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Ejection Fraction

  • change in ejection fraction, would expect a decline in EF of 2-3% per year, concerning if rapid progression, i.e., 10% decline or more - Use absolute change, updated to 5% decline for 1 year

NTproBNP

  • % change over a period of time – a decrease is correlated with improvement, measured annually

SDTM Examples: Basic Systolic Function

This section illustrates example analysis datasets for the following endpoints:

  • Percent change in ejection fraction over time (1 year)
  • Decline in ejection fraction over time (1 year) grouped by a decline greater than 5%
  • Percent change in NTproBNP over time (1 year)

Source Data

The SDTM examples used as the source data are from Section 2.1, Basic Systolic Function. The ADSL draws from the DM dataset. The CV dataset shows two visits for subject DMD-EF-01-101. The records for which CVTESTCD = "LVEF_C" and "RVEF_C" were selected for analysis. The records in the LB dataset where LBTESTCD = "BNPPRONT" were used to compute the percent change over time and as a potential covariate.

Example Analysis Datasets

The tables below show the analysis dataset metadata and parameters used for this example.

Analysis Datasets

The ADaM model requires a one-record-per-subject analysis dataset, ADSL, which contains subject characteristics and covariates that are important for analyses. Also, stratification variables can be created in the ADSL to subset the data. More than one SDTM dataset is used as input to the ADSL. As an example, a flag indicating concomitant medication use of ACE inhibitors (ACEINHFL) was derived from CM. Body surface area at screening (BSASC), was derived from the VS dataset using height and weight at the screening visit. Note that based on the dates shown in DM, the screening visit and visit 1 occurred at the same time in this example.

The ADCVNTP dataset includes tests pertinent to these analyses. The records from CV where CVTESTCD = "LVEF_C" and "RVEF_C" and the records from LB where LBTESTCD = "BNPPRONT" were selected. Many lab draws may occur throughout the year, but only those linked to a specific visit were included. By subsetting the LB dataset by LBLNKID not missing, laboratory data that aligns with CV data can be filtered out and sorted using USUBJID and VISIT. If LBLNKID is not available, a windowing strategy could be used to select the laboratory draw closest to that visit for merging with CV, computed in AVISIT.

The ADCVMR dataset is an efficacy analysis dataset with only a few records for more complex modeling of changes in ejection fraction, plus the ProB-type test results. It is an ADaM Basic Data Structure (BDS) dataset, with additional variables added from ADCVNTP.

ADSL Analysis Dataset

This is a simplified example ADSL dataset; it is expected that the ADaMIG is referenced. Analysis age (AAGE) was included to provide age with more precision. The Body Surface Area (BSA) at screening is named BSASC as per the ADAMIG v1.2. There are many possible calculations for BSA; for this example, the Du Bois method was used (ref: https://www.calculator.net/body-surface-area-calculator.html).

ADSL Variable Metadata

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adsl.xpt

RowSTUDYIDUSUBJIDBRTHDTAAGEAGEAGEUSEXRACETRTSDTRFICDTDTHDTDTHFLTRT01PITTFLACEINHFLHEIGHTSCWEIGHTSCBSASC
1DMD-EFLGEDMD-EF-01-10107FEB201012.312YEARSMBLACK OR AFRICAN AMERICAN16JUN202216JUN2022

Drug AYY119200.82
2DMD-EFLGEDMD-EF-01-10101MAY200814.114YEARSMASIAN13JUN202213JUN2022

Drug AYY115300,95
3DMD-EFLGEDMD-EF-01-10110JUL200319.019YEARSMNATIVE HAWAIIAN OR OTHER PACIFIC ISLANDER15JUL2202215JUL2022

Drug BYN140451,30
4DMD-EFLGEDMD-EF-01-10115JAN199923.723YEARSMWHITE06SEP202206SEP202223NOV2023YDrug BYY132421,21
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ADCVNTP Analysis Dataset

In this example, columns for derived variables BASE, CHG, PCHG and CHGCAT1 have been added to facilitate analyses of the efficacy endpoints. Specifically, example demographic data for ADSL were created for an 8 year old male. Also, a custom variable for BSA at baseline (BSABL), and an example of a stratification variable for subjects with was added from ADSL.

Parameter Value List - ADCVNTP [ADCVNTP]

ADCVNTP Variable Metadata

Efficacy Analysis Example 1

This example dataset shows the findings and additional analysis variables associated with:

  • Left Ventricular Ejection Fraction, Calculated (%)
  • Right Ventricular Ejection Fraction, Calculated (%)
  • N-Terminal ProB-type Natriuretic Peptide (pg/mL)

Dataset Wrapper Debug Message

Please add a row column to your dataset.

Rows 1-2:Show the baseline ejection fraction measurements at VISIT 1.
Row 3:Shows the baseline N-Terminal ProB-type Natriuretic Peptide test results at VISIT 1.
Rows 4-5:Show the baseline ejection fraction measurements at VISIT 6.
Row 6:Shows the baseline N-Terminal ProB-type Natriuretic Peptide test results at VISIT 6.
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adcvntp.xpt

RowSTUDYIDUSUBJIDAAGEAGEUSEXRACETRT01PTRT01AITTFLHEIGHTWEIGHTBSAACEINHFLPARAMPARAMCDPARAMNAVALAVISITAVISITNVISITADTABLFLBASECHGPCHGCHGCAT1SRCDOMSRCVARSRCSEQ
1DMD-EFLGEDMD-EF-01-10112.3YEARSMBLACK OR AFRICAN AMERICANDrug ADrug AY119200.82YLeft Ventricular Ejection Fraction, Calculated (%)LVEF_C167Visit 1 (Baseline)1VISIT 116MAY2022Y67


CVCVTESTCD3
2DMD-EFLGEDMD-EF-01-10112.3YEARSMBLACK OR AFRICAN AMERICANDrug ADrug AY119200.82YRight Ventricular Ejection Fraction, Calculated (%)RVEF_C274Visit 1 (Baseline))1VISIT 116MAY2022Y74


CVCVTESTCD7
3DMD-EFLGEDMD-EF-01-10112.3YEARSMBLACK OR AFRICAN AMERICANDrug ADrug AY119200.82YN-Terminal ProB-type Natriuretic Peptide (IU/L)BNPPRONT340Visit 1 (Baseline)1VISIT 116MAY2022Y40


LBLBTESTCD1
4DMD-EFLGEDMD-EF-01-10112.3YEARSMBLACK OR AFRICAN AMERICANDrug ADrug AY132321.08YLeft Ventricular Ejection Fraction, Calculated (%)LVEF_C160Visit 6 (1 Year)6VISIT 606APR2023
67-7-10.447761Decline >=5.0%CVCVTESTCD11
5DMD-EFLGEDMD-EF-01-10112.3YEARSMBLACK OR AFRICAN AMERICANDrug ADrug AY132321.08YRight Ventricular Ejection Fraction, Calculated (%)RVEF_C261Visit 6 (1 Year)6VISIT 606APR2023
74-13-17.567568Decline >=5.0%CVCVTESTCD15
6DMD-EFLGEDMD-EF-01-10112.3YEARSMBLACK OR AFRICAN AMERICANDrug ADrug AY132321.08YN-Terminal ProB-type Natriuretic Peptide (IU/L)BNPPRONT3900Visit 6 (1 Year)6VISIT 106APR2023
408602,150Increase GT 100 pg/mLLBLBTESTCD2
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ADCVCMR Analysis Dataset

The dataset above can also be set up to provide multivariate analyses by taking the lab tests of interest (Paramcd = BNPPRONT) or other analysis datasets, and  merging variables of interest with the ADCVNTP dataset. This summary dataset is created from other ADaM datasets as the source and only variable used in the analysis are kept. 

ADCVCMR Variable Metadata

Efficacy Analysis Example 2
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adcvcmr.xpt

RowSTUDYIDUSUBJIDBRTHDTTRT01PAAGEAGUSEXRACETRT01AITTFLBSAACEINHFLBNPPRONTPARAMPARAMCDPARAMNAVALAVISITAVISITNADTABLFLBASECHGPCHGCHGCAT1
1DMD-EFLGEDMD-EF-01-10107FEB2010Drug A12.3YEARSMBLACK OR AFRICAN AMERICANDrug AY0.82Y40Left Ventricular Ejection Fraction, Calculated (%)LVEF_C170Visit 1 (Baseline)116MAY2022Y70


2DMD-EFLGEDMD-EF-01-10107FEB2010Drug A12.3YEARSMBLACK OR AFRICAN AMERICANDrug AY0.82Y40Right Ventricular Ejection Fraction, Calculated (%)RVEF_C275Visit 1 (Baseline)116MAY2022Y75


3DMD-EFLGEDMD-EF-01-10107FEB2010Drug A12.3YEARSMBLACK OR AFRICAN AMERICANDrug AY1.08Y900Left Ventricular Ejection Fraction, Calculated (%)LVEF_C165Visit 6 (1 Year)606APR2023
70-5-10.447761Decline >=5.0%
4DMD-EFLGEDMD-EF-01-10107FEB2010Drug A12.3YEARSMBLACK OR AFRICAN AMERICANDrug AY1.08Y900Right Ventricular Ejection Fraction, Calculated (%)RVEF_C270Visit 6 (1 Year)606APR2023
75-5-17.567568Decline >=5.0%
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Example Analysis Results Metadata (ARM) Tables

For more details on ARM, see the ADaMIG and the Analysis Results Metadata (ARM) v1.0 for Define-XML v2.0 (https://www.cdisc.org/standards/foundational/adam).

Table 1. A simple comparison of change by treatment groups over one year.

Display

Table 14.xx.xx Change in Left Ventricular Ejection Fraction Percent Over 1 Year

Analysis ResultComparison of Change of Ejection Fraction Percent for the Treatment Groups (1 Year)
Analysis Variables(s)CHG
Analysis ReasonPrimary efficacy endpoint as prespecified in the SAP
Analysis PurposePrimary outcome measure

Data References

(incl. selection criteria)

PARAMCD = "LVEF_C"

Where ITTFL = "Y" and AVISITN = 6;

Documentation

Comparison of Means with 95% confidence interval

Programming Statements 

(Add programming language statements here: SAS, R, etc.)

Proc means DATA=ADCVNTP N MEAN clm STDERR;

/* Subset the data. Can run again selecting for paramcd="RVEF_C"*/

Where PARAMCD = 'LVEF_C' and ITTFL = "Y" and AVISITN = 6 ;

Class TRT01P;

Var CHG; 

run;


Table 2. This table demonstrates a model over multiple time points, adding some of the covariates that were retained in the analysis dataset. 

Display

Table 14.xx.xx Percent Change in Left Ventricular Ejection Fraction Percent Over Time (Yearly)

Analysis ResultComparison of Percent Change of Ejection Fraction for the Treatment Groups Over Time ( yearly)
Analysis Variables(s)CHG
Analysis ReasonPrimary efficacy endpoint as prespecified in the SAP
Analysis PurposePrimary outcome measure

Data References

(incl. selection criteria)

PARAMCD = "LVEF_C"

Where ITTFL = "Y"

Documentation

 The mixed model using lsmeans to compare treatment groups

Programming Statements 

(Add programming language statements here: SAS, R, etc.)

/* Note that CHG is only computed post-baseline, so subset for the yearly visits, i.e. 6, 12, 18 etc. */

Proc  mixed DATA=ADCVNTP;

Class  TRT01P AVISITN;

/* Subset by param, as there are two parameters with CHG calculated*/

Where ITTFL = "Y" and AVISITN IN(6,12,18,24,36,48)  and PARAMCD = "LVEF_C"; 

Model PCHG=AVISITN*TRT01P/Solution;

RANDOM INTERCEPT / SUBJECT=STUYDID TYPE=UN;

LSMEANS TRT01P*AVISITN/ CL PDIFF;

RUN;


Table 3. This example uses the dataset ADCVCMR, with BNPPRONT as an additional covariate.

Display

Table 14.xx.xx Percent change in NTproBNP over 1 Year

Analysis ResultComparison of Percent Change of NTproBNP for the Treatment Groups Over a period of time.
Analysis Variables(s)PCHG
Analysis ReasonPrimary efficacy endpoint as prespecified in the SAP
Analysis PurposePrimary outcome measure

Data References

(incl. selection criteria)

PARAMCD = L_VEFC;

ITTFL = "Y" and AVISIT GE 6;

Documentation

Multiple Regression Model


Proc reg data=ADCVCMR ;

Where PARAMCD = L_VEFC and ITTFL = "Y" and AVISIT GE 6;

Model PCHG = AAGE SEX RACE BNPPRONT;

run;

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