Oral Nitrates Research Articles

Prolonged heparin after uncomplicated coronary interventions: a prospective randomized trial

Acute ischemic cardiac complications remain a problem in percutaneous transluminal coronary angioplasty (PTCA). The majority of PTCA-related cardiac complications are caused by abrupt vessel closure, which in the majority of cases occurs immediately after the procedure.1,2 Intraprocedural antiplatelet therapy and anticoagulant therapy have been shown to reduce significantly the incidence of ischemic complications occurring during the intervention,3-6 yet it is unclear whether prolonged postprocedural heparin therapy can prevent abrupt vessel closure. Some authors suggest discontinuation of heparin after PTCA,7 whereas in many centers heparin is routinely administered for 12 to 24 hours after the intervention. Prolonged heparin administration increases peripheral vessel complications and prolongs the hospital stay.8 The aim of this study was to evaluate whether discontinuation of heparin after an uncomplicated PTCA increased in-hospital ischemic cardiac complications. Methods Patients with a successful PTCA who had no noncoronary indication for prolonged heparin administration and gave informed consent were randomly assigned into 2 groups. Patients in the first group (heparin group) received continuous heparin infusion of 1000 units/h for 12 to 20 hours. The arterial sheath was removed a few hours after the discontinuation of heparin. The patients were usually discharged the second day after the procedure. In the second group (control group), no heparin was given after the intervention, the sheath was removed 3 to 4 hours after the procedure, and the patients were generally discharged the following day. PTCA procedures were performed by the femoral route according to techniques previously described by using 5F, 6F, or 7F guiding systems. Intraprocedural treatment consisted of oral or intracoronary nitrates, a bolus of 5000 to 20,000 units of heparin, and 250 mg acetylsalicylic acid intravenously for patients who were not already receiving aspirin therapy. Nonionic contrast medium was used in all cases. Sheath removal in both groups was performed with manual or mechanical compression followed by 6 hours of pressure dressing and bed rest. An electrocardiogram (ECG) and creatine kinase (CK) levels were obtained the day after PTCA and in case of prolonged chest pain. In cases of acute prolonged chest pain or new ECG modifications suspicious of abrupt vessel closure, repeat angiography was considered. Primary end points were the occurrence of myocardial From the Department of Cardiology, University Hospital. Submitted Feb. 26, 1997; accepted Feb. 17, 1998. Reprint requests: Bernhard Meier, MD, University Hospital, 3010 Bern, Switzerland. Copyright © 1998 by Mosby, Inc. 0002-8703/98/$5.00 + 0 4/1/90240 Prolonged heparin after uncomplicated coronary interventions: A prospective, randomized trial

Current Treatment and Future Prospects for the Management of Acute Coronary Syndromes

Management of acute coronary syndromes, particularly unstable angina, acute myocardial infarction and non-Q-wave myocardial infarction, is one of the most common and costly problems facing modern medicine. Furthermore, the increasing availability of new research and clinical information relevant to the treatment of these conditions means that continuing reappraisal of management strategies is necessary. Accordingly, the Ushuaia conference, Tierra Del Fuego, Argentina, was convened to discuss current approaches and future treatment prospects for patients with these conditions. The conference was comprised of leading Argentinian cardiologists whose primary aim was to formulate consensus recommendations regarding the management of patients with acute coronary syndromes. The first of the major recommendations for the pharmacological management of acute coronary syndromes arising from the Ushuaia Consensus Conference was that aspirin (200 to 500mg initially, then 100 to 325 mg/day) should be administered to all patients except those for whom aspirin is absolutely (or relatively, depending on the clinician's discretion) contraindicated. In such cases, ticlopidine is a suitable alternative. Intravenous nitrates are indicated for patients with angina pain (24 to 48 hours' duration), ECG changes, recurrence of angina, or signs of heart failure; in other cases, oral, transdermal or sublingual nitrates may be administered. Use of beta-blockers is recommended except when absolutely contraindicated or when there is a strong suspicion of vasospasm as a dominant mechanism in angina. Intravenous administration of these agents is preferred in patients with tachycardia, arterial hypertension or angina. Calcium antagonists are generally not recommended as first choice therapy, but can be indicated (preferably using agents that decrease heart rate) when beta-blockers are contraindicated or when there is a strong suspicion of vasospasm as a dominant mechanism in angina. Calcium antagonists are also useful in combination with other drugs in patients with high blood pressure or treatment-refractory recurrent angina. Subcutaneous low molecular weight heparins and intravenous unfractionated heparin provide similar results and are indicated in a number of clinical situations. Emergency videocoronary angiography (VCA) is indicated in patients with persistent clinical and haemodynamic instability, recurrent ischaemia with heart failure, and refractory angina. Patients should also be referred for VCA if they have signs of left ventricular dysfunction, post-acute myocardial infarction angina with ECG changes, or ischaemia during functional studies. Post-VCA treatment will be determined by anatomical findings during VCA. Future prospects in the management of acute coronary syndromes include the development of more accurate prognostic markers and means of stratifying risk, such as sophisticated ECG criteria, serum markers of necrosis (e.g. troponin T and I), markers of thrombosis (e.g. D-dimer and fibrinopeptide A levels), markers of inflammation (e.g. reactive protein C, cell adhesion receptor expression, neopterine), and markers of 'good' prognosis (e.g. interleukin-10). Other pharmacological approaches under investigation include platelet IIb/IIIa receptor antagonists, clopidogrel and hirudin. Novel agents, such as anti-Xa, pentasaccharide, anti-tissue factor compounds, Ib receptor-blocking agents, agents that influence vascular endothelium and control cellular acidosis (e.g. HOE 642), macrolide antibiotics, HLA-DR system blockers and fusion compounds, are also in various stages of investigation or development.

Oral nitrates: more than symptomatic therapy in coronary artery disease?

The predominant venodilator properties of the nitrates and their augmentation of collateral coronary blood flow to the ischemic myocardium endows them with some ideal characteristics for treating myocardial ischemic syndromes. Additional efficacy stems from the ability of the nitrates to replenish the deficient endothelium-derived relaxing factor (EDRF), nitric oxide (NO), in patients with coronary heart disease and also to inhibit platelet aggregation. In stable angina pectoris, the antianginal and antiischemic effects of oral nitrates are well established. Continuous administration of nitrates may lead to tolerance of their clinical efficacy. Recent studies, however, have demonstrated that when used in recommended doses, tolerance can be avoided during long-term treatment with oral nitrates without provocation of anginal attacks during periods of low nitrate levels at night and early hours of the morning. Thus, prolonged treatment with an asymmetric twice-daily regimen of immediate-release isosorbide-5-mononitrate in patients with stable angina pectoris does not give rise to clinical tolerance, prolongs exercise duration, and delays the onset of myocardial ischemia. In unstable angina pectoris, nitrates rapidly relieve chest pain and ameliorate the electrocardiographic signs of myocardial ischemia. In patients with acute myocardial infarction, early treatment with nitrates prevents left ventricular dilatation, improves pumping function, and reduces the risk of ventricular arrhythmias. In patients with chronic heart failure, oral nitrates improve exercise tolerance and, when given in combination with the systemic arterial dilator hydralazine, extend survival. Meta-analysis of published studies has demonstrated that both intravenous and oral nitrates reduced infarct size and morbidity and mortality in patients with acute myocardial infarction. In the ISIS 4 post-infarction study, isosorbide-5-mononitrate 60 mg once daily was not superior to placebo in reducing mortality risk. However, in the GISSI 3 study, the combination of nitrates with an angiotensin-converting enzyme (ACE) inhibitor reduced mortality risks by 17% in patients with acute myocardial infarction. In both the ISIS 4 and GISSI 3 studies, 62% and 57% of the patients in the placebo and control groups, respectively, were treated with nitrates for control of rest angina, myocardial ischemia, and or left ventricular failure symptoms, and this widespread use of open-label nitrates in the control groups may have diluted the true beneficial effects of nitrates in both studies. Taken together, these many studies with oral nitrate treatment in coronary heart disease and heart failure clearly emphasize that these drugs are safe and play more than a symptomatic role in the management of patients with acute and chronic ischemic syndromes due to coronary artery disease.

Secondary preventive potential of nitrates in ischaemic heart disease.

Nitrates exert their anti-anginal activity by a number of mechanisms. By reducing venous return and left ventricular end-diastolic pressure they lower myocardial oxygen demand and at the same time enhance blood flow to the sub-endocardium. They also directly increase myocardial oxygen supply by dilating the coronary artery stenoses and increasing collateral blood flow. These pharmacodynamic attributes are clinically efficacious in all the ischaemic myocardial syndromes. In stable angina pectoris, nitrates reduce myocardial ischaemia and ischaemic pain and increase exercise tolerance. In unstable angina, nitrates similarly reduce electrocardiographic evidence of myocardial ischaemia and relieve anginal pain. Following acute myocardial infarction, nitrates reduce ventricular dilatation and by so doing reduce pulmonary congestion and mitral regurgitation. The weak anti-aggregatory effect of nitrates on platelets may also play an adjuvant role in their anti-ischaemic activity. Early small-scale studies with both intravenous and oral nitrates demonstrated a trend to reduced mortality and reinfarction in survivors of acute myocardial infarction. However, the later and larger ISIS-4 and GISSI-3 trials have not confirmed this trend possibly due to the smaller doses of nitrates used and the diluting effect of the widespread use of open-label nitrates in the placebo group. In patients with congestive heart failure, including those of ischaemic aetiology, nitrates together with hydralazine have clearly demonstrated a significant reduction in the medium term mortality risk. Nitrates have the undoubted ability, probably greater than any other single anti-anginal drug, to rapidly and often completely relieve the pain and breathlessness associated with myocardial ischaemia. They are haemodynamically efficacious in reducing dilatation of the ischaemic left ventricle and enhancing coronary blood flow to ischaemic areas. Although their preventative impact in survivors of acute myocardial infarction awaits clarification, they have been shown in combination with hydralazine to extend survival in patients with congestive heart failure, including those of ischaemic origin.

Prevention of tolerance to hemodynamic effects of nitrates with concomitant use of hydralazine in patients with chronic heart failure

This study was designed to determine the effect of oral hydralazine on the development of nitrate tolerance in patients with chronic congestive heart failure. Early development of nitrate tolerance with either continuous administration of intravenous or topical nitrate preparations or frequent dosing of oral nitrates leads to significant attenuation of nitrate-mediated hemodynamic and anti-ischemic effects. In recent animal experiments, prevention of nitroglycerin-induced hemodynamic tolerance with a concomitant use of hydralazine was demonstrated. This finding may have important clinical relevance. Twenty-eight patients with chronic heart failure due to left ventricular systolic dysfunction were randomized to receive either a continuous infusion (24 h) of nitroglycerin alone (group I, 14 patients) or concomitantly with oral hydralazine (75 mg four times a day [group II, 14 patients]). The effect of nitroglycerin in each group was evaluated by analysis of variance for repeated measures. The power of the analysis to detect a 5.4-mm Hg (20%) change in mean pulmonary artery wedge pressure was 90%. Baseline hemodynamic variables as well as the initial hemodynamic response to nitroglycerin were comparable in both groups. Compared with the initial response to nitroglycerin, a significant attenuation of effect was found in group I at 24 h in mean (+/- SE) pulmonary artery pressure (27 +/- 4% vs. 10 +/- 3%, p < 0.05) and mean pulmonary artery wedge pressure (40 +/- 4% vs. 16 +/- 4%, p < 0.05). In group II, conversely, oral hydralazine prevented nitroglycerin-induced hemodynamic tolerance and resulted in a persistent effect on mean pulmonary artery and wedge pressures throughout the study period (31 +/- 3% vs. 27 +/- 4%, p = 0.13 and 37 +/- 4% vs. 34 +/- 6%, p = 0.40, respectively). In addition, the initial effect on blood pressure was attenuated at 24 h in group I (5 +/- 2% vs. 12 +/- 3%, p < 0.05) but not in group II (15 +/- 3% vs. 17 +/- 2%, p = 0.46). In patients with chronic heart failure due to left ventricular systolic dysfunction, the concomitant use of oral hydralazine prevents early development of nitrate tolerance and results in a persistent nitrate-mediated hemodynamic effect on systemic and pulmonary artery and left ventricular filling pressures. These data may support the concurrent use of hydralazine in patients with heart failure treated with organic nitrates.

ISIS-4: A randomised factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58 050 patients with suspected acute myocardial infarction

58 050 patients entering 1086 hospitals up to 24 h (median 8 h) after the onset of suspected acute myocardial infarction (Ml) with no clear contraindications to the study treatments (in particular, no cardiogenic shock or persistent severe hypotension) were randomised in a "2 x 2 x 2 factorial" study. The treatment comparisons were: (i) 1 month of oral captopril (6·25 mg initial dose titrated up to 50 mg twice daily) versus matching placebo; (ii) 1 month of oral controlled-release mononitrate (30 mg initial dose titrated up to 60 mg once daily) versus matching placebo; and (iii) 24 h of intravenous magnesium sulphate (8 mmol initial bolus followed by 72 mmol) versus open control. There were no significant "interactions" between the effects of these three treatments, and the results for each are based on the randomised comparison of about 29 000 active versus 29 000 control allocated patients. Captopril There was a significant 7% (SD 3) proportional reduction in 5-week mortality (2088 [7·19%] captopril-allocated deaths vs 2231 [7·69%] placebo; 2p=0·02), which corresponds to an absolute difference of 4·9 SD 2·2 fewer deaths per 1000 patients treated for 1 month. The absolute benefits appeared to be larger (perhaps about 10 fewer deaths per 1000) in certain higher-risk groups, such as those presenting with a history of previous Ml or with heart failure. The survival advantage appeared to be maintained in the longer term (5·4 [SD 2·8] fewer deaths per 1000 at 12 months). Captopril was associated with an increase of 52 (SD 2) patients per 1000 in hypotension considered severe enough to require termination of study treatment, of 5 (SD 2) per 1000 in reported cardiogenic shock, and of 5 (SD 1) per 1000 in some degree of renal dysfunction. It produced no excess of deaths on days 0-1, even among patients with low blood pressure at entry. Mononitrate There was no significant reduction in 5-week mortality, either overall (2129 [7·34%] mononitrate-allocated deaths vs 2190 [7·54%] placebo) or in any subgroup examined (including those not receiving short-term non-study intravenous or oral nitrates at entry). Further follow-up did not indicate any later survival advantage. The only significant side-effect of the mononitrate regimen studied was an increase of 15 (SD 2) per 1000 in hypotension. Those allocated active treatment had somewhat fewer deaths on days 0-1, which is reassuring about the safety of using nitrates early in acute MI. Magnesium There was no significant reduction in 5-week mortality, either overall (2216 [7·64%] magnesium- allocated deaths vs 2103 [7·24%] control) or in any subgroup examined (including those treated early or late after symptom onset or in the presence or absence of fibrinolytic or antiplatelet therapies, or those at high risk of death). Further follow-up did not indicate any later survival advantage. In contrast with some previous small trials, there was a significant excess with magnesium of 12 (SD 3) per 1000 in heart failure and of 5 (SD 2) per 1000 in reported cardiogenic shock during or just after the infusion period. Magnesium was also associated with an increase of 11 (SD 2) per 1000 in hypotension considered severe enough to require termination of study treatment, of 3 (SD 0·6) per 1000 in bradycardia, and of 3 (SD 0·4) per 1000 in a cutaneous flushing or burning sensation (but assessment of magnesium involved open control). There was no evidence of a net adverse effect on mortality on days 0-1. Because of its size, ISIS-4 provides reliable evidence about the effects of adding each of these three treatments to established treatments for acute Ml. Intravenous magnesium was ineffective, and although oral nitrate therapy appeared safe it did not produce a clear reduction in 1-month mortality. Other trials have shown that starting long-term converting enzyme inhibitor (CEI) therapy in the weeks or months after Ml in patients with impaired ventricular function avoids about 2 deaths per 1000 patients per month of treatment. ISIS-4, GISSI-3, and smaller studies now collectively demonstrate that, for a wide range of patients without clear contraindications, CEI therapy started early in acute MI prevents about 5 deaths per 1000 in the first month (2p=0·006), with somewhat greater benefits in higher-risk patients. This benefit from 1 month of early CEI treatment seems to persist for at least the first year.

1006-41 Effect of Previous Treatment with Aspirin or Nitrates on the Clinical Manifestation of Acute Coronary Syndrome

Aspirin (ASA) and nitrates inhibit platelet aggregation by different mechanisms, and it has been suggested that their antiaggregating effects could be additive. To analyze the influence of previous treatment with aspirin (ASA) or nitrates on the clinical manifestations of acute coronary syndrome, a series of 323 pts consecutively admitted to the cardiology emergency room with unstable angina (UA) or acute myocardial infarction (MI), and with a previous history of coronary heart disease, was prospectively characterized. A standardized questionnaire was used to determine risk factors, previous cardiac history, and use of drugs preceding the index event. Previous use was defined as any dose of ASA during the week before, or of oral or transdermal nitrates during the 24 h before the onset of the event. The final diagnosis by serial ECGs and enzyme determinations, was UA in 226 pts, and MI in 95. Fifty-one pts had received previous treatment with ASA but not with nitrates, 51 had received nitrates but not ASA, 105 had received both drugs and 94 had received neither ASA nor nitrates. The final diagnosis was MI in 12 (24%) pts who had received ASA, 12 (24%) in pts who had received nitrates, 21 (20%) in pts on both ASA and nitrates, and 43 (46%) in those receiving neither ASA nor nitrates (p = 0.0003). Multiple logistic regression analysis identified prior ASA and prior nitrates, but not age, sex, risk factors, previous myocardial infarction, or prior treatment with betablockers or Ca ++ entry blockers, as independent predictors of UA vs MI. The regression model did not detect any interaction between ASA and nitrates. These results suggest that both prior treatment with ASA and with nitrates modify the clinical manifestations of acute ischemic syndrome reducing its severity, and that these effects are compatible with their effects being additive.

Translating safety, efficacy and compliance into economic value for controlled release dosage forms.

Advanced controlled release (CR) dosage forms are relative newcomers to pharmaceutical markets, and few studies relate their efficacy, safety or compliance benefits to economic value. This literature review was undertaken to assess the cost effectiveness of CR dosage forms using such measures as purchase costs, total treatment costs, and economic value of improved therapeutic outcomes compared with those with non-CR dosage forms. Three therapeutic areas were examined: cardiovascular therapy, pain management and estrogen replacement therapy. In cardiovascular therapy, prescription costs of sustained release (SR) verapamil were significantly higher than for conventional release verapamil. However, these were more than offset by lower physician, hospital and laboratory expenditures for the SR group, in whom compliance was superior. Similarly, patients receiving SR diltiazem had better prescription refill compliance than those using a conventional formulation of the drug, as well as significantly lower aggregate healthcare costs during a 1-year study period. These lower costs with both SR verapamil and diltiazem may relate to better compliance. CR nifedipine has lower daily acquisition costs than the conventional form, simplifies the dosage regimen to once daily, extends the indications of the drug to hypertension as well as angina, and reduces vasodilatory adverse effects by reducing peak plasma drug concentrations and the postdose rate of increase in concentration. Compared with oral clonidine given twice daily, transdermal clonidine, given once weekly, had higher purchase costs, but was associated with improved compliance, reduced adverse effects (due to control of plasma concentrations), and lower nondrug health costs, such as physician, hospital and laboratory costs. Lower costs were also found for once daily oral formulations of various antihypertensives, suggesting that the economics of both types of CR dosage forms related to compliance. CR metoprolol 50 or 100mg and conventional release atenolol 50mg, each given once daily, provided effective beta1-adrenoceptor blockade. The conventional formulation caused deterioration in the sense of well-being that was temporally associated with sharp peaking of its plasma concentrations. Such peaking did not occur with either dose of CR metoprolol, nor did any deterioration in the sense of well-being. Transdermal nitroglycerin (glyceryl trinitrate), compared with long-acting oral nitrates, improved quality of life (QOL) {despite a higher incidence of some adverse effects, such as headache, dizziness and skin irritation}. Furthermore, in some studies, this formulation reduced angina attacks, sublingual nitroglycerin use, and hospitalisation or emergency room use. Cost comparisons between transdermal products favoured those that have superior adhesion.(ABSTRACT TRUNCATED AT 400 WORDS)

Comparative study of gallopamil versus nifedipine in patients with ischemic heart disease

In order to compare the anti-ischemic activity of gallopamil and nifedipine, a cross-over, double-blind, randomised trial was carried out in 30 male out-patients with a history of stable exertional angina, proven coronary disease and a positive stress test (ST-segment depression ≥ 1 mm). After a first 1-week wash-out period on placebo, the patients were randomised to gallopamil, 150 mg/day (50, 50 and 50) or nifedipine, 30 mg/day (10, 10 and 10) for 28 days. After a second 1-week wash-out period active treatments were crossed for another 28 days. At the end of each drug or placebo period, a physical examination, laboratory tests and a stress test were performed. Oral short-acting nitrates were permitted throughout the trial periods. Twenty-one patients finished all periods of the study. Both drugs reduced the maximum ST-segment depression during the exercise test: from 2.45 ± 0.97 mm (placebo) to 1.95 ± 0.82 mm (gallopamil, P < 0.05) and from 2.50 ± 0.93 mm (placebo) to 1.75 ± 0.84 mm (nifedipine, P < 0.05). Gallopamil but not nifedipine increased stress tolerance significantly: from 486 ± 156 s (placebo) to 598 ± 138 s (gallopamil, P < 0.05) and from 509 ± 113 s (placebo) to 567 ± 191 s (nifedipine, NS). No significant differences were found between drugs. Both calcium antagonists, gallopamil and nifedipine, showed similar efficacy in treating myocardial ischemia.

Desensitization of nitrate-induced venodilation: reversal with oral N-acetylcysteine in humans.

The objective of this study was to determine whether the dorsal hand vein could be used as a model to study tolerance to oral nitrates, and whether oral N-acetylcysteine (NAC) could reverse tolerance if present. Dose-response curves to nitroglycerin were constructed for 11 normotensive volunteers before and during treatment with a sustained-release formulation of isosorbide dinitrate, 80 mg, three times daily for 7 days and followed by concurrent treatment with NAC at a mean dose of 150 mg/kg/day, in divided doses, for 2 days. In separate studies, dose-response curves were constructed for seven normotensive volunteers before and after treatment with oral NAC at the same dose for 2 days. Nitroglycerin's Emax was significantly attenuated from 115 +/- 36 to 77 +/- 22% after treatment with isosorbide dinitrate alone (p < 0.009). Concurrent treatment with NAC reversed this decrease, as nitroglycerin's Emax of 108 +/- 26% during coadministration of isosorbide dinitrate and NAC was not different from its Emax in the control period. There was also no difference in the dose of phenylephrine required to cause 80% of maximal venoconstriction throughout the study. These studies demonstrate that smooth muscle tolerance to nitrates can be demonstrated in medium-sized veins in humans. In addition, high-dose oral NAC can reverse existing tolerance to oral nitrates in human veins. These results indicate that the dorsal hand vein compliance technique is a good model for the clinical investigation of tolerance to nitrates in humans.

Efficacy of isosorbide mononrtrate in angina pectoris

The rapid development of tolerance has limited the applicability of oral and transdermal nitrates in the long-term management of patients with chronic stable angina pectoris. Recent well-controlled trials have demonstrated that asymmetrical, or eccentric, dosing of oral isosorbide mononitrate, in which 20-mg doses are taken at 8 a.m. and 3 p.m., provides at least 12 hours of antianginal coverage. There is no evidence for the development of tolerance with this schedule, which allows for a 17-hour nitrate withdrawal period. Likewise, the asymmetrical 20-mg twice daily regimen has not been associated with the zero-hour effect that has been reported with higher oral doses of isosorbide mononitrate and with intermittent nitroglycerin patch therapy. This approach also avoids the development of a clinical rebound phenomenon, as measured by increased episodes of angina and nitroglycerin consumption, compared with the pretreatment period, during the nitrate-free interval at night and the early hours of the morning.

Role of nitrates in angina pectoris

Nitrates are used extensively for the treatment of angina pectoris. However, continuous therapy with either oral nitrates or nitroglycerin patches leads to rapid development of tolerance, with loss or diminution of antianginal and anti-ischemic effects. The only practical way to avoid the development of tolerance is to use intermittent daily therapy with nitrates. Nitroglycerin patches applied for 10–12 hours during the day increase exercise duration for 8–12 hours, but a rebound increase in anginal attacks during the nitratefree interval may occur. Oral isosorbide-5-mononitrate, 20 mg twice a day, with the first dose administered in the morning and the second dose 7 hours later, increases exercise duration for at least 12 hours without the development of tolerance to either the morning or afternoon dose. This dosing regimen has been shown not to produce a rebound phenomenon during the periods of low nitrate levels at night and early hours of the morning. Isosorbide dinitrate (30 mg) prescribed at 7 am and 1 pm does not produce tolerance to the 7 am dose, but effects of the afternoon dose have not been evaluated. Recent data suggest that isosorbide dinitrate given 3 or 4 times daily produces tolerance and this dosing schedule is inadequate for antianginal prophylaxis. It should be recognized that intermittent oral or patch therapy with nitrates during the day leaves the patient unprotected at night and early hours of the morning. If this is of concern, additional therapy with another class of antianginal agent, preferably a long-acting β blocker or a long-acting calcium antagonist should be instituted.

Effects of nitrates on mortality in acute myocardial infarction and in heart failure.

1. Seven randomized controlled trials of intravenous nitroglycerin in a total of about 850 patients have been reported. Overall, there were 51 deaths (12.5%) in the nitroglycerin group and 87 (20%) in the control group. This indicates a 48% reduction in the odds of death (P less than 0.001, 95% confidence limits (25% to 64%)). 2. There are five randomized trials of oral nitrates after acute myocardial infarction. In these trials, 11.8% of the patients in the nitrate group compared with 13.3% in the control group died. This indicates a nonsignificant 12% reduction in the odds of death but the 95% confidence interval overlaps widely with the i.v. trials. If all trials of i.v. or oral nitrates are considered the reduction in the odds of death is 32% (P less than 0.01). 3. Nitrates have a beneficial effect on haemodynamics in heart failure but the data on mortality effects are sparse. In combination with hydralazine, however, long-term mortality was reduced in the V-HEFT trial of chronic heart failure.

One-year follow-up after recombinant tissue plasminogen activator administered to patients with acute myocardial infarction

Of 106 patients seen within 4 h of chest pain with 107 episodes of acute myocardial infarction, nine died before or during hospitalization mainly from cardiogenic shock, and four died during the next year, three were sudden deaths. The 93 survivors were reviewed at a mean of 53 (range 49-70) weeks after infarction. Of these 93, 18 had had attempted angioplasty (successful in 12) and 15 had had coronary artery bypass grafting (including one patient who had coronary artery bypass grafting performed after unsuccessful angioplasty). The remaining 61 patients continued on medical therapy only. During the one-year follow-up two patients suffered reinfarction and a further 22 had one or more cardiac admissions, mostly for chest pain. At review, 22 patients had angina (16 New York Heart Association Grade I or II) and five dyspnoea (all NYHA Grade II). Forty-three patients were taking oral nitrates, 53 were receiving calcium antagonists, 54 were using betablocking agents and 73 used anti-platelet agents. However, many of these patients continued on anti-anginal therapy prophylactically after their myocardial infarction, without continuing chest pain. Thus after recombinant tissue plasminogen activator therapy and following hospital discharge the mortality rate for patients with acute myocardial infarction was four out of 97 (4.1%) and reinfarction rate among survivors was two out of 93 (2.2%). Although the incidence of cardiac symptoms was low this may be partly due to the high incidence of angioplasty and coronary artery grafting, together with the use of anti-anginal agents.

Chronopharmacology of Oral Nitrates in Healthy Subjects

The pharmacokinetics and the hemodynamic effects (blood pressure, heart rate) of oral organic nitrates have been investigated in healthy subjects after oral single-dose application either in the morning or in the evening. Isosorbide-5-monitrate (IS-5-MN, 60 mg) was administered as an immediate-release tablet or as a slow-release formulation. Isosorbide dinitrate (ISDN, 20 mg) was ingested as an immediate-release tablet. After administration of IS-5-MN as an immediate-release tablet, the drug was more rapidly absorbed in the morning (tmax of 0.9 h) than in the evening (tmax of 2.1 h). The rapid absorption led to more pronounced effects in the morning, at which time maximum drug concentrations occurred at the same time as peak effects were observed. After evening administration, however, peak effects were in advance of the maximum drug concentrations. No chronokinetics were observed after application of the slow-release formulation of IS-5-MN. In accordance with the results of the immediate-release formulation, peak effects of the slow-release preparation occurred significantly earlier than peak drug concentrations after evening than after morning dosing. ISDN bioavailability was higher after morning than after evening administration and hemodynamic effects were more pronounced in the evening than in the morning. These results show that daily variations in pharmacokinetics and/or hemodynamic effects can be observed with oral nitrates. In addition, galenic formulation can influence the time-specified pharmacokinetics of IS-5-MN.

An Overview of Therapeutic Interventions in Myocardial Infarction

The high risk of subsequent mortality and morbidity following the occurrence of a myocardial infarction (MI) underlies the importance of instituting effective preventive regimens as part of the overall management of these patients. The aim of such treatment is to prolong survival by preventing sudden and non-sudden death and further major cardiovascular events. Currently available data from randomised, controlled clinical trials in MI patients indicate that early treatment with thrombolytic agents [streptokinase, anisolyated plasminogen streptokinase activator complex (APSAC) or recombinant tissue-type plasminogen activator (rt-PA)] in the first few hours after onset of symptoms significantly reduces the short term mortality following MI, with follow-up studies at 1 year indicating that the early benefits persist long term. The optimum time for initiation of thrombolytic therapy is within 6 hours of onset, but treatment started between 7 and 24 hours after onset can also be beneficial. Similarly, there is good evidence that beta-blockers (e.g. propranolol, timolol, metoprolol, atenolol) and aspirin are effective in reducing both the mortality and reinfarction rate following MI. With beta-blockers, a policy of starting treatment early intravenously and continuing orally for 2 to 3 years seems likely to save more lives than either strategy alone; however, contraindications to beta-blockade reduce the number of patients eligible to receive this treatment. In the case of aspirin, the optimum dosage has yet to be determined, but on the basis of present evidence, it seems reasonable to start treatment early with doses of 160 to 325 mg daily and continue for a year or 2 after recovery. Other studies have shown that long term oral anticoagulant therapy is also effective in reducing the mortality and reinfarction rate after MI. Subcutaneous heparin therapy given for 10 days in patients with acute anterior MI reduces the frequency of left ventricular mural thrombosis, while intravenous heparin given for greater than or equal to 4 days improves coronary artery patency rates following administration of a thrombolytic agent. In a comparison with low dose aspirin, intravenous heparin proved more effective in maintaining coronary artery patency rates after rt-PA thrombolysis. There is also evidence that oral nitrates may reduce mortality in MI patients, especially in those with heart failure. However, current data on the use of antiarrhythmic drugs do not support the routine of these drugs following MI. Similarly, with lipid-lowering agents, the evidence that lowering cholesterol is beneficial in reducing mortality after MI is at present inconclusive. Further studies with these groups of drugs are awaited with interest.(ABSTRACT TRUNCATED AT 400 WORDS)

Anti-anginal therapy and quality of life A comparison of the effects of transdermal nitroglycerin and long-acting oral nitrates

A total of 112 male patients with severe effort-induced angina pectoris (New York Heart Association functional classes II and III) participated in a randomized open trial consisting of a 6 month phase with 3 month treatment cross-overs. The aim of the study was to compare the effect of transdermal nitroglycerin (TN) patches and long-acting oral nitrates (LAON) on quality of life (QL). During the cross-over period 30 patients (20 on TN and 10 on LAON) withdrew from the study, over half of them within the first month. Although the results should be interpreted with some caution, they showed that improvement in QL was present for both treatments but greater during the transdermal therapy (unadjusted p = 0.07, adjusted p = 0.03). Anginal attacks were associated with improved QL scores, and fewer attacks occurred on TN ( p = 0.06). Improvement in QL was most pronounced in patients whose recorded duration of angina was less than 8 years.

Pharmacology and therapeutic effects of nicorandil

Nicorandil, a nicotinamide derivative, is an orally efficacious antianginal drug possessing a nitrate moiety in its chemical structure. This drug is an effective and well-tolerated treatment for various types of angina pectoris. Its general efficacy is similar to that of nitrates, with several unique effects on the cardiovascular system. Nicorandil causes sustained dilation of both the arterial resistance and conductive vessels, thus markedly dilating the coronary artery and increasing coronary blood flow. In addition, nicorandil, unlike nitroglycerin or isosorbide dinitrate, possesses little hemodynamic effect on heart rate, blood pressure, or cardiac contractility with clinical doses yielding antianginal effects. The mechanism causing coronary vasodilation has not been completely clarified but appears to be associated partly with increases in c-GMP, as well as the hyperpolarization of the smooth muscle membrane. Nicorandil, in single oral doses of 10-30 mg, has been shown to be effective in chronic stable angina, as assessed objectively by increases in exercise duration and/or the time to onset of ST-segment depression during treadmill exercise. In open studies and controlled efficacy evaluations, nicorandil in daily oral doses of 15-40 mg demonstrated significant effectiveness in the treatment of various types of angina pectoris. Headaches due to vasodilation may occur, and some side effects occurred in 5.1-34% of patients receiving nicorandil, but were generally minor in nature. There was no depressant effect on atrioventricular conduction, which occurs frequently in patients treated with calcium antagonists of the verapamil and diltiazem type. Nicorandil may be effective even in patients with rest and effort angina who do not respond to combination therapy with calcium antagonists and oral nitrates. Thus, nicorandil appears to be a valuable addition to the arsenal of antianginal drugs due to its low incidence of serious side effects.

Intermittent nitrate therapy in angina pectoris

The rationale for intermittent nitrate therapy is based on the pathophysiology of nitroglycerin tolerance and the diurnal pattern of symptoms encountered in patients with chronic stable angina. Nitrate tolerance was first observed as tolerance to headache in industrial toxicology. When long-acting nitrates for chronic stable angina became available, similar tolerance was observed but not thought to indicate tolerance to a haemodynamic or therapeutic effect. Subsequently, Needleman and coworkers (J Pharmacol Exp Ther 1973; 187: 324) defined in vitro the phenomenology of vascular smooth muscle tolerance to nitroglycerin-induced relaxation and reversibility was demonstrated. More recently, a potential molecular explanation for nitrate tolerance has been proposed: sulfhydryl group depletion in smooth muscle cells resulting in reduced formation of S-nitrosothiols on nitrate exposure with resultant reduced activation of cyclic GMP. In vivo, other mechanisms, including fluid retention and neurohumoral responses to vasodilation may also be important. The first demonstration that nitrate tolerance affected the therapeutic efficacy of long-acting nitrates was reported by Parker and coworkers in 1982 (Circulation 1987; 76: 572-6). This landmark study was not given much credence at the time because it appeared to be in conflict with earlier reports. However, in the past 6 years development of tolerance has been demonstrated with a variety of oral nitrates, transdermal nitroglycerin and intravenous nitroglycerin. When plasma concentrations are held constant, tolerance to antianginal effects is demonstrable within 24h, but varies markedly in severity from individual to individual.(ABSTRACT TRUNCATED AT 250 WORDS)

Effectiveness of interval nitrate therapy in angina pectoris

Because of rapid tolerance development, the use of multiple daily doses of oral nitrates or continuous application of transdermal nitrate systems can no longer be considered justified. Only with an interval treatment, which prevents nitrate accumulation in the plasma such that, from low baseline values, renewed administration of the drug results in a marked increase in plasma concentration, is it possible to utilize the antianginal and antiischaemic effects of nitrates for meaningful long-term treatment. For isosorbide dinitrate and isosorbide 5-mononitrate, as well as for transdermal nitroglycerin systems, interval treatment dosing regimens with maintained effectiveness documented in controlled studies have been delineated. To some degree, the principle of interval treatment can be achieved with continuously applied transdermal patches designed for discontinuous release of their content, which yield maintained though somewhat attenuated effects. Recent studies have shown that the tolerance to nitroglycerin, which develops within the first 12h of contact with currently available transdermal patches, can be prevented by gradually increasing the plasma concentration during this period of time. Evidence for clinically relevant rebound phenomena during interval treatment has not been observed.