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Rationale and design of a study to evaluate effects of pitavastatin on Japanese patients with chronic heart failure
International Journal of Cardiology 156 (2012) 144–147
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International Journal of Cardiology j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / i j c a r d
Rationale and design of a study to evaluate effects of pitavastatin on Japanese patients with chronic heart failure The pitavastatin heart failure study (PEARL study) Hiroshi Mizuma a, Teruo Inoue b, Hiroyuki Takano a, Satoshi Shindo a, Toru Oka a, Daisuke Fujimatsu c, Yoichi Kuwabara a, Koichi Node c, Issei Komuro a,⁎ and On behalf of the PEARL Study Investigators a b c
Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, Chiba, Japan Department of Cardiovascular Medicine, Dokkyo Medical University, Mibu, Japan Department of Cardiovascular and Renal Medicine, Saga University Faculty of Medicine, Saga, Japan
a r t i c l e
i n f o
Article history: Received 7 January 2010 Received in revised form 2 October 2010 Accepted 23 October 2010 Available online 13 November 2010 Keywords: Chronic heart failure Statin Hypercholesterolemia Randomized controlled trial
a b s t r a c t Background: HMG-CoA reductase inhibitors (statins) are known to have pleiotropic effects in addition to their lipid-lowering effect. Many studies have suggested cardioprotective effects of statins, however, recent largescale clinical trials using rosuvastatin, a hydrophilic statin, have failed to show beneficial effects on cardiovascular events in patients with severe heart failure. We have designed the study to evaluate the effects of pitavastatin, a lipophilic statin, on Japanese patients with mild to moderate heart failure. Methods and results: Five hundred seventy-seven patients with chronic heart failure were enrolled. We used a prospective, randomized, open-label, and blinded-endpoint evaluation (PROBE) design. Patients aged 20–79 years old with symptomatic (NYHA functional class II or III) heart failure and a left ventricular ejection fraction of ≤ 45% were randomly allocated to either receive pitavastatin (2 mg/day) or not in addition to conventional therapy for heart failure by using the minimization method. Follow-up will be continued until March 2011. The primary endpoint is a composite of cardiac death and hospitalization for worsening heart failure. Conclusions: The PEARL study will provide important data on the role of pitavastatin in the treatment of Japanese patients with mildly symptomatic heart failure (UMIN-ID: UMINC000000428). © 2010 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Heart failure is a complex clinical syndrome that results from structural and functional disorders of the heart associated with a variety of cardiovascular diseases. The number of patients with heart failure has been increasing and heart failure is becoming a major public health problem. Over the past 20 years, there has been considerable progress in the treatment of chronic heart failure (CHF) with appearance of angiotensin-converting enzyme (ACE) inhibitors, angiotensin-II receptor blockers (ARB), β blockers and aldosterone antagonists. However, the number of deaths due to CHF has been increasing steadily and further strategies for CHF are needed. 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, commonly called statins, are the most widely used agents for the treatment of hypercholesterolemia. Clinical trials have shown ⁎ Corresponding author at: Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine. 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. Tel.: +81 43 226 2097; fax: +81 43 226 2557. E-mail address: [email protected] (I. Komuro). 0167-5273/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2010.10.022
that treatment with statins significantly reduces the incidence of cardiovascular events in patients with coronary artery diseases [1–4]. In addition to their lipid-lowering actions, statins have also been reported to have various pleiotropic effects, including antiinflammatory effects, antioxidant effects, angiogenic effects, protective effects of endothelial cells, and inhibitory effects on neurohormonal activation [5]. It has been demonstrated that statins inhibit the progression of heart failure in animal models with non-ischemic heart failure [6–8]. These effects of statins suggest its potential to ameliorate components of the complex pathophysiology of CHF and to contribute to a promising treatment for CHF in the future. Many observational studies and retrospective analyses have suggested that treatment with statins decreases the incidence of heart failure in patients with coronary artery disease and reduces mortality of patients with CHF [9–12]. Prospective small trials have also confirmed the beneficial effects of statins on heart failure [13–17]. On the other hand, recent two prospective randomized large clinical trials have shown that statin treatment has no effect on the clinical outcomes of patients with CHF [18,19]. However, it remains unclear whether treatment with statins on CHF patients would show the same
H. Mizuma et al. / International Journal of Cardiology 156 (2012) 144–147
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Table 1 Inclusion criteria. 1. Age 20–79 years at the time of randomization 2. NYHA functional class II or III 3. Left ventricular ejection fraction as measured by echocardiography of ≤45% 4. Stable NYHA class for 2 or more weeks before the randomization 5. Mild hypercholesterolemia (serum total cholesterol ≤250 mg/dl and/or serum LDL-cholesterol ≤170 mg/dl) NYHA, New York Heart Association; LDL, low-density lipoprotein.
results with different study designs in relation to the type of statin used, characteristics of the patients, severity of heart failure, and the endpoints examined. Pitavastatin is a lipophilic statin and has longeracting effects on low-density lipoprotein (LDL)-cholesterol reduction and high-density lipoprotein cholesterol increase. Pitavastatin also has a high bioavailability and is minimally metabolized by the cytochrome P450 system [20–22]. The Pitavastatin Heart Failure (PEARL) study was designed to evaluate the beneficial effects of pitavastatin on the incidence of cardiac death and hospitalization for worsening heart failure in Japanese patients with CHF. Fig. 1. Study design.
2. Methods 2.1. Study population We enrolled 577 symptomatic CHF patients with mild hypercholesterolemia between June 2006 and June 2008. The inclusion criteria are: between 20 and 79 years of age; New York Heart Association (NYHA) functional class II or III; left ventricular ejection fraction (LVEF) as measured by echocardiography of ≤ 45%; stable NYHA class for 2 or more weeks prior to the randomization; mild hypercholesterolemia (serum total cholesterol concentration of ≤ 250 mg/dl and/or serum LDL-cholesterol concentration of ≤170 mg/dl); and availability of written informed consent of the patient (Table 1). The exclusion criteria are: receiving treatment with a statin prior to the randomization; history of acute myocardial infarction within 3 months prior to the randomization, percutaneous coronary intervention (PCI), or coronary artery bypass grafting, or cardiac resynchronization therapy-pacemaker or -defibrillator implantation performed within 3 months prior to the randomization; malignancy; serious renal or hepatic dysfunction; collagen disease; pregnancy or possible pregnancy; and lack of informed consent (Table 2). 2.2. Study design The PEARL study is a multicenter, prospective, randomized, open-label, blindedendpoint (PROBE) trial being carried out in Japan. The eligible patients are allocated randomly to either the pitavastatin group (2 mg/day) or the control group (no statin). As the usual daily dosage of pitavastatin is 1–2 mg in Japan, we used 2 mg of pitavastatin in the present study. Patient allocation was performed by the minimization method on the basis of the following baseline variables: age, gender, serum total cholesterol concentration, LVEF, history of ischemic heart disease, and history of hospitalization for CHF. According to the protocol, all the patients will be followed up for an average of 3 years until March 2011. If any patients in the control group need further reduction of the serum total cholesterol concentration, lipid-lowering agents except statins can be administered (Fig. 1). 2.3. Endpoints The primary endpoint is a composite of cardiac death and hospitalization due to worsening CHF. The secondary endpoints are all-cause death, cardiac death, hospitalization due to worsening CHF, myocardial infarction, unstable angina, stroke,
Table 2 Exclusion criteria. 1. Administration of statins before randomization. 2. Unstable decompensated heart failure at randomization. 3. Acute myocardial infarction within 3 months prior to the randomization. 4. Percutaneous coronary intervention, coronary artery bypass grafting, or cardiac resynchronization therapy-pacemaker or -defibrillator implantation performed within 3 months prior to the randomization. 5. Malignancy. 6. Serious renal or hepatic dysfunction. 7. Collagen disease. 8. Pregnancy or possible pregnancy. 9. Lack of informed consent. 10. Judged by the investigator to be ineligible for inclusion in the study.
PCI, and surgical therapy for worsening CHF. Tertiary endpoints include evaluations for cardiac function by echocardiography, NYHA class, incidence of new-onset atrial fibrillation, serum high-sensitivity C-reactive protein, B-type natriuretic peptide (BNP), norepinephrine, tumor necrosis factor-α, interleukin-6, and tenascin C, and urinary 8-isoprostane. We also evaluate left ventricular systolic function, volume and myocardial perfusion by 99mTc-sestamibi quantitative gated single-photon emission computed tomography (SPECT) and measure surrogate markers for CHF by blood tests. 2.4. Sample size calculation We assumed that the hazard ratio of cardiac events (cardiac death and hospitalization for worsening heart failure) of the pitavastatin group to the control group was 0.57 based on the previous reports [11,23]. On condition that the patients are evenly allocated and followed up for 24–48 months (median 36 months) after the enrollment, at least 200 patients are required for each arm to provide 80% power to detect a hazard ratio of 0.57 using a 2-sided significance level of 0.05 by the log-rank test. After considering maximum 15% for the loss of follow-up or unsuitable for analysis, we have expected that more than 470 patients are needed to be enrolled in this study. 2.5. Statistical analysis Continuous variables such as laboratory data are expressed by mean ± standard deviation (SD) at each period. Group comparisons between the pitavastatin group and the control group will be calculated by Student t-test, Analysis of Variance (ANOVA), Chi-square test, Fisher's exact test, or the Mann–Whitney U-test, as appropriate. Comparisons within groups will be assessed by paired t-test or the Kruskal–Wallis test. Cumulative event rate for primary and secondary events will be determined by lifetable method, and the difference between the groups will be tested by log-rank test or Cox proportional hazards regression model. Univariate predictive variables will be backward eliminated in multivariable models with the likelihood ratio criterion, and hazard ratios with 95% confidence intervals will be reported. All primary analyses will be done by intention-to-treat. Statistical analysis will be performed with SPSS 17.0 and Sample Power (SPSS Inc, Chicago, Il). 2.6. Study management Data on the primary and secondary endpoints and adverse events will be collected at various time-points and interim analyses will be performed every year after the initiation of the study to evaluate the events and the treatment safety. An independent endpoint committee (Appendix 1) consisting of three members, who are blinded to any information relating to the group allocations, evaluates each event and classifies the results. An independent data and safety monitoring board (Appendix 2) is composed of three members and reviews all reports from the endpoint committee to advise early termination of the study for safety, scientific or ethical reasons. A steering committee (Appendix 3) is responsible for the study design and scientific execution of the study. 2.7. Baseline characteristics Finally, 577 patients were randomly assigned to two groups. Of the total, 289 were assigned to the pitavastatin group and 288 to the control group. The baseline characteristics of the patients enrolled are presented in Table 3. The mean age was 62.7 years and 18.5% of the patients were female. The mean blood pressure was 119.4/
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H. Mizuma et al. / International Journal of Cardiology 156 (2012) 144–147
Table 3 Baseline characteristics (n = 577). Mean age, years Females (%) Mean systolic blood pressure (mmHg) Mean diastolic blood pressure (mmHg) NYHA functional class II (%) III (%) Mean LVEF (%) Mean total cholesterol (mg/dl) Mean LDL-cholesterol (mg/dl) Median (interquartile range) BNP (pg/ml) Medical history Ischemic heart disease (%) Medication ACE inhibitors/ARBs (%) Diuretics (%) β blockers (%) Digitalis glycoside (%) Calcium channel blockers (%)
62.7 ± 11.9 18.5 119.4 ± 17.9 71.9 ± 11.2 89.6 10.4 35.0 ± 8.5 202.3 ± 32.4 125.6 ± 30.5 126.0 (52.2–288.5) 28.6 83.8 74.8 72.5 24.9 16.0
NYHA, New York Heart Association; LVEF, left ventricular ejection fraction; LDL, low-density lipoprotein; BNP, B-type natriuretic peptide; ACE inhibitors/ARBs, angiotensin-converting enzyme inhibitors or angiotensin-II receptor blockers. 71.9 mmHg and 89.6% of the patients were classified to NYHA functional class II. The mean LVEF was 35.0% and 28.6% of the patients had a history of ischemic heart disease. The mean serum levels of total cholesterol and LDL-cholesterol were 202.3 mg/dl and 125.6 mg/dl, respectively. The median serum BNP in the patients was 126.0 pg/ml.
3. Discussion The PEARL study has been carefully designed to address critical unanswered questions. Does pitavastatin have the beneficial effects on the incidence of cardiac death and hospitalization for worsening heart failure in Japanese patients with CHF? It is well known that treatment with statins significantly reduces the incidence of cardiovascular events in patients at high risk, especially those with coronary artery diseases, irrespective of the baseline cholesterol levels [24]. Several retrospective analyses and large observational studies have suggested that treatment with statins decreases the incidence of CHF and reduces mortality in patients with CHF [9–12]. Furthermore, prospective trials assessing the effects of statins on surrogate endpoints such as biomarkers and echocardiographic parameters demonstrated the beneficial effects of statins on patients with CHF [13–17]. Meta-analyses of statin treatment in randomized clinical trials also confirmed a reduction of cardiovascular mortality in patients with CHF of both ischemic and nonischemic etiologies [5]. These results support the pleiotropic effects of statins demonstrated by basic research and the beneficial effects of statins on patients with CHF. Recently, the results of two prospective randomized trials have been published [18,19]. The CORONA (Controlled rosuvastatin multinational study in heart failure) study randomized 5,011 patients with symptomatic CHF of ischemic etiology to 10 mg rosuvastatin or placebo [18]. The primary endpoint was a composite of death from cardiovascular causes, nonfatal myocardial infarction, and nonfatal stroke. A daily dose of 10 mg rosuvasatin did not reduce the primary composite cardiovascular outcome, death from cardiovascular causes, nonfatal myocardial infarction, nor nonfatal stroke. The GISSI (Gruppo Italiano per lo Studio della Sopravvivenza nell'Insufficienza cardiaca)–HF(Heart Failure) trial randomized 4631 patients with symptomatic CHF of both ischemic and nonischemic etiologies to 10 mg rosuvastatin or placebo [19]. The primary endpoints were time to death, and time to death or admission to hospital for cardiovascular reasons. The treatment with rosuvastatin did not affect the primary endpoints in the 2 studies [18,19]. However, the CORONA study showed that there were fewer hospitalization for cardiovascular causes which was one of the secondary endpoints in the rosuvastatin
group. It remains unknown at present whether the results of the CORONA study and the GISSI-HF trial can be applied in the different patient selection or in the different kind of statin. Concerns have been raised about the possible deleterious effects of statins. Circulating lipoproteins have the ability to bind and detoxify bacterial lipopolysaccharide. Because lipopolysaccharide stimulates the release of inflammatory cytokines, statins may increase inflammation in patients with CHF [25]. Moreover, statins decrease the synthesis of not only cholesterol but also of other downstream products in the mevalonate pathway. Coenzyme Q10 (ubiquinone), which is an essential cofactor in the mitochondrial electron transport chain, is one of the downstream products. Because coenzyme Q10 plays an important role in the mitochondrial respiratory chain and has an antioxidant function [26,27], statins may reduce adenosine triphosphate production and aggravate heart failure. In the PEARL study, we use pitavastatin to evaluate the beneficial effects of statin therapy on Japanese patients with CHF. Pitavastatin is a statin which was developed in Japan and has potent lipid-lowering effect [20–22]. Pitavastatin is a lipophilic agent, while rosuvastatin is a hydrophilic agent. Pitavastatin is distributed selectively to the liver and is excreted in bile without metabolic modification [28]. The renal excretion rate is less than 2% and the terminal elimination half-life of 11 h [29]. It has been reported that the degree of reduction in plasma coenzyme Q10 by lovastatin, pravastatin, simvastatin, and atorvastatin corresponds closely to the degree of reduction of the serum or plasma LDL-cholesterol level [30]. A recent study showed that atorvastatin significantly reduced the plasma level of coenzyme Q10 but pitavastatin did not affect it in Japanese patients with heterozygous familial hypercholesterolemia, although both statins reduced the serum LDL-cholesterol levels by the same degree [31]. Statins potently reduce the serum LDL-cholesterol level by inhibiting the synthesis of mevalonate and inducing the expression of LDL receptors mainly in the hepatocytes. Pitavastatin has been reported to most strongly increase the LDL receptor mRNA expression among all statins [32]. These data indicate that there is minimal likelihood of deleterious effects resulting from inhibition of the mevalonate pathway in case of pitavastatin. As pitavastatin is hardly metabolized through the cytochrome P450-mediated pathway, pitavastatin is expected to have little interaction with other agents metabolized through the P450 pathway [33]. This property may be potentially beneficial for patients with CHF who take several kinds of medicines for the treatment of heart failure. There are some differences in the characteristics of patients and protocol among the PEARL study, the CORONA study, and the GISSI-HF trial. The ratio of patients with ischemic heart failure was 40% in the GISSI-HF trial, and 100% in the CORONA study, while only 28.6% of patients have ischemic heart failure in the PEARL study. The mean age of the patients was 73, 68, and 63 years in the CORONA, the GISSI-HF, and the PEARL, respectively. The enrolled patients appear to be less symptomatic in the PEARL study (NYHA II 89.6%, III 10.4%, IV 0%) than in the CORONA study (NYHA II 37.0%, III 61.5%, IV 1.5%) and the GISSI-HF trial (NYHA II 62.5%, III 35.0%, IV 2.5%). The differences in severity of CHF patients may affect the results of those trials. Furthermore, all the patients enrolled in the PEARL study are Japanese. There are differences in the responses to therapeutic drugs between Asian and Western populations [34]. Asian patients frequently exhibit high responses to therapeutic drugs [34]. This phenomenon is also recognized in cardiovascular drugs including statins. Pharmacokinetic investigations have demonstrated higher plasma levels of statins in Asians as compared with Caucasians [35]. The high responses of Asians to statins are thought to be related to genetic differences in the metabolism of statins [35]. The kind of statins used in the PEARL study, the CORONA study, and the GISSI-HF trial are also different. Pitavastatin used in the PEARL study has many characteristics different from rosuvastatin used in the other two studies, such as lipophilicity and bioavailability.
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The PEARL study is the first study to evaluate the effects and safety of pitavastatin in Japanese patients with moderate CHF. This study is expected to clarify whether pitavastatin might have beneficial effects on the patients receiving current standard therapy for CHF. Acknowledgment This study is supported by a research grant from the Japan Heart Foundation. The authors gratefully acknowledge the assistance of Ms. Naomi Harada, Mr. Hiroshi Komoda, Ms. Chiharu Kawaguchi, and Ms. Sae Katafuchi. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [36]. Appendix 1. Independent Endpoint Committee Yuji Kira (Showa General Hospital); Hiroyuki Morita (The University of Tokyo); Yuji Hashimoto (Kameda General Hospital). Appendix 2. Independent Data and Safety Monitoring Board Akira Yamashina (Tokyo Medical University); Tsutomu Yamazaki (The University of Tokyo); Naoki Ishizuka (International Medical Center of Japan). Appendix 3. Steering Committee Issei Komuro, Yoichi Kuwabara, and Hiroyuki Takano (Chiba University); Koichi Node (Saga University); Teruo Inoue (Dokkyo Medical University); Hiroshi Ito (Akita University); Toshiharu Himi (Kimitsu Chuou Hospital); Takanobu Tomaru (Toho University Sakura Medical Center); Junji Kanda (Asahi Chuo Hospital); Satoshi Kobayashi (Chibaken Saiseikai Narashino Hospital); Mitsuyuki Shimizu (Jikei University School of Medicine, Kashiwa Hospital); Akira Miyazaki, Toshihisa Inoue, and Akira Aouda (Chiba Cardiovascular Center); Fumitaka Nakamura (Teikyo University Chiba Medical Center); Tatsuji Kanoh (Juntendo University); Youichi Katoh (Juntendo University Urayasu Hospital); Yoshihiko Seino (Nippon Medical School Chiba Hokusoh Hospital); Michiaki Hiroe (International Medical Center of Japan); Junichi Yamazaki (Toho University Omori Medical Center); Kyoichi Mizuno (Nippon Medical School); Toyoaki Murohara (Nagoya University); Masashi Kitakaze (National Cardiovascular Center); Kenji Kawajiri (Matsubara Tokushukai Hospital); Yoshihiko Saito (Nara Medical University); Kengo Kusano (Okayama University); Masakazu Kohno (Kagawa University); Keijiro Saku (Fukuoka University); Katsusuke Yano (Nagasaki International University); Koji Oku (Nagasaki Medical Center); Hisao Ogawa (Kumamoto University); Tetsunori Saika (Oita University). References [1] LaRosa JC, He J, Vupputuri S. Effect of statins on risk of coronary disease: a metaanalysis of randomized controlled trials. JAMA 1999;282:2340–6. [2] Pignone M, Phillips C, Mulrow C. Use of lipid lowering drugs for primary prevention of coronary heart disease: meta-analysis of randomised trials. BMJ 2000;321:983–6. [3] Wilt TJ, Bloomfield HE, MacDonald R, et al. Effectiveness of statin therapy in adults with coronary heart disease. Arch Intern Med 2004;164:1427–36. [4] Baigent C, Keech A, Kearney PM, et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90, 056 participants in 14 randomised trials of statins. Lancet 2005;366:1267–78. [5] Ramasubbu K, Estep J, White DL, Deswal A, Mann DL. Experimental and clinical basis for the use of statins in patients with ischemic and nonischemic cardiomyopathy. J Am Coll Cardiol 2008;51:415–26.
147
[6] Ichihara S, Noda A, Nagata K, et al. Pravastatin increases survival and suppresses an increase in myocardial matrix metalloproteinase activity in a rat model of heart failure. Cardiovasc Res 2006;69:726–35. [7] Zacà V, Rastogi S, Imai M, et al. Chronic monotherapy with rosuvastatin prevents progressive left ventricular dysfunction and remodeling in dogs with heart failure. J Am Coll Cardiol 2007;50:551–7. [8] Yoshida M, Shiojima I, Ikeda H, Komuro I. Chronic doxorubicin cardiotoxicity is mediated by oxidative DNA damage-ATM-p53-apoptosis pathway and attenuated by pitavastatin through the inhibition of Rac1 activity. J Mol Cell Cardiol 2009;47: 698–705. [9] Shepherd J, Blauw GJ, Murphy MB, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet 2002;360: 1623–30. [10] Mozaffarian D, Nye R, Levy WC. Statin therapy is associated with lower mortality among patients with severe heart failure. Am J Cardiol 2004;93:1124–9. [11] Horwich TB, MacLellan WR, Fonarow GC. Statin therapy is associated with improved survival in ischemic and non-ischemic heart failure. J Am Coll Cardiol 2004;43:642–8. [12] Go AS, Lee WY, Yang J, Lo JC, Gurwitz JH. Statin therapy and risks for death and hospitalization in chronic heart failure. JAMA 2006;296:2105–11. [13] Node K, Fujita M, Kitakaze M, Hori M, Liao JK. Short-term statin therapy improves cardiac function and symptoms in patients with idiopathic dilated cardiomyopathy. Circulation 2003;108:839–43. [14] Mozaffarian D, Minami E, Letterer RA, Lawler RL, McDonald GB, Levy WC. The effects of atorvastatin (10 mg) on systemic inflammation in heart failure. Am J Cardiol 2005;96:1699–704. [15] Tousoulis D, Antoniades C, Vassiliadou C, et al. Effects of combined administration of low dose atorvastatin and vitamin E on inflammatory markers and endothelial function in patients with heart failure. Eur J Heart Fail 2005;7:1126–32. [16] Wojnicz R, Wilczek K, Nowalany-Kozielska E, et al. Usefulness of atorvastatin in patients with heart failure due to inflammatory dilated cardiomyopathy and elevated cholesterol levels. Am J Cardiol 2006;97:899–904. [17] Sola S, Mir MQ, Lerakis S, Tandon N, Khan BV. Atorvastatin improves left ventricular systolic function and serum markers of inflammation in nonischemic heart failure. J Am Coll Cardiol 2006;47:332–7. [18] Kjekshus J, Apetrei E, Barrios V, et al. Rosuvastatin in older patients with systolic heart failure. N Engl J Med 2007;357:2248–61. [19] Tavazzi L, Maggioni AP, Marchioli R, et al. Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebocontrolled trial. Lancet 2008;372:1231–9. [20] Flores NA. Pitavastatin Nissan/Kowa Yakuhin/Novartis/Sankyo. Curr Opin Investig Drugs 2002;3:1334–41. [21] Saito Y, Yamada N, Teramoto T, et al. A randomized, double-blind trial comparing the efficacy and safety of pitavastatin versus pravastatin in patients with primary hypercholesterolemia. Atherosclerosis 2002;162:373–9. [22] Iglesias P, Díez JJ. New drugs for the treatment of hypercholesterolaemia. Expert Opin Investig Drugs 2003;12:1777–89. [23] Anker SD, Clark AL, Winkler R, et al. Statin use and survival in patients with chronic heart failure–results from two observational studies with 5200 patients. Int J Cardiol 2006;112:234–42. [24] Sever PS, Dahlöf B, Poulter NR, et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes TrialLipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled tria. Lancet 2003;361:1149–58. [25] Rauchhaus M, Coats AJ, Anker SD. The endotoxin-lipoprotein hypothesis. Lancet 2000;356:930–3. [26] Turunen M, Olsson J, Dallner G. Metabolism and function of coenzyme Q. Biochim Biophys Acta 2004;1660:171–99. [27] Littarru GP, Tiano L. Bioenergetic and antioxidant properties of coenzyme Q10: recent developments. Mol Biotechnol 2007;37:31–7. [28] Mukhtar RY, Reid J, Reckless JP. Pitavastatin. Int J Clin Pract 2005;59:239–52. [29] Kajinami K, Mabuchi H, Saito Y. NK-104: a novel synthetic HMG-CoA reductase inhibitor. Expert Opin Investig Drugs 2000;9:2653–61. [30] Hargreaves IP, Duncan AJ, Heales SJ, Land JM. The effect of HMG-CoA reductase inhibitors on coenzyme Q10: possible biochemical/clinical implications. Drug Saf 2005;28:659–76. [31] Kawashiri MA, Nohara A, Tada H, et al. Comparison of effects of pitavastatin and atorvastatin on plasma coenzyme Q10 in heterozygous familial hypercholesterolemia: results from a crossover study. Clin Pharmacol Ther 2008;83: 731–9. [32] Morikawa S, Umetani M, Nakagawa S, et al. Relative induction of mRNA for HMG CoA reductase and LDL receptor by five different HMG-CoA reductase inhibitors in cultured human cells. J Atheroscler Thromb 2000;7:138–44. [33] Fujino H, Saito T, Tsunenari Y, Kojima J. Interaction between several medicines and statins. Arzneimittelforschung 2003;53:145–53. [34] Kim K, Johnson JA, Derendorf H. Differences in drug pharmacokinetics between East Asians and Caucasians and the role of genetic polymorphisms. J Clin Pharmacol 2004;44:1083–105. [35] Liao JK. Safety and efficacy of statins in Asians. Am J Cardiol 2007;99:410–4. [36] Coats AJ. Ethical authorship and publishing. Int J Cardiol 2009;131:149–50.
Contents lists available at ScienceDirect
International Journal of Cardiology j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / i j c a r d
Rationale and design of a study to evaluate effects of pitavastatin on Japanese patients with chronic heart failure The pitavastatin heart failure study (PEARL study) Hiroshi Mizuma a, Teruo Inoue b, Hiroyuki Takano a, Satoshi Shindo a, Toru Oka a, Daisuke Fujimatsu c, Yoichi Kuwabara a, Koichi Node c, Issei Komuro a,⁎ and On behalf of the PEARL Study Investigators a b c
Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, Chiba, Japan Department of Cardiovascular Medicine, Dokkyo Medical University, Mibu, Japan Department of Cardiovascular and Renal Medicine, Saga University Faculty of Medicine, Saga, Japan
a r t i c l e
i n f o
Article history: Received 7 January 2010 Received in revised form 2 October 2010 Accepted 23 October 2010 Available online 13 November 2010 Keywords: Chronic heart failure Statin Hypercholesterolemia Randomized controlled trial
a b s t r a c t Background: HMG-CoA reductase inhibitors (statins) are known to have pleiotropic effects in addition to their lipid-lowering effect. Many studies have suggested cardioprotective effects of statins, however, recent largescale clinical trials using rosuvastatin, a hydrophilic statin, have failed to show beneficial effects on cardiovascular events in patients with severe heart failure. We have designed the study to evaluate the effects of pitavastatin, a lipophilic statin, on Japanese patients with mild to moderate heart failure. Methods and results: Five hundred seventy-seven patients with chronic heart failure were enrolled. We used a prospective, randomized, open-label, and blinded-endpoint evaluation (PROBE) design. Patients aged 20–79 years old with symptomatic (NYHA functional class II or III) heart failure and a left ventricular ejection fraction of ≤ 45% were randomly allocated to either receive pitavastatin (2 mg/day) or not in addition to conventional therapy for heart failure by using the minimization method. Follow-up will be continued until March 2011. The primary endpoint is a composite of cardiac death and hospitalization for worsening heart failure. Conclusions: The PEARL study will provide important data on the role of pitavastatin in the treatment of Japanese patients with mildly symptomatic heart failure (UMIN-ID: UMINC000000428). © 2010 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Heart failure is a complex clinical syndrome that results from structural and functional disorders of the heart associated with a variety of cardiovascular diseases. The number of patients with heart failure has been increasing and heart failure is becoming a major public health problem. Over the past 20 years, there has been considerable progress in the treatment of chronic heart failure (CHF) with appearance of angiotensin-converting enzyme (ACE) inhibitors, angiotensin-II receptor blockers (ARB), β blockers and aldosterone antagonists. However, the number of deaths due to CHF has been increasing steadily and further strategies for CHF are needed. 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, commonly called statins, are the most widely used agents for the treatment of hypercholesterolemia. Clinical trials have shown ⁎ Corresponding author at: Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine. 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. Tel.: +81 43 226 2097; fax: +81 43 226 2557. E-mail address: [email protected] (I. Komuro). 0167-5273/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2010.10.022
that treatment with statins significantly reduces the incidence of cardiovascular events in patients with coronary artery diseases [1–4]. In addition to their lipid-lowering actions, statins have also been reported to have various pleiotropic effects, including antiinflammatory effects, antioxidant effects, angiogenic effects, protective effects of endothelial cells, and inhibitory effects on neurohormonal activation [5]. It has been demonstrated that statins inhibit the progression of heart failure in animal models with non-ischemic heart failure [6–8]. These effects of statins suggest its potential to ameliorate components of the complex pathophysiology of CHF and to contribute to a promising treatment for CHF in the future. Many observational studies and retrospective analyses have suggested that treatment with statins decreases the incidence of heart failure in patients with coronary artery disease and reduces mortality of patients with CHF [9–12]. Prospective small trials have also confirmed the beneficial effects of statins on heart failure [13–17]. On the other hand, recent two prospective randomized large clinical trials have shown that statin treatment has no effect on the clinical outcomes of patients with CHF [18,19]. However, it remains unclear whether treatment with statins on CHF patients would show the same
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Table 1 Inclusion criteria. 1. Age 20–79 years at the time of randomization 2. NYHA functional class II or III 3. Left ventricular ejection fraction as measured by echocardiography of ≤45% 4. Stable NYHA class for 2 or more weeks before the randomization 5. Mild hypercholesterolemia (serum total cholesterol ≤250 mg/dl and/or serum LDL-cholesterol ≤170 mg/dl) NYHA, New York Heart Association; LDL, low-density lipoprotein.
results with different study designs in relation to the type of statin used, characteristics of the patients, severity of heart failure, and the endpoints examined. Pitavastatin is a lipophilic statin and has longeracting effects on low-density lipoprotein (LDL)-cholesterol reduction and high-density lipoprotein cholesterol increase. Pitavastatin also has a high bioavailability and is minimally metabolized by the cytochrome P450 system [20–22]. The Pitavastatin Heart Failure (PEARL) study was designed to evaluate the beneficial effects of pitavastatin on the incidence of cardiac death and hospitalization for worsening heart failure in Japanese patients with CHF. Fig. 1. Study design.
2. Methods 2.1. Study population We enrolled 577 symptomatic CHF patients with mild hypercholesterolemia between June 2006 and June 2008. The inclusion criteria are: between 20 and 79 years of age; New York Heart Association (NYHA) functional class II or III; left ventricular ejection fraction (LVEF) as measured by echocardiography of ≤ 45%; stable NYHA class for 2 or more weeks prior to the randomization; mild hypercholesterolemia (serum total cholesterol concentration of ≤ 250 mg/dl and/or serum LDL-cholesterol concentration of ≤170 mg/dl); and availability of written informed consent of the patient (Table 1). The exclusion criteria are: receiving treatment with a statin prior to the randomization; history of acute myocardial infarction within 3 months prior to the randomization, percutaneous coronary intervention (PCI), or coronary artery bypass grafting, or cardiac resynchronization therapy-pacemaker or -defibrillator implantation performed within 3 months prior to the randomization; malignancy; serious renal or hepatic dysfunction; collagen disease; pregnancy or possible pregnancy; and lack of informed consent (Table 2). 2.2. Study design The PEARL study is a multicenter, prospective, randomized, open-label, blindedendpoint (PROBE) trial being carried out in Japan. The eligible patients are allocated randomly to either the pitavastatin group (2 mg/day) or the control group (no statin). As the usual daily dosage of pitavastatin is 1–2 mg in Japan, we used 2 mg of pitavastatin in the present study. Patient allocation was performed by the minimization method on the basis of the following baseline variables: age, gender, serum total cholesterol concentration, LVEF, history of ischemic heart disease, and history of hospitalization for CHF. According to the protocol, all the patients will be followed up for an average of 3 years until March 2011. If any patients in the control group need further reduction of the serum total cholesterol concentration, lipid-lowering agents except statins can be administered (Fig. 1). 2.3. Endpoints The primary endpoint is a composite of cardiac death and hospitalization due to worsening CHF. The secondary endpoints are all-cause death, cardiac death, hospitalization due to worsening CHF, myocardial infarction, unstable angina, stroke,
Table 2 Exclusion criteria. 1. Administration of statins before randomization. 2. Unstable decompensated heart failure at randomization. 3. Acute myocardial infarction within 3 months prior to the randomization. 4. Percutaneous coronary intervention, coronary artery bypass grafting, or cardiac resynchronization therapy-pacemaker or -defibrillator implantation performed within 3 months prior to the randomization. 5. Malignancy. 6. Serious renal or hepatic dysfunction. 7. Collagen disease. 8. Pregnancy or possible pregnancy. 9. Lack of informed consent. 10. Judged by the investigator to be ineligible for inclusion in the study.
PCI, and surgical therapy for worsening CHF. Tertiary endpoints include evaluations for cardiac function by echocardiography, NYHA class, incidence of new-onset atrial fibrillation, serum high-sensitivity C-reactive protein, B-type natriuretic peptide (BNP), norepinephrine, tumor necrosis factor-α, interleukin-6, and tenascin C, and urinary 8-isoprostane. We also evaluate left ventricular systolic function, volume and myocardial perfusion by 99mTc-sestamibi quantitative gated single-photon emission computed tomography (SPECT) and measure surrogate markers for CHF by blood tests. 2.4. Sample size calculation We assumed that the hazard ratio of cardiac events (cardiac death and hospitalization for worsening heart failure) of the pitavastatin group to the control group was 0.57 based on the previous reports [11,23]. On condition that the patients are evenly allocated and followed up for 24–48 months (median 36 months) after the enrollment, at least 200 patients are required for each arm to provide 80% power to detect a hazard ratio of 0.57 using a 2-sided significance level of 0.05 by the log-rank test. After considering maximum 15% for the loss of follow-up or unsuitable for analysis, we have expected that more than 470 patients are needed to be enrolled in this study. 2.5. Statistical analysis Continuous variables such as laboratory data are expressed by mean ± standard deviation (SD) at each period. Group comparisons between the pitavastatin group and the control group will be calculated by Student t-test, Analysis of Variance (ANOVA), Chi-square test, Fisher's exact test, or the Mann–Whitney U-test, as appropriate. Comparisons within groups will be assessed by paired t-test or the Kruskal–Wallis test. Cumulative event rate for primary and secondary events will be determined by lifetable method, and the difference between the groups will be tested by log-rank test or Cox proportional hazards regression model. Univariate predictive variables will be backward eliminated in multivariable models with the likelihood ratio criterion, and hazard ratios with 95% confidence intervals will be reported. All primary analyses will be done by intention-to-treat. Statistical analysis will be performed with SPSS 17.0 and Sample Power (SPSS Inc, Chicago, Il). 2.6. Study management Data on the primary and secondary endpoints and adverse events will be collected at various time-points and interim analyses will be performed every year after the initiation of the study to evaluate the events and the treatment safety. An independent endpoint committee (Appendix 1) consisting of three members, who are blinded to any information relating to the group allocations, evaluates each event and classifies the results. An independent data and safety monitoring board (Appendix 2) is composed of three members and reviews all reports from the endpoint committee to advise early termination of the study for safety, scientific or ethical reasons. A steering committee (Appendix 3) is responsible for the study design and scientific execution of the study. 2.7. Baseline characteristics Finally, 577 patients were randomly assigned to two groups. Of the total, 289 were assigned to the pitavastatin group and 288 to the control group. The baseline characteristics of the patients enrolled are presented in Table 3. The mean age was 62.7 years and 18.5% of the patients were female. The mean blood pressure was 119.4/
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Table 3 Baseline characteristics (n = 577). Mean age, years Females (%) Mean systolic blood pressure (mmHg) Mean diastolic blood pressure (mmHg) NYHA functional class II (%) III (%) Mean LVEF (%) Mean total cholesterol (mg/dl) Mean LDL-cholesterol (mg/dl) Median (interquartile range) BNP (pg/ml) Medical history Ischemic heart disease (%) Medication ACE inhibitors/ARBs (%) Diuretics (%) β blockers (%) Digitalis glycoside (%) Calcium channel blockers (%)
62.7 ± 11.9 18.5 119.4 ± 17.9 71.9 ± 11.2 89.6 10.4 35.0 ± 8.5 202.3 ± 32.4 125.6 ± 30.5 126.0 (52.2–288.5) 28.6 83.8 74.8 72.5 24.9 16.0
NYHA, New York Heart Association; LVEF, left ventricular ejection fraction; LDL, low-density lipoprotein; BNP, B-type natriuretic peptide; ACE inhibitors/ARBs, angiotensin-converting enzyme inhibitors or angiotensin-II receptor blockers. 71.9 mmHg and 89.6% of the patients were classified to NYHA functional class II. The mean LVEF was 35.0% and 28.6% of the patients had a history of ischemic heart disease. The mean serum levels of total cholesterol and LDL-cholesterol were 202.3 mg/dl and 125.6 mg/dl, respectively. The median serum BNP in the patients was 126.0 pg/ml.
3. Discussion The PEARL study has been carefully designed to address critical unanswered questions. Does pitavastatin have the beneficial effects on the incidence of cardiac death and hospitalization for worsening heart failure in Japanese patients with CHF? It is well known that treatment with statins significantly reduces the incidence of cardiovascular events in patients at high risk, especially those with coronary artery diseases, irrespective of the baseline cholesterol levels [24]. Several retrospective analyses and large observational studies have suggested that treatment with statins decreases the incidence of CHF and reduces mortality in patients with CHF [9–12]. Furthermore, prospective trials assessing the effects of statins on surrogate endpoints such as biomarkers and echocardiographic parameters demonstrated the beneficial effects of statins on patients with CHF [13–17]. Meta-analyses of statin treatment in randomized clinical trials also confirmed a reduction of cardiovascular mortality in patients with CHF of both ischemic and nonischemic etiologies [5]. These results support the pleiotropic effects of statins demonstrated by basic research and the beneficial effects of statins on patients with CHF. Recently, the results of two prospective randomized trials have been published [18,19]. The CORONA (Controlled rosuvastatin multinational study in heart failure) study randomized 5,011 patients with symptomatic CHF of ischemic etiology to 10 mg rosuvastatin or placebo [18]. The primary endpoint was a composite of death from cardiovascular causes, nonfatal myocardial infarction, and nonfatal stroke. A daily dose of 10 mg rosuvasatin did not reduce the primary composite cardiovascular outcome, death from cardiovascular causes, nonfatal myocardial infarction, nor nonfatal stroke. The GISSI (Gruppo Italiano per lo Studio della Sopravvivenza nell'Insufficienza cardiaca)–HF(Heart Failure) trial randomized 4631 patients with symptomatic CHF of both ischemic and nonischemic etiologies to 10 mg rosuvastatin or placebo [19]. The primary endpoints were time to death, and time to death or admission to hospital for cardiovascular reasons. The treatment with rosuvastatin did not affect the primary endpoints in the 2 studies [18,19]. However, the CORONA study showed that there were fewer hospitalization for cardiovascular causes which was one of the secondary endpoints in the rosuvastatin
group. It remains unknown at present whether the results of the CORONA study and the GISSI-HF trial can be applied in the different patient selection or in the different kind of statin. Concerns have been raised about the possible deleterious effects of statins. Circulating lipoproteins have the ability to bind and detoxify bacterial lipopolysaccharide. Because lipopolysaccharide stimulates the release of inflammatory cytokines, statins may increase inflammation in patients with CHF [25]. Moreover, statins decrease the synthesis of not only cholesterol but also of other downstream products in the mevalonate pathway. Coenzyme Q10 (ubiquinone), which is an essential cofactor in the mitochondrial electron transport chain, is one of the downstream products. Because coenzyme Q10 plays an important role in the mitochondrial respiratory chain and has an antioxidant function [26,27], statins may reduce adenosine triphosphate production and aggravate heart failure. In the PEARL study, we use pitavastatin to evaluate the beneficial effects of statin therapy on Japanese patients with CHF. Pitavastatin is a statin which was developed in Japan and has potent lipid-lowering effect [20–22]. Pitavastatin is a lipophilic agent, while rosuvastatin is a hydrophilic agent. Pitavastatin is distributed selectively to the liver and is excreted in bile without metabolic modification [28]. The renal excretion rate is less than 2% and the terminal elimination half-life of 11 h [29]. It has been reported that the degree of reduction in plasma coenzyme Q10 by lovastatin, pravastatin, simvastatin, and atorvastatin corresponds closely to the degree of reduction of the serum or plasma LDL-cholesterol level [30]. A recent study showed that atorvastatin significantly reduced the plasma level of coenzyme Q10 but pitavastatin did not affect it in Japanese patients with heterozygous familial hypercholesterolemia, although both statins reduced the serum LDL-cholesterol levels by the same degree [31]. Statins potently reduce the serum LDL-cholesterol level by inhibiting the synthesis of mevalonate and inducing the expression of LDL receptors mainly in the hepatocytes. Pitavastatin has been reported to most strongly increase the LDL receptor mRNA expression among all statins [32]. These data indicate that there is minimal likelihood of deleterious effects resulting from inhibition of the mevalonate pathway in case of pitavastatin. As pitavastatin is hardly metabolized through the cytochrome P450-mediated pathway, pitavastatin is expected to have little interaction with other agents metabolized through the P450 pathway [33]. This property may be potentially beneficial for patients with CHF who take several kinds of medicines for the treatment of heart failure. There are some differences in the characteristics of patients and protocol among the PEARL study, the CORONA study, and the GISSI-HF trial. The ratio of patients with ischemic heart failure was 40% in the GISSI-HF trial, and 100% in the CORONA study, while only 28.6% of patients have ischemic heart failure in the PEARL study. The mean age of the patients was 73, 68, and 63 years in the CORONA, the GISSI-HF, and the PEARL, respectively. The enrolled patients appear to be less symptomatic in the PEARL study (NYHA II 89.6%, III 10.4%, IV 0%) than in the CORONA study (NYHA II 37.0%, III 61.5%, IV 1.5%) and the GISSI-HF trial (NYHA II 62.5%, III 35.0%, IV 2.5%). The differences in severity of CHF patients may affect the results of those trials. Furthermore, all the patients enrolled in the PEARL study are Japanese. There are differences in the responses to therapeutic drugs between Asian and Western populations [34]. Asian patients frequently exhibit high responses to therapeutic drugs [34]. This phenomenon is also recognized in cardiovascular drugs including statins. Pharmacokinetic investigations have demonstrated higher plasma levels of statins in Asians as compared with Caucasians [35]. The high responses of Asians to statins are thought to be related to genetic differences in the metabolism of statins [35]. The kind of statins used in the PEARL study, the CORONA study, and the GISSI-HF trial are also different. Pitavastatin used in the PEARL study has many characteristics different from rosuvastatin used in the other two studies, such as lipophilicity and bioavailability.
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The PEARL study is the first study to evaluate the effects and safety of pitavastatin in Japanese patients with moderate CHF. This study is expected to clarify whether pitavastatin might have beneficial effects on the patients receiving current standard therapy for CHF. Acknowledgment This study is supported by a research grant from the Japan Heart Foundation. The authors gratefully acknowledge the assistance of Ms. Naomi Harada, Mr. Hiroshi Komoda, Ms. Chiharu Kawaguchi, and Ms. Sae Katafuchi. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [36]. Appendix 1. Independent Endpoint Committee Yuji Kira (Showa General Hospital); Hiroyuki Morita (The University of Tokyo); Yuji Hashimoto (Kameda General Hospital). Appendix 2. Independent Data and Safety Monitoring Board Akira Yamashina (Tokyo Medical University); Tsutomu Yamazaki (The University of Tokyo); Naoki Ishizuka (International Medical Center of Japan). Appendix 3. Steering Committee Issei Komuro, Yoichi Kuwabara, and Hiroyuki Takano (Chiba University); Koichi Node (Saga University); Teruo Inoue (Dokkyo Medical University); Hiroshi Ito (Akita University); Toshiharu Himi (Kimitsu Chuou Hospital); Takanobu Tomaru (Toho University Sakura Medical Center); Junji Kanda (Asahi Chuo Hospital); Satoshi Kobayashi (Chibaken Saiseikai Narashino Hospital); Mitsuyuki Shimizu (Jikei University School of Medicine, Kashiwa Hospital); Akira Miyazaki, Toshihisa Inoue, and Akira Aouda (Chiba Cardiovascular Center); Fumitaka Nakamura (Teikyo University Chiba Medical Center); Tatsuji Kanoh (Juntendo University); Youichi Katoh (Juntendo University Urayasu Hospital); Yoshihiko Seino (Nippon Medical School Chiba Hokusoh Hospital); Michiaki Hiroe (International Medical Center of Japan); Junichi Yamazaki (Toho University Omori Medical Center); Kyoichi Mizuno (Nippon Medical School); Toyoaki Murohara (Nagoya University); Masashi Kitakaze (National Cardiovascular Center); Kenji Kawajiri (Matsubara Tokushukai Hospital); Yoshihiko Saito (Nara Medical University); Kengo Kusano (Okayama University); Masakazu Kohno (Kagawa University); Keijiro Saku (Fukuoka University); Katsusuke Yano (Nagasaki International University); Koji Oku (Nagasaki Medical Center); Hisao Ogawa (Kumamoto University); Tetsunori Saika (Oita University). References [1] LaRosa JC, He J, Vupputuri S. Effect of statins on risk of coronary disease: a metaanalysis of randomized controlled trials. JAMA 1999;282:2340–6. [2] Pignone M, Phillips C, Mulrow C. Use of lipid lowering drugs for primary prevention of coronary heart disease: meta-analysis of randomised trials. BMJ 2000;321:983–6. [3] Wilt TJ, Bloomfield HE, MacDonald R, et al. Effectiveness of statin therapy in adults with coronary heart disease. Arch Intern Med 2004;164:1427–36. [4] Baigent C, Keech A, Kearney PM, et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90, 056 participants in 14 randomised trials of statins. Lancet 2005;366:1267–78. [5] Ramasubbu K, Estep J, White DL, Deswal A, Mann DL. Experimental and clinical basis for the use of statins in patients with ischemic and nonischemic cardiomyopathy. J Am Coll Cardiol 2008;51:415–26.
147
[6] Ichihara S, Noda A, Nagata K, et al. Pravastatin increases survival and suppresses an increase in myocardial matrix metalloproteinase activity in a rat model of heart failure. Cardiovasc Res 2006;69:726–35. [7] Zacà V, Rastogi S, Imai M, et al. Chronic monotherapy with rosuvastatin prevents progressive left ventricular dysfunction and remodeling in dogs with heart failure. J Am Coll Cardiol 2007;50:551–7. [8] Yoshida M, Shiojima I, Ikeda H, Komuro I. Chronic doxorubicin cardiotoxicity is mediated by oxidative DNA damage-ATM-p53-apoptosis pathway and attenuated by pitavastatin through the inhibition of Rac1 activity. J Mol Cell Cardiol 2009;47: 698–705. [9] Shepherd J, Blauw GJ, Murphy MB, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet 2002;360: 1623–30. [10] Mozaffarian D, Nye R, Levy WC. Statin therapy is associated with lower mortality among patients with severe heart failure. Am J Cardiol 2004;93:1124–9. [11] Horwich TB, MacLellan WR, Fonarow GC. Statin therapy is associated with improved survival in ischemic and non-ischemic heart failure. J Am Coll Cardiol 2004;43:642–8. [12] Go AS, Lee WY, Yang J, Lo JC, Gurwitz JH. Statin therapy and risks for death and hospitalization in chronic heart failure. JAMA 2006;296:2105–11. [13] Node K, Fujita M, Kitakaze M, Hori M, Liao JK. Short-term statin therapy improves cardiac function and symptoms in patients with idiopathic dilated cardiomyopathy. Circulation 2003;108:839–43. [14] Mozaffarian D, Minami E, Letterer RA, Lawler RL, McDonald GB, Levy WC. The effects of atorvastatin (10 mg) on systemic inflammation in heart failure. Am J Cardiol 2005;96:1699–704. [15] Tousoulis D, Antoniades C, Vassiliadou C, et al. Effects of combined administration of low dose atorvastatin and vitamin E on inflammatory markers and endothelial function in patients with heart failure. Eur J Heart Fail 2005;7:1126–32. [16] Wojnicz R, Wilczek K, Nowalany-Kozielska E, et al. Usefulness of atorvastatin in patients with heart failure due to inflammatory dilated cardiomyopathy and elevated cholesterol levels. Am J Cardiol 2006;97:899–904. [17] Sola S, Mir MQ, Lerakis S, Tandon N, Khan BV. Atorvastatin improves left ventricular systolic function and serum markers of inflammation in nonischemic heart failure. J Am Coll Cardiol 2006;47:332–7. [18] Kjekshus J, Apetrei E, Barrios V, et al. Rosuvastatin in older patients with systolic heart failure. N Engl J Med 2007;357:2248–61. [19] Tavazzi L, Maggioni AP, Marchioli R, et al. Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebocontrolled trial. Lancet 2008;372:1231–9. [20] Flores NA. Pitavastatin Nissan/Kowa Yakuhin/Novartis/Sankyo. Curr Opin Investig Drugs 2002;3:1334–41. [21] Saito Y, Yamada N, Teramoto T, et al. A randomized, double-blind trial comparing the efficacy and safety of pitavastatin versus pravastatin in patients with primary hypercholesterolemia. Atherosclerosis 2002;162:373–9. [22] Iglesias P, Díez JJ. New drugs for the treatment of hypercholesterolaemia. Expert Opin Investig Drugs 2003;12:1777–89. [23] Anker SD, Clark AL, Winkler R, et al. Statin use and survival in patients with chronic heart failure–results from two observational studies with 5200 patients. Int J Cardiol 2006;112:234–42. [24] Sever PS, Dahlöf B, Poulter NR, et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes TrialLipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled tria. Lancet 2003;361:1149–58. [25] Rauchhaus M, Coats AJ, Anker SD. The endotoxin-lipoprotein hypothesis. Lancet 2000;356:930–3. [26] Turunen M, Olsson J, Dallner G. Metabolism and function of coenzyme Q. Biochim Biophys Acta 2004;1660:171–99. [27] Littarru GP, Tiano L. Bioenergetic and antioxidant properties of coenzyme Q10: recent developments. Mol Biotechnol 2007;37:31–7. [28] Mukhtar RY, Reid J, Reckless JP. Pitavastatin. Int J Clin Pract 2005;59:239–52. [29] Kajinami K, Mabuchi H, Saito Y. NK-104: a novel synthetic HMG-CoA reductase inhibitor. Expert Opin Investig Drugs 2000;9:2653–61. [30] Hargreaves IP, Duncan AJ, Heales SJ, Land JM. The effect of HMG-CoA reductase inhibitors on coenzyme Q10: possible biochemical/clinical implications. Drug Saf 2005;28:659–76. [31] Kawashiri MA, Nohara A, Tada H, et al. Comparison of effects of pitavastatin and atorvastatin on plasma coenzyme Q10 in heterozygous familial hypercholesterolemia: results from a crossover study. Clin Pharmacol Ther 2008;83: 731–9. [32] Morikawa S, Umetani M, Nakagawa S, et al. Relative induction of mRNA for HMG CoA reductase and LDL receptor by five different HMG-CoA reductase inhibitors in cultured human cells. J Atheroscler Thromb 2000;7:138–44. [33] Fujino H, Saito T, Tsunenari Y, Kojima J. Interaction between several medicines and statins. Arzneimittelforschung 2003;53:145–53. [34] Kim K, Johnson JA, Derendorf H. Differences in drug pharmacokinetics between East Asians and Caucasians and the role of genetic polymorphisms. J Clin Pharmacol 2004;44:1083–105. [35] Liao JK. Safety and efficacy of statins in Asians. Am J Cardiol 2007;99:410–4. [36] Coats AJ. Ethical authorship and publishing. Int J Cardiol 2009;131:149–50.