Evidence map›Paper›PMID 30255348›Full record

ArticleDrug safety2019

Implications of Individual QT/RR Profiles-Part 2: Zero QTc/RR Correlations Do Not Prove QTc Correction Accuracy in Studies of QTc Changes.

Marek Malik, Christine Garnett, Katerina Hnatkova, Jose Vicente, Lars Johannesen, Norman Stockbridge

Erratum issuedAbstract read
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In one paragraph

Article in Drug safety, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 5 papers.

0numbers the graph read from it
0cells of the map it votes in
5citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

5 citing papers in PubMed.

  1. Trial
  2. Article
  3. Sources of QTc variability: Implications for effective ECG monitoring in clinical practice.Annals of noninvasive electrocardiology : the official journal of the International Society for Holter and Noninvasive Electrocardiology, Inc · 2020
    Review
  4. Article
  5. Article
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

6 authors.

Marek MalikNational Heart and Lung Institute, Imperial College, Dovehouse Street, London, SW3 6LY, England, UK. marek.malik@btinternet.com.ORCID 0000-0002-3792-1407
Christine GarnettDivision of Cardiovascular and Renal Products, Office of New Drugs, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA.
Katerina HnatkovaNational Heart and Lung Institute, Imperial College, Dovehouse Street, London, SW3 6LY, England, UK.
Jose VicenteDivision of Cardiovascular and Renal Products, Office of New Drugs, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA.
Lars JohannesenDivision of Clinical Pharmacology I, Office of Clinical Pharmacology, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA.
Norman StockbridgeDivision of Cardiovascular and Renal Products, Office of New Drugs, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA.

Funding

British Heart Foundation NH/16/2/32499
6 · The paper itself

Abstract

introductionIn studies of drug-induced corrected QT (QTc) changes, fixed universal heart rate (HR) corrections (e.g., the Fridericia correction) are potentially misleading when assessing the effects of drugs that change HR. When data-specific corrections are designed, tests of their validity are needed. The proposed tests include zero correlations between QTc and corresponding RR values in the complete study data (pooling on-treatment and off-treatment interval measurements).

objectiveTo document that this approach is potentially highly misleading, a statistical modeling study was conducted based on the full profiles of QT/RR data of 523 healthy subjects-254 females, mean age 33.5 years.

methodsIn each of the subjects, 50 baseline QT/RR readings were selected to model baseline data. In repeated experiments, groups of ten and 50 subjects were randomly selected and drug-induced HR increases between 0 and 25 beats per minute combined with QTc changes between - 20 and + 20 ms were modeled. In each experiment, subject-specific as well as population-specific HR corrections were designed so that the QTc interval data were uncorrelated to the corresponding RR interval data.

resultsThe simulation experiments showed that when zero correlations of QTc data with RR data are combined with more than trivial HR increases, the HR corrections are substantially biased and underestimate or fully eliminate any drug-induced QTc interval changes. This result is in full agreement with theoretical considerations of HR correction principles.

conclusionsThe lack of correlation of QTc versus RR durations including on-treatment data does not prove any validity of HR corrections. Correlations of QTc versus RR in study data pooling on- and off-drug measurements should not be used to prove the appropriateness of HR corrections.

Indexed as

Models, CardiovascularModels, StatisticalAdultElectrocardiographyFemaleHeart RateHumansLong QT SyndromeMaleSensitivity and SpecificitySpecies Specificity

Identifiers

PMID30255348
PMCPMC6426831

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.