CONTROVERSIES IN HEART FAILURE

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HEART FAILURE

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CONTROVERSIES IN HEART FAILURE Are Beneficial Effects of Angiotensin-Converting Enzyme Inhibitors Attenuated by Aspirin in Patients with Heart Failure? Donald Hall, MD

Aspirin is an effective drug that, through lnhibition of platelet aggregation, has been shown to lower morbidity and mortality in almost every aspect of coronary artery disease (CAD), including primary prevention, secondary prevention after myocardial infarction, unstable angina pectoris, and after coronary artery bypass surgery.8,13, 18, 30, 32, 53 Aspirin is inexpensive and easy to use. Angiotensin-converting enzyme (ACE) inhibitors are also effective drugs that, in heart failure, through a number of actionsincluding improved hemodynamics centered on systemic arterial vasodilation, enhanced renal perfusion and function, rectification of electrolyte disturbances, arrhythmia suppression, and as a favorable influence on hypertrophy and cell proliferation-also have been shown to ameliorate symptoms and lower morbidity and m~rtality.~, 38, 50-52 Because CAD is the commonest cause of heart failure,36,52 there is considerable potential for combined treatment with aspirin and an ACE inhibitor with the intention of providing the benefits of both drugs. Is it possible to double the

benefit? There are abundant data from shortterm experimental and clinical investigations questioning the expedience of this practice and, based on results of the major, placebocontrolled, long-term, morbid-event studies with ACE inhibitors (Table 1): 38, 50-52 it looks much more as if the yield of the interaction with aspirin is a consistent lessening of the risk reduction for cardiovascular events by UP to 50%. THE INTERACTION

It is not surprising that clinicians cannot obtain additive gains by stimulating with one drug the same system that is inhibited by another because, in one basic aspect, the pharmacodynamic mechanisms of aspirin and ACE inhibitors are mutually counteractive. ACE inhibition stimulates prostaglandin synthesis.12,15, 16, 19, 33, 48 In addition to a reduction in vasoconstrictive and sodium and water retaining factors incurred through blockade of angiotensin I1 (AT 11) generation, lnhibitors of

From the Cardiac Outpatient Clinic, German Heart Center, Technical University of Munich, Munich, Germany

CARDIOLOGY CLINICS VOLUME 19 NUMBER 4 NOVEMBER 2001

597

+

90

Control

Heart failure Aspirin No aspirin 7-day mortality Aspirin No aspirin 30-day mortality Aspirin No aspirin

-6 -10

- 15

-7

-4 - 10

CAD NonCAD

91

- 27

-13 - 26

NonCAD

34

ACE

- 12

CAD

33

53

Comments

Risk reduction in patients taking aspirin is consistently about half of that in patients not taking aspirin

Mortality reduction only with Enalapril and only due to reduction in sudden death but not heart failure deaths

Significantly less favorable outcome in patients with aspirin (combined analysis with SOLVD Prevention)

Significantly lesser effect on mortality in patients taking aspirin

Significant excess in mortality in patients with enalapril and aspirin

Authors: "even greater benefit in those not receiving aspirin"

'In patients reported to be taking aspirin or, if the number taking aspirin was not reported, in patients with coronary artery disease (CAD) who are more likely to be taking aspirin; the risk reduction is consistently about half of that of patients not taking aspirin. n = number of patients enrolled; AM1 = acute myocardial infarction; EF = ejection fraction; NYHA = New York Heart Association Classification; ISDN = isosorbide dinitrate; AIRE = Acute Infarction Ramipril Efficacy; CCS-I = Chinese Cardiac Study; CONSENSUS I1 = second Cooperative North Scandinavian ENalapril Survival Study; GISSI-3 = Gruppo Italian0 per lo studio della nell' Infarto myocardico; ISIS4 = Intemahonal Study of Infarct Survival; SAVE = Survival And Ventricular Enlargement; SOLVD = Studies of Left Ventricular Dysfunction; V-Hen I1 = Veterans Administration Vasodilator Heart Failure Trial. From Hall D: The aspirin-angiotensin-convertingenzyme inhibitor tradeoff To halve and halve not. J Am Call Cardiol 35:1808-1812, 2000; with permission.

All

Various ACE inhibitors versus Control

Latini et alUl n = 96712 AM1 (Meta-analysis:CCS-1, CONSENSUS 11, GISSI-3, ISIS-4)

Not reported

Placebo

72 54 51

Enalapril Hydralazine ISDN

Placebo

Placebo

Enalapril

70

Enalapril

Enalapril (15 mg) versus Hydralazine (199 mg) + ISDN (100 mg)

Placebo

83

Placebo

Enalapril (16 mg) versus

V-HeFT 117 n = 804 EF 545%, peak O2 consumption <25 mL/kg/ min

SOLVDS' Treatment n = 2569 EF S35%, NYHA 11-111

Placebo

56

Enalapril

Not reported

59

Placebo 83

No aspirin

59

Captopril

Enalapril

All

Enalapril (17 mg) versus

- 29

Aspirin

78

Placebo

SOLVD5' Prevention n = 4228 EF 535%, asymptomatic

- 20

Enalapril (versus Placebo)

77

Enalapril

Captopril (150 mg in 79%) versus Placebo

- 27

No aspirin

78

Placebo +8

- 15

Aspirin

77

Change of Risk for Cardiovascular Event ("A)

Ramipril

Patients Taking Aspirin (%)

SAVE" n = 2231 AMI, EF ?40%, asymptomatic

All

All

Coronary Artery Disease ("A)

Enalapril (20 mg in 82%) versus Placebo

Ramipril (10 mg in 77%) versus Placebo

Drug (Dose)

CONSENSUS 1149 n = 6090 AMI, heart failure in 19%

AMI, clinical evidence of heart failure

AIREm n = 2006

Study

Table 1. THE MAJOR, RECENTLY REPORTED, LONG-TERM, MORBID-EVENT STUDIES WITH ANGIOTENSIN-CONVERTING ENZYME INHIBITORS*

CONTROVERSIES IN HEART FAILURE

ACE also antagonize the action of structurally identical kininase 11, thereby impeding the degradation of bradykinin, a potent vasodilator in its own right, which also enlists further vasodilatory and diuretic support by enhancing production of prostaglandins. Aspirin, in contrast, inhibits prostaglandin synthesis, and its intended action in CAD is achieved through blockade of the enzyme cyclooxygenase, which catalyzes the first step in the biosynthesis of platelet thromboxane A, (TXA,) and all other prostaglandins from arachidonic

ROLE OF THE PROSTAGLANDIN SYSTEM Circulatory and Renal Effects

Is the prostaglandin system really so important? In normotensive, euvolemic, sodium-replete subjects, it may be difficult to objectify any hemodynamic effects of prostaglandin synthesis inhibition. Nevertheless, disabling this system at the level of cyclooxygenase unquestionably can lead to an increase in peripheral resistance. In hypertensive patients, interactions with aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDS) have been reported to attenuate the blood pressure-lowering effects of nearly every antihypertensive drug ever used clinically, such as p-adrenergic blockers, diuretics, direct-acting and a-blocking vasodilators, and ACE inhibitors.', 5, 15,26, 31,37, 43-46, 48, 5G58 In patients with left ventricular (LV) dysfunction and no or only mild degrees of heart failure, hemodynamic effects of aspirin may be discrete and elude detection on an individual basis. In a canine model of heart failure, a significant interaction between an ACE inhibitor and aspirin could not be detected.14In patients with severe heart failure, however, this is not the case. As the severity of the disease increases, there is escalation of neurohormornal activity with increases in vasoconstrictive AT 11, norepinephrine, and vasopressin together with a parallel increase in vasodilator prostaglandin synthesis to a degree sufficient to restrain the pressor action and maintain a balance of forces, still de-

599

ranged but preserving perfusion to vital org a n ~ .15, ~ 16, , 42 Treatment with ACE inhibitors fortifies the restraint of the prostaglandin system, the activity of which is additionally stimulated by the use of diuretics.6,17, 27 Under these circumstances, the relevance and magnitude of the restraining forces can best be appreciated by turning them off. Instead of the significant increase in cardiac output and significant decreases in systemic vascular resistance and LV filling pressure when enalapril was given without aspirin, when given with or on the day after a 350-mg dose of aspirin, in a placebo-controlled study enalapril did not elicit significant changes in any hemodynamic parameter.22In fact, when enalapril was given with or on the day after aspirin, instead of a decrease in systemic vascular resistance, which simply failed to materialize, compared with placebo, there was an actual increase which persisted throughout the day and at the baseline measurements on the following day. In heart failure, aspirin can not only offset direct hemodynamic benefits of ACE inhibition but also encumber optimal treatment through adverse effects on renal function, which can surreptitiously worsen the condition and necessitate initiation of or increased use of diuretics. As cardiac output decreases, prostaglandins assume an increasingly important role in maintaining renal blood flow. Aspirin and other NSAIDS can cause depression of the glomerular filtration rate not only in patients with compromised renal perfusion owing to heart failure or other causes but also in normal 34, 39 Because prostaglandins act on the renal tubules to favor natriuresis and water excretion, the effects of the diuretic drugs used as a cornerstone of most heart failure regimens are also attenuated by interactions with aspirin and similar drugs.2, 3, lo,24, 37*39, 47, 54 Additionally, the prostaglandins stimulated in response to elevated levels of norepinephrine, AT 11, and vasopressin also function as a negative feedback loop to restrain the action of vasopressin on hydroosmotic water flow in the distal tubule and collecting ducts, and experimental studies have repeatedly demonstrated enhanced vasopressin action after prostaglandin synthesis inhibiti~n.~, 11,23, 59 In patients with severe heart

600

HALL

failure, in spite of diuretic treatment and ACE inhibition, which may lower prevailing vasopressin levels, loss of the inhibitory action of prostaglandins after a single dose of aspirin imposed a further burden on circulatory homeostasis by increasing total body water with significant decreases in serum sodium concentration and plasma osmolality.21This interaction not only dictates the need for higher diuretic dosages, but, in some patients, the changes in fluid volume and composition were of sufficient magnitude to result in hyponatremia, which by itself may be associated with a less favorable prognosis.29 Table 2 shows a summary of documented effects of aspirin that can discount effects of established treatment, prevent improvement, or even worsen heart failure. Depending on the degree of heart failure and neurohumoral activation, the magnitude may range from subtle to overt.

ATTRITION OF THE POTENTIAL BENEFIT OF TREATMENT WITH ANGIOTENSIN-CONVERTING ENZYME INHIBITORS BY ASPIRIN Even though the prostaglandin-dependent hemodynamic and renal effects of ACE inhibitors may be counteracted by aspirin, ACE inhibition, per se, still is achieved when aspirin is given concomitantly. Plasma active re-

Table 2. DOCUMENTED EFFECTS OF ASPIRIN THAT CAN WORSEN, PREVENT IMPROVEMENT, OR DEPRECIATE EFFECTS OF ESTABLISHED TREATMENT OF HEART FAILURE Effect

Hemodynamic Counteraction of vasodilator effects of angiotensinconverting enzyme inhibitors Renal Decrease in glomerular filtration rate Attenuated effects of diuretics Enhanced action of vasopressin

Clinical Manifestation

No decrease or increase in peripheral resistance; no increase in cardiac output; attenuated filling pressure reduction Inadequate response to diuretics Inadequate response to diuretics Increase in total body water; decrease in serum sodium and plasma osmolality

nin concentrations are increased, and there is a reduction in plasma norepinephrine associated with slowing of the heart rate and tendencial decreases in mean right atrial and pulmonary artery pressures indicating maintenance of prostaglandin-independent effectsZ2Effects on myocardial hypertrophy and cell proliferation may be unaltered, but the clinical relevance remains to be established. Arrhythmia suppression may persist, and this could account for the findings in the second Veterans Administration Cooperative Vasodilator-Heart Failure Trial (V-HeFT 11)’ comparing enalapril with the combination of hydralazine and isosorbide dinitrate. Approximately half of the patients had CAD, and it seems reasonable to assume that most were taking aspirin although the number was not specified. In patients without CAD, there was a trend toward a preferential beneficial effect on mortality, in which those on enalapril fared better than those on hydralazine and isosorbide dh~itrate.~ Overall, there was no difference in mortality from pump failure between the two drug regimens, and the significantly better outcome in the enalapril group was exclusively owing to a reduction in sudden death. The question arises whether it could be possible that, in the patients with CAD, vasodilation with either an ACE inhibitor or with hydralazine plus isosorbide dinitrate was equally affected by aspirin leading to no change in heart failure deaths. The major studies have demonstrated some benefits of treatment with an ACE inhibitor when aspirin was given concomitantly. As in the V-HeFT I1 Trial, however, the benefits were conspicuously and consistently less in patients reported to be taking aspirin, or in those studies in which the number taking aspirin was not reported, than in patients with CAD who were more likely to be taking aspirin (see Table 1). Even in patients with no overt manifestations of heart failure in the Studies of Left Ventricular Dysfunction (SOLVD)Prevention Trial,4O possibly by virtue of the large number of patients, there was a significantly lesser reduction in mortality by enalapril in patients taking aspirin4Iand, similarly, a significantly less favorable outcome of treatment with enalapril was reported in patients also receiving aspirin from the com-

CONTROVERSIES IN HEART FAILURE

bined analysis of the SOLVD Prevention and Treatment Trials.41In two further studies, Survival and Ventricular Enlargement (SAVE) Study using captopriP8 and Acute Infarction Ramipril Efficacy (AIRE) each of which enrolled only about half the number of patients as in the SOLVD Prevention Trial, the trend to a more favorable outcome without aspirin is unmistakable, and this was explicitly pointed out by the authors of the AIRE study.5O The second Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS 11)1"9the largest of the studies, showed a trend to less favorable outcome in patients receiving enalapril as compared with placebo. This could be attributable, at least in part, to the findings of a recent analysis carried out specifically to address the question of an interaction between aspirin and ACE inhibitors, in which a significant excess in mortality was observed when enalapril was randomized to patients using aspirin.35 With the intention of ruling out an interaction between ACE inhibitors and aspirin, Latini et a12*undertook a meta-analysis of four studies encompassing more than 96,000 patients after MI. There were no significant differences in the risk reductions in two very disparate groups of patients treated with ACE inhibitors: (1)those concomitantly treated with aspirin and (2) those who did not receive aspirin. Conspicuously, there was not even a significant reduction in the incidence of heart failure. The combined analysis did show, however, that the trend was toward a proportional reduction in heart failure in patients receiving aspirin (3.3%)-less than one-half of that in those not receiving aspirin (8.8%). Differences in the reduction of 7-day mortality (150/, versus 7%) and 30-day mortality (10% versus 6%) in control subjects in the noaspirin and aspirin groups, respectively, were discarded as nonsignificant, but, on the basis of the data available, this study had only 13% power to detect whether any of these differences were significant. Overall, it appears that the risk reduction on treatment with an ACE inhibitor in patients taking aspirin is consistently diminished to approximately one-half of that of patients not taking aspirin (see Table 1).20 Even in patients al-

601

ready taking aspirin, however, administration of an ACE inhibitor has been shown to decrease independently the rate of ischemic events.38,52 Accordingly, because it can be assumed that the effects of aspirin remain intact when aspirin and ACE inhibitors are given together and that the studies include basically the same patients with the same endpoints, it must be interpreted that aspirin is only detracting from effectiveness and that benefits otherwise derived through prevention of ischemic events are offset by a deleterious effect on the heart failure. It is apparent that ACE inhibitors work better when given without aspirin.

AN ASPIRIN-BASED COMPROMISE IS NOT THE SOLUTION

Can the problem be circumvented with a lower dose of aspirin? Probably not. The author's hospital records document that on repeated occasions, in patients admitted to our service with seemingly terminal, intravenous catecholamine-dependent heart failure, there is marked improvement, stabilization, and abatement of hyponatremia with dramatically reduced diuretic requirements after discontinuation of a daily 100-mg dose of aspirin with no additional therapeutic manipulations.

Summary

To whatever extent the improvement in symptoms and survival rendered by treatment with ACE inhibitors is attributable to their effects on the circulation and the kidneys, this benefit can be rescinded by concomitant administration of aspirin. Although some useful prostaglandin-independent actions may persist, shutting down the entire prostaglandin system and trading off a substantial portion of the potential risk reduction with forfeit of salutary hemodynamic and renal effects is a high price to pay just to suppress production of TXA,. In patients requiring treatment for heart failure, if possible, aspirin should be avoided and the integrity of prostaglandin metabolism respected; the

602

HALL

severer the heart failure, the more compelling. There are other ways to inhibit platelet aggregation, some equally effective or even better than aspirin. Orally active platelet glycoprotein IIb/IIIa receptor antagonists, which may be more efficient than aspirin, have been developed and are now in clinical testing. Ticlopidine and clopidogrel, although more expensive than aspirin, are as easy to use and at least as effective as aspirin. Finally, because patients with severer heart failure are likely to be those with very low ejection fractions, these patients are good candidates for oral anticoagulation even though this treatment requires additional monitoring.

References 1. Abdel-Haq B, Magagna A, Favilla S, et al: Hemodynamic and humoral interactions between perindopril and indomethacin in essential hypertensive subjects. J Cardiovasc Pharmacol 18(suppl):33-36, 1991 2. Berg KN, Loew D Inhibition of furosemide-induced natriuresis by acetylsalicylic acid in dogs. Scand J Clin Lab Invest 37125-131, 1977 3. Brater DC: Analysis of the effect of indomethacin on the response to furosemide in man. J Pharmacol Exp Ther 210:386393, 1979 4. Bisordi JE, Schlondorff D, Hays RM: Interaction of vasopressin and prostaglandins in the toad urinary bladder. J Clin Invest 66:1200-1210, 1980 5. Brown J, Dollery C, Valdes G: Interaction of nonsteroidal anti-inflammatory drugs with antihypertensive and diuretic agents. Control of vascular reactivity by endogenous prostanoids. Am J Med 81:43-57, 1986 6. Ciabattoni G, Pugliese F, Cinotti GA: Characterization of furosemide-induced activation of the renal prostaglandin system. Eur J Pharmacol 60:181-90, 1979 7. Cohn JN, Johnson G, Ziesche S, et al: A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med 325:303-10, 1991 8. Coronary Drug Project Group: Aspirin in coronary heart disease. J Chronic Dis 29:625442, 1976 9. Curtiss C, Cohn JN, Vrobel T, et al: Role of the reninangiotensin system in the systemic vasoconstriction of chronic congestive heart failure. Circulation 58:763-770, 1978 10. Donker AJM, Arisz L, Brentjens A: The effect of indomethacin on kidney function and plasma renin activity in man. Nephron 17:288-296, 1976 11. Dusing R, Herrmann R, Glanzer K, et al: Renal prostaglandins and water balance: Studies in normal volunteer subjects and in patients with central diabetes insipidus. Clin Sci 61:61-67, 1981 12. Dzau VJ, Swartz SL: Dissociation of the prostaglandin and renin angiotensin systems during captopril therapy for chronic congestive heart failure secondary to coronary artery disease. Am J Cardiol6O:llOl1105, 1987

13. Elwood P, Sweetnam P: Aspirin and secondary mor-

tality after myocardial infarction. Lancet 2:13131315, 1979 14. Evans M, Burnett JC, Redfield MM: Effect of low dose aspirin on cardiorenal function and acute hemodynamic response to enalaprilat in a canine model of severe heart failure. J Am Coll Cardiol 25:1445-1450, 1995 15. Dzau VJ, Packer M, Lilly LS, et al: Prostaglandins in severe congestive heart failure: Relation to activation of the renin-angiotensin system and hyponatremia. N Engl J Med 310:347-352, 1984 16. Dzau VJ, Swartz SL, Creager MA: The role of prostaglandins in the pathophysiology of and therapy for congestive heart failure. Heart Failure 26-13, 1986 17. Favre L, Glasson PH, Riondel A, et al: Interaction of diuretics and non-steroid anti-inflammatory drugs in man. Clin Sci 64:407418, 1983 18. Goldman S, Copeland J, Moritz T, et al: Improvement in early saphenous vein graft patency after coronary artery bypass surgery with anti-platelet therapy: Results of a Veterans Administration Cooperative Study. Circulation 771324-1332, 1988 19. Goldstone R, Martin K, Zipser R, et al: Evidence for a dual action of converting enzyme inhibitors on blood pressure in man. Prostaglandins 22:587-598, 1981 20. Hall, D. The aspirin-angiotensin converting enzyme inhibitor tradeoff To halve and halve not. J AM Coll Cardiol 35,1808-1812, 2000 21. Hall D, Rudolph W Adverse effect of aspirin on water metabolism in severe heart failure treated with enalapril. J Am Coll Cardiol 23:213A, 1994 22. Hall D, Zeitler H, Rudolph W: Counteraction of the vasodilator effects of enalapril by aspirin in severe heart failure. J Am Coll Cardiol 20:1549-1555, 1992 23. Handler J S Vasopressin-prostaglandin interactions in the regulation of epithelial cell permeability to water. Kidney Int 19:831-838, 1981 24. Herchuelz A, Derenne F, Deger F, et al: Interaction between nonsteroidal anti-inflammatory drugs and loop diuretics: Modulation by sodium balance. J Pharmacol Exp Ther 248:1175-1181, 1989 25. Kimberly RE', Plotz PH: Aspirin-induced depression of renal function. N Engl J Med 296:41&424, 1977 26. Koopmans PP, Thein TN, Gribnau FWJ: Influence of nonsteroidal anti-inflammatory drugs on diuretic treatment of mild to moderate essential hypertension. Br Med J 289:1492-1494, 1984 27. Kramer HJ, Dusing R, Stinnesbeck B, et a1 of conventional and antikaliuretic diuret renal prostaglandin system. Clin Sci 59:67-75, 1980 28. Latini, R, Tognoni G, Maggioni A, et al: Clinical effects of early ACE inhibitor treatment for acute myocardial infarction are similar in the presence and absence of aspirin: Systematic analysis of individual data from nearly 96,000 randomized patients. J Am Coll Cardiol 35301-1807, 2000 29. Lee WH, Packer M: Prognostic importance of serum sodium concentration and its modification by converting-enzyme inhibition in patients with severe chronic heart failure. Circulation 73:257-267, 1986 30. Lewis HD, Davis JW, Archibald DG, et al: Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina: Results of a Veterans Administration Cooperative Study. N Engl J Med 309:396-403, 1983 31. Lopez-Ovejero JA, Weber MA, Sealey JE, et al: Effects of indomethacin alone and during diuretic or P-adre-

CONTROVERSIES IN HEART FAILURE noreceptor blockade therapy on blood pressure and the renin system in essential hypertension. Clin Sci 55(suppl):203-205, 1978 32. Manson JE, Stampfer MJ, Colditz GA, et a1 A prospective study of aspirin use and primary prevention of cardiovascular disease in women. JAMA 266:521527, 1991 33. Moore TJ, Crantz FR, Hollenberg NK, et a1 Contribution of prostaglandins to the antihypertensive action of captopril in essential hypertension. Hypertension 3~168-173, 1981 34. Muther RS, Potter DM, Bennett WM: Aspirin-induced depression of glomerular filtration rate in normal humans: Role of sodium balance. Ann Intern Med 94:317-321, 1981 35. Nguyen KN, Aursnes I, Snapinn S, et al: Interaction between enalapril and aspirin on mortality after acute myocardial infarction: Subgroup analysis of the Cooperative New Scandinavian Enalapril Survival study I1 (CONSENSUS11). J Am Coll Cardiol 79:115119, 1997 36. Parmley WW: Pathophysiology of congestive heart failure. Am J Cardiol 55:9A-l4A, 1985 37. Patak RV, Mookejee BK, Bentzel CJ, et al: Antagonism of the effects of furosemide by indomethacin in normal and hypertensive man. Prostaglandins 10:649-659, 1975 38. Pfeffer MA, Braunwald E, Moyk LA, et al: Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction: Results of the Survival and Ventricular Enlargement Trial. N Engl J Med 327669477, 1992 39. Pirson Y, van Ypersele SC: Renal side effects of nonsteroidal antiinflammatory drugs: Clinical relevance. Am J Kidney Dis 8:338-344, 1986 40. Pitt 8: Use of converting enzyme inhibitors in patients with asymptomatic left ventricular dysfunction. J Am Coll Cardiol22:158A-l61A, 1993 41. Pitt B, Yusuf S, SOLVD investigators: Studies of left ventricular dysfunction (SOLVD): Subgroup results [abstract]. J Am Coll Cardiol 19:215A, 1992 42. Rowe BP: The influence of indomethacin on blood pressure during the infusion of vasopressors. Hypertension 8:772-778, 1986 43. Rubin P, Jackson G, Blashke T Studies of the clinical pharmacology of prazosin. Br J Clin Pharmacol 10:33-39, 1980 44. Rubin LJ, Lazar JD: Influence of prostaglandin synthesis inhibitors on pulmonary vasodilatory effects of hydralazine in dogs with hypoxic pulmonary vasoconstriction. J Clin Invest 67193-200, 1981 45. Salvetti A, Pedrinelli R, Magagna A, et al: The influence on some pharmacological action of atenolol. In

46.

47.

48. 49.

50.

51.

52.

53.

54. 55. 56.

57. 58. 59.

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Dunn MJ (ed): Prostaglandins and the Kidney. New York, Plenum Press, 1982, pp 287-295 Silberbauer K, Stanek B, Tempe1 H: Acute hypotensive effect of captopril modified by prostaglandin synthesis inhibition. Br J Clin Pharmacol 14(suppl): 87-93, 1982 Smith DE, Brater DC, Lin ET, et al: Attenuation of furosemide’s diuretic effect by indomethacin: Pharmacokinetic evaluation. J Pharmacokinet Biopharm 7265-275, 1979 Swartz SL, Williams GH, Hollenberg NK, et al: Captopril induced changes in prostaglandin production. J Clin Invest 65:1257-1264, 1980 Swedberg K, Held P, Kjekshus J, et al: Effects of the early administration of enalapril on mortality in patients with acute myocardial infarction: Results of the Cooperative New Scandinavian Enalapril Survival Study I1 (CONSENSUS 11). N Engl J Med 327678484, 1992 The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators: Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. Lancet 342821-828, 1993 The SOLVD Investigators: Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 325:293-302, 1991 The SOLVD Investigators: Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med 327685491, 1992 The Steering Committee of the Physicians’ Health Study Research Group: Final Report on the aspirin component of the ongoing physicians’ health study. N Engl J Med 318:262-264, 1988 Tweeddale MG, Ogilvie R I Antagonism of spironolactone-induced natriuresis by aspirin in man. N Engl J Med 289:198-200, 1973 Vane J R Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nature 231:232-235, 1971 Watkins J, Abbott EC, Hensby CN, et al: Attenuation of the hypotensive effect of propranolol and thiazide diuretics by indomethacin. Br Med J 281:702-705, 1980 Webster J, Hawksworth GM, McLean I, et al: Flurbiprofen interaction with single doses of atenolol and propranolol. Br J Clin Pharmacol 18:861-866, 1984 Witzgall H, Scherer 8, Weber PC: Involvement of prostaglandins in actions of captopril. Clin Sci 63(~~ppl):265-267, 1982 Zusman RM: Prostaglandins, vasopressin, and renal water reabsorption. Med Clin North Am 65:915-925, 1981

Address reprint requests to Donald Hall, MD German Heart Center Technical University of Munich Lazerettstrasse 36 80636 Munich Germany e-mail: hall8dhm.mhn.de