Gaps in the ARB Knowledge Base: Are ARBs Effective Anti–Atrial Fibrillation Agents?

Abstract

The impact of atrial fibrillation (AF) on the overall health of the patient is underestimated by many health care practitioners. Aging is the most important pathogenetic factor for this disease and, with the aging of the population, AF will soon reach epidemic levels. Although the surface electrocardiograph indicates the presence of this arrhythmia, there are numerous mechanisms that could be causing it. Therefore, the clinician has to choose which intervention might be best. However, currently available therapeutics, both pharmacologic and nonpharmacologic, are inadequate. This paper will discuss the clinical impact of AF, its various treatment options, how inhibitors of the renin‐angiotensin‐aldosterone system (RAAS) can impact atrial electrophysiology, and therapeutic evidence to support the use of RAAS modulation in AF.

Lyndon Johnson once told a story about a man who was interviewing for a job as a switchman on a railroad. He was asked the question, “What would you do if you looked to your right and saw a train coming into the station 100 miles an hour without braking, and you looked to your left and you saw another train coming into the station 100 miles an hour without braking? What would you do?” And he said, “I’d go get my brother, Jeb.”“Why would you get your brother, Jeb?”“Because Jeb ain’t never seen a train crash.”

The field of cardiovascular (CV) disease is like these two trains coming into the station. The impact of the disease state is underestimated, and currently available therapeutics are inadequate. One of the areas where this is happening is atrial fibrillation (AF), which is at epidemic levels. At many hospitals, including Lankanau Hospital in Philadelphia, AF is the number one reason for inpatient CV consultation. And as the population ages, there is a greater incidence of AF, but also type 2 diabetes mellitus and hypertension.

Clinical Impact of AF

Aging is by far the most important pathogenetic factor for AF. For every year a person lives past 50, 1% of atrial musculature is replaced with fibrous tissue. Therefore, in a 100‐year‐old person, almost half the atrium is replaced with fibrous tissue. It is this fibrosis that acts as a substrate for AF in the elderly. Prevalence is increased as well because physicians are more aware of the disease and spend more time monitoring patients. In addition, better technology has enabled better detection of the arrhythmia. AF has an important impact on public health largely because it is an important risk factor for stroke due to the formation of blood clots in the atrium, which can dislodge and block blood flow in cerebral vessels. Strokes from AF tend to be disabling or fatal. AF is also a risk factor for heart failure (HF) due to potentially deleterious hemodynamic and electrophysiologic changes, which could accelerate the progression of left ventricular dysfunction in patients with underlying HF.

AF: Treatment Options

Treatment of AF starts with prevention. This is where agents that inhibit the renin‐angiotensin‐aldosterone system (RAAS) may prove most useful. In addition, for patients who have the disease, these agents may be useful as adjuvant therapy along with membrane‐active drugs. Once the arrhythmia is established, RAAS inhibitors do not have enough of an electrophysiologic impact on the atrium to be stand‐alone drugs. This is important because it is good to be in sinus rhythm. A misleading message from trials such as the Atrial Fibrillation Follow‐Up Investigation of Rhythm Management (AFFIRM) and Rate Control versus Electrical Cardioversion (RACE) study was that rate control was as good as rhythm control. This is nonsensical. ¹ , ² Rate control is a default strategy that is pursued in people when attempts at sinus rhythm have failed. Patients who have symptomatic AF need sinus rhythm, and there is reason to believe that sinus rhythm is associated with better outcomes. A post hoc analysis from AFFIRM that looked at the value of sinus rhythm clearly showed that it is associated with better survival. ³ The problem was that patients had to be taking an antiarrhythmic drug to be in sinus rhythm. The drug was usually amiodarone and the benefits of this drug in this study were offset by serious adverse effects. In the Placebo‐Controlled, Double‐Blind, Parallel Arm Trial to Assess the Efficacy of Dronedarone 400 mg bid for the Prevention of Cardiovascular Hospitalization or Death from Any Cause in Patients With Atrial Fibrillation/Atrial Flutter (ATHENA) trial, the use of the antiarrhythmic drug, dronedarone, in patients was associated with fewer hospitalizations compared with patients with AF who were not treated with that drug. ⁴ The relevant message is that it is good to be in sinus rhythm.

An algorithm depicting a modification of the treatment algorithm in the 2006 American Heart Association/American College of Cardiology (AHA/ACC) treatment guidelines for AF is shown in Figure 1. The key point in this new algorithm is the idea that prevention is a good idea. An intervention that has relatively low risk and is effective at preventing AF should be contemplated in patients with a high risk of developing AF. ⁵

Figure 1.

 Atrial fibrillation treatment options. AADs indicates antiarrhythmic drugs; CCB, calcium channel blocker; ACEI, angiotensin‐converting enzyme inhibitor; ARB, angiotensin receptor blocker; PUFA, polyunsaturated fatty acid; PV, pulmonary vein. Adapted with permission from Prystowsky. ⁵

In clinical practice, we already do this. A patient who has hypertensive heart disease is at high risk for AF. With “upstream therapy,” the goal is to prevent AF before it starts. Therapeutic candidates for upstream therapy include angiotensin‐converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARB), statins, fish oil, anti‐inflammatory agents, β‐blockers, and proliferator‐activated receptor γ modulators.

RAAS Inhibitors and Their Effects on Atrial Electrophysiology

There is no way to dissociate the antihypertensive effects, antifibrotic effects, and anti‐inflammatory effects of a drug from its direct electrophysiologic effects. In a canine right ventricle pacing model, AF duration was increased relative to controls due to pacing‐induced atrial electrical remodeling caused by the formation of fibrous tissue. Tissue fibrosis creates a substrate that causes persistent arrhythmias independent of action potential duration. Although enalapril attenuates the development of interstitial fibrosis, it has no impact on the atrial effective refractory period, conduction velocity, or wavelength of conduction. Thus, angiotensin II may contribute to the development of atrial fibrosis but may do so even with minimal direct electrophysiologic effects. ⁶ , ⁷

So, how do these drugs work? Figure 2 provides a schematic of possible ways ARBs might affect AF. There are many different things going on, suggesting a sort of “dirty molecule” description. However, this is not necessarily a bad thing, because the most effective and most frequently used therapy available for AF is amiodarone, a drug that has a number of electrophysiologic effects in the atrium that may be beneficial. The mechanism of action for this drug is still unclear, however, and no single concept can explain its benefits.

Figure 2.

 Potential mechanism explaining the benefits of angiotensin receptor blockers (ARBs).

ARBs possess several mechanisms that might affect atrial electrophysiology and thereby prevent AF. Moreover, not only is it not known how these drugs work, but it is not known what causes AF. At least 10 different diseases are collectively called AF, which all look the same on the surface electrocardiograph. However, the mechanisms for AF vary greatly from a patient without obvious structural heart disease who has a pulmonary vein trigger, to a patient with end‐stage HF. We believe that patients in the latter category, with “substrate‐related AF,” have several rotors in both atria that interact with each other in a hopelessly complicated electrophysiologic milieu.

Treating AF is like treating bacterial pneumonia and not knowing what the organism is. A shotgun approach is used with the hope that you can treat some people, but realizing that a lot of people will not be treated effectively.

Therapeutic Evidence for RAAS Modulation

Trials with RAAS inhibitors have shown diverse outcomes. Some ACE and ARB trials have shown efficacy, but other trials have not. In many circumstances, one class is not necessarily superior to the other, although there are data indicating that HF‐related AF may be better treated with ARBs than with ACE inhibitors. The largest effect size appears to be in patients with HF and left ventricular hypertrophy. In patients with hypertension without hypertrophy, there does not appear to be as much of a treatment effect. In the Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM) program, candesartan demonstrated benefit in all 3 parts of the study, including patients with low ejection fraction. ⁸ The Losartan Intervention For Endpoint Reduction in Hypertension Study (LIFE) showed that losartan was superior to atenolol in suppressing AF as well as significantly reducing stroke. ⁹ The Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET), on the other hand, showed only a nominal effect on AF development with telmisartan. ¹⁰ In the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocradico–Atrial Fibrillation (GISSI‐AF) trial, however, valsartan was not associated with a reduction in the incidence of recurrent AF. ¹¹

The ongoing Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events (ACTIVE I) study uses irbesartan in one of its treatment arms. In the factorial design of this study, 9000 patients are being evaluated for their response to irbesartan vs placebo for the prevention of vascular events including stroke, myocardial infarction, vascular death, and HF hospitalizations. This is the largest trial ever conducted studying the effect of blood pressure lowering in patients with AF. Baseline parameters show that more than 60% of patients were already taking ACE inhibitors and more than 65% of patients had permanent AF. ¹²

RAAS Inhibition as Adjunctive Therapy

The goal of adjunctive therapy is to improve the efficacy of a membrane‐active drug such as amiodarone by adding an ACE inhibitor or ARB. A study by Madrid and colleagues ¹³ demonstrated that irbesartan augmented the effect of amiodarone while Yin and colleagues ¹⁴ showed a similar response with both losartan and perindopril in a patient population with lone AF or AF in the absence of structural heart disease.

Conclusions

There is likely added benefit of using RAAS modulators and perhaps drugs from other classes for patients with AF, but the mechanism by which this occurs is unclear. Another unexplored area is dosage. It may not be accurate to presume that doses that lower blood pressure or are used for treating HF will be the same doses to cause anti‐fibrillatory effects. Getting answers is not easy since large numbers of patients are needed to study multiple doses in multiple arms to determine efficacy in prevention studies. Adequately powered, better prospective studies are needed to study RAAS inhibitors alone and in combination with membrane‐active agents, perhaps even in combination with other therapeutic procedures, such as catheter ablation.

Disclosures:  Dr Kowey has indicated that he owns stock, stock options, or bonds from CardioNet. He has received grants for educational activities from Medtronic, Inc, Boston Scientific, and St. Jude Medical. He also served as an advisor or consultant for sanofi‐aventis, GlaxoSmithKline, AstraZeneca Pharmaceuticals LP, Johnson & Johnson Pharmaceutical Research & Development, LLC, Solvay Pharmaceuticals, Inc, and Boehringer Ingelheim Pharmaceuticals, Inc. The author acknowledges the assistance of Practicum Educational Services in preparing this article and styling the paper for journal submission. Editorial support was provided by Ronald K. Miller, PhD, and funded by Daiichi Sankyo, Inc. The author received an honorarium from Daiichi Sankyo, Inc, for time and effort spent preparing this article.