Comparative efficacy and tolerability of anti-epileptic drugs for refractory focal epilepsy: systematic review and network meta-analysis reveals the need for long term comparator trials

Abstract

Aims: To evaluate the comparative efficacy (50% reduction in seizure frequency) and tolerability (premature withdrawal due to adverse events) of anti-epileptic drugs (AEDs) for refractory epilepsy.

Methods: We searched Cochrane Central Register of Controlled Trials (Cochrane Library 2009, issue 2) including Epilepsy Group's specialized register, MEDLINE (1950 to March 2009), EMBASE (1980 to March 2009), and Current Contents Connect (1998 to March 2009) to conduct a systematic review of published studies, developed a treatment network and undertook a network meta-analysis.

Results: Forty-three eligible trials with 6346 patients and 12 interventions, including placebo, contributed to the analysis. Only three direct drug comparator trials were identified, the remaining 40 trials being placebo-controlled. Conventional random-effects meta-analysis indicated all drugs were superior in efficacy to placebo (overall odds ratio (OR] 3.78, 95% CI 3.14, 4.55) but did not permit firm distinction between drugs on the basis of the efficacy or tolerability. A Bayesian network meta-analysis prioritized oxcarbazepine, topiramate and pregabalin on the basis of short term efficacy. However, sodium valproate, levetiracetam, gabapentin and vigabatrin were prioritized on the basis of short-term efficacy and tolerability, with the caveat that vigabatrin is recognized as being associated with serious visual disturbance with chronic use.

Conclusion: Of the wide range of AEDs licensed for the treatment of refractory epilepsy, sodium valproate, levetiracetam and gabapentin demonstrated the best balance of efficacy and tolerability. Until regulators mandate greater use of active comparator trials with longer term follow-up, network meta-analysis provides the only available means to quantify these clinically important parameters.

Keywords: anticonvulsants/therapeutic use; comparative study; epilepsy/drug therapy; meta-analysis; review; treatment outcome.

Figure 1

Study selection for inclusion in network meta-analysis

Figure 2

AEDs included within the network meta-analysis. Each AED represents a node within the star-shaped network. The links between the nodes represent direct comparative data, where the number along the line indicates the number of studies for that particular link within the network. The red (dotted) line represents a loop of direct comparative data, which allows mixed treatment comparison (* includes the 3-arm study)

Figure 3

(A) Forest plot (RevMan v5.0) of the odds ratios for efficacy (50% responder rate) of randomized controlled trials comparing an AED vs. placebo as add-on treatment for refractory epilepsy, respectively. The black squares represent the odds ratio for individual studies of AED vs. placebo and the horizontal line represents the 95% confidence interval of the odds ratio. The black diamond represents the random-effects pooled odds ratio for studies reporting on the same AED where its width represents the 95% confidence intervals. Estimates to the right of the vertical line (i.e. odds ratio >1) are indicative of a statistically significant increase in efficacy, relative to placebo, in patients randomized to the active intervention. (B) Forest plot (RevMan v5.0) of the odds ratios for tolerability (withdrawal from treatment due to an intolerable adverse event) of randomized controlled trials comparing an AED vs. placebo as add-on treatment for refractory epilepsy, respectively. The black squares represent the odds ratio for individual studies of AED vs. placebo and the horizontal line represents the 95% confidence interval of the odds ratio. The black diamond represents the random-effects pooled odds ratio for studies reporting on the same AED where its width represents the 95% confidence intervals. Estimates to the right of the vertical line (i.e. odds ratio >1) are indicative of a statistically significant increase in withdrawal rate, relative to placebo, in patients randomized to the active intervention. (C) Summary Forest plot (RevMan v5.0) of the odds ratio for efficacy (50% responder rate) of randomized controlled trials comparing an AED vs. placebo as add-on treatment for refractory epilepsy. (D) Summary Forest plot (RevMan v5.0) of the odds ratio for tolerability (withdrawal from treatment due to an intolerable adverse event) of randomized controlled trials comparing an AED vs. placebo as add-on treatment for refractory epilepsy

Figure 4

(A) Box plots (WinBUGS) of the risk ratios of AEDs vs. placebo as estimated by the network meta-analysis regarding efficacy (50% responder rate). The individual plots represent the 95% credible interval (horizontal black line either side of the green box) and the interquartile range (green box, representing where 25% to 75% of the data lies); the vertical black line reflects the median risk ratio (RR). A larger RR is indicative of a greater proportion of patients achieving a 50% reduction in seizure frequency, relative to placebo. Where the 95% credible interval crosses the line of unity, this is indicative of a non-statistically significant difference to placebo. AEDs are listed in descending rank order. (B) Box plots (WinBUGS) of the risk ratios of AEDs vs. placebo as estimated by the network meta-analysis regarding tolerability (premature discontinuation). The individual plots represent the 95% credible interval (horizontal black line either side of the green box) and the interquartile range (green box, representing where 25% to 75% of the data lies); the vertical black line reflects the median risk ratio (RR). A larger RR is indicative of a greater proportion of patients withdrawing from treatment prematurely, relative to placebo. Where the 95% credible interval crosses the line of unity, this is indicative of a non-statistically significant difference to placebo. AEDs are listed in descending rank order

Figure 5

A comparison of the number needed to treat vs. number needed to harm (with 95% credible intervals) for efficacy (50% responder rate) and tolerability (withdrawal rate), respectively. Drugs in the lower right of the plot (i.e. low NNT and high NNH) are highly efficacious and well tolerated; conversely, drugs in the upper left of the plot (i.e. high NNT and low NNH) are less effective and poorly tolerated. Note that equal weighting of the efficacy and tolerability endpoints has been applied (i.e. the same emphasis is placed on achieving a 50% reduction in seizure rate in one patient as for incurring a premature withdrawal due to an intolerable adverse event in another). , gabapentin (GBP); , lacosamide (LCS); , lamotrigine (LMG); , levetiracetam (LEV); , oxcarbazepine (OXC); , pregabalin (PGB); , sodium valproate (VPA); , tiagabine (TGB); , topiramate (TPM); , vigabatrin (VGB); , zonisamide (ZNS)