Management of Angina Pectoris: The Role of Spinal Cord Stimulation

Siegfried Eckert; Dieter Horstkotte. Published: 06/02/2009

Abstract and Introduction

Abstract

Progress in prevention as well as drug and interventional therapy has improved the prognosis of patients with cardiovascular disorders. Many patients at risk have advanced coronary artery disease (CAD), have had multiple coronary interventions, and present with significant co-morbidity. Despite adequate risk factor modulation and often several revascularization procedures, some of these patients still have refractory angina pectoris. Apart from advanced CAD and insufficient collateralization, the cause is often endothelial dysfunction. For this situation, one treatment option is neuromodulation. Controlled studies suggest that, in patients with chronic refractory angina pectoris, spinal cord stimulation (SCS) provides a relief from symptoms equivalent to that provided by surgical therapy, but with fewer complications and lower rehospitalization rates. SCS may result in significant long-term pain relief with improved quality of life. In patients with refractory angina undergoing SCS, some studies have shown not only a symptomatic improvement, but also a decrease in myocardial ischemia and an increase in coronary blood flow. Discussion is ongoing as to whether this is a direct effect on parasympathetic vascodilation or merely a secondary phenomenon resulting from increased physical activity following an improvement in clinical symptoms. Results from nuclear medical studies have sparked discussion about improved endothelial function and increased collateralization. SCS is a safe treatment option for patients with refractory angina pectoris, and its long-term effects are evident. It is a procedure without significant complications that is easy to tolerate. SCS does not interact with pacemakers, provided that strict bipolar right-ventricular sensing is used. Use in patients with implanted cardioverter defibrillators is under discussion. Individual testing is mandatory in order to assess optimal safety in each patient.

Introduction

Therapeutic options for the management of angina pectoris in patients with coronary artery disease (CAD) have improved over the past 2 decades. Nevertheless, angina pectoris is a common and important symptom affecting many patients with CAD, as well as some with endothelial dysfunction.

Despite optimal drug therapy and no option for coronary revascularization procedures (percutaneous coronary intervention [PCI] or aortocoronary bypass [ACB]), some patients with CAD have persistent angina pectoris class III or IV according to the Canadian Cardiovascular Society (CCS).[1] The treatment of these patients with non-responding angina pectoris presents a medical challenge. We have no accurate figures on the occurrence and frequency of refractory angina, nor is the prevalence of angina pectoris known in most communities. The overall prevalence of patients referred for coronary angiography with refractory angina varies from 5% to 15%.[2]

Various treatment concepts have been developed for patients with therapy-resistant angina pectoris and have been applied in clinical studies: long-term intermittent urokinase therapy,[3] surgical and percutaneous transmyocardial laser revascularization,[4-6] enhanced external counterpulsation,[7,8] percutaneous in situ coronary venous arterialization,[9] and transcutaneous electrical nerve and spinal cord stimulation (SCS).[10-19] The latter has been established as the most applicable. It is recommended as the therapy of choice by the European Society of Cardiology Joint Study Group on the Treatment of Refractory Angina.[2]

In this article, we review the role of SCS in the management of severe angina pectoris in patients with ischemic heart disease and endothelial dysfunction.

Endothelial Dysfunction and Coronary Artery Disease

Stable and Refractory Angina Pectoris

Endothelial dysfunction is usually diagnosed in the presence of angina pectoris without obstructive CAD and coronary artery spasm. Patients with such a diagnoses experience typical anginal chest pain and experience positive exercise stress testing. About 15-20% of patients undergoing cardiac catheterization for the assessment of typical chest pain have these characteristics,[20] and most of them have a good prognosis.[21]

Endothelial dysfunction often marks the onset of atherosclerosis, stays with the patient for the rest of his or her life, and at the end-stages of CAD following PCI, causes higher rates of relapse and re-intervention.[22] Endothelial dysfunction can be ascertained invasively and non-invasively. After excluding hemodynamically relevant epicardial stenoses by determining the fractional flow reserve (FFR), the functional status of a coronary artery can be determined by coronary flow reserve (CFR).[23] As a non-invasive procedure, ammonia positron emission tomography (PET)[24] and flow-mediated dilatation of the brachial artery (FMD) can be used.[22]

The survival of patients with CAD is increasing as a result of improved prevention and coronary intervention, which in turn is leading to an increase in the prevalence of patients with refractory angina pectoris.

It is important to underline that angina pectoris is a clinic diagnosis. Imbalance in myocardial oxygen demand and supply can produce myocardial ischemia. This may cause angina pectoris and lead to a reduction in left-ventricular contractility, as well as cause arrhythmia, myocardial infarction, and possibly death. Angina pectoris is commonly due to atherosclerosis of the coronary arteries, but it can also occur in conjunction with endothelial dysfunction due to insufficient coronary vasodilatation.

Anti-anginal drug therapy improves the imbalance of the myocardium by interacting with heart rate, cardiac pre- and afterload, as well as coronary vascular tone. Hemodynamically significant coronary stenoses with and without angina pectoris may be dilated (PCI) or operated on (ACB).[22]

Refractory angina pectoris (CCS class III and IV)[1] is a chronic condition characterized by the presence of angina due to coronary insufficiency in the co-presence of CAD that cannot be controlled by a combination of medical therapy, angioplasty, and coronary bypass surgery.[2] Patients with endothelial dysfunction can also experience refractory angina.

Before selecting patients with refractory angina for SCS, a re-evaluation of their medical therapy is required in order to ensure an optimal treatment regimen[2,25] (Table I). Myocardial ischemia should be present, and other causes of chest pain, such as musculoskeletal pain, esophageal reflux, gastrointestinal disorder, pericardial disease, vascular disease (aortic dissection, pulmonary embolism), infection, panic disorder, and pulmonary conditions that cause chest pain, must be excluded.[1,26]

Table I. Steps in Optimizing Medication and Management in Patients With Chronic Refractory Angina.

Pharmacologic Therapy

The therapeutic options for endothelial dysfunction and stable CAD are comparable and aim at correcting the imbalanced redox potential. Treating the classical risk factors with lifestyle modification and drug therapy has facilitated the successful prevention of clinical cardiovascular events and has prolonged life expectancy.

In many randomized studies, a reduction in increased low-density lipoprotein cholesterol and triglyceride, as well as an increase in reduced high-density lipoprotein cholesterol have contributed to stabilizing plaque, have frequently demonstrated a regression of coronary atherosclerosis, and have improved endothelial function.[22] Controlling hypertension, cessation of smoking, increasing physical activity, and reducing weight all help to halt the progress of atherosclerosis and to reduce acute events. Lifestyle changes in the form of increased physical activity with or without weight reduction frequently lead to a reduction in angina pectoris and improved myocardial perfusion.[22] In randomized studies, it was possible to show that, compared with coronary intervention (PCI), increasing physical activity resulted in a better event-free survival rate, a higher exercise capacity, and a higher oxygen uptake, and was more cost effective; it achieved clinical improvement in CCS class I at half the total cost of the interventional strategy.[27,28]

Spinal Cord Stimulation (SCS) in Angina Pectoris

Pathophysiologic Mechanisms of Pain

Pain arises when specific nerve endings in organs (nociceptors) are stimulated. Nociceptors end as free, non-corpuscular nerve endings in all the different types of tissue within our bodies, e.g. in the adventitia of coronary arteries. Angina pectoris results from ischemic episodes, reduced blood flow through hemodynamically significant stenoses of the epicardial vessels or endothelial dysfunction, stimulating chemosensitive and mechanoreceptive receptors in the heart. Activation of these receptors results in the release of prostaglandins, adenosine, bradykinin, and other substances that excite the sensory ends of the sympathetic and vagal afferent fibers.[29] The nociceptive information of the elicited stimulus that causes angina pectoris is conveyed by visceral afferent nerve fibers, converging in common pathways, into the dorsal spinal cord at C7-T5 level where they have synaptic connections with other neurons.[30] Afferent fibers from the heart and cutaneous input are assumed to converge on specific interneurons in the same segment of the spinal cord.[31] Angina pectoris is felt in areas that refer to the dermatome, from where afferent nerves project to the same segment of spinal cord as from the heart. Two different classes of fibers conduct the received signals to the central nervous system: thin medullated Aδ-fibers and non-medullated C-fibers. The majority of nociceptors are slow-conducting C-fibers that convey dull pain, whereas the fast-conducting Aδ-fibers convey stabbing pain.

SCS Techniques

During transcutaneous electric nerve stimulation (TENS), two or four adhesive electrodes are attached epicutaneously so that the induced paresthesia is located by the patient in the area with the highest projected pain intensity during typical angina pectoris. The stimulation intensity is selected below the individual pain threshold.

During SCS, a 4- or 8-pole electrode is advanced to C7/T1 using x-ray vision after puncturing of the epidural space under a local anesthetic at T6-7. The electrodes are placed according to the area of distribution of the electrically induced paresthesia. This area should correlate as closely as possible with the area affected by angina pectoris.[19,32] The stimulation electrode is guided under sterile conditions and connected to an external portable stimulation device followed by a positive test period, the duration of which depends on the frequency of angina. As soon as the frequency and intensity of angina pectoris have significantly decreased (more than 50%), the stimulation electrode is subcutaneously lengthened under general anesthesia and usually connected to a stimulation aggregate implanted in the left upper abdomen. Using a programming device, the patient can then switch the aggregate on and off telemetrically, as well as alter the stimulation intensity within stipulated ranges.

Mechanisms of Action of SCS in the Treatment of Cardiac Ischemic Syndromes

The following mechanisms may explain the positive effects of SCS in chronic refactory angina pectoris: reduced pain perception, decreased sympathetic tone, reduced myocardial oxygen demand, improved coronary microcirculatory blood flow, and positive effects on cerebral blood flow (CBF).[33]

Reduction of Pain Perception. Segmental pain inhibition through neurostimulation has been under discussion since the mid-1960s.[34] By applying electrical stimulation regionally and below the pain threshold, sensitive afferent fibers (A-fibers) are selectively activated. In the spinal dorsal horn, this should then lead to a consecutive presynaptic inhibition of nociceptive afferences (A- and C-fibers) with local analgesia. In the last few years, mechanisms involved in the modulation of important neurotransmitters have been discovered, contributing to our understanding of pain inhibition through SCS. SCS leads to an augmented release of the inhibitory neurotransmitter GABA. This results in a decrease in the release of exitatory amino acids (glutamate and aspartate). In a rat model, local infusion with a GABAb-receptor antagonist in the dorsal horn transiently abolished the SCS-induced suppression of glutamate and aspartate release. The elevation in GABA release, in response to SCS, did not reach statistical significance.[35,36] A combination of subtherapeutic intrathecal doses of a GABAb-receptor agonist and an adenosine A1 agonist has been found to potentiate the effects of SCS in rats that were not initially responsive to SCS.[35,36] SCS has been found to enhance the release of β-endorphin.[37] β-Endorphin can help to reduce pain perception. It can unfold a cardioprotective effect following myocardial ischemia by decreasing myocardial contractility and subsequent oxygen consumption, and possibly by decreasing the release of norepinephrine (noradrenaline).[38]

Decreased Sympathetic Tone. Several studies on the effect of TENS and SCS on cardiac metabolism and hemodynamics have demonstrated that no changes occur under basal conditions, but manifest when the heart is stressed.[39]

The anti-ischemic effect of SCS is not due to reduced cardiac sympathetic activity. SCS decreases overall sympathetic activity, which may benefit the heart, possibly by reducing oxygen demand.[11] This could be demonstrated with SCS during tachycardial atrial stimulation. The total body norepinephrine spillover was reduced while the cardiac norepinephrine spillover was not affected.[11] Regional and overall sympathetic activity can be differentiated using the isotope dilution technique.[40] In this technique, the norepinephrine spillover and clearance are determined simultaneously in a steady state by infusing tritium-labeled norepinephrine. This avoids an increase in cardiac norepinephrine spillover, which can happen when total body norepinephrine spillover is determined individually in addition to determination of the plasma concentration of endogenous norepinephrine.

Neurostimulation suppressed activity generated by intrinsic cardiac neurons in animal experiments.[41] Spinal cord neurons primarily influence the intrinsic nervous system via axons coursing the intrathoracic sympathetic nervous system. Transient regional myocardial ischemias can markedly increase the activity of the intrinsic nervous system and thus lead to cardiac dysrhythmia.[42] In sympathetic stress situations, SCS is able to lower heart rate.[43] This reduced cardiac sympathetic activity under SCS can also be ascertained in an influencing of heart rate variability.[44] Activation of spinal cord neurons during SCS induces a conformational change in the intrinsic cardiac nervous system that persists for a considerable period of time after termination. This remodeling of the intrinsic cardiac nervous system can override excitatory inputs to it arising from the ischemic myocardium.[45] Further studies are required to investigate whether ventricular tachycardia or sudden cardiac death could thus be avoided.

Effect on Cerebral Blood Flow. Non-invasive techniques for determining cerebral perfusion and measuring functional activity (e.g. PET, functional MRI, or magnetoencephalography) have contributed to a better understanding of cerebral function in healthy subjects and in those with various diseases and the ways in which cerebral function can be influenced through interventions.[45] Changes in regional blood flow in areas involved with nociception and cardiovascular control have been documented in patients treated with SCS for refractory angina.[46] The cerebral areas demonstrating a relative increase or decrease in CBF could possibly be determined by the underlying disease (pain during clinical examination, one-sided or two-sided for paired organs) and the measuring methods, as well as the type of intervention.[47,48] In patients with documented CAD, typical anginal and ischemic electrocardiographic changes can be triggered during dobutamine infusion. Dynamic PET examinations during induced ischemia reveal increased and decreased regional CBF.[48] During SCS, increased and decreased regional CBF can also be observed with and without stimulation in patients with refractory angina.[49] In these two different patient groups, there are correlations within the following regions: increased CBF in the hypothalamus, and in the periaqueductal grey area and bilaterally in the thalamus, and decreased CBF in the posterior insular cortex, an area that modulates sympathetic effects.[48,49] The well supported effects of SCS are possibly attained by influencing central structures within the area of pain perception and processing. The thalamus may act as a filter for afferent pain signals.[48,50]

Effect on Coronary Blood Flow. SCS has repeatedly demonstrated an anti-anginal effect by reducing angina pectoris and the use of short-acting nitrates, increasing exercise tolerance, and decreasing ST-segment depression on the electrocardiogram.[51-55] Discussion about the effect of SCS on myocardial blood flow is ongoing.

SCS has been demonstrated to reduce catecholamine levels.[56] A direct sympatholytic effect is under discussion. Stimulating the dorsal paths in the spinal cord leads in turn to stimulation of segmental reflex paths and an inhibition of tonic activity in the sympathetic nervous system.[57] Vasodilatation of the microvessels leads to improved myocardial perfusion. Even in patients with refractory angina pectoris, coronary reserve is not completely eliminated.[47] One study was able to demonstrate a significant increase in cardiac index and a decrease in pressure frequency product as an indirect indicator for a reduction in myocardial oxygen consumption.[46]

Changes in myocardial perfusion can be directly visualized by intracoronary pressure and flow measurements. Non-invasive methods, such as stress echocardiography and nuclear medical techniques like myocardial scintigraphy and PET, indirectly illustrate myocardial perfusion by measuring contractility of the left ventricle (wall motion analyses) and differences in activity of enriched nucleotides in the myocardial cells.

Not even the use of different methods to evaluate myocardial perfusion, with varying study designs and clear results, have been able to explain the key issue of the anti-ischemic effect of SCS.

In 15 patients, stress echocardiography with adenosine led to a slight decrease in pumping function during SCS, in comparison to baseline without stimulation.[58] This may be interpreted as an indirect indication of improved myocardial perfusion.

For direct measurement of blood flow in a coronary artery, a catheter or wire has to be introduced. This can contribute to a reduction in flow within the vessel, depending on the diameter of the catheter. The different studies employ a variety of systems and conditions. Chauhan et al.[57] examined 34 patients with syndrome X (endothelial dysfunction) and 15 patients with CAD. Measurements were taken using an 8-French catheter in a presumed healthy vessel – left coronary artery without significant stenoses – at rest, with and without neurostimulation (TENS). An increase in flow velocity was ascertained. The authors concluded that the site of action was at the microcirculatory level, and that the effects may be mediated by neural mechanisms.

Norrsell et al.[59] examined eight patients with advanced CAD and four patients with syndrome X. A Doppler guidewire was placed in the vessel, corresponding to the ischemic area on a prior myocardial scintigram. Perfusion at rest and with right-ventricular stimulation, with and without SCS, was examined. The result was negative. There were no significant changes in coronary flow velocity during maximum pacing frequency when stimulation was introduced.

In a prospective study in 31 patients with advanced CAD, Diedrichs et al.[60] demonstrated an improvement in myocardial perfusion with sestamibi-single-photon emission computed tomography (MIBI-SPECT) scintigraphy after 12 months, but not after 3 months. Thus the reduction in ischemia does not seem to be a direct effect of neurostimulation, but might be due to an increased exercise tolerance of the patients with improved cardiac blood flow because of a better collateralization.

PET examinations of myocardial perfusion with SCS have also revealed different results. In eight patients undergoing SCS, De Landsheere et al.[61] found no increase in regional myocardial perfusion in ischemic regions when stimulated. Hautvast et al.[62] postulated a homogenization of myocardial blood flow. In nine patients with CAD, no significant difference in coronary blood flow due to SCS was revealed during dipyridamole stress testing after 6 weeks of SCS. Total resting blood flow remained unchanged, but flow reserve decreased. In a pilot study, we examined six patients with advanced CAD.[63] Perfusion at rest and during the maximum hemodynamic effect of intravenous adenosine was studied by ammonia PET at baseline and 13 ± 0.5 months after SCS. We found a significant increase in myocardial blood flow and a reduction in minimal coronary resistance after 1 year.[63] Figure 1 shows increased myocardial perfusion in the basal posterior wall of a 62-year-old man undergoing SCS. His history is typical for patients with refractory angina pectoris: severely restricted left-ventricular function in conjunction with advanced coronary triple vessel disease, two myocardial infarctions, two operative myocardial revascularizations, three catheter interventions, all therapeutic options exhausted, and angina upon slight physical exercise. In all patients, additional 18 F-fluorodeoxyglucose positron emission tomography ( 18 F-FDG-PET) was performed at baseline to distinguish vital myocardial regions from non-vital regions (figure 2). Fifty patients are included in an ongoing prospective study of the same design.[64]

Figure 1.  Improvement in myocardial blood flow in the inferior wall of the heart in a 65-year-old man after 1 year of spinal cord stimulation. (a) Baseline examination; and (b) 1-year follow-up.

Figure 2.  Assessment of viability by positron emission tomography (PET) imaging. Baseline examination: (a) discrimination between vital and non-vital myocardium using 18 F-fluorodeoxyglucose positron emission ( 18 F-FDG-PET). Detection of ischemia by ammonia PET at (b) rest and (c) stress.

The results pertaining to improved myocardial perfusion following SCS are not uniform. The number of patients included in studies is small, and follow-up intervals differ. A direct effect of neuromodulation on myocardial perfusion is not conclusive, even with a positive result. The discussion addresses a relative redistribution of myocardial perfusion from non-ischemic to ischemic myocardial areas when stimulated. Since the differences are slight and the reduction in myocardial perfusion in the non-ischemic areas presumes a significantly higher level than the increase to be achieved in the ischemic areas, ischemia is not to be expected in the non-ischemic areas. In the ischemic areas, however, a significant increase in perfusion is to be expected. This explains the symptomatic improvement, which may be explained by a direct effect due to vasodilatation, in particular, of the microvessels, with a reduction in minimum coronary resistance, and an indirect effect due to an improved collateralization (development of collateral vessels).

Improvement in myocardial perfusion through an indirect improvement in endothelial function can be explained by the presumed increase in exercise tolerance and quality of life when angina pectoris is reduced.[27] Whether or not the anti-anginal and anti-ischemic effects of SCS are mediated by an increase in coronary flow velocity is a discussion still ongoing. The effect is derived through decreased myocardial oxygen consumption.[11]

Clinical Experience with SCS in Angina Pectoris

Angina pectoris is a projected pain that is caused by insufficient perfusion of the myocardium due to significant coronary stenoses or reduced vasodilatatory capacity, particularly of the microcirculation. CAD is frequently accompanied by endothelial dysfunction. In the majority of patients with significant coronary stenoses and exercise-induced ischemia, pain relief can be achieved following revascularization and/or through risk factor modulation with improvement in endothelial function (Table I). TENS and SCS are recognized therapies in patients with refractory angina pectoris.[2] In many clinical studies, the effectiveness of these therapies have been demonstrated in patients (approximately 2500) with CAD and endothelial dysfunction:[2,21,54,55,59,65-70] fewer angina pectoris episodes and less short-acting nitroglycerin (glyceryl trinitrate) or mononitrate intake per time period; increase in exercise tolerance, time to angina, and the appearance of ST-segment depression; extended walking distance in the 6-minute walk test before onset of angina; improvement in quality of life; and fewer stays in hospital as well as visits to the physician due to cardiac-related symptoms.

Table I. Steps in Optimizing Medication and Management in Patients With Chronic Refractory Angina.

Despite these well known symptomatic improvements, SCS is still not recognized by many cardiologists. Its acceptance in European countries is low and varies (countries employing SCS in descending order of frequency are: Sweden, Italy, Germany, and Denmark). Since to date there are no systematic investigations regarding the distribution of SCS in patients with refractory angina pectoris, statistics come from manufacturers only (total 400-500 patients/year; in Germany, a total of 225 patients since 1998).

In a randomized, prospective study, the effectiveness of SCS was compared with that of operative myocardial revascularization (ACB).[18] SCS (n = 53, 41 males) and ACB (n = 51, 42 males) scored equally in subjective symptomatic improvement. Compared with the SCS group, after 6 months of follow-up, the ACB group had an increased exercise tolerance, as well as less ST-segment depression on maximum and comparable workloads. The maximum workload capacity was lower in the SCS group, and the ST-segment depression on maximum workload was higher than that in the ACB group. The mortality rate was lower in the SCS group (one SCS patient vs seven ACB patients). After 5 years, survival and quality of life were comparable between the two groups.[19] Secondary prevention was poor in both groups (SCS/ACB): aspirin (acetylsalicylic acid) 42%/33%, β-adrenoceptor antagonists 43%/24%, lipid-lowering drugs 6%/3% and ACE inhibitors 7%/8%.

Since patients experience retrosternal prickling during active SCS, a blind, placebo-controlled SCS study in patients with refractory angina pectoris is not an option. Eddicks and coworkers[54] have examined the therapeutic effects of subthreshold SCS. Twelve responders to SCS were randomized into four consecutive treatment arms, each for 4 weeks, with various stimulation timing and output parameters. One group was defined as a control-subthreshold stimulation (0.1 V) without retrosternal prickling. Walking distance, angina pectoris, short-acting nitroglyerin intake, and quality of life only improved in the groups sensing stimulation. This study showed for the first time that a placebo effect in conjunction with SCS is unlikely. The option of using subthreshold stimulation in active yet blind patient treatment is an attractive concept for further studies.

Safety Aspects

SCS is a safe, recognized, and effective therapy for patients with refractory angina pectoris.[2,70-73] Critics of SCS object that patients no longer receive warning signals (angina pectoris) and thus endanger themselves as their exercise levels increase.[74] Angina pectoris is the cardinal symptom of acute myocardial ischemia including infarction, and it is possible that effective pain relief through SCS may conceal such an infarction.[75] In many studies, it has been shown, however, that angina pectoris could be significantly reduced with SCS. Quality of life improves and cardiovascular event rates are significantly lower.[12,70,76,77] Of course, myocardial infarctions cannot be prevented through SCS: advancing CAD, plaque ruptures, or bypass closures can still be responsible for these.

In a prospective study, Andersen and coworkers[74] investigated the possibility that SCS used for pain relief might conceal acute myocardial infarction. During the observation period of up to 37 months (108.6 patient-years), ten out of 50 patients experienced a myocardial infarction. Nine of these ten patients with acute infarction recognized that the precordial pain was clearly different and definitely more severe than their usual angina. Angina was not influenced by SCS. The mean number of admissions for chest pain, angina, or observation, in case of acute myocardial infarction, was not significantly different in the ten patients with acute myocardial infarction compared with patients without infarction during the 3-year period before SCS treatment or during SCS treatment.

SCS is used in patients with advanced CAD. Patients with CAD can also experience disorders that necessitate the use of permanent pacemaker (PPM) treatment for bradyarrhythmias or an implantable cardioverter defibrillator (ICD) for ventricular tachycardias.

The experiences of various groups confirm the safety of SCS in patients with PPM.[78-84] SCS does not interact with pacemakers, provided that strict bipolar right-ventricular sensing is used. Unipolar SCS has been reported to cause PPM inhibition, and should not be considered.[7,81] The amplitudes of the stimulator noise are often seen on the intracardiac electrogram (figure 3). There were no interactions between the two systems during T-wave sensing with unipolar PPM. Individual testing is mandatory to assess safety in each patient.

 

Figure 3.  Intracardiac electrograms showing stimulator noise amplitudes in patients with permanent pacemakers undergoing spinal cord stimulation (SCS): no noise interference.

In the future, more patients with refractory angina will have pacemakers (including left-ventricular stimulation) and ICDs. An increase in patients with ICDs has already been observed over the past decade. In line with current information, many patients included in ESBY (Electrical Stimulation versus Bypass Surgery in Severe Angina Pectoris) study have an indication for ICD therapy due to severely impaired left-ventricular function. Thus, the treatment of one condition must be compatible with the treatment of the others.

The literature only contains case studies of combined SCS and ICD therapy.[85] Problems can arise, on the one hand, from a false detection of SCS spikes with consecutive antitachycardia therapy and, on the other hand, from the suppression of therapy in conjunction with a threat of arrhythmia, since spikes are often still falsely interpreted as ‘rhythm’ below the intervention threshold.

Many ICD systems use an automated gain-control during bipolar sensing. According to our experience, ICD-SCS combination therapy may be safely performed.[86,87] Differentiated testing is unavoidable. In a prospective study in five patients within a follow-up of 12.2 ± 10.5 (2-40) months, no interaction between SCS and ICD therapy was documented.[87] We evaluated possible interactions under general anesthesia with the highest SCS amplitude (10.5 V/450 ms) and the most sensitive bipolar sensing during induced ventricular fibrillation (twice) [figure 4].

Figure 4.  Spinal cord stimulation (SCS) and implantable cardioverter defibrillator therapy: no interaction by induction (a) and termination (b) of ventricular fibrillation (highest sensitivity).

TENS therapy should not be performed in patients in conjunction with SCS, PPM, cardiac resynchronization therapy (CRT), or ICD since inhibitions cannot be excluded. The general recommendations regarding minimization of interactions and infections should be observed for SCS as for other stimulation therapies. MRI and diathermia should not be performed due to possible warming of the leads.

Stress tolerance in patients with SCS is not limited by the wearing of the system, but by progressive CAD, restricted left-ventricular function, and possible concomitant diseases.

Cameron[55] has summarized direct SCS-related complications from the literature over the last 20 years, covering a total of 2753 patients: lead migration 13.2%, lead breakage 9.1%, and infection 3.4%. Through optimization of implantation technique and perioperative management, these complications can be reduced.[80,81] In the German Angina Register[76,88] including 101 patients, the frequency of these complications is as follows: lead migration 5%, lead breakage 5%, and infection 3%. In the 1-year follow-up, 8% died: sudden cardiac death occurred in 3%, heart failure in 2%, and malignoma in 3%. One patient experienced a myocardial infarction and one patient underwent PCI.

SCS shows a long-term beneficial effect, even in patients with unstable angina.[51] The target values of concomitant risk factors must be reduced prior to commencing SCS and then be aligned long-term through interventions (Table I, figure 5).

Table I. Steps in Optimizing Medication and Management in Patients With Chronic Refractory Angina.

Figure 5.  Therapeutic options in the cardiovascular continuum for patients with unstable angina. ACB = aortocoronary bypass; CRT = cardiac resynchronization therapy; ICD = implantable cardioverter defibrillator; PCI = percutaneous coronary intervention; PPM = permanent pacemaker; SCS = spinal cord stimulation.

Conclusion

Refractory angina pectoris during end-stage CAD and with endothelial dysfunction is a specific coronary syndrome that is chiefly caused by microcirculatory disturbances. Already receiving the best use of evidence-based therapies and with no interventional options, these patients can benefit from SCS. SCS is safe and effective for treating refractory angina pectoris – reducing both the number of anginal episodes and the intensity of the angina pectoris. With SCS the dosage of short-term effective nitrates per time period is reduced. The work period during exercise tests is significantly prolonged. SCS leads to a significant reduction in hospital admission for cardiac causes, without masking myocardial ischemias or myocardial infarction. The implantation costs are balanced out by savings in aftercare (fewer consultations and hospital stays).

SCS is an excellent alternative for patients at an increased risk of requiring operative revascularization. For patients with refractory angina who are waiting for heart transplantation, SCS is also a good bridging option.

In small studies, an improvement in myocardial blood flow in vital ischemic myocardial areas has also been proved. It has yet to be investigated whether SCS, in addition to a proven improvement in symptoms, also reduces mortality.

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88. Theres H, Eckert S, Eddicks S. Spinal cord stimulation (SCS) zur Behandlung der refraktären angina pectoris in Deutschland – Ergebnisse nach 12 Monaten Verlauf im Rahmen des Deutschen SCS Registers. Clin Res Cardiol 2007; 96 Suppl. 1: 522

Authors

Siegfried Eckert and Dieter Horstkotte, Department of Cardiology, Heart and Diabetes Center North Rhine-Westphalia, Ruhr-University Bochum, Bad Oeynhausen, Germany

Technorati Tags: coronary heart disease,coronary,angina pectoris,spinal cord stimulation,anasthesia

Good and bad news for possible warfarin competitors

July 17, 2009 by Lisa Nainggolan

Boston, MA - An investigational factor Xa inhibitor, edoxaban (Daiichi-Sankyo), is being tested as a once-daily drug in a phase 3 trial in over 16 000 patients with atrial fibrillation, following unexpected results from a pharmacokinetic analysis of the agent in a phase 2 study. The latter was presented at the International Society of Thrombosis and Haemostasis (ISTH) 2009 Congress this week [1].

The phase 2 pharmacokinetics data, which was a subanalysis of an international phase 2 study presented at the American Society of Hematology 2008 Annual Meeting, were reported at ISTH by Dr Robert P Giugliano (Brigham and Women’s Hospital, Boston, MA). The findings were "a little surprising," Giugliano told heartwire, because "what we learned was that once-daily dosing caused less bleeding than twice-daily dosing, even when you used the same total dose."

Delivering a compound twice a day generally allows for more consistent drug levels in the blood, he explains, because the C_min (trough) levels of the agent do not dip as low and the C_max (peaks) do not go as high as when the drug is given once daily. But "we found the most important parameter that predicted bleeding was the C_min, the trough level," he noted.

Consequently, in the multinational phase 3 study, known as ENGAGE-AF TIMI 48, patients will be randomized either to 30 mg or 60 mg of edoxaban once daily or to warfarin, dosed once daily with adjustments to maintain an internalized normalized ratio (INR) between 2.0 and 3.0. Giugliano said that the 30-mg once-daily dose of edoxaban "looks to have less bleeding than warfarin and the 60-mg dose looks to have bleeding similar to warfarin."

The primary end point of ENGAGE-AF will be the prevention of stroke and systemic embolic events (SEE), and the primary safety assessment will be the incidence of bleeding. The trial is expected to conclude in the first half of 2012.

Learning from the mistakes of others

Giugliano says he feels "pretty confident" about this drug. "Because it’s not the first one out, we’ve been able to learn from other people’s mistakes, and right from the get-go we wanted to pick two doses. We realized it would be difficult to beat warfarin, so we’re happy to be just as good as warfarin but to have equal or less bleeding. Even if we have equal bleeding to warfarin and are as good as it on the efficacy side, you don’t have to monitor [edoxaban], it doesn’t have a lot of drug-drug interactions, and it doesn’t matter what you eat, so it’s easier to use."

Another investigational, once-daily factor Xa inhibitor, rivaroxaban (Xarelto, Johnson & Johnson), is currently in limbo in the US after the FDA declined to approve it for the prevention of deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients undergoing hip- or knee-replacement surgery, despite a recommendation for approval from its Cardiovascular and Renal Drugs Advisory Committee earlier this year, as reported by heartwire. Bristol-Myers Squibb also has a factor Xa inhibitor in development, apixaban.

Warfarin analog disappoints in phase 2

Meanwhile, tecarfarin (Aryx Therapeutics), another new potential competitor to warfarin, has disappointed in a recent phase 2/3 trial [3]. Tecarfarin, like warfarin, is a selective inhibitor of vitamin-K epoxide reductase (VKOR), but unlike warfarin, it is not dependent upon cytochrome P450 enzymes for metabolism.

In the study, EmbraceAC, in 600 patients with a variety of underlying conditions—such as AF, implanted prosthetic heart valves, and a history of venous thromboembolic disease—tecarfarin failed to show superiority (as measured by time in the therapeutic INR range) over warfarin. The company says this is because the warfarin patients did much better than expected in the trial, due to the centralized dosing control center employed. It is still analyzing the data to determine a future strategy for tecarfarin.

Sources

1. Giugliano R, Rohatagi S, Kastrissios H, et al. The relationship between oral factor Xa inhibitor DU-176B pharmacokinetics and the probability of bleeding events (BE) in patients with atrial fibrillation (AF). International Society of Thrombosis and Haemostasis 2009 Congress; July 11-16, 2009; Boston, MA. Abstract OC-WE-003.
2. Daiichi Sankyo. Analysis of edoxaban phase II data provides insight into reduced bleeding events seen in once-daily dosing [press release]. July 15, 2009.
3. Aryx Therapeutics. Efficacy of tecarfarin mirrors earlier studies while primary end point missed [press release]. July 8, 2009.

Technorati Tags: warfarin,Clopidogrel,coronary,coronary heart disease,edoxaban,rivaroxaban,apixaban,tecarfarin

Revascularization can boost diastolic function, too

July 27, 2009 by Steve Stiles

Perugia, Italy - Yes, diastolic function can improve after revascularization in the setting of ischemic LV systolic dysfunction, notes a small study that isn’t revelatory but confirms and quantifies a phenomenon that has long seemed likely without having been clearly demonstrated, according to researchers [1].

They saw significant improvement in LV diastolic filling on tissue-Doppler imaging (TDI) and in LVEF on conventional echocardiography in 26 patients who underwent PCI or CABG of coronaries serving hibernating, hypo-, or akinetic myocardium, which was demonstrated by dobutamine-echo viability imaging.

"These results support the tenet that in ischemic heart disease, systolic and diastolic function go hand-in-glove and directly demonstrate that revascularizing chronically viable, dyssynergic myocardium may also beneficially impact diastolic function," write the authors, led by Dr Erberto Carluccio (Ospedale Silvestrini, Perugia, Italy) in the June 2009 issue of the European Heart Journal.

The work lends "further support to the concept that a thorough search for viability (and, hence, for possible revascularization) should be part of the diagnostic workup of patients with ischemic cardiomyopathy."

In clinical practice, the overwhelming focus of revascularization in this setting has been on improvement in systolic function, observed primary author Dr Giuseppe Ambrosio (Ospedale Silvestrini) for heartwire. It has followed intuitively that deficits in diastolic function might also improve, but "sometimes, things that seem obvious are not put to the test," he said. So he and his group used pulsed-wave Doppler and TDI techniques available only in recent years to quantify changes in parameters that reflect diastolic function in revascularized hibernating myocardium.

Seven patients undergoing PCI and 24 undergoing CABG, all with chronic ischemic cardiomyopathy, a mean LVEF of 32%, a mean regional wall-motion score of 2.45 (2=hypokinesia; 3=akinesia), and viable myocardium in abnormally contracting regions (as measured by low-dose dobutamine echocardiography) were evaluated at baseline and after at least four months (mean, eight months).

At baseline, 10 and 16 patients, respectively, showed restrictive and nonrestrictive diastolic filling patterns at transmitral pulsed-wave Doppler imaging; after revascularization, only three patients still showed a restrictive filling pattern (p=0.016), according to the authors. The improvement appeared unrelated to changes in systolic function.

On TDI, overall early diastolic annular velocity (E’) had improved by 32% (p=0.0028) and the ratio of global peak early diastolic flow velocity to E’ (E/E’), a gauge of filling pressure, had fallen by 19% (p=0.0378)

Also improving were mean LVEF (from 32% to 43%; p=0.0004), end-diastolic volume index (124 mL/m² to 106 mL/m²; p=0.0024), and end-systolic volume index (85 mL/m² to 63 mL/m²; p=0.0004)

Mean NYHA functional class improved from 2.9 to 1.7 (p=0.0002); the gains correlated significantly with the degree of contractile-function improvement and the number of myocardial segments showing functional recovery after revascularization. They were also significantly related to improvement in E/E’ (p=0.0328), but not to improvement in E’.

The message of the study, said Ambrosio, is simple, but in practice it isn’t frequently considered: viability studies should be performed in patients with ischemic cardiomyopathy and ventricular dysfunction, and when viability is seen in poorly functioning segments served by a diseased coronary, revascularization can potentially improve both systolic and diastolic performance.

Source

1. Carluccio E, Biagioli P, Alunni G, et al. Effect of revascularizing viable myocardium on left ventricular diastolic function in patients with ischaemic cardiomyopathy. Eur Heart J 2009; 30:1501-1509.

Technorati Tags: ischaemic cardiomyopathy,catheterization,coronary heart disease,CABG

Hypersensitivity likely the culprit in late stent thrombosis

July 24, 2009 by Lisa Nainggolan

Bern, Switzerland - A small Swiss study has shown that late hypersensitivity reactions likely play a major role in the pathogenesis of very late stent thrombosis in patients with drug-eluting stents (DES) [1]. Dr Stéphane Cook (University Hospital, Bern, Switzerland) and colleagues report their findings online July 20, 2009 in Circulation.

Senior author Dr Stephan Windecker (University Hospital) told heartwire: "This is a small paper explaining from a pathophysiologic standpoint a very rare clinical problem. People should not be worried, because it’s a very rare adverse event and first-generation DES have been shown to be safe overall—the incidence of death or MI as compared with bare-metal stents is not increased—so there is no concern about this."

In an accompanying editorial [2], Dr William Wijns (Cardiovascular Center Aalst, Belgium) says that Cook et al "now confirm that local hypersensitivity reactions are the more likely mechanisms of very late stent thrombosis through excessive positive remodeling." Wijns told heartwire, "In retrospect, this new study explains a lot of controversies we didn’t understand." Thus, the seemingly erratic pattern of very late stent thrombosis, the steady linear increase over time with no evidence of decreased event density with extended follow-up, and the weak association with discontinued dual antiplatelet therapy (in contrast to early thrombotic events) "are all consistent with the evoked mechanism of action," he says.

The work also raises a number of new questions and has implications for future research, says Wijns.

An unusual reaction explaining many mysteries

The new study looked at just 28 patients with very late stent thrombosis and 26 controls. Of the 28 patients with late stent thrombosis, 10 patients underwent both thrombus aspiration and intravascular ultrasound (IVUS). Incomplete stent apposition (ISA), also known as malapposition, and evidence of vessel remodeling were present in 73% of cases. Histopathological analysis showed much higher numbers of eosinophils in the specimens from very late DES thrombosis compared with other causes of MI—particularly with sirolimus-eluting stents—and a correlation with the extent of stent malapposition.

Windecker said: "This is an extension of work we have previously published showing an exceedingly high incidence of stent apposition in those presenting with very late stent thrombosis. What we did in this new study was correlate those findings with histopathological analysis of thrombus aspirates from living patients, and we found that the extent of vessel remodeling as diagnosed by IVUS correlated directly with the amount of eosinophilic infiltrates." An increase in eosinophils is "very unusual" he noted, and "implies a hypersensitivity reaction."

Wijns says that what Cooke et al found "in all those cases was that there was necrotizing vasculitis around the stent struts and that explains why the wall is moving away from the stent, this phenotype of malapposition." However, malapposition itself is "a moving target" he explained, "as early IVUS studies have shown it can be there from the onset and disappear, it can be present from the onset and stay as it is, or it can also be absent initially and then appear—perhaps the latter instances are the ones that are potentially related to this delayed inflammatory reaction," he observes. But whether malapposition per se is sufficient to trigger thrombosis "is unclear," he says.

Also, this study "cannot tell us exactly which component of the drug-polymer device is responsible for the late hypersensitivity reaction because, by definition, late hypersensitivity reactions can present themselves even ages after the causal agent has gone. So it’s not excluded that it could be the drug [on the DES], but I think most people agree that the polymer is likely the guilty one," Wijns added.

Windecker says: "People always wondered why it is that very late stent thrombosis occurs at a steady rate, why the stents don’t heal, and why the risk doesn’t seem to stop after a certain period in time. Now, with these hypersensitivity reactions, we may have a partial explanation, because hypersensitivity reactions can occur at any time."

No change in advice for those affected by stent thrombosis

Wijns says there are few practical consequences of the new findings. Removal of the DES is not possible, says Windecker, so the only course of action is medical treatment, a rescue primary PCI to open the occluded stent, give appropriate antiplatelet therapy, "and hope the stent stays open," he says. "There’s really not much more that you can do."

Desensitization is not an option either, Windecker explains, because "this [hypersensitivity] reaction is not IgG-mediated, which you could suppress, rather it is T-cell or eosinophil-mediated, so the only thing you could perhaps consider is local administration of steroids, but you would have to be very careful to weigh the risks of this against the benefits of therapy."

Future directions

Wijns says this work indicates that researchers looking for the optimal drug-polymer device may be wise in the future to narrow their search for constituents down to polymers and drugs that have been used extensively in humans for other indications, with known outcomes.

It is also essential that pooling of data, following the same protocol, is performed going forward in patients presenting with stent thrombosis. This is especially important in Europe, where many new DES are available, he says. Central analysis of removed thrombus, invasive imaging by IVUS or optical coherence tomography, and efforts to help identify systemic biomarkers that could predict events, or at least those patients most at risk, "should be encouraged," he notes.

"Although stent thrombosis is rare, malapposition is not an infrequent finding, seen in 8% to 13% of patients nine to 12 months after implantation of first-generation DES. Linking this phenotype to biomarker changes may help to identify patients most at risk of late stent thrombosis, perhaps the patient subset that will benefit from long-term dual antiplatelet therapy," he observes.

"Only when we have such a biomarker will we know the fraction of patients at risk of this very rare side effect, and from there the fraction who will have the event is even lower by several orders of magnitude," he commented to heartwire. "This is no reason to panic, rather the opposite," he states, "because at last we understand what the mechanism is."

Sources

1. Cook S, Ladich E, Nakazawa G, et al. Correlation of intravascular ultrasound findings with Histopathological analysis of thrombus aspirates in patients with very late drug-eluting stent thrombosis. Circulation 2009; 120: 391-399.
2. Wijns W. Late stent thrombosis after drug-eluting stent. Seeing is understanding. Circulation 2009; 120: 364-365.

Technorati Tags: stent thrombosis,drug-eluting stent,DES,catheterization,coronary heart disease,thrombus

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Successful Clopidogrel Desensitization After Drug-Eluting Stent Implantation

Ryan T. Kammer, PharmD

Published: 07/15/2009

Abstract and Introduction

Abstract

A 55-year-old male was admitted with a recent non-ST-elevation myocardial infarction (NTEMI) and taken to the catheterization laboratory for further management. Culprit lesions were identified in the distal right coronary artery and ramus intermedius, requiring 2 paclitaxel-eluting stents (Taxus®, Boston Scientific Corp., Natick, Massachusetts) and a bare-metal stent, respectively. The patient was started on ticlopidine therapy due to a history of clopidogrel-associated skin rash. One day after ticlopidine initiation, the patient developed pruritus and a maculopapular rash of the trunk area. The patient was discharged briefly on aspirin and cilostazol therapy with readmission plans for clopidogrel desensitization. A modified protocol was successfully utilized to desensitize the patient.

Introduction

Thienopyridine therapy is a necessity after implantation of a drug-eluting stent (DES). Recent guidelines2 mandate a minimum of 12 months of thienopyridine therapy in an attempt to prevent late stent thrombosis, a devastating and possibly fatal complication associated with DES. Rarely, patients develop a rash from clopidogrel that requires discontinuation of the drug. Desensitization is an option because clopidogrel skin reactions are thought to involve an Ig-E-mediated component.^[1] Successful densensitization has been reported in the immunology,^[1,3] cardiology,^[4-6] and recently, in the pharmacy literature.^[7] It is important to continue to report strategies for desensitization to a therapy that is imperative after coronary artery stenting, especially in those patients who react to both currently available thienopyridine derivatives.

Case Presentation

This case describes a 55-year-old male transferred to our facility for coronary angiography following a NSTEMI. His history revealed prior DES implantation in the right coronary artery (RCA) following an inferior-wall myocardial infarction and documented clopidogrel intolerance due to rash. Catheterization revealed a patent stent, but significant lesions in the distal RCA and ramus intermedius (RI). The decision was made to proceed with percutaneous intervention, which involved implantation of 2 DES in the RCA and a bare-metal stent (BMS) in the RI lesion. The planned antiplatelet regimen post procedure was aspirin and ticlopidine. However, after ticlopidine initiation, the patient developed significant pruritus and a maculopapular rash of the trunk region. The rash resolved following ticlopidine discontinuation and intravenous administration of a dose of methylprednisolone and diphenhydramine. A consulting immunologist recommended a clopidogrel desensitization protocol. Thus, the patient was briefly discharged on aspirin and cilostazol with readmission plans for desensitization in the cardiac intensive care unit. He was successfully desensitized 4 days later using a modified protocol from Lee-Wong M et al1 (Table 1).

Table 1. Oral Desensitization Protocol

The protocol involves an escalating regimen of 15 doses administered orally in 30-minute intervals over a 7-hour period. The patient is continuously monitored, and an anaphylaxis regimen consisting of antihistamines and epinephrine is readily available. A 4-day course of corticosteroids may prevent recurrent or protracted anaphylactic reactions that occur in up to 20% of patients.8 If a minor reaction such as hives develops, an antihistamine is administered and the offending dose is repeated in 30 minutes. Once tolerated, the dose escalation schedule proceeds. In this case, doses were compounded in the pharmacy, with protocol modification of dose 13 to 18.75 mg = 1/4 tablet (from 20 mg), and dose 14 to 37.5 mg = 1/2 tablet (from 40 mg). This patient tolerated the entire protocol without evidence of a reaction and was discharged home the following day. The patient was extensively counseled on the risk of resensitization if subsequent clopidogrel doses were missed.

Discussion

Thienopyridine therapy is mandated after DES implantation. Unfortunately, when challenged with clopidogrel allergy or intolerance, options are limited, but include ticlopidine therapy, a cilostazol regimen or clopidogrel desensitization.

Despite potential blood dyscrasias, many clinicians initially attempt ticlopidine therapy. Unfortunately, the cross-sensitivity rate between clopidogrel and ticlopidine is unknown and occurrences are only described in case reports^[7] such as this one. This patient reacted to both drugs whose chemical structure differs only by a carboxymethyl side chain added to clopidogrel.^[5] The use of cilostazol after DES deployment has been described in the literature,^[9,10] but heart failure often prohibits its use. Ultimately, clopidogrel desensitization may be required, thus reports of success and failure with published protocols must continue to be circulated.

Conclusion

This is a case of successful clopidogrel desensitization after coronary intervention involving DES implantation in a patient allergic to both clopidogrel and ticlopidine. At 15-month follow up, the patient remains on clopidogrel therapy with patent stents.

References

1. Lee-Wong M, Gadhvi, D, Resnick D. Clopidogrel desensitization. Ann Allergy Asthma Immunol 2006;96:756-757.
2. Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 Guidelines for the management of patients with unstable angina/Non-ST-elevation myocardial infarction: Executive summary. Circulation 2007;116:803-877.
3. Vigo PG, MacDowell AL, Wedner HJ. Successful desensitization with clopidogrel after a positive skin test. Ann Allergy Asthma Immunol 2005;94:132.
4. Camara MG, Almeda FQ. Clopidogrel (Plavix) desensitization: A case series. Catheter Cardiovasc Interv 2005;65:525-527.
5. Walker NE, Fasano MB, Horwitz PA. Desensitization for the management of clopidogrel hypersensitivity: Initial clinical experience. J Invasive Cardiol 2006;18:341-344.
6. Von Tiehl KF, Price MJ, Valencia R, et al. Clopidogrel desensitization after drug-eluting stent placement. J Am Coll Cardiol 2007;50:2039-2043.
7. Owen P, Garner J, Hergott L, Page II RL. Clopidogrel desensitization: Case report and review of published protocols. Pharmacotherapy 2008;28:259-270.
8. Lieberman P. Biphasic anaphylactic reactions. Ann Allergy Asthma Immunol 2005;95:217.
9. Makkar K, Wilensky RL, Julien MB, et al. Rash with both clopidogrel and ticlopidine in two patients following percutaneous coronary intervention with drug-eluting stents. Ann Pharmacother 2006;40:1204-1207.
10. Park SJ, Shim WH, Ho DS, et al. A paclitaxel-eluting stent for the prevention of coronary restenosis. N Engl J Med 2003;348:1537-1545.

Technorati Tags: myocardial infarction,catheterization,clopidogrel,coronary heart disease,coronary,plavix

Overview of the presentation and management of atrial fibrillation

Sep 13, 2001 by Morton F Arnsdorf, MD

Atrial fibrillation (AF) is a relatively common arrhythmia that can have adverse consequences related to a reduction in cardiac output and to atrial thrombus formation that can lead to systemic embolization [1-4]. There are four major issues that must be addressed in the treatment of AF:

· Reversion to sinus rhythm

· Maintenance of sinus rhythm

· Control of the ventricular rate in

patients with chronic AF

· Prevention of systemic

embolization

Therapy is also influenced by whether the AF is paroxysmal or chronic (show figure 1A-1B).

The following discussion will focus on three areas: a brief summary of these four treatment issues, each of which is discussed in detail separately; the presentation and management of recent onset AF; and the mortality risk associated with AF.

GENERAL TREATMENT ISSUES

Reversion to sinus rhythm – There are two standard and a number of experimental approaches to converting AF to sinus rhythm. The standard approaches are synchronized internal or external DC cardioversion and pharmacologic cardioversion with class IA (eg, quinidine, procainamide, disopyramide), IC (eg, flecainide, propafenone), or III antiarrhythmic agents (amiodarone, sotalol). The experimental approaches are surgical or percutaneous catheter ablation. (See "Restoration of sinus rhythm in atrial fibrillation: Therapeutic options" and see "Nonpharmacologic strategies to prevent recurrent atrial fibrillation").

DC cardioversion is indicated in patients who are hemodynamically unstable. In stable patients in whom spontaneous reversion due to correction of an underlying disease is not likely, either medical or electrical cardioversion can be performed. Rate control with an atrioventricular (AV) nodal blocker (calcium channel blocker, beta blocker, or, if the patient has heart failure or hypotension, digoxin) should be attained before instituting class IA drugs because of possible recurrence with atrial flutter and a very rapid ventricular rate. Successful reversion to and maintenance of sinus rhythm is more likely if the AF has been present for less than one year and if the left atrium is not enlarged [1,5].

Maintenance of sinus rhythm – Only 20 to 30 percent of patients who are successfully cardioverted maintain sinus rhythm for more than one year without chronic antiarrhythmic therapy [1,2,4]. This is more likely in patients with AF for less than one year, no enlargement of the left atrium, and a reversible cause of AF such as hyperthyroidism, pericarditis, and cardiac surgery.

It has been thought that the drugs that are most likely to maintain sinus rhythm suppress triggering ectopic beats and arrhythmias, and affect atrial electrophysiologic properties to diminish the likelihood of AF. There is therefore a strong rationale for prophylactic antiarrhythmic drug therapy in patients who have a moderate to high risk for recurrence, provided that it is effective and that both toxicity and proarrhythmic effects are low.

Class IA, IC, and III drugs are useful for maintenance of sinus rhythm. The choice may vary with the clinical setting (show algorithm 1) [6]. As an example, amiodarone may be preferred in patients with a reduced left ventricular ejection fraction, while disopyramide is generally avoided in patients with heart failure. Concurrent administration of an AV nodal blocker is indicated in patients who have demonstrated a moderate to rapid ventricular response to AF. (See "Antiarrhythmic drugs to maintain sinus rhythm after cardioversion in atrial fibrillation: Recommendations").

There are alternative methods to maintain sinus rhythm in selected patients who are refractory to conventional therapy. These include combined drug therapy, surgical and radiofrequency ablative procedures, and insertion of an implantable atrial defibrillator. (See "Nonpharmacologic strategies to prevent recurrent atrial fibrillation").

Slowing the ventricular rate in chronic atrial fibrillation – The administration of medications to control the ventricular rate in AF slow AV nodal conduction by the following physiologic mechanisms (show figure 2) [1,2]. (See "Control of ventricular rate in atrial fibrillation: Pharmacologic therapy"):

· Further blockade of the calcium channel as occurs with calcium channel blockers, particularly verapamil and diltiazem

· Decreased sympathetic tone resulting from beta blockade

· Enhancement of parasympathetic tone with vagotonic drugs, the most important of which is digoxin

The factors that determine the choice between these drugs are discussed below (see "Initial rate control with mild to moderate symptoms" below). The nonpharmacologic therapies for achieving rate control in patients with AF who do not respond to pharmacologic therapy include surgery and radiofrequency catheter ablation. (See "Control of ventricular rate in atrial fibrillation: Nonpharmacologic therapy").

Prevention of systemic embolization – Separate issues are involved with anticoagulation during cardioversion to sinus rhythm and in patients with chronic AF.

Anticoagulation during restoration of sinus rhythm – Based upon observational studies, guidelines published in January 2001 by the Sixth American College of Chest Physicians (ACCP) Consensus Conference on Antithrombotic Therapy strongly recommended that outpatients without a contraindication to warfarin who have been in AF for more than 48 hours should receive three to four weeks of warfarin prior to and after cardioversion with a target INR of 2.5 (range 2.0 to 3.0) [7]. The rationale for this approach is that over 85 percent of left atrial thrombi resolve after four weeks of warfarin therapy [8].

Anticoagulation prior to cardioversion is also mandatory for patients with AF who have valvular disease, evidence of left ventricular dysfunction, recent thromboembolism, or when AF is of unknown duration, as in an asymptomatic patient. (See "Anticoagulation during restoration of sinus rhythm in atrial fibrillation").

An alternative approach that eliminates the need for prolonged anticoagulation prior to cardioversion, particularly in low risk patients who would benefit from earlier cardioversion, is the use of transesophageal echocardiographic-guided cardioversion (see "Role of transesophageal echocardiography" below).

A different approach may be used in patients with AF of less than 48 hours duration who do not have a history of a prior thromboembolic event, left ventricular dysfunction, or rheumatic heart disease. Such patients have a low risk (0.8 percent in one study) of clinical thromboembolism if converted early, even without screening TEE [9]. Acute anticoagulation with intravenous heparin is indicated only if the patient is admitted to the hospital and cardioversion is delayed beyond 48 hours (see "Indications for hospitalization" below).

The optimal therapy after cardioversion in this group is uncertain. Our current practice is to administer aspirin for a first episode of AF that converts spontaneously and warfarin for at least four weeks to all other patients.

Anticoagulation in chronic AF – In patients with chronic AF who are not anticoagulated, the incidence of clinically evident embolization is about 5 percent per year; in addition, the overall incidence of cerebrovascular embolization is 28 percent compared to 7 percent in patients in sinus rhythm [10]. The prevalence of stroke associated with AF increases strikingly with age.

Warfarin is associated with a 45 to 82 percent reduction in the risk of stroke in patients with chronic AF (show figure 3). Anticoagulation is beneficial in all age groups, including patients over age 75 (show figure 4), and is also effective as secondary prevention in patients with nonrheumatic AF who have had a recent transient ischemic attack or minor stroke [6,11]. The true efficacy of warfarin is likely to be even higher than suggested by these results, since many of the strokes in the warfarin-treated groups occurred in patients who were noncompliant at the time of the stroke. (See "Anticoagulation to prevent embolization in chronic atrial fibrillation: Recommendations").

Rhythm control versus rate control with anticoagulation - Most physicians prefer rhythm control, with the restoration and maintenance of sinus rhythm, to persistence of AF, with rate control and anticoagulation. However, there are few data available to suggest which approach is superior as both have strengths and weakness:

· Reversion of AF and maintenance of sinus rhythm restores normal hemodynamics and may prevent embolism. However, this approach usually requires chronic administration of antiarrhythmic drugs, which are not always effective and are associated with many side effects, including the risk of proarrhythmia. (See "Antiarrhythmic drugs to maintain sinus rhythm after cardioversion in atrial fibrillation: Clinical trials-I"). Although nonpharmacologic therapies are available, they are still investigational and their long-term efficacy and safety have not been demonstrated. (See "Nonpharmacologic strategies to prevent recurrent atrial fibrillation").

· Rate control with anticoagulation is not associated with chronic administration of antiarrhythmic drugs. However, this approach is associated with risks from anticoagulation, a continued small risk of embolism, and suboptimal hemodynamics that may be of particular importance for the patient with underlying left ventricular dysfunction. (See "Hemodynamic consequences of atrial fibrillation and cardioversion to sinus rhythm"). In addition, adequate rate control with pharmacologic therapy is occasionally difficult to achieve, and nonpharmacologic approaches, particularly radiofrequency ablation of the atrioventricular node and pacemaker insertion, may be necessary.

Two trials have compared these two approaches. In the PIAF trial, 252 patients with AF of 7 to 360 days duration were randomly assigned to rate control with diltiazem or rhythm control with amiodarone [12]. Patients who did not revert on amiodarone were electrically cardioverted and maintained on the drug; all patients received anticoagulation during the duration of the trial. After a one year follow-up, there was no difference in the quality of life between the two groups; patients with rhythm control had better exercise tolerance but required more frequent hospitalization.

In the STAF trial, 200 patients with chronic AF were randomly assigned to external or internal cardioversion followed by amiodarone or a class I antiarrhythmic drug or to rate control and anticoagulation [13]. After a mean follow-up of 20 months, there was no difference in the primary end point (death, stroke or transient ischemic attack, cardiopulmonary resuscitation, or systemic embolization) or in secondary end points (bleeding worsening heart failure, changes in left ventricular function, atrial size, or quality of life). However, the number of hospitalizations and length of stay was greater in the rhythm control group due to repeat cardioversions and adjustment of antiarrhythmic drug therapy. Furthermore, at three years, only 23 percent of patients remained in sinus rhythm.

These data suggest that both approaches are acceptable and that the choice should be individualized for the needs of the patient. Further information about the safety and efficacy of these two approaches will come from another ongoing trial, AFFIRM, which will include 5300 patients who will be followed for 3.5 years [14].

Cost-effectiveness – Attempts have been made to assess the cost-effectiveness of these two approaches. One study used a Markov decision-analytic model comparing no therapy, warfarin, cardioversion followed by quinidine, or cardioversion followed by amiodarone; the last approach was the best strategy [4].

A second report used the same model in a cohort of 70 year-old patients with different baseline risks of stroke [15]. The following results were noted:

· Strategies using cardioversion alone were more effective and less costly than other approaches.

· For patients at high risk for a stroke (5.3 percent per year), cardioversion was the most cost-effective approach ($9300 per quality-adjusted life-years), followed by repeated cardioversion plus amiodarone therapy upon relapse.

· The same strategy was preferred for patients at moderate risk of stroke (3.6 percent per year), but it was more costly ($18,900 per quality-adjusted life-years).

· For patients with the lowest risk of stroke (1.6 percent per year), cardioversion alone followed by aspirin therapy upon relapse was the best approach.

PRESENTATION AND MANAGEMENT OF RECENT ONSET ATRIAL FIBRILLATION - Most patients with recent onset AF present with symptoms related to the arrhythmia. Typical symptoms include palpitations, a sense of the heart racing, fatigue, lightheadedness, increased urination, or mild shortness of breath. More severe symptoms and signs include dyspnea, angina, hypotension, presyncope, or infrequently syncope. In addition, some patients present with an embolic event or the insidious onset of right-sided heart failure (as manifested by peripheral edema, weight gain, and ascites). Except for embolization, these symptoms are primarily due to a rapid ventricular rate.

A rationale approach to the management of patients with new onset AF is presented in algorithm 2 [16] and is in general agreement with guidelines for the acute management of recent onset AF were published in August 2000 by the American Heart Association in collaboration with the International Liaison Committee on Resuscitation (ILCOR) (show algorithm 2, show table 1 and show table 2) [17]. (See "Guidelines for advanced cardiovascular life support: Treatment of tachycardias").

Emergency room reversion of new onset AF - An important issue is whether patients who have an uncomplicated clinical status and are low-risk can be managed in the emergency room or an observational unit [18-21]. This issue was addressed in a study of 289 patients who were stable, did not have heart disease, and did not have another indication for hospital admission [20]. Chemical cardioversion was attempted in 62 percent and was successful in 50 percent; 28 percent underwent electric cardioversion with a success rate of 89 percent. Overall, 97 percent of patients were discharged home directly from the emergency room. Similar results were noted in another report of 51 patients who underwent attempted chemical cardioversion, followed by electrical reversion if AF was still present; all patients were successful reverted and discharged from the emergency room [21].

Thus, emergency room or observational unit treatment of new onset AF in clinically stable patients is safe and cost-effective [19]. (See "Restoration of sinus rhythm in atrial fibrillation: Recommendations", section on Atrial fibrillation and stable hemodynamics).

Indications for hospitalization - Traditionally, many patients with new onset AF, particularly those without spontaneous reversion, are admitted to the hospital. A frequent reason for admission to the hospital is to "rule out" an acute myocardial infarction. However, AF is rarely the manifestation of an asymptomatic acute ischemic event or myocardial infarction. As a result, there is no reason to admit the patient for this indication unless there are other clinical reasons to consider the diagnosis, such as classic ischemic chest pain or an electrocardiogram demonstrating an acute infarct or ischemia [22,23]. (See "Causes of atrial fibrillation", section on Coronary disease).

There are, however, several indications for which hospitalization is often required:

· For the treatment of an associated medical problem, which is often the reason for the arrhythmia

· For elderly patients who are more safely treated for AF in hospital

· For patients with significant underlying heart disease who have hemodynamic consequences from the AF or who are at risk for a complication resulting from therapy of the arrhythmia

Search for an underlying cause – When faced with a patient who presents with rapid AF, there needs to be a quick assessment for an underlying cause, such as heart failure, pulmonary problems, hypertension, or hyperthyroidism, and for the urgency for heart rate slowing. Therapy for a precipitating cause of AF may result in reversion to sinus rhythm and, unless the patient is hemodynamically unstable, should be initiated prior to therapy aimed at reverting AF. (See "Causes of atrial fibrillation").

Serum should be obtained for measurement of thyroid stimulating hormone (TSH). This should be done even if there are no symptoms suggestive of hyperthyroidism, since the risk of AF is increased up to threefold in patients with subclinical hyperthyroidism (show figure 5). Patients with low TSH values (<0.5 mU/L with the newer sensitive assays) and normal thyroid hormone levels probably have subclinical hyperthyroidism. In one series of 726 patients with recent onset AF, 39 (5.4 percent) had low serum TSH values; 14 of these patients were taking thyroxine supplements for previous hyperthyroidism or hypothyroidism [24]. (See "Subclinical hyperthyroidism").

In the patient in whom AF appears to have been precipitated by an acute and reversible medical problem, cardioversion should be postponed until the condition has been successfully treated, which will often lead to spontaneous reversion. If this treatment is to be initiated as an outpatient, anticoagulation with warfarin should be begun with cardioversion performed, if necessary, after three to four weeks of adequate anticoagulation. If the patient is to be admitted to hospital for treatment of the underlying disease, it is prudent to begin heparin therapy and then institute oral warfarin. Cardioversion is again performed after three to four weeks of adequate anticoagulation if the patient does not revert to sinus rhythm.

Spontaneous reversion of AF – Recent onset AF often spontaneously reverts to sinus rhythm, the incidence of which is related to the duration of the arrhythmia. This was illustrated in a study of 1822 patients admitted to the hospital because of AF: 356 had an arrhythmia duration less than 72 hours, 68 percent of whom spontaneously reverted to sinus rhythm [25]. Two-thirds of those with spontaneous reversion had an AF duration of less than 24 hours, which was the only predictor of spontaneous reversion. Identical findings were noted in another report of 375 patients with AF of less than 48 hours duration; two-thirds reverted spontaneously [9]. (See "Paroxysmal atrial fibrillation").

Indications for urgent cardioversion - There are settings in which the rapid heart rate produces complications requiring urgent cardioversion. These include:

· Active ischemia

· Significant hypotension, to which poor left ventricular systolic function, diastolic dysfunction, or associated mitral or aortic valve disease may contribute

· The presence of a preexcitation syndrome, which may lead to an extremely rapid ventricular rate (show table 2)

(See "Restoration of sinus rhythm in atrial fibrillation: Recommendations", section on DC electroversion).

Initial rate control with mild to moderate symptoms - Most patients with acute AF do not require immediate reversion. Initial treatment directed at slowing the ventricular rate will usually result in improvement or resolution of the associated symptoms. As noted above, this can be achieved with beta blockers, calcium channel blockers (primarily verapamil and diltiazem), or digoxin. The drug selected and the route of administration (oral versus intravenous) are dictated by the clinical presentation. (See "Control of ventricular rate in atrial fibrillation: Pharmacologic therapy").

· Digoxin is usually the preferred drug in patients with AF due to heart failure. In addition to the direct vagotonic effect of digoxin on the AV node (which may require several hours to become apparent), the improvement in left ventricular function and systemic hemodynamics result in withdrawal of sympathetic tone and a further decrease in the ventricular rate. Not infrequently, the improvement in hemodynamics results in reversion of the arrhythmia. Digoxin can also be used in patients who cannot take or who respond inadequately to beta blockers or calcium channel blockers. The effect of digoxin is additive to both of these drugs.

· In most other situations, a beta blocker or calcium channel blocker is preferred since, in the absence of heart failure, digoxin is less effective for rate control than beta blockers and calcium channel blockers, is less likely to control the ventricular rate during exercise (when vagal tone is low and sympathetic tone is high), has little ability to terminate the arrhythmia, and often does not slow the heart rate in patients with recurrent AF.

Beta blockers and calcium channel blockers are also effective if heart failure or hypotension is due to the rapid arrhythmia. If, however, there is doubt about the origin of the heart failure, the initial dose should be small (since these drugs impair contractility), with upward titration based upon heart rate slowing, blood pressure, and symptomatic improvement.

The choice between a beta blocker or a calcium channel blocker is frequently based upon physician and patient preference, although it may be influenced by other problems that are present. As an example, beta blockers are particularly useful when the ventricular response increases to inappropriately high rates during exercise, after an acute myocardial infarction, and when exercise-induced angina pectoris is also present. On the other hand, a calcium channel blocker is preferred in patients with chronic lung disease. The use of both a beta blocker and calcium channel blocker should be avoided, if possible.

Elective cardioversion - The next step after control of the ventricular rate in patients with mild to moderate symptoms involves a decision about reversion of the AF. The role for cardioversion depends upon the duration of the arrhythmia as well as the presence of a reversible etiologic factor. (See "Cardioversion for specific arrhythmias-I").

Immediate cardioversion - If the duration of the arrhythmia is 48 hours or less and there are no associated cardiac abnormalities (particularly mitral valve disease or significant left ventricular enlargement due to a cardiomyopathy), there is a low risk of systemic embolization [9] and electrical or pharmacologic cardioversion can be attempted after systemic heparinization. Anticoagulation is indicated for three to four weeks after cardioversion because de novo thrombus formation and embolization can occur. (See "Anticoagulation during restoration of sinus rhythm in atrial fibrillation").

Delayed cardioversion – It is preferable to anticoagulate with warfarin, establishing an INR of 2 to 3 for approximately three to four weeks to allow any left atrial thrombi to resolve [8], before attempted cardioversion if:

· The duration of the arrhythmia is more than 48 hours or of unknown duration

· There is associated mitral valve disease or significant cardiomyopathy and heart failure

· The patient has a prior history of a thromboembolic event

During this time, rate control should be maintained with an oral AV nodal blocker as described above.

Role of transesophageal echocardiography – Transesophageal echocardiography (TEE) immediately prior to elective cardioversion should be considered for those patients at increased risk for left atrial thrombi (eg, rheumatic mitral valve disease, recent thromboembolism, severe left ventricular systolic dysfunction). Cardioversion should be delayed if thrombi are seen in any cardiac chamber.

The role of routine TEE prior to elective cardioversion in nonvalvular AF of more than 48 hours duration is uncertain. Several studies have found that stable patients receiving heparin in whom no thrombi are seen on TEE can be safely treated without prolonged anticoagulation prior to cardioversion (show table 3A-3B) [26-29]. (See "Anticoagulation during restoration of sinus rhythm in atrial fibrillation").

The ACUTE trial compared a TEE-guided strategy (anticoagulation with heparin immediately before TEE and cardioversion, and then continued with warfarin for four weeks after cardioversion) with a conventional strategy (three weeks of anticoagulation before cardioversion, followed by four weeks of anticoagulation after cardioversion) in 1222 patients with AF of more than two days duration who were undergoing electrical cardioversion [28]. There was no difference between the two groups in the incidence of ischemic stroke, TIA, or all embolic events within eight weeks of cardioversion (0.8 versus 0.5 percent for the conventional strategy). However, patients undergoing the TEE-guided strategy had a lower incidence of hemorrhagic events (2.9 versus 5.5 percent), a shorter mean time to cardioversion (3 versus 30.6 days), and a greater incidence of successful reversion (71 versus 65 percent).

These data suggest that the TEE-guided strategy is an alternative to a conventional approach and may be of particular use in the patient with AF of less than three weeks duration or who has an increased risk of hemorrhagic complications during prolonged warfarin therapy [30].

AF in underlying cardiomyopathy - Patients with an underlying cardiomyopathy who, as a result of AF, have severe heart failure that persists despite adequate slowing of the ventricular rate, often require rapid restoration of sinus rhythm. (See "Treatment of atrial fibrillation in congestive heart failure and cardiomyopathy").

There may be a role for TEE in this setting. Cardioversion is likely to be safe if there is no evidence for thrombus in the left atrium or appendage and no "smoke" in the left atrium (show echocardiogram). The patient should be placed on heparin prior to reversion and anticoagulated with warfarin for at least three to four weeks after restoration of sinus rhythm.

GENDER DIFFERENCES – The importance of gender differences in the presentation and treatment of AF was examined in a study of 900 men and women with new-onset AF who were followed for more than four years [31]. The following findings were noted:

· At the time of presentation, women were older than men (65.4 versus 60.5 years) and were more likely to seek medical advice because of symptoms perhaps due in part to higher heart rates during AF (126 versus 119 beats per min).

· The rate of cardioversion and use of cardiac medications was the same. However, women > or =75 years of age were 54 percent less likely to receive warfarin, but were twice as likely to receive aspirin therapy; this difference was the same even for those with one or more stroke risk factors.

· During follow-up, women were more likely to have recurrent episodes of paroxysmal AF (48 versus 31 percent at one year), but the progression to permanent AF at three years was the same (19 percent).

· There was no sex difference in the incidence of stroke, myocardial infarction, major bleeds, or cardiovascular death. However, among patients treated with warfarin, women were 3.4 times more likely to experience a major bleed than men.

MORTALITY – Although the morbidity associated with AF, primarily heart failure and stroke, is well established, it is not clear if AF itself results in excess mortality. Patients under the age of 60 who have AF but no apparent heart disease (called lone AF) have been considered a group with a better prognosis. (See "Causes of atrial fibrillation", section on Lone atrial fibrillation).

However, AF is a risk factor for increased mortality in otherwise healthy older individuals. Among subjects age 55 to 94 from the original 5209 subjects in the Framingham Heart Study, AF almost doubled the risk of death in both men and women without underlying cardiovascular disease [32]. After adjustment for other risk factors, AF was still associated with an increased risk of death (odds ratio 1.5 for men and 1.9 for women) (show figure 6).

The coexistence of cardiovascular disease and chronic AF worsens the patient’s prognosis, doubling the cardiovascular mortality [33]. In patients with a recent myocardial infarction, for example, the presence of AF increases mortality [34-36]. However, this effect is primarily due to associated risk factors, such as heart failure and cardiogenic shock, not AF itself [35,36]. (See "Supraventricular arrhythmias after myocardial infarction").

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32. Benjamin, EJ, Wolf, PA, D’Agostino, RB, et al. Impact of atrial fibrillation on the risk of death: The Framingham Heart Study. Circulation 1998; 98:946.

33. Kannel, WB, Abbott, RD, Savage, DD, McNamara, PM. Epidemiologic features of chronic atrial fibrillation. N Engl J Med 1982; 306:1018.

34. Crenshaw, BS, Ward, SR, Granger, CB, et al. Atrial fibrillation in the setting of acute myocardial infarction: the GUSTO-I experience. Global Utilization of Streptokinase and TPA for Occluded Coronary Arteries. J Am Coll Cardiol 1997; 30:406.

35. Goldberg, RJ, Seeley, D, Becker, RC, et al. Impact of atrial fibrillation of the in-hospital and long-term survival of patients with acute myocardial infarction: A community-wide perspective. Am Heart J 1990; 119:996.

36. Eldar, M, Canettii, M, Rotstein, Z, et al, for the SPRINT and Thrombolytic Survey Groups. Significance of paroxysmal atrial fibrillation complicating acute myocardial infarction in the thrombolytic era. Circulation 1998; 97:965.

Technorati Tags: Amiodarone,antiarrhythmic drug,arrhythmia,atrial fibrillation,myocardial infarction

Gene variants influence heart-failure risk, response to beta blockers

July 21, 2009 by Steve Stiles

Washington, DC – Increasingly in explorations of why African Americans and whites with heart failure seem to respond differently to some drug therapies, genotype rules; race is a distraction.

A large, prospective study published online July 20, 2009 in the Journal of the American College of Cardiology suggests that much of the perceived differences in beta-blocker effectiveness, as well as variability in beta-blocker responses among African Americans, may be attributed to a couple of gene variants that affect beta receptors and their signaling pathways [1]. When those polymorphisms are controlled for, the supposed racial distinctions in beta-blocker response disappear, according to the authors, led by Dr Sharon Cresci (Washington University School of Medicine, St Louis, MO).

Of their 2460 patients with systolic heart failure followed for a median of 46 months, including 711 African Americans and 1749 whites, 2039 (about 82%) were treated with a beta blocker. Of those, 66% received carvedilol and 24% were given metoprolol.

All patients were genotyped for polymorphisms of beta-1 adrenergic receptor (ADRB1) Arg389gly (which encodes for beta receptors, the target of beta blockers) and for G-protein receptor kinase 5 (GRK5) Gln41Leu (which regulates beta-receptor signaling pathways). Both polymorphisms are "overrepresented" in African Americans compared with whites, Cresci et al explain, and "may play roles in determining individual clinical responses to beta blockade in heart failure."

G-protein receptor kinases desensitize and thereby "turn off" the beta receptors, primary author Dr Gerald W Dorn (Washington University School of Medicine) told heartwire. "It’s the body’s way of beta blocking."

Dorn and his colleagues previously found that 41% of a sample of African Americans carried at least one allele of the GRK5 variant, which was associated with significant improvement in heart-failure prognosis in the absence of beta-blocker therapy [2]. Similar survival times were seen in those without the variant who were taking beta blockers. But beta blockade in black patients with the variant didn’t further prolong survival in this comparatively small study.

As described by heartwire in its coverage at the time, the polymorphism that is common in African Americans (but rare in whites) can make it appear that beta blockers don’t improve their heart-failure survival. In effect, according to Dorn, the drugs are unable to extend the benefit already conferred by the GRK5 variant.

The apparent lack of beta-blocker effect masks the benefit observed in African Americans without the variant. They and the white patients showed similar survival gains on beta blockers.

The larger current study extends those findings in a more expansive population, Dorn said. In it, mortality was about 31% and was similarly reduced in whites and African Americans. The reduction in adjusted hazard ratio (HR) was significant in the former (HR 0.679, p=0.005) but not in the latter (HR 0.698, p=0.1).

Among the patients not taking beta blockers, the ADRB1 Gly389 variant was associated with a mortality HR of 1.98 (p=0.03) in whites, and the Leu41 variant of GRK5 was associated with a mortality HR of 0.325 (p<0.01) in African Americans.

Among those who were on beta blockers, African Americans genotyped as ADRB1 Gly389Gly GRK5 Gln41Gln showed a mortality reduction (HR 0.385, p=0.012) similar to that of whites with the same variants (HR 0.529, p=0.010), consistent with the smaller study’s results.

Their data, write Cresci et al, show that the two polymorphisms can have a significant influence on heart-failure prognosis and outcomes "in the same manner as clinical risk modifiers." They also suggest that variations in apparent beta-blocker efficacy in their population associated with beta-receptor signaling-pathway gene polymorphisms, "rather than race, are the major factor contributing to apparent differences in beta-blocker treatment effect between [whites] and African Americans."

Sources

1. Cresci S, Kelly RJ, Cappola TP, et al. Clinical and genetic modifiers of long-term survival in heart failure. J Am Coll Cardiol 2009; 54:432-444). DOI:10.1016/j.jacc.2009.05.009. Available at: http://content.onlinejacc.org.
2. Liggett SB, Cresci S, Kelly RJ, et al. A GRK polymorphism that inhibits beta-adrenergic receptor signaling is protective in heart failure. Nat Med 2008; 14:510-517.

Technorati Tags: carvedilol,metoprolol,beta blocker,heart failure

Control of ventricular rate in atrial fibrillation: Pharmacologic therapy

Technorati Tags: Amiodarone,antiarrhythmic drug,arrhythmia,atrial fibrillation,myocardial infarction

May 24, 2004 by Morton F Arnsdorf, MD

The ventricular response to atrial fibrillation (AF) is variable and in certain settings may provide important clinical clues to confounding factors. As an example, there is a circadian rhythm for both AV nodal refractoriness and concealed conduction, accounting for the circadian variation in ventricular response rate [1]. These are attenuated in patients with CHF in whom there is altered autonomic neural control with sympathetic nervous system activation and vagal withdrawal.

In the typical patient with AF, the ventricular rate during the day varies between 90 and 170 beats/min in the absence of atrioventricular (AV) nodal disease, drugs that affect conduction, or high vagal tone as may occur in a well conditioned athlete. In comparison, a ventricular rate below 60 beats/min in the absence of digitalis or some other drug that slows AV conduction suggests AV nodal disease, which is often associated with the sick sinus syndrome. On the other hand, a ventricular rate above 200 beats/min suggests catecholamine excess, parasympathetic withdrawal, or the existence of an accessory bypass tract as occurs in the preexcitation syndrome. The QRS complexes are widened in the latter situation and must be distinguished from a rate related or underlying bundle branch block. (See

"Tachyarrhythmias associated with the Wolff-Parkinson-White syndrome").

Physiologically, the AV node has been called a "slow response" tissue, since the generation of its action potential depends on calcium ions flowing through a kinetically slow channel. The activation and reactivation characteristics of these calcium channels results in normally slow conduction through the AV node. (See "Myocardial action potential and action of antiarrhythmic drugs"). Moreover, the AV node is richly supplied by both components of the autonomic nervous system: the sympathetic nerves increasing and the parasympathetic nerves decreasing AV nodal conduction. These electrophysiologic properties are depicted in Figure 1 (show figure 1). The advent of radiofrequency ablation has permitted a more detailed analysis of the electrophysiologic anatomy of the AV node. This technique established additional anatomic complexity related to the presence of slow and fast input tracts.

The pharmacologic therapies for achieving rate control in AF will be reviewed here. The role of radiofrequency ablation and other nonpharmacologic therapies for rate control of AF and an overview of the management of AF are discussed elsewhere. (See "Control of ventricular rate in atrial fibrillation: Nonpharmacologic therapy" and see "Overview of the presentation and management of atrial fibrillation").

PHARMACOLOGIC TREATMENT – The pharmacologic strategies used to control the ventricular rate in AF by slowing AV nodal conduction are based upon these physiologic mechanisms (show figure 2) [2,3]:

• Further blockade of the calcium channel as occurs with calcium channel antagonists, particularly verapamil and diltiazem.

• Decreased sympathetic tone resulting from beta blockade as produced by short, moderate, and long acting drugs.

• Enhancement of parasympathetic tone with vagotonic drugs, the most important of which are the digitalis glycosides, particularly digoxin.

• A combination of the above.

In general, the calcium antagonists are effective while the patient is at rest and during exercise, digitalis is more effective during rest than with exercise; and beta blockers are more effective during exercise than at rest. In one study of 12 patients with chronic AF, the effect of five different drug regimens (digoxin 0.25 mg daily, diltiazem-CD 240 mg daily, atenolol 50 mg daily, digoxin plus diltiazem, and digoxin plus atenolol) on heart rate were compared [4]. Digoxin plus atenolol was the most effect regimen for controlling the mean ventricular rate during 24 hours and reducing the peak heart rate during exercise; digoxin and diltiazem as single agents were the least effective (show figure 3).

Some patients have either an incomplete response to pharmacologic therapy or intolerable drug-induced side effects. Rarely such a patient will require nonpharmacologic intervention including surgery or radiofrequency AV nodal ablation or modification. (See "Nonpharmacologic strategies to prevent recurrent atrial fibrillation").

Digitalis – Digoxin remains the most widely used drug in the United States to control the ventricular rate in AF, acting primarily by vagotonic inhibition of AV nodal conduction. In one survey of office visits during 1994 to 1996 by patients in AF, 53 percent who were treated with a rate slowing agent were receiving digoxin alone while 15 percent were using a calcium channel blocker and 13 percent a beta blocker [5].

Despite these differences in utilization, digoxin is generally less effective for rate control than beta blockers or calcium channel blockers, is less likely to control the ventricular rate during exercise (when vagal tone is low and sympathetic tone is high), has little or no ability to terminate the arrhythmia, and often does not slow the heart rate with recurrent AF [6,7]. Thus, large doses of digoxin are often required for monotherapy, and patients frequently require the addition of a beta blocker [8-10] or calcium channel blocker for optimal rate control [11,12].

As a result, digoxin should no longer be used as a first-line drug, except for the patient with congestive heart failure [6,7]. In this setting, the increase in cardiac contractility and improvement in hemodynamics will both relieve symptoms of low output and reduce reflex sympathetic activation.

Digoxin can be administered orally, intravenously, or intramuscularly, although we do not use intramuscular injection because the absorption is erratic. (See "Method of digitalization" for a review of dosing regimens). Intravenous digoxin begins to act within 15 to 30 minutes, with a peak effect attained in one to five hours. This relatively slow onset of action may be undesirable in symptomatic patients who have AF and a rapid ventricular response. If such a patient is hemodynamically stable, we may choose to initiate therapy with a fast-acting intravenous calcium channel blocker (verapamil or diltiazem) or an intravenous beta blocker such as esmolol (see below). The simultaneous use of digoxin and esmolol is also effective in this setting [10].

Plasma digoxin levels should be monitored periodically. Although the correlation between drug concentration and ventricular rate control is poor, the presence of a low digoxin level is useful in that it allows a higher dose to be administered.

Junctional escape beats (as detected by the equality of all the longest observed R-R intervals on the electrocardiogram) are common when digitalis has successfully slowed the ventricular rate. Giving more digoxin in this setting will increase the degree of AV nodal block and produce periods of regular junctional rhythm. The change from single junctional escapes to periodic junctional rhythm usually signifies the development of digoxin toxicity. (See "Electrocardiographic and electrophysiologic features of atrial fibrillation-I", section on Effect of high degrees of AV nodal block and exit block on ventricular response for a review of the electrocardiographic manifestations of digitalis toxicity in this setting).

Verapamil – Verapamil increases refractoriness and decreases conduction velocity in the AV node It is therefore useful for reducing the ventricular response to AF [11-18] Although the drug is often used in combination with digoxin, monotherapy with oral verapamil is often possible [16-18].

Intravenous verapamil can be given acutely in a dose of 5 to 10 mg over two to three minutes; this dose can be repeated every 15 to 30 minutes, as necessary. The maintenance infusion rate is approximately 0.125 mg/min. The onset of action is within two minutes and the peak effect occurs in 10 to 15 minutes. Control of the ventricular response is lost in roughly 90 minutes if repeated boluses or a maintenance infusion are not given.

The initial dose of oral verapamil is 40 mg three or four times per day increased to a maximum of 480 mg/day if hepatic function is relatively normal. Side effects are common at this dose. The equivalent dose of sustained release verapamil can be used once per day, but a divided dose often must be used to maintain rate control. With either preparation, it should be remembered that the older patient metabolizes verapamil more slowly and is therefore more likely to develop side effects, especially cardiac,which are often related to the blood level.

Although it slows the ventricular rate, verapamil rarely reverts AF to sinus rhythm. It may also have the following additional actions:

• The effect on sinoatrial (SA) nodal function is variable. Although the drug has a direct effect of the sinus node (which generates a slow action potential mediated by calcium ion fluxes), the vasodilator effect of verapamil causes a reflex release of catecholamines that usually maintains or slightly accelerates the SA nodal rate. However, SA nodal function may be depressed in patients with the sick sinus syndrome, presumably via blockade of calcium channels and an inability of the sinus node to respond to catecholamines. Thus, if the normal reflex mechanism is impaired by therapy with a beta blocker, the addition a calcium channel blocker can lead to slowing or, rarely, failure of SA nodal function.

• Verapamil can produce high degree AV block (with or without underlying AV nodal disease) and therefore should not be given to patients with second or third degree AV block. For similar reasons, verapamil must be used with extreme caution when given with other drugs that slow AV nodal conduction (eg, beta blockers or digoxin).

• Verapamil can paradoxically increase the ventricular response in patients with AF and preexcitation by impairing conduction via the normal AV node-His-Purkinje system and therefore improving antegrade conduction over the accessory pathway.

• Verapamil has a negative inotropic effect. As a result, it should be used with caution in patients with heart failure and should not be given if the patient is hypotensive. It should also be used cautiously with other negative inotropes, such as beta blockers.

• Verapamil interacts with digoxin, resulting in an increase in digoxin levels. This is dose related (often occurring when verapamil doses are over 240 mg/day) and generally occurs after seven days of therapy with both agents. Similar to the digoxin-quinidine interaction, verapamil reduces the renal clearance of digoxin; it may also interfere with its hepatic metabolism [19-21]. (See "Digoxin drug interactions").

Diltiazem – Diltiazem may have a less pronounced negative inotropic effect than verapamil [22] and the intravenous preparation is useful for acute control of the ventricular rate in AF [23-25]. Unlike verapamil, there is an FDA approved regimen for a continuous, 24 hour intravenous infusion. The Diltiazem Atrial Fibrillation/Atrial Flutter Study Group regimen consists of a bolus of 20 mg alone or followed in 15 minutes by another 25 mg followed by a continuous infusion at a rate of 10 to 15 mg/h [24]. This regimen controlled the ventricular rate in 83 percent of patients, usually within four minutes. Oral therapy with diltiazem is also effective for chronic rate control, although the oral drug is not yet approved by the FDA for this indication [26,27]. There is, however, an FDA approved regimen for a continuous intravenous infusion.

In one study, the use of one or two boluses of intravenous diltiazem followed by a continuous infusion was evaluated in 84 consecutive patients with AF, atrial flutter, or both [25]. The first bolus was 20 mg given over two minutes, and, if no therapeutic response was seen (20 percent reduction in heart rate from the baseline, conversion to sinus rhythm, or a heart rate less than 100 beats/min) within 15 minutes, a second bolus of 25 mg was given over two minutes. Continuous infusions of 5, 10 and 15 mg/h were then given to responders, while nonresponders were withdrawn from the study.

• The overall response rate was 94 percent.

• The continuous infusion maintained adequate rate control for 10 hours or longer in a dose-dependent fashion – 47 percent at 5 mg/h; 68 percent after titration to 10 mg/h; and 76 percent after titration to 15 mg/h (show figure 4).

• By the end of infusion, 18 percent had converted to sinus rhythm.

• Hypotension occurred in 13 percent and was symptomatic in almost four percent. All patients responded to isotonic saline.

Diltiazem should be given with similar caution to verapamil in patients with severe congestive heart failure (NYHA class III or IV), although diltiazem is less likely to worsen myocardial function [25]; a history of sinus node disease; second- or third-degree AV block; the preexcitation syndrome since conduction in the accessory pathway may be facilitated; the concurrent intake of other drugs that slow AV conduction; and hypotension (systolic blood pressure less than 90 mmHg).

Esmolol and other beta blockers – Esmolol, a rapidly acting beta blocker that is administered intravenously, is useful for rate control in acute AF either alone or with digoxin [10,28,29]. Esmolol begins to act in one to two minutes, is metabolized by red blood cell esterase, and has a short duration of action of 10 to 20 minutes. A bolus of 0.5 mg/kg is infused over one minute, followed by 50 µg/kg/min for four minutes. If the response is inadequate, another bolus is given followed by an infusion of 100 µg/kg/min for another five minutes. The bolus is repeated and the infusion is increased by 50 µg/kg/min up to a maximum of 200 µg/kg/min. Alternatively, an infusion can be started at 50 µg/kg/min without a bolus, and the rate of administration can be increased by 50 µg/kg/min every 30 minutes.

Metoprolol and propranolol can also be given intravenously. However, these preparations are not always used for acute rate control because they have half-lives that are much longer than esmolol.

Oral beta blockers are widely used as primary therapy for rate control in chronic AF. Beta blockers decrease the resting heart rate and blunt the heart rate response to exercise. However, they may also reduce exercise tolerance [30,31].

Certain types of AF may be triggered by sympathetic surges [32], a setting in which beta blockers may in theory be beneficial. However, bradycardia-dependent or vagally-mediated AF may be more common, and the use of beta blockers may render such an individual more liable to AF by inducing sinus bradycardia.

Despite these potential concerns, beta blockers are used frequently alone or in combination with digoxin or calcium channel blockers for control of the ventricular response in patients with chronic AF.

Beta blockers may have adverse effects with which the clinician should be familiar. Some of these complications may be important in AF including worsening heart failure, hypotension, bronchospasm, and high-degree AV block.

Amiodarone – Amiodarone has been approved by the Food and Drug Administration only for the treatment of life-threatening ventricular arrhythmias. It is, however, quite effective in the treatment of AF and flutter, both for rate control and for maintenance of sinus rhythm after successful cardioversion [33-35]. In one study, for example intravenous amiodarone (7 mg/kg), flecainide, or placebo was given to 98 patients with recent onset AF (0.5 to 72 hours) [35]. Even when AF did not revert to sinus rhythm, amiodarone promptly slowed the ventricular rate during the eight hour observation period (show figure 5).

These beneficial effects on the AV node with slowing of the ventricular rate can be achieved at low doses (200 to 400 mg/day) of amiodarone that minimize its potentially serious toxicity. This agent may be particularly indicated when other AV nodal blocking agents fail to adequately slow the ventricular rate or when these agents are not well tolerated.

RECOMMENDATIONS – The following recommendations should be considered as guidelines for controlling the ventricular response that may need to be amended in individual patients with a particular confounding factor. It should be appreciated, however, that the best therapy of AF may be reversion to and maintenance of normal sinus rhythm. Restoration of sinus rhythm will diminish symptoms and prevent potentially life-threatening thromboembolic events, at the risk of potentially serious complications from antiarrhythmic drugs. Some small trials have compared these two approaches. The data suggest that suggest that both are acceptable and that the choice should be individualized for the needs of the patient. (See "Overview of the presentation and management of atrial fibrillation", section on Rhythm control versus rate control with anticoagulation).

Acute rate control – Intravenous diltiazem, using the regimen and paying attention to the cautions described above, has become our drug of choice, even in patients with heart failure. Intravenous digoxin may also be useful in patients with heart failure. Although intravenous esmolol is also very effective, many patients have contraindications or relatively contraindications to the use of beta blockers. However, the very short half life of esmolol permits a therapeutic trial to be performed at reduced risk. These drugs can be given in combination as indicated.

Amiodarone also appears to be effective for acute control of the ventricular response to AF. However, more studies remain to be performed and amiodarone does not have FDA approval for this indication.

Chronic rate control – Similar considerations apply to chronic control of the ventricular rate (show algorithm 1). A beta blocker or calcium channel blocker is preferred in patients not in heart failure. Beta blockers are often contraindicated or relatively contraindicated, and many patients cannot tolerate the associated decrease in exercise tolerance and other side effects and toxicities. We reserve digoxin for patients with CHF or for those who cannot take or who respond inadequately to one of the other AV nodal blocking agents. The effect of digoxin is additive to both beta blockers and calcium channel blockers.

The choice between a beta blocker or a calcium channel blocker is frequently based upon physician and patient preference, although it may be influenced by other problems that are present. As an example, beta blockers are particularly useful when the ventricular response increases to inappropriately high rates during exercise, after an acute myocardial infarction, and when exercise-induced angina pectoris is also present. On the other hand, a calcium channel blocker is preferred in patients with chronic lung disease. The use of both a beta blocker and calcium channel blocker should be avoided if possible.

Among the beta blockers, atenolol and nadolol have the advantages of a long half-life, and atenolol, in our experience, produces less central nervous system side effects than other beta blockers. Long-acting propranolol and metoprolol preparations are also effective if tolerated. We generally begin with 25 mg of atenolol per day and gradually increase the daily dose to 100 mg, and sometimes 200 mg, if necessary.

Among the calcium channel blockers, verapamil has a somewhat greater blocking effect on the AV node than diltiazem, and the choice between these agents is often dictated by side effects. Diltiazem may be preferred in patients with heart failure.

The use of amiodarone is problematic given existing FDA regulations. There is a feeling, however, that amiodarone may soon be considered the best drug for long-term control of the ventricular response in AF, especially in patients with congestive heart failure. It may also be the best drug for maintaining sinus rhythm after successful cardioversion.

Interventional therapy – Consideration should be given to complete AV ablative therapy and the use of a pacemaker in patients in whom adequate heart rate control cannot be achieved pharmacologically (show algorithm 1). Surgery for the maintenance of normal sinus rhythm is still experimental, and surgical ablation of the AV node or His bundle has no theoretical advantage over radiofrequency catheter ablation. (See "Control of ventricular rate in atrial fibrillation: Nonpharmacologic therapy").

Radiofrequency ablation of one of the AV nodal inputs, modifying but not destroying the AV node, is an alternative. With continued technical improvements, this procedure may become preferred over drugs or complete AV ablation.

References

1. Hayano, J, Sakata, S, Okada, A, et al. Circadian rhythms of atrioventricular conduction properties in chronic atrial fibrillation with and without heart failure. J Am Coll Cardiol 1998; 31:158.

2. Pritchett, EL. Management of atrial fibrillation. N Engl J Med 1992; 326:1264.

3. The National Heart, Lung and Blood Institute Working Group on Atrial Fibrillation. Atrial fibrillation: Current understandings and research imperatives. J Am Coll Cardiol 1993; 22:1830.

4. Farshi, R, Kistner, D, Sarma, JSM, et al. Ventricular rate control in chronic atrial fibrillation during daily activity and programmed exercise: A crossover open-label study of five drug regimens. J Am Coll Cardiol 1999; 33:304.

5. Stafford, RS, Robson, DC, Misra, B, et al. Rate control and sinus rhythm maintenance in atrial fibrillation: National trends in medication use, 1980-1996. Arch Intern Med 1998; 158:2144.

6. Falk, RH, Leavitt, JI. Digoxin for atrial fibrillation: A drug whose time has gone? Ann Intern Med 1991; 114:993.

7. Sarter, BH, Marchlinsky, FE. Redefining the role of digoxin in the treatment of atrial fibrillation. Am J Cardiol 1992; 69:71G.

8. David, D, Segni, ED, Klein, HO, Kaplinsky, E. Inefficacy of digitalis in the control of heart rate in patients with chronic atrial fibrillation: Beneficial effect of an added beta-adrenergic blocking agent. Am J Cardiol 1979; 44:1378.

9. Khalsa, A, Edvardsson, N, Olsson, SB. Effects of metoprolol on heart rate in patients with digitalis treated chronic atrial fibrillation. Clin Cardiol 1978; 1:91.

10. Shettigar, UR, Toole, JG, Appunn, DO. Combined use of esmolol and digoxin in the acute treatment of atrial fibrillation or flutter. Am Heart J 1993; 126:368.

11. Klein, HO, Pauzner, H, Di Segni, E, et al. The beneficial effects of verapamil in chronic atrial fibrillation. Arch Intern Med 1979; 139:747.

12. Panidis, IP, Morganroth, J, Baessler, C. Effectiveness and safety of oral verapamil to control exercise-induced tachycardia in patients with atrial fibrillation. Am J Cardiol 1983; 52:1197.

13. Tommaso, C, McDonough, T, Parker, M, Talano, JV. Atrial fibrillation and flutter. Immediate control and conversion with intravenously administered verapamil. Arch Intern Med 1983; 143:877.

14. Hwang, MH, Danoviz, J, Pacold, I, et al. Double blind crossover randomized trial of intravenously administered verapamil: Its use for atrial fibrillation and flutter following open heart surgery. Arch Intern Med 1984; 144:491.

15. Waxman, HL, Myerburg, RJ, Appel, R, Sung, RJ. Verapamil for control of ventricular rate in paroxysmal supraventricular tachycardia and atrial fibrillation or flutter: A double blind randomized cross-over study. Ann Intern Med 1981; 94:1.

16. Stern, EH, Pitchon, R, King, BD, et. al. Clinical use of oral verapamil in chronic and paroxysmal atrial fibrillation. Chest 1982; 81:308.

17. Lang, R, Klein, HO, Weiss, E, et al. Superiority of oral verapamil therapy to digoxin in treatment of chronic atrial fibrillation. Chest 1983; 83:491.

18. Lundstrom, T, Ryden, L. Ventricular rate control and exercise performance in chronic atrial fibrillation: Effects of diltiazem and verapamil. J Am Coll Cardiol 1990; 16:86.

19. Klein HO, Long R, Weiss E, et al. The influence of verapamil on serum digoxin. Circulation 1982; 65:998.

20. Hori, P, Okamura, N, Aiba, T, Tanigawara, Y. Role of P-glycoprotein in renal tubular secretion of digoxin in isolated perfused rat kidney. J Pharmacol Exp Ther 1993; 266:1620.

21. Hedman, A, Angelin, B, Arvidsson, A, et al. Digoxin-verapamil interaction: Reduction of biliary but not renal digoxin clearance in humans. Clin Pharmacol Ther 1991; 49:256.

22. Böhm, M, Schwinger, RH, Erdman, E. Different cardiodepressant potency of various calcium channel antagonists in human myocardium. Am J Cardiol 1990; 65:1039.

23. Ellenbogen, KA, Dias, VC, Plumb, VJ, et al. A placebo-controlled trial of continuous intravenous diltiazem infusion for 24-hour heart rate control during atrial fibrillation and atrial flutter: A multicenter study. J Am Coll Cardiol 1991; 18:891.

24. Salerno, DM, Dias, VC, Kleiger, RE, et al. Efficacy and safety of intravenous diltiazem for treatment of atrial fibrillation and atrial flutter: The Diltiazem-Atrial Fibrillation/Flutter Study Group. Am J Cardiol 1989; 63:1046.

25. Ellenbogen, KA, Dias, VC, Cardello, FP, et al. Safety and efficacy of intravenous diltiazem in atrial fibrillation or atrial flutter. Am J Cardiol 1995; 75:45.

26. Steinberg, JS, Katz, RJ, Bren, GB, et al. Efficacy of oral diltiazem to control ventricular response in chronic atrial fibrillation at rest and during exercise. J Am Coll Cardiol 1987; 9:405.

27. Roth, A, Harrison, E, Mitani, G, et al. Efficacy and safety of high-dose diltiazem alone and in combination with digoxin for control of heart rate at rest and during exercise in patients with chronic atrial fibrillation. Circulation 1986; 73:316.

28. Platia, EV, Michelson, EL, Porterfield, JK, et al. Esmolol versus verapamil in the acute treatment of atrial fibrillation or atrial flutter: A multicenter study. Am J Cardiol 1989; 63:925.

29. Schwartz, M, Michelson, EL, Sawin, HS, MacVaugh, H III. Esmolol: Safety and efficacy in post-operative cardiothoracic patients with supraventricular tachyarrhythmias. Chest 1988; 93:705.

30. DiBianco, R, Morganroth, J, Freitag, RJ, et al. Effects of nadolol on the spontaneous and exercise provoked heart rate in patients with chronic atrial fibrillation receiving stable doses of digoxin. Am Heart J 1984; 108:1121.

31. Atwood, JE, Sullivan, M, Forbes, S, et al. Effect of beta-adrenergic blockade on exercise performance in patients with chronic atrial fibrillation. J Am Coll Cardiol 1987; 10:314.

32. Rawles, JM, Metcalfe, MJ, Jennings, K. Time of occurrence, duration and ventricular rate of paroxysmal atrial fibrillation: the effect of digoxin. Br Heart J 1990; 63:225.

33. Estes, NA 3d. Evolving strategies for the management of atrial fibrillation. The role of amiodarone. JAMA 1992; 267:3332.

34. Disch, DL, Greenberg, ML, Holzberger, PT, et al. Managing chronic atrial fibrillation: A Markov decision analysis comparing warfarin, quinidine and low-dose amiodarone. Ann Intern Med 1994; 120:449.

35. Donovan, KD, Powers, BM, Hockings, BE, et al. Intravenous flecainide versus amiodarone for recent onset atrial fibrillation. Am J Cardiol 1995; 75:693.

Control of ventricular rate in atrial fibrillation: Nonpharmacologic therapy

Technorati Tags: Amiodarone,antiarrhythmic drug,arrhythmia,atrial fibrillation,myocardial infarction

 Apr 9, 2004 by Morton F Arnsdorf, MD

The ventricular response to atrial fibrillation (AF) is variable and in certain settings may provide important clinical clues to confounding factors. As an example, there is a circadian rhythm for both AV nodal refractoriness and concealed conduction, accounting for the circadian variation in ventricular response rate [1]. These are attenuated in patients with CHF in whom there is altered autonomic neural control with sympathetic nervous system activation and vagal withdrawal.

In the typical patient with AF, the ventricular rate during the day varies between 90 and 170 beats/min in the absence of atrioventricular (AV) nodal disease, drugs that affect conduction, or high vagal tone as may occur in a well conditioned athlete. In comparison, a ventricular rate below 60 beats/min in the absence of digitalis or some other drug that slows AV conduction suggests AV nodal disease, which is often associated with the sick sinus syndrome. On the other hand, a ventricular rate above 200 beats/min suggests catecholamine excess, parasympathetic withdrawal, or the existence of an accessory bypass tract as occurs in the preexcitation syndrome. The QRS complexes are widened in the latter situation and must be distinguished from a rate related or underlying bundle branch block. (See "Tachyarrhythmias associated with the Wolff-Parkinson-White syndrome").

Physiologically, the AV node has been called a "slow response" tissue, since the generation of its action potential depends on calcium ions flowing through a kinetically slow channel. The activation and reactivation characteristics of these calcium channels results in normally slow conduction through the AV node. (See "Myocardial action potential and action of antiarrhythmic drugs"). Moreover, the AV node is richly supplied by both components of the autonomic nervous system: the sympathetic nerves increasing and the parasympathetic nerves decreasing AV nodal conduction. These electrophysiologic properties are depicted in Figure 1 (show figure 1). The advent of radiofrequency ablation has permitted a more detailed analysis of the electrophysiologic anatomy of the AV node. This technique established additional anatomic complexity related to the presence of slow and fast input tracts; this issue will be discussed below.

The nonpharmacologic therapies for achieving rate control in patients with AF who do not respond to pharmacologic therapy will be reviewed here. The pharmacologic therapies for rate control in AF and an overview of the management of AF are discussed separately. (See "Control of ventricular rate in atrial fibrillation: Pharmacologic therapy" and see "Overview of the presentation and management of atrial fibrillation").

NONPHARMACOLOGIC THERAPIES – Both surgery and radiofrequency catheter ablation have been successfully utilized in AF. "Corridor" and "maze" operations have been described for maintaining normal sinus rhythm, and the results to date have been encouraging. (See "Nonpharmacologic strategies to prevent recurrent atrial fibrillation").

AV nodal-His bundle ablation – Radiofrequency catheter ablation of the AV node and/or the His bundle can be performed in cases of AF in which adequate rate control cannot be achieved with pharmacologic therapy [2-7]. The interruption of conduction by a catheter that delivers radiofrequency energy usually produces complete AV nodal block, and patients then require the implantation of a permanent pacemaker to adequately control the ventricular rate (show figure 2A-2B). In a prospective study of 156 patients who underwent ablation of the AV node, for example, 96 percent had persistent complete AV block; 33 percent of patients had no escape rhythm, while 35 percent had an escape rhythm with an escape rate <40 beats per minute [6]. The number of radiofrequency ablation applications did not correlate with the presence or absence of an escape rhythm. In the NASPE Prospective Catheter Ablation Registry, 646 patients underwent AV nodal ablation for rate control; the ablation was acutely successful in 97.4 percent, but during follow-up 3.5 percent had recurrence of AV conduction [8].

AV nodal ablation with implantation of a permanent pacemaker does not adversely affect long-term outcome. In a series of 350 patients with AF who underwent this procedure, the survival of those who did not have a prior myocardial infarction, a history of heart failure, and did not require drug therapy after ablation was the same as the expected survival in the general population and that of patients who received pharmacologic therapy for rate control [9].

Ablation in patients with left ventricular dysfunction – Patients with AF and poor left ventricular function represent a group in which AV nodal ablation is the preferred nonpharmacologic approach. The efficacy of ablation was evaluated in a trial in which 66 patients with clinical congestive heart failure, AF, and a resting rate >90 beats/min were randomized to pharmacologic AV nodal blockade or AV nodal ablation and implantation of a VVIR pacemaker [10]. After a 12 month follow-up, patients undergoing AV nodal ablation and a pacemaker had significantly less palpitations, dyspnea with exertion, exercise intolerance, easy fatiguability, and chest discomfort than those receiving pharmacologic therapy. There was, however, no difference in overall quality of life, NYHA functional class, or objective measures of cardiac function; cardiac performance remained stable over time in both groups.

Type of pacemaker – If complete AV block is produced and a pacemaker is required, a ventricular unit (VVI pacing) with a rate-adaptive sensor is used. (See "Modes of cardiac pacing: Nomenclature and selection" for a discussion of the characteristics of the different types of pacemakers discussed below). Short-term studies have suggested that the majority of patients with a history of paroxysmal AF do not convert to chronic AF (ie, the AF remains paroxysmal) unless they have significant underlying heart disease; thus, dual chamber pacing is preferred to maintain normal physiology and AV synchrony during sinus rhythm [11]. (See "Paroxysmal atrial fibrillation"). However, one long-term study of 62 patients with paroxysmal AF who underwent ablation and pacemaker implantation found that, by 30 months, 42 percent had developed chronic AF [12]. The estimated incidence of chronic AF after seven years was 75 percent. A pilot study found that single lead VDDR pacing with automatic mode switch, ie, VVIR pacing if AF occurs, can also be used in these patients [13].

Nevertheless, it remains uncertain if pacing the atrium will prevent recurrent AF after AV nodal ablation. This was addressed in one report that compared the outcome with DDDR pacing to that with VDD pacing in 67 patients [14]. Although both are physiologic pacing modalities and maintain AV synchrony, DDDR pacing provides the ability to pace the atrium, permitting an evaluation of the potential benefits of atrial pacing. The time to the first episode of AF was the same with both pacing modalities (0.37 days versus 0.5 days for VDD). After a six month follow-up, there was no difference between the two groups in the number of AF episodes or the incidence of permanent AF (35 versus 32 percent). (See "Nonpharmacologic strategies to prevent recurrent atrial fibrillation").

One concern with these pacemakers is that recurrent AF may result in very rapid ventricular responses due to tracking of the atrial impulses. Newer pacemakers are capable of automatic mode switching, which occurs when a rapid increase in rate is sensed, eliminating atrial tracking. Atrial sensing recognizes a return to normal sinus rhythm and the automatic mode switching returns function to a DDD mode. A somewhat simpler approach is to limit the atrial tracking rate by setting the pacemaker to a relatively low upper rate limit. However, this reduces the maximal pacing response to sinus rhythm and sequential A-V pacing may be lost with a sinus tachycardia. The DDIR may be set in a nontracking mode in which case, the rate-adaptive sensor, is programmed to allow a rate higher than the sinus rate. However, one study of 48 patients with a history of paroxysmal atrial tachyarrhythmias and complete heart who had a mode switching pacemaker found that this pacing mode improved symptoms and exercise time more effectively than conventional DDDR or VVIR modes of pacing [15]. A second study randomized 56 patients with symptomatic, drug-refractory paroxysmal AF to continued medical therapy, AV nodal ablation and DDDR pacing with mode switching, or ablation and VVIR pacing [16]. Ablation and DDDR pacing with mode switching produced more symptomatic benefit than medical therapy or ablation and VVIR pacing; however, the incidence of chronic AF at six weeks was higher with ablation and pacing compared to medical therapy (32 versus 0 percent).

Other complications of ablation – Another concern with AV nodal ablation is the risk for cardiac complications. Ventricular fibrillation has been reported, but this complication can be minimized by post-ablation pacing at a higher rate. In a review of 235 patients who underwent radiofrequency ablation of the AV node for drug refractory atrial arrhythmias, the incidence of ventricular fibrillation was six percent when the post-ablation chronic pacing rate was < or = 70 beats per minute [17]. By comparison, no episodes occurred when a pacing rate of 90 was used for the first three months after the ablation. A possible mechanism for post-ablation ventricular arrhythmia is activation of the sympathetic nervous system and a prolongation in action potential duration; pacing at a rate of 90 decreases sympathetic nervous system activity [18].

A second potential complication is hemodynamic deterioration and congestive heart failure. In one study of 108 patients who underwent AV nodal ablation for drug refractory AF, 8 patients developed acute pulmonary edema or congestive heart failure at a mean of 3 and 8 weeks, respectively, after the procedure [19]. The most common cause was a worsening of mitral regurgitation. Compared to those who did not develop this complication, patients who developed hemodynamic deterioration had a larger left ventricular end diameter at baseline but a similar left ventricular end systolic diameter and degree of mitral regurgitation.

Quality of life – Outcomes and quality of life are significantly improved in those patients with medically refractory chronic or paroxysmal AF who undergo catheter ablation and permanent pacemaker insertion. Among 107 such patients in one report, for example, ablative treatment was associated with reductions in [20]:

• Physician visits (10 versus 5 in those receiving only medical therapy)

• Hospital admissions (2.8 versus 0.17)

• Antiarrhythmic drug trials

• Episodes of congestive heart failure (18 versus 8).

The majority of patients have a reduction in symptoms and episodes of congestive heart failure and an improvement in functional class. A meta-analysis of 21 studies involving 1181 patients found that there was a significant improvement in all 19 outcome measures evaluated, including quality of life, ventricular function, exercise duration, and health care use [21]. While this is often due to an increase in left ventricular ejection fraction and reduction in mitral regurgitation, improvement in some patients occurs independently of these variables and probably results from the slower and more regular heart rate [22]. The meta-analysis found that the calculated one-year total and sudden death mortality rates after ablation and pacing therapy were comparable to those seen with medical therapy (6.3 and 2 percent, respectively) [21].

Need for anticoagulation – While AV nodal ablation results in adequate heart rate control, it does not stop the atria from fibrillating. As a result, there is a need for long-term anticoagulation similar to that in patients with chronic AF whose heart rate control is achieved pharmacologically. The incidence of embolic events was evaluated in one study of 585 patients who underwent AV nodal ablation and pacemaker implantation; antiplatelet agents were used in 202 patients and warfarin in 187 [23]. After a follow-up of 34 months, the actuarial rate for thromboembolism at one, five and seven years was 1, 4.2, and 7.4 percent, respectively, which compares favorably to the incidence among patients treated with pharmacologic AV nodal blockade; the only predictor of a thromboembolic event was the presence of chronic atrial fibrillation. (See "Anticoagulation to prevent embolization in chronic atrial fibrillation: Recommendations").

AV nodal conduction modification – Another method is to modify, not ablate, AV nodal conduction with radiofrequency energy. The AV node has two atrial inputs, the so-called fast and slow pathways. Radiofrequency ablation of one of these inputs (especially the slow pathway), analogous to that used to ablate reentrant AV nodal tachycardia, can reduce the number of beats that successfully reach the infranodal conduction system and the ventricles [24-27].

Most patients in whom this technique is performed do not require a permanent pacemaker [4,5,28,29]. One study, for example, evaluated 19 patients with chronic or paroxysmal AF refractory to multiple medical trials [5]. Short-term rate control was achieved in 14 by AV nodal modification without the production of pathologic AV block; four patients required a permanent pacemaker. During a mean eight month follow-up, only one of the fourteen patients had recurrence symptomatic AF with a rapid rate; the patient responded to a second modification procedure.

While AV nodal modification may eliminate the need for a pacemaker, it is somewhat less successful than AV nodal ablation. This was illustrated in a study that compared these two techniques in 120 patients, 60 of whom underwent AV ablation and 60 who had modification [28]. All patients undergoing AV nodal ablation had complete AV block produced; full or partial success with AV nodal modification was achieved in 57 percent of patients, while failure to produce adequate AV nodal modification induced complete AV block in 15 percent. During a 26 month follow-up, recurrence of AF with a rapid rate was uncommon in both groups but occurred more frequently in those with AV nodal modification (12 versus 6 percent with AV nodal ablation).

AV nodal modification is also less successful than nodal ablation in patients with heart failure as ablation but not modification produces significant improvements in left ventricular ejection fraction and quality of life [30].

Another concern with AV nodal modification is that the ventricular response tends to increase after several months, and a repeat ablation may be required. This may be related to the electrophysiologic properties of the remaining fast pathway. Although selective ablation of the slow pathway will lower the ventricular rate during AF, it may be insufficient to provide adequate rate control in patients who have a fast pathway that has a short refractory period, ie, a short Wenckebach cycle length [26]. In addition, selective ablation of the slow pathway may not provide adequate rate control during periods of excessive sympathetic stimulation, which can enhance conduction through the fast pathway [27].

Another consideration is the cost of radiofrequency ablation techniques. In a series of 24 patients, charges were lower initially for patients treated with AV nodal modification ($13,109 versus $28,302) and remained lower at one year and 10 years, even after adjustment for a higher failure and recurrence rate in patients initially treated with modification [31].

INVESTIGATIONAL METHODS – A novel approach to modify the AV node and produce rate control is with gene therapy. This was examined in an animal study that infected the heart with recombinant adenovirus encoding the Galpha(i2) subunit, an inhibitory component of the beta adrenergic signaling pathway [32]. The overexpression of Galpha(i2) mimicked the effect of beta blockers, suppressing AV nodal conduction and slowing the heart rate in during AF, without producing complete heart block.

RECOMMENDATIONS – Consideration should be given to complete AV ablative therapy and the use of a pacemaker in patients in whom adequate heart rate control cannot be achieved pharmacologically (show algorithm 1). Surgery for the maintenance of normal sinus rhythm is still experimental, and surgical ablation of the AV node or His bundle has no theoretical advantage over radiofrequency catheter ablation.

Radiofrequency ablation of one of the AV nodal inputs, modifying but not destroying the AV node, is attractive. With continued technical improvements, this procedure may become preferred over drugs or complete AV ablation.

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