Effect of treating isolated systolic hypertension on the risk of developing various types and subtypes of stroke: the Systolic Hypertension in the Elderly Program (SHEP).

CONTEXT: The Systolic Hypertension in the Elderly Program (SHEP) demonstrated that treating isolated systolic hypertension in older patients decreased incidence of total stroke, but whether all types of stroke were reduced was not evaluated. OBJECTIVE: To investigate antihypertensive drug treatment effects on incidence of stroke by type and subtype, timing of strokes, case-fatality rates, stroke residual effects, and relationship of attained systolic blood pressure to stroke incidence. DESIGN: The SHEP study, a randomized, double-blind, placebo-controlled trial began March 1, 1985, and had an average follow-up of 4.5 years. SETTING AND PARTICIPANTS: A total of 4736 men and women aged 60 years or older with isolated systolic hypertension at 16 clinical centers in the United States. INTERVENTIONS: Patients were randomly assigned to receive treatment with 12.5 mg/d of chlorthalidone (step 1); either 25 mg/d of atenolol or 0.05 mg/d of reserpine (step 2) could be added (n = 2365); or placebo (n = 2371). MAIN OUTCOME MEASURES: Occurrence, type and subtype, and timing of first strokes and stroke fatalities; and change in stroke incidence for participants (whether in active treatment or placebo groups) reaching study-specific systolic blood pressure goal (decrease of at least 20 mm Hg from baseline to below 160 mm Hg) compared with participants not reaching goal. RESULTS: A total of 85 and 132 participants in the active treatment and placebo groups, respectively, had ischemic strokes (adjusted relative risk [RR], 0.63; 95% confidence interval [CI], 0.48-0.82); 9 and 19 had hemorrhagic strokes (adjusted RR, 0.46; 95% CI, 0.21-1.02); and 9 and 8 had strokes of unknown type (adjusted RR, 1.05; 95% CI, 0.40-2. 73), respectively. Four subtypes of ischemic stroke were observed in active treatment and placebo group participants, respectively, as follows: for lacunar, n = 23 and n = 43 (adjusted RR, 0.53; 95% CI, 0.32-0.88); for embolic, n = 9 and n = 16 (adjusted RR, 0.56; 95% CI, 0.25-1.27); for atherosclerotic, n = 13 and n = 13 (adjusted RR, 0. 99; 95% CI, 0.46-2.15); and for unknown subtype, n = 40 and n = 60 (adjusted RR, 0.64; 95% CI, 0.43-0.96). Treatment effect was observed within 1 year for hemorrhagic strokes but was not seen until the second year for ischemic strokes. Stroke incidence significantly decreased in participants attaining study-specific systolic blood pressure goals. CONCLUSIONS: In this study, antihypertensive drug treatment reduced the incidence of both hemorrhagic and ischemic (including lacunar) strokes. Reduction in stroke incidence occurred when specific systolic blood pressure goals were attained. JAMA. 2000;284:465-471

Efficacy of carotid endarterectomy for asymptomatic carotid stenosis. The Veterans Affairs Cooperative Study Group.

BACKGROUND: The efficacy of carotid endarterectomy in patients with asymptomatic carotid stenosis has not been confirmed in randomized clinical trials, despite the widespread use of operative intervention in such patients. METHODS: We conducted a multicenter clinical trial at 11 Veterans Affairs medical centers to determine the effect of carotid endarterectomy on the combined incidence of transient ischemic attack, transient monocular blindness, and stroke. We studied 444 men with asymptomatic carotid stenosis shown arteriographically to reduce the diameter of the arterial lumen by 50 percent or more. The patients were randomly assigned to optimal medical treatment including antiplatelet medication (aspirin) plus carotid endarterectomy (the surgical group; 211 patients) or optimal medical treatment alone (the medical group; 233 patients). All the patients at each center were followed independently by a vascular surgeon and a neurologist for a mean of 47.9 months. RESULTS: The combined incidence of ipsilateral neurologic events was 8.0 percent in the surgical group and 20.6 percent in the medical group (P < 0.001), giving a relative risk (for the surgical group vs. the medical group) of 0.38 (95 percent confidence interval, 0.22 to 0.67). The incidence of ipsilateral stroke alone was 4.7 percent in the surgical group and 9.4 percent in the medical group. An analysis of stroke and death combined within the first 30 postoperative days showed no significant differences. Nor were there significant differences between groups in an analysis of all strokes and deaths (surgical, 41.2 percent; medical, 44.2 percent; relative risk, 0.92; 95 percent confidence interval, 0.69 to 1.22). Overall mortality, including postoperative deaths, was primarily due to coronary atherosclerosis. CONCLUSIONS: Carotid endarterectomy reduced the overall incidence of ipsilateral neurologic events in a selected group of male patients with asymptomatic carotid stenosis. We did not find a significant influence of carotid endarterectomy on the combined incidence of stroke and death, but because of the size of our sample, a modest effect could not be excluded.

The history of leeching and hirudin.

Leeching is an art dating back at least to ancient Egypt. It reached its zenith in the late 18th and early 19th centuries. The antithrombotic quality of leech saliva was first noted by Haycraft in 1884 and the active anticoagulant ingredient isolated in 1904 by Jacoby. He gave this agent the name 'hirudin'. Hirudin was isolated in pure crystalline form by Markwardt in 1957 and first produced in quantity by genetic engineering in 1986. The salivary glands of several species of leech also contain other biologically active substances which are currently undergoing investigation.

Comprehensive criteria for assessing therapy-induced toxicity.

Methods of assessing and reporting toxic reactions induced by therapy, particularly chemotherapy, need improvements. Accurate and reliable reporting of therapy-induced toxicity will be necessary for quality clinical research including drug development and for implementation of complex multimodality treatments, currently, however, the extent and quality of reporting of toxic reactions vary widely. Whereas standard and widely accepted criteria have been established for assessing and reporting therapeutic response, no such criteria exist for toxicity. We have developed comprehensive criteria for assessing and reliably reporting toxic reactions. We have reduced the degree of subjectivity in assigning grades by using primarily objective methods. An attempt has been made to standardize the "morbidity impact" of each toxicity grade irrespective of the organ system involved.

Carotid endarterectomy: what is its current status?

The plethora of recent articles regarding carotid endarterectomy has tended to confuse rather than clarify its indications, efficacy, and acceptability. The National Institutes of Health has recently funded two large multicenter controlled clinical trials, one including asymptomatic persons with carotid stenoses, and the other, patients having transient ischemic episodes or minor strokes. Eight academic professors of neurology (four), neurosurgery (two), and vascular surgery (two) with a long and abiding interest in cerebrovascular disease prepared a statement delineating acceptable levels of mortality and morbidity from this procedure. These might serve as guidelines until the large trials have been completed.

The effect of the experimental antitumor agent caracemide on brain choline acetyltransferase.

Caracemide was found to inhibit choline acetyltransferase (CAT) from rat brain. A concentration of 0.5 mM caracemide inhibited the enzyme by 93%, whereas a degradation product from caracemide, N-(methylcarbamoyloxy)acetamide, produced only a 50% inhibition. Two other degradation products, N-(methyl-carbamoyloxy)-N'-methylurea and N-hydroxy-N'-methylurea, lacked any inhibitory activity. With bovine brain CAT, caracemide showed noncompetitive inhibition with the substrate choline, Km 337 microM, Ki240 microM, Vmax 2.83 nmol acetylcholine formed/min/mg protein and mixed inhibition with the substrate acetyl-CoA, Km 21 microM, Ki 146 microM, Vmax 3.85 nmol acetylcholine formed/min/mg protein.

Inhibition of brain choline acetyltransferase by tetraplatin.

Tetraplatin inhibited choline acetyltransferase (CAT) from rat and bovine brain with I50 values of 13.5 and 40 microM, respectively. At 0.5 mM concentration, tetraplatin exhibited inhibition of the rat brain enzyme by 89%, whereas cisplatin yielded only 18% inhibition. With bovine CAT, tetraplatin showed noncompetitive inhibition with the substrate choline, Km 337 microM, Ki 29 microM, Vmax 2.83 nmoles acetylcholine formed/min/mg protein, and competitive inhibition with the substrate acetyl-CoA, Km 21 microM, Ki 16 microM, Vmax 3.85 nmoles acetylcholine formed/min/mg protein.

Vertebral artery trauma: transcatheter embolization.

Injuries of the vertebral arteries in four patients were treated by transcatheter embolization. Embolotherapy was performed after incomplete or unsuccessful surgery in three of the patients and as a preventive measure in lieu of surgery in the fourth patient. All procedures were successful and without complications. An injured vertebral artery is usually extremely difficult to approach surgically, but because of extensive collateral blood supply it is usually expendable; therefore, it becomes an inviting target for management by interventional angiographic techniques. Embolotherapy of an injured vertebral artery is easier, faster, and safer than its surgical ligation and, therefore, decidedly superior. With few exceptions, embolotherapy should be considered the preferred method in the management of vertebral artery trauma.

Central nervous system (CNS) penetration of homoharringtonine (HHT).

Generally tritiated homoharringtonine ([3H]HHT, 150 microCi, 430 micrograms) was administered intravenously to seven patients at varying times before surgical resection of malignant brain tumor. Plasma, urine, cerebrospinal fluid (CSF), and tumor specimens were obtained during surgery, and the concentrations of HHT, its major metabolite, and [3H]HHT equivalent were determined chromatographically and radiochemically. For [3H]HHT equivalent, the concentration in tumor ranged from 0.6 to 4.3 ng/g and the ratio of tumor to plasma concentration from 0.5 to 1.8. In one patient who had CSF available for drug determination, the CSF to plasma ratio of total [3H]HHT was 0.3 at 45 minutes after drug administration and less than 0.2 ng/ml was unchanged HHT. For unchanged HHT, drug concentration in tumor ranged from undetectable (4 patients) to 1.8 ng/g. A major metabolite of HHT was detectable in the tumor specimens of all the patients. These results indicate that homoharringtonine can penetrate into brain tumors; in 3 patients with brain tumors, the ratios of HHT concentration in the tumor to that in the concurrent plasma were greater than one.

Multi-infarct dementia.

The participation of vascular disease in elderly dementia has been clarified to a significant degree in the past decade. The term multi-infarct dementia implies that severe mental impairment can result from thrombosis of large and medium arteries or from multifocal emboli of either cardiac or arterial origin. This is markedly different from the concept, which, unfortunately, is still the generally current view in the lay press, in some medical journals, and in advertisements of pharmaceutical companies, that gradual narrowing of cervical and cerebral arteries produces chronic hypoperfusion of the brain and is the basis of mental deterioration. This concept of generalized cerebral arteriosclerosis or arteriosclerotic dementia is no longer acceptable. Most patients with MID can be distinguished from those suffering from other types of dementia by employing a clinical ischemic score supplemented by electrophysiologic studies, CCT, and neuropsychological testing. Furthermore, the association of MID with severe hypertension and thromboembolism makes early diagnosis imperative, because appropriate treatment may arrest progression and even provide some improvement.

Treatment-related leukoencephalopathy. A study of three cases and literature review.

The etiology and pathogenesis of treatment-related leukoencephalopathy remain obscure. The evidence is substantial, however, that radiation therapy in combination with higher cerebral concentrations of certain chemotherapeutic agents such as MTX increases the likelihood of permanent damage. There is no therapy of apparent benefit for treatment-related leukoencephalopathy, but reasonable alternatives include 1) withholding chemotherapy and/or radiation, 2) administering calcium leucovorin in high doses intravenously in methotrexate-induced leukoencephalopathy (26), or 3) perfusing the subarachnoid space (2) from above through an Ommaya reservoir and out from below through a lumbar puncture needle or lumbar subarachnoid catheter. Because CT scan abnormalities and subtle mental or intellectual changes are often noted before the full-blown clinical presentation, a prospective study involving periodic CT scanning as well as formal neuropsychologic testing appears worthwhile in all patients who are to receive cranial irradiation and/or chemotherapy in the prophylaxis or active treatment of CNS disease in order to detect and perhaps even to prevent this adverse side effect of cancer therapy.