Treating depression in patients with ischaemic heart disease: which agents are best to use and to avoid?

There are a number of dimensions to the complex relationship between cardiovascular disease and affective disorders including: (i) patients with depression are at an increased risk of dying from sudden cardiovascular death compared with the general population; (ii) patients with depression over the course of a lifetime have a higher rate of symptomatic and fatal ischaemic heart disease compared with a control group without depression; and, (iii) patients after either a myocardial or a cerebrovascular infarction who are depressed have a higher mortality rate than their medically comparable nondepressed counterparts. The deleterious impact of depression on the prognosis of cardiac disease and the suggestion that treatment of depression may reduce cardiac mortality has led clinicians to seek safe and effective treatment for patients with comorbid depression and ischaemic disease. Though they are robustly effective, the tricyclic antidepressants are type 1A antiarrhythmic agents and presumably carry the same risk in patients with ischaemic disease as treatment with other type 1 antiarrhythmics such as moricizine. Short term studies of the safety of other antidepressant agents, specifically amfebutamone (bupropion) and the selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors (SSRIs) fluoxetine, paroxetine and sertraline, suggest that these medications have a benign cardiovascular profile in patients with depression and pre-existing cardiac disease. However, given the methodological limitations of study design and the relatively small number of patients included, it is premature to conclude that SSRIs are a 'safe' treatment in patients with heart disease. Thus, clinicians must still make treatment decisions on a case by case basis, considering the type and severity of depression and cardiovascular disease, as well as what is known about the cardiovascular effects and therapeutic profile of the different classes of antidepressant medications.     

HMG-CoA reductase inhibitors in the prevention of stroke

Stroke is a heterogeneous disorder, with the definition including both haemorrhagic and ischaemic stroke. Although these subtypes of stroke have different underlying pathophysiological mechanisms, atherosclerosis plays a pivotal role in both. Most risk factors for cardiovascular disease are also risk factors for stroke. Patients with a history of cardiovascular events are at an increased risk of stroke. Although hypercholesterolaemia is the most characteristic risk factor for atherosclerotic diseases, recent data suggest that the correlation between cholesterol levels and either ischaemic or haemorrhagic stroke is weak. However, the interpretation of these results is hampered by the inconsistent use of classifications of the various subtypes of stroke in studies. Pooled data on the effect of HMG-CoA reductase inhibitors show a 30% risk reduction in strokes. These beneficial effects are obtained from studies in middle aged patients with ischaemic heart disease, the interpretation being that the effects of HMG-CoA reductase inhibitors on stroke are mediated via (i) cholesterol-lowering effects on the coronary vasculature or (ii) cholesterol-independent effects of these agents. The results cannot be extrapolated to the elderly, among whom stroke most frequently occurs.     

Mortality rates in patients with Barrett's oesophagus

Background  Patients with Barrett’s oesophagus are at increased risk of oesophageal adenocarcinoma. Observational studies have suggested increase in overall mortality also but data are conflicting. Aim  To assess the cause of death in patients with Barrett’s oesophagus compared with the general population. Methods  Patients with Barrett’s oesophagus were identified retrospectively in four hospitals in Leicestershire, UK using electronic endoscopy and histopathology records from 1997 to 2003. Data on deaths from this cohort of patients were identified through the Office of National Statistics and compared with age– and gender‐adjusted mortality in the Leicestershire region. Results  In all, 1272 Barrett’s patients were identified with 245 deaths in this cohort. Overall mortality was found to be increased [male standardized mortality ratio (SMR) = 552, 95% CI = 466–638; female SMR 455, 95% CI = 357–552]. The main disease areas that were responsible for this increase were oesophageal adenocarcinoma (n = 25, male SMR = 2171, 95% CI = 991–3351; female SMR = 1300, 95% CI = 26–2574), bronchopneumonia (n = 70, male SMR = 146, 95% CI = 55–236; female SMR = 436, 95% CI = 272–601) and ischaemic heart disease (n = 51, male SMR = 186, 95% CI = 97–2748; female SMR = 205, 95% CI = 105–306). Conclusions  Patients with Barrett’s oesophagus die more commonly of bronchopneumonia and ischaemic heart disease compared with oesophageal adenocarcinoma, and overall mortality in this group may be increased.     

Is hypertension a leading cause of heart failure in Chinese?

1. There is considerable uncertainty regarding the importance of various risk factors in the development of heart failure. Most data are from Caucasian populations, where hypertension and coronary artery disease appear dominant. 2. Because it cannot be presumed that risk factor profiles will be identical for all races, we reviewed the literature on the aetiology of heart failure in Chinese. 3. There are, apparently, no long-term prospective studies defining the risk factors for heart failure in Chinese. Studies from Hong Kong in the 1990s point to an overlap of risk factors (especially hypertension, ischaemic heart disease and diabetes) and a high prevalence of diastolic heart failure (66%). Antihypertensive drug treatment appears likely to protect against the development of heart failure but end-points from formal trials are too small to be certain. 4. Available data, short of being definitive, point to hypertension being the most important identifiable risk factor in Chinese with heart failure. This may change with diabetes mellitus becoming more prevalent in the Chinese population.     

Clinical pharmacology of etoricoxib

Etoricoxib is a highly selective COX-2 inhibitor (coxib) approved in Europe for the treatment of osteoarthritis (OA), rheumatoid arthritis and acute gouty arthritis. Etoricoxib is an effective analgesic drug that has shown some improved efficacy versus traditional NSAIDs and it is the only coxib approved for the treatment of acute gouty arthritis. Moreover, recent studies evidence its efficacy in patients with ankylosing spondylitis. In the Etoricoxib Diclofenac Gastrointestinal Evaluation study performed in patients with OA, etoricoxib significantly reduced the rate of discontinuation by 50% due to gastrointestinal adverse events versus diclofenac. Comparable rates of thrombotic cardiovascular events were detected. Rates of discontinuation due to hypertension-related adverse effects were higher on etoricoxib than diclofenac. Similarly to other selective COX-2 inhibitors, etoricoxib is contraindicated in patients with ischaemic heart disease or stroke and it should be used with caution in patients with risk factors for heart disease. The European Medicines Agency has contraindicated the use of etoricoxib in patients with uncontrolled hypertension. Selective COX-2 inhibitors remain an appropriate choice in patients at low cardiovascular risk, but with increased risk of gastrointestinal complications.     

Systematic review: coxibs,non‐steroidal anti‐inflammatory drugs or no cyclooxygenase inhibitors in gastroenterological high‐risk patients?

Selective cyclooxygenase-2 inhibitors have been marketed as alternatives of conventional, non-steroidal anti-inflammatory drugs with the purpose of reducing/eliminating the risk of ulcer complications. Unexpectedly, randomized-controlled trials revealed that long-term use of coxibs, such as rofecoxib, significantly increased the risk of myocardial infarction and stroke, while the use of valdecoxib was associated with potentially life-threatening skin reactions. Subsequently, rofecoxib and valdecoxib were withdrawn from the market. Although more strict precautions for other coxibs, such as celecoxib, etoricoxib, lumiracoxib and parecoxib, may be accepted/recommended by regulatory agencies, a critical review of published data suggests that their use may not be justified - even in high-risk patients - taking benefits, costs and risks into consideration. Clinicians should, therefore, never prescribe coxibs to patients with cardiovascular risk factors, and should only reluctantly prescribe coxibs to patients with a history of ulcer disease or dyspepsia to overcome persistent pain due to, e.g. rheumatoid arthritis or osteoarthritis. Instead, they should consider using conventional non-steroidal anti-inflammatory drugs in combination with a proton pump inhibitor or a prostaglandin analogue, especially for patients with increased cardiovascular risks, i.e. established ischaemic heart disease, cerebrovascular disease and/or peripheral arterial disease, or alternatively acetaminophen. An evidence-based algorithm for treatment of a chronic arthritis patient with one or more gastrointestinal risk factors is presented.     

Deaths from lung cancer and ischaemic heart disease due to passive smoking in New Zealand

Passive smoking is increasingly recognised as a public health hazard. Among New Zealanders who have never smoked, the prevalence of exposure to spousal smoking has been estimated to be 12.7% for men and 16.1% for women. The prevalence of exposure to passive smoking in the workplace has been estimated to be 33.6% and 23.4% for never smoking men and women respectively. The pooled risk estimates from epidemiological studies of the health effects of passive smoking were used to estimate the numbers of deaths from lung cancer and ischaemic heart disease attributable to passive smoking in New Zealand in 1985. The pooled relative risk estimates for lung cancer mortality were 1.3 (95% confidence interval (CI): 1.1-1.5) in both men and women exposed to passive smoking at home, and 2.2 (CI 1.4-3.0) in both men and women exposed to passive smoking at work. Using these relative risk estimates, it was calculated that 30 lung cancer deaths (range: 11-41) were attributable to involuntary smoking in New Zealand in 1985. From pooled relative risk estimates of ischaemic heart disease death of 1.3 (CI 1.1-1.6) and 1.2 (CI 1.1-1.4) for exposure to spousal smoking in men and women respectively, it was estimated that a further 91 ischaemic heart disease deaths (range: 39-177) were due to passive smoking at home. The number of ischaemic heart disease deaths due to passive smoking in the workplace was even higher, at 152 (range: 62-224), assuming relative risks of 2.3 (CI 1.4-3.4) and 1.9 (CI 1.4-2.5) for men and women respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Coronary heart disease in relation to age, sex, and the menopause

Examination of the Registrar General's mortality data suggested that women do not lose protection from coronary heart disease (CHD) after the menopause. Apparently, at around the age of 50 men begin to lose a factor that had previously put them at increased risk of developing CHD compared with women. Male sex hormones may be risk factors for CHD, and further studies are needed to clarify their role in the aetiology of CHD in men.     

Influences of maternal nutritional status on vascular function in the offspring

Fetal growth restriction leading to low birthweight is associated with increased risk of ischaemic heart disease and hypertension in later life. Increasingly, it is recognised that cardiovascular risk may also be initiated in early life when the fetus and neonate are exposed to maternal nutritional excess. This review summarises the studies in man and animals that have investigated the potential role of vascular disorders in the aetiology of atherosclerosis and hypertension arising from early life nutritional deprivation or excess. Malfunction of the arterial endothelial cell layer in the offspring has been frequently described in association with both maternal under and overnutritional states and may play a permissive role in the origin of these disorders. Also prevalent is evidence for increased stiffness of the large arteries which may contribute to systolic hypertension. Further investigation is required into the intriguing suggestion that early life nutritional imbalance may adversely influence vascular angiogenesis leading to rarefaction and increased peripheral vascular resistance.     

Moderate alcohol use and reduced mortality risk: Systematic error in prospective studies

The majority of prospective studies on alcohol use and mortality risk indicates that abstainers are at increased risk of mortality from both all causes and coronary heart disease (CHD). This meta-analysis of 54 published studies tested the extent to which a systematic misclassification error was committed by including as ‘abstainers’ many people who had reduced or stopped drinking, a phenomenon associated with ageing and ill health. The studies judged to be error free found no significant all-cause or cardiac protection, suggesting that the cardiac protection afforded by alcohol may have been over-estimated. Estimates of mortality from heavier drinking may also be higher than previously estimated.     

Statins: new data in secondary prevention and diabetes. Pravastatin and simvastatin are the best-assessed statins

The efficacy of pravastatin and simvastatin was first shown several years ago in patients with coronary heart disease. Other trials have since been published. In the HPS trial, which studied patients with coronary heart disease, other cardiovascular conditions, or diabetes, simvastatin significantly reduced the risk of death, coronary events and stroke when compared with placebo. In the ALLHAT-LLT trial, in patients with treated hypertension, pravastatin did not reduce overall mortality. In the PROSPER trial, in patients aged over 70 with cardiovascular disease or cardiovascular risk factors, pravastatin reduced the incidence of coronary events relative to placebo, but did not reduce overall mortality. Pharmacovigilance studies suggest there is no difference between these four statins in terms of their potential to cause rhabdomyolysis. Taken together, these trials show that statin use can be extended to patients with levels of LDL-cholesterol over 2.4 mmol/l (0.9 g/l) if they have coronary heart disease (and no hypercholesterolaemia), a history of ischaemic stroke, or lower-limb arterial disease. Statins can also be prescribed for diabetic patients with no signs of cardiovascular disease but whose LDL-cholesterol exceeds 3.4 mmol/l (1.3 g/l). Clinical trial data support the use of pravastatin or simvastatin in these situations, at a dose of 20 or 40 mg daily. Plasma creatine phosphokinase assay should be done if muscle symptoms occur or if the patient has a particular risk of rhabdomyolysis.     

Prescription of anti-oedema agents and short-term mortality in older patients with acute ischaemic stroke

BACKGROUND AND OBJECTIVE: In Western countries, stroke is the third most common cause of death and one of the main causes of disability in individuals aged over 65 years. Mortality at 1 month after stroke is still high, at around 25-30%. Despite the widespread use of anti-oedema agents in clinical practice, there are only a few studies that have investigated the effect of these drugs on stroke outcome. In this study we evaluated the effect of intravenously administered glycerol or mannitol individually and in combination with corticosteroids, on short-term mortality (30 days). The sample included patients aged over 65 years who were admitted to hospital for acute ischaemic stroke. STUDY DESIGN: This was a retrospective cohort study. The odds ratio, estimated by means of multivariate logistic regression method, was used to compare short-term mortality risk across treatment groups after adjusting for possible confounders. METHODS: This study included 442 consecutive patients aged over 65 years with severe ischaemic stroke who were admitted to either the University School of Internal Medicine (Ferrara) or the Geriatric Department (Perugia), Italy, over a 4-year period (1996-2000). All patients underwent a computed tomography (CT) scan of the brain within 72 hours of admission. Stroke type was classified according to the system used by the Oxfordshire Community Stroke Project. The data recorded included: (i) clinical features of stroke; (ii) detailed medical history, including vascular risk factors (arterial hypertension, diabetes mellitus, atrial fibrillation, coronary heart disease, congestive heart failure, alcohol abuse, smoking, previous transient ischaemic attacks or stroke); (iii) 12-lead ECG; and (iv) routine blood analysis and urine tests. RESULTS: No reduction in short-term mortality risk was observed in patients treated with intravenous (IV) glycerol. However, an increase in short-term mortality risk was observed in the patients who were concurrently treated with IV corticosteroids. Similarly, treatment with mannitol did not reduce the risk of short-term mortality; however, concurrent treatment with IV corticosteroids did not show a significant rise in short-term mortality risk. When treatment with IV glycerol and mannitol was considered together, the treatment did not decrease short-term mortality risk, while concurrent therapy with corticosteroids was associated with an increase in short-term mortality risk. CONCLUSION: This study does not support the use of IV osmotic agents such as glycerol or mannitol in the prevention of short-term mortality in older patients with acute ischaemic stroke. Furthermore, our data suggest a possible harmful effect of IV corticosteroids on short-term mortality risk.     

Direct and indirect costs of cardiovascular and cerebrovascular complications of type II diabetes

Macroangiopathy (atherosclerosis) is a common chronic complication in non-insulin-dependent diabetes mellitus (NIDDM, type II diabetes) with a significant attendant mortality and morbidity. While there are inherent difficulties in estimating the economic burden of large vessel disease in type II diabetes, this has been attempted in several studies by use of insurance claims, hospital inpatient statistics, and extrapolation from standard mortality data. This evidence suggests that the macrovascular complications of type II diabetes (ischaemic heart disease, peripheral vascular disease, and cerebrovascular disease) account for approximately one-third of all healthcare expenditures and one-quarter of disability related to type II diabetes in developed countries. The large and growing economic burden of these complications of diabetes in developing countries is unknown.     

Myocardial insulin resistance and cardiac complications of diabetes

Cardiovascular disease is a major cause of mortality and morbidity in individuals with obesity, type 2 diabetes and the metabolic syndrome. The mechanisms for this are partially understood, but include increased atherosclerosis, hypercoagulability and increased hypertension. Epidemiological data suggests however, that a component of the excess cardiovascular mortality occurs independently of underlying coronary artery disease. Indeed, diabetes is an independent risk factor for the development of heart failure and the mechanisms responsible remain to be clarified. Insulin resistance in skeletal muscle, adipose tissue and the liver are widely recognized features of obesity and type 2 diabetes, and contribute to the pathogenesis of impaired glucose homeostasis. Insulin resistance has also been described in the vasculature, and may contribute to endothelial dysfunction and atherosclerosis. The heart is an insulin responsive organ and less is known about whether or not the heart becomes insulin resistant in diabetes and what the pathogenic consequences of this might be. This review will discuss the currently available evidence from human and animal studies, that the heart may become insulin resistant in obesity and type 2 diabetes. The potential consequences of this on cardiac structure, function and metabolism will be discussed as well as recent data from transgenic mice with perturbed cardiac insulin sensitivity that have shed interesting new insight into potential mechanisms linking cardiac insulin resistance with myocardial dysfunction in diabetes.     

EFFECTS OF ANTIHYPERTENSIVE DRUGS ON CARDIOVASCULAR RISK FACTORS

1. Large scale studies have failed to show a substantial benefit of antihypertensive therapy on the incidence of ischaemic heart disease. 2. This may be due to adverse effects of antihypertensive drugs on plasma lipoproteins or because of failure to adequately manage other risk factors for atherogenesis. 3. Hypercholesterolaemia is very common in patients receiving antihypertensive therapy, and is difficult to manage successfully using existing treatment strategies. 4. The achievement of a reduction in mortality and morbidity from ischaemic heart disease amongst hypertensive patients represents a major challenge. Success will probably depend upon the development of adequate methods of lowering plasma cholesterol levels.     

Ticlopidine. An updated review of its pharmacology and therapeutic use in platelet-dependent disorders

Ticlopidine inhibits platelet aggregation induced by adenosine diphosphate (ADP) and most other platelet agonists in ex vivo studies of human platelets. The drug also improves other abnormalities of platelet function seen in patients with cerebrovascular disease, peripheral arterial disease, ischaemic heart disease or other conditions involving platelet hyperaggregation. Abnormal platelet activity has been implicated in a variety of clinical conditions in which patients are at high risk of thromboembolic events, and thus the effectiveness of ticlopidine has been investigated in such patients. Since the initial review of the drug appeared in the Journal, data from several large multicentre studies have shown that ticlopidine has a substantial benefit to offer patients who have experienced transient ischaemic attacks or stroke, and in those with peripheral arterial disease or ischaemic heart disease. Ticlopidine reduces the incidence of further stroke, myocardial infarction or vascular death, and is superior to placebo and aspirin in this regard in studies of patients with recent stroke or transient ischaemic attacks, or intermittent claudication. Ticlopidine is equally effective in both men and women and also improves symptoms of claudication in patients with peripheral arterial disease, and appears to reduce anginal pain. Patients with subarachnoid haemorrhage and sickle cell disease have shown some improvement with ticlopidine administration. The drug reduces thromboembolic events and re-stenosis in patients undergoing haemodialysis and cardiac surgery, and appears to prevent the progression of nonproliferative diabetic retinopathy. Ticlopidine in large clinical trials is associated with a higher incidence of adverse effects than placebo and an overall incidence similar to aspirin. Most adverse effects do not require withdrawal of treatment. Gastrointestinal symptoms (particularly diarrhoea) are most common, occurring almost twice as frequently with ticlopidine as with aspirin. Other adverse effects associated with ticlopidine include skin rash, haemorrhagic disorders, and haematological effects; these latter effects require careful monitoring of patients during the initial weeks of therapy. In conclusion, ticlopidine is a valuable addition to the prophylactic treatments available for the management of patients with cerebrovascular disease, peripheral arterial disease or ischaemic heart disease, who present a high risk of thromboembolic events. Although tolerability may be a problem for some patients, the overall benefit conferred by the drug would appear to outweigh this potential disadvantage. Because of its antiplatelet activity, ticlopidine has a promising role in other disorders mediated by platelet dysfunction. However, the precise role of the drug in these additional therapeutic indications awaits clarification with wider clinical experience.     

Impact of increased heart rate on clinical outcomes in hypertension: implications for antihypertensive drug therapy

Thirty-eight studies have been published to date on the association between elevated heart rate and mortality. After adjustment for other risk factors, only two studies for all-cause mortality and four studies for cardiovascular mortality reported an absence of association between heart rate and mortality in male populations. This relationship has been found to be generally weaker among females. Most of these studies investigated samples of general populations. The four studies performed in hypertensive men found a positive association between heart rate and all-cause mortality (hazard ratios ranging from 1.9 to 2.0) or cardiovascular mortality (hazard ratios ranging from 1.3 to 1.7). In spite of this evidence, elevated heart rate remains a neglected cardiovascular risk factor in both genders. The pathogenetic mechanisms connecting high heart rate, hypertension, atherosclerosis and cardiovascular events have also been explicated in many studies. Elevated heart rate is due to an increased sympathetic and decreased parasympathetic tone. This altered balance of the autonomic nervous system tone could explain the increase in events with the increased heart rate. However, it has also been proved that blood flow changes associated with high heart rate favour both the formation of the atherosclerotic lesion and the occurrence of the cardiovascular event. Reduction of heart rate in hypertensive patients with increased heart rate could be an additional goal of antihypertensive therapy. Several trials retrospectively showed the beneficial effect of cardiac-slowing drugs, such as beta-adrenoceptor antagonists (beta-blockers) and non-dihydropyridine calcium channel antagonists, on mortality, notably in patients with coronary heart disease, but no published data are available in patients with hypertension free of coronary heart disease. Other antihypertensive drugs that have been shown to reduce the heart rate are centrally acting drugs and angiotensin II receptor antagonists, but their bradycardic effect is rather weak. The f-channel antagonist ivabradine is a selective heart rate-lowering agent with no effect on blood pressure. Although it has not been proven in existing trials, it would seem reasonable to recommend antihypertensive agents that decrease the heart rate in hypertensive patients with a heart rate higher than 80-85 beats per minute. Since the fast heart rate per se causes cardiovascular damage, all drugs that lower the heart rate have the potential of further reducing cardiovascular events in patients with elevated heart rate. Unfortunately, lowering of the heart rate is not a clinically recognised goal. Prospective trials investigating whether treatment of high heart rate can prevent cardiovascular events, notably in hypertensive patients, are warranted.     

Converting enzyme inhibitors for the treatment of hypertension in the elderly

Recent epidemiological studies have confirmed that high blood pressure increases the risk of cardiovascular morbidity and mortality not only in young and middle-aged subjects but also in elderly patients. For this reason there is an increasing tendency to treat hypertension also in this age group. However in doing so several problems may be encountered, if the particular physiopathological characteristics of these patients are not taken into account. Recently captopril has been proposed as a useful agent in these cases since it does not reduce coronary, cerebral and renal blood flow and does not cause orthostatic hypotension. These properties are of the utmost importance because elderly patients often present a decreased renal function, ischaemic heart disease, cerebrovascular disease and an impaired baroreflex sensitivity. Although to date no controlled studies have been published on the use of captopril in hypertensives over 60 years old, the results of a recent captopril surveillance programme indicate that this agent is efficacious and well tolerated in these patients.     

56例风湿性心脏病的特点和死因分析

目的探讨风湿性心脏病的特点和死因。方法对56例风湿性心脏病患者的临床资料进行回顾性分析。结果侵害二尖瓣的比例最高为85.8%,死亡率为30.4%,多瓣同时受累患者的死亡率最高;心力衰竭引起的死亡率最高为64.7%。结论风湿性心脏病最主要侵害二尖瓣;多瓣同时受累患者的死亡率最高;心力衰竭是引起风湿性心脏病患者死亡的最主要原因。     

Systemic antiatherosclerotic treatment for the peripheral arterial occlusive disease patient

Symptomatic and asymptomatic peripheral arterial occlusive disease (PAD) is indicative of widespread atherosclerosis. The major threat is from cardiovascular ischaemic events; thus, an important therapeutic goal is to modify atherosclerotic risk factors. Data from several large drug trials indicate that patients with PAD may gain as much, if not more, benefit from aggressive secondary prevention than those with other manifestations of atherothrombosis. In fact, the level of care for patients with PAD is lower as compared with those with ischaemic heart disease, although PAD is defined to be a coronary artery risk equivalent. This paper reviews observational data and generalisation from trials in patients with other manifestations of cardiovascular disease that support the importance of treating key risk factors such as smoking, diabetes, hypertension and hyperlipidaemia in PAD patients.