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!

Overview!

Introduction!

Background !

Stress methods!

Dipyridamole !

Research study!

Results!

Conclusion!

2!

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!

Introduction!

Background !

Stress methods!

Dipyridamole !

Research study!

Results!

Conclusion!

4!

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!

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!

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!

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!

Introduction!

Background !

Stress methods!

Dipyridamole !

Research study!

Results!

Conclusion!

9!

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)!

Stress methods!Exercise!

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•  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!

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!

Stress methods!

Pros !•  Short half-life ( <10 seconds) !•  To stop treatment, just stop infusion !

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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!

Stress methods!

Pros !•  Short half-life (<2 minutes ) !•  To stop treatment, just stop infusion !•  Can be used in place of adenosine or dipyridamole !

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Cons !•  Requires an infusion pump!•  Numerous side effects!•  Contradictions: recent heart attack, unstable angina,

hypertension, beta blockers, …!

Dobutamine !•  Inotropic and chronotropic !•  !1 - adrenergic agonist!

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!

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!

Stress methods!

17!

New Options!Vasodilators in development!•  Binodenoson !•  Apadenoson!•  CGS-21680!

All target A2A receptors for coronary vasodilation!

Introduction!

Background !

Stress methods!

Dipyridamole !

Research study!

Results!

Conclusion!

18!

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)!

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Typical stress protocol!•  Dipyridamole dose by weight!•  Slow dipyridamole infusion!•  Tracer (99mTc-myoview or 201Tl)!•  Aminophylline (pro-rated by weight)!

Dipyridamole !Why there are side effects?!

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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!

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!

Introduction!

Background !

Stress methods!

Dipyridamole !

Research study!

Results!

Conclusion!

22!

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!

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 !

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Common for everyone!

Relative high frequency of occurrence!

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!

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!

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Introduction!

Background !

Stress methods!

Dipyridamole !

Research study!

Results!

Conclusion!

27!

Results !The initial analysis began with graphing most combinations!

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Results - Demographics !

29!

Results - Side effects overview !

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Most patients (77%) experienced at least one side effect with headaches being the most common !

Results - Any side effect !

The chance of feeling any side effect is influenced by age and sex !

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Results - Headaches !

Headache occurrence and severity are influenced by age, sex !BMI and diabetic status!

32!

Results - Nausea !

Nausea occurrence and severity were influenced by age and daily aspirin usage !

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Results - Dizziness!

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Daily ASA usage reduced dizziness severity, while diabetic patients felt dizzy more often !

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.!

Results - ʻOtherʼ side effects !

ʻOtherʼ side effects represents 36 (16%) of all side effects reported!

36!

Results - Categorized severity !

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Overall side effect severity and occurrence is affected by age and daily aspirin usage!

Results - Predicting severity !Predicting severity with multiple linear regression!

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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!

Results - Predicting occurrence!Predicting occurrence with multiple logistic regression!

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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!

Results - Summary!

Abbreviations: Freq, frequency; Sev, severity; #, decreased; $, increased;! -, no significant correlation; * p-value = 0.054; ** p-value = 0.069!

40!

Introduction!

Background !

Stress methods!

Dipyridamole !

Research study!

Results!

Conclusion!

41!

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 !

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)!

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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 !

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Consent form!

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Questionnaire + Data Sheet!

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Statistics software used!

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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/

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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!

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