Chronic stable angina is a common condition associated with significant morbidity and mortality. Despite the availability of traditional pharmacologic approaches, as well as surgical and percutaneous revascularization, many patients continue to have symptoms of angina.1 Therefore, there continues to be a need for the development of novel approaches to the therapy of angina.2
Early studies suggested that both phlebotomy and therapy with diuretics had favorable effects on the development of myocardial ischemia.3,4 In a study designed to determine if diuretic therapy could prevent nitrate tolerance, the combination of hydrochlorothiazide and amiloride was documented to have significant antianginal effects.5 In this report it was hypothesized that the observed antianginal effect might have resulted from sustained effects of the diuretic on intravascular volume and/or the unique effects of amiloride. Amiloride, the prototypical compound of a family of sodium/hydrogen exchange inhibitor, has been shown to have a protective effect on the myocardium in the setting of acute ischemia.6-8 Prevention of nitrate tolerance was the focus of that investigation, and therapy with calcium channel antagonists and beta blockers was not permitted.
Therefore, the ability of diuretic therapy to improve exercise capacity in patients treated with other antianginal therapy remains unknown. The aim of the present study was to evaluate whether therapy with a diuretic has antianginal effects in patients with stable angina who are already treated with a traditional antianginal regimen.
The study population included 40 patients (23 men and 17 women) with chronic stable angina on optimal medical therapy. Eligible patients had stable exertional angina for at least 6 months, despite use of standard antianginal therapy, and had typical anginal symptoms during exercise. Background medical therapy of angina had to be unchanged for the last 3 months. All had documented coronary artery disease, with angiographic evidence of ≥75% stenoses in at least 1 major coronary, left ventricular ejection fraction of ≥50% by 2 dimensional echocardiography, and a previous positive treadmill stress test with chest pain and at least ≥1 mm horizontal or down sloping ST-segment depression. Exclusion criteria were patients with history of congestive heart failure, significant cardiac valvular disease, hypertrophic cardiomyopathy, vasospastic angina, unstable angina or myocardial infarction within 6 months, surgical or percutaneous revascularization within 6 months, exercise capacity limited by either claudication or noncardiac dyspnea, pacemaker dependency, atrial fibrillation, left branch block, resting ST depression, clinically significant anemia or hepatic disease, serum creatinine ≥1.3 mg/dL or potassium ≥5.5 mEq/L, and current use of digoxin or diuretic therapy.
The study design was randomized, double blinded, and placebo controlled. After a baseline evaluation of all inclusion and exclusion criteria, informed consent was obtained. The following day, between 8 and 10 am, subjects performed a treadmill exercise test using the standard Bruce protocol. Study subjects were then randomized to receive either diuretic (25 mg hydrochlorothiazide combined with 5 mg amiloride) or matching placebo for a period of 21 days in a double-blind manner. All patients were followed weekly to verify blood pressure, heart rate, weight, and adverse events, as well as to document study medication compliance. During week 2, a blood sample for serum potassium and creatinine was obtained from all patients. At day 21 all patients underwent a repeat treadmill exercise test in the morning in the fasting state. Baseline antianginal therapy was not modified during the study period.
Study of Left Ventricular Function
All patients underwent transthoracic echocardiography according to the guidelines of the American Society of Echocardiography,9 using the parasternal and the apical views to calculate dimensions and evaluate global and regional left ventricular function. Left ventricular end-diastolic and end-systolic diameters were obtained from the parasternal long-axis view. Left ventricular end-diastolic volume and end-systolic volumes were obtained from the apical 4- and 2-chamber views using a modified Simpson's rule.
All tests were performed according to recommendations of the American College of Cardiology and American Heart Association 2002 guidelines for exercise testing10 and executed by 1 investigator who was blinded to study treatment. Treadmill exercise testing was carried out using the standard Bruce protocol. A 13-lead electrocardiogram (12 conventional leads plus CM5) was recorded in the sitting and standing positions before exercise, during each work stage, immediately after the end of exercise, and during the recovery period. Patients were instructed to indicate the onset of angina (P1) and were encouraged to continue exercise to moderate angina (P2), the point at which they would normally discontinue activity because of angina. Blood pressure was measured with the same arm-cuff sphygmomanometer in the sitting and standing positions before exercise testing, during the last 30 seconds of each work stage, at both P1 and P2, and during recovery. Exercise was continued until moderate angina (P2) or until 1 of the following was observed: horizontal or down-sloping ST-segment depression of ≥3 mm, systolic blood pressure higher than 220 mm Hg, or a decrease in systolic blood pressure of ≥10 mm Hg. Total walking time in seconds performed indicated the exercise capacity of the patients.
The 13-lead electrocardiogram was continuously monitored throughout the test for rhythm, rate, and ST-segment changes. The ST-segment shift was measured 80 ms after the J point using the end of the P-R segment as reference. An investigator blinded to study treatment allocation interpreted all tests. The ST changes were measured from the lead exhibiting the greatest ST-segment change during the baseline treadmill exercise test.
The primary end point of the study was the change in total treadmill walking time in seconds to moderated angina (P2).
The study complies with the Declaration of Helsinki. The Ethics Committee of Hospital de Clínicas de Porto Alegre, Brazil, approved the protocol and all patients gave written informed consent.
Based on the results of a previous report,5 sample size calculations indicated that 30 patients would be needed to demonstrate an improvement in treadmill walking time of 40 seconds with 90% power (alpha of 0.05). To account for potential dropouts, 40 patients were selected to participate. Differences in mean values between groups were compared using a 2-tailed unpaired student's t-test (parametric variables). Qualitative variables were compared with a Pearson chi-square test. Continuous variables are expressed as mean ± standard error of the mean (SEM). A 2-sided P value of less than 0.05 was considered to indicate statistical significance. All calculations were performed using the SPSS 11.5 software package (SPSS Inc. Chicago, Illinois).
Baseline demographic characteristics of the patients in diuretic and placebo-treated groups are presented in Table 1. Twenty patients were randomized to diuretic therapy (14 men, age 64 ± 2 years) and 20 to the placebo arm (9 men, age 61 ± 3 years). There were no significant differences between groups in terms of baseline characteristics. Left ventricular ejection fraction was approximately 60% in both groups. The groups were well matched in terms of baseline heart rate, blood pressure, and concomitant medications. The number of patients taking 1 (7 vs 11), 2 (7 vs 7), or 3 (6 vs 2) antianginal medications was similar between groups (respectively, diuretic and placebo), P = NS.
Diuretic therapy was associated with a significant increase on total treadmill walking time to moderate angina (P2) of 63 ± 17 seconds as compared with 19 ± 9 seconds in the placebo group (44 seconds of difference between groups, P = 0.026; Figure 1). There was a 25% increment in walking time in 8 patients (40%) in the combined hydrochlorothiazide and amiloride therapy group versus 1 patient (5%) in the placebo group (P = 0.02). The results of the treadmill exercise testing are presented in Table 2. The diuretic group also demonstrated a significant reduction in the ST-segment depression at peak exercise of 0.6 ± 0.2 mm as compared with 0.1 ± 0.2 mm in the placebo group (difference 0.5 mm, P = 0.03).
There were no significant changes in resting arterial blood pressure at baseline and at day 21 in either treatment group. Systolic blood pressure at peak exercise was similar in both groups. Peak systolic blood pressure during the exercise test was 162 ± 6 vs 160 ± 5 mm Hg (P = 0,8) at baseline and 165 ± 5 vs 161 ± 5 mm Hg (P = 0.6) at the end of the treatment period, respectively, placebo versus diuretic groups. There was also no significant difference comparing the changes in systolic pressure per MET at peak exercise (-2.1 ± 1.7 vs -3.4 ± 1.1 mm Hg/MET, P = 0.5, respectively, placebo vs diuretic group). Heart rate responses during exercise were also similar in the 2 groups.
There were no significant changes in body weight, serum creatinine, or potassium at baseline and week 2 in either group. All patients randomized remained stable and completed the study. No patient developed an unstable ischemic syndrome or reported an increase in angina symptoms during the study period. No serious adverse events occurred. All concurrent medications were not modified during the study period.
The findings of the present study indicate that in patients with exertional angina, therapy with the combination of hydrochlorothiazide and amiloride significantly increases treadmill walking time and reduces electrocardiographic evidence of ischemia. It is important to note that this antianginal effect of diuretic therapy was observed in patients already taking 1 or more standard long-acting antianginal drugs. It is important to emphasize that these patients had normal left ventricular function and did not have symptoms of heart failure.
Although the mechanism behind the antianginal effect of diuretic therapy is not clear, our findings provide evidence that diuretic therapy has a potential role in the treatment of patients with chronic stable angina.
A limited number of studies have assessed the effects of diuretic therapy on myocardial ischemia. Nechwatal et al4 reported improvement in angina and an increase in exercise performance in patients with stable coronary artery disease treated with acute use of furosemide. Serro-Azul et al,11 in a double-blind, placebo-controlled, cross-over study, assessed the effects of chlorthalidone in 15 elderly patients with hypertension, documented coronary artery disease, and evidence of inducible myocardial ischemia and normal left ventricular function. They reported an increase in exercise performance and a reduction in myocardial ischemia during day-life activities as assessed by Holter monitoring.
Parker et al,5 during an investigation to determine whether diuretic therapy could prevent the development of tolerance to nitroglycerin, observed that diuretic therapy with hydrochlorothiazide plus amiloride improved exercise capacity in normotensive patients with stable angina. In that investigation, only therapy with nitrates was permitted and, therefore, the potential benefit of the association of diuretics with calcium channel antagonists and beta blockers was not evaluated.
A potential mechanism of the antianginal effect observed in our study is changes in intravascular volumes associated with diuretic therapy. It is conceivable that diuretic therapy prevented increase in left ventricular end-diastolic pressure during exercise resulting in decreased myocardial oxygen consumption. In addition, reduction of left ventricular end-diastolic pressure may lead to improvement in transcoronary pressure gradient leading to an increase in myocardial oxygen supply. In our study arterial blood pressure and rate-pressure product at exercise peak was similar between groups; it is well known that rate-pressure product is not the only determinant of oxygen demand because it does not account for changes in filling pressures, ventricular volume, and contractility.
Alternatively, a specific effect of amiloride on myocardial response to ischemia may account for our findings. Amiloride has been show to be cardioprotective in the setting of ischemia, particularly in the setting of ischemia followed by reperfusion.12 Despite substantial documentation of this effect in animal models there have been no studies examining the impact of amiloride on human myocardium. Amiloride could exert antianginal effects via inhibition of myocardial Na+/H+ exchangers (NHE). This ion-exchange mechanism transports Na+ ions and H+ ions in opposite directions. Seven different isoforms of the exchanger have been identified to date. NHE-1, the ubiquitous plasma-membrane isoform, is the molecular homologue of the cardiac sarcolemmal Na+/H+ exchanger. NHE-1 is specifically targeted by amiloride and analogous drugs.13 The myocardial NHE represents 1 of the main mechanisms for intracellular pH regulation in response to ischemia-induced acidosis.14 Karmazyn was the first investigator to show that amiloride enhanced the postischemic recovery of contractile function and reduced creatine kinase leakage in rat hearts subjected to global ischemia and reperfusion.15 Extensive studies using NHE-1 inhibitors have consistently shown protective effects against ischemia and reperfusion injury in a variety of animal models.16
This investigation documents that the combination of hydrochlorothiazide and amiloride is an effective antianginal therapy in patients already treated with other antianginal agents. It is interesting that the role of multiple drug therapy for angina remains controversial, with few convincing data supporting the use of multiple drugs.17 Despite this uncertainty, the present data would support a therapeutic use of diuretics in patients with angina despite optimal medical management, when revascularization procedures are not feasible or have not been successful.
The apparent lack of effect in blood pressure associated to the diuretic combination might have been underestimated. Although blood pressure was obtained with the same arm-cuff sphygmomanometer standardizations and blood pressure at rest and during exercise test was similar in both groups, 24 hour blood pressure ambulatory monitoring might have identified subtle changes in response to diuretic therapy.
In view of the fact that 70% of the patients had a history of hypertension one might speculate that they may have diastolic dysfunction resulting in a marked increase in left ventricular end-diastolic pressure during exercise that might be prevented by diuretic therapy. Therefore, our findings may not be applicable to patients who do not have hypertension.
Our study was not designed for evaluating the individual antianginal effects of hydrochlorothiazide and amiloride alone. Additional studies are necessary to explain the relative contribution of the diuretic effect and the inhibition of NHE to improvement of angina.
We thank Dr. Jeferson Wollmeister for the interpretation of stress tests and Dr. Mario Wagner for his assistance with statistical analysis.
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