Effects of low-dose angiotensin II receptor blocker candesartan on cardiovascular events in patients with coronary artery disease
Article Outline
Abstract
Objectives
The purpose of this study was to investigate the effects of angiotensin II receptor blockers on the prevention of cardiovascular events in patients with coronary artery disease (CAD).
Background
Angiotensin II may contribute to the pathogenesis of CAD. Long-term clinical trials have shown that blockade of the renin-angiotensin system can reduce cardiovascular events in patients with acute myocardial infarction complicated by heart failure.
Methods
Patients with a history of coronary intervention and no significant coronary stenosis on follow-up angiography 6 months after intervention were randomly assigned into a candesartan group (n = 203; baseline treatment plus candesartan 4 mg/d) or a control group (n = 203; baseline treatment alone). The primary end point was a composite of revascularization, nonfatal myocardial infarction, or cardiovascular death. The secondary end point was hospitalization for cardiovascular causes.
Results
There were no changes in blood pressure and in other coronary risk factors in either group during a mean follow-up of 24 months. Primary end point risk was significantly lower in the candesartan group (n = 12) than in control group patients (n = 25) (P = .03). Candesartan treatment reduced primary end point risk (5.9% vs 12.3% for control subjects; relative risk, 0.47; 95% CI, 0.24 to 0.93). The incidence of all events including secondary end points and noncardiovascular death was significantly lower in the candesartan group than in control group patients (23 vs 40 cases) (P = .02).
Conclusions
Relatively low-dose candesartan, which did not alter blood pressure levels, reduces cardiovascular risk in high-risk patients with CAD.
The tissue renin-angiotensin system plays a major role in the pathobiology of vascular disorders such as coronary artery disease (CAD) and heart failure.1 Long-term clinical trials have been performed to investigate the effects of angiotensin-converting enzyme (ACE) inhibitors in patients with acute myocardial infarction complicated by heart failure, with several of these studies showing that blockade of the renin-angiotensin system can reduce cardiovascular events.2, 3, 4, 5, 6 Recent findings have also been reported from the Heart Outcomes Prevention Evaluation (HOPE) study, in which ACE inhibitors were used for the treatment of patients with cardiovascular risk factors but without left ventricular dysfunction.7 Findings confirmed that treatment with ACE inhibitors reduced cardiovascular morbidity and mortality rates in these patients and that these results were independent of reduction in blood pressure (BP). ACE inhibition not only inhibits the production of angiotensin II but also simultaneously inhibits the breakdown of bradykinin and thereby raises bradykinin levels. Elevated levels of bradykinin promote the production of nitric oxide (NO) and prostacyclin and provide protective cardiovascular effects.1 At present, there is no clear evidence as to whether the favorable effects of ACE inhibition on patients with CAD are due to angiotensin II blockade or to increased bradykinin levels.
In recent years, as angiotensin II receptor blockers (ARBs) have become available for clinical practice, they have been found to be superior to ACE inhibitors for directly blocking the effects of angiotensin II. Candesartan cilexetil is a long-acting, specific antagonist that has a high affinity for angiotensin II receptors.8 Although this drug is reported to provide effects equivalent to those of ACE inhibitors with regard to improving cardiac function in patients with heart failure,9 no evidence is available with regard to its effect on cardiovascular events after coronary intervention.
The current study was designed to investigate prospectively the effects of candesartan on cardiovascular events in patients with CAD after chronic coronary intervention.
Methods
Patient population
All subjects were current outpatients at Ogaki Municipal Hospital who had a history of coronary intervention and showed no significant coronary stenosis on follow-up angiography 6 months after intervention. Patients with congestive heart failure (ejection fraction <0.40) or with malignancy and patients receiving dialysis treatment were excluded from the study. A total of 406 patients were consecutively enrolled from August through December 1999 and were randomly assigned to a candesartan group (n = 203) or a control group (n = 203). Baseline treatment was continued in both groups; patients in the candesartan group were additionally treated with 4 mg/d candesartan. No placebo tablets were administered in the control group. The study protocol was approved by the ethics committee of our hospital. The aims of the study were explained to each patient, and informed consent was obtained before random assignment. The trial was carried out in accordance with the Declaration of Helsinki.
Follow-up and end points
A prospective survey of cardiovascular events was performed during a mean follow-up period of 24 months. The primary end point was a composite of revascularization, nonfatal myocardial infarction, or cardiovascular death. The secondary end point was hospitalization for cardiovascular causes (worsening angina or heart failure). Worsening angina was defined as symptomatic chest pain that required coronary angiography but that was treated medically rather than by intervention. These cardiovascular events were diagnosed by at least two cardiologists. The incidence of all events including primary end point, secondary end point, and noncardiovascular death was also analyzed.
Statistical analysis
Results are expressed as mean ± SD. Differences in baseline characteristics were assessed by using the unpaired Student t test and χ2 test as appropriate. The changes in BP level and laboratory values were assessed by using a 2-way analysis of variance, in which the factors were time and treatment. Analyses of the primary and secondary end points were performed according to the intention-to-treat principle. Survival curves were estimated by using the Kaplan-Meier product-limit method and compared by using the Mantel (log-rank) test. Relative risk and 95% CIs were calculated by using the Cox regression model. In subjects who had multiple nonfatal cardiac events, analysis was limited to first events. A P value of <.05 was considered to indicate statistical significance.
Results
Changes in CAD risk factors
In the process of clinical treatment, study drug administration was discontinued in 9 patients in the candesartan group because of dizziness or lightheadedness, leaving a total of 194 patients followed up in the candesartan group. In the control group, 2 patients relocated during the follow-up period, and their clinical conditions were confirmed by telephone interview with the patients. No differences at baseline were noted between the 2 groups with regard to factors such as age, sex, body mass index, ejection fraction, history of myocardial infarction, heart failure, or incidence of coronary risk factors (Table I). Mean BP was 129/76 mm Hg for the candesartan group and 128/76 mm Hg for the control group. During the follow-up period, these BP levels were 128/75 mm Hg and 128/75 mm Hg at 1 year and 127/75 mm Hg and 126/76 mm Hg at 2 years in the candesartan and control groups, respectively. There were no significant differences between the 2 groups at baseline or at follow-up and no significant changes in BP at 1 and 2 years after the start of treatment in either of the 2 groups. No differences were noted between the candesartan group and the control group with regard to baseline lipid profiles (total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides), fasting serum glucose, HbA1c, C-reactive protein (CRP), or insulin level, and no significant changes in these biochemical data were noted during the follow-up period (Table II).
Table I. Baseline clinical characteristics and risk factors of study patients
| Characteristics | Candesartan group (n = 203) | Control group (n = 203) |
|---|---|---|
| Mean age (y) | 65 ± 9 | 65 ± 10 |
| Male (%) | 150 (74) | 157 (77) |
| Body mass index (kg/m2) | 24 ± 2 | 23 ± 2 |
| Ejection fraction* | 0.63 ± 0.1 | 0.62 ± 0.1 |
| History of (%) | ||
| Myocardial infarction | 136 (67) | 143 (70) |
| Congestive heart failure | 6 (3) | 3 (1) |
| Smoking status (%) | ||
| Current smoker | 51 (25) | 43 (21) |
| Exsmoker | 75 (37) | 88 (43) |
| Hypertension (%) | 98 (48) | 80 (39) |
| Diabetes (%) | 55 (27) | 46 (23) |
| Hypercholesterolemia (%) | 103 (51) | 93 (46) |
* Assessed by cardiac echocardiography. |
Table II. Blood pressure and laboratory values at baseline and at follow-up
| Variable | Candesartan group (n = 194) | Control group (n = 201) | ||||
|---|---|---|---|---|---|---|
| Baseline | Year 1 | Year 2 | Baseline | Year 1 | Year 2 | |
| Blood pressure (mm Hg) | ||||||
| Systolic | 129 ± 13 | 128 ± 12 | 127 ± 14 | 128 ± 14 | 128 ± 13 | 126 ± 13 |
| Diastolic | 76 ± 8 | 75 ± 7 | 75 ± 8 | 76 ± 8 | 75 ± 8 | 76 ± 8 |
| Total cholesterol (mmol/L) | 4.84 ± 0.72 | 4.94 ± 0.91 | 4.86 ± 0.75 | 4.84 ± 0.80 | 4.86 ± 0.67 | 5.09 ± 0.78 |
| HDL cholesterol (mmol/L) | 1.27 ± 0.31 | 1.22 ± 0.31 | 1.22 ± 0.31 | 1.27 ± 0.36 | 1.22 ± 0.36 | 1.22 ± 0.34 |
| LDL cholesterol (mmol/L) | 2.95 ± 0.65 | 3.00 ± 0.78 | 2.95 ± 0.75 | 2.90 ± 0.78 | 2.95 ± 0.67 | 2.95 ± 0.67 |
| Triglycerides (mmol/L) | 1.42 ± 0.82 | 1.54 ± 1.00 | 1.48 ± 0.82 | 1.43 ± 0.87 | 1.54 ± 0.93 | 1.47 ± 0.98 |
| FSG (mmol/L) | 6.55 ± 1.78 | 6.49 ± 1.78 | 6.38 ± 1.61 | 6.49 ± 2.11 | 6.55 ± 1.94 | 6.66 ± 1.94 |
| HbA1C (%) | 5.6 ± 1.1 | 5.6 ± 1.2 | 5.3 ± 1.0 | 5.6 ± 1.0 | 5.5 ± 1.3 | 5.2 ± 1.1 |
| CRP (mg/dL) | 0.4 ± 1.7 | 0.2 ± 0.3 | 0.3 ± 0.4 | 0.3 ± 0.6 | 0.2 ± 0.3 | 0.3 ± 0.3 |
| IRI (pmol/L) | 86.1 ± 129 | 71.8 ± 71.8 | 71.8 ± 64.6 | 71.8 ± 86.1 | 86.1 ± 115 | 93.3 ± 115 |
Cardiovascular end points
Table III shows cardiac events and noncardiovascular death during a mean follow-up period of 24 months. The composite primary end point developed in 12 patients in the candesartan group (8 cases of revascularization, 2 cases of nonfatal myocardial infarction, and 2 cases of cardiovascular death) and in 25 patients in the control group (15 cases of revascularization, 1 case of nonfatal myocardial infarction, and 9 cases of cardiovascular death), with these values being significantly lower for the candesartan group (P = .03) (Figure 1, A). Culprit lesions required for intervention were common in newly progressive sites in both groups (75% in the candesartan group and 80% in the control group). In all patients, at least 6 months had elapsed at the start of the trial since the final coronary intervention, and lesion progression rather than restenosis was observed. Cardiovascular death was caused by myocardial infarction in 1 case and sudden cardiac death in 1 case in the candesartan group, and by myocardial infarction in 2 cases, sudden cardiac death in 4 cases, dissecting aortic aneurysm in 1 case, arrhythmia in 1 case, and heart failure in 1 case in the control group.
Table III. Cardiovascular events and noncardiovascular death during the follow-up period
| Event | Candesartan group (n = 194) | Control group (n = 203) | P* |
|---|---|---|---|
| Primary end point | 12 | 25 | .03 |
| Revascularization | 8 | 15 | |
| Nonfatal myocardial infarction | 2 | 1 | |
| Cardiovascular death | 2 | 9 | |
| Secondary end point | 9 | 16 | .14 |
| Worsening angina | 9 | 14 | |
| Congestive heart failure | 0 | 2 | |
| Noncardiovascular death | 2 | 2 | |
| All events | 23 | 40 | .02 |
* P values were calculated by the log-rank tests from time to event. |
Figure 1.
Kaplan-Meier estimates of cardiovascular events and all events in the candesartan group and the control group.
Secondary end points developed in 9 patients in the candesartan group (9 cases of hospitalization for worsening angina) and in 16 patients in the control group (14 cases of hospitalization for worsening angina and 2 cases of hospitalization for heart failure). The frequencies of secondary end points did not differ significantly between the 2 groups (Figure 1, B). There were 2 cases of death from noncardiovascular causes in each group. A combination of primary end point, secondary end point, and noncardiovascular death showed significantly fewer events in the candesartan group than in the control group (P = 0.02) (Figure 1, C).
Treatment with candesartan reduced primary end point risk (5.9% compared with 12.3% in the control group; relative risk, 0.47; 95% CI, 0.24 to 0.93; P = .03). The relative risk of the secondary end point in the candesartan group was 0.55 (4.4% compared with 7.9% in the control group), but it did not reach significance (95% CI, 0.24 to 1.23; P = .14). The incidence of all events was significantly lower in the candesartan group than in the control group (11.3% vs 19.7%; relative risk, 0.55; 95% CI, 0.33 to 0.92; P = .02) (Figure 2).
Figure 2.
Beneficial effects of candesartan on cardiovascular events and all events.
Use of other drugs
To further analyze the effects of candesartan on all events in this study, we assigned the patients into subgroups according to the concomitant therapy. In patients treated with ACE inhibitors, treatment with candesartan did not result in a significant additional reduction in total cardiac events (14.0% vs 15.5% in the control group), whereas candesartan had a significantly beneficial effect among patients not receiving ACE inhibitors (10.6% vs 21.4% in the control, P = .01). Candesartan also had a statistically significant effect among patients not receiving β-blockers (12.6% vs 21.7% in the control, P = .03). However, although the difference did not reach the statistical significance because of the small number of subjects, the effects of candesartan were essentially the same for each subgroup according to the different drug administration status (Table IV).
Table IV. Interaction with other medications on all events
| Medication | Candesartan group (n = 203) | Control group (n = 203) | P* |
|---|---|---|---|
| ACE inhibitors (%) | 6/43 (14.0) | 9/58 (15.5) | .83 |
| No ACE inhibitors (%) | 17/160 (10.6) | 31/145 (21.4) | .01 |
| β-Blockers (%) | 1/29 (3.4) | 2/28 (7.1) | .61 |
| No β-blockers (%) | 22/174 (12.6) | 38/175 (21.7) | .03 |
| Statins (%) | 7/75 (9.3) | 12/65 (18.5) | .14 |
| No statins (%) | 16/128 (12.5) | 28/138 (20.3) | .10 |
| Aspirin (%) | 14/138 (10.1) | 26/136 (19.1) | .04 |
| No aspirin (%) | 9/65 (13.8) | 14/67 (20.9) | .36 |
* χ2 Test or Fisher's exact test. |
Discussion
This is the first study to demonstrate that ARB candesartan effectively reduces cardiovascular events in patients with CAD, even at a relatively low dose that did not affect BP. The present study targeted patients with CAD who had a history of coronary intervention.
Although these patients are almost asymptomatic and in a stable clinical condition, they are considered to be at high risk for recurrence of cardiovascular events.
Low-dose ARB
In the current study, even though candesartan was given at a low dose (4 mg/d), which produced no effect on BP at 1 and 2 years after the start of treatment according to office values, inhibition of cardiac events began to be noticed relatively soon after the start of treatment, and over the course of the study, we noted an increasing difference between the candesartan group and the control group in this regard. Thus, our study clearly showed that the angiotensin II–blocking effects of candesartan were due to vasoprotective action independent of any reduction in BP. The HOPE study, using ACE blockers, also showed only modest BP-lowering,7 indicating that the reduction in cardiovascular events associated with the inhibition of the renin-angiotensin system seems to be by a mechanism other than reduction of BP.
The current study used a fixed low dose of candesartan. Only 9 patients (4%) were intolerant of candesartan; of the remaining study population, mean BP levels were unchanged after the start of treatment. This suggests that secondary prevention with a low dose of candesartan is applicable in many patients with CAD regardless of BP levels.
Mechanisms
After 1 and 2 years of candesartan treatment, no significant changes were noted in lipid profile (total cholesterol, HDL cholesterol, LDL cholesterol or triglycerides), fasting serum glucose, HbA1c, or insulin level. Also, no significant differences in these parameters were noted between the candesartan group and the control group. The benefits obtained from candesartan treatment thus appeared not to be associated with these known cardiovascular risk factors. In recent years, there has also been considerable focus on CRP as a factor in risk assessment for patients with CAD10; our study showed no effects of candesartan on CRP.
These findings suggest that ARBs provide an organ-preserving action that is not mediated by BP reduction or improvement in other cardiovascular risk factors. It has been assumed that the prevention of cardiovascular events by the ACE inhibitors used to date may be due to increases in NO and prostacyclin levels resulting from elevated bradykinin concentrations.1 The ARB used in the current study provided cardiac event–inhibiting effects equivalent to those obtained in earlier clinical trials of ACE inhibitors.2, 3, 4, 5, 6 Cardiovascular-event–inhibiting effects specific to angiotensin II receptor antagonism may include (1) improvement of vascular endothelial function, (2) inhibition of vasoconstriction, and (3) stabilization of vulnerable plaques. Further research on the mechanisms of benefit from ARBs is required.
Concomitant drugs
According to the analysis of the subgroup with the use of other concomitant drugs, the cardiovascular-event–inhibiting effects of candesartan were also significant in patients receiving conventional drugs. The HOPE study7 showed similar positive findings with regard to the cardiovascular-event–inhibiting effects of ACE inhibitors in patients receiving conventional agents for secondary prevention (therapy with antiplatelet agents, statins or β-blockers). These findings suggest that inhibition of the renin-angiotensin system is important in the inhibition of cardiovascular events independent of the effects of other drugs. The current study showed clearly for the first time the additional benefits of ARBs in patients with CAD.
The beneficial effects of candesartan were noted only in the group without ACE inhibitors or β-blockers. The additional benefits of ARBs in patients under treatment with ACE inhibitors have been reported from a clinical trial, namely the Valsartan in Heart Failure Trial (Val-HeFT) study.11 In that study, the subjects were patients with heart failure who were treated with a different ARB (valsartan); patients already under treatment with ACE inhibitors showed greater improvement in cardiovascular outcome when treated concomitantly with valsartan. These findings indicate the importance of blocking the renin-angiotensin system to reduce mortality and morbidity in patients with cardiovascular disease. However, the current study did not show the efficacy of combination therapy with ARBs and ACE inhibitors.
Study limitations
This study was limited in that no placebo was used for the control group. This is a single-center study that is limited by the relatively small sample size, no placebo, and unblinded design. However, one advantage of implementing the trial in this locality and at this institution was that almost all of the patients who had CAD events came to our hospital. This means that full follow-up data obtained by using identical diagnostic criteria were obtained for each of the enrolled patients. Also, at revascularization, it was possible to investigate in detail any changes in coronary artery lesions. Placebo-controlled studies enrolling more patients will be required to confirm the results obtained in this study.
In conclusion, additional ARB therapy with relatively low-dose candesartan inhibits cardiovascular events in high-risk patients with CAD. These findings indicate the importance of inhibition of angiotensin II independent of conventional cardiovascular risk factors to prevent cardiovascular events.
References
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PII: S0002-8703(03)00443-5
doi:10.1016/S0002-8703(03)00443-5
© 2003 Mosby, Inc. All rights reserved.
