Intra-aortic Balloon Counterpulsation and Infarct Size. Part 2
The methods used in the Counterpulsation to Reduce Infarct Size Pre-PCI Acute Myocardial Infarction (CRISP AMI) trial have been previously reported. In brief, CRISP AMI was a prospective, open, international, multicenter (N = 30) randomized controlled trial to determine if a routine strategy of IABC insertion prior to primary PCI reduced infarct size in patients with acute anterior STEMI without cardiogenic shock. Patients in the standard of care group of the trial received primary PCI without planned IABC support.
Institutional review boards and ethics committees approved the trial, and each enrolled patient provided written informed consent. The Duke Clinical Research Institute (Durham, North Carolina) coordinated the trial and carried out the data management and analyses with oversight from the steering committee. An independent data and safety monitoring board monitored the study and oversaw the safety and efficacy of the trial. Members of the steering committee were involved in study design, provided oversight during the conduct of the study, and had full access to the data after data lock and unblinding.
Study Population
To determine if IABC reduces infarct size, a population of adult patients within 6 hours of chest pain onset and planned primary PCI for acute anterior STEMI with significant myocardium at risk were sought for inclusion into the study. A 12-lead electrocardiogram demonstrating ST-segment elevation of 2 mm or higher in 2 contiguous anterior leads or a total elevation of 4 mm or higher in anterior leads was required for inclusion demonstrating significant at-risk myocardium. Patients with indications for planned IABC insertion such as cardiogenic shock, inability to undergo IABC implantation, fibrinolysis within 72 hours of presentation, or known contraindication for cardiac magnetic resonance imaging (MRI) for end point assessment were excluded. Because the primary end point was infarct size, patients with known prior myocardial infarction (MI) or coronary artery bypass graft surgery also were excluded.
Interventions and Procedures
Patients were randomized to prereperfusion initiation of IABC and mechanical reperfusion with PCI (IABC plus PCI) or primary PCI alone. Patients randomized to receive counterpulsation therapy were required to have the intra-aortic balloon inserted and pumping prior to PCI (defined by insertion of the guidewire into the infarct-related artery). Patients randomized to PCI alone may have had subsequent insertion of IABC if there was clinical deterioration. Criteria provided to investigators considering rescue IABC and crossover to counterpulsation included sustained hypotension or cardiogenic shock, uncontrolled arrhythmias, and acute mitral regurgitation or ventricular septal defect.
To ensure rapid reperfusion, sites with demonstrated ability to meet guideline standards were chosen (median door-to-device time <90 minutes). A 24-hour interactive voice response system was used for stratified block randomization, which was based on a computer-generated algorithm. Allocation occurred in random blocks and was stratified by region. In addition, data regarding the timing of first medical contact, randomization, IABC insertion, and first device were captured and monitored by the steering committee and the data and safety monitoring board during the conduct of the trial to ensure continued high-quality care.
Intra-aortic Balloon Counterpulsation and Infarct Size
Primary percutaneous reperfusion for patients with acute ST-segment elevation myocardial infarction (STEMI) has been shown to reduce mortality and is considered the standard of care when available. The benchmarked standards for time to reperfusion have shortened over time; despite significant reductions in door-to-balloon times over the past few years in the United States, the STEMI mortality rate has not significantly improved.
Patients with acute STEMI, representing 30% to 45% of approximately 1.5 million hospitalizations for acute coronary syndromes annually in the United States, are still at substantial acute mortality risk with 1-year mortality estimated to be between 6% and 15%. This may be related to microvascular obstruction resulting in no reflow at the time of mechanical reperfusion and infarct expansion over time. Additionally, this increase in infarct size is associated with adverse remodeling and decreased left ventricular (LV) function leading to heart failure and long-term morbidity following STEMI.
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Intra-aortic balloon counterpulsation (IABC) mechanically augments coronary blood flow, unloads the left ventricle, and reduces myocardial oxygen demand. These favorable hemodynamic effects have led to demonstrated improvements in outcomes, and the recommendation that patients with acute MI and cardiogenic shock be treated with IABC support and reperfusion. Although an older randomized trial of IABC in patients undergoing percutaneous transluminal coronary angioplasty for high-risk STEMI showed a modest potential effect on recurrent ischemia, more recent observational studies suggest a possible clinical benefit in patients with high-risk STEMI receiving IABC prior to reperfusion with percutaneous coronary intervention (PCI) and stenting, with increased clinical use at an early stage in the United States.16 Preclinical animal studies have demonstrated that unloading of the left ventricle with IABC prior to reperfusion reduces infarct size and myocardial salvage.
Therefore, we performed a randomized controlled trial to determine if IABC inserted prior to primary PCI compared with primary PCI alone (standard of care) reduced infarct size in patients with acute anterior STEMI without cardiogenic shock. In addition, a 6-month follow-up for clinical events including all-cause mortality, repeat infarction, and new congestive heart failure was planned.
Comparison of Strategies for Sustaining Weight Loss
Context Behavioral weight loss interventions achieve short-term success, but re-gain is common.
Objective To compare 2 weight loss maintenance interventions with a self-directed control group.
Design, Setting, and Participants Two-phase trial in which 1032 overweight or obese adults (38% African American, 63% women) with hypertension, dyslipidemia, or both who had lost at least 4 kg during a 6-month weight loss program (phase 1) were randomized to a weight-loss maintenance intervention (phase 2). Enrollment at 4 academic centers occurred August 2003-July 2004 and randomization, February-December 2004. Data collection was completed in June 2007.
Interventions After the phase 1 weight-loss program, participants were randomized to one of the following groups for 30 months: monthly personal contact, unlimited access to an interactive technology–based intervention, or self-directed control.
Main Outcome Changes in weight from randomization.
Results Mean entry weight was 96.7 kg. During the initial 6-month program, mean weight loss was 8.5 kg. After randomization, weight regain occurred. Participants in the personal-contact group regained less weight (4.0 kg) than those in the self-directed group (5.5 kg; mean difference at 30 months, −1.5 kg; 95% confidence interval [CI], −2.4 to −0.6 kg; P = .001). At 30 months, weight regain did not differ between the interactive technology–based (5.2 kg) and self-directed groups (5.5 kg; mean difference −0.3 kg; 95% CI, −1.2 to 0.6 kg; P = .51); however, weight regain was lower in the interactive technology–based than in the self-directed group at 18 months (mean difference, −1.1 kg; 95% CI, −1.9 to −0.4 kg; P = .003) and at 24 months (mean difference, −0.9 kg; 95% CI, −1.7 to −0.02 kg; P = .04). At 30 months, the difference between the personal-contact and interactive technology–based group was −1.2 kg (95% CI −2.1 to −0.3; P = .008). Effects did not differ significantly by sex, race, age, and body mass index subgroups. Overall, 71% of study participants remained below entry weight.
Conclusions The majority of individuals who successfully completed an initial behavioral weight loss program maintained a weight below their initial level. Monthly brief personal contact provided modest benefit in sustaining weight loss, whereas an interactive techonology–based intervention provided early but transient benefit.
Nearly two-thirds of US adults are overweight or obese. Together overweight and obesity are the second leading cause of preventable death, primarily through effects on cardiovascular disease (CVD) risk factors (hypertension, dyslipidemia, and type 2 diabetes). Weight loss improves these risk factors, and evidence suggests that benefits persist as long as weight loss is maintained. Relatively short-term (ie, 4-6 months) behavioral interventions for adults result in clinically significant weight loss, but regain is an intractable problem. Given the vast scope of the overweight and obesity epidemic, there is a critical need for practical, affordable, and scalable intervention strategies that effectively maintain weight loss. Such strategies may also play an important role in preventing weight gain among normal-weight individuals, thereby reducing the incidence of overweight and obesity.
Prediction of Erectile Function Following Treatment for Prostate Cancer. Part 3
Statistical Analysis
Having functional erections suitable for intercourse was defined as the patient selecting the response option of “firm enough for intercourse” to the EPIC-26 question, “How would you describe the usual quality of your erections during the last 4 weeks?” (other responses indicated erectile dysfunction). Erectile function 2 years after treatment was modeled separately, according to planned treatment, using logistic regression. The pretreatment patient and disease characteristics as well as planned treatment details considered are summarized in eTable 1.
Multivariable model development used a backward elimination selection procedure with 2-sided α = .05. Model selection was internally validated using bootstrap resampling (500 resamples), and bootstrap estimates of parameter estimates, standard errors, pointwise 95% confidence intervals for model-predicted probabilities, and area under the receiver operating characteristic curve (AUC) were also obtained for each final model. Individual predicted probabilities of functional erections at 2 years were calculated using the inverse logistic function {exp[X′β]/[1 + exp(X′β)]}, where X′β is the sum with X representing individual characteristics observed and β representing the associated log odds ratios for the individual characteristics estimated from the model.
The omission of 2-year nonrespondents from model development assumes data are missing completely at random. A sensitivity analysis assessed the effect of this assumption by refitting each final model using a model weighted for inverse probability of response; the probability of response was estimated using multivariable logistic regression including factors associated with nonresponse (education level, number of comorbid conditions, race, and pretreatment sexual functioning). This approach had little effect on the estimates, and results were not reported.
Use of medications or devices to assist erection function as measured by patient self-report at 2 years was summarized overall and in detail among the subset of 694 men who were potent (ie, reported functional erections) before treatment, excluding patients with implanted erectile aid devices.
All analyses were performed using SAS version 9.1 (SAS Institute Inc, Cary, North Carolina).
External Validation
The community-based Cancer of the Prostate Strategic Urologic Research Endeavor the CaPSURE cohort registry served as an external validation cohort for the developed models. Men in the CaPSURE cohort reported HRQOL at baseline and every 6 months in follow-up; sexual function and bother (severity and impact of patient-reported erectile dysfunction) were determined from the UCLA Prostate Cancer Index (UCLA-PCI), the instrument from which the EPIC-26 was previously derived and from which it retained 6 items. Characteristics of the CaPSURE cohort have been previously described.
Of the 1913 CaPSURE patients who completed pretreatment and 2 years posttreatment evaluation of sexual HRQOL using the UCLA-PCI, 1655 had data for all available model covariates available for validation. The PROSTQA model–predicted probability of 2-year erectile function was computed for each CaPSURE patient (from the inverse logistic function of the final model equations) and compared with his reported (actual) 2-year erectile function (the definition of erectile function used in the CaPSURE validation was the same as that in the PROSTQA cohort). Validation was assessed by AUC from fitting univariable logistic regression of reported 2-year erectile function on model-predicted probability, and calibration was assessed by examining the average model-predicted probability vs observed proportion of men reporting functional erections at 2 years, which is summarized overall and according to quintiles of the distribution of model-predicted probabilities.
Prediction of Erectile Function Following Treatment for Prostate Cancer. Part 2
Individual characteristics, such as pretreatment erectile function, that influence posttreatment sexual outcome are known to vary at diagnosis, yet tools to predict posttreatment erectile dysfunction based on pretreatment sexual HRQOL at baseline have been limited. Treatment refinements, such as nerve-sparing techniques, can mitigate erectile dysfunction consequences of prostate cancer treatment, while other treatment variations, such as use of neoadjuvant hormone therapy, can adversely affect sexual outcome. Although associations of these and other factors with patient-reported sexual outcome have been studied, information regarding how the combination of pretreatment patient characteristics and treatment factors relate to individualized sexual outcome remains limited.
We sought to determine whether an individual man's sexual outcomes after the most common treatments for early-stage prostate cancer (radical prostatectomy, external radiotherapy, or brachytherapy) can be predicted accurately based on baseline characteristics and treatment planning details.
Study Patients and Measures
The Prostate Cancer Outcomes and Satisfaction With Treatment Quality Assessment (PROSTQA) is a prospective, longitudinal, multicenter cohort comprising men with previously untreated clinical stage T1 to T2 prostate cancer who had elected prostatectomy, external beam radiotherapy, or brachytherapy as primary treatment and were enrolled from 2003 to 2006 at 9 US university-affiliated hospitals into an institutional review board–approved protocol after providing written informed consent.
Patient demographic, race/ethnicity, and clinical data were collected (because such factors have known associations with prostate cancer aggressiveness) by research coordinators via direct patient contact, eg, clinical visits supplemented by medical record review. Details of treatment, such as plan for nerve sparing during prostatectomy or neoadjuvant hormone therapy with radiation, were collected prior to treatment to enable predictive models based on pretreatment information. Patient-reported outcome measures, including the Expanded Prostate Cancer Index Composite (EPIC-26) and information regarding use of medications or devices for erectile dysfunction, were collected by third-party telephone interview before treatment and at 2, 6, 12, and 24 months after treatment; men who completed a pretreatment evaluation (1201/1371 eligible patients who had agreed to be contacted) comprised the PROSTQA cohort.
Among the 1201 men registered for follow-up, 1027 (86%) completed the 24-month interview and are the focus of this study. Their primary treatment included either prostatectomy (n = 524), external beam radiotherapy (n = 241), or brachytherapy (n = 262).
Participant Characteristics by Meat Consumption. Part 2
We tested the proportional hazard assumption for each meat intake variable in relation to colon or rectal cancer using the likelihood ratio test, comparing models with and without product terms for meat consumption (quintiles) and follow-up time (years). We evaluated effect modification of the RR for colon and rectal cancer in relation to meat consumption by other covariates using the likelihood ratio test comparing models with and without interaction terms. The Wald statistic was used to test for homogeneity of the RR for proximal and distal colon cancers.63 All P values were 2-sided and considered significant at P<.05. All analyses were conducted using SAS version 9.0 (SAS Institute Inc, Cary, NC).
Participant Characteristics by Meat Consumption
Men and women reported a wide range in consumption of red and processed meat in 1992/1993. A 10-fold difference was observed between the lowest and highest quintiles of red meat in men and a 17-fold difference in women (Table 1). Men reported greater consumption of red and processed meat than did women; median intake was 427 g/wk and 274 g/wk for red meat among men and women, respectively, and 95 g/wk and 43 g/wk for processed meat, respectively. There was little variation in the consumption of poultry and fish by quintiles of red meat intake. Men also reported substantially higher intake of red and processed meats in 1982 than did women (data not shown). Approximately half of the men and women in the top tertile for consumption of red or processed meat in 1982 were also in the highest tertile in 1992/1993 (data not shown). The absolute levels of meat consumption in 1982 could not be compared with consumption in 1992/1993 due to differences in the questionnaires.
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Men and women who reported higher intake of red meat in 1992/1993 were more likely to report lower educational attainment, no recreational physical activity, higher body mass index, current cigarette smoking, beer and liquor drinking, higher total daily energy intake, low fruit intake in 1992/1993, and little or no intake of vegetables or high-fiber grain foods in 1982 compared with those with lower red meat intake. Men and women who reported lower red meat intake tended to report multivitamin use in 1982, wine drinking, and (in women) use of hormone therapy in 1992/1993.
Meat Consumption and Colon Cancer Incidence
Table 2 shows the relationship between colon cancer incidence and meat consumption as reported in 1992/1993. Higher intake of red and processed meat was associated with higher colon cancer risk in men and women in models that adjusted only for age and energy intake. However, the positive associations were attenuated in analyses that further adjusted for nondietary factors, including education, body mass index, cigarette smoking, recreational physical activity, use of multivitamins or aspirin, and (in women) use of hormone therapy. Further adjustment for dietary factors had little effect on the RR estimates. No association was observed between colon cancer incidence and consumption frequency of beef, pork, or lamb as a main dish, or with reported preference for red meat doneness (data not shown).
Incident Colon and Rectal Cancer
A total of 1197 incident cancers of the colon (International Classification of Diseases codes: C18.0, C18.2-C18.9)56-57 and 470 cancers of the rectosigmoid junction (C19.0)56-57 or rectum (C20.9)56-57 were identified. Of these, 665 colon and 291 rectal cancers were diagnosed in men, and 532 colon and 179 rectal cancers in women. A total of 1335 (80%) of 1667 colorectal cancers were self-reported on the 1997, 1999, or 2001 questionnaires and subsequently verified by medical record abstraction or linkage with state cancer registries; another 43 (3%) were identified while verifying a different reported cancer; and 289 (17%) were identified as interval deaths, defined as persons who died with colon or rectal cancer recorded on death certificate but not reported on the questionnaire. Linkage with state cancer registries confirmed the diagnosis of colon or rectal cancer in 74% of interval deaths. Subsite-specific analyses were conducted on 667 proximal (cecum to splenic flexure) and 408 distal (descending to sigmoid colon) colon cancers, excluding those with overlapping or unspecified site codes. We also present the results from analyses of 470 cancers of the rectosigmoid and rectum combined but not from separate analyses of the rectosigmoid junction (214 cases) or rectum (246 cases). The remaining 10 cases were unspecified (not able to distinguish as rectum or rectosigmoid junction).
Meat Consumption
Dietary assessment in 1992/1993 was based on a 68-item modified Block58 food-frequency questionnaire (FFQ); nutrient values were estimated using the Dietary Analysis System version 3.8a.59 Participants were asked to report their usual eating habits during the past year, including average frequency and serving size (small, medium, or large) of each food and beverage listed. Consumption of each meat item in grams per week was estimated by taking the product of average frequency per week, number of grams in a medium serving, and serving size (0.5 for small, 1.0 for medium, and 1.5 for large). Intake of red meat, poultry and fish, and processed meat (g/wk) was computed by summing across meat items that contributed to each meat group and categorizing by quintile. The lowest quintile of intake served as the referent group for analyses.
We considered red meat to include the following individual or grouped items on the questionnaire: bacon; sausage; hamburgers, cheeseburgers, meatloaf, or casserole with ground beef; beef (steaks, roasts, etc, including sandwiches); beef stew, or pot pie with carrots or other vegetables; liver, including chicken livers; pork, including chops, roast; hot dogs; and ham, bologna, salami, or lunchmeat. Food items classified as poultry and fish included chicken or turkey (roasted, stewed, broiled, ground, including sandwiches); fried chicken; fried fish or fish sandwich; tuna, tuna salad, tuna casserole; and other fish (broiled or baked). We considered processed meat to include bacon; sausage; hot dogs; and ham, bologna, salami, or lunchmeat. We computed the ratio of red meat-to-poultry and fish by dividing red meat intake by intake of poultry and fish (g/wk); individuals were assigned to the lowest or highest quintile when either value was 0. An additional question, “How often did you eat beef, pork, or lamb as a main dish, eg, steak, roast ham, etc (4-6 ounces)?” was included for comparison with other studies that included this question. Participants were also asked, “When you eat red meat such as beef, pork, or lamb, how well done is it cooked?” with the following possible responses on the questionnaire, “well-done, medium well done, medium rare, rare, and don’t eat red meat.”
Long-term Mortality and Survival. Part 4
We acknowledge that 7 of the original 69 centers did not participate in our long-term program, reducing our cohort by 11%; however, we believe this reduction had little effect because the in-hospital mortality by study group was similarly distributed among the 62 centers participating in this study vs the 7 centers that did not (data available from authors upon request). Additionally, although 87% of participating centers had complete 5-year survival data, 13% of patients were lost to follow-up between 6 weeks and 5 years and were censored in survival analyses. The distribution of these patients among the study groups, however, was similar.
Regarding secondary dose-relationship analyses, we suggest cautious interpretation. The relationships, which contrasted 3 groups (control-no drug, low-dose, high-dose) were based on dose criteria that—although defined prospectively—were made intentionally rigid, thereby minimizing clinician subjectivity in dose choice, use of comingled (low-high) doses, or inadequate- or excessive-dose regimens. While we believe our findings are reliable for the predefined subgroup, we recognize that a sizeable number of patients not meeting the criteria were not included in the analysis. Thus, the dose/relationship findings only are suggestive and should be interpreted as such.
CONCLUSIONS
The association between aprotinin and long-term mortality indicates that serious safety concerns extend beyond the perioperative period. Therefore, continued use of aprotinin in this population does not appear prudent, given that safer alternatives—aminocaproic acid and tranexamic acid—are available.
Author Affiliations: Ischemia Research and Education Foundation, San Bruno, Calif (Drs Mangano, Miao, Titov, and Dietzel); Department of Anesthesia, Papworth Hospital, Cambridge, England (Dr Vuylsteke); Department of Anesthesia, Escorts Heart Institute, New Delhi, India (Dr Juneja); Department of Cardiac Anesthesia and Intensive Care, Institute of Cardiology, Bucharest, Romania (Dr Filipescu); Klinik und Poliklinik für Anaesthesiologie und Spezielle Intensivmedizin, University of Bonn, Bonn, Germany (Dr Hoeft); Department of Anesthesiology, Yale University, New Haven, Conn (Dr Fontes); Department of Cardiac Anesthesia, St Luke's Roosevelt Hospital, New York, NY (Dr Hillel); Institut für Anaesthesiologie, Ludwig-Maximilians Universität, Munich, Germany (Dr Ott); Department of Laboratory Medicine, University of California School of Medicine, San Francisco (Dr Levin). Dr Tudor is now with ALZA Corporation, Mountain View, Calif, and Dr Fontes is now with Weill Medical College of Cornell University, New York, NY.
Long-term Mortality and Survival. Part 3
Clinical Implications
We estimate that over the past year, aprotinin was prescribed worldwide to at least 200 000 cardiac surgery patients having a profile similar to patients in our study. For such patients, our study found a 5% absolute increase in 5-year mortality (1% per year for 5 years) associated with aprotinin use, compared with either aminocaproic or tranexamic acid use. Thus, in 2006 alone, had aprotinin been replaced with either of these generic agents, we estimate that approximately 2000 deaths per year for the next 5 years (or 10 000 total deaths) might have been avoided.
Limitations
Large-scale randomized controlled trials are accepted as the criterion standard for efficacy, but for assessment of post-marketing safety, these are uncommonly performed even when mandated by regulatory agencies. Further, even clinical trials are subject to the serious limitation of patient selection bias, given post-marketing imbedded practice—a consideration that has been recognized1 and thoroughly addressed and is based on a clinician's hesitancy to either withhold a perceived effective therapy (placebo group assignment) or administer a perceived unsafe drug (drug group assignment). Despite the well-known limitations of observational studies, we note that our conclusions survived multiple primary and secondary covariate challenges and were consistent across multiple risk groups. Despite differences in use patterns by center and by country for the biochemically similar lysine analogs, aminocaproic acid and tranexamic acid, their long-term survival patterns were virtually identical. This likely reflected that drug effect predominated over any selection pattern biases that may have existed, findings confirmed by the negligible effects of propensity adjustment on their relative survival patterns, even when a nonparsimonious approach was taken.
Regarding the concern that patients receiving aprotinin may have had more complex or advanced preoperative disease, we believe that such differences had little effect on our 5-year mortality findings for a number of reasons: (1) all variables were assessed in proportional hazard and logistic regression analyses and found to have little effect on the association between aprotinin and mortality with or without propensity correction; (2) none of the imbalances (bleeding agent vs no bleeding agent groups) remained significant following propensity adjustment; (3) among the patients with risk factors for in-hospital renal, cardiovascular, and cerebrovascular events, the associations for aprotinin—and lack of association for aminocaproic and tranexamic acid—persisted; (4) these associations prevailed for at-risk patients as characterized by risk indices for in-hospital and long-term events (Cleveland Clinic, Society of Thoracic Surgeons, additive EuroSCORE, logistic EuroSCORE, Veterans Affairs indices) and although these indices were developed primarily for in-hospital events, we believe they are useful in this study for descriptive purposes; and (5) regarding survival, our findings using proportional hazard techniques and adjusted mortality (survival) curves indicate that the association between aprotinin and mortality remained significant when adjusted for pre-existing disease. Thus, we believe that our findings are substantive for effect size and consistency among risk groups, as well as for their conformity with the earlier IMAGE trial and US Food and Drug Administration review findings regarding aprotinin's association with acute occlusion of newly placed coronary vein grafts.
Long-term Mortality and Survival. Part 2
These observations suggest that the deleterious perioperative safety findings previously reported for the serine protease antagonist aprotinin are not self-limited, as has been suggested, but that their consequences likely continue over months to years following administration of aprotinin. To provide insight into this observation, we cite 3 related areas of research: (1) clinical experiences suggesting an association of aprotinin with thrombosis (arterial, venous, coronary graft); (2) the natural history of acute thrombosis as it relates to long-term outcome; and (3) prior experiences addressing long-term effects of acute, time-limited therapy.
Concerns of a possible relationship between aprotinin and thrombosis arose soon after approval,14-15 suggesting that an antagonist of serine protease activity (aprotinin) might be expected to promote thrombosis, given that tissue plasminogen activator, an agonist of serine protease activity, prevents coronary occlusion effects in similar patients.42 Several other studies, however, did not find an association of aprotinin with thrombosis.43-45
The US Food and Drug Administration then conducted a retrospective review of 1307 placebo-treated and 2004 aprotinin-treated patients, finding a statistically significant association between aprotinin use and coronary graft closure (occluded grafts). Based on those data, a prospective randomized trial (International Multicenter Aprotinin Graft Patency Experience) was conducted, which found a statistically significant 41% increase in coronary graft occlusion occurring within 2 weeks of aprotinin use vs placebo (the primary end point).16 Given the US Food and Drug Administration's analysis and the prospective results of the IMAGE study, there exists reasonable evidence to suggest that graft occlusion may occur within days of aprotinin use in at least some at-risk patients.
The natural history of acute coronary thrombosis and occlusion, as well as the experiences in the settings of medical and surgical revascularization, also suggests that clinical sequelae may manifest after months to years following arterial occlusion, as also noted in the accompanying commentary to the IMAGE study. Our observation of significant effects long after aprotinin administration is not surprising given the experiences with the serine protease agonist therapy, tissue plasminogen activator, the acute administration of which produces effects lasting for 5 years or longer. Similar examples are provided by the long-term effects of fibrinolytics (streptokinase), as well as β-blockers (atenolol) in surgical patients. Other perioperative studies indicate that seemingly reversible perioperative adverse events, such as postoperative myocardial ischemia, can have fatal consequences that only are realized months to years after hospital discharge. Accordingly, the long-term adverse effects of aprotinin detected in our study appear consistent with reported clinical observations in similar patients, in whom the effects of an acutely administered therapy can manifest over multiple years.