Dipyridamole Stress Echo
Dipyridamole was the first pharmacological stress agent used for the diagnosis of coronary artery disease. Its main cardiac imaging applications stem from two fundamental properties: the hyperaemic effect and the pro-ischaemic effect, which are closely linked and can be considered as two different aspects of the same phenomenon, which requires endogenous adenosine accumulation as the common biochemical pathway. The predominance of the hyperaemic over the ischaemic manifestation depends on the dose of dipyridamole and on the underlying coronary anatomy. With relatively low intravenous dipyridamole doses, in the presence of absent to moderate coronary artery disease, the hyperaemic effect will prevail. With relatively high doses, in the presence of moderate to severe coronary artery disease, the ischaemic effect will dominate.
Pharmacology and Pathophysiology
Dipyridamole is a vasodilator test that reduces myocardial oxygen supply through flow maldistribution (steal) phenomena by stimulating A2A adenosinergic receptors present on the endothelial and smooth muscle cells of coronary arterioles. Dipyridamole increases endogenous adenosine levels by reduction of cellular reuptake and metabolism. It acts as a prodrug, increasing the interstitial levels of adenosine by the combined effect of inhibition of cellular uptake of adenosine and inhibition of its breakdown by adenosine deaminase. The peak vasodilatory effect is obtained 4–8 minutes after the end of infusion, and the half-life is about 6 hours, which suggests that the antidote aminophylline that blocks adenosine receptors should be routinely given at the end of the stress, even in negative cases. The dipyridamole dose usually employed for stress echocardiography testing (0.84 mg/kg) causes a three- to fourfold increase in coronary blood flow in normals over resting values, and a threefold increase in adenosine concentration in systemic venous blood.
Dipyridamole provokes ischaemia mainly through steal phenomena, although the coadministration of atropine may also increase myocardial oxygen demand to a significant extent. Coronary collateral circulation provides the morphological background facilitating horizontal steal. In the absence of collateral circulation, the most likely mechanism of dipyridamole-induced ischaemia is the vertical steal. The cardioprotective effect on viable myocardium can also be evoked by very low, subhyperaemic doses. The three effects – viability, hyperaemia, and ischaemia – are elicited with different, increasing doses.
The standard dipyridamole protocol consists of an intravenous infusion of 0.84 mg/kg over 10 min, in two separate infusions: 0.56 mg/kg over 4 min, followed by 4 min of no dose and, if still negative, and additional 0.28 mg/kg over 2 min. If no end-point is reached, atropine (doses of 0.25 mg up to a maximum of 1 mg) is added. The same overall dose of 0.84 mg/kg can also be given over 6 min, as currently suggested by the 2008 expert consensus statement of the European Association of Echocardiography (Figure 1). Aminophylline (240 mg IV) should be available for immediate use in case an adverse dipyridamole-related event occurs and routinely infused at the end of the test, regardless of the result. All caffeine-containing foods (coffee, tea, chocolate, bananas, and cola drinks) should be avoided for 12 h before testing, and all theophylline-containing drugs (aminophylline) should be discontinued for at least 24 h.
Feasibility and Safety
Minor, but limiting, side effects preclude the achievement of maximal pharmacological stress in <5% in patients with dipyridamole stress. Therefore, pharmacological stress tests should always be performed with an attending physician present. The safety profile of dipyridamole is shown in Table 1. Roughly two-thirds of patients studied with the high-dose dipyridamole protocol experience minor side effects such as flushing and headache, which reflect the systemic vasodilatory effect of the drug. These side effects usually disappear following administration of aminophylline at the end of testing. On rare occasions, dipyridamole-induced ischaemia becomes resistant to aminophylline. In these cases, the administration of nitrates is necessary to reverse ischaemia. Aminophylline is routinely given at the end of testing, also in negative cases. Major life-threatening complications – i.e., myocardial infarction, third-degree atrio-ventricular block, cardiac asystole, sustained ventricular tachycardia, or pulmonary edema – occur in about 1 in 1,000 cases, as shown by series encompassing over 35,000 patients- with high-dose stress echocardiography techniques.
Table 1. Safety profile of dipyridamole stress echocardiography
|Submaximal test (%)||5|
|Side effects||1/1000 exams|
|High grade AV block||++|
Indications and Contraindications
Fast, high-dose dipyridamole is an appropriate choice for pharmacological stress echocardiography used for the detection of coronary artery disease, especially in patients with inability or contraindications to exercise, or with resting images of borderline quality. Dipyridamole stress echo, as well as all stress echo techniques, is indicated in symptomatic patients with intermediate pre-test likelihood of obstructive CAD (class I, level of evidence A), and for prognostic stratification in patients with known CAD (class I, level of evidence A). It is contraindicated in asymptomatic patients as a screening test. It is appropriate in intermediate-risk patients undergoing elective high-risk noncardiac surgery, whereas appropriateness is uncertain in intermediate-risk patients undergoing intermediate-risk noncardiac surgery. Dipyridamole stress echo is technically easier than exercise or dobutamine, since the image quality is less degraded by tachycardia, hyperventilation and hypercontractility, and among pharmacological stresses, dipyridamole is safer than dobutamine. It is subjectively better tolerated by the patients than adenosine. Patients with second- or third- degree atrioventricular block or with sick sinus syndrome should not receive dipyridamole (unless they have a functioning pacemaker). Also in patients with bronchial asthma or a tendency to bronchospasm dipyridamole testing is not indicated (Table 2). Patients using dipyridamole chronically should not undergo adenosine testing for at least 24 h after withdrawal of therapy, because their blood levels of adenosine could be unpredictably high. Withdrawal of long-term theophylline or caffeine for at least 24 h is also required in order to have adenosine receptors free. Inotropic and vasodilator stresses should both be used in a stress echocardiography laboratory, for several reasons. Basically, each test has different limitations and specific advantages: a versatile use of both makes it possible to tailor the stress to the individual patient. Whatever type of stress is the laboratory’s first choice, in the case of submaximal results due to limiting side effects, the second choice should be used, to avoid the inaccuracies of nondiagnostic submaximal testing.
Table 2. Indications for dipyridamole stress echocardiography
|Diagnosis of CAD in patients unable to exercise||♦|
|Diagnosis of CAD in patients with sufficient image quality||♦|
|High-risk noncardiac surgery in intermediate risk patients||♦|
|Need to evaluate therapy efficacy in patients unable to exercise||♦|
|Intermediate-risk noncardiac surgery in intermediate-risk patients||♦|
|Diagnosis of viability in EF<35% and intolerant to dobutamine||♦|
|First-line test in patients capable to exercise and good acoustic window||♦|
|Asthma, theophylline therapy||♦|
|Chronic dipyridamole therapy, recent (<12 h) coffee, tea, chocolate ingestion||♦|
Diagnostic accuracy for detection of Coronary Artery Disease
Exercise, high-dose dobutamine, and high-dose dipyridamole (accelerated or with atropine) are equally potent ischaemic stressors for inducing wall abnormalities in presence of a critical coronary artery stenosis. Both ESC guidelines on stable angina and EAE expert consensus document on stress echocardiography underline that they have similar accuracies in detecting angiographically assessed coronary artery disease. Several meta-analysis pooled data of dipyridamole stress echo, including standard dose with high-dose and high-dose plus atropine: its accuracy has been consistently shown to be high, with an overall sensitivity of 72% (95% confidence interval: 69-75%) and overall specificity of 95% (95% confidence interval: 93-96%) in a meta-analysis of 58 studies (all generations of protocols included). A few differences should be expected depending on the subset of patients: sensitivity tends to be lower in less severe forms of single-vessel disease compared to multi-vessel disease; specificity is very high in patients with angiographically normal coronary arteries; overall accuracy is also higher in patients who had not previously suffered from myocardial infarction (83%). The overall diagnostic accuracy is therefore similar to other forms of stress testing, such as exercise echocardiography or stress SPECT.
In the videos, a positive dipyridamole stress test (mid-anterior and apical-anterior segments) is shown.
|Video 1||Video 2|
The echocardiographic hallmark of myocardial viability by pharmacological stress echocardiography is represented by a transient recovery in contractile function, which is present in viable, but not in necrotic tissue. Several studies have documented the ability of pharmacological stress echocardiography to predict functional recovery in patients with left ventricular dysfunction and chronic coronary artery disease after a revascularization procedure. By far, the widest experience is available with low-dose dobutamine stress echocardiography, the preferred stressor for assessing myocardial viability. However, in patients in whom low-dose dobutamine is unsafe or not tolerated, low-dose dipyridamole can be an effective alternative. Low-dose (0.56 mg/kg) and infra-low-dose (0.28 mg/kg) dipyridamole recognizes myocardial viability with high specificity (higher than dobutamine), good sensitivity (lower than dobutamine), and excellent prognostic value (comparable to dobutamine). The VIDA Study Group demonstrated in 307 patients with severe left ventricular dysfunction undergoing coronary revascularization, that the presence and extent of myocardial viability identified by low dose dipyridamole was associated with a higher probability of survival. The extent of myocardial viability was related to better survival when a high number of segments transiently improved their function. When coronary revascularization was undertaken in the absence or with a small area of viable myocardium, the procedure was linked to a higher incidence of cardiac death.
An example of myocardial viability with low-dose dipyridamole is shown in the video.
The prognostic value of dipyridamole stress echocardiography based on wall motion abnormalities has been proven in different subsets of patients with chronic coronary artery disease, recent myocardial infarction, or major noncardiac vascular surgery. The prognostic value has been extensively demonstrated in special patient subsets, including hypertensives, elderly patients, women, patients with left bundle branch block, with right bundle branch block and/or left anterior hemiblock, outpatients, patients with single-vessel disease, and in a chest pain unit. Dipyridamole stress results can predict subsequent cardiac death, mainly on the basis of two parameters: dipyridamole time (i.e., the interval between test onset and appearance of obvious dyssynergies) and peak wall motion score index. The prognostic value of dipyridamole stress echocardiography is independent of and additive to simpler clinical and laboratory variables such as resting echocardiography and exercise electrocardiography testing, and it has also been confirmed by prospective large-scale multicenter studies. The prognostic value of dipyridamole stress echocardiography has also been evaluated in direct head-to-head comparisons with other forms of stress testing, and it was shown to be similar to dobutamine echocardiography and probably better than perfusion scintigraphy. Ongoing ischaemic therapy at the time of testing not only lowers the diagnostic sensitivity in a way somewhat symmetrical to the effects on exercise testing ,but also heavily modulates the prognostic value of pharmacological stress echocardiography. In the presence of concomitant anti-ischaemic therapy, a positive test is more prognostically malignant, and a negative test less prognostically benign.
The diagnostic and prognostic value of coronary flow reserve
Whenever suitable technology and dedicated expertise are available, coronary flow reserve (CFR) assessment with pulsed Doppler velocity imaging on the left anterior descending (LAD) coronary artery should be performed (Figure 2). Besides the classic projections for stress echocardiography testing, specific projection for LAD coronary artery imaging should be integrated into the cardiac imaging sequence (Figure 3). The posterior descending artery and the left circumflex artery can be imaged with dedicated imaging projections, but with a lower success rate. CFR and wall motion analysis offer complementary information during stress echo. The assessment of CFR adds sensitivity for LAD disease, with a modest loss in specificity over conventional wall motion. From the pathophysiological viewpoint, wall motion positivity requires ischaemia as a necessary pre-requisite, whereas CFR can be impaired in the absence of induced ischaemia. A normal CFR has a higher negative predictive value. The combination of conventional wall motion analysis with 2D echocardiography and CFR with pulsed Doppler flowmetry of the mid-distal LAD artery has been shown to provide an added and complementary power of prognostication in patients with known or suspected coronary artery disease, normal coronary arteries, diabetes, idiopathic dilated cardiomyopathy, left bundle branch block. A reduced CFR is an additional parameter of severity in the risk stratification of the stress echocardiographic response, whereas patients with a negative test for wall motion criteria and normal CFR have a favorable outcome.
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