Circulation Journal ORIGINAL ARTICLE Official Journal of the Japanese Circulation Society http://www.j-circ.or.jp Ischemic Heart Disease Beta-Blocker Prescription Among Japanese Cardiologists and Its Effect on Various Outcomes Takahide Kohro, MD; Dobun Hayashi, MD**; Tsutomu Yamazaki, MD*; Ryozo Nagai MD**; The JCAD Investigators

Background: Beta-blockers are underprescribed for coronary artery disease (CAD) patients in Japan. Consid- ering the vast amount of evidence showing their benefits in this group of patients, the aim of the present study was to investigate the use of β-blockers in a large cohort of CAD patients.

Methods and Results: The 13,812 patients with angiographically confirmed CAD were followed up for 2.7 years. From this group, 4,160 (30.1%) patients were prescribed β-blockers at the time of discharge. These patients were significantly more likely to have hypertension, hyperlipidemia, obesity, a family history of ischemic diseases and a higher number of diseased arteries. The rate of continuation for β-blockers was 90.8%. A propen- sity score matching analysis showed no additional benefits of β-blockers in reducing all-cause mortality, cardiac events and cerebrovascular events. Lipophilic β-blockers were significantly more effective than hydrophilic ones in reducing all-cause mortality (hazard ratio 0.467, 95% confidence interval 0.247–0.880, P=0.019).

Conclusions: Despite the low prescription rate of β-blockers for CAD patients among Japanese physicians, the continuation rate was relatively high. Lipophilic β-blockers may be a better choice than hydrophilic β-blockers in terms of mortality risk, although a randomized control study would need to be conducted to verify this assertion. (Circ J 2010; 74: 962 – 969)

Key Words: Beta-blocker; Coronary artery disease; Observational cohort; Propensity score matching analysis

eta-blockers are underprescribed by Japanese physi- patients with confirmed coronary artery disease (CAD), de- cians, possibly because of their deleterious effects fined as ≥75% stenosis in at least 1 branch of the coronary B on metabolic profiles,1,2 and patients with bronchial arteries in accordance with the American Heart Association insufficiency,3 or physicians’ high awareness of bradycardia (AHA) classification. We concluded thatβ -blockers were and hypotension induced by the drugs. It has been reported less likely to be prescribed in Japan than in the West,10 but that even for patients with myocardial ischemia, calcium considering the enormous evidence of the beneficial effects antagonists are preferred over β-blockers for the treatment of β-blockers in patients with cardiovascular diseases, we felt of angina,4 maybe from fear of coronary spasm, the rate of that a more thorough investigation of β-blocker usage was which is reported to be higher in the Japanese population necessary. It has also been reported that different β-blockers than in Westerners.5 Although β-blockers were being used produce different outcomes in certain situations,11 so in the off-label for congestive heart failure (CHF) in clinical present study we looked at how various classes ofβ -blockers settings, it was only in 2002 that was officially are used and what effects they had on outcomes. approved for the treatment of CHF in Japan. Today, carve- dilol remains the only β-blocker approved for the treatment of CHF in Japan. On the other hand, there is ample evidence Methods that β-blockers are beneficial in reducing cardiovascular Patients risks in many conditions.6–9 The protocol and major outcomes of this study have been published previously.12,13 Briefly, patients who underwent Editorial p 848 coronary angiography (CAG) at each participating institute and who were diagnosed as having ≥75% stenosis according We conducted a large observational study (the JCAD study) to the AHA classification in at least 1 branch of the coronary to investigate the background and treatment of Japanese arteries were registered. All CAGs were performed with

Received August 18, 2009; accepted January 12, 2010; released online March 17, 2010 Time for primary review: 19 days Department of Translational Research for Healthcare and Clinical Science, *Department of Clinical Epidemiology & Systems, Graduate School of Medicine and **Department of Cardiovascular Medicine, The University of Tokyo, Tokyo, Japan Mailing address: Tsutomu Yamazaki, MD, Department of Clinical Epidemiology & Systems, Graduate School of Medicine, The Uni- versity of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan ISSN-1346-9843 doi: 10.1253/circj.CJ-09-0613 All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: [email protected]

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Table 1. Background Characteristics of Patients With or Without β-Blockers Without β-blockers With β-blockers P value (n=9,652) (n=4,160) Age 65.53±9.90 65.32±9.63 0.110 Male 7,466 (77.4%) 3,160 (76.0%) 0.075 Hypertension 5,345 (55.4%) 2,606 (62.6%) <0.001 Hyperlipidemia 5,122 (53.1%) 2,425 (58.3%) <0.001 IFG 3,857 (40.0%) 1,713 (41.2%) 0.181 Obesity 3,035 (31.4%) 1,407 (33.8%) 0.006 Smoking 3,834 (39.7%) 1,603 (38.5%) 0.190 Drinking 3,625 (37.6%) 1,589 (38.2%) 0.476 Family history 1,533 (15.9%) 748 (18.0%) 0.002 CHF 1,005 (10.4%) 393 (9.4%) 0.128 LMT disease 415 (4.3%) 207 (5.0%) 0.079 No. of affected arteries 1.73±0.79 1.89±0.81 <0.001 Statins 3,207 (33.2%) 1,864 (44.8%) <0.001 Fibrates 285 (3.0%) 163 (3.9%) 0.003 CCBs 4,913 (50.9%) 2,015 (48.4%) 0.008 ACEIs 2,823 (29.2%) 1,543 (37.1%) <0.001 ARBs 1,176 (12.2%) 692 (16.6%) <0.001 α-blockers 187 (1.9%) 131 (3.1%) <0.001 ATs 8,088 (83.8%) 3,960 (95.2%) <0.001 Nitrates 5,805 (60.1%) 2,514 (60.4%) 0.750 P values of age and number of affected arteries were calculated by Kruskal-Wallis test. All other P values were calcu- lated by chi-square test. IFG, impaired fasting glycemia; CHF, congestive heart failure; LMT, left main trunk; CCB, calcium-channel blocker; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin-receptor blocker; AT, antithrombotic.

Figure 1. The continuation rate of each class of drug was calculated as the rate of patients who took the medication from the time of discharge through to final follow-up date. ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin-receptor blocker; CCB, calcium-channel blocker; AT, antithrombotic.

written informed consent. Of the 15,628 patients who were cardial infarction (2,955 patients), history of myocardial initially registered in the study, 13,812 were followed up and infarction (OMI: 3,913 patients), and unstable angina pectoris included in the present analysis. Among these, 10,626 of (UAP: 2,049). Patients were followed up for an average of the patients were male and 3,186 were female. Diagnoses at 2.7 years. the time of registration included the following: acute myo-

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Table 2. Classification ofβ -Blockers According to Solubility or Receptor Selectivity Solubility classification Receptor selectivity classification Lipophilic β-blockers (n=3,257) No. and dosage (mg)* β1 selective (n=2,493) Amosulalol hydrochloride 2 20.0±14.1 hydrochloride hydrochloride 53 14.9±6.2 hydrochloride 128 7.5±4.1 Betaxolol hydrochloride hydrochloride 12 79.2±25.7 fumarate Bisoprolol fumarate 574 4.1±2.5 hydrochloride malonate 5 0.9±0.2 tartrate Carvedilol 1,421 10.3±5.5 Metoprolol tartrate 913 49.0±28.6 αβ-blockers (n=1,491) 47 6.2±2.2 Amosulalol hydrochloride hydrochloride 1 40 Arotinolol hydrochloride 5 11.0±5.5 Bevantolol hydrochloride hydrochloride 96 32.6±20.5 Carvedilol hydrochloride Hydrophilic β-blockers (n=903) Non-selective β-blockers (n=176) Acebutolol hydrochloride 9 144.4±52.7 Bopindolol malonate Atenolol 774 34.4±17.0 hydrochloride Bufetolol hydrochloride 1 10 hydrochloride Bunitrolol hydrochloride 1 20 hydrochloride Carteolol hydrochloride 19 12.5±3.7 Celiprolol hydrochloride 95 243.3±403.2 Nipradilol Labetalol hydrochloride 3 133.3±28.9 Oxprenolol hydrochloride Nadolol 1 30 Pindolol Propranolol hydrochloride Total 4,160 (30.1% of all patients included in the analysis) *Dosage is represented as mean ± 1SD.

Figure 2. The continuation rate of each class of β-blocker was calculated as the rate of patients who took the medication from the time of discharge through to final follow-up date.

Data Registration and Gathering smoking in the 2 years prior to registration; hyperlipidemia, All follow-up data were gathered electronically over the in- serum total cholesterol ≥220 mg/dl and/or low-density-lipopro- ternet. At the time of registration, a diagnosis of CAD had tein cholesterol ≥140 mg/dl and/or triglycerides ≥150 mg/dl; been given by the attending physician. The brand names and impaired fasting glycemia (IFG), defined as fasting blood dosages of all the drugs that the patients were taking were glucose ≥110 mg/dl (diabetes mellitus was included in this registered by the attending physicians. The definition of each study); hypertension, systolic blood pressure ≥140 mmHg risk factor was as follows: smoking, at least 1 incidence of and/or diastolic blood pressure ≥90 mmHg; obesity, body

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Table 3. Background Characteristics of Matched Patients With or Without β-Blockers Without β-blockers With β-blockers P value (n=3,892) (n=3,892) Age 65.34±9.84 65.34±9.65 0.553 Male 2,965 (76.2%) 2,954 (75.9%) 0.770 Hypertension 2,448 (62.9%) 2,417 (62.1%) 0.468 Hyperlipidemia 2,221 (57.1%) 2,265 (58.2%) 0.313 IFG 1,591 (40.9%) 1,617 (41.5%) 0.549 Obesity 1,306 (33.6%) 1,321 (33.9%) 0.719 Smoking 1,459 (37.5%) 1,488 (38.2%) 0.498 Drinking 1,522 (39.1%) 1,491 (38.3%) 0.471 Family history 671 (17.2%) 683 (17.5%) 0.720 CHF 393 (10.1%) 391 (10.0%) 0.940 LMT disease 200 (5.1%) 191 (4.9%) 0.640 No. of affected arteries 1.88±0.81 1.88±0.81 0.946 Statins 1,703 (43.8%) 1,734 (44.6%) 0.479 Fibrates 159 (4.1%) 151 (3.9%) 0.643 CCBs 1,933 (49.7%) 1,900 (48.8%) 0.454 ACEIs 1,448 (37.2%) 1,444 (37.1%) 0.925 ARBs 657 (16.9%) 641 (16.5%) 0.627 α-blockers 122 (3.1%) 116 (3.0%) 0.693 ATs 3,697 (95.0%) 3,697 (95.0%) 1.000 Nitrates 2,409 (61.9%) 2,390 (61.4%) 0.658 P values of age and number of affected arteries were calculated by Kruskal-Wallis test. All other P values were calcu- lated by chi-square test. Abbreviations see in Table 1. mass index ≥25; familial history, first-degree relative with history of CAD, CHF, left main trunk disease, and number of CAD; and drinking, having a habit of alcohol consumption. affected arteries) and drug classes (statins, fibrates, calcium- These data were obtained from each patient by the attending channel blockers (CCBs), angiotensin-converting enzyme physicians. Careful attention was paid to data security. inhibitors (ACEIs), angiotensin-receptor blocker (ARBs),α - 1 blockers, antithrombotics (ATs), and nitrates) was used to Investigations generate a propensity score for each individual in the dataset. The endpoints in this report are the composite of all-cause Propensity score matching was performed using a 5-digit, deaths and cardiocerebrovascular events, the latter comprising greedy 1:1 matching algorithm.14 Kaplan-Meier curves were cardiac events, cerebral events and vascular events, and some depicted with hazard ratios (HR) calculated by univariate of the components of the composite endpoint (ie, all-cause Cox regression analysis to examine incidence over time. deaths, cardiac events and cerebral events). Cardiac events Data for patients who were lost to follow-up were censored were defined as fatal and non-fatal myocardial infarction (MI), at the time of last contact. Medication at the time of dis- UAP, CHF, coronary bypass graft surgery, resuscitated cardiac charge was used for survival analysis, which was performed arrest or cardiopulmonary arrest on arrival. Cerebral events on the assumption that the medication did not change through were defined as cerebral hemorrhage, cerebral infarction or the follow-up period (intention-to-treat principle). Statistical transient ischemic attack. Aortic dissection and rupture of analysis was performed with SAS version 9.1 (SAS Institute aortic aneurysm were classified as vascular events. All events Inc, Cary, NC, USA). were assessed and registered by the attending physicians.

Ethical Considerations Results The protocol used in this study was approved by the Central Patients’ Backgrounds Institutional Review Board of the University of Tokyo. Written As shown in Table 1, those patients who were given β- informed consent was given by all patients. blockers had significantly higher rates of hypertension, hyper- lipidemia, obesity, family history of ischemic diseases and Statistical Analyses had a higher number of diseased arteries. With regard to con- For each class of drugs, the continuation rate was defined as comitantly prescribed drugs, those patients who were given the rate of patients who took the medication from the time of β -blockers were also significantly more likely to be prescribed discharge through to follow-up date. Because the data for statins, fibrates,α -1 blockers, ACEIs, ARBs, and ATs, and each patient, including prescriptions, were registered by the were significantly less likely to be prescribed CCBs. attending physicians every 6 months, we assumed that a drug was discontinued if a patient continued to be followed up, Continuation Rate of Each Class of Drug but the drug that the patient had been prescribed was not Figure 1 shows the continuation rate of several classes of registered. The logistic model, which included both patient drugs that were prescribed for the patients in this cohort. background characteristics (age, sex, hypertension, hyper- Fibrates continued to be administered to 70.5% of the pa- lipidemia, IFG, obesity, smoking, drinking of alcohol, family tients who were prescribed the medicine at the time of

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Figure 3. Patients who were taking β-blockers were matched with those who were not taking β-blockers based on propensity scores calculated by logistic regression. Kaplan-Meier analysis was performed on the 2 groups with various endpoints. HR, hazard ratio; CI, confidence interval.

discharge, while ARBs, CCBs, β-blockers, statins, and ATs β -blockers at discharge were matched with those who were continued to be administered to over 90% of the patients not given β-blockers at discharge. As shown in Table 3, who were prescribed the drugs at the time of discharge. all background characteristics and medication were well matched. Figure 3 shows the Kaplan-Meier plot for endpoint Continuation Rate of β-Blockers When Classified According accumulation and HRs. There were no significant differences to Lipophilicity/Receptor Binding Specificity between those who were given β-blockers and those were Beta-blockers can be classified according to their solubility not given β-blockers for any of the endpoints. or ability to specifically bind toβ -1 receptors. Table 2 shows the classification, number of patients taking the drug, and Differences in Effect of β-Blockers on Endpoints According mean dosage of all the β-blockers that physicians prescribed to Lipophilicity in this study. Figure 2 shows the continuation rate for β- We sought to investigate if there were any differences in blockers of each class. The continuation rate of hydrophilic effectiveness between lipophilic and hydrophilic β-blockers β -blockers (84.4%) was significantly lower than that of lipo- on the endpoints. We performed propensity score matching philic β-blockers (89.3%, P<0.001). The continuation rate between those who were given lipophilic β-blockers and of non-selective β-blockers (79.1%) was significantly lower those who were given hydrophilic β-blockers. As shown in than that of β-1-selective β-blockers (87.2%, P=0.003) or α- Table 4, all background characteristics and medication were β -selective β-blockers (87.7%, P=0.002). well matched. Figure 4 shows the Kaplan-Meier plot for endpoint accumulation and HRs. For the composite end- Effect of β-Blockers on Endpoints points, cardiac endpoints and cerebral endpoints, there were In order to investigate the effect ofβ -blockers, we performed no significant differences between lipophilic and hydrophilic a propensity score matching analysis. Those who were given β -blockers for outcome. For all-cause mortality, lipophilic

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Table 4. Background Characteristics of Matched Patients With Hydrophilic or Lipophilic β-Blockers Hydrophilic β-blockers Lipophilic β-blockers P value (n=856) (n=856) Age 65.27±9.09 65.24±9.98 0.825 Male 650 (75.9%) 666 (77.8%) 0.359 Hypertension 571 (66.7%) 563 (65.8%) 0.683 Hyperlipidemia 514 (60.0%) 519 (60.6%) 0.805 IFG 356 (41.6%) 343 (40.1%) 0.523 Obesity 304 (35.5%) 313 (36.6%) 0.651 Smoking 333 (38.9%) 324 (37.9%) 0.655 Drinking 345 (40.3%) 356 (41.6%) 0.589 Family history 169 (19.7%) 162 (18.9%) 0.668 CHF 32 (3.7%) 30 (3.5%) 0.796 LMT disease 53 (6.2%) 43 (5.0%) 0.293 No. of affected arteries 1.87±0.82 1.87±0.81 0.948 Statins 413 (48.2%) 400 (46.7%) 0.529 Fibrates 32 (3.7%) 32 (3.7%) 1.000 CCBs 470 (54.9%) 450 (52.6%) 0.332 ACEIs 239 (27.9%) 217 (25.4%) 0.229 ARBs 135 (15.8%) 143 (16.7%) 0.600 α-blockers 25 (2.9%) 21 (2.5%) 0.550 ATs 808 (94.4%) 810 (94.6%) 0.832 Nitrates 529 (61.8%) 537 (62.7%) 0.690 P values of age and number of affected arteries were calculated by Kruskal-Wallis test. All other P values were calcu- lated by chi-square test. Abbreviations see in Table 1.

β -blockers showed a significantly better outcome compared cian abided by the prescription and β-blockade therapy was to hydrophilic β-blockers (HR 0.467, 95% confidence interval well tolerated. We could not show any beneficial effect of 0.247–0.880, P=0.019). β -blockers on such endpoints as cardiac events, all-cause mortality, cerebral events, or the composite of such events (Figure 3), even when we matched the background and Discussion medication pattern of those who were given β-blockers and In this study of a large cohort of Japanese patients with those who were not (Table 3). Before matching, patients angiographically determined CAD, we showed that despite who were prescribed β-blockers had a significantly higher the low prescription rate ofβ -blockers among Japanese phy- rate of hypertension, hyperlipidemia, obesity, family history sicians, the continuation rate was relatively high and that of CAD and a higher number of diseased arteries (Table 1). lipophilic β-blockers may be a better choice than hydrophilic It is possible that other factors that were not measured in ones if mortality risks are considered. this study were unbalanced between the groups and affected As mentioned earlier, Japanese physicians have been re- the results so that beneficial effects were not observed for luctant to adopt β-blockers as a treatment for hypertension. β -blockers. This problem in evaluating the efficacy of drugs Although the guidelines for the management of hypertension in observational studies is known as “confounding by indica- published by the Japanese Society of Hypertension in 2009 tion”.19 include β-blockers as a first-line therapy for hypertension,15 Beta-blockers can be classified according to such properties among Japanese physicians it is generally perceived that as lipophilicity, β-receptor-blockade specificity and intrinsic compared to CCBs, ACEIs and ARBs, β-blockers are more sympathomimetic activity, which, aside from the class effect difficult to use because of their unfavorable effects on glu- of β-blockers, reportedly cause differences in various out- cose metabolism1,2 and pulmonary diseases.16 Cardiologists comes,20 with several clinical studies supporting this claim.7,8,21 are also highly aware of the bradycardia and hypotension In the present study, lipophilic β-blockers reduced the risk induced byβ -blockers. Previous reports have shown that even of all-cause mortality significantly more than hydrophilicβ - for patients with CAD, the prescription rate of β-blockers is blockers, which is in contrast to a recent observational study significantly lower in Japan (≈30%4,17) than in the West that showed that the survival rate among 3 β-blockers, 2 of (≈85%18). which were lipophilic and 1 of which was hydrophilic, did That trend was also observed in this study, in which only not differ after acute MI when adjusted for several factors.22 30.1% of CAD patients were prescribed β-blockers. Despite However, the results of several randomized, controlled clini- the fact that in this study we combined α-β-blockers and cal trials using a hydrophilic β-blocker have failed to show pure β-blockers under the same classification ofβ -blockers, any benefit in reducing cardiovascular or all-cause mortality unlike in our previous report,10 the overall prescription rate against placebo in hypertensive patients.21,23 Although the was still lower than that reported in Western studies. findings in our study cannot be directly extrapolated to daily However, this study showed that the adherence rate of practice, careful consideration may be needed when select- β -blockers was over 90%, suggesting that for those patients ing a medication. in whom β-blockers were indicated, the attending physi- Although β-blockers have recently been called into ques-

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Figure 4. Patients who were taking lipophilic β-blockers were matched with those who were taking hydrophilic β-blockers based on propensity scores calculated by logistic regression. Kaplan-Meier analysis was performed on the 2 groups with vari- ous endpoints. HR, hazard ratio; CI, confidence interval.

tion as a first-line therapy for hypertension,24,25 certain types Adherence to guidelines that are based on rigid scientific have been shown to be effective in reducing cardiovascular evidence is necessary for the improvement of care, and obser- risks for patients with comorbidities, such as CHF7,8,26 or vational studies similar to the JCAD study are warranted in OMI.9,27,28 We could not show that β-blockers as a class the future to monitor and improve cardiovascular care. confer beneficial effects in reducing cardiovascular, cerebro- vascular or all-cause mortality endpoints nor the composite Study Limitations of such endpoints in this study, which may be attributed to This study was an observational study and not a randomized “confounding by indication”. Within the β-blocker drug controlled study. Although survival analysis was performed class, it appears that lipophilic β-blockers may be superior with propensity score matching, it is possible that factors to hydrophilic β-blockers in reducing all-cause mortality, that were not measured in this study were skewed between although a randomized controlled study is needed to confirm groups and affected the results. One major factor could be that result. chronic kidney disease. No data regarding renal function was In conclusion, this study showed that despite the low pre- obtained in this study because, unlike the way it is viewed scription rate ofβ -blockers for CAD patients among Japanese today, it was not regarded as a strong component of cardio- physicians, the continuation rate was relatively high, which vascular risk at the time the study was planned. It should also suggests that they are well tolerated. We could not show a be noted that while analysis was performed on the assump- clear benefit ofβ -blockers for various outcomes, which might tion that patients were continually taking the medicines, it is be attributed to “confounding by indication”. Better outcomes possible that the prescription at the time of discharge was with lipophilic β-blockers compared with hydrophilic β- changed later in the follow-up period, which is suggested in blockers were observed for all-cause mortality, although the results of the continuation rate of drugs we have shown. further investigation is needed to confirm this finding.

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Acknowledgments disease in Japan: The Japanese Coronary Artery Disease Study (The JCAD Study). Circ J 2006; 70: 1256 – 1262. This work was supported by a grant from the Japan Heart Foundation. 14. Parsons LS. Reducing bias in a propensity score matched-pair sam- We thank Mr Hiroki Sato (National Defense Medical College) for his ple using greedy matching techniques. In: The Twenty-Sixth Annual cooperation during this study. SAS Users Group International Conference. Cary, NC: SAS Insti- tute, 2004; 214 – 226. 15. The Japanese Society of Hypertension. Guidelines for the Manage- References ment of Hypertension (JSH 2009). Hypertens Res 2009; 32: 3 – 1. Gress TW, Nieto FJ, Shahar E, Wofford MR, Brancati FL. Hyper- 107. tension and antihypertensive therapy as risk factors for type 2 dia- 16. Kendall MJ, Beeley L. Beta-adrenoceptor blocking drugs: Adverse betes mellitus: Atherosclerosis Risk in Communities Study. N Engl reactions and drug interactions. Pharmacol Ther 1983; 21: 351 – J Med 2000; 342: 905 – 912. 369. 2. Mancia G, Grassi G, Zanchetti A. New-onset diabetes and anti- 17. Sakamoto T, Kojima S, Ogawa H, Shimomura H, Kimura K, Ogata hypertensive drugs. J Hypertens 2006; 24: 3 – 10. Y, et al. Effects of early statin treatment on symptomatic heart 3. Chafin CC, Soberman JE, Demirkan K, Self T. Beta-blockers after failure and ischemic events after acute myocardial infarction in myocardial infarction: Do benefits ever outweigh risks in asthma? Japanese. Am J Cardiol 2006; 97: 1165 – 1171. Cardiology 1999; 92: 99 – 105. 18. Boden WE, O’Rourke RA, Teo KK, Hartigan PM, Maron DJ, 4. Tanihata S, Nishigaki K, Kawasaki M, Takemura G, Minatoguchi Kostuk WJ, et al. Optimal medical therapy with or without PCI for S, Fujiwara H. Outcomes of patients with stable low-risk coronary stable coronary disease. N Engl J Med 2007; 356: 1503 – 1516. artery disease receiving medical- and PCI-preceding therapies in 19. Grobbee DE, Hoes AW. Confounding and indication for treatment Japan: J-SAP study 1-1. Circ J 2006; 70: 365 – 369. in evaluation of drug treatment for hypertension. BMJ 1997; 315: 5. Pristipino C, Beltrame JF, Finocchiaro ML, Hattori R, Fujita M, 1151 – 1154. Mongiardo R, et al. Major racial differences in coronary constrictor 20. Hjalmarson A. Cardioprotection with beta-adrenoceptor blockers: response between Japanese and Caucasians with recent myocardial Does lipophilicity matter? Basic Res Cardiol 2000; 95(Suppl 1): infarction. Circulation 2000; 101: 1102 – 1108. I-41 – I-45. 6. von Arnim T. Medical treatment to reduce total ischemic burden: 21. The Dutch TIA Trial Study Group. Trial of secondary prevention Total ischemic burden bisoprolol study (TIBBS), a multicenter trial with atenolol after transient ischemic attack or nondisabling isch- comparing bisoprolol and nifedipine: The TIBBS Investigators. emic stroke. Stroke 1993; 24: 543 – 548. J Am Coll Cardiol 1995; 25: 231 – 238. 22. Gottlieb SS, McCarter RJ. Comparative effects of three beta block- 7. CIBIS-II Investigators and Committees. The Cardiac Insufficiency ers (atenolol, metoprolol, and propranolol) on survival after acute Bisoprolol Study II (CIBIS-II): A randomised trial. Lancet 1999; myocardial infarction. Am J Cardiol 2001; 87: 823 – 826. 353: 9 – 13. 23. Eriksson S, Olofsson B, Wester P. Atenolol in secondary preven- 8. MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic tion after stroke. Cerebrovasc Dis 1995; 5: 21 – 25. heart failure: Metoprolol CR/XL Randomised Intervention Trial in 24. Lindholm LH, Carlberg B, Samuelsson O. Should beta blockers Congestive Heart Failure (MERIT-HF). Lancet 1999; 353: 2001 – remain first choice in the treatment of primary hypertension? A 2007. meta-analysis. Lancet 2005; 366: 1545 – 1553. 9. Dargie HJ. Effect of carvedilol on outcome after myocardial infarc- 25. Bradley HA, Wiysonge CS, Volmink JA, Mayosi BM, Opie LH. tion in patients with left-ventricular dysfunction: The CAPRICORN How strong is the evidence for use of beta-blockers as first-line randomised trial. Lancet 2001; 357: 1385 – 1390. therapy for hypertension? Systematic review and meta-analysis. 10. Kohro T, Hayashi D, Okada Y, Yamazaki T, Nagai R. Effects of J Hypertens 2006; 24: 2131 – 2141. medication on cardiovascular events in the Japanese coronary artery 26. Yamaji M, Tsutamoto T, Tanaka T, Kawahara C, Nishiyama K, disease (JCAD) study. Circ J 2007; 71: 1835 – 1840. Yamamoto T, et al. Effect of carvedilol on plasma adiponectin 11. Kataoka M, Satoh T, Yoshikawa T, Nakamura I, Kohno T, concentration in patients with chronic heart failure. Circ J 2009; Yoshizawa A, et al. Comparison of the effects of carvedilol and 73: 1067 – 1073. metoprolol on exercise ventilatory efficiency in patients with con- 27. Viscoli CM, Horwitz RI, Singer BH. Beta-blockers after myocar- gestive heart failure. Circ J 2008; 72: 358 – 363. dial infarction: Influence of first-year clinical course on long-term 12. Hayashi D, Yamazaki T. Design and rationale of the Japanese Coro- effectiveness. Ann Intern Med 1993; 118: 99 – 105. nary Artery Disease (JCAD) Study: A large-scale, multicentered pro- 28. Freemantle N, Cleland J, Young P, Mason J, Harrison J. Beta spective cohort study. Jpn Heart J 2004; 45: 895 – 911. blockade after myocardial infarction: Systematic review and meta 13. The Japanese Coronary Artery Disease (JCAD) Study Investigators. regression analysis. BMJ 1999; 318: 1730 – 1737. Current status of the background of patients with coronary artery

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