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J Am Coll Cardiol, 2004; 44:159-164, doi:10.1016/j.jacc.2004.03.056 © 2004 by the American College of Cardiology Foundation |
* Research Center, Montreal Heart Institute, Montreal, Quebec, Canada
Institute for Effectiveness Research, Bridgewater, New Jersey, USA
Manuscript received January 8, 2004; revised manuscript received March 17, 2004, accepted March 22, 2004.
* Reprint requests and correspondence: Dr. Jean-Claude Tardif, Montreal Heart Institute, 5000 Belanger Street, Montreal, Quebec, Canada H1T 1C8.
jean-claude.tardif{at}icm-mhi.org
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Abstract |
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BACKGROUND: Atrial fibrillation is the most common significant cardiac arrhythmia, and angiotensin II has been implicated in its pathophysiology.
METHODS: This was a retrospective, longitudinal cohort study from a database of 8 million people in the U.S. Patients age 
18 years with hypertension were eligible if they filled a prescription for either an ACEI or a CCB between January 1995 and June 1999. The use of all other antihypertensive medications was permitted. Patient chronic disease burden was assessed using a modified Charlson index. Patients were matched on a propensity score generated from a logistic regression model. A survival analysis approach was used to compare the incidence of AF between groups. The final cohorts were evaluated until June 2002, and the average follow-up was 4.5 years.
RESULTS: After cohort matching, 10,926 patients were included in the analysis and divided equally into the ACEI and CCB groups. Mean patient age was 65 years. The adjusted hazards ratio (95% confidence interval [CI]) in the ACEI versus CCB groups for the entire follow-up period was 0.85 (95% CI: 0.74 to 0.97) for new-onset AF, and the adjusted incidence ratio for AF-related hospitalizations was 0.74 (95% CI: 0.62 to 0.89).
CONCLUSIONS: Angiotensin-converting enzyme inhibition was associated with a reduced incidence of AF for patients with hypertension in a usual care setting. These results need to be confirmed in a large-scale randomized clinical trial.
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Hypertension affects approximately 20% of the adult population worldwide (or approximately 700 million people). The prevalence of this condition significantly increases with age, and it is estimated that up to 40% of people over the age of 60 have hypertension. This finding has particular importance in light of aging populations. Hypertension is associated with significant morbidity and mortality mainly from cardiovascular diseases and especially strokes (6). Optimal medical therapy for patients diagnosed with hypertension remains controversial. Because experimental and early clinical studies have suggested that inhibition of the renin-angiotensin system might have a role in preventing AF (7–10), angiotensin-converting enzyme inhibitors (ACEI) could be associated with additional clinical benefits as compared with other antihypertensive drug classes. Therefore, we assessed the impact of treatment with ACEI on the occurrence of AF in a large cohort of hypertensive patients. We used calcium-channel blockers (CCB) as the blood pressure lowering comparator in this study because they have been suggested to have favorable effects on atrial electrical remodeling and AF and because they represent the most frequently prescribed antihypertensive drug class after ACEI (11,12).
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Methods |
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18 years of age were eligible if they filled a prescription for either an ACEI or a long-acting CCB between January 1, 1995, and June 30, 1999 (the "index prescription"). Patients were also required to have at least one diagnosis of hypertension from one or more medical visits during the time period six months before and subsequent to the index prescription. Patients were required to be continuously medical and pharmacy benefit-eligible six months before the index prescription and during the entire study follow-up period. In addition, at least six months of index drug exposure during the study follow-up period was required. Furthermore, any eligible patients who had a prescription of any antihypertensive agent before the index prescription were taken out of the study. Any eligible ACEI patients who used CCB or CCB patients who used ACEI during the study follow-up period were excluded. However, use of other antihypertensive medications subsequent to the index prescription was permitted, and was evaluated for both comparison groups. The final cohorts in the study were evaluated until June 30, 2002, unless patients either deceased or lost medical or pharmacy eligibility (these patients were censored at the onset of benefit termination or date of death). Patient chronic disease burden was assessed using a modified Charlson index (13). The Charlson index utilized the presence of the International Classification of Diseases-Ninth Revision diagnosis codes for encounters during the six-month period before the index prescription to identify the presence of 17 chronic diseases, including myocardial infarction (MI), congestive heart failure (CHF), diabetes, peripheral vascular disease, dementia, cancer, and others. Each condition was assigned a weight from 1 to 6, and they were summed to derive an overall composite index for each patient that represents the patient's total chronic disease burden.
The medication possession ratio was used as a proxy of length of index medication exposure during the follow-up period. It was defined as the total days' supply of index medication over the study duration divided by the total follow-up time on each patient and multiplied by 100.
Propensity scoring was used to minimize potential baseline differences that could bias final outcome measurements, because patient demographic characteristics and pre-existing medical conditions may have influenced a physician's choice of antihypertensive therapy. Logistic regression was used to create propensity scores and to match cohorts between the comparison groups. The propensity score translates to the conditional probability of receiving a treatment given pre-treatment characteristics. The index medication was modeled as the dependent variable in the logistic regression while adjusting for significant independent variables. These factors were identified by clinical rationale and a stepwise model selection process. They included age, gender, prior diagnosis of CHF, coronary heart disease (CHD), renal disease, stroke, acute MI, angina, complicated hypertension, AF, hyperlipidemia, diabetes, and Charlson index. Clinically valid interactions of medical conditions were also adjusted in the model. Patients from each comparison group were matched based on a minimum difference in propensity scores generated from the final logistic regression model, with the difference not exceeding 0.01.
Outcomes. The purpose of the study was to compare long-term occurrence of AF between patients on ACEI versus those on CCB. The comparison of ACEI and CCB patients that were matched based on the propensity scoring methodology outlined above is presented.
The main outcome for this study was the occurrence of AF during follow-up in two different ways: new-onset AF condition and AF-related hospitalizations. The presence of a new-onset AF condition was evaluated and defined as any new diagnosis of AF during follow-up. The time elapsed between the index prescription and the first onset of newly occurring diagnosis of AF was also assessed. Inpatient care incidence was measured by the presence of any hospitalization related to a diagnosis of AF. Study outcome was assessed at three time periods: three years after index prescription, five years after index prescription, and for the entire follow-up period.
Statistical analysis. A survival analysis approach was used to compare the time elapsed from index prescription to newly diagnosed AF between patients on ACEI versus on CCB. The analysis of newly diagnosed AF was performed in patients without a prior history of AF. The survival analyses were conducted in two ways: using Kaplan-Meier survival curves and using proportional hazards regression models.
The incidence rates per 1,000 person-years were calculated for AF. Poisson regression models were used to estimate the incidence ratio between the comparison groups and the corresponding 95% confidence interval for AF-related hospitalizations. We fitted the models using the Genmod procedure (SAS version 8.2, SAS Institute, Cary, North Carolina ). The covariates used in the final Poisson regression and the proportional hazards regression were based on clinical rationale and a stepwise statistical model selection process. They included gender, age, medication possession ratio, Charlson index, and the presence (yes/no) of pre-existing conditions including CHF, CHD, renal disease, stroke, hyperlipidemia, and diabetes. Only significant covariates at p < 0.10 level remained in the final model. SAS version 8.2 (SAS Institute) was used for all statistical analyses.
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Results |
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Main outcome: AF.
Incidence rate of new-onset AF
The incidence rate of new-onset AF during the entire study follow-up period was less in the ACEI group as compared with the CCB group (17.9 vs. 18.9 per 1,000 patient-years). The hazard ratio for patients treated with an ACEI was 0.85 (95% confidence interval [CI]: 0.74 to 0.97) (Table 2).
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Discussion |
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Atrial fibrillation has been described as one of two emerging cardiovascular epidemics at the turn of the century (14). Indeed, hospitalizations for AF from 1985 through 1999 increased from 154,086 to 376,487 for a first-listed diagnosis and from 787,750 to 2,283,673 for any diagnosis in the U.S. In addition, the prevalence of this age-related arrhythmia is expected to further increase with the aging population (1,14). Therefore, any therapy that reduces AF in high-risk populations will likely have a significant impact on resource allocation.
Hypertension has been shown to be the most prevalent, independent, and potentially modifiable risk factor for AF (3,4). Of note, the absolute incidence of AF at six and seven years in our study was somewhat higher than expected, although very limited data are available from previous studies of hypertensive patients (4). Myocardial adaptation to chronically elevated blood pressure has been very well documented and includes left ventricular (LV) hypertrophy, left atrial (LA) enlargement, and modifications of atrial mechanical function. These compensatory changes secondary to hypertension may promote atrial arrhythmias. Left ventricular mass has been identified as an independent predictor of AF in hypertensive patients (15,16). In the Framingham cohort, the risk of developing AF increased by 28% for each 4-mm increase in LV thickness (4). Left atrial enlargement is a known predisposing factor for the development of AF. Numerous cohort studies have reported a significant correlation between LA size and AF (3,4,15). Left atrial enlargement occurs frequently in hypertensive patients and may precede LV hypertrophy in some cases (17). Numerous studies have reported that the magnitude of LA enlargement correlated with the severity of hypertension (18,19). Furthermore, atrial stretch has been shown to shorten the effective refractory period and lengthen intraatrial conduction time (20,21). These findings support the hypothesis that hypertension predisposes to AF through atrial enlargement and electrophysiologic remodeling.
There is evidence suggesting a role for the renin-angiotensin system in the pathophysiology of AF. Angiotensin II has been shown to increase atrial pressure and stretch, which are associated with electrophysiologic changes described above, thereby promoting AF (22). Angiotensin II is also a potent promoter of fibrosis, leading to cardiac myoblast proliferation and reduced collagenase activity (23–25). Atrial fibrosis is a frequent finding in patients with AF, which may explain intraatrial conduction disturbances and the persistent susceptibility for AF (26). Increased ACE expression and alterations in the angiotensin II receptor expression have been observed in the atria of AF patients. Furthermore, an ACEI-dependent increase in levels of activated extracellular signal-regulated kinases Erk1/Erk2 and Erk-activating kinases MEK1/2 was found in patients with AF by examining atrial tissue samples obtained during open-heart surgery (27,28). There is also evidence suggesting that ACE polymorphism also plays a role in predisposing to AF (29). The ACEI enalapril has been shown to decrease mitogen-activated protein kinase activation, atrial fibrosis, and AF promotion in a dog model of heart failure (30). Enalapril was also shown to decrease atrial structural and functional remodeling in the same model (7). In addition, the angiotensin II receptor antagonist candesartan was reported to prevent the promotion of AF by suppressing the development of structural remodeling (interstitial fibrosis) in a dog rapid pacing model (31). Early clinical trials evaluating the effect of ACEI in patients with reduced LV function secondary to acute MI and angiotensin receptor antagonists in patients with AF who underwent cardioversion have reported significant reductions in the incidence and recurrence of atrial arrhythmias, respectively (8,9). More recently, treatment with enalapril was reported to reduce the recurrence of AF after cardioversion in patients with chronic AF treated with amiodarone (32,33). Furthermore, our group has published results strongly suggesting a beneficial effect of enalapril on AF development in patients with chronic LV dysfunction (10).
In addition to its role in atrial structural remodeling, angiotensin II has also been shown to modify electrophysiologic remodeling. The atrial effective refractory period has been shown to shorten in chronic AF (34). Inhibition of endogenous angiotensin II (either through ACEI or angiotensin II type 1 receptor antagonism) has been shown to prevent atrial effective refractory period shortening and loss of atrial effective refractory period rate adaptation during rapid atrial pacing (22). These results taken together provide two plausible explanations for the preventive effects of ACEI against AF, namely via prevention of structural and electrophysiologic remodeling.
Clinical implications. Although a beneficial effect of ACEI on AF has been convincingly demonstrated in patients with LV systolic dysfunction, hypertension is a much more prevalent condition, and extending the clinical benefits of ACEI to this patient population has important clinical implications. Our results suggest that treatment of hypertension with ACEI rather than other antihypertensive medications may significantly decrease the occurrence of AF.
Study limitations. Treatment allocation was not randomized, and this large-scale longitudinal cohort study is, therefore, subject to potential confounders like treatment selection bias. However, propensity scoring was used to minimize or adjust for as many of these factors as possible.
Conclusions. Angiotensin-converting enzyme inhibition was associated with a reduced incidence of AF for patients with hypertension in a managed care setting. These results need to be confirmed in a large-scale randomized clinical trial.
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Footnotes |
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