints:

1.Effectiveness
Primary Endpoint:
Percent LDL-C change vs. placebo
- At day 510
- Average over days 90 – 540

Inclisiran achieves durable and potent LDL-C reduction with only 2x yearly injection
With excellent safety profile in a high cardiovascular risk population.

https://esc365.escardio.org/Congress/ESC-CONGRESS-2019/Late-Breaking-Science-orion-11-trial
10.DAPA-HF
The Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure Trial (DAPA-HF):
Results in Nondiabetic Patients
• Purpose: to evaluate the safety and efficacy
of dapagliflozin, an SGLT2 inhibitor, in
patients with HFrEF with and without T2DM.
• Trial Design: Phase 3 randomized, double-
blinded, parallel comparison of dapagliflozin
10 mg./day + standard therapy versus
placebo + standard therapy in 4744 HFrEF
patients with and without T2DM. N=4744.
20 countries. Median 18.2 months follow-
up.
• Primary Endpoints: composite of first
worsening of HF or CV death.
In those with and without T2DM, dapagliflozin +
standard therapy reduced the risk of the
composite primary endpoint.

AHA Scientific Sessions 2019, Philadelphia, Pennsylvania

11.EVOLUT/PARTNER-3
• EVOLUT-TAVR was noninferior to
SAVR for the treatment of
mortality/disabling stroke at 24
months in low-risk patients with
severe symptomatic aortic
stenosis.

• PARTNER-3:Transcatheter aortic
valve replacement (TAVR) was
superior to surgical aortic valve
replacement (SAVR) for the
composite of death from any
cause, stroke or rehospitalization at
one year in low-risk patients with
severe symptomatic aortic
stenosis.
12. PIONEER/PARAGON
 PIONEER-HF
Sacubitril/valsartan reduced NT-proBNP more than enalapril among patients with ADHF
Study

 Methodology: • Primary endpoint: Time-averaged reduction in

 Eligible patients were randomized in a 1:1 fashion to sacubitril/valsartan (n = 440) NT-proBNP: sacubitril/valsartan vs. enalapril: -
or enalapril (n = 441). 46.7% vs. -25.3%, p < 0.001
 Initial dose of sacubitril/valsartan was 24/26 or 49/51 mg, and for enalapril was 2.5
or 5 mg, both given orally twice daily.
 A 36-hour washout period for sacubitril/valsartan was incorporated into the protocol.
During the 8-week trial period, the goal was to increase sacubitril/valsartan to
97/103 mg twice daily and enalapril to 10 mg twice daily.
 Total number of enrollees: 881
 Duration of follow-up: 8 weeks
 Mean patient age: 61 years
 Percentage female: 28%

Secondary outcomes:

 Change in troponin T: -36.6% vs. 25.2%, p < 0.05

 Worsening renal function: 13.6% vs. 14.7%, p > 0.05
 Hyperkalemia: 11.6% vs. 9.3%, p > 0.05
 Symptomatic hypotension: 15.0% vs. 12.7%, p > 0.05
 Death: 2.3% vs. 3.4%, p > 0.05
 Rehospitalization for HF: 8.0% vs. 13.8%, HR 0.56,
95% CI 0.37-0.84

Sacubitril/valsartan reduced NT-proBNP more than enalapril among patients with ADHF; noted as early
as 1 week after drug initiation
https://www.acc.org/latest-in-cardiology/clinical-trials/2018/11/10/01/50/pioneer-hf
ARNI- HFpEF
13.AUGUSTUS
 AUGUSTUS Apixaban Plus P2Y12 Inhibitor the Best Combo in A-fib Patients With ACS or Undergoing PCI

 Methodology:
• Enrollment included 4614 patients from 33 countries

• In an international trial with a two-by-two factorial design, we randomly assigned patients with atrial fibrillation who had an acute coronary syndrome or had
undergone PCI and were planning to take a P2Y12 inhibitor to receive apixaban or a vitamin K antagonist and to receive aspirin or matching placebo for 6 months.

• The primary outcome was major or clinically relevant non major bleeding. Secondary outcomes included death or hospitalization and a composite of ischemic events.
 Important results:

• Kaplan–Meier Curves for Primary Outcome of Major or Clinically Relevant Non major Bleeding.

In patients with AF and a recent ACS or PCI treated with a P2Y12 inhibitor, apixaban without aspirin resulted in less
bleeding and fewer hospitalizations without significant differences in the incidence of ischemic events than regimens
that included a vitamin K antagonist, aspirin, or both

N Engl J Med. 2019 March. DOI: 10.1056/NEJMoa1817083

14.APPLE HEART
****
15.CABANA
CABANA**
• The Catheter Ablation vs Antiarrhythmic Drug Therapy for Atrial
Fibrillation (CABANA) trial tested the hypothesis that ablative therapy
for AF is more effective than drug therapy
• 2204 symptomatic and inadequately treated patients with AF.
• catheter ablation, did not significantly reduce the primary composite
endpoint of death, disabling stroke, serious bleeding, or cardiac arrest
(8.0% vs 9.2%, respectively; HR, 0.86
Chronic CAD
• COMPASS: Rv+aspirin vs Aspirin- stable CV diseases
• EVAPORATE: hints at slowed plaque progression with Icosapent
• POPular-AGE: > 70 yr long term clopi use is reasonable
• AFIRE STUDY: Af+ stable angina- Rv monotherapy non-inferior
• DANAMI-16 yr: In AMI PCI initially resulted in better long-term outcome
• SYNTAXES : Except TVD –low-inter. Syntax did as well as CABG
• Advance registry [ iFFR]
• GLASSY: Ticagreor monotherapy vs DAPT [ Sub-study of Global-Leaders]
• DEFINE-PCI: Residual ischemia after successful PCI
ACS
• TREAT: Tica in place of clopidogrel after thrombolysis for AMI
• SAFARI-STEMI: Radial access not superior to Femoral
• TWILIGHT-ACS
• AUGUSTUS –ACS
• Popular-Genetics: In pri-PCI genotype-guided strategy P2Y2 inhibitors
• SASSICAIA: different DAPT loading
• HiSTORIC Trial: Single Tn T is fine
• Australian RAPID-TnT: 0-1 hr protocol as good
• MRUSMI: Sono-thrombolysis
SAFARI-STEMI
• The SAFARI-STEMI trial compared radial access with femoral access
among patients undergoing primary PCI for STEMI.
• At 30 days, there was no difference in all-cause mortality or any of the
individual ischemic outcomes.
COLCOT trial

• Among patients who suffered a recent myocardial infarction, low-

dose colchicine was effective at preventing major adverse
cardiovascular events compared with placebo.
• Benefit was primarily due to a reduction in the incidence of stroke
and urgent hospitalization for unstable angina leading to
revascularization.
• The study drug was well tolerated and associated with a similar
incidence of infection and diarrhea compared with placebo.
• The benefit of colchicine was purported to be due to anti-
inflammatory properties of the drug.
AF-NOACS
• ANNEXXA-4
• ENTRUST
• AVERT
• COMPASS
• Alcohol-Af
• LOW-CARB A FIB
• ENTRUST-AF PCI trial: Edoxaban in AF- PCI
• AVERT : Apixaban- VTE in cancer
 Rivaroxaban and aspirin compared with aspirin in women and men with chronic coronary or peripheral artery
COMPASS disease
Primary Outcome: CV death, stroke, MI
 Methodology:
• Objective : To determine the effects of the combination of
Rivaroxaban+Aspirin compared with aspirin alone in women
and men
• Outcomes:
• Primary outcome: CV death, stroke or myocardial
infarction
• Safety outcome: ISTH major bleeding (modified)

Major Bleeding:

Rivaroxaban 2.5mg twice-daily plus

aspirin 100mg once-daily vs. aspirin
100mg once-daily produced similar
benefits and similar risks of bleeding in
women and men.

Late Breaking Science, FP Number : 187, Presented at ESC Congress 2019

HF
• CARDIO-MEMS: Sensor that detects PA pressures in ambulatory HF
pts: 58% reduction in HF hospitalisation at 1 year
• Sub-studies of DAPA-HF
• PANORAMA-HF trial [ pediatric HF-ARNI]
• PANACHE: NELAADENOSON in HFpEF
• EVALUATE HF: Sac/Val did not reduce central aortic stiffness
• OPTIMZER SMART
• MOMENTUM-3: Heart mate-III
• HOPEFUL HEART TRIAL: HF-comorbid depression
 Optimizer Smart System (Impulse Dynamics)
• Delivers non-excitatory electrical
signals during absolute refractory
period (cardiac contractility
modulation therapy) to the right
ventricle in patients with
chronic heart failure

• FIX-HF-5 Pivotal Trial (US) – a multi-

center, randomized study included
428 patients with NYHA Class III or IV
symptoms and EF ≤35% who were
randomized to receive either an
Optimizer® III System implant plus
Optimal Medical Management (OMM,
n=215) or OMM alone (n=213).
VALVES-TAVI
• RECOVERY: In asymptomatic AS- early AVR better
• PARTNER-2A : 2 YR[ interm-risk]
• TAVR-BICUSPID
• GALILEO: anticoagulation after TAVI RIVA VS ANTI-PLATELET RX]
• COAPT: Mitra-clip in functional MR in HF
MISC
• RADIANCE-II-[PARADISE ULTRASOUND SYSTEM FOR RENAL DENERVATION]
• VITAL: n3 FA/vitamin D not protective
• PATCH: SLE mother ↓ CHB using Hydroxy Chloroquine
• WARP-IT: Antibiotic envelope around devices
• POET: Partial oral tt of IE
• IRAD: Aortic dissection
• HOT-PE: Low-risk PTE –home treatment
• Hope-4 : Community based early detection-CVD reduces
• FLU-SHOT: less CV
FDA approvals/Warnings
• Super-Saturated Oxygen (SSO₂) therapy system
• TAVR-LOW RISK
• High dose EPA for CV reduction [REDUCE-IT]
• Optimizer Smart System (Impulse Dynamics)
• Lotus Edge joins the Sapien and CoreValve/Evolut families of TAVR
devices
• FDA has approved Sacubitril/valsartan in children 1 year and older for
HFREF
• Fluoroquinolones: ↑aor c aneurysms
THE LIST IS END-LESS

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