Complement in Sickle Cell Disease: Are We Ready for Prime Time?

Sickle cell disease (SCD) is a widely spread inherited hemoglobinopathy that includes a group of congenital hemolytic anemias, all characterized by the predominance of sickle hemoglobin (HbS). Its features are anemia, predisposal to bacterial infections and complications such as vaso-occlusive crisis (VOC) or delayed hemolytic transfusion reaction (DHTR), which lead to increased rate of morbidity and mortality even in the era of hydroxyurea. The interaction between sickle cells, neutrophils, platelets or endothelial cells in small vessels results in hemolysis and has been considered the disease's main pathophysiological mechanism. Complement activation has been reported in small cohorts of SCD patients, but the governing mechanism has not been fully elucidated. This will be important to predict the patient group that would benefit from complement inhibition. Until now, eculizumab-mediated complement inhibition has shown beneficial effects in DHTR, with limited reports in patients with VOC. In the meantime, several innovative agents are under clinical development Our state-of-the-art review summarizes current data on 1) complement activation in SCD both in steady state and crisis, 2) underlying mechanisms of complement over-activation for the clinician in the context of SCD, 3) actions of hydroxyurea and new therapeutic approaches including indirect involvement in complement activation, and 4) novel paradigms in complement inhibition.

Reinforcing adherence to lipid-lowering therapy after an acute coronary syndrome: A pragmatic randomized controlled trial.

BACKGROUND AND AIMS: Achieving the low-density lipoprotein cholesterol (LDL-C) goal following an acute coronary syndrome (ACS) is a milestone often missed due to suboptimal adherence to secondary prevention treatments. Whether improved adherence could result in reduced LDL-C levels is unclear. We aimed to evaluate whether an educational-motivational intervention increases long-term lipid-lowering therapy (LLT) adherence and LDL-C goal attainment rate among post-ACS patients. METHODS: IDEAL-LDL was a parallel, two-arm, single-center, pragmatic, investigator-initiated randomized controlled trial. Hospitalized patients for ACS were randomized to a physician-led integrated intervention consisting of an educational session at baseline, followed by regular motivational interviewing phone sessions or usual care. Co-primary outcomes were the LLT adherence (measured by Proportion of Days Covered (PDC); good adherence defined as PDC>80%), and LDL-C goal (<70 mg/dl or 50% reduction from baseline) achievement rate at one year. RESULTS: In total, 360 patients (mean age 62 years, 81% male) were randomized. Overall, good adherence was positively associated with LDL-C goal achievement rate at one year. Median PDC was higher in the intervention group than the control group [0.92 (IQR, 0.82-1.00) vs. 0.86 (0.62-0.98); p = 0.03] while the intervention group had increased odds of good adherence (odds ratio: 1.76 (95% confidence interval 1.02 to 2.62; p = 0.04). However, neither the LDL-C goal achievement rate (49.6% in the intervention vs. 44.9% in the control group; p = 0.49) nor clinical outcomes differed significantly between the two groups. CONCLUSIONS: Α multifaceted intervention improved LLT adherence in post-ACS patients without a significant difference in LDL-C goal attainment.

Complement in sickle cell disease and targeted therapy: I know one thing, that I know nothing.

Sickle cell disease (SCD) is a common inherited clinical syndrome, characterized by the presence of hemoglobin S. Anemia, susceptibility to infections and episodes of vaso-occlusive crisis (VOC) are among its features. Since SCD complications (VOC or delayed hemolytic transfusion reaction/DHTR) lead to significant morbidity and mortality, a number of studies have addressed their pathophysiology Although SCD pathophysiology has been mainly attributed to the interaction between sickle cells and neutrophils, platelets or endothelial cells in small vessels leading to hemolysis, the role of complement activation has been increasingly investigated. Importantly, complement inhibition with eculizumab has shown beneficial effects in DHTR. Given the unmet clinical need of novel therapeutics in SCD, our review summarizes current understanding of (a) complement system for the clinician, (b) complement activation in SCD both in asymptomatic state and severe clinical manifestations, (c) probable underlying mechanisms of complement activation in SCD, and (d) new therapeutic perspective of complement inhibition.

Risk for Recurrent Cardiovascular Events and Expected Risk Reduction With Optimal Treatment 1 Year After an Acute Coronary Syndrome.

According to the latest European Society of Cardiology Guidelines for the diagnosis and management of chronic coronary syndromes, patients who suffered an acute coronary syndrome fall into a chronic stable phase after 1 year. In these patients, the estimated 10-year risk for recurrent cardiovascular events varies considerably. We applied the SMART (Second Manifestations of Arterial Disease) risk score in 281 patients 1 year after an acute coronary syndrome to estimate the 10-year risk for recurrent cardiovascular events (subsequent nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death). We assessed the distribution of the estimated risk and the potential risk reduction that might be achieved with optimal guideline-directed management of modifiable risk factors (systolic blood pressure, low-density lipoprotein cholesterol, smoking, and body mass index). In our cohort, the median SMART score was 16.1% (interquartile range [IQR] 9.7 to 27.3), particularly increased in patients with older age, diabetes, polyvascular disease or chronic kidney disease (median 28.6%, IQR 20.8 to 52.9; 23.8%, 4.8 to 41.6; 29.4%, 18.8 to 49.7; 53.8%, 26.5 to 71.6, respectively). If all modifiable risk factors met guideline-recommended targets, the median SMART risk score would be 9.6% (IQR 6.3 to 20.9), with 51% of the patients at a 10-year risk <10%, while 11% and 15% at 20% to 30% and >30% risk, respectively. In conclusion, the SMART score had a wide distribution in patients with chronic coronary syndromes. A quarter of patients remained at a >20% 10-year risk, even with optimal risk factor management, clearly underlining that residual risk is an unmet clinical challenge.

Treatment practices and lipid profile of patients with acute coronary syndrome: results from a tertiary care hospital.

Background: Considering the increasing burden of cardiovascular risk factors and recent advances on the management of acute coronary syndromes (ACS), we studied the epidemiological characteristics and treatment strategies of patients presenting with ACS. We also evaluated the lipid profile and attainment of lipid goals in a 'real world' clinical setting.Methods: This was a substudy of IDEAL-LDL (Motivational interviewing to support low-density lipoprotein cholesterol (LDL-C) therapeutic goals and lipid-lowering therapy compliance in patients with acute coronary syndromes), a single-centre, prospective, randomised controlled trial. Baseline data from a total of 357 ACS patients were gathered using standardised methods.Results: Median age of patients was 60 years and 81.2% were males. Arterial hypertension and smoking were the most prevalent risk factors for coronary artery disease (CAD). Patients with ST-elevation myocardial infarction (STEMI) were heavier smokers, but were younger and exercised more compared to those with non-ST-elevation acute coronary syndrome (NSTE-ACS). Conversely, more NSTE-ACS patients had arterial hypertension, dyslipidaemia and diabetes mellitus. One-fifth of ACS patients was treated conservatively without a percutaneous coronary intervention (PCI). A combination of statin, dual antiplatelet therapy and beta-blockers were prescribed to 79.6% of patients upon discharge. A renin-angiotensin-aldosterone system inhibitor and a beta-blocker were prescribed to 67.3 and 91.8% of patients with LVEF ≤40%, respectively. Of patients with prior history of CAD, 63.1%, 71.4% and 58.3% received regularly statins, antiplatelets and beta-blocker treatment, respectively. Only 22.3% of these CAD patients had an optimal LDL-C of <70 mg/dl at admission.Conclusions: In hospitalised patients with ACS, management practices differed by ACS type and discharge medication was, mostly, in line with the latest guidelines. However, medication adherence and lipid lowering goals of secondary CAD prevention were largely unachieved.

Motivational interviewing to support LDL-C therapeutic goals and lipid-lowering therapy compliance in patients with acute coronary syndromes (IDEAL-LDL) study: rationale and design.

BACKGROUND: Achieving low-density lipoprotein cholesterol (LDL-C) target levels after an acute coronary syndrome (ACS) is of paramount importance, and is often burdened by undertreatment and medication or lifestyle non-adherence issues. OBJECTIVE: We examined the effect of a patient-centered, physician-led motivational intervention following ACS on relevant secondary prevention aspects. METHODS-DESIGN: The IDEAL-LDL is a single-center, randomized controlled clinical trial, conducted among patients hospitalized due to an ACS. Following discharge, all patients undergo a baseline assessment of lipid profile. Patients in the intervention group receive an in-person educational session and an informative leaflet, and also undergo two phone-based, motivational interviewing sessions at 1 and 6 months. These interventions emphasize on LDL-C goals, adherence to lipid-lowering medication, and healthy dietary-lifestyle habits, and are not provided to patients in the control group, who receive usual care. At 12 months after each patient's discharge, an in-person interview and lipid profile reassessment are performed. The primary outcomes are the assessment of LDL-C goal achievement (<70 mg/dL or >50% reduction from baseline levels) from baseline to 1 year and changes in medication adherence. Secondary outcomes relate to the incidence of the composite outcome of cardiovascular death, nonfatal myocardial infarction/stroke, need for myocardial revascularization, and recurrent hospitalization during the follow-up period. DISCUSSION: This paper describes the protocol, design, and rationale for key methodology for an ongoing clinical trial featuring a simple and feasible intervention. Similar adherence efficacy trials have not led to sufficient improvements, and there remains a gap regarding how adherence interventions should be implemented into clinical care.