The Economic Impact of Levothyroxine Dose Adjustments: the CONTROL HE Study.

BACKGROUND: In general, hypothyroidism can be adequately treated with a consistent daily dose of levothyroxine. However, the need for levothyroxine dose adjustments is frequent in clinical practice. The extent to which levothyroxine dose adjustments increase the utilization of healthcare resources has not previously been described in the clinical literature. OBJECTIVE: The primary objective of our study was to measure the effect of levothyroxine dose adjustments in terms of their utilization of healthcare resources including direct and indirect costs. A secondary goal was to identify any differences in patient characteristics that may be responsible for levothyroxine dose adjustments. METHODS: A retrospective medical chart review was conducted among patients of selected healthcare providers in the USA. Patients who were recently started on levothyroxine therapy (<6 months) were excluded to avoid situations that were more likely attributable to treatment initiation than inadequate therapeutic effect. Trained nurses extracted data from patient charts and electronic medical record systems for review. We analyzed the cost of resources consumed by the frequency of levothyroxine dose changes over 24 months: 0 dose changes (no dose adjustment group); one dose change, two dose changes, three or more dose changes (≥1 dose adjustment group). RESULTS: The study included 454 patients. Overall estimated resource utilization was higher per patient in the ≥1 dose adjustment group (US$5824) vs. the no dose adjustment group (US$3166) during the 24-month study period. When direct and indirect costs were combined, overall costs of care were greatest in patients requiring three or more dose adjustments (US$8220/patient). Patients in this cohort incurred 2.5-fold greater total costs compared with patients requiring no dose adjustments (US$8220 vs. US$3166). Among the 58 patients in the group requiring three or more dose adjustments, mean direct medical costs were significantly higher than in the patients requiring no dose adjustments (US$6387 vs. US$2182). Patients with at least one dose adjustment experienced a 40.3% increase in lost productivity vs. patients who had no dose adjustments (US$1381 vs. US$984). Loss of productivity was highest among patients with three or more levothyroxine dose adjustments. Among this cohort, there was an 86.4% increase in lost productivity vs. patients who had no levothyroxine dose adjustments (US$1833 vs. US$984). CONCLUSIONS: Patients experiencing multiple levothyroxine dose adjustments were shown to consume more healthcare resources, resulting in higher costs than those who required no dose adjustments. Each care episode contributed to lost time and wages with total estimated lost productivity escalating with increasing levothyroxine dose adjustments over a 24-month period.

Comorbidities, Concomitant Medications, and Diet as Factors Affecting Levothyroxine Therapy: Results of the CONTROL Surveillance Project.

BACKGROUND: The CONTROL Surveillance Project was a comprehensive patient-based survey conducted among hypothyroid patients undergoing treatment. The primary objective of the study was to specifically quantify the prevalence of factors adversely affecting levothyroxine therapy. METHODS: Participants were selected from a large proprietary database. Those eligible for the study completed a 21-question survey. RESULTS: Of the eligible hypothyroid patients, 925 (92.5%) were being treated with levothyroxine monotherapy. The mean age was 60.4 years; 755 (81.6%) were female and 168 (18.2%) were male. Almost half of those receiving levothyroxine (435, 47.0%) had at least one comorbid condition that could adversely affect its absorption: gastroesophageal reflux disease (33.8% of patients), irritable bowel syndrome (9.7%), lactose intolerance (7.8%), or a history of gastric bypass surgery or bowel resection (3.0%). Other factors reported by many patients that could adversely affect levothyroxine absorption included use of prescription medications (20.6%) and over-the-counter medications (34.3%) used to treat comorbid gastrointestinal (GI) conditions; use of dietary supplements (51.8%, primarily calcium and iron); and intake of foods/beverages high in fiber, iodine, or soy (68.0%). Of the 13.4% who reported difficulty controlling their hypothyroid symptoms, significantly more patients with comorbid GI conditions reported such difficulty (7.8 versus 5.6%, P < 0.01). Frequent changes in levothyroxine dosing (two or more dose changes in the past year) were reported by 8.0% of survey participants. Those with GI comorbidities were nearly twice as likely to have such changes (5.0 versus 3.0%, P < 0.01). CONCLUSION: Better initial workup of patients, including identification of relevant GI comorbidities and allergies, may help in the early detection of factors that may affect the performance of levothyroxine.

Effects of extended-release dipyridamole in vitro on thrombin indices measured by calibrated automated thrombography in poststroke survivors.

Randomized trials suggested superior stroke prevention with extended-release dipyridamole (ERD) in combination with low-dose aspirin than either with aspirin or dipyridamole alone. Thrombin generation (TG) is a critical step in clot formation and represents a cornerstone biomarker of atherothrombosis. We, therefore, sought to define the effect of ERD in escalating concentrations on the time course of TG using the Calibrated Automated Thrombogram (CAT) technology in patients after ischemic stroke. Serial plasma samples were obtained from 20 patients with ischemic stroke documented by neuroimaging and who were treated with aspirin for at least 30 days. The impact of 75-, 150-, 250-, and 300-nM ERD on TG was assessed using fluorogenic substrate CAT technology. The following integrated CAT indices were calculated for each ERD dose and compared with the vehicle: TGmax, start time (tstart) peak time (tpeak), and mean time (tmean). Preincubation of platelet-poor plasma with ERD resulted in a dose-dependent significant inhibition of TG. The TGmax was gradually reduced from 447 ± 21 nM at baseline to 354 ± 31 nM (P = 0.008) for 75-nM ERD, 298 ± 24 nM for 150-nM ERD, 248 ± 26 nM for 250-nM ERD, and finally to 240 ± 23 nM for 300-nM ERD (P < 0.0001 for all). The tmean was reduced only for the highest (250-300 nM) ERD concentrations. The tstart was only slightly delayed, but not different (1.5 vs. 1.8 vs.1.9 minutes; P = 0.09), for all ERD concentrations. The tpeak was not affected by ERD. ERD in vitro affects thrombin activity indices predominantly by a dose-dependent inhibition of endogenous thrombin potential and demonstrated a trend to delayed initiation of thrombin production. These preliminary data, while intriguing, require confirmation in poststroke patients receiving orally dosed ERD to determine whether these findings are clinically relevant.

Effects of dabigatran in vitro on thrombin biomarkers by Calibrated Automated Thrombography in patients after ischemic stroke.

Randomized trials suggest superior and safe stroke prevention in patients with atrial fibrillation after anticoagulation with dabigatran (D) at a 150 mg BID as described in the RE-LY prospective randomized open-label trial when compared to warfarin. Thrombin generation (TG) is a cornerstone of coagulation cascade, and represents a critical biomarker of atherothrombosis. We, therefore, sought to define the effect of D in escalating concentrations on the time course of TG using the Calibrated Automated Thrombogram(®) (CAT) technology in patients after ischemic stroke. Serial plasma samples were obtained from 20 patients with ischemic stroke documented by neuroimaging, who were treated with aspirin for at least 30 days. The impact of 0.1, 0.23, 0.46, 0.69 mM D in platelet-poor plasma (PPP) on TG indices was assessed using fluorogenic substrate CAT device. The following integrated CAT parameters: TGmax, start time (t-start) peak time (t-peak), and mean time (t-mean) were calculated for each D dose and compared with those of the vehicle. Preincubation of PPP with D resulted in dose-dependent significant inhibition of most TG indices. The TGmax was gradually reduced from 447 ± 21 nM at baseline and reach significance for 0.46 mM D (355 ± 44 nM, P = 0.03); and decreased further at 0.69 mM D to 302 ± 27 nM (P = 0.01). The t-peak has been achieved 2-3 times later than after vehicle already at 0.23 nM D. The t-start was delayed 3-4 fold starting from 0.23 mM concentration of D (P < 0.001 for all), but not different from D 0.1 mM (1.5 vs. 1.6; P = 0.34). The t-mean was not significantly affected by D. D in vitro impacts indices of TG predominantly by dose dependent inhibition of endogenous TG, and delayed thrombin production. This preliminary evidence, while intriguing, requires confirmation in post-stroke patients receiving orally dosed D in order to determine whether these findings are clinically relevant.