Research Spotlight

Packer, M., Anker, S.D., Butler, J., Filippatos, G., Pocock, S.J., Carson, P., Januzzi, J., Verma, S., Tsutsui, H., Brueckmann, M., Jamal, W., Kimura, K., Schnee, J., Zeller, C., Cotton, D., Bocchi, E., Böhm, M., Choi, D.J., Chopra, V., Chuquiure, E., Giannetti, N., Janssens, S., Zhang, J., Gonzalez Juanatey, J.R., Kaul, S., Brunner-La Rocca, H.P., Merkely, B., Nicholls, S.J., Perrone, S., Pina, I., Ponikowski, P., Sattar, N., Senni, M., Seronde, M.F., Spinar, J., Squire, I., Taddei, S., Wanner, C. and Zannad, F. (2020). “Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure.” N Engl J Med Aug 29. [Epub ahead of print.].

Full text of this article.

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 m(2) 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.

Zannad, F., Ferreira, J.P., Pocock, S.J., Anker, S.D., Butler, J., Filippatos, G., Brueckmann, M., Ofstad, A.P., Pfarr, E., Jamal, W. and Packer, M. (2020). “SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR-Reduced and DAPA-HF trials.” Lancet Aug 28;S0140-6736(20)31824-9. [Epub ahead of print.].

Full text of this article.

BACKGROUND: Both DAPA-HF (assessing dapagliflozin) and EMPEROR-Reduced (assessing empagliflozin) trials showed that sodium-glucose co-transporter-2 (SGLT2) inhibition reduced the combined risk of cardiovascular death or hospitalisation for heart failure in patients with heart failure with reduced ejection fraction (HFrEF) with or without diabetes. However, neither trial was powered to assess effects on cardiovascular death or all-cause death or to characterise effects in clinically important subgroups. Using study-level published data from DAPA-HF and patient-level data from EMPEROR-Reduced, we aimed to estimate the effect of SGLT2 inhibition on fatal and non-fatal heart failure events and renal outcomes in all randomly assigned patients with HFrEF and in relevant subgroups from DAPA-HF and EMPEROR-Reduced trials. METHODS: We did a prespecified meta-analysis of the two single large-scale trials assessing the effects of SGLT2 inhibitors on cardiovascular outcomes in patients with HFrEF with or without diabetes: DAPA-HF (assessing dapagliflozin) and EMPEROR-Reduced (assessing empagliflozin). The primary endpoint was time to all-cause death. Additionally, we assessed the effects of treatment in prespecified subgroups on the combined risk of cardiovascular death or hospitalisation for heart failure. These subgroups were based on type 2 diabetes status, age, sex, angiotensin receptor neprilysin inhibitor (ARNI) treatment, New York Heart Association (NYHA) functional class, race, history of hospitalisation for heart failure, estimated glomerular filtration rate (eGFR), body-mass index, and region (post-hoc). We used hazard ratios (HRs) derived from Cox proportional hazard models for time-to-first event endpoints and Cochran’s Q test for treatment interactions; the analysis of recurrent events was based on rate ratios derived from the Lin-Wei-Yang-Ying model. FINDINGS: Among 8474 patients combined from both trials, the estimated treatment effect was a 13% reduction in all-cause death (pooled HR 0·87, 95% CI 0·77-0·98; p=0·018) and 14% reduction in cardiovascular death (0·86, 0·76-0·98; p=0·027). SGLT2 inhibition was accompanied by a 26% relative reduction in the combined risk of cardiovascular death or first hospitalisation for heart failure (0·74, 0·68-0·82; p<0·0001), and by a 25% decrease in the composite of recurrent hospitalisations for heart failure or cardiovascular death (0·75, 0·68-0·84; p<0·0001). The risk of the composite renal endpoint was also reduced (0·62, 0·43-0·90; p=0·013). All tests for heterogeneity of effect size between trials were not significant. The pooled treatment effects showed consistent benefits for subgroups based on age, sex, diabetes, treatment with an ARNI and baseline eGFR, but suggested treatment-by-subgroup interactions for subgroups based on NYHA functional class and race. INTERPRETATION: The effects of empagliflozin and dapagliflozin on hospitalisations for heart failure were consistent in the two independent trials and suggest that these agents also improve renal outcomes and reduce all-cause and cardiovascular death in patients with HFrEF.

Spinner, C.D., Gottlieb, R.L., Criner, G.J., Arribas López, J.R., Cattelan, A.M., Soriano Viladomiu, A., Ogbuagu, O., Malhotra, P., Mullane, K.M., Castagna, A., Chai, L.Y.A., Roestenberg, M., Tsang, O.T.Y., Bernasconi, E., Le Turnier, P., Chang, S.C., SenGupta, D., Hyland, R.H., Osinusi, A.O., Cao, H., Blair, C., Wang, H., Gaggar, A., Brainard, D.M., McPhail, M.J., Bhagani, S., Ahn, M.Y., Sanyal, A.J., Huhn, G. and Marty, F.M. (2020). “Effect of Remdesivir vs Standard Care on Clinical Status at 11 Days in Patients With Moderate COVID-19: A Randomized Clinical Trial.” Jama Aug 21;e2016349. [Epub ahead of print.].

Full text of this article.

IMPORTANCE: Remdesivir demonstrated clinical benefit in a placebo-controlled trial in patients with severe coronavirus disease 2019 (COVID-19), but its effect in patients with moderate disease is unknown. OBJECTIVE: To determine the efficacy of 5 or 10 days of remdesivir treatment compared with standard care on clinical status on day 11 after initiation of treatment. DESIGN, SETTING, AND PARTICIPANTS: Randomized, open-label trial of hospitalized patients with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and moderate COVID-19 pneumonia (pulmonary infiltrates and room-air oxygen saturation >94%) enrolled from March 15 through April 18, 2020, at 105 hospitals in the United States, Europe, and Asia. The date of final follow-up was May 20, 2020. INTERVENTIONS: Patients were randomized in a 1:1:1 ratio to receive a 10-day course of remdesivir (n = 197), a 5-day course of remdesivir (n = 199), or standard care (n = 200). Remdesivir was dosed intravenously at 200 mg on day 1 followed by 100 mg/d. MAIN OUTCOMES AND MEASURES: The primary end point was clinical status on day 11 on a 7-point ordinal scale ranging from death (category 1) to discharged (category 7). Differences between remdesivir treatment groups and standard care were calculated using proportional odds models and expressed as odds ratios. An odds ratio greater than 1 indicates difference in clinical status distribution toward category 7 for the remdesivir group vs the standard care group. RESULTS: Among 596 patients who were randomized, 584 began the study and received remdesivir or continued standard care (median age, 57 [interquartile range, 46-66] years; 227 [39%] women; 56% had cardiovascular disease, 42% hypertension, and 40% diabetes), and 533 (91%) completed the trial. Median length of treatment was 5 days for patients in the 5-day remdesivir group and 6 days for patients in the 10-day remdesivir group. On day 11, patients in the 5-day remdesivir group had statistically significantly higher odds of a better clinical status distribution than those receiving standard care (odds ratio, 1.65; 95% CI, 1.09-2.48; P = .02). The clinical status distribution on day 11 between the 10-day remdesivir and standard care groups was not significantly different (P = .18 by Wilcoxon rank sum test). By day 28, 9 patients had died: 2 (1%) in the 5-day remdesivir group, 3 (2%) in the 10-day remdesivir group, and 4 (2%) in the standard care group. Nausea (10% vs 3%), hypokalemia (6% vs 2%), and headache (5% vs 3%) were more frequent among remdesivir-treated patients compared with standard care. CONCLUSIONS AND RELEVANCE: Among patients with moderate COVID-19, those randomized to a 10-day course of remdesivir did not have a statistically significant difference in clinical status compared with standard care at 11 days after initiation of treatment. Patients randomized to a 5-day course of remdesivir had a statistically significant difference in clinical status compared with standard care, but the difference was of uncertain clinical importance.

Ma, Y., Zhang, X., Li, C., Liu, S., Xing, Y. and Tao, F. (2020). “Spinal N-Cadherin/CREB Signaling Contributes to Chronic Alcohol Consumption-Enhanced Postsurgical Pain.” J Pain Res 13: 2065-2072.

Full text of this article.

BACKGROUND: It has been reported that N-cadherin and cAMP response element binding protein (CREB) in the spinal cord are critical for synaptogenesis and regulation of excitatory synapse function, which could underlie chronic pain development. The aim of the present study was to investigate the role of spinal N-cadherin/CREB signaling in postsurgical pain chronicity following chronic alcohol consumption. METHODS: C57BL/6 male mice were randomly assigned into different groups. Plantar incision was used to induce postsurgical pain. Chronic alcohol consumption was conducted by giving mice unlimited access to different concentrations of ethanol for five weeks. We measured paw withdrawal thresholds to test postsurgical pain. Using Western blotting, we examined the expression of N-Cadherin and CREB in the spinal dorsal horn. We further performed intrathecal injection of specific N-cadherin and CREB inhibitors to assess the role of spinal N-cadherin/CREB signaling in chronic alcohol consumption-enhanced postsurgical pain. RESULTS: We observed that the chronic alcohol consumption significantly prolonged postsurgical pain and enhanced plantar incision-increased N-cadherin expression and CREB phosphorylation at the Ser133 in the spinal cord. Intrathecal injection of specific N-cadherin and CREB inhibitors attenuated chronic alcohol consumption-prolonged postsurgical pain. CONCLUSION: Our results suggest that spinal N-cadherin/CREB signaling is involved in chronic alcohol consumption-caused postsurgical pain chronicity.

Gonzalez, A.M., Piedra-Cascón, W., Zandinejad, A. and Revilla-León, M. (2020). “Fiber-reinforced composite fixed dental prosthesis using an additive manufactured silicone index.” J Esthet Restor Dent.

Full text of this article.

OBJECTIVE: Digital tools such as facial and intraoral digitizers and additive manufacturing (AM) technologies assist restorative treatments. The objective of the present manuscript was to describe a workflow procedure for treatment planning and fabricating a fiber-reinforced composite fixed dental prosthesis (FDP) replacing an absent maxillary lateral incisor, using additively manufactured silicone indices to facilitate the clinical intervention. CLINICAL CONSIDERATIONS: The elaboration of a direct fiber-reinforced composite restoration is a technique sensitive procedure which might be time-consuming for the clinician. The digital waxing helped to determine the exact position and size of the lingual wings and connectors of the fiber-reinforced FDP and to design a three-piece index. And the AM of the index helped to transfer the information to the patient’s dentition accurately. CONCLUSIONS: The protocol minimizes the time of clinical intervention by facilitating the transference of the virtual diagnostic waxing teeth into the patient’s mouth. The three-piece silicone index provides an individualized path of insertion of each index part while also providing a customized space and location of the lingual wings of the restoration. CLINICAL SIGNIFICANCE: The usage of AM silicone indices facilitates the clinical intervention by translating the size and position of the diagnostic wax-up teeth into the patient´s mouth, minimizing clinical procedure’s time.