Pharmacologic stress testing: Understanding the options

TECHNOLOGISTS' SECTION Pharmacologic stress testing: Understanding the options Michael P. White, CNMT

Myocardial peffusion imaging (MPI) is a vital tool for determining the presence, localization, and severity of coronary artery disease. MPI allows physicians to evaluate myocardial blood flow by dilating the coronary vasculature with exercise or pharmacologic stressors. Normal arteries dilate to a much greater degree than a diseased artery; as a result, the areas beyond a stenosis in a diseased vessel appear relatively hypoperfused, After the injection of a perfusion tracer such as thallium-201, technetinm-99m sestarnibi, or Tc-99m tetrofosmin, the radiopharmaceutical is extracted by the myocardium roughly in proportion to the blood flow. Single photon emission computed tomographic (SPECT) images can then be acquired; the images reflect myocardial blood flow at the time of the injection, differentiating normal and hypoperfused areas. The evaluation of patients with known or suspected coronary artery disease has shifted to a more elderly and disabled population during the last several years. As this population continues to age, their ability to perform adequate levels of exercise decreases. Since the inception of MPI, the number of patients receiving pharmacologic stress evaluations has increased from a very small percentage to as high as 30% to 50% in some laboratories. 1 The clinical rule of thumb is that exercise perfusion imaging is performed in patients who can exercise, vasodilator stressors are given to patients who can not, and inotropic stressors are given to patients in whom vasodilators are contraindicated. Investigators have shown that the ability to exercise adequately (achieve >85% of age-predicted maximal heart rate [220 - age]) has a direct impact on myocardial perfusion defect size.Z,3 Several factors can contribute to a patient's inability to reach that end point, including but not limited to peripheral vascular disease, prior stroke, disabling arthriFrom the Nuclear Cardiology Laboratory, Division of Cardiology, Hartford Hospital, Hartford, Conn, and the University of Connecticut School of Medicine, Division of Medicine and Diagnostic Imaging and Therapeutics, Farmington, Conn. Reprint requests: Michael P. White, CNMT, Nuclear Cardiology Laboratory, Hartford Hospital, 80 Seymour St, SB222, Hartford, CT 06102; mwhite @harthosp.org. J Nucl Cardiol 1999;6:672-5. Copyright © 1999 by the American Society of Nuclear Cardiology. 1071-3581/99/$8.00 + 0 43/1/101774 672

tis, orthopedic problems (back pain, knee/hip replacement), chronic pulmonary disease, I]-blocking drug therapy, poor exercise capacity, recent myocardial infarction (<5 days), or left bundle-branch block, which can cause false-positive exercise MPI study results. 4 Several pharmacologic stressors have been developed to avoid underestimation of perfusion defects. Two vasodilator stress agents, adenosine (Adenoscan, Fujisawa USA, Deerfield, Ill) and dipyridamole (Persantine, Dupont, Wilmington, Del), are available commercially for MPI. Adenosine acts by binding to adenosinespecific cell-surface receptors; dipyridamole acts by blocking cellular uptake of adenosine, thereby increasing the extracellular levels of adenosine. Both agents can combine infusion with low-level exercise.5 This addition provides important hemodynamic data and helps to reduce side effects and the subdiaphragmatic activity associated with pharmacologic stress imaging. In addition, low-level exercise combined with dipyridamole increases the sensitivity as well as the size of the perfusion defect when compared with dipyridamole alone. 6 This improvement has not been observed with adenosine.7 A third pharmacologic stressor, the catecholamine dobutamine, has not been Food and Drug Administration approved for MPI but has commonly been used with MPI to increase heart rate, blood pressure, myocardial blood flow, and contractility. My aim is to help technologists understand the mechanisms of action for each of the 3 pharmacologic stressors mentioned and to outline the indications, adverse effects, and administration protocols of each.

Dipyridamole Dipyridamole acts as an indirect vasodilator by blocking the cellular uptake of adenosine and increasing the internally produced (endogenous) levels of adenosine that cause vasodilatation. Dipyridamole increases coronary blood flow from 2- to 5-fold above resting flow rates (more than can be achieved with exercise)8 and appears to have a greater impact on normal versus diseased vessels. In contrast with exercise stress, dipyridamole stress produces little or no increase in heart rate or blood pressure. In fact, a small decrease in blood pressure is usually noted as a result of the generalized vasodilatation.

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Table 1. Summary of side effects Symptom Chest pain (%) Dyspnea (%) Dizziness (%) Arm heaviness (%) Nausea (%) Throat tightness (%) Flushing (%) Headache (%) Claudication (%) Arrythmias (%) Atrioventricular block (%)

Exercise 13 11 3 0 0 0 0 0 5 11 0

Dipyridamole 16 3 11 0 3 5 19 55 0 0 0

Adenosine 24 16 5 8 11 17 56 24 0 0 11

Dobutamine 17 5 0 3 3 5 11 5 0 5 0

Reprinted with permission from J Nud Cardiol.15

Although significant ischemia or infarction (rarely) can result from dipyridamole infusion, electrocardiographic changes occur in only about 30% of patients with documented coronary disease. 9 In the United States, the recommended dose for dipyridamole stress testing is 0.56 mg/kg infused over a period of 4 minutes (Figure 1, A). In Europe, a dose 50% higher has been suggested for use with echocardiography. ~0 In initial studies of >3900 patients, serious side effects occurred in <1% of patients. The hyperemic phase of dipyridamole occurs in the 15- to 30-minute range. Side effects are easily countered with 50 to 100 mg of aminophylline injected over a period of 1 minute and may be repeated up to a total dose of 250 mg. Injections of aminophylline should be delayed for 1 to 2 minutes after radioisotope injection to ensure adequate tracer uptake.

Adenosine Adenosine, a naturally occurring molecule, regulates blood flow in various vascular beds, including the myocardium, and is a direct coronary vasodilator. Like dipyridamole, adenosine reduces coronary vascular resistance and increases coronary blood flow (4 to 6 times resting flow). 8 However, adenosine is fast-acting and has the shortest duration of hyperemic flow or side effects because of its half-life (<10 seconds) in contrast to the half-life of dipyridamole (>30 minutes). Adenosine is typically infused at a rate of 0.140 mg/kg/min; isotope injections are made after 3 minutes and the infusion is continued for an additional 3 minutes (Figure 1, B). In addition, radioisotope injections during the adenosine infusion should be made in a vein other than the one used for the infusion; if the same vein must be used, caution should be exercised to

avoid delivering a bolus of adenosine. Aminophylline is also used to counter any side effects from the adenosine infusion.

Dobutamine Dobutamine is a powerful, positive inotropic agent with effects similar to exercise and with similar contraindications. Unlike the vasodilators discussed previously, it increases heart rate, blood pressure, and myocardial contractility. This agent has been used by echocardiographers with success, primarily because of the increase in contractility achieved with dobutamine. Areas of normal myocardium demonstrate exaggerated wall motion, whereas areas of ischemia do not. 11 Dobutamine is given intravenously with an infusion pump at an incremental rate from 5 gg/kg/min to a maximum rate of 40 gg/kg/min 5 (Figure 1, C). The infusion is stopped when the patient reaches >85% of age-predicted maximum heart rate or other standard end points. Atropine (0.5 to 1.0 mg) is used if patients do not achieve target heart rate with the maximal dobutamine dose; an inability to achieve 85% of the maximum predicted heart rate with MPI has been associated with reduction in defect size and sensitivity. 2 Perfusion tracers are injected 1 minute before termination of the infusion. [3-Blockers such as metoprolol or esmolol should be available during dobutamine stress testing to counter any serious side effects.

Symptoms and Adverse Events Side effects of some kind may occur in 70% to 80% of patients undergoing pharmacologic stress testing. 1 Serious side effects (myocardial infarction, death) are extremely rare; the most common side effects are chest

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Journal of Nuclear Cardiology November/December 1999

Table 2. Contraindications to pharmacologic stress testing

Monitor heart rate, blood pressure, ECG I

Dipyridamole infusion

Time (minutes)

I

I

I

I

Perfusion Tracer Injection

I

I

I

1

I

I

I

Peffusion

Imaging

I

I

//

I I I I I I I I I I I I I 0

4

8

10

I

15

+

75-105

Aminophylline (if needed)

Monitor heart rate, blood pressure, ECG

I I

I I

0

I I 3

Imping

,

,

Time (minutes)

Peffusion

Aminophylline (if needed)

Adenosine Infusion

I I 6

I I

I I

I I 8

I I

I I

I I

I I

I I

//

//

15

I

I

~__

75-105

Perfusion Tracer Injection

Monitor heart rate, blood pressure, ECG I

Dobutamine Infusion

4 1 ~ 1

E~ I/kg/min•*If heart rate <85%

MPHR, atropine (0.5 - 1.0 rag) administered prior to radiopharrnaceutical injection

Time

'

'

'

'

'

(minutes)

0

3

6

9

12

I

I

1

I 30

Peffusion Tracer Injection

.'/"

I 90-120

Adenosine or dipyridamole* Bronchospastic disease Baseline hypotension (systolic blood pressure <90 mm Hg) Acute myocardial infarction (within 24 hours) Acute coronary syndromes Second-degree or higher atrioventricular block (without functioning pacemaker) Hypersensitivity to adenosine or dipyridamole Dobutaminet Severe hypotension or hypertension Uncontrolled atrial flutter or fibrillation Recurrent ventricular tachycardia Severe left ventricular outflow obstruction Recent acute myocardial infarction Acute coronary syndrome Large aortic aneurysms Decompensated heart failure *Oral dipyridamole and products containing methylxanthines should be held for 24 hours before stress testing; patients should be instructed not to eat for at least 4 hours before testing. "l'13-Blocker therapy should be discontinued for 24 to 48 hours before testing; patients should be instructed not to eat 4 hours before testing.

Peffusion Imaging

Figure 1. Flow diagram representing stress protocols for (top) dipyridamole, (middle) adenosine, and (bottom) dobutamine. For all pharmacologicstressprotocolsimagingshouldbegin 60 to 90 minutes after radiopharmaceutical injection.

tightness, flushing, nausea, dyspnea, epigastric discomfort, and light-headedness. 12-]4 However, the safety of all 3 of the agents discussed have been proven in large numbers of studies. Adenosine has also been associated with varying degrees of heart block. Dobutamine has similar side effects and includes palpitations and the more troublesome atrial or ventricular arrythmias but excludes the side effect of heart block. Recently published data evaluated the use of Tc-99m tetrofosmin in the same patients undergoing stress testing with exercise, adenosine, dipyridamole, and dobutamine. 15 More side effects were seen with adenosine than the other stresses; however, all were well-tolerated, and side effects resolved quickly after the infusion was completed (Table 1). Contralndications and Preparations Pharmacologic stress testing may not always be possible if a contraindication exists (Table 2). Adenosine and

dipyridamole testing require that the patient not ingest certain products for at least 24 hours, including methylxanthine-containing products (coffee, tea, chocolate, over-the-counter cold preparations, etc), theophylline, and oral persantine. Dobutamine testing requires that 13blocker therapy be withheld for 24 to 48 hours. All stresstest patients should be instructed to refrain from eating for at least 4 hours before testing. Conclusion Pharmacologic stress testing is not always the lastresort method of evaluating a patient. There are circumstances in which pharmacologic testing is preferred to exercise--for example, in the first days after acute myocardial infarction, when exercise testing is contraindicated. However, several studies have demonstrated that the safety and efficacy of dipyridamole stress testing within the first 48 hours after a myocardial infarction provides valuable information to aid in the decision to refer the patient for a more invasive procedure or to take a conservative approach. Second, a phenomenon associated with left bundle-branch block is anteroseptal defects during exercise treadmill testing, which are less commonly seen with vasodilator stress.

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The choice of pharmacologic stress agent remains with the referring physician, taking into account the known side effects, the patient's ability to tolerate them, and the desired information. All pharmacologic stress agents discussed yield similar diagnostic accuracy for detecting coronary artery disease, although vasodilators produce higher flow rates than catecholamines. Furthermore, the addition of low-level exercise improves the target-to-background ratio and reduces side effects. Most importantly, pharmacologic stress offers physicians a means to evaluate a patient who is unable to exercise adequately or not at all.

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8. 9.

10.

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