Non-invasive imaging techniques for early diagnosis of bilateral cardiac dysfunction in pulmonary hypertension: current ...
Pulmonary Arterial Hypertension: Current Therapeutic Strategies
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Prescribers Face Growing Web Of Restrictions On PAH Therapies
A new report finds commercial insurers are adding more restrictions on therapies for pulmonary arterial hypertension.
As treatment options for people with pulmonary arterial hypertension (PAH) expand, the path to insurance coverage for new therapies is becoming more complicated, according to a new report published in the Journal of Managed Care & Specialty Pharmacy.
A team of investigators used the Tufts Medical Center Specialty Drug Evidence and Coverage database to analyze how 17 major insurance plans treated PAH drugs, and to note changes in coverage provisions over time. The 17 health plans represented 70% of the commercially insured population in the United States, about 188 million people.
The analysis was based on 13 PAH drugs, including phosphodiesterase-5 inhibitors (PDE5is), endothelin receptor antagonists (ERAs), soluble guanylate cyclase (sGC) stimulators, and prostacyclin pathway agents (PPAs). It was based on rules in place between August 2017 and August 2022, and thus the analysis did not include sotatercept (Winrevair), Merck's latest PAH therapy, which was just approved in March of this year.
In broad terms, the report found payers instituted more coverage restrictions as time went on. In 2017, 38% of policies had at least one restriction on PAH prescriptions. By 2022, 73% of policies included at least one restriction. In particular, the investigators found step therapy protocols increased significantly over time, from 29% of plans including step therapy requirements, to 46%. Such requirements mandate that patients try particular drugs in a certain order, only moving to another "step" if the previous therapy fails.
Corresponding author James Chambers, PhD, MPharm, MSc, told Managed Healthcare Executive, that although there was a trend toward more step therapy requirements, it was not universal.
"It was surprising to observe the wide variation in step therapy protocols," he said. "Four payers included step therapy protocols in all coverage policies for PAH drugs, while three payers did not have any such requirements."
Chambers, an associate professor at the Tufts Medical Center Institute for Clinical Research and Health Policy Studies, said the variance means that patients with PAH will experience unequal access to therapies, depending on which health plan they have.
The investigators also found that 10 plans required at least one drug to be prescribed by a specialist (cardiologist or pulmonologist), while seven plans had no specialist prescribing requirements.
Chambers said payers generally do not publicly disclose their reasons for imposing restrictions, but the report notes that generics were the most common step required, and the proportion of plans with step requirements in a given class increased as generics became available in that class.
"I think it is fair to say that plans often use step therapy to control costs and that the increased use of step therapy may reflect pharmaceutical budgets becoming increasingly stretched," he said.
Chambers added that step therapy can also be a tool when payers negotiate coverage for drug companies; with payers offering preferential coverage for products with the largest rebates.
Another key finding from the study, though, is that policies and coverage are changing rapidly. The report found that between 40% and 75% of PAH coverage policies underwent revision each year of the analysis. They said that was consistent with previous research showing payers frequently review and revise their policies. Chambers and colleagues wrote that there appeared to be a lull in revisions in 2020, which they said may have been related to shifting priorities associated with the COVID-19 pandemic.
For providers, Chambers said the shifting policies amount to an added layer of complication.
"Instead of basing treatment decisions solely on a patient's clinical presentation, prescribers must also consider the patient's insurance coverage," he said. "These restrictions often result in more paperwork (including appeals) and additional time spent navigating the plan's coverage requirements."
Though such complications might be frustrating, Chambers said they are likely to increase over time.
"Our research has found that plans' use of step therapy (and other utilization management tools) is on the rise, and I would expect to see that trend continue," he said.
Expression Of Vasoactive Intestinal Peptide And Related Receptors In Overcirculation-Induced Pulmonary Hypertension In Piglets
Animals and surgical procedure.These experiments were conducted in agreement with the guide for the care and use of laboratory animals of the U.S. National Institutes of Health. Seventeen 3-wk-old piglets were included in this study, with approval by the Committee on the Care and Use of Animals in Research of the Faculty of Medicine of the Free University of Brussels. The left subclavian artery was dissected and anastomosed to the pulmonary arterial trunk, according to the adapted Blalock-Taussig procedure (11). After randomization, the anastomosis was ligated in eight animals (sham-operated controls).
Hemodynamic evaluation and tissue preparation.After a 3-mo observation period, the animals were anesthetized, ventilated, and equipped with catheters and an ultrasonic flow probe on the pulmonary arterial trunk for measurements of mean pulmonary artery pressure (PAP), occluded PAP (PAPO), systemic arterial pressure (SAP), cardiac output (Q), pulmonary arterial flow, heart rate (HR), and blood gases. Pulmonary vascular resistance (PVR) was defined by multipoint (PAP-PAPO)/Q plots obtained by rapid inflation of the inferior vena cava balloon (11,12). Hemodynamic and blood gas measurements were obtained after ensuring steady-state conditions (stable HR, SAP, and PAP) for 60 min after shunt closure (11). After measurements, the animals were killed with an overdose of anesthesia. Pulmonary tissue samples were immediately frozen in liquid nitrogen and stored at −80°C, or after overnight fixation in 10% formalin, embedded in paraffin for real-time quantitative PCR and histologic procedures, respectively.
Morphometry.Pulmonary arterial morphometry was performed on sections stained immunohistochemically with anti-α-smooth muscle actin antibody, as reported previously (11). Only arteries with an external diameter (ED) <500 μm and a complete muscular coat were measured and assigned to five groups according to the ED: 0–75, 76–150, 151–225, 226–300, and 300–500 μm. Medial thickness (MT) was related to arterial size using the following formula: %MT = (2 × MT)/(ED × 100).
RNA isolation and reverse transcription.Total RNA was extracted from whole lung tissue samples (100 mg), using TRIzol reagent (Invitrogen, http://www.Invitrogen.Com), according to the manufacturer's protocol. The extracted RNA was quantified by absorbance at 260 nm (BioPhotometer, Eppendorf, http://www.Eppendorf.De), and its concentration was adjusted at 0.25 μg/μL. Reverse transcription was performed with the GeneAmp PCR system 2400 (Applied Biosystems, http://www.Appliedbiosystems.Com), using 1 μg of total RNA in a total reaction volume of 20 μL, containing random hexamers, a mix of deoxyribonucleotides, reverse transcription buffer, DTT, ribonuclease inhibitor, and Superscript II reverse transcriptase (Applied Biosystems), according to the manufacturer's instructions. The cDNA synthesis was conducted using the following cycle procedure: 22°C for 40 min, 42°C for 1 h, and 99°C for 5 min.
Real-time quantitative PCR.Amplification of reverse-transcribed cDNA sequence for VIP, PACAP, PAC1, VPAC1, and VPAC2 was obtained by SYBR Green real-time quantitative PCR (Applied Biosystems). The primer sequences (Table 1) were designed on Primer Express software (Applied Biosystems), knowing the already reported porcine sequence for VPAC1 (GenBank NM214036) and the human sequences for VIP (GenBank NM003381), PACAP (GenBank NM001117), VPAC2 (GenBank NM003382), and PAC1 (GenBank NM001118). Gene expressions were normalized using hypoxanthine-guanine phosphoribosyltransferase (HPRT) housekeeping gene product as an endogenous reference (11). The primers were produced on an automated synthesizer (Applied Biosystems), according to the manufacturer's protocol (Eurogentec, http://www.Eurogentec.Com). SYBR Green real-time quantitative PCR analysis was performed with the GeneAmp PCR system 7700 (Applied Biosystems). For each gene, the procedure was realized in duplicate with 25 μL reaction volume containing 10 ng of cDNA, 5 pmol/μL of each primer, and 12.5 μL of SYBR Green PCR Master Mix (Applied Biosystems). Measurements were made in duplicate. Amplification was conducted as follows: initial denaturation (95°C for 10 min), then a two-step cycle program (15 s at 95°C followed by 1 min at 60°C) repeated 40 times. To ensure the quality of measurements, we systematically included both negative (no template control) and positive controls in duplicate in each plate. The statistical analysis of PCR results was completed with the comparison between the Ct values of the gene of interest and HPRT (ΔCt). Relative gene expression was obtained by ΔΔCt methods (ΔCtsample − ΔCtcalibrator), with the sham group as a calibrator, to compare every unknown-sample gene expression levels. The conversion between ΔΔCt and relative gene expression levels is given by fold induction = 2−ΔΔCt (12).
Table 1 Primers used for RTQ-PCR for the genes of interest and HPRT gene Immunohistochemistry.The immunohistochemistry analysis was performed using the avidin–biotin complex technique (13). After routine deparaffinization and rehydration, microwave heat pretreatment in citrate buffer was performed before immunolabeling with primary antibodies against VIP, PACAP, and PAC1. Whole lung sections were washed in Tris-buffered saline for 30 min, treated with normal goat serum (1/10 dilution) for 1 h, and incubated overnight at 4°C with a commercial primary antibody (rabbit polyclonal IgG; Table 2). After rinsing, the tissue sections were incubated for 30 min with a goat biotinylated anti-rabbit IgG at 1/300 dilution (BA-1000, Vector Laboratories, http://www.Vectorlabs.Com), followed by incubation with the ABC reagent (Vectastain Elite ABC Kit Standard, PK-6100, Vector Laboratories). After 30 min, the slides were rinsed again before developing in 5% diaminobenzidine tetrahydrochloride chromogenic solution (Dakocytomation, http://www.Dako.Com). Finally, the specimens were routinely dehydrated, mounted in DPX agent, and coverslipped. Human tissue samples were used as positive controls (liver for VPAC receptors, placenta for PACAP and PAC1, and colon for VIP). Negative controls were generated by omitting the primary antibody.
Table 2 Primary antibodies used for immunohistochemistry Data analysis.The values are reported as mean ± SEM. Tests of statistical significance were performed using the SigmaStat version 3.0 software (Systat Software, http://www.Sigmaplot.Com). The effects of the shunt on hemodynamic parameters were analyzed by a repeated-measures ANOVA. For relative amounts of mRNA, statistical significance between groups was determined by a one-tailed unpaired t test, after ensuring normality and equality of variance (14). Correlations between PAP, PVR, or MT and mRNA contents were calculated by means of a linear regression analysis. A p value of less than 0.05 was considered as significant.
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