Antiplatelet therapy in the prevention of ischemic vascular events: literature review and evidence-based guidelines for drug selection.

BACKGROUND: New antiplatelet drugs are being developed and many clinical trials evaluating the benefits of antiplatelet drugs for the secondary prevention of ischemic events in patients with atherosclerotic vascular disease have been performed. HYPOTHESIS: An updated systematic review and evidence-based guidelines for the appropriate selection of antiplatelet drugs may be beneficial to physicians and healthcare organizations attempting to create or update current clinical practice guidelines or clinical pathways aimed at caring for these patients. METHODS: (1) A systematic review of the recent literature on the relative efficacy and safety of aspirin, ticlopidine, and clopidogrel was undertaken; (2) an evidence-based, expert panel approach using a modified Delphi technique to create explicit guidelines for prescribing antiplatelet therapy was instituted; and (3) the recommendations of an expert panel were summarized. RESULTS: Consensus guidelines were developed for the utilization of aspirin, ticlopidine, or clopidogrel for the prevention of ischemic events in patients with manifestations of atherosclerotic vascular disease (prior myocardial infarction, prior ischemic stroke, or established peripheral arterial disease) who are at increased risk for recurrent ischemic events. Based on efficacy and safety, clopidogrel was recommended as the drug of choice for patients with established peripheral arterial disease; aspirin or clopidogrel should be considered in patients with prior myocardial infarction (with clopidogrel favored for patients who have had a recurrent event while on aspirin or in whom aspirin is contraindicated); aspirin or clopidogrel should be considered as first-line treatment in patients with prior ischemic (nonhemorrhagic) stroke--however, clopidogrel is the favored drug in patients in whom other antiplatelet drugs are either contraindicated or who have had recurrent events while on therapy. CONCLUSIONS: Myocardial infarction, ischemic stroke, and peripheral arterial disease are all clinical manifestations of the same underlying disease process (atherosclerosis), with thrombus formation on the disrupted atherosclerotic plaque (atherothrombosis) being a common precipitating factor of ischemic events in patients suffering from these disorders. An evidence-based approach was used to develop a practice guideline, based on available published evidence, for the appropriate utilization of antiplatelet agents (aspirin, ticlopidine, or clopidogrel). These guidelines may be of use to multidisciplinary teams wishing to create or update clinical guidelines or clinical pathways which address the care of patients with atherosclerotic vascular disease. New antiplatelet agents such as clopidogrel may be more effective and associated with lower risk of selected adverse effects (such as gastrointestinal distress, gastrointestinal hemorrhage, and neutropenia) than those previously used to prevent thrombus formation in the setting of atherosclerotic arterial disease. Combination antiplatelet therapy is being evaluated as an option for those patients who experience recurrent events on a single antiplatelet agent.

Neurohormonal changes after implantation of a left ventricular assist system.

In patients with left ventricular dysfunction, neurohormonal levels are valuable indicators of the severity of heart disease and prognosis. For patients with severe left ventricular dysfunction, left ventricular assist systems (LVAS) are effective as short-term bridges to heart transplantation and are currently being investigated for long-term use. Unknown, however, are the effects of mechanical unloading of the left ventricle on neurohormone levels during the initial weeks after LVAS implantation, and whether these changes are similar to the neurohormonal level decreases observed after cardiac transplantation. This study was undertaken to determine the effect of LVAS support on plasma norepinephrine (PNE) levels during the initial weeks after device implantation. The PNE levels in five consecutive patients with left ventricular dysfunction were measured within 1 week after LVAS implantation and every week thereafter for 5 weeks. Significant decreases in PNE levels were observed after 3 weeks of LVAS support. After 5 weeks of LVAS support, PNE levels had decreased to near normal. For patients with severe left ventricular dysfunction, the improved prognosis after LVAS support may be due in part to the normalization of neurohormonal levels. The findings indicate that PNE levels may be of value in determining whether a patient can be weaned from LVAS support.

Treatment of advanced heart failure in a young man with familial cardiomyopathy.

We report the case of a young man with familial cardiomyopathy whose symptoms became difficult to control as his myopathy worsened. He had persistent cardiac arrhythmias and was intolerant of angiotensin-converting enzyme inhibitor therapy. His case illustrates the difficulties that can be encountered in treating patients with advanced heart failure.

Heart transplant rejection with hemodynamic compromise: a multiinstitutional study of the role of endomyocardial cellular infiltrate. Cardiac Transplant Research Database.

BACKGROUND: The natural history of patients experiencing hemodynamic compromise with rejection has been incompletely characterized. This multiinstitutional study examined the outcome of such episodes, particularly with regard to the extent of cellular infiltrate on the index endomyocardial biopsy. METHODS: From January 1, 1990, through June 30, 1994, 3367 patients in the Cardiac Transplant Research Database experienced 4137 episodes of rejection. Severe hemodynamic compromise occurred in approximately 5% of the rejection episodes, and this proportion remained relatively constant over time. RESULTS: Recipient risk factors for rejection with severe hemodynamic compromise included black race, female recipient sex, and diabetes. The 3-month actuarial survival rate was 60% after rejection with severe hemodynamic compromise versus 95% after rejection with no or mild compromise. Low initial biopsy score conferred a higher early survival, but a lower survival at 2 years after rejection with severe hemodynamic compromise. Among patients who survive an initial rejection episode with severe hemodynamic compromise, survival at 2 years after an episode was 46% among those who had a low initial biopsy score versus 84% with a high biopsy score. CONCLUSIONS: Rejection with hemodynamic compromise, although rare, represents a major complication of heart transplantation with a poor long-term outcome. Survivors of hemodynamically compromising rejection episodes associated with low biopsy scores in the International Society for Heart and Lung Transplantation grading system have a significantly worse long-term outcome than survivors of episodes associated with high scores. These findings suggest that immunologic mechanisms other than lymphocytic infiltration of the cardiac allograft are important and distinct causes of allograft dysfunction.

Mannitol-induced acute renal failure.

The osmotic diuretic mannitol may be used in diverse clinical settings, such as providing "renal protection" in patients at risk for acute renal failure, decreasing intracranial pressure in patients with intracranial trauma, and preventing the dialysis-disequilibrium syndrome. Mannitol is commonly used after cardiac catheterization, cardiovascular surgery, and exposure to intravenous contrast dyes. This study presents a case in which a long-term renal transplant recipient receiving cyclosporine therapy concomitantly developed acute renal failure after the administration of high-dose mannitol in an attempt to induce an osmotic diuresis. The diagnosis of "osmotic nephrosis" was confirmed by renal biopsy, and the condition was reversed by cessation of the agent. Studies in experimental animals indicate that cyclosporin A can potentiate the tubular toxicity of mannitol, but such an association has not been verified in humans. Numerous studies confirm the nephrotoxic potential of high-dose mannitol, especially in patients with renal insufficiency. The clinical utility of the osmolar gap in preventing mannitol nephrotoxicity is emphasized.

Sudden cardiac death in cardiac transplant recipients.

BACKGROUND: Sudden cardiac death (SCD) remains a significant cause of mortality in the general population. Its role in cardiac transplant patients-including its incidence, mechanism, potential risk factors, or influence on survival in this patient population-has not been well described. METHODS AND RESULTS: We undertook a retrospective analysis of the clinical and autopsy records of 257 patient deaths. SCD was analyzed in relation to severity and frequency of rejection episodes, clinical history of arrhythmias, coronary artery disease (CAD), hypertension, diabetes, left ventricular dysfunction, and clinical history of premorbid symptoms. A total of 25 patients were identified as having died of SCD, an incidence of 9.7%: 20% died < or = 12 months after transplantation, 80% died after > 12 months, and 20% died after > or = 60 months. Patient survival ranged from 2.5 to 138 months (mean, 45.7 months). The mean number of rejection episodes per patient was 2.6, most occurring within 12 months after transplantation. Echocardiography or multigated acquisition scan revealed an ejection fraction (EF) > or = 50% in 68% of patients; however, the presence of arrhythmias, primarily atrial, was evident in 68% of patients and was equally distributed between patients with EFs > or = 50% and EFs < 50%. CAD was present in 53% of patients (10 of 19) whose angiograms were available, and the appearance of CAD after transplantation was between 29 and 85 months (mean, 51.4 months). Of the 9 patients with normal cardiac catheterization studies, 6 with available autopsy reports had documented CAD. Autopsy data in 13 of 25 patients revealed CAD in 92% and rejection in 15% (International Society for Heart and Lung Transplantation grade > 3A). Of the deaths, 64% occurred within 3 months of the last endomyocardial biopsy, 96% had normal biopsies, and the only rejection was without hemodynamic compromise. CONCLUSIONS: SCD occurs relatively frequently in the cardiac transplant population, and CAD is present in most of the patients. Because the frequency of arrhythmias is relatively high in this group, more aggressive antiarrhythmic therapy may be beneficial for patients with allograft CAD in the prevention of SCD.

Coronary angioplasty, atherectomy and bypass surgery in cardiac transplant recipients.

OBJECTIVES: This study sought to analyze the outcomes of revascularization procedures in the treatment of allograft coronary disease. BACKGROUND: Allograft vasculopathy is the main factor limiting survival of heart transplant recipients. Because no medical therapy prevents allograft atherosclerosis, and retransplantation is associated with suboptimal allograft survival, palliative coronary revascularization has been attempted. METHODS: Thirteen medical centers retrospectively analyzed their complete experience with percutaneous transluminal coronary angioplasty, directional coronary atherectomy and coronary bypass graft surgery in allograft coronary disease. RESULTS: Sixty-six patients underwent coronary angioplasty. Angiographic success (< or = 50% residual stenosis) occurred in 153 (94%) of 162 lesions. Forty patients (61%) are alive without retransplantation at 19 +/- 14 (mean +/- SD) months after angioplasty. The consequences of failed revascularization were severe. Two patients sustained periprocedural myocardial infarction and died. Angiographic restenosis occurred in 42 (55%) of 76 lesions at 8 +/- 5 months after angioplasty. Angiographic distal arteriopathy adversely affected allograft survival. Eleven patients underwent directional coronary atherectomy. Angiographic success occurred in 9 (82%) of 11 lesions. Two periprocedural deaths occurred. Nine patients are alive without transplantation at 7 +/- 4 months after atherectomy. Bypass graft surgery was performed in 12 patients. Four patients died perioperatively. Seven patients are alive without retransplantation at 9 +/- 7 months after operation. CONCLUSIONS: Coronary revascularization may be an effective palliative therapy in suitable cardiac transplant recipients. Angioplasty has an acceptable survival in patients without angiographic distal arteriopathy. Because few patients underwent atherectomy and coronary bypass surgery, assessment of these procedures is limited. Angiographic distal arteriopathy is associated with decreased allograft survival in patients requiring revascularization.

Coronary angioplasty in cardiac transplant patients. Results of a multicenter study.

BACKGROUND: Accelerated allograft atherosclerosis is the main cause of death of cardiac transplant recipients after the first year after transplantation. Because no medical therapy is known to prevent or retard graft atherosclerosis and transplantation is associated with a shortened allograft survival, alternative, palliative therapy with percutaneous transluminal coronary angioplasty (PTCA) has been attempted. Because no single medical center has performed angioplasty in a large number of cardiac transplant recipients, representatives of 11 medical centers retrospectively analyzed their complete experience of coronary angioplasty in cardiac transplant patients to determine the safety, efficacy, limitations, and long-term outcome of angioplasty in allograft coronary vascular disease. METHODS AND RESULTS: Thirty-five patients underwent 51 angioplasty procedures for 95 lesions 46 +/- 5 months (mean +/- SEM) after transplantation. The primary indications for angioplasty included angiographic coronary disease in 22 cases (43%) and noninvasive evidence of ischemia in 18 procedures (35%). Angiographic success, defined as less than or equal to 50% post-PTCA stenosis, occurred in 88 of 95 lesions (93%). Mean pre-PTCA stenosis was 83 +/- 1.1%; mean post-PTCA stenosis was 29 +/- 2.1% (p less than 0.0001). Periprocedural complications included myocardial infarction and late in-hospital death in one patient and three groin hematomas. Twenty-three of the 35 patients (66%) had no major adverse outcome such as death, retransplantation, or myocardial infarction at 13 +/- 3 months after angioplasty. Four patients died less than 6 months after angioplasty, and four died more than 6 months after angioplasty (range, 6-23 months). Two patients had retransplantation 2 months after PTCA, and one patients had retransplantation 18 months after angioplasty. CONCLUSIONS: Coronary angioplasty may be applied in selected cardiac transplant recipients with comparable success and complication rates to routine angioplasty. Whether angioplasty prolongs allografts survival remains to be determined by a prospective, controlled trial.

Current treatment of dilated cardiomyopathy.

Within the last decade, the treatment for patients with dilated cardiomyopathy has changed. Clinical management of these patients is aimed at controlling congestive heart failure, treating arrhythmias, preventing pulmonary and systemic emboli, and managing chest pain. The goals of treatment for patients with dilated cardiomyopathy are to make the patient feel better and live longer. To achieve this, we direct treatment to improving left ventricular function and cardiac output and controlling arrhythmias and thromboemboli. Basic treatment begins with inotropic therapy, preload reduction, and afterload reduction. For patients with symptomatic disease, we recommend diuretics, digoxin, and converting enzyme inhibitors for first-line therapy. Patients with arrhythmias may be treated by the addition of amiodarone, a pacemaker, or an automatic implantable cardioverter-defibrillator; and most such patients need to be anticoagulated. All patients need close follow-up for possible drug toxicity associated with their regimens. Heart transplantation can be considered for patients refractory to medical treatment. Although the incidence of dilated cardiomyopathy continues to increase, we are learning better ways to treat it. In the future, new drugs with fewer side effects should be available to treat, and perhaps impede, the development of dilated cardiomyopathy.

Medical management of the transplant patient: long-term follow-up.

Of the 165 patients who have undergone cardiac transplantation at the Texas Heart Institute since 1982, 159 long-term survivors have been followed up for an average of 1 year. Here I report on post-transplant complications in both the short and long terms, giving figures and treatment protocols where applicable.

Restenosis after transluminal coronary angioplasty detected with exercise-gated radionuclide ventriculography.

Forty-one patients were evaluated with exercise-gated radionuclide ventriculography before and within 4 days after successful transluminal coronary angioplasty and 4 to 12 months later. Patients were subgrouped according to the degree of restenosis demonstrated angiographically at 4 to 12 months (Group I [n = 23]: less than or equal to 20%; Group II [n = 10]: greater than 20% but less than 50%; Group III [n = 8]: greater than or equal to 50%). Patients with abnormal findings on gated radionuclide ventriculography (less than 5 point increase in ejection fraction or wall motion deterioration) early after angioplasty were eventually found to have a greater degree of restenosis than were patients with normal findings (41.2 +/- 30.3 versus 19.0 +/- 25.4% restenosis, p less than 0.0001). The accuracy of abnormal radionuclide ventriculography in predicting 50% or greater restenosis was 73% immediately after angioplasty and 77% at the time of follow-up angiography. Gated radionuclide ventriculographic results were abnormal in 5% of Group I patients compared with 75% of Group III patients (p less than 0.01) early after angioplasty; at late follow-up, they were abnormal in 27% of Group I patients compared with 88% of Group III patients (p less than 0.01). Group I patients had a greater increase in ejection fraction than did Group III patients at early (+11.3 +/- 7.5 versus + 3.5 +/- 6.5 points, p less than 0.01) and late (+11.8 +/- 7.8 versus -1.9 +/- 8.7 points, p less than 0.0005) follow-up. It is concluded that gated radionuclide ventriculography is useful in predicting coronary restenosis after transluminal coronary angioplasty.

Partial artificial heart (ALVAD) use with subsequent cardiac and renal allografting in a patient with stone heart syndrome.

The abdominal left ventricular assist device (ALVAD) is an order of magnitude more effective than conventional intra-aortic balloon pumping (IABP) in unloading and providing circulatory support to the failing left ventricle. This is a report of a unique case which demonstrates that in the absence of pulmonary vascular obstruction or constriction, the ALVAD can substitute for both left and right heart function. A 21-year-old patient with a congenital bicuspid aortic valve developed acute valvular endocarditis which rapidly progressed to congestive heart failure. An operation was undertaken, the mitral and aortic valves were excised and replaced by porcine heterografts, and a fistula from the right sinus of Valsalva to the right ventricle was closed. When coronary circulation was restored, irreversible ischemic contracture of the left ventricle, or "stone heart" syndrome, developed and emergency ALVAD or partial artificial heart implantation was effected. This device functioned as a total artificial heart for nearly six days, while a donor heart was sought. The patient then underwent removal of the ALVAD and cardiac and renal allografting. The transplanted heart functioned well, but the patient expired fifteen days later from gram-negative sepsis.

Total support of the circulation of a patient with post-cardiotomy stone-heart syndrome by a partial artificial heart (ALVAD) for 5 days followed by heart and kidney transplantation.

A patient with acute bacterial endocarditis in whom ischaemic contracture of the left ventricle (stone-heart syndrome) developed during aortic and mitral valve replacement had an emergency implantation of an intracorporeal partial artificial heart (an abdominal left-ventricular assist device of ALVAD). This device functioned as a total artificial heart for nearly 6 days, while a donor heart for transplantation was sought. The ALVAD was then removed, and the patient received allografts of a heart and a kidney. The transplanted heart functioned well, but the patient died 15 days later from gram-negative sepsis. There was no evidence of cardiac or renal allograft rejection.