The Subcutaneous Heparin and Angioplasty Restenosis Prevention (SHARP) trial. Results of a multicenter randomized trial investigating the effects of high dose unfractionated heparin on angiographic restenosis and clinical outcome.

OBJECTIVES: We sought to determine whether 12,500 IU of unfractionated heparin given subcutaneously twice daily for 4 months after percutaneous transluminal coronary angioplasty beneficially influences the subsequent rate of angiographic restenosis and the incidence of clinical events. BACKGROUND: Heparin has been shown to exhibit powerful antiproliferative effects against smooth muscle cells in several animal models. METHODS: A randomized trial with blinded data analysis was undertaken to assess the effect of unfractionated subcutaneous heparin on angiographic restenosis after coronary angioplasty. After successful angioplasty, patients were randomized to receive no heparin or 12,500 IU of heparin given subcutaneously twice daily for 4 months. Quantitative coronary angiography was performed before angioplasty, immediately after angioplasty and at follow-up ("early" [before 4 months] or electively [at 4 months]). RESULTS: The study group comprised 339 patients, 167 randomly assigned to receive heparin, 172 to receive no heparin. Repeat cardiac catheterization was performed in 90% of randomized patients. At early and elective restudy (mean 4.2 months), the mean +/- SD difference in minimal lumen diameter between the postangioplasty and follow-up measurement was -0.55 +/- 0.58 mm for the no heparin group and -0.43 +/- 0.59 mm for the heparin group (p = NS). Clinical events during the follow-up period did not differ significantly between groups: fatal myocardial infarction (1 patient in each group), coronary bypass grafting (5 patients in each group), repeat angioplasty (12 in the no heparin, 6 in the heparin group), angina at 4-month assessment (33% in the no heparin, 32% in the heparin group). CONCLUSIONS: Long-term treatment with high dose subcutaneous heparin (12,500 IU twice daily) for 4 months did not favorably influence angiographic or clinical outcome after coronary angioplasty.

Changes in vessel wall plasminogen activator activity and smooth muscle cell proliferation and activation after arterial injury.

OBJECTIVES: The aim was to examine changes in vessel wall fibrinolytic activity following angioplasty and to assess any relationship to changes in smooth muscle cell proliferation and activation. METHODS: Balloon angioplasty was performed to the iliac arteries of New Zealand White rabbits and vessel wall changes assessed at 2 h, 1 d, 7 d, 14 d, and 1 month postprocedure. Tissue-type (tPA) and urokinase-type (uPA) plasminogen activator activity was assessed using chromogenic substrate assays, while smooth muscle cell proliferation and activation was monitored using expression of proliferating cell nuclear antigen (PCNA) and of basic fibroblast growth factor (bFGF) respectively. RESULTS: Intimal thickening progressively increased up to 1 month. uPA activity increased at 2 h [1.94(SEM 0.19) v 1.59(0.05) U.mg-1 tissue for control vessels, P = 0.03], remained increased at 24 h, but by 7 d had decreased to below control levels and remained low. In contrast, tPA activity fell significantly at 2 h [0.9(0.3) v 1.96(0.13) micrograms.mg-1 tissue for control vessels, P = 0.03], remained low at 24 h, but by 7 d had reverted back to control levels [2.19(0.39) micrograms.mg-1]. PCNA positivity of the media increased at day 1, reached maximum on day 7 [16.9(5.1)% positively staining cells] before returning to baseline by 1 month. PCNA positivity of the intima first evident at day 7 [0.7(0.3)%], reached a maximum at day 14 [4.1(0.4)%]. bFGF expression increased early at 2 h [mean(SE) positively staining cells: 15.7(5.3)% v 11.2(4.8)% for control vessels] and continued to increase, reaching a maximum in the media at day 7 [59(8.6)%] and in the intima at day 14 [57.5(5.7)%]. CONCLUSIONS: Balloon injury produced an initial fall in tPA and rise in uPA activity. tPA increased back to control levels by 7 d, while uPA fell to below control levels at 7 d and 1 month. This would be compatible with a mechanism whereby acute injury suppressed tPA and upregulated uPA activity, with increased tPA activity acting as a marker for vessel repair.

A targeted antithrombotic conjugate with antiplatelet and fibrinolytic properties which reduces in vivo thrombus formation.

OBJECTIVE: Potent therapy that could be locally delivered to inhibit blood factor-vessel wall interaction and which would remain localised to the site of damage may avoid the side effects of systemic drugs in the treatment of disorders such as subacute thrombosis of saphenous vein grafts and intravascular stents. We therefore assessed the feasibility of developing a targeted antithrombotic conjugate by covalently cross-linking urokinase to a monoclonal antibody to platelet glycoprotein IIb/IIIa (M735) and a monoclonal antibody against damaged endothelium (P14G11). METHODS: Conjugation was carried out using N-succinimidyl-3-(2-pyridyldithio) propionate as the cross-linking reagent. The conjugate was assessed in vitro and in an in vivo model of thrombosis and local delivery. RESULTS: The conjugate formed, ATC(3), retained specificity for damaged endothelial cells and platelets and had urokinase activity of approximately 10,000 IU.mg-1 protein. Persistence of urokinase activity on binding to intact platelets and scratch damaged endothelial monolayer preparations was confirmed. Platelet aggregation studies (using ADP and collagen) revealed complete inhibition by ATC(3) at a dose of 5 micrograms.ml-1 while an unconjugated mixture of M735 (20 micrograms.ml-1), P14G11 (20 micrograms.ml-1), and urokinase (200 IU.ml-1) failed to inhibit completely platelet aggregation induced by ADP. In an in vivo model of thrombosis and vascular injury, local delivery of ATC(3) significantly reduced the weight of thrombus formed [median 13 mg (interquartile range 9-20)] compared to an unconjugated mixture of M735, P14G11 and urokinase [35 mg (28-45)] and urokinase alone [41 mg (33-55)]. CONCLUSIONS: It is possible to produce a targeted antithrombotic conjugate which retains activity of all its individual components.

Therapeutic levels of nitroglycerin do not affect the uptake and release of heparin by endothelial cells in vitro.

Intravenous heparin and nitroglycerin are frequently given in combination to patients with acute coronary syndromes such as unstable angina and post myocardial infarction angina. Heparin is prescribed since it has been shown that intracoronary thrombus formation is important in the pathophysiology of these acute conditions. However, it has been demonstrated that intravenous nitroglycerin can interfere with the anticoagulant effect of heparin. The exact mechanism of the interaction is unknown but it has been suggested that there is a direct effect on plasma heparin characterised by a reduction in circulating plasma heparin levels. Heparin binds to the surface of endothelial cells in a process that is time dependent, reversible and exhibits saturation kinetics. A possible mechanism of the observed effects on the plasma heparin levels produced by nitroglycerin may be the altered handling of heparin by endothelial cells. We have investigated this further by assessing the effects of therapeutic doses of nitroglycerin on heparin uptake and release by endothelial cells, using 35S labelled heparin and human umbilical vein endothelial cell cultures.

Absence of a prothrombotic state in restenotic patients?

AIMS: To determine whether, in patients undergoing percutaneous transluminal coronary angioplasty (PTCA), there are prothrombotic markers indicating those with a predisposition to restenosis. METHODS: Venous blood samples were obtained from patients undergoing PTCA for chronic stable angina. Patients with restenotic lesions, conduit stenoses or occlusive lesions were not included in the study. Samples were assayed for coagulation factors (fibrinopeptide A, antithrombin III, protein C), fibrinolytic factors [tissue-type plasminogen activator (t-PA), alpha 2 antiplasmin, plasminogen activator inhibitor (PAI-1)] and markers of platelet activation (platelet factor 4, beta thromboglobulin). RESULTS: Of 46 patients who underwent successful PTCA, restenosis, defined as loss in absolute gain of more than 50%, occurred in 16 (35%). The minimal luminal diameter (mean +/- SD) at follow-up in those who had suffered restenosis was 1.07 +/- 0.7 mm compared with 1.73 +/- 0.5 mm in the non-restenotic patients. However, no significant differences in the levels of markers of platelet activation, coagulation factors, or fibrinolytic factors were observed between the two groups. The only significant difference between the groups was a higher platelet count in the restenotic patients [median (interquartile range): 263 (247-278) versus 224 (175-263), P < 0.05]. CONCLUSION: Our results suggest that patients who suffer restenosis following PTCA appear to have no clearly detectable pre-existing imbalance in their prothrombotic/antithrombotic status. Although the platelet count was higher in restenotic patients, the levels of markers of platelet activation were no different in the two groups. Thus, it is at present unlikely that simple blood assays before PTCA assessing an individual's 'thrombotic state' can help to predict which of the 30-40% of patients undergoing PTCA will suffer restenosis.

Angiographic restenosis after angioplasty: comparison of definitions and correlation with clinical outcome.

BACKGROUND: The aim of this study was to assess which of the currently used definitions of restenosis most closely indicates degree of recurrence and clinical status by 1) correlating percentage luminal renarrowing with restenosis defined according to each of four definitions, and 2) evaluating which definition was best predicted by clinical recurrence. METHODS: Quantitative angiography in 125 patients was undertaken either at time of early clinical presentation or at 6-month follow-up after percutaneous transluminal coronary angioplasty (PTCA). Absolute luminal diameters measured before and after PTCA and at follow-up were plotted as the percentage return from post-PTCA toward pre-PTCA value. All patients were also defined as restenosed or not restenosed according to each of the four definitions. RESULTS: The angiographic restenosis rate varied from 31% to 47%. Other than for "loss of 50% absolute gain," all definitions defined restenosis in some patients, despite the degree of return from post-PTCA to pre-PTCA value being less than 50%. Early recurrent symptoms predicted angiographic restenosis best, irrespective of angiographic definition, whereas history of recurrent angina or positive exercise testing alone at follow-up were poor predictors (range, 0.46 to 0.54). The predictive value increased (0.75 to 0.87) when exercise testing was positive in patients complaining of angina. The definition "loss of 2 standard deviations" gave the lowest values for positive or negative predictive values irrespective of clinical parameter. CONCLUSIONS: "Loss of 50% absolute gain" may be the best compromise definition. Patients admitted early with angina should undergo recatheterization, whereas exercise tests should be reserved for patients who complain of angina at routine follow-up.

Neoplastic angina: a case report.

A 54-year-old Caucasian woman, with a 1-year history of exertional angina was investigated by means of coronary angiography. On injection of contrast into both coronary arteries an unusual area of capillary blushing was seen around the point of a left main stem stenosis. At surgery a mass was seen arising from the area of the aortic root extending around the left main stem. Histology confirmed this to be an aortic paraganglioma. Three-vessel coronary artery bypass grafting was performed and at 6-month follow-up the patient remained symptom free.

Plaque herniation through an intracoronary stent.

We present a case where a Wiktor intracoronary stent was inserted for 'poor angiographic result' following balloon angioplasty. Despite appropriate positioning and repeated dilation of the stent a suboptimal result was achieved because of plaque herniation through the stent. The case emphasizes that the choice of stent used is important and will become more so as the number of choices available increases.

Prothrombin fragment F1 + 2 concentrations for monitoring anticoagulation therapy with heparin.

We have compared the activated partial thromboplastin time with measurement of prothrombin fragment F1 + 2 concentrations (ELISA assay) during a 24-h period in a group of patients (n = 10) who had undergone elective coronary angioplasty and were anticoagulated post-procedure with heparin 1000 U/h. Four hours after the procedure all the patients were adequately anticoagulated according to activated partial thromboplastin time (median ratio 4.7:1) and the prothrombin fragment F1 + 2 concentration was significantly lower than pre-angioplasty values (0.5 vs 1.4 nmol/l, p = 0.04). At 24 h the median activated partial thromboplastin time ratio was still higher than the pre-procedure value (1.35 vs 0.9, p < 0.01), but the prothrombin fragment F1 + 2 concentration had risen to 2.1 nmol/l, with more variability in individual results within the patient group for the prothrombin fragment F1 + 2 concentration than for activated partial thromboplastin time (interquartile ranges (Q1, Q3) prothrombin fragment F1 + 2, 1.2-2.5; activated partial thromboplastin time, 1.2-1.5). The activated partial thromboplastin time is the standard method of monitoring the anticoagulant effect of heparin but may not fully reflect the functional coagulation status and accurately identify individual patients with less than adequate anticoagulation. Prothrombin fragment F1 + 2 concentrations may provide a more reliable indicator in individual patients of functional coagulation status in certain important situations where anticoagulation is critical such as following complicated coronary angioplasty.

Monitoring anticoagulation following intracoronary procedures: which method?

We have assessed bedside kits for monitoring the activated partial thromboplastin time and the activated clotting time by comparing them with laboratory activated partial thromboplastin time values. To determine the accuracy of anticoagulation we have concurrently measured the plasma heparin concentrations, and plasma prothrombin fragment F1 + 2 concentrations. Serial samples were taken from patients undergoing elective percutaneous transluminal coronary angioplasty (n = 14). Readings were taken pre-procedure, 30 min after administration of a heparin bolus (10,000 U) and 1, 2 and 3 h after commencement of a constant heparin infusion (15 U/kg/h) postprocedure. Activated partial thromboplastin time results obtained with the bedside kit compared reliably with laboratory values (r = 0.8), were rapidly available and were reflected by appropriate changes in prothrombin fragment F1 + 2 and heparin concentrations. However, the relationship between activated partial thromboplastin time values and activated clotting time was less precise (r = 0.59). Therefore, for routine and frequent monitoring of anticoagulation with heparin, a bedside activated partial thromboplastin time kit provides adequate control of therapy but in instances were particularly tight control of anticoagulation is required, use of prothrombin fragment F1 + 2 concentrations may be more appropriate.

The effect of low dose nitroglycerin on plasma heparin concentrations and activated partial thromboplastin times.

We have investigated the effects of low dose nitroglycerin on the activated partial thromboplastin time (APTT), plasma heparin concentration, antithrombin III activity (AT-III) and platelet factor 4 (PF4) levels in a group of 42 patients receiving intravenous heparin and low dose nitroglycerin (GTN) following percutaneous transluminal coronary angioplasty (PTCA). Venous samples were taken before PTCA and at 2, 4 and 24 h after the start of the infusions. Despite the heparin infusion being constant, the median APTT ratio (interquartile range) was significantly lower at the 4 h sample time compared to the 2 h sample time (4.4 [3.8-4.5] vs 2.6 [1.8-4.0], P < 0.05). At this time there was also a significantly lower median plasma heparin concentration compared to the 2 h sample (0.35 [0.2-0.7] vs 0.17 [0.1-0.3] P < 0.05). There were no significant differences in AT-III activity or PF4 levels at 4 h compared to the 2 h sampling time. In another group of patients (n = 20) who received intravenous heparin alone following PTCA also at 1000 U/h there were no significant differences in median APTT ratios (4.4 [4.3-4.5] vs 4.2 [2.9-4.5]), or in median plasma heparin concentrations (0.26 [0.14-0.96] vs 0.22 [0.18-0.87]) at 4 h compared to 2 h. Our observations confirm that nitroglycerin can interfere with the anticoagulant effect of heparin even at low doses. Although the exact mechanism involved remains unknown, this study suggests it is likely to be a result of a reduction in plasma heparin levels, perhaps through acceleration of normal heparin elimination.

Angioplasty balloon compliance: can in vivo size be predicted from in vitro pressure profile measurements?

BACKGROUND AND HYPOTHESIS: This study was undertaken to determine whether the behavior of angioplasty balloons within coronary arteries may differ from that anticipated from data provided by the manufacturers. In particular, the in vitro pressure-diameter profiles may not truly represent in vivo sizes. METHODS: Thus, we assessed the degree of correlation of in vitro with in vivo measurements obtained during routine angioplasty practice. In vivo size of 2.5 mm compliant (n = 8) and 3 mm semicompliant (n = 8) balloons was assessed using quantitative angiography for first, second, and third inflations. RESULTS: In vivo size was less than expected from in vitro measurements. In general balloon diameter increased with inflation pressures up to 8 atmospheres, and some degree of elastic recoil was evident with both balloon types after the last inflation. CONCLUSION: In vivo balloon size may not be accurately predicted from manufacturers' published data. Size is more likely to be affected by factors such as lesion characteristics and elasticity of the vessel wall than by balloon material compliance characteristics.

Lone atrial fibrillation and anticoagulant therapy.

Assessment of risk of thromboembolism and potential benefit of prophylaxis with long-term anticoagulant therapy in lone atrial fibrillation is hampered by a lack of consensus regarding definition of lone atrial fibrillation. In general, patients less than 60 years of age with normal left ventricular function and left atrial size have a low risk of thromboembolic events and are unlikely to gain any significant benefit with anticoagulants; however, patients older than 60 years with impaired left ventricular function, enlarged left atrium, and/or associated conditions such as hypertension have an increased risk of thromboembolism and would benefit from long-term anticoagulant therapy. Decisions regarding anticoagulant usage would be simplified by using a scoring system containing clinical and investigational variables.

Successful operation on a coronary arteriovenous fistula in a 74 year old woman.

Coronary arteriovenous fistulas are rare and are usually diagnosed in children or young adults. Most are believed to be congenital. A right coronary arteriovenous fistula was first diagnosed in a patient of 74. Despite her age the fistula was successfully operated on and her symptoms were relieved.

Anticoagulation after intracoronary stent insertion.

Stents rarely thrombose in the first 24 hours after implantation; secondly, heparin has some influence on the extrinsic pathway. Additionally, if too much heparin is present it interferes with the INR, and the half life of prothrombin suggests that the patient should be anticoagulated with heparin for up to 96 hours after starting warfarin. This is the evidence on which our standard protocol is based.

Heparin after angioplasty: an unresolved issue?

Restenosis following coronary angioplasty remains a significant problem. Experimental work suggests that appropriate use of heparin may be beneficial through inhibition of smooth muscle cell proliferation. Possible mechanisms of this effect in various models, are discussed. Limited clinical studies to date, however, have failed to show therapeutic efficacy. Possible reasons for this lack of effect are discussed and the importance of assessing heparin in appropriate clinical trials is emphasized.

The effect of different nitrate preparations on plasma heparin concentrations and the activated partial thromboplastin time.

There is evidence that intravenous nitrates which are frequently used in acute coronary syndromes may interfere with the anticoagulant effect of heparin. We compared the effect of two different nitrate preparations on the activated partial thromboplastin time (APTT), anti-thrombin III activity (AT III) and plasma heparin levels in patients (n = 50) undergoing routine percutaneous transluminal coronary angioplasty (PTCA) for stable angina. Patients were randomized to either: (1) intravenous heparin and nitroglycerin (GTN); or (2) intravenous heparin and isosorbide dinitrate. The APTT, plasma heparin concentration and AT III activity were measured before PTCA and at 2 and 4 hours after commencement of infusions. Both groups received identical doses of heparin. Group 1 patients received a constant dose of 16.6 micrograms/minute of GTN, and group 2 patients received 33.3 micrograms/minute of isosorbide dinitrate. At 4 hours the median APTT ratio was significantly lower in group 1 compared with group 2 (2.6 versus 4.5) (P < 0.05) as was the plasma heparin concentration (0.18 U/ml versus 0.32 U/ml (P < 0.05). However, no significant difference in APTT ratios or plasma heparin concentrations were noted at any of the other sample times. AT III activity was not significantly different between the groups at any sample time. Within-group analysis showed significantly lower APTT ratio and heparin concentrations at 4 hours compared with the respective 2 hour values. These results would suggest that there is a potential impairment of anticoagulation with low-dose intravenous nitroglycerin and to a lesser extent with low-dose isosorbide dinitrate. Early and frequent monitoring may therefore be appropriate when intravenous nitrates and heparin are used in combination.