Heart failure is predominantly a condition of the elderly and is associated with substantial mortality, morbidity and functional limitation. In clinical trials of patients with left ventricular systolic dysfunction (LVSD), angiotensin-converting enzyme (ACE) inhibitors reduce the burden of heart failure. Clinical trials, however, have largely excluded older persons. This paper reviews the evidence for efficacy and effectiveness of ACE inhibitors, current patterns of use of these important agents and the challenges of prescribing ACE inhibitors for older patients with heart failure. The existing literature indicates that (1) despite a relative paucity of data from randomized controlled trials, observational studies suggest that the elderly with LVSD are as likely to benefit from ACE inhibitors as younger patients; (2) ACE inhibitors are underused in older persons despite guideline recommendations, and (3) the older population presents specific challenges in applying the clinical evidence supporting ACE inhibitors, including polypharmacy, cognitive impairment and other common comorbid conditions. Nevertheless, the judicious use of ACE inhibitors in eligible older patients will likely improve health outcomes.
Nicorandil is a drug which has been developed as an anti-anginal medication. Its structure is characterized by a dual mechanism of action. The nicotinamide moiety acts as an opener of ATP-sensitive potassium channels, whereas the NO2 group explains its nitrate-like properties. The nitric oxide-like action leads to a dilatation of the large coronary arteries, whereas its potassium channel opening action is responsible for the dilatation of coronary resistance vessels. Nicorandil has also been found to dilate veins, enabling it to decrease both preload and afterload and to increase coronary blood flow. The ATP-sensitive potassium channel opening mimics preconditioning in the absence of ischemia and may therefore exert cytoprotective effects. These have been thought to be the reason for a reduction in major coronary events and all cardiovascular events of nicorandil in addition to a specific anti-anginal medication in the Impact Of Nicorandil in Angina study. This review summarizes the pharmacologic properties of nicorandil and assesses its actual place in different cardiovascular disease states.
Background: Atrial fibrillation (AF) is the most common sustained arrhythmia encountered clinically in patients with congestive heart failure (CHF) and has been associated with increased morbidity and possibly mortality. Small retrospective studies have shown a preventive effect on AF development with the use of agents interfering with the renin-angiotensin system (RAS). Method and Results:We carried out a systematic search of the literature in the English language in order to elucidate the potential mechanism underlying this added beneficial effect of RAS inhibitors in CHF. The concepts of ionic, electrical and structural remodelling of the atrium induced by AF are discussed. Conclusion: Inhibition of RAS could prevent AF development in patients with CHF.
Objective: To compare economic impacts of anti-thromboembolism prophylaxis with two medications – new pentasaccharide fondaparinux versus low molecular weight heparin (LMWH) – in major orthopaedic surgery, such as hip and knee replacement and hip fracture repair, in Switzerland. In order to meet this objective, three parameters were determined for an observation period of 5 years. (1) Outcomes: Frequency of deep vein thrombosis (DVT), pulmonary embolism (PE) and their complications. (2) Cost burden of disease: Determination of the costs of DVT, PE and complications not prevented despite prophylaxis. (3) Total costs of prophylaxis: Costs were calculated from the perspective of the health insurance scheme. Methods: In order to determine outcomes and cost burden of disease, a model was applied which generates the post-surgery course of thromboembolic events (TE) and their complications for individual cohorts of patients undergoing hip and knee replacement surgery and hip fracture repair. These findings were allocated to the Swiss standard diagnostic and therapeutic measures (resource consumption), which enabled subsequent calculation of the costs of TE, including complications not prevented in spite of prophylaxis (cost burden of disease) based on standard Swiss tariffs. Additionally, total costs of prophylaxis, including costs of medications and monitoring, were determined. Results: In Switzerland, the following outcomes (expressed as percentage of the number of patients undergoing surgery) can be expected for TE prophylaxis with LMWH and with fondaparinux: DVT 3.4 vs. 2.3%, PE 1.4 vs. 0.7%, recurrent DVT 0.2 vs. 0.1%, post-thrombotic syndrome 4.8 vs. 3.5%. The costs of non-prevented TE and their complications add up to CHF 437 vs. CHF 306 per patient undergoing major orthopaedic surgery; the total cost burden for Switzerland amounts to CHF 13.4 million vs. CHF 9.4 million (30% less). Thus, despite higher medication costs, the use of fondaparinux instead of LMWH saves a total of CHF 105 per operated patient from the perspective of the health insurer. Conclusion: Fondaparinux is superior to LMWH in regards to both clinical efficacy and financial costs. This statement is confirmed by sensitivity analysis with different parameters over a broad range.
Objective: We investigated the influence of treatment with simvastatin and vitamins C and E on serum levels of soluble cell adhesion molecules (sCAM) as markers of atherosclerosis and endothelial activation. Methods: In 11 hypercholesterolemic patients, serum levels of sCAM were measured by enzyme immunoassay before and after 6 weeks of treatment with either simvastatin (20 mg) or vitamin C (1 g) plus vitamin E (600 mg) and after an additional 6 weeks of combined treatment. In 8 of the patients angiography was performed at study entry. Results: Baseline levels of soluble intercellular adhesion molecule-1 (sICAM-1) showed an age-dependent increase (coefficient of correlation 0.71, p = 0.014) and were higher in patients with established atherosclerotic lesions than in patients with no such lesions (369.5 ± 61.8 vs. 238.4 ± 56.4 ng/ml, p = 0.023). Whereas either treatment alone had no influence on the serum levels of sCAM, combined treatment with simvastatin and vitamins C and E reduced serum levels of soluble E-selectin from 43.2 ± 18.9 ng/ml at baseline to 39.7 ± 16.5 ng/ml (p = 0.027) at study end. Although not significant, levels of soluble P-selectin were also reduced from a mean of 125.9 ± 64.1 ng/ml at baseline to 115 ± 64.9 ng/ml (p = 0.1). Serum levels of sICAM-1 and soluble vascular cell adhesion molecule-1 (sVCAM-1) remained unchanged by this treatment. Conclusion: Combined treatment with simvastatin and vitamins C and E reduced serum levels of soluble E-selectin but had no influence on sICAM-1 and sVCAM-1 levels.
The clinical effects of intravenous β-adrenoreceptor- blocking agents (β-blockers) administered during evolving acute myocardial infarction (AMI) have varied among published studies, depending on whether or not reperfusion therapy was employed. Primary percutaneous coronary intervention (PCI) is accepted as the superior form of reperfusion therapy for AMI if it can be performed by an experienced team in a timely fashion. Intravenous β-blockers are not routinely used in this setting and their role as adjunctive medical therapy to catheter-based reperfusion requires definition. Emerging data strongly indicate that in the absence of cardiogenic shock or specific contra-indications, pre-procedural intravenous β-blockade improves survival and recovery of left ventricular function after primary PCI, and that these effects are modulated by oral β-blocker use at the time of AMI onset. In the absence of contra-indications, the available evidence supports the routine administration of intravenous β-blockers to patients with ST-segment elevation AMI managed by catheter-based reperfusion therapy, especially in patients in whom oral β-blockers were not used before admission. While no data are available on the effects of intravenous β-blocker therapy with catheter-based intervention for acute coronary syndromes other than ST-segment elevation AMI, it is reasonable to apply the aforementioned recommendations regarding primary PCI to these patients as well.
on wall motion analysis, a subjective method for evaluation of regional LV function, and a reduction in systolic endocardial excursion or myocardial thickening during increasing stress has been the universal diagnostic criterion for stress-induced ischemia [1, 5, 6] . Stress echocardiography has gained widespread use in several countries and a huge amount of experience has accumulated in the literature over the past 10–15 years. In spite of several reports of high diagnostic accuracies with regard to the presence of CAD, it has become evident that the interpretation criteria are vaguely defi ned and in case of dobutamine-atropine stress echocardiography (DASE), that the variation in test interpretation between institutions is substantial [7] . This is a problem with regard to a widespread use of the test because a high reproducibility is mandatory when results from one centre are to be extrapolated to another. In the search for a more objective and reproducible interpretation of the 2D recordings obtained during DASE, the substudies of this thesis were conducted with the following objectives: (i) To describe global and regional systolic LV function in healthy subjects undergoing DASE. (ii) To identify the cornerstones of qualitative DASE analysis and to assess the reproducibility and diagnostic performance of strictly defi ned diagnostic criteria. (iii) To investigate the usefulness of certain quantitative parameters of systolic LV function in the appreciation of stress-induced ischemia during DASE.
We conduct a prospective randomized study, the OACIS-LIPID, to determine whether early use of pravastatin can prevent secondary cardiac events in patients with acute myocardial infarction (AMI) and hyperlipidemia (HL). Three hundred and fifty Japanese patients with AMI and mild to moderate HL are randomly assigned to receive or not to receive pravastatin in an open-labeled fashion. The primary dose of pravastatin is 10 mg per day, which is a standard dose for the Japanese population. Both groups receive dietary counseling. Over a 9-month follow-up period, the combination of the endpoints (death, nonfetal myocardial infarction, unstable angina, noncardiac rehospitalization, revascularization and nonfetal stroke) will be evaluated. The results of the OACIS-LIPID study will determine the utility of a practical dose of hydroxymethylglutaryl coenzyme A reductase as an early intervention in AMI.
Lowering LDL cholesterol (LDL-C) with statins is a well-documented strategy to reduce the incidence rate of cardiovascular events and deaths. There has been consensus so far that LDL-C should at least be lowered to 100 mg/dl in individuals suffering from established atherosclerotic disease and/or diabetes mellitus. Results of recent intervention trials of highly effective statins have lead to suggest that the target for high-risk individuals be set at substantially lower concentrations. As demonstrated by the Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT) study this recommendation appears warranted particularly in patients with acute coronary syndromes. However, evidence is emerging that LDL-C levels well below 100 mg/dl would also produce significant additional clinical benefit in patients with stable coronary artery disease or type 2 diabetes.
In the present issue of Heart Drug you will fi nd nine proceedings condensed from the Educational Autumn Meeting on Advances in Cardiovascular Drug Therapy, organized by the Working Group on Cardiovascular Pharmacology and Drug Therapy of the European Society of Cardiology in Vienna, Austria, November 27–28, 2004. The following topics were presented and discussed at our Educational Autumn Meeting: Are all -blockers equal?, Advances in the treatment of hyperlipidemia, and I f current inhibition. There were three lectures on each of these topics given by distinguished experts in their fi elds who also wrote the respective papers in this issue of Heart Drug . I hope you will enjoy reading these proceedings on these exciting topics! Kurt Stoschitzky Published online: January 19, 2005
β-Blockers are important in the treatment of arterial hypertension, coronary heart disease, cardiac arrhythmias and heart failure. Their effects are mediated by the blockade of various types of β- and α-receptors, and compounds have been developed to specifically inhibit them. Nonselective β-blockers (e.g. propranolol, nadolol, penbutolol and carvedilol) differ from β1-selective blockers (e.g. metoprolol, atenolol, bisoprolol and nebivolol). Selectivity is never absolute and all β-blockers can cause problems in allergic asthma including serious side effects and death. The clinical advantage of selectivity appears to be meager, as only few patients with chronic obstructive pulmonary disease seem to benefit from increased tolerability. Another important feature is the intrinsic-sympathomimetic activity of some compounds (e. g. pindolol or oxprenolol), which is associated with negative outcomes. Vasodilation by additional α-blockade as seen with carvedilol results in metabolic neutrality and superior tolerability especially in patients with hypertension, heart failure and pAVK. Nebivolol is a β-blocker which leads to NO generation in the endothelium, and, thus, to NO-dependent vasodilation, and thus has a strong antihypertensive profile.
Background: The metabolic syndrome is associated with an increased risk of cardiovascular complications. Especially patients with evident cardiac pathology are at high risk for further complications. A sufficient weight reduction would improve the metabolic pathology and reduce the cardiovascular risk. Unfortunately, overweight and obese patients, even with complicated coronary heart disease, do not alter lifestyles regarding fat intake and physical activity, and in a quarter of these patients body weight increases in the follow-up period. Nonetheless, these patients need a weight reduction to be protected from further cardiovascular complications. Therefore, in overweight patients with insulin resistance in whom lifestyle recommendations have failed, orlistat has been used as an adjunct to decrease significantly overweight and to improve the metabolic pathology without increasing mortality. In our opinion, orlistat could also be an adjunct to lifestyle changes in adipose, diabetic patients with the metabolic syndrome and established heart pathology and signs of incipient cardiac dysfunction. Furthermore, we hypothesize that following a sufficient weight reduction improvements in metabolic pathology and, more important to us, in cardiac dysfunction should be observed. Methods: We selected 90 adipose patients with the metabolic syndrome, diabetes type 2, hypertension, mostly with coronary heart disease and concomitant cardiac dysfunction. Cardiac dysfunction was stated when the amplitude of dyspnea was greater than class 2 of the New York Heart Association (NYHA) and when resting left ventricular ejection fraction (LVEF) was <50%. Patients attended standardized nutritional counseling sessions. The caloric restriction was sufficient to create a deficit of 500 calories per day with <30% of total calories derived from fat. All patients were also enrolled in a standardized physical program and were also encouraged to walk briskly for at least 30 min per day. Patients were divided into two groups. Orlistat (120 mg t.i.d.) and placebo (1 capsule t.i.d.) were administered according to a double-blind protocol. Results: Baseline pathology was similar in the two groups, with the exception of hemoglobin (Hb) A1C, which was slightly higher in the orlistat group, the difference being statistically significant (p = 0.031). Unfortunately, lifestyle changes (diet and exercise) induced only small changes with respect to overweight in the placebo group (no orlistat). The metabolic pathology and the cardiac dysfunction did not improve. As expected, in the other group treated with orlistat in addition to lifestyle changes, weight and body mass index decreased significantly (p < 0.001 and p = 0.013, respectively). In parallel the metabolic pathology, especially dyslipidemia, was significantly reduced. Total cholesterol, LDL cholesterol, and triglycerides decreased, while HDL cholesterol increased. These changes were very significant (p < 0.001, p = 0.001, p = 0.001 and p < 0.001, respectively). Uricemia decreased slightly (p = 0.043). The diabetic pathology was also reduced. Insulin sensitivity increased in both groups, but the within group difference was not significant (p = 0.093). Glycemia and Hb A1 decreased, and serum insulin increased. These changes were significant (p = 0.005, p = 0.001 and p = 0.003, respectively). With orlistat treatment, systolic (SBP) and diastolic blood pressure (DBP) and heart rate decreased. The differences from placebo were small but statistically significant (p = 0.025, p = 0.012 and p = 0.039, respectively). As hypothesized, in the orlistat group dyspnea decreased (NYHA class improved) and the LVEF increased from 47.47 ± 3.74 to 51.76 ± 3.66%, and this difference was highly significant compared to placebo (p < 0.001). Conclusions: Unfortunately, recommendations regarding lifestyle changes (diet counseling and physical exercise) may be insufficient to reduce overweight even in patients who need this effect. On the other hand, atherogenic dyslipidemia and glycemia can be decreased with an adequate weight reduction. Our data show that a weight decrease of only 5.6 kg is sufficient to improve significantly atherogenic dyslipidemia, even if most patients remain obese since hemodynamics and cardiac function are improved. We would prefer to obtain these effects by lifestyle changes (increased physical activity and reduced caloric intake combined with a reduced fat consumption). But when these efforts fail to achieve an effect, orlistat may be a valuable adjunct to achieve these goals. Of course this drug should not be given indefinitely, because the long-term effects on the absorption of fat vitamins are poorly known and potentially dangerous.
The predominant action of β-blockers is their inhibition of the stimulating effects of adrenaline and noradrenaline on sympathetic β-adrenoceptors. In this context, they are particularly useful in the treatment of arterial hypertension, coronary artery disease, myocardial infarction, tachyarrhythmias and heart failure. However, a number of β-blockers also exert additional effects independent from the inhibition of β-receptors: nebivolol causes NO-derived vasodilation, carvedilol also inhibits sympathetic α-receptors, sotalol shows additional antiarrhythmic class III effects, and propranolol inhibits the conversion of thyroxine to triiodothyronine and shows slight antiarrhythmic class I effects. In addition, β-blockers may be used in the treatment of other diseases such as hyperthyroidism, migraine, essential tremor, portal hypertension, hypertrophic obstructive cardiomyopathy and aortic dissection. As a special feature, most β-blockers are taken up into, stored in and released from adrenergic cells together with adrenaline and noradrenaline. Consequently, plasma concentrations of these drugs are markedly increased during exercise together with those of adrenaline and noradrenaline and remaining β-blocking effects long after the withdrawal of chronic administration of β-blockers, even when they are no longer detectable in plasma. Furthermore, except for nebivolol and carvedilol, all β-blockers investigated in this context inhibit the nocturnal production and release of melatonin. Finally, all β-blockers currently used in the treatment of cardiovascular diseases are racemic mixtures consisting of (R)- and (S)-enantiomers in a fixed 1:1 ratio although they may show different pharmacokinetics, and only the (S)-enantiomers cause β-blockade whereas the (R)-forms do not contribute to this effect but may increase side effects and drug interactions. Thus, β-blockers may exert a number of interesting features in addition to their well-known effects on cardiac β-adrenoceptors.
tomatic ulcers for celecoxib versus NSAIDs were 2.01 versus 2.12% (p = 0.92) and 4.70 versus 6.00% (p = 0.49) [3] . The TARGET study (Therapeutic Arthritis Research and Gastrointestinal Event Trial) claimed that the risk of cardiovascular events was comparable among lumiracoxib, naproxen and ibuprofen. Patients in TARGET were 50 years old or older, but the study excluded patients with myocardial infarction, stroke, coronary artery bypass surgery, or congestive heart failure [4] . Less than 2% of the patients had a previous myocardial infarction or a revascularization procedure. Unfortunately, this trial, like all others in the clinical development of coxibs, did not refl ect the general population but excluded patients with known preexisting coronary artery disease. In practice, osteoarthritis frequently coexists with coronary artery disease. The reduction in the protective effect of aspirin on coronary events when coadministered with coxibs has also not been suffi ciently analyzed. In the case of patients taking low-dose aspirin, it is unnecessary to add coxibs; there is no benefi t in the reduction of ulcer complications. Moreover, questions regarding the risk of myocardial infarction remain unanswered despite polypharmacy. The review by Otterstad [1] addresses a well-known controversy about Cox-2 inhibitors and cardiovascular risk, but leaves clinical questions unanswered in the light of the Vioxx withdrawal. The main reason why clinicians choose Cox-2 inhibitors is because of their relatively lesser side effects on the gastric mucosa. In osteoarthritis patients with a risk of cardiovascular events, low-dose aspirin is advised by some clinicians along with Cox-2 inhibitors like celecoxib and lumiracoxib. This combination effectively nullifi es the benefi t of Cox-2 inhibitors on the gastrointestinal (GI) system. Low-dose aspirin also carries a risk of GI bleed [2] . The question is how many of us would use two NSAIDs for two different indications or use one NSAID for two different indications? It would be more benefi cial if these patients were prescribed aspirin at doses of 1,000 mg per day in combination with proton pump inhibitors to confer protection against cardiovascular events and GI symptoms in addition to pain relief in osteoarthritis. In the CLASS study (Celecoxib Longterm Arthritis Safety Study), for patients taking aspirin with celecoxib, the annualized incidence rates of upper GI ulcer complications alone and combined with sympPublished online: January 27, 2005
Background: There is a limited number of studies of consecutive patients suspected of having arrhythmogenic right ventricular cardiomyopathy (ARVC) as established by the Task Force report [Br Heart J 1994;71:215–218]. Objective: The aim of this study was to describe a population of ARVC patients who were referred to a university hospital for thorough clinical evaluation of right ventricle arrhythmia using both noninvasive and invasive procedures. Methods: In a prospective design 48 patients suspected of having ARVC underwent cardiac magnetic resonance imaging (MRi), contrast ventriculography, an electrophysiological test and endomyocardial biopsies from the lower septum. Results: A diagnosis of ARVC was established in 30 patients (age 40 ± 2 years, mean ± SEM) and in one third of the patients, intense running, cycling or rowing provoked palpitations and syncope. Arrhythmias were frequent premature contractions of RV origin and/or ventricular tachycardia with a left bundle branch configuration. In 14 ARVC patients the ECG trace showed right bundle branch block or inverted T waves in right precordial leads. Contrast ventriculography demonstrated RV dilatation in 11 ARVC patients and in 18 patients the septal biopsies showed fatty tissue myocardial infiltration. In 25 patients cardiac MRi showed islands of high signal intensity indicative of RV fatty infiltration. Conclusions: ARVC is a heterogeneous syndrome and an abnormal right ventricle and arrhythmias of right ventricle origin must lead to a clinical evaluation. Cardiac MRi appears to be an important diagnostic tool in patients suspected of ARVC and should be used to guide invasive procedures.
More than 15 beta-blockers are available today. They represent a class I recommendation in major cardiovascular disorders such as hypertension, coronary heart disease and chronic heart failure. If in hypertension and coronary heart disease their favorable action is considered a class effect, in heart failure some of them are of more benefit than others. Bisoprolol, carvedilol and metoprolol proved in important clinical trials significant reductions in mortality and morbidity in patients with different stages of heart failure, from asymptomatic ventricular dysfunction to NYHA class IV heart failure. The newcomer nebivolol reduced morbi-mortality in old and very old patients as shown in the recently presented SENIORS study.
Background: Although dyslipidemia is one of the main risk factors for cardiovascular diseases, very few randomized trials have provided data on the association of dyslipidemia and in-hospital mortality in patients with acute coronary syndrome (ACS). Objective: The study assessed the association of dyslipidemia and concomitant risk factors, and early lipid-lowering therapy (LLD) on in-hospital mortality in patients admitted for ACS. Methods: Using AMIS Plus registry data, 13,482 patients admitted between January 1997 and October 2003 were analyzed, and logistic regression was used for predicting in-hospital mortality. Results: Baseline characteristics of patients with dyslipidemia (n = 6,079) significantly differed from those without, and in-hospital mortality was lower (5.5 vs. 9.4%; p < 0.001). Subgroup analyses of 9,383 patients with one or more of four preexisting main risk factors (hypertension, diabetes, coronary heart disease, CHD, or dyslipidemia) showed that whenever dyslipidemia was combined with another risk factor, the mortality rate clearly decreased. Patients with dyslipidemia were, in all subgroups, significantly younger (p < 0.001) and predominantly male, and they had more frequently primary percutaneous coronary intervention (PCI). However, this was only significant in patients with hypertension or hypertension and CHD. Independent in-hospital mortality predictors were age (odds ratio, OR: 1.08 per year, 95% confidence interval, CI, 1.07–1.09), diabetes (OR: 1.96, 95% CI: 1.56–2.46, p < 0.0001) and primary PCI (OR: 0.62, 95% CI: 0.44–0.86, p < 0.0001). In patients who received LLD, mortality was significantly lower regardless of the total cholesterol level measured within 24 h after symptom onset. Conclusion: Patients with dyslipidemia admitted for ACS had significantly lower in-hospital mortality than patients without dyslipidemia, mainly but not only due to the younger age of these patients. Early administration of LLD was associated with lower in-hospital mortality.
An original article is generally considered a cornerstone of modern research. It is a detailed written presentation of novel and original data that undergo peer review. The current paper describes in detail how to draw up an original article effectively, using strategies such as modern information technology and a rational sequence of writing title page, materials and methods, figures and tables, legends, results, introduction, discussion, acknowledgements, abstract (summary), key words and reference list. As a preliminary step, important basic facts on medical writing are described, in particular the distinction between generating/collecting data and actually putting fingers to the keyboard. The Vancouver requirements and important aspects of authorship are discussed; how to choose a journal is also outlined. Finally we describe the repeated process of writing, reviewing and revising your manuscript together with your mentor or co-workers to obtain the highest level of quality before submission.
Cardiac arrest claims many lives too early. Cardiopulmonary resuscitation (CPR) is the treatment of choice in this dire situation where seconds count. Thus, a solid knowledge based on scientific data helps to guide the correct therapeutic armamentarium. Diagnostic workup, physical, electrical or pharmacological interventions are described and – where possible – classified according to published evidence. Special circumstances and ethical considerations are outlined and potentially harmful measures are summarized. Robust science should improve CPR for the majority of the patients.
