Update on the treatment and prevention of ischaemic stroke

Stroke continues to have a devastating impact on public health. Recent epidemiological studies suggest that stroke is becoming more common, perhaps due to the ageing of the population and increased survival of patients with cardiac disease. There are specific and well-defined risk factors in patients with stroke, the most important being hypertension. Treatment options to reverse the effect of acute ischaemic stroke are limited. The only approved therapy is intravenous tissue plasminogen activator (tPA). The disadvantage of tPA treatment is a rate of symptomatic haemorrhage of about 6%. Newer stroke prevention options are currently being investigated including statins, oestrogen, angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs). The challenge for physicians is to select the most effective intervention, and this depends on our knowledge of the underlying stroke mechanism and the patient's risk factors.     

Patient preferences regarding atrial fibrillation stroke prophylaxis in patients at potential risk of atrial fibrillation

Background With an increasing number of options for atrial fibrillation (AF) stroke prophylaxis, there are several medication-related factors to consider. This study aimed to gain a better understanding of which preference factors influence patient decisions when selecting AF stroke prophylaxis. Objective To determine the factors that influence patient stroke prophylaxis decisions and preferred therapeutic options. Methods A questionnaire about AF stroke prophylaxis medication options was distributed to participants at risk of AF. Preferences were elicited through ranking and rating medication preference factor statements, then selecting most and least preferred treatment options. Results Reduced stroke risk and lowest risk of an intracranial haemorrhage (ICH) had the highest median preference factor ranking of 2 (IQR, 1–3.5 for stroke reduction; 2–4 for ICH risk). Reducing stroke risk, availability of a lab test to assess drug effect, and availability of an antidote were the preference factors with the highest ratings. Apixaban was the most preferred treatment option (44% blinded to drug name, 37% unblinded) while ‘No treatment’ was the least preferred option (48% blinded, 52% unblinded). Conclusions Reducing stroke risk and limiting ICH risk were the most important medication factors to participants. High inter-participant preference variability suggests the importance of including the patient in decision-making when selecting AF stroke prophylaxis.     

Tissue plasminogen activator-based nanothrombolysis for ischemic stroke

Introduction: Thrombolysis with intravenous tissue plasminogen activator (tPA) is the only FDA approved treatment for patients with acute ischemic stroke, but its use is limited by narrow therapeutic window, selective efficacy, and hemorrhagic complication. In the past two decades, extensive efforts have been undertaken to extend its therapeutic time window and explore alternative thrombolytic agents, but both show little progress. Nanotechnology has emerged as a promising strategy to improve the efficacy and safety of tPA.

Areas covered: We reviewed the biology, thrombolytic mechanism, and pleiotropic functions of tPA in the brain and discussed current applications of various nanocarriers intended for the delivery of tPA for treatment of ischemic stroke. Current challenges and potential further directions of t-PA-based nanothrombolysis in stroke therapy are also discussed.

Expert opinion: Using nanocarriers to deliver tPA offers many advantages to enhance the efficacy and safety of tPA therapy. Further research is needed to characterize the physicochemical characteristics and in vivo behavior of tPA-loaded nanocarriers. Combination of tPA based nanothrombolysis and neuroprotection represents a promising treatment strategy for acute ischemic stroke. Theranostic nanocarriers co-delivered with tPA and imaging agents are also promising for future stroke management.     

癫痫持续状态相关危险因素分析

目的 探讨癫痫持续状态(SE)的相关危险因素情况。方法 选取亳州市人民医院收治的129例癫痫患者, 将79例SE患者作为SE组, 未发生SE 的50例患者作为对照组。回顾分析两组患者一般资料, 同时分析两组患者颅脑损伤、病毒性脑炎急性期、脑血管病等情况, 对SE的影响因素进行统计分析。结果 两组患者颅脑损伤、病毒性脑炎急性期、脑血管病、不规则服药差异有统计学意义(P<0.05), 两组患者家族史、脑皮质发育异常、CO中毒或者酒精中毒、颅内占位病变、发热、脑血管畸形差异无统计学意义(P>0.05)。通过logistic 回归分析, 颅脑损伤、病毒性脑炎急性期、脑血管病、不规则服药为SE的独立危险因素(P<0.05)。结论 颅脑损伤、病毒性脑炎急性期、脑血管病、不规则服药是SE发生的危险因素, 及时规避SE的相关危险因素, 对于临床治疗和提高预后均有重要意义。     

Non-vitamin-K oral anticoagulants (NOACs) for the prevention of secondary stroke

ABSTRACT

Introduction: In patients with atrial fibrillation (AF), oral anticoagulation with vitamin K antagonists (VKA) (warfarin, phenprocoumon) is effective both for primary and secondary stroke prevention with a 60–70% relative reduction in stroke risk compared with placebo. Mortality is reduced by 26%. VKA have a number of well-documented shortcomings which were overcome by non-vitamin-K oral anticoagulants (NOACs).

Areas covered: Results of randomized trials for four NOACs (apixaban, dabigatran, edoxaban, rivaroxaban) have been published (ARISTOTLE, RE-LY, ENGAGE, ROCKET-AF). In this review, the authors discuss the results in subgroups of patients with prior transient ischemic attacks or ischemic stroke. In aggregate, the NOACs are superior to warfarin for secondary prevention and result in a 50% reduction in intracerebral hemorrhage. Apixaban was superior to aspirin in the AVERROES trial and had a similar rate of major bleeding complications.

Expert opinion: NOACs add to the therapeutic options for secondary stroke prevention in patients with AF and offer advantages over warfarin including a favorable bleeding profile and convenience of use. Aspirin should no longer be used for secondary stroke prevention in patients with AF.     

银杏内酯注射液治疗缺血性脑卒中及不同危险因素对疗效影响的临床研究

目的 观察银杏内酯注射液治疗缺血性脑卒中的疗效,并观察银杏内酯注射液在控制相关危险因素方面的治疗特点。方法 选择缺血性脑卒中患者3 036例进行非对照、开放式、多中心临床研究,在基础治疗上使用银杏内酯注射液10 mL/次,0.9%氯化钠注射液或5%葡萄糖注射液250 mL稀释,静脉滴注,每天1次,连续使用14 d。采用美国国立卫生研究院卒中量表（NIHSS）观察神经功能缺损程度,采用改良Rankin量表观察患者日常生活能力状态（病残程度）,评价临床疗效。并观察患者合并高血压病、糖尿病、高血脂症和高尿酸血症4种危险因素在神经功能、病残程度和临床疗效的差异。结果 银杏内酯注射液能明显改善患者的神经功能（P<0.01）,减轻病残程度（P<0.01）,临床总有效率为65.72%;其中不合并4种危险因素的脑卒中患者的临床治疗总有效率为71.9%;合并高脂血症、高尿酸血症、糖尿病脑卒中患者的临床治疗总有效率分别为74.74%、75.00%、70.05%,与不合并危险因素组临床有效率基本一致;合并高血压、3种疾病和4种疾病的临床疗效相对较差,有效率分别是63.36%、42.86%和59.42%,与其他组比较有显著性差异（P<0.01）。结论 银杏内酯注射液治疗缺血性脑卒中具有较好疗效,其在控制缺血性脑卒中患者的危险因素上具有良好的治疗特点。     

Role of antihypertensive therapy with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers in combination with calcium channel blockers for stroke prevention

ObjectiveTo review the available literature on the effects of angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), and calcium channel blockers (CCBs) or combinations of these agents on stroke outcomes in hypertensive patients.Data sourcesA Medline search was conducted using the search terms stroke and antihypertensives, calcium channel blockers, angiotensin-converting enzyme inhibitors, or angiotensin II receptor blockers from 1985 to August 17, 2009.Study selectionRandomized controlled clinical trials with at least 400 randomized patients were selected if at least one of the treatment arms used a CCB, ACEI, or ARB to evaluate stroke outcomes in hypertensive patients.Data synthesisThe prevalence of stroke is high in the United States, accounting for approximately 150,000 deaths per year. Early identification and treatment of hypertension to quickly achieve blood pressure reduction is critical in the prevention of stroke. Many trials have provided evidence that CCBs, ACEIs, and ARBs are effective in stroke prevention. Most patients require two or more antihypertensive drugs to achieve blood pressure goals. Because of their complementary actions, combination antihypertensive therapy with a renin–angiotensin–aldosterone system (RAAS) blocker and a CCB may help reduce stroke incidence to a greater extent than either of the monotherapies.ConclusionA growing body of clinical trial data suggest that aggressive combination antihypertensive therapy, including a RAAS blocker and CCB, may help reduce stroke incidence. Fixed-dose combination therapy is an important consideration in optimizing blood pressure control and patient adherence to therapy in stroke prevention.     

长期卧床脑卒中患者并发坠积性肺炎的影响因素

目的 探讨长期卧床脑卒中患者并发坠积性肺炎的因素。方法 回顾性研究2011年1月至2015年8月在北京市监狱管理局中心医院诊治的长期卧床脑卒中患者220例，对患者的临床资料与预后情况进行调查，记录坠积性肺炎的发生情况，单因素与logistic回归分析坠积性肺炎发生的危险因素。结果 220例患者中发生坠积性肺炎40例，发生率为18.2%。单因素分析显示年龄、卒中类型、糖尿病、吸烟、吞咽障碍、预防性使用抗菌药物、卧床时间与坠积性肺炎相关，进一步logistic回归分析显示年龄、糖尿病、吞咽障碍、预防性使用抗菌药物、卧床时间是坠积性肺炎的危险因素（P<0.05）。坠积性肺炎患者入院21天的NIHSS评分为（11.23±3.45）分，而非坠积性肺炎患者为（4.19±3.10）分，对比差异有统计学意义（P<0.05）；同时坠积性肺炎患者入院21天的其他并发症发生率与病死率也都高于对照组，差异有统计学意义（P<0.05）。结论 长期卧床脑卒中患者并发坠积性肺炎比较常见，主要危险因素包括年龄、糖尿病、吞咽障碍、预防性使用抗菌药物、卧床时间等因素。     

New evidences for old concerns with oral anticoagulation in atrial fibrillation: focus on dabigatran

Introduction: Nonvalvular atrial fibrillation (NVAF) is associated with a fivefold excess risk of stroke. Antithrombotic therapy is crucial to reduce the risk of stroke. During past decades, vitamin K antagonists (warfarin or acenocoumarol) have been widely used for this purpose. However, they have several disadvantages that limit their daily use in clinical practice.

Areas covered: In patients with NVAF at risk of stroke, the randomized evaluation of long-term anticoagulation therapy (RE-LY) trial demonstrated that, compared with warfarin, dabigatran 150 mg b.i.d. was associated with lower rates of stroke and systemic embolism but similar rates of major hemorrhage, whereas dabigatran 110 mg b.i.d. exhibited similar rates of stroke and systemic embolism, but lower rates of major hemorrhage. Fortunately, data about dabigatran are not limited to RE-LY trial. In fact, many substudies have been drawn, providing new and important evidences about the benefits of dabigatran.

Expert opinion: The most recent evidences about efficacy and safety of dabigatran in patients with NVAF, focusing on different substudies of RE-LY trial, are reviewed. In summary, dabigatran is beneficial not only in general population with NVAF but also in different subgroups of patients or different clinical settings (i.e., CHADS2 score, INR control, type of AF, elderly, previous transient ischemic attack or stroke, cardioversion and so on).     

Minimizing the risk of hemorrhagic stroke during anticoagulant therapy for atrial fibrillation

Introduction: Oral anticoagulation (OAC) is given for ischemic stroke prevention in patients with nonvalvular atrial fibrillation. OAC’s most serious complications are major bleeding and, in particular, hemorrhagic stroke. Together with vitamin K antagonists (VKAs), direct oral anticoagulants (DOAC) are now available which have a more rapid onset/offset of action and more predictable anticoagulant effect. The advent of DOAC has given to the clinician an opportunity to tailor OAC therapy in order to maximize advantages and minimize complications.

Areas covered: This review covers data published in literature regarding the risk of hemorrhagic stroke in patients taking OAC. Bleeding risk assessment is discussed and different bleeding risk factors are presented. The paper will also review clinical studies comparing DOAC against standard anticoagulation, in regard to the risk of hemorrhagic stroke.

Expert opinion: Bleeding assessment is mandatory in order to select patients at high hemorrhagic risk who will benefit the most from close monitoring. Blood pressure, alcohol intake, concomitant medication and comorbidities should be constantly evaluated and treated accordingly. During VKA therapy, adherence and intensity of anticoagulation must be strictly monitored. DOAC are associated with lower risk of hemorrhagic stroke than VKA. However, periodic hepatic and renal checks as well as careful evaluation of time adherence are necessary to reduce the risk of bleeding.     

The expanding role of angiotensin receptor blockers in the management of the elderly hypertensive

SUMMARY

The world faces the challenge of an ageing population, and for developed countries, the particular challenge is the increasing number of very old people, over 80 years of age. Hypertension is a condition associated with increasing age, but elderly patients with hypertension are often difficult to manage. Nevertheless, treatment of hypertension is of greatest value in older patients who often have additional risk factors or cardiovascular disease. Older patients have generally tolerated antihypertensive therapy well in randomised, placebo-controlled trials. The tolerability of angiotensin receptor blockers (ARBs) is better than that of many other classes of drugs currently used for the management of hypertension and these drugs have virtually no contraindications. Thus, ARBs have a bright future in the management of hypertension and in the treatment of stroke and cognitive decline in the elderly.     

Telmisartan for the management of patients at high cardiovascular risk

Abstract

Background:

Cardiovascular disease (CVD) places a significant burden on healthcare providers. High blood pressure (BP) is the single most prevalent risk factor for CVD worldwide and is responsible for more deaths than any other risk factor. ‘Cardiovascular (CV) high-risk patients’ make up the broad cross-section of patients in the middle of the risk spectrum for CVD progression that is referred to as the CV continuum and includes those with atherothrombotic disease, those with target organ damage associated with type 2 diabetes and those with multiple risk factors. Angiotensin II is involved in CVD progression at every stage of the CV continuum, making the renin–angiotensin system a rational target for pharmacologic intervention. Angiotensin II receptor blockers (ARBs) offer a better tolerated alternative to angiotensin converting enzyme inhibitors, with greater long-term adherence. The ARB telmisartan recently received an indication for CV prevention.     

Candesartan cilexetil – a review of effects on cardiovascular complications in hypertension and chronic heart failure

ABSTRACT

Therapeutic interventions that block the renin–angiotensin–aldosterone system (RAAS) have an important role in slowing the progression of cardiovascular risk factors to established cardiovascular diseases. In recent years, angiotensin receptor blockers (ARBs) have emerged as effective and well-tolerated alternatives to an angiotensin-converting enzyme inhibitor (ACEi) for RAAS blockade. The ARB candesartan was initially established as an effective once-daily antihypertensive treatment, providing 24?h blood pressure (BP) control with a trough:peak ratio close to 100%.

Scope: A Medline literature search was undertaken to identify randomised, controlled trials that examined the efficacy and cardiovascular outcomes associated with candesartan cilexetil in hypertension and chronic heart failure (CHF).

Findings: Compared with other ARBs, candesartan demonstrates the strongest binding affinity to the angiotensin II type 1 receptor. Clinical trials have demonstrated that candesartan is well tolerated in combination with diuretics or calcium channel blockers (CCBs), making it a suitable treatment option for patients whose hypertension is not adequately controlled by monotherapy. Subsequently, candesartan became the only ARB licensed in the UK to treat patients with CHF and left ventricular ejection fraction ≤ 40% as add-on therapy to an ACEi or when an ACEi is not tolerated. Studies in patients with symptomatic HF have indicated that candesartan treatment was associated with significant relative risk reductions in cardiovascular mortality and hospitalisation due to CHF.

Conclusions: There are clear indications that the clinical benefits of candesartan may extend beyond its proven antihypertensive effects to a wider range of complica­tions across the cardiovascular continuum, including diabetes, left ventricular hypertrophy, atherosclerosis and stroke. Such results suggest that candesartan treatment may offer significant patient benefits as well as practical advantages over conventional treatment.     

The role of angiotensin antagonism in stroke prevention in patients with hypertension: focus on losartan

Summary

Optimal management of hypertension has been shown to reduce the risk of stroke. In recent years, newer classes of antihypertensive such as the angiotensin II (Ang II) antagonists have become available. Results from the Losartan Intervention for Endpoint reduction in hypertension (LIFE) study suggest the utility of this particular Ang II antagonist in stroke prevention. Treatment with a losartan-based regimen or an atenolol-based regimen produced similar reductions in blood pressure during almost 5 years of follow up. Losartan, however, reduced the risk of stroke by 25% compared with atenolol (p = 0.001). For a subgroup of patients with isolated systolic hypertension, losartan reduced the risk of stroke by 40% (p = 0.02). As well as blocking the Ang II type 1 receptor, losartan also acts as an antagonist at the thromboxane A₂ receptor and has uricosuric effects, which may provide additional mechanisms by which losartan provides protective benefits beyond its antihypertensive action. The relevance of these molecular properties of losartan over other Ang II antagonists is further supported by comparison of the outcomes obtained in clinical trials employing two other Ang II antagonists, valsartan and candesartan.     

Stroke risk reduction outweighed bleeding risk increase from vitamin K antagonist treatment among nonvalvular atrial fibrillation patients with high stroke risk and low bleeding risk

Objective: Warfarin is widely used for stroke prevention in patients with nonvalvular atrial fibrillation (NVAF). We compared the rates of stroke and major bleeding in NVAF patients with a high stroke risk and low bleeding risk profile during warfarin treated (W+) and warfarin untreated (W?) periods.

Method: Insurance claims from six commercial, Medicaid or Medicare databases were analyzed from 2000 to 2014. NVAF patients treated with warfarin, with a CHADS₂/CHA₂DS₂-VASc score ≥2, and an ATRIA score ≤3 at baseline were identified. Incidence rate ratios (IRRs) of stroke and major bleeding were calculated for W?+?versus W? episodes of person-time, as well as for first 30 days versus beyond 30 days of W?+?episodes.

Results: Among 316,145 patients, anticoagulant prophylaxis with warfarin significantly reduced stroke risk, with IRRs ranging from 0.48 (95% CI: 0.46–0.51) to 0.80 (95% CI: 0.70–0.91), and increased major bleeding risk, with IRRs ranging from 1.13 (95% CI: 1.10–1.15) to 1.95 (95% CI: 1.10–3.45). Stroke and major bleeding rates were higher during the first 30 days of W?+?than beyond.

Conclusion: In NVAF patients at high risk for stroke and low risk for bleeding, our data confirm the effectiveness of anticoagulation for stroke prevention. The decrease in stroke risk of anticoagulation may outweigh the risk of major bleeding events, particularly among elderly patients. Potential risks of warfarin during initiation warrant attention, especially among patients who stop and start therapy repeatedly.     

Stroke prevention in atrial fibrillation patients

Importance of the field: Atrial fibrillation (AF) is the most common cardiac arrhythmia encountered in clinical practice and is associated with an increased risk of stroke, mortality and significant morbidity. Given the rapidly increasing incidence and prevalence of AF, and the resulting public health burden of the consequences associated with this arrhythmia, stroke prevention is an extremely important topic.

Areas covered in this review: This review covers the epidemiology of AF, the pathophysiology of ischemic stroke in AF and current antithrombotic therapy choices for stroke prevention in this condition. In addition, this article discusses important topics such as the assessment of stroke risk stratification and bleeding risk assessment, which are key issues in deciding upon thromboprophylaxis for AF patients. Finally, the review highlights the advent of new anticoagulant therapies and discusses the future challenges for researchers in this area.

What the reader will gain: This review summarizes all of the major antithrombotic trials conducted in AF patients over the last twenty years and highlights the importance of anticoagulation therapy for the prevention of stroke, after appropriate individual stroke and bleeding risk assessment.

Take home message: Assessment of individual stroke risk and bleeding risk is key in determining appropriate thromboprophylaxis for AF patients, given the associated thromboembolic and hemorrhagic complications. The availability of newer, safer and more convenient drugs will mean that oral anticoagulation is available for a larger proportion of AF patients who may benefit from it.     

Coexistence effect of hypertension and angiotensin II on the risk of coronary heart disease: a population-based prospective cohort study among Inner Mongolians in China

Objective: To investigate the coexistence effect of hypertension and angiotensin II on the risk of coronary heart disease based on a prospective study in an Inner Mongolian population of China.

Methods: The participants were categorized into four subgroups according to hypertension status and median of angiotensin II level. Incident coronary heart disease (CHD) was defined as study outcome. A Cox proportional hazard model was used to compute hazard ratios (HRs) and 95% confidence intervals (CIs) of CHD across the four subgroups after adjusting for important confounding factors.

Results: During an average 9.2 years of follow-up, a total of 75 incident CHD cases were observed. The cumulative incidence rates of CHD among normotensives with angiotensin II ≤49?pg/mL, normotensives with angiotensin II >49?pg/mL, hypertensives with angiotensin II ≤49?pg/mL and hypertensives with angiotensin II >49?pg/mL were 1.76%, 1.50%, 4.71% and 5.62%, respectively (log-rank test, p?<?.001). Compared to the normotensives, the multivariable adjusted HRs (95% CI) of CHD with hypertensives and Ang II >49?pg/mL were 2.43 (1.41–4.17) and 1.30 (0.81–2.07), respectively. Furthermore, compared to normotensives with angiotensin II ≤49?pg/mL, the multivariate-adjusted HRs (95% CIs) of CHD for normotensives with angiotensin II >49?pg/mL, hypertensives with angiotensin II ≤49?pg/mL and hypertensives with angiotensin II >49?pg/mL were 1.33 (0.60–2.91), 2.35 (1.16–4.76) and 3.00 (1.52–5.92), respectively (p for trend <.05). The hypertensives with angiotensin II >49?pg/mL were at the highest risk of CHD.

Conclusions: Hypertension not angiotensin II was an independent risk factor for incident CHD, but the coexistence of both hypertension and high angiotensin II level further increased risk of incident CHD among the Inner Mongolians.     

When are the cardiovascular and stroke risks too high? Pharmacotherapy for stroke prophylaxis

Introduction: Stroke is a significant source of morbidity and mortality in developed countries. Cardioembolic strokes represent approximately 15–30% of all ischemic strokes. They are frequently related to atrial fibrillation (AF) and have a worse prognosis and high recurrence rates when compared to other causes (e.g. atherosclerosis).

Areas covered: This review includes a summary of general and specific scores to assess cardiovascular and stroke risks, with a focus on specific scores available in AF. Recommendations for antithrombotic therapy are also reviewed.

Expert opinion: Several scores are available for the evaluation of stroke risk. They are useful to identify the risk factors that trigger the need for medical interventions. Integrated risk scores with visual interfaces showing the risk of events, with and without the proposed interventions, can aid decision-making. The risk of stroke can definitely be considered too high in those patients with a history of stroke/transient ischemic attack, who need antiplatelet therapy (after a non-cardioembolic stroke) or anticoagulant therapy (after a cardioembolic stroke). For primary prevention of stroke, antiplatelet therapy is not usually recommended, while anticoagulation should be considered if the patient has concomitant AF and at least one additional risk factor unrelated to sex.     

Investigational drugs in phase I and phase II clincial trials for the treatment of hospital-acquired pneumonia

Introduction: Hospital acquired pneumonia (HAP) is one of the main infections acquired by patients during a stay in hospital. The main issue when dealing with patients with HAP and ventilator associated pneumonia (VAP) is the increasing role of multi-drug resistant organisms (MDROs).

Areas covered: In this review the authors summarize the actual situation of MDROs as a cause of HAP and VAP. They also review the current treatment options stated in the most important international guidelines. Finally, they focus on the investigational drugs that have reached the phase III stage of development and the novel compounds that are being studied in phase I and II clinical trials.

Expert opinion: Thanks to their excellent activity against MDROs, drugs in development for the treatment of HAP and VAP can significantly improve the therapeutic options available. In selected patients, the possibility to administer directed therapy with monoclonal antibodies to specific pathogens is an exciting strategy in the fight against widespread resistance.