Publications by authors named "Martijn H van der Ree"

7 Publications

  • Page 1 of 1

Cost-Based Price Calculation of Mexiletine for Nondystrophic Myotonia.

Value Health 2021 Jul 10;24(7):925-929. Epub 2021 Apr 10.

Medicine for Society, Platform at Amsterdam UMC - University of Amsterdam, The Netherlands; Department of Endocrinology and Metabolism, Amsterdam UMC - University of Amsterdam, The Netherlands.

Objectives: Mexiletine is a long-known drug used for the treatment of arrhythmias and repurposed in the 1980s for patients with nondystrophic myotonia (NDM). Recently, the price of mexiletine in Europe increased significantly after registration as an orphan drug for NDM. This led to international discussions on affordability and willingness to reimburse mexiletine in the absence of background information that would justify such a price. Our objective was to calculate a cost-based price for mexiletine for adult patients with NDM based on detailed information on development costs.

Methods: We calculated a fair price based on a cost-based pricing model for commercial mexiletine to treat adults with NDM using a recent European drug-pricing model as a framework to include actual costs incurred. Three scenarios were applied: 1 with minimum estimated costs, 1 with maximum estimated costs, and 1 with costs as if mexiletine was innovative.

Results: The calculated fair price of mexiletine per patient per year (PPPY) is €452 for the minimum scenario and €1996 for the maximum scenario. By using hypothetical R&D costs used for innovative drugs, the price would be €6685 PPPY. In Europe, the list price of mexiletine ranges from €30 707-60 730 PPPY, based on 600 mg daily.

Conclusions: The current list price for mexiletine in Europe is manifold higher than any scenario of the cost-based models. Accounting for the reduced costs for clinical development in a repurposing scenario, the cost-based pricing model provides a fair commercial price range, which can be used as benchmark for pricing negotiations and/or reimbursement decisions.
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http://dx.doi.org/10.1016/j.jval.2021.02.004DOI Listing
July 2021

What's in a name? further classification of patients with apparent idiopathic ventricular fibrillation.

Eur Heart J 2021 Jul;42(29):2839-2841

Heart Center, Department of Clinical and Experimental Cardiology, Amsterdam, UMC, University of Amsterdam, Cardiovascular Sciences, Meibergdreef 9, Amsterdam, the Netherlands.

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http://dx.doi.org/10.1093/eurheartj/ehab382DOI Listing
July 2021

The β-angle can help guide clinical decisions in the diagnostic work-up of patients suspected of Brugada syndrome: a validation study of the β-angle in determining the outcome of a sodium channel provocation test.

Europace 2021 Jun 14. Epub 2021 Jun 14.

Department of Clinical and Experimental Cardiology, Heart Center, Amsterdam UMC, University of Amsterdam, Cardiovascular Sciences, Meibergdreef 9, Amsterdam, The Netherlands.

Aims: In patients with Brugada syndrome (BrS) but without spontaneous Type-1 electrocardiogram, several electrocardiographic characteristics have been studied, including the β-angle. Previous studies suggested that the β-angle might be useful in distinguishing BrS-patients from patients with only suggestive repolarization patterns without performing sodium channel blocker provocation testing. In this study, we aimed to determine the diagnostic value of the β-angle in patients suspected of BrS.

Methods And Results: A large cohort (n = 1430) of consecutive patients who underwent provocation testing was evaluated. β-angles were measured in leads V1, V2, and their corresponding positions over the second and third intercostal space. Receiver-operating characteristic curves were constructed and the diagnostic accuracy of previously reported β-angle cut-offs were calculated and evaluated. The importance of the β-angle for predicting the provocation test outcome was determined using a prediction model constructed with logistic regression. The optimum β-angle cut-off in our cohort for ruling out a positive provocation test was 15°; sensitivities were 80-98% and negative predictive values were 79-96% among the right precordial leads. Previously reported β-angle cut-offs performed less well, indicated by lower Youden indices. In the optimism-corrected prediction model [C-statistic: 0.78 (95% CI: 0.75-0.81)], the β-angle had large value (Z-score: 2.1-10.3) and aided construction of a nomogram to predict test outcome.

Conclusion: To predict the outcome of provocation testing for BrS, the β-angle alone does not demonstrate strong diagnostic characteristics. However, the β-angle is an important variable to predict provocation test outcome and thus has added value.
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http://dx.doi.org/10.1093/europace/euab128DOI Listing
June 2021

Echocardiographic deformation imaging unmasks global and regional mechanical dysfunction in patients with idiopathic ventricular fibrillation: A multicenter case-control study.

Heart Rhythm 2021 May 28. Epub 2021 May 28.

Department of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands.

Background: Idiopathic ventricular fibrillation (IVF) is diagnosed in patients with sudden onset of ventricular fibrillation of unidentified origin. New diagnostic tools that can detect subtle abnormalities are needed to diagnose and treat patients with an underlying substrate.

Objective: The purpose of this study was to explore echocardiographic deformation characteristics in IVF patients.

Methods: Echocardiograms were analyzed with deformation imaging by 2-dimensional speckle tracking. Global and regional measurements of the left ventricle (LV) and right ventricle (RV) were performed. Regional LV deformation patterns were evaluated for the presence of postsystolic shortening. Regional RV deformation patterns were classified as type I (normal) or type II/III (abnormal).

Results: In total, 47 IVF patients (mean age 45 years; left ventricular ejection fraction [LVEF] 56%) and 47 healthy controls (mean age 41 years; LVEF 60%) were included. IVF patients showed more global deformation abnormalities as indicated by lower LV global longitudinal strain (18.5% ± 2.6% vs 21.6% ± 1.8%; P <.001) and higher LV mechanical dispersion (41 ± 12 ms vs 26 ± 6 ms; P <.001). In addition, IVF patients showed more regional LV postsystolic shortening compared to healthy controls (50% vs 11%; P <.001). Abnormal RV deformation patterns were observed in 16% of IVF patients and in none of the control subjects (P <.001).

Conclusion: We were able to show both regional and global echocardiographic deformation abnormalities in IVF patients. This study provides evidence that localized myocardial disease is present in a subset of IVF patients.
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http://dx.doi.org/10.1016/j.hrthm.2021.05.030DOI Listing
May 2021

Left Axis Deviation in Brugada Syndrome: Vectorcardiographic Evaluation during Ajmaline Provocation Testing Reveals Additional Depolarization Abnormalities.

Int J Mol Sci 2021 Jan 6;22(2). Epub 2021 Jan 6.

Heart Center, Department of Clinical and Experimental Cardiology, Amsterdam UMC, University of Amsterdam, Cardiovascular Sciences, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.

Patients with Brugada syndrome (BrS) can show a leftward deviation of the frontal QRS-axis upon provocation with sodium channel blockers. The cause of this axis change is unclear. In this study, we aimed to determine (1) the prevalence of this left axis deviation and (2) to evaluate its cause, using the insights that could be derived from vectorcardiograms. Hence, from a large cohort of patients who underwent ajmaline provocation testing ( = 1430), we selected patients in whom a type-1 BrS-ECG was evoked ( = 345). Depolarization and repolarization parameters were analyzed for reconstructed vectorcardiograms and were compared between patients with and without a >30° leftward axis shift. We found (1) that the prevalence of a left axis deviation during provocation testing was 18% and (2) that this left axis deviation was not explained by terminal conduction slowing in the right ventricular outflow tract (4th QRS-loop quartile: +17 ± 14 ms versus +13 ± 15 ms, nonsignificant) but was associated with a more proximal conduction slowing (1st QRS-loop quartile: +12[8;18] ms versus +8[4;12] ms, < 0.001 and 3rd QRS-loop quartile: +12 ± 10 ms versus +5 ± 7 ms, < 0.001). There was no important heterogeneity of the action potential morphology (no difference in the ventricular gradient), but a left axis deviation did result in a discordant repolarization (spatial QRS-T angle: 122[59;147]° versus 44[25;91]°, < 0.001). Thus, although the development of the type-1 BrS-ECG is characterized by a terminal conduction delay in the right ventricle, BrS-patients with a left axis deviation upon sodium channel blocker provocation have an additional proximal conduction slowing, which is associated with a subsequent discordant repolarization. Whether this has implications for risk stratification is still undetermined.
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http://dx.doi.org/10.3390/ijms22020484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7825029PMC
January 2021

Cardiac radioablation-A systematic review.

Heart Rhythm 2020 08 20;17(8):1381-1392. Epub 2020 Mar 20.

Heart Center, Department of Clinical and Experimental Cardiology, Amsterdam UMC, University of Amsterdam, Cardiovascular Sciences, Amsterdam, The Netherlands. Electronic address:

Failure of drugs and catheter ablation procedures for the treatment of ventricular arrhythmias is still extremely relevant. Recently, stereotactic body radiotherapy has been introduced to treat therapy refractory patients. In this systematic review (International Prospective Register of Systematic Reviews, CRD42019133212), we aimed to summarize electrophysiological and histopathological effects of radioablation in animals, patients, and extracted and perfused hearts. A systematic search was performed in OVID MEDLINE, OVID Embase, the Cochrane Central Register of Controlled Trials, Web of Science, Google Scholar, ClinicalTrials.gov, and World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) from inception to September 2019. Identified records were independently screened for eligibility by 2 reviewers. Risk of bias and methodological quality were assessed using the SYRCLE, ROBINS-I, or Murad tool and tailored to the different study designs. We included 13 preclinical and 10 clinical publications. Large heterogeneity in study designs prompted a narrative synthesis approach. Baseline, (pre-)procedural details, outcome, target tissue analyses, and safety data were extracted and summarized. In animal studies evaluating electrophysiological parameters, radioablation induced a reduction in voltage/potential amplitude or bidirectional block in target areas in 93.2% of animals. Atrioventricular block (first to third degree) was induced in 78.3% of animals, and in studies evaluating ventricular arrhythmia inducibility, 75% reduction was achieved. In patients, predominantly ventricular tachycardias were targeted with >85% reduction in arrhythmia episodes during follow-up with an encouraging short-term safety profile. Preclinical and clinical evidence on the efficacy and safety of radioablation is limited in both quantity and quality. The results of radioablation for therapy refractory patients with ventricular tachycardia are promising, but further research is needed.
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http://dx.doi.org/10.1016/j.hrthm.2020.03.013DOI Listing
August 2020

Pregnancy in Catecholaminergic Polymorphic Ventricular Tachycardia.

JACC Clin Electrophysiol 2019 03 26;5(3):387-394. Epub 2018 Dec 26.

Heart Rhythm Services, Division of Cardiology, University of British Columbia, Vancouver, British Columbia, Canada. Electronic address:

Objectives: This investigation was a retrospective study of catecholaminergic polymorphic ventricular tachycardia (CPVT) patients in Canada and the Netherlands to compare pregnancy, postpartum, and nonpregnant event rates.

Background: CPVT is characterized by life-threatening arrhythmias during exertion or emotional stress. The arrhythmic risk in CPVT patients during pregnancy is unknown.

Methods: Baseline demographics, genetics, treatment, and pregnancy complications were reviewed. Event rate calculations assumed a 40-week pregnancy and 24-week postpartum period.

Results: Ninety-six CPVT patients had 228 pregnancies (median 2 pregnancies per patient; range: 1 to 10; total: 175.4 pregnant patient-years). The median age of CPVT diagnosis was 40.7 years (range: 12 to 84 years), with a median follow-up of 2.9 years (range: 0 to 20 years; total 448.1 patient-years). Most patients had pregnancies before CPVT diagnosis (82%). Pregnancy and postpartum cardiac events included syncope (5%) and an aborted cardiac arrest (1%), which occurred in patients who were not taking beta-blockers. Other complications included miscarriages (13%) and intrauterine growth restriction (1 case). There were 6 cardiac events (6%) during the nonpregnant period. The pregnancy and postpartum event rates were 1.71 and 2.85 events per 100 patient-years, respectively, and the combined event rate during the pregnancy and postpartum period was 2.14 events per 100 patient-years. These rates were not different from the nonpregnant event rate (1.46 events per 100 patient-years).

Conclusions: The combined pregnancy and postpartum arrhythmic risk in CPVT patients was not elevated compared with the nonpregnant period. Most patients had pregnancies before diagnosis, and all patients with events were not taking beta-blockers at the time of the event.
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http://dx.doi.org/10.1016/j.jacep.2018.10.019DOI Listing
March 2019
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