Stopping Dual Antiplatelet Therapy Research Articles

P98 A CASE OF “RECURRENT” AORTIC VALVE STENOSIS

Abstract Clinical Case A 80–year–old man underwent coronary angiography in 2006 because of stable angina. There was chronic total occlusion of middle left anterior descending artery requiring percutaneous intervention. In 2009 he underwent coronary angiography for recurrent angina: a severe stent restenosis was treated with stenting in stent (DES in BMS). The patient was subsequently asymptomatic till 2018 when he complained of exertional dyspnea and angina. Stent patency and severe aortic valve stenosis (AVA 0.85 cm2) were documented. The patient underwent successful transcatheter aortic valve implantation and discharged with dual antiplatelet therapy (DAPT) (Asa 100 mg and Clopidogrel 75 mg). Clinical and echocardiographic follow–up was unremarkable (mean prosthetic gradient 17 mmHg, DVI=0.45). In July 2021 during a cardiological check the patient complained of bruising: ASA was discontinued. In February 2022 the patient suffered from an exertional angina. A dipyridamole stress–echocardiography failed to demonstrate inducible ischemia, although the patient experienced angina at the peak load step. Transthoracic echocardiogram (TTE) revealed high mean trans–prosthetic aortic gradient (52 mmHg, DVI=0.18). A trans–esophageal echocardiogram (TEE) showed reduced mobility of the thickened left coronary and non–coronary aortic prosthetic leaflets. In the hypothesis of prosthetic valve thrombosis, warfarin (INR range 2–3) was started after stopping clopidogrel. After three months a TTE showed normalized mean trans–prosthetic gradients (17 mmHg, DVI=0.5). When a 6 month–period of anticoagulant therapy was accomplished, warfarin was stopped and DAPT administered again. In September 2022 the patient complained of worsening dyspnea and chest pain on exertion. At TTE mean trans–prosthetic gradients (46 mmHg) was increased. A new TEE showed thickening of non–coronary and right coronary leaflets, suggestive of recurrent valve thrombosis. After stopping DAPT, warfarin was started again with good result (mean prosthetic gradient 12 mmHg, DVI=0.5). Conclusion Thrombosis of aortic valve prothesis is an infrequent event usually occurring in early post–implantation period. In our case it occurred four years after implantation following DAPT interruption. The likely initial prosthetic valve degeneration together with a simplification of DAPT may have had a causative role. Since the proved efficacy of warfarin and the limited experience of DOAC in this field, the patient was given warfarin sine die.

Management of Antithrombotic Therapy in Post Percutaneous Coronary Intervention Patient Undergoing Pericardiostomy due to Large Pericardial Effusion: A Case Report

Background : Stent thrombosis is a serious complication following percutaneous coronary intervention (PCI), and dual antiplatelet therapy (DAPT) is necessary to avoid it. Surgery, on the other hand, is a common cause for stopping DAPT. Because patients were exposed to the possibility of a major adverse cardiovascular event (MACE) when DAPT was stopped, this circumstance poses a clinical dilemma. Objective : This case report aimed to describe the management of antithrombotic therapy in post PCI patient requiring DAPT who underwent pericardiostomy. Case : A 69-year-old woman with large pericardial effusion without cardiac tamponade, breast cancer on chemo- therapy, heart failure stage C NYHA functional class II, chronic coronary syndrome post-DES implantation at proximal-mid LAD, and hypertension. The patient underwent pericardiotomy procedures five days after DAPT discontinuation. For the bridging therapy, continuous UFH administration was initiated at a dose of 18 IU/kg/hour after the cessation of DAPT. The UFH dose was adjusted to achieve activated partial thromboplastin time (APTT) 1.5 to 2.0 times the control value. The UFH was discontinued 6 hours before surgery. After surgery, UFH infusion was restarted 6 hours after the confirmation of hemostasis. The administration of UFH then continued until three days after DAPT was restarted. No complications were found during and after the pericar- diostomy. Conclusion : We reported an antithrombotic treatment strategy in a post PCI patient undergoing pericardiostomy with discontinuation of DAPT, which was successfully treated with UFH without any complication. The UFH has been widely used in perioperative settings as a bridging therapy during the interruption of DAPT and may be considered in this condition.

Dual antiplatelet therapy for reduction in mortality in patients with acute and chronic coronary syndromes.

Dual antiplatelet therapy (DAPT) is a foundation of successful coronary artery disease management. DAPT is recommended according to ESC guidelines for 6 months following elective percutaneous coronary intervention and for 12 months following the acute coronary syndrome (ACS). ACS are the most cost-consuming type of the ischemic heart disease, which prominently requires hospital treatment. This risk significantly increases shortly after stopping DAPT, which is typical in most patients after 12 months following acute myocardial infarction (AMI). Therefore, one of the goals of long-term treatment of such patients should be the identification of those at increased risk of subsequent events, for whom prolonged DAPT will bring clinical benefits. It has been documented that prasugrel and ticagrelor, compared to clopidogrel, significantly reduce the incidence of major adverse cardiovascular events (MACE) in ACS patients. In addition to lowering composite ischemic endpoint, ticagrelor significantly reduced all-cause and cardiovascular mortality. The long-term use of ticagrelor in patients with a previous myocardial infarction was also related to a significant reduction in MACE. In patients who had a myocardial infarction 1–3 years earlier, the addition of ticagrelor to aspirin resulted in a substantial reduction in the composite endpoint of cardiovascular death, myocardial infarction, or stroke at the expense of a small but significant increase in bleedings. Hypothetical calculations have shown that replacing clopidogrel with ticagrelor in all patients with AMI in Poland would save more than three thousand lives within 12 months after AMI and more than a thousand within the following 2 years.

Conventional Angiography in the Assessment of Recently Symptomatic Patients with Ipsilateral Carotid Stenosis

Background and PurposeBenefits of revascularization for moderate and severe (≥50%) carotid stenosis were established based on digital subtraction angiography (DSA). We aimed to assess the discrepancy between invasive and non-invasive angiography in a consecutive, prospective cohort of patients with recent stroke and non-invasive imaging suggesting ≥50% ipsilateral carotid stenosis. Materials and MethodsWe reviewed prospectively-collected data for consecutive patients admitted with recent stroke/TIA and ≥50% ipsilateral carotid stenosis on non-invasive imaging over 28 months. All patients underwent DSA to confirm the degree of stenosis per NASCET criteria. All patients with <50% stenosis by DSA were treated with medical therapy only and their recurrent event rates were assessed at 6 months. Results148 symptomatic patients with ≥50% ipsilateral carotid stenosis on CTA (82%) and MRA (18%) underwent DSA to confirm degree of stenosis. Median age was 73 years and 64% were male. DSA demonstrated <50% stenosis in 28 patients (19%). Median presenting NIHSS was 1 (IQR 0-3). Median carotid stenosis evaluated by non-invasive imaging was 70% (IQR 60-85%) and by DSA was 40% (IQR 30-45%). One of 28 patients (4%) experienced recurrent nondisabling stroke (NIHSS 1) after stopping dual antiplatelet therapy. ConclusionIn nearly one-in-five cases with recent stroke due to ipsilateral carotid stenosis deemed to be candidates for revascularization based on CTA or MRA, DSA led to institution of medical therapy only due to insufficiently severe stenosis. In patients treated with medical therapy based on the findings of <50% stenosis on DSA, the rate of recurrent stroke is low.

Combined aspirin and clopidogrel therapy in phacoemulsification cataract surgery: a risk factor for ocular hemorrhage?

To evaluate the safety of phacoemulsification cataract surgery in the patients undergoing dual antiplatelet therapy with aspirin and clopidogrel. Consecutive patients undergoing phacoemulsification cataract surgery with a clear corneal incision under topical anesthesia were eligible for inclusion in the study. Thirty-eight eyes from 38 patients on combined aspirin and clopidogrel therapy who continued the treatment were classified into the maintenance group, a matched group of 38 eyes from 38 patients on no antiplatelet/anticoagulant therapy as the control group. The best-corrected visual acuity (BCVA) and incidences of complications were compared between the two groups. There was no significant difference in final BCVA between the maintenance group and the control group (p = 0.178). No significant difference existed in the incidences of hemorrhagic or non-hemorrhagic complications between the two groups (p = 0.529 and p = 0.589, respectively). Moreover, no surgery was postponed or cancelled due to hemorrhagic complications in either group, and no cardiovascular events occurred during the follow-up. There was no case of anterior chamber hemorrhage, vitreous hemorrhage, or suprachoroidal hemorrhage. Our outcomes indicated that phacoemulsification cataract surgery using a clear corneal incision with topical anesthesia could be safely done without stopping dual antiplatelet therapy with aspirin and clopidogrel.

Neutrophil/Lymphocyte Ratio in Patients Undergoing Noncardiac Surgery After Coronary Stent Implantation

Perioperative cell count-associated predictors, including the neutrophil/lymphocyte ratio (N/LR) and platelet/lymphocyte ratio (P/LR), are associated with poor clinical outcomes including myocardial injury. Study investigators aimed to examine the association among the perioperative N/LR, P/LR, and postoperative major adverse cardiovascular and cerebral events (MACCE) after noncardiac surgery in patients with drug-eluting stent (DES) insertion. Retrospective and observational. Single university hospital. The study comprised 965 patients who underwent noncardiac surgery within 6 months after DES implantation. None. Baseline perioperative clinical parameters, including N/LR and P/LR measured before surgery, immediately after surgery, and on postoperative day (POD) 1, were obtained. MACCE was defined as a composite of nonfatal myocardial infarction, coronary revascularization, nonhemorrhagic stroke, and pulmonary embolism within 1 month after surgery. Multivariate logistic regression analysis and propensity score matching were used to identify predictors of MACCE after surgery. MACCE occurred in 67 patients (6.9%) and was more common in patients with N/LR on POD 1 >4.3 (multivariable-adjusted odds ratio [OR] 2.03, 95% confidence interval [CI] 1.12-2.79; p = 0.040 and as a continuous N/LR [OR 1.17, 95% CI 1.08-1.27; p < 0.001]). This association was consistent after propensity score matching and was stronger when the antiplatelet agent was stopped before surgery (OR 3.02, 95% CI 2.14-4.48; p = 0.006 for stopping dual antiplatelet therapy). In patients undergoing noncardiac surgery within 6 months after DES implantation, elevated N/LR on POD 1 is independently associated with postoperative MACCE. Elevated postoperative N/LR as a marker of systemic inflammation may help to predict the development of MACCE in these high-risk patients.

Development of a risk score for predicting the benefit versus harm of extending dual antiplatelet therapy beyond 6 months following percutaneous coronary intervention for stable coronary artery disease.

BackgroundDecisions on dual antiplatelet therapy (DAPT) duration should balance the opposing risks of ischaemia and bleeding. Our aim was to develop a risk score to identify stable coronary artery disease (SCAD) patients undergoing PCI who would benefit or suffer from extending DAPT beyond 6 months.MethodsRetrospective analysis of a cohort of patients who completed 6 months of DAPT following PCI. Predictors of ischaemic and bleeding events for the 6–12 month period post-PCI were identified and a risk score was developed to estimate the likelihood of benefiting from extending DAPT beyond 6 months. Incidence of mortality, ischaemic and bleeding events for patients treated with DAPT for 6 vs. 6–12 months, was compared, stratified by strata of the risk score.ResultsThe study included 2,699 patients. Over 6 months’ follow up, there were 78 (2.9%) ischaemic and 43 (1.6%) bleeding events. Four variables (heart failure, left ventricular ejection fraction ≤30%, left main or three vessel CAD, status post (s/p) PCI and s/p stroke) predicted ischemic events, two variables (age>75, haemoglobin <10 g/dL) predicted bleeding. In the lower stratum of the risk score, 6–12 months of treatment with DAPT resulted in increased bleeding (p = 0.045) with no decrease in ischaemic events. In the upper stratum, 6–12 months DAPT was associated with reduced ischaemic events (p = 0.029), with no increase in bleeding.ConclusionIn a population of SCAD patients who completed 6 months of DAPT, a risk score for subsequent ischaemic and bleeding events identified patients likely to benefit from continuing or stopping DAPT.

P4619Accelerated accrural of ischaemic events after stopping dual antiplatelet therapy at 12 months in a real-world acute myocardial infarction cohort

P4619Accelerated accrural of ischaemic events after stopping dual antiplatelet therapy at 12 months in a real-world acute myocardial infarction cohort

Postoperative Bleeding Following Preoperative Clopidogrel Administration in Patients with Haemoglobin Level Above 110 g/L Undergoing Urgent CABG.

IntroductionPatients with acute coronary syndrome usually receive dual antiplatelet therapy (DAPT) (usually clopidogrel + aspirin) prior to coronary catheterization, and approximately 10% of these patients require coronary artery bypass grafting (CABG). DAPT has favorable effects on prevention of thrombus formation, but it can have deleterious effects on surgical hemostasis. Anaemia, if present, gives additional risk to such patients. The aim of this study was to examine if DAPT affects postoperative bleeding in patients with haemoglobin levels above 110 g/L, who underwent urgent or emergent CABG, less than five days after stopping DAPT therapy.MethodsData were collected prospectively on 122 CABG patients, operated by a surgical team from March 2008 to August 2013. Patients were stratified into two groups: group 1 received DAPT within 5 days of CABG (n=65), and group 2 where DAPT was discontinued for more than 5 days prior to CABG (n=57). All patients were diagnosed with acute coronary syndrome preoperatively, and all of them had haemoglobin levels above 110 g/L. Patients who needed reoperation, combined procedures, or off-pump revascularization were excluded.ResultsThere was no hospital mortality. Mean chest tube losses after the surgical revascularization did not differ significantly, but group 1 received a higher quantity of transfused red blood cells and platelets.ConclusionUrgent and emergent surgical revascularization using extracorporeal circulation in patients with acute coronary syndrome whose preoperative haemoglobin levels are above 110 g/L is a safe and effective procedure. We suggest that, where indicative, one may perform CABG in less than 5 days after the clopidogrel discontinuation.

One-year outcome of a prospective trial stopping dual antiplatelet therapy at 3months after everolimus-eluting cobalt-chromium stent implantation: ShortT and OPtimal duration of Dual AntiPlatelet Therapy after everolimus-eluting cobalt-chromium stent (STOPDAPT) trial.

There has been no previous prospective study evaluating dual antiplatelet therapy (DAPT) duration shorter than 6 months after cobalt-chromium everolimus-eluting stent (CoCr-EES) implantation. STOPDAPT trial is a prospective multi-center single-arm study evaluating 3-month DAPT duration after CoCr-EES implantation. The primary endpoint was a composite of cardiovascular death, myocardial infarction (MI), stroke, definite stent thrombosis (ST) and TIMI major/minor bleeding at 1 year. Between September 2012 and October 2013, a total of 1525 patients were enrolled from 58 Japanese centers, with complete 1-year follow-up in 1519 patients (99.6 %). Thienopyridine was discontinued within 4 months in 1444 patients (94.7 %). The event rates beyond 3 months were very low (cardiovascular death: 0.5 %, MI: 0.1 %, ST: 0 %, stroke: 0.7 %, and TIMI major/minor bleeding: 0.8 %). Cumulative 1-year incidence of the primary endpoint was 2.8 % [upper 97.5 % confidence interval (CI) 3.6 %], which was lower than the pre-defined performance goal of 6.6 % (P < 0.0001). Using the CoCr-EES group in the RESET trial as a historical comparison group, where nearly 90 % of patients had continued DAPT at 1 year, cumulative incidence of the primary endpoint tended to be lower in the STOPDAPT than in the RESET (2.8 versus 4.0 %, P = 0.06) and adjusted hazard ratio was 0.64 (95 % CI 0.42–0.95, P = 0.03). The cumulative incidence of definite/probable ST was lower in the STOPDAPT than in the RESET [0 patient (0 %) versus 5 patients (0.3 %), P = 0.03]. In conclusion, stopping DAPT at 3 months in selected patients after CoCr-EES implantation was at least as safe as the prolonged DAPT regimen adopted in the historical control group.Electronic supplementary materialThe online version of this article (doi:10.1007/s12928-015-0366-9) contains supplementary material, which is available to authorized users.

TCT-556 One-year Outcome of a Prospective Trial Stopping Dual Antiplatelet Therapy at 3-Month after Everolimus-eluting Cobalt-chromium Stent Implantation: ShortT and OPtimal duration of Dual AntiPlatelet Therapy after everolimus-eluting cobalt-chromium stent (STOPDAPT) trial

Prolonged dual antiplatelet therapy (DAPT) after coronary stent implantation is associated with higher risk for bleeding. Second-generation drug-eluting stents (G2-DES), cobalt-chromium everolimus-eluting stent (CoCr-EES) in particular, are reported to have lower risk for stent thrombosis (ST)

Coming safely to a stop: a review of platelet activity after cessation of antiplatelet drugs.

The platelet P2Y12 antagonists are widely used, usually in combination with aspirin, to prevent atherothrombotic events in patients with acute coronary syndromes during percutaneous coronary intervention and after placement of arterial stents. Inhibition by clopidogrel or prasugrel lasts for the lifetime of the affected platelets and platelet haemostatic function gradually recovers after stopping the drug, as new unaffected platelets are formed. The optimal durations for dual antiplatelet therapy are prescribed by clinical guidelines. Continuation beyond the recommended duration is associated with an increased mortality, mainly associated with major bleeding. Fear of a 'rebound' of prothrombotic platelet activity on stopping the drug has provoked much discussion and many studies. However, review of the available literature reveals no evidence for production of hyper-reactive platelets after cessation of clopidogrel in patients who are stable. Any increase in acute coronary and other vascular events after stopping seems most likely therefore to be due to premature discontinuation or disruption of treatment while thrombotic risk is still high. No difference in rebound was found with the newer P2Y12 inhibitors, although ticagrelor and prasugrel are more potent platelet inhibitors than clopidogrel. Recent randomized controlled trials confirm it is safe to stop the thienopyridine and continue with aspirin alone in most patients after the duration of treatment recommended by the guidelines. Decisions on when to stop therapy in individuals, however, remain challenging and there is a growing rationale for platelet testing to assist clinical judgement in certain situations such as patients stopping dual antiplatelet therapy before surgery or in individuals at highest bleeding or thrombotic risk.

Discontinuation of Dual Antiplatelet Therapy Over 12 Months after Acute Coronary Syndromes Increases Risk for Adverse Events in Patients Treated with Percutaneous Coronary Intervention: Systematic Review and Meta‐Analysis

Duration of dual antiplatelet therapy (DAPT) following acute coronary syndrome (ACS) hospitalization remains to be defined, both for patients treated medically and for those undergoing percutaneous transluminal coronary angioplasty (PTCA). PubMed, Cochrane, and Google Scholar were systematically searched for studies including patients presenting with ACS, and treated either with DAPT longer than or shorter than 12 months. Multivariable-adjusted risk estimates for death and recurrent ACS with stopping DAPT after 12 months (odds ratios [OR] 95% confidence intervals [CI]) were pooled after logarithmic transformation according to random-effect models with inverse-variance weighting. Five studies with 49,586 patients were included. Median age was 66 (64-67) years, with 67% (65-75) males. Myocardial infarction (MI) represented the admission diagnosis for 88% (60-100) of the patients, and 66% (50-74) were treated with stenting. After a follow-up of 2.1 years (1.5-2.7), 40% (35-46) still on DAPT after 12 months and the rates of death or recurrent ACS were 16.6 (14.5-17.0). Risk of adverse events for patients stopping DAPT after 1 year was significantly increased (OR = 1.19 [1.07-1.32]) for those receiving stents, but not for patients managed medically (OR = 1.13 [0.95-1.35]). The increased risk did not vary according to age, gender, myocardial infarction as admission diagnosis, and kind of stent. Interruption of DAPT over 12 months after ACS increases the risk of adverse events for patients treated with PTCA, but not for those managed conservatively, independently from baseline features and admission diagnosis. This hypothesis-generating finding should be tested in randomized controlled trials.

Evolving Antithrombotic Strategies in Patients With Atrial Fibrillation Undergoing Percutaneous Coronary Intervention: Results From a Survey Among US Cardiologists

Many patients treated with oral anticoagulants for atrial fibrillation undergo percutaneous stent implantation, where dual antiplatelet therapy (DAPT) is also recommended. The current evidence to support triple oral antithrombotic therapy (TOAT) in these patients is limited, and new strategies are being discussed to optimize outcomes. There will be variation in antithrombotic strategies in patients with atrial fibrillation needing stenting. We surveyed US-based cardiologists serving as clinical investigators in academic sites and posted an online "question of the month" on cardiosource.org. Seventy-five (10.7%) responses were received to the email survey and 119 to the online question. Bare-metal stenting (BMS) was a priori preferred over drug-eluting stenting (DES) for 50.6% of patients. Only 8.8% of the responders chose newer anticoagulants in addition to DAPT as the preferred oral anticoagulant. For duration of TOAT, 79.4% of physicians recommended stopping DAPT at 1 month when BMS was used in patients presenting without acute coronary syndrome (ACS) vs 57.4% in patients with ACS. In patients implanted with a DES, 73.5% and 76.5% preferred stopping DAPT at 6 to 12 months (no ACS vs ACS, respectively). When asked which of the 2 antiplatelet agents they would recommend stopping after the above durations, 50% chose to quit aspirin. The survey highlights an interest in the new strategy of dropping aspirin, but the lack of concrete evidence triggers undesired diversity in clinical approaches. High-quality data on the efficacy and safety of such interventions are needed to further consolidate these approaches.

ADP-Receptor Inhibitors in the Perioperative Period: The Good, the Bad, and the Ugly

THE MANAGEMENT OF P2Y12-receptor inhibitors in the perioperative period represents a very common, yet controversial, area of the daily practice of most anesthesiologists. Dual antiplatelet therapy (DAPT), consisting of a P2Y12-receptor inhibitor in addition to aspirin, represents the standard of care for patients with coronary stents. Premature discontinuation of DAPT may lead to stent thrombosis (ST) with subsequent acute coronary events. Therefore, clinicians need to carefully balance the procedural bleeding risk while continuing therapy versus the thrombotic risk associated with stopping DAPT.

Abstract 84: Impact of Education on Dual Antiplatelet Therapy Adherence

Background: Lack of education is associated with adverse outcomes following percutaneous coronary intervention (PCI). Whether or not this is due to medication non-compliance, which is a risk factor for cardiac events, is unclear. Methods: PARIS (Patterns of Non-Adherence to Anti-Platelet Regimens in Stented Patients) is a multi-center, multinational, prospective registry of patients that have undergone stent implantation. The primary outcome is non-adherence to dual antiplatelet therapy (DAPT) defined as discontinuation, interruption, or disruption. Independently adjudicated outcomes were measured at 30 days after procedure. Discontinuation was defined as stopping DAPT because therapy was no longer needed, in contrast to interruption (stopping DAPT on under physician guidance because of a procedure or surgery), and disruption (stopping DAPT due to bleeding or non-compliance). Results: Among 5033 patients, the average age was 64 years, 74.5% were male, 40.9% presented with ACS, and 82% received a drug-eluting stent. At 30 days, the overall incidence of non-adherence was 2.1%. For either aspirin or thienopyridine, disruption occurred because of bleeding in 31.4% and because of non-compliance in 62.7%. There was a significant association between education level and overall non-adherence (p=0.006) (see table). A higher proportion of non-adherent patients achieved less than secondary education (22.3% vs.11.9%, p=0.0013) or secondary education (50.9% vs. 38.8%, p=0.016), while there was no significant difference in patients with higher levels of education. After adjusting for age, those who achieved university compared with less than secondary education had a lower risk of non-adherence (odds ratio 0.53, 95% confidence interval: 0.30-0.92, p=0.03). Conclusion: In this study, lower education levels were associated with non-adherence to DAPT within 30 days after PCI. This underlines the importance of patient education tools, especially for those with lower education status to enhance compliance in the real world.

Minimal withdrawal of dual antiplatelet agents under the guidance of a point-of-care platelet activity assay early after drug-eluting stent implantation for surgical removal of renal cell carcinoma

A 58-year-old man presented with unstable angina, for whom drug-eluting stent (DES) was successfully implanted in mid portion of left anterior descending artery and diagonal branch bifurcation. During hospitalization, renal cell carcinoma was incidentally found. Right radical nephrectomy was planned 5 weeks after the DES insertion to minimize thrombotic risk following discontinuation of antiplatelet agents. Seven days and 5 days prior to the operation, clopidogrel and aspirin were withdrawn respectively while platelet activity was serially monitored using VerifyNow Aspirin/P2Y12® assay. According to the results of the assay, the infusion of tirofiban was started from the third day after stopping dual antiplatelet therapy and maintained till 8 h prior to the nephrectomy. With the help of this bridge therapy, the surgery was successfully performed and histology confirmed a renal cell carcinoma. Clopidogrel and aspirin were resumed the next day after the operation. Eight days after his nephrectomy, the patient was discharged without stent thrombosis or bleeding complication.