Secondary prevention of coronary heart disease in elderly patients following myocardial infarction: are all HMG-CoA reductase inhibitors alike?

Cardiovascular disease remains the leading cause of mortality in elderly patients. While coronary heart disease (CHD) morbidity and mortality have decreased over the last 25 years, the percentage reduction in elderly patients is nearly 50% lower than that for the general adult population. Therefore, aggressive primary and secondary prevention of CHD is imperative for our society, and hyperlipidaemia remains the major modifiable risk factor in the elderly population. However, there appears to be a reluctance among practitioners to treat hyperlipidaemia in elderly patients, a bias that is particularly important given the absolute benefits of treating such patients. While many of the major clinical trials involving HMG-CoA reductase inhibitors (statins) in patients with CHD focused on younger individuals, subsequent subgroup analyses of elderly patients have shown consistent reductions in all-cause mortality, major CHD events and numbers of revascularization procedures. Intensive statin therapy in the setting of acute myocardial infarction (MI) has also been shown to reduce the risk of death, MI, unstable angina, revascularization and stroke in elderly patients. Furthermore, three recent articles that have evaluated intensive lipid-lowering in the elderly population have extended the known benefits of such therapy to elderly patients with acute coronary syndrome and stable CHD.Elderly patients often take multiple medications and are at significant risk of drug-drug interactions. Several available statin medications are metabolized by cytochrome P450 (CYP) 3A4 and can therefore interact with commonly used medications such as amiodarone, macrolide antibacterials, calcium channel antagonists, fibric acid derivatives and ciclosporin. These interactions can result in an increased frequency of statin-related hepatotoxicity and myopathy.There are currently six commercially available statin medications on the US market, three of which, lovastatin, simvastatin and pravastatin, are available in generic formulations, and are thus less expensive. Of the commercially available statins, rosuvastatin, atorvastatin and simvastatin have the highest potency. While rosuvastatin currently lacks clinical event data, atorvastatin has the most clinical event data for CHD and even stroke prevention. Although pravastatin has lower potency than other described statins, it also has the lowest risk of drug-drug interactions involving CYP.     

HMG-CoA reductase inhibitors in osteoporosis: do they reduce the risk of fracture?

Osteoporosis affects a large number of people in industrialised countries. It has clinical and public-health impacts, most importantly due to subsequent fractures. Osteoporotic fractures are one of the most common causes of disability and are associated with enormous healthcare expenditure. The majority of existing treatment options for osteoporosis only inhibit bone resorption and prevent excessive bone loss but are not capable of stimulating bone formation. However, several recent in vitro and in vivo studies in animals demonstrated that HMG-CoA reductase inhibitors stimulate the production of bone morphogenetic protein (BMP-2), which is a potent regulating protein in osteoblast differentiation and activity. This suggests that HMG-CoA reductase inhibitors may have an anabolic effect on bones, making them a potentially interesting treatment option for osteoporosis. Additionally, several studies in humans showed that some HMG-CoA reductase inhibitors may have a beneficial effect on bone turnover and may lead to an increase in bone mineral density. Consequently, several observational studies tried to evaluate whether use of HMG-CoA reductase inhibitors is associated with a decreased risk of fractures. Even though not all results of these epidemiological studies, using different designs in different study populations, were entirely consistent, they provided substantial evidence that HMG-CoA reductase inhibitor use may decrease the bone fracture risk by approximately 50%. On the other hand, reanalysis of two randomised controlled trials of HMG-CoA reductase inhibitor therapy, designed to assess cardiovascular outcomes, could not show that patients treated with HMG-CoA reductase inhibitors had a lower fracture risk in comparison with placebo-treated patients. Therefore, to conclusively assess the potential of HMG-CoA reductase inhibitors in the prevention and treatment of osteoporosis, randomised controlled trials need to be performed to address this conflicting issue. Until the results of such trials are available, practitioners should prescribe the drugs that have been proven to reduce the risk of osteoporotic fractures.     

Are all heparins safe for on-pump heart surgery?

ABSTRACT

Background: Intravenous Panpharma heparin^® was used in all on-pump cardiac surgery in our heart-surgery department for a short period. This brand of heparin replaced the previous Choay heparin^® heparin supplied by the Sanofi-Aventis Laboratory. Unusual postoperative bleedings over this period prompted us to evaluate postoperative hemostasis by comparing these two heparins.

Methods: We compared data from patients who had undergone on-pump cardiac surgery during Panpharma heparin^® period (group P, 257 patients) to those how received Choay heparin^® (group C, 194 patients).

Results: Despite group P receiving a significantly lower dose of heparin (mean dose 21,000 IU/CEC) compared to group C (mean dose 22,000 IU/CEC) (p = 0.05), the number of surgical re-explorations needed to perfect postoperative hemostasis was significantly higher for group P (3.5% vs. 0) (p = 0.01). Heparin anti-Xa activity after surgery was higher in group P at postoperative h1 and h12 compared to group C, which explained reoperations for hemostasis.

Conclusion: Despite standardization, variations remain regarding anticoagulant activity between different manufacturing processes and heparin preparations. Surgical teams need to be aware that the biological effects of different brands of heparin may not be as expected and could endanger a usually safe procedure, such as cardiac surgery.     

HMG-CoA reductase inhibitors: do they have potential in the treatment of polycystic ovary syndrome?

Many women of reproductive age are affected by polycystic ovary syndrome (PCOS), a heterogeneous endocrinopathy characterized by androgen excess, chronic oligo-anovulation and/or polycystic ovarian morphology. In addition, PCOS is often associated with insulin resistance, systemic inflammation and oxidative stress, which, on one hand, lead to endothelial dysfunction and dyslipidaemia with subsequent cardiovascular sequelae and, on the other hand, to hyperplasia of the ovarian theca compartment with resultant hyperandrogenism and anovulation. Traditionally, HMG-CoA reductase inhibitors (statins) have been used to treat dyslipidaemia by blocking HMG-CoA reductase (the rate-limiting step in cholesterol biosynthesis); however, they also possess pleiotropic actions, resulting in antioxidant, anti-inflammatory and anti-proliferative effects. Statins offer a novel therapeutic approach to PCOS in that they address the dyslipidaemia associated with the syndrome, as well as hyperandrogenism or hyperandrogenaemia. These actions may be due to an inhibition of the effects of systemic inflammation and insulin resistance/hyperinsulinaemia. Evidence to date, both in vitro and in vivo, suggests that statins have potential in the treatment of PCOS; however, further clinical trials are needed before they can be considered a standard of care in the medical management of this common endocrinopathy.     

Who should receive HMG CoA reductase inhibitors?

During the last decade, the development of the HMG CoA reductase inhibitors, commonly referred to as 'statins', has contributed greatly to cholesterol lowering therapy and cardiovascular risk reduction. These agents are well tolerated and efficacious. Data on nearly 30,000 patients from five long-term randomised, placebo-controlled trials of statins have clearly demonstrated that a broad range of individuals can benefit from such therapy. These include men or women, younger or older individuals, those with elevated or normal cholesterol levels, with or without myocardial infarction or symptomatic coronary heart disease, with or without hypertension or diabetes mellitus, and those who are smokers or non-smokers. Benefits include reductions in the risks for myocardial infarction, and coronary, cardiovascular and all-cause mortality, stroke and the need for coronary revascularisation. Results of the recently completed Heart Protection Trial have clearly confirmed the results of the earlier trials and support the use of statin therapy in secondary prevention. The role of statins in acute coronary syndromes is being actively evaluated and appears promising. In primary prevention, the data are not as convincing and generalisations cannot be made as to whether, and in which subgroup, drug therapy to lower low density lipoprotein (LDL) cholesterol should be initiated. There are important cost implications to consider and the use of statin therapy has to be judged on an individual basis, particularly in those with high or very high LDL cholesterol levels and/or with multiple risk factors rendering them at high short- and long-term risk of coronary heart disease. There is evidence of a 'care gap' in translating trial data into practice, even in secondary prevention, and this needs closing in order to improve patient outcomes.     

Is N-acetyl cysteine protective against monocrotaline-induced toxicity?

Abstract

Monocrotaline (MCT) is a pyrrolizidine alkaloid which induces cardio-pulmonary toxicity and hepatotoxicity in animals and humans. MCT is frequently ingested because of food grain contamination accidentally or in the form of herbal medicine preparations. The aim of this study was to observe the protective effect of N-acetyl cysteine (NAC) on MCT-induced pulmonary toxicity and hepatotoxicity. According to our results (right ventricular pressures [RVPs], ratios of right ventricle (RV)/heart weight (HW), plasma AST levels, liver glutathione levels, liver MDA levels and liver histopathological examinations of groups), protective effects were observed with NAC treatment in both MCT-induced pulmonary toxicity and hepatotoxicity.     

Anti-oxidants-- a protective role in cardiovascular disease?

Established risk factors for cardiovascular disease (CVD), such as hypertension, smoking and diabetes mellitus, explain only some of the observed variation in clinical events. This has maintained interest in other nutritional and biochemical factors that might contribute to the underlying pathophysiology of CVD. All of these risk factors are associated with increased oxidative stress in the vessel wall, which may contribute to CVD by several mechanisms. Studies in animal models of CVD have suggested that natural and synthetic anti-oxidants can prevent the development of clinical end points. These observations have generated the hypothesis that anti-oxidant therapy might also prevent CVD in human populations. This has been supported by epidemiological studies showing a negative correlation between circulating concentrations or dietary intake of natural anti-oxidant vitamins and CVD event rate. Many studies have also demonstrated a beneficial effect of anti-oxidants on surrogate markers of CVD such as endothelial function and lipoprotein oxidation. However, the results of large prospective randomised controlled intervention trials, mostly involving vitamin E in patients at increased risk of CVD, have been disappointing and have failed to demonstrate the anticipated benefits. This paper will critically examine the evidence and try to offer some explanation for the apparent failure of animal and epidemiological data to translate into meaningful clinical benefits.     

Anti-oxidants - a protective role in cardiovascular disease?

Established risk factors for cardiovascular disease (CVD), such as hypertension, smoking and diabetes mellitus, explain only some of the observed variation in clinical events. This has maintained interest in other nutritional and biochemical factors that might contribute to the underlying pathophysiology of CVD. All of these risk factors are associated with increased oxidative stress in the vessel wall, which may contribute to CVD by several mechanisms. Studies in animal models of CVD have suggested that natural and synthetic anti-oxidants can prevent the development of clinical end points. These observations have generated the hypothesis that anti-oxidant therapy might also prevent CVD in human populations. This has been supported by epidemiological studies showing a negative correlation between circulating concentrations or dietary intake of natural anti-oxidant vitamins and CVD event rate. Many studies have also demonstrated a beneficial effect of anti-oxidants on surrogate markers of CVD such as endothelial function and lipoprotein oxidation. However, the results of large prospective randomised controlled intervention trials, mostly involving vitamin E in patients at increased risk of CVD, have been disappointing and have failed to demonstrate the anticipated benefits. This paper will critically examine the evidence and try to offer some explanation for the apparent failure of animal and epidemiological data to translate into meaningful clinical benefits.     

Are aromatase inhibitors effective in endometriosis treatment?

INTRODUCTION: Current therapies for endometriosis cannot completely cure the disease, and patients present with high recurrence rates. Novel medical approaches are, therefore, needed. AREAS COVERED: In endometriosis, aromatase was long thought to be involved in the in situ formation of estrogens, leading to a positive feedback loop favoring estrogens, themselves inducing prostaglandin production and inflammation. This hypothesis led to aromatase inhibitors (AIs) being proposed as the new medical therapy for endometriosis, as reported in all the studies reviewed here. Recent findings nevertheless indicate that aromatase may be less implicated in endometriosis than previously postulated. More than 10 years after the first successful treatment of a rare and severe case of postmenopausal endometriosis with an AI, there are only three small randomized controlled trials in the literature. EXPERT OPINION: Until recently, AIs were thought to be an alternative to current medical therapies for endometriosis. However, recent findings question their real utility in clinical practice in the context of this disease. Because there is no strong evidence of their efficacy or benefit compared to other molecules in existing clinical trials, AIs need to be investigated further in well-designed studies to confirm/disprove their hypothetical impact on endometriotic lesions.     

NGF and heart: Is there a role in heart disease?

The review emphasizes the role of NGF, the most representative member of the neurotrophins family, in cardiac physiopathology with a particular focus on healing and sprouting processes occurring after tissue damage. Cardiac and circulating NGF levels dramatically increase following myocardial injury (MI). A very early rise of this neurotrophin is indeed observed soon after MI (hours). Such a rise may lead to sympathetic nerve sprouting which may underlie the later genesis of arrhythmias but may also favor the healing process. At later times (months after), when heart failure develops, the opposite is detected and NGF tissue levels are below the normal range, an event that may in turn participate to defective innervation and cardiac failure. Through a careful analysis of preclinical and clinical studies, this review proposes that time is the key variable when studying these opposite changes in NGF expression observed following MI and attempting to interpret and correlate them with cardiac physiopathology. The examination of the results leads to the speculation that NGF modulation may be a pharmacological target for interventions in specific stages of heart dysfunction following MI.     

Should ranolazine be used for all patients with ischemic heart disease or only for symptomatic patients with stable angina or for those with refractory angina pectoris? A critical appraisal

Introduction: Ranolazine is a novel antianginal and anti-ischemic agent, that, unlike other available antianginal drugs in the United States (beta-blockers, organic nitrates, and calcium channel blockers), has no significant effect on either heart rate or blood pressure. Its exact mechanism of action is unknown. Ranolazine does increase electrocardiographic QTc interval in a dose-related manner, but at therapeutic doses it has no proarrhythmic effects. Ranolazine (ER) at doses of 500 and 1,000 mg twice daily is currently approved for the treatment of angina pectoris either as monotherapy or added to beta-blockers, nitrates, and calcium channel blockers. Ranolazine (ER) is currently not approved for the treatment of unstable angina, silent ischemia, or cardiac arrhythmias. The most common adverse effects reported in clinical trials during ranolazine (ER) treatment are dizziness, headaches, constipation, and nausea.

Areas covered: Recent changes in ranolazine (ER) labeling have led to its increased use for treating patients with ischemic heart disease. This review addresses its appropriate use. All publications were reviewed and those relevant were included.

Expert opinion: Ranolazine (ER) is an effective antianginal and anti-ischemic agent, but I restrict its use to treat patients with stable angina pectoris.     

Therapeutic opportunities in Alzheimer disease: one for all or all for one?

In recent years, Alzheimer disease (AD) has received great attention as an incurable and fatal disease that threatens the lives of aging individuals. Debates regarding areas of research and treatment designs have made headlines as scientists in the field question ongoing work. Despite these academic quarrels, significant insights concerning the cellular and molecular basis of AD have illuminated the potential causes and consequences of AD pathogenesis in the human brain. Additionally, assigning relationships among scientific evidence is difficult due to the nature of the disease. It is crucial to note that all findings do not constitute causality as AD has many stages of progression, and therefore a particular finding may reflect disease epiphenomenon. Determining the primary causes of disease are even more problematic when considering that a succinct timeline in which a normal aging brain develops AD-like changes due to a single cause may not be appropriate, as increasing lines of evidence indicate that multiple factors likely contribute to the clinical manifestation of AD. Implications for therapeutic strategies are dramatically affected by viewing AD as a multi-factorial disease state, one specific treatment may not be able to prevent or reverse AD if this is indeed the case. In this regard, the current focus on individual therapeutic targets may prove to be ineffective in the successful treatment of AD; however, if taken in combination, these singular therapies may likely result in the global suppression of AD. In this review, the scientific basis for common AD therapeutics as well as the efficacy of these treatments will be discussed.