Udho Thadani

Oral Isosorbide dinitrate in angina pectoris: Comparison of duration of action and dose-response relation during acute and sustained therapy

The effects of different oral doses of isosorbide dinitrate administered acutely and four times daily during sustained therapy were studied in 12 patients with angina pectoris. After administration of 30, 60 and 120 mg of isosorbide dinitrate, the average plasma concentrations were higher and the area under the plasma concentration time curve was greater during sustained than during acute therapy (p less than 0.01). Reduction in standing systolic blood pressure was greater during acute than during sustained therapy (p less than 0.001). This reduction in systolic blood pressure was dose-related and persisted for 8 hours during acute therapy, but was not dose-related and was demonstrable for only 4 hours during sustained therapy. Compared with placebo therapy, exercise duration to the onset of angina and to the development of moderate angina increased significantly after each dose of isosorbide dinitrate for 8 hours during acute therapy but for only 2 hours during sustained therapy. During acute therapy, administration of a single dose of 15 or 30 mg of isosorbide dinitrate produced similar improvement in exercise tolerance as did a dose of 60 or 120 mg. During sustained therapy (15 mg four times daily), exercise tolerance increased to the same magnitude as with doses of 30, 60 or 120 mg four times daily. In most patients, near maximal improvement in exercise tolerance occurred after a dose of 15 or 30 mg four times daily. It is concluded that during sustained therapy with isosorbide dinitrate, partial tolerance to the antianginal and circulatory effects develops rapidly.

Comparative efficacy of 200, 300 and 400 mg of bepridil for chronic stable angina pectoris

A total of 178 patients participated in a 14-week, multicenter, double-blind, parallel study to evaluate the comparative efficacy and safety of single daily doses of 200, 300 and 400 mg of bepridil hydrochloride and placebo in the treatment of patients with chronic stable angina pectoris. The results showed that weekly angina attacks and nitroglycerin consumption were significantly reduced from baseline levels with all doses of bepridil (p less than 0.01), and the reductions were consistently greater than those in the placebo group. For the 400-mg dose the reductions in angina attacks and nitroglycerin consumption were significantly greater (p less than or equal to 0.05) than those in the placebo group at all but 1 evaluation point. Exercise tolerance improved significantly during bepridil administration (p less than or equal to 0.05), and a significant linear dose response was noted for total exercise time, total work and time to onset of angina. In addition, bepridil was significantly superior to placebo for these parameters at doses of 300 (p less than or equal to 0.05) and 400 mg (p less than or equal to 0.01). There were small reductions in heart rate (mean 3.7 beats/min) and prolongation of QT and QTc intervals (approximately 30 to 40 milliseconds) associated with bepridil treatment. Bepridil was well tolerated by patients in this study. When adverse effects occurred, they most frequently involved the gastrointestinal and central nervous systems. Of the patients receiving bepridil, 6% discontinued therapy because of adverse effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of zatebradine (ULFS 49 CL), a sinus node inhibitor, on heart rate and exercise duration in chronic stable angina pectoris

Zatebridine selectively reduces resting and exercise heart rate without any other myocardial effects. In this study, despite significant reductions in resting and exercise heart rate, there were no clinically significant effects on myocardial ischemia, suggesting that the anti-ischemic effect of heart rate reduction should be reevaluated.

Combination propranolol and bepridil therapy in stable angina pectoris

The safety and efficacy of bepridil plus propranolol therapy were investigated in a placebo-controlled, parallel-design, double-blind trial in 56 patients who were not responding to propranolol alone. Patients entering the study were receiving an average propranolol dosage of 131 mg/day (range 20 to 240). For the first 2 weeks of the study they were given placebo in addition to their propranolol dose, and then were randomized to receive continued placebo plus propranolol or bepridil plus propranolol therapy. The bepridil dosage was adjusted over the 8 weeks of active treatment to an average of 273 mg/day (range 200 to 400). The double-blind treatment period was followed by a 3-week washout period during which all patients received propranolol and placebo. The effects of treatment on the frequency of angina attacks, nitroglycerin consumption, exercise performance (treadmill-modified Bruce protocol) and Holter electrocardiogram (ECG) were assessed. Propranolol and bepridil plasma levels also were obtained. Improved antianginal efficacy and reduced nitroglycerin consumption were noted when bepridil was added to propranolol (p less than 0.01). During 8 weeks of combination treatment, exercise tolerance increased 1.0 +/- 1.2 minutes from a baseline of 7.3 +/- 2.2 with bepridil plus propranolol compared with an increase of 0.02 +/- 1.3 minutes from a baseline of 7.6 +/- 2.9 with placebo plus propranolol (p less than 0.01). With bepridil plus propranolol, there were also increases in exercise time to onset of angina (p less than 0.04), exercise time to 1-mm electrocardiographic ST-segment depression (p less than 0.06) and total work (p less than 0.03) compared with placebo plus propranolol therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Additional Antianginal and Anti-Ischemic Efficacy of Mibefradil in Patients Pretreated With a Beta Blocker for Chronic Stable Angina Pectoris

This study assessed the safety, tolerability, and efficacy of mibefradil when added to beta-blocker monotherapy in patients with chronic stable angina pectoris. Two hundred five patients were randomized to receive double-blind treatment with either placebo (n = 70), mibefradil 25 mg (n = 67), or mibefradil 50 mg (n = 68) for 2 weeks. Exercise tolerance tests (ETTs) were performed at the end of the run-in (baseline) and double-blind treatment periods, and patients maintained an anginal diary. Compared with placebo, treatment with mibefradil 50 mg resulted in significant increases in exercise duration (36 +/- 51 seconds; p = 0.036), time to onset of angina (48 +/- 65 seconds; p = 0.002), and time to persistent 1-mm ST-segment depression (47 +/- 77 seconds; p = 0.004). Greater reductions in heart rate, blood pressure, and the rate-pressure product were more apparent at each stage of the ETT in the 50-mg mibefradil group than in the placebo group. Daily treatment with mibefradil 50 mg was associated with a significant decrease in the number of weekly anginal attacks (-2.1 +/- 4.0, p = 0.020) compared with placebo. The addition of mibefradil to existing beta-blocker therapy was well tolerated. Dizziness was the most frequently reported adverse event in the mibefradil 50-mg dose, and occurred with an incidence of 4.4%. The addition of mibefradil 50 mg, administered once daily, to patients on stable beta-blocker therapy produced additive antianginal and anti-ischemic effects and was well tolerated.

Evaluation of a prolonged infusion of recombinant tissue-type plasminogen activator (Duteplase) in preventing reocclusion following successful thrombolysis in acute myocardial infarction☆

The hypothesis that an infusion of recombinant tissue-type plasminogen activator (rt-PA) maintained for up to 24 hours could prevent reocclusion after early coronary patency had been established was evaluated in patients with acute myocardial infarction. The rt-PA studied was an investigational double chain rt-PA (Duteplase, Burroughs Wellcome Co.), administered according to body weight. Coronary patency was documented in 139 of 213 patients who had 90-minute angiograms recorded after an initial lytic dose of rt-PA. In these responders a further 90-minute infusion at one third the initial lytic dose was given before assignment to 1 of 4 maintenance dose rates (0.012, 0.024, 0.036, 0.048 MIU/kg/hour) which were continued for the subsequent 9 to 21 hours. The principal end point was the status of the infarct-related coronary artery 12 to 24 hours after the start of therapy, and before termination of rt-PA, in patients with initially patent vessels at 90 minutes. Of the 103 responders with repeat angiograms after a 9 to 21 hour maintenance infusion of rt-PA, a total of 17 (16.5%) patients reoccluded across all doses administered. There was no significant relationship between the maintenance dose rate and the incidence of reocclusion. However, there was strong association between total dose of rt-PA administered and the incidence (16%) of serious or life-threatening bleeding exclusive of surgery. Other factors associated with serious bleeding included low body weight, female gender, and total duration of rt-PA infusion. Reocclusion was independent of the 90-minute Thrombolysis in Myocardial Infarction trial perfusion grade and diameter of infarct vessel. Rethrombosis after establishment of early patency after rt-PA remains a significant problem that is unaffected by sustained rt-PA infusion in doses that can be tolerated.

Effect of Morning Versus Evening Dosing of Diltiazem on Myocardial Ischemia Detected by Ambulatory Electrocardiographic Monitoring in Chronic Stable Angina Pectoris

Myocardial ischemia occurs frequently during daily life and has a circadian pattern similar to that reported for myocardial infarction and sudden death. Because of the increased risk of myocardial ischemia in the morning hours, it has been suggested that the administration of anti-ischemic medication before bedtime may be more effective than the traditional morning dosing. This randomized, double-blind, placebo-controlled, crossover study evaluated the effects of 480-mg/day diltiazem (given either in the A.M. or the P.M.) on myocardial ischemia using ambulatory electrocardiographic monitoring in 68 patients with chronic stable angina and > or = 2 minutes of ischemia per 48 hours. During treatment with diltiazem, the duration and number of myocardial ischemic episodes were reduced by 45% (94 to 52 minutes, p <0.004) and by 40% (4.5 to 2.7 episodes, p <0.003), respectively. The duration and number of myocardial ischemic episodes during daytime (6 A.M. to 6 P.M.) hours were also reduced by 52% (74 to 36 minutes, p <0.002) and by 48% (3.1 to 1.6 episodes, p <0.001), respectively. There was no significant difference between A.M. and P.M. dosing. Morning ischemia (6 A.M. to noon), considered separately from daytime ischemia, was also significantly reduced by both A.M. and P.M. dosing regimens, with no difference between the regimens. The results of this study showed that both A.M. and P.M. dosing of long-acting diltiazem were equally effective in suppressing episodes of ambulatory myocardial ischemia at all times.

Myocardial infarct artery patency and reocclusion rates after treatment with duteplase at the dose used in the International Study of Infarct Survival-3

Duteplase, 98% double-chain recombinant tissue-type plasminogen activator, was administered intravenously in 488 patients with acute myocardial infarction in a multicenter, open, safety and patency study. Duteplase dosing was based on body weight. Duteplase was administered as a bolus of 0.04 MIU/kg of thrombolytic activity followed by 0.36 MIU/kg over 1 hour and 0.067 MIU/kg/hour for 3 additional hours. The patency rate of the infarct-related artery at 90 minutes was 69% (330 of 478). The reocclusion rate at 3 to 48 hours was 6% (18 of 301). Reinfarction occurred in 7.6% of patients (37 of 488), but 12 reinfarctions occurred after coronary angioplasty. Serious bleeding occurred in 7.6% of patients (37 of 488), predominantly at the catheterization entry site. There were 3 instances of central nervous system bleeding, 1 fatal. Fibrinogen levels declined to 83% of baseline at 24 hours. Weight-based dosing may explain the low incidence of serious bleeding in this study. The in-hospital mortality was 6.6% (32 of 488). This study documents that the dose of duteplase used in the International Study of Infarct Survival-3 results in a 90-minute coronary artery patency rate and safety profile comparable to those reported in published studies on the approved dose of alteplase.

Pigment Epithelial-Derived Factor and Acute Coronary Syndrome: A Novel Protective Biomarker but Not for Routine Clinical Use at Present

er values indicate greater risk) have been reported to correlate with a poor outcome [7–16] . However, at present, the effect of biomarker-targeted therapy in ACS (with the exception of LDL-targeted treatment with statins [17–19] ) remains to be proven. The search for novel biomarkers which provide additional prognostic information is under active investigation at present, and several novel biomarkers of inflammation, coagulation, oxidative stress, and endothelial damage, among others, are being actively pursued [15, 20–28] . In patients with heart failure, high-sensitivity troponin has recently been shown to correlate with left-ventricular end-diastolic pressure and microvascular endothelial dysfunction and, therefore, might help guide ongoing therapy in these patients [29] . In this issue of Cardiology , Liu et al. [30] report yet another biomarker, pigment epithelial-derived factor (PEDF), which they conclude is protective against ACS. PEDF is a 50-kDa glycoprotein which belongs to the serpin protease inhibitor supergene family [31, 32] . It is widely expressed throughout the human body and has been shown to have anti-inflammatory, anti-oxidant, anti-angiogenic, anti-thrombotic, anti-tumorigenic, neutrophilic, and neuroprotective characteristics [31–33] . They report that their ACS patients (n = 200), comprising patients with unstable angina and myocardial infarction, had significantly lower mean values of PEDF (7.31 ± 2.21 μg/ml) than age-matched controls (n = 160) without The acute coronary syndrome (ACS) is invariably a consequence of plaque rupture inside the coronary artery vessel wall, with resultant disruption of the endothelial lining, subsequent deposition of platelets over the exposed area, and variable superimposed thrombus formation [1–4] . Resultant clinical presentation of unstable angina, acute non-ST-segment elevation or ST-segment elevation myocardial infarction, or sudden ischemic cardiac death is determined by the location and size of the ruptured plaque, extent of the superimposed thrombus, and distal platelet or thrombus embolization [1–4] . Clinical risk factors, such as older age, gender, family history of coronary artery disease (CAD), diabetes mellitus, previous history of a myocardial infarction, severity of underlying CAD, extent of myocardial damage, hypertension and chronic kidney disease, determine the outcome of these patients [5, 6] . In addition, several established biomarkers, such as peak creatine kinase-MB, peak troponin T and I, and elevated B-type natriuretic peptide, provide prognostic information [5, 6] . Total, and lowand high-density-lipoprotein cholesterol, and newer biomarkers, such as lipoprotein-associated phospholipase A 2 , high-sensitivity C-reactive protein, DNA polymorphism, fibrinogen, fibrinogen degradation products and heat shock protein (HSP70), provide prognostic information for subsequent death and myocardial infarction in patients with established CAD [7–16] . Higher values of these biomarkers (with the exception of HDL where lowReceived: August 27, 2013 Accepted: August 27, 2013 Published online: October 31, 2013

Is risk factor control and guideline-based medical therapy optimal in patients with nonobstructive coronary artery disease? A Veterans Affairs study.

Background:Aggressive risk factor modification using evidence-based secondary prevention strategies is recommended in coronary artery disease (CAD). Utilization of such strategies was compared in patients with nonobstructive CAD (NOCAD) and obstructive CAD (OCAD). Methods:Patients undergoing coronary angiography (excluding normal coronary angiograms), between January 2006 and June 2006, at the Veterans Affairs Medical Center were included. Demographic, clinical and treatment data were compared between the groups at baseline and 1 year. Results:Of the 354 patients who underwent coronary angiography, 222 (63%) had follow-up data available at 12 ± 2 months. The mean age in the NOCAD (n = 119) and OCAD (n = 103) groups was similar. There was a lower prevalence of hypertension and heart failure (P < 0.05) in the NOCAD group. Compared with the OCAD group, aspirin use was similar but statin use was lower in the NOCAD group (P = 0.008). At 1 year, statin use (P = 0001) and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use (P = 0.001) were significantly lower, whereas the use of aspirin was numerically lower (P = 0.06) in the NOCAD group. Mean low-density lipoprotein cholesterol levels were at goal (<100 mg/dL) in the NOCAD group at baseline and 1 year, whereas the same slightly worsened in the OCAD group at 1 year. Conclusions:The use of evidence-based medical therapy is lower in patients with NOCAD compared with those with OCAD. Improved awareness among health care providers and a unified effort to implement secondary prevention strategies may help correct such deficiencies.