TITLE: Technegas Plus Generators: A Review of the Clinical Effectiveness, Cost Effectiveness, and Guidelines DATE: 28 July 2016 CONTEXT AND POLICY ISSUES Pulmonary embolism (PE) is a relatively common pulmonary vascular disorder with an annual incidence in the US of 69 events per 100,000 people, with an increased risk with age and pregnancy. 1-4 Despite the severe and potentially fatal condition of PE, its diagnosis remains a challenging one. 5,6 In addition to clinical assessment, laboratory tests such as blood gas analysis, and chest X ray, accurate diagnosis of PE requires biochemical tests such as D-dimer levels, and imaging techniques such as ventilation-perfusion scintigraphy (V/Q scan), ventilation-perfusion SPECT (single-photon emission computed tomography), computed tomography (CT), computed tomography pulmonary angiography (CTPA), or echocardiography. 7-9 In V/Q scans, perfusion studies involve the intravenous injection of radioactive technetium macro aggregated albumin (Tc99m-MAA). Ventilation studies of V/Q scans are in general performed after inhalation of 99m technetium-labelled aerosols of diethylene triamine pentaacetic acid (99m Tc-DTPA), or an ultrafine dispersion of 99m technetium-labelled carbon (Technegas). Physical properties of the inhaled gases affect lung scintigraphy quality which depends on the evenness of radiotracer distribution and degree of aerosol deposition, 10-12 with Technegas having better potential for ventilation studies because the particles have much smaller size than 99mTc-DTPA droplets. Uneven distribution patterns (central or focal peripheral deposition of radiotracers) could lead to an increased incidence of misdiagnosis. A mismatch in V/Q scan (perfusion deficit with normal ventilation) is a sign of high probability for PE. Suboptimal peripheral penetration may also lead to a reverse mismatch phenomenon (an absence of ventilation with preservation of some perfusion) that can obscure the diagnosis of PE. 13 Technegas is generated by the TechnegasPlus Generator System Ventilation Assistance Unit, a product of Cyclofarm, which was approved for use in Canada in 2006. 14 Disclaimer: The Rapid Response Service is an information service for those involved in planning and providing health care in Canada. Rapid responses are based on a limited literature search and are not comprehensive, systematic review s. The intent is to provide a list of sources of the best evidence on the topic that CADTH could identify using all reasonable efforts w ithin the time allow ed. Rapid responses should be considered along w ith other types of information and health care considerations. The information included in this response is not intended to replace professional medical advice, nor should it be construed as a recommendation for or against the use of a particular health technology. Readers are also cautioned that a lack of good quality evidence does not necessarily mean a lack of effectiveness particularly in the case of new and emerging health technologies, for w hich little information can be found, but w hich may in future prove to be effective. While CADTH has taken care in the preparation of the report to ensure that its contents are accurate, complete and up to date, CADTH does not make any guarantee to that effect. CADTH is not liable for any loss or damages resulting from use of the information in the report. Copyright: This report contains CADTH copyright material and may contain material in w hich a third party ow ns copyright. This report may be used for the purposes of research or private study only. It may not be copied, posted on a w eb site, redistributed by email or stored on an electronic system w ithout the prior w ritten permission of CADTH or applicable copyright ow ner. Links: This report may contain links to other information available on the w ebsites of third parties on the Internet. CADTH does not have control over the content of such sites. Use of third party sites is governed by the owners own terms and conditions.
This Rapid Response report aims to review the clinical and cost-effectiveness of Technegas Plus Generators compared to aerosol nebulizers in patients undergoing ventilation perfusion lung scans. Guidelines on the use of Technegas Plus Generators in patients undergoing ventilation perfusion lung scans will also be examined. RESEARCH QUESTIONS 1. What is the clinical effectiveness of Technegas Plus Generators versus aerosol nebulizers in patients undergoing ventilation perfusion lung scans? 2. What is the cost effectiveness of Technegas Plus Generators versus aerosol nebulizers in patients undergoing ventilation perfusion lung scans? 3. What are the evidence-based guidelines on the use of Technegas Plus Generators for patients undergoing ventilation perfusion lung scans? KEY FINDINGS Evidence from one head-to-head non randomized study that compared differences in ventilation studies performed with 99mTc-diethylenetriaminepentaacetate (DTPA) and Technegas showed that the unevenness of radiotracer deposition, the degree of central peripheral deposition, and the extent of reverse mismatch were more pronounced with 99mTc-DTPA than with Technegas in patients with obstructive or non-obstructive disease. In obstructive disease patients, the degree of focal peripheral deposition was more pronounced with 99mTc-DTPA than with Technegas, and the mismatch perfusion rate was more frequent with Technegas than with 99mTc-DTPA, leading to a more precise diagnosis of PE in this patient group. The authors concluded that Technegas is the preferred aerosol compared to 99mTc-DTPA, especially in obstructive disease. There is no evidence found on the cost-effectiveness of Technegas Plus Generators and no guidelines were identified. METHODS Literature Search Strategy A limited literature search was conducted on key resources including PubMed, The Cochrane Library, University of York Centre for Reviews and Dissemination (CRD) databases, Canadian and major international health technology agencies, as well as a focused Internet search. Methodological filters were applied to limit retrieval to health technology assessments, systematic reviews, meta-analyses, randomized controlled trials, randomized controlled trials, non-randomized studies, economic studies and guidelines. Where possible, retrieval was limited to the human population. The search was also limited to English language documents published between January 1, 2010 and July 30, 2016. Technegas Plus generators 2
Selection Criteria and Methods One reviewer screened the titles and abstracts of the retrieved publications and examined the full-text publications for the final article selection. Selection criteria are outlined in Table 1. Population Intervention Comparator Outcomes Study Designs Table 1: Selection Criteria Patients undergoing ventilation perfusion lung scans Technegas Plus Generators Aerosol Nebulizers Clinical effectiveness (safety and harms), cost effectiveness, and guidelines Health technology assessments (HTA), systematic reviews (SR), meta-analyses (MA), randomized controlled trials (RCTs), non-rcts, economic evaluations, guidelines Exclusion Criteria Articles were excluded if they did not meet the selection criteria in Table 1, if they were published prior to January 2010, if they were duplicate publications of the same study, or if they were referenced in a selected systematic review. Critical Appraisal of Individual Studies The quality of the included clinical trials was assessed using the Downs and Black checklists. 15 Numeric scores were not calculated. Instead, the strengths and limitations of the study are summarized and presented narratively. SUMMARY OF EVIDENCE Quantity of Research Available The literature search yielded 525 citations. After screening of abstracts from the literature search and from other sources, three potentially relevant studies were selected for full-text review. One study was included in the review. The PRISMA flowchart in Appendix 1 details the process of the study selection. Summary of Study Characteristics A detailed summary of the included study design, population, interventions and comparators, and outcomes is provided in Appendix 2. The included Swedish study 16 is a 2010 head-to-head non-rct cohort study that compared differences in ventilation studies performed with 99mTc-DTPA and Technegas in 63 patients with chronic obstructive lung diseases or non-obstructive diseases (i.e., history of malignancy, history of PE or deep venous thrombosis, history of ischemic heart disease or heart failure, lung transplantation) for lung function evaluation. Outcomes were unevenness of radiotracer Technegas Plus generators 3
deposition, degree of central deposition or focal deposition in peripheral airways, mismatch perfusion and reverse mismatch perfusion rates. Summary of Critical Appraisal The included study 16 was not a randomized controlled study, but had the hypothesis, method of selection from source population and representation, main outcomes, interventions, patient characteristics, main findings, losses to follow-up clearly described. The physicians were unaware of clinical information and masked from the type of intervention. The outcomes were mainly limited to image quality and clinical relevance was unclear as patient outcomes or accuracy of diagnoses were not reported. Estimates of random variability and actual probability values were provided. It is unclear whether the study had sufficient power to detect a clinically important effect. Details of the strengths and limitations of the included studies are summarized in Appendix 3. Summary of Findings Main findings of included studies are summarized in detail in Appendix 4. 1. What is the clinical effectiveness of Technegas Plus Generators versus aerosol nebulizers in patients undergoing ventilation perfusion lung scans? The literature search found one head-to-head non randomized study that compared differences in ventilation studies performed with 99mTc-DTPA and Technegas in 63 patients with obstructive or non-obstructive lung diseases. 16 Outcomes were unevenness of radiotracer deposition, degree of central deposition or focal deposition in peripheral airways, mismatch perfusion rates and the extent of reverse mismatch. The unevenness of radiotracer deposition and the degree of central peripheral deposition were more pronounced with 99mTc-DTPA than with Technegas in patients with obstructive or nonobstructive disease. The degree of focal peripheral deposition was not different between the two methods in non-obstructive disease patients, but was more pronounced in 99mTc-DTPA studies than Technegas studies in obstructive disease patients. The mismatch perfusion rate was not different between the two methods in non-obstructive disease patients, but was more frequent with Technegas than with 99mTc-DTPA in obstructive disease. The extent of reverse mismatch was less with Technegas than with 99mTc-DTPA in patients of both groups. The authors concluded that Technegas is the preferred aerosol compared to 99mTc-DTPA, especially in obstructive disease. 2. What is the cost effectiveness of Technegas Plus Generators versus aerosol nebulizers in patients undergoing ventilation perfusion lung scans? There was no evidence found on the cost effectiveness of Technegas Plus Generators versus aerosol nebulizers in patients undergoing ventilation perfusion lung scans. Technegas Plus generators 4
3. What are the evidence-based guidelines on the use of Technegas Plus Generators for patients undergoing ventilation perfusion lung scans? There was no evidence found on the guidelines on Technegas Plus Generators in patients undergoing ventilation perfusion lung scans. Limitations The evidence on the comparative clinical effectiveness of Technegas Plus Generators and aerosol nebulizers is limited to one head-to-head non-randomized trial reporting differences in ventilation studies performed with 99mTc-DTPA and Technegas. The extent to which the differences in image quality affected clinical outcomes is unclear, and it is unclear whether the study had sufficient power to detect a clinically important effect. CONCLUSIONS AND IMPLICATIONS FOR DECISION OR POLICY MAKING Evidence from one head-to-head non randomized study that compared differences in ventilation studies performed with 99mTc-diethylenetriaminepentaacetate (DTPA) and Technegas showed that the use of Technegas leads to a better scintigraphy quality due the more pronounced unevenness of radiotracer deposition, degree of central peripheral deposition, and extent of reverse mismatch with 99mTc-DTPA than with Technegas in patients with obstructive or nonobstructive disease. Technegas also can lead to more precise diagnosis of PE in patients with obstructive diseases thanks to less pronounced focal peripheral deposition of radiotracers, a higher rate of mismatch perfusion rate and a lower extent of reverse mismatch. There was no cost-effectiveness evidence or guidelines found on the use of Technegas Plus Generators. PREPARED BY: Canadian Agency for Drugs and Technologies in Health Tel: 1-866-898-8439 www.cadth.ca Technegas Plus generators 5
REFERENCES 1. Naess IA, Christiansen SC, Romundstad P, Cannegieter SC, Rosendaal FR, Hammerstrom J. Incidence and mortality of venous thrombosis: a population-based study. J Thromb Haemost. 2007 Apr;5(4):692-9. 2. Silverstein MD, Heit JA, Mohr DN, Petterson TM, O'Fallon WM, Melton LJ, III. Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year populationbased study. Arch Intern Med. 1998 Mar 23;158(6):585-93. 3. Anderson FA, Jr., Wheeler HB, Goldberg RJ, Hosmer DW, Patwardhan NA, Jovanovic B, et al. A population-based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism. The Worcester DVT Study. Arch Intern Med. 1991 May;151(5):933-8. 4. White RH. The epidemiology of venous thromboembolism. Circulation. 2003 Jun 17;107(23 Suppl 1):I4-I8. 5. Stein PD, Sostman HD, Dalen JE, Bailey DL, Bajc M, Goldhaber SZ, et al. Controversies in diagnosis of pulmonary embolism. Clin Appl Thromb Hemost. 2011 Apr;17(2):140-9. 6. Douma RA, Kamphuisen PW, Buller HR. Acute pulmonary embolism. Part 1: epidemiology and diagnosis. Nat Rev Cardiol. 2010 Oct;7(10):585-96. 7. Torbicki A, Perrier A, Konstantinides S, Agnelli G, Galie N, Pruszczyk P, et al. Guidelines on the diagnosis and management of acute pulmonary embolism: the Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC). Eur Heart J. 2008 Sep;29(18):2276-315. 8. Henzler T, Barraza JM, Jr., Nance JW, Jr., Costello P, Krissak R, Fink C, et al. CT imaging of acute pulmonary embolism. J Cardiovasc Comput Tomogr. 2011 Jan;5(1):3-11. 9. PIOPED Investigators. Value of the ventilation/perfusion scan in acute pulmonary embolism. Results of the prospective investigation of pulmonary embolism diagnosis (PIOPED). JAMA. 1990 May 23;263(20):2753-9. 10. Bajc M, Neilly JB, Miniati M, Schuemichen C, Meignan M, Jonson B, et al. EANM guidelines for ventilation/perfusion scintigraphy : Part 1. Pulmonary imaging with ventilation/perfusion single photon emission tomography. Eur J Nucl Med Mol Imaging. 2009 Aug;36(8):1356-70. 11. Bajc M, Neilly JB, Miniati M, Schuemichen C, Meignan M, Jonson B. EANM guidelines for ventilation/perfusion scintigraphy : Part 2. Algorithms and clinical considerations for diagnosis of pulmonary emboli with V/P(SPECT) and MDCT. Eur J Nucl Med Mol Imaging. 2009 Sep;36(9):1528-38. 12. Freeman LM, Blaufox MD. Reply: SPECT V/Q scans [letter]. Journal of Nucleic Medicine. 2009;51:654-5. Technegas Plus generators 6
13. Shih WJ, Bognar B. Reverse mismatched ventilation-perfusion pulmonary imaging with accumulation of technetium-99m-dtpa in a mucous plug in a main bronchus: a case report. J Nucl Med Technol. 1999 Dec;27(4):303-5. 14. Medical Devices Active Licence Listing (MDALL) [Internet]. [2004 -]. Ottawa: Health Canada [cited 2016 Jul 7]. Available from: https://health-products.canada.ca/mdalllimh/index-eng.jsp 15. Downs SH, Black N. The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions. J Epidemiol Community Health. 1998 Jun;52(6):377-84. 16. Jögi J, Jonson B, Ekberg M, Bajc M. Ventilation-perfusion SPECT with 99 m Tc-DTPA versus Technegas: a head-to-head study in obstructive and nonobstructive disease. J Nucl Med. 2010 May;51(5):735-41. Technegas Plus generators 7
Appendix 1: Selection of Included Studies 525 citations identified from electronic literature search and screened 522 citations excluded 3 potentially relevant articles retrieved for scrutiny (full text, if available) 0 relevant reports retrieved from other sources (grey literature, hand search) 3 potentially relevant reports 2 reports excluded (irrelevant population, interventions or outcomes) 1 report included in review Technegas Plus generators 8
Appendix 2: Characteristics of Included Studies First Author, Year, Country Clinical studies Jogi, 16 2010, Sweden Table A1: Characteristics of Included Study Study Objectives The aim of the present head-tohead study was to systematically investigate differences in ventilation studies performed with 99mTcdiethylenetriaminep entaacetate (DTPA) and Technegas (p 735) Interventions/ Comparators 99mTcdiethylenetriaminepentaac etate (DTPA) Technegas Patients 30 patients with COPD 33 patients with nonobstructive lung diseases (history of PE or deep venous thrombosis, history of malignancy, lung transplantation, history of ischemic heart disease or heart failure) Main Study Outcomes Unevenness of radiotracer deposition Degree of focal deposition in peripheral airways Mismatch perfusion Extent of reverse mismatch COPD: chronic obstructive pulmonary disease; PE: pulmonary embolism Technegas Plus generators 9
Appendix 3: Summary of Critical Appraisal of Included Study Table A2: Summary of Critical Appraisal of Included Study First Author, Strengths Publication Year Critical appraisal of included clinical trials (Downs and Black) 15 ) Jogi, 16 2010 hypothesis clearly described method of selection from source population and representation described physicians unaware of clinical information and masked from type of intervention main outcomes, interventions, patient characteristics, and main findings clearly described estimates of random variability and actual probability values provided losses to follow-up described Limitations patients not randomized, not blinded unclear whether study had sufficient power to detect a clinically important effect Technegas Plus generators 10
Appendix 4: Main Study Findings and Authors Conclusions Table A3: Main Study Findings and Authors Conclusions First Author, Publication Year Main Study Findings Authors Conclusions Research question 1 (clinical effectiveness of Technegas Plus Generators versus aerosol nebulizers in patients undergoing ventilation perfusion lung scans) Jogi, 16 2010 Unevenness of radiotracer deposition (units; median; 25 th 75 th percentlile) More pronounced in 99mTc-diethylenetriaminepentaacetate (DTPA) studies than Technegas studies in all patients Technegas: 3.5 (1.5 6) DTPA: 5.0 (2.5 7) P < 0.0001 This intraindividual comparative study shows that Technegas is the preferred radioaerosol, particularly in obstructive disease (p 735) Degree of central peripheral deposition (units; median; 25 th 75 th percentlile) More pronounced in 99mTc-diethylenetriaminepentaacetate (DTPA) studies than Technegas studies in all patients Technegas: 3.5 (1.5 6) DTPA: 5.0 (2.5 7) P < 0.0001 Degree of focal peripheral deposition (units; median; 25 th 75 th percentlile) Not different between the 2 methods in non-obstructive disease patients More pronounced in 99mTc-DTPA studies than Technegas studies in obstructive disease patients Technegas: 1.5 (0.5 3.5) DTPA: 3.5 (2-5) P = 0.0002 Mismatch perfusion (%; median; 25 th 75 th percentlile) Not different between the 2 methods in non-obstructive disease patients More frequent in Technegas studies than 99mTc-DTPA studies in obstructive disease Technegas: 0 (0-5) DTPA: 0 (0-0) P = 0.0160 Extent of reverse mismatch (%; median; 25 th 75 th percentlile) Less in Technegas studies than 99mTc-DTPA studies in all patients Technegas: 12.5 (7.5) DTPA: 22.5 (15-55) P < 0.0001 Research question 2 (cost effectiveness of Technegas Plus Generators versus aerosol nebulizers in patients undergoing ventilation perfusion lung scans) There was no evidence found on the cost effectiveness of Technegas Plus Generators versus aerosol nebulizers in patients undergoing ventilation perfusion lung scans Technegas Plus generators 11
Table A3: Main Study Findings and Authors Conclusions First Author, Publication Year Main Study Findings Authors Conclusions Research question 3 (guidelines on Technegas Plus Generators in patients undergoing ventilation perfusion lung scans) There was no evidence found on the guidelines for Technegas Plus Generators in patients undergoing ventilation perfusion lung scans Technegas Plus generators 12