Weighting Components of Composite End Points in
Clinical Trials
An Approach Using Disability-Adjusted Life-Years
Keun-Sik Hong, MD, PhD; Latisha K. Ali, MD; Scott L. Selco, MD, PhD;
Gregg C. Fonarow, MD; Jeffrey L. Saver, MD
Downloaded from http://stroke.ahajournals.org/ by guest on June 16, 2017
Background and Purpose—Conventional analysis of vascular prevention trials assigns equal weight to disparate vascular
events in a composite end point at variance with the public’s perception of their differential impact on health outcome.
This study sought to apply the disability-adjusted life-year (DALY) metric to differential weighting individual vascular
end points in trial analyses.
Methods—DALY values for the most common major end points in vascular prevention trials (nonfatal myocardial
infarction, nonfatal stroke, and vascular death), were derived by using World Health Organization Global Burden of
Disease Project methodology. The standardized DALYs for each event were applied to recent major primary and
secondary vascular prevention trials and to hypothetical model trials.
Results—Standardized DALYs lost were 7.63 for nonfatal stroke, 5.14 for nonfatal myocardial infarction, and 11.59 for
vascular death. In the published trials analyses, the direction of treatment effects was consistent between DALY and
standard event analysis, but the rank order of treatment effect changed for 10 of 18 trials. The DALY analysis also
permitted derivation of number-needed-to-treat values to gain 1 DALY: 2.1 for anticoagulation in atrial fibrillation, 2.7
for carotid endarterectomy in symptomatic stenosis, and 4.7 for clopidogrel added to aspirin in acute coronary syndrome.
Hypothetical trial analyses demonstrated that the DALY metric more finely discriminates treatment effects.
Conclusions—Compared with a nonfatal myocardial infarction, a nonfatal stroke causes a 1.48-fold greater loss and
vascular death a 2.25-fold greater loss of DALY. DALY analysis integrates these valuations in a summary metric reflecting
the net impact of therapy on patient and societal health, complementing conventional end point analyses. (Stroke. 2011;42:
1722-1729.)
Key Words: DALY 䡲 vascular disease 䡲 clinical trial 䡲 treatment effect
D
iseases and their treatment can influence many organs in
diverse ways. Consequently, in all medical specialties,
composite end points are increasingly used in randomized
clinical trials. Composite end points capture the number of
patients who have 1 or more of several events of interest. By
incorporating a range of important end points in a single
metric, composite end points can index the overall impact of
therapeutic interventions and reduce sample size requirements. However, composite end points have well-recognized
limitations that arise from the common practice of weighting
all end point components equally, irrespective of their relative
impact on the life of the patient. If positive results are driven
by less-salient end points, the trial may give the misleading
impression of broad benefit. If treatment exerts differential
benefit and harm on different end point components, a
treatment may reduce the net number of events but actually
worsen global health-related quality of life. Many clinical
trialists and statisticians have recognized the desirability of
differential weighting of clinical trial end points, but a widely
acceptable weighting method has not been advanced.
In vascular disease prevention trials, this tension has given
rise to 2 opposing approaches in end point selection: the
organ-specific and the multiorgan paradigm. The organspecific approach asserts that end points should focus on the
same vascular bed as the presenting event, because recurrent
events are likely to cluster in that vascular bed.1 Including
events outside the presenting vascular bed may dilute the
measurement of a desired effect on the target organ at greatest
risk.2 A weakness of the organ-specific argument is that, even
if less frequent, events outside the initially symptomatic
vascular bed are clinically relevant and accumulate as time
goes by.3 In contrast, the multiorgan paradigm uses compos-
Received August 28, 2010; accepted January 19, 2011.
From the Department of Neurology (K.-S.H.), Clinical Research Center, Ilsan Paik Hospital, Inje University, Goyang, Korea; Department of Neurology
(L.K.A., J.L.S.), UCLA Stroke Center, University of California, Los Angeles, CA; Stroke Center (S.L.S.), Rose Dominican Hospitals–Siena Campus, Las
Vegas, NV; and Department of Medicine (G.C.F), Ahmanson-UCLA Cardiomyopathy Center, University of California, Los Angeles, CA.
The online-only Data Supplement is available at http://stroke.ahajournals.org/content/full/stroke.110.600106/DC1.
Correspondence to Jeffrey L. Saver, MD, UCLA Stroke Center, 710 Westwood Plaza, Los Angeles, CA 90095. E-mail [email protected]
© 2011 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org
DOI: 10.1161/STROKEAHA.110.600106
1722
Hong et al
DALY Analysis for Weighting Vascular Outcomes
Downloaded from http://stroke.ahajournals.org/ by guest on June 16, 2017
ite outcomes, such as the first occurrence of nonfatal stroke,
transient ischemic attack, nonfatal myocardial infarction
(MI), angina, or vascular death, but has generally weighted
each of these disparate events equally.
The disability-adjusted life-year (DALY) metric, which the
World Health Organization Global Burden of Disease Project
(WHO-GBDP) developed to measure the global burden of
diseases,4 is a promising metric to weight components of
composite end points in clinical trials. The DALY method
converts hundreds of health conditions into a uniform,
patient-centered metric of healthy life-years lost by quantifying years lost due to premature mortality and optimum health
years lost due to living with disability.
The objective of this study was to develop standardized
DALY values for the most common end points assessed in
vascular disease prevention trials, that is, nonfatal stroke,
nonfatal MI, and vascular death; to apply these values to
completed vascular prevention trials to quantify the efficacy
of existing prevention treatments; and to compare DALY
measures with conventional measures of clinical efficacy.
Methods
Trial Selection and Data Collection
For the analysis, we selected pivotal primary and secondary prevention trials of antiplatelets, statins, antihypertensives, and surgery,
including (1) diverse treatment interventions in diverse target populations, (2) recent trials of major clinical importance, and (3) a subset
of trials in which tested treatments exerted opposite-direction effects
on coronary and cerebrovascular end point events (as these pose
special difficulty to traditional end point analysis). Technical inclusion criteria were (1) randomized controlled trial; (2) individual
event numbers for nonfatal stroke, nonfatal MI, vascular death, and
composite end point (nonfatal stroke, nonfatal MI, and vascular
death) separately stated or could be directly estimated from published tables; (3) ⬎6-month follow-up; and (4) trial reported in
English.
For each trial, we abstracted data for event numbers and annual
event rates for nonfatal stroke, nonfatal MI, vascular death, and the
composite end point. For event numbers, when ⬎1 outcome event
occurred in 1 patient, only the first event was included (refer to the
online-only Data Supplementary).
DALY Formulas
A DALY measures the total amount of optimal life-years lost from
a disease process, whether from premature mortality or from incapacity associated with nonfatal conditions. Formally, DALYs are
derived from the formula DALY⫽YLL⫹YLD, where YLL is the
years of life lost due to premature death and YLD is the years of
healthy life lost due to disability. YLL and YLD are derived by the
following formulas4,5:
YLL[r,K]⫽KCerA/(r⫹␤)2{e⫺(r⫹␤)(L⫹A)[⫺(r⫹␤)(L⫹A)⫺1]
⫺e⫺(r⫹␤)A[⫺(r⫹␤)A⫺1]}⫹[(1⫺K)/r](1⫺e⫺rL)
YLD[r,K]⫽DWKCerAv/(r⫹␤)2{e⫺(r⫹␤)(Ld⫹Av)[⫺(r⫹␤)(Ld⫹Av)⫺1]
⫺e⫺(r⫹␤)Av[⫺(r⫹␤)Av⫺1]}⫹[(1⫺K)/r](1⫺e⫺rLd)
where K is the age-weighting modulation factor (K⫽1 or 0); ␤, the
parameter from the age-weighting function (␤⫽0.04 or 0); r, the
discount rate (r⫽0.03 or 0), C, a constant (C⫽0.1658), A, the age of
death; L, life expectancy of the general population at age A; DW, the
disability weight; Av, age at the vascular event; and Ld, the duration
of disability (life expectancy after the vascular event at age Av).
As in the WHO-GBDP, we applied a 3% annual discount rate
(r⫽0.03) and age weighting (K⫽1, ␤⫽0.04): DALY [3,1]. The
1723
discount rate is the standard health-policy modeling assumption that
values a year of healthy life gained in the future less than a year of
healthy life gained in the immediate present. The age weighting is
another health policy assumption that assigns different values to
different years of life: higher in young adult ages than in infancy or
at old ages. The values of the age-weighting modulation factor,
age-weighting function, constant, and discount rate were derived by
the WHO-GBDP from extensive computational modeling.
Life Expectancy Estimation
In this study-level analysis, we did not have available individual
patient ages at the time of each end point vascular event. Instead, we
used a standardized DALY value for each event type, derived by
applying a standard age to all vascular events. In the primary
analysis, we set this age to 60. In sensitivity analyses, we varied this
assumption to ages 50 and 70. Life expectancies at ages 50, 60, and
70 for MI survivors and for the general population were taken from
the Framingham Heart Study (FHS) cohort, as were life expectancies
for stroke survivors at ages 60 and 70.6 The life expectancy of stroke
survivors at age 50, not provided in the FHS, was assigned as 11.4
years (3 years shorter than that of MI survivors), based on the FHS
observations of the stroke and MI survivors in 50-, 60-, and
70-year-olds. In the FHS, at age 60, the life expectancy for a stroke
survivor is 8.9 years (men and women combined); for an MI
survivor, 11.2 years; and for the general population, 22.25 years.
Accordingly, the age of death was determined as 60 for vascular
death, 68.9 for stroke survivors, and 71.2 for MI survivors.
Whereas life expectancy of the general population at age 60 could
be taken from the FHS, those of age 68.9 and 71.2 were not provided
in the FHS.6 Because the life expectancies of the FHS general
population are quite close to those of the US white population,7 we
used those values: 16.36 years (women and men combined) at age 68
to 69 and 14.62 years at age 71 to 72 (the Figure).
DWs for Each Vascular Event
We used the DW provided in the WHO-GBDP for the chronic
poststroke state of 0.266 and for vascular death of 1.0.8 For the
chronic post-MI state, the WHO-GBDP does not currently provide a
unified DW, but one can be derived from the WHO-GBDP–specific
DWs for the 2 most common disabling sequelae of MI: chronic heart
failure (CHF; DW⫽0.201) and angina pectoris (AP; DW⫽0.124).8
However, these conditions occur in only a subset of post-MI patients,
and even among these, only intermittently. Because the DW of
WHO-GBDP was originally derived under the assumption of chronic
and persistent symptom and sign, only the disabling days should be
counted in deriving a unified DW for the chronic post-MI state.
Thus, we used density values that were derived from days of
symptom occurrence divided by 365 days. Accordingly, the DW for
MI can be derived by the following formula:
DWMI⫽(PCHF⫻DensityCHF⫻DWCHF)
⫹(PAP⫻DensityAP⫻DWAP)
where PCHF or PAP is the proportion of MI survivors experiencing
CHF or AP, respectively; and DensityCHF or DensityAP, the number
of days per year that these individuals experience CHF or AP,
respectively (days divided by 365 days).
From the literature review, we projected PAP as 19.8% and PCHF
as 16.9%.9,10 For density values, literature review suggested post-MI
angina frequencies of 1.2% for daily angina, 3.0% for weekly angina
(angina symptom per 2 to 7 days: 81.1 days per year), and 15.6% for
angina attacks ⬍1 day per week for 4 weeks (angina attack per 8 to
28 days: 20.3 days per year), yielding a DensityAP of 0.14. For CHF,
DensityCHF was assigned a value of 1.0 under the assumption of
daily symptoms or restriction in daily activities. From these, the
DWMI was determined as 0.037.
By applying the values of life expectancies and DWs to the
aforementioned formulas, we converted the outcomes of nonfatal
stroke, nonfatal MI, and vascular death into DALYs (online-only
Data Supplement). To compare the DALY approach with the
1724
Stroke
June 2011
Downloaded from http://stroke.ahajournals.org/ by guest on June 16, 2017
Figure. Life expectancies and disabilityadjusted life-years (DALYs) for stroke
and myocardial infarction (MI) survivors.
YLD indicates years of healthy life lost
due to disability; YLL, years of life lost
due to premature death.
conventional equal-weighted event analysis, values of the number
needed to treat (NNT) for 1 year were derived: NNTevent, for
preventing 1 event; NNTDALY⫽100/[DALY saved for 100 patientyears]), for preventing 1 DALY loss (online-only Data Supplement).
Hypothetical Model Trials Analysis
To further illustrate the perspectives afforded by DALY analysis, we
also assessed DALYs saved in 6 hypothetical model trials demonstrating 2 different patterns of treatment effect (effective only for
stroke prevention or MI prevention) in 3 different populations:
population at equal risk for stroke and MI, stroke-prone population,
and MI-prone population. For this analysis, we explored the effect of
removing age weighting only (DALY [3,0]) and removing both age
weighting and future discounting (DALY [0,0]) (online-only Data
Supplement).
Results
Trials Characteristics
On the basis of expert consensus, we selected 18 trials: 11
secondary stroke prevention trials, 4 secondary prevention
trials in coronary heart disease (CHD), and 3 primary prevention trials; 9 trials tested antithrombotics; 3, statins; 3,
antihypertensives; 2, estrogens; and 1, surgery (Table 1;
full names of the trials are provided in the in online-only
Data Supplement). Table 1 shows that patients in stroke
trials had higher stroke rates, and treatments had a greater
impact on stroke prevention, whereas patients in CHD
trials had higher MI rates and treatments had a greater
impact on MI prevention.
DALYs Lost for Individual Vascular Events
Table 2 shows the calculated DALYs [3,1] lost for each
vascular event at various ages. For the primary analysis,
setting vascular events at age 60, the DALYs [3,1] lost due to
nonfatal stroke, nonfatal MI, and vascular death were 7.63,
5.14, and 11.59, respectively. The contributions of YLL to
total DALY lost were 77.9% for nonfatal stroke and 94.6%
for nonfatal MI. Changing the average age of vascular events
to 50 magnified the DALYs lost across all vascular event
categories and changing to age 70 reduced them.
DALYs Saved by Individual Trials
Table 3 shows the DALYs saved for individual vascular
events from each trial treatment per 100 patient-years of
intervention. The DALYs saved for the composite end point
of nonfatal stroke, nonfatal MI, and vascular death by
individual trial treatments ranged from ⫺6.47 to 46.96, that
is, from losing 6.47 years to saving 46.96 years of healthy
life.
Based on the magnitude of DALYs saved for the composite end point, the trials were coarsely classified into 4 groups:
Hong et al
Table 1.
DALY Analysis for Weighting Vascular Outcomes
1725
Characteristics of Included Trials
Annual Rate, %/Year, A/C
Trial
No. of Randomized
Patients, A/C
FU, Y
Age, Y
Female, %
Stroke*
MI
Composite End Point
6.79⫾2.92/8.42⫾3.69
Intervention, A/C
Population
1380⫾1111/1377⫾1108
2.9⫾1.0
64.9⫾3.5
42.2⫾19.8
4.47⫾2.13/6.25⫾3.31
1.53⫾0.83/1.59⫾0.71
WFR/PLC
Stroke⫹AF
225/214
2.3
70.5
43.5
3.94/11.85
3.16/2.96
8.28/15.56
UK-TIA
ASA 300 mg/PLC
Stroke
806/814
4.0
59.5
29.0
2.84/3.32
2.50/2.71
5.89/6.45
TASS
TCP/ASA
Stroke
1529/1540
3.3
63.2
35.0
3.60/4.55
1.36/1.18
5.77/6.55
CAPRIE_Stroke
CLP/ASA
Stroke
3233/3198
1.9
64.7
37.0
5.20/5.65
0.73/0.85
7.15/7.71
ESPS-2
DP-ASA/ASA
Stroke
1650/1649
2.0
66.6
42.3
4.76/6.25
1.06/1.18
8.24/9.73
ESPRIT
DP-ASA/ASA
Stroke
1363/1376
3.5
63.0
35.0
2.40/3.05
0.96/1.33
3.31/4.27
WASID
WFR/ASA
Stroke
289/280
1.8
62.8
40.0
9.41/11.50
2.22/1.39
13.11/13.08
Stroke trials
EAFT
SPARCL
ATV/PLC
Stroke
2365/2366
4.9
62.5
41.0
2.51/2.95
0.77/1.14
3.16/3.86
Perindopril⫾IDP/
PLC
Stroke
3051/3054
3.9
64.0
30.0
2.70/3.80
0.97/1.30
4.10/5.50
WEST
Estrogen/PLC
Stroke
337/327
2.8
71.5
100.0
6.68/6.12
1.59/1.86
9.33/8.85
NASCET
CEA/medical
Stroke
328/331
2.0
65.5
31.5
5.18/9.67
NR
6.40/11.03
5037⫾2112/5046⫾2117
3.0⫾2.3
61.3⫾2.2
24.4⫾10.6
0.88⫾0.52/1.05⫾0.57
3.96⫾2.88/5.21⫾3.80
6.26⫾4.90/7.87⫾6.05
PROGRESS
CHD trials
Downloaded from http://stroke.ahajournals.org/ by guest on June 16, 2017
CURE
CLP⫹ASA/ASA
CHD
6259/6303
0.75
64.2
38.5
1.61/1.89
6.96/9.11
12.50/15.64
TRITON-TIMI 38
PRG⫹ASA/CLP
⫹ASA
CHD
6813/6795
1.2
61.0
26.0
0.91/0.88
5.89/7.82
7.81/9.65
CARE
Pravastatin/PLC
CHD
2081/2078
5.0
59.0
14.0
0.51/0.76
1.57/2.12
2.71/3.61
TNT
ATV 80 mg/ATV
10 mg
CHD
4995/5006
4.9
61.0
19.0
0.49/0.66
1.41/1.78
2.00/2.56
5209⫾3054/5071⫾2844
4.5⫾0.8
68.6⫾6.9
63.7⫾36.7
0.63⫾0.30/0.80⫾0.51
1.08⫾0.98/1.21⫾1.32
2.04⫾1.23/2.36⫾1.71
Primary prevention
trials
HOPE
Ramipril/PLC
High risk
4645/4652
4.5
66.0
26.7
0.75/1.08
2.20/2.72
3.11/3.95
SCOPE
Candersartan/PLC
HT, elderly
2477/2460
3.7
76.4
64.5
0.85/1.11
0.67/0.61
2.30/2.58
Estrogen/PLC
General
8506/8102
5.2
63.3
100.0
0.29/0.21
0.37/0.30
0.70/0.55
WHI
Full names of the trials with references are provided in the in online-only Data Supplement.
Plus/minus values indicate mean⫾SD. A/C indicates active/control groups; FU, follow-up (mean or median); MI, myocardial infarction; WFR, warfarin; PLC, placebo;
AF, atrial fibrillation; ASA, aspirin; TCP, ticlopidine; CLP, clopidogrel; DP, dipyridamole; ATV, atorvastatin; IPD, indapamide; CEA, carotid endarterectomy; CHD, coronary
heart disease; PRG, prasugrel; HT, hypertensive; and NR, not reported.
*Stroke (or MI) includes fatal and nonfatal stroke (or MI). CAPRIE-Stroke included the stroke subgroup.
(1) trials with the greatest DALYs saved of ⬇20 or more (3
trials); (2) trials saving 5 to 12 DALYs (6 trials); (3) trials
with a relatively small DALY gain of ⬍5 (6 trials); and (4)
trials showing DALYs lost (treatment harm, 3 trials).
Table 2.
DALYs [3,1] for Individual Vascular Events
YLD 关3,1兴
YLL 关3,1兴
DALY 关3,1兴
Nonfatal stroke
1.69
5.94
7.63
Nonfatal MI
0.28
Vascular death
0
Age 60
4.86
5.14
11.59
11.59
10.49
Age 50
Nonfatal stroke
2.58
7.91
Nonfatal MI
0.42
6.31
6.73
Vascular death
0
16.79
16.79
5.06
Age 70
Nonfatal stroke
1.00
4.06
Nonfatal MI
0.16
3.69
3.85
Vascular death
0
7.24
7.24
DALY indicates disability-adjusted life-year; YLD, years of healthy life lost
due to disability; YLL, years of life lost due to premature death; and MI,
myocardial infarction. For DALY 关3,1兴, both future discounting and age
weighting were applied.
All stroke and CHD secondary prevention trials nominally
reduced nonfatal recurrent events in the initially presenting
vascular bed. However, 7 trials (5 stroke trials, 1 CHD trial,
and 1 primary prevention trial) showed discrepant treatment
effects on other vascular events. Overall, 2 stroke trials and 1
primary prevention trial showed net harm (DALYs lost).
NNTevent, NNTDALY, and Comparison of
Treatment Effects
NNT values per event and per DALY are shown in Table 4.
Whether a trial treatment was beneficial or harmful was consistent between the DALY and composite-events conventional
analyses. However, applying DALYs substantially changed the
rank order of treatment effect magnitude compared with the
conventional approach: only 8 of 18 trials retained their original
ranks (Table I in the online-only Data Supplement). Although
the trial with the greatest benefit (anticoagulation for secondary
stroke prevention in atrial fibrillation) was consistent between
the DALY and conventional approaches, the most harm was
observed in anticoagulation for symptomatic intracranial stenosis with the DALY approach and for estrogen for secondary
stroke prevention with the conventional approach.
Sensitivity Analysis
Treatment effects were magnified by changing the age at
vascular events to 50 and reduced by changing the age at
1726
Stroke
June 2011
Table 3.
DALYs [3,1] Saved for 100 Patient-Years of Treatment in Each Trial
Population
Composite
End Point
Nonfatal
Stroke
Nonfatal
MI
Vascular
Death
EAFT
Stroke
46.96
NASCET
Stroke
37.62
61.46
4.32
⫺18.81
30.78
NR
6.84
CHD
21.42
2.75
10.83
7.84
Stroke
11.58
11.36
⫺0.15
0.38
CHD
9.17
0.01
9.75
⫺0.59
Group 1
CURE
Group 2
ESPS-2
TRITON-TIMI 38
PROGRESS
Stroke
8.79
6.74
1.56
0.49
ESPRIT
Stroke
8.51
3.91
0.46
4.13
HOPE
Primary prevention
7.70
1.56
0.90
5.24
CARE
CHD
6.65
2.20
2.07
2.38
TASS
Stroke
5.84
6.06
NR
Stroke
4.48
2.45
1.91
0.13
CHD
4.10
1.14
1.47
1.49
⫺0.23
Group 3
Downloaded from http://stroke.ahajournals.org/ by guest on June 16, 2017
SPARCL
TNT
CAPRIE_Stroke
Stroke
4.16
3.53
0.38
0.24
UK-TIA
Stroke
2.98
3.94
1.20
⫺2.16
SCOPE
Primary prevention
2.69
1.91
⫺0.31
1.09
⫺0.17
Group 4
Primary prevention
⫺1.11
⫺0.60
⫺0.34
WEST
Stroke
⫺5.53
2.09
⫺0.89
⫺6.73
WASID
Stroke
⫺6.47
15.38
⫺1.41
⫺20.45
WHI
Full names of the trials with references are provided in the in online-only Data Supplement.
DALY indicates disability-adjusted life-year; MI, myocardial infarction; CHD, coronary heart disease; and NR, not
reported. See text for criteria for group designations.
vascular events to 70, but their ranks remained generally
stable whether age 60, 50, or 70 was used (Tables I an II in
the online-only Data Supplement).
Hypothetical Trials
Table 5 shows the comparison of hypothetical trials in terms
of NNTevent and NNTDALY. Compared with the conventional
NNTevent, NNTDALY more finely discriminated the differences in treatment effects between 6 hypothetical settings.
The discriminating power remained robust when age weighting and both age weighting and future discounting were
removed.
Discussion
This study provides standardized DALY values for the most
common components of composite end points used in contemporary vascular prevention trials and demonstrates that
treatment effects of diverse vascular prevention trials can be
presented as a summary patient-centered metric of healthy
life-years gained or lost. Formal analysis indicated that the
major vascular events routinely assessed in prevention trials
are not of equal importance. Rather, compared with a nonfatal
MI, a nonfatal stroke causes a 1.48-fold greater loss of
disability-adjusted life-years and vascular death, a 2.25-fold
greater loss.
A fundamental principle of evidence-based medicine is
that assessment of a treatment effect should encompass all of
the outcomes that a treatment might alter, in proportion to the
degree that they are valued by the patient and society.
Consequently, the desirability of weighting components of
composite end points in clinical trials has been widely
recognized.11,12 Several weighting approaches have been
suggested, but none to date has captured general allegiance.12–15 Most prior weighting algorithms were derived by
using informal methods and thin theoretical foundations, thus
limiting their acceptance. In contrast, the DALY approach
has a strong methodologic framework (person trade-off analyses by internationally representative health providers) and a
rich theoretical grounding. It has already achieved wide
acceptance as a tool for international health policy analysis
and decision-making by the WHO and many health planning
authorities. This extensive acceptance in arenas external to
clinical trial design gives DALYs credibility and authority for
porting into clinical trial planning and analysis.
Another health-adjusted life-year metric, the qualityadjusted life-year (QALY), is also an attractive candidate for
weighting outcome end points and already has been used in
cost-effectiveness analyses of clinical trial results. Compared
with QALYs, DALY analysis has some advantages. QALYs
are derived from patients or healthy individuals with a limited
experience of diverse disease states and use a wide variety
of techniques.16 As a result, considerable variation across
studies occurs in the quality-of-life weights assigned to the
same health states. In contrast, DALYs are derived from
Hong et al
Table 4.
Comparison of NNTDALY
[3,1]
DALY Analysis for Weighting Vascular Outcomes
and NNTevent Analysis for Treatment Efficacies
Composite End Point
Trial
1727
Nonfatal Stroke
Nonfatal MI
NNTDALY
Vascular Death
NNTDALY
NNTevent
NNTDALY
NNTevent
NNTevent
NNTDALY
NNTevent
EAFT
2.1
13.8
1.6
12.4
NASCET
2.7
21.6
3.3
24.8
NR
NR
119.0
⫺5.3
14.6
⫺61.6
169.4
ESPS-2
8.6
67.1
8.8
67.2
⫺648.7
⫺3334.4
265.7
3079.6
2358.3
Stroke trials
23.2
PROGRESS
11.4
71.4
14.8
113.1
64.2
330.1
203.5
ESPRIT
11.8
104.3
25.6
194.9
218.0
1120.6
24.2
280.4
TASS
17.1
129.0
16.5
125.9
NR
⫺440.3
⫺5103.1
SPARCL
22.3
142.3
40.9
311.9
52.4
269.3
796.7
9233.6
NR
CAPRIE_Stroke
24.1
179.2
28.3
215.9
263.8
1356.1
408.3
4731.6
UK-TIA
33.6
177.5
25.4
193.7
83.2
427.8
⫺46.2
⫺535.9
WEST
⫺18.1
⫺208.6
47.7
364.3
⫺112.4
⫺577.8
⫺14.9
⫺172.2
WASID
⫺15.5
⫺4538.8
6.5
49.6
⫺71.1
⫺365.4
⫺4.9
⫺56.7
Downloaded from http://stroke.ahajournals.org/ by guest on June 16, 2017
CHD trials
CURE
4.7
31.8
36.4
277.7
9.2
47.5
12.8
147.8
TRITON-TIMI 38
10.9
54.1
11963.8
91284.0
10.3
52.7
⫺170.7
⫺1977.8
CARE
15.0
111.5
45.5
346.9
48.3
248.3
42.0
486.5
TNT
24.4
177.3
88.0
671.3
68.0
349.0
67.1
778.1
HOPE
13.0
120.3
64.1
489.2
111.1
571.1
19.1
221.3
SCOPE
37.1
351.3
52.3
399.0
⫺324.6
⫺1668.4
91.8
1064.0
⫺90.1
⫺627.8
⫺166.5
1270.6
⫺295.2
⫺1517.4
⫺588.0
⫺6814.6
Primary prevention trials
WHI
Full names of the trials with references are provided in the in online-only Data Supplement.
NNTevent indicates the number needed to treat for 1 y to prevent event; NNTDALY, the number needed to treat for 1 y to avert 1 DALY lost.
NNT indicates number needed to treat; DALY, disability-adjusted life-year; MI, myocardial infarction; CHD, coronary heart disease;
and NR, not reported.
broadly experienced health professionals in a single, explicit, and broad-based disease comparison framework,
resulting in internally coherent weightings for a broad
range of conditions.
Table 5.
The functional limitations that vascular events can impose
on an individual’s remaining life are critically important to
patients, families, and society. However, conventional composite end point analysis, counting the number of acute
Hypothetical Trials Analysis
Event No., Control/Intervention
NNT for Composite End Point
Population and Intervention Nonfatal Stroke Nonfatal MI Vascular Death NNTevent NNTDALY 关3,1兴 NNTDALY 关3,0兴 NNTDALY 关0,0兴
Population at equal risk for
stroke and MI
Stroke effective
160/96
160/160
100/84
50
5.9
3.9
2.6
MI effective
160/160
160/96
100/84
50
7.8
4.9
3.0
Stroke effective
160/96
80/80
80/64
50
5.9
3.9
2.6
MI effective
160/160
80/48
80/72
100
15.6
9.7
6.1
Stroke effective
80/48
160/160
80/72
100
8.5
6.6
3.9
MI effective
80/80
160/96
80/64
50
5.7
4.2
2.3
Population at unequal risk
for stroke and MI
Stroke-prone population,
age 60
MI-prone population,
age 50
NNT indicates number needed to treat; MI, myocardial infarction; and DALY, disability-adjusted life-year. For each hypothetical trial,
assumptions of age at onset, event rate, and relative risk reduction by treatment are described in the online-only Data Supplement.
For DALY 关3,0兴, age weighting was removed; for DALY 关0,0兴, both future discounting and age weighting were removed.
1728
Stroke
June 2011
Downloaded from http://stroke.ahajournals.org/ by guest on June 16, 2017
events, provides only a 1-time, snapshot metric that fails to
capture the lifelong impact of disease. In contrast, the DALY
metric reflects the disparity across the individual vascular
events in both event-related premature mortality and reduced
human flourishing during an individual’s remaining years of
life.
The different contributions of disability and premature
mortality to the valuations in our study are noteworthy. The
DW assigned to the chronic poststroke state was 7 times
higher than that for the chronic post-MI state, reflecting the
greater frequency and disabling impact of neurologic deficits
after stroke than functionally limiting CHF and chronic
angina after MI. Consequently, years lost due to disability
contributed substantially, 22.1%, to the total DALYs lost due
to nonfatal stroke events. In contrast, years lost due to
disability only accounted for 5.4% of the loss of optimal
health for nonfatal MI, with premature mortality exerting the
overwhelming effect.
Weighting the components of composite end points allowed us to derive a single DALY value that summarized for
diverse vascular prevention treatments each intervention’s net
impact on patient health. For treatments that had opposingdirection effects on different end points, a widely recognized
challenge to interpretation of composite end points, the
DALY resolved and quantified the overall benefit or risk of
intervention. Across all treatments, the DALY metric allowed
comparisons to be made of the relative degree of benefit
delivered by diverse therapies. The greatest benefits were
seen in secondary prevention trials, in which enrolled patients
are at highest risk for new events; carotid endarterectomy in
symptomatic carotid stenosis, anticoagulation for secondary
prevention in atrial fibrillation, and clopidogrel added to
aspirin in the first year after acute coronary syndrome.
Concurrent validity for the DALY findings is provided by
the general consistency of benefit and harm shown with
conventional composite end point analysis and DALY analysis. In addition, the DALY analysis permitted a more refined
discrimination of interventional efficacy. Across all trials,
NTT values to gain 1 healthy life-year were nearly an order
of magnitude lower than those needed to avert 1 vascular
event. In the hypothetical trial models, DALY analysis
demonstrated more clearly than did conventional analysis the
variation in degree of benefit obtained when an intervention
effective for a specific event is used in patients at high or low
risk for that event.
This study has limitations. We analyzed the 3 most
common and important end points used in vascular prevention trials. Additional work is needed to derive and apply to
clinical trials DALY values for other end points, including
unstable angina, transient ischemic attack, hospitalizations
for revascularization procedures, and major bleeding
episodes.
We performed an analysis of study-level, not individual
patient-level, clinical trial data. The most precise application
of DALY analysis to clinical trials would use patient-level
data, allowing life expectancy calculations to take into
account age, sex, country of residency, and other specific
characteristics of each patient.17 However, often only studylevel data are available for analysis. For such settings, a
standardized DALY for a prototypical age is useful to convert
event counts into DALY values.
An additional limitation of the current analysis is that it
focuses on only the first postrandomization vascular event,
not all events that may eventually occur. The DALY values
that we used only partially capture recurrent events, through
reduced life expectancy values, but a more comprehensive
depiction of treatment effect would be provided by actual
ascertainment and disability weighting of all postrandomization events, not just first events. When patient-level data of
subsequent events are available, the DALY metric could
directly index the impact of these subsequent events. For
example, if a patient had an MI at age 60 and then a stroke at
65 and then die at 70, and the life expectancy of the general
population at age 70 is 15.35 years (from the FHS6), the
DALY lost for this patient would be the sum of the YLD lost
to nonfatal MI for 10 years, YLD to nonfatal stroke for 5
years, and YLL to 15.35 years of premature death (Table III
in the online-only Data Supplement).
In trial analyses, we used the same patient ages for MI,
stroke, and vascular death events. This approach contrasts
with epidemiologic observations showing that MIs tend to
occur in younger individuals than do strokes. However, this
study measured the burden of stroke and MI in clinical trial
populations, and the ages at which MI and stroke occur in a
given trial tend to be much closer than in the general
population. Life expectancy assumptions were based on FHS
data, which had published salient life-expectancy data of
poststroke, post-MI, and general populations. The results are
therefore most applicable to white populations, but the
underlying method can be generalized to other populations
whenever salient life-expectancy data are available. Our
analyses assumed the same DWs for nonfatal stroke (or MI)
across all trials. This assumption does not always hold. For
example, strokes experienced by an atrial fibrillation population tend to be more disabling than are strokes in other
populations.18 Data on event severity were generally not
available for the trials that we analyzed. When available,
incorporating event-severity data will permit more refined
DALY estimates of treatment effect.17,19
Whereas conventional event-rate analysis of treatment
effect is based on direct observations, health-adjusted lifeyear metrics (that is, QALY or DALY) inevitably require
several assumptions when determining life expectancies after
each vascular event and quantifying health state values.
However, equal weighting to different outcomes of different
impact on health should be reappraised as reflected in recent
debates on the findings of the Carotid Revascularization
Endarterectomy versus Stenting Trial.20 In the Carotid Revascularization Endarterectomy versus Stenting Trial,
quality-of-life analyses among survivors at 1 year indicated
that stroke had a greater adverse effect on a broad range of
health status domains than did MI, consonant with our
findings. That the general DALY approach has undergone
extensive validation by the WHO and is an accepted foundation for planning global health policies supports its being
considered a valuable technique for evaluating treatment
effects of vascular prevention trials.
Hong et al
DALY Analysis for Weighting Vascular Outcomes
The present study demonstrates that the detailed and
nuanced WHO-GBDP DALY framework can be applied to
weight composite end point events in cardiovascular trials.
The DALY approach, as an integrated, patient-centered
outcome metric, complements conventional end point analyses and delineates more clearly the summary impact of a
therapy on patient and societal health.
Sources of Funding
This work was supported by a grant (A060171) of the Korea Health
21 R&D project, Ministry of Health, Welfare and Family Affairs,
Republic of Korea (K.-S.H.); National Heart, Lung, and Blood
Institute (G.C.F.); National Institutes of Health–National Institute of
Neurological Disorders and Stroke award P50 NS044378 (J.L.S.);
and an American Heart Association PRT Outcomes Research Center
Award (J.L.S.).
Disclosures
Downloaded from http://stroke.ahajournals.org/ by guest on June 16, 2017
K.-S.H. is involved in the design and is a site investigator of
multicenter clinical trials sponsored by Korea Otsuka and Boryung
and has received lecture honoraria from Sanofi-Aventis (modest).
J.L.S. is a scientific consultant regarding trial design and conduct to
AGA Medical and CoAxia (all modest); has received lecture
honoraria from Boehringer Ingelheim (modest); is a site investigator
in the NIH IRIS, ARUBA, CREST, and SAMMPRIS multicenter
clinical trials for which the University of California Regents received
payments based on the clinical trial contracts for the number of
subjects enrolled; has served as a site investigator in a multicenter
trial sponsored by AGA Medical for which the University of
California Regents received payments based on the clinical trial
contract for the number of subjects enrolled; and is funded by
National Institutes of Health–National Institute of Neurological
Disorders and Stroke awards P50 NS044378 and U01 NS 44364; and
is an employee of the University of California, which holds a patent
on retriever devices for stroke. G.C.F. has received research funding
by the National Heart, Lung, and Blood Institute (significant); served
as a consultant for Novartis and Pfizer (modest) and honoraria from
Bristol Myers Squibb, Sanofi-Aventis, Astra-Zeneca, MerckSchering Plough, and Pfizer (significant); and is an employee of the
University of California, which holds a patent on retriever devices
for stroke. S.L.S. has received lecture honoraria from EKR Therapeutics and Sanofi-Aventis.
References
1. Vickrey BG, Rector TS, Wickstrom SL, Guzy PM, Sloss EM, Gorelick
PB, Garber S, McCaffrey DF, Dake MD, Levin RA. Occurrence of
secondary ischemic events among persons with atherosclerotic vascular
disease. Stroke. 2002;33:901–906.
2. Albers GW. Choice of endpoints in antiplatelet trials: which outcomes are
most relevant to stroke patients? Neurology. 2000;54:1022–1028.
3. Hardie K, Hankey GJ, Jamrozik K, Broadhurst RJ, Anderson C. Ten-year
survival after first-ever stroke in the Perth Community Stroke Study.
Stroke. 2003;34:1842–1846.
4. Murray CJ. Rethinking DALYs. In: Murray CJL and Lopez AD, eds. The
Global Burden of Disease, vol 1 of the Global Burden of Disease and
Injury Series. Cambridge, MA: Harvard University Press; 1996:1–98.
1729
5. Fox-Rushby JA, Hanson K. Calculating and presenting disabilityadjusted life-years (DALYs) in cost-effectiveness analysis. Health Policy
Planning. 2001;16:326 –331.
6. Peeters A, Mamun AA, Willekens F, Bonneux L. A cardiovascular life
history: a life course analysis of the original Framingham Heart Study
cohort. Eur Heart J. 2002;23:458 – 466.
7. Arias E. United States life tables 2004. National Vital Statistics Reports.
2007;56:1– 40.
8. WHO. Global burden of disease 2004 update: disability weights for
diseases and conditions. 2008. (www.who.int/healthinfo/global_burden_
disease/GBD2004_DisabilityWeights.pdf). Accessed April 2, 2009.
9. Maddox TM, Reid KJ, Spertus JA, Mittleman M, Krumholz HM,
Parashar S, Ho PM, Rumsfeld JS. Angina at 1 year after myocardial
infarction: prevalence and associated findings. Arch Intern Med. 2008;
168:1310 –1316.
10. Lloyd-Jones D, Adams R, Carnethon M, De Simone G, Ferguson TB,
Flegal K, Ford E, Furie K, Go A, Greenlund K, Haase N, Hailpern S, Ho
M, Howard V, Kissela B, Kittner S, Lackland D, Lisabeth L, Marelli A,
McDermott M, Meigs J, Mozaffarian D, Nichol G, O’Donnell C, Roger
V, Rosamond W, Sacco R, Sorlie P, Stafford R, Steinberger J, Thom T,
Wasserthiel-Smoller S, Wong N, Wylie-Rosett J, Hong Y, Committee
AHAS, Stroke Statistics Subcommittee. Heart disease and stroke statistics–2009 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2009;
119:e21– e181.
11. Montori VM, Permanyer-Miralda G, Ferreira-Gonzalez I, Busse JW,
Pacheco-Huergo V, Bryant D, Alonso J, Akl EA, Domingo-Salvany A,
Mills E, Wu P, Schunemann HJ, Jaeschke R, Guyatt GH. Validity of
composite end points in clinical trials. BMJ. 2005;330:594 –596.
12. Ferreira-Gonzalez I, Busse JW, Heels-Ansdell D, Montori VM, Akl EA,
Bryant DM, Alonso-Coello P, Alonso J, Worster A, Upadhye S, Jaeschke
R, Schunemann HJ, Permanyer-Miralda G, Pacheco-Huergo V,
Domingo-Salvany A, Wu P, Mills EJ, Guyatt GH. Problems with use of
composite end points in cardiovascular trials: systematic review of randomised controlled trials. BMJ. 2007;334:786.
13. Califf RM, Harrelson-Woodlief L, Topol EJ. Left ventricular ejection
fraction may not be useful as an end point of thrombolytic therapy
comparative trials. Circulation. 1990;82:1847–1853.
14. Hallstrom AP, Litwin PE, Weaver WD. A method of assigning scores to
the components of a composite outcome: an example from the MITI trial.
Control Clin Trials. 1992;13:148 –155.
15. Neaton JD, Gray G, Zuckerman BD, Konstam MA. Key issues in end
point selection for heart failure trials: composite end points. J Card Fail.
2005;11:567–575.
16. Tengs TO, Wallace A. One thousand health-related quality-of-life
estimates. Med Care. 2000;38:583– 637.
17. Hong KS, Saver JL. Years of disability-adjusted life gained as a result of
thrombolytic therapy for acute ischemic stroke. Stroke. 2010;41:
471– 477.
18. Connolly S, Pogue J, Hart R, Pfeffer M, Hohnloser S, Chrolavicius S,
Yusuf S. Clopidogrel plus aspirin versus oral anticoagulation for atrial
fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for
prevention of Vascular Events (ACTIVE W): a randomised controlled
trial. Lancet. 2006;367:1903–1912.
19. Hong KS, Saver JL. Quantifying the value of stroke disability outcomes:
WHO global burden of disease project disability weights for each level of
the modified Rankin Scale. Stroke. 2009;40:3828 –3833.
20. Brott TG, Hobson RW II, Howard G, Roubin GS, Clark WM, Brooks W,
Mackey A, Hill MD, Leimgruber PP, Sheffet AJ, Howard VJ, Moore WS,
Voeks JH, Hopkins LN, Cutlip DE, Cohen DJ, Popma JJ, Ferguson
RD, Cohen SN, Blackshear JL, Silver FL, Mohr JP, Lal BK, Meschia JF.
Stenting versus endarterectomy for treatment of carotid-artery stenosis.
N Engl J Med. 2010;363:11–23.
Weighting Components of Composite End Points in Clinical Trials: An Approach Using
Disability-Adjusted Life-Years
Keun-Sik Hong, Latisha K. Ali, Scott L. Selco, Gregg C. Fonarow and Jeffrey L. Saver
Downloaded from http://stroke.ahajournals.org/ by guest on June 16, 2017
Stroke. 2011;42:1722-1729; originally published online April 28, 2011;
doi: 10.1161/STROKEAHA.110.600106
Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2011 American Heart Association, Inc. All rights reserved.
Print ISSN: 0039-2499. Online ISSN: 1524-4628
The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://stroke.ahajournals.org/content/42/6/1722
Data Supplement (unedited) at:
http://stroke.ahajournals.org/content/suppl/2011/05/02/STROKEAHA.110.600106.DC1
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published
in Stroke can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office.
Once the online version of the published article for which permission is being requested is located, click
Request Permissions in the middle column of the Web page under Services. Further information about this
process is available in the Permissions and Rights Question and Answer document.
Reprints: Information about reprints can be found online at:
http://www.lww.com/reprints
Subscriptions: Information about subscribing to Stroke is online at:
http://stroke.ahajournals.org//subscriptions/
SUPPLEMENTAL MATERIAL
Supplemental material 1. Annual event rate abstraction
For each trial, we abstracted data for event numbers and annual event rates for nonfatal
stroke, nonfatal MI, vascular death, and composite endpoint. For event numbers, if more than one
outcome event occurred in one patient, only the first event was included. If the event number was
duplicated across individual events, we first abstracted the numbers of nonfatal stroke, nonfatal MI,
and composite endpoint, and then recalculated the numbers of vascular death. However, for the
Women’s Health Initiative (WHI) trial, the sum of fatal and nonfatal stroke events was less than all
stroke events.1 Therefore, we estimated the nonfatal stroke events by subtracting fatal stroke from
all stroke. The annual event rates were abstracted if directly stated and otherwise derived from the
event number and person-years of follow-up. The person-years were derived in following
hierarchical order based on the available data: 1) person-years directly stated in the article, 2)
derivation from displayed number of patients at risk in survival curves, and 3) number of patients
multiplied by mean or median duration of follow-up years.
Reference
1.
Writing Group for the Women's Health Initiative Investigators. Risks and Benefits of Estrogen
Plus Progestin in Healthy Postmenopausal Women: Principal Results From the Women's
Health Initiative Randomized Controlled Trial. Jama. 2002;288:321-333.
Supplemental material 2. DALY derivation for each vascular event
DALY lost due to vascular death at age of 60
DALY =YLL (YLD=0)
YLL[r,K]=KCerA/(r+β)2{e-(r+β)(L+ A)[-(r+ β)(L+A)-1]-e-(r+β)A[-(r+β)A-1]}+[(1-K)/r](1- e-rL)
K: age-weighting modulation factor (K=1 or 0), β: parameter from age weighting function (β
=0.04 or 0), r: discount rate (r=0.03 or 0), C: constant (C=0.1658), A: age of death, L: life
expectancy of general population at age A
For YLL[3,1]:
K=1, r=0.03, β =0.04, A=60
L: life expectancy of 60 year-old person without cardiovascular disease (CVD) from the
Framingham Heart Study (FHS) cohort: Men, 20; Women, 24.5; average: 22.25
YLL[3,1] = 11.59
DALY[3,1] for vascular death at age of 60 = 11.59
DALY lost for stroke survivor at age of 60 (Figure 1)
YLD[r,K]=DWKCerAv/(r+β)2{e-(r+β)(Ld+Av)[-(r+β)(Ld+Av)-1]-e-(r+β)Av[-(r+β)Av -1]}+[(1-K)/r](1- e-rLd)
DW: disability weight, K: age-weighting modulation factor (K=1 or 0), β: parameter from age
weighting function (β =0.04 or 0), r: discount rate (r=0.03 or 0), C: constant (C=0.1658), Av: age
at vascular event, Ld: duration of disability after vascular event (=life expectancy of a survivor
after vascular event at age Av)
For YLD[3,1]:
DW=0.266 (from the WHO-GBDP), K=1, r=0.03, β=0.04, Av=60
Ld: life expectancy of 60 year-old person with stroke from the FHS cohort, Ld=8.90
YLD[3,1]=1.69
YLL[r,K]=KCerA/(r+β)2{e-(r+β)(L+ A)[-(r+ β)(L+A)-1]-e-(r+β)A[-(r+β)A-1]}+[(1-K)/r](1- e-rL)
K: age-weighting modulation factor (K=1 or 0), β: parameter from age weighting function (β
=0.04 or 0), r: discount rate (r=0.03 or 0), C: constant (C=0.1658), A: age of death, L: life
expectancy of general population at age A
For YLL[3,1]:
K=1, r=0.03, β =0.04, A=68.9
L: life expectancy of 68.9 year-old general population from US life table 2004 for white, L=16.36
The life expectancy of 68.9 year-old general population was not provided in the FHS article.
Since the life expectancy of FHS population are quite close to US white population, we
employed the life expectancy of this age from US white population life tables.
YLL[3,1] at age of 68.9 = 7.75
YLL[3,1] at age of 60 = (YLL[3,1] at age of 68.9) x erxLd = 7.75xe0.03x8.90 = 5.94
Finally, DALY[3,1] = YLL + YLD = 5.94 + 1.69 = 7.63
DALY lost for MI survivor (Figure 1)
For YLD[3,1]:
DW=0.037 (from frequency- and density-weighting), K=1, r=0.03, β =0.04, Av=60
Ld: life expectancy of 60 year-old person with MI from the FHS cohort, Ld=11.2
YLD[3,1]=0.28
For YLL[3,1]:
K=1, r=0.03, β =0.04, A=71.2
L: life expectancy of 71.2 year-old general population from US life table 2004 for white, L=14.62
The life expectancy of 71.2 year-old general population was not provided in the FHS article.
Since the life expectancy of FHS population are quite close to US white population, we
employed the life expectancy of this age from US white population life tables.
YLL[3,1] at age of 71.2 = 6.80
YLL[3,1] at age of 60 = (YLL[3,1] at age of 71.2) x erxLd = 7.75xe0.03x11.2 = 4.86
Finally, DALY[3,1] = YLL + YLD = 4.86 + 0.28 = 5.14
Supplemental material 3. NNT to save one DALY and one event by each trial treatment
We converted the each vascular event rates into DALYs lost per 100 person-years. By
comparing the DALYs lost between active arm and control arm, we generated the DALYs saved by
each trial treatment for a 100 person-years, and calculated NNTs.
The following table is an example of our derivation from the European Atrial Fibrillation Trial
(EAFT).1
Anticoagulation
Placebo
Nonfatal stroke
18
47
Nonfatal MI
2
5
Vascular death
22
11
Composite outcome
42
63
Follow-up person-year
507
405
Nonfatal stroke
3.55
11.60
Nonfatal MI
0.39
1.23
Vascular death
4.34
2.72
Composite outcome
8.28
15.56
Nonfatal stroke
27.09 (= 3.55 X 7.63)
88.55 (= 3.55 X 7.63)
Nonfatal MI
2.03 (= 0.39 X 5.14)
6.35 (= 1.23 X 5.14)
Vascular death
50.29 (= 4.34 X 11.59)
31.48 (= 2.72 X 11.59)
Composite outcome
79.41
126.37
Event number
Event rate per 100 person-year
DALYs lost per 100 person-year
The DALYs saved from anticoagulation treatment for a 100 person-years were 61.46 for
nonfatal stroke, 4.32 for nonfatal MI, -18.81 for vascular death, and 46.96 for the composite
outcome.
For nonfatal stroke, the NNTevent can be derived from the following calculation: 100/(11.63.55)=12.4. NNTDALY can be calculated as follows: 100/(88.55-27.09)=1.6.
Supplemental material 4. Hypothetical model trials assumption and age-weighting and
future discounting
Hypothetical model trials assumption
In order to further illustrate the perspectives afforded by DALY analysis, we also generated six
model trials demonstrating two different patterns of treatment effect in three different populations.
The treatment effect patterns studied were an intervention effective for stroke prevention but
ineffective for MI prevention and an intervention effective for MI prevention but ineffective for
stroke prevention. The model populations were: 1) patients at equal risk for stroke or MI, 2) strokeprone patients at higher stroke risk than MI, and 3) MI-prone patients at higher MI risk than stroke.
In these six models (two treatment effect patterns crossed with three model populations), we
assessed the treatment effect on DALYs for a sample size of 4000 person-years in each arm.
Relative risk reductions were set at 40% on the endpoints for which the treatment was effective
and nil for the ineffective endpoints.
For the trials of patients (the average age set to 60) at equal risk for stroke and MI, the annual
event rates of control arms were assumed to be 5% for stroke, 5% for MI, and 8% for the
composite endpoint. Case fatality rates of 20% were chosen for both stroke and MI, and other
vascular death rate was set to 0.5% annually. These assumed control arm event rates were based
on data from the systematic review of published stroke prevention trials.1 It is widely recognized
that stroke prevalent age is higher than that of MI. Therefore, for population at unequal risk for
stroke and MI, the average age was set at 60 for the stroke-prone population and 50 for the MIprone population. For the stroke-prone population, annual event rates of control arms were
assumed to be 5% for stroke and 2.5% for MI. For the MI-prone population, annual event rates of
control arms were assumed to be 2.5% for stroke and 5% for MI.
Based on these assumptions, we generated the tabular outcome events, and then derived
NNTevent and NNTDALY for each hypothetical trials.
Future discounting and age-weighting
The future discounting is a standard health policy modeling assumption that values a year of
healthy life lost in the future less than a year of healthy life lost in the immediate present. The ageweighting reflects another assumption that assigns different values to different years of life, higher
in young adult ages than in infancy or old ages. As in the WHO-GBDP, we employed an annual
3% of discount rate (r=0.03) and age-weighting (K=1, β=0.04) for the primary DALY analysis
(DALY[3,1]).
However, there have been some ethical criticisms on applying discount rate and ageweighting: DALY[3,1].2 For this reason, the 2000 WHO-GBDP also provided DALY with 3%
discounting and non age-weighting: DALY[3,0], and DALY without both discounting and ageweighting: DALY[0,0], in addition to the standard DALY[3,1].3 To explore the effect of removing
these assumptions, for the hypothetical trials, we also calculated additional sets of DALYs, in
which the age-weighting was not employed (DALY[3,0]) or both were not employed (DALY[0,0]).
References
1. Hong KS, Yegiaian S, Lee M, Saver JL. Declining Stroke Recurrence Rates in Secondary
Prevention Trials over the Past 50 Years and Consequences for Current Trial Design. 2010
International Stroke Conference (abstract).
2. Murray CJ. Rethinking DALYs. In The Global Burden of Disease, ed. C. J. L. Murray and A. D.
Lopez, Vol. 1 of Global Burden of Disease and Injury Series. Cambridge, MA: Harvard
University Press.; 1996:1-98.
3. WHO. The global burden of disease 2000: Version 2 methods and results
(http://www.who.int/healthinfo/paper50.pdf). Accessed 10/28/2009.
Supplemental material 5. Included published trials
Secondary Stroke Prevention Trials
European Atrial Fibrillation (EAFT)1
North American Symptomatic Carotid Endarterectomy (NASCET)2
European Stroke Prevention Study-2 (ESPS-2)3
Perindopril Protection Against Recurrent Stroke Study (PROGRESS)4
European/Australasian Stroke Prevention in Reversible Ischaemia Trial (ESPRIT)5
Ticlopidine Aspirin Stroke Study (TASS)6
Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL)7
Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) stroke subgroup8
United Kingdom Transient Ischaemic Attack (UK-TIA)9, 10
Women’s Estrogen for Stroke Trial (WEST)11
Warfarin-Aspirin Symptomatic Intracranial Disease (WASID)12
Secondary Coronary Heart Disease Prevention Trials
Clopidogrel in Unstable angina to prevent Recurrent Events (CURE)13
Prasugrel Thrombolysis in Myocardial Infarction (TRITON-TIMI 38)14
Cholesterol and Recurrent Events (CARE)15
Treating to New Targets (TNT)16
Primary Prevention Trials
Heart Outcomes Prevention Evaluation (HOPE)17
Study on Cognition and Prognosis in the Elderly (SCOPE)18
Women’s Health Initiative (WHI)19
References for included trials
1.
Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack or
minor stroke. EAFT (European Atrial Fibrillation Trial) Study Group. Lancet.
1993;342:1255-1262.
2.
Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid
stenosis. North American Symptomatic Carotid Endarterectomy Trial Collaborators. N
Engl J Med. 1991;325:445-453.
3.
Diener HC, Cunha L, Forbes C, Sivenius J, Smets P, Lowenthal A. European Stroke
Prevention Study. 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of
stroke. J Neurol Sci. 1996;143:1-13.
4.
Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6,105
individuals with previous stroke or transient ischaemic attack. Lancet. 2001;358:10331041.
5.
Halkes PH, van Gijn J, Kappelle LJ, Koudstaal PJ, Algra A. Aspirin plus dipyridamole
versus aspirin alone after cerebral ischaemia of arterial origin (ESPRIT): randomised
controlled trial. Lancet. 2006;367:1665-1673.
6.
Hass WK, Easton JD, Adams HP, Jr., Pryse-Phillips W, Molony BA, Anderson S, Kamm B.
A randomized trial comparing ticlopidine hydrochloride with aspirin for the prevention of
stroke in high-risk patients. Ticlopidine Aspirin Stroke Study Group. N Engl J Med.
1989;321:501-507.
7.
Amarenco P, Bogousslavsky J, Callahan A, 3rd, Goldstein LB, Hennerici M, Rudolph AE,
Sillesen H, Simunovic L, Szarek M, Welch KM, Zivin JA. High-dose atorvastatin after
stroke or transient ischemic attack. N Engl J Med. 2006;355:549-559.
8.
A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic
events (CAPRIE). CAPRIE Steering Committee. Lancet. 1996;348:1329-1339.
9.
United Kingdom transient ischaemic attack (UK-TIA) aspirin trial: interim results. UK-TIA
Study Group. Br Med J (Clin Res Ed). 1988;296:316-320.
10.
Farrell B, Godwin J, Richards S, Warlow C. The United Kingdom transient ischaemic
attack (UK-TIA) aspirin trial: final results. J Neurol Neurosurg Psychiatry. 1991;54:10441054.
11.
Viscoli CM, Brass LM, Kernan WN, Sarrel PM, Suissa S, Horwitz RI. A Clinical Trial of
Estrogen-Replacement Therapy after Ischemic Stroke. N Engl J Med. 2001;345:12431249.
12.
Chimowitz MI, Lynn MJ, Howlett-Smith H, Stern BJ, Hertzberg VS, Frankel MR, Levine SR,
Chaturvedi S, Kasner SE, Benesch CG, Sila CA, Jovin TG, Romano JG. Comparison of
warfarin and aspirin for symptomatic intracranial arterial stenosis. N Engl J Med.
2005;352:1305-1316.
13.
The Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators.
Effects of Clopidogrel in Addition to Aspirin in Patients with Acute Coronary Syndromes
without ST-Segment Elevation. N Engl J Med. 2001;345:494-502.
14.
Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, Neumann
FJ, Ardissino D, De Servi S, Murphy SA, Riesmeyer J, Weerakkody G, Gibson CM,
Antman EM. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N
Engl J Med. 2007;357:2001-2015.
15.
Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, Brown L, Warnica
JW, Arnold JM, Wun CC, Davis BR, Braunwald E. The effect of pravastatin on coronary
events after myocardial infarction in patients with average cholesterol levels. Cholesterol
and Recurrent Events Trial investigators. N Engl J Med. 1996;335:1001-1009.
16.
LaRosa JC, Grundy SM, Waters DD, Shear C, Barter P, Fruchart J-C, Gotto AM, Greten H,
Kastelein JJP, Shepherd J, Wenger NK, the Treating to New Targets Investigators.
Intensive Lipid Lowering with Atorvastatin in Patients with Stable Coronary Disease. N
Engl J Med. 2005;352:1425-1435.
17.
Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensinconverting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The
Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. 2000;342:145153.
18.
Lithell H, Hansson L, Skoog I, Elmfeldt D, Hofman A, Olofsson B, Trenkwalder P, Zanchetti
A. ; SCOPE Study Group. The Study on Cognition and Prognosis in the Elderly (SCOPE):
principal results of a randomized double-blind intervention trial. Journal of Hypertension.
2003;21:875-886.
19.
Writing Group for the Women's Health Initiative Investigators. Risks and Benefits of
Estrogen Plus Progestin in Healthy Postmenopausal Women: Principal Results From the
Women's Health Initiative Randomized Controlled Trial. Jama. 2002;288:321-333.
Supplemental Table 1. Ranks of treatment effect of included trials for composite endpoint
Rank
Conventional approach
DALY approach
Age 60
Age 50
Age 70
1
EAFT
EAFT
EAFT
EAFT
2
NASCET
NASCET
NASCET
NASCET
3
CURE
CURE
CURE
CURE
4
TRITON-TIMI 38
ESPS-2
ESPS-2
ESPS-2
5
ESPS-2
TRITON-TIMI 38
PROGRESS
TRITON-TIMI 38
6
PROGRESS
PROGRESS
TRITON-TIMI 38
PROGRESS
7
ESPRIT
ESPRIT
ESPRIT
ESPRIT
8
CARE
HOPE
HOPE
HOPE
9
HOPE
CARE
CARE
CARE
10
TASS
TASS
TASS
TASS
11
SPARCL
SPARCL
SPARCL
SPARCL
12
TNT
CAPRIE_Stroke
CAPRIE_Stroke
TNT
13
UK-TIA
TNT
TNT
CAPRIE_Stroke
14
CAPRIE_Stroke
UK-TIA
UK-TIA
UK-TIA
15
SCOPE
SCOPE
SCOPE
SCOPE
16
WASID
WHI
WHI
WHI
17
WHI
WEST
WEST
WEST
18
WEST
WASID
WASID
WASID
Supplemental Table 2. Sensitivity analyses varing the assumption of age of onset to ages 50 and 70
For age of onset at 50, DALYs[3,1] saved for 100 patient-years and NNT for saving one DALY[3,1] and preventing one event
Composite endpoint
Nonfatal stroke
Nonfatal MI
Vascular death
DALY
saved
NNT for
one
DALY
NNT for
one
event
DALY
saved
NNT for
one
DALY
NNT for
one
event
DALY
saved
NNT for
one
DALY
NNT for
one
event
DALY
saved
NNT for
one
DALY
NNT for
one
event
EAFT
62.89
1.6
13.8
84.49
1.2
12.4
5.65
17.7
119.0
-27.25
-3.7
-61.6
NASCET
52.23
1.9
21.6
42.32
2.4
24.8
NR
NR
NR
9.91
10.1
169.4
ESPS-2
15.96
6.3
67.1
15.61
6.4
67.2
-0.20
-495.4
-3334.4
0.55
183.2
3079.6
PROGRESS
12.02
8.3
71.4
9.27
10.8
113.1
2.04
49.0
330.1
0.71
140.5
2358.3
ESPRIT
11.97
8.4
104.3
5.38
18.6
194.9
0.60
166.5
1120.6
5.99
16.7
280.4
TASS
8.01
12.5
129.0
8.34
12.0
125.9
NR
NR
NR
-0.33
-303.9
-5103.1
SPARCL
6.04
16.5
142.3
3.36
29.7
311.9
2.50
40.0
269.3
0.18
550.0
9233.6
CAPRIE_Str
5.71
17.5
179.2
4.86
20.6
215.9
0.50
201.5
1356.1
0.35
281.8
4731.6
Stroke trials
UK-TIA
3.85
25.9
177.5
5.41
18.5
193.7
1.57
63.6
427.8
-3.13
-31.9
-535.9
WEST
-8.04
-12.4
-208.6
2.88
34.7
364.3
-1.16
-85.9
-577.8
-9.75
-10.3
-172.2
WASID
-10.32
-9.69
-4538.8
21.15
4.73
49.6
-1.84
-54.3
-365.4
-29.62
-3.4
-56.7
CURE
29.31
3.4
31.8
3.78
26.5
277.7
14.18
7.1
47.5
11.36
8.8
147.8
TRITON-TIMI 38
11.93
8.4
54.1
0.01
8702.0
91284.0
12.77
7.8
52.7
-0.85
-117.8
-1977.8
CARE
9.19
10.9
111.5
3.02
33.1
346.9
2.71
36.9
248.3
3.45
29.0
486.5
TNT
5.65
17.7
177.3
1.56
64.0
671.3
1.93
51.9
349.0
2.16
46.3
778.1
HOPE
10.91
9.2
120.3
2.14
46.6
489.2
1.18
84.9
571.1
7.59
13.2
221.3
SCOPE
3.80
26.3
351.3
2.63
38.0
399.0
-0.40
-247.9
-1668.4
1.58
63.4
1064.0
WHI
-1.52
-66.0
-627.8
-0.83
-121.2
-1270.6
-0.44
-225.5
-1517.4
-0.25
-405.9
-6814.6
CHD trials
Primary prevention
trials
For age of onset at 70, DALYs[3,1] saved for 100 patient-years and NNT for saving one DALY[3,1] and preventing one event
Composite endpoint
Nonfatal stroke
Nonfatal MI
Vascular death
DALY
saved
NNT for
one
DALY
NNT for
one
event
DALY
saved
NNT for
one
DALY
NNT for
one
event
DALY
saved
NNT for
one
DALY
NNT for
one
event
DALY
saved
NNT for
one
DALY
NNT for
one
event
EAFT
32.24
3.1
13.8
40.76
2.5
12.4
3.23
30.9
119
-11.75
-8.5
-61.6
NASCET
24.69
4.1
21.6
20.41
4.9
24.8
NR
NR
NR
4.27
23.4
169.4
ESPS-2
7.65
13.1
67.1
7.53
13.3
67.2
-0.12
-866.1
-3334.4
0.24
425.4
3079.6
PROGRESS
5.95
16.8
71.4
4.47
22.4
113.1
1.17
85.7
330.1
0.31
325.7
2358.3
ESPRIT
5.52
18.1
104.3
2.60
38.5
194.9
0.34
291.1
1120.6
2.58
38.7
280.4
TASS
3.88
25.8
129
4.02
24.9
125.8
NR
NR
NR
-0.14
-704.8
-5103.1
SPARCL
3.13
31.9
142.3
1.62
61.6
311.9
1.43
69.9
269.3
0.08
1275.4
9233.6
CAPRIE_Str
2.78
36.0
179.2
2.34
42.7
215.9
0.28
352.2
1356.1
0.15
653.5
4731.6
UK-TIA
2.16
46.3
177.5
2.61
38.3
193.7
0.90
111.1
427.8
-1.35
-74.0
-535.9
WEST
-3.48
-28.7
-208.6
1.39
72.0
364.3
-0.67
-150.1
-577.8
-4.20
-23.8
-172.2
WASID
-3.63
-27.6
-4538.8
10.20
9.8
49.6
-1.05
-94.9
-365.4
-12.77
-7.8
-56.7
CURE
14.83
6.7
31.8
1.82
54.9
277.7
8.11
12.3
47.5
4.90
20.4
147.8
TRITON-TIMI 38
6.94
14.4
54.1
0.01
18040.3
91284
7.30
13.7
52.7
-0.37
-273.2
-1977.8
CARE
4.50
22.2
111.5
1.46
68.6
346.9
1.55
64.5
248.3
1.49
67.2
486.5
TNT
2.79
35.9
177.3
0.75
132.7
671.3
1.10
90.7
349
0.93
107.5
778.1
HOPE
4.98
20.1
120.3
1.03
96.7
489.2
0.67
148.3
571.1
3.27
30.6
221.3
SCOPE
1.72
58.2
351.3
1.27
78.8
399
-0.23
-433.4
-1668.4
0.68
147.0
1064
WHI
-0.76
-131.9
-627.8
-0.40
-251.1
-1270.6
-0.25
-394.1
-1517.4
-0.11
-941.2
-6814.6
Stroke trials
CHD trials
Primary prevention
trials
Supplemental Table 3. DALY analysis for subsequent vascular events
Nonfatal MI at 60,
nonfatal stroke at 65,
and death at 70
Nonfatal stroke at 60,
nonfatal MI at 65,
and death at 70
Nonfatal MI at 60,
and death at 70
YLD to
nonfatal MI
YLD to
nonfatal stroke
0.26
(for 10 years
from age of 60)
0.13
(for 5 years
from age of 65)
0.26
(for 10 years
from age of 60)
0.93
(for 5 years
from age of 65)
1.85
(for 10 years
from age of 60)
Nonfatal stroke at 60,
and death at 70
Nonfatal MI at 60,
and death at 65
1.85
(for 10 years
from age of 60)
0.15
(for 5 years
from age of 60)
YLL to
premature
death
7.24
DALY
7.24
9.22
7.24
7.50
7.24
9.09
9.36
9.51
8.43
Nonfatal stroke at 60,
and death at 65
1.05
9.36
10.41
(for 5 years
from age of 60)
For a patient who has an MI at age 60, and then a stroke at 65, and then die at 70, the DALY
lost of this patient would be the sum of the YLD lost to nonfatal MI for 10 years (as he will have
post-MI disability until death even after the subsequent stroke), YLD to nonfatal stroke for 5 years,
and YLL due to premature death at 70.
The life expectancies for general population at 60, 65 and 70 were assumed to be 22.5, 18.93,
and 15.35 years. The life expectancies at 60 and 70 were derived from the data of Framingham
study and that at 65 were derived from the extrapolation of these two values. Although, in the
main analysis, the DALYs lost for nonfatal stroke and nonfatal MI at 60 were calculated from the
assumption of the life expectancy at 60 for stroke survivors as 8.9 years and for MI survivors as
11.2 years based on Framingham study observation, here we assume that patients with nonfatal
event without subsequent events will die at 65 or 70 for convenient comparison.
When compared to the DALY lost values for nonfatal MI (5.14) and nonfatal stroke (7.63) at 60
provided in table 2 of the manuscript, those for nonfatal MI at 60 and death at 70 (7.50) and
nonfatal stroke at 60 and death at 70 (9.09) in the above table are magnified. This difference is
mainly caused by whether future discounting for death event was applied or not. In our main
analysis, we were to derive the DALY lost value for the vascular event at 60. In this case, since
the death is the future event for patients with nonfatal event, the DALY lost of the future death
needs to be discounted (annual discount rate of 3%).1 However, in this supplemental analysis, as
we are to demonstrate how the DALY metric incorporates the subsequent events, we do not apply
the future discounting assuming that we prospectively capture the subsequent events.
Reference
1. Fox-Rushby JA, Hanson K. Calculating and presenting disability adjusted life years (DALYs)
in cost-effectiveness analysis. Health Policy and Planning. 2001;16:326-331.