Significant Reduction In Stroke Research Articles

Is a systolic blood pressure target <140 mmHg indicated in all hypertensives? Subgroup analyses of findings from the randomized FEVER trial

Major guidelines recommend lowering systolic blood pressure (SBP) to <140 mmHg in all hypertensives, but evidence is missing whether this is beneficial in (i) uncomplicated hypertensives, (ii) grade 1 hypertensives, and (iii) elderly hypertensives. Providing this missing evidence is important to justify efforts and costs of aggressive therapy in all hypertensives. Felodipine Event Reduction (FEVER) was a double-blind, randomized trial on 9711 Chinese hypertensives, in whom cardiovascular outcomes were significantly reduced by more intense therapy (low-dose hydrochlorothiazide and low-dose felodipine) achieving a mean of 138 mmHg SBP compared with less-intense therapy (low-dose hydrochlorothiazide and placebo) achieving a mean of 142 mmHg. FEVER included older and younger patients, and patients with and without diabetes or cardiovascular disease. In the analyses here reported, Cox regression models assessed outcome differences between more and less-intense treatments in groups of patients with different baseline characteristics. Significant reductions in stroke were found in uncomplicated hypertensives (-39%, P = 0.002), in hypertensives with randomization SBP <153 mmHg (-29%, P = 0.03), and in elderly hypertensives (-44%, P < 0.001), when their SBP was lowered by more intense treatment. Significant reductions (between -29 and -47%, P = 0.02 to <0.001) were also found in all cardiovascular events and all deaths. Achieving mean SBP values <140 mmHg by adding a small dose of a generic drug prevented 2.1 (uncomplicated hypertensives) and 5.2 (elderly) cardiovascular events every 100 patients treated for 3.3 years. These analyses provide strong support, missing so far, to guidelines recommending goal SBP <140 mmHg in uncomplicated hypertensives, individuals with moderately elevated BP and elderly hypertensives.

Do recommendations for the management of hypertension improve cardiovascular outcome? The canadian experience.

The Canadian Hypertension Education Program (CHEP) was established in 1999 as a response to the result of a national survey that showed that a high percentage of Canadians were unaware of having hypertension with only 13% of those treated for hypertension having their blood pressure controlled. The CHEP formulates yearly recommendations based on published evidence. A repeat survey in 2006 showed that the percentage of treated hypertensive patients with the blood pressure controlled had risen to 65.7%. Over the first decade of the existence of the CHEP, the number of prescriptions for antihypertensive medications had increased by 84.4% associated with a significant greater decline in the yearly mortality from stroke, heart failure and myocardial infarction and a significant decrease in the hospitalization for stroke and heart failure. Therefore, the introduction of the CHEP and the yearly issue of updated recommendations resulted in a significant increase in the awareness, diagnosis and treatment of hypertension and in a significant reduction in stroke and cardiovascular morbidity and mortality. The CHEP model could serve as a template for its adoption to other regions or countries.

Impact of dronedarone in atrial fibrillation and flutter on stroke reduction

Dronedarone has been developed for treatment of atrial fibrillation (AF) or atrial flutter (AFL). It is an amiodarone analogue but noniodinized and without the same adverse effects as amiodarone. This is a review of 7 studies (DAFNE, ADONIS, EURIDIS, ATHENA, ANDROMEDA, ERATO and DIONYSOS) on dronedarone focusing on efficacy, safety and prevention of stroke. There was a dose-finding study (DAFNE), 3 studies focusing on maintenance of sinus rhythm (ADONIS, EURIDIS and DIONYSOS), 1 study focusing on rate control (ERATO) and 2 studies investigating mortality and morbidity (ANDROMEDA and ATHENA). The target dose for dronedarone was established in the DAFNE study to be 400 mg twice daily. Both EURIDIS and ADONIS studies demonstrated that dronedarone was superior to placebo for maintaining sinus rhythm. However, DIONYSOS found that dronedarone is less efficient at maintaining sinus rhythm than amiodarone. ERATO concluded that dronedarone reduces ventricular rate in patients with chronic AF. The ANDROMEDA study in patients with severe heart failure was discontinued because of increased mortality in dronedarone group. Dronedarone reduced cardiovascular hospitalizations and mortality in patients with AF or AFL in the ATHENA trial. Secondly, according to a post hoc analysis a significant reduction in stroke was observed (annual rate 1.2% on dronedarone vs 1.8% on placebo, respectively [hazard ratio 0.66, confidence interval 0.46 to 0.96, P = 0.027]). In total, 54 cases of stroke occurred in 3439 patients (crude rate 1.6%) receiving dronedarone compared to 76 strokes in 3048 patients on placebo (crude rate 2.5%), respectively. Dronedarone can be used for maintenance of sinus rhythm and can reduce stroke in patients with AF who receive usual care, which includes antithrombotic therapy and heart rate control.

Comparison of Different Antithrombotic Regimens for Patients With Atrial Fibrillation Undergoing Drug-Eluting Stent Implantation

The optimal antithrombotic strategy for patients with atrial fibrillation (AF) undergoing drug-eluting stent (DES) implantation is unknown. The 622 consecutive AF patients undergoing DES implantation were prospectively enrolled. Among them, 142 patients (TT group) continued triple antithrombotic therapy comprising aspirin, clopidogrel and warfarin after discharge; 355 patients (DT group) had dual antiplatelet therapy; 125 patients (WS group) were discharged with warfarin and a single antiplatelet agent. Target INR was set as 1.8-2.5 and was regularly monitored after discharge. The TT group had a significant reduction in stroke and major adverse cardiac and cerebral events (MACCE) (8.8% vs 20.1% vs 14.9%, P=0.010) as compared with either the DT or WS group. In the Cox regression analysis, administration with warfarin (hazard ratio (HR) 0.49; 95% confidence interval (CI) 0.31-0.77; P=0.002) and baseline CHADS(2) score >or=2 (HR 2.09; 95%CI 1.27-3.45; P=0.004) were independent predictors of MACCE. Importantly, the incidence of major bleeding was comparable among 3 groups (2.9% vs 1.8% vs 2.5%, P=0.725), although the overall bleeding rate was increased in the TT group. Kaplan-Meier analysis indicated that the TT group was associated with the best net clinical outcome. The cardiovascular benefits of triple antithrombotic therapy were confirmed by reducing the MACCE rate, and its major bleeding risk might be acceptable if the INR is closely monitored.

Using Diuretics in Practice—One Opinion

Using Diuretics in Practice—One Opinion

Does the prevention of complications explain the survival benefit of organized inpatient (stroke unit) care?: further analysis of a systematic review.

Systematic reviews have shown that organized inpatient (stroke unit) care reduces the risk of death after stroke. However, it is unclear how this is achieved. We tested whether stroke unit care could reduce deaths by preventing complications. We updated a collaborative systematic review of 31 controlled clinical trials (6936 participants) to include reported interventions and complications during early hospital care plus the certified cause of death during follow up. Each secondary analysis used data from between 7 and 17 studies (1652 to 3327 participants). Complications were grouped as physiological, neurological, cardiovascular, complications of immobility, and others. Bayesian hierarchical models were used to estimate odds ratios for features occurring in stroke units versus conventional care. Based on the data of 17 trials (3327 participants), organized (stroke unit) care reduced case fatality during scheduled follow up (OR: 0.75; 95% credible intervals: 0.59 to 0.92), in particular deaths certified as attributable to complications of immobility (0.59; 0.41 to 0.86). Stroke unit care was associated with statistically significant increases in the reported use of oxygen (2.39; 1.39 to 4.66), measures to prevent aspiration (2.42; 1.36 to 4.36), and paracetamol (2.80; 1.14 to 4.83) plus a nonsignificant reduction in the use of urinary catheterization. Stroke units were associated with statistically significant reductions in stroke progression/recurrence (0.66; 0.46 to 0.95) and in some complications of immobility: chest infections (0.60; 0.42 to 0.87), other infections (0.56; 0.40 to 0.84), and pressure sores (0.44; 0.22 to 0.85). There were no significant differences in cardiovascular, physiological, or other complications. Organized inpatient (stroke unit) care appears to reduce the risk of death after stroke through the prevention and treatment of complications, in particular infections.

Perspective on the efficacy analysis of the Vitamin Intervention for Stroke Prevention trial

The pathogenesis of stroke is very different from that of myocardial infarction; most strokes are embolic, and as elevated plasma total homocysteine (tHcy) increases thrombosis, it increases the risk of cardioembolic strokes, particularly in atrial fibrillation, as well as the risk of deep vein thrombosis leading to paradoxical embolism, and elevated tHcy also increases strokes from cortical vein thrombosis. The main study results of the Vitamin Intervention for Stroke Prevention (VISP) trial showed no benefit of vitamin therapy for homocysteine lowering. However, there were a number of problems with the trial including: 1. We did not use a placebo control; we used a multiple vitamin containing low doses of folate and B6, and the recommended daily intake of B12; 2. Patients with low serum B12 levels in both arms of the trial received injections of B12; and 3. Folate fortification of grain products in North America coincided with the initiation of the trial. We therefore conducted a hypothesis-driven analysis of a subgroup of VISP from which patients who could not have responded to the study treatment were excluded, i.e., those with low or very high serum B12, and those with renal failure. In the remaining 2155 patients, there was a significant reduction of stroke, coronary events and death (p=0.049). When the participants were stratified according to the median entry level of B12 (313 pmol/L), it became apparent that serum B12 status was the key determinant of response, those with high serum B12 at entry who received high-dose vitamin had a 33% reduction of events compared to those with low B12 who received low-dose vitamins; the other two groups were intermediate (p=0.02 for survival free of stroke, coronary and death in the Kaplan-Meier analysis). In this efficacy analysis, we found a significant reduction of vascular risk with vitamin therapy. Similarly, the Heart Outcomes Prevention Evaluation 2 trial showed a 25% significant reduction of stroke with vitamin therapy (p=0.03). The authors thought this result was a chance finding, because they did not think that stroke and myocardial infarction would be biologically different; however, stroke and myocardial infarction have very different pathogenesis, so that conclusion is unwarranted. It seems likely that even if vitamin therapy does not significantly reduce coronary events, it will reduce the risk of stroke.

Abstract 4200: Does Homocysteine Lowering Impact Cardiovascular Outcomes? A Bayesian Meta-Analysis of NORVIT and HOPE-2 Trials

Background: In HOPE-2 trial, homocysteine lowering with B vitamins failed to reduce clinical outcomes compared to placebo except for a significant reduction in stroke (P=0.03). The stroke benefit was thought to “represent either an overestimate of the real effect or a spurious result due to play of chance, and that a meta-analysis should be able to clarify the issue”. Objective: To perform a Bayesian meta-analysis by integrating prior information from the NORVIT trial with the empirical evidence from HOPE-2 (the only 2 large completed placebo-controlled trials of homocysteine lowering). Methods: Posterior probabilities that the benefit (P b ) or harm (P h ) exceeds a specified difference (δ&lt;0%, 10%) were estimated via the Bayes’ theorem: posterior α evidence x prior. Only data from comparison of combination vitamin therapy group vs placebo was utilized from NORVIT to match the HOPE-2 treatment groups for primary composite endpoint of cardiovascular death, myocardial infarction (MI) or stroke and the individual endpoints. Superiority or inferiority was inferred at a posterior probability of benefit or harm &gt;0.950. Results: The P h exceeded P b for the primary composite endpoint and each of the individual components except for stroke where the probability of any benefit (δ&gt;0%) was 0.992 and the probability of &gt;10% risk reduction (δ&gt;10%) was 0.930. Conclusions: Thus, a Bayesian meta-analysis helps clarify the issue, and suggests a low likelihood of coronary benefit and a high likelihood of stroke benefit with homocysteine-lowering therapy compared to placebo. These data are consistent with the epidemiologic observations of a stronger association of elevated homocysteine with stroke compared to CAD (adjusted odds ratio of 1.32 (1.18–1.49) vs 1.19 (1.12–1.25) for +5μmol/L increase in homocysteine level observed in prospective studies). Ongoing trials should further clarify the impact of homocysteine lowering.

Can the Renin-Angiotensin System Protect Against Stroke? A Focus on Angiotensin II Receptor Blockers

From a patient's perspective, stroke is the most devastating form of cardiovascular disease, representing the number one cause of permanent disability in the United States. Treatment of hypertension significantly reduces the risk of stroke; however, it is unclear whether all antihypertensive agents are equivalent in this regard. Angiotensin-converting enzyme (ACE) inhibitors have been shown to reduce the risk of cardiovascular events, including stroke. Although attenuation of the renin-angiotensin system (RAS) is often credited with the blood pressure-independent effects of this class of agents, this hypothesis has not been confirmed with regard to the end point of stroke. In fact, drugs that activate the RAS, such as diuretics and dihydropyridine calcium channel blockers, are as effective or superior to ACE inhibitors for stroke prevention. Angiotensin II receptor blockers (ARBs) selectively block the angiotensin II subtype I receptor, which results in a reflexive increase in levels of angiotensin II and unopposed activation of angiotensin II subtype 2 receptors. Clinical trials comparing ARBs with active controls have reported significant reductions in stroke in ARB-treated patients. Data on ARBs and other drugs that activate the RAS (diuretics and dihydropyridine calcium channel blockers) support a potential role for the RAS in protecting against stroke. Ongoing trials with ARBs are evaluating stroke as a primary end point, and results should help to further elucidate the role of ARBs in this disease. Until then, it is prudent to treat hypertension with an agent or combination of agents that are likely to result in a rapid and sustained reduction in blood pressure, taking into consideration patient characteristics, comorbidities, tolerability, and cost.

P.2.009 Mirtazapine orally disintegrating tablet (ODT) for the treatment of depressive patients with insomnia and anxiety symptoms

None of the clinical trials of omega-3 fatty acids using combinations of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were able to show any effect on cardiovascular outcomes, despite reductions in triglyceride levels. In contrast, the Reduction of Cardiovascular Events With Icosapent Ethyl–Intervention Trial (REDUCE-IT), which employed high-dose (4 g) purified EPA, demonstrated a 25% reduction in atherosclerotic cardiovascular disease–related events compared with placebo (hazard ratio 0.75; 95% confidence interval 0.68–0.83; P < 0.001). Moreover, REDUCE-IT is the first clinical trial using a lipid-lowering agent as adjuvant therapy to a statin to show a significant reduction in cardiovascular mortality. Significant reductions in stroke, need for revascularization, and myocardial infarction were also observed. The pharmacology of EPA is distinct from that of DHA, with a differential effect on membrane structure, lipoprotein oxidation, and the production of downstream metabolites that promote the resolution of inflammation. Attained plasma levels of EPA may be an important determinant of efficacy, with a substudy of REDUCE-IT suggesting that the threshold for clinical benefit of EPA is approximately 100 μg/mL, a level achieved in only a minority of patients in other studies. No similar clinical trials of DHA monotherapy have been conducted, so no such threshold has been established. The results of the REDUCE-IT and the Japan EPA Lipid Intervention Study (JELIS) together affirm the efficacy of EPA therapy for cardiovascular disease risk reduction in certain patient populations.

Blood pressure and the cystic fibrosis gene: evidence for lower pressure rises with age in female carriers.

Individuals homozygous for the autosomal recessive disorder CF are known to have low blood pressure, thought to be caused by greatly increased sweat salt loss. We examined whether carriers of the CF gene also have low blood pressure. Our pilot studies had suggested an effect limited to females, leading to 2 further studies in white females. In the first, blood pressure was measured in 232 known CF mutation carriers and compared with 246 mutation-negative control subjects. The carriers showed a significantly lower rate of increase in systolic blood pressure with age than the controls, especially after age 50 (3.5% per decade compared with 5.4% per decade, P=0.010). In a small substudy, sweat sodium and chloride levels were highest in those CF carriers with the lowest blood pressures. In the second study, CF carrier status was investigated in 563 normotensive females and in 607 women with essential hypertension diagnosed to test whether a lower incidence of carriers in the hypertensives suggested a protective effect. Twenty-five of the normotensives (4.4%) were carriers compared with 21 (3.5%) of the hypertensive group (P=0.45). Older CF carrier females had lower systolic and diastolic pressures than matched control subjects, with a tendency for blood pressure to increase less with age. This could result in significant reduction in stroke and heart disease. The effect on blood pressure is insufficient to prevent hypertension, though it remains conceivable that the severity might be ameliorated in carriers.

Statins: potent vascular anti-inflammatory agents

Atherosclerosis is a multifactorial condition that can result in cardiovascular disease. Statin therapy is thought to mediate cardioprotective effects that influence endothelial function, inflammatory responses, plaque stability and thrombus formation, processes involved in atherosclerosis. Although reduction in low-density lipoprotein cholesterol (LDL-C) potentially plays a role in all of these effects, several lines of evidence also implicate nonlipidmediated 'pleiotropic' effects. For example, statin therapy confers a lower risk for coronary heart disease than placebo in patients with comparable serum cholesterol levels, and confers a greater magnitude of clinical benefit than expected based on LDL-C levels alone. Moreover, while nonstatin lipid-lowering therapy does not necessarily reduce stroke risk, statins have shown a significant reduction in stroke. Statins exert their pleiotropic effects, in part, by improving endothelial function via up-regulation of endothelial nitric oxide synthase enzyme activity. Markers of inflammation such as high sensitivity C-reactive protein have been also shown to add further prognostic information about patients at risk of cardiovascular disease who may benefit from statin therapy. Further studies are still needed to determine whether statins have direct effects on inflammatory pathways.

Perspectives from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial - Lipid Lowering Trial and the Anglo-Scandinavian Cardiac Outcomes Trial - Lipid Lowering Arm

The design, process and outcomes are compared between two large clinical trials of LDL cholesterol reduction with statin treatment in patients with known high blood pressure. This new information is placed in the context of previous clinical trials of cholesterol reduction, which have provided analyses of sub-groups with high blood pressure. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial failed to find a significant reduction of total mortality (primary endpoint), cardiovascular mortality or major cardiovascular events. This differed sharply from the Anglo-Scandinavian Cardiac Outcomes Trial, Lipid Lowering Arm, which was stopped before the planned termination due to a marked reduction (36%) in coronary death or myocardial infarction (primary endpoint). This trial also found significant reductions in stroke (27%) and separately, all major vascular events (21%). The two studies were similar in that they each contained over 10 000 participants with documented high blood pressure requiring drug therapy and they both used a fixed dose of a single statin. Pravastatin (40 mg/day) was used in the former and atorvastatin 10 mg/day in the latter. The major difference was that the control group in the Anglo-Scandinavian trial was treated with placebo with a double blind design whereas antihypertensive and lipid-lowering trial was open label with controls receiving usual care. The benefit of achieving and maintaining significant LDL cholesterol reduction in patients with high blood pressure was convincingly demonstrated in the Anglo-Scandinavian trial. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial failed to achieve similar success due to use of a less effective drug and loss of the differential effect with increasing statin treatment in the usual care control group.

Differentialtherapie mit Calciumantagonisten

Efficacy of Calcium Antagonists: Calcium-channel blockers (CCBs) have long been recognized as potent agents for hypertensive therapy, with substantial blood pressure reduction in all age groups and races. CCBs improve endothelial function, may positively influence atherosclerosis in carotid arteries, reduce left ventricular hypertrophy, and hypertrophy of the resistance vessels, and improve arterial compliance. They do not adversely affect lipids and serum glucose. Use in Pracice: CCBs are also a heterogenous class of drugs composed of the phenylalkylamine verapamil, the benzothiazepine diltiazem, and the large group of dihydropyridines (DHPs) with the prototype nifedipine, and an increasing number of newer agents (e.g. nitrendipine, nisoldipine, amlodipine, felodipine, lacidipine and lercanidipine). DHPs are primarily vasodilators, lowering blood pressure by decreasing peripheral vascular resistance at the level of the small arterioles which can be followed by an autonomic counterregulation especially in drugs with a rapid onset of action. This is markedly reduced or abolished in the treatment with the modern long acting DHPs and is also not the case in the treatment with non-DHPs. Prospective randomized controlled outcome studies demonstrated a significant reduction in stroke in elderly patients with isolated systolic hypertension compared with placebo (Syst-Eur [Syst-China]), and no significant differences in cardiovascular mortality and combined morbidity compared with diuretics, beta blockers or ACE-Inhibitors (STOP-2, INSIGHT, NORDIL, ALLHAT, INVEST). To normalize the blood pressure it is mostly necessary to combine antihypertensive drugs. Here are CCBs ideal partners for a therapy with ACE-inhibitors, AT1 antagonists or beta blockers (DHP) and diuretics (verapamil). With respect to the antihypertensive differential therapy the author recommends CCBs based on studies with the evidence grade 1-3; especially for elderly hypertensives (with isolated systolic hypertension and a high risk of stroke), for patients with COPD and asthma bronchiale, Raynaud's syndrome or Prinzmetal-angina, patients with diastolic function disturbances including diastolic heart failure or hypertensives with massive left ventricular hypertrophy (in combination with ACE or AT1 inhibitors).

Antithrombotic Secondary Prevention After Stroke.

In patients with transient ischemic attack (TIA) or ischemic stroke of noncardiac origin, antiplatelet drugs are able to decrease the risk of stroke by 11% to 15%, and decrease the risk of stroke, myocardial infarction (MI), and vascular death by 15% to 22%. Aspirin leads to a moderate but significant reduction of stroke, MI, and vascular death in patients with TIA and ischemic stroke. Low doses are as effective as high doses, but are better tolerated in terms of gastrointestinal side effects. The recommended aspirin dose, therefore, is between 50 and 325 mg. Bleeding complications are not dose-dependent, and also occur with the lowest doses. The combination of aspirin (25 mg twice daily) with slow-release dipyridamole (200 mg twice daily) is superior compared with aspirin alone for stroke prevention. Ticlopidine is effective in secondary stroke prevention in patients with TIA and stroke. For some end points, it is superior to aspirin. Due to its side-effect profile (neutropenia, thrombotic thrombocytopenic purpura ), ticlopidine should be given to patients who are intolerant of aspirin. Prospective trials have not indicated whether ticlopidine is suggested for patients who have recurrent cerebrovascular events while on aspirin. Clopidogrel has a better safety profile than ticlopidine. Although not investigated in patients with TIA, clopidogrel should also be effective in these patients assuming the same pathophysiology than in patients with stroke. Clopidogrel is second-line treatment in patients intolerant for aspirin, and first-line treatment for patients with stroke and peripheral arterial disease or MI. A frequent clinical problem is patients who are already on aspirin because of coronary heart disease or a prior cerebral ischemic event, and then suffer a first or recurrent TIA or stroke. No single clinical trial has investigated this problem. Therefore, recommendations are not evidence-based. Possible strategies include the following: continue aspirin, add dipyridamole, add clopidogrel, switch to ticlopidine or clopidogrel, or switch to anticoagulation with an International Normalized Ratio (INR) of 2.0 to 3.0. The combination of low-dose warfarin and aspirin was never studied in the secondary prevention of stroke. In patients with a cardiac source of embolism, anticoagulation is recommended with an INR of 2.0 to 3.0. At the present time, anticoagulation with an INR between 3.0 and 4.5 cannot be recommended for patients with noncardiac TIA or stroke. Anticoagulation with an INR between 3.0 and 4.5 carries a high bleeding risk. Whether anticoagulation with lower INR is safe and effective is not yet known. Treatment of vascular risk factors should also be performed in secondary stroke prevention.

Antithrombotic Secondary Prevention After Stroke.

In patients with transient ischemic attack (TIA) or ischemic stroke of noncardiac origin, antiplatelet drugs are able to decrease the risk of stroke by 11% to 15%, and decrease the risk of stroke, myocardial infarction (MI), and vascular death by 15% to 22%. Aspirin leads to a moderate but significant reduction of stroke, MI, and vascular death in patients with TIA and ischemic stroke. Low doses are as effective as high doses, but are better tolerated in term of gastrointestinal side effects. The recommended aspirin dose, therefore, is between 50 and 325 mg. Bleeding complications are not dose-dependent, and also occur with the lowest doses. The combination of aspirin (25 mg twice daily) with slow release dipyridamole (200 mg twice daily) is superior compared with aspirin alone for stroke prevention. Ticlopidine is effective in secondary stroke prevention in patients with TIA and stroke. For some endpoints, it is superior to aspirin. Due to its side effect profile (neutropenia, thrombotic thrombocytopenic purpura ), ticlopidine should be given to patients who are intolerant of aspirin. Prospective trials have not indicated whether ticlopidine is suggested for patients who have recurrent cerebrovascular events while on aspirin. Clopidogrel has a better safety profile than ticlopidine. Although not investigated in patients with TIA, clopidogrel should also be effective in these patients assuming the same pathophysiology than in patients with stroke. Clopidogrel is second-line treatment in patients intolerant for aspirin, and first-line treatment for patients with stroke and peripheral arterial disease or MI. A frequent clinical problem is patients who are already on aspirin because of coronary heart disease or a prior cerebral ischemic event, and then suffer a first or recurrent TIA or stroke. No single clinical trial has investigated this problem. Therefore, recommendations are not evidence-based. Possible strategies include the following: continue aspirin, add dipyridamole, add clopidogrel, switch to ticlopidine or clopidogrel, or switch to anticoagulation with an International Normalized Ratio (INR) of 2.0 to 3.0. The combination of low-dose warfarin and aspirin was never studied in the secondary prevention of stroke. In patients with a cardiac source of embolism, anticoagulation is recommended with an INR of 2.0 to 3.0. At the present time, anticoagulation with an INR between 3.0 and 4.5 can not be recommended for patients with noncardiac TIA or stroke. Anticoagulation with an INR between 3.0 and 4.5 carries a high bleeding risk. Whether anticoagulation with lower INR is safe and effective is not yet known. Treatment of vascular risk factors should also be performed in secondary stroke prevention.

Continuing controversy in the management of concomitant coronary and carotid disease: an overview

Objectives: To perform an analytical overview of the risk factors, pathogenesis of stroke and the strategies for the management of concomitant coronary artery disease and carotid artery stenosis (CAS). Four strategies were analysed; CABG in the presence of CAS, combined (CE+CABG), reverse (CABG+CE<3 months) and prior staged (CE+CABG<3 months). Methods: A literature search formed the basis of a reference database. Outcome was assessed by the 30-day permanent stroke and mortality rate for the different approaches. Accrued rates of permanent stroke and mortality rate were expressed in terms of mean stroke and mortality rate (MSR, MMR). Data was analysed comparatively and expressed in terms of P value, odds ratio and confidence limits. Results: 33 different risk factors for stroke at CABG were identified. Significant factors included: ascending aortic atheroma, emergency procedures, impaired left ventricular function, cardioplegia and peripheral vascular disease. Risk of stroke at CABG increased with higher grade CAS (50 vs. 80%, P=0.009). Pathogenesis of stroke at CABG is multifactorial; the role of flow limiting CAS is controversial and other mechanisms are implicated. Analysis of the four strategies revealed that in the Prior Stage ( n=573) the MSR was 1.5% and MMR 5.9%, in the Unprotected CABG+CAS series the MSR was 3.8% ( n=840) and MMR ( n=596) 4.4%, in the Reverse stage series ( n=83) the MSR was 2.4%, and MMR 4.8%. For Combined procedures ( n=3295) the MSR was 3.9% and MMR 4.5%. Comparative analysis indicated a significant reduction in stroke for Prior vs. Combined (1.5 vs. 3.9%, P=0.007, odds 0.39, CI 0.2–0.77) with a higher mortality (5.9 vs. 4.5%, P=0.1, odds 1.41, CI 0.96–2.06, NS). The stroke rate in the Prior stage also remained significantly lower compared to the Unprotected CABG group both mixed ( P=0.015) and asymptomatic CAS ( P=0.047). When total risks (MSR+MMR), were analysed, similar results were found between the groups; Prior 7.4%, Reverse stage 7.2%, Combined 8.4%, Unprotected CABG+>50% CAS 11.5%. Conclusions: Stroke at CABG is due to multiple risk factors, one of which is high-grade carotid stenosis. Pathophysiology of stroke, although multifactorial, supports embolism rather than flow limitation as the primary mechanism. Lack of randomised trials has made it impossible to draw firm conclusions regarding the best management strategy. There was no significant difference in the overall stroke and mortality risk between the various strategies, however, subgroup analysis suggests that, when carefully selected, patients do better by staging the operations. In our opinion patients without severe cardiac disease should be considered for Prior staging and the rest for Combined procedure. The role of reverse staging needs further evaluation.

Is it advantageous to lower cholesterol in the elderly hypertensive?

Hypertension is often associated with other risk factors for cardiovascular disease, including elevated levels of cholesterol, and casual systolic hypertension is a very prevalent finding in the elderly (50% of women over the age of 80 have casual systolic blood pressures > or = 160 mmHg). Total cholesterol levels steadily increase with age from 20 to 65, following which they decrease slightly in men and tend to plateau in women. Elevated cholesterol levels are not uncommon in the elderly (61% of women aged between 65 and 74 have total cholesterol levels over 6.2 mmol/L [240 mg/dL]). From the data available, it is reasonable to conclude that after the age of 65, increased blood lipids, although still a risk factor for coronary heart disease (CHD), become less pronounced as risk factors and that by 75 years of age their predictive value has disappeared. Indeed, in the very elderly, there is evidence to suggest that high total cholesterol is associated with longevity. In elderly hypertensives with elevated serum cholesterol, differing risks have been reported. The European Working Party on Hypertension in the Elderly (EWPHE) trial suggested a negative relationship between cholesterol and mortality, while the Systolic Hypertension in the Elderly Program (SHEP) trial suggested a positive relationship. With regards to intervention, it is well documented that antihypertensive treatment in elderly hypertensives up to the age of 80 who have blood pressures over 160 mmHg systolic is associated with significant reductions in stroke and cardiovascular events. The efficacy of dietary modification in reducing cholesterol in the elderly has been supported by some studies but not by all. Three major intervention trails using statins have shown that in elderly patients up to the age of 70-75 who have established CHD, lipid-lowering therapy can be of benefit. The experience from these and other trials suggests that statins are generally well tolerated in the elderly. It is difficult and premature to extrapolate these results to elderly patients who have hypertension and raised cholesterol levels without established CHD. Further trials are required before routinely suggesting it is advantageous to lower cholesterol in an elderly hypertensive who does not have pre-existing evidence of CHD. It is possible that large numbers may prove to require treatment.

Aspirin in the prevention of strokes

Aspirin leads to a moderate but significant reduction of stroke, myocardial infarction (MI), and vascular deaths in patients with transient ischemic attack (TIA) and ischemic stroke. Low doses are as effective as high doses but are better tolerated in terms of gastro-intestinal side-effects. The recommended daily aspirin dose is therefore between 50 and 325 mg. Bleeding complications are not dose dependent and occur with the lowest doses.

Oral Anticoagulant Therapy Recommendations

Oral Anticoagulant Therapy Recommendations