Nitrate Therapy Research Articles

Mibefradil, a T-Type Channel-Selective Calcium Antagonist: Clinical Trials in Chronic Stable Angina Pectoris

Pharmacotherapy with nitrates, β-blockers, and calcium antagonists is the cornerstone of management of patients with chronic stable angina pectoris. While these agents are all effective, their use may be limited by pharmacologic tolerance, side effects, and drug interactions. Mibefradil is a recently developed calcium antagonist with a unique chemical structure, pharmacologic profile, and mode of action. Unlike all previously available calcium antagonists, mibefradil acts primarily by selective blockade of T-type calcium channels, rather than L-type channels, at clinically relevant concentrations. It has been evaluated as a treatment for angina in placebo-controlled and active-controlled clinical trials. Treatment with 50 mg mibefradil resulted in a significant improvement in exercise tolerance test duration in three of the five placebo-controlled trials, and a significant improvement in time to onset of angina in two of the five trials. Time to onset of ischemia as evaluated by 0.1 mV ST-segment depression was increased in all five placebo-controlled trials. Treatment with 100 mg mibefradil resulted in significant improvement in all three exercise tolerance test parameters in all studies. Mibefradil further improved exercise tolerance test duration and other efficacy parameters when administered concomitantly to patients on background β-blocker or nitrate therapy. In addition, treatment with mibefradil was associated with a dose-dependent decrease in heart rate, double product, frequency of anginal attacks, nitroglycerin consumption, and both frequency and duration of silent ischemic episodes. In comparative trials, 100 mg mibefradil once daily was superior in efficacy to 10 mg amlodipine once daily and was at least equivalent to diltiazem in both efficacy and tolerability. Mibefradil was safe and well tolerated in all studies.

NO problem for nitroglycerin: organic nitrate chemistry and therapy

Nitroglycerin (GTN) has been used clinically in the treatment of angina for over a century and is representative of the organic nitrates vasodilators. These are effective therapeutic agents that allow facile sublingual or transdermal administration. The vasodilatory mechanism involves activation of guanylate cyclase and is widely believed to involve biotransformation by chemical reaction of a nitrate with sulfhydryl or ferrous groups to yield nitric oxide. However, the chemistry of organic nitrates is poorly studied, provides scant support for these postulated reactions and provides a challenge for the chemist.

Choosing the most appropriate treatment for stable angina. Safety considerations.

The goals of stable angina pectoris treatment are: (i) symptom relief and increase in angina-free walking time; and (ii) reduction of mortality and adverse outcome. Strategies used for plaque stabilisation resulting in a reduction in cardiovascular mortality and morbidity are: smoking cessation; aspirin (acetylsalicylic acid); blood pressure control; lipid lowering agents when low density lipoprotein cholesterol is elevated despite dietary therapy; coronary bypass surgery in patients with left main stem disease or triple vessel coronary disease and diminished left ventricular function; and use of estrogen in postmenopausal women. For symptom relief and to increase angina-free walking time, long acting nitrates, beta-blockers, calcium antagonists and potassium channel openers can be used. Drugs from these 3 classes are all effective when used optimally and choice of initial therapy should consider the presence of concomitant disease and underlying left ventricular function. However, none of the long acting nitrates provide continuous prophylaxis because nitrate tolerance develops during long term therapy. In patients with uncomplicated stable angina, nitrates, beta-blockers and calcium antagonists are all effective. Intermittent nitrate therapy is not associated with tolerance, but headache is a common adverse effect and the patient is unprotected at night and in the early hours of the morning. Concomitant treatment with a beta-blocker may be beneficial if the patient experiences withdrawal or early morning angina. For patients with stable angina and hypertension, therapy with a beta-blocker or a calcium antagonist rather than nitrate is indicated. beta-Blockers are preferred in patients who have had a myocardial infarction, or in those with a history of supraventricular tachyarrhythmias. beta-Blockers may produce excessive slowing of the heart rate, fatigue and bronchospasm in susceptible patients. Calcium antagonists are indicated as initial therapy when beta-blockers are either not tolerated or contraindicated. beta-Blockers and nondihydropyridine calcium antagonists should not be used in patients with sinus bradycardia and those with greater than first degree atrioventricular (AV) block because of the possibility of further slowing of heart rate and/or the development of high grade AV block. When monotherapy with one class is ineffective or associated with adverse effects, the patient should be switched to another class rather than given an additional drug. Optimal monotherapy is often as effective as combination therapy. If maximum monotherapy is only partially effective, a combination therapy which is not additive in terms of adverse effects should be chosen. Triple therapy may be deleterious and no more effective than dual therapy.

Unexpected, Tolerance-Devoid Vasomotor and Platelet Actions of Pentaerythrityl Tetranitrate

Efficacy of nitrate therapy is limited by tolerance. A surprising upregulation of ex vivo platelet activity, a decrease in platelet thiol levels, and an enhanced release of vasoconstrictors from platelets is associated with enhanced superoxide-mediated oxidant stress leading to vascular tolerance to nitrates. We tested the NO-donor pentaerythrityl tetranitrate (PETN), which to date had not been precisely tested either with regard to the induction of tolerance or to a potential development of changes in platelet activity in comparison with glycerol trinitrate (GTN). Long-term instrumented dogs nonintermittently received: 1.5 microg/kg/min GTN, i.v., with or without vitamin C (55 microg/kg/min, i.v.) or PETN 4 x 60 mg/day orally for 5 days. Tested daily were (a) the dilation of the epicardial arteries, (b) thrombin-induced (0.5 U/ml) increases of the intracellular Ca2+ concentration and aggregability of platelets, (c) concentrations of reduced low-molecular-weight thiols (LMTs) in plasma and platelets, and (d) formation of reactive oxygen species (ROSs). During nonintermittent PETN and during GTN with additional vitamin C, a 9.8 +/- 0.4% coronary artery dilation was observed in contrast to that with GTN alone, which resulted in complete tolerance at day 4. This vascular tolerance was associated with enhanced platelet activity and formation of ROSs (incubated platelets) and a 38 +/- 3% reduction in LMT. These unfavorable changes were absent in the presence of PETN or with additional vitamin C as an antioxidant. Vascular tolerance associated with platelet upregulation is avoided either by nonintermittent nitroglycerin (5 days) when vitamin C is coadministered or by pentaerythrityl tetranitrate without the coadministration of vitamin C.

Effects of enalapril during continuous nitrate therapy: Analysis of diameter of coronary arteries and platelet cyclic guanosine monophosphate

To investigate the effects of enalapril, an angiotensin-converting enzyme inhibitor, on nitrate tolerance during continuous nitrate therapy, coronary artery diameters and platelet cyclic guanosine monophosphate (cGMP) levels were measured before and 2 minutes after intracoronary injection of nitroglycerin 200 μg in 60 patients with coronary artery disease and were compared among 20 patients treated with nitrates (nitrate group), 20 patients treated with both nitrates and enalapril (enalapril group), and 20 untreated patients (control group). The percent increase in platelet cGMP and coronary dilatation in the nitrate group was significantly less than in the control group, but the percent increase in the enalapril group was significantly greater than that in the nitrate group. These results indicate that enalapril may be helpful as concomitant therapy to maintain the effect of nitrates during continuous nitrate therapy. (Am Heart J 1997;134:614-21.)

Adjunctive therapy for acute myocardial infarction

Based on results from a multitude of clinical trials of acute myocardial infarction, the beneficial role of a variety of pharmacologic agents, used in conjunction with thrombolytic therapy, has emerged. This is particularly true for aspirin, beta-blockers, heparin, and angiotensin-converting enzyme inhibitors. In addition, the dosage and timing of their administration have been shown to be crucial to their efficacy. The scientific and pathophysiologic basis as well as practical recommendations regarding their use are discussed. The exact role of nitrate therapy and potential for magnesium are presented in addition to data on agents that might be detrimental in the early stages of acute myocardial infarction.

Reverse remodeling in heart failure with intensification of vasodilator therapy.

Heart failure therapy with beta-receptor blockade has been shown to effect a partial reversal of left ventricular (LV) remodeling in heart failure. We tested the hypothesis that, in the absence of beta blockade, uptitration of angiotensin-converting enzyme (ACE) inhibitor and nitrate therapy over conventional dosages would improve symptoms as well as LV function in patients with severe heart failure. For patients with nonischemic or ischemic cardiomyopathy, intensive high-dose angiotensin-converting enzyme inhibitor and nitrate therapy was uptitrated. Echocardiograms were obtained semiannually and evaluated in a blinded fashion. Of 99 patients in the study, aged 55 +/- 13 years, with heart failure for 5.2 +/- 3.1 years, 74 were men, 69 were Caucasian, and 34 had ischemic cardiomyopathy. The final dosage of enalapril was 40 +/- 23 mg/day of isosorbide dinitrate it was 153 +/- 127 mg/day. Initial New York Heart Association classification improved from 2.8 +/- 0.9 to 1.7 +/- 0.9 (p < 0.001) in 2.7 years of follow-up. Of the 99 patients, 72 further improved their ejection fraction. For the whole group, ejection fraction increased from 21 +/- 9% to 30 +/- 13% in 6 months (p < 0.001), with a reduction in LV end-diastolic size from 6.6 +/- 0.9 to 6.3 +/- 1.0 cm (p = 0.002), a decrease in the severity of mitral regurgitation from mild/moderate to only mild. Resting heart rate declined with no change over time in systemic systolic blood pressure. Final ejection fraction for nonischemic patients (n = 65) was 36 +/- 16% versus 23 +/- 9% for the ischemic population. Uptitration of high-dose ACE inhibitor and nitrate therapy to higher doses is well tolerated in severe heart failure, further improves both clinical status and LV systolic function, and is more effective in nonischemic than in ischemic cardiomyopathy.

Antianginal and Anti-ischemic Effects of Mibefradil in the Treatment of Patients with Chronic Stable Angina Pectoris

Five placebo-controlled, double-blind, multicenter, parallel-design studies were performed to evaluate the antianginal and anti-ischemic characteristics of the novel T-channel-selective calcium antagonist, mibefradil, in the treatment of patients with chronic stable angina pectoris. Of the 5 studies, 2 were monotherapy dose-finding trials and 3 were conducted in patients receiving background antianginal therapy: either β blockers (2 studies) or long-acting nitrates (1 study). A total of 865 patients were randomized to 1 of 4 mibefradil dose groups (25, 50, 100, and 150 mg; n = 565) and placebo (n = 300). The antianginal and anti-ischemic effects of mibefradil were assessed across all 5 studies by evaluating exercise tolerance test variables, weekly number of anginal attacks and short-acting nitroglycerin consumption, and in both dose-finding studies, the number and total duration of silent ischemic episodes (48-hour Holter monitoring). A statistically significant increase in exercise duration was achieved in 3 of 5 studies with the 50-mg dose of mibefradil and in 3 of 3 studies with the 100-mg dose of the compound over the effects observed in the placebo groups. A significant delay in time to onset of ischemia during exercise was induced in all studies with the 50- and 100-mg doses of mibefradil. The 25-mg dose of mibefradil was not significantly better than placebo, and the effects of the 150-mg dose of the compound were similar to those observed with the 100-mg dose. Across all studies, a dose-related decrease was observed in the number of weekly anginal attacks and in weekly nitroglycerin consumption. Similarly, a significant dose-related decrease in the number and duration of silent ischemic episodes was observed during Holter monitoring for 48 hours in the 2 dose-finding studies. The antianginal and anti-ischemic effects were associated with a dose-related decrease in heart rate and double product both at rest and at exercise termination. Treatment with the 50- and 100-mg doses of mibefradil was found to be well tolerated and safe compared with placebo, a finding that held true for patients on chronic β-blocker or long-acting nitrate therapy. Taken together, these studies indicate that mibefradil is an effective and well-tolerated once-daily treatment for chronic stable angina pectoris at doses of 50 and 100 mg, which are the lowest and highest effective doses of the compound, respectively.

Effect of Chronic Nitrate Treatment on Retinal Vessel Caliber in Open-angle Glaucoma

A recent report has suggested that nitrate therapy may delay the progression of glaucomatous damage. To investigate the mechanism that may mediate this effect, we sought to determine whether nitrate therapy is associated with retinal vasodilatation in patients with glaucoma. Retinal venous and arterial diameters were determined from color fundus photographs of the optic nerve head obtained during a retrospective study designed to investigate any potential effects of chronic nitrate treatment on the progression of glaucomatous pathology. Fourteen eyes of 14 patients who were receiving chronic nitrate therapy for systemic diseases unrelated to glaucoma were randomly selected. Vascular measurements were compared with those of 15 eyes of 15 control patients with glaucoma who did not receive any nitrate therapy. In comparison with control patients, nitrate-treated patients showed significant average vasodilatation of 17% (P = .008) and 13% (P = .01) in the superior and inferior temporal retinal veins, respectively. A 5% increase in average retinal arterial diameter was also detected, but this was not statistically significant. Chronic nitrate treatment is associated with retinal venous dilatation in patients with glaucoma. Although not assessed in this study, it is possible that a protective effect of nitrates may be mediated by a vasoactive effect leading to improved perfusion of the retina and perhaps the optic nerve head, in a similar fashion to what has been observed in the circulation of the heart. Additional studies of the effect of nitrates on the ocular circulation are needed, however, to support this speculation.

Nisoldipine Coat-Core

Nisoldipine coat-core is an extended-release once-daily formulation of a dihydropyridine calcium antagonist effective in the treatment of chronic stable angina pectoris. With immediate-release formulations of nisoldipine, plasma drug concentrations that produce therapeutic effects result rapidly, but are not sustained and do not maintain the effects throughout a 12-hour dosage interval. In contrast, with nisoldipine coat-core, a gradual increase in plasma nisoldipine concentrations occurs over 12 hours and therapeutic concentrations are then maintained for the duration of a 24-hour dosage interval. In dosages of 10 to 60 mg once daily, nisoldipine coat-core controls symptoms of angina and improves exercise-induced signs of ischaemia in patients with stable angina. Compared with placebo, daily nisoldipine coat-core doses of > or = 20 mg provide statistically significant increases in total exercise time and time to produce angina and a trend towards an increase in the time to produce 1 mm ST segment depression, in exercise tests conducted approximately 23 hours postdose. When administered in 20 and 40 mg daily doses, nisoldipine coat-core produces improvements in exercise test parameters that are similar to those seen with amlodipine 5 or 10 mg/day or regular-release or sustained-release (SR) diltiazem 240 mg/day. The frequency of daily angina attacks and consumption of short-acting nitrates are also reduced by nisoldipine to a similar extent to that observed with these other agents. After longer term (1 year) administration of 10 to 60 mg daily, improvements in exercise test parameters are maintained, with equivalent anti-ischaemic efficacy seen in patients receiving nisoldipine coat-core alone or with background nitrate or beta-blocker therapy. Adverse events associated with nisoldipine coat-core are typical of the dihydropyridine class of calcium antagonists, with peripheral oedema and headache being most common. Nisoldipine coat-core appears to be associated with fewer deaths than placebo, notably in the DEFIANT-II (Doppler Flow and Echocardiography in Functional Cardiac Insufficiency: Assessment of Nisoldipine Therapy II) study, where only 1 death occurred with nisoldipine compared with 7 in the placebo group. Nisoldipine should not be taken during phenytoin therapy. In addition, grapefruit juice should be avoided during nisoldipine therapy and nisoldipine should not be taken concurrently with high-fat meals. Thus, the coat-core formulation of nisoldipine appears to have overcome the limitations of the shorter duration of action of immediate-release nisoldipine. Nisoldipine coat-core is well tolerated and once-daily administration produces a long duration of effective anti-ischaemic relief in patients with chronic stable angina pectoris.

82. Comparison of multiple-dose and once-daily nitrate therapy in patients with stable angina pectoris: effects on quality of life indices

82. Comparison of multiple-dose and once-daily nitrate therapy in patients with stable angina pectoris: effects on quality of life indices

Sleep-Related Myocardial Ischemia and Sleep Structure in Patients With Obstructive Sleep Apnea and Coronary Heart Disease

Patients with coronary heart disease (CHD) and obstructive sleep apnea may have an increased cardiac risk due to nocturnal myocardial ischemia triggered by apnea-associated oxygen desaturation. Sleep structure in patients with obstructive sleep apnea is fragmented by activation of the central nervous system (CNS) (arousal) due to obstructive apneas. Nocturnal myocardial ischemia may lead to activation of the CNS as well. Fourteen patients with obstructive sleep apnea and CHD disease and seven patients suffering from obstructive sleep apnea without CHD were studied. Overnight sleep studies and simultaneous six-lead ECG recordings were performed. In addition, sleep studies and ECG recordings were performed with administration of a sustained-release nitrate in these patients in a double-blinded crossover design. Analysis of three nights' recordings revealed 144 episodes of nocturnal myocardial ischemia in six subjects. Five patients had underlying CHD and one patient exhibited diffuse wall defects of the coronary arteries; also, 85.4% of ischemic episodes were concomitant with apneas and oxygen desaturation > 3%, and 77.8% of ischemic episodes occurred during rapid eye movement (REM) sleep, although total amount of REM sleep was only 18% of total sleep time. Mean oxygen saturation was significantly lower (p < 0.05) during apnea-associated ischemic episodes than during nonapnea-associated ischemia (77.3% vs 93.1%). Nitrate administration did not reduce ischemic episodes. Sleep architecture (macrostructure) exhibited a reduction in sleep stages non-REM 3 and 4 and REM sleep. Comparing the microstructure of sleep (arousals) within episodes with and without ischemia but similar criteria like sleep stage, apnea activity, and oxygen saturation, we found significantly more (p < 0.01) and severe (p < 0.001) arousals during periods with myocardial ischemia than during control episodes. In addition, microstructure of sleep was disturbed by myocardial ischemia itself in absence of apneas. It is concluded that patients with CHD and obstructive sleep apnea are endangered by apnea-associated ischemia and that these ischemic episodes lead to activation of the CNS and additional fragmentation of sleep. Patients with nocturnal ischemia should be screened for underlying sleep apnea even if nitrate therapy fails.

Nitrate tolerance, rebound, and their clinical relevance in stable angina pectoris, unstable angina, and heart failure

Vascular tolerance develops rapidly in isolated vascular strips exposed to millimolar concentrations of nitroglycerin. Several mechanisms, including depletion of sulfhydryl groups, reduced biotransformation of nitrates to NO or nitrosothiols, oxygen free radical injury, and downregulation of a membrane-bound enzyme or a nitrate receptor, have been proposed, but the exact mechanism responsible for in-vitro tolerance remains unknown. In-vivo tolerance of the beneficial effects of nitrates on hemodynamics, myocardial ischemia, and exercise performance develops rapidly. It has been suggested, but remains to be proven, that development of venous tolerance and not arterial tolerance is responsible for the attenuation of nitrate effects during long-term nitrate therapy. Several mechanisms, including neurohormonal activation, depletion of sulfhdryl groups, and the shift of fluid from the extravascular to intravascular compartment have been implicated. However, the use of agents to counteract these mechanisms (ACE inhibitors, sulfhydryl donors, diuretics) has produced conflicting results. Thus, at present the mechanism responsible for in vivo tolerance to nitrates remains unknown. Both in vitro and in vivo vascular tolerance to nitrates can be prevented or minimized by providing nitrate-free or low-nitrate intervals. However, during nitrate-free periods, rebound phenomena (rest angina in patients with ischemic heart disease or a deterioration in exercise performance prior to the renewal of the morning dose in patients with stable angina) remain a clinical concern. When treating patients with stable angina pectoris, it must be recognized that none of the nitrate preparations or formulations can provide round-the-clock antianginal or antiischemic prophylaxis. In these patients, beneficial antianginal and antiischemic effects of nitrates for 10-14 hours during the daytime can be maintained by using formulations and dosing regimens that avoid or minimize the development of tolerance (standard formulation of isosorbide-5-mononitrate, 20 mg in the morning and 7 hours later; slow-release formulation of isosorbide-5-mononitrate, 120-240 mg once a day; or nitroglycerin patch delivering 0.6 nitroglycerin per hour for 10-12 hours each day). Only the patch on and off treatment is associated with nitrate rebound. Although intermittent nitrate therapy is not associated with the development of tolerance, this strategy cannot be recommended for treating unstable angina because rebound angina during nitrate-free periods complicates clinical decision making. In the acute phase of unstable angina, continuous treatment with intravenous nitroglycerin is recommended because it permits rapid up- or down-titration. Tolerance towards antianginal and antiischemic effects does develop in a substantial number of patients with 24 hours, but this can be overridden by dose escalation and restoration of the therapeutic effectiveness of nitroglycerin. Tolerance towards the beneficial effects of nitrates on hemodynamics and on exercise performance also develops rapidly during continuous or long-term nitrate therapy, and for these reasons nitrates are not used as first-line therapy to treat chronic heart failure. In combination with hydralazine, high-dose isosorbide dinitrate (30-40 mg four times a day) improves survival, but this combination therapy is inferior to ACE inhibitors.

Comparison of multiple-dose and once-daily nitrate therapy in patients with stable angina pectoris: effects on quality-of-life indices

In a 6-month self-controlled study, the effects of multiple-dose and once-daily nitrate therapy on anginal symptoms and quality of life were evaluated in 1212 patients with stable angina pectoris. Quality of life was assessed by a test battery based on the exercise tolerance index of Wiklund, the psychological well-being index of Dupuy, and the Short-Form 36 questionnaire of Stewart. The internal consistency and reliability of the multi-item scales were estimated by Cronbach's alpha coefficients. The effects of the two treatment regimens on pain index and number of additional sublingual nitrate tablets required were similar. However, based on New York Heart Association (NYHA) angina classification, patients showed a statistically significant better improvement with the once-daily than with the multiple-dose regimen: between the first and second evaluation 281 patients improved by one category and 62 patients worsened by one category. Mobility and psychological distress indices also indicated statistically significant higher scores for the once-daily treatment regimen. It can be concluded from this study that once-daily nitrate not only provides a better NYHA angina classification than multiple-dose therapy but also provides a better quality of life as estimated by improvement of mobility and distress indices. Patient compliance, estimated by using the number of patients who reported forgetting to take medication, was greatly improved (from 16% to 21% improvement).

New Aspects of Nitrate Therapy in Ischaemic Heart Disease

New Aspects of Nitrate Therapy in Ischaemic Heart Disease

Baroreflex resetting but no vascular tolerance in response to transdermal glyceryl trinitrate in conscious rabbits.

1. We investigated whether acute (5 h) and chronic (3 days) transdermal glyceryl trinitrate (GTN) patches could cause the development of tolerance in terms of haemodynamics and vascular reactivity in the conscious rabbit. The effects of haemodynamic tolerance were assessed on arterial pressure, heart rate and the baroreflex control of heart rate, while hindquarter vascular reactivity in response to dilator and constrictor drugs and reactive hyperaemia were used to assess vascular tolerance. 2. Seven days prior to experiments, an inflatable cuff, a pulsed Doppler flow probe and an indwelling intra-aortic catheter (for i.a. agonist infusions) were implanted around the lower abdominal aorta. 3. In acute experiments, the effects of 0-5 h treatment with transdermal GTN (0 Sham), 10 or 20 mg 24 h-1) on MAP, HR and the baroreflex were examined. Chronic experiments were performed on three separated days (days 0 - before, 4 - with GTN patch and 8 - recovery). On each day, the baroreflex, reactive hyperaemic responses and hindquarter vascular dose-response curves to i.a. GTN, adenosine, acetylcholine, S-nitroso-N-acetylpenicillamine (SNAP) and methoxamine were assessed. On days 1-4, GTN was administered transdermally via a patch(es) (10 mg 24 h-1 (low dose) or 20 mg 24 h-1 (high dose); renewed every 24 h). 4. Acute treatment with 20 mg GTN 24 h-1, but not with 0 (n = 4) or 10 mg GTN 24 h-1 (n = 4), caused a significant fall in MAP (8 +/- 1 mmHg; n = 4) and resetting of the baroreflex by 5 h. Chronic GTN caused a significant fall in MAP of 8 +/- 2 and 8 +/- 2 mmHg on day 4 with low (n = 8) and high dose (n = 8), respectively, with no change in HR. There was no significant change to hindquarter vascular reactivity to i.a. infusion of GTN, nor were there any significant differences in the reactivity to i.a. adenosine, acetylcholine, SNAP or methoxamine with either low or high doses of GTN. 5. Chronic GTN treatment with low and high dose patches caused a parallel leftward shift ('resetting') of the baroreflex on day 4. By day 8, the baroreflex had still not recovered from this leftward shift 6. In the rabbit, chronic exposure to clinical nitrate patches caused haemodynamic compensation and baroreflex resetting but no evidence of vascular reactivity tolerance. Novel NO donor drugs and delivery regimens which provide intermittent dosing may prevent the development of haemodynamic resetting rather then preventing vascular tolerance, a commonly perceived difficulty in chronic nitrate therapy.

Effects of enalapril during continuous nitrate therapy — analysis of diameter of coronary arteries, platelet cGMP and neurohormonal factors

Effects of enalapril during continuous nitrate therapy — analysis of diameter of coronary arteries, platelet cGMP and neurohormonal factors

Resolution of rate-related left bundle branch block after nitrate therapy

Resolution of rate-related left bundle branch block after nitrate therapy

Discordance between Meta-analyses and Large-Scale Randomized, Controlled Trials: Examples from the Management of Acute Myocardial Infarction

Clinicians making treatment decisions are faced with ever-growing numbers of therapies, each supported by different types of clinical data. By bringing together large amounts of data, meta-analysis has emerged as a useful tool for generating hypotheses with which to plan definitive trials, and it has also been recommended as a basis for decision making in the absence of definitive trials. In several instances, early meta-analyses have provided evidence of efficacy that was subsequently confirmed. However, in other instances, the results of initial meta-analyses have disagreed with the results of subsequent large-scale trials. Nitrate and magnesium therapy for acute myocardial infarction are two contemporary examples of treatments about which hypothesis-generating meta-analyses and subsequent large trials have disagreed. We review the issues surrounding the interpretation of meta-analyses in these cases, and we suggest that the appropriate use of meta-analyses in clinical decision making be carefully placed in the context of a review of pathophysiologic principles and the results of basic laboratory research and individual trials.

Prognostic value of dobutamine stress echocardiography in patients referred because of suspected coronary artery disease

To determine whether dobutamine stress echocardiography (DSE) provides prognostic information beyond that available from routine clinical data, we reviewed the outcome of 210 consecutive patients referred for DSE to evaluate chest pain, perioperative risk, and myocardial viability. Dobutamine was infused in increments of 10 μg/kg/min in 5-minute stages to a maximum of 40 μg/kg/min. The dobutamine stress echocardiogram was considered abnormal only if dobutamine induced a new wall motion abnormality as determined by review of the digitized echocardiographic images in a quad screen format and on videotape. Thirty percent of tests were abnormal. An abnormal test was more common (p ≤ 0.02) in men and patients with angina pectoris, in patients taking nitrate therapy, or those with prior myocardial infarction or abnormal left ventricular wall motion at rest. Twenty-two deaths, 17 of which were cardiac, occurred over a median follow-up of 240 days (range 30 to 760). Sixteen cardiac deaths occurred in the 63 patients with versus 1 cardiac death among the 147 without a new wall motion abnormality (p ≤ 0.0001). Other variables associated with cardiac death (p ≤ 0.05) were age >65 years, nitrate therapy, ventricular ectopy during DSE, suspected angina pectoris, and hospitalization at the time of DSE. When cardiac death, myocardial infarction, and revascularization procedures were all considered as adverse outcomes, a new wall motion abnormality continued to be the most powerful predictor of an adverse cardiac event. We conclude that DSE provides greater prognostic information than that available from clinical data in a population known or suspected to have coronary artery disease and unable to exercise.