Implementing the new European Regulations on medical devices-clinical responsibilities for evidence-based practice: a report from the Regulatory Affairs Committee of the European Society of Cardiology.

The new European Union (EU) law governing the regulatory approval of medical devices that entered into force in May 2017 will now take effect from 26 May 2021. Here, we consider how it will change daily practice for cardiologists, cardiac surgeons, and healthcare professionals. Clinical evidence for any high-risk device must be reported by the manufacturer in a Summary of Safety and Clinical Performance (SSCP) that will be publicly available in the European Union Database on Medical Devices (Eudamed) maintained by the European Commission; this will facilitate evidence-based choices of which devices to recommend. Hospitals must record all device implantations, and each high-risk device will be trackable by Unique Device Identification (UDI). Important new roles are envisaged for clinicians, scientists, and engineers in EU Expert Panels-in particular to scrutinize clinical data submitted by manufacturers for certain high-risk devices and the evaluations of that data made by notified bodies. They will advise manufacturers on the design of their clinical studies and recommend to regulators when new technical specifications or guidance are needed. Physicians should support post-market surveillance by reporting adverse events and by contributing to comprehensive medical device registries. A second law on In Vitro Diagnostic Medical Devices will take effect from 2022. We encourage all healthcare professionals to contribute proactively to these new systems, in order to enhance the efficacy and safety of high-risk devices and to promote equitable access to effective innovations. The European Society of Cardiology will continue to advise EU regulators on appropriate clinical evaluation of high-risk devices.

The need for transparency of clinical evidence for medical devices in Europe.

To use medical devices rationally, health-care professionals must base their choices of which devices to recommend for individual patients on an objective appraisal of their safety and clinical efficacy. The evidence submitted by manufacturers when seeking approval of their high-risk devices must be publicly available, including technical performance and premarket clinical studies. Giving physicians access to this information supplements the peer-reviewed scientific literature and might be essential for comparing alternative devices within any class. Interested patients should be encouraged to review the evidence for any device that has been recommended for them. The new EU law on medical devices states that the manufacturer is to prepare a summary of the evidence for any implantable or high-risk device. Defining its content, however, has been delegated to implementing legislation, which is now being considered. From a clinical perspective, it is imperative that all evidence reviewed by notified bodies and regulatory authorities is disclosed-with the exception, if justified, only of technical specifications that are considered confidential or manufacturing details that are protected as intellectual property-and public access to this evidence must be guaranteed by EU law. From ethical and other perspectives, there are no grounds for less clinical evidence being available to health-care professionals about the medical devices that they use than is already available for new pharmaceutical products. Full transparency is needed; without it, informed decisions relating to the use of new medical devices will remain impossible.

Long-Term Durability of Transcatheter Valves: The Importance of Accurate Data.

As transcatheter valves are offered to progressively lower-risk patients, it is increasingly important to have accurate data about durability. Structural valve deterioration (SVD) implies an adverse change in the morphology of the leaflets and function of the valve compared with the state at implantation. However, a recent European statement allows SVD to be defined solely by a threshold mean gradient ≥20 mm Hg. Absolute mean gradients above this threshold may be observed immediately after implantation and represent patient-prosthesis mismatch and not SVD. This paper describes a definition of SVD more in keeping with routine clinical practice, incorporating a change in leaflet morphology and an increase in the grade of transvalvar regurgitation or an increase in gradient from the post-implantation study.

Valvular heart disease in the community: a European experience.

The Euro Heart Survey on valvular heart disease included 5001 patients from 92 centers in 25 European countries in 2001: 71.9% had native valve disease and 28.1% had previously undergone valve surgery. Aortic stenosis (AS) and mitral regurgitation (MR) accounted for 43.1 and 33.6%, respectively, of single-valve diseases and were mostly caused by degenerative diseases. Mean age was 69 and 65 years, respectively, and at least one comorbidity was present in 36.3% of patients with AS and 41.7% with MR. Analysis of the therapeutic decision in patients with severe valve diseases showed that symptomatic patients were frequently denied surgery (32.3% in AS after the age of 75 and 51.3% in MR), more on the basis of age and left ventricular function than comorbidities. There was a better concordance between practice and guidelines concerning interventions in asymptomatic patients. These findings underline the need for better implementation of guidelines.

A new scoring system to determine thromboembolic risk after heart valve replacement.

OBJECTIVE: To determine the most important inflammatory and hematologic predictors of thromboembolism (TE) in patients undergoing valve replacement (VR) to be used in conjunction with clinical risk factors for preoperative risk profiling. METHODS AND RESULTS: Preoperative and immediately postoperative clinical, echocardiographic, hematologic, biochemical and microbiological parameters were examined prospectively in 370 patients undergoing VR (249 AVR, 93 MVR, 28 DVR). Mean follow-up was 4.4 years (max 6.6 years; total 1566 pt/yrs), and 96 TE events were documented (28 major and 68 minor). INR data were collected on all patients. Laboratory values were considered elevated if they exceeded the 80th percentile of those of 70 controls with the same distribution of age and gender. IgA antibody to Chlamydia pneumoniae (CP)>or=1:64 was considered indicative of significant infection. Predictors of TE on multivariate analysis following AVR were (hazard ratios): CP infection (2.6), previous TE (2.5), raised eosinophils (2.4), cancer history (2.1), postoperative infection (2.0), hypertension (2.0), CABG x 3/4 (2.0), and diabetes (1.9). Predictors of TE following MVR/DVR were raised mean platelet volume (4.0), raised factor VII (3.1), CP infection (2.7), previous mitral valvotomy (2.5), raised fibrinogen (2.2), and raised reticulocytes (2.0). These risk factors were additive when present in the same patient, enabling a scoring system to be developed that accurately predicted risk of TE based on number of risk factors. CONCLUSIONS: Selected blood tests and clinical risk factors provide a scoring system that accurately predicts TE risk and may guide prosthesis choice and antithrombotic management.

Pseudomesothelioma resulting from metastatic malignant melanoma.

Isolated pleural metastatic melanoma is an uncommon clinical condition. Clinical diagnosis can be difficult and therapeutic options are limited. We describe a case where there was isolated pleural metastasis, 10 years following complete excision of a superficial melanotic lesion, which presented like a malignant mesothelioma ('pseudomesothelioma').

Better anticoagulation control improves survival after valve replacement.

OBJECTIVE: We sought to assess the effect of anticoagulation control on long-term survival after valve replacement with the Medtronic Hall valve (Medtronic, Inc, Minneapolis, Minn). METHODS: Prospective follow-up data, including 82,297 international normalized ratios, were collected for 1476 patients undergoing single valve replacement with the Medtronic Hall valve between 1979 and 1994, with follow-up to the end of 1998. After excluding 204 patients who either died within 30 days or had fewer than 10 international normalized ratios recorded beyond 30 days, there were 10,203 patient years of follow-up for analysis. Anticoagulation variability was measured as the percentage of international normalized ratios outside a target range of 2.0 to 4.0 for each patient. RESULTS: Linearized rates for late death rose progressively with increasing deciles of anticoagulation variability for both aortic and mitral valve replacement (2.7% and 3.3% per year, respectively, in deciles 1 and 2 up to 9.5% and 14.6% per year, respectively, in deciles 6-10; P <.001). Survival at 15 years after aortic valve replacement was 59% for low anticoagulation variability (deciles 1 and 2), 55% for intermediate anticoagulation variability (decile 3), and 28% for high anticoagulation variability (deciles 4-10); survivals at 15 years after mitral valve replacement were 56%, 42%, and 24%, respectively (P <.001 between low-intermediate anticoagulation variability and high anticoagulation variability for both aortic and mitral valve replacement). On multivariate analysis, significant predictors of reduced survival were anticoagulation variability per 20% increase (hazard ratio, 1.8), diabetes (hazard ratio, 1.6), decade of age (hazard ratio, 1.6), concomitant coronary artery bypass grafting (hazard ratio, 1.5), male sex (hazard ratio, 1.4), hypertension (hazard ratio, 1.4), New York Heart Association class III or IV (hazard ratio, 1.3), and non-sinus rhythm (hazard ratio, 1.2). Patients with low anticoagulation variability who were in sinus rhythm and did not have diabetes, coronary bypass grafting, or hypertension had survivals equal to those of the age- and sex-matched general population at 15 years. The incidence of valve-related deaths was significantly higher with high anticoagulation variability compared with the incidence with low-intermediate anticoagulation variability for both aortic (1.4% vs 0.5% per year, P <.001) and mitral valve replacement (1.5% vs 0.5% per year, P <.001). By means of univariate analysis, high anticoagulation variability was significantly associated with New York Heart Association class III or IV at 5 years postoperatively (P <.001) and with age of greater than 60 years at the time of the operation (P =.002). CONCLUSIONS: High anticoagulation variability is the most important independent predictor of reduced survival after valve replacement with a mechanical valve. Better anticoagulation control should improve survival.

Prosthesis size and long-term survival after aortic valve replacement.

OBJECTIVE: This study was undertaken to quantify the relationship between prosthesis size adjusted for patient size (prosthesis-patient size) and long-term survival after aortic valve replacement. METHODS: Data from nine representative sources on 13,258 aortic valve replacements provided 69,780 patient-years of follow-up (mean 5.3 +/- 4.7 years), with reliable survival estimates to 15 years. Prostheses included 5757 stented porcine xenografts, 3198 stented bovine pericardial xenografts, 3583 mechanical valves, and 720 allografts. Manufacturers' labeled prosthesis size was 19 mm or smaller in 1109 patients. Expressions of prosthesis-patient size assessed were indexed internal prosthesis orifice area (in centimeters squared per square meter of body surface area) and standardized internal prosthesis orifice size (Z, the number of SDs from mean normal native aortic valve size). Multivariable hazard domain analysis with balancing score and risk factor adjustment quantified the association of prosthesis-patient size with survival. RESULTS: Prosthesis-patient size down to at least 1.1 cm(2)/m(2) or -3 Z did not adversely affect intermediate- or long-term survival (P >.2). However, 30-day mortality increased 1% to 2% when indexed orifice area fell below 1.2 cm(2)/m(2) (P =.002) or standardized orifice size fell below -2.5 Z (P =.0003). The increased early risk affected fewer than 1% of patients receiving bioprostheses but about 25% of those receiving mechanical devices. CONCLUSIONS: Aortic prosthesis-patient size down to 1.1 cm(2)/m(2) or -3 Z did not reduce intermediate- or long-term survival after aortic valve replacement. However, patient-prosthesis size under 1.2 cm(2)/m(2) or -2.5 Z was associated with a 1% to 2% increase in 30-day mortality. Prosthesis-patient sizes this small or smaller were rarely implanted in patients receiving bioprostheses.

Pulmonary blastoma: medium-term results from a regional center.

BACKGROUND: Pulmonary blastomas are rare lung tumors that morphologically resemble fetal pulmonary structure and can exist in two forms, biphasic and monophasic. We reviewed our experience over a 12-year period with emphasis on the clinical features, management, and outcome. METHODS: Patients with a diagnosis of pulmonary blastoma from January 1988 to July 1999 were identified from the database of the Department of Histopathology, Llandough Hospital, Cardiff. Specimens had been obtained from bronchoscopy, fine-needle aspiration, trucut biopsy, and thoracotomy. RESULTS: Six patients were identified from 2,720 histologically proven lung cancers (0.2%). Median age was 35.5 years and sex ratio was equal. Overall, 4 patients underwent resection and are all alive (median, 43.5 months). Three of these had advanced tumors at presentation (stage IIIb or IV), two of which were successfully downstaged with neoadjuvant chemotherapy, and the third treated with postoperative radiotherapy. Nonresected cases succumbed at a median of 5.5 months. CONCLUSIONS: Although pulmonary blastomas are rare, those affected represent a group of patients with advanced tumors for whom a coordinated approach from both oncologists and surgeons can achieve excellent medium-term results.

Clinical evaluation of new heart valve prostheses: update of objective performance criteria.

This article summarizes the long-term clinical results of the Food and Drug Administration-approved heart valves, provides current updates to the objective performance criteria (OPC) used to evaluate new heart valve prostheses, and documents the steps that the International Organization for Standardization Committee used to arrive at the updated OPC. Data were extracted from 19 Food and Drug Administration summaries of safety and effectiveness data reports (31 series) and 56 literature articles (85 series) published from 1999 to 2012. The OPC were calculated for five valve-related complications by valve type (mechanical and bioprosthetic) and valve position (aortic and mitral).

Three decades of experience in the surgical multi-modality management of pleural mesothelioma.

BACKGROUND: Optimal management of diffuse malignant pleural mesothelioma (DMPM) remains unclear. We report our 30-year surgical experience with DMPM with emphasis on surgical procedure and post-operative adjuvant therapy. METHODS: During the period of the study, 217 patients with DMPM were referred for surgical opinion. Patients who only had pleural biopsies were excluded (n=78). Consecutive patients who underwent surgical treatment were included (n=139). Surgical options were extra-pleural pneumonectomy (EPP) for Butchart stage I disease in clinically fit patients (n=49) or pleurectomy/decortication in patients who were either not fit for EPP or had advanced disease (Butchart stage II and III) or both (n=90). Post-operative adjuvant therapy included either chemotherapy, radiotherapy, both or none. RESULTS: The median follow-up was 10.0 months. The longest survival (median 26.0 months, IQR: 11.14-40.9 months) occurred in the pleurectomy/decortication group who received both post-operative chemotherapy and radiotherapy (n=24) (p<0.001). EPP whether or not combined with adjuvant therapy provided no significant survival advantage in comparison to pleurectomy/decortication (overall median survival 10.3 months vs 10.1 months, p=0.09). On univariate analysis, pleurectomy/decortication combined with chemotherapy and radiotherapy was the strongest predictor of prolonged survival (Hazard Ratio=3.6). Multivariate analysis with the inclusion of histological type, surgical procedure and type of adjuvant therapy, EPP without adjuvant therapy was an independent risk-factor for decreased survival (Hazard Ratio=9.2). CONCLUSIONS: In this series, cytoreductive surgery combined with post-operative adjuvant therapy provided better survival despite either advanced disease or surgically less fit patients. Thus, pleurectomy/decortication may be the procedure of choice, given that neither surgical procedure (EPP or PD) is not curative.

What are the characteristics of patients with severe, symptomatic, mitral regurgitation who are denied surgery?

AIM: To identify the proportion and characteristics of patients with severe symptomatic mitral regurgitation (MR) who are denied surgery. METHODS AND RESULTS: In the Euro Heart Survey on valvular heart disease, 396 patients had severe symptomatic MR as assessed by Doppler-echocardiography (grade > or =3/4) and New York Heart Association class II or greater. Patient characteristics were analysed according to the decision to operate or not. A decision not to operate was taken in 193 patients (49%). In multivariable analysis, decreased left ventricular ejection fraction (LVEF) [OR = 1.39 per 10% decrease, 95% CI (1.17-1.66), P = 0.0002], non-ischaemic aetiology [OR = 4.44, 95% CI (1.96-10.76), P = 0.0006], older age [OR = 1.40 per 10-year increase, 95% CI (1.15-1.72), P = 0.001], increased Charlson comorbidity index [OR = 1.38 per 1 point increase, 95% CI (1.12-1.72), P = 0.004], and grade 3 MR [OR = 2.23, 95% CI (1.28-3.29), P = 0.005] were associated with the decision not to operate. One-year survival was 96.0 +/- 1.4% in patients with a positive decision for intervention vs. 89.5 +/- 2.3% in those with a negative decision (P = 0.02). CONCLUSION: Surgery was denied in 49% of patients with severe symptomatic MR. Impaired LVEF, older age, and comorbidity were the most striking characteristics of patients who were denied surgery. The weight of age and LVEF in the decision do not seem justified according to current knowledge.

Increased sensitivity to warfarin after heart valve replacement.

BACKGROUND: The dosage requirement of warfarin to achieve a given international normalized ratio (INR) often varies considerably between the immediate postoperative period and long-term follow-up in patients with prosthetic heart valves, leading to INR instability. OBJECTIVE: To document the extent of warfarin sensitivity in a prospective study of patients receiving heart valve replacements. METHODS: Clinical and laboratory data regarding anticoagulation for 111 patients who received warfarin following heart valve replacement were collected during their hospital stay (induction period) and between 1 and 3 months after surgery (follow-up period). RESULTS: Mean patient age was 65.39 +/- 10.55 years (range 29-85), with 66 men. The mean INR value during the follow-up period was, on average, 0.21 higher than the induction period (2.81 +/- 0.5 vs 2.6 +/- 0.6; p = 0.007). The mean follow-up warfarin dose was 1.54 mg higher than the mean induction warfarin dose (5.09 +/- 2.03 vs 3.55 +/- 1.94 mg; p < 0.001). The warfarin dose index, which indicates relative sensitivity of warfarin, decreased from 1.16 to 0.65 (p < 0.001). Although the INR values during the induction and follow-up periods were similar, the dose requirement in the follow-up period was, on average, 43% higher than that of the induction period. CONCLUSIONS: Immediately after heart valve replacement, patients are more sensitive to warfarin and should receive a lower warfarin dose during the initial phase of oral anticoagulation treatment. This enhanced sensitivity decreases with time. Patients require frequent monitoring and are likely to need an increase in the warfarin dose to avoid insufficient anticoagulation during the early follow-up period.

Bilateral cervical lung hernia with T1 nerve compression.

Lung hernia is a rare condition. Approximately one third of cases occur in the cervical position. We report a case of bilateral cervical lung hernia associated with neuralgic pain that was repaired using bovine pericardium and biological glue.

Long-term outcome of bronchoscopically resected endobronchial typical carcinoid tumors.

BACKGROUND: Typical pulmonary carcinoid tumors represent less than 1% of lung tumors. In a subgroup of patients with this abnormality, the tumor is entirely endobronchial. We assessed the long-term outcome of such cases in which the patient was managed with endobronchial resection only. METHODS: Patients who underwent bronchoscopic resection for a typical carcinoid tumor were identified through case records and histology reports. Data were collected retrospectively, but follow-up was on a prospective basis through the outpatient clinic. RESULTS: Between 1978 and 2004, 28 patients underwent bronchoscopic resection of endobronchial carcinoid tumors. The mean age was 49 years (standard deviation, 19 years; age range, 11-82 years), with 46% (13/28) of the patients being male. The tumor arose from the left bronchial tree in 61% (17/28), with the most common site being the left lower lobe bronchus (8/28). On average, patients required 5 bronchoscopic resections to achieve complete resection. The median follow-up was 8.8 years (interquartile range, 4.5-13.7 years). At 1 and 10 years, 100% and 94% of patients were disease free, respectively. The 1- and 10-year survivals were 89% (interquartile range, 84%-93%) and 84% (interquartile range, 77%-91%), respectively. CONCLUSION: In a selected group of patients, proximal polypoid typical bronchial carcinoid tumors can be treated endobronchially with good outcome.