Economic assessment of the secondary prevention of ischaemic events with lysine acetylsalicylate

OBJECTIVE: To analyse the economic benefits, in comparison with placebo, of the secondary prevention of ischaemic stroke and myocardial infarction (MI) with lysine acetylsalicylate (Kardégic) in patients with a history of ischaemic stroke, MI or stable and unstable angina pectoris. DESIGN AND SETTING: This was a modelling study from the perspectives of direct medical costs, the social security system and society in France. METHODS: Efficacy data for the secondary prevention of ischaemic events were derived from the Antiplatelet Trialists' Collaboration meta-analysis on antithrombotics. The rates and costs of ischaemic disease and of serious gastrointestinal adverse affects arising from long term aspirin treatment, as well as the costs of treatment with lysine acetylsalicylate, were taken from published sources, using French data where possible. RESULTS: From the social security perspective, the estimated cost-effectiveness ratios show that the prevention of MI in patients with a history of unstable angina (with a 1-year follow-up) is a cost-saving strategy, with net benefits ranging from $US5703 (1996 prices) per avoided MI for lysine acetylsalicylate 300 mg/day to $US5761 per avoided MI for lysine acetylsalicylate 75 mg/day. The prevention of MI and stroke is also a cost-saving strategy in patients with prior MI [net benefits in a 2-year follow-up (5% discount rate) ranging from $US15 to $US494 per avoided MI and from $US37 to $US1170 per avoided stroke]. This was also true in patients with prior ischaemic stroke (net benefits in a 3-year follow-up ranging from $US610 to $US2082 per avoided MI and from $US176 to $US599 per avoided stroke). Finally, a 4-year follow-up in patients with a history of stable angina pectoris shows that prophylactic treatment with lysine acetylsalicylate is associated with net costs per avoided MI, ranging from $US4375 to $US3608 per avoided event. Sensitivity analysis confirmed that prophylaxis with lysine acetylsalicylate in patients at high risk of cardiovascular and cerebrovascular events results in savings in social security expenditure. CONCLUSIONS: Our results underline the high economic benefit of using lysine acetylsalicylate to prevent secondary ischaemic stroke and MI in patients at high risk of cardiovascular and/or cerebrovascular events, leading to savings for the social security system and society.     

Efficacy and costs of secondary prevention with antiplatelets after ischaemic stroke

Ischaemic stroke and other atherothrombotic events substantially increase the medico-economic burden because of their high treatment costs and long-lasting disabilities with need for chronic care. Studies have shown that the cost of stroke represents approximately 3 - 5% of the annual health budget. Antiplatelet agents play a major role in secondary stroke prevention. Acetylsalicylic acid (ASA), ASA combined with extended-release dipyridamole (ER-Dip), and clopidogrel are all acceptable choices for first-line treatment in the secondary prevention of stroke. The newer antiplatelets, however, are more expensive than ASA, and their cost-effectiveness is not easily estimated. ASA has to be given to 33 stroke patients to prevent one future stroke, myocardial infarction (MI) or vascular death compared with placebo. Adding ER-Dip to ASA increases the benefit for the patients. A total of 33 stroke patients had to be treated with this combination, instead of ASA, to prevent one stroke. However, the combination of ASA plus ER-Dip does not prevent MI, vascular death or the combined end point of either stroke or death. Clopidogrel is more effective than ASA in preventing a combined end point of ischaemic stroke, MI, or vascular death, but it has not been shown to be superior to ASA in preventing recurrent stroke in transient ischaemic attack or stroke patients. Several subgroups, such as stroke patients with additional peripheral artery disease, patients with prior coronary artery bypass, patients with insulin-dependent diabetes, and patients with recurrent vascular events, were identified, in whom the benefit of clopidogrel is amplified. Taking economical aspects into account, the fixed combination of ASA and ER-Dip can be recommended for secondary stroke prevention as a first-line alternative to ASA in patients without major comorbidity. In patients with higher comorbidity, clopidogrel may be more effective for the individual patient compared with ASA, and might also be cost-effective. Furthermore, in patients with ASA intolerance clopidogrel is a useful, but expensive, alternative.     

阿司匹林联合双嘧达莫用于缺血性脑卒中二级预防的Meta分析

目的以阿司匹林为对照组,系统评价阿司匹林双嘧达莫联合用药,对缺血性脑卒中二级预防的有效性和安全性。方法通过卒中、非致死性卒中、各种原因引起的死亡及非致死性卒中与各种原因引起的死亡联合事件发生的相对危险度,分析联合用药的有效性,通过出血性并发症及脑出血发生的相对危险度,分析联合用药的安全性。结果 a.与阿司匹林相比较,联合用药能更有效的预防卒中的发生(RR=0.86 95%CI[0.74,1.00]),使非致死性卒中的发生率降低22%(RR=0.78 95%CI[0.67,0.90]),也能明显降低非致死性卒中与各种原因引起的死亡联合事件的发生率(RR=0.87 95%CI[0.79,0.96])。但是,联合用药对各种原因引起的死亡无效(RR=0.98,95%CI[0.85,1.13])。b.与阿司匹林相比较,联合用药不会增加出血性并发症的发生率(RR=0.95,95%CI[0.80,1.12]),但可以使脑出血的发生率增加14%(RR=1.14,95%CI[0.54,2.42]),尽管这一结果无明显统计学意义。结论与阿司匹林相比较,联合用药对卒中、非致死性卒中及非致死性卒中与各种原因引起的死亡联合事件的预防更有效,联合用药不会增加出血性并发症的发生率,但能轻微增加脑出血的发生率。     

A benefit-risk assessment of agents used in the secondary prevention of stroke.

Stroke is a major cause of morbidity and mortality. Full assessment of stroke or transient ischaemic attack (TIA) patients is required to identify all risk factors and apply appropriate secondary preventative strategies. Antiplatelet therapies are effective in the secondary prevention of ischaemic stroke and can be justified despite adverse effects such as gastrointestinal haemorrhage. Aspirin (acetylsalicylic acid), aspirin plus dipyridamole, ticlopidine and clopidogrel are all of value but their adverse effect profiles vary significantly. Combinations of antiplatelet agents may offer additional benefit but not all combinations have been studied in stroke patients. Anticoagulation with agents such as warfarin is effective with coexisting atrial fibrillation and other conditions predisposing to cardioembolic stroke. Antihypertensive agents have been extensively studied in the primary prevention of stroke; however, relatively few trials of antihypertensive agents in the secondary prevention of stroke are available. The incidence of adverse effects of antihypertensive agents is relatively low and the benefit-risk profile would tend to favour their use in the secondary prevention of stroke. Recent studies of ACE inhibitors have identified an important role for these agents in the secondary prevention of stroke even in those who are normotensive and in those who have had a haemorrhagic stroke. The incidence of serious adverse effects with ACE inhibitors appears relatively low. Lipid-lowering agents may have a role to play in certain groups of patients with stroke. The incidence of adverse effects is relatively low with HMG-CoA reductase inhibitors. Cigarette smoking is an important risk factor for stroke and evidence is available that smoking cessation does reduce the individual's risk of stroke. Pharmacological agents are available to help smoking cessation. In patients with diabetes mellitus, intensive regimens with insulin and oral hypoglycaemic agents have so far not definitively been shown to reduce the incidence of macrovascular complications such as stroke. Tight glycaemic control has been shown to improve microvascular complications such as retinopathy, nephropathy and neuropathy and hence this is reason enough to advocate the use of these agents. Future developments in the treatment of diabetes may help. Secondary prevention of stroke has improved greatly over the past decade and hopefully will continue to improve. The use of pharmacological agents available currently and in the future will be clarified and refined as further clinical trials report.     

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.     

Update on the treatment and prevention of ischaemic stroke

SUMMARY

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.     

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.     

Dipyridamole/aspirin combination in secondary stroke prevention: effects on absolute myocardial blood flow and coronary vascular resistance

OBJECTIVE: In the European Stroke Prevention Study (ESPS 2), oral administration of a fixed combination of 200 mg extended-release dipyridamole and 25 mg aspirin (twice daily) after ischemic stroke or transient ischemic attack, significantly reduced the risk of stroke compared to placebo as well as compared to aspirin or dipyridamole alone. However, the i.v. application of dipyridamole over 4 - 6 min is known to increase myocardial blood flow up to 6-fold, and thereby potentially provoke ischemic wall motion abnormalities in patients with coronary artery disease. We therefore assessed the cardiac side effects of the dipyridamole/aspirin combination on absolute myocardial blood flow (MBF) and coronary vascular resistance (CVR). METHODS: MBF and CVR were measured using 150-water positron emission tomography in 24 patients after stroke or transient ischemic attack, before and 6.7 +/- 1.9 days after starting the dipyridamole/aspirin combination (Aggrenox) therapy. RESULTS: Resting MBF increased by 39% (max. 112%), from 0.92 +/- 0.13 (ml x g(-1) x min(-1)) at baseline to 1.28 +/- 0.27 (ml x g(-1) x min(-1)) under ongoing dipyridamole/aspirin combination therapy (p < 0.0005). CVR consecutively decreased from 105.3 +/- 16.9 to 74.1 +/- 16.5 (mmHg x ml(-1) x g x min) (p < 0.0005). The relative increase in MBF correlated negatively with the body surface area. No correlation was found between relative MBF increase and duration of dipyridamole/aspirin combination therapy (range 4 - 10 days). CONCLUSIONS: Orally administered dipyridamole/aspirin combination therapy in secondary stroke prevention increases MBF and decreases CVR significantly. These cardiac side effects of the dipyridamole/aspirin combination should be taken into account in stroke patients with proven or suspected coronary artery disease, particularly in combination with a small body surface area.     

Atorvastatin in prevention of stroke and transient ischaemic attack

Besides blood pressure-lowering drugs and, in certain circumstances, antithrombotic agents, statins are among the most effective drugs in reducing the risk of stroke in populations of patients at high vascular risk, as well as the risk of major coronary events. In secondary prevention of stroke, statins clearly reduced the risk of major coronary events. In the SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) trial, compared with placebo, the patients with a recent stroke or transient ischaemic attack without coronary heart disease randomised to atorvastatin 80 mg/day had a significant 16% relative risk reduction of stroke and a 35% reduction in the risk of major coronary events. This was obtained despite the fact that 25% of patients allocated to the placebo arm were prescribed a commercially available statin outside the trial. A post-hoc analysis used blinded low-density lipoprotein cholesterol (LDL-C) measurements (taken at study visits during the trial) as a marker of adherence to lipid-lowering therapy. Compared with the group with no change or an increase in LDL-C (the group adherent to placebo or not taking a statin), the group with >or= 50% reduction in LDL-C had a significant 31% reduction in the risk of stroke. The next step is to define whether or not achieving a LDL-C of < 70 mg/dl is better than a standard dose of statin (LDL approximately 100 - 110 mg/dl) in the secondary prevention of stroke. Statins are effective in reducing both first-ever and recurrent stroke, and this effect seems driven by the extent of LDL-C lowering.     

Atorvastatin in prevention of stroke and transient ischaemic attack

Besides blood pressure-lowering drugs and, in certain circumstances, antithrombotic agents, statins are among the most effective drugs in reducing the risk of stroke in populations of patients at high vascular risk, as well as the risk of major coronary events. In secondary prevention of stroke, statins clearly reduced the risk of major coronary events. In the SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) trial, compared with placebo, the patients with a recent stroke or transient ischaemic attack without coronary heart disease randomised to atorvastatin 80 mg/day had a significant 16% relative risk reduction of stroke and a 35% reduction in the risk of major coronary events. This was obtained despite the fact that 25% of patients allocated to the placebo arm were prescribed a commercially available statin outside the trial. A post-hoc analysis used blinded low-density lipoprotein cholesterol (LDL-C) measurements (taken at study visits during the trial) as a marker of adherence to lipid-lowering therapy. Compared with the group with no change or an increase in LDL-C (the group adherent to placebo or not taking a statin), the group with ≥ 50% reduction in LDL-C had a significant 31% reduction in the risk of stroke. The next step is to define whether or not achieving a LDL-C of < 70 mg/dl is better than a standard dose of statin (LDL ～ 100 – 110 mg/dl) in the secondary prevention of stroke. Statins are effective in reducing both first-ever and recurrent stroke, and this effect seems driven by the extent of LDL-C lowering.     

Clopidogrel for the secondary prevention of stroke

Patients suffering a transient ischaemic attack (TIA) or ischaemic stroke (IS) have a high risk of recurrence. The inhibition of platelet function is effective in the reduction of secondary vascular events in patients with TIA or stroke. This is true for acetylsalicylic acid (ASA), clopidogrel, ticlopidine and the combination of ASA plus slow-release dipyridamole. This overview analyses the results of recent trials and presents ongoing or future trials with clopidogrel as well as the combination of clopidogrel plus ASA. Clopidogrel is superior to ASA in the prevention of vascular events in patients with IS, myocardial infarction (MI) or peripheral arterial disease (PAD). The difference is highest for high-risk patients such as diabetics, patients who underwent coronary bypass surgery and patients with a remote prior history of ischaemic events. A prediction model is presented which allows the identification of patients in whom clopidogrel is superior to ASA for the secondary prevention of stroke. The combination of clopidogrel and ASA is better than ASA alone in patients undergoing coronary stent implantations and patients with unstable angina or non-Q-wave MI. In high-risk patients with TIA or stroke, the addition of ASA to clopidogrel is not superior to ASA monotherapy but results in a higher rate of bleeding complications. The long-term combination therapy is currently investigated in several large trials in > 30,000 patients, with a large number of stroke patients.     

A radomized trial comparing ticlopidine with aspirin for the prevention of ischemic cerebral stroke

The effects and safety of ticlopidine in the prevention of ischernic cerebral stroke were studied and compared with those of low-dose aspirin.Patients (n=329) with TIA or mild ischemic cerebral stroke were randomly assigned to ticlopidine group (165 cases) or aspirin group (164 cases). These patients were randomly allocated to receive either ficlopidine 250 mg or aspirin 50 mg daily and did not take any other platelet antiaggregating     

低分子肝素防治急性缺血性卒中合并下肢深静脉血栓的临床研究

目的探讨低分子肝素防治急性缺血性卒中合并下肢深静脉血栓(deep-vein thrombosis,DVT)的临床效果。方法选择我院收治急性缺血性脑卒中患者200例,将其分为实验组和对照组,每组100例。实验组患者在常规治疗的基础上给予低分子肝素(low-molecular-weight hep-arins,LMWH)5000u进行腹部皮下注射,每12h注射1次,连用14d;实验组患者仅作常规治疗。对比两组患者的治疗效果,治疗期间和治疗后3个月内的临床结局以及不良反应,观察DVT的发生率。结果治疗两个疗程后,实验组有效率为89.0%,对照组有效率为80.0%,实验组疗效明显优于对照组(P<0.05);治疗期间以及治疗后3个月实验组DVT的发生率为11.0%,对照组DVT的发生率为26.0%,两者差异有显著性(P<0.01),实验组患者的PE发生率、出血性阻塞发生率和死亡率也显著低于对照组;实验组和对照组不良反应的发生率相似,实验组为81.0%,实验组为86.0%,两者无统计学差异,实验组患者没有出现严重的出血并发症。结论低分子肝素可有效降低急性缺血性脑卒中患者下肢深静脉血栓的发病率,值得临床推广使用。     

瑞舒伐他汀用于缺血性脑卒中二级预防的疗效及安全性观察

目的:研究瑞舒伐他汀用于缺血性脑卒中二级预防的疗效及安全性。方法:选择我院90例缺血性脑卒中合并高脂血症患者,随机分为瑞舒伐他汀组、辛伐他汀组和饮食控制组,每组30例,瑞舒伐他汀组患者于每晚餐后顿服瑞舒伐他汀钙片10 mg,辛伐他汀组于每晚餐后顿服辛伐他汀片40 mg,饮食控制组采用饮食控制手段,不服用他汀类降脂药物,疗程均为12周。12周后观察3组患者的降脂疗效及安全性。结果:各组患者TC、TG和LDL-C水平均明显降低,但瑞舒伐他汀组的TC、TG、LDL-C水平降低较其他2组明显(P<0.05),3组疗效比较差异有统计学意义(P<0.05)。瑞舒伐他汀钙10 mg组的胆固醇达标率优于辛伐他汀组和饮食控制组,组间差异有统计学意义(χ2=7.937,P<0.05)。结论:瑞舒伐他汀钙用于缺血性脑卒中的二级预防疗效显著,且安全性好,值得临床推广。     

Blood pressure reduction in the primary and secondary prevention of stroke

Control of hypertension is well established for the primary prevention of stroke. Prior studies, on the other hand, conflict over whether hypertension remains a risk factor for recurrent stroke and if blood pressure reduction is associated with better outcomes in this subset of patients. We review current evidence regarding the role of BP lowering for primary and secondary prevention of stroke. Current evidence amassed from both primary and secondary prevention trials demonstrate that BP reduction is a crucial common element in overall reduction of stroke risk.     

Clinical pharmacokinetics of antiplatelet agents used in the secondary prevention of stroke

Stroke is one of the leading causes of death and debilitation. Several million stroke survivors are alive throughout the world today. Prevention of recurrent stroke is of major importance to stroke survivors. Several pharmacological agents are currently available for use in secondary stroke prevention.Clopidogrel, the combination of immediate-release aspirin and extended-release dipyridamole and aspirin alone are the most widely recommended agents for use in the secondary prevention of strokes. Clopidogrel has shown superiority over aspirin in the combined endpoints of stroke, death and myocardial infarction. The immediate-release aspirin/extended-release dipyridamole combination has shown superiority to aspirin alone in the secondary prevention of stroke.Dipyridamole has been studied as an antiplatelet agent for several decades. Early trials to prove its efficacy compared with aspirin were not favourable, and patients often experienced many adverse effects. Researchers began developing an extended-release formulation in an effort to maintain therapeutic blood concentrations with less frequent daily administration and better adverse effect profile. Pharmacokinetic analysis of this new product showed it to have a more consistent and reproducible absorption compared with immediate-release dipyridamole. The rate of absorption of extended-release dipyridamole is considerably slower than that of immediate-release dipyridamole, while similar plasma concentrations are maintained to optimise antiplatelet efficacy. This allows extended-release dipyridamole to be administered twice daily rather than four times daily.A large-scale randomised trial was conducted with extended-release dipyridamole 200mg in combination with immediate-release aspirin 25mg given twice daily. The combination product showed a greater efficacy at preventing a recurring stroke then either agent administered alone. Indirect comparisons with clopidogrel show that the combination of immediate-release aspirin/extended-release dipyridamole may be more effective than clopidogrel at preventing a recurring stroke.     

Adverse effects and drug interactions of antithrombotic agents used in prevention of ischaemic stroke

Stroke is the third most common cause of death in the US. Primary prevention of stroke can be achieved by control of risk factors including hypertension, diabetes mellitus, elevated cholesterol levels and smoking. Approximately one-third of all ischaemic strokes occur in patients with a history of stroke or transient ischaemic attack (TIA). The mainstay of secondary prevention of ischaemic stroke is the addition of medical therapy with antithrombotic agents to control the risk factors for stroke. Antithrombotic therapy is associated with significant medical complications, particularly bleeding.Low-dose aspirin (acetylsalicylic acid) has been shown to be as effective as high-dose aspirin in the prevention of stroke, with fewer adverse bleeding events. Aspirin has been shown to be as effective as warfarin in the prevention of noncardioembolic ischaemic stroke, with significantly fewer bleeding complications. Ticlopidine may be more effective in preventing stroke than aspirin, but is associated with unacceptable haematological complications. Clopidogrel may have some benefit over aspirin in preventing myocardial infarction, but has not been shown to be superior to aspirin in the prevention of stroke. The combination of clopidogrel and aspirin may be more effective than aspirin alone in acute coronary syndromes, but the incidence of adverse bleeding is significantly higher. Furthermore, the combination of aspirin with clopidogrel has not been shown to be more effective for prevention of recurrent stroke than clopidogrel alone, while the rate of bleeding complications was significantly higher with combination therapy. The combination of aspirin and extended-release dipyridamole has been demonstrated to be more effective than aspirin alone, with the same rate of adverse bleeding complications as low-dose aspirin. When selecting the appropriate antithrombotic agent for secondary prevention of stroke, the adverse event profile of the drug must be taken into account when assessing the overall efficacy of the treatment plan.