Evidence Of Treatment Benefit Research Articles

Association of Supporting Trial Evidence and Reimbursement for Off-Label Use of Cancer Drugs

In many health systems, access to off-label drug use is controlled through reimbursement restrictions by health insurers, especially for expensive cancer drugs. To determine whether evidence from randomized clinical trials is associated with reimbursement decisions for requested off-label use of anticancer drugs in the Swiss health system. This cross-sectional study used reimbursement requests from routinely collected health records of 5809 patients with drug treatment for cancer between January 2015 and July 2018 in 3 major cancer centers, covering cancer care of approximately 5% of the Swiss population, to identify off-label drug use. For each off-label use indication with 3 or more requests, randomized clinical trial evidence on treatment benefits was systematically identified for overall survival (OS) or progression-free survival (PFS). Data were analyzed from August 2018 to December 2020. Available randomized clinical trial evidence on benefits for OS or PFS for requested off-label use indications. The main outcome was the association between evidence for treatment benefit (expressed as improved OS or PFS) and reimbursement in multivariable regression models. Among 3046 patients with cancer, 695 off-label use reimbursement requests in 303 different indications were made for 598 patients (median [interquartile range] age, 64 [53-73] years; 420 [60%] men). Off-label use was intended as first-line treatment in 311 requests (45%). Reimbursement was accepted in 446 requests (64%). For 71 indications, including 431 requests for 376 patients, there were 3 or more requests. Of these, 246 requests (57%) had no supporting evidence for OS or PFS benefit. Reimbursement was granted in 162 of 246 requests without supporting evidence (66%). Of 117 requests supported by OS benefit, 79 (67%) were reimbursed, and of 68 requests supported by PFS benefit alone, 54 (79%) were reimbursed. Evidence of OS benefit from randomized clinical trials was not associated with a higher chance of reimbursement (odds ratio, 0.76, 95% CI, 0.45-1.27). These findings suggest that in a health care system enabling access to off-label use, it was frequently intended as a first-line treatment in cancer care. Availability of randomized clinical trial evidence showing survival benefit was not associated with reimbursement decisions for off-label anticancer drug treatment in Switzerland. A transparent process with criteria considering clinical evidence is needed for evidence-based reimbursement decisions to ensure fair access to cancer treatments.

Using the Bayesian credible subgroups method to identify populations benefiting from treatment: An application to the Look AHEAD trial.

Traditionally, subgroup analyses are used to assess whether patient characteristics moderate treatment effectiveness with general disregard for issues of multiplicity. Using data from The Action for Health in Diabetes (Look AHEAD) trial in the United States, we aim to identify a subgroup where all of its types of members experience a treatment benefit defined as reducing the likelihood of a major cardiovascular event under an intensive lifestyle and weight-loss intervention. We apply the credible subgroups method to a Bayesian logistic model with a conservative prior that is sceptical of large treatment effect heterogeneity. The covariate profiles for which there is sufficient evidence of treatment benefit are, coarsely, middle-aged women, in poor subjective general health and with moderately to poorly controlled diabetes. There is at least 80% posterior probability that the conditional average treatment effect is positive for all covariate profiles fitting this description, which account for 0.5% of trial participants. Conversely, the covariate profiles that are likely to be associated with no benefit are middle aged and older men in excellent subjective general health, with well-controlled diabetes. These profiles apply to less than 2% of trial participants. More information is required to determine treatment benefit or no benefit for the remainder of the trial population.

Thrombolysis in elderly stroke patients in Italy (TESPI) trial and updated meta-analysis of randomized controlled trials.

Since its approval, the use of alteplase had been limited to patients aged ≤80 years. TESPI trial had been designed to evaluate whether alteplase treatment within 3 h in patients with acute ischemic stroke aged >80 years resulted in favorable benefit/risk ratio compared with standard care. The meta-analysis of randomized controlled trials was updated to put findings in the context of all available evidence. TESPI was a multicenter, open-label with blinded outcome evaluation, randomized, controlled trial. Main clinical endpoints were 90-day favorable functional outcome (mRS score 0-2) and mortality and symptomatic intracerebral hemorrhage. The trial was prematurely terminated for ethical reasons after publication of IST-3 trial which provided evidence of treatment benefit in elderly. Of the planned 600 patients, 191 (88 assigned to alteplase) were enrolled. Overall, 24/83 (28.9%) alteplase patients had a favorable outcome compared to 22/95 (23.2%) controls (non-significant absolute difference of 5.7% for alteplase; OR 1.35, 95% CI 0.69-2.64, P = 0.381). Rates of death were non-significantly lower in the alteplase patients (18.1% vs. 26.5%); rates of symptomatic intracerebral hemorrhage were similar between the two groups (5.9% vs. 5.1%). The updated meta-analysis showed consistent results with prior estimates and add weights. The effects of alteplase observed in this interrupted trial did not reach statistical significance, probably for the small numbers, but are consistent with and add weight to the sum total of the randomized evidence demonstrating that alteplase is beneficial in patients with acute ischemic stroke aged over 80 years, particularly if given within 3 h.

From Clinical Trials to Bedside: the Use of Antihypertensives in Aged Individuals. Part 1: Evaluation and Evidence of Treatment Benefit

Use of antihypertensives in older adults can be complicated by the potential for undesired effects on comorbidities, adverse effects of the drugs, and overall medication burden. The purpose of this two-part review is to discuss contemporary issues encountered in the management of hypertension in aged individuals, with a particular focus on the individualization of treatment. In part 1, we discuss the evaluation of the aged hypertensive patient and review the clinical trial evidence for treatment benefit of hypertension in the elderly. Elderly patients with suspected hypertension need careful evaluation of their blood pressure, as errors in measurement technique, inaccurate devices, or overreliance on office blood pressure readings may lead to under- or over-treatment, thereby increasing risks of adverse medication effects and/or cardiovascular events. Epidemiologic evidence in older adults suggests a link between low blood pressure and increased mortality. However, key prospective hypertension trials such as HYVET and SPRINT, which were focused in mostly healthy, community-dwelling elderly cohorts, have unequivocally demonstrated benefits of lowering blood pressure in reducing cardiovascular events in the very elderly. Recent evidence also suggests benefit in reducing the risks of cognitive impairment. Hypertension is a major modifiable risk factor and the benefits of treatment in lowering cardiovascular events are realized for most individuals, even at advanced ages.

Evidence-Based Medicine

Descriptions of “evidence-based” approaches to medical care are now ubiquitous in both the popular press and medical journals. The term evidence-based medicine (EBM) was first coined in 1992, and over the last two decades, the field has experienced rapid growth, and its principles now permeate both graduate medical education and clinical practice. The field of EBM has been in constant evolution since its introduction and continues to undergo refinements as its principles are tested and applied in a wide variety of clinical circumstances. This review presents a brief history of EBM, EBM: fundamental tenets, a critical appraisal of a single study, reporting guidelines for single studies, a critical appraisal of a body of evidence, evidence-based surgery, and limitations in EBM. Tables list strength of evidence for treatment decisions (EBM working group), Oxford Centre for Evidence-Based Medicine revised levels of evidence for treatment benefits , “4S” approach to finding resources for EBM, critical appraisal of individual studies examining therapeutic decisions, reporting guidelines by study design, and key resources for evidence-based surgery. This review contains 6 tables and 85 references

Evidence-Based Medicine

Descriptions of “evidence-based” approaches to medical care are now ubiquitous in both the popular press and medical journals. The term evidence-based medicine (EBM) was first coined in 1992, and over the last two decades, the field has experienced rapid growth, and its principles now permeate both graduate medical education and clinical practice. The field of EBM has been in constant evolution since its introduction and continues to undergo refinements as its principles are tested and applied in a wide variety of clinical circumstances. This review presents a brief history of EBM, EBM: fundamental tenets, a critical appraisal of a single study, reporting guidelines for single studies, a critical appraisal of a body of evidence, evidence-based surgery, and limitations in EBM. Tables list strength of evidence for treatment decisions (EBM working group), Oxford Centre for Evidence-Based Medicine revised levels of evidence for treatment benefits , “4S” approach to finding resources for EBM, critical appraisal of individual studies examining therapeutic decisions, reporting guidelines by study design, and key resources for evidence-based surgery. This review contains 6 tables and 85 references

Treatment options for post-transplantation diabetes mellitus.

Treatment options for management of post-transplantation diabetes mellitus (PTDM) are limited with regards to the availability of strong clinical evidence base. This is a concern as PTDM is common after solid organ transplantation and associated with poor clinical outcomes. PTDM and type 2 diabetes mellitus are distinct pathophysiological entities that have important differences with regards to aetiology, clinical course and management. Therefore, any clinical evidence of treatment benefit from the general population with type 2 diabetes mellitus may not be directly translated to the solid organ transplant recipient. In addition, the potential risk and benefit of using many of these therapeutic agents must take account of the complicated post-transplantation milieu of immunosuppression. While there is reasonable evidence base for treatment of diabetes mellitus in the general population, the same is not true in a post-transplantation setting. In this article the treatment options available for PTDM will be discussed, with a transplant-specific focus on the pros and cons of each particular component of the glucose lowering therapy armoury.

Antiretroviral treatment of adult HIV infection: 2014 recommendations of the International Antiviral Society-USA Panel.

New data and antiretroviral regimens expand treatment choices in resource-rich settings and warrant an update of recommendations to treat adults infected with human immunodeficiency virus (HIV). To provide updated treatment recommendations for adults with HIV, emphasizing when to start treatment; what treatment to start; the use of laboratory monitoring tools; and managing treatment failure, switches, and simplification. An International Antiviral Society-USA panel of experts in HIV research and patient care considered previous data and reviewed new data since the 2012 update with literature searches in PubMed and EMBASE through June 2014. Recommendations and ratings were based on the quality of evidence and consensus. Antiretroviral therapy is recommended for all adults with HIV infection. Evidence for benefits of treatment and quality of available data increase at lower CD4 cell counts. Recommended initial regimens include 2 nucleoside reverse transcriptase inhibitors (NRTIs; abacavir/lamivudine or tenofovir disoproxil fumarate/emtricitabine) and a third single or boosted drug, which should be an integrase strand transfer inhibitor (dolutegravir, elvitegravir, or raltegravir), a nonnucleoside reverse transcriptase inhibitor (efavirenz or rilpivirine) or a boosted protease inhibitor (darunavir or atazanavir). Alternative regimens are available. Boosted protease inhibitor monotherapy is generally not recommended, but NRTI-sparing approaches may be considered. New guidance for optimal timing of monitoring of laboratory parameters is provided. Suspected treatment failure warrants rapid confirmation, performance of resistance testing while the patient is receiving the failing regimen, and evaluation of reasons for failure before consideration of switching therapy. Regimen switches for adverse effects, convenience, or to reduce costs should not jeopardize antiretroviral potency. After confirmed diagnosis of HIV infection, antiretroviral therapy should be initiated in all individuals who are willing and ready to start treatment. Regimens should be selected or changed based on resistance test results with consideration of dosing frequency, pill burden, adverse toxic effect profiles, comorbidities, and drug interactions.

Vitamin A and fish oils for retinitis pigmentosa

Retinitis pigmentosa (RP) comprises a group of hereditary eye diseases characterized by progressive degeneration of retinal photoreceptors. It results in severe visual loss that may lead to legal blindness. Symptoms may become manifest during childhood or adulthood, and include poor night vision (nyctalopia) and constriction of peripheral vision (visual field loss). This field loss is progressive and usually does not reduce central vision until late in the disease course.The worldwide prevalence of RP is one in 4000, with 100,000 patients affected in the USA. At this time, there is no proven therapy for RP. The objective of this review was to synthesize the best available evidence regarding the effectiveness and safety of vitamin A and fish oils (docosahexaenoic acid (DHA)) in preventing the progression of RP. We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (2013, Issue 7), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to August 2013), EMBASE (January 1980 to August 2013), Latin American and Caribbean Health Sciences Literature Database (LILACS) (January 1982 to August 2013), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 20 August 2013. We included randomized controlled trials (RCTs) evaluating the effectiveness of vitamin A, fish oils (DHA) or both, as a treatment for RP. We excluded cluster-randomized trials and cross-over trials. We pre-specified the following outcomes: mean change from baseline visual field, mean change from baseline electroretinogram (ERG) amplitudes, and anatomic changes as measured by optical coherence tomography (OCT), at one year; as well as mean change in visual acuity at five-year follow-up. Two authors independently evaluated risk of bias for all included trials and extracted data from the publications. We also contacted study investigators for further information on trials with publications that did not report outcomes on all randomized patients. We reviewed 394 titles and abstracts and nine ClinicalTrials.gov records and included three RCTs that met our eligibility criteria. The three trials included a total of 866 participants aged four to 55 years with RP of all forms of genetic predisposition. One trial evaluated the effect of vitamin A alone, one trial evaluated DHA alone, and a third trial evaluated DHA and vitamin A versus vitamin A alone. None of the RCTs had protocols available, so selective reporting bias was unclear for all. In addition, one trial did not specify the method for random sequence generation, so there was an unclear risk of bias. All three trials were graded as low risk of bias for all other domains. We did not perform meta-analysis due to clinical heterogeneity of participants and interventions across the included trials.The primary outcome, mean change of visual field from baseline at one year, was not reported in any of the studies. No toxicity or adverse events were reported in these three trials. No trial reported a statistically significant benefit of vitamin supplementation on the progression of visual field loss or visual acuity loss. Two of the three trials reported statistically significant differences in ERG amplitudes among some subgroups of participants, but these results have not been replicated or substantiated by findings in any of the other trials. Based on the results of three RCTs, there is no clear evidence for benefit of treatment with vitamin A and/or DHA for people with RP, in terms of the mean change in visual field and ERG amplitudes at one year and the mean change in visual acuity at five years follow-up. In future RCTs, since some of the studies in this review included unplanned subgroup analysis that suggested differential effects based on previous vitamin A exposure, investigators should consider examining this issue. Future trials should take into account the changes observed in ERG amplitudes and other outcome measures from trials included in this review, in addition to previous cohort studies, when calculating sample sizes to assure adequate power to detect clinically and statistically meaningful difference between treatment arms.

Randomized Trial of Early Developmental Intervention on Outcomes in Children after Birth Asphyxia in Developing Countries

To determine if early developmental intervention (EDI) improves developmental abilities in resuscitated children. This was a parallel group, randomized controlled trial of infants unresponsive to stimulation who received bag and mask ventilation as part of their resuscitation at birth and infants who did not require any resuscitation born in rural communities in India, Pakistan, and Zambia. Intervention infants received a parent-implemented EDI delivered with home visits by parent trainers every other week for 3 years starting the first month after birth. Parents in both intervention and control groups received health and safety counseling during home visits on the same schedule. The main outcome measure was the Mental Development Index (MDI) of the Bayley Scales of Infant Development, 2nd edition, assessed at 36 months by evaluators unaware of treatment group and resuscitation history. MDI was higher in the EDI (102.6±9.8) compared with the control resuscitated children (98.0±14.6, 1-sided P=.0202), but there was no difference between groups in the nonresuscitated children (100.1±10.7 vs 97.7±10.4, P=.1392). The Psychomotor Development Index was higher in the EDI group for both the resuscitated (P=.0430) and nonresuscitated children (P=.0164). This trial of home-based, parent provided EDI in children resuscitated at birth provides evidence oftreatment benefits on cognitive and psychomotor outcomes. MDI and Psychomotor Development Index scores of both nonresuscitated and resuscitated infants were within normal range, independent of early intervention.

Ethics for the Pediatrician

Ethics for the Pediatrician

Long-term follow-up of patients with candiduria

Candiduria is commonly encountered in hospitalized patients, particularly those with indwelling urinary catheters. While risk factors and therapy are well described in previous studies, little is known about long-term outcomes and recurrence rates of candiduria. We studied 188 patients with candiduria in a retrospective chart review at a single institution from January 1999 to December 2000. Data were collected regarding risk factors and underlying disease, therapy, follow-up cultures until December 2003, and mortality. Ninety-one patients with at least one follow-up culture >1 month after the initial culture (range 2-48) were available for further study. In this group, patients receiving antifungal therapy for asymptomatic candiduria were paradoxically more likely to have subsequent positive urine cultures than patients who never received antifungal therapy. Six patients developed candidemia during follow-up, although in none was this considered to represent a consequence of candiduria. Mortality rate at the end of the follow-up period (mean of 18 months) was 43%, including one death attributed to candidemia. Therapy for candiduria does not appear to reduce candiduria recurrence rates through 48 months of follow-up and little evidence of treatment benefit was identified.

102 Withdrawal of enzyme replacement therapy in Fabry disease: Indirect evidence of treatment benefit?

102 Withdrawal of enzyme replacement therapy in Fabry disease: Indirect evidence of treatment benefit?

WITHDRAWN: 63 Withdrawal of enzyme replacement therapy in Fabry disease: Indirect evidence of treatment benefit?

WITHDRAWN: 63 Withdrawal of enzyme replacement therapy in Fabry disease: Indirect evidence of treatment benefit?

Withdrawal of enzyme replacement therapy in Fabry disease: Indirect evidence of treatment benefit?

Withdrawal of enzyme replacement therapy in Fabry disease: Indirect evidence of treatment benefit?

Treating hypertension in the elderly: protagonist viewpoint.

Cardiovascular disease is the main cause of serious illness and death in the United States. Increasing age is a strong predictor of cardiovascular events, driven largely by such major conditions as hypertension and diabetes mellitus. Systolic hypertension probably reflects progressive stiffening of large and small arteries; close to 90% of all Americans will have this diagnosis by their 80s. Regardless of age, systolic hypertension is a powerful risk factor for stroke, heart failure, and other cardiovascular outcomes. Treating hypertension in the elderly sharply decreases the probability of these events. Clinical trial evidence does not include patients with stage 1 systolic hypertension (140-159 mm Hg), although the results in stage 2 are so convincing that it is very reasonable (as concluded by national guidelines committees) to extrapolate benefits and recommend treatment to patients in the less-severe group. Whereas evidence of treatment benefits in patients aged 80 years and older is limited, sufficient octogenarians have been studied to confidently assert that strokes, at least, can be prevented. Another potentially important benefit that is yet to be fully confirmed is that treating hypertension in older people may also reduce the incidence of dementia.

What should cardiologists be telling general practitioners/family physicians?

Within the next 20 years cardiovascular disease is expected to become the leading cause of premature death and overall mortality worldwide. Because cardiovascular disease is multifactorial in nature, global risk assessment is required. Treatments for cardiovascular disease are among the most evidence-based therapies available to clinicians, and evidence of treatment benefit has resulted in clear guidelines regarding which interventions to use. Nevertheless, there is considerable variation within health care systems with regard to the diagnosis, management and follow-up of patients with cardiovascular disease. Two recent European surveys, conducted among patients and physicians, have provided evidence of factors that may contribute to this variability in clinical performance.

Steroid trials in the assessment of reversibility of air flow limitation: a survey of current clinical practice of chest physicians

To evaluate how steroid trials are currently used in the assessment of reversibility of air flow limitation, a postal questionnaire was sent to 355 consultant members of the British Thoracic Society working in England and Wales; 253 questionnaires were returned (71% response rate). Two respondents did not undertake steroid trials; of the remaining 251, 75% prescribed 30-40 mg oral prednisolone, with the commonest treatment period being 2 weeks. A high dose steroid inhaler was sometimes used as an alternative by 31% of respondents. Although 71% of respondents made lung function measurements on several occasions before starting steroids and 76% made measurements during treatment, 78% assessed patients on only one occasion at the end of the trials to ascertain its outcome. Weight, blood pressure and glycosuria were measured less frequently after the steroid treatment compared to the pre-trial period. Blood glucose and serum electrolytes were infrequently measured both before and after treatment. Wide variations exist in steroid trial regimens and current practice may neither provide definitive evidence of treatment benefit nor an adequate safeguard for patients against potential side-effects.