Masahiro Yasaka

Dual Antithrombotic Therapy Increases Severe Bleeding Events in Patients With Stroke and Cardiovascular Disease A Prospective, Multicenter, Observational Study

Background and Purpose— We sought to determine the incidence and severity of bleeding events in patients with stroke and cardiovascular diseases who were taking oral antithrombotic agents in Japan, where the incidence of hemorrhagic stroke is higher than in Western countries. Methods— A prospective, multicenter, observational study was conducted; 4009 patients who were taking oral antithrombotic agents for stroke and cardiovascular diseases were enrolled. The patients were classified into 4 groups according to their antithrombotic treatment: the single antiplatelet agent group (47.2%); the dual antiplatelet agent group (8.7%); the warfarin group (32.4%); and the warfarin plus antiplatelet agent group (11.7%). The primary end point was life-threatening or major bleeding according to the MATCH trial definition. Results— During a median follow-up of 19 months, there were 57 life-threatening and 51 major bleeding events, including 31 intracranial hemorrhages. The annual incidence of the primary end point was 1.21% in the single antiplatelet agent group, 2.00% in the dual antiplatelet agent group, 2.06% in the warfarin group, and 3.56% in the warfarin plus antiplatelet agent group (P<0.001). After adjustment for baseline characteristics, adding an antiplatelet agent to warfarin increased the risk of the primary end point (relative risk=1.76; 95% CI, 1.05 to 2.95), and adding another antiplatelet agent to single antiplatelet agent therapy increased the secondary end point of any bleeding, including minor events (relative risk=1.37; 95% CI, 1.07 to 1.76). Conclusions— The incidence of bleeding events during antithrombotic therapy in Japan was similar to that reported for Western countries, although the trials used different study designs. Dual antithrombotic therapy was independently related to an increased risk of bleeding events.

Correction of INR by prothrombin complex concentrate and vitamin K in patients with warfarin related hemorrhagic complication

We investigated the effect of prothrombin complex concentrate (PCC, median 500 IU) and vitamin K (10-20 mg) or either on blood coagulation and clinical findings in 17 patients with major hemorrhagic complication during warfarin treatment. Their international normalized ratio (INR) at admission was median 2.7 (2.0-above 10.0). In 11 patients treated with PCC and vitamin K, INR decreased to median 1.13 (0.91-1.36) 10 min after the administration with elevation of plasma levels of coagulant factors II, VII, IX, X and protein C.INR decreased abruptly after the administration of PCC without vitamin K in two patients but it increased again 12-24 h after, with decrease of coagulant factors levels. In one of them, a hematoma of the brain enlarged with INR re-increase 12-24 h after the administration. In four patients treated with vitamin K alone, INR decreased slowly from 2.69 (1.03-3.35) to 1.28 (1.25-1.44) 12-24 h after the administration in parallel with gradual increase of the coagulant factors.PCC administration with or without vitamin K seems to be more effective in rapidly correcting increased INR levels than vitamin K treatment without PCC. PCC without vitamin K may result in re-increase of INR and clinical deterioration.

Grading Carotid Stenosis Using Ultrasonic Methods

The controversy as to whether Doppler ultrasonic methods should play a role in clinical decision-making in the prevention of stroke is attributable to reported disagreement between angiographic and ultrasonic results and the lack of internationally accepted ultrasound criteria for describing the degree of stenosis. Foremost among the explanations for both is the broad scatter of peak systolic velocities in the stenosis, the criterion that has so far received most attention. Grading based on a set of main and additional criteria can overcome diagnostic errors. Morphological measurements (B-mode images and color flow imaging) are the main criteria for low and moderate degrees of stenosis. Increased velocities in the stenosis indicate narrowing, but the appearance of collateral flow and decreased poststenotic flow velocity prove a high degree stenosis (≥70%), additionally allowing the estimation of the hemodynamic effect in the category of high-degree stenosis. Additional criteria refer to the effect of a stenosis on prestenotic flow (common carotid artery), the extent of poststenotic flow disturbances, and derived velocity criteria (diastolic peak velocity and the carotid ratio). This multiparametric approach is intended to increase the reliability and the standard of reporting of ultrasonic results for arteriosclerotic disease of the carotid artery.

Distribution of atherosclerosis and risk factors in atherothrombotic occlusion.

Background and Purpose The present study was performed to determine the relation between distribution of atherosclerosis and risk factors in Japanese patients with atherothrombotic occlusion. Methods We studied 154 patients with atherothrombotic occlusion of the extracranial internal carotid artery (n=75, ICA group), the horizontal portion of the middle cerebral artery (n=47, MCA group), and the basilar artery (n=32, BA group), all of which were confirmed by cerebral angiography. We investigated the distribution of atherosclerosis of the three sites and compared the risk factors for atherosclerosis between the three groups. We used 113 subjects without stroke as the control group. Results A strong correlation was present between atherosclerosis of the extracranial internal carotid artery and that of the basilar artery. However, only a weak correlation existed between atherosclerosis of the middle cerebral artery and that of the other vessels. Although the prevalence of smoking and hypertension was higher and high density lipoprotein cholesterol levels were lower in the three groups than in the control subjects, no significant differences were found in age, sex, prevalence of smoking and hypertension, serum levels of triglycerides, and high density lipoprotein cholesterol among the three groups. The prevalence of coronary heart disease and diabetes mellitus and the serum levels of hemoglobin Ale, total cholesterol, and low density lipoprotein cholesterol were higher in the ICA and BA groups than in the MCA group. The prevalence of electrocardiographic evidence of left ventricular hypertrophy was higher in the MCA group than in the other groups. Conclusions In addition to smoking, hypertension, and low concentration of high density lipoprotein cholesterol, diabetes mellitus and hypercholesterolemia seem to be associated with atherosclerosis of the extracranial internal carotid artery and the basilar artery, and advanced hypertension may play a role in the development of middle cerebral artery occlusion.

Aortic Arch Atherosclerotic Lesions and the Recurrence of Ischemic Stroke

Background and Purpose— Aortic arch atherosclerotic lesions are often associated with embolic brain infarction. We investigated the relationship between stroke recurrence and the characteristics of aortic arch atherosclerotic lesions. Methods— Among 487 stroke patients who underwent transesophageal echocardiography, 283 patients with brain embolism diagnosed without significant occlusive lesions (≥50%) in their cerebral arteries were included in this study. We measured the intimamedia thickness (IMT) and evaluated the extension and mobility of the aortic arch atherosclerotic lesions. During a mean follow-up period of 3.4 years, we investigated the relationship between stroke recurrence and the various characteristics of the aortic arch atherosclerotic lesions. Results— An IMT ≥4.0 mm was found in 67 patients (25.3%). In 51 of these patients, the aortic lesions extended to the origin of the branches of the arch. Recurrences of cerebral ischemic events were found in 32 patients (recurrence group) and not in the other 251 (nonrecurrence group). Aortic atheroma ≥4.0 mm (41% versus 22%), aortic atheroma extending to the branches (63% versus 39%), and both (38% versus 16%) were more frequently seen in the recurrence group than in the nonrecurrence group (P < 0.05, P < 0.1, P < 0.01, respectively). After adjustment for age and the presence of hypertension, an aortic atheroma that was ≥4.0 mm as well as extending to the branches was found to be an independent predictor of ischemic stroke recurrence (hazard ratio=2.42, P < 0.05). Conclusions— Stroke recurrence is associated with the severity of the atheroma (IMT ≥4.0 mm) and plaque extension to the branches.

Guidelines for the intravenous application of recombinant tissue-type plasminogen activator (alteplase), the second edition, October 2012: a guideline from the Japan Stroke Society.

In Japan, intravenous alteplase, a recombinant tissue-type plasminogen activator (rt-PA), was approved for an indication of ischemic stroke in 2005 on the basis of the results of a clinical trial with a unique dose of the drug (0.6 mg/kg). The Japan Stroke Society published the guidelines for intravenous application of rt-PA and organized training sessions for proper use all over Japan in an effort to promote the safe, widespread use of intravenous alteplase. Seven years following its approval, clinical experience with intravenous alteplase has accumulated, additional evidence of intravenous alteplase has been found in Japan and overseas, and the medical environment has substantially changed, including approvals for new drugs and medical devices. Notably, the use of alteplase in the extended therapeutic time window (within 4.5 hours of symptom onset) became covered by insurance in Japan in August 2012. To address these changing situations, we have decided to prepare the revised guidelines. In preparing the second edition, we took care to make its contents more practical by emphasizing information needed in clinical practice. While the first edition was developed with emphasis on safety in light of limited clinical experience with intravenous alteplase in Japan in 2005, this second edition is a substantial revision of the first edition mainly in terms of eligibility criteria, on the basis of accumulated evidence and the clinical experience.

Antithrombotic Therapy Influences Location, Enlargement, and Mortality from Intracerebral Hemorrhage

Background: To determine whether the use of oral antithrombotic agents before the onset of intracerebral hemorrhage (ICH) affects hematoma features and early patient outcome. Methods: A retrospective, multicenter study involving 1,006 consecutive Japanese patients (607 men, 67 ± 12 years of age) hospitalized within 24 h after the onset of nontraumatic ICH was conducted. Results: One hundred and eighty patients were taking oral antiplatelet agents (17.9%, AP group), 67 were taking warfarin (6.7%, W group), and 21 were taking both (2.1%, W + AP group). After adjustment for age, sex, and known confounders, the taking of each kind of antithrombotic therapy was independently related to cerebellar hemorrhage; the odds ratios (OR) and 95% CI, with patients taking no antithrombotic agents as the reference group, were 2.31 (1.23–4.32) for the AP group, 2.90 (1.26–6.63) for the W group, and 3.43 (1.02–11.59) for the W + AP group. Similarly, the taking of each kind of antithrombotic therapy was independently related to hematoma enlargement within the initial 24 h (OR and 95% CI: AP group, 1.92, 1.10–3.34; W group, 4.80, 2.12–10.87; W + AP group, 4.94, 1.31–18.61) and mortality at 3 weeks post-ICH (OR and 95% CI: AP group, 2.70, 1.56–4.68; W group, 2.50, 1.05–5.96; W + AP group, 9.41, 2.78–31.88). Conclusions: Prior medication with antiplatelet agents, warfarin, or both was predictive of cerebellar hemorrhage, hematoma enlargement, and early death in Japanese ICH patients.

Effect of Prothrombin Complex Concentrate on Hematoma Enlargement and Clinical Outcome in Patients with Anticoagulant-Associated Intracerebral Hemorrhage

Background: The present study was carried out to determine the effect of prothrombin complex concentrate (PCC) on hematoma enlargement (HE) and the early clinical outcome of intracerebral hemorrhage (ICH) patients on long-term warfarin treatment. Methods: Themedical records and computed tomography (CT) images of 50 consecutive ICH patients on long-term warfarin treatment (35 men, 15 women; 69 ± 12 years old) were reviewed. International normalized ratio (INR) values, frequency of HE and clinical outcome were compared between patients treated with and without PCC. Results: INR values on admission were above 2.0 in 37 patients, of whom 19 were given PCC (PCC group) and 18 were not given PCC (control group). In these 37 patients, the frequency of HE (p = 0.017), the number of patients with a poor clinical outcome (modified Rankin Scale score ≧3 at 30 days or at discharge; p = 0.045) and in-hospital mortality (p = 0.042) were significantly higher in the control than in the PCC group. On multivariate logistic regression analysis with adjustment, PCC administration was independently associated (odds ratio 0.03, 95% confidence interval 0.00–0.63; p = 0.023) with a reduction in poor clinical outcome in ICH patients whose INR values were >2.0 on admission. Conclusions: Immediate INR reversal with PCC may prevent HE and subsequent poor outcome.

Atherosclerosis Found on Carotid Ultrasonography Is Associated With Atherosclerosis on Coronary Intravascular Ultrasonography

Little has been reported on the relationship between left main coronary artery atherosclerosis and carotid ultrasonographic results. We evaluated the association between carotid and coronary atherosclerosis assessed by coronary intravascular ultrasonography (IVUS) in 45 patients.

Transoral Carotid Ultrasonography

BACKGROUND AND PURPOSE We attempted ultrasonographic evaluation of the distal extracranial internal carotid artery (ICA) using the transoral method (transoral carotid ultrasonography [TOCU]). METHODS The subjects consisted of five healthy volunteers and seven stroke patients. Examinations were performed with a color Doppler flow imaging system equipped with convex array transducers (7 or 9.5 MHz), originally designed for transrectal use. After local anesthesia of the pharynx, we inserted a probe covered with thin gum transorally, touching the tip to the pharyngeal posterolateral wall. We then attempted to detect the ICA and measure flow velocity of the distal extracranial ICA using principal images obtained by TOCU. RESULTS TOCU was successfully performed in all subjects without any difficulty. In the healthy volunteers, the ICA was identified at a depth of 2.2+/-0.6 cm and visualized as a vertical linear vessel 2.9+/-0.3 cm in length and bent slightly backward. The diameter and mean flow velocity of the distal extracranial ICA were 4.7+/-0.2 mm and 50+/-7 cm/s, respectively. In the stroke patients, some remarkable findings were obtained, including a narrow ICA with low flow velocity in a patient with possible ICA dissection, a lucent echo without flow signal in a patient with acute cardioembolic ICA occlusion, and decreased ICA flow velocity in a patient with ipsilateral MCA stenosis. CONCLUSIONS These preliminary data demonstrate the potential applicability of TOCU to the evaluation of flow in the far distal extracranial ICA. TOCU definitely warrants further investigation in patients with carotid artery disease.