Evolving trends in risk profiles and causes of death after heart transplantation: a ten-year multi-institutional study.

BACKGROUND: As therapeutic options evolve for advanced heart failure, the appropriate role for cardiac transplantation will require survival analyses that reflect changing trends in causes of death and patient and institutional risk profiles. Results from multi-institutional studies could be used to monitor progress in individual centers. METHODS: Between 1990 and 1999, 7290 patients undergoing cardiac transplantation in 42 institutions entered a formal outcomes study. Changing survival, causes of death, and patient risk profiles were analyzed. Multivariable risk-factor equations were applied to a single institution (300 primary heart transplants) to examine differences in risk-adjusted expected versus observed actuarial outcomes over time. RESULTS: Overall survival in the 42 institutions improved during the decade (P =.02). One- and 3-year cardiac transplant research database survival was as follows: era 1 (1990-1992), 84% and 76%, respectively; era 2 (1993-1995), 85% and 79%, respectively; and era 3 (1996-1999), 85% and 79%, respectively. Causes of death changed over time. Pretransplantation risk profiles increased over time (P =.0001), with increases in reoperations, devices, diabetes, severely ill recipients, pulmonary vascular resistance, sensitization, ischemic times, donor age, and donor inotropic support. Three-year actuarial survival in a single institution was 3% less than risk-adjusted predicted survival in era 1, 1% higher than predicted in era 2, and 7% higher than predicted in era 3. CONCLUSIONS: Survival after cardiac transplantation is gradually improving, despite increasing risk profiles. Further improvement requires periodic re-evaluation of risk profiles and causes of death to target areas of surveillance, therapy, and research. By using these methods, progress at individual institutions can be assessed in a time-related, risk-adjusted manner that also reflects changing institutional experience, expertise, or both.

Pitfalls in assessing the quality of care for patients with cardiovascular disease.

PURPOSE: There are no clinical performance measures for cardiovascular diseases that span the continuum of hospital through postdischarge ambulatory care. We tested the feasibility of developing and implementing such measures for patients with acute myocardial infarction, congestive heart failure, or hypertension. SUBJECTS AND METHODS: After reviewing practice guidelines and the medical literature, we developed potential measures related to therapy, diagnostic evaluation, and communication. We tested the feasibility of implementing the selected measures for 518 patients with myocardial infarction, 396 with heart failure, and 601 with hypertension who were enrolled in four major U.S. managed care plans at six geographic sites, using data from administrative claims, medical records, and patient surveys. RESULTS: Difficulties in obtaining timely data and small numbers of cases adversely affected measurement. We encountered 6- to 12-month delays, disagreement between principal discharge diagnosis as coded in administrative and records data (for 9% of myocardial infarction and 21% of heart failure patients), missing medical records (20% for both myocardial infarction and heart failure patients), and problems in identifying physicians accountable for care. Low rates of performing key diagnostic tests (e.g., ejection fraction) excluded many cases from measures of appropriate therapy that were conditional on test results. Patient survey response rates were low. CONCLUSIONS: Constructing meaningful clinical performance measures is straightforward, but implementing them on a large scale will require improved data systems. Lack of standardized data captured at the point of clinical care and low rates of eligibility for key measures hamper measurement of quality of care.

Health-related quality of life measurement in heart failure: challenges for the new millennium.

Health-related quality of life (HRQL), representing a patient-driven end point, has been increasingly emphasized in randomized clinical trials of new heart failure therapies. Measurement of HRQL depends on the use of validated instruments, with attention paid to the timing of administration and analysis of data in the context of conventional morbidity and mortality end points. In a review of HRQL measurement in heart failure drug trials published from 1966 to 1999, we found that important data, such as the number of participating subjects, are often lacking. HRQL is analyzed as a stand-alone end point without consideration of the underlying clinical trajectory of the disease. Improvements in trials methodology are warranted if quality-of-life data are to be meaningful in the determination of drug efficacy in heart failure.

Angiography of potential cardiac donors.

OBJECTIVES: This retrospective review of organ donor records was designed to evaluate the practice of donor angiography in one organ procurement organization and determine the outcomes of angiography and its impact on the timing of the organ donation process. BACKGROUND: Concerns about transmission of atherosclerosis from donor to recipient have been heightened by the increasing prevalence of older donors. Guidelines that advocate the use of angiography in specific settings have been published, but no formal large-scale review has been performed. METHODS: For the period January 1993 through June 1997, we reviewed all New England Organ Bank records of donors between the ages of 40 and 65 including any from whom at least one solid organ was procured. Data abstracted included the presence of risk factors, timing of the evaluation process and angiographic findings. RESULTS: Coronary angiography was performed in 119 donors aged 40 and older; 64.7% of these hearts were transplanted. Thirty-eight hearts were transplanted from donors not subjected to angiography and outcomes were poorer compared with donors who underwent angiography. Advanced donor age was the only significant predictor of coronary artery disease. The duration of the procurement process was not prolonged by the performance of angiography. CONCLUSIONS: Donor coronary angiography does not complicate the donation process. Older donor age is the most powerful predictor of coronary artery disease and may explain prior observations of poorer outcome with older donor hearts. These factors should be considered when angiography is performed as part of the heart donor evaluation.

Impact of underuse, overuse, and discretionary use on geographic variation in the use of coronary angiography after acute myocardial infarction.

BACKGROUND: Geographic variation in the use of medical procedures has been well documented. However, it is not known whether this variation is due to differences in use when procedures are indicated, discretionary, or contraindicated. OBJECTIVES: To examine whether use of coronary angiography after acute myocardial infarction (AMI) according to appropriateness criteria varied across geographic regions and whether underuse, overuse, or discretionary use accounted for variation in overall use. DESIGN: Retrospective cohort study using data from the Cooperative Cardiovascular Project. SETTING: Ninety-five hospital referral regions. PATIENTS: There were 44,294 Medicare patients hospitalized with AMI during 1994 or 1995, classified according to appropriateness for angiography. MAIN OUTCOME MEASURE: Variation in use of angiography, as measured by the difference between high and low rates of use across regions. RESULTS: Across regions, variation in the use of angiography was similar for indications judged necessary; appropriate, but not necessary; or uncertain. Variation was lowest for indications judged unsuitable (difference between high rate and low rate across regions = 16.3%; 95% CI = 12.6%; 20.6%). The primary cause of variation in the overall rate of angiography was due to use for indications judged appropriate, but not necessary or uncertain. When variation associated with these indications was accounted for, the difference between the resulting high and low overall rates was 10.8% (9.4%, 12.4%). In contrast, variation in the overall rate remained high when underuse in necessary situations or overuse in unsuitable situations was accounted for. CONCLUSIONS: Across regions, practice was more similar for patients categorized unsuitable for angiography than for patients with other indications. Variation in overall use of angiography appeared to be driven by utilization for discretionary indications rather than by underuse or overuse. If equivalent rates across geographic areas are judged desirable, then greater effort must be directed toward defining care for patients with discretionary indications.

Safety, tolerability, and efficacy of cyclosporine microemulsion in heart transplant recipients: a randomized, multicenter, double-blind comparison with the oil-based formulation of cyclosporine--results at 24 months after transplantation.

BACKGROUND: The widespread use of cyclosporine has improved the survival of cardiac transplant patients as a result of reduced morbidity and mortality from rejection and infection. The original oil-based form of cyclosporine demonstrated unpredictable absorption resulting in an increased frequency of acute and chronic rejection in patients with poor bioavailability. The primary end. points of the present, prospective, randomized multicenter, double-blind trial were to compare the efficacy of the micro-emulsion form of cycolsporine (CsA-NL) with the oil-based formulation as determined by cardiac allograft and recipient survival and the incidence and severity of the acute rejection episodes and to determine the safety and tolerability of CsA-NL compared with Sandimmune CsA-(SM) in the study population. The 6-month analysis of the study showed reduced number of CsA-NL patients requiring antilymphocyte antibody therapy for rejection, fewer International Society of Heart and Lung Transplantation grade > or =3A rejections in female patients and fewer infections. Our report represents the final analysis of the results 24 months after transplantation. METHODS: A total of 380 patients undergoing de novo cardiac transplants at 24 centers in the United States, Canada, and Europe were enrolled in this double-blind, randomized trial evaluating the efficacy and safety of CsA-NL versus CsA-SM. Acute allograft rejection was diagnosed by endomyocardial biopsy and graded according to the International Society of Heart and Lung Transplantation nomenclature. Kaplan-Meier analysis and Fisher's exact test were used for comparisons between groups. RESULTS: After 24 months, allograft and recipient survival were identical in both groups. There were fewer CsA-NL patients (6.9%) requiring antilymphocyte antibody therapy for rejection than in the CsA-SM-treated patient group (17.7%, P=0.002). There were fewer discontinuations of study drug for treatment failures in the CsA-NL groups (7; 3.7%) compared with the CsA-SM group (18; 9.4%, P=0.037). The average corticosteroid dose was lower in the CsA-NL group (0.37 mg/kg/day) compared with the CsA-SM group (0.48 mg/kg/day, P=0.034) over the 24-month study period. Overall, there was no difference in blood pressure or creatinine between the two study groups. CONCLUSIONS: The final results of this multi-center, randomized study of two forms of cyclosporine confirmed that there were fewer episodes of rejection requiring antilymphocyte antibodies and fewer study discontinuations for treatment failures in CsA-NL-treated patients compared to those treated with CsA-SM. The use of CsA-NL did not predispose these patients to a higher risk of adverse events.

Update on recent clinical trials in congestive heart failure.

Understanding of the pathophysiology of heart failure has advanced over the last decade, resulting in new therapeutic advances. Convincing data exist that angiotensin-converting enzyme (ACE) inhibition and adrenergic blockade are the most important therapies and have the capacity to improve survival and lower morbidity. Higher doses of both ACE inhibitors and beta-blockers appear to provide additional benefits. The aldosterone antagonist spironolactone, when used in severe heart failure, provides additional survival advantage when added to standard triple therapy. Angiotensin receptor blockers have not been shown to be superior to ACE inhibitors, and their role in heart failure treatment requires further investigation. No trial's data support the use of inotropic agents or calcium channel blockers in heart failure. A number of new therapeutic agents, including vasopressin antagonists and tumor necrosis factor-alpha receptor antibody are in phase II and III clinical trials. If proved beneficial, they may provide new treatment options for patients with heart failure. Nevertheless, the current challenge is to increase the use of proven therapies, namely ACE inhibitors and beta-blockers, to improve outcomes in the rapidly growing population of patients with congestive heart failure.

Safety, tolerability and efficacy of cyclosporine microemulsion in heart transplant recipients: a randomized, multicenter, double-blind comparison with the oil based formulation of cyclosporine--results at six months after transplantation.

BACKGROUND: The introduction of cyclosporine has resulted in significant improvement in the survival of cardiac allograft recipients due to decreased mortality from infection and rejection. The original oil-based cyclosporine formulation exhibits variable and unpredictable bioavailability that correlates with an increased incidence of acute and chronic rejection in those patients in whom this is most pronounced. The primary objectives of this prospective, multicenter, randomized, double-blind study in cardiac transplant patients were: to compare the efficacy of cyclosporine microemulsion (CsA-NL) with oil-based cyclosporine (CsA-SM) as measured by cardiac allograft and recipient survival and the incidence and severity of acute rejection episodes; and to assess the safety and tolerability of CsA-NL compared with CsA-SM in this population. This report represents the analysis of results 6 months after transplantation. METHODS: A total of 380 patients undergoing their first cardiac transplant at 24 centers in the United States, Canada, and Europe were enrolled in this double-blind, randomized trial examining the safety and efficacy of CsA-NL versus CsA-SM. Rejection was diagnosed using endomyocardial biopsy and were graded according to standardized criteria of the International Society of Heart and Lung Transplantation (ISHLT). Clinical parameters were monitored during the study. Survival and freedom from were used for analysis as was Fisher's exact test for comparisons between groups. RESULTS: At 6 months after transplantation, allograft and patient survival were the same for both groups. The frequency of ISHLT grade 3A or greater episodes in the two groups was identical. Fewer CsA-NL patients (5.9%) required antilymphocyte antibody (ATG or OKT-3) therapy for rejection compared with the CsA-SM-treated patients (14.1%, P=0.01). Females with ISHLT rejection grade > or = 3A treated with CsA-NL had a 46% lower incidence of rejection compared with the CsA-SM-treated group (31.3% vs. 57.6%, P=0.032). Fewer infections were seen in the CsA-NL. With the exception of baseline and 1 week posttransplant creatinines which were higher in the CsA-NL group, the overall creatinine was not significantly different between the two groups. CONCLUSIONS: This multicenter, randomized study of cardiac transplant recipients documented less severe rejection (in particular those requiring antibody therapy) and a lower incidence of infection in CsA-NL-treated patients. Results from the female subgroup analysis suggest that the improved bioavailability of CsA-NL might reduce the frequency of rejection episodes in female patients. The use of CsA-NL was not associated with an increased risk of adverse events.

Cardiac glycosides in the next millennium.

Despite the documented efficacy of cardiac glycosides in improving symptoms in patients with heart failure caused by systolic ventricular dysfunction, considerable debate continues as to whether the use of this class of drugs should continue into the next millennium. In this review, the authors briefly examine the basic pharmacology of these drugs relevant to the treatment of heart failure, emphasizing their role in reducing sympathetic nervous system activity in patients with advanced heart failure. Next, withdrawal trials and the Digoxin Investigation Group dataset are reviewed in some detail. Despite these important additional data on the safety and efficacy of digitalis use in heart failure that became available in the 1990s, considerable controversy remains. Perhaps most importantly, if the mechanism by which these drugs improve symptoms in patients with heart failure is principally mediated by sympatholytic activity, do they remain relevant as beta-adrenergic antagonists become standard therapy for this disease?

Digitalis.

Cardiac glycosides have played a prominent role in the therapy of congestive heart failure since William Withering codified their use in his late 18th century monograph on the efficacy of the leaves of the common foxglove plant (Digitalis purpurea). Despite their widespread acceptance into medical practice in the ensuing 200 years, both the efficacy and the safety of this class of drugs continue to be a topic of debate. Moreover, despite the fact that the molecular target for the cardiac glycosides, the alpha-subunit of sarcolemmal Na+K+-ATPase (or sodium pump) found on most eukaryotic cell membranes, has been known for several decades, it remains controversial whether the sympatholytic or positive inotropic effects of these agents is the mechanism most relevant to relief of heart failure symptoms in humans with systolic ventricular dysfunction. Herein, we review the molecular and clinical pharmacology of this venerable class of drugs, as well as the manifestations of digitalis toxicity and their treatment. We also review in some detail recent clinical trials designed to examine the efficacy of these drugs in heart failure, with a focus on the Digoxin Investigation Group data set. Although, in our opinion, the data on balance warrant the continued use of these drugs for the treatment of symptoms of heart failure in patients already receiving contemporary multidrug therapy for this disease, the use of digitalis preparations will inevitably decline with the maturation of newer pharmacotherapies.

Effect of local medical opinion leaders on quality of care for acute myocardial infarction: a randomized controlled trial.

CONTEXT: The effectiveness of recruiting local medical opinion leaders to improve quality of care is poorly understood. OBJECTIVE: To evaluate a guideline-implementation intervention of clinician education by local opinion leaders and performance feedback to (1) increase use of lifesaving drugs (aspirin and thrombolytics in eligible elderly patients, beta-blockers in all eligible patients) for acute myocardial infarction (AMI), and (2) decrease use of a potentially harmful therapy (prophylactic lidocaine). DESIGN: Randomized controlled trial with hospital as the unit of randomization, intervention, and analysis. SETTING: Thirty-seven community hospitals in Minnesota. PATIENTS: All patients with AMI admitted to study hospitals over 10 months before (1992-1993, N=2409) or after (1995-1996, N=2938) the intervention. INTERVENTION: Using a validated survey, we identified opinion leaders at 20 experimental hospitals who influenced peers through small and large group discussions, informal consultations, and revisions of protocols and clinical pathways. They focused on (1) evidence (drug efficacy), (2) comparative performance, and (3) barriers to change. Control hospitals received mailed performance feedback. MAIN OUTCOME MEASURES: Hospital-specific changes before and after the intervention in the proportion of eligible patients receiving each study drug. RESULTS: Among experimental hospitals, the median change in the proportion of eligible elderly patients receiving aspirin was +0.13 (17% increase from 0.77 at baseline), compared with a change of -0.03 at control hospitals (P=.04). For beta-blockers, the respective changes were +0.31 (63% increase from 0.49 at baseline) vs +0.18 (30% increase from baseline) for controls (P=.02). Lidocaine use declined by about 50% in both groups. The intervention did not increase thrombolysis in the elderly (from 0.73 at baseline), but nearly two thirds of eligible nonrecipients were older than 85 years, had severe comorbidities, or presented after at least 6 hours. CONCLUSIONS: Working with opinion leaders and providing performance feedback can accelerate adoption of some beneficial AMI therapies (eg, aspirin, beta-blockers). Secular changes in knowledge and hospital protocols may extinguish outdated practices (eg, prophylactic lidocaine). However, it is more difficult to increase use of effective but riskier treatments (eg, thrombolysis) for frail elderly patients.

Delayed hospital presentation in patients who have had acute myocardial infarction.

BACKGROUND: In patients who have had acute myocardial infarction, the delay between the onset of symptoms and hospital presentation is a critical factor in determining the initial management strategy and outcomes of treatment. OBJECTIVE: To examine the determinants of delayed hospital presentation in patients who have had acute myocardial infarction. DESIGN: Retrospective chart review. SETTING: 37 hospitals in Minnesota. PATIENTS: 2409 persons hospitalized with acute myocardial infarction between October 1992 and July 1993. MAIN OUTCOME MEASURE: Hospital presentation delayed more than 6 hours after the onset of symptoms of acute myocardial infarction. RESULTS: Information on length of delay was available for 2404 patients. Of these patients, 969 (40%) delayed presentation to the hospital for more than 6 hours after the onset of symptoms. Factors associated with prolonged delay included advanced age and female sex. The presence of chest discomfort and a history of mechanical revascularization significantly reduced the risk for prolonged delay. Risk for delay was greatest during the evening and early morning hours (6:00 p.m. to 6:00 a.m.) Patients with a history of hypertension were more likely to delay presentation. Only 42% of all patients hospitalized with acute myocardial infarction had used emergency medical transport services. CONCLUSIONS: Patients who have had acute myocardial infarction often delay hospital presentation. Educational interventions that encourage the prompt use of emergency medical transport services and target specific patient populations, such as elderly persons, women, and persons with cardiac risk factors, may be most successful in reducing the length of delay and improving the outcomes of patients with acute myocardial infarction.

Coronary angiography and angioplasty after acute myocardial infarction.

PURPOSE: To assess the data that support the use of coronary angiography and angioplasty after acute myocardial infarction, that identify the risks of these procedures, and that analyze their use and costs. DATA SOURCES: English-language articles published between 1970 and June 1995 identified through a search of the MEDLINE database. STUDY SELECTION: Studies that contained information about benefits, risks, use, and costs of coronary angiography and angioplasty after acute myocardial infarction. DATA EXTRACTION: Descriptive and analytic data from each study were collected. DATA SYNTHESIS: The outcome for patients who have complications of myocardial infarction (such as shock) is poor. Such patients usually undergo angiography, although the evidence that supports this practice is weak. Preliminary data suggest that patients who immediately have angiography and angioplasty after acute myocardial infarction have better outcomes than do patients who receive thrombolytic therapy with angioplasty only for specific indications in experienced centers. After the acute phase of myocardial infarction, patients who have noninvasive evidence of persistent or recurrent ischemia are believed to benefit from angiography. In the remaining patients, however, angiography after myocardial infarction has not been shown to be beneficial. Coronary angiography is done in 30% to 81% of patients after acute myocardial infarction in different settings and regions; for many of these patients, the benefit is questionable. Better outcomes are not always associated with more frequent use of the procedure. In the United States, catheterizations after myocardial infarction cost approximately $1 billion per year. CONCLUSIONS: Although many patients benefit from angiography and angioplasty after myocardial infarction, others probably do not. Substantial resources are at stake.

Bradycardia: a late complication following cardiac transplantation.

Symptomatic bradycardia occurred in 11 of 213 patients (5.2%) surviving > 1 year after orthotopic heart transplantation, most of whom were managed with permanent pacemakers. Evidence for sinus and/or atrioventricular node dysfunction was present in many cases, but patients at risk for this complication could not be predicted from baseline clinical characteristics.

Adherence to national guidelines for drug treatment of suspected acute myocardial infarction: evidence for undertreatment in women and the elderly.

BACKGROUND: Evidence-based guidelines for the treatment of patients with acute myocardial infarction (AMI) have been published and disseminated by the American College of Cardiology and the American Heart Association. Few studies have examined the rates of adherence to these guidelines in eligible populations and the influence of age and gender on highly effective AMI treatments in community hospital settings. METHODS: Medical records of 2409 individuals admitted to 37 Minnesota hospitals between October 1992 and July 1993 for AMI, suspected AMI, or rule-out AMI, and meeting electrocardiographic, laboratory, and clinical criteria suggestive of AMI were reviewed to determine the proportion of eligible patients who received thrombolytic, beta-blocker, aspirin, and lidocaine hydrochloride therapy. The effects of patient age, gender, and hospital teaching status on the use of these treatments were estimated using logistic regression models. RESULTS: Eligibility for treatment ranged from 68% (n=1627) for aspirin therapy, 38% (n=906) for lidocaine therapy, and 30% (n=734) for thrombolytic therapy to 19% (n=447) for beta-blocker therapy. Seventy-two percent of patients eligible to receive a thrombolytic agent received this therapy; 53% received beta-blockers; 81% received aspirin; and 88% received lidocaine. Among patients ineligible for lidocaine therapy (n=1503), 20% received this agent. Use of study drugs was lower among eligible elderly patients, especially those older than 74 years (thrombolytic agent: odds ratio, 0.2; 95% confidence interval, 0.1 to 0.4; aspirin: odds ratio, 0.4, 95% confidence interval, 0.3 to 0.6; beta-blocker: odds ratio, 0.4; 95% confidence interval, 0.2 to 0.8). Female gender was associated with lower levels of aspirin use among eligible patients (odds ratio, 0.7; 95% confidence interval, 0.6 to 0.9); and there was a trend toward lower levels of beta-blocker and thrombolytic use among eligible women. CONCLUSIONS: Use of lifesaving therapies for eligible patients with AMI is higher than previously reported, particularly for aspirin and thrombolytic use in nonelderly patients. Lidocaine is still used inappropriately in a substantial proportion of patients with AMI. Increased adherence to AMI treatment guidelines is required for elderly patients and women.