Author + information
- Received March 31, 2008
- Revision received January 8, 2009
- Accepted January 12, 2009
- Published online May 5, 2009.
- Robby Nieuwlaat, PhD*,* (, )
- Luc W. Eurlings, MD*,
- John G. Cleland, MD, PhD†,
- Stuart M. Cobbe, MD, PhD‡,
- Panos E. Vardas, MD, PhD§,
- Alessandro Capucci, MD, PhD∥,
- José L. López-Sendòn, MD, PhD¶,
- Joan G. Meeder, MD, PhD#,
- Yigal M. Pinto, MD, PhD** and
- Harry J.G.M. Crijns, MD, PhD*
- ↵*Reprint requests and correspondence:
Dr. Robby Nieuwlaat, Department of Cardiology, University Hospital Maastricht, P. Debyelaan 25, 6202AZ Maastricht, the Netherlands
Objectives Our aim was to identify shortcomings in the management of patients with both atrial fibrillation (AF) and heart failure (HF).
Background AF and HF often coincide in cardiology practice, and they are known to worsen each other's prognosis, but little is known about the quality of care of this combination.
Methods In the observational Euro Heart Survey on AF, 5,333 AF patients were enrolled in 182 centers across 35 European Society of Cardiology member countries in 2003 and 2004. A follow-up survey was performed after 1 year.
Results At baseline, 1,816 patients (34%) had HF. Recommended therapy for HF with left ventricular systolic dysfunction (LVSD) with a beta-blocker and either an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker was prescribed in 40% of HF patients, while 29% received the recommended drug therapy for both LVSD-HF and AF, consisting of the combination of a beta-blocker, either ACEI or angiotensin II receptor blocker, and oral anticoagulation. Rate control was insufficient with 40% of all HF patients with permanent AF having a heart rate ≤80 beats/min. In the total cohort, HF patients had a higher risk for mortality (9.5% vs. 3.3%; p < 0.001), (progression of) HF (24.8% vs. 5.0%; p < 0.001), and AF progression (35% vs. 19%; p < 0.001) during 1-year follow-up. Of all recommended drugs for AF and LVSD-HF, only ACEI prescription was associated with improved survival during 1-year follow-up (odds ratio: 0.51 [95% confidence interval: 0.31 to 0.85]; p = 0.011).
Conclusions The prescription rate of guideline-recommended drug therapy for AF and LVSD-HF is low. Randomized controlled trials targeting this highly prevalent subgroup with AF and HF are warranted.
Atrial fibrillation (AF) and heart failure (HF) often co-exist. The Framingham Heart study showed that in a general population of ≥50 years, the incidence of HF among AF patients was 33 in 1,000 patient-years, and the incidence of AF among HF patients was 54 in 1,000 patient-years (1). The Euro Heart Surveys of current cardiology practice in patients with AF or with HF showed that HF is present in 34% of AF patients, and AF in 42% of HF patients (2,3). Both HF (4) and AF (5) alone are associated with an increase in mortality, and when these pathologies coincide, mortality is even higher (1). The development of AF is likely to cause worsening of HF and greatly complicates management. Worsening of HF is also likely to provoke the onset of AF. AF and worsening HF constitute a classic ‘vicious circle’ of deterioration in HF.
Separate guidelines exist for the management of AF and HF, both with paragraphs on their combined management that differ in their recommendations (6–8). This may add confusion to what is already a complex situation. Little information is available regarding the combined management of AF and HF in clinical practice. For these reasons, we investigated guideline adherence regarding drug therapy when both AF and HF were encountered in the Euro Heart Survey on AF. In addition, we investigated the impact of HF and its management on the management, progression, and prognosis of AF patients during 1-year follow-up.
Survey methods, center participation, patient characteristics, management, and definitions of the baseline and follow-up survey of the Euro Heart Survey on AF have previously been described (2,9). In summary, 5,333 ambulant and hospitalized patients with AF were enrolled in cardiology practices of 182 hospitals among 35 countries in 2003 to 2004. Patients were enrolled if they were ≥18 years of age and if they had an electrocardiogram or Holter recording showing AF during the qualifying admission/consultation or in the preceding 12 months. A follow-up was performed to assess mortality and incidence of major adverse events during 1 year.
The previous publications on the general results of the baseline and follow-up surveys of the Euro Heart Survey on AF contain definitions of variables reported here (2,9). Definitions of variables specific for this paper are listed in the following text.
HF: the presence of signs and symptoms of either right (elevated central venous pressure, hepatomegaly, dependent edema) or left ventricular failure (exertional dyspnea, cough, fatigue, orthopnea, paroxysmal nocturnal dyspnea, cardiac enlargement, rales, gallop rhythm, pulmonary venous congestion) or both, confirmed by noninvasive or invasive measurements demonstrating objective evidence of cardiac dysfunction.
Heart failure with left ventricular systolic dysfunction (LVSD-HF): a clinical diagnosis of HF in combination with echocardiographic study within the preceding year showing left ventricular ejection fraction <45% (8).
Heart failure with preserved left ventricular systolic function (PSF-HF): a clinical diagnosis of HF in combination with echocardiographic left ventricular ejection fraction ≥45% (8).
Recommended drug therapy: according to both the European Society of Cardiology and American College of Cardiology/American Heart Association 2001 guidelines on HF (10,11), valid during the recruitment period of the survey, the combination of a beta-blocker and an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) was considered to be “recommended drug therapy for LVSD-HF.” Guidelines for both AF (12) and HF (11) also recommended use of oral anticoagulants (OAC) in patients with HF and AF. Therefore, a combination of beta-blocker, ACEI, or ARB and OAC at discharge or end of visit was defined as “recommended drug treatment for LVSD-HF and AF” and we will also refer to this as “the full package.” There is less evidence of the efficacy of these drugs in PSF-HF.
Contraindications for recommended drug therapy: for “recommended drug therapy for LVSD-HF,” we took into account the following potential contraindications: ventricular rate <50 beats/min, renal failure, chronic obstructive pulmonary disease (COPD), sick sinus syndrome, systolic blood pressure <85 mm Hg, and atrioventricular block grade 2 to 3. For the full package of “recommended therapy for AF and LVSD-HF” the same contraindications were used, with the addition of major bleeding and malignancy as potential contraindications for OAC. All these contraindications are also applicable to PSF-HF patient and were only taken in account for analysis when explicitly stated in the text.
Rate control drugs: drug therapy at discharge or end of visit with beta-blockers, digoxin, digitoxin, diltiazem, verapamil, and also amiodarone and sotalol, since these 2 drugs have rate control properties.
CHADS2score: stroke risk score, calculated by adding 1 point for each of the following conditions: congestive HF, hypertension, age ≥75 years or diabetes, and 2 points for prior stroke or transient ischemic attack (13).
Data analysis was performed with SPSS statistical software (version 12.01, SPSS Inc., Chicago, Illinois). Continuous variables are reported as mean (±SD), or with a skewed distribution as median (25th to 75th percentile), and categorical variables as observed number (percentage). Differences were tested with independent ttest for continuous variables with normal distribution, Mann-Whitney for continuous variables with skewed distribution, and with chi-square statistic for categorical variables.
Multivariable logistic regression was performed to identify patient characteristics that were associated with a lower or higher likelihood to receive appropriate drug therapy among HF patients. In these analyses we incorporated the following covariates: age, sex, body mass index, systolic blood pressure at baseline, ventricular rate at baseline, coronary artery disease (CAD), valvular heart disease, hypertension, hyperlipidemia, diabetes, prior stroke/transient ischemic attack, prior other thromboembolism, prior major bleeding, AF type, renal failure, prior malignancy, peripheral vascular disease, COPD, AF symptoms, prior minor bleeding, sick sinus syndrome, hyperthyroidism, prior ventricular fibrillation, prior ventricular tachycardia, atrioventricular block grade 2 to 3, sinus rhythm at end of visit, New York Heart Association (NYHA) functional class, and type of HF (LVSD-HF vs. PSF-HF) only when being the central issue. Further, we performed multivariable logistic regression to assess the independent effect of HF, type of HF, and appropriate drug therapy on mortality during 1-year follow-up. In these analyses we incorporated the same covariates as mentioned in the prior text, with the following additional covariates: rate or rhythm control, antiplatelet drug, dihydropyridin calcium-channel blocker, statin, and also the individual drugs OAC, ACEI, ARB, and beta-blocker, or their combination as “appropriate therapy” as needed depending on the central issue. Diuretics were kept out of the models because it represented a surrogate of HF severity and masked the effect of HF and NYHA functional class on outcomes due to this colinearity.
The effect of individual drugs on outcomes might be biased by the absence of randomization, and therefore a propensity score for each drug was added to multivariable models in order to correct as well as possible for the propensity of a physician to select patients for the concerning drug. Individual propensity scores were calculated by means of backward deletion logistic regression (see methodology in the next paragraph). The propensity scores for all drugs were added as continuous variables to the multivariable logistic regression analyses. Propensity scores were kept in the model regardless of their significance until the associated drug was deleted.
For all multivariable logistic regression analyses, variables were removed stepwise from the model when the p value exceeded 0.10. Variables with p values <0.05 in the final model were considered to be significant contributors and were kept in the model. Hereafter, all variables in the final models were tested for interactions and significant interactions were added to the models. These models were validated by means of bootstrapping, which was performed with 100 samples for each multivariable logistic regression analysis. Bootstrapping provided information on the effect stability of each factor and interaction as a predictor of the outcome variable. Effects that were unstable were stepwise left out of the model, which eventually resulted in the final model with only stable significant effects. The final models are reported here, with the net odds ratio (OR), 95% confidence interval (CI), and p value.
Among 5,333 patients in the Euro Heart Survey on AF, 1,816 patients (34%) had HF, 3,482 (66%) did not, and for 35 patients (0.66%) HF status was unknown.
AF patients with HF were older and had more comorbidities than AF patients without HF (Table 1).As a consequence, HF patients were far more often categorized in CHADS2stroke risk score 2 or higher (Fig. 1).Most patients having AF and HF (74%) were in NYHA functional class II or III.
Among 1,088 HF patients with recent echocardiographic information, 42% had a decreased and 58% preserved left ventricular systolic function. AF patients with LVSD-HF were younger and more often had a history of CAD, especially myocardial infarction, and had a larger left atrial size (Table 1). Patients with PSF-HF were more likely to be women and to have associated conditions, mainly mitral stenosis or valve surgery, and hypertension.
Management of patients with AF and HF
Chest X-ray and transthoracic echocardiography were more likely and interventions to restore sinus rhythm less likely to be performed in HF patients (Table 2).Digitalis, beta-blockers, diuretics, OAC, and ACEIs were more often prescribed in patients with HF. In patients with LVSD-HF, diuretics, amiodarone, and digitalis use was higher than in PSF-HF, while no difference was found for ACEI, ARB, beta-blocker, verapamil, diltiazem, aspirin, or OAC (Table 2).
Among patients having both AF and HF, drug therapy for LVSD-HF was given in 40% (Fig. 2),which changed only marginally to 44% after exclusion of 595 patients with potential contraindications for a beta-blocker, ACEI, or ARB (see the Methods section). Recommended LVSD-HF drug prescription was similar in LVSD-HF and PSF-HF patients (45% vs. 41%; p = 0.218) (Fig. 2), also after exclusion of potential contraindications (50% vs. 48%; p = 0.745). No effect of HF type on prescription on recommended therapy was observed in multivariable analysis.
The full package of recommended drug therapy for LVSD-HF and AF was given in 29% of the 1,816 patients with AF and HF (Fig. 2), which increased slightly to 32% after exclusion of 673 patients with potential contraindications for recommended therapy for LVSD-HF and AF. Women (OR: 0.65 [95% CI: 0.51 to 0.82]; p < 0.001) and patients with COPD (OR: 0.43 [95% CI: 0.31 to 0.59]; p < 0.001), sinus rhythm at discharge (OR: 0.63 [95% CI: 0.47 to 0.84]; p < 0.001), or high systolic blood pressure at baseline (OR: 0.99 per 1 mm Hg increase [95% CI: 0.99 to 1.00]; p = 0.018) were less likely to receive this optimal treatment among all HF patients, while patients with CAD (OR: 1.37 [95% CI: 1.08 to 1.73]; p = 0.010), hyperlipidemia (OR: 1.49 [95% CI: 1.17 to 1.90]; p = 0.001), diabetes (OR: 1.31 [95% CI: 1.00 to 1.70]; p = 0.048), and first detected AF as compared with paroxysmal and permanent AF (overall p < 0.001) had a higher chance for receiving recommended therapy. Prescription of the full package was higher in LVSD-HF than in PSF-HF patients (35% vs. 28%; p = 0.014) (Fig. 2), which was nonsignificant after exclusion of patients with potential contraindications (38% vs. 32%; p = 0.126). No significant effect of HF type on this appropriate drug prescription was observed in multivariable analysis.
The combination of a beta-blocker and digitalis was given to 20% of all HF patients, and 40% received any combination of rate control drugs. These prescription rates were similar in HF patients with permanent AF, 24% and 38%, respectively, while 16% did not receive any rate control drugs. Only 40% of patients with HF and permanent AF had a resting heart rate ≤80 beats/min at baseline. Patients with LVSD-HF were more likely to receive multiple rate control drugs than those with PSF-HF (50% vs. 37%; p < 0.001).
HF patients with an ACEI/ARB more often received a beta-blocker (46% vs. 37%; p = 0.001) and also OAC (69% vs. 63%; p = 0.013) than patients without an ACEI/ARB. In the same manner, patients with a beta-blocker more often received OAC (72% vs. 63%; p < 0.001).
Adverse events, disease progression, and treatment during 1-year follow-up
During 1-year follow-up, AF patients with HF had a substantially worse outcome than those without HF in univariable analysis, and also a higher cardiovascular and all-cause mortality after correction for differences in baseline characteristics in multivariable analysis (Table 3).
Among HF patients, old age, prior major bleeding, prior stroke or transient ischemic attack, and low systolic blood pressure at baseline were significantly associated with a higher all-cause mortality (Table 4).However, being in sinus rhythm at discharge, female sex, and ACEI use were associated with a lower mortality. No effect was found of HF type with regard to mortality. Receipt of recommended drug therapy for LVSD-HF and also for AF and LVSD-HF combined was not associated with a better outcome among all HF patients, nor in patients with LSVD-HF or PSF-HF.
AF was more likely to progress during 1 year in patients with HF (35% vs. 19%; p < 0.001), but progression was similar in those with LVSD-HF and PSF-HF (both 35%; p = 0.947). Among patients with a first episode of AF and without HF at baseline, 7% were diagnosed with HF in the following year.
This analysis of the Euro Heart Survey on AF provides a unique and comprehensive overview of patient characteristics, treatment, and outcome of patients who have both HF and AF. Our analysis confirms that patients with combined AF and HF have a grim prognosis with a 1-year mortality of 9.5% and worsening of HF in almost 25%. These patients might be severely undertreated, with regard to drug therapy for stroke prevention, HF therapy, and rate control.
Stroke risk in HF and AF
The 2001 HF and AF guidelines (10–12) recommended OAC in all AF patients with HF. In contrast, 32% of our population did not receive OAC, and this could not be fully explained by the presence of potential contraindications. A previous analysis of the Euro Heart Survey on AF also showed that OAC therapy was hardly tailored to the CHADS2score and that patients with HF were not more likely to receive OAC than other patients with AF (14). The 2006 AF guidelines—which consider LVSD-HF to be at higher risk than PSF-HF—only recommend OAC in HF patients when there is at least 1 other CHADS2stroke risk factor present (6). Nevertheless, using the 2006 criteria, still 94% of all HF patients should have received OAC in our survey. In addition, the 6% of HF patients who exclusively had HF as a risk factor are likely to develop another risk factor in time. Therefore the straightforward recommendation to routinely prescribe OAC to all patients with AF and HF might improve appropriate OAC application in this patient group.
Combined management of HF and AF
In HF patients, less diagnostic testing like thyroid function or exercise tests, in order to find a cause for AF, had been performed. It seems that with the combined presentation of AF and HF a reciprocal cause for both diseases is assumed, and no further diagnostic testing is deemed necessary. This is in contrast to the AF guidelines, which recommend intense screening for pathologic causes.
In HF, both ARBs and ACEIs reduce morbidity and mortality and are therefore recommended by the HF guidelines. Also, both drugs have the potential to decrease atrial pressure, reduce (atrial) fibrosis and AF recurrence (15–17). It is therefore encouraging to see that ACEI prescription was higher in the HF group. Beta-blockers are also recommended in patients with LVSD-HF, but only 50% actually received this drug. The combination of either an ACEI or ARB with a beta-blocker (“recommended drug therapy for LVSD-HF”) was prescribed in only 44% of patients with HF and AF who did not have potential contraindications. Digitalis should be added to a beta-blocker for rate control in patients with LVSD-HF and AF. However, 78% of patients with LVSD-HF did not receive this combination, and only one-half of the patients received more than 1 rate control drug. Considering the fact that few of these patients had a ventricular rate below 80 beats/min, rate control was probably inadequate.
Taking into account the fact that OAC was highly recommended in all patients with AF and HF by the 2001 AF guidelines, only 32% of patients without contraindications received the full package of ACEI/ARB, beta-blocker, and OAC. These individual drugs tended to cluster within patients, which might indicate general unawareness of recommended therapy in specific physicians, but possibly also clustering of contraindications for multiple drugs in patients, or the requirement of extra reinforcement by the presence of another comorbidity requiring the same drugs.
Reciprocal impact of HF and AF, and the effect of drug therapy
In agreement with previous observational results, we showed that HF dramatically worsens prognosis of AF patients (1). Having sinus rhythm at discharge (even though associated with low adherence to HF and AF treatment) and receiving an ACEI was associated with a lower risk for all-cause mortality, but no difference in mortality was found between a rate and rhythm control strategy. Probably sinus rhythm simply reflects a better hemodynamic cardiac situation and might therefore be an independent prognostic marker rather than a treatment target. In contrast to ACEI, the effect of beta-blockers on mortality in patients with HF and AF is not yet established in a prospective manner and our results add doubt since no protective effect was found during 1-year follow-up. Interestingly, very few studies addressing the effect of beta-blockers in HF patients having AF have been published. Carvedilol is the only beta-blocker with a proven protective effect in this specific population, although solely based on 1 small prospective randomized trial (18). Larger prospective randomized trials assessing the effect of carvedilol and other beta-blockers in patients with both HF and AF are needed to asses whether or not a beta-blocker is favorable. Until then, it is recommended to start a beta-blocker in patients with HF and AF. The low stroke rates with lack of differences between groups might indicate that the actual risk of stroke is comparable in patients with HF versus without HF and LVSD-HF versus PSF-HF, or that OAC is more effective in the groups with presumed higher stroke risk (HF and LVSD-HF). Either way, the high OAC application rate in combination with the low rate of stroke and also bleeding points towards an increasing the appropriate use of antithrombotic treatment, although 1 of 3 patients was still undertreated.
Patients with AF and HF had evidence of substantial left ventricular and left atrial structural remodeling compared with patients without HF. In addition, they had more advanced forms of AF, were more likely to progress to persistent and permanent AF, and were less likely to undergo cardioversion. This reinforces the notion that HF and AF are part of a vicious circle of deterioration but also suggests that this complex disease combination may instill a sense of therapeutic futility and nihilism among clinicians that adversely affects the management of both conditions. Indeed, only 32% of patients without potential contraindications received combined treatment with OAC, beta-blockers, and ACEIs or ARBs suggesting a large shortfall in the quality of care.
LVSD-HF versus PSF-HF
Our findings that PSF-HF patients were older, more often women, and more frequently had a history of hypertension, and that LVSD-HF patients more often had a history of vascular disease, are in line with previous reports (19,20).
In the 2005 HF guidelines no treatment recommendation is given for PSF-HF other than treating associated diseases like hypertension (7,8). Adding to this their high morbidity and mortality and our findings that only few receive recommended therapy for LVSD-HF stresses the importance for further research on the optimal treatment of HF patients with PSF. It is remarkable though that we did not find a difference between LVSD-HF and PSF-HF for the application of recommended drugs for LVSD-HF. This might indicate that left ventricular function does not play a major role in the decision to apply recommended therapy in patients with AF and HF. However, the high presence of other pathologies in PSF-HF warranting the same drugs—as shown by the positive association of diabetes with prescription of recommended drugs—might mask an actual higher application rate due to left ventricular dysfunction in LVSD-HF. Nevertheless, the application rates of recommended drugs in LVSD-HF were low and warrant investigation of the reasons for undertreatment of this HF group with the strongest evidence base.
No differences in major adverse events between PSF-HF and LVSD-HF were observed. One explanation for the disparity between clinical trials and surveys is that the higher cardiovascular mortality associated with LVSD-HF is offset by a higher noncardiovascular mortality in PSF-HF associated with the higher rate of comorbidities in this population. Furthermore, in patients with PSF-HF, AF might worsen outcome even more than in LVSD-HF patients (21).
Patients with AF and HF were more often lost to follow-up after 1 year (25% vs. 18%; p < 0.001) and we might have underestimated mortality and incidence of adverse events in this group, compared with patients with solely AF. In 37% of HF patients we could not determine type of HF (LVSD-HF or PSF-HF) due to the absence of recent echocardiography data. We have not been able to extract all potential contraindications for recommended drug therapy, like periodic bradycardia, hyperkalemia, chronic liver disease, and refusal of therapy. Further, the values for the potential contraindications ventricular rate and systolic blood pressure in this survey were snapshots and might have been different in the past. Therefore, we cannot assess whether different values in the past were reason for not prescribing beta-blockers. We did not have information on drug dosages and since dosing of recommended drugs in daily practice is frequently lower than proven effective in trials, this might partially explain the absence of efficacy of some drugs in our survey. A mere 36% of AF patients without HF were using diuretics. In this patient group, diagnosis of HF is frequently overlooked (22), leading to a higher event rate in the presumed solely AF group. There was no clear widespread consensus for the exact diagnosis of HF at the time of designing the survey, which might make our definition of HF prone to discussion. Nevertheless, we aimed to assess adequacy of treatment of patients with AF and HF, and once the physician considered the patients in our survey to have both pathologies they should treat them as such. Finally, >50% of the population was enrolled in university hospitals, which usually see more severely diseased patients than other hospitals, but are often well informed on evidence-based medicine, and recommended therapy application rates might even be lower in other settings.
The authors thank the Euro Heart Survey team, national coordinators, investigators, and data collection officers for performing the survey.
This study was supported by AstraZeneca, Sanofi-Aventis, and Eucomed. Additional support was received from the Austrian Heart Foundation, Austrian Society of Cardiology, French Federation of Cardiology, Hellenic Cardiological Society, Netherlands Heart Foundation, Portuguese Society of Cardiology, Spanish Cardiac Society, and the Swedish Heart and Lung Foundation. Dr. Cleland is a consultant for Biosense Webster, which makes equipment for ablation of atrial fibrillation. Dr. Capucci is a consultant for CVT and Medico.
- Abbreviations and Acronyms
- angiotensin-converting enzyme inhibitor
- atrial fibrillation
- angiotensin II receptor blocker
- coronary artery disease
- confidence interval
- chronic obstructive pulmonary disease
- heart failure
- left ventricular systolic dysfunction
- New York Heart Association
- oral anticoagulation
- odds ratio
- preserved systolic function
- Received March 31, 2008.
- Revision received January 8, 2009.
- Accepted January 12, 2009.
- American College of Cardiology Foundation
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