Ccs

The Chinese Cardiac Study (CCS) (101) assessed the efficacy of early captopril use on mortality and mortality after AMI. A total of 14,962 patients in China up to 36 h (mean 16.6 h) after the onset of suspected AMI, without clear contraindications, were randomized to either 4 wk of oral captopril (6.25 mg initial dose, 12.5 mg 2 h later, and then 12.5 mg 3X daily) or placebo. Although no significant reduction in the overall 4-wk mortality was found, the incidence of heart failure was significantly reduced in the

Fig. 7. Six-week survival curves for lisinopril-treated patients and controls. The curves separated early (d 0 to 1) and continued to diverge throughout the next 6 wk, supporting the argument for the early institution of therapy with ACE inhibitors in selected patients. Patients allocated lisinopril had an 11% lower risk of death than the controls (6.3 vs 7.1%). Data from ref. 9.

Fig. 7. Six-week survival curves for lisinopril-treated patients and controls. The curves separated early (d 0 to 1) and continued to diverge throughout the next 6 wk, supporting the argument for the early institution of therapy with ACE inhibitors in selected patients. Patients allocated lisinopril had an 11% lower risk of death than the controls (6.3 vs 7.1%). Data from ref. 9.

captopril group (17 vs 18.7%; p = 0.01). Also, the anterior wall infarction of captopril treated group was found to have a lower mortality (8.6 vs 10.2%, p = 0.02). Thus, early captopril use in AMI was found to prevent about 6 deaths per 1000 patients treated and about 15 deaths due to heart failure per 1000 patients in the first 4 wk with greater benefits. In the subgroup of patients with anterior MI, ACE inhibitor therapy prevented 16 deaths per 1000 patients with no benefit for the inferior infarction group. Furthermore, after analyzing patient subgroups by heart rate at presentation, there were no benefits of ACE inhibition when heart rate is slow or heart block and hypotension are present. This is believed to be due to the parasympathetic effect of ACE inhibition.

These studies have particular clinical relevance because they address the patient during the very acute phase of the infarct, prior to the time when any screening tests or evaluations for LV function could be done. Indeed, their strength is generalizability and ease of application. This strategy led to a significant benefit of 5 lives saved per 1000 patients treated per year, and extended the use of ACE inhibitors to the majority of post-MI patients.

Fig. 8. Effects on mortality during the first 5 wk; there were 7.19% deaths in the captopril group compared with 7.69% deaths in the placebo group. Relative reduction in mortality for captopril-treated patients was 7% absolute risk reduction was 0.5% (95% CI: 0.13-1%; p = 0.02) Data from ref. 100.

The time course of benefit becomes particularly relevant in encouraging the early use of ACE inhibition in patients with MI. In the ISIS-4 and GISSI-3 studies, encompassing 77,444 patients, 219 lives were saved by 4-6 wk of ACE inhibition. Latini and coworkers (102) analyzed the time course of the total survival difference between active therapy and control. In both studies, patients were treated within 24 h of presentation. By the end of the first d of therapy, there were already 65 fewer deaths in the treatment arm than in the control group, so that 29.7% of the total difference between groups was already present at the end of d 1. By the end of d 7, the difference between groups had increased to 145 lives, or 66.2% of the total number of lives destined to be saved. The sum total benefit of the remaining weeks of therapy accounted for a minority (33.8%) of lives saved. One must consider whether attenuation of LV remodeling accounts for early survival benefit, or whether any convincing explanation of the early benefit of ACE inhibitor therapy must invoke an anti-ischemic mechanism. Pertinent to the findings of Vaughan and coworkers (52) described before, the association of activation of the renin-angiotensin system with greater risk of acute ischemic events has clinical significance. Specifically, if inhibition of the renin-angiotensin system prevents MI and other ischemia through alterations in the fibrinolytic system, then the early benefit of ACE inhibition observed in GISSI-3 and ISIS-4 could be more easily explained.

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