Acetylsalicylsyre i doser på mere end 300 mg daglig kan nedsætte den antihypertensive effekt af ACE-hæmmere. Behandling med lav-dosis acetylsalicylsyre påvirker ikke ACE hæmmeres antihypertensive eller hjertebeskyttende effekt. Ved samtidig behandling med NSAIDs og ACE hæmmere er der risiko for nyresvigt. Riskoen synes størst hos patienter med andre risikofaktorer.
Kober L;Torp-Pedersen C;Carlsen JE;Bagger H;Eliasen P;Lyngborg K;Videbaek J;Cole DS;Auclert L;Pauly NC, N Engl J Med, 1995, 333:1670-1676; A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. Trandolapril Cardiac Evaluation (TRACE) Study Group
BACKGROUND. Treatment with angiotensin-converting-enzyme (ACE) inhibitors reduces mortality among survivors of acute myocardial infarction, but whether to use ACE inhibitors in all patients or only in selected patients is uncertain. METHODS. We screened 6676 consecutive patients with 7001 myocardial infarctions confirmed by enzyme studies. A total of 2606 patients had echocardiographic evidence of left ventricular systolic dysfunction (ejection fraction, < or = 35 percent). On days 3 to 7 after infarction, 1749 patients were randomly assigned to receive oral trandolapril (876 patients) or placebo (873 patients). The duration of follow-up was 24 to 50 months. RESULTS. During the study period, 304 patients (34.7 percent) in the trandolapril group died, as compared with 369 (42.3 percent) in the placebo group (P = 0.001). The relative risk of death in the trandolapril group, as compared with the placebo group, was 0.78 (95 percent confidence interval, 0.67 to 0.91). Trandolapril also reduced the risk of death from cardiovascular causes (relative risk, 0.75; 95 percent confidence interval, 0.63 to 0.89; P = 0.001) and sudden death (relative risk, 0.76; 95 percent confidence interval, 0.59 to 0.98; P = 0.03). Progression to severe heart failure was less frequent in the trandolapril group (relative risk, 0.71; 95 percent confidence interval, 0.56 to 0.89; P = 0.003). In contrast, the risk of recurrent myocardial infarction (fatal or nonfatal) was not significantly reduced (relative risk, 0.86; 95 percent confidence interval, 0.66 to 1.13; P = 0.29). CONCLUSIONS. Long-term treatment with trandolapril in patients with reduced left ventricular function soon after myocardial infarction significantly reduced the risk of overall mortality, mortality from cardiovascular causes, sudden death, and the development of severe heart failure. That mortality was reduced in a randomized study enrolling 25 percent of consecutive patients screened should encourage the selective use of ACE inhibition after myocardial infarction
Guazzi MD;Campodonico J;Celeste F;Guazzi M;Santambrogio G;Rossi M;Trabattoni D;Alimento M, Clin Pharmacol Ther, 1998, 63:79-86; Antihypertensive efficacy of angiotensin converting enzyme inhibition and aspirin counteraction
OBJECTIVE: Blockade of bradykinin breakdown and enhancement of prostaglandin release probably participate in the antihypertensive activity of angiotensin converting enzyme (ACE) inhibitors. Cyclooxygenase blockers may attenuate the efficacy of ACE inhibitors by interfering with prostaglandin synthesis, and patients taking aspirin may not benefit from ACE inhibition. This study was designed to evaluate the incidence of the counteractive phenomenon and to define minimal aspirin dosage that causes an antagonistic effect. METHODS: These were 26 patients with mild to moderate hypertension (group 1) and 26 patients with severe untreated primary hypertension (group 2). Enalapril (20 mg twice a day) was used as a single drug in group 1 and was added to the combination of long-acting nifedipine (30 mg/day) and atenolol (50 mg/day) in group 2. Aspirin was tested at doses of 100 and 300 mg/day, and an attenuation of more than 20% of the mean blood pressure decrease produced by enalapril was the criteria that defined antagonism. RESULTS: The 100 mg dose was ineffective. However, 300 mg aspirin had an antagonistic effect in 57% of patients in group 1 and 50% of patients in group 2: mean arterial pressure was lowered by 63% and 91% less, respectively. Results were independent of the drug administration order. In 'responders,' aspirin significantly attenuated the renin rise associated with ACE inhibition. CONCLUSIONS: These findings suggest that a number of ACE-inhibited patients are susceptible to 300 mg/day aspirin, regardless of hypertension severity. Antagonism may be mediated through prostaglandin inhibition according to predominance, in an individual patient, of prostaglandin activation (also as a renin secretory stimulus) or angiotensin blockade by enalapril
Meune C;Mahe I;Mourad JJ;Cohen-Solal A;Levy B;Kevorkian JP;Jondeau G;Habib A;Lebret M;Knellwolf AL;Simoneau G;Caulin C;Bergmann JF, Eur J Heart Fail, 2003, 5:271-279; Aspirin alters arterial function in patients with chronic heart failure treated with ACE inhibitors: a dose-mediated deleterious effect
BACKGROUND: By inhibiting prostaglandin synthesis, aspirin can interfere with both arterial functional and angiotensin-converting enzyme inhibitor (ACEI) properties and be deleterious in chronic heart failure (CHF). AIM: Our aim was to prospectively evaluate the effect of aspirin on arterial functional properties in CHF patients treated with ACEIs. METHODS AND RESULTS: Over three consecutive treatment periods of 7 days, 18 patients received placebo, followed by aspirin 100 mg/day, and then aspirin 325 mg/day. Single blind prospective assessment of reflected wave and time reflection by radial applanation tonometry; pulse wave velocity; blood pressure; thromboxane B2 (TxB2) and prostaglandins in plasma and urine was performed. Aspirin 325 mg/day induced a significant increase in augmentation index of reflected wave (P<0.0001 and P=0.0013 vs. placebo and aspirin 100 mg, respectively) and a significant decrease in reflected wave traveling times (P=0.0007 vs. placebo). Aspirin 100 mg/day produced a similar, though non-significant, trend in these parameters compared with placebo. Both aspirin treatments produced a statistically significant decrease in serum TxB2 (P<0.0001) but did not have an effect on the metabolite of prostaglandin I2 (P=0.136). CONCLUSION: This study demonstrates the existence of a dose-mediated deleterious effect of aspirin upon arterial functional properties in CHF patients treated with ACEI
Krumholz HM;Chen YT;Wang Y;Radford MJ, Arch Intern Med, 2001, 161:538-544; Aspirin and angiotensin-converting enzyme inhibitors among elderly survivors of hospitalization for an acute myocardial infarction
BACKGROUND: Aspirin and angiotensin-converting enzyme (ACE) inhibitors are recommended for secondary prevention after acute myocardial infarction (AMI), but several studies have suggested that the combination of these medications may produce a negative interaction. OBJECTIVE: To evaluate the effect and interaction of aspirin and ACE inhibitors on mortality among elderly patients who survived a hospitalization for AMI. METHODS: We evaluated the effect and interaction of aspirin and ACE inhibitors on mortality in patients aged 65 years and older who survived hospitalization with a confirmed AMI who were ideal candidates for the therapies. RESULTS: Among the 14 129 patients, 26% received aspirin only, 20% received ACE inhibitors only, 38% received both, and 16% received neither at discharge. In the multivariate analysis, patients who received both aspirin and ACE inhibitors alone had a significantly lower 1-year mortality (adjusted risk ratio [ARR], 0.86 [95% confidence interval (CI), 0.78-0.95] vs 0.85 [95% CI, 0.77-0.93], respectively) compared with patients who received neither aspirin nor ACE inhibitors at discharge. Prescribing both aspirin and ACE inhibitors was associated with a slightly lower risk of mortality (ARR, 0.81; 95% CI, 0.74-0.88) than that seen in aspirin-only or ACE inhibitor-only groups, but the difference was not significantly different from the use of either medication alone. CONCLUSIONS: The benefit of ACE inhibitors and aspirin is consistent with what would be expected from overall results of randomized trials; prescribed together, the effect is slightly greater than with either one alone, but not significantly or substantially so
Aumegeat V;Lamblin N;de GP;Mc Fadden EP;Millaire A;Bauters C;Lablanche JM, Chest, 2003, 124:1250-1258; Aspirin does not adversely affect survival in patients with stable congestive heart failure treated with Angiotensin-converting enzyme inhibitors
BACKGROUND: Experimental studies and retrospective analyses of mortality trials with angiotensin-converting enzyme inhibitors (ACE-Is) have suggested that aspirin may reduce the beneficial effect of these drugs. The aim of this study was to assess a possible detrimental effect of aspirin on survival in stable patients with left ventricular systolic dysfunction who had congestive heart failure and had been treated with ACE-Is. METHODS AND RESULTS: We performed a retrospective analysis in 755 consecutive stable patients with left ventricular systolic dysfunction. A Cox regression model was used to select independent predictors of survival and to test for a possible interaction between aspirin and ACE-Is with an adjustment to differences in clinical characteristics in subgroups of patients. Of the 755 patients, 328 (43.4%) had proven ischemic cardiomyopathy, 693 patients (91.8%) were receiving ACE-Is, and 317 patients were receiving aspirin (mean [+/- SD] dose, 183 +/- 65 mg/d; 74% of the patients receiving < or = 200 mg/d). During a median follow-up period of 1,996 days, there were 273 cardiac-related deaths, 14 urgent transplantations, 71 nonurgent transplantations, and 46 noncardiac-related deaths, and 3 patients were lost to follow-up. The cardiovascular mortality rates were 11.5% and 19.0%, respectively, at 1 and 2 years. There were no interactions among aspirin, ACE-Is, and survival in the overall population (p = 0.21), or in subgroups of patients with ischemic cardiomyopathy (p = 0.41) or with nonischemic cardiomyopathy (p = 0.74). CONCLUSIONS: In this population of stable patients with left ventricular systolic dysfunction, our retrospective analysis did not demonstrate any interaction between the use of aspirin and survival in patients receiving ACE-Is
MacIntrye IM;Jhund PS;McMurray JJ, Cardiovasc Drugs Ther, 2005, 19:261-265; Aspirin inhibits the acute arterial and venous vasodilator response to captopril in patients with chronic heart failure
PURPOSE: The potentially beneficial hemodynamic effects of angiotensin-converting enzyme (ACE) inhibitors in heart failure may relate, in part, to their ability to increase the production of vasodilator prostanoids. Low dose aspirin is commonly prescribed in CHF and may attenuate the vasodilator effects of ACE inhibitors. We sought to determine the effects of low dose aspirin on the peripheral hemodynamic effects of captopril in patients with chronic heart failure (CHF). METHODS: Nine patients with chronic heart failure were randomized in a placebo controlled, cross over study, to 75 mg of aspirin daily or placebo. After 7 days treatment the response to 25 mg of captopril was evaluated over 180 min using venous occlusion plethysmography. Forearm blood flow (FBF) and forearm venous capacitance (FVC) were measured. RESULTS: Mean arterial pressure and heart rate did not change. After placebo, FBF increased in response to captopril (+18%, 95%CI 24.2, 11.8), a response inhibited by aspirin (-1.4%, 2.9, -5.7), p < 0.005. After placebo, FVC increased in response to captopril (+7.6%, 9.8, 5.4), which was also inhibited by aspirin (+2.0%, 4.6, -0.6), aspirin vs. placebo, p = 0.02). CONCLUSION: In patients with chronic heart failure even low dose aspirin inhibits both the acute arterial and venous dilator responses to captopril. This action of aspirin may reduce the long-term clinical benefits of ACE inhibitors
MacIntrye IM;Jhund PS;McMurray JJV, Tomt indhold, 2005, 19(4): 261-265-265; Aspirin inhibits the acute arterial and venous vasodilator response to captopril in patients with chronic heart failure
Purpose: The potentially beneficial hemodynamic effects of angiotensin-converting enzyme (ACE) inhibitors in heart failure may relate, in part, to their ability to increase the production of vasodilator prostanoids. Low dose aspirin is commonly prescribed in CHF and may attenuate the vasodilator effects of ACE inhibitors. We sought to determine the effects of low dose aspirin on the peripheral hemodynamic effects of captopril in patients with chronic heart failure (CHF). Methods: Nine patients with chronic heart failure were randomized in a placebo controlled, cross over study, to 75 mg of aspirin daily or placebo. After 7 days treatment the response to 25 mg of captopril was evaluated over 180 min using venous occlusion plethysmography. Forearm blood flow (FBF) and forearm venous capacitance (FVC) were measured. Results: Mean arterial pressure and heart rate did not change. After placebo, FBF increased in response to captopril (+18%, 95%CI 24.2, 11.8), a response inhibited by aspirin (-1.4%, 2.9, -5.7), p < 0.005. After placebo, FVC increased in response to captopril (+7.6%, 9.8, 5.4), which was also inhibited by aspirin (+2.0%, 4.6, -0.6), aspirin vs. placebo, p = 0.02). Conclusion: In patients with chronic heart failure even low dose aspirin inhibits both the acute arterial and venous dilator responses to captopril. This action of aspirin may reduce the long-term clinical benefits of ACE inhibitors. < copyright > 2005 Springer Science + Business Media, Inc
McAlister FA;Ghali WA;Gong Y;Fang J;Armstrong PW;Tu JV, Circulation, 2006, 113:2572-2578; Aspirin use and outcomes in a community-based cohort of 7352 patients discharged after first hospitalization for heart failure
BACKGROUND: The safety of aspirin in heart failure (HF) has been called into question, particularly in those patients (1) without coronary disease, (2) with renal dysfunction, or (3) treated with low-dose angiotensin-converting enzyme (ACE) inhibitors and high-dose aspirin. METHODS AND RESULTS: We examined prescription patterns and outcomes (all-cause mortality and/or HF readmission) in patients discharged from 103 Canadian hospitals between April 1999 and March 2001 after a first hospitalization for HF. Of 7352 patients with HF (mean age, 75 years; 44% without coronary disease and 29% with renal dysfunction), 2785 (38%) died or required HF readmission within the first year. Compared with nonusers, aspirin users were no more likely to die or require HF readmission (hazard ratio [HR], 1.02 [0.91 to 1.16]), even in patients without coronary disease (HR, 0.98 [0.78 to 1.22]) or patients with renal dysfunction (HR, 1.13 [0.94 to 1.36]). On the other hand, users of ACE inhibitors were less likely to die or require HF readmission (HR, 0.87 [0.79 to 0.96]), even if they were using aspirin (HR, 0.86 [0.77 to 0.95]). There were no dose-dependent interactions between aspirin and ACE inhibitors. CONCLUSIONS: In this observational study, aspirin use was not associated with an increase in mortality rates or HF readmission rates, and aspirin did not attenuate the benefits of ACE inhibitors, even in patients without coronary disease, patients with renal dysfunction, or patients treated with high-dose aspirin and low-dose ACE inhibitors
Guazzi M;Brambilla R;Reina G;Tumminello G;Guazzi MD, Arch Intern Med, 2003, 163:1574-1579; Aspirin-angiotensin-converting enzyme inhibitor coadministration and mortality in patients with heart failure: a dose-related adverse effect of aspirin
BACKGROUND: It is debated whether in patients with chronic heart failure (CHF), aspirin may contrast the clinical benefits of angiotensin-converting enzyme inhibitors (ACEIs). Two major unresolved issues in patients with CHF are whether these agents together can affect mortality and whether the interaction is related with the dose of aspirin. We aimed at exploring these possibilities. METHODS: We evaluated more than 4000 hospitalizations with a principal discharge diagnosis of CHF from January 10, 1990, to December 31, 1999. The final analysis was restricted to 344 patients taking ACEIs who satisfied the selection criteria, in whom reliable information was available concerning drug therapy during follow-up. In these patients, treatment included no aspirin in 235 (group 1), a low dose (< or =160 mg) in 45 (group 2), and a high dose (> or = 325 mg) in 64 (group 3). RESULTS: During a mean follow-up of 37.6 months, there were 84 (36%) deaths in group 1, 15 (33%) in group 2, and 35 (55%) in group 3. By the Kaplan-Meier approach, survival was similar in groups 1 and 2, and significantly (P =.009) worse in group 3 compared with groups 1 and 2. After adjusting for potential confounding factors (including treatment, cause of heart disease, age, smoking, and diabetes mellitus), a time-dependent multivariate Cox proportional hazards regression analysis showed that the combination of high-dose aspirin with an ACEI was independently associated with the risk of death (hazard ratio, 1.03; P =.01) and that the combination of low-dose aspirin with an ACEI was not (hazard ratio, 1.02; P =.18). CONCLUSION: These results support the possibility that in some patients with CHF who are taking an ACEI, a dose-related effect of aspirin may adversely affect survival
Moore TJ;Crantz FR;Hollenberg NK;Koletsky RJ;Leboff MS;Swartz SL;Levine L;Podolsky S;Dluhy RG;Williams GH, Hypertension, 1981, 3:168-173; Contribution of prostaglandins to the antihypertensive action of captopril in essential hypertension
To determine whether prostaglandins contribute to the depressor response to the converting enzyme inhibitor, captopril, we measured the plasma prostaglandin levels by radioimmunoassy before and after captopril administration, and then examined the effect of prostaglandin synthetase inhibition on captopril's antihypertensive effect. When a single oral captopril dose (25-100 mg) was given to 31 sodium-restricted patients with essential hypertension, the levels of the stable transformation product of prostacyclin remained unmeasurable and that of thromboxane A2 did not change, while the metabolite of PGE2 (PGE-M) increased by 53% (34 +/- 4pg/ml pre-captopril, 52 +/- 5 pg/ml after; p less than 0.001). As expected, blood pressure (BP) and angiotension II (AII levels fell, and kinin levels rose (all changes p less than 0.001). We then blocked prostaglandin synthesis in 18 of these subjects for 24 hours with either indomethacin (n = 10) or aspirin (n = 8) before repeating the captopril dose, to assess the importance of these PGE-M increments. The PGE-M responses to captopril were effectively blocked in nine of 10 subjects receiving indomethacin and four of eight receiving aspirin. In these 13 patients, the depressor response to captopril was significantly blunted (-20 +/- 3mm Hg pre-synthetase inhibition vs - 13 +/- 2 mm Hg post; p less than 0.05). When these agents did not block the PGE-M response to captopril, the BP response was also unchanged (-15 +/- 4mm Hg pre, -18 +/- 5mm Hg post). Neither indomethacin nor aspirin changed the AII or kinin responses to captopril. We conclude that the prostaglandins may be important mediators of captopril's antihypertensive effect in the sodium-restricted state
Hall D;Zeitler H;Rudolph W, J Am Coll Cardiol, 1992, 20:1549-1555; Counteraction of the vasodilator effects of enalapril by aspirin in severe heart failure
OBJECTIVES. This study was undertaken to determine if a standard dose of aspirin interacts relevantly with the circulatory effects of enalapril in severe heart failure. BACKGROUND. The frequent association of heart failure with coronary artery disease confers potential for combined treatment with an angiotensin-converting enzyme inhibitor and the prostaglandin synthesis inhibitor aspirin, the pharmacodynamic actions of which are, in part, mutually opposed. METHODS. In 18 patients, on 3 consecutive days, hemodynamic measurements were performed at baseline and 4 h after administration of a double placebo, enalapril (10 mg) plus placebo and enalapril plus aspirin (350 mg) according to a double-blind, randomized, crossover protocol. RESULTS. Enalapril given before aspirin led to significant decreases in systemic vascular resistance, left ventricular filling pressure and total pulmonary resistance together with a significant increase in cardiac output. When given with or on the day after aspirin, enalapril did not elicit significant changes in any of these variables. There was a clear tendency to lower values for pulmonary artery pressure on all regimens, and slowing of the heart rate was incurred whether or not aspirin had been given. Chi-square analysis of the individual responses showed that the probability of effecting a decrease in systemic vascular resistance > or = 300 dynes.s.cm-5 was six times greater when enalapril was given without aspirin (p < 0.01). CONCLUSIONS. In severe heart failure, the prostaglandin synthesis inhibition by aspirin counteracts the systemic arterial vasodilation of angiotensin-converting enzyme inhibition with enalapril and substantiates its dependence on the integrity of prostaglandin metabolism. Trends toward reductions of pulmonary artery pressure and slowing of the heart rate were still observed, presumably subsequent to lowered norepinephrine concentrations indicating maintenance of prostaglandin-independent actions of angiotensin-converting enzyme inhibition
Pedone C;Cecchi E;Matucci R;Pahor M;Carosella L;Bernabei R;Mugelli A, Drugs Aging, 2005, 22(7):605-614; Does aspirin attenuate the beneficial effect of ACE inhibitors in elderly people with heart failure?
Background: Several studies have raised concerns over a possible reduction in the beneficial effects of ACE inhibitors on mortality in people also taking aspirin (acetylsalicylic acid). Objective: We performed this study to determine whether there is a reduction in the beneficial effects of ACE inhibitors on mortality in elderly people with heart failure also taking aspirin. Participants: 822 patients discharged from hospital wards with a diagnosis of heart failure participated in the GIFA (Italian Group of Pharmacoepidemiology in the Elderly) study. Measurements: We analysed the characteristics of the participants according to the type of therapy prescribed (no ACE inhibitor/no aspirin, ACE inhibitor/no aspirin, no ACE inhibitor/aspirin and ACE inhibitor/aspirin). We calculated the hazard ratios (HRs) for dying associated with each of these treatments, and calculated the synergy index to identify any negative interaction between ACE inhibitor and aspirin. Results: The mean age of study participants was 79 ± 7.3 (SD) years. Of the 629 (76.5%) patients discharged on ACE inhibitor and/or aspirin therapy, 31.0% were taking both drugs. Compared with no therapy with ACE inhibitor or aspirin, the HR for death was 0.65 (95% CI 0.31, 1.36) for aspirin users, 0.45 (95% CI 0.27, 0.74) for ACE inhibitor users and 0.37 (95% CI 0.19, 0.70) for ACE inhibitor/aspirin users. The synergy index was 0.98 (95% CI 0.34, 2.80), suggesting no interaction between the drugs. Conclusions: Our data do not support the existence of a negative interaction between ACE inhibitors and aspirin in elderly patients with heart failure. < copyright > 2005 Adis Data Information BV. All rights reserved
Stys T;Lawson WE;Smaldone GC;Stys A, Arch Intern Med, 2000, 160:1409-1413; Does aspirin attenuate the beneficial effects of angiotensin-converting enzyme inhibition in heart failure?
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
Lapane KL;Hume AL;Barbour MM;Lipsitz LA, J Am Geriatr Soc, 2002, 50:1198-1204; Does aspirin attenuate the effect of angiotensin-converting enzyme inhibitors on health outcomes of very old patients with heart failure?
OBJECTIVES: Concomitant ischemic heart disease (IHD) is common in older individuals with heart failure (HF). We estimated the effect of aspirin use on the rate of mortality, morbidity, and decline in physical functioning in nursing home residents with HF taking angiotensin-converting enzyme (ACE) inhibitors. DESIGN: We conducted a retrospective cohort study using a nursing home database linking resident information collected via the Minimum Data Set (MDS) with drug utilization data. SETTING: Nursing homes in four states (1992-1995). PARTICIPANTS: Of 49,779 residents with HF admitted to these homes, 12,703 residents were taking an ACE inhibitor; 2,046 of these took aspirin. MEASUREMENTS: Medicare enrollment files provided the date of death, and we used the Part A Medicare files to identify hospital admissions. The activity of daily living scale from repeat MDS assessments allowed us to evaluate decline in physical function. Cox proportional hazards models provided adjusted estimates of the aspirin effect, with nonusers as the reference group. RESULTS: The overall mortality rate, hospitalization rate,and rate of decline in physical function of aspirin users were not different from those of nonusers (e.g., hospitalization rate ratio = 0.99, 95% confidence interval = 0.92-1.07). This effect did not vary by presence of concomitant IHD or by dose or type of ACE inhibitor. CONCLUSION: In a cohort of older HF residents receiving ACE inhibitors in nursing homes, we found that treatment with aspirin did not appear to affect outcomes negatively
Nawarskas JJ;Townsend RR;Cirigliano MD;Spinler SA, Am J Hypertens, 1999, 12:784-789; Effect of aspirin on blood pressure in hypertensive patients taking enalapril or losartan
The ability of angiotensin converting enzyme (ACE) inhibitors to lower blood pressure may in part be due to the formation of vasodilatory prostaglandins. Inhibition of prostaglandin synthesis with aspirin may therefore theoretically attenuate the antihypertensive effect of ACE inhibitors. This trial studied the interaction between aspirin (ASA) and enalapril, an ACE inhibitor, and ASA and losartan, an angiotensin subtype 1 receptor antagonist. Seventeen essential hypertensive patients were studied, maintained on a stable dose of either enalapril (n = 7) or losartan (n = 10) monotherapy for > or =12 weeks before and throughout the study. Each patient received a 2-week course of placebo, 81 mg/day ASA, and 325 mg/day ASA, each treatment separated by a 2-week washout period. Blood pressure (BP) and serum thromboxane B2 (TXB2) samples were obtained at the end of each treatment period. Placebo was compared with each dose of ASA for each group. In both the enalapril and losartan groups, mean, systolic, and diastolic BP were unchanged with the addition of ASA. Concentrations of TXB2 were suppressed to <10% in both groups with ASA. This study demonstrates that 81 to 325 mg/day ASA exerts no significant effect on BP in essential hypertensives taking enalapril or losartan
Pfeffer MA;Braunwald E;Moye LA;Basta L;Brown EJ;Cuddy TE;Davis BR;Geltman EM;Goldman S;Flaker GC;., N Engl J Med, 1992, 327:669-677; Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. The SAVE Investigators
BACKGROUND. Left ventricular dilatation and dysfunction after myocardial infarction are major predictors of death. In experimental and clinical studies, longterm therapy with the angiotensin-converting--enzyme inhibitor captopril attenuated ventricular dilatation and remodeling. We investigated whether captopril could reduce morbidity and mortality in patients with left ventricular dysfunction after a myocardial infarction. METHODS. Within 3 to 16 days after myocardial infarction, 2231 patients with ejection fractions of 40 percent or less but without overt heart failure or symptoms of myocardial ischemia were randomly assigned to receive doubleblind treatment with either placebo (1116 patients) or captopril (1115 patients) and were followed for an average of 42 months. RESULTS. Mortality from all causes was significantly reduced in the captopril group (228 deaths, or 20 percent) as compared with the placebo group (275 deaths, or 25 percent); the reduction in risk was 19 percent (95 percent confidence interval, 3 to 32 percent; P = 0.019). In addition, the incidence of both fatal and nonfatal major cardiovascular events was consistently reduced in the captopril group. The reduction in risk was 21 percent (95 percent confidence interval, 5 to 35 percent; P = 0.014) for death from cardiovascular causes, 37 percent (95 percent confidence interval, 20 to 50 percent; P less than 0.001) for the development of severe heart failure, 22 percent (95 percent confidence interval, 4 to 37 percent; P = 0.019) for congestive heart failure requiring hospitalization, and 25 percent (95 percent confidence interval, 5 to 40 percent; P = 0.015) for recurrent myocardial infarction. CONCLUSIONS. In patients with asymptomatic left ventricular dysfunction after myocardial infarction, long-term administration of captopril was associated with an improvement in survival and reduced morbidity and mortality due to major cardiovascular events. These benefits were observed in patients who received thrombolytic therapy, aspirin, or beta-blockers, as well as those who did not, suggesting that treatment with captopril leads to additional improvement in outcome among selected survivors of myocardial infarction
Harjai KJ;Nunez E;Turgut T;Newman J, Am J Cardiol, 2001, 87:483-7, A7; Effect of combined aspirin and angiotensin-converting enzyme inhibitor therapy versus angiotensin-converting enzyme inhibitor therapy alone on readmission rates in heart failure
An adverse interaction between aspirin and angiotensin-converting enzyme (ACE) inhibitors is suspected in patients with heart failure, but the effect of combined therapy with these agents on hospital readmission rates is unknown. Our study found that combining aspirin with ACE inhibitors is associated with higher early readmission rates than use of ACE inhibitors alone, particularly in patients with depressed ejection fraction and in those without coronary artery disease
The SOLVD investigators, N Engl J Med, 1992, 327:685-691; Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. The SOLVD Investigattors
BACKGROUND. It is not known whether the treatment of patients with asymptomatic left ventricular dysfunction reduces mortality and morbidity. We studied the effect of an angiotensin-converting--enzyme inhibitor, enalapril, on total mortality and mortality from cardiovascular causes, the development of heart failure, and hospitalization for heart failure among patients with ejection fractions of 0.35 or less who were not receiving drug treatment for heart failure. METHODS. Patients were randomly assigned to receive either placebo (n = 2117) or enalapril (n = 2111) at doses of 2.5 to 20 mg per day in a double-blind trial. Follow-up averaged 37.4 months. RESULTS. There were 334 deaths in the placebo group, as compared with 313 in the enalapril group (reduction in risk, 8 percent by the log-rank test; 95 percent confidence interval, -8 percent [an increase of 8 percent] to 21 percent; P = 0.30). The reduction in mortality from cardiovascular causes was larger but was not statistically significant (298 deaths in the placebo group vs. 265 in the enalapril group; risk reduction, 12 percent; 95 percent confidence interval, -3 to 26 percent; P = 0.12). When we combined patients in whom heart failure developed and those who died, the total number of deaths and cases of heart failure was lower in the enalapril group than in the placebo group (630 vs. 818; risk reduction, 29 percent; 95 percent confidence interval, 21 to 36 percent; P less than 0.001). In addition, fewer patients given enalapril died or were hospitalized for heart failure (434 in the enalapril group; vs. 518 in the placebo group; risk reduction, 20 percent; 95 percent confidence interval, 9 to 30 percent; P less than 0.001). CONCLUSIONS. The angiotensin-converting--enzyme inhibitor enalapril significantly reduced the incidence of heart failure and the rate of related hospitalizations, as compared with the rates in the group given placebo, among patients with asymptomatic left ventricular dysfunction. There was also a trend toward fewer deaths due to cardiovascular causes among the patients who received enalapril
The SOLVD investigators, N Engl J Med, 1991, 325:293-302; Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. The SOLVD Investigators
BACKGROUND. Patients with congestive heart failure have a high mortality rate and are also hospitalized frequently. We studied the effect of an angiotensin-converting-enzyme inhibitor, enalapril, on mortality and hospitalization in patients with chronic heart failure and ejection fractions less than or equal to 0.35. METHODS. Patients receiving conventional treatment for heart failure were randomly assigned to receive either placebo (n = 1284) or enalapril (n = 1285) at doses of 2.5 to 20 mg per day in a double-bind trial. Approximately 90 percent of the patients were in New York Heart Association functional classes II and III. The follow-up averaged 41.4 months. RESULTS. There were 510 deaths in the placebo group (39.7 percent), as compared with 452 in the enalapril group (35.2 percent) (reduction in risk, 16 percent; 95 percent confidence interval, 5 to 26 percent; P = 0.0036). Although reductions in mortality were observed in several categories of cardiac deaths, the largest reduction occurred among the deaths attributed to progressive heart failure (251 in the placebo group vs. 209 in the enalapril group; reduction in risk, 22 percent; 95 percent confidence interval, 6 to 35 percent). There was little apparent effect of treatment on deaths classified as due to arrhythmia without pump failure. Fewer patients died or were hospitalized for worsening heart failure (736 in the placebo group and 613 in the enalapril group; risk reduction, 26 percent; 95 percent confidence interval, 18 to 34 percent; P less than 0.0001). CONCLUSIONS. The addition of enalapril to conventional therapy significantly reduced mortality and hospitalizations for heart failure in patients with chronic congestive heart failure and reduced ejection fractions
Smith SR;Coffman TM;Svetkey LP, J Am Soc Nephrol, 1993, 4:1133-1139; Effect of low-dose aspirin on thromboxane production and the antihypertensive effect of captopril
Some of the antihypertensive effects of angiotensin-converting enzyme (ACE) inhibitors occur through nonangiotensin II-mediated mechanisms. One of these is through decreased kinin degradation, leading to enhanced production of vasodilator arachidonic acid metabolites. It was reasoned that if ACE inhibition also leads to an increase in the production of the potent vasoconstrictor thromboxane A2, then maneuvers that selectively inhibit thromboxane production without reducing prostaglandins (PG) E2 + PGI2 might enhance the antihypertensive effect of ACE inhibition. This double-blinded, randomized, crossover study was therefore undertaken to determine: (1) if captopril increases platelet and/or renal thromboxane production; and (2) if low-dose aspirin enhances the antihypertensive effect of captopril. Patients with mild essential hypertension and no other significant medical problems were studied. In a double-blinded, random order, patients took captopril alone (25 mg every 12 h) for 2 wk and captopril plus aspirin (75 mg/day) for another 2 wk. Active treatment periods were preceded by 2 wk of single-blind placebo. Fifteen patients with a mean age of 53 yr and an average mean arterial pressure (MAP) of 114 +/- 8 (+/- SD) mm Hg were studied. Serum thromboxane B2 was higher (P < 0.05) during treatment with captopril/placebo (600 +/- 46 (+/- SE) pg/mL) than during the two washout periods combined (420 +/- 57 and 553 +/- 78) and was lowest (P < 0.0005) during treatment with captopril/aspirin (302 +/- 36). Captopril treatment significantly increased the urinary excretion of PGE2 (P = 0.038). Captopril/placebo significantly lowered MAP (P < 0.05) to 105.0 +/- 3.7 mm Hg compared with the washout period. However, the addition of aspirin to captopril caused no additional lowering of MAP (105.2 +/- 2.8 mm Hg). It was concluded that treatment with captopril does increase platelet thromboxane production. However, lowering platelet thromboxane with low doses of aspirin may not enhance the antihypertensive effect of captopril
The Acute Infarction Ramipril Efficacy Study Investigators, Lancet, 1993, 342:821-828; Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators
Survival after acute myocardial infarction has been enhanced by treatment with thrombolytic agents, aspirin, and beta-adrenoceptor blockade. However there remains a substantial subgroup of patients who manifest clinical evidence of heart failure despite the first two of these treatments, and for whom beta-adrenoceptor antagonists are relatively or absolutely contraindicated. These patients have a greatly increased risk of fatal and non-fatal ischaemic, arrhythmic, and haemodynamic events. In this selected high-risk subset of patients we investigated the effect of therapy with the angiotensin converting enzyme (ACE) inhibitor rampiril, postulating that it would lengthen survival. 2006 patients who had shown clinical evidence of heart failure at any time after an acute myocardial infarction (AMI) were recruited from 144 centres in 14 countries. Patients were randomly allocated to double-blind treatment with either placebo (992 patients) or ramipril (1014 patients) on day 3 to day 10 after AMI (day 1). Patients with severe heart failure resistant to conventional therapy, in whom the attending physician considered the use of an ACE inhibitor to be mandatory, were excluded. Follow-up was continued for a minimum of 6 months and an average of 15 months. On intention-to-treat analysis mortality from all causes was significantly lower for patients randomised to receive ramipril (170 deaths; 17%) than for those randomised to receive placebo (222 deaths; 23%). The observed risk reduction was 27% (95 % Cl 11% to 40%; p = 0.002). Analysis of prespecified secondary outcomes revealed a risk reduction of 19% for the first validated outcome (i.e., first event in an individual patient)--namely, death, severe/resistent heart failure, myocardial infarction, or stroke (95% Cl 5% to 31%; p = 0.008). Oral administration of rampiril to patients with clinical evidence of either transient or ongoing heart failure, initiated between the second and ninth day after myocardial infarction, resulted in a substantial reduction in premature death from all causes. This benefit was apparent as early as 30 days and was consistent across a range of subgroups
Yusuf S;Sleight P;Pogue J;Bosch J;Davies R;Dagenais G, N Engl J Med, 2000, 342:145-153; Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators
BACKGROUND: Angiotensin-converting-enzyme inhibitors improve the outcome among patients with left ventricular dysfunction, whether or not they have heart failure. We assessed the role of an angiotensin-converting-enzyme inhibitor, ramipril, in patients who were at high risk for cardiovascular events but who did not have left ventricular dysfunction or heart failure. METHODS: A total of 9297 high-risk patients (55 years of age or older) who had evidence of vascular disease or diabetes plus one other cardiovascular risk factor and who were not known to have a low ejection fraction or heart failure were randomly assigned to receive ramipril (10 mg once per day orally) or matching placebo for a mean of five years. The primary outcome was a composite of myocardial infarction, stroke, or death from cardiovascular causes. The trial was a two-by-two factorial study evaluating both ramipril and vitamin E. The effects of vitamin E are reported in a companion paper. RESULTS: A total of 651 patients who were assigned to receive ramipril (14.0 percent) reached the primary end point, as compared with 826 patients who were assigned to receive placebo (17.8 percent) (relative risk, 0.78; 95 percent confidence interval, 0.70 to 0.86; P<0.001). Treatment with ramipril reduced the rates of death from cardiovascular causes (6.1 percent, as compared with 8.1 percent in the placebo group; relative risk, 0.74; P<0.001), myocardial infarction (9.9 percent vs. 12.3 percent; relative risk, 0.80; P<0.001), stroke (3.4 percent vs. 4.9 percent; relative risk, 0.68; P<0.001), death from any cause (10.4 percent vs. 12.2 percent; relative risk, 0.84; P=0.005), revascularization procedures (16.3 percent vs. 18.8 percent; relative risk, 0.85; P<0.001), cardiac arrest (0.8 percent vs. 1.3 percent; relative risk, 0.62; P=0.02), [corrected] heart failure (9.1 percent vs. 11.6 percent; relative risk, 0.77; P<0.001), and complications related to diabetes (6.4 percent vs. 7.6 percent; relative risk, 0.84; P=0.03). CONCLUSIONS: Ramipril significantly reduces the rates of death, myocardial infarction, and stroke in a broad range of high-risk patients who are not known to have a low ejection fraction or heart failure
Oosterga M;Anthonio RL;de Kam PJ;Kingma JH;Crijns HJ;van Gilst WH, Am J Cardiol, 1998, 81:1178-1181; Effects of aspirin on angiotensin-converting enzyme inhibition and left ventricular dilation one year after acute myocardial infarction
There are conflicting reports on the interaction of aspirin with angiotensin-converting enzyme inhibitors in heart failure and systemic hypertension. A post hoc analysis of the Captopril and Thrombolysis Study (CATS) study was conducted. At randomization, 94 patients (31.5%) took aspirin. In patients who took aspirin, the cumulative alpha-hydroxy butyrate dehydrogenase release was 1,151 +/- 132 IU/L in patients randomized to captopril compared with 1,401 +/- 136 IU/L in patients randomized to placebo (difference -250 +/- 189 [95% confidence interval (CI) -620 to 120]). This difference was comparable to the difference in patients who did not use aspirin (-199 +/- 147 [95% CI -488 to 897]). One year after acute myocardial infarction, an increase in left ventricular end-diastolic volume index of 2.2 +/- 3.0 ml/m2 in captopril-treated and 1.9 +/- 2.9 ml/m2 in placebo-treated patients was observed in patients who took aspirin (difference 0.4 +/- 4.2 [95% CI -8.2 to 8.9]). This difference was also comparable to the difference in patients who did not take aspirin (2.2 +/- 3.8 [95% CI -5.2 to 9.7]). One year after acute myocardial infarction, patients who did take aspirin had a mean change in LV end-diastolic volume index of 2.1 +/- 2.1 ml/m2 compared with 8.4 +/- 1.9 ml/m2 in patients who did not use aspirin (p = 0.02). Thus, aspirin does not attenuate the acute and long-term effects of angiotensin-converting enzyme inhibition after acute myocardial infarction, but independently reduces LV dilation after myocardial infarction
Teo KK;Yusuf S;Pfeffer M;Torp-Pedersen C;Kober L;Hall A;Pogue J;Latini R;Collins R, Lancet, 2002, a, 360:1037-1043; Effects of long-term treatment with angiotensin-converting-enzyme inhibitors in the presence or absence of aspirin: a systematic review
BACKGROUND: Results from a retrospective analysis of the Studies of Left Ventricular Dysfunction (SOLVD) study suggest that angiotensin-converting-enzyme (ACE) inhibitors may be less effective in patients receiving aspirin. We aimed to confirm or refute this theory. METHODS: We used the Peto-Yusuf method to undertake a systematic overview of data for 22060 patients from six long-term randomised trials of ACE inhibitors to assess whether aspirin altered the effects of ACE inhibitor therapy on major clinical outcomes (composite of death, myocardial infarction, stroke, hospital admission for congestive heart failure, or revascularisation). FINDINGS: Baseline characteristics, and prognosis in patients allocated placebo, differed strikingly between those who were and were not taking aspirin at baseline. Results from analyses of all trials, except SOLVD, did not suggest any significant differences between the proportional reductions in risk with ACE inhibitor therapy in the presence or absence of aspirin for the major clinical outcomes (p=0.15), or in any of its individual components, except myocardial infarction (interaction p=0.01). Overall, ACE inhibitor therapy significantly reduced the risk of the major clinical outcomes by 22% (p<0.0001), with clear reductions in risk both among those receiving aspirin at baseline (odds ratio 0.80, [99% CI 0.73-0.88]) and those who were not (0.71 [99% CI 0.62-0.81], interaction p=0.07). INTERPRETATION: Considering the totality of evidence on all major vascular outcomes in these trials, there is only weak evidence of any reduction in the benefit of ACE-inhibitor therapy when added to aspirin. However, there is definite evidence of clinically important benefits with respect to these major clinical outcomes with ACE-inhibitor therapy, irrespective of whether concomitant aspirin is used
Teo KK;Yusuf S;Pfeffer M;Torp-Pedersen C;Kober L;Hall A;Pogue J;Latini R;Collins R, Lancet, 2002, b, 360:1037-1043; Effects of long-term treatment with angiotensin-converting-enzyme inhibitors in the presence or absence of aspirin: a systematic review
BACKGROUND: Results from a retrospective analysis of the Studies of Left Ventricular Dysfunction (SOLVD) study suggest that angiotensin-converting-enzyme (ACE) inhibitors may be less effective in patients receiving aspirin. We aimed to confirm or refute this theory. METHODS: We used the Peto-Yusuf method to undertake a systematic overview of data for 22060 patients from six long-term randomised trials of ACE inhibitors to assess whether aspirin altered the effects of ACE inhibitor therapy on major clinical outcomes (composite of death, myocardial infarction, stroke, hospital admission for congestive heart failure, or revascularisation). FINDINGS: Baseline characteristics, and prognosis in patients allocated placebo, differed strikingly between those who were and were not taking aspirin at baseline. Results from analyses of all trials, except SOLVD, did not suggest any significant differences between the proportional reductions in risk with ACE inhibitor therapy in the presence or absence of aspirin for the major clinical outcomes (p=0.15), or in any of its individual components, except myocardial infarction (interaction p=0.01). Overall, ACE inhibitor therapy significantly reduced the risk of the major clinical outcomes by 22% (p<0.0001), with clear reductions in risk both among those receiving aspirin at baseline (odds ratio 0.80, [99% CI 0.73-0.88]) and those who were not (0.71 [99% CI 0.62-0.81], interaction p=0.07). INTERPRETATION: Considering the totality of evidence on all major vascular outcomes in these trials, there is only weak evidence of any reduction in the benefit of ACE-inhibitor therapy when added to aspirin. However, there is definite evidence of clinically important benefits with respect to these major clinical outcomes with ACE-inhibitor therapy, irrespective of whether concomitant aspirin is used
Avanzini F;Palumbo G;Alli C;Roncaglioni MC;Ronchi E;Cristofari M;Capra A;Rossi S;Nosotti L;Costantini C;Pietrofeso R, Am J Hypertens, 2000, 13:611-616; Effects of low-dose aspirin on clinic and ambulatory blood pressure in treated hypertensive patients. Collaborative Group of the Primary Prevention Project (PPP)--Hypertension study
Nonsteroidal antiinflammatory drugs may affect blood pressure (BP) control in hypertensive patients receiving drug treatment, but data on the effects of low-dose aspirin are scanty. This study assessed the effects of chronic treatment with low doses of aspirin (100 mg/day) on clinic and ambulatory systolic (SBP) and diastolic (DBP) BP in hypertensives on chronic, stable antihypertensive therapy. The study was conducted in the framework of the Primary Prevention Project (PPP), a randomized, controlled factorial trial on the preventive effect of aspirin or vitamin E in people with one or more cardiovascular risk factors. Fifteen Italian hypertension units studied 142 hypertensive patients (76 men, 66 women; mean age 59 +/- 5.9 years) treated with different antihypertensive drugs: 71 patients were randomized to aspirin and 71 served as controls. All patients underwent a clinic BP evaluation with an automatic sphygmomanometer and a 24-h ambulatory BP monitoring, at baseline and after 3 months of aspirin treatment. At the end of the study the changes in clinic SBP and DBP were not statistically different in treated and untreated subjects. Ambulatory SBP and DBP after 3 months of aspirin treatment were similar to baseline: deltaSBP -0.5 mmHg (95% confidence intervals [CI] from -1.9 to +2.9 mm Hg) and deltaDBP -1.1 mm Hg (95% CI from -2.5 to +0.3 mm Hg). The pattern was similar in the control group. No interaction was found between aspirin and the most used antihypertensive drug classes (angiotensin converting enzyme inhibitors and calcium antagonists). Despite the relatively small sample size our results seem to exclude any significant influence of low-dose aspirin on BP control in hypertensives under treatment
Peterson JG;Topol EJ;Sapp SK;Young JB;Lincoff AM;Lauer MS, Am J Med, 2000, 109:371-377; Evaluation of the effects of aspirin combined with angiotensin-converting enzyme inhibitors in patients with coronary artery disease
BACKGROUND: Several studies have suggested that there may be an interaction between angiotensin-converting enzyme (ACE) inhibitors and aspirin in patients with congestive heart failure, such that their benefits are attenuated when used in combination. Whether this interaction exists in patients with coronary artery disease is not known. SUBJECTS AND METHODS: Patients enrolled in two large trials, Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO-I) and Evaluation in PTCA to Improve Long-Term Outcome with Abciximab GP IIb/IIIa Blockade (EPILOG), were stratified according to use of aspirin and ACE inhibitors on discharge from the hospital. In the EPILOG trial, left ventricular systolic function was assessed by contrast ventriculography. The primary endpoint was all-cause mortality at 1 year. EPILOG patients, all of whom were receiving aspirin, were also examined for the combined endpoint of death or nonfatal myocardial infarction. Stratified and multivariate analyses were used to adjust for baseline differences in patient characteristics. RESULTS: We studied 31,622 patients in the GUSTO-I trial and 2,619 patients in the EPILOG trial. There were 615 deaths among the GUSTO-I patients and 45 deaths among the EPILOG patients at 1 year. Unadjusted mortality was greater among patients treated with both ACE inhibitors and aspirin than among patients treated with aspirin alone (3.3% versus 1.6%, P <0.001 for GUSTO-I; and 3.7% versus 1.2%, P <0.001 for EPILOG). Similarly, the composite endpoint of death or nonfatal myocardial infarction was more frequent among EPILOG patients who were taking ACE inhibitors (6.3% versus 3.3%, P = 0. 001). After adjusting for confounders, combined use of aspirin and ACE inhibitors was associated with increased mortality in GUSTO-I patients (hazard ratio [HR] = 2.2, 95% confidence interval [CI]: 1.1 to 4.3, P = 0.03) compared with aspirin alone. In EPILOG patients, after adjusting for clinical factors and extent of left ventricular dysfunction, the combination of aspirin and ACE inhibitors was associated with an increased risk of death (HR = 2.1, 95% CI: 1.1 to 3.8, P = 0.02) and of death or nonfatal myocardial infarction (HR = 1.5, 95% CI: 1.1 to 2.5, P = 0.02) compared with aspirin alone. CONCLUSION: These observational findings suggest the possibility of an interaction between aspirin and ACE inhibitors among patients with ischemic heart disease. Further study of this issue is warranted
Magagna A;bdel-Haq B;Favilla S;Taddei S;Salvetti A, Blood Press, 1994, 3:236-241; Hemodynamic and humoral effects of low-dose aspirin in treated and untreated essential hypertensive patients
Aspirin at low doses is used as an inhibitor of platelet aggregation and is frequently administered to essential hypertensive patients with arterial thrombotic complications. However, it is unknown whether aspirin can modify blood pressure values either in treated or untreated hypertensive patients, as described for other non steroidal anti-inflammatory drugs. Thus 30 patients. 10 with mild uncomplicated and untreated essential hypertension, 10 with essential hypertension under chronic treatment with captopril, 50 mg bid, and 10 with essential hypertension under chronic treatment with atenolol, 100 mg oid, received aspirin, 100 mg oid, and the corresponding placebo for one month, according to a double blind randomized cross-over design. At the end of each treatment, blood pressure, heart rate, generated serum thromboxane B2 and urinary excretion of thromboxane B2 and 6 keto prostaglandin F1 alpha and plasma renin activity were measured. Both in treated and untreated essential hypertensive patients, aspirin administration did not affect blood pressure, heart rate and urinary 6 keto prostaglandin F1 alpha, while it significantly reduced serum and urinary excretion of thromboxane B2 and plasma renin activity. In conclusion, while the present data confirm that low doses of aspirin selectively inhibit thromboxane B2 synthesis, they indicate that aspirin at 100 mg oid can be administered to treated and untreated essential hypertensive patients without any harmful effect on blood pressure values
Polonia J;Boaventura I;Gama G;Camoes I;Bernardo F;Andrade P;Nunes JP;Brandao F;Cerqueira-Gomes M, J Hypertens, 1995, 13:925-931; Influence of non-steroidal anti-inflammatory drugs on renal function and 24h ambulatory blood pressure-reducing effects of enalapril and nifedipine gastrointestinal therapeutic system in hypertensive patients
OBJECTIVE: To evaluate the influence of non-steroidal anti-inflammatory drugs (NSAIDs; aspirin and indomethacin) on the renal and antihypertensive effects of enalapril and nifedipine gastrointestinal therapeutic system (GITS) in patients with essential hypertension. DESIGN AND METHODS: In a crossover study, 18 patients on an unrestricted-salt diet were randomly assigned to receive either enalapril (20-40 mg/day) or nifedipine-GITS (30-60 mg/day) for 4-8 weeks, followed by aspirin (100 mg/day for 2 weeks) and then indomethacin (75 mg/day for 1 week). Blood pressure was measured by 24h ambulatory monitoring. RESULTS: Enalapril and nifedipine-GITS significantly reduced blood pressure compared with placebo. Aspirin did not alter the antihypertensive effect of either drug. Indomethacin attenuated (by 45%) the antihypertensive effect of enalapril throughout the 24h period of evaluation, but did not interfere with the effect of nifedipine. Furthermore, indomethacin significantly reduced the fractional excretion of sodium and plasma levels of prostaglandins in a similar way when added to either the enalapril or the nifedipine regimen. CONCLUSIONS: Vasodilatory prostaglandins are probably involved in the antihypertensive effects of enalapril but not of nifedipine, and this interaction seems to be independent of any indomethacin-induced decrease in renal sodium excretion. Nifedipine may be an appropriate drug to treat hypertensive patients requiring concomitant therapy with NSAID
Mahe I;Meune C;Diemer M;Caulin C;Bergmann JF, Drug Saf, 2001, b, 24:167-182; Interaction between aspirin and ACE inhibitors in patients with heart failure
Both aspirin (acetylsalicylic acid) and ACE inhibitors are often used concomitantly, especially in patients with both heart failure and ischaemic heart disease, which is the most common underlying cause of heart failure. The safety of the association has been questioned because both drugs affect a related prostaglandin-mediated pathway. Thanks to their vasodilating properties, prostaglandins play an important role in heart failure where peripheral vasoconstriction occurs. Some of the beneficial effects of ACE inhibitors might be related to reduced degradation of bradykinin that enhances the synthesis of prostaglandins, while aspirin, through inhibiting the enzyme cyclo-oxygenase, inhibits the production of prostaglandins. To date no prospective study has been conducted to investigate the effect of long term aspirin treatment in the postinfarction period allowing the possible impact of the interaction between aspirin and ACE inhibitors upon survival to be confirmed or negated. However, the practitioner needs to know how to optimise the treatment of his or her patients. In order to stimulate arguments for and against the use of aspirin in patients with heart failure receiving ACE inhibitors, we searched MEDLINE from 1960 to 2000 using the key words heart failure, aspirin, and ACE inhibitors for English language articles and conducted a review of the available data. We report on the potential mechanisms of the interaction and the results of experimental studies on haemodynamic parameters. Results of retrospective clinical studies, subgroup analysis that were undertaken to evaluate the overall action upon haemodynamic parameters and survival of the association are summarised. Conflicting conclusions have been reported in the literature. Many explanations can be advanced to try to understand these conflicting conclusions: differences in study design (results of retrospective trials have to be interpreted with caution); differences in the choice of the evaluation parameter (problem of the clinical relevance of haemodynamic parameters); differences in the characteristics of the patient (different underlying cardiopathy, e.g. heart failure, hypertension or ischaemic cardiopathy); and differences in the type and the dosage of each treatment (especially ACE inhibitors and aspirin since an interaction might occur more often with dosage of aspirin greater than 250mg)
Takkouche B;Etminan M;Caamano F;Rochon PA, Drug Saf, 2002, 25:373-378; Interaction between aspirin and ACE Inhibitors: resolving discrepancies using a meta-analysis
BACKGROUND: Recently, studies have attempted to explore the interaction between ACE inhibitors and aspirin (acetylsalicylic acid) when both drugs are used concomitantly to reduce mortality in patients with coronary artery disease. Results have been conflicting due, in part, to sub-optimal methods used to explore this interaction. METHODS: We reviewed systematically all studies on mortality in patients treated with ACE inhibitors and aspirin and conducted a meta-analysis in order to explore the interaction between both drugs and resolve discrepancies. To be included, each study had to provide data on mortality of patients who received both drugs, either drug and no drug. These data were necessary to calculate the synergy index (S) and its 95% confidence interval (CI) that we used to quantify the effect due to interaction between ACE inhibitors and aspirin. After testing for heterogeneity of effects, we pooled the S values from the individual studies into one summary measure. Subsequently, we compared our results with those obtained through the most common but incorrect method of evaluating interaction. This method uses significance testing of the relative risk of mortality when a 'product term' between ACE inhibitors and aspirin is entered in a logistic regression model. RESULTS: Eight studies met the inclusion criteria. The pooled synergy index S indicates slight but precise antagonism between ACE inhibitors and aspirin (S = 0.91; 95% CI 0.80 to 1.03). In contrast, the pooled 'product term' is not significant and would have lead to the conclusion of absence of interaction (p = 0.15). CONCLUSION: There seems to be an antagonistic interaction between ACE inhibitors and aspirin. Former discrepancies were due to inadequate assessment of interaction. Results from the Studies on Left Ventricular Dysfunction (SOLVD) and Heart Outcome Prevention Evaluation (HOPE) trials that assessed the effect of combined administration of ACE inhibitors and aspirin were not included in this meta-analysis because those trials did not provide enough data to compute the S statistic. It is possible that results from on-going trials such as Women's Atovarstatin Trial on Cholesterol (WATCH) will shed more light on ACE inhibitor and aspirin interaction in the future
Takkouche B;Etminan M;Caamano F;Rochon PA, Drug Saf, 2, 25:373-378; Interaction between aspirin and ACE inhibitors: Resolving discrepancies using a meta-analysis
Background: Recently, studies have attempted to explore the interaction between ACE inhibitors and aspirin (acetylsalicylic acid) when both drugs are used concomitantly to reduce mortality in patients with coronary artery disease. Results have been conflicting due, in part, to sub-optimal methods used to explore this interaction. Methods: We reviewed systematically all studies on mortality in patients treated with ACE inhibitors and aspirin and conducted a meta-analysis in order to explore the interaction between both drugs and resolve discrepancies. To be included, each study had to provide data on mortality of patients who received both drugs, either drug and no drug. These data were necessary to calculate the synergy index (S) and its 95% confidence interval (CI) that we used to quantify the effect due to interaction between ACE inhibitors and aspirin. After testing for heterogeneity of effects, we pooled the S values from the individual studies into one summary measure. Subsequently, we compared our results with those obtained through the most common but incorrect method of evaluating interaction. This method uses significance testing of the relative risk of mortality when a 'product term' between ACE inhibitors and aspirin is entered in a logistic regression model. Results: Eight studies met the inclusion criteria. The pooled synergy index S indicates slight but precise antagonism between ACE inhibitors and aspirin (S = 0.91; 95% CI 0.80 to 1.03). In contrast, the pooled 'product term' is not significant and would have lead to the conclusion of absence of interaction (p = 0.15). Conclusion: There seems to be an antagonistic interaction between ACE inhibitors and aspirin. Former discrepancies were due to inadequate assessment of interaction. Results from the Studies on Left Ventricular Dysfunction (SOLVD) and Heart Outcome Prevention Evaluation (HOPE) trials that assessed the effect of combined administration of ACE inhibitors and aspirin were not included in this meta-analysis because those trials did not provide enough data to compute the S statistic. It is possible that results from on-going trials such as Women's Atovarstatin Trial on Cholesterol (WATCH) will shed more light on ACE inhibitor and aspirin interaction in the future
Nguyen KN;Aursnes I;Kjekshus J, Am J Cardiol, 1997, 79:115-119; Interaction between enalapril and aspirin on mortality after acute myocardial infarction: subgroup analysis of the Cooperative New Scandinavian Enalapril Survival Study II (CONSENSUS II)
The use of angiotensin-converting enzyme (ACE) inhibitors early after an acute myocardial infarction to reduce mortality has been studied in several trials with inconsistent results. Aspirin (ASA) has become a well-documented therapeutic adjunct in patients with coronary heart disease. Attention has recently been focused on a possible interaction between ASA and ACE inhibitors. We therefore reanalyzed data from the Cooperative New Scandinavian Enalapril Survival Study II (CONSENSUS II) to find any evidence of differential effects of the ACE inhibitor enalapril in subgroups defined by use of ASA at baseline. Logistic regression tested the multiplicative interaction. We used Rothman synergy index S, which would be equal to unity under additivity, and less than unity when suggesting antagonism, to examine the postulated interaction with departure from an additive model. Logistic regression showed that the enalapril-ASA interaction term was a significant predictor of mortality at the end of the study (p = 0.047), and was a borderline significant predictor of mortality 30 days after randomization (p = 0.085). The Rothman synergy index S was 0.66 (95% confidence interval 0.46 to 0.94) for mortality at the end of the study, and 0.68 ( 0.44 to 1.04) for 30-day mortality, indicating antagonism between enalapril and ASA with departure from an additive model. Thus, we found evidence of enalapril-ASA interaction. The effect of enalapril was less favorable among patients taking ASA than among patients not taking ASA at baseline
Flather MD;Yusuf S;Kober L;Pfeffer M;Hall A;Murray G;Torp-Pedersen C;Ball S;Pogue J;Moye L;Braunwald E, Lancet, 2000, 355:1575-1581; Long-term ACE-inhibitor therapy in patients with heart failure or left-ventricular dysfunction: a systematic overview of data from individual patients. ACE-Inhibitor Myocardial Infarction Collaborative Group
BACKGROUND: We undertook a prospective systematic overview based on data from individual patients from five long-term randomised trials that assessed inhibitors of angiotensin-converting enzyme (ACE) in patients with left-ventricular dysfunction or heart failure. METHODS: Three of the trials enrolled patients within a week after acute myocardial infarction. Data were combined by use of the Peto-Yusuf method. FINDINGS: Overall 12,763 patients were randomly assigned treatment or placebo and followed up for an average of 35 months. In the three post-infarction trials (n=5,966), mortality was lower with ACE inhibitors than with placebo (702/2995 [23.4%] vs 866/2971 [29.1%]; odds ratio 0.74 [95% CI 0.66-0-83]), as were the rates of readmission for heart failure (355 [11.9%] vs 460 [15.5%]; 0.73 [0.63-0.85]), reinfarction (324 [10.8%] vs 391 [13.2%]; 0.80 [0.69-0.94]), or the composite of these events (1049 [35.0%] vs 1244 [41.9%]; 0.75 [0.67-0.83]; all p<O.001). For all five trials the ACE inhibitor group had lower rates of death than the placebo group (1,467/6,391 [23.0%] vs 1,710/6,372 [26.8%]; 0.80 [0.74-0.87]) and lower rates of reinfarction (571 [8.9%] vs 703 [11.0%]; 0.79 [0.70-0.89]), readmission for heart failure (876 [13.7%] vs 1202 [18.9%]; 0.67 [0.61-0.74]), and the composite of these events (2161 [33.8%] vs 2610 [41.0%]; 0.72 [0.67-0.78]; all p<0.0001). The benefits were observed early after the start of therapy and persisted long term. The benefits of treatment on all outcomes were independent of age, sex, and baseline use of diuretics, aspirin, and beta-blockers. Although there was a trend towards greater reduction in risk of death or readmission for heart failure in patients with lower ejection fractions, benefit was apparent over the range examined
Zanchetti A;Hansson L;Leonetti G;Rahn KH;Ruilope L;Warnold I;Wedel H, J Hypertens, 2002, 20:1015-1022; Low-dose aspirin does not interfere with the blood pressure-lowering effects of antihypertensive therapy
BACKGROUND: It has been reported that aspirin (ASA) may interfere with the blood pressure (BP)-lowering effect of various antihypertensive agents and attenuate the beneficial effects of angiotensin-converting enzyme (ACE) inhibitors in patients with congestive heart failure. METHODS AND RESULTS: Data from the Hypertension Optimal Treatment (HOT) Study, in which 18 790 intensively treated hypertensive patients were randomized to either ASA 75 mg daily or placebo for 3.8 years (with a 15% reduction in cardiovascular events and a 36% reduction in myocardial infarction in ASA-treated patients), were reanalysed for the whole group of patients and for various subgroups with particular attention to the possible effects of ASA on BP and renal function. In ASA-treated and placebo-treated patients: (1) systolic blood pressure (SBP) and diastolic blood pressure (DBP) values achieved with antihypertensive treatment were superimposable, with clinically irrelevant differences; (2) these superimposable SBP and DBP were achieved with antihypertensive therapies, that were quantitatively and qualitatively similar, and (3) changes in serum creatinine and in estimated creatinine clearance and the number of patients developing renal dysfunction were also similar. Furthermore, the cardiovascular benefits of ASA were of the same magnitude in hypertensive patients receiving or not receiving ACE-inhibitors. CONCLUSIONS: Even long-term, low-dose ASA does not interfere with the BP-lowering effect of antihypertensive agents, including combinations with ACE inhibitors, or with renal function. No negative interaction occurs between ACE inhibition and the cardiovascular benefits of small dose of ASA. Our conclusions cannot be extended to larger doses of ASA, or to patients with congestive heart failure
Seelig CB;Maloley PA;Campbell JR, South Med J, 1990, 83:1144-1148; Nephrotoxicity associated with concomitant ACE inhibitor and NSAID therapy
Angiotensin-I converting enzyme (ACE) inhibitors and nonsteroidal anti-inflammatory drugs (NSAIDs) can be nephrotoxic and may synergistically compromise renal function. A computer-assisted study was done to asses the prevalence of compromised renal function and the clinical importance of this drug interaction. A search of the records of all patients seen in the University of Nebraska Medical Center Internal Medicine Clinic was conducted to identify cases involving renal insufficiency, therapy with ACE inhibitors, or therapy with NSAIDs. Records of cases meeting these criteria were reviewed for clinical correlation and revealed 2278 patients treated with NSAIDs, 328 with ACE inhibitors, and 162 with both. No nephrotoxicity was found in conjunction with monotherapy, but three cases of reversible renal failure were found in conjunction with combination therapy. Significant nephrotoxicity during the concomitant use of ACE inhibitors and NSAIDs is not uncommon, and attention should be drawn to this potentially important interaction
Teerlink JR;Massie BM, Am Heart J, 1999, 138:193-197; The interaction of ACE inhibitors and aspirin in heart failure: torn between two lovers
Harjai KJ;Solis S;Prasad A;Loupe J, Int J Cardiol, 2003, 88:207-214; Use of aspirin in conjunction with angiotensin-converting enzyme inhibitors does not worsen long-term survival in heart failure
BACKGROUND: A negative interaction has been shown to exist between aspirin and angiotensin-converting enzyme inhibitors (ACE-I) in subjects with heart failure. We explored the effect of combined ACE-I and aspirin therapy compared to ACE-I without aspirin on clinical outcomes in patients with heart failure. METHODS: 430 consecutive subjects (70+/-14 years, 55% male, 41% with coronary artery disease) released from the hospital with a primary diagnosis of heart failure were classified into three groups based on the use of aspirin and ACE-I at discharge: ACE-I without aspirin (group I, n=134), ACE-I with aspirin (group II, n=138) and no ACE-I (group III, n=158). Follow-up (all-cause mortality and the composite end-point of mortality or emergent heart transplant) was available in 406 (94%) patients at a median duration of 28 months. Differences in outcomes between patient groups were compared using contingency tables, Kaplan-Meier survival, and Cox regression analyses. Similar analyses were conducted in four predefined subsets (patients with and without coronary artery disease, and those with left ventricular ejection fraction <or=45%, and >45%). RESULTS: Death and the composite end-point occurred in 155 (38%) and 165 (41%) patients, respectively. In the total cohort as well as in the four subsets, the treatment group showed no association with clinical outcomes in univariate or multivariate analyses. CONCLUSIONS: In patients with a principal discharge diagnosis of heart failure, the use of aspirin, in combination with ACE-I, does not worsen long-term survival compared to the use of ACE-I without aspirin