A Review of the Role of Tests of Coronary Reactivity in Clinical Practice.

Vasoreactivity testing is used by cardiologists in the diagnosis of coronary spasm endotypes, such as epicardial and microvascular spasm. Intracoronary injection of acetylcholine and ergonovine is defined as a standard class I method according to the Coronary Vasomotion Disorder (COVADIS) Group. Because single vasoreactivity testing may have some clinical limitations in detecting the presence of coronary spasm, supplementary or sequential vasoreactivity testing should be reconsidered. The majority of cardiologists do not consider pseudonegative results when performing these vasoreactivity tests. Vasoreactivity testing may have some limitations when it comes to documenting clinical spasm. In the future, cardiologists around the world should use multiple vasoreactivity tests to verify the presence or absence of epicardial and microvascular spasms in the cardiac catheterisation laboratory.

Clinical Limitations of Vasoreactivity Testing as a Diagnostic Tool in Patients with Vasospastic Angina.

The Japanese Circulation Society guidelines recommend a class I vasoreactivity test to diagnose patients with vasospastic angina (VSA). However, the acetylcholine or ergonovine test has been established as the gold standard for variant angina (VA). The sensitivity and specificity of intracoronary vasoreactivity testing in patients with VA were acceptable. Cardiologists have employed these vasoreactivity tests to conveniently diagnose the presence of coronary spasms in patients with all VSA. The majority of VSAs may have lower disease activity than VA cases. We have summarized the usefulness of spasm provocation tests in patients with VA and VSA. A positive-provoked spasm diagnosed by standard vasoreactivity testing may indicate a disease state similar to that of VA, whereas a negative-provoked spasm after standard vasoreactivity testing may indicate a lower disease state than that of VA. Cardiologists should reconsider the limited usefulness of vasoreactivity testing when diagnosing the presence of coronary spasms in all VSAs, but not VA.

Safety and potential usefulness of sequential intracoronary acetylcholine and ergonovine administration for spasm provocation testing.

BACKGROUND: Although guidelines recommend intracoronary acetylcholine (ACh) and ergonovine (ER) provocation testing for diagnosis of vasospastic angina, the feasibility and safety of sequential (combined) use of both pharmacological agents during the same catheterization session remain unclear. OBJECTIVES: In this study, we investigated the feasibility and safety of sequential intracoronary ACh and ER administration for coronary spasm provocation testing. METHODS: The study included 235 patients who showed positive results on ACh and ER provocation testing. Initial intracoronary ACh administration was followed by ER administration for left coronary artery (LCA) spasm provocation testing. Subsequently, the right coronary artery (RCA) was subjected to sequential ACh and ER administration for provocation testing. The primary outcome of the study was the safety of sequential intracoronary ACh and ER provocation testing, which was assessed based on a composite of all-cause death, sustained ventricular tachycardia and fibrillation, and cardiogenic shock. RESULTS: Even in patients with negative results on sequential intracoronary ACh and ER provocation testing in the LCA and only ACh administration into the RCA, additional administration of ER into the RCA showed a positive provocation test result in 33 of 235 (14.0%) patients; three (1.3%) patients developed adverse effects (cardiogenic shock occurred in all cases) during LCA provocation testing. We observed no deaths attributable to spasm provocation testing. CONCLUSION: Sequential administration of intracoronary ACh and ER was associated with a relatively low major complication rate and may be safe and potentially useful for diagnosis of vasospastic angina.

Safety and potential usefulness of novel coronary spasm provocation testing protocolCoronary spasm represents a subtype of ischemic heart disease, potentially leading to heart attack. Although guidelines recommend intracoronary administration of different pharmacological agents, acetylcholine (ACh) and ergonovine (ER), for coronary spasm provocation testing, the feasibility and safety of sequential (combined) use of both drugs are unclear. In the present study, we showed that sequential administration of intracoronary ACh and ER was associated with a relatively low major complication rate and may be safe and potentially useful for diagnosis of coronary vasospasm.

Insights into the invasive diagnostic challenges of coronary artery vasospasm - A systematic review.

Coronary provocation testing is an essential diagnostic procedure when evaluating vasospastic angina. Invasive methods using acetylcholine or ergonovine are considered the current gold standard. Despite efforts from global cardiovascular institutions, current protocols vary in dosage, administration time, and procedural approach. In addition, concerns over the specificity of findings and potential complications have limited routine uptake of this procedure in clinical practice. This systematic review evaluates current diagnostic protocols, focusing on invasive provocation testing. We included studies using intracoronary provocation testing with acetylcholine or ergonovine for the assessment of coronary artery vasospasm that detailed specific elements of the procedure (dosage, administration time, etc.) and included ≥50 patients. A total of 28 articles met strict inclusion criteria. Our review highlights the heterogeneity between current diagnostic protocols for invasive provocation testing. We believe standardization of a diagnostic protocol will encourage both current and future cardiologists to incorporate such procedures in the evaluation of variant angina.

Pharmacological coronary spasm provocative testing in clinical practice: A French Coronary Atheroma and Interventional Cardiology Group (GACI) position paper.

Vasospastic angina, also described as Prinzmetal angina, was first described as a variant form of angina at rest with transient ST-segment elevation; it is common and present in many clinical scenarios, including chronic and acute coronary syndromes, sudden cardiac death, arrhythmia and syncope. However, vasospastic angina remains underdiagnosed, and provocative tests are rarely performed. The gold-standard diagnostic approach uses invasive coronary angiography to induce coronary spasm using ergonovine, methylergonovine or acetylcholine as provocative stimuli. The lack of uniform protocol decreases the use and performance of these tests, accounting for vasospastic angina underestimation. This position paper from the French Coronary Atheroma and Interventional Cardiology Group (GACI) aims to review the indications for provocative tests, the testing conditions, drug protocols and positivity criteria.

Non-invasive diagnosis of vasospastic angina.

Vasospastic angina (VSA), or variant angina, is an under-recognized cause of chest pain and myocardial infarction, especially in Western countries. VSA leads to a declined quality of life and is associated with increased morbidity and mortality. Currently, the diagnosis of VSA relies on invasive testing that requires the direct intracoronary administration of ergonovine or acetylcholine. However, invasive vasoreactivity testing is underutilized. Several non-invasive imaging alternatives have been proposed to screen for VSA. This review aims to discuss the strengths and limitations of available non-invasive imaging tests for vasospastic angina.

Intra-brachial ergonovine, not acetylcholine, is associated with radial artery vasospasm in patients with coronary vasospasm.

BACKGROUND: The intracoronary provocation test is expensive and may cause complications. Therefore, we investigated the sensitivity, specificity and safety of different drug- and dose-peripheral artery provocation tests in the diagnosis of coronary artery spasm (CAS). METHODS: The patients who had repeated chest pain as well as both coronary and radial stenoses <50% were selected. These patients were divided into CAS group (n = 24) and control group (n = 33) after the intracoronary ergonovine provocation test. All patients underwent radial artery provocation tests at different dose-acetylcholine (200 µg, 400 µg and 800 µg) and ergonovine (60 µg, 100 µg and 160 µg). The predictive values of radial provocation tests for CAS diagnosis were analysed using receiver operator characteristic (ROC) curves. RESULTS: In radial acetylcholine provocation tests, 200 µg of acetylcholine failed to induce radial artery spasm, and the radial artery stenosis degree was not significantly different between the CAS group and control group at 400 µg and 800 µg of acetylcholine (all p > 0.05). In the radial artery ergonovine provocation tests, the radial artery stenosis degree was all significantly higher in the CAS group than in the control group at the three different doses (all p < 0.05). The specificity and sensitivity of radial ergonovine provocation tests were 90.91% and 50.00% at 60 µg, 96.97% and 66.67% at 100 µg, and 90.91% and 95.83% at 160 µg. Only the radial 160 µg-ergonovine provocation test caused CAS in one case. CONCLUSION: The radial acetylcholine provocation test has no diagnostic value for CAS. The radial 160 µg-ergonovine provocation test has higher sensitivity and specificity for CAS diagnosis, but its safety should be paid attention to.

[Multicenter, Randomized, Double-Blind, and Positive Drug-Controlled Clinical Trial on Prevention of Postpartum Hemorrhage after Vaginal Delivery with Ergometrine Maleate].

Objective: To evaluate the safety and efficacy of using ergometrine maleate injection combined with oxytocin injection, with oxytocin injection as the control, to prevent postpartum hemorrhage after vaginal delivery. Methods: A total of 305 cases who underwent vaginal delivery between December 2018 and November 2019 in 16 hospitals across China were enrolled and included in the full analysis set (FAS) and the safety analysis set (SS). Among the 299 subjects who completed the trial, 277 were included in the per protocol set (PPS). The subjects were randomly assigned by 1∶1 ratio to two groups, 152 cases in Group A, the experimental group receiving oxytocin injection plus ergometrine injection, and 153 cases in Group B, the control group, receiving oxytocin injection. The difference in total bleeding volume at 2 h, 6 h and 24 h postpartum in the two groups was documented and compared. Other measures were also compared between the two groups, including the proportion of additional use of uterotonics and hemostatic drugs or other hemostatic measures 2 h and 24 h postpartum, the proportion of subjects needing blood transfusion, the time of placenta retention, proportion of subjects with prolonged hospital stay due to uterine asthenia, the vital signs, lab test indicators and the incidence of adverse reactions in the two groups. Results: The total bleeding volume at 2 h, 6 h and 24 h after delivery was significantly lower in the experimental group (P<0.05). There was no significant difference between the two groups in the proportion of additional use of uterotonics and hemostatic drugs or other hemostatic measures 2 h and 24 h postpartum, the proportion of subjects needing blood transfusion and the time of placenta retention, heart rate, respiration, lab test indicators, or the incidence of adverse reaction (P>0.05). Conclusion: Ergometrine maleate injection showed evident therapeutic efficacy in preventing hemorrhage after vaginal delivery, causing fewer adverse reactions and ensuring greater safety, and therefore, presenting promising prospects for clinical application.

Recurrent Myocardial Infarction in a Patient With MINOCA and a Negative Ergometrine Provocation Test.

This case highlights the diagnostic challenge associated with coronary vasospasm, especially when accompanied by no provoked spasms on the ergometrine test in the acute setting of myocardial infarction with nonobstructive coronary arteries. Inexplicable myocardial infarction with nonobstructive coronary arteries after extensive evaluation should alert the clinician to the possibility of coronary vasospasm and the necessity of acetylcholine provocative testing in spite of a negative ergometrine provocation test. (Level of Difficulty: Intermediate.).

Nilotinib related acute myocardial infarction with nonobstructive coronary arteries: a case report and literature review.

BACKGROUND: Myocardial Ischemia with No Obstructive Coronary Artery Disease (MINOCA) is a common cause of type 2 acute myocardial infarction (AMI) which requires careful differential diagnosis. Coronary artery spasm (CAS) syndrome is one etiology that can lead to MINOCA. Nilotinib, a targeted treatment for chronic myeloid leukemia (CML), has been reported to be related with increased risk of adverse vascular events. CASE PRESENTATION: A 67-year-old male patient was admitted to hospital with acute chest pain. He had a past medical history of CML and a history of treatment with nilotinib for 12 months. Coronary angiography (CAG) showed no significant stenosis. Since the onset of angina was generally in the early morning, and ECG and echocardiography suggested right coronary artery (RCA) disease, an ergonovine provocation test was performed to confirm the diagnosis of CAS. After intracoronary administration of ergonovine, middle and distal RCA showed over 90% vasoconstriction. Nilotinib related MINOCA, CAS and CML were diagnosed. Lifestyle changes (cessation of smoking), anti-spasmodics, statin treatment and adjustment of the nilotinib dose (from 200 mg bid, to 150 mg bid) were recommended for this patient. Six-month's follow-up showed good recovery with no onsets of angina. CONCLUSIONS: Physicians should be vigilant to adverse vascular events when treating patients who have been prescribed nilotinib. It is suggested that in patients with MINOCA who have a history of treatment with nilotinib, CAS-induced MINOCA should be included in the differential diagnosis. Further studies are needed to clarify the mechanism and to find better management.

Intracoronary ergonovine testing among 505 consecutive Japanese patients with angina-like chest pain and unobstructed coronary artery disease.

Intracoronary ergonovine (ER) testing is useful for the detection of epicardial spasm (ES) and coronary microvascular spasm (CMS). We retrospectively analyzed the incidence of ES and CMS in consecutive Japanese patients with unobstructed coronary artery disease. From January 1991 to February 2019, we performed intracoronary ER testing of 1196 patients. Among these patients, a total of 505 consecutive patients (207 women, mean age 64 ± 11 years) who underwent first diagnostic angiography for suspected myocardial ischemia and had unobstructed coronary arteries (< 50%) were enrolled. Resting chest pain was reported by 229 patients, exertional chest pain was reported by 62 patients, exertional and resting chest pain was reported by 61 patients, and another chest symptom (not typical chest pain but suspected to be myocardial ischemia) was reported by 153 patients. ES was defined as ≥ 90% stenosis and usual chest symptoms and ischemic ECG changes, while CMS was defined as < 75% stenosis (no epicardial spasm) and usual chest symptoms and ischemic ECG changes. We performed intracoronary ER testing on both coronary arteries in 86% (432/505) of all subjects. Overall, ES was found in 82 patients (16%), whereas CMS was revealed in 12 patients (2%). In patients with ES, women made up 9%, and 70% of the patients had resting chest pain. In contrast, women composed 67% (8/12) of those with CMS, and 5 patients with CMS had another chest symptom. Ventricular fibrillation was observed in two patients who had sinus rhythm after thump version or cardiac resuscitation. However, we observed no irreversible complications during ER testing. CMS was recognized in only 2% of consecutive Japanese patients with unobstructed coronary artery disease by intracoronary ER testing, whereas ES was revealed in 16% of those patients. CMS was often observed in women.

A multicenter, double-blind, randomized controlled clinical trial comparing ergometrine with oxytocin and oxytocin alone for prevention of postpartum hemorrhage at cesarean section / 中华妇产科杂志

Objective:To compare oxytocin combined with ergometrine with oxytocin alone in terms of primary prophylaxis for postpartum hemorrhage (PPH) at the time of cesarean section (CS).Methods:This was a multicenter double-blind randomized controlled interventional study comparing ergometrine combined with oxytocin and oxytocin alone administered at CS. From December 2018 to November 2019, a total of 298 parturients were enrolled in 16 hospitals nationwide. They were randomly divided into experimental group (ergometrine intra-myometrial injection following oxytocin intravenously; 148 cases) and control group (oxytocin intra-myometrial injection following oxytocin intravenously; 150 cases) according to 1∶1 random allocation. The following indexes were compared between the two groups: (1) main index: blood loss 2 hours (h) after delivery; (2) secondary indicators: postpartum blood loss at 6 h and 24 h, placental retention time, incidence of PPH, the proportion of additional use of uterine contraction drugs, hemostatic drugs or other hemostatic measures at 2 h and 24 h after delivery, the proportion requiring blood transfusion, and the proportion of prolonged hospital stay due to poor uterine involution; (3) safety indicators: nausea, vomiting, dizziness and other adverse reactions, and blood pressure at each time point of administration.Results:(1) The blood loss at 2 h after delivery in the experimental group [(402±18) ml] was less than that in the control group [(505±18) ml], and the difference was statistically significant ( P<0.05). (2) The blood loss at 6 h and 24 h after delivery in the experimental group were less than those in the control group, and the differences were statistically significant (all P<0.05). There were no significant differences between the two groups in the incidence of PPH, the proportion of additional use of uterine contraction drugs, hemostatic drugs or other hemostatic measures at 2 h and 24 h after delivery, the proportion requiring blood transfusion, and the proportion of prolonged hospital stay due to poor uterine involution (all P>0.05). (3) Adverse reactions occurred in 2 cases (1.4%, 2/148) in the experimental group and 1 case (0.7%, 1/150) in the control group. There was no significant difference between the two groups ( P>0.05). The systolic blood pressure within 2.0 h and diastolic blood pressure within 1.5 h of drug administration in the experimental group were higher than those in the control group, and the differences were statistically significant ( P<0.05), but the blood pressure of the two groups were in the normal range. Conclusion:The use of ergometrine injection in CS could reduce the amount of PPH, which is safe and feasible.

A case report: intracoronary acetylcholine testing without a pacemaker may be one option in the left coronary artery.

BACKGROUND: The intracoronary acetylcholine (ACh) and ergonovine (ER) test is employed as a pharmacological spasm provocation test. ACh causes vasoconstriction in patients with coronary endothelial dysfunction such as coronary atherosclerosis, while ER induces coronary vasoconstriction through the activation of coronary smooth muscle. CASE SUMMARY: An 84-year-old Japanese man was admitted to our hospital due to resting angina and syncope. Computed tomography coronary angiography (CTCAG) revealed severe proximal left anterior descending (LAD) coronary artery stenosis, but hybrid images of CTCAG and thallium-adenosine myocardial scintigraphy revealed no ischaemia. During syncope, inverted T waves on V5, V6 leads were recognized. After coronary arteriography, mild atherosclerotic stenosis (50%) was found at the proximal LAD artery, and we administered intracoronary ER 104 µg and 80 µg into the left and right coronary arteries because of suspected coronary spasm. However, no provoked spasm was obtained in either vessel. We administered 20, 50, and 100 µg intracoronary ACh into the left coronary artery (LCA) for 30 s without a pacemaker, because neither bradycardia nor cardiac arrest has occurred. Diffuse distal spasm was provoked after the administration of 100 µg ACh and the patient complained of typical chest pain and prodrome before syncope. The patient was diagnosed with coronary spastic angina by the ACh test but not the ER test. DISCUSSION: Different coronary responses between ACh and ER were observed in this case. Intracoronary ACh testing without a pacemaker may be one option in the LCA if no bradycardia or arrest occurs.

[Methergin pour le diagnostic de l'angor spastique : voie intraveineuse ou intracoronaire ?] / Comparative performance of intravenous and intracoronary ergonovine provocation in vasospastic angina.

BACKGROUND: Vasospastic angina is an infrequent underlying cause of angina and is under-diagnosed. Ergonovine provocation tests can be performed via intravenous or intracoronary injections. Although the safety profile of intracoronary injection has been well documented, no study has yet compared the intracoronary and intravenous injections regarding the positivity rate of the test. AIMS: This study sought to compare the positivity rate of intravenous versus intracoronary injection of ergonovine in the diagnosis of vasospastic angina. METHODS: Between January 2010 and February 2018, 427 patients with suspected vasospastic angina underwent an ergonovine provocation test in 2 tertiary hospitals in France and were retrospectively included in this study. Injection was performed via the intravenous or the intracoronary route. The primary endpoint was the positivity rate of the test. Propensity score matching was used to account for confounding factors. RESULTS: 427 patients were included in the study. Mean age was 60.3 (+/- 12.4) years. There were 247 (58%) females and 97 (23%) smokers. The intracoronary route was used in 199 (47%) patients. The indication for the test was acute coronary syndrome for 121 (28%). No rhythmic complications or deaths were reported. After propensity-matching, the baseline characteristics of the 2 groups (148 patients in each) were comparable. The positivity rate was 24% in the intracoronary group and 9% in the intravenous group (OR [95%CI]: 3.2 [1.6, 6.4]). CONCLUSIONS: Intracoronary injection of ergonovine is safe and associated with a positivity rate of the test three times higher compared to intravenous injection.

Coronary artery spasm-induced acute myocardial infarction in patients with myocardial infarction with non-obstructive coronary arteries.

Coronary artery spasm-induced acute myocardial infarction (CASIAMI) is one of the etiologies of myocardial infarction with non-obstructive coronary arteries (MINOCA). We retrospectively analyzed the incidence and clinical characteristics of Japanese patients with CASIAMI and non-obstructive coronary arteries. We experienced 62 patients with MINOCA (10 thrombosis, 7 unknown causes, and 45 CASIAMI) among 991 patients with suspected AMI. Pharmacological spasm provocation testing was performed in 37 patients. CASIAMI without obstructive coronary arteries was found in 4.5% of patients with suspected AMI and was observed in 73% of patients with MINOCA. Patients with CASIAMI were frequently males and had relatively small AMIs. Spontaneous spasm was recognized in 8 patients. We could reproduce provoked spasm in 37 patients with MINOCA, including 23 patients with multiple spasm. No patients died during the follow-up period. The clinical outcomes in patients with CASIAMI under optimal coronary vasodilators were satisfactory.

Feasibility of right coronary artery first ergonovine provocation test.

BACKGROUND: Intracoronary (IC) provocation angiography is recommended when variant angina is suspected. However, specific procedure-related factors remain uncertain. METHODS: Intracoronary ergonovine infusion was used for the provocation test. About 10, 20, and 40 µg of ergonovine were sequentially injected into the right coronary artery (RCA). During a negative or intermediate response or depending on the clinician's discretion, the left coronary artery (LCA) was injected with incremental doses of 20, 40, and 80 µg of ergonovine or vice versa. If significant coronary spasm or positive clinical findings were noted, the test was stopped immediately and IC nitroglycerine was injected. RESULTS: We reviewed a total of 725 patients (male: 402; mean age: 58.5 years). Spasm-positive response was observed in 269 patients (37.1%), intermediate response in 113 patients (15.6%), and negative response in 343 patients (47.3%). The right radial artery approach was used in most cases (92.6%), and the RCA first approach was mainly chosen (95.0%). The provocation results in the RCA and LCA (93.4%, 381/408) were highly consistent, and the clinically significant discrepancy rate (RCA positive/LCA negative or RCA negative/LCA positive) was 1.5% (6/408). The RCA-alone provocation test can identify spasm-positive response in 93.4% of the patients (228/244). The mean procedure time was 39.9 ± 11.0 min, and approximately 3.3% (24/725) of the patients developed acute complications. CONCLUSIONS: The RCA-first IC ergonovine provocation test is feasible, and the RCA-alone spasm provocation could be acceptable except in an intermediate response, highly clinically suspected cases, or high-risk patients.

Pharmacological spasm provocation testing in 2500 patients: provoked spasm incidence, complications and cardiac events.

Pharmacological spasm provocation tests such as acetylcholine (ACh) and ergonovine (ER) had been performed in the clinic. We retrospectively analyzed the incidence of provoked spasm, complications during testing and the cardiac events after these tests. From January 1991 and October 2018, we performed pharmacological spasm provocation tests in 2500 patients: 1810 ACh tests, 1232 ER tests, 542 both tests, and 310 ACh added after ER tests. ACh was injected in incremental doses of 20/50/100/200 µg into the LCA and 20/50/80 µg into the RCA. ER was administered as a total dose of 64 µg into the LCA and 40 µg into the RCA. When adding ACh after ER, the total dose was 50/80 µg into the RCA and 100/200 µg into the LCA. Positive spasm was defined as ≥ 90% stenosis and usual chest pain or ischemic ECG changes. Mean follow-up duration was 47.5 ± 29.9 months. Overall, provoked positive spasm was found in 1095 patients (43.8%). The incidence of positive provoked spasm during ACh testing was significantly higher than that during other tests (ACh: 48.7% vs. ER: 28.9%, Both: 24%, ACh added after ER: 33.5%, p < 0.001). Multiple spasms were remarkably more frequent during ACh testing compared with the other 3 types of testing (ACh: 28.2% vs. ER: 7.4%, Both: 4.1%, ACh added after ER: 13.2%, p < 0.001). No death or acute myocardial infarction was observed, while major complications during ACh testing were significantly more frequent than during ER testing. Readmission due to recurrent angina pectoris in spasm-positive patients was remarkably more frequent than in spasm-negative patients. The incidence of sudden cardiac death, ventricular fibrillation, and acute coronary syndrome were not different between the spasm-positive and spasm-negative groups during the follow-up periods. We could perform all spasm provocation tests without any irreversible complications. All sequential spasm provocation tests were useful for documenting coronary spasm.