Leo F. Buckley

Anticoagulants: A Review of the Pharmacology, Dosing, and Complications

Anticoagulants remain the primary strategy for the prevention and treatment of thrombosis. Unfractionated heparin, low molecular weight heparin, fondaparinux, and warfarin have been studied and employed extensively with direct thrombin inhibitors typically reserved for patients with complications or those requiring intervention. Novel oral anticoagulants have emerged from clinical development and are expected to replace older agents with their ease of use and more favorable pharmacodynamic profiles. Hemorrhage is the main concerning adverse event with all anticoagulants. With their ubiquitous use, it becomes important for clinicians to have a sound understanding of anticoagulant pharmacology, dosing, and toxicity.

Interleukin-1 Blockade In Acute Decompensated Heart Failure: A Randomized, Double-Blinded, Placebo-Controlled Pilot Study.

Background: Heart failure is an inflammatory disease. Patients with acute decompensated heart failure (ADHF) exhibit significant inflammatory activity on admission. We hypothesized that Interleukin-1 blockade, with anakinra (Kineret, Swedish Orphan Biovitrum), would quench the acute inflammatory response in patients with ADHF. Methods: We randomized 30 patients with ADHF, reduced left ventricular ejection fraction (<40%), and elevated C reactive protein (CRP) levels (≥5 mg/L) to either anakinra 100 mg twice daily for 3 days followed by once daily for 11 days or matching placebo, in a 1:1 double blinded fashion. We measured daily CRP plasma levels using a high-sensitivity assay during hospitalization and then again at 14 days and evaluated the area-under-the-curve and interval changes (delta). Results: Treatment with anakinra was well tolerated. At 72 hours, anakinra reduced CRP by 61% versus baseline, compared with a 6% reduction among patients receiving placebo (P = 0.004 anakinra vs. placebo). Conclusions: Interleukin-1 blockade with anakinra reduces the systemic inflammatory response in patients with ADHF. Further studies are warranted to determine whether this anti-inflammatory effect translates into improved clinical outcomes.

Intravenous Diuretic Therapy for the Management of Heart Failure and Volume Overload in a Multidisciplinary Outpatient Unit

OBJECTIVES This study sought to evaluate the effectiveness of intravenous (IV) diuretic treatment for volume management in heart failure (HF). BACKGROUND Limited data exist regarding IV diuretics for the outpatient treatment of volume overload in HF patients. METHODS We analyzed 60 consecutive patients with chronic HF and clinical evidence of worsening congestion who received a bolus and 3-h IV infusion of furosemide at an outpatient HF clinic. Diuretic dosing was derived from the maintenance oral loop diuretic dose with a standardized conversion algorithm. Outcomes included urine output during the visit, weight loss at 24 h, and hospitalization and mortality at 30 days. Safety outcomes included hypokalemia and worsening of renal function. Outcomes were analyzed across subgroups defined by maintenance diuretic dose and ejection fraction (EF). RESULTS The median age of the cohort was 70 years (interquartile range [IQR]: 58 to 80 years), and the median daily loop diuretic dose was 240 mg (IQR: 80 to 800 mg) oral furosemide or equivalent. Twenty-six patients (43.3%) were women, and 36 (60%) had an EF ≤45%. For the entire cohort, the median urine output and 24-h weight loss were 1.1 l (IQR: 0.6 to 1.4 l) and 1.1 kg (IQR: 0.2 to 1.9 kg), respectively. Outcomes were similar across patients with varying maintenance diuretic doses (<40 mg, 40 to 160 mg, 160 to 300 mg, or >300 mg of furosemide or equivalent) and in patients with reduced or preserved EF. Transient worsening of renal function and hypokalemia occurred in 10 patients (8.9%) and 4 patients (3.5%). Although hospitalization was reported as imminent for 28 patients (52.8%), the observed rate of all-cause hospitalization was 31.7% at 30 days with no deaths. CONCLUSIONS Short courses of IV diuretics for volume management in patients with HF were safe and associated with significant urine output and weight loss across a wide range of maintenance diuretic doses and EF. This strategy may provide an alternative to hospitalization for the management of selected HF patients.

Intensive Versus Standard Blood Pressure Control in SPRINT-Eligible Participants of the ACCORD-BP Trial

OBJECTIVE We sought to determine the effect of intensive blood pressure (BP) control on cardiovascular outcomes in participants with type 2 diabetes mellitus (T2DM) and additional risk factors for cardiovascular disease (CVD). RESEARCH DESIGN AND METHODS This study was a post hoc, multivariate, subgroup analysis of ACCORD-BP (Action to Control Cardiovascular Risk in Diabetes Blood Pressure) participants. Participants were eligible for the analysis if they were in the standard glucose control arm of ACCORD-BP and also had the additional CVD risk factors required for SPRINT (Systolic Blood Pressure Intervention Trial) eligibility. We used a Cox proportional hazards regression model to compare the effect of intensive versus standard BP control on CVD outcomes. The “SPRINT-eligible” ACCORD-BP participants were pooled with SPRINT participants to determine whether the effects of intensive BP control interacted with T2DM. RESULTS The mean baseline Framingham 10-year CVD risk scores were 14.5% and 14.8%, respectively, in the intensive and standard BP control groups. The mean achieved systolic BP values were 120 and 134 mmHg in the intensive and standard BP control groups (P < 0.001). Intensive BP control reduced the composite of CVD death, nonfatal myocardial infarction (MI), nonfatal stroke, any revascularization, and heart failure (hazard ratio 0.79; 95% CI 0.65–0.96; P = 0.02). Intensive BP control also reduced CVD death, nonfatal MI, and nonfatal stroke (hazard ratio 0.69; 95% CI 0.51–0.93; P = 0.01). Treatment-related adverse events occurred more frequently in participants receiving intensive BP control (4.1% vs. 2.1%; P = 0.003). The effect of intensive BP control on CVD outcomes did not differ between patients with and without T2DM (P > 0.62). CONCLUSIONS Intensive BP control reduced CVD outcomes in a cohort of participants with T2DM and additional CVD risk factors.

A review of PCSK9 inhibition and its effects beyond LDL receptors

Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an integral role in the degradation of low-density lipoprotein receptors (LDL-R), making it an intriguing target for emerging pharmacotherapy. Two PCSK9 inhibitors, alirocumab and evolocumab, have been approved and are available in the United States and European Union. However, much of the PCSK9 story remains to be told. The pipeline for additional pharmacotherapy options is rich with several compounds under development, using alternative strategies for inhibiting PCSK9. Perhaps, more intriguing is the interaction between PCSK9 and non-LDL-R targets, including mediators of inflammation and immunological processes, which remain under intense investigation. This review will discuss the currently available PCSK9 inhibitors, the development of novel approaches to PCSK9 modulation, and the potential non-LDL-R-mediated effects of PCSK9 inhibition.

Dietary Fat, Sugar Consumption, and Cardiorespiratory Fitness in Patients With Heart Failure With Preserved Ejection Fraction

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Obesity Contributes to Exercise Intolerance in Heart Failure With Preserved Ejection Fraction

Heart failure with preserved ejection fraction (HFpEF) is a clinical syndrome of exertional breathlessness and/or fatigue caused by impaired cardiac function, preserved left ventricular ejection fraction, and impaired diastolic function [(1)][1]. The incidence and prevalence of HFpEF in the United

Effects of Sodium-Glucose Cotransporter 2 Inhibitors on 24-Hour Ambulatory Blood Pressure: A Systematic Review and Meta-Analysis

Background Sodium‐glucose cotransporter 2 (SGLT2) inhibitors are a novel class of antihyperglycemic agents that improve glycemic control by increasing glycosuria. Additional benefits beyond glucose lowering include significant improvements in seated clinic blood pressure (BP), partly attributed to their diuretic‐like actions. Less known are the effects of this class on 24‐hour ambulatory BP, which is a better predictor of cardiovascular risk than seated clinic BP. Methods and Results We performed a meta‐analysis of randomized, double‐blind, placebo‐controlled trials to investigate the effects of SGLT2 inhibitors on 24‐hour ambulatory BP. We searched all studies published before August 17, 2016, which reported 24‐hour ambulatory BP data. Mean differences in 24‐hour BP, daytime BP, and nighttime BP were calculated by a random‐effects model. SGLT2 inhibitors significantly reduce 24‐hour ambulatory systolic and diastolic BP by −3.76 mm Hg (95% CI, −4.23 to −2.34; I2=0.99) and −1.83 mm Hg (95% CI, −2.35 to −1.31; I2=0.76), respectively. Significant reductions in daytime and nighttime systolic and diastolic BP were also found. No association between baseline BP or change in body weight were observed. Conclusions This meta‐analysis shows that the reduction in 24‐hour ambulatory BP observed with SGLT2 inhibitors is a class effect. The diurnal effect of SGLT2 inhibitors on 24‐hour ambulatory BP may contribute to their favorable effects on cardiovascular outcomes.

Interleukin-1 blockade in heart failure with preserved ejection fraction: rationale and design of the Diastolic Heart Failure Anakinra Response Trial 2 (D-HART2)

Heart failure with preserved ejection fraction (HFpEF) now accounts for the majority of confirmed HF cases in the United States. However, there are no highly effective evidence‐based treatments currently available for these patients. Inflammation correlates positively with adverse outcomes in HF patients. Interleukin (IL)‐1, a prototypical inflammatory cytokine, has been implicated as a driver of diastolic dysfunction in preclinical animal models and a pilot clinical trial. The Diastolic Heart Failure Anakinra Response Trial 2 (D‐HART2) is a phase 2, 2:1 randomized, double‐blind, placebo‐controlled clinical trial that will test the hypothesis that IL‐1 blockade with anakinra (recombinant human IL‐1 receptor antagonist) improves (1) cardiorespiratory fitness, (2) objective evidence of diastolic dysfunction, and (3) elevated inflammation in patients with HFpEF (http://www.ClinicalTrials.gov NCT02173548). The co–primary endpoints will be placebo‐corrected interval changes in peak oxygen consumption and ventilatory efficiency at week 12. In addition, secondary and exploratory analyses will investigate the effects of IL‐1 blockade on cardiac structure and function, systemic inflammation, endothelial function, quality of life, body composition, nutritional status, and clinical outcomes. The D‐HART2 clinical trial will add to the growing body of evidence on the role of inflammation in cardiovascular disease, specifically focusing on patients with HFpEF.

Interleukin-1 Blockade in Recently Decompensated Systolic Heart Failure: Results From REDHART (Recently Decompensated Heart Failure Anakinra Response Trial)

Background An enhanced inflammatory response predicts worse outcomes in heart failure (HF). We hypothesized that administration of IL-1 (interleukin-1) receptor antagonist (anakinra) could inhibit the inflammatory response and improve peak aerobic exercise capacity in patients with recently decompensated systolic HF. Methods and Results We randomly assigned 60 patients with reduced left ventricular ejection fraction (<50%) and elevated C-reactive protein levels (>2 mg/L), within 14 days of hospital discharge, to daily subcutaneous injections with anakinra 100 mg for 2 weeks, 12 weeks, or placebo. Patients underwent measurement of peak oxygen consumption (VO2 [mL/kg per minute]) and ventilatory efficiency (the VE/VCO2 slope). Treatment with anakinra did not affect peak VO2 or VE/VCO2 slope at 2 weeks. At 12 weeks, patients continued on anakinra showed an improvement in peak VO2 from 14.5 (10.5–16.6) mL/kg per minute to 16.1 (13.2–18.6) mL/kg per minute (P=0.009 for within-group changes), whereas no significant changes occurred within the anakinra 2-week or placebo groups. The between-groups differences, however, were not statistically significant. The incidence of death or rehospitalization for HF at 24 weeks was 6%, 31%, and 30%, in the anakinra 12-week, anakinra 2-week, and placebo groups, respectively (log-rank test P=0.10). Conclusions No change in peak VO2 occurred at 2 weeks in patients with recently decompensated systolic HF treated with anakinra, whereas an improvement was seen in those patients in whom anakinra was continued for 12 weeks. Additional larger studies are needed to validate the effects of prolonged anakinra on peak VO2 and rehospitalization for HF. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT01936909.