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Dose requirements of hydralazine in patients with severe chronic congestive heart failure
Dose Requirements of Hydralazine in Patients With Severe Chronic Congestive Heart Failure
MILTON PACKER, MD, FACC JOSE MELLER, MD, FACC NORMA MEDINA, RN RICHARD GORLIN, MD, FACC MICHAEL V. HERMAN, MD, FACC New York, New York
To evaluate the doses of hydralazine needed to obtain significant hemodynamic responses in severe chronic refractory heart failure, 45 consecutive patients received incremental doses of the drug during invasive hemodynamic monitoring. Twenty-six patients (group A) responded to the oral administration of single doses of 100 mg of hydralazine, whereas 19 patients (42 percent) (group B) did not. Of the patients in group B, 14 responded to 150 to 300 mg orally as a single dose, 3 patients required a single dose of 600 or 800 mg orally and 2 patients responded only to intravenous administration of the drug. In spite of the different dosage requirements of hydralazine, the hemodynamic responses to effective doses were similar in the two groups. The control etiologic, pathophysiologic and hemodynamic variables were similar in both groups, except that patients in group B had higher control values for mean right atrial pressure (14.0 4- 1.5 versus 9.2 4- 1.3 mm Hg; p <0.025) and left ventricular filing pressure (25.2 4- 1.2 versus 21.7 41.0 mm Hg; p <0.05) than patients in group A. Twenty-one of 29 patients (72 percent) with a control mean right atrial pressure of less than 14 mm Hg responded to 100 mg of hydralazine, whereas this dose was effective in only 5 (31 percent) of 16 patients with a higher pressure value (p
<0.02). In conclusion, the doses required for effective hydralazine therapy in patients with severe heart failure are variable and are generally higher than those utilized in hypertensive patients. This may be related to varying degrees of vascular hyporesponsiveness or drug malabsorption, or both, observed in states of high venous pressure. The failure of hydralazine to produce clinical improvement in an individual patient may therefore be due to the administration of subtherapeutic quantities of the drug.
From the Division Of Cardiology, Department of Medicine, The Moufit Sinai School of Medicineof The City university of New Yo~-k,New York, New York. This work was supported in part by grants from the Heart ResearchFoundation, Inc., New York, New York and the Kriendler-Berns Foundation, New York~ New York. Address for reprints: Milton Packer, MD, Division of Cardiology, The Mount Sinai Medical Center, 1 Gustave Levy Place, New York, New York 10029.
Hydralazine produces significant hemodynamic and clinical improvement in many patients with severe chronic congestive heart failure. 1-5 The drug reduces impedance to left ventricular outflow, thereby substantially increasing cardiac output and stroke volume. With institution of maintenance therapy, dyspnea and fatigue diminish, and hemodynamic and clinical benefits are sustained during long-term outpatient use.3, 4 Despite early favorable reports, more recent studies have indicated that the response to hydralazine therapy in patients with heart failure is variable. 6-I° Whereas marked symptomatic improvement occurs in many patients, 1,5 others experience little objective clinical benefit 6-s and a significant number of patients manifest only minimal hemodynamic responses. 9-11 Because previous studies have utilized fixed doses of the drug, it is not known whether the limited response in some patients is due to the administration of insufficient quantities of the drug or to the patients' inability to respond favorably to the drug's pharmacologic effects. To resolve this quest;on, we evaluated the hemodynamic effects
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of progressively larger doses of hydralazine in patients with heart failure who failed to respond to conventional doses. Methods
Patients: We evaluated 45 consecutive patients with severe chronic congestive heart failure refractory to optimal conventional therapy with digitalis and diuretic agents. All were in New York Heart Association functional class IV. 12 There were 34 men and 11 women with an age range of 39 to 89 years (mean 64). All patients had persistent dyspnea at rest or on minimal exertion and progressive fatigue or azotemia, or both, with increments in diuretic dosage. The cause of the heart failure was idiopathic cardiomyopathy in 15 patients, ischemic cardiomyopathy in 21 and advanced valve regurgitation of rheumatic origin in 6 (affecting the mitral valve in 3, the aortic valve in 2 and both valves in 1); 3 patients had had prosthetic valve replacement (of the mitral valve in 1 and both the aortic and mitral valves in the other 2). The diagnosis was based on clinical, electrocardiographic, echocardiographic and radioisotopic criteria and was confirmed with cardiac catheterization studies in 22 patients. Eight patients had clinical or angiographic evidence of severe mitral regurgitation. The duration of heart failure ranged from 2 to 8 years. Normal sinus rhythm was present in 35 patients, atrial fibrillation in 5 and ventricular pacemaker rhythm in 5. Symptoms persisted despite therapeutic doses of digoxin and furosemide, the latter in daily doses of 80 to 400 mg. Six patients were evaluated after an empiric trial of oral hydralazine (150 to 300 mg daily) had failed to produce clinical improvement. All patients were studied during a period of relative clinical stability. No patient had sustained a myocardial infarction within 3 months or had an acute exacerbation of congestive heart failure within 7 days before evaluation. Maintenance therapy with prazosin or hydralazine was withheld for at least 2 weeks before the present study. Hemodynamic measurements: After written informed consent was obtained from the patient, right heart catheterization was performed with a triple lumen flow-directed balloon-tipped catheter (Edwards or Instrumentation Laboratories) through which measurements of right atrial, pulmonary arterial and pulmonary capillary wedge pressures were made. Arterial cannulas were inserted percutaneously or by cutdown procedure into the radial artery in 39 patients; in the other 6, systemic arterial pressure was measured using standard cuff methods. All measurements were made with zero reference level at the mid axillary line with the patient supine. Left ventricular filling pressure was measured as mean pulmonary capillary wedge pressure or as pulmonary arterial diastolic pressure after its identity with wedge pressure was established. Cardiac output (by the thermodilution method) was determined in triplicate using a bedside cardiac computer (Instrumentation Laboratories) and iced injectate. Heart rate was derived from a continuously recorded electrocardiogram. Before each dose of hydralazine was given, a stable control period was established and verified by repeated determinations of the following hemodynamic variables for a minimum of 3 hours with a variation of less than 10 percent: mean arterial pressure, heart rate, mean pulmonary arterial pressure, left ventricular filling pressure, mean right atrial pressure and cardiac output. All variables were redetermined every 30 minutes for 3 hours after each oral dose of hydralazine; and every 10 minutes for 30 to 40 minutes after each intravenous
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dose. A response to the drug was defined as a decrease in systemic vascular resistance greater than 20 percent from control values, the reduction persisting for at least 1 hour a~ assessed with three consecutive determinations. Drug administration: After all medications were withheld for 12 to 24 hours and a stable control period was achieved, each patient received a single dose of 100 mg of hydralazine orally. If there was no response to this dose within 2 or 3 hours, the patient was given a dose of 150 to 200 mg orally. This second dose followed the initial dose by 18 to 24 hours, in 7 patients and by only 2 to 3 hours in the remaining 12. If there was no significant hemodynamic response to the second dose, 20 mg hydralazine was administered intravenously 2 to 3 hours later. In three patients who responded only to intravenous hydralazine single doses of 600 or 800 mg of the drug were administered orally 24 hours later after all hemodynamic variables had returned to control values. Maintenance therapy was instituted in each patient with the dose of hydralazine determined to be effective by invasive monitoring. Clinical symptoms were carefully recorded in each case. Data analysis: Mean systemic and pulmonary arterial pressures were determined with electronic filtration; in patients with indirectly measured systemic pressures, mean pressure was calculated as diastolic pressure plus one-third of the systolic minus the diastolic pressure. Derived hemodynamic variables were determined as follows: Cardiac index - cardiac output/body surface area (liters/rain per m2); systemic vascular resistance = 80 × (mean arterial pressure mean right atrial pressure)/cardiac output (dynes s cm-5); and pulmonary vascular resistance = 80 X (mean pulmonary arterial pressure - left ventricular filling pressure/cardiac output (dynes s cm-5). For each patient, the dose of hydralazine that produced a significant decrease in systemic vascular resistance was selected as the effective dose for that patient. All hemodynamic variables at the time of the maximal decrease in systemic vascular resistance were compared with the control values before administration of hydralazine utilizing the t test for paired data. The patients were then classified into two groups according to whether the effective dose of hydralazine was 100 mg (group A) or greater (group B). This dose was chosen as the point of separation because it is the maximal single dose of hydralazine currently used in patients with heart failure. 2 The underlying etiologic, pathophysiologic and hemodynamic variables in patients in groups A and B were compared using the t test for independent variables and the chi square method with the Yates correction for continuity. The responses to 100 mg of hydralazine were then evaluated in relation to the control value for mean right atrial pressure by analysis of variance utilizing the arc sine transformation for proportions 13 and the chi square method for 4 X 2 tables. Results
Hemodynamic responses to effective doses of hydralazine (Table I): Twenty-six patients (group A) responded to the administration of the initial dose of 100 mg of hydralazine; 19 patients (group B, 42 percent) did not. In group B, a second dose of 150 to 200 mg was effective in 14 patients; 7 of these received the second dose 24 hours after and 7 received it within 3 hours after the initial 100 mg dose. N o significant h e m o d y n a m i c effects could be demonstrated in five patients even with a cumulative dose of 300 mg orally over 2 to 3 hours; however, all five patients subsequently responded to intravenous injection of 20 mg of hydralazine.
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TABLE I
Summary of Hemodynamic Changes With Effective Doses of Hydralazine in Groups A and B Group A Cardiac index (L/min'per m 2) Left ventricular filling pressure (mm Hg) Mean arterial pressure (mm Hg) Mean pu monary arter a pressure (ram Hg) Mean right atrial pressure (mm Hg) Heart rate (beats/min) Systemic vascular resistance (dynes s cm -5) Pulmonary vascular resistance (dynes s cm -s)
C H Ct H C H C Pt C§ H C H C pI C H
Group B
1.94 4- 0.10 2.98 4- 0.16" 21.7 4- 1.0 17.8 4- 0.9* 79,2 4- 2.0 66.1 4- 2.0* ;36.1 q- 1.4 33.0 4- 1.7" 9.2 4- 1.3 8.7 4- 1.4 84 4- 3 88 4- 4 1807 4- 100 977 4- 62* 380 4- 35 266 4- 29*
1.79 2.84 25,2 21.5 83.9 73.3 39.8 37.8 14.0 14.7 88 95 1818 974 386 280
444444444~ 444444-
0.09 0.18" 1.2 1.2t 3,4 3.2* 1.8 1.7 1.5 1.6
4I 3t 82 57* 33 27*
* p <0.001 (peak hydralazine effect versus control). t p <0.05 (control group A versus control group B). p <~0.01 (peak hydralazine effect versus control), p <0,025 (control group A versus control group B). IF p <0.05 (peak hydralazine effect versus contro ) C ~ control; H = hydralazine.
In both groups of patients, effective doses of hydralazine produced substantial increases in cardiac index and marked decreases in systemic vascular resistance associated with moderate reductions in left ventricular filling pressure and mean arterial pressure. HeArt rate increased slightly in both groups and there were no overall changes in mean right atrial pressure (Table
I). The control cardiac index, mean arterial pressure, heart rate and systemic and pulmonary vascular resistances in groups A and B and the changes in these variables produced by hydralazine in the two groups were similar. Groups A and B Were not significantly different with respect to the number of patients with ischemic heart disease (9 in group A, 12 in group B) or the number of patients with evidence of severe mitra! regurgitation (6 in group A, 2 in group B). Role of right atrial pressure and left ventrieular filling pressure: Only two variables differed significantly in groups A andB. Patients in group B had higher control values for mean right atrial pressure (14.0 + 1.5 versus 9.2 + 1.3 mm Hg; p <0.025) and left ventricular filling pressure (25.5 + 1.2 versus 21.7 ± 1.0 mm Hg; p <0.05) than.those of patients in group A (values expressed as mean ± standard error of the mean). Only 5 (19 percent) of the 26 patients in group A had a mean right atrial pressure of 14 mm Hg or greater, compared with 11 (58'percent) of 19 patients in group B (p <0.02). The changes in mean right atrial and left ventricular filling pre'ssures during hydralazine therapy in the two groups were similar. Figure 1 demonstrates that the higher the control mean right atrial pressure, the smaller was the decrease in systemic vascular resistance with 100 mg doses of hydralazine (linearity significant at p <0.025 by analysis of variance) and the fewer the number of 15atients who
responded to this dose (p <0.05 by chi square analysis). Twenty-one (72 percent) of 29 patients with a mean right atrial pressure at less than 14 mm Hg responded to 100 mg of hydralazine, compared with only 5 (31 percent) of 16 patients with a higher pressure value (p <0.02). Five of the eight patients whose mean right atrial pressure was 5 mm Hg or less in the control period had a greater than 20 percent decrease in mean arterial pressure with t h e 100mg dose of hydralazine; this decrease was accompanied by dizziness in four of the five. Symptomatic hypotension did not recur in these four patients when the dose of hydralazine was reduced to
60Z
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o 50O3 20hi t--
p lou') ~
0
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14/21
<6 6-I~5 t 4 - 2 0 > 2 0 MEAN RIGHT ATRIAL PRESSURE (mm Hg)
FIGURE 1. Relation between the control mean right atrial pressure and the percent decrease (% ~) in systemic vascular resistance observed after the administration of single oral doses of 100 mg of hydralazine in 45 patients. Data expressed as mean 4- standard error of the mean. The' proportion of patients who responded to hydralazine at each level of mean right atrial pressure is shown within each bar,
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75 mg. Of the 37 patients with a mean right atrial pressure greater than 5 mm Hg, only 1 (with a mean right atrial pressure 9 mm Hg) had a greater than 20 percent decrease in this pressure with the 100 mg dose; this decrease was accompanied by dizziness, which did not recur with a subsequent reduction in dosage to 75 mg. Massive drug dosage: In three of the five patients who responded only to intravenous hydralazine therapy, an attempt was made to reproduce the effects of intravenous administration by administering massive oral doses of the drug after hemodynamic variables had returned to control values. In one patient a single oral dose of 600 mg proved effective; although the hemodynami c response was smaller than that observed after the 20 mg intravenous dose. In the other tw o patients, the response to a single oral dose of 800 mg of hydralazine was similar to that observed after intravenous administration of the drug. Figure 2 illustrates the response in one of these two patients. No s!gnificant hemodynamic changes had been seen in either patient with oral isosorbide dinitrate (single doses of 100 to.200 mg in one patient and 80 mg in the other) despite rapid responses in both patients to 10 mg of isosorbide dinitrate administered sublingually. Maintenance therapy: In twp patients hydralazine therapy was instituted with dose s ranging from 75 to 800 mg orally in 38 patients and 20 mg intravenously in 2 patients, administered every 8 to 12 hours (Fig. 3, top). Daily doses, therefore, ranged from 150 to 2,400 mg daily orally and 60 mg daily intravenously (Fig. 3, bottom). After 1 week of maintenance therapy, four of the six patients who had'failed to benefit from small em-
pirically determined doses of the drug manifested sustained improvement with the larger doses determined by invasive testing. Headaches were observed in 12 patients (5 in group A and 7 in group B), but were generally mild and subsided in all cases despite continued administration of the drug. Symptomatic hypotension was observed in five patients (all in group A), as outlined earlier. Within 7 days of institution of therapy, administration of the drug was discontinued in three patients in group A (because of episodes of ischemic chest pain in one, severe nausea and vomiting in the second and hypotension and tachycardia in the third) and in three patients in group B (because of hypotension and tachycardia in one and severe nausea and vomiting in the other two). Discussion
Dose requirements of hydralazine therapy: Our results indicate that the dose requirements of hydralazine in patients with severe chronic heart f~ilure are highly variable and are generally much larger than those commonly utilized in antihypertensive 'therapy. Whereas hypertensive patients usually respond to doses of 50 mg or less, 14J5 patients with heart failure rarely demonstrate hemodynamic effects with single doses smaller than 75 m g J ,16 Furthermore, in the present series of 45 patients, more than 40 percent required single doses of hydralazine that were substantially larger than 100 mg in order to reduce significantly systemic vascular resistance. Effective doses ranged a~ high as 800 mg Orally as a single dose and up to 2,400 mg daily,
DoseRequ/)'ernents ~
2oi HYDRALAZINE DOSE---~
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200 rng
20rag
16
800mg
12
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LVFP 3~
(mmHg)
24,
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N=45
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78 70
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75
100
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150-300 >300 or IV
N=45
2o
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(dynes- 1200
12
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4 FIGURE 2. Graph showing no significant hemodynamic effects in a 62
year old man after the administration of a cumulative oral (PO) dose of 300 mg of hydralaz!ne during a 3 hour period. However, marked responses were observed after the administration of 20 mg intravenously (IV). This response was reproduced 24 hours later under similar pretreatment conditions by the administration of a single dose of 800 mg orally. Each interval on the time scale represents 30 minutes. CI = cardiac index; LVFP -- left ventricular filling pressure; MAP = mean arterial pressure; SVR = systemic vascular resistance.
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0
150-225 300
400-900 >900 or IV
HYDRALAZINE (mg) FIGURE 3. Dose requirements of hydralazine in 45 patients. The number of patients who responded at each dose level is illustrated. Top, effective single doses of the drug. Bottom, daily dosage requirements based on a dose schedule of every 8 to 12 hours.
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HYDRALAZINE IN HEART FAILURE--PACKER ET AL.
and occasionally a patient responded only to intravenous administration. This may explain why previous investigators utilizing fixed schedules of smaller doses of hydralazine in patients with heart failure have reported inconsistent effects on cardiac index and little objective improvement in exercise tolerance, s-l~ Indeed, in four of our patients, the administration of these larger doses was effective in lessening dyspnea and fatigue, whereas smaller doses tried empirically before invasive testing had not produced symptomatic benefit. Although our study population may be preselected to some extent because of a tendency for patients to be referred after failure of an empiric trial with hydralazine (the true proportion of patients requiring large doses of the drug may be smaller), only six patients were evaluated after failure of previous hydralazine therapy. Reasons for large dose requirements: The reasons for the unusually large dosage requirements for hydralazine in patients with severe heart failure are unknown. One might have expected patients with heart failure to be more sensitive than hypertensive patients to hydralazine because, in heart failure, compensatory reflexes that might counteract peripheral vasodilatation are attenuated, 17-21 hepatic metabolic inactivation of the drug may be diminished by the effects of hepatic venous congestion 22,23 and renal clearance of the agent is reduced. 16,24However, recent evidence has indicated that the peripheral vasculature in patients with heart failure may be hyporesponsive to endogenous or exogenous vasodi!ator stimuli, either because of increased vascular stiffness secondary to an increase in sodium content within the arterial vessel walls or because of an increase in tissue pressure in edematous states. 25-27 This is consistent with our finding that patients requiring very large doses of hydralazine manifested higher ventricular filling pressures than did patients who responded to smaller doses. This may also explain why the development of tolerance to vasodilator therapy in hypertensive patients is associated with fluid retention and why responsiveness to the drug is restored after the administration of diuretic agents. 2s,29 Malabsorption of hydralazine may explain the failure of several patients to respond to massive doses of the drug (300 m g during a 3 hour period) administered orally although they had marked hemodynamic changes when small doses of the drug were administered intravenously. Since patients requiring very large doses demonstrated significantly higher mean right atrial pressures than did patients who responded to smaller doses~ impaired drug absorption could be related to mesenteric venous congestion, a factor that may explain the relotive ineffectiveness of other cardiovascular agents administered orally to patients with severe heart failure. 3°-32 Indeed, two of our patients in group B did not respond to massive doses of isosorbide dinitrate administered oral'l:~, whereas small doses administered sublingually produced marked hemodynamic changes. Although enhanced metabolic inactivation of the drug by genetically rapid hepatic acetylator enzymes can
result in a greater dosage requirement of hydralazine in some hypertensive patients, 24,33the magnitude of this effect is too small to account for the unusually large doses needed by the patients in our group B and would not explain the ineffectiveness in these patients of other orally administered drugs metabolized by other enzyme systems. Ribner et al. 11 suggested that patients with a high level of systemic vascular resistance before treatment may not respond to hydralazine because the effectiveness of vasodilators in patients with severely limited cardiac reserve is impaired. A major limitation of their study is the use of a fixed schedule of hydralazine administration with an upper dosage limit of 400 mg daily. By using progressive increments in dosage where indicated, we could find no differences in the pretreatment systemic vascular resistance between patients in groups A and B. Furthermore, the hemodynamic responses to effective doses of hydralazine were similar qualitatively and quantitatively in both groups, the only difference being the dose of the drug needed to produce the observed hemodynamic effects. Side effects of large dose hydralazine therapy: In spite of these very large doses of hydralazine, acute adverse reactions were no more frequent in patients in group B than in those in group A. In fact, symptomatic hypotension was observed only with doses of 100 mg and only in patients in group A with low mean right atrial pressure. An initial dose of 75 mg of hydralazine seems warranted, therefore, in patients whose pretreatment mean right atrial pressure is less than 6 mm Hg. Whether long-term therapy will place patients in group B at greater risk of having hydralazine-induced systemic lupus erythematosus than group A remains to be determined.34, 35 Implications: This study underscores the need for the administration of unusually large doses of hydralazine to produce significant impr0vement in left ventricular performance in patients with severe chronic heart failure. The dose required is highly variable (75 mg to 800 mg as a single dose) and is generally larger than that usually needed in hypertensive patients. In more than 40 percent of patients, significant hemodynamic effects are seen only with single doses greater than 100 rag, and occasionally a patient will respond only to intravenous administration of the agent. As a result, the failure of hydralazine to produce clinical improvement in an individual patient may be due to the administration of subtherapeutic quantities of the drug. Verification and quantification of hemodynamic changes by invasive studies may be necessary in patients who fail to respond to small empirically determined doses.
Acknowledgments
We are greatly indebted to the nurses of the Alfred L. Rose Cardiac Care Unit of the Mount Sinai Medical Center for their invaluable assistance.
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HYDRALAZINE IN HEART FAILURE--PACKER ET AL.
References 1. Chatterjee K, Parmley WW, Massie B, et al. Oral hydralazine for chronic refractory heart failure. Circulation 1976; 54:879-83. 2. Franciosa JA, Pierpont G, Cohn J. Hemodynamic improvement after oral hydralazine in left ventricular failure. Ann Intern Med 1977; 86:388-93. 3. Chatterjee K, Ports T, Rubin S, et al. Sustained beneficial hemodynamic effects during long term hydralazine in patients with chronic heart failure (abstr). Circulation 1978; 58:Supp111:11-28. 4. Fitchett DH, Marin Neto JA, Oakley CM, Goodwin JF. Hydralazine in the management of left ventricular failure. Am J Cardio11979; 44:303-9, 1979. 5. Massie B, Greenberg B, Brundage B, Chalterjee K, Botvinick E, Parmley WW. Beneficial effects of hydralazine in severe mitral regurgitation. Circulation 1978; 58:273-9. 6. Packer M, Meller J, Medina N, Gorlin R, Herman MV. Usefulness of echocardiographicallydetermined left ventricular volume as a noninvasive predictor of hydralazine response in heart failure (abstr). C!in Res 1979; 27:192A. 7. Packer M, Meller J, Gorlin R, Teichholz LE, Herman MV. Dose dependent reduction in right and left ventricular filling pressures with hydra!azine (abstr). Am J Cardiol 1978; 41:420. 8. Jacobs W, Herrick A, Loeb H, Gunnar R. Noninvasive assessment of daily hydralazine therapy in patients with advanced cardiac failure (abstr). Circulation 1977; 56, 57: Supp1111:111-275. 9. Franciosa JA, Cohn JN. Immediate effects of hydralazine-isosorbide dinitrate combination on exercise capacity and exercise hemodynamics in patients with left ventricular failure. Circulation 1979; 59:1085-97. 10. Lejemtel T, Hellman C, Elkayam U, et al. Hemodynamic and renal responses to oral hydralazine therapy in severe heart failure (abstr). Circulation 1977; 56, 57:Supp1111:111-9. 11. Ribner HS, Lejemtel TH, Elkayam U, Sonnenblick EH. Relationship between initial systemic vascular resistance and the response to vasodilators in severe congestive heart failure (abstr). Am J Cardiol 1979; 43: 404. 12. Criteria Committee of the New York Heart Association. Nomenclature and Criteria for Diagnosis of Diseases of the Heart and Great Vessels. 7th ed. Boston: Little, Brown, 1973; 286. 13. Snedecor GW, Cochran WG. Statistical Methods. Ames, Iowa: The Iowa state University Press, 1967: 327. 14. Zacest R, Gilmore E, Koch-Weser J, Treatment of essential hypertension with combined vasodilator and beta adrenergic blockade, N Engl J Med 1972; 286:617-22. 15. Kach-Weser J. Hydralazine. N Engl J Med 1976; 295:320-23. 16. Packer M, Meller J, Gorlin R, Teichholz L, Herman MV. Pharmacodynamics of hydralazine in refractory heart failure (abstr). Circulation 1977; 56, 57: Supp1111:111-176. 17. Chidsey CA, Braunwald E, Morrow AG. Catecholamine excretion and cardiac stores of norepinephrine in congestive heart failure. Am J Med 1965; 39:442-51. 18. Chidsey CA, Kaiser GA, Sonnenblick EH, Spann JF, Braunwald E. Cardiac norepinephrine stores in experimental heart failure in
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the dog. J Clin Invest 1964; 43:2386-93. 19. Kramer RS, Mason DT, Braunwald E. Augmented sympathetic neurotransmitter activity in the peripheral vascular bed of patients with congestive heart failure and cardiac norepinephrine depletion. Circulation ~1968;38:629-34. 20. Hlggins CB, Vatner SF, Eckberg DL, Braunwald E. Alterations in the baroreceptor reflex in conscious dogs with heart failure. J Clin Invest 1972; 51:715-24. 21. Gellhorn E. The significance Of the state of the central autonomic nervous system for quantitative and qualitative aspects of some cardiovascular reactions. Am Heart J 1964; 67:106-20. 22. Hepner GW, Vesell ES, Tanlum KR. Reduced drug elimination in congestive heart failure. Studies using aminopyrine as a model drug. Am J Med 1978; 65:271-6. 23. Tokola O, Pelkonen O, Karki NT, Luoma P, Kaltiala EH, Larmi TKI. Hepatic drug-oxidizing enzyme systems and urinary D-glucaric acid excretion in patients with congestive heart failure. Br J Clin Pharmacol 1975; 2:429-36. 24. Reidenberg MM, Drayer D, Demarco AL, Bello C. Hydralazine elimination in man. Clin PharmacolTher 1973; 14:970-7. 25. Mason DT, Zelis R, Longhurst I, Lee G. Cardiocirculatory responses to muscular exercise in congestive heart failure. Progr Cardiovasc Dis 1977; 19:475-89. 26. Zelis R, Longhurst J, Capone RJ, Mason DT. A comparison of regional blood flow and oxygen utilization during dynamic forearm exercise in normal subjects and patients with congestive heart failure. Circulation 1974; 50:137-43. 27. Zelis R, Mason DT, Braunwald E. A comparison of the effects of vasodilator stimuli on peripheral resistance vessels in normal subjects and in patients with congestive heart failure. J Clin Invest 1968; 47:960-70. 28. Finnerty FA, Davidov M, Mroczek WJ, Gavrilovich L. Influence of extracellular fluid volume on response to antihypertensive drugs. Circ Res 1970; 27 Suppl 1:71-80. 29. Koch-Weser J. Vasodilator drugs in the treatment of hypertension. Arch Intern Med 1974; 133:1017-27. 30. Craig LC, Lawn B, Levine SA. Resistance and sensitivity to digitalis. JAMA 1958; 166:2139-44. 31. Smith TW, Haber E: Digitalis. N Engl J Med 1973; 289:106372. 32. Crouthamel WG. The effect of congestive heart failure on quinidin'e pharmacokinetics. Am Heart J 1975; 90:335-9. 33. Zacest R, Koch-Weser J. Relationship of hydralazine plasma concentration to dosage and hypotensive action. Clin Pharmacol Ther 1972; 13:420-25. 34. Alarcon-Segovia D, Wakim HC, Worlhington IW, Ward LE. Clinical and experimental studies on the hydralazine syndrome and its relationship to systemic lupus erythematosus. Medicine 1967; 46: 1-33. 35. Perry HM. Late toxicity to hydraiazine resembling systemic lupus erythematosus or rheumatoid arthritis. Am J Med 1973; 54~5872.
Volume 45
MILTON PACKER, MD, FACC JOSE MELLER, MD, FACC NORMA MEDINA, RN RICHARD GORLIN, MD, FACC MICHAEL V. HERMAN, MD, FACC New York, New York
To evaluate the doses of hydralazine needed to obtain significant hemodynamic responses in severe chronic refractory heart failure, 45 consecutive patients received incremental doses of the drug during invasive hemodynamic monitoring. Twenty-six patients (group A) responded to the oral administration of single doses of 100 mg of hydralazine, whereas 19 patients (42 percent) (group B) did not. Of the patients in group B, 14 responded to 150 to 300 mg orally as a single dose, 3 patients required a single dose of 600 or 800 mg orally and 2 patients responded only to intravenous administration of the drug. In spite of the different dosage requirements of hydralazine, the hemodynamic responses to effective doses were similar in the two groups. The control etiologic, pathophysiologic and hemodynamic variables were similar in both groups, except that patients in group B had higher control values for mean right atrial pressure (14.0 4- 1.5 versus 9.2 4- 1.3 mm Hg; p <0.025) and left ventricular filing pressure (25.2 4- 1.2 versus 21.7 41.0 mm Hg; p <0.05) than patients in group A. Twenty-one of 29 patients (72 percent) with a control mean right atrial pressure of less than 14 mm Hg responded to 100 mg of hydralazine, whereas this dose was effective in only 5 (31 percent) of 16 patients with a higher pressure value (p
<0.02). In conclusion, the doses required for effective hydralazine therapy in patients with severe heart failure are variable and are generally higher than those utilized in hypertensive patients. This may be related to varying degrees of vascular hyporesponsiveness or drug malabsorption, or both, observed in states of high venous pressure. The failure of hydralazine to produce clinical improvement in an individual patient may therefore be due to the administration of subtherapeutic quantities of the drug.
From the Division Of Cardiology, Department of Medicine, The Moufit Sinai School of Medicineof The City university of New Yo~-k,New York, New York. This work was supported in part by grants from the Heart ResearchFoundation, Inc., New York, New York and the Kriendler-Berns Foundation, New York~ New York. Address for reprints: Milton Packer, MD, Division of Cardiology, The Mount Sinai Medical Center, 1 Gustave Levy Place, New York, New York 10029.
Hydralazine produces significant hemodynamic and clinical improvement in many patients with severe chronic congestive heart failure. 1-5 The drug reduces impedance to left ventricular outflow, thereby substantially increasing cardiac output and stroke volume. With institution of maintenance therapy, dyspnea and fatigue diminish, and hemodynamic and clinical benefits are sustained during long-term outpatient use.3, 4 Despite early favorable reports, more recent studies have indicated that the response to hydralazine therapy in patients with heart failure is variable. 6-I° Whereas marked symptomatic improvement occurs in many patients, 1,5 others experience little objective clinical benefit 6-s and a significant number of patients manifest only minimal hemodynamic responses. 9-11 Because previous studies have utilized fixed doses of the drug, it is not known whether the limited response in some patients is due to the administration of insufficient quantities of the drug or to the patients' inability to respond favorably to the drug's pharmacologic effects. To resolve this quest;on, we evaluated the hemodynamic effects
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HYDRALAZINE IN HEART FAILURE--PACKER ET AL,
of progressively larger doses of hydralazine in patients with heart failure who failed to respond to conventional doses. Methods
Patients: We evaluated 45 consecutive patients with severe chronic congestive heart failure refractory to optimal conventional therapy with digitalis and diuretic agents. All were in New York Heart Association functional class IV. 12 There were 34 men and 11 women with an age range of 39 to 89 years (mean 64). All patients had persistent dyspnea at rest or on minimal exertion and progressive fatigue or azotemia, or both, with increments in diuretic dosage. The cause of the heart failure was idiopathic cardiomyopathy in 15 patients, ischemic cardiomyopathy in 21 and advanced valve regurgitation of rheumatic origin in 6 (affecting the mitral valve in 3, the aortic valve in 2 and both valves in 1); 3 patients had had prosthetic valve replacement (of the mitral valve in 1 and both the aortic and mitral valves in the other 2). The diagnosis was based on clinical, electrocardiographic, echocardiographic and radioisotopic criteria and was confirmed with cardiac catheterization studies in 22 patients. Eight patients had clinical or angiographic evidence of severe mitral regurgitation. The duration of heart failure ranged from 2 to 8 years. Normal sinus rhythm was present in 35 patients, atrial fibrillation in 5 and ventricular pacemaker rhythm in 5. Symptoms persisted despite therapeutic doses of digoxin and furosemide, the latter in daily doses of 80 to 400 mg. Six patients were evaluated after an empiric trial of oral hydralazine (150 to 300 mg daily) had failed to produce clinical improvement. All patients were studied during a period of relative clinical stability. No patient had sustained a myocardial infarction within 3 months or had an acute exacerbation of congestive heart failure within 7 days before evaluation. Maintenance therapy with prazosin or hydralazine was withheld for at least 2 weeks before the present study. Hemodynamic measurements: After written informed consent was obtained from the patient, right heart catheterization was performed with a triple lumen flow-directed balloon-tipped catheter (Edwards or Instrumentation Laboratories) through which measurements of right atrial, pulmonary arterial and pulmonary capillary wedge pressures were made. Arterial cannulas were inserted percutaneously or by cutdown procedure into the radial artery in 39 patients; in the other 6, systemic arterial pressure was measured using standard cuff methods. All measurements were made with zero reference level at the mid axillary line with the patient supine. Left ventricular filling pressure was measured as mean pulmonary capillary wedge pressure or as pulmonary arterial diastolic pressure after its identity with wedge pressure was established. Cardiac output (by the thermodilution method) was determined in triplicate using a bedside cardiac computer (Instrumentation Laboratories) and iced injectate. Heart rate was derived from a continuously recorded electrocardiogram. Before each dose of hydralazine was given, a stable control period was established and verified by repeated determinations of the following hemodynamic variables for a minimum of 3 hours with a variation of less than 10 percent: mean arterial pressure, heart rate, mean pulmonary arterial pressure, left ventricular filling pressure, mean right atrial pressure and cardiac output. All variables were redetermined every 30 minutes for 3 hours after each oral dose of hydralazine; and every 10 minutes for 30 to 40 minutes after each intravenous
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dose. A response to the drug was defined as a decrease in systemic vascular resistance greater than 20 percent from control values, the reduction persisting for at least 1 hour a~ assessed with three consecutive determinations. Drug administration: After all medications were withheld for 12 to 24 hours and a stable control period was achieved, each patient received a single dose of 100 mg of hydralazine orally. If there was no response to this dose within 2 or 3 hours, the patient was given a dose of 150 to 200 mg orally. This second dose followed the initial dose by 18 to 24 hours, in 7 patients and by only 2 to 3 hours in the remaining 12. If there was no significant hemodynamic response to the second dose, 20 mg hydralazine was administered intravenously 2 to 3 hours later. In three patients who responded only to intravenous hydralazine single doses of 600 or 800 mg of the drug were administered orally 24 hours later after all hemodynamic variables had returned to control values. Maintenance therapy was instituted in each patient with the dose of hydralazine determined to be effective by invasive monitoring. Clinical symptoms were carefully recorded in each case. Data analysis: Mean systemic and pulmonary arterial pressures were determined with electronic filtration; in patients with indirectly measured systemic pressures, mean pressure was calculated as diastolic pressure plus one-third of the systolic minus the diastolic pressure. Derived hemodynamic variables were determined as follows: Cardiac index - cardiac output/body surface area (liters/rain per m2); systemic vascular resistance = 80 × (mean arterial pressure mean right atrial pressure)/cardiac output (dynes s cm-5); and pulmonary vascular resistance = 80 X (mean pulmonary arterial pressure - left ventricular filling pressure/cardiac output (dynes s cm-5). For each patient, the dose of hydralazine that produced a significant decrease in systemic vascular resistance was selected as the effective dose for that patient. All hemodynamic variables at the time of the maximal decrease in systemic vascular resistance were compared with the control values before administration of hydralazine utilizing the t test for paired data. The patients were then classified into two groups according to whether the effective dose of hydralazine was 100 mg (group A) or greater (group B). This dose was chosen as the point of separation because it is the maximal single dose of hydralazine currently used in patients with heart failure. 2 The underlying etiologic, pathophysiologic and hemodynamic variables in patients in groups A and B were compared using the t test for independent variables and the chi square method with the Yates correction for continuity. The responses to 100 mg of hydralazine were then evaluated in relation to the control value for mean right atrial pressure by analysis of variance utilizing the arc sine transformation for proportions 13 and the chi square method for 4 X 2 tables. Results
Hemodynamic responses to effective doses of hydralazine (Table I): Twenty-six patients (group A) responded to the administration of the initial dose of 100 mg of hydralazine; 19 patients (group B, 42 percent) did not. In group B, a second dose of 150 to 200 mg was effective in 14 patients; 7 of these received the second dose 24 hours after and 7 received it within 3 hours after the initial 100 mg dose. N o significant h e m o d y n a m i c effects could be demonstrated in five patients even with a cumulative dose of 300 mg orally over 2 to 3 hours; however, all five patients subsequently responded to intravenous injection of 20 mg of hydralazine.
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TABLE I
Summary of Hemodynamic Changes With Effective Doses of Hydralazine in Groups A and B Group A Cardiac index (L/min'per m 2) Left ventricular filling pressure (mm Hg) Mean arterial pressure (mm Hg) Mean pu monary arter a pressure (ram Hg) Mean right atrial pressure (mm Hg) Heart rate (beats/min) Systemic vascular resistance (dynes s cm -5) Pulmonary vascular resistance (dynes s cm -s)
C H Ct H C H C Pt C§ H C H C pI C H
Group B
1.94 4- 0.10 2.98 4- 0.16" 21.7 4- 1.0 17.8 4- 0.9* 79,2 4- 2.0 66.1 4- 2.0* ;36.1 q- 1.4 33.0 4- 1.7" 9.2 4- 1.3 8.7 4- 1.4 84 4- 3 88 4- 4 1807 4- 100 977 4- 62* 380 4- 35 266 4- 29*
1.79 2.84 25,2 21.5 83.9 73.3 39.8 37.8 14.0 14.7 88 95 1818 974 386 280
444444444~ 444444-
0.09 0.18" 1.2 1.2t 3,4 3.2* 1.8 1.7 1.5 1.6
4I 3t 82 57* 33 27*
* p <0.001 (peak hydralazine effect versus control). t p <0.05 (control group A versus control group B). p <~0.01 (peak hydralazine effect versus control), p <0,025 (control group A versus control group B). IF p <0.05 (peak hydralazine effect versus contro ) C ~ control; H = hydralazine.
In both groups of patients, effective doses of hydralazine produced substantial increases in cardiac index and marked decreases in systemic vascular resistance associated with moderate reductions in left ventricular filling pressure and mean arterial pressure. HeArt rate increased slightly in both groups and there were no overall changes in mean right atrial pressure (Table
I). The control cardiac index, mean arterial pressure, heart rate and systemic and pulmonary vascular resistances in groups A and B and the changes in these variables produced by hydralazine in the two groups were similar. Groups A and B Were not significantly different with respect to the number of patients with ischemic heart disease (9 in group A, 12 in group B) or the number of patients with evidence of severe mitra! regurgitation (6 in group A, 2 in group B). Role of right atrial pressure and left ventrieular filling pressure: Only two variables differed significantly in groups A andB. Patients in group B had higher control values for mean right atrial pressure (14.0 + 1.5 versus 9.2 + 1.3 mm Hg; p <0.025) and left ventricular filling pressure (25.5 + 1.2 versus 21.7 ± 1.0 mm Hg; p <0.05) than.those of patients in group A (values expressed as mean ± standard error of the mean). Only 5 (19 percent) of the 26 patients in group A had a mean right atrial pressure of 14 mm Hg or greater, compared with 11 (58'percent) of 19 patients in group B (p <0.02). The changes in mean right atrial and left ventricular filling pre'ssures during hydralazine therapy in the two groups were similar. Figure 1 demonstrates that the higher the control mean right atrial pressure, the smaller was the decrease in systemic vascular resistance with 100 mg doses of hydralazine (linearity significant at p <0.025 by analysis of variance) and the fewer the number of 15atients who
responded to this dose (p <0.05 by chi square analysis). Twenty-one (72 percent) of 29 patients with a mean right atrial pressure at less than 14 mm Hg responded to 100 mg of hydralazine, compared with only 5 (31 percent) of 16 patients with a higher pressure value (p <0.02). Five of the eight patients whose mean right atrial pressure was 5 mm Hg or less in the control period had a greater than 20 percent decrease in mean arterial pressure with t h e 100mg dose of hydralazine; this decrease was accompanied by dizziness in four of the five. Symptomatic hypotension did not recur in these four patients when the dose of hydralazine was reduced to
60Z
hl rt"
~- 4 0 ._J
o 50O3 20hi t--
p lou') ~
0
T/E
14/21
<6 6-I~5 t 4 - 2 0 > 2 0 MEAN RIGHT ATRIAL PRESSURE (mm Hg)
FIGURE 1. Relation between the control mean right atrial pressure and the percent decrease (% ~) in systemic vascular resistance observed after the administration of single oral doses of 100 mg of hydralazine in 45 patients. Data expressed as mean 4- standard error of the mean. The' proportion of patients who responded to hydralazine at each level of mean right atrial pressure is shown within each bar,
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HYDRALAZINE IN HEART FAILURE--PACKER ET AL.
75 mg. Of the 37 patients with a mean right atrial pressure greater than 5 mm Hg, only 1 (with a mean right atrial pressure 9 mm Hg) had a greater than 20 percent decrease in this pressure with the 100 mg dose; this decrease was accompanied by dizziness, which did not recur with a subsequent reduction in dosage to 75 mg. Massive drug dosage: In three of the five patients who responded only to intravenous hydralazine therapy, an attempt was made to reproduce the effects of intravenous administration by administering massive oral doses of the drug after hemodynamic variables had returned to control values. In one patient a single oral dose of 600 mg proved effective; although the hemodynami c response was smaller than that observed after the 20 mg intravenous dose. In the other tw o patients, the response to a single oral dose of 800 mg of hydralazine was similar to that observed after intravenous administration of the drug. Figure 2 illustrates the response in one of these two patients. No s!gnificant hemodynamic changes had been seen in either patient with oral isosorbide dinitrate (single doses of 100 to.200 mg in one patient and 80 mg in the other) despite rapid responses in both patients to 10 mg of isosorbide dinitrate administered sublingually. Maintenance therapy: In twp patients hydralazine therapy was instituted with dose s ranging from 75 to 800 mg orally in 38 patients and 20 mg intravenously in 2 patients, administered every 8 to 12 hours (Fig. 3, top). Daily doses, therefore, ranged from 150 to 2,400 mg daily orally and 60 mg daily intravenously (Fig. 3, bottom). After 1 week of maintenance therapy, four of the six patients who had'failed to benefit from small em-
pirically determined doses of the drug manifested sustained improvement with the larger doses determined by invasive testing. Headaches were observed in 12 patients (5 in group A and 7 in group B), but were generally mild and subsided in all cases despite continued administration of the drug. Symptomatic hypotension was observed in five patients (all in group A), as outlined earlier. Within 7 days of institution of therapy, administration of the drug was discontinued in three patients in group A (because of episodes of ischemic chest pain in one, severe nausea and vomiting in the second and hypotension and tachycardia in the third) and in three patients in group B (because of hypotension and tachycardia in one and severe nausea and vomiting in the other two). Discussion
Dose requirements of hydralazine therapy: Our results indicate that the dose requirements of hydralazine in patients with severe chronic heart f~ilure are highly variable and are generally much larger than those commonly utilized in antihypertensive 'therapy. Whereas hypertensive patients usually respond to doses of 50 mg or less, 14J5 patients with heart failure rarely demonstrate hemodynamic effects with single doses smaller than 75 m g J ,16 Furthermore, in the present series of 45 patients, more than 40 percent required single doses of hydralazine that were substantially larger than 100 mg in order to reduce significantly systemic vascular resistance. Effective doses ranged a~ high as 800 mg Orally as a single dose and up to 2,400 mg daily,
DoseRequ/)'ernents ~
2oi HYDRALAZINE DOSE---~
IOOrng
200 rng
20rag
16
800mg
12
.'-.\
2.E
U3
~-
8
F-
4
,,
0
CI 2.41 (I/min/m=) 2,O
Z LLI
LVFP 3~
(mmHg)
24,
MAP (rnmHg)
N=45
O
0=
78 70
rood
75
100
N
150-300 >300 or IV
N=45
2o
Z
SVR
(dynes- 1200
12
sec-cm-S) 800 i
i
i
i
i
i
i
i
DAY
i
i
i
I
i
I
i
i
I
i £.
i
i
i
l
i
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i
i
i
i
i
i
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i
2
4 FIGURE 2. Graph showing no significant hemodynamic effects in a 62
year old man after the administration of a cumulative oral (PO) dose of 300 mg of hydralaz!ne during a 3 hour period. However, marked responses were observed after the administration of 20 mg intravenously (IV). This response was reproduced 24 hours later under similar pretreatment conditions by the administration of a single dose of 800 mg orally. Each interval on the time scale represents 30 minutes. CI = cardiac index; LVFP -- left ventricular filling pressure; MAP = mean arterial pressure; SVR = systemic vascular resistance.
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0
150-225 300
400-900 >900 or IV
HYDRALAZINE (mg) FIGURE 3. Dose requirements of hydralazine in 45 patients. The number of patients who responded at each dose level is illustrated. Top, effective single doses of the drug. Bottom, daily dosage requirements based on a dose schedule of every 8 to 12 hours.
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HYDRALAZINE IN HEART FAILURE--PACKER ET AL.
and occasionally a patient responded only to intravenous administration. This may explain why previous investigators utilizing fixed schedules of smaller doses of hydralazine in patients with heart failure have reported inconsistent effects on cardiac index and little objective improvement in exercise tolerance, s-l~ Indeed, in four of our patients, the administration of these larger doses was effective in lessening dyspnea and fatigue, whereas smaller doses tried empirically before invasive testing had not produced symptomatic benefit. Although our study population may be preselected to some extent because of a tendency for patients to be referred after failure of an empiric trial with hydralazine (the true proportion of patients requiring large doses of the drug may be smaller), only six patients were evaluated after failure of previous hydralazine therapy. Reasons for large dose requirements: The reasons for the unusually large dosage requirements for hydralazine in patients with severe heart failure are unknown. One might have expected patients with heart failure to be more sensitive than hypertensive patients to hydralazine because, in heart failure, compensatory reflexes that might counteract peripheral vasodilatation are attenuated, 17-21 hepatic metabolic inactivation of the drug may be diminished by the effects of hepatic venous congestion 22,23 and renal clearance of the agent is reduced. 16,24However, recent evidence has indicated that the peripheral vasculature in patients with heart failure may be hyporesponsive to endogenous or exogenous vasodi!ator stimuli, either because of increased vascular stiffness secondary to an increase in sodium content within the arterial vessel walls or because of an increase in tissue pressure in edematous states. 25-27 This is consistent with our finding that patients requiring very large doses of hydralazine manifested higher ventricular filling pressures than did patients who responded to smaller doses. This may also explain why the development of tolerance to vasodilator therapy in hypertensive patients is associated with fluid retention and why responsiveness to the drug is restored after the administration of diuretic agents. 2s,29 Malabsorption of hydralazine may explain the failure of several patients to respond to massive doses of the drug (300 m g during a 3 hour period) administered orally although they had marked hemodynamic changes when small doses of the drug were administered intravenously. Since patients requiring very large doses demonstrated significantly higher mean right atrial pressures than did patients who responded to smaller doses~ impaired drug absorption could be related to mesenteric venous congestion, a factor that may explain the relotive ineffectiveness of other cardiovascular agents administered orally to patients with severe heart failure. 3°-32 Indeed, two of our patients in group B did not respond to massive doses of isosorbide dinitrate administered oral'l:~, whereas small doses administered sublingually produced marked hemodynamic changes. Although enhanced metabolic inactivation of the drug by genetically rapid hepatic acetylator enzymes can
result in a greater dosage requirement of hydralazine in some hypertensive patients, 24,33the magnitude of this effect is too small to account for the unusually large doses needed by the patients in our group B and would not explain the ineffectiveness in these patients of other orally administered drugs metabolized by other enzyme systems. Ribner et al. 11 suggested that patients with a high level of systemic vascular resistance before treatment may not respond to hydralazine because the effectiveness of vasodilators in patients with severely limited cardiac reserve is impaired. A major limitation of their study is the use of a fixed schedule of hydralazine administration with an upper dosage limit of 400 mg daily. By using progressive increments in dosage where indicated, we could find no differences in the pretreatment systemic vascular resistance between patients in groups A and B. Furthermore, the hemodynamic responses to effective doses of hydralazine were similar qualitatively and quantitatively in both groups, the only difference being the dose of the drug needed to produce the observed hemodynamic effects. Side effects of large dose hydralazine therapy: In spite of these very large doses of hydralazine, acute adverse reactions were no more frequent in patients in group B than in those in group A. In fact, symptomatic hypotension was observed only with doses of 100 mg and only in patients in group A with low mean right atrial pressure. An initial dose of 75 mg of hydralazine seems warranted, therefore, in patients whose pretreatment mean right atrial pressure is less than 6 mm Hg. Whether long-term therapy will place patients in group B at greater risk of having hydralazine-induced systemic lupus erythematosus than group A remains to be determined.34, 35 Implications: This study underscores the need for the administration of unusually large doses of hydralazine to produce significant impr0vement in left ventricular performance in patients with severe chronic heart failure. The dose required is highly variable (75 mg to 800 mg as a single dose) and is generally larger than that usually needed in hypertensive patients. In more than 40 percent of patients, significant hemodynamic effects are seen only with single doses greater than 100 rag, and occasionally a patient will respond only to intravenous administration of the agent. As a result, the failure of hydralazine to produce clinical improvement in an individual patient may be due to the administration of subtherapeutic quantities of the drug. Verification and quantification of hemodynamic changes by invasive studies may be necessary in patients who fail to respond to small empirically determined doses.
Acknowledgments
We are greatly indebted to the nurses of the Alfred L. Rose Cardiac Care Unit of the Mount Sinai Medical Center for their invaluable assistance.
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HYDRALAZINE IN HEART FAILURE--PACKER ET AL.
References 1. Chatterjee K, Parmley WW, Massie B, et al. Oral hydralazine for chronic refractory heart failure. Circulation 1976; 54:879-83. 2. Franciosa JA, Pierpont G, Cohn J. Hemodynamic improvement after oral hydralazine in left ventricular failure. Ann Intern Med 1977; 86:388-93. 3. Chatterjee K, Ports T, Rubin S, et al. Sustained beneficial hemodynamic effects during long term hydralazine in patients with chronic heart failure (abstr). Circulation 1978; 58:Supp111:11-28. 4. Fitchett DH, Marin Neto JA, Oakley CM, Goodwin JF. Hydralazine in the management of left ventricular failure. Am J Cardio11979; 44:303-9, 1979. 5. Massie B, Greenberg B, Brundage B, Chalterjee K, Botvinick E, Parmley WW. Beneficial effects of hydralazine in severe mitral regurgitation. Circulation 1978; 58:273-9. 6. Packer M, Meller J, Medina N, Gorlin R, Herman MV. Usefulness of echocardiographicallydetermined left ventricular volume as a noninvasive predictor of hydralazine response in heart failure (abstr). C!in Res 1979; 27:192A. 7. Packer M, Meller J, Gorlin R, Teichholz LE, Herman MV. Dose dependent reduction in right and left ventricular filling pressures with hydra!azine (abstr). Am J Cardiol 1978; 41:420. 8. Jacobs W, Herrick A, Loeb H, Gunnar R. Noninvasive assessment of daily hydralazine therapy in patients with advanced cardiac failure (abstr). Circulation 1977; 56, 57: Supp1111:111-275. 9. Franciosa JA, Cohn JN. Immediate effects of hydralazine-isosorbide dinitrate combination on exercise capacity and exercise hemodynamics in patients with left ventricular failure. Circulation 1979; 59:1085-97. 10. Lejemtel T, Hellman C, Elkayam U, et al. Hemodynamic and renal responses to oral hydralazine therapy in severe heart failure (abstr). Circulation 1977; 56, 57:Supp1111:111-9. 11. Ribner HS, Lejemtel TH, Elkayam U, Sonnenblick EH. Relationship between initial systemic vascular resistance and the response to vasodilators in severe congestive heart failure (abstr). Am J Cardiol 1979; 43: 404. 12. Criteria Committee of the New York Heart Association. Nomenclature and Criteria for Diagnosis of Diseases of the Heart and Great Vessels. 7th ed. Boston: Little, Brown, 1973; 286. 13. Snedecor GW, Cochran WG. Statistical Methods. Ames, Iowa: The Iowa state University Press, 1967: 327. 14. Zacest R, Gilmore E, Koch-Weser J, Treatment of essential hypertension with combined vasodilator and beta adrenergic blockade, N Engl J Med 1972; 286:617-22. 15. Kach-Weser J. Hydralazine. N Engl J Med 1976; 295:320-23. 16. Packer M, Meller J, Gorlin R, Teichholz L, Herman MV. Pharmacodynamics of hydralazine in refractory heart failure (abstr). Circulation 1977; 56, 57: Supp1111:111-176. 17. Chidsey CA, Braunwald E, Morrow AG. Catecholamine excretion and cardiac stores of norepinephrine in congestive heart failure. Am J Med 1965; 39:442-51. 18. Chidsey CA, Kaiser GA, Sonnenblick EH, Spann JF, Braunwald E. Cardiac norepinephrine stores in experimental heart failure in
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the dog. J Clin Invest 1964; 43:2386-93. 19. Kramer RS, Mason DT, Braunwald E. Augmented sympathetic neurotransmitter activity in the peripheral vascular bed of patients with congestive heart failure and cardiac norepinephrine depletion. Circulation ~1968;38:629-34. 20. Hlggins CB, Vatner SF, Eckberg DL, Braunwald E. Alterations in the baroreceptor reflex in conscious dogs with heart failure. J Clin Invest 1972; 51:715-24. 21. Gellhorn E. The significance Of the state of the central autonomic nervous system for quantitative and qualitative aspects of some cardiovascular reactions. Am Heart J 1964; 67:106-20. 22. Hepner GW, Vesell ES, Tanlum KR. Reduced drug elimination in congestive heart failure. Studies using aminopyrine as a model drug. Am J Med 1978; 65:271-6. 23. Tokola O, Pelkonen O, Karki NT, Luoma P, Kaltiala EH, Larmi TKI. Hepatic drug-oxidizing enzyme systems and urinary D-glucaric acid excretion in patients with congestive heart failure. Br J Clin Pharmacol 1975; 2:429-36. 24. Reidenberg MM, Drayer D, Demarco AL, Bello C. Hydralazine elimination in man. Clin PharmacolTher 1973; 14:970-7. 25. Mason DT, Zelis R, Longhurst I, Lee G. Cardiocirculatory responses to muscular exercise in congestive heart failure. Progr Cardiovasc Dis 1977; 19:475-89. 26. Zelis R, Longhurst J, Capone RJ, Mason DT. A comparison of regional blood flow and oxygen utilization during dynamic forearm exercise in normal subjects and patients with congestive heart failure. Circulation 1974; 50:137-43. 27. Zelis R, Mason DT, Braunwald E. A comparison of the effects of vasodilator stimuli on peripheral resistance vessels in normal subjects and in patients with congestive heart failure. J Clin Invest 1968; 47:960-70. 28. Finnerty FA, Davidov M, Mroczek WJ, Gavrilovich L. Influence of extracellular fluid volume on response to antihypertensive drugs. Circ Res 1970; 27 Suppl 1:71-80. 29. Koch-Weser J. Vasodilator drugs in the treatment of hypertension. Arch Intern Med 1974; 133:1017-27. 30. Craig LC, Lawn B, Levine SA. Resistance and sensitivity to digitalis. JAMA 1958; 166:2139-44. 31. Smith TW, Haber E: Digitalis. N Engl J Med 1973; 289:106372. 32. Crouthamel WG. The effect of congestive heart failure on quinidin'e pharmacokinetics. Am Heart J 1975; 90:335-9. 33. Zacest R, Koch-Weser J. Relationship of hydralazine plasma concentration to dosage and hypotensive action. Clin Pharmacol Ther 1972; 13:420-25. 34. Alarcon-Segovia D, Wakim HC, Worlhington IW, Ward LE. Clinical and experimental studies on the hydralazine syndrome and its relationship to systemic lupus erythematosus. Medicine 1967; 46: 1-33. 35. Perry HM. Late toxicity to hydraiazine resembling systemic lupus erythematosus or rheumatoid arthritis. Am J Med 1973; 54~5872.
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