Statin Therapy for Primary Prevention of Atrial Fibrillation: Guided by CHADS₂/CHA₂DS₂VASc Score

Abstract

Atrial fibrillation (AF) is the most common arrhythmia and is associated with increased cardiovascular morbidity and mortality. The anti-arrhythmic effect of statins on AF prevention appears to be highly significant in most clinical studies. However, some discrepancies do exist among different clinical studies. Different clinical settings and types of stains used may explain these differences between trials. The CHADS₂ and CHA₂DS₂VASc scoring systems have been used for stroke risk stratification in AF patients. The recent study suggested that these scores can also be used to guide statin therapy for AF prevention. Patients with higher scores had a higher risk of developing AF and gained more benefits from statins therapy than those with lower scores. This review article focused on the ability of these scores to predict AF prevention by statins.

Introduction

Atrial fibrillation (AF) is the most common clinically significant arrhythmia and it is associated with increased hospitalization, all-cause mortality, and health care costs.¹⁾,²⁾,³⁾,⁴⁾,⁵⁾ The chief hazard of this arrhythmia is ischemic stroke and heart failure, which might cause hemodynamic compromise and lead to further morbidity and mortality.²⁾ Risk factors for AF include old age, male gender, congestive heart failure, hypertension, diabetes mellitus, vascular disease, pulmonary disease, valvular heart disease, and chronic kidney disease.²⁾,³⁾,⁶⁾,⁷⁾,⁸⁾ Because of the rising prevalence of these co-morbidities and the increasing elderly population, the overall economic burden from AF is likely to increase in the following decades. Therefore, there is an urgent need to identify preventive measures in the occurrence of new-onset AF.⁹⁾

Classical anti-arrhythmic drugs are often characterized by several adverse effects and relative inefficacy.⁵⁾ Safer and more efficacious therapeutic agents are needed for AF prevention.⁹⁾ It has been shown that "upstream therapies", which aim at reversal of atrial substrate derangement, could be used for AF prevention. Accordingly, the current focus has been shifted to non-antiarrhythmic drugs such as statins, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, and omega-3 polyunsaturated fatty acids. An increasing number of animal experiments and clinical studies have investigated the beneficial role of statins in AF prevention,¹⁰⁾,¹¹⁾ and meta-analyses showed that the use of statins was significantly associated with a decreased risk of AF.¹²⁾,¹³⁾,¹⁴⁾ In addition, a recent guideline suggests that statins could be used for AF prevention in those with heart failure or undergoing cardiac surgery.¹⁵⁾ However, whether statins may prevent AF in patients other than these subgroups remains a subject of debate. This review article focused on the ability of cardiovascular co-morbidity scoring systems in predicting AF prevention by statins.

Heterogeneity Across Studies

Despite increasing evidence supporting the concept of using statins for AF prevention, clinical studies yielded conflicting results.¹⁶⁾,¹⁷⁾,¹⁸⁾,¹⁹⁾ Meta-analyses of randomized controlled trials and observational studies reveal that statin therapy is useful for primary prevention of AF,¹²⁾,¹³⁾,¹⁴⁾ but significant heterogeneity exists across these studies.¹⁴⁾,²⁰⁾ For example, in a recent meta-analysis by Fauchier et al.,²¹⁾ the most significant benefits of statins appear to be the prevention of postoperative AF and secondary prevention of AF. Other meta-analyses are also in agreement,¹³⁾,²²⁾ and Bang et al.²³⁾ assumed that the AF prevention effect of statins may be diverse in different clinical settings. These findings suggest that underlying co-morbidities may play an important role in selecting suitable patients for statin therapy.¹³⁾

Consequently, the AF preventive effect of statins might be inconsistent in different clinical setting.¹¹⁾ Therefore, recent studies have used co-morbidities scoring systems to identify patients who may benefit most from statin therapy for AF prevention. The CHADS₂ (Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, prior Stroke or transient ischemic attack) and CHA₂DS₂ VASc (Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, prior Stroke or transient ischemic attack, Vascular disease, Age 65-74 years, Sex category) scores include many cardiovascular co-morbidities, which were reportedly important risk factors for the development of AF. Recent studies show that high CHADS₂ scores are associated with an increased risk of new-onset AF,²⁴⁾,²⁵⁾,²⁶⁾ AF recurrence after ablation,²⁷⁾ and the electroanatomical remodeling of the left atrium.²⁸⁾ Moreover, the findings of our recent nationwide cohort studies suggest that the CHADS₂ and CHA₂DS₂ VASc score can be used to guide the upstream therapy of AF.²⁹⁾,³⁰⁾

CHADS₂/CHA₂DS₂VASc Score to Predict Atrial Fibrillation Prevention Outcome

The CHADS₂ scoring system, which was initially developed for the risk stratification of strokes in patients with AF, is a convenient way to evaluate the complexity of cardiovascular co-morbidities. Our recent study shows that this score may help in identifying the patients who could benefit most from statin use for AF prevention.²⁹⁾ The nationwide cohort, which included 27002 elderly hypertensive patients, demonstrates that CHADS₂ score is useful for predicting the effectiveness of statins. Patients with a CHADS₂ score ≥2 had a 31% risk reduction of AF, but those with CHADS₂ score of 1 gained no significant benefits.²⁹⁾ Another cohort study, which included 171885 patients aged ≥50 years, show identical results. Statin therapy provided no obvious beneficial effect in those with a CHADS₂ score of 0 and had the best effect for those with a CHADS₂ score of 2.³⁰⁾ Those with higher CHADS₂ score have a higher risk of AF, and gain more benefits from statins therapy than those with a lower CHADS₂ score. This implies that the CHADS₂ score could be used to guide the upstream therapy for AF prevention.

The CHA₂DS₂VASc scoring system was recently developed for stroke risk stratification in AF patients. Our study shows that patients with a CHA₂DS₂VASc score ≥1 benefit from statin use, especially those with score ≥3.³⁰⁾ Those with score of 1 gain 20% AF risk reduction from statin therapy, while those with score of 2 gain 30%, and those with score ≥3 gain 40%. In contrast, the therapy provides no obvious beneficial effect in those with a CHA₂DS₂VASc score of 0. From this point of view, CHADS₂ and CHA₂DS₂-VASc scores are not only clinical predictors for stroke risk stratification, but are also useful scoring systems for predicting the effectiveness of statin in AF prevention. However, the role of CHADS₂ and CHA₂DS₂VASc score in upstream therapy for AF requires further study.

Possible Mechanisms of Atrial Fibrillation Prevention by Statin

Atrial fibrillation is a progressive disease that depends on the electrophysiological and anatomical remodeling of atrial substrates.⁴⁾,³¹⁾ Several mechanisms including myocardial inflammation, oxidative stress, endothelial dysfunction, and alternation in ion channel conductance might contribute to atrial substrate remodeling and AF development.³²⁾ Therapeutic approaches aiming at antagonizing atrial remodeling could be of some benefit in the prevention of AF.³³⁾,³⁴⁾ Recent evidence emphasizes a role for systemic inflammation in the development and persistence of AF,³⁵⁾,³⁶⁾ linking inflammatory markers, such as C-reactive protein (CRP), to this arrhythmia.³⁷⁾,³⁸⁾ Moreover, there are several possible mechanisms by which statins can act on atrial remodeling, such as anti-inflammatory and antioxidant properties, modulation of endothelial function, and alteration of ion channel conductance.¹¹⁾,³⁹⁾,⁴⁰⁾,⁴¹⁾,⁴²⁾,⁴³⁾,⁴⁴⁾,⁴⁵⁾ These beneficial effects of statins are partly attributed to their anti-inflammatory property,⁴⁶⁾,⁴⁷⁾ which might be unrelated to their lipid lowering effect.¹³⁾,⁴³⁾,⁴⁶⁾,⁴⁷⁾,⁴⁸⁾ Clinical studies⁴⁹⁾,⁵⁰⁾,⁵¹⁾,⁵²⁾,⁵³⁾ indicate that statin treatment can reduce inflammation, which may explain the potential beneficial effect of statins for AF prevention. These concepts suggest that the anti-arrhythmic effect of statins tend to be more pronounced in patients with more systemic inflammation and damaged atrial tissue. Patients with no systemic inflammation or those with normal atrial substrate are unlikely to benefit from statin therapy for AF prevention.

Recent studies demonstrate that CHADS₂ score is useful for predicting CRP levels, left atrium thrombus formation, and the prognosis in patients with AF.⁵⁴⁾,⁵⁵⁾ This relation between CHADS₂ score and CRP has potential implications for predicting the effect of statin on AF prevention. Evidence from the Justification for the Use of statins in primary Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial hint at this mechanism.¹⁸⁾ In the JUPITER trial, patients with high-sensitivity CRP had a better AF protective effect from statin therapy. Therefore, we proposed that those with higher CHADS₂ scores have more severe inflammation, and the anti-inflammatory effect of statins may be more obvious in these patients. Furthermore, female gender and vascular disease, differential factors between CHA₂DS₂VASc and CHADS₂ scores, are also related to increasing systemic inflammation.⁵⁶⁾,⁵⁷⁾,⁵⁸⁾ Therefore, patients with higher CHADS₂ and CHA₂DS₂VASc scores may have a more severe inflammation, and the anti-inflammatory effect of statin may be more obvious in these patients. The current data and JUPITER trial support the statin anti-inflammatory hypothesis and provide an explanation of statin's AF prevention effects in patients with high CHADS₂ and CHA₂DS₂VASc scores.

Effect of Statin Type and Gender in Atrial Fibrillation Prevention by Statin

In addition to the effect of patient' characteristics, previous meta-analyses show that there is a type-dependent efficacy of statin in reducing the risk of new-onset AF.¹³⁾ A recent nationwide propensity score-matched study from Denmark also indicate that different statins have diverse effect in preventing new-onset AF.¹⁹⁾ In a meta-analysis by Fang et al.,¹³⁾ the beneficial effect was noted in the atorvastatin and simvastatin subgroup, but not in pravastatin or rosuvastatin subgroup. Our recent study, on 135275 Taiwanese patients, shows that the level of efficacy in reducing the risk of new-onset AF is related to the type of statin.⁵⁹⁾ The study used the defined daily dose, as recommended by the World Health Organization guidelines for assuming average maintenance dose per day of a drug,³⁰⁾,⁶⁰⁾ as statins dosage equivalency (simvastatin 30 mg, lovastatin 45 mg, pravastatin 30 mg, fluvastatin 60 mg, atorvastatin 20 mg, and rosuvastatin 10 mg). The results show that fluvastatin and pravastatin provide no significant AF risk reduction. Lovastatin has the strongest AF preventive effect, followed by simvastatin, rosuvastatin, and atorvastatin. A meta-analysis by Wang et al.²²⁾ and a clinical study by Komatsu et al.¹⁶⁾ (atorvastatin 10 mg/day vs. pravastatin 10 mg/day, no significant difference in lipid profile between groups) also show that atorvastatin is more effective than pravastatin. Therefore, the heterogeneity across studies is partially caused by the type of statin used.

Another interesting finding in our recent nationwide cohort study is the effect of gender.⁵⁹⁾ Male and female patients gain different AF preventive effect from different statins. Male patients gain obvious beneficial effects from rosuvastatin and atorvastatin (high-potency statins), whereas female patient gain these benefits from lovastatin and simvastatin (lipophilic statins). This finding is comparable to the result of subgroup analysis from the JUPITER trial,¹⁸⁾ which show that females do not benefit from the AF preventive effect of rosuvastatin, while males do. Different statins show divergent potency in regression of atherosclerosis,⁶¹⁾ as well as anti-inflammatory and anti-oxidant effects.⁶²⁾,⁶³⁾,⁶⁴⁾ Males and females are also different in the distribution of cardiovascular diseases and metabolic syndrome,⁵⁹⁾,⁶⁵⁾ inflammatory and oxidative status.⁶⁶⁾,⁶⁷⁾,⁶⁸⁾ Therefore, the distinct efficacy of different statins between genders might be attributable to a complex mechanism involving atherosclerotic, and inflammatory status.⁵⁹⁾ Female patients gain the AF preventive effect from lipophilic statins via modulation of inflammatory and metabolic abnormality, and male patients gain the AF prevention effect from high-potency statins via deceleration the progression of atherosclerotic diseases. The implications of these findings warrant further investigation.

Conclusion

Statin therapy is significantly associated with a decreased risk of AF in selected population. Recent studies suggest that those with higher CHADS₂ and CHA₂DS₂VASc scores will benefit most from statin use for the prevention of AF. Statins provide limited benefits in primary prevention of AF in patients with low CHADS₂ and CHA₂DS₂-VASc scores. The CHADS₂ and CHA₂DS₂VASc scoring systems are useful for identifying the patients who will benefit most from statins for AF prevention. While these clinical evidences mainly come from retrospective cohort studies, more randomized prospective trials are necessary to further support these conclusions.