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Activation of the hemostatic mechanism has been described during thrombolytic therapy. This phenomenon has been detected by new methods of assessing hemostatic system function, based on immunoenzymatic or radioimmunoassays. However, these methods are extremely sensitive and, unless they are performed in expert laboratories, carefully following the recommended procedures, they generate in vitro artifacts. A description of these methods is provided, as well as a critical review of the available studies. The correct use of these methods will provide us with an understanding of the complex response of the hemostatic system to pharmacologic thrombolysis.

The handgrip test has been proposed for the evaluation of the hemodynamic reserve in patients with coronary artery disease and to quantitate the impairment of left ventricular (LV) function. The present study was designed to evaluate the effect of thrombolytic therapy in patients with refractory unstable angina in order to test the hypothesis that a reduction in intracoronary thrombosis could ameliorate their hemodynamic response to the handgrip test. During left heart catheterization, 20 patients with refractory unstable angina of recent onset performed a handgrip test before (HG1) and 24-72 hours after (HG2) being randomized to receive recombinant tissue-type plasminogen activator or placebo, according to a double-blind parallel group design. HG1 induced an increase in heart rate (p [less than] 0.001), in systolic pressure (p [less than] 0.001), and a reduction in ejection fraction (p [less than] 0.05). Changes in LV end-diastolic pressure during baseline handgrip were highly different in individual patients, resulting in a trend toward an increase. Similarly, a different individual response was observed in the behavior of the isovolumetric and relaxation indices. In comparison with HG1, no difference was detected during HG2 in the 2 treatment groups with respect to changes in LV volumes, ejection fraction, LV systolic and diastolic pressures, +dP/dt, (dP/dt)/P, -dP/dt, and tau index. In patients with refractory unstable angina of recent onset, the handgrip test performed before and after thrombolysis did not prove to be useful in assessing directional changes of LV performance, mainly because of the different individual response to the baseline handgrip test.

The elastic behavior of the dilated coronary vessel has been reported to affect the immediate results of coronary angioplasty. To determine whether elastic recoil may also influence the long-term restenosis process, 98 consecutive patients with unstable angina and 1-vessel disease were studied. An automated coronary quantitative program was used for the assessment of balloon and coronary luminal diameters. Elastic recoil was defined as the percent reduction between minimal balloon diameter at the highest inflation pressure and minimal lesion diameter immediately after coronary angioplasty. Follow-up coronary arteriography was performed 8 to 12 months after the procedure in all patients. The mean elastic recoil averaged 17.7 [+ or -] 16% and was correlated to the degree of residual stenosis immediately after coronary angioplasty (r = 0.64; p 50% diameter stenosis at follow-up, developed in 53 patients (54%). There was no correlation between the degree of elastic recoil and the changes in minimal lesion diameter observed during follow-up, whereas a positive correlation between the amount of elastic recoil and the incidence of restenosis was documented (r = 0.84); p

In 30 consecutive patients with Prinzmetal's angina pectoris, the antiischemic effect of felodipine, a new long-acting vasoselective calcium antagonist, administered at doses of 10 and 20 mg once daily was compared with that of the well-established therapeutic regimen with nifedipine administered at a dose of 20 mg 4 times daily. Twenty-four-hour Holter monitoring was performed during a 2-day placebo run-in and at the end of each of 3 consecutive 6-day periods during which the 3 active treatments were administered in randomized sequence. Three patients withdrew, whereas 27 completed the study. The therapeutic regimens tested proved to be similarly effective; primary end points (ischemic episodes recorded by Holter monitoring, and anginal attacks reported on diary cards) occured in 5 patients (19%) during nifedipine treatment, and in 7 (26%) and 3 (11%) during felodipine treatment with 10 and 20 mg, respectively (p = not significant). The distribution of residual ischemic episodes demonstrated that treatment with felodipine once daily provides 24-hour antiischemic protection. Twenty-six patients were followed up with 20 mg of felodipine once daily for a mean of 6 [+ or -] 5 months, and 21 of them (81%) remained free of symptoms and Holter-recorded ischemic attacks. It is concluded that for Prinzmetal's angina pectoris, 24-hour antiischemic protection may be achieved with administration of felodipine once daily. The availability of a simplified therapeutic approach may constitute a real advantage in terms of patient compliance and improving the quality of life. (Am J Cardiol 1991;68:1587-1592)

Plasma levels and 24-hour urine excretion of fibrinopeptide A were measured in a consecutive series of 179 patients with angina pectoris. Sixty-four patients had stable angina and 115 patients had unstable angina. Urine was collected over 24 hours the day before coronary arteriography, and blood samples were taken at the end of urine collection. When the values of fibrinopeptide A in plasma and in the 24-hour urine specimens were compared, no significant correlation was found in patients with either stable (rs = 0.16, difference not significant) and unstable (rs = 0.07, difference not significant) angina. The concentrations of fibrinopeptide A in the plasma did not differ significantly when patients with stable angina (range 0.1 to 82.6, median 7.4 ng/mL) were compared with patients with unstable angina (range 0.2 to 61.7, median 7.4 ng/mL, p = 0. 055), whereas fibrinopeptide A 24-hour urinary excretion was significantly higher in patients with unstable angina (range 0.3 to 38.1 median 11.8 [mu]g/24 hr) than in patients with stable angina p < 0.001). Twenty-four-hour urine excretion of fibrinopeptide A in patients with unstable angina and angiographically documented intracoronary thrombi were higher than the corresponding values in patients with unstable angina without such angiographic characteristic (p < 0.001). The largest increase in plasma and urine concentration of fibrinopeptide A was observed in patients whose first episode of angina at rest occurred within the previous 48 hours. We conclude that the cumulative thrombin activity, assessed by 24-hour urinary excretion of fibrinopeptide A, is a more useful index, compared with single fibrinopeptide A measurement in plasma, for discriminating between patients with stable and with unstable angina pectoris., Unstable angina is thought to result, at least in most cases, from the formation of a blood clot at the site of a ruptured atherosclerotic plaque. This clot formation, or thrombosis, appears to be the dynamic result of clot-forming influences on one hand and clot-dissolving influences on the other. Much of the evidence implicating clots in the progression of unstable angina comes from modern imaging methods in which the clots, or thrombi, are directly visualized. However, imaging techniques do not indicate the presence of clots in all patients with unstable angina. It would be useful to have biochemical tests that indicate the dynamic state of clot formation. One substance that might be a good candidate for biochemical analysis is fibrinopeptide A. One of the many steps in clot formation is the enzymatic conversion of fibrinogen, a soluble blood protein, into fibrin, a fibrous protein that constitutes much of the thrombus. Fibrinopeptide A is a by-product of this enzymatic conversion, and therefore its measurement might be expected to provide an indication of clot formation within the body. However, analysis of fibrinopeptide A within the blood has proved disappointing in this regard. Because fibrinopeptide is also known to rapidly disappear from the blood (half will disappear within five minutes), the inability to make useful measurements in the blood may be a matter of timing. A study was conducted to determine if the fibrinopeptide A that accumulates in the urine might be more useful as a diagnostic tool. When urine samples collected over a 24-hour period were analyzed, it was found that patients with unstable angina had significantly higher amounts of fibrinopeptide A than did patients with stable heart disease. In contrast, there were no significant differences in the fibrinopeptide A measured in the blood plasma. This is a biochemical indication of ongoing clot-forming activity in some patients. It should be emphasized that although the average urinary level fibrinopeptide A of the patients with unstable angina was elevated, many of these patients were found to have fibrinopeptide A levels within the normal range. (Consumer Summary produced by Reliance Medical Information, Inc.)

Ischemic syndromes are a collection of disorders in which the heart muscle does not receive an adequate supply of blood. Atherosclerosis, in which the arteries of the heart are partially blocked by fat-laden lesions, is very common in ischemic heart disease, but it is also common among people without ischemic heart disease. Ischemic heart disease may be stable or unstable. An example of a stable ischemic condition is stable angina, in which drugs designed to relax the blood vessels and improve blood flow often control the problem. Unstable ischemic syndromes include unstable angina and myocardial infarction (heart attack). These unstable conditions appear to be associated with the formation of blood clots, or thrombi, within the arteries of the heart. The formation of these blood clots seems to begin in an atherosclerotic lesion. Since atherosclerosis is so common, it is important to determine why some atherosclerotic conditions are stable and lead to only relatively benign disease while others are unstable and are more likely to result in heart attack or sudden death. To evaluate the distinctions among different patients with atherosclerosis, samples of artery tissue were examined from patients with stable, unstable, and nonischemic disease. These specimens were obtained during autopsy or surgery. It was found that extensive narrowing (stenosis) of the coronary arteries was common; it was present in 90 percent of cases of stable and unstable disease. Furthermore, stenosis was found in about half the patients with nonischemic disease. Researchers observed, however, that the composition of the plaque seemed to influence the likelihood of clot formation within the artery. Thrombi were more likely to be associated with atherosclerotic lesions that were mostly fatty pulp, that is, pultaceous. In contrast, thrombi were less likely to be associated with atherosclerotic lesions that were mostly fibrous. Since a primary step in the development of a thrombus is the adherence of platelets (cells involved in clotting) to the surface of the atherosclerotic lesion, it would seem that the characteristics of this surface play a major role in the progression of thrombosis. (Consumer Summary produced by Reliance Medical Information, Inc.)

The clinical characteristics of 65 patients with mixed angina were classified by means of (1) a questionnaire investigating the proportion of symptoms occurring at rest and on effort, (2) an exercise stress test, (3) 24-hour ambulatory Holter monitoring, and (4) coronary arteriography. According to the questionnaire, the proportion of effort-induced anginal episodes ranged from 1 to 99%. The ischemic threshold during exercise testing ranged from 110 x [10.sup.2] to 350 x 102 mm Hg x beats/min. At least 1 episode of ST-segment depression was observed in 29 of the 65 patients during Holter monitoring. Ischemic episodes during Holter monitoring were more frequent (p < 0.05) in patients reporting >= 50% of anginal attacks on effort, with moderate to severe limitation of exercise capacity and with multivessel coronary artery disease. The effect on ambulatory ischemia of a 6-week treatment with a [Beta] blocker (metoprolol CR, 200 mg once daily) or a dihydropyridine calcium antagonist (nifedipine retard 20 mg twice daily) were then compared according to a double-blind, parallel group design. Metoprolol significantly reduced the number and duration of the ischemic episodes during daily life (p < 0.05) irrespective of the patients' clinical characteristics. Nifedipine was ineffective, particularly in patients with angina predominantly on effort and with a moderate to severe reduction in exercise tolerance. it is concluded that in patients with mixed angina, ischemic episodes during daily life are more likely to occur in patients with a clinical presentation suggesting poor coronary reserve. The administration of a [Beta] blocker is highly effective in reducing ambulatory ischemia and should be considered as initial antiischemic treatment for mixed angina. (Am J Cardiol 1991;67:946-952), Angina pectoris is chest pain caused by a reduction in blood flow to the heart (ischemia). Mixed angina occurs both when the person is resting and when making a physical effort. There is disagreement about how to treat mixed angina. Beta blockers reduce oxygen consumption and are effective against effort-induced angina, but they may worsen spontaneous episodes. Calcium antagonists increase oxygen supply, and reduce symptoms at rest, but are less effective in reducing demand-related attacks. In an effort to define mixed angina more objectively and to document the effects of a calcium antagonist (nifedipine) and a beta blocker (metoprolol) during daily life, 65 patients with widely varying mixed angina were studied. Continuous, 24-hour monitoring showed that the incidence of ischemic episodes was greater among those with more exercise-induced ischemia, greater limitation of exercise tolerance, and multi-vessel coronary disease. Most ischemic episodes were symptomless, or silent, which is associated with a worse prognosis. Metoprolol reduced ischemic episodes in almost all patients, whereas nifedipine did not reduce ischemia, and may possibly have increased it in patients with effort-induced angina and low exercise tolerance. Nifedipine may prevent coronary spasm and be especially effective among patients with ischemia at rest, but this study was too small to measure the effect. (Consumer Summary produced by Reliance Medical Information, Inc.)

To verify that myocardial ischemia occurring during either the overbreathing or recovery phase of the hyperventilation test is based on different pathogenetic mechanisms, 2 consecutive series of patients, selected on the basis of their response to a run-in hyperventilation test, were studied. Group I comprised 15 patients who developed ST-segment depression early during overbreathing, whereas group II consisted of 12 patients showing ST-segment depression late during the recovery phase. A single oral dose of felodipine 10 mg or of placebo was administered on 2 consecutive days according to a randomized, double-blind, crossover design, and the hyperventilation test was repeated, on both days of the study, 3 to 5 hours after drug intake. In group I, ST-segment depression occurred after placebo in all patients during overbreathing, with an increase in rate pressure product (from 112 [+ or -] 31 at baseline to 168 [+ or -] 55 mm Hg X beats/min/100 at the onset of ST-segment depression; p [is less than]0.01). After felodipine, 13 patients continued to show ST-segment depression during overbreathing, together with an increase in rate pressure product (from 107 [+ or -] 24 at baseline to 158 [+ or -] 46 mm Hg X beats/min/100 at the onset of electrocardiographic changes; p [is less than]0.01). In group II, all 12 patients showed ST-segment depression during recovery after placebo, with a rate pressure product comparable to baseline conditions (112 [+ or -] 35 at baseline vs 102 [+ or -] 27 mm Hg X beats/min/100 at the onset of ST-segment depression; difference not significant). After felodipine, no patient developed ST-segment depression or chest pain. These findings confirm that early hyperventilation-induced ST-segment depression is related to increased oxygen consumption, which cannot be prevented by felodipine. On the other hand, felodipine is highly effective in preventing delayed ischemia, which is due to a primary reduction in coronary blood flow. (Ann J Cardiol 1990;66:1304-1308), Coronary artery disease (CAD) is a progressive condition in which the blood vessels supplying the heart are partially or completely occluded, resulting in diminished blood flow to that organ. Ischemia, or decreased blood flow to the heart, can be experimentally induced in patients with CAD by having them hyperventilate (breathe deeply and rapidly). The ischemia that results from this process can occur immediately or during the recovery phase. It has been hypothesized that immediate ischemia is mediated by increased oxygen demand by the heart (in the face of poor coronary reserve), while ischemia during recovery is mediated by constriction of the coronary vessels. This hypothesis was tested by using the selective calcium antagonist felodipine, which inhibits coronary vasoconstriction, but has no appreciable effect on cardiac oxygen consumption. Ninety-seven patients with a history of angina pectoris (chest pain) and CAD were evaluated. Following administration of either felodipine or a placebo, patients were asked to hyperventilate for five minutes. Measurements were made of cardiac oxygen consumption during hyperventilation and 10 minutes into the recovery phase. Hyperventilation caused cardiac ischemia in all patients; in those who experienced ischemia occurred during hyperventilation, no effect of felodipine was observed. In patients with recovery-phase ischemia, prior administration of felodipine blocked the induction of ischemia. This indicates that two different mechanisms are, in fact, responsible for hyperventilation-induced ischemia. (Consumer Summary produced by Reliance Medical Information, Inc.)

Narrowing or occlusion of the coronary arteries (which supply the heart) causes a decrease in the cardiac blood supply (myocardial ischemia) and can result in pain in the region of the heart (angina pectoris). This pain is exacerbated by exercise and stress. When the pain worsens, and begins to occur even during periods of rest, the condition is referred to as unstable angina. This development frequently precedes acute myocardial infarction (heart attack; an acute total blockage of one or more of the coronary arteries resulting, if not promptly treated, in permanent cardiac damage and even death). Unstable angina usually responds to treatment with vasodilator medications (which relax blood vessels), but a subset of patients do not improve with this therapy, and are at great risk of suffering a heart attack. Drugs that prevent clotting (such as heparin) and that dissolve existing blood clots (such as tissue-type plasminogen activator or streptokinase) may have beneficial effects in this group of high-risk patients. To investigate this theory, 24 vasodilator-resistant unstable angina patients were randomly assigned to receive either heparin alone or heparin plus recombinant tissue-type plasminogen activator (rt-PA). Recurrent ischemic attacks were documented in 9 of 12 patients who received heparin alone; none of the patients who were given rt-PA experienced these symptoms. Statistical modeling demonstrated that there was a significantly greater tendency among the rt-PA patients to remain symptom-free over time (up to three days). Quantitative coronary angiography (an X-ray technique for visualizing the coronary arteries) did not reveal any change in the size of ischemia-related heart lesions after either treatment. Treatment with rt-PA does not confer a permanent improvement in coronary artery status nor obviate the need for procedures which improve cardiac blood flow; however, rt-PA may allow these procedures to be performed in more optimal circumstances. (Consumer Summary produced by Reliance Medical Information, Inc.)

It is well known that constriction of the coronary arteries, the vessels that deliver blood to the heart muscle itself, can cause angina, a painful and potentially dangerous heart condition. Measurement of coronary artery constriction in patients suffering from chest pain, however, relies on invasive tests such as angiography that carry a certain risk. The hyperventilation test, in which patients breathe deeply and rapidly for five minutes while the electrical activity of the heart and blood pressure are recorded, is proposed as an alternative to invasive methods for estimating the extent of blood vessel constriction. To test this possibility, 83 patients hospitalized for chest pain or for narrowing of one or more coronary arteries underwent hyperventilation and exercise stress testing. Changes in their electrocardiograms that reflect coronary artery constriction were noted. Patients who showed such changes (Group I) returned the next day and were tested in the same way after receiving a calcium antagonist drug, which reduces blood pressure and oxygen demand by the heart. An equal number of patients whose electrocardiograms had not been affected by hyperventilation served as a control group (Group II). Fifteen out of 16 Group I patients had a more normal electrocardiogram after medication, while there was no change for Group II patients. In addition, exercise duration increased for Group I patients, but not for Group II members. These results suggest that the outcome of the hyperventilation test can serve as a screening measure for patients with stable exertional angina and vasoconstriction to help determine who will benefit from treatment with calcium blockers. (Consumer Summary produced by Reliance Medical Information, Inc.)