How real can we get in generating real world evidence? Exploring the opportunities of routinely collected administrative data for evaluation of medical devices.

Real-world data are considered a potentially valuable source of evidence for assessing medical technologies in clinical practice, but their widespread use is hampered by numerous challenges. Using the case of coronary stents in Italy, we investigate the potential of administrative databases for estimating costs and health outcomes associated with the use of medical devices in real world conditions. An administrative dataset was created ad hoc by merging hospital records from patients admitted between 2013 and 2019 for stent implantations with ambulatory records, pharmaceutical use data and vital statistics. Health outcomes were multifold: all-cause and cardiac mortality and myocardial infarction, within 30 days, 1, 2, 5 years. Costs were estimated from the National Health System perspective. We used multivariable Cox models and propensity score (PS) methods (PS matching; stratification on PS; inverse probability of treatment weighting using PS; PS adjustment). 257,907 coronary stents were implanted in 113,912 patients. For all health outcomes and follow-up times, and across all methods, patients receiving drug-eluting stents (DES) presented lower risk. For all-cause mortality, the DES patient advantage over bare-metal stent (BMS) patients declined over time but remained significant even at 5 years. For myocardial infarction, results remained quite stable. The DES group presented lower cumulative total costs (ranging from 3264 to 2363 Euros less depending on methods). Our results confirm the consolidated evidence of the benefits of DES compared to BMS. The consistency of results across methods suggests internal validity of the study, while highlighting strengths and limitations of each depending on research context. Administrative data yield great potential to perform comparative effectiveness and cost-effectiveness analysis of medical devices provided certain conditions are met.

An Analysis of Cost-Effectiveness of Stents Used in the Treatment of Coronary Artery Disease

Background: There is only limited information about the cost-effectiveness of drug-eluting stents compared with bare-metal stents in Turkey. Aims: To evaluate bare-metal and drug-eluting stents used in the treatment of coronary artery disease from the perspective of the reimbursement institution with cost-effectiveness analysis. Study Design: Retrospective cost-effectiveness analysis. Methods: In our study, 329 patients diagnosed with coronary artery disease and treated with bare-metal or drug-eluting stents in the cardiology clinics of a public university hospital between January 1 and December 31, 2016 were investigated. Bare-metal and drug-eluting stents used in the treatment of coronary artery disease were evaluated retrospectively with cost-effectiveness analysis from the perspective of the reimbursement institution. Results: The cost of treatment with a bare-metal stent was 2,131.41 Turkish Liras, and the cost of treatment with a drug-eluting stent was 3,546.14 Turkish Liras; the Quality Adjusted Life Years value of treatment with a bare-metal stent was 0.8371, and the Quality Adjusted Life Years value of treatment with a drug-eluting stent was 0.8924. All these data were analyzed by decision tree. As a result of decision tree analysis, the weighted cost of treatment with a bare-metal stent was 2,340.71 Turkish Liras and weighted Quality Adjusted Life Years value was 0.8332; and the weighted cost of treatment with drug-eluting stent was 3,970.90 Turkish Liras and the weighted Quality Adjusted Life Years value of the treatment with drug-eluting stent was 0.8911. With these values, the additional cost-effectiveness ratio was calculated as 28,179.12 Turkish Liras per acquired Quality Adjusted Life Years. The additional cost-effectiveness ratio is in the first zone in the cost-effectiveness plane and below the very threshold of cost-effectiveness. Conclusion: In our study, it was concluded that drug-eluting stents are cost effective compared with bare-metal stents in the treatment of coronary artery disease. Considering the cost and effectiveness of the drug-eluting stent, it is thought that increasing reimbursement for this technology by the reimbursement agency would be beneficial for the service provider.

Assessment of Second- and Third-Generation Drug-Eluting Stents on Chronic Coronary Angioscopy　- Multicenter Study on Intra-Coronary AngioScopy After Stent (MICASA) Prospective Data Analysis.

BACKGROUND: The vascular response, in terms of quality and quantity, of the second- and third-generation drug-eluting stents (2G- and 3G-DES, respectively) was assessed prospectively on coronary angioscopy (CAS).Methods and Results:The Multicenter study on Intra-Coronary AngioScopy After Stent (MICASA) is a multicenter CAS registry. A total of 107 DES (71 2G- and 36 3G-DES) were prospectively observed on CAS 8.7±2.7 months after percutaneous coronary intervention. Neointimal coverage (NC) grade was evaluated using a 4-point grading scale, from 0 (no coverage) to 3 (complete coverage). Plaque yellow color (YC) was also assessed using a 4-point grading system, from 0 (white) to 3 (bright yellow). Max-NC (2G-DES vs. 3G-DES: 2.14±0.68 vs. 2.44±0.73, P=0.023); min-NC (1.07±0.48 vs. 1.39±0.60, P=0.002), and dominant-NC (1.57±0.69 vs. 2.08±0.84, P=0.002) were significantly higher and the YC grade (1.23±0.82 vs. 0.86±0.76, P=0.031) significantly lower in the 3G-DES group than in the 2G-DES group. There was no significant difference in the presence of thrombus (28.2% vs. 22.2%, P=0.51) between the 2G- and 3G-DES groups. CONCLUSIONS: The higher NC grade and lower YC grade in 3G-DES than in 2G-DES might be associated with better long-term clinical outcome, which remains to be determined in future studies.

[Better regulatory framework needed for medical devices]. / Bättre regelverk behövs för medicintekniska produkter - HTA-utredning av läkemedelsavgivande stentar och ballonger vid benartärsjukdom visar på bristerna.

We summarize an HTA report regarding patient values of drug-eluting stents and balloons for treatment of atherosclerotic disease in the lower extremities. We found 17 randomized controlled trials, 4 cohort studies and 13 case series. The total number of studied patients was substantial (about 3,000) but there was a strong heterogeneity regarding site of lesion, symptom pattern, device, drug used and outcome measures, making the analysis difficult and based on relatively small subgroups. We found low certainty of evidence (GRADE ++) for a reduced risk of restenosis in patients with critical ischemia and lesions below the knee, and also a modest beneficial effect on ischemic symptoms in a mixed patient population. However, we also identified a worrying safety signal, with increased risk for amputation in a group of patients with below-the-knee disease and critical ischemia. The results highlight the need for a structured system for validation of medical devices, a system analogous to that currently used for evaluation of new pharmacological products.

Paclitaxel Drug-Eluting Stents in Peripheral Arterial Disease: A Health Technology Assessment.

BACKGROUND: Peripheral arterial disease is a condition in which atherosclerotic plaques partially or completely block blood flow to the legs. Although percutaneous transluminal angioplasty and metallic stenting have high immediate success rates in treating peripheral arterial disease, long-term patency and restenosis rates in long and complex lesions remain unsatisfactory. OBJECTIVE: The objective of this analysis was to evaluate the clinical effectiveness, safety, cost-effectiveness and budget impact of Zilver paclitaxel self-expanding drug-eluting stents for the treatment of de novo or restenotic lesions in above-the-knee peripheral arterial disease. DATA SOURCES: Literature searches were performed using Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid Embase, EBSCO Cumulative Index to Nursing & Allied Health Literature (CINAHL), and EBM Reviews. For the economic review, a search filter was applied to limit search results to economics-related literature. Data sources for the budget impact analysis included expert opinion, published literature, and Ontario administrative data. REVIEW METHODS: Systematic reviews, meta-analyses, randomized controlled trials, and observational studies were included in the clinical effectiveness review, and full economic evaluations were included in the economic literature review. Studies were included if they examined the effect of Zilver paclitaxel drug-eluting stents in de novo or restenotic lesions in above-the-knee arteries. For the budget impact analysis, 3 scenarios were constructed based on different assumptions. RESULTS: One randomized controlled trial reported a significantly higher patency rate with Zilver paclitaxel drug-eluting stents for lesions ≤ 14 cm than with angioplasty or bare metal stents. One observational study showed no difference in patency rates between Zilver paclitaxel drug-eluting stents and paclitaxel drug-coated balloons. Zilver paclitaxel drug-eluting stents were associated with a significantly higher event-free survival rate than angioplasty, but the event-free survival rate was similar for Zilver paclitaxel drug-eluting stents and paclitaxel drug-coated balloons. No economic evaluations compared Zilver paclitaxel drug-eluting stents with bare metal stents or angioplasty for peripheral arterial disease. A budget impact analysis showed that the cost savings associated with funding of Zilver paclitaxel drug-eluting stents would be $470,000 to $640,000 per year, assuming that the use of the Zilver paclitaxel drug-eluting stent was associated with a lower risk of subsequent revascularization. CONCLUSIONS: Based on evidence of low to moderate quality, Zilver paclitaxel drug-eluting stents were associated with a higher patency rate than angioplasty or bare metal stents, and with fewer adverse events than angioplasty. The effectiveness and safety of Zilver paclitaxel drug-eluting stents and paclitaxel drug-coated balloons were similar.

Socioeconomic inequalities in quality of care and outcomes among patients with acute coronary syndrome in the modern era of drug eluting stents.

BACKGROUND: The rapidly changing landscape of percutaneous coronary intervention provides a unique model for examining disparities over time. Previous studies have not examined socioeconomic inequalities in the current era of drug eluting stents (DES). METHODS AND RESULTS: We analyzed 835 070 hospitalizations for acute coronary syndrome (ACS) from the Healthcare Cost and Utilization Project across all insurance types from 2008 to 2011, examining whether quality of care and outcomes for patients with ACS differed by income (based on zip code of residence) with adjustment for patient characteristics and clustering by hospital. We found that lower-income patients were less likely to receive an angiogram within 24 hours of a ST elevation myocardial infarction (STEMI) (69.5% for IQ1 versus 73.7% for IQ4, P<0.0001, OR 0.79 [0.68 to 0.91]) or within 48 hours of a Non-STEMI (47.6% for IQ1 versus 51.8% for IQ4, P<0.0001, OR 0.86 [0.75 to 0.99]). Lower income was associated with less use of a DES (64.7% for IQ1 versus 71.2% for IQ4, P<0.0001, OR 0.83 [0.74 to 0.93]). However, no differences were found for coronary artery bypass surgery. Among STEMI patients, lower-income patients also had slightly increased adjusted mortality rates (10.8% for IQ1 versus 9.4% for IQ4, P<0.0001, OR 1.17 [1.11 to 1.25]). After further adjusting for time to reperfusion among STEMI patients, mortality differences across income groups decreased. CONCLUSIONS: For the most well accepted procedural treatments for ACS, income inequalities have faded. However, such inequalities have persisted for DES use, a relatively expensive and until recently, controversial revascularization procedure. Differences in mortality are significantly associated with differences in time to primary PCI, suggesting an important target for understanding why these inequalities persist.

Evaluation of a policy of selective drug-eluting stent implantation for patients at high risk of restenosis.

Drug-eluting stent (DES) deployment during percutaneous coronary intervention (PCI) has reduced target-vessel revascularisation rates (TVR). The selective use of DES in patients at highest risk of restenosis may allay concerns about universal compliance of dual antiplatelet therapy for one year, and potentially reduce costs. If this strategy achieved acceptably low TVR rates, such an approach could be attractive. Late clinical outcomes were examined in 2115 consecutive patients (mean age 63±12 years, 75% male, 22% diabetics) who underwent PCI in the first three years from October 2003, after commencing the following selective criteria for DES use: left main stenosis; ostial lesions of major epicardial arteries; proximal LAD lesions; lesions≥20mm in length with vessel diameter≤3.0mm; lesions in vessels≤2.5mm; diabetics with vessel(s)≤3.0mm; and in-stent restenosis. Among patients undergoing PCI, 2075 (98%) patients received stents (29%≥1 DES and 71% bare metal stent [BMS]), and among those who received DES, there was a 92% compliance with these criteria. There were no differences in clinical outcomes between the two stent groups except for definite stent thrombosis, which occurred in 2% after DES, and 0.6% after BMS at one year (p=0.002). With BMS, large coronary arteries (≥3.5mm), intermediate (3-3.49mm) and small arteries (<3mm) in diameter had a TVR rate at one year of 3.6%, 7.2% and 8.2% respectively (p=0.005). It is possible to use selective criteria for DES while maintaining low TVR rates. The TVR rate with BMS was low in those with stent diameters≥3.5mm. The higher DES stent thrombosis rate reflects first generation DES use, though whether routine second generation DES use reduces these rates needs confirmation.

Angioscopic assessment of arterial repair following biodegradable polymer-coated biolimus A9-eluting stent implantation. - Comparison with durable polymer-coated sirolimus-eluting stent-.

BACKGROUND: Second-generation drug-eluting stents (DES) are expected to show better arterial repair than older DES. We angioscopically compared the biodegradable polymer-coated biolimus A9-eluting stent (BES) and durable polymer-coated sirolimus-eluting stent (SES) to explore differences in arterial repair. METHODS AND RESULTS: Angioscopy was performed 9 ± 1 months after 15 BES and 16 SES were implanted initially in the native coronary artery. Heterogeneity of neointimal coverage (NIC) as well as the dominant NIC grade was examined. NIC was defined as: grade 0 = fully visible struts; grade 1 = struts bulging into the lumen, but covered; grade 2 = embedded, but translucent struts; grade 3 = invisible struts. Heterogeneity was judged when the NIC grade varied ≥ 1. In-stent late loss (0.06 ± 0.23 vs. 0.07 ± 0.18 mm, P = 0.80), and dominant NIC grade (1.5 ± 0.8 vs. 1.3 ± 0.7, P = 0.45) were similar for BES and SES. Within the stents, NIC was more heterogeneous in SES than in BES (P = 0.035). 80% of BES showed homogeneous NIC, while 56% of SES had heterogeneous NIC. CONCLUSIONS: BES showed limited late loss similar to that for SES. Nonetheless, the NIC with BES was more homogeneous than that with SES. Biodegradable polymer-coated BES may have an advantage in homogeneous NIC.

Colonic stents: the modern treatment of colonic obstruction.

Colonic stents traditionally have been used for the management of colorectal cancer, either as a palliative treatment or as a bridge to surgery. More recently, colonic stents have also been advocated as part of the therapy of benign strictures. A number of colonic stents are available worldwide, four of which are made in the USA. These stents are classified as covered or uncovered, with similar clinical applications. Technical and clinical success rates are similar among these different stents, as well as the rate of complications, which mainly consist of obstruction and migration. The deployment systems utilize fluoroscopy, endoscopy, or both. More recently, stents became available that are deployed "through the scope" (TTS) making the procedure faster. However, this advance does not exclude the use of fluoroscopy, particularly in those cases where the direct visualization of the proximal end of the stricture is absent. The increasing experience in the management of colorectal cancer with colonic stents decreases the morbidity and mortality, as well as cost, in comparison with surgical intervention for acute colonic obstruction. Management with colonic stents can also rule out proximal synchronous lesions after initial decompression prior to definitive surgery. Benign conditions may also be treated with stents. A multidisciplinary approach for the use of colonic stents during assessment and management of acute colonic obstruction is necessary in order to achieve a satisfactory outcome, whether that be better quality of life or improved survival.

A comparative assessment by optical coherence tomography of the performance of the first and second generation of the everolimus-eluting bioresorbable vascular scaffolds.

AIMS: The first generation of the everolimus-eluting bioresorbable vascular scaffold (BVS 1.0) showed an angiographic late loss higher than the metallic everolimus-eluting stent Xience V due to scaffold shrinkage. The new generation (BVS 1.1) presents a different design and manufacturing process than the BVS 1.0. This study sought to evaluate the differences in late shrinkage, neointimal response, and bioresorption process between these two scaffold generations using optical coherence tomography (OCT). METHODS AND RESULTS: A total of 12 lesions treated with the BVS 1.0 and 12 selected lesions treated with the revised BVS 1.1 were imaged at baseline and 6-month follow-up with OCT. Late shrinkage and neointimal area (NIA) were derived from OCT area measurements. Neointimal thickness was measured in each strut. Strut appearance has been classified as previously described. Baseline clinical, angiographic, and OCT characteristics were mainly similar in the two groups. At 6 months, absolute and relative shrinkages were significantly larger for the BVS 1.0 than for the BVS 1.1 (0.98 vs. 0.07 mm² and 13.0 vs. 1.0%, respectively; P = 0.01). Neointimal area was significantly higher in the BVS 1.0 than in the BVS 1.1 (in-scaffold area obstruction of 23.6 vs. 12.3%; P < 0.01). Neointimal thickness was also larger in the BVS 1.0 than in the BVS 1.1 (166.0 vs. 76.4 µm; P < 0.01). Consequently, OCT, intravascular ultrasound, and angiographic luminal losses were higher with the BVS 1.0 than with the BVS 1.1. At 6 months, strut appearance was preserved in only 2.9% of the BVS 1.0 struts, but remained unchanged with the BVS 1.1 indicating different state of strut microstucture and/or their reflectivity. CONCLUSION: The BVS 1.1 has less late shrinkage and less neointimal growth at 6-month follow-up compared with the BVS 1.0. A difference in polymer degradation leading to changes in microstructure and reflectivity is the most plausible explanation for this finding.

Value of the SYNTAX score for risk assessment in the all-comers population of the randomized multicenter LEADERS (Limus Eluted from A Durable versus ERodable Stent coating) trial.

OBJECTIVES: We aimed to assess the predictive value of the SYNTAX score (SXscore) for major adverse cardiac events in the all-comers population of the LEADERS (Limus Eluted from A Durable versus ERodable Stent coating) trial. BACKGROUND: The SXscore has been shown to be an effective predictor of clinical outcomes in patients with multivessel disease undergoing percutaneous coronary intervention. METHODS: The SXscore was prospectively collected in 1,397 of the 1,707 patients enrolled in the LEADERS trial (patients after surgical revascularization were excluded). Post hoc analysis was performed by stratifying clinical outcomes at 1-year follow-up, according to 1 of 3 SXscore tertiles. RESULTS: The 1,397 patients were divided into tertiles based on the SXscore in the following fashion: SXscore8 and 16 (SXhigh) (n=461). At 1-year follow-up, there was a significantly lower number of patients with major cardiac event-free survival in the highest tertile of SXscore (SXlow=92.2%, SXmid=91.1%, and SXhigh=84.6%; p<0.001). Death occurred in 1.5% of SXlow patients, 2.1% of SXmid patients, and 5.6% of SXhigh patients (hazard ratio [HR]: 1.97, 95% confidence interval [CI]: 1.29 to 3.01; p=0.002). The myocardial infarction rate tended to be higher in the SXhigh group. Target vessel revascularization was 11.3% in the SXhigh group compared with 6.3% and 7.8% in the SXlow and SXmid groups, respectively (HR: 1.38, 95% CI: 1.1 to 1.75; p=0.006). Composite of cardiac death, myocardial infarction, and clinically indicated target vessel revascularization was 7.8%, 8.9%, and 15.4% in the SXlow, SXmid, and SXhigh groups, respectively (HR: 1.47, 95% CI: 1.19 to 1.81; p<0.001). CONCLUSIONS: The SXscore, when applied to an all-comers patient population treated with drug-eluting stents, may allow prospective risk stratification of patients undergoing percutaneous coronary intervention. (LEADERS Trial Limus Eluted From A Durable Versus ERodable Stent Coating; NCT00389220).

The interface of medical devices and pharmaceuticals: Part II.

The technical challenges of developing combination products were addressed in Part I of this two part article. Part II reviews the preclinical tests and shelf-life testing that are required using drug eluting stents and drug eluting beads as examples. Regulatory considerations and ways to simplify development are also examined.