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Chapter 18: patient-reported outcomes.

Bradley C Johnston, Donald L Patrick, Tahira Devji, Lara J Maxwell, Clifton O Bingham III, Dorcas E Beaton, Maarten Boers, Matthias Briel, Jason W Busse, Alonso Carrasco-Labra, Robin Christensen, Bruno R da Costa, Regina El Dib, Anne Lyddiatt, Raymond W Ostelo, Beverley Shea, Jasvinder Singh, Caroline B Terwee, Paula R Williamson, Joel J Gagnier, Peter Tugwell, Gordon H Guyatt

Key Points:

• Summary data on patient-reported outcomes (PROs) are important to ensure healthcare decision makers are informed about the outcomes most meaningful to patients.
• Authors of systematic reviews that include PROs should have a good understanding of how patient-reported outcome measures (PROMs) are developed, including the constructs they are intended to measure, their reliability, validity and responsiveness.
• Authors should pre-specify at the protocol stage a hierarchy of preferred PROMs to measure the outcomes of interest.

Cite this chapter as: Johnston BC, Patrick DL, Devji T, Maxwell LJ, Bingham III CO, Beaton D, Boers M, Briel M, Busse JW, Carrasco-Labra A, Christensen R, da Costa BR, El Dib R, Lyddiatt A, Ostelo RW, Shea B, Singh J, Terwee CB, Williamson PR, Gagnier JJ, Tugwell P, Guyatt GH. Chapter 18: Patient-reported outcomes. In: Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA (editors). Cochrane Handbook for Systematic Reviews of Interventions version 6.4 (updated August 2023). Cochrane, 2023. Available from www.training.cochrane.org/handbook .

18.1 Introduction to patient-reported outcomes

18.1.1 what are patient-reported outcomes.

A patient-reported outcome (PRO) is “any report of the status of a patient’s health condition that comes directly from the patient without interpretation of the patient’s response by a clinician or anyone else” (FDA 2009). PROs are one of several clinical outcome assessment methods that complement biomarkers, measures of morbidity (e.g. stroke, myocardial infarction), burden (e.g. hospitalization), and survival used and reported in clinical trials and non-randomized studies (FDA 2018).

Patient-reported outcome measures (PROMs) are instruments that are used to measure the PROs, most often self-report questionnaires. Although investigators may address patient-relevant outcomes via proxy reports or observations from caregivers, health professionals, or parents and guardians, these are not PROMs but rather clinician-reported or observer-reported outcomes (Powers et al 2017).

PROs provide crucial information for patients and clinicians facing choices in health care. Conducting systematic reviews and meta-analyses including PROMs and interpreting their results is not straightforward, and guidance can help review authors address the challenges.

The objectives of this chapter are to: (i) describe the category of outcomes known as PROs and their importance for healthcare decision making; (ii) illustrate the key issues related to reliability, validity and responsiveness that systematic review authors should consider when including PROs; and (iii) address the structure and content (domains, items) of PROs and provide guidance for combining information from different PROs. This chapter outlines a step-by-step approach to addressing each of these elements in the systematic review process. The focus is on the use of PROs in randomized trials, and what is crucial in this context when selecting PROs to include in a meta-analysis. The principles also apply to systematic reviews of non-randomized studies addressing PROs (e.g. dealing with adverse drug reactions).

18.1.2 Why patient-reported outcomes?

PROs provide patients’ perspectives regarding treatment benefit and harm, directly measure treatment benefit and harm beyond survival, major morbid events and biomarkers, and are often the outcomes of most importance to patients and families.

Self-reported outcomes often correlate poorly with physiological and other outcomes such as performance-related outcomes, clinician-reported outcomes, or biomarkers. In asthma, Yohannes and colleagues (Yohannes et al (1998) found that variability in exercise capacity contributed to only 3% of the variability in breathing problems on a patient self-report questionnaire. In chronic obstructive pulmonary disease (COPD), the reported correlations between forced expiratory volume (FEV1) and quality of life (QoL) are weak (r=0.14 to 0.41) (Jones 2001). In peripheral arterial occlusive disease, correlations between haemodynamic variables and QoL are low (e.g. r=–0.17 for QoL pain subscale and Doppler sonographic ankle/brachial pressure index) (Müller-Bühl et al 2003). In osteoarthritis, there is discordance between radiographic arthritis and patient-reported pain (Hannan et al 2000). These findings emphasize the often important limitations of biomarkers for informing the impact of interventions on the patient experience or the patient’s perspective of disease (Bucher et al 2014).

PROs are essential when externally observable patient-important outcomes are rare or unavailable. They provide the only reasonable strategy for evaluating treatment impact of many conditions including pain syndromes, fatigue, disorders such as irritable bowel syndrome, sexual dysfunction, and emotional function and adverse effects such as nausea and anxiety for which physiological measurements are limited or unavailable.

18.2 Formulation of the review

In this section we describe PROMs in more detail and discuss some issues to consider when deciding which PROMs to address in a review.

A common term used in the health status measurement literature is construct . Construct refers to what PROMs are trying to measure, the concept that defines the PROM such as pain, physical function or depressive mood. Constructs are the postulated attributes of the person that investigators hope to capture with the PROM (Cronbach and Meehl 1955).

Many different ways exist to label and classify PROMs and the constructs they measure. For instance, reports from patients include signs (observable manifestations of a condition), sensations (most commonly classified as symptoms that may be attributable to disease and/or treatment), behaviours and abilities (commonly classified as functional status), general perceptions or feelings of well-being, general health, satisfaction with treatment, reports of adverse effects, adherence to treatment, and participation in social or community events and health-related quality of life (HRQoL).

Investigators can use different approaches to capture patient perspectives, including interviews, self-completed questionnaires, diaries, and via different interfaces such as hand-held devices or computers. Review authors must identify the postulated constructs that are important to patients, and then determine the extent to which the PROMs used and reported in the trials address those constructs, the characteristics (measurement properties) of the PROMs used, and communicate this information to the reader (Calvert et al 2013).

Focusing now on HRQoL, an important PRO, some approaches attempt to cover the full range of health-related patient experience – including, for instance, self-care, and physical, emotional and social function – and thus enable comparisons between the impact of treatments on HRQoL across diseases or conditions. Authors often call these approaches generic instruments (Guyatt et al 1989, Patrick and Deyo 1989). These include utility measures such as the EuroQol five dimensions questionnaire (EQ-5D) or the Health Utilities Index (HUI). They also include health profiles such as the Short Form 36-item (SF-36) or the SF-12; these have come to dominate the field of health profiles (Tarlov et al 1989, Ware et al 1995, Ware et al 1996). An alternative approach to measuring PROs is to focus on much more specific constructs: PROMs may be specific to function (e.g. sleep, sexual function), to a disease (e.g. asthma, heart failure), to a population (e.g. the frail elderly) or to a symptom (pain, fatigue) (Guyatt et al 1989, Patrick and Deyo 1989). Another domain-specific measurement system now receiving attention is Patient-Reported Outcomes Measurement Instruments System (PROMIS). PROMIS is a National Institutes of Health funded PROM programme using computerized adaptive testing from large item banks for over 70 domains (e.g. anxiety, depression, pain, social function) relevant to wide variety of chronic diseases (Cella et al 2007, Witter 2016, PROMIS 2018).

Authors often use the terms ‘quality of life’, ‘health status’, ‘functional status’, ‘HRQoL’ and ‘well-being’ loosely and interchangeably. Systematic review authors must therefore consider carefully the constructs that the PROMs have actually measured. To do so, they may need to examine the items or questions included in a PROM.

Another issue to consider is whether and how the individual items of instruments are weighted. A number of approaches can be used to arrive at weights (Wainer 1976). Utility instruments designed for economic analysis put greater emphasis on item weighting, attempting ultimately to present HRQoL as a continuum anchored between death and full health. Many PROMs weight items equally in the calculation of the overall score, a reasonable approach. Readers can refer to a helpful overview of classical test theory and item response theory to understand better the merits and limitations of weighting (Cappelleri et al 2014).

Table 18.2.a presents a framework for considering and reporting PROMs in clinical trials, including their constructs and how they were measured. A good understanding of the PROMs identified in the included studies for a review is essential to appropriate analysis of outcomes across studies, and appraisal of the certainty of the evidence.

Table 18.2.a Checklist for describing and assessing PROMs in clinical trials. Adapted from Guyatt et al (1997)

18.3 Appraisal of evidence

18.3.1 measurement of pros: single versus multiple time-points.

To be useful, instruments must be able to distinguish between situations of interest (Boers et al 1998). When results are available for only one time-point (e.g. for classification), the key issue for PROMs is to be able to distinguish individuals with more desirable scores from those whose scores are less desirable. The key measurement issues in such contexts are reliability and cross-sectional construct validity (Kirshner and Guyatt 1985, Beaton et al 2016).

In longitudinal studies such as randomized trials, investigators usually obtain measurements at multiple time-points, for example at the beginning of the trial and again following administration of the interventions. In this context, PROMs must be able to distinguish those who have experienced positive changes over time from those who have experienced negative changes, those who experienced less positive change, or those who experienced no change at all, and to estimate accurately the magnitude of those changes. The key measurement issues in these contexts – sometimes referred to as evaluative – are responsiveness and longitudinal construct validity (Kirshner and Guyatt 1985, Beaton et al 2016).

18.3.2 Reliability

Intuitively, many think of reliability as obtaining the same scores on repeated administration of an instrument in stable respondents. That stability (or lack of measurement error) is important, but not sufficient. Satisfactory instruments must be able to distinguish between individuals despite measurement error.

Reliability statistics therefore look at the ratio of the variability between respondents (typically the numerator of a reliability statistic) and the total variability (the variability between respondents and the variability within respondents). The most commonly used statistics to measure reliability is a kappa coefficient for categorical data, a weighted kappa coefficient for ordered categorical data, and an intraclass correlation coefficient for continuous data (de Vet et al 2011).

Limitations in reliability will be of most concern for the review author when randomized trials have failed to establish the superiority of an experimental intervention over a comparator intervention. The reason is that lack of reliability cannot create intervention effects that are not present, but can obscure true intervention effects as a result of random error. When a systematic review does not find evidence that an intervention affects a PROM, review authors should consider whether this may be due to poor reliability (e.g. if reliability coefficients are less than 0.7) rather than lack of an effect.

18.3.3 Validity

Validity has to do with whether the instrument is measuring what it is intended to measure. Content validity assessment involves patient and clinician evaluation of the relevance and comprehensiveness of the content contained in the measures, usually obtained through qualitative research with patients and families (Johnston et al 2012). Guidance is available on the assessment of content validity for PROMs used in clinical trials (Patrick et al 2011a, Patrick et al 2011b).

Construct validity involves examining the logical relationships that should exist between assessment measures. For example, in patients with COPD, we would expect that patients with lower treadmill exercise capacity generally will have more dyspnoea (shortness of breath) in daily life than those with higher exercise capacity, and we would expect to see substantial correlations between a new measure of emotional function and existing emotional function questionnaires.

When we are interested in evaluating change over time – that is, in the context of evaluation when measures are available both before and after an intervention – we examine correlations of change scores. For example, patients with COPD who deteriorate in their treadmill exercise capacity should, in general, show increases in dyspnea, while those whose exercise capacity improves should experience less dyspnea. Similarly, a new emotional function instrument should show concurrent improvement in patients who improve on existing measures of emotional function. The technical term for this process is testing an instrument’s longitudinal construct validity. Review authors should look for evidence of the validity of PROMs used in clinical studies. Unfortunately, reports of randomized trials using PROMs seldom review or report evidence of the validity of the instruments they use, but when these are available review authors can gain some reassurance from statements (backed by citations) that the questionnaires have been previously validated, or could seek additional published information on named PROMs. Ideally, review authors should look for systematic reviews of the measurement properties of the instruments in question. The Co nsensus-based s tandards for the selection of health m easurement in struments (COSMIN) website offers a database of such reviews ( COSMIN Database of Systematic Reviews ). In addition, the Patient-Reported Outcomes and Quality of Life Instruments Database ( PROQOLID ) provides documentation of the measurement properties for over 1000 PROs.

If the validity of the PROMs used in a systematic review remains unclear, review authors should consider whether the PROM is an appropriate measure of the review’s planned outcomes, or whether it should be excluded (ideally, this would be considered at the protocol stage), and any included results should be interpreted with appropriate caution. For instance, in a review of flavonoids for haemorrhoids, authors of primary trials used PROMs to ascertain patients’ experience with pain and bleeding (Alonso-Coello et al 2006). Although the wording of these PROMs was simple and made intuitive sense, the absence of formal validation raises concerns over whether these measures can give meaningful data to distinguish between the intervention and its comparators.

A final concern about validity arises if the measurement instrument is used with a different population, or in a culturally and linguistically different environment from the one in which it was developed. Ideally, PROMs should be re-validated in each study, but systematic review authors should be careful not to be too critical on this basis alone .

18.3.4 Responsiveness

In the evaluative context, randomized trial participant measurements are typically available before and after the intervention. PROMs must therefore be able to distinguish among patients who remain the same, improve or deteriorate over the course of the trial (Guyatt et al 1987, Revicki et al 2008). Authors often refer to this measurement property as responsiveness; alternatives are sensitivity to change or ability to detect change.

As with reliability, responsiveness becomes an issue when a meta-analysis suggests no evidence of a difference between an intervention and control. An instrument with a poor ability to measure change can result in false-negative results, in which the intervention improves how patients feel, yet the instrument fails to detect the improvement. This problem may be particularly salient for generic questionnaires that have the advantage of covering all relevant areas of HRQoL, but the disadvantage of covering each area superficially or without the detail required for the particular context of use (Wiebe et al 2003, Johnston et al 2016a). Thus, in studies that show no difference in PROMs between intervention and control, lack of instrument responsiveness is one possible reason. Review authors should look for published evidence of responsiveness. If there is an absence of prior evidence of responsiveness, this represents a potential reason for being less certain about evidence from a series of randomized trials. For instance, a systematic review of respiratory muscle training in COPD found no effect on patients’ function. However, two of the four studies that assessed a PROM used instruments without established responsiveness (Smith et al 1992).

18.3.5 Reporting bias

Studies focusing on PROs often use a number of PROMs to measure the same or similar constructs. This situation creates a risk of selective outcome reporting bias, in which trial authors select for publication a subset of the PROMs on the basis of the results; that is, those that indicate larger intervention effects or statistically significant P values (Kirkham et al 2010). Further detailed discussion of selective outcome reporting is presented in Chapter 7 (Section 7.2.3.3) ; see also Chapter 8 (Section 8.7) .

Systematic reviews focusing on PROs should be alert to this problem. When only a small number of eligible studies have reported results for a particular PROM, particularly if the PROM is mentioned in a study protocol or methods section, or if it is a salient outcome that one would expect conscientious investigators to measure, review authors should note the possibility of reporting bias and consider rating down certainty in evidence as part of their GRADE assessment (see Chapter 14 ) (Guyatt et al 2011). For instance, authors of a systematic review evaluating the responsiveness of PROs among patients with rare lysosomal storage diseases encountered eligible studies in which the use of a PRO was described in the methods, but there were either no data or limited PRO data in the results. When authors did present some information about results, the reports sometimes included only interim or end-of-study results. Such instances are likely to be an indication of selective outcome reporting bias: it seems implausible that, if results showed apparent benefit on PROs, investigators would mention a PRO in the methods and subsequently fail to report results (Johnston et al 2016b).

18.4 Synthesis and interpretation of evidence

18.4.1 selecting from multiple proms.

The definition of a particular PRO may vary between studies, and this may justify use of different instruments (i.e. different PROMs). Even if the definitions are similar (or if, as happens more commonly, the investigators do not define the PRO), the investigators may choose different instruments to measure the PROs, especially if there is a lack of consensus on which instrument to use (Prinsen et al 2016).

When trials report results for more than one instrument, authors should – independent of knowledge of the results and ideally at the protocol stage – create a hierarchy based on reported measurement properties of PROMs (Tendal et al 2011, Christensen et al 2015), considering a detailed understanding of what each PROM measures (see Table 18.2.a ), and its demonstrated reliability, validity, responsiveness and interpretability (see Section 18.3 ). This will allow authors to decide which instruments will be used for data extraction and synthesis. For example, the following instruments are all validated, patient-reported pain instruments that an investigator may use in a primary study to assess an intervention’s usefulness for treating pain:

• 7-item Integrated Pain Score;
• 10-point Visual Analogue Scale for Pain;
• 20-item McGill Pain Questionnaire; and
• 56-item Brief Pain Inventory (PROQOLID 2018).

In some clinical fields core outcome sets are available to guide the use of appropriate PROs (COMET 2018). Only rarely do these include specific guidance on which PROMs are preferable, although methods have been proposed for this (Prinsen et al 2016). Within the field of rheumatology, the Outcome Measures in Rheumatology (OMERACT) initiative has developed a conceptual framework known as OMERACT Filter 2.0 to identify both core domain sets (what outcome should be measured) and core outcome measurement sets (how the outcome should be measured, i.e. which PROM to use) (Boers et al 2014). This is a generic framework and applicable to those developing core outcome sets outside the field of rheumatology.

As an example of a pre-defined hierarchy, for knee osteoarthritis, OMERACT has used a published hierarchy based on responsiveness for extraction of PROMs evaluating pain and physical function for performing systematic reviews (Juhl et al 2012).

Authors should decide in advance whether to exclude PROMs not included in the hierarchy, or to include additional measures where none of the preferred measures are available.

18.4.2 Synthesizing data from multiple PROMs

While a hierarchy can be helpful in identifying the review authors’ preferred measures, and excluding some measures considered inappropriate, it remains likely that authors will encounter studies using several different PROMs to measure a given construct, either within one study or across multiple studies. Authors must then decide how to approach synthesis of multiple measures, and among them, consider which measures to include in a single meta-analysis on a particular construct (Tendal et al 2011, Christensen et al 2015).

When deciding if statistical synthesis is appropriate, review authors will often find themselves reading between the lines to try and get a precise notion of the underlying construct for the PROMs used. They may have to consult the articles that describe the development and prior use of PROMs included in the primary studies, or look at the instruments to understand the concepts being measured.

For example, authors of a Cochrane Review of cognitive behavioural therapy (CBT) for tinnitus included HRQoL as a PRO (Martinez-Devesa et al 2007), assessed with different PROMs: four trials using the Tinnitus Handicap Questionnaire; one trial the Tinnitus Questionnaire; and one trial the Tinnitus Reaction Questionnaire. Review authors compared the content of the PROMs and concluded that statistical pooling was appropriate.

The most compelling evidence regarding the appropriateness of including different PROMs in the same meta-analysis would come from a finding of substantial correlations between the instruments. For example, the two major instruments used to measure HRQoL in patients with COPD are the Chronic Respiratory Questionnaire (CRQ) and the St. George’s Respiratory Questionnaire (SGRQ). Correlations between the two questionnaires in individual studies have varied from 0.3 to 0.6 in both cross-sectional (correlations at a point in time) and longitudinal (correlations of change) comparisons (Rutten-van Mölken et al 1999, Singh et al 2001, Schünemann et al 2003, Schünemann et al 2005). In one study, investigators examined the correlations between group mean changes in the CRQ and SGRQ in 15 studies including 23 patient groups and found a correlation of 0.88 (Puhan et al 2006).

Ideally, the decision to combine scores from different PROMs would be based not only on their measuring similar constructs but also on their satisfactory validity, and, depending on whether before and after intervention or only after intervention measurements were available, and on their responsiveness or reliability. For example, extensive evidence of validity is available for both CRQ and the SGRQ. The CRQ has, however, proved more responsive than the SGRQ: in an investigation that included 15 studies using both instruments, standardized response means of the CRQ (median 0.51, interquartile range (IQR) 0.19 to 0.98) were significantly higher (P <0.001) than those associated with the SGRQ (median 0.26, IQR −0.03 to 0.40) (Puhan et al 2006). As a result, pooling results from trials using these two instruments could lead to underestimates of intervention effect in studies using the SGRQ (Puhan et al 2006, Johnston et al 2010). This can be tested using a sensitivity analysis of studies using the more responsive versus less responsive instrument.

Usually, detailed data such as those described above will be unavailable. Investigators must then fall back on intuitive decisions about the extent to which different instruments are measuring the same underlying concept. For example, the authors of a meta-analysis of psychosocial interventions in the treatment of pre-menstrual syndrome faced a profusion of outcome measures, with 25 PROMs used in their nine eligible studies (Busse et al 2009). They dealt with this problem by having two experienced clinical researchers, knowledgeable to the study area and not otherwise involved in the review, independently examine each instrument – including all domains – and group 16 PROMs into six discrete conceptual categories. Any discrepancies were resolved by discussion to achieve consensus. Table 18.4.a details the categories and the included instruments within each category.

Authors should follow the guidance elsewhere in this Handbook on appropriate methods of synthesizing different outcome measures in a single analysis ( Chapter 10 ) and interpreting these results in a way that is most meaningful for decision makers ( Chapter 15 ).

Table 18.4.a Examples of potentially combinable PROMs measuring similar constructs from a review of psychosocial interventions in the treatment of pre-menstrual syndrome (Busse et al 2009). Reproduced with permission of Karger

Having decided which PROs and subsequently PROMs to include in a meta-analysis, review authors face the challenge of ensuring the results they present are interpretable to their target audiences. For instance, if told that the mean difference between rehabilitation and standard care in a series of randomized trials using the CRQ was 1.0 (95% CI 0.6 to 1.5), many readers would be uncertain whether this represents a trivial, small but important, moderate, or large effect (Guyatt et al 1998, Brozek et al 2006, Schünemann et al 2006). Similarly, the interpretation of a standardized mean difference is challenging for most (Johnston et al 2016b). Chapter 15 summarizes the various statistical presentation approaches that can be used to improve the interpretability of summary estimates. Further, for those interested in additional guidance, the GRADE working group summarizes five presentation approaches to enhancing the interpretability of pooled estimates of PROs when preparing ‘Summary of findings’ tables (Thorlund et al 2011, Guyatt et al 2013, Johnston et al 2013).

18.5 Chapter information

Authors: Bradley C Johnston, Donald L Patrick, Tahira Devji, Lara J Maxwell, Clifton O Bingham III, Dorcas Beaton, Maarten Boers, Matthias Briel, Jason W Busse, Alonso Carrasco-Labra, Robin Christensen, Bruno R da Costa, Regina El Dib, Anne Lyddiatt, Raymond W Ostelo, Beverley Shea, Jasvinder Singh, Caroline B Terwee, Paula R Williamson, Joel J Gagnier, Peter Tugwell, Gordon H Guyatt

Funding: DB is on the executive of OMERACT (Outcome Measurement in Rheumatology) (unpaid position). OMERACT is supported through partnership with multiple industries and OMERACT funds support staff to assist in the development of methods and materials around core outcome set development that influenced this chapter. The Parker Institute, Bispebjerg and Frederiksberg Hospital (RC) is supported by a core grant from the Oak Foundation (OCAY-13-309). TD has received funding from the Canadian Institutes of Health Research for research related to patient-reported outcomes and minimal important differences. RWO received research grants (paid to the Institute) from Netherlands Organisation Scientific Research (NWO); Netherlands Organisation for Health Research and Development (ZonMw); Wetenschappelijk College Fysiotherapie/KNGF Ned Ver Manuele Therapie; European Chiropractors’ Union; Amsterdam Movement Sciences; National Health Care Institute (ZiN); De Friesland Zorgverzekeraar. PRW’s work within the COMET Initiative is funded through grant NIHR Senior Investigator Award (NF-SI_0513-10025).

18.6 References

Alonso-Coello P, Zhou Q, Martinez-Zapata MJ, Mills E, Heels-Ansdell D, Johanson JF, Guyatt G. Meta-analysis of flavonoids for the treatment of haemorrhoids. British Journal of Surgery 2006; 93 : 909-920.

Beaton D, Boers M, Tugwell P. Assessment of Health Outcomes. In: Firestein G, Budd R, Gabriel SE, McInnes IB, O'Dell J, editors. Kelley and Firestein's Textbook of Rheumatology . 10th ed. Philadelphia (PA): Elsevier; 2016. p. 496-508.

Boers M, Brooks P, Strand CV, Tugwell P. The OMERACT filter for Outcome Measures in Rheumatology. Journal of Rheumatology 1998; 25 : 198-199.

Boers M, Kirwan JR, Wells G, Beaton D, Gossec L, d'Agostino MA, Conaghan PG, Bingham CO, 3rd, Brooks P, Landewe R, March L, Simon LS, Singh JA, Strand V, Tugwell P. Developing core outcome measurement sets for clinical trials: OMERACT filter 2.0. Journal of Clinical Epidemiology 2014; 67 : 745-753.

Brozek JL, Guyatt GH, Schünemann HJ. How a well-grounded minimal important difference can enhance transparency of labelling claims and improve interpretation of a patient reported outcome measure. Health and Quality of Life Outcomes 2006; 4 : 69.

Bucher HC, Cook DJ, Holbrook AM, Guyatt G. Chapter 13.4: Surrogate Outcomes. In: Guyatt G, Rennie D, Meade MO, Cook DJ, editors. Users' Guides to the Medical Literature: A Manual for Evidence-Based Clinical Practice . 3rd ed. New York: McGraw-Hill Education; 2014.

Busse JW, Montori VM, Krasnik C, Patelis-Siotis I, Guyatt GH. Psychological intervention for premenstrual syndrome: a meta-analysis of randomized controlled trials. Psychotherapy and Psychosomatics 2009; 78 : 6-15.

Calvert M, Blazeby J, Altman DG, Revicki DA, Moher D, Brundage MD. Reporting of patient-reported outcomes in randomized trials: the CONSORT PRO extension. JAMA 2013; 309 : 814-822.

Cappelleri JC, Jason Lundy J, Hays RD. Overview of classical test theory and item response theory for the quantitative assessment of items in developing patient-reported outcomes measures. Clinical Therapeutics 2014; 36 : 648-662.

Cella D, Yount S, Rothrock N, Gershon R, Cook K, Reeve B, Ader D, Fries JF, Bruce B, Rose M. The Patient-Reported Outcomes Measurement Information System (PROMIS): progress of an NIH Roadmap cooperative group during its first two years. Medical Care 2007; 45 : S3-S11.

Christensen R, Maxwell LJ, Jüni P, Tovey D, Williamson PR, Boers M, Goel N, Buchbinder R, March L, Terwee CB, Singh JA, Tugwell P. Consensus on the Need for a Hierarchical List of Patient-reported Pain Outcomes for Metaanalyses of Knee Osteoarthritis Trials: An OMERACT Objective. Journal of Rheumatology 2015; 42 : 1971-1975.

COMET. Core Outcome Measures in Effectiveness Trials 2018. http://www.comet-initiative.org .

Cronbach LJ, Meehl PE. Construct validity in psychological tests. Psychological Bulletin 1955; 52 : 281-302.

de Vet HCW, Terwee CB, Mokkink LB, Knol DL. Measurement in Medicine: A Practical Guide . Cambridge: Cambridge University Press; 2011.

FDA. Guidance for Industry: Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims. Rockville, MD; 2009. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM193282.pdf .

FDA. Clinical Outcome Assessment Program Silver Spring, MD: US Food and Drug Administration; 2018. https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugDevelopmentToolsQualificationProgram/ucm284077.htm .

Guyatt G, Walter S, Norman G. Measuring change over time: assessing the usefulness of evaluative instruments. Journal of Chronic Diseases 1987; 40 : 171-178.

Guyatt G, Oxman AD, Akl EA, Kunz R, Vist G, Brozek J, Norris S, Falck-Ytter Y, Glasziou P, DeBeer H, Jaeschke R, Rind D, Meerpohl J, Dahm P, Schünemann HJ. GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables. Journal of Clinical Epidemiology 2011; 64 : 383-394.

Guyatt GH, Veldhuyzen Van Zanten SJ, Feeny DH, Patrick DL. Measuring quality of life in clinical trials: a taxonomy and review. CMAJ: Canadian Medical Association Journal 1989; 140 : 1441-1448.

Guyatt GH, Naylor CD, Juniper E, Heyland DK, Jaeschke R, Cook DJ. Users' guides to the medical literature. XII. How to use articles about health-related quality of life. Evidence-Based Medicine Working Group. JAMA 1997; 277 : 1232-1237.

Guyatt GH, Juniper EF, Walter SD, Griffith LE, Goldstein RS. Interpreting treatment effects in randomised trials. BMJ 1998; 316 : 690-693.

Guyatt GH, Thorlund K, Oxman AD, Walter SD, Patrick D, Furukawa TA, Johnston BC, Karanicolas P, Akl EA, Vist G, Kunz R, Brozek J, Kupper LL, Martin SL, Meerpohl JJ, Alonso-Coello P, Christensen R, Schünemann HJ. GRADE guidelines: 13. Preparing summary of findings tables and evidence profiles-continuous outcomes. Journal of Clinical Epidemiology 2013; 66 : 173-183.

Hannan MT, Felson DT, Pincus T. Analysis of the discordance between radiographic changes and knee pain in osteoarthritis of the knee. Journal of Rheumatology 2000; 27 : 1513-1517.

Johnston BC, Thorlund K, Schünemann HJ, Xie F, Murad MH, Montori VM, Guyatt GH. Improving the interpretation of quality of life evidence in meta-analyses: the application of minimal important difference units. Health and Quality of Life Outcomes 2010; 8 : 116-116.

Johnston BC, Thorlund K, da Costa BR, Furukawa TA, Guyatt GH. New methods can extend the use of minimal important difference units in meta-analyses of continuous outcome measures. Journal of Clinical Epidemiology 2012; 65 : 817-826.

Johnston BC, Patrick DL, Thorlund K, Busse JW, da Costa BR, Schünemann HJ, Guyatt GH. Patient-reported outcomes in meta-analyses-part 2: methods for improving interpretability for decision-makers. Health and Quality of Life Outcomes 2013; 11 : 211-211.

Johnston BC, Miller PA, Agarwal A, Mulla S, Khokhar R, De Oliveira K, Hitchcock CL, Sadeghirad B, Mohiuddin M, Sekercioglu N, Seweryn M, Koperny M, Bala MM, Adams-Webber T, Granados A, Hamed A, Crawford MW, van der Ploeg AT, Guyatt GH. Limited responsiveness related to the minimal important difference of patient-reported outcomes in rare diseases. Journal of Clinical Epidemiology 2016a; 79 : 10-21.

Johnston BC, Alonso-Coello P, Friedrich JO, Mustafa RA, Tikkinen KA, Neumann I, Vandvik PO, Akl EA, da Costa BR, Adhikari NK, Dalmau GM, Kosunen E, Mustonen J, Crawford MW, Thabane L, Guyatt GH. Do clinicians understand the size of treatment effects? A randomized survey across 8 countries. CMAJ: Canadian Medical Association Journal 2016b; 188 : 25-32.

Jones PW. Health status measurement in chronic obstructive pulmonary disease. Thorax 2001; 56 : 880-887.

Juhl C, Lund H, Roos EM, Zhang W, Christensen R. A hierarchy of patient-reported outcomes for meta-analysis of knee osteoarthritis trials: empirical evidence from a survey of high impact journals. Arthritis 2012; 2012 : 136245.

Kirkham JJ, Dwan KM, Altman DG, Gamble C, Dodd S, Smyth R, Williamson PR. The impact of outcome reporting bias in randomised controlled trials on a cohort of systematic reviews. BMJ 2010; 340 : c365.

Kirshner B, Guyatt G. A methodological framework for assessing health indices. Journal of Chronic Diseases 1985; 38 : 27-36.

Martinez-Devesa P, Waddell A, Perera R, Theodoulou M. Cognitive behavioural therapy for tinnitus. Cochrane Database of Systematic Reviews 2007; 9 : CD005233.

Müller-Bühl U, Engeser P, Klimm H-D, Wiesemann A. Quality of life and objective disease criteria in patients with intermittent claudication in general practice. Family Practice 2003; 20 : 36-40.

Patrick DL, Deyo RA. Generic and disease-specific measures in assessing health status and quality of life. Medical Care 1989; 27 : S217-232.

Patrick DL, Burke LB, Gwaltney CJ, Leidy NK, Martin ML, Molsen E, Ring L. Content validity--establishing and reporting the evidence in newly developed patient-reported outcomes (PRO) instruments for medical product evaluation: ISPOR PRO good research practices task force report: part 1--eliciting concepts for a new PRO instrument. Value in Health 2011a; 14 : 967-977.

Patrick DL, Burke LB, Gwaltney CJ, Leidy NK, Martin ML, Molsen E, Ring L. Content validity--establishing and reporting the evidence in newly developed patient-reported outcomes (PRO) instruments for medical product evaluation: ISPOR PRO Good Research Practices Task Force report: part 2--assessing respondent understanding. Value in Health 2011b; 14 : 978-988.

Powers JH, 3rd, Patrick DL, Walton MK, Marquis P, Cano S, Hobart J, Isaac M, Vamvakas S, Slagle A, Molsen E, Burke LB. Clinician-Reported Outcome Assessments of Treatment Benefit: Report of the ISPOR Clinical Outcome Assessment Emerging Good Practices Task Force. Value in Health 2017; 20 : 2-14.

Prinsen CA, Vohra S, Rose MR, Boers M, Tugwell P, Clarke M, Williamson PR, Terwee CB. How to select outcome measurement instruments for outcomes included in a "Core Outcome Set" - a practical guideline. Trials 2016; 17 : 449.

PROMIS. Patient Reported Outcomes Measurement Information System 2018. http://www.healthmeasures.net/explore-measurement-systems/promis .

PROQOLID. Patient Reported Outcomes and Quality of Life Instruments Database 2018. https://eprovide.mapi-trust.org/about/about-proqolid .

Puhan MA, Soesilo I, Guyatt GH, Schünemann HJ. Combining scores from different patient reported outcome measures in meta-analyses: when is it justified? Health and Quality of Life Outcomes 2006; 4 : 94-94.

Revicki D, Hays RD, Cella D, Sloan J. Recommended methods for determining responsiveness and minimally important differences for patient-reported outcomes. Journal of Clinical Epidemiology 2008; 61 : 102-109.

Rutten-van Mölken M, Roos B, Van Noord JA. An empirical comparison of the St George's Respiratory Questionnaire (SGRQ) and the Chronic Respiratory Disease Questionnaire (CRQ) in a clinical trial setting. Thorax 1999; 54 : 995-1003.

Schünemann HJ, Best D, Vist G, Oxman AD, Group GW. Letters, numbers, symbols and words: how to communicate grades of evidence and recommendations. Canadian Medical Association Journal 2003; 169 : 677-680.

Schünemann HJ, Goldstein R, Mador MJ, McKim D, Stahl E, Puhan M, Griffith LE, Grant B, Austin P, Collins R, Guyatt GH. A randomised trial to evaluate the self-administered standardised chronic respiratory questionnaire. European Respiratory Journal 2005; 25 : 31-40.

Schünemann HJ, Akl EA, Guyatt GH. Interpreting the results of patient reported outcome measures in clinical trials: the clinician's perspective. Health Qual Life Outcomes 2006; 4 : 62.

Singh SJ, Sodergren SC, Hyland ME, Williams J, Morgan MD. A comparison of three disease-specific and two generic health-status measures to evaluate the outcome of pulmonary rehabilitation in COPD. Respiratory Medicine 2001; 95 : 71-77.

Smith K, Cook D, Guyatt GH, Madhavan J, Oxman AD. Respiratory muscle training in chronic airflow limitation: a meta-analysis. American Review of Respiratory Disease 1992; 145 : 533-539.

Tarlov AR, Ware JE, Jr., Greenfield S, Nelson EC, Perrin E, Zubkoff M. The Medical Outcomes Study. An application of methods for monitoring the results of medical care. JAMA 1989; 262 : 925-930.

Tendal B, Nuesch E, Higgins JP, Jüni P, Gøtzsche PC. Multiplicity of data in trial reports and the reliability of meta-analyses: empirical study. BMJ 2011; 343 : d4829.

Thorlund K, Walter SD, Johnston BC, Furukawa TA, Guyatt GH. Pooling health-related quality of life outcomes in meta-analysis-a tutorial and review of methods for enhancing interpretability. Research Synthesis Methods 2011; 2 : 188-203.

Wainer H. Estimating coefficients in linear models: It don't make no nevermind. Psychological Bulletin 1976; 83 : 213-217.

Ware J, Jr., Kosinski M, Keller SD. A 12-Item Short-Form Health Survey: construction of scales and preliminary tests of reliability and validity. Medical Care 1996; 34 : 220-233.

Ware JE, Jr., Kosinski M, Bayliss MS, McHorney CA, Rogers WH, Raczek A. Comparison of methods for the scoring and statistical analysis of SF-36 health profile and summary measures: summary of results from the Medical Outcomes Study. Medical Care 1995; 33 : As264-279.

Wiebe S, Guyatt G, Weaver B, Matijevic S, Sidwell C. Comparative responsiveness of generic and specific quality-of-life instruments. Journal of Clinical Epidemiology 2003; 56 : 52-60.

Witter JP. Introduction: PROMIS a first look across diseases. Journal of Clinical Epidemiology 2016; 73 : 87-88.

Yohannes AM, Roomi J, Waters K, Connolly MJ. Quality of life in elderly patients with COPD: measurement and predictive factors. Respiratory Medicine 1998; 92 : 1231-1236.

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How to present patient cases

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• Mary Ni Lochlainn , foundation year 2 doctor 1 ,
• Ibrahim Balogun , healthcare of older people/stroke medicine consultant 1
• 1 East Kent Foundation Trust, UK

A guide on how to structure a case presentation

This article contains...

-History of presenting problem

-Medical and surgical history

-Drugs, including allergies to drugs

-Family history

-Social history

-Review of systems

-Findings on examination, including vital signs and observations

-Differential diagnosis/impression

-Investigations

-Management

Presenting patient cases is a key part of everyday clinical practice. A well delivered presentation has the potential to facilitate patient care and improve efficiency on ward rounds, as well as a means of teaching and assessing clinical competence. 1

The purpose of a case presentation is to communicate your diagnostic reasoning to the listener, so that he or she has a clear picture of the patient’s condition and further management can be planned accordingly. 2 To give a high quality presentation you need to take a thorough history. Consultants make decisions about patient care based on information presented to them by junior members of the team, so the importance of accurately presenting your patient cannot be overemphasised.

As a medical student, you are likely to be asked to present in numerous settings. A formal case presentation may take place at a teaching session or even at a conference or scientific meeting. These presentations are usually thorough and have an accompanying PowerPoint presentation or poster. More often, case presentations take place on the wards or over the phone and tend to be brief, using only memory or short, handwritten notes as an aid.

Everyone has their own presenting style, and the context of the presentation will determine how much detail you need to put in. You should anticipate what information your senior colleagues will need to know about the patient’s history and the care he or she has received since admission, to enable them to make further management decisions. In this article, I use a fictitious case to show how you can structure case presentations, which can be adapted to different clinical and teaching settings (box 1).

Box 1: Structure for presenting patient cases

Presenting problem, history of presenting problem, medical and surgical history.

Drugs, including allergies to drugs

Family history

Social history, review of systems.

Findings on examination, including vital signs and observations

Differential diagnosis/impression

Investigations

Case: tom murphy.

You should start with a sentence that includes the patient’s name, sex (Mr/Ms), age, and presenting symptoms. In your presentation, you may want to include the patient’s main diagnosis if known—for example, “admitted with shortness of breath on a background of COPD [chronic obstructive pulmonary disease].” You should include any additional information that might give the presentation of symptoms further context, such as the patient’s profession, ethnic origin, recent travel, or chronic conditions.

“ Mr Tom Murphy is a 56 year old ex-smoker admitted with sudden onset central crushing chest pain that radiated down his left arm.”

In this section you should expand on the presenting problem. Use the SOCRATES mnemonic to help describe the pain (see box 2). If the patient has multiple problems, describe each in turn, covering one system at a time.

Box 2: SOCRATES—mnemonic for pain

Associations

Time course

Exacerbating/relieving factors

“ The pain started suddenly at 1 pm, when Mr Murphy was at his desk. The pain was dull in nature, and radiated down his left arm. He experienced shortness of breath and felt sweaty and clammy. His colleague phoned an ambulance. He rated the pain 9/10 in severity. In the ambulance he was given GTN [glyceryl trinitrate] spray under the tongue, which relieved the pain to 5/10. The pain lasted 30 minutes in total. No exacerbating factors were noted. Of note: Mr Murphy is an ex-smoker with a 20 pack year history”

Some patients have multiple comorbidities, and the most life threatening conditions should be mentioned first. They can also be categorised by organ system—for example, “has a long history of cardiovascular disease, having had a stroke, two TIAs [transient ischaemic attacks], and previous ACS [acute coronary syndrome].” For some conditions it can be worth stating whether a general practitioner or a specialist manages it, as this gives an indication of its severity.

In a surgical case, colleagues will be interested in exercise tolerance and any comorbidity that could affect the patient’s fitness for surgery and anaesthesia. If the patient has had any previous surgical procedures, mention whether there were any complications or reactions to anaesthesia.

“Mr Murphy has a history of type 2 diabetes, well controlled on metformin. He also has hypertension, managed with ramipril, and gout. Of note: he has no history of ischaemic heart disease (relevant negative) (see box 3).”

Box 3: Relevant negatives

Mention any relevant negatives that will help narrow down the differential diagnosis or could be important in the management of the patient, 3 such as any risk factors you know for the condition and any associations that you are aware of. For example, if the differential diagnosis includes a condition that you know can be hereditary, a relevant negative could be the lack of a family history. If the differential diagnosis includes cardiovascular disease, mention the cardiovascular risk factors such as body mass index, smoking, and high cholesterol.

Highlight any recent changes to the patient’s drugs because these could be a factor in the presenting problem. Mention any allergies to drugs or the patient’s non-compliance to a previously prescribed drug regimen.

To link the medical history and the drugs you might comment on them together, either here or in the medical history. “Mrs Walsh’s drugs include regular azathioprine for her rheumatoid arthritis.”Or, “His regular drugs are ramipril 5 mg once a day, metformin 1g three times a day, and allopurinol 200 mg once a day. He has no known drug allergies.”

If the family history is unrelated to the presenting problem, it is sufficient to say “no relevant family history noted.” For hereditary conditions more detail is needed.

“ Mr Murphy’s father experienced a fatal myocardial infarction aged 50.”

Social history should include the patient’s occupation; their smoking, alcohol, and illicit drug status; who they live with; their relationship status; and their sexual history, baseline mobility, and travel history. In an older patient, more detail is usually required, including whether or not they have carers, how often the carers help, and if they need to use walking aids.

“He works as an accountant and is an ex-smoker since five years ago with a 20 pack year history. He drinks about 14 units of alcohol a week. He denies any illicit drug use. He lives with his wife in a two storey house and is independent in all activities of daily living.”

Do not dwell on this section. If something comes up that is relevant to the presenting problem, it should be mentioned in the history of the presenting problem rather than here.

“Systems review showed long standing occasional lower back pain, responsive to paracetamol.”

Findings on examination

Initially, it can be useful to practise presenting the full examination to make sure you don’t leave anything out, but it is rare that you would need to present all the normal findings. Instead, focus on the most important main findings and any abnormalities.

“On examination the patient was comfortable at rest, heart sounds one and two were heard with no additional murmurs, heaves, or thrills. Jugular venous pressure was not raised. No peripheral oedema was noted and calves were soft and non-tender. Chest was clear on auscultation. Abdomen was soft and non-tender and normal bowel sounds were heard. GCS [Glasgow coma scale] was 15, pupils were equal and reactive to light [PEARL], cranial nerves 1-12 were intact, and he was moving all four limbs. Observations showed an early warning score of 1 for a tachycardia of 105 beats/ min. Blood pressure was 150/90 mm Hg, respiratory rate 18 breaths/min, saturations were 98% on room air, and he was apyrexial with a temperature of 36.8 ºC.”

Differential diagnoses

Mentioning one or two of the most likely diagnoses is sufficient. A useful phrase you can use is, “I would like to rule out,” especially when you suspect a more serious cause is in the differential diagnosis. “History and examination were in keeping with diverticular disease; however, I would like to rule out colorectal cancer in this patient.”

Remember common things are common, so try not to mention rare conditions first. Sometimes it is acceptable to report investigations you would do first, and then base your differential diagnosis on what the history and investigation findings tell you.

“My impression is acute coronary syndrome. The differential diagnosis includes other cardiovascular causes such as acute pericarditis, myocarditis, aortic stenosis, aortic dissection, and pulmonary embolism. Possible respiratory causes include pneumonia or pneumothorax. Gastrointestinal causes include oesophageal spasm, oesophagitis, gastro-oesophageal reflux disease, gastritis, cholecystitis, and acute pancreatitis. I would also consider a musculoskeletal cause for the pain.”

This section can include a summary of the investigations already performed and further investigations that you would like to request. “On the basis of these differentials, I would like to carry out the following investigations: 12 lead electrocardiography and blood tests, including full blood count, urea and electrolytes, clotting screen, troponin levels, lipid profile, and glycated haemoglobin levels. I would also book a chest radiograph and check the patient’s point of care blood glucose level.”

You should consider recommending investigations in a structured way, prioritising them by how long they take to perform and how easy it is to get them done and how long it takes for the results to come back. Put the quickest and easiest first: so bedside tests, electrocardiography, followed by blood tests, plain radiology, then special tests. You should always be able to explain why you would like to request a test. Mention the patient’s baseline test values if they are available, especially if the patient has a chronic condition—for example, give the patient’s creatinine levels if he or she has chronic kidney disease This shows the change over time and indicates the severity of the patient’s current condition.

“To further investigate these differentials, 12 lead electrocardiography was carried out, which showed ST segment depression in the anterior leads. Results of laboratory tests showed an initial troponin level of 85 µg/L, which increased to 1250 µg/L when repeated at six hours. Blood test results showed raised total cholesterol at 7.6 mmol /L and nil else. A chest radiograph showed clear lung fields. Blood glucose level was 6.3 mmol/L; a glycated haemoglobin test result is pending.”

Dependent on the case, you may need to describe the management plan so far or what further management you would recommend.“My management plan for this patient includes ACS [acute coronary syndrome] protocol, echocardiography, cardiology review, and treatment with high dose statins. If you are unsure what the management should be, you should say that you would discuss further with senior colleagues and the patient. At this point, check to see if there is a treatment escalation plan or a “do not attempt to resuscitate” order in place.

“Mr Murphy was given ACS protocol in the emergency department. An echocardiogram has been requested and he has been discussed with cardiology, who are going to come and see him. He has also been started on atorvastatin 80 mg nightly. Mr Murphy and his family are happy with this plan.”

The summary can be a concise recap of what you have presented beforehand or it can sometimes form a standalone presentation. Pick out salient points, such as positive findings—but also draw conclusions from what you highlight. Finish with a brief synopsis of the current situation (“currently pain free”) and next step (“awaiting cardiology review”). Do not trail off at the end, and state the diagnosis if you are confident you know what it is. If you are not sure what the diagnosis is then communicate this uncertainty and do not pretend to be more confident than you are. When possible, you should include the patient’s thoughts about the diagnosis, how they are feeling generally, and if they are happy with the management plan.

“In summary, Mr Murphy is a 56 year old man admitted with central crushing chest pain, radiating down his left arm, of 30 minutes’ duration. His cardiac risk factors include 20 pack year smoking history, positive family history, type 2 diabetes, and hypertension. Examination was normal other than tachycardia. However, 12 lead electrocardiography showed ST segment depression in the anterior leads and troponin rise from 85 to 250 µg/L. Acute coronary syndrome protocol was initiated and a diagnosis of NSTEMI [non-ST elevation myocardial infarction] was made. Mr Murphy is currently pain free and awaiting cardiology review.”

Originally published as: Student BMJ 2017;25:i4406

Competing interests: None declared.

Provenance and peer review: Not commissioned; externally peer reviewed

• ↵ Green EH, Durning SJ, DeCherrie L, Fagan MJ, Sharpe B, Hershman W. Expectations for oral case presentations for clinical clerks: opinions of internal medicine clerkship directors. J Gen Intern Med 2009 ; 24 : 370 - 3 . doi:10.1007/s11606-008-0900-x   pmid:19139965 . OpenUrl CrossRef PubMed Web of Science
• ↵ Olaitan A, Okunade O, Corne J. How to present clinical cases. Student BMJ 2010;18:c1539.
• ↵ Gaillard F. The secret art of relevant negatives, Radiopedia 2016; http://radiopaedia.org/blog/the-secret-art-of-relevant-negatives .

Clinical outcome

A clinical outcome is a measurable change in symptoms, overall health, ability to function, quality of life, or survival outcomes that result from giving care to patients. Clinical outcomes may be used in clinical settings, such as a hospital or doctor’s office, to measure the success of care or to assess a person’s response to an already approved treatment. One or more clinical outcomes may be used in clinical trials as an endpoint to determine how well a new therapy works and/or the safety of a new therapy.

Sourced From U.S. Food and Drug Administration (FDA) Patient-Focused Drug Development Glossary Glossary from “BEST (Biomarkers, EndpointS, and other Tools) Resource” [Internet]. Learn More U.S. Food and Drug Administration (FDA): Multiple Endpoints in Clinical Trials Guidance for Industry U.S. Food and Drug Administration (FDA): Surrogate Endpoint Resources for Drug and Biologic Development

• Glossary: Clinician-reported outcomes (ClinRO)
• Glossary: Patient-reported outcome
• Glossary: Surrogate endpoint

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Thick Liquids and Clinical Outcomes in Hospitalized Patients With Alzheimer Disease and Related Dementias and Dysphagia

• 1 Northwell, New Hyde Park, New York
• 2 Department of Medicine, Zucker School of Medicine at Hofstra/Northwell, Northwell, Hempstead, New York
• 3 Institute of Health System Science, Feinstein Institutes for Medical Research, Northwell, Manhasset, New York
• 4 School of Communication Sciences and Disorders, Faculty of Health, Dalhousie University, Halifax, Nova Scotia, Canada
• 5 Division of Geriatrics and Gerontology, Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison
• 6 Geriatric Research Education and Clinical Center, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin
• Invited Commentary Thinning Evidence for Thickened Liquid Diets in Dementia and Dysphagia Eric Widera, MD JAMA Internal Medicine

Question   Are thick liquids associated with improved clinical outcomes in hospitalized patients with Alzheimer disease and related dementias (ADRD) and oropharyngeal dysphagia?

Findings   This matched cohort study of 8916 patients with ADRD and dysphagia found no difference in mortality rates between patients receiving thick vs thin liquids. Compared with patients receiving thin liquids, patients receiving thick liquids were less likely to be intubated, but more likely to have respiratory complications (eg, pneumonia).

Meaning   Findings of this study highlight the need for prospective studies to evaluate the effectiveness of thick liquids for improving clinical outcomes in hospitalized patients with ADRD and dysphagia.

Importance   Oropharyngeal dysphagia is common in hospitalized patients with Alzheimer disease and related dementias (ADRD). Although the use of thick liquids in patients with dysphagia has been shown to reduce aspiration on direct visualization, there is no clear evidence that this practice translates into improved clinical outcomes.

Objectives   To determine whether a diet of thick liquids compared with thin liquids is associated with improved outcomes in hospitalized patients with ADRD and dysphagia.

Design, Setting, and Participants   This cohort study included adults aged 65 years and older with ADRD who were admitted to the medicine service across 11 diverse hospitals in New York between January 1, 2017, and September 20, 2022, with clinical suspicion of dysphagia during hospitalization and survival for at least 24 hours after hospital arrival. Patients were grouped according to whether at least 75% of their hospital diet consisted of a thick liquid diet or a thin liquid diet. Propensity score matching was used to balance covariates across the 2 groups for the following covariates: demographics (eg, age, sex), baseline clinical characteristics (eg, Charlson Comorbidity Index), and acute presentation (eg, respiratory diagnosis, illness severity, delirium).

Main Outcomes and Measures   Hospital outcomes included mortality (primary outcome), respiratory complications (eg, pneumonia), intubation, and hospital length of stay (LOS).

Results   Of 8916 patients with ADRD and dysphagia included in the propensity score matched analysis, the mean (SD) age was 85.7 (8.0) years and 4829 were female (54.2%). A total of 4458 patients receiving a thick liquid diet were matched with 4458 patients receiving a thin liquid diet. There was no significant difference in hospital mortality between the thick liquids and thin liquids groups (hazard ratio, 0.92; 95% CI, 0.75-1.14]; P  = .46). Compared with patients receiving thin liquids, patients receiving thick liquids were less likely to be intubated (odds ratio [OR], 0.66; 95% CI, 0.54-0.80), but they were more likely to have respiratory complications (OR, 1.73; 95% CI, 1.56-1.91).

Conclusions and Relevance   This cohort study emphasizes the need for prospective studies that evaluate whether thick liquids are associated with improved clinical outcomes in hospitalized patients with ADRD and dysphagia.

• Invited Commentary Thinning Evidence for Thickened Liquid Diets in Dementia and Dysphagia JAMA Internal Medicine

Read More About

Makhnevich A , Perrin A , Talukder D, et al. Thick Liquids and Clinical Outcomes in Hospitalized Patients With Alzheimer Disease and Related Dementias and Dysphagia. JAMA Intern Med. Published online May 06, 2024. doi:10.1001/jamainternmed.2024.0736

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• Review Article
• Published: 02 July 2013

Presentation, management, and outcomes of ischaemic heart disease in women

• Viola Vaccarino 1 ,
• Lina Badimon 2 ,
• Roberto Corti 3 ,
• Cor de Wit 4 ,
• Maria Dorobantu 5 ,
• Olivia Manfrini 8 ,
• Akos Koller 6 ,
• Axel Pries 7 ,
• Edina Cenko 8 &
• Raffaele Bugiardini 8  

Nature Reviews Cardiology volume  10 ,  pages 508–518 ( 2013 ) Cite this article

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• Coronary artery disease and stable angina
• Therapeutics

Scientific interest in ischaemic heart disease (IHD) in women has grown considerably over the past 2 decades. A substantial amount of the literature on this subject is centred on sex differences in clinical aspects of IHD. Many reports have documented sex-related differences in presentation, risk profiles, and outcomes among patients with IHD, particularly acute myocardial infarction. Such differences have often been attributed to inequalities between men and women in the referral and treatment of IHD, but data are insufficient to support this assessment. The determinants of sex differences in presentation are unclear, and few clues are available as to why young, premenopausal women paradoxically have a greater incidence of adverse outcomes after acute myocardial infarction than men, despite having less-severe coronary artery disease. Although differential treatment on the basis of patient sex continues to be described, the extent to which such inequalities persist and whether they reflect true disparity is unclear. Additionally, much uncertainty surrounds possible sex-related differences in response to cardiovascular therapies, partly because of a persistent lack of female-specific data from cardiovascular clinical trials. In this Review, we assess the evidence for sex-related differences in the clinical presentation, treatment, and outcome of IHD, and identify gaps in the literature that need to be addressed in future research efforts.

Important differences exist between women and men in clinical presentation, recognition of symptoms by patients and physicians, outcome, and response to treatment for ischaemic heart disease (IHD)

Among patients with IHD, environmental or behavioural causes of sex-related differences in outcomes might be more important than biological factors

Onset of IHD in women, manifesting as an acute myocardial infarction before the age of 65 years, is associated with adverse outcomes compared with men of a similar age

A traditional diagnostic strategy, focusing on detection of severe coronary stenoses, is likely to be inadequate in women

Additional invasive testing aimed at determining endothelial coronary dysfunction might be useful to risk-stratify women with chest pain and minimal or no obstructive coronary artery disease

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Go, A. S. et al . Heart disease and stroke statistics—2013 update: a report from the American Heart Association. Circulation 127 , e6–e245 (2013).

PubMed   Google Scholar  

Poon, S. et al . Bridging the gender gap: insights from a contemporary analysis of sex-related differences in the treatment and outcomes of patients with acute coronary syndromes. Am. Heart J. 163 , 66–73 (2012).

Article   PubMed   Google Scholar  

Rajadurai, J. et al . Women's cardiovascular health: perspectives from South-East Asia. Nat. Rev. Cardiol. 9 , 464–477 (2012).

Vaccarino, V. Ischemic heart disease in women: many questions, few facts. Circ. Cardiovasc. Qual. Outcomes 3 , 111–115 (2010).

Article   PubMed   PubMed Central   Google Scholar  

Murabito, J. M., Evans, J. C., Larson, M. G. & Levy, D. Prognosis after the onset of coronary heart disease. An investigation of differences in outcome between the sexes according to initial coronary disease presentation. Circulation 88 , 2548–2555 (1993).

Article   CAS   PubMed   Google Scholar  

Lerner, D. J. & Kannel, W. B. Patterns of coronary heart disease morbidity and mortality in the sexes: a 26-year follow-up of the Framingham population. Am. Heart J. 111 , 383–390 (1986).

Hemingway, H. et al . Prevalence of angina in women versus men: a systematic review and meta-analysis of international variations across 31 countries. Circulation 117 , 1526–1536 (2008).

Hochman, J. S. et al . Sex, clinical presentation, and outcome in patients with acute coronary syndromes. N. Engl. J. Med. 341 , 226–232 (1999).

Berger, J. S. et al . Sex differences in mortality following acute coronary syndromes. JAMA 302 , 874–882 (2009).

Article   CAS   PubMed   PubMed Central   Google Scholar  

Genders, T. S. et al . A clinical prediction rule for the diagnosis of coronary artery disease: validation, updating, and extension. Eur. Heart J. 32 , 1316–1330 (2011).

Milner, K. A., Funk, M., Arnold, A. & Vaccarino, V. Typical symptoms are predictive of acute coronary syndromes in women. Am. Heart J. 143 , 283–288 (2002).

Canto, J. G. et al . Association of age and sex with myocardial infarction symptom presentation and in-hospital mortality. JAMA 307 , 813–822 (2012).

CAS   PubMed   PubMed Central   Google Scholar  

Milner, K. A. et al . Gender differences in symptom presentation associated with coronary heart disease. Am. J. Cardiol. 84 , 396–399 (1999).

Bugiardini, R. Women, 'nonspecific' chest pain, and normal or near-normal coronary angiograms are not synonymous with favourable outcome. Eur. Heart J. 27 , 1387–1389 (2006).

Kreatsoulas, C., Shannon, H. S., Giacomini, M., Velianou, J. L. & Anand, S. S. Reconstructing angina: cardiac symptoms are the same in women and men. JAMA Intern. Med. 173 , 829–833 (2013).

Mackay, M. H., Ratner, P. A., Johnson, J. L., Humphries, K. H. & Buller, C. E. Gender differences in symptoms of myocardial ischaemia. Eur. Heart J. 32 , 3107–3114 (2011).

Bugiardini, R. & Bairey Merz, C. N. Angina with “normal” coronary arteries: a changing philosophy. JAMA 293 , 477–484 (2005).

Bugiardini, R. et al . Angina, “normal” coronary angiography, and vascular dysfunction: risk assessment strategies. PLoS Med. 4 , e12 (2007).

Shaw, L. J., Bugiardini, R. & Merz, C. N. Women and ischemic heart disease: evolving knowledge. J. Am. Coll. Cardiol. 54 , 1561–1575 (2009).

Mosca, L., Mochari-Greenberger, H., Dolor, R. J., Newby, L. K. & Robb, K. J. Twelve-year follow-up of American women's awareness of cardiovascular disease risk and barriers to heart health. Circ. Cardiovasc. Qual. Outcomes 3 , 120–127 (2010).

Mosca, L. et al . Fifteen-year trends in awareness of heart disease in women: results of a 2012 American Heart Association national survey. Circulation 127 , 1254–1263 (2013).

Fukuoka, Y. et al . Is severity of chest pain a cue for women and men to recognize acute myocardial infarction symptoms as cardiac in origin? Prog. Cardiovasc. Nurs. 22 , 132–137 (2007).

Rosengren, A. et al . Sex, age, and clinical presentation of acute coronary syndromes. Eur. Heart J. 25 , 663–670 (2004).

Mulvagh, S. L. et al . Contrast echocardiography: current and future applications. J. Am. Soc. Echocardiogr. 13 , 331–342 (2000).

Nandalur, K. R., Dwamena, B. A., Choudhri, A. F., Nandalur, M. R. & Carlos, R. C. Diagnostic performance of stress cardiac magnetic resonance imaging in the detection of coronary artery disease: a meta-analysis. J. Am. Coll. Cardiol. 50 , 1343–1353 (2007).

Centers for Disease Control and Prevention (CDC). Prevalence of heart disease—United States, 2006–2010. MMWR Morb. Mortal. Wkly Rep. 60 , 1377–1381 (2011).

Gibbons, R. J. et al . ACC/AHA 2002 guideline update for exercise testing: summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1997 Exercise Testing Guidelines). Circulation 106 , 1883–1892 (2002).

Shaw, L. J. et al . The value of estimated functional capacity in estimating outcome: results from the NHBLI-Sponsored Women's Ischemia Syndrome Evaluation (WISE) Study. J. Am. Coll. Cardiol. 47 , S36–S43 (2006).

Mieres, J. H. et al . Role of noninvasive testing in the clinical evaluation of women with suspected coronary artery disease: consensus statement from the Cardiac Imaging Committee, Council on Clinical Cardiology, and the Cardiovascular Imaging and Intervention Committee, Council on Cardiovascular Radiology and Intervention, American Heart Association. Circulation 111 , 682–696 (2005).

Grzybowski, A. et al . How to improve noninvasive coronary artery disease diagnostics in premenopausal women? The influence of menstrual cycle on ST depression, left ventricle contractility, and chest pain observed during exercise echocardiography in women with angina and normal coronary angiogram. Am. Heart J. 156 , 964.e1–964.e5 (2008).

Article   Google Scholar  

Shaw, L. J. et al . Insights from the NHLBI-Sponsored Women's Ischemia Syndrome Evaluation (WISE) study: part I: gender differences in traditional and novel risk factors, symptom evaluation, and gender-optimized diagnostic strategies. J. Am. Coll. Cardiol. 47 (Suppl.), S4–S20 (2006).

Lanza, G. A. & Crea, F. Primary coronary microvascular dysfunction: clinical presentation, pathophysiology, and management. Circulation 121 , 2317–2325 (2010).

Maseri, A., Crea, F., Kaski, J. C. & Crake, T. Mechanisms of angina pectoris in syndrome X. J. Am. Coll. Cardiol. 17 , 499–506 (1991).

Bugiardini, R., Pozzati, A., Ottani, F., Morgagni, G. L. & Puddu, P. Vasotonic angina: a spectrum of ischemic syndromes involving functional abnormalities of the epicardial and microvascular coronary circulation. J. Am. Coll. Cardiol. 22 , 417–425 (1993).

Gan, S. C. et al . Treatment of acute myocardial infarction and 30-day mortality among women and men. N. Engl. J. Med. 343 , 8–15 (2000).

Bugiardini, R., Manfrini, O. & De Ferrari, G. M. Unanswered questions for management of acute coronary syndrome: risk stratification of patients with minimal disease or normal findings on coronary angiography. Arch. Intern. Med. 166 , 1391–1395 (2006).

Scanlon, P. J. et al . ACC/AHA guidelines for coronary angiography: executive summary and recommendations. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Coronary Angiography) developed in collaboration with the Society for Cardiac Angiography and Interventions. Circulation 99 , 2345–2357 (1999).

Ong, P. et al . High prevalence of a pathological response to acetylcholine testing in patients with stable angina pectoris and unobstructed coronary arteries. The ACOVA Study (Abnormal COronary VAsomotion in patients with stable angina and unobstructed coronary arteries). J. Am. Coll. Cardiol. 59 , 655–662 (2012).

Budoff, M. J. et al . Diagnostic performance of 64-multidetector row coronary computed tomographic angiography for evaluation of coronary artery stenosis in individuals without known coronary artery disease: results from the prospective multicentre ACCURACY (Assessment by Coronary Computed Tomographic Angiography of Individuals Undergoing Invasive Coronary Angiography) trial. J. Am. Coll. Cardiol. 52 , 1724–1732 (2008).

Beigel, R. et al . Prognostic implications of nonobstructive coronary artery disease in patients undergoing coronary computed tomographic angiography for acute chest pain. Am. J. Cardiol. 111 , 941–945 (2013).

Lin, F. Y. et al . Mortality risk in symptomatic patients with nonobstructive coronary artery disease: a prospective 2-centre study of 2,583 patients undergoing 64-detector row coronary computed tomographic angiography. J. Am. Coll. Cardiol. 58 , 510–519 (2011).

Min, J. K. et al . Age- and sex-related differences in all-cause mortality risk based on coronary computed tomography angiography findings results from the International Multicentre CONFIRM (Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicentre Registry) of 23,854 patients without known coronary artery disease. J. Am. Coll. Cardiol. 58 , 849–860 (2011).

Martinez, M. W. et al . Myocardial infarction with normal coronary arteries: a role for MRI? Clin. Chem. 53 , 995–996 (2007).

Steg, P. G. et al . Impact of collateral flow to the occluded infarct-related artery on clinical outcomes in patients with recent myocardial infarction: a report from the randomized occluded artery trial. Circulation 121 , 2724–2730 (2010).

Wolff, S. D. et al . Myocardial first-pass perfusion magnetic resonance imaging: a multicentre dose-ranging study. Circulation 110 , 732–737 (2004).

Schwitter, J. et al . MR-IMPACT: comparison of perfusion-cardiac magnetic resonance with single-photon emission computed tomography for the detection of coronary artery disease in a multicentre, multivendor, randomized trial. Eur. Heart J. 29 , 480–489 (2008).

Panting, J. R. et al . Abnormal subendocardial perfusion in cardiac syndrome X detected by cardiovascular magnetic resonance imaging. N. Engl. J. Med. 346 , 1948–1953 (2002).

Schwitter, J. Extending the frontiers of cardiac magnetic resonance. Circulation 118 , 109–112 (2008).

Reynolds, H. R. et al . Mechanisms of myocardial infarction in women without angiographically obstructive coronary artery disease. Circulation 124 , 1414–1425 (2011).

Mieres, J. H. et al . American Society of Nuclear Cardiology consensus statement: Task Force on Women and Coronary Artery Disease—the role of myocardial perfusion imaging in the clinical evaluation of coronary artery disease in women [correction]. J. Nucl. Cardiol. 10 , 95–101 (2003).

Klocke, F. J. et al . ACC/AHA/ASNC guidelines for the clinical use of cardiac radionuclide imaging--executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/ASNC Committee to revise the 1995 guidelines for the clinical use of cardiac radionuclide imaging). Circulation 108 , 1404–1418 (2003).

Matsunari, I. et al . Attenuation-corrected rest thallium-201/stress technetium 99m sestamibi myocardial SPECT in normals. J. Nucl. Cardiol. 5 , 48–55 (1998).

Hemingway, H. et al . Incidence and prognostic implications of stable angina pectoris among women and men. JAMA 295 , 1404–1411 (2006).

Daly, C. et al . Gender differences in the management and clinical outcome of stable angina. Circulation 113 , 490–498 (2006).

Fox, K. et al . Guidelines on the management of stable angina pectoris: executive summary: the Task Force on the Management of Stable Angina Pectoris of the European Society of Cardiology. Eur. Heart J. 27 , 1341–1381 (2006).

Crilly, M., Bundred, P., Hu, X., Leckey, L. & Johnstone, F. Gender differences in the clinical management of patients with angina pectoris: a cross-sectional survey in primary care. BMC Health Serv. Res. 7 , 142 (2007).

Johnston, N., Schenck-Gustafsson, K. & Lagerqvist, B. Are we using cardiovascular medications and coronary angiography appropriately in men and women with chest pain? Eur. Heart J. 32 , 1331–1336 (2011).

Vaccarino, V., Krumholz, H. M., Berkman, L. F. & Horwitz, R. I. Sex differences in mortality after myocardial infarction. Is there evidence for an increased risk for women? Circulation 91 , 1861–1871 (1995).

Wenger, N. K., Shaw, L. J. & Vaccarino, V. Coronary heart disease in women: update 2008. Clin. Pharmacol. Ther. 83 , 37–51 (2008).

Champney, K. P. et al . The joint contribution of sex, age and type of myocardial infarction on hospital mortality following acute myocardial infarction. Heart 95 , 895–899 (2009).

Jneid, H. et al . Sex differences in medical care and early death after acute myocardial infarction. Circulation 118 , 2803–2810 (2008).

Capewell, S. et al . Short-term and long-term outcomes in 133,429 emergency patients admitted with angina or myocardial infarction in Scotland, 1990–2000: population-based cohort study. Heart 92 , 1563–1570 (2006).

Fuster, V. Elucidation of the role of plaque instability and rupture in acute coronary events. Am. J. Cardiol. 76 , 24C–33C (1995).

Fibrinolytic Therapy Trialists' (FTT) Collaborative Group. Indications for fibrinolytic therapy in suspected acute myocardial infarction: collaborative overview of early mortality and major morbidity results from all randomised trials of more than 1,000 patients. Lancet 343 , 311–322 (1994).

Tamis-Holland, J. E. et al . Benefits of direct angioplasty for women and men with acute myocardial infarction: results of the Global Use of Strategies to Open Occluded Arteries in Acute Coronary Syndromes Angioplasty (GUSTO II-B) angioplasty substudy. Am. Heart J. 147 , 133–139 (2004).

Kim, E. S. & Menon, V. Status of women in cardiovascular clinical trials. Arterioscler. Thromb. Vac. Biol. 29 , 279–283 (2009).

Article   CAS   Google Scholar  

Bavry, A. A. et al . Invasive therapy along with glycoprotein IIb/IIIa inhibitors and intracoronary stents improves survival in non-ST-segment elevation acute coronary syndromes: a meta-analysis and review of the literature. Am. J. Cardiol. 93 , 830–835 (2004).

Glaser, R. et al . Benefit of an early invasive management strategy in women with acute coronary syndromes. JAMA 288 , 3124–3129 (2002).

Lansky, A. J. et al . Percutaneous coronary intervention and adjunctive pharmacotherapy in women: a statement for healthcare professionals from the American Heart Association. Circulation 111 , 940–953 (2005).

Cho, L. et al . Clinical benefit of glycoprotein IIb/IIIa blockade with abciximab is independent of gender: pooled analysis from EPIC, EPILOG and EPISTENT trials. Evaluation of 7E3 for the prevention of ischemic complications. Evaluation in percutaneous transluminal coronary angioplasty to improve long-term outcome with abciximab GP IIb/IIIa blockade. Evaluation of platelet IIb/IIIa inhibitor for stent. J. Am. Coll. Cardiol. 36 , 381–386 (2000).

Boersma, E. et al . Platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndromes: a meta-analysis of all major randomised clinical trials. Lancet 359 , 189–198 (2002).

Healy, B. The Yentl syndrome. N. Engl. J. Med. 325 , 274–276 (1991).

Bugiardini, R., Oestrada, J. L., Nikus, K., Hall, A. S. & Manfrini, O. Gender bias in acute coronary syndromes. Curr. Vasc. Pharmacol. 8 , 276–284 (2010).

Blomkalns, A. L. et al . Gender disparities in the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes: large-scale observations from the CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the American College of Cardiology/American Heart Association Guidelines) national quality improvement initiative. J. Am. Coll. Cardiol. 45 , 832–837 (2005).

Anand, S. S. et al . Differences in the management and prognosis of women and men who suffer from acute coronary syndromes. J. Am. Coll. Cardiol. 46 , 1845–1851 (2005).

Dey, S. et al . Sex-related differences in the presentation, treatment and outcomes among patients with acute coronary syndromes: the Global Registry of Acute Coronary Events. Heart 95 , 20–26 (2009).

Vaccarino, V. et al . Sex and racial differences in the management of acute myocardial infarction, 1994 through 2002. N. Engl. J. Med. 353 , 671–682 (2005).

Karp, I., Chen, S. F. & Pilote, L. Sex differences in the effectiveness of statins after myocardial infarction. CMAJ 176 , 333–338 (2007).

Walsh, J. M. & Pignone, M. Drug treatment of hyperlipidemia in women. JAMA 291 , 2243–2252 (2004).

Shekelle, P. G. et al . Efficacy of angiotensin-converting enzyme inhibitors and beta-blockers in the management of left ventricular systolic dysfunction according to race, gender, and diabetic status: a meta-analysis of major clinical trials. J. Am. Coll. Cardiol. 41 , 1529–1538 (2003).

First International Study of Infarct Survival Collaborative Group. Randomised trial of intravenous atenolol among 16,027 cases of suspected acute myocardial infarction: ISIS-1. Lancet 2 , 57–66 (1986).

Institute of Medicine (eds Wizemann, T. & Pardue, M.) Exploring the Biological Contributions to Human Health: Does Sex Matter? (The National Academy Press, 2001).

Aldea, G. S. et al . Effect of gender on postoperative outcomes and hospital stays after coronary artery bypass grafting. Ann. Thorac. Surg. 67 , 1097–1103 (1999).

Stern, S. & Bayes de Luna, A. Coronary artery spasm: a 2009 update. Circulation 119 , 2531–2534 (2009).

Selzer, A., Langston, M., Ruggeroli, C. & Cohn, K. Clinical syndrome of variant angina with normal coronary arteriogram. N. Engl. J. Med. 295 , 1343–1347 (1976).

Seung-Woon, R. et al . The impact of gender difference on angiographic characteristics during intracoronary acetylcholine provocation test in Korean patients [abstract TCT-437]. J. Am. Coll. Cardiol. 60 (Suppl. B), B124 (2012).

Google Scholar  

Bory, M. et al . Coronary artery spasm in patients with normal or near normal coronary arteries. Long-term follow-up of 277 patients. Eur. Heart J. 17 , 1015–1021 (1996).

Pozzati, A., Pancaldi, L. G., Di Pasquale, G., Pinelli, G. & Bugiardini, R. Transient sympathovagal imbalance triggers “ischemic” sudden death in patients undergoing electrocardiographic Holter monitoring. J. Am. Coll. Cardiol. 27 , 847–852 (1996).

Yoo, S. Y. & Kim, J. Y. Recent insights into the mechanisms of vasospastic angina. Korean Circ. J. 39 , 505–511 (2009).

Egashira, K. et al . Basal release of endothelium-derived nitric oxide at site of spasm in patients with variant angina. J. Am. Coll. Cardiol. 27 , 1444–1449 (1996).

Walling, A. et al . Long-term prognosis of patients with variant angina. Circulation 76 , 990–997 (1987).

Mishra, P. K. Variations in presentation and various options in management of variant angina. Eur. J. Cardiothorac. Surg. 29 , 748–759 (2006).

Waters, D. D. et al . Factors influencing the long-term prognosis of treated patients with variant angina. Circulation 68 , 258–265 (1983).

Ong, P., Athanasiadis, A., Borgulya, G., Voehringer, M. & Sechtem, U. 3-year follow-up of patients with coronary artery spasm as cause of acute coronary syndrome: the CASPAR (coronary artery spasm in patients with acute coronary syndrome) study follow-up. J. Am. Coll. Cardiol. 57 , 147–152 (2011).

Asbury, E. A., Creed, F. & Collins, P. Distinct psychosocial differences between women with coronary heart disease and cardiac syndrome X. Eur. Heart J. 25 , 1695–1701 (2004).

Camici, P. G. & Crea, F. Coronary microvascular dysfunction. N. Engl. J. Med. 356 , 830–840 (2007).

Khuddus, M. A. et al . An intravascular ultrasound analysis in women experiencing chest pain in the absence of obstructive coronary artery disease: a substudy from the National Heart, Lung and Blood Institute-sponsored Women's Ischemia Syndrome Evaluation (WISE). J. Interv. Cardiol. 23 , 511–519 (2010).

Wenger, N. K. Women and coronary heart disease: a century after Herrick: understudied, underdiagnosed, and undertreated. Circulation 126 , 604–611 (2012).

Bairey Merz, C. N. et al . Insights from the NHLBI-Sponsored Women's Ischemia Syndrome Evaluation (WISE) study: part II: gender differences in presentation, diagnosis, and outcome with regard to gender-based pathophysiology of atherosclerosis and macrovascular and microvascular coronary disease. J. Am. Coll. Cardiol. 47 (3 Suppl.), S21–S29 (2006).

Jespersen, L. et al . Stable angina pectoris with no obstructive coronary artery disease is associated with increased risks of major adverse cardiovascular events. Eur. Heart J. 33 , 734–744 (2012).

Kaski, J. C. et al . Cardiac syndrome X: clinical characteristics and left ventricular function. Long-term follow-up study. J. Am. Coll. Cardiol. 25 , 807–814 (1995).

Gulati, M. et al . Adverse cardiovascular outcomes in women with nonobstructive coronary artery disease: a report from the Women's Ischemia Syndrome Evaluation Study and the St James Women Take Heart Project. Arch. Intern. Med. 169 , 843–850 (2009).

Johnson, B. D. et al . Prognosis in women with myocardial ischemia in the absence of obstructive coronary disease: results from the National Institutes of Health-National Heart, Lung, and Blood Institute-Sponsored Women's Ischemia Syndrome Evaluation (WISE). Circulation 109 , 2993–2999 (2004).

Oerlemans, J. G., Lagro-Janssen, A. L. & Bakx, C. Angina pectoris and normal coronary arteries: prevalence and prognosis in men and women [Dutch]. Ned. Tijdschr. Geneeskd. 144 , 522–527 (2000).

CAS   PubMed   Google Scholar  

von Mering, G. O. et al . Abnormal coronary vasomotion as a prognostic indicator of cardiovascular events in women: results from the National Heart, Lung, and Blood Institute-Sponsored Women's Ischemia Syndrome Evaluation (WISE). Circulation 109 , 722–725 (2004).

Bugiardini, R., Manfrini, O., Pizzi, C., Fontana, F. & Morgagni, G. Endothelial function predicts future development of coronary artery disease: a study of women with chest pain and normal coronary angiograms. Circulation 109 , 2518–2523 (2004).

Pepine, C. J. et al . Coronary microvascular reactivity to adenosine predicts adverse outcome in women evaluated for suspected ischemia: results from the National Heart, Lung and Blood Institute WISE (Women's Ischemia Syndrome Evaluation) Study. J. Am. Coll. Cardiol. 55 , 2825–2832 (2010).

Britten, M. B., Zeiher, A. M. & Schächinger, V. Microvascular dysfunction in angiographically normal or mildly diseased coronary arteries predicts adverse cardiovascular long-term outcome. Coron. Artery Dis. 15 , 259–264 (2004).

Fragasso, G. et al . Coronary slow-flow causing transient myocardial hypoperfusion in patients with cardiac syndrome X: long-term clinical and functional prognosis. Int. J. Cardiol. 137 , 137–144 (2009).

Bugiardini, R., Borghi, A., Biagetti, L. & Puddu, P. Comparison of verapamil versus propranolol therapy in syndrome X. Am. J. Cardiol. 63 , 286–290 (1989).

Xhyheri, B. & Bugiardini, R. Diagnosis and treatment of heart disease: are women different from men? Prog. Cardiovasc. Dis. 53 , 227–236 (2010).

Kaski, J. C., Rosano, G., Gavrielides, S. & Chen, L. Effects of angiotensin-converting enzyme inhibition on exercise-induced angina and ST segment depression in patients with microvascular angina. J. Am. Coll. Cardiol. 23 , 652–657 (1994).

Nalbantgil, I. et al . Therapeutic benefits of cilazapril in patients with syndrome X. Cardiology 89 , 130–133 (1998).

Pauly, D. F. et al . In women with symptoms of cardiac ischemia, nonobstructive coronary arteries, and microvascular dysfunction, angiotensin-converting enzyme inhibition is associated with improved microvascular function: A double-blind randomized study from the National Heart, Lung and Blood Institute Women's Ischemia Syndrome Evaluation (WISE). Am. Heart J. 162 , 678–684 (2011).

Akashi, Y. J., Nef, H. M., Mollmann, H. & Ueyama, T. Stress cardiomyopathy. Annu. Rev. Med. 61 , 271–286 (2010).

Yoshioka, T. et al . Clinical implications of midventricular obstruction and intravenous propranolol use in transient left ventricular apical ballooning (Tako-tsubo cardiomyopathy). Am. Heart J. 155 , 526.e1–526.e7 (2008).

Wittstein, I. S. et al . Neurohumoral features of myocardial stunning due to sudden emotional stress. N. Engl. J. Med. 352 , 539–548 (2005).

Bielecka-Dabrowa, A. et al . Takotsubo cardiomyopathy—the current state of knowledge. Int. J. Cardiol. 142 , 120–125 (2010).

Akashi, Y. J., Goldstein, D. S., Barbaro, G. & Ueyama, T. Takotsubo cardiomyopathy: a new form of acute, reversible heart failure. Circulation 118 , 2754–2762 (2008).

Edwards, F. H., Carey, J. S., Grover, F. L., Bero, J. W. & Hartz, R. S. Impact of gender on coronary bypass operative mortality. Ann. Thorac. Surg. 66 , 125–131 (1998).

Weintraub, W. S., Wenger, N. K., Jones, E. L., Craver, J. M. & Guyton, R. A. Changing clinical characteristics of coronary surgery patients. Differences between men and women. Circulation 88 , II79–II86 (1993).

Woods, S. E., Noble, G., Smith, J. M. & Hasselfeld, K. The influence of gender in patients undergoing coronary artery bypass graft surgery: an eight-year prospective hospitalized cohort study. J. Am. Coll. Surg. 196 , 428–434 (2003).

Vaccarino, V., Abramson, J. L., Veledar, E. & Weintraub, W. S. Sex differences in hospital mortality after coronary artery bypass surgery: evidence for a higher mortality in younger women. Circulation 105 , 1176–1181 (2002).

Kelsey, S. F. et al . Results of percutaneous transluminal coronary angioplasty in women. 1985–1986 National Heart, Lung, and Blood Institute's Coronary Angioplasty Registry. Circulation 87 , 720–727 (1993).

Holubkov, R. et al . Angina 1 year after percutaneous coronary intervention: a report from the NHLBI Dynamic Registry. Am. Heart J. 144 , 826–833 (2002).

Jacobs, A. K. et al . Better outcome for women compared with men undergoing coronary revascularization: a report from the Bypass Angioplasty Revascularization Investigation (BARI). Circulation 98 , 1279–1285 (1998).

Thompson, C. A. et al . Gender-based differences of percutaneous coronary intervention in the drug-eluting stent era. Catheter. Cardiovasc. Interv. 67 , 25–31 (2006).

Abbott, J. D. et al . Gender-based outcomes in percutaneous coronary intervention with drug-eluting stents (from the National Heart, Lung, and Blood Institute Dynamic Registry). Am. J. Cardiol. 99 , 626–631 (2007).

Argulian, E. et al . Gender differences in short-term cardiovascular outcomes after percutaneous coronary interventions. Am. J. Cardiol. 98 , 48–53 (2006).

Yang, F., Minutello, R. M., Bhagan, S., Sharma, A. & Wong, S. C. The impact of gender on vessel size in patients with angiographically normal coronary arteries. J. Interv. Cardiol. 19 , 340–344 (2006).

Mehilli, J. et al . Gender and restenosis after coronary artery stenting. Eur. Heart J. 24 , 1523–1530 (2003).

Dickerson, J. A., Nagaraja, H. N. & Raman, S. V. Gender-related differences in coronary artery dimensions: a volumetric analysis. Clin. Cardiol. 33 , E44–E49 (2010).

Vaccarino, V. et al . Sex differences in mortality after acute myocardial infarction: changes from 1994 to 2006. Arch. Intern. Med. 169 , 1767–1774 (2009).

PubMed   PubMed Central   Google Scholar  

Vaccarino, V., Parsons, L., Every, N. R., Barron, H. V. & Krumholz, H. M. Sex-based differences in early mortality after myocardial infarction. National Registry of Myocardial Infarction 2 Participants. N. Engl. J. Med. 341 , 217–225 (1999).

Andrikopoulos, G. K. et al . Younger age potentiates post myocardial infarction survival disadvantage of women. Int. J. Cardiol. 108 , 320–325 (2006).

Koek, H. L. et al . Short- and long-term prognosis after acute myocardial infarction in men versus women. Am. J. Cardiol. 98 , 993–999 (2006).

Radovanovic, D. et al . Gender differences in management and outcomes in patients with Acute Coronary Syndromes: results on 20,290 patients from the AMIS Plus Registry. Heart 93 , 1369–1375 (2007).

Vaccarino, V. et al . Sex differences in health status after coronary artery bypass surgery. Circulation 108 , 2642–2647 (2003).

Vaccarino, V. et al . Gender differences in recovery after coronary artery bypass surgery. J. Am. Coll. Cardiol. 41 , 307–314 (2003).

Abramson, J. L., Veledar, E., Weintraub, W. S. & Vaccarino, V. Association between gender and in-hospital mortality after percutaneous coronary intervention according to age. Am. J. Cardiol. 91 , 968–971 (2003).

Rosengren, A. et al . Sex differences in survival after myocardial infarction in Sweden; data from the Swedish National Acute Myocardial Infarction Register. Eur. Heart J. 22 , 314–322 (2001).

Russo, A. M. et al . Influence of gender on arrhythmia characteristics and outcome in the Multicentre UnSustained Tachycardia Trial. J. Cardiovasc. Electrophysiol. 15 , 993–998 (2004).

Salomaa, V. et al . Decline in out-of-hospital coronary heart disease deaths has contributed the main part to the overall decline in coronary heart disease mortality rates among persons 35 to 64 years of age in Finland: the FINAMI study. Circulation 108 , 691–696 (2003).

MacIntyre, K. et al . Gender and survival: a population-based study of 201,114 men and women following a first acute myocardial infarction. J. Am. Coll. Cardiol. 38 , 729–735 (2001).

Centers for Disease Control and Prevention (CDC). State-specific mortality from sudden cardiac death—United States, 1999. MMWR Morb. Mortal. Wkly Rep. 51 , 123–126 (2002).

Njølstad, I., Arnesen, E. & Lund-Larsen, P. G. Smoking, serum lipids, blood pressure, and sex differences in myocardial infarction. A 12-year follow-up of the Finnmark Study. Circulation 93 , 450–456 (1996).

Kemp, H. G. Jr, Vokonas, P. S., Cohn, P. F. & Gorlin, R. The anginal syndrome associated with normal coronary arteriograms. Report of a six year experience. Am. J. Med. 54 , 735–742 (1973).

Cannon, R. O. 3rd et al . Abnormal cardiac sensitivity in patients with chest pain and normal coronary arteries. J. Am. Coll. Cardiol. 16 , 1359–1366 (1990).

Cannon R. O. 3rd & Epstein, S. E. “Microvascular angina” as a cause of chest pain with angiographically normal coronary arteries. Am. J. Cardiol. 61 , 1338–1343 (1988).

Reis, S. E. et al . Coronary flow velocity response to adenosine characterizes coronary microvascular function in women with chest pain and no obstructive coronary disease. Results from the pilot phase of the Women's Ischemia Syndrome Evaluation (WISE) study. J. Am. Coll. Cardiol. 33 , 1469–1475 (1999).

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Acknowledgements

The authors of this Review are members of the European Society of Cardiology Working Group on Coronary Pathophysiology and Microcirculation, and acknowledge the European Society of Cardiology for financial support. Dr Vaccarino is supported by the National Institutes of Health, grant K24HL077506.

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Viola Vaccarino

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Lina Badimon

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Maria Dorobantu

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Akos Koller

Charité-Universitätsmedizin Berlin, Germany

Department of Experimental, Diagnostics and Specialized Medicine, Section of Cardiology, Policlinico Sant'Orsola-Malpighi, Bologna, 40138, Italy

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V. Vaccarino, R. Corti, O. Manfrini, E. Cenko, and R. Bugiardini researched data for the article. V. Vaccarino, L. Badimon, M. Dorobantu, O. Manfrini, A. Pries, E. Cenko, and R. Bugiardini contributed substantially to the discussion of content. The article was written by V. Vaccarino, R. Corti, and R. Bugiardini. V. Vaccarino, L. Badimon, R. Corti, C. de Wit, M. Dorobantu, O. Manfrini, A. Koller, E. Cenko, and R. Bugiardini reviewed/edited the manuscript before submission.

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Vaccarino, V., Badimon, L., Corti, R. et al. Presentation, management, and outcomes of ischaemic heart disease in women. Nat Rev Cardiol 10 , 508–518 (2013). https://doi.org/10.1038/nrcardio.2013.93

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• Management and outcome of oncological patients under immune checkpoint inhibitors presenting at the emergency department
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• http://orcid.org/0009-0004-2545-3062 Francesco Pini ,
• Bogdan Grigoriu ,
• Ameye Lieveke ,
• Anne-Pascale Meert
• Jules Bordet Institute , Brussels , Belgium
• Correspondence to Dr Francesco Pini, Jules Bordet Institute, Brussels, Belgium; francesco.pini{at}hotmail.com

Introduction With the rising use of immune checkpoint inhibitors ( ICIs ) in oncology, emergency physicians are increasingly confronted with their immune-related adverse events ( irAEs ). We described the types of irAEs presenting to the ED of a Belgian cancer centre and determined associations with the development of an irAE and other patient’s characteristics. Secondary objectives describe the therapeutic management and determine 7 and 30-day mortality.

Methods A retrospective chart review of ED visits of patients on ICI from 15 December 2016 to 6 December 2020 was performed. Clinical presentation, cancer characteristics and type of ICI were extracted by a single abstractor. We recorded any suspicion of irAE in the ED and confirmation of an irAE was based on the patient’s oncologist report. Outcome was based on mortality at date of last follow-up.

Results 227 patients on ICI presented to the ED, with a total of 451 visits. 54 (12%) of the visits resulted in a diagnosis of irAE. Four clinical features were associated with an irAE: gastrointestinal complaints (p=0.01), skin rashes (p=0.02), acute renal failure (p=0.002) and abnormal liver function (p=0.04). An irAE was also associated with three different factors: a cancer status in remission (OR=5.33, 95% CI 2.57 to 11.04), a combination of two ICIs (OR=4.43, 95% CI 2.09 to 9.42) and a medical history of irAE (OR=2.44, 95% CI 1.27 to 4.68). 30-day mortality was lower in the irAE group (0%) than in the non-irAE group (13%, 95% CI 9% to 19%).

Conclusions Oncological patients under ICI presenting in the ED are more likely to have an irAE if they present with gastrointestinal and dermatological complaints, acute renal failure and abnormal liver function. This is also true for patients with any history of irAE, a concomitant use of two ICIs and with a cancer status in remission.

• Medical Oncology

Data availability statement

Data are available upon reasonable request. Data are available on reasonable request.

https://doi.org/10.1136/emermed-2023-213605

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WHAT IS ALREADY KNOWN ON THIS TOPIC

Immune checkpoint inhibitors (ICI) are increasingly used in oncology and managing them in an emergency setting can be challenging. A few studies evaluated their acute management, but little is known on how to distinguish patients presenting to the ED with side effects from other conditions.

WHAT THIS STUDY ADDS

In this observational study of oncological patients on ICI presenting to an ED, an immune-related adverse event was more likely if they had gastrointestinal and dermatological complaints, acute renal failure or abnormal liver function, as well as history of adverse reaction to ICI, a concomitant use of two ICIs and a cancer status in remission.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

Our findings may allow emergency physicians to more quickly recognise an immune-related side effect and initiate treatment sooner.

Introduction

The human immune system is balanced between its action of destroying foreign antigens on the one hand, and the controlling of the development of autoimmune phenomena on the other hand. This complex balance is maintained, among other means, by cellular signalling pathways that inhibit or stimulate the immune system. Some inhibitory pathways, such as the programmed cell death protein 1 / programmed cell death ligand 1 pathway and the cytotoxic T-lymphocyte-associated protein 4 / protein B7 pathway, can be overexpressed by cancer cells to prevent their destruction. 1 Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that can overcome this immune inhibition, thereby potentially inducing cancer cell destruction.

The efficacy of ICI has been initially demonstrated in the advanced stages of melanoma 2 and certain non-small cell lung cancers. 3 4 Their indications have progressively been extended to many other cancers in combination with or as an alternative to chemotherapy, and they have now become a therapeutic standard in oncology. Patients on ICI are at risk of developing side effects that mimic autoimmune reactions, which may be challenging to differentiate from other manifestations such as cancer progression or infections. Some of these immune-related adverse events ( irAEs ) may be severe enough to require intensive care management. 5 Virtually, all organs can be affected, with variable timing and frequency depending on the type and number of ICIs used. 6–8 Prognosis is largely dependent on the nature of the irAE, with pulmonary involvement having a poor prognosis. 7 A recent British study 9 showed that among 300 ED visits of patients on ICI, 2% resulted in death associated with irAE.

Rapid identification of an irAE is essential and lack of knowledge about these toxicities may delay management and aggravate patient’s outcome. 10 This is especially important considering the specificity of the treatment, which may require high doses of corticosteroids or other immunosuppressive agents. 11 12 A 2019 French single-centre retrospective study based on 409 patients treated with ICI 13 found only 50% of irAE diagnoses are made in the ED. This study also identified potential factors favouring the development of irAE such as cancer in remission, concomitant use of multiple ICIs, as well as a higher number of ICI doses.

Previous investigations have shed some light on the acute presentation and management of oncological patients on ICI. 7 9 13 14 Unfortunately, there is insufficient evidence to guide physicians in how to differentiate irAEs from other diseases. Our study aimed to evaluate the frequency of irAE and determine which factors might be associated with the development of an adverse effect. The secondary objectives were to identify the therapeutic management as well as to determine mortality at 7 and 30 days after ED presentation.

This retrospective monocentric study was carried out at the Jules Bordet Institute in Brussels, Belgium. It is a specialised centre in oncology and onco-haematology, which possesses an ED managing the patients of the institute only.

Patients were selected by matching those who received therapy with at least one ICI (avelumab/Bavencio, durvalumab/Imfinzi, pembrolizumab/Keytruda, nivolumab/Opdivo, atezolizumab/Tecentriq or ipilimumab/Yervoy), with those who visited the ED over a 4-year period from 15 December 2016 to 6 December 2020. Of these, patients who received their last dose more than 6 months previously and those under the age of 18 years were excluded.

Data collection

Data for the study were extracted from the electronic medical records of visits documented by emergency physicians during the study period. Extraction of the data was performed by a single investigator, and then the validity of the data was crosschecked by an independent researcher. All information was then encoded and anonymised with the REDCap computer software.

Among the general data, we collected the chief complaint at the ED visit. If the patient was sent to the ED following an abnormal routine laboratory result, the laboratory result was considered as a chief complaint. Chief complaints were then categorised into seven main clinical presentations. Those categories were arbitrarily decided by the authors, based on main system involvement. We also collected the primary cancer location, a history of autoimmune diseases and irAE, as well as cancer status. A cancer in remission was considered when cancer has responded partially/completely to a treatment and is not actively progressing, based on the last oncology consultation/imagery preceding the emergency visit. Immunotherapy was assessed according to the ICI used, the time from the first dose to the ED visit, the time from the last dose to the ED visit and the total number of doses already received. The final diagnosis of the emergency physician, internist and/or oncologist was recorded. An adverse event was categorised as an irAE if the oncologist/internist in the inpatient or outpatient setting considered the irAE probable or definite; the grade of the irAE was also recorded and classified using the Common Terminology Criteria for Adverse Events from the National Cancer Institute. 15 We recorded a suspicion of irAE if the emergency doctor considered an irAE in the differential diagnosis. Therapeutic management of irAE described the necessity of discontinuation of immunotherapy, temporary or permanently. Patient prognosis was measured by mortality 7 and 30 days after consultation. Mortality was determined based on death certificates last checked on 12 June 2021, which are automatically updated every 2 weeks with the national database of Belgium.

Statistical analysis

The sample size for this study was pragmatic: a 4-year period was chosen based on limiting factors, mostly time available for data collection. Statistical analysis included a descriptive analysis, a comparison between the irAE and the non-irAE group and an assessment of mortality at 7 and 30 days after ED presentation. Categorical data were compared using χ 2 or Fisher’s exact test when appropriate. Wilcoxon test was used for continuous data comparisons. For descriptive analysis and comparison between the irAE and non-irAE groups, when the same patient visited the ED more than once, each visit was considered. If a patient presented the same irAE twice in less than 30 days, the second visit was excluded. Logistic regression was used to assess which explanatory variables are independently associated to irAE. For demographic analyses, and the assessment of mortality, only the first ED visit was considered. Mortality was assessed using the Kaplan-Meier and Cox proportional hazards model. For all statistical analyses, the significance threshold was set at p<0.05.

Patient and public involvement

Patients or the public were not involved in the design, or conduct, or reporting, or dissemination plans of our research.

During the 4-year study period, the Institute recorded a total of 9355 ED visits. Of these, 227 patients receiving ICI therapy made 451 ED visits. The population was mostly male (63.4%), with a median age of 64 (55–69) years. Bronchopulmonary cancers accounted for more than half of the cases (53.7%), followed by melanoma (21.6%) and bladder cancers (15.9%). Pembrolizumab was the most commonly used checkpoint inhibitor (43.6%), followed by nivolumab (34.8%) and atezolizumab (10.6%). The characteristics of the patients are summarised in table 1 .

• View inline

Patient characteristics on first ED visit

The chief complaints at the ED were classified into seven categories ( table 2 ). Among the 451 ED visits, the most frequent clinical presentations were 70 (15.5%) fever, 69 (15.3%) dyspnoea, 37 (8.2%) musculoskeletal pain, 36 (8%) asthenia, 30 (6.7%) abdominal pain and 28 (6.2%) diarrhoea ( table 2 ).

Clinical variables for irAE and non-irAE on all ED visits

Out of the 451 ED visits, there were 54 (12%) that resulted in a diagnosis of an irAE. 43 (79.6%) of irAEs had been suspected by the emergency doctor. Visits for gastrointestinal symptoms (p=0.01), acute renal failure (p=0.002), abnormal liver function (elevation of aspartate aminotransferase and/or alanine aminotransferase) (p=0.04) and skin rashes (p=0.02) were more frequently associated with an irAE. Within the gastrointestinal symptoms group, diarrhoea was associated with developing an irAE (p<0.001).

The most frequent irAEs were colitis/diarrhoea (24.1%), pneumonia (24.1%), hepatitis (9.3%) and dermatitis (9.3%). Most patients had severe irAEs of grades III–IV (n=36; 66.6%). Only two patients had (3.6%) grade I events. Five patients had multiple simultaneous irAEs. The characteristics of the irAE are summarised in table 3 .

Characteristics of irAE on all ED visits

The development of irAE was associated with a cancer status in remission (OR=5.33, 95% CI 2.57 to 11.04), any history of irAE (OR = 2.44, 95% CI 1.27 to 4.68) and the use of two ICIs (OR=4.43, 95% CI 2.09 to 9.42) . When added to the logistic regression model, a history of autoimmune disease, timing between the first dose of ICI and the ED visit or number of doses of immunotherapy before presenting to the ED were not retained as independently associated to irAE: respective p values of 0.21, 0.27 and 0.41 ( table 4 ). ICI treatment had to be stopped in 40 (72.7%) of patients with irAEs. This interruption was permanent in 37 (92.5%) cases.

Logistic regression model for predictive factors associated with an irAE

We assessed mortality in the 6 months after the first ED visit ( figure 1 ). Patients diagnosed with irAE had a lower mortality rate: HR 0.31 (95% CI 0.12 to 0.86; p=0.02). The 30-day mortality after ED presentation was 0% in the irAE group versus 13% (95% CI 9% to 19%) in the non-irAE group.

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Mortality rate after first ED visit. irAE, immune-related adverse event.

In this single-centre study of the ED of an oncology referral centre, 5% of visits involved patients treated with ICI. Out of those visits, 12% ultimately resulted in the diagnosis of irAE. We found that patients with gastrointestinal and dermatological chief complaints, and those diagnoses with renal failure and abnormal liver function, were more likely to have an irAE, although the last two of these were rare. Cancer in remission, history of an irAE and simultaneous treatment with two ICIs were also associated with an irAE.

The frequency of irAEs in our retrospective study is lower than in the literature. Indeed, different studies have found values of <10%, 14 14.4%, 13 25% 7 and 32.7%. 9 This low frequency is likely because our hospital is specialised in oncology, and less severe irAEs are caught earlier in consultation by the oncologist. The same is true for the high percentage of irAE suspected in the ED (79.6%), as our emergency staff only manages oncological patients and receives continuous information about new cancer drugs. Still, it is important to note that some rare and particularly severe adverse events were missed in the ED such as myocarditis, Guillain-Barré syndrome and a cytokine-releasing syndrome. It seems essential to stay aware of the high variability that these adverse events can present.

The association of an irAE with cancer status in remission has been previously shown. A recent meta-analysis of 51 studies 16 found progression-free survival (clinical endpoint measuring the time during or after treatment when the cancer does not progress) in the irAE group was 17.61 months (95% CI 10.1 to 25.1) compared with 2.23 months in the non-irAE group (95% CI 1.77 to 2.68) for melanomas, and similar figures were found for other metastatic neoplasms. The author explains this association by a potential cross-reactivity of the immune system between antigens from healthy cells and antigens from cancer cells. We hypothesised that patients with a positive therapeutic response would benefit from prolonged treatment, thus raising the probability of developing an irAE. However, in our cohort, the time between ICI therapy initiation and emergency visit was similar in both groups. Therefore, a high degree of suspicion for toxicity should remain when facing patients under immunotherapy, regardless of the time from initiation of the treatment.

We also found a significant association between a history of irAE (regardless of the grade) and the development of another irAE. Ongoing research 17 is attempting to identify markers that predispose or facilitate the development of irAEs. However, much more research is needed in this area.

The development of an irAE was three times more likely in patients treated with two ICIs than those with a single ICI. The only combination used in our population was nivolumab with ipilimumab used in the treatment of melanoma. This combination has also been linked to the development of a higher grade side effect in patients with melanoma. 18

Although a history of autoimmune disease has been associated with an almost twofold increase in hospitalisations resulting in a diagnosis of irAE by Kehl et al , 19 we did not find this to be true of our population. However, Kehl’s study excluded autoimmune hypothyroidism, which accounts for the majority of the history of autoimmune disease in our population. As the number of our patients with other autoimmune diseases is statistically insufficient, we cannot draw a clear conclusion on this subject.

ICI treatment had to be stopped in more almost three-quarters of the patients with irAEs, resulting in a permanent interruption in almost all cases. Our high frequency of permanent discontinuation of ICI may be explained by the fact that our study includes only ED presentations, which are usually severe. Indeed, two-thirds of the irAEs in our population were grade ≥III. Discontinuation may raise concerns about a possible neoplastic progression after ICI discontinuation, but this may not be a significant issue in practice. One study from Schadendorf et al evaluated patient prognosis after discontinuation of a nivolumab-ipilimumab combination due to irAE and showed no significant decrease in progression-free survival at 18 months when the development of irAE required discontinuation of ICI (p=0.97). 20 Nevertheless, we cannot confirm whether this trend is maintained in the long run. A study 21 analysed reintroduction of ICI in a population with a grade ≥II irAE, and over half of patients did not redevelop a grade ≥II irAE. Given the apparent association between the development of an irAE and a positive therapeutic response, it seems essential to assess for each patient the benefit-risk balance of reintroducing ICI after the occurrence of an irAE.

The 30-day mortality after ED presentation after the first visit only was significantly lower in the irAE group. This was also found by Grangeon et al in patients with non-small cell lung cancer (HR 0.42; 95% CI 0.32 to 0.57; p<0.001). 22 This reduction in mortality is likely related to the positive therapeutic response to the immunotherapy, as Zaorsky et al found >40% of deaths in oncological patients are related to their cancer. 23 This high difference in mortality could be explained because most irAEs are rapidly reversible if appropriately treated. This favourable outcome appears to be maintained in the long term, but further investigation is warranted to confirm this trend.

Limitations

This study suffers the inherent biases from retrospective data collection. It is important to note that our study only evaluated urgent presentations, we cannot apply these results to all patients undergoing ICI treatment. Also, as our centre is specialised in oncology, the acute management of irAE is not generalisable to non-oncological hospitals. Finally, we decided to consider multiple visits in the descriptive analysis, which may skew the data.

Conclusions

More than 1 in 10 patients under ICI presenting to the ED have an irAE. Certain presentations, the history of an irAE and cancer in remission increase the likelihood of an irAE. Early recognition is helpful as patients with irAE often need to discontinue the medication.

Ethics statements

Patient consent for publication.

Not applicable.

Ethics approval

This study involves human participants and was approved by the ethics committee of Jules Bordet Institute, Brussels, Belgium on 5 January 2021 (Reference No OM011). It was a retrospective study.

• Michielin O ,
• van Akkooi ACJ ,
• Ascierto PA , et al
• Liao G , et al
• Rodríguez-Abreu D ,
• Robinson AG , et al
• Lemiale V ,
• Meert A-P ,
• Vincent F , et al
• Henderson R ,
• El Majzoub I ,
• Qdaisat A ,
• Thein KZ , et al
• Eigentler TK ,
• Hassel JC ,
• Berking C , et al
• Cooksley T ,
• Al-Sayed T , et al
• Simmons D ,
• Brahmer JR ,
• Lacchetti C ,
• Schneider BJ , et al
• Hryniewicki AT ,
• Shatsky RA , et al
• Peyrony O ,
• Tieghem Y ,
• Franchitti J , et al
• Aksun MS , et al
• ↵ Common terminology criteria for adverse events (CTCAE) version 5 . US Department of Health and Human Services, National Institutes of Health, National Cancer Institute .
• Hussaini S ,
• Chehade R ,
• Boldt RG , et al
• Ye Y , et al
• Chiarion-Sileni V ,
• Gonzalez R , et al
• Awad MM , et al
• Schadendorf D ,
• Wolchok JD ,
• Hodi FS , et al
• Allouchery M ,
• Lombard T ,
• Martin M , et al
• Grangeon M ,
• Tomasini P ,
• Chaleat S , et al
• Zaorsky NG ,
• Churilla TM ,
• Egleston BL , et al

Handling editor Darryl Wood

Contributors FP, A-PM, BG and AL take responsibility for study conception and design. FP takes responsibility for data collection and as guarantor of the integrity of the data. AL takes responsibility for the accuracy of the statistical analysis. FP, A-PM and BG take responsibility for the interpretation and drafting of the manuscript.

Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

Competing interests None declared.

Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

Provenance and peer review Not commissioned; externally peer reviewed.

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Clinical Presentation and Outcomes of Patients With Cancer-Associated Isolated Distal Deep Vein Thrombosis

Affiliations.

• 1 Department of Medicine, Sunnybrook Heath Sciences Centre, University of Toronto, Toronto, ON, Canada.
• 2 Department of Internal Medicine, Hospital General Universitario Santa Lucía, Universidad Católica San Antonio de Murcia, Murcia, Spain.
• 3 Cardiovascular Medicine Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
• 4 Thrombosis Research Group, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
• 5 YNHH/Yale Center for Outcomes Research and Evaluation (CORE), New Haven, CT.
• 6 Cardiovascular Research Foundation (CRF), New York, NY.
• 7 Department of Vascular Medicine and Therapeutics, Hôpital Nord-CHU St-Etienne, Saint-Etienne, France.
• 8 Department of Internal Medicine and Emergency Room, Ospedale Buon Consiglio Fate bene fratelli, Naples, Italy.
• 9 Department of Internal Medicine, Hospital de Mataró, Barcelona, Spain.
• 10 University Clinic of Pneumology and Allergy Skopje, Skopje, Republic of Macedonia.
• 11 Department of Pneumonology, Hospital Universitario Virgen de Valme, Sevilla, Spain.
• 12 Department of Internal Medicine, Hospital de Poniente, El Ejido, Almeria, Spain.
• 13 Department of Internal Medicine, Pius Hospital de Valls, Tarragona, Spain.
• 14 Chair for the Study of Thromboembolic Disease, Faculty of Health Sciences, UCAM-Universidad Católica San Antonio de Murcia, Murcia, Spain.
• 15 CIBER Enfermedades Respiratorias (CIBERES), Madrid, Spain.
• PMID: 37471683
• DOI: 10.1200/JCO.23.00429

Purpose: Patients with isolated distal deep vein thrombosis (DVT) have lower rates of adverse outcomes (death, venous thromboembolism [VTE] recurrence or major bleeding) than those with proximal DVT. It is uncertain if such findings are also observed in patients with cancer.

Methods: Using data from the international Registro Informatizado de la Enfermedad TromboEmbolica venosa registry, we compared the risks of adverse outcomes at 90 days (adjusted odds ratio [aOR]; 95% CI) and 1 year (adjusted hazard ratio [aHR; 95% CI]) in 886 patients with cancer-associated distal DVT versus 5,196 patients with cancer-associated proximal DVT and 5,974 patients with non-cancer-associated distal DVT.

Results: More than 90% of patients in each group were treated with anticoagulants for at least 90 days. At 90 days, the adjusted risks of death, VTE recurrence, or major bleeding were lower in patients with non-cancer-associated distal DVT than in patients with cancer-associated distal DVT (reference): aOR = 0.16 (0.11-0.22), aOR = 0.34 (0.22-0.54), and aOR = 0.47 (0.27-0.80), respectively. The results were similar at 1-year follow-up: aHR = 0.12 (0.09-0.15), aHR = 0.39 (0.28-0.55), and aHR = 0.51 (0.32-0.82), respectively. Risks of death, VTE recurrence, and major bleeding were not statistically different between patients with cancer-associated proximal versus distal DVT, both at 90 days: aOR = 1.11 (0.91-1.36), aOR = 1.10 (0.76-1.62), and aOR = 1.18 (0.76-1.83), respectively, and 1 year: aHR = 1.01 (0.89-1.15), aHR = 1.02 (0.76-1.35), and aHR = 1.10 (0.76-1.61), respectively. However, more patients with cancer-associated proximal DVT, compared with cancer-associated distal DVT, developed fatal pulmonary embolism (PE) during follow-up: The risk difference was 0.40% (95% CI, 0.23 to 0.58).

Conclusion: Cancer-associated distal DVT has serious and relatively comparable outcomes compared with cancer-associated proximal DVT. The lower risk of fatal PE from cancer-associated distal DVT needs further investigation.

• Anticoagulants / therapeutic use
• Hemorrhage / complications
• Hemorrhage / drug therapy
• Neoplasms* / complications
• Neoplasms* / drug therapy
• Pulmonary Embolism* / complications
• Risk Factors
• Venous Thromboembolism* / epidemiology
• Venous Thromboembolism* / etiology
• Venous Thrombosis* / etiology
• Anticoagulants

ORIGINAL RESEARCH article

Changes in the investigation and management of suspected myocardial infarction and injury during covid-19: a multi-centre study using routinely collected healthcare data provisionally accepted.

• 1 University of Oxford, United Kingdom
• 2 Oxford University Hospitals NHS Trust, United Kingdom
• 3 NIHR Imperial Biomedical Research Centre, United Kingdom
• 4 NIHR Oxford Biomedical Research Centre, United Kingdom
• 5 NIHR Leicester Biomedical Research Centre, United Kingdom
• 6 NIHR Biomedical Research Centre at Guy’s, King's College London, United Kingdom
• 7 NIHR Biomedical Research Centre, University College London Hospitals NHS Foundation Trust, United Kingdom
• 8 University College London, United Kingdom
• 9 Amsterdam University Medical Center, Netherlands
• 10 NIHR Biomedical Research Centre, Royal Marsden NHS Foundation Trust, United Kingdom
• 11 Leeds Biomedical Research Centre (NIHR), United Kingdom
• 12 NIHR Bristol Biomedical Research Centre, United Kingdom
• 13 NIHR Manchester Biomedical Research Centre (BRC), United Kingdom
• 14 NIHR Southampton Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, United Kingdom
• 15 Guy's and St Thomas' NHS Foundation Trust, United Kingdom

The final, formatted version of the article will be published soon.

Objective The COVID-19 pandemic was associated with a reduction in the incidence of myocardial infarction (MI) diagnosis, in part because patients were less likely to present to hospital. Whether changes in clinical decision making with respect to the investigation and management of patients with suspected MI also contributed to this phenomenon is unknown. Methods Multicentre retrospective cohort study in three UK centres contributing data to the National Institute for Health Research Health Informatics Collaborative. Patients presenting to the Emergency Department (ED) of these centres between 1st January 2020 and 1st September 2020 were included. Three time epochs within this period were defined based on the course of the first wave of the COVID-19 pandemic: pre-pandemic (epoch 1), lockdown (epoch 2), post-lockdown (epoch 3). Results During the study period, 10,670 unique patients attended the ED with chest pain or dyspnoea, of whom 6,928 were admitted. Despite fewer total ED attendances in epoch 2, patient presentations with dyspnoea were increased (p Conclusions The first wave of the COVID-19 pandemic was associated with significant changes not just in presentation, but also the investigation, management, and outcomes of patients presenting with suspected myocardial injury or MI.

Keywords: Troponin, COVID-19, emergency department, Myocardial Infarction, Myocardial injury

Received: 25 Mar 2024; Accepted: 02 May 2024.

Copyright: © 2024 Chammas, Yuan, Little, Roadknight, Varnai, Chang, Sze, Davies, Tsui, Salih, Glampson, Papadimitriou, Mulla, Woods, O'Gallagher, Shah, Williams, Asselbergs, Mayer, Lee, Herbert, Johnson, Grant, Curzen, Shah, Perera, Patel, Channon, Kaura, Mayet, Eyre, Squire, Kharbanda, Lewis and Wijesurendra. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Andrew Lewis, University of Oxford, Oxford, OX1 2JD, England, United Kingdom Dr. Rohan Wijesurendra, University of Oxford, Oxford, OX1 2JD, England, United Kingdom

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