Pre-hospital fibrinolysis in the management of patients with ST elevation acute coronary syndrome: review of the evidence, implementation and future directions.

Time to reperfusion is among the strongest predictors of clinical outcome in patients who present with ST elevation acute myocardial infarction. When time to access is equivalent, primary percutaneous coronary intervention has demonstrated superior outcomes to fibrinolysis. However, where significant delays exist in accessing percutaneous intervention, fibrinolysis has an important role. The potential for fibrinolysis delivery in the pre-hospital setting means that delays to primary percutaneous intervention need to be considered from the time that the patient becomes eligible for fibrinolysis in the field. This can be particularly challenging in patients with symptom duration ofless than two hours, as some evidence suggests fibrinolysis may be particularly beneficial in this early phase. Additionally, access to primary percutaneous intervention provided by an experienced operator, in a timely manner at any time of the day or night, is not an available option in many healthcare settings. This review focuses on the current evidence and practice of pre-hospital fibrinolysis and assesses potential roles for this therapy in the future.

Anti-Platelet Therapy for Acute Coronary Syndrome: A Review of Currently Available Agents and What the Future Holds.

Dual anti-platelet therapy remains a cornerstone in the management of patients suffering from acute coronary syndromes (ACS). The combination of aspirin and clopidogrel has been shown to result in significant reductions in cardiovascular end points including recurrent infarction and death in several randomised control trial of patients with ACS. However, many patients still experience ischaemic events on the combination of aspirin and clopidogrel. Aspirin is a relatively weak anti platelet agent. Clopidogrel is a pro drug that required activation by hepatic metabolism and hence its onset of action is delayed; there is genetic variation in the clinical response to the drug, the platelet inhibition is irreversible and no intravenous form is available. Consequently new anti-platelet agents have been developed to address the short falls of this combination therapy. This paper discusses existing anti-platelet regimes and focuses on novel antiplatelet agents that are currently under clinical evaluation.

High-dose tirofiban with enoxaparin and inflammatory markers in high-risk percutaneous intervention.

AIM: The study assessed the benefit of high bolus dose tirofiban (HD-tirofiban) with enoxaparin compared with HD-tirofiban with unfractionated heparin (UFH). The study examined markers of platelet activation, thrombin generation and inflammation. MATERIALS AND METHODS: The study is a prospective single centre open-label trial of patients with high-risk acute coronary syndrome treated with percutaneous intervention (PCI) who were randomized to anticoagulation with UFH or enoxaparin with HD-tirofiban (25 microg kg(-1) bolus). This study measured a panel of platelet activation markers, inflammatory biomarkers and thrombus generation between the two groups. RESULT: Sixty patients undergoing high-risk PCI were enroled in the study. Platelet inhibition as assessed by whole blood aggregometry following HD-tirofiban infusion was similar in both the UFH and enoxaparin groups. CD40 ligand expression on platelets was significantly reduced following PCI with HD-tirofiban and either UFH or enoxaparin. Following PCI, there were significant reductions measured in other markers of platelet activation including PAC-1, P selectin, factor V/Va, platelet-monocyte aggregates and monocyte expression of Mac-1 as determined by analysis of venous blood samples using flow cytometry. Prothrombin fragment 1+2, D-dimer, von Willebrand factor and high sensitive C-reactive protein levels were significantly less post PCI in the enoxaparin group compared with those patients receiving UFH. CONCLUSION: The combination of HD tirofiban with enoxaparin resulted in an attenuated inflammatory response when compared with that of the combination of HD tirofiban with UFH.

Failure of current public educational campaigns to impact on the initial response of patients with possible heart attack.

AIMS: The National Heart Foundation of Australia recognizes that the risk of lethal arrhythmias is greater very early after the onset of myocardial infarction and that the more promptly flow can be restored in the infarct-related artery the greater will be the benefits for survival and preservation of heart function. The Heart Foundation has therefore conducted several public media campaigns to encourage patients to seek help more promptly and evaluated their impact. METHODS: Since 1996, we have conducted four surveys of delays preceding admission of patients to coronary care units throughout Australia to assess the impact of the Heart Foundation's media campaigns. Data were collected on 1665 patients who presented to 73 hospitals; information on patient delay was available for 1178 of them. RESULTS: There were no significant differences in patient delay (median 1.5-2.0 h) in the four surveys from 1996 to 2002, nor when patients were categorized by age, sex, presenting diagnosis or history of previous myocardial infarction or coronary revascularization by percutaneous or surgical techniques. CONCLUSION: New approaches are needed to reduce patient-related delay after the onset of symptoms suggesting possible myocardial infarction.

Actinomycin-eluting stent for coronary revascularization: a randomized feasibility and safety study: the ACTION trial.

OBJECTIVES: We sought to demonstrate the safety and performance of the actinomycin D-coated Multilink-Tetra stent(Guidant Corp., Santa Clara, California) in the treatment of patients with single de novo native coronary lesions. BACKGROUND: Drug-eluting stents (DES) releasing sirolimus or paclitaxel dramatically reduce restenosis. The anti-proliferative drug, actinomycin D, which is highly effective in reducing neointimal proliferation in preclinical studies, was selected for clinical evaluation. METHODS: The multi-center, single-blind, three-arm ACTinomycin-eluting stent Improves Outcomes by reducing Neointimal hyperplasia (ACTION) trial randomized 360 patients to receive a DES (2.5 or 10 microg/cm(2) of actinomycin D) or metallic stent (MS). The primary end points were major adverse cardiac events (MACE) at 30 days, diameter stenosis by angiography, tissue effects, and neointimal volume by intravascular ultrasound (IVUS) at six months. When early monitoring revealed an increased rate of repeat revascularization, the protocol was amended to allow for additional follow-up for DES patients. Angiographic control of MS patients was no longer mandatory. RESULTS: The biased selection of DES patients undergoing IVUS follow-up invalidated the interpretation of the IVUS findings. The in-stent late lumen loss and that at the proximal and distal edges were higher in both DES groups than in the MS group and resulted in higher six-month and one-year MACE (34.8% and 43.1% vs. 13.5%), driven exclusively by target vessel revascularization without excess death or myocardial infarction. CONCLUSIONS: The results of the ACTION trial indicate that all anti-proliferative drugs will not uniformly show a drug class effect in the prevention of restenosis.

Actinomycin-eluting stent for coronary revascularization: a randomized / feasibility and safety study: the ACTION trial

OBJECTIVES: We sought to demonstrate the safety and formance of the actinomycin D-coated Multilink-Tetra stent(Guidant Corp., Santa Clara,California) in the treatment of patients with single de novo native coronary lesions. BACKGROUND: Drug-eluting stents (DES) releasing sirolimus or paclitaxel dramatically reduce restenosis. The anti-proliferative drug, actinomycin D, which is highly effective in reducing neointimal proliferation in preclinical studies, was selected for clinical evaluation. METHODS: The multi-center, single-blind,three-arm ACTinomycin-eluting stent Improves Outcomes by reducing Neointimal hyperplasia (ACTION) trial randomized 360 patients to receive a DES (2.5 or 10 microg/cm(2) of actinomycin D) or metallic stent (MS). The primary end points were major adverse cardiac events (MACE) at 30days, diameter stenosis by angiography, tissue effects, and neointimal volume by intravascular ultrasound (IVUS) at six months. When early monitoring revealed an increased rate of repeat revascularization, the protocol was amended to allow for additional follow-up for DES patients. Angiographic control of MS patients was no longer mandatory. RESULTS: The biased selection of DES patients undergoing IVUS follow-up invalidated the interpretation of the IVUS findings. The in-stent late lumen loss and that at the proximal and distal edges were higher in both DES groups than in the MS group and resulted in higher six-month and one-year MACE (34.8% and 43.1% vs. 13.5%), driven exclusively by target vessel revascularization without excess death or myocardial infarction...

Five-year angiographic patency of radial artery bypass grafts.

BACKGROUND: Little information exists regarding mid-term and long-term patency of radial artery grafts. METHODS AND RESULTS: We performed restudy coronary angiography at 5.2+/-0.4 years after surgery on 50 asymptomatic patients who had undergone coronary artery bypass graft surgery, using at least 1 radial artery graft, to determine both graft patency and presence of narrowing. We examined preoperative clinical or angiographic variables that might predict graft occlusion. Radial artery graft patency was 89%, with 91% of grafts free of narrowing. Preoperative New York Heart Association anginal class < or =2, target vessel proximal stenosis < or =70%, and small target vessel supply territory were predictive of graft occlusion. CONCLUSIONS: At 5 years after surgery, radial artery grafts have disease-free patency rates that are similar to other graft types.

Use of an accelerated chest pain assessment protocol in patients at intermediate risk of adverse cardiac events.

OBJECTIVE: To determine the feasibility, safety and effectiveness of a structured clinical pathway for stratification and management of patients presenting with chest pain and classified as having intermediate risk of adverse cardiac outcomes in the subsequent six months. DESIGN: Prospective clinical audit. PARTICIPANTS AND SETTING: 630 consecutive patients who presented to the emergency department of a metropolitan tertiary care hospital between January 2000 and June 2001 with chest pain and intermediate-risk features. INTERVENTION: Use of the Accelerated Chest Pain Assessment Protocol (ACPAP), as advocated by the "Management of unstable angina guidelines--2000" from the National Heart Foundation and the Cardiac Society of Australia and New Zealand. MAIN OUTCOME MEASURE: Adverse cardiac events during six-month follow-up. RESULTS: 409 patients (65%) were reclassified as low risk and discharged at a mean of 14 hours after assessment in the chest pain unit. None had missed myocardial infarctions, while three (1%) had cardiac events at six months (all elective revascularisation procedures, with no readmissions with acute coronary syndromes). Another 110 patients (17%) were reclassified as high risk, and 21 (19%) of these had cardiac events (mainly revascularisations) by six months. Patients who were unable to exercise or had non-diagnostic exercise stress test results (equivocal risk) had an intermediate cardiac event rate (8%). CONCLUSIONS: This study validates use of ACPAP. The protocol eliminated missed myocardial infarction; allowed early, safe discharge of low-risk patients; and led to early identification and management of high-risk patients.

Angiographic follow-up and clinical experience with the flexible Tantalum Cordis stent.

The Cordis stent is a flexible, highly radioopaque intracoronary stent engineered from a single Tantalum filament folded into a sinusoidal helical coil. It is premounted on a semicompliant balloon expandable stent delivery system. From September 1995-March 1996, 147 Cordis stents were deployed in 105 patients (aged 58+/-12 yr, 71% male). Clinical indications for stenting were unstable angina in 59 (55%), stable angina in 41 (38%), and acute myocardial infarction in 7 (7%). The target vessel was the right coronary artery in 45%, the left anterior descending in 31%, and the circumflex artery in 22%. One stent was deployed in a vein graft, and one stent was deployed in a left internal mammary artery graft. Stent deployment was achieved in all but one patient. Acute in-stent thrombosis occurred in 3 patients (2.9%). Two of these patients required urgent coronary artery bypass surgery. Subacute stent thrombosis occurred in 2 patients (1.9%). Minimum lumen diameter increased from 0.70+/-0.41 mm to 3.50+/-0.60 mm following stent placement. All patients received aspirin. Eighty-one patients (77%) received ticlopidine, and 4 patients (4%) received warfarin therapy. The mean hospital stay was 3.4+/-2.3 days. Six-month follow-up angiography was performed on 50 out of 55 eligible patients at one of the two institutions involved in this study. Computer-assisted quantitative coronary angiography defined a restenosis rate of 26%. Repeat revascularization was required in 8 patients (14.5%) at 6-mo follow-up. The Tantalum Cordis intracoronary stent is an effective and safe means of treating coronary lesions, even in patients with unstable ischemic syndromes. Acute and subacute rates of in-stent thrombosis were acceptable, and the long-term angiographic restenosis rates and need for repeat revascularization were favorable.

Multiple stent implantation in single coronary arteries: acute results and six-month angiographic follow-up.

A total of 147 stents were implanted (in overlapping manner in 76% of vessels) in a single coronary artery in 59 patients (60 vessels, 97 lesions, 2.45 stents/vessel) over a period of 18 mo using high pressure stent deployment without ultrasound guidance. The indications for stenting were suboptimal percutaneous transluminal coronary angioplasty (PTCA) result (45%), primary prevention of restenosis (44%), acute closure (10%), and restenosis after plain balloon angioplasty (1%). One patient required emergency coronary artery bypass grafting (CABG) (extensive dissection), and one required early intervention with plain balloon angioplasty and intracoronary urokinase for stent thrombosis. There were no deaths. Thirteen patients had recurrence of angina within 6 mo and angiograms were performed in all. These showed intrastent restenosis in nine (all had successful repeat plain balloon angioplasty), development of new disease in other vessels along with restenosis close to the stent in the target vessel in one (underwent elective CABG) and normal angiograms with widely patent stents in three. Forty-five patients (77%) remained free of recurrent angina and 25 of these had follow-up angiograms (56%) at a mean of 172 days, two showing restenosis. Thus, the restenosis rate per patient in the symptomatic group (angiographic follow-up in 100%) was 77% and in the asymptomatic group (angiographic follow-up in 56%) was 8%. The restenosis rate in the subgroup with bailout stenting (n = 6) was 20% (angiographic follow-up in 83%). The overall restenosis rate per patient was 32% (overall angiographic follow-up in 66%). During the 6-mo follow-up period, one patient underwent elective CABG (1.7%), one sustained a non-Q myocardial infarction (1.7%), nine had repeat PTCA to the target vessel (15.5%), and there were no deaths. The event-free survival rate was 77%. Multiple stent implantation aided by high pressure stent deployment without ultrasound guidance and with adjunctive optimal antiplatelet therapy without oral anticoagulation seems to be a useful and effective revascularisation strategy to deal with long lesions and acute dissections with a high procedural success rate. The restenosis rate is acceptable and is not appreciably high as reported in previous studies from the "warfarin era."

Interventional management of acute myocardial infarction (AMI).

The best way to limit infarct size and improve survival in patients with early heart attacks is to restore as quickly as possible patency in the infarct-related artery and blood flow to the threatened myocardium. The value of thrombolytic therapy and aspirin has been shown in large clinical trials. A regimen of accelerated recombinant tissue plasminogen activator is more effective than those using streptokinase. In older patients, there is a greater risk of haemorrhagic stroke; nevertheless, thrombolytic treatment saves more lives because the mortality of myocardial infarction (MI) is higher. Thrombolytic therapy fails to restore blood flow sufficiently rapidly or completely in nearly one-fifth of patients. Its efficacy, therefore, has been compared with immediate or direct angioplasty (PTCA). If it can be done promptly enough, PTCA is superior in preventing recurrent ischaemia and the combined outcome of death or non-fatal reinfarction, and is associated with a lesser risk of intracranial haemorrhage. It may also be cheaper because patients spend less time in hospital and fewer of them require late revascularisation. PTCA should be considered for patients with cardiogenic shock or for those in whom there is a contraindication to thrombolytic therapy. The benefits of prompt treatment have been reduced by excessive delay in reaching hospital and door-to-needle time. After fibrinolysis, coronary angiography and PTCA may be reserved for those with spontaneous angina or exercise-induced ischaemia.

Growth factors released into the coronary circulation after vascular injury promote proliferation of human vascular smooth muscle cells in culture.

OBJECTIVES: This study sought to 1) assess in vivo release of platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF) into the coronary circulation after vascular injury in human subjects; and 2) evaluate mitogenic effects of PDGF and bFGF on the patient's own vascular smooth muscle cells (VSMCs). BACKGROUND: Circumstantial evidence suggests involvement of PDGF and bFGF peptides in the neointimal response to vascular injury. To date, no study has shown biologically active growth factors within the coronary circulation after vascular injury in human subjects. METHODS: In 18 patients, plasma PDGF AB, platelet factor 4 (PF4) and beta-thromboglobulin (beta-TG) levels were measured in coronary sinus blood obtained before and up to 30 min after angioplasty. In five patients undergoing atherectomy, coronary sinus serum was added to cultured VSMCs derived from atherectomy tissue to assess the mitogenic potential of the serum. Mitogenicity attributable to PDGF and bFGF was determined using neutralizing antibodies to these factors. PDGF A, PDGF B and bFGF were localized within the atherectomy tissue using immunocytochemical analysis. RESULTS: Before angioplasty, PDGF AB, PF4 and beta-TG levels were elevated threefold in patients scheduled for angioplasty compared with those in control patients (p < 0.01). Within 5 min of angioplasty, PDGF AB levels increased twofold and returned toward preangioplasty levels at 30 min; PF4 and beta-TG levels remained elevated. Serum obtained at 30 min after atherectomy showed a sixfold increase in mitogenicity compared with preatherectomy serum (p = 0.01). This increase in mitogenicity was reduced by 20%, 40% and 65% in the presence of neutralizing antibodies to PDGF, bFGF and PDGF + bFGF, respectively. PDGF A, PDGF B and bFGF were visualized within the intima of the atherectomy tissue. CONCLUSIONS: The change in plasma PDGF level is consistent with first-phase release of PDGF after vascular injury. The increase in mitogenicity of serum suggests that PDGF and bFGF are biologically active.

Elective implantation of intracoronary stents without intravascular ultrasound guidance or subsequent warfarin.

Two hundred forty-three stents (203 Palmaz-Schatz, 40 Glanturco-Roubin) were electively Implanted in 188 lesions in 168 patients (mean age 58 +/- 10 years, 77% males) using angiographic but not ultrasound guidance. Patients were treated subsequently with aspirin and observed in hospital for up to 7 days. Those with acute myocardial infarction, radiolucent defects in coronary arteries suggestive of thrombus, and results that were not optimal after stent implantation were anticoagulated with warfarin and not Included in the study. Two had subacute stent thrombosis and two patients non-Q-wave myocardial infarction in-hospital. At follow-up (median 149 days) none had had subacute stent thrombosis, one suffered non-Q-wave myocardial infarction, none had died, and none had developed major complications at the vascular access site. Fourteen (8%) had undergone further revascularisation procedures. This initial experience suggests that aspirin is sufficient to prevent subacute stent thrombosis after elective high pressure assisted coronary stent implantation without intravascular ultrasound guidance if the angiographic appearance after stent deployment is optimal.

The effect of oral anticoagulant therapy on APTT results from a bedside coagulation monitor.

OBJECTIVE: The Ciba Corning 512 coagulation monitor (CC512) can be used to monitor heparin therapy by performing an activated partial thromboplastin time (APTT) at the patient's bedside. This study was designed to compare the CC512 results to results using the laboratory system. The relative sensitivities of both systems to the effect of oral anticoagulant therapy also was investigated. METHODS: Activated partial thromboplastin times were performed with both the CC512 and laboratory system on 74 specimens from patients receiving i.v. heparin therapy, and on 14 specimens from patients on warfarin only. Heparin assays were performed on 43 of the specimens from the heparinized patients. RESULTS: When a patient was receiving heparin only, the APTT results of the CC512 proved to be similar to existing laboratory methods. The CC512 APTT results of patients on warfarin only were markedly prolonged, whereas the laboratory APTTs were only slightly affected. CONCLUSION: The CC512 results were comparable to the laboratory system. However, the CC512 APTT was more sensitive to the effect of warfarin than the laboratory APTT system used in this study. CC512 APTT results on a patient receiving both oral and intravenous anticoagulation could be misleading.

Percutaneous transluminal coronary angioplasty: clinical and quality of life outcomes one year later.

BACKGROUND: The quality of life status of patients prior to and following percutaneous transluminal coronary angioplasty (PTCA) has not been comprehensively investigated. AIM: This study was carried out to determine the effect that PTCA has on patients' quality of life. METHODS: Data on 209 patients were collected one day pre-PTCA and at a mean of two and 11 months post-PTCA. Data on symptomatic status, functional capacity, life satisfaction and psychological well-being were analysed quantitatively. Clinical outcomes, patient perception of PTCA and employment status wee analysed by descriptive statistics. RESULTS: Highly significant improvement in all quality of life measures was found at the early follow-up (p < .001). This improvement was sustained at the late follow-up. At the late follow-up, 58% of patients felt that PTCA had been very beneficial to their health and well-being, and 79% of workers had returned to work. PTCA was primarily successful in 91% of vessels dilated. There were no procedural-related deaths, 12 patients (6%) developed acute occlusion and three patients (1.5%) experienced myocardial infarction (MI). A symptomatic restenosis rate of 16% was found, including 19 patients (9%) requiring repeat PTCA and 14 (7%) undergoing coronary artery bypass grafting (CABG). CONCLUSION: These findings suggest that, after PTCA, the majority of patients experienced improved quality of life which was sustained one year later.

LATE assessment of thrombolytic efficacy with alteplase (rt-PA) six-24 hours after onset of acute myocardial infarction.

Conflicting results on the benefit of thrombolytic therapy administered six to 24 hours after the onset of myocardial infarction (MI) led to the LATE trial. Five thousand seven hundred and eleven patients were treated with recombinant tissue plasminogen activator (t-PA) or placebo, treatment was begun between six and 24 hours after the onset of infarction. For patients treated within 12 hours, there was a relative reduction in 35 day mortality of 25%, but no benefit for those treated at 12 to 24 hours. The benefits were confined to those whose treatment was begun within three hours of admission to hospital. These results widen the window for effective treatment from six to 12 hours after the onset of infarction, but emphasise the need for expeditious treatment when the diagnosis of MI is suspected.

Clinical results and quality of life after percutaneous transluminal coronary angioplasty: a preliminary report.

To evaluate the effect of percutaneous transluminal coronary angioplasty (PTCA) on quality of life, data on symptomatic status, functional capacity, life satisfaction, and psychological wellness were collected on 102 patients at 1 day pre-PTCA and 2 months post-PTCA, and on the first 50 of these patients at 10 months post-PTCA. There were highly significant changes (p < 0.001) in all quality of life measures between pre-PTCA and the 1st follow-up measurements. No further significant changes occurred in these measures between the 1st and 2nd follow-up measurements, indicating that the initial improvement in quality of life was sustained over this period. Data on primary success rate, complications, and pre- and post-PTCA risk factor scores are also reported.