Left ventricular outflow tract (LVOT) obstruction is a leading cause of mortality and exclusion from transcatheter mitral valve replacement (TMVR). Intentional laceration of the anterior mitral valve ...leaflet to prevent LVOT obstruction (LAMPOON) is a transcatheter mimic of surgical chord-sparing leaflet resection.
The purpose of this prospective multicenter trial was to study LAMPOON with transseptal (Edwards Lifesciences, Irvine, California) TMVR in annuloplasty rings or native mitral annular calcification (MAC).
Subjects at high or extreme surgical risk and prohibitive risk of LVOT obstruction from TMVR were included. Eligibility was modified midtrial to exclude subjects with threatened LVOT obstruction from a Sapien 3 valve fabric skirt. The primary endpoint was procedure survival with successful LAMPOON, with successful TMVR, without reintervention, and with LVOT gradient <30 mm Hg (“optimal”) or <50 mm Hg (“acceptable”). Secondary endpoints included 30-day mortality and major adverse cardiovascular events. There was universal source-data verification and independent monitoring. All endpoints were independently adjudicated. Central laboratories analyzed echocardiogram and CT images.
Between June 2017 and June 2018, 30 subjects were enrolled equally between the MAC and ring arms. LAMPOON traversal and midline laceration was successful in 100%. Procedure survival was 100%, and 30-day survival was 93%. Primary success was achieved in 73%, driven by additional procedures for paravalvular leak (10%) and high-skirt neo-LVOT gradients observed before a protocol amendment. There were no strokes.
LAMPOON was feasible in native and annuloplasty ring anatomies in patients who were otherwise ineligible for treatment, with acceptable safety. LAMPOON was effective in preventing LVOT obstruction from TMVR. Despite LAMPOON, TMVR using Sapien 3 in annuloplasty rings and MAC still exhibits important limitations. (NHLBI DIR LAMPOON Study: Intentional Laceration of the Anterior Mitral Leaflet to Prevent Left Ventricular Outflow Tract Obstruction During Transcatheter Mitral Valve Implantation; NCT03015194)
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The aim of this study was to define risk factors and develop a predictive risk score for new pacemaker implantation (PMI) after transcatheter aortic valve replacement (TAVR).
TAVR has become an ...accepted treatment alternative for patients with severe aortic stenosis at elevated surgical risk. New PMI is a common occurrence after TAVR and is associated with poorer outcomes.
All patients without prior valve procedures undergoing elective TAVR with the Edwards SAPIEN 3 at a single institution (n = 1,266) were evaluated. Multivariate analysis was performed to evaluate for predictors of PMI in this population in a derivation cohort of patients with complete data (n = 778), and this model was used to develop the Emory risk score (ERS), which was tested in a validation cohort (n = 367).
Fifty-seven patients (7.3%) in the derivation cohort required PMI. In a regression model, history of syncope (odds ratio OR: 2.5; p = 0.026), baseline right bundle branch block (OR: 4.3; p < 0.001), QRS duration ≥138 ms (OR: 2.5; p = 0.017), and valve oversizing >15.6% (OR: 1.9; p = 0.041) remained independent predictors of PMI and were included in the ERS. The ERS was strongly associated with PMI (per point increase OR: 2.2; p < 0.001) with an area under the receiver-operating characteristic curve of 0.778 (p < 0.001), which was similar to its performance in the derivation cohort.
A history of syncope, right bundle branch block, longer QRS duration, and higher degree of oversizing are predictive of the need for PMI after TAVR. Additionally, the ERS for PMI was developed and validated, representing a simple bedside tool to aid in risk stratification for patients for undergoing TAVR.
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As new rare-disease drug therapy, gene therapies, and high-priced cancer drugs receive US Food and Drug Administration approval, there is an increasing potential for drug super spender individuals ...with more than $250,000 annual drug cost.
To categorize all members in a large, commercially insured population by their total annual combined drug costs from both medical and pharmacy benefits and to determine the trend in drug super spender prevalence.
Using a commercially insured population with integrated medical and pharmacy benefits, all unique members with any enrollment between January 2016 and December 2019 were identified. The sum of total cost for all pharmacy claims plus all medical benefit claim lines for drugs was determined for each member, for each calendar year. Cost was defined as the plan plus member liability at network-discounted price, with no further adjustment for any coupons or rebates. Descriptive statistics were used to describe the drug super spender growth.
There was an average of 17.9 million members per year with at least 1 month of eligibility through the 4-year study period. In 2016, a total of 2,994 members with more than $250,000 drug cost per member accounted for $1,324 million drug spend. In 2019, there were 5,894 super spender members (97% increase), accounting for $2,579 million drug cost (95% increase), which was 9.6% of $26,618 million total drug spend.
In this large, commercially insured population, a small (32 per 100,000) number of drug super spender members comprise a disproportionate portion of the total drug expenditures, at $1 of every $10 dollars of total drug expenditures. Health plans need to understand the drug super spender trend and develop strategies to maintain health care affordability.
This study was funded internally by Prime Therapeutics LLC. Drs Starner and Gleason are employees of Prime Therapeutics LLC, a pharmacy benefits management company. Dr Bowen is a former employee of Prime Therapeutics LLC.
Synthetic auxotrophy in which bacterial viability depends on the presence of a synthetic amino acid provides a robust strategy for the containment of genetically modified organisms and the ...development of safe, live vaccines. However, a simple, general strategy to evolve essential proteins to be dependent on synthetic amino acids is lacking. Using a temperature-sensitive selection system, we evolved an Escherichia coli (E. coli) sliding clamp variant with an orthogonal protein–protein interface, which contains a Leu273 to p-benzoylphenyl alanine (pBzF) mutation. The E. coli strain with this variant DNA clamp has a very low escape frequency (<10–10), and its growth is strictly dependent on the presence of pBzF. This selection strategy can be generally applied to create ncAA dependence of other organisms with DNA clamp homologues.
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, genetic, chronic, and life-threatening blood disease with an estimated prevalence of 13 per 1,000,000 persons reported in the United States. ...Available at analysis, PNH treatment included the use of C5 inhibitors (C5is), which prevent formation of membrane attack complex and consequently intravascular hemolysis. Limited real-world evidence suggests some individuals with PNH continue to experience anemia and breakthrough hemolysis (BTH) after C5i treatment, indicating unmet needs.
To describe real-world treatment patterns and outcomes among individuals treated with C5is, eculizumab (ECU), and ravulizumab (RAV), focusing on affordability challenges and therapy unmet needs from a US payer perspective.
This retrospective cohort study was conducted using deidentified data from Prime Therapeutics' approximately 15 million commercially insured US members with integrated medical and pharmacy claims data. Members were identified between January 1, 2018, and December 31, 2020. Inclusion criteria for cohort identification were adults aged 18 years or older at ECU or RAV index date requiring 2 or more claims for ECU or 1 or more claims for RAV. ECU and RAV users were excluded if they had a claim indicating treatment for a US Food and Drug Administration (FDA)-approved non-PNH indication. Members were required to be continuously enrolled 6 months before and 12 months after their index ECU or RAV claim. Real-world C5i claims-based treatment dosage and frequency patterns were compared with FDA-labeled dosing. Clinical outcomes, including transfusions and BTH events, were identified in the pre-index and post-index periods. Health care resource use and costs were calculated after network discounts, including member share.
A total of 86 commercial members met analysis criteria: 34 in the ECU cohort and 52 in the RAV cohort. The mean age was 42.6 years, and 54.6% were female. Estimated higher-than-label PNH-recommended dosage occurred in 38.2% of ECU and 9.6% of RAV members. In total, 29.4% of ECU and 17.3% of RAV members had 4 or more transfusions in the post-index period. Additionally, 29.4% of ECU and 13.5% of RAV members had 1 or more BTH episodes. Post-index period mean per member total health care costs were $711,785 among ECU members and $624,911 among RAV members, and C5i costs accounted for 79.7% and 85.6% of total health care costs, respectively.
Although all members received at minimum FDA-approved dosages, transfusions and BTH events continue to occur for some members. These findings indicate potentially inadequate therapy responses in a substantial subset of C5i users, adding additional therapy costs to an already extremely expensive therapy.
This study was funded by Apellis Pharmaceuticals. Drs Broderick and Fishman report employment by Apellis Pharmaceuticals and own stock options. Dr Burke reports employment by Prime Therapeutics, LLC, which has received research funding from Apellis Pharmaceuticals. Dr Gleason reports employment by Prime Therapeutics, LLC, which has received research funding from Apellis Pharmaceuticals; serves on the advisory committee at the Institute for Clinical and Economic Review; and has served on the Board of Directors at the Academy of Managed Care Pharmacy.
We describe an approach for the development of fluorescent sensors of metabolite binding in which a genetically encoded fluorescent non-canonical amino acid (fNCAA) containing a 7-hydroxycoumarin ...moiety (7-HCAA) forms a FRET pair with native tryptophan residues. Although previous studies demonstrated the potential for using 7-HCAA as an acceptor for tryptophan, this approach has not yet been explored within a single protein containing multiple tryptophan residues. A structure-based analysis of a hexokinase enzyme with multiple native tryptophan residues identified glutamate 50 as a potential site of 7-HCAA incorporation; Glu50 moves closer to the native tryptophans upon substrate binding. Substitution of 7-HCAA at residue 50 led to an increase in FRET efficiency in the presence of the substrate; this effect was not observed in a control protein where no change in distance between 7-HCAA and the native tryptophans occurs on substrate binding. This system was then used to directly observe differences in binding affinity of the hexokinase that occur at a number of pH values. Our approach builds on previous research in that it eliminates the need for the incorporation of multiple fNCAAs or fluorescent labels within a target protein and can be used to study substrate binding with native ligands. As such, it serves to expand the versatility of FRET-based techniques.
Cystic fibrosis (CF) is a chronic, progressive genetic disease caused by mutations in the CF transmembrane conductance regulator (
) gene resulting in a dysfunctional CFTR protein. ...Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) is a triple combination oral drug therapy with an annual cost greater than $300,000 and available to nearly 90% of the CF population based on age and genotype. Limited real-world direct medical cost offset data are available for ELX/TEZ/IVA among commercially insured individuals.
To describe and compare total cost of care and health care resource utilization (HRU) 180 days before and 180 days after first ELX/TEZ/IVA drug claim among CFTR modulator treatment-naive, commercially insured members.
This study was a retrospective analysis of integrated pharmacy and medical claims data from 17.9 million commercially insured members. A 180-day prestudy and 180-day poststudy design was used to compare outcomes prior to and following ELX/TEZ/IVA initiation. Study inclusion was limited to members with first ELX/TEZ/IVA claim (index date) between October 21, 2019, and December 31, 2021, continuously enrolled 180 days before and 180 days after index date, and no CFTR-modulator drug claim 180 days prior to index date. Total paid amounts from medical and pharmacy claims after network discounts (defined as total cost of care), HRU, and pulmonary exacerbation events were summarized using descriptive statistics and compared using Wilcoxon signed rank test.
494 members newly initiating ELX/TEZ/IVA met inclusion criteria. Prestudy to poststudy mean member total cost of care increased from $58,180 to $198,815 (difference: $140,635;
< 0.001). Mean member medical benefit costs decreased from $28,764 to $12,484 (difference: -$16,280;
< 0.001), whereas mean member pharmacy benefit costs increased from $29,416 to $186,331 (difference: $156,915;
< 0.001). Mean member inpatient hospitalizations (62% absolute reduction;
< 0.001), emergency department visits (43% absolute reduction;
< 0.01), and pulmonary exacerbation events (44% absolute reduction;
< 0.001) were significantly lower in the postperiod compared with the preperiod.
Among members with CF newly initiating CFTR modulator with ELX/TEZ/IVA, mean member total cost of care increased 3-fold despite significant and meaningful reductions in pulmonary exacerbation events, HRU, and medical benefit spend. Pharmacy benefit spend outpaced medical benefit spend at a rate of $9.64 to $1 in the 180 days following ELX/TEZ/IVA initiation. Real-world data should be used to objectively measure the clinical and economic benefits of costly medications, such as CFTR modulators, to align price with value.
Drs Marshall, Espinosa, Starner, and Gleason are employees of Prime Therapeutics. The study was funded by Prime Therapeutics.
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