Meta-analysis Comparing Long-Term Clinical Outcomes of Percutaneous Coronary Intervention versus no Intervention in Patients with Chronic Total Occlusion.

Chronic total occlusion (CTO) percutaneous coronary intervention (PCI) has substantially improved due to increasing operator experience and advancements in equipment, techniques, and management algorithms. However, the overall benefit of CTO PCI remains controversial, particularly since only a few randomized trials have been reported to date. Methods: We performed a meta-analysis to evaluate the efficacy of CTO PCI. The study outcomes were the occurrence of all-cause mortality, myocardial infarction, repeat revascularization, stroke, or freedom from angina at the longest documented follow-up period. Results: In five trials including 1790 patients, the mean age was 63 ± 10 years, 17% were female, with a median follow-up of 2.9 years. The procedural success rate ranged from 73% to 97% and the right coronary artery was the most involved artery (52%). There was no significant difference between CTO PCI and no intervention regarding all-cause mortality (odds ratio [OR]: 1.10, 95% confidence interval [CI]: 0.49-2.47, P = 0.82), myocardial infarction (OR: 1.20, 95% CI: 0.81-1.77, P = 0.36), repeat revascularization (OR: 0.67, 95% CI: 0.40-1.14, P = 0.14), or stroke (OR: 0.60, 95% CI: 0.26-1.36, P = 0.22). In two trials including 686 patients, significantly more patients were free of angina at 1 year, defined as the Canadian Cardiovascular Society grading of angina pectoris Grade 0, in the CTO PCI group compared to the no intervention group (OR: 0.52, 95% CI: 0.35-0.76, P < 0.001). Meta-regression analyses based on various trial-level covariates (gender, diabetes, previous myocardial infarction, PCI or coronary artery bypass graft, SYNTAX or J-CTO scores, and CTO-related artery percentages) did not suggest any statistically significant relationships. Conclusions: CTO PCI appears to have a similar efficacy profile compared to no intervention at long-term follow-up, but with a significant improvement of angina favoring PCI-treated patients. Further adequately powered and long-term trials are required to identify the best management strategy for patients with coronary CTO.

Spontaneous Reperfusion in Patients with Transient ST-Elevation Myocardial Infarction-Prevalence, Importance and Approaches to Management.

Patients with transient ST-elevation myocardial infarction (STEMI) or spontaneous resolution (SpR) of the ST-segment elevation on electrocardiogram could potentially represent a unique group of patients posing a therapeutic management dilemma. In this review, we discuss the potential mechanisms underlying SpR, its relation to clinical outcomes and the proposed management options for patients with transient STEMI with a focus on immediate versus early percutaneous coronary intervention. We performed a structured literature search of PubMed and Cochrane Library databases from inception to December 2020. Studies focused on SpR in patients with acute coronary syndrome were selected. Available data suggest that deferral of angiography and revascularization within 24-48 h in these patients is reasonable and associated with similar or perhaps better outcomes than immediate angiography. Further randomized trials are needed to elucidate the best pharmacological and invasive strategies for this cohort.

Precision Treatment in ACS-Role of Assessing Fibrinolysis.

Despite advancements in pharmacotherapy and interventional strategies, patients with acute coronary syndrome (ACS) remain at risk of recurrent thrombotic events. In addition to an enhanced tendency to thrombus formation, impairment in the ability to naturally dissolve or lyse a developing thrombus, namely impaired endogenous fibrinolysis, is responsible for a major part of this residual risk regardless of optimal antiplatelet medication. Global assessment of endogenous fibrinolysis, including a point-of-care assay, can identify patients with ACS at persistent high cardiovascular risk and might play an important role in allowing the personalisation of potent antithrombotic therapy to enhance fibrinolytic status, providing precision treatment of ACS to improve long-term outcome.

Effect of remote ischaemic conditioning on platelet reactivity and endogenous fibrinolysis in ST-elevation myocardial infarction: a substudy of the CONDI-2/ERIC-PPCI randomized controlled trial.

AIMS: Remote ischaemic conditioning (RIC) has been shown to reduce myocardial infarct size in animal models of myocardial infarction. Platelet thrombus formation is a critical determinant of outcome in ST-segment elevation myocardial infarction (STEMI). Whether the beneficial effects of RIC are related to thrombotic parameters is unclear. METHODS AND RESULTS: In a substudy of the Effect of Remote Ischaemic Conditioning on clinical outcomes in STEMI patients undergoing Primary Percutaneous Coronary Intervention (ERIC-PPCI) trial, we assessed the effect of RIC on thrombotic status. Patients presenting with STEMI were randomized to immediate RIC consisting of an automated autoRIC™ cuff on the upper arm inflated to 200 mmHg for 5 min and deflated for 5 min for four cycles (n = 53) or sham (n = 47). Venous blood was tested at presentation, discharge (48 h) and 6-8 weeks, to assess platelet reactivity, coagulation, and endogenous fibrinolysis using the Global Thrombosis Test and thromboelastography. Baseline thrombotic status was similar in the two groups. At discharge, there was some evidence that the time to in vitro thrombotic occlusion under high shear stress was longer with RIC compared to sham (454 ± 105 s vs. 403 ± 105 s; mean difference 50.1 s; 95% confidence interval 93.7-6.4, P = 0.025), but this was no longer apparent at 6-8 weeks. There was no difference in clot formation or endogenous fibrinolysis between the study arms at any time point. CONCLUSION: RIC may reduce platelet reactivity in the first 48 h post-STEMI. Further research is needed to delineate mechanisms through which RIC may reduce platelet reactivity, and whether it may improve outcomes in patients with persistent high on-treatment platelet reactivity.

Impact of Preadmission Morphine on Reinfarction in Patients With ST-Elevation Myocardial Infarction Treated With Percutaneous Coronary Intervention: A Meta-Analysis.

Opiates are the traditional analgesics used in patients with ST-elevation myocardial infarction (STEMI). Pharmacodynamic studies indicate that opiates delay the absorption of orally administered P2Y12 inhibitors and the onset of platelet inhibition. Whether these negative effects on platelet inhibition have an impact on clinical outcomes is unclear. A systematic review and meta-analysis was performed searching PubMed, MEDLINE, and Cochrane Central Register of Controlled Trials to identify studies comparing morphine and no-morphine treatment in STEMI patients undergoing primary percutaneous coronary intervention. The primary end point was the occurrence of in-hospital myocardial infarction, and secondary end points were in-hospital stroke and death. Four observational studies were identified, including 3,220 patients with STEMI. Morphine-treated patients had a higher unadjusted rate of reinfarction compared with patients not receiving morphine (1.5% vs. 0.67%, odds ratio (OR) 2.41; 95% confidence interval (CI), 1.11-5.21; P = 0.03). Unadjusted mortality rate was lower in morphine-treated patients (1.7% vs. 4.2%, OR 0.43, 95% CI, 0.23-0.81; P = 0.009). Exclusion of the study with baseline differences between groups showed more frequent reinfarction in the morphine group, but this was no longer statistically significant (1.3% vs. 0.5%, OR 2.02; 95% CI, 0.39-10.43; P = 0.40). There was no difference in stroke according to morphine treatment. Patients pretreated with morphine appear to have a higher rate of reinfarction than patients not receiving morphine. This may be attributable to opiate-related delay in P2Y12 inhibitor absorption and resultant delay in onset of platelet inhibition. These concerning findings indicate the need for prospective, randomized trials to assess the impact of opiates on clinical outcomes in STEMI.

Apixaban enhances endogenous fibrinolysis in patients with atrial fibrillation.

AIMS: Approximately 20% of ischaemic stroke patients exhibit spontaneous arterial recanalization, attributable to endogenous fibrinolysis, which strongly relates to improved functional outcome. The impact of oral anticoagulants on endogenous fibrinolysis is unknown. Our aim was to test the hypothesis that apixaban enhances endogenous fibrinolysis in non-valvular atrial fibrillation (NVAF). METHODS AND RESULTS: In a prospective cross-sectional analysis, we compared endogenous fibrinolysis in NVAF patients (n = 180) taking aspirin, warfarin, or apixaban. In a prospective longitudinal study, patients were tested before and after apixaban (n = 80). Endogenous fibrinolysis was assessed using the Global Thrombosis Test (GTT) and thromboelastography (TEG). Endogenous fibrinolysis [measured by GTT lysis time (LT)] was shorter on apixaban compared with warfarin or aspirin [median 1850 (IQR 1591-2300) vs. 2758 (2014-3502) vs. 2135 (1752-2463) s, P < 0.0001]. Among TEG indices, a small but significant difference in clot lysis time (CLT) was observed [apixaban 60.0 (45.0-61.0) vs. warfarin 61.0 (57.0-62.0) vs. aspirin 61.0 (59.0-61.0) min, P = 0.036]. Apixaban improved endogenous fibrinolysis measured using the GTT [LT pre-treatment 2204 (1779-2738) vs. on-treatment 1882 (1607-2374) s, P = 0.0003], but not by using TEG. Change in LT (ΔLT) with apixaban correlated with baseline LT (r = 0.77, P < 0.0001). There was weak correlation between ΔLT and ΔCLT in response to apixaban (r = 0.28, P = 0.02) and between on-apixaban LT and CLT (r = 0.25, P = 0.022). CONCLUSION: Apixaban enhances endogenous fibrinolysis, with maximal effect in those with impaired fibrinolysis pre-treatment. Apixaban-treated patients exhibit more favourable fibrinolysis profiles than those taking warfarin or aspirin. Whether apixaban may confer additional thrombotic risk reduction in NVAF patients with impaired fibrinolysis, compared to warfarin, merits further study.

Impaired endogenous fibrinolysis at high shear using a point-of-care test in STEMI is associated with alterations in clot architecture.

Impaired endogenous fibrinolysis is an adverse prognostic biomarker in acute coronary syndrome (ACS). Abnormally dense in vitro fibrin thrombi have been demonstrated in ACS patients and related to hypofibrinolysis using cumbersome, laboratory-based methods. We aimed to assess endogenous fibrinolysis using a point-of-care technique and relate this to clot architecture. From patients with ST-segment elevation myocardial infarction (STEMI), venous blood was drawn immediately on arrival to assess thrombotic status. Blood was assessed using the point-of-care Global Thrombosis Test which measures occlusive thrombus formation under high shear and subsequently endogenous fibrinolysis (lysis time, LT). Two samples per patient were run in parallel. In one channel, the measurement was allowed to proceed as normal. In the other, after occlusion, thrombus was extracted, washed, fixed in glutaraldehyde, dried, sputter-coated, and assessed using scanning electron microscope. Endogenous fibrinolysis was strongly associated fibrin fibre thickness (p = 0.0001). As LT increased (less efficient fibrinolysis), the fibrin network of the thrombus was significantly more compact and dense, with thinner fibrin fibres and smaller gaps. Fibrin fibre thickness correlated inversely with LT (r = - 0.89, p = 0.001). Adverse clot architecture in vitro is directly related to impaired endogenous fibrinolysis using a relatively new point-of-care technique in patients with STEMI. This may transform the relevance of fibrin clot architecture from an off-line laboratory association to being directly relevant to endogenous fibrinolysis at the patient bedside, which could be used as a near-patient test to guide prognosis and assess the effect of treatment.

Impaired endogenous fibrinolysis in ST-segment elevation myocardial infarction patients undergoing primary percutaneous coronary intervention is a predictor of recurrent cardiovascular events: the RISK PPCI study.

Aims: The endogenous fibrinolytic system serves to prevent lasting thrombotic occlusion and infarction following initiation of coronary thrombosis. We aimed to determine whether impaired endogenous fibrinolysis can identify patients with ST-segment elevation myocardial infarction (STEMI) who remain at high cardiovascular risk despite dual antiplatelet therapy (DAPT). Methods and results: A prospective, observational study was conducted in 496 patients presenting with STEMI for primary percutaneous coronary intervention (PPCI). Blood was tested on arrival pre-PPCI, at discharge and at 30 days to assess thrombotic status using the automated point-of-care global thrombosis test and patients followed for 1 year for major adverse cardiovascular events (MACEs). Endogenous fibrinolysis was significantly impaired [baseline lysis time (LT) ≥2500 s] in 14% of patients and was highly predictive of recurrent MACE [hazard ratio (HR) 9.1, 95% confidence interval (CI) 5.29-15.75; P < 0.001], driven by cardiovascular death (HR 18.5, 95% CI 7.69-44.31; P < 0.001) and myocardial infarction (HR 6.2, 95% CI 2.64-14.73; P < 0.001), particularly within 30 days. Fibrinolysis remained strongly predictive of MACE after adjustment for conventional risk factors (HR 8.03, 95% CI 4.28-15.03; P < 0.001). Net reclassification showed that adding impaired fibrinolysis improved the prediction of recurrent MACE by >50% (P < 0.001). Patients with spontaneous ST-segment resolution pre-PPCI had more rapid, effective fibrinolysis [LT 1050 (1004-1125) s vs. 1501 (1239-1997) s, P < 0.001] than those without. Lysis time was not altered by standard of care STEMI treatment including DAPT and was unchanged at 30 days. Conclusion: Endogenous fibrinolysis assessment can identify patients with STEMI who remain at very high cardiovascular risk despite PPCI and DAPT. Further studies are needed to assess whether these patients may benefit from additional, personalized antithrombotic/anticoagulant medication to reduce future cardiovascular risk. Clinical trial registration: http://www.clinicaltrials.gov. Unique identifier: NCT02562690.

Effect of P2Y12 inhibitors on thrombus stability and endogenous fibrinolysis.

Although used routinely to reduce thrombotic events in patients with coronary disease, the effects of P2Y12 inhibitors on thrombus stability and endogenous fibrinolysis are largely unknown. Blood taken from patients pre- and post-aspirin (n = 20) and on aspirin alone and on dual antiplatelet therapy comprising aspirin plus clopidogrel (n = 20), ticagrelor (n = 20) or cangrelor (n = 20), was tested using the Global Thrombosis Test. The number of "rebleeds" or drops (D) after early platelet-rich thrombus formation (occlusion time, OT), and before final lasting occlusion, was used as an inverse measure of thrombus stability. Whilst clopidogrel had no effect, ticagrelor and cangrelor both increased D significantly, reflecting increased thrombus instability [D pre- and post-clopidogrel 4.3 ±â€¯1.6 vs. 4.5 ±â€¯1.4, p = 0.833; pre- and post-ticagrelor 4.1 ±â€¯2.4 vs. 6.8 ±â€¯5.1, p = 0.048; pre- and post-cangrelor 3.6 ±â€¯2.0 vs. 7.9 ±â€¯8.9, p = 0.046]. Platelet reactivity was reduced by all P2Y12 inhibitors, demonstrated by OT prolongation (clopidogrel 378 ±â€¯87 s vs. 491 ±â€¯93 s, p < 0.001; ticagrelor 416 ±â€¯122 s vs. 549 ±â€¯121 s, p < 0.001; cangrelor 381 ±â€¯146 s vs. 613 ±â€¯210 s, p < 0.001). The magnitude of OT prolongation compared to baseline (ΔOT) was significantly greater for cangrelor compared to clopidogrel and ticagrelor. Cangrelor was the only agent to enhance fibrinolysis (lysis time pre- and post-cangrelor 1622[1240-2048]s vs. 1388[960-1634]s, p = 0.005). We demonstrate the ability to assess the effect of pharmacotherapy on thrombus stability in vitro and show that P2Y12 inhibitors potentiate thrombus instability at high shear. Cangrelor, and to a lesser extent ticagrelor, de-stabilised thrombus formation and cangrelor also enhanced fibrinolysis. Potentiation of thrombus instability could become a new pharmacological target, that may be particularly important in acute coronary syndromes.

Morphine Analgesia Pre-PPCI Is Associated with Prothrombotic State, Reduced Spontaneous Reperfusion and Greater Infarct Size.

The emergency management of ST-elevation myocardial infarction (STEMI) involves treatment with dual-antiplatelet therapy (DAPT) and primary percutaneous coronary intervention (PPCI). Pain is generally treated with opiates, which may delay gastric transit and reduce DAPT absorption. We sought to assess the effect of morphine on reperfusion, infarct size and thrombotic status in 300 patients presenting for PPCI. Morphine was given in a non-randomized fashion as required by emergency teams en route to the heart attack centre. All patients received DAPT and PPCI according to standard care, with optional glycoprotein IIb/IIIa inhibitor (GPI) use. Patients were assessed for ST-segment resolution, coronary flow, thrombotic status and peak troponin. Patients receiving morphine (n = 218; 72.7%) experienced less spontaneous ST-segment resolution pre-PPCI, lower rate of TIMI 2/3 flow in the infarct-related artery pre-PPCI and higher peak troponin level post-PPCI (median [interquartile range]; 1,906 [1,002-4,398] vs. 1,268 [249-2,920] ng/L; p = 0.016) than those who did not. Patients receiving morphine exhibited significantly enhanced platelet reactivity and impaired endogenous fibrinolysis on arrival, compared with no-morphine patients. Morphine administration was an independent predictor of failure of spontaneous ST-segment resolution after adjustment for other variables (odds ratio: 0.26; confidence interval: 0.08-0.84; p = 0.025). Among patients receiving GPI, there was no difference in pre-PPCI flow or peak troponin according to morphine use, suggesting that the adverse effects of morphine relate to delayed DAPT absorption, which may be overcome by GPI. Our hypothesis-generating data suggest that morphine use in STEMI is associated with enhanced platelet reactivity, reduced spontaneous myocardial reperfusion (pre-PPCI) and larger infarct size, and these adverse effects may be influenced by GPI use. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02562690.

Is there a Role for Oral Triple Therapy in Patients with Acute Coronary Syndromes Without Atrial Fibrillation?

BACKGROUND: Acute Coronary Syndrome (ACS) patients, despite treatment with Dual Anti- Platelet Therapy (DAPT), have up to 10% risk of recurrent Major Adverse Cardiac Events (MACE) in the short term. METHODS: Here we review studies using more potent antithrombotic agent combinations to reduce this risk, namely Triple Therapy (TT) with the addition of an oral anticoagulant, PAR-1 antagonist, or cilostazol to DAPT (mainly aspirin and clopidogrel), and discuss the limitations of trials to date. RESULTS: Generally speaking, TT leads to an increase in bleeding. Vorapaxar showed a signal for reducing ischaemic events, but increased intracranial haemorrhage 3-fold in the subacute phase of ACS, although remains an option for secondary prevention beyond the immediate subacute phase, particularly if prasugrel or ticagrelor are not available. Non-Vitamin K Oral Anticoagulants (NOACs) all increased bleeding, with only modest reduction in MACE noted with low dose rivaroxaban. Rivaroxaban can be considered combined with aspirin and clopidogrel in ACS patients at high ischaemic and low bleeding risk, without prior stroke/TIA. The combination of P2Y12 inhibitor and NOAC, without aspirin, looks promising. DAPT may be replaced, not by TT, but by dual therapy comprising a NOAC with a P2Y12 inhibitor. CONCLUSION: More potent antithrombotic regimens increase bleeding and should only be considered on an individual basis, after careful risk stratification. Accurate risk stratification of ACS patients, for both ischaemic and bleeding risk, is essential to allow individualised treatment.

Should STEMI Patients Receive Opiate Analgesia? The Morphine Paradox.

BACKGROUND: The very significant benefit of P2Y12 receptor inhibitor administration in patients with ST-elevation myocardial infarction (STEMI), in reducing future ischaemic events and stent thrombosis, is undisputed. Morphine analgesia is very frequently co-administered to these patients for pain relief, along with antiplatelet therapy, at the time of presentation, and prior to reperfusion with primary percutaneous coronary intervention. METHODS: Research and online content related to opiates use in STEMI was reviewed. Bibliographies of retrieved studies were searched manually for additional studies and reviews. RESULTS: There is sufficient data from pharmacokinetic and pharmacodynamic studies showing that the co-administration of morphine with oral P2Y12 receptor inhibitor results in delayed antiplatelet effects. However, whether this results in adverse outcomes remains unclear. Data from studies reporting the effect of morphine on clinical outcomes in STEMI are inconsistent, although they tend to be underpowered to show an effect on hard clinical outcomes, but some clearly show a relationship between morphine use and infarct size. Strategies to overcome the potentially significant negative impact of morphine on platelet reactivity in STEMI are discussed. CONCLUSION: Whilst clearly definitive, adequately powered, randomised controlled trials are lacking, we would recommend avoiding the combination of morphine with oral P2Y12 receptor inhibitors and recommend alternative strategies including intravenous platelet inhibitor strategies, in high risk patients.

Percutaneous coronary intervention with drug-eluting stent versus coronary artery bypass grafting: A meta-analysis of patients with left main coronary artery disease.

BACKGROUND: The relative efficacy and safety of percutaneous coronary intervention (PCI) with drug-eluting stents (DES), in comparison to coronary artery bypass grafting (CABG) for left main coronary artery disease (LMCAD) remains controversial. METHODS: We performed a meta-analysis of randomised studies comparing patients with LMCAD treated with PCI with DES versus those treated with CABG, with respect to clinical outcomes at 1, 3 and 5years. A secondary meta-analysis was performed according to low (<32), or high (≥33) SYNTAX score. RESULTS: Five studies comprising 4595 patients were included. There was no significant difference in all-cause death at all time points or when stratified with respect to SYNTAX score. The need for repeat revascularization was significantly higher with PCI at all time-points, and regardless of SYNTAX score. There was significant association between need for repeat revascularization with PCI and diabetics (p=0.04). At 5years, non-fatal MI was higher with PCI owing to increased non-procedural events (OR 3.00; CI 1.45-6.21; p=0.003). CABG showed higher rate of stroke at 1year (OR 0.21; CI 0.07-0.63; p=0.005). There was no difference in non-fatal MI or stroke at other time points, nor according to SYNTAX score. CONCLUSIONS: PCI with DES or CABG are equivalent strategies for LMCAD up to 5years with respect to death, regardless of SYNTAX score. PCI increases the rate of non-procedural MI at 5years. CABG avoids the need for repeat revascularization, especially in diabetics, but this benefit is offset by higher rate of stroke in the first year of follow up.

Use of bioresorbable vascular scaffold: a meta-analysis of patients with coronary artery disease.

BACKGROUND: Differences in outcomes between bioresorbable vascular scaffold (BVS) systems and drug-eluting metal stents (DES) have not been fully evaluated. We aimed to compare clinical and angiographic outcomes in randomised studies of patients with coronary artery disease (CAD), with a secondary analysis performed among registry studies. METHODS: A meta-analysis comparing outcomes between BVS and DES in patients with CAD. Overall estimates of treatment effect were calculated with random-effects model and fixed-effects model. RESULTS: In 6 randomised trials (3818 patients), BVS increased the risk of subacute stent thrombosis (ST) over and above DES (OR 2.14; CI 1.01 to 4.53; p=0.05), with a trend towards an increase in the risk of myocardial infarction (MI) (125 events in those assigned to BVS and 50 to DES; OR 1.36; CI 0.97 to 1.91; p=0.07). The risk of in-device late lumen loss (LLL) was higher with BVS than DES (mean difference 0.08 mm; CI 0.03 to 0.13; p=0.004). There was no difference in the risk of death or target vessel revascularisation (TVR) between the two devices. In 6 registry studies (1845 patients), there was no difference in the risk of death, MI, TVR or subacute ST between the two stents. Final BVS dilation pressures were higher in registry than in randomised studies (18.7±4.6 vs 15.2±3.3 atm; p<0.001). CONCLUSIONS: Patients treated with BVS had an increased risk of subacute ST and slightly higher LLL compared with those with DES, but this might be related to inadequate implantation techniques, in particular device underexpansion.

Spontaneous Coronary Artery Dissection: The Phantom Menace.

We present a case of a 66-year-old lady with chest pain, without dynamic 12-lead electrocardiographic (ECG) changes and normal serial troponin. Coronary angiography revealed a linear filing defect in the first obtuse marginal branch of the circumflex artery indicating coronary artery dissection, with superadded thrombus. She was managed medically with dual antiplatelet therapy and has responded well. Spontaneous coronary artery dissection (SCAD) is a rare cause of cardiac chest pain, which can be missed without coronary angiography. Unlike most other lesions in patients with unstable symptoms, where coronary intervention with stenting is recommended, patients with SCAD generally fare better with conservative measures than with intervention, unless there is hemodynamic instability.