PHEBP: Clinical Trials for the Treatment of Heart Disease

Question 1

What are examples of Observational and Experimental studies?

Answer 1

Observational studies:
-Cross sectional study
-Case control study
-Cohort (longitudinal) study
Observing, not interfering with exposure

Experimental studies:
-Clinical trial/interventional study
-Randomized controlled trial
Do interfere with exposure

Question 2

What is a randomised controlled trial?

Answer 2

Intervention group -> Health outcome
Control group -> health outcome
Parallel group design (single intervention)

Question 3

What is the main strength of randomised controlled trials?

Answer 3

If the randomized controlled trial has been
well-conducted, a difference in outcome
between intervention and control groups
will reflect either:
-a causal relationship OR chance/random error
BUT NOT due to bias or confounding

Question 4

What kind of interventions can be tested in experimental studies?

Answer 4

Eg. drugs
A wide range!
* Medical treatment
* Surgical treatment
* Public health interventions (e.g. healthy lifestyle
interventions)
* More difficult
– Long-term interventions (loss to follow-up,
expensive, participant burden)
– Interventions to change ‘lifestyle behaviours’

Question 5

How do you evaluate medical intervention?

Answer 5

• You give a medical intervention to an ill
  patient – what is likely to happen?
  patient is likely to improve - strong placebo effect because people believe they are being adequately treated, the warm, comforting environment, food etc.

Question 6

Why do patients tend to get better?

Answer 6

• Natural tendency to recover, biological healing and
  repair (especially with good nursing care)
• The placebo effect – when people believe that they
  are receiving a treatment (even if actually neutral)
  their recovery is improved
• Effect of treatment

Question 7

Why do we need a control group?

Answer 7

• Need for a CONTROL group –
• Because some patients will get better by
  themselves; need for comparison group
• Need for a PLACEBO CONTROL group
• To take account of ‘placebo effect’ the benefit
  obtained from receiving apparently helpful
  treatment (even if treatment has neutral effect)
• the placebo needs to be appropriate (e.g.
  medical or surgical like the treatment)

Question 8

What is a control group in practice?

Answer 8

• CONTROL groups –
  – Sometimes receiving no active treatment (placebo
  only)
  – Sometimes receiving USUAL CARE (i.e. existing
  pattern of treatment, but without the new
  intervention)

Question 9

What is Transcatheter Mitral-valve repair in
patients with heart failure: RCT?

Answer 9

High-risk patients: heart failure and severe secondary mitral regurgitation (poor prognosis)

Random allocation:

Intervention group:
Transcatheter mitral valve repair + medical therapy
Control group:
Medical Therapy alone (usual care)

Question 10

How do you allocate patients to interventions and control groups?

Answer 10

Intervention group -> Health outcome
Control (placebo) -> Health outcome

Question 11

What is the importance of randomisation?

Answer 11

Allocation to INTERVENTION and CONTROL groups needs to be RANDOM
i.e. every participant has an equal chance of
being in each group

Question 12

How is randomisation done?

Answer 12

• Toss of (balanced) coin
• Random number tables
• Computer generated codes
• External Randomisation service (CTU)
  NOT allocating systematically or by day of week
  admitted etc

Question 13

Why is random allocation important?

Answer 13

• best way of ensuring that the characteristics of patients in the INTERVENTION and CONTROL groups are similar – aiming for balanced baseline differences (such as age, sex, disease severity, disease duration)
• It avoids BIAS – specifically allocation bias
• Any differences in health outcomes at the end of trial are due to the intervention and not differences in characteristics in the intervention and control groups

One group will be given placebos, the other will be given new treatments.

Question 14

What is blinding?

Answer 14

• Keep `key people’ blinded (kept unaware of which treatment arms participants have been assigned to) to randomization code
• Can apply to:-
• The patient
• The outcome assessor
• The statistician/analyst
  Patient OR outcome assessor blind = single blind
  Patient AND outcome assessor blind = double blind
  Only once the analysis is complete are they unblinded.

Question 15

What is the importance of blinding?

Answer 15

• Blinding of observers/assessors avoids:
• Selection bias (who to invite/recruit to trial)
• Assessor bias (how outcome is recorded)
• Keeps assessors objective (decisions to
  withdraw patients/amount of encouragement)
• Blinding of participants avoids:
• Selection bias (whether to participate in trial)
• Response bias (systematic differences in how
  outcomes reported by participants)
• Can affect compliance and completion of
  participants

Question 16

Which trial outcome do you use?

Answer 16

• Could be:-
  – Symptom
  – Clinical sign
  – Biochemical test
  – Development of clinical disease
  – Death
• Should be an important one (for both patient and doctor)
• Ideally objectively measured
• Can have several outcomes, but must specify primary and secondary outcomes in advance

Trial is changed based on the results of the primary outcome. Patients have a huge role so they have a say in what care they are given to ensure it is important to both the patient and the doctor.

Question 17

What is the outcome of the blinding assessment?

Answer 17

Intervention group -> Health outcome
Control group -> Health outcome
Need to be sure that assessment of outcome will be
exactly the same in intervention and control!

Question 18

What are the randomised controlled trial designs?

Answer 18

• 3 basic designs available –
  – Parallel group design
  – Crossover trial design
  – Factorial design (2 or more interventions)

Question 19

What are cross over design trials?

Answer 19

You have the required population with eligibility criteria.
You get the sample from that
Take baseline measurements
Randomise
Administer therapy or control
Assess response
Wash out period
Switch

Question 20

What are the advantages and disadvantages of a cross over trial design?

Answer 20

• Advantage:
  Need considerably fewer
  participants (as they act as their own controls
  and within-individual comparisons are made,
  rather than between-individual comparisons)
• However;
  –cannot be used to assess treatments with prolonged
  effects (which may carry over into the second period)
  –Disease may not remain stable over trial period
  –More burden on participants, longer trial period, could result in more drop-outs

Question 21

What are the blind trial designs?

Answer 21

• Are usually applied to trials involving individual
  patients
• Could also use them to randomise groups containing
  many individuals (cluster randomized trials)
  – e.g. General Practices
  – e.g. Primary Care Trust
  – e.g. Primary Schools
  To examine impact of community intervention

Question 22

What are the blind trial analysis?

Answer 22

AREVA: Multicenter randomized
comparison of low-dose vs. standard
dose anticoagulation in patients with
mechanical prosthetic heart values

There were lots of different hospitals involved in this example.

Question 23

What are the AREVA intervention studies?

Answer 23

Who is eligible to take part in trial must be
clearly defined & is more detailed than that given above.

Patients with mechanical heart valve (aorta / mitral) aged 20-75yrs

Standard level of anti-coagulation -> Number with event
Lower level of anti-coagulation -> Number with event

Question 24

How do you analyse a trial?

Answer 24

• Step 1 - to compare the characteristics of
  intervention and control groups at entry to the
  trial
• What are the important characteristics you
  would want to check for similarities?

This is looking to see how well the randomisation worked - need to see if there are similar values throughout - need to test for statistical difference. Look at key characteristics and disease severity.

Question 25

What should the intention to treat be through a trial analysis?

Answer 25

• Should we only analyze data from the participants who completed the intervention?
• Not all patients in a study will do exactly what are
  supposed to!
• Some control patients will end up being on
  treatment (often most severely ill)
• Some intervention patients will end up coming
  off active treatment (often most severely ill)
  If we analyse on basis of what actually received
  (on treatment’ or per protocol’ analysis) could
  provide biased estimate of treatment effect
• Analysis on the basis of original randomization
  (ignores drop outs/crossovers), so preserves the
  randomisation at baseline (important for avoiding
  bias)
• likely to underestimate effect of intervention
  (depending on how much lack of adherence took
  place)
• BUT – provides an UNBIASED estimate of
  intervention effect - gives an indication of
  treatment policy rather than specific effect (more
  relevant for prevention)
• Should be main analysis presented

It is likely to underestimate the effects, but it will be unbias.

Question 26

What is the importance of participant adherence and types of analysis?

Answer 26

Primary Outcome: Prevalence of Allergy to One or More Foods:

IIT- 20% Non-significant reduction in prevalence in EIG
PP- 67% significant reduction in prevalence in EIG

Question 27

What is per protocol analysis?

Answer 27

• Per protocol analysis
• Carries out the analysis on the basis of the
  treatment actually taken
• Less likely to underestimate effect of intervention
• BUT may be BIASED (exactly how depends on
  number and characteristics of drop-outs)
• Should generally be a subsidiary analysis
  Only analyse patients that had adhered to the protocol as necessary.

Question 28

What is a hemorrhagic event in an AREVA trial?

Answer 28

Intention-to-treat analysis
Eg.
Risk of event in low dose: 34 / 188 = 18.1%
Risk of event in high dose: 56 / 192 = 29.2%
Risk Ratio (relative risk): 18.1 / 29.2 = 0.62

The risk of a haemorrhagic event in the low dose group is 38% lower than the risk in the standard dose group.

(Absolute) Risk difference: 18.1 – 29.2 = -11.1%

Low dose reduces haemorrhagic event by 11.1% compared to standard dose

Risk of event in standard dose = 29.2%
Risk of event in low dose = 18.1%
(Absolute) Risk difference = 11.1%

Low dose reduces haemorrhagic event by 11.1% compared to standard dose. If 100 people were given low dose rather than high dose there would be 11.1 fewer haemorrhagic events

Question 29

How do you determine the Number Needed to Treat (NNT)?

Answer 29

How many patients do you need to treat to
prevent one additional outcome?
NNT = 1 / Absolute Risk Difference

NNT is the inverse of the Absolute Risk Difference;
So if 9 people were given low dose rather than high dose there would be 1 fewer haemorrhagic event

Question 30

How do you interpret a trial?

Answer 30

• Are there any limitations in trial design (esp randomisation, controlling, blinding, outcome assessment, analysis) which offer alternative explanations for any difference observed?
  (i.e, was bias [systematic error] present?)
• Are the results consistent with those of other trials?
• How generalisable are results:-
  – To all participants with the same age, gender, disease characteristics as those recruited? (recruitment rate)
  – To other, different individuals (judgement)