Tafamidis medication adherence and persistence in patients with transthyretin amyloid cardiomyopathy in Japan.

AIMS: This study aimed to describe baseline characteristics and adherence among patients with transthyretin amyloid cardiomyopathy (ATTR-CM) treated with tafamidis (VYNDAQEL®) in Japan using the Japanese Medical Data Vision (MDV) database. METHODS AND RESULTS: This study was a non-interventional, retrospective cohort study of adult (≥18 years old) patients in the Japanese MDV claims database diagnosed with ATTR-CM and with at least two tafamidis prescriptions of dose strength 4 × 20 mg/day between 1 March 2019 and 31 August 2021. The date of the first prescription was defined as the index date, with follow-up time defined as the time between the first and last prescription plus the days' supply from the last refill. Baseline characteristics were assessed during a 12 month pre-index period. Adherence was measured using two metrics: (i) the modified medication possession ratio (mMPR), calculated by taking the sum of days supplied for all fills within the follow-up period, divided by the number of days of follow-up, and reported as a percentage, with patients classified as adherent with an mMPR of ≥80%, and (ii) the proportion of days covered (PDC), calculated by taking the total number of days' supply dispensed during the follow-up period divided by the number of days of follow-up, adjusting for any days' supply overlap. A total of 210 patients were identified; the mean (standard deviation) age of the cohort was 77 (5.9) years, and the majority (89%) were male. The most common baseline cardiovascular comorbidities were heart failure (85%), ischaemic heart disease (66%), hypertensive diseases (49%), and diabetes (35%); 75% of patients received heart failure medications in the 12 months prior to index, with the most common being beta-blockers (49%), diuretics (48%), angiotensin receptor blockers (30%), angiotensin-converting enzyme inhibitors (22%), and sodium-glucose cotransporter-2 inhibitors (8.1%). Over an average 14 month follow-up, mean mMPR was 96% with a median of 100% [inter-quartile range (IQR): 97-101%]; 93% of patients were adherent (defined as an mMPR ≥ 80%). In the same follow-up period, mean PDC was 93.6% with a median of 99% (IQR: 93-100%). Persistence was high with 78% of patients having a 0 day gap between prescription refills. CONCLUSIONS: This study found high adherence rates to tafamidis in this real-world Japanese patient population. Adherence rates in this study were similar to those reported by the tafamidis clinical trial and a previously published US commercial claims adherence analysis. Further studies should be conducted to assess the impact of real-world adherence on real-world outcomes.

Sublobar resection or lobectomy and postoperative respiratory complications in emphysematous lungs.

OBJECTIVES: Pulmonary resection in patients with severe emphysema may impact postoperative respiratory complications. Low-attenuation areas evaluated using three-dimensional computed tomography to assess emphysematous changes are strongly associated with postoperative respiratory complications. Herein, we investigated the relationship between low-attenuation area, the surgical procedure and resected lung volume, which has not been explored in previous studies. METHODS: We retrospectively evaluated patients with primary or metastatic lung cancer who underwent surgical resection. The low-attenuation area percentage (low-attenuation area/total lung area × 100) and resected lung volume were calculated using three-dimensional computed tomography software, and the relationship with postoperative respiratory complications was analysed. RESULTS: Postoperative respiratory complications occurred in 66 patients (17%) in the total cohort (n = 383). We set the median value of 1.1% as the cut-off value for low-attenuation area percentage to predict postoperative respiratory complications, which occurred in 24% and 10% of patients with low-attenuation area >1.1% and <1.1%, respectively (P < 0.001). Postoperative respiratory complications occurred in approximately one-third of the patients with low-attenuation area >1.1%, whose resected lung volume was ≥15.8% or ≥5 resected subsegments. Multivariable analysis revealed that sublobar resection was associated with a significantly lower risk of postoperative respiratory complications in patients with low-attenuation area >1.1% (odds ratio 0.4, 95% confidence interval 0.183-0.875). CONCLUSIONS: Emphysema is a risk factor for postoperative respiratory complications, and lobectomy is an independent predictive risk factor. Preserving more lung parenchyma may yield better short-term prognoses in patients with emphysematous lungs.

Clinical implications of subclinical left ventricular dysfunction in heart failure with preserved ejection fraction: The PARAGON-HF study.

AIMS: Left ventricular (LV) subclinical impairment has been described in heart failure with preserved ejection fraction (HFpEF). We assessed the relationship between LV myocardial deformation by strain imaging and recurrent hospitalization for heart failure (HF) or cardiovascular death in a large international HFpEF population. METHODS AND RESULTS: We assessed two-dimensional speckle-tracking based global longitudinal strain (GLS) in 790 patients (mean age 74 ± 8 years, 54% female) with adequate image quality enrolled in the PARAGON-HF echocardiography study. We examined the relationship of GLS with total HF hospitalizations and cardiovascular death (the primary composite outcome) after accounting for clinical confounders. Approximately 47% of the population had evidence of LV subclinical dysfunction, defined as absolute GLS <16%. Impaired GLS was significantly associated with higher values of circulating baseline N-terminal pro-B-type-natriuretic peptide. After a median follow-up of 3.0 years, there were 407 total HF hospitalizations and cardiovascular deaths. After multivariable adjustment, worse GLS was associated with a greater risk for the primary composite outcome (adjusted hazard ratio per 1% decrease: 1.06; 95% confidence interval 1.02-1.11; p = 0.008). GLS did not modify the treatment effect of sacubitril/valsartan compared with valsartan for the composite outcome (p for interaction >0.1). CONCLUSIONS: In a large HFpEF population, impaired LV function was observed even among patients with preserved ejection fraction, and was associated with an increased risk of total HF hospitalizations or cardiovascular death, accounting for clinical confounders. These findings highlight the key role of subtle LV systolic impairment in the pathophysiology of HFpEF.

Real-world Practical Experience of Angiotensin Receptor-neprilysin Inhibitor in Older Japanese Patients with Chronic Heart Failure.

Introduction: Sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor (ARNI), is superior to enalapril for chronic heart failure (CHF) with reduced ejection fraction (EF). However, its efficacy and safety in older Japanese patients in clinical practice are poorly understood. We aimed to investigate the efficacy and safety of ARNI compared with angiotensin receptor blocker (ARB) in older patients with CHF in real-world clinical practice. In addition, nutritional status and body composition were investigated as essential indicators of efficacy. Methods: This retrospective single-center observational study enrolled 55 consecutive older patients (aged ≥75 years) with CHF who received ARNI (n = 27) or ARB (n = 28) therapy between October 2020 and March 2021. Blood samples were collected before (baseline) and 4, 12, and 24 weeks after ARNI or ARB therapy initiation. Furthermore, echocardiography was performed before (baseline) and 24 weeks after ARNI or ARB therapy initiation. The efficacy endpoints were changes in N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, left ventricular EF, nutritional status, and body composition changes. The controlling nutritional status (CONUT) score and geriatric nutritional risk index were investigated as nutritional status indices. The safety endpoints were symptomatic hypotension, renal function exacerbation, and hyperkalemia in patients who continued ARNI or ARB therapy for >24 weeks without additional nonpharmacological treatment. Results: There were no significant changes in NT-proBNP levels and estimated glomerular filtration rates; however, there was a significant CONUT score improvement in the ARNI group (least-squares mean difference, -1.0; 95% confidence interval, -1.4 to -0.3; p = 0.04). The initial ARNI dose could not be uptitrated in five patients (19%) due to hypotension. Conclusions: ARNI exhibited significant improvement in the nutritional status in older patients with CHF compared with ARB. However, the ARNI dose should be adjusted according to the patient's blood pressure.

Prognostic Impact of Hyperpolypharmacy Due to Noncardiovascular Medications in Patients After Acute Decompensated Heart Failure　- Insights From the Clue of Risk Stratification in the Elderly Patients With Heart Failure (CURE-HF) Registry.

BACKGROUND: Hyperpolypharmacy is associated with adverse outcomes in older adults, but because literature on its association with cardiovascular (CV) outcomes after acute decompensated heart failure (ADHF) is sparse, we investigated the relationships among hyperpolypharmacy, medication class, and death in patients with HF.Methods and Results: We evaluated the total number of medications prescribed to 884 patients at discharge following ADHF. Patients were categorized into nonpolypharmacy (<5 medications), polypharmacy (5-9 medications), and hyperpolypharmacy (≥10 medications) groups. We examined the relationship of polypharmacy status with the 2-year mortality rate. The proportion of patients taking ≥5 medications was 91.3% (polypharmacy, 55.3%; hyperpolypharmacy, 36.0%). Patients in the hyperpolypharmacy group showed worse outcomes than patients in the other 2 groups (P=0.002). After multivariable adjustment, the total number of medications was significantly associated with an increased risk of death (hazard ratio [HR] per additional increase in the number of medications, 1.05; 95% confidence interval [CI], 1.01-1.10; P=0.027). Although the number of non-CV medications was significantly associated with death (HR, 1.07; 95% CI, 1.02-1.13; P=0.01), the number of CV medications was not (HR, 1.01; 95% CI, 0.92-1.10; P=0.95). CONCLUSIONS: Hyperpolypharmacy due to non-CV medications was associated with an elevated risk of death in patients after ADHF, suggesting the importance of a regular review of the prescribed drugs including non-CV medications.

Clinical Profile and Prognosis of Dementia in Patients With Acute Decompensated Heart Failure　- From the CURE-HF Registry.

BACKGROUND: Acute decompensated heart failure (ADHF) has a poor prognosis and common comorbidities may be contributory. However, evidence for the association between dementia and clinical outcomes in patients with is sparse and it requires further investigation into risk reduction.Methods and Results: We assessed the clinical profiles and outcomes of 1,026 patients (mean age 77.8 years, 43.2% female) with ADHF enrolled in the CURE-HF registry to evaluate the relationship between investigator-reported dementia status and clinical outcomes (all-cause death, cardiovascular (CV) death, non-CV death, and HF hospitalization) over a median follow-up of 2.7 years. In total, dementia was present in 118 (11.5%) patients, who experienced more drug interruptions and HF admissions due to infection than those without dementia (23.8% vs. 13.1%, P<0.01; 11.0% vs. 6.0%, P<0.01, respectively). Kaplan-Meier analysis revealed that dementia patients had higher mortality rates than those without dementia (log-rank P<0.001). After multivariable adjustment for demographics and comorbidities, dementia was significantly associated with an increased risk of death (adjusted hazard ratio, 1.43; 95% confidence interval, 1.06-1.93, P=0.02) and non-CV death (adjusted hazard ratio, 1.65; 95% confidence interval, 1.04-2.62, P=0.03), but no significant associations between dementia and CV death or HF hospitalization were observed (both, P>0.1). CONCLUSIONS: In ADHF patients dementia was associated with aggravating factors for HF admission and elevated risk of death, primarily non-CV death.

Regional contributions to impaired myocardial mechanical function in heart failure with preserved ejection fraction.

AIMS: Hypertensive heart disease (HHD) is recognized as a key clinical precursor to heart failure with preserved ejection fraction (HFPEF). However, pathophysiological transition from HHD to HFPEF is not well understood. We sought determine whether regional differences in impaired myocardial function may underlie the greater mechanical dysfunction seen in HFPEF compared to HHD. METHODS AND RESULTS: We used standardized echocardiography to assess regional myocardial deformation in a cohort of n = 327 adults with preserved left ventricular (LV) ejection fraction (≥45%), including: n = 129 with HFPEF, n = 158 with HHD and no heart failure, and n = 40 normotensive controls. From detailed measurements of LV systolic strain performed in multiple views, we derived and then compared regional measures of basal, mid-ventricular, and apical longitudinal strains. In models adjusting for clinical covariates, basal and mid-ventricular LV myocardial deformation was more impaired in HHD than in controls (P ≤ 0.003), whereas apical deformation was more impaired in HFPEF than in HHD (P = 0.005). In multivariable-adjusted analyses, only apical strain remained independently associated with HFPEF vs. HHD status [odds ratio 1.18 (1.02-1.37), P = 0.030 per 1% decrease in apical strain]. Compared to other regional strains, apical longitudinal strain optimally differentiated HFPEF from HHD (area under the receiver operating curve: apical longitudinal strain = 0.67; mid-ventricular longitudinal strain = 0.59; basal longitudinal strain = 0.60). CONCLUSION: We found that while apical mechanical function is preserved in HHD, it was impaired in HFPEF and may contribute to the transition from an asymptomatic heart disease to a symptomatic heart disease.

Association between complete revascularization of the coronary artery and clinical outcomes in peripheral artery disease: a sub-analysis of the I-PAD Nagano registry.

Peripheral artery disease (PAD) is commonly caused by atherosclerosis and has an unfavorable prognosis. Complete revascularization (CR) of the coronary artery reduces the risk of major adverse cardiovascular event (MACE) in patients with coronary artery disease (CAD). However, the impact of CR in patients with PAD has not been established to date. Therefore, we evaluated the impact of CR of CAD on the five-year clinical outcomes in patients with PAD. This study was based on a prospective, multicenter, observational registry in Japan. We enrolled 366 patients with PAD undergoing endovascular treatment. The primary endpoint was MACE, defined as a composite of all-cause death, non-fatal myocardial infarction, and non-fatal stroke. After excluding ineligible patients, 96 and 68 patients received complete revascularization of the coronary artery (CR group) and incomplete revascularization of the coronary artery (ICR group), respectively. Freedom from MACE in the CR group was significantly higher than in the ICR group at 5 years (66.7% vs 46.0%, p < 0.01). Multivariate analysis revealed that CR emerged as an independent predictor of MACE (Hazard ratio: 0.56, 95% confidential interval: 0.34-0.94, p = 0.03). CR of CAD was significantly associated with improved clinical outcomes in patients with PAD undergoing endovascular treatment.

Effect of patisiran on stroke volume in hereditary transthyretin-mediated amyloidosis: insights from pressure-volume analysis of the APOLLO study.

AIMS: Transthyretin-mediated (ATTR) amyloidosis is caused by deposition of transthyretin protein fibrils in the heart, nerves, and other organs. Patisiran, an RNA interference therapeutic that inhibits hepatic synthesis of transthyretin, was approved for the treatment of hereditary ATTR amyloidosis with polyneuropathy based on the phase 3 APOLLO study. We use left ventricular (LV) stroke volume (SV) to quantify LV function overtime and non-invasive pressure-volume techniques to delineate the effects of patisiran on LV mechanics in the pre-specified cardiac subpopulation of the APOLLO study. METHODS AND RESULTS: Left ventricular SV was assessed by transthoracic echocardiography at baseline, and after 9 and 18 months of therapy. To determine the mechanisms underlying changes in LV SV, non-invasive pressure-volume parameters, including the end-systolic and end-diastolic pressure-volume relationship, were derived using single beat techniques. At baseline, the mean SV was 51 ± 14 ml. At 9 months, the least-squares mean change in SV was -0.3 ± 1.2 ml for patisiran and -5.4 ± 1.9 ml for placebo (p = 0.021). At 18 months, the least-squares mean change in SV was -1.7 ± 1.3 ml for patisiran and - 8.1 ± 2.3 ml for placebo (p = 0.016). Decline in LV SV was driven by diminished LV capacitance in placebo relative to patisiran. CONCLUSIONS: Patisiran may delay progression of LV chamber dysfunction starting at 9 months of therapy. These data elucidate the mechanisms by which transthyretin-reducing therapies modulate progression of cardiac disease and need to be confirmed in ongoing phase 3 trials.

A Simple Score to Identify Increased Risk of Transthyretin Amyloid Cardiomyopathy in Heart Failure With Preserved Ejection Fraction.

Importance: Transthyretin amyloid cardiomyopathy (ATTR-CM) is a form of heart failure (HF) with preserved ejection fraction (HFpEF). Technetium Tc 99m pyrophosphate scintigraphy (PYP) enables ATTR-CM diagnosis. It is unclear which patients with HFpEF have sufficient risk of ATTR-CM to warrant PYP. Objective: To derive and validate a simple ATTR-CM score to predict increased risk of ATTR-CM in patients with HFpEF. Design, Setting, and Participants: Retrospective cohort study of 666 patients with HF (ejection fraction ≥ 40%) and suspected ATTR-CM referred for PYP at Mayo Clinic, Rochester, Minnesota, from May 10, 2013, through August 31, 2020. These data were analyzed September 2020 through December 2020. A logistic regression model predictive of ATTR-CM was derived and converted to a point-based ATTR-CM risk score. The score was further validated in a community ATTR-CM epidemiology study of older patients with HFpEF with increased left ventricular wall thickness ([WT] ≥ 12 mm) and in an external (Northwestern University, Chicago, Illinois) HFpEF cohort referred for PYP. Race was self-reported by the participants. In all cohorts, both case patients and control patients were definitively ascertained by PYP scanning and specialist evaluation. Main Outcomes and Measures: Performance of the derived ATTR-CM score in all cohorts (referral validation, community validation, and external validation) and prevalence of a high-risk ATTR-CM score in 4 multinational HFpEF clinical trials. Results: Participant cohorts included were referral derivation (n = 416; 13 participants [3%] were Black and 380 participants [94%] were White; ATTR-CM prevalence = 45%), referral validation (n = 250; 12 participants [5%]were Black and 228 participants [93%] were White; ATTR-CM prevalence = 48% ), community validation (n = 286; 5 participants [2%] were Black and 275 participants [96%] were White; ATTR-CM prevalence = 6% ), and external validation (n = 66; 23 participants [37%] were Black and 36 participants [58%] were White; ATTR-CM prevalence = 39%). Score variables included age, male sex, hypertension diagnosis, relative WT more than 0.57, posterior WT of 12 mm or more, and ejection fraction less than 60% (score range -1 to 10). Discrimination (area under the receiver operating characteristic curve [AUC] 0.89; 95% CI, 0.86-0.92; P < .001) and calibration (Hosmer-Lemeshow; χ2 = 4.6; P = .46) were strong. Discrimination (AUC ≥ 0.84; P < .001 for all) and calibration (Hosmer-Lemeshow χ2 = 2.8; P = .84; Hosmer-Lemeshow χ2 = 4.4; P = .35; Hosmer-Lemeshow χ2 = 2.5; P = .78 in referral, community, and external validation cohorts, respectively) were maintained in all validation cohorts. Precision-recall curves and predictive value vs prevalence plots indicated clinically useful classification performance for a score of 6 or more (positive predictive value ≥25%) in clinically relevant ATTR-CM prevalence (≥10% of patients with HFpEF) scenarios. In the HFpEF clinical trials, 11% to 35% of male and 0% to 6% of female patients had a high-risk (≥6) ATTR-CM score. Conclusions and Relevance: A simple 6 variable clinical score may be used to guide use of PYP and increase recognition of ATTR-CM among patients with HFpEF in the community. Further validation in larger and more diverse populations is needed.

Gender difference in heart failure with preserved ejection fraction: clinical profiles, examinations, and prognosis.

Heart failure with preserved ejection fraction (HFpEF) has currently become a major concern in the aging society owing to its substantial and growing prevalence. Recent investigations regarding sacubitril/valsartan have suggested that there is a gender difference in the efficacy of the medication in HFpEF cohort. However, information of gender difference in clinical profiles, examination, and prognosis have not been well investigated. The present study aimed to evaluate the differences in baseline characteristics and outcomes between women and men in a Japanese HFpEF cohort. We analyzed the data from our prospective, observational, and multicenter cohort study. Overall, 1036 consecutive patients hospitalized for acute decompensated heart failure were enrolled. We defined patients with an ejection fraction (EF) of ≥ 50% as HFpEF. Patients with severe valvular disease were excluded; the remaining 379 patients (women: n = 201, men: n = 178) were assessed. Women were older than men [median: 85 (79-89) years vs. 83 (75-87) years, p = 0.013]. Diabetes mellitus, hyperuricemia, and coronary artery disease were more prevalent in men than in women (34.8% vs. 23.9%, p = 0.019, 23.6% vs. 11.4%, p = 0.002, and 23.0% vs. 11.9%, p = 0.005, respectively). EF was not significantly different between women and men. The cumulative incidence of cardiovascular death or hospitalization for congestive heart failure (CHF) was significantly lower in women than in men (log-rank p = 0.040). Women with HFpEF were older and less often exhibited an ischemic etiology; further, they were associated with a lower risk for cardiovascular death or hospitalization for CHF compared with men in the Japanese population.

Association of Left Atrial Structure and Function With Heart Failure in Older Adults.

BACKGROUND: Limited data exist to characterize novel measures of left atrial (LA) structure and function in older adults without prevalent heart failure (HF). OBJECTIVES: The aim was to assess reference range of LA measures, their associations with N-terminal pro-B-type natriuretic-peptide (NT-proBNP) and the related risk for incident HF or death. METHODS: We analyzed LA structure (LA maximal [LAViMax] and minimal volume indexed by body surface area) and function (LA emptying fraction, LA reservoir, conduit, and contraction strain) in 4,901 participants from the ARIC (Atherosclerosis Risk In Communities) study (mean age 75 ± 5 years, 40% male, and 19% Black) without prevalent HF. We assessed sex-specific 10th and 90th percentile ARIC-based reference limits in 301 participants free of prevalent cardiovascular disease, and related LA measures to NT-proBNP and incident HF or death (median follow-up of 5.5 years) in the whole ARIC cohort. RESULTS: Approximately 20% of the overall population had LA abnormalities according to the ARIC-based reference limit. Each LA measure was associated with NT-proBNP and, except for LAViMax, with incident HF or death after multivariable adjustment (including left ventricular function and NT-proBNP). Results were consistent in participants with normal LAViMax (P for interaction > 0.05). LA measures were prognostic for both incident HF with preserved ejection fraction or death and incident HF with reduced ejection fraction or death. When added to HF risk factors and NT-proBNP (baseline C-statistics = 0.74) all LA measures, except for LAViMax, significantly enhanced the prognostic accuracy. CONCLUSIONS: Novel measures of LA structure and function, but not standard assessment by LAViMax, are associated with increased risk of incident HF or death regardless of measures of left ventricular function and NT-proBNP.

Comparison of prognostic impact of anticoagulants in heart failure patients with atrial fibrillation and renal dysfunction: direct oral anticoagulants versus vitamin K antagonists.

Although high thromboembolic risk was assumed in elderly patients with heart failure (HF) and atrial fibrillation (AF), inadequate control of prothrombin time/international normalized ratio was often observed in patients using vitamin K antagonists (VKAs). We hypothesized that patients treated with direct oral anticoagulants (DOAC) would have a better outcome than those treated with VKAs. The aim of this study was to compare the efficacies of DOACs and VKAs in elderly patients with HF and AF. We retrospectively analyzed data from a multicenter, prospective observational cohort study. A total of 1036 patients who were hospitalized for acute decompensated HF were enrolled. We assessed 329 patients aged > 65 years who had non-valvular AF and divided them into 2 groups according to the anticoagulant therapy they received. A subgroup analysis was performed using renal dysfunction based on estimated glomerular filtration rate (eGFR; mL/min/1.73 m2). The primary outcome was all-cause mortality, and the secondary outcomes were non-cardiovascular death or stroke. The median follow-up period was 730 days (range 334-1194 days). The primary outcome was observed in 84 patients; non-cardiovascular death, in 25 patients; and stroke, in 14 patients. The Kaplan-Meier analysis revealed that all-cause mortality was significantly lower in the DOAC group than in the VKA group (log-rank p = 0.033), whereas the incidence rates of non-cardiovascular death (log-rank p = 0.171) and stroke (log-rank p = 0.703) were not significantly different in the crude population. DOAC therapy was not associated with lower mortality in the crude population (log-rank p = 0.146) and in the eGFR ≥ 45 mL/min/1.73 m2 subgroup (log-rank p = 0.580). However, DOAC therapy was independently associated with lower mortality after adjustments for age, diabetes mellitus, and albumin level (hazard ratio, 0.55; 95% confidence interval, 0.30-0.99; p = 0.045) in the eGFR < 45 mL/min/1.73 m2 subgroup. Compared with VKA therapy, DOAC therapy was associated with lower risk of all-cause mortality in the elderly HF patients with AF and renal dysfunction.

Impact of Chronic Obstructive Pulmonary Disease in Patients With Heart Failure With Preserved Ejection Fraction: Insights From PARAGON-HF.

Background Little is known about the impact of chronic obstructive pulmonary disease (COPD) in patients with heart failure with preserved ejection fraction (HFpEF). Methods and Results We examined outcomes in patients with heart failure with preserved ejection fraction, according to COPD status, in the PARAGON-HF (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in Heart Failure With Preserved Ejection Fraction) trial. The primary outcome was a composite of first and recurrent hospitalizations for heart failure and cardiovascular death. Of 4791 patients, 670 (14%) had COPD. Patients with COPD were more likely to be men (58% versus 47%; P<0.001) and had worse New York Heart Association functional class (class III/IV 24% versus 19%), worse Kansas City Cardiomyopathy Questionnaire Clinical Summary Scores (69 versus 76; P<0.001) and more frequent history of heart failure hospitalization (54% versus 47%; P<0.001). The decrement in Kansas City Cardiomyopathy Questionnaire Clinical Summary Scores with COPD was greater than for other common comorbidities. Patients with COPD had echocardiographic right ventricular enlargement, higher serum creatinine (100 µmol/L versus 96 µmol/L) and neutrophil-to-lymphocyte ratio (2.7 versus 2.5), than those without COPD. After multivariable adjustment, COPD was associated with worse outcomes: adjusted rate ratio for the primary outcome 1.51 (95% CI, 1.25-1.83), total heart failure hospitalization 1.54 (95% CI, 1.24-1.90), cardiovascular death (adjusted hazard ratio [HR], 1.42; 95% CI, 1.10-1.82), and all-cause death (adjusted HR, 1.52; 95% CI, 1.25-1.84). COPD was associated with worse outcomes than other comorbidities and Kansas City Cardiomyopathy Questionnaire Clinical Summary Scores declined more in patients with COPD than in those without. Conclusions Approximately 1 in 7 patients with heart failure with preserved ejection fraction had concomitant COPD, which was associated with greater functional limitation and a higher risk of heart failure hospitalization and death. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01920711.

Association of Hyper-Polypharmacy With Clinical Outcomes in Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Polypharmacy is associated with a poor prognosis in the elderly, however, information on the association of polypharmacy with cardiovascular outcomes in heart failure with preserved ejection fraction is sparse. This study sought to investigate the relationship between polypharmacy and adverse cardiovascular events in patients with heart failure with preserved ejection fraction. METHODS: Baseline total number of medications was determined in 1758 patients with heart failure with preserved ejection fraction enrolled in the Americas regions of the TOPCAT trial (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist), by 3 categories: nonpolypharmacy (<5 medications), polypharmacy (5-9), and hyper-polypharmacy (≥10). We examined the relationship of polypharmacy status with the primary outcome (cardiovascular death, HF hospitalization, or aborted cardiac arrest), hospitalizations for any reason, and serious adverse events. RESULTS: The proportion of patients taking 5 or more medications was 92.5% (inclusive of polypharmacy [38.7%] and hyper-polypharmacy [53.8%]). Over a 2.9-year median follow-up, compared with patients with polypharmacy, hyper-polypharmacy was associated with an increased risk for the primary outcome, hospitalization for any reason and any serious adverse events in the univariable analysis, but not significantly associated with mortality. After multivariable adjustment for demographic and comorbidities, hyper-polypharmacy remained significantly associated with an increased risk for hospitalization for any reason (hazard ratio, 1.22 [95% CI, 1.05-1.41]; P=0.009) and any serious adverse events (hazard ratio, 1.23 [95% CI, 1.07-1.42]; P=0.005), whereas the primary outcome was no longer statistically significant. CONCLUSIONS: Hyper-polypharmacy was common and associated with an elevated risk of hospitalization for any reason and any serious adverse events in patients with heart failure with preserved ejection fraction. There were no significant associations between polypharmacy status and mortality.

Inflammation-based assessment for the risk stratification of mortality in patients with heart failure.

The Glasgow Prognostic Score (GPS) has been established as a useful resource to evaluate inflammation and malnutrition and predict prognosis in several cancers. However, its prognostic significance in patients with heart failure (HF) is not well established. To investigate the association between the GPS and mortality in patients with HF, we assessed 870 patients who were 20 years old and more and had been admitted for acute decompensated HF. The GPS ranged from 0 to 2 points as previously reported. Over the 18-month follow-up (follow-up rate, 83.9%), 143 patients died. Increasing GPS was associated with higher HF severity assessed by New York Heart Association functional class and B-type natriuretic peptide (BNP) levels. Kaplan-Meier analysis showed significant associations for mortality and increased GPS. In multivariate analysis, compared to the GPS 0 group, the GPS 2 group was associated with high mortality (hazard ratio 2.92, 95% confidence interval 1.77-4.81, p < 0.001) after adjustment for age, sex, blood pressure, HF history, HF severity, hemoglobin, renal function, sodium, BNP, left ventricular ejection fraction, and anti-HF medications. In conclusion, high GPS was significantly associated with worse prognosis in patients with HF. Inflammation-based assessment by the GPS may enable simple evaluation of HF severity and prognosis.

Influence of study discontinuation during the run-in period on the estimated efficacy of sacubitril/valsartan in the PARAGON-HF trial.

AIMS: The 4822 patients randomized in the PARAGON-HF trial were a subset of 5746 initially eligible patients who entered sequential run-in periods. We identified patient factors associated with study discontinuation during the run-in period and estimated the implications of these discontinuations for the overall study result. METHODS AND RESULTS: We utilized multivariable logistic regression models to identify patient factors associated with study discontinuation during the run-in period. The efficacy of sacubitril/valsartan in a broader cohort approximating the full run-in population was estimated by weighting randomized patients according to the inverse probability of run-in completion. A total of 924 (16.1%) subjects failed to complete the run-in period. In multivariable models, non-completion was associated with region other than Central Europe, lower systolic blood pressure, lower serum sodium, lower haemoglobin, lower estimated glomerular filtration rate, higher N-terminal pro-B-type natriuretic peptide, higher New York Heart Association functional class, prior heart failure (HF) hospitalization, and lack of prior use of renin-angiotensin system inhibitors or beta-blocker. In repeat analysis of the effect of randomized treatment in PARAGON-HF giving greater weight to participants resembling those who failed to complete the run-in period, the incidence of HF hospitalizations and cardiovascular death was higher, and sacubitril/valsartan treatment reduced the composite of total HF hospitalizations and cardiovascular death compared with valsartan (rate ratio 0.86; 95% confidence interval 0.74-1.00). CONCLUSION: Patients with more advanced HF were at higher risk for non-completion of the run-in period in PARAGON-HF. Re-analysis of study outcomes accounting for the effect of run-in non-completion did not alter the estimated treatment effects of sacubitril/valsartan vs. valsartan.

Left atrial structure and function of the amyloidogenic V122I transthyretin variant in elderly African Americans.

AIMS: African-American carriers of the transthyretin (TTR) valine-to-isoleucine substitution (V122I) are at increased risk of heart failure, yet many have relatively subtle abnormalities of left ventricular (LV) function. We sought to explore the influence of this mutation on left atrial (LA) structure and function in this population. METHODS AND RESULTS: We assessed 1225 genotyped African-Americans (age range, 67-89 years) participating in the Atherosclerosis Risk in Communities study who underwent echocardiography and were in sinus rhythm at study Visit 5 (2011 to 2013). Six LA parameters [LA maximum/minimum volume index, ejection fraction, and LA reservoir, conduit, and contractile longitudinal strains (LS)] were compared between V122I TTR variant carriers (n = 46) and non-carriers (n = 1179). LA minimum volume index was significantly greater and LA contractile LS was worse in carriers than non-carriers (19.5 ± 10.6 mL/m2 vs. 16.3 ± 8.4 mL/m2 ; 15.0 ± 5.8% vs. 16.8 ± 5.7%, respectively, both P < 0.05). Carriers had a significantly higher number of LA abnormalities than non-carriers (1.8 ± 2.2 vs. 1.1 ± 1.6, P = 0.009). The number of subjects with at least four LA abnormalities was significantly increased among carriers compared with non-carriers (27% vs. 12%; odds ratio 2.43; 95% confidence interval 1.06-5.58 after adjusting for age, sex, body mass index, and LV wall thickness and global LS). CONCLUSIONS: Left atrial enlargement and dysfunction were common in V122I TTR carriers with sinus rhythm than non-carriers, suggesting that abnormalities of LA function may represent early markers of subclinical disease in these individuals.