Ulcerative colitis (UC) and Crohn's disease (CD) are chronic, relapsing inflammatory bowel diseases associated with significant morbidity. Conventional therapies for these diseases include corticosteroids, aminosalicylates, immunomodulators, and monoclonal antibodies. Over the years tumor necrosis factor (TNF)-α antagonists alone or in combination with other therapies have emerged as the cornerstone of treatment for induction and maintenance of remission of moderate to severe UC and CD. Unfortunately, some patients with moderate to severe UC and CD are unable to attain or maintain remission with TNF-α antagonist treatment. Vedolizumab, a humanized monoclonal antibody, is the first integrin receptor antagonist approved that selectively antagonizes α4β7 gastrointestinal integrin receptors. US Food and Drug Administration approval is for treatment of patients with moderate to severe active UC and CD who have inadequate response with, lost response to, or are intolerant to a TNF-α antagonist or an immunomodulator; or have inadequate response with, are intolerant to, or demonstrate dependence on corticosteroids. When administered according to approved dosing in patients with moderate to severe CD and UC, vedolizumab induces clinical response rates up to 31.4% and 47.1% at week 6, and clinical remission rates up to 39% and 41.8% at week 52, respectively. Serious adverse events reported with vedolizumab include serious infections, malignancies, and anaphylaxis. Since vedolizumab is gastrointestinal selective, to date, it has not shown evidence of causing progressive multifocal leukoencephalopathy; however, postmarketing studies monitoring for this adverse effect are ongoing. Further assessment of vedolizumab earlier in the course of these diseases and in combination with other therapies is warranted.
Objective: To review the pharmacological characteristics, clinical evidence, and place in therapy of voxelotor for the treatment of sickle cell disease (SCD). Data Sources: A comprehensive literature search of PubMed (1966 to April 2020) was conducted. Key search terms included GBT440, sickle cell, and voxelotor. Other sources were derived from bibliographies of articles, product labeling, manufacturer’s website, and news releases. ClinicalTrials.gov was searched for additional studies. Study Selection and Data Extraction: All English-language articles identified from the data sources were reviewed and evaluated. Case reports/series and phase 1 through 3 clinical trials were included. Data Synthesis: SCD is an inherited disorder associated with significant morbidity and early mortality. Three medications approved for SCD reduce SCD-associated complications but do not selectively ameliorate the underlying disease. Voxelotor is a novel agent that targets the pathophysiology of SCD. A phase 3 trial reported an increase in mean Hb level from baseline for voxelotor compared with placebo (1.1 vs −0.1 g/dL; P < 0.001). Voxelotor is generally well tolerated, with common adverse effects including headache, diarrhea, nausea, and arthralgia. Relevance to Patient Care and Clinical Practice: Voxelotor may be considered for patients with SCD who have continued anemia and hemolysis despite being on maximum tolerated dose of hydroxyurea or in those who are hydroxyurea intolerant. Voxelotor is costly; therefore, both cost and benefit should be weighed before prescribing. Conclusion: Voxelotor appears to be safe and effective as monotherapy or in combination with hydroxyurea for patients with SCD who are 12 years of age and older.
Background: Adults with sickle cell disease (SCD) often present with extremely painful acute vaso-occlusive crises (VOC). VOC guidelines quote studies supporting early initiation of opioids, but are lacking in a standardized approach to achieve adequate analgesia and subsequent de-escalation. Various SCD studies comparing continuous basal versus demand bolus patient-controlled analgesia (PCA) show conflicting outcomes. Thus the objective of our pilot was to develop a standardized approach to pain management utilizing PCA and a Tiered Oral Therapy Protocol (TOTP) in an effort to affect healthcare utilization by decreasing length of stay without increasing readmission rates. Methods: We studied admissions of 31 SCD (any genotype) patients (8 males, 23 females) ≥ 18 years old, all African-American, admitted for VOC, and treated by hospitalist providers using TOTP on one medical unit at Virginia Commonwealth University Health System from July 2018 to June 2019. Inpatient admissions for one calendar year prior to the initial TOTP admission served as the patient's historical control. TOTP is guided by the patient's individualized treatment plan and starts with continuation of their home basal dosing, demand dose only PCA, and immediate-release oral opioids for additional breakthrough pain. TOTP goals are aggressive up-titration of opioids until adequate analgesia. After a period of stability the next phase encourages timely, aggressive down-titration of opioids to speed discharge. We primarily compared length of stay (LOS), hospital charges, and 30-day readmission rates for TOTP vs historical controls. Secondarily, we compared adverse safety events: opioid-related rapid responses, naloxone administration, or falls. Results: Utilization of TOTP resulted in reductions in LOS (21%, 4.7 days controls vs. 3.7 days TOTP, p<0.014), and hospital charges ($1,627,497.73 controls vs. $944,528.96 TOTP, p=0.1403), and an insignificant increase in the 30-day readmission rate (35.6% controls vs. 42.7% TOTP, p=0.5027). Hospital charge data is difficult to interpret as a full year of post TOTP encounters are not available for all patients. There were no TOTP vs. historical control differences in opioid-related safety events. Conclusion: Standardization of therapy using the TOTP improved length of stay and reduced charges for patients with sickle cell disease admitted for acute VOC without increasing adverse safety events or significantly impacting the 30 day readmission rate. We have enlarged this pilot to include other VCU medical units, to test whether we can reproduce our initial one-unit success. Further, we recommend TOTP implementation and testing in other hospitals to exclude secondary trends, since TOTP was but one among several interventions in a VCU Adult SCD Medical Home. Figure Disclosures Smith: Novartis: Consultancy, Honoraria.
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