Efficacy of trimetazidine in patients with recurrent angina: a subgroup analysis of the TRIMPOL II study.

OBJECTIVES: The revascularization procedures become more and more popular to treat coronary artery disease, in many countries. Some patients are free of angina after revascularization, without any documented re-stenosis present with recurrent angina symptoms after a period of time. The aim of this work was to assess the efficacy of trimetazidine in the subpopulation of patients with a history of PTCA or CABG, who were included in the TRIMPOL II study. METHODOLOGY: A subgroup of 94 patients was retrospectively analysed from the TRIMPOL II study, a multicentre, double-blind randomised placebo-controlled trial in 426 patients with stable effort angina. These patients have a history of revascularization for coronary artery disease, and they are still symptomatic after 6 months despite a treatment with metoprolol (50 mg twice daily). They were randomly allocated to receive either trimetazidine (20 mg 3 times daily) or placebo for 12 weeks, on top of the beta-blocker. Exercise test parameters, clinical efficacy and safety were assessed. Results were analysed using the Student test, the Mann-Whitney test or the Shapiro-Wilk test. RESULTS: Compared to placebo, the 12-week treatment with trimetazidine significantly improved: time to 1 mm ST segment depression (385.1 s +/- 144.6 s versus 465.0 s +/- 143.8 s [p < 0.01]); exercise test duration (466.9 s +/- 144.8 s versus 524.4 s +/- 131.5 s [p = 0.048]), total workload (9.0 m.e. +/- 2.4 m.e versus 10.1 m.e. +/- 2.4 m.e [p = 0.035]) as well as time to onset of angina (433.6 s +/- 164 s versus 508.1 s +/- 132.4 s [p = 0.031]). Weekly number of angina attacks and nitrate consumption were significantly reduced in the trimetazidine group when compared to placebo. Three mild gastro-intestinal side-effects were reported in the trimetazidine group. CONCLUSION: These results show that trimetazidine provides anti-anginal efficacy in post-revascularized patients with recurrent angina despite a monotherapy with metoprolol. The treatment was well accepted.

Combination treatment in stable effort angina using trimetazidine and metoprolol: results of a randomized, double-blind, multicentre study (TRIMPOL II). TRIMetazidine in POLand.

AIMS: To assess the antiischaemic efficacy and tolerability of the metabolic agent trimetazidine in combination with metoprolol in patients with stable effort angina. METHODS: This was a randomized, multicentre, double-blind, placebo-controlled parallel group study. A total of 426 male and female patients with stable, effort-induced angina and documented coronary artery disease received either placebo or trimetazidine 20 mg three times daily in addition to metoprolol 50 mg twice daily. Treadmill exercise tests were performed at weeks (-1), 0, 4 and 12. RESULTS: After 12 weeks, there were significantly greater improvements in the metoprolol + trimetazidine group than in the metoprolol + placebo group in: time to 1 mm ST segment depression, total workload, time to onset of angina, maximum ST segment depression, mean weekly number of angina attacks, mean weekly nitrate consumption, and grade of anginal pain. There was no evidence of any development of tolerance to trimetazidine. The tolerability of trimetazidine was excellent. CONCLUSIONS: Therapy with trimetazidine plus metoprolol produced significant improvements in exercise stress tests and the symptoms of angina relative to metoprolol alone. With its metabolic effect, devoid of any haemodynamic action, trimetazidine is useful for combination therapy in patients with stable angina insufficiently controlled by monotherapy with a beta-blocker.

Advantages of exercise echocardiography in comparison to dobutamine echocardiography in the diagnosis of coronary artery disease in hypertensive subjects.

OBJECTIVE: The aim of the study was to compare the efficacy and safety of two stress echocardiography methods, exercise and dobutamine, in the diagnosis of coronary artery disease in hypertensive patients with angina. PATIENTS AND METHODS: A total of 197 treated hypertensive patients, age 53 +/- 9 years (65 women) with no history of myocardial infarction referred for coronary angiography were prospectively investigated with exercise electrocardiography (ECG), exercise and dobutamine echocardiography. RESULTS: Sensitivity of the exercise ECG, exercise echocardiography and dobutamine echocardiography did not differ (77%, 82% and 75%). Negative predictive value of exercise ECG was significantly lower than exercise echocardiography (64% vs 79%, P < 0.01). Specificity and positive predictive value of exercise ECG were markedly lower than exercise and dobutamine echocardiography (57%, 96%, 98% and 72%, 97%, 98%, P < 0.0001 for both stress echocardiography vs ECG). Specificity and sensitivity of diagnostic methods were not influenced by the presence of echocardiographic left ventricular hypertrophy. Dobutamine infusion in comparison to exercise was more often associated with substantial arterial blood pressure rise or fall (7% vs 2%, P < 0.05) and with simple ventricular ectopy (15,7% vs 6,1%, P < 0.05). CONCLUSIONS: In hypertensive patients with the symptoms of angina, both stress echo methods are significantly more specific than the exercise ECG test. Maximal exercise is associated with less frequent side effects than infusion of dobutamine, so exercise echocardiography may be preferred in the diagnosis of angina in hypertensive patients.

Availability of on-site catheterization and clinical outcomes in patients receiving fibrinolysis for ST-elevation myocardial infarction.

AIMS: To compare management and clinical outcomes in hospitals stratified by the availability of on-site catheterization in InTIME-II, a multicentre trial comparing alteplase with lanoteplase for acute myocardial infarction. METHODS AND RESULTS: We studied 15,078 patients enrolled in 35 countries and 855 hospitals. Thirty-one percent of hospitals had 24-h, 25% day-only, and 44% no on-site catheterization facilities. Rates of cardiac angiography (57%, 38%, 26%) and revascularization (37%, 21%, 17%) were higher in hospitals with increasing access to on-site facilities(P<0.0001). The presence of a 24-h on-site facility was the strongest predictor of angiography during the index admission (odds ratio 4.17, 95% CI 3.85-4.54). There were no major differences in patient outcomes at 30 days when hospitals were stratified by availability of on-site catheterization. Adjusted 1-year mortality was similar between groups of hospitals (odds ratio for day-only 0.94 [0.80-1.09] and odds ratio for no availability 0.95 [0.83-1.10] compared to hospitals with 24-h facilities). CONCLUSIONS: There is a marked variation in procedure use by the availability of on-site catheterization with no major differences in patient outcomes. There is a need for additional randomized trials in the current era to address both the appropriate selection of patients and timing of invasive procedures in ST-elevation acute myocardial infarction.

[How efficacy of antianginal drugs should be evaluated]. / Jak oceniac skutecznosc leków wiencowych.

This article studies the different methods of antianginal drug evaluation in the long-term treatment of ischemic heart disease. Subjective and objective methods are discussed with their limitations. The authors review serial ECG stress testing, this being the most frequently used method of antianginal pharmacotherapy evaluation. Safety, selected topics related to bioethics and statistical analysis in the clinical evaluation of drugs are discussed. Meta-analyses and clinical multicenter mega-trials, which are currently gaining in popularity and are likely to play an important role in the complex process of therapeutic decision making in the future, are discussed in the final section of this paper.

[Comparative evaluation of antianginal efficacy of isosorbide dinitrate in various doses in patients with stable angina]. / Porównawcza ocena aktywnosci przeciwdlawicowej róznych dawek dwuazotanu izosorbitolu u chorych ze stabilna choroba wiencowa.

In a randomized, double-blind, placebo (P) controlled with cross-over design study 38 male patients with stable angina and angiographically proven coronary artery disease, received isosorbide dinitrate (ISDN) in various single doses: 10 mg, 20 mg, 20 mg slow-release (-SR), 40 mg-SR, 80 mg-SR and 120 mg-SR. Evaluation of antianginal efficacy and the effect of ISDN on the simple hemodynamic parameters was performed by analysis of walking times on the treadmill: total, to angina and to ischemia (WTI) as well as: heart rate and systolic blood pressure at rest and during exercise. Exercise stress tests on the treadmill were performed: preceding drug administration, 2 hours and 6 h after. 6 h after taking the drug all doses of ISDN improved significantly all three analysed walking times on the treadmill, for example WTI in comparison to P (p < 0.001): 10 mg by 34.6%, 20 mg by 49.6%, 20 mg-SR by 42.9%, 40 mg-SR by 52.5%, 80 mg-SR by 66.0%, and 120 mg-SR by 58.4%. ISDN 20 mg was more active antianginally than 10 mg, but was connected with more severe orthostatic hypotension and headaches. ISDN 20 mg-SR was weaker in the improvement of coronary reserve than ISDN 20 mg, but it gave less adverse effects. The elevation of ISDN-SR dose was effective in the improvement of coronary reserve up to 80 mg-SR (without further benefits after 120 mg-SR). The antianginal efficacy of doses: 40 mg-SR, 80 mg-SR and 120 mg-SR was not significantly different.

A randomized comparison of elective high-pressure stenting with balloon angioplasty: six-month angiographic and two-year clinical follow-up. On behalf of AS (Angioplasty or Stent) trial investigators.

BACKGROUND: Previous randomized trials have shown beneficial effects of coronary stenting on restenosis and event-free survival rates. However, it has not yet been fully established if routine high-pressure stenting with an antiplatelet regimen can show similar results. METHODS: We compared the 6-month angiographic restenosis rate and 2-year event-free survival rate in 400 patients randomly assigned to stent or angioplasty. Aspirin and ticlopidine were prescribed in both groups. RESULTS: The procedural success rate did not significantly differ between the stent and angioplasty groups (97.92% vs 97.45%, P = not significant). No stent thrombosis was found. The 6-month restenosis rate was lower in the stent group (18. 18% vs 24.87%, P =.055). At 2 years target lesion revascularization rate was 17.19% in the stent group and 25.51% in the angioplasty group (P =.02, 33% reduction). No significant differences with regard to death and myocardial infarction were observed. Event-free survival rate at 6, 12, and 24 months was 86.77% vs 78.84%, 84.13% vs 76.70%, and 83.07% vs 73.54% for stent and angioplasty groups, respectively (P =.0172). CONCLUSIONS: The 6-month angiographic and 2-year clinical outcomes were better in patients who received stent than in those after balloon angioplasty. The difference in 2-year event-free survival rate was explained by a reduction in target lesion revascularization rate in the stent group.

[Evaluation of antianginal efficacy of long-term therapy with low dose isosorbide dinitrate in patients with stable angina pectoris]. / Ocena skutecznosci przeciwdlawicowej terapii przewleklej nizszymi dawkami dwuazotanu izosorbitolu u chorych ze stabilna choroba wiencowa.

UNLABELLED: The aim of this study was to evaluate two ways of long-term therapy with lower doses of oral isosorbide dinitrate (ISDN) in normal tablets and in sustained-release form (SR), in patients with stable angina. METHODS: In double-blind, placebo (PL) controlled with cross-over design study 38 male patients with stable angina and angiographically proven coronary artery disease, received ISDN in normal tablets in two doses: 10 mg and 20 mg, and also two doses SR: 20 mg-SR and 40 mg-SR or PL in the first ingestion and in long-term therapy in two 7 day phases: 4-times-daily (4x) every 6 h and 3-times-daily (3x) with 12 h interval. In 3x patients received ISDN only in doses: 20 mg, 20 mg-SR and 40 mg-SR. After the first ingestion and on the last day of long-term phases, exercise stress tests on the treadmill were performed: preceding ingestion, 2 h and 6 h after. Evaluation of antianginal efficacy of ISDN was performed by analysis of walking times: total, to angina and to ischemia (WTI). RESULTS: 6 h after first ingestion all doses of ISDN improved significantly WTI in comparison to PL: 10 mg by 34.6% (p < 0.01), 20 mg by 49.6% (p < 0.0001), 20 mg-SR by 42.9% (p < 0.001) and 40 mg-SR by 52.5% (p < 0.0001). None of the doses improved significantly WTI in the long-term 4x phase, in 3x--only 40 mg-SR by 12.1% (p < 0.05). CONCLUSIONS: Tolerance to anti-anginal efficacy of ISDN in lower doses in long-term therapy 4-times-daily, every 6 h, was found. A 12-h interval is sufficient to prevent tolerance in long-term treatment of sustained-release ISDN in 40 mg dose. Intermitted dosing of nitrates, as a prevention of tolerance, and the practical results of works using other pharmacologic interventions in a clinical setting are discussed in the final section of this paper.

What intervals in oral therapy of isosorbide dinitrate in various doses are sufficient to prevent nitrate tolerance?

INTRODUCTIONS: The organic nitrates are effective anti-anginal drugs during initial treatment, but their therapeutic value is compromised by the rapid development of tolerance during sustained therapy. The only widely accepted method of preventing tolerance is the use of intermittent administration, but without specifying to what extent the length of interval is dependent on type and dose of nitrate. The aim of this study was to evaluate how long periods free of nitrates are sufficient to prevent tolerance in long-term therapy with oral sustained-release isosorbide dinitrate (ISDN). MATERIAL AND METHODS: In a double-blind study, 38 patients with stable angina, received ISDN: 40 mg, 80 mg and 120 mg or placebo in the first ingestion (1st) and in long-term therapy in four 7 day phases: 4-times-daily (4x), 3-times-daily (3x) with 12 h nitrate-free interval, twice-daily (2x) with 18 h interval and once-daily (1x). After 1st and on the last day of each long-term phases, exercise tests with the analysis of walking times: total, to angina and to ischaemia (WTI) were performed: preceding ingestion, 2 h and 6 h after. RESULTS: Six hours after 1st all doses WTI improved significantly in comparison to placebo (p < 0.0001): 40 mg by 52.5%, 80 mg by 66.0% and 120 mg by 58.4%. None of the ISDN doses improved significantly WTI in 4x phase; in 3x, only 40 mg by 12.1% (p < 0.05); in 2x, only 80 mg by 22.3% (p < 0.05) and in once-daily, 80 mg by 27.2% and 120 mg by 36.2% (p < 0.01). CONCLUSION: 12 h nitrate-free interval is sufficient in order to prevent tolerance in long-term treatment of sustained-release ISDN with 40 mg dose, 18 h with 80 mg and 24 h with 120 mg doses.

[How nitrate tolerance be prevented in the treatment of ischemic heart disease?]. / Jak zapobiegac tolerancji azotanów w leczeniu choroby niedokrwiennej serca?

Organic nitrates are widely used for chronic treatment of ischaemic heart disease. However, the clinical value of long-term nitrate therapy is limited by the development of tolerance to their anti-anginal effects. This paper examines the different effects of nitrates, especially cellular effects. The theories put forward to explain nitrate tolerance are examined, including recent work on vascular superoxide and endothelin-1 regulation. Clinically, tolerance can be prevented by intermitted dosing of nitrates. This topic, and the practical results of work using other pharmacologic interventions in a clinical setting are discussed in the final section of this article.

Ice/Water Interface: Zeta Potential, Point of Zero Charge, and Hydrophobicity.

The ice/water interface is a common and important part of many biological, environmental, and technological systems. In contrast to its importance, the system has not been extensively studied and is not well understood. Therefore, in this paper the properties of the H(2)O ice/water and D(2)O ice/water interfaces were investigated. Although the zeta potential vs pH data points were significantly scattered, it was determined that the isoelectric point (iep) of D(2)O ice particles in water at 3.5 degrees C containing 10(-3) M NaCl occurs at about pH 3.0. The negative values of the zeta potential, calculated from the electrophoretic mobility, seem to decrease with decreasing content of NaCl, while the iep shifts to a higher pH. The point of zero charge (pzc) of D(2)O ice and H(2)O ice, determined by changes in pH of 10(-4) M NaCl aqueous solution at 0.5 degrees C after the ice particle addition, was found to be very different from the iep and equal to pH 7.0 +/- 0.5. The shift of the iep with NaCl concentration and the difference in the positions of the iep and pzc on the pH scale point to complex specific adsorption of ions at the interface. Interestingly, similar values of iep and pzc were found for very different systems, such as hydrophilic ice and highly hydrophobic hexadecane droplets in water. A comparison of the zeta potential vs pH curves for hydrophilic ice and hydrophobic materials that do not possess dissociative functional groups at the interface (diamond, air bubbles, bacteria, and hexadecane) indicated that all of them have an iep near pH 3.5. These results indicate that the zeta potential and surface charge data alone cannot be used to delineate the electrochemical properties of a given water/moiety interface because similar electrical properties do not necessary mean a similar structure of the interfacial region. A good example is the aliphatic hydrocarbon/water interface in comparison to the ice/water interface. Although the experiments were carried out with care, both the zeta potential, measured with a precise ZetaPlus meter, and DeltapH values (a measure of surface charge) vs pH were significantly scattered, and the origin of dissemination of the data points was not established. Differently charged ice particles and not fully equilibrium conditions at the ice/water interface may have been responsible for the dissemination of the data. Copyright 1999 Academic Press.

The antiischemic effects and tolerability of trimetazidine in coronary diabetic patients. A substudy from TRIMPOL-1.

Diabetes mellitus, a disease with a wide prevalence, has major cardiovascular effects, being a risk factor for the development of ischemic heart disease and congestive heart failure. The aim of this open, multicenter study was to assess the antiischemic efficacy and tolerability of trimetazidine, a metabolic agent acting at the myocardial mitochondrial level, in diabetic patients with stable effort angina treated previously with a single conventional antianginal drug. Fifty diabetic patients (mean age 58 years) with proven coronary artery disease, stable effort angina for at least 3 months, and positive, comparable results of two initial treadmill exercise tests separated by a 1-week interval were included in the study. They continued their conventional antianginal monotherapy with a long-acting nitrate, beta-blocker, or calcium channel blocker. After stabilization, 4-week therapy with trimetazidine, three times daily, 20 mg was initiated in combination with previous treatment. The results showed a significant improvement in exercise tolerance (440.2 vs. 383.2 s; P < 0.01), time to 1-mm ST-segment depression (358.3 vs. 301.6 s; P < 0.01), time to onset of anginal pain (400.0 vs. 238.3 s; P < 0.01), and total work (9.39 vs. 8.67 metabolic equivalents, P < 0.01). Maximal ST-segment depression was attenuated compared with baseline (1.82 vs. 1.91 mm). Other findings included a significant decrease in the mean frequency of anginal episodes (3.06 vs. 4.79 per week; P < 0.01) and in mean nitrate consumption (2.29 vs. 4.2 doses/week). These results suggest that trimetazidine may be effective and is well tolerated as combination therapy for diabetic coronary artery disease patients uncontrolled with a single hemodynamic agent.

Multicenter randomized trial and a systematic overview of lidocaine in acute myocardial infarction.

BACKGROUND: More than 20 randomized trials and 4 meta-analyses have been conducted on the use of prophylactic lidocaine in acute myocardial infarction (MI). The results suggest that lidocaine reduces ventricular fibrillation (VF) but increases mortality rates in acute MI. METHODS AND RESULTS: Patients with ST-elevation MI who were examined <6 hours after symptom onset (n = 903) were randomly assigned to either lidocaine or no lidocaine and to either streptokinase and heparin or heparin alone. Lidocaine was given as 4 boluses of 50 mg each every 2 minutes, then an infusion of 3 mg/min for 12 hours, then 2 mg/min for 36 hours. We compared the incidence of in-hospital death and ventricular arrhythmias. We then performed a meta-analysis of prophylactic lidocaine in acute MI that included these and prior trial results. The rates of VF and death with and without lidocaine were calculated for each trial, then odds ratios (OR) with confidence intervals (CI) were calculated for the risk of these events overall with and without lidocaine. Patients given lidocaine in the randomized study had significantly less VF (2.0% vs 5.7% without lidocaine, P =.004) and a trend toward increased mortality rates (9.7% vs 7.0%, P =.145). Meta-analysis revealed nonsignificant trends toward reduced VF (OR 0.71, 95% CI 0.47 to 1. 09) and increased mortality rates (OR 1.12, 95% CI 0.91 to 1.36) with lidocaine. CONCLUSIONS: Lidocaine reduces VF but may adversely affect mortality rates. The routine use of prophylactic lidocaine in acute MI is not recommended.

Prophylactic lidocaine use in acute myocardial infarction: incidence and outcomes from two international trials. The GUSTO-I and GUSTO-IIb Investigators.

BACKGROUND: Early meta-analyses suggested that prophylactic lidocaine use reduces ventricular fibrillation but increases mortality rates after acute myocardial infarction. We determined the frequency and effect on clinical outcomes with its use in the thrombolytic era. METHODS AND RESULTS: We studied 43,704 patients enrolled in GUSTO-I or GUSTO-IIb who had ST-segment elevation, underwent thrombolysis, and survived at least 1 hour after enrollment. Odds ratios (OR) and confidence intervals (CI) were calculated for the risk of asystole, atrioventricular block, ventricular fibrillation, and ventricular tachycardia during hospitalization; for 24-hour, in-hospital, and 30-day mortality rates; and for 24-hour and 30-day mortality rates after adjustment for baseline predictors of death. In GUSTO-I and GUSTO-IIb, 16% and 3.5% of patients, respectively, received prophylactic lidocaine. They had a lower risk of death at 24 hours (OR 0.81, 95% CI 0.67 to 0.97) and trends toward lower odds of in-hospital death (OR 0.90, 95% CI 0.81 to 1.01) and death at 30 days (OR 0.92, 95% CI 0.82 to 1. 02). After adjustment for baseline characteristics, however, the odds of death were similar with or without lidocaine (OR 0.90 and 0. 97, respectively). Outside the United States, lidocaine was associated with higher incidences of all serious arrhythmias, but in US patients it conferred a lower likelihood of ventricular fibrillation and no increase in asystole, atrioventricular block, or mortality rates. CONCLUSIONS: Prophylactic lidocaine use has decreased with the advent of thrombolysis, although its use may not be associated with increased mortality rates.

[The diagnostic value of resting electrocardiography in stable coronary artery disease]. / Wartosc diagnostyczna spoczynkowego badania elektrokardiograficznego w rozpoznawaniu stabilnej choroby wiencowej.

The relation of resting electrocardiographic (ECG) patterns to angiographic features was assessed in 566 patients with chest pain regarded as definite or probable stable angina pectoris. The indications for catheterization in each patient were determined at the discretion of the attending physician. All patients underwent diagnostic coronary angiography (clinically important coronary artery disease was defined as > or = 70 per cent narrowing of the diameter of at least one major vessel or > or = 50 per cent of the left main coronary artery) and standard 12 lead electrocardiography which was interpreted by 2 cardiologists independently in coordinating centre. The signs of impaired coronary blood flow were assessed by abnormalities of repolarization (among others S-T segment, the T wave), depolarization and presence of disturbances of cardiac rythm. The resting routine electrocardiogram was assigned to one of three categories: normal, nonspecific abnormalities or typical for coronary insufficiency. The typical pattern for ischemia was present in 104 patients (18%), nonspecific abnormalities were present in 185 patients (33%) and electrocardiogram was normal in 277 patients (49%). Sensitivity and specificity of the typical for coronary insufficiency resting ECG was calculated: 23% and 87% respectively for the entire group, 33% and 81% in women, 20% and 93% in men. In the group with normal resting electrocardiographic pattern 55% of patients have significant stenosis in at least one major coronary artery.

[Plasma volume expansion may explain the attenuation of antianginal activity of oral isosorbide dinitrate in long-term therapy]. / Powiekszanie sie objetosci osocza moze tlumaczyc oslabienie aktywnosci przeciwdlawicowej doustnego dwuazotanu izosorbitolu w terapii przewleklej.

UNLABELLED: The aim of the study was to evaluate whether tolerance to oral isosorbide dinitrate in sustained-release form (ISDN-SR) may be related to reduction in hematocrit (HCT)--an indirect indicator of plasma volume expansion. METHODS: In a double blind, cross-over and placebo (P) controlled study 38 men, with mean age 52.5 +/- 7.4 years, with stable angina and angiographically proven coronary artery disease, received ISDN-SR 120 mg or P as initial dose and after 7 days of therapy: 4-times-daily (ISDN-SR 480 mg a day) and once-daily (ISDN-SR 120 mg a day). Venous HCT was measured: before treatment and after each of the 3 long-term phases. Antianginal efficacy of ISDN-SR 120 mg was evaluated by analysis of walking time to ischemia (WTI) on treadmill during stress tests performed 2 and 6 hours after drug ingestion in acute and long-term therapy. RESULTS: 6 hours after first ingestion of ISDN-SR 120 mg the mean walking time to ischaemia WTI was significantly improved in comparison to P by 58.4% (p < 0.0001) and after 7 days of once-daily treatment by 36.2% (p < 0.01) but not after the 4-times-daily period (NS). HCT fell from mean 43.2 +/- 3.6% before and 42.0 +/- 3.4% (NS) after P phase, to 40.5 +/- 3.0% (p < 0.05) after 4-times-daily period, but HCT remained unchanged after one week of once-daily treatment (NS). CONCLUSIONS: Significant reduction in hematocrit--an indirect indicator of plasma volume expansion--during oral ISDN-SR 120 mg in long-term therapy 4-times-daily, when tolerance occurred, but not once-daily (without tolerance), may contribute to the mechanism of attenuation of antianginal activity of nitrates.

Evaluation of a weight-adjusted single-bolus plasminogen activator in patients with myocardial infarction: a double-blind, randomized angiographic trial of lanoteplase versus alteplase.

BACKGROUND: Lanoteplase (nPA) is a rationally designed variant of tissue plasminogen activator with greater fibrinolytic potency and slower plasma clearance than alteplase. METHODS AND RESULTS: InTIME (Intravenous nPA for Treatment of Infarcting Myocardium Early), a multicenter, double-blind, randomized, double-placebo angiographic trial, evaluated the dose-response relationship and safety of single-bolus, weight-adjusted lanoteplase. Patients (n=602) presenting within 6 hours of acute myocardial infarction were randomized and treated with either a single-bolus injection of lanoteplase (15, 30, 60, or 120 kU/kg) or accelerated alteplase. The primary objective was to determine TIMI grade flow at 60 minutes. Angiographic assessments were also performed at 90 minutes and on days 3 to 5. Follow-up was continued for 30 days. Lanoteplase achieved its primary objective, demonstrating a dose-response in TIMI grade 3 flow at 60 minutes (23.6% to 47.1% of subjects, P<0. 001). Similar results were observed at 90 minutes (26.1% to 57.1%, P<0.001). At 90 minutes, coronary patency (TIMI 2 or 3) increased across the dose range up to 83% of subjects at 120 kU/kg lanoteplase compared with 71.4% with alteplase. Thus, at this dose, lanoteplase was superior to alteplase in restoring coronary patency (difference, 12%; 95% CI, 1% to 23%). The early safety experience in this study suggests that lanoteplase was well tolerated at all doses with safety comparable to that of alteplase. CONCLUSIONS: Lanoteplase, a single-bolus, weight-adjusted agent, increased coronary patency at 60 and 90 minutes in a dose-dependent fashion. Coronary patency at 90 minutes was achieved more frequently with 120 kU/kg lanoteplase than alteplase. In this study, safety with lanoteplase and alteplase was comparable. InTIME-II, a worldwide mortality trial, will evaluate efficacy and safety with this promising new agent.