Treatment of Chronic Nonvalvular Atrial Fibrillation in the Elderly: A Decision Analysis I. GARY

NAGLIE, MD, ALLAN S. DETSKY, MD, PhD

The

objective of the study was to determine the preferred treatment strategy for elderly patients with chronic nonvalvular atrial fibrillation (CNVAF). A Markov decision-analytic model was used to compare three treatment strategies for CNVAF: 1) warfarin; 2) aspirin; and 3) no treatment. Five-year quality-adjusted life years (QALYs) were calculated for male and female cohorts aged 70 and 75 years. In the baseline analysis (effectiveness of warfarin 0.70, effectiveness of aspirin 0.45, utility of warfarin 0.99, and utility of aspirin 0.999) the quality-adjusted survival rates for 70-year-old males were 4.03 QALYs on warfarin, 4.02 QALYs on aspirin, and 3.95 QALYs on no treatment. Results were similar for all age and sex cohorts. Sensitivity analyses revealed that the results were very sensitive to the effectiveness of aspirin and the disutility of warfarin. The authors conclude that the optimal strategy for the treatment of CNVAF in elderly patients varies with the disutility assigned to warfarin therapy and the effectiveness value for aspirin therapy. Key words: chronic atrial fibrillation; elderly; anticoagulation; warfarin; aspirin; decision analysis; Markov analysis; quality of life. (Med Decis Making 1992;12:239-249) =

=

=

=

Atrial fibrillation, an arrhythmia common in the general population, is most often associated with nonvalvular heart disease.1-4 Data from the Framingham study’ demonstrate that: 1) the incidence of chronic nonvalvular atrial fibrillation (CNVAF) increases steadily with age after the sixth decade of life; 2) individuals who have CNVAF carry about a fivefold increased risk of stroke; and 3) of those individuals with CNVAF, the elderly have the highest incidence of stroke. Therefore, one may conclude that among individuals with CNVAF, the elderly may benefit most from therapy to prevent thromboembolic complications. Four reported randomized trials have studied the effectiveness of warfarin versus aspirin and/or placebo in reducing the incidence of stroke in subjects with CNVAF: 1) the Copenhagen AFASAK Study’; 2) the American multicenter Stroke Prevention in Atrial Fibrillation (SPAF) StUdy7 ; 3) the Boston Area Randomized Trial of Anticoagulation in Atrial Fibrillation (BAATAF)’; and 4) the Canadian Atrial Fibrillation An-

ticoagulation

(CAFA) trial.9 These trials provide inforimportant factors that are relevant decisions pertaining to CNVAF:

mation about three to treatment

1. THE EFFECTIVENESS OF TREATMENTS

All the trials indicated that warfarin effectively reduces the incidence of strokes in individuals with CNVAF. The effectiveness of aspirin remains controversial, as trial results are conflicting. If aspirin is effective in reducing stroke events, it is probably less effective than warfarin.

2. BLEEDING SIDE EFFECTS

Treatment with warfarin

somewhat lesser lead to bleeding degree, aspirin most related to these complications. Although bleeding treatments is not life-threatening and does not result in permanent morbidity, major extracranial and intracranial bleeds and fatal bleeds do occur. treatment

with

and,

to

a

can

Received June 27, 1991, from the Division of General Internal

Medicine, Geriatric Medicine, and Clinical Epidemiology, The To-

3. DISUTILITY OF TREATMENTS

Hospital; Clinical Epidemiology Unit, The Toronto Hospital; and Departments of Medicine and Health Administration, University of Toronto, Toronto, Ontario, Canada. Revision accepted for pubronto

Warfarin therapy and, to a lesser extent, aspirin therapy, may lead to lifestyle changes and mild side effects that are associated with a diminution of quality of life (referred to in this report as the disutility of the medications). The randomized trials provide data regarding the benefits and disadvantages of the various treatment options in a disaggregate fashion, and they do not provide a summary conclusion as to which is the bet-

lication December 12, 1991. Presented in part at the American Federation for Clinical Research annual meeting, May 5, 1991, in Seattle, Washington. Dr. Naglie was supported by an Ontario Ministry of Health Research Personnel Development Program Fellowship (02448) and Dr. Detsky was supported by a National Health Research Scholar Award From Health and Welfare Canada (6606-2849-48). Address correspondence and reprint requests to Dr. Naglie: the Toronto Hospital, General Division, 200 Elizabeth Street, EN G-238, Toronto, Ontario M5G 2C4, Canada.

239

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240

strategy when all factors

taken into particularly subgroups of patients in which the stroke risks, bleeding risks, and/or medication disutilities may differ. For example, if a subgroup of individuals consider the lifestyle changes associated with taking warfarin to be particularly onerous, they may opt for a less effective treatment that is more acceptable to them. We performed a decision analysis to quantify the net benefits of warfarin therapy, aspirin therapy, and no treatment for elderly patients with CNVAF. This analysis, which incorporated the effectiveness of each treatment, the bleeding complications associated with it, and its disutility, indicates which treatment strategy is preferable. The analysis can be used to assist with treatment decisions for specific patient subgroups simply by modifying the values of certain variables so that they fit the specifications of the subgroups. ter treatment

account. This is

are

true for

(depicted as a node containing an &dquo;M&dquo;). Figure displays the Markov health states for the subtrees depicting the three treatment strategies. The health subtree

1B

states are:

1. WELL-the state for

adverse event (stroke

all

or

patients

who have had

no

bleed) and the initial state for

patients. 2.

(one

STROKE SHORT-TERM MORBIDITY-a

for

cycle)

patients

temporary

who have survived

a

state

stroke.

3. STROKE-WELL-the state for patients who have had nonfatal stroke that has resolved to the extent that it has left no residual functional disability. a

4.

had

DISABLED-the state for patients who have nonfatal stroke that has resulted in a permanent

STROKE a

disability. 5.

(one

BLEED SHORT-TERM MORBIDITY-a

cycle)

for

patients

temporary

who have survived

a

state

bleed.

Methods A decision-analytic model was constructed to describe the possible outcomes of the three treatment strategies for elderly patients with CNVAF: 1) warfarin therapy; 2) initial treatment with aspirin, with a switch to warfarin in the event of a stroke (aspirin strategy); and 3) no initial treatment, with the initiation of warfarin therapy in the event of a stroke (no-treatment strategy) (figs. 1-3). Outcomes, expressed in terms of five-year quality-adjusted survival, were assessed for males and females aged 70 and 75 years at the starting point of the analysis. Markov subtrees were used to model the chance events associated with the three treatment strategies, since Markov modeling is particularly useful in depicting the natural history of chronic diseases, especially those that involve events, such as embolic strokes, that may occur repeatedly and at any point over a long period of time.lo.’1 Each Markov subtree considers a hypothetical cohorts of patients who all begin in the same health state (the WELL state) and who are followed for a defined period of time during which they can change states of health. In the primary analysis, patients were followed for five years. This relatively short follow-up period was chosen because we did not want to extrapolate results over a long time horizon when many of the variables were derived from studies with short follow-up periods.

The Decision Model The initial treatment decision for patients who have CNVAF is a choice between treatment with warfarin or with aspirin, or no treatment. Figure 1A shows the square decision node that represents the choice among the three treatment options. The chance events related to each treatment choice are represented by a Markov

FIGURE 1.

The decision tree. A, treatment

states for individual treatment

Markov

cycle.

Downloaded from mdm.sagepub.com at UCSF LIBRARY & CKM on March 20, 2015

options. B, Markov health options. C, chance events during each

241

1-----

6. BLEED-WELL-the state for patients who have had nonfatal major bleed that has resolved and has left no residual functional disability.

and who experience a stroke are switched to warfarin in the next cycle according to recommendations by the American College of Chest Physicians.3,12 Patients on warfarin or aspirin who experience a major bleed are transferred to no treatment in the next cycle according to common clinical practice. Several assumptions were made in developing this

a

7.

had

DISABLED-the state for patients who have nonfatal major bleed that has resulted in a per-

BLEED

a

manent functional

disability.

8. STROKE-BLEED DISABLED-the state for patients who have had both a nonfatal stroke and a nonfatal major bleed and who are left with a permanent functional

disability.

10. DEAD-the absorbing state that includes patients who have died from strokes, major bleeds, and

age-sex-specific

=

decision-analytic model, including: refer only to major bleeds, defined as those which are intracranial or retroperitoneal or that lead directly to hospitalization, transfusion, or death. Minor bleeds are considered only indirectly as part of the disutility of being on 1.

Bleeding complications

which

9. STROKE-BLEED WELL-the state for patients who have had both a nonfatal stroke and a nonfatal major bleed, but who are left with no functional disability.

’

I

FIGURE 3.

=

’

---..

The bleed subtree. *The Markov state for the start of the next cycle for disabled bleed survivors depends on the health state short-term morbidity. prior to the bleed event. STM

The stroke subtree. *The Markov state for the start of the next cycle for disabled stroke survivors depends on the health state short-term morbidity. prior to the stroke event. STM FIGURE 2.

anticoagulant

Figures 1C, 2, and 3 demonstrate a set of subtrees that represent the chance adverse events for patients during each Markov cycle. In these figures, the terminal (rectangular) nodes represent the health states in which the patients begin the next cycle. All patients, regardless of treatment option (warfarin, aspirin, or no treatment), begin the Markov process in the WELL state. The hypothetical Markov cohorts are then followed through 60 cycles, each of one-month duration. During each cycle patients may die of age-sex-specific causes (fig. 1C). If they survive, they may have a stroke or a bleed or may remain event-free. A patient who does not have an adverse event during a cycle remains in the same state in which he or she began the cycle. Stroke and bleed events may be fatal (DEAD) or nonfatal (figs. 2 and 3). Those who have a nonfatal event will either be disabled long-term or will have no longterm functional deficit. Those with no long-term disability proceed to a short-term morbidity health state for one cycle prior to entering a well state (STROKEWELL or BLEED-WELL). Patients who are on aspirin or no treatment who have had no previous major bleed

or

aspirin therapy.

embolic events other than strokes are account for about 90% of embolic events and for the major morbidity and mortality associated with CNVAF . 6-9,13,14 2.

not

causes.

are

Systemic

considered, since strokes

3. For patients who have experienced a stroke, warfarin is assumed to be as effective in preventing further strokes as it is in preventing initial stroke events. (No currently available data specifically address this issue.)

4. Stroke outcomes (death, long-term disability) are assumed to be the same for all three treatment strategies since available data are insufficient to determine whether patients on warfarin or aspirin who go on to have a stroke have better outcomes than do patients who have a stroke on no treatment. 5. Patients who

a stroke are assumed for another stroke (2 X baseline)15-18 and patients who experience a bleed are assumed to be at increased risk for another bleed (1.5

experience

to be at increased risk

x

baseline).19 6. Patients disabled from

stroke or bleed who ex(stroke or bleed) are assumed to be at increased risk of dying from the second event (1.5 x baseline). Patients who have had two

perience

a

subsequent

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a

event

242

TIN 1

Probability and Utility Values for Baseline Analysis

0

disabling to

die if

(stroke

events

(strokes and/or bleeds)

they experience

or

a

are

assumed

subsequent major

event

bleed).

Probabilities and UUlities (Table 1) Probability values for the transitions between Markov health states were based on values from the medical literature. For the purpose of the Markov analysis, stroke and bleeding rates were converted to probabilities using the following expression: p(t) 1 el-rtJ, where p(t) is the probability of an event’s occurring over a time interval t, r is the rate, and e is the exponential.&dquo; The sources for the values used in the baseline analysis are described below.

studies have reported that patients with CNVAF who have a nonfatal stroke are at increased risk for another stroke?5-18 For the baseline analysis, the probability of stroke recurrence was considered to be double the probability of an initial stroke (literature range; one to four times the baseline probability of an initial stroke). The risk of dying of a stroke in the Framingham study,23 as measured by the 30-day case fatality rate, was 17% for those with CNVAF. The overall risks of dying of a stroke in the AFASAK, SPAF, and BAATAF studies were 22%, 10%, and 8%, respectively. Two retrospective reviews of hospitalized patients with stroke and CNVAF16,24 reported fatal strokes in 31% and 38% of patients. For the baseline analysis, the probability of dying from a stroke was considered to be 20% (literature range; 8% -38% ). In the AFASAK trial, of the 28 nonfatal strokes, 15 were disabling (53.6%) and 13 (46.4%) were nondisabling. In the SPAF study, of the 60 nonfatal strokes, 28 (42%) were moderately to severely disabling and 38 (58%) were minimally disabling. In the BAATAF study, of the 14 nonfatal strokes, eight (57%) resulted in no functional disability and six (43%) were disabling. In a retrospective review of 74 nonfatal strokes in patients with atrial fibrillation,24 43 (58%) were disabling and 31 (42%) were nondisabling. For the baseline analysis, the probability of being disabled from a nonfatal stroke was considered to be 45% (literature range: 42% -58%). 2. EFFECTIVENESS OF WARFARIN AND

EFFECTIVENESS OF ASPIRIN

=

1. STROKE EVENTS AND OUTCOMES

Several clinical and epidemiologic studies have assessed the incidence of stroke in patients with CNV AF .5.20-24 The Framingham study’ found that the age-specific stroke incidence rates in persons with CNVAF were: 1) 60-69 years old, 2.1% per year; 2) 7079 years old, 4.9% per year; and 3) 80-89 years old, 7.2% per year. The Whitehall study of London civil servantS2’ noted that the stroke incidence in CNVAF

patients 60-69 years of age was 2.7% per year. The Japanese study22 reported a 5% per year incidence of stroke in patients with atrial fibrillation. The placebo group in the AFASAK study6had a mean age of 74.6 years and a stroke incidence of 5.0% per year. The placebo group in the SPAF study7 had a mean age of 66.6 years and a stroke incidence of 5.7% per year. The placebo group in the BAATAF study$ had a mean age of 67.5 years and a stroke incidence of 2.98% per year. A

yearly stroke incidence of 5% was chosen for the analysis (literature range: 2.7%-7.2%). Several

baseline

Values for the effectivenesses of warfarin and aspirin reducing the risk of stroke were derived from the randomized trials of patients with CNVAF 6-9 The AFASAK, SPAF, and BAATAF studies found 69%, 67%o, and 86% risk reductions of stroke events with warfarin, respectively (risk reduction = 1 - [probability of stroke on treatment - probability of stroke on placebo]). The CAFA study was stopped prior to completion because of the positive results from the AFASAK and SPAF trials. At the termination of the trial, a 56% risk reduction in stroke events was noted for patients on warfarin. The AFASAK and SPAF studies also randomized patients to an aspirin arm. In the AFASAK trial, patients in the aspirin arm of the study received 75 mg once a day, and no risk reduction of stroke events was found compared with placebo. In the SPAF study, patients randomized to aspirin treatment received 325 mg once a day and a 45% risk reduction in stroke events was noted (95% confidence interval: 9% -63% ). The BAATAF trial did not include an aspirin group to which patients were randomized, but control patients were not discouraged from taking aspirin if they wished to. An analysis of control patients taking aspirin suggested that aspirin did not confer any benefit over placebo. For the baseline analysis, warfarin was considered to be 70% effective in reducing stroke events in

Downloaded from mdm.sagepub.com at UCSF LIBRARY & CKM on March 20, 2015

243

(literature range: 56% -86% ). The effectiveness of

as-

remains in

pirin question in view of the conflicting trial results. For the baseline analysis we considered aspirin to be 45% effective in reducing stroke events, based on data from the SPAF trial. Because of the uncertainty surrounding this value, a sensitivity analysis was performed over a wide range of values for this variable (0-63% l. 3. BLEEDING EVENTS AND OUTCOMES

The reported rates of bleeding complications associated with long-term anticoagulant therapy vary widely. In a review on this subject, Levine et al .25 idenrandomized trials of anticoagulation in patients with myocardial infarction that provided sufficient information to calculate bleeding rates. The rates of major bleeds in these studies varied between 0 and

tified five

7.9% per year. In the AFASAK

trial, 21 of 335 patients on warfarin withdrawn because of bleeding complications, and one patient had a fatal intracerebral bleed. Only one of the bleeding complications was severe enough to necessitate blood transfusion. If we assume that only the bleed necessitating transfusion and the intracranial bleed were major bleeds, the bleeding rate was 0.8% per year, with a 50% case fatality rate. In the aspirin group, two of 336 patients were withdrawn for

were

bleeding complications, neither of which were major bleeds. There was no reported bleeding complication in the placebo group. In the SPAF trial, major bleeds occurred at a rate of 1.5% per year in patients assigned to warfarin., 1.4% per year in patients assigned to aspirin, and 1.9% per year in patients assigned to placebo. The case fatality

considered to be 1.0% per year (literature range: 02.0% per year). The major bleeding rate on no treatment was assigned a value of 0.8% per year (literature range: 0-1.9% per year). The probability of dying from a major bleed was considered to be 15% based on the review by Levine et ale and the CNVAF randomized trials’-9 (literature range: 0-50%). Based on data from the SPAF study, the probability of being disabled from a major bleed was estimated to be 7% (literature range: 0-15%). 4. AGE-SEX-SPECIFIC MORTALITY AND

DISEASE-SPECIFIC MORTALITY

The

age-sex-specific mortalities were

derived from

1980-1982 Canadian life tables.28 A baseline

analysis

carried out using mortality values for males and females aged 70 and 75 years of age at the start of the analysis. These mortality figures were then adjusted for the excess mortality associated with CNVAF. A study by Gajewski and Singer2’ provides data on the agespecific excess mortality associated with CNVAF. In patients 60 years of age or older, the annual excess death rate was 3.2% in those with a significant associated condition (coronary heart disease, hypertension, mitral stenosis, other) and 2.5% in those with no significant associated condition. For the baseline analysis the disease-specific excess mortality was estimated at 3.0% per year. Since the decision model considers deaths from strokes and bleeds as well as diseasespecific excess mortality, there is a possibility that some deaths may have been double-counted. Therefore, the analysis was repeated using a wide range of values for the excess mortality associated with CNVAF (range: 04%). was

for bleeds were 14% on placebo, 20% on aspirin, and 25% on warfarin. In the CAFA study, major bleeds occurred at rates of 2.5% per year in patients randomized to warfarin and 0.5% per year in patients randomized to placebo. In the BAATAF study, major bleeds (as defined in our study) occurred at rates of 1.6% per year in patients assigned to warfarin therapy and 1.8% per year in patients assigned to the control group. The case fatality rate for major bleeds was 12.5% in both the warfarin and the control groups. If one considers only the most severe bleeds (intracranial, requiring four or more units of blood within 48 hours or fatal), the rate was double in the warfarin versus the control group

The outcome measure used in this analysis is fiveyear survival adjusted for quality of life (quality-adQALYs). Each Markov health state justed life years is associated with an assigned utility value between zero and one. The utility that is associated with spending one cycle in a given state is referred to as the incremental utility. The utility accrued for the entire Markov process is calculated by multiplying the total number of cycles spent in each state by the incremental utility of each state. The Markov model, therefore, yields a patient’s prognosis in terms of quality-

(0.4% versus 0.2% per year). For the baseline analysis the major bleeding rate on warfarin was considered to be 1.6% per year (literature range: 0.8% -2.5% per yearl. This relatively low bleeding rate probably relates to the tendency to use lower doses of war-farin than in the past. Recent studies suggest that the risk of bleeding on warfarin can be markedly reduced by using a less intense anticoagulation regimen.2h,27 ’I’he major bleeding rate on aspirin was

survival. The utility values chosen for this analysis represent the consensus of three internists. Considering the literature on quality of life after stroke,30-33 we assigned a utility of 0.5 for disabling strokes. Since the vast majority of disabling bleeding events are caused by intracranial bleeds, we also assigned a utility of 0.5 for bleeds resulting in long-term disability. For strokes and bleeds that result in only short-term morbidity, a

rates

5. UTILITY VALUES

=

adjusted

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244

Table 2 .

Five-Year Quality-adjusted Survival for Baseline Analysis*

present the sensitivity analyses for only one group, 70-

year-old

males.

Results

*QALYs

=

Table 3 0

quality-adjusted

life years; M

=

male; F

male; F

=

female.

Five-Year Quality-adjusted Survival When One Assumes No Disutility Associated with Warfarin and Aspirin Treatments*

*Utility of taking warfarin/aspirin M

=

=

=

1.0. QALYs

=

quality-adjusted life years;

female.

The five-year- quality-adjusted survivals for males and females aged 70 and 75 years old are summarized in table 2. Using the baseline values for the probabilities and utilities (table 1), warfarin and aspirin strategies yield almost identical quality-adjusted survivals for all patient cohorts. Both warfarin. and aspirin strategies are preferable to the no-treatment strategy for all patient groups. Comparing warfarin therapy with no treatment: 1) the net gain for 70-year-old patients is 0.08 QALY for men and women (a 2.0% increase in quality-adjusted survival for men and a 1.9% increase for women); and 2) the net gain for 75-year-old patients is 0.07 QALY for men and women (a 1.9% increase in quality-adjusted survival for men and a 1.7% increase for women). Comparing aspirin therapy with no treatment : 1) the net

utility value period after

of 0.75 was assigned for the one-month the stroke (i.e., one week deducted from overall survival). Taking medications can diminish the quality of life because of side effects of the medications as well as required lifestyle changes. Patients who are on warfarin therapy must subject themselves to frequent blood sampling, must avoid activities that can predispose them to bleeds, and may be susceptible to minor bleeding events (bruising, epistaxis, hematuria, hemoptysis). Torrance&dquo; estimated that the utility value associated with taking antihypertensive therapy is in the range between 0.95-0.99. Weinstein and Stason35 assigned a utility of 0.99 to antihypertensive therapy. We chose a utility value of 0.99 for warfarin therapy (estimated range: 0.95-1.0). Once-daily aspirin therapy (325 mg) is generally well tolerated, but can occasionally result in some gastrointestinal upset or minor bleeding problem. Since we considered the side effects of once-daily aspirin to be significantly less than those of antihypertensive medications or warfarin, we assigned a utility value of 0.999 to aspirin therapy (estimated range: 0.985-1.0).

CALCULATIONS

Tree design and analysis were done on a Compaq XT computer using the SMLTREE decision analysis software (James P. Hollenberg, New York, New York).

The decision was analyzed at baseline for male and female subjects with CNVAF aged 70 and 75 years at the starting point of the analysis. Sensitivity analyses were carried out for all patient cohorts, but because of the similarity of the results for all the cohorts, we

gain for 70-year-old patients is 0.07 for men and 0.08 QALY for women (a 1.8% inQALY crease in quality-adjusted survival for men and a 1.9% increase for women); and, 2) the net gain for 75-yearold patients is 0.06 QALY for men and 0.07 QALY for women (a 1.6% increase in quality-adjusted survival for men and a 1.7% increase for women). Because of the controversy associated with assigning utility values of less than 1.0 to warfarin. and aspirin therapies (0.99 and 0.999, respectively), the analysis was repeated using utility values of 1.0 for both warfarin and aspirin treatments (table 3). When it is assumed that there is no disutility associated with the treatments themselves, the results are similar for all patient cohorts, with warfarin therapy being the preferable strategy. When warfarin is compared with aspirin, the net gain in quality-adjusted survival is 0.030.04 QALY (range across both ages and both sexes), a 0.7% -1.0% increase in quality-adjusted survival). When warfarin is compared to no treatment, the net gain in quality-adjusted survival with warfarin is 0.10-0.12 QALY, a 2.7% -2.9% increase in quality-adjusted survival. When aspirin is compared with no treatment, aspirin therapy is the preferable strategy, with a net gain in qualityadjusted survival of 0.07-0.08 QALY, a 1.8% -2.0% increase in quality-adjusted survival. Table 4 considers the expected outcomes for the different treatment strategies using the baseline variables (table 1), but extending the time horizon of the analysis over the life expectancy of the patients (adjusted for the presence of CNVAF). Based on the Framingham data,’ the stroke rate for patients 80 years of age or older was considered to be 7%/year. When warfarin is compared with aspirin, warfarin results in a net gain of 0.01-0.10 QALY (range across both ages and both sexes), a 0.23%-1.2% increase in qualityadjusted life expectancy (QALE). When warfarin is

I

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245

Table 4 . Quality-adjusted Baseline

Life

justed survival was 3.80 QALYs on warfarin, 4.12 QALYs on aspirin, and 4.07 QALYs on no treatment. Relative to warfarin, aspirin increased quality-adjusted survival

Expectancy for

Analysis*

by

8.4% and no treatment increased

quality-adjusted by 7.1%. Sensitivity analyses were carried out on the baseline analysis to determine how stable the results of the survival

’QALYs

=

quality-adjusted

life years; M

=

male; F

=

female.

compared with no treatment, warfarin results in a net gain of 0.09-0.41 QALY, a 2.1% -5.2% increase in QALE. When aspirin is compared with no treatment, aspirin results in a net gain of 0.08-0.31 QALY, a 1.9% -3.9% increase in QALE. In comparison with the results of the primary analysis (table 2), warfarin is slightly preferable to aspirin, and the increases in quality-adjusted survival with warfarin and aspirin versus no treatment are greater. These differences are most pronounced for the patient group with the longest life expectancy (i.e., 70-year-old women). Best-case and worst-case scenarios were developed for the warfarin strategy. The best-case scenario was created by choosing probability and utility values that would maximize the expected outcome with warfarin treatment relative to the other treatment strategies (table 5). Aspirin was considered to be ineffective and the risk of bleeding on warfarin was considered to be relatively low and equal to the bleeding risk on aspirin and no treatment. For the best-case scenario (70-yearold man), the quality-adjusted survival was 4.11 QALYs on warfarin and 3.89 QALYs on aspirin and no treatment (a 5.7% increase in quality-adjusted survival with warfarin). The worst-case scenario was created by choosing the probability and utility values that would minimize the expected outcome with warfarin treatment relative to the other treatment strategies (table 5). For this scenario (70-year-old man) the quality-ad-

Table 1 e

Threshold Values for Comparisons Between Treatment

*Threshold values for each variable t

=

no

were

sought over the

threshold value found between 0 and 1.0; N/A

=

model are when one or several of the baseline variables are changed. All variables were varied over a wide range of values. Because the results were similar for both sexes and all ages, we describe only the results for 70year-old males. Table 6 summarizes the baseline values for variables in the analysis and the threshold values for the variables when comparisons are made between the different treatment strategies (warfarin versus aspirin, warfarin versus no treatment, and aspirin versus no treatment). A threshold value represents the value of a variable for which the quality-adjusted survival is the same for the two treatment options being compared (with all other variables in the analysis maintained at

Table 5 o

Strategies*

range between 0 and 1.0. p not

Values for Best- and Worst-case Scenarios for Warfarin

=

the

probability of

a

variable;

applicable.

Downloaded from mdm.sagepub.com at UCSF LIBRARY & CKM on March 20, 2015

u

=

the

utility of a variable.

246

their baseline values). For all values above/below the threshold value, one of the strategies is favored over the other. For example, if one considers a comparison between warfarin and no treatment, the threshold value for the yearly stroke rate is 1.6% per year. For all yearly stroke rates greater than 1.6% per year the analysis favors the warfarin strategy, while for all yearly stroke rates less than 1.6% per year the analysis favors the no-treatment

strategy.

When warfarin is compared with aspirin therapy in the baseline analysis, the results are essentially identical (4.03 versus 4.02 QALYs), suggesting that a decision between these treatment strategies is a &dquo;toss-up.&dquo; Since the outcomes for these treatment options are so similar, the results are sensitive to changes in virtually all the variables in the analysis. Relatively small changes &dquo;

in most of the variables can push the analysis to favor either aspirin or warfarin treatment. In contrast, the results of the comparisons of warfarin with no treatment and aspirin with no treatment are quite stable over a wide range of values for most of the variables in the analysis. In the comparison between warfarin therapy and no treatment, the results are sensitive to four variables: stroke rate, warfarin effectiveness, major bleed rate on warfarin, and utility of warfarin therapy. However, the threshold values for all of these variables, except for the utility of

warfarin therapy, are outside the literature ranges for these variables. Therefore, the results comparing warfarin with no treatment are exclusively sensitive to the utility value assigned to warfarin therapy. In the comparison between aspirin and no treatment, the results

FIGURE 5. One-way sensitivity analysis of the effectiveness of aspirin. QALYs quality-adjusted life years. =

Downloaded from mdm.sagepub.com at UCSF LIBRARY & CKM on March 20, 2015

247

sensitive to four variables: aspirin effectiveness, stroke rate, major bleed rate on aspirin, and utility of aspirin therapy. The threshold values for all these variables, except for the effectiveness of aspirin, are outside the likely ranges for these variables. Therefore, the results comparing aspirin with no treatment are sensitive only to the value assigned to the effectiveness of are

aspirin. The results of the analysis are stable over a wide range of values assigned to the excess mortality associated with CNVAF (0-5%). The results are also stable over a wide range of values for the probability of having a recurrent stroke or bleed (1-5 times the probability of having an initial stroke or bleed). The results are not sensitive to the utility values assigned for a disabling stroke and a disabling bleed. Figure 4 is a one-way sensitivity analysis of the utility of warfarin therapy. This analysis considers the outcomes (in QALYs) for the three treatment strategies over a range of values for the utility of warfarin, while all other variables are maintained at their baseline values. The graph demonstrates that the analysis is very sensitive to the value assigned to the utility of warfarin treatment for values between 0.95 and 1.0. Over this range of values the outcome varies to the extent of making warfarin the least favored strategy to making it the most favored strategy. Figure 5 is a one-way sensitivity analysis of the effectiveness of aspirin in reducing the incidence of stroke events. If aspirin is ineffective, as suggested by the AFASAK trial, aspirin treatment is the least favored strategy. If, on the other hand, aspirin is more than 46% effective (the upper 95% confidence interval in SPAF study was 63%), aspirin therapy becomes the

preferable treatment option. Figure 6 is a three-way sensitivity analysis that

con-

siders the combined effects of three variables (effec-

tiveness of aspirin, effectiveness of warfarin, and utility of warfarin) when warfarin therapy is compared with aspirin therapy. Each point that falls on a line represents a threshold value, such that the quality-adjusted survival is the same for patients treated with warfarin and those treated with aspirin. The region that falls above a chosen line represents the area in which aspirin treatment is the better strategy. The region below a chosen line represents the area in which warfarin is the preferable treatment option. For example, if warfarin is 70% effective and the utility of being on warfarin therapy is 0.99 (baseline values), initial aspirin treatment is the better strategy for all aspirin effectiveness values above 46%. This graph clearly demonstrates the marked influence the utility value of warfarin therapy has on the outcome of the analysis. If warfarin is 70% effective, for warfarin utility values of 0.97, 0.98, and 1.0, aspirin is the preferable treatment for all aspirin effectiveness values above 4%, 25%, and

67%,

respectively.

Diseussion For many years physicians have struggled with the decision of whether or not to anticoagulate elderly patients who have CNVAF. Four recent randomized trials6-9 have provided some answers, but have also

raised some new questions. All four studies suggest that anticoagulation therapy is effective in preventing strokes in patients with CNVAF, but controversy remains as to whether aspirin is more effective than placebo. In this paper we have considered three treatment strategies for elderly patients with CNVAF: 1) treatment with warfarin; 2) initial treatment with aspirin, with a switch to warfarin if the patient has a stroke; and 3) no initial treatment, with the initiation of warfarin therapy if the patient has a stroke.

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analysis reveals that the decision beand aspirin is a &dquo;toss-up&dquo; (if we assume that the stroke risk reduction with aspirin is 45%) and that both the warfarin and aspirin strategies are preferable to no treatment (table 2). When the time horizon of the analysis is extended over the lifetime of the patient rather than over five years (table 4), the QALE is slightly longer with warfarin versus aspirin, but significantly longer with warfarin versus no treatment. Our results comparing the QALE with warfarin versus no treatment are very similar to those of Beck and Pauker,36 who designed a Markov analysis to assess the role of anticoagulation in the management of atrial fibrillation and the tachycardia-bradycardia syndrome. For a 70-year-old woman, our results demonstrate a 5.2% increase in QALE on warfarin therapy and their results indicate a 5.6% increase in QALE on The baseline

tween warfarin

anticoagulation. The results of the analysis are very sensitive to the value assigned to the effectiveness of aspirin therapy in reducing the incidence of strokes (fig. 5) and to the value assigned to the utility of warfarin treatment (figs. 4 and 6). The results of the randomized trials regarding the effectiveness of aspirin are contradictory, suggesting a range of effectiveness from 0 (AFASAK) to as high as 63% (SPAF upper 95% confidence interval). Over this range of values the results of the analysis vary from the extreme of aspirin’s being the worst strategy to the extreme of aspirin’s being the best strategy. Further information about the effectiveness of aspirin from other studies is required before definitive answers can be reached regarding the role of aspirin therapy in the treatment of CNVAF. The analysis underscores the importance of considering the effects that treatments themselves can have on quality of life. Warfarin therapy necessitates frequent physician visits, numerous blood tests, and an alteration in lifestyle. Patients on warfarin treatment have increased susceptibility to minor and major bleeding events and must live with this ever-present risk. These negative aspects of warfarin therapy may be partially balanced by the awareness that warfarin is effective in reducing embolic events. The knowledge that warfarin is effective in reducing stroke events, however, may influence some patients to remain on warfarin therapy despite what they perceive to be significant disruption to their quality of life related to taking the medication. To date no published study has actually measured the utility of being on warfarin. Torrance estimated the utility of being on antihypertensive therapy to be between 0.95 and 0.99,34 and Weinstein and Stason35 assigned a utility value of 0.99 to being on antihypertensive therapy. The baseline value we assigned to the utility of being on warfarin therapy was 0.99, assuming that the qualify of life on warfarin therapy is less than the quality of life of being in perfect health (utility of 1.0). The utility value of 0.99 suggests that, on average,

patients would be willing to give up 1% of their lives (18 days over a five-year period) in order to avoid taking warfarin treatment. In comparing warfarin with aspirin, the threshold value for the utility of being on warfarin treatment is 0.989 (table 6), with values lower than this favoring the aspirin strategy. In comparing warfarin with no treatment, the threshold value is 0.970, with values lower than this favoring the no-initial-treatment option. These threshold values are within the narrow range of values (0.95-0.99) Torrance suggested for the utility of being on antihypertensive medications.34 Graphs of the oneway sensitivity analysis of the utility of being on warfarin therapy (fig. 4) and the three-way sensitivity analysis of the effectiveness of warfarin, the effectiveness of aspirin, and the utility of being on warfarin treatment (fig. 6) further demonstrate the impacts that relatively small changes in the value assigned to the utility of being on warfarin therapy can have on the results. These findings are very similar to those of Tsevat and colleagues ’17 who developed a decision analysis to assess the outcomes in patients with dilated cardiomyopathy treated with or without warfarin. The results of their analysis were also very sensitive to the utility value assigned to being on warfarin treatment. In summary, this study illustrates how decision analysis can use information about treatment benefits and side effects from clinical trials to help identify a preferable treatment strategy. The results of the analysis indicate that even though aspirin may be less effective than warfarin, it may become the preferable strategy because of less bleeding complications and less of an impact on lifestyle than with warfarin. The results highlight the importance of considering the effects that medications may have on quality of life. Randomized trials studying treatment options for CNVAF6-9 have not considered the potential diminution in quality of life related to warfarin therapy. Future research should focus on measuring the impact of taking warfarin on quality of life, on assessing the effectiveness of aspirin in reducing embolic events in CNVAF, and on identifying specific patient risk factors for strokes and bleeds. When this information is available, the decision model can be used to identify the best treatment strategy for specific patient subgroups with CNVAF. The authors thank Drs. Jack Hirsh and Andreas helpful reviews of the manuscript.

Laupacis for their

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