Patient safety meta-analysis

The best overall evidence of the safety of diuretics in old people comes from the large-scale outcome trials in hypertensive patients (11,13,15,17,18). These studies in over 10000 subjects aged over 60 years showed clearly that thiazide-based treatment reduces the risk of stroke, coronary heart disease events, and cardiovascular events in older hypertensive patients. A meta-analysis (163) of randomized trials lasting at least 1 year and involving 16164 individuals aged at least 60 years showed that diuretics were superior to beta-blockers with regard to all endpoints (stroke, coronary heart disease events, cardiovascular mortality, and all-cause mortality). The beneficial effects noted in these trials should dispel any doubts about the safety and efficacy of diuretics in old people. 

A Cochrane meta-analysis studied the efficacy and safety of mucolytic agents in COPD patients. The meta-analysis included 30 trials and 7436 patients [93 ]. Mucolytics appeared to have a safe profile, without any effect on mortality (OR = 0.75, 95% Cl = 0.35,1.64) or the frequency of adverse effects. 

Liang J, Jiang MJ, Deng X, Xiao Zhou X. Efficacy and safety of telbivudine compared to Entecavir among HBeAg+ chronic hepatitis B patients a meta-analysis study. Hepat Mon 2013 13(6) e7862. 

One meta-analysis examined the safety and efficacy of LMWH and heparinoids in 11 randomized trials of 3048 patients with acute ischemic stroke. It reported a reduction in the incidence of deep venous thrombosis (DVT) (odds ratio (OR) 0.27,... 

Individually, the cholinesterase inhibitors improve memory in patients with AD. There have been no head-to-head comparisons made of the drugs to determine w hether one is more effective than the others and no trials of agents in combination. The main know n differences are the side effect profiles, titration schedules and the dosing regimens (Table 39.1). The most common side effects of treatment with cholinesterase inhibitors are gastrointestinal and include nausea, vomiting and diarrhea. A meta-analysis of the efficacy and safety of these agents revealed that despite many clinical studies show ing... 

There has been a meta-analysis of 15 trials from Africa, Europe, and Asia of the use of varying doses of artesunate plus lumefantrine compared with several alternative antimalarial drugs in 1869 patients conducted by the manufacturers Novartis into its clinical safety and tolerability in the treatment of uncomplicated malaria (13). The most common adverse events were gastrointestinal—nausea (6.3%), abdominal pain (12%), vomiting (2.4%), anorexia (13%)—or central nervous—headache (21%) or dizziness (16%). There were 20 serious adverse events with artesunate plus lumefantrine, but only one (hemolytic anemia) was possibly due to artesunate plus lumefantrine. There was no QT prolongation associated with artesunate plus lumefantrine. 

Wehling M. Meta-analysis of flecainide safety in patients with supraventricular arrhythmias. Arzneimittelforschung 2002 52(7) 507-14. 

Leflunomide has anti-inflammatory, immunosuppressive, and virustatic effects. Its efficacy has been demonstrated in patients with rheumatoid arthritis and psoriatic arthritis and other conditions in randomized, double-blind, placebo-controlled trials and other studies (8-32), and it was approved for treatment of adult rheumatoid arthritis in August 1998 (Table 1) (33). In three large phase III trials (US301, n = 482 MN301, n = 358 MN302, n = 999), leflunomide was as effective and well tolerated as methotrexate and sulfasalazine and superior to placebo (34). These data were confirmed by a meta-analysis (35,36). Leflunomide is therefore indicated for patients with rheumatoid arthritis who have failed first-line disease modifying anti-rheumatic drug therapy on the basis of efficacy, safety, and costs (36). It is effective as monotherapy and in combination with methotrexate or infliximab (6). 

Wahlgren CF, Lillieborg S. SpUt-skin grafting with hdo-caine-prilocaine cream a meta-analysis of efficacy and safety in geriatric versus nongeriatric patients. Plast Reconstr Surg 2001 107(3) 750-6. 

The safety of combined ACE-1 and ARB therapy is an important issue that was evaluated in recent meta-analysis in patients with chronic proteinuric... 

When designing a meta-analysis, the inclusion criteria of trials and patients should be carefully considered. Trials should provide information that is relevant to the safety outcome. For example, if the safety issue is a long-latency outcome such as a malignancy, short-term trials may not be relevant and including them may even produce misleading results. Casting a wide net... 

When designing a meta-analysis, there may exists large trials in terms of fhe number of patients or follow-up time with good safety outcome ascertainment. If these trials are include in the meta-analysis, they may dominate the overall meta-analysis results. It may be worthwhile to design the meta-analysis so as not to include these trials. The resulting meta-analysis would summarize the information from the smaller trials, and the larger trials can be evaluated as additional, independent sources of information. The rosiglitazone meta-analysis example is this chapter takes this approach. 

Shorf of prospectively collecting fhe safety outcome, the outcome can be retrospectively obtained and adjudicated with a well-defined procedure. This approach was faken in fhe antidepressant meta-analysis example in this chapter. This approach requires detailed extensive patient-level data. It is also helpful to have fhe individual sfudy protocol to understand the information collected in fhe frials. Wifh fhis version of a retrospective outcome ascertainment, attention should be given to potential differential outcome ascertainment between the treatment arms. If the outcome was not actively solicited, there may be differences in reporting between the arms because of unrelated side effecfs of fhe freafmenf. For example, if a drug has more side effecfs, fhe patienf may be more likely to have encounters with the study investigators and report the safety outcome. 

Meta-analysis has been increasingly used to address drug safety issues [16,17]. In particular, meta-analysis using individual patient data (IPD) has been advocated because of its many advantages [2,18]. 

Askling J, Fahrbach K, Nordstrom B, Ross S, Schmid CH, and Symmons D. 2011. Cancer risk with tumor necrosis factor alpha (TNF) inhibitors meta-analysis of randomized controlled trials of adalimumab, etanercept, and infliximab using patient level data. Pharmacoepidemiology and Drug Safety 20 119-130. 

The discovery and development efforts that led to successful approval of boceprevir and telaprevir have produced tangible benefits to HCV patients worldwide. Meta-analyses designed to compare the efficacy and safety of boceprevir and telaprevir have been reported. Cooper and coworkers concluded that boceprevir and telaprevir appear comparable in terms of SVR, relapse, or discontinuation of therapy for patients treated under standard or response-guided therapy durations. In a separate analysis, Sitole and co-workers concluded that the triple therapies utilizing either boceprevir or telaprevir for HCV genotype 1 infection resulted in more patients reaching SVR but also in more drug-related adverse events. Additionally, this study noted that short-term treatment response... 

Observational studies The risks of testosterone therapy in men are poorly understood. In an extensive meta-analysis of data from 51 selected studies testosterone treatment was found to be associated with significant increases in hemoglobin (mean 0.80 g/dl) and hematocrit (mean 3.2%) and a reduction in high-density lipoprotein cholesterol (mean —0.01 mmol/1) [42 ]. There were no significant effects on mortality or prostate or cardiovascular outcomes. The authors stressed that these findings are of unknown clinical significance. Current evidence about the safety of testosterone treatment in men in terms of patient-important outcomes is of low quality and is hampered by the fact that follow-up is generally brief. 

Wang et al. evaluated 11 clinical smdies conducted in China on efficacy and safety of hupA in the treatment of AD, and four placebo-controlled, randomized trials (Table 39.2) using MMSE and ADL as outcome measures were included in their meta-analysis. A total of 474 AD patients were included, 235 received 0.3-0.5 mg of hupA p.o. daily for 8-24 weeks, and 239 in the control group. The results presented a significant improvement in both MMSE and ADL and a metaregression showed that the estimated effect size of MMSE and ADL was increased over the treatment time. Adverse events were mild-to-moderate peripheral... 

The efficacy and safety of a fentanyl ionto-phoretic transdermal system have been explored in a meta-analysis of six trials [72 ]. In comparisons of the fentanyl transdermal system and morphine in patient-controlled analgesia, fewer of those who received fentanyl withdrew because of adverse effects, fewer had nausea and pruritus, and none had respiratory depression however, more had headaches. 

Concerns have been raised about the longterm safety of LAB As the overall and respiratory adverse effects were reviewed in SEDA-30 (p. 198) and SEDA-31 (p. 309). Meta-analysis, using data from 33 826 patients with asthma, has shown that LABAs are associated with an increased risk of exacerbations requiring hospitalization (OR = 2.6 95% Cl — 1.6, 4.3), life-threatening exacerbations (OR = 1.8 95% Cl = 1.1, 3.9), and death from asthma (OR — 3.5 95% Cl... 

Upper Respiratory Tract A Cochrane meta-analysis studied the effect of intranasal ipratropium versus placebo on the severity of rhinorrhea and nasal congestion in children and adults with the common cold [45 ]. Seven trials, studying 2144 patients were included in the study. Safety assessment showed an association of ipratropium with nasal dryness (OR = 2.55, 95% Cl = 1.50, 4.33), mouth dryness (OR = 3.59, 95% Cl = 1.38, 9.38) and epistaxis (OR = 3.21,95% Cl - 1.68,6.13). 

A meta-analysis of 11 randomised clinical trials also studied the efficacy and safety of roflumilast versus placebo. This meta-analysis included a total population of 9675 patients, with the study duration ranging from 12 to 52 weeks [9qM] meta-analysis did not find any effect of roflumilast on mortality. However, there were more withdrawals due to adverse effects in roflumilast arm (RR = 1.62,95% Cl = 1.44,1.82). Marginally more patients experienced an adverse effect compared to control (RR = 1.08,95% Cl = 1.02,1.14). 

Yan JH, Gu WJ, Pan L. Efficacy and safety of roflumilast in patients with stable chronic obstructive pulmonary disease a meta-analysis. 

Wang P, Zhou S, Zhou R, Liu G, Tang P, He J, et al. The effectiveness and safety of triple-antiplatelet treatment based on cilostazol for patients receiving percutaneous coronary intervention a meta-analysis. Clin Cardiol October 2012 35(10) 598-604. 

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