Phosphodiesterase Type 5 Inhibitors and Oral Nitrates in Male Patients with Ischemic Heart Disease.

PURPOSE OF REVIEW: This review sought to define the mechanism of the drug-drug interaction between phosphodiesterase-type-5 (PDE-5) inhibitors and organic nitrates as well as the clinical impact and recommended management across different clinical scenarios. RECENT FINDINGS: This drug-drug interaction results in hemodynamically significant hypotension during episodic PDE-5 use and acute nitrate administration mainly during cardiovascular emergencies with multiple studies describing the expected impact. Chronic co-administration of long-acting nitrates and PDE-5 inhibitors has been observed in practice in a small percentage of patients despite the labeled contraindication without noted adverse effects. Acute nitrate therapy should be avoided in the context of episodic PDE-5 exposure, likely identified through systematic processes. Few data exist defining risk with lower-intensity daily PDE-5 administration. Chronic co-administration is not recommended but may be navigated with careful risk-benefit determination. Future directions also aim to identify potential areas where nitrate synergy may achieve clinical benefit.

Management of Iron Deficiency in Heart Failure: A Review of Evidence.

ABSTRACT: Iron deficiency is common in patients with heart failure and has been associated with worse outcomes, including increases in mortality, disease progression, and hospitalizations. As such, several studies have evaluated the role of iron supplementation in mitigating these risks. Evidence for the role of intravenous iron in improving exercise capacity, quality of life, and hospitalizations is promising, although the benefits of oral iron remain less clear. This review will evaluate the literature surrounding iron supplementation in heart failure and provide practical recommendations for its management.

Evaluation of cardiomyopathy in acute myeloid leukemia patients treated with anthracyclines.

BACKGROUND: Acute myeloid leukemia patients receive anthracycline-containing induction chemotherapy. Anthracyclines cause cardiotoxicity; however, there is a paucity of data reflecting the risk of cardiotoxicity in the acute myeloid leukemia population, and risk factors for development of reduced left ventricular ejection fraction are not well established in this population. METHODS: A retrospective cohort study of adult acute myeloid leukemia patients receiving anthracycline-containing induction chemotherapy between March 2011 and August 2017 was performed. Baseline and all additional cardiac monitoring within one year of induction were collected. Home medications and new medication initiation were determined via the electronic health record and new outpatient prescriptions. RESULTS: Of 97 evaluable patients, 25 (25.8%) developed reduced left ventricular ejection fraction and 18 (18.6%) experienced clinical heart failure within one year of induction. The median difference from baseline to lowest left ventricular ejection fraction was -5.0 percentage points, with a range of +10.0 to -52.5. The median time to onset of reduced left ventricular ejection fraction was 27 days, at a median cumulative anthracycline dose of 270 mg/m2. No patient-specific or medication-specific factors were significantly associated with the risk of developing reduced left ventricular ejection fraction. Of 14 patients started on medical management for reduced left ventricular ejection fraction, 10 (71%) responded to therapy. CONCLUSIONS: In this retrospective analysis, we observed that acute myeloid leukemia patients experienced reduced left ventricular ejection fraction more quickly and at lower doses than previously reported in the solid tumor population. Reduced left ventricular ejection fraction was at least partially reversible in most patients started on medical management. Although no factors were significantly associated with decreased cardiomyopathy risk, future assessment of cardioprotective medications may be warranted.

Antithrombin supplementation in adult patients receiving extracorporeal membrane oxygenation.

INTRODUCTION: Extracorporeal membrane oxygenation is associated with an increased risk of thrombosis and hemorrhage. Acquired antithrombin deficiency often occurs in patients receiving extracorporeal membrane oxygenation, necessitating supplementation to restore adequate anticoagulation. Criteria for antithrombin supplementation in adult extracorporeal membrane oxygenation patients are not well defined. METHODS: In this retrospective observational study, adult patients receiving antithrombin supplementation while supported on extracorporeal membrane oxygenation were evaluated. Antithrombin was supplemented when anti-Xa levels were subtherapeutic with unfractionated heparin infusion rates of 15-20 units/kg/h and measured antithrombin activity <50%. Patients were evaluated for changes in degree of anticoagulation and signs of bleeding 24 hours pre- and post-antithrombin supplementation. RESULTS: A total of 14 patients received antithrombin supplementation while on extracorporeal membrane oxygenation. The median percentage of time therapeutic anti-Xa levels were maintained was 0% (0-43%) and 40% (9-84%) in the pre-antithrombin and post-antithrombin groups, respectively (p = 0.13). No difference was observed in the number of patients attaining a single therapeutic anti-Xa level (pre-antithrombin = 6, post-antithrombin = 13; p = 0.37) or unfractionated heparin infusion rate (pre-antithrombin = 7.35 (1.95-10.71) units/kg/h, post-antithrombin = 6.81 (3.45-12.58) units/kg/h; p = 0.33). Thirteen patients (92%) achieved an antithrombin activity at goal following supplementation. Antithrombin activity was maintained within goal range 52% of the time during the replacement period. Four bleeding events occurred pre-antithrombin and 10 events post-antithrombin administration (p = 0.26) with significantly more platelets administered post-antithrombin (pre-antithrombin = 0.5 units, post-antithrombin = 4.5 units; p = 0.01). CONCLUSION: Therapeutic anticoagulation occurred more frequently following antithrombin supplementation; however, this difference was not statistically significant. More bleeding events occurred following antithrombin supplementation while observing an increase in platelet transfusions.

Postoperative Endothelial Cell Density Is Associated with Late Endothelial Graft Failure after Descemet Stripping Automated Endothelial Keratoplasty.

PURPOSE: To determine whether preoperative endothelial cell density (ECD) and postoperative ECD after Descemet stripping automated endothelial keratoplasty (DSAEK) are associated with late endothelial graft failure (LEGF) in the Cornea Preservation Time Study (CPTS). DESIGN: Cohort study within a multicenter, randomized clinical trial. PARTICIPANTS: A total of 1007 individuals (1223 study eyes), mean age 70 years, undergoing DSAEK for Fuchs' dystrophy (94% of eyes) or pseudophakic or aphakic corneal edema (PACE) (6% of eyes) and followed for up to 5 years. METHODS: Central ECD was determined by a central image analysis reading center. Preoperative ECD was determined for 1209 eyes that did not fail and 14 eyes that experienced LEGF. The ECD at 6 and 12 months after DSAEK, the change in ECD from preoperative to 6 and 12 months, surgeon-reported operative complications, and postoperative graft dislocation were investigated for an association with LEGFs unrelated to other postoperative events. Univariable and multivariable Cox proportional hazards regression models were used to assess associations. MAIN OUTCOME MEASURES: Late endothelial graft failure and its associations with pre- and postoperative ECD and operative complications. RESULTS: The cumulative probability of LEGF was 1.3% (95% confidence interval [CI], 0.8%-2.4%). Median (interquartile range [IQR]) preoperative ECDs were similar for eyes with LEGF (2523; 2367-3161) cells/mm2) and eyes without failure (2727; 2508-2973) cells/mm2) (P = 0.34). The ECD at 6 months was associated with LEGF (P < 0.001) in time-to-event analyses, whereas preoperative ECD was not (P = 0.55). The cumulative incidence (95% CI) of LEGF was 6.5% (3.0%, 14.0%) for 97 grafts with a 6-month ECD less than 1200 cells/mm2, 0.3% (0.0%, 2.4%) for 310 grafts with a 6-month ECD between 1200 and 2000 cells/mm2, and 0.6% (0.1%, 2.7%) for 589 grafts with a 6-month ECD greater than 2000 cells/mm2. In multivariable analyses, ECD at 6 months and operative complications were both associated with LEGF (P = 0.002 and P = 0.01, respectively), whereas graft dislocation was not (P = 0.61). CONCLUSIONS: In eyes undergoing DSAEK, preoperative ECD is unrelated to LEGF, whereas lower ECD at 6 months is associated with LEGF. Early endothelial cell loss after DSAEK and intraoperative complications should be minimized to improve graft survival.

Donor, Recipient, and Operative Factors Associated with Graft Success in the Cornea Preservation Time Study.

PURPOSE: To associate donor, recipient, and operative factors with graft success 3 years after Descemet stripping automated endothelial keratoplasty (DSAEK) in the Cornea Preservation Time Study (CPTS). DESIGN: Cohort study within a multicenter, double-masked, randomized clinical trial. PARTICIPANTS: One thousand ninety individuals (1330 study eyes) with a median age of 70 years undergoing DSAEK for Fuchs endothelial corneal dystrophy (94% of eyes) or pseudophakic or aphakic corneal edema (PACE; 6% of eyes). METHODS: Eyes undergoing DSAEK were randomized to receive a donor cornea with preservation time (PT) of 0 to 7 days (n = 675) or 8 to 14 days (n = 655). Donor, recipient, and operative parameters were recorded prospectively. Graft failure was defined as regraft for any reason, a graft that failed to clear by 8 weeks after surgery, or an initially clear graft that became and remained cloudy for 90 days. Failure in the first 8 weeks was classified further as primary donor failure or early failure, in the absence or presence of operative complications, respectively. Proportional hazards and logistic regression models were used to estimate risk ratios (RR) and 99% confidence intervals (CIs) for graft failure. MAIN OUTCOME MEASURES: Graft success at 3 years. RESULTS: One thousand two hundred fifty-one of 1330 grafts (94%) remained clear at 3 years and were considered successful. After adjusting for PT, tissue from donors with diabetes (RR, 2.35; 99% CI, 1.03-5.33) and operative complications (RR, 4.21; 99% CI, 1.42-12.47) were associated with increased risk for primary or early failure. Preoperative diagnosis of PACE (RR, 3.59; 99% CI, 1.05-12.24) was associated with increased risk for late failure by 3 years after surgery compared with Fuchs dystrophy. Graft success showed little variation among other factors evaluated, including donor age (RR, 1.19 per decade; 99% CI, 0.91-1.56 per decade), preoperative donor endothelial cell density (RR, 1.10 per 500 cells; 99% CI, 0.74-1.63 per 500 cells), graft diameter (RR, 1.22 per 1 mm; 99% CI, 0.39-3.76 per 1 mm), and injector use for graft insertion (RR, 0.92; 99% CI, 0.40-2.10). CONCLUSIONS: Descemet stripping automated endothelial keratoplasty success in the early and entire postoperative period is more likely when the donor did not have diabetes and was without operative complications and in the long-term postoperative period in recipients with Fuchs dystrophy compared with those with PACE. Mechanisms whereby diabetic donors and PACE recipients reduce the rate of graft success after DSAEK warrant further study.

The effect of donor age on penetrating keratoplasty for endothelial disease: graft survival after 10 years in the Cornea Donor Study.

OBJECTIVE: To determine whether the 10-year success rate of penetrating keratoplasty for corneal endothelial disorders is associated with donor age. DESIGN: Multicenter, prospective, double-masked clinical trial. PARTICIPANTS: A total of 1090 participants undergoing penetrating keratoplasty at 80 sites for Fuchs' dystrophy (62%), pseudophakic/aphakic corneal edema (34%), or another corneal endothelial disorder (4%) and followed for up to 12 years. METHODS: Forty-three eye banks provided corneas from donors aged 12 to 75 years, using a randomized approach to assign donor corneas to study participants without respect to recipient factors. Surgery and postoperative care were performed according to the surgeons' usual routines. MAIN OUTCOME MEASURES: Graft failure defined as a regraft or, in the absence of a regraft, a cloudy cornea that was sufficiently opaque to compromise vision for 3 consecutive months. RESULTS: In the primary analysis, the 10-year success rate was 77% for 707 corneas from donors aged 12 to 65 years compared with 71% for 383 donors aged 66 to 75 years (difference, +6%; 95% confidence interval, -1 to +12; P = 0.11). When analyzed as a continuous variable, higher donor age was associated with lower graft success beyond the first 5 years (P<0.001). Exploring this association further, we observed that the 10-year success rate was relatively constant for donors aged 34 to 71 years (75%). The success rate was higher for 80 donors aged 12 to 33 years (96%) and lower for 130 donors aged 72 to 75 years (62%). The relative decrease in the success rate with donor ages 72 to 75 years was not observed until after year 6. CONCLUSIONS: Although the primary analysis did not show a significant difference in 10-year success rates comparing donor ages 12 to 65 years and 66 to 75 years, there was evidence of a donor age effect at the extremes of the age range. Because we observed a fairly constant 10-year success rate for donors aged 34 to 71 years, which account for approximately 75% of corneas in the United States available for transplant, the Cornea Donor Study results indicate that donor age is not an important factor in most penetrating keratoplasties for endothelial disease.

Clopidogrel treatment and the incidence and severity of community acquired pneumonia in a cohort study and meta-analysis of antiplatelet therapy in pneumonia and critical illness.

Platelet activation results in the release and upregulation of mediators responsible for immune cell activation and recruitment, suggesting that platelets play an active role in immunity. Animal models and retrospective data have demonstrated benefit of antiplatelet therapy on inflammatory mediator expression and clinical outcomes. This study sought to characterize effects of clopidogrel on the incidence and severity of community-acquired pneumonia (CAP). A retrospective cohort study was conducted of Kentucky Medicaid patients (2001-2005). The exposed cohort consisted of patients receiving at least six consecutive clopidogrel prescriptions; the non-exposed cohort was comprised of patients not prescribed clopidogrel. Primary endpoints included incidence of CAP and inpatient treatment. Secondary severity endpoints included mortality, intensive care unit admission, mechanical ventilation, sepsis, and acute respiratory distress syndrome/acute lung injury. CAP incidence was significantly greater in the exposed cohort (OR 3.39, 95% CI 3.27-3.51, p < 0.0001) that remained after adjustment (OR 1.48, 95% CI 1.41-1.55, p < 0.0001). Inpatient treatment was more common in the exposed cohort (OR 1.96, 95% CI 1.85-2.07, p < 0.0001), but no significant difference remained after adjustment. Trends favoring the exposed cohort were found for the secondary severity endpoints of mechanical ventilation (p = 0.07) and mortality (p = 0.10). Pooled analysis of published studies supports these findings. While clopidogrel use may be associated with increased CAP incidence, clopidogrel does not appear to increase--and may reduce--its severity among inpatients. Because this study was retrospective and could not quantify all variables (e.g., aspirin use), these findings should be explored prospectively.

Association of colchicine use for acute gout with clinical outcomes in acute decompensated heart failure.

BACKGROUND: Gout is a common comorbidity in heart failure (HF) patients and is frequently associated with acute exacerbations during treatment for decompensated HF. Although colchicine is often used to manage acute gout in HF patients, its impact on clinical outcomes when used during acute decompensated HF is unknown. METHODS: This was a single center, retrospective study of hospitalized patients treated for an acute HF exacerbation with and without acute gout flare between March 2011 and December 2020. We assessed clinical outcomes in patients treated with colchicine for a gout flare compared to those who did not experience a gout flare or receive colchicine. The primary outcome was in-hospital all-cause mortality. RESULTS: Among 1047 patient encounters for acute HF during the study period, there were 237 encounters (22.7%) where the patient also received colchicine for acute gout during admission. In-hospital all-cause mortality was significantly reduced in the colchicine group compared with the control group (2.1% vs. 6.5%, p = .009). The colchicine group had increased length of stay (9.93 vs. 7.96 days, p < .001) but no significant difference in 30-day readmissions (21.5% vs. 19.5%, p = .495). In a Cox proportional hazards model adjusted for age, inpatient colchicine use was associated with improved survival to discharge (hazards ratio [HR] 0.163, 95% confidence interval [CI] 0.051-0.525, p = .002) and a reduced rate of in-hospital CV mortality (HR 0.184, 95% CI 0.044-0.770, p = .021). CONCLUSION: Among patients with a HF exacerbation, treatment with colchicine for a gout flare was associated with significantly lower in-hospital mortality compared with those not treated for acute gout.

The role of angiotensin receptor blockers in patients with angiotensin-converting enzyme inhibitor-induced angioedema.

OBJECTIVE: To assess the safety of using angiotensin II receptor blockers (ARBs) in patients who develop angioedema with the use of angiotensin-converting enzyme inhibitors (ACEIs). DATA SOURCES: A literature search was performed using MEDLINE (1977-January 2011) and Cochrane Library, using the terms angiotensin receptor blocker, angiotensin-converting enzyme inhibitor, and angioedema. In addition, reference citations from publications identified were reviewed. STUDY SELECTION AND DATA EXTRACTION: Only English-language publications were included. Randomized controlled trial data, observational studies (retrospective and prospective), and case reports on adults who received ACEI therapy and then an ARB as an alternative therapy were reviewed. DATA SYNTHESIS: Two randomized controlled trials and 1 meta-analysis evaluated ARB use in patients intolerant to ACEIs. Taken together, there is a conservative estimate of a 10% or less incidence of cross reactivity of angioedema in patients who receive an ARB after experiencing ACEI-associated angioedema. Angioedema related to ARBs is reported to be less severe and occurs earlier compared to angioedema that develops during ACEI therapy. CONCLUSIONS: ARBs may be an alternative for patients who develop angioedema while using an ACEI but should be reserved for patients with high therapeutic need for angiotensin inhibition. Treatment should be started with observation, patients should be educated on the signs of angioedema, and proper emergency management should be emphasized to patients and care providers.

Optimizing anticoagulation for patients receiving Impella support.

Anticoagulation of patients treated with the Impella percutaneous mechanical circulatory support (MCS) devices is complex and lacks consistency across centers, potentially increasing the risk of complications. In order to optimize safety and efficacy, an expert committee synthesized all available evidence evaluating anticoagulation for patients receiving Impella support in order to provide consensus recommendations for the management of anticoagulation with these devices. The evidence synthesis led to the creation of 42 recommendations to improve anticoagulation management related to the use of the Impella devices. Recommendations address purge solution management, intravenous anticoagulation, monitoring, evaluation and management of heparin-induced thrombocytopenia (HIT), and management during combination MCS support. The use of a heparinized, dextrose-containing purge solution is critical for optimal device function, and a bicarbonate-based purge solution may be an alternative in certain situations. Likewise, intravenous (ie, systemic) anticoagulation with heparin is often necessary, although evidence supporting the optimal assay and target range for monitoring the level of anticoagulation is generally lacking. Patients treated with an Impella MCS device may develop HIT, which is more difficult to evaluate and treat in this setting. Lastly, the use of Impella with extracorporeal membrane oxygenation or for biventricular support creates additional anticoagulation challenges.

Continuous versus intermittent infusion of furosemide in acute decompensated heart failure.

BACKGROUND: Despite advances in the treatment of chronic ambulatory heart failure, hospitalization rates for acute decompensated heart failure (ADHF) remain high. Although loop diuretics are used in nearly all patients with ADHF to relieve congestive symptoms, optimal dosing strategies remain poorly defined. METHODS AND RESULTS: This was a prospective, randomized, parallel-group study comparing the effectiveness of continuous intravenous (cIV) with intermittent intravenous (iIV) infusion of furosemide in 56 patients with ADHF. The dose and duration of furosemide as well as concomitant medications to treat ADHF were determined by physician preference. The primary end point of the study was net urine output (nUOP)/24 hours. Safety measures including electrolyte loss and hemodynamic instability were also assessed. Twenty-six patients received cIV and 30 patients received iIV dosing. The mean nUOP/24 hours was 2098+/-1132 mL in patients receiving cIV versus 1575+/-1100 mL in the iIV group (P=.086). The cIV group had significantly greater total urine output (tUOP) with 3726+/-1121 mL/24 hours versus 2955+/-1267 mL/24 hours in the iIV group (P=.019) and tUOP/mg furosemide with 38.0+/-31.0 mL/mg versus 22.2+/-12.5 mL/mg (P=.021). Mean weight loss was not significantly different between the groups. The cIV group experienced a shorter length of hospital stay (6.9+/-3.7 versus 10.9+/-8.3 days, P=.006). There were no differences in safety measures between the groups. CONCLUSIONS: The cIV of furosemide was well tolerated and significantly more effective than iIV for tUOP. In addition, continuous infusion appears to provide more efficient diuresis.