Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure.

BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure in patients regardless of the presence or absence of diabetes. More evidence is needed regarding the effects of these drugs in patients across the broad spectrum of heart failure, including those with a markedly reduced ejection fraction. METHODS: In this double-blind trial, we randomly assigned 3730 patients with class II, III, or IV heart failure and an ejection fraction of 40% or less to receive empagliflozin (10 mg once daily) or placebo, in addition to recommended therapy. The primary outcome was a composite of cardiovascular death or hospitalization for worsening heart failure. RESULTS: During a median of 16 months, a primary outcome event occurred in 361 of 1863 patients (19.4%) in the empagliflozin group and in 462 of 1867 patients (24.7%) in the placebo group (hazard ratio for cardiovascular death or hospitalization for heart failure, 0.75; 95% confidence interval [CI], 0.65 to 0.86; P<0.001). The effect of empagliflozin on the primary outcome was consistent in patients regardless of the presence or absence of diabetes. The total number of hospitalizations for heart failure was lower in the empagliflozin group than in the placebo group (hazard ratio, 0.70; 95% CI, 0.58 to 0.85; P<0.001). The annual rate of decline in the estimated glomerular filtration rate was slower in the empagliflozin group than in the placebo group (-0.55 vs. -2.28 ml per minute per 1.73 m2 of body-surface area per year, P<0.001), and empagliflozin-treated patients had a lower risk of serious renal outcomes. Uncomplicated genital tract infection was reported more frequently with empagliflozin. CONCLUSIONS: Among patients receiving recommended therapy for heart failure, those in the empagliflozin group had a lower risk of cardiovascular death or hospitalization for heart failure than those in the placebo group, regardless of the presence or absence of diabetes. (Funded by Boehringer Ingelheim and Eli Lilly; EMPEROR-Reduced ClinicalTrials.gov number, NCT03057977.).

Controlling Symmetry Breaking Charge Transfer in BODIPY Pairs.

Symmetry breaking charge transfer (SBCT) is a process in which a pair of identical chromophores absorb a photon and use its energy to transfer an electron from one chromophore to the other, breaking the symmetry of the chromophore pair. This excited state phenomenon is observed in photosynthetic organisms where it enables efficient formation of separated charges that ultimately catalyze biosynthesis. SBCT has also been proposed as a means for developing photovoltaics and photocatalytic systems that operate with minimal energy loss. It is known that SBCT in both biological and artificial systems is in part made possible by the local environment in which it occurs, which can move to stabilize the asymmetric SBCT state. However, how environmental degrees of freedom act in concert with steric and structural constraints placed on a chromophore pair to dictate its ability to generate long-lived charge pairs via SBCT remain open topics of investigation.In this Account, we compare a broad series of dipyrrin dimers that are linked by distinct bridging groups to discern how the spatial separation and mutual orientation of linked chromophores and the structural flexibility of their linker each impact SBCT efficiency. Across this material set, we observe a general trend that SBCT is accelerated as the spatial separation between dimer chromophores decreases, consistent with the expectation that the electronic coupling between these units varies exponentially with their separation. However, one key observation is that the rate of charge recombination following SBCT was found to slow with decreasing interchromophore separation, rather than speed up. This stems from an enhancement of the dimer's structural rigidity due to increasing steric repulsion as the length of their linker shrinks. This rigidity further inhibits charge recombination in systems where symmetry has already enforced zero HOMO-LUMO overlap. Additionally, for the forward transfer, the active torsion is shown to increase LUMO-LUMO coupling, allowing for faster SBCT within bridging groups.By understanding trends for how rates of SBCT and charge recombination depend on a dimer's internal structure and its environment, we identify design guidelines for creating artificial systems for driving sustained light-induced charge separation. Such systems can find application in solar energy technologies and photocatalytic applications and can serve as a model for light-induced charge separation in biological systems.

Inferring the Energetics of CO2-Aniline Adduct Formation from Vibrational Spectroscopy.

Control of atmospheric CO2 is an important contemporary scientific and engineering challenge. Toward this goal, the reaction of CO2 with amines to form carbamate bonds is an established method for CO2 capture. However, controllable reversal of this reaction remains difficult and requires tuning the energetics of the carbamate bond. Through IR spectroscopy, we show that a characteristic frequency observed upon carbamate formation varies as a function of the substituent's Hammett parameter for a family of para-substituted anilines. We present computational evidence that the vibrational frequency of the adducted CO2 serves as a predictor of the energy of formation of the carbamate. Electron donating groups typically enhance the driving force of carbamate formation by transferring more charge to the adducted CO2 and thus increasing the occupancy of the antibonding orbital in the carbon-oxygen bonds. Increased occupancy of the antibonding orbital within adducted CO2 indicates a weaker bond, leading to a red-shift in the characteristic carbamate frequency. Our work serves the large field of CO2 capture research where spectroscopic observables, such as IR frequencies, are more easily obtainable and can stand in as a descriptor of driving forces.

Aggregation of Charge Acceptors on Nanocrystal Surfaces Alters Rates of Photoinduced Electron Transfer.

Semiconductor nanocrystals (NCs) interfaced with molecular ligands that function as charge and energy acceptors are an emerging platform for the design of light-harvesting, photon-upconverting, and photocatalytic materials. However, NC systems explored for these applications often feature high concentrations of bound acceptor ligands, which can lead to ligand-ligand interactions that may alter each system's ability to undergo charge and energy transfer. Here, we demonstrate that aggregation of acceptor ligands impacts the rate of photoinduced NC-to-ligand charge transfer between lead(II) sulfide (PbS) NCs and perylenediimide (PDI) electron acceptors. As the concentration of PDI acceptors is increased, we find the average electron transfer rate from PbS to PDI ligands decreases by nearly an order of magnitude. The electron transfer rate slowdown with increasing PDI concentration correlates strongly with the appearance of PDI aggregates in steady-state absorption spectra. Electronic structure calculations and molecular dynamics (MD) simulations suggest PDI aggregation slows the rate of electron transfer by reducing orbital overlap between PbS charge donors and PDI charge acceptors. While we find aggregation slows electron transfer in this system, the computational models we employ predict ligand aggregation could also be used to speed electron transfer by producing delocalized states that exhibit improved NC-molecule electronic coupling and energy alignment with NC conduction band states. Our results demonstrate that ligand aggregation can alter rates of photoinduced electron transfer between NCs and organic acceptor ligands and should be considered when designing hybrid NC:molecule systems for charge separation.

Dabigatran for Prevention of Stroke after Embolic Stroke of Undetermined Source.

BACKGROUND: Cryptogenic strokes constitute 20 to 30% of ischemic strokes, and most cryptogenic strokes are considered to be embolic and of undetermined source. An earlier randomized trial showed that rivaroxaban is no more effective than aspirin in preventing recurrent stroke after a presumed embolic stroke from an undetermined source. Whether dabigatran would be effective in preventing recurrent strokes after this type of stroke was unclear. METHODS: We conducted a multicenter, randomized, double-blind trial of dabigatran at a dose of 150 mg or 110 mg twice daily as compared with aspirin at a dose of 100 mg once daily in patients who had had an embolic stroke of undetermined source. The primary outcome was recurrent stroke. The primary safety outcome was major bleeding. RESULTS: A total of 5390 patients were enrolled at 564 sites and were randomly assigned to receive dabigatran (2695 patients) or aspirin (2695 patients). During a median follow-up of 19 months, recurrent strokes occurred in 177 patients (6.6%) in the dabigatran group (4.1% per year) and in 207 patients (7.7%) in the aspirin group (4.8% per year) (hazard ratio, 0.85; 95% confidence interval [CI], 0.69 to 1.03; P = 0.10). Ischemic strokes occurred in 172 patients (4.0% per year) and 203 patients (4.7% per year), respectively (hazard ratio, 0.84; 95% CI, 0.68 to 1.03). Major bleeding occurred in 77 patients (1.7% per year) in the dabigatran group and in 64 patients (1.4% per year) in the aspirin group (hazard ratio, 1.19; 95% CI, 0.85 to 1.66). Clinically relevant nonmajor bleeding occurred in 70 patients (1.6% per year) and 41 patients (0.9% per year), respectively. CONCLUSIONS: In patients with a recent history of embolic stroke of undetermined source, dabigatran was not superior to aspirin in preventing recurrent stroke. The incidence of major bleeding was not greater in the dabigatran group than in the aspirin group, but there were more clinically relevant nonmajor bleeding events in the dabigatran group. (Funded by Boehringer Ingelheim; RE-SPECT ESUS ClinicalTrials.gov number, NCT02239120.).

Influence of neprilysin inhibition on the efficacy and safety of empagliflozin in patients with chronic heart failure and a reduced ejection fraction: the EMPEROR-Reduced trial.

AIMS: We evaluated the influence of sacubitril/valsartan on the effects of sodium-glucose cotransporter 2 (SGLT2) inhibition with empagliflozin in patients with heart failure and a reduced ejection fraction. METHODS AND RESULTS: The EMPEROR-Reduced trial randomized 3730 patients with heart failure and an ejection fraction ≤40% to placebo or empagliflozin (10 mg/day), in addition to recommended treatment for heart failure, for a median of 16 months. A total of 727 patients (19.5%) received sacubitril/valsartan at baseline. Analysis of the effect of neprilysin inhibition was 1 of 12 pre-specified subgroups. Patients receiving a neprilysin inhibitor were particularly well-treated, as evidenced by lower systolic pressures, heart rates, N-terminal prohormone B-type natriuretic peptide, and greater use of cardiac devices (all P < 0.001) when compared with those not receiving sacubitril/valsartan. Nevertheless, when compared with placebo, empagliflozin reduced the risk of cardiovascular death or hospitalization for heart failure in patients receiving or not receiving sacubitril/valsartan [hazard ratio 0.64 (95% CI 0.45-0.89), P = 0.009 and hazard ratio 0.77 (95% CI 0.66-0.90), P = 0.0008, respectively, interaction P = 0.31]. Empagliflozin slowed the rate of decline in estimated glomerular filtration rate by 1.92 ± 0.80 mL/min/1.73 m2/year in patients taking a neprilysin inhibitor (P = 0.016) and by 1.71 ± 0.35 mL/min/1.73 m2/year in patients not taking a neprilysin inhibitor (P < 0.0001), interaction P = 0.81. Combined inhibition of SGLT2 and neprilysin was well-tolerated. CONCLUSION: The effects on empagliflozin to reduce the risk of heart failure and renal events are not diminished in intensively treated patients who are receiving sacubitril/valsartan. Combined treatment with both SGLT2 and neprilysin inhibitors can be expected to yield substantial additional benefits.

Regional and ethnic influences on the response to empagliflozin in patients with heart failure and a reduced ejection fraction: the EMPEROR-Reduced trial.

AIMS: The aim of this article is to explore the influence of region and race/ethnicity on the effects of empagliflozin in the Empagliflozin Outcome Trial in Patients with Chronic Heart Failure and a Reduced Ejection Fraction (EMPEROR-Reduced) trial. METHODS AND RESULTS: Of 3730 patients, 1353 (36.3%) were enrolled in Europe, 1286 (34.5%) in Latin America, 425 (11.4%) in North America, and 493 (13.2%) in Asia; 2629 (70.5%) were White, 257 (6.9%) Black, and 672 (18.0%) Asian. Placebo event rates (per 100 patient-years) for cardiovascular death or heart failure (HF) hospitalization varied by region (Asia 27.7, North America 26.4, Latin America 21.4, and Europe 17.5) and race/ethnicity (Black 34.4, Asian 24.3, and White 18.7); driven by differences in HF hospitalization. The ratio of total HF hospitalization to cardiovascular death varied from 5.4 in Asia and 4.8 in North America to 2.1 in Europe; and from 4.8 in Black and 4.2 in Asian to 2.2 in White patients. Groups with the highest ratio had the greatest reduction in the primary outcome with empagliflozin. Inclusion of outpatient worsening HF episodes added more events in Europe vs. other regions; enhanced the placebo event rates in Europe vs. other regions; and increased the relative risk reduction with empagliflozin in Europe from 6% to 26%. CONCLUSIONS: There were notable differences in the placebo event rates for major HF events across diverse regions and race/ethnic groups. The benefit of empagliflozin was most pronounced in groups with the highest ratio of HF hospitalization to cardiovascular death. Regional differences were attenuated when the definition of HF events was expanded to include outpatient worsening HF events.

Sensitivity of sum frequency generation experimental conditions to thin film interference effects.

Sum-frequency generation (SFG) spectroscopy has furthered our understanding of the chemical interfaces that guide key processes in biology, catalysis, environmental science, and energy conversion. However, interpreting SFG spectra of systems containing several internal interfaces, such as thin film electronics, electrochemical cells, and biofilms, is challenging as different interfaces within these structures can produce interfering SFG signals. One potential way to address this issue is to carefully select experimental conditions that amplify the SFG signal of an interface of interest over all others. In this report, we investigate a model two-interface system to assess our ability to isolate the SFG signal from each interface. For SFG experiments performed in a reflective geometry, we find that there are few experimental conditions under which the SFG signal originating from either interface can be amplified and isolated from the other. However, by performing several measurements under conditions that alter their interference, we find that we can reconstruct each signal even in cases where the SFG signal from one interface is more than an order of magnitude smaller than its counterpart. The number of spectra needed for this reconstruction varies depending on the signal-to-noise level of the SFG dataset and the degree to which different experiments in a dataset vary in their sensitivity to each interface. Taken together, our work provides general guidelines for designing experimental protocols that can isolate SFG signals stemming from a particular region of interest within complex samples.

Singlet Fission Involves an Interplay between Energetic Driving Force and Electronic Coupling in Perylenediimide Films.

Due to its ability to offset thermalization losses in photoharvesting systems, singlet fission has become a topic of research interest. During singlet fission, a high energy spin-singlet state in an organic semiconductor divides its energy to form two lower energy spin-triplet excitations on neighboring chromophores. While key insights into mechanisms leading to singlet fission have been gained recently, developing photostable compounds that undergo quantitative singlet fission remains a key challenge. In this report, we explore triplet exciton production via singlet fission in films of perylenediimides, a class of compounds with a long history of use as industrial dyes and pigments due to their photostability. As singlet fission necessitates electron transfer between neighboring molecules, its rate and yield depend sensitively on their local arrangement. By adding different functional groups at their imide positions, we control how perylenediimides pack in the solid state. We find inducing a long axis displacement of ∼3 Šbetween neighboring perylenediimides gives a maximal triplet production yield of 178% with a fission rate of ∼245 ps despite the presence of an activation barrier of ∼190 meV. These findings disagree with Marcus theory predictions for the optimal perylenediimide geometry for singlet fission, but do agree with Redfield theory calculations that allow singlet fission to occur via a charge transfer-mediated superexchange mechanism. Unfortunately, triplets produced by singlet fission are found to decay over tens of nanoseconds. Our results highlight that singlet fission materials must be designed to not only produce triplet excitons but to also facilitate their extraction.

Tiotropium Respimat inhaler and the risk of death in COPD.

BACKGROUND: Tiotropium delivered at a dose of 5 µg with the Respimat inhaler showed efficacy similar to that of 18 µg of tiotropium delivered with the HandiHaler inhalation device in placebo-controlled trials involving patients with chronic obstructive pulmonary disease (COPD). Although tiotropium HandiHaler was associated with reduced mortality, as compared with placebo, more deaths were reported with tiotropium Respimat than with placebo. METHODS: In this randomized, double-blind, parallel-group trial involving 17,135 patients with COPD, we evaluated the safety and efficacy of tiotropium Respimat at a once-daily dose of 2.5 µg or 5 µg, as compared with tiotropium HandiHaler at a once-daily dose of 18 µg. Primary end points were the risk of death (noninferiority study, Respimat at a dose of 5 µg or 2.5 µg vs. HandiHaler) and the risk of the first COPD exacerbation (superiority study, Respimat at a dose of 5 µg vs. HandiHaler). We also assessed cardiovascular safety, including safety in patients with stable cardiac disease. RESULTS: During a mean follow-up of 2.3 years, Respimat was noninferior to HandiHaler with respect to the risk of death (Respimat at a dose of 5 µg vs. HandiHaler: hazard ratio, 0.96; 95% confidence interval [CI], 0.84 to 1.09; Respimat at a dose of 2.5 µg vs. HandiHaler: hazard ratio, 1.00; 95% CI, 0.87 to 1.14) and not superior to HandiHaler with respect to the risk of the first exacerbation (Respimat at a dose of 5 µg vs. HandiHaler: hazard ratio, 0.98; 95% CI, 0.93 to 1.03). Causes of death and incidences of major cardiovascular adverse events were similar in the three groups. CONCLUSIONS: Tiotropium Respimat at a dose of 5 µg or 2.5 µg had a safety profile and exacerbation efficacy similar to those of tiotropium HandiHaler at a dose of 18 µg in patients with COPD. (Funded by Boehringer Ingelheim; TIOSPIR ClinicalTrials.gov number, NCT01126437.).

Low glomerular filtration rate, recurrent stroke risk, and effect of renin-angiotensin system modulation.

BACKGROUND AND PURPOSE: To investigate the association of low estimated glomerular filtration rate (eGFR) <60 mL/min with recurrent stroke risk and to evaluate whether add-on renin-angiotensin system modulator therapy is associated with lower recurrent stroke risk in patients with low eGFR. METHODS: We analyzed the database of a multicenter trial involving 18,666 patients with recent ischemic stroke followed for 2.5 years. Primary outcome was time to first recurrent stroke. Independent associations of low eGFR with outcome in the entire cohort and add-on telmisartan treatment with outcome among those with low eGFR were evaluated. RESULTS: Low eGFR was observed in 3630 (20.1%) patients. Patients with low eGFR were older, more likely women, with a known history of hypertension. In unadjusted analyses, patients with low eGFR were more likely to experience a recurrent stroke (hazard ratio, 1.34; 95% confidence interval, 1.20-1.49). After adjusting for confounders, low eGFR was still associated with recurrent stroke but to a lesser extent (hazard ratio, 1.16; 95% confidence interval, 1.04-1.31). Telmisartan treatment among patients with low eGFR was not independently associated with recurrent stroke (hazard ratio, 1.08; 95% confidence interval, 0.89-1.31). CONCLUSIONS: Low eGFR is independently associated with a higher risk of recurrent stroke, but short-term add-on telmisartan therapy does not seem to mitigate this risk. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00153062.

The Tiotropium Safety and Performance in Respimat Trial (TIOSPIR), a large scale, randomized, controlled, parallel-group trial-design and rationale.

BACKGROUND: Tiotropium bromide is an effective therapy for COPD patients. Comparing across programs tiotropium Respimat Soft Mist inhaler was at least as efficacious as tiotropium HandiHaler, however, concerns have been raised about tiotropium's safety when given via Respimat. METHODS: The TIOSPIR trial (NCT01126437) compares the safety and efficacy of tiotropium Respimat 5 µg once daily (marketed) and 2.5 µg once daily (investigational) with tiotropium HandiHaler 18 µ once daily (marketed). The hypotheses to be tested are 1). that tiotropium Respimat 5 µg once daily and Respimat 2.5 µg once daily are non-inferior to HandiHaler in terms of all-cause mortality, and 2). that tiotropium Respimat 5 µg once daily is superior to HandiHaler in terms of time to first exacerbation. A spirometry substudy evaluates the bronchodilator efficacy. The trial is a randomized, double-blind, double dummy, event-driven, parallel group study. Participants can use any background treatment for COPD except inhaled anticholinergic agents. The study encompasses a wide range of COPD patients, e.g. patients with stable cardiac diseases including arrhythmia can be included. Clinical sites are international and include both primary care as well as specialists. RESULTS: To date, over 17,000 participants have been randomized from over 1200 sites in 50 countries with an anticipated treatment duration of 2-3 years. CONCLUSION: TIOSPIR will provide precise estimates of the relative safety and efficacy of the Respimat and HandiHaler formulations of tiotropium, assess potential dose-dependence of important outcomes and provide information on the clinical epidemiology of COPD in a large international patient cohort.

Impact of resting heart rate on mortality, disability and cognitive decline in patients after ischaemic stroke.

AIMS: Recurrent stroke is a frequent and disabling event. A high heart rate is associated with cardiovascular outcomes. We investigated the effects of the resting heart rate on cardiovascular and neurological outcomes after recurrent stroke in the high-risk population of the PRoFESS study. METHODS AND RESULTS: A total of 20,165 patients after ischaemic stroke (mean age 66.1, SD 8.6 years) assigned to the treatment arms of the PRoFESS trial were pooled divided by quintiles of the baseline heart rate and analysed according to cardiovascular and functional outcomes after stroke: recurrent stroke and major cardiovascular outcomes such as stroke, myocardial infarction, and worsening or new-onset heart failure as well as death from cardiovascular and non-cardiovascular causes. Pre-defined endpoints were disability after a recurrent stroke, assessed with the modified Rankin scale (mRS) and the Barthel index at 3 months, and cognitive function, assessed with the Mini-Mental State Examination (MMSE) score at 4 weeks after randomization and at the penultimate visit. Patients in the two highest quintiles of heart rate (77-82 and >82 b.p.m.) were at a higher risk for total death [hazard ratio (HR) 1.42, 95% CI 1.19-1.69 and HR 1.74, 95% CI 1.48-2.06, P < 0.0001] compared with the lowest quintile. Similar results were observed for vascular death [71-≤76 b.p.m., HR 1.39 (1.11-1.74), P < 0.0001] and non-vascular death [from >82 b.p.m., HR 1.66 (1.29-2.13), P = 0.0016]. Myocardial infarction (P = 0.7084) and recurrent stroke (P = 0.1379) were not significantly associated with the baseline heart rate. Hazard ratios were adjusted to multiple confounders including the baseline blood pressure. In the group of patients with a recurrent stroke, an association of a lower heart rate to better outcomes was measured with the Barthel index across all heart rate groups. In addition, there was a significant association of the baseline heart rate to the occurrence of significant cognitive decline according to an MMSE score ≤24 points at 1 month and at the penultimate visit or a decline of ≥2 points between these two time periods. Better independence score at a low heart rate were observed. CONCLUSION: The heart rate is a risk indicator for mortality in patients with stroke and, importantly, a low heart rate is associated with a better functional outcome and less cognitive decline after an ischaemic stroke. TRIAL REGISTRATION: ClinicalTrials.gov, number NTC00153062.

Obesity and recurrent vascular risk after a recent ischemic stroke.

BACKGROUND AND PURPOSE: Although obesity is an established risk factor for the occurrence of a primary stroke, little is known about the impact of baseline obesity on recurrent vascular risk among patients with recently symptomatic cerebrovascular disease. We evaluated the association of obesity with future vascular risk in patients with a recent history of stroke. METHODS: We analyzed the database of a multicenter trial involving 20 332 patients with recent ischemic stroke followed for 2.5 years. Subjects were divided into 3 groups according to recognized body mass index categories representing lean, overweight, and obese. Primary outcome was time to first recurrent stroke and secondary outcome time to stroke, myocardial infarction, or vascular death. The independent association of obesity with outcome was assessed by controlling for other known risk factors. RESULTS: Of 20 246 eligible subjects, 4805 (24%) were obese. After adjusting for confounders, compared with the lean group, being overweight (hazard ratio, 0.95; 95% CI, 0.85-1.06) or obese (hazard ratio, 0.95; 95% CI, 0.83-1.08) was not associated with increased recurrent stroke risk, but being overweight (hazard ratio, 0.84; 95% CI, 0.77-0.92) or obese (hazard ratio, 0.86; 95% CI, 0.77-0.96) was associated with lower risk of a major vascular event. CONCLUSIONS: Obesity is not related to recurrent stroke risk, but obese patients with stroke are at lower overall vascular risk than their leaner counterparts, supporting the widely held notion of the existence of a cardiovascular "obesity paradox."

Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke.

BACKGROUND: Recurrent stroke is a frequent, disabling event after ischemic stroke. This study compared the efficacy and safety of two antiplatelet regimens--aspirin plus extended-release dipyridamole (ASA-ERDP) versus clopidogrel. METHODS: In this double-blind, 2-by-2 factorial trial, we randomly assigned patients to receive 25 mg of aspirin plus 200 mg of extended-release dipyridamole twice daily or to receive 75 mg of clopidogrel daily. The primary outcome was first recurrence of stroke. The secondary outcome was a composite of stroke, myocardial infarction, or death from vascular causes. Sequential statistical testing of noninferiority (margin of 1.075), followed by superiority testing, was planned. RESULTS: A total of 20,332 patients were followed for a mean of 2.5 years. Recurrent stroke occurred in 916 patients (9.0%) receiving ASA-ERDP and in 898 patients (8.8%) receiving clopidogrel (hazard ratio, 1.01; 95% confidence interval [CI], 0.92 to 1.11). The secondary outcome occurred in 1333 patients (13.1%) in each group (hazard ratio for ASA-ERDP, 0.99; 95% CI, 0.92 to 1.07). There were more major hemorrhagic events among ASA-ERDP recipients (419 [4.1%]) than among clopidogrel recipients (365 [3.6%]) (hazard ratio, 1.15; 95% CI, 1.00 to 1.32), including intracranial hemorrhage (hazard ratio, 1.42; 95% CI, 1.11 to 1.83). The net risk of recurrent stroke or major hemorrhagic event was similar in the two groups (1194 ASA-ERDP recipients [11.7%], vs. 1156 clopidogrel recipients [11.4%]; hazard ratio, 1.03; 95% CI, 0.95 to 1.11). CONCLUSIONS: The trial did not meet the predefined criteria for noninferiority but showed similar rates of recurrent stroke with ASA-ERDP and with clopidogrel. There is no evidence that either of the two treatments was superior to the other in the prevention of recurrent stroke. (ClinicalTrials.gov number, NCT00153062.)

Telmisartan to prevent recurrent stroke and cardiovascular events.

BACKGROUND: Prolonged lowering of blood pressure after a stroke reduces the risk of recurrent stroke. In addition, inhibition of the renin-angiotensin system in high-risk patients reduces the rate of subsequent cardiovascular events, including stroke. However, the effect of lowering of blood pressure with a renin-angiotensin system inhibitor soon after a stroke has not been clearly established. We evaluated the effects of therapy with an angiotensin-receptor blocker, telmisartan, initiated early after a stroke. METHODS: In a multicenter trial involving 20,332 patients who recently had an ischemic stroke, we randomly assigned 10,146 to receive telmisartan (80 mg daily) and 10,186 to receive placebo. The primary outcome was recurrent stroke. Secondary outcomes were major cardiovascular events (death from cardiovascular causes, recurrent stroke, myocardial infarction, or new or worsening heart failure) and new-onset diabetes. RESULTS: The median interval from stroke to randomization was 15 days. During a mean follow-up of 2.5 years, the mean blood pressure was 3.8/2.0 mm Hg lower in the telmisartan group than in the placebo group. A total of 880 patients (8.7%) in the telmisartan group and 934 patients (9.2%) in the placebo group had a subsequent stroke (hazard ratio in the telmisartan group, 0.95; 95% confidence interval [CI], 0.86 to 1.04; P=0.23). Major cardiovascular events occurred in 1367 patients (13.5%) in the telmisartan group and 1463 patients (14.4%) in the placebo group (hazard ratio, 0.94; 95% CI, 0.87 to 1.01; P=0.11). New-onset diabetes occurred in 1.7% of the telmisartan group and 2.1% of the placebo group (hazard ratio, 0.82; 95% CI, 0.65 to 1.04; P=0.10). CONCLUSIONS: Therapy with telmisartan initiated soon after an ischemic stroke and continued for 2.5 years did not significantly lower the rate of recurrent stroke, major cardiovascular events, or diabetes. (ClinicalTrials.gov number, NCT00153062.)

Level of systolic blood pressure within the normal range and risk of recurrent stroke.

CONTEXT: Recurrent stroke prevention guidelines suggest that larger reductions in systolic blood pressure (SBP) are positively associated with a greater reduction in the risk of recurrent stroke and define an SBP level of less than 120 mm Hg as normal. However, the association of SBP maintained at such levels with risk of vascular events after a recent ischemic stroke is unclear. OBJECTIVE: To assess the association of maintaining low-normal vs high-normal SBP levels with risk of recurrent stroke. DESIGN, SETTING, AND PATIENTS: Post hoc observational analysis of a multicenter trial involving 20,330 patients (age ≥50 years) with recent non-cardioembolic ischemic stroke; patients were recruited from 695 centers in 35 countries from September 2003 through July 2006 and followed up for 2.5 years (follow-up ended on February 8, 2008). Patients were categorized based on their mean SBP level: very low-normal (<120 mm Hg), low-normal (120-<130 mm Hg), high-normal (130-<140 mm Hg), high (140-<150 mm Hg), and very high (≥150 mm Hg). MAIN OUTCOME MEASURES: The primary outcome was first recurrence of stroke of any type and the secondary outcome was a composite of stroke, myocardial infarction, or death from vascular causes. RESULTS: The recurrent stroke rates were 8.0% (95% CI, 6.8%-9.2%) for the very low-normal SBP level group, 7.2% (95% CI, 6.4%-8.0%) for the low-normal SBP group, 6.8% (95% CI, 6.1%-7.4%) for the high-normal SBP group, 8.7% (95% CI, 7.9%-9.5%) for the high SBP group, and 14.1% (95% CI, 13.0%-15.2%) for the very high SBP group. Compared with patients in the high-normal SBP group, the risk of the primary outcome was higher for patients in the very low-normal SBP group (adjusted hazard ratio [AHR], 1.29; 95% CI, 1.07-1.56), in the high SBP group (AHR, 1.23; 95% CI, 1.07-1.41), and in the very high SBP group (AHR, 2.08; 95% CI, 1.83-2.37). Compared with patients in the high-normal SBP group, the risk of secondary outcome was higher for patients in the very low-normal SBP group (AHR, 1.31; 95% CI, 1.13-1.52), in the low-normal SBP group (AHR, 1.16; 95% CI, 1.03-1.31), in the high SBP group (AHR, 1.24; 95% CI, 1.11-1.39), and in the very high SBP group (AHR, 1.94; 95% CI, 1.74-2.16). CONCLUSION: Among patients with recent non-cardioembolic ischemic stroke, SBP levels during follow-up in the very low-normal (<120 mm Hg), high (140-<150 mm Hg), or very high (≥150 mm Hg) range were associated with increased risk of recurrent stroke. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00153062.

A randomized Phase II trial evaluating efficacy, safety, and tolerability of oral BI 409306 in attenuated psychosis syndrome: Design and rationale.

AIM: Attenuated psychosis syndrome (APS), a condition for further study in the Diagnostic and Statistical Manual of Mental Disorders-5, comprises psychotic symptoms that are qualitatively similar to those observed in schizophrenia but are less severe. Patients with APS are at high risk of converting to first-episode psychosis (FEP). As evidence for effective pharmacological interventions in APS is limited, novel treatments may provide symptomatic relief and delay/prevent psychotic conversion. This trial aims to investigate the efficacy, safety, and tolerability of BI 409306, a potent and selective phosphodiesterase-9 inhibitor, versus placebo in APS. Novel biomarkers of psychosis are being investigated. METHODS: In this Phase II, multinational, double-blind, parallel-group trial, randomized (1:1) patients will receive BI 409306 50 mg or placebo twice daily for 52 weeks. Patients (n = 300) will be enrolled to determine time to remission of APS, time to FEP, change in everyday functional capacity (Schizophrenia Cognition Rating Scale), and change from baseline in Brief Assessment of Cognition composite score and Positive and Negative Syndrome Scale scores. Potential biomarkers of psychosis under investigation include functional measures of brain activity and automated speech analyses. Safety is being assessed throughout. CONCLUSIONS: This trial will determine whether BI 409306 is superior to placebo in achieving sustainable remission of APS and improvements in cognition and functional capacity. These advances may provide evidence-based treatment options for symptomatic relief in APS. Furthermore, the study will assess the effect of BI 409306 on psychotic conversion and explore the identification of patients at risk for conversion using novel biomarkers.

Empagliflozin in Patients With Heart Failure, Reduced Ejection Fraction, and Volume Overload: EMPEROR-Reduced Trial.

BACKGROUND: Investigators have hypothesized that sodium-glucose cotransporter 2 (SGLT2) inhibitors exert diuretic effects that contribute to their ability to reduce serious heart failure events, and this action is particularly important in patients with fluid retention. OBJECTIVES: This study sought to evaluate the effects of the SGLT2 inhibitor empagliflozin on symptoms, health status, and major heart failure outcomes in patients with and without recent volume overload. METHODS: This double-blind randomized trial compared the effects of empagliflozin and placebo in 3,730 patients with heart failure and a reduced ejection fraction, with or without diabetes. Approximately 40% of the patients had volume overload in the 4 weeks before study enrollment. RESULTS: Patients with recent volume overload were more likely to have been hospitalized for heart failure and to have received an intravenous diuretic agent in an outpatient setting in the previous 12 months, and to experience a heart failure event following randomization, even though they were more likely to be treated with high doses of a loop diuretic agent as an outpatient (all p < 0.001). When compared with placebo, empagliflozin reduced the composite risk of cardiovascular death or hospitalization for heart failure, decreased total hospitalizations for heart failure, and improved health status and functional class. Yet despite the predisposition of patients with recent volume overload to fluid retention, the magnitude of these benefits (even after 1 month of treatment) was not more marked in patients with recent volume overload (interaction p values > 0.05). Changes in body weight, hematocrit, and natriuretic peptides (each potentially indicative of a diuretic action of SGLT2 inhibitors) did not track each other closely in their time course or in individual patients. CONCLUSIONS: Taken together, study findings do not support a dominant role of diuresis in mediating the physiological changes or clinical benefits of SGLT2 inhibitors on the course of heart failure in patients with a reduced ejection fraction. (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction [EMPEROR-Reduced]; NCT03057977).

Concentration-dependent clinical and prognostic importance of high-sensitivity cardiac troponin T in heart failure and a reduced ejection fraction and the influence of empagliflozin: the EMPEROR-Reduced trial.

AIMS: Circulating troponin is an important measure of risk in patients with heart failure, but it has not been used to determine if disease severity influences the responses to drug treatments in randomized controlled trials. METHODS AND RESULTS: In the EMPEROR-Reduced trial, patients with class II-IV heart failure and a reduced ejection fraction were randomly assigned to placebo or empagliflozin 10 mg daily and followed for the occurrence of serious heart failure and renal events. High-sensitivity cardiac troponin T (hs-cTnT) was measured in 3636 patients (>97%) at baseline, and patients were divided into four groups based on the degree of troponin elevation. With increasing concentrations of hs-cTnT, patients were progressively more likely to have diabetes and atrial fibrillation, to have New York Heart Association class III-IV symptoms and been hospitalized for heart failure within the prior year, and to have elevated levels of natriuretic peptides and worse renal function (P-trend < 0.0001 for all comparisons), but importantly, the troponin groups did not differ with respect to ejection fraction. A linear relationship was observed between the logarithm of hs-cTnT and the combined risk of cardiovascular death or hospitalization for heart failure (P = 0.0015). When treated with placebo, patients with the highest levels of hs-cTnT had risks of cardiovascular death and hospitalization for heart failure that were 3-5 fold greater than those with values in the normal range. Patients with higher levels of hs-cTnT were also more likely to experience worsening of renal function and serious adverse renal events and showed the least improvement in health status (as measured by the Kansas City Cardiomyopathy Questionnaire). When compared with placebo, empagliflozin reduced the combined risk of cardiovascular death or hospitalization for heart failure, regardless of the baseline level of hs-cTnT, whether the effects of treatment were analysed as hazard ratios or absolute risk reductions. CONCLUSIONS: Elevations in hs-cTnT reflect the clinical severity, stability and prognosis of patients with heart failure and a reduced ejection fraction, with biomarkers, comorbidities, clinical course and risks that are proportional to the magnitude of hs-cTnT elevation. Empagliflozin exerted favourable effects on heart failure and renal outcomes, regardless of the baseline concentration of hs-cTnT.