Modified-Release Prednisone May Be Well-Tolerated, Effective in Rheumatoid Arthritis

Modified-release prednisone was well tolerated and reduced morning stiffness of joints in patients with rheumatoid arthritis (RA), according to the results of a double-blind, randomized controlled trial reported in the January 19 issue of The Lancet.

“Circadian rhythms are changed in patients with rheumatoid arthritis,” write Frank Buttgereit, MD from the Charité University Medicine in Berlin, Germany, and colleagues. “A new modified-release delivery system has been developed which adapts the release of the administered glucocorticoid to the circadian rhythms of endogenous cortisol and disease symptoms to improve the benefit–risk ratio of glucocorticoid therapy in rheumatoid arthritis. . . . The Circadian Administration of Prednisone in Rheumatoid Arthritis (CAPRA-1) study (EMR 62 215-003) assessed the efficacy and safety of a new modified-release prednisone tablet compared with immediate-release prednisone in patients with rheumatoid arthritis.”

In this 12-week, multicenter trial, 288 patients with active RA were randomized to receive either a modified-release prednisone tablet at bedtime or an immediate-release prednisone tablet in the morning. With the modified-release tablet, prednisone was released 4 hours after ingestion. The main endpoint was duration of morning stiffness of the joints, and analysis was by intent-to-treat.

From baseline to end of treatment, the mean relative change in duration of morning stiffness of the joints was higher with modified-release prednisone than with immediate-release prednisone (–22.7% vs –0.4%; difference, 22·4%; 95% confidence interval [CI], 0.49 – 44.30; P = .045). In the prednisone modified-release group, mean reduction from baseline in duration of morning stiffness was 44.0 ± 136.6 minutes. The absolute difference between the groups was 29.2 minutes (95% CI –2.59 to 61.9) favoring modified-release prednisone (P = .072).

Both treatments had a similar safety profile.

“Modified-release prednisone is well tolerated, convenient to administer, and produces a clinically relevant reduction of morning stiffness of the joints in addition to all known therapeutic effects of immediate-release prednisone,” the study authors write. “Interleukin 6 serum concentrations were also significantly reduced by modified-release prednisone after 3 months but were unchanged by immediate-release prednisone.”

Study limitations include that it was not designed to evaluate IL-6 in statistical confirmatory tests.

“Modified-release prednisone provides an improvement with respect to conventional glucocorticoids for the treatment of rheumatoid arthritis,” the authors conclude. “We should stress that patients need to be carefully advised with regard to the correct timing of this evening drug to achieve this beneficial effect in clinical practice. This new prednisone tablet might also be an option for the treatment of other diseases such as polymyalgia rheumatica or even asthma.”

Merck KGaA supported the study and employs one of its authors. Two of the authors have disclosed relevant financial relationships with Abbott, Bristol-Myers Squibb, Merck Pharma GmbH, Organon, Pfizer, Wyeth, Amgen, Roche, the Deutsche Forschungsgemeinschaft, the Federal Ministry of Education and Research Germany, and/or Schering-Plough. Nitec Pharma GmbH employs two of the authors.

In an accompanying editorial, Johannes W.J. Bijlsma, MD, PhD, and Johannes W.G. Jacobs, MD, PhD, from University Medical Centre Utrecht in the Netherlands, call these results “clearly relevant for daily clinical practice,” despite remaining questions regarding long-term efficacy, the effect on radiologic joint destruction, and long-term adverse events.

“Additional and more long-term data on the modified-release formulation are therefore needed, although Buttgereit’s study provides proof-of-principle for this chronotherapy,” Drs. Bijlsma and Jacobs write.

Dr. Bijlsma has disclosed receiving consultancy fees from Nitec, and Dr. Jacobs has disclosed no relevant financial relationships.

Clinical Context

Glucocorticoids have considerable benefits for inflammatory conditions, but there are potential serious adverse effects that lead to recommendations to use the lowest dose necessary. To optimize treatment outcomes, a modified-release system was developed that releases prednisone about 4 hours after ingestion to allow adaptation to the circadian rhythm of endogenous cortisol and symptoms of RA by preventing the proinflammatory impulse of cytokines in the morning. Early morning stiffness is a disabling and common symptom in patients with RA.

This study is a multicenter, double-blind, randomized controlled trial to compare the effect of modified-release vs standard prednisone on morning stiffness in patients with RA with significant morning stiffness, conducted at 17 centers in Germany and 12 centers in Poland.

Study Highlights

• Included were 288 patients with RA by the American College of Rheumatology criteria; active inflammatory component with 45 minutes or longer average duration of morning stiffness; maximum pain intensity of 30 mm or more on a 0- to 100-mm visual analog scale (VAS; 0 = no pain; 100 = maximal pain); and erythrocyte sedimentation rate (ESR) of 28 mm or higher or C-reactive protein 1.5 times or higher than normal.
• Patients had to have received prednisone for at least 3 months with stable dose of 2.5 to 10 mg daily for at least 1 month and disease-modifying rheumatic drugs for at least 3 months.
• Excluded were those taking biological agents within 4 months or who had renal or hepatic impairment or other significant diseases.
• 144 were randomized to modified-release and 144 to standard prednisone for 12 weeks after a run-in of 2 weeks, using a double-dummy technique. A dose of usual prednisone was maintained.
• Doses were given at 0600 to 0800 hours and once at bedtime at 2200 hours.
• Visits were conducted at weeks 0 (baseline), 2, 6, and 12, and patients completed a daily diary.
• The diary documented time of awakening, medication intake, joint stiffness duration, sleep quality, intensity on VAS (0 mm = very good to 100 mm = very bad), use of analgesics in the prior 24 hours, and recurrence of stiffness in the daytime.
• The 28-joint disease activity score (DAS28) was assessed at each visit for 28 joints with the global patient assessment of disease activity, short-form 36, health status using the health assessment questionnaire, ESR, C-reactive protein, and IL-6 levels.
• Primary outcome was relative change in duration of morning stiffness.
• Secondary outcomes were recurrence of joint stiffness, pain intensity, sleep quality, and DAS28.
• Mean age was 55 years, 86% were women, 99% were white, mean duration of morning stiffness at baseline was 164 minutes, mean pain score was 58 mm on VAS, 61% had duration of 5 or more years of RA, and the mean stable daily dose of prednisone was 6.5 mg.
• 87% completed the study with the most common reason for dropout being adverse events.
• Mean duration of therapy was 83 days in both groups.
• Modified-release prednisone was linked with significantly greater reduction in duration of morning stiffness vs immediate-release prednisone (reduction of 44 minutes vs baseline).
• The absolute difference between treatment groups was 29.2 minutes.
• Improvement in morning stiffness duration was evident after 2 weeks with 10% difference and increased to 38% difference from week 7 to 12.
• Other secondary variables were similar between the groups with no difference seen for ESR and C-reactive protein but significantly lower IL-6 level for the modified-release group at week 12 (P = .02).
• Adverse events were reported in 41% of both groups with one third attributable to the medications.
• Worsening of RA was the most common, followed by upper abdominal pain, nasopharyngitis, headache, flushing, and nausea.
• 8% and 7% of those in the modified- and immediate-release groups, respectively, experienced premature discontinuation.
• Only 1 serious adverse effect (depressed consciousness) was attributable to medication and occurred in a patient taking the immediate-release prednisone.

Pearls for Practice

• Modified-release prednisone vs immediate-release prednisone therapy for 12 weeks is associated with shorter duration of morning stiffness in patients with RA.
• Adverse effect profile is similar for modified-release compared with immediate-release prednisone for 12 weeks.

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Exposure to Environmental Tobacco Smoke in Infancy Linked to Allergic Reactions

Children exposed to environmental tobacco smoke in early infancy have a higher incidence of allergic reactions to food and indoor inhalants, according to the results of a prospective birth cohort study

“Exposure to environmental tobacco smoke (ETS) increases the risk of respiratory illness in children but data are inconclusive regarding the risk of IgE [immunoglobulin E] sensitisation,” write Dr. Eva Lannerö, from the Institute of Environmental Medicine, Karolinska Institutet in Stockholm, Sweden, and colleagues. “In the present study, we aimed to assess the separate roles of smoke exposure in utero and postnatally for IgE sensitisation to important inhalant and food allergens at 4 years of age.”

Family members completed questionnaires on environmental factors and symptoms of allergic disease for 4089 children when the children were 2 months, 1, 2, and 4 years old. In a subset of 2614 children, blood was collected at age 4 years and was analyzed for IgE antibodies to common inhalant and food allergens. Logistic regression with adjustments for potential confounders was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs).

Maternal smoking during pregnancy did not seem to be associated with the risk for IgE sensitization. In contrast, there was a dose–response effect for ETS exposure from parental smoking during the child’s first few months of life and IgE sensitization. Children exposed to ETS at 2 months of age had an increased risk for sensitization to inhalant and food allergens (adjusted OR, 1.28; 95% CI, 1.01 – 1.62), especially for cat dander (adjusted OR, 1.96; 95% CI, 1.28 – 2.99) and for food allergens (adjusted OR, 1.46; 95% CI, 1.11 – 1.93). The IgE-sensitizing effect of ETS seemed to be restricted to infants of parents who did not have allergic diseases and to ETS exposure during early infancy.

Limitations of the study include difficulty in distinguishing the effects of tobacco exposure in utero and postnatally; reliance on questionnaire data on children at age 2 months; possible disease-related or recall bias, or both; lack of objective assessments of smoke exposure; and possible uncontrolled confounding.

“Our data indicate that exposure in early infancy to ETS increases the risk of IgE sensitisation to indoor inhalant and food allergens,” the study authors write. “The finding of dose–response relationships supports the interpretation of causality…. These effects may be of great clinical relevance as sensitisation is important for incident asthma among children and adults.”

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REVIEW OF ADVERSE EFFECT PROFILE, SAFETY, AND DOSING OF ANTIDEPRESSANTS

In 2002, 8.5% of the US population purchased at least one prescription antidepressant.¹ Given this relatively high rate of antidepressant use, best practices should be followed in choosing the correct medication and dosing, to avoid adverse events or ineffective treatment.

Two of the major classes of antidepressants that are more commonly prescribed are the selective serotonin reuptake inhibitors (SSRIs) and the tricyclic antidepressants (TCAs). The SSRIs are generally the antidepressants of first choice. They are relatively safe and effective. The Cochrane Collaboration reviewed 32 well-conducted trials and found SSRIs to be just as effective as TCAs with fewer adverse effects in the elderly population.² In the inpatient population, TCAs appear to be slightly more effective than SSRIs, but TCAs were noted to have decreased tolerability.³ Given the popularity and tolerability of SSRIs, this review focuses mainly on this group of antidepressants and also touches on some of the newer unique antidepressants.

ADVERSE EFFECT PROFILE OF ANTIDEPRESSANTS

Most medications in the SSRI class are well tolerated. The 2 most frequently reported adverse effects are gastrointestinal distress and sexual adverse effects. Gastrointestinal distress can be seen at the beginning of therapy and with dose increases, but over time this category of adverse effects tends to decrease. On the other hand, sexual dysfunction due to the blockade of specific serotonin receptors (the common mechanism of action of most of the drugs in this class of antidepressants), namely the 5-HT_1b, 5-HT_2a, and 5-HT_2c receptors, is of particular concern for the long-term compliance with these antidepressant medications for patients. This concern is exacerbated by an already high underlying prevalence of sexual dysfunction in patients with depression. Authors have estimated that 30-70% of patients with depression have sexual dysfunction that can be attributed to various causes, including the depression itself, other related medical or psychiatric conditions, or deterioration of social relationships.⁴

Patients taking bupropion have been reported to experience the least amount of sexual dysfunction compared to other commonly used antidepressants, with 22-25% of patients still reporting difficulties compared to rates in the 40% range for other medications especially in the SSRI class.⁴ Strategies for addressing sexual dysfunction may include augmentation with bupropion, drug holidays, decreasing dose, changing medications, adding medications intended to treat erectile dysfunction, and waiting for tolerance.

Other common adverse effects are pronounced in specific medications. Citalopram, for example has the greatest risk of somnolence, weight gain, memory impairment, and sexual dysfunction. This is secondary to citalopram’s affinity for histamine receptors.⁵ Paroxetine has the greatest risk of anticholinergic adverse effects, which may include dry mouth, constipation, dizziness, tachycardia, blurred vision, and urinary retention. A recent adverse effect that has come to light with SSRIs is an increase in bleeding risk, mainly upper gastrointestinal bleeding. Those at highest risk are the elderly and those who have had previous gastrointestinal bleeding.⁶

Another common adverse effect seen with SSRIs and selective serotonin and norepinephrine reuptake inhibitors (SSNRIs) is discontinuation syndrome, which occurs when the medication is stopped suddenly and consists of symptoms such as gastrointestinal distress, influenza-like symptoms, sensory disturbances (eg, electric shocks), and psychological symptoms of depressed mood and anxiety. Of all the SSRIs and SSNRIs, discontinuation syndrome is most frequently reported with paroxetine and venlafaxine. Many authors believe this adverse effect is secondary to the shorter half-life of these medications. However, multiple cases of discontinuation syndrome have also been reported with fluoxetine. In the case of fluoxetine, the discontinuation syndrome appears to be delayed, which may be a result of the medication’s longer half-life. Discontinuation syndrome has also been noted in neonates whose mothers have been taking SSRIs or SSNRIs.

Sleep can also be affected by antidepressants. As a general rule, SSRIs tend to have alerting effects and decrease sleep efficiency. Bupropion also can cause sleep disturbances. However, the newer antidepressant mirtazapine can increase sleep efficiency.

Mirtazapine, a noradrenergic and serotonergic antidepressant, has a unique tolerability and adverse-effect profile. On the positive side, multiple studies suggest that sexual dysfunction may be lower with mirtazapine than with SSRIs or SSNRIs. However, the main adverse effect with mirtazapine is weight gain. This adverse event may be overstated; one long-term study showed only an average gain of 3.3 kg with mirtazapine compared to a 2.7 kg weight gain with placebo.⁷ That said, SSRIs have also been implemented in weight gain during long-term therapy.

SAFETY OF ANTIDEPRESSANTS The role antidepressants have in self-harming behaviors is both complex and controversial. Antidepressants now carry a black box warning from the US Food and Drug Administration (FDA) for use in children, adolescents, and young adults. Yet, multiple epidemiological studies suggest that antidepressants can decrease suicide and suicidal behavior. One study found that the rate of teenage suicide rose as the number of prescriptions fell.8 While associations are not causations, certainly this new research points to the need for more clarification. Appropriate medication therapy should not be withheld from younger patients, but appropriate consent should be obtained following a detailed discussion of risks and benefits. In the cases of mild depression, psychotherapy and other modalities should be tried first. Until recently, monoamine oxidase inhibitors (MAOIs) have generally fallen out of favor with practitioners given their dietary restrictions and drug interactions. However, the selegiline transdermal system has decreased some of these risks; at the lowest dose, the MAOI diet does not need to be followed with this therapy.9 Generally, SSRIs are relatively safe in overdose, which is in sharp contrast to TCAs. Nevertheless, at least a theoretical risk remains of cardiotoxicity secondary to active metabolites. For example, citalopram has an active metabolite, didesmethylcitalopram, which can prolong the QT interval. Limited research regarding the safety of mirtazapine overdose exists, although overdose deaths have been reported when mirtazapine is used in combination with TCAs. Furthermore, rare cases of bone-marrow suppression have been reported with mirtazapine.10 Duloxetine was approved by the FDA in 2004. Duloxetine is an SSNRI that shows equal serotonin and norepinephrine reuptake inhibition at all doses. Both of the SSNRIs venlafaxine and duloxetine increase blood pressure, and, at least in the case of venlafaxine, hypertensive crisis has been reported.5 While all antidepressants (with the possible exception of escitalopram) have case reports of hepatotoxicity, this risk is slightly greater with duloxetine.

DOSING OF ANTIDEPRESSANTS

The goal in prescribing antidepressants is to quickly relieve symptoms at the lowest possible dose and with a minimum of adverse effects. As a general rule, to minimize the chance of dose-dependent adverse effects, the prescribing physician should start with the lowest effective dose and then titrate upward until the therapeutic goals are achieved. This strategy is especially important with certain classes of antidepressants that have significant adverse effects, such as the TCAs. However, a strategy of titration is not without risk; an unduly slow titration can cause a delay in reaching therapeutic effectiveness and can increase the risk of patient discontinuation for other reasons (ie, if the medication is determined to be ineffective by the patient). Note that many antidepressants are available in lower doses to help with titration and that lower doses may also be necessary in the case of concomitant medical illness.

Citalopram’s efficacy can start at 20 mg, but, generally, 40 mg per day is the effective dosage, and it can be titrated up to 60 mg per day. Patient with more severe symptoms will generally require higher doses. Fluoxetine has similar dosing guidelines. As a general rule, the maximum recommended dosage of paroxetine is 50 mg per day, though many patients respond with dosages as low as 20 mg per day. The lowest effective dosage for sertraline is 50 mg per day, and the maximum daily dose is 200 mg. The reference dose of duloxetine is 60 mg daily, but acceptable dosages range from 40-120 mg per day.¹¹ While duloxetine is generally well tolerated, adverse events such as gastrointestinal distress tend to cause a higher discontinuation rate in comparison to other antidepressants. For this reason, duloxetine can be started at a dose as low as 30 mg and titrated. For venlafaxine, a “standard” dose is approximately 150 mg and “high” dose is 300 mg a day.⁷ Venlafaxine is generally given in the extended-release formulation and not the immediate-release formulation for dosing convenience and to minimize the risk of gastrointestinal side effects.

The treatment of depression continues to evolve, with an increasing number of treatment options available. Even as medication choices increase, physicians should keep in mind that all medications carry risks that must be weighed against the risk of not treating symptoms.

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Warfarin vs Aspirin in Atrial Fibrillation — New Perspectives

Introduction Stroke is one of the most significant risks associated with atrial fibrillation, yet many patients with an indication for poststroke warfarin therapy do not receive this treatment. In part, this is because of uncertainty regarding the balance of risks and benefits of warfarin therapy, especially in high-risk populations. A recent meta-analysis and randomized trial provide new insights into this issue. Commentary Approximately 2.2 million people in the United States have atrial fibrillation. It is a common problem that increases in prevalence as patients grow older — from 2.3% among adults over age 40 to 5.9% among people older than 65 years, with the median age being 75. There does not appear to be a predilection based on gender, although the absolute number of women older than 75 with atrial fibrillation exceeds the number of men at those ages. Atrial fibrillation is the most common cause of cardioembolic stroke. The current meta-analysis suggests that the annual risk for stroke among patients with atrial fibrillation and no history of anticoagulation or prior cerebrovascular disease is between 2.5% and 4%. A recent systematic review found that the risk for stroke in the setting of atrial fibrillation was most significantly elevated by a history of prior stroke or transient ischemic attack. Other factors that increased the risk for stroke in patients with atrial fibrillation were advanced age and a history of hypertension or diabetes mellitus. However, female sex and a history of heart failure or coronary artery disease were not conclusively linked with an increased risk for stroke. Current guidelines recommend warfarin adjusted to achieve an international normalized ratio (INR) between 2 and 3 to prevent stroke among patients with atrial fibrillation and a history of prior cerebrovascular disease, prosthetic heart valve, or mitral stenosis.Warfarin therapy should also be considered for patients age 75 or over and those with hypertension, diabetes, heart failure, or a documented left ventricular ejection fraction of less than 35%. Other patients with atrial fibrillation may receive aspirin for stroke prevention. There is evidence that many patients with atrial fibrillation do not receive their recommended treatment. In a study of 405 patients with atrial fibrillation, only 51% were discharged from the hospital with a prescription for warfarin, and fewer than half of patients over age 80 received warfarin. This phenomenon may be in part the result of previous reviews of randomized controlled trials that questioned whether anticoagulation provides a significant clinical benefit compared with antiplatelet therapy for patients with atrial fibrillation. A meta-analysis of 5 studies of patients with nonrheumatic atrial fibrillation found no benefit of anticoagulation with warfarin vs all antiplatelet therapy in terms of overall mortality or death resulting from stroke. The 32% reduction in the risk for nonfatal stroke in the warfarin vs antiplatelet treatment groups was of borderline statistical significance, and this result was not significant when a trial with weak methodology was excluded. Moreover, warfarin was associated with a nonsignificant 45% increase in the risk of major bleeding events vs antiplatelet therapy. Another review that limited its meta-analysis to treatment with warfarin vs aspirin for patients with atrial fibrillation found a more robust protective effect against stroke with warfarin, which also produced superior results for all cardiovascular outcomes. The difference is that the other meta-analysis examined all antiplatelet therapy, not just aspirin. However, warfarin also increased the risk of major bleeding vs aspirin, meaning that for every 1000 patients with atrial fibrillation treated with warfarin instead of aspirin, 23 additional ischemic strokes would be prevented at the cost of 9 additional cases of major bleeding. The current meta-analysis of warfarin vs antiplatelet therapy includes data from 8 trials involving a total of 9598 patients with atrial fibrillation. Six trials used aspirin as the antiplatelet agent, and 1 trial used dual antiplatelet therapy with aspirin and clopidogrel. The dose of aspirin ranged between 75 mg and 325 mg daily. The minimal target INR for warfarin therapy was 1.5, and 6 trials reported that at least 50% of their study cohort achieved the target INR. Treatment with warfarin reduced the risk of all strokes by 32% compared with antiplatelet therapy (P = .0007). This means that 13 additional strokes would be prevented by treating 1000 patients with warfarin instead of antiplatelet agents for 1 year. Warfarin also reduced the risk of ischemic stroke by nearly half compared with antiplatelet therapy. Warfarin was not superior to antiplatelet therapy in terms of prevention of disabling or fatal strokes or vascular death. Overall rates of mortality were also similar between the 2 treatments. However, warfarin reduced the risk of myocardial infarction by 31% compared with antiplatelet therapy (P = .06). There were 41 intracranial hemorrhages reported during the trials, and warfarin increased the risk of hemorrhage by 98% compared with antiplatelet treatment. Although older adults bear the greatest risk for stroke in atrial fibrillation, the choice for stroke prevention in this important patient group has not been as scrutinized as it has among younger patients. The authors of the Birmingham Atrial Fibrillation Treatment of the Aged Study (BAFTA) note that the average age in previous studies of stroke prevention among patients with atrial fibrillation is 69 years. Therefore, they compared warfarin and aspirin therapy among patients age 75 or older. The trial recruited patients from 260 general practices in England and Wales. A total of 973 patients with atrial fibrillation and no risk factors for major bleeding were randomized in an open-label design to receive either aspirin 75 mg daily or warfarin; the target INR range was 2 to 3. The primary study outcome was the combined rate of stroke, intracranial hemorrhage, and clinically significant arterial embolism. The average age of study subjects was 81.5 years, and 20% of participants were at least 85 years old. There was a history of stroke or transient ischemic attack in 12% of participants, and similar proportions of patients in the 2 treatment groups were receiving aspirin or warfarin at baseline. The average follow-up time for study outcomes was 2.7 years. One third of patients randomized to receive warfarin stopped taking it, and the remaining patients were in the target INR range two thirds of the time. The use of blood pressure and lipid-lowering medications was similar between treatment groups. Warfarin reduced the rate of the combined primary outcome by 52% compared with aspirin. Warfarin was as effective in the primary outcome among patients at age 85 or older as it was in younger patients and was also more effective when examining patient subgroups based on gender, previous history of stroke, or baseline risk of stroke. At the same time, warfarin was not more effective than aspirin in the prevention of nonstroke vascular events or overall mortality rates. A surprising finding was that there was no significant increase in the risk of major hemorrhage with warfarin vs aspirin therapy. However, the confidence intervals in this finding were wide, suggesting that a larger patient cohort or greater adherence to randomized therapy could have demonstrated a significant difference between treatments. The researchers also note that their target INR was lower than in previous studies, which could also account for lower rates of hemorrhage among participants receiving warfarin. Reducing the risk of stroke is one of the most important aspects of caring for patients with atrial fibrillation, and improvements in therapy beyond anticoagulation or antiplatelet therapy may have lessened the risk for stroke over the last decade. In BAFTA, the annual rate of stroke among patients with at least a moderate baseline risk was 3.3%, which compared favorably with a predicted rate of 9.9% based on previous reports. In addition, a recent trial of clopidogrel plus aspirin vs warfarin for stroke prevention among patients with atrial fibrillation and at least 1 other risk factor for stroke also found a lower than expected rate of vascular events, with an annual rate of stroke of 3.93% in the warfarin arm of the trial. This trial was stopped early because of the apparent superiority of warfarin compared with aspirin plus clopidogrel in vascular outcomes. Whereas the risk of stroke and vascular events among patients with atrial fibrillation may be decreasing, the risk of mortality among patients with this condition appears to be stagnant. In a study that followed a cohort of patients with atrial fibrillation in a Minnesota community, the risk of mortality was essentially unchanged between 1980 and 2000. During the first 4 months after diagnosis with atrial fibrillation, the mean hazard ratio of overall mortality was 9.62 when comparing patients with atrial fibrillation vs age- and gender-matched control subjects without atrial fibrillation, and this risk fell to 1.66 thereafter. Could greater adherence to recommendations for warfarin therapy in atrial fibrillation improve the rate of mortality associated with this condition? The current articles do not find a direct mortality benefit of warfarin vs antiplatelet treatment, but it would be reasonable to believe that greater adherence to guidelines among thousands of patients could reduce not only the rate of stroke in atrial fibrillation, but also the death rate. Physicians should consider this possibility when evaluating patients with atrial fibrillation.

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