AFFIRM Study Research Articles

Comparative efficacy of subcutaneous versus intravenous natalizumab on annualized relapse rate: A post-hoc analysis of the REFINE study

BackgroundThe non-inferiority of the efficacy of subcutaneous (SC) vs intravenous (IV) administration of natalizumab (NTZ) once every 4 weeks in relapsing-remitting multiple sclerosis (RRMS) was recently demonstrated on the primary outcome of the REFINE study, i.e. MRI “combined unique active lesions number” (CUAL). To provide further evidence on the comparative efficacy of the two NTZ formulations, the effect of NTZ-SC vs NTZ-IV on annualized relapse rate (ARR) was investigated re-analysing the REFINE dataset. MethodsPost-hoc analysis of the REFINE study dataset aimed at exploring the non-inferiority of the efficacy of NTZ-SC vs NTZ-IV on ARR, i.e. the main secondary outcome of the REFINE study. Robustness of the non-inferiority analysis on CUAL with respect to the presence of cases from the SC arm who received a rescue treatment, including NTZ-IV, was also assessed by sensitivity analyses. Three non-inferiority margins were selected, corresponding to 25 %, 33 %, and 50 % fractions of the effect size of NTZ-IV vs placebo observed in the AFFIRM study on ARR (i.e. 0.125, 0.170, and 0.250). ResultsNinety-nine RRMS patients were included. The mean difference in the effect of NTZ-SC vs NTZ-IV on ARR was close to 0. The lower bound of the 95 % confidence interval (worst case scenario) was –0.119, corresponding to 25 % (p = 0.025) of the effect of NTZ-IV vs placebo on ARR. Sensitivity analyses confirmed the results of the primary non-inferiority analysis on the outcome CUAL. ConclusionsNTZ-SC resulted not inferior to NTZ-IV on ARR for all the non-inferiority margins. The non-inferiority analysis of the efficacy of NTZ-SC vs NTZ-IV on CUAL was demonstrated to be robust with respect to rescued patients.

Non-inferiority analysis of subcutaneous versus intravenous 300 mg monthly natalizumab administration: A post hoc analysis of the REFINE study

To quantify the probability that monthly intravenous (IV) and subcutaneous (SC) natalizumab (NTZ) had similar efficacy in relapsing-remitting multiple sclerosis (RRMS), non-inferiority of efficacy of NTZ-SC versus NTZ-IV on combined MRI unique active lesions number (CUAL) was explored re-analysing the REFINE data set. Non-inferiority margins were selected equal to 25%/33%/50% fractions of the effect size of NTZ-IV versus placebo observed in the AFFIRM study. Ninety-nine RRMS were included. NTZ-SC resulted not inferior to NTZ-IV on CUAL for all margins at 2.5% significance level, and, in worst-case scenario, its effect over NTZ-IV did not exceed 3.5% (or 2.8%) of the effect of NTZ-IV versus placebo.

The impact of visit-to-visit heart rate variability on all-cause mortality in atrial fibrillation.

We aimed to investigate the association between visit-to-visit heart rate variability (VVHRV) and all-cause mortality in patients diagnosed with atrial fibrillation (AF). Previous studies have shown a positive correlation between VVHRV and several adverse outcomes. However, the relationship between VVHRV and the prognosis of AF remains uncertain. In our study, we aimed to examine the relationship between VVHRV and mortality rates among 3983 participants with AF, who were part of the AFFIRM study (Atrial Fibrillation Follow-Up Investigation of Rhythm Management). We used the standard deviation of heart rate (HRSD) to measure VVHRV and divided the patients into four groups based on quartiles of HRSD (1st, <5.69; 2nd, 5.69-8.00; 3rd, 8.01-11.01; and 4th, ≥11.02). Our primary endpoint was all-cause death, and we estimated the hazard ratios for mortality using the Cox proportional hazard regressions. Our analysis included 3983 participants from the AFFIRM study and followed for an average of 3.5 years. During this period, 621 participants died from all causes. In multiple-adjustment models, we found that the lowest and highest quartiles of HRSD independently predicted an increased risk of all-cause mortality compared to the other two quartiles, presenting a U-shaped relationship (1st vs 2nd, hazard ratio = 2.28, 95% CI = 1.63-3.20, p < .01; 1st vs. 3rd, hazard ratio = 2.23, 95% CI = 1.60-3.11, p < .01; 4th vs. 2nd, hazard ratio = 1.82, 95% CI = 1.26-2.61, p < .01; and 4th vs. 3rd, hazard ratio = 1.78, 95% CI = 1.25-2.52, p < .01). In patients with AF, we found that both lower VVHRV and higher VVHRV increased the risk of all-cause mortality, indicating a U-shaped curve relationship.

Abstract 13898: A Comparison of Rate Control Agents in Patients With Atrial Fibrillation: Follow-up Investigation of Affirm Study

Introduction: There is limited data from randomized controlled trials comparing rate control agents in patients with atrial fibrillation (AF). We used patient-level data from the AFFIRM trial to compare outcomes in patients randomized to the rate control arm who were treated with a single rate control agent at baseline, including beta-blockers (BB), calcium channel blockers (CCB), or digoxin. Methods: Patient-level data from the AFFIRM trial was provided through the NHLBI BioLINCC biologic specimens and data repository information coordinating center. Different data sets were used to obtain the data for analysis. The independent variable for this analysis was the initial study drug used, which was classified as BB, CCB, or digoxin. The dependent variables were time to first hospitalization and time to death. Cox proportional hazards survival models were used to control for baseline differences between groups. Results: We analyzed 1144 out of 2027 participants assigned to the rate control group who were on a single rate control agent at the start of the trial. 485 (42.5%) participants were in the BB group, 344 (30%) in the CCB group, and 315 (27.5%) in the digoxin group. The mean age was 69.6 ± 8.0 and the majority of participants (62.9%) were male. Significant differences in baseline characteristics were present between groups, including sex, history of heart disease, left ventricular (LV) ejection fraction, LV diastolic dimension, and history of pulmonary disease. Hospitalization and death occurred in 55.9% and 12.5% of those in the BB group, 58.4% and 16.7% in the CCB group, and 55.2% and 21.1% in the digoxin group, respectively. After adjustment for differences in baseline characteristics, there were no significant differences in time to hospitalization or death for any group compared to another. Conclusions: In the AFFIRM trial, the initial rate control drug used was not associated with statistically significant differences in time to hospitalization or death after controlling for differences in baseline characteristics. There is limited data at present to guide the selection of rate control agents in patients with AF.

A mixed-methods exploration of faith, spirituality, and health program interest among older African Americans with HIV

Persons living with HIV (PLWH) are living into old age with more complex care needs that non-PLWH. Promoting quality of life should include advance care planning (ACP) education, particularly among African Americans. We explored faith/spirituality-related correlates of interest in a future quality of life program among African American PLWH. Data were from the AFFIRM study. Participants were recruited from an HIV clinic and completed surveys, interviews, and focus groups. Quantitative analyses included Logistic regression. Qualitative data were coded using grounded theory. Nearly half of participants had less than a high school education (47.9%), and roughly 90% had heard of at least one ACP-related topic (86.6%; N = 315). Qualitative themes related to quality of life and faith/spirituality were: (1) Coping with life challenges; (2) Motivation to improve health for loved ones; and (3) Support programs for people with HIV (N = 39). Satisfaction with religion/spirituality was associated with greater interest in a future program (p < .05); discussing ACP before getting sick was associated with less interest (p < .05). Prioritizing skill-building and grounding in spirituality with input from faith leaders can reduce ACP inequities and improve health outcomes among African Americans.

Advanced Prostate Cancer: AUA/ASTRO/SUO Guideline PART II.

The summary presented herein represents Part II of the two-part series dedicated to Advanced Prostate Cancer: AUA/ASTRO/SUO Guideline discussing prognostic and treatment recommendations for patients with castration-resistant disease. Please refer to Part I for discussion of the management of patients with biochemical recurrence without metastatic disease after exhaustion of local treatment options as well as those with metastatic hormone-sensitive prostate cancer. The Advanced Prostate Cancer Panel created evidence- and consensus-based guideline statements to aid clinicians in the management of patients with advanced prostate cancer. Such statements are summarized in figure 1[Figure: see text] and detailed herein. The systematic review utilized to inform this guideline was conducted by an independent methodological consultant. A research librarian conducted searches in Ovid MEDLINE (1998 to January Week 5 2019), Cochrane Central Register of Controlled Trials (through December 2018), and Cochrane Database of Systematic Reviews (2005 through February 6, 2019). An updated search was conducted prior to publication through January 20, 2020. The methodology team supplemented searches of electronic databases with the studies included in the prior AUA review and by reviewing reference lists of relevant articles. This guideline attempts to improve a clinician's ability to treat patients diagnosed with advanced prostate cancer. Continued research and publication of high-quality evidence from future trials will be essential to improve the level of care for these patients.

The risk of cesarean delivery after labor induction among women with prior pregnancy complications: a subgroup analysis of the AFFIRM study

BackgroundTo determine the risk of cesarean delivery after labor induction among patients with prior placenta-mediated pregnancy complications (pre-eclampsia, late pregnancy loss, placental abruption or intrauterine growth restriction).MethodsThe AFFIRM database includes patient level data from 9 randomized controlled trials that evaluated the role of LMWH versus no LMWH during pregnancy to prevent recurrent placenta-mediated pregnancy complications. The primary outcome of this sub-study was the proportion of women who had an unplanned cesarean delivery after induction of labor compared to after spontaneous labor.ResultsThere were 512 patients from 7 randomized trials included in our sub-study. There was no difference in the risk of cesarean delivery between women with labor induction (21/148, 14.2%) and spontaneous labor (79/364, 21.7%) (odds ratio (OR) 0.60, 95% CI, 0.35–1.01; p = 0.052). Among 274 women who used LMWH prophylaxis during pregnancy, the risk of cesarean delivery was lower among those that underwent labor induction (9.8%) compared to spontaneous labor (22.4%) (OR 0.38, 95% CI, 0.17–0.84; p = 0.01).ConclusionsThe risk of cesarean delivery is not increased after labor induction among a higher risk patient population with prior pregnancy complications. Our results suggest that women who receive LMWH during pregnancy might benefit from labor induction.

Awareness of Fetal Movements and Care Package to Reduce Fetal Mortality (AFFIRM): A Stepped Wedge, Cluster-Randomised Trial

(Abstracted from Lancet 2018;392:1629–1638) Two to 6 million pregnancies were estimated to have ended in stillbirth in 2015. The aim of the AFFIRM study was to test the hypothesis that introduction of a reduced fetal movement care package for pregnant women and clinicians that increased women's awareness of the need for prompt reporting of RFM and that standardized management, including timely delivery, would alter the incidence of stillbirth.

Awareness of fetal movements and care package to reduce fetal mortality (AFFIRM): a stepped wedge, cluster-randomised trial

SummaryBackground2·6 million pregnancies were estimated to have ended in stillbirth in 2015. The aim of the AFFIRM study was to test the hypothesis that introduction of a reduced fetal movement (RFM), care package for pregnant women and clinicians that increased women's awareness of the need for prompt reporting of RFM and that standardised management, including timely delivery, would alter the incidence of stillbirth.MethodsThis stepped wedge, cluster-randomised trial was done in the UK and Ireland. Participating maternity hospitals were grouped and randomised, using a computer-generated allocation scheme, to one of nine intervention implementation dates (at 3 month intervals). This date was concealed from clusters and the trial team until 3 months before the implementation date. Each participating hospital had three observation periods: a control period from Jan 1, 2014, until randomised date of intervention initiation; a washout period from the implementation date and for 2 months; and the intervention period from the end of the washout period until Dec 31, 2016. Treatment allocation was not concealed from participating women and caregivers. Data were derived from observational maternity data. The primary outcome was incidence of stillbirth. The primary analysis was done according to the intention-to-treat principle, with births analysed according to whether they took place during the control or intervention periods, irrespective of whether the intervention had been implemented as planned. This study is registered with www.ClinicalTrials.gov, number NCT01777022.Findings37 hospitals were enrolled in the study. Four hospitals declined participation, and 33 hospitals were randomly assigned to an intervention implementation date. Between Jan 1, 2014, and Dec, 31, 2016, data were collected from 409 175 pregnancies (157 692 deliveries during the control period, 23 623 deliveries in the washout period, and 227 860 deliveries in the intervention period). The incidence of stillbirth was 4·40 per 1000 births during the control period and 4·06 per 1000 births in the intervention period (adjusted odds ratio [aOR] 0·90, 95% CI 0·75–1·07; p=0·23).InterpretationThe RFM care package did not reduce the risk of stillbirths. The benefits of a policy that promotes awareness of RFM remains unproven.FundingChief Scientist Office, Scottish Government (CZH/4/882), Tommy's Centre for Maternal and Fetal Health, Sands.

P968Burden of comorbidities, quality of anticoagulation control and outcomes: an analysis from the AFFIRM study

P968Burden of comorbidities, quality of anticoagulation control and outcomes: an analysis from the AFFIRM study

LB02: The AFFIRM study: Can promoting awareness of fetal movements and focusing interventions reduce fetal mortality? A stepped-wedge cluster randomised trial

LB02: The AFFIRM study: Can promoting awareness of fetal movements and focusing interventions reduce fetal mortality? A stepped-wedge cluster randomised trial

Systolic Blood Pressure Visit-to-Visit Variability and Major Adverse Outcomes in Atrial Fibrillation: The AFFIRM Study (Atrial Fibrillation Follow-Up Investigation of Rhythm Management).

URL: http://www.clinicaltrials.gov. Unique identifier: NCT00000556.

The association between health-related quality-of-life scores and clinical outcomes in metastatic castration-resistant prostate cancer patients: Exploratory analyses of AFFIRM and PREVAIL studies

BackgroundOur exploratory analysis examined the association between health-related quality of life (HRQoL) (baseline and change over time) and clinical outcomes (overall survival [OS]/radiographic progression-free survival [rPFS]) in metastatic castration-resistant prostate cancer (mCRPC). MethodsHRQoL, OS and rPFS were assessed in phase III trials comparing enzalutamide with placebo in chemotherapy-naïve (PREVAIL; NCT01212991) or post-chemotherapy (AFFIRM; NCT00974311) mCRPC. HRQoL was assessed using the Functional Assessment of Cancer Therapy-Prostate (FACT-P). Multivariate analyses evaluated the prognostic significance of baseline and time-dependent scores after adjusting for treatment and clinical/demographic variables. Hazard ratios (HRs) and 95% confidence intervals (CIs) represented the hazard of rPFS or OS per minimally important difference (MID) score change in HRQoL variables. ResultsIn baseline and time-dependent multivariate analyses, OS was independently associated with multiple HRQoL measures across both studies. In time-dependent analyses, a 10-point (upper bound of MID range) increase (improvement) in FACT-P total score was associated with reductions in mortality risk of 19% in AFFIRM (HR 0.81 [95% CI 0.78–0.84]) and 21% in PREVAIL (HR 0.79 [0.76–0.83]). For baseline analyses, a 10-point increase in FACT-P total score was associated with reductions in mortality risk of 12% (HR 0.88 [0.84–0.93]) and 10% (HR 0.90 [0.86–0.95]) in AFFIRM and PREVAIL, respectively. rPFS was associated with a subset of HRQoL domains in both studies. ConclusionSeveral baseline HRQoL domains were prognostic for rPFS and OS in patients with mCRPC, and this association was maintained during treatment, indicating that changes in HRQoL are informative for patients' expected survival.

Have You Talked about It: Advance Care Planning among African Americans Living with HIV in Baltimore.

Advance care planning (ACP) is the process of planning for when individuals are unable to make their own healthcare decisions. Research suggests ACP is understudied among HIV-positive African Americans. We explored ACP knowledge, preferences, and practices with HIV-positive African Americans from an urban HIV-specialty clinic (AFFIRM study). Participants completed surveys and interviews. Descriptive analyses and Poisson regression were conducted on survey data. Qualitative interviews were coded using grounded theory/constant comparative method. Participants were mostly male (55.1%). Half rated their current pain as at least six out of ten (50.8%). Two-thirds had discussed ACP with providers or supporters (66.2%). Qualitative themes were: (1) impact of managing pain on quality of life and healthcare, (2) knowledge/preferences for ACP, and (3) sources of HIV supportive care and coping (N=39). Correlates of having discussed ACP included: moderate pain intensity (p<0.10), including supporters in health decisions (p<0.001), religious attendance (p<0.05), and knowledge of healthcare mandates (p<0.01; N=276). Findings highlight the need for patient education to document healthcare preferences and communication skills development to promote inclusion of caregivers in decision-making.

Assumption versus evidence: the case of digoxin in atrial fibrillation and heart failure.

Despite development of new and innovative medical therapies, still millions of patients with chronic heart failure (HF) with reduced ejection fraction and/or atrial fibrillation (AF) are treated with cardiac glycosides (overall 122 millions of patients defined daily dose prescriptions 2013 in Germany).1 Randomized evidence for efficacy of this treatment strategy is, however, sparse. For HF with reduced ejection fraction (HFrEF), the only randomized controlled outcome trial (RCT) of reasonable size is the DIG trial.2 Although the DIG Trial could not demonstrate a benefit on total mortality in the overall trial population, hospitalization for worsening of HF was significantly reduced. Moreover, subgroup analysis suggested a benefit on total mortality in patients with low plasma levels of digoxin.3,4 Randomized controlled outcome trials prospectively investigating the impact of digoxin on mortality and morbidity in patients with AF are not available. In the very recent past, quite a number of cohort studies, post hoc analyses of RCTs (initiated to investigate other treatments), and meta-analyses,5–11 which are all liable to prescription bias as randomization was not targeting digoxin therapy,12 retrospectively investigated whether digoxin treatment would eventually increase mortality in AF. These analyses surely are invaluable sources to generate important hypotheses to be investigated in prospective RCTs, which are costly, time consuming, and in need of high resources. However, it is very important to interpret their results with caution, and potential sources of bias require careful assessment and discussion. The AFFIRM study originally investigated survival outcome of patients with AF randomized to treatment for either rate (defined as therapy with beta blocker, calcium-channel blocker, digoxin, and combinations of these drugs) or rhythm control (antiarrhythmic drug use upon discretion of the treating physician).13 Rhythm control did not offer advantages over rate control. In a first post hoc analysis of …

Oxaliplatin and 5-FU/folinic acid (modified FOLFOX6) with or without aflibercept in first-line treatment of patients with metastatic colorectal cancer: the AFFIRM study

The combination of aflibercept with FOLFIRI has been shown to significantly prolong overall survival in patients with metastatic colorectal cancer (mCRC) after progression on oxaliplatin-based therapy. This trial evaluated the addition of aflibercept to oxaliplatin-based first-line treatment of patients with mCRC. Patients with mCRC were randomized to receive first-line therapy with mFOLFOX6 plus aflibercept (4 mg/kg) or mFOLFOX6 alone. The primary end point of this phase II study was the progression-free survival (PFS) rate at 12 months in each arm. The analysis of efficacy between the arms was a pre-planned secondary analysis. Of 236 randomized patients, 227 and 235 patients were evaluable for the primary efficacy analysis and safety, respectively. The probabilities of being progression-free at 12 months were 25.8% [95% confidence interval (CI) 17.2-34.4] for the aflibercept/mFOLFOX6 arm and 21.2% (95% CI 12.2-30.3) for the mFOLFOX6 arm. The median PFS was 8.48 months (95% CI 7.89-9.92) for the aflibercept/mFOLFOX6 arm and 8.77 months (95% CI 7.62-9.27) for the mFOLFOX6 arm; the hazard ratio of aflibercept/mFOLFOX6 versus mFOLFOX6 was 1.00 (95% CI 0.74-1.36). The response rates were 49.1% (95% CI 39.7-58.6) and 45.9% (95% CI 36.4-55.7) for patients treated with and without aflibercept, respectively. The most frequent treatment-emergent grade 3/4 adverse events (AEs) excluding laboratory abnormalities reported for aflibercept/mFOLFOX6 versus mFOLFOX6 were neuropathy (16.8% versus 17.2%) and diarrhea (13.4% versus 5.2%). Neutropenia grade 3/4 occurred in 36.1% versus 29.3%. The most common vascular endothelial growth factor inhibition class-effect grade 3/4 AEs for aflibercept/mFOLFOX6 versus mFOLFOX6 were hypertension (35.3% versus 1.7%), proteinuria (9.2% versus 0%), deep vein thrombosis (5.9% versus 0.9%) and pulmonary embolism (5.9% versus 5.2%). No difference in PFS rate was observed between treatment groups. Adding aflibercept to first-line mFOLFOX6 did not increase efficacy but was associated with higher toxicity. NCT00851084, www.clinicaltrials.gov, EudraCT 2008-004178-41.

Relationship between quality of life (QoL) and clinical outcomes in metastatic castration-resistant prostate cancer (mCRPC) patients after chemotherapy: Results from the AFFIRM study.

5060Background: We investigated the association between QoL and clinical outcomes such as overall survival (OS) and radiographic progression-free survival (rPFS) from AFFIRM (NCT00974311; Scher et ...

The AfFIRM Study: A multicenter phase 2 study of single-agent filanesib (ARRY-520) in patients with advanced multiple myeloma.

TPS8613 Background: An unmet medical need exists for patients (pts) with multiple myeloma (MM) whose disease has progressed despite prior exposure to immunomodulatory agents (IMiDs) and proteasome ...

Circulating tumor cell (CTC) enumeration in men with metastatic castration-resistant prostate cancer (mCRPC) treated with enzalutamide post-chemotherapy (phase 3 AFFIRM study).

5035 Background: CTC enumeration is a biomarker associated with clinical outcomes in patients (pts) with mCRPC. CTC count at baseline (BL) and post-treatment is prognostic for survival. Enzalutamid...

A kick in the right direction - reduced fetal movements and stillbirth prevention

Multiple studies using various approaches have associated reduced fetal movements (RFM) with stillbirth and small for gestational age infants [1,2]. More recently, RFM has been linked to neurodevelopmental delay and a lack of response to treatment for hypoxic-ischaemic encephalopathy [3,4]. The relationship between adverse pregnancy or infant outcome is thought to be mediated by placental dysfunction [5]; thus RFM represents a symptom of placental insufficiency, when a placenta cannot meet the metabolic demands of the growing fetus. This hypothesis is now supported by evidence of changes in placental structure, inflammation and function in women who present with RFM [6,7]. Critically, some of these changes in placental size, structure and pathology differentiate between pregnancies with RFM that end in healthy pregnancy or adverse outcomes [8,9]. Thus, assessment of fetal growth and placental function in mothers presenting with RFM may offer new avenues to identify babies at risk of stillbirth to target intervention. A prospective control study found that 67 out of 303 women (22%) presenting with RFM to St Mary’s Hospital, Manchester, UK had adverse perinatal outcome. Significant predictors of adverse outcome were diastolic blood pressure, estimated weight centile, liquor volume and log[human placental lactogen (hPL)] [10]. Four cases had abnormalities on cardiotocography and 20 cases had abnormal ultrasound findings and 24 had an hPL <0.8 MoM; further work is needed to predict remaining adverse pregnancy outcomes in women with RFM. Recent interest in placental biomarkers, particularly placental growth factor (PlGF), shows encouraging data to predict adverse outcomes (e.g. true fetal growth restriction) in late pregnancy and should be explored in high-risk mothers with RFM [11]. A feasibility study of 120 women found that an intensive approach to the management of RFM using a biomarker was well adhered to and women’s anxiety decreased after investigation irrespective of the management strategy [12]. Encouragingly, the rate of composite adverse perinatal outcome reduced from 29% to 12%. This indicates that a larger definitive trial should be conducted [12]. Current data, based on a large quality improvement study, suggest that mothers should be educated about reporting changes in fetal movements and units should provide standardised care including cardiotocography/non-stress test and ultrasound scan [13]. However, implementing these changes into clinical practice has been more challenging. The UK Royal College of Obstetricians and Gynaecologists (RCOG) introduced a guideline for the management of RFM in 2011 [14]. A cross-sectional survey of UK maternity units in 2013 found that 12% of units had no guideline, and where guidelines were in place they contained a median of 7/12 recommendations ranging from 3-11. Two key challenges i) to improve maternal education about fetal movements and ii) to standardise high-quality care when women present with RFM need to be addressed to reduce stillbirths using a RFM-based approach. The AFFIRM study, a stepped-wedge customised trial will address the hypothesis that education for mothers and professionals, in combination with a standard management plan can reduce stillbirth [15]. It is hoped that this strategy understanding the associations with RFM, developing effective investigations in combination with intervention will reduce stillbirth.