defining response & reducing harms from clinical therapies ... · defining response &...

Defining response & reducing

harms from clinical therapies:

Lessons from CRT

Dr David Warriner BSc MRCP DipSEM

Cardiology Registrar, UK

@DrDavidWarriner

#PODC2016

Conflicts of interest

I refuse all meals, gifts or payments from

any industry representative.

For my full disclosure see:

http://www.whopaysthisdoctor.org

UK Drs - please consider signing up too!

@DrDavidWarriner

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http://www.whopaysthisdoctor.org

Who am I?

Cardiology Registrar in Sheffield, South Yorkshire, UK

PhD: “The HF syndrome & predicting response to CRT”

Passionate about preventing overdiagnosis

Empowering patients, championing common sense

Not bowing to those with vested interests

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Why am I here?

Attended PODC 2014, 2015 and 2016 (?2017)

Cardiologists were noticeable in their absence (n = 2)

But, cardiologists MUST be part of the solution

Based AoMRC for 12/12 on #choosingwisely in UK

Written, blogged & tweeted – too much medicine

Original member of Overdiagnosis UK group

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@DrDavidWarriner

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Preventing Overdiagnosis

Cardiology

Heart Failure

CRT

Response

Vested interests Overtreatment Harm Guidelines Industry Decision making

Objectives

@DrDavidWarriner

#PODC2016

Learn little about heart failure and CRT

Consider problem of defining CRT response

Apply the concepts of Preventing Overdiagnosis to CRT

Cardiology

Cardiac devices e.g. pacemakers & defibrillators

Devices market worth £9 billion (€13 billion) globally in 2015

1 million devices implanted yearly (2011) & increasing

In 2014, CRT-P £8k (€9.5k) and CRT-D £18k (€22k)

R&D is important, as are devices and manufacturers

BUT - wary of influence of industry & opinion leaders

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What is Heart Failure (HF)?

American College of Cardiology:

“HF is a complex clinical syndrome

that results from any structural or

functional impairment of ventricular

filling or ejection of blood”.

Yancy et al (2013)

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The problem of HF

Prevalence - 1-2% Europe* (>10% if >70 years)

Aetiology - 62% coronary artery disease

Physiology - 50% LV systolic dysfunction (LVSD)

Symptoms - Fatigue, breathlessness & swelling

Treatment - Diuretics, β-blockers, ACE-I & MRA

*Slides prepared pre-Brexit – 1% of UK population

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The problem of HF

Most common cause of hospitalisation > 65 years

6 month re-admission rate is 50%

Average length of inpatient stay is 2 weeks

2% of the annual NHS budget (£2 billion/€2.5 billion)

Average 5 year survival is only 50%

In short, HF is common, costly and deadly

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Cardiac Anatomy

LV

RV

RA LA

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TV MV

Severe LV Systolic Dysfunction

LV

RV

RA LA

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Conduction System

1 - SA node

2 - Bachmann’s Bundle

3 - AV node

4 - His bundle

5 – Purkinje fibres

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Dyssynchrony

Atrio-ventricular, inter-ventricular & intra-ventricular

ECG – measure conduction delay e.g. PRd, QRSd

Common in LVSD-heart failure, ≥ 30% of patients

Due to ischaemia, scar and adverse dilation

Impairs cardiac filling and cardiac function

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Conduction delay

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Cardiac Resynchronisation

Therapy (CRT)

First introduced in early 1990’s

Patients with refractory heart failure

Already taking optimal medical therapy

RV apical pacing alone led to LVSD

Heart transplants are a scarce resource

Where next for these breathless patients?

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CRT

A pacemaker with 3 leads - RA, RV and LV

Electrically ‘rewires’ a dysynchronous heart

Improves symptoms, morbidity and mortality

Patients must fulfill specific pre-implantation criteria

Efficacy proven in many trials & NICE/AHA/ESC approved

CRT-P = pacemaker only vs CRT-D = defibrillator function

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CRT implantation

The procedure takes between 1 – 3 hours

Aseptic technique under LA and sedation

Incision in left pectoral region and subcutaneous pocket made

Venous access gained to cephalic, axillary or subclavian vein

Leads then passed to RA, RV and LV (via CS)

Screwed into generator and skin sutured close

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CRT-D

RA

RV

LV

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Indications

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* With LBBB ~ Class IV patients must be ambulatory

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Trials

Response

~70% of patients “respond” to CRT

Definition of response is very variable

Therefore, how can you tell if a patient has got better?

Must define response, in order to predict it

Subjective e.g. functional class or quality of life

Objective e.g. imaging, biomarker or exercise capacity

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Preventing overdiagnosis

Majority of trials industry funded

Majority of trials positive

Majority of trials exclude significant comorbidity

No universal consensus on “response”

Response is not just a one-off biomarker

1/3 patients risk of harm w/o likelihood of benefit

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*Pause*

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#PODC2016

EXPERTS HOLD SUMMIT

NEWS FLASH! NEW “LIVE SAVING” CRT DEVICE

IN SMALL GROUPS YOU’LL BE GIVEN A SERIES

OF TASKS TO WORK ON OVER NEXT 60 MIN.

DICUSSING HOW TO MEASURE

RESPONSE FROM SUCH A HEART FAILURE

DEVICE

Preventing Overdiagnosis does...

….. defining response.

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Task No. 1

How would you define

response to a

treatment and why?

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Defining response

Halting disease progression and sequelae

Reducing admissions & mortality is important

But patients also want to feel better

Doctors also want patients to feel better

If the patient feels no better – why was this implanted?

Is response even the right word….

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Possible measures of response?

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Scientific Real World

Surrogate Symptoms

Task No. 2

Which would be the

best measure of

response and why?

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Rank these in order (1-4)

Real World e.g. 6WMD

Exercise -

Scientific e.g. CPET

Surrogate e.g. LV volumes or EF%

Symptoms e.g. NYHA, MLWHFQ

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Defining response

In research, usually a combination of measures

In clinic, usually only symptom based

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Response isn’t Black and

Super-responders Responders Non-responders ???

Much better Better No better Worse

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A combination e.g. research

Which combination?

How many?

How measured?

By whom?

What if mixed results?

What is the key measure?

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Combination. Sure?

Bleeker et al (2006) 70% of CRT

responders improved by at least one

NYHA functional class but only 56% of

patients had >15% reduction in LVEDV

and 51% met both criteria

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Symptoms alone e.g. clinic

Single clinic visit post implant

Usually assessed by the implanting physician

If feel better – discharged back to referrer

If not – look at reasons why

May look at device optimisation

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Symptoms alone. Sure?

MIRACLE-ICD Trial (CRTD vs ICD)

62% vs 46% improved ≥ 1 NYHA class

CONTAK CD TRIAL (CRT on vs CRT off)


MIRACLE Trial (CRT vs OMT)


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Threshold of response

Low e.g. 1% improvement

Clinically Meaningless

Most will be responders

Scientifically unsound

High e.g. 99% improvement

Clinically Implausible

Few will be responders

Scientifically unsound

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Task No. 3

What threshold of improvement should

define response and why?

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0% 100%

Definitions of response in CRT

Subjective

Symptoms – 1 point in NYHA functional class

Quality of Life – 10% in MLWHFQ score

Objective

Imaging – 10-15% in LV volumes

Exercise - 1.0 ml/kg/min in peak VO2 or 10% in 6MWD

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@DrDavidWarriner

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Quality of Life Examples

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Peak VO2 Examples

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6MWD Examples

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LV volume Examples

Timing of response

Early – low dropout, acute response, delayed effect?

Late – higher dropout, all responders, confounders

Single – definitive, simpler stats, binary, chance

Multiple – progressive, ecological validity, richer data

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Task No. 4

What time interval(s) should be used to

measure response and why?

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Baseline Hours Days Weeks Months Years

Timing interval

Complex.

Arguably, a higher frequency of sampling

over a longer time period, more likely to

equate to “response means response”

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Timing interval Hauptman et al (2004): Variation in clinical HF status

116 patients with NYHA 3-4 class LVSD-HF over 6 weeks

30% better, 53% unchanged, 17% worse (statistically significant)

Better – 148m in 6MWD & 17 point in KCCQ

Worse - 107m in 6MWD & 7 point in KCCQ

Random variation – 30% patients improve w/o intervention

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The problem of syndromes

ACC: “HF is a complex clinical syndrome”

Yancy et al (2013)

It is not a single disease, like hypertension for

example, measuring BP, prescribing a single

drug and then remeasuring BP

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AHA Guidelines 2009

Cardiac factors influencing

symptoms, including “ventricular

distensibility, valvular regurgitation,

pericardial restraint, conduction

disturbance, cardiac rhythm and right

ventricular function.”

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AHA guidelines 2009 cont.

Non-cardiac factors influencing

symptoms such as “abnormal

peripheral vascular function, skeletal

muscle physiology, pulmonary dynamics,

neurohormonal and reflex autonomic

activity, and renal sodium handling.”

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Task No. 5

Is measuring response be a

challenge and why?

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Yes.

Brand new, innovative, expensive device

To improve LV systolic function

BUT

LVSD-HF isn’t a simple, single organ disease

It’s a complex, multi-organ syndrome

Therefore, not just LV systolic function that determines symptoms

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Comorbidity in HF is common

“Over 40% of patients will have 5 or more

comorbidities accounting for 80% of total inpatient

episodes” Braunstein et al (2003)

AF (30%)

Chronic kidney disease (50%)

Chronic lung disease (20%)

OSA/CSA (10/30%)

Sarcopenia (10%)

Anaemia (20%)

Chronic liver disease (50%) Diabetes (20%)

Endothelial dysfunction (30%) Cerebrovascular disease (9%)

Thyroid disease (14%)

Osteoporosis (5%)

Major Trials

RAFT – “major coexisting illness were

excluded” (Medtronic)

MADIT – “pre-existing cerebral disease, liver or renal

failure” were excluded (Boston)

COMPANION – no comment and major co-morbidity not

listed (Guidant)

CARE-HF – < 6/52 MI, AF or needing PPM/ICD and major

comorbidity not listed (Medtronic)

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Major Infection – 2%

Pneumothorax – 1%

Haemotoma – 3%

Death – 1%

Lead displacement – 6%

Failure – 8%

CS dissection/perforation 1%

Complications from CRT are

not uncommon

Phrenic nerve stimulation

Pericarditis

Vascular injury

Minor

Box change (1-4 yrs)

Shocks (inappopriate/not)

Lead/Device failure

Upper limb DVT

Objectives

Learn little about heart failure and CRT

Consider problem of defining CRT response

Apply the concepts of Preventing Overdiagnosis to CRT

@DrDavidWarriner

#PODC2016

Balance of probabilities

@DrDavidWarriner

#PODC2016

70% Response

90% Caucasian

75% Male

No comorbidity

30% Non-response

10% Complications

40% ≥ 5 Co-morbidities

Ethnic minority

Female

Summary

Defining response to treatments is problematic

We want our patients to feel better, as do they

Not just improve abstract imaging or biomarkers

Need a open conversation on what we define as better

Otherwise comparing and applying data is meaningless

Response = significant, sustained, multifactorial, specific

@DrDavidWarriner

#PODC2016

Conclusions

1/3 of patients don’t derive benefit from CRT

This is overtreatment

But…

Because we are unable agree on “response”

Therefore we are unable to predict “response”

Unable to identify a priori and prevent possible harm

@DrDavidWarriner

#PODC2016

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