Non-cardiac side effects during myocardial perfusion imaging (Thesis presentation)
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This study examined factors that influence the non-cardiac side effects of dipyridamole when used for myocardial perfusion stress testing. The study interviewed patients at a cardiac imaging center about side effects experienced after dipyridamole stress testing. Statistical analysis found that age, sex, BMI, diabetes status, and daily aspirin use correlated with the occurrence and severity of certain side effects like headaches, nausea and dizziness. Specifically, side effect frequency decreased with age and daily aspirin use reduced severity of dizziness, flushing and nausea. The study provided insight into predicting side effect outcomes to better inform patients.
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Non-cardiac side effects during myocardial perfusion imaging (Thesis presentation)
- 1. Factors influencing non-cardiac side effects of dipyridamole (Persantine®) when used for myocardial perfusion stress testing! Robert Miner BSc (MRS), M.R.T.(N.), MSc candidate (MRS, Nuclear Medicine)! Charles Sturt University! 2011 CAMRT Saskatoon! 1!
- 2. Overview! Introduction! Background ! Stress methods! Dipyridamole ! Research study! Results! Conclusion! 2!
- 3. Introduction ! Learning objectives! • Review options for pharmacological stress testing! • Describe the generally accepted explanation for side effects ! • Present a study on what influences the side effects of! dipyridamole! Study background ! • Conducted at the Ottawa Cardiovascular Center (OCC)! • Relied on interview and image data ! • Image data not discussed here! • Undertaken as part of a masterʼs thesis! 3!
- 4. Introduction! Background ! Stress methods! Dipyridamole ! Research study! Results! Conclusion! 4!
- 5. Background ! Heart disorders! • Congenital defects! • Infection! • Tumours! • Muscle disorders! • Arrhythmias! • Impaired blood supply! o Major cause of heart ʻdiseaseʼ in developed countries! o Insufficient blood flow to the heart muscle! o Typically caused by a narrowing of arteries due to! atherosclerosis! 5!
- 6. Background ! Useful modalities for detecting heart disorders! • ECG! • Chest X-ray! • Angiography! • Ultrasound ! • Magnetic resonance imaging (MRI)! • Computed tomography (CT angiography)! • Nuclear Medicine! o PET! o SPECT ! o Primarily shows function rather than structure! o Non-invasive! 6!
- 7. Background ! Nuclear medicine imaging modalities ! Positron emission tomography (PET)! • Uses a select few positron emitting isotopes ! • Attenuation correction always performed (typically CT)! • Can have better resolution than SPECT! Single photon emission computed tomography (SPECT)! • Uses gamma ray emitting isotopes (e.g. 99mTc, 201Tl)! • CT attenuation correction not available on all systems! • Most widely used - widely available! 7!
- 8. Background ! SPECT radiopharmaceuticals for myocardial perfusion imaging (MPI)! 201Tl (thallous chloride)! • 3 day half life! • Low gut activity! • Must image immediately after stress! 99mTc-tetrofosmin and 99mTc-sestamibi! • 6 hour half life! • Gut activity can be an issue! • Flexible timing for rest and stress imaging! 8!
- 9. Introduction! Background ! Stress methods! Dipyridamole ! Research study! Results! Conclusion! 9!
- 10. Stress methods! Why stress? ! 10! • To create a difference in blood flow between normal and ! diseased arteries! • This difference in blood flow can be induced by: ! o Increased oxygen demand (exercise)! o Forced vasodilation (pharmacological)!
- 11. Stress methods! Exercise! 11! • Treadmill or upright stationary bicycle ! • Can be used for regular or MPI stress testing ! • Provides ECG and blood pressure information! • Patients need to achieve a target heart rate or ! stress images are not ʻdiagnosticʼ!
- 12. Stress methods! Pharmacological stress! 12! Inotropic and chronotropic agents! • Dobutamine or arbutamine ! • Increases blood pressure and or heart rate! • Used when dipyridamole or adenosine is contradicted! Vasodilators! • Dipyridamole or adenosine! • Increases blood flow!
- 13. Stress methods! Pros ! • Short half-life ( <10 seconds) ! • To stop treatment, just stop infusion ! 13! Cons ! • Requires an infusion pump! • Numerous side effects! • Contradictions: asthma, broncospasms, hypotension,…! • Patient must abstain from caffeine and xanthines (chocolate) for 12-24 hours! Adenosine ! • Vasodilator ! • Non-selective agonist for A1, A2a, A2b, A3 receptors!
- 14. Stress methods! Pros ! • Short half-life (<2 minutes ) ! • To stop treatment, just stop infusion ! • Can be used in place of adenosine or dipyridamole ! 14! Cons ! • Requires an infusion pump! • Numerous side effects! • Contradictions: recent heart attack, unstable angina, hypertension, beta blockers, …! Dobutamine ! • Inotropic and chronotropic ! • !1 - adrenergic agonist!
- 15. Stress methods! Pros ! • Long half-life (~60+ minutes) allows easy administration of dipyridamole and tracer dose! • The effects are easily reversed with aminophylline! 15! Cons ! • Requires dose to be pro-rated to weight ! • Must be infused slowly ! • Numerous side effects! • Contradictions: asthma, broncospasms, hypotension, …! • Patient must abstain from caffeine and xanthines (chocolate) for 12-24 hours! Dipyridamole (Persantine®)! • Vasodilator ! • Non-selective agonist for A1, A2a, A2b, A3 receptors!
- 16. Stress methods! Pros ! • Half-life: 33-108 minutes! • Easy bolus administration with unit doses! • Studies show as effective as adenosine or dipyridamole! • Claims to have fewer side effects ! 16! Cons ! • Not available in Canada ! • Side effects similar to adenosine and dipyridamole! New Options! Regadenoson! • Vasodilator - approved by the FDA in 2008 ! • Selective agonist for A2a receptor!
- 17. Stress methods! 17! New Options! Vasodilators in development! • Binodenoson ! • Apadenoson! • CGS-21680! All target A2A receptors for coronary vasodilation!
- 18. Introduction! Background ! Stress methods! Dipyridamole ! Research study! Results! Conclusion! 18!
- 19. Dipyridamole ! How does it work?! • Inhibits the degradation of naturally occurring adenosine! • Indirectly increases adenosine level in the blood! • Activates all adenosine receptor subtypes (A1, A2a, A2b, A3)! 19! Typical stress protocol! • Dipyridamole dose by weight! • Slow dipyridamole infusion! • Tracer (99mTc-myoview or 201Tl)! • Aminophylline (pro-rated by weight)!
- 20. Dipyridamole ! Why there are side effects?! 20! Nonselective receptor stimulation causes side effects ! • Activation of adenosine receptor subtypes (A1, A2A, A2B, A3)! • Some organs may heavily express some receptor types! Organs/systems at risk of being affected:! • A1 - atrioventricular nodal conduction! • A2A - coronary vasodilation! • A2A - peripheral vasodilation! • A2B - coronary vasodilation! • A2B - peripheral vasodilation! • A3 - bronchoconstriction!
- 21. Physiology of side effects! 21! A1 causes changes in ! atrioventricular nodal conduction! A3 causes ! bronchoconstriction! A2A and A2B cause ! coronary vasodilation! A2A and A2B cause ! peripheral vasodilation!
- 22. Introduction! Background ! Stress methods! Dipyridamole ! Research study! Results! Conclusion! 22!
- 23. Research study ! Background! • Non-cardiac side effects – not heart rate, blood pressure or pulmonary response! • Focusing on what the patient feels (symptoms)! Methodology !! • Patients randomly recruited for this study were: ! o Scheduled for MPI pharmacological stress testing! o Able to communicate in English! 23!
- 24. Research study! Methodology (continued)! • Consent form signed (ethics)! • Demographic data during initial interview:! o age ! o sex ! o BMI ! o daily ASA usage ! o diabetic status! o smoking status ! 24! Common for everyone! Relative high frequency of occurrence!
- 25. Research study! Methodology (continued)! Questionnaire questions on side effects:! • Did you experienced any of the following: ! o chest pain ! o headache ! o dizziness ! o nausea ! o flushing! o other! • If so, how severe was it (on a scale of 1 to 10)?! Questionnaire was completed before the patient left the clinic! 25! the top five side effects in the product monograph ! asked to specify!
- 26. Research study ! Statistical analysis!! What was considered significant for this talk? ! Bivariate analysis (two-tailed test with an "-level of 0.05):! • p-value (p ≤ 0.05) ! • Pearsonʼs correlation coefficient (r2) greater than 0.20! Multivariate analysis (multiple linear and logistic regression):! • p value (p ≤ 0.05) ! • Sample size (> 10 samples per independent variable)! • Adjusted r2 value (> 0.10)! Pairing of data types determined the statistical test for analysis! 26!
- 27. Introduction! Background ! Stress methods! Dipyridamole ! Research study! Results! Conclusion! 27!
- 28. Results ! The initial analysis began with graphing most combinations! 28!
- 29. Results - Demographics ! 29!
- 30. Results - Side effects overview ! 30! Most patients (77%) experienced at least one side effect with headaches being the most common !
- 31. Results - Any side effect ! The chance of feeling any side effect is influenced by age and sex ! 31!
- 32. Results - Headaches ! Headache occurrence and severity are influenced by age, sex ! BMI and diabetic status! 32!
- 33. Results - Nausea ! Nausea occurrence and severity were influenced by age and daily aspirin usage ! 33!
- 34. Results - Dizziness! 34! Daily ASA usage reduced dizziness severity, while diabetic patients felt dizzy more often !
- 35. Results – Flushing / Chest pain! Daily ASA usage reduced flushing severity…! Age, sex, BMI or smoking status did not affect flushing occurrence or severity.! 35! Diabetic status influenced the occurrence, but not severity, of chest pain.!
- 36. Results - ʻOtherʼ side effects ! ʻOtherʼ side effects represents 36 (16%) of all side effects reported! 36!
- 37. Results - Categorized severity ! 37! Overall side effect severity and occurrence is affected by age and daily aspirin usage!
- 38. Results - Predicting severity ! Predicting severity with multiple linear regression! 38! In this model headache severity (HS) can be calculated:! Independent predictors of headache severity: ! BUT: this model only accounts for predicting 10% of the factors affecting headache severity - there are other factors at play.! HS = 9.20 - 0.054*Age - 1.01*Sex - 1.073*Diabetic! This model has an adjusted r2 = 0.104 at p = 0.028!
- 39. Results - Predicting occurrence! Predicting occurrence with multiple logistic regression! 39! BUT: this model only accounts for predicting ~11% of the factors ! affecting headache severity - there are other factors at play.! Independent predictors of headache occurrence: ! In this model the probability of a headache (PH) can be calculated:! This model has an adjusted r2 = 0.106 at p = 0.004!
- 40. Results - Summary! Abbreviations: Freq, frequency; Sev, severity; #, decreased; $, increased;! -, no significant correlation; * p-value = 0.054; ** p-value = 0.069! 40!
- 41. Introduction! Background ! Stress methods! Dipyridamole ! Research study! Results! Conclusion! 41!
- 42. Conclusion ! This study has shown:! • Patient data can indicate the possible side effect outcome ! • Overall side effect frequency is less for elderly patients! 42! The most influential factors are:! • Age:! • overall side effect frequency decreases with age! • Daily aspirin usage ! • decreases dizziness, flushing and nausea severity ! • Diabetic status! • diabetics have increased frequency of dizziness and ! chest pain but decreased headache severity !
- 43. Conclusion ! Limitations! • Number of patients was too low to effectively apply multiple linear and logistic regression for all side effects! • Study was performed at a clinic (no in-patients)! 43! Practical applications! • Able to better inform patients on their possible side effects! • This could prove valuable in:! o reducing patient anxiety! o improving patient cooperation !
- 44. 44!
- 46. Questionnaire + Data Sheet! 46!
- 47. Statistics software used! 47! AcaStat provided multiple logistic analysis. http://www.acastat.com/ Prism was primarily used for general statistical analysis and all graphing. http://www.graphpad.com/ Instat provided multiple linear regression analysis. http://www.graphpad.com/ Used to record data. Data was sorted and formatted for other stats packages. http://www.microsoft.com/
- 48. References! 1. Crawford E, Husain S. Nuclear cardiac imaging terminology and technical aspects. Society of! Nuclear Medicine Technologist section. Reston, Virginia: Society of Nuclear Medicine 2003! 2. Kumar V, Cotran R, Robin, S. Basic Pathology. (7th ed.) Philadelphia, PA: Saunders; 2003.! 3. Bierhals A, Woodward P. Cardiac evaluation: the current status of outcomes-based imaging. ! In: Medina L, Blackmore C. Evidence-based Imaging. New York: Springer; 2006:252- 366.! 4. Vesely M, Dilsizan V. Nuclear cardiac stress testing in the era of molecularmedicine. Journal ! of Nuclear Medicine Technology. 2008;49:399-413.! 5. Taylor A, Schuster D, Alazaraki N. A clinician’s guide to nuclear medicine (2nd ed). Reston VA:! Society of Nuclear Medicine; 2006! 6. EANM. Myocardial perfusion imaging. A technologist’s guide. Vienna, Austria: European Association of Nuclear Medicine; 2004! 7. Heller G, Mann A, Hendel, R. Nuclear cardiology technical applications. New York: ! McGraw- Hill Medical; 2009! 8. Botvinick E. Current methods of pharmacological stress testing and the potential advantages ! of new agents. Journal of Nuclear Medicine; 2009:37:14-25! 48!
- 49. References! 9. Heller G, Mann A, Hendel R. Nuclear cardiology technical applications. New York: ! McGraw-Hill Medical; 2009! 10. Strauss W, Miller D, Wittry M, Cerqueria M, Garcia E, Abdulmassi I, et al. SNM procedure! guideline for myocardial perfusion imaging (version 3). Society of Nuclear Medicine. Reston,! VA.; 2002! 11. Perper E, Segall G. Safety of dipyridamole-thallium imaging in high risk patients with ! known or suspected coronary artery disease. Journal of Nuclear Medicine Technology.1991;32, 2107-2114.! 12. Henzlova M, Cerqueira M, Hansen C, Taillefer R, Yao S. ASNC imaging guidelines for nuclear! cardiology procedures. American Society of Nuclear Cardiology. 2009! 13. Boehringer Ingelheim. Persantine (dipyridamole) product insert. Boehringer Ingelheim Ltd, ! Burlington, Ontario. 2005; Document number 22C071/CA/3! 14. British Pain Society and British Geriatrics Society. Guidance on the assessment of pain in! older people. http://www.bgs.org.uk/Publications/Publication% ! 20Downloads/Sep2007PainAssessment.pdf) Accessed on May 7, 2010.! 49!
- 50. References! 15. National institute of health. Pain intensity instruments. 2003! http://painconsortium.nih.gov/pain_scales/index.html. Accessed on May 7, 2010.! 16. Motulsky H. Prism 5 Statistics Guide. GraphPad Software Inc., San Diego CA. ! www.graphpad.com. 2007;12-13;122-124! 17. Polgar S, Thomas S. Introduction to research in the health sciences. Toronto, ! Churchill Livingstone Elsevier. 2008! 18. Chuan C, Sample size estimation using Krejcie and Morgan and Cohen statistical power ! analysis: a comparison. Jurnal Penyelidkan; (7) 2006 ! 19. Brace N, Kemp R, and Snelgar R. SPSS for Psychologists (3rd ed.) Lawrence Erlbaum ! associates Mahwah New Jersey. 2006! 20. Meyers D, Topham L, Ballow J, Totah D, Wilke R. Adverse reactions to dipyridamole in patients! undergoing stress/rest cardiac perfusion testing. Journal of Nuclear Medicine Technology.! 2002;30:21-24.! 21. White M. Myocardial stress testing: understanding the options. Journal of Nuclear! Cardiology. 1999;6:672-675.! 50!
- 51. References! 22. Kruuse C, Lassen H, Iversen HK, Oestergaard S, Olesen J. Dipyridamole may induce! migraine in patients with migraine without aura. Cephalalgia. 2006 Aug;26(8):925-933 ! 23. Wantanabe K, Sekiya M, Ikeda S, Masao M, Masayuki K, Seishi K. Comparison of adenosine! triphosphate and dipyridamole by thallium-201 myocardial scintigraphy. Journal of Nuclear Medicine. 1997;38:577-581.! 24. Ranhosky, A., Rawson, J., (1990). The safety of intravenous dipyridamole thallium myocardial ! perfusion imaging. Intravenous dipyridamole thallium imaging study group. Journal of the ! American Heart Association. 1990;81:1205-1209.! 25. Lalonde D, Taillefer R, Lambert R, Bisson G, Basile F, Prieto I, Benjamin C. Thallium-201! Dipyridamole imaging: comparison between a standard dose and a high dose of dipyridamole ! in the detection of coronary artery disease. Journal of Nuclear Medicine. 1994;35:1245-1253! 26. Javadi1 H, Shariati M, Mogharrabi1 M, Asli I, Jallalat S, Hooman A, et al. The Association ! of Dipyridamole Side Effects with Hemodynamic Parameters, ECG Findings, and Scintigraphy! Outcomes. Journal of Nuclear Medicine Technology. 2010;38:149–152! 27. Thurnheer R, Laube I, Kaufmann P, Stumpe K, Stammberger U, Bloch, K, et al.! Practicability and safety of dipyridamole cardiac imaging in patients with severe chronic ! obstructive pulmonary disease. European Journal of Nuclear Medicine. 1999; 26:812-817.! 51!
- 52. References! 28. Kubo S, Tadamura E, Toyoda H, Mamede M, Yamamuro M, Magata Y, et al. ! Effect of caffeine intake on myocardial hyperemic flow induced by adenosine triphosphate ! and dipyridamole. Journal of Nuclear Medicine. 2004;45:730-738! 29. Druz R. Current advances in vasodilator pharmacological stress perfusion imaging. ! Seminars in Nuclear Medicine. 2009;39:204-209! 30. Johnson S, Peters S. Advances in pharmacological stress agents: focus on Regadenoson. ! Journal of Nuclear Medicine Technologist. 2010;38:163-171! 31. Iskandrian A, BatemanT, Belardinelli L, Blackburn B, Cerqueira M, Hendel R, et al. ! Adenosine versus regadenoson comparative evaluation in myocardial perfusion imaging: ! Results of the ADVANCE phase 3 multicenter international trial. American Society of ! Nuclear Cardiology. 2007.06.114! 32. Cerqueira M, Nguyen P, Staehr P, Underwood S, Iskandrian A. Effects of Age, Gender, Obesity,! and Diabetes on the Efficacy and Safety of the Selective A2AAgonist Regadenoson Versus ! Adenosine in Myocardial Perfusion Imaging: Integrated ADVANCE-MPI Trial Results. J. Am.! Coll. Cardiol. Img. 2008;1;307-316 ! 52!
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- 54. Links! Regadenoson product monograph can be found at:! http://www.astellas.us/docs/lexiscan.pdf! Dipyridamole product monograph can be found at:! http://www.boehringer-ingelheim.ca/en/Home/Human_Health/Our_Products/ Product_Monographs/Persantine-pm.pdf! 54!