Evaluation of the F2R IVS-14A/T PAR1 polymorphism with subsequent cardiovascular events and bleeding in patients who have undergone percutaneous coronary intervention.

Abnormal platelet reactivity is associated with recurrent ischemia and bleeding following percutaneous coronary intervention (PCI). Protease-activated receptor-1 (PAR1), encoded by F2R, is a high affinity thrombin receptor on platelets and the target of the antiplatelet drug vorapaxar. The intronic single nucleotide polymorphism F2R IVS-14 A/T affects PAR1 receptor density and function. We hypothesized that carriers of the T allele, who have been shown to have decreased platelet reactivity, would be at lower risk for thrombotic events, but higher risk for bleeding following PCI. Using BioVU, the Vanderbilt DNA repository linked to the electronic medical record, we studied 660 patients who underwent PCI for unstable or stable coronary artery disease. Primary outcome measures were major adverse cardiovascular events (MACE, composite of revascularization, MI, stroke, death) and bleeding (assessed by Bleeding Academic Research Consortium scale) over 24 months. The minor allele (T) frequency was 14.8 %. There were no genotypic differences in the frequency of MACE (33.7, 28.8, and 31.6 % for A/A, A/T, and T/T respectively, P = 0.50) or bleeding (15.7, 14.7, and 18.8 % for A/A, A/T, and T/T respectively, P = 0.90). In a Cox regression model, fully adjusted for age, race, sex, BMI, and smoking status, carrying a T allele was not associated with MACE (HR 1.19, 95 % CI 0.89-1.59, P = 0.23) or bleeding (HR 0.73, 95 % CI 0.37-1.4, P = 0.34). In conclusion, in our population, F2R IVS-14 PAR1 variability does not affect risk of MACE or bleeding following PCI.

Considerations in antithrombotic therapy among patients undergoing transcatheter aortic valve implantation.

Aortic stenosis (AS) accounts for the majority of valvular abnormalities requiring surgical intervention. Platelet dysfunction has been demonstrated among patients with severe aortic stenosis which may predispose patients to bleeding or ischemic events. Surgical aortic valve replacement (AVR) is the standard therapy for severe symptomatic AS; however, a number of patients have very high or prohibitive surgical risk. Transcatheter aortic valve implantation (TAVI) has been shown to be superior to medical therapy among inoperable patients and non-inferior to AVR in patients with high surgical risk. In comparison to AVR, TAVI has been associated with a higher incidence of ischemic cerebrovascular events, conduction abnormalities necessitating permanent pacemaker placement, and vascular complications. Current practice guidelines recommend dual antiplatelet therapy (DAPT) following TAVI using a combination of low dose aspirin and clopidogrel for 3-6 months. This regimen may be adjusted in patients with clinical bleeding events or indications for concomitant systemic anticoagulation. Recent and ongoing trials aim to clarify the optimum antithrombotic regimen and duration of therapy following TAVI. Collectively, early studies have not revealed additional benefit of adding clopidogrel to aspirin therapy in regards to reducing ischemic events, but have shown a trend towards increase in major bleeding. TAVI has proven successful, and as its breadth of utility is expanded, further studies are needed to define optimum antithrombotic therapy following TAVI. This article will review the current data for antiplatelet and anticoagulant therapy following TAVI.

Combining PCI and CABG: the role of hybrid revascularization.

Hybrid coronary revascularization combines the benefits of both percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) in the treatment of multivessel coronary artery disease (CAD) by combining the benefits of the LIMA-to-LAD graft and drug eluting stent (DES) to non-LAD regions. Through this approach, a patient receives the long-term benefit of the LIMA graft and avoids the morbidity of a full sternotomy and saphenous vein grafts. Available data related to outcomes following hybrid revascularization is limited to small studies. In this review we seek to provide an overview of hybrid revascularization in the era of modern drug eluting stent technology, discuss appropriate patient selection, and comment on future trial design. Additionally, we review the recent literature pertaining to the hybrid approach.

Persistent high on-treatment platelet reactivity in acute coronary syndrome.

Persistent high on-treatment platelet reactivity in acute coronary syndrome (ACS) patients managed with appropriate antiplatelet therapy has been correlated with increased risk of cardiovascular events; however, the evolution of this phenomenon overtime is not well known. We investigated platelet activity at a three month follow-up after initial presentation with an ACS. We enrolled a total of 124 patients in the study, 65 were diagnosed with ACS and 59 controls who presented with non-cardiac chest pain for baseline comparisons. Of the enrolled patients, we had 25 ACS patients return, in stable condition, three months after their initial presentation for repeat platelet functional testing. Epinephrine (EPI), adenosine diphosphate (ADP), and arachidonic acid induced platelet aggregation were monitored at baseline with repeat measurement of EPI- and ADP-stimulated aggregation at follow-up. In addition, P-selectin and PAC-1 expression were monitored at presentation and at a three month follow-up period. ACS patients were maintained on aspirin therapy during the intervening period. At the three month follow-up visit, ACS patients initiated on aspirin had no significant percentage change in aggregation to submaximal concentrations of EPI and ADP. They also had no significant percentage change in PAC-1 or P-selectin expression. This study demonstrates persistent high on-treatment platelet reactivity in ACS patients at a three month follow-up, which may place these patients at increased risk of recurrent cardiovascular events.

Anchoring IgG-degrading enzymes to the surface of platelets selectively neutralizes antiplatelet antibodies.

Immune thrombocytopenia (ITP) is an acquired bleeding disorder characterized by immunoglobulin G (IgG)-mediated platelet destruction. Current therapies primarily focus on reducing antiplatelet antibodies using immunosuppression or increasing platelet production with thrombopoietin mimetics. However, there are no universally safe and effective treatments for patients presenting with severe life-threatening bleeding. The IgG-degrading enzyme of Streptococcus pyogenes (IdeS), a protease with strict specificity for IgG, prevents IgG-driven immune disorders in murine models, including ITP. In clinical trials, IdeS prevented IgG-mediated kidney transplant rejection; however, the concentration of IdeS used to remove pathogenic antibodies causes profound hypogammaglobulinemia, and IdeS is immunogenic, which limits its use. Therefore, this study sought to determine whether targeting IdeS to FcγRIIA, a low-affinity IgG receptor on the surface of platelets, neutrophils, and monocytes, would be a viable strategy to decrease the pathogenesis of antiplatelet IgG and reduce treatment-related complications of nontargeted IdeS. We generated a recombinant protein conjugate by site-specifically linking the C-terminus of a single-chain variable fragment from an FcγRIIA antibody, clone IV.3, to the N-terminus of IdeS (scIV.3-IdeS). Platelets treated with scIV.3-IdeS had reduced binding of antiplatelet IgG from patients with ITP and decreased platelet phagocytosis in vitro, with no decrease in normal IgG. Treatment of mice expressing human FcγRIIA with scIV.3-IdeS reduced thrombocytopenia in a model of ITP and significantly improved the half-life of transfused platelets expressing human FcγRIIA. Together, these data suggest that scIV.3-IdeS can selectively remove pathogenic antiplatelet IgG and may be a potential treatment for patients with ITP and severe bleeding.

Recurrent myocardial infarction associated with gefitinib therapy.

Gefitinib is an epidermal growth factor tyrosine kinase inhibitor used as a targeted chemotherapeutic agent in the treatment of lung cancer and other solid malignancies. Unlike other tyrosine kinase inhibitors, gefitinib is not recognized as having significant cardiotoxicity though it has been reported to be capable of potentiating ADP-induced activation and thromboxane A(2) generation in platelets which could promote thrombosis. We report a case of recurrent myocardial infarction with angiographically documented vulnerable plaque rupture in a patient receiving chronic gefitinib therapy for metastatic carcinoid tumor. Platelet function studies revealed marked ADP-induced platelet activation that was only suppressed by high-dose clopidogrel. Measurement of urine 11-dehydro-thromboxane B(2) also indicated persistent thromboxane A(2) generation despite aspirin therapy, an emerging risk factor for adverse cardiovascular events.

Percutaneous Interventions for Secondary Mitral Regurgitation.

Mitral regurgitation is frequently associated with ventricular dysfunction and carries a high mortality. Guideline-directed medical therapy, surgical mitral valve repair or replacement, and, in the setting of advanced heart failure, heart transplant and left ventricular assist devices have been the mainstay of treatment. However, rapid advancement in the field has resulted in approval of edge-to-edge mitral valve repair with the MitraClip, and there are several novel catheter-based percutaneous options in clinical trials. Percutaneous options, while promising, must be deployed in patients who are most likely to benefit, and thus, understanding the pathophysiology of specific subgroups of patients with functional mitral regurgitation (eg, disproportionate versus proportionate mitral regurgitation) is key to the success of new devices. We review the pathophysiology, percutaneous therapeutic treatment options, and ongoing clinical trials for functional mitral regurgitation.

Association of asymptomatic peripheral arterial disease with vascular events in patients with stroke or transient ischemic attack.

BACKGROUND AND PURPOSE: Patients with stroke and patients with transient ischemic attack (TIA) are at high risk for vascular events and may not exhibit the signs and symptoms of peripheral arterial disease (PAD). We investigated if asymptomatic PAD detected by ankle brachial index <0.9 is independently associated with recurrent vascular events in patients with stroke or TIA. METHODS: In this prospective longitudinal hospital-based cohort study, asymptomatic PAD was detected by ankle brachial index measurement in consecutive patients with stroke and patients with TIA. They were assessed for stroke risk factors, ankle brachial index measurement, and laboratory parameters known to be associated with stroke risk. These patients were followed for composite vascular events, including stroke, TIA, myocardial infarction, and vascular death. RESULTS: In a 1-year period, 102 patients were evaluated, of whom 26% had asymptomatic PAD. All patients were followed for a median period of 2.1 years from the index stroke/TIA (range, 1.0 to 2.7 years) for vascular events. Kaplan-Meier curve showed fewer patients with asymptomatic PAD remained free of composite vascular events (48% compared with 84% in the no-PAD group; log rank, P=0.0001). Asymptomatic PAD was significantly associated with composite vascular events before (hazard ratio, 4.2; 95% CI, 1.9 to 9.3; P=0.0003) and after adjustment for confounders (hazard ratio, from Model 1, 2.8; 95% CI, 1.1 to 7.2; P=0.03 and Model 2, 3.4; 95% CI, 1.4 to 8.2, P=0.006). Asymptomatic PAD was also significantly associated with stroke before (hazard ratio, 6.5; 95% CI, 2.1 to 19.9; P=0.001) and after adjustment for confounders (hazard ratio from Model 1, 4.8; 95% CI, 1.5 to 15.3; P=0.009 and Model 2, 5.2; 95% CI, 1.5 to 17.6; P=0.008). CONCLUSIONS: In patients with stroke or TIA, asymptomatic PAD is independently associated with recurrent vascular events and stroke.

Definitions of peri-procedural myocardial infarction and the association with one-year mortality: Insights from CHAMPION trials.

BACKGROUND: Controversies exist over the appropriate definition for peri-procedural myocardial infarction (PPMI) and its association with mortality. This study aims to evaluate one-year survival following percutaneous coronary intervention (PCI) and the association of different definitions of PPMI with survival among patients with stable angina (SA) or acute coronary syndrome (ACS) in the contemporary era. METHODS: We used data from the CHAMPION PLATFORM and CHAMPION PCI trials of patients undergoing PCI and conducted univariable and multivariable Cox proportional hazard regression models to evaluate mortality risk during the first year after PCI. A blinded events committee adjudicated suspected PPMI defined by biomarker elevations ≥3× the upper limit of normal (ULN) or new Q-waves. We further analyzed PPMI by the magnitude of CK-MB elevation ([a] 3 to <5× ULN, [b] 5 to <10× ULN, [c] ≥10× ULN) or by the 2nd universal definition of myocardial infarction (UDMICK-MB) excluding patients with evidence of myocardial infarction (MI) prior to PCI. RESULTS: Of 13,968 patients, 11% initially presented with SA, and 89% with ACS. One-year mortality was 3.4% (SA: 1.5%; ACS: 3.6%). PPMI occurred in 6.3% of the patients (3 to <5× ULN: 2.5%; 5 to <10× ULN: 2.1%; ≥10× ULN: 1.6%; UDMICK-MB: 2.7%). After multivariable adjustment, a significantly higher risk of one-year mortality was observed for patients with PPMI compared with patients without PPMI (HR 2.35 [1.74-3.18], p < 0.001; 3 to <5× ULN: 1.55 [0.92-2.62], p = 0.10; 5 to <10× ULN: 1.22 [0.67-2.20], p = 0.52; ≥10× ULN: 4.78 [3.06-7.47], p < 0.001; UDMICK-MB: 2.19 [1.29-3.73], p = 0.004). CONCLUSION: PPMI occurred in 6.3% of the patients and was associated with increased risk of death within one year. Survival was not significantly impacted by PPMI if defined by periprocedural CK-MB elevations <10× ULN alone and without additional evaluation of symptoms or evidence of ischemia. These findings highlight the importance of PPMI for long-term outcome in the contemporary era and of its definition in the planning and interpretation of clinical trials.

Aspirin resistance in patients with stable coronary artery disease with and without a history of myocardial infarction.

BACKGROUND: Aspirin therapy is a cornerstone in the prevention of atherothrombotic events, but recurrent vascular events are estimated to occur in 8-18% of patients taking aspirin for secondary prevention after 2 years. Estimates of biologic aspirin resistance vary from 5% to 60%, depending on the assay used. However, the relationship between biologic measurements of aspirin resistance and adverse clinical events remains unclear. OBJECTIVE: To determine whether patients with documented myocardial infarction (MI) while on aspirin therapy (cases) were more likely to be aspirin resistant than were patients with coronary artery disease (CAD) who had no history of MI (controls) and to assess clinical predictors of aspirin resistance in patients with stable CAD. METHODS: This case-control study examined aspirin responses using the VerifyNow Aspirin Assay system in 50 cases and 50 controls who had taken a dose of aspirin within 48 hours of presentation to the clinic visit. Odds ratios were estimated to determine the association between aspirin resistance and MI. Independent predictors of aspirin resistance were determined using univariate and multivariate analyses. RESULTS: An increase in the prevalence of aspirin resistance among cases (16% vs 12% in controls) was not observed (OR 1.40; 95% CI 0.45 to 4.37; p = 0.566). In the overall CAD population, female sex was independently associated with aspirin resistance (OR 4.01; 95% CI 1.15 to 13.92; p = 0.029). CONCLUSIONS: Additional large studies are required to understand whether biologically defined aspirin resistance is associated with increased risk for cardiovascular events, with special attention paid to sex differences.

Landmark Fractional Flow Reserve Trials.

Fractional flow reserve (FFR) has become widely used for physiologic assessment of intermediate coronary lesions. The Fractional Flow Reserve to Determine Appropriateness of Angioplasty in Moderate Coronary Stenoses (DEFER) trial established the safety of deferring angioplasty for moderate lesions that are not functionally significant. DEFER and Fractional Flow Reserve versus Angiography for Multivessel Evaluation 1 trials established the feasibility of FFR-guided intervention in stable and unstable patients with moderate coronary lesions, translating to improved clinical outcome and reduced number of unnecessary stents. This article reviews the trials establishing FFR as an important tool for on-the-table functional assessment of coronary lesions.

QT interval prolongation and torsades de pointes in a patient undergoing treatment with vorinostat: a case report and review of the literature.

Vorinostat is a histone deacetylase inhibitor used in the treatment of recurrent or persistent cases of cutaneous T-cell lymphoma (CTCL). A retrospective review of 116 patients from phase I and II clinical trials who had a baseline and at least one subsequent ECG revealed that four patients had Grade 2 and one patient had Grade 3 QTc interval prolongation; however, a MEDLINE search found no reported cases of torsades de pointes (TdP) in patients treated with vorinostat. We describe the case of a 49 year-old male with a history of CTCL actively undergoing treatment with vorinostat. During day 1 of hospitalization, he developed a pulseless polymorphic ventricular tachycardia requiring resuscitation. He was found to have a QTc of 826 ms. Following correction of potassium and magnesium, QTc gradually decreased and no further ventricular arrhythmia was noted. Other factors implicated in this case included concurrent sertraline and doxepin therapy (both drugs have been associated with the development of TdP in overdose). The mechanism of development of TdP in this patient is postulated to be related to vorinostat use in combination with hypokalemia and concomitant treatment with medications associated with QTc prolongation. This case highlights the importance of post-market surveillance.