Journal of the American College of Cardiology Vol. 45, No. 5, 2005 2005 by the American College of Cardiology Foundation ISSN 0735-1097/05/$30.00 Published by Elsevier Inc. doi:10.1016/j.jacc.2004.06.080 Cardiovascular Morbidity and Mortality in Hyertensive Patients With a History of Atrial Fibrillation The Losartan Intervention for End Point Reduction in Hyertension (LIFE) Study Kristian Wachtell, MD, PHD,* Björn Hornestam, MD, PHD, Mika Lehto, MD, David J. Slotwiner, MD, FACC, Eva Gerdts, MD, PHD, Michael H. Olsen, MD, PHD,* Peter Auru, MD, Björn Dahlöf, MD, PHD, FACC, Hans Ibsen, MD,* Stevo Julius, MD, FACC,# Sverre E. Kjeldsen, MD, PHD, FACC,** Lars H. Lindholm, MD, Markku S. Nieminen, MD, Jens Rokkedal, MD,* Richard B. Devereux, MD, FACC Glostru, Denmark; New York, New York; Göteborg and Umeå, Sweden; Helsinki, Finland; Bergen and Oslo, Norway; West Point, Pennsylvania; and Ann Arbor, Michigan OBJECTIVES BACKGROUND METHODS RESULTS CONCLUSIONS We assessed the imact of antihyertensive treatment in hyertensive atients with electrocardiograhic (ECG) left ventricular (LV) hyertrohy and a history of atrial fibrillation (AF). Otimal treatment of hyertensive atients with AF to reduce the risk of cardiovascular morbidity and mortality remains unclear. As art of the Losartan Intervention For End oint reduction in hyertension (LIFE) study, 342 hyertensive atients with AF and LV hyertrohy were assigned to losartan- or atenolol-based theray for 1,471 atient-years of follow-u. The rimary comosite end oint (cardiovascular mortality, stroke, and myocardial infarction) occurred in 36 atients in the losartan grou versus 67 in the atenolol grou (hazard ratio [HR] 0.58, 95% confidence interval [CI] 0.39 to 0.88, 0.009). Cardiovascular deaths occurred in 20 versus 38 atients in the losartan and atenolol grous, resectively (HR 0.58, 95% CI 0.33 to 0.99, 0.048). Stroke occurred in 18 versus 38 atients (HR 0.55, 95% CI 0.31 to 0.97, 0.039), and myocardial infarction in 11 versus 8 atients ( NS). Losartan-based treatment led to trends toward lower all-cause mortality (30 vs. 49, HR 0.67, 95% CI 0.42 to 1.06, 0.090) and fewer acemaker imlantations (5 vs. 15, 0.065), whereas hositalization for heart failure took lace in 15 versus 26 atients and sudden cardiac death in 9 versus 17, resectively (both NS). The benefit of losartan was greater in atients with AF than those with sinus rhythm for the rimary comosite end oint ( 0.019) and cardiovascular mortality ( 0.039). Losartan is more effective than atenolol-based theray in reducing the risk of the rimary comosite end oint of cardiovascular morbidity and mortality as well as stroke and cardiovascular death in hyertensive atients with ECG LV hyertrohy and AF. (J Am Coll Cardiol 2005; 45:705 11) 2005 by the American College of Cardiology Foundation Atrial fibrillation and flutter (AF) increase the risk of cardiovascular morbidity and mortality (1,2), and hyerten- See age 720 sive atients have u to a 42% increased risk of develoing AF (1,3). Because many hyertensive atients develo AF, the addition of AF to hyertension contributes to increased From the *Deartment of Medicine, Glostru University Hosital, Glostru, Denmark; Division of Cardiology, Weill Medical College of Cornell University, New York, New York; Deartment of Medicine, Sahlgrenska University Hosital/ Östra, Göteborg, Sweden; Deartment of Cardiology, Helsinki University Central Hosital, Helsinki, Finland; Deartment of Cardiology, Haukeland University Hosital, Bergen, Norway; Merck Research Laboratories, West Point, Pennsylvania; #Deartment of Medicine, University of Michigan, Ann Arbor, Michigan; **Deartment of Preventive Medicine, Umeå University Hosital, Umeå, Sweden; and the Deartment of Medicine, Ullevål University Hosital, Oslo, Norway. Drs. Wachtell, Gerdts, Olsen, Dahlöf, Ibsen, Kjeldsen, Nieminen, Rokkedal, and Devereux have received suort for research from Merck and Co., Inc. Drs. Wachtell, Olsen, Dahlöf, Ibsen, Julius, Kjeldsen, Lindholm, Nieminen, and Devereux have received occasional seaking and consulting honoraria from Merck and Co., Inc., and Dr. Auru was an emloyee of Merck and Co. Manuscrit received January 26, 2004; revised manuscrit received May 27, 2004, acceted June 9, 2004. rates of cardiovascular morbidity and mortality in hyertension. Traditionally, restoration of sinus rhythm by direct current conversion has been attemted in atients with AF (4), although this treatment remains controversial. A recent study showed that management of AF with a rhythmcontrol strategy offered no survival advantage over the rate-control strategy (5). Therefore, combined use of digoxin and either beta-blockers or calcium antagonists to treat hyertension and achieve rate control may be increasingly referred by clinicians (4). However, no data are available to determine whether traditional beta-blocker based theray or direct inhibition of the renin-angiotensin system reduces cardiovascular mortality and morbidity more in hyertensive atients with AF. As reviously described (6 8), the Losartan Intervention For End oint reduction in hyertension (LIFE) study rimary hyothesis was that selective angiotensin-ii tye 1 recetor blockade with losartan would be more effective than beta-blockade with atenolol in reducing cardiovascular morbidity and mortality in hyertensive atients with electrocardiograhic (ECG) left ventricular (LV) hyertrohy. Therefore, we analyzed the outcome in
706 Wachtell et al. JACC Vol. 45, No. 5, 2005 Treatment of LV Hyertrohy and AF March 1, 2005:705 11 Abbreviations and Acronyms AF atrial fibrillation CI confidence interval ECG electrocardiograhic HF heart failure HR hazard ratio LIFE Losartan Intervention For End oint reduction in hyertension study LV left ventricular MI myocardial infarction the subgrou of hyertensive atients with ECG LV hyertrohy (n 342) who had a history of AF or electrocardiograhically verified AF at the start of the LIFE study to evaluate the treatment effect of a secific angiotensin-ii recetor versus beta-blockade on cardiovascular morbidity and mortality in hyertensive atients with ECG LV hyertrohy. METHODS Study oulation. The LIFE study was a rosective, randomized, double-blind, arallel-grou study with a double-dummy technique. The rimary objective and main outcome, as well as the comlete study rotocol with study design, organization, clinical measures, end oint definitions, exclusion criteria, basis for choice of comarative agents, statistical considerations, and baseline characteristics, have been reviously ublished (6 8). Patients age 55 to 80 years, having reviously treated or untreated hyertension and ECG LV hyertrohy by either Cornell voltage-duration or Sokolow-Lyon voltage criteria (9), were randomized to initial theray with 50 mg/day losartan or atenolol after one to two weeks of lacebo if they had a sitting systolic blood ressure of 160 to 200 mm Hg and/or diastolic blood ressure of 95 to 115 mm Hg. In both grous, hydrochlorothiazide was added in the case of insufficient ressure lowering. Thereafter the study drug was increased to 100 mg/day and sulemented with additional antihyertensive theray in order to reach a target blood ressure of 140/90 mm Hg. Patients were enrolled from June 1995 to May 1997 and were followed for four years or longer. Of 342 LIFE study articiants (3.7% of 9,193) who had either electrocardiograhically documented AF or a history of AF (n 324) or atrial flutter (n 18) reorted by the investigator at baseline, 157 were randomized to losartan and 185 to atenolol. Centralized ECG reading confirmed that 135 atients (40%) had ersistent or ermanent AF documented by electrocardiograhy. The care of atients AF was left to the discretion of the hysician. Statistical analysis. All end oints were analyzed using the intention-to-treat aroach, all randomized atients were included in their randomized treatment grou, and all available follow-u data were included from randomization through the study termination date. Only end oints confirmed by the Endoint Committee were included in analyses. Patients with multile end oints were counted as having had an event in all relevant end oint analyses; however, only the first event in a secific category counted in any individual analysis. The difference between treatment grous with resect to clinical events was assessed by Cox regression models with the degree of LV hyertrohy (as measured by both Cornell voltage-duration roduct and Sokolow-Lyon voltage) and the Framingham risk score (10) at baseline and difference in blood ressure during treatment as covariates. This adjusted analysis was chosen a riori rimarily to account for any difference in key risk redictors at baseline; additional adjustments based on findings in the resent study are described. The risk reduction for losartan versus atenolol was calculated as: 100 (1 relative risk). Event rates over time are resented as Kalan-Meier curves: the numbers below the curves reresent the number of event-free atients remaining in follow-u at the corresonding time oint. Differences in baseline characteristics were assessed by Student t test and chi-square for categorical variables. Tests were erformed at two-sided 5% significance levels. For further details, see Dahlöf et al. (8). RESULTS History of AF versus sinus rhythm. Demograhic characteristics of atients with or without a history of AF at enrollment in the LIFE study are comared in Table 1. Heart rate was similar at baseline and during treatment in atients with a history of AF comared with atients in sinus rhythm ( NS). Patients with a history of AF had, comared with those without, higher rates of cardiovascular and all-cause mortality, fatal and non-fatal stroke, heart failure (HF), revascularization, and sudden cardiac death, but statistically similar rates of myocardial infarction (MI) and hositalization for angina ectoris (Table 2). Treatment of atients with a history of AF. Patients with a history of AF assigned to losartan- or atenolol-based treatment had comarable demograhic characteristics (Table 1). During the study medications were titrated similarly in the two treatment arms. At end oint or termination of follow-u 8.3% and 11.4% of losartan- and atenolol-treated atients, resectively, received 50 mg of study drug alone; 12.7% and 14.5%, resectively, received 50 mg of study drug lus hydrochlorothiazide or other medications; and 43% and 31%, resectively, received 100 mg of the study drug with or without hydrochlorothiazide or additional medications. Furthermore, hydrochlorothiazide was administered in 61% of study duration in losartan-treated and 52% of study duration in atenolol-treated atients ( NS). Patients with a history of AF had a similar high revalence of use of another antihyertensive theray (e.g., centrally acting and/or non-dihydroyridine calcium channel blocker) and received similar concomitant treatment with other rate-controlling, antiarrhythmic and liidlowering drugs during the study (Table 3). Most atients adhered to the treatment regimen, and crossover treatment occurred mainly in atients who discontinued study medication. Among atients originally assigned to losartan,
JACC Vol. 45, No. 5, 2005 March 1, 2005:705 11 Wachtell et al. Treatment of LV Hyertrohy and AF 707 Table 1. Characteristics of Losartan- and Atenolol-Treated Patients With Atrial Fibrillation Characteristic All Nonatrial Fibrillation (n 8,851) All History of AF* (n 342) Losartan (n 157) Atenolol (n 185) Demograhic and clinical Age (yrs) 66.8 7.0 70.3 6.4 69.9 6.7 70.7 6.2 Women, n (%) 4,815 (54.4) 148 (43.3) 64 (41.0) 84 (45.2) Ethnic origin, n (%) White 8,179 (96.2) 324 (94.7) ns 146 (93.6) 178 (95.7) Black 520 (5.9) 13 (3.8) 8 (5.1) 5 (2.7) Hisanic 98 (1.1) 2 (0.6) 0 2 (1.1) Asian 41 (0.5) 2 (0.6) 1 (0.6) 1 (0.5) Other 13 (0.1) 1 (0.3) 1 (0.6) 0 Blood ressure (mm Hg) 174/98 14/10 176/96 14/10 ns/ 177/97 14/10 175/96 14/10 Heart rate (beats/min) 74 11 75 14 75 14 76 14 Body mass index (kg/m 2 ) 28.0 4.8 27.4 4.6 27.1 4.6 27.6 4.6 Cornell voltage-duration roduct (mv ms) 2,820 1,033 3,051 1,392 2,968 1,392 3,120 1,393 Sokolow-Lyon (mv) 29.9 10.5 32.0 10.6 32.3 11.1 31.8 10.2 Framingham risk score 0.222 0.094 0.265 0.103 0.270 0.104 0.262 0.103 Current smokers, n (%) 1,450 (16.4) 49 (14.3) ns 20 (12.8) 29 (15.6) Current atrial fibrillation, n (%) 135 (39.5) 51 (32.5) 64 (34.6) Medical history Coronary heart disease, n (%) 1,162 (13.1) 882 (25.7) 44 (28.2) 44 (23.7) Cerebrovascular disease, n (%) 679 (7.7) 49 (14.3) 20 (12.8) 29 (15.6) Periheral vascular disease, n (%) 480 (5.4) 40 (11.7) 14 (9.0) 26 (14.0) Diabetes mellitus, n (%) 1,112 (12.6) 83 (24.3) 34 (21.8) 49 (26.3) Isolated systolic hyertension, n (%) 1,252 (14.3) 68 (20.3) 27 (17.6) 41 (22.5) Statistical significance: *comared with atients with vs. without AF; all NS comared to losartan; 0.001; 0.05; 0.01; systolic blood ressure 160 and diastolic ressure 90 mm Hg. 27.6% crossed over to beta-blockade, and among those originally assigned to atenolol, 34.9% crossed over to angiotensin-converting enzyme inhibition/angiotensin-ii recetor blockade by the study s end. Patients who discontinued losartan were no more likely to receive oen-label beta-blockade than atients who discontinued atenolol (27.6% vs. 31.7%, NS). Oen-label combination theray of beta-blocker and angiotensin-converting enzyme inhibition/angiotensin-ii recetor blockade during the study was seen in 14.6% and 21.6%, resectively, among losartan- and atenolol-assigned atients ( 0.123). Systolic, diastolic, and mean blood ressures were reduced substantially in both losartan- and atenolol-treated atients (Fig. 1). Average blood ressure at the last visit before a rimary end oint, or at the end of follow-u, was 145/81 and 147/79 mm Hg in the losartan and atenolol grous, resectively, showing reductions of 31/17 and 26/16 mm Hg. The average reduction in heart rate during the first 12 months of treatment was significantly greater in atenolol-treated atients (9.9 beats/min vs. 3.5 beats/min, 0.001), but very similar at study end (Fig. 2). There was a trend toward higher serum otassium during treatment in Table 2. End Points in Patients With and Without Atrial Fibrillation End Point Atrial Fibrillation (n 342) Nonatrial Fibrillation (n 8,851) Adjusted Hazard Ratio* Unadjusted Hazard Ratio Rate n (%) Rate n (%) 95% CI Value 95% CI Primary comosite end oint 70.0 103 30.1 23.5 993 11.2 2.23 1.81 2.74 0.001 2.95 2.4 3.62 0.001 Comonents 0.001 Cardiovascular mortality 36.1 58 17.0 8.7 380 4.3 3.06 2.31 4.06 0.001 4.19 3.18 5.52 0.001 Stroke 35.8 56 16.4 11.2 485 5.5 2.44 1.84 3.25 0.001 3.08 2.33 4.08 0.001 Myocardial infraction 11.3 19 5.6 8.4 367 4.1 1.03 0.65 1.64 0.895 1.34 0.85 2.13 0.209 Other resecified end oints Total mortality 50.2 79 23.1 17.1 735 8.3 2.32 1.83 2.93 0.001 2.99 2.37 3.78 0.001 Hositalization for Angina ectoris 7.1 12 3.5 5.6 247 2.8 0.95 2.16 4.24 0.866 1.26 0.7 2.24 0.440 Heart failure 24.1 41 12.0 6.1 265 3.0 3.02 1.56 3.59 0.001 4.15 2.99 5.76 0.001 Revascularization 15.6 26 7.6 4.7 205 2.3 2.37 1.56 3.59 0.001 3.37 2.24 5.06 0.001 Sudden cardiac death 15.5 26 7.6 3.7 164 1.9 2.93 1.92 4.48 0.001 4.21 2.78 6.36 0.001 *For degree of left ventricular hyertrohy, Framingham risk score, and treatment allocation. Per 1,000 atient-years of follow-u. Comosite end oint of resuscitated cardiac arrest, cardiac death within 24 h. CI confidence interval. Value
708 Wachtell et al. JACC Vol. 45, No. 5, 2005 Treatment of LV Hyertrohy and AF March 1, 2005:705 11 Table 3. Concomitant Drug at Baseline, at End Point, or Termination of Follow-U (n 342) Losartan (%) (n 157) Atenolol (%) (n 185) Concomitant Treatment Previous Treatment By Study End Previous Treatment* By Study End K-vitamin antagonist 37 (23.7) 69 (44.2) 32 (17.2) 80 (43.0) Asirin, cloidogrel, diyridamole, ticlide 3 (1.9) 11 (7.1) 2 (1.1) 12 (6.5) Other latelet inhibitors 0 (0) 4 (2.6) 0 (0) 4 (2.2) Digoxin 82 (52.6) 89 (57.1) 104 (55.9) 107 (57.5) Veraamil 11 (7.1) 10 (6.4) 12 (6.5) 16 (8.6) Diltiazem 9 (5.8) 14 (9.0) 6 (3.2) 15 (8.1) Class IA antiarrhythmic drug 9 (5.8) 12 (7.7) 9 (4.8) 10 (5.4) Class IC antiarrhythmic drug 6 (3.8) 6 (3.8) 6 (3.2) 6 (3.2) Class III antiarrhythmic drug 1 (0.6) 7 (4.5) 3 (1.6) 13 (7.0) Beta-blocker 52 (33.3) 42 (27.6) 59 (31.7) 59 (31.7) ACE inhibitors or angiotensin II recetor blocker 42 (26.9) 52 (33.3) 56 (30.1) 65 (34.9) Other concomitant antihyertensive agents 38 (24.2) 76 (48.4) 45 (24.3) 100 (54.1) HMG-CoA reductase enzyme inhibitor 10 (6.4) 37 (23.7) 16 (8.6) 43 (23.1) *All NS comared with losartan at baseline. All NS comared with losartan during study. Either discontinued study and treated oen-label or rotocol violator. ACE angiotensin-converting enzyme; HMG-CoA HMG-coenzyme A. Figure 1. Systolic, diastolic, and mean arterial blood ressure in hyertensive atients with atrial fibrillation during follow-u; intention-to-treat analysis. atients with a history of AF comared with those in sinus rhythm (4.21 0.41 mmol/l vs. 4.17 0.39 mmol/l, 0.06). Among atients with a history of AF there was no difference in serum otassium during treatment between losartan-treated and atenolol-treated grous (4.20 0.43 mmol/l vs. 4.22 0.40 mmol/l, NS). Clinical outcome. Patients with a history of AF on losartan treatment had a significantly lower rate of the rimary comosite end oint than those treated with atenolol during 1,471 atient-years of follow-u (Table 4, Fig. 3). Losartantreated atients also had lower rates of cardiovascular death and stroke, with no difference in MI rate. The treatment effects on hemorrhagic or ischemic stroke were similar (data not shown). There was no evidence of interaction between treatment and gender for any re-secified end oint (all 0.144). A acemaker was imlanted in 15 (8.1%) atenolol-treated and 5 (3.2%) losartan-treated atients, resectively, during the study ( 0.065). Furthermore, losartan tended to reduce the revalence of electrocardiograhically documented AF by 14% at the annual visits during the following 4.8 years observation (losartan 50.3% vs. atenolol 55.7%, hazard ratio [HR] 0.86, 95% confidence interval [CI] 0.64 to 1.15, 0.30). Comaring atients with or without AF at baseline and using tests for interaction in Cox regression models with Framingham risk score and measures of ECG LV mass as covariates, the benefit of losartan was greater in atients with a history of AF than in other atients for both the rimary comosite end oint ( 0.019 for interaction) and for cardiovascular mortality ( 0.039 for interaction). Alternative adjustment for differences in the revalence of eriheral vascular disease, diabetes, and isolated systolic hyertension instead of Framingham Risk Score yielded HRs associated with losartan treatment of 0.61 for the rimary comosite end oint (95% CI 0.41 to 0.92, 0.019), 0.64 for cardiovascular mortality (95% CI 0.37 to 1.11, 0.114), 0.52 for stroke (95% CI 0.29 to 0. 92, 0.024), 1.70 for MI (95% CI 0.68 to 4.28, 0.260), and 0.74 for total mortality (95% CI 0.47 to 1.18, 0.206). Other secondary end oints did not attain statistical significant difference (data not shown). Among atients with a history of AF but without clinically recognized diabetes or coronary, cerebral, or eriheral vascular disease at enrollment in the LIFE study, the comosite end oint occurred in 10 of 77 atients in the losartan grou versus 22 of 82 in the atenolol grou (26.3 vs. 62.8 er 1,000 atient-years; HR 0.57, 95% CI 0.38 to 0.87, 0.008). The secondary end oint of stroke occurred in 5 versus 17 atients (13.1 vs. 47.1 er 1,000 atient-years) in the losartan and atenolol grous, resectively (HR 0.52, 95% CI 0.29 to 0.92, 0.025). A arallel albeit non-significant trend was seen for cardiovascular death (12.8 vs. 25.7 deaths er 1,000 atient-years; HR 0.60, 95% CI 0.35 to 1.03, 0.06), but not for MI or other secondary end oints (data not shown).
JACC Vol. 45, No. 5, 2005 March 1, 2005:705 11 Wachtell et al. Treatment of LV Hyertrohy and AF 709 Figure 2. Heart rate in hyertensive atients with a history of atrial fibrillation treated with losartan and atenolol during follow-u. * 0.01. ** 0.001. DISCUSSION The resent study extends knowledge of AF and its treatment in several regards. First, we show that AF is associated with increased cardiovascular morbidity and mortality in hyertensive atients at high risk because of the resence of LV hyertrohy, as reviously shown in redominately normotensive oulations (11). Second, the resent results rovide the first evidence that greater rognostic benefit is rovided to hyertensive atients with AF by one versus another medication with similar blood ressure lowering, building on revious evidence of the benefits of effective blood ressure control (12 14). The rate of the comosite end oint in the LIFE study, as well as the rates of cardiovascular mortality and stroke, was significantly lower with losartan- comared to atenolol-based theray, beginning at one year of treatment. Third, the resent study is the first to suggest that losartan is better than atenolol in reducing recurrence of AF in atients with a history of AF. Given the frequent occurrence of reduced exercise tolerance and increased dysnea in AF comared with sinus rhythm, keeing atients in sinus rhythm is often a clinical riority. Our study did not show reductions of MI and hositalizations for angina ectoris or HF with losartan in hyertensive atients with a history of AF. However, betablockade is a well-documented treatment for ischemic heart disease and has shown substantial effect on morbidity and mortality in atients with angina ectoris, revious MI, and HF. A study of atients with hyertension and HF showed a 50% reduction in sudden death and a 30% reduction in hositalizations for HF with metorolol comared with lacebo treatment (15) on to of standard treatments, including angiotensin-converting enzyme inhibition. Furthermore, beta-blocker use has been shown to indeendently reduce the risk of um failure death in atients with AF (16). That treatment with losartan did as well as atenolol in MI and hositalization for angina and HF is reassuring because of the high risk of coronary events in hyertensive atients with LV hyertrohy. Another imortant observation of this study is the fact that beta-blocker treatment did not seem to reduce the risk of sudden cardiac death comared with losartan treatment. This is surrising, as many regard beta-blocker theray as a first-line intervention for revention of sudden cardiac death (17). In the merged Euroean Myocardial Infarct Amiodarone Trial (EMIAT) and Canadian Amiodarone Myocardial Infarction Trial (CAMIAT) databases, concomitant use of beta-blockers and amiodarone rovided a survival benefit, esecially for arrhythmic cardiac death (18). In our study, even though the difference in sudden cardiac death did not attain statistical significance, there was a 48% risk reduction favoring the losartan-treated atients. Furthermore, beta-blocker treated atients seemed to need increased acemaker imlantation even though atients at baseline had heart rates averaging 75 beats/min. Losartan also reduced heart rate, albeit less than atenolol, with less heart rate difference at the end of study (Fig. 2). This might be due to blockade of symathetic nervous system activation by renin-angiotensin system blockade by losartan. Mechanisms. One exlanation for the added effects by losartan on cardiovascular morbidity and mortality in this hyertensive oulation with LV hyertrohy could be the Table 4. End Points in Losartan- and Atenolol-Treated Patients With Atrial Fibrillation End Point Losartan (n 157) Atenolol (n 185) Adjusted Hazard Ratio* Unadjusted Hazard Ratio Rate n (%) Rate n (%) 95% CI Value 95% CI Primary comosite end oint 50.3 36 22.9 88.8 67 36.2 0.58 0.39 0.88 0.009 0.58 0.39 0.87 0.009 Comonents Cardiovascular mortality 26.2 20 12.7 45.2 38 20.5 0.58 0.33 0.99 0.048 0.58 0.33 0.99 0.045 Stroke 24.1 18 11.5 46.5 38 20.5 0.55 0.31 0.97 0.039 0.55 0.31 0.97 0.038 Myocardial infarction 14.2 11 7.0 8.9 8 4.3 1.49 0.60 3.72 0.392 1.63 0.65 4.04 0.296 Other re-secified end oints Total mortality 40.1 30 19.1 59.4 49 26.5 0.67 0.43 1.06 0.090 0.67 0.42 1.05 0.079 Hositalization for Angina ectoris 7.7 6 3.8 6.5 6 3.2 1.18 0.38 3.69 0.778 0.65 0.34 1.22 0.182 Heart failure 19.1 15 9.6 30.1 26 14.1 0.66 0.35 1.25 0.206 1.14 0.37 3.53 0.824 Revascularization 14.2 11 7.0 16.9 15 8.1 0.82 0.38 1.79 0.615 0.83 0.38 1.82 0.647 Sudden cardiac death 11.4 9 5.7 19.3 17 9.2 0.57 0.25 1.29 0.179 0.59 0.26 1.33 0.204 *For degree of left ventricular hyertrohy, electrocardiograhic atrial fibrillation, Framingham Risk Score, and treatment allocation. Per 1,000 atient-years of follow-u. Comosite end oint of resuscitated cardiac arrest, cardiac death within 24 h. CI confidence interval. Value
710 Wachtell et al. JACC Vol. 45, No. 5, 2005 Treatment of LV Hyertrohy and AF March 1, 2005:705 11 Figure 3. Kalan-Meier curves in each treatment grou of hyertensive atients with a history of atrial fibrillation for occurrence of (A) the rimary comosite end oint; (B) cardiovascular death; (C) fatal or non-fatal myocardial infarction; (D) fatal or non-fatal stroke; and (E) all-cause mortality. arallel effects of losartan on regression of atrial and ventricular hyertrohy. We have recently shown in the LIFE echocardiograhy substudy that atients with LV hyertrohy also exhibit increased left atrial size and hyertrohy (19), which have been associated with increased risk of stroke in oulation of normotensive and hyertensive adults (20). Further analyses from the LIFE echocardiograhy study will investigate whether left atrial diameter decreases with reduction in LV mass during treatment and whether this is related to a reduction in subsequent events. Another ossible exlanation for reduced vascular events with losartan treatment could be greater effects on arterial atherothrombosis or on coagulation system activation in atients with AF. However, the fact that the benefit of losartan was not limited to high-risk atients with either vascular disease or diabetes, but also occurred in atients with hyertension and AF alone, suggests that the benefits of losartan in atients with AF are due to revention of vascular disease as well as reduced rogression of established arterial disease. Furthermore, our study does not suggest high serum otassium as the cause of increased cardiovascular morbidity and mortality, because our hyertensive atients with AF treated with losartan had a slightly higher serum otassium level than those treated with atenolol. Study limitations. The articiants in the LIFE study were selected for hyertension and ECG LV hyertrohy but also for lack of current need for atenolol, losartan, or angiotensin-converting enzyme inhibitors, or known intol-
JACC Vol. 45, No. 5, 2005 March 1, 2005:705 11 Wachtell et al. Treatment of LV Hyertrohy and AF 711 erance to rimary study treatment. Furthermore, in view of the relatively low roortion of atients treated with nondihydroyridine calcium blockers, most atients in the resent study could be rate-controlled by digoxin alone or by no antiarrhythmic treatment during the study. However, in view of the large number of hyertensive atients age 55 to 80 years with LV hyertrohy meeting the LIFE study blood ressure criteria, estimated at 3.9 million in the U.S. and 4.8 million in the Euroean Union (21,22), a considerable number of hyertensive atients with AF might have their risk of cardiovascular events and stroke reduced by losartan theray. Although the analysis of AF was not re-secified in the LIFE study analysis lan from 1995, evaluation of treatment effects in the subgrou of atients with AF at baseline was a lanned secondary analysis before termination (Setember 2001) and unblinding. Furthermore, since the sub-study oulation was recruited for hyertension and ECG LV hyertrohy and not for AF, balanced randomization is not guaranteed. Because outcomes were analyzed by the intention-to-treat rincile and without restriction after study drug discontinuation, oen-label use of angiotensin-ii recetor blocker/ angiotensin-converting enzyme inhibitor/beta-blocker may have diminished the difference between the grous. Conclusions. Losartan-based antihyertensive theray was more effective than an atenolol-based regimen in reducing the risk of the rimary comosite end oint of cardiovascular morbidity and cardiovascular mortality as well as the secondary end oints of stroke and cardiovascular death in hyertensive atients with ECG LV hyertrohy and a history of AF. Hyertensive atients with AF who do not need beta-blockade for heart rate control seem to benefit more from losartan-based treatment than from conventional antihyertensive and anti-arrhythmic treatment. 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