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.

What is the meaning of provoked spasm phenotypes by vasoreactivity testing?

Coronary artery epicardial spasm is involved in the pathogenesis of many cardiac disorders. Vasoreactivity testing, such as intracoronary injection of acetylcholine (ACH) or ergonovine (ER), is the gold standard method for the diagnosis of vasospastic angina. Provoked epicardial spasm phenotypes are classified as focal spasm and diffuse spasm. Multiple factors, including sex, ethnicity, and use of coronary vasoactive stimulators, are related to the provoked phenotypes of epicardial spasm. Diffuse-provoked spasm is often observed in females, where focal-provoked spasm is markedly more common in males. ACH provokes more diffuse and distal spasms, whereas ER induces more focal and proximal spasms. Yellow plaque and coronary thrombi are often observed in lesions with focal spasms, and intimal thickness with a sonolucent zone is significantly more common in lesions with focal spasm. Furthermore, clinical outcomes in patients with focal spasm are unsatisfactory compared with those in patients with diffuse spasm. However, the reproducibility and eternality of provoked spasm phenotypes by vasoreactivity testing is uncertain. Coronary atherosclerosis or endothelial damage may affect coronary vasomotor tone. Although coronary artery spasm may persist in the same coronary artery, provoked coronary spasm phenotypes may exhibit a momentary coronary reaction by intracoronary ACH or ER testing.

Role of polyunsaturated fatty acids in Japanese patients with coronary spastic angina.

BACKGROUND: n-3 polyunsaturated fatty acids (PUFAs) reduce the risk of ischemic heart disease. However, there are few reports of a relationship between n-3 PUFAs and coronary spastic angina (CSA). This study aimed to assess the age-dependent role of serum levels of fatty acid in patients with CSA. METHODS AND RESULTS: We enrolled 406 patients who underwent ergonovine tolerance test (ETT) during coronary angiography for evaluation of CSA. All ETT-positive subjects were diagnosed as having CSA. We categorized the patients by age and results of ETT as follows: (1) young (age ≤ 65 years) CSA-positive (n = 32), (2) young CSA-negative (n = 134), (3) elderly (age > 66 years) CSA-positive (n = 36), and (4) elderly CSA-negative (n = 204) groups. We evaluated the serum levels of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), arachidonic acid, and dihomo-gamma-linolenic acid. In the young groups, the serum levels of EPA (64.3 ±â€¯37.7 µg/mL vs. 49.4 ±â€¯28.8 µg/mL, p = 0.015) and DHA (135.7 ±â€¯47.6 µg/mL vs. 117.4 ±â€¯37.6 µg/mL, p = 0.020) were significantly higher in the CSA-positive group than in the CSA-negative group, respectively. However, this was not the case with elderly groups. In the multivariate analysis in young groups, the serum levels of EPA (p = 0.028) and DHA (p = 0.049) were independently associated with the presence of CSA, respectively. CONCLUSION: Our results suggested that the higher serum levels of EPA and/or DHA might be involved in the pathophysiology of CSA in the young population but not in the elderly population.

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.

Bronchial Asthma and Rest Angina: Is It Safe to Perform Acetylcholine Spasm Provocation Tests in These Patients?

Objective Acetylcholine (ACh) use in patients with bronchial asthma (BA) is contraindicated. We examined the clinical usefulness and safety of ACh spasm provocation tests in rest angina patients with BA. Patients The study subjects were 495 rest angina patients (mean age: 64.4±10.9 years old, male: 81.0%). Organic stenosis was found in 69 patients (13.9%). Methods We investigated 495 rest angina patients who underwent ACh spasm provocation tests. ACh was injected in incremental doses of 20/50/100/200 µg into the left coronary artery and 20/50/80 µg into the right coronary artery. Provoked positive spasm was defined as transient ≥90% luminal narrowing and usual chest pain or ischemic electrocardiogram changes. Results Among 495 rest angina patients, 13 (2.6%) were complicated with BA. Eleven patients with BA were controlled under medications, and two patients had a history of medication for BA. The clinical characteristics were not markedly different between rest angina patients with and without BA. The rate of multi-vessel spasm was markedly higher in patients with BA than that in those without BA. No complications during ACh spasm provocation tests were recognized in rest angina patients with BA, whereas major complications in those without BA were observed in eight patients including two ventricular fibrillations, three non-sustained ventricular tachycardias, and three shocks. We were able to perform all 495 ACh spasm provocation tests without any irreversible complications, while electrical defibrillation was necessary for 2 patients without BA. Conclusion We were able to perform ACh spasm provocation tests in rest angina patients with BA irrespective of the off-label use of ACh.

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.

Transitional changes of acetylcholine spasm provocation test procedures.

Intracoronary acetylcholine (ACh) testing has become popular in the world as a spasm provocation test as well as an ergonovine test. Intracoronary ACh test based on the Japanese Circulation Society guidelines is necessary to insert a temporary pace maker (PM). We analyzed the ACh spasm provocation test procedures retrospectively. We performed 1829 ACh spasm provocation testing during 28 years. We investigated the procedural approach sites of artery and vein. Femoral artery and vein approach, brachial artery and femoral vein approach, brachial artery and vein approach, radial artery and brachial vein approach, radial artery and femoral vein approach were performed in 292 patients (16.0%), 498 patients (27.2%), 589 patients (32.2%), 252 patients (13.8%), and 175 patients (9.6%), respectively. We could perform the ACh testing by the femoral artery and brachial artery in all patients, while the success rate of radial artery approach was 97.1%. We could also insert the temporary PM by the brachial vein in 94.8% (841/887) of the study patients, whereas we could insert the temporary PM in all femoral vein approach [100% (965/965)]. We experienced the pulmonary embolism by the femoral artery and vein approach in two patients, while we also had the arterio-venous fistula necessary for surgical repair in two patients by the brachial artery and vein approach. Although there was no difference about the procedure-related major complications among the various procedures, we had no pulmonary embolism or arterio-venous fistula by the radial artery and brachial vein approach. Considering the disinfection with povidone iodine, procedural performance or procedure-related complications by the ACh testing, we recommend that radial artery and brachial vein approach is more comfortable method of the future ACh testing not only for patients but also for operators.

Vasospastic Angina Diagnosed by the Spasm Provocation Test with the Combined Use of the Acetylcholine and Ergonovine Provocation Tests.

The spasm provocation test (SPT) is important for diagnosing vasospastic angina (VSA), and acetylcholine (ACh) is usually used for this test in Japan. However, some patients with VSA have negative SPT results with the use of the standard ACh regimen alone. We herein report two cases in which VSA was diagnosed by the SPT with the combined use of ACh and ergonovine (EM). VSA could not be diagnosed in either case by the SPT using ACh infusions alone. For patients with negative SPT results, cardiologists should consider performing the SPT using a combination of ACh and EM.

Ergometrine-induced atrial fibrillation at caesarean section.

A 36-year-old woman with a history of one previous caesarean section presented to the birthing suite of a regional hospital with spontaneous rupture of membranes at 39+2/40 weeks. Syntocinon was administered to initiate uterine contractions in the absence of labour, as the patient desired vaginal birth. A caesarean section was subsequently indicated and ergometrine was administered for uterine atony. The patient immediately developed atrial fibrillation (AF). AF is the most common sustained arrhythmia in the general population, but is rare in the obstetric population. AF occurring in an intrapartum setting following the administration of syntocinon and ergometrine, is not documented in the literature. We suggest the initiation of paroxysmal AF was precipitated by an abrupt alteration in autonomic tone caused by administration of syntocinon followed by ergometrine.

Uterotonic agents for preventing postpartum haemorrhage: a network meta-analysis.

BACKGROUND: Postpartum haemorrhage (PPH) is the leading cause of maternal mortality worldwide. Prophylactic uterotonic agents can prevent PPH, and are routinely recommended. The current World Health Organization (WHO) recommendation for preventing PPH is 10 IU (international units) of intramuscular or intravenous oxytocin. There are several uterotonic agents for preventing PPH but there is still uncertainty about which agent is most effective with the least side effects. This is an update of a Cochrane Review which was first published in April 2018 and was updated to incorporate results from a recent large WHO trial. OBJECTIVES: To identify the most effective uterotonic agent(s) to prevent PPH with the least side effects, and generate a ranking according to their effectiveness and side-effect profile. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (24 May 2018), and reference lists of retrieved studies. SELECTION CRITERIA: All randomised controlled trials or cluster-randomised trials comparing the effectiveness and side effects of uterotonic agents with other uterotonic agents, placebo or no treatment for preventing PPH were eligible for inclusion. Quasi-randomised trials were excluded. Randomised trials published only as abstracts were eligible if sufficient information could be retrieved. DATA COLLECTION AND ANALYSIS: At least three review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. We estimated the relative effects and rankings for preventing PPH ≥ 500 mL and PPH ≥ 1000 mL as primary outcomes. Secondary outcomes included blood loss and related outcomes, morbidity outcomes, maternal well-being and satisfaction and side effects. Primary outcomes were also reported for pre-specified subgroups, stratifying by mode of birth, prior risk of PPH, healthcare setting, dosage, regimen and route of administration. We performed pairwise meta-analyses and network meta-analysis to determine the relative effects and rankings of all available agents. MAIN RESULTS: The network meta-analysis included 196 trials (135,559 women) involving seven uterotonic agents and placebo or no treatment, conducted across 53 countries (including high-, middle- and low-income countries). Most trials were performed in a hospital setting (187/196, 95.4%) with women undergoing a vaginal birth (71.5%, 140/196).Relative effects from the network meta-analysis suggested that all agents were effective for preventing PPH ≥ 500 mL when compared with placebo or no treatment. The three highest ranked uterotonic agents for prevention of PPH ≥ 500 mL were ergometrine plus oxytocin combination, misoprostol plus oxytocin combination and carbetocin. There is evidence that ergometrine plus oxytocin (RR 0.70, 95% CI 0.59 to 0.84, moderate certainty), carbetocin (RR 0.72, 95% CI 0.56 to 0.93, moderate certainty) and misoprostol plus oxytocin (RR 0.70, 95% CI 0.58 to 0.86, low certainty) may reduce PPH ≥ 500 mL compared with oxytocin. Low-certainty evidence suggests that misoprostol, injectable prostaglandins, and ergometrine may make little or no difference to this outcome compared with oxytocin.All agents except ergometrine and injectable prostaglandins were effective for preventing PPH ≥ 1000 mL when compared with placebo or no treatment. High-certainty evidence suggests that ergometrine plus oxytocin (RR 0.83, 95% CI 0.66 to 1.03) and misoprostol plus oxytocin (RR 0.88, 95% CI 0.70 to 1.11) make little or no difference in the outcome of PPH ≥ 1000 mL compared with oxytocin. Low-certainty evidence suggests that ergometrine may make little or no difference to this outcome compared with oxytocin meanwhile the evidence on carbetocin was of very low certainty. High-certainty evidence suggests that misoprostol is less effective in preventing PPH ≥ 1000 mL when compared with oxytocin (RR 1.19, 95% CI 1.01 to 1.42). Despite the comparable relative treatment effects between all uterotonics (except misoprostol) and oxytocin, ergometrine plus oxytocin, misoprostol plus oxytocin combinations and carbetocin were the highest ranked agents for PPH ≥ 1000 mL.Misoprostol plus oxytocin reduces the use of additional uterotonics (RR 0.56, 95% CI 0.42 to 0.73, high certainty) and probably also reduces the risk of blood transfusion (RR 0.51, 95% CI 0.37 to 0.70, moderate certainty) when compared with oxytocin. Carbetocin, injectable prostaglandins and ergometrine plus oxytocin may also reduce the use of additional uterotonics but the certainty of the evidence is low. No meaningful differences could be detected between all agents for maternal deaths or severe morbidity as these outcomes were rare in the included randomised trials where they were reported.The two combination regimens were associated with important side effects. When compared with oxytocin, misoprostol plus oxytocin combination increases the likelihood of vomiting (RR 2.11, 95% CI 1.39 to 3.18, high certainty) and fever (RR 3.14, 95% CI 2.20 to 4.49, moderate certainty). Ergometrine plus oxytocin increases the likelihood of vomiting (RR 2.93, 95% CI 2.08 to 4.13, moderate certainty) and may make little or no difference to the risk of hypertension, however absolute effects varied considerably and the certainty of the evidence was low for this outcome.Subgroup analyses did not reveal important subgroup differences by mode of birth (caesarean versus vaginal birth), setting (hospital versus community), risk of PPH (high versus low risk for PPH), dose of misoprostol (≥ 600 mcg versus < 600 mcg) and regimen of oxytocin (bolus versus bolus plus infusion versus infusion only). AUTHORS' CONCLUSIONS: All agents were generally effective for preventing PPH when compared with placebo or no treatment. Ergometrine plus oxytocin combination, carbetocin, and misoprostol plus oxytocin combination may have some additional desirable effects compared with the current standard oxytocin. The two combination regimens, however, are associated with significant side effects. Carbetocin may be more effective than oxytocin for some outcomes without an increase in side effects.

Uterotonic agents for preventing postpartum haemorrhage: a network meta-analysis.

BACKGROUND: Postpartum haemorrhage (PPH) is the leading cause of maternal mortality worldwide. Prophylactic uterotonic drugs can prevent PPH, and are routinely recommended. There are several uterotonic drugs for preventing PPH but it is still debatable which drug is best. OBJECTIVES: To identify the most effective uterotonic drug(s) to prevent PPH, and generate a ranking according to their effectiveness and side-effect profile. SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register (1 June 2015), ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) for unpublished trial reports (30 June 2015) and reference lists of retrieved studies. SELECTION CRITERIA: All randomised controlled comparisons or cluster trials of effectiveness or side-effects of uterotonic drugs for preventing PPH.Quasi-randomised trials and cross-over trials are not eligible for inclusion in this review. DATA COLLECTION AND ANALYSIS: At least three review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. We estimated the relative effects and rankings for preventing PPH ≥ 500 mL and PPH ≥ 1000 mL as primary outcomes. We performed pairwise meta-analyses and network meta-analysis to determine the relative effects and rankings of all available drugs. We stratified our primary outcomes according to mode of birth, prior risk of PPH, healthcare setting, dosage, regimen and route of drug administration, to detect subgroup effects.The absolute risks in the oxytocin are based on meta-analyses of proportions from the studies included in this review and the risks in the intervention groups were based on the assumed risk in the oxytocin group and the relative effects of the interventions. MAIN RESULTS: This network meta-analysis included 140 randomised trials with data from 88,947 women. There are two large ongoing studies. The trials were mostly carried out in hospital settings and recruited women who were predominantly more than 37 weeks of gestation having a vaginal birth. The majority of trials were assessed to have uncertain risk of bias due to poor reporting of study design. This primarily impacted on our confidence in comparisons involving carbetocin trials more than other uterotonics.The three most effective drugs for prevention of PPH ≥ 500 mL were ergometrine plus oxytocin combination, carbetocin, and misoprostol plus oxytocin combination. These three options were more effective at preventing PPH ≥ 500 mL compared with oxytocin, the drug currently recommended by the WHO (ergometrine plus oxytocin risk ratio (RR) 0.69 (95% confidence interval (CI) 0.57 to 0.83), moderate-quality evidence; carbetocin RR 0.72 (95% CI 0.52 to 1.00), very low-quality evidence; misoprostol plus oxytocin RR 0.73 (95% CI 0.60 to 0.90), moderate-quality evidence). Based on these results, about 10.5% women given oxytocin would experience a PPH of ≥ 500 mL compared with 7.2% given ergometrine plus oxytocin combination, 7.6% given carbetocin, and 7.7% given misoprostol plus oxytocin. Oxytocin was ranked fourth with close to 0% cumulative probability of being ranked in the top three for PPH ≥ 500 mL.The outcomes and rankings for the outcome of PPH ≥ 1000 mL were similar to those of PPH ≥ 500 mL. with the evidence for ergometrine plus oxytocin combination being more effective than oxytocin (RR 0.77 (95% CI 0.61 to 0.95), high-quality evidence) being more certain than that for carbetocin (RR 0.70 (95% CI 0.38 to 1.28), low-quality evidence), or misoprostol plus oxytocin combination (RR 0.90 (95% CI 0.72 to 1.14), moderate-quality evidence)There were no meaningful differences between all drugs for maternal deaths or severe morbidity as these outcomes were so rare in the included randomised trials.Two combination regimens had the poorest rankings for side-effects. Specifically, the ergometrine plus oxytocin combination had the higher risk for vomiting (RR 3.10 (95% CI 2.11 to 4.56), high-quality evidence; 1.9% versus 0.6%) and hypertension [RR 1.77 (95% CI 0.55 to 5.66), low-quality evidence; 1.2% versus 0.7%), while the misoprostol plus oxytocin combination had the higher risk for fever (RR 3.18 (95% CI 2.22 to 4.55), moderate-quality evidence; 11.4% versus 3.6%) when compared with oxytocin. Carbetocin had similar risk for side-effects compared with oxytocin although the quality evidence was very low for vomiting and for fever, and was low for hypertension. AUTHORS' CONCLUSIONS: Ergometrine plus oxytocin combination, carbetocin, and misoprostol plus oxytocin combination were more effective for preventing PPH ≥ 500 mL than the current standard oxytocin. Ergometrine plus oxytocin combination was more effective for preventing PPH ≥ 1000 mL than oxytocin. Misoprostol plus oxytocin combination evidence is less consistent and may relate to different routes and doses of misoprostol used in the studies. Carbetocin had the most favourable side-effect profile amongst the top three options; however, most carbetocin trials were small and at high risk of bias.Amongst the 11 ongoing studies listed in this review there are two key studies that will inform a future update of this review. The first is a WHO-led multi-centre study comparing the effectiveness of a room temperature stable carbetocin versus oxytocin (administered intramuscularly) for preventing PPH in women having a vaginal birth. The trial includes around 30,000 women from 10 countries. The other is a UK-based trial recruiting more than 6000 women to a three-arm trial comparing carbetocin, oxytocin and ergometrine plus oxytocin combination. Both trials are expected to report in 2018.Consultation with our consumer group demonstrated the need for more research into PPH outcomes identified as priorities for women and their families, such as women's views regarding the drugs used, clinical signs of excessive blood loss, neonatal unit admissions and breastfeeding at discharge. To date, trials have rarely investigated these outcomes. Consumers also considered the side-effects of uterotonic drugs to be important but these were often not reported. A forthcoming set of core outcomes relating to PPH will identify outcomes to prioritise in trial reporting and will inform futures updates of this review. We urge all trialists to consider measuring these outcomes for each drug in all future randomised trials. Lastly, future evidence synthesis research could compare the effects of different dosages and routes of administration for the most effective drugs.

Patients with acute myocardial infarction and non-obstructive coronary arteries: safety and prognostic relevance of invasive coronary provocative tests.

Aims: Functional alterations of epicardial coronary arteries or coronary microcirculation represent a frequent cause of myocardial infarction and non-obstructive coronary arteries (MINOCA). We aimed at assessing the prognostic value of intracoronary provocative tests in patients presenting with MINOCA and in which other causes of MINOCA have been excluded. Methods and results: We prospectively evaluated patients with a diagnosis of MINOCA, excluding patients with aetiologies other than suspected coronary vasomotor abnormalities. Immediately after coronary angiography, an invasive provocative test using acetylcholine or ergonovine was performed. The incidence of death from any cause, cardiac death, and recurrence of acute coronary syndrome (ACS) was assessed at follow-up. We also assessed angina status using Seattle Angina Questionnaires (SAQ). We enrolled 80 consecutive patients [mean age 63.0 ± 10.7 years, 40 (50%) male]. Provocative test was positive in 37 (46.2%) patients without any complication. Among patients with a positive test, epicardial spasm was detected in 24 (64.9%) patients and microvascular spasm in 13 (35.1%) patients. After a median follow-up of 36.0 (range 12.0-60.0) months, patients with a positive test had a significantly higher occurrence of death from any cause [12 (32.4%) vs. 2 (4.7%); P = 0.002], cardiac death [7 (18.9%) vs. 0 (0.0%); P = 0.005], and readmission for ACS [10 (27.0%) vs. 3 (7.0%); P = 0.015] as well as a worse angina status as assessed by SAQ [Seattle score: 88.0 (33.0-100.0) vs. 100.0 (44.0-100.0); P = 0.001] when compared with patients with a negative test. Conclusions: We demonstrate that in patients presenting with MINOCA and suspected coronary vasomotor abnormalities, a positive provocative test for spasm is safe and identifies a high-risk subset of patients.

Clinical outcome according to spasm type of single coronary artery provoked by intracoronary ergonovine tests in patients without significant organic stenosis.

BACKGROUND: This study aimed to evaluate clinical implications of single vessel coronary spasm provoked by intracoronary ergonovine provocation test in Korean population. METHOD: A total of 1248 patients who presented with single vessel coronary artery spasm induced by intracoronary ergonovine provocation test, excluding 1712 with negative spasms, multiple and mixed coronary artery spasms and missing data among 2960 patients in the VA-KOREA (Vasospastic Angina in Korea) registry, were classified into diffuse (n=705) and focal (n=543) groups. RESULTS: The 24-month incidences of a composite primary endpoints (cardiac death, new-onset arrhythmia, and acute coronary syndrome) were determined. Over a median follow-up of 30months, the composite primary end point occurred more frequently in the focal type patients than in the diffuse type patients (primary endpoint: adjusted hazard ratio [aHR], 1.658; 95% confidence interval [CI] 1.272 to 2.162, P<0.001). Especially, unstable angina in ACS components played a major role in this effect (hazard ratio [HR], 2.365; 95% confidence interval [CI] 1.100 to 5.087, P=0.028). CONCLUSION: Focal type of single vessel coronary artery spasm in vasospastic angina (VSA) patients is found to be associated with worse clinical outcomes. It is thought that the effect is stemmed from unstable angina among ACS rather than the other components of primary endpoint. Therefore, focal type of single vessel coronary artery spasm in patients with VSA should be more carefully assessed and managed with appropriate medication.

Transient sick sinus syndrome with complete atrioventricular block associated with ergonovine intake: A case report.

RATIONALE: More mature or older women are more likely to undergo in vitro fertilization and embryo implant. These women have a greater chance of receiving ergonovine therapy because of a suspected abortion. We present this case report to call attention to a latent lethal adverse effect in everyday obstetric practice using ergonovine. It requires more attention and close monitoring PATIENT CONCERNS:: We presented the case of a 38-year-old female patient with general weakness and mild chest tightness after ergonovine use. DIAGNOSES: She was diagnosed as transient sick sinus syndrome and complete atrioventricular block with junctional escape rhythm after diagnostic work up. INTERVENTIONS: Conservative treatment with discontinuation of ergonovine and bed rest. OUTCOMES: Her sinus rhythm returned to normal the day after ergonovine was discontinued. The patient remained symptom-free since recovery of her sinus rhythm. LESSONS: Ergonovine may cause symptomatic and lethal bradyarrhythmia. Withdrawal of the causative medication and adequate supportive care can lead to a favorable outcome in these patients. More related cases should be reported. Further evaluation for treatment and prognosis are necessary.

Safety of intracoronary provocative testing for the diagnosis of coronary artery spasm.

AIMS: Systematic review of literature to evaluate safety of intracoronary (i.c.) pharmacologic testing with acetylcholine (ACh), or ergonovine (ERGO), to induce coronary artery spasm. METHODS AND RESULTS: Review of all relevant publications using MEDLINE and EMBASE databases yielded 10 publications, totalling 9,444 patients. Prevalence of provoked spasm varied from 2.3% to 54.7% of patients tested in the selected studies. The wide variability in prevalence was due to heterogeneity of study populations and provocation protocols. No deaths were reported. Overall occurrence of major (0.8%) and minor (4.7%) complications for i.c. pharmacologic testing was low. Compared to ERGO, ACh showed significantly higher rate of major (1.09% vs 0.15%; p<0.001) and minor complications (5.87% vs 2.36%; p<0.001). CONCLUSION: Provocative testing with i.c. ACh or ERGO are safe and can facilitate the diagnosis of inducible coronary artery spasm during diagnostic coronary angiography. These tests should be part of the routine armamentarium of interventional cardiologists.

Carbetocin versus syntometrine for prevention of postpartum hemorrhage after cesarean section.

OBJECTIVE: To compare effectiveness and tolerability of carbetocin versus syntometrine in prevention of postpartum hemorrhage (PPH) after cesarean section (CS). METHODS: A double-blind randomized study conducted on 300 pregnant subjected randomly either to single 100 µg IV dose of carbetocin (150 women) or combination of 5 IU oxytocin and 0.2 mg ergometrine (150 women) after fetal extraction and before placental removal. Primary outcome parameter was the occurrence of PPH. Other parameters were hemoglobin and hematocrit changes, the need of additional oxytocic, hemodynamic changes and occurrence of side effects. RESULTS: There was no significant difference between the two study groups regarding hemoglobin and hematocrit at start of CS and after 2 days of surgery and mean blood loss during the operation (p > 0.05). There was a highly significant difference between the two study groups regarding incidence of primary PPH (2.7% versus10%) and the need of additional oxytocic (3.3% versus17.3%). Women in oxytocin group showed a statistically significant lower systolic and diastolic blood pressure at 1, 5 and 30 min than women in carbetocin group. Women in carbetocin group experienced more metallic taste, flushing, headache, dizziness, dyspnea and itching, while women in oxytocin methergine group experienced more palpitations. CONCLUSIONS: Carbetocin is a reasonable effective alternative to syntometrine in prevention of PPH after cesarean delivery.

Overview of complications during pharmacological spasm provocation tests.

Pharmacological spasm provocation tests are invasive methods and we always have the potential to encounter complications when performing these tests. In 1980, Buxton et al. reported three deaths when they performed intravenous ergonovine testing. However, we now employ the intracoronary ergonovine test instead of the intravenous injection of ergonovine from a safety procedure point of view. Past serious major complications of intravenous ergonovine tests, intracoronary ergonovine tests, and intracoronary acetylcholine tests were 0.31% (26/8419), 0.51% (11/2173), and 0.95% (148/15,527), respectively. Selective intracoronary testing had the serious major complications in 0.89% of patients including just one death (0.006%) and two acute myocardial infarctions (0.01%). Selective spasm provocation tests had no additional risks compared with performing diagnostic coronary angiography alone. In the Western countries, the pharmacological spasm provocation tests are not familiar in the clinic except for some specialized institutions. We need international clinical studies using the same protocol of spasm provocation tests to compare the frequency, clinical features, and prognosis of acetylcholine- or ergonovine-provoked coronary spasm between Western and Asian countries. And we hope that Western guidelines give spasm provocation testing a class I indication similar to Japanese Circulation Society guidelines because coronary artery spasm may have fewer racial differences and borders.