Rahul Chaudhary

PCSK9 Inhibitors: A New Era of Lipid Lowering Therapy.

Hyperlipidemia is a well-established risk factor for developing cardiovascular disease (CVD). The recent American College of Cardiology and American Heart Association guidelines on lipid management emphasize treatment of individuals at increased risk for developing CVD events with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) at doses proven to reduce CVD events. However, there are limited options for patients who are either intolerant to statin therapy, develop CVD despite being on maximally tolerated statin therapy, or have severe hypercholesterolemia. Recently the Food and Drug Administration approved two novel medications for low-density lipoprotein (LDL)-cholesterol reduction: Evolocumab and Alirocumab. These agents target and inactivate proprotein convertase subtilsin-kexin type 9 (PCSK9), a hepatic protease that attaches and internalizes LDL receptors into lysosomes hence promoting their destruction. By preventing LDL receptor destruction, LDL-C levels can be lowered 50%-60% above that achieved by statin therapy alone. This review explores PCSK-9 biology and the mechanisms available to alter it; clinical trials targeting PCSK9 activity, and the current state of clinically available inhibitors of PCSK9.

Cryoballoon versus radiofrequency ablation for atrial fibrillation: A meta-analysis of 16 clinical trials

Introduction: We aimed to study the procedural characteristics, efficacy and safety of cryoballoon ablation (CBA) versus radiofrequency ablation (RFA) for catheter ablation of paroxysmal atrial fibrillation (AF). Methods: A systematic literature search was performed using PubMed, EMBASE, Web of Science, and Cochrane Central Register of Controlled Trials to clinical trials comparing CBA and RFA for AF. Outcomes were evaluated for efficacy, procedure characteristics and safety. For each study, odd ratio (OR) and 95% confidence intervals (CIs) were calculated for endpoints for both approaches. Results: We analyzed a total of 9,957 participants (3,369 in the CBA and 6,588 in RFA group) enrolled in 16 clinical trials. No significant difference was observed between CBA and RFA with regards to freedom from atrial arrhythmia at 12-months, recurrent atrial arrhythmias or repeat catheter ablation. CBA group had a significantly higher transient phrenic nerve injury (OR 14.19, 95% CI: 6.92-29.10; p<0.001) and persistent phrenic nerve injury (OR 4.62, 95% CI: 1.97-10.81; p<0.001); and a significantly lower pericardial effusion/cardiac tamponade (OR 0.43, 95% CI: 0.26-0.72; p=0.001), and groin site complications (OR 0.60, 95% CI: 0.38-0.93; p=0.02). No significant difference was observed in overall complications, stroke/thromboembolic events, major bleeding, and minor bleeding. Conclusion: CBA was non-inferior to RFA for catheter ablation of paroxysmal AF. RF ablation was associated with a higher groin complications and pericardial effusion/cardiac tamponade, whereas CBA was associated with higher rates of transient and persistent phrenic nerve injury.

Ivabradine Heart Failure and Beyond

Heart failure affects over 5 million people in the United States and carries a high rate of mortality. Ivabradine, a new agent has been added to the current medical options for managing heart failure. It is a selective funny current (If) inhibitor in sinoatrial node and slows its firing rate, prolonging diastolic depolarization without a negative inotropic effect. Ivabradine was only recently approved by Food and Drug administration after the results of Systolic Heart Failure Treatment with the If Inhibitor Ivabradine (SHIFT) trial, for a reduction in rehospitalizations from chronic heart failure. This trial assessed patients with stable heart failure with reduced ejection fraction and a heart rate of at least 70 beats per minute at rest on maximally tolerated beta-blocker therapy and demonstrated statistically significant reduction in heart failure hospitalization and deaths. Additionally, ivabradine has been associated with reduced cardiac remodeling, reduced heart rate variability, improvement in exercise tolerance, improved heart failure class of New York Heart Association, and better quality of life. It has also been tried in other conditions, such as inappropriate sinus tachycardia and cardiogenic shock, and is currently in phase II trial for patients with newly diagnosed multiple organ dysfunction syndrome.

Safety and efficacy of uninterrupted periprocedural apixaban in patients undergoing atrial fibrillation catheter ablation: A metaanalysis of 1,057 patients

Apixaban (factor Xa inhibitor) is a novel anticoagulant and may be beneficial during atrial fibrillation (AF) ablation for prevention of thromboembolic events. However, the adverse effects of periprocedural apixaban therapy have not been thoroughly evaluated. A meta-analysis was performed to evaluate the safety of apixaban for anticoagulation in AF ablation. We searched the online databases till October 2015 for studies comparing Apixaban with Vitamin K antagonists in atrial fibrillation patients undergoing catheter ablation. Primary outcome of our study was composite of thromboembolic event and bleeding (includes major and minor bleeding). A total of 1,057 atrial fibrillation patients in 3 studies undergoing catheter ablation were included in this analysis. Zero thromboembolic events were reported in the apixaban group and 1 in the VKA group with no statistical difference (OR 0.75; 95% CI 0.03-18.49). No major differences were observed for the primary outcome (OR 0.92; 95% CI 0.54-1.55), risk of overall bleeding (OR 0.94, 95% CI 0.55- 1.58), major bleeding (OR1.37; 95% CI 0.33-5.67), minor bleeding (OR 0.89; 95% CI 0.50-1.55), pericardial effusion (OR 0.50; 95% CI 0.18-1.38) and groin hematoma (OR 1.36; 95% CI 0.70-2.65). Uninterrupted apixaban administration in patients undergoing AF catheter ablation was non-inferior to VKA without increasing the risk of major and minor bleeding.

Efficacy of aspirin (325 mg) + omeprazole (40 mg) in treating coronary artery disease

ABSTRACT Introduction: Aspirin is indicated for primary and secondary prevention of cardiovascular diseases (CVD) by major guidelines. However, its use may be associated with gastrointestinal (GI) toxicities, including, but not limited to, GI bleeding. This may lead to increased morbidity and mortality, as well as diminished compliance, which again leads to increased risk of major cardiovascular events. Modified formulations of aspirin often have comparable risks of GI toxicity despite their dose or formulation and have had limited success to prevent GI toxicities. Simultaneous treatment with Proton pump inhibitors (PPIs) has been used successfully to prevent GI toxicities from aspirin. However, addition of an extra medication may lead to lower compliance and hence ineffective or less than optimal treatment. Areas covered: After a selective literature search, a brief review of the available evidence regarding GI toxicity of aspirin and the protective effects of PPIs was conducted. The concept of combination tablets, and the available data about Aralez Pharmaceuticals’ YOSPRALA (aspirin (81 mg or 325 mg) and omeprazole (40 mg) fixed dose combination tablet being evaluated for secondary prevention of cardiovascular and cerebrovascular events in patients at risk for GI complications of aspirin therapy) is also presented. Expert opinion: The available evidence suggests that PPIs are the best option to prevent aspirin-related GI toxicities, but compliance is low in people who are prescribed both aspirin and PPI. Combination tablets containing both aspirin and a PPI may be a good option for providing protection against GI toxicities in people who require aspirin for secondary prevention of cardiovascular diseases.

Risk factors associated with plasma omega-3 fatty acid levels in patients with suspected coronary artery disease

INTRODUCTION We sought to determine the associations between plasma eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) levels and various cardiovascular risk factors and with the use of fish oil supplements (FOS). PATIENTS AND METHODS Patients with suspected coronary artery disease (CAD) undergoing cardiac catheterization (n=433) were studied. Serum fatty acid (FA) composition, the concentrations of lipids and biomarkers of oxidative stress, and dietary/lifestyle factors were measured. RESULTS FOS use was associated with a higher plasma EPA+DHA levels (3.7±1.5 vs. 2.6±1.1%, p<0.0001). However, there was no relationship between FOS dose (mg/day) and EPA+DHA levels in 76 patients reporting FOS use (r=-0.21, p=0.07). Lower levels were inversely associated with risk factor profiles including lower ApoB100/ApoA1 ratios (p<0.001). DISCUSSION AND CONCLUSIONS Higher EPA+DHA levels characterized patients with lower CAD risk. The lack of relations between FOS dose and plasma EPA+DHA levels likely reflects uncaptured variability in EPA+DHA content of supplements.

Thrombin-Induced Platelet-Fibrin Clot Strength Identified by Thrombelastography: A Novel Prothrombotic Marker of Coronary Artery Stent Restenosis.

BACKGROUND AND OBJECTIVE In-stent restenosis (ISR) is a limitation of percutaneous coronary intervention and has been linked to specific clinical and angiographic variables. We aimed to simultaneously assess thrombosis biomarkers and lipid levels in patients with and without ISR. METHODS Consecutive patients (n = 170) with a history of coronary stenting undergoing elective angiography were studied. Blood samples for thrombelastography, light transmittance aggregometry, and lipid levels were obtained prior to cardiac catheterization. RESULTS Sixty-nine patients (41%) had ISR (>50% luminal diameter stenosis). Among patients with ISR, 40 (58%) had ISR in more than one stent bed. Patients with ISR were more often female (37.7% vs. 21.8%, P = 0.04), had higher thrombin-induced platelet-fibrin clot strength (TIP-FCS) (69.9 mm vs. 65.6 mm, P < 0.001), and a higher ApoB/A1 ratio (0.65 vs. 0.59, P = 0.03). In patients on dual antiplatelet therapy (n = 86), there were no differences in ADP-, arachidonic acid-, and collagen-induced platelet aggregation between groups. The frequency of patients with ISR increased with TIP-FCS quartiles and by ROC analysis, TIP-FCS = 67.0 mm was the cutpoint for identification of ISR (AUC = 0.80 (95%CI 0.73-0.87, P < 0.0001). By multivariate analysis, TIP-FCS ≥67.0 mm strongly associated with ISR (OR = 7.3, P = 0.004). CONCLUSION Patients with ISR identified at the time of cardiac catheterization have a prothrombotic phenotype indicated by high TIP-FCS, a novel marker. Studies to confirm the prognostic utility of high TIP-FCS for the development of ISR are ongoing.

On-X Valve: The Next Generation Aortic Valve.

The On-X valve is a newer generation mechanical bileaflet valve. Its key features include the use of pure pyrolytic carbon (devoid of silicon), a length-to-diameter ratio similar to a native valve, an inlet flared orifice, a leaflet opening up to 90 degrees, a shorter leaflet closing angle, a 2-point leaflet contact, and an actuated pivot. These features have translated into increased strength, improved valve hemodynamics, reduced hemolysis, and thrombogenicity. The 2014 American Heart Association/American College of Cardiology guidelines for the management of patients with valvular heart disease recommend an international normalized ratio (INR) of 2.5 (range, 2–3) in patients with a mechanical valve at the aortic position. However, based on the results of the Prospective Randomized On-X Anticoagulation Clinical Trial (PROACT), the Food and Drug Administration approved this valve in April 2015 in the aortic position with a lower INR goal of 1.5–2.0. This reduction in INR goals led to a statistically significant reduction in the combined endpoint of clots, bleeding events, and stroke rates with 9/patient-years for the lower INR group compared with 12/patient-years in the standard INR group. This review compares the currently available literature on the On-X valve with that of other contemporary valves.

Statin therapy and inflammation in patients with diabetes treated with high dose aspirin

BACKGROUND Statin and aspirin form the therapeutic cornerstone in patients with coronary artery disease (CAD) and diabetes. Little is known about relationship of statins with blood thrombogenicity and inflammation in these patients. METHODS Two hundred nine consecutive patients with diabetes and suspected CAD undergoing elective cardiac catheterization were divided in groups based on statin treatment in the Multi-Analyte, Thrombogenic, and Genetic Markers Atherosclerosis study. Urinary 11-dehydrothromboxane B2 (11-dh-TxB2), lipid profile and oxLDL/β2GPI were measured by AspirinWorks™ ELISA assay, vertical density gradient ultracentrifugation and immunoassay respectively. Thrombelastography, and ADP- and collagen-induced light transmittance aggregometry assessed thrombogenicity. CAD was classified as none/minor [<20% diameter stenosis (DS)], moderate (20-75% DS), or severe (>75% DS). RESULTS Severe, moderate, and no CAD was observed in 66, 19, and 15% of patients respectively. Patients on statins had significantly lower 11-dh-TxB2, collagen-induced aggregation, total cholesterol, total LDL, LDL3, oxidized-LDL, Apo B100, and ApoB100/A1 ratio (p<0.01 for all). Statin therapy demonstrated a lower proportion of patients with high urinary 11-dh-TxB2 (>1500pg 11-dh-TxB2/mg creatinine) (25 vs. 57%, p=0.01). CONCLUSION Statins along with aspirin, confers additional anti-inflammatory and antithrombotic effect in diabetics with CAD. Urinary 11-dh-TxB2 may be a useful biomarker for personalizing statin therapy.

Combination oral antithrombotic therapy for the treatment of myocardial infarction: recent developments

ABSTRACT Introduction: There have been significant new developments in the treatment of patients with myocardial infarction with respect to oral antithrombotic agents over the past decade. Recent studies have explored the potential utility of targeting the dual pathway inhibition of platelet function with single or dual antiplatelet agents and the thrombin pathway with direct thrombin inhibitors or factor Xa inhibitors. Areas covered: In this review, the authors focus on the recent developments of oral antithrombotic agents including antiplatelet and antithrombin agents. It is based on literature covering: aspirin, P2Y12 receptor blockers, PAR-1 inhibitors, direct thrombin inhibitors and factor Xa inhibitors from PubMed since 2008. Expert opinion: Since thrombus formation involves multiple pathways including platelet activation and aggregation and coagulation, simultaneous and optimal blockade of these pathways is essential to prevent thrombotic complications and to avoid excessive bleeding in the myocardial infraction setting. Despite an improved anti-ischemic effect associated with potent P2Y12 inhibitors plus aspirin, the degree of adverse event reduction compared to clopidogrel therapy in large scale trials is modest along with significantly greater bleeding. Recent studies suggest that targeting the thrombin pathway in addition to antiplatelet agents in high risk patients may further mitigate the risk of ischemic event occurrences with improved safety profiles.