Adequacy of Inclusion of Older Adults in NIH‐Funded Phase III Clinical Trials

In the United States, the population aged 65 and older is rapidly growing, and this group uses more healthcare resources and has unique healthcare needs that do not exist in younger populations. However, it was reported that older adults are excluded or underrepresented in clinical trials for several diseases. We examined phase III clinical trials funded by the National Institutes of Health found in www.clinicaltrials.gov from 1965 to 2015 that addressed top causes for hospitalization and/or disability‐adjusted life years in older adults: congestive heart failure (n = 45), cardiac dysrhythmias (n = 24), coronary atherosclerosis (n = 106), heart attack (n = 76), stroke (n = 113), chronic obstructive pulmonary disease (n = 14), pneumonia (n = 48), lung cancer (n = 117), prostate cancer (n = 65), and osteoarthritis (n = 15). We then analyzed the representation of older adults in these studies. We found that 33% of studies had arbitrary upper age limits, and 67% of studies reported mean and/or median ages that skewed younger than expected for the disease or condition of interest. Beyond explicit exclusion by age, older adults were often implicitly excluded based on various comorbid conditions such as polypharmacy/concomitant medication (37%) or cardiac issues (30%). We conclude that outcomes of these trials may not be fully generalizable to the general population of older adults. J Am Geriatr Soc 67:218–222, 2019.     

Issues in extrapolating from clinical trials to clinical practice and outcomes

Extrapolation of clinical trial results to clinical practice requires consideration of whether the trial patients were representative of clinical practice, whether the trial therapy studied was optimal, whether the sample size was adequate, and the impact of adjunctive treatments.
In thrombolytic trials in particular, regional variations in attitudes to coronary angiography may have affected outcomes. Clinical trial results need to be interpreted in the light of the cost effectiveness of the application.
The assessment of clinical outcomes depends on interplay between the structure and process of care, patient factors and chance. Large standardised databases are necessary to assess clinical practice and outcomes.     

Pragmatic Trials in Long-Term Care: Research Challenges and Potential Solutions in Relation to Key Areas of Care

As a method of research, pragmatic trials are recommended so as to generate results that are applicable to real-world care. This intent is especially important for the millions of older adults who receive long-term care in thousands of nursing homes and assisted living communities across the country—and many millions more around the globe. This article presents key points raised by experts participating in a conference funded by the National Institute of Aging held at the 2021 conference of the Society for Post-Acute and Long-term Care Medicine. The purpose of the conference was to convene leading clinicians, researchers, and industry partners to address special considerations of pragmatic trials in long-term care. Cross-cutting and unique challenges and solutions to conducting pragmatic trials were discussed focusing on 3 areas of clinical relevance to long-term care: (1) functional care and outcomes, (2) psychosocial care and quality of life, and (3) medical care and outcomes, with a special focus on persons with dementia. Challenges and innovative solutions were organized across the 9 domains of the revised Pragmatic-Explanatory Continuum Indicator Summary (PRECIS) Tool, and future research recommendations for pragmatic trials in long-term care were identified.     

CONSORT2010声明：报告平行对照随机临床试验指南的更新

CONSORT声明被广泛应用于提高随机对照临床试验的报告质量。Kenneth Schulz等对CONSORT声明的最新版本CONSORT2010作了详细说明,该版本基于新获得的方法学证据和经验的积累对报告指南作了更新。为了鼓励更多的人使用“CONSORT 2010声明”,本文可从WWW．bmj．com免费获取,也将在Lancet,Obstetrics and Gynecology,PLoS Medicine,Annals of Internal Medicine,Open Medicine,Journal of Clinical Epidemiology,BMC Medicine和Trials等杂志发表。     

Alternatives to mega-trials in cardiovascular disease

Summary This article considers the dominant role of trials involving thousands of patients-the mega-trials—in cardiovascular disease. Problems with large trials mean that alternative strategies must be developed to aid the introduction of new drugs. The limitations of meta-analysis, and of trials with combined and surrogate endpoints are discussed. Properly organized trials designed to establish whether or not two treatments have an equivalent effect seem to offer the best alternative to mega-trials.     

Clinical trials in North America

Abstract:  Majority of patients with Hodgkin lymphoma are cured with current therapy. The short and long-term toxicity of therapy is a current issue, most especially the radiation-induced second tumors and cardiac abnormalities. Optimal therapy of advanced disease is being compared to ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine). More intensive chemotherapy may result in higher response but greater toxicity. Regimens requiring radiotherapy are also at risk of long-term toxicity. New targeted biologic therapy is under current investigation.     

Use of electronic healthcare records in large‐scale simple randomized trials at the point of care for the documentation of value‐based medicine

A solid foundation of evidence of the effects of an intervention is a prerequisite of evidence‐based medicine. The best source of such evidence is considered to be randomized trials, which are able to avoid confounding. However, they may not always estimate effectiveness in clinical practice. Databases that collate anonymized electronic health records (EHRs) from different clinical centres have been widely used for many years in observational studies. Randomized point‐of‐care trials have been initiated recently to recruit and follow patients using the data from EHR databases. In this review, we describe how EHR databases can be used for conducting large‐scale simple trials and discuss the advantages and disadvantages of their use.     

Physicians’ preferences for active-controlled versus placebo-controlled trials of new antihypertensive drugs

OBJECTIVE: To evaluate physicians' preferences for referring patients to, and using information from, active-controlled trials (ACTs) versus placebo-controlled trials (PCTs) of new antihypertensive drugs. DESIGN AND SETTING: Nationwide mailed survey, with telephone contact of nonresponders to assess nonresponse bias. PARTICIPANTS: One thousand two hundred primary care physicians randomly selected from the American Medical Association's Master File. Of 1,154 physicians eligible to respond, 651 (56.4%) returned completed questionnaires. MEASUREMENTS AND MAIN RESULTS: We measured physicians' stated willingness to encourage hypertensive patients to enroll in ACTs and PCTs of new antihypertensive drugs, their views of the relative merits of ACTs versus PCTs, their stated willingness to prescribe new drugs tested in ACTs or PCTs, and their views regarding the overall justifiability of the 2 designs. Physicians were significantly more likely to indicate they would encourage their patients to enroll in ACTs than in PCTs (P <.0001). Physicians thought ACTs provided more valuable information for their practices, were more likely to lead to a public health benefit, offered enrolled patients greater opportunity for personal benefit, and were less likely to expose enrolled patients to unnecessary risks (all P <.0001). Physicians were more likely to prescribe new drugs that had been compared in ACTs (P <.0001), and viewed ACTs as a more justifiable method for testing new antihypertensive drugs (P <.0001). There was no evidence of nonresponse bias for these main results. CONCLUSIONS: Although PCTs remain the standard method for testing new antihypertensive drugs, physicians strongly prefer ACTs. Using ACTs to test new antihypertensive drugs may enhance the efficiency of patient recruitment and more strongly influence physicians' prescribing practices.     

Clinical trials update from the European Society of Cardiology–Heart Failure meeting 2015: AUGMENT‐HF,TITRATION, STOP‐HF,HARMONIZE, LION HEART,MOOD‐HF,and renin–angiotensin inhibitors in patients with heart and renal failure

This article provides an overview on the key trials relevant to the pathophysiology, prevention, and treatment of heart failure (HF) presented at the Heart Failure Association (HFA) of the European Society of Cardiology (ESC) annual meeting held in Seville, Spain in May 2015. Trials reported include AUGMENT‐AF (myocardial injections of calcium‐alginate hydrogel), a propensity score‐matched study of renin–angiotensin system antagonists in patients with HF and severe renal dysfunction, HARMONIZE (sodium zirconium cyclosilicate used to bind potassium), TITRATION, comparing two regimes for introducing LCZ696, STOP‐HF, a trial of intramyocardial stromal cell‐derived factor‐1, MOOD‐HF (escitalopram for patients with heart failure and depression), and LION HEART, a trial of intermittent levosimendan therapy. Unpublished reports should be considered as preliminary, since analyses may change in the final publication.     

Selection of patients for randomised trials: a study based on the MACOP-B vs CHOP in NHL study

Background: Selection of patients for a clinical trial is affected by awareness of the existence of the trial, interest in the study question and clinical practices and views of the clinicians.
Aims: To investigate the selectivity that may have occurred at Peter MacCallum Cancer Institute (PMCI) during the ANZ Lymphoma Group trial of MACOP-B vs CHOP in non-Hodgkin's lymphoma (NHL).
Methods: NHL patients at PMCI in the study period were assessed against the trial's eligibility criteria. Comparisons were made between eligible (except for consent) non-trial patients and all patients actually randomised into the trial.
Results: Of 497 patients presenting during the trial period, 320 (64%) did not meet the specified eligibility criteria, 102 (21%) were unsuitable on other grounds (age and medical) and 75 (15%) were eligible. Of those eligible, 43 (57%) were entered into the trial and 32 (43%) were not. Four non-trial patients had inappropriate application of eligibility criteria and 13 unknown reason. Eligible non-trial patients were similar to trial patients in most patient and tumour characteristics and overall survival. Significantly more non-trial patients had higher stage disease (p = 0.02). More non-trial patients had lower grade histology, but this was not significant.
Conclusions: Physician selectivity occurred with respect to patient entry, but trial and non-trial patients were similar in most characteristics. Eligibility criteria should specify that patients can withstand all trial drugs and patient availability for treatment and follow-up. PMCI trial accural could have been up to 33% greater. These results suggest the trial accrual period could have been 25% shorter. Patient entry into this trial by PMCI clinicians compared favourably with other centres. (Aust NZ J Med 1994; 24: 536–540.)     

The efficacy and safety of direct oral anticoagulants in patients with chronic renal insufficiency: A review of the literature

Direct oral anticoagulants (DOACs) have been shown to be superior to vitamin K antagonists (VKAs) in regards to safety and efficacy in numerous clinical trials and are now the preferred oral anticoagulant by multiple professional societies. However, patients with significant levels of organ dysfunction were excluded from all major clinical trials, leaving the clinical benefit in these subsets uncertain. Patients with chronic kidney disease (CKD) specifically often require anticoagulation for acute or long‐term indications such as venous thromboembolism, atrial fibrillation, or mechanical heart valves. The efficacy and safety of anticoagulation in patients with renal failure is less certain, however, particularly with DOACs which have altered pharmacokinetics in patients with renal failure and limited observational data on their use in this population. In this review, we compile the most up to date data on the DOAC use in patients with CKD. DOAC use in patients with ESRD and advanced CKD is increasing despite the presence of a clear benefit, and with the potential for increased risk of bleeding compared to warfarin. Apixaban has the greatest amount of outcomes research supporting its use over warfarin in this patient population; however, further research on DOAC safety and efficacy in those with advanced CKD is still needed.     

Top 10 landmark studies in hypertension

The field of hypertension has evolved considerably over the last 70 years, from a belief that elevated blood pressure was an inevitable consequence of aging and beneficial, to maintaining perfusion to overwhelming proof of the cardiovascular morbidity and mortality associated with elevated blood pressure. The authors reviewed the literature on hypertension and selected 10 studies pivotal in changing physicians’ attitudes regarding the management, treatment, and outcomes of hypertensive patients. Four studies cover treatment initiation and blood pressure goals, two studies compare pharmacologic antihypertensive agents, and the final four address the approach to blood pressure control in special populations (diabetes mellitus and chronic kidney disease). The authors readily acknowledge the many other contributions to the field of hypertension not profiled here.     

Special considerations for therapeutic choice of non–vitamin K antagonist oral anticoagulants for Japanese patients with nonvalvular atrial fibrillation

Nonvalvular atrial fibrillation (AF ) is a risk factor for stroke in elderly patients. Although warfarin has been used to prevent AF ‐associated stroke for more than 50 years, non–vitamin K antagonist oral anticoagulants (NOACs ) including dabigatran, rivaroxaban, apixaban, and edoxaban recently have been developed to overcome the disadvantages of warfarin. Based on the results of NOAC clinical trials, Savelieva and Camm made recommendations regarding selection of NOACs in patients with nonvalvular AF . Recent accumulating evidence indicates that NOACs work differently in Asian and non‐Asian individuals. In this review, we discuss the results of the large, randomized, phase 3 international clinical trials on NOACs , the subanalyses of Asians, and a Japanese phase 3 clinical trial of rivaroxaban to discriminate Japanese patient–specific characteristics with regard to their responses to NOACs and make recommendations. Our analysis revealed that rivaroxaban decreased the incidence of gastrointestinal (GI ) bleeding compared with warfarin in Japanese patients. The efficacy results showed that rivaroxaban significantly decreased the incidence of ischemic stroke (hazard ratio: 0.40, 95% confidence interval: 0.17‐0.96) compared with warfarin. The lower incidence of GI bleeding and ischemic stroke may be specific to Japanese patients. Based on the present and previous results, the following recommendations regarding the selection of NOACs are added in the Camm chart for Japanese patients: edoxaban for patients with a high risk of bleeding and those with a previous stroke; and rivaroxaban for patients with a high risk of ischemic stroke and a low bleeding risk, and those with previous GI bleeding.     

The Current Focus of Heart Failure Clinical Trials

Background

Heart failure (HF) is a major global health problem. Clinical trials test efficacy, effectiveness, and safety of novel and emerging therapies in HF. We sought to determine the salient features of ongoing interventional clinical trials in HF.