Proteins of the bromodomain and extra-terminal (BET) domain family are epigenetic readers that bind acetylated histones through their bromodomains to regulate gene transcription. Dual-bromodomain BET ...inhibitors (DbBi) that bind with similar affinities to the first (BD1) and second (BD2) bromodomains of BRD2, BRD3, BRD4 and BRDt have displayed modest clinical activity in monotherapy cancer trials. A reduced number of thrombocytes in the blood (thrombocytopenia) as well as symptoms of gastrointestinal toxicity are dose-limiting adverse events for some types of DbBi
. Given that similar haematological and gastrointestinal defects were observed after genetic silencing of Brd4 in mice
, the platelet and gastrointestinal toxicities may represent on-target activities associated with BET inhibition. The two individual bromodomains in BET family proteins may have distinct functions
and different cellular phenotypes after pharmacological inhibition of one or both bromodomains have been reported
, suggesting that selectively targeting one of the bromodomains may result in a different efficacy and tolerability profile compared with DbBi. Available compounds that are selective to individual domains lack sufficient potency and the pharmacokinetics properties that are required for in vivo efficacy and tolerability assessment
. Here we carried out a medicinal chemistry campaign that led to the discovery of ABBV-744, a highly potent and selective inhibitor of the BD2 domain of BET family proteins with drug-like properties. In contrast to the broad range of cell growth inhibition induced by DbBi, the antiproliferative activity of ABBV-744 was largely, but not exclusively, restricted to cell lines of acute myeloid leukaemia and prostate cancer that expressed the full-length androgen receptor (AR). ABBV-744 retained robust activity in prostate cancer xenografts, and showed fewer platelet and gastrointestinal toxicities than the DbBi ABBV-075
. Analyses of RNA expression and chromatin immunoprecipitation followed by sequencing revealed that ABBV-744 displaced BRD4 from AR-containing super-enhancers and inhibited AR-dependent transcription, with less impact on global transcription compared with ABBV-075. These results underscore the potential value of selectively targeting the BD2 domain of BET family proteins for cancer therapy.
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FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
AbstractObjectiveTo assess the associations between statins and adverse events in primary prevention of cardiovascular disease and to examine how the associations vary by type and dosage of ...statins.DesignSystematic review and meta-analysis.Data sourcesStudies were identified from previous systematic reviews and searched in Medline, Embase, and the Cochrane Central Register of Controlled Trials, up to August 2020.Review methodsRandomised controlled trials in adults without a history of cardiovascular disease that compared statins with non-statin controls or compared different types or dosages of statins were included.Main outcome measuresPrimary outcomes were common adverse events: self-reported muscle symptoms, clinically confirmed muscle disorders, liver dysfunction, renal insufficiency, diabetes, and eye conditions. Secondary outcomes included myocardial infarction, stroke, and death from cardiovascular disease as measures of efficacy.Data synthesisA pairwise meta-analysis was conducted to calculate odds ratios and 95% confidence intervals for each outcome between statins and non-statin controls, and the absolute risk difference in the number of events per 10 000 patients treated for a year was estimated. A network meta-analysis was performed to compare the adverse effects of different types of statins. An Emax model based meta-analysis was used to examine the dose-response relationships of the adverse effects of each statin.Results62 trials were included, with 120 456 participants followed up for an average of 3.9 years. Statins were associated with an increased risk of self-reported muscle symptoms (21 trials, odds ratio 1.06 (95% confidence interval 1.01 to 1.13); absolute risk difference 15 (95% confidence interval 1 to 29)), liver dysfunction (21 trials, odds ratio 1.33 (1.12 to 1.58); absolute risk difference 8 (3 to 14)), renal insufficiency (eight trials, odds ratio 1.14 (1.01 to 1.28); absolute risk difference 12 (1 to 24)), and eye conditions (six trials, odds ratio 1.23 (1.04 to 1.47); absolute risk difference 14 (2 to 29)) but were not associated with clinically confirmed muscle disorders or diabetes. The increased risks did not outweigh the reduction in the risk of major cardiovascular events. Atorvastatin, lovastatin, and rosuvastatin were individually associated with some adverse events, but few significant differences were found between types of statins. An Emax dose-response relationship was identified for the effect of atorvastatin on liver dysfunction, but the dose-response relationships for the other statins and adverse effects were inconclusive.ConclusionsFor primary prevention of cardiovascular disease, the risk of adverse events attributable to statins was low and did not outweigh their efficacy in preventing cardiovascular disease, suggesting that the benefit-to-harm balance of statins is generally favourable. Evidence to support tailoring the type or dosage of statins to account for safety concerns before starting treatment was limited.Systematic review registrationPROSPERO CRD42020169955.
Self-monitoring of blood pressure (BP) appears to reduce BP in hypertension but important questions remain regarding effective implementation and which groups may benefit most. This individual ...patient data (IPD) meta-analysis was performed to better understand the effectiveness of BP self-monitoring to lower BP and control hypertension.
Medline, Embase, and the Cochrane Library were searched for randomised trials comparing self-monitoring to no self-monitoring in hypertensive patients (June 2016). Two reviewers independently assessed articles for eligibility and the authors of eligible trials were approached requesting IPD. Of 2,846 articles in the initial search, 36 were eligible. IPD were provided from 25 trials, including 1 unpublished study. Data for the primary outcomes-change in mean clinic or ambulatory BP and proportion controlled below target at 12 months-were available from 15/19 possible studies (7,138/8,292 86% of randomised participants). Overall, self-monitoring was associated with reduced clinic systolic blood pressure (sBP) compared to usual care at 12 months (-3.2 mmHg, 95% CI -4.9, -1.6 mmHg). However, this effect was strongly influenced by the intensity of co-intervention ranging from no effect with self-monitoring alone (-1.0 mmHg -3.3, 1.2), to a 6.1 mmHg (-9.0, -3.2) reduction when monitoring was combined with intensive support. Self-monitoring was most effective in those with fewer antihypertensive medications and higher baseline sBP up to 170 mmHg. No differences in efficacy were seen by sex or by most comorbidities. Ambulatory BP data at 12 months were available from 4 trials (1,478 patients), which assessed self-monitoring with little or no co-intervention. There was no association between self-monitoring and either lower clinic or ambulatory sBP in this group (clinic -0.2 mmHg -2.2, 1.8; ambulatory 1.1 mmHg -0.3, 2.5). Results for diastolic blood pressure (dBP) were similar. The main limitation of this work was that significant heterogeneity remained. This was at least in part due to different inclusion criteria, self-monitoring regimes, and target BPs in included studies.
Self-monitoring alone is not associated with lower BP or better control, but in conjunction with co-interventions (including systematic medication titration by doctors, pharmacists, or patients; education; or lifestyle counselling) leads to clinically significant BP reduction which persists for at least 12 months. The implementation of self-monitoring in hypertension should be accompanied by such co-interventions.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Antihypertensives are effective at reducing the risk of cardiovascular disease, but limited data exist quantifying their association with serious adverse events, particularly in older people with ...frailty. This study aimed to examine this association using nationally representative electronic health record data.
This was a retrospective cohort study utilising linked data from 1,256 general practices across England held within the Clinical Practice Research Datalink between 1998 and 2018. Included patients were aged 40+ years, with a systolic blood pressure reading between 130 and 179 mm Hg, and not previously prescribed antihypertensive treatment. The main exposure was defined as a first prescription of antihypertensive treatment. The primary outcome was hospitalisation or death within 10 years from falls. Secondary outcomes were hypotension, syncope, fractures, acute kidney injury, electrolyte abnormalities, and primary care attendance with gout. The association between treatment and these serious adverse events was examined by Cox regression adjusted for propensity score. This propensity score was generated from a multivariable logistic regression model with patient characteristics, medical history and medication prescriptions as covariates, and new antihypertensive treatment as the outcome. Subgroup analyses were undertaken by age and frailty. Of 3,834,056 patients followed for a median of 7.1 years, 484,187 (12.6%) were prescribed new antihypertensive treatment in the 12 months before the index date (baseline). Antihypertensives were associated with an increased risk of hospitalisation or death from falls (adjusted hazard ratio aHR 1.23, 95% confidence interval (CI) 1.21 to 1.26), hypotension (aHR 1.32, 95% CI 1.29 to 1.35), syncope (aHR 1.20, 95% CI 1.17 to 1.22), acute kidney injury (aHR 1.44, 95% CI 1.41 to 1.47), electrolyte abnormalities (aHR 1.45, 95% CI 1.43 to 1.48), and primary care attendance with gout (aHR 1.35, 95% CI 1.32 to 1.37). The absolute risk of serious adverse events with treatment was very low, with 6 fall events per 10,000 patients treated per year. In older patients (80 to 89 years) and those with severe frailty, this absolute risk was increased, with 61 and 84 fall events per 10,000 patients treated per year (respectively). Findings were consistent in sensitivity analyses using different approaches to address confounding and taking into account the competing risk of death. A strength of this analysis is that it provides evidence regarding the association between antihypertensive treatment and serious adverse events, in a population of patients more representative than those enrolled in previous randomised controlled trials. Although treatment effect estimates fell within the 95% CIs of those from such trials, these analyses were observational in nature and so bias from unmeasured confounding cannot be ruled out.
Antihypertensive treatment was associated with serious adverse events. Overall, the absolute risk of this harm was low, with the exception of older patients and those with moderate to severe frailty, where the risks were similar to the likelihood of benefit from treatment. In these populations, physicians may want to consider alternative approaches to management of blood pressure and refrain from prescribing new treatment.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
IMPORTANCE: Deprescribing of antihypertensive medications is recommended for some older patients with polypharmacy and multimorbidity when the benefits of continued treatment may not outweigh the ...harms. OBJECTIVE: This study aimed to establish whether antihypertensive medication reduction is possible without significant changes in systolic blood pressure control or adverse events during 12-week follow-up. DESIGN, SETTING, AND PARTICIPANTS: The Optimising Treatment for Mild Systolic Hypertension in the Elderly (OPTIMISE) study was a randomized, unblinded, noninferiority trial conducted in 69 primary care sites in England. Participants, whose primary care physician considered them appropriate for medication reduction, were aged 80 years and older, had systolic blood pressure lower than 150 mm Hg, and were receiving at least 2 antihypertensive medications were included. Participants enrolled between April 2017 and September 2018 and underwent follow-up until January 2019. INTERVENTIONS: Participants were randomized (1:1 ratio) to a strategy of antihypertensive medication reduction (removal of 1 drug intervention, n = 282) or usual care (control, n = 287), in which no medication changes were mandated. MAIN OUTCOMES AND MEASURES: The primary outcome was systolic blood pressure lower than 150 mm Hg at 12-week follow-up. The prespecified noninferiority margin was a relative risk (RR) of 0.90. Secondary outcomes included the proportion of participants maintaining medication reduction and differences in blood pressure, frailty, quality of life, adverse effects, and serious adverse events. RESULTS: Among 569 patients randomized (mean age, 84.8 years; 276 48.5% women; median of 2 antihypertensive medications prescribed at baseline), 534 (93.8%) completed the trial. Overall, 229 (86.4%) patients in the intervention group and 236 (87.7%) patients in the control group had a systolic blood pressure lower than 150 mm Hg at 12 weeks (adjusted RR, 0.98 97.5% 1-sided CI, 0.92 to ∞). Of 7 prespecified secondary end points, 5 showed no significant difference. Medication reduction was sustained in 187 (66.3%) participants at 12 weeks. Mean change in systolic blood pressure was 3.4 mm Hg (95% CI, 1.1 to 5.8 mm Hg) higher in the intervention group compared with the control group. Twelve (4.3%) participants in the intervention group and 7 (2.4%) in the control group reported at least 1 serious adverse event (adjusted RR, 1.72 95% CI, 0.7 to 4.3). CONCLUSIONS AND RELEVANCE: Among older patients treated with multiple antihypertensive medications, a strategy of medication reduction, compared with usual care, was noninferior with regard to systolic blood pressure control at 12 weeks. The findings suggest antihypertensive medication reduction in some older patients with hypertension is not associated with substantial change in blood pressure control, although further research is needed to understand long-term clinical outcomes. TRIAL REGISTRATION: EudraCT Identifier: 2016-004236-38; ISRCTN identifier: 97503221
BACKGROUND/OBJECTIVES
Randomized controlled trials are used to inform clinical guidelines on the management of hypertension in older adults, but it is unclear to what extent these trials represent ...the general population attending routine clinical practice. This study aimed to define the proportion and characteristics of patients eligible for hypertension trials conducted in older people.
DESIGN
Cross‐sectional study.
SETTING
A total of 24 general practices in England.
PARTICIPANTS
Anonymized electronic health record data from all individuals aged 80 and older.
MEASUREMENTS
Descriptive statistics were used to define the proportion and characteristics of patients eligible for two previous medication intensification trials (HYVET, SPRINT) and one medication reduction trial (OPTiMISE). A logistic regression model was constructed to estimate predictors of eligibility for each trial.
RESULTS
Of 15,376 patients identified, 268 (1.7%; 95% confidence interval CI = 1.5–2.0%), 5,290 (34.4%; 95%CI = 33.7–35.2%), and 3,940 (25.6%; 95%CI = 24.9–26.3%) were eligible for the HYVET, SPRINT, and OPTiMISE trials, respectively. Between 5.6% and 30.7% of exclusions from each trial were due to eligibility criteria excluding those with high or uncontrolled blood pressure. Frailty (odds ratio OR = .44; 95%CI = .36–.54 OPTiMISE), cardiovascular polypharmacy (OR = .61; 95%CI = .55–.68 SPRINT) and multimorbidity (OR = .72; 95%CI = .64–.82 SPRINT) were associated with a lower likelihood of being eligible for one or more of the trials.
CONCLUSION
A possible unintended consequence of blood pressure criteria used by trials attempting to answer different primary questions is that for many older patients, no trial evidence exists to inform treatment decisions in routine practice. Caution should be exercised when applying results from existing trials to patients with frailty or multimorbidity.
See related editorial by Jeff D. Williamson in this issue.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
AbstractObjectiveTo examine the association between antihypertensive treatment and specific adverse events.DesignSystematic review and meta-analysis.Eligibility criteriaRandomised controlled trials ...of adults receiving antihypertensives compared with placebo or no treatment, more antihypertensive drugs compared with fewer antihypertensive drugs, or higher blood pressure targets compared with lower targets. To avoid small early phase trials, studies were required to have at least 650 patient years of follow-up.Information sourcesSearches were conducted in Embase, Medline, CENTRAL, and the Science Citation Index databases from inception until 14 April 2020.Main outcome measuresThe primary outcome was falls during trial follow-up. Secondary outcomes were acute kidney injury, fractures, gout, hyperkalaemia, hypokalaemia, hypotension, and syncope. Additional outcomes related to death and major cardiovascular events were extracted. Risk of bias was assessed using the Cochrane risk of bias tool, and random effects meta-analysis was used to pool rate ratios, odds ratios, and hazard ratios across studies, allowing for between study heterogeneity (τ2).ResultsOf 15 023 articles screened for inclusion, 58 randomised controlled trials were identified, including 280 638 participants followed up for a median of 3 (interquartile range 2-4) years. Most of the trials (n=40, 69%) had a low risk of bias. Among seven trials reporting data for falls, no evidence was found of an association with antihypertensive treatment (summary risk ratio 1.05, 95% confidence interval 0.89 to 1.24, τ2=0.009). Antihypertensives were associated with an increased risk of acute kidney injury (1.18, 95% confidence interval 1.01 to 1.39, τ2=0.037, n=15), hyperkalaemia (1.89, 1.56 to 2.30, τ2=0.122, n=26), hypotension (1.97, 1.67 to 2.32, τ2=0.132, n=35), and syncope (1.28, 1.03 to 1.59, τ2=0.050, n=16). The heterogeneity between studies assessing acute kidney injury and hyperkalaemia events was reduced when focusing on drugs that affect the renin angiotensin-aldosterone system. Results were robust to sensitivity analyses focusing on adverse events leading to withdrawal from each trial. Antihypertensive treatment was associated with a reduced risk of all cause mortality, cardiovascular death, and stroke, but not of myocardial infarction.ConclusionsThis meta-analysis found no evidence to suggest that antihypertensive treatment is associated with falls but found evidence of an association with mild (hyperkalaemia, hypotension) and severe adverse events (acute kidney injury, syncope). These data could be used to inform shared decision making between doctors and patients about initiation and continuation of antihypertensive treatment, especially in patients at high risk of harm because of previous adverse events or poor renal function.RegistrationPROSPERO CRD42018116860.
IMPORTANCE: Evidence to support initiation of pharmacologic treatment in low-risk patients with mild hypertension is inconclusive, with previous trials underpowered to demonstrate benefit. Clinical ...guidelines across the world are contradictory. OBJECTIVE: To examine whether antihypertensive treatment is associated with a low risk of mortality and cardiovascular disease (CVD) in low-risk patients with mild hypertension. DESIGN, SETTING, AND PARTICIPANTS: In this longitudinal cohort study, data were extracted from the Clinical Practice Research Datalink, from January 1, 1998, through September 30, 2015, for patients aged 18 to 74 years who had mild hypertension (untreated blood pressure of 140/90-159/99 mm Hg) and no previous treatment. Anyone with a history of CVD or CVD risk factors was excluded. Patients exited the cohort if follow-up records became unavailable or they experienced an outcome of interest. EXPOSURES: Prescription of antihypertensive medication. Propensity scores for likelihood of treatment were constructed using a logistic regression model. Individuals treated within 12 months of diagnosis were matched to untreated patients by propensity score using the nearest-neighbor method. MAIN OUTCOMES AND MEASURES: The rates of mortality, CVD, and adverse events among patients prescribed antihypertensive treatment at baseline, compared with those who were not prescribed such treatment, using Cox proportional hazards regression. RESULTS: A total of 19 143 treated patients (mean SD age, 54.7 11.8 years; 10 705 55.9% women; 10 629 55.5% white) were matched to 19 143 similar untreated patients (mean SD age, 54.9 12.2 years; 10 631 55.5% female; 10 654 55.7% white). During a median follow-up period of 5.8 years (interquartile range, 2.6-9.0 years), no evidence of an association was found between antihypertensive treatment and mortality (hazard ratio HR, 1.02; 95% CI, 0.88-1.17) or between antihypertensive treatment and CVD (HR, 1.09; 95% CI, 0.95-1.25). Treatment was associated with an increased risk of adverse events, including hypotension (HR, 1.69; 95% CI, 1.30-2.20; number needed to harm at 10 years NNH10, 41), syncope (HR, 1.28; 95% CI, 1.10-1.50; NNH10, 35), electrolyte abnormalities (HR, 1.72; 95% CI, 1.12-2.65; NNH10, 111), and acute kidney injury (HR, 1.37; 95% CI, 1.00-1.88; NNH10, 91). CONCLUSIONS AND RELEVANCE: This prespecified analysis found no evidence to support guideline recommendations that encourage initiation of treatment in patients with low-risk mild hypertension. There was evidence of an increased risk of adverse events, which suggests that physicians should exercise caution when following guidelines that generalize findings from trials conducted in high-risk individuals to those at lower risk.
The Excited Spin State of 1I/2017 U1 'Oumuamua Belton, Michael J. S.; Hainaut, Olivier R.; Meech, Karen J. ...
Astrophysical journal. Letters,
04/2018, Volume:
856, Issue:
2
Journal Article
Peer reviewed
Open access
We show that 'Oumuamua's excited spin could be in a high-energy long axis mode (LAM) state, which implies that its shape could be far from the highly elongated shape found in previous studies. CLEAN ...and ANOVA algorithms are used to analyze 'Oumuamua's lightcurve using 818 observations over 29.3 days. Two fundamental periodicities are found at frequencies (2.77 0.11) and (6.42 0.18) cycles/day, corresponding to (8.67 0.34) hr and (3.74 0.11) hr, respectively. The phased data show that the lightcurve does not repeat in a simple manner, but approximately shows a double minimum at 2.77 cycles/day and a single minimum at 6.42 cycles/day. 'Oumuamua could be spinning in either the LAM or short axis mode (SAM). For both, the long axis precesses around the total angular momentum vector with an average period of (8.67 0.34) hr. For the three LAMs we have found, the possible rotation periods around the long axis are 6.58, 13.15, or 54.48 hr, with 54.48 hr being the most likely. 'Oumuamua may also be nutating with respective periods of half of these values. We have also found two possible SAM states where 'Oumuamua oscillates around the long axis with possible periods at 13.15 and 54.48 hr. In this case any nutation occurs with the same periods. Determination of the spin state, the amplitude of the nutation, the direction of the total angular momentum vector (TAMV), and the average total spin period may be possible with a direct model fit to the lightcurve. We find that 'Oumuamua is "cigar-shaped," if close to its lowest rotational energy, and an extremely oblate spheroid if close to its highest energy state.
In recent years, national and international guidelines have recommended the use of out-of-office blood pressure monitoring for diagnosing hypertension. Despite evidence of cost-effectiveness, critics ...expressed concerns this would increase cardiovascular morbidity. We assessed the impact of these changes on the incidence of hypertension, out-of-office monitoring and cardiovascular morbidity using routine clinical data from English general practices, linked to inpatient hospital, mortality, and socio-economic status data. We studied 3 937 191 adults with median follow-up of 4.2 years (49% men, mean age=39.7 years) between April 1, 2006 and March 31, 2017. Interrupted time series analysis was used to examine the impact of changes to English hypertension guidelines in 2011 on incidence of hypertension (primary outcome). Secondary outcomes included rate of out-of-office monitoring and cardiovascular events. Across the study period, incidence of hypertension fell from 2.1 to 1.4 per 100 person-years. The change in guidance in 2011 was not associated with an immediate change in incidence (change in rate=0.01 95% CI, −0.18–0.20) but did result in a leveling out of the downward trend (change in yearly trend =0.09 95% CI, 0.04–0.15). Ambulatory monitoring increased significantly in 2011/2012 (change in rate =0.52 95% CI, 0.43–0.60). The rate of cardiovascular events remained unchanged (change in rate =−0.02 95% CI, −0.05–0.02). In summary, changes to hypertension guidelines in 2011 were associated with a stabilisation in incidence and no increase in cardiovascular events. Guidelines should continue to recommend out-of-office monitoring for diagnosis of hypertension.
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