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Review Article |

Does Aspirin Attenuate the Beneficial Effects of Angiotensin-Converting Enzyme Inhibition in Heart Failure? FREE

Tomasz Stys, MD; William E. Lawson, MD; Gerald C. Smaldone, MD, PhD; Adam Stys, MD
[+] Author Affiliations

From the Cardiology Division (Drs T. Stys and Lawson) and Pulmonary and Critical Care Medicine Division (Dr Smaldone), Department of Medicine, State University of New York, Stony Brook, and Sioux Valley Canby Campus, Canby, Minn (Dr A. Stys).


Arch Intern Med. 2000;160(10):1409-1413. doi:10.1001/archinte.160.10.1409.
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Published online

Ischemic heart disease is the most common underlying cause of congestive heart failure, and thus aspirin (acetylsalicylic acid [ASA]) and angiotensin-converting enzyme (ACE) inhibitors are commonly used together for treatment in this setting. The issue of possible attenuation of the effect of ACE inhibitors by ASA has been an area of intense debate. Currently, it is perceived that a significant part of the beneficial effect of ACE inhibitors is related to augmentation of bradykinin levels, which among other effects stimulate the release of prostacyclin. Aspirin, on the other hand, inhibits the production of prostacyclin by blocking cyclooxygenase. Prostaglandins play an important endogenous vasodilatory role and counteract the enhanced peripheral vasoconstriction state in congestive heart failure. Thus, the counteracting effect of ASA on the augmentation of prostacyclin synthesis by ACE inhibitors could result in a potential reduction of the beneficial effects of the ACE inhibitor's and could be of great importance. This article reviews reports from large clinical trials pertaining to this issue and relates their findings to the currently available theoretical bases for support of the counteracting effect of ASA on augmentation of prostacyclin synthesis by ACE inhibitors. The clinical implications of such an interaction are discussed.

Angiotensin-converting enzyme (ACE) inhibitors have been one of the most important advances in the treatment of congestive heart failure (CHF). They have been demonstrated to produce beneficial hemodynamic, symptomatic, and prognostic effects in patients with CHF and to improve both the function and the survival of these patients.14 As a group, ACE inhibitors have been clearly documented to be similar in their effect on conversion of angiotensin I to angiotensin II and have a similar therapeutic profile in the treatment of CHF. However, it appears that the benefit of ACE inhibition cannot be entirely explained by the inhibition of the formation of angiotensin II. It has been found that although even very small doses of ACE inhibitor can completely inhibit ACE and angiotensin II production initially, progressively larger doses are required to maintain ACE inhibition. Also, ACE inhibitors appear to produce persistent benefits, even though circulating levels of angiotensin II (initially suppressed) gradually return to those seen before treatment.5,6

Angiotensin-converting enzyme is also identical to kininase II, and as such degrades kinins. Therefore, ACE inhibitors reduce the degradation of bradykinin, a potent vasodilator, which among other mechanisms acts through the enhancement of synthesis of vasodilatory prostaglandins.7,8 It is thought that this mechanism is responsible for a significant portion of the beneficial cardiac effects of ACE inhibitors.9,10

The important role of aspirin (acetylsalicylic acid [ASA]) in the prevention of occlusive vascular disease has been clearly established, and its use in the treatment and prevention of coronary artery disease is of primary importance.1113 Aspirin exerts its inhibitory effect on platelet aggregation through the blockade of the enzyme cyclooxygenase and thus inhibits the production of prostaglandins.14 This effect of attenuation of prostaglandin synthesis by ASA is the opposite of the effect exerted by ACE inhibitors.

Considering the fact that ischemic heart disease is the most common underlying cause of CHF,15 the concomitant use of these 2 fundamental agents, ASA and ACE inhibitors, is very common. Thus, the counteracting effect of ASA on the augmentation of prostacyclin synthesis by ACE inhibitors could result in a potential reduction of the beneficial effects of ACE inhibitors and could be of great importance.

In this article, we review reports from large clinical trials whose findings pertain to the counteracting effect of ASA on the augmentation of prostacyclin synthesis by ACE inhibitors and relate those findings to the currently available theoretical bases for support of such an interaction.

Prostaglandins serve as an important endogenous vasodilator mechanism in circulatory homeostasis and are thought to constitute an important counter-regulatory pathway to the enhanced peripheral vasoconstriction state of heart failure.10 Dzau et al10 observed that mean circulating levels of vasodilating prostaglandins were 3 to 10 times higher in patients with CHF (severe CHF with hyponatremia) than in normal individuals, and that their plasma levels correlated with the degree of activation of the renin angiotensin system. Thus, one could expect that the response to inhibition of the prostaglandin synthetic pathway might be different in patients with coronary disease and preserved left ventricular function as opposed to those with significant ventricular dysfunction. Administration of indomethacin (which also inhibits cyclooxygenase) to patients with heart failure results in vasoconstriction and a fall in cardiac output, renal blood flow, and glomerular filtration rate. Effects are more prominent in patients with hyponatremia.10,16

The contribution of bradykinin to the effect of ACE inhibition has been the subject of debate. It is possible that the inhibitory effect of ACE inhibitors on the degradation of bradykinin is responsible for a significant portion of the beneficial cardiac effects of ACE inhibitors.810,17 Bradykinin is a potent vasodilator that, among other vasodilating substances, enhances the release of prostacyclin.9,10 This could be a significant mechanism of action of ACE inhibitors, counteracting the neurohumoral changes occurring in patients with heart failure, and thus the concomitant use of prostaglandin synthesis inhibitors could attenuate the beneficial effects of ACE inhibition. Several long-term studies address the possibility of such an interaction.

Townend et al18 showed that single doses of indomethacin attenuated the increase in cardiac output and renal blood flow in response to captopril therapy, but did not attenuate the increase in forearm or calf blood flow. Hall et al19 noted that a single dose of ASA, 350 mg, attenuated the decrease in systemic vascular resistance, left ventricular filling pressure, and total pulmonary resistance as well as the increase in cardiac output elicited by enalapril maleate therapy. Nashimura et al20 showed that indomethacin therapy attenuated the peripheral hemodynamic effects of captopril therapy in patients with heart failure. These findings were not confirmed by studies of van Wijngaarden et al,21 who found that even though the combination of ASA and captopril reduced the levels of prostaglandins, there was no discernible difference in the hemodynamic effects of captopril therapy alone or with ASA. The fact that a lower dose of ASA (<300 mg) was used in this study might explain the discrepancy, as other authors who used low doses of ASA (<300 mg) also did not find a significant hemodynamic interaction.22,23 Low doses of ASA have been shown to inhibit thromboxane synthesis, but higher doses of ASA (>325 mg) are required to inhibit synthesis of vasodilating prostaglandins.24 Therefore, a higher dose of ASA would be necessary to inhibit the presumed vasodilating prostaglandin-mediated hemodynamic effect of ACE inhibitors. Thus, prostaglandin synthesis would not be inhibited by lower doses of ASA (80-100 mg), which would still exert the intended antiplatelet action through blockade of thromboxane synthesis.

On the other hand, Evans et al25 found that ASA, 325 mg, had no adverse effects on hemodynamic, neurohumoral, or renal function in heart failure. Furthermore, ASA had no adverse effect on the acute response to enalapril therapy.

Spaulding et al26 showed that enalapril therapy reduced systemic vascular resistance more effectively when given in combination with ticlopidine hydrochloride, a potent antiplatelet agent not affecting prostaglandin synthesis, than when combined with ASA. The authors suggested that in patients with well-established indications for ACE inhibitors and platelet inhibition, alternative antiplatelet agents to ASA might be of greater efficacy.

The currently available data on the acute hemodynamic effect of antagonism of ACE inhibitors by ASA remain conflicting and must be interpreted with caution, especially with regard to the long-term concomitant administration of ASA and ACE inhibitors.

The issue of possible attenuation of the effect of ACE inhibitors in heart failure by ASA became a topic of intense debate following the reports of the possibility of such an interaction from the Studies of Left Ventricular Dysfunction (SOLVD). These results showed that in contrast to the overall effect, enalapril therapy had no beneficial effect on mortality among those taking ASA.2729 Other trials also reported a tendency toward reduced benefit from ACE inhibition among patients taking ASA, although the existing data are still controversial and inconclusive.2931

Nguyen et al32 conducted a retrospective subgroup analysis of data from the Cooperative New Scandinavian Enalapril Survival Study II (CONSENSUS II) and showed that the enalapril-ASA interaction was a significant predictor of mortality at the end of the study, and thus concluded that the effect of enalapril therapy was less favorable among patients taking ASA than among patients not taking ASA at baseline. At the same time, the authors did not find a significant interaction with regard to nonfatal major events. The finding of long-term enalapril-ASA antagonism seems to be consistent with the main effect of enalapril therapy, ie, the reduction of progression to CHF. The retrospective character of this study does impose significant limitations on the interpretation of the data. Also, as the authors of this study comment, it is possible that the non-ASA group consisted of a sicker population. Angiotensin-converting enzyme inhibitors have been shown to be more effective in patients with more advanced heart failure.32,33 Other authors argue that the patients receiving ASA were more likely to have had previous coronary disease and, more importantly, carotid disease, thus putting these patients at an increased risk for cerebral effects of acute blood reduction in the early acute infarct period.34

On the other hand, Isnard et al35 studied 317 patients with left ventricular dysfunction (left ventricular ejection fraction <35%) and found that over a mean period of 5.7 years ASA therapy exerted favorable effects on long-term prognosis for these patients with ischemic left ventricular systolic dysfunction, whether they were treated with ACE inhibitors or not.35

Despite this, it is also worth noting that while ASA therapy has been shown to improve both short- and long-term prognosis for patients with coronary artery disease and well-preserved left ventricular function,1113 its role in high-risk patients with significant ventricular damage is uncertain and remains an area of debate. This is evidenced in the reports of the Aspirin Myocardial Infarction Study (AMIS)36 and Persantine-Aspirin Reinfarction Study II (PARIS II)37 trials on the influence of baseline characteristics on the outcomes. The AMIS trial, one of the largest in terms of number of patients studied, number of years conducted, and duration of trial-agent exposure, showed a trend toward increased mortality with ASA therapy in most subgroups studied.36 The PARIS trial showed an overall trend toward benefit with ASA therapy, but showed an opposite trend among patients with heart failure or major ventricular dysfunction.37 Similarly, the data from Swedish Angina Pectoris Aspirin Trial (SAPAT) supported the long-term use of ASA in patients with coronary artery disease and well-preserved ventricular function, but at the same time showed that ASA therapy could possibly be harmful in patients with major ventricular damage.12 On the other hand, Oosterga et al,38 after conducting a post hoc analysis of the Captopril and Thrombolysis Study (CATS), found that ASA therapy did not attenuate the acute and long-term effects of ACE inhibition after acute myocardial infarction, but rather independently reduces left ventricular dilation after myocardial infarction (Table 1).29,38

Table Graphic Jump LocationData From Large Clinical Trials Investigating the Interaction of Angiotensin-Converting Enzyme (ACE) Inhibitors and Aspirin (ASA)*

These results provide interesting and provocative data not only with regard to a possible negative interaction between ACE inhibitors and ASA, but also with regard to the role of ASA therapy in heart failure in general. It is important to realize that until further studies clarify these issues, the evidence for harm or benefit from ASA therapy in patients with heart failure remains inconclusive.

Pulmonary factors appear to be important determinants of exercise intolerance in patients with heart failure.39,40 It has been described that patients with chronic severe cardiomyopathy tend to have predominantly restrictive lung disease.41 The reduction in pulmonary diffusing capacity for carbon monoxide (DLCO) has also been well documented in patients with chronic heart failure.3941 It appears that reduced alveolar-capillary membrane diffusing capacity is the major component of impaired pulmonary gas transfer, and this has been shown to correlate well with the maximal exercise capacity and the functional status of patients.40

Angiotensin-converting enzyme is highly concentrated on the luminal surface of the lung blood vessels. As a consequence, pulmonary circulation is the major conversion site of angiotensin I to angiotensin II, as well as being a site for the inactivation of circulating bradykinin during its passage through the lung.42,43 As mentioned earlier in this article, bradykinin is a potent vasodilator that enhances the release of prostacyclin and other vasodilating substances.9,10 Angiotensin-converting enzyme inhibitors reduce the exposure of the lung vessels to angiotensin II and simultaneously potentiate the influence of bradykinin and vasodilating prostaglandins within the lungs. As commented earlier, bradykinins are assumed to play a significant part in the mechanism of action of ACE inhibitors in heart failure.

Guazzi et al44 showed that enalapril therapy improved DLCO and lung volumes (forced expiratory volume in 1 second and maximal voluntary ventilation), which were reduced in patients with heart failure compared with control subjects. Changes in DLCO were counteracted by ASA therapy (325 mg/d). The authors concluded that ACE inhibition exerts a modulatory influence on pulmonary function, which at least in part is mediated through prostaglandins, whose primary feature is an improvement in alveolar-capillary membrane diffusing capacity and functional capacity.44

In another study, Guazzi et al45 confirmed the above findings and also reported that enalapril therapy caused an improvement in peak exercise oxygen uptake that was counteracted by ASA therapy. In the same study, it was shown that losartan potassium, an angiotensin receptor (AT1) blocker, resulted in a comparable improvement in &;O2max and exercise tolerance in patients with heart failure. Losartan, however, does not affect DLCO significantly, and its effect was not counteracted by ASA therapy. The authors concluded that AT1 receptor blockers may represent an alternative to or even an advance beyond ACE inhibitors for the treatment of heart failure because of their similar efficacy and lack of counteraction with ASA therapy.45

It appears that decreased alveolar membrane diffusing capacity is a major reason for impaired pulmonary gas transfer in patients with heart failure, and this appears to correlate with maximum exercise capacity and the functional status of patients. Prostaglandin-mediated functional improvement of the alveolar-capillary membrane appears to contribute to the beneficial effect of ACE inhibition in heart failure and may be negated by ASA administration.

The data that support the evidence for a negative interaction between ASA and ACE inhibitors in patients with heart failure are still not adequate. The clinical trials that report such an interaction were not specifically designed to analyze this issue, but rather were conducted as retrospective analyses of data from existing trials. Existing data documenting the counteraction of hemodynamic and pulmonary effects of ACE inhibitors by ASA and the reports from clinical trials appear intriguing, yet it is important to realize that further studies and a randomized prospective clinical trial are necessary to further clarify this issue. Until more definite data become available, it might be prudent to lower the dose of ASA to 80 to 100 mg in patients with heart failure who are concurrently treated with ACE inhibitors. Alternatively, either an effective antiplatelet agent, such as clopidogrel bisulfate or ticlopidine hydrochloride, could be used in combination with ACE inhibitors or, in the course of therapy, ACE inhibitors could be titrated upward to overcome the potential attenuation of full-dose ASA therapy (≥325 mg/d). The use of an AT1 blocker in place of an ACE inhibitor may also represent an alternative treatment.

Accepted for publication September 8, 1999.

Corresponding author: William E. Lawson, MD, Cardiology Division, Department of Medicine, HSC T-17, 020, State University of New York at Stony Brook, Stony Brook, NY 11794-8171 (e-mail: wlawson@ts.uh.sunysb.edu).

Kjekshus  JSwedberg  KSnapinn  SCooperative New Scandinavian Enalapril Survival Study (CONSENSUS) Trial Group, Effects of enalapril on long-term mortality in severe congestive heart failure. Am J Cardiol. 1992;69103- 107
The Studies of Left Ventricular Dysfunction (SOLVD) Investigators, Effect of enalapril on survival in patients with reduced left ventricular ejection fraction and congestive heart failure. N Engl J Med. 1991;325293- 302
The Studies of Left Ventricular Dysfunction (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. 1992;327685- 691
Pfeffer  MABraunwald  EMoye  LA  et al. Survival and Ventricular Enlargement (SAVE) Investigators, 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. 1992;327669- 677
Cleland  JSemple  PHodsman  PBall  SFord  IDargie  H Angiotensin II levels, hemodynamics, and sympathoadrenal function after low-dose enalapril in heart failure. Am J Med. 1984;77880- 886
Cleland  JGFDargie  HJMcAlpine  H  et al.  Severe hypotension after first dose of enalapril in heart failure. BMJ (Clin Res Ed). 1985;2911309- 1312
Grainer  KVMorrow  JDLoveland  JKing  DJBrown  NJ Effect of bradykinin receptor blockade on the response to angiotensin-enzyme inhibitor in normotensive and hypertensive subjects. N Engl J Med. 1998;3391285- 1291
Vanhoutte  PM Endothelium and control of vascular function [state of the art lecture]. Hypertension. 1989;13658- 667
Moore  TJCrantz  FRHollenberg  NK  et al.  Contribution of prostaglandins to the antihypertensive action of captopril in essential hypertension. Hypertension. 1981;3168- 173
Dzau  VJPacker  MLilly  LSSwartz  SLHollenberg  NKWilliams  GH Prostaglandins in severe congestive heart failure: relation to activation of renin-angiotensin system and hyponatremia. N Engl J Med. 1984;310347- 352
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. 1989;321129- 135
Jull-Moller  SEdvardsson  NJahnmatz  BRosen  ASorensen  SOmblus  RSwedish Angina Pectoris Aspirin Trial (SAPAT) Group, Double-blinded trial of aspirin in primary prevention of myocardial infarction in patients with stable chronic angina pectoris. Lancet. 1992;3401421- 1425
The SALT Collaborative Group, Swedish Aspirin Low-dose Trial (SALT) of 75 mg aspirin as secondary prophylaxis after cerebrovascular ischemic events. Lancet. 1991;3381345- 1349
FitzGerald  GAOates  JAHawinger  J  et al.  Endogenous biosynthesis of prostacycline and thromboxane and platelet function during chronic administration of aspirin in men. J Clin Invest. 1983;71676- 688
Parmley  WW Pathophysiology of congestive heart failure. Am J Cardiol. 1985;567A- 11A
Sbarouni  EBradshaw  AAndreotti  FTuddenham  EOakley  CMCleland  JG Relationship between hemostatic abnormalities and neuroendocrine activity in heart failure. Am Heart J. 1994;127607- 612
Gainer  JVMorrow  JDLoveland  AKing  DJBrown  NJ Effect of bradykinin-receptor blockade on the response to angiotensin-converting-enzyme inhibitor in normotensive and hypertensive subjects. N Engl J Med. 1998;3391285- 1292
Townend  JNDoran  JLote  CJDavies  MK Peripheral haemodynamic effects of inhibition of prostaglandin synthesis in congestive heart failure and interactions with captopril. Br Heart J. 1995;73434- 441
Hall  DZeitler  HRudolph  W Counteraction of the vasodilator effects of enalapril by aspirin in severe heart failure. J Am Coll Cardiol. 1992;201549- 1555
Nishimura  HKubo  SUeyama  MKubota  JKawamura  K Peripheral hemodynamic effects of captopril in patients with congestive heart failure. Am Heart J. 1989;117100- 105
van Wijngaarden  JSmit  AJde Graeff  PA  et al.  Effects of acetylsalicylic acid on peripheral hemodynamics in patients with chronic heart failure treated with angiotensin-converting enzyme inhibitors. J Cardiovasc Pharmacol. 1994;23240- 245
Smith  SRCoffman  TMSvetkey  LP Effect of low-dose aspirin on thromboxane production and the antihypertensive effect of captopril. J Am Soc Nephrol. 1993;41133- 1139
Baur  LHSchipperheyn  JJvan der Laarse  A  et al.  Combining salicylate and enalapril in patients with coronary artery disease and heart failure. Br Heart J. 1995;73227- 236
Weksler  BBPett  SBAlonso  D  et al.  Differential inhibition by aspirin of vascular and platelet prostaglandin synthesis in atherosclerotic patients. N Engl J Med. 1983;308800- 805
Evans  MABurnett  JC  JrRedfield  MM Effect of low-dose aspirin on cardiorenal function and acute hemodynamic response to enalapril at in a canine model of severe heart failure. J Am Coll Cardiol. 1995;251445- 1450
Spaulding  CCharbonnier  BCohen-Solal  A  et al.  Acute hemodynamic interaction of aspirin and ticlopidine with enalapril: results of a double-blind, randomized comparative trial. Circulation. 1998;98757- 765
Pitt  B Use of converting enzyme inhibitors in patients with asymptomatic left ventricular dysfunction. J Am Coll Cardiol. 1993;22(suppl A)158A- 161A
Al-Khadra  ASSalem  DNRand  WMUdelson  JESmith  JJKonstam  MA Antiplatelet agents and survival: a cohort analysis from the Studies of Left Ventricular Dysfunction (SOLVD) trial. J Am Coll Cardiol. 1998;31419- 425
Cleland  JGFBulpitt  CJFalk  RH  et al.  Is aspirin safe for patients with heart failure? Br Heart J. 1995;74215- 219
Cleland  JGF ACE inhibitors for myocardial infarction: how should they be used? Eur Heart J. 1995;16153- 159
Nguyen  KNAursnes  ISnapinn  SKjekshus  J Antagonism between enalapril and aspirin: subgroup analysis of the Cooperative New Scandinavian Enalapril Survival Study II (CONSENSUS II) [abstract]. J Am Coll Cardiol. 1995;25(suppl A)23A
Nguyen  KNAursnes  IKjekshus  J Interaction between enalapril and aspirin on mortality after acute myocardial infarction: subgroup analysis of the Cooperative New Scandinavian Enalapril Survival Study II (CONSENSUS II). Am J Cardiol. 1997;79115- 119
Smith  GDEgger  M Who benefits from medical interventions? treating low-risk patients can be a high risk strategy. BMJ. 1994;30872- 74
Coats  AJ Enalapril, aspirin interaction [letter]. Am J Cardiol. 1997;801122
Isnard  RBaroin  JPDrobinski  G  et al.  Influence of aspirin on long-term prognosis of patients with left ventricular systolic dysfunction [abstract]. Circulation. 1998;17300
Aspirin Myocardial Infarction Study Research Group, A randomized, controlled trial of aspirin in persons recovered from myocardial infarction. JAMA. 1980;243661- 669
Klimt  CRKnatterud  GLStamler  JMeier  P Persantine-Aspirin Reinfarction Study, part II: secondary coronary prevention with persantine and aspirin. J Am Coll Cardiol. 1986;7251- 269
Oosterga  MAnthonio  RLde Kam  PJKingma  JHCrijns  HJGMvan Gilst  WH Effects of aspirin on angiotensin-converting enzyme inhibition and left ventricular dilation one year after acute myocardial infarction. Am J Cardiol. 1998;811178- 1181
Kraemer  MDKubo  SHRector  TSBrunsvold  NBank  AJ Pulmonary and peripheral vascular factors are important determinants of peak exercise oxygen uptake in patients with heart failure. J Am Coll Cardiol. 1993;21641- 648
Puri  SBaker  BLDutka  DP  et al.  Reduced alveolar-capillary membrane diffusing capacity in chronic heart failure: its pathophysiological relevance and relationship to exercise performance. Circulation. 1995;912769- 2774
Naum  CCSciurba  FCRogers  RM Pulmonary function abnormalities in chronic severe cardiomyopathy preceding cardiac transplantation. Am Rev Respir Dis. 1992;1451334- 1338
Ryan  JWRyan  USSchultz  DRWhitaker  CChung  A Subcellular localization of pulmonary angiotensin-converting enzyme (kininase II). Biochem J. 1975;146497- 499
Helmer  OM Differentiation between two forms of angiotensin by means of spirally cut strips of rabbit aorta. Am J Physiol. 1957;188571- 577
Guazzi  MMarenzi  GAlimento  MContini  MAgostoni  P Improvement of alveolar-capillary membrane diffusing capacity with enalapril in chronic heart failure and counteracting effect of aspirin. Circulation. 1997;951930- 1936
Guazzi  MMelzi  GAgostoni  P Comparison of changes in respiratory function and exercise oxygen uptake with losartan versus enalapril in congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol. 1997;801572- 1576

Figures

Tables

Table Graphic Jump LocationData From Large Clinical Trials Investigating the Interaction of Angiotensin-Converting Enzyme (ACE) Inhibitors and Aspirin (ASA)*

References

Kjekshus  JSwedberg  KSnapinn  SCooperative New Scandinavian Enalapril Survival Study (CONSENSUS) Trial Group, Effects of enalapril on long-term mortality in severe congestive heart failure. Am J Cardiol. 1992;69103- 107
The Studies of Left Ventricular Dysfunction (SOLVD) Investigators, Effect of enalapril on survival in patients with reduced left ventricular ejection fraction and congestive heart failure. N Engl J Med. 1991;325293- 302
The Studies of Left Ventricular Dysfunction (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. 1992;327685- 691
Pfeffer  MABraunwald  EMoye  LA  et al. Survival and Ventricular Enlargement (SAVE) Investigators, 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. 1992;327669- 677
Cleland  JSemple  PHodsman  PBall  SFord  IDargie  H Angiotensin II levels, hemodynamics, and sympathoadrenal function after low-dose enalapril in heart failure. Am J Med. 1984;77880- 886
Cleland  JGFDargie  HJMcAlpine  H  et al.  Severe hypotension after first dose of enalapril in heart failure. BMJ (Clin Res Ed). 1985;2911309- 1312
Grainer  KVMorrow  JDLoveland  JKing  DJBrown  NJ Effect of bradykinin receptor blockade on the response to angiotensin-enzyme inhibitor in normotensive and hypertensive subjects. N Engl J Med. 1998;3391285- 1291
Vanhoutte  PM Endothelium and control of vascular function [state of the art lecture]. Hypertension. 1989;13658- 667
Moore  TJCrantz  FRHollenberg  NK  et al.  Contribution of prostaglandins to the antihypertensive action of captopril in essential hypertension. Hypertension. 1981;3168- 173
Dzau  VJPacker  MLilly  LSSwartz  SLHollenberg  NKWilliams  GH Prostaglandins in severe congestive heart failure: relation to activation of renin-angiotensin system and hyponatremia. N Engl J Med. 1984;310347- 352
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. 1989;321129- 135
Jull-Moller  SEdvardsson  NJahnmatz  BRosen  ASorensen  SOmblus  RSwedish Angina Pectoris Aspirin Trial (SAPAT) Group, Double-blinded trial of aspirin in primary prevention of myocardial infarction in patients with stable chronic angina pectoris. Lancet. 1992;3401421- 1425
The SALT Collaborative Group, Swedish Aspirin Low-dose Trial (SALT) of 75 mg aspirin as secondary prophylaxis after cerebrovascular ischemic events. Lancet. 1991;3381345- 1349
FitzGerald  GAOates  JAHawinger  J  et al.  Endogenous biosynthesis of prostacycline and thromboxane and platelet function during chronic administration of aspirin in men. J Clin Invest. 1983;71676- 688
Parmley  WW Pathophysiology of congestive heart failure. Am J Cardiol. 1985;567A- 11A
Sbarouni  EBradshaw  AAndreotti  FTuddenham  EOakley  CMCleland  JG Relationship between hemostatic abnormalities and neuroendocrine activity in heart failure. Am Heart J. 1994;127607- 612
Gainer  JVMorrow  JDLoveland  AKing  DJBrown  NJ Effect of bradykinin-receptor blockade on the response to angiotensin-converting-enzyme inhibitor in normotensive and hypertensive subjects. N Engl J Med. 1998;3391285- 1292
Townend  JNDoran  JLote  CJDavies  MK Peripheral haemodynamic effects of inhibition of prostaglandin synthesis in congestive heart failure and interactions with captopril. Br Heart J. 1995;73434- 441
Hall  DZeitler  HRudolph  W Counteraction of the vasodilator effects of enalapril by aspirin in severe heart failure. J Am Coll Cardiol. 1992;201549- 1555
Nishimura  HKubo  SUeyama  MKubota  JKawamura  K Peripheral hemodynamic effects of captopril in patients with congestive heart failure. Am Heart J. 1989;117100- 105
van Wijngaarden  JSmit  AJde Graeff  PA  et al.  Effects of acetylsalicylic acid on peripheral hemodynamics in patients with chronic heart failure treated with angiotensin-converting enzyme inhibitors. J Cardiovasc Pharmacol. 1994;23240- 245
Smith  SRCoffman  TMSvetkey  LP Effect of low-dose aspirin on thromboxane production and the antihypertensive effect of captopril. J Am Soc Nephrol. 1993;41133- 1139
Baur  LHSchipperheyn  JJvan der Laarse  A  et al.  Combining salicylate and enalapril in patients with coronary artery disease and heart failure. Br Heart J. 1995;73227- 236
Weksler  BBPett  SBAlonso  D  et al.  Differential inhibition by aspirin of vascular and platelet prostaglandin synthesis in atherosclerotic patients. N Engl J Med. 1983;308800- 805
Evans  MABurnett  JC  JrRedfield  MM Effect of low-dose aspirin on cardiorenal function and acute hemodynamic response to enalapril at in a canine model of severe heart failure. J Am Coll Cardiol. 1995;251445- 1450
Spaulding  CCharbonnier  BCohen-Solal  A  et al.  Acute hemodynamic interaction of aspirin and ticlopidine with enalapril: results of a double-blind, randomized comparative trial. Circulation. 1998;98757- 765
Pitt  B Use of converting enzyme inhibitors in patients with asymptomatic left ventricular dysfunction. J Am Coll Cardiol. 1993;22(suppl A)158A- 161A
Al-Khadra  ASSalem  DNRand  WMUdelson  JESmith  JJKonstam  MA Antiplatelet agents and survival: a cohort analysis from the Studies of Left Ventricular Dysfunction (SOLVD) trial. J Am Coll Cardiol. 1998;31419- 425
Cleland  JGFBulpitt  CJFalk  RH  et al.  Is aspirin safe for patients with heart failure? Br Heart J. 1995;74215- 219
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