- Email: [email protected]
Effect of controlled-release nifedipine on left ventricular hypertrophy in Japanese patients with hypertension: An open-label, uncontrolled study
VOL. 62, No. 11, NOVEMBER 2001
Effect of Controlled-Release Nifedipine on Left Ventricular Hypertrophy in Japanese Patients with Hypertension: An Open-Label, Uncontrolled Study Masaki Shimoyama, MD, PhD, 1 Hiroshi Ochi, MD, 1 Shin-ichi Takeda, MD, PhD, 1 Tetsuya Doi, MD, PhD, 2 Yoshiharu Kinugasa, MD, 2 Akihiro Endoh, MD, PhD, 3 Toru Kinugawa, MD, PhD, 3 Kazuhide Ogino, MD, PhD, 3 Ichiro Hisatome, MD, PhD, 3 Chiaki Shigemasa, MD, PhD,3 and Issei Komuro, MD, PhD4
7Department of Medicine, Philanthropic Hospital of Yonago, 2Department of Cardiovascular Medicine, San-in Industrial and Accidental Hospital, 3Division of Cardiology, Department of Medicine I, Tottori University, Faculty of Medicine, Yonago, and 4Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, Chiba, Japan
ABSTRACT
Background: Although the safety and efficacy of various calcium antagonists have been demonstrated in the treatment of hypertension, short-acting nifedipine has been reported to have no beneficial effect in hypertensive patients with myocardial ischemia and heart failure. Objective: The purpose of this study was to examine the tolerability and efficacy of once-daily nifedipine coat-core (CR), a long-acting nifedipine formulation, in the treatment of Japanese patients with hypertension and left ventricular hypertrophy (LVH). Methods: Patients were treated with 40 mg nifedipine CR once daily for 12 months. Blood pressure and heart rate were measured every month. Echocardiography and chest radiography were performed and plasma levels of atrial natriuretic peptide and brain natriuretic peptide were measured before and after 12 months of treatment. Results: A total of 15 hypertensive patients with LVH (6 men and 9 women; mean age, 51 + 3 years; blood pressure, >140/90 mm Hg) were treated. Within 2 months of initiating nifedipine treatment, mean blood pressure was significantly reduced (P < 0.05 vs baseline) to <140/80 mm Hg, and this effect was sustained throughout the 12-month study period. Cardiothoracic ratio was significantly reduced by -13% (P < 0.001 vs baseline). Nifedipine induced regression of LVH, as evidenced by significant decreases (P < 0.001 vs baseline) in interventricular septal wall thickness, left ventricular posterior wall thickness, Acceptedfor publicationAugust21, 2001.
Printed in the USA.Reproduction in whole or part is not permitted.
0011-393X/01/$19.00
773
CURRENT THERAPEUTIC RESEARCH®
left ventricular mass, and left ventricular mass index. Serum levels of natriuretic peptides were also significantly reduced (P < 0.001 vs baseline). There were no significant changes in glucose and lipid metabolism parameters. No patients experienced any adverse events during treatment. Conclusions: The results of this study indicate that treatment with nifedipine CR was well tolerated and resulted in a significant reduction in blood pressure, regression of LVH and cardiac enlargement, and a decrease in serum natriuretic peptide levels in this sample of Japanese hypertensive patients with LVH. These results suggest that long-acting calcium antagonists such as nifedipine CR may be useful in the treatment of hypertensive patients with LVH. Key words: hypertension, left ventricular hypertrophy, calcium antagonist, natriuretic peptide. (Curt Ther Res Clin Exp. 2001;62:773-782)
INTRODUCTION Left ventricular hypertrophy (LVH) is an independent risk factor for cardiovascular morbidity and mortality in patients with hypertension. 1-3 The Framingham Heart Study showed that the risk of acute myocardial infarction and angina pectoris increased in the presence of LVH.4-6 It has also been demonstrated that the incidence of sudden cardiac death and the severity of myocardial infarction are increased in hypertensive patients with LVH.4-6 These results suggest that it is important to treat patients with hypertension and LVH to prevent further cardiovascular complications and that reversal of LVH may decrease cardiovascular morbidity and mortality. Numerous studies have shown that antihypertensive drugs induce regression of hypertensive LVH.7 Calcium antagonists are 1 class of agents recommended in several institutional guidelines 8-1° as a first-line treatment for hypertension. The safety and efficacy of various calcium antagonists in the treatment of hypertension have been well established. However, it has been reported that calcium antagonists are not suitable for the treatment of hypertension because of the increased risk of cardiovascular events associated with these agents. 1~ Nifedipine, a representative short-acting calcium antagonist, has not been reported to reduce mortality in hypertensive patients with ischemic heart disease, possibly because it stimulates the sympathetic nervous system. ~-~3 In contrast, amlodipine, a representative long-acting calcium antagonist, has been demonstrated to reduce mortality and the incidence of cardiovascular events in patients with congestive heart failure or ischemic heart disease possibly because it does not enhance neurohormonal activity. 14-~7 These results suggest that long-acting, but not short-acting, calcium antagonists are suitable for the treatment of patients with hypertension and hypertensive complications.
774
M. Shimoyama et al.
Nifedipine gastrointestinal therapeutic system (GITS), a once-daily, longacting nifedipine formulation, is widely used for the treatment of hypertensive patients. Results from the International Nifedipine GITS Study of Intervention as a Goal in Hypertension Treatment (INSIGHT) trial ~8 indicate that treatment with nifedipine GITS was more effective than diuretics and beta-blockers in controlling blood pressure and reducing cardiovascular and cerebrovascular morbidity and mortality in high-risk hypertensive patients. Nifedipine coat-core (CR), a long-acting, once-daily formulation of nifedipine, has recently become available in Japan. Nifedipine CR consists of a tablet and a hydrophilic matrix (an expandable hydrogel layer of polyethylene oxide and hydroxypropylmethylcellulose) that releases the drug slowly from the tablet as it erodes. However, the effects of nifedipine CR in patients with hypertension and with various hypertensive complications have not been clarified. Therefore, in this study, we sought to determine the tolerability and efficacy of nifedipine CR in Japanese patients with essential hypertension and LVH.
PATIENTS AND METHODS Entry Criteria and Screening Between April 1999 and July 1999, -200 hypertensive patients in the Department of Medicine, Philanthropic Hospital of Yonago, Yonago, Japan, were screened. Patients underwent routine laboratory testing, including assays for serum electrolytes, serum creatinine, blood urea nitrogen, fasting blood glucose, immunoreactive insulin, total cholesterol, high-density lipoprotein cholesterol (HDL-C), and triglycerides, as well as chest radiography and electrocardiography. Previously untreated patients with essential hypertension and LVH were enrolled based on the results of the laboratory tests and guidelines of the World Health Organization. ~9 Patients could not have been treated with any antihypertensive drugs or drugs that could influence blood pressure. Hypertension was defined as systolic blood pressure (SBP) >140 mm Hg or diastolic blood pressure (DBP) ->90 mm Hg. Blood pressure and heart rate were measured on at least 2 separate days before treatment. Secondary hypertension was excluded based on a clinical history, physical examination, routine laboratory tests 0ncluding measurements of plasma renin activity, aldosterone, catecholamine, and cortisoi), and an excretory urogram or renal arteriogram. Patients who had signs or symptoms of cardiac or renal failure, diabetes, pulmonary disease, angina pectoris, or myocardial infarction were excluded. Informed consent was obtained from all study participants. To confirm the presence of hypertensive LVH, echocardiography was recorded and left ventricular mass (LVM) and LVM index (LVMI) were calculated according to the formulas of the American Society of Echocardiography. 2°'21 Asymmetric septal hypertrophy was ruled out. In addition, serum concentrations of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) were measured.
775
CURRENT THERAPEUTICRESEARCH®
Study Design After the initial evaluation, enrolled patients were treated with a 40-mg tablet of nifedipine CR once daily for 12 months. Every month, patients made hospital visits, during which blood pressure and heart rate were measured and physical examinations were performed. Echocardiography, plasma ANP and BNP concentration measurements, and routine laboratory tests were performed before the initiation of therapy and after 1 year of therapy with nifedipine CR. Cardiologists blinded to the study objectives assessed the findings on echocardiography and chest radiography. Statistical Analysis Continuous variables were compared using the Student t test. P < 0.05 was considered statistically significant. RESULTS A total of 15 patients (6 men and 9 women; mean age, 51 + 3 years; range, 35-64 years) were enrolled. Before treatment, all patients had severe hypertension (mean BP, 196.5/110.5 mm Hg) (Figure). Hypercholesterolemia was observed in 5 patients at baseline, and HDL-C levels were low in 2 patients. Triglyceride and insulin levels were high in 8 and 2 patients, respectively. However, no lipid-lowering drug was administered because the hypercholesterolemia and hypertriglyceridemia were mild (HDL-C, 220-240 mg/dL; triglycerides, 150-230 mg/dL). After 12 months of once-daily treatment with nifedipine CR 40 mg, both SBP and DBP were reduced significantly from baseline (P < 0.001), and 2 months of treatment with nifedipine CR lowered both SBP and DBP to <140/80 mm Hg (P < 0.05 vs baseline) (Figure). The antihypertensive effect of nifedipine CR continued throughout the 12-month treatment period (Figure). Nifedipine CR had no significant effect on heart rate or glucose and lipid metabolism parameters (Figure, Table I). Chest radiography revealed that the cardiothoracic ratio, a measure of cardiac size, was significantly reduced by -13% after treatment (P < 0.001 vs baseline) (Table II). No patients complained of any adverse effects (eg, flushing, headache, palpitation, abdominal discomfort, edema). Echocardiography findings showed a significant reduction in the thickness of the interventricular septal wall and the left ventricular posterior wall (25% and 31%, respectively; P < 0.001 vs baseline) after treatment with nifedipine CR (Table IF). LVM and LVMI were also significantly decreased after treatment (41% and 49%, respectively; P < 0.001 vs baseline) (Table I1). Fractional shortening and the E/A wave ratio increased significantly after treatment with nifedipine CR (P < 0.05 and P < 0.001, respectively) (Table II). The plasma concentration of BNP, but not that of ANP, was significantly elevated before treatment. The BNP level was significantly reduced by 89% (P < 0.001 vs baseline) and was normalized after treatment (Table II). Treatment
776
M. Shimoyama et al.
20O 180 160
140 120
I
I
0
6
ll2
;
;
;2
120 110
~
9o 8O
70
C
100
o~
E e~
75
2=
50
I
0
I
6
112
Time (month)
Figure. The effect of nifedipine coat-core treatment on (A) systolic blood pressure (SBP), (B) diastolic blood pressure (DBP), and (C) heart rate. Data are expressed as mean _+ SEM. *P < 0.05 versus baseline (month 0).
with nifedipine CR also induced a significant 66% decrease in plasma ANP levels (P < 0.001) (Table II). DISCUSSION
The results of this study suggest that treatment with nifedipine CR was well tolerated and induced significant regression of LVH and cardiac enlargement
777
CURRENT THERAPEUTIC RESEARCH®
Table I. Effects of 12 months of t r e a t m e n t w i t h nifedipine coat-core on serum biochemistry parameters in Japanese hypertensive patients w i t h left ventricular hypertrophy. Baseline FBS, m g / d L IRI, IJU/mL TC, m g / d L TG, m g / d L HDL-C, m g / d L BUN, m g / d L Cr, m g / d L Sodium, mEq/L Potassium, mEq/L Chloride, mEq/L
94.9 7.87 209.3 175.6 43.2 14.9 0.72 140.2 3.9 97.5
± ± ± ± ± ± ± ± + ±
1.9 0.78 7.9 13.8 3.5 2.9 0.21 2.5 0.9 2.9
12 Months 96.1 9.03 209.1 169.0 44.4 13.2 0.73 138.9 4.0 95.9
± 1.7 ± 0.95 +__ 6.9 ± 11.7 + 3.3 ___ 3.4 + 0.19 _ 3.0 ± 0.7 ± 3.7
Reference Values 60-110 <5 120-220 50-150 40-87 9-24 0.8-1.2 135-147 3.6-5.0 98-108
FBS = fasting blood glucose; IRI = immunoreactive insulin; TC = serum total cholesterol; TG = triglycerides; HDL-C = high-density lipoprotein cholesterol; BUN = blood urea nitrogen; Cr = creatinine.
along with a marked reduction of natriuretic peptide levels and improvement of left ventricular systolic and diastolic function in h y p e r t e n s i v e patients with LVH. Hypertrophy of the heart often leads to dilated cardiomyopathy and eventually causes congestive heart failure after sustained overload. 22'23 In addition,
T a b l e II. Effects of 12 months of t r e a t m e n t w i t h nifedipine coat-core on hypertensive cardiac hypertrophy, left ventricular function, cardiac size, and natriuretic peptides. Baseline Height, cm Body weight, kg Dd, m m Ds, m m IVS, m m PW, m m LVM, g LVMI, g / m 2 FS, % E/A wave ratio CTR, % ANP, p g / m L BNP, p g / m L
162.5 63.9 46.00 28.33 13.00 13.47 297.96 1 79.79 37.30 0.52 55.20 37.27 108.21
+ 2.1 + 13.0 ± 1.15 ± 0.49 ± 0.52 ± 0.39 ± 17.30 ± 13.01 ± 1.72 ± 0.05 ___ 0.75 ± 5.44 ± 19.25
12 Months 162.5 63.3 44.07 25.87 9.80 9.33 175.19 105.86 42.47 0.76 47.87 12.67 11.32
+ 2.1 ± 6.8 + 1.04 + 0.49* ± 0.36 t ± 0.25 t ± 9.00 t ___ 6.75 t + 1.40" ± 0.07 t + 0.95 t ± 1.03 t ± 2.83 t
Reference Values --41-51 30-42 7-11 7-11 -->28 >1.0 <50 <40 <20
Dd = left ventricular dimensions at end diastole; Ds = left ventricular dimensions at end systole; IVS = interventricular septal wall thickness; PW = left ventricular posterior wall thickness; LVM = left ventricular mass; LVMI = LVM index; FS = fractional shortening; CTR = cardiothoracic ratio; ANP = atrial natriuretic peptide; BNP = brain natriuretic peptide. *P < 0.05 versus baseline, tp < 0.001 versus baseline.
778
M. Shimoyama et aL
plasma levels of ANP and BNP have been reported to increase in patients with essential hypertension who have LVH,24-26 and plasma BNP levels are known to decrease with regression of LVH.27'28 BNP is known to be a useful biochemical marker of left ventricular dysfunction and hypertensive LVH and has diagnostic, therapeutic, and prognostic implications. 29 Thus, the LVH regression and reduction of BNP levels observed in this study suggest that nifedipine CR may be useful in the treatment of hypertensive LVH and in the prevention of hypertensive heart failure. Nifedipine has been reported to be of little benefit in the treatment of hypertension, possibly because it induces reflex stimulation of the sympathetic nervous system and neurohormonal activation. 11-13 In addition, it has been reported that nitrendipine, another short-acting calcium antagonist, does not induce the regression of left ventricular wall thickness or LVM, although it does lower blood pressure. 3° However, amlodipine, a long-acting calcium antagonist, has been shown to be effective in the treatment of hypertension possibly because it does not enhance neurohormonal activity. ~4-17 These observations suggest that long-acting calcium antagonists, but not short-acting calcium antagonists, may be beneficial in the treatment of hypertension. Results of the INSIGHT trial ~8 indicate that treatment with nifedipine GITS, a long-acting formulation, was more effective than diuretics and beta-blockers in controlling blood pressure and reducing cardiovascular and cerebrovascular morbidity and mortality in high-risk hypertensive patients. These results suggest that the long-acting calcium antagonists may be useful in the treatment of hypertensive patients with complications such as LVH. Two recent meta-analyses of large clinical trials in hypertensive patients revealed that treatment with calcium antagonists reduced the incidence of cardiovascular events compared with placebo. 3~'32 In addition, treatment with calcium antagonists reduced the incidence of stroke compared with treatment with diuretics or beta-blockers. However, treatment with calcium antagonists has not been shown to reduce the occurrence of coronary heart disease and heart failure in hypertensive patients. 3~'32 Nevertheless, since most of the previous large clinical trials of calcium antagonists examined the effects of shortacting agents, the effects of long-acting agents are still not known. Additional large clinical trials of long-acting calcium antagonists are needed. Nifedipine CR consists of a coat-core tablet and a hydrophilic matrix (an expandable hydrogel layer of polyethylene oxide and hydroxypropylmethylcellulose) that releases the drug slowly as it erodes. The diameters of the coatcore tablet and the core are 9 mm and 5 ram, respectively. The coat-core tablet is coated with common film-forming materials and pigments used to protect photodegradation of nifedipine. Drug concentrations after administration of the nifedipine CR formulation peak within 4 hours after administration, and are sustained at that level at least 24 hours after administration. Nifedipine GITS differs from the nifedipine CR formulation in that it involves an osmotic pump process that provides approximately zero-order delivery of the drug. 33 Drug
779
CURRENT THERAPEUTIC RESEARCH®
c o n c e n t r a t i o n s f r o m t h e nifedipine GITS f o r m u l a t i o n p e a k within 6 h o u r s after a d m i n i s t r a t i o n a n d are s u s t a i n e d until at least 24 h o u r s after a d m i n i s t r a t i o n . In this study, we i n v e s t i g a t e d the effects of nifedipine CR on h y p e r t e n s i o n and on h y p e r t e n s i v e LVH. However, this w a s an open-label, u n c o n t r o l l e d study; therefore, we could not e v a l u a t e w h e t h e r this d r u g w a s s u p e r i o r to o t h e r ant i h y p e r t e n s i v e drugs. In addition, since nifedipine GITS w a s not available in Japan, we could not c o m p a r e nifedipine CR with nifedipine GITS. N e v e r t h e l e s s , it is well k n o w n t h a t effective a n t i h y p e r t e n s i v e t h e r a p y r e d u c e s t h e incidence of c a r d i o v a s c u l a r e v e n t s in h y p e r t e n s i v e patients. CONCLUSIONS T h e results of this s t u d y indicate t h a t nifedipine CR w a s well t o l e r a t e d and i n d u c e d a significant r e d u c t i o n in b l o o d p r e s s u r e , r e g r e s s i o n of LVH and cardiac e n l a r g e m e n t , a n d a d e c r e a s e in s e r u m natriuretic p e p t i d e levels in this s a m p l e of J a p a n e s e h y p e r t e n s i v e p a t i e n t s with LVH. T h e s e r e s u l t s s u g g e s t t h a t long-acting calcium a n t a g o n i s t s m a y b e useful in the t r e a t m e n t of h y p e r t e n s i v e p a t i e n t s with LVH. REFERENCES 1. Multiple Risk Factor Intervention Trial Research Group. Multiple Risk Factor Intervention Trial. Risk factor changes and mortality results. JAMA. 1982;248:1465-1477. 2. Messerli FH, Ventura HO, Elizardi DJ, et al. Hypertension and sudden death. Increased ventricular ectopic activity in left ventricular hypertrophy. Am J Med. 1984; 77:18-22. 3. Koren MJ, Devereux RB, Casale PN, et al. Relation of left ventricular mass and geometry to morbidity and mortality in uncomplicated essential hypertension. Ann Intern Med. 1991;114:345-352. 4. Levy D, Garrison RJ, Savage DD, et al. Left ventricular mass and incidence of coronary heart disease in elderly cohort. The Framingham Heart Study. Ann Intern Med. 1989;110:101-107. 5. Levy D, Garrison RJ, Savage DD, et al. Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. NEngl JMed. 1990;322:1561-1566. 6. Vasan RS, Levy D. The role of hypertension in the pathogenesis of heart failure. A clinical mechanistic overview. Arch Intern Med. 1996;156:1789-1796. 7. Dahlof B, Pennert K, Hansson L. Reversal of left ventricular hypertrophy in hypertensive patients. A metaanalysis of 109 treatment studies. Am J Hypertens. 1992;5: 95-110. 8. The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med. 1997;157:2413-2446. 9. 1999 World Health Organization-lnternational Society of Hypertension Guidelines for the Management of Hypertension. Guidelines Subcommittee. J Hypertens. 1999; 17:151-183. 10. Guidelines Subcommittee of the Japanese Society of Hypertension. Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH 2000) [in Japanese]. Hypertens R es. 2000(Suppi);20001-20125.
780
M. Shimoyama et aL
11. Psaty BM, Heckbert SR, Koepsell TD, et al. The risk of myocardial infarction associated with antihypertensive drug therapies. JAMA. 1995;274:620-625. 12. Goidbourt U, Behar S, Reicher-Reiss H, et al. Early administration of nifedipine in suspected acute myocardial infarction. The Secondary Prevention Reinfarction Israel Nifedipine Trial 2 Study. Arch Intern Med. 1993;153:345-353. 13. Furberg CD, Psaty BM, Meyer JV. Nifedipine. Dose-related increase in mortality in patients with coronary heart disease. Circulation. 1995;92:1326-1331. 14. Deanfield JE, Detry JM, Lichtlen PR, et al. Amlodipine reduces transient myocardial ischemia in patients with coronary artery disease: Double-blind Circadian AntiIschemia Program in Europe (CAPE) Trial. J A m Coil CardioL 1994;24:1460-1467. 15. Packer M, O'Connor CM, Ghali JK, et al, for the Prospective Randomized Amlodipine Survival Evaluation Study Group. Effect of amlodipine on morbidity and mortality in severe chronic heart failure. N Engl J Med. 1996;335:1107-1114. 16. Pitt B, Byington RP, Furberg CD, et al, for the PREVENT Investigators. Effect of amlodipine on the progression of atherosclerosis and the occurrence of clinical events. Circulation. 2000;102:1503-1510. 17. Miller M, Byington R, Hunninghake D, et al, for the Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial (PREVENT) Investigators. Sex bias and underutilization of lipid-lowering therapy in patients with coronary artery disease at academic medical centers in the United States and Canada. Arch Intern Med. 2000; 160:343-347. 18. Brown MJ, Palmer CR, Castaigne A, et al. Morbidity and mortality in patients randomised to double-blind treatment with a long-acting calcium-channel blocker or diuretic in the International Nifedipine GITS Study: Intervention as a Goal in Hypertension Treatment 0NSIGHT). Lancet. 2000;356:366-372. 19. World Health Organization. Atrial hypertension: Report of a WHO Expert Committee. World Health Organ Tech Res Ser. 1978;628:1-12. 20. Sahn DJ, DeMaria A, Kisslo J, Weyman A. Recommendations regarding quantitation in M-mode echocardiography: Results of a survey of echocardiographic measurements. Circulation. 1978;58:1072-1083. 21. Devereux RB, Reichek N. Echocardiographic determination of left ventricular mass in man. Circulation. 1978;55:613-618. 22. Katz AM. Cardiomyopathy of overload: A major determinant of prognosis in congestive heart failure. NEngl JMed. 1990;322:100-110. 23. Levy D, Larson MG, Vasan RS, et al. The progression from hypertension to congestive heart failure. JAMA. 1996;275:11557-11562. 24. Kohno M, Yasunari K, Yokokawa K, et al. Circulating atrial natriuretic polypeptide in essential hypertension. A m Heart J. 1987;113:1160-1163. 25. Kohno M, Horio T, Yokokawa K, et al. Brain natriuretic peptide as a cardiac hormone in essential hypertension. A m J Med. 1992;92:29-34. 26. Nishikimi T, Yoshihara F, Morimoto A, et al. Relationship between left ventricular geometry and natriuretic peptide levels in essential hypertension. Hypertension. 1996;28:22-30. 27. Kohno M, Horio T, Yokokawa K, et al. Brain natriuretic peptide as a marker for hypertensive left ventricular hypertrophy: Changes during 1-year antihypertensive therapy with angiotensin-converting enzyme inhibitor. A m J Med. 1995;98:257-265. 28. Suzuki M, Yamamoto K, Watanabe S, et al. Association between elevated brain natriuretic peptide levels and the development of left ventricular hypertrophy in patients with hypertension. A m J Med. 2000;108:627-633.
781
CURRENT THERAPEUTIC RESEARCH®
29. Cowie MR, Struthers AD, Wood DA, et al. Value of natriuretic peptides in assessment of patients with possible new heart failure in primary care. Lancet. 1997;350:13491353. 30. Drayer JI, Hall WD, Smith VE, et al. Effect of the calcium channel blocker nitrendipine on left ventricular mass in patients with hypertension. Clin Pharmacol Ther. 1986; 40:679-685. 31. Pahor M, Psaty BM, Alderman MH, et al. Health outcomes associated with calcium antagonists compared with other first-line antihypertensive therapies: A metaanalysis of randomised controlled trials. Lancet. 2000;356:1949-1954. 32. Blood Pressure Lowering Treatment Trialists' Collaboration. Effects of ACE inhibitors, calcium antagonists, and other blood-pressure-lowering drugs: Results of prospectively designed overviews of randomised trials. Lancet. 2000;356:1955-1964. 33. Grundy JS, Foster RT. The nifedipine gastrointestinal therapeutic system (GITS). Evaluation of pharmaceutical, pharmacokinetic and pharmacological properties. C/in Pharmacokinet. 1996;30:28-51.
Address correspondence to: Masaki S h i m o y a m a , MD, PhD Division of Cardiology D e p a r t m e n t of Medicine I Tottori University, Faculty of Medicine 36-1 Nishi-machi, Yonago 683-8504 Japan E-marl: [email protected]
782
Effect of Controlled-Release Nifedipine on Left Ventricular Hypertrophy in Japanese Patients with Hypertension: An Open-Label, Uncontrolled Study Masaki Shimoyama, MD, PhD, 1 Hiroshi Ochi, MD, 1 Shin-ichi Takeda, MD, PhD, 1 Tetsuya Doi, MD, PhD, 2 Yoshiharu Kinugasa, MD, 2 Akihiro Endoh, MD, PhD, 3 Toru Kinugawa, MD, PhD, 3 Kazuhide Ogino, MD, PhD, 3 Ichiro Hisatome, MD, PhD, 3 Chiaki Shigemasa, MD, PhD,3 and Issei Komuro, MD, PhD4
7Department of Medicine, Philanthropic Hospital of Yonago, 2Department of Cardiovascular Medicine, San-in Industrial and Accidental Hospital, 3Division of Cardiology, Department of Medicine I, Tottori University, Faculty of Medicine, Yonago, and 4Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, Chiba, Japan
ABSTRACT
Background: Although the safety and efficacy of various calcium antagonists have been demonstrated in the treatment of hypertension, short-acting nifedipine has been reported to have no beneficial effect in hypertensive patients with myocardial ischemia and heart failure. Objective: The purpose of this study was to examine the tolerability and efficacy of once-daily nifedipine coat-core (CR), a long-acting nifedipine formulation, in the treatment of Japanese patients with hypertension and left ventricular hypertrophy (LVH). Methods: Patients were treated with 40 mg nifedipine CR once daily for 12 months. Blood pressure and heart rate were measured every month. Echocardiography and chest radiography were performed and plasma levels of atrial natriuretic peptide and brain natriuretic peptide were measured before and after 12 months of treatment. Results: A total of 15 hypertensive patients with LVH (6 men and 9 women; mean age, 51 + 3 years; blood pressure, >140/90 mm Hg) were treated. Within 2 months of initiating nifedipine treatment, mean blood pressure was significantly reduced (P < 0.05 vs baseline) to <140/80 mm Hg, and this effect was sustained throughout the 12-month study period. Cardiothoracic ratio was significantly reduced by -13% (P < 0.001 vs baseline). Nifedipine induced regression of LVH, as evidenced by significant decreases (P < 0.001 vs baseline) in interventricular septal wall thickness, left ventricular posterior wall thickness, Acceptedfor publicationAugust21, 2001.
Printed in the USA.Reproduction in whole or part is not permitted.
0011-393X/01/$19.00
773
CURRENT THERAPEUTIC RESEARCH®
left ventricular mass, and left ventricular mass index. Serum levels of natriuretic peptides were also significantly reduced (P < 0.001 vs baseline). There were no significant changes in glucose and lipid metabolism parameters. No patients experienced any adverse events during treatment. Conclusions: The results of this study indicate that treatment with nifedipine CR was well tolerated and resulted in a significant reduction in blood pressure, regression of LVH and cardiac enlargement, and a decrease in serum natriuretic peptide levels in this sample of Japanese hypertensive patients with LVH. These results suggest that long-acting calcium antagonists such as nifedipine CR may be useful in the treatment of hypertensive patients with LVH. Key words: hypertension, left ventricular hypertrophy, calcium antagonist, natriuretic peptide. (Curt Ther Res Clin Exp. 2001;62:773-782)
INTRODUCTION Left ventricular hypertrophy (LVH) is an independent risk factor for cardiovascular morbidity and mortality in patients with hypertension. 1-3 The Framingham Heart Study showed that the risk of acute myocardial infarction and angina pectoris increased in the presence of LVH.4-6 It has also been demonstrated that the incidence of sudden cardiac death and the severity of myocardial infarction are increased in hypertensive patients with LVH.4-6 These results suggest that it is important to treat patients with hypertension and LVH to prevent further cardiovascular complications and that reversal of LVH may decrease cardiovascular morbidity and mortality. Numerous studies have shown that antihypertensive drugs induce regression of hypertensive LVH.7 Calcium antagonists are 1 class of agents recommended in several institutional guidelines 8-1° as a first-line treatment for hypertension. The safety and efficacy of various calcium antagonists in the treatment of hypertension have been well established. However, it has been reported that calcium antagonists are not suitable for the treatment of hypertension because of the increased risk of cardiovascular events associated with these agents. 1~ Nifedipine, a representative short-acting calcium antagonist, has not been reported to reduce mortality in hypertensive patients with ischemic heart disease, possibly because it stimulates the sympathetic nervous system. ~-~3 In contrast, amlodipine, a representative long-acting calcium antagonist, has been demonstrated to reduce mortality and the incidence of cardiovascular events in patients with congestive heart failure or ischemic heart disease possibly because it does not enhance neurohormonal activity. 14-~7 These results suggest that long-acting, but not short-acting, calcium antagonists are suitable for the treatment of patients with hypertension and hypertensive complications.
774
M. Shimoyama et al.
Nifedipine gastrointestinal therapeutic system (GITS), a once-daily, longacting nifedipine formulation, is widely used for the treatment of hypertensive patients. Results from the International Nifedipine GITS Study of Intervention as a Goal in Hypertension Treatment (INSIGHT) trial ~8 indicate that treatment with nifedipine GITS was more effective than diuretics and beta-blockers in controlling blood pressure and reducing cardiovascular and cerebrovascular morbidity and mortality in high-risk hypertensive patients. Nifedipine coat-core (CR), a long-acting, once-daily formulation of nifedipine, has recently become available in Japan. Nifedipine CR consists of a tablet and a hydrophilic matrix (an expandable hydrogel layer of polyethylene oxide and hydroxypropylmethylcellulose) that releases the drug slowly from the tablet as it erodes. However, the effects of nifedipine CR in patients with hypertension and with various hypertensive complications have not been clarified. Therefore, in this study, we sought to determine the tolerability and efficacy of nifedipine CR in Japanese patients with essential hypertension and LVH.
PATIENTS AND METHODS Entry Criteria and Screening Between April 1999 and July 1999, -200 hypertensive patients in the Department of Medicine, Philanthropic Hospital of Yonago, Yonago, Japan, were screened. Patients underwent routine laboratory testing, including assays for serum electrolytes, serum creatinine, blood urea nitrogen, fasting blood glucose, immunoreactive insulin, total cholesterol, high-density lipoprotein cholesterol (HDL-C), and triglycerides, as well as chest radiography and electrocardiography. Previously untreated patients with essential hypertension and LVH were enrolled based on the results of the laboratory tests and guidelines of the World Health Organization. ~9 Patients could not have been treated with any antihypertensive drugs or drugs that could influence blood pressure. Hypertension was defined as systolic blood pressure (SBP) >140 mm Hg or diastolic blood pressure (DBP) ->90 mm Hg. Blood pressure and heart rate were measured on at least 2 separate days before treatment. Secondary hypertension was excluded based on a clinical history, physical examination, routine laboratory tests 0ncluding measurements of plasma renin activity, aldosterone, catecholamine, and cortisoi), and an excretory urogram or renal arteriogram. Patients who had signs or symptoms of cardiac or renal failure, diabetes, pulmonary disease, angina pectoris, or myocardial infarction were excluded. Informed consent was obtained from all study participants. To confirm the presence of hypertensive LVH, echocardiography was recorded and left ventricular mass (LVM) and LVM index (LVMI) were calculated according to the formulas of the American Society of Echocardiography. 2°'21 Asymmetric septal hypertrophy was ruled out. In addition, serum concentrations of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) were measured.
775
CURRENT THERAPEUTICRESEARCH®
Study Design After the initial evaluation, enrolled patients were treated with a 40-mg tablet of nifedipine CR once daily for 12 months. Every month, patients made hospital visits, during which blood pressure and heart rate were measured and physical examinations were performed. Echocardiography, plasma ANP and BNP concentration measurements, and routine laboratory tests were performed before the initiation of therapy and after 1 year of therapy with nifedipine CR. Cardiologists blinded to the study objectives assessed the findings on echocardiography and chest radiography. Statistical Analysis Continuous variables were compared using the Student t test. P < 0.05 was considered statistically significant. RESULTS A total of 15 patients (6 men and 9 women; mean age, 51 + 3 years; range, 35-64 years) were enrolled. Before treatment, all patients had severe hypertension (mean BP, 196.5/110.5 mm Hg) (Figure). Hypercholesterolemia was observed in 5 patients at baseline, and HDL-C levels were low in 2 patients. Triglyceride and insulin levels were high in 8 and 2 patients, respectively. However, no lipid-lowering drug was administered because the hypercholesterolemia and hypertriglyceridemia were mild (HDL-C, 220-240 mg/dL; triglycerides, 150-230 mg/dL). After 12 months of once-daily treatment with nifedipine CR 40 mg, both SBP and DBP were reduced significantly from baseline (P < 0.001), and 2 months of treatment with nifedipine CR lowered both SBP and DBP to <140/80 mm Hg (P < 0.05 vs baseline) (Figure). The antihypertensive effect of nifedipine CR continued throughout the 12-month treatment period (Figure). Nifedipine CR had no significant effect on heart rate or glucose and lipid metabolism parameters (Figure, Table I). Chest radiography revealed that the cardiothoracic ratio, a measure of cardiac size, was significantly reduced by -13% after treatment (P < 0.001 vs baseline) (Table II). No patients complained of any adverse effects (eg, flushing, headache, palpitation, abdominal discomfort, edema). Echocardiography findings showed a significant reduction in the thickness of the interventricular septal wall and the left ventricular posterior wall (25% and 31%, respectively; P < 0.001 vs baseline) after treatment with nifedipine CR (Table IF). LVM and LVMI were also significantly decreased after treatment (41% and 49%, respectively; P < 0.001 vs baseline) (Table I1). Fractional shortening and the E/A wave ratio increased significantly after treatment with nifedipine CR (P < 0.05 and P < 0.001, respectively) (Table II). The plasma concentration of BNP, but not that of ANP, was significantly elevated before treatment. The BNP level was significantly reduced by 89% (P < 0.001 vs baseline) and was normalized after treatment (Table II). Treatment
776
M. Shimoyama et al.
20O 180 160
140 120
I
I
0
6
ll2
;
;
;2
120 110
~
9o 8O
70
C
100
o~
E e~
75
2=
50
I
0
I
6
112
Time (month)
Figure. The effect of nifedipine coat-core treatment on (A) systolic blood pressure (SBP), (B) diastolic blood pressure (DBP), and (C) heart rate. Data are expressed as mean _+ SEM. *P < 0.05 versus baseline (month 0).
with nifedipine CR also induced a significant 66% decrease in plasma ANP levels (P < 0.001) (Table II). DISCUSSION
The results of this study suggest that treatment with nifedipine CR was well tolerated and induced significant regression of LVH and cardiac enlargement
777
CURRENT THERAPEUTIC RESEARCH®
Table I. Effects of 12 months of t r e a t m e n t w i t h nifedipine coat-core on serum biochemistry parameters in Japanese hypertensive patients w i t h left ventricular hypertrophy. Baseline FBS, m g / d L IRI, IJU/mL TC, m g / d L TG, m g / d L HDL-C, m g / d L BUN, m g / d L Cr, m g / d L Sodium, mEq/L Potassium, mEq/L Chloride, mEq/L
94.9 7.87 209.3 175.6 43.2 14.9 0.72 140.2 3.9 97.5
± ± ± ± ± ± ± ± + ±
1.9 0.78 7.9 13.8 3.5 2.9 0.21 2.5 0.9 2.9
12 Months 96.1 9.03 209.1 169.0 44.4 13.2 0.73 138.9 4.0 95.9
± 1.7 ± 0.95 +__ 6.9 ± 11.7 + 3.3 ___ 3.4 + 0.19 _ 3.0 ± 0.7 ± 3.7
Reference Values 60-110 <5 120-220 50-150 40-87 9-24 0.8-1.2 135-147 3.6-5.0 98-108
FBS = fasting blood glucose; IRI = immunoreactive insulin; TC = serum total cholesterol; TG = triglycerides; HDL-C = high-density lipoprotein cholesterol; BUN = blood urea nitrogen; Cr = creatinine.
along with a marked reduction of natriuretic peptide levels and improvement of left ventricular systolic and diastolic function in h y p e r t e n s i v e patients with LVH. Hypertrophy of the heart often leads to dilated cardiomyopathy and eventually causes congestive heart failure after sustained overload. 22'23 In addition,
T a b l e II. Effects of 12 months of t r e a t m e n t w i t h nifedipine coat-core on hypertensive cardiac hypertrophy, left ventricular function, cardiac size, and natriuretic peptides. Baseline Height, cm Body weight, kg Dd, m m Ds, m m IVS, m m PW, m m LVM, g LVMI, g / m 2 FS, % E/A wave ratio CTR, % ANP, p g / m L BNP, p g / m L
162.5 63.9 46.00 28.33 13.00 13.47 297.96 1 79.79 37.30 0.52 55.20 37.27 108.21
+ 2.1 + 13.0 ± 1.15 ± 0.49 ± 0.52 ± 0.39 ± 17.30 ± 13.01 ± 1.72 ± 0.05 ___ 0.75 ± 5.44 ± 19.25
12 Months 162.5 63.3 44.07 25.87 9.80 9.33 175.19 105.86 42.47 0.76 47.87 12.67 11.32
+ 2.1 ± 6.8 + 1.04 + 0.49* ± 0.36 t ± 0.25 t ± 9.00 t ___ 6.75 t + 1.40" ± 0.07 t + 0.95 t ± 1.03 t ± 2.83 t
Reference Values --41-51 30-42 7-11 7-11 -->28 >1.0 <50 <40 <20
Dd = left ventricular dimensions at end diastole; Ds = left ventricular dimensions at end systole; IVS = interventricular septal wall thickness; PW = left ventricular posterior wall thickness; LVM = left ventricular mass; LVMI = LVM index; FS = fractional shortening; CTR = cardiothoracic ratio; ANP = atrial natriuretic peptide; BNP = brain natriuretic peptide. *P < 0.05 versus baseline, tp < 0.001 versus baseline.
778
M. Shimoyama et aL
plasma levels of ANP and BNP have been reported to increase in patients with essential hypertension who have LVH,24-26 and plasma BNP levels are known to decrease with regression of LVH.27'28 BNP is known to be a useful biochemical marker of left ventricular dysfunction and hypertensive LVH and has diagnostic, therapeutic, and prognostic implications. 29 Thus, the LVH regression and reduction of BNP levels observed in this study suggest that nifedipine CR may be useful in the treatment of hypertensive LVH and in the prevention of hypertensive heart failure. Nifedipine has been reported to be of little benefit in the treatment of hypertension, possibly because it induces reflex stimulation of the sympathetic nervous system and neurohormonal activation. 11-13 In addition, it has been reported that nitrendipine, another short-acting calcium antagonist, does not induce the regression of left ventricular wall thickness or LVM, although it does lower blood pressure. 3° However, amlodipine, a long-acting calcium antagonist, has been shown to be effective in the treatment of hypertension possibly because it does not enhance neurohormonal activity. ~4-17 These observations suggest that long-acting calcium antagonists, but not short-acting calcium antagonists, may be beneficial in the treatment of hypertension. Results of the INSIGHT trial ~8 indicate that treatment with nifedipine GITS, a long-acting formulation, was more effective than diuretics and beta-blockers in controlling blood pressure and reducing cardiovascular and cerebrovascular morbidity and mortality in high-risk hypertensive patients. These results suggest that the long-acting calcium antagonists may be useful in the treatment of hypertensive patients with complications such as LVH. Two recent meta-analyses of large clinical trials in hypertensive patients revealed that treatment with calcium antagonists reduced the incidence of cardiovascular events compared with placebo. 3~'32 In addition, treatment with calcium antagonists reduced the incidence of stroke compared with treatment with diuretics or beta-blockers. However, treatment with calcium antagonists has not been shown to reduce the occurrence of coronary heart disease and heart failure in hypertensive patients. 3~'32 Nevertheless, since most of the previous large clinical trials of calcium antagonists examined the effects of shortacting agents, the effects of long-acting agents are still not known. Additional large clinical trials of long-acting calcium antagonists are needed. Nifedipine CR consists of a coat-core tablet and a hydrophilic matrix (an expandable hydrogel layer of polyethylene oxide and hydroxypropylmethylcellulose) that releases the drug slowly as it erodes. The diameters of the coatcore tablet and the core are 9 mm and 5 ram, respectively. The coat-core tablet is coated with common film-forming materials and pigments used to protect photodegradation of nifedipine. Drug concentrations after administration of the nifedipine CR formulation peak within 4 hours after administration, and are sustained at that level at least 24 hours after administration. Nifedipine GITS differs from the nifedipine CR formulation in that it involves an osmotic pump process that provides approximately zero-order delivery of the drug. 33 Drug
779
CURRENT THERAPEUTIC RESEARCH®
c o n c e n t r a t i o n s f r o m t h e nifedipine GITS f o r m u l a t i o n p e a k within 6 h o u r s after a d m i n i s t r a t i o n a n d are s u s t a i n e d until at least 24 h o u r s after a d m i n i s t r a t i o n . In this study, we i n v e s t i g a t e d the effects of nifedipine CR on h y p e r t e n s i o n and on h y p e r t e n s i v e LVH. However, this w a s an open-label, u n c o n t r o l l e d study; therefore, we could not e v a l u a t e w h e t h e r this d r u g w a s s u p e r i o r to o t h e r ant i h y p e r t e n s i v e drugs. In addition, since nifedipine GITS w a s not available in Japan, we could not c o m p a r e nifedipine CR with nifedipine GITS. N e v e r t h e l e s s , it is well k n o w n t h a t effective a n t i h y p e r t e n s i v e t h e r a p y r e d u c e s t h e incidence of c a r d i o v a s c u l a r e v e n t s in h y p e r t e n s i v e patients. CONCLUSIONS T h e results of this s t u d y indicate t h a t nifedipine CR w a s well t o l e r a t e d and i n d u c e d a significant r e d u c t i o n in b l o o d p r e s s u r e , r e g r e s s i o n of LVH and cardiac e n l a r g e m e n t , a n d a d e c r e a s e in s e r u m natriuretic p e p t i d e levels in this s a m p l e of J a p a n e s e h y p e r t e n s i v e p a t i e n t s with LVH. T h e s e r e s u l t s s u g g e s t t h a t long-acting calcium a n t a g o n i s t s m a y b e useful in the t r e a t m e n t of h y p e r t e n s i v e p a t i e n t s with LVH. REFERENCES 1. Multiple Risk Factor Intervention Trial Research Group. Multiple Risk Factor Intervention Trial. Risk factor changes and mortality results. JAMA. 1982;248:1465-1477. 2. Messerli FH, Ventura HO, Elizardi DJ, et al. Hypertension and sudden death. Increased ventricular ectopic activity in left ventricular hypertrophy. Am J Med. 1984; 77:18-22. 3. Koren MJ, Devereux RB, Casale PN, et al. Relation of left ventricular mass and geometry to morbidity and mortality in uncomplicated essential hypertension. Ann Intern Med. 1991;114:345-352. 4. Levy D, Garrison RJ, Savage DD, et al. Left ventricular mass and incidence of coronary heart disease in elderly cohort. The Framingham Heart Study. Ann Intern Med. 1989;110:101-107. 5. Levy D, Garrison RJ, Savage DD, et al. Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. NEngl JMed. 1990;322:1561-1566. 6. Vasan RS, Levy D. The role of hypertension in the pathogenesis of heart failure. A clinical mechanistic overview. Arch Intern Med. 1996;156:1789-1796. 7. Dahlof B, Pennert K, Hansson L. Reversal of left ventricular hypertrophy in hypertensive patients. A metaanalysis of 109 treatment studies. Am J Hypertens. 1992;5: 95-110. 8. The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med. 1997;157:2413-2446. 9. 1999 World Health Organization-lnternational Society of Hypertension Guidelines for the Management of Hypertension. Guidelines Subcommittee. J Hypertens. 1999; 17:151-183. 10. Guidelines Subcommittee of the Japanese Society of Hypertension. Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH 2000) [in Japanese]. Hypertens R es. 2000(Suppi);20001-20125.
780
M. Shimoyama et aL
11. Psaty BM, Heckbert SR, Koepsell TD, et al. The risk of myocardial infarction associated with antihypertensive drug therapies. JAMA. 1995;274:620-625. 12. Goidbourt U, Behar S, Reicher-Reiss H, et al. Early administration of nifedipine in suspected acute myocardial infarction. The Secondary Prevention Reinfarction Israel Nifedipine Trial 2 Study. Arch Intern Med. 1993;153:345-353. 13. Furberg CD, Psaty BM, Meyer JV. Nifedipine. Dose-related increase in mortality in patients with coronary heart disease. Circulation. 1995;92:1326-1331. 14. Deanfield JE, Detry JM, Lichtlen PR, et al. Amlodipine reduces transient myocardial ischemia in patients with coronary artery disease: Double-blind Circadian AntiIschemia Program in Europe (CAPE) Trial. J A m Coil CardioL 1994;24:1460-1467. 15. Packer M, O'Connor CM, Ghali JK, et al, for the Prospective Randomized Amlodipine Survival Evaluation Study Group. Effect of amlodipine on morbidity and mortality in severe chronic heart failure. N Engl J Med. 1996;335:1107-1114. 16. Pitt B, Byington RP, Furberg CD, et al, for the PREVENT Investigators. Effect of amlodipine on the progression of atherosclerosis and the occurrence of clinical events. Circulation. 2000;102:1503-1510. 17. Miller M, Byington R, Hunninghake D, et al, for the Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial (PREVENT) Investigators. Sex bias and underutilization of lipid-lowering therapy in patients with coronary artery disease at academic medical centers in the United States and Canada. Arch Intern Med. 2000; 160:343-347. 18. Brown MJ, Palmer CR, Castaigne A, et al. Morbidity and mortality in patients randomised to double-blind treatment with a long-acting calcium-channel blocker or diuretic in the International Nifedipine GITS Study: Intervention as a Goal in Hypertension Treatment 0NSIGHT). Lancet. 2000;356:366-372. 19. World Health Organization. Atrial hypertension: Report of a WHO Expert Committee. World Health Organ Tech Res Ser. 1978;628:1-12. 20. Sahn DJ, DeMaria A, Kisslo J, Weyman A. Recommendations regarding quantitation in M-mode echocardiography: Results of a survey of echocardiographic measurements. Circulation. 1978;58:1072-1083. 21. Devereux RB, Reichek N. Echocardiographic determination of left ventricular mass in man. Circulation. 1978;55:613-618. 22. Katz AM. Cardiomyopathy of overload: A major determinant of prognosis in congestive heart failure. NEngl JMed. 1990;322:100-110. 23. Levy D, Larson MG, Vasan RS, et al. The progression from hypertension to congestive heart failure. JAMA. 1996;275:11557-11562. 24. Kohno M, Yasunari K, Yokokawa K, et al. Circulating atrial natriuretic polypeptide in essential hypertension. A m Heart J. 1987;113:1160-1163. 25. Kohno M, Horio T, Yokokawa K, et al. Brain natriuretic peptide as a cardiac hormone in essential hypertension. A m J Med. 1992;92:29-34. 26. Nishikimi T, Yoshihara F, Morimoto A, et al. Relationship between left ventricular geometry and natriuretic peptide levels in essential hypertension. Hypertension. 1996;28:22-30. 27. Kohno M, Horio T, Yokokawa K, et al. Brain natriuretic peptide as a marker for hypertensive left ventricular hypertrophy: Changes during 1-year antihypertensive therapy with angiotensin-converting enzyme inhibitor. A m J Med. 1995;98:257-265. 28. Suzuki M, Yamamoto K, Watanabe S, et al. Association between elevated brain natriuretic peptide levels and the development of left ventricular hypertrophy in patients with hypertension. A m J Med. 2000;108:627-633.
781
CURRENT THERAPEUTIC RESEARCH®
29. Cowie MR, Struthers AD, Wood DA, et al. Value of natriuretic peptides in assessment of patients with possible new heart failure in primary care. Lancet. 1997;350:13491353. 30. Drayer JI, Hall WD, Smith VE, et al. Effect of the calcium channel blocker nitrendipine on left ventricular mass in patients with hypertension. Clin Pharmacol Ther. 1986; 40:679-685. 31. Pahor M, Psaty BM, Alderman MH, et al. Health outcomes associated with calcium antagonists compared with other first-line antihypertensive therapies: A metaanalysis of randomised controlled trials. Lancet. 2000;356:1949-1954. 32. Blood Pressure Lowering Treatment Trialists' Collaboration. Effects of ACE inhibitors, calcium antagonists, and other blood-pressure-lowering drugs: Results of prospectively designed overviews of randomised trials. Lancet. 2000;356:1955-1964. 33. Grundy JS, Foster RT. The nifedipine gastrointestinal therapeutic system (GITS). Evaluation of pharmaceutical, pharmacokinetic and pharmacological properties. C/in Pharmacokinet. 1996;30:28-51.
Address correspondence to: Masaki S h i m o y a m a , MD, PhD Division of Cardiology D e p a r t m e n t of Medicine I Tottori University, Faculty of Medicine 36-1 Nishi-machi, Yonago 683-8504 Japan E-marl: [email protected]
782