Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002962 (angina)
 21,142 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We here present a Japanese family with type I hereditary heparin cofactor II (HC II) deficiency. The propositus (a 61-year-old man) suffered from angina pectoris and coronary artery disease was confirmed by coronary angiography. He underwent percutaneous transluminal coronary angioplasty (PTCA) four times in one year. Combined use of heparin, aspirin, and nitrates could not prevent the return of his symptoms and restenosis of segment 6 of the left anterior descending artery. His HC II activity and antigen levels were 49% and 50%, respectively, and his daughter also showed similar low levels. Cerebral infarction had occurred in two family members. Argatroban, a selective potent thrombin inhibitor, was administered after the fourth PTCA for the purpose of preventing reocclusion and achieved a successful outcome. A relationship between HC II deficiency and thrombosis has not yet been established. Our case suggests that standard heparin therapy is not effective in preventing restenosis in such individuals, in whom the process is accelerated by thrombin generation at the site where PTCA produces rupture of the atherosclerotic plaque. Argatroban may be more effective under low HC II conditions because of its potent inhibition of thrombin activity at sites of vascular wall damage.
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PMID:Hereditary heparin cofactor II deficiency and coronary artery disease. 161 93

Several new anticoagulants and antiplatelet agents have been developed for use in coronary angioplasty, but almost all have been associated with an increased incidence of bleeding complications. Hirulog, a direct thrombin inhibitor, has several theoretical advantages over heparin. It is unclear, however, whether the use of hirulog as a substitute for heparin in angioplasty would result in a higher incidence of bleeding or other side effects. The safety profile of hirulog was compared with that of heparin in a randomized, double-blind trial in 4312 patients who were scheduled to undergo angioplasty for unstable or postinfarction angina. The goal of anticoagulation was to achieve an activated clotting time of approximately 350 seconds with hirulog (bolus dose of 1.0 mg/kg body weight followed by a 4-hour infusion of 2.5 mg/kg per hour and a 14- to 20-hour infusion of 0.2 mg/kg per hour) or heparin (bolus dose of 175 units/kg followed by an 18- to 24-hour infusion of 15 units/kg per hour). Adverse events were recorded prospectively by study personnel and confirmed independently by clinical monitors blinded to treatment assignment. Compared with heparin in an intention-to-treat analysis, hirulog therapy was associated with either equivalent or lower rates of side effects. Most of the side effects of hirulog and heparin were related to hemorrhagic complications such as intravascular puncture site hemorrhage (29.1% vs 61.6%; p < 0.001), hematuria (16.6% vs 20.6%; p = 0.001), bleeding requiring red cell transfusion (3.7% vs 8.6%; p < 0.001), or hematemesis (0.8% vs 1.9%; p = 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Comparative safety profiles of hirulog and heparin in patients undergoing coronary angioplasty. The Hirulog Angioplasty Study Investigators. 766 14

Both aspirin and beta-adrenergic blocking drugs have been shown to reduce the risk of death or acute myocardial infarction (AMI) in patients with unstable angina, but their effect during chronic use on the presentation of acute coronary syndromes is less well defined. Calcium antagonists and oral nitrates are also widely prescribed for patients with coronary disease, but their effect on presentation of acute myocardial ischemia is unknown. We retrospectively examined the effects of prior aspirin and anti-ischemic medical therapy on clinical events in 410 patients hospitalized for unstable angina. Ischemic pain occurred at rest for a duration of 5 to 60 minutes. During hospitalization, 97% of patients received aspirin and all received the direct thrombin inhibitor bivalirudin for at least 72 hours. Despite being older and more likely to have risk factors for coronary disease and poor outcome, patients receiving aspirin before admission were less likely to present with non-Q-wave AMI (5% vs 14% in patients not on aspirin, p = 0.004). Prior beta blocker, calcium antagonist, or nitrate administration did not appear to modify presentation as unstable angina or non-Q-wave AMI. In a multivariate model, the combined incidence of death, AMI not present at enrollment, or recurrent angina was best predicted by age (adjusted odds ratio [95% confidence interval] 2.38 [1.14 to 3.98]) and presence of electrocardiographic changes with pain on presentation (adjusted odds ratio 2.83 [1.50 to 5.35]) but was not related to prior or in-hospital medical therapy. Thus, aspirin but not anti-ischemic therapy before hospitalization of patients with unstable angina was associated with a decreased incidence of non-Q-wave AMI on admission.
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PMID:Effects of prior aspirin and anti-ischemic therapy on outcome of patients with unstable angina. TIMI 7 Investigators. Thrombin Inhibition in Myocardial Ischemia. 952 73

Thrombin has been suggested as one of the main pharmacologic targets in unstable coronary syndromes. Electrocardiographic signs of ischemia during continuous monitoring convey prognostic information in these patients. This study assessed the anti-ischemic and clinical effects of the novel low-molecular weight thrombin inhibitor inogatran in patients with unstable angina and non-Q-wave infarction without persistent ST-segment elevation on hospital admission. Within 24 hours of the last episode of chest pain, 324 patients were randomized to 72 hours of treatment with inogatran or heparin. Continuous ST-segment analysis with computerized vectorcardiography was used to monitor ischemia for 24 hours. The occurrence of cardiac events during the first 7 days were studied and compared with ischemic episodes during the initial 24 hours. The heparin-treated patients had less episodes of ischemia (ST vector magnitude [ST-VM]: 1 +/- 2.6 vs 2 +/- 4.5, p < 0.001 and ST change vector magnitude [STC-VM]: 3 +/- 4.7 vs 6 +/- 7.6, p < 0.001) than the patients receiving inogatran. This was paralleled by a lower incidence of the combined end point of death, nonfatal infarction, refractory or recurrent angina during the first 7 days for the heparin-treated patients (35%) compared with the inogatran-treated patients (50%) (p < 0.05). Patients who had episodes of ischemia in spite of anti-ischemic therapy were at increased risk of all events studied. Heparin is more effective than inogatran in suppressing myocardial ischemia and clinical events at short-term follow-up. Continuous ST-segment monitoring with vectorcardiography identifies nonresponders who are at an increased level of risk.
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PMID:Heparin is more effective than inogatran, a low-molecular weight thrombin inhibitor in suppressing ischemia and recurrent angina in unstable coronary disease. Thrombin Inhibition in Myocardial Ischemia (TRIM) Study Group. 957 50

The dosing of anticoagulants during coronary angioplasty is commonly guided by measurements of activated clotting time (ACT), but the usefulness of these measurements remains uncertain. The Hirulog Angioplasty Study was a randomized, double-blind comparison of heparin versus bivalirudin in 4,312 patients undergoing angioplasty for unstable or postinfarction angina. In 4,098 of the patients randomized, the balloon was inflated. All patients had ACT measurements 5 minutes after a weight-adjusted bolus of heparin or bivalirudin, and patients undergoing complicated or prolonged angioplasty procedures lasting >45 minutes had additional ACT measurements to guide further anticoagulant therapy. The analysis presented in this article evaluated the relation between the initial or maximum ACT measurements and the risk of abrupt vessel closure during heparin or bivalirudin therapy. Abrupt vessel closure occurred in 189 of 2,039 patients (9.3%) treated with heparin, and in 189 of 2,059 patients (9.2%) treated with bivalirudin (p = not significant). An inverse relation between the risk of abrupt closure and initial ACT measurements was observed in heparin-treated patients: the probability of abrupt vessel closure decreased by 1.3% for every 10-second increase in the initial ACT response to heparin therapy (p = 0.02). Among 903 of 2,039 heparin-treated patients (44%) who received additional heparin for prolonged or complicated procedures, the likelihood of abrupt vessel closure also decreased by 1.1% for every 10-second increase in ACT (p = 0.04). In 2,059 patients treated with bivalirudin, however, no relation between the probability of abrupt vessel closure and the initial ACT measurement was observed (p = 0.88). From the results it was concluded that when heparin is used during coronary angioplasty, the risk of abrupt vessel closure is related to patient responsiveness to anticoagulation therapy. Heparin-resistant patients are more likely to experience abrupt vessel closure than patients who have high ACT values in response to initial therapy. In contrast, when bivalirudin is used during coronary angioplasty, a flat relation between the risk of abrupt vessel closure and ACT values is seen. This suggests that the direct thrombin inhibitor, bivalirudin, provides more even levels of anticoagulation and more predictable levels of risk of abrupt closure than heparin. Measurements of ACT may not be necessary when bivalirudin is used during coronary angioplasty.
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PMID:Relation between abrupt vessel closure and the anticoagulant response to heparin or bivalirudin during coronary angioplasty. 980 92

Despite use of heparin and aspirin, 5-10% of patients with unstable angina develop myocardial infarction (MI) or refractory angina in the hospital. We tested the hypothesis that recombinant hirudin (lepirudin), a direct thrombin inhibitor, is superior to heparin, an indirect thrombin inhibitor, in patients with acute ischemic syndromes who were receiving aspirin. Patients (n = 10,141) with unstable angina or suspected acute MI without ST-segment elevation were randomly assigned heparin (5,000-U bolus, then 15-U/kg per hour infusion; n = 5,058) or hirudin (0.4-mg/kg bolus, then 0.15-mg/kg per hour infusion; n = 5,083) for 72 hours in a double-blind trial. The primary outcome measure was cardiovascular death or new MI at 7 days. Analysis was by intention to treat. At 7 days, 213 patients (4.2%) in the heparin group and 182 (3.6%) in the hirudin group had experienced cardiovascular death or new MI (relative risk = 0.84; 95% CI = 0.69-1.02; p = 0.077). The number of patients with cardiovascular death, new MI, or refractory angina at 7 days was 340 (6.7%) with heparin and 284 (5.6%) with hirudin (relative risk = 0.82; 95% CI = 0.70-0.96; p = 0.0125). These differences were primarily observed during the 72-hour treatment period (cardiovascular death or MI relative risk = 0.76; 95% CI = 0.59-0.99; p = 0.039; cardiovascular death, MI, or refractory angina relative risk = 0.78; 95% CI = 0.63-0.96; p = 0.019). Although there was an excess of major bleeding with hirudin requiring transfusion (59 [1.2%] vs 34 [0.7%] with heparin; p = 0.01), there was no excess in life-threatening episodes (20 in each group) or strokes (14 in each group). Data from the Organization to Assess Strategies for Ischemic Syndromes (OASIS)-2 trial suggest that a direct thrombin inhibitor, recombinant hirudin, is more effective than an indirect thrombin inhibitor, heparin, in preventing cardiovascular death, MI, or refractory angina. Recombinant hirudin also has an acceptable safety profile in patients with unstable angina or acute MI without ST-segment elevation.
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PMID:Design, baseline characteristics, and preliminary clinical results of the Organization to Assess Strategies for Ischemic Syndromes-2 (OASIS-2) trial. 1050 39

In the current study, we investigated molecular markers of coagulation activity, ie, prothrombin fragment 1+2 (F1+2), thrombin-antithrombin (TAT) complex, soluble fibrin (SF), and D-dimer, and their relation to death, myocardial infarction, and refractory angina during and after anticoagulant treatment in unstable coronary artery disease. Patients with unstable coronary artery disease (N=320) were randomized to a 72-hour infusion with either inogatran, a low-molecular-mass direct thrombin inhibitor, or unfractionated heparin. During the 30-day follow-up, a 40% lower event rate was seen in patients with high compared with low baseline levels of TAT or SF. High baseline levels of coagulation activity were correlated with a larger decrease during treatment. Patients with decreased compared with raised F1+2 or TAT levels after 6 hours of treatment had a 50% lower event rate at 30 days (F1+2, P=0.04; TAT, P=0.02). At the cessation of antithrombin treatment, there was a clustering of cardiac events that tended to be related to a rise in the levels of TAT and the other markers. During long-term follow-up (median, 29 months), there was a relation between higher baseline levels of D-dimer (P=0.003) and increased mortality. High baseline levels of molecular markers of coagulation activity might identify patients with a thrombotic condition (as the major cause of instability) who are good responders to anticoagulant therapy, with a larger decrease in coagulation activity during treatment and a decreased risk of ischemic events. However, this early benefit is lost during long-term follow-up when high baseline levels of coagulation activity are associated with a raised risk of early reactivation and increased mortality.
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PMID:Coagulation activity and clinical outcome in unstable coronary artery disease. 1139 20

Direct thrombin inhibitors in cardiovascular patients are discussed. Patients presenting with acute coronary syndromes (ACS) of ST- and non-ST-segment elevation myocardial infarction (STEMI and NSTEMI, respectively) or unstable angina develop mural thrombi within minutes of plaque disruption or erosion. Initial acute therapy includes heparin and aspirin. Up to 60% of patients have coronary revascularization to reduce the high risk of death, new myocardial infarction (MI), or recurrent angina. In addition, heparin may initiate a serious allergic, prothrombotic drug reaction, heparin-induced thrombocytopenia (HIT), in 1-5% of patients. Acute cessation of heparin and initiation of direct thrombin inhibitor (DTI) therapy for suspected HIT are vital and well established. Several clinical trials comparing DTIs with heparin have been done in ACS and percutaneous coronary intervention (PCI), and have shown excellent potency in inhibiting thrombus formation and reducing coronary events. An overview of results from published studies evaluating the use of bivalent and univalent DTIs in the cardiovascular patient is presented. Four DTIs are discussed: two r-hirudins (lepirudin and desirudin), both bivalent with stable chain and renal excretion; bivalirudin, bivalent with rapid-chain metabolism; and argatroban, univalent with hepatic metabolism. The extensive clinical experience with r-hirudin in cardiovascular patients suggests that it is an excellent choice for managing patients with HIT and is easy to use in converting to warfarin, since it does not significantly change the prothrombin time.
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PMID:Direct thrombin inhibitor therapy in the cardiovascular patient. 1459 79

Unstable coronary artery disease is in most cases associated with plaque rupture, activation of the coagulation system and subsequent intracoronary thrombus formation which may cause myocardial cell damage. The aim of the present analysis was to assess the relation between troponin T, markers of coagulation activity, i.e. prothrombin fragment 1+2, thrombin-antithrombin complex, soluble fibrin and D-dimer, and ischemic events, i.e. death, myocardial (re-)infarction or refractory angina. 320 patients with unstable coronary artery disease were randomized to 72 hours infusion with inogatran, a low molecular weight direct thrombin inhibitor, or unfractionated heparin. Patients with elevated troponin levels had higher levels of prothrombin fragment 1+2, soluble fibrin and D-dimer before, during, and at 24 hours after cessation of anticoagulant treatment. These troponin-positive patients tended to have worse short-term clinical outcome, without relation to markers of coagulation activity. Troponin-negative patients with unchanged or early increased thrombin generation during treatment had a cluster of ischemic events within 24 hours after cessation of the study drug. The 30-day ischemic event rate was 19 % in troponin-negative patients with unchanged or early increased prothrombin fragment 1+2, and 5.7 % in patients with decreased prothrombin fragment 1+2, p=0.006, and similarly 15 % in troponin-negative patients with unchanged or early increased thrombin-antithrombin complex and 4.5 % in patients with decreased thrombin-antithrombin complex, p=0.02. In conclusion, in unstable coronary artery disease a troponin elevation indicates higher risk and higher coagulation activity. However, among the troponin negative patients, with a lower risk and lower coagulation activity, a part of the patients seem to be non-responders to treatment with a thrombin inhibitor expressed as unchanged or raised coagulation activity and a raised risk of ischemic events early after cessation of treatment.
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PMID:Myocardial damage, coagulation activity and the response to thrombin inhibition in unstable coronary artery disease. 1496 Nov 68

Efegatran is a thrombin inhibitor which is being developed by IVAX for the potential treatment of thromboembolic disorders [343400]. Efegatran was synthesized by the Hungarian Institute for Drug Research (IDR), which conducted phase II trials for angina in Hungary, and phase II trials for thrombosis in collaboration with Lilly in the US [182552]. However, nodevelopment has been reported by Lilly since IDR was taken over by IVAX in 1999 [343400]. In phase I/II trials in patients with unstable angina, the drug produced a dose-dependent increase in clotting time [279819]. In preliminary dose-ranging trials in unstable angina, the compound had a similar efficacy to heparin at the highest dose studied (0.1mg/kg bolus plus a 48 h infusion of 0.84 mg/kg/h). Thrombophlebitis was the only side effect observed [169368].
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PMID:Efegatran. Institute for drug research/IVAX. 1600 14


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