Manivannan Srinivasan

Bivalirudin versus unfractionated heparin: a meta-analysis of patients receiving percutaneous coronary intervention for acute coronary syndromes

Objective Acute coronary syndrome (ACS) encompasses ST segment elevation myocardial infarction (STEMI), with generally high thrombus burden and non-ST segment elevation ACS (NSTE-ACS), with lower thrombus burden. In the setting of percutaneous coronary intervention (PCI) for ACS, bivalirudin appears superior to unfractionated heparin (UFH), driven by reduced major bleeding. Recent trials suggest that the benefit of bivalirudin may be reduced with use of transradial access and evolution in antiplatelet therapy. Moreover, a differential role of bivalirudin in ACS cohorts is unknown. Methods A meta-analysis of randomised trials comparing bivalirudin and UFH in patients with ACS receiving PCI, with separate analyses in STEMI and NSTE-ACS groups. Overall estimates of treatment effect were calculated with random-effects model. Results In 5 trials of STEMI (10 358 patients), bivalirudin increased the risk of acute stent thrombosis (ST) (OR 3.62; CI 1.95 to 6.74; p<0.0001) compared with UFH. Bivalirudin reduced the risk of major bleeding only when compared with UFH plus planned glycoprotein IIb/IIIa inhibitors (GPI) (OR 0.49; CI 0.36 to 0.67; p<0.00001). In 14 NSTE-ACS trials (25 238 patients), there was no difference between bivalirudin and UFH in death, myocardial infarction or ST. However, bivalirudin reduced the risk of major bleeding compared with UFH plus planned GPI (OR 0.52; CI 0.43 to 0.62; p<0.00001), or UFH plus provisional GPI (OR 0.68; CI 0.46 to 1.01; p=0.05). The reduction in major bleeding with bivalirudin was not related to vascular access site. Conclusions Bivalirudin increases the risk of acute ST in STEMI, but may confer an advantage over UFH in NSTE-ACS while undergoing PCI, reducing major bleeding without an increase in ST.

Relative effects of different non-vitamin K antagonist oral anticoagulants on global thrombotic status in atrial fibrillation

Abstract Non-vitamin K antagonist oral anticoagulants (NOACs) reduce the risk of thromboembolism in patients with atrial fibrillation (AF). There has been no head-to-head comparison of the effect of these agents on ex vivo thrombotic and thrombolytic status. Enhanced platelet reactivity and impaired endogenous thrombolysis are risk factors for recurrent thrombotic events. We aimed to assess the comparative effect of NOACs and warfarin using an ex vivo test of thrombosis and thrombolysis. Eighty patients with newly diagnosed non-valvular AF were tested before, and after being established on apixaban (n = 20), dabigatran (n = 20), rivaroxaban (n = 20), or warfarin (n = 20). Thrombotic status was assessed with the automated, point-of-care Global Thrombosis Test (GTT) that assesses both platelet reactivity and endogenous thrombolysis from native blood. The time taken to form an occlusive thrombus (occlusion time, OT) and the time required to restore flow through endogenous thrombolysis (lysis time, LT) were measured. All anticoagulants caused OT prolongation compared to baseline (apixaban 403 ± 102s vs. 496 ± 125s, p = 0.006; dabigatran 471 ± 106s vs. 656 ± 165s, p < 0.00001; rivaroxaban 381 ± 119s vs. 579 ± 158, p < 0.00001; warfarin 420 ± 145s vs. 604 ± 124s, p < 0.00001). Apixaban reduced LT from baseline (1895[1702–2167]s vs. 1435[347–1990]s; p = 0.006). A trend for LT reduction was seen with other NOACs (dabigatran 1594[1226–2069]s vs. 1539[561–2316]s, p = 0.499; rivaroxaban 2085[1366–2428]s vs. 1885[724–2420]s, p = 0.295) but not with warfarin (1490[1206–1960]s vs. 1776[1545–2334], p = 0.601). Our results suggest that NOACs and warfarin have a similar favorable effect on reducing platelet reactivity. All NOACs exhibited a trend toward enhancing endogenous thrombolytic status, although this was significant only for apixaban. This raises the possibility of using NOACs to enhance impaired endogenous fibrinolysis in patients at high-thrombotic risk.

“Mind the gap” acute coronary syndrome in women: A contemporary review of current clinical evidence

The incidence and prevalence of coronary artery disease in women has exceeded that in men over the past four decades, and although a significant decline in mortality has occurred in the past two decades, there is a growing body of evidence suggesting that there are gender differences between the clinical manifestations and course of coronary artery disease, as well as differences in treatment and treatment response. This review article considers the current literature regarding the gender-specific manifestation of acute coronary syndromes. Through the review of basic science articles, subsets of trial data, and meta-analyses, the gender-specific differences in within acute coronary syndromes are considered in terms of diagnostic dilemmas, pathophysiology, and treatment options (including pharmacological, percutaneous and surgical methods). Finally, acute coronary syndromes and their management in the special circumstance of pregnancy are also reviewed.

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.

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.

MORPHINE USE IMPAIRS THROMBOTIC STATUS IN PATIENTS WITH ST-ELEVATION MYOCARDIAL INFARCTION UNDERGOING PRIMARY PERCUTANEOUS CORONARY INTERVENTION

Patients presenting with ST-elevation myocardial infarction (STEMI) exhibit a prothrombotic state and are treated with antiplatelet medications and primary percutaneous coronary intervention (PPCI). Morphine is widely used as an analgesic in patients with STEMI. However, it is also known to delay

98 Assessment of Endogenous Thrombolysis Predicts Cardiovascular Risk in Patient with ST-elevation Myocardial Infarction

Background Increasingly potent antithrombotic medications have been developed to reduce thrombosis in patients presenting with ST-elevation MI (STEMI). These reduce thrombosis but increase bleeding risk. Identification of STEMI patients at high risk of recurrent thrombosis could allow targeted treatment with potent antithrombotic medications, with less potent agents in others, to reduce bleeding. We aimed to assess the risk of thrombosis by assessing platelet reactivity, as well as the efficacy of endogenous thrombolysis, the innate ability to dissolve thrombus. Methods In 150 patients with STEMI, global thrombotic status was assessed at baseline, immediately before primary percutaneous coronary intervention (PPCI), at hospital discharge and at 30 days. Peripheral, non-anticoagulated blood was tested using the point-of-care Global Thrombosis Test, which assesses the time to form an occlusive thrombus under high shear (occlusion time, OT), and the time to dissolve this in vitro formed thrombus, through endogenous thrombolysis (lysis time, LT). Results Impaired endogenous thrombolysis (prolonged LT ≥3000s), seen in 9% of patients pre-PPCI, was significantly associated to the occurrence of major adverse cardiac events at 30 days (HR: 3.26, 95% CI: 2.32–29.19, p = 0.004), driven by cardiovascular death (HR: 3.12, 95% CI: 3.82–35.23, p < 0.001). Enhanced (rapid) endogenous thrombolysis (median LT 1040s [IQR: 940–1105]s), seen in 17% of patients pre-PPCI, was associated with spontaneous coronary reperfusion, ST-segment resolution, TIMI-2/3 flow pre-PPCI, favourable outcomes and longer baseline OT (515 ± 178 vs. 385 ± 177, p < 0.001). Pre-PPCI OT was shorter in those with recurrent myocardial infarction and stroke than those without (244 ± 130s vs. 414 ± 183s, p = 0.025). OT was prolonged at hospital discharge (500 ± 141s vs. 407 ± 184s, p < 0.001) and 30 days (577 ± 131s vs. 407 ± 184s, p < 0.001) compared to baseline, likely due to the effects of antiplatelet medication. Conclusions In patients with STEMI, endogenous thrombolysis, when impaired, is associated with increased cardiovascular risk, and when enhanced, with spontaneous reperfusion and favourable outcomes. Identification of impaired endogenous thrombolytic status may serve as a novel biomarker to identify high-risk patients who may benefit from enhanced pharmacotherapy to reduce adverse events.

Treatment of calcified coronary artery lesions

ABSTRACT Heavily calcified coronary plaques represent a complex lesion subset and a challenge to the interventional cardiologist, as they are often resistant to simple plaque modification with conventional balloon angioplasty. Inadequate plaque modification can lead to stent underdeployment, which itself predisposes to in-stent restenosis and stent thrombosis. Over the years, a number of mechanical devices ranging from modified angioplasty balloons to atherectomy devices have become available in order to tackle such lesions. Here we review these devices concentrating on the evidence behind their use.

14 Bivalirudin Versus Unfractioned Heparin in Patients Receiving Percutaneous Coronary Intervention for Acute Coronary Syndromes

Background In the setting of percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS), bivalirudin has been shown to be superior to unfractionated heparin (UFH) in reducing major adverse cardiac events, driven by a reduction in major bleeding. With increasing use of radial access and potent anti-platelet therapy, recent trials suggest that the previous benefit observed with bivalirudin may now be substantially reduced. ACS encompasses both ST-elevation ACS (STE-ACS), with generally high thrombus burden and non-ST-elevation ACS (NSTE-ACS), with lower thrombus burden. Whether bivalirudin offers differential clinical benefit in these two groups, is unknown. Methods We conducted a meta-analysis of randomised trials comparing bivalirudin and UFH in patients receiving PCI for ACS divided into STE-ACS and NSTE-ACS groups. Overall estimates of effect were calculated with a fixed-effects model or random-effects model. Results In STE-ACS, 6 trials (10,368 patients) were identified. Compared to UFH, bivalirudin increased the risk of myocardial infarction (MI) (OR 1.41; CI 1.02–1.95; p = 0.04) and acute stent thrombosis (ST) (OR 3.81; CI 2.15–6.74; p < 0.00001), and reduced the risk of major bleeding when comparing bivalirudin combined with provisional glycoprotein IIb/IIIa inhibitor (GPI) use versus UFH with planned GPI use (OR 0.51; CI 0.41–0.64; p < 0.00001). We identified 15 NSTE-ACS trials (25,250 patients). There was no difference between bivalirudin and UFH in the occurrence of death (OR 0.98; CI 0.71–1.33; p = 0.88), MI (OR 1.09; CI 0.98–1.21; p = 0.12), or ST (OR 1.20; CI 0.85–1.70; p = 0.31). However, bivalirudin significantly reduced the risk of major bleeding compared to UFH, either with provisional use of GPI in both arms (OR 0.62; CI 0.48–0.81; p = 0.0005), or in the bivalirudin arm only (OR 0.53; CI 0.44–0.63; p < 0.00001). Conclusions Although in STE-ACS, bivalirudin is associated with an increased risk of ischaemic events, it may confer an advantage over UFH in NSTE-ACS patients undergoing PCI, with a reduction in major bleeding and without an increase in ischaemic events. Large scale multi-centre randomised trials are needed to elucidate the optimal anti-thrombotic regimen in patients presenting with STE-ACS undergoing PCI in the contemporary era.

Ischaemic heart disease in men

To the Editor: A recent study in Heart by Edwards and colleagues found an interesting association between rheumatoid factor (RF) and ischaemic heart disease.1 In a forthcoming study we examined independently the related subject of the role of systemic inflammation in relation to clinical outcome.2 This subsequent study reports an association between systemic inflammation, as measured by C reactive protein (CRP), and all-cause mortality (n = 22 982). We also found a weak association with heart disease, but the study was, we …