Assessment of the impact of scheduled postmarketing safety summary analyses on regulatory actions.

In addition to standard postmarketing drug safety monitoring, Section 915 of the Food and Drug Administration Amendments Act of 2007 (FDAAA) requires the US Food and Drug Administration (FDA) to conduct a summary analysis of adverse event reports to identify risks of a drug or biologic product 18 months after product approval, or after 10,000 patients have used the product, whichever is later. We assessed the extent to which these analyses identified new safety signals and resultant safety-related label changes. Among 458 newly approved products, 300 were the subjects of a scheduled analysis; a new safety signal that resulted in a safety-related label change was found for 11 of these products. Less than 2% of 713 safety-related label changes were based on the scheduled analyses. Our study suggests that the safety summary analyses provide only marginal value over other pharmacovigilance activities.

Participation of women in clinical trials for new drugs approved by the food and drug administration in 2000-2002.

OBJECTIVE: This study aimed to track the inclusion of women in clinical trials for new drugs approved by the Food and Drug Administration (FDA) between 2000 and 2002 and to evaluate the extent of analyses by sex. METHODS: Data were extracted from FDA reviewers' reports, summaries of clinical trials in New Drug Applications (NDAs), and product labeling and organized into a Microsoft Access database. The information collected includes subject enrollment by sex per clinical phase and sex differences in pharmacokinetics, safety, and efficacy as determined by either sponsors or reviewers. RESULTS: There were 67 New Molecular Entities (NMEs) approved by the FDA between 2000 and 2002. A total of 397,825 subjects were enrolled in 2,323 clinical trials. If 9 sex-specific NMEs are excluded, 297,697 subjects were enrolled in 1,974 clinical trials. Forty-seven percent of participants were male, 49% were female, and 4% of subjects were not specified. Of the 58 sex-nonspecific products in the study, 71% (41 of 58) of sex analyses were performed either by the sponsor or FDA reviewers. Twenty-five NMEs were found to have sex differences in pharmacokinetics, efficacy or adverse events. However, no recommendation was made to adjust dosage based on sex differences. CONCLUSIONS: The percentages of women and men participating in clinical trials varied by year, phase, and product type. However, the overall participation by women and men was comparable, suggesting an improvement in including more women in clinical trials when compared with the previous FDA study evaluating women's participation from 1995 through 1999. As with the previous study, however, a significant underrepresentation of women in early phase trials and in certain areas, such as cardiovascular products, was observed and continues to be an issue of concern. Lack of appropriate analyses by sex should also be noted as an issue of concern.

Benchmarking operator performance in percutaneous coronary intervention: a novel approach using 30-day events.

The infrequency of adverse in-hospital events limits scorecarding individual angioplasty operators. We assessed 30-day events for this purpose. Thirty-nine operators performed 1,950 coronary interventions from 1 April to 30 September 1998. Thirty-day follow-up was obtained in 1,896 (97.2%), who form the basis for this analysis. We recorded 16 baseline variables and chose an endpoint of mortality or target vessel revascularization. The endpoint occurred in 103 (5.4%) patients by 30 days. Independent predictors were identified by multivariate modeling. The expected event rate for the set of patients treated by each operator was determined. Two operators had significantly more adverse events by 30 days than predicted and two others had an event rate approaching significance. Two of these four performed at least 60 procedures during the 6-month period. With 30-day events, operators whose complication rates exceed laboratory standards can be identified with achievable sample sizes. Volume alone does not appear to be sufficient assurance of quality outcomes.

Excimer laser coronary angioplasty and intracoronary radiation for in-stent restenosis: six-month angiographic and clinical outcomes.

BACKGROUND: The purpose of this study was to evaluate 6-month clinical and angiographic outcomes in patients treated with excimer laser coronary angioplasty (ELCA) and intracoronary radiation (ICR) for in-stent restenosis (ISR). METHODS: A consecutive series of 175 patients with ISR treated with ELCA+ICR (gamma and beta emitters) were compared to 33 patients with ISR treated with ELCA alone. Baseline characteristics were similar between groups. ELCA+ICR and ELCA-alone patients had similar lesion lengths (25.0+/-12.0 vs. 24.0+/-16.8 mm, P=NS) in predominantly saphenous vein grafts (SVG, 38% vs. 42%, P=NS). RESULTS: Procedural success was high (ELCA+ICR, 97.0% vs. ELCA alone, 98.5%, P=NS), with no perforations or acute vessel closures. ELCA+ICR therapy reduced target vessel revascularization (TVR; 27% vs. 64%, P<.0001) and major adverse cardiac events [MACE: death, myocardial infarction (MI), or TVR; 30% vs. 64%, P<.0001] compared to ELCA alone. Late loss was 0.66+/-0.90 mm in ELCA+ICR patients and 0.85+/-0.60 mm in ELCA-alone patients (P=NS). Angiographic binary restenosis (>50%) was significantly reduced with adjunctive ICR (28% vs. 54%, P=.014). CONCLUSION: Radiation therapy with ELCA significantly reduces angiographic binary restenosis at 6 months in patients with diffuse ISR, driven predominantly by reduced percutaneous TVR.

Frequency of major adverse cardiac events within one month of coronary angioplasty: a useful measure of operator performance.

OBJECTIVES: To test one-month outcomes in a single center for their statistical power to corroborate conclusions derived from large multicenter databases. BACKGROUND: Only with large, multicenter databases has it been possible to demonstrate more frequent occurrences of complications in patients treated by "low-volume operators." Critics feel that such analyses mask excellent performance by many "low-volume operators." METHODS: In a high-volume cardiac catheterization laboratory in a large, nonuniversity teaching hospital, baseline clinical and angiographic characteristics were collected for a consecutive series of 1,029 patients treated by 37 percutaneous transluminal coronary intervention (PTCI) operators over a four-month period. One-month follow-up was obtained in 967 (94%) patients who form the basis for this analysis. RESULTS: Only the group of operators performing <50 cases annually had a major adverse cardiac event (MACE) (death, myocardial infarction or symptom-driven revascularization) rate at one month significantly greater than predicted from baseline characteristics. (Observed rate: 15.1%, expected: 9.7%, 95% confidence interval [CI]: 4.7%, 14.6%.) The difference was driven by the significantly more frequent rate at which repeat revascularization was performed in patients treated by that group of operators (observed: 13.8%, expected: 7.1%, 95% CI: 2.8%, 11.4%). CONCLUSIONS: As is true of analyses of large multicenter databases, lower volume operators as a group have less good outcomes than those performing more. The greater statistical power provided by one-month MACE rate offers advantages over the use of in-hospital complications for the analysis of operator performance.

Procedural results of coronary angioplasty but not late mortality have improved in patients with depressed left ventricular function.

BACKGROUND: Published experience with coronary angioplasty in patients with severely depressed left ventricular (LV) ejection fraction indicates that procedural complications are more frequent in such patients than in those with normal or near normal LV function. Although the immediate outcomes of transcatheter revascularization in unselected populations have improved substantially since the procedures upon which these reports were based were performed, outcomes with this subset of patients has not been recently reviewed. HYPOTHESIS: This study was undertaken to document the results of the application of current transcatheter technology to this patient subset. METHODS: We analyzed data from 194 consecutive patients with a visually estimated LV ejection fraction < 30%, who underwent coronary angioplasty in this institution between January 1, 1995, and April 30, 1996, and compared their outcomes with those of 1,390 patients with normal LV function treated concurrently. RESULTS: Angiographic success in the two groups was similar. The hospital mortality of the patients with low ejection fraction was higher (2.6 vs. 0.6%, p = 0.02) than in concurrently treated patients with normal LV function. Other procedural complications were no more frequent than in such patients. Late mortality in patients with low ejection fraction was 16%, a similar value to that in older reports. CONCLUSION: Compared with older reports, current hospital outcomes of coronary angioplasty are improved in patients with severely depressed LV function. Unfortunately, late outcomes are not demonstrably better.

New devices enhance hospital results of coronary angioplasty.

After rigorous screening by means of registries and controlled trials, various atherectomy devices, excimer laser catheters, and endoluminal stents were approved for general clinical use. Few data are available describing their safety and effectiveness after approval. This analysis was undertaken to assess the impact on patient outcomes of the unrestricted clinical application of new transcatheter devices for coronary angioplasty. Thirty-six cardiologists performed 3,113 transcatheter procedures during 1995. Each chose the transcatheter modality best suited to the clinical and angiographic features of the patient. Baseline clinical and angiographic data and initial outcome were recorded by cardiac catheterization laboratory personnel. In-hospital events were obtained by independent chart review. Balloon angioplasty alone was employed in 1,089 (35.0%) patients. A stent was deployed after balloon angioplasty in 1,029 (33.1%) patients. An atherectomy or laser device was used without stent support in 631 (20.3%) patients, and stent support was added in an additional 364 (11.7%) patients. In all three new device categories the angiographic success (final luminal narrowing <50%) rate was better than in balloon angioplasty for type-C lesions and for chronic occlusions. The frequency of adverse events in the aggregate was not increased with device use, but the frequency of coronary artery bypass surgery was reduced with stent use. The frequency of non-Q-wave myocardial infarction was greater with devices than with balloon angioplasty alone. After adjustment for the differences in baseline clinical and angiographic variables by means of multivariate analysis, each of the three new device categories was independently associated with an increased chance of angiographic and procedural success compared to balloon angioplasty. The availability of new transcatheter devices for clinical practice enhances patient outcomes during hospitalization for the procedure.

Value of the electrocardiogram in determining cardiac events and mortality in myotonic dystrophy.

Electrocardiograms were recorded at baseline and regular intervals in 53 patients with myotonic dystrophy who were followed for a mean of 6.3 +/- 4.0 years. Patients with cardiac events had a significantly prolonged PR interval (p <0.001), a later age of onset of neuromuscular symptoms (p <0.05), and were older (p <0.005).

Effects of endoluminal coronary stents on the frequency of coronary artery bypass grafting after unsuccessful percutaneous transluminal coronary vascularization.

Coronary artery stents have been rapidly incorporated into clinical practice so that they are currently deployed in nearly 50% of all patients undergoing angioplasty procedures in a busy laboratory. A decline in the frequency of coronary bypass surgery for unsuccessful angioplasty is associated with this change in practice-a decline in the use of atherectomy devices and no increase in length of stay for angioplasty patients.

Morbidity and mortality rates in elderly patients undergoing percutaneous coronary transluminal angioplasty.

Although successful dilatation of a target lesion by means of percutaneous transluminal coronary angioplasty (PTCA) can be attained as frequently in elderly as in younger patients, elderly patients have a higher risk of complications. Furthermore, cohorts of patients older than 75 years and undergoing PTCA include more women and more cases of unstable angina, factors that increase the risk of complications. Included in this analysis of 3199 PTCAs performed between January 1991 and September 1992 were 474 (14.8%) patients who were > or = 75 years old. Age was an independent risk factor for death, acute myocardial infarction, need for transfusion, and need for arterial repair after PTCA. The frequency of successful dilatation of individual lesions, emergency coronary bypass surgery, or repeated PTCA of the same lesion was not related to age. In previous studies no association has been demonstrated between age and increased risk of in-hospital reclosure. The presence of more severe coronary disease and of the greater frequency of coexisting morbid conditions makes elderly patients less able to tolerate unsuccessful or complicated PTCA.

Discordance in the predictors of mortality vs. those of ischemic complications following transcatheter coronary intervention.

Outcomes of percutaneous transluminal coronary angioplasty (PTCA) depend upon the skill of the angioplasty team and on the characteristics of the patient population. Comparisons of outcomes from different laboratories must take into account the latter. A discordance may exist between the baseline predictors of death in hospital following PTCA and those for periprocedural ischemia. Baseline clinical and procedural characteristics of 3,725 patients who underwent PTCA during 1991 and 1992 were compared with complications by multivariate analysis. The age of the patient and the occurrence of an MI within the previous 30 days were the most powerful independent predictors of death. Ischemic complications were not independently associated with these factors. Emergency CABG was associated independently with target lesion complexity and abrupt reclosure, with unstable angina or attempted saphenous vein graft dilatation. Thus, mortality may more directly reflect baseline clinical characteristics than the skill of operators in avoiding ischemic complications.