EDmoRlAL5
What is the Optimum Dose of Dipyridamole for Cardiac Imaging? Abdulmassih S. Iskandrian, MD yocardial perfusion imaging during pharma- probably related to patient selection, specifically the cologically induced coronary hyperemia has prevalenceof previousAMI, and the extent and severity .proved to be useful in the diagnosis of coro- of CAD. In this issueof The American Journal of Carnary artery dii (CAD) and risk stratification.‘-9 diology, Casanovaet all* reported that the doseof dipyDespite important differences in the pharmacokinetics ridamole is also important in determining the sensitivity of dipyridamole and adenosine, several studies have by 2dimensional echocardiography. They studied 57 shown similar high sensitivities and specificities for de- patients on the average of 9 days after uncomplicated tecting CAD with both agents (80 to 90% each). The AMI. Each patient underwent thallium imaging and 2standard dose of dipyridamole in humans is based on dimensional echocardiographyat 2 different doses,stanprior experimental animal work and is 140 pg/kg/min dard (0.56 mg/kg) and high (0.84 mg/kg). for 4 minutes (total 0.56 mg/kg).lO The recommended New or worsening wall motion abnormalities were dose of adenosineis 140 ~g/kg/min for 6 minutes.2~3~7detectedin 4 patients (7%) at the standard doseand in The standard doseof dipyridamole has been reported to 24 (42%) at the high dose.More patients with multivesproduce maximal coronary hyperemia in most but not se1than l-vessel CAD had a reversible abnormality (15 all patients. Therefore, a 50% higher dose (total dose of 24 vs 9 of 31). Of 33 patients who did not have a 0.84 mg/kg) has been used by someinvestigators, espe- reversible abnormality, 2 had no significant CAD, and cially those in Europe and those using dipyridamole 42 had l-vessel and 9 had multivessel CAD. with 2-dimensional echocardiography.6Jl Maximal corHowever, the extent and severity of the thallium abonary hyperemia (in a normal coronary artery), just as normality were not significantly different at the 2 doses; maximal exercise,is not necessaryto produce perfusion 39 patients (68%) had reversible defects on both the abnormalities in most patients. The use of pharmaco standard and high doses.All patients with multivessel logic stress testing after acute myocardial infarction CAD, and approximately 50% with l-vessel CAD had (AMI) has shown that important prognostic informa- reversible defects. The remaining 18 patients who did tion regarding the extent of necrosis,myocardial viabili- not have reversible defects had fmed defects in the inty and &hernia in the infarct zone, and ischemia in farct zone (2 with no significant CAD, and 16 with lremote zones suggesting multivessel CAD can be ob vesselCAD). Thus, the high doseof dipyridamole was tained.8~9The relative merits of pharmacologic stress superior to the standard dosewhen 2-dimensional echotesting compared with those of submaximal or maximal cardiography was used, but not with thallium. Furtherexercisetesting combined with perfusion imaging is not more, with either the standard or high dose, more payet clear; there is an ongoing multicenter trial to ad- tients had a reversible thallium abnormality than a 2dressthis specific issue,and hopefully the results will be dimensional echocardiographicabnormality. The differences between the thallium and 2-dimenavailable in the near future. Abnormal test results during pharmacologic stress sional echocardiographicresults are basedon important testing are defined as the presenceof a fmed or revers- differences in the mechanismof the production of perible perfusion defect when thallium- or technetium-la- fusion defectsand wall motion abnormalities. Perfusion beled imaging agents are used and as the presenceof a defectsare due to either differencesin regional coronary fmed, new or worsening wall motion abnormality when blood flow or ischemia. In a given patient, someperfu2-dimensional echocardiography is used. Reversible de- sion defects may be due to flow heterogeneity and othfects and new or worsening wall motion abnormalities ers to ischemia. However, wall motion abnormalities by are considered as markers of ischemia, whereas fmed 2-dimensional echocardiography are due to ischemia. defects and wall motion abnormalities represent scar, Becausewith pharmacologic stresstesting, unlike exeralthough recently it has becomeclear that as much as cise testing, the increase in double product and thus myocardial oxygen demand is minimal, the ischemia is 50% of fmed defects contain viable myocardium. The sensitivity of 2diiensional echocardiography most likely due to coronary steal (either intercoronary with pharmacologic stress testing for detecting CAD or transmural). This topic was recently discus&l3 has varied between 10 and 90%.1,3-6Such variation is Consistent with the ischemia and steal concept, more patients in the study of Casanova et all* had ST-segFrom the Philadelphia Heart Institute, Presbyterian Medical Center, ment depressionwith the high dosethan with the stanPhiladelphia, Pennsylvania. Manuscript received and accepted April dard dose (25 vs 7%). Lattanzi et al” reported that 23, 1992. antianginal medications significantly decreasedthe senAddress for reprints: Abdulmassih S. Lkandrian, MD, University of PennsylvaniaSchoolof Medicine, Philadelphia Heart Institute, Pres- sitivity of 2diiensional echocardiography.The differbyterian Medical Center, 51 N. 39th Street, Philadelphia, Pennsylvania encemay to a small degreebe due to the effect of medications on blunting the heart rate increase,but is proba19104.
M
EDITORIALS
1485
bly more likely due to their effects on the redistribution of the flow, and decreasing the pressure reduction acrossthe coronary stenosisby dilating the stenosissegment. Should all patients receive high-dose dipyridamole? The answer is probably no, becausethe high dose produced more side effects than did the standard dose (57 vs 7%), although most side effectswere minor. Furthermore, the high dosedid not appear to affect the thallium results, where most perfusion defectsmay not necessarily be due to ischemia. More importantly, this study showedthat evenwith the high dose,abnormalities were less often detected by 2-dimensional echocardiography than by standard-dosethallium. It is possiblethat a certain mass of ischemic myocardium should be present before a visible wall motion abnormality can be detected. This is especially important in the infarct zone, where the adjacent myocardium may have a fmed wall motion abnormality. Dobutamine thallium and 2-dimensionalechocardiographic imaging are alternative techniques to exercise te&ing.1e16The mechanism of production of perfusion defects or wall motion abnormalities is based on the ability of dobutamine to produce a supply-demandimbalance due to increasesin heart rate and contractility. In many but not all patients, there is also an increasein systolic blood pressure.Thus, the mechanismof action of dobutamine appearsto resemblethat of exercise,and both are different from adenosine and dipyridamole. However, I do not believe that dobutamine should be used in patients after AMI, becauseof its &agonist activity, especially considering that doses up to 40 pgg/ kg/min are often used. This appearsto be in sharp contrast to the conventional wisdom of using /3 blockers in such patients; the arrhythmogenic properties of highdose dobutamine are also of concern. Thus, at the present time, if pharmacologic stress testing is used in patients after AMI, a standard doseof dipyridamole or adenosinecombined with thallium ap pears to have advantagesover standard- or high-dose2dimensional echocardiography. The use of sestamibi rather than thallium may have a slight advantage by enabling simultaneous measurementof left ventricular ejection fraction by first-pass radionuclide angiography. The prognostic importance of the resting ejection fraction has beenwelldocumented in such patients. Further
1486
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 70
studies are needed to compare the prognostic importance of perfusion, 2-dimensional echocardiographand exercisetesting.
REFERENCES
1. Beller GA. Pharmacologicstressimaging. JAMA 1991;265:633-638.
2. Verani MS, Mahmarkn JJ, Hixson JB, BoyceTM, StaudacherRA. Diagnosis
of coronary artery diseaseby wntrolled coronary vasodilationwith adenosineand thallium-201 scintigraphy in patients unable to exercise. Circulation 1990;82: 80-87.
3. Nguyen T, Hw J, Ogilby JD, IskandrianAS. Sie photonemissioncomputed tomography with thallium-201 during adenosin&duced coronary hype& correlation with coronary arteriography, exercisethallium imaging and twodimensionalechocardiography.J Am Co11Cwdiol 1990,16:1375-1383. 4. Martin TW, Seaworth JF, JohnsJP, Pupa LE, CondosWR. Comparisonof adenwine, dipyridamole and dobutaminein stresse&cardiography. Ann Intern Med 1992;116:190-196. 5. Zoghbi WM, Cheirif I, I&man NS, Verani MS, Trakhtenbroit A. Diagnosis of ischemicheart diseasewith adenazineechocanliography.J Am till Cardiol 1991;18:1271-1279. 6. PicanoE, Sionetti I, Masini M, Marxilli M, Lattanxi F, D&ante A, De Nes M, L’Abbate A. Transient myowrdial dysfunctionduring pharmacologicvasodilation as an index of reduced coronary -e: a coronary hemodynamicand echwardiographic study. J Am Call Cardiol 1986;8:84-90. 7. Ggilby JD, Islmndrian AS, Untereker WJ, Heo J, Nguyen TN, Mercuro J. Effect of intravenousadenwine infusion on myocardial perfusion and function: hemodynamicangiographicand scintigraphic study. Circnlorion (m press). 1. Gimple LW, Hutter AM, Guiney TE, Boucher CA. Progn&ic utility of predischargedipyridamole&allium imagingwmpared to predischargesubmaximal exerciseekctrography and maximal exercisethallium imaging after unwmplicated acute mywardiil infarction. Am J Cardiol 1989;64:1243-1248. 9. Brown KA, O’Meara J, ChambersCE, Plante DA. Ability of dipyridamolethallium-201 imagingoneto four daysalter acutemyocardial infarction to predict in-hospital and late tectnrent myowrdkl ischemic events. Am J Cardiol 1990;65:160-167. 10. Gould KL. Noninvasiveassessment of coronary steno+ by myocardiil perfusionimagingduring pharmawlogic coronary vascdiition. I. physiologicbasisand exnerimental validation. Am J Cardiol 1978:41:267-278. Ii. Lattami F, Picano E, BologneseL, Piccinino C, SarassoG, Grlandini A, L’Abbate A. Inhibition of dipyridamole-inducedischemiaby antianginal therapy in humans.Correlation with ~exerciseelectmwrdiography. ~Circbion 1991;83: 12561262. 12. CasanovaR. Patroncini A. Guidalotti PL. Caoacci PF. Jawni F. Fabbri M. Mare& A. Dose and test for ‘dipyridamoleinfusion and card& imaging early after uncomplicated acute myowrdial infarction. Am J Cardiol 1992;70: 1402-1406. lg. Iskandrian AS. Myowrdial iwhemia during pharmacologicstress testing (ed). Circulation (ii press). 14. Previtali M, Lanxarini L, Ferrario M, Tortorici M, Mussini A, Montema&i C. Dobutamine vs dipyridamole echocardiographyin coronary artery disease. Circularion 1991;83(suppl111):27-31. IS. Elliott BM, RobinsonJG, Zelhter JL, Hendrix GH. Dobutaminethallium201imaging.Assessiicardiacrislc9 associatedwith vasah surgery.Circulation 1991;84(sup~l1II):IIE54-111-60. 16. PemtellDJ, Underwood SR, Swanton RI-I, Walker JM, Ell PJ. Dobutamine thallium myocardial perfusion tomography. J Am CON Cardiol 1991;18: 1471-1479.
DECEMBER 1, 1992
What is the Optimum Dose of Dipyridamole for Cardiac Imaging? Abdulmassih S. Iskandrian, MD yocardial perfusion imaging during pharma- probably related to patient selection, specifically the cologically induced coronary hyperemia has prevalenceof previousAMI, and the extent and severity .proved to be useful in the diagnosis of coro- of CAD. In this issueof The American Journal of Carnary artery dii (CAD) and risk stratification.‘-9 diology, Casanovaet all* reported that the doseof dipyDespite important differences in the pharmacokinetics ridamole is also important in determining the sensitivity of dipyridamole and adenosine, several studies have by 2dimensional echocardiography. They studied 57 shown similar high sensitivities and specificities for de- patients on the average of 9 days after uncomplicated tecting CAD with both agents (80 to 90% each). The AMI. Each patient underwent thallium imaging and 2standard dose of dipyridamole in humans is based on dimensional echocardiographyat 2 different doses,stanprior experimental animal work and is 140 pg/kg/min dard (0.56 mg/kg) and high (0.84 mg/kg). for 4 minutes (total 0.56 mg/kg).lO The recommended New or worsening wall motion abnormalities were dose of adenosineis 140 ~g/kg/min for 6 minutes.2~3~7detectedin 4 patients (7%) at the standard doseand in The standard doseof dipyridamole has been reported to 24 (42%) at the high dose.More patients with multivesproduce maximal coronary hyperemia in most but not se1than l-vessel CAD had a reversible abnormality (15 all patients. Therefore, a 50% higher dose (total dose of 24 vs 9 of 31). Of 33 patients who did not have a 0.84 mg/kg) has been used by someinvestigators, espe- reversible abnormality, 2 had no significant CAD, and cially those in Europe and those using dipyridamole 42 had l-vessel and 9 had multivessel CAD. with 2-dimensional echocardiography.6Jl Maximal corHowever, the extent and severity of the thallium abonary hyperemia (in a normal coronary artery), just as normality were not significantly different at the 2 doses; maximal exercise,is not necessaryto produce perfusion 39 patients (68%) had reversible defects on both the abnormalities in most patients. The use of pharmaco standard and high doses.All patients with multivessel logic stress testing after acute myocardial infarction CAD, and approximately 50% with l-vessel CAD had (AMI) has shown that important prognostic informa- reversible defects. The remaining 18 patients who did tion regarding the extent of necrosis,myocardial viabili- not have reversible defects had fmed defects in the inty and &hernia in the infarct zone, and ischemia in farct zone (2 with no significant CAD, and 16 with lremote zones suggesting multivessel CAD can be ob vesselCAD). Thus, the high doseof dipyridamole was tained.8~9The relative merits of pharmacologic stress superior to the standard dosewhen 2-dimensional echotesting compared with those of submaximal or maximal cardiography was used, but not with thallium. Furtherexercisetesting combined with perfusion imaging is not more, with either the standard or high dose, more payet clear; there is an ongoing multicenter trial to ad- tients had a reversible thallium abnormality than a 2dressthis specific issue,and hopefully the results will be dimensional echocardiographicabnormality. The differences between the thallium and 2-dimenavailable in the near future. Abnormal test results during pharmacologic stress sional echocardiographicresults are basedon important testing are defined as the presenceof a fmed or revers- differences in the mechanismof the production of perible perfusion defect when thallium- or technetium-la- fusion defectsand wall motion abnormalities. Perfusion beled imaging agents are used and as the presenceof a defectsare due to either differencesin regional coronary fmed, new or worsening wall motion abnormality when blood flow or ischemia. In a given patient, someperfu2-dimensional echocardiography is used. Reversible de- sion defects may be due to flow heterogeneity and othfects and new or worsening wall motion abnormalities ers to ischemia. However, wall motion abnormalities by are considered as markers of ischemia, whereas fmed 2-dimensional echocardiography are due to ischemia. defects and wall motion abnormalities represent scar, Becausewith pharmacologic stresstesting, unlike exeralthough recently it has becomeclear that as much as cise testing, the increase in double product and thus myocardial oxygen demand is minimal, the ischemia is 50% of fmed defects contain viable myocardium. The sensitivity of 2diiensional echocardiography most likely due to coronary steal (either intercoronary with pharmacologic stress testing for detecting CAD or transmural). This topic was recently discus&l3 has varied between 10 and 90%.1,3-6Such variation is Consistent with the ischemia and steal concept, more patients in the study of Casanova et all* had ST-segFrom the Philadelphia Heart Institute, Presbyterian Medical Center, ment depressionwith the high dosethan with the stanPhiladelphia, Pennsylvania. Manuscript received and accepted April dard dose (25 vs 7%). Lattanzi et al” reported that 23, 1992. antianginal medications significantly decreasedthe senAddress for reprints: Abdulmassih S. Lkandrian, MD, University of PennsylvaniaSchoolof Medicine, Philadelphia Heart Institute, Pres- sitivity of 2diiensional echocardiography.The differbyterian Medical Center, 51 N. 39th Street, Philadelphia, Pennsylvania encemay to a small degreebe due to the effect of medications on blunting the heart rate increase,but is proba19104.
M
EDITORIALS
1485
bly more likely due to their effects on the redistribution of the flow, and decreasing the pressure reduction acrossthe coronary stenosisby dilating the stenosissegment. Should all patients receive high-dose dipyridamole? The answer is probably no, becausethe high dose produced more side effects than did the standard dose (57 vs 7%), although most side effectswere minor. Furthermore, the high dosedid not appear to affect the thallium results, where most perfusion defectsmay not necessarily be due to ischemia. More importantly, this study showedthat evenwith the high dose,abnormalities were less often detected by 2-dimensional echocardiography than by standard-dosethallium. It is possiblethat a certain mass of ischemic myocardium should be present before a visible wall motion abnormality can be detected. This is especially important in the infarct zone, where the adjacent myocardium may have a fmed wall motion abnormality. Dobutamine thallium and 2-dimensionalechocardiographic imaging are alternative techniques to exercise te&ing.1e16The mechanism of production of perfusion defects or wall motion abnormalities is based on the ability of dobutamine to produce a supply-demandimbalance due to increasesin heart rate and contractility. In many but not all patients, there is also an increasein systolic blood pressure.Thus, the mechanismof action of dobutamine appearsto resemblethat of exercise,and both are different from adenosine and dipyridamole. However, I do not believe that dobutamine should be used in patients after AMI, becauseof its &agonist activity, especially considering that doses up to 40 pgg/ kg/min are often used. This appearsto be in sharp contrast to the conventional wisdom of using /3 blockers in such patients; the arrhythmogenic properties of highdose dobutamine are also of concern. Thus, at the present time, if pharmacologic stress testing is used in patients after AMI, a standard doseof dipyridamole or adenosinecombined with thallium ap pears to have advantagesover standard- or high-dose2dimensional echocardiography. The use of sestamibi rather than thallium may have a slight advantage by enabling simultaneous measurementof left ventricular ejection fraction by first-pass radionuclide angiography. The prognostic importance of the resting ejection fraction has beenwelldocumented in such patients. Further
1486
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 70
studies are needed to compare the prognostic importance of perfusion, 2-dimensional echocardiographand exercisetesting.
REFERENCES
1. Beller GA. Pharmacologicstressimaging. JAMA 1991;265:633-638.
2. Verani MS, Mahmarkn JJ, Hixson JB, BoyceTM, StaudacherRA. Diagnosis
of coronary artery diseaseby wntrolled coronary vasodilationwith adenosineand thallium-201 scintigraphy in patients unable to exercise. Circulation 1990;82: 80-87.
3. Nguyen T, Hw J, Ogilby JD, IskandrianAS. Sie photonemissioncomputed tomography with thallium-201 during adenosin&duced coronary hype& correlation with coronary arteriography, exercisethallium imaging and twodimensionalechocardiography.J Am Co11Cwdiol 1990,16:1375-1383. 4. Martin TW, Seaworth JF, JohnsJP, Pupa LE, CondosWR. Comparisonof adenwine, dipyridamole and dobutaminein stresse&cardiography. Ann Intern Med 1992;116:190-196. 5. Zoghbi WM, Cheirif I, I&man NS, Verani MS, Trakhtenbroit A. Diagnosis of ischemicheart diseasewith adenazineechocanliography.J Am till Cardiol 1991;18:1271-1279. 6. PicanoE, Sionetti I, Masini M, Marxilli M, Lattanxi F, D&ante A, De Nes M, L’Abbate A. Transient myowrdial dysfunctionduring pharmacologicvasodilation as an index of reduced coronary -e: a coronary hemodynamicand echwardiographic study. J Am Call Cardiol 1986;8:84-90. 7. Ggilby JD, Islmndrian AS, Untereker WJ, Heo J, Nguyen TN, Mercuro J. Effect of intravenousadenwine infusion on myocardial perfusion and function: hemodynamicangiographicand scintigraphic study. Circnlorion (m press). 1. Gimple LW, Hutter AM, Guiney TE, Boucher CA. Progn&ic utility of predischargedipyridamole&allium imagingwmpared to predischargesubmaximal exerciseekctrography and maximal exercisethallium imaging after unwmplicated acute mywardiil infarction. Am J Cardiol 1989;64:1243-1248. 9. Brown KA, O’Meara J, ChambersCE, Plante DA. Ability of dipyridamolethallium-201 imagingoneto four daysalter acutemyocardial infarction to predict in-hospital and late tectnrent myowrdkl ischemic events. Am J Cardiol 1990;65:160-167. 10. Gould KL. Noninvasiveassessment of coronary steno+ by myocardiil perfusionimagingduring pharmawlogic coronary vascdiition. I. physiologicbasisand exnerimental validation. Am J Cardiol 1978:41:267-278. Ii. Lattami F, Picano E, BologneseL, Piccinino C, SarassoG, Grlandini A, L’Abbate A. Inhibition of dipyridamole-inducedischemiaby antianginal therapy in humans.Correlation with ~exerciseelectmwrdiography. ~Circbion 1991;83: 12561262. 12. CasanovaR. Patroncini A. Guidalotti PL. Caoacci PF. Jawni F. Fabbri M. Mare& A. Dose and test for ‘dipyridamoleinfusion and card& imaging early after uncomplicated acute myowrdial infarction. Am J Cardiol 1992;70: 1402-1406. lg. Iskandrian AS. Myowrdial iwhemia during pharmacologicstress testing (ed). Circulation (ii press). 14. Previtali M, Lanxarini L, Ferrario M, Tortorici M, Mussini A, Montema&i C. Dobutamine vs dipyridamole echocardiographyin coronary artery disease. Circularion 1991;83(suppl111):27-31. IS. Elliott BM, RobinsonJG, Zelhter JL, Hendrix GH. Dobutaminethallium201imaging.Assessiicardiacrislc9 associatedwith vasah surgery.Circulation 1991;84(sup~l1II):IIE54-111-60. 16. PemtellDJ, Underwood SR, Swanton RI-I, Walker JM, Ell PJ. Dobutamine thallium myocardial perfusion tomography. J Am CON Cardiol 1991;18: 1471-1479.
DECEMBER 1, 1992
