Version June 2024
INTRODUCTION — For the majority of patients undergoing a stress test, the primary goal is to identify myocardial ischemia due to coronary heart disease (CHD). Depending on the stress test modality, ischemia may manifest in the form of symptoms, hemodynamic findings, electrocardiographic abnormalities, stress-induced perfusion defects, or regional wall motion abnormalities.
In patients with known or suspected CHD, the presence and extent of ischemia on stress testing are used to guide medical therapy and/or determine the need for further diagnostic and therapeutic procedures. Thus, factors that impact the sensitivity and specificity of stress testing for the detection of ischemia may lead to either patients not receiving appropriate therapy or to unnecessary procedures and treatment with their attendant risks and costs, respectively. Many factors (eg, pre-existing electrocardiographic abnormalities, sex, body habitus, etc) can affect a stress test’s ability to accurately identify myocardial ischemia.
The interaction between major cardiovascular medications, dietary factors (namely items containing caffeine), and stress testing and our recommendations for continuing or discontinuing the individual drug or dietary component will be discussed here. Indications and procedures for stress testing are discussed separately. (See "Selecting the optimal cardiac stress test" and "Stress testing for the diagnosis of obstructive coronary heart disease" and "Exercise ECG testing: Performing the test and interpreting the ECG results" and "Overview of stress radionuclide myocardial perfusion imaging" and "Overview of stress echocardiography".)
STRESS TESTING CONCEPTS — Before discussing the impact of medications and dietary factors on the detection of myocardial ischemia on stress testing, important concepts regarding stress testing for coronary heart disease (CHD) must be considered.
●The manifestations of CHD identified following stress with exercise or dobutamine require the ability to increase myocardial oxygen demand by increasing heart rate, blood pressure, and/or left ventricular contractility above a certain threshold to provoke myocardial ischemia. Vasodilator-stress induced manifestations of CHD depend on a hyperemic coronary blood flow differential between normal and abnormal coronary arteries, and are not dependent on increasing heart rate, blood pressure, or contractility. (See "Exercise ECG testing: Performing the test and interpreting the ECG results" and "Overview of stress radionuclide myocardial perfusion imaging" and "Overview of stress echocardiography".)
●While the presence of myocardial ischemia on stress testing generally correlates with the extent and severity of angiographic epicardial coronary artery stenosis, in a subset of patients, microvascular dysfunction and/or lesions not visible by standard invasive coronary angiography may produce myocardial ischemia on stress testing. Thus, a positive stress test in the absence of angiographic stenosis is not always a false positive test given the limitations of conventional coronary angiography. (See "Microvascular angina: Angina pectoris with normal coronary arteries".)
●One of the goals of medical and procedural therapies to treat CHD is to alleviate symptoms by reducing myocardial ischemia. As such, the goal of stress testing in patients with established (and treated) CHD is to consider the effectiveness of therapy, and this goal should be taken into consideration when deciding whether to continue or discontinue medications for stress testing.
●Many factors influence a stress test’s ability to identify myocardial ischemia. For the exercise electrocardiogram, common factors that affect the sensitivity and/or specificity include pre-existing electrocardiographic abnormalities, workload, sex, and prior coronary revascularization. For most imaging modalities, large body habitus may be associated with artifacts and limitations that can reduce both the sensitivity and the specificity of the test. Thus, although certain medications and dietary elements may affect the performance of both exercise and pharmacologic stress testing, a comprehensive understanding of the limitations of invasive coronary angiography in identifying CHD as well as a review of other factors that may affect test performance are crucial to clinical decision making. (See "Exercise ECG testing: Performing the test and interpreting the ECG results" and "Overview of stress radionuclide myocardial perfusion imaging" and "Overview of stress echocardiography".)
OUR APPROACH TO MEDICATIONS AND STRESS TESTING — In general, our approach, which is consistent with professional society guidelines, is to continue all or nearly all medications at the time of stress testing. Rarely, if the stress test is being performed primarily to diagnose the presence and/or extent of coronary heart disease (CHD), we will withhold certain medication(s) prior to stress testing (eg, methylxanthines, beta blockers, calcium channel blockers) in order to optimize the sensitivity and specificity of the test, but only after weighing the risks and benefits of withholding the medication(s) and considering possible alternatives.
The decision to continue or discontinue any medication(s) or to make certain dietary modifications prior to stress testing should be made on an individual basis. Factors involved in this decision include the indication for stress testing, indication for any medication(s) the patient is taking which may need to be stopped, and the potential harm to the patient from temporarily discontinuing the medication(s).
To obtain the maximal benefit of stopping any medication(s), the medication(s) should be withheld for four to five half-lives prior to the stress test being performed. Discontinuation of therapies for four to five half-lives will reverse the hemodynamic impact of antianginal treatment with nitrates, beta blockers, and calcium channel blockers. This can be accomplished, when practical and safe for the patient, by withholding antianginal medications such as beta blockers, calcium channel blockers, and nitrates for at least 48 hours prior to a diagnostic stress test [1].
MEDICATIONS THAT MAY REDUCE TEST SENSITIVITY — There are a number of medications and substances (eg, beta blockers, calcium channel blockers, caffeine, etc) that may alter the sensitivity of stress testing. In general, these medications impact heart rate, blood pressure, or both, with the notable exception of methylxanthines, which impact vasodilator stress testing via their effect on adenosine 2A receptors.
Methylxanthines — Methylated xanthines (ie, methylxanthines) should be withheld prior to stress testing with vasodilator agents. In our practice, we withhold caffeine-containing products (a list of which can be accessed here) and theophylline for at least 12 hours before the test and dipyridamole-containing medications for at least 48 hours, a practice that is consistent with professional society guidelines [1].
If caffeine has been consumed within 12 hours of the start of the vasodilator infusion, options include:
●Exercise instead of vasodilator as the stress mechanism, if feasible.
●Dobutamine instead of vasodilator stress as the stress mechanism.
●A two-day rest-stress SPECT MPI protocol with resting imaging on day 1 and vasodilator stress testing and imaging on day 2 with no caffeine for at least 12 hours prior to the vasodilator stress administration.
●Rescheduling on a different day and reinforcing the importance of not consuming caffeine for at least 12 hours prior to the test.
In patients with recent (<48 hours) use of oral dipyridamole or medications containing dipyridamole (eg, Aggrenox), adenosine and regadenoson are contraindicated; however, exercise testing, or pharmacologic stress testing utilizing IV dipyridamole or dobutamine may be administered safely and efficaciously [1].
Methylxanthines, including caffeine, aminophylline, theophylline, pentoxifylline, and theobromine, are competitive inhibitors of adenosine receptors and may significantly attenuate the coronary vasodilatory effects of all vasodilator stress agents used for stress imaging through its effects on A2A receptors, which mediate coronary vasodilation. In a multicenter, double-blind, randomized study to investigate the effects of caffeine on radionuclide myocardial perfusion imaging (rMPI) in patients with coronary heart disease (CHD), individuals with at least one segment with a reversible defect received caffeine tablets (200 or 400 mg) or placebo 90 minutes before a repeat regadenoson stress SPECT five days after the initial study [2]. The mean number of segments with reversible defects decreased in both groups who received caffeine, compared with no significant change in the placebo group.
These findings are generally in agreement with nonrandomized smaller human studies and animal experiments. However, two studies (one using positron emission tomography [PET], one using SPECT) have reported discordant findings to those described in the randomized trial of caffeine [3,4]. Both studies were small (fewer than 50 patients), and the average dose of caffeine was 200 mg in one study [4] and significantly lower in the other study [3].
Beta blockers — In our practice, we do not routinely discontinue beta blocker therapy prior to stress testing. If the stress test is being performed primarily to diagnose the presence and/or extent of CHD, we will rarely withhold beta blocker therapy prior to stress testing in order to optimize the sensitivity and specificity of the test, but only after weighing the risks and benefits of withholding the medication and considering possible alternatives. This is done on a case-by-case basis. Other practices may routinely withhold beta blocker therapy prior to testing in order to enhance test sensitivity [5].
The effects of beta blockers on the performance of both exercise testing and pharmacologic stress imaging have been inconsistent, with insufficient data to recommend withholding beta blocker therapy in all patients referred for stress testing. This is in line with 2002 American College of Cardiology/American Heart Association (ACC/AHA) Exercise Testing Guidelines and the 2016 American Society of Nuclear Cardiology (ASNC) imaging guidelines for SPECT nuclear cardiology procedures, which state that the discontinuation of these medications is left to the discretion of the referring provider and that it appears unnecessary for physicians to accept the risk of stopping beta blockers before testing when a patient exhibits possible symptoms of ischemia [1,6].
Beta blockers decrease myocardial oxygen demand by reducing myocardial contractility, heart rate, and blood pressure.
●Nonselective beta blockers share some of the same pathways as the adenosine 2A receptors through their interaction with beta-2 receptors and may interfere with adenosine induced vasodilation [7-11]. This is probably the same mechanism which interferes with dobutamine induced vasodilation [12-14].
●Nonselective beta blockers will also prevent the paradoxical vasoconstriction in abnormal coronary arteries [7,15,16]. The resulting favorable effect on vasomotor tone may have the added benefit of preventing coronary steal and improving endocardial perfusion [17].
●Conversely, selective beta blockers without vasodilating properties may cause vasoconstriction and decreased flow in normal coronaries.
Despite these mechanistic properties of beta blockers and decades of exercise and pharmacologic stress testing, there are conflicting data and no large-scale studies on the effect of beta blocker use on the performance of stress testing. No consensus exists on withholding or continuing beta-blocker treatment before either exercise or pharmacologic stress testing.
●Although beta blockers have been shown to markedly reduce maximal exercise heart rate, no differences in exercise stress test performance were found in a cohort of 3047 men being evaluated for possible CHD (including 2847 taking beta blockers and 200 not taking beta blockers) [18].
●For exercise rMPI, small nonrandomized clinical studies suggest an overall decrease in the sensitivity in detecting coronary artery disease (CAD) in patients on beta blockers [19,20]. In one of these studies, patients with chronic stable angina and CHD undergoing exercise thallium-201 SPECT demonstrated significantly smaller perfusion defects both with exercise and with redistribution in the group receiving beta blockers compared with placebo even though beta blockers were held 48 hours before the stress test [19].
●Small retrospective cohort studies have evaluated the effects of beta-blocker use on vasodilator stress rMPI with mixed results, with studies showing both reduced sensitivity and no reduction in sensitivity for detection of CHD with versus without beta blockers [11,21].
●Studies have also shown decreased sensitivity of stress echocardiography for the detection of ischemia in patients treated with beta blockers. The anti-ischemic effects of propranolol were demonstrated in a study of 17 patients with known reversible defects on rMPI who subsequently underwent simultaneous dobutamine stress echocardiography and technetium-99m sestamibi MPI both before and after propranolol administration; heart rate, rate-pressure product, extent and severity of perfusion defects, and the number of abnormal echocardiographic segments were smaller after propranolol administration [22].
In patients who fail to achieve 85 percent of their maximal predicted heart rate during dobutamine stress testing, atropine has been used to augment the heart rate response. Administration of atropine improves the hemodynamic response to dobutamine in the setting of beta-blocker administration, decreases the number of inconclusive tests [23], and increases the recognition of ischemia [24]. However, the effect of beta blockers to reduce the severity of dobutamine-induced echocardiographic segmental wall motion abnormalities is not completely abolished with atropine administration [25]. Again, however, studies are limited in number, sample size, and study design.
Calcium channel blockers — In our practice, we do not routinely discontinue calcium channel blocker therapy prior to stress testing. Rarely, if the stress test is being performed primarily to diagnose the presence and/or extent of CHD, we will withhold calcium channel blocker therapy prior to stress testing in order to optimize the sensitivity and specificity of the test, but only after weighing the risks and benefits of withholding the medications and considering possible alternatives. This is done on a case-by-case basis.
Similar to beta blockers, studies examining the effects of calcium channel blockers on stress testing performance have been small and nonrandomized. However, given the small number of studies, there is insufficient evidence to recommend withholding calcium channel blocker therapy in all patients referred for stress testing. This is in line with the 2016 ASNC imaging guidelines for SPECT nuclear cardiology procedures, which state that the discontinuation of these medications is left to the discretion of the referring provider [1]. For example, if the patient has known CHD on medical therapy and requires a stress test for follow-up assessment, we would perform the stress test while the patient remains on the calcium channel blocker to test the effectiveness of medical therapy. On the other hand, if a patient on a calcium channel blocker for hypertension is referred for new symptoms suggesting angina in the absence of known CHD, the provider may stop the calcium channel blocker prior to stress testing if it is deemed safe to do so.
Calcium channel blockers have effective antianginal properties that are comparable to beta blockers [26]. However, they are different in their effect on the myocardium (contractility, heart rate) and peripheral vasculature. Calcium channel blockers increase coronary blood flow and reduce myocardial oxygen demand, which results in improved diastolic and systolic function [27,28].
●Three studies of patients with chronic stable angina receiving nifedipine showed improvements in exercise duration and ST segment changes during exercise stress testing compared with those who received placebo [29-31].
●In another study of patients who underwent dobutamine-atropine stress echocardiography who had angiographically documented CHD, antianginal treatment with calcium channel blockers (nifedipine or diltiazem) decreased the sensitivity of the test for detection of ischemia from 100 to 88 percent, increased the requirement for atropine administration, and reduced the severity of echocardiographic findings [32].
●In patients who underwent dipyridamole thallium-201 MPI with and without anti-ischemic treatment (serving as their own controls), treatment with antianginal drugs (calcium channel blockers in 81 percent) resulted in reduced size and severity of MPI defects [33]. This study also demonstrated a reduction in sensitivity for the detection of single vessel CHD with the use of calcium channel blockers.
Nitrates — Similar to other vasoactive medications, studies examining the effects of nitrates on stress testing performance have been small and nonrandomized. Furthermore, long-acting nitrates are generally not utilized in patients without presumed or known CHD. There is insufficient evidence to recommend withholding nitrate therapy in patients referred for stress testing, especially since testing in situations following nitrate treatment may be to assess the effectiveness of medical therapy. This is in line with the 2016 ASNC imaging guidelines for SPECT nuclear cardiology procedures, which state that the discontinuation of these medications is left to the discretion of the referring provider [1].
●Nitrates have been shown to dilate large epicardial vessels and smaller resistance vessels and also decrease diastolic filling pressure, thereby increasing coronary perfusion, decreasing coronary steal, and improving myocardial perfusion [34-37].
●Nitrates may also prevent exercise-induced paradoxical coronary vasoconstriction [38].
●Patients with known CHD undergoing exercise stress testing have been shown to have a delay in the onset and reduced magnitude of ST-segment depression with long-acting nitrate administration [39].
Nitrate therapy has been shown to reduce the extent and severity of ischemia assessed by exercise MPI despite having no significant effect on heart rate, blood pressure, or double product (product of heart rate and systolic blood pressure) [40,41]. Similar results have been observed in patients receiving nitrate therapy who have undergone dobutamine stress echocardiography and dipyridamole stress thallium-201 MPI [32,33].
Angiotensin converting enzyme inhibitors and angiotensin receptor blockers — In our practice, we do not discontinue therapy with an angiotensin converting enzyme inhibitor (ACEI) or an angiotensin receptor blocker (ARB) prior to stress testing.
In animal experiments, ACEI have been shown to increase coronary blood flow at rest and during myocardial ischemia as well as to reduce experimental infarct size [42-44]. These beneficial effects are assumed to be secondary to nitric oxide-dependent vasodilation and accumulation of bradykinin. In human studies, ACEI have demonstrated several beneficial hemodynamic effects, including attenuation of acetylcholine-induced coronary vasoconstriction [45] improvement in endothelium-dependent brachial artery flow-mediated vasodilation [46], attenuation of sympathetic coronary vasoconstriction [47], and optimization of myocardial metabolism [48].
One study in humans measuring myocardial blood flow (using PET) in symptomatic patients with CHD demonstrated that the acute administration of quinaprilat 10 mg IV increased myocardial blood flow to ischemic regions [49]. However, other studies of patients with known myocardial ischemia and CHD treated with ACEI have shown no reduction in ischemia at one and three weeks but did demonstrate increased time to ST segment depression (ie, ischemia) only after 12 weeks of treatment [50,51].
ARBs may improve endothelial function, as shown by reports of their favorable effect on brachial artery flow-mediated vasodilation and improvement in coronary microvascular function and flow reserve [52,53]. One study of myocardial blood flow (using PET and N-13 ammonia) in 16 patients with mild stable coronary heart disease revealed improved endothelial-dependent flow increase and adenosine-induced vasodilation following valsartan administration [54]. Notably, the improvement in coronary flow preceded any reduction in blood pressure.
L-arginine — In our practice, we do not routinely discontinue L-arginine therapy prior to stress testing, given the limited data.
L-arginine administration improves brachial artery flow-mediated dilation and augments coronary endothelium-dependent vasodilation in patients with microvascular angina [55,56]. In a double-blind, placebo-controlled study of 22 patients with stable angina, oral supplementation of 6 g/day of L-arginine increased exercise duration, maximum workload, and time to onset of ST-segment depression [57].
MEDICATIONS THAT MAY REDUCE THE SPECIFICITY OF THE STRESS TEST — There are fewer medications and substances that may reduce the specificity of the test compared with those that may reduce the sensitivity of the test. In general, these medications alter the response of the electrocardiogram (ECG), producing changes suggestive of ischemia when no ischemia is present.
Digoxin — Digoxin is probably the most widely known medication that can produce ECG changes at rest and during exercise stress testing in the absence of angiographic coronary heart disease (CHD). In our practice, we do not routinely discontinue digoxin therapy prior to stress testing. This is in agreement with the 2002 American College of Cardiology/American Heart Association (ACC/AHA) exercise testing guidelines which recommend beginning with an exercise ECG stress test in patients taking digoxin with less than 1 mm of ST depression. However, in patients taking digoxin with greater than 1 mm resting ST depression, or those in whom an exercise test without imaging was nondiagnostic or indeterminate, an exercise test with imaging may be performed [6].
Digoxin can induce coronary vasoconstriction leading to decreased subendocardial perfusion and may also increase intracellular calcium concentrations [34,58]. However, the effect on ST depression may not be due to this vasoconstriction since the administration of nitrates has been shown to reverse the vasoconstriction but not the ECG changes [58]. The effect of digoxin on Na/K ATPase may change the cellular membrane depolarization, and this could also result in ECG changes in the absence of ischemia.
In two studies, digoxin produced abnormal exercise-induced ST depression in 25 to 40 percent of apparently healthy normal subjects, and the effect is directly related to age [59,60]. This effect was not present after the discontinuation of digoxin for 12 days, but the latter is not a practical approach in the clinical setting [59].
Estrogens — In our practice, we do not routinely discontinue estrogen therapy prior to stress testing.
In general, there is a paucity of conclusive data regarding the effects of estrogen on stress testing.
●In premenopausal women, the accuracy of the exercise ECG has been shown to vary with estrogen levels during the menstrual cycle [61].
●One study demonstrated more ST segment depression in 90 percent of patients with established CHD after two weeks of treatment with estrogens [62]. In another study, normalization of an abnormal ST segment response to exercise was seen in women undergoing repeat exercise testing following an intervening oophorectomy [63].
●Another study of 404 women with normal radionuclide myocardial perfusion imaging (rMPI) following exercise stress testing reported a significantly higher rate of ECG positivity in women taking hormone replacement therapy [64].
These studies, however, have many limitations, and no current recommendations exist to withhold estrogen therapy prior to stress testing or to use specific types of tests.
Diuretics — Stress testing should not be performed in patients with profound hypokalemia. For potassium levels between 3 and 4 mEq/L, stress testing may be considered on a case-by-case basis [65,66].
Diuretics can be associated with ECG changes due to electrolyte imbalances. In patients with significant hypokalemia (below 3 mEq/L), exercise testing should be delayed until adequate potassium repletion has occurred. The ECG changes are less prominent at potassium levels between 3 and 4 mEq/L, and patients may begin with exercise testing without imaging, but others may also begin with stress imaging, especially if more prominent ECG changes are present.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stress testing and cardiopulmonary exercise testing".)
SUMMARY AND RECOMMENDATIONS
●Medications and dietary ingestions may reduce the ability of an exercise electrocardiogram (ECG) or stress imaging test to detect myocardial ischemia and coronary heart disease (CHD). The decision to continue or withhold any medications or dietary ingestions prior to stress testing must be individualized according to the specific medication or the dietary ingestion, and the patient-specific factors. (See 'Introduction' above and 'Stress testing concepts' above.)
●In general, our approach, which is consistent with professional society guidelines, is to continue all or nearly all medications at the time of stress testing. Rarely, if the stress test is being performed primarily to diagnose the presence and/or extent of CHD, we will withhold certain medication(s) prior to stress testing, but only after weighing the risks and benefits of withholding the medication(s) and considering possible alternatives. (See 'Our approach to medications and stress testing' above.)
•We ask patients to withhold caffeine at least 12 hours and dipyridamole-containing medications for at least 48 hours prior to vasodilator stress testing. If caffeine has been consumed, then options include (see 'Methylxanthines' above):
-Exercise stress testing instead of vasodilator stress testing (if feasible)
-Dobutamine stress testing instead of vasodilator stress testing
-A two-day rest-stress SPECT MPI protocol with resting imaging on day 1 and stress testing and imaging on day 2 following at least 12 hours without caffeine
-Having the patient return on a different day and reinforce the importance of not consuming caffeine for at least 12 hours prior to the test
•Beta blockers, calcium channel blockers, and nitrates – We do not routinely discontinue therapy with beta blockers, calcium channel blockers, and nitrates in all patients referred for stress testing. This approach is based on limited data showing inconsistent results from withholding therapy. However, in select patients in whom the stress test is being performed primarily to diagnose the presence and/or extent of CHD, we will rarely withhold therapy prior to stress testing in order to optimize the sensitivity and specificity of the test, but only after weighing the risks and benefits of withholding the medications and considering possible alternatives. This is done on a case-by-case basis.
If testing is performed to evaluate the effectiveness of therapy in patients with known CHD, then treatment with beta blockers, calcium channel blockers, and nitrates should be continued. (See 'Beta blockers' above and 'Calcium channel blockers' above and 'Nitrates' above.)
•Angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARBs) – We do not discontinue therapy with an ACEI or ARB prior to stress testing, based on limited available data which are inconclusive regarding the effect of ACEIs or ARBs on the results. (See 'Angiotensin converting enzyme inhibitors and angiotensin receptor blockers' above.)
•Digoxin – While digoxin can cause ECG changes during exercise stress testing in the absence of angiographic CHD, we do not routinely discontinue digoxin therapy prior to stress testing. In patients taking digoxin with greater than 1 mm resting ST depression, or those in whom an exercise test without imaging was nondiagnostic or indeterminate, an exercise test with imaging should be performed. (See 'Digoxin' above.)
•Diuretics – Stress testing should not be performed in patients with profound hypokalemia. In our practice, we do not routinely discontinue diuretics prior to stress testing. (See 'Diuretics' above.)
ACKNOWLEDGMENT — The authors and UpToDate thank Dr. Sarkis Baghdasarian, who contributed to earlier versions of this topic review.
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