Some Recent Major Clinical Trials in Cardiology:

Critical Appraisal from a Statistician’s Perspective

Stuart Pocock and Tim Collier

London School of Hygiene and Tropical Medicine

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The Trials

CABANA

ATTR-ACT

COAPT

DECLARE

REDUCE-IT

AUGUSTUS

PARTNER 3

CABANA trial [JAMA 2019;321 p 1261-]

2204 patients with atrial fibrillation

Ablation therapy vs Drug therapy

9.2% not ablated 27.5% ablated

Primary endpoint: death, stroke, serious bleed, cardiac arrest

over mean 4 years follow-up

Main problem: how to handle the crossovers

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Key Findings from the CABANA trial

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Interpreting CABANA

Analysis by Intention to Treat (ITT)

An unbiased comparison of strategies as given

But dilution bias due to crossover

Per Protocol Analysis of Compliers

Nearer to actual treatment effect

But potential selection bias

As Treated Analysis, including Crossovers

Even more potential for bias

Controversy remains, trial inconclusive

Lack of clinical equipoise

Buxton’s law: “it is always too early for rigorous

evaluation, until unfortunately it’s suddenly too late”

Can non-randomized evidence help?

US administrative database of AF patients in 2009-16[Noseworthy et al, EHJ in press]

ablation vs medical therapy[N=12,032] [N=171,728]

for death, stroke, major bleed and cardiac arrest:

hazard ratio 0.75 (95% CI 0.70, 0.81) P<0.001

using propensity score weighted analysis

in routine care, ablation associated with reduction in the primary CABANA endpoint

but could residual selection bias exist? 8

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ATTR-ACT trial ESC August 2018 NEJM 2018;379 p1007-

tafamidis in transthyretin amyloid cardiomyopathy

441 patients randomized in 2:1:2 ratio to:

80 mg tafamidis vs 20 mg tafamidis vs placebo

follow-up for 30 months

primary hierarchical analysis:all cause death then no. of CV hospitalizationsusing win ratio and Finkelstein-Schoenfeld test

tafamidis dose groups pooled

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ATTR-ACT Results for All-Cause Death and for

Cardiovascular-Related Hospitalization (CVH)

Tafamidis

[N=264]

Placebo

[N=177]

Hazard Ratio (95% CI)

(Risk Ratio for CVH rate)P-value

Deaths 39 (14.8%) 38 (21.5%) 0.70 (0.51-0.96) 0.026

Number with ≥1 CVH 138 (52.3%) 107 (60.5%) 0.80 (0.62-1.03) 0.078

Number of CVHs (including repeats) 267 231

CVH rate per year 0.48 0.70 0.71* (0.54-0.93) 0.0068

*using negative binomial model to allow for non-independence of repeat hospitalizations

Primary Analysis: Win Ratio method

patients stratified by transthyretin gene TTR status (variant

or wild type) and by NYHA class (I/II or III)

within each stratum, compare every tafamidis patient with

every placebo patient to see who “won” by:

1) who died first (they “lose”)

2) if neither died, who had the most CVHs (they “lose”)

Nos. of patients (tafamidis vs placebo)

class I/II class III

variant 34 v 24 29 v 19 17203 patient pairs

wild type 152 v 90 49 v 44

tafamidis had 8595 wins, 5071 losses and 3537 ties

win ratio = 8595/5071 = 1.70 (95% CI 1.26, 2.29) P=0.0006

Graphic Display of Win Ratio

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Interpretation of ATTR-ACT

combining death and CVHs strengthens the evidence

also highly significant steady improvements

in 6 minute walk test and quality of life

overwhelming evidence that tafamidis is effective

a major breakthrough for a largely undiagnosed condition

results by dose (80 mg vs 20 mg) still to come

COAPT trial [TCT Sept 2018 and NEJM 2018;397 p2307-]

transcatheter mitral-valve repair in heart failure patients

mitraclip device vs control

302 patients 312 patients

3% no procedure attempted 1% underwent mitraclip

primary endpoint over 24 months:

hospitalizations for heart failure, including repeats

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key results of COAPT(HFH = heart failure hospitalisation)

device

[N=302]

control

[N=312]

≥1 HFH 92 151

no. of HFHs 160 283

no. of deaths 80 121

NNT to prevent 1 HFH 3.1 (95% CI 1.9, 7.9)

NNT to prevent a death 5.9 (95% CI 3.9, 11.7)

hazard ratio for HFH 0.53 (95% CI 0.40, 0.70)

hazard ratio for death 0.62 (95% CI 0.46, 0.82)

“analysis of the primary endpoint, all HFHs, used a joint

frailty model to account for correlated events and the

competing risk of death” 17

MITRA-FR trial [ESC and NEJM 2018;379 p2297-]

in patients with severe secondary mitral regurgitation

mitraclip device vs control

152 patients 152 patients

8 no procedure attempted 2 underwent mitraclip

primary endpoint over 12 months:death or heart failure hospitalisation

hazard ratio 1.11 (95% CI 0.69, 1.77) P=.66

mitraclip device seems ineffective

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A comparison of the COAPT and MITRA-FR

Why do COAPT and MITRA-FR give different results?

possible explanation include:

1) difference in patients randomized?

2) differences in medical therapy before and during trial?

3) differences in procedural performances?

4) COAPT patients were truly refractory to medical therapy?

5) MITRA-FR has only 1 year’s follow-up?

6) the play of chance?

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*co-primary endpoints

DECLARE-TIMI 58 trial [AHA Nov 2018][NEJM online Nov 2018]

dapagliflozin vs placebo in 17160 type 2 diabetics

41% with established CVD, 59% at high risk

median 4.2 years follow-up

dapa placebo hazard ratio (95% CI)

no. of patients 8582 8578

CV death, MI, ischaemic stroke* 756 803 0.93 (0.84, 1.03) P=.17

CV death, heart failure hospn.* 417 496 0.83 (0.73, 0.95) P=.005

renal composite outcome 127 238 0.53 (0.43, 0.66) P<.001

heart failure hospn. 212 286 0.73 (0.61, 0.88) P<.001

CV death 245 249 0.98 (0.82, 1.17) P=.81

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DECLARE has 2 co-primary endpoints

only one was significant at P<0.0231

hence in NEJM no P-values for secondary endpoints

but we know: renal composite P<0.0001heart failure hospn. P<0.001

time for a re-think on handling secondary endpoints

hierarchical testing is a flawed methodology

correction for multiple testing a better approach

“a P value is no substitute for a brain”

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combining evidence across trials and subgroup analyses

a systematic review [Zelniker et al, Lancet online Nov 2018]

CV death, MI and stroke

pre-existing diseaseEMPA-REGCANVASDECLARE

multiple risk factorsCANVASDECLARE

effect on MACE only in pre-existing disease?note interaction P=0.07

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heart failure hospitalisation and CV death

history of heart failure hazard ratio

EMPA-REG

CANVAS

DECLARE

no history of heart failure

EMPA-REG

CANVAS

DECLARE

consistency of treatment effect

ongoing trials in heart failure patients: EMPEROR, DAPA-HF24

Effect of SGLT 2 inhibitor on mortality

hazard ratio (95% CI)

cardiovascular death

EMPA-REG 0.62 (0.49, 0.77) P<.0001

CANVAS 0.87 (0.72, 1.06) P=.16

DECLARE 0.98 (0.82, 1.17) P=.82

all-cause death

EMPA-REG 0.68 (0.57, 0.82) P<.0001

CANVAS 0.87 (0.74, 1.01) P=.08

DECLARE 0.93 (0.82, 1.04) P=.23

interaction P= 0.007 and 0.018 respectively

evidence that drug effects on mortality do differ25

REDUCE-IT trial [AHA & NEJM online Nov 2018]

icosapent ethyl (4 g per day) vs placebo in 8179 patients

eligible patients: established cardiovascular disease (71%)OR

diabetes plus other risk factors (29%)

prior statin, triglycerides 135 to 499 mg/dl and LDL-C 41 to 100 mg/dl

median follow-up 4.9 years

primary endpoint:CV death, MI, stroke, coronary revasc or stable angina

key secondary endpoint: CV death, MI or stroke 26

Background

Low dose omega-3 mixtures show no CV benefit

Meta-analysis of 10 trials with 77917 patients[Aung et al JAMA Cardiol 2018;3 p 225-]

for any major vascular event:hazard ratio 0.97 (95% CI 0.93 to 1.01) P=.10

JELIS trial [Lancet 2007;369 p 109-]

eicosapentaenoic acid (1.8 g daily) + statin vs statin alone

18645 Japanese patients with total cholesterol ≥6.5 mmol/lopen-label with blinded adjudication, mean 4.6 years follow-up

primary endpoint: any major coronary event8.7% vs 10.1%, hazard ratio 0.81 (95% CI 0.69, 095) P=0.011

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Primary Endpoint, its components and mortality

icosapent

ethyl

placebo

[N=4089] [N=4090] hazard ratio (95% CI)

primary composite 17.2% 22.0% 0.75 (0.68, 0.83) P<.001

myocardial infarction 6.1% 8.7% 0.69 (0.58, 0.81) P=.001

urgent revasc 5.3% 7.8% 0.65 (0.55, 0.78) P<.001

unstable angina 2.6% 3.8% 0.68 (0.53, 0.87) P=.002

stroke 2.4% 3.3% 0.72 (0.55, 0.93) P=.01

CV death 4.3% 5.2% 0.80 (0.66, 0.98) P=.03

all-cause death 6.7% 7.6% 0.87 (0.74, 1.02) P=.09

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Here is a positive trial in an otherwise negative field

Should we believe it? Try Bayesian methods

1) Pessimists prior: use the meta-analysis

belief that this drug is same as all the others

2) Realist’s prior: this one may be a bit different

could be worse, could be better

3) Optimist’s prior: prior evidence is irrelevant

this is a different drug, use a vague prior

new trial only slightly influences belief

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new trial is large enough to overcome caution

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Adverse Event profile of icosapent ethyl

atrial fibrillation +1.4% P=.003

peripheral edema +1.5% P=.002

serious bleeding +0.6% P=.06

constipation +1.8% P<.001

diarrhoea -2.1% P<.001

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balance against benefit:primary endpoint -4.8% P<.001

CHMP (EMA) opinion in Oct 2018:“the benefit-risk balance of omega-3 ethyl esters in secondary prevention after myocardial infarction is not favourable”.Will REDUCE-IT change that view?

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PARTNER trial [ACC and NEJM online march 2019]

1000 patients with severe aortic stenosis and low surgical risk

transcatheter aortic valve replacement (TAVR)versus

surgical aortic valve replacement (SAVR)

primary composite endpoint at 1 year:all-cause death, stroke and re-hospitalization

confined to as-treated population

analysis by intention to treat not done

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TAVR SAVR Hazard ratio (95% CI) P-value

No. randomized 503 497

Procedure not received 7 43

As treated population 496 454

Death, stroke or

rehospitalization (primary)42 (8.5%) 68 (15.1%) 0.54 (0.37-0.79) 0.001

All-cause death 5 (1.0%) 11 (2.5%) 0.41 (0.14-1.17) 0.09

Stroke 6 (1.2%) 14 (3.1%) 0.38 (0.15-1.00) 0.04

Death or stroke 9 (1.8%) 22 (4.9%) 0.36 (0.17-0.79) 0.008

Death or disabling stroke 5 (1.0%) 13 (2.9%) 0.34 (0.12-0.97) 0.03

Rehospitalization 36 (7.3%) 49 (1.0%) 0.65 (0.42-1.00) 0.046

Major bleed 38 (7.7%) 117 (25.9%) 0.25 (0.17-0.37) <0.001

Key One-Year Outcomes for PARTNER 3

Comparison of PARTNER 1, 2 and 3 trials in High,

Intermediate and Low Risk Patients

Comparison of PARTNER 1, 2 and 3 trials in High,

Intermediate and Low Risk Patients

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Interpretation of PARTNER 3

in low-risk patients, TAVR has fewer deaths, strokes and re-hospitalizations over 1 year than SAVR

also 30-day improvements in NYHA class, 6 minute walk test and quality of life

this extends use of TAVR into a low-risk population

but such patients have a good prognosis

need to consider long term strategy (including repeat procedures)

debate on relative merits of initial TAVR vs SAVR in context of long-term patient care

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AUGUSTUS trial [ACC and NEJM online March 2019]

4614 patients with atrial fibrillation and ACS and/or PCI

An open label 2 x 2 factorial trial:

apixiban vs vitamin K agonist (VKA)

AND

aspirin vs placebo

P2Y12 inhibitor for 6 monthsaspirin on actual day of ACS and/or PCI

primary outcome over 6 months:major bleed or clinically relevant non-major (CRNM) bleed

for all patients

Key Results for AUGUSTUS trial

1) Apixiban vs VKA

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Apixiban

[N=2306]

VKA

[N=2308]HR (95% CI) P-value

Major + CRNM bleed

(primary endpoint)10.5% 14.7% 0.69 (0.58-0.81) <0.0001

Major bleed 3.0% 4.6% 0.64 (0.47-0.86) 0.005

Hospitalization 22.5% 26.3% 0.83 (0.74-0.93) 0.002

Death or ischemic event* 6.2% 6.5% 0.94 (0.75-1.18) 0.592

*ischemic events are: MI, stroke, stent thrombosis, urgent revascularization

Apixiban group have significantly fewer

bleeding events and hospitalizations

No difference in deaths and ischemic events

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Aspirin group has significantly more bleeding eventsNo difference in hospitalizations, deaths and ischemic events

Interaction tests performed: all P ≥0.20ie no evidence that effect of apixiban vs VKAdepends on whether patients got aspirin or placebo

Aspirin

[N=2307]

Placebo

[N=2307]HR (95% CI) P-value

Major + CRNM bleed

(primary endpoint)16.1% 9.0% 1.90 (1.60-2.25) <0.0001

Major bleed 4.7% 2.9% 1.70 (1.25-2.32) 0.001

Hospitalization 25.4% 23.4% 1.10 (0. 98-1.24) 0.123

Death or ischemic event* 5.9% 6.8% 0.88 (0.70-1.11) 0.251

*ischemic events are: MI, stroke, stent thrombosis, urgent revascularization

2) Aspirin vs Placebo

AUGUSTUS Primary Outcome by the 4 Randomized

Treatment Groups

plus 3 other Key Outcomes by the 4 Randomized Treatment

Groups

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Should AUGUSTUS trial have stopped early?

DMC recommended continue

clear interim evidence of safety (bleeding) superiority

of apixiban over VKA and placebo over aspirin

but more evidence needed on efficacy (ischaemic events)

network meta-analysis including AUGUSTUS

For post-PCI patients with atrial fibrillation:

Non-VKA oral anticoagulant (eg apixiban) plus

P2Y12-inhibitor (eg clopidogrel ) but without aspirin is the

preferred regimen

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Methodological Challenges

Problems of treatment crossovers: alternatives to ITT

Hierarchical methods for combining fatal and non-fatal events

Repeat event analyses (not just time-to-first)

Joint frailty models for competing risk of death

Interpreting a new trial when prior trials disagree

Flaws in hierarchical testing of secondary endpoints

Potential value of Bayesian methods

Interventions for low-risk patients, in context of lifetime strategy

2 x 2 Factorial Trials and their interpretation

When not to stop a trial early