The Pathology of Lone Atrial Fibrillation

1. Toby R. Engel, MD and
2. Simon K. Topalian, MD

+Author Affiliations

1.
Camden, NJ
2.
Dr. Engel is Professor of Medicine and Dr. Topalian is Fellow in Cardiovascular Disease at Cooper University Hospital, The Robert Wood Johnson Medical School.

Lone atrial fibrillation (AF) is AF in the absence of structural heart disease. Persistent lone AF is a paroxysm that does not spontaneously resolve. The article by Paraskevaidis et al in this issue of CHEST (see page 488) concerns the use of echocardiography to predict the successful cardioversion of persistent lone AF and, perhaps more importantly, the maintenance of sinus rhythm. To accomplish this, the authors used a relatively new echocardiographic measurement, the absence of a “notch” in the early systolic mitral annulus motion (if you will, the absence of NESMAM). Keep in mind that left atrial enlargement and other previously described echocardiographic predictors of the maintenance of sinus rhythm measure cardiac structure, and that structural disease is absent by definition in patients with lone AF. Left atrial appendage flow velocity1 has been used but is based on data from a population that has or is at risk for structural disease.

Is the use of cardioversion in patients with persistent lone AF warranted in the first place? There is a risk using antiarrhythmic drugs. Cardioversion to sinus rhythm has not reduced the incidence of subsequent thromboembolism compared to anticoagulation therapy.2345 Even palpitations are generally not worrisome (except perhaps to the physician), and quality of life is not improved by treatment to maintain sinus rhythm.6 Presumably, the inauspicious results of treatment are because the treatment is not a “permanent fix,” and paroxysms of AF are not 100% eliminated. However, treatment would make more sense if one could predict which individuals would receive a permanent fix with cardioversion for the treatment of AF.

The idea that we can identify patients who better respond to treatment would seem to make the diagnosis of lone AF an oxymoron, because the term lone implies no distinguishing features: the AF stands alone. The duration of AF is generally not useful to consider in this regard (it was not in this study) because patients with persistent lone AF usually present for treatment rather soon after onset of the condition. Otherwise, the classic indications that AF will recur subsequent to cardioversion, such as left atrial size, depend on a structural change. Yet, Paraskevaidis et al have suggested that we can predict who will benefit in the long term from cardioversion of lone AF by Doppler interrogation of the left atrial appendage and analysis of mitral annulus motion on M-mode echocardiography. A flow velocity of > 20 cm/s was useful. More importantly, often in AF (in two thirds of their lone AF patients) there is NESMAM. The notch was seen in 88% of patients who went on to revert to AF after undergoing cardioversion but was absent in 90% of those who remained in sinus rhythm at the 1-year follow-up. The data of Paraskevaidis et al require confirmation but would clarify an otherwise confusing and controversial issue regarding the selection of patients with lone AF for cardioversion. It would be even more exciting to learn whether the absence of NESMAM predicts the maintenance of sinus rhythm in a population of patients who have undergone cardioversion but were then not treated with antiarrhythmic drugs, since often the presumed requirement for such drugs discourages cardioversion.

The explanation for NESMAM is obscure. The abnormal annulus motion coincides with the timing of atrial relaxation had there been a sinus rhythm. A stiff atrium may relate, for example, to the loss of myofibrils, to collagen formation, or to interstitial fibrosis. Indeed, this pathologic process may not reflect a causative disease per se but rather an adaptive process reflecting the duration of the AF (so-called remodeling). These processes coincide with the electrophysiologic remodeling that explains why AF more often recurs or is more easily induced after there has been faster or longer lasting arrhythmia (“AF begets AF”),7 albeit these could be independent processes. It is further confusing that lone AF with a chronic uncontrolled ventricular response could cause tachycardia-induced cardiomyopathy. Is the AF then to be called lone AF?

In sum, it is unclear whether NESMAM identifies lone AF patients who indeed have structural changes that require further elucidation (and, technically, do not have lone AF) or whether AF itself causes the structural changes that lead to NESMAM, predisposing the patient to recurrence. Thus, the work of Paraskevaidis et al should not only stimulate confirmation of this practical guide to cardioversion but also investigation into better explanations for the occurrence of apparent lone AF.
References

1. ↵
Antonielli, E, Pizzuti, A, Palinkas, A, et al (2002) Clinical value of left atrial appendage flow for prediction of long-term sinus rhythm maintenance in patients with nonvalvular atrial fibrillation. J Am Coll Cardiol 39,1443-1449
Abstract/FREE Full Text
2. ↵
Hohnloser, ASH, Kuck, KH, Lilienthal, J Rhythm or rate control in atrial fibrillation: Pharmacologic Intervention in Atrial Fibrillation (PIAF); a randomized trial. Lancet 2000;356,1789-1794
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3. ↵
Wyse, DG, Waldo, AL, DiMarco, JP, et al A comparison of rate control in patients with atrial fibrillation: The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) Investigators. N Engl J Med 2002;347,1825-1833
Abstract/FREE Full Text
4. ↵
Carlsson, J, Miketic, S, Windeler, J, et al Randomized trial of rate-control versus rhythm-control in persistent atrial fibrillation: the Strategies of Treatment of Atrial Fibrillation (STAF) study. J Am Coll Cardiol 2003;41,1690-1696
Abstract/FREE Full Text
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Van Gelder, IC, Hagens, VE, Bosker, HA, et al A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation. N Engl J Med 2002;347,1834-1840
Abstract/FREE Full Text
6. ↵
Jenkins L. Quality of life in atrial fibrillation: the AFFIRM study. Am Heart J 2005 (in press)
7. ↵
Wijffels, MC, Kirchhof, CJ, Dorland, R, et al Atrial fibrillation begets atrial fibrillation: a study in awake chronically instrumented goats. Circulation 1995;92,1954-1968
Abstract/FREE Full Text

Articles citing this article

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o L. G. Futterman
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Atrial FibrillationAm J Crit Care September 1, 2005 14:438-440
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Low Testosterone Levels Associated With Lone Atrial Fibrillation in Men

Reuters Health Information 2009. © 2009 Reuters Ltd.
Republication or redistribution of Reuters content, including by framing or similar means, is expressly prohibited without the prior written consent of Reuters. Reuters shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. Reuters and the Reuters sphere logo are registered trademarks and trademarks of the Reuters group of companies around the world.

By Will Boggs, MD

NEW YORK (Reuters Health) Feb 20 - Reduced testosterone levels in men may increase the risk of lone atrial fibrillation (AF), according to a report in the January issue of Clinical Cardiology.

"Since AF is associated with significant morbidity and mortality, it may be important to discriminate those who are susceptible to AF by some certain biomarkers such as C-reactive protein, brain natriuretic peptide, endothelin-1, and maybe testosterone," Dr. Jiangtao Lai from School of Medicine Zhejiang University, Hangzhou, China, told Reuters Health.

Dr. Lai and colleagues examined whether testosterone and estradiol levels differed between 58 men with lone AF and 58 healthy men matched by age, race, and ethnicity.

Mean testosterone levels in men with lone AF were significantly lower than those in healthy controls, the authors report, but mean estradiol levels did not differ significantly between the 2 groups.

In a logistic regression analysis, sex hormone levels, age, body mass index, and blood pressure were not independent predictors of lone AF.

"We can't say that testosterone predicts lone AF since this was a relatively small sample study and this might potentially lead to spurious findings," Dr. Lai said. "We plan to investigate the possible association between testosterone level and the risk for lone AF in more subjects, more strictly designed studies, or prospective studies if possible."

Clin Cardiol 2009;32:43-46.

Summary and Comment
Colonoscopy-Related Bleeding and Perforation

Older age, male sex, polypectomy, and performance by a low-volume endoscopist were risk factors for bleeding or perforation in a population-based study in Canada.

Data on perforation rates in clinical practice are limited because most reports of such complications come from individual centers. Now, researchers in Canada have conducted a population-based study to determine the rates of — and risk factors for — colonoscopy-related bleeding and perforation. Using physician claims databases, they identified all individuals aged 50 to 75 who underwent outpatient colonoscopy in British Columbia, Alberta, Ontario, or Nova Scotia between April 1, 2002, and March 31, 2003 (n=97,091). Then, they used administrative data to identify people who were admitted to the hospital with colonoscopy-related bleeding or perforation within 30 days after the procedure.

Pooled rates of bleeding and perforation were 1.64 per 1000 procedures and 0.85 per 1000 procedures, respectively; the death rate — determined only for Ontario — was 0.074 per 1000 procedures (approximately 1 per 13,500). Predictors of having either bleeding or perforation were older age, male sex, polypectomy, and completion of the colonoscopy by an individual with a low annual colonoscopy volume (<300 per year). When the analysis was limited to colonoscopies performed by gastroenterologists, only polypectomy was associated with bleeding or perforation.

Comment: In general, these data are in line with single-center reports and with the few available population-based studies. Clearly, older age and polypectomy are risk factors for perforation, and polypectomy is the major risk factor for bleeding. Whether male sex is actually a risk factor is uncertain; this study could not account for the number of polyps removed per colonoscopy, and men are more likely than women both to have multiple polyps and to have more large polyps. Based on findings from other investigations, large polyp size is definitely a risk factor for bleeding. Of considerable importance is the observation that lower annual colonoscopy volumes are associated with higher complication rates. This effect disappeared when investigators considered only procedures done by gastroenterologists, suggesting that the more extensive training received by these specialists eliminates the volume effect. If this finding is corroborated by further study, it could have important implications — perhaps for training and perhaps for the appropriate volume of colonoscopy needed to maintain adequate skills.

— Douglas K. Rex, MD

Published in Journal Watch Gastroenterology February 27, 2009

Citation(s):

Rabeneck L et al. Bleeding and perforation after outpatient colonoscopy and their risk factors in usual clinical practice. Gastroenterology 2008 Dec; 135:1899.

Medline abstract (Free)

Statins for Primary Prevention of Cardiovascular Disease — The JUPITER Study

Among patients with high CRP levels, rosuvastatin lowered risk for adverse cardiovascular events.

One of 2008’s most hotly debated studies has the potential to change prevention recommendations for millions of Americans. In the industry-sponsored JUPITER study, researchers investigated the role of statins in primary prevention when patients’ cholesterol levels were not markedly high but high-sensitivity C-reactive protein (hsCRP) was elevated (JW Nov 18 2008). Nearly 18,000 subjects (ages: men, ≥50; women, ≥60) without known cardiovascular (CV) disease and with normal LDL-cholesterol levels (<130 mg/dL), but with high hsCRP levels (≥2 mg/L), were randomized to receive daily rosuvastatin (Crestor; 20 mg) or placebo. Extensive exclusion criteria eliminated many patients (e.g., those with diabetes, uncontrolled hypertension, or various other chronic diseases; those who used cholesterol-lowering drugs).

After a median follow-up of 1.9 years (the trial was stopped early, due to markedly positive results for rosuvastatin), rosuvastatin lowered LDL-cholesterol levels by a mean of 50% and hsCRP levels by 37%. Incidence of the primary endpoint (first major cardiovascular event, including unstable angina, myocardial infarction, stroke, arterial revascularization, or death from cardiovascular causes) was significantly lower in the rosuvastatin group than in the placebo group (hazard ratio, 0.56), as was overall mortality (HR, 0.8). For every 1000 patients who received rosuvastatin for 1 year, roughly six fewer primary-endpoint events and three fewer deaths occurred. Incidences of physician-reported diabetes and glycosylated hemoglobin levels were both significantly higher in the rosuvastatin group than in the placebo group.

So, where do we go from here? Statins lowered the rate of adverse CV events in this large study of apparently healthy subjects who were at CV risk because of high hsCRP levels; however, in an accompanying editorial, the author notes that the absolute effect size was relatively modest and that the higher incidence of diabetes and lack of long-term data on hazards of therapy are worrisome. Nonetheless, these data almost certainly will prompt review of current guidelines on use of statins in primary prevention, as well as generate a flurry of calls to physicians about hsCRP testing. Some media reports on JUPITER have couched the study results as supporting widespread use of hsCRP testing, but the editorialist reminds us that this is a randomized trial of statin therapy, not of hsCRP testing, and he advocates selective rather than routine CRP testing (JW Nov 18 2008).

— Kirsten E. Fleischmann, MD, MPH

Published in Journal Watch General Medicine December 29, 2008

Stem-Cell Biology Moves Closer to Becoming Stem-Cell Medicine

For a topic to be a Journal Watch Top Story in 2 successive years is unusual, but that is the case with stem cells.

As I summarized in 2007 (JW Dec 28 2007), the great excitement about the potential of embryonic stem cells (ESCs) to treat disease had been tempered by scientific obstacles and ethics questions. No person could be treated by his or her own genetically identical ESCs, because they are long gone. And, using ESCs from a genetically dissimilar embryo would not only impart risk for immune rejection and require immunosuppression but also would raise ethics concerns for some.

As a way around these difficulties, scientists asked an audacious question: What if one could "reprogram" the genes of a specialized adult cell so as to transform it back into a cell with all the potential of an ESC? In 2006, a Japanese team identified a handful of genes that are turned on exclusively in ESCs. In 2007, that Japanese team and several American teams used retroviruses to insert four of those genes into easily obtained skin cells, from mice and humans. Remarkably, this genetic reprogramming transformed the specialized cells into what were called induced pluripotent stem (iPS) cells, which had all the potential of ESCs: They could figuratively turn back the clock and create, for each individual, cells that were equivalent to his or her own long-lost, genetically identical ESCs.

Studies in rodents showed that these iPS cells indeed could fulfill their potential: They effectively cured sickle cell anemia (JW Dec 13 2007) and Parkinson disease in mice. Other researchers created iPS cells from patients with Parkinson disease, Huntington disease, and type 1 diabetes, bringing us one step closer to therapeutic applications for humans (JW Aug 26 2008). Two of the four genes used in creating iPS cells were oncogenes, which, along with the retroviral vector used to deliver them to the cell, imparted risk for iPS cells to become cancerous. However, late in 2008, Japanese and American teams reported that iPS cells could be produced even more simply — without oncogenes or retroviruses (JW Oct 28 2008). Even more remarkably, an American team reported being able to use reprogramming to transform one specialized cell (a pancreatic exocrine cell) into another (a pancreatic β cell) in living mice, thereby curing experimentally produced diabetes, without ever creating iPS cells ex vivo (JW Sep 23 2008).

These discoveries demonstrate that specialized adult cells are much more "plastic" than once imagined and appear to eliminate some of the thornier scientific challenges — as well as the ethics concerns — of stem-cell therapy.

— Anthony L. Komaroff, MD

Published in Journal Watch General Medicine December 29, 2008

Editorial

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Nature Genetics 41, 265 (2009)
doi:10.1038/ng0309-265

Modern lights

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Introduction

Hairless dogs have imperfect teeth; long-haired and coarse-haired animals are apt to have, as is asserted, long or many horns; pigeons with feathered feet have skin between their outer toes; pigeons with short beaks have small feet, and those with long beaks large feet. Hence if man goes on selecting, and thus augmenting any peculiarity, he will almost certainly modify unintentionally other parts of the structure, owing to the mysterious laws of correlation.
–Charles Darwin, The Origin of Species (1859)

Evolutionary biology is a living science. As the scientific world celebrates the 200th anniversary of Darwin's birth and the 150th anniversary of the publication of The Origin of Species, this simple fact is perhaps the most difficult to get across to a skeptical public. The lack of broad acceptance of evolution has many causes, but perhaps the most maddening is the widely-held notion that Charles Darwin had only one idea (natural selection), which, though it has long since been found wanting (the argument goes), has been used by his successors to account for every conceivable event in the history of life on the basis of nothing more than the incomplete fossil record.

That the richness of modern evolutionary theory—informed now by a flood of molecular and genomic data—is poorly conveyed to high school and university students seems inarguable. In a 2005 correspondence in Nature, Michael Lynch noted that most students are not exposed to the rigorously quantitative nature of much of population genetics, which furthers the impression that evolution is "one of the softer areas of science." It's heartening to see some steps being taken to address this problem. Sean Carroll has written accessible books for a general audience, introducing evolutionary genetics and 'evo-devo' approaches. At the university level, the new evolution textbook by Barton et al. provides perhaps the most thorough integration of evolution and quantitative genetics yet, and one hopes that it's widely adopted.

These resources could serve as stepping stones to the primary literature, which, on a weekly basis, provides evidence of the richness of the 150-year-long research program inspired by Darwin and Wallace. Not everyone will be regularly reading PNAS and Evolution, of course, but our colleagues at Nature have compiled "15 Evolutionary Gems"—a series of stellar evolutionary biology papers published in the last decade in Nature, complete with helpful summaries.

This issue of Nature Genetics also highlights a Darwinian question, in particular, the one outlined in the quote highlighted above. Although Darwin was not the first naturalist to show interest in the 'laws of correlation', its inclusion in the Origin suggests how much pleiotropy, as we would call it, is intertwined with evolvability. The two papers on pages 299 and 371 from Trudy Mackay and colleagues provide new insight into the molecular basis of pleiotropy in the context of complex traits in Drosophila. Together, the two papers show that several hundred transcripts are associated with phenotypic variation of each of the behavioral and life-history traits they examined. Previous work in Nature ( 452, 470–473; 2008) and in this journal ( 41, 166–167; 2009) suggests that the extent of genetic buffering is such that mutations affecting transcript levels of many of these genes may in the end have little phenotypic effect. Although these are still early days, the integration of studies of pleiotropy and genetic buffering should provide an unprecedented molecular view of the course of, and constraints on, evolution. That we are just now getting answers to questions that were central to Darwin's argument—that there is great ferment in the field—should be seen as a great strength of evolutionary studies.

As for the man himself, we'll let William Bateson have the last word. In his essay "Hereditary and Variation in Modern Lights," written in 1909 to commemorate the centenary of Darwin's birth, he said: "When we reflect on the intricacies of genetic problems as we must now conceive them there come moments when we feel almost thankful that the Mendelian principles were unknown to Darwin. The time called for a bold pronouncement, and he made it, to our lasting profit and delight."

Statin Adherence Associated With Lower All-Cause Mortality, Even in Primary Prevention from Heartwire — a professional news service of WebMD Michael O'Riordan To earn CME related to this news article, click here. February 17, 2009 — Primary- and secondary-prevention patients who consistently take their statin medication have a significantly lower risk of death than those who do not adhere to therapy, a new study has shown [1]. Individuals who took their medication at least 90% of the time had a 45% reduction in the risk of all-cause mortality, compared with less adherent patients, report investigators. "The observed benefits from statins were greater than expected from randomized clinical trials, emphasizing the importance of promoting statin therapy and increasing its continuation over time for both primary and secondary prevention," write Dr Varda Shalev (Tel Aviv University, Israel) and colleagues in the February 9, 2009 issue of the Archives of Internal Medicine. The study, a retrospective analysis of 229,918 individuals enrolled in a health-maintenance organization, evaluated the effect of statin therapy in patients with and without preexisting coronary heart disease (CHD). As the authors point out, the benefits of statin therapy are well documented, but the effect of lipid-lowering therapy on all-cause mortality in a primary-prevention cohort is more controversial. A 2007 opinion article by Drs John Abramson (Harvard Medical School, Boston, MA) and Jim Wright (University of British Columbia, Vancouver), published in the Lancet [2], for example, and reported by heartwire at that time, argued that the bulk of the evidence did not support statin therapy for primary prevention in women or in people over age 65. In this most recent analysis, investigators evaluated the mortality benefit of primary prevention in 136,052 patients without a history of heart disease followed for an average of four years. The secondary-prevention cohort consisted of 93,866 patients followed for an average of five years. Adherence to statin therapy was measured by the number of dispensed statin prescriptions during the interval between the first prescription and the end of follow-up. In the primary- and secondary-prevention cohorts, continuously taking statins, defined as taking the drugs 90% of the time during the follow-up period, was associated with 45% and 51% reductions, respectively, in the risk of death, compared with individuals who took the medication less than 10% of the time. The reduction in risk was more pronounced among individuals with high baseline low-density lipoprotein-cholesterol (LDL-C) levels and those receiving intensive lipid-lowering therapy. Proportion of Days Covered With Statins and All-Cause Mortality Proportion of days covered with statin therapy during study period, % Hazard ratio (95% CI), primary-prevention cohort Hazard ratio (95% CI), secondary-prevention cohort <10 1 (reference) 1 (reference) 10 - 19 1.35 (1.22 - 1.50) 1.28 (1.18 - 1.39) 50 - 59 0.77 (0.67 - 0.88) 0.69 (0.63 - 0.76) ≥90 0.55 (0.49 - 0.61) 0.49 (0.46 - 0.53) "Our findings confirm that the benefits of statins extend to unselected patients in community settings," write Shalev and colleagues. "Higher continuity of treatment and increased drug efficacy are associated with better survival among both primary-prevention and secondary-prevention cohorts." The group notes that the benefits observed in this study are much larger than mortality benefits observed in clinical trials, in which only a modest reduction in all-cause mortality or no reduction at all is noted. Studies in unselected patient populations, such as this observational study, might "better capture the overall benefits of statins that may result from their anti-inflammatory, antithrombotic, or antiapoptotic effects, as well as from their action on nitric-oxide synthase," they suggest. The researchers point out that the study is limited by its design and the fact that the evaluation of statin therapy was based on dispensing information. Shalev V, Chodick G, Silber H, et al. Continuation of statin treatment and all-cause mortality. Arch Intern Med 2009; 169:260-268. Abramson J, Wright J. Are lipid-lowering guidelines evidence-based? Lancet 2007; 369:168-169. The complete contents of Heartwire, a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals. Related Links Resource Centers Landmark Statin Trials Resource Center Michael O'Riordan is a journalist theheart.org, part of the WebMD Professional Network. Previously, he worked for WebMD Canada. Michael studied at Queen's University in Kingston and the University of Toronto and has a master's degree in journalism from the University of British Columbia, where he specialized in medical reporting. He can be contacted at MORiordan@webmd.net. Heartwire 2009. © 2009 Medscape

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Propranolol Wipes out Emotional Response to Fearful Memory Information from Industry Cymbalta is now approved for fibromyalgia Learn more about this option for patients with fibromyalgia with chronic widespread pain. Important Safety Information. Prescribing Information. NEW YORK (Reuters Health) Feb 17 - The beta-blocker propranolol can eliminate the fearful aspect of an emotional memory, according to psychologists at the University of Amsterdam, The Netherlands. "Once emotional memory is established, it appears to last forever," Dr. Merel Kindt and associates report in February 15 early online issue of Nature Neuroscience. However, "if emotional memory could be weakened or even erased, then we might be able to eliminate the root of many psychiatric disorders, such as post-traumatic stress disorder." They comment that reactivated fear memories following induction of a fear association in rats could be prevented long-term by infusion of propranolol into the amygdala. To see whether propranolol would have a similar effect in humans, Dr. Kindt's group conducted a randomized trial in 40 volunteers, in whom fearful memories were created on day one by applying a mild shock when they looked at pictures of spiders. The conditioned fear response was measured as potentiation of the eyeblink startle reflex to a loud noise by electromyography of the right orbicularis oculi muscle. The next day, subjects exhibited similar startle responses when again shown the spider pictures. On day three, 20 subjects were given oral propranolol 40 mg and 20 were given placebo. Subsequently, during reactivation of the fear memory, propranolol was found to have eliminated the differential startle response, whereas the differential startle response remained stable in the placebo group. "Notably," Dr. Kindt and colleagues write, "the propranolol manipulation left the declarative memory for the acquired contingency between the conditioned and unconditioned stimulus intact, but this knowledge no longer produced emotional effects." "Disrupting the reconsolidation of fear memory opens up new avenues for providing a long-term cure for patients with emotional disorders," they conclude. Nat Neurosci 2009.

SUMMARY AND COMMENT

Low-Dose or High-Dose PPI for Bleeding Peptic Ulcers?

February 20, 2009 | David J. Bjorkman, MD, MSPH (HSA), SM (Epid.)

Recent study findings indicate that low-dose proton-pump inhibitor therapy might be as effective as high-dose therapy in preventing rebleeding from peptic ulcers after endoscopic therapy.

Reviewing: Andriulli A et al. Am J Gastroenterol 2008 Dec 103:3011

Box 1. The Polycap and the Comparator Groups Used in the Indian Polycap Study

Polycap: atenolol, thiazide, ramipril, simvastatin and aspirin Comparator A: aspirin Comparator B: simvastatin Comparator C: thiazide Comparator D: thiazide and ramipril Comparator E: thiazide and atenolol Comparator F: ramipril and atenolol Comparator G: thiazide, ramipril and atenolol Comparator H: thiazide, ramipril, atenolol and aspirin

References

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ABSTRACT

Background Genetic variability among patients plays an important role in determining the dose of warfarin that should be used when oral anticoagulation is initiated, but practical methods of using genetic information have not been evaluated in a diverse and large population. We developed and used an algorithm for estimating the appropriate warfarin dose that is based on both clinical and genetic data from a broad population base.

Methods Clinical and genetic data from 4043 patients were used to create a dose algorithm that was based on clinical variables only and an algorithm in which genetic information was added to the clinical variables. In a validation cohort of 1009 subjects, we evaluated the potential clinical value of each algorithm by calculating the percentage of patients whose predicted dose of warfarin was within 20% of the actual stable therapeutic dose; we also evaluated other clinically relevant indicators.

Results In the validation cohort, the pharmacogenetic algorithm accurately identified larger proportions of patients who required 21 mg of warfarin or less per week and of those who required 49 mg or more per week to achieve the target international normalized ratio than did the clinical algorithm (49.4% vs. 33.3%, P<0.001, among patients requiring 21 mg per week; and 24.8% vs. 7.2%, P<0.001, src="http://content.nejm.org/math/ge.gif" alt="≥" border="0">49 mg per week).

Conclusions The use of a pharmacogenetic algorithm for estimating the appropriate initial dose of warfarin produces recommendations that are significantly closer to the required stable therapeutic dose than those derived from a clinical algorithm or a fixed-dose approach. The greatest benefits were observed in the 46.2% of the population that required 21 mg or less of warfarin per week or 49 mg or more per week for therapeutic anticoagulation.

Source Information

Address reprint requests to the International Warfarin Pharmacogenetics Consortium at 300 Pasteur Dr., Ln. 301, Mailstop 5120, Stanford, CA 94305, or at iwpc@pharmgkb.org.

SUMMARY AND COMMENT Adjusting Warfarin When INR Isn’t in Therapeutic Range January 15, 2009 | Allan S. Brett, MD | General Medicine Data suggest that warfarin dose shouldn’t be changed unless INR is 1.7 or 3.3 (when the target is 2.0–3.0). Reviewing: Rose AJ et al. J Thromb Haemost 2009 Jan 7:94

January 7, 2008 — Vitamin D deficiency appears to be a risk factor for developing cardiovascular disease, a new study suggests [1].

The study, published online January 7, 2008 in Circulation, was conducted by a group led by Dr Thomas Wang, Massachusetts General Hospital, Boston. They conclude: "These findings may have potentially broad public health implications, given the high prevalence of vitamin D deficiency in developed countries, the contribution of lifestyle and geography to vitamin D status, and the ease, safety, and low cost of treating vitamin D deficiency."

They add that further clinical and experimental studies may be warranted to validate their findings, to investigate the mechanisms underlying increased cardiovascular risk, and to determine whether correction of vitamin D deficiency could contribute to the prevention of cardiovascular disease.

A common problem

Wang et al explain that vitamin D deficiency is highly prevalent in the US and worldwide, affecting as many as one third to one half of otherwise healthy middle-aged to elderly adults, and that limited cutaneous synthesis due to inadequate sun exposure or pigmented skin and inadequate dietary intake are the principal causes of low vitamin D levels.

They note that although the best-characterized sequelae of vitamin D deficiency involve the musculoskeletal system, a growing body of evidence suggests that low levels of vitamin D may adversely affect the cardiovascular system. Vitamin D receptors have a broad tissue distribution that includes vascular smooth muscle, endothelium, and cardiomyocytes, and there are higher rates of coronary heart disease and hypertension with increasing distance from the equator, a phenomenon that has been attributed to the higher prevalence of vitamin D deficiency in regions with less exposure to sunlight.

But they caution that prospective data are needed because vitamin D deficiency could be a consequence of cardiovascular disease rather than a cause. Thus, they prospectively investigated the relation of vitamin D status to the incidence of cardiovascular events in a large, ambulatory, community-based population from the Framingham Offspring Study who were all free of cardiovascular disease at baseline.

In the 1739 participants (mean age 59 years; 55% women; all white), vitamin D status was assessed by measuring 25-dihydroxyvitamin D (25-OH D) levels. Overall, 28% of individuals had levels below 15 ng/mL, and 9% had levels below 10 ng/mL, thresholds which characterize varying degrees of vitamin D deficiency.

During a mean follow-up of 5.4 years, 120 individuals developed a first cardiovascular event. After adjustment for conventional cardiovascular risk factors, individuals with 25-OH D levels below 15 ng/mL had an increased risk for incident cardiovascular events compared with those with 25-OH D levels above 15 ng/mL. The higher risk associated with vitamin D deficiency was particularly evident among individuals with hypertension, in whom 25-OH D levels below 15 ng/mL were associated with a 2-fold risk of cardiovascular events. But there was no correlation seen in participants without hypertension.

Hazard ratio for heart disease for 25-OH D levels below 15 ng/mL

Group	Hazard ratio (95% CI)	P value
All participants	1.62 (1.11 - 2.36)	0.01
Those with hypertension	2.13 (1.30 - 3.48)	0.003
Those without hypertension	1.04 (0.55 - 1.96)	Ns

There was also a graded increase in cardiovascular risk as levels of 25-OH D decreased, and further adjustment for C-reactive protein, physical activity, or vitamin use did not affect the findings.

Hazard ratio for heart disease according to level of 25-OH D

Level of 25-OH D	Hazard ratio (95% CI)
10-15 ng/mL	1.53 (1.00 - 2.36)
<>	1.80 (1.05 - 3.08)

P for linear trend 0.01.

The authors note that these data indicate that increased cardiovascular risk is present at 25-OH D levels (<>

On the possible mechanisms, Wang et al point out that 1,25-OH D is involved in the regulation of the renin-angiotensin axis, and putative vascular effects of vitamin D are wide-ranging and include modulation of smooth muscle cell proliferation, inflammation, and thrombosis.

They add that potential interaction between vitamin D deficiency and hypertension suggested in this study fits in with the observation that both hypertension and vitamin D deficiency may influence cardiac and vascular remodeling, and with data suggesting that vitamin D deficiency directly promotes the development of hypertension.

They point out that in small clinical trials, vitamin D supplementation has promoted reductions in blood pressure, left ventricular hypertrophy, and inflammatory cytokines, although vitamin D supplements were not associated with a reduction in cardiovascular events in the Women's Health Initiative. But they add that the Women's Health Initiative was a fracture-prevention trial and was not designed to evaluate cardiovascular risk, the dose of vitamin D used was far below the amount necessary to correct vitamin D deficiency, patients in the placebo arm were also allowed to take vitamin D supplements which could have masked any benefit, and the trial did not address whether vitamin D supplementation benefited individuals with vitamin D deficiency, because enrollment was performed irrespective of vitamin D status. They note however that vitamin D did appear to reduce cardiovascular risk in obese individuals, who are prone to endogenous vitamin D deficiency, and also in those with multiple coronary risk factors.

The National Institutes of Health, the US Department of Agriculture, and the American Heart Association supported this study. One of the study authors has received honoraria from Abbott Laboratories and Genzyme. The other study authors have disclosed no relevant financial relationships.

Source

1. Wang TJ, Pencina MJ, Booth SL, et al. Vitamin D deficiency and risk of cardiovascular disease. Circulation. 2008. Published online before print DOI: 10.1161/CIRCULATIONAHA.107.706127.

The complete contents of Heartwire, a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals.

Learning Objectives for This Educational Activity

Upon completion of this activity, participants will be able to:

1. Describe the epidemiology of vitamin D deficiency and its potential effect on cardiovascular disease.
2. Identify the risk for cardiovascular disease associated with vitamin D deficiency.

Clinical Context

Vitamin D deficiency may be present in up to one half of older adults, and inadequate sun exposure, skin pigmentation, and dietary deficiency can all contribute to reduced body stores of vitamin D. Although the negative effects of vitamin D deficiency on bone health are well documented, there is emerging evidence that vitamin D is important in cardiovascular health. Vitamin D may decrease renin activity as well as lower blood pressure, and there is evidence that vitamin D helps to regulate the growth and proliferation of vascular smooth muscle cells.

The current study of the Framingham Offspring Cohort examines the relationship between serum levels of 25-OH D, the best marker of vitamin D stores in the body, and cardiovascular events.

Study Highlights

• The current study excluded Framingham Offspring participants with preexisting cardiovascular or kidney disease.
• All participants underwent a baseline examination for cardiovascular risk factors. Serum levels of 25-OH D and C-reactive protein were included in these analyses, and researchers calculated Vitamin D intake from diet and supplement sources.
• The main outcome of the study was the relationship between levels of 25-OH D and the risk for a cardiovascular event, which was determined after a review of medical records and included diagnoses of myocardial infarction, coronary insufficiency (prolonged chest pain with documented electrocardiographic changes), angina, stroke, transient ischemic attack, peripheral claudication, and heart failure. This main result was adjusted for multiple possible confounders of cardiovascular risk.
• Data from 1739 participants were included in the study. The mean age of the subjects was 59 years, and 55% of participants were women. The rates of hypertension and diabetes mellitus were 40% and 8%, respectively, at baseline.
• The mean concentration of 25-OH D was 19.7 ng/mL, 28% of subjects were found to have a 25-OH D level less than 15 ng/mL, and 9% had a level lower than 10 ng/mL.
• The mean duration of follow up was 5.4 years. During this period, 120 subjects had a primary cardiovascular event.
• The fully adjusted hazard ratio for a cardiovascular event associated with a 25-OH D level of less than 15 ng/mL vs higher levels was 1.62 (P = .01). Further adjustment for vitamin D supplementation and physical activity failed to alter this main result.
• There was a nonlinear increase in the risk for a cardiovascular event as 25-OH D levels fell. Compared with subjects with a 25-OH D level of 15 ng/mL or more, participants with levels of 10 to 15 ng/mL and less than 10 ng/mL experienced hazard ratios of 1.53 and 1.80, respectively, for an incident cardiovascular event.
• Lower levels of vitamin D increased the risk for cardiovascular events among participants with hypertension but not among subjects without hypertension.

Pearls for Practice

• Up to one half of older adults may have vitamin D deficiency, and multiple factors can account for this deficiency. Vitamin D deficiency has been associated with increasing risk factors for cardiovascular disease.
• The current study suggests that vitamin D deficiency can independently increase the risk for cardiovascular disease in a nonlinear fashion.

Dronedarone reduces CV mortality in atrial fibrillation

12 February 2009

MedWire News: The antiarrhythmic drug dronedarone reduces the risk for cardiovascular hospitalization and death in patients with atrial fibrillation (AF), a large clinical trial has shown.

The ATHENA study was a placebo-controlled, double-blind study that assessed the efficacy of dronedarone in patients with high-risk AF or atrial flutter (Afl). Dronedarone is a benzofuran derivative with a pharmacologic profile similar to that of amiodarone but different relative effects on individual ion channels.

The study enrolled 4628 patients at 550 sites in 37 countries; all had AF/Afl and additional risk factors for death. They were randomized to take dronedarone 400 mg twice daily or placebo and followed-up for a mean duration of 21 months.

The study drug was discontinued prematurely in 30.2% and 30.8% of the dronedarone and placebo groups, respectively, mostly because of adverse events.

The primary outcome – a composite of hospitalization for cardiovascular events or death – occurred in 31.9% of the dronedarone group versus 39.4% of the placebo group, a statistically significant difference (hazard ratio[HR]=0.76, p<0.001).

The main effect of dronedarone was to reduce cardiovascular deaths (HR=0.71, p=0.03), mainly from arrhythmia, whereas the rate of death from any cause was not significantly different between the groups (HR=0.84, p=0.18).

Dronedarone was associated with a significantly higher frequency of adverse events versus placebo; common side effects included bradycardia, QT-interval prolongation, diarrhea, nausea, rash, and an increase in serum creatinine.

Rates of thyroid or pulmonary disorders did not differ between the treatment groups, although the trial investigators remark that the duration of follow-up may have been too short for these effects to emerge.

Furthermore, the very high rate of study-drug discontinuation may have resulted in an underestimate of the benefit of dronedarone, say the investigators, but may also have limited the likelihood of demonstrating an increase in the rate of adverse events.

ATHENA is the first trial of an antiarrhythmic drug to assess the effect of treatment on morbidity/mortality. “Therefore, it is not possible to know the relative efficacy or safety of dronedarone as compared with other drugs for this outcome,” write Stefan Hohnloser (JW Goethe University, Frankfurt, Germany) and co-authors in the New England Journal of Medicine.

“The efficacy and tolerability of dronedarone and amiodarone as used to prevent the recurrence of AF are currently being investigated in an ongoing randomized trial.”

MedWire is an independent clinical news service provided by Current Medicine Group, a part of Springer Science+Business Media. © Current Medicine Group Ltd; 2009

N Engl J Med 2009; 360: 668–678

Summary and Introduction

Summary

There are at least four well-confirmed genes responsible for Alzheimer's disease (AD), the most common form of dementia. In addition, many reports indicate an association between the disease and genetic variations in different gene candidates. The complexity and interpretation of these studies are discussed using, as an example, the recent discovery of the association between AD and the SORL1 gene. The knowledge obtained from AD genetics is applicable to many other forms of dementia, which are also genetically complex disorders and are almost all associated with the deposition of different aberrant proteins in the brain.

Hancock MJ, Maher GC, Latimer J, et al
Lancet. 2007;370:1638-1643

Abstract

Previous recommendations have noted that nonsteroidal anti-inflammatory drugs (NSAIDs) and spinal manipulation therapy can be helpful for patients with acute low back pain, but the current study compares this approach with a "usual care" group, who received advice on physical activity and regular doses of paracetamol. The researchers' findings are surprising and should change the way clinicians think about the management of low back pain.

This study was selected from Medscape Best Evidence, which uses the McMaster Online Rating of Evidence System. Of a possible top score of 7, this study was ranked as 6 for relevance and 5 newsworthiness by clinicians who used this system.

Commentary

Low back pain is one of the most common and difficult to treat conditions encountered in the acute care setting. The lifetime prevalence of low back pain is between 60% and 85%, and 15% of the population may have low back pain at any one time.^[1] This complaint also exacts a significant toll on society at large. In an analysis of the cost of medical conditions to American businesses in terms of medical visits, prescription drug use, absence from work, and short-term disability, mechanical low back pain ranked number 4 on the top 10 most costly physical diagnoses.^[2] Moreover, "other" back pain and spinal injury were also in the top 10.

Current recommendations for the management of low back pain include early mobilization and physical activity.^[1] Acetaminophen, NSAIDs, and muscle relaxants are recommended to reduce pain and improve function within the first 6 weeks after the manifestation of acute symptoms. Spinal manipulation therapy is also often recommended in such cases. Such treatments, however, cannot prevent the development of nonspecific low back pain or chronic back pain among patients with acute pain. Prevention of chronic back pain focuses more on behavior and maintenance of activity as opposed to pharmacotherapy.

NSAIDs have been demonstrated to improve low back pain compared with placebo, according to a 2008 systematic review by the Cochrane Collaboration Review Group.^[3] Researchers analyzed 65 trials involving a total of 11,237 patients with low back pain. Overall, NSAIDs were more effective than placebo in the management of acute low back pain. However, NSAIDs also increased the risks for adverse events compared with placebo.

These improvements using NSAIDs vs. placebo are modest, and whether NSAIDs confer greater benefit than acetaminophen (paracetamol) is controversial. The review cites 6 studies that investigated this issue, only one of which was of high quality. Most of these studies focused on acute low back pain and failed to demonstrate superiority of one treatment over another. The one high-quality study examined patients with chronic low back pain, not acute pain, and NSAIDs were more effective than paracetamol in this group.

The body of research into the efficacy of spinal manipulative therapy is more complicated and difficult to interpret. The techniques for manipulative therapy are more heterogenous than medical therapy, and studies have compared manipulative therapy with multiple different control treatments, making it difficult to draw a conclusion regarding treatment efficacy. However, one review classified control treatments from studies of spinal manipulative therapy into 7 broad categories and pooled results from 39 randomized controlled trials.^[4] Spinal manipulative therapy was significantly superior to sham therapy, resulting in a mean of 10 mm of improvement vs sham therapy on a 100-mm pain scale. However, spinal manipulation therapy was not superior to general practitioner care, analgesics, physical therapy, back exercises, or back school. The authors examined variables affecting pain outcomes, and they found that the profession of the person performing spinal manipulation did not alter the main study result.

Together, these reviews of NSAIDs and spinal manipulative therapy do not provide overwhelming evidence of superior efficacy of either treatment over good routine care of acute low back pain. Furthermore, the current study puts these treatments to the test in a common practice environment. Patients seeking relief of acute low back pain in general practitioners' offices were eligible for study participation. Those with a history of back pain in the month prior to study enrollment or evidence of nerve root compromise on physical examination were excluded.

All participants were given paracetamol 1 gm to be taken 4 times daily until complete recovery or a maximum of 4 weeks elapsed. Subjects were assigned to receive diclofenac 50 mg twice daily and placebo spinal manipulation therapy, spinal manipulation therapy and placebo tablets imitating diclofenac, or double placebo. Spinal manipulation therapy was delivered 2 or 3 times per week and allowed for the use of high-velocity thrust procedures according to the judgment of experienced physiotherapists. The placebo used to replace spinal therapy was detuned pulse ultrasound.

The primary outcome was the number of days until either the first pain-free day or the first of 7 consecutive days with at least minimal pain. Secondary outcomes included pain, function, and disability.

There were 240 patients with moderate levels of pain and disability at baseline who underwent randomization. On average, subjects took approximately two thirds of the recommended dose of paracetamol and 72% of the recommended dose of diclofenac. The median number of spinal manipulation therapy sessions per week was 2.3, and only a small percentage of subjects underwent high-velocity thrust techniques.

Patients had difficulty discerning placebo from active treatments, indicating that the blinding techniques were adequate. The median number of days to recovery among subjects receiving diclofenac was 13, compared with 16 days among participants receiving placebo, which was not a statistically significant difference. In both the spinal manipulation therapy group and the placebo group, the median number of days to recovery was 15. Even the combination of diclofenac and spinal manipulation therapy failed to promote faster rates of improvement vs double placebo. Moreover, both active treatments failed to improve secondary outcomes of pain, disability, or function compared with placebo. Participants reported that the overall perceived effect was similar regardless of study treatment.

The authors of the current study address a major reason for the negative results in their study compared with results of previous research on NSAIDs for acute low back pain. They note that many of these earlier trials failed to include clinicians' advice for basic back care as well as regular treatment with paracetamol. Although NSAIDs and spinal manipulation therapy may be more effective than placebo, the current research suggests that they are no more effective than paracetamol and sound advice.

At the same time, NSAIDs raise significant safety concerns. The prevalence of NSAID-related gastropathy is approximately 25% to 50% among chronic NSAID users. Furthermore, a meta-analysis that examined the gastrointestinal risk associated with specific NSAIDs found that NSAIDs increased the risk for all gastrointestinal complications by 54%.^[5] The NSAIDs most associated with these complications were (in order of the frequency of complications) indomethacin, naproxen, and diclofenac. The relative risk for gastrointestinal complications with indomethacin reached its maximum after only 14 days of therapy. Tenoxicam, meloxicam, and ibuprofen produced nonsignificant increases in the risk for gastrointestinal complications.

NSAIDs can have deleterious effects on the kidneys as well. A study of 90 patients with osteoarthritis examined renal function when patients were treated with amtolmetin guacyl (the prodrug of tolmetin), diclofenac, or rofecoxib for 17 days.^[6] Researchers found that diclofenac was associated with an increase in serum creatinine and a reduction in daily urine volume. Rofecoxib, which was withdrawn from the market in 2004, increased blood pressure values while reducing daily urine volume and creatinine clearance. However, amtolmetin did not significantly affect any of the parameters of renal function.

Spinal manipulation therapy also has possible adverse consequences. In a review of the medical literature regarding spinal manipulation therapy published between 2001 and 2006, researchers found that more than 200 patients receiving spinal manipulation were suspected to have been seriously harmed.^[7] Most data regarding serious adverse effects were from case reports, and vertebral artery dissection was identified as the most common serious adverse event. Mild adverse events of spinal manipulation therapy were very common, occurring in 30% to 61% of all patients. However, some clinical trials of spinal manipulation therapy have demonstrated that these techniques are safe for the management of low back pain.^[8,9]

However, the more pertinent question regarding the possible negative consequences of spinal manipulation therapy may be financial. One of the larger trials focusing on the effectiveness of spinal manipulation therapy for back pain included a financial analysis.^[10] This study involved 181 general practices in the United Kingdom. The researchers found that mean annual treatment costs relative to standard clinical care were 195 pounds sterling for spinal manipulation. However, spinal manipulation improved the outcome of quality-adjusted life years vs best care, and the authors concluded that spinal manipulation is a cost-effective addition to "best care" for back pain in general practice. Moreover, the researchers found that spinal manipulation alone improved therapeutic value for the money compared with manipulation followed by a supervised exercise program.

Another study conducted by chiropractic researchers in the United States found that chiropractic care was more expensive than medical care for patients with both acute and chronic low back pain.^[11] However, at the same time, patients with chronic low back pain receiving chiropractic care experienced better outcomes in pain and functional disability compared with patients receiving medical care exclusively. The authors conclude that chiropractic care appears cost-effective for chronic low back pain, although it may not be as cost-effective for patients with acute low back pain.

The current study by Hancock and colleagues would certainly suggest that the added cost and adverse events associated with spinal manipulation therapy are not justified by more rapid improvement in low back pain. In addition, the study suggests that patients should not be exposed to the risk of taking NSAIDs when there is little added therapeutic benefit associated with such treatment. It is also worth noting that recent research into the early prescribing of opioids for low back pain found this practice to be associated with higher mean disability duration, elevated mean medical costs, and an increased risk for surgery and late opioid use compared with usual practice.^[12]

Although it may be difficult for both patients and providers to accept that time appears to be the best therapy for low back pain, most cases of back pain improve significantly within 2 weeks, and 90% of patients report significant improvement at 2 months.^[1] Clinicians should certainly encourage appropriate activity and recommend paracetamol/acetaminophen to improve symptoms of acute low back pain, but it appears that giving the body time to recover is the key element of treatment. This common diagnosis requires prescriptive restraint, and patients will benefit from this practice in the long run.

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