The Scientometric Study On Chronotherapy And System Review Of Hypertension's Chronotherapy

Part Ⅰ: Scientometric Study on Chronotherapy[Objectives] Scientometrics is a useful tool to analysis and evaluate scientific production of a subject or a special topic. Chronotherapy is a new interdisciplinary subject that has received profound attention recently. It is essential to reveal and assess the current status, research level on chronotherapy in China and in foreign countries, explore the hot topics and developing tendency in the near future. The purpose was to find out the status, hot topics and tendency on chronotherapy, provide some more useful information, e.g. the domain-focused journals, leading authors, geographic distribution for specialists, researchers and system reviewers and give a faster and better way to obtain the information related to chronotherapeautic studies. [Materials and methods] Data for analysis were collected from Chinese biomedical literature databases(CBM) & Chinese Medical Current Contents(CMCC), MEDLINE, EMBASE, All EBM Reviews and Cumulative Index to Nursing & Allied Health(CINAHL) in OVID and ISI Web of Science (Science Citation Index Expanded). The queries for general search were performed and the related articles were retrieved respectively. The full-text databases of Chinese Scientific and Technical Periodicals, Chinese Academic Electronic Journals and foreign electronic journals were used to check the contents. CERM and ProCite5 software were used to manage and analyze the searched papers, assisted by hand-searching and check. Scientometric and bibliometric methods were used to analysis the output, distribution of authors, subject headings, organizations or nations etal. [Results] A total of 172 records were identified from CBM & CMCC dated from 1978 to 2003.They distributed in 131 kinds of journals scattered in many fields, and 47.09% of publications were located in Chinese traditional medicine. There were 104 journals published one article and only one published five articles. The subject headings were about Chinese traditional medicine, cardiovascular diseases, neoplasms, asthma, diabetes mellitus and general review of chronotherapy etc.A total of 831 records were collected from four databases in OVID which came from EMBASE, MEDLINE, All EBM Reviews and CINAHL in descending order. They related to 436 types of publications and distributed in 48 nations and regions. United States of America was the top productive country, supplying together 28.64% sum of research papers. France, Japan, Italy, Germany, United Kingdom, Canada, Russia and China were ranked from the second to the ninth.There were 27 journals that recorded five or more articles respectively, supplying together 30.32% sum of all chronotherapeutic articles. Ten periodicals published by USA and five by UK. Chronobiology International, Pathologie Biologie, European journal of cancer, Seminars in Oncology and Blood Pressure Monitoring were ranked from the first to fifth. There were 11 researchers contributed at least five papers individually, providing 22.86% articles all together, for instance, Levi F was the leading author with 62 papers. There were 10 core institutes which were Paul Brousse Hospital, University of Connecticut School of Medicine, University of Minnesota, Jichi Medical School, City Clinic Hospital No 60, University of Texas, and so on.A total of 260 records were retrieved from SCI dated from 1997 to 2003. Their total cited times were 2208. We found out 8 papers which were totally cited 849 times and the highest one cited by 307 times and the corresponding topics were mainly on chronotherapy in cancer or cardiovascular disease.[Conclusions] The chronological distribution of chronotherapeutic literature suggested that there was a break-through in 1999 and occurred new hot topic related to chronotherapy. It was also showed that a great progress had made in United States, France, Japan, Italy and Germany et al. The domestic articles and publications scattered in many fields before 1993, a slow but stable growth existed in China form 1993 to 1997, and then there was an up-trend in recent seven years and the speed seemed a litter faster than the past.On the basis of data from domestic and abroad, people had pay more and more attentions on chronotherapy in recent years. There was an up-trend in the developed countries where the eminent scientists, core publications and important institutions had formed and taken an important role on the research and application of chronotheray. On contract, no core authors, no core journals or institutes in China up till now.Based on citation data and subject analysis, the hot topics on chronotherapy are in the areas of tumor chemotherapy and cardiovascular disease treatment, especially focusing on control trials of metastatic colorectal cancer and hypertension treatment. Comparing with the foreign researchresults, we found that Chinese medical professionals addressed chronotherapeautic application in traditional medicine many years ago and made a litter progress in cancer chemotherapy in recent seven years.The lists of leading authors, core publication sources, important institutes and geographic distributions relating to chronotherapy provide an available and helpful information and evidence for clinicians and the Cochrane system reviewers.Part Ⅱ: Chronotherapy in Hypertensive Patients— a Cochrane System Review[Objectives] The primary objective was assessment of the long-term effects on morbidity and mortality of chronotherapy regimens as compared to routine or conventional drug therapy regimens in patients with elevated blood pressure, and the evaluation of the economics and compliance of chronotherapy for hypertension. The secondary objectives were to compare the blood pressure lowering efficacy of chronotherapy regimens with routine or conventional regimens and to compare withdrawals due to adverse effects with chronotherapy regimens with routine or conventional regimens.[Materials and methods] Patients with primary hypertension would be included and the secondary hypertension would be excluded. The types of studies were about all randomized or quasi-randomized trials of at least 2-week treatment duration when we assessed the effectiveness and safety. We would include all RCTs and non RCTs relating economics or compliance of chronotherapy for hypertension. MEDLINE (from 1966 to 2004), EMBASE (from 1982 to 2004) and The Cochrane Library and Chinese Biological Medical Database (CBM from 1978 to 2004) and Chinese Medical Current Contents (CMCC from 1982 to 2004) or Ovid Web Online about Evidence-Based-Medicine were searched by using the Cochrane standard search strategy for randomized controlled trials plus the additional terms of ["chronotherapy" or "chronotherapeutic" or "chronomodulated"] and ["hypertension" or "hypertensive" or "blood pressure"]. In addition we searched reference lists of review articles and relevant journals. The reviewers obtained the full text of all potentially relevant studies for independent assessment and independently selected trials for inclusion and exclusion. Disagreement would be resolved by discussion. Two reviewers will independently use a data extraction form to extract data on patients, methods, interventions and outcomes. Missing data would be obtained from the authors whenever possible. The quality of all included trials would be assessed with by two independent reviewers. All included trials would becombined using Review Manager(RevMan)4.2.6. software. For continuous outcomes (BP, HR), the weighted mean difference (WMD) and 95% confidence intervals would be calculated. For dichotomous outcomes, the Peto OR would be calculated with 95% confidence intervals. Funnel plots will be used to test for publication bias. Tests for heterogeneity would be made using a standard chi-square statistic. If heterogeneity was not significant for any of the outcomes, sensitivity analyses would not be performed and a fixed effect model would be used. If significant heterogeneity was found a random effect model will be used, and sensitivity analyses would be performed using methodological quality as a categorizing variable.,(Results] A total of 33 randomized trials including 20375 patients met our inclusion criteria. There were 9 described the methods of allocation sequence, 14 double blind RCTs, 11 reported the masking procedures, 6 ensured adequate allocation concealment, 17 baselines comparable and 6 analyses by intention-to-treat in all the trials. Calcium Channel Blockers(CCBs)5 RCTs compared chrono-drugs with placebo relating changes BP, HR and adverse effect. The data showed that when chrono-durgs verapamil dosage was more than 180 mg, the BP were significantly reduced during the entire 24h, daytime and nighttime (24h SBP/DBP: -3.7mm Hg/-3.6mmHg~-17.3/-13.4mm Hg; daytime SBP/DBP: -5.50mm Hg/-5.20mm Hg~-19.70mm Hg/-15.80mm Hg; nighttime SBP/DBP: -3.50mmHg/-3.30mmHg~-15.30mmHg/-11.80mmHg), and dose-dependently significantly reduced BP. All dosages but COER-verapamil 100mg significantly reduced morning SBP (-6.40 mm Hg~-26.40 mm.Hg) and significantly reduced morning DBP (-3.60 mm Hg~-20.10 mm Hg) . When chrono-drugs were more than 300mg, the HR was significant reduced during the entire 24h (-5.5~-10.4 beats/min) , daytime (-8.00 beats/min 95% CI [-10.63,-5.37] vs -13.70 beats/min 95% CI [-16.32, -11.08] in the 360mg and 540mg, respectively) and nighttime (-3.70 beats/min 95% CI [-6.06,-1.34] vs -6.80 beats/min 95% CI [-9.29. -4.31 ] in the 360mg and 540mg, respectively). The total frequency of adverse effective events were similar between chrono-drug and placebo group (Peto OR 1.08, 95% CI [0.80, 1.47]).4 RCTs compared chrono-drugs with conventional antihypertensive agents. Meta-analysis indicated that conventional antihypertensive agents reduced more on 24 h SBP than chronotherapeutic drugs (WMD=2.57 mm Hg, 95% CI [1.16, 3.97]) , but no significance on 24 h DBP (WMD=0.31 mm Hg, 95% CI [-0.62, 1.24]) .Clinical systolic and diastolic BP were reduced by 13.6 mm Hg and 7.8 mm Hg for the chronotherapeutic group and by 13.5 and 7.1 mm Hg for the routine group. There was no significance on SBP(0.06 mm Hg , 95% CI [-0.44,0.56]), a significance on DBP (95% CI [0.38, 0.95]) , but only a little more reduction in chronotherapeutic group. There were more significant reduction on morning BP and rate-pressureproduct (WMD=-555.84 mmHg×beats/min, 95% CI [-835.77, -271.91], daytime rate-pressure product (-676mmHg×beats/min. 95% CI [-1120.96, -231.04]) in chronotherapeautic group, but similar reduction on night rate-pressure product (47 mmHg×beats/min, 95% CI [-327.12, 421.12]) between two groups. The total frequency of adverse effective events (Peto OR 0.87, 95% CI [0.67, 1.13]) and withdrew due to adverse events (Peto OR 1.09, 95% CI [ 1.00, 1.18]) were similar between chronotherapy and routine treatment group.Differential effects and safety of morning and evening dosing of CCBs on BP and HR were compared in 7 RCTs . The data indicated that both morning dosing and evening dosing similarly reduced the 24h SBP and HR (SBP WMD =-0.58mmHg, 95% CI [-1.80, 0.64]; HR WMD =-0.77 beats/min, 95% CI [-1.69, 0.14]) , but morning dosing more reduced 1.02 mm Hg compared with evening dosing (95% CI [-1.95, -0.09]). The daytime SBP and HR reduction were similar independently the dosing time (SBP WMD =-0.51 mmHg, 95% CI [-2.10, 1.09]; HR WMD =0.32 beats/min, 95% CI [-0.90, 1.55]), but the daytime DBP was greater reduced 1.38 mm Hg in the dosing evening compared to dosing morning(95% CI[-2.40, 0.35]). The nighttime BP reduction were no significant between the dosing morning and dosing evening (SBP WMD=1.01 mm Hg, 95% CI [-0.89, 2.91]; DBP WMD=0.43 mmHg, 95% CI [-1.07, 1.94]),but dosing morning significantly reduced HR (WMD =-2.30 beats/min, 95% CI [-3.32, -1.29]).The BP and HR of CCBs dosing evening significantly reduced during morning compared to dosing morning (SBP WMD =2.78 mmHg, 95% CI [0.98, 4.57]; DBP WMD =1.99 mmHg, 95% CI [0.66, 3.31]; HR WMD =2.68 beats/min, 95% CI [1.12, 4.23]) . There was no significant diffenence observed in the adverse effect (headache, constipation and cough) between morning vs evening dosing. Angiotensin-Converting Enzyme Inhibitors(ACEI)The available data indicated that the BP reduction were similar for both morning and evening administration during entire 24h (SBP WMD=1.76 mmHg 95% CI [-2.79, 6.31], DBP WMD=1.93mm Hg 95% CI[-3.16, 7.03]) .daytime (SBP WMD=-1.37 mmHg 95% Cl [-4.65, 1.91], DBP WMD=-1.20 mmHg 95% CI [-3.40, 1.01]) , nighttime (SBP WMD=2.71 mmHg 95% CI [-0.84, 6.25], DBP WMD=1.62 mmHg 95% CI [-0.77, 4.01]) and clinical BP (SBP WMD=-0.28 mmHg 95%CI[-3.15, 2.58]-, DBP WMD=-0.07 mmHg95%CI [-2.22, 2.08]) in6 RCTs, but the morning BP were highly significant reduced with evening administration compared with moming(SBP 13 mmHg 95% CI [10.44, 15.56], DBP 10 mm Hg 95% CI [7.22, 12.78]. Both treatment time had no effects on HR during the 24h period (WMD=0.70 beats/min, 95% CI [-2.31, 3.70]) .daytime (WMD=-2.13 mmHg 95% CI [-5.70, 1.43]) and nighttime (-0.05 beats/min 95% CI [WMD=-3.22, 3.12]) .The available data suggested that chronotherapy of ACEI significantly reduced the BPthroughout the entire 24h (SBP-1.90 kPa 95% CI [-2.24, -1.56], DBP-1.00 kPa 95% CI [-1.29, -0.71]) and the early morning (SBP -3.20 kPa 95% CI [-3.79, -2.61], DBP -1.10 kPa 95% CI [-1.48, -0.72]) . Angiotensin II Receptor Blockers(ARBs)The data suggested that both morning and evening administration of ARBs single had no effects on clinical BP (SBP -0.40 mmHg 95% CI [-7.80, 7.00], DBP -0.60 mmHg 95% CI [-5.15, 3.95]) , daytime BP (SBP 1.30 mmHg 95% CI [-6.62, 9.22], DBP-0.10 mmHg 95% CI [-7.01, 6.81]) and nighttime BP (SBP-3.20 mmHg 95% CI [-18.60, 12.20], DBP 0.00 mmHg 95% CI [-9.96, 9.96]) in 2 RCTs. The timing of ARBs single administration had no effects on HR during daytime and nighttime.The data showed that chronotherapy of combined ARBs significantly reduced 3 mmHg DBP (95% CI [-5.32, -0.68]) during 24h period compared with routine therapy in 2 RCTs, but no effect on daytime BP (SBP: 2.00 mmHg 95% CI [-0.79, 4.79], DBP: 1.00 mmHg 95% CI [-0.52, 2.52]). Chronotherapy significantly reduced 4 mm Hg SBP (95% CI [-6.29, -1.71]) and 5 mm Hg DBP (95% CI [-6.52, -3.48]) during nighttime compared with routine therapy. Alpha-blockersThe data indicated that both morning and evening administrations of a -blockers single had no effects on seated, lying and standing BP and HR in 2 RCTs. Polytherapy of a -blockers significantly reduced BP independently from dosing time (SBP: -5.60 mm Hg 95% CI [-16.30. 5.10]; DBP: -3.40 mmHg 95% CI [-9.83, 3.03]) . DiureticData from a trial related to the influence of long-acting diuretic administration time indicated that there were similar BP reductions on day time DBP (0.00 mmHg, 95%CI[-4.04, 4.04]) and night time BP (SBP: -2.00 mmHg, 95%CI[-6.74, 2.74]; DBP: 0.00 mmHg, 95% CI [-3.42, 3.42]) . ComplianceThe available data indicated that there was no significance difference of drug compliance between morning dosing and evening dosing groups. Cardiovascular Disease-related EventsThere were 364 primary cardiovascular disease-related events that occurred in the chronotherapy group vs 365 in routine group, the Peto OR was 1.01 (95% CI, 0.87 to 1.17; P = 0.87). For fatal or nonfatal stroke, Peto OR was 1.15 (95% CI, 0.89 to 1.47; P = 0.29). For fatal or nonfatal myocardial infarction, Peto OR was 0.81 (95% CI, 0.64 to 1.02; P = 0.07) , and for cardiovascular disease-related death, Peto OR 1.08 (95% CI, 0.86 to 1.36; P = 0.51) . The PetoOR was 1.04 (95% CI, 0.94 to 1.16; P = 0.44) for any prespecified cardiovascular disease-related event and 1.07(95% CI, 0.92 to 1.26; P = 0.37) for all-cause mortality. Nonstroke hemorrhage was more common with participants in the COER-verapamil group (n = 118) compared with the atenolol or hydrochlorothiazide group (n = 79) and Peto OR was 1.51 (95% CI, 1.14 to 2.01; P = 0.004 ) . For death or hospitalization due to serious adverse event, Peto OR was 1.03 (95%CI, 0.95 to 1.12; P = 0.43) . [Conclusions]The available evidence suggested that chronotherapeutic agents were effective in blood pressure control in those selected for entry into these trials, provided dose-dependent significantly reduced BP in all related intervals e.g. 24 h, day or night time, in the morning or evening et al. Further more significant reduction of BP and rate pressure product were obtained during the morning period when circadian BP was highest compared with other conventional once-daily antihypertensive agents or placebo. The total frequency of adverse effective events was similar between chrono-drug and placebo group or between chronotherapy and routine treatment group. Chronotherapeutic agents were safe, well tolerated.The available evidence indicated that the effectiveness of chrono-drugs of CCBs in reducing cardiovascular disease was similar but not better than diuretic or beta-blocker treatment.Except the morning BP, the data from the dosing time of CCBs and ACEI between morning and evening indicated that there had no significant difference on BP reduction during the every time intervals of the 24 h period. The drug induced morning systolic and diastolic BP significantly reduction in the evening dosing group. The compliance of morning dosing was similar with evening dosing. Side effects were generally safe, well tolerated, irrespective of the time administration.