How Should Functionally Equivalent Drugs be Reimbursed?

Statutory reimbursement agencies as well as private insurers throughout member states of the Organization for Economic Cooperation and Development (OECD) reimburse the cost of medicines on the basis of criteria that include robust clinical evidence, budget impact analysis, and incremental cost effectiveness. The Centers for Medicare and Medicaid Services (CMS) in the US are no exception to this rule and are, in principle, seeking to maximize benefit for their Medicare enrollees, whilst ensuring reasonable drug outlays for the small number of drugs that they reimburse. This paper provides a retrospective analysis of the way two functionally equivalent drugs are treated for reimbursement purposes by the CMS; the period under consideration was 2001–3. The two drugs, epoetin-α and darbepoetin-α, are used for the treatment of anemia in renal failure and in patients receiving chemotherapy. By reviewing the publicly available pharmacological and clinical data of epoetin-α and darbepoetin-α, the paper confirms the two drugs’ functional equivalence, despite their structural differences. The implications of dose conversion ratios and costs to Medicare are subsequently explored. It is argued that the issue of dose equivalence between epoetin-α and darbepoetin-α has significant implications for patients, practitioners, and payors. A payor’s perspective is adopted in this respect, whereby clinical evidence and pricing data are used simultaneously. Based on the clinical evidence, a dose conversion ratio for epoetin-α:darbepoetin-α is established, which achieves a comparable clinical effect for the two drugs and this is set to be <254IU:1μg. The incremental costs to Medicare are calculated subsequently. The Average Wholesale Price and the Outpatient Prospective Payment System rule that Medicare uses to reimburse providers are used and suggest that treatment of cancer patients with chemotherapy-related anemia with epoetin-α would save Medicare an estimated $US600 million each year. Patients would also benefit significantly in terms of lower co-payments for epoetin-α. The evidence is supportive of the decision made by the CMS to reimburse the two drugs at the rate reflecting the achievement of comparable clinical effects and therefore reducing the pass-through payments for darbepoetin-α to zero for the 2002–3 fiscal year.     

Liver histology, blood biochemistry and RNA, DNA and subcellular protein composition of various skeletal muscles of rats with experimental cirrhosis: implications for alcoholic muscle disease.

(1) Liver cirrhosis was induced in male rats by treatment with carbon tetrachloride and phenobarbitone for 130-142 days. Detailed histological examination showed all livers from rats treated with carbon tetrachloride had annular fibrosis, necrosis, loss of normal hepatic architecture and other features that were consistent with an established micronodular cirrhosis. (2) Plasma biochemical analysis showed a significant reduction in total protein concentration (13%), which was due entirely to a reduction in plasma albumin (29%). There were also large increases in the plasma activities of alkaline phosphatase (110%) and aspartate aminotransferase (159%), when compared to phenobarbitone-treated controls. Plasma cholesterol was also increased (67%), but other plasma analytes were not significantly altered. (3) The soleus (Type I), plantaris (Type II) and gastrocnemius (Types I and II) muscles were dissected and examined for possible differential effects. There were minor reductions in all three muscle weights, but these changes did not reach statistical significance. The protein, RNA and DNA concentrations, total muscle content and content relative to body weight in cirrhotic rats were also not significantly altered in any of the muscles. Cirrhosis did not cause any perturbations in derived parameters, i.e. amount of synthetic apparatus per cell, RNA/DNA ratio, apparent cell size, protein/DNA ratio and the capacity for protein synthesis or RNA/protein ratio. (4) The gastrocnemius was fractionated into soluble, stromal and myofibrillar proteins. The concentrations and contents of all three proteins were unaltered in cirrhotic animals, compared to controls. (5) It is concluded that in this experimental model of cirrhosis there were no effects on those skeletal muscle variables which are strikingly altered by chronic alcohol feeding.(ABSTRACT TRUNCATED AT 250 WORDS)     

Obstructive sleep apnoea and oral breathing in patients free of nasal obstruction.

Although there is an association between nasal obstruction, oral breathing and obstructive sleep apnoea syndrome (OSAS), it remains unknown whether increased oral breathing occurs in patients with OSAS who are free of nasal obstruction. The present study evaluated the relationship between breathing route and OSAS in patients without nasal obstruction. The breathing route of 41 snorers (25 male; aged 26-77 yrs) with normal nasal resistance was examined during overnight polysomnography using a nasal cannula/pressure transducer and an oral thermistor. In total, 28 patients had OSAS (apnoeics) and 13 patients were simple snorers. Apnoeics had a higher percentage of oral and oro-nasal breathing epochs. Oral and oro-nasal breathing epochs were positively related with apnoea/hypopnoea index (AHI) and duration of apnoeas/hypopnoeas and inversely related to oxygen saturation. Additionally, oro-nasal breathing epochs correlated with body mass index (BMI). In multiple linear regression analysis, oral breathing epochs were independently related only to AHI (r2 = 0.443), and oro-nasal breathing epochs were independently related to AHI (r2 = 0.736) and BMI (r2 = 0.036). In conclusion, apnoeics spent more time breathing orally and oro-nasally than simple snorers, and the apnoea/hypopnoea index is a major determinant of the time spent breathing orally and oro-nasally.     

The path to care in autism: Is it better now?

Parents of children with autism often report problems associated with obtaining a diagnosis of their child's condition, family support, information, and appropriate services. To evaluate any changes in the situation over the last two decades, the families of all members of the West Midlands Autistic Society, age 19 years and below, were asked to fill in a questionnaire that covered aspects of detection, diagnosis, help and information received, and educational provision. Responses were obtained from 127 families, the children of whom formed an older group ages 10 years and above (n=67) and a younger group ages 9 years and below (n=61). Findings show that there have been improvements for the younger group in some areas, such as earlier referral, diagnosis, and statementing. However, the situation with respect to advice given by professionals and the support and provision available after referral is still much the same as that experienced by families of the older group of children. Many difficulties and hurdles remain which hinder parents and children on the path to care in autism.     

Effects of rehabilitation on chest wall volume regulation during exercise in COPD patients.

In order to investigate underlying mechanisms, the present authors studied the effect of pulmonary rehabilitation on the regulation of total chest wall and compartmental (ribcage, abdominal) volumes during exercise in patients with chronic obstructive pulmonary disease. In total, 20 patients (forced expiratory volume in one second, mean +/- SEM 39 +/- 3% predicted) undertook high-intensity exercise 3 days x week(-1) for 12 weeks. Before and after rehabilitation, the changes in chest wall (cw) volumes at the end of expiration (EEV) and inspiration (EIV) were computed by optoelectronic plethysmography during incremental exercise to the limit of tolerance (W(peak)). Rehabilitation significantly improved W(peak) (57+/-7 versus 47+/-5 W). In the post-rehabilitation period and at identical work rates, significant reductions were observed in minute ventilation (35.1+/-2.7 versus 38.4+/-2.7 L x min(-1)), breathing frequency (26+/-1 versus 29+/-1 breaths x min(-1)) and EEV(cw) and EIV(cw) (by 182+/-79 and 136+/-37 mL, respectively). Inspiratory reserve volume was significantly increased (by 148+/-70 mL). Volume reductions were attributed to significant changes in abdominal EEV and EIV (by 163+/-59 and 125+/-27 mL, respectively). The improvement in W(peak) was similar in patients who progressively hyperinflated during exercise and those who did not (24 and 26%, respectively). In conclusion, pulmonary rehabilitation lowers chest wall volumes during exercise by decreasing the abdominal volumes. The improvement in exercise capacity following rehabilitation is independent of the pattern of exercise-induced dynamic hyperinflation.     

Late left ventricular diastolic flow propagation velocity determined by color M-mode Doppler in the assessment of diastolic dysfunction.

BACKGROUND: Early color M-mode Doppler flow propagation (Ep) through the left ventricle (LV) has been proposed as a useful noninvasive index for assessing LV relaxation, whereas data concerning late velocity propagation (Ap) is lacking. METHODS: We studied 51 patients with delayed relaxation (group I) and 50 with pseudonormal filling pattern (group II). Another 51 aged-matched healthy persons served as the control group. RESULTS: Patients showed increased left atrial dimensions, atrial wave of the pulmonary vein flow, and Ap, and reduced LV ejection fraction, Ep, and Ep/Ap ratio compared with the control group. Patients in group II revealed increased left atrial dimensions (P =.001), atrial wave of the pulmonary vein flow (P <.001), and Ep/Ap ratio (P <.001), and reduced LV ejection fraction and Ap (P <.001) compared with group I. Regression analysis showed that the strongest independent variable distinguishing normal from pseudonormal filling pattern was the Ep/Ap ratio. CONCLUSION: Ap evaluation offers a new diagnostic diastolic index, especially in the field of the pseudonormal pattern where the separation from normal is difficult.     

Plasma atrial natriuretic peptide and renin-aldosterone in patients with cirrhosis and ascites: basal levels, changes during daily activity and nocturnal diuresis.

Measurements of plasma atrial natriuretic peptide concentrations at 8 AM showed raised levels in 21 patients with cirrhosis and ascites (10.5 +/- 0.8 pmol/L) compared with levels in 10 age-matched controls (4.1 +/- 0.64 pmol/L; p less than 0.0001). In eight patients and 10 controls, atrial natriuretic peptide, plasma renin activity, plasma aldosterone and urinary sodium excretion were measured every 4 hr for 24 hr. Subjects were mobile between 8 AM and 11 PM and supine from 11 PM to 8 AM. In controls, urinary sodium excretion was highest between 4 PM and 11 PM (19.34 +/- 3.74 mumol/min) and lowest between midnight and 8 AM (7.06 +/- 1.23 mumol/min; p less than 0.001). In patients, urinary sodium excretion was 0.63 +/- 0.14 mumol/min between 4 PM and midnight and 1.85 +/- 0.71 mumol/min (p less than 0.08) between midnight and 8 AM. In patients during the day, mean plasma atrial natriuretic peptide concentration did not change despite large individual variation, but large, sustained rises in plasma renin activity and plasma aldosterone were seen. Correlations were noted between atrial natriuretic peptide and urinary sodium excretion between midnight and 8 AM (r = 0.65; p less than 0.02) and 4 PM and midnight (r = 0.54; p less than 0.05) but not between 8 AM and 4 PM. Plasma renin activity dropped from 12.54 +/- 2.49 at midnight to 7.41 +/- 0.88 pmol/hr/ml at 8 AM (p less than 0.05); plasma aldosterone decreased from 1,032 +/- 101 to 798 +/- 56 pmol/L (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)