Clinical outcomes of intravenous iron therapy in patients with heart failure and iron deficiency: Meta-analysis and trial sequential analysis of randomized clinical trials.

BACKGROUND: Iron deficiency in patients with heart failure (HF) is underdiagnosed and undertreated. The role of intravenous (IV) iron is well-established to improve quality of life measures. Emerging evidence also supports its role in preventing cardiovascular events in patients with HF. METHODOLOGY: We conducted a literature search of multiple electronic databases. Randomized controlled trials that compared IV iron to usual care among patients with HF and reported cardiovascular (CV) outcomes were included. Primary outcome was the composite of first heart failure hospitalization (HFH) or CV death. Secondary outcomes included HFH (first or recurrent), CV death, all-cause mortality, hospitalization for any cause, gastrointestinal (GI) side effects, or any infection. We performed trial sequential and cumulative meta-analyses to evaluate the effect of IV iron on the primary endpoint, and on HFH. RESULTS: Nine trials enrolling 3337 patients were included. Adding IV iron to usual care significantly reduced the risk of first HFH or CV death [risk ratio (RR) 0.84; 95 % confidence interval (CI) 0.75-0.93; I2 = 0 %; number needed to treat (NNT) 18], which was primarily driven by a reduction in the risk of HFH of 25 %. IV iron also reduced the risk of the composite of hospitalization for any cause or death (RR 0.92; 95 % CI 0.85-0.99; I2 = 0 %; NNT 19). There was no significant difference in the risk of CV death, all-cause mortality, adverse GI events, or any infection among patients receiving IV iron compared to usual care. The observed benefits of IV iron were directionally consistent across trials and crossed both the statistical and trial sequential boundaries of benefit. CONCLUSION: In patients with HF and iron deficiency, the addition of IV iron to usual care reduces the risk of HFH without affecting the risk of CV or all-cause mortality.

Clinical Profiles, Outcomes, and Sex Differences of Patients With STEMI: Findings From the NORIN-STEMI Registry.

Background: Low- and middle-income countries account for most of the global burden of coronary artery disease. There is a paucity of data regarding epidemiology and outcomes for ST-segment elevation myocardial infarction (STEMI) patients in these regions. Objectives: The authors studied the contemporary characteristics, practice patterns, outcomes, and sex differences in patients with STEMI in India. Methods: NORIN-STEMI (North India ST-Segment Elevation Myocardial Infarction Registry) is an investigator-initiated prospective cohort study of patients presenting with STEMI at tertiary medical centers in North India. Results: Of 3,635 participants, 16% were female patients, one-third were <50 years of age, 53% had a history of smoking, 29% hypertension, and 24% diabetes. The median time from symptom onset to coronary angiography was 71 hours; the majority (93%) presented first to a non-percutaneous coronary intervention (PCI)-capable facility. Almost all received aspirin, statin, P2Y12 inhibitors, and heparin on presentation; 66% were treated with PCI (98% femoral access) and 13% received fibrinolytics. The left ventricular ejection fraction was <40% in 46% of patients. The 30-day and 1-year mortality rates were 9% and 11%, respectively. Compared with male patients, female patients were less likely to receive PCI (62% vs 73%; P < 0.0001) and had a more than 2-fold greater 1-year mortality (22% vs 9%; adjusted HR: 2.1; 95% CI: 1.7-2.7; P < 0.001). Conclusions: In this contemporary registry of patients with STEMI in India, female patients were less likely to receive PCI after STEMI and had a higher 1-year mortality compared with male patients. These findings have important public health implications, and further efforts are required to reduce these gaps.

Coronary flow abnormalities in chronic kidney disease: A systematic review and meta-analysis.

BACKGROUND: Coronary vasomotion abnormalities have been described in small studies but not studied systematically. We aimed to review the present literature and analyze it to improve our understanding of chronic kidney disease (CKD) related-coronary microvascular dysfunction. OBJECTIVE: Coronary flow reserve (CFR) is a well-known measure of coronary vasomotion. We aimed to assess the difference in CFR among participants with and without CKD. METHODS: PubMed, Embase, and Cochrane CENTRAL were systematically reviewed to identify studies that compared CFR in participants with and without CKD. We estimated standardized mean differences in mean CFR reported in these studies. We performed subgroup analyses according to imaging modality, and the presence of significant epicardial coronary artery disease. RESULTS: In 14 observational studies with 5966 and 1410 patients with and without CKD, the mean estimated glomerular filtration rate (eGFR) was 29 ± 04 and 87 ± 25 ml/min/1.73 m2 , respectively. Mean CFR was consistently lower in patients with CKD in all studies and the cumulative mean difference was statistically significant (2.1 ± .3 vs. 2.7 ± .5, standardized mean difference -.8, 95% CI -1.1, -.6, p < .05). The lower mean CFR was driven by both significantly higher mean resting flow velocity (.58 cm/s, 95% CI .17, .98) and lower mean stress flow velocity (-.94 cm/s, 95% CI -1.75, -.13) in studies with CKD. This difference remained significant across diagnostic modalities and even in absence of epicardial coronary artery disease. In meta-regression, there was a significant positive relationship between mean eGFR and mean CFR (p < .05). CONCLUSION: Patients with CKD have a significantly lower CFR versus those without CKD, even in absence of epicardial coronary artery disease. There is a linear association between eGFR and CFR. Future studies are required to understand the mechanisms and therapeutic implications of these findings. KEY POINTS: In this meta-analysis of observational studies, there was a significant reduction in coronary flow reserve in studies with chronic kidney disease versus those without. This difference was seen even in absence of epicardial coronary artery disease. In meta-regression, a lower estimate glomerular filtration rate was a significant predictor of lower coronary flow reserve. Coronary microvascular dysfunction, rather than atherosclerosis-related epicardial disease may underly increase cardiovascular risk in a patient with chronic kidney disease.

Eosinophilic Myocarditis: When Allergies Attack the Heart!

Eosinophilic myocarditis is a clinical condition whereby myocardial injury is mediated by eosinophilic infiltration. A number of underlying causes, including reactive, clonal, or idiopathic hypereosinophilic syndrome, may trigger eosinophilia. Disease presentation may vary from mild subclinical variants to fulminant myocarditis with thromboembolic complications, and in some cases, endomyocardial and valvular fibrosis may be seen. A detailed examination coupled with the use of multimodality imaging, and endomyocardial biopsy may help establish diagnosis. Treatment is aimed at symptomatic management and treating the underlying cause of eosinophilia, such as withdrawal of implicated drugs, antihelminthic therapy for infection, immunosuppression for autoimmune conditions, and targeted therapy with tyrosine kinase inhibitors in cases with clonal myeloid disorders.

Therapeutic angiogenesis in coronary artery disease: a review of mechanisms and current approaches.

INTRODUCTION: Despite tremendous advances, the shortcomings of current therapies for coronary disease are evidenced by the fact that it remains the leading cause of death in many parts of the world. There is hence a drive to develop novel therapies to tackle this disease. Therapeutic approaches to coronary angiogenesis have long been an area of interest in lieu of its incredible, albeit unrealized potential. AREAS COVERED: This paper offers an overview of mechanisms of native angiogenesis and a description of angiogenic growth factors. It progresses to outline the advances in gene and stem cell therapy and provides a brief description of other investigational approaches to promote angiogenesis. Finally, the hurdles and limitations unique to this particular area of study are discussed. EXPERT OPINION: An effective, sustained, and safe therapeutic option for angiogenesis truly could be the paradigm shift for cardiovascular medicine. Unfortunately, clinically meaningful therapeutic options remain elusive because promising animal studies have not been replicated in human trials. The sheer complexity of this process means that numerous major hurdles remain before therapeutic angiogenesis truly makes its way from the bench to the bedside.

Perioperative pharmacotherapy to prevent cardiac complications in patients undergoing noncardiac surgery.

Introduction: Despite advances in surgical and anesthetic techniques, perioperative cardiovascular complications are a major cause of 30-day perioperative mortality. Major cardiovascular complications after noncardiac surgery include myocardial ischemia, congestive heart failure, arrhythmias, and cardiac arrest. Along with surgical risk assessment, perioperative medical optimization can reduce the rates and clinical impact of these complications.Areas Covered: In this review, the authors discuss the pharmacological basis, existing evidence, and professional society recommendations for drug management in preventing cardiovascular complications in patients undergoing noncardiac surgery.Expert opinion: Perioperative management of cardiovascular disease is an increasingly important and growing area of clinical practice. Societal guidelines regarding the use of most routine cardiovascular medications are based on a number of large clinical studies and provide a basic foundation to guide management. However, the heterogeneous nature of patients, as well as surgeries, makes it practically impossible to devise a 'one size fits all' recommendation in this setting. Thus, the importance of a more individualized approach to perioperative risk stratification and management is being increasingly recognized. The underlying comorbidities and cardiac profile as well as the risk of cardiac complications associated with the planned surgery must be factored in to understand the nuance of the management strategies.

Targeting CD38 Enhances the Antileukemic Activity of Ibrutinib in Chronic Lymphocytic Leukemia.

PURPOSE: CD38 has emerged as a high-impact therapeutic target in multiple myeloma, with the approval of daratumumab (anti-CD38 mAb). The clinical importance of CD38 in patients with chronic lymphocytic leukemia (CLL) has been known for over 2 decades, although it's relevance as a therapeutic target in CLL remains understudied. EXPERIMENTAL DESIGN: We investigated the biological effects and antitumor mechanisms engaged by daratumumab in primary CLL cells. Besides its known immune-effector mechanisms (antibody-dependent cell-mediated cytotoxicity, complement-dependent death, and antibody-dependent cellular phagocytosis), we also measured direct apoptotic effects of daratumumab alone or in combination with ibrutinib. In vivo antileukemic activity was assessed in a partially humanized xenograft model. The influence of CD38 on B-cell receptor (BCR) signaling was measured via immunoblotting of Lyn, Syk, BTK, PLCγ2, ERK1/2, and AKT. RESULTS: In addition to immune-effector mechanisms; daratumumab also induced direct apoptosis of primary CLL cells, which was partially dependent on FcγR cross-linking. For the first time, we demonstrated the influence of CD38 on BCR signaling where interference of CD38 downregulated Syk, BTK, PLCγ2, ERK1/2, and AKT; effects that were further enhanced by addition of ibrutinib. In comparison to single-agent treatment, the combination of ibrutinib and daratumumab resulted in significantly enhanced anti-CLL activity in vitro and significantly decreased tumor growth and prolonged survival in the in vivo CLL xenograft model. CONCLUSIONS: Overall, our data demonstrate the antitumor mechanisms of daratumumab in CLL; furthermore, we show how cotargeting BTK and CD38 lead to a robust anti-CLL effect, which has clinical implications.

Impact of psychiatric comorbidities on health care utilization and cost of care in multiple myeloma.

Approximately one third of cancer patients suffer from comorbid mood disorders that are associated with increased cost and poorer outcomes. The majority of patients with multiple myeloma (MM) are treated with corticosteroids; as many as three fourths of those taking corticosteroids develop neuropsychiatric complications, likely increasing morbidity and cost of care. MM patients diagnosed between 1991 and 2010 and reported in the Surveillance Epidemiology, and End Results-Medicare database were characterized as MM-Only, MM+Psychiatric (any psychiatric condition, preexisting or post-MM), or MM+Depression (depression as the only psychiatric diagnosis, preexisting or post-MM). Differences in demographic characteristics, occurrence of clinical myeloma-defining events (MDEs), health care utilization (inpatient, outpatient, ambulatory claims), and cost of care during the first 6 months of MM diagnosis were analyzed. Psychiatric comorbidities were reported more frequently in females, and racial minorities had lower rates of psychiatric comorbidities. All clinical MDEs were more common in the MM+Psychiatric and MM+Depression groups; within them, the majority were more common in patients diagnosed with the psychiatric condition or depression after MM compared with it being a preexisting condition. Health care utilization in all treatment settings was higher in those with psychiatric comorbidities. Cost of care within the first 6 months after MM diagnosis was significantly higher in the MM+Psychiatric and MM+Depression groups. This increase in cost was more pronounced for patients from racial minorities diagnosed with a psychiatric condition, including depression. Psychiatric comorbidities significantly impact the clinical presentations, health care utilization, and cost among patients with MM. These findings need to be addressed for improved survivorship of MM patients.

Equal Treatment and Outcomes for Everyone with Multiple Myeloma: Are We There Yet?

Multiple myeloma treatment has changed tremendously over recent years leading to overall improvement in patient outcomes. With therapeutic advancements, patient care has become increasingly complex and variability is seen in healthcare delivery as well as outcomes when various patient subgroups are analyzed based on sociodemographic factors. It is imperative to understand this variability so that while overall the outcomes get better, specific focus is placed on subgroups that may remain disadvantaged and may not be able to fully access the advancements in therapeutics. Research in multiple myeloma has specifically looked at several such patient subgroups based on socioeconomic status, age, race/ethnicity, insurance carrier, and geographic location that may affect healthcare utilization and patient outcomes. Exploring and understanding these would certainly help address disparities and lead to further equity in healthcare access and, hopefully, patient outcomes.