Randomised comparison of subcutaneous heparin, intravenous heparin, and aspirin in unstable angina. Studio Epoorine Sottocutanea nell'Angina Instobile (SESAIR) Refrattorie Group

Intravenous heparin has been used in the control of myocardial ischaemia in patients with unstable angina. We set out to assess the efficacy of subcutaneous heparin in reducing myocardial ischaemia in patients with unstable angina. 343 of 399 patients with unstable angina were monitored for 24 h and 108 were refractory to conventional antianginal treatment and were entered into a randomised multicentre trial. 37 patients were assigned to heparin infusion (partial thromboplastin time 1.5-2 times baseline), 35 to subcutaneous heparin (adjusted dose with partial thromboplastin time 1.5-2 times baseline), and 36 to aspirin (325 mg daily). All had additional conventional antianginal therapy. After the run-in patients were monitored for 3 days. The primary endpoint was reduced myocardial ischaemia assessed by the number of anginal attacks, silent ischaemic episodes, and duration of ischaemia per day. At 1 week and 1 month we accounted for anginal attacks and other clinical events (myocardial infarction, revascularisation procedures, and death). Aspirin did not significantly affect the incidence of myocardial ischaemia. On the first 3 days, infused and subcutaneous heparin significantly decreased the frequency of angina (on average by 91% and 86%, respectively), episodes of silent ischaemia (by 56% and 46%), and the overall duration of ischaemia (66% and 61%) versus run-in day and aspirin (p < 0.001 for all variables). The favourable effects of heparin therapy remained evident during follow-up. Only minor bleeding complications occurred. Subcutaneous heparin is effective in the control of myocardial ischaemia in patients with unstable angina.     

Effect of intravenous heparin infusion on thrombin-antithrombin complex and fibrinopeptide A in unstable angina

BACKGROUND: In unstable angina, the clinical efficacy of heparin is limited in time, and recurrence of adverse events has been reported after discontinuation of the anticoagulant. METHODS: In 21 episodes of unstable angina, we used the plasma level of fibrinopeptide A (FPA) and of thrombin-antithrombin complex (TAT) to evaluate the pattern of thrombin inhibition by heparin and the effect of stopping heparin and initiating aspirin. RESULTS: At admission, the plasma level of FPA was increased: median value 3.7 ng/mL compared with 5.5 ng/mL in a control group of 20 patients with early myocardial infarction (not significant). The following findings were observed during a 4-day course of intravenous heparin infusion: (1) FPA decreased significantly 6 hours after the start of therapy; (2) FPA was lower when activated partial thromboplastic time (aPTT) was >1.5 times baseline; (3) there was a significant negative correlation between aPTT and FPA. Twenty-four hours after heparin was discontinued and aspirin initiated, a significant increase in TAT and FPA in plasma was observed. CONCLUSIONS: The results confirm ongoing fibrin formation in the active phase of unstable angina, indicate incomplete and variable inhibition of thrombin by heparin during continuous infusion, and suggest a risk of re-emergence of thrombosis (in spite of initiating aspirin) 24 hours after withdrawal of heparin. Data demonstrate a better control of thrombin activity when heparin is infused at rates that maintain aPTT at >1.5 times baseline, as currently recommended in unstable angina.     

Tirofiban. A review of its use in acute coronary syndromes

Tirofiban is an intravenously administered nonpeptide glycoprotein IIb/IIIa receptor antagonist which specifically inhibits fibrinogen-dependent platelet aggregation and prolongs bleeding times in patients with acute coronary syndromes. Adenosine diphosphate (ADP)-induced platelet aggregation returns to near-baseline levels within 4 to 8 hours after cessation of a tirofiban infusion, a finding consistent with the drug's elimination half-life of approximately 2 hours. Three large clinical trials have shown that, when administered with a standard heparin and aspirin regimen, tirofiban reduces the risk of ischaemic complications in patients with unstable angina/non-Q-wave myocardial infarction (MI) and in patients undergoing percutaneous revascularisation. In PRISM-PLUS, a study involving 1915 patients with unstable angina/non-Q-wave MI, administration of intravenous tirofiban (0.4 microgram/kg/min loading dose for 30 minutes followed by a 0.10 microgram/kg/min infusion) with heparin for at least 48 (mean 71.3) hours reduced the 7-day risk of the composite end-point of MI, death and refractory ischaemia by 32% compared with heparin alone. The between-group risk reduction remained significant at 30 days (22%) and 6 months (19%). Similarly, in high-risk patients undergoing coronary angioplasty in RESTORE, the addition of tirofiban (10 micrograms/kg bolus in the 3 minutes prior to intervention followed by 0.15 microgram/kg/min for 36 hours) to a standard heparin regimen significantly reduced the risk of ischaemic complications by 38% on day 2 and 27% on day 7 compared with heparin alone. Although interim analysis in PRISM-PLUS showed that the use of tirofiban without heparin increased the 7-day risk of death compared with heparin alone, this finding was inconsistent with the effects of tirofiban on the risk of death in PRISM, a study involving 3232 patients with unstable angina/non-Q-wave MI. Tirofiban is generally well tolerated. Bleeding complications were the most commonly reported events associated with tirofiban in clinical trials, but the rate of major bleeding in tirofiban recipients was not significantly different from that reported with heparin. Thrombocytopenia (platelet count < 90,000 cells/microliter) occurred slightly more frequently with tirofiban (with or without heparin) than with heparin alone. CONCLUSIONS: Tirofiban reduces the risk of ischaemic complications in patients with unstable angina/non-Q-wave MI and high-risk patients undergoing revascularisation when used against a background of heparin and aspirin. Furthermore, the drug has an acceptable tolerability profile. Therefore, intravenous tirofiban is likely to be used as an adjunct to heparin and aspirin in patients with acute coronary syndromes including high-risk patients undergoing revascularisation.     

Unstable angina in coronary intensive care units without hemodynamics: is admissible a strategy limiting the indications for coronarography?

In coronary care units (CCU) without cardiac catheterization facilities, coronary angiography is rarely carried out when a successful medical treatment in the acute phase of unstable angina has been obtained. However, the unstable angina still has an uncertain prognosis when the remission of pain is obtained with drugs. This study presents a follow-up of 147 consecutive patients (aged 66.8 +/- 10.4 years) admitted to our CCU in 1991 and 1992 for unstable angina; 33 of them (22.4%) were in Braunwald class I. 2 (1.4%) in class II and 112 (76.2%) in class III. The patients were treated according to the usual therapy protocols and class III patients received i.v. heparin. In selected cases we used thrombolysis (10 patients) and intra-aortic balloon pump (5 patients). During hospitalization 1 patient died (0.7%), 5 patients (3.4%) suffered an acute myocardial infarction and 9 patients (6.1%) had angina. Stabilization of unstable angina was achieved in 132 patients (89.9%): in 113 (76.8%) during the first 48 hours, and in 19 (12.9%) later. Coronary angiography was carried out in non-stabilized patients and in 46 (34.8%) of the 132 with successful treatment (Group I). Eighty-six patients, without indication to coronary angiography were discharged in medical therapy (Group II). During the follow-up (mean of 15.0 +/- 9.0 months) Group I 10 patients (18.2%) had cardiac events (death, myocardial infarction, or recurrent angina) vs 26 of Group II (p < 0.05). In Group I coronary angiography together with clinical criteria of high risk allowed the identification of candidates to coronary revascularization (61.8% of Group I patients while). These data show that the initial success of treatment during the acute phase of unstable angina should not be considered as a favourable prognostic index. Coronary angiography appears to be indicated for clinical evaluation and therapeutical decision.     

Current approach in antithrombotic treatment during coronary interventions: specific thrombocyte aggregation inhibitors and direct thrombin antagonists in high-risk patients

Patients undergoing angioplasty (PTCA) for unstable angina, postinfarction angina, or complex coronary lesions represent a high risk group for ischemic complications. High dose heparin and aspirin are used routinely to prevent thrombotic complications. However, new approaches designed to avoid platelet aggregation, including development of specific platelet GP IIb/IIIa receptor antagonists and specific thrombin inhibitors, demonstrate a significant reduction of thrombotic events following coronary interventions compared to heparin alone. Bleeding complications are not increased if conjunctive heparin administration is weight-adjusted. Pathophysiology of acute coronary closure, mechanisms of action of the new anti-thrombotic drugs, and current and future clinical applications are discussed.     

Clinical characteristics determining the mode of presentation in patients with acute coronary syndromes

OBJECTIVES: The purpose of this study was to examine clinical characteristics of patients with acute coronary syndromes to identify factors that influence the mode of presentation. BACKGROUND: In acute coronary syndromes, presentation with myocardial infarction or unstable angina has major prognostic implications, yet clinical factors affecting the mode of presentation are not well defined. METHODS: A prospective cohort study was made of 1,111 patients with acute coronary syndromes. Baseline demographic, clinical and biochemical data were compared in groups with myocardial infarction (n = 633) and unstable angina (n = 478). RESULTS: The risk of myocardial infarction relative to unstable angina was increased by age >70 years (odds ratio [OR] 2.21; 95% confidence interval [CI] 1.33 to 3.66), male gender (OR 1.56; CI 1.13 to 2.16) and cigarette smoking (OR 1.49; CI 1.09 to 2.03). A rise in admission creatinine from the 10th to the 90th centile of the distribution also increased the odds of myocardial infarction (OR 1.30; CI 1.05 to 1.94). Conversely, the risk of myocardial infarction relative to unstable angina was reduced by previous treatment with aspirin (OR 0.37; CI 0.27 to 0.52), hypertension (OR 0.64; CI 0.47 to 0.86) and previous acute coronary syndromes (OR 0.36; CI 0.26 to 0.51) and revascularization procedures (OR 0.36; CI 0.21 to 0.62). CONCLUSIONS: The clinical presentation of acute coronary syndromes may be influenced by various factors that have the potential to influence the coagulability of the blood, the collateralization of the coronary circulation and myocardial mass. Myocardial infarction is favored by cigarette smoking, advanced age and renal impairment, while unstable angina is favored by treatment with aspirin, hypertension, previous revascularization and previous coronary syndromes.     

Abciximab. An updated review of its use in ischaemic heart disease

Abciximab is a glycoprotein IIb/IIIa receptor antagonist that has proven to be of significant clinical value in improving patient outcome after percutaneous coronary revascularisation. Primarily, the drug inhibits platelet aggregation, but it may also have anticoagulant activity and other beneficial effects, such as inhibiting migration and promoting apoptosis of smooth muscle cells. Large well designed studies have found administration of abciximab (as an adjunct to heparin and aspirin) during percutaneous coronary revascularisation to significantly reduce the incidence of ischaemic complications occurring in the 30 days after the procedure. Significant benefit, particularly on the incidence of myocardial infarction, was still evident after 6 months in 2 of 4 major trials. Abciximab provides particular benefit in patients with unstable angina or myocardial infarction who are undergoing percutaneous coronary revascularisation. The benefits of the drug are additive to those achieved with coronary stenting. Very preliminary data suggest that abciximab may improve coronary blood flow after myocardial infarction and allow reperfusion to be achieved with reduced thrombolytic doses. Caution is required to minimise the risk of bleeding complications with the use of abciximab in combination with heparin and aspirin. Careful patient selection, use of an appropriate heparin regimen, early vascular sheath removal and meticulous femoral artery access site care are recommended. Thrombocytopenia can occur with abciximab treatment, but severe cases are uncommon (< 2% of patients) and can be treated with platelet transfusions. The high acquisition cost of abciximab may be partly or fully offset by the costs averted by the reduced incidence of ischaemic complications and need for urgent and/or repeat revascularisation in high risk patients who receive the drug. However, if bleeding complications occur, this adds to treatment costs. Cost effectiveness analyses generally support the use of abciximab in high risk patients. CONCLUSIONS: Abciximab can be recommended for the prevention of acute ischaemic events in most patients undergoing percutaneous coronary revascularisation, but careful patient selection and strict adherence to the recommended treatment protocol are required to reduce the risk of bleeding complications and thrombocytopenia. Its use in high risk patients is largely supported by pharmacoeconomic data. Further pharmacoeconomic information is needed to establish the drug as a standard of care for all patient groups. The indications for abciximab are likely to expand as more data on its use in acute coronary syndromes become available.     

Advances in the medical management of acute coronary syndromes

Many advances in the treatment of acute coronary syndromes have been realized over recent years. In ST elevation myocardial infarction, new aggressive thrombolytic regimens improve early reperfusion and improve survival. The current focus is on bolus thrombolysis, glycoprotein IIb/IIIa inhibition, and low-molecular-weight heparin as adjuncts. In unstable angina and non-ST elevation myocardial infarction, two major advances are IIb/IIIa inhibition and low-molecular-weight heparin, each of which significantly improves the outcome of patients and which have just been approved for use by the Food and Drug Administration. Following acute coronary syndromes, cholesterol lowering with statin drugs has a major effect, even in the large group of patients with average cholesterol levels. Use of clopidogrel, a more potent antiplatelet agent than aspirin, appears to decrease recurrent ischemic events, which has highlighted the potential benefits of oral IIb/IIIa inhibitors, which are much more potent antiplatelet agents. An additional focus has been on ensuring that patients actually receive the currently available medications. With a great number of new medical treatments, the outcome of patients with acute coronary syndromes has improved and will continue to improve as we enter the next millennium.     

Differential suppression of thromboxane biosynthesis by indobufen and aspirin in patients with unstable angina

BACKGROUND: We have previously reported aspirin failure in suppressing enhanced thromboxane (TX) biosynthesis in a subset of episodes of platelet activation during the acute phase of unstable angina. The recent discovery of a second prostaglandin H synthase (PGHS-2), inducible in response to inflammatory or mitogenic stimuli, prompted us to reexamine TXA2 biosynthesis in unstable angina as modified by two cyclooxygenase inhibitors differentially affecting PGHS-2 despite a comparable impact on platelet PGHS-1. METHODS AND RESULTS: We randomized 20 patients (15 men and 5 women aged 59+/-10 years) with unstable angina to short-term treatment with aspirin (320 mg/d) or indobufen (200 mg BID) and collected 6 to 18 consecutive urine samples. Urinary 11-dehydro-TXB2 was extracted and measured by a previously validated radioimmunoassay as a reflection of in vivo TXA2 biosynthesis. Metabolite excretion averaged 102 pg/mg creatinine (median value; n=76) in the aspirin group and 55 pg/mg creatinine (median value; n=99) in the indobufen group (P<.001). There were 16 samples (21%) with 11-dehydro-TXB2 excretion >200 pg/mg creatinine among patients treated with aspirin versus 6 such samples (6%) among those treated with indobufen (P<.001). In vitro and ex vivo studies in healthy subjects demonstrated the capacity of indobufen to largely suppress monocyte PGHS-2 activity at therapeutic plasma concentrations. In contrast, aspirin could only inhibit monocyte PGHS-2 transiently at very high concentrations. CONCLUSIONS: We conclude that in unstable angina, episodes of aspirin-insensitive TXA2 biosynthesis may reflect extraplatelet sources, possibly expressing the inducible PGHS in response to a local inflammatory milieu, and a selective PGHS-2 inhibitor would be an ideal tool to test the clinical relevance of this novel pathway of arachidonic acid metabolism in this setting.     

A risk-benefit assessment of abciximab in angioplasty

Advances in percutaneous coronary intervention (PCI) have allowed procedures to be performed on a variety of patients with a spectrum of challenging coronary anatomy. Abciximab has permitted further expansion and has made the procedure safer. Abciximab is a chimerised murine monoclonal antibody directed against the platelet glycoprotein (GP) IIb-IIIa receptor. Binding to this receptor inhibits platelet aggregation to a wide variety of biological agonists. It also binds to alphavbeta3 and leucocyte MAC-1 receptors; the biological significance of its affinity to these receptors is unclear. Abciximab has an extremely short plasma half-life. Since abciximab binds to the platelet GP IIb-IIIa receptor with great avidity it has an extremely long biological half-life. The use of abciximab is currently confined primarily to PCIs. The first large trial, EPIC, established that abciximab, given with aspirin (acetylsalicylic acid) and heparin, reduced the frequency of peri-procedural ischaemic events by 35% in high-risk patients. For this reduction a bolus of 0.25 mg/kg was followed by a 12-hour infusion of abciximab. However, the transfusion rate was doubled. A subsequent trial, EPILOG, indicated that reduction of the dose of heparin along with expeditious removal of arterial access sheaths, reduced the rate of haemorrhagic complications to a level comparable with placebo-treated patients. while also amplifying the reduction in ischaemic events. In a third trial, EPISTENT, this benefit was shown to include patients undergoing elective coronary stent implantation. Additional trials have demonstrated that the same effect is present in patients undergoing primary PCI for acute myocardial infarction and in patients undergoing PCI for refractory unstable angina pectoris. In the latter situation, treatment with abciximab for 18 to 24 hours preceding the intervention reduced the rate of myocardial infarction even before the procedure was begun. The rationale for the use abciximab is thus clearly established. Bleeding complications can be reduced by limiting the heparin dose, avoiding unneeded venous access site punctures, and expeditious removal of arterial sheaths. In emergency coronary artery bypass surgery, platelet transfusion reduces the number of receptors occupied per platelet and is likely to reduce the degree of postoperative bleeding. The cost of abciximab remains an issue; however, this is partially offset by the reduction in ischaemic complications and accompanying resource use. In patients undergoing elective coronary stenting, abciximab use reduced the long term rate of target vessel revascularisation. The degree to which this reduction results in further cost savings will require further analysis.     

Seroprevalence of hepatitis E virus among United Nations Mission in Haiti (UNMIH) peacekeepers, 1995

In the management of unstable angina and non-Q-wave acute myocardial infarction (AMI), there is considerable debate regarding the use of invasive strategy versus conservative strategy. The Thrombolysis In Myocardial Infarction (TIMI) III B trial found similar clinical outcomes for the 2 strategies, but the Veterans Administration Non-Q-Wave Infarction Strategies in-Hospital trial found a higher mortality with the invasive strategy. Both these trials were conducted before platelet glycoprotein IIb/IIIa inhibition and coronary stenting, both of which improve clinical outcome. Thus, there is a need to reexamine the question of which management strategy is optimal in the current era of platelet glycoprotein IIb/IIIa inhibition and new coronary interventions. The Treat Angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy (TACTICS-TIMI 18) trial is an international, multicenter, randomized trial that is evaluating the clinical efficacy of early invasive and early conservative treatment strategies in patients with unstable angina or non-Q-wave AMI treated with tirofiban, heparin, and aspirin. Patients are randomized to an invasive strategy, involving cardiac catheterization within 4 to 48 hours and revascularization with angioplasty or bypass surgery if feasible, versus a conservative strategy, where patients are referred for catheterization only for recurrent pain at rest or provokable ischemia. The primary end point is death, MI, or rehospitalization for acute coronary syndromes through a 6-month follow-up. The trial is also testing the "troponin hypothesis," that baseline troponins T and I will be useful in selecting an optimal management strategy.     

A clinical trial of a chest-pain observation unit for patients with unstable angina. Chest Pain Evaluation in the Emergency Room (CHEER) Investigators

BACKGROUND: Nearly half of patients hospitalized with unstable angina eventually receive a non-cardiac-related diagnosis, yet 5 percent of patients with myocardial infarction are inappropriately discharged from the emergency department. We evaluated the safety, efficacy, and cost of admission to a chest-pain observation unit (CPU) located in the emergency department for such patients. METHODS: We performed a community-based, prospective, randomized trial of the safety, efficacy, and cost of admission to a CPU as compared with those of regular hospital admission for patients with unstable angina who were considered to be at intermediate risk for cardiovascular events in the short term. A total of 424 eligible patients were randomly assigned to routine hospital admission (a monitored bed under the care of the cardiology service) or admission to the CPU (where patients were cared for according to a strict protocol including aspirin, heparin, continuous ST-segment monitoring, determination of creatine kinase isoenzyme levels, six hours of observation, and a study of cardiac function). The CPU was managed by the emergency department staff. Patients whose test results were negative were discharged, and the others were hospitalized. Primary outcomes (nonfatal myocardial infarction, death, acute congestive heart failure, stroke, or out-of-hospital cardiac arrest) and use of resources were compared between the two groups. RESULTS: The 212 patients in the hospital-admission group had 15 primary events (13 myocardial infarctions and 2 cases of congestive heart failure), and the 212 patients in the CPU group had 7 events (5 myocardial infarctions, 1 death from cardiovascular causes, and 1 case of congestive heart failure). There was no significant difference in the rate of cardiac events between the two groups (odds ratio for the CPU group as compared with the hospital-admission group, 0.50; 95 percent confidence interval, 0.20 to 1.24). No primary events occurred among the 97 patients who were assigned to the CPU and discharged. Resource use during the first six months was greater among patients assigned to hospital admission than among those assigned to the CPU (P<0.01 by the rank-sum test). CONCLUSIONS: A CPU located in the emergency department can be a safe, effective, and cost-saving means of ensuring that patients with unstable angina who are considered to be at intermediate risk of cardiovascular events receive appropriate care.     

Cardiology. II. Coronary heart disease, myocardial infarction

Within the last 30 years pharmacotherapy has significantly contributed to an improvement of the prognosis of patients with coronary artery disease. With regard to antianginal drugs beta-blocker therapy has in particular enabled a risk reduction in patients with unstable angina, acute myocardial infarction and following acute myocardial infarction. Antithrombotic therapy has largely been influenced by platelet inhibitors. Acetylsalicylic acid (ASA) has convincingly shown to enable a risk reduction in patients with stable angina, unstable angina, acute myocardial infarction and in the secondary prevention following myocardial infarction. The introduction of thienopyridines has led to a further improvement of antiplatelet therapy. Thus, the combination of ticlopidine + ASA was combined with a significant risk reduction of subacute stent thrombosis and has enabled stent implantation to become a breakthrough technology. Clopidogrel, another thienopyridine has been shown to be superior in comparison to a monotherapy with ASA in patients with atherothrombotic diseases. The introduction of glycoproteine-IIb-IIIa-receptor antagonists has led to a significant risk reduction of periinterventional complications in patients with unstable angina. The combination of heparin + ASA was clearly superior to a monotherapy with ASA in patients with unstable angina. Recently, a further improvement of prognosis with low molecular weight heparin has been reported. Due to somewhat conflicting results, the definite role of direct thrombin inhibitors like hirudin still has to be defined. A possible risk reduction in patients with unstable coronary syndromes has been reported. Reperfusion therapy with fibrinolytic agents has revolutionised the therapy of patients with acute myocardial infarction throughout the last decades. In numerous trials successful fibrinolysis has convincingly shown to improve the prognosis of patients with acute myocardial infarction and thus is still considered to be the gold standard of treatment in acute myocardial infarction.     

Thrombolysis in the management of acute myocardial infarction. Current status and future perspectives

The optimal thrombolytic regimen is front-loaded alteplase with vigorous heparinization: the reperfusion treatment that leads to the lowest 30 day mortality. The role of heparin alone or in combination with thrombolysis is still unclear. Hirudin does not provide benefit over heparin, as we have seen in the trials, and glycoprotein blockers are promising in PTCA. They can also be effective in unstable angina and possibly in acute myocardial infarction.     

Anti-ischemic and anti-anginal effects of thoracic epidural anesthesia versus those of conventional medical therapy in the treatment of severe refractory unstable angina pectoris

BACKGROUND: Cardiac sympathetic blockade by thoracic epidural anesthesia (TEA) dilates stenotic coronary arteries and has been used to control pain in patients with unstable angina. The aim of the present study was to evaluate the potential anti-ischemic effects of cardiac sympathetic blockade by TEA in severe, refractory, unstable angina. METHODS AND RESULTS: Forty patients with unstable angina refractory to standard anti-anginal therapy were randomized to receive either continuous epidural infusion of bupivacaine (TEA, Th1 to Th5) or to standard anti-anginal therapy including beta-blockers, calcium antagonists, aspirin, heparin, and nitroglycerin infusion (control group). The primary end points were number of anginal attacks and severity of myocardial ischemia assessed by 48-hour ambulatory Holter monitoring. The incidence of myocardial ischemia was lower in the TEA group (22% versus 61%; P<.05). The number of ischemic episodes per patient was 1.0+/-0.6 in the TEA group and 3.6+/-0.9 in the control group (P<.05). The episode duration per patient was 4.1+/-2.5 minutes and 19.7+/-6.2 minutes in the TEA and the control groups, respectively (P<.05). The mean area-under-the-ST-time-curve was 6.8+/-4.3 and 32.2+/-14.3 (mm-min) in the TEA and the control groups, respectively (P<.05). Fifteen anginal attacks were recorded in the control group and one attack in the TEA group (0.83+/-0.21 versus 0.06+/-0.06/patient, respectively, P<.01). CONCLUSIONS: The anti-ischemic and anti-anginal effects of continuous TEA are superior to those of conventional therapy in the treatment of refractory unstable angina.     

Saikosaponin b2 induces differentiation without growth inhibition in cultured B16 melanoma cells

Some patients of ischemic heart disease have low uptake in 123I-labeled beta methyl-iodophenyl penta-decanoic acid (BMIPP) SPECT in spite of normal uptake in thallium-201 (Tl) SPECT. To investigate their clinical significance, we performed both T1 and BMIPP myocardial SPECT in 26 cases with stable angina (n = 16) and unstable angina (n = 10), and compared with clinical backgrounds electrocardiogram (ECG) and left ventriculography (LVG). In 11 patients of them, the uptake of BMIPP was moderately reduced. We divided 26 cases into two groups according to uptake of BMIPP (normal/reduced). The two groups had no differences in length of angina attack and duration of disease, but they had a significant difference in the abnormality of either ECG or LVG. Three to six months after PTCA, we examined LVG in 18 cases, 12 of 16 cases with the abnormality of LVG showed the improvement of wall motion. We concluded the reduced uptake of BMIPP with normal uptake of Tl was related to more severe ischemia in cases with unstable angina.     

Comparative efficacy of the intravenous administration of linsidomine, a direct nitric oxide donor, and isosorbide dinitrate in severe unstable angina. A French multicentre study. French Group of Investigators

AIMS: Although linsidomine shares common properties with nitrovasodilators, it releases nitric oxide directly without catalytic involvement by thiols. We conducted a prospective, randomized, multicentre, parallel group, single-blind study to compare the efficacy of intravenous administration of linsidomine with that of isosorbide dinitrate in unstable angina. METHODS AND RESULTS: Between November 1990 and July 1992, 568 patients with suspected unstable angina (class IIIB of the Braunwald classification) received a continuous infusion of either linsidomine (1 mg.h-1 on average) or isosorbide dinitrate (2.5 mg.h-1 on average) for 72 h. All patients received concomitant aspirin and intravenous heparin, 81% beta-blockers and 38% calcium antagonists. Holter monitoring was performed in all patients and analysed blindly. Only 25% of the patients had at least one episode of chest pain during the study (24.6% vs 25.8% in the linsidomine and isosorbide dinitrate groups, P = 0.74), of which 12% were associated with ECG changes. Holter criteria yielded similar results in both groups: 33% of patients presented episodes of myocardial ischaemia (32.6% vs 33.9% in the linsidomine and isosorbide dinitrate groups, P = 0.74), while 45% showed episodes of ventricular arrhythmia (43.5% vs 46.5% in the linsidomine and isosorbide dinitrate groups, P = 0.48). The incidence of serious clinical events at 72 h (death, myocardial infarction or myocardial revascularization) was 6.5% (5% vs 8% in the linsidomine and isosorbide dinitrate groups, P = 0.17). CONCLUSION: Intravenous linsidomine is at least as efficacious as isosorbide dinitrate in the stabilization of patients with severe unstable angina.     

Therapy and prevention of cerebral ischemia

Two large randomized studies - NINDS and ECASS - have shown that fibrinolytics, when given early enough, reduce morbidity and mortality in acute stroke. The treatment has to be initiated within three hours after onset of symptoms. In middle cerebral artery stroke, fibrinolysis can be performed within six hours from onset, guided by computed tomography criteria. Thereafter, s.c. low-molecular-weight heparin can still improve the fate of the patient. Currently, the potential benefit or harm of unfractionated heparin and aspirin is not yet known. However, large-scale studies using standard heparin, aspirin of low-molecular-weight heparin are in progress with results expected soon. After the acute stage of stroke, risk factors have to be eliminated or modified, and anticoagulants, platelet inhibitors and, in selected cases, carotid endarterectomy are useful in preventing recurrent stroke or other vascular events.     

Enoxaparin for unstable angina and ancrod for cardiac surgery following heparin allergy

OBJECTIVE: To describe a patient who presented with heparin allergy and required alternate anticoagulation for unstable angina and coronary artery bypass surgery. To review therapeutic alternatives to porcine heparin for patients with hypersensitivity or intolerance to standard heparin anticoagulation. CASE SUMMARY: A 74-year-old man with a 15-year-old coronary artery bypass graft presented to the emergency room with unstable angina and was scheduled for urgent coronary artery revascularization. A bolus dose of porcine heparin was administered followed by a continuous infusion. Shortly afterward the patient developed a type I allergic reaction to the porcine heparin that was confirmed by rechallenge. Three alternatives to porcine heparin were tried, including bovine lung heparin, low-molecular-weight heparin (enoxaparin), and ancrod. The patient was found to be cross-sensitive to bovine lung heparin, but tolerated enoxaparin for unstable angina without cross-sensitivity. Anticoagulation for cardiopulmonary bypass was achieved with an infusion of ancrod that was later reversed with cryoprecipitate. The patient was discharged postoperatively on day 5 without the complication of excessive bleeding. DISCUSSION: Type I allergic reaction to unfractionated heparin is a rare occurrence and could be the result of a variety of factors. Possible causes for the reaction include a porcine protein, a preservative contained in the heparin solution, or a hapten formed between heparin and a plasma protein. We considered four alternatives to heparin anticoagulation: rush desensitization, bovine lung heparin, low-molecular-weight heparin, and ancrod. The patient was cross-sensitive to bovine lung heparin, but was able to tolerate low-molecular-weight heparin (enoxaparin). This was unexpected because enoxaparin is derived from unfractionated porcine heparin. Testing for cross-sensitivity had no value in this case, as two negative subcutaneous test doses were followed by dramatic reactions when the drugs were given intravenously. Although enoxaparin has been used for anticoagulation during bypass surgery, there is more experience with ancrod as an alternative to heparin. Repeat bypass surgery, which normally results in above-average blood loss, was successfully performed with a very low fibrinogen concentration (< 0.15 g/L) during ancrod anticoagulation. CONCLUSIONS: We conclude that ancrod was a safe and effective alternative to heparin for coronary artery bypass surgery in this patient in whom a heparin product had caused a hypersensitivity reaction. We discovered on two occasions that a negative subcutaneous test dose for heparin allergy did not predict a severe type I allergic reaction when the heparin was later administered intravenously. Furthermore, we found that a low-molecular-weight heparin administered subcutaneously for a short period of time did not cause cross-sensitivity in a patient with a type I allergy to unfractionated heparin.     

Coronary stenting in unstable angina: early and late clinical outcomes

OBJECTIVE: To examine the procedural and long term success of coronary stenting in patients presenting with unstable angina and the effect of warfarin on the clinical outcome of these high risk patients. DESIGN: A nonrandomized, retrospective analysis of patients presenting with unstable angina. SETTING: A tertiary care, Canadian university-affiliated teaching hospital. PATIENTS: Of 1250 patients who underwent percutaneous transluminal coronary angioplasty between January 1994 and June 1995, 365 underwent coronary stenting. The study population consisted of the 156 patients presenting with unstable angina who underwent coronary stenting. Patients with Canadian Cardiovascular Society class IV and postinfarction angina were included. INTERVENTIONS: Stent delivery by standard techniques to the target lesion was successful in all patients. At discharge, 88 patients were prescribed warfarin, ticlopidine and acetylsalicylic acid (ASA); the remaining 68 patients received only ticlopidine and ASA. Late clinical outcomes were assessed by telephone interview. RESULTS: The overall procedural success rate was 96%. One patient died in hospital (0.6%). Other events were abrupt closure (1.9%), myocardial infarction (1.9%) and urgent bypass surgery (1.9%). During follow-up, target vessel reintervention was needed in 19.6% of patients. Early and late clinical outcomes did not differ significantly between anticoagulated patients and those treated with antiplatelet agents alone, but anticoagulated patients had a significantly longer hospital stay. CONCLUSIONS: Coronary stenting in patients with unstable angina was associated with excellent procedural success and favourable late clinical outcomes. Warfarin added no apparent additional clinical benefit to antiplatelet agents in this high risk population.