Efficacy and safety in clinical trials in cardiovascular disease

Mortality and morbid events are insensitive guides to the efficacy and safety of interventions in chronic cardiovascular disease (CVD). To enhance the ability to find new and effective long-term treatments, especially for the early stages of CVD, a revised strategy for clinical trials should emphasize efficacy on disease progression while monitoring symptoms and quality of life as guides to clinical benefit. Mortality, which is uncommon except in acute or advanced disease, provides at best a crude guide to net efficacy and safety. It must be monitored to support demonstrated efficacy on disease progression without adverse safety effects. This revised approach, made possible by our enhanced ability to monitor the progression of disease, should make it possible to study earlier disease and to improve cardiovascular health while reducing health care costs.     

慢性肾脏疾病的最新调脂进展

血脂异常是慢性肾脏疾病的常见并发症,也是导致动脉粥样硬化性心血管疾病的独立危险因素.慢性肾脏病患者心血管疾病的发病率及病死率明显增加.尽管许多研究证实他汀降脂药物可以明显降低心血管疾病的发病率及死亡率,但是对于慢性肾脏疾病患者的调脂治疗能否降低心血管疾病的发病率及死亡率仍存在争议.现主要针对慢性肾脏疾病患者采取药物调脂治疗,降低心血管事件及保护肾脏的有效性及药物的安全性等问题的最新临床研究现状进行综述.     

Cardiovascular protection with sodium-glucose co-transporter-2 inhibitors in type 2 diabetes: Does it apply to all patients?

Patients with type 2 diabetes (T2D) are at an increased risk of cardiovascular disease (CVD). Cardiovascular risk in these patients should be considered as a continuum, and comprehensive treatment strategies should aim to target multiple disease risk factors. Large-scale clinical trials of sodium-glucose co-transporter-2 (SGLT2) inhibitors have shown an impact on cardiovascular outcomes, including heart failure hospitalization and cardiovascular death, which appears to be independent of their glucose-lowering efficacy. Reductions in major cardiovascular events appear to be greatest in patients with established CVD, particularly those with prior myocardial infarction, but are independent of heart failure or renal risk. Most large-scale trials of SGLT2 inhibitors predominantly include patients with T2D with pre-existing CVD and high cardiovascular risk at baseline, limiting their applicability to patients typically observed in clinical practice. Real-world evidence from observational studies suggests that there might also be beneficial effects of SGLT2 inhibitors on heart failure hospitalization and all-cause mortality in various cohorts of lower risk patients. The most common adverse events reported in clinical and observational studies are genital infections; however, the overall risk of these events appears to be low and easily managed. Similar safety profiles have been reported for elderly and younger patients. There is still some debate regarding the safety of canagliflozin in patients at high risk of fracture and amputation. Outstanding questions include specific patterns of cardiovascular protection according to baseline risk.     

Oxidative Stress and Cardiovascular Disease: Antioxidants and Unresolved Issues

Experimental and clinical studies suggest that oxidative stress contributes to the development and progression of cardiovascular disease. However, clinical trials with classic vitamin antioxidants failed to demonstrate any benefit in cardiovascular outcomes. Recent advances in our understanding of mechanisms involved in free radical generation reinstate that a more comprehensive approach targeting the prevention of reactive oxygen species (ROS) formation early in the disease process may prove beneficial. Experimental studies and reviews in oxidative stress were selected to provide a better understanding of the roles of the reactive species in the initiation and progression of cardiovascular disease (CVD). Clinical studies that evaluated the efficacy of several classes of antioxidants in CVD were included in the second part of this review to discuss future therapeutic guidelines based on currently available evidence. In conclusion, before a potential role for antioxidants in the treatment of CVD is eliminated, more carefully designed studies with classic as well as new antioxidants in well‐defined patient populations are warranted to provide a definitive answer.     

Anxiety and Cardiovascular Disease Risk: a Review

Unrecognized anxiety is a difficult clinical presentation in cardiology. Anxiety leads to recurring emergency department visits and the need for numerous diagnostic evaluations to rule out cardiovascular disease (CVD). This review focuses broadly on anxiety and its subtypes in relation to the onset and progression of CVD while describing helpful guidelines to better identify and treat anxiety. Potential mechanisms of cardiopathogenesis are also described. An emerging literature demonstrates that anxiety disorders increase the risk for incident CVD but a causal relationship has not been demonstrated. Anxiety portends adverse prognosis in persons with established CVD that is independent from depression. The level of clinical priority received by depression should be extended to research and clinical intervention efforts in anxiety. Anxiety holds direct relevance for uncovering mechanisms of cardiopathogenesis, developing novel therapeutic strategies, and initiating clinical interventions in the population at risk of developing heart disease, or those already diagnosed with CVD.     

Burden of cardiovascular disease in Canada

BACKGROUND: This report updates the death estimates for cardiovascular disease (CVD) in Canada and introduces a population-based perspective on disease prevalence and health-related quality of life (HRQOL) burden. METHODS: The Canadian Mortality Database was used to estimate the mortality of men and women in different age groups for the 139 Canadian health regions from 1950 to 1999. Heart disease prevalence and its impact on HRQOL were estimated using the 2000-2001 Canadian Community Health Survey (CCHS). Life table techniques were used to estimate the impact of heart disease on life and health expectancy. RESULTS: Although CVD remains the leading cause of death in Canada, between 1950 and 1999 the death rates from CVD dropped from 702 per 100,000 to 288 per 100,000 men, and from 562 per 100,000 to 175 per 100,000 women. Results from the CCHS indicated that 5.4% of men and 4.6% of women reported having heart disease as diagnosed by a medical professional. Of these individuals, 14% of men and 21% of women reported difficulty ambulating - about six times more than people without heart disease. In total, 4.5 years of life expectancy and 2.8 years of health expectancy were lost due to CVD. The study also found large differences in the burden of CVD among men and women and across the 139 Canadian health regions. CONCLUSIONS: CVD is a major disease burden in terms of both mortality and HRQOL and is an important source of health inequalities between populations in Canada. Any attempt to improve the health of Canadians or to reduce health inequalities should include interventions to reduce CVD mortality and morbidity. Given the present impact of CVD on HRQOL, reducing or eliminating heart disease may potentially result in an increase in life expectancy that will be larger than the gains in health expectancy.     

The art of cardiovascular risk assessment

Cardiovascular disease (CVD) remains the leading cause of death in the United States. Healthcare expenditures have been principally allocated toward treatment of CVD at the end of the health/disease continuum, rather than toward health promotion and disease prevention. A focused effort on both primordial and primary prevention can promote cardiovascular health and reduce the burden of CVD. Risk‐factor assessment for predicting atherosclerotic CVD events serves as the foundation of preventive cardiology and has been driven by population‐based scoring algorithms based on traditional risk factors. Incorporating individual nontraditional risk factors, biomarkers, and selective use of noninvasive measures may help identify more at‐risk patients as well as truly low‐risk individuals, allowing for better targeting of treatment intensity. Using a combination of validated population‐based atherosclerotic CVD risk‐assessment tools, nontraditional risk factors, social health determinants, and novel markers of atherosclerotic disease, we should be able to improve our ability to assess CVD risk. Through scientific evidence, clinical judgment, and discussion between the patient and clinician, we can implement an effective evidence‐based strategy to assess and reduce CVD risk.     

Assessment of capacity for cardiovascular disease control and prevention in Thailand: a qualitative study

The present study explored community members' knowledge and perceptions about cardiovascular disease (CVD), risk factors and prevention, and identified the current capacity of primary care providers to manage and control CVD at the provincial level. A qualitative study, including in-depth interviews and focus group discussions, was conducted in Suphan Buri Province, Thailand. Participants included community members, CVD patients and healthcare providers in health centers and hospitals. The results showed that community members had little knowledge about the symptoms and signs of heart attack or stroke. They perceived that existing health centers and community hospitals were not sufficiently equipped to treat CVD patients. Primary healthcare workers reported that they lacked skills to manage heart disease, particularly emergency care. Physicians said that they had too little time to educate patients and felt that medical schools should update their curricula, including practical training on CVD management in a low-resource setting. Nurses reported that they had inadequate training in health education for the prevention of CVD. There was a problem of inadequate feedback mechanisms in the existing referral system for continuing improvement. All of the health professionals agreed that more community participation and the involvement of non-health sectors and non-government organizations were needed in the national CVD control program. In conclusion, capacity building for strengthening CVD prevention and control at the primary care level should be implemented. The existing training and education systems have to be revised with an orientation towards health promotion and disease prevention. Publicity of CVD burden and preventive measures, and local programs, should be implemented with community participation.     

Subclinical cardiovascular disease in older adults: insights from the Cardiovascular Health Study

Knowledge about the epidemiology of subclinical cardiovascular disease (SCVD) in older adults may hold the key for improved opportunities for primary prevention of cardiovascular disease (CVD), a top clinical and public health priority. This review reports findings on the prevalence of SCVD and the ability of SCVD measures to predict incident and adverse outcomes from one of the largest (N=5888) and most comprehensive prospective observational studies on SCVD in older adults, the Cardiovascular Health Study. According to a composite index that combined SCVD measures from different vascular beds, the overall prevalence of SCVD was 37%, making it as common as clinically overt CVD in older adults. SCVD measures strongly predicted incident CVD, stroke, mortality, frailty, and physical and cognitive decline, even after adjustment for traditional CVD risk factors. Ongoing research will address the potential use of SCVD for clinical decision making in older adults.     

Regression of Atherosclerosis

Atherosclerotic cardiovascular disease (CVD) is a complex disorder that leads to premature death and hospitalization. Several drugs have been, or are currently being tested for their ability to reduce cardiovascular mortality and/or promote regression of atherosclerotic lesions. In addition to "hard end point" clinical trials in which total and cardiovascular mortality as well as risk of incident myocardial infarction are considered as outcomes, trials with surrogate end points using imaging biomarkers can rapidly assess the efficacy of new cardiovascular drugs. Low-density lipoprotein-based therapies with statins have been shown to promote atherosclerosis regression, and several other drugs targeting high-density lipoproteins or inflammation/oxidation are currently being tested in both outcomes and imaging trials in which atherosclerosis regression is anticipated. In this review, we focus on the latest progress in CVD and highlight novel drugs that tackle atherosclerosis as well as the currently used and upcoming imaging techniques to optimally measure atherosclerosis progression.     

Efficacy of medical treatment in Cushing's disease: a systematic review

Due to the positive effects demonstrated in randomized clinical trials on cardiovascular surrogate markers and bone metabolism, a positive effect of growth hormone (GH) treatment on clinically relevant end‐points seems feasible. In this review, we discuss the long‐term efficacy and safety of GH treatment in adult patients with growth hormone deficiency (GHD) with emphasis on morbidity: fatal and nonfatal cardiovascular disease (CVD) and stroke, fractures, fatal and nonfatal malignancies and recurrences, and diabetes mellitus. A positive effect of GH treatment on CVD and fracture risk could be concluded, but study design limitations have to be considered. Stroke and secondary brain tumours remained more prevalent. However, other contributing factors have to be taken into account. Regrowth and recurrences of (peri)pituitary tumours were not increased in patients with GH treatment compared to similar patients without GH treatment. All fatal and nonfatal malignancies were not more prevalent in GH‐treated adults compared to the general population. However, follow‐up time is still relatively short. The studies on diabetes are difficult to interpret, and more evidence is awaited. In clinical practice, a more individualized assessment seems appropriate, taking into consideration the underlying diagnosis of GHD, other treatment regimens, metabolic profile and the additional beneficial effects of GH set against the possible risks. Large and thoroughly conducted observational studies are needed and seem the only feasible way to inform the ongoing debate on health care costs, drug safety and clinical outcomes.     

Physical activity and cardiovascular disease prevention in women: A review of the epidemiologic evidence

Epidemiologic studies suggest that as little as 30 minutes of moderate-intensity physical activity per day can lower the risk of developing cardiovascular disease in women. Sedentary individuals who become physically active even at older ages derive cardiovascular benefits. Physical activity appears to slow the initiation and progression of CVD through salutary effects not only on adiposity but also on insulin sensitivity, glycemic control, incident type 2 diabetes, blood pressure, lipids, endothelial function, hemostasis, and inflammatory defense systems. Public health initiatives that promote moderate increases in physical activity may offer the best balance between efficacy and feasibility to improve cardiovascular health in sedentary populations.     

Cardiovascular risk assessment tools in Asia

Cardiovascular disease (CVD) is becoming the most important burden to health care systems in most part of the world, especially in Asia. Aiming at identifying high risk individuals and tailoring preventive treatment, many cardiovascular risk assessment tools have been established and most of them were developed in Western countries. However, these cardiovascular risk assessment tools cannot be used interchangeably without recalibration because of the different risk factor profiles (ie, greater absolute burden of hypertension and lower level of total‐cholesterol in Asians and higher prevalence of metabolic disorders in South Asians) and different CVD profiles (higher ratio of stroke/coronary heart disease in Asians) between Western and Asian populations. Original risk models such as Prediction for ASCVD Risk in China (China‐PAR) and Japan Arteriosclerosis Longitudinal Study (JALS) score have been developed and well validated for specific countries, while most of countries/regions in Asia are using established models. Due to higher incidence of stroke in Asians, risk factors like hypertension should weigh more in cardiovascular risk assessment comparing with Western populations, but their actual proportions should be based on CVD profiles in specific countries/regions. The authors encourage the development of new cardiovascular risk assessment tools for Asians, if possible. Still, modifying established models with native epidemiological data of risk factor as well as CVD is acceptable in regions where health care resources are insufficient.     

Chronic kidney disease and cardiovascular risk

Chronic kidney disease (CKD) is a global public health concern, and there is emerging a strong relationship between CKD and increased cardiovascular disease (CVD) risk. CKD in the presence of other co-morbidities such as type 2 diabetes mellitus (T2DM) and hypertension (HTN) can lead to early progression to end-stage renal disease (ESRD/stage V CKD) and confer a greater risk for CVD morbidity and mortality. CVD events are the leading cause of premature death in patients with CKD, even before their progression to ESRD, with the rate of CVD progression being twice as common compared with the general population. The higher mortality from CVD persists even after adjusting for most of the traditional risk factors, suggesting the possible contributions of uremia-related, nontraditional risk factors. This has led to the current understanding that the pathophysiology of CVD in CKD involves a complex interplay of both the traditional as well as nontraditional, uremia-related risk factors. This review will elaborate on the pathophysiology of CVD in CKD and will discuss the role of microalbuminuria (MAU)-proteinuria as a potential diagnostic and prognostic tool for CVD in CKD risk assessment.     

The importance of treating tobacco dependence

Smoking is a well-established risk factor for cardiovascular disease (CVD). Stopping smoking confers significant health benefits and is especially important for those with pre-exisiting CVD. Healthcare facilities should have systems in place to enable the identification of people who smoke, and ensure that smokers receive evidence based treatments to provide the best possible chances of stopping for good. Physicians have a crucial role to play to prompt quit attempts by giving brief advice to stop, and offering cessation support. Behavioural support strategies such as telephone, individual and group-based counselling improve the chances of long-term abstinence. Nicotine replacement therapy, bupropion and varenicline are medicines that have proven efficacy in aiding smoking cessation and increase the odds of quitting about 2-3 fold compared to placebo. Even patients with established cardiovascular disease can safely use nicotine replacement therapy to help them quit. For the greatest chance of success, physicians should recommend a combination of behavioural support and pharmacotherapy.     

Oxidized PLs and Vascular Inflammation

Future innovative therapies targeting cardiovascular disease (CVD) have the potential to improve health outcomes and to contain rising healthcare costs. Unsustainable increases in the size, cost and duration of clinical trial programs necessary for regulatory approval, however, threaten the entire innovation enterprise. Rising costs for clinical trials are due in large part to increasing demands for hard cardiovascular clinical endpoints as measures of therapeutic efficacy. The development and validation of predictive and surrogate biomarkers, as laboratory or other objective measures predictive or reflective of clinical endpoints, are an important part of the solution to this challenge. This review will discuss insights applicable to CVD derived from the use of predictive biomarkers in oncologic drug development, the evolving role of high density lipoprotein (HDL) in CVD drug development and the impact biomarkers and surrogates have on the continued investment from multiple societal sources critical for innovative CVD drug discovery and development.     

The Role of Ezetimibe in the Treatment of Cardiovascular Disease

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide. Despite the success of treatment of CVD with statin therapy, a number of patients remain at high risk for CVD. Ezetimibe is a non-statin agent that inhibits intestinal cholesterol absorption, leading to reductions in low-density lipoprotein cholesterol (LDL-C). A number of clinical studies evaluating the use of ezetimibe therapy have resulted in discordant data regarding its safety and efficacy. In this review, we discuss the findings from these studies as well as potential indications for the use of ezetimibe for LDL-C lowering and cardiovascular event reduction.     

Mind-Body Connection: Cardiovascular Sequelae of Psychiatric Illness

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the world. Mental health disorders are associated with the onset and progression of cardiac disease. The adverse sequelae of this association include worsened quality of life, adverse cardiovascular outcomes, and heightened mortality. The increased prevalence of CVD is partly explained by increased rates of traditional cardiovascular risk factors including hypertension, hyperlipidemia, diabetes mellitus, obesity, and smoking, but mental illness is an independent risk factor for CVD and mortality. Given the association between mental health disorders and poor cardiovascular health, it is vital to have an early and accurate identification and treatment of these disorders. Our review article shares the current literature on the adverse cardiovascular events associated with psychiatric disorders. We present a review on depression, anxiety, bipolar disorder, schizophrenia, type A and D personality disorders, obsessive-compulsive disorder, and stress.     

Approach to Cardiovascular Disease Prevention in Patients With Chronic Kidney Disease

OPINION STATEMENT: Chronic kidney disease (CKD) is associated with a large burden of cardiovascular risk factors ultimately leading to increased cardiovascular events and mortality. Prevention of cardiovascular disease (CVD) in CKD involves early identification of individuals at high-risk of renal disease. In fact, substantial evidence points to a complex bidirectional relationship between CKD and CVD. Therefore, most interventions directed at CKD prevention should include multiple risk factor interventions with the goal of preventing CVD events while slowing progression of CKD. Clearly, prevention of CVD in CKD is a complex task and requires a multidisciplinary team approach, with a well-defined program, rational targets for each risk factor, and implementation of the most effective intervention strategies. Although several interventions to prevent CVD have proven effective in the general population and in individuals at high risk for CVD, a true benefit in patients with CKD remains to be demonstrated for several of them. A few rational targets of intervention should be optimal blood pressure control, reduction of proteinuria, treatment of dyslipidemia, good control of diabetes, smoking cessation, dietary salt restriction, achievement of normal body mass index, partial correction of anemia, and management of mineral metabolism abnormalities. Lifestyle modification and pharmacological therapy with renin-angiotensin blockers, β-blockers, diuretics, statins, and aspirin should be encouraged in the early stages of CKD.