Effect of testing for cancer on cancer- or venous thromboembolism (VTE)-related mortality and morbidity in people with unprovoked VTE

BACKGROUND: Venous thromboembolism (VTE) is a collective term for two conditions: deep vein thrombosis (DVT) and pulmonary embolism (PE). A proportion of people with VTE have no underlying or immediately predisposing risk factors and the VTE is referred to as unprovoked. Unprovoked VTE can often be the first clinical manifestation of an underlying malignancy. This has raised the question of whether people with an unprovoked VTE should be investigated for an underlying cancer. Treatment for VTE is different in cancer and non‐cancer patients and a correct diagnosis would ensure that people received the optimal treatment for VTE to prevent recurrence and further morbidity. Furthermore, an appropriate cancer diagnosis at an earlier stage could avoid the risk of cancer progression and lead to improvements in cancer‐related mortality and morbidity. This is the third update of the review first published in 2015. OBJECTIVES: To determine whether testing for undiagnosed cancer in people with a first episode of unprovoked VTE (DVT of the lower limb or PE) is effective in reducing cancer‐ or VTE‐related mortality and morbidity and to determine which tests for cancer are best at identifying treatable cancers early. SEARCH METHODS: The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase and CINAHL databases and World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registers to 5 May 2021. We also undertook reference checking to identify additional studies. SELECTION CRITERIA: Randomised and quasi‐randomised trials in which people with an unprovoked VTE were allocated to receive specific tests for identifying cancer or clinically indicated tests only were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, assessed risk of bias and extracted data. We assessed the certainty of the evidence using GRADE criteria. We resolved any disagreements by discussion. The main outcomes of interest were all‐cause mortality, cancer‐related mortality and VTE‐related mortality. MAIN RESULTS: No new studies were identified for this 2021 update. In total, four studies with 1644 participants are included. Two studies assessed the effect of extensive tests including computed tomography (CT) scanning versus tests at the physician's discretion, while the other two studies assessed the effect of standard testing plus positron emission tomography (PET)/CT scanning versus standard testing alone. For extensive tests including CT versus tests at the physician's discretion, the certainty of the evidence, as assessed according to GRADE, was low due to risk of bias (early termination of the studies). When comparing standard testing plus PET/CT scanning versus standard testing alone, the certainty of evidence was moderate due to a risk of detection bias. The certainty of the evidence was downgraded further as detection bias was present in one study with a low number of events. When comparing extensive tests including CT versus tests at the physician's discretion, pooled analysis on two studies showed that testing for cancer was consistent with either benefit or no benefit on cancer‐related mortality (odds ratio (OR) 0.49, 95% confidence interval (CI) 0.15 to 1.67; 396 participants; 2 studies; low‐certainty evidence). One study (201 participants) showed that, overall, malignancies were less advanced at diagnosis in extensively tested participants than in participants in the control group. In total, 9/13 participants diagnosed with cancer in the extensively tested group had a T1 or T2 stage malignancy compared to 2/10 participants diagnosed with cancer in the control group (OR 5.00, 95% CI 1.05 to 23.76; low‐certainty evidence). There was no clear difference in detection of advanced stages between extensive tests versus tests at the physician's discretion: one participant in the extensively tested group had stage T3 compared with four participants in the control group (OR 0.25, 95% CI 0.03 to 2.28; low‐certainty evidence). In addition, extensively tested participants were diagnosed earlier than control group (mean: 1 month with extensive tests versus 11.6 months with tests at physician's discretion to cancer diagnosis from the time of diagnosis of VTE). Extensive testing did not increase the frequency of an underlying cancer diagnosis (OR 1.32, 95% CI 0.59 to 2.93; 396 participants; 2 studies; low‐certainty evidence). Neither study measured all‐cause mortality, VTE‐related morbidity and mortality, complications of anticoagulation, adverse effects of cancer tests, participant satisfaction or quality of life. When comparing standard testing plus PET/CT screening versus standard testing alone, standard testing plus PET/CT screening was consistent with either benefit or no benefit on all‐cause mortality (OR 1.22, 95% CI 0.49 to 3.04; 1248 participants; 2 studies; moderate‐certainty evidence), cancer‐related mortality (OR 0.55, 95% CI 0.20 to 1.52; 1248 participants; 2 studies; moderate‐certainty evidence) or VTE‐related morbidity (OR 1.02, 95% CI 0.48 to 2.17; 854 participants; 1 study; moderate‐certainty evidence). Regarding stage of cancer, there was no clear difference for detection of early (OR 1.78, 95% 0.51 to 6.17; 394 participants; 1 study; low‐certainty evidence) or advanced (OR 1.00, 95% CI 0.14 to 7.17; 394 participants; 1 study; low‐certainty evidence) stages of cancer. There was also no clear difference in the frequency of an underlying cancer diagnosis (OR 1.71, 95% CI 0.91 to 3.20; 1248 participants; 2 studies; moderate‐certainty evidence). Time to cancer diagnosis was 4.2 months in the standard testing group and 4.0 months in the standard testing plus PET/CT group (P = 0.88). Neither study measured VTE‐related mortality, complications of anticoagulation, adverse effects of cancer tests, participant satisfaction or quality of life. AUTHORS' CONCLUSIONS: Specific testing for cancer in people with unprovoked VTE may lead to earlier diagnosis of cancer at an earlier stage of the disease. However, there is currently insufficient evidence to draw definitive conclusions concerning the effectiveness of testing for undiagnosed cancer in people with a first episode of unprovoked VTE (DVT or PE) in reducing cancer‐ or VTE‐related morbidity and mortality. The results could be consistent with either benefit or no benefit. Further good‐quality large‐scale randomised controlled trials are required before firm conclusions can be made

Peripheral arterial disease: diagnostic challenges and how photoplethysmography may help

Peripheral arterial disease (PAD) affects approximately 20% of patients aged ≥60 years.1 A GP with an average list size of 1800 patients can expect to have 50–60 patients with PAD. Ankle-brachial pressure index (ABPI), which is the ratio of the ankle to brachial systolic pressure measured by sphygmomanometer and hand-held Doppler ultrasound probe, is used to assess PAD in general practice. ABPI has been shown to have a sensitivity of 95% and specificity of 99% compared to angiographic imaging,2 however it is relatively time-consuming and requires adequately trained staff. There are limitations with ABPI in patients with diabetes, renal disease, and older people where an underestimation of disease can occur with a falsely high ratio due to the presence of incompressible calcified blood vessels

Advancing PPG signal quality and know-how through knowledge translation - from experts to student and researcher

Objective: Despite the vast number of photoplethysmography (PPG) research publications and growing demands for such sensing in Digital and Wearable Health platforms, there appears little published on signal quality expectations for morphological pulse analysis. Aim: to determine a consensus regarding the minimum number of undistorted i.e., diagnostic quality pulses required, as well as a threshold proportion of noisy beats for recording rejection. Approach: Questionnaire distributed to international fellow researchers in skin contact PPG measurements on signal quality expectations and associated factors concerning recording length, expected artifact-free pulses (“diagnostic quality”) in a trace, proportion of trace having artifact to justify excluding/repeating measurements, minimum beats required, and number of respiratory cycles. Main Results: 18 (of 26) PPG researchers responded. Modal range estimates considered a 2-min recording time as target for morphological analysis. Respondents expected a recording to have 86–95% of diagnostic quality pulses, at least 11–20 sequential pulses of diagnostic quality and advocated a 26–50% noise threshold for recording rejection. There were broader responses found for the required number of undistorted beats (although a modal range of 51–60 beats for both finger and toe sites was indicated). Significance: For morphological PPG pulse wave analysis recording acceptability was indicated if <50% of beats have artifact and preferably that a minimum of 50 non-distorted PPG pulses are present (with at least 11–20 sequential) to be of diagnostic quality. Estimates from this knowledge transfer exercise should help inform students and researchers as a guide in standards development for PPG study design

Pharmacological treatment of vascular risk factors for reducing mortality and cardiovascular events in patients with abdominal aortic aneurysm

Background: Pharmacological prophylaxis has been proven to reduce the risk of cardiovascular events in individuals with atherosclerotic occlusive arterial disease. However, the role of prophylaxis in individuals with abdominal aortic aneurysm (AAA) remains unclear. Several studies have shown that despite successful repair, those people with AAA have a poorer rate of survival than healthy controls. People with AAA have an increased prevalence of coronary heart disease and risk of cardiovascular events. Despite this association, little is known about the effectiveness of pharmacological prophylaxis in reducing cardiovascular risk in people with AAA. This is an update of a Cochrane review first published in 2014. Objectives: To determine the long-term effectiveness of antiplatelet, antihypertensive or lipid-lowering medication in reducing mortality and cardiovascular events in people with abdominal aortic aneurysm (AAA). Search methods: For this update the Cochrane Vascular Information Specialist (CIS) searched the Cochrane Vascular Specialised Register (14 April 2016). In addition, the CIS searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2016, Issue 3) and trials registries (14 April 2016) and We also searched the reference lists of relevant articles. Selection criteria: Randomised controlled trials in which people with AAA were randomly allocated to one prophylactic treatment versus another, a different regimen of the same treatment, a placebo, or no treatment were eligible for inclusion in this review. Primary outcomes included all-cause mortality and cardiovascular mortality. Data collection and analysis: Two review authors independently selected studies for inclusion, and completed quality assessment and data extraction. We resolved any disagreements by discussion. Only one study met the inclusion criteria of the review, therefore we were unable to perform meta-analysis. Main results: No new studies met the inclusion criteria for this update. We included one randomised controlled trial in the review. A subgroup of 227 participants with AAA received either metoprolol (N = 111) or placebo (N = 116). There was no clear evidence that metoprolol reduced all-cause mortality (odds ratio (OR) 0.17, 95% confidence interval (CI) 0.02 to 1.41), cardiovascular death (OR 0.20, 95% CI 0.02 to 1.76), AAA-related death (OR 1.05, 95% CI 0.06 to 16.92) or increased nonfatal cardiovascular events (OR 1.44, 95% CI 0.58 to 3.57) 30 days postoperatively. Furthermore, at six months postoperatively, estimated effects were compatible with benefit and harm for all-cause mortality (OR 0.71, 95% CI 0.26 to 1.95), cardiovascular death (OR 0.73, 95% CI 0.23 to 2.39) and nonfatal cardiovascular events (OR 1.41, 95% CI 0.59 to 3.35). Adverse drug effects were reported for the whole study population and were not available for the subgroup of participants with AAA. We considered the study to be at a generally low risk of bias. We downgraded the quality of the evidence for all outcomes to low. We downgraded the quality of evidence for imprecision as only one study with a small number of participants was available, the number of events was small and the result was consistent with benefit and harm. Authors' conclusions: Due to the limited number of included trials, there is insufficient evidence to draw any conclusions about the effectiveness of cardiovascular prophylaxis in reducing mortality and cardiovascular events in people with AAA. Further good-quality randomised controlled trials that examine many types of prophylaxis with long-term follow-up are required before firm conclusions can be made

Nurses’ and patients’ experiences and preferences of the Ankle-Brachial Pressure Index and Multi-site Photoplethysmography for the diagnosis of peripheral arterial disease: A qualitative study

Peripheral arterial disease is a global health problem, affecting around 20% of people aged over 60 years. Whilst ankle-brachial pressure index (ABPI) is regularly used for diagnosis, it has a number of limitations, which have presented a need for alternative methods of diagnosis. Multi-site photoplethysmography (MPPG) is one such method, but evidence of acceptability of both methods is lacking. This study aims to describe and compare preferences and experiences amongst nurses and patients of ABPI and MPPG use in primary care. We used qualitative research methods in the context of a clinical diagnostic study comparing ABPI with MPPG. Use of ABPI and MPPG by 13 nurses were observed with 51 patients across general practice surgeries in North-East England in 2015/16. Follow-up semi-structured interviews were conducted with 12 nurses and 27 patients. Data were thematically analysed. Two major themes were identified: (1) device preferences; (2) test discomfort and anxiety. There was a compelling preference for MPPG due to ease of use, speed of the test, patient comfort, and perceived device accuracy/objectivity. However some patients struggled to identify a preference, describing ambivalence to medical testing. ABPI was deemed uncomfortable and painful, particularly when the blood pressure cuff was inflated at the lower limbs. There was also evidence of anxiety amongst patients when their foot pulses were not identified using ABPI. Whilst ABPI is a non-invasive and routine procedure it was associated with a number of drawbacks in clinical practice. Nurses required considerable dexterity to employ the test, and it resulted in anxiety amongst some patients. Conversely, MPPG was deemed to be easier and quicker to use, and perceived to be less subjective. Should diagnostic accuracy and cost be comparable to ABPI, then the findings of this study suggest MPPG would be preferable to ABPI for patients as well as nurses

Cost Impact Analysis of Using The Improve® Tool For Venous Thromboembolism Risk Assessment In Medical Patients Admitted to The UK NHS Hospitals to Inform NICE Clinical Guideline Recommendation

© 2018 The Author(s). This an open access work distributed under the terms of the Creative Commons Attribution Licence (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.Peer reviewedFinal Accepted Versio

Effect of testing for cancer on cancer- or venous thromboembolism (VTE)-related mortality and morbidity in people with unprovoked VTE

Background: Venous thromboembolism (VTE) is a collective term for two conditions: deep vein thrombosis (DVT) and pulmonary embolism (PE). A proportion of people with VTE have no underlying or immediately predisposing risk factors and the VTE is referred to as unprovoked. Unprovoked VTE can often be the first clinical manifestation of an underlying malignancy. This has raised the question of whether people with an unprovoked VTE should be investigated for an underlying cancer. Treatment for VTE is different in cancer and non-cancer patients and a correct diagnosis would ensure that people received the optimal treatment for VTE to prevent recurrence and further morbidity. Furthermore, an appropriate cancer diagnosis at an earlier stage could avoid the risk of cancer progression and lead to improvements in cancer-related mortality and morbidity. This is an update of a review first published in 2015. Objectives: To determine whether testing for undiagnosed cancer in people with a first episode of unprovoked VTE (DVT of the lower limb or PE) is effective in reducing cancer or VTE-related mortality and morbidity and to determine which tests for cancer are best at identifying treatable cancers early. Search methods: The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase and CINAHL databases and World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registers to 11 July 2018. We also undertook reference checking to identify additional studies. Selection criteria: Randomised and quasi-randomised trials in which people with an unprovoked VTE were allocated to receive specific tests for identifying cancer or clinically indicated tests only were eligible for inclusion. Primary outcomes included all-cause mortality, cancer-related mortality and VTE-related mortality. Data collection and analysis: Two review authors independently selected studies, assessed risk of bias and extracted data. We resolved any disagreements by discussion. Main results: No new studies were identified for this 2018 update. In total, four studies with 1644 participants are included. Two studies assessed the effect of extensive tests including computed tomography (CT) scanning versus tests at the physician's discretion, while the other two studies assessed the effect of standard testing plus positron emission tomography (PET)/CT scanning versus standard testing alone. For extensive tests including CT versus tests at the physician's discretion, the quality of the evidence, as assessed according to GRADE, was low due to risk of bias (early termination of the studies). When comparing standard testing plus PET/CT scanning versus standard testing alone, the quality of evidence was moderate due to a risk of detection bias. The quality of the evidence was downgraded further as detection bias was present in one study with a low number of events. When comparing extensive tests including CT versus tests at the physician's discretion, pooled analysis on two studies showed that testing for cancer was consistent with either benefit or no benefit on cancer-related mortality (odds ratio (OR) 0.49, 95% confidence interval (CI) 0.15 to 1.67; 396 participants; 2 studies; P = 0.26; low-quality evidence). One study (201 participants) showed that, overall, malignancies were less advanced at diagnosis in extensively tested participants than in participants in the control group. In total, 9/13 participants diagnosed with cancer in the extensively tested group had a T1 or T2 stage malignancy compared to 2/10 participants diagnosed with cancer in the control group (OR 5.00, 95% CI 1.05 to 23.76; P = 0.04; low-quality evidence). There was no clear difference in detection of advanced stages between extensive tests versus tests at the physician's discretion: one participant in the extensively tested group had stage T3 compared with four participants in the control group (OR 0.25, 95% CI 0.03 to 2.28; P = 0.22; low-quality evidence). In addition, extensively tested participants were diagnosed earlier than control group (mean: 1 month with extensive tests versus 11.6 months with tests at physician's discretion to cancer diagnosis from the time of diagnosis of VTE). Extensive testing did not increase the frequency of an underlying cancer diagnosis (OR 1.32, 95% CI 0.59 to 2.93; 396 participants; 2 studies; P = 0.50; low-quality evidence). Neither study measured all-cause mortality, VTE-related morbidity and mortality, complications of anticoagulation, adverse effects of cancer tests, participant satisfaction or quality of life. When comparing standard testing plus PET/CT screening versus standard testing alone, standard testing plus PET/CT screening was consistent with either benefit or no benefit on all-cause mortality (OR 1.22, 95% CI 0.49 to 3.04; 1248 participants; 2 studies; P = 0.66; moderate-quality evidence), cancer-related mortality (OR 0.55, 95% CI 0.20 to 1.52; 1248 participants; 2 studies; P = 0.25; moderate-quality evidence) or VTE-related morbidity (OR 1.02, 95% CI 0.48 to 2.17; 854 participants; 1 study; P = 0.96; moderate-quality evidence). Regarding stage of cancer, there was no clear difference for detection of early (OR 1.78, 95% 0.51 to 6.17; 394 participants; 1 study; P = 0.37; low-quality evidence) or advanced (OR 1.00, 95% CI 0.14 to 7.17; 394 participants; 1 study; P = 1.00; low-quality evidence) stages of cancer. There was also no clear difference in the frequency of an underlying cancer diagnosis (OR 1.71, 95% CI 0.91 to 3.20; 1248 participants; 2 studies; P = 0.09; moderate-quality evidence). Time to cancer diagnosis was 4.2 months in the standard testing group and 4.0 months in the standard testing plus PET/CT group (P = 0.88). Neither study measured VTE-related mortality, complications of anticoagulation, adverse effects of cancer tests, participant satisfaction or quality of life. Authors' conclusions: Specific testing for cancer in people with unprovoked VTE may lead to earlier diagnosis of cancer at an earlier stage of the disease. However, there is currently insufficient evidence to draw definitive conclusions concerning the effectiveness of testing for undiagnosed cancer in people with a first episode of unprovoked VTE (DVT or PE) in reducing cancer- or VTE-related morbidity and mortality. The results could be consistent with either benefit or no benefit. Further good-quality large-scale randomised controlled trials are required before firm conclusions can be made

Systematic Review of Economic Models Used to Compare Techniques for Detecting Peripheral Arterial Disease

Background and objective Peripheral arterial disease (PAD) is a common condition, in which atherosclerotic narrowing in the arteries restricts blood supply to the leg muscles. In order to support future model-based economic evaluations comparing methods of diagnosis in this area, a systematic review of economic modelling studies was conducted. Methods A systematic literature review was performed in June 2017 to identify model-based economic evaluations of diagnostic tests to detect PAD, with six individual databases searched. The review was conducted in accordance with the methods outlined in the Centre for Reviews and Dissemination’s guidance for undertaking reviews in healthcare, and appropriate inclusion criteria were applied. Relevant data were extracted, and studies were quality assessed. Results Seven studies were included in the final review, all of which were published between 1995 and 2014. There was wide variation in the types of diagnostic test compared. The majority of the studies (six of seven) referenced the sources used to develop their model, and all studies stated and justified the structural assumptions. Reporting of the data within the included studies could have been improved. Only one identified study focused on the cost-effectiveness of a test typically used in primary care. Conclusions This review brings together all applied modelling methods for tests used in the diagnosis of PAD, which could be used to support future model-based economic evaluations in this field. The limited modelling work available on tests typically used for the detection of PAD in primary care, in particular, highlights the importance of future work in this area

Prospective assessment of the diagnostic accuracy of multi-site photoplethysmography pulse measurements for diagnosis of peripheral artery disease in primary care

Peripheral arterial disease (PAD) is associated with cerebral and coronary artery disease. Symptomatic PAD affects about 5% of people over 55 years; many more have asymptomatic PAD. Early detection enables modification of arterial disease risk factors. Diagnostically, assessment of symptoms or signs can be unreliable; ankle brachial pressure index (ABPI) testing is time-consuming and few healthcare professionals are properly trained. This study assessed the diagnostic accuracy of multi-site photoplethysmography (MPPG), an alternative non-invasive test for PAD, in primary care. PAD patients identified from general practice registers were age- and sex-matched with controls. Participants were assessed using MPPG, ABPI and duplex ultrasound (DUS). Outcome measures were sensitivity and specificity of MPPG and ABPI (relative to DUS) and concordance. MPPG test results were available in 249 of 298 eligible participants from 16 practices between May 2015 and November 2016. DUS detected PAD in 101/249 (40.6%). MPPG sensitivity was 79.8% (95% confidence interval [CI] 69.9-87.6%), with specificity 71.9% (95% CI 63.7-79.2%). ABPI sensitivity was 80.2% (95% CI 70.8-87.6%), with specificity 88.6% (95% CI 82-93.5%). With comparable sensitivity to ABPI, MPPG is quick, automated and simpler to do than ABPI; it offers the potential for rapid and accessible PAD assessments in primary care