Pleiotropic effects of statins in atrial fibrillation patients: the evidence

Figures & data

Figure 1 Atrial fibrillation and pleiotropic effect of statins.

Table 1 Experimental studies on the effect of statins on atrial fibrillation

Author	Study type	Study result
Tsai et al^Citation19	Rats infused long term with Ang II exhibited higher levels of activated Rac1, phospho-STAT3, collagen synthesis, and atrial fibrosis.	Oral losartan and simvastatin attenuated these effects
Chello et al^Citation21	Experiments on right atrial segments obtained before the onset of cardiopulmonary bypass in two groups of patients. In chronic AF or sinus rhythm in either presence or absence of 5 μm simvastatin	Chronic AF upregulates CD40 expression + platelet adhesion to the endocardium. Simvastatin is effective in modulating this expression
Shiroshita-Takeshita et al^Citation66	Experimental dogs were subjected to two-week VTP in the absence and presence of simvastatin (20 or 80 mg/day) or fenofibrate. Simvastatin vs. fenofibrate on CHF-related atrial remodeling.	Simvastatin prevented VTP-induced DAF and attenuated CHF-induced conduction abnormalities, atrial fibrosis and attenuated VTP-induced left-ventricular nitric-oxide synthase and nitrotyrosine increases, along with hemodynamic dysfunction and significantly attenuate TGF-β1-stimulated alpha-smooth muscle actin (alpha-SMA) expression
Kumagai et al^Citation59	Twenty dogs with sterile pericarditis model given atorvastatin orally (2 mg/kg/day)	On the second postoperative day, the atorvastatin group had a lower CRP level (7.6 ± 0.5 vs. 11.7 ± 1.3)
Shiroshita-Takeshita et al^Citation28	Dogs subjected to ATP at 400 bpm in the absence and presence of treatment with simvastatin, vitamin C, and combined vitamins C and E.	Simvastatin attenuates AF promotion by atrial tachycardia in dogs, an effect not shared by antioxidant vitamins

Abbreviations: AF, atrial fibrillation; ATP, atrial tachypacing; CHF, coronary heart failure; CRP, C-reactive protein; DAF, pacing-induced AF; TGF-β1, transforming growth factor-β1; VTP, ventricular tachypacing AF.

Table 2 Result from major randomized trials and meta-analyses

Author	Meta-analyses	Study types	Conclusion
Fauchier et al^Citation68	Six studies with 3,557 patients	Three studies investigated the use of statins in patients with PAF (1) or persistent AF undergoing electrical cardioversion (2), and three investigated the use of statins in primary prevention of AF in cardiac surgery patients or after ACS	Statins were significantly associated with a decreased risk of AF compared with control (p = 0.02). Benefit of statin therapy seemed more marked in secondary prevention of AF (p = 0.06) than for new-onset or postoperative AF (p = 0.23).
Liu et al^Citation67	Six RCTs and 10 observational studies	7,041 patients	No significant effect of statins on AF development (RR = 0.76, 95% CI:0.55–1.05; p = 0.09) observational studies showed statin use ↓ the relative risk for AF by 23%. This effect was greatest in the post-operative patients (RR = 0.61, 95% CI: 0.49–0.76)
Liakopoulos^Citation109	Three RCT (randomized prospective clinical trials), 16 observational studies	31,725 cardiac surgery patients	Preoperative statin therapy resulted in a 1.5% absolute risk reduction (2.2 vs 3.7%; P < 0.0001) and 43% odds reduction for early all-cause mortality (OR 0.57; 95% CI: 0.49–0.67).
Patel et al^Citation69	Fourteen trials reporting the results of 15 unique analyses	7,402 patients on statin therapy vs. nonstatins	Statin ↓ any AF by 45% (Q statistic p = 0.001). Statins ↓ new-onset AF by 32% (OR 0.68; 95% CI: 0.51–0.90), recurrent AF by 57% (OR 0.43; 95% CI: 0.24–0.79), recurrent AF after cardioversion by 42% (OR 0.58; 95% CI: 0.32–1.05) and postoperative AF by 58% (OR 0.42; 95% CI: 0.27–0.65).
Author	Randomized trials	Study types	Conclusion
McLean et al^Citation70	Two large, randomized trials: PROVE IT-TIMI 22 and phase Z of the A to Z trial,	Low-vs. high-dose statin therapy to evaluate whether higher-intensity statin therapy ↓ the risk of AF onset at two-years follow-up	Neither study showed ↓ AF risk with higher-dose statin. In PROVE IT-TIMI 22, 2.9% versus 3.3% in the high-versus standard-dose statin, respectively, In both trials, C-reactive protein levels (plasma or serum) tended to be higher among patients experiencing the onset of AF
Coletta et al^Citation97	GISSI-HF trial: a randomized, double-blind, placebo-controlled trial,	7046 patients with clinical evidence of HF of any cause, median followed up at 3·9 years	Rosuvastatin 10 mg daily did not affect clinical outcomes in patients with chronic heart failure of any cause (p = 0.943)
Hanna et al^Citation95	Data from ADVANCENT(SM), a multicenter registry	25,268 patients with reduced LVEF ≤ 40%	In multivariable analysis, lipid-lowering drug use remained significantly associated with reduced odds of AF (OR [OR] 0.69, 95% CI: [CI] 0.64–0.74),
Dickinson et al^Citation96	SCD-HeFT study of followed up of median of 45.5 months.	2521 functional class II and III HF patients with LVEF ≤ 35%, ischemic and nonischemic CM	Mortality risk significantly lower in those taking a statin (HR [95% CI], 0.70 [0.58–0.83]). In all subgroups: ischemic CM(0.69 [0.56–0.86]), and nonischemic CM(0.67 [0.47–0.96]), ICD (0.66 [0.46–0.95], nonICD (0.71 [0.57–0.87]), NYHA II (0.62 [0.48–0.79]), NYHA III (0.79 [0.61–1.03]).
Adabag et al^Citation71	Cohort: an average follow-up of 4.8 years	13,783 patients, CAD patients	No difference in AF incidence with statin treatment (p = 0.09). No effects of statin treatment on AF incidence in CHD patients; however, AF was reduced in a subset of patients with CHF (p = 0.04)

Abbreviations: AF, atrial fibrillation; CAD, coronary artery disease; ACS, acute coronary syndrome, CHF, coronary heart failure; PAF, paroxysmal atrial fibrillation; LVEF, left-ventricular ejection fraction.

Table 3 Most recent studies on the relation of atrial fibrillation, inflammation, and the role of statins

Author	Study type	Study substrate	Drug tested	Study result
Dernellis and Panaretou^Citation45	Prospective with 4–6 months follow up	80 patients with PAF	Atorvastatin (40 patients) vs placebo (40 patients)	Lower median CRP levels and significant reduction in the number of episodes of PAF which completely resolved in 26/40 (65%) of treatment group. vs. 4/40 (10%) in placebo group.
Tziakas et al^Citation63	Prospective, assess the effect of statins on collagen type I degradation and C-reactive protein in patients with CAD and AF	106 patients with CAD + AF	Statin vs. no statins	Carboxy-terminal telopeptide of collagen type I levels significantly higher (p < 0.001) in statin-treated patients and lower (p < 0.001) CRP level.
Marcus et al^Citation47	Cross-sectional analysis of 971 participants in the Heart and Soul Study,	46 AF patients IL-6, CRP, TNF-α, CD-40 ligand, monocyte chemo-attractant protein-1 and fibrinogen levels measured.		IL-6 was the only biomarker significantly associated with AF (median IL-6 3.76 and 2.52 pg/ml in those with and without AF, respectively; p = 0.0005; adjusted OD 1.77; p = 0.032).
Ramani et al^Citation73	Observational retrospective	1,526 ACS patients	Statin therapy vs. no statins	Univariate analysis, patients on statins less likely to have new-onset AF (OD; 0.40, 95% CI: 0.33 to 0.69, p < 0.01). This persisted in the multivariate model (OD; 0.57, 95% CI: 0.39 to 0.83; p < 0.01) after correcting for age, race, DM, chest pain, and ACE-I use.
Young-Xu et al^Citation11	Prospective observational	449 with CAD were followed for an average of five years	Statin therapy vs. no statins	Statin significantly ↓ risk of developing AF (OD; 0.48, 95% CI: 0.28 to 0.83).
Neuman et al^Citation22	Derivatives of reactive-oxidative metabolites (DROMS) and ratios of oxidized to reduced glutathione (E(h) GSH) and cysteine (E(h) cysh) to quantify oxidative stress, hs-CRP, IL-β and 6 and TNF-α	40 male individuals, with or without persistent or permanent AF		Univariate, conditional logistical regression analysis showed that oxidative stress but not inflammatory markers were statistically associated with AF (p < 0.05).
After cardioversion
Humphries et al^Citation76	Prospective, Canadian Registry of Atrial Fibrillation.	625 patients with new onset AF	Statin therapy vs. no statins	74% reduction in the odds of recurrent AF in statins group.
Loricchio et al^Citation77	Prospective study to test the relation of CRP to the rate of recurrence of AF	102 patients nonvalvular persistent AF; 1 year follow up	------------------	CRP independently associated with AF recurrence during follow-up (p = 0.003).
Ozaydin et al^Citation78	Prospective study; three months of follow-up	48 patients with AF	Atorvastatin vs. placebo	Atorvastatin significantly reduced risk of developing AF (p = 0.024).
Watanabe et al^Citation75	Prospective, follow-up period of 140 ± 144 days	106 patients symptomatic AF ≥ 1 day + cardioversion	------------------	hs-CRP level an independent predictor of AF recurrence (OR 5.30, 95% CI: 2.46–11.5) after adjustment of CV risks.
Siu et al^Citation12	Retrospective study; mean follow-up of 44 months	62 patients with lone, persistent AF lasting ≥ 3 months	Statin therapy vs. no statins	Statins significantly decrease AF recurrence after successful cardioversion.
Tveit et al^Citation74	Open, controlled multicenter study.	Patients (n = 114) who had atrial fibrillation >48 hours	Pravastatin 40 mg three weeks. Before and six weeks. After electrical conversion	Pravastatin did not reduce the recurrence rate of atrial fibrillation after electrical cardioversion.
After ablation
Al Chekakie et al^Citation79	Retrospective study	177 patients	ACE-I (31 patients) or ARB (18 patients) and statins (50 patients)	Statins did not decrease the recurrence rate, but ARB did
Richter et al^Citation80	Retrospective analyses of prospective study, a median follow-up of 12.7 months	234 patients with drug-resistant paroxysmal (n = 165) or persistent AF (n = 69)	Statins(113 patients) ACE-Is, or ARBs (124 patients), or statin + ACE-I or ARB (n = 75)	Statin use (HR, 1.06; P = 0.79), ACE-I or ARB use (HR 1.12; P = 0.59), and their combined use (statin + ACE-I/ARB; HR 1.17; p = 0.54) did not significantly influence ablation outcome as assessed by Cox regression analysis.
In patients with pacemaker
Tsai et al^Citation82	Open-label prospective randomized design/one-year follow-up. Bradyarrhythmias and implantation of an atrial-based or dual-chamber pacemaker	52 on atorvastatins and 54 no statin.	Atorvastatin 20 mg/d	After one-year follow-up atrial high rate episodes 5.8% of statin group and 19.2% in the no statin group. p = 0.041, mean left atrial volume of the statin group significantly lower than nonstatin group (39.7 ± 1.7 vs. 43.7 ± 1.9 ml; p = 0.0001).
Gillis et al^Citation81	Observational cohort study on patients Dual-chamber pacemaker testing AT/AF recurrence	185 patients with P AF	Statin therapy vs. no statins	AT/AF burden was significantly lower in the group on statin therapy.
Amit et al^Citation83	A cohort + over a three-year period	264 patients (49% women, mean age [± SD] 71 ± 12 yr.	Statin therapy vs. no statins	Statin had no protective effect against the risk of AF in patients with permanent pacemaker.
Bhavnani et al^Citation84	Prospective	1,445 patients with ICD	Statin therapy vs. no statins	Statin ↓ AF/AFL tachyarrhythmia detection and inappropriate shock therapy.
In perioperative AF
Kourliouros et al^Citation104	A retrospective study	680 patients underwent CABG surgery and/or aortic valve replacement	Simvastatin 40 or 10 mg Atorvastatin 40 or 10 mg	Statin treatment reduces the incidence of AF after cardiac surgery. Higher-dose statins have the greatest preventative effect.
Subramaniam et al^Citation105	Observational cohort study	2,497 adult patients who underwent isolated CABG	Statin therapy vs. no statins	Preoperative statin intake did not reduce the frequency of major perioperative morbid events after isolated CABG.
Virani et al^Citation115	A retrospective study	4,044 cardiac surgeries	Statin therapy vs. no statins	Preoperative statin therapy not ↓ risk in the entire cohort or in subgroups undergoing isolated CABG, isolated valve surgery or subgroup with EF < 35%.
Lertsburapa et al^Citation107	Nested cohort evaluation from the randomized, controlled AF Suppression Trials I, II, and III.	331 patients undergoing cardiothoracic surgery	Statin therapy vs. no statins	40 mg of atorvastatin associated with a 40% reduction in patients’ odds of developing post-cardiothoracic surgery AF
Patti et al^Citation110	Prospective randomized study ARMYDA-3	200 elective cardiac surgery patients (cardiopulmonary bypass) no statin treatment or history of AF	Atorvastatin (40 mg/d, n = 101) or placebo (n = 99)	Atorvastatin significantly reduced the incidence of AF versus placebo (35% vs. 57%; p = 0.003).
Mariscalco et al^Citation106	Retrospective longitudinal observational study	405 patients underwent isolated CABG	Statin treatment vs. no statins	Statins were associated with a 42% reduction in risk of AF after CABG
Knayzer et al^Citation103	Prospective study	156 CABG patients	Statin therapy vs. no statins	Preoperative treatment with statins may ↓ postoperative inflammatory response
Ozaydin et al^Citation108	Observational study	362 patients	Statin therapy vs. no statins	Postoperative AF less and shorter duration in statin group vs. no statins group (p = 0.03 and 0.0001), respectively.
Marín et al^Citation13	Prospective study	234 patients underwent CABG	Statin therapy vs. no statins	Statin ↓ arrhythmia (OD; 0.52, 95% CI; 0.28 to 0.96, p = 0.038).

Abbreviations: AF, atrial fibrillation; ACE-1, angiotensin-converting enzyme inhibitors; ARBs, angiotensin receptor blockers; ACS, acute coronary syndrome; CI, confidence intervals; CABG, coronary artery bypass grafting; CRP, C-reactive protein; hs-CRP, high senstivity-CRP; OR, odds ratio; HR, hazard ratio; EF, ejection fraction; ICD, implantable cardioverter defibrillator; AFL, atrial flutter; AT, atrial tachyarrhythmia; CV, cardiovascular; DM, diabetes mellitus.

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