Daniel E. Singer, MD; Yuchiao Chang, PhD; Margaret C. Fang, MD, MPH; Leila H. Borowsky, MPH; Niela K. Pomernacki, RD; Natalia Udaltsova, PhD; Alan S. Go, MD
Grant Support: By the National Institute on Aging (R01 AG15478); the National Heart, Lung, and Blood Institute (U19 HL091179); and the Eliot B. and Edith C. Shoolman fund of the Massachusetts General Hospital. Dr. Fang's efforts were also partially supported by the National Institute on Aging (K23 AG28978).
Potential Financial Conflicts of Interest:Consultancies: D.E. Singer (Boehringer Ingelheim, Bayer, AstraZeneca, Sanofi-Aventis, Daiichi Sankyo, Johnson & Johnson). Honoraria: D.E. Singer (Bristol-Myers Squibb, Pfizer). Grants received: D.E. Singer (Daiichi Sankyo), A.S. Go (Johnson & Johnson).
Reproducible Research Statement:Study protocol and statistical code: Available from Dr. Singer (e-mail, email@example.com). Data set: Not available.
Requests for Single Reprints: Daniel E. Singer, MD, Clinical Epidemiology Unit, Massachusetts General Hospital, 50 Staniford Street, 9th Floor, Boston, MA 02114; e-mail, firstname.lastname@example.org.
Current Author Addresses: Drs. Singer and Chang and Ms. Borowsky: Clinical Epidemiology Unit, Massachusetts General Hospital, 50 Staniford Street, 9th Floor, Boston, MA 02114.
Dr. Fang: University of California, San Francisco, 505 Parnassus Avenue, Box 0131, San Francisco, CA 94143.
Ms. Pomernacki and Drs. Udaltsova and Go: Division of Research, Kaiser Permanente of Northern California, 2000 Broadway Street, Oakland, CA 94612-2304.
Author Contributions: Conception and design: D.E. Singer, Y. Chang, M.C. Fang, A.S. Go.
Analysis and interpretation of the data: D.E. Singer, Y. Chang, M.C. Fang, L.H. Borowsky, N.K. Pomernacki, N. Udaltsova, A.S. Go.
Drafting of the article: D.E. Singer.
Critical revision of the article for important intellectual content: D.E. Singer, Y. Chang, M.C. Fang, L.H. Borowsky, A.S. Go.
Final approval of the article: D.E. Singer, Y. Chang, M.C. Fang, L.H. Borowsky, N.K. Pomernacki, N. Udaltsova, A.S. Go.
Provision of study materials or patients: A.S. Go.
Statistical expertise: D.E. Singer, Y. Chang.
Obtaining of funding: D.E. Singer, A.S. Go.
Administrative, technical, or logistic support: D.E. Singer, L.H. Borowsky, N.K. Pomernacki, A.S. Go.
Collection and assembly of data: D.E. Singer, M.C. Fang, N. Udaltsova, A.S. Go.
Singer D., Chang Y., Fang M., Borowsky L., Pomernacki N., Udaltsova N., Go A.; The Net Clinical Benefit of Warfarin Anticoagulation in Atrial Fibrillation. Ann Intern Med. 2009;151:297-305. doi: 10.7326/0003-4819-151-5-200909010-00003
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Published: Ann Intern Med. 2009;151(5):297-305.
Guidelines recommend warfarin use in patients with atrial fibrillation solely on the basis of risk for ischemic stroke without antithrombotic therapy. These guidelines rely on ischemic stroke rates observed in older trials and do not explicitly account for increased risk for hemorrhage.
To quantify the net clinical benefit of warfarin therapy in a cohort of patients with atrial fibrillation.
Mixed retrospective and prospective cohort study of patients with atrial fibrillation between 1996 and 2003.
An integrated health care delivery system.
13Â 559 adults with nonvalvular atrial fibrillation.
Warfarin exposure, patient characteristics, CHADS2 score (1 point for each of congestive heart failure, hypertension, age, and diabetes and 2 points for stroke), and outcome events were ascertained from health plan records and databases. Net clinical benefit was defined as the annual rate of ischemic strokes and systemic emboli prevented by warfarin minus intracranial hemorrhages attributable to warfarin, multiplied by an impact weight. The base-case impact weight was 1.5, reflecting the greater clinical impact of intracranial hemorrhage versus thromboembolism.
Patients accumulated more than 66Â 000 person-years of follow-up. The adjusted net clinical benefit of warfarin for the cohort overall was 0.68% per year (95% CI, 0.34% to 0.87%). Adjusted net clinical benefit was greatest for patients with a history of ischemic stroke (2.48% per year [CI, 0.75% to 4.22%]) and for those 85 years or older (2.34% per year [CI, 1.29% to 3.30%]). The net clinical benefit of warfarin increased from essentially zero in CHADS2 stroke risk categories 0 and 1 to 2.22% per year (CI, 0.58% to 3.75%) in CHADS2 categories 4 to 6. The patterns of results were preserved when weighting factors for intracranial hemorrhage of 1.0 and 2.0 were used.
Residual confounding is a possibility. Some outcome events were probably missed by the screening algorithm or when medical records were unavailable.
Expected net clinical benefit of warfarin therapy is highest among patients with the highest untreated risk for stroke, which includes the oldest age category. Risk assessment that incorporates both risk for thromboembolism and risk for intracranial hemorrhage provides a more quantitatively informed basis for the decision on antithrombotic therapy in patients with atrial fibrillation.
National Institute on Aging; National Heart, Lung, and Blood Institute; and Massachusetts General Hospital.
Hua Chiew Hospital. Bangkok 10100. Thailand
September 1, 2009
Valvular and nonvalvular atrial fibrillation
I read with interest the article by Singer and colleagues. (1) The purpose of the study is to evaluate the benefit of warfarin therapy in patients with nonvalvular atrial fibrillation. The authors use ICD-9-CM code 427.31 to identify patients with atrial fibrillation. However, ICD-9- CM code 427.31 includes both valvular and nonvalvular atrial fibrillation. No further investigations such as echocardiography have been made to exclude valvular atrial fibrillation from their databases.
1. Singer DE, Chang Y, Fang MC, Borowsky LH, Pomernacki NK, Udaltsova N, Go AS. The net clinical benefit of warfarin anticoagulation in atrial fibrillation. Ann Intern Med. 2009; 151: 297-305.
James L. Meisel
Boston University School of Medicine
September 8, 2009
Singer et al have further validated the benefit of anticoagulation with adjusted-dose warfarin for populations at high risk for thromboembolic stroke due to nonvalular atrial fibrillation (1,2). Increased net clinical benefit may accrue to older patients, those with a history of ischemic stroke or TIA and those with CHADS2 scores of 2 or more (3).
The mnemonic "CHADS2 (85x2)" may help clinicians recall the thrust of the latest research (3,4,5). In this adaptation, age>=85, like a history of ischemic stroke or TIA, would be given a double point value. Thus age>=85 alone would raise a patient's CHADS2 score to 2, i.e., into the high risk zone. Age 75-84, like a history of congestive heart failure, hypertension and diabetes mellitus, would remain less potent but validated risk factors.
Weighing the probable benefit of stroke prevention against bleeding risk, especially in the elderly, remains an important part of individualized decision-making. This is especially true since "CHADS2 (85x2)", while at the moment a logical tool to help physicians decide who should receive chronic anticoagulation, has not been independently validated and is partially dependent upon a large, well done but nonrandomized observational assessment (3).
1. Singer DE, Albers GW, Dalen JE, Fang MC, Go AS, Halperin JL, et al; American College of Chest Physicians. Antithrombotic therapy in atrial fibrillation: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133:546S-592S.
2. Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA. 2001;285:2864-70.
3. Singer DE, Chang Y, Fang MC, Borowsky LH, Pomernacki NK, Udaltsova N, et al. The net clinical benefit of warfarin anticoagulation in atrial fibrillation. Ann Intern Med. 2009;151:297-305.
4. van Walraven C, Hart RG, Connolly S, Austin PC, Mant J, Hobbs FD, et al. Effect of age on stroke prevention therapy in patients with atrial fibrillation: the atrial fibrillation investigators. Stroke. 2009 Apr;40:1410-6.
5. Mant J, Hobbs FD, Fletcher K, Roalfe A, Fitzmaurice D, Lip GY, et al; BAFTA investigators. Warfarin versus aspirin for stroke prevention in an elderly community population with atrial fibrillation (the Birmingham Atrial Fibrillation Treatment of the Aged Study, BAFTA): a randomised controlled trial. Lancet. 2007;370:493-503.
The University of Texas at Austin and the University of Texas Health Science Center at San Antonio
September 10, 2009
Net clinical benefit of warfarin in atrial fibrillation
Calculating net clinical benefit of warfarin therapy in atrial fibrillation is an important concept (1,2). Three other issues, however, should be considered in the future:
First, warfarin therapy affects other major events and may substantially reduce myocardial infarction and death (3).
Second, because INR control varies in different settings, and because a 10% improvement in INR time in the therapeutic range (TTR) has been associated with a greater than 10% reduction in event rates (3,4), the relationship between INR control and event rates needs to be more thoroughly defined if one is going to be able to determine how INR control may affect the net clinical benefit in his/her own setting. Veeger, et al. found that the bottom quartile of approximately 4,000 patients was in range only 10 to 20% of the time and accounted for more than half of the major events (5). Jones, et al found that the bottom quartile of 2,223 patients was in range only about 28% of the time (4). Further, since event rates increase exponentially as the INR moves further out of range, being slightly out of the target range may have little impact, while being at the extremes (1.5 > INR > 5) may carry a very high risk. Therefore, one needs to know what the event rates were when the INR was within the target range, TTR +/- 0.3 INR units, below an INR of 1.5 and above an INR of 5.0 if one is going to estimate the net clinical benefit in his/her own setting.
Third, one needs to consider how evolving methods to improve INR control may alter the net clinical benefit. As noted by Hart and Halperin, the TTR of 65% reported by Singer, et al is often considered "high"(2). By combining INR self-testing and computer management, however, Harper, et al reported an 80% TTR with no INRs > 5 (6). An interim analysis of our similar study found a TTR of 78.9% that increased to 94% when the range was expanded slightly by +/- 0.3 INR units (7). Approximate TTR values were 90% for the top quartile and 60% for the lowest quartile, and percent time > 5 or < 1.5 was only 0.27%. Such improved INR control is estimated to yield a 30 to 50% reduction in both thromboembolic and major bleeding events compared to "typical" management; changes that should have a substantial impact on the net clinical benefit of warfarin.
1. Singer DE, Chang Y, Fang MC, et al. The net clinical benefit of warfarin anticoagulation in atrial fibrillation. Annals of Internal Medicine 2009; 151:297-305.
2. Hart RG and Halperin JL. Do current guidelines result in overuse of warfarin anticoagulation in patients with atrial fibrillation? Annals of Internal Medicine 2009; 151:355-356.
3. White HD, Gruber M, Feyzi J, Kaatx S, et al. Comparison of outcomes among patients randomized to warfarin therapy according to anticoagulant control: results from SPORTIF III and V. Archives of Internal Medicine 2007; 167:239-245.
4. Jones M, McEwan P, Morgan CL, Peters JR, Goodfellow J, Currie CJ. Evaluation of the pattern of treatment, level of anticoagulation control, and outcome of treatment with warfarin in patients with non-valvar atrial fibrillation: a record linkage study in a large British population. Heart 2005; 91:472-477.
5. Veeger NJGM, Piersma-Wichers M, Hillege HL, Crijns HJGM, van Der Meer J. Early detection of patients with a poor response to vitamin K antagonists: the clinical impact of individual time within target range in patients with heart disease. Journal of Thrombosis and Haemostasis 2006; 4:1625-1627.
6. Harper PL and Pollock D. Anticoagulation self-management using near patient testing and decision support software provided via an Internet Website improved anticoagulation control in patients on long-term warfarin. Blood 2008; 112: Abstract 278.
7. Bussey HI, Walker MB, Bussey-Smith KL, Frei CR. Interim analysis of triple intervention to improve International Normalized Ratio (INR) in warfarin-treated patients. (abstract PP-MO-469) International Society of Thrombosis and Haemostasis Congress, July, 2009 (online at http://isth2009.com/abstract_submission.html)
consultant on ClotFree management system, co-owner of patent on 3 vitamin K antagonists, stock holder HemoSense (Inverness Medical)
Douglas D Edwards
UCSF School of Pharmacy
September 21, 2009
Nonfatal major stroke may be worse than death
The weighting factors used for intracranial hemorrhages (ICH) in the calculation of net clinical benefit do not adequately reflect existing knowledge about patient preferences, and particularly about individual differences in preference. Regrettably, the authors write as though net clinical benefit could meaningfully direct treatment decisions in the absence of preference information, or as though the relevant preferences were obvious and likely to be constant across patients, neither of which is the case.
An ICH weight of 1.5 (relative to thromboembolism) was used in the main analysis, on the basis that intracerebral hemorrhages (a subcategory of ICH) are especially likely to be fatal compared to ischemic stroke, with ICH weights of 1 and 2 used in the sensitivity analysis(1). On the other hand, empirical studies of the perceived utility of major stroke have shown that substantial fractions of patients (>40% in some studies) view a nonfatal major stroke as literally worse than death, and even the averaged utility over all patients may be worse than that of death(2-4). For this reason, ICH weights less than 1 should have been taken seriously and included in the sensitivity analysis. Also, the variance in patient preferences in these empirical studies was very high, underscoring the importance of eliciting patient preferences in clinical practice.
I am likewise concerned that the authors' presentation of this study, even with the admission that it was not randomly sampled, may in practice give aid and comfort to the use of risk evaluation scoring methods like the CHADS2 score for the purpose of defensive medicine. A recent study from this same ATRIA study group has shown that such risk evaluation scoring methods are only moderately better than chance when used to predict thromboembolism in patients not being treated with warfarin(5). The major problem with warfarin therapy is still underuse, not overuse, even in cases where it is uncontroversially indicated(6). Bleeds due to warfarin overuse are much easier to trace to the physician than ischemic strokes due to underuse.
Preference information regarding warfarin therapy and stroke, particularly major stroke, should be elicited from every patient with diagnosed atrial fibrillation, regardless of any risk evaluation score. Only with that information in hand should clinical decisions be made. Risk evaluation scores alone should never be used to rule out warfarin therapy.
1. Singer DE, Chang Y, Fang MC, Borowsky LH, Pomernacki NK, Udaltsova N, Go AS. The net clinical benefit of warfarin anticoagulation in atrial fibrillation. Ann Intern Med. 2009 Sep 1;151(5):297-305.
2. Gage BF, Cardinalli AB, Owens DK. The effect of stroke and stroke prophylaxis with aspirin or warfarin on quality of life. Arch Intern Med. 1996 Sep 9;156(16):1829-1836.
3. Samsa GP, Matchar DB, Goldstein LB, Bonito A, Duncan PW, Lipscomb J, Enarson C, Witter D, Venus P, Paul JE, Weinberger M. Utilities for major stroke: results from a survey of preferences among persons at increased risk for stroke. Am Heart J. 1998 Oct;136(4 Pt 1):703-713.
4. Post PN, Stiggelbout AM, Wakker PP. The utility of health states after stroke: a systematic review of the literature. Stroke. 2001 Jun;32(6):1425-1429.
5. Fang MC, Go AS, Chang Y, Borowsky L, Pomernacki NK, Singer DE. Comparison of risk stratification schemes to predict thromboembolism in people with nonvalvular atrial fibrillation. J Am Coll Cardiol. 2008 Feb 26;51(8):810-815.
6. Lewis WR, Fonarow GC, LaBresh KA, Cannon CP, Pan W, Super DM, Sorof SA, Schwamm LH. Differential use of warfarin for secondary stroke prevention in patients with various types of atrial fibrillation. Am J Cardiol. 2009 Jan 15;103(2):227-231.
I am involved in a dispute involving student academic freedom with regard to the expression of opinions related to those expressed in this letter. None of the authors of any of the articles cited are parties to this dispute.
Lincoln Medical Center
October 1, 2009
In Response: The Net Clinical Benefit of Warfarin Antocoagulation in Atrial Fibrillation
Current guidelines from the ACC/AHA (American College of Cardiology/American Heart Association) recommend that warfarin be given to patients with atrial fibrillation on the basis of stroke risk. This strategy maximizes stroke reduction only if the effect of warfarin is uniform across all risk factors. Singer et al (1) present data that suggest otherwise. Their subgroup analysis found that men and women with atrial fibrillation have markedly different relative risk reductions (RRR) when treated with warfarin (adjusted RRR ~34% in men vs. 55% in women). Formal testing for treatment by covariate interaction (not reported by the authors) might confirm that benefit of warfarin significantly differs in different subgroups of patients. Although female gender is not currently considered an indication for warfarin, the data generate a hypothesis that certain patient subgroups may reap greater benefit from warfarin therapy than other subgroups. The presence of hypertension supports the use of warfarin by current guidelines, but subgroup analysis shows little, if any, additional benefit in hypertensives than non-hypertensives (absolute stroke reduction with warfarin of 1.11 per 100 person years in patients with hypertension vs. 0.95 in patients without hypertension). An optimal strategy for stroke reduction in patients with atrial fibrillation should not be based on factors that imply a high risk of stroke (as recommended by current guidelines), but rather the factors that imply a greater benefit of treatment.
1. Singer DE, Chang Y, Fang MC, Borowsky LH, Pomernacki NK, Udaltsova N, et al. The Net Clinical Benefit of Warfarin Anticoagulation in Atrial Fibrillation. Ann Intern Med. 2009;151:297-305. [PMID: 19721017]
October 20, 2009
Interesting findings in this study
With regards to the article published oin volume 151, Page 297, about anticoagulation (1), it caught our attention because of how low the incidence of hemorrhagic events was in the assessed population. According to our experience, we are under the impression that the major hemorrhagic complications that occur in patients with Atrial Fibrilation are more frequent than the numbers presented in this study, because these patients often have several comorbidities (2,3). We were wondering if this difference could be due to the selection of cases that was made. The patients with the worse clinical conditions probably didnÂ´t receive Warfarin (such as patients with liver failure, cognitive deficits, etc). That could have easily happened, since the study was a cohort. We would like to have a response from the authors.
1. Singer DE, Chang Y, Fang MC, Borowsky LH, Pomernacki NK, Udaltsova N, Go AS. The net clinical benefit os warfarin anticoagulation in atrial fibrillation. Ann Intern Med. 2009; 151:297-305.
2. Risk factors and efficacy of antithrombotic therapy in atrial fibrillation. Analysis of pooled data from Five randomized controlled Trial. Arch Inter Med. 1994;154:1449-57. [PMID: 8018000]
3. Go AS, Hylek EM, Borowsky LH, Phillips KA, Selby JV, Singer DE. Warfarin use among laboratory patients with nonvalvular atrial fibrillation: the anticoagulation and risk factors in atrial fibrillation (ATRIA) study. Ann Intern Med. 1999; 131:927-34. [ PMID: 10610643]
Daniel E. Singer
Massachusetts General Hospital
October 29, 2009
Improving the Net Clinical Benefit of Warfarin Anticoagulation for Atrial Fibrillation
We support Bussey's emphasis on the importance of maximizing 'time in therapeutic range (TTR).' The benefits and risks of warfarin therapy in atrial fibrillation are strongly dependent on maintaining the international normalized ratio (INR) in the optimal range (1, 2). That is why we reported the overall TTR, 65%, for our ATRIA cohort (3). At lower TTR values, the expected net clinical benefit will be lower and at higher TTR values, the net clinical benefit will increase regardless of clinical risk category as long as the distribution of out-of-range values does not change markedly. As pointed out, having more extreme out-of-range low or high INR values will have a strong negative effect on the net benefit conferred by any given level of TTR. It is remarkable that warfarin's striking efficacy has been demonstrated in studies where the INR was in range only ~two-thirds of the time (e.g., in the BAFTA trial (4)). It is clear that substantially higher overall TTR levels can currently be achieved in selected populations (2). More widespread use of organized anticoagulation management services, INR self-testing, improved dosing algorithms, and possibly employing genetic testing for warfarin sensitivity all have the potential for more widespread improvement in TTR levels and increased net clinical benefit in patients with atrial fibrillation.
The final sentence in Budhraja's letter aptly summarizes the motivation for our paper (3). To generate an optimal estimate of the adjusted absolute net benefit of warfarin therapy, we allowed the effect of warfarin to vary by patient subgroup in our models, independent of the statistical significance of any individual interaction term. In fact, most of the interaction terms were not statistically significant and, except for the lowest stroke risk categories, the interaction effects were small. Before firmly concluding that the relative risk reduction conferred by warfarin differs in any specific subgroup, such effect modification should be confirmed in other large databases, in particular those from randomized trials.
As Budhraja notes, ischemic stroke risk off warfarin is only one determinant of net clinical benefit. But, it is a very important determinant. Unfortunately, current risk stratification schemes for patients with AF have very limited accuracy (5). Future research should emphasize improved risk prediction in AF. Better risk prediction will facilitate achieving increased net benefit of warfarin both at the population and the individual patient levels.
1. Singer DE, Chang Y, Fang MC, Borowsky LH, Pomernacki NK, Udaltsova N, Go AS. Should patient characteristics influence target anticoagulation intensity for stroke prevention in nonvalvular atrial fibrillation: The ATRIA Study. Circulation Cardiovascular Qual Outcomes. 2009;2:297-304.
2. Connolly SJ, Pogue J, Eikelboom J, Flaker G, Commerford P, Franzosi MG, et al; ACTIVE W Investigators. Benefit of oral anticoagulant over antiplatelet therapy in atrial fibrillation depends on the quality of international normalized ratio control achieved by centers and countries as measured by time in therapeutic range. Circulation. 2008;118:2029-37. [PMID: 18955670]
3. Singer DE, Chang Y, Fang MC, Borowsky LH, Pomernacki NK, Udaltsova N, Go AS.The net clinical benefit of warfarin anticoagulation in atrial fibrillation. Ann Intern Med. 2009 Sep 1;151(5):297-305. [PMID: 19721017]
4. Mant J, Hobbs FD, Fletcher K, Roalfe A, Fitzmaurice D, Lip GY, Murray E; BAFTA investigators; Midland Research Practices Network (MidReC). Warfarin versus aspirin for stroke prevention in an elderly community population with atrial fibrillation (the Birmingham Atrial Fibrillation Treatment of the Aged Study, BAFTA): a randomised controlled trial.Lancet. 2007 Aug 11;370(9586):493-503. [PMID: 17693178]
5. Fang MC, Go AS, Chang Y, Borowsky L, Pomernacki NK, Singer DE; ATRIA Study Group. Comparison of risk stratification schemes to predict thromboembolism in people with nonvalvular atrial fibrillation. J Am Coll Cardiol. 2008;51:810-5. [PMID: 18294564]
Consultancies: D.E. Singer: AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Johnson & Johnson, Merck, Sanofi-Aventis. Honoraria: D.E. Singer: Bristol-Myers Squibb, Pfizer. Grants received: D.E. Singer: Daiichi Sankyo A.S. Go: Johnson & Johnson
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