Clinical Writing for Interventional Cardiologists

What you will learn• Introduction• General principles for clinical writing• Specific techniques• Practical session: critical review of a published article• Writing the Title and the Abstract• Bibliographic search and writing the Introduction• Principles of statistics and writing the Methods• Practical session: writing the Abstract• Writing the Results• Writing the Discussion• Writing Tables and preparing Figures• Principles of peer-review• Principles of grant writing/regulatory submission• Clinical writing at a glance• Conclusions and take home messages

Materials and methods

How was the problem studied?

The answer is in the Methods

Materials and methods

The Methods section is often the less read section, but it is the most important because allow us to understand how the study was conducted, thus giving us an idea of the value of its results

Expanded IMRAD algorithmIntroduction Background

Limitations of current evidenceStudy hypothesis

Methods DesignPatientsProceduresFollow-upEnd-pointsAdditional analysesStatistical analysis

Results Baseline and procedural dataEarly outcomesMid-to-long term outcomesAdditional analyses

Discussion Summary of study findingsCurrent research contextImplications of the present studyAvenues for further researchLimitations of the present studyConclusions

• Describe with full details what was done to answer the research question

• In the beginning include a clear statement of study design:“The study was a double-blind, randomized, parallel design … designed to compare the efficacy and safety of …”

• Include also a sentence about IRB approval, informed consent, or compliance with animal welfare regulations:“The protocol was approved by the institutional review board, and all patients gave informed consent …”

Materials and methods

Materials and methods

RRISC JACC 2006

• State the protocol/procedures. Repeat the question and the aims:“We tested the efficacy of drug XX administered orally in a dose of XX mg, given XX times daily for up to XX months.”“There were 2 primary endpoints. The first was event-free survival at XX days, with an event defined as…”

• Describe materials/methods or subjects adequately

• Write in a logical order (usually chronological) • Describe analytical methods

Materials and methods

• Use subheadings (design, patients, procedures, follow-up, endpoints….)

• Do not include results in Methods

• Include appropriate figures and tables if useful to graphically explain concepts

• Write in past tense

• Use active voice whenever possible

• Cite references for published methods

• Describe new methods fully

Materials and methods

• Briefly address questions you can anticipate from the reader, e.g. justify/clarify the design of your study:

“Intra-luminal recanalization of long coronary artery

occlusions cannot be obtained in all patients. …. We

thus tested the feasibility and safety of subintimal

angioplasty in patients in whom standard intra-luminal

approaches had failed and who were not candidate to

bypass surgery because of severe comorbidities…”

Materials and methods

If you prevent major limitations in your study, treat them in a matter-of-fact way:

"This study was performed as part of a routine clinical assessment, so that no attempt was made to ensure either fasting of the patient or performance of the test at a particular time of day."

Materials and methods

What you will learn

• Principles of statistics and writing the Methods

– study designs– intention-to-treat vs per-protocol analysis– type I and type II errors– p values and confidence intervals

• State clearly the design of the study

• Was it retrospective or prospective?

• Was it a registry or controlled study?

• Did you randomly allocated patients?

• Did you follow a protocol (may add figure)?

You can also include here details of IRB approval

Design subsection

Prospective non-RCT study

RESOLUTE EuroIntervention 2007

Prospective non-RCT study

Cavallini et al. EHJ 2005

Retrospective non-RCT study

Biondi-Zoccai et al. EHJ 2006

Prospective RCT study

Tapas NEJM 2008

TAPAS 1 year Lancet 2008

Prospective RCT study • State clearly:

• If the trial was double-blind / single-blind / open-label

• If blinded, how blinding was granted

• how randomization was performed

ENDEAVOR II Circulation 2006

Prospective RCT study

RRISC JACC 2006

Patient subsection

• State clearly how you selected patients

• Specific inclusion criteria?

• Specific exclusion criteria?

You can include here details of written informed

consent Tapas NEJM 2008

Patient subsection

• State clearly how you performed the procedure

• Any novel approaches or devices?

• Complete with details on concomitant or post-intervention medications

• If evaluating bio-markers, state clearly which ones, which essay is used and how it works

You can include here pictures detailing what you did/use

Procedure subsection

TAPAS NEJM 2008

Procedure subsection

Lefevre et al. CCI 2000

Procedure subsection

Lefevre et al. CCI 2000

Procedure subsection

• State clearly outcomes and who adjudicated them (independent CEC?)

• Define each outcome thoroughly (death, MI, RR, TVF, TVR, TLR, ST, bleedings…)

• Define the timing of follow-up and specify info on follow-up means (how patients were contacted?)

• Make sure you use validated or consensus definitions / classifications (if available, otherwise you are in trouble!)

Outcome subsection

Outcome subsection

ENDEAVOR II

Circulation 2006

Outcome subsection

Spaulding et al.

NEJM 2007

• Focus on additional analyses that may be pertinent to the study– QCA: late loss, binary restenosis…

– TIMI score, Myocardial Blush Grade

– IVUS: neointimal hyperplasia volume, minimal lumen area…

– CT: coronary stenosis > 50%...

– MRI: myocardial infarction mass…

– Echocardiography: LV ejection fraction…

• Quote thoroughly for established methods

• Define explicitly terms and ways to compute secondary variables

Additional analysis subsection

Additional analysis subsection

TAPAS NEJM 2008

What you will learn

• Principles of statistics and writing the Methods

– study designs– intention-to-treat vs per-protocol analysis– type I and type II errors– p values and confidence intervals

• Explain how you handled and reported categorical and continuous variables

• Explain how you tested for significance at both univariate and multivariate analysis

• Define tails and threshold p value

• State width of confidence intervals

• Provide sample size computation

• Spell out which software package was used

Quote extensively and be ready to defend

yourself if you use sophisticated analytic tools

Statistics subsection

Variables

nominal ordinal discrete continuous

orderedcategories

ranks counting measuring

Death: yes/noTLR: yes/no

TIMIflow

BMIBlood pressure

QCA data (MLD, late loss)

Stent diameterStent length

Types of variables

Radial/brachial/femoral

QUANTITYCATEGORY

• Categorical variables are probably the most

important ones provided by a clinical study, as

hard clinical end-points are always expressed so

• Specifically, focus on:

• Choose few statistics, and use them consistently• Provide confidence intervals (usually 95%)• May also provide number needed to treat/harm

Categorical variables

a b

c d

TVFNo TVF

Endeavor

Driver

Absolute Risk = [ d / ( c + d ) ]

Absolute Risk Reduction = [ d / ( c + d ) ] - [ b / ( a + b ) ]

Relative Risk = [ d / ( c + d ) ] / [ a / ( a + b ) ]

Relative Risk Reduction = 1 - RR

Odds Ratio = (d/c)/(b/a) = ( a * d ) / ( b * c )

Compare event rates

Absolute Risk (AR) 7.9% (47/592) & 15.1% (89/591)

Absolute Risk Reduction (ARR) 7.9% (47/592) – 15.1% (89/591) = -7.2%

Relative Risk (RR)7.9% (47/592) / 15.1% (89/591) = 0.52(given an equivalence value of 1)

Relative Risk Reduction (RRR)1 – 0.52 = 0.48 or 48%

Odds Ratio (OR) 8.6% (47/545) / 17.7% (89/502) = 0.49(given an equivalence value of 1)

Odds Ratio Reduction (ORR)1 – 0.49 = 0.51 or 51%

STENT * TVF Crosstabulation

Count

502 89 591545 47 592

1047 136 1183

DriverEndeavor

STENT

Total

no yesTVF

Total

Compare event rates

Continuous variables • Continuous variables are important for the

appraisal of baseline/procedural characteristics (eg stent length per lesion), or additional analyses (eg QCA)

• Focus on these points:

• Provide mean and standard deviation

• Or median (interquartile range) if non-Gaussian

• May check for normality assumptions

Cardiology

xxN

Characteristics:-summarises information well-discards a lot of information

(dispersion??)

Assumptions:-data are not skewed

– distorts the mean– outliers make the mean very different

-Measured on measurement scale– cannot find mean of a categorical measure

‘average’ stent diameter may be meaningless

Mean (arithmetic)

Cardiology

What is it?– The one in the middle– Place values in order– Median is central

Definition:– Equally distant from all other values

Used for:– Ordinal data– Skewed data / outliers

Median

Cardiology

Mean is usually best– If it works– Useful properties (with standard deviation [SD])– But…

Driver Endeavor17 21 19 2119 2117 2118 6

Mean 18 18Median 18 21

Lesion length

Comparing Measures of central tendency

Cardiology

It also depends on the underlying distribution…

Symmetric? mean = median = mode

Comparing Measures of central tendency

Value

Freq

uenc

y

Cardiology

It also depends on the underlying distribution…

Asymmetric? mean ≠ median ≠ mode

0

5

10

15

20

25

30

0 1 2 3 4 5 6 7 8 9

Number of Endeavor implanted per patient

Freq

uenc

y

Mode Mode Median Median Mean Mean

Comparing Measures of central tendency

Cardiology

0 0.30 0.60 0.90 1.20 1.50

Late loss

Freq

uenc

y

DriverEndeavor

Measures of dispersion: examples

Cardiology

0 0.30 0.60 0.90 1.20 1.50

Late loss

Freq

uenc

y

DriverEndeavor

Measures of dispersion: examples

Cardiology

0 0.30 0.60 0.90 1.20 1.50

Late loss

Freq

uenc

y

DriverEndeavor

Measures of dispersion: examples

Cardiology

• Standard deviation (SD)– Used with mean– Parametric tests

• Interquartile range– Used with median– 25% (1/4) to 75% (3/4) percentile– Non-parametric tests

• Range– First to last value– Not commonly used

Measures of dispersion: types

Cardiology

Standard deviation (SD):– approximates population σ as N increases

Advantages:– with mean enables powerful synthesis

mean±1*SD 68% of datamean±2*SD 95% of data (1.96)mean±3*SD 99% of data (2.86)

Disadvantages:– is based on normal assumptions

1)( 2

--

Nxx

SDSD

Standard deviation

Cardiology

Rules of thumb

1. Refer to previous data or analyses (eg landmark articles, large databases)

2. Inspect tables and graphs (eg outliers, histograms)

3. Check rough equality of mean, median, mode

4. Perform ad hoc statistical tests• Levene’s test for equality of means• Kolmogodorov-Smirnov tests• …

Testing normality assumptions

Inferential statistics

P values tell you whether there is a DIFFERENCE and its DIRECTION

Confidence intervals tell you what is the MAGNITUDE (or SIZE) of such difference

2.1 vs 2.4%

Difference and direction

0.3 vs 2.8%

Size of the difference

7.2 vs 2.4%

Sample size calculation

To compute the sample size for a study we need:1. Preferred alpha value2. Preferred beta value (remember: power is (1-beta)x100)3. Control event rate or average value

(with measure of dispersion if appliable)4. Expected relative reduction in experimental group

ENDEAVOR II Circulation 2006

Whenever designing Whenever designing a study or analyzing a study or analyzing

a dataset, it is a dataset, it is important to important to

estimate the sample estimate the sample size or the power of size or the power of

the comparisonthe comparison

Intention-to-treat analysis

• Intention-to-treat (ITT) analysis is an analysis based on the initial treatment intent, irrespectively of the treatment eventually administered

• ITT analysis is intended to avoid various types of bias that can arise in intervention research, especially procedural, compliance and survivor bias

• However, ITT dilutes the power to achieve statistically and clinically significant differences, especially as drop-in and drop-out rates rise

Per-protocol analysis

• In contrast to the ITT analysis, the per-protocol (PP) analysis includes only those patients who complete the entire clinical trial or other particular procedure(s), or have complete data

• In PP analysis each patient is categorized according to the actual treatment received, and not according to the originally intended treatment assignment

• PP analysis is largely prone to bias, and is useful almost only in equivalence or non-inferiority studies

ITT vs PP

100 pts enrolled RANDOMIZATION

50 pts to group A (more toxic)

50 pts to group B (conventional Rx, less toxic)

45 pts treated with A, 5 shifted to B because of poor

global health (all 5 died)

50 patients treated with B (none died)

ACTUAL THERAPY

• ITT: 10% mortality in group A vs 0% in group B, p=0.021 in favor of B

• PP: 0% (0/45) mortality in group A vs 9.1% (5/55) in group B, p=0.038 in favor of A

Questions?

Take home messages

The most important points to remember when writing the Methods section are:

1. State exactly what you did, no more than that

2. Concentrate on the primary aim of the study, not on the ancillary goals

3. Ensure reproducibility

Take home messages

When writing the Methods always ask yourself in every step:

1. What has been done

2. How it has been done

3. When it has been done

4. Who did it

For further slides on these topics please feel free to visit the

metcardio.org website:

http://www.metcardio.org/slides.html