Abstract
Aims
The aim of this study was to examine the effect of dapagliflozin on the incidence of ventricular arrhythmias and sudden death in patients with heart failure and reduced ejection ...fraction (HFrEF).
Methods and results
In a post hoc analysis of DAPA-HF, we examined serious adverse event reports related to ventricular arrhythmias or cardiac arrest, in addition to adjudicated sudden death. The effect of dapagliflozin, compared with placebo, on the composite of the first occurrence of any serious ventricular arrhythmia, resuscitated cardiac arrest, or sudden death was examined using Cox proportional hazards models. A serious ventricular arrhythmia was reported in 115 (2.4%) of the 4744 patients in DAPA-HF (ventricular fibrillation in 15 patients, ventricular tachycardia in 86, ‘other’ ventricular arrhythmia/tachyarrhythmia in 12, and torsade de pointes in 2 patients). A total of 206 (41%) of the 500 cardiovascular deaths occurred suddenly. Eight patients survived resuscitation from cardiac arrest. Independent predictors of the composite outcome (first occurrence of any serious ventricular arrhythmia, resuscitated cardiac arrest or sudden death), ranked by chi-square value, were log-transformed N-terminal pro-B-type natriuretic peptide, history of ventricular arrhythmia, left ventricular ejection fraction, systolic blood pressure, history of myocardial infarction, male sex, body mass index, serum sodium concentration, non-white race, treatment with dapagliflozin, and cardiac resynchronization therapy. Of participants assigned to dapagliflozin, 140/2373 patients (5.9%) experienced the composite outcome compared with 175/2371 patients (7.4%) in the placebo group hazard ratio 0.79 (95% confidence interval 0.63–0.99), P = 0.037, and the effect was consistent across each of the components of the composite outcome.
Conclusions
Dapagliflozin reduced the risk of any serious ventricular arrhythmia, cardiac arrest, or sudden death when added to conventional therapy in patients with HFrEF.
Clinical trial registration
ClinicalTrials.gov unique identifier: NCT03036124 (DAPA-HF).
Graphical Abstract
DAPA-HF: trial design and main findings. BMI, body mass index; BP, blood pressure; CI, confidence interval; HF, heart failure; HFrEF, heart failure and reduced ejection fraction; HR, hazard ratio; LVEF, left ventricular ejection fraction; MI, myocardial infarction; NT-proBNP, N-terminal pro-B-type natriuretic peptide.
Background
The aims of this study were to: (i) report the baseline characteristics of patients enrolled in the Dapagliflozin And Prevention of Adverse‐outcomes in Heart Failure (DAPA‐HF) trial, (ii) ...compare DAPA‐HF patients to participants in contemporary heart failure (HF) registries and in other recent HF trials, and (iii) compare individuals with diabetes, pre‐diabetes and a normal glycated haemoglobin (HbA1c) in DAPA‐HF.
Methods and results
Adults with HF in New York Heart Association functional class ≥ II, a left ventricular ejection fraction ≤ 40%, an elevated N‐terminal pro‐B‐type natriuretic peptide concentration and receiving standard treatment were eligible for DAPA‐HF, which is comparing dapagliflozin 10 mg once daily to matching placebo. In patients without a history of diabetes, previously undiagnosed diabetes was defined as a confirmed HbA1c ≥ 6.5%. Among patients without known or undiagnosed diabetes, pre‐diabetes was defined as a HbA1c ≥ 5.7% The remainder of patients, with a HbA1c < 5.7%, were defined as normoglycaemic. Of the 4744 patients (mean age 66 years; 23% women) randomized, 42% had known diabetes and 3% undiagnosed diabetes. Of the remainder, 67% had pre‐diabetes and 33% normal HbA1c. Overall, DAPA‐HF patients were generally similar to those in recent registries and in relevant trials and had high levels of background therapy: 94% angiotensin‐converting enzyme inhibitor/angiotensin receptor blocker/angiotensin receptor–neprilysin inhibitor, 96% beta‐blocker, and 71% mineralocorticoid receptor antagonist; 26% had a defibrillator. Patients with diabetes had worse HF status, more co‐morbidity, and greater renal impairment but received similar HF therapy. Patients with diabetes received non‐insulin hypoglycaemic therapy alone in 49%, insulin alone in 11%, both in 14%, and none in 26%.
Conclusions
Patients randomized in DAPA‐HF were similar to those in other contemporary HF with reduced ejection fraction (HFrEF) registries and trials. These patients were receiving recommended HFrEF therapy and those with diabetes were also treated with conventional glucose‐lowering therapy. Consequently, DAPA‐HF will test the incremental efficacy and safety of dapagliflozin in HFrEF patients with and without diabetes.
Clinical Trial Registration: ClinicalTrials.gov Identifier NCT03036124
Abstract
Aims
In the DAPA-HF trial, the SGLT2 inhibitor dapagliflozin reduced the risk of worsening heart failure (HF) and death in patients with HF and reduced ejection fraction. We examined whether ...this benefit was consistent in relation to background HF therapy.
Methods and results
In this post hoc analysis, we examined the effect of study treatment in the following yes/no subgroups: diuretic, digoxin, mineralocorticoid receptor antagonist (MRA), sacubitril/valsartan, ivabradine, implanted cardioverter-defibrillating (ICD) device, and cardiac resynchronization therapy. We also examined the effect of study drug according to angiotensin-converting enzyme inhibitor/angiotensin receptor blocker dose, beta-blocker (BB) dose, and MRA (≥50% and <50% of target dose). We analysed the primary composite endpoint of cardiovascular death or a worsening HF event. Most randomized patients (n = 4744) were treated with a diuretic (84%), renin–angiotensin system (RAS) blocker (94%), and BB (96%); 52% of those taking a BB and 38% taking a RAS blocker were treated with ≥50% of the recommended dose. Overall, the dapagliflozin vs. placebo hazard ratio (HR) was 0.74 95% confidence interval (CI) 0.65–0.85 for the primary composite endpoint (P < 0.0001). The effect of dapagliflozin was consistent across all subgroups examined: the HR ranged from 0.57 to 0.86 for primary endpoint, with no significant randomized treatment-by-subgroup interaction. For example, the HR in patients taking a RAS blocker, BB, and MRA at baseline was 0.72 (95% CI 0.61–0.86) compared with 0.77 (95% CI 0.63–0.94) in those not on all three of these treatments (P-interaction 0.64).
Conclusion
The benefit of dapagliflozin was consistent regardless of background therapy for HF.
This study uses cetacean sighting data, acquired via a citizen science programme, to update distributions and spatial trends of whales and dolphins in waters around the Svalbard Archipelago during ...the period 2005–2019. Distributions, based on kernel density estimates, from an early period (2005–2019) and a recent period (2015–19) were compared to identify potential shifts in distribution in this area, which is experiencing rapid warming and concomitant sea-ice losses. Among the three Arctic endemic cetaceans, white whales (Delphinapterus leucas, also known as beluga) had a stable, coastal distribution throughout the study, whereas narwhals (Monodon monoceros) and bowhead whales (Balaena mysticetus) were observed only north of the archipelago, but with increasing frequency during the recent period. White-beaked dolphins (Lagenorhynchus albirostris) had a stable distribution along the continental shelf break, west and south of Svalbard. Sperm whale observations shifted from west of Bjørnøya during the early period to being concentrated around the north end of Prins Karls Forland, west of Spitsbergen during the recent period. The four summer-resident baleen whales—blue whales (Balaenoptera musculus), fin whales (Balaenoptera physalus), humpback whales (Megaptera novaeangliae) and minke whales (Balaenoptera acutorostrata)—have shifted their distributions from the continental shelf break west of Spitsbergen during the early period into fjords and coastal areas during the recent period. These changes coincide with increased inflows of Atlantic Water into the fjords along the west coast of Spitsbergen and across the north of the archipelago.
Abstract
Aims
Concern about hypotension often leads to withholding of beneficial therapy in patients with heart failure and reduced ejection fraction (HFrEF). We evaluated the efficacy and safety of ...dapagliflozin, which lowers systolic blood pressure (SBP),according to baseline SBP in Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure trial (DAPA-HF).
Methods and results
Key inclusion criteria were: New York Heart Association Class II−IV, left ventricular ejection fraction ≤ 40%, elevated N-terminal pro-B-type natriuretic peptide level, and SBP ≥95 mmHg. The primary outcome was a composite of worsening heart failure or cardiovascular death. The efficacy and safety of dapagliflozin were examined using SBP as both a categorical and continuous variable. A total of 1205 patients had a baseline SBP <110 mmHg; 981 ≥ 110 < 120; 1149 ≥ 120 < 130; and 1409 ≥ 130 mmHg. The placebo-corrected reduction in SBP from baseline to 2 weeks with dapagliflozin was −2.54 (−3.33 to −1.76) mmHg (P < 0.001), with a smaller between-treatment difference in patients in the lowest compared to highest SBP category. Patients in the lowest SBP category had a much higher rate (per 100 person-years) of the primary outcome 20.6, 95% confidence interval (95% CI) 17.6–24.2 than those in the highest SBP category (13.8, 11.7–16.4). The benefit and safety of dapagliflozin was consistent across the range of SBP; hazard ratio (95% CI) in each SBP group, lowest to highest: 0.76 (0.60–0.97), 0.76 (0.57–1.02), 0.81 (0.61–1.08), and 0.67 (0.51–0.87), P interaction = 0.78. Study drug discontinuation did not differ between dapagliflozin and placebo across the SBP categories examined.
Conclusion
Dapagliflozin had a small effect on SBP in patients with HFrEF and was superior to placebo in improving outcomes, and well tolerated, across the range of SBP included in DAPA-HF.
Clinical Trial Registration:
ClinicalTrials.gov NCT03036124.
Graphical Abstract
Tamoxifen is an established treatment for breast cancer, but its long-term effects on survival and on secondary cancers are not fully evaluated.
We studied 30 years outcome of 4124 postmenopausal ...patients who were randomized to receive (totally) two or five years of adjuvant tamoxifen.
After 5 years of follow-up, when tamoxifen treatment was finished in both groups, until 15 years of follow-up, overall mortality (HR 0.80, 95% CI 0.72–0.90, p < 0.001), breast cancer mortality for all patients (HR 0.80, 95% CI 0.68–0.94, p = 0.006) and breast cancer mortality for patients with estrogen receptor positive disease (HR 0.67, 95% CI 0.55–0.83, p < 0.001) were significantly reduced in the five-year group as compared to the two-year group. After 15 years, the difference remained but did not further increase.
In the five-year group, the incidence of contralateral breast cancer was gradually reduced during the entire period of observation. The incidence of lung cancer was also reduced in the five-year group. In contrast there was an increased endometrial cancer incidence in the five-year group and for those receiving 40 mg of tamoxifen this incidence was further increased.
Three more years of tamoxifen therapy reduced the risk of breast cancer mortality. The difference was established during the first 15 years after randomization. Moreover, the incidence of contralateral breast cancer gradually decreased for 30 years. The incidence of lung cancer was reduced in the five-year group. In contrast the incidence of endometrial cancer was increased.
•After 30 years of follow-up, 5 years as compared to 2 years of tamoxifen.•Had reduced breast cancer mortality.•Had reduced all-cause mortality.•Had reduced the incidence of contralateral disease.•Had increased the incidence of endometrial cancer.
There is an ongoing scientific discussion, that anti-cancer effects induced by radiofrequency (RF)-hyperthermia might not be solely attributable to subsequent temperature elevations at the tumor site ...but also to non-temperature-induced effects. The exact molecular mechanisms behind said potential non-thermal RF effects remain largely elusive, however, limiting their therapeutical targetability.INTRODUCTIONThere is an ongoing scientific discussion, that anti-cancer effects induced by radiofrequency (RF)-hyperthermia might not be solely attributable to subsequent temperature elevations at the tumor site but also to non-temperature-induced effects. The exact molecular mechanisms behind said potential non-thermal RF effects remain largely elusive, however, limiting their therapeutical targetability.Therefore, we aim to provide an overview of the current literature on potential non-temperature-induced molecular effects within cancer cells in response to RF-electromagnetic fields (RF-EMF).OBJECTIVETherefore, we aim to provide an overview of the current literature on potential non-temperature-induced molecular effects within cancer cells in response to RF-electromagnetic fields (RF-EMF).This literature review was conducted following the PRISMA guidelines. For this purpose, a MeSH-term-defined literature search on MEDLINE (PubMed) and Scopus (Elsevier) was conducted on March 23rd, 2024. Essential criteria herein included the continuous wave RF-EMF nature (3 kHz - 300 GHz) of the source, the securing of temperature-controlled circumstances within the trials, and the preclinical nature of the trials.MATERIAL AND METHODSThis literature review was conducted following the PRISMA guidelines. For this purpose, a MeSH-term-defined literature search on MEDLINE (PubMed) and Scopus (Elsevier) was conducted on March 23rd, 2024. Essential criteria herein included the continuous wave RF-EMF nature (3 kHz - 300 GHz) of the source, the securing of temperature-controlled circumstances within the trials, and the preclinical nature of the trials.Analysis of the data processed in this review suggests that RF-EMF radiation of various frequencies seems to be able to induce significant non-temperature-induced anti-cancer effects. These effects span from mitotic arrest and growth inhibition to cancer cell death in the form of autophagy and apoptosis and appear to be mostly exclusive to cancer cells. Several cellular mechanisms were identified through which RF-EMF radiation potentially imposes its anti-cancer effects. Among those, by reviewing the included publications, we identified RF-EMF-induced ion channel activation, altered gene expression, altered membrane potentials, membrane oscillations, and blebbing, as well as changes in cytoskeletal structure and cell morphology.RESULTSAnalysis of the data processed in this review suggests that RF-EMF radiation of various frequencies seems to be able to induce significant non-temperature-induced anti-cancer effects. These effects span from mitotic arrest and growth inhibition to cancer cell death in the form of autophagy and apoptosis and appear to be mostly exclusive to cancer cells. Several cellular mechanisms were identified through which RF-EMF radiation potentially imposes its anti-cancer effects. Among those, by reviewing the included publications, we identified RF-EMF-induced ion channel activation, altered gene expression, altered membrane potentials, membrane oscillations, and blebbing, as well as changes in cytoskeletal structure and cell morphology.The existent literature points toward a yet untapped therapeutic potential of RF-EMF treatment, which might aid in damaging cancer cells through bio-electrical and electro-mechanical molecular mechanisms while minimizing adverse effects on healthy tissue cells. Further research is imperative to definitively confirm non-thermal EMF effects as well as to determine optimal cancer-type-specific RF-EMF frequencies, field intensities, and exposure intervals.CONCLUSIONThe existent literature points toward a yet untapped therapeutic potential of RF-EMF treatment, which might aid in damaging cancer cells through bio-electrical and electro-mechanical molecular mechanisms while minimizing adverse effects on healthy tissue cells. Further research is imperative to definitively confirm non-thermal EMF effects as well as to determine optimal cancer-type-specific RF-EMF frequencies, field intensities, and exposure intervals.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
This study presents comprehensive mapping of the current distribution of pinnipeds and polar bears (Ursus maritimus) around Svalbard based on a regional marine mammal sightings programme and explores ...time-trends (2005–2018). Walruses (Odobenus rosmarus) were observed with high frequency and in high numbers around previously identified haul-out sites. At-sea walruses were seen close to the coast in shallow waters. Ringed seals (Pusa hispida) were observed in coastal areas throughout Svalbard, often in association with tidewater glacier fronts. There was no increase in the mean latitude for ringed seal observations, but there was an increased frequency of observations at around 82°N, which reflects their following a northward shift in the ice edge during summer foraging trips. Bearded seals (Erignathus barbatus) were observed frequently in north-western Spitsbergen and shared many habitat features with ringed seals. There was a slight increase in the mean latitude of bearded seal observations and a decreased frequency of observation in the southern parts of the archipelago, suggesting that this species might be shifting its distribution. Harbour seal (Phoca vitulina) observations within fjords have increased, likely as a consequence of increased inflow of Atlantic water into west coast fjords. Harp seals (Pagophilus groenlandicus) were observed with high frequency north of Svalbard. Hooded seals (Cystophora cristata) were observed only rarely. Polar bears were reported most frequently, undoubtedly as a result of an effort bias favouring this species. In spite of biases, citizen-based observations are useful for assessing broad distributional patterns of marine mammals through time.
Non-temperature-induced effects of radiofrequency electromagnetic fields (RF) have been controversial for decades. Here, we established measurement techniques to prove their existence by ...investigating energy deposition in tumor cells under RF exposure and upon adding amplitude modulation (AM) (AMRF). Using a preclinical device LabEHY-200 with a novel in vitro applicator, we analyzed the power deposition and system parameters for five human colorectal cancer cell lines and measured the apoptosis rates in vitro and tumor growth inhibition in vivo in comparison to water bath heating. We showed enhanced anticancer effects of RF and AMRF in vitro and in vivo and verified the non-temperature-induced origin of the effects. Furthermore, apoptotic enhancement by AM was correlated with cell membrane stiffness. Our findings not only provide a strategy to significantly enhance non-temperature-induced anticancer cell effects in vitro and in vivo but also provide a perspective for a potentially more effective tumor therapy.
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