Claims-based cardiovascular outcome identification for clinical research: Results from 7 large randomized cardiovascular clinical trials.

BACKGROUND: Medicare insurance claims may provide an efficient means to ascertain follow-up of older participants in clinical research. We sought to determine the accuracy and completeness of claims- versus site-based follow-up with clinical event committee (+CEC) adjudication of cardiovascular outcomes. METHODS: We performed a retrospective study using linked Medicare and Duke Database of Clinical Trials data. Medicare claims were linked to clinical data from 7 randomized cardiovascular clinical trials. Of 52,476 trial participants, linking resulted in 5,839 (of 10,497 linkage-eligible) Medicare-linked trial participants with fee-for-service A and B coverage. Death, myocardial infarction (MI), stroke, and revascularization incidences were compared using Medicare inpatient claims only, site-reported events (+CEC) only, or a combination of the 2. Randomized treatment effects were compared as a function of whether claims-based, site-based (+CEC), or a combined system was used for event detection. RESULTS: Among the 5,839 study participants, the annual event rates were similar between claims- and site-based (+CEC) follow-up: death (overall rate 5.2% vs 5.2%; adjusted κ 0.99), MI (2.2% vs 2.3%; adjusted κ 0.96), stroke (0.7% vs 0.7%; adjusted κ 0.99), and any revascularization (7.4% vs 7.9%; adjusted κ 0.95). Of events detected by claims yet not reported by CEC, a minority were reported by sites but negatively adjudicated by CEC (39% of MIs and 18% of strokes). Differences in individual case concordance led to higher event rates when claims- and site-based (+CEC) systems were combined. Randomized treatment effects were similar among the 3 approaches for each outcome of interest. CONCLUSIONS: Claims- versus site-based (+CEC) follow-up identified similar overall cardiovascular event rates despite meaningful differences in the events detected. Randomized treatment effects were similar using the 2 methods, suggesting claims data could be used to support clinical research leveraging routinely collected data. This approach may lead to more effective evidence generation, synthesis, and appraisal of medical products and inform the strategic approaches toward the National Evaluation System for Health Technology.

Use of endpoint adjudication to improve the quality and validity of endpoint assessment for medical device development and post marketing evaluation: Rationale and best practices. A report from the cardiac safety research consortium.

This white paper provides a summary of presentations, discussions and conclusions of a Thinktank entitled "The Role of Endpoint Adjudication in Medical Device Clinical Trials". The think tank was cosponsored by the Cardiac Safety Research Committee, MDEpiNet and the US Food and Drug Administration (FDA) and was convened at the FDA's White Oak headquarters on March 11, 2016. Attention was focused on tailoring best practices for evaluation of endpoints in medical device clinical trials, practical issues in endpoint adjudication of therapeutic, diagnostic, biomarker and drug-device combinations, and the role of adjudication in regulatory and reimbursement issues throughout the device lifecycle. Attendees included representatives from medical device companies, the FDA, Centers for Medicare and Medicaid Services (CMS), end point adjudication specialist groups, clinical research organizations, and active, academically based adjudicators. The manuscript presents recommendations from the think tank regarding (1) rationale for when adjudication is appropriate, (2) best practices establishment and operation of a medical device adjudication committee and (3) the role of endpoint adjudication for post market evaluation in the emerging era of real world evidence.

Long-Term Clinical Outcomes of Silzone Era St. Jude Medical Mechanical Heart Valves.

BACKGROUND AND AIM OF THE STUDY: Since the voluntary recall of St. Jude Medical (SJM) Silzone impregnated heart valves, no large-scale study has examined their long-term outcomes. METHODS: Using Medicare-linked records from the Society of Thoracic Surgeons Adult Cardiac Surgery Database (1993-2004), the clinical outcomes were evaluated through eight years among those patients who received SJM mechanical heart valves during the Silzone era (March 1998 to December 1999; n = 3,775), relative to those in both the pre-Silzone era (January 1993 to February 1998; n = 13,570) and the post-Silzone era (January 2000 to December 2004; n = 6,882). An inverse probability weighting was used to balance the observed differences in case mix. RESULTS: During the Silzone era, 79% of all implanted mechanical heart valves were manufactured by SJM. By eight years post-implantation, the most common adverse events in this Medicare-linked cohort (median age 71 years) were death (43.5%) and thromboembolism (14.7%), while valve reoperation (1.7%) and endocarditis (1.4%) were less common. Patients treated during the Silzone era experienced a lower associated risk of mortality to eight years than those in both the pre-Silzone era (adjusted hazards ratio (HR) 0.93, 95% confidence interval (CI) 0.88-0.98) and post-Silzone era (adjusted HR 0.92, CI 0.67-0.98), while the adjusted eight-year risks of reoperation, thromboembolism and endocarditis were similar across the three eras for the overall cohort and among both aortic valve and mitral valve patients. CONCLUSION: Medicare patients who received SJM mechanical heart valves during the Silzone era experienced similar clinical outcomes as those treated before or after the Silzone era. These data do not substantiate continued public health concerns associated with Silzone era valve prostheses among older individuals.

Integrating Patient-Generated Health Data Throughout the Total Product Life Cycle of Medical Devices.

Nearly ubiquitous use of personal electronics, wearable sensors, and other types of digital health technologies, along with wireless connectivity, makes the capture of health data directly from an individual easier, enabling the use of patient-generated health data (PGHD) as a potential bridge between a patient's home and the healthcare system. This type of real-world data may be a completely new type of information, or it may be a more frequent collection of traditional information over longer time periods to form a longitudinal view of a patient's health status that can inform decision-making in clinical, medical product regulatory, and coverage and reimbursement settings. The U.S. Food and Drug Administration's Center for Devices and Radiological Health (CDRH) has been exploring and advancing the collection and use of PGHD since 2016, hosting a public meeting on the topic in May 2021. This manuscript presents highlights from various discussions at this meeting including those on the importance of stakeholder engagement, characteristics of high data quality, and PGHD in practice in patient-driven registries, as well as a look forward to some of the opportunities in the field.

Evaluation of cardiovascular implantable electronic device leads post implant: ElectroPhysiology Predictable And SuStainable Implementation Of National Registries (EP PASSION).

Post-market evaluation is important to ensure the ongoing safety and effectiveness of cardiovascular implantable electronic device (CIED) leads. The Twenty-First Century Cures Act and subsequent Food and Drug Administrative (FDA) Guidance provide an opportunity to leverage real-world data sources for this purpose. The past 4 years have seen the development of EP PASSION: a multi-stakeholder, collaborative effort between the FDA, CIED manufacturers, Heart Rhythm Society, and academics. Using real-world data, EP PASSION enables longitudinal evaluation of the long-term safety of CIED leads, addressing limitations of current approaches to generate evidence that informs regulatory, clinical, and manufacturer decision-making. This state of the art article describes the impetus for and launch of EP PASSION, the lessons learned, its current state, the current analytic approach, and the strengths and limitations of leveraging extant data sources for post-market lead evaluation. We also compare EP PASSION to traditional post-approval studies and describe possible future directions.

Disproportionality analysis for signal detection of implantable cardioverter-defibrillator-related adverse events in the Food and Drug Administration Medical Device Reporting System.

BACKGROUND: The Food and Drug Administration (FDA) became aware of lead fracture and inappropriate shock events related to Sprint Fidelis leads in January 2007. The manufacturer announced a voluntary market withdrawal in October 2007. AIM: Our aim was to retrospectively evaluate this safety signal using disproportionality analysis to estimate whether disproportionality analysis could have detected this particular safety signal earlier than actually occurred. MATERIALS AND METHODS: The Manufacturer and User Facility Device Experience (MAUDE) database contains reports on device-related adverse events, of which, FDA receives several hundred thousand every year. For each manufacturer, a list of the top lead brand names was ranked by frequency of reports. We used the Multi-item Gamma Poisson Shrinker (MGPS) method for analysis. We isolated 11 top-reported implantable cardioverter defibrillator (ICD) lead brand names. Using MGPS methodology, we calculated the one-sided 95% lower confidence bound EB05 on the empirical Bayes geometric mean of the reporting ratio. RESULTS: We performed individual MGPS analysis for each of the top reported adverse events in 2006 for ICD leads. Fidelis had the highest EB05 scores for lead fractures and inappropriate shock. DISCUSSION: Through disproportionality analysis of the MAUDE database, we were able to identify known safety signals associated with the Medtronic Sprint Fidelis lead. CONCLUSION: If utilized at the time, this disproportionality analysis would have identified signals earlier for lead fractures, oversensing, high impedance, and inappropriate shock.

Planning the Safety of Atrial Fibrillation Ablation Registry Initiative (SAFARI) as a Collaborative Pan-Stakeholder Critical Path Registry Model: a Cardiac Safety Research Consortium "Incubator" Think Tank.

Atrial fibrillation (AF) is a major public health problem in the United States that is associated with increased mortality and morbidity. Of the therapeutic modalities available to treat AF, the use of percutaneous catheter ablation of AF is expanding rapidly. Randomized clinical trials examining the efficacy and safety of AF ablation are currently underway; however, such trials can only partially determine the safety and durability of the effect of the procedure in routine clinical practice, in more complex patients, and over a broader range of techniques and operator experience. These limitations of randomized trials of AF ablation, particularly with regard to safety issues, could be addressed using a synergistically structured national registry, which is the intention of the SAFARI. To facilitate discussions about objectives, challenges, and steps for such a registry, the Cardiac Safety Research Consortium and the Duke Clinical Research Institute, Durham, NC, in collaboration with the US Food and Drug Administration, the American College of Cardiology, and the Heart Rhythm Society, organized a Think Tank meeting of experts in the field. Other participants included the National Heart, Lung and Blood Institute, the Centers for Medicare and Medicaid Services, the Agency for Healthcare Research and Quality, the Society of Thoracic Surgeons, the AdvaMed AF working group, and additional industry representatives. The meeting took place on April 27 to 28, 2009, at the US Food and Drug Administration headquarters in Silver Spring, MD. This article summarizes the issues and directions presented and discussed at the meeting.

Trends and Outcomes of Catheter Ablation for Ventricular Tachycardia in a Community Cohort.

OBJECTIVES: This study examined the trend in growth of catheter ablation for ventricular tachycardia (VT) performed in the United States with analysis of rates and predictors of major adverse events. BACKGROUND: Sustained VT is a significant cause of sudden death, heart failure (HF), and recurrent shocks in implantable cardioverter-defibrillator (ICD) recipients. Catheter ablation for VT reduces arrhythmia recurrence. Limited data are available regarding the use, safety, and long-term outcomes after VT ablation. METHODS: Using the U.S. Medicare database linked to the Social Security Death Index, we examined the annual use of VT ablation in 21,073 patients over 12 years, with 30-day risk of mortality, nonfatal major adverse events (MAEs), 1-year risk of mortality, re-hospitalization, repeat ablation, and factors associated with adverse outcomes. RESULTS: Among 21,073 patients (age 70 ± 9 years; 77% men; 90% white), there were 1,581 (7.5%) non-fatal MAEs within 30 days. There were 963 (4.6%) vascular complications, 485 (2.3%) pericardial complications, and 201 (1%) strokes and/or transient ischemic attacks. Mechanical circulatory support use was infrequent (2.3%). The 30-day and 1-year mortality rates were 4.2% and 15.0%, respectively. The 1-year incidence of repeat ablation was 10.2 per 100 person-years and re-hospitalization for HF or VT was 15.4 per 100 person-years and 18 per 100 person-years, respectively. Patients with an ICD had increased 30-day (4.9% vs. 0.86%) and 1-year mortality (17.5% vs. 2.54% [22.9 per 100 person-years vs. 3.1 per 100 person-years]; hazard ratio [HR]: 2.93; 95% confidence interval [CI]: 2.21 to 3.88). Rates of hospitalization for HF (18 per 100 person-years vs. 1.8 per 100 person-years; HR: 4.00; 95% CI: 2.78 to 5.78) or VT recurrence (22.7 per 100 person-years vs. 2.1 per 100 person-years; HR: 5.70; 95% CI: 4.09 to 7.96) were also higher at 1 year. Between 2000 and 2012, annual VT ablation volumes increased >4-fold. CONCLUSIONS: Catheter ablation for VT is frequently performed. Short-term MAEs and 1-year mortality is significant and is highest in patients with an ICD. These findings may provide greater insight of outcomes in an unselected real-world population undergoing VT ablation.

Sex-Specific Outcomes After Transcatheter Aortic Valve Replacement: A Review of the Literature.

Transcatheter aortic valve replacement (TAVR) is a safe and effective therapy for aortic valve replacement in patients ineligible for or at high risk for surgery. However, outcomes after TAVR based on an individual's sex remain to be fully elucidated. We searched PUBMED and EMBASE using the keywords: "transcatheter aortic valve replacement," "transcatheter aortic valve implantation," "sex differences," "gender," "sex characteristics" and collected information on baseline features, procedural characteristics, and postprocedural outcomes in women. Inclusion/exclusion resulted in 23 publications. Women had less preexisting comorbidities than men. Most studies reported better survival in women (range of hazard ratio [95% CI] = 0.27 [0.09-0.84] to 0.91 [0.75-1.10]). At 30 days, women also had more vascular complications (6-20% vs 2-14%) and higher bleeding rates (10-44% vs 8-25%). Stroke rates were similar at 30 days (women, 1-7%; men, 1-5%). This literature review showed better survival in women than men after TAVR. However, women had more vascular complications and bleeding; stroke rates were similar. These findings may partly be explained by fewer baseline comorbidities in women. These results should be interpreted with caution as most measures only include unadjusted percentages.

Sex-Specific Outcomes After Transcatheter Aortic Valve Replacement: FDA Patient-Level Meta-Analysis of Premarket Clinical Trials.

BACKGROUND: Transcatheter aortic valve replacement (TAVR) is a less invasive alternative approach to surgery. Individual randomized clinical trials evaluating the safety and efficacy of TAVR were mostly underpowered for conducting separate analyses for women and men. We pooled data from premarket TAVR clinical trials comparing short (30 days)- and long-term (∼2 years) outcomes by sex. METHODS: Patient-level data from the TAVR arms of six clinical trials were pooled (2515 patients). Random-effects models for time-to-event outcomes (odds ratios [ORs] for 30-day outcomes and hazard ratios [HRs] for complete follow-up for mortality, ischemic stroke, kidney injury, major bleeding, myocardial infarction, and device migration) and dichotomous outcomes (ORs for reintervention, rehospitalization, and pacemaker implantation) were then fit to directly compare outcomes between women and men. RESULTS: Overall, the pattern of individual comorbidities was more severe in men. There was no difference in mortality risk at 30 days (female-to-male OR = 1.00 [0.69-1.46]); however, at follow-up completion (∼2 years post-TAVR), women had a 24% lower mortality risk than men (HR = 0.76 [95% CI: 0.65-0.89]). Women also had a 30% lower risk of kidney injury at 30 days (OR = 0.70 [0.49-0.98]), which increased to 33% over the complete follow-up period (HR = 0.67 [0.51-0.87]). Major bleeding was more common in women compared to men at both 30 days (OR = 1.44 [1.19-1.76]) and long-term follow-up (HR = 1.22 [1.04-1.43]). For dichotomous outcomes, women had a 68% lower risk for reinterventions (OR = 0.32 [0.18-0.58]). We did not observe any difference in the risk of ischemic stroke, myocardial infarction, device migration, rehospitalizations, or pacemaker implantations between sexes. CONCLUSIONS: This patient-level data meta-analysis of six premarket clinical trials found that women who received TAVR had fewer comorbidities at baseline. Acute outcomes (30 day) with respect to mortality were similar. Women were observed to have a lower risk of kidney injury, but higher risk of major bleeding compared to men receiving TAVR at 30 days. At complete follow-up, statistically significant advantages for women emerged in improved survival and lower reintervention risk. No differences in ischemic stroke, pacemaker implantation, or rehospitalization were observed. That women are healthier at baseline and develop fewer postprocedural complications than men may explain their higher survival.

Improving Heart Failure Therapeutics Development in the United States: The Heart Failure Collaboratory.

The current heart failure clinical trial environment is strained by increasing complexity and cost, regulatory requirements, competing demands on stakeholders, implementation challenges, and decreasing patient and investigator participation. To begin the process of developing potentially effective strategies and tactics, stakeholders including patients; investigators; academic leaders; pharmaceutical and device industry representatives; society representatives; third-party payers; and government representatives from the U.S. Food and Drug Administration, National Institutes of Health, and Centers for Medicare and Medicaid Services convened in March of 2017. This paper summarizes the discussions, outlines current challenges and actionable opportunities, and makes targeted recommendations to achieve the goals of improving efficiency in clinical trials and speeding the development of effective heart failure therapies, including the formation of an organized Heart Failure Collaboratory.

Preprocedure hyperglycemia is more strongly associated with restenosis in diabetic patients after percutaneous coronary intervention than is hemoglobin A1C.

BACKGROUND: Although more frequent in diabetic patients, restenosis after percutaneous coronary intervention (PCI) is less common in those with good glycemic control. High circulating insulin levels may also be associated with more frequent restenosis. METHODS: Fasting blood samples were obtained from 162 diabetic patients immediately prior to the PCI and analyzed for glucose, hemoglobin A1C, and insulin. Nine-month follow-up information was obtained in 145 (89.5%) patients. Target vessel revascularization (TVR) was the surrogate for restenosis. RESULTS: Patients were divided into quartiles with regard to their blood levels. Insulin, calculated insulin resistance, and hemoglobin A1C were not associated with increased TVR rates. Glucose level was significantly associated (P=.02). Patients in the two lower quartiles (glucose < or = 128 mg/dl) had a 9-month TVR rate of 12.7% while those in the two higher quartiles (>128 mg/dl) had a rate of 33.8% (P=.005). Level of glucose was independent of hemoglobin A1C. In patients whose A1C level was < or = 7%, the TVR rate was greater in those with a glucose level >128 mg/dl (39.1% vs. 10.6%, P=.009). Similarly, in patients with a hemoglobin A1C level >7%, the TVR rate was lower in patients with a glucose level < or = 128 mg/dl, but this difference did not reach statistical significance (16.6% vs. 31.3%, P=.3). CONCLUSIONS: Hemoglobin A1C, insulin, and insulin resistance at the time of the PCI are not associated with restenosis. Periprocedural hyperglycemia may promote restenosis in diabetics.

Impact of chronic renal insufficiency on clinical outcomes in patients undergoing percutaneous coronary intervention with sirolimus-eluting stents versus bare metal stents.

Patients with chronic renal insufficiency (CRI) have higher rates of target vessel revascularization and mortality. The efficacy of sirolimus-eluting stents (SESs) to improve the clinical outcomes of these patients is unknown. We investigated the effect of SESs versus bare metal stents (BMSs) on outcomes of patients with CRI. Among the first 1,522 patients treated with SESs, 76 were identified with CRI and 1,446 without CRI. In-hospital and 1- and 6-month clinical outcomes were compared with 153 patients with CRI who were treated with BMSs. Patients with CRI were older, hypertensive, and diabetic and had more previous myocardial infarctions, revascularizations, and decreased left ventricular function (p <0.001). These patients had more saphenous vein graft lesions, were treated with more debulking devices (p <0.003), and had higher rates of in-hospital complications and mortality (p <0.001) compared with those without CRI. Among patients with CRI, treatment with SESs did not affect clinical outcomes at 1 month and was associated with lower incidences of target vessel revascularization (7.1% vs 22.1%, p = 0.02) at 6 months but did not affect other events, including mortality (16.7% vs 14.7% p = 0.89), compared with BMSs. However, treatment with SESs in patients without CRI was associated with significantly lower rates of major adverse cardiac events at 6 months (p <0.001). In conclusion, percutaneous coronary intervention with SESs in patients with CRI is associated with low rates of repeat revascularization compared with BMSs but has no effect on mortality at 6 months.

Improving the Safety and Effectiveness of Medical Device Therapy in Women.

When not enough women are included in many clinical trials, an information gap on medical device safety and effectiveness exists, which can make it difficult to detect sex-specific results. In this article we discuss potential reasons for the underrepresentation of women and the regulatory research conducted by the U.S. Food and Drug Administration (FDA) used in supporting regulatory decisions. We demonstrate that important differences in cardiovascular device performance between women and men exist. Furthermore, concrete steps are outlined on the possible ways these sex-specific results can be detected and how a recent FDA Action Plan and Guidance Document aim at encouraging female participation in clinical trials and the appropriate analysis thereof.

Toward Sex-Specific Guidelines for Cardiac Resynchronization Therapy?

An important treatment for patients with heart failure is cardiac resynchronization therapy (CRT). Even though only 20% of women were included in clinical trials for CRT, a benefit has been shown in recent studies for subgroups of women compared to their male counterparts. Given this low inclusion rate of women in clinical studies, professional society guideline-based CRT recommendations, such as those by the American College of Cardiology Foundation (ACCF)/American Heart Association (AHA)/Heart Rhythm Society (HRS), may not truly represent the best treatment for women, especially since most of the reports that showed this greater benefit in women were published after the latest guidelines. Despite having research and multiple publications regarding sex-specific heart failure outcomes and response to CRT, the ACCF/AHA/HRS guidelines have not yet been updated to account for the recent information regarding the differences in benefit for women and men with similar patient characteristics. This review discusses the physiology behind CRT, sex-specific characteristics of heart failure, and cardiac electrophysiology and summarizes the current sex-specific literature to encourage consideration of CRT guidelines for women and men separately.

Predictors of subacute stent thrombosis: results of a systematic intravascular ultrasound study.

BACKGROUND: Factors leading to subacute stent thrombosis after percutaneous coronary intervention (PCI) have not been well established. We assessed the pre- and post-PCI intravascular ultrasound (IVUS) characteristics of subacute stent thrombosis. METHODS AND RESULTS: We analyzed 7484 consecutive patients without acute myocardial infarction who were treated with PCI and stenting and underwent IVUS imaging during the intervention. Twenty-seven (0.4%) had angiographically documented subacute closure <1 week after PCI (median time to subacute closure, 24 hours). Subacute closure lesions were compared with a control group (selected to be 3 times the abrupt closer group) matched by procedure date (within 6 months), age, gender, stable or unstable angina, lesion location, and additional treatment (balloon angioplasty or atherectomy). Postintervention IVUS did not identify a cause in 22% and did identify at least 1 cause for abrupt closure in 78% of patients (versus 33% in matched lesions, P=0.0002). In 48% of the patients, there were multiple causes in 48% (versus 3% in matched lesions, P<0.0001). Causes included dissection (17%), thrombus (4%), and tissue protrusion within the stent struts leading to lumen compromise lumen (4%). A total of 83% of patients with >1 of these abnormal morphologies also had reduced lumen dimensions post-PCI (final lumen <80% reference lumen). Preprocedural lesion characteristics were not different from matched lesions. CONCLUSIONS: Subacute stent thrombosis is infrequently related to the preintervention lesion characteristics. Inadequate postprocedure lumen dimensions, alone or in combination with other procedurally related abnormal lesion morphologies (dissection, thrombus, or tissue prolapse), contribute to this phenomenon.

Association of serum antibodies to heat-shock protein 65 with coronary calcification levels: suggestion of pathogen-triggered autoimmunity in early atherosclerosis.

BACKGROUND: Previous studies demonstrated an association between antibodies to mycobacterial heat-shock protein 65 (mHSP65) and carotid artery thickening. We examined whether mHSP65 antibodies are associated with levels of coronary calcification that appear to reflect preclinical coronary artery disease (CAD). METHODS AND RESULTS: Serum specimens from 201 healthy asymptomatic subjects (52% male; mean age, 56.6 years) undergoing electron-beam computed tomographic imaging were used to measure levels of mHSP65 and human HSP60 antibodies and antibodies to several infectious pathogens. We found that 84% of the study subjects had anti-mHSP65 IgG antibodies. Mean titers of mHSP65 antibodies were higher (1:394 versus 1:267, P=0.012) in individuals with than in those without elevated levels of coronary calcium (calcium score > or =150). Increasing titers of mHSP65 antibodies were significantly associated, in a dose-response manner, with elevated levels of coronary calcification. Individuals with the highest titers of mHSP65 antibodies (> or =1:800) had an adjusted odds ratio (OR) of 14.3 for having elevated coronary calcium (P=0.004). Association of mHSP65 antibodies with elevated coronary calcification levels was independent of CAD risk factors after multivariate adjustment (P=0.037). Interestingly, mHSP65 antibody titers were correlated with Helicobacter pylori infection (P=0.004), which maintained significance after adjustment for CAD risk factors and seropositivities to other pathogens (adjusted OR, 3.1; 95% CI, 1.4 to 6.6). No association was found between antibodies to human HSP60 and levels of coronary calcification. CONCLUSIONS: Antibodies to mHSP65 are associated with elevated levels of coronary calcification and correlated with H pylori infection, suggesting that pathogen-triggered autoimmunity plays a role in early atherosclerosis.

Stroke complicating percutaneous coronary interventions: incidence, predictors, and prognostic implications.

BACKGROUND: Stroke associated with percutaneous coronary intervention (PCI) is an infrequent although devastating complication. We investigated the incidence, predictors, and prognostic impact of periprocedural stroke in unselected patients undergoing PCI. METHODS AND RESULTS: A total of 9662 patients who underwent 12 407 PCIs between January 1990 and July 1999 were retrospectively studied. Stroke was diagnosed in 43 patients (0.38% of procedures). Patients with stroke were older (72+/-11 versus 64+/-11 years, P<0.001), had lower left ventricular ejection fraction (42+/-12 versus 46+/-13%, P=0.04) and more diabetes (39.5% versus 27.2%, P=0.07), and experienced a higher rate of intraprocedural complications necessitating emergency use of intra-aortic balloon pump (IABP) (23.3% versus 3.3%, P<0.001). In-hospital mortality (37.2% versus 1.1%, P<0.001) and 1-year mortality (56.1% versus 6.5%, P<0.001) were higher in patients with stroke. Compared with hemorrhagic stroke, patients with ischemic stroke had higher rate of in-hospital major adverse cardiac events (57.1% versus 25%, P=0.037). Multivariate logistic regression analysis identified emergency use of IABP as the strongest predictors for stroke (OR=9.6, CI 3.9 to 23.9, P<0.001), followed by prophylactic use of IABP (OR=5.1), age >80 years (OR=3.2, compared with age <50 years), and vein graft intervention (OR=2.7). CONCLUSIONS: Stroke associated with contemporary PCI is associated with substantial increased mortality. Elderly patients who experience intraprocedural complications necessitating the use of IABP are at particularly high risk.

Oral rapamycin to inhibit restenosis after stenting of de novo coronary lesions: the Oral Rapamune to Inhibit Restenosis (ORBIT) study.

OBJECTIVES: The aim of this study was to establish safety and feasibility of oral Rapamycin at two doses-2 mg and 5 mg-in achieving low rates of repeat target lesion revascularization (TLR) in de novo native coronary artery lesions. BACKGROUND: Drug-eluting stents have shown the ability to limit restenosis. Oral Rapamycin is an alternative strategy that can target multiple coronary lesions suitable for treatment with any approved metal stent and at potentially lower cost. METHODS: The Oral Rapamune to Inhibit Restenosis (ORBIT) study is an open-label study of 60 patients with de novo lesions treated with bare metal stents in up to two vessels. After a loading dose of 5 mg, patients received a daily dose of 2 mg (n = 30) and 5 mg (n = 30) for 30 days. Six-month angiographic, intravascular ultrasound (IVUS), and clinical follow-up were conducted. RESULTS: Baseline clinical and procedural characteristics were similar: 10% of patients in the 2-mg group and 30% in the 5-mg group did not complete the course; 43% in the 2-mg group and 66% in the 5-mg group had side effects. At six-month follow-up, late loss (0.6 +/- 0.5 mm vs. 0.7 +/- 0.5 mm; p = NS), in-stent binary restenosis (7.1% vs. 6.9%; p = NS), in-stent percent volume obstruction by IVUS (29% vs. 24%; p = NS), and clinically driven TLR (14.3% vs. 6.9%; p = NS) were similar in 2-mg and 5-mg groups. CONCLUSIONS: Oral Rapamycin for the prevention of restenosis is safe, feasible, and associated with low rates of repeat revascularization. Although associated with certain side effects, it may be considered for patients undergoing multivessel stents if proven in larger randomized studies.

Clinical, angiographic, and intravascular ultrasound characteristics of early saphenous vein graft failure.

OBJECTIVES: We sought to examine saphenous vein graft (SVG) lesions that fail within the first year after operation. BACKGROUND: Saphenous vein grafts remain patent for approximately 10 years; however, up to 15% to 20% of SVGs become occluded within the first year. METHODS: We studied 100 patients who underwent percutaneous coronary intervention (PCI) for early (<1 year post-implantation) SVG failure lesions and compared them with a diabetes- and hypercholesterolemia-matched cohort of late SVG failures (>1 year). Coronary angiography and intravascular ultrasound images were analyzed. RESULTS: The majority of patients in both groups were males who presented with unstable angina; 36% were diabetic. Graft ages were 6.0 +/- 2.9 months and 105.4 +/- 50.8 months, respectively. The early SVG failure lesion location was more often ostial or proximal (62% vs. 42%, respectively). Early SVG failures were angiographically smaller than late failures (reference: 2.47 +/- 0.86 mm vs. 3.26 +/- 0.83 mm, p < 0.001) but had similar lesion lengths. Intravascular ultrasound showed that early failure lesions had smaller proximal and distal reference lumen areas (7.3 +/- 6.8 mm2 vs. 10.6 +/- 3.8 mm2, p = 0.026) and greater reference plaque burden than late failures (52.3% vs. 36.1%, p < 0.001). After PCI, 20.6% of early and 30.6% of late failure lesions had creatine kinase-myocardial band (CK-MB) greater than twice normal. CONCLUSIONS: Early SVG failure is mostly proximal or ostial, lesions appear focal, and early SVGs appear smaller than late SVGs. Intravascular ultrasound shows significant reference segment plaque burden, suggesting more severe, diffuse SVG disease.