Advertisement

Rate-control versus Rhythm-control Strategies and Outcomes in Septuagenarians with Atrial Fibrillation

      Abstract

      Background

      The prevalence of atrial fibrillation substantially increases after 70 years of age. However, the effect of rate-control versus rhythm-control strategies on outcomes in these patients remains unclear.

      Methods

      In the randomized Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial, 4060 patients (mean age 70 years, range 49-80 years) with paroxysmal and persistent atrial fibrillation were randomized to rate-control versus rhythm-control strategies. Of these, 2248 were 70-80 years, of whom 1118 were in the rate-control group. Propensity scores for rate-control strategy were estimated for each of the 2248 patients and were used to assemble a cohort of 937 pairs of patients receiving rate-control versus rhythm-control strategies, balanced on 45 baseline characteristics.

      Results

      Matched patients had a mean age of 75 years; 45% were women, 7% were nonwhite, and 47% had prior hospitalizations due to arrhythmias. During 3.4 years of mean follow-up, all-cause mortality occurred in 18% and 23% of matched patients in the rate-control and rhythm-control groups, respectively (hazard ratio [HR] associated with rate control, 0.77; 95% confidence interval [CI], 0.63-0.94; P = .010). HRs (95% CIs) for cardiovascular and noncardiovascular mortality associated with rate control were 0.88 (0.65-1.18) and 0.62 (0.46-0.84), respectively. All-cause hospitalization occurred in 61% and 68% of rate-control and rhythm-control patients, respectively (HR 0.76; 95% CI, 0.68-0.86). HRs (95% CIs) for cardiovascular and noncardiovascular hospitalization were 0.66 (0.56-0.77) and 1.07 (0.91-1.27), respectively.

      Conclusion

      In septuagenarian patients with atrial fibrillation, compared with rhythm-control, a rate-control strategy was associated with significantly lower mortality and hospitalization.

      Keywords

      In the randomized Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial, although there was no significant reduction in all-cause mortality among patients in the rate-control group, compared with those in the rhythm-control group (P = .08), a subgroup analysis suggested that among those 65-80 years of age, there was a significant reduction in mortality in the rate-control strategy group.
      • Wyse D.G.
      • Waldo A.L.
      • DiMarco J.P.
      • et al.
      A comparison of rate control and rhythm control in patients with atrial fibrillation.
      However, baseline characteristics of this older subgroup were not presented, and it remained unknown whether the beneficial effect of a rate-control strategy among older AFFIRM patients may have been confounded by between-group imbalances in potential baseline confounders. The prevalence and incidence of atrial fibrillation increased after the eighth decade of life,
      • Feinberg W.M.
      • Blackshear J.L.
      • Laupacis A.
      • Kronmal R.
      • Hart R.G.
      Prevalence, age distribution, and gender of patients with atrial fibrillation. Analysis and implications.
      • Wolf P.A.
      • Abbott R.D.
      • Kannel W.B.
      Atrial fibrillation: a major contributor to stroke in the elderly. The Framingham Study.
      and yet, the optimal management strategy for atrial fibrillation in these patients has not been fully defined.
      • Chinitz J.S.
      • Halperin J.L.
      • Reddy V.Y.
      • Fuster V.
      Rate or rhythm control for atrial fibrillation: update and controversies.
      Therefore, in the current analysis, we compared the effect of rate- versus rhythm-control strategies on outcomes in a propensity-matched cohort of AFFIRM participants 70-80 years of age.
      • Roy B.
      • Desai R.V.
      • Mujib M.
      • et al.
      Effect of warfarin on outcomes in septuagenarian patients with atrial fibrillation.
      • In patients 70 to 80 years of age with atrial fibrillation, compared with a rhythm-control strategy, a rate-control strategy using beta-blockers, digoxin, diltiazem and verapamil was superior in reducing the risk of mortality and hospitalization.
      • Until further evidence emerges, patients with atrial fibrillation in the eighth decade of life may be better managed with a traditional rate-control strategy.

      Materials and Methods

      Study Design and Participants

      The current analysis is based on a public-use copy of the AFFIRM data obtained from the National Heart, Lung, and Blood Institute. The design and results of the AFFIRM trial have been previously reported.
      • Wyse D.G.
      • Waldo A.L.
      • DiMarco J.P.
      • et al.
      A comparison of rate control and rhythm control in patients with atrial fibrillation.
      • Corley S.D.
      • Epstein A.E.
      • DiMarco J.P.
      • et al.
      Relationships between sinus rhythm, treatment, and survival in the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) Study.
      • Epstein A.E.
      • Vidaillet H.
      • Greene H.L.
      • et al.
      Frequency of symptomatic atrial fibrillation in patients enrolled in the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study.
      • Pawar P.P.
      • Jones L.G.
      • Feller M.
      • et al.
      Association between smoking and outcomes in older adults with atrial fibrillation.
      • The AFFIRM Investigators
      Baseline characteristics of patients with atrial fibrillation: the AFFIRM Study.
      Briefly, 4060 patients 65-80 years of age with paroxysmal and persistent atrial fibrillation were randomized to receive rate-control (n = 2027) versus rhythm-control (n = 2033) strategies. To be eligible, patients <65 years of age had to have one of the following risk factors for stroke or death: hypertension, diabetes, heart failure, previous stroke, previous transient ischemic attack, systemic embolism, left atrial enlargement by echocardiography, or reduced left ventricular ejection fraction. Patients were followed-up for 6 years (mean, 3.4 years, through October 31, 2001). The current study is restricted to 2248 AFFIRM patients 70-80 years of age, of whom 1118 were in the rate-control group.

      Rate-control versus Rhythm-control Strategies

      Patients in the rate-control group received beta-blockers, digoxin, verapamil, diltiazem, or a combination of these drugs. In the rate-control group, the therapeutic goal was to control heart rate to 80 beats per minute or less at rest and to 110 beats per minute or less during the 6-minute walk test. Patients in the rhythm-control group received cardioversion or medication, or both, as necessary to maintain normal sinus rhythm. Medications used in the rhythm-control group included amiodarone, disopyramide, flecainide, moricizine, procainamide, propafenone, quinidine, sotalol, or a combination of these drugs, following specific guidelines for the use of anti-arrhythmic drugs.

      Outcomes

      The primary end point in the AFFIRM trial was all-cause mortality, which also was the primary outcome for the current analysis. Secondary outcomes included cause-specific mortality, all-cause and cause-specific hospitalization, stroke, and major bleeding. Cardiovascular mortality referred to death due to cardiac or vascular causes. Cardiac death included mortality resulting from cardiac ischemia, arrhythmia, and nonarrhythmic causes, including heart failure. Vascular death included noncerebral hemorrhage, vascular catastrophe, pulmonary embolism, and cerebrovascular events. Noncardiovascular death referred to mortality occurring due to cancer, sepsis, trauma, pulmonary disease, noncardiac surgery, suicide, or other specific noncardiovascular cause.

      Assembly of a Balanced Study Cohort

      Considering that the between-group balance achieved by randomization may be lost, at least in part, in the subgroup of patients 70-80 years of age, we used propensity score approach to assemble a cohort in which the rate-control and the rhythm-control groups would be balanced on key measured baseline confounders.
      • Rosenbaum P.R.
      • Rubin D.B.
      The central role of propensity score in observational studies for causal effects.
      • Rubin D.B.
      Using propensity score to help design observational studies: Application to the tobacco litigation.
      We began by estimating propensity scores for the receipt of rate-control strategy for each of the 2248 participants using a nonparsimonious multivariable logistic regression model.
      • Ahmed A.
      • Husain A.
      • Love T.E.
      • et al.
      Heart failure, chronic diuretic use, and increase in mortality and hospitalization: an observational study using propensity score methods.
      • Ahmed A.
      • Fonarow G.C.
      • Zhang Y.
      • et al.
      Renin-angiotensin inhibition in systolic heart failure and chronic kidney disease.
      In the model, rate-control strategy was used as the dependent variable, and 45 clinically relevant baseline characteristics displayed in Figure 1 were included as covariates. Absolute standardized differences were estimated to evaluate the prematch imbalance and postmatch balance and presented as a Love plot.
      • Ahmed A.
      • Rich M.W.
      • Zile M.
      • et al.
      Renin-angiotensin inhibition in diastolic heart failure and chronic kidney disease.
      • Mujib M.
      • Patel K.
      • Fonarow G.C.
      • et al.
      Angiotensin-converting enzyme inhibitors and outcomes in heart failure and preserved ejection fraction.
      An absolute standardized difference of 0% indicates no residual bias, and differences <10% are considered inconsequential.
      Figure thumbnail gr1
      Figure 1Absolute standardized differences comparing baseline characteristics of the subset of AFFIRM patients 70-80 years of age with atrial fibrillation randomized to rate-control versus rhythm-control strategies, before and after propensity score matching.
      Using a greedy matching protocol, we matched patients in the rate-control group with those in the rhythm-control group who had similar propensity scores to 5, 4, 3, 2, and 1 decimal places in 5 repeated steps.
      • Ahmed M.I.
      • White M.
      • Ekundayo O.J.
      • et al.
      A history of atrial fibrillation and outcomes in chronic advanced systolic heart failure: a propensity-matched study.
      We began by multiplying the raw propensity scores by 100,000. For example, propensity scores of 0.56519791 and 0.56519653 for a pair of patients were converted to 56,519.79 and 56,519.65. Because propensity score for each patient is a unique number, we rounded them to nearest values divisible by 0.25 (eg, 56,519.75) and matched. We then removed all patients matched by 5 decimal points from the file and repeated the process to match the remaining patients by 4 decimal points by multiplying the raw propensity scores by 10,000. This process was then repeated 3 more times, each time multiplying by 1000, 100, and 10 to match by 3, 2, and 1 decimal points, respectively. In all, we were able to match 937 patients in the rate-control group with 937 patients in the rhythm-control group who had similar propensity scores.

      Statistical Analysis

      For descriptive analyses, Pearson's chi-squared test, Wilcoxon rank-sum test, McNemar test, and paired-sample t test were used as appropriate for pre- and postmatch between-group comparisons. To estimate the association between rate-control strategy and outcomes, we used Kaplan-Meier and Cox proportional hazard analyses. Proportional hazards assumptions were checked using log-minus-log scale survival plots. We conducted a formal sensitivity analysis to quantify the degree of a hidden bias that would need to be present to invalidate our main conclusions.
      • Rosenbaum P.R.
      Sensitivity to hidden bias.
      Subgroup analyses were conducted to determine the homogeneity of the effect of rate-control versus rhythm-control strategy on outcomes. Finally, the association of rate-control strategy with all-cause mortality also was examined in the full prematch cohort of 2248 participants using 3 different approaches: unadjusted; multivariable-adjusted (entering all covariates displayed in Figure 1); and propensity score-adjusted. All statistical tests were 2-tailed, and a P-value <.05 was considered significant. All data analyses were performed using SPSS 18 for Windows (SPSS, Inc., Chicago, Ill).

      Results

      Baseline Characteristics

      Matched patients had a mean age of 75 years; 45% were women, 7% were nonwhite, and 47% had prior hospitalizations due to arrhythmias. Baseline characteristics of patients in the rate-control and rhythm-control strategies are displayed in Table 1. After matching, standardized differences for most measured covariates were <5% and the difference was <10% for all the covariates, suggesting substantial balance across the groups (Figure 1).
      Table 1Baseline Characteristics of the Subset of AFFIRM Patients 70-80 Years with Atrial Fibrillation Randomized to Rate-control versus Rhythm-control Strategies, Before and After Propensity Score Matching
      Variables

      Mean ± SD or n (%)
      Before Propensity Matching (n = 2248)After Propensity Matching (n = 1874)
      Rate-control Strategy (n = 1118)Rhythm-control Strategy (n = 1130)P ValueRate-control Strategy (n = 937)Rhythm-control Strategy (n = 937)P Value
      Age (years)75 ± 375 ± 3.56875 ± 375 ± 3.891
      Female524 (47)497 (44).169421 (45)425 (45).892
      Non-whites89 (8)77 (7).29971 (8)64 (7).589
      History of smoking80 (7)72 (6).45964 (7)61 (7).852
      Past medical history
       Hypertension764 (68)779 (69).758645 (69)639 (68).804
       Coronary artery disease404 (36)491 (44)<.001378 (40)374 (40).879
       Heart failure259 (23)270 (24).684219 (23)214 (23).825
       Diabetes mellitus197 (18)190 (17).613162 (17)163 (17)1.000
       Cerebrovascular events160 (14)167 (15).753134 (14)135 (14)1.000
       Valvular heart disease170 (15)166 (15).732140 (15)140 (15)1.000
       Symptomatic bradycardia96 (9)104 (9).60882 (9)85 (9).869
       Peripheral vascular disease87 (8)92 (8).75377 (8)75 (8).933
       Cardioversion392 (35)535 (47)<.001385 (41)381 (41).848
       Coronary artery bypass graft145 (13)174 (15).099138 (15)141 (15).897
       Pacemaker implantation87 (8)98 (9).44279 (8)74 (8).736
       Hospitalization for arrhythmia502 (45)566 (50).014440 (47)444 (47).885
       Duration of hospitalization for arrhythmia2.4 ± 3.72.7 ± 3.7.0522.5 ± 3.82.5 ± 3.6.901
      Symptoms during atrial fibrillation in the last 6 months
       Fatigue622 (56)647 (57).438542 (58)535 (57).778
       Dyspnea610 (55)593 (53).322502 (54)506 (54).893
       Palpitation524 (47)523 (46).781433 (46)427 (46).816
       Dizziness381 (34)397 (35).599325 (35)325 (35)1.000
       Chest pain255 (23)253 (22).812204 (22)209 (22).823
       Diaphoresis188 (17)200 (18).579162 (17)158 (17).851
       Leg swelling234 (21)241 (21).818206 (22)191 (20).427
       Orthopnea157 (14)170 (15).501139 (15)140 (15)1.000
       Paroxysmal nocturnal dyspnea72 (6)80 (7).54663 (7)62 (7)1.000
       Panic102 (9)114 (10).43890 (10)85 (9).751
       Syncope46 (4)50 (4).71640 (4)44 (5).728
       Other symptoms117 (11)108 (10).47395 (10)95 (10)1.000
      Medications used within 6 months before randomization
       Warfarin932 (83)969 (86).117796 (85)800 (85).842
       Digoxin604 (54)598 (53).600495 (53)499 (53).891
       Beta-blocker452 (40)478 (42).368380 (41)389 (42).709
       Diuretics502 (45)519 (46).625430 (46)417 (45).584
       Angiotensin-converting enzyme inhibitor415 (37)414 (37).813346 (37)345 (37)1.000
       Diltiazem354 (32)328 (29).174279 (30)279 (30)1.000
       Verapamil122 (11)101 (9).117100 (11)92 (10).582
       Aspirin299 (27)294 (26).696255 (27)246 (26).675
       Lipid-lowering agents216 (19)234 (21).411190 (20)193 (21).910
       Nitrate208 (19)250 (22).038189 (20)192 (21).907
       Heparin195 (17)196 (17).952164 (18)162 (17).950
      Anti-arrhythmic drug failure181 (16)177 (16).733147 (16)157 (17).587
      Ventricular heart rate (beats per minute)74 ± 1472 ± 14.00173 ± 1473 ± 14.585
      Systolic BP (mm Hg)136 ± 19135 ± 20.304136 ± 19136 ± 19.817
      Diastolic BP (mm Hg)75 ± 1075 ± 10.47975 ± 1075 ± 10.968
      International normalization ratio
      Based on available data from 1877 and 1578 pre- and postmatch patients, respectively.
      2.3 ± 0.72.3 ± 0.7.4842.3 ± 0.72.3 ± 0.7.461
      AFFIRM = Atrial Fibrillation Follow-up Investigation of Rhythm Management; BP = blood pressure.
      Based on available data from 1877 and 1578 pre- and postmatch patients, respectively.

      Rate-control Strategy and Mortality

      All-cause mortality occurred in 18% and 23% of matched patients randomized to receive rate-control versus rhythm-control strategies, respectively (hazard ratio [HR] when the rate-control strategy was compared with the rhythm-control strategy, 0.77; 95% confidence interval [CI], 0.63-0.94; P = .010; Table 2, Figure 2). This association was homogeneous across various subgroups of patients (Figure 3). There was no association with cardiovascular mortality, but there was a significant reduction in noncardiovascular mortality (HR 0.62; 95% CI, 0.46-0.84; P = .002; Table 3). Unadjusted, multivariable-adjusted and propensity score-adjusted associations with all-cause mortality in the 2248 patients in the prematch cohort are presented in Table 2. Electrocardiographic data at 12 months was available from 1591 of the 1874 matched patients. Of these, 796 (50%) were in the rhythm-control group, of which, 604 (76%) were in sinus rhythm.
      Table 2All-cause Mortality in the Subset of AFFIRM Patients 70-80 Years with Atrial Fibrillation
      Events (%)Absolute Risk Difference
      Absolute risk difference was calculated by subtracting the percentage of events in the rhythm control group from that in the rate control group.
      Hazard Ratio (95% CI)P Value
      Rate-control StrategyRhythm-control Strategy
      Prematch (n = 2248)n = 1118n = 1130
       Randomized, subgroup of patients age 70-80 years210 (19%)252 (22%)−3%0.82 (0.69-0.99).039
       Additional multivariable-adjustment
      Adjusted for all 45 baseline characteristics displayed in Figure 1.
      0.80 (0.66-0.96).018
       Additional adjustment for propensity scores0.83 (0.69-1.00).048
      Postmatch (n = 1874)n = 937n = 937
       Propensity-matched172 (18%)215 (23%)−5%0.77 (0.63-0.94).010
      AFFIRM = Atrial Fibrillation Follow-up Investigation of Rhythm Management.
      Absolute risk difference was calculated by subtracting the percentage of events in the rhythm control group from that in the rate control group.
      Adjusted for all 45 baseline characteristics displayed in Figure 1.
      Figure thumbnail gr2
      Figure 2Kaplan-Meier plot for all-cause mortality among a propensity-matched subset of AFFIRM patients aged 70-80 years with atrial fibrillation, by rate-control versus rhythm-control strategies. CI = confidence interval; HR = hazard ratio.
      Figure thumbnail gr3
      Figure 3Effect of a rate-control (vs rhythm-control) strategy on all-cause mortality in subgroups of propensity-matched subset of AFFIRM patients aged 70-80 years with atrial fibrillation. CI = confidence interval.
      Table 3Other Outcomes among the Subset of AFFIRM Patients Aged 70-80 Years with Atrial Fibrillation
      OutcomesEvents (%)Absolute Risk Difference
      Absolute risk difference was calculated by subtracting the percentage of events in the rate control group from that in the rhythm control group.
      Hazard Ratio (95% CI)P Value
      Rate-control strategy (n = 937)Rhythm-control Strategy (n = 937)
      Cardiovascular mortality84 (9%)92 (10%)1%0.88 (0.65-1.18).39
       Due to cardiac causes65 (7%)74 (8%)1%0.85 (0.61-1.18).33
      Arrhythmic35 (4%)45 (5%)1%0.75 (0.48-1.16).20
      Nonarrhythmic30 (3%)29 (3%)0%1.00 (0.60-1.66)1.00
       Due to vascular causes19 (2%)18 (2%)0%1.01 (0.53-1.93).97
      Noncardiovascular mortality70 (8%)108 (12%)4%0.62 (0.46-0.84).002
      All-cause hospitalization571 (61%)641 (68%)7%0.76 (0.68-0.86)<.001
       Cardiovascular288 (31%)387 (41%)10%0.66 (0.56-0.77)<.001
       Noncardiovascular283 (30%)254 (27%)3%1.07 (0.91-1.27).42
      Stroke41 (4%)44 (5%)1%0.90 (0.59-1.37).61
      Major bleeding
      Major bleeding was defined as bleeding requiring transfusion or surgery, or both.
      78 (8%)72 (8%)0%1.05 (0.77-1.45).75
      AFFIRM = Atrial Fibrillation Follow-up Investigation of Rhythm Management; CI = confidence interval.
      Absolute risk difference was calculated by subtracting the percentage of events in the rate control group from that in the rhythm control group.
      Major bleeding was defined as bleeding requiring transfusion or surgery, or both.

      Rate-control Strategy and Hospitalization

      All-cause hospitalization occurred in 61% and 68% of matched patients randomized to receive rate-control versus rhythm-control strategies, respectively (HR associated with the rate-control strategy, 0.76; 95% CI, 0.68-0.86; P <.001; Table 3). There was a significant reduction in cardiovascular hospitalization (HR 0.66; 95% CI, 0.56-0.77; P <.001), but had no association with noncardiovascular hospitalization (Table 3). There was no difference in incident stroke and major bleeding events between the 2 groups (Table 3).

      Discussion

      Findings from the current study demonstrate that in septuagenarian patients with paroxysmal and persistent atrial fibrillation, compared with a rhythm-control strategy, the use of a rate-control strategy was associated with a significant reduction in all-cause mortality, which was mostly via a reduction in the noncardiovascular deaths. A rate-control strategy also was associated with a significant reduction in the risk of all-cause hospitalization, which was mostly mediated by a reduction in cardiovascular hospitalization. There was no difference in incident stroke or major bleeding between the 2 treatment strategies. These findings suggest that the harmful effects of a rhythm-control strategy for atrial fibrillation management may be more pronounced among septuagenarians, a large and growing population at high risk for incident atrial fibrillation and its complications.
      Our findings are consistent with the subgroup analysis that was presented by AFFIRM investigators in patients 65-80 years of age. Because none of the drugs used in the rate-control strategy has been shown to reduce mortality in patients with atrial fibrillation, the mortality difference observed in our study is likely an effect of the drugs used for rhythm control. Deaths due to anti-arrhythmic drugs are often attributed to their pro-arrhythmic properties and thus, cardiovascular in nature. Thus, the higher risk of noncardiovascular mortality in patients in the rhythm-control strategy group is rather intriguing. Although amiodarone was the most commonly used rhythm-control drug, its use in AFFIRM patients with pre-existing pulmonary disease was not associated with higher death due to pulmonary causes.
      • Olshansky B.
      • Sami M.
      • Rubin A.
      • et al.
      Use of amiodarone for atrial fibrillation in patients with preexisting pulmonary disease in the AFFIRM study.
      It has been suggested that a careful selection of anti-arrhythmic drugs, adjustment of their dosages based on hepatic and renal function, and close electrocardiographic monitoring may have resulted in lower arrhythmia-related adverse events.
      • Kaufman E.S.
      • Zimmermann P.A.
      • Wang T.
      • et al.
      Risk of proarrhythmic events in the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study: a multivariate analysis.
      This observation is consistent with findings from other randomized trials in which a rhythm-control strategy was associated with significantly increased cardiovascular hospitalizations without increased mortality.
      • Carlsson J.
      • Miketic S.
      • Windeler J.
      • et al.
      Randomized trial of rate-control versus rhythm-control in persistent atrial fibrillation: the Strategies of Treatment of Atrial Fibrillation (STAF) study.
      • Hohnloser S.H.
      • Kuck K.H.
      • Lilienthal J.
      Rhythm or rate control in atrial fibrillation—pharmacological Intervention in Atrial Fibrillation (PIAF): a randomised trial.
      • Van Gelder I.C.
      • Hagens V.E.
      • Bosker H.A.
      • et al.
      A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation.
      Misclassification of deaths due to cardiovascular causes as noncardiovascular is another potential explanation. In AFFIRM, the prevalence of sinus rhythm in the rhythm-control group decreased from 82% at 1 year to 63% at 5 years.
      • Wyse D.G.
      • Waldo A.L.
      • DiMarco J.P.
      • et al.
      A comparison of rate control and rhythm control in patients with atrial fibrillation.
      The higher cardiovascular hospitalization in the rhythm-control group may be due, in part, to relapse from sinus rhythm to atrial fibrillation.
      • Saksena S.
      • Slee A.
      • Waldo A.L.
      • et al.
      Cardiovascular outcomes in the AFFIRM Trial (Atrial Fibrillation Follow-Up Investigation of Rhythm Management). An assessment of individual antiarrhythmic drug therapies compared with rate control with propensity score-matched analyses.
      However, the higher all-cause and cardiovascular hospitalization in the rhythm-control group also may be in part due to specific procedures used for rhythm-control strategy.
      These findings have important implications for both the care of older adults with atrial fibrillation and reduction of health care costs. Controlling the cost of Medicare through reduction of 30-day all-cause hospital readmission for older Medicare beneficiaries is a goal of the new US health care reform law.
      • Tilson S.
      • Hoffman G.J.
      Addressing Medicare Hospital Readmissions. CRS Report for Congress: Prepared for Members and Committees of Congress.
      Older patients with atrial fibrillation have high hospital admission and readmission rates.
      • Amin A.N.
      • Jhaveri M.
      • Lin J.
      Temporal pattern and costs of rehospitalization in atrial fibrillation/atrial flutter patients with one or more additional risk factors.
      • Amin A.N.
      • Jhaveri M.
      • Lin J.
      Hospital readmissions in US atrial fibrillation patients: occurrence and costs.
      Findings of the current analyses suggest that until further evidence emerges, older adults with atrial fibrillation may be best served by traditional rate-control rather than rhythm-control strategies. Despite the older age of the patients in our analysis, these trial-eligible patients may be healthier than their real-world counterparts.
      • Zhang Y.
      • Kilgore M.L.
      • Arora T.
      • et al.
      Design and rationale of studies of neurohormonal blockade and outcomes in diastolic heart failure using OPTIMIZE-HF registry linked to Medicare data.
      • Masoudi F.A.
      • Havranek E.P.
      • Wolfe P.
      • et al.
      Most hospitalized older persons do not meet the enrollment criteria for clinical trials in heart failure.
      • Fiocca L.
      • Guagliumi G.
      • Rossini R.
      • et al.
      Characteristics and outcomes of patients with ST-segment elevation myocardial infarction excluded from the harmonizing outcomes with revascularization and stents in acute myocardial infarction (HORIZONS-AMI) Trial.
      Whether the adverse effect of a rhythm-control strategy might be more pronounced in a broader population of older adults with atrial fibrillation and multiple comorbid conditions is unknown. Therefore, these findings would need to be confirmed in large prospective randomized clinical trials of real-world patients with atrial fibrillation.
      Several limitations of our study need to be acknowledged. Although treatment strategy was randomized and the older subsets used in the current analysis were further balanced via propensity matching, bias due to unmeasured confounders is possible. Findings from our sensitivity analysis suggest that a hidden covariate could potentially explain away this association if it also would increase the odds of rate control by 6.8%. However, such an unmeasured covariate would need to be a near-perfect predictor of death and also could not be associated with any of the 45 measured balanced covariates, which is highly unlikely. We had no data on heart rate during follow-up. However, strict rate control has not been shown to be associated with better outcomes.
      • Van Gelder I.C.
      • Groenveld H.F.
      • Crijns H.J.
      • et al.
      Lenient versus strict rate control in patients with atrial fibrillation.
      The prevalence of use of beta-blockers was low, and only 14 patients had ablation-based rhythm-control therapy, which may limit generalizability to contemporary younger patients with severe symptoms associated with atrial fibrillation. Although ablation can be useful in these patients, the long-term effect of this invasive procedure on mortality and morbidity has not been examined in a randomized controlled trial.
      • Redberg R.F.
      Clinical benefit of catheter ablation for atrial fibrillation: comment on “Discerning the incidence of symptomatic and asymptomatic episodes of atrial fibrillation before and after catheter ablation (DISCERN AF)”.
      Finally, AFFIRM did not enroll patients over the age of 80 years, who have the highest prevalence of atrial fibrillation.
      In conclusion, in septuagenarian patients with atrial fibrillation, the use of rate-control strategy was associated with a significantly lower risk of mortality and hospitalization than those treated with a rhythm-control strategy.

      References

        • Wyse D.G.
        • Waldo A.L.
        • DiMarco J.P.
        • et al.
        A comparison of rate control and rhythm control in patients with atrial fibrillation.
        N Engl J Med. 2002; 347: 1825-1833
        • Feinberg W.M.
        • Blackshear J.L.
        • Laupacis A.
        • Kronmal R.
        • Hart R.G.
        Prevalence, age distribution, and gender of patients with atrial fibrillation. Analysis and implications.
        Arch Intern Med. 1995; 155: 469-473
        • Wolf P.A.
        • Abbott R.D.
        • Kannel W.B.
        Atrial fibrillation: a major contributor to stroke in the elderly. The Framingham Study.
        Arch Intern Med. 1987; 147: 1561-1564
        • Chinitz J.S.
        • Halperin J.L.
        • Reddy V.Y.
        • Fuster V.
        Rate or rhythm control for atrial fibrillation: update and controversies.
        Am J Med. 2012; 125: 1049-1056
        • Roy B.
        • Desai R.V.
        • Mujib M.
        • et al.
        Effect of warfarin on outcomes in septuagenarian patients with atrial fibrillation.
        Am J Cardiol. 2012; 109: 370-377
        • Corley S.D.
        • Epstein A.E.
        • DiMarco J.P.
        • et al.
        Relationships between sinus rhythm, treatment, and survival in the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) Study.
        Circulation. 2004; 109: 1509-1513
        • Epstein A.E.
        • Vidaillet H.
        • Greene H.L.
        • et al.
        Frequency of symptomatic atrial fibrillation in patients enrolled in the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study.
        J Cardiovasc Electrophysiol. 2002; 13: 667-671
        • Pawar P.P.
        • Jones L.G.
        • Feller M.
        • et al.
        Association between smoking and outcomes in older adults with atrial fibrillation.
        Arch Gerontol Geriatr. 2012; 55: 85-90
        • The AFFIRM Investigators
        Baseline characteristics of patients with atrial fibrillation: the AFFIRM Study.
        Am Heart J. 2002; 143: 991-1001
        • Rosenbaum P.R.
        • Rubin D.B.
        The central role of propensity score in observational studies for causal effects.
        Biometrika. 1983; 70: 41-55
        • Rubin D.B.
        Using propensity score to help design observational studies: Application to the tobacco litigation.
        Health Serv Outcomes Res Methodol. 2001; 2: 169-188
        • Ahmed A.
        • Husain A.
        • Love T.E.
        • et al.
        Heart failure, chronic diuretic use, and increase in mortality and hospitalization: an observational study using propensity score methods.
        Eur Heart J. 2006; 27: 1431-1439
        • Ahmed A.
        • Fonarow G.C.
        • Zhang Y.
        • et al.
        Renin-angiotensin inhibition in systolic heart failure and chronic kidney disease.
        Am J Med. 2012; 125: 399-410
        • Ahmed A.
        • Rich M.W.
        • Zile M.
        • et al.
        Renin-angiotensin inhibition in diastolic heart failure and chronic kidney disease.
        Am J Med. 2013; 126: 150-161
        • Mujib M.
        • Patel K.
        • Fonarow G.C.
        • et al.
        Angiotensin-converting enzyme inhibitors and outcomes in heart failure and preserved ejection fraction.
        Am J Med. 2013; 126: 401-410
        • Ahmed M.I.
        • White M.
        • Ekundayo O.J.
        • et al.
        A history of atrial fibrillation and outcomes in chronic advanced systolic heart failure: a propensity-matched study.
        Eur Heart J. 2009; 30: 2029-2037
        • Rosenbaum P.R.
        Sensitivity to hidden bias.
        in: Observational Studies. Vol 1. Springer-Verlag, New York2002: 105-170
        • Olshansky B.
        • Sami M.
        • Rubin A.
        • et al.
        Use of amiodarone for atrial fibrillation in patients with preexisting pulmonary disease in the AFFIRM study.
        Am J Cardiol. 2005; 95: 404-405
        • Kaufman E.S.
        • Zimmermann P.A.
        • Wang T.
        • et al.
        Risk of proarrhythmic events in the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study: a multivariate analysis.
        J Am Coll Cardiol. 2004; 44: 1276-1282
        • Carlsson J.
        • Miketic S.
        • Windeler J.
        • et al.
        Randomized trial of rate-control versus rhythm-control in persistent atrial fibrillation: the Strategies of Treatment of Atrial Fibrillation (STAF) study.
        J Am Coll Cardiol. 2003; 41: 1690-1696
        • Hohnloser S.H.
        • Kuck K.H.
        • Lilienthal J.
        Rhythm or rate control in atrial fibrillation—pharmacological Intervention in Atrial Fibrillation (PIAF): a randomised trial.
        Lancet. 2000; 356: 1789-1794
        • Van Gelder I.C.
        • Hagens V.E.
        • Bosker H.A.
        • et al.
        A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation.
        N Engl J Med. 2002; 347: 1834-1840
        • Saksena S.
        • Slee A.
        • Waldo A.L.
        • et al.
        Cardiovascular outcomes in the AFFIRM Trial (Atrial Fibrillation Follow-Up Investigation of Rhythm Management). An assessment of individual antiarrhythmic drug therapies compared with rate control with propensity score-matched analyses.
        J Am Coll Cardiol. 2011; 58: 1975-1985
        • Tilson S.
        • Hoffman G.J.
        Addressing Medicare Hospital Readmissions. CRS Report for Congress: Prepared for Members and Committees of Congress.
        Congressional Research Service, Washington, DC2012
        • Amin A.N.
        • Jhaveri M.
        • Lin J.
        Temporal pattern and costs of rehospitalization in atrial fibrillation/atrial flutter patients with one or more additional risk factors.
        J Med Econ. 2012; 15: 548-555
        • Amin A.N.
        • Jhaveri M.
        • Lin J.
        Hospital readmissions in US atrial fibrillation patients: occurrence and costs.
        Am J Ther. 2013; 20: 143-150
        • Zhang Y.
        • Kilgore M.L.
        • Arora T.
        • et al.
        Design and rationale of studies of neurohormonal blockade and outcomes in diastolic heart failure using OPTIMIZE-HF registry linked to Medicare data.
        Int J Cardiol. 2013; 166: 230-235
        • Masoudi F.A.
        • Havranek E.P.
        • Wolfe P.
        • et al.
        Most hospitalized older persons do not meet the enrollment criteria for clinical trials in heart failure.
        Am Heart J. 2003; 146: 250-257
        • Fiocca L.
        • Guagliumi G.
        • Rossini R.
        • et al.
        Characteristics and outcomes of patients with ST-segment elevation myocardial infarction excluded from the harmonizing outcomes with revascularization and stents in acute myocardial infarction (HORIZONS-AMI) Trial.
        Am J Cardiol. 2013; 111: 196-201
        • Van Gelder I.C.
        • Groenveld H.F.
        • Crijns H.J.
        • et al.
        Lenient versus strict rate control in patients with atrial fibrillation.
        N Engl J Med. 2010; 362: 1363-1373
        • Redberg R.F.
        Clinical benefit of catheter ablation for atrial fibrillation: comment on “Discerning the incidence of symptomatic and asymptomatic episodes of atrial fibrillation before and after catheter ablation (DISCERN AF)”.
        JAMA Intern Med. 2013; 173: 157