Controlled studies and registries

Christian Torp-PedersenAalborg University

James Lind 1747• He divided twelve scorbutic sailors into six groups of

two. They all received the same diet but, in addition, group one was given a quart of cider daily, group two twenty-five drops of elixir of vitriol (sulfuric acid), group three six spoonfuls of vinegar, group four half a pint of seawater, group five received two oranges and one lemon, and the last group a spicy paste plus a drink of barley water. The treatment of group five stopped after six days when they ran out of fruit, but by that time one sailor was fit for duty while the other had almost recovered. Apart from that, only group one also showed some effect of its treatment.

First modern trial 1948After acceptance of a patient by the panel, and before admission to the streptomycincentre, the appropriate numbered envelope was opened at the central office the card inside told if the patient was to be an S or a C case, and this information was then givento the medical officer of the centre. Patients were not told before admission that they were to get special treatment. C patients did not know throughout their stay in hospital that they were control patients in a special study; they were in fact treated as they would have been in the past,the sole difference being that they had been admitted to the centre more rapidly than was normal.

Br Med J. 1948 Oct 30; 2(4582): 769–782.

Controlled - RandomizedControlled – Everything defined in advance,

protocol available before trial closure- Well defined particiants- Well defined procedures- Clearly defined intervention- Prespecified single (or few) endpoints

Randomized

• Control of confounding• The only way to avoid unknown confounders• Randomisation is only truly effective if the

trial is also blinded

Blinding

• The patient should be unaware of treatment allocation

• The treating physician should be unaware• An independent safety committee MUST be

aware

Ethics

• Overall ethics a clinically important problem No treatment known to be superiorInformation to patients

• Formal ethicsCommittee approvalSigned informed consent

Randomization

• = random allocation of participants to a treatment arm, – like tossing a coin– usually using a computerized random number

generator• Each participant has a known chance (e.g. 50%)

of being allocated to a treatment group.– Equal group size maximizes statistical power

• Neither the investigator nor the participant can influence or predict the allocation.

Methods of Randomization

• Simple randomization may result in relevant imbalances in small studies – with regard to baseline characteristics– number of participants assigned to a treatment

• Specific methods of randomization:– block randomization: ensures that there is an equal

distribution within a block of patients– stratified randomization: ensures equal distribution

in relevant patient subgroups

Block Randomization

• Blocks are randomly allocated and a block size of e.g. 4 may consist of one of the following balanced treatment allocations:1) AABB2) ABAB3) ABBA4) BAAB5) BBAA6) BABA

Stratified Randomization

• Randomization occurs separately in relevant strata e.g. age < 75 and >= 75

• Stratified randomization prevents imbalances in relevant subgroups

• Block randomization is possible in strata.

Example of Stratified and Block Randomization

“Eligible patients were randomly assigned in a 1:1 ratio, with the use of an interactive Web-response system, to undergo PCI with the use of everolimus eluting stents or to undergo CABG. Randomization was computer-generated and was performed in random block sizes of 6 and 8, with stratification according to the participating center.”

Seung-Jung Park et al. for the BEST Trial investigators, N Engl J Med 2015

Blinding• means masking the identity of the treatment• Different ways of blinding

– Single-blinded: usually only the patient is blinded • e.g. for a surgical intervention

– Double-blinded: Neither the investigator nor the participant are aware of the allocated treatment

• e.g. for a pharmacotherapy

– Triple-blinded: additionally the endpoint evaluation committee is blinded with regard to the treatment assignment

How to Blind

• Use of a placebo– can be a dummy remedy e.g. pill with same size and colour– double-dummy: In case of comparison of two

interventions with different aspects each patient receives a true intervention and an indistinguishable dummy for the other treatment

– sham operation (anesthesia and incision)

Simplicity HTN-3 - Rationale•Prior unblinded studies have suggested that catheter-based renal-artery denervation reduces blood pressure in patients with resistant hypertension•We designed a prospective, single-blind (patient), randomized, sham-controlled trial. Patients with severe resistant hypertension were randomly assigned in a 2:1 ratio to undergo renal denervation or a sham procedure. Before randomization, patients were receiving a stable antihypertensive regimen involving maximally tolerated doses of at least three drugs, including a diuretic. The primary efficacy end point was the change in office systolic blood pressure at 6 months; a secondary efficacy end point was the change in mean 24-hour ambulatory systolic blood pressure.

Bhatt DL et al. for the SYMPLICITY HTN-3 Investigators, New Engl J Med 2014

Simplicity HTN-3 - Results

Bhatt DL et al. for the SYMPLICITY HTN-3 Investigators, New Engl J Med 2014

Office blood pressure Ambulatory 24h blood pressure

What Can we Learn from the Simplicity HTN-3 Trial?

• A sham procedure, if ethically acceptable, is essential to distinguish between placebo effect and the effect of a surgical intervention.

• Blinding is essential when assessing the effect of an intervention on blood pressure.

• Enrolment of highly selected patients e.g. with resistant hypertension is challenging and results in high screening failure as discussed in the morning.

PROBE DesignBlinding Only the Outcome Assessment

• PROBE = Prospective, randomised, open-label, blinded-endpoint evaluation

• The PROBE design is used when (double-)blinding is very difficult or too complex e.g.– laboratory-guided treatment– characteristic side effects– device study

• A very/too complex study procedure may increase the likelihood of – selecting particularly compliant patients and – study discontinuation of participants

PROBE Design for RE-LY® Study – The Rationale for the Use in an Anticoagulation TRIAL

• The laboratory-guided treatment of vitamin K antagonists including sham INR-measurements requires a very complex blinding.

• A blinded study design may have led to frequent and uncontrolled unblinding when measuring global coagulation tests.

• To minimize a potential investigator bias in the assessment of events several safeguards have been included in the protocol of the RE-LY ® study:– outcomes were objective, clearly defined and clinically relevant– outcome events were adjudicated by blinded adjudication

committee– dose of dabigatran was blinded.

Connolly SJ et al. N Engl J Med 2009;361:1139–51; Supplement

PROBE Design vs. Double-Dummy Design

Advantages• More economic• Less complex and

therefore– more similar to clinical

routine– lower drop-out rate

Disadvantages• Differential probability of

reporting events (reporting bias)

• A blinded endpoint committee can only evaluate endpoints which have been reported.

Parallel Group vs. Crossover

A

B

A

B

wash-out period

Crossover Design

Advantages• Smaller sample size as

no between-subject variability

Disadvantages• Not for acute treatment• Only for temporary

treatment• Is wash-out period

reliable?• Patient completely lost

if drop-out occurs before second treatment period

Factorial Design

• Allows testing more than one hypothesis in one study increases efficiency of research

• Usually a two-by-two factorial design

Treatment A 0 0 1 1Treatment B 1 0 1 0

Factorial Design – An example

INFUSE-AMI study, Gibson CM et al. Am Heart J 2011;161:478-486.e7

Analysis of variance models were performed to exclude significant interactions between the 2 levels of randomization.

Factorial Design

Advantages• smaller sample size

than two separate trials• can assess interaction =

modification of the effect of one treatment by the other treatment

Disadvantages• added complexity• the chance of adverse

effects increases with 2 drugs

Study Reporting

• Standards for reporting of trials– Consolidated Standards of Reporting Trials

(CONSORT) statement for interventional trials– STROBE statement observational trials

• Gives the gold standard how to report (and therefore already design) your clinical study

Checklist CONSORT Statement

* Schulz KF, Altman DG, Moher D. CONSORT 2010 statement: updated guidelines for reporting parallel group randomized trials. Ann Intern Med 2010;152:726-32

Checklist CONSORT Statement

* Schulz KF, Altman DG, Moher D. CONSORT 2010 statement: updated guidelines for reporting parallel group randomized trials. Ann Intern Med 2010;152:726-32

Advantages of an RCT

• Randomization– avoids selection bias – controls for known and unknown confounders

• Double blinding avoids – reporting bias– observation bias

• Analysis of RCTs– give strong evidence of causal relationship– multiple outcomes can be examined

BMJ 2003

What is STROBE

STrengthening the Reporting of OBservational studies in Epidemiology.

http://www.strobe-statement.org/index.php?id=available-checklists

• STROBE checklists • Version 4 as published in Oct / Nov 2007! • STROBE checklist for cohort, case-control, and cross-sectional studies

(combined) download PDF / Word

• STROBE checklist for cohort, case-control, and cross-sectional studies (combined) PLOS Medicine requirements download PDF / Word

• Checklist for cohort studies download PDF / Word

• Checklist for case-control studies download PDF / Word

• Checklist for cross-sectional studies download PDF / Word

• Draft STROBE checklist for conference abstractsdownload PDF

Weakness of epidemiology

• Prospective is rarely real – few databases are visited for the first time

• In epidemiology you only know what you are doing when you have done it

To deal with weaknesses – analyses of sensitivity

• Shake all definitions• Analyse with several techniques• Define important subgroups• Confirm in other databases

Fig 1 Flow chart of study population.

Olesen J B et al. BMJ 2011;342:bmj.d124

Fig 3 Kaplan-Meier estimate of probability of remaining free of thromboembolism with CHA2DS2-VASc score 0 and 1.

Olesen J B et al. BMJ 2011;342:bmj.d124

CHA2DS2-VAScThromboembilism pr. 100 years – 1 year of observation

0 1

2

When do problems occur

Bleeding after AF discharge

Hansen, Arch Int Med, 2010

Treatment exposure and bleeding risk

Treatment

No. of events

Treatment duration

years

Incidencerate

% / years

Numbers needed to

harm (NNH) per years

Warfarin 3 642 93 492 3.9 Reference

Aspirin 2 694 72 146 3.7 -500

Clopidogrel 105 1 865 5.6 59

Clopidogrel+aspirin 94 1 264 7.4 28

Warfarin+aspirin 1 209 17 712 6.9 34

Warfarin+clopidogrel 69 496 13.9 10

Warfarin+aspirin+clopidogrel 64 408 15.7 8

Hansen, Arch Int Med, 2010

Combinations of treatments

Lamberts, JACC, 2013

Lamberts, JACC, 2013

AMI and PCI in 12000 patients – with AF

9000 patients with stable coronary artery disease and AFMyocardial infarction+coronary death

Lamberts, Circulation 2014

Bleeding

Lamberts, Circulation 2014

Lamberts, Circulation 2014

All cause death

Special populations

renal disease

Olesen, NEJM 2012

Shah, Circulation 2014

Discontinuation of medication

Raunsø, EHJ, 2011

Discontinuation of warfarin in AF

Raunsø, EHJ, 2011

Lessons• The randomised trial is the best way to clarify effect of new

treatments• All aspects of a trial must be regorously adhered to• Randomised trials will never be available for all questions• Observational studies are often much larger than controlled studies• There is always a much increased risk of confounding• They can test situations not explored in trials• They can test situation trials will never explore• Observational register studies are in their essence large scale

”experience” • Observational studies are much more common than controlled

studies and heavily influence guidlines and policy