A. Ramasamy

Persistence with nebivolol in the treatment of hypertension: a retrospective claims analysis.

Abstract Objective: Examine drug persistence by evaluating the hazard of discontinuation and of switching to different antihypertensive drugs in patients initiating treatment with a recently approved β-blocker, nebivolol, versus other β-blockers. Methods: This retrospective analysis included all patients diagnosed with hypertension in the MarketScan Database (January 2007 – December 2008) with at least two medical claims and no prior β-blocker prescriptions within 6 months of the initial prescription date. Multivariate Cox proportional hazard models (adjusted for baseline differences in demographics, previous use of other antihypertensive medications, initial doses and supply of medication, and number of distinct prescriptions at baseline) were used to assess the hazard of discontinuation, defined as the first prescription gap of ≥30 days, and to assess the hazard of switching to another antihypertensive drug, defined as a prescription fill for another antihypertensive drug within 15 days before and 30 days after discontinuation of the initial β-blocker. Results: Of the 173,200 patients included in the study population, the adjusted hazard of discontinuation for nebivolol-initiated patients was 8–20% lower than that of patients who initiated treatment with atenolol (hazard ratio [HR] 0.82, p < 0.001), metoprolol (HR 0.91, p < 0.001), carvedilol (HR 0.92, p < 0.001), or other β-blockers (HR 0.80, p < 0.001). The adjusted hazard of nebivolol-treated patients switching to a different antihypertensive medication was 12–22% lower than that of the other four β-blocker cohorts (atenolol: HR 0.80, p < 0.001; metoprolol: HR 0.86, p < 0.001; carvedilol: HR 0.88, p < 0.001; other β-blockers: HR 0.78, p < 0.001). Sensitivity analyses defined discontinuation as prescription gaps of ≥45 days and ≥60 days and showed a lower hazard of discontinuation among patients initiating nebivolol than among patients initiating all other drug cohorts (p < 0.001). Limitations: Comparisons of non-randomized treatment groups may be confounded by unobserved differences in patients’ baseline characteristics. Conclusions: Initiation with nebivolol was associated with greater persistence than initiation with atenolol, carvedilol, metoprolol, or other β-blockers.

Mixed-Methods Development of a New Patient-Reported Outcome Instrument for Chronic Low Back Pain: Part 1 – The Patient Assessment for Low Back Pain - Symptoms (PAL-S)

Abstract We describe the mixed-methods (qualitative and quantitative) development and preliminary validation of the Patient Assessment for Low Back Pain–Symptoms (PAL-S), a patient-reported outcome measure for use in chronic low back pain (cLBP) clinical trials. Qualitative methods (concept elicitation and cognitive interviews) were used to identify and refine symptom concepts and quantitative methods (classical test theory and Rasch measurement theory) were used to evaluate item- and scale-level performance of the measure using an iterative approach. Patients with cLBP participated in concept elicitation interviews (N = 43), cognitive interviews (N = 38), and interview-based assessment of paper-to-electronic mode equivalence (N = 8). A web-based sample of patients with self-reported cLBP participated in quantitative studies to evaluate preliminary (N = 598) and revised (n = 401) drafts and a physician-diagnosed cohort of patients with cLBP (N = 45) participated in preliminary validation of the measure. The PAL-S contained 14 items describing symptoms (overall pain, sharp, prickling, sensitive, tender, radiating, shocking, shooting, burning, squeezing, muscle spasms, throbbing, aching, and stiffness). Item-level performance, scale structure, and scoring seemed to be appropriate. One-week test–retest reproducibility was acceptable (intraclass correlation coefficient 0.81 [95% confidence interval, 0.61-0.91]). Convergent validity was demonstrated with total score and MOS-36 Bodily Pain (Pearson correlation −0.79), Neuropathic Pain Symptom Inventory (0.73), Roland-Morris Disability Questionnaire (0.67), and MOS-36 Physical Functioning (−0.65). Individual item scores and total score discriminated between numeric rating scale tertile groups and painDETECT categories. Respondent interpretation of paper and electronic administration modes was equivalent. The PAL-S has demonstrated content validity and is potentially useful to assess treatment benefit in cLBP clinical trials.

Assessment of Patient-Reported Outcome Instruments to Assess Chronic Low Back Pain

Objective To identify patient-reported outcome (PRO) instruments that assess chronic low back pain (cLBP) symptoms (specifically pain qualities) and/or impacts for potential use in cLBP clinical trials to demonstrate treatment benefit and support labeling claims. Design Literature review of existing PRO measures. Methods Publications detailing existing PRO measures for cLBP were identified, reviewed, and summarized. As recommended by the US Food & Drug Administration (FDA) PRO development guidance, standard measurement characteristics were reviewed, including development history, psychometric properties (validity and reliability), ability to detect change, and interpretation of observed changes. Results Thirteen instruments were selected and reviewed: Low Back Pain Bothersomeness Scale, Neuropathic Pain Symptom Inventory, PainDETECT, Pain Quality Assessment Scale Revised, Revised Short Form McGill Pain Questionnaire, Low Back Pain Impact Questionnaire, Oswestry Disability Index, Pain Disability Index, Roland-Morris Disability Questionnaire, Brief Pain Inventory and Brief Pain Inventory Short Form, Musculoskeletal Outcomes Data Evaluation and Management System Spine Module, Orebro Musculoskeletal Pain Questionnaire, and the West Haven-Yale Multidimensional Pain Inventory Interference Scale. The instruments varied in the aspects of pain and/or impacts that they assessed, and none of the instruments fulfilled all criteria for use in clinical trials to support labeling claims based on recommendations outlined in the FDA PRO guidance. Conclusions There is an unmet need for a validated PRO instrument to evaluate cLBP-related symptoms and impacts for use in clinical trials.

The Pain Assessment for Lower Back Symptoms (Pal-S): Refinement of A New Pro Instrument Through A Mixed Methods Approach

BACKGROUND & OBJECTIVE Objectives The Pain Assessment in Low Back Pain Symptoms (PAL-S) is a Patient Reported Outcome (PRO) instrument being developed to assess the key symptoms of chronic low back pain (cLBP). Qualitative development included both concept elicitation and cognitive interviews. As part of the ongoing development of the instrument, we further evaluated and refined the PAL-S using a mixed methods approach. Methods Adults self-reporting a clinical diagnosis of cLBP were recruited from an existing US-based commercial survey panel to participate in a pilot quantitative study. Qualifying participants completed a web-based survey consisting of the 14-item PAL-S and items assessing clinical, treatment, and demographic characteristics. Study data was analyzed to assess itemand scale-level performance of the PAL-S using Rasch Measurement Theory analyses. Following analysis and modification, two waves of cognitive interviews were conducted to evaluate respondent understanding of the revised PAL-S. Results The dataset included 598 respondents (mean age: 55.5±12.6; 67.9% female; 88.0% white; and 54.0% married) who had cLBP for mean of 15.2±11.5 years. The Rasch analyses item threshold maps showed only two items having ordered thresholds, suggesting that respondents experienced increased difficulty distinguishing between options at the lower levels of the 0-10 scale. Simulations collapsing the responses to a best-fit 4-point response scale resulted in improved ordering of thresholds, suggesting a more optimal response option structure. Based on these findings, the numeric response scale of the PAL-S items was replaced with a 4-point verbal rating scale incorporating response choices such as not at all, slight, moderate, and severe. Findings from eight cognitive interviews confirmed patient comprehension and relevance of the revised instrument. Conclusion The mixed-methods approach proved valuable to the ongoing development of the PAL-S, as Rasch analyses identified a need for refinement of the response scale. The measurement properties of the revised PAL-S will be evaluated in additional web-based and clinic-based quantitative studies. Although a number of patient-reported outcome (PRO) instruments are available in low back pain (LBP), none of them were developed based on the most recent FDA PRO Guidance (2009) and would not be acceptable to the FDA to support labeling claims. Consequently, Forest Research Institute and partner Grunenthal in collaboration with experts have developed the Pain Assessment for Lower Back-Symptoms (PAL-S) instrument. The PAL-S was developed using state of the science best practices and in accordance with the FDA PRO Guidance (2009) to ensure evidence of content validity and measurement appropriate to support a labeling claim using PRO data. The early development work to create the PALS has included: • Completion of systematic reviews of the LBP literature and existing PRO instruments • The formation of an expert panel of clinical and methodological experts to provide advice during the development process • The completion of forty-three qualitative concept elicitation interviews conducted to identify the LBP-related concepts that are most important and relevant to the patients’ experience • A formal item-generation process in which evidence from the concept elicitation interviews, systematic literature reviews, and expert input was used to develop the content of the PAL-S • Four waves of qualitative cognitive interviews with patients with LBP to evaluate and refine the draft instruments This process has resulted in a 14-item developmental version ready for further quantitative testing. The primary aim is to collect initial quantitative data to further evaluate the performance of the PAL-S as appropriate PRO measures for use as endpoints in clinical studies of low back pain. The information gathered in this study will be used in the process of instrument refinement (item response theory, item reduction and/or modification), assessment of measurement characteristics, and finalization of the scoring approach to support the use of the PAL-S in subsequent studies.