| This
is an analysis of data from the major trial of carvedilol in heart
failure. There was no difference in clinical endpoints, withdrawals,
or adverse event rates in patients who received either high, intermediate
or low doses of drugs that interfere with the renin-angiotensin system.
This shows that degree interference does not alter the response to
beta-blockade.
Physicians frequently prescribe beta-blockers for patients with
heart failure who are receiving agents that inhibit the renin-angiotensin
system. These include angiotensin converting enzyme (ACE) inhibitors
and angiotensin receptor blockers (ARBs). It is not clear whether
a specific dose of these agents may somehow alter the response to
beta-blockade in chronic heart failure.
The recently completed CarvedilOl ProspEctive RaNdomIzed CUmulative
Survival (COPERNICUS) trial included 2,289 severe heart failure
patients randomized to carvedilol or placebo. Most of these patients
received either an ACE inhibitor or ARB. Investigators stopped this
trial early because a meaningful reduction in risk of death accrued
to the carvedilol arm.
To evaluate how drugs that interfere with the renin-angiotensin
system affect response to beta-blockade in heart failure, investigators
conducted an evaluation of COPERNICUS data. This analysis evaluates
specific safety and efficacy outcomes according to high, intermediate,
low or no dose of ACE inhibitors or ARBs.
Investigators defined high, intermediate and low dose groups based
on doses patients received in the trial.
| |
High dose
(n = 686)
|
Intermediate dose
(n = 855)
|
Low dose
(n = 673)
|
| Enalapril |
20-100
|
10-15
|
1.25-7.5
|
| Captopril |
75-400
|
27.5-62.5
|
6.25-25
|
| Lisinopril |
20-80
|
15
|
1.25-7.5
|
| Perindopril |
6-8
|
4
|
1-2
|
| Losartan |
75-200
|
50
|
6.25-25
|
| Ramipril |
7.5-40
|
5
|
0.06-2.5
|
| Quinapril |
40-80
|
15-20
|
5-10
|
| Fosinopril |
30-60
|
15-20
|
5-10
|
| Benazepril |
40-80
|
20-30
|
5-10
|
| Cilazapril |
7.5-75
|
5
|
0.5-2.5
|
| Trandolapril |
4
|
1-2
|
0.5
|
| Valsartan |
4
|
1-2
|
0.5
|
| Irbesartan |
300
|
150
|
75
|
| Candesartan |
16-150
|
8
|
<8
|
Carvedilol to placebo hazard ratios suggested no influence of ACE
inhibitor or ARB on several clinical endpoints. Major clinical event
risk declined to a similar degree regardless of high, intermediate,
or low dose. No differences were statistically significant.
Risk of Outcome Variables (Hazard Ratio), by Dose Level of ACE Inhibitor
or ARB
| |
High dose
(n = 686)
|
Intermediate
dose
(n = 855)
|
Low dose
(n = 673)
|
No dose
(n = 65)
|
| All cause mortality
|
0.70
|
0.65
|
0.63
|
0.51
|
| Death
or any hospitalization |
0.76
|
0.81
|
0.75
|
0.68
|
| Death
or cardiovascular hospitalization |
0.67
|
0.76
|
0.78
|
0.70
|
| Death or HFHospitalization
|
0.69
|
0.68
|
0.72
|
0.77
|
Treatment was well tolerated in all 4 of the subgroups. Permanent
withdrawal rates were lower for carvedilol vs. placebo at high,
intermediate and low doses of ACE inhibitor or ARB.
Furthermore, frequency of adverse events did not vary among the
high, intermediate and low dose groups. Serious adverse event rates
ranged from 37.0% to 42.5% for carvedilol and 43.8% to 47.9% for
placebo.
This new data suggests that patients do not need to be receiving
a high dose of a drug that inhibits the renin-angiotensin system
before they receive carvedilol.
Furthermore, carvedilol prolongs life. Therefore, patients on low
doses of an agent that interferes with the renin-angiotensin system
should start on carvedilol rather than receive an uptitrated dose
of ACE inhibitor or ARB.
|
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