Corine van Marrewijk

Factors and forces influencing stent-graft migration after endovascular aortic aneurysm repair.

Purpose: To assess and validate the clinical features predisposing to stent-graft migration and to calculate the distal displacement forces exerted at the proximal fixation site following endovascular aortic aneurysm repair (EVAR). Methods: Demographic, anatomical, and graft-related features from 2862 patients were analyzed in a regression model to identify variables associated with stent-graft migration, which was defined as device movement >5 mm or considered significant by the investigator. Using the principles of continuity and momentum, a mathematical model of blood flow was created. The pulse pressure, proximal aortic and distal iliac diameters, and the degree of iliac angulation were varied in the calculations, and the distal displacement force exerted at the proximal fixation site was calculated. Results: Ninety-nine patients developed stent-graft migration, which was clinically relevant in 85 (3.0%). Hypertension (p=0.015), smoking (p=0.009), maximal aortic diameter (p=0.004), and distal transverse aortic diameter (p=0.03) correlated with migration in the univariate analysis, but iliac angulation did not quite achieve significance (p=0.06). On multivariate analysis, current smoking, hypertension, distal transverse aortic diameter, maximum common iliac diameter, and increasing proximal graft size were significantly associated with stent-graft migration. The mathematical model calculated the distal displacement force exerted on the proximal fixation site of the stent-graft and validated the clinical findings. The ratio of graft-diameter change from proximal aorta to distal iliac influenced the greatest increase in the displacement force. Conclusions: The mathematical model validated hypertension, aneurysm morphology, and endograft size as clinical factors significantly associated with stent-graft migration. These findings may have important implications for the choice and design of future stent-grafts.

The significance and management of different types of endoleaks

Development of endovascular abdominal aortic aneurysm repair (EVAR) has been accompanied by previously unencountered complications. The most challenging but least understood of these complications is the incomplete seal of the endovascular graft (endoleak), a phenomenon that has a variety of causes. An important consequence of endoleakage may be persistent pressurization of the aneurysm sac, which may ultimately lead to post-EVAR rupture. Data of 110 European centers were recorded in a central database (EUROSTAR). Patient, anatomic characteristics, and operative and device details were correlated with the occurrence of different types of endoleaks. Outcome events during follow-up, particularly expansion of the aneurysm, incidence of conversion to open repair, and post-EVAR rupture were assessed in the different categories of endoleaks and in a group of patients without any endoleak. Type I and III endoleak were associated with an increased frequency of open conversions or risk of rupture of the aneurysm. Device-related endoleaks also correlated with an increased need for secondary interventions. These types of endoleaks need to be treated without delay, and when no other possibilities are present, an open conversion to avert the risk of rupture should be considered. Type II endoleaks do not pose an indication for urgent treatment. However, they may not be harmless, because there was a frequent association with enlargement of aneurysm and reinterventions. Our findings suggest that more frequent surveillance examinations are indicated than in patients without collateral endoleak. The indication for intervention is primarily dictated by documented expansion of the aneurysm.

Pragmatic trials in primary care. Methodological challenges and solutions demonstrated by the DIAMOND-study

BackgroundPragmatic randomised controlled trials are often used in primary care to evaluate the effect of a treatment strategy. In these trials it is difficult to achieve both high internal validity and high generalisability. This article will discuss several methodological challenges in designing and conducting a pragmatic primary care based randomised controlled trial, based on our experiences in the DIAMOND-study and will discuss the rationale behind the choices we made. From the successes as well as the problems we experienced the quality of future pragmatic trials may benefit.DiscussionThe first challenge concerned choosing the clinically most relevant interventions to compare and enable blinded comparison, since two interventions had very different appearances. By adding treatment steps to one treatment arm and adding placebo to both treatment arms both internal and external validity were optimized. Nevertheless, although blinding is essential for a high internal validity, it should be warily considered in a pragmatic trial because it decreases external validity. Choosing and recruiting a representative selection of participants was the second challenge. We succeeded in retrieving a representative relatively large patient sample by carefully choosing (few) inclusion and exclusion criteria, by random selection, by paying much attention to participant recruitment and taking the participants reasons to participate into account. Good and regular contact with the GPs and patients was to our opinion essential. The third challenge was to choose the primary outcome, which needed to reflect effectiveness of the treatment in every day practice. We also designed our protocol to follow every day practice as much as possible, although standardized treatment is usually preferred in trials. The aim of this was our fourth challenge: to limit the number of protocol deviations and increase external validity.SummaryIt is challenging to design and conduct a pragmatic trial. Thanks to thorough preparation, we were able to collect highly valid data. To our opinion, a critical deliberation of where on the pragmatic – explanatory spectrum you want your trial to be on forehand, in combination with consulting publications especially on patient recruitment procedures, has been helpful in conducting a successful trial.

Causes and outcomes of open conversion and aneurysm rupture after endovascular abdominal aortic aneurysm repair: Can type II endoleaks be dangerous?

The feasibility of endovascular abdominal aortic aneurysm repair (EVAR) and the short-term advantages compared with conventional open surgery are no longer in doubt. In patients with suitable aortoiliac anatomy the primary success rate, represented by successful access and endograft deployment, is almost 98%. In studies in which EVAR and open aneurysm repair were compared, there were no unfavorable results for the endovascular method. But late complications have plagued the stentgraft approach, with rupture of the aneurysm being the most dramatic evidence of treatment failure. Conversion to open surgery is either performed for manifest rupture of the aneurysm or for impending rupture, indicated by radiologic or ultrasonographic studies. In almost any current overview of EVAR the need for intensive surveillance to identify indicators for an increased risk of rupture is emphasized. Nevertheless, comprehensive surveillance is time consuming and expensive for the health care system, and it requires rigorous patient compliance—conditions that often are not met in everyday practice. In addition, there is uncertainty which signs and findings at regular imaging are accurate indicators for an increased risk of conversion to open surgery or aneurysm rupture. For instance, the role of endoleaks, in particular, type II or side branch perfusion endoleaks, is controversial. These aspects were analyzed in detail in this overview of the EUROSTAR series. METHODS The EUROSTAR experience The EUROSTAR registry was established in 1996 for the purpose of collation and analysis of data from patients who undergo endovascular treatment for abdominal aortic aneurysm. Risk factors and risk classifications as recorded at baseline by 101 participating centers were used for correlation with aneurysm rupture and conversion to open surgery during followup. Participation in the registry is voluntary and there is no outside monitoring of the data of individual centers. Data on 3,529 patients, who underwent treatment between January 1994 and July 2001, were collected and entered in the database. A separate retrospective cohort consisted of 454 patients; all other patients were prospectively enrolled in the database. The following commercially available devices were included in the series: (1) Vanguard, Boston Scientific Corporation, Natick, MA—936 patients; (2) AneuRx, Medtronic AVE, Santa Rosa, CA—805 patients; (3) Talent, World Medical Manufacturing Corp, Sunrise, FL—552 patients; (4) Zenith, William Cook Europe, Bjaeverskov, Denmark—464 patients; (5) Stentor, Mintec Inc, Freeport, Bahamas—311 patients; (6) Excluder, WL Gore & Associates, Inc, Flagstaff, AZ—218 patients; (7) Ancure, Guidant Corporation, Menlo Park, CA—142 patients; (8) other devices—101 patients (Fig. 1). Inclusion criteria comprised an elective abdominal aortic aneurysm operation and an anatomic configuration suitable for implantation of a bifurcated (3,248 patients), straight tube (144 patients), or an aorto-uni-iliac tube (137 patients). Preoperative medical risk factors and morphologic variables were prospectively recorded, as were details of the endovascular procedure, the completion angiography, and the postoperative course. Followup visits, according to a fixed schedule, included No competing interests declared.

Early Assessment of Thiopurine Metabolites Identifies Patients at Risk of Thiopurine-induced Leukopenia in Inflammatory Bowel Disease

Background and aims: Only a quarter of thiopurine-induced myelotoxicity in inflammatory bowel disease [IBD] patients is related to thiopurine S-methyltransferase deficiency. We determined the predictive value of 6-thioguanine nucleotide [6-TGN] and 6-methylmercaptopurine ribonucleotide [6-MMPR] concentrations 1 week after initiation [T1] for development of leukopenia during the first 8 weeks of thiopurine treatment. Methods: The study was performed in IBD patients starting thiopurine therapy as part of the Dutch randomized controlled TOPIC trial [ClinicalTrials.gov NCT00521950]. Blood samples for metabolite measurement were collected at T1. Leukopenia was defined by leukocyte counts of <3.0 × 109/L. For comparison, patients without leukopenia who completed the 8 weeks on the stable dose were selected from the first 272 patients of the TOPIC trial. Results: Thirty-two patients with, and 162 patients without leukopenia were analysed. T1 threshold 6-TGN concentrations of 213 pmol/8 × 108 erythrocytes and 3525 pmol/8 × 108 erythrocytes for 6-MMPR were defined: patients exceeding these values were at increased leukopenia risk (odds ratio [OR] 6.2 [95% CI: 2.8–13.8] and 5.9 [95% CI: 2.7–13.3], respectively). Leukopenia rates were higher in patients treated with mercaptopurine, compared with azathioprine (OR 7.3 [95% CI: 3.1–17.0]), and concurrent anti-TNF therapy (OR 5.1 [95% CI: 1.6–16.4]). Logistic regression analysis of thiopurine type, threshold concentrations, and concurrent anti-tumour necrosis factor [TNF] therapy revealed that elevations of both T1 6-TGN and 6-MMPR resulted in the highest risk for leukopenia, followed by exceeding only the T1 6-MMPR or 6-TGN threshold concentration (area under the curve 0.84 [95% CI: 0.76–0.92]). Conclusions: In ~80% of patients, leukopenia could be explained by T1 6-TGN and/or 6-MMPR elevations. Validation of the predictive model is needed before implementing in clinical practice.

Serotonin receptor 3A polymorphism c.-42C > T is associated with severe dyspepsia

BackgroundThe association between anxiety and depression related traits and dyspepsia may reflect a common genetic predisposition. Furthermore, genetic factors may contribute to the risk of having increased visceral sensitivity, which has been implicated in dyspeptic symptom generation. Serotonin (5-HT) modulates visceral sensitivity by its action on 5-HT3 receptors. Interestingly, a functional polymorphism in HTR3A, encoding the 5-HT3 receptor A subunit, has been reported to be associated with depression and anxiety related traits. A functional polymorphism in the serotonin transporter (5-HTT), which terminates serotonergic signalling, was also found associated with these psychiatric comorbidities and increased visceral sensitivity in irritable bowel syndrome, which coexistence is associated with higher dyspeptic symptom severity. We investigated the association between these functional polymorphisms and dyspeptic symptom severity.MethodsData from 592 unrelated, Caucasian, primary care patients with dyspepsia participating in a randomised clinical trial comparing step-up and step-down antacid drug treatment (The DIAMOND trial) were analysed. Patients were genotyped for HTR3A c.-42C > T SNP and the 44 bp insertion/deletion polymorphism in the 5-HTT promoter (5-HTTLPR). Intensity of 8 dyspeptic symptoms at baseline was assessed using a validated questionnaire (0 = none; 6 = very severe). Sum score ≥20 was defined severe dyspepsia.ResultsHTR3A c.-42T allele carriers were more prevalent in patients with severe dyspepsia (OR 1.50, 95% CI 1.06-2.20). This association appeared to be stronger in females (OR 2.05, 95% CI 1.25-3.39) and patients homozygous for the long (L) variant of the 5-HTTLPR genotype (OR 2.00, 95% CI 1.01-3.94). Females with 5-HTTLPR LL genotype showed the strongest association (OR = 3.50, 95% CI = 1.37-8.90).ConclusionsThe HTR3A c.-42T allele is associated with severe dyspeptic symptoms. The stronger association among patients carrying the 5-HTTLPR L allele suggests an additive effect of the two polymorphisms. These results support the hypothesis that diminished 5-HT3 mediated antinociception predisposes to increased visceral sensitivity of the gastrointestinal tract. Moreover, the HTR3A c.-42C > T and 5-HTTLPR polymorphisms likely represent predisposing genetic variants in common to psychiatric morbidity and dyspepsia.

More Dose-dependent Side Effects with Mercaptopurine over Azathioprine in IBD Treatment Due to Relatively Higher Dosing

Background: There are substantial global differences in the preference for mercaptopurine (MP) or its prodrug azathioprine (AZA) as first-choice thiopurine to treat inflammatory bowel diseases. Studies comparing both agents are scarce. Our aim was to compare AZA and MP in thiopurine-naive patients with inflammatory bowel disease for the frequency of side effects and efficacy. Methods: Post hoc analysis of the “Thiopurine response Optimization by Pharmacogenetic testing in Inflammatory bowel disease Clinics” (TOPIC) trial, in which thiopurine-naive patients with inflammatory bowel disease with an indication for a thiopurine were randomized for a genotype-based dose versus standard of care. For this study, Cox proportional hazard ratios (HRs) were calculated to compare AZA and MP for discontinuation rates within 5 months, incidence of hepatotoxicity, leukopenia, and gastrointestinal side effects. Treatment efficacy was compared by logistic regression. Results: Patient characteristics were similar for patients treated with AZA (n = 494, 64.4%) and MP (n = 273, 35.6%), yet patients with MP were relatively higher dosed compared with those on AZA. Discontinuation rates within 5 months were not different, 39.3% (AZA) and 38.1% (MP), HR 0.92 (95% confidence interval, 0.72–1.17; P = 0.50); however, patients on MP were more often subjected to dose reductions (30% versus 14%, P < 0.01). Higher rates of hepatotoxicity, HR 1.93 (95% confidence interval, 1.35–2.76; P < 0.01) and leukopenia, HR 2.55 (95% confidence interval, 1.51–4.30; P < 0.01) were observed with MP, which annulled in a secondary analysis with adjustment for the higher dose and metabolite levels. Conclusions: Patients treated with MP were relatively higher dosed, which resulted in more dose-dependent side effects and a higher rate of dose reductions.

Leefstijladviezen, medicatie-instructies en het belang van therapietrouw bij maagklachten

SamenvattingFransen GAJ, Mesters I, Van Marrewijk CJ, Mujakovic S, Knottnerus JA, Muris JWM. Leefstijladviezen, medicatie-instructies en het belang van therapietrouwe bij maagklachten. Huisarts Wet 2007;50(9):445-52.Inleiding Therapietrouw is essentieel om het effect van een behandeling te kunnen evalueren. Veel patiënten met een eerste episode van maagklachten houden zich echter niet aan medicatie-instructies en zeggen geen leefstijladviezen te hebben gekregen. Hierin kan voorlichting door huisartsen een rol spelen.Doel Met dit onderzoek wilden we inzicht krijgen in de voorlichting door huisartsen over leefstijladviezen, medicatie-instructies en therapietrouw.Methode Vragenlijstonderzoek bij huisartsen (n = 114).Resultaten Huisartsen rapporteren dat ze regelmatig leefstijladviezen geven: respectievelijk 73%, 69% en 60% geeft meestal/altijd adviezen over alcoholgebruik, roken en voeding. Het overgrote deel, 95-99%, zegt meestal/altijd instructies te geven over frequentie, dosering en behandelduur van medicatie. Bij een eerste episode van maagklachten adviseert 76% van de huisartsen zelden of nooit om maagzuurremmers te gebruiken op geleide van klachten. Veertien procent geeft aan doorgaans schriftelijke voorlichtingsmaterialen te gebruiken en 61% vraagt regelmatig na of de patiënt de medicatie volgens voorschrift heeft ingenomen.Conclusie In tegenstelling tot wat patiënten melden, zeggen huisartsen gewoonlijk medicatie-instructies en leefstijladviezen te geven. De voorlichting wordt weinig ondersteund met schriftelijke materiaal, wat wellicht zou kunnen bijdragen aan de lage therapietrouw. Hoewel weinig artsen aanbevelen om op geleide van klachten maagzuurremmers te gebruiken, lijken veel patiënten dit toch te doen. Dit kan betekenen dat de medicatie-instructie en het belang van therapietrouw niet voldoende duidelijk zijn voor patiënten.AbstractFransen GAJ, Mesters I, Van Marrewijk CJ, Mujakovic S, Knottnerus JA, Muris JWM. Lifestyle advice, medication instructions and the importance of adherence in case of dyspepsia. Huisarts Wet 2007;50(9):445-52.Background Dyspepsia is a worldwide problem, often treated with acid-suppressants or by a change in lifestyle. However preliminary results from a large RCT investigating the most effective treatment for dyspepsia indicate that only 11% of patients with a first episode of dyspepsia indicated that they had received lifestyle advice and about 50% fail to follow the correct medication instructions. The aim of this study was to investigate which medication instructions and lifestyle advice GPs normally give to their patients with dyspepsia.Method A questionnaire was sent to 259 Dutch GPs participating in an RCT investigating dyspepsia. The questionnaire could be returned anonymously and free of charge. Two reminders were sent out.Results The questionnaire was returned by 114 GPs, 60% of whom usually or always provided nutritional advice, 68% (almost) always advised the patient to stop smoking, and 72% (almost) always advised a reduction in alcohol consumption. The recommendation regarding raising the head end of the bed was provided less often (35% usually/always). Only 14% of the GPs commonly provided written information to support their lifestyle advice. Most GPs found it fairly to highly important that the patient adhere to doses (93%) and duration (95%) of the treatment; 40% of the GPs found adherence to the daily intake schedule very important. As many as 75% of the GPs seldom or never advised on demand use of medication in cases of a first episode of complaints, 39% of the GPs in cases of persisting complaints and only 7% in cases of relapsing complaints seldom or never advised on demand use.Discussion In contrast to the reports from patients, GPs stated that they frequently made recommendations regarding lifestyle. The instructions were often unsupported by written educational materials, which might contribute to low adherence rates and low recall by patients. Most GPs considered compliance with prescribed medication to be very important, but 20% of the GPs did not commonly check compliance. While patients might take their medication on demand, most GPs did not advise on demand use, especially in cases of a first episode of complaints.

Prognostic impact of a suboptimal number of analyzed metaphases in normal karyotype lower-risk MDS

Conventional karyotype is one of the most relevant prognostic factors in MDS. However, about 50% of patients with MDS have a normal karyotype. Usually, 20-25 normal metaphases (nMP) are considered to be optimal to exclude small abnormal clones which might be associated with poor prognosis. This study evaluated the impact of examining a suboptimal number of metaphases in patients recruited to the EUMDS Registry with low and intermediate-1 risk according to IPSS. Only 179/1049 (17%) of patients with a normal karyotype had a suboptimal number of nMP, defined as less than 20 metaphases analyzed. The outcome (overall survival and progression-free survival) of patients with suboptimal nMP was not inferior to those with higher numbers of analyzed MP both in univariate and multivariate analyses. For patients with an abnormal karyotype, 224/649 (35%) had a suboptimal number of MP assessed, but this did not impact on outcome. For patients with a normal karyotype and suboptimal numbers of analyzable metaphases standard evaluation might be acceptable for general practice, but we recommend additional FISH-analyses or molecular techniques, especially in candidates for intensive interventions.

Labile plasma iron levels predict survival in patients with lower-risk myelodysplastic syndromes

Red blood cell transfusions remain one of the cornerstones in supportive care of lower-risk patients with myelodysplastic syndromes. We hypothesized that patients develop oxidant-mediated tissue injury through the formation of toxic iron species, caused either by red blood cell transfusions or by ineffective erythropoiesis. We analyzed serum samples from 100 lower-risk patients with myelodysplastic syndromes at six-month intervals for transferrin saturation, hepcidin-25, growth differentiation factor 15, soluble transferrin receptor, non-transferrin bound iron and labile plasma iron in order to evaluate temporal changes in iron metabolism and the presence of potentially toxic iron species and their impact on survival. Hepcidin levels were low in 34 patients with ringed sideroblasts compared to 66 patients without. Increases of hepcidin and non-transferrin bound iron levels were visible early in follow-up of all transfusion-dependent patient groups. Hepcidin levels significantly decreased over time in transfusion-independent patients with ringed sideroblasts. Increased soluble transferrin receptor levels in transfusion-independent patients with ringed sideroblasts confirmed the presence of ineffective erythropoiesis and suppression of hepcidin production in these patients. Detectable labile plasma iron levels in combination with high transferrin saturation levels occurred almost exclusively in patients with ringed sideroblasts and all transfusion-dependent patient groups. Detectable labile plasma iron levels in transfusion-dependent patients without ringed sideroblasts were associated with decreased survival. In conclusion, toxic iron species occurred in all transfusion-dependent patients and in transfusion-independent patients with ringed sideroblasts. Labile plasma iron appeared to be a clinically relevant measure for potential iron toxicity and a prognostic factor for survival in transfusion-dependent patients. clinicaltrials.gov Identifier: 00600860.