Treatment of unprotected left main coronary artery stenosis with a drug eluting stent in a heart transplant patient with allograft vasculopathy.

High risk angioplasty with drug eluting stent placement into an unprotected left main coronary artery in a heart transplant recipient with allograft vasculopathy is reported. Ten month angiographic follow up is reported. The literature is reviewed and current methods of revascularisation are described in detail. This is the first report of drug eluting stent use in this clinical situation.

Biomarker profiling of plasma from acute coronary syndrome patients. Application of ProteinChip Array analysis.

AIM: Acute coronary syndrome (ACS) is one of the leading causes of death in the world and remains a complex pathophysiologic process involving inflammatory, hemostatic and vascular processes. The purpose of this study was to identify unique proteomic biomarkers present in patients with ACS using a newly developed proteomic profiling technique, surface enhanced laser desorption/ionization (SELDI). METHODS: Citrated plasma samples obtained from clinically confirmed cases of ACS (n=100) and age matched controls (n=25) were profiled using SELDI-time of flight (TOF)-mass spectrometry (Ciphergen Biosystems, Freemont, CA, USA). A strong anion exchange (SAX) ProteinChip Array was used to profile these samples. In addition to spectra profiles, protein density plots were be obtained from the generated molecular profile. RESULTS: The SELDI profile in the molecular weight (MW) range of 0-150 kDa revealed a prominent 66.3 kDa albumin peak along with several distinct components at 28 kDa, 13.7 kDa and 6.5 kDa. Additional minor molecular components were also noted in the lower MW range (<6 kDa). There was a cluster of peaks between 10 and 12 kDa that were unique to the patients with ACS; about 1/3 of the ACS patients exhibited these peaks as evident in the ProteinChip Array spectrum. None of the age-matched controls exhibited the peaks in this MW range, nor did the normal human plasma pool that was used as an additional control. The relative intensity of these novel molecular components in the range of 10-12 kDa represent unique proteins/peptides which are generated in specific pathologic states associated with ACS. CONCLUSIONS: These observations suggest that patients with ACS have a unique cluster of molecular components that are present in their SELDI profile. It might be possible to use these patterns to identify high-risk patients who may be more susceptible to the development of unstable plaque, which may eventually lead to myocardial infarction. Identification and characterization of these molecular components will also help in the understanding of the pathogenesis of ACS. These unique peaks may represent pathologic proteins, novel inflammatory mediators or protease cleavage products. Further studies need to be done to better characterize and identify these molecular components and their pathologic role in ACS.

A randomized trial of the low-molecular-weight heparin certoparin to prevent restenosis following coronary angioplasty.

OBJECTIVES: The objectives of this study were to evaluate the effectiveness and safety of the low-molecular-weight heparin (LMWH) certoparin in preventing restenosis following balloon coronary angioplasty. BACKGROUND: Restenosis following coronary angioplasty continues to limit the long-term efficacy of this procedure. Animal studies have indicated a potential role for LMWH in reducing restenosis by limiting smooth muscle proliferation. METHODS: This study tested the effects of certoparin, self-administered for 3 months, in reducing restenosis following balloon coronary angioplasty. One hundred and eighteen patients with 158 lesions treated with angioplasty were enrolled in this randomized, placebo-controlled trial. One hundred and two patients completed the study. The endpoint was relative loss measured with quantitative coronary angiography. RESULTS: The relative loss for placebo was 0.19 +/- 0.23 compared to 0.14 +/- 0.21 for LMWH (p = NS). The minimum lumen diameter (MLD) was 1.47 +/- 0.66 for placebo and 1.40 +/- 0.57 for the LMWH (p = NS). There was a reduction (31% for LMWH; 49% for placebo PSDP) in the percent of patients having binary restenosis (MLD < 50% of reference diameter). At the end of the study 77% of the placebo patients and 76% of the LMWH group were asymptomatic (p = NS). There was a low rate of bleeding complications and these were minor. Bone density scans showed that there was no significant occurrence of osteoporosis with 3 months of LMWH. CONCLUSIONS: Administration of certoparin for 3 months is safe, but appears ineffective in reducing post-PTCA restenosis.

Use of vascular sealing devices (VasoSeal and Perclose) versus assisted manual compression (Femostop) in transcatheter coronary interventions requiring abciximab (ReoPro).

UNLABELLED: Transcatheter coronary interventions requiring abciximab (ReoPro) are associated with vascular access site complications. Several devices have been developed to aid in the closure of the femoral arteriotomy, including collagen plug devices (VasoSeal, AngioSeal), percutaneous suture closure (Perclose), and aids to manual compression (Femostop). In 185 patients who received abciximab plus aspirin and heparin for transcatheter coronary interventions, we compared femoral arteriotomy closure by three different methods: VasoSeal, Perclose, and Femostop. A composite endpoint of late complications defined as an access site-related bleed or hematoma that required blood transfusion or an extended hospital stay, pseudoaneurysm, arteriovenous fistula, arterial or venous thrombosis was compared. VasoSeal was initially successful in 41/52 patients (78.8%). The 11 patients who failed to have adequate hemostasis with VasoSeal required manual compression aided by Femostop, but had no late complications. There was one access site infection and one fatal retroperitoneal hematoma unrelated to the vascular access site (surgically explored). There were no late complications. Perclose was successful in 48/56 patients (85.7%). One Perclose failure required surgical repair for an extensive arteriotomy. The other Perclose failure required manual compression aided by Femostop, but had no late complications. There were no access site infections requiring intravenous antibiotics. There was one retroperitoneal bleed that extended the patient's hospital stay and for which a blood transfusion was required. Femostop was successful in 77/77 patients (100%). There were no infections. Late complications occurred in four patients. These included three episodes of bleeding or hematomas requiring blood transfusion, and one pseudoaneurysm. CONCLUSION: In patients receiving abciximab in addition to aspirin and heparin, VasoSeal and Perclose are at least as safe as Femostop when used to achieve homeostasis after sheath removal. VasoSeal and Perclose have a significantly lower initial rate of successful hemostasis than Femostop. The numbers of late complications between the VasoSeal, Perclose, and Femostop groups were not significantly different. In those patients in whom VasoSeal or Perclose failed, no late complications occurred. Access site infections were no different between VasoSeal, Perclose, and Femostop.

Clinical experience with combined treatment of thrombin inhibitors and GPIIb/IIIa inhibitors in patients with HIT.

Despite the use of potent anticoagulants such as r-hirudin and argatroban, the morbidity/mortality of heparin-induced thrombocytopenia (HIT) patients remains high. In the last several months, we have treated three HIT-positive patients with a combined therapy of thrombin inhibitor and GPIIb/IIIa inhibitor when treatment with thrombin inhibitor alone failed to alleviate acute thrombosis. Combination therapies included r-hirudin (Refludan) with tirofiban (Aggrastat) or argatroban (Novastan) with ReoPro. A reduced dose of the thrombin inhibitor with the standard dose of the antiplatelet drug was the dosing regimen used. In all cases, there was no overt bleeding that required intervention and all patients had improved or fully recovered. This first report of the use of GPIIb/IIIa inhibitors with thrombin inhibitors in HIT patients with active thrombosis suggests that this combined therapy may be more effective than thrombin inhibitor treatment alone. The data from these three cases warrant testing of this therapeutic regimen in larger studies to determine optimal dosing strategies.

Thrombogenesis in myocardial infarction and related syndromes: the role of molecular markers in diagnosis and management.

Anticoagulant therapy has undergone some major developments in recent years. Conventional drugs that produce anticoagulant effects such as heparin and oral anticoagulants are no longer considered the only candidates for the anticoagulant/antithrombotic management of patients. Recombinant hirudin, glycoproteins IIb/IIIa targeting antibodies, synthetic peptides such as Hirulog and efegatran are being tested for their efficacy. These drugs produce their effects at different sites. To monitor their overall effects on the hemostatic system, molecular markers offer a practical and reliable approach. Markers of thrombin generation are useful for the monitoring of antithrombin drugs whereas, the efficacy of antiplatelet drugs can be assessed by monitoring the platelet release products. Furthermore, polytherapy using several anticoagulant and antithrombotic drugs in combination has been considered. In these situations, the use of molecular markers may also prove to be invaluable. The introduction of simple technology such as the test strip or particle agglutination methods may be available for the measurement of many of these markers in the near future. This will be useful for ready availability and reduced cost for individual marker testing. Furthermore, this type of technology can be used at bedside, off-site, and in doctor's offices. It is clear that the molecular marker profiling provides useful information on the nature of pathophysiology of a given thrombotic disorder. However, for practical use, a cost-effective and simpler assay-based approach will enhance their use, and these tests will be readily accepted at the laboratory and clinical levels.

Useful laboratory tests for studying thrombogenesis in acute cardiac syndromes.

We review laboratory tests that evaluate thrombogenesis during acute coronary syndromes. These tests have been found to be valuable research tools in more clearly understanding the pathophysiology of acute coronary syndromes. In particular, we describe tissue factor, tissue factor pathway inhibitor, prothrombin fragment 1.2, thrombin-antithrombin complex, fibrinopeptide A, tissue plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1), t-PA-PAI complex, Bbeta 15-42-related peptides, fibrinogen degradation products, fibrin degradation products, D-dimer, platelet factor 4, beta-thromboglobulin, 5-hydroxytryptamine, thromboxane B2, prostacyclin, endothelin, angiotensin-converting enzyme, soluble thrombomodulin, C1-esterase inhibitor, anaphylotoxins C3a, C4a, and C5a, bradykinin, tumor necrosis factor, leukotriene C4, platelet activating factor, anti-phospholipid antibody, and von Willebrand factor. Some of these tests may prove to be useful in clinical diagnosis and management of acute coronary syndromes. Clinical outcome studies are needed to determine which tests may be cost effective and medically useful.

Rescue angioplasty in the thrombolysis in myocardial infarction (TIMI) 4 trial.

Rescue percutaneous transluminal coronary angioplasty (PTCA) has been used to establish reperfusion after failed thrombolysis, and the goal of this study was to examine the angiographic and clinical outcomes after rescue PTCA performed for an occluded artery 90 minutes after thrombolysis. Four hundred two patients with acute myocardial infarction were randomized to receive either anistreplase (APSAC), recombinant tissue plasminogen activator, or their combination in the Thrombolysis in Myocardial Infarction (TIMI) 4 trial. The angiographic and clinical outcomes of patients with a patent artery 90 minutes after thrombolysis were compared with those of patients with an occluded artery treated in a nonrandomized fashion with either rescue or no rescue PTCA. At 90 minutes, the number of frames required to opacify standard landmarks (corrected TIMI frame count) was significantly lower (i.e., flow was faster) after successful rescue PTCA (27 +/- 11) than that in patent arteries after successful thrombolysis (39 +/- 20, p < 0.001), and the incidence of TIMI grade 3 flow was correspondingly higher after successful rescue PTCA (87% vs 65%, p = 0.002). In-hospital adverse outcomes (death, recurrent acute myocardial infarction, severe congestive heart failure, cardiogenic shock or an ejection fraction <40%) occurred in 29% of successful rescue PTCAs and in 83% of failed rescue PTCAs (p = 0.01). Among all patients in whom rescue PTCA was performed (successes and failures combined), 35% of patients experienced an adverse outcome, which was the same as the 35% incidence observed in patients not undergoing rescue PTCA (p = NS) and tended to be higher than the 23% incidence observed in patients with patent arteries (p = 0.07). Although successful rescue PTCA for an occluded artery at 90 minutes results in restoration of flow that is superior to that of successful thrombolysis, the incidence of adverse events for the strategy of rescue PTCA as a whole was the same as that of undertaking no PTCA.

Impact of diabetes mellitus on percutaneous revascularization (CAVEAT-I). CAVEAT-I Investigators. Coronary Angioplasty Versus Excisional Atherectomy Trial.

We examined the relation between diabetes mellitus and outcomes in patients undergoing percutaneous coronary revascularization in the Coronary Angioplasty Versus Excisional Atherectomy Trial (CAVEAT-I), a randomized trial comparing treatment with either percutaneous transluminal coronary angioplasty or directional atherectomy for de novo lesions in native coronary arteries. Acute success and complication rates, 6-month angiographic restenosis rates, and 1-year clinical outcomes were compared between diabetic and nondiabetic patients undergoing each procedure. Acute success rates between diabetic (n = 191) and nondiabetic (n = 821) patients were similar for both revascularization techniques. Except for the need for dialysis, complication rates were also similar. Six months after atherectomy, diabetic patients had significantly more angiographic restenosis than nondiabetics (59.7% vs 47.4%) and significantly smaller minimum luminal diameters (1.20 vs 1.40 mm). Diabetics undergoing atherectomy required more frequent bypass surgery (12.8% vs 8.5%) and more repeat percutaneous revascularizations (36.5% vs 28.1%) than nondiabetics undergoing atherectomy. Restenosis rates, minimum luminal diameters and repeat revascularizations between diabetics and nondiabetics undergoing angioplasty were similar. The higher restenosis and repeat revascularization rates and the smaller minimum luminal diameter at follow-up in diabetic patients suggest that atherectomy may provide only modest benefit for these patients. The increased restenosis rate in diabetics undergoing atherectomy (but not angioplasty) requires further evaluation.

A comparison of debulking versus dilatation of bifurcation coronary arterial narrowings (from the CAVEAT I Trial). Coronary Angioplasty Versus Excisional Atherectomy Trial-I.

We compared the effectiveness of percutaneous transluminal coronary angioplasty and directional coronary atherectomy for the management of bifurcation coronary lesions in 1,012 patients enrolled in the Coronary Angioplasty Versus Excisional Atherectomy Trial-I. Directional coronary atherectomy was associated with less angiographic residual stenosis, but with a higher rate of side-branch closure and non-Q-wave myocardial infarction.

Abrupt closure: the CAVEAT I experience. Coronary Angioplasty Versus Excisional Atherectomy Trial.

OBJECTIVES: This study sought to assess the incidence and consequences of abrupt closure in a series of patients undergoing directional coronary atherectomy versus percutaneous coronary angioplasty. BACKGROUND: Abrupt closure with coronary angioplasty has been associated with adverse outcome. The results from the Coronary Angioplasty Versus Excisional Atherectomy Trial (CAVEAT) I, a randomized trial of coronary angioplasty versus directional coronary atherectomy, were analyzed. METHOD: This multicenter trial enrolled 1,012 patients from 1991 to 1992. All records from patients with abrupt closure, which was coded as a discrete complication, were reviewed. RESULTS: Abrupt closure occurred in 60 patients (5.9%) and was associated with a significantly longer hospital stay (median 8 vs. 3 days). Severe proximal target vessel tortuosity was more common in patients with abrupt closure (20.3% vs. 11.6%, p = 0.046), as was preexistent coronary artery thrombus (30.5% vs. 18.3%, p = 0.02). Abrupt closure was associated with a marked increase in subsequent complications (myocardial infarction 46.7% vs. 2.1%, emergency bypass surgery 38.3% vs. 0.32%, death 33% vs. 0%) and occurred more frequently in the directional coronary atherectomy group (8.0% vs. 3.8%, p = 0.005). In the coronary angioplasty group, the occlusion usually occurred at the target lesion (91%), presumably related to the effects of barotrauma. In the directional coronary atherectomy group, the site of the occlusion was the target lesion in only 58% (p = 0.045). The remaining occlusions related to problems with the technique (guide catheter or nose cone trauma), reflecting the fact that directional coronary atherectomy is a more complex procedure. CONCLUSIONS: Abrupt closure remains the principal determinant of adverse outcome after percutaneous procedures for the treatment of coronary artery disease. Although abrupt closure is more common with directional atherectomy than angioplasty, the sequelae are similar.

Assessment of outcome of bifurcation lesions and non-bifurcation lesions treated in the CAVEAT trial. CAVEAT investigator group.

Registry data suggests that bifurcation lesions are associated with reduced success during percutaneous revascularization. We studied 1012 CAVEAT patients to compare procedural outcomes in patients with and without bifurcation lesions whose target vessel was treated with either atherectomy or angioplasty. Bifurcation lesions have increased angiographic complexity and interventions on them are associated with lower acute procedural success rates compared to non-bifurcation lesions. Subgroup analysis suggests that atherectomy treatment of bifurcation lesions improves acute procedural success rates and lowers restenosis rates compared to angioplasty treatment of bifurcation lesions but atherectomy of bifurcation lesions is associated with higher acute complication rates than angioplasty of bifurcation lesions.

Length of hospital stay and complications after percutaneous transluminal coronary angioplasty. Clinical and procedural predictors. Heparin Registry Investigators.

BACKGROUND: Although several studies have established that the complications of percutaneous transluminal coronary angioplasty (PTCA) are related to clinical and angiographic variables such as advanced age and lesion complexity, it is uncertain whether the use of hospital resources after PTCA also depends on the same baseline variables. The purpose of this study was to identify the factors responsible for prolonged hospital stay after PTCA. METHODS AND RESULTS: The study cohort included 591 consecutive patients undergoing conventional balloon angioplasty at nine medical centers in North America. Major or minor complications occurred in 91 patients (15.4%) and were observed to be related to several baseline characteristics, including unstable angina, multivessel coronary artery disease, patient age, and lesion complexity. Compared with a median length of hospital stay of 2.0 days after PTCA (25th, 75th percentiles: 2.0, 4.0) for the entire cohort of patients, the length of stay was increased in patients with unstable angina (3.0 days [2.0, 5.0]; P = .002), multivessel coronary artery disease (3.0 [2.0, 5.5]; P = .001), age > 65 years (3.0 [2.0, 5.5]; P = .02), complex lesions (3.0 [2.0, 6.0]; P = .001), and filling defects (6.0 [2.0, 11.0]; P < .001). The length of stay was more strikingly increased, however, in patients who experienced major or minor PTCA complications, such as emergency bypass surgery (9.0 days [8.0, 18.0]; P < .001), Q-wave or non-Q-wave myocardial infarction (8.0 [6.0, 15.5]; P < .001), transfusion unrelated to bypass surgery (8.0 [4.0, 12.0]; P < .001), or abrupt vessel closure (6.0 [3.0, 10.5]; P < .001). On stepwise multiple linear regression, PTCA complications appeared to be the strongest predictors of length of hospital stay (all P < .001) and overwhelmed the weaker relation between length of stay and several individual baseline variables. Inclusion of a composite clinical risk score (reflecting the presence of unstable angina, multivessel disease, advanced age, complex lesions, or filling defects) in the regression model confirmed that patients with several high-risk baseline variables had a significant increase in length of stay after PTCA (P = .003), but PTCA complications remained the strongest predictors of length of stay. CONCLUSIONS: Although PTCA complications were correlated with baseline variables such as unstable angina, multivessel disease, advanced age, complex lesions, and filling defects, excess length of stay after PTCA was most strongly influenced by the development of minor and major PTCA complications. Because patients with several baseline risk factors experienced significantly prolonged hospitalizations, improved selection of patients may contribute to reductions in length of stay after PTCA. A greater reduction in resource use after PTCA, however, would be expected from developing new treatments to decrease PTCA complications rather than limiting the access of patients with unstable angina, advanced age, or complex lesions to PTCA.

Successful treatment of heparin-associated thrombocytopenia and thrombosis using Hirulog.

Heparin-associated thrombocytopenia is a serious medical problem, especially when the patient requires continued anticoagulation. Hirulog is an immediate-acting intravenous anticoagulant that can be substituted for heparin. A new use of Hirulog in the treatment of life-threatening heparin-associated thrombocytopenia with thrombosis (HATT) is presented. Two patients suffering from the HATT syndrome were successfully treated with Hirulog to prevent further thrombosis. A third patient had developed heparin-associated thrombocytopenia after coronary artery bypass surgery in the past and was subsequently treated with Hirulog during a peripheral angioplasty procedure. Hirulog was an effective and predictable anticoagulant for these patients and was free from adverse effects.

Directional atherectomy versus balloon angioplasty for coronary ostial and nonostial left anterior descending coronary artery lesions: results from a randomized multicenter trial. The CAVEAT-I investigators. Coronary Angioplasty Versus Excisional Atherectomy Trial.

OBJECTIVES: We hypothesized that atherectomy would be superior to balloon angioplasty for ostial and nonostial left anterior descending coronary artery lesions. BACKGROUND: Balloon angioplasty of ostial coronary artery lesions has been associated with a lower procedural success rate and a higher rate of complications and of restenosis than angioplasty of nonostial stenoses. Directional coronary atherectomy has been proposed as an alternative therapy for ostial lesions. METHODS: In the Coronary Angioplasty Versus Excisional Atherectomy Trial (CAVEAT-I), 1,012 patients were randomized to undergo either procedure; 563 patients had proximal left anterior descending coronary artery lesions, of which 74 were ostial. We compared balloon angioplasty with directional atherectomy for early and 6-month results for ostial as well as nonostial proximal left anterior descending coronary artery lesions. RESULTS: Directional atherectomy led to an initially higher gain in minimal lumen diameter for ostial lesions (1.13 vs. 0.56 mm, respectively, p < 0.001) but a higher rate of adjudicated non-Q wave myocardial infarction (24% vs. 13%, respectively, p < 0.001) than balloon angioplasty and no improvement in restenosis rates (48% vs. 46%, respectively). In the nonostial proximal left anterior descending coronary artery lesions, angiographic restenosis was reduced (51% vs. 66%, p = 0.012), but this was also associated with a higher rate of periprocedural myocardial infarction (8% vs. 2%, p = 0.008 by site and 24% vs. 8%, p < 0.001 by adjudication) and no difference in the need for subsequent coronary artery bypass surgery (7.3% vs. 8.4%, respectively) or repeat percutaneous coronary intervention (24% vs. 26%, respectively). CONCLUSIONS: For ostial left anterior descending coronary artery stenoses, both procedures yielded similar rates of initial success and restenosis, but atherectomy was associated with more non-Q wave myocardial infarction. In this trial the predominant angiographic benefit (increased early gain and less angiographic restenosis) of atherectomy for the left anterior descending coronary artery was in proximal nonostial lesions. However, the tradeoffs for this angiographic advantage were more in-hospital myocardial infarctions and no decrease in clinical restenosis.

A multicenter, randomized trial of coronary angioplasty versus directional atherectomy for patients with saphenous vein bypass graft lesions. CAVEAT-II Investigators.

BACKGROUND: Directional coronary atherectomy and percutaneous transluminal coronary angioplasty have both been used in symptomatic patients with coronary saphenous vein bypass graft stenoses. The relative merits of plaque excision and removal versus balloon dilatation remain uncertain. We compared outcomes after directional coronary atherectomy or angioplasty in patients with de novo bypass graft stenoses. METHODS AND RESULTS: Fifty-four North American and European sites randomized 305 patients with de novo vein graft lesions to atherectomy (n = 149) or angioplasty (n = 156). Quantitative coronary angiography at a core laboratory assessed initial and 6-month results. Initial angiographic success was greater with atherectomy (89.2% versus 79.0%), as was initial luminal gain (1.45 versus 1.12 mm, P < .001). Distal embolization was increased with atherectomy (P = .012), and a trend was shown toward more non-Q-wave myocardial infarction (P = .09). Although the 6-month net minimum luminal diameter gain was 0.68 mm for atherectomy and 0.50 mm for angioplasty, the restenosis rates were similar, 45.6% for atherectomy and 50.5% for angioplasty (P = .491). At 6 months, there was a trend toward decreased repeated target-vessel interventions for atherectomy (P = .092); in addition, 13.2% of patients treated with atherectomy versus 22.4% of the angioplasty patients (P = .041) required repeated percutaneous intervention of the initial target lesion. CONCLUSIONS: Atherectomy of de novo vein graft lesions was associated with improved initial angiographic success and luminal diameter but also with increased distal embolization. There was no difference in 6-month restenosis rates, although primary atherectomy patients tended to require fewer target-vessel revascularization procedures.

Predictors of successful PTCA using coronary perfusion balloon catheters.

The purpose of this retrospective study was to define clinical, angiographic and procedural predictors of successful PTCA using perfusion balloon catheters (PBC). Age, gender, diabetes, clinical state (stable or unstable angina), coronary vessel, AHA/ACC lesion type, lesion contour, pre-procedural thrombus, percent stenosis, lesion length, balloon size, maximum PBC pressure, and maximum inflation time were analyzed for 207 lesions in 193 successive patients. Unsuccessful results occurred more frequently in patients with unstable angina, pre-PTCA thrombus, and those treated with smaller balloon catheter diameter. Logistical regression analysis identified larger balloon size (odds ratio [OR] = 0.447 [95% confidence interval 0.203, 0.986], p < .05); and absence of thrombus (OR = 2.217 [95% confidence interval 1.066, 4.610], p < .05) as predictors of success. This study suggests that small vessel size, approximated by balloon size selection, and the presence of pre-PTCA thrombus reduces the likelihood of success, especially in the setting of unstable angina. In these cases other percutaneous interventions may be warranted.

Evaluation of hemostatic and fibrinolytic alterations associated with daily administration of low-molecular-weight heparin for a 12-week period.

The PTCA procedure fails in 30-50% of patients due to late restinosis, meaning that this is a problem of 100,000-150,000 people per year in the USA alone. It has been found that heparin and low-molecular-weight heparin (LMWH) have an inhibitory effect on smooth muscle cell (SMC) proliferation and migration, the major causes of restinosis. However, little is known about the toxicity and side effects of these drugs when used for a long period as may be required for prophylaxis of PTCA restinosis. To investigate possible side effects, non-human primates received daily injections of 1 mg/kg s.c. LMWH (Mono-Embolex) over a 12-week period. The hemostatic system was monitored through measurement of ACT-celite, APTT, Heptest, TT(10U/mL), TFPI, Anti-IIa activity, Anti-Xa activity, ACA-Heparin, AT III, factor VIII R:Ag, fibrinogen, and thrombomodulin levels. Elisa tests for t-PA, PAI-1, u-PA, FgDP, TDP, and D-Di levels were used for measurements of fibrinolytic activity. Increased values of ACT, APTT, Heptest, TT, Anti-IIa, Anti-Xa, ACA-Heparin, and TFPI were observed four hours after LMWH injections. AT III, vWFAg, fibrinogen and thrombomodulin showed no change from the pre-study baseline. An accumulation effect was seen in the APTT and Heptest over the 12 weeks. After the first week the blood levels of Anti-IIa activity remained elevated at 20% inhibition rather than 0% 24 hrs after drug administration. This activity slowly decreased after discontinuation of drug. The Anti-Xa blood level activity remained elevated at 40% inhibition 24 hrs after drug administration 2 weeks into the study, and this activity was detectable even 2 weeks after cessation of drug administration. There was increasing activity of the fibrinolytic system with LMWH treatment. After two weeks t-PA increased two-fold to 6 ng/mL but returned to baseline at six weeks. There was a corresponding increase of the TDP but not a clear increase in D-Di and FgDP. The increase of u-PA was limited to the first days of LMWH treatment only. The PAI-1 activity increased gradually over the entire study period. No bleeding complications occurred throughout the study. The long-term administration of Mono-Embolex as projected for the use in the prophylaxis of restinosis following PTCA appears to be safe for patients.

The relation of clinical outcome to dissection and thrombus formation during coronary angioplasty. Heparin Registry Investigators.

BACKGROUND: Although the development of thrombus or dissection during percutaneous transluminal coronary angioplasty (PTCA) increases the risk of abrupt vessel closure, the magnitude of the effect is difficult to define. OBJECTIVE: The aim of the study was to determine prospectively the effect of the development of thrombus or dissection on PTCA procedural outcome. METHODS: Data from 591 consecutive angioplasty procedures involving 756 lesions at 9 clinical centers were included in a prospective registry with a core angiographic laboratory. RESULTS: Clinical success (defined as < 50% stenosis of all target lesions assessed in a core angiographic laboratory, with no major complications of death, Q wave or non-Q wave myocardial infarction or emergency CABG) was achieved in 497 patients (84%). Major complications occurred in 45 (7.6%). Abrupt vessel closure, including both established closure (TIMI grade 0 or I flow) and impending closure (> 50% stenosis, TIMI grade 0-2 flow, plus use of additional interventions) occurred in 65 patients (11%). Angiographically visible dissections developed in 40% of lesions; more severe grades of dissection were associated with reduced success rates, and increased incidence of and abrupt vessel closure and major complication. Angiographic evidence of thrombus (filling defects) developed in 12.3% of lesions; the presence of thrombus was associated with significantly lower procedural success (61% vs. 86%) and significantly higher rates of abrupt vessel closure (28% vs 7%) and major complications (24% vs. 6%). With multivariable analysis, thrombus was identified as an independent predictor of procedural success, abrupt vessel closure, and major complications. CONCLUSIONS: The development of severe dissections or thrombus following PTCA is associated with significantly lower procedural success rates and higher rates of abrupt vessel closure and major complications. Patients who develop severe dissection or thrombus may be appropriate candidates for more aggressive forms of therapy.

Comparison of front-loaded recombinant tissue-type plasminogen activator, anistreplase and combination thrombolytic therapy for acute myocardial infarction: results of the Thrombolysis in Myocardial Infarction (TIMI) 4 trial.

OBJECTIVES: The aim of our study was to determine a superior thrombolytic regimen from three: anistreplase (APSAC), front-loaded recombinant tissue-type plasminogen activator (rt-PA) or combination thrombolytic therapy. BACKGROUND: Although thrombolytic therapy has been shown to reduce mortality and morbidity after acute myocardial infarction, it has not been clear whether more aggressive thrombolytic-antithrombotic regimens could improve the outcome achieved with standard regimens. METHODS: To address this issue, 382 patients with acute myocardial infarction were randomized to receive in a double-blind fashion (along with intravenous heparin and aspirin) APSAC, front-loaded rt-PA or a combination of both agents. The primary end point "unsatisfactory outcome" was a composite clinical end point assessed through hospital discharge. RESULTS: Patency of the infarct-related artery (Thrombolysis in Myocardial Infarction [TIMI] grade 2 or 3 flow) at 60 min after the start of thrombolysis was significantly higher in rt-PA-treated patients (77.8% vs. 59.5% for APSAC-treated patients and 59.3% for combination-treated patients [rt-PA vs. APSAC, p = 0.02; rt-PA vs. combination, p = 0.03]). At 90 min, the incidence of both infarct-related artery patency and TIMI grade 3 flow was significantly higher in rt-PA-treated patients (60.2% had TIMI grade 3 flow vs. 42.9% and 44.8% of APSAC- and combination-treated patients, respectively [rt-PA vs. APSAC, p < 0.01; rt-PA vs. combination, p = 0.02]). The incidence of unsatisfactory outcome was 41.3% for rt-PA compared with 49% for APSAC and 53.6% for the combination (rt-PA vs. APSAC, p = 0.19; rt-PA vs. combination, p = 0.06). The mortality rate at 6 weeks was lowest in the rt-PA-treated patients (2.2% vs. 8.8% for APSAC and 7.2% for combination thrombolytic therapy [rt-PA vs. APSAC, p = 0.02; rt-PA vs. combination, p = 0.06]). CONCLUSIONS: Front-loaded rt-PA achieved significantly higher rates of early reperfusion and was associated with trends toward better overall clinical benefit and survival than those achieved with a standard thrombolytic agent or combination thrombolytic therapy. These findings support the concept that more rapid reperfusion of the infarct-related artery is associated with improved clinical outcome.