Long COVID in a highly vaccinated but largely unexposed Australian population following the 2022 SARS-CoV-2 Omicron wave: a cross-sectional survey.

OBJECTIVE: To estimate the prevalence of long COVID among Western Australian adults, a highly vaccinated population whose first major exposure to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was during the 2022 Omicron wave, and to assess its impact on health service use and return to work or study. STUDY DESIGN: Follow-up survey (completed online or by telephone). SETTING, PARTICIPANTS: Adult Western Australians surveyed 90 days after positive SARS-CoV-2 test results (polymerase chain reaction or rapid antigen testing) during 16 July - 3 August 2022 who had consented to follow-up contact for research purposes. MAIN OUTCOME MEASURES: Proportion of respondents with long COVID (ie, reporting new or ongoing symptoms or health problems, 90 days after positive SARS-CoV-2 test result); proportion with long COVID who sought health care for long COVID-related symptoms two to three months after infection; proportion who reported not fully returning to previous work or study because of long COVID-related symptoms. RESULTS: Of the 70 876 adults with reported SARS-CoV-2 infections, 24 024 consented to contact (33.9%); after exclusions, 22 744 people were invited to complete the survey, of whom 11 697 (51.4%) provided complete responses. Our case definition for long COVID was satisfied by 2130 respondents (18.2%). The risk of long COVID was greater for women (v men: adjusted risk ratio [aRR], 1.5; 95% confidence interval [CI], 1.4-1.6) and for people aged 50-69 years (v 18-29 years: aRR, 1.6; 95% CI, 1.4-1.9) or with pre-existing health conditions (aRR, 1.5; 95% CI, 1.4-1.7), as well as for people who had received two or fewer COVID-19 vaccine doses (v four or more: aRR, 1.4; 95% CI, 1.2-1.8) or three doses (aRR, 1.3; 95% CI, 1.1-1.5). The symptoms most frequently reported by people with long COVID were fatigue (1504, 70.6%) and concentration difficulties (1267, 59.5%). In the month preceding the survey, 814 people had consulted general practitioners (38.2%) and 34 reported being hospitalised (1.6%) with long COVID. Of 1779 respondents with long COVID who had worked or studied before the infection, 318 reported reducing or discontinuing this activity (17.8%). CONCLUSION: Ninety days after infection with the Omicron SARS-CoV-2 variant, 18.2% of survey respondents reported symptoms consistent with long COVID, of whom 38.7% (7.1% of all survey respondents) sought health care for related health concerns two to three months after the acute infection.

Diuretic use and outcomes in patients with heart failure with reduced ejection fraction: Insights from the VICTORIA trial.

AIMS: In VICTORIA, vericiguat compared with placebo reduced the risk of cardiovascular death (CVD) and heart failure hospitalization (HFH) in patients enrolled after a worsening heart failure (WHF) event. We examined clinical outcomes and efficacy of vericiguat as it relates to background use of loop diuretics in patients with WHF. METHODS AND RESULTS: We calculated the total daily loop diuretic dose equivalent to furosemide dosing at randomization and categorized these as: no loop diuretic, 1-39, 41-80, 40, and >80 mg total daily dose (TDD). The primary composite outcome of CVD/HFH and its components were evaluated based on TDD loop diuretic and expressed as adjusted hazard ratios with 95% confidence intervals. Post-randomization rates of change in TDD were also examined. Of 4974 patients (98% of the trial) with diuretic dose information available at randomization, 540 (10.8%) were on no loop diuretic, 647 (13.0%) were on 1-39, 1633 (32.8%) were on 40, 1185 (23.8%) were on 41-80, and 969 (19.4%) were on >80 mg TDD. Patients with higher TDD had a higher rate of primary and secondary clinical outcomes. There were no significant interactions with TDD at randomization and efficacy of vericiguat versus placebo for any outcome (all pinteraction > 0.5). Post-randomization diuretic dose changes for vericiguat and placebo showed similar rates of up-titration (19.6 and 20.2/100 person-years), down-titration (16.8 and 18.1/100 person-years), and stopping diuretics (22.9 and 24.2/100 person-years). CONCLUSIONS: Loop diuretic TDD at randomization was independently associated with worse outcomes in this high-risk population. The efficacy of vericiguat was consistent across the range of diuretic doses.

Protective effect of PDE4B subtype-specific inhibition in an App knock-in mouse model for Alzheimer's disease.

Meta-analysis of genome-wide association study data has implicated PDE4B in the pathogenesis of Alzheimer's disease (AD), the leading cause of senile dementia. PDE4B encodes one of four subtypes of cyclic adenosine monophosphate (cAMP)-specific phosphodiesterase-4 (PDE4A-D). To interrogate the involvement of PDE4B in the manifestation of AD-related phenotypes, the effects of a hypomorphic mutation (Pde4bY358C) that decreases PDE4B's cAMP hydrolytic activity were evaluated in the AppNL-G-F knock-in mouse model of AD using the Barnes maze test of spatial memory, 14C-2-deoxyglucose autoradiography, thioflavin-S staining of ß-amyloid (Aß) plaques, and inflammatory marker assay and transcriptomic analysis (RNA sequencing) of cerebral cortical tissue. At 12 months of age, AppNL-G-F mice exhibited spatial memory and brain metabolism deficits, which were prevented by the hypomorphic PDE4B in AppNL-G-F/Pde4bY358C mice, without a decrease in Aß plaque burden. RNA sequencing revealed that, among the 531 transcripts differentially expressed in AppNL-G-F versus wild-type mice, only 13 transcripts from four genes - Ide, Btaf1, Padi2, and C1qb - were differentially expressed in AppNL-G-F/Pde4bY358C versus AppNL-G-F mice, identifying their potential involvement in the protective effect of hypomorphic PDE4B. Our data demonstrate that spatial memory and cerebral glucose metabolism deficits exhibited by 12-month-old AppNL-G-F mice are prevented by targeted inhibition of PDE4B. To our knowledge, this is the first demonstration of a protective effect of PDE4B subtype-specific inhibition in a preclinical model of AD. It thus identifies PDE4B as a key regulator of disease manifestation in the AppNL-G-F model and a promising therapeutic target for AD.

Recurrent Hospitalizations and Response to Vericiguat in Heart Failure and Reduced Ejection Fraction.

BACKGROUND: In VICTORIA (Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction), vericiguat compared with placebo reduced cardiovascular death or heart failure (HF) hospitalization in patients with HF with reduced ejection fraction. OBJECTIVES: This study explored the association between vericiguat and recurrent hospitalizations and subsequent mortality after HF hospitalization. METHODS: The treatment effect of vericiguat on the burden of HF hospitalizations was evaluated by assessing total HF hospitalization and cardiovascular death in the overall trial and based on baseline N-terminal pro-B-type natriuretic peptide levels with and without adjustment for VICTORIA model covariates (ie, baseline variables associated with the primary endpoint) assessed via the Andersen-Gill method. Associations between vericiguat and recurrent hospitalization and mortality adjusted for VICTORIA model covariates are reported. RESULTS: There were 1,222 total HF hospitalizations and cardiovascular deaths among 2,526 patients in the vericiguat group and 1,336 total events among 2,524 patients in the placebo group (unadjusted HR: 0.89 [95% CI: 0.81-0.97] and adjusted HR: 0.92 [95% CI: 0.84-1.01]). In the subgroup with N-terminal pro-B-type natriuretic peptide levels ≤2,816 pg/mL (ie, Q1 and Q2; median or below), there was a suggestion of a benefit with vericiguat (adjusted HRs of 0.80 [95% CI: 0.64-1.01] and 0.77 [95% CI: 0.62-0.94], respectively) compared with those above this value (adjusted HRs of 1.12 [95% CI: 0.93-1.34] and 0.87 [95% CI: 0.74-1.04] for Q3 and Q4). There was no significant difference in treatment effect between patients with vs without an HF hospitalization. After HF hospitalization, the all-cause mortality rate (events per 100 patient-years) was 48.6 for vericiguat and 44.1 for placebo. CONCLUSIONS: Additional investigation of the association between vericiguat and cardiovascular death and total HF hospitalizations by recurrent event analysis did not show a statistically significant reduction in events. Mortality was high after HF hospitalization, emphasizing the need for further therapies to reduce morbidity and mortality. (Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction [VICTORIA]; NCT02861534).

Platelets in Hemostasis, Thrombosis, and Inflammation After Major Trauma.

Trauma currently accounts for 10% of the total global burden of disease and over 5 million deaths per year, making it a leading cause of morbidity and mortality worldwide. Although recent advances in early resuscitation have improved early survival from critical injury, the mortality rate in patients with major hemorrhage approaches 50% even in mature trauma systems. A major determinant of clinical outcomes from a major injury is a complex, dynamic hemostatic landscape. Critically injured patients frequently present to the emergency department with an acute traumatic coagulopathy that increases mortality from bleeding, yet, within 48 to 72 hours after injury will switch from a hypocoagulable to a hypercoagulable state with increased risk of venous thromboembolism and multiple organ dysfunction. This review will focus on the role of platelets in these processes. As effectors of hemostasis and thrombosis, they are central to each phase of recovery from injury, and our understanding of postinjury platelet biology has dramatically advanced over the past decade. This review describes our current knowledge of the changes in platelet behavior that occur following major trauma, the mechanisms by which these changes develop, and the implications for clinical outcomes. Importantly, supported by research in other disease settings, this review also reflects the emerging role of thromboinflammation in trauma including cross talk between platelets, innate immune cells, and coagulation. We also address the unresolved questions and significant knowledge gaps that remain, and finally highlight areas that with the further study will help deliver further improvements in trauma care.

Accelerometer vs. other activity measures in heart failure with preserved ejection fraction: the VITALITY-HFpEF trial.

AIMS: The relationship between accelerometry data and changes in Kansas City Cardiomyopathy Questionnaire-Physical Limitation Score (KCCQ-PLS) or 6 min walk test (6MWT) is not well understood. METHODS AND RESULTS: VITALITY-HFpEF accelerometry substudy (n = 69) data were assessed at baseline and 24 weeks. Ordinal logistic regression models were used to assess the association between accelerometry activity and deterioration, improved, or unchanged KCCQ-PLS (≥8.33 and ≤ -4.17 points) and 6MWT (≥32 vs. ≤ -32 m). KCCQ-PLS score deteriorated in 16 patients, improved in 34, and was unchanged in 19. 6MWT deteriorated in 8 patients, improved in 21, and was unchanged in 19. Mean accelerometer wear was 21.4 (±2.1) h/day. Changes in hours active from baseline to 24 weeks were not significantly different among patients who exhibited deterioration, improvement, or no change in KCCQ-PLS [odds ratio (OR) 0.91, 95% confidence interval (CI) 0.71-1.18; P = 0.48] or 6MWT (OR 1.21, 95% CI 0.91-1.60; P = 0.18). Similar lack of association was observed for other accelerometry metrics and change in KCCQ and 6MWT. These findings were unaffected when KCCQ and 6MWT were examined as continuous variables. CONCLUSIONS: Accelerometer-based activity measures did not correlate with subjective or objective standard measures of health status and functional capacity in heart failure with preserved ejection fraction. Further investigation of their relationships to clinical outcomes is required.

Widening the Prostacyclin Paradigm: Tissue Fibroblasts Are a Critical Site of Production and Antithrombotic Protection.

BACKGROUND: Prostacyclin is a fundamental signaling pathway traditionally associated with the cardiovascular system and protection against thrombosis but which also has regulatory functions in fibrosis, proliferation, and immunity. Prevailing dogma states that prostacyclin is principally derived from vascular endothelium, although it is known that other cells can also synthesize it. However, the role of nonendothelial sources in prostacyclin production has not been systematically evaluated resulting in an underappreciation of their importance relative to better characterized endothelial sources. METHODS: To address this, we have used novel endothelial cell-specific and fibroblast-specific COX (cyclo-oxygenase) and prostacyclin synthase knockout mice and cells freshly isolated from mouse and human lung tissue. We have assessed prostacyclin release by immunoassay and thrombosis in vivo using an FeCl3-induced carotid artery injury model. RESULTS: We found that in arteries, endothelial cells are the main source of prostacyclin but that in the lung, and other tissues, prostacyclin production occurs largely independently of endothelial and vascular smooth muscle cells. Instead, in mouse and human lung, prostacyclin production was strongly associated with fibroblasts. By comparison, microvascular endothelial cells from the lung showed weak prostacyclin synthetic capacity compared with those isolated from large arteries. Prostacyclin derived from fibroblasts and other nonendothelial sources was seen to contribute to antithrombotic protection. CONCLUSIONS: These observations define a new paradigm in prostacyclin biology in which fibroblast/nonendothelial-derived prostacyclin works in parallel with endothelium-derived prostanoids to control thrombotic risk and potentially a broad range of other biology. Although generation of prostacyclin by fibroblasts has been shown previously, the scale and systemic activity was unappreciated. As such, this represents a basic change in our understanding and may provide new insight into how diseases of the lung result in cardiovascular risk.

Oral nitrate supplementation improves cardiovascular risk markers in COPD: ON-BC, a randomised controlled trial.

BACKGROUND: Short-term studies suggest that dietary nitrate (NO3 -) supplementation may improve the cardiovascular risk profile, lowering blood pressure (BP) and enhancing endothelial function. It is not clear if these beneficial effects are sustained and whether they apply in people with COPD, who have a worse cardiovascular profile than those without COPD. Nitrate-rich beetroot juice (NR-BRJ) is a convenient dietary source of nitrate. METHODS: The ON-BC trial was a randomised, double-blind, placebo-controlled parallel group study in stable COPD patients with home systolic BP (SBP) measurement ≥130 mmHg. Participants were randomly allocated (1:1) using computer-generated, block randomisation to either 70 mL NR-BRJ (400 mg NO3 -) (n=40) or an otherwise identical nitrate-depleted placebo juice (0 mg NO3 -) (n=41), once daily for 12 weeks. The primary end-point was between-group change in home SBP measurement. Secondary outcomes included change in 6-min walk distance (6MWD) and measures of endothelial function (reactive hyperaemia index (RHI) and augmentation index normalised to a heart rate of 75 beats·min-1 (AIx75)) using an EndoPAT device. Plasma nitrate and platelet function were also measured. RESULTS: Compared with placebo, active treatment lowered SBP (Hodges-Lehmann treatment effect -4.5 (95% CI -5.9- -3.0) mmHg), and improved 6MWD (30.0 (95% CI 15.7-44.2) m; p<0.001), RHI (0.34 (95% CI 0.03-0.63); p=0.03) and AIx75 (-7.61% (95% CI -14.3- -0.95%); p=0.026). CONCLUSIONS: In people with COPD, prolonged dietary nitrate supplementation in the form of beetroot juice produces a sustained reduction in BP, associated with an improvement in endothelial function and exercise capacity.

Immature platelet dynamics are associated with clinical outcomes after major trauma.

BACKGROUND: Major trauma results in dramatic changes in platelet behavior. Newly formed platelets are more reactive than older platelets, but their contributions to hemostasis and thrombosis after severe injury have not been previously evaluated. OBJECTIVES: To determine how immature platelet metrics and plasma thrombopoietin relate to clinical outcomes after major injury. METHODS: A prospective observational cohort study was performed in adult trauma patients. Platelet counts and the immature platelet fraction (IPF) were measured at admission and 24 hours, 72 hours, and 7 days after injury. Thromboelastometry was performed at admission. Plasma thrombopoietin, c-Mpl, and GPIbα were quantified in a separate cohort. The primary outcome was in-hospital mortality; secondary outcomes were venous thromboembolic events and multiple organ dysfunction syndrome (MODS). RESULTS: On admission, immature platelet counts (IPCs) were significantly lower in nonsurvivors (n = 40) than in survivors (n = 236; 7.3 × 109/L vs 10.6 × 109/L; P = .009), but IPF did not differ. Similarly, impaired platelet function on thromboelastometry was associated with lower admission IPC (9.1 × 109/L vs 11.9 × 109/L; P < .001). However, at later time points, we observed significantly higher IPF and IPC in patients who developed venous thromboembolism (21.0 × 109/L vs 11.1 × 109/L; P = .02) and prolonged MODS (20.9 × 109/L vs 11 × 109/L; P = .003) than in those who did not develop complications. Plasma thrombopoietin levels at admission were significantly lower in nonsurvivors (P < .001), in patients with MODS (P < .001), and in those who developed venous thromboembolism (P = .04). CONCLUSION: Lower levels of immature platelets in the acute phase after major injury are associated with increased mortality, whereas higher immature platelet levels at later time points may predispose to thrombosis and MODS.

Pulmonary Mucosa-Associated Lymphoid Tissue Lymphoma Treated with Radiation Therapy: A Case Report and Review of the Literature.

Introduction: Mucosa-associated lymphoid tissue lymphoma (MALT lymphoma or MALToma) is a prevalent type of primary pulmonary lymphoma. Typically, the primary therapeutic approaches involve surgery or chemotherapy, although there have been instances of radiation therapy being employed. Case Report: We present a case of pulmonary MALToma that exhibited progression despite rituximab therapy. Subsequently, the patient demonstrated a positive response to radiation therapy. Conclusion: This case highlights the potential efficacy of radiation therapy as a treatment option for pulmonary MALToma, especially in cases where other conventional treatments like rituximab have proven ineffective. Further research and studies are warranted to better understand the role of radiation therapy in managing pulmonary MALToma and to determine optimal treatment strategies for patients with this condition.

Illustrated Abstracts of the 5th EUPLAN International Conference.

These illustrated capsules have been prepared by some speakers of State-of-the-Art talks and of original investigations, presented at the 5th European Platelet Network (EUPLAN) International Conference, which was held at the Università degli Studi di Milano (Italy) on September 28-30, 2022. The programme featured various state-of-the-art lectures and a selection of oral presentations covering a broad range of topics in platelet and megakaryocyte biology, from basic science to recent advances in clinical studies. As usual, the meeting brought together senior scientists and trainees in an informal atmosphere to discuss platelet science in person.

Cost-Effectiveness of Vericiguat in Patients With Heart Failure With Reduced Ejection Fraction: The VICTORIA Randomized Clinical Trial.

BACKGROUND: The VICTORIA trial (Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction) demonstrated that, in patients with high-risk heart failure, vericiguat reduced the primary composite outcome of cardiovascular death or heart failure hospitalization relative to placebo. The hazard ratio for all-cause mortality was 0.95 (95% CI, 0.84-1.07). In a prespecified analysis, treatment effects varied substantially as a function of baseline NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels, with survival benefit for vericiguat in the lower NT-proBNP quartiles (hazard ratio, 0.82 [95% CI, 0.69-0.97]) and no benefit in the highest NT-proBNP quartile (hazard ratio, 1.14 [95% CI, 0.95-1.38]). An economic analysis was a major secondary objective of the VICTORIA research program. METHODS: Medical resource use data were collected for all VICTORIA patients (N=5050). Costs were estimated by applying externally derived US cost weights to resource use counts. Life expectancy was projected from patient-level empirical trial survival results with the use of age-based survival modeling methods. Quality-of-life adjustments were based on prospectively collected EQ-5D-based utilities. The primary outcome was the incremental cost-effectiveness ratio, comparing vericiguat with placebo, assessed from the US health care sector perspective over a lifetime horizon. Cost-effectiveness was estimated using the total VICTORIA cohort, both with and without interaction between treatment and baseline NT-proBNP. RESULTS: Life expectancy modeling results varied according to whether the observed heterogeneity of treatment effect by baseline NT-proBNP values was incorporated into the modeling. Including the interaction term, the vericiguat arm had an estimated quality-adjusted life expectancy of 4.56 quality-adjusted life-years (QALYs) compared with 4.13 QALYs for placebo (incremental discounted QALY, 0.43). Without the treatment heterogeneity/interaction term, vericiguat had 4.50 QALYs compared with 4.33 QALYs for placebo (incremental discounted QALY, 0.17). Incremental discounted costs (vericiguat minus placebo) were $28 546 with the treatment interaction and $20 948 without it. Corresponding incremental cost-effectiveness ratios were $66 509 per QALY allowing for treatment heterogeneity and $124 512 without heterogeneity. CONCLUSIONS: Vericiguat use in the VICTORIA trial met criteria for intermediate value, but the incremental cost-effectiveness ratio estimates were sensitive to whether the analysis accounted for observed NT-proBNP treatment effect heterogeneity. The cost-effectiveness of vericiguat was driven by the projected incremental life expectancy among patients in the lowest 3 quartiles of NT-proBNP. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02861534.

Relationship between baseline electrocardiographic measurements and outcomes in patients with high-risk heart failure: Insights from the VerICiguaT Global Study in Subjects with Heart Failure with Reduced Ejection Fraction (VICTORIA) trial.

AIMS: Whether electrocardiographic (ECG) measurements predict mortality in chronic heart failure with reduced ejection fraction (HFrEF) is unknown. METHODS AND RESULTS: We studied 4880 patients from the Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction (VICTORIA) trial with a baseline 12-lead ECG. Associations between ECG measurements and mortality were estimated as hazard ratios (HR) and adjusted for the Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) risk score, N-terminal pro-B-type natriuretic peptide, and index event. Select interactions between ECG measurements, patient characteristics and mortality were examined. Over a median of 10.8 months, there were 824 cardiovascular (CV) deaths (214 sudden) and 1005 all-cause deaths. Median age was 68 years (interquartile range [IQR] 60-76), 24% were women, median ejection fraction was 30% (IQR 23-35), 41% had New York Heart Association class III/IV, and median MAGGIC score was 24 (IQR 19-28). After multivariable adjustment, significant associations existed between heart rate (per 5 bpm: HR 1.02), QRS duration (per 10 ms: HR 1.02), absence of left ventricular hypertrophy (HR 0.64) and CV death, and similarly so with all-cause death (HR 1.02; HR 1.02; HR 0.61, respectively). Contiguous pathologic Q waves were significantly associated with sudden death (HR 1.46), and right ventricular hypertrophy with all-cause death (HR 1.44). The only sex-based interaction observed was for pathologic Q waves on CV (men: HR 1.05; women: HR 1.64, pinteraction = 0.024) and all-cause death (men: HR 0.99; women: HR 1.57; pinteraction = 0.010). Whereas sudden death doubled in females, it did not differ among males (male: HR 1.25, 95% confidence interval [CI] 0.87-1.79; female: HR 2.50, 95% CI 1.23-5.06; pinteraction = 0.141). CONCLUSION: Routine ECG measurements provide additional prognostication of mortality in high-risk HFrEF patients, particularly in women with contiguous pathologic Q waves.

Mitochondrial metabolites predict adverse cardiovascular events in individuals with diabetes.

Metabolic mechanisms underlying the heterogeneity of major adverse cardiovascular (CV) event (MACE) risk in individuals with type 2 diabetes mellitus (T2D) remain unclear. We hypothesized that circulating metabolites reflecting mitochondrial dysfunction predict incident MACE in T2D. Targeted mass-spectrometry profiling of 60 metabolites was performed on baseline plasma samples from the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS; discovery cohort) and Exenatide Study of Cardiovascular Event Lowering (EXSCEL; validation cohort) biomarker substudy cohorts. A principal components analysis metabolite factor comprising medium-chain acylcarnitines (MCACs) was associated with MACE in TECOS and validated in EXSCEL, with higher levels associated with higher MACE risk. Meta-analysis showed that long-chain acylcarnitines (LCACs) and dicarboxylacylcarnitines were also associated with MACE. Metabolites remained associated with MACE in multivariate models and favorably changed with exenatide therapy. A third cohort (Cardiac Catheterization Genetics [CATHGEN]) with T2D was assessed to determine whether these metabolites improved discriminative capability of multivariate models for MACE. Nine metabolites (MCACs and LCACs and 1 dicarboxylacylcarnitine) were associated with time to MACE in the CATHGEN cohort. Addition of these metabolites to clinical models minimally improved the discriminative capability for MACE but did significantly down reclassify risk. Thus, metabolites reporting on dysregulated mitochondrial fatty acid oxidation are present in higher levels in individuals with T2D who experience subsequent MACE. These biomarkers may improve CV risk prediction models, be therapy responsive, and highlight emerging risk mechanisms.

Age, Sex, and Outcomes in Heart Failure With Reduced EF: Insights From the VICTORIA Trial.

BACKGROUND: Age and sex influence treatment and outcomes in patients with heart failure (HF). OBJECTIVES: The authors examined the associations of age and sex with clinical characteristics, background therapies, outcomes, and response to vericiguat in this post hoc analysis of 5,050 VICTORIA (Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction) patients with HF and reduced ejection fraction; 1,568 (31%) were ≥75 years of age, of whom 445 (24%) were women. METHODS: Clinical characteristics were compared across age (<65, 65 to <75, and ≥75 years) and sex. The treatment effect of vericiguat was estimated by age and sex on the primary composite outcome (time to first HF hospitalization or cardiovascular death) using Cox proportional hazards regression. RESULTS: Compared with younger patients, those ≥75 years of age had more class III and IV symptoms, higher N-terminal pro-B-type natriuretic peptide levels, and worse kidney function but had the lowest use of triple therapy. No sex differences in triple therapy existed by age, but achieving target doses of triple therapy was less likely in older patients. Men ≥75 years of age were more than twice as likely to receive defibrillators and 65% more likely to undergo cardiac resynchronization than women. The primary composite outcome was nominally lower in women than men across all age groups. Vericiguat dosing did not differ between sexes in each age group, and its beneficial effect on the primary endpoint was not modified by age (continuous age, Pinteraction = 0.169; categorical age, Pinteraction = 0.189); and sex (3-way interaction; P = 0.847). CONCLUSIONS: Although elderly women received less intense background HF therapy than men, their prognosis was nominally better. The benefit of vericiguat was independent of age and sex. (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction [HFrEF] [MK-1242-001] [VICTORIA]; NCT02861534).

Evolution of NT-proBNP During Prerandomization Screening in VICTORIA: Implications for Clinical Outcomes and Efficacy of Vericiguat.

BACKGROUND: Selecting high-risk patients with heart failure with potentially modifiable cardiovascular events is a priority. Our objective was to evaluate NT-proBNP (N-terminal pro-B-type natriuretic peptide) changes during a 30-day screening to establish (1) the frequency and direction of changes; (2) whether a relationship exists between changes in NT-proBNP and the primary composite outcome of cardiovascular death and heart failure hospitalization; and (3) whether changes in NT-proBNP relate to vericiguat's clinical benefit. METHODS: VICTORIA (A Study of Vericiguat in Participants With Heart Failure With Reduced Ejection Fraction) randomized 5050 patients with heart failure with reduced ejection fraction and a recent worsening heart failure event. We studied 3821 patients who had NT-proBNP measured during screening and at randomization. RESULTS: Sixteen hundred exhibited a >20% reduction, 1412 had ≤20% change, and 809 showed a >20% rise in NT-proBNP levels. As compared with the primary composite outcome of 28.4/100 patient-years (497 events; 31.1%) in patients with a >20% decline in NT-proBNP, those with >20% during screening had worse outcomes; 48.8/100 patient-years (359 events; 44.4%); adjusted hazard ratio, 1.61 (95% CI, 1.39-1.85). Those patients with a ≤20% change in NT-proBNP had intermediate outcomes; 39.2/100 patient-years (564 events; 39.9%); adjusted hazard ratio, 1.33 (95% CI, 1.17-1.51). No relationship existed between NT-proBNP changes during screening and vericiguat's effect on cardiovascular death and heart failure hospitalization. CONCLUSIONS: Substantial differences occurred in the rates of cardiovascular death and heart failure hospitalization, especially in patients with a >20% change in NT-proBNP levels during screening interval. Sequential NT-proBNP levels add important prognostic information meriting consideration in future heart failure trials. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02861534.

Background Medical Therapy and Clinical Outcomes From the VICTORIA Trial.

BACKGROUND: We examined whether the primary composite outcome (cardiovascular death or heart failure hospitalization) was related to differences in background use and dosing of guideline-directed medical therapy in patients with heart failure with reduced ejection fraction enrolled in VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction), a randomized trial of vericiguat versus placebo. METHODS: We evaluated the adherence to guideline use of angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, angiotensin receptor-neprilysin inhibitors, beta-blockers, and mineralocorticoid receptor antagonists. We assessed basic adherence; indication-corrected adherence accounting for guideline indications and contraindications; and dose-corrected adherence (indication-corrected adherence+≥50% of drug dose target). Associations between study treatment and the primary composite outcome according to the adherence to guidelines were assessed using multivariable adjustment; adjusted hazard ratios with 95% CIs and Pinteraction are reported. RESULTS: Of 5050 patients, 5040 (99.8%) had medication data at baseline. For angiotensin-converting enzyme inhibitor, angiotensin-receptor blockers, and angiotensin receptor-neprilysin inhibitors, basic adherence to guidelines was 87.4%, indication-corrected was 95.7%, and dose-corrected was 50.9%. For beta-blockers, basic adherence was 93.1%, indication-corrected was 96.2%, and dose-corrected was 45.4%. For mineralocorticoid receptor antagonists, basic adherence was 70.3%, indication-corrected was 87.1%, and dose-corrected was 82.2%. For triple therapy (angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, or angiotensin receptor-neprilysin inhibitors+beta-blocker+mineralocorticoid receptor antagonist), basic adherence was 59.7%, indication-corrected was 83.3%, and dose-corrected was 25.5%. Using basic or dose-corrected adherence, the treatment effect of vericiguat was consistent across adherence to guidelines groups, with or without multivariable adjustment with no treatment heterogeneity. CONCLUSIONS: Patients in VICTORIA were well treated with heart failure with reduced ejection fraction medications. The efficacy of vericiguat was consistent across background therapy with very high adherence to guidelines accounting for patient-level indications, contraindications, and tolerance. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02861534.

STREAM-2: Half-Dose Tenecteplase or Primary Percutaneous Coronary Intervention in Older Patients With ST-Segment-Elevation Myocardial Infarction: A Randomized, Open-Label Trial.

BACKGROUND: ST-segment-elevation myocardial infarction (STEMI) guidelines recommend pharmaco-invasive treatment if timely primary percutaneous coronary intervention (PCI) is unavailable. Full-dose tenecteplase is associated with an increased risk of intracranial hemorrhage in older patients. Whether pharmaco-invasive treatment with half-dose tenecteplase is effective and safe in older patients with STEMI is unknown. METHODS: STREAM-2 (Strategic Reperfusion in Elderly Patients Early After Myocardial Infarction) was an investigator-initiated, open-label, randomized, multicenter study. Patients ≥60 years of age with ≥2 mm ST-segment elevation in 2 contiguous leads, unable to undergo primary PCI within 1 hour, were randomly assigned (2:1) to half-dose tenecteplase followed by coronary angiography and PCI (if indicated) 6 to 24 hours after randomization, or to primary PCI. Efficacy end points of primary interest were ST resolution and the 30-day composite of death, shock, heart failure, or reinfarction. Safety assessments included stroke and nonintracranial bleeding. RESULTS: Patients were assigned to pharmaco-invasive treatment (n=401) or primary PCI (n=203). Median times from randomization to tenecteplase or sheath insertion were 10 and 81 minutes, respectively. After last angiography, 85.2% of patients undergoing pharmaco-invasive treatment and 78.4% of patients undergoing primary PCI had ≥50% resolution of ST-segment elevation; their residual median sums of ST deviations were 4.5 versus 5.5 mm, respectively. Thrombolysis In Myocardial Infarction flow grade 3 at last angiography was ≈87% in both groups. The composite clinical end point occurred in 12.8% (51/400) of patients undergoing pharmaco-invasive treatment and 13.3% (27/203) of patients undergoing primary PCI (relative risk, 0.96 [95% CI, 0.62-1.48]). Six intracranial hemorrhages occurred in the pharmaco-invasive arm (1.5%): 3 were protocol violations (excess anticoagulation in 2 and uncontrolled hypertension in 1). No intracranial bleeding occurred in the primary PCI arm. The incidence of major nonintracranial bleeding was low in both groups (<1.5%). CONCLUSIONS: Halving the dose of tenecteplase in a pharmaco-invasive strategy in this early-presenting, older STEMI population was associated with electrocardiographic changes that were at least comparable to those after primary PCI. Similar clinical efficacy and angiographic end points occurred in both treatment groups. The risk of intracranial hemorrhage was higher with half-dose tenecteplase than with primary PCI. If timely PCI is unavailable, this pharmaco-invasive strategy is a reasonable alternative, provided that contraindications to fibrinolysis are observed and excess anticoagulation is avoided. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02777580.