Low-density lipoprotein reduction in high-risk patients: How low do you go?

Cardiovascular disease and its clinical sequelae remain the leading causes of morbidity and mortality in many regions of the world. Dyslipidemia is a critical risk factor to intercept in both the primary and secondary prevention of acute cardiovascular events. The prospective, placebo-controlled clinical trials conducted with statins over the course of the past 15 years have conclusively demonstrated that these drugs significantly reduce risk for fatal and nonfatal myocardial infarction, ischemic stroke, unstable angina, and frequency of myocardial ischemia, as well as cardiovascular and all-cause mortality. Of considerable interest is the fact that, even under the exquisitely controlled circumstances of a clinical trial, endpoint reductions in these trials typically occur in the range of 20% to 35%. Understandably, much attention is now being focused on deriving the pharmacologic means by which to further increase the magnitude of endpoint reduction. Epidemiologic investigation has demonstrated that the relationship between cholesterol and risk for atherosclerotic disease is a continuous one. Consequently, it is reasonable to assume that more aggressive reductions of low-density lipoprotein (LDL) cholesterol might result in even greater reductions of cardiovascular event rates and atheromatous plaque progression than heretofore observed. Two recent clinical trials, Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) and Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE IT), prospectively tested and confirmed the validity of more aggressive LDL cholesterol lowering in high-risk patients with established coronary artery disease.     

LDL cholesterol: How low to go?

Epidemiology and the results of large-scale outcome trials indicate that the association of LDL with atherosclerotic cardiovascular disease is causal, and continuous not only across levels seen in the general population but also down to sub-physiological values. There is no scientific basis, therefore, to set a target or ‘floor’ for LDL cholesterol lowering, and this presents a clinical and conceptual dilemma for prescribers, patients, and payers. With the advent of powerful agents such as proprotein convertase/subtilisin kexin type 9 (PCSK9) inhibitors, LDL cholesterol can be lowered profoundly but health economic constraints mandate that this therapeutic approach needs to be selective. Based on the need to maximize the absolute risk reduction when prescribing combination lipid-lowering therapy, it is appropriate to prioritize patients with the highest risk (aggressive and established CVD) who will obtain the highest benefit, that is, those with elevated LDL cholesterol on optimized statin therapy.     

LDL reduction: How low should we go and is it safe?

High-dose statin therapy or combination statin treatment is necessary for most patients to achieve aggressive lowdensity lipoprotein cholesterol goals. Adding ezetimibe or bile acid sequestrants appears unlikely to increase the risk of myopathy. Although the combination of niacin or fenofibrate with moderate-dose statins appears to be reasonably safe, the safety of combination with highdose statins has yet to be determined. To enhance patient outcomes, attention must be paid to characteristics that predict muscle and hepatic statin toxicity when considering using high-dose statin or combination statin therapy     

Depression and CHD risk: How should we intervene?

Opinion statement Depression is common in the community and is a risk factor for the development of coronary heart disease (CHD). In patients with CHD, the prevalence of major depression is nearly 20% and the prevalence of minor depressive disorder is approximately 27%. When present in patients with existing CHD, depression is independently associated with worse outcome, including higher morbidity and mortality, and worse health status. Observational studies suggest that use of antidepressant medications in patients with CHD is associated with decreased risk of cardiovascular events. However, only one randomized controlled trial, the ENRICHD (Enhancing Recovery in Coronary Heart Disease) study, was designed to evaluate whether treatment of depression in patients with CHD can improve cardiac prognosis. Although the study showed that cognitive behavior therapy was better than usual care in improving depression, there was no improvement in all-cause mortality or recurrent cardiac events. There have been no clinical trials specifically designed to evaluate whether pharmacologic treatment of depression improves cardiovascular outcomes in patients with CHD. Thus, there is a clear need for additional trials testing interventions to improve cardiac prognosis based on treatment of depression. In the meantime, depression remains an important illness in its own right and deserves treatment. Safe and effective treatments of depression in patients with CHD include cognitive behavior therapy and selective serotonin reuptake inhibitors.     

High blood pressure in dementia: How low can we go?

Hypertension is an important public health concern. The prevalence keeps increasing, and it is a risk factor for several adverse health outcomes including a decline in cognitive function. Recent data also show that the prevalence of hypertension and age‐related dementia is rising in Asian countries, including in the oldest old group. This study aims to discuss possible treatments for high blood pressure in the elderly and propose an optimal target for BP relative to cognitive outcomes. This review discusses several studies on related blood pressure treatments that remain controversial and the consequences if the treatment target is too low or aggressive. Longitudinal, cross‐sectional, and RCT studies were included in this review. An optimum systolic blood pressure of 120‐130 mm Hg is recommended, especially in nondiabetic hypertensive patients with significant risk factors. In the oldest old group of patients, hypertension might have a protective effect. The use of calcium channel blockers (CCB) and angiotensin receptor blocker (ARB) is independently associated with a decreased risk of dementia in older people. However, personalized care for patients with hypertension, especially for patients who are frail or very old, is encouraged.     

Low-density lipoprotein reduction: Is the risk worth the benefit?

Outcomes from recent lipid-lowering trials have led to an update of the third Report of the National Cholesterol Education Program (NCEP) Adult Treatment Panel’s guidelines for treatment of hypercholesterolemia in adults. The updated NCEP guidelines now offer an optional goal of low-density lipoprotein (LDL) cholesterol of less than 70 mg/dL for high-risk individuals. Epidemiologic and clinical trial data suggest that for every 30-mg/dL change in LDL, the relative risk for coronary heart disease changes by about 30%. Statin therapy effectively lowers LDL and has an overall excellent safety profile in clinical trials. However, the use of high-dose statin therapy also entails greater risk of adverse events, such as myopathy and liver function test abnormalities, and this must be carefully weighed against the potential benefit for each patient. Alternative approaches targeting high-density lipoproteins and triglycerides may offer yet another option for coronary heart disease prevention in high-risk patients.     

How should we manage the patient?

The patient with HCV infection may present with a variety of problems and range from the asymptomatic patient with mild liver damage to a patient presenting with complications of cirrhosis or hepatocellular carcinoma. The diagnosis of hepatitis C may be a complete surprise to the patient or be an expected diagnosis in someone with known risk factors. Similarly the physician may be faced with a patient who knows very little about hepatitis C or someone who has read extensively on the subject. The initial consultation is useful for gaining information on the patient's background, physical examination may give useful clinical clues on the stage of the liver disease. The consultation gives the physician a chance to educate the patient on the current thinking on hepatitis C and to organize confirmatory and other investigations that will help decide on the next line of management, i.e. whether the patient is a candidate for combination therapy of interferon and ribavirin.     

PCSK9 inhibition: the dawn of a new age in cholesterol lowering?

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a circulating enzyme of hepatic origin that plays a key role in LDL receptor turnover. Genetic studies have confirmed that individuals with gain-of-function PCSK9 mutations have increased PCSK9 activity, elevated LDL-cholesterol levels and a severe form of familial hypercholesterolaemia. Those with variants leading to reduced PCSK9 have lower LDL-cholesterol levels and a reduced risk of coronary heart disease, and this has led to the development of various strategies aimed at reducing circulating PCSK9. Monoclonal antibodies to PCSK9, given every 2–4 weeks by subcutaneous injection, have been shown to reduce LDL-cholesterol by 50–60% compared with placebo in individuals with and without diabetes. PCSK9 inhibition also reduces lipoprotein(a), an atherogenic lipid particle, by around 20–30%. Major cardiovascular outcome trials for two agents, evolocumab and alirocumab, are expected to report from 2017. These trials involve over 45,000 participants and are likely to include about 15,000 individuals with diabetes. PCSK9-binding adnectins have been employed as an alternative method of removing circulating PCSK9. Small interfering RNA targeting messenger RNA for PCSK9, which acts by reducing hepatic production of PCSK9, is also under investigation. These agents may only need to be given by subcutaneous injection once every 4–6 months. Ongoing trials will determine whether anti-PCSK9 antibody therapy safely reduces cardiovascular risk, although high cost may limit its use. Development of PCSK9-lowering technologies cheaper than monoclonal antibodies will be necessary for large numbers of individuals to benefit from this approach to lowering cholesterol.     

Computed tomography colonography and radiation risk: How low can we go?

Computed tomography colonography(CTC) has become a key examination in detecting colonic polyps and colorectal carcinoma(CRC). It is particularly useful after incomplete optical colonoscopy(OC) for patients with sedation risks and patients anxious about the risks or potential discomfort associated with OC. CTC's main advantages compared with OC are its non-invasive nature, better patient compliance, and the ability to assess the extracolonic disease. Despite these advantages, ionizing radiation remains the most significant burden of CTC. This opinion review comprehensively addresses the radiation risk of CTC, incorporating imaging technology refinements such as automatic tube current modulation, filtered back projections, lowering the tube voltage, and iterative reconstructions as tools for optimizing low and ultra-low dose protocols of CTC. Future perspectives arise from integrating artificial intelligence in computed tomography machines for the screening of CRC.     

How should we measure blood pressure in the doctor's office?

BACKGROUND: Blood pressure is the most ubiquitous diagnostic recording made in the doctor's office, but the measurement is subject to a number of sources of bias, which may lead to over- or underestimation. The current study examined the systematic influence of the way in which the measurements were taken - by the physician, by a nurse, or with the patient sitting alone, using an automated device. SUBJECTS AND METHODS: Blood pressure was measured in 17 essential hypertensive and 10 white-coat hypertensive individuals. On separate clinic visits, measurements were taken by the attending physician, by a nurse and using an automated device (Arteriosonde 1216). RESULTS: A repeated-measures ANOVA revealed that, for systolic pressure, there was a significant effect of measurement modality on blood pressure. Physician systolic pressures were on average approximately 10 mmHg higher than those taken by a nurse, nurse pressures being approximately 7 mmHg higher than those recorded using Arteriosonde. The effect on diastolic pressure was similar but smaller, and no nurse-Arteriosonde difference was observed. CONCLUSIONS: We conclude that the routine clinical assessment of blood pressure would be more representative of daily ambulatory pressure if an automated device, without doctor or nurse present, were used.     

How should we treat gastric cancer in the very elderly?

Background/Aims: We aimed to clarify the clinicopathological features of gastric cancer in very elderly patients and to identify appropriate surgical therapy for them, focused particularly on their prognosis. Methodology: Patients who underwent gastrectomy for gastric cancer in Oita University Hospital were included in this study. The patients were divided into two groups: the very elderly group (80 years or older) (E group) and the middle-aged group (ranging from 40 to 79 years) (M group). Their clinicopathological features and postoperative survival were compared. Results: Type 3,4 macroscopic types, INFγ and number of dissected lymph nodes were significantly less in the E group than in the M group (p=0.0092, p=0.0077, p=0.0475, respectively). Overall survival and disease-free survival were shorter for the E group (p=0.0898, p=0.0566, respectively). When other cause-related deaths were considered to be lost to follow-up, there was no significant difference between the E group and the M group. Conclusions: Whenever radical resection is possible, surgical resection for gastric cancer, even in the very elderly, should not be denied. Nevertheless, surgeons should try to do less invasive surgery, especially for the very elderly.