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.

Left Ventricular Unloading With Impella Versus IABP in Patients With VA-ECMO: A Systematic Review and Meta-Analysis.

Venoarterial extracorporeal membrane oxygenation (VA-ECMO) use for circulatory support in cardiogenic shock results in increased left ventricular (LV) afterload. The use of concomitant Impella or intra-aortic balloon pump (IABP) have been proposed as adjunct devices for LV unloading. The authors sought to compare head-to-head efficacy and safety outcomes between the 2 LV unloading strategies. We conducted a search of Medline, EMBASE, and Cochrane databases to identify studies comparing the use of Impella to IABP in patients on VA-ECMO. The primary outcome of interest was in-hospital mortality. The secondary outcomes included transition to durable LV assist devices/cardiac transplantation, stroke, limb ischemia, need for continuous renal replacement therapy, major bleeding, and hemolysis. Pooled risk ratios (RRs) with 95% confidence interval and heterogeneity statistic I2 were calculated using a random-effects model. A total of 7 observational studies with 698 patients were included. Patients on VA-ECMO unloaded with Impella vs IABP had similar risk of short-term all-cause mortality, defined as either 30-day or in-hospital mortality- 60.8% vs 64.9% (RR 0.93 [0.71 to 1.21], I2 = 71%). No significant difference was observed in transition to durable LV assist devices/cardiac transplantation, continuous renal replacement therapy initiation, stroke, or limb ischemia between the 2 strategies. However, the use of VA-ECMO with Impella was associated with increased risk of major bleeding (57.2% vs 39.7%) (RR 1.66 [1.12 to 2.44], I2 = 82%) and hemolysis (31% vs 7%) (RR 4.61 [1.24 to 17.17], I2 = 66%) compared with VA-ECMO, along with IABP. In conclusion, in patients requiring VA-ECMO for circulatory support, the concomitant use of Impella or IABP had comparable short-term mortality. However, Impella use was associated with increased risk of major bleeding and hemolysis.

Myocardial Scintigraphy in Diagnosing Cardiac Transthyretin Amyloidosis.

Myocardial scintigraphy with technetium-99m pyrophosphate is a minimally invasive technique that can distinguish between transthyretin amyloidosis (ATTR) and light-chain amyloidosis. We present a case in which it helped determine the amyloidosis type in a 74-year-old man with cardiac amyloidosis and multiple previous admissions for acute decompensated heart failure. The patient presented with increasing abdominal girth and bilateral lower extremity edema. His medical history also included atrial fibrillation, liver cirrhosis, hypertension, stage 3 chronic kidney disease, and peripheral vascular disease. We prescribed guideline-directed medical therapy for his acute decompensated heart failure with cardiorenal syndrome and his decompensated cirrhosis. Two years previously, a presumptive diagnosis of ATTR cardiomyopathy had been made on the basis of the patient's age, predominantly cardiac involvement, an unremarkable serum protein electrophoresis result, and an abnormal free κ/λ light-chain ratio of 2.24. Over the next year, the patient's clinical condition had worsened with the development of liver cirrhosis and peripheral neuropathy, and his free κ/λ light-chain ratio had become even more abnormal. At the current presentation, a technetium-99m pyrophosphate nuclear scintigram revealed a free κ/λ light-chain ratio of 1.52. This, combined with the patient's age and slow progression of primarily cardiac disease, supported the diagnosis of ATTR, and we prescribed tafamadis. This case suggests that technetium-99m pyrophosphate scintigraphy is valuable in definitively diagnosing ATTR cardiomyopathy and selecting patients who may benefit from disease-modifying therapy.

Meta-Analysis Comparing Venoarterial Extracorporeal Membrane Oxygenation With or Without Impella in Patients With Cardiogenic Shock.

Cardiogenic shock is associated with high short-term mortality. Venoarterial extracorporeal membrane oxygenation (VA-ECMO) is increasingly used as a mechanical circulatory support strategy for patients with refractory cardiogenic shock. A drawback of this hemodynamic support strategy is increased left ventricular (LV) afterload, which is mitigated by concomitant use of Impella (extracorporeal membrane oxygenation with Impella [ECPELLA]). However, data regarding the benefits of this approach are limited. We conducted a systematic search of Medline, EMBASE, and Cochrane databases to identify studies including patients with cardiogenic shock reporting clinical outcomes with Impella plus VA-ECMO compared with VA-ECMO alone. Primary outcome was short-term all-cause mortality (in-hospital or 30-day mortality). Secondary outcomes included major bleeding, hemolysis, continuous renal replacement therapy, weaning from mechanical circulatory support, limb ischemia, and transition to destination therapy with LV assist device (LVAD) or cardiac transplant. Of 2,790 citations, 7 observational studies were included. Of 1,054 patients with cardiogenic shock, 391 were supported with ECPELLA (37%). Compared with patients on only VA-ECMO support, patients with ECPELLA had a lower risk of short-term mortality (risk ratio [RR] 0.89 [0.80 to 0.99], I2 = 0%, p = 0.04) and were significantly more likely to receive a heart transplant/LVAD (RR 2.03 [1.44 to 2.87], I2 = 0%, p <0.01). However, patients with ECPELLA had a higher risk of hemolysis (RR 2.03 [1.60 to 2.57], I2 = 0%, p <0.001), renal failure requiring continuous renal replacement therapy (RR 1.46 [1.23 to 174], I2 = 11%, p <0.0001), and limb ischemia (RR 1.67 [1.15 to 2.43], I2 = 0%, p = 0.01). In conclusion, among patients with cardiogenic shock requiring VA-ECMO support, concurrent LV unloading with Impella had a lower likelihood of short-term mortality and a higher likelihood of progression to durable LVAD or heart transplant. However, patients supported with ECPELLA had higher rates of hemolysis, limb ischemia, and renal failure requiring continuous renal replacement therapy. Future prospective randomized are needed to define the optimal treatment strategy in this high-risk cohort.

The Impact of Environmental Factors on the Mortality of Patients With Chronic Heart Failure.

Outcomes of acute heart failure hospitalizations are worse during the winter than the rest of the year. Seasonality data are more limited for outcomes in chronic heart failure and the effect of environmental variables is unknown. In this population-level study, we merged 20-year data for 555,324 patients with heart failure from the national Veterans Administration database with data on climate from the National Oceanic and Atmospheric Administration and air pollutants by the Environmental Protection Agency. The outcome was the all-cause mortality rate, stratified by geographical location and each month. The impact of environmental factors was assessed through Pearson's correlation and multiple regression with a family-wise α = 0.05. The monthly all-cause mortality was 13.9% higher in the winter than the summer, regardless of gender, age group, and heart failure etiology. Winter season, lower temperatures, and higher concentrations of nitrogen dioxide were associated with a higher mortality rate in multivariate analysis of the overall population. Different environmental factors were associated in regions with similar patterns of temperature and precipitation. The only environmental factor associated with the mortality rate of patients dwelling in large urban centers was the air quality index. In conclusion, the mortality in chronic heart failure exhibits a seasonal pattern, regardless of latitude or climate. In this group of patients, particularly those of male gender, a higher mortality was associated with environmental factors and incorporating these factors in treatment plans and recommendations could have a favorable cost-benefit ratio.

The Effect of Calcium Channel Blockers on Moderate or Severe Albuminuria in Diabetic, Hypertensive Patients.

OBJECTIVES: Inhibitors of the renin-angiotensin system are recommended for the management of albuminuria in patients with hypertension and diabetes mellitus, but there is little consensus about alternative therapies. Calcium channel blockers are recommended for the management of hypertension, but the data are controversial regarding their role in patients with albuminuria. This review was designed to assess the efficacy of calcium channel blockers compared with inhibitors of the renin-angiotensin system in decreasing albuminuria in diabetic, hypertensive patients with nephropathy. METHODS: We searched MEDLINE, Embase, CENTRAL, and ClinicalTrials.gov for records that compared calcium channel blockers to inhibitors of the renin-angiotensin system and reported pre- and postintervention albuminuria measurements. Two reviewers independently screened abstracts for randomized, controlled trials in adults. We used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to select 29 trials from 855 records. We synthesized the data through a random-effects model. RESULTS: We analyzed data from 2113 trial participants with hypertension and diabetes mellitus who had the equivalent of ≥30 mg/day of urinary albumin excretion. Inhibitors of the renin-angiotensin system were more effective than calcium channel blockers in decreasing albuminuria (standardized difference in means -0.442; confidence interval, -0.660 to -0.225; P < .001). This finding was independent of the blood pressure response to treatment. There was no difference between the 2 drug classes regarding markers of renal function. CONCLUSIONS: Inhibitors of the renin-angiotensin system are superior to calcium channel blockers for the reduction of albuminuria in nephropathy due to hypertension and diabetes mellitus. The net clinical benefit, however, is small.

Prognostic Utility of Troponin I and N Terminal-ProBNP among Patients with Heart Failure due to Non-Ischemic Cardiomyopathy and Important Correlations.

BACKGROUND: Heart Failure (HF) is accompanied by a high cost of care and gloomy prognosis despite recent advances in its management. Therefore, efforts to minimize HF rehospitalizations is a major focus of several studies. METHODS: We conducted a retrospective cohort study of 140 patients 18 years and above who had baseline clinical parameters, echocardiography, NT-ProBNP, troponin I and other laboratory parameters following a 3-year electronic medical record review. Patients with coronary artery disease, preserved ejection fraction, pulmonary embolism, cancer, and end-stage renal disease were excluded. RESULTS: Of the 140 patients admitted with HF with reduced Ejection Fraction (HFrEF) secondary to non-ischemic cardiomyopathy, 15 were re-hospitalized within 30 days of discharge while 42 were rehospitalized within 6 months after discharge for decompensated HF. Receiver operating characteristic (ROC) cutoff points were obtained for NT-ProBNP at 5178 pg/ml and serum troponin I at 0.045 ng/ml. After Cox regression analysis, patients with HFrEF who had higher hemoglobin levels had reduced odds of re-hospitalization (p = 0.007) within 30 days after discharge. NT-ProBNP and troponin I were independent predictors of re-hospitalization at 6 months after discharge (p = 0.047 and p = 0.02), respectively, after Cox regression analysis. CONCLUSION: Troponin I and NT-ProBNP at admission are the best predictors of re-hospitalization 6 months after discharge among patients with HFrEF. Hemoglobin is the only predictor of 30 -day rehospitalization among HFrEF patients in this study. High-risk patients may require aggressive therapy to improve outcomes.

Relationship between pulmonary hypertension and outcomes among patients with heart failure with reduced ejection fraction.

Objectives: To identify predictors of pulmonary hypertension (PHT) and the predictive value of PHT for rehospitalization among patients with heart failure with reduced ejection fraction (HFrEF). Methods: A retrospective study of 351 hospitalized patients with heart failure (HF). Patients 18 years and above with HFrEF secondary to non-ischemic cardiomyopathy were reviewed. Patients with coronary artery disease, preserved ejection fraction and other secondary causes of PHT apart from HF were excluded. PHT as a predictor of 30-day and six-month re-admission was assessed as well as important possible predictors of PHT. Cox regression analysis, multiple linear regression as well as other statistical tools were employed as deemed appropriate. Results: Thirty-seven (37) and 99 patients were re-hospitalized within 30 days and 6 months after discharge for decompensated HF, respectively. After Cox regression analysis, higher hemoglobin reduced the odds of rehospitalization for decompensated HF (p = 0.015) within 30 days after discharge while higher pulmonary artery systolic pressure (PASP) (p = 0.002) and blood urea nitrogen (BUN) (p = 0.041) increased the odds of rehospitalization within 6 months of discharge. The predictors of the PHT among patients with HFrEF after multiple linear regression were low BMI (p = 0.027), increasing age (p = 0.006) and increased left atrial diameter (LAD) on echocardiography (p = 0.0001). Conclusion: Patients with HFrEF have a high predisposition to developing PHT if at admission, they have low BMI, dilated left atrium or are older. Patients with one or more of these attributes may need more intensive therapy to reduce the risk of developing PHT and in turn reduce readmission rates.

The Effect of Vegan Diets on Blood Pressure in Adults: A Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Vegan diets are increasing in popularity and have beneficial effects on glycemia and blood lipids, but the evidence is inconclusive regarding their effect on blood pressure. The purpose of this study was to review the effect of vegan diets on blood pressure in adults. METHODS: We searched MEDLINE, EMBASE, CENTRAL, and ClinicalTrials.gov for records that compared a vegan diet with any less restrictive diet and reported pre- and postintervention systolic and diastolic blood pressures. Two reviewers independently screened abstracts for randomized, controlled clinical trials in individuals ≥18 years of age and older. We used the PRISMA guidelines to select 11 clinical trials from 1673 records. Data synthesis was performed through a random-effects model. RESULTS: The pooled data included 983 participants. Compared with less restrictive diets, a vegan diet did not result in a significant change in systolic (-1.33 mm Hg; 95% confidence interval [CI], -3.50-0.84; P = .230) or diastolic (-1.21 mm Hg; 95% CI, -3.06-0.65; P = .203) blood pressure. A prespecified subgroup analysis of studies with baseline systolic blood pressure ≥130 mm Hg revealed that a vegan diet resulted in a mean decrease in the systolic (-4.10 mm Hg; 95% CI, -8.14 to -0.06; P = .047) and diastolic (-4.01 mm Hg; 95% CI, -5.97 to -2.05; P = 0.000) blood pressures. CONCLUSION: The changes in blood pressure induced by a vegan diet without caloric restrictions are comparable with those induced by dietary approaches recommended by medical societies and portion-controlled diets.

Low Skeletal Muscle Mass Independently Predicts Mortality in Patients with Chronic Heart Failure after an Acute Hospitalization.

BACKGROUND: Heart failure (HF) is a syndrome associated with exercise intolerance, and its symptoms are more common in patients with low skeletal muscle mass (SMM). Estimation of muscle mass can be cumbersome and unreliable, particularly in patients with varying body weight. The psoas muscle area (PMA) can be used as a surrogate of sarcopenia and has been associated with poor outcomes in other populations. OBJECTIVES: The aim of this study was to assess if sarcopenia is associated with the survival of patients with HF after an acute hospitalization. METHOD: We retrospectively studied a cohort of 160 patients with HF who had abdominopelvic computed tomography during an acute hospitalization. We obtained standardized measurements of their PMA and defined sarcopenia as the lowest gender-based tertile of the said area. The patients were followed until death or discontinuation of care. We used Kaplan-Meier estimates and Cox regression analysis to assess the relationship between sarcopenia and all-cause mortality. RESULTS: We found that the 52 patients with sarcopenia had 4.5 times the risk of all-cause mortality at 1 year compared to the rest of the cohort (CI 1.784-11.765; p = 0.0016) after adjusting for significant covariates. Stratification by age and sex revealed that this association could be limited to males and patients < 75 years old. CONCLUSION: The PMA, used as a surrogate of low SMM, is independently associated with an increased risk of late mortality after an acute hospitalization in patients with HF.

Clinical outcomes of Β-blocker therapy in cocaine-associated heart failure.

BACKGROUND: Cocaine is associated with deleterious effects in the heart, including HFrEF. Although ß-blockers are recommended for this condition in other populations, their use is discouraged in cocaine users due to the possibility of exacerbating cocaine-related cardiovascular complications. This study was designed to determine if patients with heart failure and a reduced ejection fraction (HFrEF) who continue to use cocaine have better outcomes when they receive ß-blocker therapy than when they do not. METHODS: We performed a retrospective analysis of 72 ß-blocker-naïve patients with HFrEF and active cocaine use. Patients who were prescribed ß-blockers as part of their therapy were compared to those who were not, and clinical and structural outcomes were compared after 12 months of treatment. RESULTS: When patients with HFrEF and active cocaine use received ß-blocker therapy, they were more likely to have an improvement in their New York Heart Association functional class (p = 0.0106) and left ventricular ejection fraction (p = 0.0031) than when they did not receive ß-antagonists. In addition, the risk of cocaine-related cardiovascular events (p = 0.0086) and of heart failure hospitalizations (p = 0.0383) was significantly lower in patients who received ß-blockade than those who did not. CONCLUSIONS: ß-Blocker therapy is associated with improvement in the exercise tolerance and the left ventricular ejection fraction in patients with HFrEF and active cocaine use. They are also associated with a lower incidence of cocaine-related cardiovascular events and HFrEF-related readmissions.

Brugada Phenocopy Induced by Recreational Drug Use.

Recreational drugs are commonly abused in all age groups. Intoxication with these substances can induce silent but significant electrocardiographic signs which may lead to sudden death. In this case study, we present a 49-year-old male with no medical comorbidities who came to the emergency department requesting opioid detoxification. Toxicology screen was positive for cocaine, heroin, and cannabis. Initial electrocardiogram (EKG) showed features of a Brugada pattern in the right precordial leads, which resolved within one day into admission. This presentation is consistent with the recently recognized clinical entity known as Brugada phenocopy.

Improvement in clinical outcomes of patients with heart failure and active cocaine use after ß-blocker therapy.

BACKGROUND: Cocaine use has a high prevalence in the United States and can be associated with significant cardiovascular disease, even in asymptomatic users. ß-Adrenergic receptor hyperactivation is the underlying pathophysiologic pathway of cocaine cardiotoxicity. ß-Blocker therapy is controversial in patients with active cocaine use. HYPOTHESIS: ß-Blocker therapy is associated with clinical improvement in patients with heart failure despite active cocaine use. METHODS: In a single-center, retrospective chart analysis, patients with newly diagnosed heart failure and active cocaine use who had been started on ß-blocker therapy were reviewed. The New York Heart Association (NYHA) functional class and the left ventricular ejection fraction (LVEF) were recorded at baseline and after 12 monthsnthsnths of ß-blocker use. Patients were excluded if they had been on prior ß-blocker therapy, had other reasons for volume overload, had chronic kidney disease stages G4 or G5, or had a life expectancy <12 months. RESULTS: Thirty-eight patients were identified; most were African American males. A statistically significant improvement was found in both NYHA functional class (P < 0.0001) and LVEF (P < 0.0001) after 12 months of ß-blocker therapy. No major adverse cardiovascular events occurred in this population. CONCLUSIONS: ß-Blocker use in cocaine users with heart failure with a reduced ejection fraction is associated with a lower NYHA functional class and a higher LVEF at 12-month follow-up. No major adverse cardiovascular events were observed.

Atrial Fibrillation in Patients with Heart Failure: Current State and Future Directions.

Heart failure affects nearly 26 million people worldwide. Patients with heart failure are frequently affected with atrial fibrillation, and the interrelation between these pathologies is complex. Atrial fibrillation shares the same risk factors as heart failure. Moreover, it is associated with a higher-risk baseline clinical status and higher mortality rates in patients with heart failure. The mechanisms by which atrial fibrillation occurs in a failing heart are incompletely understood, but animal studies suggest they differ from those that occur in a healthy heart. Data suggest that heart failure-induced atrial fibrosis and atrial ionic remodeling are the underlying abnormalities that facilitate atrial fibrillation. Therapeutic considerations for atrial fibrillation in patients with heart failure include risk factor modification and guideline-directed medical therapy, anticoagulation, rate control, and rhythm control. As recommended for atrial fibrillation in the non-failing heart, anticoagulation in patients with heart failure should be guided by a careful estimation of the risk of embolic events versus the risk of hemorrhagic episodes. The decision whether to target a rate-control or rhythm-control strategy is an evolving aspect of management. Currently, both approaches are good medical practice, but recent data suggest that rhythm control, particularly when achieved through catheter ablation, is associated with improved outcomes. A promising field of research is the application of neurohormonal modulation to prevent the creation of the "structural substrate" for atrial fibrillation in the failing heart.

Effect of lonidamine on alpha2-macroglobulin, hemopexin and alpha1-antitrypsin in the rat testis and epididymis.

In a recent study (Leone et al., 2000) we reported that lonidamine (LND), an antispermatogenic drug, affected the concentration of selected testicular and epididymal proteins in the rat. Thus, the effect of LND on alpha2-macroglobulin (alpha2-M) and on other two acute phase proteins (APP), hemopexin (HPX) and alpha1-antitrypsin (alpha1-AT) was examined here. LND was administered orally at the dose of 100 mg/kg, the animals were killed after 24 and 48 hr and the samples were analyzed by immunoblotting. The drug did not induce any significant change of alpha2-M in the serum or testis and of HPX and alpha1-AT in the serum, testis or epididymis. Thus, the antispermatogenic action of LND was not accompanied by a significant change of these inflammatory markers, even if it did cause a decrease of alpha1-inhibitor-3, a negative APP, as previously reported (Leone et al., 2000).

Effect of renal impairment on the pharmacokinetics of cibenzoline.

Sixteen subjects completed an open-label study designed to assess the effect of renal impairment on the disposition of cibenzoline. The study included 10 patients with mild or moderate renal impairment creatinine clearance less than 60 ml/min/70 kg) and six healthy subjects in the same age range, each of whom received a single 130 mg oral dose of cibenzoline. The pharmacokinetic parameters observed in the healthy volunteers were similar to those reported previously. Maximum plasma concentration, time of maximum concentration, and apparent volume of distribution after single doses in patients with renal impairment were in the same range as those observed in healthy volunteers. The elimination half-life increased with decreasing renal function from a mean value of approximately 8 hours in healthy volunteers to more than 20 hours in patients with moderate renal impairment. Renal clearance and the fraction of the dose excreted unchanged in the urine decreased with decreasing creatinine clearance. The results of this study suggest that the dosage of cibenzoline should be reduced or the dosage interval increased in patients with reduced renal function to avoid excessive drug accumulation.