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Oral nitrate supplementation improves cardiovascular risk markers in COPD: ON-BC, a randomised controlled trial.
Alasmari, AM, Alsulayyim, AS, Alghamdi, SM, Philip, KEJ, Buttery, SC, Banya, WAS, Polkey, MI, Armstrong, PC, Rickman, MJ, Warner, TD, et al
The European respiratory journal. 2024;(2)
Abstract
BACKGROUND Short-term studies suggest that dietary nitrate (NO3 -) supplementation may improve the cardiovascular risk profile, lowering blood pressure (BP) and enhancing endothelial function. It is not clear if these beneficial effects are sustained and whether they apply in people with COPD, who have a worse cardiovascular profile than those without COPD. Nitrate-rich beetroot juice (NR-BRJ) is a convenient dietary source of nitrate. METHODS The ON-BC trial was a randomised, double-blind, placebo-controlled parallel group study in stable COPD patients with home systolic BP (SBP) measurement ≥130 mmHg. Participants were randomly allocated (1:1) using computer-generated, block randomisation to either 70 mL NR-BRJ (400 mg NO3 -) (n=40) or an otherwise identical nitrate-depleted placebo juice (0 mg NO3 -) (n=41), once daily for 12 weeks. The primary end-point was between-group change in home SBP measurement. Secondary outcomes included change in 6-min walk distance (6MWD) and measures of endothelial function (reactive hyperaemia index (RHI) and augmentation index normalised to a heart rate of 75 beats·min-1 (AIx75)) using an EndoPAT device. Plasma nitrate and platelet function were also measured. RESULTS Compared with placebo, active treatment lowered SBP (Hodges-Lehmann treatment effect -4.5 (95% CI -5.9- -3.0) mmHg), and improved 6MWD (30.0 (95% CI 15.7-44.2) m; p<0.001), RHI (0.34 (95% CI 0.03-0.63); p=0.03) and AIx75 (-7.61% (95% CI -14.3- -0.95%); p=0.026). CONCLUSIONS In people with COPD, prolonged dietary nitrate supplementation in the form of beetroot juice produces a sustained reduction in BP, associated with an improvement in endothelial function and exercise capacity.
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Dietary nitrate supplementation to enhance exercise capacity in hypoxic COPD: EDEN-OX, a double-blind, placebo-controlled, randomised cross-over study.
Pavitt, MJ, Lewis, A, Buttery, SC, Fernandez, BO, Mikus-Lelinska, M, Banya, WAS, Feelisch, M, Polkey, MI, Hopkinson, NS
Thorax. 2022;(10):968-975
Abstract
RATIONALE Dietary nitrate supplementation improves skeletal muscle oxygen utilisation and vascular endothelial function. We hypothesised that these effects might be sufficient to improve exercise performance in patients with COPD and hypoxia severe enough to require supplemental oxygen. METHODS We conducted a single-centre, double-blind, placebo-controlled, cross-over study, enrolling adults with COPD who were established users of long-term oxygen therapy. Participants performed an endurance shuttle walk test, using their prescribed oxygen, 3 hours after consuming either 140 mL of nitrate-rich beetroot juice (BRJ) (12.9 mmol nitrate) or placebo (nitrate-depleted BRJ). Treatment order was allocated (1:1) by computer-generated block randomisation. MEASUREMENTS The primary outcome was endurance shuttle walk test time. The secondary outcomes included area under the curve to isotime for fingertip oxygen saturation and heart rate parameters during the test, blood pressure, and endothelial function assessed using flow-mediated dilatation. Plasma nitrate and nitrite levels as well as FENO were also measured. MAIN RESULTS 20 participants were recruited and all completed the study. Nitrate-rich BRJ supplementation prolonged exercise endurance time in all participants as compared with placebo: median (IQR) 194.6 (147.5-411.7) s vs 159.1 (121.9-298.5) s, estimated treatment effect 62 (33-106) s (p<0.0001). Supplementation also improved endothelial function: NR-BRJ group +4.1% (-1.1% to 14.8%) vs placebo BRJ group -5.0% (-10.6% to -0.6%) (p=0.0003). CONCLUSION Acute dietary nitrate supplementation increases exercise endurance in patients with COPD who require supplemental oxygen. Trial registration number ISRCTN14888729.
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Impact of dietary nitrate supplementation on exercise capacity and cardiovascular parameters in chronic respiratory disease: a systematic review and meta-analysis.
Alsulayyim, AS, Alasmari, AM, Alghamdi, SM, Polkey, MI, Hopkinson, NS
BMJ open respiratory research. 2021;(1)
Abstract
BACKGROUND Dietary nitrate supplementation, usually in the form of beetroot juice, may improve exercise performance and endothelial function. We undertook a systematic review and meta-analysis to establish whether this approach has beneficial effects in people with respiratory disease. METHODS A systematic search of records up to March 2021 was performed on PubMed, CINAHL, MEDLINE (Ovid), Cochrane and Embase to retrieve clinical trials that evaluated the efficacy of dietary nitrate supplementation on cardiovascular parameters and exercise capacity in chronic respiratory conditions. Two authors independently screened titles, abstracts and full texts of potential studies and performed the data extraction. RESULTS After full-text review of 67 papers, eleven (two randomised controlled trials and nine crossover trials) involving 282 participants met the inclusion criteria. Three were single dose; seven short term; and one, the largest (n=122), done in the context of pulmonary rehabilitation. Pooled analysis showed that dietary nitrate supplementation reduced systolic blood pressure (BP), diastolic BP and mean arterial pressure (mean difference (95% CI), -3.39 mm Hg (-6.79 to 0.01); p=0.05 and -2.20 mm Hg (-4.36 to -0.03); p=0.05 and -4.40 mm Hg (-7.49 to -1.30); p=0.005, respectively). It was associated with increased walk distance in the context of pulmonary rehabilitation (standardised mean difference (95% CI), 0.47 (0.11 to 0.83), p=0.01), but no effect was identified in short-term studies (0.08 (-0.32 to 0.49). CONCLUSION Dietary nitrate supplementation may have a beneficial effect on BP and augment the effect of pulmonary rehabilitation on exercise capacity. Short-term studies do not suggest a consistent benefit on exercise capacity. PROSPERO REGISTRATION NUMBER CRD42019130123.
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Contemporary perspectives in COPD: Patient burden, the role of gender and trajectories of multimorbidity.
Buttery, SC, Zysman, M, Vikjord, SAA, Hopkinson, NS, Jenkins, C, Vanfleteren, LEGW
Respirology (Carlton, Vic.). 2021;(5):419-441
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An individual's experience of COPD is determined by many factors in addition to the pathological features of chronic bronchitis and emphysema and the symptoms that derive directly from them. Multimorbidity is the norm rather than the exception, so most people with COPD are living with a range of other medical problems which can decrease overall quality of life. COPD is caused by the inhalation of noxious particles or gases, in particular tobacco smoke, but also by early life disadvantage impairing lung development and by occupations where inhaled exposures are common (e.g. industrial, farming and cleaning work). Wealthy people are therefore relatively protected from developing COPD and people who do develop the condition may have reduced resources to cope. COPD is also no longer a condition that predominantly affects men. The prevalence of COPD among women has equalled that of men since 2008 in many high-income countries, due to increased exposure to tobacco, and in low-income countries due to biomass fuels. COPD is one of the leading causes of death in women in the USA, and death rates attributed to COPD in women in some countries are predicted to overtake those of men in the next decade. Many factors contribute to this phenomenon, but in addition to socioeconomic and occupational factors, there is increasing evidence of a higher susceptibility of females to smoking and pollutants. Quality of life is also more significantly impaired in women. Although most medications (bronchodilators and inhaled corticosteroids) used to treat COPD demonstrate similar trends for exacerbation prevention and lung function improvement in men and women, this is an understudied area and clinical trials frequently have a preponderance of males. A better understanding of gender-based predictors of efficacy of all therapeutic interventions is crucial for comprehensive patient care. There is an urgent need to recognize the increasing burden of COPD in women and to facilitate global improvements in disease prevention and management in this specific population. Many individuals with COPD follow a trajectory of both lung function decline and also multimorbidity. Unfavourable lung function trajectories throughout life have implications for later development of other chronic diseases. An enhanced understanding of the temporal associations underlying the development of coexisting diseases is a crucial first step in unravelling potential common disease pathways. Lessons can be learned from exploring disease trajectories of other NCD as well as multimorbidity development. Further research will be essential to explain how early life risk factors commonly influence trajectories of COPD and other diseases, how different diseases develop in relation to each other in a temporal way and how this ultimately leads to different multimorbidity patterns in COPD. This review integrates new knowledge and ideas pertaining to three broad themes (i) the overall burden of disease in COPD, (ii) an unappreciated high burden in women and (iii) the contrast of COPD trajectories and different multimorbidity patterns with trajectories of other NCD. The underlying pathology of COPD is largely irreversible, but many factors noted in the review are potentially amenable to intervention. Health and social care systems need to ensure that effective treatment is accessible to all people with the condition. Preventive strategies and treatments that alter the course of disease are crucial, particularly for patients with COPD as one of many problems.
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Objectively Measured Physical Activity as a COPD Clinical Trial Outcome.
Burtin, C, Mohan, D, Troosters, T, Watz, H, Hopkinson, NS, Garcia-Aymerich, J, Moy, ML, Vogiatzis, I, Rossiter, HB, Singh, S, et al
Chest. 2021;(6):2080-2100
Abstract
BACKGROUND Reduced physical activity is common in COPD and is associated with poor outcomes. Physical activity is therefore a worthy target for intervention in clinical trials; however, trials evaluating physical activity have used heterogeneous methods. RESEARCH QUESTION What is the available evidence on the efficacy and/or effectiveness of various interventions to enhance objectively measured physical activity in patients with COPD, taking into account the minimal preferred methodologic quality of physical activity assessment? STUDY DESIGN AND METHODS In this narrative review, the COPD Biomarker Qualification Consortium (CBQC) task force searched three scientific databases for articles that reported the effect of an intervention on objectively measured physical activity in COPD. Based on scientific literature and expert consensus, only studies with ≥ 7 measurement days and ≥ 4 valid days of ≥ 8 h of monitoring were included in the primary analysis. RESULTS Thirty-seven of 110 (34%) identified studies fulfilled the criteria, investigating the efficacy and/or effectiveness of physical activity behavior change programs (n = 7), mobile or electronic-health interventions (n = 9), rehabilitative exercise (n = 9), bronchodilation (n = 6), lung volume reduction procedures (n = 3), and other interventions (n = 3). Results are generally variable, reflecting the large differences in study characteristics and outcomes. Few studies show an increase beyond the proposed minimal important change of 600 to 1100 daily steps, indicating that enhancing physical activity levels is a challenge. INTERPRETATION Only one-third of clinical trials measuring objective physical activity in people with COPD fulfilled the preset criteria regarding physical activity assessment. Studies showed variable effects on physical activity even when investigating similar interventions.
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Pre-operative optimisation for chronic obstructive pulmonary disease: a narrative review.
Lee, AHY, Snowden, CP, Hopkinson, NS, Pattinson, KTS
Anaesthesia. 2021;(5):681-694
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Chronic obstructive pulmonary disease is a condition commonly present in older people undergoing surgery and confers an increased risk of postoperative complications and mortality. Although predominantly a respiratory disease, it frequently has extra-pulmonary manifestations and typically occurs in the context of other long-term conditions. Patients experience a range of symptoms that affect their quality of life, functional ability and clinical outcomes. In this review, we discuss the evidence for techniques to optimise the care of people with chronic obstructive pulmonary disease in the peri-operative period, and address potential new interventions to improve outcomes. The article centres on pulmonary rehabilitation, widely available for the treatment of stable chronic obstructive pulmonary disease, but less often used in a peri-operative setting. Current evidence is largely at high risk of bias, however. Before surgery it is important to ensure that what have been called the 'five fundamentals' of chronic obstructive pulmonary disease treatment are achieved: smoking cessation; pulmonary rehabilitation; vaccination; self-management; and identification and optimisation of co-morbidities. Pharmacological treatment should also be optimised, and some patients may benefit from lung volume reduction surgery. Psychological and behavioural factors are important, but are currently poorly understood in the peri-operative period. Considerations of the risk and benefits of delaying surgery to ensure the recommended measures are delivered depends on patient characteristics and the nature and urgency of the planned intervention.
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Oral nitrate supplementation to enhance pulmonary rehabilitation in COPD: ON-EPIC a multicentre, double-blind, placebo-controlled, randomised parallel group study.
Pavitt, MJ, Tanner, RJ, Lewis, A, Buttery, S, Mehta, B, Jefford, H, Curtis, KJ, Banya, WAS, Husain, S, Satkunam, K, et al
Thorax. 2020;(7):547-555
Abstract
RATIONALE Dietary nitrate supplementation has been proposed as a strategy to improve exercise performance, both in healthy individuals and in people with COPD. We aimed to assess whether it could enhance the effect of pulmonary rehabilitation (PR) in COPD. METHODS This double-blind, placebo-controlled, parallel group, randomised controlled study performed at four UK centres, enrolled adults with Global Initiative for Chronic Obstructive Lung Disease grade II-IV COPD and Medical Research Council dyspnoea score 3-5 or functional limitation to undertake a twice weekly 8-week PR programme. They were randomly assigned (1:1) to either 140 mL of nitrate-rich beetroot juice (BRJ) (12.9 mmol nitrate), or placebo nitrate-deplete BRJ, consumed 3 hours prior to undertaking each PR session. Allocation used computer-generated block randomisation. MEASUREMENTS The primary outcome was change in incremental shuttle walk test (ISWT) distance. Secondary outcomes included quality of life, physical activity level, endothelial function via flow-mediated dilatation, fat-free mass index and blood pressure parameters. RESULTS 165 participants were recruited, 78 randomised to nitrate-rich BRJ and 87 randomised to placebo. Exercise capacity increased more with active treatment (n=57) than placebo (n=65); median (IQR) change in ISWT distance +60 m (10, 85) vs +30 m (0, 70), estimated treatment effect 30 m (95% CI 10 to 40); p=0.027. Active treatment also impacted on systolic blood pressure: treatment group -5.0 mm Hg (-5.0, -3.0) versus control +6.0 mm Hg (-1.0, 15.5), estimated treatment effect -7 mm Hg (95% CI 7 to -20) (p<0.0005). No significant serious adverse events or side effects were reported. CONCLUSIONS Dietary nitrate supplementation appears to be a well-tolerated and effective strategy to augment the benefits of PR in COPD. TRIAL REGISTRATION NUMBER ISRCTN27860457.
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Pulmonary rehabilitation in patients with mustard gas lung disease: a study protocol for a randomized controlled trial.
Sedighi Moghadam, MR, Ghanei, M, Kenn, K, Hopkinson, NS
Trials. 2019;(1):132
Abstract
BACKGROUND More than 60,000 people have health problems due to chemical weapons exposure during the Iran-Iraq war. Respiratory consequences of mustard gas exposure are common and disabling; medical interventions have limited effect. Patients complain of cough, sputum, breathlessness and exercise limitation. We hypothesized that patients with this condition would benefit from pulmonary rehabilitation. METHODS We outline the protocol for an assessor-blind, two-armed, parallel-design randomized controlled clinical trial (IRCT2016051127848N1). Sixty patients with respiratory disease due to documented sulfur mustard gas exposure will be randomized to either take part in a 6-week pulmonary rehabilitation programme or receive usual care. Inclusion criteria include forced expiratory volume in 1 second < 80% predicted and Medical Research Council dyspnoea score ≥ 3. The primary endpoint will be the change in cycle endurance time at 70% baseline exercise capacity at 6 weeks. Lung function, physical activity, the strength and endurance of the quadriceps muscle, and quality of life will also be compared. Outcomes will be assessed at 6 weeks and 12 months. Health care utilization will also be assessed. DISCUSSION If the study confirms that rehabilitation is effective for patients with mustard gas lung disease this should prompt provision of the intervention to this patient group. TRIAL REGISTRATION Iranian Registry of Clinical Trials, IRCT2016051127848N1 . Registered on 24 May 2016.
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Redefining Cut-Points for High Symptom Burden of the Global Initiative for Chronic Obstructive Lung Disease Classification in 18,577 Patients With Chronic Obstructive Pulmonary Disease.
Smid, DE, Franssen, FME, Gonik, M, Miravitlles, M, Casanova, C, Cosio, BG, de Lucas-Ramos, P, Marin, JM, Martinez, C, Mir, I, et al
Journal of the American Medical Directors Association. 2017;(12):1097.e11-1097.e24
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BACKGROUND Patients with chronic obstructive pulmonary disease (COPD) can be classified into groups A/C or B/D based on symptom intensity. Different threshold values for symptom questionnaires can result in misclassification and, in turn, different treatment recommendations. The primary aim was to find the best fitting cut-points for Global initiative for chronic Obstructive Lung Disease (GOLD) symptom measures, with an modified Medical Research Council dyspnea grade of 2 or higher as point of reference. METHODS After a computerized search, data from 41 cohorts and whose authors agreed to provide data were pooled. COPD studies were eligible for analyses if they included, at least age, sex, postbronchodilator spirometry, modified Medical Research Council, and COPD Assessment Test (CAT) total scores. MAIN OUTCOMES Receiver operating characteristic curves and the Youden index were used to determine the best calibration threshold for CAT, COPD Clinical Questionnaire, and St. Georges Respiratory Questionnaire total scores. Following, GOLD A/B/C/D frequencies were calculated based on current cut-points and the newly derived cut-points. FINDINGS A total of 18,577 patients with COPD [72.0% male; mean age: 66.3 years (standard deviation 9.6)] were analyzed. Most patients had a moderate or severe degree of airflow limitation (GOLD spirometric grade 1, 10.9%; grade 2, 46.6%; grade 3, 32.4%; and grade 4, 10.3%). The best calibration threshold for CAT total score was 18 points, for COPD Clinical Questionnaire total score 1.9 points, and for St. Georges Respiratory Questionnaire total score 46.0 points. CONCLUSIONS The application of these new cut-points would reclassify about one-third of the patients with COPD and, thus, would impact on individual disease management. Further validation in prospective studies of these new values are needed.
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Acute Dietary Nitrate Supplementation and Exercise Performance in COPD: A Double-Blind, Placebo-Controlled, Randomised Controlled Pilot Study.
Curtis, KJ, O'Brien, KA, Tanner, RJ, Polkey, JI, Minnion, M, Feelisch, M, Polkey, MI, Edwards, LM, Hopkinson, NS
PloS one. 2015;(12):e0144504
Abstract
BACKGROUND Dietary nitrate supplementation can enhance exercise performance in healthy people, but it is not clear if it is beneficial in COPD. We investigated the hypotheses that acute nitrate dosing would improve exercise performance and reduce the oxygen cost of submaximal exercise in people with COPD. METHODS We performed a double-blind, placebo-controlled, cross-over single dose study. Subjects were randomised to consume either nitrate-rich beetroot juice (containing 12.9 mmoles nitrate) or placebo (nitrate-depleted beetroot juice) 3 hours prior to endurance cycle ergometry, performed at 70% of maximal workload assessed by a prior incremental exercise test. After a minimum washout period of 7 days the protocol was repeated with the crossover beverage. RESULTS 21 subjects successfully completed the study (age 68 ± 7 years; BMI 25.2 ± 5.5 kg/m2; FEV1 percentage predicted 50.1 ± 21.6%; peak VO2 18.0 ± 5.9 ml/min/kg). Resting diastolic blood pressure fell significantly with nitrate supplementation compared to placebo (-7 ± 8 mmHg nitrate vs. -1 ± 8 mmHg placebo; p = 0.008). Median endurance time did not differ significantly; nitrate 5.65 (3.90-10.40) minutes vs. placebo 6.40 (4.01-9.67) minutes (p = 0.50). However, isotime oxygen consumption (VO2) was lower following nitrate supplementation (16.6 ± 6.0 ml/min/kg nitrate vs. 17.2 ± 6.0 ml/min/kg placebo; p = 0.043), and consequently nitrate supplementation caused a significant lowering of the amplitude of the VO2-percentage isotime curve. CONCLUSIONS Acute administration of oral nitrate did not enhance endurance exercise performance; however the observation that beetroot juice caused reduced oxygen consumption at isotime suggests that further investigation of this treatment approach is warranted, perhaps targeting a more hypoxic phenotype. TRIAL REGISTRATION ISRCTN Registry ISRCTN66099139.