This presentation reviews the evidence regarding use of early polytherapy in patients with epilepsy with regards to seizure control and adverse effects. The advantages and disadvantages of polytherapy compared to monotherapy is addressed.
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Treatment of epilepsy polytherapy vs monotherapy
1. Treatment of Epilepsy:
Sequential Monotherapy Vs
Early Rational Polytherapy
Dr Pramod Krishnan
Consultant Neurologist and Epileptologist
HOD Neurology,
Manipal Hospital, Bengaluru
2. Caveats
• This discussion is mainly relevant to focal and unclassified epilepsy and
not to genetic generalized epilepsy and specific epilepsy syndromes.
• This topic is not focused on drug resistant epilepsy.
• There are no suitable trials of monotherapy vs polytherapy for
comparison as synergistic ASD combinations, correct daily dose,
selection of appropriate ASDs for specific epilepsy types are not
factored into the study.
3. Introduction
• 50% of epilepsy patients become seizure free with the first ASD.
• Monotherapy is the recommended first treatment strategy.
• In the remaining patients, higher dose monotherapy with the same
ASD, substitution monotherapy or add-on therapy (polytherapy) can be
considered.
• Treating epilepsy is an exciting challenge in view of the large number
of ASDs available, their varied mechanisms of action,
pharmacokinetics and adverse effect profile.
• Newer ASDs have given new life to polytherapy in epilepsy.
4.
5. Conventional AEDs
Newer AEDs
Monotherapy
Polytherapy
Comparative RCTs
Drops outs due to drug
interactions, adverse effects
CBZ, PHT, VPA
ESM (only in absences)
Polytherapy in DREs
Rational polytherapy
RCTs of monotherapy
(TIG failed)
Serious adverse effects
(FBM, VGB)
RCTs of add-on trials in DRE
LTG, TPM, OXC,
LEV, GBP, ZSN,
LCM
Specific indications
VGB in West syn
STR/TPM in SMEI
PER in PME
LTG/TPM/RFM in LGS
6. GABAergic:
Prolongs Cl- channel opening: Phenobarbitone
Opens Cl- channel more often: Clobazam
Inhibits GABA transaminase: Vigabatrin
Blocks synaptic GABA reuptake: Tiagabine
Ca channel blockers:
High voltage activated channel:
Gabapentin, Pregabalin
Low voltage activated channel:
Ethosuximide
Zonisamide:
Blocks Na channels.
Blocks T type Ca channel.
Potentiates GABA
Fast inactivation of VGSC:
PHT, OXC, CBZ.
Slow inactivation of VGSC:
LCS, Eslicarbazepine.
Others: LTG, VPA, TPM,
FBM, ZSN, Rufinamide.
7. Patient oriented
choice of ASD
Disease oriented
choice of ASD
Patient factors
Drug
Epilepsy
Physiological variables: age,
gender, weight
Comorbidities
Concomitant drugs
Psychosocial variables
Seizure type: focal, generalised
Epilepsy Syndrome: LGS, JME
EEG and other clinical
features.
Pharmacokinetics
Pharmacodynamics
EBM: RCTs, meta-analysis,
guidelines.
Expert opinion
Pharmacogenomics.
Clinical experience
8. Monotherapy
• Simpler regimen, therefore better
compliance.
• Less adverse effects.
• Less expensive.
• Less drug interactions.
• Efficacy of each drug can be
assessed better.
Polytherapy
• Better efficacy
• Cost of therapy may be less than
the cost of seizure recurrence.
• Newer ASDs are better tolerated
and are ideal for polytherapy.
They have less drug interactions,
more diverse mechanism of
action, favourable
pharmacokinetics .
Conventional ASDs are not favorable for polytherapy:
• Overlapping mechanism of action, therefore less benefit and more adverse
effects.
• Enzyme induction/ inhibition, therefore more drug interactions.
• Narrow therapeutic window.
9. Problems with higher dose monotherapy
• Incremental benefit in seizure control diminishes with increasing dose.
• Using an ASD at maximum tolerable dose (MTD) is not more effective
than moderate doses (MD).
• Most of the adverse effects are dose dependent, therefore higher dose
results in greater occurrence of adverse effects.
• Paradoxical seizure worsening can occur, especially with PHT.
• Single or limited mechanism of action limits the efficacy.
10. Alternate monotherapy
• 10-12% of patients achieve seizure freedom after a trial of second ASD
monotherapy.
• A different mechanism of action than the first ASD may help.
• The speed and duration of drug withdrawal, dose escalation of the
newly introducing drug, and risk assessment or measures to avoid
seizure worsening related to drug switch are not clearly defined but
largely depend on skills and experiences of caring physicians.
12. When Drug A is largely ineffective, rapid substitution can be done.
When Drug A is partially effective, Drug B can be added to Drug A.
ITD= initial target dose
MD= moderate dose
MTD= maximally tolerable dose
13. Rational polytherapy
• When initial monotherapy fails, early polytherapy can be considered.
• Rational Polytherapy is a hypothesis not evidence-based but driven by
theoretical considerations from preclinical experiments and clinical
observations.
• It is focused at producing desirable pharmacodynamic drug interactions of
ASDs by combining drugs having different MOAs but avoiding drugs having
adverse pharmacological (pharmacokinetic and/or pharmacodynamic)
interactions, similar side effects profiles, and narrow therapeutic index.
14. Rational polytherapy in epilepsy
Process of selecting ASD drug in rational polytherapy
ASD 1 ASD 2
Select drug based on epilepsy type. Drugs matching the partner drug.
Drug with no previous exposure. Titrate dose upwards slowly.
Drug proven effective, at least partially, in
previous exposure.
Drugs known to have synergistic
interactions in combination.
Non-enzyme-inducing ASD or ASD showing
no or low risk of pharmacokinetic
interactions.
Drugs with a high therapeutic index or
good tolerability profile.
Drug effective for the patient’s comorbidities
or at least not deleterious to the comorbidities.
Reduce dose of 1st drug once 2nd drug
reaches target dose.
15. • 347 patients with epilepsy not controlled with VPA, CBZ, PHT or PB monotherapy.
• LTG was added and in responders, LTG monotherapy was attempted.
• Overall, 73% patients completed the add-on phase (47% responders), 41% attempted AED withdrawal
and 23% achieved LTG monotherapy.
• The addition of LTG to VPA (64% responders) produced a significantly better response (P<0.001) than
adding it to CBZ (41% responders) or PHT (38% responders).
• This effect was significant in partial as well as tonic-clonic seizures.
16.
17.
18. Desirable and Undesirable ASD combinations (some examples)
Combination Desirability Rationale
PHT/CBZ +LTG - EIAEDs decrease LTG, more pharmacodynamic neurotoxic adverse effects.
PHT/CBZ +OXC - EIAEDs decrease OXC, OXC inhibits CYP 2C19 and may increase PHT
levels; increased neurotoxic adverse effects.
PHT/CBZ +TPM - EIAEDs decrease TPM, TPM inhibits CYP 2C19 and may increase PHT
levels; increased neurotoxic adverse effects.
PHT/CBZ +LEV + Possible synergism.
LTG/OXC +
(GBP/PGB/LEV)
++ Possible synergism.
LTG/OXC +TPM + Possible synergism.
LTG/OXC +ZSN +/- Possible additive effects as they have similar mechanism.
VPA +PHT - Increased free PHT fraction and PHT side effects. May be synergistic.
VPA +CBZ - VPA increases CBZ epoxide and CBZ side effects. Both block Na channels.
VPA +LTG ++ Synergistic. Dose adjustment required. Risk of LTG rash.
VPA +TPM + Synergistic. Risk of neurotoxic side effects. TPM may offset weight gain due
to VPA.
VPA +LEV ++ Synergistic.
VPA +ZSN + Synergistic.
21. • Retrospective study of patients with newly diagnosed epilepsy.
• Those who failed to respond to the first AED at doses > 50% DDD.
• 3 cohorts: increased dosage of monotherapy, combination therapy, and
alternative monotherapy.
22. Results
• 502 patients (277 male, 55.2%) were
included, with median duration of
follow‐up of 32 months (range =
8‐127).
• The probability of seizure freedom
was significantly higher in patients
receiving combination therapy (n =
323) compared to the alternative
therapy cohort (n = 76, P < 0.001)
and increased dosage cohort (n =
103, P = 0.025).
23. Is compliance better with monotherapy
• Drug non-adherence rate in epilepsy is 25-66%.
• Patient related factors are probably most important because side-effects
and long-term effects of ASDs are major concerns of patients.
• Among medication-related factors, dosing frequency was the single
most important factor affecting the medication adherence.
• Adherence was better with newer ASDs.
• Conflicting data regarding monotherapy Vs polytherapy.
• Prevalence of moderate to high drug-adherence was 58% in
monotherapy and 62% in polytherapy.
24. Is polytherapy associated with more adverse
drug interactions?
• Adverse drug interactions are usually due to enzyme inducing ASDs.
• Most newer ASDs are neither broad-spectrum enzyme inducers nor
substrates of hepatic metabolism, thus the potential of adverse
pharmacokinetic drug interactions is significantly reduced.
• Pharmacodynamic interactions may be additive, supra-additive, and
infra-additive interactions in either therapeutic or adverse effects.
• The rationale of polytherapy is to combine drugs carrying synergistic
interactions (supra-additive efficacy or infra-additive toxicity) to
improve therapeutic index of the regimen.
25. Is polytherapy associated with more adverse
effects?
• No difference in side effects between patients on monotherapy and
polytherapy.
• In one study whereas TDL was ≤2 in a majority of patients under
monotherapy but usually ≥2, often ≥4, in patients under polytherapy without
reporting any excess side effects.
Canevini, M.P., et al. 2010. Epilepsia 51, 797–804
• Adverse effects are determined more by individual susceptibility, type of
ASDs used, and physicians’ skills than number of ASDs and TDL.
• Previous assumption of monotherapy being associated with less side effects
than polytherapy is probably not tenable any more in the era of new ASDs.
26. • Of 809 patients enrolled, 709 had localization related epilepsy and 627 were on
polytherapy.
• ASD loads increased with increasing number of ASDs in the treatment regimen.
• ASD loads were calculated as the sum of prescribed daily dose (PDD)/defined daily
dose (DDD) ratios for each co-prescribed ASD.
27. • The number of spontaneously reported
AEs correlated with the number of AEs
identified by the Adverse effect profile
(AEP) questionnaire.
• AEP scores did not differ between
patients with monotherapy and patients
with polytherapy, and there was no
correlation between AEP scores and ASD
load.
• Conclusions: AEs did not differ between
monotherapy and polytherapy patients,
and did not correlate with ASD load,
possibly as a result of physicians’
intervention in individualizing treatment.
28. Are monotherapy and polytherapy similar in
efficacy?
• Numerous studies have shown seizure free rates and adverse effect rates
to be similar in the two groups, with a trend favoring duotherapy/
polytherapy.
Kwan, P., Brodie, M.J., 2000b. Seizure 9, 464–468.
Deckers, et al. 2003. Epilepsy Res. 53, 1–17.
Beghi, et al. 2003. Epilepsy Res. 57, 1–13.
• Several studies have shown a clear benefit with polytherapy with respect
to seizure free rates and adverse events.
Lee, B.I., et al. 2018. Seizure 55, 17–24.
Kwan, P., Brodie, M.J., 2000a. N. Engl. J. Med. 342, 314–319.
30. Conventional practice
• This was advocated during the era of first line ASDs.
• Start polytherapy after failure of two sequential monotherapy trials at
maximum tolerated dose.
• This fulfils criteria for drug resistant epilepsy.
33. • Prospective study of 248 patients in whom treatment with the first ASD was
unsuccessful.
• They were offered either ASD substitution or combination (add-on).
• Patients were considered to be seizure-free if they had no seizures for at least 1 year.
34. Results
• Patients who received substituted monotherapy (n=35) and those who
received add-on treatment (n=42) had similar seizure-free rates (17%
vs. 26%) and incidence of intolerable side effects (26% vs. 12%).
• More patients became seizure-free with a combination of a sodium
channel blocker and an ASD with multiple MOA (36%) compared to
other combinations (7%; P= 0:05).
• None of the 11 patients who received add-on treatment after a second
drug had also failed became seizure-free, compared to 26% in those
who received add-on as soon as the first tolerated AED proved to be
ineffective (n=42, p= 0:05).
35. • Multicentre, parallel-group, open-label study.
• Patients with cryptogenic or symptomatic partial epilepsy not controlled after
single or sequential ASD monotherapies were randomised to monotherapy
with an alternative ASD or to adjunctive therapy with a second ASD.
• Patients were followed up until withdrawal from the allocated treatment or
for 12 months, whichever first.
36. Results
• Of a total of 157 patients (including 94 previously exposed to only one
ASD), 76 were randomised to alternative monotherapy and 81 to
adjunctive therapy.
• The 12-month cumulative probability of remaining on the assigned
treatment was 55% in patients randomised to alternative monotherapy
and 65% in those randomized to adjunctive therapy (P = 0.74).
• The 12-month probability of remaining seizure-free was 14 and 16%,
respectively (P = 0.74).
• Adverse effects were similar in the two groups.
• No significant differences in outcome were identified.
37. • People with Epilepsy aged ≥ 2 years of age and having failed initial monotherapy due
to seizure recurrence or ASD withdrawal due to adverse effects.
• 331 patients (157 males, 174 females), 124 children and 207 adults.
38.
39. Summary
Alternate Monotherapy vs Add-on Therapy
VPA was the most commonly used ASD, followed by CBZ, PB and OXC.
239 for alternate monotherapy and 92 for add on therapy.
Patients receiving add-on treatment had longer disease, more than one seizure type, focal
epilepsy, and lack of comorbidity.
TPM was the most common medicine chosen in the two groups.
Cumulative time-dependent probability of remaining in the study was similar.
Treatment failure was similar in both groups (27.5% vs 25%).
Mean retention time was similar (454.4 days vs 447.4 days).
12 month seizure remission was similar in both groups (53.6% vs 51.1%)
Incidence of adverse effects were similar in the two groups.
Frequency of hospitalisations and OPD consultations were similar.
QOLIE 31 scores were similar in the two groups.
41. • 130 adult patients with untreated generalized tonic–clonic and/or partial seizures
were randomized to equal drug loads of either CBZ monotherapy (400 mg/d) or
polytherapy (CBZ 200 mg/d + VPA 300 mg/d).
• Outcome was measured by seizure counts, clinimetric epilepsy scales, and
neuropsychological tests at baseline, at 2 and 12 months, and irregularly between
2 and 12 months.
42. Summary
• No statistical differences were found between the two treatments in the
reduction of seizure frequencies, in overall neurotoxicity, or in overall
systemic toxicity.
• The frequencies and clinimetric scores of certain adverse effects did
differ (e.g., more monotherapy patients remained sedated, and more
polytherapy patients gained weight).
• Fewer polytherapy patients withdrew because of adverse effects (14 vs.
22%), although not statistically significant.
• Neuropsychological assessment did not show significant differences.
43. • Unblinded, randomized, 60-week superiority trial in patients with partial or
generalized epilepsy.
• Patients having ≥2 unprovoked seizures with at least one seizure during previous
three months.
• After randomization into CBZ-CR or LTG + VPA, patients entered into 8-week
titration phase (TP), followed by 52-week maintenance phase (MP).
44. Results
• Median doses: CBZ-CR was 600 mg/d, and LTG + VPA was 75 mg/
day + 500 mg/day.
• Among 207 randomized patients, 202 underwent outcome analysis (104
in CBZ-CR, 98 in LTG + VPA).
• Completion rate: 62.5% in CBZ-CR, 65.3% in LTG + VPA (p = 0.678).
• Seizure free rate: LTG + VPA (64.1%) and CBZ-CR (47.8%) (P = 0.034).
• Time to first seizure was shorter with CBZ-CR (p = 0.041).
• Incidence of adverse effects: 57.7% in CBZ-CR, 60.2% in LTG + VPA.
45. Conclusions
• Early polytherapy is an important option especially with newer ASDs.
• Seizure free rates are usually higher in the polytherapy group.
• Adverse effects are slightly less in the polytherapy group.
• Cost, compliance and reduced drug interaction are touted as advantages of
monotherapy, but not necessarily so.
• Polytherapy may be avoided in patients with multiple comorbidities and
comedications.
• Polytherapy may be preferred when efficacy is more important, in view of
synergistic effect of AED combinations.
• Treatment decisions should be individualised for optimal results.
