Meta-Analysis of the Cardiovascular Outcomes with Dipeptidyl Peptidase 4 Inhibitors: Validation of the Current FDA Mandate

Background

Earlier meta-analyses have demonstrated a significant reduction in major adverse cardiovascular events (MACE) with dipeptidyl peptidase 4-inhibitor (DPPI) use, as compared with placebo or alternative anti-diabetic therapies. However, the large phase III/IV trials, namely SAVOR-TIMI 53 and the EXAMINE trials, failed to demonstrate any significant differences in MACE between DPPI and placebo. We aimed to perform an updated meta-analysis of randomized controlled trials (RCTs) to investigate the differences in cardiovascular death, myocardial infarction (MI), and stroke between DPPI and placebo/alternative agents.

Methods

We searched the MEDLINE, EMBASE, and Cochrane databases for relevant phase III/IV RCTs. Unpublished trials with results available on national clinical trials registers were also included. RCTs with follow-up duration ≥24 weeks were included if they compared DPPI with placebo or an alternative anti-diabetic agent.

Results

A total of 82 RCTs including 73,678 patients were included. We did not observe any significant difference in the pooled odds of cardiovascular death, MI, or stroke in the composite DPPI arm as compared with the control arm. Similarly, the pooled odds of all-cause death and MACE were statistically similar between the two groups. None of the clinical outcomes studied demonstrated evidence of statistical heterogeneity or publication bias. Due to a larger sample size and a longer duration of follow-up, both SAVOR-TIMI 53 and EXAMINE trials had a considerably larger contribution to the pooled estimates in our meta-analysis, driving the updated pooled estimates towards null for all clinical outcomes assessed.

Conclusions

DPPI use was not associated with increased incidence of cardiovascular mortality, MI, stroke, or MACE compared with placebo or alternative anti-diabetic agents.     

Cost Effectiveness of Eplerenone in Patients with Heart Failure after Acute Myocardial Infarction Who were Taking Both ACE Inhibitors and β-Blockers

Background

The EPHESUS (Eplerenone Post-Acute Myocardial Infarction Heart Failure and Survival Study) showed that the use of aldosterone blockade with eplerenone decreased mortality in patients with heart failure after acute myocardial infarction, and a subsequent analysis showed eplerenone to be highly cost effective in this population.

Objective

To assess the cost effectiveness of eplerenone in an EPHESUS subgroup population who were taking both ACE inhibitors and β-blockers (β-adrenoceptor antagonists) at baseline.

Intervention

In the EPHESUS, a total of 6632 patients were randomized to receive eplerenone 25–50 mg/day (n = 3319) or placebo (n = 3313) concurrently with standard therapy and were followed for up to 2.5 years. Of these, 4265 (64.3%) patients (eplerenone: n = 2113; placebo: n = 2152) were taking both ACE inhibitors and β-blockers at baseline.

Methods and Main Outcome Measures

Resource use after the initial hospitalization included additional hospitalizations, outpatient services, emergency room visits, and medications. Eplerenone was priced at an average wholesale price of $US3.60 per day (year 2004 value). Bootstrap methods were used to estimate the fraction of the joint distribution of the cost and effectiveness. A net-benefit regression model was used to derive the propensity score-adjusted cost-effectiveness curve. The incremental cost effectiveness of eplerenone in cost per life-year gained (LYG) and cost per quality-adjusted life-year (QALY) gained beyond the trial period was estimated using data from the Framingham Heart Study, the Saskatchewan Health database, and the Worcester Heart Attack Registry. Both costs and effectiveness were discounted at 3%. Allthough not all resource use could be accounted for, the overall perspective was societal.

Results

As in the overall EPHESUS population, the total direct treatment costs were higher in the eplerenone arm than the placebo arm for patients who were taking both ACE inhibitors and β-blockers ($US14 563 vs $US12 850, difference = $US1713; 95% CI 721, 2684). The number of LYGs with eplerenone compared with placebo was 0.1665 based on the Framingham data, 0.0979 using the Saskatchewan data, and 0.2172 using the Worcester data. The incremental cost-effectiveness ratio (ICER) was $US10 288/LYG with the Framingham data, $US17 506/LYG with the Saskatchewan data, and $US7888/LYG with the Worcester data (99% <$US50 000/LYG for all three sources). The ICERs were systematically higher when calculated as the cost per QALY gained ($US14 926, $US25 447, and $US11 393, respectively) as the utilities were below 1 with no difference between the treatment arms.

Conclusions

As for the overall EPHESUS population, aldosterone blockade with eplerenone is effective in reducing mortality and is cost effective in increasing years of life for the EPHESUS subgroup of patients who were taking both ACE inhibitors and β-blockers.     

Cost Effectiveness of Angiotensin Receptor Blocker Monotherapy in Patients with Hypertension in the Netherlands

Background and Objective

Health gains and related cost savings achieved by optimizing treatment in hypertensive patients is highly important. The aim of this study was to evaluate the costs and cost effectiveness of treatment with angiotensin II receptor antagonists (angiotensin II receptor blockers [ARBs]) in patients with essential hypertension and to compare within-trial with real-life dosing of ARBs.

Methods

Cost effectiveness was estimated based on a published clinical trial comparing the BP-lowering effects of olmesartan, losartan, valsartan, and irbesartan. BP lowering after 8 weeks of treatment was entered into the Framingham risk functions to estimate cardiovascular complications after 1 and 5 years, using an international health economics model that was adapted to the Netherlands. Dutch costs (2006 values) and complications derived from the model were discounted at 4% and 1.5%, respectively, and cost effectiveness was expressed in net costs per cardiovascular complication averted. In a drug-utilization study, pharmacy dispensing records were used to evaluate differences between within-trial and daily-practice dosing and related costs for treatment in the Netherlands.

Results

After 8 weeks, the trial-based analysis showed that treatment with olmesartan versus losartan, valsartan, and irbesartan resulted in a significantly larger decrease in BP (11.5 vs 8.2, 7.9 and 9.9 mmHg [p<0.05], respectively) and consequently more complications averted. Cost effectiveness for olmesartan, losartan, valsartan, and irbesartan was estimated at €39 100, €77 100, €70 700, and €50 900 per cardiovascular complication averted, respectively. The incremental cost-effectiveness analysis indicated the most favorable cost-effectiveness outcome for olmesartan, with lower costs and less cardiovascular complications for olmesartan compared with the other three ARBs. The drug-utilization analysis showed that the dosing followed within clinical trials was not found in daily practice. On average, losartan, valsartan, and irbesartan were administered at doses above those used in clinical trials, whereas olmesartan was dosed lower than in clinical trials, resulting in relatively lower costs.

Conclusion

Based on the exact trial data, olmesartan was estimated to be the most favorable option of the four ARBs based on within-trial decreases in BP levels after 8 weeks and in terms of cost-effectiveness for this particular Dutch setting. However, for definite conclusions to be drawn, this hypothesis-generating study requires confirmation from further prospective studies comparing ARBs based on comparable BP control and including hard endpoints.     

Predictors of Annual Pharmaceutical Costs in Australia for Community-Based Individuals with, or at Risk of, Cardiovascular Disease

Background

Cardiovascular disease (CVD) remains a leading cause of death across the world and poses a significant economic burden. Research regarding per-person use and cost of cardiovascular pharmaceuticals in Australia, as well as potential predictors of pharmaceutical costs in populations using the ‘bottom up’ costing approach, is limited. Previous studies have adopted ‘top down’ costing approaches and have been based largely on hypothetical examples and considered only inpatient settings.

Objective

To determine the distribution of pharmaceutical costs (from a governmental perspective) related to each cardiovascular risk factor for individuals with, or at high risk of, CVD by analysing data for Australian participants enrolled in the Reduction of Atherothrombosis for Continued Health (REACH) Registry.

Methods

2873 participants were recruited for the REACH Registry through 273 general (primary care) practices in Australia. Included among data collected at baseline was a cardiovascular medicines review. Average weighted costs per person were estimated using Government-reimbursed prices (2007). Annual costs were stratified by sex, age, disease group and other co-morbidities. A multivariate linear regression model was utilized to reveal the predictors of the pharmaceutical costs.

Results

The average annual median cost of cardiovascular pharmaceuticals per person was Australian dollars ($A)1310. Use of lipid-lowering agents, non-aspirin (acetylsalicylic acid) antiplatelet agents and thiazolidinediones (glitazones) added significantly to the average annual per-person costs. The multivariate regression model showed that the predictors of annual pharmaceutical costs were dyslipidemia (β coefficient value [marginal annual cost associated with a condition] $A691; p< 0.001), hypertension ($A346; p< 0.001), vascular disease ($A340; p<0.001), diabetes mellitus ($A298; p<0.001), and obesity ($A52; p = 0.03). The same predictors, together with sex, were shown to have an impact on the number of medicines used.

Conclusions

Among community-based Australians with, or at risk of, CVD, independent drivers of annual cardiovascular pharmaceutical costs are dyslipidemia (which accounts for half of perperson costs), followed by hypertension, established CVD, and diabetes. Obesity also independently adds to the cost of cardiovascular pharmaceuticals in community-based Australians with, or at risk of, CVD.     

Statins for Cardiovascular Prevention According to Different Strategies

Background

Several studies have shown that treatment with HMG-CoA reductase inhibitors (statins) can reduce coronary heart disease (CHD) rates. However, the cost effectiveness of statin treatment in the primary prevention of CHD has not been fully established.

Objective

To estimate the costs of CHD prevention using statins in Switzerland according to different guidelines, over a 10-year period.

Methods

The overall 10-year costs, costs of one CHD death averted, and of 1 year without CHD were computed for the European Society of Cardiology (ESC), the International Atherosclerosis Society (IAS), and the US Adult Treatment Panel III (ATP-III) guidelines. Sensitivity analysis was performed by varying number of CHD events prevented and costs of treatment.

Results

Using an inflation rate of medical costs of 3%, a single yearly consultation, a single total cholesterol measurement per year, and a generic statin, the overall 10-year costs of the ESC, IAS, and ATP-III strategies were 2.2, 3.4, and 4.1 billion Swiss francs (SwF [SwF1 = $US0.97]). In this scenario, the average cost for 1 year of life gained was SwF352, SwF421, and SwF485 thousand, respectively, and it was always higher in women than in men. In men, the average cost for 1 year of life without CHD was SwF30.7, SwF42.5, and SwF51.9 thousand for the ESC, IAS, and ATP-III strategies, respectively, and decreased with age. Statin drug costs represented between 45% and 68% of the overall preventive cost. Changing the cost of statins, inflation rates, or number of fatal and non-fatal cases of CHD averted showed ESC guidelines to be the most cost effective. Conclusion: The cost of CHD prevention using statins depends on the guidelines used. The ESC guidelines appear to yield the lowest costs per year of life gained free of CHD.     

Cardiovascular safety of lumiracoxib: a meta-analysis of randomised controlled trials in patients with osteoarthritis

Purpose

To re-evaluate the cardiovascular risk of lumiracoxib compared with other non-steroidal anti-inflammatory drugs (NSAIDs) or placebo in patients with osteoarthritis.

Methods

We conducted a meta-analysis of randomised controlled trials of lumiracoxib versus placebo or other NSAIDs in patients with osteoarthritis reported up to January 2010. Both published and unpublished trials were included. PubMed searches using predefined search criteria (lumiracoxib AND osteoarthritis, limits: none; COX-189 AND osteoarthritis, limits: none) were used to obtain the relevant published trials. Novartis granted explicit access to their company studies and the right to use these study reports for the purposes of publication in peer reviewed journals. Endpoints were the Antiplatelet Trialists’ Collaboration (APTC) endpoint and individual cardiovascular endpoints.

Results

Meta-analysis of 6 trials of lumiracoxib versus placebo revealed no difference in cardiovascular outcomes. Meta-analysis of 12 trials of lumiracoxib versus other NSAIDs also revealed no difference. The pooled odds ratios were: 1.16 (95% CI 0.82, 1.63); 1.66 (95% CI 0.84, 3.29); 0.95 (95% CI 0.52, 1.76) and 1.04 (95% CI 0.60, 1.80) for the APTC endpoint, myocardial infarction, stroke and cardiovascular death respectively.

Conclusions

The results suggest that there were no significant differences in cardiovascular outcomes between lumiracoxib and placebo or between lumiracoxib and other NSAIDs in patients with osteoarthritis. Wide confidence intervals mean that further research is needed in this area to confirm these findings.     

Predicting the Impact of Polypill Use in a Metabolic Syndrome Population: An Effectiveness and Cost-Effectiveness Analysis

Background

Individuals with metabolic syndrome (MetS) are at increased risk of cardiovascular disease (CVD), often requiring combination drug therapy for control of risk factors and subsequent risk reduction. This study aims to compare the long-term effectiveness and cost effectiveness of the polypill (a multi-component tablet), and its components (alone or in combination), in a MetS population.

Methods and Results

A Markov state transition model, using individual subject data from the Australian Diabetes, Obesity and Lifestyle study, was constructed to simulate the effects of the treatment versus no treatment on CVD events, and costs over 10 years. In 1,991 individuals classified as MetS and free of existing diabetes mellitus or CVD, treatment with the polypill (or its components) was effective at reducing cardiovascular events [statin: 171, aspirin (actetylsalicylic acid): 201, antihypertensive: 186 per 1,000 individuals]. The more drug therapies employed the greater the reduction, with the polypill reducing up to 351 cardiovascular events per 10,000 individuals. Cost-effectiveness analyses were sensitive to drug treatment costs and effectiveness of treatment. At a cost of AUD$42 per person per annum, aspirin was considered cost saving. All other treatment strategies, including the polypill, were not cost effective.

Conclusion

The polypill is likely to be effective in the reduction of cardiovascular events in a MetS population. It is, however, not cost effective. Nevertheless, in a high-risk population, among whom combination therapy is often prescribed, the polypill is likely to be more cost effective than antihypertensive therapy alone or dual therapy with a statin and antihypertensive combination.     

Cost Effectiveness of Ezetimibe in Patients with Cardiovascular Disease and Statin Intolerance or Contraindications

Objective

To evaluate the cost effectiveness of long-term ezetimibe monotherapy in patients with established cardiovascular disease (CVD) who do not tolerate statins or in whom they are contraindicated.

Methods

A Markov model was used to estimate the potential costs and benefits associated with ezetimibe monotherapy compared with no treatment. The benefits associated with ezetimibe treatment were informed by a systematic review of clinical evidence and a published relationship linking changes in low-density lipoprotein cholesterol (LDL-C) levels to cardiovascular events.

Results

In the absence of data from clinical outcome trials, surrogate endpoints such as changes in lipid levels were used as indicators of clinical outcomes. A meta-analysis of seven placebo-controlled trials included in the review showed that ezetimibe was associated with a statistically significant mean reduction (from baseline to endpoint) in LDL-C of 18.56% (95% CI ?19.68, ?17.44; p < 0.00001) compared with placebo. Using 10 000 Monte Carlo simulations, it is estimated that ezetimibe monotherapy would prevent an average of 49 nonfatal myocardial infarctions, 11 nonfatal strokes, and 37 cardiovascular deaths in a cohort of 1000 patients aged 55 years with a baseline LDL-C concentration of 4.0 mmol/L. Events avoided provide an additional 211 quality-adjusted life-years (QALYs) over the 45 years modeled. With a mean incremental cost of £4 861 000 (year 2006 value), the discounted cost per QALY is £23 026 (Jackknife CI 22 979, 23 074). The model is reasonably robust to variations in key parameters. Incremental cost-effectiveness ratios fall below £20 000 per QALY for cohorts with baseline LDL-C values >4.5 mmol/L.

Conclusion

Ezetimibe monotherapy compared with no treatment is a cost-effective alternative for individuals with a history of CVD and high LDL-C levels, who do not tolerate statins or in whom they are contraindicated.     

Effect of Time to Titration to Maximum Dose of Statins on Cardiovascular Outcomes

Background

Recent trials have shown that high-dose HMG-CoA reductase inhibitor (statin) therapy reduces cardiovascular events in high-risk subjects within weeks of initiating therapy. We investigated the effect of time to titration to maximum dose of statin therapy on cardiovascular events.

Methods

From a list of all patients actively taking simvastatin 80 mg/day as of April 2003 at our hospital, two clinical pharmacists reviewed 213 electronic medical records including pharmacy records from November 1992 to April 2003. Data on cardiovascular risk factors, laboratory results, titration schedules, and outcomes were extracted from the electronic database. Titration period time frames were compared between patient groups using a Student t-test and multiple-variable logistic regression to account for other risk factors.

Results

Titration schedules and time frames to attain a regimen of simvastatin 80 mg/day were available for 154 (73%) subjects. Titrations ranged from 1 to 8 and averaged 2.3± 1.3 titrations per patient (median titrations = 2) over 1 month to 8.4 years. On follow-up, 47 patients experienced 80 cardiovascular-related outcomes. The average time to titration to maximum dose of statin therapy was longer for patients who experienced a cardiac event than for those who did not (3.5 ± 2.2 vs 2.1 ± 1.8 years; p = 0.0004). After accounting for other risk factors, the titration period was still significantly related to the presence of a cardiac event (p = 0.0060, odds ratio per month increase in the titration period 1.3, 95% CI 1.08, 1.58).

Conclusions

Despite potential limitations, the results of our study show that an excessive delay in titrating statin therapy to the optimal dose may lead to an increased risk of atherosclerosis-related events in high-risk patients.     

β-Blockers Reduce Mortality in Patients Undergoing High-Risk Non-Cardiac Surgery

Background

β-Adrenergic receptor antagonists (β-blockers) are frequently used with the aim of reducing perioperative myocardial ischemia and infarction. However, randomized clinical trials specifically designed to evaluate the effects of β-blockers on mortality in patients undergoing non-cardiac surgery have yielded conflicting results.

Objective

This study aimed to examine the effect of perioperative β-blockers on total and cardiovascular mortality in patients undergoing non-cardiac surgery.

Methods

We conducted a meta-analysis of randomized clinical trials that examined the effects of β-blockers versus placebo on cardiovascular and all-cause mortality in patients undergoing non-cardiac surgery. We extracted data from articles published before 30 November 2009 in peer-reviewed journals indexed in MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE and CINAHL. Data extraction was carried out independently by two reviewers on the basis of an intent-to-treat approach, and inconsistencies were discussed and resolved in conference. The present meta-analysis was undertaken according to the Quality of Reporting of Meta-analyses (QUORUM) statement.

Results

A total of 2148 records were screened, from which we identified 74 randomized controlled trials for non-cardiac surgery. After excluding 49 studies that did not report the clinical outcome of interest or were subanalyses or presented duplicate data, the final search left 25 clinical trials. Treatment with β-blockers had no significant effect on all-cause mortality (odds ratio [OR] 1.15; 95% confidence interval [CI] 0.92, 1.43; p = 0.2717) or cardiovascular mortality (OR 1.13; 95% CI 0.85,1.51; p = 0.5855). However, surgical risk category markedly differed across the studies. According to Joint American College of Cardiology and American Heart Association guidelines for perioperative assessment of patients having non-cardiac surgery, five trials evaluated the effect of β-blockers in patients treated with emergency and vascular surgery (high-risk category) whereas 15 and five trials evaluated the effect of β-blockers in intermediate low and intermediate high surgical risk categories, respectively. Subgroup analyses showed that the surgical risk category and dose titration of β-blockers to target heart rate affected the estimate of the effect of β-blockers for all-cause and cardiovascular mortality. β-Blockers reduced total mortality by 61% more in patients who underwent high-risk surgery than in those who underwent intermediate high- or intermediate low-risk surgery. When cardiovascular mortality was assessed, the benefit of β-blockers was 74% greater in trials that titrated β-blockers to heart rate than in trials that did not, although formal statistical significance was not achieved.

Conclusions

These data suggest that β-blockers may be useful for reducing mortality in patients who undergo high-risk non-cardiac surgery.     

The Cost Effectiveness of Statin Therapies in Spain in 2010, after the Introduction of Generics and Reference Prices

Background

HMG-CoA reductase inhibitors (statins) are the first-line drugs for use in the reduction of low-density lipoprotein cholesterol (LDL-C) levels and prevention of coronary heart disease (CHD) in patients with hypercholesterolemia. Generic statins could change the cost effectiveness of statin therapies in Spain, and more population groups could be included in the recommendations for reduction of cholesterol levels based on cost effectiveness.

Objectives

The objectives of this study were: (i) to assess the cost effectiveness of available statins for the reduction of LDL-C levels in Spain in 2010, after the introduction of generics and reference prices; (ii) to assess the cost effectiveness of combination therapy using a statin plus cholestyramine or ezetimibe; and (iii) to estimate the mean cost per patient to achieve National Cholesterol Education Program (Adult Treatment Panel-III) therapeutic objectives.

Methods

The following treatments were evaluated: rosuvastatin 5–20mg/day; atorvastatin, simvastatin, and pravastatin 10–40mg/day; lovastatin and fluvastatin 20–80mg/day; and combination therapy with a statin plus either cholestyramine 12–24g/day or ezetimibe 10mg/day. The cost effectiveness was evaluated in terms of cost per percentage point reduction in LDL-C, comparing the annual treatment costs with the effectiveness in reducing LDL-C. Treatment costs included those for medications (2010 wholesale prices), control measures, and treatment of adverse drug effects. The effectiveness of statins was estimated by developing a meta-analysis of clinical trials published between 1993 and 2005 that met several inclusion criteria. Average and incremental cost-effectiveness ratios were calculated to assess the efficiency of individual statin and combination therapies in reducing LDL-C levels.

Results

The effectiveness in terms of percentage reduction in LDL-C ranged from 19% for pravastatin 10mg/day to 55% for atorvastatin 80mg/day. Annual treatment costs ranged from €189.7 for simvastatin 10mg/day to €759.3 for atorvastatin 80mg/day. The cost-effectiveness ratios, in terms of cost per percentage point reduction in LDL-C, were: €6 for simvastatin, €10–12 for rosuvastatin, €10 for lovastatin, €13–16 for atorvastatin, €13–14 for fluvastatin, and €14–20 for pravastatin. Rosuvastatin + ezetimibe, simvastatin + ezetimibe, and atorvastatin + ezetimibe were the most cost-effective combination therapies for reducing LDL-C levels. Rosuvastatin was the most cost-effective statin for achieving the LDL-C therapeutic goal in patients at high risk for CHD, with a mean cost per patient of €516. Simvastatin was the most cost-effective statin to achieve the LDL-C goal in patients with moderate or low CHD risk, with a cost per patient of €217 and €190, respectively.

Conclusion

Rosuvastatin should be the first-choice agent in patients with high CHD risk, while simvastatin should be the first choice in patients with moderate or low risk. The addition of ezetimibe to rosuvastatin, simvastatin, or atorvastatin should be the preferred combination therapies when greater LDL-C reductions are required. The cost effectiveness of all statin therapies has increased in Spain after the introduction of generic statins and reference prices.     

Placebo? no thanks, it might be bad for me!

Objective

To assess the potential damage to patients from the inappropriate use of placebo.

Methods

Pivotal clinical trials of new drugs were evaluated for the treatment of multiple sclerosis following effective treatment with beta interferons and glatiramer acetate. The differences in the relapse rate between the experimental arms of the trials with interferons and glatiramer and the placebo groups were calculated.

Results

In ten pivotal trials, 2,752 patients were given placebo instead of the best proven treatments. The annualized relapse rate was reported for 2,405 of these patients. Patients receiving placebo suffered 630 more relapses than those treated with interferons or glatiramer.

Conclusions

The inappropriate use of placebo in clinical trials unduly harms patients. The use of standard active comparators would preserve patients’ rights and better define the respective clinical value of new medicines     

Effects of nicotine withdrawal on cognition in a clinical trial setting

Rationale

Smoking withdrawal has been widely established to produce a range of impairments to the quality of several major domains of cognitive function including attention, working memory and episodic memory.

Objectives

This study was conducted to determine the degree to which smoking withdrawal will produce impairments in cognitive function in phase I clinical trials.

Methods

Healthy male volunteers who were housed in a clinical trial facility for 16 days underwent periods of ad libitum smoking and smoking withdrawal.

Results

Smoking withdrawal disrupted aspects of attention and episodic verbal recall and recognition.

Conclusions

This study confirms previous work showing cognitive declines in smoking withdrawal and illustrates that such effects occur in ongoing safety and tolerability studies of new medicines and thus require careful consideration for the assessment of cognitive function in such trials as well as the accurate attribution of adverse events to the safety profiles of the medicines.     

A double-blind, placebo controlled, randomized trial of riluzole as an adjunct to risperidone for treatment of negative symptoms in patients with chronic schizophrenia

Rationale

Several recent studies have focused on glutamate modulating agents for symptoms relief in schizophrenia, especially negative symptoms which are resistant to conventional therapies.

Objectives

We aimed to assess the efficacy and tolerability of riluzole, an anti-glutamate agent with neuroprotective properties, as an adjunct to risperidone in improving negative symptoms of schizophrenia.

Methods

In this randomized double-blind placebo-controlled parallel-group study, 50 patients with chronic schizophrenia and a score of ≥20 on the negative subscale of positive and negative syndrome scale (PANSS) were enrolled in the active phase of their illness. Participants were equally randomized to receive riluzole (100 mg/day) or placebo in addition to risperidone (up to 6 mg/day) for 8 weeks. Participants were rated by PANSS every 2 weeks. The primary outcome of this study was the difference in the decrease of PANSS negative subscale score from baseline to the study endpoint between the two groups.

Results

By the study endpoint, riluzole-treated patients showed significantly greater improvement in the negative symptoms (P?<?0.001) as well as the PANSS total and general psychopathology subscale scores (P?=?0.001 and P?<?0.001; respectively) compared to the placebo group. Treatment group was the only significant predictor of changes in negative symptom in this trial (β?=??0.56, P?<?0.001). No significant difference was observed between two groups in the frequency of side effects.

Conclusion

These preliminary findings suggest that riluzole may be a safe and effective medication for the treatment of negative symptoms in patients with chronic schizophrenia. Further research and replication of study findings is warranted.

Clinical trial registry name and registration number

Iranian registry of clinical trials www.irct.ir, IRCT201107281556N26     

Magnitude of change with antidepressants and placebo in antidepressant clinical trials using structured,taped and appraised rater interviews (SIGMA-RAPS) compared to trials using traditional semi-structured interviews

Rationale

Although newer interview methods such as Structured Interview Guide for the Montgomery-Asberg Depression Rating Scale (SIGMA; MADRS) with audiotaping and Rater Applied Performance Scale (RAPS) appraisal have been introduced to improve reliability of ratings in antidepressant clinical trials, there is limited evidence that these methods actually improve trial outcome.

Objective

The objective of this study uis to evaluate outcome in four similarly designed trials of two recently approved antidepressants: two trials randomly used taped SIGMA interviews with RAPS appraisal and two trials used traditional semi-structured MADRS interviews.

Methods

We reviewed data from patients who were screened (N?=?243) and randomized (N?=?148), evaluating the magnitude of change with placebo and antidepressants on mean total MADRS score.

Results

Depressed patients assigned to placebo in trials using taped SIGMA interviews with RAPS appraisal had a significantly larger MADRS change score (M?=??11.5?±?12.7) compared to patients assigned to placebo in trials using traditional semi-structured interviews (?5.4?±?8.9; F(df?=?1.57)?=?5.58, p?=?0.022). The error variance was also significantly larger in the placebo arm of trials using SIGMA interviews (F?=?5.43, p?=?0.023). Depressed patients assigned to antidepressants had similar outcome in all of the four trials.

Conclusion

The recently suggested modifications in obtaining clinical data in antidepressant trials such as taped SIGMA interviews with RAPS rating appraisals may in fact result in a higher magnitude of placebo response and a lower magnitude of antidepressant-placebo differences compared to the traditional methods of collecting clinical data. These results were unexpected and indicate the necessity to test new methods prospectively, no matter how intuitively sensible they seem, prior to their implementation.     

The use of the EVITA algorithm for clinical assessment of novel agents used in prostate cancer,metastatic melanoma,and systemic lupus erythematosus

Purpose

Existing health technology assessment methods can be time-consuming and complicated to use in practice. EValuation of pharmaceutical Innovations with regard to Therapeutic Advantage (EVITA) is a recently developed drug assessment strategy that provides a detailed and clinically relevant evaluation of new agents compared to standard therapies. We therefore sought to use EVITA to evaluate eight novel agents recently introduced to clinical practice or in late-stage trials for the treatment of prostate cancer, metastatic melanoma, or systemic lupus erythematosus (SLE).

Methods

Eight agents (abiraterone, enzalutamide, sipuleucel-T, Prostvac, radium 223, ipilimumab, vemurafenib, and belimumab) were selected for study using the EVITA algorithm. A comprehensive literature search was performed to find clinical trial data, which were then classified using the EVITA protocol. EVITA was also compared to results from health technology assessments (HTAs) or reimbursement decisions.

Results

The EVITA scores for the eight drugs ranged from 5.5 to 9: all the selected agents are therefore classed as ‘recommended’ and are likely to produce a therapeutic advantage. In particular, vemurafenib is likely to be highly beneficial to patients with metastatic melanoma and radium 223 to patients with metastatic prostate cancer affecting the bone. The EVITA results were generally concordant with HTAs.

Conclusions

All the agents show favourable EVITA scores and are therefore recommended for clinical practice. EVITA is an easy-to-use tool that provides clinical context to the assessment of newly introduced agents and can be easily used by non-specialists.