Use Of Long-acting Nitrates Research Articles

Analysis of changes in pharmacotherapy of stable angina over the five-year period at specialized out-patient level of medical care (pharmacoepidemiological study)

Introduction: Ischemic heart disease (IHD) remains the leading cause of death both in Europe and in Russia. The most common form of IHD is stable angina. There is compelling evidence that strict adherence to clinical guidelines greatly contributes to mortality reduction. However, the gap between modern knowledge and use of guideline-recommended medications remains significant. As shown by Western practice, one of the possible solutions of this problem is regular conduction of pharmacoepidemiological studies.
 Objective: Investigate the dynamics of drug prescription rates in patients with stable angina over the five-year period on the example of routine clinical practice of outpatient cardiology institution of Moscow for the purpose of further eliminating the prescribing gap for guideline recommended pharmacological strategies.
 Materials and methods: Our research work was performed as a retrospective pharmacoepidemiological study including two stages with five-year interval using cross-section method.
 Results and discussion: We found a significant increase in use of antiplatelets (82.7 vs. 56.2%, p<0.05) and statins (45.6 vs. 16.1%, p<0.05). Despite the unchanged use of ACE inhibitors, the prescription rate of angiotensin receptor blockers II increased (14.7 vs. 9.7%, p<0.05). Analysis of anti-ischemic pharmacotherapy revealed an increase in beta-adrenoblockers use (74.3 vs. 63.6%, р<0.05) and a decrease in use of long-acting nitrates (26.3 vs. 31.1%, р<0.05) and calcium channel blockers (35.7 vs. 39.6%, р<0.05). Significant changes were found in prescription rates and dosage regimens of single medications in each pharmacological group. The study results demonstrated an increase in frequency of capturing data on lipid profile and diet recommendations in patient records.
 Conclusion: Such type of pharmacoepidemiological study carried out for the first time made it possible to investigate the dynamics of specialists’ adherence to guidelines of stable angina pharmacotherapy in routine outpatient clinical practice.

Nicorandil and Long-acting Nitrates: Vasodilator Therapies for the Management of Chronic Stable Angina Pectoris.

Nicorandil and long-acting nitrates are vasodilatory drugs used commonly in the management of chronic stable angina pectoris. Both nicorandil and long-acting nitrates exert anti-angina properties via activation of nitric oxide (NO) signalling pathways, triggering vascular smooth muscle cell relaxation. Nicorandil has additional actions as an arterial K+ ATP channel agonist, resulting in more "balanced" arterial and venous vasodilatation than nitrates. Ultimately, these drugs prevent angina symptoms through reductions in preload and diastolic wall tension and, to a lesser extent, epicardial coronary artery dilatation and lowering of systemic blood pressure. While there is some evidence to suggest a modest reduction in cardiovascular events among patients with stable angina treated with nicorandil compared to placebo, this prognostic benefit has yet to be proven conclusively. In contrast, there is emerging evidence to suggest that chronic use of long-acting nitrates might cause endothelial dysfunction and increased cardiovascular risk in some patients.

Association Between Use of Long-Acting Nitrates and Outcomes in Heart Failure With Preserved Ejection Fraction.

Nitrates may be beneficial in heart failure with preserved ejection fraction (HFpEF) by enhancing cGMP signaling and improving hemodynamics, but real-world data on potential efficacy are lacking. We linked the Swedish Heart Failure Registry to national registries with International Classification of Diseases, Tenth Revision comorbidity diagnoses and demographic and socioeconomic data. In HFpEF, defined as left ventricular ejection fraction ≥40%, we derived propensity scores for nitrate use using 52 baseline variables. The association between nitrate use and all-cause mortality and the composite of all-cause mortality or first heart failure hospitalization was assessed in a cohort matched 2:1 untreated to treated based on age and propensity score. In the overall HFpEF cohort (n=19 047; mean [SD] age, 76 [12] years; 46% women), nitrates were used in 17%, and the crude 1-year survival for treated versus untreated patients was 79% (95% confidence interval [CI], 78%-80%) versus 84% (95% CI, 83%-84%) respectively; hazard ratio was 1.48 (95% CI, 1.40-1.56; P<0.001) during a median 755-day follow-up. Matching yielded 2235 treated versus 4470 untreated patients, with 1-year survival of 80% (95% CI, 78%-82%) versus 79% (95% CI, 78%-81%) and hazard ratio of 1.06 (95% CI, 0.98-1.15; P=0.12). Nitrates were associated with worse composite outcome in the matched HFpEF cohort, with 1-year event-free survival of 62% (95% CI, 60%-64%) versus 65% (95% CI, 63%-66%) and hazard ratio of 1.11 (95% CI, 1.04-1.18; P=0.003). These patterns were reproduced in several consistency analyses. In HFpEF, the use of nitrates was not associated with improvements in all-cause mortality or heart failure hospitalization.

Coronary Artery Bypass Surgery in Diffuse Advanced Coronary Artery Disease: 1-Year Clinical and Angiographic Results

Proper treatment of patients with diffuse, severe coronary artery disease (CAD) is a challenge due to its complexity. Thus, data on the outcomes after coronary artery bypass graft (CABG) in this population is scarce. In this study, we aimed to determine the impact of CABG on the clinical and functional status, as well as graft patency in those individuals. Patients with severe and diffuse CAD who underwent incomplete CABG due to complex anatomy or extensive distal coronary involvement were evaluated preoperatively and 1 year after surgery. Postoperative coronary angiography was performed to evaluate graft patency. Graft occlusion was defined as the complete absence of opacification of the target vessel. Stratified analysis of graft occlusion was performed by graft type and territories, defined as left anterior descending artery (LAD), the left circumflex branch, and the right coronary artery territories; the latter two, grouped, were further classified as non-LAD territory. A total of 57 patients were included, in whom 131 grafts were placed. There was a significant improvement in Canadian Cardiovascular Society angina symptom severity (Z = -6.1; p < 0.001) and maximum oxygen uptake (p < 0.001), with a corresponding decrease in the use of long-acting nitrates (p < 0.001). The overall graft occlusion rate was 19.1%, with no significant difference between LAD and non-LAD territories (p = 0.08). However, a significantly lower occlusion rate was noted for the internal mammary artery (IMA) grafts when compared with saphenous vein grafts (p = 0.01), though this difference was only significant in the LAD territory (p = 0.04). Overall, the use of venous graft was the only predictor occlusion at 1 year (odds ratio: 4.03; p = 0.016). In patients with diffuse CAD, incomplete CABG surgery resulted in a significant clinical improvement, with acceptable graft occlusion rates at 1 year, particularly for IMA grafts to the LAD territory.

Abstract 260: Components of Change Processes of Quality of Life among Stable Coronary Patients with or without Percutaneous Coronary Intervention

Background: Percutaneous coronary intervention (PCI) plus intensive pharmacologic and lifestyle intervention (optimal medical therapy, OMT) to OMT alone was compared in reducing the risk of cardiovascular events in a total of 2,287 patients with stable coronary disease in the COURAGE trial, in which health related quality of life data were measured repeatedly over time for a median of 4.6 years. We examined components of changes in angina-related quality of life over time. Methods: Angina-specific health status was assessed with the Seattle Angina Questionnaire (SAQ). Scores range from 0 to 100; higher scores indicate better health status. Linear piece-wise latent growth curve modeling was conducted to reveal the components of process and risk factors of SAQ score changes over time. Results: For each domain the change process can be divided into two components: a process of improvement from baseline to 6 or 12 months during which the scores significantly increase with a steep upward trajectory till reaching the maximum score value; and followed by a process of stabilization during which the scores kept stable or in a downward slope until the end of the follow-up. Patients in both PCI and OMT alone groups experienced significant increase on SAQ scores over time in each domain. PCI had significant impact in the process of improvement: patients with PCI had about 0.603 (SE=0.193, p-value=0.002) and 0.442(SE=0.22, p-value =0.044) points increase per month in scores in the domains of physical limitation and angina frequency, respectively; the benefit of PCI decreased in the process of stabilization until it disappeared so that the scores in both groups were eventually similar (Table 1). The important risk factors of change in SAQ scores were the use of long-acting nitrates at randomization, the Charlson comorbidity index, and several additional factors that differed by domain. Conclusions: Mechanism and processes of change in angina-related quality of life and health status were significantly related to the impact of adding PCI to OMT. Piece-wise growth curve modeling can be used to capture advantages of PCI over OMT and identify patient characteristics associated with subsequent measures of angina.

Ranolazine for the Treatment of Chronic Angina and Potential Use in Other Cardiovascular Conditions

Chronic angina, a condition that impairs quality of life and is associated with decreased life expectancy, affects &6.4 million Americans.1 Current therapies that reduce angina frequency and nitrate consumption and increase the threshold at which demand-induced myocardial ischemic symptoms become evident include drugs (nitrates, β-blockers, calcium antagonists), exercise conditioning, enhanced external counterpulsation, and coronary revascularization.1–3 Several new investigational drugs are being tested for the treatment of chronic angina.4–9 This review will focus on sustained-release ranolazine, a drug that reduces angina symptoms, with a mechanism of action different from that of currently available pharmacological therapies.8–29 Ranolazine was approved on January 27, 2006, in the United States for use in patients with chronic angina who continue to be symptomatic on β-blockers, calcium antagonists, or nitrates. Ranolazine ([(+) N -(2,6-dimethylphenyl)-4(2-hydroxy-3-(2-methoxyphenoxy)-propyl)-1-piperazine acetamide dihydrochloride]) is an active piperazine derivative that was patented in 1986 and is available in an oral and intravenous form (Figure 1). The immediate-release ranolazine (not in current use) had an average terminal elimination half-life ranging from 1.4 to 1.9 hours and a 10-fold peak/trough difference with dosing of 240 to 400 mg 3 times per day.19 Early studies with immediate-release ranolazine provided evidence of antiischemic/antianginal properties in patients with chronic angina without clinically significant changes in heart rate or blood pressure and are reviewed elsewhere.20–24 Unless otherwise stated, the remainder of this review refers to sustained-release ranolazine. Figure 1. Chemical structure and metabolism of ranolazine. Reprinted with permission from J Clin Pharmacol . 2005;45:422–433.17 Ranolazine (Ranexa; CV Therapeutics Inc, Palo Alto, Calif) is manufactured in a sustained-release form that has a prolonged absorption phase with maximal plasma concentrations (Cmax) typically seen 4 to 6 hours after administration. The average terminal elimination half-life is &7 hours after multiple dosing to steady state, and the …

Clinical outcome after multivessel coronary stent implantation

Background Percutaneous transluminal coronary angioplasty (PTCA) has been shown to be an effective therapy for multivessel coronary artery disease, although more frequent acute complications and an increased need to repeat revascularization than with single-vessel PTCA continue to be limitations. Intracoronary stent placement has been shown to reduce the rate of acute complications and the need for subsequent revascularization. We sought to evaluate the outcome among patients undergoing successful multivessel coronary intervention with stents. Methods The participants were 175 patients without coronary artery bypass grafts who underwent multivessel coronary revascularization in which stent placement was attempted in all treated segments from January 1992 through March 1998 at our institution. Clinical and angiographic characteristics and outcomes were analyzed. Results Stent placement was attempted for 428 coronary lesions. The angiographic success rate was 100%. Modified American College of Cardiology–American Heart Association type B2 and C lesions accounted for 74.5% of the lesions. Three patients (1.7%) died in the hospital. No patient had Q-wave myocardial infarction or needed coronary artery bypass grafting. Procedural success was achieved for 172 patients (98.3%). The Kaplan-Meier probability of freedom from death or myocardial infarction at 12 months was 96.6%, of any revascularization was 81.7%, and of death, myocardial infarction, and any revascularization combined was 79.8%. The use of long-acting nitrates at 12 months was reduced (34.3% versus 19.1%, P = .01). Conclusions Multivessel coronary stent placement is associated with an excellent procedural success rate despite a high rate of adverse lesion characteristics and a high event-free survival rate during the follow-up period. The likelihood that revascularization will not have to be repeated during the first follow-up year is significantly better than that for historic controls of multivessel PTCA. (Am Heart J 1999;138:1105-10.)

Modulation of Lipoprotein(a) Atherogenicity by High Density Lipoprotein Cholesterol Levels in Middle-Aged Men With Symptomatic Coronary Artery Disease and Normal to Moderately Elevated Serum Cholesterol

Objectives. This study sought to examine whether lipoprotein(a) levels predict coronary artery lumen changes in patients with symptomatic coronary artery disease (CAD) and normal to moderate hypercholesterolemia.Background. Recent conflicting reports have confirmed or refuted the association of lipoprotein(a) with clinical events or angiographically verified disease progression.Methods. The association between serum lipoprotein(a) and changes in coronary artery lumen was studied in 704 men entered into the Regression Growth Evaluation Statin Study (REGRESS), a double-blind, placebo-controlled, quantitative angiographic study that assessed the effect of 2 years of pravastatin treatment. The primary end points were changes in average mean segment diameter (MSD) and average minimal obstruction diameter (MOD). Pavastatin- and placebo-treated patients were classified as having progressing, regressing or stable CAD, and median lipoprotein(a) concentrations were compared. Bivariate and multivariate regression analyses were performed in the overall patient group and in high risk subgroups.Results. Pravastatin treatment did not affect serum apolipoprotein(a) levels. Median in-trial (sampled at 24 months) apolipoprotein(a) levels for regressing, stable and progressing CAD were, respectively, 130, 162 and 251 U/liter in placebo-treated patients and 143, 224 and 306 U/liter in pravastatin-treated patients. Predictors of MSD and MOD changes were baseline MSD and MOD, in-trial apolipoprotein(a), in-trial high density lipoprotein (HDL) cholesterol and baseline use of long-acting nitrates. The multivariate models predicted 14% of MSD changes and 12% of MOD changes; apolipoprotein(a) predicted only 2.6% and 4.8%, respectively. However, in patients with in-trial HDL cholesterol levels <0.7 mmol/liter, apolipoprotein(a) predicted up to 37% of the arteriographic changes.Conclusions. Serum lipoprotein(a) levels predict coronary artery lumen changes in normal to moderately hypercholesterolemic white men with CAD; its atherogenicity is marked in the presence of concomitant hypoalphalipoproteinemia.

A Reappraisal of Nitrate Therapy

Nitroglycerin and the long-acting nitrates are beneficial in stable and unstable angina pectoris and acute myocardial infarction and as adjunctive therapy in congestive heart failure. Nitroglycerin compounds relax vascular smooth muscle, producing venous, arterial, and arteriolar dilatation. These actions are modulated by stimulation of intracellular cyclic guanosine monophosphate. Nitrate efficacy in ischemic heart disease is due to peripheral venous and arterial vasodilatation that results in decreased myocardial oxygen consumption. Nitrates also dilate coronary arteries and collaterals, reverse coronary vasoconstriction, and enlarge some coronary atherosclerotic lesions. Nitrates improve exercise performance in stable angina pectoris. Intravenous nitroglycerin should be used in the initial treatment of unstable angina. Nitrates may be beneficial in myocardial infarction for control of ischemic pain, acute hypertension, and left ventricular failure. In subjects with congestive heart failure, nitrates reduce symptoms and improve exercise tolerance. Nitrate tolerance is a problem with continuous nitrate therapy. Tolerance is most likely to occur with frequent dosing or the use of long-acting nitrates, particularly transdermal nitroglycerin disks, and can be prevented or reversed with intermittent-dosing regimens.

Treatment of angina pectoris with dipyridamole: A long-term double blind study

In a double blind study of 7 months' duration, 56 patients with chronic angina pectoris associated with ischemic heart disease received dipyridamole (50 mg tid) or placebo in carefully randomized order. Patients were observed for 4 months while on previous medication, usually nitrates, to determine baseline values. They were also followed for 2 months without any long-acting vasodilator drugs after completion of the double blind study. Of 28 patients on dipyridamole, 22 (78.6 per cent) had a satisfactory ( excellent or good) clinical response, 1 had a fair response, and 5 responded poorly. In 28 on placebo, response was satisfactory in none, fair in 3, and poor in 25. Response to the drug was statistically highly significant compared to placebo, P < 0.001. The first signs of improvement occurred after 2 or 3 months of therapy, with maximal improvement at 3 to 6 months. In most of the satisfactory responses, anginal attacks disappeared completely, nitroglycerin was no longer required, and walking distance increased 4–6-fold. Prolonged dipyridamole therapy usually produced a greater beneficial effect than the previous use of long-acting nitrates. No adverse reactions were experienced on the drug or on placebo. This double blind study appears to confirm the results of previous investigations and demonstrates that dipyridamole is an effective, well tolerated agent for long-term treatment of angina pectoris. It is sometimes of benefit in patients unresponsive to other vasodilator drugs.