Dual-pathway inhibition for secondary and tertiary antithrombotic prevention in cardiovascular disease.

Advances in antiplatelet therapies for patients with cardiovascular disease have improved patient outcomes over time, but the challenge of balancing the risks of ischaemia and bleeding remains substantial. Moreover, many patients with cardiovascular disease have a residual risk of ischaemic events despite receiving antiplatelet therapy. Therefore, novel strategies are needed to prevent clinical events through mechanisms beyond platelet inhibition and with an acceptable associated risk of bleeding. The advent of non-vitamin K antagonist oral anticoagulants, which attenuate fibrin formation by selective inhibition of factor Xa or thrombin, has renewed the interest in dual-pathway inhibition strategies that combine an antiplatelet agent with an anticoagulant drug. In this Review, we highlight the emerging pharmacological rationale and clinical development of dual-pathway inhibition strategies for the prevention of atherothrombotic events in patients with different manifestations of cardiovascular disease, such as coronary artery disease, cerebrovascular disease and peripheral artery disease.

The efficacy and safety of cangrelor in single vessel vs multivessel percutaneous coronary intervention: Insights from CHAMPION PHOENIX.

BACKGROUND: The intravenous, rapidly acting P2Y12 inhibitor cangrelor reduces the rate of ischemic events during PCI with no significant increase in severe bleeding. However, the efficacy and safety of cangrelor compared with clopidogrel in patients treated with single vessel (SV)-percutaneous coronary intervention (PCI) or multivessel (MV)-PCI remains unexplored. METHODS: We studied the modified intention-to-treat population of patients from the CHAMPION PHOENIX trial who were randomized to either cangrelor or clopidogrel. We used logistic regression and propensity score matching to evaluate the effect of cangrelor compared with clopidogrel on the primary efficacy outcome (composite of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis) at 48 hours. The safety outcome was moderate or severe Global Utilization of Streptokinase and tPA for Occluded Arteries bleeding at 48 hours. HYPOTHESIS: Cangrelor is as efficacious and safe as clopidogrel in both SV and MV PCI. RESULTS: Among 10 854 patients, 9204 (85%) underwent SV- and 1650 (15%) MV-PCI. After adjustment, cangrelor was associated with similar reductions vs clopidogrel in the primary efficacy outcome in patients undergoing SV-PCI (4.5% vs 5.2%; odds ratio [OR] 0.81 [0.66-0.98]) or MV-PCI (6.1% vs 9.8%, OR 0.59 [0.41-0.85]; Pint 0.14). Similar results were observed after propensity score matching (SV-PCI: 5.5% vs 5.9%, OR 0.93 [0.74-1.18]; MV-PCI: 6.2% vs 8.9%, OR 0.67 [0.44-1.01]; Pint 0.17). There was no evidence of heterogeneity in the treatment effect of cangrelor compared with clopidogrel for the safety outcome. CONCLUSIONS: In patients undergoing SV- or MV-PCI, cangrelor was associated with similar relative risk reductions in ischemic complications and no increased risk of significant bleeding compared with clopidogrel, which highlights the expanding repertoire of options for use in complex PCI.

Efficacy and safety of alirocumab in patients with or without prior coronary revascularization: Pooled analysis of eight ODYSSEY phase 3 trials.

BACKGROUND AND AIMS: Patients with atherosclerotic cardiovascular disease (ASCVD) and prior revascularization are at high risk of further cardiovascular events and may require additional lipid-lowering therapies beyond maximally tolerated statin therapy. We assessed the efficacy and safety of alirocumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, in patients with ASCVD, with or without prior coronary revascularization (percutaneous coronary intervention [PCI] or coronary artery bypass graft [CABG]). METHODS: Data from eight controlled (placebo/ezetimibe) phase 3 ODYSSEY trials were pooled and stratified by trial design: alirocumab 150 mg or 75 mg with possible dose increase to 150 mg (75/150 mg) every 2 weeks (Q2W) versus placebo, and alirocumab 75/150 mg Q2W versus ezetimibe. Most patients received background maximally tolerated statin therapy. RESULTS: Among 4629 randomized patients with hypercholesterolemia, 3382 had ASCVD including 2191 with prior revascularization. Although baseline characteristics were comparable between alirocumab and control groups, revascularized patients were more likely to be male, have had prior myocardial infarction/stroke, have higher lipoprotein (a) and PCSK9 levels, and were more often treated with high-intensity statin therapy. Alirocumab significantly reduced low-density lipoprotein cholesterol (LDL-C; primary endpoint; p < 0.0001), lipoprotein (a), non-high-density lipoprotein cholesterol, and apolipoprotein B levels from baseline to week 24 (vs. control), regardless of stratified treatment group or revascularization status. On-treatment LDL-C levels with alirocumab ranged from 45.6 to 64.8 mg/dL. Alirocumab had a similar safety profile regardless of revascularization status, and higher rates of injection-site reactions versus controls. CONCLUSIONS: Alirocumab is generally well-tolerated and effective with a similar safety profile in high-risk patients with or without prior revascularization (PCI/CABG).

Impact of proton pump inhibitors and dual antiplatelet therapy cessation on outcomes following percutaneous coronary intervention: Results From the PARIS Registry.

BACKGROUND: Proton pump inhibitors (PPI) may decrease the availability of clopidogrel by competitive antagonism, leading to a potential increase in ischemic events. METHODS: We evaluated patients from the all-comer PARIS registry treated with dual antiplatelet therapy (DAPT) with aspirin and clopidogrel following coronary stenting for outcomes stratified by PPI use. Two-year major adverse cardiovascular events (MACE), composite of cardiac death, myocardial infarction, definite or probable stent thrombosis or target lesion revascularization (TLR), and net adverse cardiac events (NACE), composite of MACE or Bleeding Academic Research consortium (BARC) type 3 or 5 bleeding were assessed. We also explored associations between PPI use and patterns of 2-year DAPT cessation. RESULTS: The cohort comprised 4635 patients (23% PPI users) with mean age 64.4 ±11.4 years. Two year adjusted risk of MACE (HR: 1.27, 95% CI: 1.04-1.55), NACE (HR: 1.21, 95% CI: 1.01-1.44) and TLR (HR: 1.33, 95% CI: 1.04-1.71) were significantly higher in PPI users vs. non-users, without a difference in bleeding. Although the incidence of 2-year DAPT discontinuation and interruption was similar, DAPT disruption was significantly lower among PPI users vs. non-users (10.0% vs. 14.7%, P <0.0001). Compared to non-PPI users on continued DAPT, disruption was associated with higher MACE in both PPI users (HR: 2.34, 95% CI: 1.38-3.97) and non-users (HR: 1.41, 95% CI: 1.02-1.94) but greater BARC 3,5 bleeding only in non-PPI users (HR: 2.06, 95% CI: 1.21-3.51). CONCLUSIONS: In clopidogrel treated PCI patients, the 2-year adjusted risk of MACE and NACE was significantly higher in PPI users driven by higher TLR compared to non-PPI users, without a difference in bleeding. PPI use was associated with lower incidence of DAPT disruption without an increase in disruption related bleeding compared to non-PPI users on DAPT. © 2016 Wiley Periodicals, Inc.

Safety and Tolerability of CSL112, a Reconstituted, Infusible, Plasma-Derived Apolipoprotein A-I, After Acute Myocardial Infarction: The AEGIS-I Trial (ApoA-I Event Reducing in Ischemic Syndromes I).

BACKGROUND: Human or recombinant apolipoprotein A-I (apoA-I) has been shown to increase high-density lipoprotein-mediated cholesterol efflux capacity and to regress atherosclerotic disease in animal and clinical studies. CSL112 is an infusible, plasma-derived apoA-I that has been studied in normal subjects or those with stable coronary artery disease. This study aimed to characterize the safety, tolerability, pharmacokinetics, and pharmacodynamics of CSL112 in patients with a recent acute myocardial infarction. METHODS: The AEGIS-I trial (Apo-I Event Reducing in Ischemic Syndromes I) was a multicenter, randomized, double-blind, placebo-controlled, dose-ranging phase 2b trial. Patients with myocardial infarction were stratified by renal function and randomized 1:1:1 to CSL112 (2 g apoA-I per dose) and high-dose CSL112 (6 g apoA-I per dose), or placebo for 4 consecutive weekly infusions. Coprimary safety end points were occurrence of either a hepatic safety event (an increase in alanine transaminase >3 times the upper limit of normal or an increase in total bilirubin >2 times the upper limit of normal) or a renal safety event (an increase in serum creatinine >1.5 times the baseline value or a new requirement for renal replacement therapy). RESULTS: A total of 1258 patients were randomized, and 91.2% received all 4 infusions. The difference in incidence rates for an increase in alanine transaminase or total bilirubin between both CSL112 arms and placebo was within the protocol-defined noninferiority margin of 4%. Similarly, the difference in incidence rates for an increase in serum creatinine or a new requirement for renal replacement therapy was within the protocol-defined noninferiority margin of 5%. CSL112 was associated with increases in apoA-I and ex vivo cholesterol efflux similar to that achieved in patients with stable coronary artery disease. In regard to the secondary efficacy end point, the risk for the composite of major adverse cardiovascular events among the groups was similar. CONCLUSIONS: Among patients with acute myocardial infarction, 4 weekly infusions of CSL112 are feasible, well tolerated, and not associated with any significant alterations in liver or kidney function or other safety concern. The ability of CSL112 to acutely enhance cholesterol efflux was confirmed. The potential benefit of CSL112 to reduce major adverse cardiovascular events needs to be assessed in an adequately powered phase 3 trial. CLINICAL TRIAL REGISTRATION: URL: https://clinicaltrials.gov. Unique identifier: NCT02108262.

Bivalirudin is associated with improved clinical and economic outcomes in heart failure patients undergoing percutaneous coronary intervention: Results from an observational database.

BACKGROUND: Outcomes with bivalirudin compare favorably with heparin ± GPIIb/IIIa receptor inhibition (heparin ± GPI) during percutaneous coronary intervention (PCI). Patients with congestive heart failure (CHF) have increased risk for complications. The objective was to investigate clinical and economic outcomes for bivalirudin ± GPI vs. heparin ± GPI among PCI patients with CHF. METHODS: Using the Premier Hospital Database, PCI patients with CHF were stratified by anticoagulant: bivalirudin, bivalirudin ± GPI, heparin and heparin ± GPI. The probability of receiving bivalirudin ± GPI was estimated using individual and hospital variables. Using propensity scores, each bivalirudin ± GPI patient was matched to a heparin ± GPI patient. The primary outcome was in-hospital death. Bleeding rates, transfusion, length of stay and in-hospital cost were ascertained. RESULTS: Overall, 116,313 patients at 315 hospitals received bivalirudin (n = 45,559) bivalirudin + GPI (n = 8,115), heparin (n = 27,972) or heparin + GPI (n = 34,667). Patients had STEMI (21.2%), NSTEMI (29.1%), unstable angina (16.6%), stable angina (5.7%) or other ischemic heart disease (24.2%). Of these, 79.1% of bivalirudin patients matched, resulting in 84,948 analyzed patients. Compared with heparin ± GPI patients, bivalirudin ± GPI patients had fewer deaths (3.3% vs. 3.9%; p < 0.0001), less clinically apparent bleeding (10.2% vs. 11.4%; p < 0.0001), clinically apparent bleeding with transfusion (2.7% vs. 3.2%, p <0.0001), and transfusion (8.5% vs. 9.8%, p < 0.0001). Patients receiving bivalirudin had shorter length of stay (6.3 vs. 6.8 days; p < 0.0001) and lower in-hospital cost (mean $26,706 vs. $27,166 [median $19,414 vs. $19,798]; p < 0.0001). In conclusion, this is the largest retrospective analysis of PCI patients with CHF and demonstrates bivalirudin ± GPI compared with heparin ± GPI is associated with lower inpatient rates of death, bleeding, and cost.

A reevaluation of the costs of heart failure and its implications for allocation of health resources in the United States.

The annual cost of heart failure (HF) is estimated at $39.2 billion. This has been acknowledged to underestimate the true costs for care. The objective of this analysis is to more accurately assess these costs. Publicly available data sources were used. Cost calculations incorporated relevant factors such as Medicare hospital cost-to-charge ratios, reimbursement from both government and private insurance, and out-of-pocket expenditures. A recently published Atherosclerosis Risk in Communities (ARIC) HF scheme was used to adjust the HF classification scheme. Costs were calculated with HF as the primary diagnosis (HF in isolation, or HFI) or HF as one of the diagnoses/part of a disease milieu (HF syndrome, or HFS). Total direct costs for HF were calculated at $60.2 billion (HFI) and $115.4 billion (HFS). Indirect costs were $10.6 billion for both. Costs attributable to HF may represent a much larger burden to US health care than what is commonly referenced. These revised and increased costs have implications for policy makers.

Impact of reduced glomerular filtration rate on outcomes in patients with ST-segment elevation myocardial infarction undergoing fibrinolysis: a CLARITY-TIMI 28 analysis.

Reduced glomerular filtration rate (GFR) is associated with adverse outcomes in patients with cardiovascular disease. We explored the relationship between GFR and angiographic and clinical outcomes in ST-segment elevation myocardial infarction (STEMI) patients receiving pharamacologic reperfusion, with or without clopidogrel. Data were available to estimate GFR in 3,252 STEMI patients undergoing fibrinolysis, randomized to clopidogrel versus placebo in the CLARITY-TIMI 28 trial. Patients with a creatinine > 2.5 mg/dl were excluded from the trial. We compared outcomes between patients with no, mild or moderate reductions in baseline estimated GFR (ml/min/1.73 m²) of ≥ 90, 60-89, and <60, respectively. Compared to patients with no (n = 841) or mildly reduced GFR (n = 1897), those with moderately reduced GFR (n = 514) were older, more often female, and were more likely to have diabetes and hypertension (P ≤ 0.001 for all). The risk of the primary endpoint (an occluded infarct-related artery on angiography or death/myocardial infarction by day 8), 30 day cardiovascular events (death, myocardial infarction, or urgent revascularization for recurrent ischemia) and 30 day Thrombolysis in Myocardial Infarction (TIMI) major or minor bleeding increased as GFR declined (P for trend 0.003, <0.0001, and 0.0008 respectively). The adjusted risk of 30 day ischemic complications remained higher in patients with moderately reduced versus normal GFR (OR 1.5, 95% CI 1.0-2.1, P = 0.04). Treatment with clopidogrel tended to yield greater benefit in patients with normal or mildly reduced GFR versus in patients with moderately reduced GFR. In conclusion, STEMI patients with reduced GFR treated with medical reperfusion, including dual antiplatelet therapy, have higher rates of adverse clinical outcome. Further research on optimal STEMI therapy in this high-risk group is warranted.

Intracoronary delivery of eptifibatide with the ClearWay® RX infusion catheter.

Acute coronary syndromes are caused by plaque rupture and the formation of an occlusive thrombus. Intracoronary (IC) bolus administration of eptifibatide may result in higher levels of platelet glycoprotein IIb/IIIa (GP IIb/IIIa) receptor occupancy (RO) in the local coronary bed, disaggregate thrombus in the epicardial artery, and microvasculature and thereby improve coronary flow. We report the use of the ClearWay® catheter to deliver IC eptifibatide to the lesion, theoretically thereby achieving higher local coronary concentrations of the eptifibatide, achieving a longer residence time and maximizing drug bioavailability at the site of the thrombus over the standard intravenous delivery mechanism and over intracoronary bolus administration via the guide catheter. This may then lead to superior thrombus disaggregation and improved microvascular perfusion. © 2011 Wiley-Liss, Inc.

Incremental benefit of 80-lead electrocardiogram body surface mapping over the 12-lead electrocardiogram in the detection of acute coronary syndromes in patients without ST-elevation myocardial infarction: Results from the Optimal Cardiovascular Diagnostic Evaluation Enabling Faster Treatment of Myocardial Infarction (OCCULT MI) trial.

BACKGROUND: The initial 12-lead (12L) electrocardiogram (ECG) has low sensitivity to detect myocardial infarction (MI) and acute coronary syndromes (ACS) in the emergency department (ED). Yet, early therapies in these patients have been shown to improve outcomes. OBJECTIVES: The Optimal Cardiovascular Diagnostic Evaluation Enabling Faster Treatment of Myocardial Infarction (OCCULT-MI) trial was a multicenter trial comparing a novel 80-lead mapping system (80L) to standard 12L ECG in patients with chest pain and presumed ACS. This secondary analysis analyzed the incremental value of the 80L over the 12L in the detection of high-risk ECG abnormalities (ST-segment elevation or ST depression) in patients with MI and ACS, after eliminating all patients diagnosed with ST-elevation MI (STEMI) by 12L ECG. METHODS: Chest pain patients presenting to one of 12 academic EDs were diagnosed and treated according to the standard care of that site and its clinicians; the clinicians were blinded to 80L results. MI was defined by discharge diagnosis of non-ST-elevation MI (NSTEMI) or unstable angina (UA) with an elevated troponin. ACS was defined as discharge diagnosis of NSTEMI or UA with at least one positive test result (troponin, stress test, angiogram) or revascularization procedure. RESULTS: Of the 1,830 patients enrolled in the trial, 91 patients with physician-diagnosed STEMI and 225 patients with missing 80L or 12L data were eliminated from the analysis; no discharge diagnosis was available for one additional patient. Of the remaining 1,513 patients, 408 had ACS, 206 had MI, and one had missing status. The sensitivity of the 80L was significantly higher than that of the 12L for detecting MI (19.4% vs. 10.4%, p = 0.0014) and ACS (12.3% vs. 7.1%, p = 0.0025). Specificities remained high for both tests, but were somewhat lower for 80L than for 12L for detecting both MI and ACS. Negative and positive likelihood ratios (LR) were not statistically different between groups. In patients with severe disease (defined by stenosis > 70% at catheterization, percutaneous coronary intervention, coronary artery bypass graft, or death from any cause), the 80L had significantly higher sensitivity for detecting MI (with equivalent specificity), but not ACS. CONCLUSIONS: Among patients without ST elevation on the 12L ECG, the 80L body surface mapping technology detects more patients with MI or ACS than the 12L, while maintaining a high degree of specificity.

Association between percutaneous coronary intervention and long-term C-reactive protein levels in patients with acute coronary syndromes.

C-reactive protein (CRP) is an independent predictor of risk in ACS patients, and it has been previously shown that percutaneous coronary intervention (PCI) is associated with an early rise in CRP. To assess the long-term relationship between PCI and CRP, we compared CRP levels at baseline, 30 days, 4 months and 24 months among patients in the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 trial who were treated with PCI and those who did not receive PCI. At study entry, CRP was significantly higher among patients who had undergone PCI (13.2 vs. 9.5 mg/l, P < 0.001). However, by day 30 CRP was significantly lower among patients who had undergone PCI for management of the index event (1.5 vs. 2.1 mg/l, P < 0.001) and remained lower at 4 months and by end of study (average 2 years after ACS). Using a multivariable model, we observed that PCI was associated with 8.6% lower CRP level at month 4 (P = 0.05) and 14.2% at approximately 2 years (P = 0.0028). These analyses suggest that although PCI may acutely increase inflammation, it may also serve a role in decreasing inflammation associated with atherosclerotic plaques via long-term mechanical stabilization.

Benefits of pharmacological facilitation with glycoprotein IIb-IIIa inhibitors in diabetic patients undergoing primary angioplasty for STEMI. A subanalysis of the EGYPT cooperation.

The Early Glycoprotein IIb-IIIa inhibitors in Primary angioplasty (EGYPT) cooperation aimed at evaluating, by pooling individual patient's data of randomized trials, the benefits of pharmacological facilitation with Gp IIb-IIIa inhibitors among STEMI patients undergoing primary angioplasty. In the current study we analyze the benefits of early Gp IIb-IIIa inhibitors in diabetic patients. The literature was scanned by formal searches of electronic databases (MEDLINE, EMBASE) from January 1990 to October 2007. We examined all randomized trials on facilitation by early administration of Gp IIb-IIIa inhibitors in STEMI. No language restrictions were enforced. Individual patients' data were obtained from 11 out of 13 trials, including 1,662 patients. Diabetes was present in 281 (16.9%). Early Gp IIb-IIIa inhibitors were associated with improved preprocedural TIMI 3 flow (26.0% vs. 13.1%, P = 0.006), postprocedural TIMI 3 flow (90.1% vs. 75.0%, P = 0.18), MBG 3 (40.8% vs. 30.4%, P = 0.004), and less distal embolization (11.6% vs. 20.8%, P = 0.05). However, early Gp IIb-IIIa inhibitors did not significantly reduce mortality (8.3% vs. 9.5%, P = 0.64). This meta-analysis shows that pharmacological facilitation with early administration of Gp IIb-IIIa inhibitors in STEMI patients with diabetes undergoing primary angioplasty, is associated with significant benefits in terms of preprocedural and postprocedural TIMI flow, improved myocardial perfusion, without significant benefits in mortality.

The Risk Score Profile: a novel approach to characterising the risk of populations enrolled in clinical studies.

AIMS: Interpreting the results and practice implications of clinical studies requires accurate characterisation of the baseline risk of the population. We evaluated the Thrombolysis in Myocardial Infarction (TIMI) risk score for STEMI as a tool to describe and compare the risk profile of populations enrolled in three clinical trials (InTIME-II, ASSENT-2 and MAGIC) and the National Registry of Myocardial Infarction. METHODS AND RESULTS: The risk score was calculated for each patient (N=121,085) and the frequency distribution plotted for each population. The Risk Score Profiles were compared using the Kolmogorov-Smirnov test. The Risk Score Profile demonstrated a striking concordance between the baseline risk of patients in InTIME-II and ASSENT-2 (median scores in each= 3[1,4], P=0.11). In contrast, the distributions in MAGIC (designed to enroll high risk) and NRMI (registry) were shifted significantly toward higher risk (median scores=4[3,5] for MAGIC and 4[2,6] in NRMI, P < 0.0001 for each vs. InTIME-II). A graded relationship between the risk score and mortality was evident in each study (P<0.0001). CONCLUSIONS: The frequency distribution of the TIMI Risk Score, or similar tools for risk assessment, may be used to quantify and readily compare the risk profile of populations enrolled in clinical studies.