Definition Of Treatment Failure Research Articles

Risk factors associated with failure 1 year after retropubic or transobturator midurethral slings

The objective of the study was to identify predictors of recurrent urinary incontinence (UI) 1 year after treatment with tension-free vaginal tape (TVT) and transobturator tape (TOT). One hundred sixty-two women with urodynamic stress urinary incontinence (SUI) were included in a clinical trial comparing TVT with TOT with at least 1 year of follow-up were included in this analysis. Potential clinical and urodynamic predictors for development of "any recurrent UI" or "recurrent SUI" 1 year after surgery were evaluated using logistic regression models. Subjects who received concurrent prolapse surgery and those taking anticholinergic medications preoperatively were more likely to develop any recurrent UI. Increasing age was independently associated with recurrent SUI. Risk factors were similar for TVT and TOT for both definitions of treatment failure. Concurrent prolapse surgery and preoperative anticholinergic medication use are associated with increased risk of developing recurrent UI 1 year after TVT or TOT. Increasing age is specifically associated with the recurrence of SUI symptoms.

Improvement in Symptoms and Function After Autologous Chondrocyte Implantation in Patients Who Failed Prior Treatment: Results of the Study of Treatment of Articular Repair (STAR) (SS-20)

Patients who have moderate to large symptomatic chondral knee lesions, significant functional impairment and pain, and failed prior cartilage repair procedures can expect durable and significant functional improvement and symptom reductions following ACI. The purpose of this study was to assess the efficacy of ACI in patients who within the 3 years prior to study enrollment had failed a prior, non-ACI, index surgical treatment for articular cartilage defect(s) of the distal femur. This was a 4 year, prospective, multicenter study of ACI performed in patients who, by predefined criteria, failed a prior, non-ACI, index treatment that included microfracture, osteochondral autograft, or debridement. The primary endpoint was assessment of durability of ACI (Carticel®) compared to the durability of the prior, non-ACI, index treatment for each patient. Secondary endpoints included improvements in function and reduction in symptoms as captured by the KOOS, Modified Overall Cincinnati Knee Scale, VAS current knee condition, and SF-36. Serious adverse events, including surgeries after ACI (SSP-subsequent surgical procedures), irrespective of relationship to ACI, were recorded. A sample size of 100 provided 90% power at α=0.05. 154 patients received ACI following determination that they had failed the prior, non-ACI, index treatment. 82% (126/154) of patients completed the protocol. At baseline, mean age was 34.5 years; mean lesion size was 4.6 cm2. Index lesion was located in the MFC, LFC and trochlea in 66%, 18%, and 16% of patients, respectively. Multiple lesions were observed in 50 patients. The mean Modified Overall Cincinnati Knee score at baseline was 3.26, indicating moderate to significant limitations with activities of daily living. By the end of the study, 76% (117/154) of patients were ACI treatment successes (did not meet the a priori definition of treatment failure). Significant mean improvements from baseline to 48 month follow-up were observed for the following reported outcome scores (p<0.001). Preoperative to postoperative (48 month) mean values, respectively, are KOOS Pain: 48.7 to 72.2; KOOS Symptoms: 51.8 to 70.8; KOOS Sports/Recreation: 25.9 to 55.8; KOOS Knee Quality: 20.9 to 52.2; KOOS ADL: 58.6 to 81.0; Modified Overall Cincinnati Knee Scale: 3.26 to 6.31; VAS: 28.8 to 69.9; and SF-36 Physical Component Summary Scale: 33.0 to 44.4. 49% (76/154) of patients had an SSP, irrespective of relationship to ACI. The most common findings at SSPs were arthrofibrosis or joint adhesions and graft overgrowth. Having an SSP was not predictive of ACI failure. Patients who have moderate to large symptomatic chondral knee lesions, significant functional impairment and pain, and failed prior cartilage repair procedures can expect durable and significant functional improvement and symptom reductions following ACI.

Disability as an outcome in MS clinical trials

Inferences about long-term effects of therapies in multiple sclerosis (MS) have been based on surrogate markers studied in short-term trials. Preventing progressive disability is the key therapeutic goal but there remains no validated definition for its measurement in a trial context. Meanwhile, MS trials continue to shorten and to depend on unvalidated surrogates. Since there have been no treatment claims for improving unremitting disability, worsening of disability in the placebo/control arm must occur for effectiveness on this outcome to be shown. We examined widely-used clinical surrogates of long-term disability progression in individual patients with MS within a unique database from the placebo arms of 31 randomized clinical trials. Detection of treatment effects in secondary progressive MS trials is undermined by noise in disability measurement. Whereas existing measures can be partially validated in secondary progressive MS, this is not the case in relapsing-remitting MS. Here, examination of widely used definitions of treatment failure demonstrated that disability progression was no more likely than similarly defined improvement. Existing definitions of disease progression in short-term intervention trials in relapsing-remitting patients reflect random variation, measurement error, and remitting relapses. Clinical surrogates of unremitting disability used in trials of relapsing-remitting multiple sclerosis cannot be validated. Trials have been too short or degrees of disability change too small to measure the key outcomes. These analyses highlight the difficulty in determining effectiveness of therapy in chronic diseases.

Current Evidence and Therapeutic Strategies for Multiple Sclerosis

In the previous two decades several immunomodulatory and immunosuppressive therapies have been shown to favorably impact the inflammatory activity and course of multiple sclerosis. There are now six approved therapies for the disease. Clinical decision-making has become more complex because of the increasing number of available drugs, the lack of head-to-head comparisons that allow direct comparisons of efficacy, and special factors that may influence efficacy such as neutralizing antibodies against beta-interferon preparations. Furthermore, all current therapies are partially effective; therefore, most patients experience breakthrough disease activity while using them, and there are no validated treatment failure definitions or management algorithms. This review outlines current evidence supporting efficacy of available drugs and scenarios for which more studies are required, and highlights the need for emerging therapies and strategies for multiple sclerosis management, including investigative oral and parenteral agents and combination therapy approaches.

“Contents May Vary”: A Pilot Study of Treatment Histories of OCD Patients

Definitions of treatment failure and the labelling of patients as non-responsive typically require treatments to have been offered and failed. For pharmacological treatments, treatment quality is relatively easy to define; this is much more difficult with psychological treatments. This study examined patient recollections of previous therapy for obsessive compulsive disorder (OCD). A Treatment History Questionnaire was administered to a sample of 57 apparently treatment refractory OCD patients from a specialist national OCD treatment unit and a national charity for OCD sufferers. On average, respondents reported an 8$\frac{1}{2}$ year wait between the obsessional symptoms interfering significantly with their lives and being diagnosed. Forty-three percent recalled having received either cognitive behaviour therapy (CBT) or behaviour therapy as the first treatment; 31% of the group did not know what type of therapy they had received. The components of therapy that respondents recalled were analysed and contrasted with minimal therapy criteria. These criteria appear not to have been met in most patients who understood that they had received “CBT”. The implications of this study for assessment of treatment integrity and the classification of patients as “treatment resistant” are discussed.

Performance of Immunologic Responses in Predicting Viral Load Suppression

World Health Organization (WHO) guidelines for the use of antiretroviral therapy (ART) in resource-limited settings state that CD4 cell counts may be used to indicate when ART regimens should be changed because of treatment failure. The performance of immunologic monitoring for this purpose has not been evaluated, however. Participants aged > or =18 years from the British Columbia HIV/AIDS Drug Treatment Program who had CD4 cell counts < or =200 cells/microL or an AIDS diagnosis at baseline had CD4 cell counts measured at 6 and 12 months after treatment initiation. Logistic regression analysis was used to calculate sensitivity, specificity, and positive and negative predictive values for immunologic responses in terms of predicting failure to achieve 2 viral load measurements < 500 copies/mL within 1 year. Viral load suppression occurred in 674 (60%) of 1125 subjects. Using no increase in CD4 cell counts at 6 months as a definition of treatment failure had a sensitivity of 34%, specificity of 94%, positive predictive value of 75%, and negative predictive value of 71% for predicting failure to achieve virologic suppression. Using 12-month CD4 cell count values, the measurements were 35%, 95%, 79%, and 73%, respectively. Immunologic criteria to predict which patients have not achieved virologic suppression results in significant misclassification of therapeutic responses.

Resistance to sulphadrug-based antifolate therapy in malaria: are we looking in the right place?

Sulphadrug treatment failure in malaria therapy cannot solely be ascribed to the build-up of genetic resistance within the parasitic genome. Although numerous in vitro studies have tried to determine the exact genetic markers that could predict treatment outcome in patients, this research has not been conclusive. Sulphadrugs work by competitive inhibition with pABA at one point of the pathway to de novo folate synthesis. However, evidence suggests that the malaria parasite is capable of overcoming this competitive inhibition by switching over to other metabolic pathways, like direct folate salvage from a person's bloodstream. In other words, increased folic acid administration, via diet or supplementation, may have reduced the effectiveness of sulphadrugs more than genetic mutations. Although in vitro studies are valuable for understanding disease mechanisms, we should not forget that the human being is infinitely more complex than any laboratory model.

Treatment Options for Erectile Dysfunction in Patients Failing Oral Drug Therapy

Oral drug therapy is the first line treatment for erectile dysfunction. Efficacy of oral drugs does not exceed 70%, while drop-out rate is high. Therefore, salvage strategies and second/third line treatment options are necessary to restore erectile function in such patients. The article reviews currently available data and comment on key issues that urologists address on their every day clinical practice. In order to do so, a literature-based critical presentation on the current methodological problems on definition of treatment failure, treatment outcome assessment and alternative therapeutic options was made. Emphasis was given in identifying truly non-responders, as proper instructions for oral drug administration and psychosexual counselling may reverse a substantial number of non-responders to responders. Medication, clinical and patient/partner related issues have been identify that may lead to treatment failure. Treatment outcome assessment based not only on quality of erectile response, but also on side effects profile and patient satisfaction is recommended. Treatment options for truly non-responders include intracavernosal injections, combination therapies, and penile prosthesis. Management strategy however, must identify patient and partner needs and expectations and involve them in the decision-making.

What is “biochemical failure” in prostate cancer?

Increases in prostate-specific antigen (PSA) are often used as a surrogate endpoint (e.g., for mortality) when evaluating potential benefits of therapy for cancer of the prostate (CaP). In this context, different definitions of “failure” have evolved for each type of treatment (e.g., surgery, radiation), leading to potential confusion when physicians and patients evaluate data on outcomes. Our purpose was to compare existing, and evaluate a new, definition(s) of PSA failure. Patients were from an ongoing study of 1320 men diagnosed with CaP in the New England Veterans Affairs Healthcare System during 1991–1995. To ensure an adequate spectrum of CaP, a random sample of 125 men with CaP who died were first identified, and 125 age-matched men with CaP who were still alive were selected from the same VA sites. Data regarding baseline characteristic and post-treatment PSA (4–9 year follow-up) were collected. Proportions of men with PSA failure and median time to PSA failure were determined, regardless of actual therapy received, based on criteria a) after prostatectomy (any detectable PSA); b) after radiotherapy, as per the American Society of Therapeutic Radiation and Oncology (ASTRO) (three consecutive rises after a nadir PSA); and c) applying a threshold for PSA slope (1 ng/mL/year). Among 250 men, 12 (4.8%) were excluded (e.g., unavailable records). For the remaining 238 patients, surgical failure was evident in 165 (69.3%), whereas ASTRO classified 86 (36.1%) as having failed; kappa statistic for concordance = 0.28 (95% confidence interval 0.17–0.38), indicating “poor” agreement. The median time to PSA failure also varied widely: 4.5 months for surgery vs. 37.6 months per ASTRO. Failure based on PSA slope identified 112 men (47.1%); the median time to failure (22.7 months) was also intermediate between the existing approaches. Currently used definitions of treatment failure in CaP can produce substantially different results when assessing the same clinical phenomena. A new definition of PSA failure, based on slope of PSA, is easy to use and applicable regardless of type of treatment. This research can improve the ability of providers (and their patients) to make informed and appropriate decisions regarding treatment for prostate cancer.

Antiretroviral failure: a biopsychosocial approach.

How to manage patients who have failed one or more intensive antiretroviral regimens is one of the most vexing questions in the current treatment of HIV. An increasingly common scenario involves a patient who may have initially responded favorably to antiretroviral therapy, but whose viral load is now increasing. Such a patient may have been exposed to numerous antiretroviral drugs in a succession of combination regimens. In these scenarios, consultants are often asked to help design salvage regimens. When a patient's antiretroviral therapy is identified as "failing," the natural impulse is to seek another regimen that will succeed. The desire to fully suppress viral replication, however, must be tempered by a full appreciation of the implications of changing therapy. The clinician should consider two factors. First, the overall success rates of salvage regimens are significantly lower than the success rates of initial therapies, probably for two reasons: (a) cross-resistance between agents used in the salvage regimen and agents used in previous failing regimens and (b) reduced adherence to salvage regimens caused by increased complexity, pill burden, and toxicity. Second, if a salvage regimen is not fully suppressive or is not taken correctly, it may lead to the selection of additional resistance mutations, making the patient's virus even more difficult to treat in the future. Every change in therapy, therefore, carries significant risks. Such changes should generally be undertaken with reluctance and only when the anticipated benefits clearly outweigh these risks. Unfortunately, no clear definition of treatment failure is available to guide clinicians in changing therapy. Table 1 lists some of the many definitions of treatment failure currently in use among HIV clinicians. Depending on the definitions chosen (and the sensitivity of the viral-load assay used), many patients are virologic failures but remain immunologic and clinical successes. Although there is good …

The natural history of multiple sclerosis: implications for trial design.

The understanding of the natural history of multiple sclerosis has many implications for the design and interpretation of randomized controlled trials. Selection criteria, patient stratification, outcome measurements, and definitions of treatment failure can influence randomized controlled trial results and limit comparisons among trials. The focus of future studies should shift from short-term determinations of efficacy to definitive evaluations of long-term effectiveness. This will require novel investigative strategies such as the use of historic controls derived from natural history studies.

Salvage treatment against human immunodeficiency virus

Despite dramatic declines in human immunodeficiency virus (HIV)-associated morbidity and mortality as a result of highly active antiretroviral combination therapies, including protease inhibitors, treatment failure occurs at such high rates as 20-50%. As drug regimens are very demanding, even short decreases of drug concentrations may trigger resistance. Viral loads can be decreased to very low concentrations, and there is no strict cut-off regarding the definition of treatment failure. Nevertheless, continuous detection of HIV of more than 50 copies per mL blood plasma is a predictor of increasing viral loads and of a suboptimal response to therapy. From a theoretical point of view, treatment changes should be made at low HIV RNA levels, but fewer options often dictate a more conservative approach. Drug susceptibility testing will be of increasing value, especially in patients experiencing drug failure for the first time. Success of salvage therapies is closely connected with the use of new compounds including new drug classes. As drugs susceptible to a multi-drug-resistant HIV are not yet available, regimens with more than three or even with five to nine drugs are used in clinical trials. Salvage therapies often fail in virological terms, ie in 50-80% of patients, depending primarily on the treatment history, but immunological and clinical stability can often be achieved.

Virological treatment failure of protease inhibitor therapy in an unselected cohort of HIV-infected patients.

To determine the rate of virological treatment failure with protease inhibitor therapy in unselected patients and to assess underlying risk factors. Retrospective study in two German tertiary care treatment centres. A total of 198 HIV-infected patients treated with protease inhibitors in 1996. Levels of HIV RNA 1-6 months after start of treatment; definition of treatment failure of < 1 log10 reduction in plasma HIV RNA within 6 months after starting protease inhibitor therapy; multivariate analysis of risk factors for treatment failures. A total of 226 treatment episodes with protease inhibitors were evaluable (saquinavir, 83; ritonavir, 47; indinavir, 96). The rate of virological treatment failure was 44% (saquinavir, 64%; ritonavir, 38%; indinavir, 30%). In a multivariate analysis, the following independent risk factors for virological failure were found: CD4 cell count, pretreatment with antiretroviral drugs (number), and protease inhibitor (compound). The relative risk reduction for each CD4 cell count increase was 0.997 (P = 0.012), 2.64 for pretreatment with one or two drugs versus no drug (P = 0.05), 2.97 for pretreatment with more than two drugs versus no drug (P = 0.05), and 4.62 for treatment with saquinavir versus indinavir (P = 0.001). An unexpectedly high rate of virological treatment failure of protease inhibitor therapy was found in an unselected cohort of HIV-infected patients. Response to antiretroviral combination therapy in normal clinical practice may considerably differ from results of randomized clinical trials. Further studies are warranted to find optimal treatment strategies for both initial and salvage therapy.

Meta-analysis of the placebo-treated groups in clinical trials of progressive MS

The behavior of the control groups can substantially affect the power and outcome of a clinical trial. We report a meta-analysis of the control groups of four large, double-blind, placebo-controlled clinical trials of immuno-suppressive treatment of progressive MS to address the sensitivity of five hypothetical definitions of treatment failure (TF). The rate of TF in the aggregate control groups (n = 427) was 31% when a confirmed increase of 1.0 expanded disability status scale (EDSS) point was required at the end of the trial; it was 51% when confirmation was not required and TF was allowed at the first point where the criteria for TF were met. The rate of confirmed TF was 45% when the TF criteria were indexed to baseline EDSS, accounting for the observed differences in staying times at different EDSS levels. We developed models predicting TF in progressive MS. In addition to baseline EDSS, the pyramidal functional score and, for one definition, brainstem functional score were associated with probability of TF.

Comparison of three nonsurgical treatments for bleeding esophageal varices

Ninety-seven patients with recent or active variceal bleeding were randomly assigned to oral propranolol, endoscopic sclerotherapy plus oral propranolol, or transhepatic sclerotherapy plus oral propranolol. The effects of treatment on the number of units transfused, rebleeding of any magnitude, major rebleeding, and death were assessed in these patients, 82% of whom were alcoholic and 81% Child's Class C. After a minimum follow-up interval of 2 yr (range, 27–65 mo), major rebleeding rates were 65% for propranolol alone, 45% for endoscopic sclerotherapy plus propranolol, and 60% for transhepatic sclerotherapy plus propranolol. The corresponding death rates were 81% for propranolol alone, 55% for endoscopic sclerotherapy plus propranolol, and 66% for transhepatic sclerotherapy plus propranolol (p = 0.03). Thirty-three patients (34%) never received propranolol: 8 due to medical contraindications and 25 because they died or bled enough to meet the definition of treatment failure within 3 or 4 days of randomizations (no significant differences among treatment groups). Patients assigned to propranolol alone bled sooner, bled more units, and had a higher mortality rate than patients treated by endoscopic sclerotherapy plus propranolol. Patients treated with transhepatic sclerotherapy plus propranolol had intermediate results. Propranolol alone is inadequate treatment for esophageal variceal bleeding in patients with advanced liver disease.

Comparison of Three Nonsurgical Comparison Treatments for Bleeding Esophageal Varices

Ninety-seven patients with recent or active variceal bleeding were randomly assigned to oral propranolol, endoscopic sclerotherapy plus oral propranolol, or transhepatic sclerotherapy plus oral propranolol. The effects of treatment on the number of units transfused, rebleeding of any magnitude, major rebleeding, and death were assessed in these patients, 82% of whom were alcoholic and 81% Child's Class C. After a minimum follow-up interval of 2 yr (range, 27–65 mo), major rebleeding rates were 65% for propranolol alone, 45% for endoscopic sclerotherapy plus propranolol, and 60% for transhepatic sclerotherapy plus propranolol. The corresponding death rates were 81% for propranolol alone, 55% for endoscopic sclerotherapy plus propranolol, and 66% for transhepatic sclerotherapy plus propranolol (p = 0.03). Thirty-three patients (34%) never received propranolol: 8 due to medical contraindications and 25 because they died or bled enough to meet the definition of treatment failure within 3 or 4 days of randomizations (no significant differences among treatment groups). Patients assigned to propranolol alone bled sooner, bled more units, and had a higher mortality rate than patients treated by endoscopic sclerotherapy plus propranolol. Patients treated with transhepatic sclerotherapy plus propranolol had intermediate results. Propranolol alone is inadequate treatment for esophageal variceal bleeding in patients with advanced liver disease.

A Tri-Institutional Comparison of Tissue and Mechanical Valves using a Patient-Oriented Definition of “Treatment Failure”

Selection of valve type for predominant usage is obscured by limiting the analysis to prosthesis-related rather than patient-oriented failure modes. In this report, “treatment failure” is defined as a valve-related death or permanent patient disability; successful reoperations are excluded, and emboli with permanent residua are included. Results with the Starr-Edwards Silastic ball valve (Oregon) and the Hancock (Stanford) and Carpentier-Edwards (Vancouver) porcine valves are compared using this new definition of treatment failure.

The relative roles of neurological examination, functional abilities, and computed tomography in the definition of treatment failure in patients with anaplastic gliomas

Forty-one patients with anaplastic gliomas undergoing postoperative treatment and evaluation underwent bimonthly evaluation of the following indices of treatment failure: neurological examination; Karnofsky functional rating; and computed tomography (CT) brain scanning. Treatment failure was declared when neurological examination or Karnofsky rating showed increased impairment or when CT scan revealed an increase in tumor sizes. Most often, all three indices simultaneously indicated treatment failure. In only 6 of 41 cases the CT scan alone was the first indication of treatment failure. During the first 6 months of follow-up, tumor enlargement on CT scan as a sole index of treatment failure occurred in only 3 of 26 cases that showed evidence of treatment failure during that time. For patients with glioblastoma, about 6% of treatment failures within 6 months are predicted to be missed by Karnofsky rating plus neurological examination, whereas CT scan alone is predicted to miss about 30%. It would seem reasonable to rely on the neurological examination and Karnofsky rating for follow-up during the first 6 months after surgery, without routine serial CT scanning during that time.