Table 6.
Effect of ACEI/ARB combination in cardiovascular diseases
| Trial acronym (year of publication) | Population | Patient no. | Comparators | Mean follow-up duration | Major efficacy end points | Major adverse events (in particular hypotension, renal impairment and hyperkalaemia) |
|---|---|---|---|---|---|---|
| Hypertension | ||||||
| ONTARGET (2008) Yusuf et al., 2008c | Established atherosclerotic diseases or DM with end-organ damage | 25 620 | Ramipril (10 mg daily) versus telmisartan (80 mg daily) versus combination | 56 months | Combination therapy was associated with trend in greater reduction in mean blood pressure but no difference in primary outcome (death from cardiovascular causes, myocardial infarction, stroke or hospitalization for heart failure) | Combination therapy was associated with greater discontinuation of study medication due to: (i) hypotensive symptoms (ramipril 1.7% vs. telmisartan 2.7% vs. combination 4.8%, P < 0.001); (ii) renal impairment (ramipril 0.7% vs. talmisartan 0.8% vs. combination 1.1%. P < 0.001); and (iii) hyperkalaemia (not mentioned) |
| Myocardial infarction | ||||||
| VALIANT (2003) Pfeffer et al., 2003 | AMI with heart failure and/or left ventricular systolic dysfunction | 14 793 | Valsartan (20–160 mg twice daily) versus captopril (6.25–50 mg thrice daily) versus both (valsartan 20–80 mg twice daily + captopril 6.25–50 mg thrice daily) | 24.7 months | Combination therapy did not improve mortality | Adverse events resulting in dose reduction: (i) hypotension (valsartan 15.1%* vs. captopril 11.9% vs. combination 18.2%*); (ii) renal causes (valsartan 4.9%* vs. captopril 3.0% vs. combination 4.8%*); and (iii) hyperkalemia (valsartan 1.3% vs. captopril 0.9% vs. combination 1.2%) *P < 0.05 |
| ONTARGET (2008) Yusuf et al., 2008c | Established atherosclerotic diseases or DM with end-organ damage | 25 620 | Ramipril (10 mg daily) versus telmisartan (80 mg daily) versus combination | 56 months | The incidence of cardiovascular events were similar among the groups (ramipril group 16.5% vs. telmisartan group 16.7% [P = 0.83] versus combination group 16.3% [P = 0.38]) | Combination therapy was associated with trend in greater reduction in mean blood pressure, but no difference in primary outcome (death from cardiovascular causes, myocardial infarction, stroke or hospitalization for heart failure) |
| Heart failure | ||||||
| Val-HeFT (2001) Cohn et al., 2001 | NYHA class II–IV; receiving standard therapy | 5010 | Valsartan (160 mg twice daily) + ACEI | 23 months | Combination therapy reduced the incidence of the combined endpoints by 13.2% (P = 0.009) driven by reduction in heart failure hospitalization (13.8% with valsartan vs. 18.2% with placebo, P < 0.001) | Adverse events leading to discontinuation of study medication: (i) hypotension (valsartan 1.3% vs. placebo 0.8%, P = 0.124); (ii) renal impairment (valsartan 1.1% vs. placebo 0.2%, P < 0.001); mean change of serum potassium level (0.12 mmol·L−1with candesartan vs. 0.07 decrease with placebo, P < 0.001) |
| CHARM-added (2003) McMurray et al., 2003 | NYHA class II–IV; being treated with ACEI | 2548 | Candesartan (32 mg daily) + ACEI or placebo | 41 months | Candesartan + ACEI was associated with lower composite end points, defined as cardiovascular death or unplanned admission to hospital for the management of worsening congestive heart failure (38 vs. 42%, P = 0.011) | Adverse events leading to drug discontinuation: (i) (i) hypotension (candesartan 4·5% vs. placebo 3·1%, P = 0·079); (ii) increase in creatinine (candesartan 7·8% vs. placebo 4·1%, P = 0·0001); and (iii) hyperkalaemia (candesartan 3·4% vs. placebo 0·7%, P < 0.0001) |
| Stroke | ||||||
| ONTARGET (2008) Yusuf et al., 2008c | Established atherosclerotic diseases or DM with end-organ damage | 25 620 | Ramipril (10 mg daily) versus telmisartan (80 mg daily) versus combination | 56 months | Combination therapy did not reduce the risk of stroke or transient ischaemic attacks | As above |
| Diabetic nephropathy | ||||||
| Jennings et al., 2007 | DM nephropathy | 315 | ACEI/ARB | Not applicable | ACEI/ARB combination was associated with reduced proteinuria, but also worsening of renal renal function | ACEI/ARB combination was associated with a mean decrease in GFR of 3.87 mL/min (P = 0.03). Serum potassium was increased by a mean of 0.2 mmol/l (95% CI 0.08–0.32; P < 0.01) with combination therapy |
| ONTARGET (2008) Yusuf et al., 2008c | Established atherosclerotic diseases or DM with end-organ damage | 25 620 | Ramipril (10 mg daily) versus telmisartan (80 mg daily) versus combination | 56 months | Ramipril/telmisartan combination reduced proteinuria more than monotherapy, but was associated with worsened major renal outcomes | As above |