Botulinum toxin A is effective to treat tension-type headache caused by hemifacial spasm.

OBJECTIVE: We examined the relationship between hemifacial spasm (HFS; a form of cranio-cervical dystonia) and chronic primary headache, including tension-type headache (TTH). We also examined whether botulinum toxin A (BoNT/A) therapy for HFS ameliorates concomitant TTH. METHODS: Fifty-one HFS patients receiving BoNT/A therapy were recruited. Patients' characteristics (including age, gender, chronic headache history, exercise habits, stiff neck, cervical spondylolysis history), stress factors, worsening/new onset of headache associated with HFS, and dose of BoNT/A were examined. We diagnosed headache types according to The International Classification of Headache Disorders, 3rd edition, beta. Numerical Rating Scale (NRS) and Headache Impact Test-6 (HIT-6) scores for headache severity were compared between the 6-week baseline before BoNT/A therapy and 6-week follow-up after BoNT/A therapy. RESULTS: Of 51 patients with HFS, 17 (33.3%) reported worsening or new onset of headache (especially TTH) associated with HFS (Group-S), and 34 were not aware of headache (Group-N). Twelve patients (70.6%) in group-S reported improvement of headache after BoNT/A therapy. NRS (from 7 [5-9] to 0 [0-5], p<0.01) and HIT-6 (from 55 [54-64] to 44 [36-52], p<0.001) scores were significantly improved after BoNT/A therapy. Logistic regression analysis revealed significant interaction between TTH associated with HFS and the presence of stress factors (odds ratio 43.11: 2.95-629.39, p<0.001) and history of chronic headache (odds ratio 28.53: 2.96-275.10, p<0.001). CONCLUSIONS: Primary headache, especially TTH, is associated with HFS. BoNT/A therapy for HFS may also be indirectly effective for treatment of TTH.

Characteristics of Cerebral White Matter Lesions on MRI in Juvenile Patients with Migraine.

OBJECTIVE: Cerebral white matter lesions (WMLs) have been frequently observed on MRI in patients with migraine. We investigated characteristics of WMLs in migraine and tried to determine the relationship between its causal mechanism and arteriosclerosis. METHODS: A head MRI was performed in juvenile migraine patients. The distributions of deep and periventricular WMLs were separately studied in the anterior and posterior circulation. Grading was conducted according to the Fazekas classification. Arteriosclerotic risk factors were identified, and their effects on WMLs were investigated. RESULTS: WMLs were observed in 85 (40.5%) of 210 patients in our hospital. This is significantly higher than the 10 (19.2%) of 63 patients in the control group (p < 0.01). WMLs were significantly observed on the anterior territory of the deep white matter (p < 0.01) and the posterior territory of the periventricular white matter (p < 0.05). Multivariable analysis revealed that the occurrence of WMLs was not related to arteriosclerotic risk factors, while migraine (p < 0.01) and aging (p < 0.05) were significant risk factors. CONCLUSION: While migraine was a risk factor of WMLs, its relationship with arteriosclerotic factors was weak. Accordingly, a mechanism other than arteriosclerosis may be involved.

Bromocriptine Mesylate Attenuates Amyotrophic Lateral Sclerosis: A Phase 2a, Randomized, Double-Blind, Placebo-Controlled Research in Japanese Patients.

OBJECTIVE: Bromocriptine mesylate (BRC), a dopamine D2 receptor agonist has been shown to confer neuroprotection, sustained motor function and slowed disease progression in mouse models of amyotrophic lateral sclerosis (ALS) Here we report a first in human trial in ALS. DESIGN: A multicenter, Riluzole add-on, randomized, double-blind, placebo controlled 102-week extension BRC clinical trial. METHODS: The trial was conducted between January 2009 and March 2012 on 36 Japanese ALS patients. A 12-week treatment with Riluzole observational period was followed by combined treatment (Riluzole + BRC; n = 29 or Riluzole + placebo; n = 7). The dosing commenced at 1.25 mg/day increasing in steps at two weeks intervals to a maximum of 15 mg/day. The efficacy of BRC was evaluated by comparing BRC and placebo groups upon completion of stepwise dosing at 14 weeks 2 points (1st endpoint) and upon completion or discontinuation of the study (2nd endpoint) of the dosing. RESULTS: Statistics analyses revealed a marginal BRC treatment efficacy with P≦20%to placebo by 1st and 2nd endpoint analysis. In the 1st endpoint analysis, BRC group was significantly effective on the scores of ALSAQ40-communicaton (P = 1.2%), eating and drinking (P = 2.2%), ALSFRS-R total (P = 17.6%), grip strength (P = 19.8%) compared to the placebo group. In the 2nd endpoint analysis, differences between the scores of Limb Norris Scale (P = 18.3%), ALSAQ40-communication (P = 11.9%), eating and drinking (P = 13.6%), and neck forward-bent test (P = 15.4%) of BRC group were detected between the two groups. There was no significant difference between the treatment groups for adverse events or serious drug reactions incidence. CONCLUSIONS: BRC sustains motoneuronal function at least in part through BRC treatment. Further analysis involving a Phase 2b or 3 clinical trial is required but BRC currently shows promise for ALS treatment. TRIAL REGISTRATION: UMIN Clinical Trials UMIN000008527.

Examination of fluctuations in atmospheric pressure related to migraine.

BACKGROUND: Japan has four seasons and many chances of low atmospheric pressure or approaches of typhoon, therefore it has been empirically known that the fluctuation of weather induces migraine in people. Generally, its mechanism has been interpreted as follows: physical loading, attributed by atmospheric pressure to human bodies, compresses or dilates human blood vessels, which leads to abnormality in blood flow and induces migraine. We report our examination of the stage in which migraine tends to be induced focusing on the variation of atmospheric pressure. FINDINGS: Subjects were 34 patients with migraine, who were treated in our hospital. The patients included 31 females and three males, whose mean age was 32 ± 6.7. 22 patients had migraine with aura and 12 patients had migraine without aura. All of patients with migraine maintained a headache diary to record atmospheric pressures when they developed a migraine. The standard atmospheric pressure was defined as 1013 hPa, and with this value as the criterion, we investigated slight fluctuations in the atmospheric pressure when they developed a migraine. It was found that the atmospheric pressure when the patients developed a migraine was within 1003-1007 hPa in the approach of low atmospheric pressure and that the patients developed a migraine when the atmospheric pressure decreased by 6-10 hPa, slightly less than the standard atmospheric pressure. CONCLUSION: Small decreases of 6-10 hPa relative to the standard atmospheric pressure of 1013 hPa induced migraine attacks most frequently in patients with migraine.

Theoretical analysis of headache recurrence in patients administered triptans for migraine based on receptor occupancy.

BACKGROUND: In this study, we retrospectively analyzed the relationship between headache recurrence and serotonin 5-HT1B/1D receptor occupancy (Φ1B and Φ1D). Triptans marketed in Japan (sumatriptan, zolmitriptan, eletriptan, rizatriptan, naratriptan) were investigated. METHODS: Receptor occupancies were calculated from both the pharmacokinetic and pharmacodynamic data of triptans. We examined the relationships between recurrence rate and elimination half-lives, and Ф1B and Ф1D, as calculated from the time-course of plasma drug concentration obtained from other studies. The time until Ф1B and Ф1D became 50% or less, 40% or less, and 30% or less was calculated as duration time to examine the relationship with recurrence rate. RESULTS: For Ф1B, eletriptan remained at a low level. For Ф1D, it was indicated that all triptans obtained an occupancy of 80% or higher at maximum. For all items, though recurrence tended to be lower along with longer half-life, no significant statistical correlation was found. For both Ф1B and Ф1D, the recurrence rate tended to be lower as the duration became longer. In addition, a significant correlation was observed for Ф1D (p < 0.05). For clarifying the Ф value and time period most closely correlated with recurrence rate, recurrence and Ф1B and Ф1D at 6, 12, and 18 h after administration were calculated. The most significant correlation was observed between recurrence rate and Ф1D at 12 h after administration (p < 0.01). CONCLUSIONS: As an index for evaluating headache recurrence following triptan administration, recurrence rate and Ф1D value at 12 h after administration were found to be most closely correlated and useful for analysis. Our results indicate that headache recurrence inhibition can be evaluated using these values.

Theory-based analysis of clinical efficacy of triptans using receptor occupancy.

BACKGROUND: Triptans, serotonin 5-HT1B/1D receptor agonists, exert their action by targeting serotonin 5-HT1B/1D receptors, are used for treatment of migraine attack. Presently, 5 different triptans, namely sumatriptan, zolmitriptan, eletriptan, rizatriptan, and naratriptan, are marketed in Japan. In the present study, we retrospectively analyzed the relationships of clinical efficacy (headache relief) in Japanese and 5-HT1B/1D receptor occupancy (Φ1B and Φ1D). Receptor occupancies were calculated from both the pharmacokinetic and pharmacodynamic data of triptans. METHODS: To evaluate the total amount of exposure to drug, we calculated the area under the plasma concentration-time curve (AUCcp) and the areas under the time curves for Ф1B and Ф1D (AUCФ1B and AUCФ1D). Moreover, parameters expressing drug transfer and binding rates (Acp, AФ1B, AФ1D) were calculated. RESULTS: Our calculations showed that Фmax1B and Фmax1D were relatively high at 32.0-89.4% and 68.4-96.2%, respectively, suggesting that it is likely that a high occupancy is necessary to attain the clinical effect. In addition, the relationships between therapeutic effect and AUCcp, AUCΦ1B, AUCΦ1D, and Acp · AUCcp differed with each drug and administered form, whereas a significant relationship was found between the therapeutic effect and AΦ1B · AUCΦ1B or AΦ1D · AUCΦ1D that was not affected by the drug and the form of administration. CONCLUSIONS: These results suggest that receptor occupancy can be used as a parameter for a common index to evaluate the therapeutic effect. We considered that the present findings provide useful information to support the proper use of triptans.

Relationship between atherosclerotic risk factors and aortic plaques in patients with first-ever ischaemic stroke.

OBJECTIVE: Aortic plaque is considered a risk factor of ischaemic stroke, and both ulceration and plaque thickness are considered important. However, the relative importance of aortic plaque and carotid plaque remains unclear. The purpose of this study is to clarify the relation between aortic and carotid plaque lesions and atherosclerotic risk factors in patients with acute ischaemic stroke. METHODS: We enrolled 76 patients with first-ever ischaemic stroke, undergoing transoesophageal echocardiography, whose aetiology of ischaemic stroke was unknown. We divided the patients into two groups according to aortic plaque thickness, based on previous reports, i.e., a high-risk group (over 4mm) and a low-risk group (less than 4mm). We also examined several atherosclerotic risk factors. RESULTS: Mean age, gender and hypertension was not significantly different between the low-risk and high-risk group. HDL-cholesterol (P<0.01), LDL/HDL ratio (P<0.05), non-HDL-cholesterol (P<0.05), HbA1c (P<0.05) and eGFR (P<0.01) were significantly different between the two groups. Max plaque thickness in the carotid artery was correlated with aortic plaque lesions. CONCLUSION: Multiple atherosclerotic risk factors are associated with greater aortic plaque lesions. Aortic plaque is important not only as an embolic source, but also as one of the atherosclerotic markers.

Benefit of cilostazol in patients with high risk of bleeding: subanalysis of cilostazol stroke prevention study 2.

BACKGROUND: The Cilostazol Stroke Prevention Study 2 (CSPS 2) showed that cilostazol significantly reduced the risk of stroke by 25.7% relative to aspirin, with significantly fewer hemorrhagic events, in patients with prior ischemic stroke, excluding cardioembolic stroke. However, whether the benefit of cilostazol is sustained in patients with a high risk of bleeding has not been examined. METHODS: We conducted a subanalysis of CSPS 2 to examine whether known risk factors for hemorrhagic stroke, such as stroke subtype and systolic blood pressure (SBP), influence the efficacy of the study drugs on hemorrhagic stroke. The relative risk reduction of hemorrhagic stroke was determined from the incidences calculated by the person-year method. The cumulative incidence rates of ischemic stroke and hemorrhagic stroke were estimated and plotted using the Kaplan-Meier method. Incidences of serious hemorrhage and hemorrhage requiring hospital admission were also evaluated in the two treatment groups. Hazard ratios (HR) and 95% confidence intervals (95% CI) calculated by the Cox proportion hazard model for cilostazol versus aspirin were assessed, and a log-rank test was used for the comparison between treatments. RESULTS: The incidence of hemorrhagic stroke was significantly lower in the cilostazol group than in the aspirin group among patients with prior lacunar stroke (0.36 vs. 1.20% in person-year, HR 0.35, 95% CI 0.18-0.70, p < 0.01), but not among those with prior atherothrombotic stroke (0.31 vs. 0.59% in person-year, HR 0.53, 95% CI 0.14-2.0, p = 0.34). The incidence of hemorrhagic stroke was significantly lower in the cilostazol group than in the aspirin group throughout all SBP categories (Poisson regression model including time-dependent covariates, p < 0.01) including SBP above 140 mm Hg (cilostazol 0.45% vs. aspirin 1.44% in person-year; Poisson regression model including time-dependent covariates, p = 0.02). Cilostazol, compared with aspirin, significantly reduced the incidence of cerebral hemorrhage (HR 0.36, 95% CI 0.19-0.70, p < 0.01), overall hemorrhage requiring hospital admission (HR 0.53, 95% CI 0.29-0.97, p = 0.04), and gastrointestinal (GI) bleeding requiring hospital admission (HR 0.44, 95% CI 0.21-0.90, p = 0.03). CONCLUSIONS: Hemorrhagic stroke was less frequent in the cilostazol group than in the aspirin group among patients with lacunar stroke as well as those with increased blood pressure levels. As for extracranial hemorrhage requiring hospitalization, GI bleeding was also less frequent in the cilostazol than in the aspirin group. Cilostazol is supposed to be a therapeutic option to replace aspirin for secondary stroke prevention, especially in these subgroups with high risks for hemorrhagic events.

[Evaluation of drug information service available for physicians regarding low-dose aspirin-induced gastrointestinal lesions].

Low-dose aspirin-induced gastrointestinal lesions are becoming an important problem in clinical practice. In our investigation of such adverse effects, we obtained 4 important findings considered useful for physicians, as follows; 1) even when aspirin was given at a dose, the incidence rate of gastrointestinal lesions was higher than with other non-steroidal anti-inflammatory drugs (NSAIDs), 2) the odds ratios for gastrointestinal lesions induced by aspirin with a histamine H2 receptor antagonist and proton pump inhibitor were 0.6 and 0.4, respectively, as compared with aspirin alone, 3) it is difficult to administer aspirin, which exerts an antiplatelet effect, without inducing gastrointestinal lesions, and 4) these gastrointestinal lesions appears early, especially within 2 years after administration. We distributed a questionnaire to 41 physicians to confirm our findings, and compared high (n=20) and low (n=21) frequency aspirin prescription groups. The recognition rate of points 1 and 3 noted above in the high group was significantly elevated as compared to the low group, whereas there no significant difference in regard to the information in point 4 between the groups and the rate of recognition was low. Moreover, only 27% of the surveyed physicians were familiar with all 4 points. Prior to receiving this information, 17% of the physicians gave no related instructions their patients, which was reduced to 0% after receiving this information. Furthermore, 98% of those surveyed found the information to be useful. Our results suggest that these 4 points of information regarding potential adverse gastrointestinal effects of low-dose aspirin are useful for physicians.

The relationship between low-density lipoprotein cholesterol levels and the incidence of cardiovascular disease in high-risk patients treated with pravastatin: main results of the APPROACH-J study.

This study aimed to evaluate the relationship between low-density lipoprotein cholesterol (LDL-C) levels and cardiovascular disease (CVD) in high-risk patients with hypercholesterolemia without a history of CVD. Patients who were receiving or started treatment with pravastatin, were followed-up for 2 years. Patients were divided into quartiles according to on-treatment LDL-C. The maximum contrast method based on the Cox proportional hazards model was used to evaluate the relationship between achieved LDL-C and the incidence of CVD. Incidence of CVD was also compared according to whether a number of risk factor targets were achieved. A total 6,229 patients were enrolled, with 4,916 having reported LDL-C values. During the 2 years, 69 cases of CVD (6.7/1000 patient years), including 36 coronary artery disease (CAD) (3.5/1000 patient years) and 28 strokes (2.7/1000 patient years), occurred. The comparison of on-treatment LDL-C level quartiles suggested that the incidence of all CVD decreased linearly as the LDL-C levels decreased. Incidence of CAD showed a curvilinear relationship to LDL-C levels, suggesting some attenuation of risk below LDL-C of 119 mg/dL. The incidence of all CVD and CAD tended to be decreased as the number of achieved risk factor targets increased. In conclusion, through our observational study, it was shown that a linear relationship between the incidence of CVD and LDL-C was observed in high-risk hypercholesterolemic patients. The low incidence of CVD in the present study may be associated with multifactorial management of conventional risk factors including high LDL-C levels. However, prospective, randomized studies are needed to confirm these findings.

The evaluation method for antiplatelet effect of acetylsalicylic acid.

Reduced platelet aggregation by acetylsalicylic acid administration has been associated with adverse outcomes in patients with thrombotic diseases, thus it is important to determine aspirin resistance in those cases. The antiplatelet effect of acetylsalicylic acid is rarely measured, but it has many problems. The aim of this study was to find the evaluation method for antiplatelet effect after administration of acetylsalicylic acid. We developed a particle counting method based upon laser light scattering, and utilized the platelet aggregation agonists, collagen, at 0.25, 0.5 and 1.0 µg/mL, and adenosine diphosphate (ADP), at 0.5, 1.0 and 2.0 µM, to determine their effective concentrations. Seventeen healthy volunteers were administered acetylsalicylic acid at 162 mg/day, with platelet aggregation determined before and 20 min after administration. In all subjects, the rate of platelet aggregation induced by 1.0 µg/mL of collagen before taking acetylsalicylic acid was the highest value obtained, while 20 min after acetylsalicylic acid administration, aggregation induced by collagen at 1.0 µg/mL was significantly decreased as compared to before administration. As for the other concentrations of collagen and all those of ADP tested, platelet aggregation was either not significantly induced before taking acetylsalicylic acid or the rate of aggregation was not significantly decreased after taking acetylsalicylic acid. Our results indicate that collagen at 1.0 µg/mL is appropriate as a platelet aggregation agonist for evaluating the antiplatelet effect of acetylsalicylic acid. Thus, it is useful that the measurement is performed only once.

[Migraine and stroke].

We reviewed the literature concerning the relationship between migraine and ischemic stroke, and compared our data with reported findings. The incidence of migrainous stroke, strictly defined according to the International Classification of Headache 3 beta version, is quite low. A European MRI study indicated that the relative risk of ischemic stroke is increased two-fold in migraine patients with aura, and white matter lesions are located predominantly in the posterior circulation region. The risk of ischemic stroke in patients with migraine aura under 45 years old was reduced to the control level in the group that avoided oral contraceptives and quit smoking. Migraine is a relatively low risk factor for ischemic stroke, in contrast to classic risk factors for stroke, such as hypertension, diabetes mellitus, and atrial fibrillation. Our data concerning the location of white matter lesions showed predominance in the anterior circulation region, in marked contrast to the European study. The reason for this difference remains unknown. It is possible that the white matter lesions in some migraine patients could be caused by reversible vasoconstriction syndrome.

[Diagnosis and potential treatment of antiphospholipid syndrome-related mainly on ischemic stroke].

Antiphospholipid syndrome (APS) was defined in 2006 by an international consensus as an autoimmune disease that manifests clinically as recurrent thrombotic complications or fetal loss and serologically as elevated plasma levels of antiphospholipid antibodies (aPLs). aPLs are a heterogeneous group of antibodies directed against anionic phospholipids, phospholipid-binding plasma proteins, and phospholipid-protein complexes. Standard ELISA for anticardiolipin (aCL) and anti-ß2-glycoprotein I antibodies and clotting assays for lupus anticoagulant (LA) are recommended for detecting aPLs. Phosphatidylserine-dependent anti-prothrombin antibody (aPS/PT) assay may also be useful as a confirmatory test for APS. aPLs are an independent risk factor for initial occurence of ischemic stroke, especially in young adults. APS patients with thrombotic stroke frequently have other, often conventional, vascular risk factors. Guidelines issued in 2011 by the American Heart Association and American Stroke Association recommended antiplatelet therapy for patients with cryptogenic ischemic stroke or TIA and who test positive for aPL. In contrast, oral anticoagulants with a target international normalized ratio (INR) of 2.0-3.0 are recommended for patients with ischemic stroke who meet all the criteria for APS. Recently, 3 new anticoagulants for stroke prevention, dabigatran, rivaroxaban, and apixaban, have been studied in phase 3 clinical trials in patients with atrial fibrillation. However, optimal treatment for catastrophic APS is unknown. Current treatment guidelines emphasize the importance of early diagnosis and recommend aggressive therapies to avoid a fatal outcome. Combinations of high doses of intravenous heparin, steroids, and immunoglobulins and/or repeated plasma exchanges can be considered as treatments of choice for this severe condition.

Preventive effect of cyproheptadine hydrochloride in refractory patients with frequent migraine.

Cyproheptadine hydrochloride (CH) is rarely used to treat adult patients with migraine in Japan because it causes sleepiness. In this study, we investigated the preventive effect of CH in 12 patients who had failed to respond to conventional preventive treatments among 103 migraine patients treated at our hospital. These 12 subjects had all received unsuccessful migraine prophylaxis with lomerizine, valproic acid and topiramate, or had discontinued these treatments due to adverse reactions. Initially, the subjects were given 4 mg CH before sleeping. In those who experienced no clinically significant sleepiness following the treatment, the drug was orally administered at 4 mg after breakfast as well (8 mg per day in total). Drug efficacy was evaluated by examining the frequency of migraine at one month and three months after the start of treatment. The frequency of migraine was dramatically reduced in all patients within 7 to 10 days after starting treatment. The average frequency of migraine during the three-month period was 2.6 episodes per month, representing a significant (p < 0.01) reduction from the pretreatment frequency of over 10 per month. Our results indicate that CH may be effective as a migraine-preventive treatment for patients in whom conventional drugs have been ineffective or have caused side effects. But this study is not a double blind randomized trial, and an open study with no control group.

Prediction of antiplatelet effects of aspirin in vivo based on in vitro results.

The aim of this study was to establish a method to predict the antiplatelet effects of aspirin in vivo based on in vitro results. Aspirin in 5 different concentrations was added to the platelet-rich plasma samples, and the rates of platelet aggregation induced by collagen were determined in vitro. In addition, platelet aggregation and plasma drug concentration values were determined in vivo before and after the administration of aspirin (162 mg). The 50% effective concentration (EC50) values obtained from the in vivo and in vitro experiments were shown to have relevance, because the EC50 ratio for each subject was the same (0.23 ± 0.03). The actual and predicted values for the rate of inhibition of platelet aggregation were well correlated (P < .0001, r = .95) when the predicted rate was determined using the present method. Our results suggest that the antiplatelet effects of aspirin can be predicted using blood samples obtained before its administration.

Theoretical investigation of aspirin dosage regimen to exhibit optimal antiplatelet effects and decrease risk of upper gastrointestinal lesions.

We investigated dosage regimens for aspirin therapy in regard to antiplatelet effects in patients without gastrointestinal lesions. Findings for inhibition of biosynthesis of thromboxane B(2) (TXB(2)) and prostaglandin E(2) (PGE(2)) were simulated based on pharmacokinetic and pharmacodynamic models using an irreversible process of inhibition of cyclooxygenase-1 (COX-1) by aspirin. We found that the inhibition of biosynthesis of TXB(2) at a steady state was greater than 90% when the dose of aspirin administered exceeded 81 mg, which was considered to exhibit a sufficient antiplatelet effect. Furthermore, it was confirmed that a dose of 162 mg or more is needed to exert an immediate antiplatelet effect on the initial day of administration. On the other hand, the inhibition of biosynthesis of PGE(2) ranged from 40-90% when aspirin was administered at a dose of 10.125-324 mg. Thus, the risk of gastrointestinal lesions differed in a dosage-dependent manner. The biosynthesis inhibition of PGE(2) was calculated to be 37.9%, with that value set as the target level for prevention of gastrointestinal disorders. We also noted a difference between platelets and gastric mucosa cells in regard to the turnover rate of COX-1, and attempted to simulate the inhibition of biosynthesis of TXB(2) and PGE(2) following administration of aspirin. However, it was not possible, as the inhibition of biosynthesis of TXB(2) was greater than 90% and that of PGE(2) was less than 37.9%, even with various dosage regimens. Our findings suggest that it is difficult to determine a rational dosage regimen of aspirin to exert an antiplatelet effect without inducing gastrointestinal lesions.

Adherence to preferable behavior for lipid control by high-risk dyslipidemic Japanese patients under pravastatin treatment: the APPROACH-J study.

AIM: We evaluated the impact of adherence to preferable behavior on serum lipid control assessed by a self-reported questionnaire in high-risk patients taking pravastatin for primary prevention of coronary artery disease. METHODS: High-risk patients taking pravastatin were followed for 2 years. Questionnaire surveys comprising 21 questions, including 18 questions concerning awareness of health, and current status of diet, exercise, and drug therapy, were conducted at baseline and after 1 year. Potential domains were established by factor analysis from the results of questionnaires, and adherence scores were calculated in each domain. The relationship between adherence scores and lipid values during the 1-year treatment period was analyzed by each domain using multiple regression analysis. RESULTS: A total of 5,792 patients taking pravastatin were included in the analysis. Multiple regression analysis showed a significant correlation in terms of "Intake of high fat/cholesterol/sugar foods" (regression coefficient -0.58, p=0.0105) and "Adherence to instructions for drug therapy" (regression coefficient -6.61, p<0.0001). Low-density lipoprotein cholesterol (LDL-C) values were significantly lower in patients who had an increase in the adherence score in the "Awareness of health" domain compared with those with a decreased score. There was a significant correlation between high-density lipoprotein (HDL-C) values and "Awareness of health" (regression coefficient 0.26; p= 0.0037), "Preferable dietary behaviors" (regression coefficient 0.75; p<0.0001), and "Exercise" (regression coefficient 0.73; p= 0.0002). Similar relations were seen with triglycerides. CONCLUSION: In patients who have a high awareness of their health, a positive attitude toward lipid-lowering treatment including diet, exercise, and high adherence to drug therapy, is related with favorable overall lipid control even in patients under treatment with pravastatin.