Intracranial hemorrhage after coronary thrombolysis with tissue plasminogen activator.

PURPOSE AND METHODS: We analyzed the clinical, laboratory, and radiologic data in nine patients who sustained an intracranial hemorrhage (ICH) after receiving intravenous recombinant tissue plasminogen activator (rt-PA) and heparin for treatment of acute myocardial infarction (MI). Our purpose was to delineate the clinical and radiologic features of the ICHs, as well as to determine their potential risk factors and mechanisms. RESULTS: Among 1,700 patients with an acute MI treated with an investigational two-chain rt-PA, duteplase (Burroughs Wellcome Co., Research Triangle Park, NC), nine (0.53%) developed symptomatic ICH. Neurologic symptoms occurred between 7 and 96 hours after onset of rt-PA therapy. All patients received heparin concomitantly for prevention of coronary reocclusion. The activated partial thromboplastin times (aPTTs) in five of eight (63%) patients at onset of ICH were excessively prolonged (greater than two times control); hypofibrinogenemia occurred in only one of five (20%) patients tested; and thrombocytopenia was present in only one of the nine (11%) patients. Fibrin degradation products (FDPs) were elevated in all five patients tested. Minor hemorrhage (not requiring transfusion) outside the central nervous system occurred in five of the nine patients with ICH. The ICHs were often of lobar location and of moderate to large size. They occurred at multiple sites in three patients, and were fatal in four instances (44%). CONCLUSIONS: The incidence of ICH in this series was low, and consistent with figures reported from studies with alteplase in patients with acute MI. The mechanisms of these hemorrhages remain unclear; while hypofibrinogenemia was not a uniform finding, excessive prolongation of the aPTT and elevated FDPs may have contributed to the occurrence of ICH in some patients. Still unidentified local cerebrovascular factors may play an additional role in causing ICH. In order to further clarify the mechanisms of ICH in the setting of thrombolytic therapy, prospective data collection on probable risk factors for ICH in patients with acute MI treated with rt-PA will be required.     

Effect of continued rt-PA administration on the residual stenosis after initially successful recanalization in acute myocardial infarction - a quantitative coronary angiography study of a randomized trial

Quantitative angiography was performed in 68 out of 123 patientstreated with intravenous rt-PA for acute myocardial infarction.At 90 min angiography, the median minimal cross-sectional areawas 1.11 mm² and the median percentage area stenosis was 80%.A percentage area stenosis greater than 70% was seen in 78%of the patients. Patients with a patent infarct related artery at the first angiogramwere randomized to receive subsequent infusions either of rt-PA+ heparin or placebo + heparin. There was a persistent trendof improvement in minimal lumen diameter and percentage diameterstenosis of the residual stenosis in the infarct related arteryin both treatment groups when re-examined 6–24 hours laterand at the time of hospital discharge. A reduction in ‘plaquearea’, the area between the detected and the referencecontours of the infarct related segment, was more frequentlyseen in patients receiving a second infusion of rt-PA than inpatients with no prolonged thrombolytic therapy (83% versus57%, P<0.025, chi square).     

Effect of continued rt-PA administration on the residual stenosis after initially successful recanalization in acute myocardial infarction - a quantitative coronary angiography study of a randomized trial

Quantitative angiography was performed in 68 out of 123 patientstreated with intravenous rt-PA for acute myocardial infarction.At 90 min angiography, the median minimal cross-sectional areawas 1.11 mm² and the median percentage area stenosis was 80%.A percentage area stenosis greater than 70% was seen in 78%of the patients. Patients with a patent infarct related artery at the first angiogramwere randomized to receive subsequent infusions either of rt-PA+ heparin or placebo + heparin. There was a persistent trendof improvement in minimal lumen diameter and percentage diameterstenosis of the residual stenosis in the infarct related arteryin both treatment groups when re-examined 6–24 hours laterand at the time of hospital discharge. A reduction in ‘plaquearea’, the area between the detected and the referencecontours of the infarct related segment, was more frequentlyseen in patients receiving a second infusion of rt-PA than inpatients with no prolonged thrombolytic therapy (83% versus57%, P<0.025, chi square).     

Enoxaparin in Unstable Angina/Non-ST-Segment Elevation Myocardial Infarction: Treatment Benefits in Prespecified Subgroups

Background: Two large-scale phase III clinical trials, the Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-wave Coronary Events (ESSENCE) trial and the Thrombolysis in Myocardial Infarction (TIMI) 11B study, have shown the low-molecular-weight heparin, enoxaparin, to be more effective than unfractionated heparin (UFH) in reducing the risk of death and severe cardiac events in patients with rest unstable angina and/or non-ST-segment elevation myocardial infarction (NSTEMI). However, patients with NSTEMI acute coronary syndromes are a heterogeneous group. Methods: A meta-analysis using pooled data from ESSENCE and TIMI 11B was performed to examine the efficacy of enoxaparin in different patient subgroups. In addition, a statistical model was developed to test which factors best predicted an enhanced treatment effect. Results: Enoxaparin was more effective than intravenous dose-adjusted UFH in reducing the incidence of the composite endpoint (including death, myocardial infarction or recurrent angina prompting urgent revascularization) in the majority of subgroups at 43 days after randomization. Univariate analyses revealed that there was a greater benefit with enoxaparin in patients with ST-segment deviation or elevated cardiac enzyme markers on admission, women, nonsmokers and patients with characteristics indicative of higher cardiac risk, including prior percutaneous coronary interventions, being at least 65 years old, prior angina and prior aspirin use. Multivariate statistical modelling of treatment effect revealed that ST-segment depression and electrocardiographic changes were the best predictors of an enhanced treatment effect. Conclusions: These data reinforce previous evidence suggesting that enoxaparin administered subcutaneously twice daily may be considered as an alternative to intravenous UFH in the acute treatment of a broad range of patients with unstable coronary artery disease. Abbreviated Abstract: Two clinical trials have shown the low-molecular-weight heparin, enoxaparin, to be more effective than unfractionated heparin in reducing risk of death and severe cardiac events in patients with rest unstable angina or non-ST-segment elevation myocardial infarction. A meta-analysis using pooled data was performed to examine the efficacy of enoxaparin in different patient subgroups. A statistical model was developed to aid prediction of enhanced treatment effect. The greater efficacy of enoxaparin in comparison with unfractionated heparin was demonstrated in the majority of patient groups. Statistical modeling of treatment effect showed ST-segment depression and electrocardiographic changes to be the best predictors of an enhanced treatment effect.     

A case report of reversible posterior encephalopathy syndrome with intracranial hemorrhage in a child

Introduction:The objective is to analyze the clinical diagnosis and treatment of children with rescindable posterior encephalopathy syndrome (PRES) and intracranial hemorrhage (ICH) to improve the pediatrician''s understanding of PRES combined with ICH in children.Patient concerns and Diagnosis:After liver transplantation, the patient developed symptoms of epilepsy and coma. Meanwhile, massive necrosis of acute cerebral infarction and small hemorrhage was observed in the left cerebellar hemisphere and left occipital lobe, respectively. The above symptoms were initially diagnosed as PRES.Interventions and outcomes:After adjusting the anti-rejection drug regimen, it was found that the child''s neurological symptoms were relieved, and the limb motor function gradually recovered during follow-up. Imaging examination showed significant improvement on abnormal signals in brain.Conclusion:In general, children with PRES may further develop ICH and contribute to a poor prognosis. Early diagnosis, detection of risk factors and timely adjustment of medication regimen are the keys to prevent irreversible brain damage.     

A randomized trial of intravenous heparin in conjunction with anistreplase (anisoylated plasminogen streptokinase activator complex) in acute myocardial infarction: The Duke University clinical cardiology study (DUCCS) 1

Objectives. We designed a randomized trial to evaluate the effects of heparin administration in conjunction with anistreplase (anisoyiated plasminogen streptekinase activator complex [APSAC]) on arterial patency and clinical end points.Background. The role of conjunctive intravenous heparin therapy with APSAC has not been tested despite the recommendations that intravenous heparin should be used.Methods. Four hours after APSAC administration, 250 patients with acute myocardial infarction were randomly assigned to receive 325 mg of either aspirin alone or aspirin and a continuous infusion of heparin (15 IU/kg body weight per h). Clinical ischemic events and bleeding complications were monitored On hospital day 5, coronary arteriography and left veetriculography were performed.Results. The primary end point of the trial (the combined outcome of death, reinfarction, recurrent ischemia and occlusion of the infarct-related artery) occurred in 42% of the heparin-treated group versus 43% of the group without heparin (p = 0.94). A patent infarct-related artery was present in 80% of the treated with heparin and in 73% of those treated without heparin (p = 0.26). Left ventricular function, as measured by ejection fraction, was well preserved in both groups (52% vs. 50.5%, respectively, p = 0.29). The overall bleeding rate was higher in patients with (32%) than without (17.2%) heparin (p = 0.006).Conclusions. Weight-adjusted intravenous heparin therapy after APSAC in acute myocardial infarction does not reduce the combined incidence of death, reinfarction, recurrent ischemia and ccclusion of the infarct-related artery. Furthermore, withholding intravenous heparin therapy is associated with a 46% reduction in bleeding complications. Our findings do not support the addition of intravenous heparin after APSAC therapy, as currently recommended, and suggest that a strategy of withholding heparin is simpler and safer and does not place the patient at increased risk for ischemic complications after myocardial infarction.     

Acute Administration of Angiotensin Converting Enzyme Inhibitors in Thrombolysed Myocardial Infarction Patients Is Associated with a Decreased Incidence of Heart Failure,but an Increased Re-Infarction Risk

Introduction: Ventricular remodeling starts very early after the onset of an acute myocardial infarction (AMI), and can be prevented by ACE-inhibitors. However, very limited data are available on the effect of acute (< 9 hours) treatment with angiotensin converting enzyme (ACE) inhibitors after an AMI on mortality, heart failure and re-infarction. The aim of the present study was to evaluate the effects of acute ACE-inhibitor treatment.Methods: We performed a pooled analysis of three very similar randomized, placebo-controlled multi-center trials. In 845 thrombolysed patients with mainly first anterior MI, patients were randomised to acute ACE-inhibitor treatment (< 9 hours after MI) or placebo.Results: After acute ACE-inhibitor treatment we observed similar 3-months mortality rates, and a significant reduction in the incidence of 3-months heart failure (26.1 vs. 19.3%; RR 0.67; 95% CI 0.45–1.0) as compared to placebo. In contrast, acute ACE-inhibitor treatment was associated with a significant 2.0 times increased 3-months re-infarction risk (7.0 vs. 3.6%; RR 2.0; 95% CI 1.1 to 3.8). Subgroup-analysis showed that patients with small infarct sizes treated with acute ACE-inhibitor (peak CPK < 1000 IU) had a 7.6 times higher re-infarction risk (95% CI 1.7 to 33) than patients with small infarctions treated with placebo.Conclusions: Acute ACE-inhibitor treatment in thrombolysed patients with mainly first anterior AMI resulted in a reduction of heart failure and similar mortality, but an increase in re-infarction rates, especially in patients with small infarct sizes. These results warrant caution for the very early use of ACE-inhibitors in smaller infarctions, although this needs to be confirmed in a larger prospective randomised clinical trial.     

Lower-dose heparin with fibrinolysis is associated with lower rates of intracranial hemorrhage

BACKGROUND: The optimal heparin dose as an adjunct to fibrinolysis and its role in causing intracranial hemorrhage (ICH) is unclear. METHODS: We reviewed the heparin regimens and rates of ICH in 3 sets of recent fibrinolytic trials: (1) studies with accelerated recombinant tissue plasminogen activator (TPA, alteplase) plus intravenous heparin, in which the heparin regimen was changed during the course of the trial; (2) phase III trials with accelerated TPA plus intravenous heparin; and (3) trials of new single-bolus fibrinolytic agents. RESULTS: Lower rates of ICH were observed among studies of accelerated TPA that reduced the heparin dose mid-trial (TIMI 9A --> 9B: 1.87% --> 1.07%, GUSTO-IIa --> IIb: 0.92% --> 0.71%, TIMI 10B: 2.80% --> 1.16%). Rates of ICH with accelerated TPA gradually increased from GUSTO-I (0.72%) in 1990 to 1993 to ASSENT-2 (0.94%) in 1997 to 1998. However, this trend was reversed in InTIME-II, which used the lowest heparin dose and most aggressive activated partial thromboplastin time monitoring and observed an ICH rate of 0.64% with accelerated TPA. Lower ICH rates were also observed when the heparin dose was reduced with single-bolus tenecteplase (TNK-TPA) and lanoteplase. CONCLUSIONS: Nonrandomized comparisons with accelerated TPA suggest that lower doses of intravenous heparin are associated with lower rates of ICH. This observation also appears to apply to single-bolus TNK-TPA and novel plasminogen activator. A lower-dose, weight-adjusted heparin regimen (60 U/kg bolus; maximum, 4000 U; 12 U/kg per hour infusion; maximum, 1000 U/h) with earlier monitoring of activated partial thromboplastin time is currently recommended in the revised American College of Cardiology/American Heart Association myocardial infarction guidelines and should be used in clinical practice.     

Risk Factors for Early Intracerebral Hemorrhage after Intravenous Thrombolysis with Alteplase

Aim: Intracerebral hemorrhage (ICH) is one of the most severe complications of thrombolysis. Symptomatic ICHs are associated with adverse outcomes. It has been reported that symptomatic ICHs most commonly occur within the first few hours after the initiation of intravenous thrombolysis. Our aim here was to determine the risk factors for early ICH (within 12 h) after thrombolysis.Methods: We analyzed patients with acute ischemic stroke who received intravenous alteplase at two hospitals affiliated to Wenzhou Medical University between March 2008 and November 2017. The ICH diagnosis time was defined as the time from the intravenous administration of alteplase to the first detection of hemorrhage on computed tomography. Demographic data, medical history, clinical features, and laboratory examination results were collected. Univariate analysis followed by multivariable logistic regression analysis was performed to determine the predictors of early ICH (within 12 h) after thrombolysis.Results: Among 197 patients, early ICH (within 12 h) after thrombolysis occurred in 13 patients (6.6%). In the univariate analysis, patients with early ICHs were significantly correlated with prior stroke (P = 0.04). After adjusting for potential confounders in the multivariate analysis, prior stroke (odds ratio [OR]: 5.752, 95% confidence interval [CI]: 1.487–22.248; P = 0.011) and atrial fibrillation (OR: 5.428, 95% CI: 1.427–20.640; P = 0.013) were associated with early ICH.Conclusions: Prior stroke and atrial fibrillation are independent risk factors for early ICHs (within 12 h) after intravenous thrombolysis with alteplase.     

An Automated Strategy for Bedside aPTT Determination and Unfractionated Heparin Infusion Adjustment in Acute Coronary Syndromes: Insights from PARAGON A

Background: Intravenous unfractionated heparin remains a cornerstone of anticoagulation therapy for patients with acute coronary syndromes, but regulation to a target aPTT is challenging. We assessed unfractionated heparin infusion regulation by bedside, whole-blood aPTT testing and computerized, algorithmic infusion adjustment, and further evaluated the relationship of achieving the target aPTT with clinical outcomes. Methods and Results: We studied 1,275 patients randomized to unfractionated heparin in PARAGON-A, which tested lamifiban with or without unfractionated heparin versus unfractionated heparin. All patients had baseline and 6-hour blinded, bedside aPTTs, then aPTTs per algorithm. A central computer translated encrypted values to algorithmic dose-adjustment commands. We assessed the ability to achieve and maintain aPTTs of 50–70 seconds and associations of 6- and 12-hour aPTTs and time-to-target with 30-day outcomes.Overall, the median 6-hour aPTT was 50–70 seconds and remained so throughout infusion. Individually, only 33.6% of patients achieved 6-hour target-range aPTTs, and only 40% of all aPTTs were in-range. After achieving target, only 42% of subsequent measures were in-range. Thirty-day death or myocardial infarction (death/MI) increased non-significantly as time-to-target increased (p = 0.08). Thirty-day mortality was similar if target aPTT was reached, regardless of timing. Death/MI trended lower if target aPTT was reached by 8 hours (p = 0.10). The best clinical outcomes were associated with in-range aPTTs. Conclusions: This study represents the most systematic monitoring and regulation of unfractionated heparin anticoagulation to date. Although average anticoagulation achieved target range, wide inter- and intra-patient variability may have important implications for clinical outcomes. Abbreviated abstract: Using systematic aPTT testing and computer-directed, algorithmic unfractionated heparin infusion adjustment in 1,275 acute coronary syndrome patients, the overall median aPTT was 50–70 seconds. However, only 33.6% of patients achieved this target 6-hour aPTT range. Only 40% of all aPTTs, and after achieving target, only 42% of subsequent measures, were in this range. Thirty-day death or myocardial infarction increased with increasing time to target aPTT (for trend, p = 0.08). The best outcomes were associated with 6- and 12-hour aPTTs in the target range. Wide inter- and intra-patient variability despite highly systematic, controlled unfractionated heparin infusion regulation has important implications for unfractionated heparin use.     

Bivalirudin use in patients undergoing percutaneous coronary intervention for acute myocardial infarction. Insights from the prospective,multi-centre EUROVISION registry

Abstract

Background: The effectiveness of bivalirudin in patients undergoing percutaneous coronary intervention for acute myocardial infarction has been tested in clinical trials, but its use in a real-world scenario has never been reported.

Methods: From the total number of patients enrolled in the EUROVISION registry, 678 subjects affected by ST-elevation myocardial infarction were selected and included in the analysis. Posology and usage patterns of bivalirudin, as evaluated by dose and time of drug bolus and infusion administered, were evaluated. The 30-day outcome has been assessed by efficacy and safety endpoints.

Results: All patients received an initial intravenous bolus of bivalirudin (0.70 ± 0.25 mg/kg) followed by an infusion (1.58 ± 0.47 mg/kg/h; duration: 60 [30, 107] min) in 99.3% of cases. An additional bolus (0.49 ± 0.06 mg/kg) was administered in 9.3% of patients. Bivalirudin infusion was prolonged after procedure in 62.2%. Death occurred in 2.1% of patients, non-fatal myocardial reinfarction in 0.3%, unplanned revascularization in 0.6% and non-fatal stroke in 0.4%. Acute stent thrombosis was not observed. Major bleeding occurred in 1.5% of patients.

Conclusions: Bivalirudin usage in the setting of primary PCI provided excellent results in terms of 30-day outcome even in a real-world population.     

Platelet activation determined by flow cytometry persists despite antithrombotic therapy in patients with unstable angina and non-Q-wave myocardial infarction

Background: Current strategies in the treatment of patients with acute coronary syndromes include antiplatelet agents and thrombin antagonists, most commonly aspirin and heparin, respectively. Cardiac events, however, occur despite what is considered to be maximal medical treatment.Methods: We determined the percentage of activated platelets in whole blood samples taken from 22 patients with unstable angina and non-Q-wave myocardial infarction participating in the TIMI III B trial. Platelet activation was assessed using a monoclonal antibody to the surface-expressed -granule protein, P-selectin, and flow cytometry. All patients received a full complement of antiischemic medications as well as intravenous heparin and oral aspirin, and were then randomized to tissue plasminogen activator or placebo.Results: Platelet activation prior to randomization was increased threefold to fourfold compared with healthy volunteers (11.4 ± 11.4% vs. 2.5 ± 2.0%; p < 0.01). Serial measurements performed 12, 24, 48, and 96 hours after treatment initiation revealed that platelet activation persisted. No differences in patients experiencing recurrent ischemic events (n=9) or those randomized to a 90-minute, accelerated infusion of tissue plasminogen activator (n=12) were observed.Conclusions: A modest degree of platelet activation is seen for at least 96 hours and possibly longer in patients with unstable angina and non-Q-wave myocardial infarction, despite being treated with intravenous heparin and oral aspirin. These findings support current efforts to identify more potent and selective antithrombotic treatment strategies.Presented in part at the American Heart Association's 66th Scientific Session, Atlanta, GA, November 8–11, 1993.     

Argatroban and Alteplase in Patients with Acute Myocardial Infarction: The ARGAMI Study

ARGAMI was designed to assess safety and efficacy of argatroban compared with heparin as adjunctive treatment to alteplase in the treatment of patients with acute myocardial infarction. ARGAMI consisted of an open-dose finding study (35 patients) followed by a placebo-controlled study with double dummy technique and 2:1 (argatroban:heparin) randomization. An argatroban dosage of 100g/kg bolus plus 3g/kg/min infusion for 72 hours was selected for the randomized study in which 82 patients were allocated to argatroban and 45 to heparin (5000U intravenous bolus, 1000U/h infusion). Patency of the infarct-related artery (Thrombolysis in Myocardial Infarction [TIMI] grade 2 or 3 flow) after 90 minutes was obtained in 62 patients (76%) allocated to argatroban versus 37 patients (82%) allocated to heparin (p=ns). Angiograms after 24 hours and 5 to 10 days showed low reocclusion rates in both groups. Bleeding complications were observed in 16 patients allocated to argatroban (19.5%) and in 9 patients allocated to heparin (20.0%). One patient allocated to heparin suffered from hemorrhage stroke. Argatroban, given as adjunctive treatment to alteplase, is tolerated well in patients with acute myocardial infarction. Safety and efficacy of the combination alteplase and argatroban (with this dose regimen) are similar to those of alteplase and heparin.     

Once-Daily Enoxaparin in The Outpatient Setting Versus Unfractionated Heparin in Hospital for the Treatment of Symptomatic Deep-Vein Thrombosis

Background: Once- and twice-daily low-molecular-weight heparin administered in hospital have been shown to be effective and safe for treating deep-vein thrombosis. The aim of this study was to compare the efficacy and safety of deep-vein thrombosis treatment using once-daily subcutaneous enoxaparin in the outpatient setting with intravenous unfractionated heparin in hospital.Methods: This randomized, parallel-group, open-label study was conducted in 18 centers in 4 countries. In total, 298 patients with symptomatic deep-vein thrombosis who were eligible for home treatment were randomized to treatment with enoxaparin in the outpatient setting (1.5 mg/kg subcutaneously once-daily) or unfractionated heparin in hospital (5000 IU bolus and 1250 IU/hour intravenous infusion) for ≥5 days. Clinical endpoints were assessed during a 6-month follow-up period.Results: Among all patients treated with enoxaparin, there was a trend towards fewer recurrent deep-vein thromboses (1.3% vs. 5.4%; p = 0.060) and pulmonary emboli (1.3% vs. 4.1%; p = 0.17) compared with patients treated with unfractionated heparin. When considering a post-hoc combined endpoint of deep-vein thrombosis and pulmonary embolism, significantly fewer events occurred in the enoxaparin group than in the unfractionated-heparin group (2.7% vs. 8.8%; p = 0.026). The incidences of bleeding events and adverse events in the enoxaparin and unfractionated-heparin groups were similar.Conclusions: Once-daily subcutaneous enoxaparin in the outpatient setting is at least as effective and as well tolerated as in-hospital intravenous unfractionated heparin for treatment of deep-vein thrombosis.     

Echocardiographic evaluation of intravenous streptokinase in myocardial infarction in the acute phase

The effects of intravenous fibrinolysis on left ventricular function in acute myocardial infarction were investigated by two-dimensional echocardiography in patients aged less than 70 for whom fibrinolysis was not contra-indicated and who were admitted less than 6 hours after the onset of a first myocardial infarction without heart failure. The 12 patients thus recruited were male; their mean age was 55 years and the infarct was anterior in 6 cases and posterior in 6 cases. Streptokinase was administered first by bolus intravenous injection (250,000 IU over 20 min), then by intravenous infusion (100,000 IU over 12 hours); this was followed by heparin. No other medication was given, except for intravenous lidocaine and oral nifedipine. Two-dimensional echocardiography was performed after 24 hours and on the 21st day, using the apical, two-cavities projection. The ejection fraction and the percentage of shortening in 16 ventricular segments (8 in the anterior and 8 in the inferior territories) were evaluated from systolic and diastolic ventricular contours. Ventricular angiography and coronary arteriography were performed concomitantly with echocardiography. No significant improvement in ejection fraction was observed. On both day 1 and day 21, the kinetics of the lower segments was improved and that of the anterior segments was distinctly reduced in inferior infarcts. The kinetics of all segments, irrespective of their territory, was significantly improved in anterior infarcts.     

Management of Anaphylactoid Reactions to Intravenous N-Acetylcysteine

Study Objective: To develop management guidelines for the treatment of anaphylactoid reactions to intravenous N-acetylcysteine (NAC) and to assess the safety of restarting the infusion after a reaction. Methods: In phase 1, we used a 6-year retrospective case series of hospitalized patients and a review of the literature to develop the management guidelines for anaphylactoid reactions to intravenous NAC. In phase 2, these guidelines were evaluated prospectively in our poison-control center. Results: In phase 1, the charts of 11 patients with anaphylactoid reactions (9 cutaneous and 2 systemic) were reviewed. In most cases, no treatment or treatment with diphenhydramine alone or with salbutamol was sufficient to continue or restart NAC infusion safely. On the basis of our findings in those patients and on published experience, we concluded that anaphylactoid reactions to intravenous NAC are dose-related and that antihistamines are useful in controlling and in preventing recurrence of anaphylactoid symptoms. We developed the following guidelines: flushing requires no treatment, urticaria should be treated with diphen hydramine, and NAC infusion should be continued in both cases. Angioedema and respiratory symptoms each require the administration of diphenhydramine and symptomatic therapy. In these cases, NAC infusion should be stopped but, when necessary, can be restarted 1 hour after the administration of diphenhydramine in the absence of symptoms. In phase 2, 50 patients (31 cutaneous and 19 systemic reactions) were treated prospectively with the use of these guidelines. Recurrence of symptoms occurred in only one case involving a deviation from the guidelines. The NAC infusion was restarted immediately after the administration of diphenhydramine in a patient who sustained a systemic reaction. Conclusion: Non–life-threatening anaphylactoid reactions to intravenous NAC are treated easily and the infusion may be continued or restarted safely after the administration of diphenhydramine. [Bailey B, McGuigan MA: Management of anaphylactoid reactions to intravenous N-acetylcysteine. Ann Emerg Med June 1998;31: 710-715.]     

Safety of immediate reversal of anticoagulation by protamine to reduce bleeding complications after infarct artery stenting for acute myocardial infarction and adjunctive abciximab therapy

Infarct artery stenting with adjunctive abciximab therapy is widely used treatment for patients with acute myocardial infarction (AMI). However, bleeding complications have been associated with a worse clinical outcome. Randomized trials in elective patients have shown that postprocedural protamine administration is safe and associated with a significant reduction in bleeding complications. The aim of the current study was to evaluate in STEMI patients undergoing primary percutaneous coronary intervention (PCI) with abciximab and stenting whether immediate reversal of anticoagulation by protamine is safe and associated with a reduction in the occurrence of bleeding complications. From January 2004 to June 2005, 254 patients with STEMI had immediate reversal of anticoagulation by protamine administration after infarct artery stenting and received abciximab therapy without heparin infusion (Group 1). These patients were compared with a control group of 265 patients (June 2002–December 2003) treated with the standard heparin therapy: bolus in order to achieve an activated coagulation time of 250–300 s during PCI plus 12-h infusion (7 UI/kg/h; Group 2). We excluded patients undergoing IABP implantation. The two groups were similar in all baseline characteristics. There were no differences in in-hospital mortality, reinfarction, urgent target vessel revascularization, stroke or acute or subacute stent thrombosis, while Group 1 patients showed a lower incidence of major bleeding complications (ACUITY scale: 1.1 vs. 4.0%, P = 0.035) and a shorter length of hospital stay (3.5 ± 1.7 vs. 4.0 ± 1.6 days, P = 0.002) as compared with heparin treated patients. Among patients undergoing primary stenting with abciximab administration, immediate post-PCI reversal anticoagulation by protamine without associated heparin infusion is safe and associated with a significant reduction in major bleeding complications.     

Low molecular weight heparin as an adjunct to thrombolysis for acute myocardial infarction: the FATIMA study

Objective—To investigate the feasibility of fixed dose, weight adjusted subcutaneous low molecular weight heparin (LMWH), with monitoring of anti-Xa levels and assessment of coronary patency rates after three to five days, thereby giving an initial indication of its safety and efficacy.
Design—In 30 patients with acute myocardial infarction, LMWH (nadroparine) was given as a body weight adjusted intravenous bolus with thrombolysis (rt-PA infusion) and in weight adjusted subcutaneous doses at six hours, and every 12 hours thereafter for 72 hours. The target range was defined prospectively as 0.35-0.70 anti-factor Xa activity (aXa) units. The aXa level was measured every six hours. Coronary angiography was performed in all patients within five days after the start of thrombolytic treatment to determine patency (TIMI 2 and 3 flow) of the infarct related artery.
Results—The mean (SEM) aXa level over 72 hours was 0.52 (0.08) U/ml; from 12 hours onwards 88% of all aXa measurements were within the target range. At angiography, a patent infarct related artery was present in 24 of the 30 patients. No major bleeding complications occurred, though minor bleeding complications were observed in two patients.
Conclusions—This small study indicates that LMWH is feasible as an adjunct to thrombolysis in patients with acute myocardial infarction. The aXa levels were within the target range and patency rates at three to five days were around 80%, with no major bleeding complications.

Keywords: acute myocardial infarction;  thrombolysis;  low molecular weight heparin;  FATIMA study     

Coronary arteriography in acute transmural myocardial infarction

Coronary arteriography was performed 16 ± 3 days (range 7 to 21 days) in 106 patients with acute transmural myocardial infarction (61 posterior infarct, 45 anterior infarct). Coronary arteriography was performed without serious complications. Only 44 per cent of patients with anterior infarct had total occlusion of the left anterior descending artery while a significant stenosis of the vessel was observed in the others ?27 per cent had a single vessel disease, 49 per cent had two lesions and 22 per cent had three lesions; one patient had angiographically normal coronary arteries. Among the patients with posterior infarction, 21 per cent had one vessel disease and double or triple lesions accounted for 39 per cent of each.Sixty per cent of patients with anterior infarction and 45 per cent with posterior infarction had no collateral vessels. In the others patients collateral circulation had a protective effect only in anterior infarction. Age has no effect on the distribution and number of lesions nor on the development of a collateral circulation. The location and severity of the lesions were not different in patients who presented with arrythmias and those who did not.     

Intravenous nitroglycerin unloading in acute myocardial infarction.

Low-dose intravenous nitroglycerin infusion can be safely administered during acute myocardial infarction to unload the left ventricle and salvage ischemic myocardium and left ventricular geometry and function. In an experimental conscious dog model, low-dose infusion titrated to decrease mean blood pressure by 10% over the first 6 hours after coronary artery ligation resulted in 51% decrease in infarct size, 54% decrease in preload, and more than 50% increase in collateral blood flow. The same benefits were seen when methoxamine was given to counteract that 10% decrease in blood pressure. Similar short-term nitroglycerin infusion also limited remodeling in the dog model. More important, no myocardial salvage was seen with excessive nitroglycerin-induced hypotension to levels less than 80 mm Hg. Clinically, prolonged low-dose nitroglycerin infusion was evaluated in a prospective, randomized, single-blinded, placebo-controlled study of 310 patients with acute infarction: 154 received nitroglycerin and 156 received placebo. Nitroglycerin was titrated to reduce mean blood pressure by 10% in normotensive patients and up to 30% in hypertensive (blood pressure greater than 140/90 mm Hg) patients, but not to less than 80 mm Hg. Nitroglycerin produced several benefits compared with placebo: (1) smaller creatine kinase infarct size; (2) less regional left ventricular dysfunction, better global ejection fraction, and less infarct expansion and thinning; (3) better clinical functional status and hemodynamics; (4) fewer inhospital complications such as acute left ventricular failure and dilation due to marked infarct expansion, left ventricular thrombus, cardiogenic shock, and infarct extension; and (5) fewer deaths up to 1 year in patients with anterior Q-wave infarction.