Thrombin formation and fibrinolytic activity in patients with acute myocardial infarction or unstable angina: in-hospital course and relationship with recurrent angina at rest.

OBJECTIVES: The goal of this study was to investigate possible differences in thrombin generation or fibrinolytic capacity in patients with unstable angina (UA) or acute myocardial infarction (AMI) with or without recurrent angina at rest. BACKGROUND: Angina at rest in patients with AMI or UA is generally produced by a reduction in coronary flow, but it is unclear whether patients with or without this event differ in their thrombin generation or in their fibrinolytic capacities, which might influence the course of the culprit lesion. METHODS: Thrombin-antithrombin complex (TAT), D-dimer, fibrinogen and plasminogen activator inhibitor (PAI-1) antigen plasma levels were determined in 40 patients with AMI and in 23 with UA on admission, at 10 days and at three months. RESULTS: First day values for TAT, fibrinogen and D-dimer were comparable in patients with AMI and in those with UA. At 10 days they increased significantly in each group, and at 3 months they decreased to a similar extent. First day PAI-1 levels, however, were highest in both groups and declined in AMI patients at 10 days and at three months, whereas they also decreased at 10 days in UA patients but not any further at three months. Ten patients with AMI (25%) and 12 with UA (52%) developed in-hospital angina at rest. First day values for TAT, fibrinogen and D-dimer were similar in patients with or without angina, but PAI-1 levels were higher in the former subset (p < 0.008). At 10 days, however, TAT (p < 0.013) and D-dimer (p < 0.013) were higher in patients who developed angina than in those who did not. CONCLUSIONS: The higher inhibition of fibrinolytic activity in the first day in patients with AMI or UA who will develop recurrent angina suggests that maintenance of a prothrombotic status may contribute to its mechanisms, perhaps by preventing passivation of the culprit thrombus/plaque. This is consistent with greater thrombin generation and greater levels of fibrynolitic products at 10 days observed in these patients compared with those who attain early stability.

[Practice guidelines of the Spanish Society of Cardiology. Recommendations for the use of antithrombotic treatment in cardiology]. / Guías de actuación clínica de la Sociedad Española de Cardiología. Recomendaciones para el uso del tratamiento antitrombótico en cardiología.

The indications for the use of antithrombotic therapy are evolving as new drugs become available or new indications or dosages are recommended for drugs already in use. This document reviews and updates the former one published in 1994. To that end, an exhaustive revision of the literature published in the last 15 years has been undertaken. Following the evidence based medicine dictates, and aiming to select all the relevant publications for each pathology, all studies were selected through MEDLINE, using the specified key words for each subject, and were filtered using the following steps: a) only randomized, controlled studies, meta-analysis, guidelines and review articles were chosen; b) then, the Best-Evidence and Cochrane Collaboration databases were consulted; c) finally, the evidence based medicine validation, relevance and applicability criteria were assessed for each publication. The use of antiaggregants and anticoagulants are given for the following conditions: a) prevention of deep vein thrombosis and pulmonary embolism; b) prevention of systemic emboli in patients with lone atrial fibrillation, atrial fibrillation associated or not with rheumatic heart disease, in patients with biological or mechanical cardiac valvular prostheses and in dilated cardiomyopathy; c) antithrombotic therapy in coronary heart disease and in coronary intervention; d) the interactions with oral anticoagulants and how to control these therapies are also discussed.

[Persistent activation and/or reactivation in the subacute phase of unstable angina. Reasons for prolonged antithrombotic treatment]. / Persistencia y/o reactivación de la enfermedad en la fase subaguda de la angina inestable. Razones para la administración de un tratamiento antitrombótico prolongado.

Coronary artery thrombosis, due to a rupture of the vulnerable plaque, plays an important role in acute coronary syndromes. The interaction between platelets and thrombin with ruptured vulnerable plaque trigger a complex mechanism. The clinical manifestations depend on the extent and duration of thrombus formation. In the acute phase, aspirin, heparin and the new drugs reduce ischemic clinical outcomes. However, clinical rebound after withdrawal antithrombotic therapy has been observed and, follow-up studies have also documented a high risk of recurrence in the following months. A hypercoagulable state, thrombin generation and activation and haematological rebound is shown in acute coronary syndrome patients. Thus, the goal of treatment could be to control thrombotic response in the acute phase and to allow the healing and stabilization of the culprit lesion to avoid clinical ischemic events in the long-term.

Prevention of ischemic rigor contracture during coronary occlusion by inhibition of Na(+)-H+ exchange.

OBJECTIVE: To determine the effect of Na(+)-H+ exchange blockade on ischemic rigor contracture and reperfusion-induced hypercontracture. METHODS: Thirty-six pigs were submitted to 55 min of coronary occlusion and 5 h reperfusion. Myocardial segment length analysis with ultrasonic microcrystals was used to detect ischemic rigor (reduction in passive segment length change) and hypercontracture (reduction in end-diastolic length). RESULTS: Pretreatment with the new, highly selective Na(+)-H+ exchange inhibitor HOE642 before occlusion reduced ischemic rigor (P < 0.05), attenuated segment shrinkage (P < 0.05) during subsequent reperfusion, dramatically reduced infarct size (P < 0.0001) and attenuated arrhythmias (P < 0.01). Inhibition of Na(+)-H+ exchange only during reperfusion by means of direct intracoronary infusion of HOE642 into the area at risk prevented reperfusion arrhythmias but had no effect on final infarct size, while treatment with intravenous HOE642 immediately before reperfusion had no detectable effects. CONCLUSION: These results indicate that inhibition of Na(+)-H+ exchange during ischemia is necessary to limit myocardial necrosis secondary to transient coronary occlusion, and that this action could by mediated by a protective effect against ischemic contracture. Inhibition of Na(+)-H+ exchange only during reperfusion has a partial and transient beneficial effect, but only when the inhibitor reaches the area at risk before reflow.

Intimal injury in a transiently occluded coronary artery increases myocardial necrosis. Effect of aspirin.

This study tested the hypothesis that intimal injury in a transiently occluded coronary artery limits myocardial salvage. The effect of intimal injury on reactive hyperaemia was investigated in 17 pigs submitted to a 30-min occlusion of the left anterior descending coronary artery (LAD), not resulting in myocardial infarction. Catheter-induced intimal damage increased local platelet deposition (99mTc) and reduced hyperaemia, but did not modify myocardial platelet or polymorphonuclear leucocyte content (myeloperoxidase activity) after 6 h reperfusion. To investigate the influence of intimal injury on the extent of myocardial necrosis secondary to a more prolonged coronary occlusion, and the role of platelets on this influence, 52 pigs were submitted to a double randomization (2x2 factorial design) to 250 mg i.v. aspirin vs. placebo and to coronary intimal injury vs. no coronary damage before a 48-min occlusion of the LAD and 6 h of reperfusion. After excluding 12 animals with reocclusion, coronary intimal injury was associated with larger infarcts (triphenyltetrazolium reaction) in animals receiving placebo (36.2+/-7.0% of the area at risk in animals with intimal injury vs. 10.8+/-3.9% in animals without coronary injury, P=0.006) but not in those receiving aspirin (20.3+/-6.5 vs. 21.7+/-6.5% of the area at risk in animals with and without intimal injury respectively). These results suggest that coronary intimal injury in the reperfused artery may have adverse effects on myocardial salvage by mechanisms other than reocclusion or embolization of platelet aggregates.

Early morning reduction in ischemic threshold in patients with unstable angina and significant coronary disease.

BACKGROUND: The objective of this study was to investigate in patients with unstable angina and significant coronary stenosis (> 70%) whether or not the morning peak of myocardial ischemia is associated with a reduction in the ischemic threshold. The morning increased incidence of ischemic episodes in stable angina appears to be attributable to a coincidence of several factors. Patients with unstable angina who remain at bed rest, however, also present a similar morning increased incidence of ischemia, but its mechanisms are not completely understood. METHODS AND RESULTS: The ischemic threshold was assessed by atrial pacing at 7 to 8 AM and at 12 to 1 PM in 46 patients. In the 34 with a positive pacing response (ST segment shift > 1.0 mm), ischemic threshold was lower at 7 to 8 AM than at 12 to 1 PM (131 +/- 16 versus 139 +/- 15 beats per minute, P < .001), whereas in the remaining 12 patients, the pacing response was negative. Moreover, 4 patients presented ST segment elevation during pacing in the morning but only 1 at noon and at a higher threshold. Baseline heart rate and diastolic blood pressure were higher at noon than in the morning (81 +/- 16 versus 76 +/- 13 beats per minute, P < .01, and 87 +/- 11 versus 82 +/- 10 mm Hg, P < .05). CONCLUSIONS: The morning lowering of ischemic threshold in the absence of increases in baseline blood pressure or heart rate suggests that a reduced coronary vasodilator capacity or an increased coronary tone may favor the increased incidence of ischemic events during this interval.

Circadian rhythm of angina in patients with unstable angina: relationship with extent of coronary disease, coronary reserve and ECG changes during pain.

A circadian distribution of ischaemic events has been identified in ambulatory patients with stable angina. However, whether a similar distribution occurs in patients with unstable angina who remain at bed rest is still uncertain. Therefore, we analysed the possible circadian presentation of episodes of angina at rest (n = 1222) in 193 patients hospitalized consecutively. The influence of extent of coronary disease (number of vessels with > 70% stenosis, 0, 1 and 2-3), type of ECG changes during pain on a 12-lead ECG, and coronary reserve, as assessed by ischaemic threshold (atrial pacing), were also evaluated. There were two peaks of highest incidence: at 0700-1000h and at 1900-2200h (P < 0.0001) which were unrelated to the extent of coronary disease, coronary reserve or type of ECG change. Patients with 1 or 2-3 vessel disease with a reduced ischaemic threshold (= < 150 beats.min-1), however, had a higher incidence of midnight angina (2300-0200h) than those with a normal threshold or with no vessel disease (P < 0.001). It is concluded that, in spite of being at bed rest, patients with unstable angina present a definite circadian distribution of angina, with peaks in the early morning and late evening. Patients with a low coronary reserve seem to have a higher incidence of midnight angina than others.

Antithrombotic properties of transdermal nitroglycerin in stable angina pectoris.

Nitroglycerin provides an external source of nitric oxide which stimulates guanylate cyclase and produces vasodilatation and inhibition of platelet function. The antithrombotic effects of intravenous nitroglycerin were recently documented in various experimental models and in patients with unstable angina. This protocol was designed to evaluate whether these effects could also be detected with transdermal nitroglycerin in patients with stable angina. In a randomized, double-blind, controlled parallel trial, 22 patients received transdermal nitroglycerin, 0.6 mg/hour (11 patients), or placebo (11 patients). Platelet aggregation to adenosine diphosphate (ADP) and to thrombin was measured in whole blood. Thrombus formation was assessed on porcine aortic media exposed to the patient's venous blood for 3 minutes at shear rates of 2,546 and 754 s-1. Platelet aggregation to ADP decreased from 7.7 +/- 0.8 to 5.3 +/- 0.8 ohms (p < 0.05) with nitroglycerin, and to thrombin from 15.6 +/- 1.2 to 12 +/- 1.2 ohms (p < 0.05). Thrombus size at the high-shear rate decreased from 2.8 +/- 0.7 to 1.0 +/- 0.3 microns 2 (p < 0.05), and at the low-shear rate from 2.5 +/- 0.5 to 1.0 +/- 0.2 microns 2 (p < 0.05). Placebo had no significant effect on platelet aggregation and platelet thrombus deposition. These parameters were all reduced by > or = 20% in 8 patients taking nitroglycerin but only in 3 patients taking placebo (p < 0.05). Transdermal nitroglycerin significantly inhibits platelet aggregation and mural thrombus formation in patients with angina pectoris.

A pilot, early angiographic patency study using a direct thrombin inhibitor as adjunctive therapy to streptokinase in acute myocardial infarction.

BACKGROUND: The success of streptokinase in acute myocardial infarction is hampered by the high failure rate to achieve early reperfusion. This study evaluates the possible benefit of Hirulog (Biogen, Cambridge, Mass), a direct thrombin inhibitor, as adjunct therapy to streptokinase to enhance early patency and prevent rethrombosis. Heparin has been shown to be of very limited benefits in this setting. METHODS AND RESULTS: Forty-five patients were randomized to Hirulog or heparin (2:1 ratio). Coronary angiography documented a TIMI 2 or 3 flow after 90 minutes in 77% of the patients treated with Hirulog and streptokinase and in 47% of patients treated with heparin and streptokinase (P < .05) and after 120 minutes in 87% and 47% of patients, respectively (P < .01). TIMI 3 flow was established in 77% of patients with Hirulog compared with 40% with heparin (P < .02). The clinical outcome and the bleeding rate was also favorable to Hirulog; no reocclusion was observed at late angiography performed 4.7 days later. CONCLUSIONS: Hirulog in this pilot study significantly improved the early patency rate of the infarct-related artery with a favorable clinical profile. This new direct thrombin inhibitor exhibits promise as adjunctive therapy to thrombolysis.

Antithrombin-III plasma activity during and after prolonged use of heparin in unstable angina.

Heparin effectively prevents the complications of unstable angina but disease reactivation has been documented following its discontinuation. To investigate whether this could be related to antithrombin-III depletion, 50 patients with unstable angina had serial determinations of activated partial thromboplastin time and of the plasma levels of heparin, antithrombin-III activity and of the thrombin-antithrombin-III complex before, during and, in a subgroup of 8 patients, 4 hours after heparin discontinuation. Heparin was administered intravenously at therapeutic doses for a mean of 7.6 +/- 4.1 days. Plasma antithrombin-III activity decreased rapidly from 1.05 +/- 0.03 to 1.0 +/- 0.03 U/ml (p < 0.03) following heparin initiation with no further significant subsequent decrease. Antithrombin-III activity returned to the control values 4 hours after the discontinuation of heparin. Thus, heparin treatment is associated with small, non-cumulative and rapidly reversible decrease in antithrombin-III activity. Reactivation of unstable angina after discontinuation of heparin must be explained by a mechanism other than antithrombin-III deficiency.

Initial experience with a direct antithrombin, Hirulog, in unstable angina. Anticoagulant, antithrombotic, and clinical effects.

BACKGROUND: Currently available antithrombotic therapy for unstable angina is unwieldy and occasionally ineffective. This study was designed to investigate the potential of Hirulog, a new synthetic specific antithrombin agent, for the management of this condition. METHODS AND RESULTS: A total of 55 patients in the acute phase of unstable angina received intravenous Hirulog according to one of two protocols. In an acute dose-escalating study, 0.02, 0.05, 0.1, 0.25, and 0.5 mg.kg-1 x h-1, each for 30 minutes, were infused in 15 patients. Prolongation of activated partial thromboplastin time (aPTT) (r = .95), fibrinopeptide A inhibition (r = .96), and Hirulog plasma levels (r = .91) correlated closely with the dose infused, with significant changes compared with baseline appearing at doses of 0.25 mg.kg-1 x h-1 and higher. The purposes of the second protocol were to determine whether the anticoagulant and antithrombotic effects of the drug were sustained during a 72-hour infusion and to assess whether such treatment prevented the complications of unstable angina. Based on the initial study, we planned to give a dose of 0.25 mg.kg-1 x h-1 to each patient until 2 patients failed therapy, then successively higher doses until a 95% success rate was achieved or adverse effects intervened, increasing the dose after two failures had occurred at each level. Five patients received the 0.25-mg.kg-1 x h-1 dose and 14 the 0.5-mg.kg-1 x h-1 dose before two failures occurred. Failure was observed in only one of 21 patients at the dose of 1 mg.kg-1 x h-1. aPTT (+/- SEM) levels increased to 62 +/- 5, 76 +/- 2, and 98 +/- 3 seconds at the three doses, with minimal intraindividual variation, and Hirulog plasma levels to 1050, 2100, and 4200 mg/mL, respectively. Fibrinopeptide A plasma levels decreased at all doses but more consistently at the dose of 1 mg.kg-1 x h-1. The overall clinical success rate was 87.5%: 60% (3/5) at the low dose, 86% (12/14) at the intermediate dose, and 95% (20/21) at the high dose. No deaths, myocardial infarctions, or bleeding complications occurred. CONCLUSIONS: In unstable angina patients, Hirulog infusions quickly and reproducibly yield stable, dose-dependent anticoagulant and antithrombotic effects with a favorable clinical efficacy profile.

Ischaemic threshold and haemodynamic changes during angina at rest in patients with unstable angina.

To examine whether increases in heart rate might be a common trigger of angina at rest, changes in heart rate, blood pressure and rate-pressure product during pain were compared with the ischaemic threshold (heart rate with ST segment shift > = 1 mm), determined by atrial pacing, in 272 patients with unstable angina. During an average of 5.9 +/- 5.2 episodes of angina, heart rate was comparable to control values (77.0 +/- 14.5 vs 75.2 +/- 11.5, beats.min-1, ns) and significantly lower than the ischaemic threshold (147.9 +/- 22.9, P < 0.00001). The rate-pressure product was also lower (955 +/- 183 vs 2033 +/- 369, x 10, P < 0.00001). Heart rate during rest angina was lower than the ischaemic threshold even when we considered only patients with ST depression during pain (n: 71, 81.4 +/- 16.0 vs 132.8 +/- 21.4, P < 0.00001), those with three-vessel disease (n: 43, 79.9 +/- 15.9 vs 136.9 +/- 22.0, P < 0.00001), or those with a low ischaemic threshold (= < 130 beats.min, n: 78, 77.0 +/- 14.9 vs 118.3 +/- 10.7, P < 0.00001). In 154 patients in whom a second pacing test was performed the response was reproducible in 137 cases (89%). Thus, heart rate barely changes during angina at rest in patients with unstable angina and is consistently much lower than the ischaemic threshold. These findings support the concept that increases in heart rate are an unlikely trigger of ischaemia at rest, even in patients with markedly reduced coronary reserve.

In-hospital prognostic relevance of a reduced ischemic threshold. Studies in 357 consecutive patients with acute coronary syndromes.

In 357 patients with unstable coronary syndromes, a reduced pacing ischemic threshold (1-mm ST-segment depression at a heart rate < or = 150 beats per minute) was an independent predictor of main in-hospital events (death, myocardial infarction, or coronary surgery), which occurred in 33 percent (65/200) of the patients with a reduced threshold and in 8 percent (13/157) of those with a normal threshold (p < 0.0001). The incidences of death and infarction in patients with a normal (> 150 beats per minute), modestly reduced (140 to 150 beats per minute), or severely reduced (< or = 130 beats per minute) threshold were progressively higher (1 percent and 4 percent; 3 percent and 12 percent; and 7 percent and 18 percent respectively; p < 0.01). Thus, a reduced coronary reserve is associated with a fourfold increase in in-hospital complications; and when the reserve is severely curtailed, there may be a sevenfold increase in mortality.

Coronary reserve, extent of coronary disease, recurrent angina and ECG changes during pain in the in-hospital prognosis of acute coronary syndromes.

The prognostic value of recurrent angina, severity of coronary disease, ECG changes during pain and coronary reserve (ischaemic threshold measured by atrial pacing: heart rate with ST segment shift = 1 mm), was evaluated in 383 consecutive patients with acute coronary syndromes. Univariate analysis showed a significant relationship between occurrence of complications (death, infarction or coronary surgery) and number of anginal episodes, extent of coronary disease, ischaemic threshold and ST depression with pain. A multivariate analysis indicated that the first three parameters were the main independent predictors. Coronary reserve was reduced (threshold < or = 150 beats.min-1) in 83% of patients who had a myocardial infarction (40), in 91% of those who died (11), in 87% of those who underwent coronary surgery (52) and in 47% of uncomplicated cases (301). Also, a low ischaemic threshold was associated with a larger number of anginal episodes than a high threshold (< or = 130 beats.min-1, 6.1 +/- 5.6 vs > 150 beats.min-1, 2.9 +/- 4.1, P < 0.0001), and in complicated patients with one-, two- or three-vessel disease ischaemic threshold (137.3 +/- 21.2, 133.3 +/- 18.9, and 135.1 +/- 21.2 beats.min-1, respectively) was lower than in the uncomplicated ones (153.4 +/- 20.1, P < 0.005; 148.2 +/- 19.1, P < 0.005; and 139.2 +/- 23.0 ns, beats.min-1). A threshold < 150 beats.min-1 and ECG changes during pain identified the subset with the highest risk for complications (59/137, 45%), whereas a threshold > 150 beats.min-1 and absence of pain or ECG changes during pain identified those with the lowest risk (5/109, 5%, P < 0.001). Thus, our findings document the prognostic significance of coronary reserve for in-hospital complications in patients with acute coronary syndromes and confirm the prognostic value of previously known risk markers. They also indicate that some of them may be significantly influenced by the status of coronary reserve.

[Prehospital fibrinolysis: a priority objective?]. / Fibrinólisis prehospitalaria: objetivo prioritario?

Clinical trials strongly suggest that the sooner thrombolysis is applied after the onset of chest pain, the greater are the derived benefits. Time delay between onset chest pain and initiation of therapy possesses three fundamental components: 1) the call for help; 2) the transportation to the hospital, and 3) the in-hospital delay for diagnosis and initiation of therapy. On the other hand, pre-hospital thrombolysis has been shown feasible and safe; more importantly, it has resulted in early identification of patients eligible for fibrinolysis, greatly accelerating the process of drug administration. A critical look at all measures that could result in more rapid treatment is now indicated. This include early identification of eligible patients, prompt clinical and electrocardiographic diagnosis, rapid transportation to hospital and undelayed drug administration by competent personnel. Every clinical center should investigate the practice in its community area to detect where, when and why time is lost between onset of pain and treatment application to institute the appropriate corrective measures.

Metaraminol-induced reversal of acute myocardial ischaemia associated with hypotension and refractory to intravenous nitroglycerin.

In seven patients, acute myocardial ischaemia associated with ST segment elevation (5.7 +/- 1.6 mm, mean +/- SEM) and arterial hypotension (systolic blood pressure 57 +/- 9 mmHg), was reversed within 9 min (mean time to reversal 274 +/- 45 s) by the intravenous administration of metaraminol (1.9 +/- 0.2 mg). This myocardial ischaemia was refractory to nitroglycerin and, in every patient, the increases in blood pressure induced by metaraminol (to a mean systolic blood pressure of 191 +/- 22 mmHg) preceded reversal of the ECG changes. It is suggested that, in some patients, transmural myocardial ischaemia of recent onset associated with hypotension can be reversed by transiently increasing blood pressure with metaraminol.

Haemodynamic effects of molsidomine in patients with severe chronic coronary disease.

The haemodynamic effects of a single dose of intravenous molsidomine were assessed in 12 patients with severe coronary disease. The investigation was carried out at rest during angina induced by pacing and after molsidomine during pacing at the rate at which angina had been produced. During angina, left ventricular systolic and end-diastolic pressure rose, left ventricular stroke work fell and coronary flow and myocardial oxygen consumption increased by 58.3% above the control levels. After the administration of molsidomine, atrial stimulation was not followed by angina and there were no significant changes in systolic blood pressure. Left ventricular end-diastolic pressure fell sharply and coronary flow and myocardial oxygen consumption were only 38% and 33% higher, respectively, than the control levels. The beneficial effects of molsidomine in ischaemic heart disease, therefore, are the result of peripheral vasodilation which, by reducing the preload and afterload, lowers the oxygen requirements of the myocardium and thus increase the threshold for angina. A direct action on the coronary network can not be excluded but if such an action does exist it must be very small in the light of the marked systemic effect.