A New Era for Anticoagulation in Atrial Fibrillation

Jessica L. Mega, M.D., M.P.H.

August 28, 2011 (10.1056/NEJMe1109748)

Article

References

For more than 50 years, warfarin has been the primary medication used to reduce the risk of thromboembolic events in patients with atrial fibrillation. Despite its clinical efficacy, warfarin has multiple, well-known limitations, including numerous interactions with other drugs and the need for regular blood monitoring and dose adjustments. Thus, clinicians and patients have been eager to embrace alternative oral anticoagulants that are equally efficacious but easier to administer.

In this issue of the Journal, Granger and colleagues report the impressive primary results of the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation trial (ARISTOTLE; ClinicalTrials.gov number, NCT00412984).1 A total of 18,201 subjects with atrial fibrillation and at least one additional risk factor for stroke were enrolled in the trial and were randomly assigned to receive the direct factor Xa inhibitor apixaban (at a dose of 5 mg twice daily) or warfarin (target international normalized ratio [INR], 2.0 to 3.0). The trial was designed to test whether apixaban was noninferior to warfarin with respect to efficacy. The investigators found that apixaban was not only noninferior to warfarin, but actually superior, reducing the risk of stroke or systemic embolism by 21% and the risk of major bleeding by 31%. In predefined hierarchical testing, apixaban, as compared with warfarin, also reduced the risk of death from any cause by 11%.

These results come on the heels of two other, large, phase 3 trials in which novel anticoagulants were compared with warfarin in patients with atrial fibrillation: the Randomized Evaluation of Long-Term Anticoagulation Therapy trial (RE-LY, NCT00262600)2 and Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF, NCT00403767).3 The RE-LY trial evaluated the direct thrombin inhibitor dabigatran in two different doses, 110 mg and 150 mg, both administered twice daily. ROCKET AF evaluated the direct factor Xa inhibitor rivaroxaban at a dose of 20 mg once daily.

The trials have a number of similar conclusions. Apixaban, dabigatran, and rivaroxaban, as compared with warfarin, all significantly reduce the risk of hemorrhagic stroke. In fact, in all the studies, the reductions in the primary efficacy end point — which included hemorrhagic as well as ischemic stroke — were greatly influenced by this dramatic reduction in the risk of hemorrhagic stroke. Of the three drugs, only dabigatran at a dose of 150 mg holds the distinction of also having significantly reduced the risk of ischemic stroke as compared with warfarin; nonetheless, even in this case, there was a greater influence on hemorrhagic stroke than on ischemic cerebrovascular events. Similarly, the risk of particularly serious bleeding was reduced with each of the three drugs, as compared with warfarin, and apixaban therapy also resulted in lower rates of all major bleeding. Thus, the newer anticoagulants boast favorable bleeding profiles as compared with warfarin in patients with atrial fibrillation.

There is also a shared theme with respect to mortality. Apixaban is the first of the newer anticoagulants to show a significant reduction in the risk of death from any cause as compared with warfarin (hazard ratio, 0.89; 95% confidence interval [CI], 0.80 to 0.99; P=0.047). Although the current findings are notable, both dabigatran and rivaroxaban, as compared with warfarin, showed similar directional trends. In the RE-LY trial, there was a borderline reduction in the risk of death from any cause with dabigatran at a dose of 150 mg, as compared with warfarin (hazard ratio, 0.88; 95% CI, 0.77 to 1.00; P=0.051). Similar trends in the risk of death from any cause were observed with rivaroxaban in the intention-to-treat analysis in ROCKET AF (hazard ratio, 0.92; 95% CI, 0.82 to 1.03; P=0.15). Thus, there is approximately a 10% reduction in the risk of death from any cause across these three trials in which the newer anticoagulants were compared with warfarin in patients with atrial fibrillation.

Despite these similarities, there are important differences in the design of the studies and in the administration of the drugs. In the RE-LY trial, the assignments to dabigatran or warfarin were not concealed. In contrast, the ROCKET AF and ARISTOTLE trials successfully achieved a double-blind design. In the RE-LY and ARISTOTLE trials, dabigatran and apixaban were administered twice daily; in ROCKET AF, rivaroxaban was administered once daily. Subjects in the RE-LY and ARISTOTLE trials could have only one additional risk factor for stroke, whereas ROCKET AF enrolled a higher-risk population. The mean percentage of time in which the INR was in the therapeutic range of 2.0 to 3.0 — a metric that assesses the quality of warfarin dosing — was 64% in the RE-LY trial, 55% in the ROCKET AF trial, and 62% in the ARISTOTLE trial. There were additional differences among the studies with respect to their statistical analysis plans and power. These factors highlight the challenges with cross-trial comparisons. Head-to-head studies, which are not currently available, would allow for direct assessments among these novel compounds.

Will these newer anticoagulants be better than warfarin for the treatment of all patients with atrial fibrillation? The direct thrombin and factor Xa inhibitors overcome the need for routine blood monitoring, and the trial results have been encouraging overall and across important subgroups. For example, in the ARISTOTLE trial, the efficacy of apixaban was consistent in subgroups according to baseline stroke risk and according to whether patients had or had not been taking warfarin before entering the study. However, switching to a newer agent may not be necessary for the individual patient in whom the INR has been well controlled with warfarin for years. In addition, although the newer anticoagulants have a more rapid onset and termination of anticoagulant action than does warfarin, agents to reverse the effect of the drugs are still under development and are not routinely available.

In addition, generic warfarin is expected to be markedly less expensive than the newer agents even after the costs associated with regular INR monitoring are considered. One analysis has suggested that dabigatran, as compared with warfarin, could be cost-effective in patients with atrial fibrillation.4 Additional data on cost-effectiveness are likely to further influence clinical decision making. Thus, although the oral direct thrombin and factor Xa inhibitors are attractive alternatives, it is likely that warfarin will continue to be used worldwide in many patients with atrial fibrillation.

The original mission to replace warfarin began with a search for drugs that were simply noninferior to warfarin. The ARISTOTLE trial, in conjunction with the RE-LY and ROCKET AF trials, suggests that apixaban, dabigatran, and rivaroxaban have gone even further. Across three large studies with different populations of patients with atrial fibrillation, the direct thrombin and factor Xa inhibitors have been shown to have a more favorable bleeding profile than warfarin and are at least as efficacious. Information about another direct factor Xa inhibitor, edoxaban, in patients with atrial fibrillation, will be available at the conclusion of the Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction Study 48 (ENGAGE AF-TIMI 48, NCT00781391).5 After all this time, a new era of anticoagulation appears to be emerging for patients with atrial fibrillation.

Disclosure forms provided by the author are available with the full text of this article at NEJM.org.

This article (10.1056/NEJMe1109748) was published on August 28, 2011, at NEJM.org.

Source Information

From the Thrombolysis in Myocardial Infarction Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston.

August 24, 2011 — The nonprofit consumer advocacy group Public Citizen is petitioning the US Food and Drug Administration (FDA) to add black box warnings to the product labels of all proton pump inhibitors (PPIs) on the market.

The black box warnings should alert clinicians and patients that these drugs can cause long-term dependence and other serious adverse effects, Public Citizen says in a statement released yesterday.

The group is also calling for patient medication guides to be distributed with all PPIs and for the makers of the drugs to notify clinicians of these adverse effects and of the need to try safer alternatives first for conditions such as gastroesophageal reflux disease (GERD).

"These drugs are being prescribed far too commonly to people who shouldn't be taking them," Sidney Wolfe, MD, director of Public Citizen's Health Research Group, said in a prepared statement. "As a result, millions of people are needlessly setting themselves up to become dependent on PPIs while exposing themselves to the serious risks associated with long-term therapy.

"The FDA should act immediately to ensure that patients and physicians are adequately warned of these effects, and reminded of the many safer alternatives for common conditions such as acid reflux," he added.

More Education, Not Warnings, Needed

Reached for independent comment, Kenneth DeVault, MD, professor and chair, Department of Medicine, Mayo Clinic, Jacksonville, Florida, told Medscape Medical News that he does not think that greater warnings are needed on PPIs, "but that education of providers and consumers is important."

"Honestly," he said, "the risks of these medications, even when over the counter, are less than some other common drugs, such as nonsteroidal anti-inflammatories and even aspirin."

Still, Dr. DeVault said he is "becoming more likely to try to find the 'lowest effective dose' " for his patients. "That might be a once-daily PPI, a lower-dose PPI, an H2 receptor blocker, or in some patients, simply leading a less 'refluxogenic lifestyle.'

"We need to make sure we understand that for a significant proportion of patients with acid reflux, this is a lifestyle condition where a better diet and weight loss may result in the patient not needing any acid blocker at all," Dr. DeVault explained.

PPIs Widely Prescribed

PPIs, which effectively suppress the production of stomach acid, are among the most widely used classes of drugs in the world. In the United States alone, an estimated 119 million PPI prescriptions were dispensed in 2009, at a price tag of $13.6 billion.

PPIs are approved to treat GERD, as well as gastric ulcers, erosive esophagitis, and stomach bleeding associated with using nonsteroidal anti-inflammatory drugs, although they are often prescribed for other reasons and for longer than indicated, some studies have suggested.

PPIs have been shown to be generally well tolerated with relatively few short-term adverse effects. Common adverse effects include headache, nausea, diarrhea, abdominal pain, fatigue, and dizziness.

Adverse effects related to long-term use of PPIs have been less well studied, but may include an increased risk for fractures of the hip, spine, and wrist; hypomagnesemia, possibly leading to cardiac arrhythmia; infections such as pneumonia and Clostridium difficile diarrhea; and reduced effectiveness of the antiplatelet clopidogrel, although the clinical significance of this is debated. Many of these possible adverse effects are already contained in PPI labeling.

Rebound Hyperacidity

A key concern of Public Citizen is the possibility of long-term dependence on PPI therapy resulting from rebound acid hypersecretion when the medication is stopped, which is not currently noted on the label.

For example, in a study published in 2009 in Gastroenterology, researchers reported that acid inhibition with a PPI for 8 weeks induces acid-related symptoms in "a significant proportion" of asymptomatic patients when therapy is withdrawn.

"We find it highly likely," the authors write, "that the symptoms observed in this trial are caused by [rebound acid hypersecretion,] and that this phenomenon is equally relevant in patients treated long term with PPIs. These results justify the speculation that PPI dependency could be 1 of the explanations for the rapidly and continuously increasing use of PPIs."

The authors of a related commentary in the journal concluded: "The current finding that these drugs induce symptoms means that such liberal prescribing is likely to be creating the disease the drugs are designed to treat and causing patients with no previous need for such therapy to require intermittent or long-term treatment."

PPIs Beneficial in Appropriate Patients

Colin W. Howden, MD, FACG, and Peter J. Kahrilas, MD, FACG, address this issue of PPI withdrawal and rebound hyperacidity in a 2010 commentary published in the American Journal of Gastroenterology.

The authors conclude: "PPI treatment continues to be the optimal management strategy for most patients with [GERD] and is indicated for chronic use as ulcer prophylaxis in nonsteroidal anti-inflammatory drug takers at high risk for bleeding.

"However, as with all drugs, PPIs should be dosed appropriately, and should be reserved for patients with conditions for which there is clear evidence of benefit from therapy," they write.

Dr. DeVault told Medscape Medical News, "There is probably a short-lived (2 weeks or so) theoretical increase in acid capacity after stopping PPI therapy, which might make it more difficult to stop the drugs in selected patients, and might even lead to acid symptoms in some normal individuals."

In contrast, he said he thinks that "a good bit of that 'rebound' is actually related to the symptoms, in that the patient simply feels better on the PPI and therefore wants to continue, but the converse remains a possibility."

"At this point," Dr. DeVault noted, "PPIs are still my first choice for acid suppression, but it is critical to evaluate the patient and not blindly continue these medications when they are not helping.

"A common mistake is for a provider to become convinced the patient has an acid-related problem and gradually escalate the degree of acid suppression, when taking a step back and doing some diagnostic evaluation may reveal that the problem is not acid-related at all," he added.

Sandra A. Fryhofer, MD Clinical Associate Professor of Medicine, Emory University School of Medicine, Atlanta, Georgia; Past President, American College of Physicians, Philadelphia, Pennsylvania

Savvy Statin Shopping

Let's go shopping. This edition of Staying Well focuses on how to be a savvy shopper in choosing a statin for your patients, a timely issue in light of the US Food and Drug Administration's (FDA's) new simvastatin warnings. Seasoned shoppers always check the sale racks first, but don't buy something -- even if on sale -- if the "size and style" aren't right. Apply this analogy to picking a statin. Although the first thing to look for is price, it should not be the only deciding factor. Simvastatin is certainly one of the cheapest statins, but is it the best choice for your patients?

My Personal Disclaimer

I admit that I have been a little lazy. For the last several years, when my patients needed statins I always started with simvastatin. It was generic. It was on all the pharmacy plans, so the price point for patients was right. Prescribing was hassle free: no cumbersome forms to fill out and explain. However, the recent FDA warnings about the dangers of high-dose simvastatin and additional warnings about dosing and drug interactions have led me to rethink this strategy and take a closer look at the different statins available. It is now time to find out the facts and make necessary changes in prescribing patterns. Maybe it's time for a new "style" of treatment. Here is some information to help you decide.

Statin Characteristics

This statin dose equivalency guide gives equivalent doses of available statins along with generic and brand names and selected characteristics (Table 1).^[1-5]

Table 1. Statin Dose Equivalency Guide

Medication	Dose Equivalent	Pharmacotherapeutic Factor	Metabolism	Metabolites
Rosuvastatin (Crestor®)	2.5 mg	Hydrophilic	CYP2C9	Active (minor) metabolite
Atorvastatin (Lipitor®)	5 mg	Lipophilic	P450 3A4 (CYP3A4)	Active metabolite
Simvastatin (Zocor®)a	10 mg	Lipophilic	P450 3A4 (CYP3A4)	Active metabolite
Lovastatin (Altoprev®, Mevacor®)	20 mg	Lipophilic	P450 3A4 (CYP3A4)	Active metabolite
Pravastatin (Pravachol®)	20 mg	Hydrophilic	Renal metabolism	No active metabolites
Fluvastatin (Lescol®, Lescol® XL)	40 mg	Lipophilic	CYP2C9	No active metabolites
Pitavastatin (Livalo®)	1 mg	Lipophilic	Little metabolism by CYP3A4	No active metabolites

^aAlso in combination medications: ezetimibe/simvastatin (Vytorin®) and niacin extended release/simvastatin (Simcor®)

Table 2 is from the FDA Drug Safety Communication and gives relative low-density lipoprotein (LDL) efficacy for the different statins. Note that pitavastatin (Livalo®) is a newer statin and was FDA approved in 2009.

Table 2. Relative LDL-Lowering Efficacy of Statin and Statin-Based Therapies

Atorva	Fluva	Pitava	Lova	Prava	Rosuva	Vytorin®a	Simva	%↓ LDL-C
--	40 mg	1 mg	20 mg	20 mg	--	--	10 mg	30%
10 mg	80 mg	2 mg	40/80 mg	40 mg	--	--	20 mg	38%
20 mg	--	4 mg	80 mg	80 mg	5 mg	10/10 mg	40 mg	41%
40 mg	--		--	--	10 mg	10/20 mg	80 mg	47%
80 mg	--		--	--	20 mg	10/40 mg	--	55%
	--		--	--	40 mg	10/80 mg	--	63%

Atorva = atorvastatin; Fluva = fluvastatin; LDL-C = low-density lipoprotein cholesterol; Pitava = pitavastatin; Lova = lovastatin; Prava = pravastatin; Rosuva = rosuvastatin; Simva = simvastatin
^aNo incremental benefit of Vytorin on cardiovascular morbidity and mortality over and above that demonstrated for simvastatin has been established.
Data from US Food and Drug Administration. June 8, 2011. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm256581.htm ^[4]

Association of Pharmacologic Factors With Adverse Effects

Statins that are hydrophilic (pravastatin and rosuvastatin) are less likely to cross skeletal muscle membranes and are less likely to cause adverse effects.^[3]

Statins that don't have active metabolites (fluvastatin, pravastatin, and pitavastatin) are less likely to cause adverse effects. Rosuvastatin has only a minor active metabolite.^[3,5]

Drug metabolism pathway plays a role in drug-drug interactions and subsequent safety. This is especially important for patients on multiple medications:

• For statins metabolized by P450 3A4 (CYP3A4) (simvastatin, lovastatin, atorvastatin), concomitant administration of medications that inhibit the CYP3A4 pathways (protease inhibitors, cyclosporine, amiodarone, fibrates) is problematic. The result is increased statin levels and increased risk for muscle tissue injury.
• On the other hand, fluvastatin and rosuvastatin (metabolized by CYP2C9) and pravastatin (metabolized by the kidneys) are considered to be safer statin choices for patients on multiple medications.^[3]

Section 1 of 4

Next: The Simvastatin Saga: Review of the FDA Drug Safety Warnings »

SUMMARY AND COMMENT

Is Folic Acid a Risk Factor for CRC?

August 12, 2011 | Douglas K. Rex, MD

No type of folate, including folic acid, increased the risk for colorectal cancer.

Reviewing: Stevens VL et al. Gastroenterology 2011 Jul 141:98

Lee JE et al. Gastroenterology 2011 Jul 141:16

According to the current study by Gorelick and colleagues, by 2025 there will be 1.2 billion persons worldwide who will be 60 years and older. Also, in persons 80 years and older — a fast-growing population in developed countries — approximately 20% experience difficulties in activities of daily living, with cognitive impairment increasing in prevalence with age. In addition, risk markers for stroke are now understood to be risk markers for Alzheimer's disease and other cognitive impairments. Vascular cognitive impairment (VCI) is a cause of microvascular brain damage, and arterial stiffness and atherosclerotic changes may be common risk factors for VCI.

This statement from the American Heart Association (AHA) and the American Stroke Association (ASA) describes vascular contributions to cognitive impairment and provides recommendations for prevention, treatment, and future research.

Study Synopsis and Perspective

Vascular changes are "important" contributors to cognitive impairment and dementia and should be routinely addressed in clinical practice, according to a new scientific statement from the AHA and ASA.

The 42-page statement, "Vascular Contributions to Cognitive Impairment and Dementia," was published online July 21 in Stroke and will appear in the September print issue of the journal. The American Academy of Neurology and the Alzheimer's Association have endorsed the statement. The Alzheimer's Association participated in its development.

In comments to Medscape Medical News, Philip B. Gorelick, MD, MPH, cochair of the writing group for the statement and director of the Center for Stroke Research at the University of Illinois College of Medicine at Chicago, said vascular factors "have long been thought to be an important contributor to cognitive decline and dementia in later life."

Still, they have not received as much attention as Alzheimer's disease, "which has been on the center stage of scientific inquiry," he added.

Introducing 'Vascular Cognitive Impairment'

Dr. Gorelick and the writing group systematically reviewed published studies, guidelines, personal files, and expert opinion to summarize existing evidence, indicate gaps in current knowledge, and, when appropriate, offer recommendations for care.

"Over time and with careful study, vascular factors have been found to play a role in both vascular and so-called neurodegenerative forms of cognitive impairment such as Alzheimer disease," Dr. Gorelick said.

On the basis of the evidence, the writing group formally introduces the construct of "vascular cognitive impairment" (VCI). This, they say, captures "the entire spectrum of cognitive disorders associated with all forms of cerebral vascular brain injury — solely stroke — ranging from mild cognitive impairment through fully developed dementia.

"The neuropathology of cognitive impairment in later life is often a mixture of Alzheimer disease and microvascular brain damage," the study authors note, "which may overlap and synergize to heighten the risk of cognitive impairment."

In this regard, magnetic resonance imaging and other neuroimaging techniques "play an important role" in detecting and defining VCI, they advise.

What's Good for the Heart Is Good for the Brain

It is now "accepted," the team writes, that many of the traditional risk markers for heart disease and stroke are also risk markers for VCI and Alzheimer's disease.

"Stroke and heart disease are linked by a number of cardiovascular risk factors, such as hypertension, hypercholesterolemia, diet, tobacco exposure, and other factors," Dr. Gorelick explained. "These vascular factors and others may play a causal role in the development of cognitive impairment and dementia in later life."

Carotid intimal-medial thickness and arterial stiffness are "emerging as markers of arterial aging and may serve as risk markers for VCI," the writing group points out.

Detection and control of the traditional risk factors for stroke and cardiovascular disease may help guard against VCI. "We encourage clinicians to use screening tools to detect cognitive impairment in their older patients and continue to treat vascular risks according to nationally- and regionally-accepted guidelines," the study authors write.

"At the very least," Dr. Gorelick said, screening for and treatment of vascular risk factors, including hypertension, hyperglycemia, and hypercholesterolemia, may reduce the occurrence of stroke and heart disease. "There may be an added benefit of prevention and treatment of vascular risk factors — the prevention of cognitive impairment and dementia in later life," he added.

Specifically, in persons at risk for VCI, the writing group concludes that

• Smoking cessation is reasonable (Class IIa; Level of Evidence A);
• Moderation of alcohol intake, weight control, and physical activity may be reasonable (all Class IIb; Level of Evidence B); and
• Use of antioxidants and B vitamins is not useful, based on current evidence (Class III; Level of Evidence A).

For individuals with vascular dementia, they conclude that

• Donepezil can be useful for cognitive enhancement (Class IIa; Level of Evidence A);
• Galantamine can be beneficial for individuals with mixed Alzheimer disease/vascular dementia (Class IIa; Level of Evidence A); and
• The benefits of rivastigmine and memantine are not well established in vascular dementia (Class IIb; Level of Evidence A).

The study authors also note that a Mediterranean-type dietary pattern has been associated with less cognitive decline in several studies and may be reasonable (Class IIb; Level of Evidence B).

Vitamin supplementation is not proven to improve cognitive function, even if homocysteine levels have been positively influenced, and its usefulness is not well established (Class IIb; Level of Evidence B). The effectiveness of antiaggregant therapy for VCI is not well established (Class IIb; Level of Evidence B).

Reached for comment, Thomas Russ, MD, PhD, from the University of Edinburgh, Scotland, said, "This is a clear outline of the difficulties surrounding the rather complicated overlap and interaction between vascular changes and the neuropathological changes of Alzheimer disease both resulting in cognitive impairment and dementia.

"The recommendations for prevention are a useful restatement of the current state of knowledge and a helpful reminder that we need to intervene sufficiently early in a condition which develops over the course of years and decades — ie, middle age," added Dr. Russ, who was not involved in the writing group.

Dr. Gorelick has disclosed no relevant financial relationships. A complete list of disclosures for writing group members is available with the original article. Dr. Russ has disclosed no relevant financial relationships.

Stroke. Published online July 21, 2011.

NSAIDs

NSAIDs are the usual first-line treatment for gout, and no specific agent is significantly more or less effective than any other.^[2] Improvement may be seen within 4 hours, and treatment is recommended for 1–2 weeks.^[2][6] They are not recommended, however in those with certain other health problems, such as gastrointestinal bleeding, renal failure, or heart failure.^[33] While indomethacin has historically been the most commonly used NSAID, an alternative, such as ibuprofen, may be preferred due to its better side effect profile in the absence of superior effectiveness.^[16] For those at risk of gastric side effects from NSAIDs, an additional proton pump inhibitor may be given.^[34]

Abstract

Objectives To examine the risk of atrial fibrillation or flutter associated with use of non-selective non-steroidal anti-inflammatory drugs (NSAIDs) or selective cyclo-oxygenase (COX) 2 inhibitors.
Design Population based case-control study using data from medical databases.
Setting Northern Denmark (population 1.7 million).
Participants 32 602 patients with a first inpatient or outpatient hospital diagnosis of atrial fibrillation or flutter between 1999 and 2008; 325 918 age matched and sex matched controls based on risk-set sampling.
Main outcome measures Exposure to NSAID use at the time of admission (current use) or before (recent use). Current use was further classified as new use (first ever prescription redemption within 60 days before diagnosis date) or long term use. We used conditional logistic regression to compute odds ratios as unbiased estimates of the incidence rate ratios.
Results 2925 cases (9%) and 21 871 controls (7%) were current users of either non-selective NSAIDs or COX 2 inhibitors. Compared with no use, the incidence rate ratio associating current drug use with atrial fibrillation or flutter was 1.33 (95% confidence interval 1.26 to 1.41) for non-selective NSAIDs and 1.50 (1.42 to 1.59) for COX 2 inhibitors. Adjustments for age, sex, and risk factors for atrial fibrillation or flutter reduced the incidence rate ratio to 1.17 (1.10 to 1.24) for non-selective NSAIDs and 1.27 (1.20 to 1.34) for COX 2 inhibitors. Among new users, the adjusted incidence rate ratio was 1.46 (1.33 to 1.62) for non-selective NSAIDs and 1.71 (1.56 to 1.88) for COX 2 inhibitors. Results for individual NSAIDs were similar.
Conclusions Use of non-aspirin NSAIDs was associated with an increased risk of atrial fibrillation or flutter. Compared with non-users, the association was strongest for new users, with a 40-70% increase in relative risk (lowest for non-selective NSAIDs and highest for COX 2 inhibitors). Our study thus adds evidence that atrial fibrillation or flutter needs to be added to the cardiovascular risks to be considered when prescribing NSAIDs.

Introduction

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used to treat inflammatory conditions and pain.^[1] By inhibiting cyclo-oxygenase (COX)-1 mediated production of prostaglandins,^[1] non-selective NSAIDs are known to cause gastrointestinal toxicity^[1] and a variety of nephrotoxic syndromes.^[2] An alternative is selective COX 2 inhibitors, available in the form of older or newer agents.^[3] The newer COX 2 inhibitors, introduced into clinical practice in 1998, were developed as NSAIDs with an improved gastrointestinal side effect profile.^[1] The cardiovascular safety of all marketed newer COX 2 inhibitors requires thorough evaluation in view of the increased cardiovascular^[4-6] and renal risk^[2] reported for several of these drugs.

Atrial fibrillation is the most common rhythm disorder observed in clinical practice. It more than doubles in prevalence during each advancing decade of life, from 0.5% at age 50-59 years to above 10% at age 80-89 years.^[7] It is associated with increased mortality and morbidity, mainly due to haemodynamic impairments that exacerbate or even cause heart failure,^[8] and a threefold to fourfold increased risk of thromboembolic stroke.^[9]

Use of NSAIDs may increase the risk of atrial fibrillation through its adverse renal effects—for example, fluid retention, electrolyte disturbances, and blood pressure destabilisation ^[2,6]—but the evidence for such effects is limited.^[10,11] Although no original research has been published on COX 2 inhibitors and atrial fibrillation, a meta-analysis summarised data from 114 clinical trials and found that rofecoxib was associated with an increased risk of cardiac arrhythmias (relative risk 2.90, 95% confidence interval 1.07 to 7.88).^[10] Because the meta-analysis included only 286 incident arrhythmias, precision was low and risk of arrhythmia subtypes such as atrial fibrillation could not be examined.^[10] Recently, traditional NSAIDs (that is, non-selective NSAIDs and older COX 2 inhibitors) have been associated with increased risk of chronic atrial fibrillation (incidence rate ratio 1.44, 1.08 to 1.91).^[11]

Any confirmed association between use of NSAIDs and atrial fibrillation would have major clinical and public health implications. Older people are of special concern because the prevalence of use of NSAIDs and the incidence of atrial fibrillation increase with age. To address the limitations of the existing literature, we conducted a large population based case-control study examining whether and to what extent use of NSAIDs increases the risk of atrial fibrillation or flutter.

Section 1 of 4

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Summary and Comment

Stroke Risk-Stratification Scores Have Limited Prognostic Value in Elders with AF

The authors suggest anticoagulation for all elders with atrial fibrillation.