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.

Improving women's health through modernization of our bioinformatics infrastructure.

Our nationwide bioinformatics infrastructure used to detect important sex differences associated with medical product use is antiquated. The Food and Drug Administration (FDA) has embarked on an ambitious bioinformatics modernization effort that will improve our ability to assess the safety and effectiveness of new medical products. This, in turn, will improve our ability to detect important sex differences.

The effect of intracoronary radiation for the treatment of recurrent in-stent restenosis in patients with chronic renal failure.

OBJECTIVES: This study was designed to analyze the in-hospital and six-month clinical and angiographic outcomes of patients with chronic renal failure (CRF) treated with intracoronary radiation for the prevention of recurrence of in-stent restenosis. BACKGROUND: Patients with CRF are at a higher risk than the general population for accelerated atherosclerotic cardiovascular disease and for restenosis after percutaneous coronary intervention. Previous studies have shown the effectiveness of both beta and gamma radiation in preventing recurrent restenosis in patients with in-stent restenosis. METHODS: We studied the in-hospital and six-month clinical and angiographic outcomes of 118 patients with CRF and 481 consecutive patients without CRF who were treated with intracoronary radiation for the prevention of recurrence of in-stent restenosis in native coronaries and saphenous vein grafts. RESULTS: Patients with CRF were usually older, women, hypertensive and diabetic, with multivessel disease and with reduced left ventricular function. In-hospital outcome for patients with CRF was marred by a higher incidence of death, non-Q-wave myocardial infarction and major vascular and bleeding complications. At six-month follow-up, the mortality rate was higher in patients with CRF, 7.6% compared with 1.9% in non-CRF patients (p = 0.003). Restenosis, target lesion revascularization (TLR) and target vessel revascularization (TVR) rates were similar in the two groups. In patients with CRF, radiation therapy compared to placebo reduced restenosis (53.8% vs. 22.6%, p = 0.04), TLR (71.4% vs. 15.3%, p < 0.0001) and TVR (78.6% vs. 23.7%, p = 0.0002). CONCLUSIONS: Intracoronary radiation for the prevention of recurrence of in-stent restenosis achieved similar rates of restenosis and revascularization procedures in patients with and without CRF. Despite this benefit, patients with renal dysfunction continued to have significantly higher in-hospital and six-month adverse outcomes.

Prolonged antiplatelet therapy to prevent late thrombosis after intracoronary gamma-radiation in patients with in-stent restenosis: Washington Radiation for In-Stent Restenosis Trial plus 6 months of clopidogrel (WRIST PLUS).

BACKGROUND: Intracoronary gamma-radiation reduces recurrent in-stent restenosis. Late thrombosis (>30 days after radiation therapy) is identified as a serious complication. The Washington Radiation for In-Stent Restenosis Trial (WRIST) PLUS, which involved 6 months of treatment with clopidogrel and aspirin, was designed to examine the efficacy and safety of prolonged antiplatelet therapy for the prevention of late thrombosis. METHODS AND RESULTS: A total of 120 consecutive patients with diffuse in-stent restenosis in native coronary arteries and vein grafts with lesions <80 mm underwent percutaneous coronary transluminal angioplasty, laser ablation, and/or rotational atherectomy. Additional stents were placed in 34 patients (28.3%). After the intervention, a closed-end lumen catheter was introduced into the artery, a ribbon with different trains of radioactive (192)Ir seeds was positioned to cover the treated site, and a dose of 14 Gy to 2 mm was prescribed. Patients were discharged with clopidogrel and aspirin for 6 months and followed angiographically and clinically. All patients but one tolerated the clopidogrel. The late occlusion and thrombosis rates were compared with the gamma-radiation-treated (n=125) and the placebo patients (n=126) from the WRIST and LONG WRIST studies (which involved only 1 month of antiplatelet therapy). At 6 months, the group receiving prolonged antiplatelet therapy had total occlusion and late thrombosis rates of 5.8% and 2.5%, respectively; these rates were lower than those in the active gamma-radiation group and similar to those in the placebo historical control group. CONCLUSIONS: Six months of clopidogrel and aspirin and a reduction in re-stenting for patients with in-stent restenosis treated with gamma-radiation is well tolerated and associated with a reduction in the late thrombosis rate compared with a similar cohort treated with only 1 month of clopidogrel and aspirin.

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.

Three-year follow-up after intracoronary gamma radiation therapy for in-stent restenosis. Original WRIST. Washington Radiation for In-Stent Restenosis Trial.

BACKGROUND: The Washington Radiation for In-Stent Restenosis Trial (WRIST) is a double-blinded randomized study evaluating the effects of intracoronary radiation therapy (IRT) in patients with in-stent restenosis (ISR). METHODS: One hundred and thirty patients with ISR (100 native coronary and 30 vein grafts) underwent PTCA, laser ablation, rotational atherectomy, and/or additional stenting (36% of lesions). Patients were randomized to either Iridium-192 IRT or placebo, with a prescribed dose of 15 Gy to a 2-mm radial distance from the center of the source. RESULTS: Angiographic restenosis (27% vs. 56%, P=.002) and target vessel revascularization (TVR; 26% vs. 66%, P<.001) were dramatically reduced at 6 months in IRT patients. Between 6 and 36 months, IRT compared to placebo patients had more target lesion revascularization (TLR; IRT=17% vs. placebo=2%, P=.002) and TVR (IRT=17% vs. placebo=3%, P=.009). At 3 years, the major adverse cardiac event (MACE) rate was significantly reduced with IRT (39% vs. 65%, P=.003). CONCLUSIONS: In WRIST, patients with ISR treated with IRT using 192Ir had a marked reduction in the need for repeat target lesion and vessel revascularization at 6 months, with the clinical benefit maintained at 3 years.

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.

Incidence, management, and outcome of coronary artery perforation during percutaneous coronary intervention.

We have analyzed the incidence, management, and outcome of 84 cases of coronary artery perforation in patients who underwent percutaneous coronary intervention at our institution. This complication was more frequent in female patients and in patients who underwent lesion modification with atheroablative devices. A total of 8 patients (9.5%) died after the procedure. They were usually older and had a higher incidence of cardiac tamponade; a larger percentage of these patients underwent emergency surgery than those who survived.

Ethnicity does not affect outcomes of coronary angioplasty.

BACKGROUND: Access to high quality medical care and especially to complex procedures may be adversely affected in members of a minority ethnic group or a lower socioeconomic class. For example, Caucasians undergo coronary artery bypass grafting (CABG) or percutaneous transluminal coronary interventions (PTCI) twice as frequently as African-Americans. Data exist to suggest that African-Americans derive less benefit than Caucasians from CABG. HYPOTHESIS: We investigated the possibility that outcomes of catheter-based coronary angioplasty might also be less favorable in minority populations. METHODS: We analyzed in-hospital outcomes in 6,559 consecutive patients who underwent PTCI in our laboratory. In 37 ethnicity was classified as "other," 5,203 (79.8%) were identified as Caucasians, 863 (13.2%), as African-Americans, and 456 (7.0%), as Hispanics. Twelve baseline clinical, angiographic, and procedural characteristics were entered into a computerized data base. Hospital complications were identified by trained quality assurance nurses. RESULTS: Substantial differences in baseline characteristics existed between the populations. Despite these differences, on univariate comparison of ethnicity and outcome, no differences between ethnic groups were found with a single exception. Mortality in Hispanics was higher than in the other two populations. (2.0 vs. 0.7 and 0.8%, respectively, p = 0.008). However, when this was adjusted for baseline characteristics, the difference was not significant. CONCLUSIONS: In contrast to previous studies suggesting less favorable outcomes of CABG in African-American patients, this analysis demonstrates an equal frequency of procedural success and rate of hospital complications for PTCI in that population, in Hispanics, and in Caucasians.

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.

Indications for Cardiac Pacemaker Implantation in Myotonic Dystrophy.

OBJECTIVES: To determine risk factors for cardiac complications in patients with myotonic dystrophy, and to determine whether permanent cardiac pacemakers may be beneficial in the treatment of myotonic dystrophy heart disease. BACKGROUND: Myotonic dystrophy affects the cardiac conduction system. Cardiac pacemakers are easily implanted and can be life-saving in patients with severe or complete heart block. METHODS: A total of 94 patients with myotonic dystrophy were examined; 46 were followed for a mean of 6.4 (+/- 3.5 SD) years to determine predictors of the end point events of sudden death, Stokes-Adams attacks, or onset of atrial fibrillation. The end points were chosen to determine when cardiac pacemakers should be implanted (Fig. 1). RESULTS: Four out of 5 patients (and all 4 patients >60 years of age) with PR intervals longer than 275 msec had sudden death (n=1), Stokes-Adams attacks (n=1), or onset of atrial fibrillation (n=2). Conversely, only 1 of 89 patients with a PR interval shorter than 275 msec had end point events; 1 patient, aged 63 years, developed left bundle branch block and palpitations accompanied by dyspnea, which responded to a pacemaker. CONCLUSIONS: We recommend that patients with myotonic dystrophy and any indication or a family history of myotonic heart disease have at least a yearly electrocardiogram, particularly if they have a prolonged baseline or progressively increasing PR interval, or symptoms suggestive of heart block.

Determination of pretest probability for detection of a cardiovascular source of emboli by transesophageal echocardiography using clinical and transthoracic echocardiographic data.

Transesophageal echocardiographic findings and their effect on disease management were evaluated in 216 patients with suspected cardiovascular source of emboli. Clinical and transesophageal echocardiographic findings were useful in defining pretest probability for finding a probable cardiovascular source of emboli on transesophageal echocardiography.

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.

Accuracy of two-dimensional echocardiographic planimetry of the mitral valve area before and after balloon valvuloplasty.

The purpose of this study was to assess the accuracy of planimetry after percutaneous balloon mitral valvuloplasty (PBMV). The mitral valve area (MVA) was estimated in 34 patients before and after PBMV, using two-dimensional echocardiographic planimetry, Doppler pressure half-time (PHT), and the Gorlin formula. There was no significant difference in the correlation of planimetry and PHT before (r = 0.53, p = 0.001) and after PBMV (r = 0.56, p < 0.001). A similar correlation was found between planimetry and the Gorlin formula (r = 0.44, p = 0.01 before PBMV, r = 0.37, p = 0.03 after PBMV). The concordance between planimetry, PHT, and the Gorlin formula in classifying patients into mild, moderate, or severe mitral stenosis was not worse after PBMV. Planimetry-derived MVA was not less accurate after PBMV than before PBMV. However, the correlation between the two echocardiographic measurements and the Gorlin formula was only moderate.