Keerati Hantrakool, MD, and Jarkarpun Chaipromprasit, MD. Division of Cardiology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand. Abstract Objectives: To determine whether the blockade of histamine H 2 -receptors using ranitidine is beneficial for the pathophysiology of chronic heart failure (CHF). Background: Because the β 1 -adrenergic blocking agent is beneficial for the pathophysiology of CHF and because activated H 2 -receptors cause activation of Gs-protein the same way as activated β 1 -adrenergic receptors do, it appears reasonable that H 2 -receptor blocking agents may be beneficial for the treatment of CHF. Methods: 50 stable symptomatic CHF patients were randomly divided into 2 groups. One group received ranitidine 300 mg/day for 16 weeks, and the other group received placebo for the same period of time. Blood levels of NTproBNP and left ventricular function obtained by echocardiography were recorded both before and after treatment in both groups. Results: Ranitidine 300 mg/d increased plasma NTproBNP levels (from 2,131 ± 3,039 pg/ml to 2,811 ± 4,714 pg/ml) while placebo decreased plasma NTproBNP levels (from 1,710 ± 1,796 pg/ml to 1,485 ± 1,660 pg/ml) but without statistical significance (p = 0.262). Conclusions: Ranitidine did not decrease NTproBNP levels in CHF patients within a 16 weeks period. Key words: Chronic Heart Failure, Ranitidine, B-Type Natriuretic Peptide, N-Terminal Pro-B-Type Natriuretic Peptide Thai Heart J 2008; 21 : 71-77 E-Journal : http://www.thaiheartjournal.org Introduction In the past, we believed that chronic heart failure (CHF) was a Cardiorenal Model and was a process of salt and water retention (1). Although diuresis did improve the symptoms, unfortunately, no mortality benefit was obtained. Later, we recognized that a Hemodynamic Model could be the cause as a result of left ventricle (LV) dysfunction (1). In order to improve the LV contraction, we pushed the heart to its limit, using an inotropic drug, a vasodilator along with diuresis. But the result was somewhat of a paradox, the mortality rate was significantly raised (2-4). And no matter what treatment we applied to patients, the disease was still in progress (1). Presently, we have recognized the pathophysiology of CHF as a Neurohormonal Model (1). When the heart failed, it activated the catecholamine and renninangiotensin-aldosterone systems. In the early phase, it helped improve the symptoms, unfortunately in the long term; there was a greater chance for the heart to fail. Correspondence to: Keerati Hantrakool, MD. Division of Cardiology, Department of Medicine, Faculty of Medicine Chulalongkorn University, Bangkok, Thailand. To begin with, the β 1 -adrenergic receptor of the catecholamine system which are abundantly found in the myocardium is the focus. When the β 1 -receptor is activated, it couples with the stimulatory G protein (G S ) which results in accumulation of cyclic adenosine monophosphate (camp) and eventually, results in the increase of intracellular calcium ion. As mentioned above, the calcium ion stimulates the heart to beat harder but in the long term, it will lead to a necrotic and apoptotic process of the myocardium. Moreover, the camp can signal the myocardium and cause it to change its structure and function. However, recently, the evidence shows that the use of a β 1 -blocker can reduce the mortality rate and slow the progression of the disease (5-8). β 1 -blockers have been one of the mainstay treatments of CHF (9-10) but notwithstanding, it cannot be used in a certain group of patients (11). In the treatment of gastric disease, we have been using histamine-2 receptor antagonists (H 2 -blocker) for decades. But the H 2 -receptor is also found at the myocardium when it was activated. It couples the G S protein the same way, although it has less potency than the β 1 -receptor agonist (12-13). So it appears that the H 2 -blocker may have a benefit in the treatment of CHF. The objective of
this study was to determine whether the blockade of histamine H 2 -receptors using ranitidine is beneficial for the pathophysiology of CHF. We conducted a doubleblind randomized placebo-controlled trial using ranitidine for treatment of CHF. Methods Outpatients from King Chulalongkorn Memorial Hospital who had stable CHF were enrolled. The inclusion criteria were patients between 15-80 years old with a left ventricular ejection fraction less than 45% from the following: cardiomyopathy; hypertensive heart disease; ischemic heart disease. The exclusion criteria were: pregnancy; severe liver or kidney disease; chronic obstructive pulmonary disease; pulmonary thromboembolism; isolated right-sided heart failure; severe valvular heart disease; intracardiac shunt; short life expectancy and patients who might not attend the program. This protocol was approved by the local ethical committees and the informed consent was obtained from all participating patients. Baseline characteristics were also recorded. The patients then were randomized into two groups. One treatment group received ranitidine 150 mg tablet twice a day, the other group received a placebo tablet twice a day for a period of 4 months. The quality of life was assessed by a questionnaire which asked how difficulty to do the daily activity. The echocardiography was performed by one physician who was blinded to the treatment group. Left ventricular ejection fraction (LVEF), left ventricular (LV) dimension, mitral inflow velocity and mitral annulus tissue velocity were recorded. The plasma level of amino-terminal pro-b type natriuresis peptide (NTproBNP) was measured before and after the treatment. Statistical analyses Statistical analysis was performed using the Statistical Package for the Social science version 16 (SPSS, Inc, Chicago, IL, USA). The use of Chi-square for qualitative data was applied. An independent-t-test for quantitative data and ANCOVA were also used to compare pre and post treatment data. All data presented in mean ± SD. A p-value of less than 0.05 was considered significant. Keerati Hantrakool, MD, and Jarkarpun Chaipromprasit, MD Results There were 50 patients randomized, 25 in each group. There were 2 patients who were lost to follow up in the ranitidine group and 3 patients in the placebo group. So there were 45 patients who completed the study. As shown in Table 1, there was no difference between both groups in terms of gender, age, body mass index, underlying disease and New York Heart Association (NYHA) functional class. Two thirds of the patients were male, the average age was 60 years old and most patients were in the NYHA functional class II. The average ejection fraction measured by the Simpson method was 30%. There were no differences between the groups in patients receiving Digitalis, a Loop diuretic, Nitrates, β 1 - blockers, an Angiotensin Converting Enzyme Inhibitor (ACEI), an Angiotensin II Receptor Blocker (ARB), and a Statin. However, in the ranitidine group patients received an Aldosterone Antagonist more than the placebo group. The ranitidine group had baseline plasma NT probnp levels of 2,131 ± 3,039 pg/ml while in the placebo group had 1,710 ± 1,796 pg/ml (p = 0.577). The plasma NTproBNP level in both groups was not in normal distribution due to high range nature of this value so logarithm transformation was performed which showed normal distributed data. At the end of the study, as shown in Table 2, the left ventricular internal diameter during systole in the placebo group had a slightly less value than the ranitidine group but when calculated to the fractional shortening and ejection fraction, it did not show any significant difference. There was no significant change in the NTproBNP levels among these two groups. Interestingly, the standard deviation of change in the NTproBNP levels of the ranitidine group is far greater than the Placebo group (3,818 and 589 pg/ml respectively). No patient from the placebo group complained about side effects while there were 3 patients from the ranitidine group who did. One had dizziness, one had a rash and one reported erectile dysfunction. Fortunately these side effects disappeared when ranitidine was discontinued. One patient in each group had heart failure worsening and required hospitalization.
Table 1. Baseline characteristics. Baseline Characteristic Gender Male Female Age Body mass index Underlying disease Diabetes melolitus Hypertension Ischemic heart disease Cardiomyopathy NYHA Functional class Fc I Fc II Fc III Systolic blood pressure Diastolic blood pressure Heart rate NT-proBNP Log (NT-proBNP) LV function LV diameter - diastole LV diameter - systole Fractional shortening LVEF (Teicholz) LVEF (Simpson) Medication Digitalis Loop diuretic Nitrate Beta-blocker ACEI ARB Spironolactone Statin Placebo group (n = 22) 16 (65.2%) 6 (34.8%) 61.7 ± 9.9 24.42 ± 3.99 9 (40.9%) 8 (36.4%) 10 (45.5%) 12 (54.5%) 0 (0%) 21 (91.3%) 2 (8.7%) 124.9 ± 21.0 75.5 ± 9.1 73.3 ± 13.0 1,710 ± 1,796 3.01 ± 0.48 62.6 ± 12.6 53.0 ± 12.6 15.9 ± 4.6 32.7 ± 8.8 30.7 ± 7.9 11 (50%) 17 (77.3%) 6 (27.3%) 12 (54.5%) 19 (86.4%) 3 (13.6%) 5 (22.7%) 11 (50.0%) Ranitidine group (n = 23) 15 (72.7%) 8 (27.3%) 59.2 ± 12.1 24.87 ± 4.85 9 (39.1%) 6 (26.1%) 15 (65.2%) 8 (34.8%) 1 (4.5%) 19 (88.9%) 2 (9.1%) 121.0 ± 20.8 74.7 ± 10.9 71.7 ± 13.5 2,131 ± 3,039 2.98 ± 0.59 61.3 ± 11.0 51.2 ± 11.8 16.5 ± 5.8 33.5 ± 11.0 29.0 ± 10.9 10 (43.5%) 20 (87.0%) 4 (17.4%) 15 (65.2%) 16 (69.6) 3 (13.0%) 13 (56.5%) 16 (69.6%) p-value 0.824 0.460 0.738 1.000 0.673 0.301 0.301 0.583 0.538 0.790 0.691 0.577 0.887 0.718 0.629 0.735 0.784 0.557 0.889 0.646 0.661 0.670 0.319 1.000 0.045 0.301
Keerati Hantrakool, MD, and Jarkarpun Chaipromprasit, MD Table 2. Pre and post treatment data between ranitidine and placebo group. Characteristic Weight Body mass index Systolic blood pressure Diastolic blood pressure Heart rate NT-proBNP NT-proBNP changeds Log (NT-proBNP) Log (NT-proBNP) Changeds LV function LV diameter - diastole LV diameter - systole Fractional shortening LVEF (Teicholz) LVEF (Simpson) Questionnaires score Control group (n=22) 63.3 ± 13.7 24.75 ± 4.29 128.1 ± 16.7 76.4 ± 8.7 74.8 ± 15.6 1,485 ± 1,660-225 ± 590 2.88 ± 0.59-0.125 ± 0.389 62.3 ± 11.4 50.1 ± 13.6 20.8 ± 9.0 40.3 ± 15.4 33.7 ± 13.5 19.6 ± 14.8 Ranitidine group (n=23) 65.4 ± 17.3 25.37 ± 4.95 127.8 ± 32.3 76.9 ± 12.5 70.7 ± 14.9 2,811 ± 4,714 680 ± 3,819 2.98 ± 0.68-0.001 ± 0.420 64.8 ± 11.9 53.8 ± 13.4 17.7 ± 8.3 35.2 ± 14.9 32.3 ± 12.5 20.2 ± 14.9 p-value 0.667 0.688 0.626 0.722 0.375 0.262 0.273 0.323 0.313 0.073 0.005 0.060 0.072 0.963 0.861 Discussion There was no statistical significance when both groups were compared in terms of NTproBNP levels, LV ejection fraction (Simpson method), NYHA function class or quality of life scores. From a previous study (14), it was shown that the usage of famotidine in CHF could decrease the plasma level of B-type natriuretic peptide (BNP). It is interesting why this result did not occur when using ranitidine. First, it may be because it is not a class effect. We know that β 1 -blockers are not a class effect to treat CHF (9-10). This may be also true for the H 2 -blockers, otherwise it could be that ranitidine has less potency than famotidine. Second, a H 2 -blocker has less potency than a β 1 - blocker, so its effect cannot outrun the β 1 -blocker s effect. And most importantly, there is an excessive amount of catecholamine stimulation (15-16) left in these patients which can reduces the H 2 -blocker s effect. Moreover, there are other proliferative signaling pathways that do not pass via the production of camp (17) and this whole process can worsen the pathophysiology of CHF. Third, the H 2 -blockers have a short half life. We had learned from a previous study that controlled release long half life metoprolol succinate form has more benefits than the short half life metoprolol tartrate form (7, 18-19). The action of the medicine used for CHF should last around the clock, and discontinuation of drug action will result in insufficiency of the treatment. Forth, there are reports about tolerance to H 2 - blockers. H 2 -blockers when administered to patients for more than a month have failed to continuously reduce gastric ph as they previously had. Whether or not this can apply to the heart is still unknown. Fifth, there are a lot of biological variations of the NTproBNP (20-22). It is said that the change in both BNP and NTproBNP value can be declared statistically significant only if their changes exceed 66-113% and 49-98% respectively (21-22). These changes may explain
why the NTproBNP levels vary. However, many studies show that the change in value of BNP or NTproBNP level which still don t exceed the values mentioned above (66-113% and 49-98% respectively) still have prognostic value (23). So, we may use them to monitor the treatment outcome. Sixth, the duration of treatment may be too short. According to the previous study, it has shown that a β 1 - blocker can decrease BNP levels by 3 months (24). Ranitidine may not display these benefits within the same extent and more time may be needed. Seventh, patient selection may be biased. Half of the patients enrolled received a β 1 -blocker and two thirds of all received ACEI while most of them did not receive the optimal doses of these drugs. Moreover, these are the differences from the previous trial when all the patients received optimal doses of both a β 1 -blocker and ACEI (14). Finally, the H 2 -blocker may not be of benefit for the treatment of CHF at all. The limitation of the study included the short duration of treatment, small sample size, patient selection bias as mentioned above and the echocardiographic data dependency on the operator. The questionnaires have not yet been standardized and validated. Conclusion Within 4 months, it is not beneficial to treat CHF patients using ranitidine when considering the factors of NTproBNP level; NYHA Functional class status; Left ventricular systolic function measured by echocardiography and quality of life. There should be a further study using a longer period, or using a longer half life medication such as an extended release or controlled release form. Moreover, there should be a comparison between the patients who previously received a β 1 -blocker and ones whom did not. Finally, a comparison between a group who has different levels of blood pressure, heart rate and left ventricular ejection fraction should be studied because these factors may give a totally different result. Acknowledgement The authors would like to thank Berlin Pharmaceutical Company who supplied the study drugs and Roche Diagnostics who supplied the NTproBNP Test for their generous and invaluable support. Both companies were not involved in the study design, patient selection, data collection and analysis process. References 1. Mann DL, Bristow MR. Mechanisms and Models in Heart Failure: The Biomechanical Model and Beyond. Circulation 2005; 111: 2837-49. 2. Packer M, Carver JR, Rodeheffer RJ, et al. Effect of oral milrinone on mortality in severe chronic heart failure. The PROMISE Study Research Group. N Engl J Med 1991; 325: 1468-75. 3. Cohn JN, Goldstein SO, Greenberg BH, et al. A Dose-Dependent Increase in Mortality with Vesnarinone among Patients with Severe Heart Failure. N Engl J Med 1998; 339: 1810-6. 4. Feldman AM, Bristow MR, Parmley WW, et al. Effects of Vesnarinone on Morbidity and Mortality in Patients with Heart Failure. N Engl J Med 1993; 329: 149-55. 5. Packer M, Fowler MB, Roecker EB, et al. Effect of Carvedilol on the Morbidity of Patients With Severe Chronic Heart Failure: Results of the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) Study. Circulation 2002; 106: 2194-9. 6. A randomized trial of beta-blockade in heart failure. The Cardiac Insufficiency Bisoprolol Study (CIBIS). CIBIS Investigators and Committees. Circulation 1994; 90: 1765-73. 7. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in-congestive Heart Failure (MERIT-HF). Lancet 1999; 353: 2001-7. 8. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet 1999; 353: 9-13. 9. Hunt SA. ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure). J Am Coll Cardiol 2005; 46: e1-82. 10. Authors/Task Force M, Swedberg K, Writing C, et al. Guidelines for the diagnosis and treatment of chronic heart failure: executive summary (update 2005): The Task Force for the Diagnosis and Treatment of Chronic Heart Failure of the European Society of Cardiology. Eur Heart J 2005; 26: 1115-40. 11. Lechat P, Escolano S, Golmard JL, et al. Prognostic Value of Bisoprolol-Induced Hemodynamic Effects in Heart Failure During the Cardiac Insufficiency BIsoprolol Study (CIBIS). Circulation 1997; 96: 2197-205. 12. Johnson CL, Weinstein H, Green JP. Studies on Histamine H2 Receptors Coupled to Cardiac Adenylate Cyclase: Blockade by H2 and H1 Receptor Antagonists. Mol Pharmacol 1979; 16: 417-28.
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ก ก ก ก ก.., ก.. ก : ก ก ก 2 ก ก ก : ก ก ก ก ก 2 กก ก ก ก กก ก ก 2 ก ก ก : 50 ก ก 2 ก ก ก 300 ก 16 ก ก ก ก ก NTproBNP, ก ก ก ก ก ก ก ก : ก 300 ก NT-proBNP ( ก 2,131 ± 3,039 pg/ml 2,811 ± 4,714 pg/ml) NT-proBNP ก ก ( ก 1,710 ± 1,796 pg/ml 1,485 ±1,660 pg/ml) (p = 0.262) : NT-proBNP 16