European Heart Journal Advance Access originally published online on February 1, 2007
European Heart Journal 2007 28(6):741-751; doi:10.1093/eurheartj/ehl436
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Enhanced cardiovascular morbidity and mortality during rhythm control treatment in persistent atrial fibrillation in hypertensives: data of the RACE study
1 Department of Cardiology, University Medical Center Groningen, University of Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands
2 Department of Cardiology, University Hospital, Maastricht, The Netherlands
Received 7 August 2006; revised 27 October 2006; accepted 23 November 2006; online publish-ahead-of-print 1 February 2007.
* Corresponding author. Tel: +31 50 3612355; fax: +31 50 3614391. E-mail address: i.c.van.gelder{at}thorax.umcg.nl
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Abstract |
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Aim To investigate the influence of hypertension on morbidity and mortality during rate and rhythm control in patients with persistent atrial fibrillation (AF).
Methods and results In the RAte Control vs. Electrical cardioversion (RACE) study, 522 patients (256 with hypertension) were randomized to rate or rhythm control. The occurrence of cardiovascular morbidity and mortality was compared between patients with and without hypertension. Patients with hypertension were older (69 ± 8 vs. 67 ± 9 years, P = 0.01), more female (P < 0.001), had more diabetes (P = 0.005), a higher CHADS2 score (2.2 ± 1.0 vs. 1.0 ± 0.9, P < 0.001), and higher systolic and diastolic blood pressures. Septal and posterior wall thicknesses were higher in hypertensives. Complaints related to AF were similar. After a median follow-up of 2.4 (range 0–3.4) years more endpoints occurred in hypertensives (25 vs. 15%). Randomized treatment strategy, i.e. rate or rhythm control, influenced the occurrence of the primary endpoint only in hypertensives. Hypertensives treated with rhythm control experienced most endpoints (incidence rates/100 person-years 13.3 vs. 7.2, relative risk 0.5 [0.3–0.9], P = 0.02), mainly thromboembolic complications, adverse effects of antiarrhythmics, and pacemaker implantations.
Conclusion In persistent AF patients with hypertension, a pharmacological rhythm control approach is associated with enhanced cardiovascular morbidity and mortality. Therefore, rate-control strategy should be considered in these patients.
Key Words: Atrial fibrillation • Hypertension • Cardioversion • Morbidity • Mortality
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Introduction |
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Atrial fibrillation (AF) is the most common cardiac arrhythmia and hypertension is its most prevalent and independent risk factor.1–3 Hypertension itself increases the risk of cardiovascular diseases.4–6 In patients with AF, it enhances the risk for stroke two to three times.7,8 Adequate treatment of hypertension reduces the risk of cardiovascular events.9–11 Optimal control of the blood pressure, however, is often not achieved.12–15 Recent data suggest that the type of antihypertensive drug also may influence prognosis. Angiotensin II receptor blockers (ARB) have been demonstrated to be more effective than beta-blockers for prevention of cardiovascular morbidity and mortality in hypertensive AF patients, irrespective of the comparable blood-pressure-lowering effect.16
Large trials have shown that in patients with persistent AF, rate control is not inferior to rhythm control therapy regarding morbidity and mortality.17–20 Whether outcome of one of both treatment strategies is affected independently by the presence of hypertension is the aim of the present subanalysis of the RAte Control vs. Electrical cardioversion (RACE) study. We now investigated (i) long-term outcome, i.e. cardiovascular morbidity and mortality in hypertensives and normotensives with persistent AF, (ii) outcome of rate- and rhythm-control treatments in hypertensives with persistent AF, and (iii) sought to find an explanation for the observed differences in outcomes between the respective groups.
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Methods |
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Study design
The study design, patient characteristics, and results of the RACE study have been published previously.18 In short, 522 patients were included with recurrent persistent AF (minimum one previous electrical cardioversion) and randomized to rate- or rhythm-control treatment. Patients were followed for at least 2 years with a maximum of 3 years. Administration of digitalis, a non-dihydropyridine calcium-channel blocker, and a beta-blocker achieved rate control, alone or in combination. The target was a resting heart rate of less than 100 bpm. Patients assigned to the rhythm-control group underwent serial electrocardioversions and institution of serial antiarrhythmic drugs, i.e. sotalol, class IC antiarrhythmic drugs and amiodarone. From 4 weeks and until 4 weeks after electrical cardioversion, all patients received acenocoumarol or fenprocoumon [target international normalized ratio (INR), 2.5–3.5]. If sinus rhythm was present at 1 month, the oral anticoagulant could be stopped or changed to aspirin (80–100 mg daily). Aspirin was also allowed in patients in the rate-control group who were less than 65 years old if they had AF without underlying cardiac disease. All other patients received oral anticoagulant therapy.
Endpoint definition
The primary endpoint was the composite of death from cardiovascular cause, heart failure, thromboembolic complications, bleeding, severe adverse effects of antiarrhythmic drugs, and the need for a pacemaker implantation. All events that occurred between randomization and the end of study were recorded. Definitions of the composites of the primary endpoint have been described before.18 A committee of experts, who were unaware of the treatment assignments, adjudicated all reported endpoints.
Other definitions
History of hypertension was based on the mean of at least two measured blood pressures >140/90 mmHg, before inclusion. The stroke risk index, CHADS2, was used to quantify the risk of stroke of all included patients. One point was assigned to patients with NYHA functional class II/III at baseline, hypertension, age >75 years, and diabetes, and two points were assigned to patients with a history of stroke.21 Interrupted oral anticoagulation use during follow-up was defined as discontinuation of anticoagulant therapy for any reason during follow-up.
Statistical analysis
Baseline descriptive statistics are the mean ± standard deviation (SD) or median (range) for continuous variables and counts with percentages for categorical variables. Differences between groups, in terms of patient characteristics at baseline, different follow-up times, and end of study, were evaluated by Student's t-test or Mann–Whitney U-test depending on the normality of the data for continuous data, and by Fisher's exact test or 
2 test for categorical data. Kaplan Meier estimates and Cox regression analyses were performed to study the influence of hypertension on the occurrence of cardiovascular morbidity and mortality over time in the study population. Linearity of the continuous variables with respect to the response variable was assessed by determining the quartiles of their distribution. Thereafter, hazard ratios for each quartile were calculated. In case of a linear trend in the estimated hazard ratios, the variable was introduced in the model as continuous. If no linearity was demonstrated, the variable was further categorized by taking together the quartiles with hazard ratios similar in magnitude, primarily the median value or otherwise based on clinical relevance. All patient characteristics, drug therapy (including oral anticoagulation use, aspirin use, and interrupted oral anticoagulation during follow-up), stroke risk factors, and three time-dependent covariates, i.e. systolic and diastolic blood pressures, and rhythm during follow-up were included. Systolic and diastolic blood pressures and rhythm, AF or sinus rhythm, during follow-up were introduced as time-dependent variables in the analyses because this allowed us to evaluate blood pressure and the rhythm, i.e. AF or sinus rhythm during follow up. All univariable predictors with P < 0.1 were included in a multivariable model. Log–log survival curves and time-dependent covariates were used to evaluate adherence of the Cox proportional hazard assumptions. In all analyses, a value of P < 0.05 was considered statistically significant. All analyses were performed according to the intention-to-treat principle.
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Results |
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Hypertensives vs. normotensives
Patient characteristics
A total of 522 patients were included in the RACE study, 256 with hypertension (Table 1). At baseline, hypertensives were older and more often females. Systolic and diastolic blood pressures were higher, and septum and posterior walls were thicker. Hypertensive patients were more often treated with ACE-inhibitors or ARB, diuretics, and dihydropyridine calcium-channel blockers (Table 2). The mean CHADS2 scores were 2.2 ± 1.0 (range 1–5) and 1.0 ± 0.9 (range 0–4) in hypertensive and normotensive patients, respectively (P < 0.001).
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Follow-up
Median follow-up was 2.4 (range 0–3.4) years. Of all hypertensives, 110 (43%) were treated with rate control and 146 (57%) with rhythm control. In the normotension group, this figure was 146 (55%) and 120 (45%), respectively. In the rhythm-control group, 51 (35%) hypertensives and 49 (41%) normotensives had sinus rhythm at study end (P = 0.4) after a median of 2 (0–11) vs. 2 (0–7) electrical cardioversions (P = 0.7), respectively. Most electrical cardioversions were performed during the first 6 months of follow-up (68%). There was no difference in distribution of electrical cardioversions between hypertensives and normotensives (Figure 1). Continuous oral anticoagulation was used in 75% of all hypertensives (87% rate control, 66% rhythm control) and in 71% of all normotensives (81% rate control, 59% rhythm control) (P = 0.3). All other patients (n = 141, 27%) had their anticoagulation interrupted or stopped. Reasons for discontinuation of anticoagulation were sinus rhythm (>1 month) in 69%, lone AF in 20%, and (non-) cardiac surgery in 11%. Aspirin was used in a small proportion of patients, and was equally distributed between hypertensives and normotensives (2 vs. 1%, respectively, P = 0.3). At the end of the study, more hypertensives used aspirin (9 vs. 3%, respectively, P = 0.006) (Table 2). During follow-up, systolic and diastolic blood pressures remained continuously higher in patients with a history of hypertension (Figure 2A), but there were no differences in atrial sizes, left atrial volume, fractional shortening, and septal and posterior wall thicknesses (data not shown). From 1 year until 2 years of follow-up, left ventricular hypertrophy, defined as septal thickness >12 mm and/or posterior wall thickness >11 mm, was more often present in hypertensives than normotensives [57 (29%) vs. 32 (15%), P < 0.001].
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Cardiovascular morbidity and mortality
The primary endpoint occurred more frequently in hypertensives (25%), in comparison to normotensives (15%) (Table 3). Cardiovascular mortality was similar in both groups. Hospital admission for heart failure and thromboembolic complications occurred more frequently in hypertensive patients. Patients admitted for heart failure were comparable with patients who did not have—with regard to medical history, drug treatment, NYHA functional class for heart failure, echocardiographic parameters, but differed in age (72 ± 10 vs. 68 ± 9, P = 0.03), presence of hypertension [16 (76%) vs. 240 (48%), P = 0.01], and left atrial size (49 ± 8 vs. 45 ± 7, P = 0.01). Heart failure occurred more often in patients on diuretics [adjusted hazard ratio 3.6 (1.3–10.4], P = 0.02), and a trend towards a relation with hypertension was observed [adjusted hazard ratio 2.6 (0.8–8.2), P = 0.096]. Most thromboembolic events occurred while patients were in AF (Figure 3). A total of 18 hypertensive patients received inadequate anticoagulant therapy (INR <2.0) and two used no anticoagulation at the moment of thromboembolic event (Figure 4). The patients with a thromboembolic complication had a significantly higher CHADS2 score compared with patients without thromboembolic complication (2.1 ± 1.2 vs. 1.5 ± 1.1, P = 0.005). Thromboembolic complications occurred more frequently in patients with hypertension [adjusted hazard ratio 2.4 (1.1–5.6), P = 0.03] and age >65 years [adjusted hazard ratio 7.6 (1.8–32.3), P = 0.006], but was not related to interruption of oral anticoagulation. The incidence of bleeding was comparable between both groups. At the moment of bleeding, the INR was >3.0 in 17 of all 21 bleedings. Almost all severe adverse effects of antiarrhythmic drugs occurred in hypertensive patients (n = 13): sick sinus syndrome or atrioventricular block (n = 7; three on flecainide, one on sotalol, three on amiodarone; in three patients unmasked by cardioversion), torsades de pointes (n = 2; one on sotalol, one on amiodarone in combination with haloperidol), ventricular fibrillation (n = 1; on flecainide), rapid atrioventricular conduction during atrial flutter (n = 1; on flecainide), and digitalis intoxication (n = 2; atrioventricular block in one and ventricular tachycardia in the other). One normotensive patient had drug-induced heart failure while being treated with flecainide. Bradyarrhythmias occurred more frequently in patients with hypertension [adjusted hazard ratio 9.0 (1.1–71.6), P = 0.04], females [adjusted hazard ratio 4.8 (1.2–18.8), P = 0.02], and patients treated with amiodarone [adjusted hazard ratio 5.8 (1.7–19.5), P = 0.004]. In hypertensives, pacemaker implantations were required for sick sinus syndrome unmasked by cardioversion (four patients), for bradycardia during AF (one patient), and after atrioventricular node ablation (two patients). In normotensives, pacemaker implantation were required for sick sinus syndrome unmasked by cardioversion (one patient) and after atrioventricular node ablation (three patients).
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Hypertensives: rate vs. rhythm control
Patient characteristics and follow-up
Baseline characteristics were comparable between hypertensive patients randomized to rate and rhythm control. Likewise, CHADS2 scores were comparable (2.3 ± 1.0 vs. 2.1 ± 1.0, P = ns), also within continuous vs. interrupted-anticoagulation-treated hypertensives (2.1 ± 1.0 vs. 2.0 ± 1.0, P = 0.3). From 3 months until 2 years of follow-up, systolic blood pressure was significantly higher in hypertensives treated with rhythm control (Figure 2B). Rhythm-control randomized hypertensives were less frequently treated with verapamil or diltiazem (Table 4). Left atrial diameter (apical view) after 1 year of follow-up was enlarged (68 ± 8 vs. 65 ± 9 mm, P = 0.01) in rate-control treated hypertensives. There were no other differences in echocardiographic parameters during follow-up between both groups.
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Cardiovascular morbidity and mortality
Randomized treatment strategy, i.e. rate or rhythm control, influenced the occurrence of the primary endpoint in hypertensives, in contrast to normotensive patients. Hypertensives treated with rhythm control experienced most endpoints (31%), in comparison to those treated with rate control (17%) (Table 5). Most endpoints occurred during AF (Figure 3). The incidence of hospital admission for heart failure was similar in rate- and rhythm-control treated hypertensives but thromboembolic complications occurred more frequently in rhythm-control-treated hypertensives (in 12 vs. 7%, respectively). There were no differences in CHADS2 scores and blood pressures between hypertensive patients randomized to rate and rhythm control with a thromboembolic complication. Eleven of the hypertensive patients received inadequate anticoagulation (INR <2.0), two used no anticoagulation, and in three anticoagulation was adequate (INR 2.0 and 3.0) (Figure 4). Almost all severe adverse effects of antiarrhythmic drugs occurred in hypertensives treated with rhythm control (11 patients). Also, more pacemaker implantations occurred in rhythm-control-treated hypertensives (4 vs. 1%, respectively). In normotensives, no remarkable 3differences were seen in occurrence of the primary endpoint according to treatment strategy (13 vs. 17%, respectively).
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By Cox regression analysis, only heart failure NYHA II/III was identified as significant independent predictor of the occurrence of the primary endpoint in the total population (Table 6). In order to investigate differences in outcome between rate- or rhythm-control treatment, we repeated the analyses after dividing the patients according to the history of hypertension. There was no association between treatment strategy and adverse outcome in normotensives, like in the total patient population (Figure 5). However, in hypertensives, rhythm control treatment was associated with the occurrence of the primary endpoint [adjusted hazard ratio 1.9 (1.1–3.5), P = 0.04] (Figure 5). None of the time-dependent variables, i.e. systolic and diastolic blood pressures and the rhythm (AF or sinus rhythm), during follow-up were predictors of the occurrence of the primary endpoint, but age and left atrial size were.
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Discussion |
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The present subanalysis of the RACE study shows that a rhythm-control strategy in patients with hypertension and persistent AF is associated with enhanced cardiovascular morbidity and mortality, largely due to more thromboembolic complications, severe adverse effects of antiarrhythmic drugs, and pacemaker implantations.
Hypertension and cardiovascular morbidity and mortality
In line with previous data, we noticed that patients with a history of hypertension, apart from higher systolic and diastolic blood pressures, differed from normotensive patients. Hypertensive patients were older and more often females.3 Diabetes mellitus was more common and the CHADS2 score was one point higher. We observed more endpoints in hypertensive than in normotensive patients with persistent AF. Only more severe heart failure, but not treatment strategy nor the underlying rhythm, was identified as independent predictor of the primary endpoint over time. This is in accordance with the data of the AFFIRM study that showed that an increasing age and more severe underlying heart disease were significantly associated with an increased risk of death.22
The higher incidence of the primary endpoint in hypertensives was driven by several of its components. First, thromboembolic complications occurred most often in hypertensives, despite the relatively high use of oral anticoagulant therapy in the RACE study, as was the case in the AFFIRM trial.23 On the other hand, this finding was not unexpected. Hypertension is known to be an important risk factor for stroke,2 worsening the risk by a two- to three-fold.8 Parameters that may have influenced the occurrence of thromboembolic complications in the present study include electrical cardioversions, use of oral anticoagulation, blood pressure during follow-up, and anti-hypertensive drugs. Number of electrical cardioversions and use of oral anticoagulation were not different between both groups. At the moment of a thromboembolic complication, though, either oral anticoagulation was not used or instituted inadequately. Furthermore, blood pressures were continuously higher in hypertensives despite the higher use of ACE-inhibitors and ARB, diuretics, and calcium-channel blockers. Although both systolic and diastolic blood pressures, as time-dependent variables, were no predictors of the occurrence of the primary endpoint, it is well known that the incidence of stroke is strongly related to the control of blood pressure.12–15 In great contrast, the AFFIRM investigators found that not hypertension, but history of stroke, myocardial infarction, female gender, and duration of qualifying AF episode were parameters associated with stroke.24 Secondly, heart failure occurred more often in patients with a history of hypertension, obviously since hypertension is an important risk factor for heart failure and blood pressures were higher in hypertensives.25,26 At baseline, however, there were no differences in cardiac function between hypertensives and normotensives. Thirdly, almost all severe adverse effects of antiarrhythmic drugs, mainly used for rhythm control, were observed in hypertensives. Most reported adverse effects in our study were not related to tachyarrhythmias, but instead, to bradyarrhythmias, like unmasking of a sick sinus syndrome and symptomatic bradycardia. This occurred often after electrical cardioversion. This may have been caused by unmasking of sick sinus syndrome or atrioventricular conduction disease by negative chronotropic as well as rhythm-control drugs. However, there were no differences in use of these drugs between normotensives and hypertensives. Another explanation could be that hypertension may lead to diastolic heart failure with elevated filling pressures also in the atria.27 The latter, in turn, may enhance atrial remodelling, stimulating atrial dilatation and fibrosis of the atria including the sinus node and atrioventricular node. Although we observed no differences in echocardiographic atrial diameters and left atrial volume, this does not exclude the presence of more severely remodelled atria in hypertensive patients.
Hypertension and outcome of rate- and rhythm-control treatment
The major finding of present study was the important difference in event-free survival between hypertensives randomized to rate and rhythm controls. This difference was not observed in normotensives. Hypertensives randomized to rhythm control had a 1.9-fold greater risk on developing cardiovascular morbidity and mortality, mainly as result of the higher prevalence of thromboembolic complications and severe adverse effects of antiarrhythmic drugs. The prevalence of heart failure was not influenced by the randomized strategy in hypertensive patients.
Hypertensive patients in both treatment strategies were comparable with regard to patient characteristics, including CHADS2 scores. During follow-up, atrial diameters, left atrial volume, and left ventricular function remained comparable. However, during almost the complete follow-up, the systolic blood pressure was significantly higher in rhythm-control randomized hypertensives (maximum mean systolic blood pressure 157 ± 24 vs. 146 ± 21 mmHg). This may relate to differences in the prescription of blood-pressure-lowering drugs between both treatment arms during follow-up. Treatment with beta blockers, ACE-inhibitors, ARB, diuretics and dihydropyridine calcium-channel blockers, and combinations (double, triple, and quadtriple antihypertensive therapy) was comparable between both groups. The prescription of verapamil and diltiazem, however, was significantly lower in patients randomized to rhythm control, possibly because verapamil and diltiazem were more often prescribed for rate control. The higher incidence of thromboembolic complications in rhythm-control randomized hypertensives may be explained by the following. First, patients treated with rhythm control more frequently discontinued oral anticoagulation after long-term (>1 month) maintenance of sinus rhythm. Though, most thromboembolic complications occurred while patients were on oral anticoagulation, which, however was instituted inadequately at the moment of the event. Secondly, (asymptomatic) recurrences of AF after restored sinus rhythm may have been responsible for thomboembolic events. Although we found that the underlying rhythm, AF or sinus rhythm as time-dependent variable, was not associated with the occurrence of the primary endpoint, this does not preclude that asymptomatic recurrences of AF may have contributed to the more thromboembolic events in the rhythm-control-treated hypertensives.28 Thirdly, hypertension per se is associated with an increased risk of thromboembolic complications after cardioversion.7 Finally, systolic blood pressure in hypertensives in the rhythm-control group was higher compared with those in the rate-control group during follow-up. It is well known that the incidence of stroke is strongly related to the control of blood pressure.12–15
In our hypertensive AF patients, rate control did not worsen prognosis. This, together with the low efficacy and high adverse event rate of the present antiarrhythmic drugs, especially in hypertensives, favours acceptance of AF in hypertensives earlier during the course of the disease. Certainly, the search for safer and more effective methods to cure AF and protect patients from thromboembolic events should continue.
Limitations
The present study is a post hoc analysis and thus not designed to determine differences in outcome with rate- or rhythm-control treatment in persistent AF patients with and without hypertension. Treatment of hypertension and aimed blood pressure were not specified.
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Conclusion |
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The present study notifies that treatment in AF may be guided by the underlying heart disease. Hypertension importantly enhances the cardiovascular risk in patients with persistent AF, predominantly if a pharmacological rhythm-control strategy is adopted. Whether this also is the case in non-pharmacological rhythm control strategies remains to be investigated.
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Acknowledgement |
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This study has been supported by grants from the Center of Health Care Insurance (OG96-047) and the Interuniversity Cardiology Institute, The Netherlands, and by an unrestricted grant from 3M Pharma, The Netherlands.
Conflict of interest: I.C.V.G. and H.J.G.M.C. received lecture fees from 3M Pharma. H.J.G.M.C. is a consultant to Sanofi-Aventis and Astrazeneca. D.J.V.V. is an Established Investigator of the Netherlands Heart Foundation (Grant D97.017).
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