Flaws In Study Design Research Articles

Methodological issues and suggestions for improvement in randomized controlled trials of Chinese herbal medicine for recurrent miscarriage

Recurrent miscarriage is a common disease in clinical obstetrics and gynecology. There is no curative treatment for recurrent miscarriage in conventional medicine. Traditional Chinese medicine (TCM) has been widely used in the treatment of recurrent miscarriage in China for thousands of years. However, randomized controlled trials (RCTs) with high quality evaluating the effectiveness and safety of Chinese herbal medicine (CHM) still lack. This study was conducted in order to identify methodological problems in published or unpublished RCTs of CHM in the treatment of recurrent miscarriage, and provide suggestions for TCM researchers to conduct high-quality clinical research. Literature searching was conducted to collect published and unpublished RCTs from six electronic literature databases, including China National Knowledge Infrastructure, Chongqing VIP Chinese Scientific Journals Database, Chinese Biomedical Literature Database, Wanfang Data, PubMed, and Cochrane Library, till December 15, 2011. The Cochrane Handbook, the CONSORT Statement and the CONSORT for TCM statement were used to assess the methodological quality in the designing and reporting of included trials. A total of 49 RCTs were included in this critical appraisal. Most of the trials were of high risk of bias with flawed study design and poor methodological quality. The main problems included: no report on random methods or sequence concealment; no calculation of sample size; no flow chart of enrollment and outcomes; no report on blinding methods; no or incomplete report on baseline data such as diagnosis criteria and causes of miscarriage recurrent, age, times of spontaneous abortion, TCM syndrome differentiation; complex CHM treatments and inappropriate control interventions; no report on follow-up and withdrawals; inappropriate outcome measurements such as middle-outcome or laboratory test results; no report on final outcome (live-birth rate). There are many methodological problems in RCTs of CHM for recurrent miscarriage. It is suggested that four issues should be taken into consideration for TCM research: basic principles of clinical research are needed in design and reporting of RCTs; definite diagnosis criteria and baseline data should be reported in detail; appropriate treatment and control interventions should be selected according to the assumption and objective of research; final outcome (live-birth rate) should be reported in outcome evaluation.

A Systematic Review of Patient Tracking Systems for Use in the Pediatric Emergency Department

BackgroundPatient safety is of great importance in the pediatric emergency department (PED). The combination of acutely and critically ill patients and high patient volumes creates a need for systems to support physicians in making accurate and timely diagnoses. Electronic patient tracking systems can potentially improve PED safety by reducing overcrowding and enhancing security. ObjectivesTo enhance our understanding of current electronic tracking technologies, how they are implemented in a clinical setting, and resulting effect on patient care outcomes including patient safety. MethodsNine databases were searched. Two independent reviewers identified articles that contained reference to patient tracking technologies in pediatrics or emergency medicine. Quantitative studies were assessed independently for methodological strength by two reviewers using an external assessment tool. ResultsOf 2292 initial articles, 22 were deemed relevant. Seventeen were qualitative, and the remaining five quantitative articles were assessed as being methodologically weak. Existing patient tracking systems in the ED included: infant monitoring/abduction prevention; barcode identification; radiofrequency identification (RFID)- or infrared (IR)-based patient tracking. Twenty articles supported the use of tracking technology to enhance patient safety or improve efficiency. One article failed to support the use of IR patient sensors due to study design flaws. ConclusionsSupport exists for the use of barcode-, IR-, and RFID-based patient tracking systems to improve ED patient safety and efficiency. A lack of methodologically strong studies indicates a need for further evidence-based support for the implementation of patient tracking technology in a clinical or research setting.

A systematic review of clinical studies of electrical stimulation for treatment of lower urinary tract dysfunction

The aim of this manuscript was to provide a systematic literature review of clinical trial evidence for a range of electrical stimulation therapies in the treatment of lower urinary tract symptoms (LUTS). The databases MEDLINE, BIOSIS Previews, Inside Conferences, and EMBASE were searched. Original clinical studies with greater than 15 subjects were included. Seventy-three studies were included, representing implanted sacral nerve stimulation (SNS), percutaneous posterior tibial nerve stimulation (PTNS), and transcutaneous electrical stimulation (TENS) therapy modalities. Median mean reductions in incontinence episodes and voiding frequency were similar for implanted SNS and PTNS. However, long-term follow-up data to validate the sustained benefit of PTNS are lacking. Despite a substantial body of research devoted to SNS validation, it is not possible to definitively define the appropriate role of this therapy owing largely to study design flaws that inhibited rigorous intention to treat analyses for the majority of these studies.

Intracranial stenting for intracranial atherosclerotic disease: still much to learn

The recently published Stenting versus Aggressive Medical Management for Preventing Recurrent stroke in Intracranial Stenosis (SAMMPRIS) study1 has provided seminal information on the treatment of symptomatic intracranial atherosclerotic disease (ICAD)....

Chinese Herbal Medicines for the Treatment of Type A H1N1 Influenza: A Systematic Review of Randomized Controlled Trials

BackgroundChinese herbs are thought to be effective for type A H1N1 influenza. Series of Chinese herbs have been authorized recommended by the Chinese government, and until now a number of clinical trials of Chinese herbs for H1N1 influenza have been conducted. However, there is no critically appraised evidence such as systematic reviews or meta-analyses on potential benefits and harms of medicinal herbs for H1N1 influenza to justify their clinical use and their recommendation.Methods and FindingsCENTRAL, MEDLINE, EMBASE, CBM, CNKI, VIP, China Important Conference Papers Database, China Dissertation Database, and online clinical trial registry websites were searched for published and unpublished randomized controlled trials (RCTs) of Chinese herbs for H1N1 influenza till 31 August, 2011. A total of 26 RCTs were identified and reviewed. Most of the RCTs were of high risk of bias with flawed study design and poor methodological quality. The combination of several Chinese herbal medicines with or without oseltamivir demonstrated positive effect on fever resolution, relief of symptoms, and global effectiveness rate compared to oseltamivir alone. However, only one herbal medicine showed positive effect on viral shedding. Most of the trials did not report adverse events, and the safety of herbal medicines is still uncertain.ConclusionsSome Chinese herbal medicines demonstrated potential positive effect for 2009 type A H1N1 influenza; however, due to the lack of placebo controlled trial and lack of repeated test of the intervention, we could not draw confirmative conclusions on the beneficial effect of Chinese herbs for H1N1 influenza. More rigorous trials are warranted to support their clinical use.

Insulin analogues and cancer risk: the emergence of second-generation studies

A number of observational studies have linked insulin glargine (A21Gly,B31Arg,B32Arg human insulin) with a putative increased cancer risk, particularly breast cancer, but many of these 'first generation' studies had study design and analysis flaws, and were inconclusive. A small number of 'second generation' studies are now emerging in which the applied pharmaco-epidemiological principles are more robust. For example, when Ruitar and colleagues (Diabetologia DOI: 10.1007/s00125-011-2312-4 ) focused specifically on breast cancer rather than all incident cancer risk, they were able to show a positive association with insulin glargine for breast cancer although there was no association with all incident cancer risk. A list of preferred qualities for pharmaco-epidemiological studies is presented.

Urinary Sodium Excretion and Cardiovascular Disease Mortality

To the Editor: Low sodium excretion was associated with higher CVD mortality in a prospective study of 3681 participants from Europe.1 The results should be interpreted with caution considering several flaws in study design, analysis, and interpretation.

Re: A critical review of recombinant human bone morphogenetic protein-2 trials in spinal surgery: emerging safety concerns and lessons learned

Because of the study design flaws and other limitations that Carragee et al. [ [1] Carragee E.J. Hurwitz E.L. Weiner B.K. A critical review of recombinant human bone morphogenetic protein-2 trials in spinal surgery: emerging safety concerns and lessons learned. Spine J. 2011; 11: 471-491 Abstract Full Text Full Text PDF PubMed Scopus (1069) Google Scholar ] have described in their critical review of recombinant human bone morphogenetic protein 2 trials in spinal surgery, the authors state that adverse experiences attributable to the product were underestimated, and that the risk of adverse events may be as high as 50 times that reported in industry-funded publications. This point cannot be overemphasized, and it is critical for the spine community to understand and appreciate this daunting possibility. A critical review of recombinant human bone morphogenetic protein-2 trials in spinal surgery: emerging safety concerns and lessons learnedThe Spine JournalVol. 11Issue 6PreviewIncreasingly, reports of frequent and occasionally catastrophic complications associated with use of recombinant human bone morphogenetic protein-2 (rhBMP-2) in spinal fusion surgeries are being published. In the original peer review, industry-sponsored publications describing the use of rhBMP-2 in spinal fusion, adverse events of these types and frequency were either not reported at all or not reported to be associated with rhBMP-2 use. Some authors and investigators have suggested that these discrepancies were related to inadequate peer review and editorial oversight. Full-Text PDF Carragee et al. respondThe Spine JournalVol. 11Issue 8PreviewWe thank Dr Woo for her important comments. In fact, the concerns of Dr Woo speak directly to the serious confusion caused by Drs Burkus's [1] and Zdeblick's correspondences [2] and articles [3–5] that categorically, but erroneously, claimed that their data demonstrated “there is no relationship between the use of rhBMP-2 in stand-alone interbody fusion cages and the postoperative development of retrograde ejaculation.” Full-Text PDF

A multi-faceted strategy to improve the use of national fertility guidelines; a cluster-randomized controlled trial

BACKGROUND Proper use of clinical practice guidelines can decrease variation in care between settings. However, actual use of fertility guidelines is suboptimal and in need of improvement. Hence, a cluster-randomized controlled trial was designed to study the effects of two strategies to implement national Dutch guidelines on comprehensive fertility care. METHODS Sixteen fertility clinics participated in the trial. A minimal, professional-oriented implementation strategy of audit and feedback was tested versus a maximal multi-faceted strategy that was both professional and patient oriented. The extent of adherence to guideline recommendations, reflected in quality indicator scores, was the primary outcome measure. To gain an insight into unwanted side effects, patient anxiety and depression scores were gathered as secondary outcomes. Data collection encompassed medical record search, patient and professional questionnaires. RESULTS A total of 1499 couples were included at baseline and 1396 at the after-measurement. No overall significant improvement in indicator scores was found for either strategy [odds ratios ranging from 0.23 (95% confidence interval (CI): 0.06-0.95) to 6.66 (95% CI: 0.33-132.8]. Secondary outcomes did not differ significantly for both groups, although selected anxiety scores appeared lower in the maximal intervention group. Process evaluation of the trial revealed positive patient experiences with the intervention material [e.g. an increased understanding of their doctor's treatment policy (61%), an increased ability to ask questions about the treatment (61%)]. Professionals' appreciation of intervention elements varied, and execution of the multi-faceted strategy appeared incomplete. DISCUSSION Absence of an intervention effect may be due to the nature of the strategies, incomplete execution or flaws in study design. Process evaluation data raise the question of whether professionals should be the only stakeholder responsible for guideline implementation. This study therefore contributes to an increased understanding of fertility guideline implementation in general, and the role of patients in particular.

Sham or Scam

Sham or Scam

Narrative Review: Should Teaching of the Respiratory Physical Examination Be Restricted Only to Signs with Proven Reliability and Validity?

To review the reported reliability (reproducibility, inter-examiner agreement) and validity (sensitivity, specificity and likelihood ratios) of respiratory physical examination (PE) signs, and suggest an approach to teaching these signs to medical students. Review of the literature. We searched Paper Chase between 1966 and June 2009 to identify and evaluate published studies on the diagnostic accuracy of respiratory PE signs. Most studies have reported low to fair reliability and sensitivity values. However, some studies have found high specificites for selected PE signs. None of the studies that we reviewed adhered to all of the STARD criteria for reporting diagnostic accuracy. Possible flaws in study designs may have led to underestimates of the observed diagnostic accuracy of respiratory PE signs. The reported poor reliabilities may have been due to differences in the PE skills of the participating examiners, while the sensitivities may have been confounded by variations in the severity of the diseases of the participating patients. IMPLICATION FOR PRACTICE AND MEDICAL EDUCATION: Pending the results of properly controlled studies, the reported poor reliability and sensitivity of most respiratory PE signs do not necessarily detract from their clinical utility. Therefore, we believe that a meticulously performed respiratory PE, which aims to explore a diagnostic hypothesis, as opposed to a PE that aims to detect a disease in an asymptomatic person, remains a cornerstone of clinical practice. We propose teaching the respiratory PE signs according to their importance, beginning with signs of life-threatening conditions and those that have been reported to have a high specificity, and ending with signs that are "nice to know," but are no longer employed because of the availability of more easily performed tests.

Design and statistical analysis of oral medicine studies: common pitfalls

A growing number of articles are emerging in the medical and statistics literature that describe epidemiologic and statistical flaws of research studies. Many examples of these deficiencies are encountered in the oral, craniofacial, and dental literature. However, only a handful of methodologic articles have been published in the oral literature warning investigators of potential errors that may arise early in the study and that can irreparably bias the final results. In this study, we briefly review some of the most common pitfalls that our team of epidemiologists and statisticians has identified during the review of submitted or published manuscripts and research grant applications. We use practical examples from the oral medicine and dental literature to illustrate potential shortcomings in the design and analysis of research studies, and how these deficiencies may affect the results and their interpretation. A good study design is essential, because errors in the analysis can be corrected if the design was sound, but flaws in study design can lead to data that are not salvageable. We recommend consultation with an epidemiologist or a statistician during the planning phase of a research study to optimize study efficiency, minimize potential sources of bias, and document the analytic plan.

Evidence that Calcium Supplements Reduce Fracture Risk Is Lacking

Credible evidence that calcium supplements reduce the risk of vertebral, nonvertebral, or hip fractures is lacking. Flaws in study design and execution such as inclusion of calcium-replete individuals, high dropout rates, and poor compliance preclude testing the hypothesis that calcium deficiency increases fracture rates or that calcium supplements reduce them. Intent-to-treat analyses of individual trials have failed to detect antifracture efficacy. Post hoc analyses of subgroups with a low calcium intake and per-protocol analyses of compliers have reported fewer fractures in the supplemented groups. However, this may be the result of confounding by violation of randomization; compliers to placebo have a lower morbidity and mortality than noncompliers. Higher hip fracture rates and cardiac mortality in patients receiving calcium supplements, as reported in some studies, may also be due to factors other than supplementation. Hypothesis testing requires that a cohort be stratified into calcium-deficient and calcium-replete groups, with each person randomized to a supplement or placebo. This design quantifies the risk of fracture attributable to calcium deficiency and any benefit that supplementation confers in the calcium-deficient and calcium-replete groups. To regard a calcium-deficient arm as unethical begs the question. Consensus statements that support the widespread use of calcium are opinion-based; they accept claims of beneficial effects despite flaws in study design, execution, and analysis; and they reject reported adverse effects because of them. Until well designed, well executed, and well analyzed studies demonstrate a net benefit in morbidity, mortality, and cost, recommendations supporting the widespread use of calcium supplementation remain belief-based and not evidence-based.

Methodological issues of genetic association studies

Genetic association studies explore the association between genetic polymorphisms and a certain trait, disease or predisposition to disease. It has long been acknowledged that many genetic association studies fail to replicate their initial positive findings. This raises concern about the methodological quality of these reports. Case-control genetic association studies often suffer from various methodological flaws in study design and data analysis, and are often reported poorly. Flawed methodology and poor reporting leads to distorted results and incorrect conclusions. Many journals have adopted guidelines for reporting genetic association studies. In this review, some major methodological determinants of genetic association studies will be discussed.

A Translational Approach to Hypertensive Heart Disease

The spectrum of the cardiac complications of arterial hypertension includes heart failure (HF), sudden death, and cardiac dysrhythmias, as well as the exacerbation of coincidental diseases (ie, atherosclerosis and chronic renal disease).1 However, knowledge of the cardiac impact of chronic elevation of arterial pressure has so evolved that hypertensive heart disease (HHD) may be thought as those consequences derived from left ventricular (LV) responses to fundamental disease mechanisms triggered by mechanical overload and neurohumoral stimuli.2 For instance, the long-held views are that LV hypertrophy (LVH), as the result of cardiomyocyte growth in response to pressure overload, serves to restore heart muscle economy back to normal and to preserve LV function.3 However, a number of alterations of the cardiomyocyte and the noncardiomyocyte components of the myocardium (including apoptosis, fibrosis, and changes in the microcirculation) also develop in HHD that lead to pathological myocardial remodeling not only in the left ventricle but also the left atrium and right ventricle.2 These alterations may explain the overall risk of LVH and its associated cardiac and noncardiac complications in hypertensive patients.4 Although LVH may be detected early and accurately in hypertensive patients by electrocardiography and echocardiography, newer cardiac imaging methods and the monitoring of several circulating biomarkers hold promise as noninvasive tools for the diagnosis of myocardial remodeling. Numerous clinical studies have shown that effective long-term antihypertensive treatment may be associated with a decreased LV mass (LVM), which has been attributed to diminished risk. However, no large study (or meta-analysis) has demonstrated that diminished risk from the contemporary reduction of arterial pressure by virtue of its a priori design. Therefore, because overall risk remains unacceptably high, especially from HF, new therapeutic strategies aimed not only to decrease arterial pressure and LVM but also to repair and even prevent myocardial remodeling …

Reply to: Austin et al. CytoJournal 2009;6:12 (Unfounded claims mar scientific critique)

To the Editor, Austin and Zhao[1] raise accusations of anticytology bias and conflict of interest in the cervical cancer screening study published by Sankaranarayanan et al.,[2] which was very surprising as these were a repetition of the same previously published (and refuted) charges. The authors note that “questions have been raised” about the Alliance for Cervical Cancer Prevention (ACCP; see www.alliance-cxca.org) and its objectivity with regard to human papillomavirus (HPV) tests. They fail to acknowledge that all these questions have been repeatedly raised by the same person (lead author on all three references cited) and that they have also been answered in a peer-reviewed journal.[3] They also fail to acknowledge that the ACCP, for the past 8 years and in 20 countries, has assessed a variety of approaches to cervical cancer screening, including cytology.[4] Contrary to what is implied by Austin and Zhao, the ACCP—and, in particular, its coordinating organization, PATH—has not received any funding from the HPV test manufacturer for this or any other ACCP study. PATH has, in fact, been working with the manufacturer to develop a lower cost and simpler alternative to their current HPV test that would be more suitable for developing-country use. Unless the authors are charging that the supposed conflict of interest led to a flawed study design (in which case they should point out the flaw) or to deliberate data manipulation (a serious charge of scientific misconduct for which they must provide solid evidence), the claims simply cloud the scientific debate with unfounded accusations and do a disservice to readers. We, as members of the ACCP, are committed to making screening and treatment technologies available that are feasible and effective in low-resource settings. If our pragmatic and evidence-based approach means that we are “enamored of the promise of science,” we have no difficulty with that charge. ACCP, without industry funding, continues to undertake a coordinated research agenda to assess cervical cancer screening and treatment approaches suited to low-resource settings, to improve service delivery systems, to ensure that community perspectives and needs are considered in programs, and to heighten awareness of cervical cancer prevention. We will continue to evaluate new data as it becomes available, but we will not sit by and watch women die needlessly when we can get started now with the tools we already have at hand and for which solid data exist—including visual inspection and, when less-expensive tests become available, HPV testing.

Dietary cholesterol and the risk of cardiovascular disease in patients: a review of the Harvard Egg Study and other data

For many years, both the medical community and the general public have incorrectly associated eggs with high serum cholesterol and being deleterious to health, even though cholesterol is an essential component of cells and organisms. It is now acknowledged that the original studies purporting to show a linear relation between cholesterol intake and coronary heart disease (CHD) may have contained fundamental study design flaws, including conflated cholesterol and saturated fat consumption rates and inaccurately assessed actual dietary intake of fats by study subjects. Newer and more accurate trials, such as that conducted by Frank B. Hu of the Harvard School of Public Health (1999), have shown that consumption of up to seven eggs per week is harmonious with a healthful diet, except in male patients with diabetes for whom an association in higher egg intake and CHD was shown. The degree to which serum cholesterol is increased by dietary cholesterol depends upon whether the individual's cholesterol synthesis is stimulated or down-regulated by such increased intake, and the extent to which each of these phenomena occurs varies from person to person. Several recent studies have shed additional light on the specific interplay between dietary cholesterol and cardiovascular health risk. It is evident that the dynamics of cholesterol homeostasis, and of development of CHD, are extremely complex and multifactorial. In summary, the earlier purported adverse relationship between dietary cholesterol and heart disease risk was likely largely over-exaggerated.

A randomized trial comparing endoscopic stenting to a sham procedure for chronic pancreatitis

A number of studies support the use of endoscopically placed pancreatic duct (PD) stents to decrease pain in chronic pancreatitis (CP). Nevertheless, flaws in study design have prevented experts from reaching a consensus. (1) Evaluate the efficacy of PD stenting to ameliorate abdominal pain in patients with CP and ductal strictures; (2) evaluate the placebo response rate from sham endoscopic therapy; (3) compare pain medication usage, healthcare utilization, psychological distress, and quality of life before and after endoscopic stenting; (4) prospectively evaluate the durability of the response. Patients with typical abdominal pain, imaging confirmation of CP and endoscopic retrograde cholangiopancreatography (ERCP) confirmation of PD stricture will complete questionnaires to assess quality of life, psychological distress, pain intensity/unpleasantness, pain medication usage, and healthcare utilization. Enrolled patients will be randomized to ERCP with sphincterotomy and PD stenting versus sham procedure. Pain level and medication usage will be assessed weekly with telephone interviews. At 6-8 weeks, patients treated with stents will undergo stent removal; those randomized to the sham procedure without significant improvement (<50% reduction in pain score) will cross over to the treatment group; and those randomized to sham procedure who experienced improvement (>50% reduction) will be followed clinically. Patients will be followed in clinic or by phone biannually (up to 3 years). The primary endpoint is improvement in abdominal pain. The secondary endpoints are reduction in narcotic use, healthcare utilization, and work days missed; return to employment; improvement in quality of life and weight gain. Proposed study. Strict inclusion criteria may limit enrollment. The proposed study represents the first trial of endoscopic stenting for symptomatic CP and ductal strictures with a credible sham procedure, assessment of multiple dimensions of pain, and psychosocial factors.

Acupuncture for Bell's Palsy

The objectives of this study were to examine the efficacy of acupuncture in hastening recovery and reducing long-term morbidity from Bell's palsy. We searched the Cochrane Neuromuscular Disease Group Trials Register, MEDLINE (January 1966-April 2006), EMBASE (January 1980-April 2006), LILACS (January 1982-April 2006), and the Chinese Biomedical Retrieval System (January 1978-April 2006) for randomized controlled trials using "Bell's palsy" and its synonyms, "idiopathic facial paralysis" or "facial palsy" as well as search terms including "acupuncture." Chinese journals in which we thought we might find randomized controlled trials or controlled clinical trials relevant to our study were hand searched. We reviewed the bibliographies of the randomized trials and contacted the authors and known experts in the field to identify additional published or unpublished data. We included all randomized or quasi-randomized controlled trials involving acupuncture in the treatment of Bell's palsy, irrespective of any language restrictions. Two review authors identified potential articles from the literature search and extracted data independently using a data extraction form. The assessment of methodological quality included allocation concealment, patient blinding, differences at baseline of the experimental groups, and completeness of follow-up. Two (2) review authors assessed quality independently. All disagreements were resolved by discussion between the review authors. Six (6) studies including a total of 537 participants met the inclusion criteria. Five (5) of them used acupuncture while another one used acupuncture combined with drugs. No trials reported on the outcomes specified for this review. Harmful side-effects were not reported in any of the trials. Flaws in study design or reporting (particularly uncertain allocation concealment and substantial loss to follow-up) and clinical differences between trials prevented conclusions about the efficacy of acupuncture. The quality of the included trials was inadequate to allow any conclusion about the efficacy of acupuncture. More research with high-quality trials is needed.

Black tea consumption dose-dependently improves flow-mediated dilation in healthy males

Flavonoids may protect against cardiovascular disease. Tea is a major source of dietary flavonoids. Studies indicate black tea improves endothelial function but data on arterial haemodynamics, blood pressure (BP) and insulin resistance are equivocal. Inconsistency may be due to flaws in study design or flavonoid doses tested. Further, no study has evaluated the dose-response curve. Our study aimed to test the effects of various doses of black tea on vascular function, BP and insulin resistance. According to a randomized, double-blind, controlled, cross-over design, 19 healthy men were assigned to receive either five treatments with a twice daily intake of black tea (0, 100, 200, 400 and 800 mg tea flavonoids/day) in five periods lasting 1 week each. Black tea dose dependently increased flow-mediated dilation (FMD) from 7.8% (control) to 9.0, 9.1, 9.6 and 10.3% after the different flavonoid doses, respectively (P = 0.0001). Already 100 mg/day (less than 1 cup of tea) increased FMD compared with control (P = 0.0113). FMD improvement after 800 mg/day was significant compared with control (P < 0.0001) but also to 100 mg/day (P = 0.0121) and 200 mg/day (P = 0.0275). Black tea intake decreased office systolic (-2.6 mmHg, P = 0.0007) and diastolic (-2.2 mmHg, P = 0.006) BP as well as stiffness index (P = 0.0159) without changes in other parameters studied. Our study is the first showing black tea ingestion dose dependently improved FMD and decreased peripheral arterial stiffness in healthy volunteers. Our data suggest that worldwide all tea drinkers could benefit from protective cardiovascular effects exerted by tea.