Recombinant Human Follicle-Stimulating Hormone Alfa Dose Adjustment in US Clinical Practice: An Observational, Retrospective Analysis of a Real-World Electronic Medical Records Database

PurposeTo determine the pattern of dose adjustment of recombinant human follicle-stimulating hormone alfa (r-hFSH-alfa) during ovarian stimulation (OS) for assisted reproductive technology (ART) in a real-world setting.MethodsThis was an observational, retrospective analysis of data from an electronic de-identified medical records database including 39 clinics in the USA. Women undergoing OS for ART (initiated 2009–2016) with r-hFSH-alfa (Gonal-f® or Gonal-f RFF Redi-ject®) were included. Assessed outcomes were patients’ baseline characteristics and dosing characteristics/cycle.ResultsOf 33,962 ART cycles, 13,823 (40.7%) underwent dose adjustments: 23.4% with ≥1 dose increase, 25.4% with ≥1 dose decrease, and 8.1% with ≥1 increase and ≥1 decrease. Patients who received dose adjustments were younger (mean [SD] age 34.8 [4.58] years versus 35.9 [4.60] years, p<0.0001) and had lower BMI (25.1 [5.45] kg/m2 versus 25.5 [5.45] kg/m2, p<0.0001) than those who received a constant dose. The proportion of patients with non-normal ovarian reserve was 38.4% for those receiving dose adjustment versus 51.9% for those with a constant dose. The mean (SD) number of dose changes/cycle was 1.61 (0.92) for cycles with any dose adjustment, 1.72 (1.03) for cycles with ≥1 dose increase, 2.77 (1.00) for cycles with ≥1 dose increase and ≥1 decrease (n=2,755), and 1.88 (1.03) for cycles with ≥1 dose decrease.ConclusionsDose adjustment during OS is common in clinical practice in the USA and occurred more often in younger versus older patients, those with a high versus non-normal ovarian reserve or those with ovulation disorders/polycystic ovary syndrome versus other primary diagnoses of infertility.

769 Differential pharmacological modulation of arrhythmic phenotype in catecholaminergic polymorphic ventricular tachycardia: not all betablockers are the same

Aims Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disorder that predisposes patients to develop catecholamine-mediated ventricular arrhythmias (VA), manifesting as exercise- or emotion-induced syncope or cardiac arrest. Due to the catecholaminergic nature of CPVT, exercise stress test (EST) represents the most important diagnostic test. Although widely used in clinical practice to monitor response to therapy, how BBs modulate the occurrence of ventricular arrhythmias during EST in CPVT patients is unclear. To compare the relative efficacy of different classes of betablockers (BBs, β1-selective BBs vs. nadolol) on the arrhythmic manifestations during ESTs performed off-therapy and on-therapy in patients with CPVT. Methods and results We selected 72 patients (45 females) with pathogenic or likely pathogenic variants on RYR2 or CASQ2 from our cohort of 246 genotype-positive CPVT patients, who had at least one EST off-therapy and at least one EST during BB therapy. Overall, 507 ESTs (77 ESTs off-therapy, 29 ESTs during β1-selective BBs, and 401 during nadolol) were prospectively collected over 11.1 ± 6.8 years of follow-up and analysed, with a median of 5 ESTs per patient [interquartile range (IQR): 3–10 ESTs, range: 2–27 ESTs]. In the absence of therapy, VT was documented in 46/77 (60%) cases. BB therapy with nadolol significantly reduced VT at EST to 10% (41/398; P < 0.001). Conversely, β1-selective BBs did not significantly decrease VT incidence at EST (13/29, 45%, P = 0.289) as compared to baseline. Importantly, nadolol was superior in preventing VT both when compared to off-therapy [odds ratio (OR): 33.9, 95% confidence interval (CI): 15.6–73.5, P < 0.001] but also when compared to β1-selective BBs [OR: 18.0, 95% CI: 6.0–53.5, P < 0.001]. Although β1-selective BBs significantly increased the total exercise time free of arrhythmias (median 248 s, IQR: 212–315 s) as compared to baseline (median 83 s, IQR: 12–207 s; P < 0.001), arrhythmia-free exercise time during nadolol (median 381 s, IQR: 251–543 s) was significantly longer as compared to both off-therapy (P < 0.001) and β1-selective BBs (P = 0.020). Multivariate mixed effects logistic regression confirmed that at parity of time of occurrence of first arrhythmia and percentage of maximal heart rate reached, both of which were significantly associated to VT occurrence (P = 0.001 for both), the use of nadolol (OR: 0.23; 95% CI: 0.09–0.60; P = 0.011) was independently associated with decreased incidence of VT. Focusing on the 14 patients (overall 133 ESTs) who had at least one ESTs after the occurrence of VT in nadolol, we dissected the effect of dose increase on the probability of VT reoccurrence. Following the documentation of breakthrough VT, increasing the dose of nadolol by 0.5 mg/kg reduced by 2.5 times the probability of having a recurrence of VT (OR: −2.49, 95% CI: −3.96 to − 1.0; P < 0.001). Conclusions Once CPVT is diagnosed, nadolol at 1 mg/kg/day should be used as preferred therapy as it has been shown to suppress VT in most patients. In rare instances in which VA persist despite an adequate nadolol dose, dose increase to 1.5 mg/kg/day may represent an efficacious antiarrhythmic strategy.

MIS-C Treatment: Is IVIG Always Necessary?

Background: MIS-C is a potentially severe inflammatory syndrome associated with SARS-CoV-2 exposure. Intravenous immunoglobulin (IVIG) is considered the first-tier therapy, but it implies infusion of large fluid volumes that may worsen cardiac function.Patients and Methods: Since April 2020, we have developed a treatment protocol that avoids the infusion of IVIG as first-line therapy in the early phase of MIS-C. In this study, we retrospectively analyzed a cohort of consecutive patients treated according to this protocol between 01/04/2020 and 01/04/2021.Results: In the last year, 31 patients have been treated according to the protocol: 25 with high-dose pulse MP (10 mg/kg) and 6 with 2 mg/kg. 67.7% of the patients responded to the initial treatment, while the others needed a step-up, either with Anakinra (25.8%) or with MP dose increase (6.5%). IVIG was administered in four patients. Overall, only one patient (3.2%) needed ICU admission and inotropic support; one patient developed a small coronary artery aneurysm.Conclusions: Timely start of MP therapy and careful fluid management might improve the outcomes of MIS-C patients.

Diuretic Changes, Health Care Resource Utilization, and Clinical Outcomes for Heart Failure With Reduced Ejection Fraction: From the Change the Management of Patients With Heart Failure Registry

Background: Diuretics are a mainstay therapy for the symptomatic treatment of heart failure. However, in contemporary US outpatient practice, the degree to which diuretic dosing changes over time and the associations with clinical outcomes and health care resource utilization are unknown. Methods: Among 3426 US outpatients with chronic heart failure with reduced ejection fraction in the Change the Management of Patients with Heart Failure registry with complete medication data and who were prescribed a loop diuretic, diuretic dose increase was defined as: (1) change to a total daily dose higher than their previous total daily dose, (2) addition of metolazone to the regimen, (3) change from furosemide to either bumetanide or torsemide, and the change persists for at least 7 days. Adjusted hazard ratios or rate ratios along with 95% CIs were reported for clinical outcomes among patients with an increase in oral diuretic dose versus no increase in diuretic dose. Results: Overall, 796 (23%) had a diuretic dose increase (18 episodes per 100 patient-years). The proportion of patients with dyspnea at rest (38% versus 26%), dyspnea at exertion (79% versus 67%), orthopnea (32% versus 21%), edema (60% versus 43%), and weight gain (40% versus 23%) were significantly (all P <0.001) higher in the diuretic increase group. Baseline angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (hazard ratio, 0.75 [95% CI, 0.65–0.87]) use were associated with lower likelihood of diuretic increase over time. Patients with a diuretic dose increase had a significantly higher number of heart failure hospitalizations (rate ratio, 2.53 [95% CI, 2.10–3.05]), emergency department visits (rate ratio, 1.84 [95% CI, 1.56–2.17]), and home health visits (rate ratio, 1.88 [95% CI, 1.39–2.54]), but not all-cause mortality (hazard ratio, 1.10 [95% CI, 0.89–1.36]). Similarly, greater furosemide dose equivalent increases were associated with greater resource utilization but not with mortality, compared with smaller increases. Conclusions: In this contemporary US registry, 1 in 4 patients with heart failure with reduced ejection fraction had outpatient escalation of diuretic therapy over longitudinal follow-up, and these patients were more likely to have sign/symptoms of congestion. Outpatient diuretic dose escalation of any magnitude was associated with heart failure hospitalizations and resource utilization, but not all-cause mortality.

Effect of high-dose posaconazole on serum levels in adult patients with hematologic malignancy

Posaconazole (POS) appears to have dose-proportional pharmacokinetics, however there is paucity of real-life data. We retrospectively evaluated 67 patients with hematological cancer who had POS dose increase from 300 mg/d to either 400 mg/d (n=52) or 300 mg twice daily (BID; n=15) and POS serum levels measured. Median POS levels were 840 ng/mL, 1625 ng/mL, and 2710 ng/mL on the 300mg/d, 400mg/d and 300mg BID doses respectively. Significant inter-patient variability in serum levels was noted.

How Sensitive is Mass-Based Inverse Optimization to IMRT Delivery Parameters?

Purpose: To determine the sensitivity of changes to IMRT delivery parameters for mass-based optimization schemes: Dose-Mass- (DM) and Energy-based (Energy), compared to Dose-Volume-based (DV) optimization. Methods: Twelve Head-and-Neck (HN) and twelve lung cases were retrospectively optimized using DM and Energy optimization. In both optimization approaches nine equidistant, split beams were used for step-and-shoot deliverable IMRT. Changes to two parameters were investigated: the number of IMRT segments (5 and 10 per beam) and the minimum allowed segment area (2 and 6 cm²). Plans were normalized such that 95% of the PTV received the same dose. Dose Indices (DIs) were used for evaluation. For the lung cases, DIs included: 1%_cord, 33%_heart, 20% and 30%_both-lungs, and 50%_ esophagus. In the HN cases: 1%_cord, 1%_brainstem, left/right parotids_50%, 50%_larynx, and 50%_esophagus. Results: The lung cases demonstrated that the Energy plans were more sensitive to segment area; changing the segment area resulted in a statistically significant dose increase for 1%_cord, 30%_both-lungs and 50%_esophagus. Changes to the number of segments yielded on average statistically significant differences in dose to 1%_cord in Energy plans, 50%_esophagus in DM plans, and 20%_both-lungs in DV plans. When the segment area was changed, the HN cases yielded statistically significant differences in doses to 1%_cord, 1%_ brainstem, 50%_left and right parotids, and 50%_larynx for the Energy plans and 50%_larynx for DM plans. Moreover, changing the number of segments resulted in significant dose decrease for 50%_parotids and 50%_esophagus for the Energy plans and 50%_larynx for DV plans. Conclusions: This study showed that both lung and HN Energy plans exhibit larger sensitivity than DV and DM plans to changing IMRT delivery parameters, especially when increasing the minimum segment area rather than with varying the number of segments.

Audit of baseline cardiometabolic monitoring for patients prescribed or advised dose increase of antipsychotic medication by the knowsley assessment team

AimsTo ascertain whether baseline monitoring of cardiometabolic health parameters was undertaken for patients prescribed dose increases of, antipsychotic medications in an outpatient setting. Whether results from baseline tests were taken into consideration when prescribing antipsychotic medications.BackgroundPeople with Severe Mental Illness have a reduction in life expectancy of 15-20 years. Chief factors implicated in this rate are smoking, obesity, metabolic dysfunction from diabetes, hypertension and stroke. Antipsychotic medications themselves are associated with increased risk of adverse cardiometabolic effects. The CATIE Study of patients prescribed atypical antipsychotics found that men were 85%, and women 137% more likely to have metabolic syndrome than control. Relative risk for type 2 diabetes and CHD in patients with metabolic syndrome is 1.5-5 times that of the general population.MethodThe Team caseload was accessed between the 6/11/18-13/11/18. Chronologically the first 40 patients on the list who had been prescribed an antipsychotic or advised re a dose increase of antipsychotic chosen. Data were then retrospectively collected from informatics and progress notes, document uploads, initial assessments and the ICE bloods system to populate an excel spreadsheet which is currently in use within North West Boroughs.ResultOf the 40 patients, 50% (20) attended for physical health review. All who did not attend initial appointment were offered a second appointment. 15% (6) did not attend 2 appointments. 35% (14) were not offered a physical health appointment. 1 patient had BP documented (from full physical review during previous episode within 12 m). 2 patients had BMI documented; Smoking, alcohol and drug use status was documented in 42.5%(17), 57.5%(23) and 67.5%(27) of patients, respectively. And 67.5% (27) of patients had an HbA1c result within past 12 months on ICE and 62.5% (25) had lipid profile. At least 10 of these bloods were not requested by our team. 7 patients were given a blood form but did not have bloods done. 57% (4 of 7) abnormal HbA1c's were acknowledged and 20% (1 of 5) lipid profiles.ConclusionThis audit demonstrates that baseline cardiometabolic monitoring could be improved for patients under the Assessment Team who are prescribed antipsychotics. Only half of the audited patients had had a physical health review, despite being prescribed, or their GP being advised regarding an increase in dose of, antipsychotic medication. It is important to note that 15% of patients were offered but failed to attend an appointment for physical health review.

Efficacy and safety of a novel dosing strategy for ruxolitinib in the treatment of patients with myelofibrosis and anemia: the REALISE phase 2 study

Anemia is a frequent manifestation of myelofibrosis (MF) and there is an unmet need for effective treatments in anemic MF patients. The REALISE phase 2 study (NCT02966353) evaluated the efficacy and safety of a novel ruxolitinib dosing strategy with a reduced starting dose with delayed up-titration in anemic MF patients. Fifty-one patients with primary MF (66.7%), post-essential thrombocythemia MF (21.6%), or post-polycythemia vera MF (11.8%) with palpable splenomegaly and hemoglobin <10 g/dl were included. Median age was 67 (45–88) years, 41.2% were female, and 18% were transfusion-dependent. Patients received 10 mg ruxolitinib b.i.d. for the first 12 weeks, then up-titrations of up to 25 mg b.i.d. were permitted, based on efficacy and platelet counts. Overall, 70% of patients achieved a ≥50% reduction in palpable spleen length at any time during the study. The most frequent adverse events leading to dose interruption/adjustment were thrombocytopenia (17.6%) and anemia (11.8%). Patients who had a dose increase had greater spleen size and higher white blood cell counts at baseline. Median hemoglobin levels remained stable and transfusion requirements did not increase compared with baseline. These results reinforce the notion that it is unnecessary to delay or withhold ruxolitinib because of co-existent or treatment-emergent anemia.

P449 Cost Effectiveness of a Proactive Therapeutic Drug Monitoring Strategy in Patients with Inflammatory Bowel Disease Receiving Infliximab

Background Proactive therapeutic drug monitoring (TDM) has not demonstrated improved therapy outcomes compared with clinically-based dosing strategies. While the use of proactive TDM incurs additional assay-related costs this strategy may be cost-effective due to TDM-driven therapy dose de-escalation and discontinuation. Methods We aimed to assess if proactive-TDM is cost-effective in clinical practice. A proactive TDM strategy was utilized in our unit with infliximab (IFX) and antibody-to-infliximab (ATI) levels assessed at trough in all inflammatory bowel disease(IBD) patients receiving IFX. Baseline demographics and IFX dosing schedules were documented. Patients were grouped based on disease activity status. Patients with IFX levels outside therapeutic range had dosing adjusted as appropriate. IFX dose adjustments were not protocolized and were at physicians discretion. IFX dosing regimens following proactive TDM were documented and net effect on IFX infusions number over the subsequent year extrapolated. Increase or decrease in drug-related costs on an annualized basis were estimated. Results 108 patients were included. Median age 36 years. 46% were female. 36% had ulcerative colitis, 60% Crohn’s disease. 35% were receiving concomitant immunomodulators. 56% were in remission at the time of TDM. 44%, 30% and 26% had IFX levels &lt; 3 µg/mL, 3 – 7 µg/mL and &gt; 7 µg/mL. IFX levels were significantly lower in patients with active disease compared with those in remission(p=0.008). Following proactive TDM assessment 37%, 11%, 36%, 13%, 2% and 1% of patients had no treatment change, therapy discontinuation, interval shortening, interval lengthening, dose increase and dose decrease respectively. Cost-effectiveness analysis focused on patients in remission (n=59). The use of proactive TDM-based IFX dosing resulted in a projected annualized reduction of 19.5 and 28.5 infusions due to IFX discontinuation and interval lengthening; the projected annualized increase in infusions was 39.1 and 4.3 due to IFX interval shortening and dose increase. This resulted in a net projected reduction of 4.7 IFX infusions per annum. Utilizing publicly available list prices for originator and biosimilar IFX and accounting for assay cost, projected cost savings resulting from proactive-TDM was 9105.0 and 6840.7 Euro per annum. Conclusion Proactive TDM in IBD patients in remission resulted in a modest reduction in the projected annualized number of infusions in our unit with consequent minor drug-related cost savings. Proactive-TDM encouraged cost-effective prescribing of IFX, however, the effect was minor. The frequency at which proactive TDM should be performed and whether subsequent rounds of proactive-TDM would continue to deliver similar cost savings is uncertain.