• <tr id="yyy80"></tr>
  • <sup id="yyy80"></sup>
  • <tfoot id="yyy80"><noscript id="yyy80"></noscript></tfoot>
  • 99热精品在线国产_美女午夜性视频免费_国产精品国产高清国产av_av欧美777_自拍偷自拍亚洲精品老妇_亚洲熟女精品中文字幕_www日本黄色视频网_国产精品野战在线观看 ?

    Beta-blocker therapy in elderly patients with renal dysfunction and heart failure

    2021-03-03 07:32:36JuanMartnezMillaMarcelinoCortGarcJuliaAnnaPalfyMikelTaiboUrquMartapezCastilloAnaDevesaArbiolAnaLucRiveroMonteagudoMarLuisaMartMariscalInJimnezVarasSemBriongosFigueroJuanAntonioFrancoPelaJosTu
    Journal of Geriatric Cardiology 2021年1期
    關(guān)鍵詞:截?cái)嘀?/a>符合率比值

    Juan Martínez-Milla?, Marcelino Cortés García, Julia Anna Palfy, Mikel Taibo Urquía,Marta López Castillo, Ana Devesa Arbiol Ana Lucía Rivero Monteagudo,María Luisa Martín Mariscal, Inés Jiménez-Varas, Sem Briongos Figuero,Juan Antonio Franco-Pelaéz, José Tu?ón,7,8

    1. Department of Cardiology, Hospital Universitario Fundación Jiménez Díaz-Quirónsalud; 2. Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain; 3. Department of Cardiology, Hospital Central de Asturias; 4. Department of Cardiology, Hospital Universitario Ruber-Quirónsalud; 5. Department of Cardiology, Hospital Universitario Infanta Leonor; 6. Department of Endocrinology, Hospital Clínico San Carlos; 7. Universidad Autónoma de Madrid; 8. CIBERCV,Madrid, Spain

    ABSTRACT OBJECTIVE To assess the role of beta-blockers (BB) in patients with chronic kidney disease (CKD) aged ≥ 75 years.METHODS AND RESULTS From January 2008 to July 2014, we included 390 consecutive patients ≥ 75 years of age with ejection fraction ≤ 35% and glomerular filtration rate (GFR) ≤ 60 mL/min per 1.73 m2. We analyzed the relationship between treatment with BB and mortality or cardiovascular events. The mean age of our population was 82.6 ± 4.1 years. Mean ejection fraction was 27.9% ± 6.5%. GFR was 60?45 mL/min per 1.73 m2 in 50.3% of patients, 45?30 mL/min per 1.73 m2 in 37.4%, and < 30 mL/min per 1.73 m2 in 12.3%. At the conclusion of follow-up, 67.4% of patients were receiving BB. The median follow-up was 28.04 (IR: 19.41?36.67) months. During the study period, 211 patients (54.1%) died and 257 (65.9%) had a major cardiovascular event (death or hospitalization for heart failure). BB use was significantly associated with a reduced risk of death (HR = 0.51, 95%CI: 0.35?0.74; P < 0.001). Patients receiving BB consistently showed a reduced risk of death across the different stages of CKD:stage IIIa (GFR = 30?45 mL/min per 1.73 m2; HR = 0.47, 95% CI: 0.26?0.86, P < 0.000 1), stage IIIb (GFR 30?45 mL/min per 1.73 m2; HR = 0.55, 95% CI: 0.26?1.06, P = 0.007), and stages IV and V (GFR < 30 mL/min per 1.73 m2; HR = 0.29, 95% CI: 0.11?0.76; P =0.047).CONCLUSIONS The use of BB in elderly patients with HFrEF and renal impairment was associated with a better prognosis.Use of BB should be encouraged when possible.

    Heart failure (HF) is one of the most prevalent cardiovascular (CV) disorders worldwide. Approximately half of all patients with HF have reduced or mid-range ejection fraction.[1,2]Due to their negative inotropic action, for many years beta-blockers (BB) were contraindicated in patients with HF. Toward the end of the last century, however, these drugs were shown to have highly positive effects in patients with HF.Since then, they have become a cornerstone in the treatment of HF with systolic dysfunction,[3]and the most recent clinical practice guidelines encourage BB use to reduce mortality and CV events.[4,5]

    Despite such advances, data remain scarce on the role of these drugs in elderly patients with chronic kidney disease (CKD). Classically, both elderly and CKD patients have been underrepresented in clinical trials, creating a gap in the evidence base. In addition, CKD is highly prevalent among elderly patients with HF and reduced ejection fraction(HFrEF).[6]As a result, though HF drugs (e.g., Angiotensin-Converting Enzyme inhibitors (ACEi)/Angiotensin Receptor Blockers (ARB), BB, Mineralocorticoid Receptor Antagonist (MRA), Angiotensin Receptor-Neprilysin Inhibitors (ARNI))provide a substantial cardiovascular (CV) benefit,the underrepresentation of elderly patients with CKD in the primary clinical trials and the existence of side effects may limit their use.[6,7]As well as ACEi/ARB and MRA,[8]the elderly may be less likely to receive BB than other populations with HFrEF,particularly in cases with associated CKD, despite the fact that there is no clear reason to avoid this medication.[9]Our study analyzes the role of BB therapy in elderly patients with HFrEF and CKD.

    METHODS

    Patients

    We carried out a single-center, observational cohort study. From January 2008 to July 2014, we consecutively enrolled 802 patients 75 years of age or older with left ventricular ejection fraction (LVEF) ≤35% as measured by 2-dimensional echocardiography. Of the total population, 390 had renal impairment, defined as a glomerular filtration rate(GFR) < 60 mL/min per 1.73 m2.

    A specific database compiled in the cardiac imaging department of Hospital Fundación Jiménez Díaz (Madrid, Spain) was used to screen for patients meeting both criteria. All patients underwent regular medical supervision according to their symptoms and the indications of their physician(cardiologists or general practitioners) to optimize treatment.

    This investigation was carried out in accordance with the principles outlined in the Declaration of Helsinki.

    Outcomes and Follow-up

    The outcomes analyzed in our study were the rate of all-cause death and major CV events. Here,CV events included death from any cause or admission due to HF. HF admission was defined as admission to a health-care facility lasting > 24 h due to the worsening of HF symptoms and followed by specific treatment for HF (regardless of the cause of cardiac decompensation). Data on clinical events and death during follow-up were collected from patients’ electronic health records or, if unavailable,from telephone interviews with patients or relatives.

    Statistical Analysis

    Data were subjected to descriptive statistical analysis via frequency measurements (absolute frequencies and percentages) for qualitative variables and using mean and standard deviation for quantitative variables. The magnitude of the effects of the variables was expressed as hazard ratio (HR) and 95% confidence interval (95% CI). Univariate analysis of the quantitative variables was performed using the Student t test when the variables were normally distributed, and the Mann-Whitney U test when distribution was not normal. Qualitative variables were analyzed using the χ2or the Fisher exact test.

    Because observational studies do not allow for randomization, we planned 2 different approaches to avoid potential confounding factors: multivariate Cox proportional hazard and propensity score(PS)-matched analysis. These two analyses were used to determine significant predictors of CV events and mortality. First, we performed a multivariate analysis with Cox (backward stepwise) regression. Of all the baseline variables collected, we selected those with the potential to act as confounding factors. The selection criteria were as follows:first, clinical and biological plausibility and, second,the statistical criterion of Mickey, excluding all those variables that returned a P value > 0.20 on univariate analysis. Second, we performed a PS-matched analysis. The PS was calculated by means of an ordered logistic regression model, taking the BB group as the dependent variables and adopting a parsimonious approach. In a first step, all the following variables were included in the univariate analysis: age, gender, hypertension, diabetes mellitus, obesity, GFR, chronic obstructive pulmonary disease (COPD), peripheral vascular disease, any degree of cognitive impairment, any degree of functional disability, ischemic origin of reduced EF, previous HF admission, sinus rhythm, wide QRS complex, LVEF, and New York Heart Association (NYHA)Class I or II (vs. III, IV, or not available) at initiation of follow-up. All variables with a P-value < 0.2 were entered into a multivariate binary logistic regression model, which served to estimate the PS of every patient. Patient matching was performed at a 1:1 ratio with the nearest neighbor method (caliper =0.2 × SD [logitPs]).

    Results are expressed as hazard ratio (HR) and 95% CI. Statistical analyses were performed with SPSS version 22.0 (SPSS, Inc, Chicago IL, USA).

    RESULTS

    Baseline Characteristics

    During the study period, 802 consecutive patients with LVEF ≤ 35% were assessed for eligibility.Of these, 390 patients were included due to associated renal impairment. Table 1 shows the baseline characteristics of our population. In terms of sex,62.3% were male, and the mean age was 82.6 ± 4.1 years. Mean LVEF was 27.9% ± 6.5%. An ischemic etiology was found in 50.6% of cases. GFR was between 60 and 45 mL/min per 1.73 m2in 50.3% of patients, 45?30 mL/min per 1.73 m2in 37.4%, and <30 mL/min per 1.73 m2in 12.3%.

    At the end of follow-up (32 ± 23 months), 263(67.4%) patients were undergoing treatment with BB. The most commonly used BB by type was bisoprolol once daily in 143 (54.4%) patients followed by carvedilol twice daily in 111 (42.2%) patients,metoprolol twice daily in 6 (2.3%) patients, and nebivolol once daily in 3 (1.1%) patients. Chronic lung disease (32.4%), followed by bradycardia (9.0%), asthenia (4.5%), and deterioration of HF (4.5%) were the most frequent reasons why study subjects did not take BB; however, in 29.7% of these patients no formal contraindication was found. Dose levels of BB used are shown in Table 2 for both the entire population and according to GFR.

    2.3 驗(yàn)證預(yù)測(cè)效果 驗(yàn)證組平均sFlt-1(3 207.79±3 206.82)pg/ml,平均PLGF(729.30±756.96)pg/ml,平均sFlt-1/PLGF(12.87±22.76),取sFlt-1/PLGF比值12.68作為截?cái)嘀?,統(tǒng)計(jì)出驗(yàn)證組的靈敏度為80.0%,特異度為92.6%,符合率為90.6%。

    Outcomes

    After a median follow-up of 28.04 (IR: 19.41?36.67) months, 211 patients (54.1%) died and 257 patients (65.9%) developed a major CV event (death or hospitalization for HF). Of the patients who died,the cause of death was CV in 56 cases (26.5%), and non-CV causes accounted for 73 deaths (34.6%). We were unable to determine the cause of death in 82 patients (38.9%). Regarding HF hospitalization alone, 146 patients (37.4%) of the total study population were admitted due to HF decompensation.We performed a multivariate analysis (Cox regression) of our study population in order to identify significant predictors of total mortality, following the methodology described above. In similar fashion, we performed another multivariate analysis(Cox regression) to determine significant predictors of CV events. Tables 3 and 4 show the results of univariate and multivariate analyses of overall mortality (Table 3) and CV events (Table 4). A multivariate Cox regression analysis revealed that the use of BB was significantly associated with lower mortality rates (HR = 0.53, 95% CI: 0.37?0.78, P logrank < 0.001), as compared with patients not receiving BB (Figure 1A). However, BB use was not significantly associated with differences in CV events.When we used propensity score matching specifically aimed at analyzing the role of BB in our population, we found that BB had benefited our population, producing a difference that reached statistical significance (HR = 0.45, 95% CI: 0.27?0.75, P =0.002) (Figure 1B). Similarly, we found no relationship between BB and CV events. Finally, a multivariate Cox analysis considering HF hospitalization alone revealed no relation between BB and a reduction in HF admissions; only ACEi/ARBs played a protective role in this regard (HR = 0.467; 95%CI: 0.313?0.696).

    When we analyze the role of BB according to eGFR, we see similar results throughout the study population. In the subgroup of patients with stage IIIa CKD (GFR 45?60/min per 1.73 m2), BB significantly reduced mortality (HR = 0.47; 95% CI:0.26?0.86; P log-rank < 0.000 1); the same was true for patients with stage IIIb (GFR = 30?45/min per 1.73 m2; HR = 0.55, 95% CI: 0.26?1.06; P log-rank =0.007) and stages IV and V disease (GFR < 30 mL/min per 1.73 m2; HR = 0.29, 95% CI: 0.11?0.76; P log-rank =0.047) (Figure 2).

    When we analyzed the population by BB dose, no differences in the mean dose of bisoprolol and carvedilol were found between the different glomerular filtration groups. A similar analysis was not done for metoprolol and nebivolol because of their low rate of use in our population.

    Table 1 Baseline characteristics.

    DISCUSSION

    Blocking the adrenergic system with BB has proven effectiveness in patients with HFrEF,[3]and this treatment is currently included in clinical guidelines.[4,5]A closer look at the studies reporting evidence in support of using these drugs, however,reveals that the populations studied present a relatively low number of comorbidities, with few patients over 75 years of age (average age commonly under 65 years),[10,11]making these studies unrepresentative of routine clinical practice.[12]Elderly patients make up a substantial portion of the population with severe left ventricular dysfunction,[9]and the rate of renal failure in this cohort is often 3-fold higher than that of the general population.[13]In addition, these patients have a higher proportion of other comorbidities and polypharmacy, and more than 70% of HF patients older than 80 years fulfil frailty criteria.[14,15]These differences are important to bear in mind when interpreting the results of randomized clinical trials on BB, and nowadays, specific data remain limited and controversial.[16]

    Table 2 Daily doses of beta-blockers used.

    Table 3 Univariate and multivariate analysis of overall mortality.

    Although the available evidence on BB therapy in patients > 70 years with HFrEF is limited, recent studies support the use of these drugs. The SENIORS trial compared the use of BB against a placebo in patients over 70 years of age with HF;[17]all patients included in the study had a clinical history of chronic HF with one or both of the following features: documented hospital admission within the previous 12 months with a discharge diagnosis of congestive HF or documented LVEF ≤ 35% within the previous 6 months. The trial demonstrated a correlation between nebivolol use and a significant(14%) reduction of the primary end-point, a composite of all-cause mortality or cardiovascular hospital admission. Though a secondary end-point, no favorable impact of nebivolol on all-cause mortality was demonstrated (HR = 0.88, 95% CI: 0.71?1.08;P=0.21).[18]We believe that the main difference between the SENIORS study and both our study and pivotal clinical trials is the inclusion of patients with preserved LVEF, since 35% of patients were reported to have LVEF > 35%. In fact, no treatment has demonstrated a clear survival benefit among patients with preserved LVEF-HF.[4,5]There is a lack of robust data evidencing decreased mortality associated with BB administration in the elderly population. Hernandezet al., in the OPTIMIZE-HF registry, suggest that BB are beneficial in elderly patients with HFrEF.[16]Few studies have reported clear benefit of BB in elderly population in terms of mortality. Our group conducted a retrospective, observational study in elderly patients (> 75 years) with HFrEF, concluding that BB therapy improves survival in patients with LVEF lesser than or equal to 0.35, although this effect seems unrelated to the dose received (P= 0.025).[18]

    Table 4 Univariate and multivariate analysis of cardiovascular events.

    Figure 1 All-cause mortality in overall population. (A): Kaplan-Meier curve showing all-cause mortality in the overall population,comparing the group under beta-blocker therapy (green) against the group not receiving this treatment (blue); (B): Kaplan-Meier curve showing all-cause mortality, comparing the group under beta-blocker therapy (green) versus the group that did not use beta-blockers(blue), after propensity score matching.

    Another issue to take into account when evaluating these patients is CKD status. We know this disorder is more prevalent in patients with HF and has an important influence on prognosis.[19,20]In addition, we know that the presence of CKD in HF patients affects the prescription, dosage, and maintenance of therapies that have demonstrated benefits in HFrEF.[4,5]In addition, advanced-stage CKD was an exclusion criterion in many of the clinical trials analyzing the role of BB therapy in patients with HFrEF.[21]Furthermore, those studies that have examined the role of BB therapy in this group of patients are mostly observational in design, and the endpoints used are less relevant (i.e., other than major factors or nonfatal clinical events).[22,23]Despite this lack in the knowledge base, presence of CKD is one of the primary factors associated with increased mortality.[22]

    Most clinical trials carried out to date use exclusion criteria based on glomerular filtration rate(GFR), and as a result patients with Stage I and II kidney disease are well-represented (GFR > 90 mL/min per 1.73 m2and 60?89 mL/min per 1.73 m2, respectively).[24,25]However, this representativeness decreases at lower GFR, and the available data on patients at stage IV and V are scant.

    This pattern can be seen in the classical studies investigating the role of BB therapy in HFrEF patients with associated Stage-IIIa, Stage-IIIb, and Stage-IV-V CKD(25). Although there is no strong evidence of the effect of BB in CKD, stage III is better represented in the different clinical trials. In the MERIT-HF trial (metoprolol vs placebo), which included patients with HFrEF, there was a significant relative risk reduction in the composite endpoint of CV hospitalization/all-cause mortality in patients with GFR of 45?60 mL/min per 1.73 m2(HR = 0.68(0.52?0.90)) and even in patients with GFR < 45 mL/min per 1.73 m2.[26]

    In the CIBIS-II trial on the effect of bisoprolol in patients with HFrEF, BB significantly reduced the mortality and HF-related hospital stay in the subgroup of patients with GFR <60 mL/min per 1.73 m2as well as those with GFR < 45 mL/min per 1.73 m2.[27]As in the SENIORS trial in patients with reduced GFR, the effect of BB was not different from the effect in patients with GFR above 60 mL/min per 1.73 m2.[28]Finally, a meta-analysis of the effect of carvedilol in the COPERNICUS (Carvedilol Prospective Randomized Cumulative Survival) and CAPRICORN (Carvedilol Post Infarct Survival Control in LV Dysfunction) trials showed that this BB significantly improved outcome in patients with eGFR between 45 and 60 mL/min per 1.73 m2.There was no interaction between the effect of carvedilol treatment and eGFR categories (< 45vs.45 to 60 mL/min per 1.73 m2).[29]

    Stages IV and V are not well-represented, though data from both the MERIT-HF and CIBIS-II trials suggest that BB are effective in patients with CKD stage IIIb-V(26,27). Specially, in the MERIT-HF study, the metoprolol/placebo hazard ratio was 0.41 (95% CI: 0.25 to 0.68) in the 493 patients with eGFR < 45 mL/min per 1.73 m2(12% of the whole study population). This subgroup had a mean eGFR of 36.6 ± 6.8 mL/min per 1.73 m2, which included patients with eGFR < 30 mL/min per 1.73 m2.[26]In the SENIORS study, only 3.1% of patients had stage IV CKD, but no subgroup analysis has been performed on these patients.[28]However, only 8% of all patients in these studies had stage 4 CKD. In a small trial of hemodyalisis patients with HF, carvedilol significantly improved the secondary combined endpoint of all-cause mortality and CV death.[30]

    Recently, Kotecha,et al.[31]published the largest meta-analysis including patients with left ventricular dysfunction and CKD. The authors considered 10 double blind placebo-controlled trials that included more than 16,000 patients. They found that BB reduced the relative risk of all-cause mortality by 27% (95% CI: 0.62?0.86) in patients with GFR of 45?60 mL/min per 1.73 m2and 29% (95% CI:0.58?0.87) in those with a GFR of 30?44 mL/min per 1.73 m2. This benefit was only seen in patients in sinus rhythm. In patients with GFR < 30 mL/min per 1.73 m2there were no enough patients to draw conclusions due to the exclusion criteria of the different trials.[31]

    Concern for increased toxicity often leads clinicians to undertreat these patients with CKD, causing less therapeutic resources to be devoted to individuals with myocardial infarction and concomitant CKD.[32]However, it has been shown that these therapeutic measures are beneficial in this population.[33]

    Our population is particularly elderly (mean age,82.6 ± 4.1 years), and as such is representative of the individuals we treat in our daily practice. There is currently no solid evidence on the role of BB in the elderly population with HF and CKD. Given this lack of data about the role of BB in this common population: elderly with HF and CKD. For this reason, we believe that our findings are relevant for overall practice. We found a significant reduction in all-cause mortality, and this benefit was maintained when separately assessing the role of BB treatment in advanced CKD patients (< 45 mL/min per 1.73 m2), as the protective effect of this treatment continues to be statistically significant in terms of all-cause mortality. The effect of treatment with BB is neutral, however, when we isolate the variable of mortality. The high rate of associated cardiovascular co-morbidities may have attenuated the beneficial effect of BB therapy in our study population in terms of CV events.

    In sum, according to our data, treatment with BB in elderly patients presenting HFrEF and CKD was associated with a lower rate of all-cause mortality.Our data thus show that BB therapy could improve the prognosis of this selected population when there is no formal contraindication for its use.

    STUDY LIMITATIONS

    Our study has certain limitations. First, the study population is relatively small, which could influence the statistical results. In addition, it is a retrospective, non-randomized study using a historical cohort from a single center. A third limitation is the relatively short follow-up period, potentially masking a long-term benefit of BB in reduction of CV events. Nevertheless, this last issue is less relevant due to the short life expectancy of elderly patients and the higher number of CV events they present.Lastly, we were unable to discern the cause of death in 82 (38.7%) patients as this information was lacking from their clinical records.

    CONCLUSIONS

    According to our results, use of BB is significantly associated with a reduction in all-cause mortality in elderly patients with HFrEF and CKD irrespective of GFR. As a result, these drugs may be beneficial for these patients provided there are no formal contraindications. Nevertheless, this is an observational study and that residual confounding may exist.

    ACKNOWLEDGMENTS

    To Oliver Shaw for editing the manuscript for aspects related to English language usage and style.

    猜你喜歡
    截?cái)嘀?/a>符合率比值
    ROC曲線在河源市新生兒G6PD缺乏癥篩查截?cái)嘀抵械膽?yīng)用
    中國(guó)實(shí)用醫(yī)藥(2020年24期)2020-09-24 03:10:13
    彩色多普勒超聲檢查在診斷乳腺良惡性腫瘤中的應(yīng)用價(jià)值
    海南省新生兒先天性甲狀腺功能減低癥流行病學(xué)特征及促甲狀腺激素篩查截?cái)嘀档脑O(shè)定
    CT與MRI在宮頸癌分期診斷中的應(yīng)用效果分析
    CT、MRI在眼眶海綿狀血管瘤與眼眶神經(jīng)鞘瘤影像學(xué)鑒別診斷中的研究
    比值遙感蝕變信息提取及閾值確定(插圖)
    河北遙感(2017年2期)2017-08-07 14:49:00
    不同應(yīng)變率比值計(jì)算方法在甲狀腺惡性腫瘤診斷中的應(yīng)用
    論連分?jǐn)?shù)的應(yīng)用
    雙電機(jī)比值聯(lián)動(dòng)控制系統(tǒng)
    五月开心婷婷网| 在线观看国产h片| 国产又色又爽无遮挡免| 欧美极品一区二区三区四区| 亚洲综合精品二区| 在线观看av片永久免费下载| 啦啦啦视频在线资源免费观看| 另类亚洲欧美激情| 亚洲av成人精品一区久久| av在线app专区| 能在线免费看毛片的网站| 午夜福利网站1000一区二区三区| 日韩 亚洲 欧美在线| 亚洲av.av天堂| 一级毛片aaaaaa免费看小| 国产精品人妻久久久久久| 极品少妇高潮喷水抽搐| 久热久热在线精品观看| 久久综合国产亚洲精品| 久久97久久精品| 日韩av不卡免费在线播放| 美女脱内裤让男人舔精品视频| 日韩 亚洲 欧美在线| 国产精品女同一区二区软件| 成人特级av手机在线观看| 欧美激情国产日韩精品一区| 国产成人a区在线观看| 久久这里有精品视频免费| 国产伦在线观看视频一区| 国产av一区二区精品久久 | av在线app专区| 五月天丁香电影| 国产免费一区二区三区四区乱码| 内射极品少妇av片p| 免费看日本二区| av在线app专区| av视频免费观看在线观看| 亚洲欧美成人精品一区二区| 高清毛片免费看| 丝袜喷水一区| 十八禁网站网址无遮挡 | 国产成人a区在线观看| 性色av一级| 99热6这里只有精品| 少妇人妻精品综合一区二区| 国产精品伦人一区二区| 麻豆精品久久久久久蜜桃| 美女cb高潮喷水在线观看| 少妇人妻久久综合中文| 亚洲成人中文字幕在线播放| 亚洲精品aⅴ在线观看| 亚洲国产高清在线一区二区三| 1000部很黄的大片| 2022亚洲国产成人精品| 制服丝袜香蕉在线| 午夜福利在线在线| 中文欧美无线码| 日本与韩国留学比较| 看非洲黑人一级黄片| 久久久久久九九精品二区国产| 久久精品熟女亚洲av麻豆精品| 狂野欧美白嫩少妇大欣赏| 狂野欧美激情性bbbbbb| 99久久人妻综合| 乱系列少妇在线播放| av又黄又爽大尺度在线免费看| 亚洲欧美精品专区久久| 边亲边吃奶的免费视频| 久久久久久九九精品二区国产| 亚洲av中文av极速乱| 最近最新中文字幕大全电影3| 超碰97精品在线观看| 最近2019中文字幕mv第一页| 黄色视频在线播放观看不卡| 国精品久久久久久国模美| 久久午夜福利片| 久久 成人 亚洲| 亚洲四区av| 性色av一级| 男人狂女人下面高潮的视频| 欧美97在线视频| 国产免费又黄又爽又色| av视频免费观看在线观看| 国产伦在线观看视频一区| 看十八女毛片水多多多| 肉色欧美久久久久久久蜜桃| 亚洲一区二区三区欧美精品| 国产一区二区在线观看日韩| 亚洲av男天堂| 免费看不卡的av| 十八禁网站网址无遮挡 | 久久毛片免费看一区二区三区| av在线老鸭窝| 黄色一级大片看看| 黄色视频在线播放观看不卡| a级毛色黄片| 国产高清三级在线| 一个人看视频在线观看www免费| 夜夜看夜夜爽夜夜摸| 2022亚洲国产成人精品| 精品国产三级普通话版| 国产一区二区在线观看日韩| 亚洲国产精品专区欧美| 精品国产三级普通话版| 色哟哟·www| 日本wwww免费看| 26uuu在线亚洲综合色| 少妇被粗大猛烈的视频| av在线蜜桃| 亚洲av福利一区| 九九久久精品国产亚洲av麻豆| 只有这里有精品99| 中文天堂在线官网| 肉色欧美久久久久久久蜜桃| 亚洲最大成人中文| 欧美日本视频| 国产亚洲av片在线观看秒播厂| 伊人久久国产一区二区| 麻豆精品久久久久久蜜桃| 久久人人爽人人片av| 国产淫语在线视频| 久久精品夜色国产| 在线观看人妻少妇| 国产精品99久久99久久久不卡 | 久久综合国产亚洲精品| 2021少妇久久久久久久久久久| 在线观看三级黄色| 国产精品女同一区二区软件| 亚洲国产av新网站| 看非洲黑人一级黄片| 国产亚洲5aaaaa淫片| 在线观看免费日韩欧美大片 | 久久97久久精品| 97精品久久久久久久久久精品| 综合色丁香网| 午夜老司机福利剧场| 狂野欧美激情性xxxx在线观看| 国模一区二区三区四区视频| 精品久久久久久久久av| 久久韩国三级中文字幕| 日韩中文字幕视频在线看片 | 97精品久久久久久久久久精品| 丝袜脚勾引网站| 久久97久久精品| av女优亚洲男人天堂| 美女xxoo啪啪120秒动态图| 亚洲欧美日韩另类电影网站 | 欧美97在线视频| 亚洲av中文字字幕乱码综合| 免费黄频网站在线观看国产| 精品亚洲成国产av| 纯流量卡能插随身wifi吗| 狠狠精品人妻久久久久久综合| 欧美精品亚洲一区二区| 超碰97精品在线观看| 一本一本综合久久| 女人十人毛片免费观看3o分钟| 久久精品久久精品一区二区三区| 男女国产视频网站| 青青草视频在线视频观看| 国国产精品蜜臀av免费| 美女xxoo啪啪120秒动态图| 国产成人精品婷婷| 一二三四中文在线观看免费高清| 自拍欧美九色日韩亚洲蝌蚪91 | 久久久久精品久久久久真实原创| 深爱激情五月婷婷| 一边亲一边摸免费视频| 精品一区在线观看国产| 日韩三级伦理在线观看| 欧美少妇被猛烈插入视频| 97超视频在线观看视频| 丰满乱子伦码专区| 日韩制服骚丝袜av| 一级毛片久久久久久久久女| 777米奇影视久久| 久久6这里有精品| 高清日韩中文字幕在线| 午夜免费鲁丝| a级毛片免费高清观看在线播放| 王馨瑶露胸无遮挡在线观看| 天美传媒精品一区二区| av不卡在线播放| 久久国产亚洲av麻豆专区| 嫩草影院入口| 视频中文字幕在线观看| 精品久久久久久久末码| 精品少妇久久久久久888优播| 能在线免费看毛片的网站| 能在线免费看毛片的网站| 最近手机中文字幕大全| 久久午夜福利片| 日韩亚洲欧美综合| 国产精品久久久久久精品电影小说 | 亚洲精品乱久久久久久| 国产成人免费无遮挡视频| 秋霞在线观看毛片| 男女无遮挡免费网站观看| 亚洲精品aⅴ在线观看| 亚洲国产av新网站| 成人免费观看视频高清| 熟妇人妻不卡中文字幕| 日本欧美视频一区| 中文字幕人妻熟人妻熟丝袜美| 成人综合一区亚洲| 观看免费一级毛片| 色5月婷婷丁香| 久久国产精品男人的天堂亚洲 | av在线app专区| 成人午夜精彩视频在线观看| 国产大屁股一区二区在线视频| 欧美97在线视频| 男女无遮挡免费网站观看| 国产成人一区二区在线| 不卡视频在线观看欧美| h日本视频在线播放| 三级国产精品欧美在线观看| 你懂的网址亚洲精品在线观看| 免费大片黄手机在线观看| 亚洲中文av在线| 一个人看的www免费观看视频| 久久女婷五月综合色啪小说| 最近中文字幕2019免费版| 三级国产精品欧美在线观看| 成人毛片60女人毛片免费| 亚洲精品久久久久久婷婷小说| 深夜a级毛片| 少妇人妻一区二区三区视频| 最新中文字幕久久久久| 久久久久久伊人网av| av在线观看视频网站免费| 免费观看a级毛片全部| 久久久成人免费电影| 国产成人免费观看mmmm| 国模一区二区三区四区视频| 天天躁日日操中文字幕| 婷婷色av中文字幕| 妹子高潮喷水视频| 欧美+日韩+精品| 亚洲无线观看免费| 汤姆久久久久久久影院中文字幕| 午夜日本视频在线| 一级毛片 在线播放| 免费大片18禁| 国产精品一区www在线观看| 80岁老熟妇乱子伦牲交| 亚洲美女黄色视频免费看| 婷婷色综合大香蕉| 亚洲国产欧美人成| 欧美国产精品一级二级三级 | 亚洲天堂av无毛| 777米奇影视久久| 午夜激情久久久久久久| 国产 精品1| 亚洲精品第二区| 另类亚洲欧美激情| 日产精品乱码卡一卡2卡三| 亚洲精品亚洲一区二区| 亚洲自偷自拍三级| 黑人高潮一二区| videossex国产| 亚洲欧美清纯卡通| 亚洲国产毛片av蜜桃av| 成人综合一区亚洲| 亚洲欧美一区二区三区黑人 | 免费在线观看成人毛片| 免费大片黄手机在线观看| 网址你懂的国产日韩在线| 免费观看a级毛片全部| 国产高清不卡午夜福利| 中文字幕人妻熟人妻熟丝袜美| 午夜福利在线观看免费完整高清在| 国内少妇人妻偷人精品xxx网站| 草草在线视频免费看| 国产精品免费大片| 超碰av人人做人人爽久久| 夜夜骑夜夜射夜夜干| 亚洲国产精品成人久久小说| 国产欧美日韩一区二区三区在线 | 日产精品乱码卡一卡2卡三| 久久影院123| 亚洲色图综合在线观看| 国产一级毛片在线| 国产大屁股一区二区在线视频| 赤兔流量卡办理| 伦理电影大哥的女人| 久久久久久久久久人人人人人人| 制服丝袜香蕉在线| 男人舔奶头视频| 色吧在线观看| 2018国产大陆天天弄谢| 99热6这里只有精品| 国产精品国产av在线观看| 日本-黄色视频高清免费观看| 免费观看在线日韩| 精品久久久久久久久av| 插阴视频在线观看视频| 精品视频人人做人人爽| 日韩国内少妇激情av| 肉色欧美久久久久久久蜜桃| 99热国产这里只有精品6| 亚洲av不卡在线观看| 亚洲欧美一区二区三区国产| 国产精品伦人一区二区| 国产淫语在线视频| 精品少妇黑人巨大在线播放| 自拍偷自拍亚洲精品老妇| 搡女人真爽免费视频火全软件| 美女cb高潮喷水在线观看| 欧美精品亚洲一区二区| 另类亚洲欧美激情| 九九在线视频观看精品| 日日啪夜夜撸| 国产亚洲午夜精品一区二区久久| 久久青草综合色| 久久久久久久久久久丰满| 在线观看免费视频网站a站| 午夜福利网站1000一区二区三区| 日本av免费视频播放| 亚洲精品乱久久久久久| 久久 成人 亚洲| 美女福利国产在线 | 少妇精品久久久久久久| 亚洲精品视频女| 又大又黄又爽视频免费| 男男h啪啪无遮挡| 韩国高清视频一区二区三区| videos熟女内射| 熟女av电影| 人体艺术视频欧美日本| 国产亚洲最大av| 毛片一级片免费看久久久久| 亚洲国产成人一精品久久久| 少妇的逼水好多| 国产黄片美女视频| 亚洲天堂av无毛| 国产成人精品婷婷| 超碰97精品在线观看| 在线观看一区二区三区激情| 全区人妻精品视频| 亚洲欧洲国产日韩| 夫妻午夜视频| 一本一本综合久久| 中文字幕亚洲精品专区| 国产成人精品久久久久久| 26uuu在线亚洲综合色| 男女国产视频网站| 极品少妇高潮喷水抽搐| 日韩成人伦理影院| 亚洲熟女精品中文字幕| 国产精品欧美亚洲77777| 王馨瑶露胸无遮挡在线观看| 久久国产精品男人的天堂亚洲 | 色综合色国产| 免费久久久久久久精品成人欧美视频 | 一个人免费看片子| 欧美亚洲 丝袜 人妻 在线| 丰满人妻一区二区三区视频av| 国产亚洲精品久久久com| 亚洲三级黄色毛片| 18+在线观看网站| 亚洲精品乱久久久久久| 久久99热6这里只有精品| 精品国产露脸久久av麻豆| 欧美日韩视频高清一区二区三区二| 老女人水多毛片| 久久精品人妻少妇| 午夜老司机福利剧场| 不卡视频在线观看欧美| 免费久久久久久久精品成人欧美视频 | 麻豆精品久久久久久蜜桃| 男女无遮挡免费网站观看| 91午夜精品亚洲一区二区三区| 久久影院123| 国产精品伦人一区二区| 九草在线视频观看| 精品一区二区免费观看| 老司机影院成人| 久久av网站| 99视频精品全部免费 在线| 亚洲一区二区三区欧美精品| 男女边吃奶边做爰视频| 麻豆乱淫一区二区| 精品人妻一区二区三区麻豆| 你懂的网址亚洲精品在线观看| 黄片wwwwww| av国产久精品久网站免费入址| 小蜜桃在线观看免费完整版高清| 日本与韩国留学比较| 一级毛片久久久久久久久女| 精品人妻一区二区三区麻豆| 黄片无遮挡物在线观看| 一区二区三区乱码不卡18| 99re6热这里在线精品视频| 亚洲自偷自拍三级| 亚洲国产成人一精品久久久| 男人舔奶头视频| 一边亲一边摸免费视频| 91精品国产九色| 成人免费观看视频高清| 日本wwww免费看| 国产v大片淫在线免费观看| 男女边摸边吃奶| 亚洲国产最新在线播放| 国产伦在线观看视频一区| 国内揄拍国产精品人妻在线| 狂野欧美白嫩少妇大欣赏| 中国美白少妇内射xxxbb| 久久精品久久久久久噜噜老黄| 精品人妻熟女av久视频| av福利片在线观看| 精品一区在线观看国产| 99热全是精品| 男女免费视频国产| 国产在视频线精品| 日韩,欧美,国产一区二区三区| av又黄又爽大尺度在线免费看| 在线亚洲精品国产二区图片欧美 | 日韩av免费高清视频| 午夜免费鲁丝| 国产午夜精品一二区理论片| 在线观看一区二区三区| 中文欧美无线码| 亚洲高清免费不卡视频| 国产视频内射| 精品人妻偷拍中文字幕| 深爱激情五月婷婷| 免费少妇av软件| 成人国产麻豆网| 国产亚洲精品久久久com| 欧美人与善性xxx| 日本猛色少妇xxxxx猛交久久| 欧美 日韩 精品 国产| 国产精品久久久久久久电影| 2018国产大陆天天弄谢| 日本一二三区视频观看| 联通29元200g的流量卡| 亚洲av中文av极速乱| 免费观看的影片在线观看| 国产精品一区二区三区四区免费观看| 麻豆国产97在线/欧美| 亚洲精品中文字幕在线视频 | 日韩免费高清中文字幕av| 精品人妻一区二区三区麻豆| 久久精品夜色国产| 看十八女毛片水多多多| 搡老乐熟女国产| 久久久a久久爽久久v久久| 国产一区二区三区av在线| 国产视频内射| 成人毛片60女人毛片免费| 亚洲国产最新在线播放| 亚洲国产日韩一区二区| 亚洲精品国产色婷婷电影| 国产欧美日韩精品一区二区| 高清日韩中文字幕在线| 蜜桃亚洲精品一区二区三区| 蜜桃亚洲精品一区二区三区| av天堂中文字幕网| 国产高清有码在线观看视频| 国产伦精品一区二区三区四那| 大码成人一级视频| 午夜激情福利司机影院| 国产免费一级a男人的天堂| 久久韩国三级中文字幕| 亚洲综合色惰| 超碰av人人做人人爽久久| 欧美97在线视频| 久久久久精品久久久久真实原创| 少妇熟女欧美另类| 欧美日韩一区二区视频在线观看视频在线| 视频中文字幕在线观看| 国产伦精品一区二区三区四那| 色婷婷av一区二区三区视频| 免费看av在线观看网站| 亚洲精品乱码久久久久久按摩| 一区二区三区乱码不卡18| 成人高潮视频无遮挡免费网站| 久久人人爽av亚洲精品天堂 | 亚洲一级一片aⅴ在线观看| 51国产日韩欧美| 久久国产精品大桥未久av | 嫩草影院入口| 免费人成在线观看视频色| 我的老师免费观看完整版| 人人妻人人添人人爽欧美一区卜 | 蜜桃在线观看..| 亚洲一级一片aⅴ在线观看| 尤物成人国产欧美一区二区三区| 欧美日韩在线观看h| 性色avwww在线观看| 亚洲国产日韩一区二区| 一级毛片电影观看| 又爽又黄a免费视频| 欧美精品一区二区免费开放| 久久久久网色| 寂寞人妻少妇视频99o| 国内精品宾馆在线| 免费观看av网站的网址| 久久国产亚洲av麻豆专区| 国产淫语在线视频| 自拍欧美九色日韩亚洲蝌蚪91 | 国产乱人偷精品视频| 视频区图区小说| 极品教师在线视频| 2022亚洲国产成人精品| 乱系列少妇在线播放| 成人毛片60女人毛片免费| 插阴视频在线观看视频| 精品酒店卫生间| 少妇裸体淫交视频免费看高清| 中国美白少妇内射xxxbb| 青青草视频在线视频观看| 日韩欧美一区视频在线观看 | 国产男女内射视频| 国产成人精品一,二区| 色婷婷av一区二区三区视频| 精品99又大又爽又粗少妇毛片| 哪个播放器可以免费观看大片| 欧美丝袜亚洲另类| 你懂的网址亚洲精品在线观看| 99久久综合免费| 看十八女毛片水多多多| 黑人高潮一二区| 观看免费一级毛片| 色婷婷av一区二区三区视频| 久久精品国产鲁丝片午夜精品| 亚洲国产av新网站| 99久久人妻综合| 少妇人妻 视频| 啦啦啦啦在线视频资源| 精品人妻偷拍中文字幕| 国产老妇伦熟女老妇高清| 纵有疾风起免费观看全集完整版| av播播在线观看一区| 亚洲欧洲国产日韩| 亚洲美女搞黄在线观看| 日韩av不卡免费在线播放| 国产美女午夜福利| 日韩人妻高清精品专区| 国产日韩欧美在线精品| 美女国产视频在线观看| 中文字幕人妻熟人妻熟丝袜美| 精品久久久久久电影网| av在线app专区| 七月丁香在线播放| 亚洲人成网站高清观看| 亚洲精品aⅴ在线观看| 美女脱内裤让男人舔精品视频| 国产高清有码在线观看视频| 国产精品99久久久久久久久| 亚州av有码| 中文字幕精品免费在线观看视频 | 国产毛片在线视频| 久久综合国产亚洲精品| 人妻 亚洲 视频| 久久ye,这里只有精品| 欧美激情国产日韩精品一区| 91在线精品国自产拍蜜月| 国产探花极品一区二区| 综合色丁香网| 亚洲中文av在线| 能在线免费看毛片的网站| 免费观看在线日韩| 一本一本综合久久| 人体艺术视频欧美日本| 毛片女人毛片| 午夜福利网站1000一区二区三区| 97精品久久久久久久久久精品| 两个人的视频大全免费| a 毛片基地| 亚洲精品久久久久久婷婷小说| 色视频www国产| 免费观看a级毛片全部| 国产91av在线免费观看| 精品国产乱码久久久久久小说| 成人二区视频| 少妇人妻 视频| 国产成人a区在线观看| 精品久久国产蜜桃| 在线播放无遮挡| 久久青草综合色| 黑丝袜美女国产一区| 大香蕉97超碰在线| 成年美女黄网站色视频大全免费 | 成人毛片60女人毛片免费| 国产精品99久久99久久久不卡 | 激情五月婷婷亚洲| 免费人成在线观看视频色| 多毛熟女@视频| 亚洲无线观看免费| 久久 成人 亚洲| 精品国产一区二区三区久久久樱花 | 免费久久久久久久精品成人欧美视频 | 亚洲,一卡二卡三卡| 人体艺术视频欧美日本| 欧美精品亚洲一区二区| 亚洲精品日韩av片在线观看| 老熟女久久久| 亚洲av福利一区| 中文字幕久久专区| a级毛片免费高清观看在线播放| 免费看不卡的av| 黄色怎么调成土黄色| 色综合色国产| 一区二区三区乱码不卡18| 寂寞人妻少妇视频99o| 国产精品99久久99久久久不卡 | 最近最新中文字幕免费大全7| 久久国产精品男人的天堂亚洲 | 欧美zozozo另类| 国产白丝娇喘喷水9色精品| 一区二区三区四区激情视频| 亚洲在久久综合| 免费观看无遮挡的男女|