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Assessment of Omecamtiv Mecarbil for the Treatment of Patients With Severe Heart Failure: A Post Hoc Analysis of Data From the GALACTIC-HF Randomized Clinical Trial.
Felker, GM, Solomon, SD, Claggett, B, Diaz, R, McMurray, JJV, Metra, M, Anand, I, Crespo-Leiro, MG, Dahlström, U, Goncalvesova, E, et al
JAMA cardiology. 2022;(1):26-34
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Abstract
IMPORTANCE Heart failure with reduced ejection fraction is a progressive clinical syndrome, and many patients' condition worsen over time despite treatment. Patients with more severe disease are often intolerant of available medical therapies. OBJECTIVE To evaluate the efficacy and safety of omecamtiv mecarbil for the treatment of patients with severe heart failure (HF) enrolled in the Global Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure (GALACTIC-HF) randomized clinical trial. DESIGN, SETTING, AND PARTICIPANTS The GALACTIC-HF study was a global double-blind, placebo-controlled phase 3 randomized clinical trial that was conducted at multiple centers between January 2017 and August 2020. A total of 8232 patients with symptomatic HF (defined as New York Heart Association symptom class II-IV) and left ventricular ejection fraction of 35% or less were randomized to receive omecamtiv mecarbil or placebo and followed up for a median of 21.8 months (range, 15.4-28.6 months). The current post hoc analysis evaluated the efficacy and safety of omecamtiv mecarbil therapy among patients classified as having severe HF compared with patients without severe HF. Severe HF was defined as the presence of all of the following criteria: New York Heart Association symptom class III to IV, left ventricular ejection fraction of 30% or less, and hospitalization for HF within the previous 6 months. INTERVENTIONS Participants were randomized at a 1:1 ratio to receive either omecamtiv mecarbil or placebo. MAIN OUTCOMES AND MEASURES The primary end point was time to first HF event or cardiovascular (CV) death. Secondary end points included time to CV death and safety and tolerability. RESULTS Among 8232 patients enrolled in the GALACTIC-HF clinical trial, 2258 patients (27.4%; mean [SD] age, 64.5 [11.6] years; 1781 men [78.9%]) met the specified criteria for severe HF. Of those, 1106 patients were randomized to the omecamtiv mecarbil group and 1152 to the placebo group. Patients with severe HF who received omecamtiv mecarbil experienced a significant treatment benefit for the primary end point (hazard ratio [HR], 0.80; 95% CI, 0.71-0.90), whereas patients without severe HF had no significant treatment benefit (HR, 0.99; 95% CI, 0.91-1.08; P = .005 for interaction). For CV death, the results were similar (HR for patients with vs without severe HF: 0.88 [95% CI, 0.75-1.03] vs 1.10 [95% CI, 0.97-1.25]; P = .03 for interaction). Omecamtiv mecarbil therapy was well tolerated in patients with severe HF, with no significant changes in blood pressure, kidney function, or potassium level compared with placebo. CONCLUSIONS AND RELEVANCE In this post hoc analysis of data from the GALACTIC-HF clinical trial, omecamtiv mecarbil therapy may have provided a clinically meaningful reduction in the composite end point of time to first HF event or CV death among patients with severe HF. These data support a potential role of omecamtiv mecarbil therapy among patients for whom current treatment options are limited. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02929329.
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Extrapolating Long-term Event-Free and Overall Survival With Dapagliflozin in Patients With Heart Failure and Reduced Ejection Fraction: An Exploratory Analysis of a Phase 3 Randomized Clinical Trial.
Docherty, KF, Jhund, PS, Claggett, B, Ferreira, JP, Bengtsson, O, Inzucchi, SE, Køber, L, Kosiborod, MN, Langkilde, AM, Martinez, FA, et al
JAMA cardiology. 2021;(11):1298-1305
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IMPORTANCE Sodium glucose cotransporter 2 inhibitors reduce morbidity and mortality in patients with heart failure and reduced ejection fraction (HFrEF). Clinicians may find estimates of the projected long-term benefits of sodium glucose cotransporter 2 inhibitors a helpful addition to clinical trial results when communicating the benefits of this class of drug to patients. OBJECTIVE To estimate the projected long-term treatment effects of dapagliflozin in patients with HFrEF over the duration of a patient's lifetime. DESIGN, SETTING, AND PARTICIPANTS Exploratory analysis was performed of Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF), a phase 3 randomized, placebo-controlled clinical trial conducted at 410 sites in 20 countries. Patients with an ejection fraction less than or equal to 40% in New York Heart Association functional classification II to IV and elevated plasma levels of N-terminal pro B-type natriuretic peptide were enrolled between February 15, 2017, and August 17, 2018, with final follow-up on June 6, 2019. Mean (SD) duration of follow-up was 17.6 (5.2) months. INTERVENTIONS Dapagliflozin, 10 mg, once daily vs placebo in addition to standard therapy. MAIN OUTCOMES AND MEASURES The primary composite outcome was time to first hospitalization for heart failure, urgent heart failure visit requiring intravenous therapy, or cardiovascular death. The trial results were extrapolated to estimate the projected long-term treatment effects of dapagliflozin over the duration of a patient's lifetime for the primary outcome and the secondary outcome of death from any cause. RESULTS A total of 4744 patients (1109 women [23.4%]; 3635 men [76.6%]) were randomized in DAPA-HF, with a mean (SD) age of 66.3 (10.9) years. The extrapolated mean event-free survival for an individual aged 65 years from a primary composite end point event was 6.2 years for placebo and 8.3 years for dapagliflozin, representing an event-free survival time gain of 2.1 years (95% CI, 0.8-3.3 years; P = .002). When considering death from any cause, mean extrapolated life expectancy for an individual aged 65 years was 9.1 years for placebo and 10.8 years for dapagliflozin, with a gain in survival of 1.7 years (95% CI, 0.1-3.3; P = .03) with dapagliflozin. Similar results were seen when extrapolated across the age range studied. In analyses of subgroups of patients in DAPA-HF, consistent benefits were seen with dapagliflozin on both event-free and overall survival. CONCLUSIONS AND RELEVANCE These findings indicate that dapagliflozin provides clinically meaningful gains in extrapolated event-free and overall survival. These findings may be helpful in communicating the benefits of this treatment to patients with HFrEF. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT03036124.
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Impact of empagliflozin on right ventricular parameters and function among patients with type 2 diabetes.
Sarak, B, Verma, S, David Mazer, C, Teoh, H, Quan, A, Gilbert, RE, Goodman, SG, Bami, K, Coelho-Filho, OR, Ahooja, V, et al
Cardiovascular diabetology. 2021;(1):200
Abstract
BACKGROUND Sodium-glucose cotransporter 2 (SGLT2) inhibition reduces cardiovascular events in type 2 diabetes (T2DM) and is associated with a reduction in left ventricular (LV) mass index. However, the impact on right ventricular (RV) remodeling is unknown. Accordingly, the objective of this study was to assess the impact of SGLT2 inhibition on RV parameters and function in T2DM and coronary artery disease (CAD). METHODS In EMPA-HEART CardioLink-6, 97 patients with T2DM and CAD were randomly assigned to empagliflozin 10 mg (n = 49) once daily or placebo (n = 48). Cardiac magnetic resonance imaging was performed at baseline and after 6 months. RV mass index (RVMi), RV end-diastolic and end-systolic volume index (RVEDVi, RVESVi) and RV ejection fraction (RVEF) were assessed in blinded fashion. RESULTS At baseline, mean RVMi (± SD) (11.8 ± 2.4 g/m2), RVEF (53.5 ± 4.8%), RVEDVi (64.3 ± 13.2 mL/m2) and RVESVi (29.9 ± 6.9 mL/m2) were within normal limits and were similar between the empagliflozin and placebo groups. Over 6 months, there were no significant differences in RVMi (- 0.11 g/m2, [95% CI - 0.81 to 0.60], p = 0.76), RVEF (0.54%, [95% CI - 1.4 to 2.4], p = 0.58), RVEDVi (- 1.2 mL/m2, [95% CI - 4.1 to 1.7], p = 0.41) and RVESVi (- 0.81 mL/m2, [95% CI - 2.5 to 0.90], p = 0.35) in the empaglifozin group as compared with the placebo group. In both groups, there was no significant correlation between RVMi and LVMi changes from baseline to 6 months. CONCLUSIONS In this post-hoc analysis, SGLT2 inhibition with empagliflozin had no impact on RVMi and RV volumes in patients with T2DM and CAD. The potentially differential effect of empagliflozin on the LV and RV warrants further investigation. CLINICAL TRIAL REGISTRATION URL: https://www.clinicaltrials.gov/ct2/show/NCT02998970?cond=NCT02998970&draw=2&rank=1 . Unique identifier: NCT02998970.
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Comparison of clinical characteristics of patients with heart failure and preserved ejection fraction with atrial fibrillation versus sinus rhythm: Insights from the APOLLON registry.
Özlek, B, Özlek, E, Tekinalp, M, Kahraman, S, Zencirkiran Agus, H, Başaran, Ö, Kaya, BC, Rencüzoğulları, İ, Mert, KU, Çakır, O, et al
Turk Kardiyoloji Dernegi arsivi : Turk Kardiyoloji Derneginin yayin organidir. 2020;(3):234-245
Abstract
OBJECTIVE The aim of this study was to assess the clinical characteristics of patients with heart failure and preserved ejection fraction (HFpEF) and atrial fibrillation (AF) and compare them with those of HFpEF patients without AF. METHODS This study was a sub-group analysis of a multicenter, observational, and cross-sectional registry conducted in Turkey (ClinicalTrials.gov identifier: NCT03026114). Patients with HFpEF were divided into 2 groups: HFpEF with AF and HFpEF with sinus rhythm (SR), and the clinical characteristics of the groups were compared. RESULTS In a total of 819 HFpEF patients (median age: 67 years; 58% women), 313 (38.2%) had AF. Compared to the patients with SR, those with AF were older (70 years vs 66 years; p<0.001) and more symptomatic, with a higher rate of classification as New York Heart Association functional class III-IV, paroxysmal nocturnal dyspnea, orthopnea, palpitations, fatigue, pulmonary crepitations, and peripheral edema. The hospitalization rate for heart failure was higher (28.4% vs 12.6%; p<0.001) in patients with AF, and participants with AF had higher level of N-terminal pro-B-type natriuretic peptide (887 pg/mL vs 394.8 pg/mL; p<0.001) and higher left atrial volume index level. Patients without AF had a higher burden of diabetes mellitus, obstructive sleep apnea, and coronary artery disease. The prescription rate of nondihydropyridine calcium blockers, digoxin, loop diuretics, and anticoagulant drugs was higher in the AF group. CONCLUSION The results of this study revealed that in a large Turkish cohort with HFpEF, significant clinical differences were present between those with and without AF and. Further prospective studies are needed to clarify the prognostic implications of AF in this growing heart failure population in our country.
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Efficacy and safety of sacubitril/valsartan compared with enalapril in patients with chronic heart failure and reduced ejection fraction: Results from PARADIGM-HF India sub-study.
Jain, AR, Aggarwal, RK, Rao, NS, Billa, G, Kumar, S
Indian heart journal. 2020;(6):535-540
Abstract
OBJECTIVES To determine efficacy and safety of sacubitril/valsartan compared with enalapril in Indian patients of PARADIGM-HF trial. METHODS A randomized, double-blind, active-controlled, phase III sub-study (NCT01035255) was conducted between April 2010 and May 2014. Patients with chronic heart failure (HF), aged >18 years with left ventricular ejection fraction ≤40% were randomized (1:1) to receive either sacubitril/valsartan 200 mg twice-daily or enalapril 10 mg twice-daily. The primary endpoint was to compare efficacy of sacubitril/valsartan to enalapril in delaying time-to-first occurrence of the composite endpoint (cardiovascular [CV] death or HF hospitalization). RESULTS The trial was stopped after a median follow-up of 27 months, because the boundary for benefit with sacubitril/valsartan had crossed. Among 637 Indian patients in PARADIGM-HF (sacubitril/valsartan, n = 322 and enalapril, n = 315), the primary outcome, CV death, and the first hospitalization for HF occurred in 21.81% and 24.76% (HR 0.89; 95% CI, 0.646-1.231), 17.45% and 20.63% (HR 0.87; 95% CI, 0.605-1.236), and 7.48% and 9.52% (HR 0.78; 95% CI, 0.461-1.350) patients in the sacubitril/valsartan and enalapril group, respectively. The all-cause mortality (19.0% vs. 21.9%) and adverse events (78.4% vs. 82.2%) were comparatively lower in the sacubitril/valsartan than enalapril group. No significant difference was seen between the benefits of treatment in Indian and the total PARADIGM-HF cohort (p value for interaction >0.05). CONCLUSION Results support the use of sacubitril/valsartan in Indian patients with chronic HF with reduced ejection fraction with treatment benefits similar to global PARADIGM-HF cohort.
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Dapagliflozin Effects on Biomarkers, Symptoms, and Functional Status in Patients With Heart Failure With Reduced Ejection Fraction: The DEFINE-HF Trial.
Nassif, ME, Windsor, SL, Tang, F, Khariton, Y, Husain, M, Inzucchi, SE, McGuire, DK, Pitt, B, Scirica, BM, Austin, B, et al
Circulation. 2019;(18):1463-1476
Abstract
BACKGROUND Outcome trials in patients with type 2 diabetes mellitus have demonstrated reduced hospitalizations for heart failure (HF) with sodium-glucose co-transporter-2 inhibitors. However, few of these patients had HF, and those that did were not well-characterized. Thus, the effects of sodium-glucose co-transporter-2 inhibitors in patients with established HF with reduced ejection fraction, including those with and without type 2 diabetes mellitus, remain unknown. METHODS DEFINE-HF (Dapagliflozin Effects on Biomarkers, Symptoms and Functional Status in Patients with HF with Reduced Ejection Fraction) was an investigator-initiated, multi-center, randomized controlled trial of HF patients with left ventricular ejection fraction ≤40%, New York Heart Association (NYHA) class II-III, estimated glomerular filtration rate ≥30 mL/min/1.73m2, and elevated natriuretic peptides. In total, 263 patients were randomized to dapagliflozin 10 mg daily or placebo for 12 weeks. Dual primary outcomes were (1) mean NT-proBNP (N-terminal pro b-type natriuretic peptide) and (2) proportion of patients with ≥5-point increase in HF disease-specific health status on the Kansas City Cardiomyopathy Questionnaire overall summary score, or a ≥20% decrease in NT-proBNP. RESULTS Patient characteristics reflected stable, chronic HF with reduced ejection fraction with high use of optimal medical therapy. There was no significant difference in average 6- and 12-week adjusted NT-proBNP with dapagliflozin versus placebo (1133 pg/dL (95% CI 1036-1238) vs 1191 pg/dL (95% CI 1089-1304), P=0.43). For the second dual-primary outcome of a meaningful improvement in Kansas City Cardiomyopathy Questionnaire overall summary score or NT-proBNP, 61.5% of dapagliflozin-treated patients met this end point versus 50.4% with placebo (adjusted OR 1.8, 95% CI 1.03-3.06, nominal P=0.039). This was attributable to both higher proportions of patients with ≥5-point improvement in Kansas City Cardiomyopathy Questionnaire overall summary score (42.9 vs 32.5%, adjusted OR 1.73, 95% CI 0.98-3.05), and ≥20% reduction in NT-proBNP (44.0 vs 29.4%, adjusted OR 1.9, 95% CI 1.1-3.3) by 12 weeks. Results were consistent among patients with or without type 2 diabetes mellitus, and other prespecified subgroups (all P values for interaction=NS). CONCLUSIONS In patients with heart failure and reduced ejection fraction, use of dapagliflozin over 12 weeks did not affect mean NT-proBNP but increased the proportion of patients experiencing clinically meaningful improvements in HF-related health status or natriuretic peptides. Benefits of dapagliflozin on clinically meaningful HF measures appear to extend to patients without type 2 diabetes mellitus. CLINICAL TRIAL REGISTRATION URL: https://www.clinicaltrials.gov. Unique identifier: NCT02653482.
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Beneficial effects of the treatment of iron deficiency on clinical condition, left ventricular function, and quality of life in patients with chronic heart failure.
Mirdamadi, A, Arefeh, A, Garakyaraghi, M, Pourmoghadas, A
Acta bio-medica : Atenei Parmensis. 2018;(2):214-218
Abstract
BACKGROUND Anemia is now considered as an important contributing factor to the deterioration of chronic heart failure. The present study aimed to assess the effects of intravenous iron therapy on clinical condition, left ventricular function and also quality of life in patients who suffered of chronic heart failure and concomitant iron deficiency. METHODS In this clinical trial, 25 consecutive patients with concomitant chronic heart failure and iron deficiency referred to Shariati hospital in Isfahan, Iran in 2013. After initial clinical, laboratory, and echocardiography assessments, the patients administered 200 mg intravenous Iron per week until compensating iron deficit. Then, all study parameters were assessed again and compared to parameters before the therapeutic intervention. RESULTS The NYHA class showed a significant improvement after the therapeutic approach. The prevalence of heart failure-related edema was also significantly reduced from 60% before treatment to 48% after that (p = 0.036). The rate of hospitalization was considerably reduced from 42% to 16% (P < 0.001). Moreover, mean 6 minute walk test (6MWT) was increased from 155.18 m to 187.40 m (P < 0.001). Comparing Left Ventricular Ejection Fraction (LVEF) after treatment to figures before the test indicated a significant improvement in this parameter (27.5% versus 33.0%, P = 0.007). The treatment of iron deficiency in this group of subjects got a significant improvement in SF36 total score. CONCLUSION In patients with chronic heart failure, the treatment of iron deficiency results in a marked improvement in functional status, ejection fraction, and also quality of life as well as a reduction in need to re-hospitalization, however renal function was deteriorated and thus more pay attention to renal function is necessary.
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Effect of Oral Iron Repletion on Exercise Capacity in Patients With Heart Failure With Reduced Ejection Fraction and Iron Deficiency: The IRONOUT HF Randomized Clinical Trial.
Lewis, GD, Malhotra, R, Hernandez, AF, McNulty, SE, Smith, A, Felker, GM, Tang, WHW, LaRue, SJ, Redfield, MM, Semigran, MJ, et al
JAMA. 2017;(19):1958-1966
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IMPORTANCE Iron deficiency is present in approximately 50% of patients with heart failure with reduced left ventricular ejection fraction (HFrEF) and is an independent predictor of reduced functional capacity and mortality. However, the efficacy of inexpensive readily available oral iron supplementation in heart failure is unknown. OBJECTIVE To test whether therapy with oral iron improves peak exercise capacity in patients with HFrEF and iron deficiency. DESIGN, SETTING, AND PARTICIPANTS Phase 2, double-blind, placebo-controlled randomized clinical trial of patients with HFrEF (<40%) and iron deficiency, defined as a serum ferritin level of 15 to 100 ng/mL or a serum ferritin level of 101 to 299 ng/mL with transferrin saturation of less than 20%. Participants were enrolled between September 2014 and November 2015 at 23 US sites. INTERVENTIONS Oral iron polysaccharide (n = 111) or placebo (n = 114), 150 mg twice daily for 16 weeks. MAIN OUTCOMES AND MEASURES The primary end point was a change in peak oxygen uptake (V̇o2) from baseline to 16 weeks. Secondary end points were change in 6-minute walk distance, plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, and health status as assessed by Kansas City Cardiomyopathy Questionnaire (KCCQ, range 0-100, higher scores reflect better quality of life). RESULTS Among 225 randomized participants (median age, 63 years; 36% women) 203 completed the study. The median baseline peak V̇o2 was 1196 mL/min (interquartile range [IQR], 887-1448 mL/min) in the oral iron group and 1167 mL/min (IQR, 887-1449 mL/min) in the placebo group. The primary end point, change in peak V̇o2 at 16 weeks, did not significantly differ between the oral iron and placebo groups (+23 mL/min vs -2 mL/min; difference, 21 mL/min [95% CI, -34 to +76 mL/min]; P = .46). Similarly, at 16 weeks, there were no significant differences between treatment groups in changes in 6-minute walk distance (-13 m; 95% CI, -32 to 6 m), NT-proBNP levels (159; 95% CI, -280 to 599 pg/mL), or KCCQ score (1; 95% CI, -2.4 to 4.4), all P > .05. CONCLUSIONS AND RELEVANCE Among participants with HFrEF with iron deficiency, high-dose oral iron did not improve exercise capacity over 16 weeks. These results do not support use of oral iron supplementation in patients with HFrEF. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT02188784.
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Sympathetic Nerve Activity Efferent Drive and Beta-Blocker Treatment - Effect of Interaction in Systolic Heart Failure.
Joho, S, Akabane, T, Ushijima, R, Hirai, T, Kinugawa, K
Circulation journal : official journal of the Japanese Circulation Society. 2016;(10):2149-54
Abstract
BACKGROUND Although both β-blocker dose (BBD) and sympathetic activity efferent drive are associated with prognosis in chronic heart failure (HF), little is known about the prognostic value of the interaction between them. METHODS AND RESULTS Potential prognostic variables including resting muscle sympathetic nerve activity (MSNA) were investigated in 133 patients with HF (ejection fraction [EF] <0.45). BBD was normalized to therapeutically equivalent doses of carvedilol. Primary cardiovascular endpoints included cardiovascular death and HF hospitalization. Predictors for outcomes were assessed on univariate, multivariate, and Kaplan-Meier analysis. EF was followed for 9 months after MSNA measurement in 102 patients. During the 1,419±824-day follow-up period, 24 patients died (sudden death, n=10; progressive HF, n=14). On multivariate Cox proportional hazard analysis, higher MSNA (P=0.037; HR, 2.01) and lower BBD (<5.0 mg/day; P=0.041; HR, 1.94) were independent predictors of cardiovascular events. Patients were divided into higher MSNA (≥64 bursts/100 beats) and lower MSNA groups. Although lower BBD remained an independent predictor in patients with higher MSNA, BBD was not statistically significant in patients with lower MSNA on univariate analysis. Additionally, there was a lower EF change in patients with lower BBD and higher MSNA. CONCLUSIONS Higher BBD might be necessary to avoid cardiovascular events in HF patients with central sympathetic overactivation. (Circ J 2016; 80: 2149-2154).
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Evaluation of Chronic Obstructive Pulmonary Disease (COPD) and reduced ejection fraction heart failure (HFrEF) discharge medication prescribing: Is drug therapy concordant with national guidelines associated with a reduction in 30-day readmissions?
Richardson, A, Tolley, E, Hartmann, J, Reedus, J, Bowlin, B, Finch, C, Sands, CW, Self, T
Respiratory medicine. 2016;:135-140
Abstract
INTRODUCTION Approximately 1 in 5 hospitalized COPD patients are readmitted within 30 days of discharge. CHF coexists in more than 20% of patients with COPD, and is associated with early readmission for COPD. Reducing 30-day hospital readmissions for COPD is of intense current interest. METHODOLOGY A retrospective chart review was performed to identify patients discharged with COPD exacerbation and HFrEF. The primary objective was to evaluate if discharge medication prescribing following guidelines for both COPD and HFrEF correlates with reduced 30-day readmission rates. RESULTS The study included 281 admissions with 39.1% prescribed appropriate discharge medications for both COPD and HFrEF; 30-day readmission rate was 24.5% for these patients compared to 31.1% that were not prescribed appropriate medications (p = 0.24). Beta blockers, ACE inhibitors or ARBS, and aldosterone antagonists were under-prescribed, but this did not significantly associate with increased readmission (p = 0.51, p = 0.23 or 0.99, and p = 0.18, respectively). Those prescribed hydralazine or nitrates were more likely to readmit (both p = 0.01). Diabetes and hyperlipidemia were associated with increased readmission (p = 0.01 and 0.05). CONCLUSIONS This study did not show a significant difference in 30-day readmission rate based on appropriate discharge medications for both COPD and HFrEF. The comorbidities diabetes and hyperlipidemia and prescription of hydralazine or nitrates were significantly associated with increased readmission rate. Larger patient populations may be needed to assess if guideline based discharge medication prescribing is associated with reduced 30-day readmissions for COPD.