Mohamed Farag

Hydralazine and nitrates alone or combined for the management of chronic heart failure: A systematic review.

BACKGROUND Hydralazine (H) and nitrates (Ns), when combined, reduced morbidity and mortality in some trials of chronic heart failure (CHF). It is unclear whether either agent used alone provides similar benefits. We aimed to evaluate the effects of H and/or N in patients with CHF. METHODS A systematic review of randomised trials assessing the effects of H and N in CHF. For meta-analysis, only the endpoints of all-cause mortality and cardiovascular mortality were considered. RESULTS In seven trials evaluating H&N in 2626 patients, combination therapy reduced all-cause mortality (OR 0.72; 95% CI 0.55-0.95; p=0.02), and cardiovascular mortality (OR 0.75; 95% CI 0.57-0.99; p=0.04) compared to placebo. However, when compared to angiotensin converting enzyme inhibitors (ACEIs), combination therapy was associated with higher all-cause mortality (OR 1.35; 95% CI 1.03-1.76; p=0.03), and cardiovascular mortality (OR 1.37; 95% CI 1.04-1.81; p=0.03). For N alone, ten trials including 375 patients reported all-cause mortality and showed a trend to harm (13 deaths in those assigned to nitrates and 7 to placebo; OR 2.13; 95% CI 0.88-5.13; p=0.09). For H alone, three trials showed no difference in all-cause mortality compared to placebo (OR 0.96; 95% CI 0.37-2.47; p=0.93), and two trials suggested inferiority to ACEI (OR 2.28; 95% CI 1.03-5.04; p=0.04). CONCLUSIONS Compared to placebo, H&N reduces mortality in patients with CHF. Whether race or background therapy influences benefit is uncertain, but on direct comparison H&N appears inferior to ACEI. There is little evidence to support the use of either drug alone in CHF.

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.

Is the diagnostic coding position of acute heart failure related to mortality? A report from the Euro Heart Failure Survey-1

Most studies on acute heart failure (HF) exploring the relationship between admissions to hospital for HF and subsequent outcomes have focused only on HF coded as the primary diagnosis, but many other patients have admissions complicated by HF requiring attention. Failure to quantify the total hospital burden of HF underestimates its health economic impact, leading to underprovision of resources for its care.

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

Adjunctive therapies to reduce thrombotic events in patients with a history of myocardial infarction: role of vorapaxar

Acute myocardial infarction (AMI) is generally attributed to coronary atherothrombotic disease. Platelet activation is essential for thrombus formation and is thus an important target for pharmacological intervention to prevent and treat AMI. Despite contemporary treatment with dual antiplatelet therapy, including acetylsalicylic acid and adenosine diphosphate receptor antagonists, patients with prior AMI remain at increased risk of future thrombotic events. This has stimulated the search for more potent antithrombotic agents. Among these is the oral protease-activated receptor-1 antagonist vorapaxar, which represents a new oral antiplatelet agent to reduce thrombotic risk in patients with atherothrombotic disease. The TRACER and the TRA 2°P-TIMI 50 trials concluded that vorapaxar in addition to standard therapy reduced ischemic adverse cardiac events. A remarkable benefit was observed in patients with stable atherosclerotic disease, particularly those with a previous history of AMI. Although favorable effects were seen in reduction of adverse cardiac events, this was associated with excess major and intracranial bleeding, particularly in patients at high risk of bleeding and those with a history of stroke or transient ischemic attack. Currently, the lack of a reliable individualized risk stratification tool to assess patients for thrombotic and bleeding tendencies in order to identify those who might gain most net clinical benefit has led to limited use of vorapaxar in clinical practice. Vorapaxar may find a niche as an adjunct to standard care in patients at high risk of thrombotic events and who are at low risk of bleeding.

Catheter ablation for AF improves global thrombotic profile and enhances fibrinolysis

Patients with atrial fibrillation (AF) are at increased risk of thrombotic events despite oral anticoagulation (OAC). Radiofrequency catheter ablation (RFCA) can restore and maintain sinus rhythm (SR) in patients with AF. To assess whether RFCA improves thrombotic status. 80 patients (71% male, 64 ± 12y) with recently diagnosed AF, on OAC and scheduled to undergo RFCA or DC cardioversion (DCCV) were recruited. Thrombotic status was assessed using the point-of-care global thrombosis test (GTT), before, and 4–6 weeks after DCCV and 3 months after RFCA. The GTT first measures the time taken for occlusive thrombus formation (occlusion time, OT), while the second phase of the test measures the time taken to spontaneously dissolve this clot through endogenous thrombolysis (lysis time, LT). 3 months after RFCA, there was a significant reduction in LT (1994s [1560; 2475] vs. 1477s [1015; 1878]) in those who maintained SR, but not in those who reverted to AF. At follow-up, LT was longer in those in AF compared to those in SR (AF 2966s [2038; 3879] vs. SR 1477s [1015; 1878]). RFCA resulted in no change in OT value, irrespective of rhythm outcome. Similarly, there was no change in OT or LT in response to DCCV, irrespective of whether SR was restored. Successful restoration and maintenance of SR following RFCA of AF is associated with improved global thrombotic status with enhanced fibrinolysis. Larger studies are required to confirm these early results and investigate whether improved thrombotic status translates into fewer thromboembolic events.

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.