Aspirin and dipyridamole and their limitations in the therapy of coronary artery disease

We have reviewed some of the voluminous literature on the effects of aspirin combined with dipyridamole on coronary thrombosis. There is clear evidence that aspirin is partially effective in preventing platelet aggregation and subsequent thrombosis in experimental constricted and damaged coronary arteries of dogs. Clinical studies show a clear reduction in myocardial infarction in male human subjects who are given aspirin as therapy for unstable angina, or as prophylaxis in asymptomatic individuals. In many studies aspirin and dipyridamole have been combined and are effective. We have not found dipyridamole to be effective in the dog with coronary artery constriction and find no substantial evidence that it is effective in preventing myocardial infarction in man. Until definitive studies show that combining dipyridamole with aspirin is more effective than aspirin alone, we do not recommend its use for prevention of coronary thrombosis.     

Intravenous obsidan-induced changes of coronary venous blood flow in patients with coronary heart disease in the presence of transient myocardial ischemia]

Intravenous obsidan was evaluated for its effects on the blood flow in the coronary sinus and the major cardiac vein in 23 coronary heart disease patients with hyperkinetic central hemodynamics. The use of the drug was found to be effective when the patients had had high baseline coronary venous blood flow. At the peak of cardiac pacing, the patients with low coronary sinus blood flow on obsidan showed decreased blood flow in the ischemic myocardial portions, developed signs of left ventricular failure and diminished anginal threshold. Those with moderate baseline blood flow on obsidan displayed an insignificant increase in anginal threshold, higher blood flow was inadequate to oxygen consumption.     

Effect of insulin and beta-adrenergic blockaders on coronary circulation in response to hypoxia

An experimental study in dogs with intact thoracic cavity under morphine-chloralose narcosis featured coronary catheterization, extracorporeal perfusion and resistography as well as catheterization of the heart cavities and the coronary sinus. Hemodynamic and respiratory parameters were recorded simultaneously. PO2, PCO2 and pH were measured in the inflowing and outflowing blood. The effect of insulin on circulatory response in acute hypoxic hypoxia was examined before and after obsidan block of beta-adrenoreactive systems. Insulin administered after the obsidan beta-adrenergic block was found to limit coronary dilatation and reduce myocardial oxygen consumption in a more pronounced measure. It is suggested that the effect of insulin on coronary dilatation is due to reduced myocardial oxygen consumption resulting from its action on the heart's beta-adrenergic systems.     

Dobutamine versus dipyridamole for inducing reversible perfusion defects in chronic multivessel coronary artery stenosis

OBJECTIVES: We hypothesized that, although the effects of dipyridamole and dobutamine on myocardial blood volume (MBV) and mean microbubble velocity (VEL) are different, the magnitude of perfusion deficit during both forms of stress is the same because both drugs unmask abnormal myocardial blood flow (MBF) reserve. BACKGROUND: Both dipyridamole and dobutamine are used clinically as pharmacologic stress agents to induce reversible perfusion defects in patients with chronic coronary artery disease (CAD), but the basis for doing so for dobutamine is not clear. METHODS: Eleven chronically instrumented closed-chest dogs with multivessel coronary stenosis were studied. Hemodynamics, radiolabeled microsphere-derived MBF, and myocardial contrast echocardiography (MCE)-derived myocardial perfusion were measured at rest, after dipyridamole infusion (0.56 mg x kg(-1)), and at peak dobutamine dose (either 30 or 40 microg x kg(-1) x min(-1)). Abnormal beds were defined as those demonstrating an MBF reserve <3 with dipyridamole. RESULTS: In the presence of either drug, MBV increased more in the normal bed than in the abnormal bed, but the increase was higher in both beds with dobutamine than with dipyridamole. The slope of the relationship between MBF reserve and MBV reserve was greater during dobutamine than dipyridamole (p < 0.05). The converse was true for VEL reserve (p < 0.05). Consequently, the relationship between the ratios of either variable, or the product of the two, between the abnormal bed and normal bed was similar for both drugs. CONCLUSIONS: Although the effects of dipyridamole and dobutamine on MBV and VEL are different, both are equally effective in detecting physiologically relevant coronary stenoses on MCE. Both can therefore be used interchangeably with myocardial perfusion imaging for the detection of CAD.     

Effects of isoptin and obsidan on the coronary blood flow and tactics in anti-angina therapy of patients with ischemic heart disease

Single intravenous doses of isoptin (10 mg) and obsidan (5 mg) were tested for their effects on hemodynamic and coronary blood flow parameters in 35 patients with coronary heart disease and functional classes II-III angina pectoris of effort. In most cases, hemodynamic and coronary blood flow responses to the drug administered were found to be identical. It was concluded that isoptin was effective as an antianginal agent in eukinetic hemodynamics, obsidan, in hyperkinetic one.     

Dipyridamole-induced ST-segment elevation indicative of transmural myocardial ischemia--a case report

Dipyridamole nuclear myocardial perfusion test is a safe and effective alternative to exercise nuclear perfusion testing for detecting myocardial ischemia. It is the procedure of choice in selected patients who are unable to exercise adequately. Intravenous dipyridamole causes coronary vasodilation with resultant maldistribution and heterogeneity of coronary flow in the presence of significant coronary artery disease. True ischemia, causing symptoms or ST-segment depression, is uncommon, in part because there is no increase in myocardial oxygen demand. A patient in whom myocardial ischemia developed, manifested by ST-segment elevation, during dipyridamole stress testing is described. Scintigraphic images illustrated a myocardial perfusion defect, which was consistent with coronary angiographic findings. This case report addresses the importance of dipyridamole-induced ST-segment elevation, its correlation with angiographic findings, and the need for continued hemodynamic and electrocardiographic monitoring in patients following dipyridamole infusion.     

Use of myocardial scintigraphy with 201T1 in combination with the dipyridamole test in patients with ischemic heart disease

Possible diagnostic use of myocardial 201T1-scintigraphy combined with the dipyridamole test in coronary patients is described. Twenty-six patients were investigated. Coronarography showed atherosclerotic lesions of coronary arteries in 12. The dipyridamole test was positive in all patients with affected coronary arteries, as evidenced by myocardial 201T1-scintigraphy. In the patients with intact coronary arteries, myocardial 201T1-scintigraphy combined with the dipyridamole test was negative in 9 cases and positive in 3. The study demonstrates high sensitivity of the method described.     

Effects of obsidan on hemodynamic indices and clinical manifestations of angina pectoris in patients with ischemic heart disease during psychoemotional stress

Obsidan was tested for effects on psychoemotional stress (PES) tolerance in 37 patients with coronary heart disease concurrent with angina pectoris. During PES testing, the course treatment of obsidan versus placebo resulted in a significant decrease in the pulse-pressure index by significantly bringing down heart rate. With this, blood pressure remained unchanged. The patients who were highly responsive to PES, as evidenced by heart rate measurement, showed a high rise in systolic and diastolic blood pressure when they were taking obsidan. The frequency of positive tests was 48.7% before obsidan therapy and 8.1% during its therapy; that was 29.8 and 8.1%, respectively, when the objective criterion for myocardial ischemia was used as ECG ST-segment displacement.     

Dipyridamole stress echocardiography and ultrasonic myocardial tissue characterization in predicting myocardial ischemia, in comparison with dipyridamole stress Tc-99m MIBI SPECT myocardial imaging

The purpose of this study was to validate whether dipyridamole stress ultrasonic tissue characterization with cyclic variation of integrated backscatter (CVIBS) compared with dipyridamole stress echocardiography and dipyridamole stress Tc99m-MIBI SPECT myocardial perfusion scintigraphy could predict myocardial ischemia in patients with chronic coronary artery disease. Twenty patients (16 M, 4 F) who had coronary angiography for stable angina pectoris were included in the study. Mean age was 62 +/- 8 years. The left ventricle was divided into 16 segments. Regional wall motion analysis and CVIBS measurements were obtained from 16 myocardial segments at rest and after dipyridamole (0.84 mg/kg) infusion. After 10 minutes, Tc-99m MIBI (10 mCi) was injected and SPECT myocardial imaging was performed. After 3 hours, 25 mCi Tc-99m MIBI was reinjected and rest images were obtained. A total of 320 ventricular wall segments were evaluated. Two hundred and six ventricular wall segments were supplied by stenotic coronary arteries and 114 segments were supplied by normal coronary arteries. Dipyridamole stress Tc-99m MIBI SPECT studies showed abnormal myocardial perfusion in 176 segments and normal perfusion in 144 segments. Transient regional wall motion abnormality was detected in 116 segments. A significant decrease in CVIBS after dipyridamole stress was detected in 184 segments. The sensitivity and specificity of dipyridamole stress echocardiography, Tc-99m MIBI SPECT, and CVIBS were 56% and 100%, 85% and 92%, and 89% and 100%, respectively, compared with the results from coronary angiography. Dipyridamole stress ultrasonic tissue characterization with CVIBS may provide more sensitive detection of myocardial ischemia than dipyridamole stress echocardiography and may be as valuable as dipyridamole stress myocardial perfusion scintigraphy.     

Intravenous dipyridamole-induced myocardial ischemia during percutaneous transluminal coronary angioplasty in humans

Percutaneous transluminal coronary angioplasty was used as a model of controlled myocardial ischemia to study the effect of intravenous dipyridamole on myocardial ischemia and coronary hemodynamics in 10 patients. All patients had 1-vessel coronary artery disease with visualized collaterals. Intravenous dipyridamole increased myocardial ischemia during inflations. ST elevation, as measured by intracoronary electrogram, increased significantly from the control inflation to the second inflation after dipyridamole injection (0.05 +/- 0.23 vs 0.44 +/- 0.43 mV, p less than 0.03). Of the 10 patients, 8 developed new or more severe angina with subsequent inflations after dipyridamole. The pulmonary artery wedge pressure increased significantly from the control inflation to the fourth inflation (15 +/- 8 vs 20 +/- 9 mm Hg, p less than 0.05). The coronary wedge pressure showed a decreasing trend with subsequent inflations after dipyridamole but did not reach statistical significance. The double product (heart rate X blood pressure) was not significantly altered by dipyridamole. The findings indicate that intravenous dipyridamole increases myocardial ischemia during balloon occlusion. The constancy of the double product and the trend toward a decrease in coronary wedge pressure suggest that dipyridamole may induce ischemia by reducing the amount of collateral flow through a coronary steal phenomenon.     

Effects of oral dipyridamole on coronary dynamics and myocardial metabolism at rest and during pacing-induced angina in patients with coronary artery disease

The effects of oral dipyridamole administration (150 mg) on coronary hemodynamics, myocardial metabolism, and pacing threshold were studied in 10 patients with significant coronary artery disease (CAD). Following dipyridamole through 120 minutes, there was no significant change in resting heart rate, arterial pressure, coronary venous flow, coronary resistance, myocardial lactate extraction, or myocardial oxygen consumption. Rapid atrial pacing performed before and at 60, 90, and 120 minutes after dipyridamole failed to demonstrate any significant reduction in pacing threshold or evidence of increased ischemia after dipyridamole. Blood dipyridamole levels showed variable and slow absorption which probably explains the difference between intravenous and oral dipyridamole on coronary dynamics and myocardial response to pacing.     

Dipyridamole is superior to dobutamine for thallium stress imaging: a randomised crossover study.

OBJECTIVE--To assess the value of dobutamine over dipyridamole as a pharmacological stressing agent in myocardial perfusion imaging with thallium-201. DESIGN--Stress and redistribution tomographic images were taken in a group of patients in a randomised crossover study of both agents. The scans were scored to give a value for the stress and redistribution images and a reversibility score (redistribution--stress). All patients had coronary angiography that was also scored. Differences between the two agents were compared by a paired t test. PATIENTS--30 patients aged 51-70 years with chest pain thought to be caused by myocardial ischaemia. 11 had had previously myocardial infarction. RESULTS--Dipyridamole caused adverse symptoms in six patients whereas dobutamine caused symptoms in 21 patients (chi 2 = 15.15, p < 0.0001). Dobutamine stress took considerably longer than dipyridamole (31 v 6 minutes) and cost more (17 pounds v 1.50 pounds). There were no significant differences between the agents in terms of total stress or redistribution scores, but regional analysis showed that dipyridamole showed significantly more defects during stress at the apex and lateral wall (p < 0.05), with no significant difference at redistribution. Dipyridamole stress also caused significantly more reversible defects at the apex (p < 0.05) and gave a better correlation than dobutamine with coronary score (dipyridamole r = 0.80, p < 0.001 v dobutamine r = 0.64, p < 0.001). In six patients who had continued to take beta blockers the results of dobutamine stress did not correlate with coronary score, r = 0.34 (NS), whereas dipyridamole studies were not affected. CONCLUSION--Compared with dobutamine, dipyridamole was as effective in producing overall perfusion defects and more effective in provoking defects at the apex and lateral segment. The dipyridamole study correlated better with coronary score and was not affected by concurrent beta blocker treatment. It was also better tolerated by the patients, was less time consuming, and was much cheaper.     

Thallium-201 scintigraphy perfusion defect with dipyridamole in a patient with a myocardial bridge

A patient with myocardial bridging and a thallium-201 scintigraphy perfusion defect after the administration of intravenous dipyridamole is presented. The same patient had a normal perfusion study on exercise stress testing. The effects of coronary vasodilators and dipyridamole on coronary artery flow patterns in patients with myocardial bridging are discussed. We suggest that coronary vasodilators may induce perfusion defects in patients with myocardial bridging and should be avoided in such patients.     

Dipyridamole cardiac imaging

Dipyridamole cardiac imaging is a useful alternative technique to exercise stress testing in the evaluation of patients with ischemic heart disease. Intravenous dipyridamole is still in the investigational phase, while oral dipyridamole is widely available. The hemodynamic effects of dipyridamole include an increase in coronary blood flow (due to coronary vasodilation) which is in excess of the increase in myocardial oxygen consumption and cardiac output. The disparity in the increase in coronary blood flow relative to the cardiac output results in an increase in myocardial thallium activity and an increase in the myocardial/background activity ratio. The quality of the thallium images is better or similar to that of exercise thallium images. The optimal dose of intravenous dipyridamole is 0.56 mg/kg, and of the oral dose it is 300 to 400 mg, although higher doses may be necessary in some patients. Analysis of the thallium images has been to a large extent based on visual inspection of the planar images. Delayed images are helpful to establish the nature of the perfusion abnormalities (transient or fixed). The process of redistribution is based on disparate rates of washout from the normal and abnormal zones. The sensitivity and specificity of dipyridamole thallium imaging, whether intravenous or oral, have been shown in a number of studies to be quite adequate and comparable to that achieved during exercise thallium imaging. Dipyridamole two-dimensional echocardiography has also been used in the detection of coronary artery disease; transient (new or worsening of preexisting) wall motion abnormalities have been found to be a specific marker of coronary artery disease. Transmural as well as regional coronary steal phenomena have been postulated as the mechanism for dipyridamole-induced regional wall motion abnormalities. Compared to exercise two-dimensional echocardiography, dipyridamole echocardiography provides high-quality studies and in higher proportions of patients. The results of dipyridamole thallium imaging have also been extremely important in identifying high-risk patients after acute myocardial infarction or patients with peripheral vascular disease undergoing elective vascular surgery; the presence of a dipyridamole-induced perfusion abnormality identifies patients at high risk for future cardiac events. Thus, dipyridamole cardiac imaging is helpful in the diagnosis of coronary artery disease and in risk stratification.     

Noninvasive assessment of coronary stenoses by myocardial perfusion imaging during pharmacologic coronary vasodilatation. I. Physiologic basis and experimental validation

This study was undertaken to establish the basic hemodynamic conditions necessary to cause abnormalities in external myocardial perfusion images of thallium-201 and technetium-99M-labeled particles as a result of defined coronary stenoses ranging from mild to severe narrowing. Twenty dogs underwent long-term instrumentation with a flow transducer and adjustable constrictor on the left circumflex coronary artery. Catheters were implanted in the aortic root and distal left circumflex coronary artery to measure pressure loss across the stenosis and in the pulmonary artery and left atrium for the injection of drugs or radionuclides, or both. All data were obtained in intact unsedated trained animals. The results from 145 images obtained at rest, during exercise or after coronary vasodilators in dogs with mild to severe coronary stenoses demonstrate the following: (1) The ratio of maximal flow in a normal to stenotic coronary artery must be at least 2:1 before defects appear in the myocardial perfusion image of thallium-201. (2) A diagnostic technique that utilizes a maximal stimulus for increasing coronary flow and an imaging agent that is distributed to the myocardium in linear proportion to coronary flow at flow rates up to 4 or 5 times resting levels will be the most sensitive method for detecting mild coronary stenoses; a diagnostic technique utilizing a submaximal stimulus for coronary flow or an imaging agent whose distribution is not proportional to flow at high flow rates will be least sensitive. (3) Myocardial perfusion imaging during coronary vasodilatation induced with intravenously administered dipyridamole is a better method for identifying moderate coronary stenoses than perfusion imaging during exercise stress in experimental animals. (4) The effect of intravenously administered dipyridamole on the coronary circulation can be closely regulated by adjusting the dose rate of infusion and can be instantaneously reversed with intravenous administration of aminophylline, a dipyridamole antagonist; dipyridamole infusion does not increase myocardial oxygen demands as much as exercise and does not Invoke myocardial ischemia as a diagnostic end point. This stimulus may therefore be more readily controlled than exercise stress and is not subject to the effects on treadmill testing of motivation, chronic lung disease, peripheral vascular disease or musculoskeletal impairment.     

Absolute quantitation of coronary steal induced by intravenous dipyridamole

OBJECTIVE: The study was done to determine whether coronary steal (defined as an absolute decrease in perfusion from resting blood flow) is induced by intravenous (IV) dipyridamole in patients with severe coronary artery disease (CAD). BACKGROUND: Myocardial ischemia during coronary vasodilation is usually attributed to coronary steal. However, there is limited data on the absolute magnitude of coronary steal in humans. METHODS: Eighteen patients with multivessel CAD underwent dynamic positron emission tomography (PET) imaging with 13NH3 at rest and after infusion of IV dipyridamole. Eight myocardial sectors were analyzed per short axis slice and myocardial blood flow calculated with a two-compartment model in absolute terms. RESULTS: Coronary steal occurred in 8 of the 18 patients. In the 8 patients with coronary steal, myocardial blood flow decreased from 90 +/- 18 ml/100 g/min at rest to 68 +/- 27 ml/100 g/min following dipyridamole in the segments with steal, and increased from 87 +/- 19 to 138 +/- 16 ml/100 g/min following dipyridamole in the segments without steal. Significant clinical correlates of coronary steal were either ST elevation or the combination of ST depression and angina. CONCLUSIONS: Coronary vasodilation with IV dipyridamole is associated with significant reductions in blood flow to collateral-dependent myocardium consistent with coronary steal in about 45% of patients with severe CAD.     

Evaluation of coronary arterial disease by oral dipyridamole stress testing using 12-lead electrocardiography

We studied the values of oral dipyridamole needed to detect coronary arterial disease using 12-lead electrocardiography. The relationship between dipyridamole-induced ST segment depression and coronary arterial lesions, coronary collaterals and myocardial infarction was investigated. 375 mg oral dipyridamole was given to 31 patients (22 with coronary arterial disease, 9 controls). 12-lead electrocardiogram was recorded before and 45 minutes after the test. The control group and the patients, who had no ST segment depression after dipyridamole, performed isometric contraction (handgrip) for 5 minutes and then the 12-lead electrocardiogram was recorded. All patients had coronary angiography. We also performed treadmill stress testing in 28 patients. Dipyridamole testing was positive (greater than or equal to 1 mm ST depression on electrocardiogram) in 7 of 22 patients with coronary arterial disease, of whom 6 had positive treadmill stress testing. Only 2 patients had previous myocardial infarction in the group with positive dipyridamole tests. Of the 15 in whom dipyridamole testing was negative, 5 had positive treadmill stress testing, while 13 of them had had previous myocardial infarction. All patients in the control group had negative dipyridamole stress testing and normal coronary angiograms. No additional ST segment changes were observed in the group who had performed isometric contraction test (both dipyridamole test negative and control groups). Sensitivity and specificity of the test were 32 and 100%, respectively. Comparison of collateral vessels between the groups positive and negative for dipyridamole revealed no difference. But the number of patients with old myocardial infarction was higher in those testing negative than in those who proved positive.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of dipyridamole and warfarin on the patency rate of coronary artery bypass grafts

Seventy consecutive patients who had undergone coronary artery bypass surgery were postoperatively treated with either dipyridamole or warfarin for 6 months. The dipyridamole series consisted of 28 patients given 150 mg dipyridamole 3 times daily and the warfarin series, of 42 patients who received the appropriate daily dose of warfarin needed to maintain the prothrombin time within the therapeutic range. The majority of patients in both series belonged to the NYHA class III. Sixty-one percent of the patients in the dipyridamole series and 66% of those of the warfarin series had triple vessel disease. In all, 70 and 105 coronary artery branches were bypassed in the dipyridamole and warfarin series, respectively. This resulted in 2.5 distal anastomoses per patient in each series. The patency of the grafts was confirmed angiographically. There was no mortality during the 23.6 +/- 2.4 months follow-up period in the dipyridamole series or the 12.8 +/- 2.7 months in the warfarin series. The patency rates were 95.7% and 88.6% in the dipyridamole and warfarin series, respectively. It is apparent that dipyridamole is not less effective than warfarin in preventing postoperative coronary graft occlusion.     

Dipyridamole dilates large coronary arteries in conscious dogs

The effects of 0.25 mg/kg dipyridamole on left ventricular (LV) pressures, LV dP/dt, heart rate, aortic pressures, left circumflex coronary blood flow, and left circumflex coronary arterial diameters and on calculations of late diastolic coronary resistance and large coronary cross-sectional area were studied in 15 conscious dogs. Injection of dipyridamole, a drug that has a mechanism of action dependent on myocardial adenosine production, caused sustained increases in mean coronary blood flow (244 +/- 28%), large coronary arterial cross-sectional area (28 +/- 3.2%), heart rate (32 +/- 3.6%), and LV dP/dt (23 +/- 3.0%) and reductions in late diastolic coronary resistance (73 +/- 2.4%) and mean arterial pressure (14 +/- 1.9%). Neither beta-adrenergic-receptor blockade alone nor in conjunction with constant heart rate affected the dilation of large coronary arteries to dipyridamole significantly. Ganglionic blockade with hexamethonium also had little effect on the response of large and small coronary vessels to dipyridamole. Surprisingly neither beta-adrenergic-receptor nor ganglionic blockade abolished the rise in LV dP/dt observed after dipyridamole. Aminophylline, however, effectively eliminated the dilation of large coronary arteries and resistance coronary vessels in response to dipyridamole. In summary, as long as dipyridamole does not induce severe sustained hypotension it exerts potent effects on both coronary arterial resistance and large coronary arteries in the conscious dog. The coronary dilation is independent of reflex adrenergic activation, but appears dependent on myocardial adenosine production.     

Pharmacological stress echocardiography in the diagnosis of coronary artery disease and myocardial ischaemia: a comparison between dobutamine and dipyridamole.

The objective of this study was to relate regional wall motion abnormalities assessed by dobutamine and dipyridamole stress echocardiography to quantitative measurements of coronary artery stenoses in consecutive patients referred for coronary angiography, and to compare haemodynamic effects of and complications related to the two agents. Patients underwent stress echoes on separate days in random sequence and had coronary angiography within 3 days of stress echocardiography. Echocardiograms were assessed by two investigators unaware of the patients' coronary anatomy. Coronary angiograms were also assessed quantitatively using the computer-assisted Cardiovascular Angiography Analysis System. There were 46 consecutive patients referred for coronary angiography; 28 were using beta-antagonists. Main outcome measures were sensitivity and specificity for dobutamine and dipyridamole stress echocardiography for detection of coronary artery disease (wall motion abnormalities at rest or stress) and myocardial ischaemia (stress induced new wall motion abnormalities). Sensitivity for the detection of myocardial ischaemia was found to be 57% for dobutamine and 64% for dipyridamole. Specificities were 78% and 89% respectively. Sensitivities for detection of coronary artery disease (lesion > or = 50% diameter stenosis) was 79% for dobutamine and 82% for dipyridamole; specificities were 78% and 89% respectively. These differences between the two agents are not significant. There were no severe side effects with either agent. Mean heart rate rose significantly with both tests but was higher with dobutamine; mean systolic blood pressure rose with dobutamine and fell with dipyridamole. It was concluded that dobutamine and dipyridamole stress echocardiography have similar sensitivities and specificities for detection of myocardial ischaemia and coronary artery disease although the haemodynamic effects of the two agents are different. Both are free from serious complications.