Proliferation signal inhibitors and post-transplant malignancies in heart transplantation: practical clinical management questions.

Although malignancy is a major threat to long-term survival of heart transplant (HT) recipients, clear strategies to manage immunosuppression in these patients are lacking. Several lines of evidences support the hypothesis of an anticancer effect of proliferation signal inhibitors (PSIs: mammalian target of rapamycin [mTOR] inhibitors) in HT recipients. This property may arise from PSI's ability to replace immunosuppressive therapies that promote cancer progression, such as calcineurin inhibitors or azathioprine, and/or through their direct biological actions in preventing tumor development and progression. Given the lack of randomized studies specifically exploring these issues in the transplant setting, a collaborative group reviewed current literature and personal clinical experience to reach a consensus aimed to provide practical guidance for the clinical conduct in HT recipients with malignancy, or at high risk of malignancy, with a special focus on advice relevant to potential role of PSIs.

Incidence and prognostic significance of atrial fibrillation in acute myocardial infarction: the GISSI-3 data.

BACKGROUND: Atrial fibrillation is the most common supraventricular arrhythmia in patients with acute myocardial infarction. Recent advances in pharmacological treatment of myocardial infarction may have changed the impact of this arrhythmia. OBJECTIVE: To assess the incidence and prognosis of atrial fibrillation complicating myocardial infarction in a large population of patients receiving optimal treatment, including angiotensin converting enzyme (ACE) inhibitors. METHODS: Data were derived from the GISSI-3 trial, which included 17 944 patients within the first 24 hours after acute myocardial infarction. Atrial fibrillation was recorded during the hospital stay, and follow up visits were planned at six weeks and six months. Survival of the patients at four years was assessed through census offices. RESULTS: The incidence of in-hospital atrial fibrillation or flutter was 7.8%. Atrial fibrillation was associated with indicators of a worse prognosis (age > 70 years, female sex, higher Killip class, previous myocardial infarction, treated hypertension, high systolic blood pressure at entry, insulin dependent diabetes, signs or symptoms of heart failure) and with some adverse clinical events (reinfarction, sustained ventricular tachycardia, ventricular fibrillation). After adjustment for other prognostic factors, atrial fibrillation remained an independent predictor of increased in-hospital mortality: 12.6% v 5%, adjusted relative risk (RR) 1.98, 95% confidence interval (CI) 1.67 to 2.34. Data on long term mortality (four years after acute myocardial infarction) confirmed the persistent negative influence of atrial fibrillation (RR 1.78, 95% CI 1.60 to 1.99). CONCLUSIONS: Atrial fibrillation is an indicator of worse prognosis after acute myocardial infarction, both in the short term and in the long term, even in an unselected population.

Is anticoagulation therapy underused in elderly patients with atrial fibrillation?

Atrial fibrillation (AF) is found in 0.4% of the adult population and is a common condition in the elderly. Its prevalence increases with age to affect 5 to 14% of those over 74 years. Recent evidence indicates that, compared with sinus rhythm, AF is associated with a 4-to 7-fold increase in the risk of stroke. However, there is strong evidence from randomised trials that full anticoagulation with warfarin substantially reduces the risk of stroke. Elderly patients are among those at higher risk and stand to gain the most from such treatment. They are also at higher risk for complications related to anticoagulant therapy and this sometimes makes clinical decisions difficult. There is a strong rationale for prescribing warfarin for all patients with AF who are over 65 years and free of contraindications. Some concerns exist about the benefit: risk ratio of warfarin in patients aged > 75 years. The answer is probably to use low intensity anticoagulant therapy (international normalised ratio 2.0 to 3.0), which is safer but no less effective than higher intensity regimens. Few data are available in the literature on physicians' attitudes to anticoagulation in elderly patients with AF. Although the results of randomised clinical trials in AF seem to suggest that anticoagulants and/or aspirin (acetylsalicylic acid) are underused in the elderly, over 90% of the patients initially screened were excluded from randomisation, making the sample highly selected. Compared with randomised controlled trials, some observational studies seem to indicate a higher likelihood of using anticoagulation and have targeted the intensity of anticoagulation according to age and clinical scenario.

Prognostic significance of maximal exercise testing after myocardial infarction treated with thrombolytic agents: the GISSI-2 data-base. Gruppo Italiano per lo Studio della Sopravvivenza Nell'Infarto.

Exercise testing helped in diagnosing postinfarction patients in the prethrombolytic era. Over the past decade acute myocardial infarction treatment has changed because of new thrombolytic therapies and consequently, the value of exercise testing is under debate. The GISSI-2 database allowed us to reevaluate the prognostic role of exercise testing in thrombolysed patients. The exercise test was performed in 6296 patients, on average 28 days after randomisation. The test was not performed in 3923 patients because of contraindications. The test was judged positive for residual ischaemia in 26% of the patients, negative in 38%, and non-diagnostic in 36%. Among the patients with a positive stress test result, 33% had symptoms, whereas 67% had silent myocardial ischaemia. The mortality rate was 7.1% among patients who did not have an exercise test and 1.7% [correction of 7.1%] for those with a positive test, 0.9% for those who had a negative test, and 1.3% for those who did not have a diagnostic test. In the adjusted analysis, symptomatic induced ischaemia, submaximal positive result, low work capacity, and abnormal systolic blood pressure were independent predictors of 6-month mortality (relative risks [RR] 2.54, 95% CI 1.27-5.08, 2.28, 1.17-4.45, 2.05, 1.23-3.42, and 1.86, 1.05-3.31, respectively). However, when these factors were tested simultaneously, only symptomatic induced ischaemia and low work capacity were confirmed as independent predictors of mortality (RR Cox 2.07, 95% CI 1.02-4.23 and 1.78, 1.06-2.99, respectively). Patients with a normal exercise response have an excellent medium-term prognosis and do not need further investigation. However, more evaluation should be devoted to the patients who cannot undergo exercise testing, because the potential to influence outcome appears to be much greater.

Thrombolytic therapy in selected patients with impending myocardial reinfarction.

BACKGROUND: In selected patients with postinfarction angina and impending reinfarction, thrombolysis with recombinant tissue-type plasminogen activator (rt-PA) or streptokinase is highly effective in avoiding a new myocardial infarction. METHODS: To avoid major cardiac events, we treated 14 consecutive patients with thrombolytic therapy because of impending reinfarction with ECG ST-segment elevation. Thirteen patients received rt-PA (100 mg over 3 hours), and one patient received streptokinase (1.5 million IU over 1 hour). All patients had failed to respond to maximal medical therapy with intravenous nitrates, beta-blockers, Ca-antagonists, heparin, and opiates. RESULTS: In all patients, clinical and ECG signs of acute ischemia resolved completely within 1 hour after beginning thrombolysis, and no patient developed biochemical markers of myocardial infarction. Ten patients underwent coronary angiography: five had three-vessel disease, two had two-vessel disease, and three had one-vessel disease. The culprit lesion was located in the left anterior descending artery in eight cases and the right coronary artery in two. No patient showed intracoronary thrombus. Four patients underwent successful, semiurgent percutaneous transluminal coronary angioplasty; three received an elective and two an urgent coronary artery bypass graft. CONCLUSIONS: Thrombolysis (or repeated thrombolysis) is effective in selected patients with clinical ECG signs of impending reinfarction. It can temporarily stabilize the condition of many patients, thus allowing safer mechanical revascularization to be performed.

[Tissue-type plasminogen activator (t-PA): comments on results of the GISSI-2 study]. / Attivatore tessutale del plasminogeno (t-PA): commento sui risultati del GISSI-2.

12,490 patients from the GISSI-2 trial were randomly allocated to alteplase (recombinant tissue-type plasminogen activator, t-PA) or streptokinase (SK) and beginning 12 hours after the start of thrombolytic therapy to subcutaneous heparin or no heparin. No significant differences in hospital mortality were found between the two thrombolytic treatments as well as between heparin and no heparin administration. The incidence of major cardiac complications was also very similar in the different groups. The incidence of major bleedings was significantly higher in SK and heparin treated patients, whereas the overall incidence of stroke was similar in all groups. SK and t-PA with or without post-thrombolytic heparin treatment appear equally effective and safe for use in routine conditions care, in all patients with acute myocardial infarction (AMI).

[Tissue-type plasminogen activator]. / Attivatore tessutale del plasminogeno.

Tissue-type plasminogen activator (t-PA) is a serine protease that converts a zymogen plasminogen into an active serine protease, namely, plasmin. Plasmin is the proteolytic enzyme that degrades fibrin. In the absence of fibrin, e.g., in circulating plasma, t-PA activates plasminogen at a very slow rate. However, when fibrin is present, this activity is enhanced two to three orders of magnitude. As a consequence of these kinetic characteristics, plasmin is predominantly generated on the fibrin surface. This in turn results in a relative sparing of circulating fibrinogen and other plasma proteins to plasmin--mediated degradation. Following the demonstration of the potential of natural t-PA as a thrombolytic agent, an intensive effort was launched to enhance its production by recombinant DNA technology. The pharmacological action and the clinical efficacy of t-PA has been tested by several Authors in the treatment of acute myocardial infarction (AMI), and more recently, of pulmonary embolism, a condition for which this drug seems to be very promising: from this point of view this short article provides evidence that the various thrombolytic agents are of equal ability in mediating the rapid lysis of a coronary thrombus after i.v. administration when given appropriately and at the proper time; clinical experience provides little support for the contention of the superiority of t-PA over other thrombolytic agents, particularly for coronary thrombolysis. We are waiting for the results that will come from the GISSI-2 study, that is comparing streptokinase (SK) vs. t-PA in AMI's patients.