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Inhibitors of Angiotensin-Converting Enzyme, Angiotensin II Receptor, Aldosterone, and Renin
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Aldosterone is important in the pathophysiology of heart failure. In a doubleblind study, we enrolled 1663 patients who had severe heart failure and a left ventricular ejection fraction of no more than 35 percent and who were being treated with an angiotensin-converting-enzyme inhibitor, a loop diuretic, and in most cases digoxin. A total of 822 patients were randomly assigned to receive 25 mg of spironolactone daily, and 841 to receive placebo. The primary end point was death from all causes.
The trial was discontinued early, after a mean follow-up period of 24 months, because an interim analysis determined that spironolactone was efficacious. There were 386 deaths in the placebo group (46 percent) and 284 in the spironolactone group (35 percent; relative risk of death, 0.70; 95 percent confidence interval, 0.60 to 0.82; P<0.001). This 30 percent reduction in the risk of death among patients in the spironolactone group was attributed to a lower risk of both death from progressive heart failure and sudden death from cardiac causes. The frequency of hospitalization for worsening heart failure was 35 percent lower in the spironolactone group than in the placebo group (relative risk of hospitalization, 0.65; 95 percent confidence interval, 0.54 to 0.77; P<0.001). In addition, patients who received spironolactone had a significant improvement in the symptoms of heart failure, as assessed on the basis of the New York Heart Association functional class (P<0.001). Gynecomastia or breast pain was reported in 10 percent of men who were treated with spironolactone, as compared with 1 percent of men in the placebo group (P<0.001). The incidence of serious hyperkalemia was minimal in both groups of patients.
Blockade of aldosterone receptors by spironolactone, in addition to standard therapy, substantially reduces the risk of both morbidity and death among patients with severe heart failure.
Summary Background Diabetes mellitus is a strong risk factor for cardiovascular and renal disease. We investigated whether the angiotensin-converting-enzyme (ACE) inhibitor ramipril can lower these risks in patients with diabetes. Methods 3577 people with diabetes included in the Heart Outcomes Prevention Evaluation study, aged 55 years or older, who had a previous cardiovascular event or at least one other cardiovascular risk factor, no clinical proteinuria, heart failure, or low ejection fraction, and who were not taking ACE inhibitors, were randomly assigned ramipril (10 mg/day) or placebo, and vitamin E or placebo, according to a two-by-two factorial design. The combined primary outcome was myocardial infarction, stroke, or cardiovascular death. Overt nephropathy was a main outcome in a substudy. Findings The study was stopped 6 months early (after 4·5 years) by the independent data safety and monitoring board because of a consistent benefit of ramipril compared with placebo. Ramipril lowered the risk of the combined primary outcome by 25% (95% CI 12-36, p=0·0004), myocardial infarction by 22% (6-36), stroke by 33% (10-50), cardiovascular death by 37% (21-51), total mortality by 24% (8-37), revascularisation by 17% (2-30), and overt nephropathy by 24% (3-40, p=0·027). After adjustment for the changes in systolic (2·4 mm Hg) and diastolic (1·0 mm Hg) blood pressures, ramipril still lowered the risk of the combined primary outcome by 25% (12-36, p=0·0004). Interpretation Ramipril was beneficial for cardiovascular events and overt nephropathy in people with diabetes. The cardiovascular benefit was greater than that attributable to the decrease in blood pressure. This treatment represents a vasculoprotective and renoprotective effect for people with diabetes.
The multicenter double-blind, randomized Bergamo Nephrologic Diabetes Complications Trial (BENEDICT) was designed to assess whether angiotensin-converting-enzyme inhibitors and non-dihydropyridine calcium-channel blockers, alone or in combination, prevent microalbuminuria in subjects with hypertension, type 2 diabetes mellitus, and normal urinary albumin excretion.
We studied 1204 subjects, who were randomly assigned to receive at least three years of treatment with trandolapril (at a dose of 2 mg per day) plus verapamil (sustained-release formulation, 180 mg per day), trandolapril alone (2 mg per day), verapamil alone (sustained-release formulation, 240 mg per day), or placebo. The target blood pressure was 120/80 mm Hg. The primary end point was the development of persistent microalbuminuria (overnight albumin excretion, > or =20 microg per minute at two consecutive visits).
The primary outcome was reached in 5.7 percent of the subjects receiving trandolapril plus verapamil, 6.0 percent of the subjects receiving trandolapril, 11.9 percent of the subjects receiving verapamil, and 10.0 percent of control subjects receiving placebo. The estimated acceleration factor (which quantifies the effect of one treatment relative to another in accelerating or slowing disease progression) adjusted for predefined baseline characteristics was 0.39 for the comparison between verapamil plus trandolapril and placebo (P=0.01), 0.47 for the comparison between trandolapril and placebo (P=0.01), and 0.83 for the comparison between verapamil and placebo (P=0.54). Trandolapril plus verapamil and trandolapril alone delayed the onset of microalbuminuria by factors of 2.6 and 2.1, respectively. Serious adverse events were similar in all treatment groups.
In subjects with type 2 diabetes and hypertension but with normoalbuminuria, the use of trandolapril plus verapamil and trandolapril alone decreased the incidence of microalbuminuria to a similar extent. The effect of verapamil alone was similar to that of placebo.
In patients with chronic heart failure (CHF), a beta-blocker is generally added to a regimen containing an angiotensin-converting-enzyme (ACE) inhibitor. It is unknown whether beta-blockade as initial therapy may be as useful.
We randomized 1010 patients with mild to moderate CHF and left ventricular ejection fraction < or =35%, who were not receiving ACE inhibitor, beta-blocker, or angiotensin receptor blocker therapy, to open-label monotherapy with either bisoprolol (target dose 10 mg QD; n=505) or enalapril (target dose 10 mg BID; n=505) for 6 months, followed by their combination for 6 to 24 months. The 2 strategies were blindly compared with regard to the combined primary end point of all-cause mortality or hospitalization and with regard to each of these end point components individually. Bisoprolol-first treatment was noninferior to enalapril-first treatment if the upper limit of the 95% confidence interval (CI) for the absolute between-group difference was <5%, corresponding to a hazard ratio (HR) of 1.17. In the intention-to-treat sample, the primary end point occurred in 178 patients allocated to bisoprolol-first treatment versus 186 allocated to enalapril-first treatment (absolute difference -1.6%, 95% CI -7.6 to 4.4%, HR 0.94; 95% CI 0.77 to 1.16). In the per-protocol sample, 163 patients allocated to bisoprolol-first treatment had a primary end point, versus 165 allocated to enalapril-first treatment (absolute difference -0.7%, 95% CI -6.6 to 5.1%, HR 0.97; 95% CI 0.78 to 1.21). With bisoprolol-first treatment, 65 patients died, versus 73 with enalapril-first treatment (HR 0.88; 95% CI 0.63 to 1.22), and 151 versus 157 patients were hospitalized (HR 0.95; 95% CI 0.76 to 1.19).
Although noninferiority of bisoprolol-first versus enalapril-first treatment was not proven in the per-protocol analysis, our results indicate that it may be as safe and efficacious to initiate treatment for CHF with bisoprolol as with enalapril.
Aldosterone blockade reduces mortality and morbidity among patients with severe heart failure. We conducted a double-blind, placebo-controlled study evaluating the effect of eplerenone, a selective aldosterone blocker, on morbidity and mortality among patients with acute myocardial infarction complicated by left ventricular dysfunction and heart failure.
Patients were randomly assigned to eplerenone (25 mg per day initially, titrated to a maximum of 50 mg per day; 3319 patients) or placebo (3313 patients) [correction] in addition to optimal medical therapy. The study continued until 1012 deaths occurred. The primary end points were death from any cause and death from cardiovascular causes or hospitalization for heart failure, acute myocardial infarction, stroke, or ventricular arrhythmia.
During a mean follow-up of 16 months, there were 478 deaths in the eplerenone group and 554 deaths in the placebo group (relative risk, 0.85; 95 percent confidence interval, 0.75 to 0.96; P=0.008). Of these deaths, 407 in the eplerenone group and 483 in the placebo group were attributed to cardiovascular causes (relative risk, 0.83; 95 percent confidence interval, 0.72 to 0.94; P=0.005). The rate of the other primary end point, death from cardiovascular causes or hospitalization for cardiovascular events, was reduced by eplerenone (relative risk, 0.87; 95 percent confidence interval, 0.79 to 0.95; P=0.002), as was the secondary end point of death from any cause or any hospitalization (relative risk, 0.92; 95 percent confidence interval, 0.86 to 0.98; P=0.02). There was also a reduction in the rate of sudden death from cardiac causes (relative risk, 0.79; 95 percent confidence interval, 0.64 to 0.97; P=0.03). The rate of serious hyperkalemia was 5.5 percent in the eplerenone group and 3.9 percent in the placebo group (P=0.002), whereas the rate of hypokalemia was 8.4 percent in the eplerenone group and 13.1 percent in the placebo group (P<0.001).
The addition of eplerenone to optimal medical therapy reduces morbidity and mortality among patients with acute myocardial infarction complicated by left ventricular dysfunction and heart failure.
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.
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.
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).
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.
Homozygous carries of the D allele of the angiotensin-converting-enzyme (ACE) gene have been reported to be at increased risk for various cardiovascular disorders, including left ventricular hypertrophy. We investigated the potential role of the ACE gene in influencing left ventricular mass.
Quantitative echocardiographic data and DNA samples were available for 2439 subjects from the Framingham Heart Study. ACE genotypes were determined by an assay based on the polymerase chain reaction. (The D allele of the ACE gene contains a deletion, whereas the I [insertion] allele does not.) Left ventricular mass and the prevalence of left ventricular hypertrophy, adjusted for clinical covariates, were analyzed according to genotype. Genetic linkage between the ACE locus and left ventricular mass was evaluated by quantitative analysis of pairs of siblings.
The ACE genotype was associated neither with left ventricular mass nor with the prevalence of left ventricular hypertrophy. Mean (+/-SE) left ventricular mass (adjusted for sex) among subjects carrying the DD, DI, and II genotypes was 165+/-1.6, 165+/-1.3, and 166+/-2.0 g, respectively (P=0.90). The prevalence of left ventricular hypertrophy among the three genotype groups was 15.6 percent, 13.6 percent, and 15.6 percent, respectively (P=0.36), and the adjusted relative risk of left ventricular hypertrophy associated with the DD genotype was 1.10 (95 percent confidence interval, 0.86 to 1.19). Linkage analysis in 759 pairs of siblings using both the ACE D/I marker and a microsatellite polymorphism at the neighboring locus for the human growth hormone gene failed to support any role of ACE in influencing left ventricular mass.
The ACE genotype showed no association with echocardiographically determined left ventricular mass, nor did it confer an increased risk of left ventricular hypertrophy. We found no appreciable role of the ACE gene in influencing left ventricular mass.
Stratum 2 of the Ramipril Efficacy in Nephropathy (REIN) study has already shown that in patients with chronic nephropathies and proteinuria of 3 g or more per 24 h, angiotensin-converting enzyme (ACE) inhibition reduced the rate of decline in glomerular filtration and halved the combined risk of doubling of serum creatinine or end-stage renal failure (ESRF) found in controls on placebo plus conventional antihypertensives. In REIN stratum 1, reported here, 24 h proteinuria was 1 g or more but less than 3 g per 24 h.
In stratum 1 of this double-blind trial 186 patients were randomised to a ramipril or a control (placebo plus conventional antihypertensive therapy) group targeted at achieving a diastolic blood pressure of less than 90 mm Hg. The primary endpoints were change in glomerular filtration rate (GFR) and time to ESRF or overt proteinuria (> or =53 g/24 h). Median follow-up was 31 months.
The decline in GFR per month was not significantly different (ramipril 0.26 [SE 0.05] mL per min per 1.73m2, control 0.29 [0.06]). Progression to ESRF was significantly less common in the ramipril group (9/99 vs 18/87) for a relative risk (RR) of 2.72 (95% CI 1.22-6.08); so was progression to overt proteinuria (15/99 vs 27/87, RR 2.40 [1.27-4.52]). Patients with a baseline GFR of 45 mL/min/1.73 m2 or less and proteinuria of 1.5 g/24 h or more had more rapid progression and gained the most from ramipril treatment. Proteinuria decreased by 13% in the ramipril group and increased by 15% in the controls. Cardiovascular events were similar. As expected, the rate of decline in GFR and the frequency of ESRF were much lower in stratum 1 than they had been in stratum 2.
In non-diabetic nephropathies, ACE inhibition confers renoprotection even to patients with non-nephrotic proteinuria.
Angiotensin II (Ang II) is a potent vasopressor peptide that interacts with 2 major receptor isoforms - AT1 and AT2. Although blood pressure is increased in AT2 knockout mice, the underlying mechanisms remain undefined because of the low levels of expression of AT2 in the vasculature. Here we overexpressed AT2 in vascular smooth muscle (VSM) cells in transgenic (TG) mice. Aortic AT1 was not affected by overexpression of AT2. Chronic infusion of Ang II into AT2-TG mice completely abolished the AT1-mediated pressor effect, which was blocked by inhibitors of bradykinin type 2 receptor (icatibant) and nitric oxide (NO) synthase (L-NAME). Aortic explants from TG mice showed greatly increased cGMP production and diminished Ang II-induced vascular constriction. Removal of endothelium or treatment with icatibant and L-NAME abolished these AT2-mediated effects. AT2 blocked the amiloride-sensitive Na(+)/H(+) exchanger, promoting intracellular acidosis in VSM cells and activating kininogenases. The resulting enhancement of aortic kinin formation in TG mice was not affected by removal of endothelium. Our results suggest that AT2 in aortic VSM cells stimulates the production of bradykinin, which stimulates the NO/cGMP system in a paracrine manner to promote vasodilation. Selective stimulation of AT2 in the presence of AT1 antagonists is predicted to have a beneficial clinical effect in controlling blood pressure.
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<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<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. (N Engl J Med 1992;327:685–91.)
Metoprolol can improve haemodynamics in chronic heart failure, but survival benefit has not been proven. We investigated whether metoprolol controlled release/extended release (CR/XL) once daily, in addition to standard therapy, would lower mortality in patients with decreased ejection fraction and symptoms of heart failure.
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 hospitalizaron in patients with chronic heart failure and ejection fractions ≤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-blind 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<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 low ejection fractions. (N Engl J Med 1991; 325:293–302.)
To evaluate the influence of the angiotensin-converting-enzyme inhibitor enalapril (2.5 to 40 mg per day) on the prognosis of severe congestive heart failure (New York Heart Association [NYHA] functional class IV), we randomly assigned 253 patients in a double-blind study to receive either placebo (n = 126) or enalapril (n = 127). Conventional treatment for heart failure, including the use of other vasodilators, was continued in both groups. Follow-up averaged 188 days (range, 1 day to 20 months). The crude mortality at the end of six months (primary end point) was 26 percent in the enalapril group and 44 percent in the placebo group - a reduction of 40 percent (P = 0.002). Mortality was reduced by 31 percent at one year (P = 0.001). By the end of the study, there had been 68 deaths in the placebo group and 50 in the enalapril group - a reduction of 27 percent (P = 0.003). The entire reduction in total mortality was found to be among patients with progressive heart failure (a reduction of 50 percent), whereas no difference was seen in the incidence of sudden cardiac death. A significant improvement in NYHA classification was observed in the enalapril group, together with a reduction in heart size and a reduced requirement for other medication for heart failure. The overall withdrawal rate was similar in both groups, but hypotension requiring withdrawal occurred in seven patients in the enalapril group and in no patients in the placebo group. After the initial dose of enalapril was reduced to 2.5 mg daily in high-risk patients, this side effect was less frequent. We conclude that the addition of enalapril to conventional therapy in patients with severe congestive heart failure can reduce mortality and improve symptoms. The beneficial effect on mortality is due to a reduction in death from the progression of heart failure.
The benefits of reducing blood pressure on the risks of major cardiovascular disease are well established, but uncertainty remains about the comparative effects of different blood-pressure-lowering regimens. We aimed to estimate effects of strategies based on different drug classes (angiotensin-converting-enzyme [ACE] inhibitors, calcium antagonists, angiotensin-receptor blockers [ARBs], and diuretics or β blockers) or those targeting different blood pressure goals, on the risks of major cardiovascular events and death.
Background: Recent reports suggest that existing antihypertensive agents may not have sufficient efficacy to control blood pressure (BP)
in many patients. Omapatrilat, an agent under development, has been shown to have significantly greater antihypertensive efficacy
than existing agents, but may also carry increased risk of angioedema. We compared the efficacy and safety of omapatrilat
to a representative angiotensin-converting enzyme (ACE) inhibitor, enalapril.
Background:
Several large-scale trials have demonstrated improved survival with ACE-inhibitor therapy started during acute myocardial infarction. A systematic overview was conducted to resolve uncertainties regarding time of initiation, time course of effect, and identification of patients in whom the benefits or the risks may be greater.
Methods and results:
This overview aimed to include individual data from all randomized trials involving more than 1000 patients in which ACE-inhibitor treatment was started in the acute phase (0 to 36 hours) of myocardial infarction and continued for a short time (4 to 6 weeks). Data were available for 98,496 patients from 4 eligible trials, and the results were consistent among the trials. Thirty-day mortality was 7.1% among patients allocated to ACE inhibitors and 7.6% among control subjects, corresponding to a 7% (SD, 2%) proportional reduction (95% CI, 2% to 11%; 2P<0.004). This represented avoidance of approximately 5 (SD, 2) deaths per 1000 patients, with most of the benefit observed within the first week. The proportional benefit was similar in patients at different underlying risk. The absolute benefit was particularly large in some high-risk groups (ie, Killip class 2 to 3, heart rate > or = 100 bpm at entry) and in anterior MI. ACE-inhibitor therapy also reduced the incidence of nonfatal cardiac failure (14.6% versus 15.2%, 2P=0.01) but was associated with an excess of persistent hypotension (17.6% versus 9.3%, 2P<0.01) and renal dysfunction (1.3% versus 0.6%, 2P<0.01).
Conclusions:
These results support the use of ACE inhibitors early in the treatment of acute MI, either to a wide range of patients or selectively in patients with anterior MI and in those at increased risk of death.
Based on data from three studies with complete recording of adverse events in about 12 000 patients each, we determined that angioedema in association with the angiotensin converting-enzyme inhibitor enalapril maleate occurred during the first week of therapy at the rate of one case per 3000 patients per week. Thereafter, the incidence was 14-fold lower, without evidence of a temporal trend in incidence beyond the first week of therapy. The cumulative incidence was one case per 1000 patients treated (0.1%). An additional 138 case reports consistent with the diagnosis of angioedema were obtained from our overall controlled and marketed experience using enalapril in more than 1.2 million patients. These reports were examined to further characterize the reaction. The cases generally were mild, and they resolved on discontinuation of drug therapy. Seven patients experienced angioedema or urticaria in association with both enalapril and captopril, a structurally different angiotensin converting-enzyme inhibitor. This further suggested that the side effect is mechanism based. If angioedema is suspected, therapy with any angiotensin converting-enzyme inhibitor should be interrupted promptly, respiratory distress should be treated appropriately, and subsequent therapy should be initiated with an agent from an alternative class of medication.
(JAMA 1988;260:967-970)
Advances in cardiovascular research during the past two decades have resulted in an improved understanding of the chain of events that lead to end-stage coronary artery disease. These developments have been paralleled by therapeutic advances that now make it possible to intervene at virtually every stage in the development of advanced cardiac disease, from asymptomatic persons at risk of developing coronary atherosclerosis to patients with end-stage heart failure. By interrupting this chain of events, perhaps at multiple sites, it may be possible to prevent or slow the development of symptomatic heart disease and hopefully prolong life. Many opportunities exist for obtaining further information regarding the underlying pathophysiology, the fundamental mechanisms of action of interventions designed to prevent and/or treat the development of myocardial ischemia and cardiac failure and for effecting favorably the natural history of various forms of heart disease.
Objectives
The purpose of this study was to evaluate the efficacy and tolerability of monotherapy with the selective aldosterone blocker eplerenone in both black and white patients with hypertension.Background
Essential hypertension and cardiovascular-renal-target organ damage is more prevalent in black than white adults in the U.S.Methods
Black (n = 348) and white (n = 203) patients with mild-to-moderate hypertension were randomized to double-blind treatment with eplerenone 50 mg, the angiotensin II receptor antagonist losartan 50 mg, or placebo once daily. Doses were increased if blood pressure remained uncontrolled. The primary end point was change in mean diastolic blood pressure (DBP) after 16 weeks of therapy.ResultsAdjusted mean changes from baseline in DBP were −5.3 ± 0.7, −10.3 ± 0.7, and −6.9 ± 0.6 mm Hg in the placebo, eplerenone-treated, and losartan-treated groups, respectively (mean ± SE, p < 0.001 eplerenone vs. placebo, p < 0.001 eplerenone vs. losartan). In black patients, DBP decreased by −4.8 ± 1.0, −10.2 ± 0.9, and −6.0 ± 0.9 mm Hg for the placebo, eplerenone-treated, and losartan-treated groups, respectively (mean ± SE, p < 0.001 eplerenone vs. placebo, p < 0.001 eplerenone vs. losartan), whereas in white patients, DBP decreased by −6.4 ± 1.0, −11.1 ± 1.1, and −8.4 ± 1.0 mm Hg, respectively (p = 0.001 eplerenone vs. placebo, p = 0.068 for eplerenone vs. losartan). For reduction of systolic blood pressure (SBP), eplerenone was superior to placebo and losartan in all patients combined and in black patients, and was superior to placebo in white patients. Eplerenone was as effective as losartan in reducing SBP and DBP in the high renin patient, but more effective than losartan in the low renin patient. Similarly, eplerenone was at least as effective as losartan in patients with differing baseline levels of aldosterone. Both eplerenone and losartan were well tolerated.Conclusions
The antihypertensive effect of eplerenone was equal in black and white patients and was superior to losartan in black patients.
Introduction: Losartan is an angiotensin II receptor blocker indicated for treatment of hypertension. It also inhibits platelet agreggation through blockade of thromboxane A2/prostaglandin H2 receptors, and has a uricosuric effect. We determined the effect on ambulatory blood pressure (ABP) of 100 mg losartan monotherapy (L100) versus 50 mg losartan/12.5 mg hydrochlorothiazide (HCTZ) combination therapy (L50H12.5C), in patients uncontrolled on 50 mg losartan. We also assessed the effects of losartan on platelet aggregation and serum urate at these clinically relevant doses.
Methods: This was a randomized, double-blind trial of L100 versus L50H12.5C, in moderate hypertensives (sitting diastolic blood pressure (DBP) ≥ 95 mmHg and <120 mmHg). After 4 weeks of placebo run-in, patients received 50 mg losartan for 6 weeks; patients uncontrolled (sitting DBP ≥ 95 mmHg) were randomized to L100 or L50H12.5C for a further 6 weeks. Platelet function was assessed by measuring percentage inhibition of platelet aggregation, and serum uric acid was also measured.
Results: Monotherapy with 50 mg losartan reduced ABP by 16.0/9.9 mmHg during the day and 9.8/5.5 mmHg at night. However, 16 out of 24 (66%) patients had uncontrolled blood pressure on this treatment. L50H12.5C further reduced daytime ABP by 10.7(10.7)/8.4(6.5) mmHg mean (SEM) compared with L100 (25.3(9.7)/22.3(4.8), P = 0.013). 50 mg losartan and L100 did not affect platelet function or uric acid levels beyond placebo values; treatment with L50H12.5C was associated with a significant rise in serum urate above levels obtained on 50 mg losartan (366.9(67.6) versus 331.6(65.0), P = 0.006), to levels similar to placebo (358.8(80.9)).
Conclusion: L50H12.5C is an effective antihypertensive regimen in patients with moderate hypertension that is uncontrolled on 50 mg losartan monotherapy, and is the preferred treatment option in these patients compared with increasing the dose of losartan. The additional benefit of losartan on platelet inhibition was not evident in our population at these doses; however, there was evidence to suggest that the uricosuric effects of losartan might ameliorate the uric acid retention effects of therapy with hydrochlorothiazide.
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.
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.
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.
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.
To compare the first dose responses to low dose angiotensin converting enzyme inhibitors (captopril, enalapril, and perindopril) in elderly patients with stable chronic heart failure.
Double blind, randomised, placebo controlled, parallel, group prospective study of elderly patients with stable chronic heart failure.
General hospital in-patient admissions for supervised diuretic withdrawal (24-48 hours) and the introduction of angiotensin converting enzyme inhibitor therapy.
48 unselected elderly (58-85 years) patients with symptomatic but stable chronic heart failure (New York Heart Association grades II-IV) confirmed by clinical history, examination, and cardiological investigations. Patients gave their written and informed consent to receive their initial treatment under double blind conditions; blood pressure was monitored and blood samples taken to measure the pharmacokinetic and neurohormonal responses.
Patients were randomised to receive a daily oral dose of placebo, captopril (6.25 mg), enalapril (2.5 mg), or perindopril (2 mg).
Blood pressure and heart rate responses, drug concentration, and plasma renin and ACE activities. Differences between treatment groups were analysed by analysis of variance.
The four randomised groups of patients had similar age, severity of heart failure (NYHA class), pretreatment diuretic dosage, plasma renin activity, and serum electrolyte state. Placebo treatment caused a modest but significant diurnal fall in blood pressure. Captopril produced a significant early (1.5 hours) and brief fall in blood pressure. The blood pressure fall with enalapril was later (4-10 hours), longer lasting, and was associated with significant slowing of supine heart rate. Though perindopril produced a similar plasma ACE inhibition to that produced by enalapril, it only caused changes in blood pressure that were similar to those caused by placebo.
This controlled study is the first to indicate a qualitative difference in the acute response to angiotensin converting enzyme inhibitors with similar structure and metabolism (that is, enalapril and perindopril). Low dose perindopril seems to be less likely to cause hypotension in patients with heart failure. The explanation for the differences is unclear but may reflect differential effects on local tissue angiotensin generation.
To define better the efficacy of vasodilator therapy in the treatment of chronic congestive heart failure, we compared the effects of hydralazine and isosorbide dinitrate with those of enalapril in 804 men receiving digoxin and diuretic therapy for heart failure. The patients were randomly assigned in a double-blind manner to receive 20 mg of enalapril daily or 300 mg of hydralazine plus 160 mg of isosorbide dinitrate daily. The latter regimen was identical to that used with a similar patient population in the effective-treatment arm of our previous Vasodilator-Heart Failure Trial.
Mortality after two years was significantly lower in the enalapril arm (18 percent) than in the hydralazine-isosorbide dinitrate arm (25 percent) (P = 0.016; reduction in mortality, 28.0 percent), and overall mortality tended to be lower (P = 0.08). The lower mortality in the enalapril arm was attributable to a reduction in the incidence of sudden death, and this beneficial effect was more prominent in patients with less severe symptoms (New York Heart Association class I or II). In contrast, body oxygen consumption at peak exercise was increased only by hydralazine-isosorbide dinitrate treatment (P less than 0.05), and left ventricular ejection fraction, which increased with both regimens during the 2 years after randomization, increased more (P less than 0.05) during the first 13 weeks in the hydralazine-isosorbide dinitrate group.
The similar two-year mortality in the hydralazine-isosorbide dinitrate arms in our previous Vasodilator-Heart Failure Trial (26 percent) and in the present trial (25 percent), as compared with that in the placebo arm in the previous trial, (34 percent) and the further survival benefit with enalapril in the present trial (18 percent) strengthen the conclusion that vasodilator therapy should be included in the standard treatment for heart failure. The different effects of the two regimens (enalapril and hydralazine-isosorbide dinitrate) on mortality and physiologic end points suggest that the profile of effects might be enhanced if the regimens were used in combination.
An acute myocardial infarction, particularly one that is large and transmural, can produce alterations in the topography of both the infarcted and noninfarcted regions of the ventricle. This remodeling can importantly affect the function of the ventricle and the prognosis for survival. In the early period, infarct expansion has been recognized by echocardiography as a lengthening of the noncontractile region. The noninfarcted region also undergoes an important lengthening that is consistent with a secondary volume-overload hypertrophy and that can be progressive. The extent of ventricular enlargement after infarction is related to the magnitude of the initial damage to the myocardium and, although an increase in cavity size tends to restore stroke volume despite a persistently depressed ejection fraction, ventricular dilation has been associated with a reduction in survival. The process of ventricular enlargement can be influenced by three interdependent factors, that is, infarct size, infarct healing, and ventricular wall stresses. A most effective way to prevent or minimize the increase in ventricular size after infarction and the consequent adverse effect on prognosis is to limit the initial insult. Acute reperfusion therapy has been consistently shown to result in a reduction in ventricular volume. The reestablishment of blood flow to the infarcted region, even beyond the time frame for myocyte salvage, has beneficial effects in attenuating ventricular enlargement. The process of scarification can be interfered with during the acute infarct period by the administration of glucocorticosteroids and nonsteroidal antiinflammatory agents, which result in thinner infarcts and greater degrees of infarct expansion. Modification of distending or deforming forces can importantly influence ventricular enlargement. Even short-term augmentations in afterload have deleterious long-term effects on ventricular topography. Conversely, judicious use of nitroglycerin seems to be associated with an attenuation of infarct expansion and long-term improvement in clinical outcome. Long-term therapy with an angiotensin converting enzyme inhibitor can favorably alter the loading conditions on the left ventricle and reduce progressive ventricular enlargement as demonstrated in both experimental and clinical studies. With the former therapy, this attenuation of ventricular enlargement was associated with a prolongation in survival. The long-term clinical consequences of long-term angiotensin converting enzyme inhibitor therapy after myocardial infarction is currently being evaluated. Although studies directed at attenuating left ventricular remodeling after infarction are in the early stages, it does seem that this will be an important area in which future research might improve long-term outcome after infarction.
In order to determine the possible role of prostaglandins in the abnormal cough reflex in patients with dry cough, the effects of a cyclooxygenase inhibitor on cough symptoms were examined. This was measured by a cough symptom score and by the cough reflex sensitivity to inhaled capsaicin in a double blind, randomized, cross-over study comparing the effects of placebo with sulindac, 200 mg daily for 1 week. We studied six hypertensive patients with angiotensin converting enzyme inhibitor-associated cough and six patients with an idiopathic, dry, unproductive cough, all of whom had an increase in the sensitivity of the cough reflex. There was no change in blood pressure control in the hypertensive patients during sulindac therapy. The patients with the angiotensin converting enzyme-associated cough had a significant reduction in the cough symptom score and also a significant increase in the dose of capsaicin causing two or more coughs (threshold sensitivity) and that causing five or more coughs (near maximum response) during sulindac therapy as compared to placebo. In those patients with idiopathic, dry, unproductive cough, sulindac did not alter the symptom of cough or the cough reflex response to capsaicin. These results suggest that prostaglandins may be involved in cough associated with angiotensin converting enzyme inhibitor therapy, but are less likely to be important in the pathogenesis of more common dry coughs of unknown cause.
This study provides data on plasma hormone levels in patients with severe clinical congestive cardiac failure who had never received therapy and in whom the presence of an accumulation of excess water and sodium had been established. Eight patients were studied; two had ischemic cardiac disease, and six had dilated cardiomyopathy. Mean hemodynamic measurements at rest were as follows: cardiac index, 1.8 l/min/m2; pulmonary wedge pressure, 30 mm Hg; right atrial pressure, 15 mm Hg. Total body water content was 16% above control, extracellular liquid was 33% above control, plasma volume was 34% above control, total exchangeable sodium was 37% above control, renal plasma flow was 29% of control, and glomerular filtration rate was 65% of control. Plasma norepinephrine was consistently increased (on average 6.3 times control), whereas adrenaline was unaffected. Although plasma renin activity and aldosterone varied widely, they were on average above normal (renin 9.5 times control, aldosterone 6.4 times control). Plasma atrial natriuretic peptide (14.3 times control) and growth hormone (11.5 times control) were consistently increased. Cortisol was also increased on average (1.7 times control). Vasopressin was increased only in one patient.
In the Medical Research Council trial for the treatment of mild hypertension, bendrofluazide showed an unexpected and sizeable benefit compared with propranolol in the reduction of stroke. It is suggested that this difference reflects the opposing actions of these drugs on the renin-angiotensin system. The hypothesis that angiotensin-II protects the distal smaller cerebral vessels, which are the usual site of vessel rupture in intracerebral haemorrhage, indicates that long-term benefit of angiotensin-converting-enzyme inhibitors in the treatment of hypertension cannot be assumed.
In a randomised, double-blind trial 60 patients with left ventricular dysfunction (ejection fraction less than 45%) but without clinical evidence of heart failure 1 week after Q wave myocardial infarction were given captopril 25 mg thrice a day, frusemide 40 mg daily, or placebo. Left ventricular volumes were measured at baseline and at 1, 3, 6, 9, and 12 months with cross-sectional echocardiography and Simpson's rule analysis of standardised apical views. The captopril group showed no significant change in left ventricular end-diastolic volume index but left ventricular end-systolic volume index was significantly reduced and stroke volume index and ejection fraction were significantly increased from 1 month on. In contrast, the frusemide and placebo groups showed significant increases in ventricular volumes, with stroke volume index unchanged and ejection fraction slightly reduced. The changes in the captopril group were significantly different from those in the other groups.
To determine whether the relationship between infarct size and ventricular performance, volume, and compliance could be altered favorably, captopril was administered to rats for 3 months following coronary artery ligation. Baseline left and right ventricular and systemic arterial pressures and aortic blood flow, and maximal stroke volume and cardiac indices attained during a volume loading, were measured. Passive pressure-volume relations of the left ventricle were determined, and the slopes of segments of this relation were analyzed to characterize ventricular chamber stiffness. In untreated rats, left ventricular end-diastolic pressure progressively rose (from 5-28 mm Hg) as a function of infarct size, whereas, in captopril-treated rats, filling pressure remained within normal limits (5 +/- 1 mm Hg) in all but those with extensive infarcts. Chronic captopril therapy reduced baseline mean arterial pressure and total peripheral resistance, yet maintained cardiac and stroke outputs in rats both with and without infarcts. In untreated rats, maximal pumping ability progressively declined with increasing infarct size, whereas, in captopril-treated rats, peak stroke volume index remained within normal limits in all but those with extensive infarcts. The in vitro left ventricular volumes of captopril-treated rats were significantly less than those of untreated rats. The maintenance of forward output from a lesser dilated left ventricle yielded an index of ejection fraction for treated rats with moderate and large infarcts that was significantly elevated compared with that of untreated rats with infarcts of comparable size. Left ventricular chamber stiffness, which fell as infarct size increased in untreated rats, was normalized by chronic captopril therapy. Thus, captopril attenuated the left ventricular remodeling (dilation) and deterioration in performance that were observed in rats with chronic myocardial infarction.
To determine whether prostaglandins are involved in circulatory homeostasis in congestive heart failure, we measured plasma levels of the metabolites of vasodilator prostaglandins I2 and E2 in 15 patients with severe chronic heart failure. Mean circulating levels of both metabolites were 3 to 10 times higher than those in normal subjects. Plasma levels of both metabolites correlated directly with plasma renin activity and plasma angiotensin II concentrations (r = 0.64 and 0.84, respectively). Individual serum sodium concentrations were inversely correlated with levels of prostaglandin E2 metabolites (r = -0.92, P less than 0.001) and plasma renin activity (r = -0.69, P less than 0.02). Of 23 patients with severe heart failure challenged with indomethacin (an inhibitor of prostaglandin synthesis), the 9 with hyponatremia had significant decreases in the cardiac index (1.99 +/- 0.12 to 1.72 +/- 0.13 liters per minute per square meter of body-surface area, P less than 0.001) and significant increases in the pulmonary capillary wedge pressure (17.4 +/- 2.0 to 24.0 +/- 1.9 mm Hg, P less than 0.001) and systemic vascular resistance (1882 +/- 239 to 2488 +/- 315 dyn x sec x cm-5, P less than 0.001), whereas the 14 patients with a normal serum sodium concentration had no significant hemodynamic changes. We conclude that both vasoconstrictor (renin-angiotensin) and vasodilator (prostaglandin) mechanisms are operative in patients with heart failure complicated by hyponatremia and that these mechanisms interact to modulate circulatory homeostasis.
An insertion (I)/deletion (D) polymorphism of the angiotensin-converting enzyme (ACE) gene has been associated with differences in the plasma levels of ACE as well as with myocardial infarction, cardiomyopathy, left ventricular hypertrophy, and coronary artery disease.
We determined the cardiac ACE activity and the ACE genotype in 71 subjects who died of noncardiac disorders. Cardiac ACE activity was significantly higher (P < .01) in subjects with the ACE DD genotype (12.7 +/- 1.9 mU/g wet wt) compared with subjects with the ID (8.7 +/- 0.8 mU/g) and the II (9.1 +/- 1.0 mU/g) genotypes. This difference was independent of sex, age, and the time required for tissue collection.
Cardiac ACE activity is highest in subjects with the DD genotype. Elevated cardiac ACE activity in these subjects may result in increased cardiac angiotensin II levels, and this may be a mechanism underlying the reported association between the ACE deletion polymorphism and the increased risk for several cardiovascular disorders.
Renal function declines progressively in patients who have diabetic nephropathy, and the decline may be slowed by antihypertensive drugs. The purpose of this study was to determine whether captopril has kidney-protecting properties independent of its effect on blood pressure in diabetic nephropathy.
We performed a randomized, controlled trial comparing captopril with placebo in patients with insulin-dependent diabetes mellitus in whom urinary protein excretion was > or = 500 mg per day and the serum creatinine concentration was < or = 2.5 mg per deciliter (221 mumol per liter). Blood-pressure goals were defined to achieve control during a median follow-up of three years. The primary end point was a doubling of the base-line serum creatinine concentration.
Two hundred seven patients received captopril, and 202 placebo. Serum creatinine concentrations doubled in 25 patients in the captopril group, as compared with 43 patients in the placebo group (P = 0.007). The associated reductions in risk of a doubling of the serum creatinine concentration were 48 percent in the captopril group as a whole, 76 percent in the subgroup with a baseline serum creatinine concentration of 2.0 mg per deciliter (177 mumol per liter), 55 percent in the subgroup with a concentration of 1.5 mg per deciliter (133 mumol per liter), and 17 percent in the subgroup with a concentration of 1.0 mg per deciliter (88.4 mumol per liter). The mean (+/- SD) rate of decline in creatinine clearance was 11 +/- 21 percent per year in the captopril group and 17 +/- 20 percent per year in the placebo group (P = 0.03). Among the patients whose base-line serum creatinine concentration was > or = 1.5 mg per deciliter, creatinine clearance declined at a rate of 23 +/- 25 percent per year in the captopril group and at a rate of 37 +/- 25 percent per year in the placebo group (P = 0.01). Captopril treatment was associated with a 50 percent reduction in the risk of the combined end points of death, dialysis, and transplantation that was independent of the small disparity in blood pressure between the groups.
Captopril protects against deterioration in renal function in insulin-dependent diabetic nephropathy and is significantly more effective than blood-pressure control alone.
Characteristics such as age and race are often cited as determinants of the response of blood pressure to specific antihypertensive agents, but this clinically important issue has not been examined in sufficiently large trials, involving all standard treatments, to determine the effect of such factors.
In a randomized, double-blind study at 15 clinics, we assigned 1292 men with diastolic blood pressures of 95 to 109 mm Hg, after a placebo washout period, to receive placebo or one of six drugs: hydrochlorothiazide (12.5 to 50 mg per day), atenolol (25 to 100 mg per day), captopril (25 to 100 mg per day), clonidine (0.2 to 0.6 mg per day), a sustained-release preparation of diltiazem (120 to 360 mg per day), or prazosin (4 to 20 mg per day). The drug doses were titrated to a goal of less than 90 mm Hg for maximal diastolic pressure, and the patients continued to receive therapy for at least one year.
The mean (+/- SD) age of the randomized patients was 59 +/- 10 years, and 48 percent were black. The average blood pressure at base line was 152 +/- 14/99 +/- 3 mm Hg. Diltiazem therapy had the highest rate of success: 59 percent of the treated patients had reached the blood-pressure goal at the end of the titration phase and had a diastolic blood pressure of less than 95 mm Hg at one year. Atenolol was successful by this definition in 51 percent of the patients, clonidine in 50 percent, hydrochlorothiazide in 46 percent, captopril in 42 percent, and prazosin in 42 percent; all these agents were superior to placebo (success rate, 25 percent). Diltiazem ranked first for younger blacks (< 60 years) and older blacks (> or = 60 years), among whom the success rate was 64 percent, captopril for younger whites (success rate, 55 percent), and atenolol for older whites (68 percent). Drug intolerance was more frequent with clonidine (14 percent) and prazosin (12 percent) than with the other drugs.
Among men, race and age have an important effect on the response to single-drug therapy for hypertension. In addition to cost and quality of life, these factors should be considered in the initial choice of a drug.
Angiotensin-converting enzyme (ACE) inhibitors may exert some of their benefits in the therapy of hypertension, congestive heart failure, and acute myocardial infarction by their improvement of endothelial dysfunction. TREND (Trial on Reversing ENdothelial Dysfunction) investigated whether quinapril might improve endothelial dysfunction in normotensive patients with coronary artery disease and no heart failure, cardiomyopathy, or major lipid abnormalities so that confounding variables that affect endothelial dysfunction could be minimized.
Using a double-blind, randomized, placebo-controlled design, we measured the effects of quinapril (40 mg daily) on coronary artery diameter responses to acetylcholine using quantitative coronary angiography. The primary response variable was the net change in the acetylcholine-provoked constriction of target segments between the baseline (prerandomization) and 6-month follow-up angiograms. The constrictive responses to acetylcholine were comparable in the placebo (n = 54) and quinapril (n = 51) groups at baseline. After 6 months, only the quinapril group showed significant net improvement in response to incremental concentrations of acetylcholine (4.5 +/- 3.0% [mean +/- SEM] versus -0.1 +/- 2.8% at 10(-6) mol/L and 12.1 +/- 3.0% versus -0.8 +/- 2.9% at 10(-4) mol/L, quinapril versus placebo, respectively; overall P = .002).
TREND shows that ACE inhibition with quinapril improved endothelial dysfunction in patients who were normotensive and who did not have severe hyperlipidemia or evidence of heart failure. These benefits of ACE inhibition are likely due to attenuation of the contractile effects and superoxide-generating effects of angiotensin II and to enhancement of endothelial cell release of nitric oxide secondary to diminished breakdown of bradykinin.
The Modification of Diet in Renal Disease Study showed a beneficial effect of a lower-than-usual blood pressure (BP) goal on the progression of renal disease in patients with proteinuria. The purpose of the present analyses was to examine the achieved BP, baseline characteristics that helped or hindered achievement of the BP goals, and safety of the BP interventions. Five hundred eighty-five patients with baseline glomerular filtration rate between 13 and 55 mL/min per 1.73 m2 (0.22 to 0.92 mL/s per 1.73 m2) were randomly assigned to either a usual or low BP goal (mean arterial pressure < or = 107 or < or = 92 mm Hg, respectively). Few patients had a history of cardiovascular disease. All antihypertensive agents were permitted, but angiotensin-converting enzyme inhibitors (with or without diuretics) followed by calcium channel blockers were preferred. The mean (+/- SD) of the mean arterial pressures during follow-up in the low and usual BP groups was 93.0 +/- 7.3 and 97.7 +/- 7.7 mm Hg, respectively. Follow-up BP was significantly higher in subgroups of patients with preexisting hypertension, baseline mean arterial pressure > 92 mm Hg, a diagnosis of polycystic kidney disease or glomerular diseases, baseline urinary protein excretion > 1 g/d, age > or = 61 years, and black race. The frequency of medication changes and incidence of symptoms of low BP were greater in the low BP group, but there were no significant differences between BP groups in stop points, hospitalizations, or death. When data from both groups were combined, each 1-mm Hg increase in follow-up systolic BP was associated with a 1.35-times greater risk of hospitalization for cardiovascular or cerebrovascular disease. Lower BP than usually recommended for the prevention of cardiovascular disease is achievable by several medication regimens without serious adverse effects in patients with chronic renal disease without cardiovascular disease. For patients with urinary protein excretion > 1 g/d, target BP should be a mean arterial pressure of < or = 92 mm Hg, equivalent to 125/75 mm Hg.
The importance of the effects of ACE inhibitors on sudden death, progressive heart failure and recurrent infarction to the reduction in overall mortality in heart failure and after myocardial infarction is disputed.
The AIRE study randomized 2006 patients with clinical or radiological evidence of heart failure within 2-9 days of a myocardial infarction to receive ramipiril 5 mg b.d. or matching placebo. Outcomes were assessed independently by members of an end-points committee blinded to treatment allocation.
Fewer patients developed severe resistant heart failure as their first validated end-point on rampril, despite the greater number of at-risk survivors, compared to placebo (n = 143 vs 178; risk reduction 23%; CI 5 to 39%; P = 0.017). Ramipril did not alter the rate of reinfarction or stroke. Irrespective of treatment allocation 182 (46%) patients developed resistant heart failure prior to death. A validated acute or remote myocardial reinfarction occurred in 76 (19%) patients prior to death and chest pain occurred in 90 (23%) patients around the time of death suggesting an ischaemic element to these deaths Eighty deaths occurred on the index admission, 167 during re-admission and 145 out-of-hospital. Sudden death accounted for 54% of all deaths and 93% of out-of-hospital deaths. Ramipril reduced the risk of sudden death by 30% (95% CI: 8-47%; P = 0.011). However, overall, 45% of those patients who died suddenly had severe or worsening heart failure prior to their death. Only 39% of sudden deaths were considered to be due to arrhythmias. Ramipril reduced the risk of death from circulatory failure by 18%, but this did not reach statistical significance (95% CI; 41 to -14%; P = 0.237). The magnitude of the effects on sudden death and death due to circulatory failure were not significantly different. However, 38% of the reduction in overall mortality was from the subgroup with sudden death who had developed prior severe resistant heart failure (placebo n = 35, ramipril n = 15), again emphasizing the marked benefit in preventing failure. Ramipril did not selectively alter the proportion of in- to out-of-hospital deaths.
Ramipril reduces mortality and progression to resistant heart failure among patients with evidence of heart failure early after myocardial infarction. Retarding the progression of heart failure appears to be a major factor contributing to the reduction in mortality both by reducing circulatory failure and by reducing sudden death.
In the Acute Infarction Ramipril Efficacy (AIRE) Study, the effect of angiotensin-converting-enzyme (ACE) inhibition on the survival of patients with clinical heart failure after acute myocardial infarction (AMI), was assessed. At an average follow-up time of 15 months after randomisation, all-cause mortality was reduced from 22.6% (placebo group) to 16.9% (ramipril group) representing an absolute mortality reduction of 5.7% and a relative risk reduction of 27% (95% CI 11-40%; p = 0.002). Our aim in this study was to assess the long-term (3 years after the AIRE Study closed) magnitude, duration, and reliability of the survival benefits observed after treatment with ramipril (target dose 5 mg twice a day) when compared with placebo.
We investigated the mortality status of all 603 patients recruited from the 30 UK centres involved in the AIRE Study. Through government records we were able to confirm the death or survival of all 603 patients exactly 3 years after the close of the AIRE Study. Follow-up was for a minimum of 42 months and a mean of 59 months. The average duration of treatment with masked trial medication was 13.4 months for placebo and 12.4 months for ramipril.
By 0000 h March 1, 1996, death from all causes had occurred in 117 (38.9%) of 301 patients randomly assigned placebo and 83 (27.5%) of 302 patients randomly assigned ramipril, representing a relative risk reduction of 36% (95% CI 15-52%; p = 0.002) and an absolute reduction in mortality of 11.4% (114 additional 5-year survivors per 1000 patients treated for an average of 12.4 months).
Our data provide robust evidence that administration of ramipril to patients with clinically defined heart failure after AMI results in a survival benefit that is not only large in magnitude, but also sustained over many years.
This study was designed to determine whether angiotensin-converting enzyme (ACE) inhibitors play a role in cardioprotection in a human model of preconditioning.
Recent studies have suggested that bradykinin may contribute to the protective effects of preconditioning in animal models. ACE inhibitors are known to inhibit the degradation of bradykinin and hence may be able to potentiate the effect of preconditioning.
We examined the effects of the ACE inhibitors captopril and lisinopril in combination with a subthreshold preconditioning stimulus (i.e., insufficient to have any protective effects alone). Human atrial trabeculae were superfused with Krebs buffer and paced at 1 Hz. They were subjected to a full or subthreshold preconditioning stimulus consisting of either 3 or 1.5 min of simulated ischemia and 7 min of reoxygenation. In each instance, this stimulus was followed by 90 min of simulated ischemia and 2 h of reoxygenation. In addition, the subthreshold preconditioned group had 20 min of previous ACE inhibitor treatment.
Recovery of contractile function (percent of baseline) was 22 +/- 1% (mean +/- SEM) in the control group versus 61 +/- 1% in the preconditioned group. The subthreshold preconditioned group and the ACE inhibitor-alone groups did not exhibit any protection; however, in combination, the protection was significant (71 +/- 4% in the captopril group, 58 +/- 8% in the lisinopril group, p < 0.005) compared with the control group. There was no significant difference between these values and recovery after the full preconditioning stimulus. Furthermore, Hoe 140, a specific bradykinin B2 receptor antagonist, abolished the protection.
To our knowledge, these are the first results in human muscle to suggest that ACE inhibitors may augment ischemic preconditioning, possibly through B2 receptor activation.
The effect of angiotensin-converting enzyme (ACE) inhibitors in slowing the decline in renal function in nondiabetic renal disease varies among studies.
To use meta-analysis to assess the effect of ACE inhibitors on the development of end-stage renal disease caused by factors other than diabetes.
The English-language medical literature, identified by a MEDLINE search and unpublished studies.
All randomized studies that compared ACE inhibitors with other antihypertensive agents and had at least 1 year of planned follow-up were selected. Studies of diabetic renal disease and renal transplants were excluded. A total of 1594 patients in 10 studies was included.
Data on end-stage renal disease, death, drop out, and blood pressure were extracted. Study investigators confirmed results and provided additional data.
Among 806 patients receiving ACE inhibitors, 52 (6.4%) developed end-stage renal disease and 17 (2.1%) died; in the 788 controls, the respective values were 72 (9.1%) and 12 (1.5%). The pooled relative risks were 0.70 (95% CI, 0.51 to 0.97) for end-stage renal disease and 1.24 (CI, 0.55 to 2.83) for death; the studies were not significantly heterogeneous. The decreases in weighted mean systolic and diastolic blood pressures during follow-up were 4.9 and 1.2 mm Hg greater, respectively, in the patients who received ACE inhibitors.
Angiotensin-converting enzyme inhibitors are more effective than other antihypertensive agents in reducing the development of end-stage nondiabetic renal disease, and they do not increase mortality. It could not be determined whether this beneficial effect is due to the greater decline in blood pressure or to other effects of ACE inhibition.
Mortality of diabetic patients with acute myocardial infarction (MI) remains high despite recent improvement in their management. There is a need to evaluate efficacy and safety of novel treatments of MI in this high-risk population. We evaluated whether treatment with an ACE inhibitor begun within 24 hours from the onset of symptoms is able to decrease mortality and morbidity of diabetic patients with acute MI.
A retrospective analysis of the data of the GISSI-3 study in patients with and without a history of diabetes was performed. Patients with suspected acute MI were randomized to treatment with lisinopril (2.5 to 5 up to 10 mg/d) with or without nitroglycerin (5 to 20 microg I.V. then 10 mg/d) begun within 24 hours and continued for 6 weeks. The main end point was mortality at 6 weeks, and the secondary end point was a combined evaluation of mortality and severe left ventricular dysfunction. Information on diabetic status was available for 18,131 patients (approximately 94% of the total population enrolled), of whom 2790 patients had a history of diabetes. Treatment with lisinopril was associated with a decreased 6-week mortality in diabetic patients (8.7% versus 12.4%; OR, 0.68; 95% CI, 0.53 to 0.86; 37+/-12 lives saved per 1000 treated patients), an effect that was significantly (P<.025) higher than that observed in nondiabetic patients. The survival benefit in diabetics was mostly maintained at 6 months despite withdrawal from treatment at 6 weeks (12.9% versus 16.1%; OR, 0.77; 95% CI, 0.62 to 0.95).
Early treatment with the ACE inhibitor lisinopril in diabetic patients with acute MI is associated with a decreased 6-week mortality. This beneficial effect supports a widespread and early use of ACE inhibitors in diabetic patients with acute MI. The burden of mortality plus morbidity for ventricular dysfunction in diabetics remains clinically important and warrants further testing of novel therapeutic approaches.
Background:
The Ramipril Efficacy In Nephropathy (REIN) study found that in patients with chronic nephropathies and proteinuria of 3 g or more per 24 h, ramipril safely reduced the rate of decline of the glomerular filtration rate (GFR) and halved the combined risk of doubling of serum creatinine or end-stage renal failure (ESRF), as compared with placebo plus conventional antihypertensive drugs at the same level of blood pressure control. At the end of the core study patients continued on or shifted to ramipril and were formally enrolled into the REIN follow-up study.
Methods:
97 patients entered the follow-up study. Patients originally randomised to ramipril continued with the same daily dose (n=51), whereas those originally on placebo plus conventional antihypertensive drugs switched to ramipril after the first visit of the follow-up study (n=46). Ramipril (1.25 to 5.00 mg/day) and conventional antihypertensive therapy were targeted at achieving diastolic blood pressure under 90 mm Hg. The main efficacy variables were GFR decline and ESRF (need for dialysis). Analysis was by intention to treat.
Findings:
During the follow-up study the mean rate of GFR decline per month decreased from 0.44 (SD 0.54) mL/min per 1.73 m2 in the core study to 0.10 (0.50) mL/min per 1.73 m2 in patients originally randomised to ramipril (p=0.017), and from 0.81 (1.12) to 0.14 (0.87) mL/min per 1.73 m2 in those originally randomised to placebo plus conventional antihypertensive therapy (p=0.017). At the final visit, mean absolute GFR values were 12 mL/min per 1.73 m2 higher (33% better) in patients randomised to ramipril than in those assigned placebo (n=26 and 17, respectively: 35.5 [19.0] vs 23.8 [9.4] mL/min per 1.73 m2, p=0.01). 19 of the patients originally on ramipril versus 35 switched from placebo to ramipril progressed to ESRF (p=0.027) during the whole observation period; of these, six (8%) versus 14 (16%) reached that endpoint during the follow-up study; and the risk ratios were 1.86 (95% CI 1.07-3.26) over the whole observation period and 2.95 (1.13-7.68) during follow-up. Beyond follow-up at month 36, the incidence of ESRF was zero in patients originally randomised to ramipril but 30% in patients on placebo plus conventional antihypertensive therapy.
Interpretation:
In patients with chronic nephropathy and high risk of rapid progression to ESRF, ramipril reversed the tendency of GFR to decline with time. Moreover, a treatment period of sufficient duration (> or =36 months) eliminated the need for dialysis. Even patients previously treated with antihypertensive drugs other than angiotensin-converting-enzyme inhibitors benefited from shifting to ramipril.
Angiotensin-converting-enzyme (ACE) inhibitors have been used for more than a decade to treat high blood pressure, despite the lack of data from randomised intervention trials to show that such treatment affects cardiovascular morbidity and mortality. The Captopril Prevention Project (CAPPP) is a randomised intervention trial to compare the effects of ACE inhibition and conventional therapy on cardiovascular morbidity and mortality in patients with hypertension.
CAPPP was a prospective, randomised, open trial with blinded endpoint evaluation. 10,985 patients were enrolled at 536 health centres in Sweden and Finland. Patients aged 25-66 years with a measured diastolic blood pressure of 100 mm Hg or more on two occasions were randomly assigned captopril or conventional antihypertensive treatment (diuretics, beta-blockers). Analysis was by intention-to-treat. The primary endpoint was a composite of fatal and non-fatal myocardial infarction, stroke, and other cardiovascular deaths.
Of 5492 patients assigned captopril and 5493 assigned conventional therapy, 14 and 13, respectively, were lost to follow-up. Primary endpoint events occurred in 363 patients in the captopril group (11.1 per 1000 patient-years) and 335 in the conventional-treatment group (10.2 per 1000 patient-years; relative risk 1.05 [95% CI 0.90-1.22], p=0-52). Cardiovascular mortality was lower with captopril than with conventional treatment (76 vs 95 events; relative risk 0.77 [0.57-1-04], p=0.092), the rate of fatal and non-fatal myocardial infarction was similar (162 vs 161), but fatal and non-fatal stroke was more common with captopril (189 vs 148; 1.25 [1-01-1-55]. p=0.044).
Captopril and conventional treatment did not differ in efficacy in preventing cardiovascular morbidity and mortality. The difference in stroke risk is probably due to the lower levels of blood pressure obtained initially in previously treated patients randomised to conventional therapy.
Estimate the effect of angiotensin converting enzyme (ACE) inhibitors on the risk of sudden cardiac death (SCD) following myocardial infarction (MI).
Trials in post-MI patients have shown that ACE inhibitor therapy reduces mortality. However, the effect on SCD as a mechanism has not been clarified.
Trials of ACE inhibitor therapy following MI reported between January, 1978 and August, 1997 were identified. Studies were included if they met the following criteria: 1) randomized comparison of ACE inhibitor to placebo within 14 days of MI; 2) study duration/blinded follow-up of > or =6 weeks; 3) the number of deaths and modes of death were reported or could be obtained from the investigators.
We identified 374 candidate articles, of which 15 met the inclusion criteria. The 15 trials included 15,104 patients, 2,356 of whom died. Most (87%) fatalities were cardiovascular and 900 were SCDs. A significant reduction in SCD risk or a trend towards this was observed in all of the larger (N > 500) trials. Overall, ACE inhibitor therapy resulted in significant reductions in risk of death (random effects odds ratio [OR] = 0.83; 95% confidence interval [CI] 0.71-0.97), cardiovascular death (OR = 0.82; 95% CI 0.69-0.97) and SCD (OR = 0.80; 95% CI 0.70-0.92).
This analysis is consistent with prior reports showing that ACE inhibitors decrease the risk of death following a recent MI by reducing cardiovascular mortality. Moreover, this analysis suggests that a reduction in SCD risk with ACE inhibitors is an important component of this survival benefit.
The survival benefit from the use of inhibitors of angiotensin-converting enzyme (ACE) in patients with acute myocardial infarction is usually presented in terms of risk ratios and lives saved per 1000 people treated. A more relevant way to present the extent of benefit would be in terms of an increase in life expectancy, but this approach has not previously been possible because of limited data on long-term outcome. We aimed to calculate the effect of trandolapril on life expectancy with follow-up data from the Trandolapril Cardiac Evaluation (TRACE) Study.
The TRACE study previously showed a significant survival benefit with trandolapril in patients with reduced left-ventricular function after an acute myocardial infarction who were treated for at least 2 years. We ascertained the survival status of all patients in the TRACE study in June, 1998, at which time they had been followed up for a minimum of 6 years. We estimated life expectancy as median lifetime, which was the time for 50% of the patients to have died. Change in life expectancy is expressed as change in median lifetime. Analysis was by intention to treat.
The life expectancy of patients was 4.6 years for those given placebo versus 6.2 years for those on trandolapril. Thus, for patients on trandolapril, median lifetime was increased by 15.3 months or 27% (95% CI 7 to 51). Analysis of follow-up after the end of the study indicated no decrease of this benefit during the course of double-blind treatment; continued use of trandolapril was recommended at study closure.
In patients with severely reduced left-ventricular function, long-term treatment with an ACE inhibitor during the critical period after myocardial infarction is associated with a substantial increase in life expectancy.
Angiotensin II (Ang II) acts at the cellular level on two receptor subtypes: the AT1 receptor which can be blocked by losartan and its analogues (the 'sartan family'), and the AT2 receptor that does not react with the above antagonists but which can be blocked by different compounds, such as PD123319. AT1 receptor blockade has proven to be a highly effective means of interference with the renin-angiotensin system (RAS) and hence of reducing high blood pressure. As a result of the terminal blockade of the RAS cascade, circulating Ang II levels tend to rise two- to threefold. The free access of such enhanced levels to uninhibited AT2 receptors may be clinically relevant, as argued in the present review. The most extensive experimental and clinical experience with AT1 receptor blockade so far has been obtained with the pioneer drug losartan, although major contributions have also been made on candesartan cilexetil, irbesartan and valsartan. All of these four drugs have been instrumental in substantial clinical trials, serving as sources of information in the clinically oriented part of this review. AT1 receptor blocking drugs generally provide a relatively gradual decrease in blood pressure, which is comparable to that obtained with conventional anti-hypertensive drugs. Clinical trials reveal an astounding lack of drug-related adverse effects, scoring even better than placebo in terms of frequencies and sometimes patterns. The trough/peak ratio on single dosages seems to have been mastered, particularly with the second generation of AT1 receptor blockers, as is evident from 24 h ambulatory blood pressure monitoring. Combination with low-dose thiazide regimens is well established. Intermediate endpoints (micro-albuminuria and left ventricular hypertrophy) appear to be controllable. Morbid cardiovascular sequelae are currently under study in comparison with beta- and calcium channel blockade.
This article has no abstract; the first 100 words appear below.
Chronic heart failure occurs most commonly after earlier myocardial infarction or in the presence of long-standing hypertension. The inability of this normally efficient muscular pump to eject or receive blood results in characteristic symptoms and signs. In patients with compensated heart failure, breathlessness and fatigue occur only with moderate or greater levels of exertion, and physical signs of increased plasma and extravascular volumes are absent. Symptoms that occur with minimal exertion or at rest, accompanied by jugular venous distention and edema of the lower extremities, reflect decompensation. Congestive heart failure, a syndrome arising from hypoperfused tissues and congested organs, has . . .
Karl T. Weber, M.D.
University of Missouri Health Sciences Center, Columbia, MO 65212
The efficacy of new antihypertensive drugs has been questioned. We compared the effects of conventional and newer antihypertensive drugs on cardiovascular mortality and morbidity in elderly patients.
We did a prospective, randomised trial in 6614 patients aged 70-84 years with hypertension (blood pressure > or = 180 mm Hg systolic, > or = 105 mm Hg diastolic, or both). Patients were randomly assigned conventional antihypertensive drugs (atenolol 50 mg, metoprolol 100 mg, pindolol 5 mg, or hydrochlorothiazide 25 mg plus amiloride 2.5 mg daily) or newer drugs (enalapril 10 mg or lisinopril 10 mg, or felodipine 2.5 mg or isradipine 2-5 mg daily). We assessed fatal stroke, fatal myocardial infarction, and other fatal cardiovascular disease. Analysis was by intention to treat.
Blood pressure was decreased similarly in all treatment groups. The primary combined endpoint of fatal stroke, fatal myocardial infarction, and other fatal cardiovascular disease occurred in 221 of 2213 patients in the conventional drugs group (19.8 events per 1000 patient-years) and in 438 of 4401 in the newer drugs group (19.8 per 1000; relative risk 0.99 [95% CI 0.84-1.16], p=0.89). The combined endpoint of fatal and non-fatal stroke, fatal and non-fatal myocardial infarction, and other cardiovascular mortality occurred in 460 patients taking conventional drugs and in 887 taking newer drugs (0.96 [0.86-1.08], p=0.49).
Old and new antihypertensive drugs were similar in prevention of cardiovascular mortality or major events. Decrease in blood pressure was of major importance for the prevention of cardiovascular events.