The value of clopidogrel versus aspirin in reducing atherothrombotic events: the CAPRIE study

Atherothrombotic disease is a growing health problem, and is increasingly more costly to manage. Clopidogrel is an advanced, specific adenosine diphosphate receptor antagonist, which has been shown to be a highly potent antiplatelet agent. Data from the Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) study have demonstrated the significantly superior clinical benefit of clopidogrel over aspirin for secondary prevention of atherothrombotic disease, with a relative risk reduction in myocardial infarction, stroke or vascular death of 8.7% (95% confidence interval 0.3, 16.5; P = 0.043). Moreover, clopidogrel demonstrated an amplified clinical benefit versus aspirin in patients at high risk of atherothrombotic events, such as those with a previous history of symptomatic atherothrombotic disease or with major risk factors such as diabetes mellitus or hypercholesterolaemia. On the basis of commonly accepted threshold criteria (Euros 20000 per life-year gained; LYG), clopidogrel in comparison with aspirin is cost-effective for the secondary prevention of atherothrombotic disease (cost per LYG ranging from Euros 19462 to Euros 3256). Economic analyses have demonstrated consistent cost-effectiveness results with clopidogrel in different countries. Moreover, in high-risk patient subgroups the cost-effectiveness of clopidogrel in comparison with aspirin was evenbetter (cost per LYG ranging from Euros 5900 to Euros 6310). Compared with other treatment strategies used for the prevention of ischaemic or atherothrombotic events, the cost-effectiveness of clopidogrel in comparison with aspirin based on CAPRIE is favourable, with most analyses in the intermediate range of cost-effectiveness. The available data thus support the use of clopidogrel as a clinically efficient and cost-effective option for secondary prevention of atherothrombotic disease, particularly in high-risk patients.     

Clopidogrel versus aspirin in patients with atherothrombosis: CAPRIE-based calculation of cost-effectiveness for Germany

ABSTRACT

Objectives: To model the 2-year cost-effectiveness of secondary prevention with clopidogrel versus aspirin (acetylsalicylic acid) (ASS) in German patients with myocardial infarction (MI), ischaemic stroke (IS) or diagnosed with peripheral arterial disease (PAD), based on CAPRIE trial data and from the perspective of German third party payers (TPP).

Methods: An existing Markov model was adapted to Germany by using German cost data. The model was extended by using different datasets for cardiovascular event survival times (Framingham vs. Saskatchewan health databases) and in two separate scenarios.

Results: The treatment with clopidogrel leads to a reduction of 13.19 vascular events per 1000 patients, of which 2.21 are vascular deaths. The overall incremental costs for the 2-year management of atherothrombotic patients with clopidogrel instead of ASS are calculated to be about €1 241 440 per 1000 patients. The number of life-years saved (LYS) has been calculated as the difference in the number of life-years lost due to vascular death or events with ASS versus clopidogrel: it is 86.35 LYS when analysis is based on Framingham data and 66.07 LYS with Saskatchewan-based survival data. The incremental costs per LYS are €14 380 and €18 790, respectively. Cost-effectiveness is sensitive to changes in survival data, discounting and daily costs of clopidogrel, but stable against substantial (± 25%) changes in all other cost data.

Conclusion: The findings for Germany are in line with published results for Belgium (€13 390 per LYS) and also with results for Italy (€17 500 per LYS), both based on Saskatchewan data, and with a French analysis based on Framingham data (€15 907 per LYS). Even if no officially accepted cost-effectiveness threshold exists for Germany at present, incremental cost-effectiveness results of less than €20 000 per LYS for the treatment with clopidogrel can be assumed to be acceptable for German third party payers.     

Comparative safety and tolerability of angiotensin II receptor antagonists.

Hypertension is a very common disease and represents a major risk factor for cardiovascular adverse events such as stroke and heart failure. In recent years, a big effort has been put into detecting and treating patients with hypertension. Several classes of drugs acting by different pharmacological mechanisms can be chosen for the treatment of hypertension. However, the long term use of all anti-hypertensive agents is sometimes limited by the occurrence of adverse effects. Thanks to continuous pharmacological research, new compounds are regularly developed and become available in clinical practice. Recently, several new, nonpeptide, orally active angiotensin II receptor antagonists have reached the market. Today, these substances represent the most specific way to block the renin angiotensin system. Numerous studies have now demonstrated that these angiotensin II antagonists are as effective as ACE inhibitors, calcium antagonists, beta-blockers or diuretics in lowering blood pressure in patients with hypertension. Given the increasing use of angiotensin II receptor antagonists in the treatment of hypertension, it is important to review their safety and tolerability. Based on the actual level of knowledge, the striking feature of this class of agents is their favourable safety and tolerability profile which appears to be equivalent to that observed with placebo. Indeed, so far, no clear class-specific adverse effect has been attributed to the angiotensin II receptor antagonists. Thus, if angiotensin II antagonists prevent target organ damage and reduce the morbidity and mortality of patients with hypertension, they may well become a first-line treatment of hypertension.     

Influence of the timing of low-dose aspirin on tolerability of prolonged-release nicotinic acid in patients at elevated cardiovascular risk

ABSTRACT

Objectives: To investigate the effect of low-dose aspirin administered in the morning or evening on the rate of discontinuation of prolonged-release nicotinic acid (Niaspan^*) due to flushing in patients at elevated cardiovascular risk.

Research design and methods: This was an observational, non-interventional study in patients at elevated cardiovascular risk due to cardiovascular disease or type?2 diabetes. Patients received prolonged-release nicotinic acid and aspirin under the usual care of their physician for 15 weeks.

Main outcome measures: The main outcome measure was the rate of treatment discontinuation for flushing. Other adverse drug reactions (ADRs) were also recorded. Lipid parameters were also measured.

Results: The patient population included 539 subjects (70% male); 36% had type?2 diabetes, 80% had prior cardiovascular disease, and 37% had a family history of cardiovascular disease. The rate of treatment discontinuation due to flushing did not differ (?p?= 0.3375) between the morning aspirin group (10.6%) and the evening aspirin group (13.8%). The overall incidence of flushing was 57%. Most flushes were of mild or moderate severity and decreases occurred over time in both frequency and intensity. ADRs unrelated to flushing occurred in 6.6% of the morning aspirin group and 7.4% of the evening aspirin group. HDL-cholesterol increased by +21.3% in the overall population, together with moderate improvements in other lipid parameters.

Conclusions: Flushing was the most common ADR with prolonged-release nicotinic acid treatment, as expected. The timing of aspirin administration did not influence the rate of treatment discontinuations for flushing. Marked increases in HDL-cholesterol were observed.     

The safety and efficacy of aspirin and clopidogrel as a combination treatment in patients with coronary heart disease

The use of aspirin and clopidogrel in combination has become part of the standard clinical care of patients with coronary artery disease. The use of this combination provides significant benefits compared with the use of aspirin alone in patients with acute coronary syndromes, and in patients treated with percutaneous coronary intervention with stent placement (both bare metal and drug-eluting stents). Clinical trials have demonstrated significant efficacy of this dual therapy; however, there is the potential for significant bleeding complications from the synergistic antiplatelet effects. In total, it appears that when there is vessel injury (mechanical from perctutaneous coronary intervention or a ruptured plaque), dual antiplatelet therapy with aspirin and clopidogrel results in improved outcomes, albeit with a small but significant inherent risk of increased bleeding.     

西洛他唑联合阿司匹林及氯吡格雷对颈动脉狭窄患者神经介入后血栓影响及安全性分析

目的 探讨西洛他唑片联合阿司匹林肠溶片及硫酸氢氯吡格雷片对颈动脉狭窄患者神经介入后血栓影响及安全性。方法 选择2015年1月-2017年12月杨凌示范区医院收治的60例行神经介入治疗的颈动脉狭窄患者,根据随机数字表法,分为观察组及对照组。两组患者采用远端保护装置,根据病变血管的特征,选择合适的支架种类进行前后扩张。对照组患者口服阿司匹林肠溶片300 mg/次,1次/d,硫酸氢氯吡格雷片75 mg/次,1次/d;观察组在对照组基础上口服西洛他唑片200 mg/d,2次/d。两组疗程均为术前1周至术后6个月。观察两组患者治疗前后的血小板聚集率、血流动力学及血脂指标,观察两组治疗过程中的不良反应、缺血事件及缺血病灶例数。结果 治疗后,两组的血小板聚集率、红细胞压积、纤维蛋白原均明显下降,同组治疗前后比较差异有统计学意义（P<0.05）;且治疗后观察组均明显低于对照组,组间差异有统计学意义（P<0.05）。治疗后,两组的总胆固醇（TC）、三酰甘油（TG）、低密度脂蛋白胆固醇（LDL-C）均明显降低,高密度脂蛋白胆固醇（HDL-C）明显上升,同组治疗前后比较差异均有统计学意义（P<0.05）;且观察组明显优于对照组,组间差异均有统计学意义（P<0.05）。两组患者的不良反应无统计学意义;观察组的缺血事件及缺血病灶发生率明显低于对照组,差异有统计学意义（P<0.05）。结论 西洛他唑片联合阿司匹林肠溶片及硫酸氢氯吡格雷片三联疗法对颈动脉狭窄患者神经介入术后抗血栓作用较好,且不增加不良反应发生率。     

Significance of aspirin and clopidogrel resistance in patients undergoing percutaneous coronary interventions

Dual antiplatelet therapy (aspirin plus clopidogrel) is mandatory in patients treated with coronary stent implantation. This strategy is highly effective in prevention of stent thrombosis until its struts are covered with endothelium. However, a substantial number of patients still suffer from recurrent ischemic coronary events despite adequate antiplatelet therapy. These events fall into three categories: stent thrombosis, in stent restenosis and events related to other non-stented coronary lesions. Some data suggest that beside other local and systemic factors resistance to aspirin and clopidogrel may be a possible cause of stent thrombosis and ischemic events in patients after coronary interventions. Several mechanisms of antiplatelet drug resistance have been reported including poor compliance, interactions with other drugs, genetic polymorphism or increased platelet turnover. More research is needed to adequately assess the clinical significance and prognostic value of antiplatelet drug resistance detected by laboratory tests in patients undergoing percutaneous intervention. We review published data on mechanisms and the clinical significance of aspirin and clopidogrel resistance in patients after coronary interventions.     

Prevention of coronary heart disease with aspirin and clopidogrel: efficacy, safety, costs and cost-effectiveness

Atherothrombotic coronary artery disease is the single most common cause of death worldwide and a growing public health problem. Platelets play a central role in the pathogenesis of atherothrombosis and are therefore commonly targeted by one or more antiplatelet drugs as part of primary and secondary atherothrombosis prevention strategies. Aspirin reduces the risk of serious vascular events (myocardial infarction, stroke or cardiovascular death) by approximately 20% in a broad range of high-risk patients and remains the first-line antiplatelet drug because of its relative safety, low cost and cost-effectiveness. Compared with aspirin alone, clopidogrel reduces the risk of serious vascular events by approximately 10% and the combination of aspirin and clopidogrel reduces the risk by approximately 20% in patients with non-ST-segment elevation acute coronary syndrome. Clopidogrel has a similar safety profile to aspirin but clopidogrel tablets are substantially more expensive. However, the incremental cost-effectiveness ratio of clopidogrel compared with aspirin is favourable, particularly in high-risk patients and is intermediate compared with a range of other effective therapeutic strategies for the treatment of coronary heart disease. Clopidogrel should be considered as a replacement for aspirin in patients who are allergic to aspirin, cannot tolerate aspirin, have experienced a recurrent atherothrombotic vascular event whilst taking aspirin and are at very high absolute risk of a serious vascular event (e.g., > 20%/year). The combination of clopidogrel and aspirin should be considered in patients with non-ST-segment elevation acute coronary syndrome or undergoing percutaneous coronary intervention.     

Comparative safety of filgrastim versus sargramostim in patients receiving myelosuppressive chemotherapy

STUDY OBJECTIVE: To compare rates of adverse events with filgrastim versus sargramostim when given prophylactically to patients receiving myelosuppressive chemotherapy. DESIGN: Retrospective review with center crossover. SETTING: Ten United States outpatient chemotherapy centers. PATIENTS: Four hundred ninety patients treated for lung, breast, lymphatic system, or ovarian tumors. INTERVENTION: Prophylactic use of filgrastim or sargramostim, with dosages at investigator discretion. MEASUREMENTS AND MAIN RESULTS: The frequency and severity of adverse events and the frequency of switching to the alternative CSF were assessed. There was no difference in infectious fever. Fever unexplained by infection was more common with sargramostim (7% vs 1%, p<0.001), as were fatigue, diarrhea, injection site reactions, other dermatologic disorders, and edema (all p<0.05). Skeletal pain was more frequent with filgrastim (p=0.06). Patients treated with sargramostim switched to the alternative agent more often (p<0.001). CONCLUSION: Adverse events were less frequent with filgrastim than with sargramostim, suggesting that quality of life and treatment costs also may differ.     

Predicting ischaemic events using platelet reactivity in patients receiving clopidogrel: Indirect meta‐comparison among VerifyNow,light transmission aggregometry and thromboelastography

The present study compared performances of the three major methods used for assessing platelet reactivity (PR)—VerifyNow, light transmission aggregometry (LTA) and thromboelastography (TEG)—to predict ischaemic events in patients receiving clopidogrel. PubMed, EMBASE and the Cochrane Library were searched from their inception to April 2019 for prospective studies that examined PR using VerifyNow, LTA or TEG and the incidence of ischaemic events. The investigated diagnostic indices include sensitivity, specificity, positive (PLR) and negative likelihood ratio (NLR), diagnostic odds ratio and area under the receiver operating characteristic curves (AUC) of VerifyNow, LTA and TEG, respectively. A total of 26 prospective studies involving 22 185 patients were included in the analysis. The pooled AUC was 0.71 (95% CI: 0.67‐0.75) for VerifyNow, 0.60 (95% CI: 0.55‐0.64) for LTA and 0.81 (95% CI: 0.77‐0.84) for TEG. Results of indirect comparisons indicated the AUC of VerifyNow was higher than that of LTA (1.18, 95% CI: 1.08‐1.30) and lower than that of TEG (0.88, 95% CI: 0.82‐0.94). TEG outperformed the other two methods for assessing PR in all predictive measures, including sensitivity, specificity, PLR and NLR. Despite a lack of studies that directly compared the three methods, our findings suggest that TEG should be recommended.     

依诺肝素和那屈肝素联合阿司匹林、氯吡格雷治疗高危急性冠脉综合征

目的比较依诺肝素和那屈肝素在高危急性冠脉综合征(ACS)患者中的安全性和有效性。方法84例高危ACS患者随机分为依诺肝素组(n=44)和那屈肝素组(n=40),均予负荷剂量阿司匹林(300mg)和氯吡格雷(300mg)口服后,继以口服维持(阿司匹林300mg/d,氯吡格雷75mg/d),皮下注射依诺肝素1mg/kg或那屈肝素0.1ml/10kg,每12小时1次,共7d。每日测定抗Xa因子活性,使用低分子肝素(LMWH)后48h行经皮冠状动脉介入治疗(PCI)。最后一次注射LMWH后8h内进入导管室,术中不追加LMWH或普通肝素(UFH)。结果第三次给药后4h两组抗Xa因子活性均>0.5IU/ml,48h后基本达到较稳定水平。30d随访中,临床主要心脏事件(MACE)、出血发生率、每日所测定的抗Xa因子活性两组均无显著性差异(P>0.05)。结论两种LMWH对高危ACS患者均安全有效。     

氯吡格雷联合阿司匹林治疗短暂性脑缺血发作的疗效和安全性观察

目的 观察氯吡格雷联合阿司匹林治疗短暂性脑缺血发作(TIA)的疗效和安全性.方法 选择2015年2月至2017年2月于本院就诊的短暂性脑缺血发作患者1 16例,根据入院时间分为对照组和研究组,各58例.对照组口服阿司匹林进行治疗,研究组口服氯吡格雷+阿司匹林进行联合治疗.评价两组治疗效果及安全性.结果 治疗3周后,对照组临床治疗有效率为77.59％,低于研究组94.83％,对照组治疗后凝血指标血浆黏度、全血黏度高切、全血黏度低切、血小板聚集率分别为(1.77±0.19)mPa·s、(6.99±0.82) mPa·s、(11.79±1.25) mPa·s、(45.17±7.85)％,均分别高于研究组(1.36±0.14)mPa·s、(5.14±0.44)mPa·s、(9.26±1.22)mPa·s、(32.88±6.01)％,两组比较差异有统计学意义(P＜0.05);对照组治疗期间不良反应发生率为3.45％,研究组为1.72％,两组比较差异无统计学意义(P＞0.05)结论 在短暂性脑缺血发作患者中应用氯吡格雷与阿司匹林联合治疗效果显著,可有效增强临床治疗效果,减少缺血性脑卒中的发生,改善预后,且安全性好.     

Fosphenytoin and phenytoin in patients with status epilepticus: improved tolerability versus increased costs.

Tonic-clonic status epilepticus (TCSE) is the most common neurological emergency and affects approximately 60000 patients each year in the US. The risk of complications increases substantially as TCSE lasts longer than 60 minutes. Ideally, drugs used to treat this condition should be well tolerated when administered as rapid intravenous infusions and should not interfere with patients' state of consciousness or cardiovascular and respiratory functions. Because of its efficacy, absence of sedation or respiratory suppression, intravenous phenytoin has largely replaced phenobarbital (phenobarbitone) as the second agent of choice (following the administration of a benzodiazepine) in the treatment of TCSE. While the efficacy of phenytoin in the treatment of acute seizures and TCSE is well established, the parenteral formulation of phenytoin has several inherent shortcomings which compromise its tolerability and limit the rate of administration. Intravenous phenytoin has been associated with fatal haemodynamic complications and serious reactions at the injection site including skin necrosis and amputation of extremities. Fosphenytoin, a phenytoin prodrug, has the same pharmacological properties as phenytoin but none of the injection site and cardiac rhythm complications of intravenous infusions of phenytoin. While fosphenytoin costs more than intravenous phenytoin, treating the acute and chronic complications of TCSE itself, and the complications of intravenous phenytoin can also be costly. All other factors being equal, there is no doubt that fosphenytoin is better tolerated and can be delivered faster than intravenous phenytoin; 2 measures that clearly improve outcome in patients with TCSE. The tolerability of intramuscular fosphenytoin also extends its use to clinical situations where prompt administration of a nondepressing anticonvulsant is indicated but secure intravenous access and cardiac monitoring are not available, such as treatment of seizures by rescue squads in the field and serial seizures in the institutionalised, elderly and other patients with intractable epilepsy.     

长期进行双联抗血小板治疗老年患者并发上消化道出血的危险因素分析

目的 探讨双联抗血小板在老年冠心病患者长期治疗中的安全性、并发上消化道出血的发生情况及预防措施.方法 收集长期双联抗血小板治疗并且符合入组标准又最终完成随诊的患者758例,观察终点包括发生消化道出血、死亡、停止应用双联抗血小板药物,最长随诊至入组后6个月.结果 男性426例,女性332例,共有48例患者发生消化道出血,同时应用质子泵抑制剂( PPI)、H2受体阻滞剂(H2RA)、麦滋林+ PPI、麦滋林+H2RA及单纯应用双联抗血小板药物(作为对照组)患者人数分别为108、240、70、102、238例,各组间年龄及阿司匹林、硫酸氢氯吡格雷的用法用量均相同,结果发现5组患者消化道出血的发生人数分别为4、12、1、3、28例.结论 双重抗血小板药物随访6个月内消化道出血的发生率约为6.3％,联合应用麦滋林类胃黏膜保护剂与PPI可最大限度减少消化道出血的发生率.     

罗氟司特治疗慢性阻塞性肺疾病患者的安全性和耐受性Meta分析

目的初步系统评价罗氟司特治疗慢性阻塞性肺疾病（COPD）患者的安全性和耐受性。方法计算机检索PubMed、ISI、ScineceDirect、OVID、http：／／clinicahrials．gov、中国生物医学文献数据库（CBM）、万方数据数字化期刊全文数据库、中国期刊全文数据库（CJFD）。纳入罗氟司特治疗COPD的临床随机对照试验（RCT）,收集罗氟司特治疗COPD患者的安全性和耐受性的临床资料。应用RevMan5．0．18软件进行Meta分析。结果共纳入6个RCT,研究地点均在国外,研究质量均较高,各试验间具有基线可比性。Meta分析结果显示：与安慰剂组对比,罗氟司特治疗COPD患者时主要不良反应为：腹泻、恶心、头痛和体质量下降,具有统计学意义（P〈0．01）。结论罗氟司特的不良反应轻微,持续时间短,多不需停、减药。需进一步研究使选择性磷酸二酯酶-4（PDE-4）抑制剂在保留或提高疗效的基础上减少药物不良反应。     

Efficacy and safety analysis of new P2Y12 inhibitors versus clopidogrel in patients with percutaneous coronary intervention: a meta-analysis

Objective:

New P2Y₁₂ inhibitors, classified as oral (prasugrel and ticagrelor) and intravenous (cangrelor and elinogrel) drugs, have shown improved antithrombotic effects compared with clopidogrel in patients with acute coronary syndrome (ACS) or patients undergoing percutaneous coronary intervention (PCI) in landmark trials. The purpose of this study was to perform a meta-analysis of randomized trials that compared new P2Y₁₂ inhibitors with clopidogrel to determine their efficacy and safety in patients undergoing PCI.

Methods:

Randomized controlled trials of at least 4 weeks, comparing new P2Y₁₂ inhibitors with clopidogrel in PCI, were identified using the electronic databases Cochrane Central Register of Controlled Trials, Medline, PubMed, Web of Science, and Google Scholar from January 1, 1980, to July 31, 2014.

Main outcome measures:

The primary efficacy endpoints were all-cause death and major adverse cardiovascular events (MACEs). The primary safety endpoint was thrombolysis in myocardial infarction (TIMI) major bleeding.

Results:

Twelve studies including 71,097 patients met the inclusion criteria. New P2Y₁₂ inhibitors significantly reduced all-cause death (odds ratio [OR]: 0.81; 95% confidence interval [CI] 0.73–0.90, p?p?p?p?=?0.03) and cardiovascular death (OR 0.82; 95% CI 0.73–0.92, p?=?0.001) compared with clopidogrel. There were no significant differences between stroke (OR 0.87; 95% CI 0.72–1.05, p?=?0.14) and major bleeding events (OR 1.22; 95% CI 0.99–1.52, p?=?0.06) between the new P2Y₁₂ inhibitor and clopidogrel groups.

Conclusion:

New P2Y₁₂ inhibitors decreased death in patients undergoing PCI compared with clopidogrel with a considerable safety and tolerability profile; however, the risk/benefit ratio of ischemic and bleeding events should be further investigated.