by Antoine T. Jenkins, PharmD, BCPS
Angiotensin II has been shown to play a role in the cardiac remodeling
that contributes to AF in both human and animal atrial models. It promotes
vasoconstriction, sodium and water retention and cardiac hypertrophy, and results
in structural changes due to fibroblast stimulation and increased fibrotic
tissue.
Thus, it seems logical that a RAS inhibitor would be useful in AF
prevention.
In addition to translational and mechanistic studies, post hoc analyses
involving RAS inhibitors performed on HF (SOLVD-enalapril, Val-HeFT-valsartan,
CHARM-candesartan) and MI trials (GISSI-3-lisinopril, TRACE-trandolapril) all
demonstrated a significant reduction in new-onset AF, and patients with left
ventricular systolic dysfunction (LVSD) derived the greatest benefit.
Several hypertension trials have examined the occurrence of new AF. For
example, secondary analysis of the LIFE study revealed that new-onset AF
occurred in 6.8% of patients treated with losartan (Cozaar, Merck) compared
with 10.1% of those randomized to atenolol (HR 0.67, 95% CI: 0.55-0.83;
P<.001). Furthermore, in the VALUE trial, the occurrence of new onset
AF (a prespecified secondary endpoint) in patients treated with valsartan
(Diovan, Novartis) was 3.67% compared with 4.34% in patients treated with
amlodipine (HR 0.84, 95% CI: 0.713-0.997; P=.045). Lastly, the recent
ONTARGET study, which evaluated telmisartan (Micardis, Boehringer Ingelheim),
ramipril or the combination in high-risk patients, assessed new-onset AF as a
secondary endpoint, and no difference was detected.
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Antoine T. Jenkins
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Several metaanalyses evaluated the use of RAS inhibitors for AF
prevention. Anand et al showed an 18% relative risk reduction in new-onset AF,
with patients who had HF deriving the greatest benefit. In this analysis, ACE
inhibitors (RR 0.75, 95% CI: 0.57-0.99) were more effective in preventing AF
than ARBs (RR 0.81, 95% CI: 0.62-1.06). Healey et al also performed a
metaanalysis with similar results, showing that RAS inhibitors reduced the risk
of AF by 28% (95% CI: 15-40%, P=.0002); patients with impaired LV
function benefited most. However, no difference was seen between ACE inhibitors
(RRR 28%, 95% CI: 0.07-0.44, P=.01) and ARBs (RRR 29%, 95% CI:
0.16-0.40, P=.0002).
Prospective studies have also yielded positive outcomes. Ozaydin et al
conducted a study (n=128) examining the use of an ACE inhibitor alone
[lisinopril, n=80; cilazapril, n=7; ramipril and quinapril, n=4; perindopril
(Aceon, Solvay), n=2; and fosinopril, n=1] and in combination with candesartan
in postoperative cardiac patients. There was a 33% occurrence of AF in the
control group, compared with the ACE inhibitor group (12%, P=.02) or the
combination group (10%, P=.01).
GISSI-AF, the largest trial to date to prospectively assess the effect
of RAS inhibition on AF prevention, was recently published in the New
England Journal of Medicine. More than 1,400 high-risk patients with a
prior history of AF were randomized to either valsartan or placebo. Primary
outcomes were time to first recurrence of AF and the proportion of patients who
had more than one recurrence over one year. After a one-year follow-up,
valsartan did not show a reduction in recurrent AF (51.4% in valsartan group
vs. 52.1% in the control group, and there was no difference in the time to
first occurrence of AF, HR 0.97, 96% CI: 0.83-1.14; P=.83). Also, more
than one AF recurrence was noted in 26.9% of valsartan-treated patients
compared with 27.9% of the control patients (OR 0.89, 99% CI: 0.64-1.23;
P=.34). As observed previously, although not statistically significant,
in patients with HF, LVSD, or both, there was a trend toward benefit in the
valsartan group (HR 0.81, 95% CI: 0.48-1.35; P=.41).
Although RAS blocking agents are routinely used in the management of
many CV conditions including HF and ACS, current data do not support their use
for the prevention of AF. The precise mechanism behind how RAS inhibitors can
reduce the occurrence of AF is unclear, although it does appear that patients
with impaired LVSD obtain better outcomes likely resulting from attenuation of
cardiac remodeling. The robust GISSI-AF investigation failed to illustrate an
overall benefit with valsartan. However, there are ongoing studies in high-risk
populations, including those with diabetes and those who have undergone cardiac
surgery that will further clarify the role of RAS inhibition in AF prevention.
Antoine Jenkins, PharmD, BCPS, is a Clinical Pharmacist, OSF St.
Francis Medical Center, Peoria, Ill.
Rhonda Cooper-DeHoff, PharmD, MS, Associate Professor, University of
Florida College of Pharmacy, Gainesville, is Cardiology Today’s regular
Pharmacology Consult columnist and a member of the CHD and Prevention section
of Cardiology Today’s editorial board.
For more information:
- Am Heart J. 2006;152:217-22.
- Am J Cardiol. 2006;97:921-925.
- Circulation. 1998;98:2765-73.
- Circulation. 2006;114:e257-e354.
- Current Opinion in Cardiology. 2005;20:31-37.
- Int J Cardiol. 2008;127:362-7.
- J Am Coll Cardiol. 2005;45:1832-9.
- J Am Coll Cardiol. 2005;45(5):712-19.
- J Hypertens. 2008;26:403-411.
- N Engl J Med. 2008;358:1547-59.
- N Engl J Med. 2009;360:1606-17.
- Pharmacotherapy. 2009;29(1):31-48.
