Patient-years Of Therapy Research Articles

P668 Post-marketing experience of vedolizumab in inflammatory bowel disease: analysis of pneumonia and other respiratory tract infections

Background: The annual incidence of pneumonia has been reported as 13.8/1000 in patients with IBD versus 7.6/1000 in healthy subjects (IRR 1.82; 95% CI: 1.75–1.88) [1]. Vedolizumab (VDZ) is a humanised monoclonal antibody that binds to α4β7 integrin, selectively blocking gut-specific lymphocyte trafficking. Gut selectivity may reduce the infection risk compared with anti-tumour necrosis factor-alpha [anti-TNFα] agents, which cause systemic immunosuppression. Here we describe pneumonia and other respiratory tract infections reported after initiation of VDZ therapy in the post-marketing (PM) setting. Methods: PM VDZ safety data from the Global Safety Database (May 2014–May 2016) were reviewed to identify reports of lower respiratory tract infections (LRTIs) and upper respiratory tract infections (URTIs) using the following MedDRA v19.0 High Level Terms: “LRT and lung infections”, “LRTIs not elsewhere classified (NEC)”, “URTIs”, and “URTIs (NEC)”. Results: During almost 50,000 (∼46,978) patient-years of VDZ therapy, 40 serious and 68 non-serious LRTI events were reported in 106 patients; 54 events were pneumonia (n=34 serious; n=20 non-serious; ∼1 event/1000 patient-years of therapy). Regarding potential risk factors for pneumonia, 2 patients had undergone surgery ≤30 days prior to the event; 2 were current/former smokers (smoking history and prior surgery information not provided in 51/54 and 16/54 patients, respectively). Other LRTI events were: bronchitis (n=1 serious; n=26 non-serious); LRTIs (not otherwise specified; n=2 serious; n=20 non-serious); lung infection (n=2 serious; n=2 non-serious); lung abscess (n=1 serious; n=0 non-serious). Most LRTIs occurred ≥2 months after first VDZ infusion (n=32/108 events; not reported [NR] n=64/108 events). There were 4 serious and 313 non-serious URTIs in 300 patients, with nasopharyngitis the most frequently reported (n=201/317 events). Most URTIs occurred ≥2 months after first VDZ infusion (n=77/317 events; NR n=182/317 events). Patient demographics/clinical characteristics are shown (Table 1). Table 1. Patient demographics and clinical characteristics Conclusions: From almost 50,000 patient-years of VDZ therapy, RTIs (including pneumonia) were infrequent and most patients continued VDZ. These data represent experience of VDZ in a “real-world” setting and complement existing data from clinical trials. Limitations associated with PM safety reporting (incomplete data, voluntary reporting and difficulty establishing a causal relationship between drug and event) must be considered when interpreting these results.

Relationship between time spent at extreme International Normalized Ratios and time in therapeutic range with bleeding and thrombosis in warfarin-treated patients.

The relationship between the time spent at extreme International Normalized Ratios (INRs) and the time in the therapeutic range (TTR) with bleeding and thrombosis in warfarin-treated patients was examined. Consecutive patients treated with warfarin for atrial fibrillation or for venous thrombosis who were managed by the anticoagulation management service or adult internal medicine clinic of a large, tertiary care, integrated health system between June 1, 2011, and October 9, 2012, were eligible for study inclusion. Data collected for the outcomes analysis included INRs and dates; current use of aspirin, clopidogrel, prasugrel, ticagrelor, ticlopidine, or nonsteroidal antiinflammatory drugs; and any clinically significant bleeding or thrombosis events identified. In the 837 patients who met the inclusion criteria, 636.5 patient-years of therapy were provided, of which 14.4 patient-years (2.26% of time) were spent at INRs of <1.5; 2.9 patient-years of therapy (0.45% of time) were spent at INRs of >4.5. The patient population had a mean individual TTR of 65%. The percentage of time at an INR of >4.5 was positively associated with an increased risk of major bleeding (p = 0.0085). The percentage of time spent with an INR of <1.5 was not associated with a significant increase in the risk of thrombosis. The percentage of time spent with an INR of >4.5 was associated with an increased risk of major bleeding in patients receiving warfarin for atrial fibrillation or for venous thrombosis at two outpatient clinics. The relationships between thrombosis risk and the TTR or the time spent at an INR of <1.5 were not significant, but the thromboembolic event rate was unusually low, as was the time spent at an INR of <1.5.

596 Increased Risk of Surgery After Attenuation of Anti-TNFα Therapy for Crohn's Disease

Background: The rate of intestinal resection among patients with Crohn's disease may be as high as 80% after 20 years of disease. By inducing mucosal healing and achieving high remission rates, TNFα antagonists reduce hospitalizations and steroid requirement. Early combination treatment with azathioprine (AZA) and anti-TNFα achieves higher remission rates than either infliximab (IFX) or AZA alone. It is presumed that IFX, adalimumab (ADA) and certolizumab (CZP) will also impact on the need for surgery. However, many patients attenuate response or flare during therapy, requiring re-induction or switch among antiTNFs. When this fails, surgery becomes necessary. The goal of our study was to identify risk factors for surgery in the setting of biologic therapy. Methods: The Consortium on Outcomes of Biologic Therapy in IBD (COBI) is a prospectively compiled database of 147 patients treated for Crohn's disease between July 2002 and September 2009 with anti-TNFα medications (for a total of 366 patient-years of therapy). We performed a retrospective analysis to determine the incidence and risk of TNFα antagonist attenuation of response or need for surgical intervention. Both univariate and multivariate analyses were performed. Results: In our cohort, 63% of patients were either re-induced with (16/93, 17%) or switched to a second TNFα antagonist (77/93, 83%). Surgery had been performed in 38% of these patients prior to anti-TNFα therapy. The mean age at the start of the first anti-TNFα was 33.5 (± 15.2) years; mean duration of disease 9.2 (± 9) years and mean duration of initial anti-TNFα treatment 36.1 (±31.2) months. There were 82, 9 and 2 patients initially started on IFX, ADA and CZP respectively; the second agent used was IFX, ADA and CZP in 1, 55 and 21 patients respectively. There were 31 patients (33%) who underwent surgery within 6 months of failing the initial regimen. Patients treated with anti-TNFα therapy for longer periods (>30 months) had increased odds of surgery (OR 3.22, 95% CI 1.03-10.06). Conclusion: Despite the efficacy of the TNFα antagonists, nearly 2/3 of patients required either re-induction or switch within the class, with surgery necessary in nearly 1/3 of those patients. Patients on long-term anti-TNFα therapy before switching had a greater risk for surgery. Earlier intervention with primary anti-TNFα therapy may decrease secondary loss of response and intestinal resection rates. Further studies are warranted to determine antiTNFα optimization strategies and whether attenuation is less likely among different antiTNFα agents.

Quality of Oral Anticoagulation Management in Pharmacist Vs Nurse Managed Models of Care

Systematic models of anticoagulation management result in better clinical outcomes than routine medical care. At the University of Illinois at Chicago Medical Center (UIMCC) systematic anticoagulation management is provided via 2 models of care: a pharmacist managed antithrombosis clinic (PMATC) and a nurse managed anticoagulation clinic (NMAC). The objective of this study was to evaluate the quality of oral anticoagulation management in these two models of care by assessing efficacy, safety, monitoring and resource utilization outcomes. A retrospective, observational cohort study was conducted between January 2005 and April 2007. A total of 200 patients, 100 in each group, were randomly selected and contributed 179.3 and 206.8 patient-years of therapy for the PMATC and NMAC respectively (p<0.0001). Venous thromboembolism and atrial fibrillation were the 2 most common indications for anticoagulation therapy, although the PMATC group managed a higher proportion of patients with shorter-term venous indications then the NMAC group (78% vs 4% respectively; p<0.0001). The PMATC group reached goal INR faster after initiating therapy then the NMAC group. (median of 9 days vs 22 days respectively; p=0.0003). The mean % of patients with INR controlled within the therapeutic range (TTR) was 65.8% in the PMATC group and 71.2% in the NMAC group (p=0.009). The PMATC group had a higher proportion of difficult to manage patients who were non-compliant with their clinic monitoring appointments and non-compliant with their warfarin therapy as compared to the NMAC group. (median number of missed appointments per year was 4.8 vs 1.0 respectively; p < 0.0001 and median number of deviations from prescribed warfarin dose was 16.6 vs 3.5 respectively; p < 0.0001). The percent of patients who developed thromboembolic events and major bleeding complications during therapy were similar in the PMATC and NMAC groups (1.2% vs 0.5% per patient-year of therapy, respectively; RR 2.40; 95% CI 0.096 to 4.26; and 4.7% vs. 4.9% per patient-year of therapy, respectively; RR 0.96; 95% CI, 0.28 to 3.30). Hospital admissions and emergency department visits due to non-therapeutic INRs were higher in the NMAC group compared to the PMATC group (9.2% vs 0.6% per patient-year of therapy, respectively; RR 0.06; 95% CI 0.004 to 0.79; and 1.5% vs 0 per patient-year of therapy, respectively.) Patients who spent > 60% of the time in therapeutic INR range had a lower median number of missed clinic monitoring appointments and a lower median number of deviations from the prescribed warfarin dose as compared to patients who spent < 60% of the time in the therapeutic INR range (1.8 vs 4.0, respectively; p=0.0002 and 9.1 vs. 12.8, respectively; p=0.02). In this study, the PMATC model showed better outcomes in attaining a faster therapeutic INR after initiating warfarin therapy and also demonstrated more judicious resource utilization by lower hospitalization rates and emergency room visits due to non-therapeutic INRs. Although the TTR was lower in the PMATC group, the 2 groups faired similarly with regards to clinical outcomes such as recurrent thromboembolism and major bleeding complications. The difference in TTR can be attributed to the higher proportion of more difficult to manage, non-compliant patients in the PMATC group. Both models of care were found to be well within acceptable limits of national benchmark quality data for systematic anticoagulation management, although the PMATC model had better resource utilization outcomes.

The rheumatoid arthritis patient in the clinic: comparing more than 1,300 consecutive DMARD courses.

Therapy of rheumatoid arthritis (RA) is typically characterized by the sequential use of disease-modifying anti-rheumatic drugs (DMARDs). This study aimed to reveal treatment patterns with traditional DMARDs and their changes during the two decades before the recent introduction of new DMARDs. A total of 593 RA patients were followed from their first presentation to our clinic throughout the course of their disease; 222 patients received their first DMARD therapy while under our care. More than 2,300 patient years of therapy were analysed for the efficacy [using C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) as surrogates] and duration of drug therapy of consecutive DMARDs. Before 1985, 65-90% of initial DMARDs were gold compounds, but their use decreased continuously thereafter. Antimalarial (AM) drugs were important initial DMARDs in new patients at all times, whereas sulphasalazine (SSZ) and methotrexate (MTX) gained increasing significance after 1985 (the first DMARD was MTX in up to 29% of new patients). Penicillamine (DPA), azathioprine (AZP), cyclosporin (CyA) and combination therapies were not usually employed initially, but were reserved for the later course of the disease. Gender, age and rheumatoid factor were not different between patients receiving different DMARDs. The baseline acute-phase response was higher in patients treated with MTX (mean CRP 3.5 mg/dl) than in those treated with SSZ (CRP 2.4 mg/dl; P < 0.05) or AM (CRP 2.1 mg/dl; P < 0.05), suggesting that MTX was used preferentially in patients with high disease activity. On the other hand, once AM or SSZ had been discontinued, MTX was the most common subsequent DMARD (in 31 and 56% respectively). Comparison of first DMARDs with subsequent ones revealed that first DMARDs were more effective: the acute-phase response decreased most prominently during first therapies (CRP reduction was 1.28 mg/dl during first courses and 0.35 mg/dl during fourth or later courses; P < 0.01); and retention rates were significantly longer for first compared with subsequent therapies (median of 24.5 months for first and 18.6 months for fourth or subsequent therapies; P < 0.001). MTX was the most commonly employed DMARD therapy for RA and was used increasingly as first therapy in newly diagnosed RA. Patients with high disease activity were given MTX therapy more often than other DMARDs, while those with low activity were more likely to receive SSZ or AM, and MTX on failure of these drugs. First DMARDs in new patients were retained longer than subsequent DMARDs, apparently because they are more effective.

Acetylcholinesterase treatment--modelling potential demand and auditing practice.

Acetylcholinesterase inhibitors represent an entirely novel treatment option for patients with Alzheimer's disease (AD). As such they represent a significant change in practice and a significant cost pressure on funding bodies. To assess the impact of cholinesterase inhibitors on routine clinical practice. We estimated potential demand for the compounds taking into account eligibility criteria and prescribing practice agreed between clinicians and funders. We then audited actual prescribing practice assessing whether the estimated demand matched actual demand and whether practice and prescribing criteria were adhered to. Over a two-year period we estimated the demand for treatment at a total of 89 patient years for the population of the audit unit. In practice only 24.5 patient years of therapy were received, the short fall apparently being due to low referral rates for treatment. Prescribing by clinicians matched practice guidelines and a high proportion of three monthly assessments using scales for cognition, function and global state were performed. Using these assessment procedures treatment successes could be differentiated from primary and secondary treatment failures and, where apparently appropriate, treatment could be stopped. In the real world of clinical practice demand for treatment in AD is modest but likely to grow and assessment with an aim to identifying those receiving benefit from treatment can be achieved.

The Purity of Cholestyramine Resin-Reply

In Reply. — We are pleased to respond to the questions about Questran raised by Dr Goldstein by assuring him that (1) the cholestyramine resin used in the Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT) was not contaminated, (2) currently marketed Questran is free of contamination, and (3) although a temporal association between cholestyramine resin and certain tumors has been observed, a causal relationship has not been established after more than 20 years of commercial availability and several hundred thousand patient-years of therapy dispensed. The questions asked by Dr Goldstein appear to arise from the fact that, in April 1988, Bristol Laboratories initiated a recall because it determined that certain batches of bulk cholestyramine resin supplied by Rohm & Haas and used in the production of Questran contained very low levels of the agricultural chemicals dichlorodiphenyldichloroethylene and dichlorobenzophenone. These chemicals are related to the manufacture of a pesticide (dicofol)

15 Years of Experience with Renal Replacement Therapy in Patients Starting Therapy before Age 20

This study retrospectively evaluates the survival on renal replacement therapy among patients starting dialysis before their twentieth birthday. The cohort included all patients starting therapy from 1972 through August, 1987 at the University of Mississippi or Kidney Care, Inc. Fifty-five patients, median age 17 years, range 5-19 years, underwent 335 patient years of therapy. Nineteen initially received CAPD; 12 home hemodialysis, 2 were transplanted prior to dialysis, and the remaining 22 patients were entered into dialysis in a free standing facility. Thirty-one patients received a cadaveric transplant and four patients received a living related transplant. The median transplant survival was 1360 days. There were 10 patients on renal replacement therapy over 10 years and a survival plot projected a 70% survival at 10 years. Nine patients died. Three percent of the time on renal replacement therapy was spent hospitalized. Although the hospitalization rate is significant, the pediatric patient may be expected to have a long survival on renal replacement therapy.

INBORN ERRORS OF UREAGENESIS; RESULTS OF THERAPY IN 44 PATIENTS

13 patients with complete deficiencies of CPS or OTC were treated for with a low protein, essential amino acid (EAA)diet plus arginine (Arg) or citrulline(Cit)(1 mmol/kg)plus 250 mg/kg of benzoate(B)(Regimen I). 5 of these patients died during 11 patient years of therapy. Phenylacetate(P)(250 mg/kg)was added in 12 patients (Regimen II) for 14 patient years, during which one patient died due to an overdose of B and P. Partition of urinary nitrogen (PUN) in 5 such patients revealed that hippurate-N(HAN) and phenylacetylglutamine-N (PAGN) respectively accounted for(m±SD) 21.8±4.2 and 38.2± 8.1% of effective urinary waste nitrogen (EWN)for a total of 60%. 7 patients with ASA synthetase deficiency (AS) were treated with Regimen I plus additional Arg to supply 2-4 mmol kg/d (Regimen III) for 18.4 patient years; one patient died. Regimen III was modified by substituting protein for the EAA and adding P for 3 patient years with no deaths. PUN in 3 AS children revealed that HAN, PAGN and Cit-N accounted for 17, 22 and 12% of EWN for a total of 51%. 17 patients with AL deficiency were treated with 1.5-2.0 g/d of protein supplemented with 2-4 mmol/kg Arg for 37 patient years; one died. ASA-N accounted for 54% of EWN in 2 patients. Thus HAN, PAGN, Cit-N and ASA-N are adequate EWN substitutes for urea and support life in these otherwise fatal diseases.

The prevention of endometrial cancer in postmenopausal women with progestogens

Due to adverse publicity alleging an increased risk of endometrial cancer with estrogen therapy, a prospective study was begun in 1976 to determine the incidence of this disease in postmenopausal women. During 5,025 patient-years of observation in 1976–1977, 6 adenocarcinomas of the endometrium were diagnosed for an incidence of 1.2: 1,000 postmenopausal women per year. No endometrial malignancies were detected in 2,552 patient-years of therapy with estrogens and progestogens. In 1,028 patient-years of observation where estrogens only was the therapy, there were 3 endometrial cancers for an incidence of 2.9: 1,000. Adenocarcinoma of the endometrium was found in 2 of the untreated group, which gave an incidence of 3.0: 1,000. The sixth endometrial cancer occurred in a patient using estrogen vaginal cream. During this same period, 139 perimenopausal and postmenopausal women were treated with progestogens for endometrial hyperplasia. The hyperplasia was reversed to normal endometrium in 133 patients (95.7%). Hyperplasia is a precancerous lesion and should be treated with either progestogens or hysterectomy. All postmenopausal women with a uterus should be given the Progestogen Challenge Test and the progestogen continued each month as long as bleeding follows. These methods will prevent most endometrial cancers.