Outcomes of Women Compared With Men After Non–ST-Segment Elevation Acute Coronary Syndromes

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY

VOL. 74, NO. 24, 2019

ª 2019 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION PUBLISHED BY ELSEVIER

Outcomes of Women Compared With Men After Non–ST-Segment Elevation Acute Coronary Syndromes Amy A. Sarma, MD,a Eugene Braunwald, MD,b Christopher P. Cannon, MD,c Jianping Guo, MAS,b KyungAh Im, PHD,b Elliott M. Antman, MD,b C. Michael Gibson, MD, MS,d L. Kristin Newby, MD, MHS,e Robert P. Giugliano, MD, SM,b David A. Morrow, MD, MPH,b Stephen D. Wiviott, MD,b Marc S. Sabatine, MD, MPH,b Michelle L. O’Donoghue, MD, MPHb

ABSTRACT BACKGROUND It remains disputed whether women are at excess risk of adverse outcomes versus men after non–ST-segment elevation acute coronary syndromes (NSTEACS) or whether differences are explained by discordant risk factors. OBJECTIVES A sex-specific analysis of cardiovascular outcomes after NSTEACS across trials conducted by the Thrombolysis In Myocardial Infarction (TIMI) Study Group was performed to determine the impact of sex on cardiovascular outcomes in this dataset. METHODS Ten TIMI trials were identified that enrolled >2,500 patients with NSTEACS within 30 days of hospitalization. Cox proportional hazards models were used to examine the association of sex with major adverse cardiovascular events (MACE) (cardiovascular death, myocardial infarction, or stroke) after adjusting for relevant risk factors in individual trials; point estimates were then combined by using random effects models. Individual components of the composite outcome and all-cause mortality were also analyzed. RESULTS Among 68,730 patients with NSTEACS, 19,827 (29%) were women. Women were older and more frequently had hypertension, diabetes, prior heart failure, and renal impairment than men. Before considering relevant confounders, women were at similar risk of MACE compared with men (hazard ratio [HR]: 1.04; 95% confidence interval [CI]: 0.99 to 1.09; p ¼ 0.16) but at higher risk of all-cause death (HR: 1.12; 95% CI: 1.01 to 1.24; p ¼ 0.03). After adjustment for baseline differences, risks of MACE (HR: 0.93; 95% CI: 0.88 to 0.98; p < 0.01) and all-cause death (HR: 0.84; 95% CI: 0.78 to 0.90; p < 0.0001) were lower among women compared with men. CONCLUSIONS After accounting for cardiovascular risk factors, women enrolled in clinical trials were at lower risk of MACE than men after NSTEACS. Women, however, remain undertreated with many evidence-based therapies. (J Am Coll Cardiol 2019;74:3013–22) © 2019 by the American College of Cardiology Foundation.

From the

a

Massachusetts General Hospital, Cardiovascular Division, Boston, Massachusetts;

b

Thrombolysis In Myocardial

Infarction Study Group, Brigham and Women’s Hospital, Cardiovascular Division, Boston, Massachusetts; cBrigham and Women’s Hospital, Cardiovascular Division, Boston, Massachusetts; dBeth Israel Deaconess Medical Center, Cardiovascular Division, Boston, Massachusetts; and the eDuke University School of Medicine, Cardiology Division, Duke Clinical Research Institute, Durham, Listen to this manuscript’s audio summary by Editor-in-Chief Dr. Valentin Fuster on JACC.org.

North Carolina. Dr. Braunwald has received research grants from GD Searle, Bristol-Myers Squibb, CV Therapeutics, Eli Lilly, Merck & Co., Johnson & Johnson, and GlaxoSmithKline; has served on the Speakers Bureau for Eli Lilly and Merck; and has served as a consultant or on advisory boards for Eli Lilly and Merck. Dr. Cannon has received research grants from Amgen, Arisaph, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Janssen, Merck, and Takeda; and has served as a consultant or on advisory boards for Alnylam, Amarin, Amgen, Arisaph, AstraZeneca, Bristol-Myers Squibb, Eisai, GlaxoSmithKline, Kowa, Merck, Pfizer, Regeneron, Takeda, Boehringer Ingelheim, LipimetiX, and Sanofi. Dr. Antman has received a research grant from Eli Lilly. Dr. Gibson has received a research grant from Janssen. Dr. Newby has served as a consultant or on advisory boards for OrthoClinical Diagnostics, Metanomics, Roche Diagnostics, and Biokier; and has received research grants from Boehringer Ingelheim and Amylin. Dr. Giugliano: has received research grants from Amgen and Merck; has received honoraria from Amgen, DaiichiSankyo, and Merck; and has served as a consultant or on advisory boards for Amarin, Amgen, Boehringer Ingelheim, BristolMyers Squibb, CVS Caremark, Daiichi-Sankyo, GlaxoSmithKline, Lexicon, Merck, Portola, and Pfizer. Dr. Morrow has received

ISSN 0735-1097/$36.00

https://doi.org/10.1016/j.jacc.2019.09.065

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Outcomes for Women and Men After NSTEACS

DECEMBER 17, 2019:3013–22

C

ABBREVIATIONS AND ACRONYMS ACS = acute coronary

ardiovascular disease remains the

independently associated with the risk of cardio-

leading cause of mortality among

vascular events during follow-up.

women (1,2). Moreover, sex-based

differences in manifestations of cardiovascu-

syndrome

lar

CAD = coronary artery disease

disease

are

increasingly

recognized.

Women tend to present with coronary disease

CI = confidence interval

at a later age and with a higher burden of

HR = hazard ratio

comorbidities than men (3–9). They are also

MACE = major adverse

more likely to exhibit atypical symptoms

cardiovascular event

(10–13) and are less likely to be treated

MI = myocardial infarction

with

NSTEACS = non–ST-segment

guideline-directed

medical

therapy

elevation acute coronary

(3,9,14–17) or cared for by a cardiologist

METHODS STUDY POPULATION. The TIMI clinical trial database

was reviewed to identify phase 3 clinical outcomes trials that enrolled patients within 30 days of an index NSTEACS event (Online Figure 1). Included trials had to have randomized >2,500 patients with NSTEACS within 30 days of hospitalization and have been published after the year 2000.

syndrome

during the index admission (3). Several

ENDPOINTS AND DATA EXTRACTION. For this anal-

PCI = percutaneous coronary

studies have shown that rates of rehospitali-

ysis, the primary outcome of interest was major

intervention

zation after acute coronary syndrome (ACS)

adverse cardiovascular events (MACE), defined as the

STEMI = ST-segment elevation

are higher among women than men, as

composite

myocardial infarction

are complication rates after percutaneous

infarction (MI), or stroke. Individual components of

TIMI = Thrombolysis In

coronary

(8,15,18–20).

the composite outcome were analyzed in addition

However, data are conflicting with respect to

to all-cause mortality. In the MERLIN-TIMI 36

Myocardial Infarction

intervention

(PCI)

of

cardiovascular

death,

myocardial

mortality risk after ACS, with some studies suggesting

(Metabolic

higher risk among women and others showing similar

Ischemia in NSTEACS-Thrombolysis In Myocardial

outcomes

between

sexes

(6,7,15,21).

Efficiency

With

Ranolazine

for

Less

Moreover,

Infarction 36) trial of an antianginal therapy (ranola-

whether observed differences in cardiovascular out-

zine), stroke was not prospectively collected as an

comes by sex result from true biological differences re-

outcome; therefore, the composite of cardiovascular

mains a topic of debate. Some recent studies suggest

death or MI is reported. The longest available follow-

that excess mortality after ACS among women

up was extracted for each trial to maximize the

may be largely accounted for by differences in baseline

number of included events.

comorbidities (5,22) or underuse of guideline-directed

STATISTICAL

medical therapy (15) rather than sex itself.

were summarized by pooling available data across

ANALYSIS. Baseline

characteristics

trials. Continuous variables were compared between

SEE PAGE 3023

women and men with the Wilcoxon rank sum test;

The present analysis of patients enrolled in

categorical variables were compared with a chi-

several large, randomized clinical trials of NSTEACS

square test. Cox proportional hazards models were

treatments

In

used to examine crude associations between sex and

Myocardial Infarction (TIMI) Study Group sought to

cardiovascular outcomes for each individual trial.

investigate

between

Because relevant confounders may have differed

women and men after non–ST-segment elevation

across trials, multivariable adjustment was conduct-

conducted whether

by

the

outcomes

Thrombolysis differed

acute coronary syndromes (NSTEACS) and, if pre-

ed for each trial individually (Online Table 1), and

sent, whether observed differences were attributable

adjusted point estimates were then combined across

to differences in baseline comorbidities and treat-

trials by using random effects models. To distinguish

ment

baseline predictors of risk from differences in

strategies

or

whether

sex

itself

was

research grants from Abbott Labs, Amgen, AstraZeneca, BRAHMS, Eisai, GlaxoSmithKline, The Medicines Company, Merck, Novartis, Pfizer, Roche, Takeda; and has served as a consultant or on advisory boards for Abbott Labs, AstraZeneca, InCardia, Peloton, Roche, Verseon, Aralez, and Bayer. Dr. Wiviott has received research grants from Amgen, Arena, AstraZeneca, BristolMyers Squibb, Daiichi-Sankyo, Eisai, Eli Lilly, Janssen, Merck, and Sanofi; and has served as a consultant or on advisory boards for Arena, AstraZeneca, Aegerion, Merck, Allergan, AngelMed, Boehringer Ingelheim, Boston Clinical Research Institute, BristolMyers Squibb, Daiichi-Sankyo, Eisai, Eli Lilly, Icon Clinical, Janssen, Lexicon, St. Jude Medical, and Xoma. Dr. Sabatine has received research grants from Amgen, AstraZeneca, Daiichi-Sankyo, Eisai, GlaxoSmithKline, Intarcia, Janssen, The Medicines Company, MedImmune, Merck, Novartis, Pfizer, Poxel, and Takeda; and has served as a consultant or on advisory boards for AstraZeneca, Bristol-Myers Squibb, CVS Caremark, Dyrnamix, Intarcia, Janssen, The Medicines Company, MedImmune, Merck, Novartis, Amgen, and Esperion. Dr. O’Donoghue has received research grants from Amgen, Merck, Eisai, AstraZeneca, GlaxoSmithKline, and The Medicines Company. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Manuscript received April 22, 2019; revised manuscript received September 18, 2019, accepted September 24, 2019.

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T A B L E 1 Pooled Baseline Characteristics Across Trials by Sex

Women (n ¼ 19,827)

Men (n ¼ 48,903)

Risk Difference* (95% CI) Women Versus Men

p Value

67 (59–74)

62 (55–70)

3.9 (3.8 to 4.1)

<0.001

Age $75 yrs

4,667/19,811 (23.6)

6,550/48,872 (13.4)

10.2 (9.5 to 10.8)

<0.001

BMI, kg/m2

28.0 (24.7–32.0)

27.7 (25.1–30.8)

0.5 (0.4 to 0.6)

<0.001

Age, yrs

Current smoker

4,073/19,811 (20.6)

16,079/48,866 (32.9)

–12.3 (–13.0 to –11.6)

<0.001

White

16,978/19,777 (85.9)

42,545/48,758 (87.3)

–1.4 (–2.0 to –0.9)

<0.001

Hypertension

15,221/19,818 (76.8)

31,458/48,861 (64.4)

12.4 (11.7 to 13.1)

<0.001

Hyperlipidemia

11,550/18,821 (61.4)

28,259/46,468 (60.8)

0.6 (–0.3 to 1.4)

0.189

Diabetes mellitus

6,861/19,826 (34.6)

13,387/48,900 (27.4)

7.2 (6.5 to 8.0)

<0.001

Prior MI

4,684/19,799 (23.7)

15,242/48,847 (31.2)

–7.6 (–8.3 to –6.8)

<0.001

Prior PCI

3,349/19,820 (16.9)

11,105/48,866 (22.7)

–5.8 (–6.5 to –5.2)

<0.001 <0.001

Prior heart failure

2,562/19,816 (12.9)

4,512/48,885 (9.2)

3.7 (3.2 to 4.2)

Baseline eGFR <60 ml/min

5,032/19,168 (26.3)

7,994/47,329 (16.9)

9.4 (8.7 to 10.1)

<0.001

Non–ST-segment elevation myocardial infarction at index event versus unstable angina

12,129/19,626 (61.8)

33,227/48,390 (68.7)

–6.9 (–7.7 to –6.1)

<0.001

Biomarker positive

12,992/17,952 (72.4)

35,141/44,905 (78.3)

–5.9 (–6.7 to –5.1)

<0.001

Time from index event to randomization, days

2.00 (0.98–5.00)

2.52 (1.00–6.00)

–0.2 (–0.3 to –0.1)

<0.001

Coronary angiography performed during index hospitalization

13,815/19,821 (69.7)

37,255/48,886 (76.2)

–6.5 (–7.3 to –5.8)

<0.001

PCI performed during index hospitalization

9,758/19,825 (49.2)

28,857/48,900 (59.0)

–9.8 (–10.6 to –9.0)

<0.001

Medication use during hospitalization or hospital discharge Aspirin

18,481/19,791 (93.4)

46,259/48,826 (94.7)

–1.4 (–1.8 to –1.0)

<0.001

P2Y12 inhibitor

11,278/14,228 (79.3)

29,919/34,752 (86.1)

–6.8 (–7.6 to –6.1)

<0.001

Statin

14,066/19,089 (73.7)

36,347/46,922 (77.5)

–3.8 (–4.5 to –3.1)

<0.001

Beta–blocker

16,089/19,820 (81.2)

39,888/48,889 (81.6)

–0.4 (–1.1 to 0.2)

0.206

ACE inhibitor or ARB

13,232/19,819 (66.8)

31,867/48,889 (65.2)

1.6 (0.8 to 2.4)

<0.001

Values are n/total number with available data (%), or median (interquartile range). *Risk differences are reported as percent differences for categorical variables and mean differences for continuous variables. ACE ¼ angiotensin-converting enzyme; ARB ¼ angiotensin receptor blocker; CI ¼ confidence interval; eGFR ¼ estimated glomerular filtration rate; BMI ¼ body mass index; MI ¼ myocardial infarction; PCI ¼ percutaneous coronary intervention.

treatments received during the index hospital stay,

Women tended to be older than men and had a

multivariable adjustment occurred in 2 steps. Model 1

higher prevalence of many comorbidities, including

adjusted for baseline predictors of risk, and model 2

hypertension, diabetes mellitus, prior heart failure,

additionally adjusted for treatments received during

and baseline renal impairment. Conversely, women

the index hospital stay (Online Table 1). Heterogene-

were less likely than men to be current smokers, have

ity across trials in the random effects models was

had a prior MI, and to have undergone prior PCI.

assessed with the Cochran Q statistic and I 2 test for heterogeneity. A pooled dataset was created to create cumulative incidence curves. A landmark analysis was conducted at 30 days to examine the timing of events. All statistical analyses were performed using SAS, version 9.4 (SAS Institute, Cary, North Carolina); and R, version 3.4.3 (R Core Team, Vienna, Austria). All tests were 2 sided, with p < 0.05 considered statistically significant.

SEX AND TREATMENT STRATEGIES FOR NSTEACS.

Differences in treatment strategies by sex for management of the qualifying NSTEACS were observed (Table 1). Overall, women were less likely than men to receive aspirin, P2Y 12 inhibitors, and statin therapy. Women were more likely than men to receive angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Beta-blocker use did not differ by sex.

RESULTS

Women were less likely than men to undergo coronary angiography (69.7% vs. 76.2%; p < 0.001) or be

Ten NSTEACS trials met the inclusion criteria and

treated with PCI (49.2% vs. 59.0%; p < 0.001) for

were

management of their NSTEACS (Table 1). When

included

in

the

current

analysis

(Online

Figure 1, Online Table 2). The mean follow-up time

excluding

across trials was 676 days. Among a total of 68,730

remained less likely than men to undergo coronary

patients, there were 19,827 (29%) women. Baseline

angiography (80.4% vs. 83.5%; p < 0.0001) or PCI

characteristics by sex are displayed in Table 1.

(73.0% vs. 79.3%; p < 0.0001) despite a diagnosis of

those

with

unstable

angina,

women

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F I G U R E 1 Relative Risk of MACE in Women Versus Men After NSTEACS

A

TRIAL

Unadj RR (95% CI)

OPUS-TIMI 16

0.96 (0.79-1.61)

A2Z-TIMI 21

0.86 (0.67-1.11)

PROVE IT-TIMI 22

1.13 (0.84-1.51)

MERLIN-TIMI 36

1.09 (0.93-1.28)

TRITON-TIMI 38

1.10 (0.96-1.25)

EARLY ACS-TIMI 39

0.99 (0.87-1.12)

ATLAS ACS 2-TIMI 51

0.97 (0.81-1.17)

SOLID-TIMI 52

1.08 (0.95-1.24)

IMPROVE-IT TIMI 40

1.03 (0.94-1.13)

LATITUDE-TIMI 60

1.15 (0.88-1.49)

OVERALL

1.04 (0.99-1.09), p = 0.16

0.5 0.6

0.8 1.0 1.2

↓ in Women

1.6

2.0

↓ in Men

I2 = <0.0001% p for heterogeneity = 0.74

Unadjusted Risk of MACE

B

TRIAL

Adj RR (95% CI)

OPUS-TIMI 16

0.76 (0.62-0.95)

A2Z-TIMI 21

0.69 (0.52-0.91)

PROVE IT-TIMI 22

1.04 (0.77-1.40)

MERLIN-TIMI 36

0.93 (0.78-1.10)

TRITON-TIMI 38

1.01 (0.88-1.17)

EARLY ACS-TIMI 39

0.91 (0.79-1.04)

ATLAS ACS 2-TIMI 51

0.85 (0.70-1.04)

SOLID-TIMI 52

0.99 (0.86-1.14)

IMPROVE-IT TIMI 40

0.94 (0.85-1.03)

LATITUDE TIMI 60

1.11 (0.84-1.48)

OVERALL

0.93 (0.88-0.98), p = 0.006

0.5 0.6

0.8 1.0 1.2

↓ in Women

1.6

↓ in Men

2.0 I2 = 0.001% p for heterogeneity = 0.17

Adjusted Risk of MACE

Continued on the next page

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DECEMBER 17, 2019:3013–22

Outcomes for Women and Men After NSTEACS

non-STEMI. Among those who underwent coronary

Further adjustment for the use of guideline-based

angiography, women were more likely than men to

therapies (model 2) did not significantly alter the

have nonobstructive coronary artery disease (CAD)

relative risk estimates for MACE (adjusted HR: 0.92;

(10.9% vs. 4.4%; p < 0.0001) and, therefore, less

95% CI: 0.87 to 0.97; p ¼ 0.001), all-cause mortality

likely to require PCI (70.4% vs. 77.1%; p < 0.0001).

(adjusted HR: 0.82; 95% CI: 0.76 to 0.88; p < 0.0001),

When high-risk patient groups were examined,

cardiovascular death (adjusted HR: 0.83; 95% CI: 0.73

women remained less likely than men to be treated

to 0.93; p ¼ 0.002), MI (adjusted HR: 0.96; 95% CI:

with aspirin, a P2Y 12 inhibitor, or statin therapy or to

0.90 to 1.02; p ¼ 0.19), or stroke (adjusted HR: 0.90;

undergo coronary angiography or PCI, including

95% CI: 0.74 to 1.09; p ¼ 0.28) by sex (Table 2).

those who had positive biomarkers or had a history of

In a landmark analysis, the crude excess risk of

PCI, hypertension, heart failure, diabetes, or hyper-

death that was observed in women was apparent

lipidemia (Online Table 3). Women were less likely

within 30 days of ACS (unadjusted HR: 1.24; 95% CI:

than men to receive antiplatelet (aspirin or P2Y12 in-

1.07 to 1.44) and became more attenuated beyond

hibitor) or statin therapy in the presence of obstruc-

that time (unadjusted HR: 1.06; 95% CI: 0.93 to 1.22).

tive CAD at coronary angiography. When restricted to

After multivariable adjustment, the risk of death in

those men and women who underwent PCI, women

women was attenuated through day 30 (adjusted HR:

were less likely to receive aspirin and statin therapy

0.91; 95% CI: 0.76 to 1.08) and was lower in women

but more likely to be treated with renin-angiotensin

than men from day 30 through follow-up (adjusted HR:

system or beta blockade (Online Table 3). SEX AND CARDIOVASCULAR RISK. In unadjusted

0.80; 95% CI: 0.74 to 0.87). The relative risk of MACE

analyses, women were at similar risk of MACE as men

(HR: 1.05; 95% CI: 0.92 to 1.20 vs. HR: 1.04; 95% CI: 0.98

(hazard ratio [HR]: 1.04; 95% confidence interval [CI]:

to 1.10, respectively) (Figure 3). After multivariable

0.99 to 1.09; p ¼ 0.16) (Figure 1A) after NSTEACS but

adjustment, the risk of MACE tended to be lower in

were at increased risk of cardiovascular death (HR: 1.16;

women through day 30 (adjusted HR: 0.86; 95% CI:

95% CI: 1.02 to 1.32; p ¼ 0.03), all-cause mortality (HR:

0.76 to 0.97) and from day 30 through long-term

1.12; 95% CI: 1.01 to 1.24; p ¼ 0.03) (Figure 2A, Central

follow up (adjusted HR: 0.93; 95% CI: 0.88 to 0.99).

was similar in women and men before and after 30 days

Illustration), and stroke (HR: 1.19; 95% CI: 1.03 to 1.37;

Qualitatively consistent results were observed

p ¼ 0.02). The risk of MI was similar irrespective of

when the overall analysis was restricted to biomarker-

patient sex (HR: 1.00; 95% CI: 0.94 to 1.06; p ¼ 0.94).

positive and -negative subgroups (Online Table 4).

After adjusting for baseline risk predictors (model 1) (Table 2), we found that women had a 7% lower risk

DISCUSSION

of MACE (adjusted HR: 0.93; 95% CI: 0.89 to 0.98; p ¼ 0.005) (Figure 1B), including a 15% lower risk of

In a large population of patients with NSTEACS

cardiovascular death (adjusted HR: 0.85; 95% CI: 0.76

enrolled across trials conducted by the TIMI Study

to 0.96; p ¼ 0.008) (Table 2), and 16% lower risk of all-

Group, we determined that women were at similar

cause death (adjusted HR: 0.84; 95% CI: 0.78 to 0.90;

unadjusted risk of MACE but were at increased risk of

p < 0.0001) (Figure 2B, Central Illustration). The

death and stroke compared with men. However,

adjusted risk of MI and stroke did not differ between

these differences appeared to be explained by sex-

women and men (adjusted HR: 0.96; 95% CI: 0.91 to

based differences in age and other presenting

1.03; p ¼ 0.23 vs. adjusted HR: 0.91; 95% CI: 0.75 to

comorbidities because women were at lower risk of

1.10; p ¼ 0.35, respectively) (Table 2).

death and MACE once these factors were considered.

F I G U R E 1 Continued

The (A) unadjusted and (B) adjusted risk of MACE (cardiovascular death, MI, or stroke) after NSTEACS across TIMI trials. Red diamonds represent HR and 95% CI. Blue squares are weighted based on the inverse variance with black lines reflecting 95% CI. A2Z-TIMI 21 ¼ A to Z trial to assess the efficacy and safety of enoxaparin with the glycoprotein IIb/IIIa inhibitor tirofiban compared with combining unfractionated heparin with tirofiban in patients with ACS; Adj ¼ adjusted; ATLAS ACS2-TIMI 51 ¼ Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome; CI ¼ confidence interval; EARLY ACS-TIMI 39 ¼ Early Glycoprotein IIb/IIIa Inhibition in Non-ST-Segment Elevation Acute Coronary Syndrome; IMPROVE-IT TIMI 40 ¼ Improved Reduction of Outcomes: Vytorin Efficacy International Trial; LATITUDE-TIMI 60 ¼ Losmapimod to Inhibit p38 MAP Kinase as a Therapeutic Target and Modify Outcomes After an Acute Coronary Syndrome; MACE ¼ major adverse cardiovascular event; MERLIN-TIMI 36 ¼ Metabolic Efficiency with Ranolazine for Less Ischemia in Non-ST-Elevation Acute Coronary Syndrome; MI ¼ myocardial infarction; NSTEACS ¼ non–ST-segment elevation acute coronary syndrome; OPUS-TIMI 16 ¼ Orbofiban in Patients with Unstable Coronary Syndrome; PROVE-IT TIMI 22 ¼ Pravastatin or Atorvastatin Evaluation and Infection Therapy; RR ¼ relative risk; SOLID-TIMI 52 ¼ Stabilization of Plaque Using Darapladib-Thrombolysis in Myocardial Infarction; TIMI ¼ Thrombolysis In Myocardial Infarction; TRITON-TIMI 38 ¼ Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel; Unadj ¼ unadjusted.

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DECEMBER 17, 2019:3013–22

F I G U R E 2 Relative Risk of All-Cause Mortality in Women Versus Men After NSTEACS

A

Unadj RR (95% CI)

TRIAL OPUS-TIMI 16

1.26 (0.97-1.63)

A2Z-TIMI 21

0.70 (0.46-1.05)

PROVE IT-TIMI 22

0.83 (0.49-1.41)

MERLIN-TIMI 36

1.27 (1.03-1.58)

TRITON-TIMI 38

1.26 (0.97-1.65)

EARLY ACS-TIMI 39

1.27 (0.98-1.63)

ATLAS ACS 2-TIMI 51

0.84 (0.62-1.14)

SOLID-TIMI 52

1.21 (1.00-1.47)

IMPROVE-IT TIMI 40

1.05 (0.95-1.16)

LATITUDE-TIMI 60

1.35 (0.85-2.17)

OVERALL

1.12 (1.01-1.24), p = 0.03

0.5 0.6

0.8 1.0 1.2

↓ in Women

1.6

2.0

↓ in Men

I2 = 38.63% p for heterogeneity = 0.06

Unadjusted Risk of Death

B

Adj RR (95% CI)

TRIAL OPUS-TIMI 16

0.89 (0.67-1.19)

A2Z TIMI 21

0.53 (0.34-0.82)

PROVE IT-TIMI 22

0.71 (0.41-1.22)

MERLIN-TIMI 36

0.87 (0.68-1.10)

TRITON-TIMI 38

0.91 (0.67-1.24)

EARLY ACS-TIMI 39

1.08 (0.81-1.46)

ATLAS ACS 2-TIMI 51

0.69 (0.50-0.95)

SOLID-TIMI 52

0.86 (0.70-1.06)

IMPROVE-IT TIMI 40

0.82 (0.73-0.91)

LATITUDE-TIMI 60

0.98 (0.59-1.63)

OVERALL

0.84 (0.78-0.90), p < 0.0001

0.5 0.6 0.8 1.0 1.2 ↓ in Women

1.6 2.0

↓ in Men

Adjusted Risk of Death

I2 = 0.02% p for heterogeneity = 0.34

The (A) unadjusted and (B) adjusted risk of all-cause mortality after NSTEACS across TIMI trials. Red diamonds represent HR and 95% CI. Blue squares are weighted based on the inverse variance with black lines reflecting 95% CI. Abbreviations as in Figure 1.

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Outcomes for Women and Men After NSTEACS

C E N T R A L IL LU ST R A T I O N Sex and Outcomes After Non–ST-Segment Elevation Acute Coronary Syndrome

All-Cause Mortality (%)

10.0%

7.5%

5.0%

2.5%

0.0% 0 Number at risk Women 19,827 Men 48,903

182

365 548 Days Since Randomization

13,461 35,264

10,156 27,370

7,060 19,477

Outcome

730

5,728 15,979 RR (95% CI)

MACE

1.04 (0.99-1.09)

All-cause mortality

1.12 (1.01-1.24)

MACE

0.93 (0.88-0.98)

All-cause mortality

0.84 (0.78-0.90)

Unadjusted Risk

Adjusted Risk

0.7

0.8

0.9

↓ in Women

1.0

1.2

↓ in Men

Relative Risk Sarma, A.A. et al. J Am Coll Cardiol. 2019;74(24):3013–22.

Unadjusted Kaplan Meier curves plotted for all-cause mortality (top panel). The unadjusted and adjusted relative risk of MACE (cardiovascular death, MI, or stroke) and all-cause mortality are plotted for women compared with men after NSTEACS (lower panel). After accounting for baseline differences (model 1), women tended to be at lower risk of recurrent cardiovascular events compared with men.

Despite women having a higher baseline risk profile,

disease manifestation, treatment, and mortality are

they remain undertreated with many relevant thera-

well described in published articles, although their

pies during hospitalization for NSTEACS.

underlying mechanisms remain the subject of debate

Although prognosis after NSTEACS has improved

(9,14). In light of the multitude of recognized differ-

over the past few decades, the age-adjusted decline in

ences in baseline comorbidities and disparities

mortality has been slower to appear among women

in treatment use between women and men, it

than men (23). Sex differences in cardiovascular

has remained unclear whether sex itself is an

3019

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DECEMBER 17, 2019:3013–22

T A B L E 2 The Unadjusted and Adjusted Risk of Cardiovascular Outcomes in Women Versus Men After NSTEACS Across TIMI Trials

Unadjusted Incidence Rate, % Total Events

Women

Men

Unadjusted HR (95% CI), Women vs. Men

CVD, MI, or stroke

8,109

11.79

11.36

All-cause death

3,974

4.47

4.12

Between-Trial Heterogeneity p Value

I2 , %

1.04 (0.99–1.09)

0.16

<0.01

0.74

1.12 (1.01–1.24)

0.03

38.63

0.06

p Value

Unadjusted model

CVD

2,429

3.34

2.82

1.16 (1.02–1.32)

0.03

46.56

0.04

MI

1,174

8.03

8.14

1.00 (0.94–1.06)

0.94

<0.01

0.95

Stroke

1,040

1.40

1.23

1.19 (1.03–1.37)

0.02

5.67

0.36

Adjusted Incidence Rate, %

Adjusted HR (95% CI), Women vs. Men

Adjusted model 1* 11.02

12.34

0.93 (0.88–0.98)

<0.01

<0.01

0.17

All-cause death

3.71

4.66

0.84 (0.78–0.90)

<0.01

0.02

0.34

CVD, MI, or stroke CVD

2.80

3.24

0.85 (0.76–0.96)

<0.01

25.48

0.11

MI

7.82

8.54

0.96 (0.91–1.03)

0.23

<0.01

0.62

Stroke

1.28

1.50

0.91 (0.75–1.10)

0.35

26.41

0.13

CVD, MI, or stroke

11.09

12.51

0.92 (0.87–0.97)

<0.01

0.02

0.23

All-cause death

3.90

5.03

0.82 (0.76–0.88)

<0.01

<0.01

0.29

Adjusted model 2†

CVD

3.13

3.63

0.83 (0.73–0.93)

<0.01

23.71

0.11

MI

7.84

8.59

0.96 (0.90–1.02)

0.19

<0.01

0.60

Stroke

1.20

1.39

0.90 (0.74–1.09)

0.28

29.01

0.12

Study outcomes including unadjusted data, *model 1 (adjusted for baseline predictors of risk), and †model 2 (adjusted for baseline predictors of risk and treatments received during the index hospitalization). See Online Table 1 for further details. Model 1 adjusted for clinical covariates and model 2 adjusted for clinical covariates in addition to treatments received during the index hospitalization. CI ¼ confidence interval; CVD ¼ cardiovascular death; HR ¼ hazard ratio; MI ¼ myocardial infarction; NSTEACS ¼ non–ST-segment elevation acute coronary syndrome; TIMI ¼ Thrombolysis In Myocardial Infarction.

independent risk factor for death and MACE after

Care for Cardiovascular Disease in China project also

NSTEACS.

reported higher unadjusted mortality rates in women

Although prior analyses suggested that women are

compared with men after ACS, a finding that was

at increased risk of adverse outcomes after ACS (9,23),

attenuated after adjustment for differences in clinical

more recent studies show that observed differences by

characteristics and in-hospital treatment strategies

sex may be explained by a higher prevalence of car-

(22). Similarly, a post hoc analysis of patients enrolled

diovascular risk factors among women (22). In the

in the TRILOGY ACS (Targeted Platelet Inhibition to

GRACE (Global Registry of Acute Coronary Events)

Clarify the Optimal Strategy to Medically Manage

registry, an excess risk of MACE was observed in

Acute Coronary Syndromes) trial showed similar out-

women compared with men with ACS who underwent

comes between women and men after medical man-

angiography, but the analysis adjusted only for age

agement of NSTEACS, but women were at lower risk of

and extent of disease (9). In contrast, the risk of death

cardiovascular events and death after multivariable

was similar by patient sex after multivariable adjust-

adjustment (6).

ment. An analysis of the National Inpatient Sample

Our analysis of 68,730 patients enrolled in 10

databases for NSTEACS found that that women expe-

NSTEACS clinical trials advances our knowledge by

rience higher in-hospital mortality than men in unad-

showing that the excess risk observed among women

justed models but a 10% lower risk of mortality after

versus men was primarily explained by differences in

multivariable adjustment (7). Another population-

age and baseline risk profiles rather than female sex

based cohort study similarly reported higher crude

itself in this dataset. The study population was multi-

rates of mortality after both ST-segment elevation

national and diverse, with a database that allowed for

myocardial infarction (STEMI) and NSTEACS among

detailed patient characterization, including data on

women versus men, which were attenuated in

coronary angiography, medication use, adjudicated

adjusted analyses (15). Excess risk was observed at 5

cardiovascular outcomes, and rigorous long-term

years after NSTEACS among women versus men but

follow-up. After carefully accounting for baseline dif-

did not differ by patient sex at earlier time points after

ferences in clinical risk, women had a lower risk of

NSTEACS (15). In a more recent analysis, the Improving

MACE and death than men. We also confirmed that

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Sarma et al.

DECEMBER 17, 2019:3013–22

Outcomes for Women and Men After NSTEACS

F I G U R E 3 Unadjusted Cumulative Incidence Curves in Women and Men

20%

MACE (%)

15%

10%

5%

0% 0 Number at risk Women 19,827 Men 48,903

182

365 548 Days Since Randomization

12,692 33,336

9,342 25,381

730

6,359 17,742

5,041 14,269

Unadjusted Kaplan-Meier curves are plotted for MACE in women and men after NSTEACS. Abbreviations as in Figure 1.

women remain undertreated with many guideline-

in randomized clinical trials; therefore, our findings

based therapies, including coronary angiography and

may not be generalizable to the general NSTEACS

many types of pharmacologic therapies, even when

patient population. Furthermore, although the study

restricted to women with stronger indications. How-

group was multinational, it was predominately white.

ever, further accounting for underuse had no effect on

However, as previously noted, the current database of

sex-based risk comparisons. The differential use of

clinical trials offered the advantage of having a sys-

therapies did not appear to be completely explained by

tematically characterized population with rigorous

a higher prevalence of obstructive CAD in men

endpoint ascertainment and central event adjudication.

compared with women. Although statistically signifi-

CONCLUSIONS

cant, the absolute difference in the use of medical therapies between women and men was relatively

In our analysis of women and men enrolled in

modest when restricted to those with confirmed CAD.

randomized trials after NSTEACS, excess risk among

Nonetheless, it is critical that continued efforts be

women

made to increase the use of guideline-directed thera-

explained by a greater burden of cardiovascular risk

pies in this high-risk population.

factors and comorbid conditions. After accounting for

STUDY LIMITATIONS. Although we performed careful

multivariable adjustment on an individual trial basis before combining data across trials, one cannot

versus

men

appeared

to

be

primarily

these differences, women were at lower risk of recurrent cardiovascular events than men. These findings underscore the fact that efforts to modify risk factors

exclude the possibility of residual confounders that

and implement appropriate treatment strategies in

may further explain differences in outcomes between

women and men may be a powerful means to further

women and men. Furthermore, the trials differed in

improve outcomes among patients with NSTEACS.

study design, timing of enrollment, experimental treatments tested, and duration of follow-up. How-

ADDRESS FOR CORRESPONDENCE: Dr. Michelle L.

ever, there was no between-trial heterogeneity across

O’Donoghue,

any adjusted random effects models, suggesting

Road, 7th Floor, Boston, Massachusetts 02115.

TIMI

Study

Group,

60

consistent results across studies. The study group was

E-mail:

a cohort of patients at moderate to high risk enrolled

@DrM_ODonoghue.

[email protected].

Fenwood Twitter:

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Sarma et al.

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Outcomes for Women and Men After NSTEACS

DECEMBER 17, 2019:3013–22

PERSPECTIVES COMPETENCY IN MEDICAL KNOWLEDGE: Women

TRANSLATIONAL OUTLOOK: Differences in baseline

experience higher rates of all-cause mortality and similar

comorbidities may largely explain discordant outcomes by

rates of MACE in clinical trials of patients after NSTEACS.

sex in clinical trials after NSTEACS. Whether differential

However, differences in risk may be largely explained by

use of guideline-directed therapies by sex further

differences in baseline comorbidities.

influences outcomes merits further investigation.

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A PPE NDI X For supplemental tables and a figure, please see the online version of this

segment-elevation myocardial infarction in the

Registry. J Am Heart Assoc 2017;6(12):e007123.

paper.

Long-term outcomes for women versus men with unstable angina/non-ST-segment elevation myocardial infarction managed medically without revascularization: insights from the TaRgeted platelet Inhibition to cLarify the Optimal strateGy to medicallY manage Acute Coronary Syndromes

KEY WORDS acute coronary syndromes, non–ST-segment elevation myocardial infarction, women