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Vasodilator therapy of hypertensive acute left ventricular failure: Comparison of captopril-prazosin with Hydralazine-isosorbide dinitrate
International Journal of Cardiology 67 (1998) 81–86
Vasodilator therapy of hypertensive acute left ventricular failure: Comparison of captopril-prazosin with Hydralazine-isosorbide dinitrate A.Q. Adigun, O.E. Ajayi, G.G. Sofowora, A.A. Ajayi* Department of Medicine, College of Health Sciences, Obafemi Awolowo University, Ile-Ife, Osun State, Nigeria Received 9 July 1998; accepted 5 August 1998
Abstract A prospective study to evaluate and compare the cardiorespiratory effects and clinical efficacy of the Neurohormonal inhibitors (Captopril 50 mg1prazosin 1 mg only) and direct arteriolar and venular dilators (Intravenous hydralazine 30 mg1oral isosorbide dinitrate 30 mg) used as vasodilator therapy, was undertaken in a randomized, single blind study in 17 Nigerian patients with hypertensive acute left ventricular failure. Both vasodilator regimes separately and significantly reduced the systolic and diastolic blood pressures (P,0.001 ANOVA), heart rate (P,0.001 ANOVA), and the respiratory rate (P,0.05 ANOVA), the double product, but increased the peak expiratory flow rate (P,0.05 ANOVA). However, the neurohormonal antagonists, captopril and prazosin (n59) caused a statistically significantly greater reduction in heart rate (P,0.05 ANOVA) respiratory rate (P,0.05 ANOVA) and induced a significantly greater increase in the self-paced exercise capacity, 24 h after initiation of treatment, (P,0.02) compared to the hydralazine and isosorbide dinitrate combination (n58). Five of the nine patients on the neurohormonal antagonist therapy were ambulant at 24 h, compared to none of the eight patients receiving conventional venular and arteriolar dilators hydralazine and isosorbide dinitrate (X 2 55.84 dfi P,0.05). There was a significant inverse correlation between the systolic blood pressure heart rate product, and the distance covered during symptom limited self paced exercise capacity (r520.58, P50.0146 ANOVA). One of eight patients in the hydralazine1isosorbide nitrate combination died, but there was no mortality in the captopril1prazosin group. These findings collectively suggest that captopril1prazosin combination may be a superior vasodilator therapy compared to hydralazine-isosorbide dinitrate, in hypertensive acute pulmonary oedema. 1998 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Acute left ventricular failure; Hypertension; Captopril; Prazosin; Isosorbide dinitrate; Hydralazine
1. Introduction Acute left ventricular failure is a life threatening medical emergency, which is a common complication of malignant hypertension. In contrast to the western experience, where coronary artery disease is prevalent, hypertensive acute pulmonary oedema is the commonest cause of sudden cardiac death in Nigerians, according to a recent autopsy series [1]. The haemodynamic hall marks of acute left ventricular failure include raised systemic and pulmonary *Corresponding author. E-mail: [email protected]
vascular resistance, diminished cardiac output and elevated left ventricular end diastolic pressure [2]. A rational therapeutic intervention to reverse the pathophysiological state, is a combination of arteriolar vasodilator to increase cardiac output and lower arterial blood pressure, and venodilator therapy to reduce pulmonary venous resistance and capillary pressure. Thus, arteriolar dilators, Nitroprusside [3] or hydralazine [4] alone or in combination with venular dilator such as isosorbide dinitrate [5] are standard adjunctive vasodilators in acute heart failure. It is established that neurohormonal activation of both the renin angiotensin and sympathetic nervous
0167-5273 / 98 / $ – see front matter 1998 Elsevier Science Ireland Ltd. All rights reserved. PII: S0167-5273( 98 )00234-4
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A.Q. Adigun et al. / International Journal of Cardiology 67 (1998) 81 – 86
systems contribute to the progressive decompensation in chronic heart failure [6], and that inhibitors of the neuroendocrine activation may be superior to conventional dilators in reducing mortality as shown in the vasodilator–heart failure study II [7]. The role of neuroendocrine stimulation in acute heart failure is however, less well known. This clarification is important for the rational vasodilator therapy of hypertensive acute left ventricular failure, and will permit a choice between neurohormonal antagonists and conventional vasodilators. The purpose of our present study is to examine and compare the cardiorespiratory effects and clinical efficacy of conventional Arteriolar and Venular dilators (hydralazine1isosorbide dinitrate) with Vasodilators with additional neurohormonal antagonist properties, (captopril1prazosin) in hypertensive acute left ventricular failure.
2. Materials and methods In a single blind, parallel group study, 17 newly diagnosed patients, presenting in the Emergency Department of our hospital over a 2 year period, with hypertensive acute left ventricular failure were randomized to receive either: (a) oral captopril 25 mg dose given twice [50 mg]1oral prazosin, 1 mg or (b) Intravenous hydralazine in 10 mg microboluses, given thrice [30 mg]1oral isosorbide dinitrate, 10 mg thrice daily [30 mg]. All the medications were to be
administered within 24 h. All the patients received the standard treatment for acute pulmonary oedema, including intranasal 100% oxygen, 4–6 l / min, Aminophylline 250 mg given intravenously over 5 min. They also all received frusemide diuretic. There was no difference in the mean frusemide dose administered between the groups, being 180637 mg in the captopril group and 160625 mg in the hydralazine group. Patients were recruited into the study after ethical committee review and approval, and if subject or close relative consented to the inclusion. Inclusion criteria were acute left ventricular failure with elevated blood pressure greater than [systolic / diastolic] 140 / 90 mmHg, with roentgenographic confirmation of pulmonary oedema and a dilated heart. The exclusion criteria were, non hypertensive acute left ventricular failure, previous treatment for heart failure with vasodilators, associated diabetes mellitus, thyrotoxicosis. The patients randomized to the two vasodilator regimes were well matched for baseline demographic and clinical characteristics as shown in Table 1. Before the initiation of adjunctive vasodilator therapy, measurements of basal sitting systolic and diastolic blood pressures, heart rate, respiratory rate and peak expiratory flow rate were undertaken. These were repeated at 2, 6, 12 and 24 h after the start of vasodilator therapy. None of the patients was ambulant on admission, but a symptom limited self paced walk test was undertaken after 24 h, as previously described [8].
Table 1 Baseline clinical data of the Nigerian patients with hypertensive acute left ventricular failure, mean6s.d. Parameter
Captopril-Prazosin
Hydralazine-Isosorbide dinitrate
n Age (Years) Sex M / F Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Heart rate (beats / mm) Respiratory rate (Cycles / min) Cardiothoracic ratio Body mass index (kg m 22 ) Serum creatinine (m / l) Frusemide dose (mg)
9 4966 6/3 179612 11866 12064 4364 0.6410.01 2260.8 5606190 188637
8 4266 5/3 19119 12964 12064 4513 0.6160.02 2260.7 6026178 160625
No significant differences.
A.Q. Adigun et al. / International Journal of Cardiology 67 (1998) 81 – 86
In patients not fully responsive to therapy, a ‘‘rescue dose’’ of the alternative treatment and haemodialysis were available.
2.1. Statistical analysis Data are expressed as mean6standard deviation or standard error of the mean, as stated. Comparability of the baseline data were by unpaired t tests. The effects of the two vasodilator regimens were analysed as differences from baseline by ]2 factor repeated measures analysis of variance (MANOVA). Proportionate data was evaluated by the X 2 test. The effect of the treatments on self paced exercise capacity was evaluated by the Mann-Whitney U test. The relationship between the systolic blood pressure heart rate product and the distance walked during self paced exercise, was evaluated by linear regression analysis. The null hypothesis was rejected at P,0.05.
83
cant reduction in systolic and diastolic blood pressure. (F512.3, df 4 , P,0.001 ANOVA). See Fig. 1. There was no significant between treatment effect in the hypotensive action. (F50.98 df n.s.). There was a significant reduction in the tachycardia associated with the acute pulmonary oedema on both vasodilator regimes (F533.1, df 4 P,0.001 ANOVA). However, the captopril1Prazosin combination caused a statistically significantly greater fall in heart rate than the hydralazine group (F54.44 df 1 P,0.05 ANOVA). The mean reduction in heart rate induced by captopril1prazosin at 2, 4, 6, 12 and 24 h respectively were 213, 218, 222 and 222 beats / mm. The corresponding values for hydralazine1isosorbide dinitrate combination being 26, 211, 214, and 218 beats / mm. (See Fig. 1).
3. Results
3.1. General All the 17 patients completed the study. One patient in the hydralazine1isosorbide dinitrate group, whose blood pressure remained uncontrolled at 250 / 120 mmHg after 6 h, received a ‘‘rescue dose’’ of captopril 25 mg1prazosin 1 mg at 8 h, after which his blood pressure fell to 160 / 100 mmHg at 12 h and again at 24 h. His data was still allotted to the hydralazine group according to the ‘intention to treat’ principle. Four patients each, in either group had elevated creatinine above 200 ml / l. These patients underwent haemodialysis after 24 h. One of these patients, in the hydralazine group, died before haemodialysis could be instituted. The others remained well after several haemodialysis sessions and satisfactory blood pressure control.
3.2. Blood pressure and heart rate Both treatment groups, separately caused signifi-
Fig. 1. Cardiorespiratory response to hydralazine-isosorbide dinitrate and captopril-prazosin in Nigerians with hypertensive acute pulmonary oedema. (Closed circles captopril-prazosin, n59, Open circles hydralazine-isosorbide dinitrate n58).
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A.Q. Adigun et al. / International Journal of Cardiology 67 (1998) 81 – 86
3.3. Pressure rate product The systolic blood pressure, heart rate product (an index of myocardial oxygen use) at baseline on admission was 21 55364842 mmHg.beat / min in the hydralazine group and 22 90463721 mmHg.beats / min in the captopril group. Both treatments caused a statistically significant reduction in the pressure rate product. In the captopril group it decreased by 769361887 mmHg beats / mm [t512.23, P50.0001] and on hydralazine by 664462999 (t56.29 P5 0.004). Although there was no difference between the regimes, the lowest absolute values of the pressure rate product at 24 h, were seen in the captopril1 prazosin group.
3.4. Respiratory rate and peak expiratory flow rate
while four were moribund at 24 h. This proportion was significantly different from the hydralazine group (X 2 df 1 55.84, P,0.05). The treatment induced increase in symptom limited distance was 0 meters in the hydralazine group, but was significantly greater and increased to 76.4627 meters in the captopril group (P,0.02) (see Fig. 2).
3.6. Correlation between pressure rate product and self paced exercise capacity There was a significant inverse correlation between the treatment induced change in the distance walked and the pressure rate product at 24 h. (r520.58, r 2 50.34, F57.62, P50.0146 ANOVA). The ambulant patients tended to have the lowest double products, at 24 h.
Both treatment regimes resulted in a statistically significant reduction in tachypnoea and dyspnoea (F529.5, df 4 , P50.001 ANOVA) see Fig. 1. However, the captopril1prazosin combination caused a statistically significantly greater reduction in the respiratory rate than the hydralazine1isosorbide dinitrate group. (F55.39, df 1 P50.034 ANOVA). The respiratory rate in the captopril group fell from 4364 cycles / min to 2565 cycles / min at 24 h, whilst in the hydralazine group it diminished from 45.563 to 3563 cycles / min, at 24 h. The fall in respiratory rate was associated with an increase in peak expiratory flow rate on both treatments with no between treatment statistically significant effect (Fig. 1). In the hydralazine1isosorbide group, the values rose from 100615 l / min to 148613 l / min and on captopril1prazosin from 139614 l / min to 201618 l / min.
3.5. Symptom limited self paced exercise capacity None of the 17 recruited patients was ambulant on admission, as they were all moribund. Twenty four hours after admission, however, there was manifest, symptomatic amelioration. However, none of the eight patients in the hydralazine group could undertake the self paced walk test, five of the nine patients in the captopril group were capable of ambulation,
Fig. 2. Change in symptom limited self paced distance covered (m) in patients with acute left ventricular failure after 24 h.
A.Q. Adigun et al. / International Journal of Cardiology 67 (1998) 81 – 86
3.7. Safety and tolerability The two treatment regimes were well tolerated, with no first dose hypotension or syncopal attack.
4. Discussion In this randomized study of hypertensive acute left ventricular failure, our results indicate that both the adjunctive regimes of intravenous hydralazine1oral isosorbide dinitrate, and the neurohormonal inhibitors; captopril (an ACE inhibitor)1prazosin (alpha 1 blocker) caused similar significant reduction in systolic and diastolic blood pressures. However, the combined captopril1prazosin caused a statistically significantly greater (P,0.05 ANOVA) reduction in respiratory and heart rates compared to the direct arteriolar and venular dilators. Further, adjunctive captopril1prazosin was associated with a greater proportion of ambulant patients (55%) and increased exercise tolerance at 24 h, compared to none (0%) observed with the direct vasodilators (Fig. 2). One subject in the hydralazine group required a ‘‘rescue’’ with captopril1prazosin, and there was one mortality (12.5%) in the hydralazine group. Thus, at equihypotensive doses, to the hydralazine1isosorbide dinitrate combination, captopril1prazosin exerted a greater clinically beneficial effect to increase ambulation, and decrease an index of myocardial oxygen demand (systolic blood pressure heart rate product) by a mechanism that may be additional to their combined arteriolar and venular dilator action. This additional action may entail an autonomic neurohumoral modulation, including a sympathoinhibitory effect, with lowered plasma noradrenaline [9] and parasympathetic augmentation [10]. Angiotensin converting enzyme inhibitors, including captopril lower blood pressure without tachycardia owing to enhancement of cardiac vagal tone [11]. The bradycardic action, with the hypotensive effect may cause a fall in the pressure rate product, as seen in this study. In an earlier study, which compared captopril to hydralazine in chronic heart failure secondary to ischaemic cardiomyopathy [12], captopril caused a significant increase in both left and right ventricular ejection fractions, associated with a reduction in
85
pulmonary artery pressure and vascular resistance [12,13], while hydralazine had no such effect. Another study compared Isosorbide dinitrate to captopril as adjunctive therapy in mild chronic heart failure [14] captopril but not isosorbide dinitrate, caused improvement in the Canadian cardiovascular society class and a reduction in the diuretic dose requirement [14]. The efficacy of captopril1prazosin in this acute study, is in conformity with the inhibition of the synergistic interaction between the renin angiotensin and the sympathetic nervous systems, which we have reported in healthy volunteers [15,16] severely hypertensive patients [17] and in chronic heart failure [18]. The impaired renal function which was documented in some of our study patients may have caused an activation of the renin angiotensin system, even in acute left ventricular failure. In conclusion, concurrent captopril and alpha 1 blocker, prazosin, may be a useful adjunctive oral treatment in hypertensive acute pulmonary oedema, a complication which is common and lethal in Nigerian hypertensive patients.
References [1] Rotimi O, Ajayi AA, Odesanmi WO. Sudden unexpected death from cardiac causes in Nigerians. A review of 50 autopsies. Int J Cardiol 1998;63:111–5. [2] Ingram RH, Braunwald E. Pulmonary oedema: cardiogenic and non cardiogenic pulmonary oedema. In: Braunwald E, editor. Heart disease. Philadelphia: WB Saunders, 1992:551–68. [3] Brush JE, Udelson JE, Bacharach SL. Comparative effects of Verapamil and Nitroprusside on left ventricular function in patients with hypertension. J Am Coll Cardiol 1989;14:515. [4] Pierpoint GL, Brown DC, Franciosa JA, Cohn JN. Effect of hydralazine on renal failure in patients with congestive heart failure. Circulation 1980;61:323. [5] Leier CV, Huss P, Magorien RD, Unverferth D. Improved exercise capacity and differing arterial and venous tolerance during chronic isosorbide dinitrate therapy for congestive heart failure. Circulation 1983;67:817. [6] Cohn JN, Levine TB, Olivari MT, et al. Plasma Noradrenaline as a guide to prognosis in patients with chronic congestive heart failure. New Engl J Med 1984;311:819. [7] Cohn JN, Johnson G, Ziesche S, Cobb F, Francis E, Tristani F, et al. A comparison of enalapril with Hydralazine-Isosorbide dinitrate in the treatment of chronic congestive heart failure. New Engl J Med 1991;325:303–10.
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[8] Ajayi AA, Balogun JA. Symptom limited self paced walking in the assessment of cardiovascular disease in patients with and without heart failure. Int J Cardiol 1991;33:233–40. [9] Bayliss J, Norrel M, Sutton G, Canepa-Anson Reid C, Poole-Wilson P. Clinical Importance of the renin angiotensin system in chronic heart failure: a double blind comparison of captopril and prazosin. Br Med J 1985;290:1861–5. [10] Flapan A, Nolan J, Nielsen J, Ewing DJ. Effect of Captopril on cardiac parasympathetic activity in chronic congestive heart failure secondary to coronary artery disease. Am J Cardiol 1992;69:532–5. [11] Ajayi AA, Campbell BC, Meredith PA, Kelman AW, Reid JL. The effect of Captopril on the reflex control of heart rate; possible mechanisms. Br J Clin Pharmacol 1985;20:17–25. [12] Schofield PM, Brooks NH, Lawrence GP, Testa HJ, Ward C. Which vasodilator drug in patients with chronic heart failure? A randomized comparison of captopril and hydralazine. Br J Clin Pharmacol 1991;31:25–32. [13] Dzau VJ, Colluici WS, Williams GH, Curfman G, Meggs L, Hollenberg NK. Sustained effectiveness of converting enzyme inhibition in patients with severe heart failure. New Engl J Med 1980;302:1373–9.
[14] Wilkes NPF, Brain E, Horschl R, Stokes GS, Nelson GC. Comparison of the immediate and long-term effects of Captopril and Isosorbide dinitrate as adjunctive treatment in mild heart failure. Br J Clin Pharmacol 1989;28:427–34. [15] Ajayi AA, Raji MA. Acute cardiovascular effects of the concurrent administration of enalapril, prazosin, or amlodipine in healthy Nigerians. Int J Cardiol 1994;44:79–84. [16] Sofowora GG, Adigun AQ, Haastrup AT, Ajayi AA. Synergism between Angiotensin converting enzyme inhibitor, and alpha 1 blocker during isometric hand grip in normal man. Tropical Cardiol (in press). [17] Ajayi AA, Afolabi MA, Balogun MO, Adigun AQ, Ajayi OE, Akintomide AO. Oral therapy with combined enalapril, prazosin and hydrochlorothiazide in the acute treatment of severe hypertension in Nigerians. Eur J Clin Pharmacol 1996;51:45–8. [18] Ajayi AA, Sofowora GG, Balogun MO. Concurrent alpha 1 adrenergic blockade and angiotensin converting enzyme inhibition in the treatment of congestive heart failure. Int J Cardiol 1996;57:173–6.
Vasodilator therapy of hypertensive acute left ventricular failure: Comparison of captopril-prazosin with Hydralazine-isosorbide dinitrate A.Q. Adigun, O.E. Ajayi, G.G. Sofowora, A.A. Ajayi* Department of Medicine, College of Health Sciences, Obafemi Awolowo University, Ile-Ife, Osun State, Nigeria Received 9 July 1998; accepted 5 August 1998
Abstract A prospective study to evaluate and compare the cardiorespiratory effects and clinical efficacy of the Neurohormonal inhibitors (Captopril 50 mg1prazosin 1 mg only) and direct arteriolar and venular dilators (Intravenous hydralazine 30 mg1oral isosorbide dinitrate 30 mg) used as vasodilator therapy, was undertaken in a randomized, single blind study in 17 Nigerian patients with hypertensive acute left ventricular failure. Both vasodilator regimes separately and significantly reduced the systolic and diastolic blood pressures (P,0.001 ANOVA), heart rate (P,0.001 ANOVA), and the respiratory rate (P,0.05 ANOVA), the double product, but increased the peak expiratory flow rate (P,0.05 ANOVA). However, the neurohormonal antagonists, captopril and prazosin (n59) caused a statistically significantly greater reduction in heart rate (P,0.05 ANOVA) respiratory rate (P,0.05 ANOVA) and induced a significantly greater increase in the self-paced exercise capacity, 24 h after initiation of treatment, (P,0.02) compared to the hydralazine and isosorbide dinitrate combination (n58). Five of the nine patients on the neurohormonal antagonist therapy were ambulant at 24 h, compared to none of the eight patients receiving conventional venular and arteriolar dilators hydralazine and isosorbide dinitrate (X 2 55.84 dfi P,0.05). There was a significant inverse correlation between the systolic blood pressure heart rate product, and the distance covered during symptom limited self paced exercise capacity (r520.58, P50.0146 ANOVA). One of eight patients in the hydralazine1isosorbide nitrate combination died, but there was no mortality in the captopril1prazosin group. These findings collectively suggest that captopril1prazosin combination may be a superior vasodilator therapy compared to hydralazine-isosorbide dinitrate, in hypertensive acute pulmonary oedema. 1998 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Acute left ventricular failure; Hypertension; Captopril; Prazosin; Isosorbide dinitrate; Hydralazine
1. Introduction Acute left ventricular failure is a life threatening medical emergency, which is a common complication of malignant hypertension. In contrast to the western experience, where coronary artery disease is prevalent, hypertensive acute pulmonary oedema is the commonest cause of sudden cardiac death in Nigerians, according to a recent autopsy series [1]. The haemodynamic hall marks of acute left ventricular failure include raised systemic and pulmonary *Corresponding author. E-mail: [email protected]
vascular resistance, diminished cardiac output and elevated left ventricular end diastolic pressure [2]. A rational therapeutic intervention to reverse the pathophysiological state, is a combination of arteriolar vasodilator to increase cardiac output and lower arterial blood pressure, and venodilator therapy to reduce pulmonary venous resistance and capillary pressure. Thus, arteriolar dilators, Nitroprusside [3] or hydralazine [4] alone or in combination with venular dilator such as isosorbide dinitrate [5] are standard adjunctive vasodilators in acute heart failure. It is established that neurohormonal activation of both the renin angiotensin and sympathetic nervous
0167-5273 / 98 / $ – see front matter 1998 Elsevier Science Ireland Ltd. All rights reserved. PII: S0167-5273( 98 )00234-4
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A.Q. Adigun et al. / International Journal of Cardiology 67 (1998) 81 – 86
systems contribute to the progressive decompensation in chronic heart failure [6], and that inhibitors of the neuroendocrine activation may be superior to conventional dilators in reducing mortality as shown in the vasodilator–heart failure study II [7]. The role of neuroendocrine stimulation in acute heart failure is however, less well known. This clarification is important for the rational vasodilator therapy of hypertensive acute left ventricular failure, and will permit a choice between neurohormonal antagonists and conventional vasodilators. The purpose of our present study is to examine and compare the cardiorespiratory effects and clinical efficacy of conventional Arteriolar and Venular dilators (hydralazine1isosorbide dinitrate) with Vasodilators with additional neurohormonal antagonist properties, (captopril1prazosin) in hypertensive acute left ventricular failure.
2. Materials and methods In a single blind, parallel group study, 17 newly diagnosed patients, presenting in the Emergency Department of our hospital over a 2 year period, with hypertensive acute left ventricular failure were randomized to receive either: (a) oral captopril 25 mg dose given twice [50 mg]1oral prazosin, 1 mg or (b) Intravenous hydralazine in 10 mg microboluses, given thrice [30 mg]1oral isosorbide dinitrate, 10 mg thrice daily [30 mg]. All the medications were to be
administered within 24 h. All the patients received the standard treatment for acute pulmonary oedema, including intranasal 100% oxygen, 4–6 l / min, Aminophylline 250 mg given intravenously over 5 min. They also all received frusemide diuretic. There was no difference in the mean frusemide dose administered between the groups, being 180637 mg in the captopril group and 160625 mg in the hydralazine group. Patients were recruited into the study after ethical committee review and approval, and if subject or close relative consented to the inclusion. Inclusion criteria were acute left ventricular failure with elevated blood pressure greater than [systolic / diastolic] 140 / 90 mmHg, with roentgenographic confirmation of pulmonary oedema and a dilated heart. The exclusion criteria were, non hypertensive acute left ventricular failure, previous treatment for heart failure with vasodilators, associated diabetes mellitus, thyrotoxicosis. The patients randomized to the two vasodilator regimes were well matched for baseline demographic and clinical characteristics as shown in Table 1. Before the initiation of adjunctive vasodilator therapy, measurements of basal sitting systolic and diastolic blood pressures, heart rate, respiratory rate and peak expiratory flow rate were undertaken. These were repeated at 2, 6, 12 and 24 h after the start of vasodilator therapy. None of the patients was ambulant on admission, but a symptom limited self paced walk test was undertaken after 24 h, as previously described [8].
Table 1 Baseline clinical data of the Nigerian patients with hypertensive acute left ventricular failure, mean6s.d. Parameter
Captopril-Prazosin
Hydralazine-Isosorbide dinitrate
n Age (Years) Sex M / F Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Heart rate (beats / mm) Respiratory rate (Cycles / min) Cardiothoracic ratio Body mass index (kg m 22 ) Serum creatinine (m / l) Frusemide dose (mg)
9 4966 6/3 179612 11866 12064 4364 0.6410.01 2260.8 5606190 188637
8 4266 5/3 19119 12964 12064 4513 0.6160.02 2260.7 6026178 160625
No significant differences.
A.Q. Adigun et al. / International Journal of Cardiology 67 (1998) 81 – 86
In patients not fully responsive to therapy, a ‘‘rescue dose’’ of the alternative treatment and haemodialysis were available.
2.1. Statistical analysis Data are expressed as mean6standard deviation or standard error of the mean, as stated. Comparability of the baseline data were by unpaired t tests. The effects of the two vasodilator regimens were analysed as differences from baseline by ]2 factor repeated measures analysis of variance (MANOVA). Proportionate data was evaluated by the X 2 test. The effect of the treatments on self paced exercise capacity was evaluated by the Mann-Whitney U test. The relationship between the systolic blood pressure heart rate product and the distance walked during self paced exercise, was evaluated by linear regression analysis. The null hypothesis was rejected at P,0.05.
83
cant reduction in systolic and diastolic blood pressure. (F512.3, df 4 , P,0.001 ANOVA). See Fig. 1. There was no significant between treatment effect in the hypotensive action. (F50.98 df n.s.). There was a significant reduction in the tachycardia associated with the acute pulmonary oedema on both vasodilator regimes (F533.1, df 4 P,0.001 ANOVA). However, the captopril1Prazosin combination caused a statistically significantly greater fall in heart rate than the hydralazine group (F54.44 df 1 P,0.05 ANOVA). The mean reduction in heart rate induced by captopril1prazosin at 2, 4, 6, 12 and 24 h respectively were 213, 218, 222 and 222 beats / mm. The corresponding values for hydralazine1isosorbide dinitrate combination being 26, 211, 214, and 218 beats / mm. (See Fig. 1).
3. Results
3.1. General All the 17 patients completed the study. One patient in the hydralazine1isosorbide dinitrate group, whose blood pressure remained uncontrolled at 250 / 120 mmHg after 6 h, received a ‘‘rescue dose’’ of captopril 25 mg1prazosin 1 mg at 8 h, after which his blood pressure fell to 160 / 100 mmHg at 12 h and again at 24 h. His data was still allotted to the hydralazine group according to the ‘intention to treat’ principle. Four patients each, in either group had elevated creatinine above 200 ml / l. These patients underwent haemodialysis after 24 h. One of these patients, in the hydralazine group, died before haemodialysis could be instituted. The others remained well after several haemodialysis sessions and satisfactory blood pressure control.
3.2. Blood pressure and heart rate Both treatment groups, separately caused signifi-
Fig. 1. Cardiorespiratory response to hydralazine-isosorbide dinitrate and captopril-prazosin in Nigerians with hypertensive acute pulmonary oedema. (Closed circles captopril-prazosin, n59, Open circles hydralazine-isosorbide dinitrate n58).
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A.Q. Adigun et al. / International Journal of Cardiology 67 (1998) 81 – 86
3.3. Pressure rate product The systolic blood pressure, heart rate product (an index of myocardial oxygen use) at baseline on admission was 21 55364842 mmHg.beat / min in the hydralazine group and 22 90463721 mmHg.beats / min in the captopril group. Both treatments caused a statistically significant reduction in the pressure rate product. In the captopril group it decreased by 769361887 mmHg beats / mm [t512.23, P50.0001] and on hydralazine by 664462999 (t56.29 P5 0.004). Although there was no difference between the regimes, the lowest absolute values of the pressure rate product at 24 h, were seen in the captopril1 prazosin group.
3.4. Respiratory rate and peak expiratory flow rate
while four were moribund at 24 h. This proportion was significantly different from the hydralazine group (X 2 df 1 55.84, P,0.05). The treatment induced increase in symptom limited distance was 0 meters in the hydralazine group, but was significantly greater and increased to 76.4627 meters in the captopril group (P,0.02) (see Fig. 2).
3.6. Correlation between pressure rate product and self paced exercise capacity There was a significant inverse correlation between the treatment induced change in the distance walked and the pressure rate product at 24 h. (r520.58, r 2 50.34, F57.62, P50.0146 ANOVA). The ambulant patients tended to have the lowest double products, at 24 h.
Both treatment regimes resulted in a statistically significant reduction in tachypnoea and dyspnoea (F529.5, df 4 , P50.001 ANOVA) see Fig. 1. However, the captopril1prazosin combination caused a statistically significantly greater reduction in the respiratory rate than the hydralazine1isosorbide dinitrate group. (F55.39, df 1 P50.034 ANOVA). The respiratory rate in the captopril group fell from 4364 cycles / min to 2565 cycles / min at 24 h, whilst in the hydralazine group it diminished from 45.563 to 3563 cycles / min, at 24 h. The fall in respiratory rate was associated with an increase in peak expiratory flow rate on both treatments with no between treatment statistically significant effect (Fig. 1). In the hydralazine1isosorbide group, the values rose from 100615 l / min to 148613 l / min and on captopril1prazosin from 139614 l / min to 201618 l / min.
3.5. Symptom limited self paced exercise capacity None of the 17 recruited patients was ambulant on admission, as they were all moribund. Twenty four hours after admission, however, there was manifest, symptomatic amelioration. However, none of the eight patients in the hydralazine group could undertake the self paced walk test, five of the nine patients in the captopril group were capable of ambulation,
Fig. 2. Change in symptom limited self paced distance covered (m) in patients with acute left ventricular failure after 24 h.
A.Q. Adigun et al. / International Journal of Cardiology 67 (1998) 81 – 86
3.7. Safety and tolerability The two treatment regimes were well tolerated, with no first dose hypotension or syncopal attack.
4. Discussion In this randomized study of hypertensive acute left ventricular failure, our results indicate that both the adjunctive regimes of intravenous hydralazine1oral isosorbide dinitrate, and the neurohormonal inhibitors; captopril (an ACE inhibitor)1prazosin (alpha 1 blocker) caused similar significant reduction in systolic and diastolic blood pressures. However, the combined captopril1prazosin caused a statistically significantly greater (P,0.05 ANOVA) reduction in respiratory and heart rates compared to the direct arteriolar and venular dilators. Further, adjunctive captopril1prazosin was associated with a greater proportion of ambulant patients (55%) and increased exercise tolerance at 24 h, compared to none (0%) observed with the direct vasodilators (Fig. 2). One subject in the hydralazine group required a ‘‘rescue’’ with captopril1prazosin, and there was one mortality (12.5%) in the hydralazine group. Thus, at equihypotensive doses, to the hydralazine1isosorbide dinitrate combination, captopril1prazosin exerted a greater clinically beneficial effect to increase ambulation, and decrease an index of myocardial oxygen demand (systolic blood pressure heart rate product) by a mechanism that may be additional to their combined arteriolar and venular dilator action. This additional action may entail an autonomic neurohumoral modulation, including a sympathoinhibitory effect, with lowered plasma noradrenaline [9] and parasympathetic augmentation [10]. Angiotensin converting enzyme inhibitors, including captopril lower blood pressure without tachycardia owing to enhancement of cardiac vagal tone [11]. The bradycardic action, with the hypotensive effect may cause a fall in the pressure rate product, as seen in this study. In an earlier study, which compared captopril to hydralazine in chronic heart failure secondary to ischaemic cardiomyopathy [12], captopril caused a significant increase in both left and right ventricular ejection fractions, associated with a reduction in
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pulmonary artery pressure and vascular resistance [12,13], while hydralazine had no such effect. Another study compared Isosorbide dinitrate to captopril as adjunctive therapy in mild chronic heart failure [14] captopril but not isosorbide dinitrate, caused improvement in the Canadian cardiovascular society class and a reduction in the diuretic dose requirement [14]. The efficacy of captopril1prazosin in this acute study, is in conformity with the inhibition of the synergistic interaction between the renin angiotensin and the sympathetic nervous systems, which we have reported in healthy volunteers [15,16] severely hypertensive patients [17] and in chronic heart failure [18]. The impaired renal function which was documented in some of our study patients may have caused an activation of the renin angiotensin system, even in acute left ventricular failure. In conclusion, concurrent captopril and alpha 1 blocker, prazosin, may be a useful adjunctive oral treatment in hypertensive acute pulmonary oedema, a complication which is common and lethal in Nigerian hypertensive patients.
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