Browsing by Subject "Drug Substitution"

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    Early adoption of dabigatran and its dosing in US patients with atrial fibrillation: results from the outcomes registry for better informed treatment of atrial fibrillation.
    (J Am Heart Assoc, 2013-11-25) Steinberg, Benjamin A; Holmes, Dajuanicia N; Piccini, Jonathan P; Ansell, Jack; Chang, Paul; Fonarow, Gregg C; Gersh, Bernard; Mahaffey, Kenneth W; Kowey, Peter R; Ezekowitz, Michael D; Singer, Daniel E; Thomas, Laine; Peterson, Eric D; Hylek, Elaine M; Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) Investigators and Patients
    BACKGROUND: Dabigatran is a novel oral anticoagulant approved for thromboprophylaxis in atrial fibrillation. Adoption patterns of this new agent in community practice are unknown. METHODS AND RESULTS: We studied patterns of dabigatran use among patients enrolled in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) Registry between June 2010 and August 2011 and followed for 12 months. Among 9974 atrial fibrillation patients included, 1217 (12%) were treated with dabigatran during the study. Overall, patients receiving dabigatran were younger (median age 72 versus 75 years, P<0.0001), more likely to be white (92% versus 89%, P=0.005), more likely to have private insurance (33% versus 25%, P<0.0001), and less likely to have prior cardiovascular disease (4% versus 33%, P<0.0001). They had more new-onset atrial fibrillation (8.8% versus 4.1%, P<0.0001), lower CHADS2 scores (estimated risk based on the presence of congestive heart failure, hypertension, aged ≥75 years, diabetes mellitus, and prior stroke or transient ischemic attack; mean 2.0 versus 2.3, P<0.0001), and lower Anticoagulation and Risk Factors in Atrial Fibrillation scores (mean 2.4 versus 2.8, P<0.0001). More than half (n=14/25, 56%) of patients with severe kidney disease were not prescribed reduced dosing, whereas 10% (n=91/920) with preserved renal function received lower dosing. Among patients not on dabigatran at baseline, 8% had dabigatran initiated during follow-up. Patient education was significantly associated with switching from warfarin to dabigatran (adjusted odds ratio for postgraduate 1.73, P=0.007), whereas antiarrhythmic drug use significantly correlated with de novo adoption of dabigatran (adjusted odds ratio 2.4, P<0.0001). CONCLUSIONS: Patients receiving dabigatran were younger and at a lower risk of stroke and bleeding. Patients appeared to drive switching from warfarin, whereas clinical characteristics influenced de novo start of dabigatran. These data suggest cautious early uptake of dabigatran, and more careful attention to dosing adjustments is warranted. CLINICAL TRIAL REGISTRATION URL: Clinicaltrials.gov. Unique identifier: NCT01165710.
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    Experience in Transitioning From Parenteral Prostacyclins to Selexipag in Pulmonary Arterial Hypertension.
    (Journal of cardiovascular pharmacology, 2020-04) Parikh, Kishan S; Doerfler, Sean; Shelburne, Nicholas; Kennedy, Karla; Whitson, Jordan; Dahhan, Talal; Fortin, Terry; Rajagopal, Sudarshan
    Parenteral prostacyclin therapies remain first-line therapy for patients with pulmonary arterial hypertension (PAH) with class IV symptoms. In selected patients who have been clinically stabilized, switching to selexipag, a chemically distinct prostacyclin receptor agonist, may alleviate risks associated with long-term parenteral therapy. We report our experience with transition of patients from parenteral prostacyclin therapy to selexipag. From January 2016 to July 2017, patients with PAH at the Duke University Pulmonary Vascular Disease Center with functional class II symptoms on stable parenteral prostacyclin therapy were offered the opportunity to transition to selexipag. A standardized protocol was developed to guide titration of therapies. Patients underwent pre- and post-transition assessments of hemodynamics, echocardiography, laboratory biomarkers, and functional status. We studied 14 patients with PAH (11 women; median age 53 years) in total. Overall, 13 patients tolerated the switch to selexipag and remained on the drug at study completion, and 1 patient passed away due to progressive liver failure. Surrogate markers including NT-proBNP, 6MWD, RV function, and TAPSE, and right heart catheterization hemodynamics were similar before and after transition. The transition from parenteral prostanoid therapy to oral selexipag was overall well-tolerated in patients with stable PAH and functional class II symptoms. Finally, doses of selexipag up to 3200 μg twice daily were well-tolerated in patients who had been treated with prior parenteral prostacyclins.
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    Guidance for switching from off-label antipsychotics to pimavanserin for Parkinson's disease psychosis: an expert consensus.
    (CNS spectrums, 2018-12) Black, Kevin J; Nasrallah, Henry; Isaacson, Stuart; Stacy, Mark; Pahwa, Rajesh; Adler, Charles H; Alva, Gustavo; Cooney, Jeffrey W; Kremens, Daniel; Menza, Matthew A; Meyer, Jonathan M; Patkar, Ashwin A; Simuni, Tanya; Morrissette, Debbi A; Stahl, Stephen M
    Patients with Parkinson's disease psychosis (PDP) are often treated with an atypical antipsychotic, especially quetiapine or clozapine, but side effects, lack of sufficient efficacy, or both may motivate a switch to pimavanserin, the first medication approved for management of PDP. How best to implement a switch to pimavanserin has not been clear, as there are no controlled trials or case series in the literature to provide guidance. An abrupt switch may interrupt partially effective treatment or potentially trigger rebound effects from antipsychotic withdrawal, whereas cross-taper involves potential drug interactions. A panel of experts drew from published data, their experience treating PDP, lessons from switching antipsychotic drugs in other populations, and the pharmacology of the relevant drugs, to establish consensus recommendations. The panel concluded that patients with PDP can be safely and effectively switched from atypical antipsychotics used off label in PDP to the recently approved pimavanserin by considering each agent's pharmacokinetics and pharmacodynamics, receptor interactions, and the clinical reason for switching (efficacy or adverse events). Final recommendations are that such a switch should aim to maintain adequate 5-HT2A antagonism during the switch, thus providing a stable transition so that efficacy is maintained. Specifically, the consensus recommendation is to add pimavanserin at the full recommended daily dose (34 mg) for 2-6 weeks in most patients before beginning to taper and discontinue quetiapine or clozapine over several days to weeks. Further details are provided for this recommendation, as well as for special clinical circumstances where switching may need to proceed more rapidly.
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    Hydroxycarbamide versus chronic transfusion for maintenance of transcranial doppler flow velocities in children with sickle cell anaemia-TCD With Transfusions Changing to Hydroxyurea (TWiTCH): a multicentre, open-label, phase 3, non-inferiority trial.
    (Lancet, 2016-02-13) Ware, Russell E; Davis, Barry R; Schultz, William H; Brown, R Clark; Aygun, Banu; Sarnaik, Sharada; Odame, Isaac; Fuh, Beng; George, Alex; Owen, William; Luchtman-Jones, Lori; Rogers, Zora R; Hilliard, Lee; Gauger, Cynthia; Piccone, Connie; Lee, Margaret T; Kwiatkowski, Janet L; Jackson, Sherron; Miller, Scott T; Roberts, Carla; Heeney, Matthew M; Kalfa, Theodosia A; Nelson, Stephen; Imran, Hamayun; Nottage, Kerri; Alvarez, Ofelia; Rhodes, Melissa; Thompson, Alexis A; Rothman, Jennifer A; Helton, Kathleen J; Roberts, Donna; Coleman, Jamie; Bonner, Melanie J; Kutlar, Abdullah; Patel, Niren; Wood, John; Piller, Linda; Wei, Peng; Luden, Judy; Mortier, Nicole A; Stuber, Susan E; Luban, Naomi LC; Cohen, Alan R; Pressel, Sara; Adams, Robert J
    BACKGROUND: For children with sickle cell anaemia and high transcranial doppler (TCD) flow velocities, regular blood transfusions can effectively prevent primary stroke, but must be continued indefinitely. The efficacy of hydroxycarbamide (hydroxyurea) in this setting is unknown; we performed the TWiTCH trial to compare hydroxyurea with standard transfusions. METHODS: TWiTCH was a multicentre, phase 3, randomised, open-label, non-inferiority trial done at 26 paediatric hospitals and health centres in the USA and Canada. We enrolled children with sickle cell anaemia who were aged 4-16 years and had abnormal TCD flow velocities (≥ 200 cm/s) but no severe vasculopathy. After screening, eligible participants were randomly assigned 1:1 to continue standard transfusions (standard group) or hydroxycarbamide (alternative group). Randomisation was done at a central site, stratified by site with a block size of four, and an adaptive randomisation scheme was used to balance the covariates of baseline age and TCD velocity. The study was open-label, but TCD examinations were read centrally by observers masked to treatment assignment and previous TCD results. Participants assigned to standard treatment continued to receive monthly transfusions to maintain 30% sickle haemoglobin or lower, while those assigned to the alternative treatment started oral hydroxycarbamide at 20 mg/kg per day, which was escalated to each participant's maximum tolerated dose. The treatment period lasted 24 months from randomisation. The primary study endpoint was the 24 month TCD velocity calculated from a general linear mixed model, with the non-inferiority margin set at 15 cm/s. The primary analysis was done in the intention-to-treat population and safety was assessed in all patients who received at least one dose of assigned treatment. This study is registered with ClinicalTrials.gov, number NCT01425307. FINDINGS: Between Sept 20, 2011, and April 17, 2013, 159 patients consented and enrolled in TWiTCH. 121 participants passed screening and were then randomly assigned to treatment (61 to transfusions and 60 to hydroxycarbamide). At the first scheduled interim analysis, non-inferiority was shown and the sponsor terminated the study. Final model-based TCD velocities were 143 cm/s (95% CI 140-146) in children who received standard transfusions and 138 cm/s (135-142) in those who received hydroxycarbamide, with a difference of 4·54 (0·10-8·98). Non-inferiority (p=8·82 × 10(-16)) and post-hoc superiority (p=0·023) were met. Of 29 new neurological events adjudicated centrally by masked reviewers, no strokes were identified, but three transient ischaemic attacks occurred in each group. Magnetic resonance brain imaging and angiography (MRI and MRA) at exit showed no new cerebral infarcts in either treatment group, but worsened vasculopathy in one participant who received standard transfusions. 23 severe adverse events in nine (15%) patients were reported for hydroxycarbamide and ten serious adverse events in six (10%) patients were reported for standard transfusions. The most common serious adverse event in both groups was vaso-occlusive pain (11 events in five [8%] patients with hydroxycarbamide and three events in one [2%] patient for transfusions). INTERPRETATION: For high-risk children with sickle cell anaemia and abnormal TCD velocities who have received at least 1 year of transfusions, and have no MRA-defined severe vasculopathy, hydroxycarbamide treatment can substitute for chronic transfusions to maintain TCD velocities and help to prevent primary stroke. FUNDING: National Heart, Lung, and Blood Institute, National Institutes of Health.
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    What to Expect When Switching to a Second Antidepressant Medication Following an Ineffective Initial SSRI: A Report From the Randomized Clinical STAR*D Study.
    (The Journal of clinical psychiatry, 2020-08-11) Rush, A John; South, Charles; Jha, Manish K; Jain, Shailesh Bobby; Trivedi, Madhukar H
    OBJECTIVE:An antidepressant medication switch often follows a failed initial trial with selective serotonin reuptake inhibitors (SSRIs). When, for whom, and how often second-step response and remission occur are unclear, as is preferred second-step trial duration. As more treatments are approved for use following 2 failed "adequate" trials, researchers and clinicians require an evidence-based definition of "adequate." METHODS:Following citalopram in the randomized Sequenced Treatment Alternatives to Relieve Depression (STAR*D) clinical trial (which ran July 2001-September 2006), participants with score ≥ 11 on the 16-item Quick Inventory of Depressive Symptomatology-Self-Rated (QIDS-SR₁₆) were randomized to bupropion sustained release, sertraline, or venlafaxine extended release (up to 14 weeks). The QIDS-SR₁₆ defined response, remission, and no clinically meaningful benefit based on the modified intent-to-treat sample. RESULTS:About 80% of 438 participants completed ≥ 6 weeks of treatment with the switch medication. All treatments had comparable outcomes. Overall, 21% (91/438) remitted, 9% (40/438) responded without remission, and 58% (255/438) had no meaningful benefit. Half of the responses and two-thirds of remissions occurred after 6 weeks of treatment. Overall, 33% of responses (43/131) occurred after ≥ 9 weeks of treatment. No baseline features differentiated early from later responders or remitters. No early triage point was found, but those with at least 20% reduction from baseline in QIDS-SR₁₆ score around week 2 were 6 times more likely to respond or remit than those without this reduction. CONCLUSIONS:Following nonefficacy with an initial SSRI, only about 20% remit and more than half achieve no meaningful benefit with a second-step switch to another monoaminergic antidepressant. A 12-week trial duration seems necessary to capture as many second-step switch responders as possible. TRIAL REGISTRATION:ClinicalTrials.gov identifier: NCT00021528.