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‘We have been left with the worst of both worlds on nurse recruitment’

STEVE FORD, EDITOR

• You are here: COPD

Diagnosis and management of COPD: a case study

04 May, 2020

This case study explains the symptoms, causes, pathophysiology, diagnosis and management of chronic obstructive pulmonary disease

This article uses a case study to discuss the symptoms, causes and management of chronic obstructive pulmonary disease, describing the patient’s associated pathophysiology. Diagnosis involves spirometry testing to measure the volume of air that can be exhaled; it is often performed after administering a short-acting beta-agonist. Management of chronic obstructive pulmonary disease involves lifestyle interventions – vaccinations, smoking cessation and pulmonary rehabilitation – pharmacological interventions and self-management.

Citation: Price D, Williams N (2020) Diagnosis and management of COPD: a case study. Nursing Times [online]; 116: 6, 36-38.

Authors: Debbie Price is lead practice nurse, Llandrindod Wells Medical Practice; Nikki Williams is associate professor of respiratory and sleep physiology, Swansea University.

• This article has been double-blind peer reviewed
• Scroll down to read the article or download a print-friendly PDF here (if the PDF fails to fully download please try again using a different browser)

Introduction

The term chronic obstructive pulmonary disease (COPD) is used to describe a number of conditions, including chronic bronchitis and emphysema. Although common, preventable and treatable, COPD was projected to become the third leading cause of death globally by 2020 (Lozano et al, 2012). In the UK in 2012, approximately 30,000 people died of COPD – 5.3% of the total number of deaths. By 2016, information published by the World Health Organization indicated that Lozano et al (2012)’s projection had already come true.

People with COPD experience persistent respiratory symptoms and airflow limitation that can be due to airway or alveolar abnormalities, caused by significant exposure to noxious particles or gases, commonly from tobacco smoking. The projected level of disease burden poses a major public-health challenge and primary care nurses can be pivotal in the early identification, assessment and management of COPD (Hooper et al, 2012).

Grace Parker (the patient’s name has been changed) attends a nurse-led COPD clinic for routine reviews. A widowed, 60-year-old, retired post office clerk, her main complaint is breathlessness after moderate exertion. She scored 3 on the modified Medical Research Council (mMRC) scale (Fletcher et al, 1959), indicating she is unable to walk more than 100 yards without stopping due to breathlessness. Ms Parker also has a cough that produces yellow sputum (particularly in the mornings) and an intermittent wheeze. Her symptoms have worsened over the last six months. She feels anxious leaving the house alone because of her breathlessness and reduced exercise tolerance, and scored 26 on the COPD Assessment Test (CAT, catestonline.org), indicating a high level of impact.

Ms Parker smokes 10 cigarettes a day and has a pack-year score of 29. She has not experienced any haemoptysis (coughing up blood) or chest pain, and her weight is stable; a body mass index of 40kg/m 2 means she is classified as obese. She has had three exacerbations of COPD in the previous 12 months, each managed in the community with antibiotics, steroids and salbutamol.

Ms Parker was diagnosed with COPD five years ago. Using Epstein et al’s (2008) guidelines, a nurse took a history from her, which provided 80% of the information needed for a COPD diagnosis; it was then confirmed following spirometry testing as per National Institute for Health and Care Excellence (2018) guidance.

The nurse used the Calgary-Cambridge consultation model, as it combines the pathological description of COPD with the patient’s subjective experience of the illness (Silverman et al, 2013). Effective communication skills are essential in building a trusting therapeutic relationship, as the quality of the relationship between Ms Parker and the nurse will have a direct impact on the effectiveness of clinical outcomes (Fawcett and Rhynas, 2012).

In a national clinical audit report, Baxter et al (2016) identified inaccurate history taking and inadequately performed spirometry as important factors in the inaccurate diagnosis of COPD on general practice COPD registers; only 52.1% of patients included in the report had received quality-assured spirometry.

Pathophysiology of COPD

Knowing the pathophysiology of COPD allowed the nurse to recognise and understand the physical symptoms and provide effective care (Mitchell, 2015). Continued exposure to tobacco smoke is the likely cause of the damage to Ms Parker’s small airways, causing her cough and increased sputum production. She could also have chronic inflammation, resulting in airway smooth-muscle contraction, sluggish ciliary movement, hypertrophy and hyperplasia of mucus-secreting goblet cells, as well as release of inflammatory mediators (Mitchell, 2015).

Ms Parker may also have emphysema, which leads to damaged parenchyma (alveoli and structures involved in gas exchange) and loss of alveolar attachments (elastic connective fibres). This causes gas trapping, dynamic hyperinflation, decreased expiratory flow rates and airway collapse, particularly during expiration (Kaufman, 2013). Ms Parker also displayed pursed-lip breathing; this is a technique used to lengthen the expiratory time and improve gaseous exchange, and is a sign of dynamic hyperinflation (Douglas et al, 2013).

In a healthy lung, the destruction and repair of alveolar tissue depends on proteases and antiproteases, mainly released by neutrophils and macrophages. Inhaling cigarette smoke disrupts the usually delicately balanced activity of these enzymes, resulting in the parenchymal damage and small airways (with a lumen of <2mm in diameter) airways disease that is characteristic of emphysema. The severity of parenchymal damage or small airways disease varies, with no pattern related to disease progression (Global Initiative for Chronic Obstructive Lung Disease, 2018).

Ms Parker also had a wheeze, heard through a stethoscope as a continuous whistling sound, which arises from turbulent airflow through constricted airway smooth muscle, a process noted by Mitchell (2015). The wheeze, her 29 pack-year score, exertional breathlessness, cough, sputum production and tiredness, and the findings from her physical examination, were consistent with a diagnosis of COPD (GOLD, 2018; NICE, 2018).

Spirometry is a tool used to identify airflow obstruction but does not identify the cause. Commonly measured parameters are:

• Forced expiratory volume – the volume of air that can be exhaled – in one second (FEV1), starting from a maximal inspiration (in litres);
• Forced vital capacity (FVC) – the total volume of air that can be forcibly exhaled – at timed intervals, starting from a maximal inspiration (in litres).

Calculating the FEV1 as a percentage of the FVC gives the forced expiratory ratio (FEV1/FVC). This provides an index of airflow obstruction; the lower the ratio, the greater the degree of obstruction. In the absence of respiratory disease, FEV1 should be ≥70% of FVC. An FEV1/FVC of <70% is commonly used to denote airflow obstruction (Moore, 2012).

As they are time dependent, FEV1 and FEV1/FVC are reduced in diseases that cause airways to narrow and expiration to slow. FVC, however, is not time dependent: with enough expiratory time, a person can usually exhale to their full FVC. Lung function parameters vary depending on age, height, gender and ethnicity, so the degree of FEV1 and FVC impairment is calculated by comparing a person’s recorded values with predicted values. A recorded value of >80% of the predicted value has been considered ‘normal’ for spirometry parameters but the lower limit of normal – equal to the fifth percentile of a healthy, non-smoking population – based on more robust statistical models is increasingly being used (Cooper et al, 2017).

A reversibility test involves performing spirometry before and after administering a short-acting beta-agonist (SABA) such as salbutamol; the test is used to distinguish between reversible and fixed airflow obstruction. For symptomatic asthma, airflow obstruction due to airway smooth-muscle contraction is reversible: administering a SABA results in smooth-muscle relaxation and improved airflow (Lumb, 2016). However, COPD is associated with fixed airflow obstruction, resulting from neutrophil-driven inflammatory changes, excess mucus secretion and disrupted alveolar attachments, as opposed to airway smooth-muscle contraction.

Administering a SABA for COPD does not usually produce bronchodilation to the extent seen in someone with asthma: a person with asthma may demonstrate significant improvement in FEV1 (of >400ml) after having a SABA, but this may not change in someone with COPD (NICE, 2018). However, a negative response does not rule out therapeutic benefit from long-term SABA use (Marín et al, 2014).

NICE (2018) and GOLD (2018) guidelines advocate performing spirometry after administering a bronchodilator to diagnose COPD. Both suggest a FEV1/FVC of <70% in a person with respiratory symptoms supports a diagnosis of COPD, and both grade the severity of the condition using the predicted FEV1. Ms Parker’s spirometry results showed an FEV1/FVC of 56% and a predicted FEV1 of 57%, with no significant improvement in these values with a reversibility test.

GOLD (2018) guidance is widely accepted and used internationally. However, it was developed by medical practitioners with a medicalised approach, so there is potential for a bias towards pharmacological management of COPD. NICE (2018) guidance may be more useful for practice nurses, as it was developed by a multidisciplinary team using evidence from systematic reviews or meta-analyses of randomised controlled trials, providing a holistic approach. NICE guidance may be outdated on publication, but regular reviews are performed and published online.

NHS England (2016) holds a national register of all health professionals certified in spirometry. It was set up to raise spirometry standards across the country.

Assessment and management

The goals of assessing and managing Ms Parker’s COPD are to:

• Review and determine the level of airflow obstruction;
• Assess the disease’s impact on her life;
• Risk assess future disease progression and exacerbations;
• Recommend pharmacological and therapeutic management.

GOLD’s (2018) ABCD assessment tool (Fig 1) grades COPD severity using spirometry results, number of exacerbations, CAT score and mMRC score, and can be used to support evidence-based pharmacological management of COPD.

When Ms Parker was diagnosed, her predicted FEV1 of 57% categorised her as GOLD grade 2, and her mMRC score, CAT score and exacerbation history placed her in group D. The mMRC scale only measures breathlessness, but the CAT also assesses the impact COPD has on her life, meaning consecutive CAT scores can be compared, providing valuable information for follow-up and management (Zhao, et al, 2014).

After assessing the level of disease burden,  Ms Parker was then provided with education for self-management and lifestyle interventions.

Lifestyle interventions

Smoking cessation.

Cessation of smoking alongside support and pharmacotherapy is the second-most cost-effective intervention for COPD, when compared with most other pharmacological interventions (BTS and PCRS UK, 2012). Smoking cessation:

• Slows the progression of COPD;
• Improves lung function;
• Improves survival rates;
• Reduces the risk of lung cancer;
• Reduces the risk of coronary heart disease risk (Qureshi et al, 2014).

Ms Parker accepted a referral to an All Wales Smoking Cessation Service adviser based at her GP surgery. The adviser used the internationally accepted ‘five As’ approach:

• Ask – record the number of cigarettes the individual smokes per day or week, and the year they started smoking;
• Advise – urge them to quit. Advice should be clear and personalised;
• Assess – determine their willingness and confidence to attempt to quit. Note the state of change;
• Assist – help them to quit. Provide behavioural support and recommend or prescribe pharmacological aids. If they are not ready to quit, promote motivation for a future attempt;
• Arrange – book a follow-up appointment within one week or, if appropriate, refer them to a specialist cessation service for intensive support. Document the intervention.

NICE (2013) guidance recommends that this be used at every opportunity. Stead et al (2016) suggested that a combination of counselling and pharmacotherapy have proven to be the most effective strategy.

Pulmonary rehabilitation

Ms Parker’s positive response to smoking cessation provided an ideal opportunity to offer her pulmonary rehabilitation (PR)  – as indicated by Johnson et al (2014), changing one behaviour significantly increases a person’s chance of changing another.

PR – a supervised programme including exercise training, health education and breathing techniques – is an evidence-based, comprehensive, multidisciplinary intervention that:

• Improves exercise tolerance;
• Reduces dyspnoea;
• Promotes weight loss (Bolton et al, 2013).

These improvements often lead to an improved quality of life (Sciriha et al, 2015).

Most relevant for Ms Parker, PR has been shown to reduce anxiety and depression, which are linked to an increased risk of exacerbations and poorer health status (Miller and Davenport, 2015). People most at risk of future exacerbations are those who already experience them (Agusti et al, 2010), as in Ms Parker’s case. Patients who have frequent exacerbations have a lower quality of life, quicker progression of disease, reduced mobility and more-rapid decline in lung function than those who do not (Donaldson et al, 2002).

“COPD is a major public-health challenge; nurses can be pivotal in early identification, assessment and management”

Pharmacological interventions

Ms Parker has been prescribed inhaled salbutamol as required; this is a SABA that mediates the increase of cyclic adenosine monophosphate in airway smooth-muscle cells, leading to muscle relaxation and bronchodilation. SABAs facilitate lung emptying by dilatating the small airways, reversing dynamic hyperinflation of the lungs (Thomas et al, 2013). Ms Parker also uses a long-acting muscarinic antagonist (LAMA) inhaler, which works by blocking the bronchoconstrictor effects of acetylcholine on M3 muscarinic receptors in airway smooth muscle; release of acetylcholine by the parasympathetic nerves in the airways results in increased airway tone with reduced diameter.

At a routine review, Ms Parker admitted to only using the SABA and LAMA inhalers, despite also being prescribed a combined inhaled corticosteroid and long-acting beta 2 -agonist (ICS/LABA) inhaler. She was unaware that ICS/LABA inhalers are preferred over SABA inhalers, as they:

• Last for 12 hours;
• Improve the symptoms of breathlessness;
• Increase exercise tolerance;
• Can reduce the frequency of exacerbations (Agusti et al, 2010).

However, moderate-quality evidence shows that ICS/LABA combinations, particularly fluticasone, cause an increased risk of pneumonia (Suissa et al, 2013; Nannini et al, 2007). Inhaler choice should, therefore, be individualised, based on symptoms, delivery technique, patient education and compliance.

It is essential to teach and assess inhaler technique at every review (NICE, 2011). Ms Parker uses both a metered-dose inhaler and a dry-powder inhaler; an in-check device is used to assess her inspiratory effort, as different inhaler types require different inhalation speeds. Braido et al (2016) estimated that 50% of patients have poor inhaler technique, which may be due to health professionals lacking the confidence and capability to teach and assess their use.

Patients may also not have the dexterity, capacity to learn or vision required to use the inhaler. Online resources are available from, for example, RightBreathe (rightbreathe.com), British Lung Foundation (blf.org.uk). Ms Parker’s adherence could be improved through once-daily inhalers, as indicated by results from a study by Lipson et al (2017). Any change in her inhaler would be monitored as per local policy.

Vaccinations

Ms Parker keeps up to date with her seasonal influenza and pneumococcus vaccinations. This is in line with the low-cost, highest-benefit strategy identified by the British Thoracic Society and Primary Care Respiratory Society UK’s (2012) study, which was conducted to inform interventions for patients with COPD and their relative quality-adjusted life years. Influenza vaccinations have been shown to decrease the risk of lower respiratory tract infections and concurrent COPD exacerbations (Walters et al, 2017; Department of Health, 2011; Poole et al, 2006).

Self-management

Ms Parker was given a self-management plan that included:

• Information on how to monitor her symptoms;
• A rescue pack of antibiotics, steroids and salbutamol;
• A traffic-light system demonstrating when, and how, to commence treatment or seek medical help.

Self-management plans and rescue packs have been shown to reduce symptoms of an exacerbation (Baxter et al, 2016), allowing patients to be cared for in the community rather than in a hospital setting and increasing patient satisfaction (Fletcher and Dahl, 2013).

Improving Ms Parker’s adherence to once-daily inhalers and supporting her to self-manage and make the necessary lifestyle changes, should improve her symptoms and result in fewer exacerbations.

The earlier a diagnosis of COPD is made, the greater the chances of reducing lung damage through interventions such as smoking cessation, lifestyle modifications and treatment, if required (Price et al, 2011).

• Chronic obstructive pulmonary disease is a progressive respiratory condition, projected to become the third leading cause of death globally
• Diagnosis involves taking a patient history and performing spirometry testing
• Spirometry identifies airflow obstruction by measuring the volume of air that can be exhaled
• Chronic obstructive pulmonary disease is managed with lifestyle and pharmacological interventions, as well as self-management

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Major Case Study: COPD

Feb 20, 2012

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Major Case Study: COPD. Emily Brantley Dietetic Intern Andrews University. Patient’s Initials: NM Primary Problem &amp; other medical conditions: COPD , DM, IBS, Pneumonia, IgA deficiency Height: 160.02 Weight: 107.2 Age: 62 years old Sex: Female. Introduction. Introduction.

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Major Case Study: COPD Emily Brantley Dietetic Intern Andrews University

Patient’s Initials: NM Primary Problem & other medical conditions: COPD, DM, IBS, Pneumonia, IgA deficiency Height: 160.02 Weight: 107.2 Age: 62 years old Sex: Female Introduction

Introduction • Reason patient was chosen for case study: • NM was chosen because of the multiple complications that she faces. • Date the study began and ended • December 5, 2013 – December 6, 2013 • Focus of this study: • Chronic Obstructive Pulmonary Disease (COPD) • NM has other comorbidities, however, NM is most often admitted to the hospital for exacerbation of COPD.

Social History • NM is a Christian woman who lives at home with her husband and pet parakeet. • She is currently on Medicare. • Retired RN. • Her three children are all adults and live within the region. • NM is a former smoker • Medical records indicate that she does not smoke or drink alcohol anymore.

Normal Anatomy and Physiology of Applicable Body Functions • COPD is characterized by slow, progressive obstruction of the airways. • There are two physical conditions that make up COPD. • Emphysema • Characterized by abnormal, permanent enlargement and destruction of the alveoli • Chronic Bronchitis • A progressive cough with inflammation of bronchi and other lung changes • Frequently, both illnesses coexist as part of this disorder. • In both cases, the disease limits the airflow 1&2

Past Medical History

Past Medical History • NM initially received the diagnosis of COPD in 1997. • American Thoracic Society states comorbidities such as cardiac disease, diabetes mellitus, hypertension, and psychological disorders are commonly reported in patients with COPD, but with great variability in reported prevalence.

Past Medical History • Pneumonia • NM has been hospitalized six times within the past year for episodes of pneumonia. • COPD is more frequently associated with pneumonia. • Corticosteroids are standard of care for acute exacerbations of COPD, but their role in the management of patients with COPD with pneumonia is less defined. 3 • Diabetes Mellitus. • The evidence for an interaction between diabetes and COPD is supported by studies that demonstrate reduced lung function as a risk factor for the development of diabetes. • Smoking has been established as a risk factor for both COPD and Diabetes Mellitus. 3 • Gastro-esophageal reflux disease (GERD). • An increased prevalence of GERD has been reported in patients with COPD. A study of 421 patients with severe COPD using 24-hour esophageal pH monitoring showed that 62% had pathological GERD, and 58% of the patients reported no symptoms of GERD.3

Past Medical History • Bronchial Asthma • Adrenal Insufficiency • Coronary Artery Disease • Trachaeomalacia • Addison’s disease • Hypothyroidism • Bipolar Disorder • Irritable Bowel syndrome • Vascular stent placement • Hyperlipidemia • Hyperthyroidism • Anemia

Present Medical Status and Treatment

Theoretical Discussion of Disease Condition • COPD is the fourth leading cause of death in America. COPD is also more prevalent in women.3&4 • The primary risk factor in the development of COPD is smoking. • Beyond the cessation of smoking, it has been shown that the inflammatory stress continues to damage the lung tissue. • Other risk factors include air pollution, secondhand smoke, history of childhood infections, and occupational exposure to certain industrial pollutants.

Theoretical Discussion of Disease Condition • Although normal lung function gradually declines with age, individuals who are smokers have a more rapid decline—twice the rate of nonsmokers. • Low body weight has also been shown to be a risk factor for the development of COPD even after adjusting for other potential risk factors including smoking and age.2 • Malnourished patients with COPD experience worsened respiratory muscle strength, decreased ventilator drive and response to hypoxia, and altered immune function.1,5&6

Usual Treatment of the Condition • An early and accurate diagnosis of COPD is the key to treatment. • Quitting smoking is the single most important thing that can be done to help treat COPD.7 • The usual treatment of COPD is composed of four main goals for effective management: • 1. Assess and monitor the disease • 2. Reduce risk factors • 3. Maintain stable COPD and respiratory status • 4. Manage any exacerbations • Once the disease progresses, rehabilitation programs along with oxygen therapy are used as treatment. • Medications include bronchodilators, glucocorticosteroids, mucolytic agents, and antibiotics to treat infections. • In cases where COPD may be advanced, there is an option for surgical intervention, such as a lung transplant.1

Patient’s Symptoms upon Admission Leading to Present Diagnosis • NM was admitted with shortness of breath, cough, diarrhea, hypokalemia and fever. • She revealed that one of the possible causes of her diarrhea may be the fact that she had “been around a couple of people with Clostridium Difficile.” • NM also showed symptoms of hyperlipidemia and hypertension • High blood pressure is a complication of COPD.6 • Hyperglycemia is a side effect of steroid therapy for COPD. • Steroids can increase the blood sugar making diabetes harder to control.8

Laboratory Findings and Interpretation

Current Medications • Depakote ER (Valproic Acid) • Lexapro (Escitaloprem) • Florinef (Fludrocortison Acitate) • Fluticasone- salmeterol • Metronidazole Flagyl • Insulin Lispro (Humalog) • Misoprostal (Cytotec) • Monelukast (Singulair) • Pantaprazole (Protonix oral) • Potassium Chloride • RisperiDONE (RisperDAL) • Rosuvastatin (Crestor) • NaCl • Tolterodine • Voriconazole

Observable Physical and Psychological Changes in Patient • NM physically looked well nourished. • She did not appear to have difficulty breathing until after she spoke for a long period of time. • She did have a severe cough that she tried to conceal. • NM was a very agreeable patient for both psychological interviews. • In spite of her COPD diagnosis and all of the multiple medical comorbidities that NM faced, she still presented a positive attitude and spoke openly about her faith.

Treatment • NM received a chest x ray that revealed consolidation in the left lung and midline lung level. • Once this was identified, she was admitted to the hospital from the Emergency room for treatment. • She was started on IV steroids, IV antibiotics, flagyl and nebulizers around the clock to see how she progressed.

Medical Nutrition Therapy

Nutrition History • Beginning in March 2012, NM began intentionally losing weight by following a PCP prescribed commercial diet known as Optifast. • Optifast offers shakes, protein bars and soups. • With this regimen, NM has lost 70 pounds since March 2012. • At home, NM usually sticks to her Optifast food items for breakfast, lunch and snacks between meals. • For dinner, she shares a meal with her husband. • He is a professional chef who is control of purchasing groceries and prepares dinner most nights.

Analysis of Previous Diet: 24 hour recall

Current Prescribed Diet • NM was on steroid therapy to treat her COPD. • Because of the steroid therapy, NM was admitted with consistently high blood glucose levels. • For this reason, doctor’s orders were given for an Average Diabetic Diet for the duration of her stay at Winter Park Memorial Hospital. • An Average Diabetic Diet provides a consistent 60-75 grams of carbohydrates for each meal. • NM’s diet order remained the same for her entire stay.

Objectives of Dietary Treatment • The objective of the Average Diabetic diet is to maintain NM’s blood sugars within normal limits or as close as possible to normal levels. • Steroid therapy that NM was undergoing to treat her COPD helps keep blood sugars high • Finger-stick blood sugar levels referred to as “Accuchecks” ranged inconsistently from 130 to 289 as seen on the lab values table above.

Patient’s Physical and Psychological Response to Diet • At home, NM followed an eating pattern similar to that of the Average Diabetic Diet but with the addition of snacks in between meals. • She denied facing vomiting or constipation while on this diet. • She did admit to experiencing diarrhea and nausea upon admission to the hospital. • As previously mentioned, NM believed she was exposed to Clostridium Difficile, to which she attributes to the cause of having diarrhea.

List nutrition-related problems with supporting evidence • COPD: Increased energy expenditure related to increased energy requirements during COPD exacerbation as evidenced by measured resting energy expenditure greater than predicted needs.

Evaluation of Present Nutritional Status • According to the diet analysis table, NM was meeting her increased caloric needs for COPD. • Her diarrhea subsided by day two of hospitalization. • Per lab values as those noted above in the table, there did not appear to be any indication of dehydration.

Calorie and Protein Guidelines • Nutritional needs are often increased in COPD due to the increased work of breathing. • Optimal nutritional status plays an important role in maintaining the integrity of the respiratory system and in allowing maximal participation in daily living.1 • Caloric requirements for COPD individually determined based on: • Patient age, weight and gender, the extent of protein energy malnutrition loss of lean body mass, current medications and other acute or chronic medical conditions. • The Mifflin St. Jeor equation may underestimate the caloric requirements of patient’s with COPD because of the caloric increase from metabolically active tissue. • To compensate for this underestimation, a stress activity factor may be added according to the degree of stress. • In most cases the total calorie intake of the COPD patient is more important than the source from calories.

Calorie and Protein Guidelines • For maintenance 1.33 x REE or 25/35 calories per kilogram is appropriate for the needs of the COPD patient. • Protein is recommended at 1.0-1.5 grams per kilogram of body weight for maintenance.1 • Below is a chart of how NM’s needs were clinically calculated during her hospital admission on December 5th through the 6th.

Need for Alternative Feeding Methods and the Patient’s Nutrition Education Process • NM was in fact meeting the additional needs required for COPD, I do not believe that there was any need for alternative feedings such as tube feeding. • Moreover, in explaining the prescribed diabetic diet to NM, no type of barrier to learning was identified.

Prognosis • NM expressed her motivation to continue to follow a diet similar to that of the Average Diabetic Diet upon her return home as long as her increased COPD needs were met. • She was aware of the effects of steroid therapy on her blood sugar levels. • NM clearly verbalized her understanding on the use of steroids, their effects on increasing blood sugar levels and the importance of meal planning especially around carbohydrates. • This was more of a motivating factor for her to continue monitoring her diet on discharge.

Summary • From this study, I learned how very serious COPD is. • It was once explained to me some time ago that COPD was like a gradual suffocating in a pillow. • Seeing NM experiencing shortness of breath during the interviews or when speaking to me during the interviews made me realize that even the slightest amount of energy requires oxygen. • Imagine not being able to breathe to conduct the simplest activities of daily living! • In addition to other medical issues as NM had, it made me realize how important nutrition energy is needed for healing.

Thank You!

References • Mahan LK, Escott-Stump S, Raymond JL. Krause’s Food, Nutrition and Diet Therapy, 13th Edition, Philadelphia, Pa: Elsevier; 2012 • Nelms M, Sucher KP, Lacey K, Roth SL. Nutrition Therapy and Pathophysiology, 2nd Edition. Cengage Learning, Inc: 2010. • Chatila WM, Thomashow BM, Make BJ. Comorbidities in Chronic Obstructive Pulmonary Disease. Journal of the American Thoracic Society. 2008 May 1; 5(4): 549-555 • Centers for Disease Control. Chronic Obstructive Pulmonary Disease (COPD) Data and Statistics. Available at: http://www.cdc.gov/copd/data.htm. Accessed December 29, 2013. • American Society for Parenteral and Enteral Nutrition. Disease-Related Malnutrition and Enteral Nutrition Therapy. Available at: http://www.nutritioncare.org/index.aspx?id=5696. Accessed January 5, 2014. • Mayo Clinic. Disease and Conditions: COPD. Available at: http://www.mayoclinic.org/diseases-conditions/seo/basics/symptoms/con-20032017. Accessed January 8, 2014. • National Institutes of Health: National Heart Lung and Blood Institute. How Is COPD Treated? Available at: http://www.nhlbi.nih.gov/health/health-topics/topics/copd/treatment.html. Accessed January 8, 2014. • British Lung Foundation. Steroids. Available at: http://www.blf.org.uk/Page/Steroids. Accessed December 29, 2013. • MedlinePlus: A service of the U.S. National Library of Medicine From the National Institutes of Health National Institutes of Health. Drugs and Supplements. Available at: http://www.nlm.nih.gov/medlineplus/druginfo/drug_Ca.html • U.S. National Library of Medicine. Drug Information from the National Library of Medicine. Available at: https://www.nlm.nih.gov/learn-about-drugs.html. Accessed January 8, 2014. • Optifast. Product Information. Available at: http://www.optifast.com/Pages/index.aspx. Accessed January 7, 2014

References: Images • http://sciencelife.uchospitals.edu/2013/05/07/qa-dr-christopher-wigfield-on-the-future-of-lung-transplantation/ • http://www.guidantwealth.com/Goal-early-retirement.html • http://www.recessionista.com • http://www.everydayhealth.com • https://www.spiriva.com/?sc=SPRACQWEBPGOGBS1105034&utm_source=google&utm_medium=cpc&utm_term=spiriva&utm_campaign=Branded&MTD=2&ENG=1 • http://www.nlm.nih.gov/medlineplus/ency/imagepages/19376.htm • http://www.cdc.gov/copd/data.htm • http://www.www.kingcounty.gov • http://www.www.anactivelife.com • http://www.optifast.com/Pages/index.aspx • www.fairmed.at • www. Eatright.org • http://www.alltheweigh.com

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Trends in cardiovascular disease incidence among 22 million people in the UK over 20 years: population based study

• Related content
• Peer review
• Geert Molenberghs , professor 4 ,
• Geert Verbeke , professor 4 ,
• Francesco Zaccardi , associate professor 5 ,
• Claire Lawson , associate professor 5 ,
• Jocelyn M Friday , data scientist 1 ,
• Huimin Su , PhD student 2 ,
• Pardeep S Jhund , professor 1 ,
• Naveed Sattar , professor 6 ,
• Kazem Rahimi , professor 3 ,
• John G Cleland , professor 1 ,
• Kamlesh Khunti , professor 5 ,
• Werner Budts , professor 1 7 ,
• John J V McMurray , professor 1
• 1 School of Cardiovascular and Metabolic Health, British Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow, UK
• 2 Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium
• 3 Deep Medicine, Nuffield Department of Women’s and Reproductive Health, University of Oxford, Oxford, UK
• 4 Interuniversity Institute for Biostatistics and statistical Bioinformatics (I-BioStat), Hasselt University and KU Leuven, Belgium
• 5 Leicester Real World Evidence Unit, Diabetes Research Centre, University of Leicester, Leicester, UK
• 6 College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
• 7 Congenital and Structural Cardiology, University Hospitals Leuven, Belgium
• Correspondence to: N Conrad nathalie.conrad{at}kuleuven.be (or @nathalie_conrad on X)
• Accepted 1 May 2024

Objective To investigate the incidence of cardiovascular disease (CVD) overall and by age, sex, and socioeconomic status, and its variation over time, in the UK during 2000-19.

Design Population based study.

Setting UK.

Participants 1 650 052 individuals registered with a general practice contributing to Clinical Practice Research Datalink and newly diagnosed with at least one CVD from 1 January 2000 to 30 June 2019.

Main outcome measures The primary outcome was incident diagnosis of CVD, comprising acute coronary syndrome, aortic aneurysm, aortic stenosis, atrial fibrillation or flutter, chronic ischaemic heart disease, heart failure, peripheral artery disease, second or third degree heart block, stroke (ischaemic, haemorrhagic, and unspecified), and venous thromboembolism (deep vein thrombosis or pulmonary embolism). Disease incidence rates were calculated individually and as a composite outcome of all 10 CVDs combined and were standardised for age and sex using the 2013 European standard population. Negative binomial regression models investigated temporal trends and variation by age, sex, and socioeconomic status.

Results The mean age of the population was 70.5 years and 47.6% (n=784 904) were women. The age and sex standardised incidence of all 10 prespecified CVDs declined by 19% during 2000-19 (incidence rate ratio 2017-19 v 2000-02: 0.80, 95% confidence interval 0.73 to 0.88). The incidence of coronary heart disease and stroke decreased by about 30% (incidence rate ratios for acute coronary syndrome, chronic ischaemic heart disease, and stroke were 0.70 (0.69 to 0.70), 0.67 (0.66 to 0.67), and 0.75 (0.67 to 0.83), respectively). In parallel, an increasing number of diagnoses of cardiac arrhythmias, valve disease, and thromboembolic diseases were observed. As a result, the overall incidence of CVDs across the 10 conditions remained relatively stable from the mid-2000s. Age stratified analyses further showed that the observed decline in coronary heart disease incidence was largely restricted to age groups older than 60 years, with little or no improvement in younger age groups. Trends were generally similar between men and women. A socioeconomic gradient was observed for almost every CVD investigated. The gradient did not decrease over time and was most noticeable for peripheral artery disease (incidence rate ratio most deprived v least deprived: 1.98 (1.87 to 2.09)), acute coronary syndrome (1.55 (1.54 to 1.57)), and heart failure (1.50 (1.41 to 1.59)).

Conclusions Despite substantial improvements in the prevention of atherosclerotic diseases in the UK, the overall burden of CVDs remained high during 2000-19. For CVDs to decrease further, future prevention strategies might need to consider a broader spectrum of conditions, including arrhythmias, valve diseases, and thromboembolism, and examine the specific needs of younger age groups and socioeconomically deprived populations.

Introduction

Since the 1970s, the prevention of coronary disease, both primary and secondary, has improved considerably, largely attributable to public health efforts to control risk factors, such as antismoking legislation, and the widespread use of drugs such as statins. 1 2

Improvements in mortality due to heart disease have, however, stalled in several high income countries, 3 and reports suggest that the incidence of heart disease might even be increasing among younger people. 4 5 6 Conversely, along with coronary heart disease, other cardiovascular conditions are becoming relatively more prominent in older people, altering the profile of cardiovascular disease (CVD) in ageing societies. The importance of non-traditional risk factors for atherosclerotic diseases, such as socioeconomic deprivation, has also been increasingly recognised. Whether socioeconomic deprivation is as strongly associated with other CVDs as with atherosclerosis is uncertain, but it is important to understand as many countries have reported an increase in socioeconomic inequalities. 7

Large scale epidemiological studies are therefore needed to investigate secular trends in CVDs to target future preventive efforts, highlight the focus for future clinical trials, and identify healthcare resources required to manage emerging problems. Existing comprehensive efforts, such as statistics on CVD from leading medical societies or the Global Burden of Diseases studies, have helped toward this goal, but reliable age standardised incidence rates for all CVDs, how these vary by population subgroups, and changes over time are currently not available. 8 9 10

We used a large longitudinal database of linked primary care, secondary care, and death registry records from a representative sample of the UK population 11 12 to assess trends in the incidence of 10 of the most common CVDs in the UK during 2000-19, and how these differed by sex, age, socioeconomic status, and region.

Data source and study population

We used anonymised electronic health records from the GOLD and AURUM datasets of Clinical Practice Research Datalink (CPRD). CPRD contains information on about 20% of the UK population and is broadly representative of age, sex, ethnicity, geographical spread, and socioeconomic deprivation. 11 12 It is also one of the largest databases of longitudinal medical records from primary care in the world and has been validated for epidemiological research for a wide range of conditions. 11 We used the subset of CPRD records that linked information from primary care, secondary care from Hospital Episodes Statistics (HES admitted patient care and HES outpatient) data, and death certificates from the Office for National Statistics (ONS). Linkage was possible for a subset of English practices, covering about 50% of the CPRD records. Data coverage dates were 1 January 1985 to 31 December 2019 for primary care data (including drug prescription data), 1 April 1997 to 30 June 2019 for secondary care data, and 2 January 1998 to 30 May 2019 for death certificates.

Included in the study were men and women registered with a general practice for at least one year during the study period (1 January 2000 to 30 June 2019) whose records were classified by CPRD as acceptable for use in research and approved for HES and ONS linkage.

Study endpoints

The primary endpoint was the first presentation of CVD as recorded in primary or secondary care. We investigated 10 CVDs: acute coronary syndrome, aortic aneurysm, aortic stenosis, atrial fibrillation or flutter, chronic ischaemic heart disease, heart failure, peripheral artery disease, second or third degree heart block, stroke (ischaemic, haemorrhagic, or unspecified), and venous thromboembolism (deep vein thrombosis or pulmonary embolism). We defined incident diagnoses as the first record of that condition in primary care or secondary care regardless of its order in the patient’s record.

Diseases were considered individually and as a composite outcome of all 10 CVDs combined. For the combined analyses, we calculated the primary incidence (considering only the first recorded CVD in each patient, reflecting the number of patients affected by CVDs) and the total incidence (considering all incident CVD diagnoses in each patient, reflecting the cumulative number of CVD diagnoses). We performed sensitivity analyses including diagnoses recorded on death certificates.

To identify diagnoses, we compiled a list of diagnostic codes based on the coding schemes in use in each data source following previously established methods. 13 14 15 We used ICD-10 (international classification of diseases, 10th revision) codes for diagnoses recorded in secondary care, ICD-9 (international classification of diseases, ninth revision) (in use until 31 December 2000) and ICD-10 codes for diagnoses recorded on death certificates (used in sensitivity analyses only), the UK Office of Population Censuses and Surveys classification (OPCS-4) for procedures performed in secondary care settings, and a combination of Read, SNOMED, and local EMIS codes for diagnoses recorded in primary care records (see supplementary table S1). 16 Supplementary texts S1, S2, and S3 describe our approach to the generation of the diagnostic code list as well as considerations and sensitivity analyses into the validity of diagnoses recorded in UK electronic health records.

We selected covariates to represent a range of known cardiovascular risk factors. For clinical data, including systolic and diastolic blood pressure, smoking status, cholesterol (total:high density lipoprotein ratio), and body mass index (BMI), we abstracted data from primary care records as the most recent measurement within two years before the incident CVD diagnosis. BMI was categorised as underweight (<18.5), normal (18.5-24.9), overweight (25-29.9), and obesity (≥30). Information on the prevalence of chronic kidney disease, dyslipidaemia, hypertension, and type 2 diabetes was obtained as the percentage of patients with a diagnosis recorded in their primary care or secondary care record at any time up to and including the date of a first CVD diagnosis. Patients’ socioeconomic status was described using the index of multiple deprivation 2015, 17 a composite measure of seven dimensions (income, employment, education, health, crime, housing, living environment) and provided by CPRD. Measures of deprivation are calculated at small area level, covering an average population of 1500 people, and are presented in fifths, with the first 20% and last 20% representing the least and most deprived areas, respectively. We extracted information on ethnicity from both primary and secondary care records, and we used secondary care data when records differed. Ethnicity was grouped into four categories: African/Caribbean, Asian, white, and mixed/other. Finally, we extracted information on cardiovascular treatments (ie, aspirin and other antiplatelets, alpha adrenoceptor antagonists, aldosterone antagonists/mineralocorticoid receptor antagonists, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, beta blockers, calcium channel blockers, diuretics, nitrates, oral anticoagulants, and statins) as the number of patients with at least two prescriptions of each drug class within six months after incident CVD, among patients alive and registered with a general practitioner 30 days after the diagnosis. Supplementary table S2 provides a list of substances included in each drug class. Prescriptions were extracted from primary care records up to 31 December 2019.

Statistical analyses

Categorical data for patient characteristics are presented as frequencies (percentages), and continuous data are presented as means and standard deviations (SDs) for symmetrically distributed data or medians and interquartile ranges (IQRs) for non-symmetrically distributed data, over the whole CVD cohort and stratified by age, sex, socioeconomic status, region, and calendar year of diagnosis. For variables with missing entries, we present numbers and percentages of records with missing data. For categorical variables, frequencies refer to complete cases.

Incidence rates of CVD were calculated by dividing the number of incident diagnoses by the number of patient years in the cohort. Category specific rates were computed separately for subgroups of age, sex, socioeconomic status, region, and calendar year of diagnosis. Age calculations were updated for each calendar year. To ensure calculations referred to incident diagnoses, we excluded individuals, from both the numerator and the denominator populations, with a disease of interest diagnosed before the study start date (1 January 2000), or within the first 12 months of registration with their general practice. Time at risk started at the latest of the patient’s registration date plus 12 months, 30 June of their birth year, or study start date; and stopped at the earliest of death, transfer out of practice, last collection date of the practice, incidence of the disease of interest, or linkage end date (30 June 2019). Disease incidence was standardised for age and sex 18 using the 2013 European standard population 19 in five year age bands up to age 90 years.

Negative binomial regression models were used to calculate overall and category specific incidence rate ratios and corresponding 95% confidence intervals (CIs). 20 Models were adjusted for calendar year of diagnosis, age (categorised into five years age bands), sex, socioeconomic status, and region. We chose negative binomial models over Poisson models to account for potential overdispersion in the data. Sensitivity analyses comparing Poisson and negative binomial models showed similar results.

Study findings are reported according to the RECORD (reporting of studies conducted using observational routinely collected health data) recommendations. 21 We performed statistical analyses in R, version 4.3.3 (R Foundation for Statistical Computing, Vienna, Austria).

Patient and public involvement

No patients or members of the public were directly involved in this study owing to constraints on funding and time.

A total of 22 009 375 individuals contributed data between 1 January 2000 and 30 June 2019, with 146 929 629 patient years of follow-up. Among those we identified 2 906 770 new CVD diagnoses, affecting 1 650 052 patients. Mean age at first CVD diagnosis was 70.5 (SD 15.0) years, 47.6% (n=784 904) of patients were women, and 11.6% (n=191 421), 18.0% (n=296 554), 49.7% (n=820 892), and 14.2% (n=233 833) of patients had a history of chronic kidney disease, dyslipidaemia, hypertension, and type 2 diabetes, respectively, at the time of their first CVD diagnosis ( table 1 ).

Characteristics of patients with a first diagnosis of CVD, 2000-19. Values are number (percentage) unless stated otherwise

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During 2017-19, the most common CVDs were atrial fibrillation or flutter (age-sex standardised incidence 478 per 100 000 person years), heart failure (367 per 100 000 person years), and chronic ischaemic heart disease (351 per 100 000 person years), followed by acute coronary syndrome (190 per 100 000 person years), venous thromboembolism (183 per 100 000 person years), and stroke (181 per 100 000 patient years) ( fig 1 ).

Incidence of a first diagnosis of cardiovascular disease per 100 000 person years, 2000-19. Incidence rates are age-sex standardised to the 2013 European standard population. Any cardiovascular disease refers to the primary incidence of cardiovascular disease across the10 conditions investigated (ie, number of patients with a first diagnosis of cardiovascular disease). See supplementary table S4 for crude incidence rates by age and sex groups. IRR=incidence rate ratio

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Temporal trends

The primary incidence of CVDs (ie, the number of patients with CVD) decreased by 20% during 2000-19 (age-sex standardised incidence rate ratio 2017-19 v 2000-02: 0.80 (95% CI 0.73 to 0.88)). However, the total incidence of CVD (ie, the total number of new CVD diagnoses) remained relatively stable owing to an increasing number of subsequent diagnoses among patients already affected by a first CVD (incidence rate ratio 2017-19 v 2000-02: 1.00 (0.91 to 1.10)).

The observed decline in CVD incidence was largely due to declining rates of atherosclerotic diseases, in particular acute coronary syndrome, chronic ischaemic heart disease, and stroke, which decreased by about 30% during 2000-19. The incidence of peripheral artery disease also declined, although more modestly (incidence rate ratio 2017-19 v 2000-02: 0.89 (0.80 to 0.98)) ( fig 1 ).

The incidence of non-atherosclerotic heart diseases increased at varying rates, with incidence of aortic stenosis and heart block more than doubling over the study period (2017-19 v 2000-02: 2.42 (2.13 to 2.74) and 2.22 (1.99 to 2.46), respectively) ( fig 1 ). These increasing rates of non-atherosclerotic heart diseases balanced the reductions in ischaemic diseases so that the overall incidence of CVD across the 10 conditions appeared to reach a plateau and to remain relatively stable from 2007-08 (incidence rate ratio 2017-19 v 2005-07: 1.00 (0.91 to 1.10)) ( fig 2 ).

Age standardised incidence of cardiovascular disease by sex, 2000-19. Any cardiovascular disease refers to the primary incidence of cardiovascular disease across the 10 conditions investigated (ie, number of patients with a first diagnosis of cardiovascular disease). IRR=incidence rate ratio

Age stratified analyses further showed that the observed decrease in incidence of chronic ischaemic heart disease, acute coronary syndrome, and stroke was largely due to a reduced incidence in those aged >60 years, whereas incidence rates in those aged <60 years remained relatively stable ( fig 3 and fig 4 ).

Sex standardised incidence of cardiovascular disease in all age groups. Any cardiovascular disease refers to the primary incidence of cardiovascular disease across the 10 conditions investigated (ie, number of patients with a first diagnosis of cardiovascular disease)

Sex standardised incidence of cardiovascular diseases by age subgroups <69 years. Any cardiovascular disease refers to the primary incidence of cardiovascular disease across the 10 conditions investigated (ie, number of patients with a first diagnosis of cardiovascular disease)

Age at diagnosis

CVD incidence was largely concentrated towards the end of the life span, with a median age at diagnosis generally between 65 and 80 years. Only venous thromboembolism was commonly diagnosed before age 45 years ( fig 5 ). Over the study period, age at first CVD diagnosis declined for several conditions, including stroke (on average diagnosed 1.9 years earlier in 2019 than in 2000), heart block (1.3 years earlier in 2019 than in 2000), and peripheral artery disease (1 year earlier in 2019 than in 2000) (see supplementary figure S1). Adults with a diagnosis before age 60 years were more likely to be from lower socioeconomic groups and to have a higher prevalence of several risk factors, including obesity, smoking, and high cholesterol levels (see supplementary table S3).

Incidence rates of cardiovascular diseases calculated by one year age bands and divided into a colour gradient of 20 quantiles to reflect incidence density by age. IQR=interquartile range

Incidence by sex

Age adjusted incidence of all CVDs combined was higher in men (incidence rate ratio for women v men: 1.46 (1.41 to 1.51)), with the notable exception of venous thromboembolism, which was similar between men and women. The incidence of aortic aneurysms was higher in men (3.49 (3.33 to 3.65)) ( fig 2 ). The crude incidence of CVD, however, was similar between men and women (1069 per 100 000 patient years and 1176 per 100 000 patient years, respectively), owing to the higher number of women in older age groups. Temporal trends in disease incidence were generally similar between men and women ( fig 2 ).

Incidence by socioeconomic status

The most deprived socioeconomic groups had a higher incidence of any CVDs (incidence rate ratio most deprived v least deprived: 1.37 (1.30 to 1.44)) ( fig 6 ). A socioeconomic gradient was observed across almost every condition investigated. That gradient did not decrease over time, and it was most noticeable for peripheral artery disease (incidence rate ratio most deprived v least deprived: 1.98 (1.87 to 2.09)), acute coronary syndrome (1.55 (1.54 to 1.57)), and heart failure (1.50 (1.41 to 1.59)). For aortic aneurysms, atrial fibrillation, heart failure, and aortic stenosis, socioeconomic inequalities in disease incidence appeared to increase over time.

Age-sex standardised incidence rates of cardiovascular diseases by socioeconomic status (index of multiple deprivation 2015). Any cardiovascular disease refers to the primary incidence of cardiovascular disease across the 10 conditions investigated (ie, number of patients with a first diagnosis of cardiovascular disease). Yearly incidence estimates were smoothed using loess (locally estimated scatterplot smoothing) regression lines

Regional differences

Higher incidence rates were seen in northern regions (north west, north east, Yorkshire and the Humber) of England for all 10 conditions investigated, even after adjusting for socioeconomic status. Aortic aneurysms and aortic stenosis had the strongest regional gradients, with incidence rates about 30% higher in northern regions compared with London. Geographical variations remained modest, however, and did not appear to change considerably over time (see supplementary figure S2).

Sensitivity analyses

In sensitivity analyses that used broader disease definitions, that included diagnoses recorded on death certificates, that relied on longer lookback periods for exclusion of potentially prevalent diagnoses, or that were restricted to diagnoses recorded during hospital admissions, temporal trends in disease incidence appeared similar (see supplementary figures S3-S6).

Secondary prevention treatments

The proportion of patients using statins and antihypertensive drugs after a first CVD diagnosis increased over time, whereas the use of non-dihydropyridines calcium channel blockers, nitrates, and diuretics decreased over time. Non-vitamin K antagonist oral anticoagulants increasingly replaced vitamin K anticoagulants (see supplementary figure S7).

The findings of this study suggest that important changes occurred in the distribution of CVDs during 2000-19 and that several areas are of concern. The incidence of non-atherosclerotic heart diseases was shown to increase, the decline in atherosclerotic disease in younger people was stalling, and socioeconomic inequalities had a substantial association across almost every CVD investigated.

Implications for clinical practice and policy

Although no causal inference can be made from our data, the decline in rates of ischaemic diseases coincided with reductions in the prevalence of risk factors such as smoking, hypertension, and raised cholesterol levels in the general population over the same period, 22 and this finding suggests that efforts in the primary and secondary prevention of atherosclerotic diseases have been successful. The decline in stroke was not as noticeable as that for coronary heart disease, which may reflect the rising incidence of atrial fibrillation. The variation in trends for peripheral artery disease could be due to differences in risk factors (eg, a stronger association with diabetes), the multifaceted presentations and causes, and the introduction of systematic leg examinations for people with diabetes. 23 24

All the non-atherosclerotic diseases, however, appeared to increase during 2000-19. For some conditions, such as heart failure, the observed increase remained modest, whereas for others, such as aortic stenosis and heart block, incidence rates doubled. All analyses in this study were standardised for age and sex, to illustrate changes in disease incidence independently of changes in population demographics. Whether these trends solely reflect increased awareness, access to diagnostic tests, or even screening (eg, for abdominal aortic aneurysm 25 ) and coding practices, is uncertain. Reductions in premature death from coronary heart disease may have contributed to the emergence of these other non-atherosclerotic CVDs. Regardless, the identification of increasing numbers of people with these problems has important implications for health services, especially the provision of more surgical and transcatheter valve replacement, pacemaker implantation, and catheter ablation for atrial fibrillation. Importantly, these findings highlight the fact that for many cardiovascular conditions such as heart block, aortic aneurysms, and non-rheumatic valvular diseases, current medical practice remains essentially focused on the management of symptoms and secondary prevention and that more research into underlying causes and possible primary prevention strategies is needed. 26 27

These varying trends also mean that the contribution of individual CVDs towards the overall burden has changed. For example, atrial fibrillation or flutter are now the most common CVDs in the UK. Atrial fibrillation is also a cause (and consequence) of heart failure, and these two increasingly common problems may amplify the incidence of each other. Venous thromboembolism and heart block also appeared as important contributors to overall CVD burden, with incidence rates similar to those of stroke and acute coronary syndrome, yet both receive less attention in terms of prevention efforts.

The stalling decline in the rate of coronary heart disease in younger age groups is of concern, has also been observed in several other high income countries, and may reflect rising rates of physical inactivity, obesity, and type 2 diabetes in young adults. 4 6 28 The stalled decline suggests prevention approaches may need to be expanded beyond antismoking legislation, blood pressure control, and lipid lowering interventions to include the promotion of physical activity, weight control, and use of new treatments shown to reduce cardiovascular risk in people with type 2 diabetes. 29 Although CVD incidence is generally low in people aged <60 years, identifying those at high risk of developing CVD at a young age and intervening before problems occur could reduce premature morbidity and mortality and have important economic implications.

Our study further found that socioeconomic inequalities may contribute to CVD burden, and that this association is not restricted to selected conditions but is visible across most CVDs. The reasons behind the observed increase in risk in relation to socioeconomic inequalities are likely to be multifactorial and to include environmental, occupational, psychosocial, and behavioural risk factors, including established cardiovascular risk factors such as smoking, obesity, nutrition, air pollution, substance misuse, and access to care. 30 How these findings apply to different countries is likely to be influenced by socioeconomic structures and healthcare systems, although health inequalities have been reported in numerous countries. 30 One important factor in the present study is that access to care is free at the point of care in the UK, 31 and yet socioeconomic inequalities persist despite universal health coverage and they did not appear to improve over time. Independently of the specificities of individual countries, our findings highlight the importance of measuring and considering health inequalities and suggest that dealing with the social determinants of health—the conditions under which people are born, live, work, and age—could potentially bring substantial health improvements across a broad range of chronic conditions.

Finally, our results reflect disease incidence based on diagnostic criteria, screening practices, availability, and accuracy of diagnostic tests in place at a particular time and therefore must be interpreted within this context. 32 Several of the health conditions investigated are likely to being sought and detected with increased intensity over the study period. For example, during the study period the definition of myocardial infarction was revised several times, 33 34 35 and high sensitivity troponins were progressively introduced in the UK from 2010. These more sensitive markers of cardiac injury are thought to have increased the detection rates for less severe disease. 36 37 Similarly, increased availability of computed tomography may have increased detection rates for stroke. 38 These changes could have masked an even greater decline in these conditions than observed in the present study. Conversely, increased use of other biochemical tests (such as natriuretic peptides) and more sensitive imaging techniques might have increased the detection of other conditions. 39 40 41 The implementation of a screening programme for aortic aneurysm and incentive programmes aimed at improving coding practices, including the documentation of CVD, associated risk factors and comorbidities, and treatment of these, are also likely to have contributed to the observed trends. 25 42 43 As a result, the difference in incidence estimates and prevalence of comorbidities over time may not reflect solely changes in the true incidence but also differences in ascertainment of people with CVD. 44 Nonetheless, long term trends in large and unconstrained populations offer valuable insights for healthcare resource planning and for the design of more targeted prevention strategies that could otherwise not be answered by using smaller cohorts, cross sectional surveys, or clinical trials; and precisely because they are based on routinely reported diagnoses they are more likely to capture the burden of disease as experienced by doctors and health services.

Strengths and limitations of this study

A key strength of this study is its statistical power, with >140 million person years of data. The large size of the cohort allowed us to perform incidence calculations for a broad spectrum of conditions, and to examine the influence of age, sex, and socioeconomic status as well as trends over 20 years. One important limitation of our study was the modest ethnic diversity in our cohort and the lack of information on ethnicity for the denominator population, which precluded us from stratifying incidence estimates by ethnic group. Our analyses were also limited by the unavailability or considerable missingness of additional variables potentially relevant to the development of CVD, such as smoking, body mass index, imaging data, women specific cardiovascular risk factors (eg, pregnancy associated hypertension and gestational diabetes), and blood biomarkers. Further research may also need to consider an even wider spectrum of CVDs, including individual types of valve disease, pregnancy related conditions, and infection related heart diseases. Research using databases with electronic health records is also reliant on the accuracy of clinical coding input by doctors in primary care as part of a consultation, or in secondary care as part of a hospital admission. We therefore assessed the validity of diagnoses in UK electronic health records data and considered it to be appropriate in accordance with the >200 independent validation studies reporting an average positive predictive value of about 90% for recorded diagnoses. 45 Observed age distributions were also consistent with previous studies and added to the validity of our approach. Nevertheless, our results must be interpreted within the context and limitations of routinely collected data from health records, diagnostic criteria, screening practices, the availability and accuracy of diagnostic tests in place at that time, and the possibility that some level of miscoding is present or that some bias could have been introduced by restricting the cohort to those patients with at least 12 months of continuous data.

Conclusions

Efforts to challenge the notion of the inevitability of vascular events with ageing, and evidence based recommendations for coronary heart disease prevention, have been successful and can serve as a model for other non-communicable diseases. Our findings show that it is time to expand efforts to improve the prevention of CVDs. Broadening research and implementation efforts in both primary and secondary prevention to non-atherosclerotic diseases, tackling socioeconomic inequalities, and introducing better risk prediction and management among younger people appear to be important opportunities to tackle CVDs.

What is already known on this topic

Recent data show that despite decades of declining rates of cardiovascular mortality, the burden from cardiovascular disease (CVD) appears to have stalled in several high income countries

What this study adds

This observational study of a representative sample of 22 million people from the UK during 2000-19 found reductions in CVD incidence to have been largely restricted to ischaemic heart disease and stroke, and were paralleled by a rising number of diagnoses of cardiac arrhythmias, valve disease, and thromboembolic events

Venous thromboembolism and heart block were important contributors to the overall burden of CVDs, with incidence rates similar to stroke and acute coronary syndromes

Improvements in rates of coronary heart disease almost exclusively appeared to benefit those aged >60 years, and the CVD burden in younger age groups appeared not to improve

Ethics statements

Ethical approval.

This study was approved by the Clinical Practice Research Datalink Independent Scientific Advisory Committee.

Data availability statement

Access to Clinical Practice Research Datalink (CPRD) data is subject to a license agreement and protocol approval process that is overseen by CPRD’s research data governance process. A guide to access is provided on the CPRD website ( https://www.cprd.com/data-access ) To facilitate the subsequent use and replication of the findings from this study, aggregated data tables are provided with number of events and person years at risk by individual condition and by calendar year, age (by five year age band), sex, socioeconomic status, and region (masking field with fewer than five events, as per CPRD data security and privacy regulations) on our GitHub repository ( https://github.com/nathalieconrad/CVD_incidence ).

Acknowledgments

We thank Hilary Shepherd, Sonia Coton, and Eleanor L Axson from the Clinical Practice Research Datalink for their support and expertise in preparing the dataset underlying these analyses.

Contributors: NC and JJVM conceived and designed the study. NC, JJVM, GM, and GV designed the statistical analysis plan and NC performed the statistical analysis. All authors contributed to interpreting the results, drafting the manuscript, and the revisions. NC, GM, and GV had permission to access the raw data and NC and GM verified the raw data. All authors gave final approval of the version to be published and accept responsibility to submit the manuscript for publication. NC and JJVM accept full responsibility for the conduct of the study, had access to aggregated data, and controlled the decision to publish. They are the guarantors. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.

Funding: This study was funded by a personal fellowship from the Research Foundation Flanders (grant No 12ZU922N), a research grant from the European Society of Cardiology (grant No App000037070), and the British Heart Foundation Centre of Research Excellence (grant No RE/18/6/34217). The funders had no role in considering the study design or in the collection, analysis, interpretation of data, writing of the report, or decision to submit the article for publication.

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: NC is funded by a personal fellowship from the Research Foundation Flanders and a research grant from the European Society of Cardiology. JMF, PSJ, JGC, NS, and JJVM are supported by British Heart Foundation Centre of Research Excellence. PSJ and JJVM are further supported by the Vera Melrose Heart Failure Research Fund. JJVM has received funding to his institution from Amgen and Cytokinetics for his participation in the steering sommittee for the ATOMIC-HF, COSMIC-HF, and GALACTIC-HF trials and meetings and other activities related to these trials; has received payments through Glasgow University from work on clinical trials, consulting, and other activities from Alnylam, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardurion, Dal-Cor, GlaxoSmithKline, Ionis, KBP Biosciences, Novartis, Pfizer, and Theracos; and has received personal lecture fees from the Corpus, Abbott, Hikma, Sun Pharmaceuticals, Medscape/Heart.Org, Radcliffe Cardiology, Alkem Metabolics, Eris Lifesciences, Lupin, ProAdWise Communications, Servier Director, and Global Clinical Trial Partners. NS declares consulting fees or speaker honorariums, or both, from Abbott Laboratories, Afimmune, Amgen, AstraZeneca, Boehringer Ingelheim, Lilly, Hanmi Pharmaceuticals, Janssen, Merck Sharp & Dohme, Novartis, Novo Nordisk, Pfizer, Roche Diagnostics, and Sanofi; and grant support paid to his university from AstraZeneca, Boehringer Ingelheim, Novartis, and Roche Diagnostics. KK has acted as a consultant or speaker or received grants for investigator initiated studies for Astra Zeneca, Bayer, Novartis, Novo Nordisk, Sanofi-Aventis, Lilly, Merck Sharp & Dohme, Boehringer Ingelheim, Oramed Pharmaceuticals, Roche, and Applied Therapeutics. KK is supported by the National Institute for Health and Care Research (NIHR) Applied Research Collaboration East Midlands (ARC EM) and the NIHR Leicester Biomedical Research Centre (BRC). CL is funded by an NIHR Advanced Research Fellowship (NIHR-300111) and supported by the Leicester BRC. PSJ has received speaker fees from AstraZeneca, Novartis, Alkem Metabolics, ProAdWise Communications, Sun Pharmaceuticals, and Intas Pharmaceuticals; has received advisory board fees from AstraZeneca, Boehringer Ingelheim, and Novartis; has received research funding from AstraZeneca, Boehringer Ingelheim, Analog Devices; his employer, the University of Glasgow, has been remunerated for clinical trial work from AstraZeneca, Bayer, Novartis, and Novo Nordisk; and is the Director of Global Clinical Trial Partners. HS is supported by the China Scholarship Council. Other authors report no support from any organisation for the submitted work, no financial relationships with any organisations that might have an interest in the submitted work in the previous three years, and no other relationships or activities that could appear to have influenced the submitted work.

Transparency: The lead author (NC) affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

Dissemination to participants and related patient and public communities: Results from this study will be shared with patient associations and foundations dedicated to preventing cardiovascular diseases, such as the European Heart Network and the American Heart Association. To reach the public, findings will also be press released alongside publication of this manuscript. Social media (eg, X) will be used to draw attention to the work and stimulate debate about its findings. Finally, the underlying developed algorithms will be freely available for academic use at https://github.com/nathalieconrad/CVD_incidence .

Provenance and peer review: Not commissioned; externally peer reviewed.

This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/ .

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• Open access
• Published: 27 June 2024

Chemotherapy-related cardiotoxicity and its symptoms in patients with breast cancer: a scoping review

• Hyunjoo Kim 1 , 2 ,
• Bomi Hong 3 ,
• Sanghee Kim 4 ,
• Seok-Min Kang 5 &
• Jeongok Park   ORCID: orcid.org/0000-0003-4978-817X 4  

Systematic Reviews volume  13 , Article number:  167 ( 2024 ) Cite this article

22 Accesses

Metrics details

Chemotherapy-related cardiotoxicity is a significant concern because it is a major cause of morbidity. This study aimed to provide in-depth information on the symptoms of chemotherapy-related cardiotoxicity (CRCT) by exploring literature that concurrently reports the types and symptoms of CRCT in patients with breast cancer.

A scoping review was performed according to an a priori protocol using the Joanna Briggs Institute’s guidelines. The participants were patients with breast cancer. The concept was the literature of specifically reported symptoms directly matched with CRCT and the literature, in English, from 2010, and the context was open. The search strategy included four keywords: “breast cancer,” “chemotherapy,” “cardiotoxicity,” and “symptoms.” All types of research designs were included; however, studies involving patients with other cancer types, animal subjects, and symptoms not directly related to CRCT were excluded. Data were extracted and presented including tables and figures.

A total of 29 articles were included in the study, consisting of 23 case reports, 4 retrospective studies, and 2 prospective studies. There were no restrictions on the participants’ sex; however, all of them were women, except for one case report. The most used chemotherapy regimens were trastuzumab, capecitabine, and doxorubicin or epirubicin. The primary CRCT identified were myocardial dysfunction and heart failure, followed by coronary artery disease, pulmonary hypertension, and other conditions. Major tests used to diagnose CRCT include echocardiography, electrocardiography, serum cardiac enzymes, coronary angiography, computed tomography, and magnetic resonance imaging. In all case reports, CRCT was diagnosed through an incidental checkup according to the patient’s symptom presentation; however, only 10 of these studies showed a baseline checkup before chemotherapy. The five most common CRCT symptoms were dyspnea, chest pain, peripheral edema, fatigue, and palpitations, which were assessed by patient-reported symptom presentation rather than using a symptom assessment tool. Dyspnea with trastuzumab treatment and chest pain with capecitabine treatment were particularly characteristic. The time for first symptom onset after chemotherapy ranged from 1 hour to 300 days, with anthracycline-based regimens requiring 3–55 days, trastuzumab requiring 60–300 days, and capecitabine requiring 1–7 days.

Conclusions

This scoping review allowed data mapping according to the study design and chemotherapy regimens. Cardiac assessments for CRCT diagnosis were performed according to the patient’s symptoms. There were approximately five types of typical CRCT symptoms, and the timing of symptom occurrence varied. Therefore, developing and applying a CRCT-specific and user-friendly symptom assessment tool are expected to help healthcare providers and patients manage CRCT symptoms effectively.

Peer Review reports

Breast cancer is currently the most common cancer worldwide. Its incidence and mortality rates in East Asia in 2020 accounted for 24% and 20% of the global rates, respectively, and these rates are expected to continue increasing until 2040 [ 1 ]. In the USA, since the mid-2000s, the incidence rate of breast cancer has been increasing by 0.5% annually, while the mortality rate has been decreasing by 1% per year from 2011 to 2020 [ 2 ]. Despite the improved long-term survival rate in patients with breast cancer due to the development of chemotherapy, the literature has highlighted that cardiotoxicity, a cardiac problem caused by chemotherapy, could be a significant cause of death among these patients [ 3 ]. Chemotherapy-related cardiotoxicity (CRCT) can interfere with cancer treatment and progress to congestive heart failure during or after chemotherapy [ 4 ], potentially lowering the survival rate and quality of life of patients with cancer [ 5 ].

The term cardiotoxicity was first used in the 1970s to describe cardiac complications resulting from chemotherapy regimens, such as anthracyclines and 5-fluorouracil. The early definition of cardiotoxicity centered around heart failure, but the current definition is broad and still imprecise [ 6 ]. The 2022 guidelines on cardio-oncology from the European Society of Cardiology (ESC) define cardiotoxicity as including cardiac dysfunction, myocarditis, vascular toxicity, arterial hypertension, and cardiac arrhythmias. Some of these definitions reflect the symptoms. For example, cardiac dysfunction, which accounts for 48% of cardiotoxicity in patients with cancer, is divided into asymptomatic and symptomatic cardiac dysfunction. Asymptomatic cardiac dysfunction is defined based on left ventricular ejection fraction (LVEF), myocardial global longitudinal strain, and cardiac biomarkers. Symptomatic cardiac dysfunction indicates heart failure and presents with ankle swelling, breathlessness, and fatigue [ 7 ]. The ESC guidelines for heart failure present more than 20 types of symptoms [ 8 ]; however, to the best of our knowledge, few studies have been conducted to determine which heart failure symptoms and their characteristics are associated with CRCT in patients with breast cancer. Similarly, there is a lack of information related to vascular toxicity such as myocardial infarction [ 7 ].

Professional societies in cardiology and oncology have proposed guidelines for the prevention and management of cardiotoxicity in patients with cancer. According to the American Society of Clinical Oncology and the ESC, it is recommended to identify high-risk patients, comprehensively evaluate clinical signs and symptoms associated with CRCT, and conduct cardiac evaluations before, during, and after chemotherapy [ 7 , 9 , 10 ]. In addition, guidelines for patients with cancer, including those for breast cancer survivorship care, emphasize that patients should be aware of the potential risk of CRCT and report symptoms, such as fatigue or shortness of breath to their healthcare providers [ 7 , 11 , 12 ]. Although these guidelines encompass cardiac monitoring as well as symptom observation, many studies have focused solely on objective diagnostic tests, such as echocardiography, cardiac magnetic resonance, and cardiac biomarkers [ 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 ], which means that there is little interest in CRCT symptoms in patients under breast cancer care.

This lack of interest in CRCT symptoms may be related to the absence of a specific symptom assessment tool for CRCT. Symptom monitoring of CRCT in patients with breast cancer was conducted through patient interviews and reported using the appropriate terminology [ 23 ]. In terms of interviews, patients with cancer experienced the burden of expressing symptoms between cardiovascular problems and cancer treatment. Qualitative research on patients with cancer indicates that these patients experience a daily battle to distinguish the symptoms they experience during chemotherapy [ 24 ]. To reduce the burden of identifying CRCT symptoms, it is crucial to educate patients with breast cancer undergoing chemotherapy about these symptoms. To report cardiotoxicity, healthcare providers in oncology can use a dictionary of terms called the Common Terminology Criteria for Adverse Events (CTCAE) for reporting adverse events in patients with cancer [ 25 ]. Patients can also use Patient-Reported Outcome (PRO), which allows unfiltered reporting of symptoms directly to the clinical database [ 26 ]. PRO consists of 78 symptomatic adverse events out of approximately 1,000 types of CTCAE [ 27 ]. Basch et al. suggested that PRO could enable healthcare providers to identify patient symptoms before they worsen, thereby improving the overall survival rate of patients with metastatic cancer [ 28 ]. This finding implies that symptoms can provide valuable clues for enhancing the timeliness and accuracy of clinical assessments of CRCT [ 29 ]. Therefore, it is necessary to explore the scope of research focusing on CRCT symptoms for prevention and early detection of CRCT in patients with breast cancer. The detailed research questions are as follows:

What are the general characteristics of the studies related to CRCT in patients with breast cancer?

What diagnostic tools and monitoring practices are used to detect CRCT?

What are the characteristics and progression of symptoms associated with CRCT?

A scoping review is a research method for synthesizing evidence that involves mapping the scope of evidence on a particular topic [ 30 ]. It aims to clarify key concepts and definitions, identify key characteristics of factors related to a concept, and highlight gaps or areas for further research [ 30 ]. This study used a scoping review methodology based on the Joanna Briggs Institute (JBI) framework. The JBI methodology, refined from the framework initially developed by Arksey and O’Malley [ 31 ], involves developing a research question, establishing detailed inclusion and exclusion criteria, and selecting and analyzing literature accordingly [ 32 ]. In contrast to systematic reviews, scoping reviews can encompass a variety of study designs and are particularly suitable when the topic has not been extensively studied [ 33 ]; hence, the decision was made to conduct a scoping review.

Development of a scoping review protocol

To conduct this review, an a priori scoping review protocol was developed to enhance transparency and increase the usefulness and reliability of the results. The protocol included the title, objective, review questions, introduction, eligibility criteria, participants, concept, context, types of evidence source, methods, search strategy, source of evidence selection, data extraction, data analysis and presentation, and deviation from the protocol [ 34 ] (Supplementary File 1).

Eligibility criteria

A participant-concept-context (PCC) framework was constructed based on the following research criteria. The participants were patients with breast cancer. The concept was that studies that specifically reported symptoms directly matched to CRCT in patients with breast cancer and the literature, published in English since 2010, in line with the year the CRCT guidelines were announced by the Cardio-Oncology Society. The context was open. We included all types of research designs. The exclusion criteria were studies that included patients with other types of cancer, involved animal subjects, and reported symptoms not directly related to CRCT.

Search strategy

The keywords consisted of “breast cancer,” “chemotherapy,” “cardiotoxicity,” and “symptoms.” The keywords for “cardiotoxicity” were constructed according to the clinical cardiotoxicity report and ESC guidelines [ 7 , 35 ]. The keywords for “symptoms” included 40 specific symptoms of arrhythmia, heart failure, and cardiac problems [ 36 , 37 ] (Supplementary Table 1). We used PubMed, Embase, and CINAHL.

Source of evidence selection

Duplicate studies were removed using EndNote 21. The titles and abstracts were then reviewed according to the inclusion criteria, the primary literature was selected, and the final literature was selected through a full-text review. Any disagreements were resolved through discussions between the investigators.

Data extraction

The data from the literature included the general characteristics of the study, as well as information on the patients, chemotherapy, cardiotoxicity, and symptoms. The general characteristics of the study included author, publication year, country of origin, study design; patient information including sample size, sex, age, cancer type, and cancer stage; chemotherapy information including chemotherapy regimen; cardiotoxicity information including type of cardiotoxicity, diagnostic tests, and times of assessment; and symptom information including type of symptom, characteristics of symptom worsening or improvement, onset time, progression time, and time to symptom improvement. Information on whether to receive chemotherapy after the diagnosis of cardiotoxicity was explored.

Data analysis and presentation

The contents of the included studies were divided into three categories: (1) general characteristics, which encompassed study designs, patients, and medications; (2) type of CRCT and cardiac assessment for CRCT; and (3) characteristics and progression of the symptoms associated with CRCT. CRCT symptom-related data are presented in tables and figures.

In total, 487 studies were identified through database searches, and 116 duplicates were subsequently removed. After reviewing the titles and abstracts, we excluded 197 studies in which participants had cancers other than breast cancer, no symptoms, or symptom-related expressions. Of the remaining 174 studies, 146 were excluded after full-text review. Among the excluded studies, 79 were mainly clinical trials that the symptoms were not directly related to CRCT, 62 did not report specific symptoms, four were in the wrong population, and one was unavailable for full-text review. An additional study was included after a review of references, bringing the final count to 29 studies included in the analysis (Fig. 1 ).

Preferred reporting items for systematic reviews flowchart

General characteristics of studies including designs, sex and age, chemotherapy regimen, and CRCT criteria

Table 1 presents the general characteristics of the studies included in this review. The majority of these studies were published in the USA ( n =14), with Japan ( n =3), and Romania ( n =2) following. The study designs primarily consisted of case reports ( n =23), retrospective studies ( n =4), and prospective studies ( n =2).

All case reports involved female patients, except for one involving a male patient. Five quantitative studies did not specify or limit the sex of the participants, and one retrospective study included only female patients. In terms of cancer stage, the majority of studies involved patients with advanced breast cancer ( n =13), while a smaller number involved patients with early-stage breast cancer ( n =4). Twelve studies did not specify the cancer stage. Approximately 20 types of chemotherapy regimens are currently in use. Trastuzumab, which is a human epidermal growth factor receptor 2 (HER2) blocker, was mentioned in the majority of studies ( n =8), followed by capecitabine (an antimetabolite) ( n =7), and doxorubicin or epirubicin (anthracycline-based chemotherapy) ( n =6). Current chemotherapy and previous treatment methods were described together, with the exception of eight studies. Six quantitative studies defined the CRCT criteria, five of which were based on decreased LVEF and one of which was based on significant cardiac symptoms and/or electrocardiogram changes. Twenty-three case reports described the cardiovascular diagnosis as CRCT.

Diagnostic tools and monitoring practice for CRCT

Table 2 displays the types of CRCT, diagnostic tools, and times of cardiac assessment according to chemotherapy regimens. The most prevalent CRCT were myocardial dysfunction and heart failure, identified in 12 case studies, respectively. This was followed by coronary artery disease, represented in 8 case studies, pulmonary hypertension in 2 case studies, and a single case study of periaortitis. The most used test for diagnosing CRCT was echocardiography ( n =22), followed by EKG ( n =20), various types of cardiac enzymes ( n =16), coronary angiography (CAG, n =12), computed tomography ( n =6), and magnetic resonance imaging (MRI, n =4). Regarding the CRCT symptom assessment tools, the CTCAE was used in two studies, the New York Heart Association classification for heart failure in two studies, the dyspnea assessment scale in one study, and symptoms of cardiac origin, which consisted of chest pain, dyspnea, and palpitations in one study.

Regarding the times of cardiac evaluation, two studies performed regular cardiac checkups including before, during, and after chemotherapy. There were 10 case studies and six quantitative studies describing cardiac function testing before chemotherapy, of which seven studies performed regular cardiac screening tests and two studies mentioned cardiac screening even after the completion of chemotherapy. The frequency of regular checkups varied from every 3 months to every two to four cycles. In all case reports ( n =23), CRCT were diagnosed through incidental checkups based on patients’ symptom presentation, and in most cases, several tests were performed subsequentially for CRCT diagnosis. In one case study, cardiac evaluation was conducted 3 days after the patient’s initial symptom presentation, when the symptoms became more severe.

Characteristics and progression of symptoms associated with CRCT

Table 3 shows the descriptive scope of the CRCT-related symptoms according to the chemotherapy regimens used in the included studies. The mapping factors included initial symptoms, symptom onset or severity, symptom progression, medical management, and CRCT results. One of the most frequent symptoms associated with CRCT was dyspnea, which was discussed in 19 studies and described as difficulty in breathing, shortness of breath, or New York Heart Association (NYHA) class II or III. When dyspnea appeared as the initial symptom of CRCT, the symptom progression was worsening in eight case studies and persistent in two cases. Chest pain was described in 12 studies as a symptom characterized by a squeezing, tingling, burning, tightened, or atypical feeling that was relieved by rest and exacerbated by exertion. Other symptoms included peripheral edema ( n =6), fatigue ( n =5), and palpitation ( n =2). The symptoms were assessed by patient-reported symptom presentation rather than using a symptom assessment tool.

The symptoms could be categorized based on the type of chemotherapy regimens used. In the case studies involving anthracycline-based regimen and HER2 blockers, dyspnea was the most frequently observed symptom ( n =7), followed by peripheral edema ( n =2), and chest pain or discomfort ( n =2). In case studies where antimetabolites were used, specifically capecitabine, chest pain was a common and prominent symptom. This chest pain typically manifested between 1 and 7 days after drug administration and persisted until treatment. Notably, four out of seven patients reported this symptom on the first day of chemotherapy, according to the case reports. The time for first symptom onset after chemotherapy ranged from 1 hour to 300 days, with anthracycline-based regimens requiring 3–55 days, trastuzumab requiring 60–300 days, and capecitabine requiring 1–7 days. Figure 2 shows the progression of symptoms in case studies, detailing the time of symptom onset, the date of symptom reporting, and the date of treatment completion following the use of chemotherapy. The studies that did not specify any of the dates of symptom onset, reporting, and completion of treatment were excluded from the figure.

Figure 3 shows symptoms according to the main types of chemotherapy regimens reported in case studies. Dyspnea with trastuzumab and chest pain with capecitabine are particularly characteristic. A retrospective study included in this scoping review reported that chest pain was the most common symptom associated with capecitabine, followed by dyspnea and palpitation [ 40 ]. Furthermore, peripheral edema was primarily observed with anthracycline, alkylating, and HER2 blockers, while fatigue was noted with various anticancer drugs, irrespective of the type of chemotherapy regimen.

Ongoing chemotherapy was discontinued after CRCT was detected in 20 case studies. When patients presented symptoms indicative of CRCT, the majority were promptly hospitalized for further evaluation, medication, or interventional treatment. The majority of studies indicated the initiation of cardiac medication ( n =21), with three case studies involving coronary intervention and two involving treatment with wearable devices. Most management procedures were conducted in a general ward or an intensive care unit.

In most case studies, symptoms improved following cardiac treatment, with either complete or partial recovery of LVEF observed in 19 instances. However, a few studies reported a poor prognosis, including two instances of death. LVEF recovered in most patients within 6 months when treated with an anthracycline-based regimen and HER2 blockers (Fig. 2 ). A retrospective study reported that the rates of complete or partial recovery of CRCT following treatment with doxorubicin-based chemotherapy and trastuzumab were 42.9% and 86.1%, respectively [ 39 ]. Another retrospective study noted that the recovery time of CRCT when treated with HER2 blockers increased in correlation with the severity of the NYHA class, ranging from 8 to 80 weeks [ 38 ]. In the case of the antimetabolite capecitabine, all patients recovered within a day to a week, except one patient who did not recover.

This scoping review was conducted to explore the scope of studies focusing on CRCT symptoms, including the general characteristics of the studies, diagnostic tools, monitoring practices related to detecting CRCT, and the characteristics and progression of symptoms associated with CRCT. The primary findings of this review were as follows: (1) common symptoms related to CRCT and differences in symptoms according to the chemotherapy regimens used were identified; (2) the symptoms reported by the patient served as clues to suspect a specific type of CRCT; and (3) regular monitoring practices for CRCT prevention and detection were insufficient.

First, the current study identified common symptoms such as dyspnea, chest pain, peripheral edema, fatigue, and palpitation associated with CRCT, as well as variations in symptoms depending on the chemotherapy regimen used in patients with breast cancer. Among these symptoms, dyspnea, edema, and chest pain were frequently observed in patients receiving anthracycline-based and/or HER2 blocker drugs. These symptoms, which are associated with heart failure, appeared later compared to those observed with capecitabine, as depicted in Fig. 2 . This may be due to the known impact of anthracycline-based and/or HER2 blocker regimens on cardiomyocytes and other cells, leading to myocardial damage [ 42 ]. Therefore, the symptoms are related to heart failure, potentially resulting from the impairment of ventricular filling or ejection in patients undergoing treatment with these regimens [ 43 ].

In a similar vein, Attin et al. (2022) documented the occurrence of symptoms such as lower extremity edema, chest pain, difficulty breathing, and fatigue before the diagnosis of CRCT in women undergoing breast cancer treatment. They conducted a retrospective and longitudinal investigation of the symptoms, signs, and cardiac tests of 15 patients who experienced CRCT, using their electronic medical records. In their study, cardiotoxicity was defined by an echocardiogram or MRI showing a decrease in LVEF of 5 to 10%, with a specialist’s confirmation note. They compared the number of symptom occurrences during the first half of the year with those during the second half of the year prior to the diagnosis of cardiotoxicity. Specifically, the frequency of lower-extremity edema significantly increased from three occurrences in the first half of the year to 17 occurrences in the second half of the year. The frequency of symptoms for dyspnea and chest pain also increased from 10 and 8 times, respectively, to 16 and 14 times in the second half of the year. While there was limited information on the doses or timing of chemotherapy, 87% of the patients received the same chemotherapy regimens, namely anthracyclines and/or HER2 blockers [ 44 ]. This suggests that the increase in symptom occurrence over time may be related to the accumulation of anthracycline and the duration of anti-HER2 therapy [ 45 ].

Salyer et al. (2019) conducted a study on the prevalent symptoms of heart failure and their clustering. They identified three symptom clusters: sickness behavior, gastrointestinal disturbance, and discomfort of illness. Notably, dyspnea, edema, and pain were grouped into the discomfort of illness cluster, which aligns with the symptoms we observed in patients treated with anthracyclines and/or HER2 blockers [ 46 ]. Therefore, it is crucial for patients undergoing treatment with anthracyclines and/or HER2 blockers to be vigilant for symptoms such as dyspnea, edema, or chest pain, as these are indicative of heart failure.

Chest pain caused by vasospasm was a predominant symptom in patients taking antimetabolite regimens such as oral capecitabine, and it manifested as the following types of cardiotoxicities: vasospasm-related arrhythmia, myocardial disease, and ischemia [ 47 ]. Vasospasm can be triggered by endothelial dysfunction, hypersensitive vascular smooth muscle, reactive oxidative stress, or chemotherapy regimens [ 48 , 49 ]. According to previous studies, in patients using antimetabolite drugs such as 5-fluorouracil or capecitabine, chest pain was usually reported to occur from several hours to 72 hours after the first administration [ 47 , 50 , 51 , 52 , 53 ]. To detect chemotherapy-related coronary vasospasm in the early stage, it is recommended to carefully monitor typical or atypical symptoms of chest pain and EKG monitoring during drug infusion [ 54 ]. Muco et al. (2022) reported severe outcomes resulting from delayed management of vasospastic angina symptoms. The patient’s cardiac evaluation was performed 3 days after the onset of symptoms, and unfortunately, she did not recover from brain damage caused by coronary vasospastic sequelae. The authors stressed the importance of medical teams recognizing the symptoms of CRCT through vigilant monitoring and patient education [ 55 ].

As seen in the symptoms of CRCT caused by heart failure and vasospasm, careful observation of symptoms and conducting appropriate tests are crucial to prevent cardiotoxicity and minimize damage. These characteristics of CRCT and the associated symptoms related to chemotherapy regimens can provide crucial educational content for healthcare providers and patients preparing for chemotherapy. In addition, CRCT and symptom progression according to chemotherapy regimens could be used to formulate research questions for future systematic reviews.

Second, the preventive management of CRCT necessitates adherence to recommended guidelines. The 2022 ESC guidelines on cardio-oncology have updated the classification of CRCT and the monitoring protocols based on the chemotherapy regimens used [ 7 ]. The CRCT identified in the current study aligns with the drug toxicity outlined in the 2022 ESC guidelines. These guidelines advocate for regular cardiac monitoring before, during, and after chemotherapy to prevent and manage CRCT induced by anthracycline and HER2 blockers [ 7 , 12 ]. In this scoping review, two of 23 records described cardiac monitoring before, during, and after chemotherapy. An Australian multicenter study revealed that 59% of patients were referred to a cardiologist before CRCT occurred, but only 15% of patients diagnosed with CRCT had consulted a cardiologist before chemotherapy [ 41 ]. Given the declining mortality rates among cancer patients, managing CRCT requires a collaborative approach between oncology and cardiology to minimize mortality and morbidity in patients with breast cancer undergoing chemotherapy [ 7 ]. Therefore, it remains crucial to emphasize adherence to cardiac monitoring guidelines and foster cooperation between oncology and cardiology.

Additionally, symptom assessment is important for the early detection of patients with CRCT. The studies included in the current scoping review assessed whether patients’ symptoms could detect CRCT using interviews with patients, the New York Heart Association classification, a dyspnea assessment scale, and CTCAE tools. The United States National Cancer Institute recommends that healthcare providers use CTCAE and patients with cancer use PRO to report adverse events, including symptoms. CTCAE is a broad and comprehensive terminology that encompasses adverse events related to cancer treatment, has been used since the 1980s [ 25 ], and is not specialized in cardiotoxicity. Additionally, a discrepancy between CTCAE and PRO discovered that healthcare providers often underestimate both the incidence and duration of symptoms compared to the patients [ 56 , 57 , 58 ]. Specifically, healthcare providers tend to report symptom severity as lower than that reported by patients. For instance, there are notable discrepancies between healthcare providers and patients when reporting severe or very severe symptoms of fatigue, dyspnea, and limb edema in patients with early-stage breast cancer undergoing chemotherapy. The reported rates were 8% and 22% for fatigue, 0% and 4% for dyspnea, and 0% and 5% for limb edema, from healthcare providers and patients, respectively. Therefore, it is necessary to develop a user-friendly questionnaire to assess the various symptoms of CRCT.

Finally, we found that once CRCT was confirmed, cardiac treatment was promptly initiated and chemotherapy was frequently halted until CRCT resolution. A Delphi study on the use of anthracycline and trastuzumab proposed altering the treatment schedule or discontinuing treatment until there was an improvement in LVEF [ 59 ]. However, the professional societies did not provide definitive recommendations regarding continuing or ceasing ongoing chemotherapy. Instead, they suggested that the decision to continue or discontinue ongoing chemotherapy should be made based on the patient’s potential risks and benefits [ 60 ]. For example, Polk et al. (2016) reported that out of 22 patients with CRCT resulting from capecitabine, six continued medications with or without cardiac treatment; some of these patients experienced the same symptoms, while others did not exhibit significant symptoms [ 40 ]. Further research is required to explore the continuation or discontinuation of chemotherapy when CRCT is confirmed.

This study has some limitations. First, although we did not restrict the patients’ sex when reviewing the literature, most patients, except for one, were female. This may be related to the lower incidence of breast cancer in men. Second, although this scoping review mapped CRCT symptoms according to chemotherapy regimens, including anthracycline-based drugs, HER2 blockers, and antimetabolites, it did not cover cardiotoxicity related to other types of chemotherapy regimens. Thus, exploring the symptoms by focusing on expanded chemotherapy regimens and cardiovascular toxic diseases will assist in overcoming this limitation. Third, of the 29 studies, 23 were case reports with some grey literature, which may be justified by the nature of scoping reviews that allow for inclusion irrespective of the data source [ 61 ] and the study type. Experimental or observational clinical studies use objective criteria, such as diagnostic tests to generate primary evidence. However, case reports have led to new medical discoveries regarding the prevention and treatment of diseases [ 62 ]. Given the nature of case reports, specific symptoms that could provide clues for evaluating CRCT in patients with breast cancer are most often found in these reports. We incorporated grey literature to gather more comprehensive information on CRCT-related symptoms. However, to mitigate the potential issue of unverified quality in grey literature, we initially organized 16 studies from peer-reviewed literature and subsequently incorporated the grey literature into our findings. This approach helped to clarify the results of the peer-reviewed literature, particularly the types of chemotherapy regimens [ 63 ]. Finally, regarding the literature selection criteria, we examined articles written in English and published since 2010, the year the cardio-oncology guidelines were announced, thereby excluding articles published before 2010.

This scoping review allowed data mapping according to the study design and chemotherapy regimens. The key messages included a type of CRCT, cardiac assessment, and in-depth information regarding the CRCT symptoms. There were approximately five typical CRCT symptoms, including dyspnea, chest pain, peripheral edema, fatigue, and palpitations, and the timing of symptom occurrence varied. The symptoms were assessed by patient-reported symptom presentation rather than using a symptom assessment tool. Therefore, developing and applying a CRCT-specific and user-friendly symptom assessment tool are expected to help healthcare providers and patients manage CRCT symptoms effectively.

Availability of data and materials

The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request.

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Acknowledgements

The authors thank Nawon Kim, a librarian at the Yonsei University Medical Library, for building search terms and guiding the database searches.

This research is supported by the Brain Korea 21 FOUR Project founded by the National Research Foundation (NRF) of Korea, Yonsei University College of Nursing.

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HK, BH, SK, and JP contributed to the study conception and design. The literature search and record screening were performed by HK and BH under the supervision of JP. Material preparation, data collection, and analysis were performed by HK, BH, and JP. The first draft of the manuscript was written by HK and JP commented on each updated version of the manuscript. The tables and figures were prepared by BH under the instruction of JP. SK helped to interpret the data and provided critical feedback on the manuscript. All authors read and approved the final manuscript.

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Kim, H., Hong, B., Kim, S. et al. Chemotherapy-related cardiotoxicity and its symptoms in patients with breast cancer: a scoping review. Syst Rev 13 , 167 (2024). https://doi.org/10.1186/s13643-024-02588-z

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