Abstract
Aims
The Hygia Chronotherapy Trial, conducted within the clinical primary care setting, was designed to test whether bedtime in comparison to usual upon awakening hypertension therapy exerts ...better cardiovascular disease (CVD) risk reduction.
Methods and results
In this multicentre, controlled, prospective endpoint trial, 19 084 hypertensive patients (10 614 men/8470 women, 60.5 ± 13.7 years of age) were assigned (1:1) to ingest the entire daily dose of ≥1 hypertension medications at bedtime (n = 9552) or all of them upon awakening (n = 9532). At inclusion and at every scheduled clinic visit (at least annually) throughout follow-up, ambulatory blood pressure (ABP) monitoring was performed for 48 h. During the 6.3-year median patient follow-up, 1752 participants experienced the primary CVD outcome (CVD death, myocardial infarction, coronary revascularization, heart failure, or stroke). Patients of the bedtime, compared with the upon-waking, treatment-time regimen showed significantly lower hazard ratio—adjusted for significant influential characteristics of age, sex, type 2 diabetes, chronic kidney disease, smoking, HDL cholesterol, asleep systolic blood pressure (BP) mean, sleep-time relative systolic BP decline, and previous CVD event—of the primary CVD outcome 0.55 (95% CI 0.50–0.61), P < 0.001 and each of its single components (P < 0.001 in all cases), i.e. CVD death 0.44 (0.34–0.56), myocardial infarction 0.66 (0.52–0.84), coronary revascularization 0.60 (0.47–0.75), heart failure 0.58 (0.49–0.70), and stroke 0.51 (0.41–0.63).
Conclusion
Routine ingestion by hypertensive patients of ≥1 prescribed BP-lowering medications at bedtime, as opposed to upon waking, results in improved ABP control (significantly enhanced decrease in asleep BP and increased sleep-time relative BP decline, i.e. BP dipping) and, most importantly, markedly diminished occurrence of major CVD events.
Trial registration
ClinicalTrials.gov, number NCT00741585.
Objectives We investigated whether reduced cardiovascular risk is more related to the progressive decrease of asleep or awake blood pressure. Background Independent studies have concluded that ...elevated sleep-time blood pressure is a better predictor of cardiovascular risk than awake or 24-h blood pressure means. However, the impact on cardiovascular risk of changes in these ambulatory blood pressure characteristics has not been properly investigated. Methods We prospectively studied 3,344 subjects (1,718 men and 1,626 women), 52.6 ± 14.5 years of age, during a median follow-up of 5.6 years. Those with hypertension at baseline were randomized to ingest all their prescribed hypertension medications upon awakening or ≥1 of them at bedtime. Blood pressure was measured for 48 h at baseline and again annually or more frequently (quarterly) if treatment adjustment was required. Results With data collected at baseline, when asleep blood pressure was adjusted by awake mean, only the former was a significant predictor of outcome in a Cox proportional hazards model also adjusted for sex, age, and diabetes. Analyses of changes in ambulatory blood pressure during follow-up revealed a 17% reduction in cardiovascular risk for each 5-mm Hg decrease in asleep systolic blood pressure mean (p < 0.001), independently of changes in any other ambulatory blood pressure parameter. Conclusions The sleep-time blood pressure mean is the most significant prognostic marker of cardiovascular morbidity and mortality. Most importantly, the progressive decrease in asleep blood pressure, a novel therapeutic target that requires proper patient evaluation by ambulatory monitoring, was the most significant predictor of event-free survival. (Prognostic Value of Ambulatory Blood Pressure Monitoring in the Prediction of Cardiovascular Events and Effects of Chronotherapy in Relation to Risk the MAPEC Study; NCT00295542 )
Background and aims
An early meta‐analysis testing the concurrent validity of the Alcohol Purchase Task (APT), a measure of alcohol's relative reinforcing value, reported mixed associations, but ...predated a large number of studies. This systematic review and meta‐analysis sought to: (1) estimate the relationships between trait‐based alcohol demand indices from the APT and multiple alcohol indicators, (2) test several moderators and (3) analyze small study effects.
Methods
A meta‐analysis of 50 cross‐sectional studies in four databases (n = 18 466, females = 43.32%). Sex, year of publication, number of APT prices and index transformations (logarithmic, square root or none) were considered as moderators. Small study effects were examined by using the Begg–Mazumdar, Egger's and Duval & Tweedie's trim‐and‐fill tests. Alcohol indicators were quantity of alcohol use, number of heavy drinking episodes, alcohol‐related problems and hazardous drinking. APT indices were intensity (i.e. consumption at zero cost), elasticity (i.e. sensitivity to increases in costs), Omax (i.e. maximum expenditure), Pmax (i.e. price associated to Omax) and breakpoint (i.e. price at which consumption ceases).
Results
All alcohol demand indices were significantly associated with all alcohol‐related outcomes (r = 0.132–0.494), except Pmax, which was significantly associated with alcohol‐related problems only (r = 0.064). The greatest associations were evinced between intensity in relation to alcohol use, hazardous drinking and heavy drinking and between Omax and alcohol use. All the tested moderators emerged as significant moderators. Evidence of small‐study effects was limited.
Conclusions
The Alcohol Purchase Task appears to have concurrent validity in alcohol research. Intensity and Omax are the most relevant indices to account for alcohol involvement.
We report the nationwide experience with solid organ transplant (SOT) and hematopoietic stem cell transplant (HSCT) recipients diagnosed with coronavirus disease 2019 (COVID‐19) in Spain until 13 ...July 2020. We compiled information for 778 (423 kidney, 113 HSCT, 110 liver, 69 heart, 54 lung, 8 pancreas, 1 multivisceral) recipients. Median age at diagnosis was 61 years (interquartile range IQR: 52‐70), and 66% were male. The incidence of COVID‐19 in SOT recipients was two‐fold higher compared to the Spanish general population. The median interval from transplantation was 59 months (IQR: 18‐131). Infection was hospital‐acquired in 13% of cases. No donor‐derived COVID‐19 was suspected. Most patients (89%) were admitted to the hospital. Therapies included hydroxychloroquine (84%), azithromycin (53%), protease inhibitors (37%), and interferon‐β (5%), whereas immunomodulation was based on corticosteroids (41%) and tocilizumab (21%). Adjustment of immunosuppression was performed in 85% of patients. At the time of analysis, complete follow‐up was available from 652 patients. Acute respiratory distress syndrome occurred in 35% of patients. Ultimately, 174 (27%) patients died. In univariate analysis, risk factors for death were lung transplantation (odds ratio OR: 2.5; 95% CI: 1.4‐4.6), age >60 years (OR: 3.7; 95% CI: 2.5‐5.5), and hospital‐acquired COVID‐19 (OR: 3.0; 95% CI: 1.9‐4.9).
The authors report the Spanish nationwide experience with solid organ and hematopoietic stem cell transplant recipients diagnosed with COVID‐19, revealing a higher incidence and more aggressive course of infection than in the general population.
Background
The prevalence of cancer patients with concomitant cardiovascular (CV) disease is on the rise due to improved cancer prognoses. The aim of this study is to evaluate the long‐term outcomes ...of cancer patients referred to a cardiology department (CD) via primary care using e‐consultation.
Methods
We analysed data from cancer patients with prior referrals to a CD between 2010 and 2021 (n = 6889) and compared two care models: traditional in‐person consultations and e‐consultations. In e‐consultation model, cardiologists reviewed electronic health records (e‐consultation) to determine whether the demand could be addressed remotely or necessitated an in‐person consultation. We used an interrupted time series regression model to assess outcomes during the two periods: (1) time to cardiology consultation, (2) rates of all‐cause and CV related hospital admissions and (3) rates of all‐cause and CV‐related mortality within the first year after the initial consultation or e‐consultation at the CD.
Results
Introduction of e‐consultation for cancer patients referred to cardiology care led to a 51.8% reduction (95%CI: 51.7%–51.9%) in waiting times. Furthermore, we observed decreased 1‐year incidence rates, with incidence rate ratios (iRRs) IC95% of .75 .73–.77 for CV‐related hospitalizations, .43 .42–.44 for all‐cause hospitalizations, and .87 .86–.88 for all‐cause mortality.
Conclusions
Compared to traditional in‐person consultations, an outpatient care program incorporating e‐consultation for cancer patients significantly reduced waiting times for cardiology care and demonstrated safety, associated with lower rates of hospital admissions.
Central illustration. The electronic consultation model offers care to all patients referred from primary care and allows the physician to decide if an in‐person consultation is necessary. This model reduces waiting times and reduces hospitalizations and mortality rates.
OBJECTIVE: We prospectively investigated in hypertensive patients with type 2 diabetes if bedtime treatment with ≥1 hypertension medications exerts better blood pressure control and cardiovascular ...risk reduction than conventional therapy, in which all medications are ingested in the morning. RESEARCH DESIGN AND METHODS: We conducted a prospective, randomized, open-label, blinded end point trial on 448 hypertensive patients with type 2 diabetes, 255 men/193 women, mean ± SD age 62.5 ± 10.8 years, randomized to ingest all their prescribed hypertension medications upon awakening or ≥1 of them at bedtime. Ambulatory blood pressure was measured for 48 h at baseline and again annually or even more frequently (quarterly) after adjustments in treatment. RESULTS: After a median follow-up of 5.4 years, patients ingesting ≥1 hypertension medications at bedtime showed a significantly lower cardiovascular risk (adjusted by age and sex) than subjects ingesting all medications upon awakening (hazard ratio 0.33 95% CI 0.21-0.54; P < 0.001). The difference between groups in the adjusted risk of major events (cardiovascular death, myocardial infarction, and stroke) was also statistically significant (0.25 0.10-0.61; P = 0.003). Patients treated at bedtime showed significantly lower sleep time blood pressure mean and higher prevalence of controlled ambulatory blood pressure (62.5 vs. 50.9%; P = 0.013). There was a significant 12% cardiovascular risk reduction per each 5 mmHg decrease in asleep systolic blood pressure during follow-up (P < 0.001). CONCLUSIONS: Among patients with diabetes, treatment with ≥1 hypertension medications at bedtime, compared with all medications upon waking, resulted in improved ambulatory blood pressure control and significantly reduced cardiovascular morbidity and mortality.
A quinine‐derived thiourea organocatalyst promoted the highly enantioselective addition of naphthols and activated phenols to ketimines derived from isatins. The reaction afforded chiral ...3‐amino‐2‐oxindoles with a quaternary stereocenter in high yields (up to 99 %) with excellent enantioselectivity (up to 99 % ee). To the best of our knowledge, this transformation is the first highly enantioselective addition of naphthols to ketimines.
Gentle persuasion: A quinine‐derived thiourea organocatalyst was found to promote the asymmetric addition of naphthols and activated phenols to ketimines derived from isatins (see scheme; Boc=tert‐butoxycarbonyl). The reaction under mild conditions afforded chiral 3‐amino‐2‐oxindoles containing a quaternary stereocenter in high yields (up to 99 %) with excellent enantioselectivity (up to 99 % ee).
Time of ingestion of hypertension medications can affect circadian patterns of BP, but whether this translates into an effect on clinical outcomes is unknown. Here, in an open-label trial, we ...randomly assigned 661 patients with CKD either to take all prescribed hypertension medications upon awakening or to take at least one of them at bedtime. We measured 48-hour ambulatory BP at baseline and 3 months after any adjustment in treatment or, at the least, annually. After a median follow-up of 5.4 years, patients who took at least one BP-lowering medication at bedtime had an adjusted risk for total cardiovascular events (a composite of death, myocardial infarction, angina pectoris, revascularization, heart failure, arterial occlusion of lower extremities, occlusion of the retinal artery, and stroke) that was approximately one-third that of patients who took all medications upon awakening (adjusted HR 0.31; 95% CI 0.21 to 0.46; P < 0.001). Bedtime dosing demonstrated a similar significant reduction in risk for a composite outcome of cardiovascular death, myocardial infarction, and stroke (adjusted HR 0.28; 95% CI 0.13 to 0.61; P < 0.001). Furthermore, patients on bedtime treatment had a significantly lower mean sleep-time BP and a greater proportion demonstrated control of their ambulatory BP (56% versus 45%, P = 0.003). Each 5-mmHg decrease in mean sleep-time systolic BP was associated with a 14% reduction in the risk for cardiovascular events during follow-up (P < 0.001). In conclusion, among patients with CKD and hypertension, taking at least one antihypertensive medication at bedtime improves control of BP and reduces the risk for cardiovascular events.
Therapeutic strategies in resistant hypertension include adding another drug or changing drugs in search for a better synergic combination. Most patients, however, receive all of their drugs in a ...single morning dose. We have evaluated the impact on the circadian pattern of blood pressure on modifying the time of treatment without increasing the number of prescribed drugs. We studied 250 hypertensive patients who were receiving 3 antihypertensive drugs in a single morning dose. Patients were randomly assigned to 1 of 2 groups according to the modification in their treatment strategychanging 1 of the drugs but keeping all 3 in the morning or the same approach but administering the new drug at bedtime. Blood pressure was measured for 48 hours before and after 12 weeks of treatment. There was no effect on ambulatory blood pressure when all of the drugs were taken on awakening. The baseline prevalence of nondipping (79%) was slightly increased after treatment (86%; P=0.131). The ambulatory blood pressure reduction was statistically significant (9.4/6.0 mm Hg for systolic/diastolic blood pressure; P<0.001) with 1 drug at bedtime. This reduction was larger in the nocturnal than in the diurnal mean of blood pressure. Thus, whereas only 16% of the patients in this group were dippers at baseline, 57% were dippers after therapy (P<0.001). Results indicate that, in resistant hypertension, time of treatment may be more important for blood pressure control and for the proper modeling of the circadian blood pressure pattern than just changing the drug combination.
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