Ticagrelor-induced renal failure leading to statin-induced rhabdomyolysis.

Renal function deterioration is a rather frequent side effect of ticagrelor; this is especially so in patients over the age of 75, with pre-existent mild renal failure and/or taking an angiotensin receptor inhibitor. We describe a patient in whom deterioration of renal function due to ticagrelor led to a rise in serum concentration of rosuvastatin which resulted in rhabdomyolysis. The presented case emphasises the importance to check renal function routinely before and one month after starting ticagrelor and to screen carefully for possible interactions with other drugs.

Lamotrigine in clinical practice: long-term experience in patients with refractory epilepsy referred to a tertiary epilepsy center.

Lamotrigine (LTG, Lamictal), one of the newer antiepileptic drugs, was admitted to the Dutch market in 1996. It was first used as adjunctive therapy and later as a monotherapy in partial and generalized epilepsy. All patients who started on LTG in 1996 or 1997 in the Epilepsy Centre Kempenhaeghe (n=314) were enrolled in this study and followed for 48 months. The data indicate that the retention rates for LTG after 1, 2, 3, and 4 years are respectively 74.4, 69.3, 63.1, and 55.6%. Patients with normal cognitive function were more likely to continue than patients with mental retardation. The main reason for discontinuing LTG therapy was lack of efficacy (19.1%). Four patients (1.4%) were seizure-free for the total follow-up period of 48 months. The most frequently reported negative side effects were dizziness and headache, both in patients who continued and in those who discontinued therapy. A large percentage of patients also reported positive side effects like "feeling/being more active" and "feeling more clear/more responsive." For the whole patient group, the plasma level of LTG was measured 277 times. Plasma levels of LTG were influenced by the patients' comedications. Plasma levels of LTG in groups taking LTG in monotherapy, LTG plus an inducer, and LTG plus valproate were 8.7, 4.8, and 8.7 mg/L, respectively. The correlation between measured plasma level and dose confirm the manufacturer's dose recommendations. The manufacturer recommends half the dosage of lamotrigine monotherapy when the patient also uses valproate. When the patient uses an inducer, the dosage of LTG must be two times the dose used in monotherapy.

Long-term effects of levetiracetam and topiramate in clinical practice: A head-to-head comparison.

OBJECTIVE: Two of the most commonly prescribed new antiepileptic drugs as add-on therapy for patients with chronic refractory epilepsies are topiramate and levetiracetam. In regulatory trials, both drugs were characterized as very promising new antiepileptic drugs. However, results from these highly controlled short-term clinical trials cannot simply be extrapolated to everyday clinical practice, also because head-to-head comparisons are lacking. Therefore, results from long-term open label observational studies that compare two or more new AEDs are crucial to determine the long-term performance of competing new antiepileptic drugs in clinical practice. METHOD: We analyzed all patients referred to a tertiary epilepsy centre who had been treated with topiramate from the introduction of the drug in spring 1993 up to a final assessment point mid-2002 and all patients who had been treated with LEV in the same centre from the introduction of the drug in early 2001 up to a final assessment point end-2003 using a medical information system. RESULTS: Three hundred and one patients were included for levetiracetam and 429 patients for TPM. Retention rate after 1 year was 65.6% for LEV-treated patients and 51.7% for TPM-treated patients (p=0.0015). Similarly, retention rates for LEV were higher at the 24-month mark: 45.8% of LEV-treated patients and 38.3% of TPM-treated patients were still continuing treatment (p=0.0046). Adverse events led to drug discontinuation in 21.9% of TPM-treated patients compared to 6.0% of LEV-treated patients (p<0.001). The number of patients discontinuing treatment because of lack of efficacy was similar for both groups. Seizure freedom rates varied between 11.6 and 20.0% for TPM and between 11.1 and 14.3% for LEV per 6-months interval. Several important AED specific adverse events leading to drug discontinuation were identified, including neurocognitive side effects from TPM and mood disorders from LEV. CONCLUSION: The retention rate for LEV is significantly higher than for TPM. LEV had a more favourable side effect profile than TPM with comparable efficacy. Patients on TPM discontinued treatment mainly because of neurocognitive side effects. In the treatment with LEV, the effects on mood must not be underestimated.

Levetiracetam in clinical practice: long-term experience in patients with refractory epilepsy referred to a tertiary epilepsy center.

OBJECTIVE: For the treatment of patients with chronic refractory epilepsies, development of new antiepileptic drugs is crucial. Three regulatory trials have demonstrated that add-on levetiracetam is efficacious in patients with localization-related epilepsy. However, results from these highly controlled short-term clinical trials cannot simply be extrapolated to everyday clinical practice. Therefore, more information is needed about the long-term profile of a new antiepileptic drug in clinical practice. METHOD: We analyzed all patients who had been treated with levetiracetam in the Epilepsy Centre Kempenhaeghe from the introduction of the drug in early 2001 up to a final assessment point, at the end of 2003, using a medical information system. RESULTS: In total, 301 patients were included. One hundred thirty-eight patients (45.8%) discontinued LEV treatment during the 24-month follow-up period. Reasons for discontinuation were lack of efficacy in 15.9% of patients, adverse events in 6.0% of patients, and a combination of lack of efficacy and adverse events in 16.3% of patients. By Kaplan-Meier survival analysis, the continuation rate was 65.6% after 1 year and 45.8% after 2 years. About 15% of patients in this highly refractory group had a 3-month remission, whereas 10% of patients became seizure-free for longer periods. The most frequently reported side effects at the time of discontinuation were mood disorders, tiredness, and sleepiness. Variables predicting (dis)continuation of levetiracetam treatment could not be identified. CONCLUSION: Levetiracetam is a new antiepileptic drug that appears to be a useful add-on treatment in patients with refractory epilepsy. Its side effect profile is mild, with mood disorders being the most dominant adverse event.

Topiramate in clinical practice: long-term experience in patients with refractory epilepsy referred to a tertiary epilepsy center.

For the treatment of patients with chronic refractory epilepsies, information about the long-term efficacy and safety profile of any new antiepileptic drug is crucial. Topiramate has been proven to be effective in patients with refractory chronic partial epilepsies in short-term controlled clinical trials, but the long-term retention, long-term efficacy, and long-term side-effect profile have not been sufficiently investigated. We analyzed all patients who had been treated with topiramate in the Epilepsy Centre Kempenhaeghe from the introduction of the drug in the spring of 1993 up to a final assessment point in mid-2002. In total, 470 patients were identified. The data show that the clinical dose achieved was about 200mg/day, reached after approximately 6 months of treatment. Further dose escalation in the survivors was slow, with a mean dose of about 300 mg/day after 24 months of treatment. Mean titration dose is 25mg/week, but titration strategy is mostly individual and responds to patient complaints. With respect to seizure frequency, 10-15% of the patients were seizure-free at the 6-month evaluation; 4 patients achieved a 2-year remission. Retention rate was 53% after 1 year, 45% after 2 years, 38% after 3 years, and 30% after 4 years. At 4 years, almost 70% of the patients had discontinued topiramate. The main reason was adverse events, which accounted for about 65% of the discontinuations. Behavioral side effects were dominant, with mental slowing (27.6%), dysphasia (16.0%), and mood problems (agitation: 11.9%) being the most frequently reported side effects. In about 10% of the patients side effects led to discontinuation despite the obvious favorable effects on seizure frequency. Comparisons between the patients who discontinued topiramate treatment and those who continued topiramate showed that discontinuation was associated with comedication (vigabatrin and lamotrigine). Our conclusion is that TPM is associated with a high incidence of side effects in clinical practice, affecting long-term retention. Meaningful prognostic factors that may help us in clinical decision making, i.e., to prevent the side effects or to help us identify those at risk, have not been found.

Randomized double-blind parallel-group study comparing cognitive effects of a low-dose lamotrigine with valproate and placebo in healthy volunteers.

PURPOSE: This study aimed at investigating the cognitive and mood effects of lamotrigine (LTG) versus valproate (VPA) and placebo (PBO). METHODS: By studying the effects in healthy volunteers, it is possible to separate the genuine effects of LTG from the cognitive improvements, caused by better seizure control. The study used a pretest-posttest comparison of 50 mg LTG, 900 mg VPA, or PBO in a double-blind single-dummy parallel-group design with 30 healthy volunteers. Study duration was 12 days (with a last control on day 13). Outcome measures included cognitive tests (FePsy neuropsychological test battery), mood scales (ASL; mood-rating scale), and a scale for subjective complaints (ABNAS Neurotoxicity scale). Total sleep time was controlled with actigraphic recordings. The results were analyzed by comparing the change over time (pretest with posttest) for the three treatments with Student's t tests. RESULTS: COGNITIVE TESTS: significant differences between the treatments were found for measurements of cognitive activation (i.e., three of the four simple reaction-time measurements showed statistically significant differences in change between PBO and LTG in favor of LTG (p=0.03; 0.03; 0.04); two of four tests showed statistically significant differences in change between LTG and VPA, both in favor of LTG (p=0.03; 0.05). SUBJECTIVE COMPLAINTS: the ABNAS-neurotoxicity scale reveals a significant reduction of drug-related cognitive complaints for the subjects taking LTG, relative to VPA (p=0.02). MOOD RATING: significant changes were found on the scale assessing "tiredness," showing increased tiredness/sedation for VPA relative to PBO (p=0.02) and on the "timid scale" for LTG reporting "being more at ease" compared with both PBO and VPA (p=0.02; 0.02). The general direction of change for the mood scales was toward "activation" for LTG (five of six scales improved), whereas for VPA, the reverse effect was found (four of six scales showed a change in the direction of "tiredness/sedation"). CONCLUSIONS: Short-term treatment in normal volunteers with a low dose of LTG resulted in improved cognitive activation on simple reaction-time measurements, a more positive subjective report about the impact of drug treatment relative to VPA, and mood changes concurring with the activating effect demonstrated by the cognitive tests.