By B. Jared. Thomas More College.

None of the studies reported cardiovascular outcomes buy 10 mg isordil, mortality discount 10mg isordil visa, or progression to ESRD buy isordil 10mg free shipping. The reduction in proteinuria was significantly greater in people with GFR <60 ml/min/1 buy isordil 10mg cheap. By contrast, proteinuria did not change from baseline in people treated with ACEI or ARB therapy alone. Compared with the ramipril + irbesartan group, there was a greater reduction in 24-hour proteinuria in the ramipril + irbesartan + spironolactone group. There was NS difference in proteinuria reduction between ramipril + spironolactone group and ramipril + irbesartan + spironolactone groups. The spironolactone-induced decrease in proteinuria was similar regardless of presence of diabetes. Four people receiving spironolactone + conventional therapy and two people receiving conventional therapy alone developed hyperkalaemia (no p value stated). Very few of the trials reported on relevant outcomes such as cardiovascular events and none reported on progression of CKD. Because of the limitations of trial design and their duration, the GDG agreed that a recommendation about the use of spironolactone should not be made based on the evidence regarding effects on proteinuria. Reference is made in a footnote to the recommendations on ACE inhibitors/ARBs. The GDG noted that hyperkalaemia was more common in people treated with spironolactone. Epidemiological studies suggest that dyslipidemia is a risk factor for CKD initiation, and that lipid lowering may slow disease progression. Elevated cholesterol and triglyceride levels are associated with a more rapid decline in kidney function. Possible mechanisms include accelerated atherosclerosis of arteries within the kidney and damaging effects of lipids on mesangial cells. Hyperlipidaemia may activate mesangial cells (which have low-density lipoprotein (LDL) receptors), leading to stimulation of mesangial cell proliferation and to increased production of macrophage chemotactic factors, accumulation of extracellular matrix, and reactive oxygen species. Studies in animal models show that reducing lipid levels with a drug such as lovastatin slows the rate of progressive injury. Treatment may reduce renal injury by decreasing albuminuria and reducing mesangial matrix accumulation and mesangial hypercellularity. No trials addressed clinically relevant markers of renal progression such as doubling of serum creatinine or time to ESRD. Three meta-analyses assessed the efficacy of statins compared to placebo in decreasing the risk of renal disease progression in adults with CKD. Study heterogeneity was mostly avoided by stratifying the data by baseline levels of proteinuria. The limitations with this meta- analysis were that the individual studies were few, small and methodologically limited. While this meta-analysis included the studies in the Douglas et al. The pooled analysis of changes in proteinuria or albuminuria was particularly marred by significant heterogeneity. However, the analysis of changes in GFR was an important outcome, and was not reported in the Douglas et al. A systematic review assessed cardiovascular outcomes, changes in GFR and 24-hour proteinuria in people with CKD randomised to statins or placebo/no treatment (50 studies, N=30,144, 133 Chronic kidney disease follow-up ranged from 2–60 months). The effects of statins versus placebo on renal disease progression in adults with varying severity and different causes of CKD are summarised in Table 10. There was significant heterogeneity in the meta-analyses for this outcome. However, there was significant between-study heterogeneity in this analysis. The GDG noted that the data assessing the impact of statins on proteinuria were derived largely from studies involving patients with (or at high risk of) overt cardiovascular disease. The Strippoli meta-analysis showed that in people with CKD not on dialysis statins significantly reduced all-cause mortality, cardiovascular mortality, non-fatal cardiovascular events and 24-hour proteinuria. However there was significant heterogeneity in the 24-hour urinary protein analysis. There was no significant benefit from statin therapy on change in GFR but that analysis was also subject to significant heterogeneity. There was therefore insufficient evidence to support a role for statin therapy on either reduction of proteinuria or progression of CKD. This is noted in a footnote to the statins recommendations in the following section. Furthermore, the expected positive association between blood cholesterol levels and cardiovascular outcomes were not observed in studies conducted in people receiving haemodialysis. The studies included evaluated multiple classes of medications, including statins, fibric acid derivatives, and probucol. Plasma triglycerides start to increase early in CKD and show the highest concentrations in nephrotic syndrome and people receiving dialysis. HDL-cholesterol concentrations are generally reduced compared with people without CKD and the distribution of subfractions is different, leading to impairment in reverse cholesterol transport and promoting atherosclerosis. Although elevated plasma LDL- cholesterol is a feature of nephritic syndrome, it is not typical of advanced CKD but, like HDL- cholesterol, there are qualitative changes in the LDL subfractions with an increase in those that are highly atherogenic. Lipoprotein (a), a risk factor for CVD in the general population is also influenced by CKD. Levels rise early in CKD and are mostly influenced by the degree of proteinuria. The hallmarks of uraemic dyslipidaemia are hypertriglyceridaemia, increased remant lipoproteins, reduced HDL-cholesterol, increased atherogenic sub-types of LDL- cholesterol, increased lipoprotein (a) and increased apolipoprotein A-IV. Statins are effective at lowering total and low-density lipoprotein (LDL)-cholesterol and fibrates reduce plasma triglyceride concentrations and raise HDL-cholesterol. Nicotinic acid appears most suited to the dyslipidaemia of CKD because it raises HDL-cholesterol, lowers lipoprotein (a), reduces triglycerides and shifts the LDL-cholesterol fraction to less atherogenic particles. SIGN guidelines recommend treatment with statins for people with stage 1–3 CKD and a predicted 10 year cardiovascular risk of ≥20%, irrespective of baseline lipid parameters. The CARI guidelines suggest that statins may retard progression of renal failure but make no specific recommendation. The UK CKD guidelines recommend that people with CKD and coronary disease should be treated according to existing guidelines and those who do not have evidence of coronary disease should be treated according to their estimated risk, using the Joint British Societies Guidelines (recognising that these guidelines specifically exclude CKD from their remit). There were very few trials of antilipemic therapies in non-dialysis CKD populations. There were no head-to-head studies of the three antilipemic therapies in adults with CKD. There were no studies that examined the efficacy of omega-3 fatty acids to reduce the risk of cardiovascular disease in adults with CKD. This study is limited by a lack of baseline proteinuria data, all the participants were men and the population did not include people with severe renal disease. Creatinine clearance overestimates GFR and it is likely that the participants identified as having chronic renal insufficiency could have had lower renal function than estimated.

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J Nerve Ment appetite suppressant d-fenfluramine buy isordil 10mg on line, which has since been Dis 1982;170(6):345–351 proven 10mg isordil. Personality features of women with good outcome cebo among 28 obese women with BED in reducing binge from restricting anorexia nervosa discount isordil 10mg fast delivery. Psychosom Med 1990;52(2): frequency; however order isordil 10mg without prescription, surprisingly, not in promoting weight 156–170. Nevertheless, fluvoxamine compared with placebo was orexia nervosa after long-term weight restoration: response to associated with significant reductions in both binge fre- d-fenfluramine challenge. Personality and symptomatological features in young, in particular. Approximately one-third of obese individuals nonchronic anorexia nervosa patients. J Psychosom Res 1980; presenting to weight loss clinics meet diagnostic criteria for 24(6):353–359. BED; therefore, effective treatments for this disorder may 12. Personality variables and disorders in an- orexia nervosa and bulimia nervosa. J Abnorm Psychol 1994; be of widespread clinical utility. Am J Psychia- ber of important issues are unresolved. BED have disturbances in eating behavior by definition, 14. Ten-year follow-up of 50 patients with bu- and are typically overweight and exhibit symptoms of anxi- limia nervosa. Bulimia nervosa: a 5- ety and depression in clinical samples. Alterations in serotonin it is surprising that the response of these presumably related activity and psychiatric symptomatology after recovery from bu- symptoms to medication is at least somewhat inconsistent, limia nervosa. Outcome, recovery, relapse and mor- tality across six years in patients with clinical eating disorders. A major problem in the develop- Psychiatr Scand 1993;87(6):437–444. L-Dopa as treatment for anorexia ner- response of binge eating to nonspecific interventions, in- vosa. In part for this reason, the effects of medi- Press, 1977:363–372. Treatment of compulsive eating disturbances once medication has been discontinued. Am J Psychol 1974;131: the role of pharmacotherapy for BED currently unresolved, 428–432. The use of diphenylhydantoin in compulsive studies to examine the potential benefits of combining med- eating disorders: further studies in anorexia nervosa. New York: Raven Press, 1977: ication with psychological treatment, especially CBT. Naloxone in the treatment of REFERENCES anorexia nervosa: effect on weight gain and lipolysis. In: Kaplan HI, Freedman AM, noses in anorexia nervosa. Comprehensive textbook of psychiatry, vol 2, 3rd 712–718. A comparative psychometric family therapy in anorexia nervosa and bulimia nervosa. Arch study of anorexia nervosa and obsessive neurosis. Long term follow-up of therapy in the short-term treatment of anorexia nervosa. Neuroleptics in the short-term treatment of vosa in women with obsessive compulsive disorder. Int J Eating anorexia nervosa: a double-blind, placebo controlled study with Dis 1986;5:1069–1075. J Clin Psy- activity in anorexia nervosa after long-term weight restoration. Obsessive-compulsive disorder: psychobiologi- treatment of anorexia nervosa. Int J Eating Dis 2000;27(3): cal approaches to diagnosis, treatment, and pathophysiology. Antiserotonin-antihista- 9-tetrahydrocannabinol in primary anorexia nervosa. J Pharmacol Exp Ther 1961; chopharmacol 1983;3:165–171. Cyproheptatadine in an- crossover study of oral clonidine in acute anorexia nervosa. Biol Psychiatry 2001;49(7): cisapride accelerates delayed gastric emptying and increases antral 644–652. Does fluoxetine augment the Garner DM, Garfinkel PE, eds. Diagnostic issues in anorexia ner- inpatient treatment of anorexia nervosa? Effects of carbohydrate depressive illness: a review of 11 studies. Comp Psychiatry 1988; and protein meals on plasma large neutral amino acids, glucose 29:427–432. Am J Psychol weight subjects normalize after weight gain. Amitriptyline in the increases serotonin transporter (SERT) binding sites and SERT treatment of anorexia nervosa: a double-blind placebo-controlled mRNA expression in discrete regions of female rat brain. In: Schatz- trial of lithium carbonate in primary anorexia nervosa. Washington, monoamine metabolism in anorexia nervosa. Arch Gen Psychiatry DC: American Psychiatric Press, 1993:49–70. Personality and symptomatological features in young, 68. Relationship of depres- nonchronic anorexia nervosa patients.

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Other outcomes are not as clearly dominant buy isordil 10 mg amex, and in fates are worse than death presumes an ecologic validity to these cases it may be useful to show the likely range of DALY ratings that may be unwarranted isordil 10mg with mastercard. One Cost-utility measures such as QALYs buy discount isordil 10mg online, DALYs discount 10 mg isordil overnight delivery, and mea- method of examining these ranges is to create sampling dis- sures like symptom-free days, have enormous appeal because tributions for costs and effectiveness measures to show the of their ability to reduce multiple effectiveness domains to precision of estimates as well as their mean. Where the measure is reduced to dollars (as in and plot these estimates as a cost-effectiveness plane. Boot- QALYs), one may even compare the values of interventions strapping techniques offer one means of describing confi- between different conditions (38), for example, if dollars dence intervals for incremental cost-effectiveness ratios expended on diabetes reap more benefits than dollars spent (ICERs) (49,50). Cost data are often highly positively on schizophrenia. But the assumptions built into such bullet skewed, and ICERs provide less biased estimates of confi- measures may have limited usefulness for informing deci- dence intervals in highly skewed cost data (43,51,52). Instead, these stakehold- cluster of points displays the sampling distribution of the ers are asking more specific questions. Most of the points fall in the lower-right quadrant, mental health commissioner asks, 'If I put an extra $3 mil- indicating that clozapine is most likely to be less costly and Chapter 57: The Economics of the Treatment of Schizophrenia 813 FIGURE 57. Ten thousand bootstrap replications plotted in the cost-effectiveness plane (intent-to-treat, N 136 clozapine and N 87 usual care; treatment crossovers excluded, N 89 clozapine and N 30usual care). The x-axis and y-axis, respec- tively, show the difference between clozapine and usual-care groups in estimated number of extrapyramidal side effects (EPS)-free months and total cost during a 2-year period. The quadrant to the lower right of the origin (0,0) contains those estimates where clozapine was found to be less costly and more effective than the usual care (80% of the estimates for the in- tent-to-treat analyses and 81% of the estimates when treat- ment crossovers are excluded). Cost-effectiveness of clozapine compared with conventional antipsychotic medication for patients in state hos- pitals. It is incumbent on mental health services re- the cost perspective (total societal cost) and for the effective- searchers to report their findings in ways that speak to fun- ness measure in question (reduction in EPS). Such displays ders and service system managers, which means providing of information give the reader/policy maker a sense of the estimates of the most likely outcome as well as the likelihood tightness of the point estimate and the risk of falling in a of alternative outcomes. One can use these sampling distributions to create cost- acceptability curves from the viewpoint of particular payers COST OF THE NEWER ANTIPSYCHOTIC for particular outcomes (e. These Saul Feldman (53) has held positions as the head of the acquisition costs are reflected in formulary budgets. Thus, he has past decade, and the market share of the newer agents has been in a position to make policy based on research, and risen as they have replaced the less costly conventional to inform policy makers with research. Distribution of (left circle) and total dollars paid (right circle) by Medicaid for antipsychotic medication prescriptions during 1998. Newer antipsychotic medications represented slightly over half of the total prescriptions, and they were responsible for 90% of the total cost. These also showed that clozapine is more effective than the usual data show that the newer agents account for 58% of all care in minimizing days hospitalized, enough so that the antipsychotic prescriptions paid for by Medicaid but for reduction in hospital days more than covers the increased $1. These charts dramatically But, from more narrow perspectives (e. For cost- This price difference between the older and the newer effectiveness studies to influence planning and policy mak- antipsychotic medications, which can be a 100-fold differ- ing, the perspectives of these different payers need to be ence (e. A hospi- than simply the cost of the medication was considered. For tal would have a great incentive to use clozapine for a heavy example, if using new and expensive medication X results user of hospital services if it has a fixed budget (the case in fewer days hospitalized than some alternative, then, all with most state hospitals), but a hospital paid a per diem else being equal, using X will reduce overall costs as long would have no such incentive. By the end of 6 months in the Connecticut study, only 11% of the Clozapine Cost Effectiveness Studies As usual care patients had begun a trial on clozapine, but by Case Examples the end of 24 months in the study, 66% had. In the VA The rub, of course, is that 'all else' is rarely equal in effec- clozapine study, 72% of the patients assigned to masked tiveness or cost-effectiveness studies, and the early cost pro- haloperidol had ceased taking the masked medication by jections concerning the impact of using clozapine often suf- the end of the 1-year study period, with 49 of 157 (31%) fered from faulty assumptions about what was equivalent. Be- amined changes in hospital use and lacked a comparison cause of the biases introduced by what is likely to be highly group (54–60). For example, the study by Meltzer and col- nonrandom discontinuation of the assigned treatment, the leagues (59) of patients with schizophrenia who were taking importance of intent-to-treat analyses and the unspecified clozapine collected retrospective cost data for 2 years before biases of crossovers-excluded analyses are well documented and after these 47 individuals began taking clozapine and (68). Regardless, when crossovers are common, analyses ex- concluded that clozapine was associated with a 23% drop cluding crossovers offer a proxy for the best-case scenarios in treatment costs. Critics focused on the who do well enough on treatment B to stay on it. Figure problem of the regression toward the mean that can be 57. The exclusion of treatment crossovers increases low point in their functioning (such as may have prompted the apparent effectiveness of clozapine (the crossovers- the initiation of clozapine), and on the other potential tem- excluded oval is shifted to the right of the intent-to-treat poral and case-mix confounds associated with mirror-image oval in Fig. For example, of conventional antipsychotics among long-term patients in in the VA study just cited, health care costs in the 6 months state hospitals (41,65,66), and in the 1-year masked trial prior to randomization were approximately $27,000 with comparing clozapine to haloperidol among veterans hospi- a standard deviation of about $17,000 (67). Each trial showed clozapine necticut clozapine study, the 95% confidence interval for to be somewhat more effective than the comparison agents, patients assigned to clozapine was $96,847 to $114,308 for and this increase in effectiveness comes at no additional cost year 2 versus $103,665 to $121,144 for those assigned to when costs are viewed from a societal perspective. With such variability, cost differences are Chapter 57: The Economics of the Treatment of Schizophrenia 815 very difficult to detect, even with the relatively large sample than or the same as the usual care and the effectiveness sizes of the VA and Connecticut trials (N 423 and 227, measures favor clozapine or are neutral). Even for individuals who are heavy service data to such a point estimate belies the broad distribution users at study entry, mounting a trial powered to detect cost of possible outcomes that are likely to occur across patients. If the trial were a study of outpatients who are infre- treating clinicians, need a sense of the range of possible quent users of expensive services like hospitals, it would outcomes and their relative likelihood to inform their deci- require even larger samples to detect cost differences apart sions about what chances they want to take. From a public health perspective, an emphasis on point Costs Associated with Risperidone, estimates of costs and effectiveness is misguided when the Olanzapine, and Quetiapine confidence intervals are so broad. Economists would call clozapine the dominant alternative in these randomized Figure 57. Distribution of (left circles) and total dollars paid (right circles) by Medicaid for antipsychotic medication prescriptions in Cali- fornia, Ohio, and New York during 1998. Because Medicaid formularies allow unrestricted and colleagues (74) and Foster and Goa (75) would not be access to any of these medications independent of location expected among treatment-refractory patients, even though in the country and the same financial incentives apply, one these patients are heavy users of inpatient services. Under would expect to see similar rates of prescribing these medica- other scenarios, these patients are the very ones for whom tions. Indeed, the distributions do appear quite similar to new interventions are associated with cost savings because each other and to the national data (Fig. That these they have higher initial rates of utilization on which to show distributions do not reflect what we know about the relative an impact (25,40). An independent study of risperidone effectiveness of these agents suggests that other factors are compared to conventional antipsychotics among outpa- strong influences on medication choice and that these influ- tients with schizophrenia using a matched comparison ences combine to create similar patterns of antipsychotic group found no difference in total treatment costs or effec- prescribing under Medicaid nationwide. These figures serve as CONCLUSION AND ADDITIONAL reminders that medications are started and discontinued for RESOURCES reasons other than effectiveness. The emphasis has been on illustrating the than dollars and does not label the cost units. Many of these studies have any findings reported as point estimates. It is important to methodologic shortcomings similar to those of the earlier tell patients, prescribers, and payers not just the best esti- cost studies of clozapine described above. Another concern mate of costs and effectiveness, but the likelihood that their is that industry sponsorship of many of these studies means costs and outcomes will fall within their acceptable ranges that they do not meet the criteria for lack of an incentive for what they are willing to pay and/or risk to gain a given for bias set forth by the New England Journal of Medicine outcome. Although their work cannot be quite arbitrary as they are prices (not costs) set by the be summarized here, useful source books include those by manufacturer.

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