Journal of the American College of Cardiology Vol. 34, No. 1, by the American College of Cardiology ISSN /99/$20.

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1 Journal of the American College of Cardiology Vol. 34, No. 1, by the American College of Cardiology ISSN /99/$20.00 Published by Elsevier Science Inc. PII S (99) Effect of Aspirin and Ifetroban on Skeletal Muscle Blood Flow in Patients With Congestive Heart Failure Treated With Enalapril Stuart D. Katz, MD,* Michael Radin, MD, FACC, Thomas Graves, PHD, Cynthia Hauck, MS, Alan Block, PHD, Thierry H. LeJemtel, MD, for the Ifetroban Study Group New York, New York; Newport Beach, California; and Princeton, New Jersey OBJECTIVES BACKGROUND METHODS RESULTS CONCLUSIONS The purpose of this study was to determine the acute and chronic effects of cyclooxygenase inhibition with aspirin and thromboxane A 2 receptor blockade with ifetroban on the chronic vasodilating effects of enalapril in the skeletal muscle circulation of patients with heart failure. Angiotensin-converting enzyme inhibition and antiplatelet therapy with aspirin independently reduce the risk for subsequent nonfatal coronary events in survivors of myocardial infarction. The safety of the combined administration of angiotensin-converting enzyme inhibitors and aspirin has been questioned due to their divergent effects on the vascular synthesis of vasodilating prostaglandins. Forearm blood flow (ml/min/100 ml) at rest and during rhythmic handgrip exercise and after transient arterial occlusion was determined by strain gauge plethysmography before and 4 h and six weeks after combined administration of enalapril with either aspirin, ifetroban or placebo in a multicenter, double-blind, randomized trial of 62 patients with mild to moderate heart failure. Before randomization, forearm hemodynamics were similar in the three treatment groups except for increased resting forearm blood flow and decreased resting forearm vascular resistance in the aspirin group when compared with the placebo group. After combined administration of enalapril and study drug for 4 h and six weeks, changes from prerandomization values of mean arterial pressure, forearm blood flow and forearm vascular resistance at rest, during handgrip exercise and after transient arterial occlusion did not differ among the three treatment groups. These findings demonstrate that the vasodilating effects of enalapril in the skeletal muscle circulation of patients with heart failure are not critically dependent on prostaglandin pathways. (J Am Coll Cardiol 1999;34:170 6) 1999 by the American College of Cardiology Angiotensin-converting enzyme (ACE) inhibition and antiplatelet therapy with aspirin independently reduce the risk for subsequent nonfatal coronary events in survivors of myocardial infarction (1,2). Whereas ACE inhibitors and aspirin have been evaluated separately in clinical trials, in clinical practice these agents are often administered together to patients with heart failure due to ischemic heart disease. The safety of the coadministration of ACE inhibitors and aspirin has been questioned due to their divergent effects From the *Columbia Presbyterian Medical Center, Division of Circulatory Physiology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York; Pacific Coast Cardiology, Newport Beach, California; Bristol Myers Squibb, Princeton, New Jersey; and Albert Einstein College of Medicine, Division of Cardiology, Department of Medicine, New York, New York. This study was supported by a research grant from Bristol Myers Squibb. Manuscript received October 13, 1998; revised manuscript received February 17, 1999, accepted March 24, on the vascular synthesis of vasodilating prostaglandins (Fig. 1) (3). The vasodilating effects of ACE inhibitors are partly attributable to the inhibition of the metabolic degradation of bradykinin, which promotes vascular synthesis of vasodilating prostaglandins (4). Aspirin is a cyclooxygenase inhibitor which dose-dependently inhibits prostaglandin synthesis in vascular tissues (5). Administration of aspirin at a dose of 350 mg attenuates the systemic vasodilating effects of acute ACE inhibition with enalapril in patients with heart failure (6). This acute hemodynamic interaction is of uncertain clinical consequence, since improvement in functional capacity in response to long-term ACE inhibition therapy is not dependent on short-term systemic hemodynamic changes, but rather is closely correlated to increased skeletal muscle blood flow during exercise (7,8). Prostaglandins are released by endothelial cells in response to shear stress and may contribute to exercise-induced hyperemia in

2 JACC Vol. 34, No. 1, 1999 July 1999:170 6 Katz et al. Aspirin Enalapril Interaction in CHF 171 Figure 1. Schematic illustration of potential interactions of angiotensin-converting enzyme (ACE) inhibitors, bradykinin and aspirin on vascular prostacyclin (PGI2) production. Whether inhibition of vascular cyclooxygenase by antiplatelet doses of aspirin attenuates bradykin-induced prostaglandin-mediated vasodilation in response to ACE inhibition is uncertain. ATII angiotensin II; stimulatory effect; inhibitory effect;? uncertain effect. the skeletal muscle circulation (9,10). Whether prostaglandins contribute to increased vasodilatory capacity in the skeletal muscle circulation during chronic ACE inhibition in patients with congestive heart failure is unknown. The current study was undertaken to determine the acute and chronic effects of cyclooxygenase inhibition with aspirin and thromboxane A 2 receptor blockade with ifetroban on the chronic vasodilating effects of enalapril in the skeletal muscle circulation of patients with heart failure. Forearm blood flow was determined at rest and during metabolic vasodilation in response to exercise and transient ischemia before and 4 h and 6 weeks after combined administration of enalapril with either aspirin, ifetroban or placebo, in a multicenter, double-blind, randomized trial. The trial was designed to test the hypothesis that aspirin, but not ifetroban or placebo, would attenuate the vasodilating effects of enalapril during chronic therapy. METHODS Study population. Sixty-two patients with stable exertional symptoms compatible with New York Heart Association class II or III heart failure for greater than three months were enrolled in the study. Patients were recruited into the study according to the following criteria: aged 21 to 80 years, left ventricular ejection fraction 0.40 (determined either by radionuclide angiography, echocardiography or ventriculography within three months of study entry), ACE inhibition therapy for 3 months and enalapril at a daily dose 10 mg for at least 4 weeks before the study and New York Heart Association functional class II or III. Stable doses of digoxin, diuretics, beta-adrenergic blocking agents and long-acting nitrates were permitted as background therapy. Criteria for exclusion from the study were: therapy with calcium channel blocking agents, ticlodipine, dipyridamole and open-label aspirin or other nonsteroidal anti-inflammatory agents, hyponatremia (serum sodium concentration 136 meq/liter), uncontrolled edema, a history of stroke or transient ischemic attack within one year, peptic ulcer disease, occult blood in a stool specimen during study screening, hematocrit 32%, history of aspirin intolerance or presence of any other known risk factor for bleeding. The study protocol was approved by the ethical review committees at each of the recruiting centers. All subjects gave written informed consent before entry into the trial. Venous occlusion plethysmography. Forearm blood flow (ml/min/100 ml of forearm volume) was determined with venous occlusion strain gauge plethysmography as previously described in detail (11). Briefly, with the arm resting comfortably 10 cm above the right atrium, a calibrated mercury-in-silastic strain gauge was placed around the widest portion of the upper third of the forearm. For each measurement, forearm venous blood flow was occluded just proximal to the elbow with the rapid inflation of a blood pressure cuff to 40 mm Hg. A wrist cuff was inflated to suprasystolic pressures 1 min before and during each measurement to exclude the hand circulation from the blood flow determination. Plethysmographic techniques were standardized across study centers and representative studies from each center were reviewed by a single investigator (S.D.K.). For determination of resting blood flow, the venous occluding cuff was inflated for 5sat15-s intervals; five plethysmographic measurements were averaged for determination of resting forearm blood flow (ml/min/100 ml). Rhythmic handgrip exercise was performed according to the protocol previously reported by Longhurst et al. (12). Subjects rhythmically squeezed a hand dynanometer in 15-s cycles which consisted of 5sofsteady handgrip pressure alternating with 10 s of rest. Exercise corresponding to 30% of a previously determined maximum voluntary contraction was performed for 3 min. Forearm blood flow was determined in the last minute of exercise during the 5-s period of each resting cycle immediately before the next handgrip contraction. Reactive hyperemia was determined after a 5-min inflation of the cuff above the elbow to suprasystolic pressure. Peak reactive hyperemia was determined as the first blood flow measurement within 5sofcuffrelease. Forearm vascular resistance was determined from the ratio of mean arterial pressure (determined by cuff method in the contralateral arm) and forearm blood flow and was expressed in arbitrary units mm Hg/ml/min/100 ml.

3 172 Katz et al. JACC Vol. 34, No. 1, 1999 Aspirin Enalapril Interaction in CHF July 1999:170 6 Drug administration. To determine the role of the prostaglandin pathway on the vasodilating action of enalapril in the skeletal muscle circulation, patients were randomly assigned to treatment with aspirin 325 mg daily, ifetroban 250 mg daily or matching placebo. A 325-mg dose of aspirin inhibits cyclooxygenase in vascular tissue and platelets, inhibits platelet aggregation and is currently the recommended dose for secondary prevention after myocardial infarction (2). Ifetroban, an investigational thromboxane A 2 receptor antagonist, is a potent long-acting inhibitor of platelet aggregation (13,14). Study protocol. The study was a multicenter, placebocontrolled, double-blind, parallel arm design trial (see Appendix for participating centers). Eligible patients meeting initial entry criteria received single-blind placebo for one to two weeks before randomization. Enalapril therapy was discontinued during single-blind placebo therapy for 72 h before determination of baseline forearm blood flow measurements on the day of randomization. Stability of the resting forearm blood flow measurement was determined before randomization. Patients with 10% variability in two consecutive resting forearm blood flow measurements (maximum three measurements) were excluded from the trial. In patients with stable resting forearm blood flow measurements, forearm blood flow was determined during rhythmic handgrip exercise and after 5 min of arterial occlusion. After completion of the prerandomization forearm blood flow measurements, subjects were randomly assigned to one of three treatment groups in a double-blind fashion: placebo q.d., acetylsalicyclic acid 325 mg q.d. or ifetroban 250 mg q.d. Enalapril 10 mg and the first dose of the assigned double-blind study drug were simultaneously administered. To determine the acute effects of study drug enalapril interaction, forearm blood flow was determined at rest, during handgrip exercise and after 5 min of arterial occlusion 4 h after the first dose of study drug and enalapril together. After completion of the acute study, patients continued their previous dose of enalapril ( 10 mg daily) and assigned study drug for six weeks. To determine the chronic effects of the study drug enalapril interaction, forearm blood flow was determined at rest, during handgrip exercise and after 5 min of arterial occlusion after six weeks of combination therapy. Background medications were held constant through the trial. Long-acting nitrate preparations were discontinued for 72 h before all blood flow measurements. Data analysis. All values are stated as means standard errors. Mean arterial pressure, forearm blood flow and forearm vascular resistance at rest, during exercise and after 5 min of arterial occlusion were compared with repeated measures analysis of variance. Correlations between measured variables of interest were determined with simple linear regression analysis. A two-tailed probability value 0.05 was considered statistically significant. The prespecified primary end point of the study was a comparison of the change in resting forearm blood Table 1. Clinical Characteristics of Study Population (Means SD) flow and resting forearm vascular resistance from prerandomization values among the three treatment groups. Secondary end points were comparisons of the changes of forearm blood flow and forearm vascular resistance from prerandomization values during rhythmic handgrip exercise and after 5 min of arterial occlusion among the three treatment groups. Twenty patients per treatment group provided 85% power to detect a clinically significant 30% change (two-sided alpha 0.05) in forearm vascular resistance, assuming a pretreatment forearm vascular resistance of 40 mm Hg/ml/min/100 ml with a standard deviation of 15 mm Hg/ml/min/100 ml. RESULTS Placebo (n 23) Aspirin (n 20) Ifetroban (n 21) Age (yr) Weight (kg) Gender (n) 17 M, 6 F 16 M, 4 F 15 M, 6 F Etiology of CHF (n) Ischemic Nonischemic LVEF Enalapril dose (mg/day) CHF congestive heart failure; F female; LVEF left ventricular ejection fraction; M male. Clinical characteristics of study population. Sixty-two patients were enrolled in the study. Five patients did not complete the trial due to clinical instability, protocol violations or technical problems with plethysmography measurements. The clinical characteristics of the 62 patients who entered the study did not differ among the three treatment groups (Table 1). The data from the 57 patients with completed forearm blood flow measurements before randomization and after 4 h and six weeks of combination therapy with enalapril and study drug are included in the analysis. Prerandomization (baseline) measurements. Before randomization resting forearm blood flow was higher and resting forearm vascular resistance was lower in patients assigned to aspirin when compared with patients assigned to placebo (both p 0.05) (Table 2). Mean arterial pressure and forearm blood flow and forearm vascular resistance during rhythmic handgrip exercise and after 5 min of arterial occlusion did not differ in the three treatment groups before randomization. Postrandomization measurements. After coadministration of enalapril and study drug, mean arterial pressure decreased from prerandomization blood pressure by 4 to 8 mm Hg after 4 h and six weeks in all three treatment groups. Changes from prerandomization blood pressure did not differ among the three treatment groups (Fig. 2). After coadministration of

4 JACC Vol. 34, No. 1, 1999 July 1999:170 6 Katz et al. Aspirin Enalapril Interaction in CHF 173 Table 2. Blood Pressure and Forearm Hemodynamics in the Three Treatment Groups (Means SEM) Before Randomization Placebo (n 19) Aspirin (n 20) Ifetroban (n 18) MAP Rest FBF * Rest FVR * 40 5 Exercise FBF Exercise FVR Postocclusion FBF Postocclusion FVR *p 0.05 vs. placebo. FBF forearm blood flow (ml/min/100 ml); FVR forearm vascular resistance (mm Hg/ml/min/100 ml); MAP mean arterial pressure (mm Hg). enalapril and study drug, small nonsignificant changes in forearm blood flow and forearm vascular resistance at rest, during rhythmic handgrip exercise and after 5 min of arterial occlusion were observed after 4 h and six weeks in all three treatment groups. Changes from prerandomization forearm blood flow and forearm vascular resistance at rest (Fig. 3), during rhythmic handgrip exercise (Fig. 4) and after 5 min of arterial occlusion (Fig. 5) after 4 h and six weeks did not differ among the three treatment groups. The changes in resting forearm vascular resistance tended to be greatest in the placebo group (p 0.20). This finding may be attributable to the greater baseline forearm vascular resistance in the placebo group. Baseline resting forearm vascular resistance correlated significantly with subsequent changes in resting forearm vascular resistance during blinded therapy (r 0.55 and r 0.72 for change in forearm vascular resistance after 4 h and six weeks, respectively, both p 0.001). Laboratory measurements. Blood urea nitrogen, serum creatinine and serum sodium did not differ among treatment groups before randomization (blood urea nitrogen 18 1, Figure 3. Changes in resting forearm blood flow (FBF, ml/min/ 100 ml, top panel) and resting forearm vascular resistance (FVR, mm Hg/ml/min/100 ml, bottom panel) from prerandomization baseline values after 4 h (black bars) and six weeks (gray bars) of combined administration of enalapril with placebo, aspirin and ifetroban. Values are expressed as means SEM. 21 3, 16 1 mg/dl, serum creatinine , , mg/dl and serum sodium , , meq/liter, in ifetroban, placebo and aspirin groups, respectively) and did not change from baseline values in any of the treatment groups during the study. Figure 2. Change from prerandomization baseline mean arterial pressure (MAP, mm Hg) after 4 h (black bars) and six weeks (gray bars) of combined administration of enalapril with placebo, aspirin and ifetroban. Values are expressed as means SEM.

5 174 Katz et al. JACC Vol. 34, No. 1, 1999 Aspirin Enalapril Interaction in CHF July 1999:170 6 Figure 4. Changes in forearm blood flow during rhythmic handgrip exercise (FBF, ml/min/100 ml, top panel) and forearm vascular resistance during rhythmic handgrip exercise (FVR, mm Hg/ml/min/100 ml, bottom panel) from prerandomization baseline values after 4 h (black bars) and six weeks (gray bars) of combined administration of enalapril with placebo, aspirin and ifetroban. Values are expressed as means SEM. Figure 5. Changes in forearm blood flow after 5 min of arterial occlusion (FBF, ml/min/100 ml, top panel) and forearm vascular resistance after 5 min of arterial occlusion (FVR, mm Hg/ml/min/ 100 ml, bottom panel) from prerandomization baseline values after 4 h (black bars) and six weeks (gray bars) of combined administration of enalapril with placebo, aspirin and ifetroban. Values are expressed as means SEM. DISCUSSION The main finding of the current study is that six weeks of therapy with aspirin, ifetroban or placebo did not alter forearm blood flow or forearm vascular resistance at rest, or during metabolic vasodilation in response to exercise or transient ischemia in patients with heart failure receiving chronic enalapril therapy. These findings demonstrate that the vasodilating effects of ACE inhibition in the skeletal muscle circulation of patients with heart failure are not critically dependent on prostaglandin pathways. Altered prostaglandin biosynthesis in heart failure. The cardiovascular actions of ACE inhibitors are mediated by reduction of the rate of synthesis of angiotensin II and reduction of the rate of metabolic degradation of bradykinin (4). Angiotensin II and bradykinin have complex mechanisms of vascular action that are partly regulated by interactions with prostaglandins. In isolated arterial preparations and cultured human endothelial cells, angiotensin II and bradykinin stimulate prostaglandin synthesis (15 17). In patients with heart failure, evaluation of the role of prostaglandins in the response to ACE inhibition is confounded by the alterations in prostaglandin metabolism related to the heart failure state. Excess production of vasodilating prostaglandins has been reported in patients with advanced heart failure and concomitant hyponatremia (18). Endothelial dysfunction in heart failure is characterized in part by evidence of increased release of vasoconstricting prostaglandins, decreased vasodilatory response to administration of exogenous arachidonic acid and decreased messenger ribonucleic acid for cyclooxygenase in aortic endothelial cells (19,20). Comparison with previous studies. The contribution of prostaglandins to the acute systemic and regional hemodynamic effects of ACE inhibition in patients with heart failure is controversial. Administration of aspirin 350 mg essentially abolished the acute systemic vasodilatory effects of enalapril 10 mg in a crossover trial of 18 patients with moderate heart failure (6). Nishimura and colleagues reported nearly complete attenuation of the acute vasodilating effects of captopril after cyclooxygenase inhibition with indomethacin in the forearm circulation of 14 patients with heart failure (21). In contrast, acute administration of 236 mg of aspirin did not attenuate the systemic blood

6 JACC Vol. 34, No. 1, 1999 July 1999:170 6 Katz et al. Aspirin Enalapril Interaction in CHF 175 pressure lowering or forearm circulation vasodilatory effects of ACE inhibition with captopril in patients with mild to moderate heart failure (22). Cyclooxygenase inhibition with indomethacin 50 mg did not alter the vasodilatory response to acute ACE inhibition in the resting forearm circulation in patients with congestive heart failure (23). The lack of effect of aspirin and ifetroban on resting forearm blood flow and forearm vascular resistance in the current study supports these latter studies. The current findings extend those of previous studies by examining both acute and chronic effects of aspirin therapy on the vasodilating effects of ACE inhibition. The vascular effects of ACE inhibitors in the skeletal muscle circulation are closely correlated with symptomatic improvement with a long time constant for both onset and offset of action (8,24 26). Forearm blood flow and vascular resistance were not expected to change at six weeks in the placebo and ifetroban treatment groups, since all patients were receiving chronic enalapril therapy before the study. Absence of change in forearm blood flow and vascular resistance at six weeks in the aspirin treatment group demonstrates that aspirin at a dosage of 325 mg/day does not attenuate the chronic vasodilating effects of enalapril in the skeletal muscle circulation. Prostaglandins and exercise hyperemia. During chronic ACE inhibition therapy, improved exercise tolerance is closely related to increased vasodilatory capacity in the exercising skeletal muscle circulation (8). The chronic vasodilatory effects of ACE inhibition in the skeletal muscle circulation during exercise may be partly attributable to the action of prostaglandins (27,28). In normal man, plasma concentrations of the stable metabolite of prostacyclin increase during exercise (29,30). Cyclooxygenase inhibition has been reported to either decrease or have no effect on exercise-induced hyperemia in the normal human forearm (30,31). Our data support the view that the prostaglandin pathway is not critical to the vasodilatory response to submaximal exercise in the forearm circulation of patients with heart failure treated with enalapril. This finding may be due to the redundancy of the metabolic vasodilatory mechanisms in the skeletal muscle circulation (32). Interpretation of study findings. A dose of 325 mg of aspirin is recommended for secondary prevention of myocardial infarction, and thus is pertinent to the question of a clinically important aspirin ACE inhibition interaction (2). This dose of aspirin is associated with near complete suppression of thromboxane A 2 synthesis in platelets, but only partial suppression of prostacyclin synthesis in vascular tissue (5). Higher or more frequent doses of aspirin, or administration of longer acting, more potent cyclooxygenase inhibitors, may have produced different effects on skeletal muscle circulation. All patients in the study were receiving chronic therapy with enalapril at the time of randomization. Accordingly, interpretation of the current findings on forearm blood flow is limited to the effects of aspirin and ifetroban on the established, chronic vasodilating action of ACE inhibitors in the skeletal muscle vasculature and may not be predictive of the effects of aspirin and ifetroban at the initiation of ACE inhibition therapy. The effect of the severity of heart failure symptoms and hyponatremia on the interaction of ACE inhibitors and aspirin cannot be determined from the current data. Whether prostaglandins contribute to the effects of chronic ACE inhibition on maximum aerobic capacity during exercise with the lower extremities in patients with congestive heart failure cannot be determined from the present study. In a previous controlled clinical trial, four weeks of aspirin therapy had no effect on maximal oxygen uptake in patients with chronic heart failure treated with enalapril (33). Conclusions. In conclusion, the current study demonstrates that the chronic vasodilating effects of ACE inhibition in the forearm circulation of patients with heart failure are not affected by concomitant administration of aspirin. These findings contrast with those of a previous report on the acute hemodynamic effects of the ACE inhibitor aspirin interaction (6) and do not support the hypothesis that aspirin therapy attenuates the long-term effects of ACE inhibition in patients with heart failure. Since a potential negative interaction between aspirin and ACE inhibitors has been reported in some retrospective analyses of post myocardial infarction trials (3,34), prospective studies are needed to determine the effects of aspirin therapy on long-term morbidity and mortality in patients with heart failure treated with ACE inhibitors. Appendix: Investigators of the Ifetroban Multicenter Study Group Principal Investigator James Arrowood, MD John Boehmer, MD Joseph Delehanty, MD Joseph Izzo, MD Stuart Katz, MD Thierry LeJemtel, MD Michael Radin, MD Satish Sharma, MD John Smith, MD Udo Thadani, MD Institution and Location Medical College of Virginia, Richmond, Virginia Hershey Medical Center, Hershey, Pennsylvania University of Rochester Medical Center, Rochester, New York Millard Fillmore Hospital, Buffalo, New York Columbia Presbyterian Medical Center, New York, New York Albert Einstein College of Medicine, Bronx, New York Heart Institute of the Desert, Rancho Mirage, California VA Medical Center, Providence, Rhode Island New England Medical Center, Boston, Massachusetts University of Oklahoma Health Science Center, Oklahoma City, Oklahoma

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