Comparative effectiveness of dopamine agonists and monoamine oxidase type-B inhibitors for Parkinson's disease: a multiple treatment comparison meta-analysis.

PURPOSE: To investigate the comparative effectiveness of dopamine agonists and monoamine oxidase type-B (MAO-B) inhibitors available for treatment of Parkinson's disease. METHODS: We performed a systematic literature search identifying randomized controlled trials investigating 4 dopamine agonists (cabergoline, pramipexole, ropinirole, rotigotine) and 3 MAO-B inhibitors (selegiline, rasagiline, safinamide) for Parkinson's disease. We extracted and pooled data from included clinical trials in a joint model allowing both direct and indirect comparison of the seven drugs. We considered dopamine agonists and MAO-B inhibitors given as monotherapy or in combination with levodopa. Selected endpoints were change in the Unified Parkinson's Disease Rating Scale (UPDRS) score, serious adverse events and withdrawals. We estimated the relative effectiveness of each dopamine agonist and MAO-B inhibitor versus comparator drug. RESULTS: Altogether, 79 publications were included in the analysis. We found all the investigated drugs to be effective compared with placebo when given as monotherapy except safinamide. When considering combination treatment, the estimated relative effects of selegiline, pramipexole, ropinirole, rotigotine, cabergoline, rasagiline and safinamide were 2.316 (1.819, 2.951), 2.091 (1.889, 2.317), 2.037 (1.804, 2.294), 1.912 (1.716, 2.129), 1.664 (1.113, 2.418), 1.584 (1.379, 1.820) and 1.179 (1.031, 1.352), respectively, compared with joint placebo and levodopa treatment. CONCLUSIONS: Dopamine agonists were found to be effective as treatment for Parkinson's disease, both when given as monotherapy and in combination with levodopa. Selegiline and rasagiline were also found to be effective for treating Parkinson's disease, and selegiline was the best option in combination with levodopa among all the drugs investigated.

Comparing Effects of Biologic Agents in Treating Patients with Rheumatoid Arthritis: A Multiple Treatment Comparison Regression Analysis.

Rheumatoid arthritis patients have been treated with disease modifying anti-rheumatic drugs (DMARDs) and the newer biologic drugs. We sought to compare and rank the biologics with respect to efficacy. We performed a literature search identifying 54 publications encompassing 9 biologics. We conducted a multiple treatment comparison regression analysis letting the number experiencing a 50% improvement on the ACR score be dependent upon dose level and disease duration for assessing the comparable relative effect between biologics and placebo or DMARD. The analysis embraced all treatment and comparator arms over all publications. Hence, all measured effects of any biologic agent contributed to the comparison of all biologic agents relative to each other either given alone or combined with DMARD. We found the drug effect to be dependent on dose level, but not on disease duration, and the impact of a high versus low dose level was the same for all drugs (higher doses indicated a higher frequency of ACR50 scores). The ranking of the drugs when given without DMARD was certolizumab (ranked highest), etanercept, tocilizumab/ abatacept and adalimumab. The ranking of the drugs when given with DMARD was certolizumab (ranked highest), tocilizumab, anakinra/rituximab, golimumab/ infliximab/ abatacept, adalimumab/ etanercept [corrected]. Still, all drugs were effective. All biologic agents were effective compared to placebo, with certolizumab the most effective and adalimumab (without DMARD treatment) and adalimumab/ etanercept (combined with DMARD treatment) the least effective. The drugs were in general more effective, except for etanercept, when given together with DMARDs.

A review and Bayesian meta-analysis of clinical efficacy and adverse effects of 4 atypical neuroleptic drugs compared with haloperidol and placebo.

AIMS: The objective of the study was to examine the efficacy and the degree of adverse effects connected with atypical neuroleptic drugs and haloperidol by using a previously described Bayesian statistical method that includes both direct and indirect comparisons simultaneously. METHODS: The authors used the results of 30 double-blind, randomized studies including comparisons of 4 atypical neuroleptics and haloperidol, head-to-head or against placebo. We calculated the response ratios for drugs against placebo and thereafter the relative response ratios for one drug against another. With uniform priors, we calculated and ranked the posterior estimates of response ratios for antipsychotic effect, weight gain, and occurrence of extrapyramidal symptoms. RESULTS: All second-generation neuroleptics analyzed are fairly effective with response ratios against placebo ranging between 1.55 (credibility interval, 1.36-1.76) and 1.99 (1.76-2.26), with clozapine being the most effective and aripiprazole the least effective among them. The risk of inducing weight gain is clearly very high for all 5 neuroleptic drugs compared with placebo with response ratios of 12.21 (10.22-15.05) for olanzapine and 11.28 (6.89-17.77) for clozapine. There is a clear increased risk of extrapyramidal adverse effects for haloperidol compared with placebo as the response ratio is 2.33 (2.03-2.49). The other drugs all have considerably less risk of extrapyramidal adverse effects. CONCLUSIONS: The 4 second-generation neuroleptics included in our meta-analysis show only small differences in overall efficacy, with clozapine being the most effective and aripiprazole the least effective among them. When the risk of adverse effects is analyzed, olanzapine and clozapine are afflicted with the highest risk of inducing weight gain and haloperidol with extrapyramidal symptoms. Even aripiprazole and risperidone, however, induce considerable weight gain compared with placebo but may be acceptable alternatives when tailoring drug treatment to the individual patient.

Meta-regression analysis of paroxetine clinical trial data: does reporting scale matter?

OBJECTIVES: It is unknown to which degree the effect of antidepressant drugs are related to baseline degree of depression, dose level, patient's age, or type of questionnaire used. We explored this for paroxetine. METHODS: We used placebo-controlled published and unpublished randomized, double-blind, clinical trials of paroxetine that included moderate to severely depressed patients in an outpatient setting. We specified random-effect models for the Hamilton 17-item and Hamilton 21-item studies separately and jointly. RESULTS: Among 35 studies retrieved, we considered 26 appropriate for a pooled analysis. Paroxetine (placebo) was given to 2958 (2123) patients. We found that the effects of paroxetine, the differences between score reduction in drug versus placebo group, are smaller in Hamilton 17 (3.8%) than in Hamilton 21 studies (7.0%). The mean difference is 3.2% (95% confidence interval, 0.94%-5.42%), statistically significant by meta-regression analysis. Treatment effects did not change with mean age of patients, early or late studies, baseline score value, or maximal daily dose. CONCLUSIONS: We forward 2 hypotheses for explanation. The Hamilton 21 studies had better selection of patients, thereby smaller effect of regression to the mean than the Hamilton 17 studies, meaning the Hamilton 21 studies reveal true somewhat higher treatment effects. Alternatively, the study groups contained some patients with psychotic symptoms tested for with the Hamilton 21-item questionnaire and thereby becoming decisive for the outcome. If so, paroxetine would have an antipsychotic effect. This is in accordance with some experimental and clinical observations.

Does atenolol differ from other beta-adrenergic blockers?

BACKGROUND: A recent meta-analysis of drug effects in patients with hypertension claims that all beta-adrenergic blockers are equally effective but less so than other antihypertensive drugs. Published comparisons of the beta-adrenergic blocker atenolol and non-atenolol beta-adrenergic blockers indicate different effects on death rates, arrhythmias, peripheral vascular resistance and prognosis post myocardial infarction, all in disfavor of atenolol. In keeping with these findings, the data presented in the meta-analysis indicate that atenolol is less effective than the non-atenolol beta-adrenergic blockers both when compared with placebo and with other antihypertensive drugs. These findings were not, however, statistically significant. METHODS: We performed an additional analysis with a Bayesian statistical method in order to make further use of the published data. RESULTS: Our calculations on the clinical data in the meta-analysis showed 13% lower risk (risk ratio 0.87) of myocardial infarction among hypertensive patients taking non-atenolol beta-adrenergic blockers than among hypertensive patients taking atenolol. The 90 % credibility interval ranged from 0.75 to 0.99, thereby indicating statistical significance. The probability of at least 10% lower risk (risk ratio

Even more suicide attempts in clinical trials with paroxetine randomised against placebo.

BACKGROUND: Following our previous publication we have received critical comments to our conclusions as well as new data that are strengthening our findings. RESULTS: With the new data, 11 suicide attempts among patients on paroxetine against 1 among patients on placebo, we found with a Bayesian technique that the posterior probability that medication with paroxetine is associated with an increased intensity per year of a suicide attempt is from 0.98 to 0.99, depending on the prior. We found that the comment to our article by GSK representatives contained errors, misunderstanding and unwillingness to accept Bayesian principles in the analysis of clinical trials. CONCLUSION: We were in our previous publication, with preliminary data and a Bayesian approach, able to raise a concern that suicide attempts might be connected with the use of paroxetine. This suspicion has now been confirmed.

Suicide attempts in clinical trials with paroxetine randomised against placebo.

BACKGROUND: Inclusion of unpublished data on the effects of antidepressants on children has suggested unfavourable risk-benefit profiles for some of the drugs. Recent meta-analyses of studies on adults have indicated similar effects. We obtained unpublished data for paroxetine that have so far not been included in these analyses. METHODS: The documentation for drug registration contained 16 studies in which paroxetine had been randomised against placebo. We registered the number of suicides, suicide attempts and ideation. We corrected for duration of medication and placebo treatment and used a standard Bayesian statistical approach with varying priors. RESULTS: There were 7 suicide attempts in patients on the drug and 1 in a patient on placebo. We found that the probability of increased intensity of suicide attempts per year in adults taking paroxetine was 0.90 with a "pessimistic" prior, and somewhat less with two more neutral priors. CONCLUSION: Our findings support the results of recent meta-analyses. Patients and doctors should be warned that the increased suicidal activity observed in children and adolescents taking certain antidepressant drugs may also be present in adults.

Clinical efficacies of antihypertensive drugs.

OBJECTIVE: According to published data, the ability to prevent various hypertension-related events differs between the various antihypertensive drug groups. Although absolute drug effects differ among studies, relative drug effects could be considered constant. We therefore explored the possibility of drawing statistically valid conclusions about the differences in clinical efficacy between various drug groups by doing an overview of published data. DESIGN: We made a meta-analysis with a Bayesian fixed effect model in which we related the drug effects to the effects of placebo drugs. We selected 27 clinical trials from the literature according to specific criteria, including results from studies reporting the effects of the newer drugs when tested against diuretics and beta-blockers, and from studies in which diuretics and beta-blockers had been tested against placebo. We calculated the posterior probability distributions of the relative effects of angiotensin-converting enzyme (ACE) inhibitors vs calcium antagonists with three different endpoints: stroke, coronary disease and heart failure with point estimates of effects and with 95% credibility intervals. As an intermediate step in this procedure we obtained similar information about the effects of the three groups of active drugs, ACE inhibitors, calcium antagonists and diuretics or beta-blockers, tested against placebo. For coronary disease we also tested calcium antagonists against diuretics or beta-blockers. RESULTS: ACE inhibitors and calcium antagonists have an almost identical ability to prevent stroke in hypertensive individuals with a risk ratio (RR) of 1.04. On the other hand, calcium antagonists reduce coronary disease by only 8% relative to placebo. When ACE inhibitors and calcium antagonists are compared with the Bayesian method, the outcome is a 14% difference in favor of the ACE inhibitors to prevent coronary disease, with a credibility interval almost reaching identity. Nor do calcium antagonists do as well as diuretics or beta-blockers in this respect, RR = 1.12 with 95% credibility interval 1.01-1.24. All the tested drug groups have a profound preventive effect on the occurrence of heart failure when given to hypertensive patients, showing reductions of 42-54%. When ACE inhibitors are compared with calcium antagonists RR = 0.79, with a credibility interval 0.65-0.95. CONCLUSION: There is statistically an indisputable difference between ACE inhibitors and calcium antagonists in respect of effects on coronary disease and heart failure when treating hypertensive individuals, ACE inhibitors being more efficacious. There are no differences in the effect on stroke. Moreover, beta-blockers or diuretics are also superior to calcium antagonists in preventing coronary events.

[Bayesian thinking on its way into medical statistics?]. / Bayesiansk tenkemåte på vei inn i medisinsk statistikk?

BACKGROUND: Bayesian statistical analysis is a paradigm quite different from traditional statistical inference. We wanted to show the usefulness of this approach for some medical problems. MATERIALS AND METHODS: We started with Bayes equation as it is used for estimating the probability of illness based on a specific laboratory test. We also looked into a recent Cochrane report on mammography that accepted two studies as valid and five others as biased. In comparison we used examples of clinical trials from other areas that have been misinterpreted by the use of a traditional statistical approach only. RESULTS: We found that by taking into account our prior beliefs about the likely effects on breast cancer mortality of routine radiological screening programmes, the new data fit well into an estimate of a 5% mortality reduction with a 77% chance that there is a positive effect of screening. INTERPRETATION: Bayesian statistics is helpful in making decisions on the basis of experimental evidence by taking into account our prior knowledge, whereas p-values in traditional statistics only give information on how often we will end up with a false positive conclusion in the long run.