Effect of statins in stroke prevention

PURPOSE OF REVIEW: This paper reviews recent studies into the outcomes of clinical trials in which statin therapy has been used in the prevention and treatment of strokes. RECENT DEVELOPMENTS: Epidemiologic studies found no or little association between blood cholesterol levels and stroke. Randomized trials have confirmed that LDL lowering decreased the risk of stroke, in diabetic or hypertensive patients with 'normal' LDL cholesterol at baseline, and in patients with coronary artery disease, with respectively 48, 27 and 25% reduction in stroke incidence. A meta-analysis of trials showed that the greater the LDL cholesterol reduction, the greater the intima-media thickness and stroke risk reductions. Even if statins also have 'pleiotropic' effects, their main action seems to be through LDL reduction. The Heart Protection Study only included strokes that occurred 4.6 years before--a time when the stroke event rate is low and the cardiac event rate is high, and so may not have had the power to find a true effect of LDL cholesterol lowering in preventing recurrent stroke. The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial may give a definite answer because SPARCL investigators included 4732 patients with brain infarction or transient ischemic attacks and no history of myocardial infarction within 6 months of their stroke event, at a time when the expected stroke rate is very high and the myocardial infarction rate is very low. The results should be announced by mid-2006. SUMMARY: The positive effect of statins on stroke observed in trials of patients with coronary heart disease depended mainly on between-group LDL reduction, but other mechanisms could be involved. Though effective in prevention of major coronary events after a first stroke, statins have not yet been proven effective in prevention of recurrent stroke.     

Recurrent hemorrhage from corpus luteum during anticoagulant therapy.

A 43-year old woman had recurrent massive intraperitoneal hemorrhage from rupture of a hemorrhagic corpus luteum in two successive menstrual cycles while receiving anticoagulant therapy. Left oophorectomy was performed on the first occasion and right salpingo-oophorectomy with left salpingectomy on the second. While the precise incidence cannot be determined, rupture from a hemorrhagic corpus luteum appears to be a rare but potentially catastrophic complication of anticoagulant therapy. Hence possible ovarian hemorrhage should be considered in women of reproductive age receiving heparin or sodium warfarin therapy.     

Epileptic seizures after a first stroke: the Oxfordshire Community Stroke Project.

OBJECTIVE: To describe the immediate and long term risk of epileptic seizures after a first ever stroke. DESIGN: Cohort study following up stroke survivors for 2 to 6.5 years; comparison with age specific incidence rates of epileptic seizures in the general population. SETTING: Community based stroke register. SUBJECTS: 675 patients with a first stroke, followed up for a minimum of 2 years. MAIN OUTCOME MEASURES: Occurrence of single and recurrent seizures. RESULTS: 52 patients had one or more post stroke seizures; in 25 the seizures were recurrent. The 5 year actuarial risk of a post stroke seizure in survivors (excluding 19 patients with a history of epilepsy and 3 patients in whom the seizure occurred shortly before death from another cause) was 11.5% (95% confidence interval 4.8% to 18.2%). The relative risk of seizures, in comparison with the general population, was estimated at 35.2 in the first year after stroke and 19.0 in year 2. The risk of seizures was increased in survivors of subarachnoid and intracerebral haemorrhage (hazard ratio for intracranial haemorrhage v cerebral infarction 10.2 (3.7 to 27.9)). The risk of seizures after ischaemic stroke was substantial only in patients presenting with severe strokes due to total anterior circulation infarction. Only 9 of 295 patients (3%) independent one month after stroke suffered a seizure between 1 month and 5 years (actuarial risk 4.2% (0.1% to 8.3%)). CONCLUSION: Stroke patients have about an 11.5% risk of single or recurrent seizures in the first 5 years after a stroke. Patients with more severe strokes or haemorrhagic strokes are at higher risk.     

Systems Pharmacology Dissection of Multi-Scale Mechanisms of Action for Herbal Medicines in Stroke Treatment and Prevention

Annually, tens of millions of first-ever strokes occur in the world; however, currently there is lack of effective and widely applicable pharmacological treatments for stroke patients. Herbal medicines, characterized as multi-constituent, multi-target and multi-effect, have been acknowledged with conspicuous effects in treating stroke, and attract extensive interest of researchers although the mechanism of action is yet unclear. In this work, we introduce an innovative systems-pharmacology method that combines pharmacokinetic prescreening, target fishing and network analysis to decipher the mechanisms of action of 10 herbal medicines like Salvia miltiorrhizae, Ginkgo biloba and Ephedrae herba which are efficient in stroke treatment and prevention. Our systematic analysis results display that, in these anti-stroke herbal medicines, 168 out of 1285 constituents with the favorable pharmacokinetic profiles might be implicated in stroke therapy, and the systematic use of these compounds probably acts through multiple mechanisms to synergistically benefit patients with stroke, which can roughly be classified as preventing ischemic inflammatory response, scavenging free radicals and inhibiting neuronal apoptosis against ischemic cerebral damage, as well as exhibiting lipid-lowering, anti-diabetic, anti-thrombotic and antiplatelet effects to decrease recurrent strokes. Relying on systems biology-based analysis, we speculate that herbal medicines, being characterized as the classical combination therapies, might be not only engaged in multiple mechanisms of action to synergistically improve the stroke outcomes, but also might be participated in reducing the risk factors for recurrent strokes.     

Projecting the number of patients with first ever strokes and patients newly handicapped by stroke in England and Wales.

The common assumption that future increases in the number of elderly people will result in a parallel increase in the burden of care of long term disabled survivors of stroke was examined. The number of patients with first ever strokes and the net number of people handicapped after these strokes in England and Wales every five years until 2023 have been projected. Between the base year 1983 and the year 2023 an increase in population of about 5% will occur; first ever strokes are projected to increase by about 30% and deaths within six months of first ever strokes by about 40%. The net number of severely handicapped people six months after a first ever stroke is projected to increase by only about 8%, however, and the net number of people who are moderately or severely handicapped by only 4%. This paradox occurs because first ever stroke often kills people who have been handicapped by other causes, particularly if they are elderly. It is concluded that despite the limitations of these data they strongly suggest that the increased burden of health care of patients with first ever strokes in the next 40 years will be primarily that of caring for those in the acute stages of stroke and not with the management of chronic handicap after a stroke.     

A Survey of Cardiac Infarctions: Hospital Experience

A study of patients with cardiac infarction, treated in hospital between 1950 and 1954 and followed up to the present, is reported. One hundred and forty-two patients suffered 169 attacks. In 95 attacks, the patients received anticoagulant therapy, with 15 acute deaths. Fifty-six were not so treated; among these there were 21 deaths. The rate of survival was best in younger patients with their first episode of infarction, without preexisting hypertension, cardiac failure, or systolic blood pressure persistently below 100. Angina preceding infarction disappeared in one-half of the subjects after the episode; half the survivors suffered recurrent myocardial infarction within five years. Moderate hypertension had no effect upon immediate or 10-year survival. No patient received long-term anticoagulant therapy. Of the survivors of acute infarction, 16 died in the first year after the acute attack, nine in the second year, nine in the third, six in the fourth and five in the fifth. At the end of five years, 51 subjects had survived 60 episodes. At the end of 10 years, 43 living patients had sustained 45 myocardial infarctions.     

Medical Oncology: Clinical Experience Over One Year

Over a one-year period, 167 patients with cancer were seen in a total of 1,931 clinic visits. Of these patients, 59 percent responded to therapy, with 20 percent achieving a complete response. The median duration of response was eight months (12+ months for complete responders, 7 months for partial responders), with only a two-month average survival for nonresponders. Seventy-seven deaths in clinic patients occurred for a death rate of 46 percent. Hospital tumor registry referrals rose 46 percent. The effect of early referrals, sources of referral, metastatic sites, chemotherapeutic drugs used, morbidity and type of therapy are also reviewed.     

Cooperative study on the value of long term anticoagulation in patients with stroke and non-rheumatic atrial fibrillation

The benefits of long term anticoagulant treatment of patients with non-rheumatic atrial fibrillation and cerebral infarction were studied by comparing two series of patients with stroke from centres with different policies on anticoagulant treatment. The long term prognosis of 50 patients from the Oxfordshire community stroke project, who did not receive anticoagulants, was compared with that of 70 similar patients from Maastricht, who were treated with anticoagulants. After a mean follow up of 27 months there was no significant difference in either the rate of survival or the rate of recurrent stroke between the two groups.These data suggest that any benefit of anticoagulation is modest. A large randomised trial is planned to establish whether long term anticoagulant treatment is of value and, if so, to what extent.     

The Results of Surgical Management of Extracranial Internal Carotid Artery Occlusion and Stenosis

Vascular reconstruction was attempted in 109 patients with carotid artery occlusion or stenosis. The follow-up on those with restored or improved flow was as long as nine years (average: two and one-half years).Arteriographic demonstration of lesions is mandatory. Complications were reduced by pre-arteriographic administration of anticoagulants and retrograde brachial arteriographic techniques.Although patients with stenosis are the best candidates, an attempt to restore flow in occluded vessels is warranted in all patients, except those with advanced disease or those who are drowsy and hemiplegic. Flow was restored in two-thirds of those who underwent early operation (under three days) and in one-quarter of those undergoing late operation. Even late operation restored flow in five of nine patients who presented with transient ischemic attacks.In completed strokes, operation should be limited to patients with: (1) minor strokes, (2) extensive strokes of short duration, and (3) extensive strokes of longer duration but with a worth-while outlook.When flow was restored or improved, symptoms were arrested in 93% of patients with transient ischemia, and at follow-up this result was maintained in 86%. Symptoms were arrested in 83% of those with strokes in evolution, and this was maintained at follow-up.Reconstruction combined with anticoagulant therapy of limited duration appears to be the optimal method of treatment.     

缺血性脑卒中二级预防研究进展

脑卒中是一种危害人类健康的全球性问题。缺血性脑卒中复发是此类疾病患者面临的最严重问题之一,而且复发后会进一步加重患者功能障碍,甚至导致死亡。二级预防的主要目的是阻止短暂性脑缺血发作后发生的脑卒中或首次脑卒中后再发的脑卒中。所以,首次卒中后尽早开展二级预防显得尤为重要。下面,我们就有关缺血性脑卒中二级预防的控制危险因素、抗栓治疗、手术治疗、及生活习惯改变等方面,将近年来研究的新进展进行总结。     

Preventive health care, 1999 update: 2. Echocardiography for the detection of a cardiac source of embolus in patients with stroke

OBJECTIVE: To develop guidelines for the use of echocardiography in the investigation of patients with stroke. OPTIONS: (1) Routine transthoracic echocardiography (TTE); (2) routine transesophageal echocardiography (TEE); (3) routine TTE followed by TEE if the TTE findings are noncontributory; (4) selective TTE or TEE in patients with cardiac disease who would not otherwise receive anticoagulant therapy. OUTCOMES: This article reviews the available evidence on the yield of TTE and TEE in detecting cardiac sources of cerebral emboli in patients with stroke, the effectiveness of treatment for cardiac sources of emboli and the effectiveness of screening echocardiography for secondary stroke prevention. EVIDENCE: MEDLINE was searched for relevant articles published from January 1966 to April 1998; also reviewed were additional articles identified from the bibliographies and citations obtained from experts. BENEFITS, HARMS AND COSTS: Echocardiography can detect intracardiac masses (thrombus, vegetation or tumour) in about 4% (with TTE) to 11% (with TEE) of stroke patients. The yield is lower among patients without clinical evidence of cardiac disease by history, physical examination, electrocardiography or chest radiography (less than 2%) than among patients with clinical evidence of cardiac disease (less than 19%). The risks of echocardiography to patients are small. TTE has virtually no risks, and TEE is associated with cardiac, pulmonary and bleeding complications in 0.18%. Patients with an identified intracardiac thrombus are at increased risk for embolic events (absolute risk uncertain, range 0%-38%), and this appears to be reduced with anticoagulant therapy (absolute risk reduction uncertain). Anticoagulant therapy carries a risk of major hemorrhage of 1% to 3% per year. The overall effectiveness of echocardiography in the prevention of recurrent stroke is unknown. VALUES: The strength of evidence was evaluated using the methods of the Canadian Task Force on Preventive Health Care. RECOMMENDATIONS: There is fair evidence to recommend echocardiography in patients with stroke and clinical evidence of cardiac disease by history, physical examination, electrocardiography or chest radiography (grade B recommendation). There is insufficient evidence to recommend for or against TEE in patients with normal results of TTE (grade C recommendation). There is insufficient evidence to recommend for or against routine echocardiography in patients (including young patients) without clinical cardiac disease (grade C recommendation). Routine echocardiography is not recommended for patients with clinical cardiac disease who have independent indications for or contraindications to anticoagulant therapy (grade D recommendation). There is fair evidence to recommend anticoagulant therapy in patients with stroke and intracardiac thrombus (grade B recommendation). There is insufficient (no) evidence to recommend for or against any specific therapy for patent foramen ovale (grade C recommendation). VALIDATION: The findings of this analysis were reviewed through an iterative process by the members of the Canadian Task Force on Preventive Health Care.     

LOW PROFILE BIOPROSTHESIS FOR CARDIAC VALVE REPLACEMENT: EARLY CLINICAL RESULTS

Between May 1976 and April 1977, 100 patients underwent cardiac valve replacement with a unique low profile glutaraldehyde-treated porcine aortic xenograft. These patients were classified in four groups: Group I, 43 patients who underwent isolated mitral valve replacement (MVR); Group II, 27 patients who had isolated aortic valve replacement (AVR); Group III, 10 patients who had MVR and AVR; and Group IV, 20 patients who had MVR or AVR associated with other cardiac procedures. The operative mortality for Group I was 2.3% (1 of 43) and 15% (3 of 20) in Group IV. The total operative mortality was 4% (4 of 100) and the late mortality was 1.02% (1 of 96 survivors), who died apparently secondary to a cardiac arrhythmia. During a follow-up period extending for 16 months, thromboembolic complications occurred early in the postoperative period in 3% (3 of 100), one patient with neurological residual, and two patients with transient symptoms only. The embolic complications occurred only in Group I. Considering all patients in whom the mitral valves were replaced, the incidence of emboli was 4.9% (3 of 61). The 96 patients did not receive anticoagulant therapy. Reoperation was necessary in one patient because of periprosthetic leak. The incidence of endocarditis was 1.02% (1 of 96 survivors). We recommend anticoagulant therapy for eight to twelve weeks postoperatively in MVR patients after bioprosthetic insertion.     

Stroke after acute myocardial infarction: relation to infarct size.

In a consecutive series of 783 patients with acute myocardial infarction, 13 (1.7%) suffered a stroke. In all but one case the strokes occurred among the 255 patients whose peak creatine kinase (CK) concentrations fell in the upper third of the range of values (over 1160 IU/l, about eight times the upper limit of normal); the exception was a patient with a pre-existing ventricular aneurysm. The incidence of stroke in the patients with CK over 1160 IU/l was 4.7%, 24 times the incidence when peak CK was below this value (0.2%). Higher peak serum enzyme concentrations were associated with an even higher incidence of stroke. Comparison of peak enzyme concentrations with cumulated CK showed a close correlation (r = 0.90 with peak CK; r = 0.85 with peak aspartate transaminase), suggesting that the peak enzyme values reflected infarct size. Thus the risk of stroke after infarction was a function of the size of the myocardial infarct; two-thirds of the patients had negligible risk of stroke and did not need anticoagulant prophylaxis.     

Identifying unprovoked thromboembolism patients at low risk for recurrence who can discontinue anticoagulant therapy

Background

Whether to continue oral anticoagulant therapy beyond 6 months after an “unprovoked” venous thromboembolism is controversial. We sought to determine clinical predictors to identify patients who are at low risk of recurrent venous thromboembolism who could safely discontinue oral anticoagulants.

Methods

In a multicentre prospective cohort study, 646 participants with a first, unprovoked major venous thromboembolism were enrolled over a 4-year period. Of these, 600 participants completed a mean 18-month follow-up in September 2006. We collected data for 69 potential predictors of recurrent venous thromboembolism while patients were taking oral anticoagulation therapy (5–7 months after initiation). During follow-up after discontinuing oral anticoagulation therapy, all episodes of suspected recurrent venous thromboembolism were independently adjudicated. We performed a multivariable analysis of predictor variables (p < 0.10) with high interobserver reliability to derive a clinical decision rule.

Results

We identified 91 confirmed episodes of recurrent venous thromboembolism during follow-up after discontinuing oral anticoagulation therapy (annual risk 9.3%, 95% CI 7.7%–11.3%). Men had a 13.7% (95% CI 10.8%–17.0%) annual risk. There was no combination of clinical predictors that satisfied our criteria for identifying a low-risk subgroup of men. Fifty-two percent of women had 0 or 1 of the following characteristics: hyperpigmentation, edema or redness of either leg; D-dimer ≥ 250 μg/L while taking warfarin; body mass index ≥ 30 kg/m²; or age ≥ 65 years. These women had an annual risk of 1.6% (95% CI 0.3%–4.6%). Women who had 2 or more of these findings had an annual risk of 14.1% (95% CI 10.9%–17.3%).

Interpretation

Women with 0 or 1 risk factor may safely discontinue oral anticoagulant therapy after 6 months of therapy following a first unprovoked venous thromboembolism. This criterion does not apply to men. (http://Clinicaltrials.gov trial register number {"type":"clinical-trial","attrs":{"text":"NCT00261014","term_id":"NCT00261014"}}NCT00261014)Venous thromboembolism is a common, potentially fatal, yet treatable, condition. The risk of a recurrent venous thromboembolic event after 3–6 months of oral anticoagulant therapy varies. Some groups of patients (e.g., those who had a venous thromboembolism after surgery) have a very low annual risk of recurrence (< 1%),¹ and they can safely discontinue anticoagulant therapy.² However, among patients with an unprovoked thromboembolism who discontine anticoagulation therapy after 3–6 months, the risk of a recurrence in the first year is 5%–27%.^3–6 In the second year, the risk is estimated to be 5%,³ and it is estimated to be 2%–3.8% for each subsequent year.^5,7 The case-fatality rate for recurrent venous thromboembolism is between 5% and 13%.^8,9 Oral anticoagulation therapy is very effective for reducing the risk of recurrence during therapy (> 90% relative risk [RR] reduction);^3,4,10,11 however, this benefit is lost after therapy is discontinued.^3,10,11 The risk of major bleeding with ongoing oral anticoagulation therapy among venous thromboembolism patients is 0.9–3.0% per year,^3,4,6,12 with an estimated case-fatality rate of 13%.¹³Given that the long-term risk of fatal hemorrhage appears to balance the risk of fatal recurrent pulmonary embolism among patients with an unprovoked venous thromboembolism, clinicians are unsure if continuing oral anticoagulation therapy beyond 6 months is necessary.^2,14 Identifying subgroups of patients with an annual risk of less than 3% will help clinicians decide which patients can safely discontinue anticoagulant therapy.We sought to determine the clinical predictors or combinations of predictors that identify patients with an annual risk of venous thromboembolism of less than 3% after taking an oral anticoagulant for 5–7 months after a first unprovoked event.     

ANTICOAGULANT DRUG TREATMENT OF CORONARY ARTERY DISEASE

Anticoagulant therapy of arteriosclerotic heart disease may prove to be most valuable when applied on a long-term basis for prevention of recurrent myocardial infarction. While its prophylactic value in impending infarction has not been established, at least the accepted treatment for the acute stage is already begun if an anticoagulant has been administered before an inevitable infarction occurs.The chief value of the anticoagulant, though, seems to lie in preventing cardiac mural thrombosis and extracardiac thromboembolism. It is by this effect, apparently, that mortality has been reduced by 50 per cent among survivors of myocardial infarction who receive continuous dicoumarin therapy.While the danger of hemorrhage is still present, it is being steadily reduced by increasing skill in the management of anticoagulant therapy, and for a long time the risk has been far outweighed by the reduction in coronary occlusion.Physicians have a duty to learn the use of anticoagulant therapy, obtain the facilities necessary for it, and apply it to patients who are able and willing to cooperate in prolonging their useful lives.     

Sulphasalazine for rheumatoid arthritis: toxicity in 774 patients monitored for one to 11 years.

Sulphasalazine is being used increasingly to treat rheumatoid arthritis, though its long term safety profile has not been established in this condition. The incidence and nature of adverse effects occurring in 774 patients with rheumatoid arthritis treated with sulphasalazine for periods ranging from one to 11 years were therefore noted. Altogether 205 of the patients stopped treatment permanently due to an adverse effect. One hundred and fifty six (76%) of these events occurred within three months and few beyond the first year. Most events were trivial and were self limiting after withdrawal of the drug; of the potentially more serious adverse effects, 33 (66%) occurred within three months of treatment. None of the patients died or suffered lasting ill effects. It is concluded that adverse effects of treatment with sulphasalazine are generally seen within three months; though regular monitoring is desirable during that period, thereafter few worrying problems occur.     

Extended Anticoagulant and Aspirin Treatment for the Secondary Prevention of Thromboembolic Disease: A Systematic Review and Meta-Analysis

Background

Patients who have had an unprovoked deep venous thrombosis (DVT) or pulmonary embolus (PE) are at a high risk for recurrent venous thromboembolism (VTE). Extended “life-long” anticoagulation has been recommended in these patients. However, the risk benefit ratio of this approach is controversial and the role of the direct oral anticoagulants (DOACs) and aspirin is unclear. Furthermore, in some patients with a “weak provoking factor” there is clinical equipoise regarding continuation or cessation of anticoagulant therapy after treatment of the acute VTE event.

Objective

A systematic review and meta-analysis to determine the risks (major bleeding) and benefits (recurrent VTE and mortality) of extended anticoagulation with vitamin k antagonists (VKA), DOACs and aspirin in patients with an unprovoked VTE and in those patients with clinical equipoise regarding continuation or cessation of anticoagulant therapy. In addition, we sought to determine the risk of recurrent VTE events once extended anti-thrombotic therapy was discontinued.

Data Sources

MEDLINE, Cochrane Register of Controlled Trials, citation review of relevant primary and review articles.

Study Selection

Randomized placebo-controlled trials (RCTs) that compared the risk of recurrent VTE in patients with an unprovoked DVT or PE who had been treated for at least 3 months with a VKA or a DOAC and were then randomized to receive an oral anti-thrombotic agent or placebo for at least 6 additional months. We included studies that included patients in whom clinical equipoise existed regarding the continuation or cessation of anticoagulant therapy.

Data Extraction

Independent extraction of articles by both authors using predefined data fields, including study quality indicators. Data were abstracted on study size, study setting, initial event (DVT or PE), percentage of patients where the initial VTE event was unprovoked, the number of recurrent VTE events, major bleeds and mortality during the period of extended anticoagulation in the active treatment and placebo arms. In addition, we recorded the event rate once extended treatment was stopped. Meta-analytic techniques were used to summarize the data. Studies were grouped according to the type of anti-thrombotic agent.

Data Synthesis

Seven studies which enrolled 6778 patients met our inclusion criteria; two studies evaluated the extended use of Coumadin, three studies evaluated a DOAC and two studies evaluated the use of aspirin. The duration of followup varied from 6 to 37 months. In the Coumadin and aspirin studies 100% of the randomized patients had an unprovoked VTE, while in the DOAC studies between 73.5% and 93.2% of the VTE events were unprovoked. In the control group recurrent VTE occurred in 9.7% of patients compared to 2.8% in the active treatment group (OR 0.21; 95% CI 0.11–0.42, p<0.0001). VKA, DOACs and aspirin significantly reduced the risk of recurrent VTE, with VKA and DOACs being significantly more effective than aspirin. Major bleeding events occurred in 12 patients in the control group (0.4%) and 25 of 3815 (0.6%) patients in the active treatment group (OR 1.64; 95% CI 0.69–3.90, NS). There were 39 (1.3%) deaths in control patients and 33 (0.9%) deaths in the anti-thrombotic group during the treatment period (OR 0.73; 95% CI 0.40–1.33, NS). Patients whose initial VTE event was a PE were more likely to have a recurrent PE than a DVT. The annualized event rate after discontinuation of extended antithrombotic therapy was 4.4% in the control group and 6.5% in the active treatment arm.

Conclusions

VKA, DOACs and aspirin significantly reduced the risk of recurrent VTE, with DOACs and VKA being more effective than aspirin. The decision regarding life-long anticoagulation following an unprovoked DVT or PE should depend on the patients’ risk for recurrent PE as well as the patients’ values and preferences.     

Thrombosis of Bj?rk-Shiley aortic valve prosthesis: report of three cases.

Thrombotic malfunction of a Björk-Shiley aortic valve prosthesis occurred in three patients 6 to 16 months postoperatively. None of the patients had been taking anticoagulants. Although the presentation was acute, prodromal symptoms could be identified retrospectively in two of the patients. Two patients survived thrombectomy. Postoperative anticoagulant therapy is recommended in patients with these prostheses despite factors that may make such therapy riskier in specific patients. Attention to the character of murmurs and of the closure sound of the prosthetic valve must be part of the routine follow-up. In the emergency situation, when delay must be avoided, catheterization and angiography are unnecessary. The operative approach consists of complete thrombectomy without replacement of the valve or any of its components unless there is obvious periprosthetic leak or prosthetic wear.     

Observations on Strokes and Cerebral Edema with Intracranial Tumours

Four patients who suffered strokes were found at autopsy to have intracranial tumours remote from the region responsible for the stroke, but the relevant cerebral white matter was swollen, pale yellow, and manifestly edematous. It is inferred from these observations that strokes in the presence of cerebral tumours may be caused by rapid fluctuations in the extent and intensity of the edema surrounding the cerebral tumour.A fifth patient is reported with recurrent strokes associated with a glioblastoma multiforme. He showed many dramatic remissions associated with treatment with adrenocorticotrophic hormone and equally prompt relapses when treatment was stopped. Similar cases in the literature are referred to. It is suggested that these hormones decrease the cerebral edema and thus produce the remissions.     

Hemorrhage During Long-Term Anticoagulant Drug Therapy—Part II: Gastrointestinal Hemorrhage

Most of the gastrointestinal hemorrhages occurring during long-term anticoagulant drug therapy of 2,013 patients (reported in the literature) were caused by underlying lesions (44 to 77). Of the 44 lesions, only seven were diagnosed before treatment was started.Most of the episodes of hemorrhage occurred with the prothrombin activity at a so-called “safe” level. Closer investigation before the anticoagulant therapy was begun might have brought the underlying lesion to light.