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n e w e ng l a n d j o u r na l
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m e dic i n e
Original Article
A BS T R AC T
BACKGROUND
RESULTS
The decrease in the LDL cholesterol level was 33.7 mg per deciliter (0.87 mmol per liter)
greater in the combined-therapy group than in the dual-placebo group, and the decrease
in systolic blood pressure was 6.2 mm Hg greater with combined therapy than with
dual placebo. The first coprimary outcome occurred in 113 participants (3.6%) in the
combined-therapy group and in 157 (5.0%) in the dual-placebo group (hazard ratio,
0.71; 95% confidence interval [CI], 0.56 to 0.90; P=0.005). The second coprimary outcome occurred in 136 participants (4.3%) and 187 participants (5.9%), respectively
(hazard ratio, 0.72; 95% CI, 0.57 to 0.89; P=0.003). Muscle weakness and dizziness were
more common in the combined-therapy group than in the dual-placebo group, but the
overall rate of discontinuation of the trial regimen was similar in the two groups.
CONCLUSIONS
The combination of rosuvastatin (10 mg per day), candesartan (16 mg per day), and
hydrochlorothiazide (12.5 mg per day) was associated with a significantly lower rate
of cardiovascular events than dual placebo among persons at intermediate risk who
did not have cardiovascular disease. (Funded by the Canadian Institutes of Health
Research and AstraZeneca; ClinicalTrials.gov number, NCT00468923.)
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The
n e w e ng l a n d j o u r na l
Me thods
Trial Design and Oversight
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ticle at NEJM.org). The results of the blood-pressurelowering analysis and the lipid-lowering
analysis are reported in accompanying articles
in the Journal.9,10 A detailed description of the trial
methods is provided in the article that focuses on
the effects of blood-pressure lowering.
The trial was designed by the steering committee who, along with staff at the Population
Health Research Institute, oversaw the conduct
of the trial, the collection and analysis of the data,
and the interpretation of the results. The first author along with three other authors from the
Population Health Research Institute had full access to the data and vouch for the accuracy and
completeness of the data and analysis and for
the fidelity of this report to the protocol. The
first author drafted the manuscript, and all the
authors made the decision to submit the manuscript for publication. Funding was provided by
the Canadian Institutes of Health Research and
AstraZeneca. AstraZeneca provided the trial drug,
served as a single voting member on the 24-member steering committee, and had no other role in
the trial. The trial was conducted at 228 centers
in 21 countries and received regulatory and ethics approval for each participating site or from a
central board that provided approval for multiple
sites. All participants provided written informed
consent.
Eligibility
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Trial Procedures
Statistical Analysis
Outcomes
R e sult s
Trial Participants and Follow-up
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The
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Table 1. Characteristics of the 12,705 Participants in the Heart Outcomes Prevention Evaluation3 Trial at Baseline.*
Candesartan
Hydrochlorothiazide
plus Rosuvastatin
(N=3180)
Characteristic
Age yr
Rosuvastatin
plus Placebo
(N=3181)
Candesartan
Hydrochlorothiazide
plus Placebo
(N=3176)
Placebo
plus Placebo
(N=3168)
65.76.3
65.86.4
65.66.4
65.76.3
1465 (46.1)
1486 (46.7)
1445 (45.5)
1478 (46.7)
2771 (87.1)
2769 (87.0)
2740 (86.3)
2754 (86.9)
889 (28.0)
851 (26.8)
893 (28.1)
891 (28.1)
1201 (37.8)
1143 (35.9)
1096 (34.5)
1148 (36.2)
392 (12.3)
417 (13.1)
407 (12.8)
400 (12.6)
196 (6.2)
178 (5.6)
190 (6.0)
167 (5.3)
834 (26.2)
841 (26.4)
834 (26.3)
826 (26.1)
89 (2.8)
80 (2.5)
95 (3.0)
86 (2.7)
1200 (37.7)
1203 (37.8)
1198 (37.7)
1213 (38.3)
2 Risk factors
1486 (46.7)
1516 (47.7)
1486 (46.8)
1438 (45.4)
3 Risk factors
795 (25.0)
750 (23.6)
743 (23.4)
780 (24.6)
138.214.8
137.915.0
138.214.7
137.914.6
81.99.4
81.89.3
82.09.3
81.89.2
73.010.3
72.610.2
72.910.1
72.510.3
Blood pressure mm Hg
Systolic
Diastolic
Heart rate beats/min
Body-mass index
27.24.8
27.14.8
27.14.8
27.14.7
Waist-to-hip ratio
0.940.08
0.940.08
0.940.08
0.940.09
Total
201.343.5
201.841.6
201.541.7
201.241.7
LDL
127.037.0
128.635.2
127.936.0
127.936.0
HDL
44.714.1
44.813.7
45.113.7
44.813.8
Cholesterol mg/dl
Triglycerides mg/dl
Median
128.3
129.2
126.5
126.5
92.0182.3
93.8176.1
92.9178.8
92.9174.9
96.0
95.4
95.4
95.4
Interquartile range
87.0106.2
86.4106.0
86.4106.0
87.0106.0
Apolipoprotein B g/liter
1.020.27
1.030.26
1.020.26
1.020.26
Interquartile range
Fasting plasma glucose mg/dl
Median
Apolipoprotein A1 g/liter
1.460.34
1.460.34
1.470.34
1.460.33
0.750.36
0.750.31
0.740.31
0.740.32
2.1
2.0
2.0
2.0
Interquartile range
1.04.1
1.03.9
1.04.0
1.03.8
0.900.22
0.890.22
0.900.22
0.900.21
14.65.2
14.55.2
14.55.1
14.35.2
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Table 1. (Continued.)
Candesartan
Hydrochlorothiazide
plus Rosuvastatin
(N=3180)
Rosuvastatin
plus Placebo
(N=3181)
Candesartan
Hydrochlorothiazide
plus Placebo
(N=3176)
Placebo
plus Placebo
(N=3168)
Chinese
922 (29.0)
932 (29.3)
922 (29.0)
915 (28.9)
Hispanic
864 (27.2)
880 (27.7)
875 (27.6)
877 (27.7)
White
651 (20.5)
635 (20.0)
633 (19.9)
627 (19.8)
South Asian
465 (14.6)
462 (14.5)
467 (14.7)
460 (14.5)
Other Asian
Characteristic
Race or ethnic group no. (%)
169 (5.3)
172 (5.4)
173 (5.4)
182 (5.7)
Black
58 (1.8)
55 (1.7)
58 (1.8)
54 (1.7)
Other
51 (1.6)
45 (1.4)
48 (1.5)
53 (1.7)
Ezetimibe
7 (0.2)
4 (0.1)
3 (0.1)
3 (0.1)
Niacin
4 (0.1)
2 (0.1)
2 (0.1)
3 (0.1)
Aspirin
358 (11.3)
328 (10.3)
381 (12.0)
326 (10.3)
Beta-blocker
259 (8.1)
245 (7.7)
265 (8.3)
251 (7.9)
Calcium-channel blocker
444 (14.0)
497 (15.6)
484 (15.2)
460 (14.5)
Alpha-blocker
38 (1.2)
38 (1.2)
34 (1.1)
31 (1.0)
Nonthiazide diuretic
13 (0.4)
23 (0.7)
16 (0.5)
13 (0.4)
Aldosterone antagonist
3 (0.1)
9 (0.3)
3 (0.1)
2 (0.1)
92 (2.9)
75 (2.4)
84 (2.6)
86 (2.7)
* Plusminus values are means SD. There were no significant differences in the baseline characteristics among the four groups. Data on
blood pressure were missing for 2 participants in the dual-placebo group, and data on central core laboratory measurements of low-density
lipoprotein (LDL) cholesterol concentration for 321 in the combined-therapy group, 335 in the rosuvastatin-plus-placebo group, 328 in the
group assigned to candesartanhydrochlorothiazide plus placebo, and 323 in the dual-placebo group. Data on age and sex were complete.
Data on other characteristics were available for 99.7% or more of the trial participants, except that some laboratory variables measured at
the central core laboratory had rates of missing data similar to that for LDL cholesterol concentration. To convert the values for cholesterol
to millimoles per liter, multiply by 0.0259. To convert the values for triglycerides to millimoles per liter, multiply by 0.01129. To convert the
values for glucose to millimoles per liter, multiply by 0.05551. To convert the values for creatinine to micromoles per liter, multiply by 88.4.
HDL denotes high-density lipoprotein.
Case definitions for the cardiovascular risk factors are provided in Table S2 in the Supplementary Appendix.
The body-mass index is the weight in kilograms divided by the square of the height in meters.
The scale of the INTERHEART Risk Score ranges from 0 to 49; low cardiovascular risk corresponds to a score of 9 or less, medium risk to a
score of 10 to 15, and high risk to a score of 16 or more.12
Race and ethnic group were determined by self-report.
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The
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140
Dual placebo
135
Rosuvastatin plus placebo
CandesartanHCTZ plus placebo
130
Combined therapy
125
120
0
Week 6
0
Year 1
Month 6
Year 2
Year 3
Year 4
Year 5
Year 6
Year 7
No. at Risk
Combined therapy
Rosuvastatin plus
placebo
CandesartanHCTZ
plus placebo
Dual placebo
2953
2957
2836
2832
2718
2741
2594
2615
1921
1929
731
728
178
167
2954
2831
2728
2619
1941
706
172
2922
2791
2701
2571
1893
696
167
B LDL Cholesterol
140
CandesartanHCTZ plus placebo
Dual placebo
120
100
90
Combined therapy
80
0
Year 1
Year 3
End of
Trial
248
232
248
232
248
232
248
232
247
247
247
247
248
248
248
248
No. at Risk
Combined therapy
Rosuvastatin plus
placebo
CandesartanHCTZ
plus placebo
Dual placebo
Figure 1. Levels of Systolic Blood Pressure and Low-Density Lipoprotein (LDL) Cholesterol, According to Trial Group.
Combined therapy is candesartanhydrochlorothiazide (HCTZ) plus rosuvastatin. To convert the values for LDL
cholesterol to millimoles per liter, multiply by 0.0259. I bars represent 95% confidence intervals.
weakness or pain was similar in the combinedMuscle weakness and dizziness were more com- therapy group and the rosuvastatin-plus-placebo
mon in the combined-therapy group than in the group, and the incidence of dizziness, lightheaddual-placebo group. The incidence of muscle edness, or hypotension was similar in the comAdverse Effects
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8
171 (5.4)
109/3001 (3.6)
140 (4.4)
418 (13.1)
141
39
4
184
141 (4.4)
463 (14.6)
136
29
2
169
79 (2.5)
24 (0.8)
39 (1.2)
3 (0.1)
29 (0.9)
11 (0.3)
31 (1.0)
75 (2.4)
21 (0.7)
31 (1.0)
1 (<0.1)
27 (0.8)
10 (0.3)
25 (0.8)
163 (5.1)
123/2982 (4.1)
122 (3.8)
141 (4.4)
159 (5.0)
113 (3.6)
136 (4.3)
147 (4.6)
Rosuvastatin
plus Placebo
(N=3181)
176
30
3
211
178 (5.6)
436 (13.7)
179 (5.6)
113/2984 (3.8)
80 (2.5)
31 (1.0)
44 (1.4)
1 (<0.1)
37 (1.2)
11 (0.3)
26 (0.8)
147 (4.6)
176 (5.5)
188 (5.9)
Candesartan
Hydrochlorothiazide
plus Placebo
(N=3176)
187
59
13
262
191 (6.0)
443 (14.0)
178 (5.6)
113/2999 (3.8)
91 (2.9)
38 (1.2)
55 (1.7)
3 (0.1)
45 (1.4)
18 (0.6)
38 (1.2)
157 (5.0)
187 (5.9)
205 (6.5)
Placebo
plus Placebo
(N=3168)
0.66 (0.520.84)
0.73 (0.590.91)
1.04 (0.921.19)
0.91 (0.731.12)
1.09 (0.851.41)
0.82 (0.601.11)
0.55 (0.320.93)
0.56 (0.360.87)
0.33 (0.033.18)
0.59 (0.370.95)
0.55 (0.251.19)
0.65 (0.391.08)
0.71 (0.560.90)
0.72 (0.570.89)
0.71 (0.570.87)
0.001
0.005
0.52
0.005
0.003
0.001
P Value
CandesartanHydrochlorothiazide plus
Rosuvastatin vs. Placebo plus Placebo
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of
* The first coprimary outcome was the composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke; the second coprimary outcome was the composite of cardiovascular
death, nonfatal myocardial infarction, nonfatal stroke, resuscitated cardiac arrest, heart failure, or revascularization; and the secondary outcome was the composite of cardiovascular death,
nonfatal myocardial infarction, nonfatal stroke, resuscitated cardiac arrest, heart failure, revascularization, or angina with objective evidence of ischemia. CI denotes confidence interval.
The hazard ratio for rosuvastatin plus placebo versus placebo plus placebo was 0.77 (95% CI, 0.61 to 0.97) and for rosuvastatin plus placebo versus candesartanhydrochlorothiazide
plus placebo was 0.82 (95% CI, 0.65 to 1.05).
The hazard ratio for candesartanhydrochlorothiazide plus placebo versus placebo plus placebo was 0.93 (95% CI, 0.75 to 1.17).
The hazard ratio for rosuvastatin plus placebo versus placebo plus placebo was 0.74 (95% CI, 0.60 to 0.93) and for rosuvastatin plus placebo versus candesartanhydrochlorothiazide
plus placebo was 0.79 (95% CI, 0.64 to 0.99).
The hazard ratio for candesartanhydrochlorothiazide plus placebo versus placebo plus placebo was 0.94 (95% CI, 0.76 to 1.15).
The secondary outcome a composite of events comprising the second coprimary outcome plus angina with evidence of ischemia and the individual outcome of angina with ob
jective evidence of ischemia were not included in the original protocol but were added by the steering committee before data lock and analysis.
** Hospitalizations were a prespecified safety outcome.
These outcomes were not prespecified in the trial protocol.
Outcome
Candesartan
Hydrochlorothiazide
plus Rosuvastatin
(N=3180)
The
m e dic i n e
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Discussion
In the HOPE-3 trial, which involved a primary
prevention population at intermediate risk and
with average lipid and blood pressure levels,
combination therapy with rosuvastatin (10 mg
per day), candesartan (16 mg per day), and hydrochlorothiazide (12.5 mg per day) for a median of 5.6 years was associated with a significantly lower risk of cardiovascular events than
dual placebo (29% lower relative risk and
1.4-percentage-point lower absolute risk of the
first primary outcome). The number needed to
treat for 5.6 years to prevent one event of the
first coprimary outcome was 72, and the number needed to treat to prevent one event of the
second coprimary outcome was 63. In a post hoc
recurrent-events analysis, the benefit was slightly larger.
The reduction in LDL cholesterol concentration was approximately 33.7 mg per deciliter
over the course of the trial (which is similar to
the 38.6 mg per deciliter [1.00 mmol per liter]
that was expected),8 and the reduction in systolic blood pressure was 6.2 mm Hg (which is
lower than the expected 8 mm Hg reduction).
Rates of adherence to rosuvastatin and to candesartanhydrochlorothiazide were high, and so
the degree of cholesterol and blood-pressure
lowering that we observed, in a large population
treated over a median of 5.6 years, is probably
more representative than that observed in small,
short-term trials involving persons with elevated
blood pressure or high lipid levels. Greater reductions in LDL cholesterol and in systolic blood
pressure could be achieved with a more intensive
regimen, and the reductions in cardiovascular
outcomes could be larger,14,15 but the safety of
such an approach would need to be established.
We performed a post hoc subgroup analysis
comparing participants in the upper third of
baseline systolic blood pressure with those in
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The
Combined therapy
n e w e ng l a n d j o u r na l
0.08
0.8
0.10
0.06
0.6
0.04
0.02
0.4
0.00
0.2
0.0
1.0
0.025
0.8
0.020
Dual placebo
0.015
0.6
0.010
0.005
0.4
0.000
0.2
0.0
m e dic i n e
B Stroke
of
Year
Year
No. at Risk
No. at Risk
Combined therapy
Rosuvastatin plus
placebo
CandesartanHCTZ
plus placebo
Dual placebo
3180
3181
3147
3142
3117
3108
3063
3061
2997
3009
2508
2505
1057
1045
272
250
3176
3125
3083
3040
2971
2461
1019
250
3168
3128
3090
3035
2958
2465
1030
238
0.020
0.015
0.6
0.010
0.005
0.4
0.000
0.2
0.0
3155
3153
3132
3127
3088
3088
3028
3041
2538
2536
1071
1061
278
256
3176
3137
3103
3067
3010
2504
1040
256
3168
3138
3107
3059
3000
2509
1054
249
1.0
0.025
0.8
3180
3181
D Coronary Revascularization
C Myocardial Infarction
1.0
Combined therapy
Rosuvastatin plus
placebo
CandesartanHCTZ
plus placebo
Dual placebo
0.020
0.8
0.015
0.6
0.010
0.005
0.4
0.000
0.2
0.0
0.025
Year
Year
No. at Risk
No. at Risk
Combined therapy
Rosuvastatin plus
placebo
CandesartanHCTZ
plus placebo
Dual placebo
3180
3181
3156
3150
3131
3126
3088
3089
3027
3040
2541
2534
1074
1061
277
257
3176
3139
3102
3066
3016
2510
1040
255
3168
3139
3113
3066
3003
2514
1051
249
Combined therapy
Rosuvastatin plus
placebo
CandesartanHCTZ
plus placebo
Dual placebo
3180
3181
3156
3153
3132
3127
3087
3087
3023
3040
2535
2534
1067
1058
276
254
3176
3137
3104
3068
3013
2509
1036
253
3168
3139
3109
3059
2997
2506
1049
243
Figure 2. KaplanMeier Curves for the Second Coprimary Outcome, Stroke, Myocardial Infarction, and Coronary Revascularization.
Shown are cumulative hazard curves for the second coprimary outcome (a composite of cardiovascular death, nonfatal myocardial in
farction, nonfatal stroke, resuscitated cardiac arrest, heart failure, or revascularization; Panel A), stroke (Panel B), myocardial infarction
(Panel C), and coronary revascularization (Panel D). The hazard ratios, 95% confidence intervals, and P values are presented for the
comparison between combined therapy (rosuvastatin plus candesartanhydrochlorothiazide) and dual placebo. The insets show the
same data on an enlarged y axis.
unclear,19 and trials of folate in Western countries have been disappointing20 (although in a recent trial in China, where dietary folate intake is
low, stroke rates were reduced21).
There were no significant differences between the combined-therapy group and the dualplacebo group in the rate of new-onset diabetes,
10
renal dysfunction, syncope, liver-function abnormalities, eye problems, or cancers. Although the
rates of muscle weakness or pain and of dizziness were higher in the combined-therapy group
than in the dual-placebo group (by 0.9 percentage
points and 2.2 percentage points, respectively),
these effects were reversible by temporary dis-
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with fixed doses of rosuvastatin and two antihypertensive agents was associated with a significantly lower risk of cardiovascular events than the
risk with placebo among intermediate-risk persons without previous cardiovascular disease.
Appendix
The authors affiliations are as follows: the Population Health Research Institute, Hamilton Health Sciences (S.Y., E.L., J.B., R.M., J.P.,
H.J.), Department of Medicine (S.Y., E.L., R.M.), School of Rehabilitation Science (J.B.), Department of Clinical Epidemiology and
Biostatistics (J.P.), McMaster University, Hamilton, ON, Li Ka Shing Knowledge Institute and Keenan Research Centre for Biomedical
Science, St. Michaels Hospital, University of Toronto, Toronto (L.A.L.), and Institut Universitaire de Cardiologie et Pneumologie de
Qubec, Universit Laval, Quebec, QC (G.D.) all in Canada; St. Johns Research Institute (P.P., D.X.), and St. Johns Medical College
(D.X.), Bangalore, India; Fundacion Oftalmolgica de Santander and Instituto Masira, Medical School, Universidad de Santander, Bucaramanga (P.L.-J.), and Universidad del Norte, Barranquilla (J.L.A.) both in Colombia; Fu Wai Hospital, Chinese Academy of
Medical Sciences and Peking Union Medical College, Beijing (J.Z., L.L.); Dante Pazzanese Institute of Cardiology (A.A.) and HCor-Heart
Hospital (L.S.P.), Sao Paulo; Institute of Cardiology, Kiev, Ukraine (A.P.); Hungarian Institute of Cardiology, Semmelweis University,
Budapest, Hungary (M.K., K. Keltai); Hatter Institute for Cardiovascular Research in Africa, Department of Medicine, University of Cape
Town, Soweto Cardiovascular Research Group, Cape Town, South Africa (K.S.); Institute of Clinical Cardiology in the Russian Cardiology Research Complex, Moscow (I.C.); the Department of Cardiology, Academic Medical Center, Amsterdam (R.J.G.P.); the Department
of Medical Sciences, Cardiology, Clinical Research Center, Uppsala University, Uppsala, Sweden (C.H.); Universiti Teknologi Majlis
Amansh Rakyat, Selayang, and University College Sedaya International University, Kuala Lumpur (K.Y.) both in Malaysia; Lady Davis
Carmel Medical Center, Ruth and Bruce Rappaport School of Medicine, TechnionIsrael Institute of Technology, Haifa, Israel (B.S.L.);
University Hospital Motol, Prague, Czech Republic (P.J.); Diabetes Research Centre (K. Khunti) and the Department of Cardiovascular
Sciences (W.D.T.), University of Leicester, and the National Institute for Health Research, Leicester Cardiovascular Biomedical Research
Unit, Glenfield Hospital (W.D.T.) both in Leicester, United Kingdom; Primary Care Diabetes and Vascular Medicine, Monash Centre
of Cardiovascular Research and Education in Therapeutics (C.M.R.), and the Department of Epidemiology and Preventive Medicine
(J.V.), Monash University, Melbourne, VIC, and the School of Public Health, Curtin University, Perth, WA (C.M.R.) both in Australia;
Instituto Cardiovascular de Rosario, Rosario, Argentina (R.D.); and College of Medicine, University of the Philippines, Manila, Philippines (A.D.).
References
1. Roth GA, Forouzanfar MH, Moran
AE, et al. Demographic and epidemiologic drivers of global cardiovascular mortality. N Engl J Med 2015;372:1333-41.
2. Lewington S, Clarke R, Qizilbash N,
Peto R, Collins R. Age-specific relevance
of usual blood pressure to vascular mortality: a meta-analysis of individual data
for one million adults in 61 prospective
studies. Lancet 2002;360:1903-13.
3. Yusuf S, Hawken S, Ounpuu S, et al.
Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART
study): case-control study. Lancet 2004;
364:937-52.
4. ODonnell MJ, Xavier D, Liu L, et al.
Risk factors for ischaemic and intracerebral haemorrhagic stroke in 22 countries
(the INTERSTROKE study): a case-control
study. Lancet 2010;376:112-23.
5. Rose G. Strategy of prevention: les-
n engl j mednejm.org
11
The
n e w e ng l a n d j o u r na l
12
of
m e dic i n e
and blood-pressure-lowering in the Anglo-Scandinavian Cardiac Outcomes Trial. Eur Heart J 2006;27:2982-8.
19. Antiplatelet Trialists Collaboration.
Collaborative overview of randomised trials of antiplatelet therapy. I. Prevention of
death, myocardial infarction, and stroke
by prolonged antiplatelet therapy in various categories of patients. BMJ 1994;308:
81-106.
20. Clarke R, Halsey J, Lewington S, et al.
Effects of lowering homocysteine levels
with B vitamins on cardiovascular disease, cancer, and cause-specific mortality: meta-analysis of 8 randomized trials
involving 37 485 individuals. Arch Intern
Med 2010;170:1622-31.
21. Huo Y, Li J, Qin X, et al. Efficacy of
folic acid therapy in primary prevention of
stroke among adults with hypertension in
China: the CSPPT randomized clinical
trial. JAMA 2015;313:1325-35.
Copyright 2016 Massachusetts Medical Society.
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