Prognostic Implications of Type 2 Diabetes Mellitus in Ischemic and Nonischemic Heart Failure

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY

VOL. 68, NO. 13, 2016

ª 2016 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION PUBLISHED BY ELSEVIER

ISSN 0735-1097/$36.00 http://dx.doi.org/10.1016/j.jacc.2016.06.061

Prognostic Implications of Type 2 Diabetes Mellitus in Ischemic and Nonischemic Heart Failure Isabelle Johansson, MD, PHD FELLOW,a Ulf Dahlström, MD, PHD,b Magnus Edner, MD, PHD,a Per Näsman, PHD,c Lars Rydén, MD, PHD,a Anna Norhammar, MD, PHDa

ABSTRACT BACKGROUND Heart failure (HF) is a common and serious complication in type 2 diabetes mellitus (T2DM). The prognosis of ischemic HF and impact of revascularization in such patients have not been investigated fully in a patient population representing everyday practice. OBJECTIVES This study examined the impact of ischemic versus nonischemic HF and previous revascularization on long-term prognosis in an unselected population of patients with and without T2DM. METHODS Patients stratified by diabetes status and ischemic or nonischemic HF and history of revascularization in the Swedish Heart Failure Registry (SwedeHF) from 2003 to 2011 were followed up for mortality predictors and longevity. A propensity score analysis was applied to evaluate the impact of previous revascularization. RESULTS Among 35,163 HF patients, those with T2DM were younger, and 90% had 1 or more associated comorbidities. Ischemic heart disease (IHD) occurred in 62% of patients with T2DM and 47% of those without T2DM, of whom 53% and 48%, respectively, had previously undergone revascularization. T2DM predicted mortality regardless of the presence of IHD, with adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of 1.40 (1.33 to 1.46) and 1.30 (1.22 to 1.39) in those with and without IHD, respectively. Patients with both T2DM and IHD had the highest mortality, which was further accentuated by the absence of previous revascularization (adjusted HR: 0.82 in favor of such treatment; 95% CI: 0.75 to 0.91). Propensity score adjustment did not change these results (HR: 0.87; 95% CI: 0.78 to 0.96). Revascularization did not abolish the impact of T2DM, which predicted mortality in those with (HR: 1.36; 95% CI: 1.24 to 1.48) and without (HR: 1.45; 95% CI: 1.33 to 1.56) a history of revascularization. CONCLUSIONS Ninety percent of HF patients with T2DM have preventable comorbidities. IHD in patients with T2DM had an especially negative influence on mortality, an impact that was beneficially influenced by previous revascularization. (J Am Coll Cardiol 2016;68:1404–16) © 2016 by the American College of Cardiology Foundation.

From the aCardiology Unit, Department of Medicine K2, Karolinska Institutet, Stockholm, Sweden; bDepartment of Cardiology and Department of Medical and Health Sciences, Linköping University, Linköping, Sweden; and the cCenter for Safety Research, KTH Royal Institute of Technology, Stockholm, Sweden. This work was supported by unrestricted grants from the Swedish HeartLung Foundation and the Regional Agreement on Medical Training and Clinical Research (ALF) between Stockholm County Council and the Karolinska Institute. Dr. Dahlström has received research grants from Linkoping University and AstraZeneca Listen to this manuscript’s

Inc.; and honoraria from expert group participation organized by different pharmaceutical companies, none of which were

audio summary by

directly related to the present publication. Dr. Rydén has received research grants from the Swedish Heart-Lung Foundation,

JACC Editor-in-Chief

AFA Insurance, and the Swedish Diabetes Foundation; honoraria from expert group participation; and personal fees for

Dr. Valentin Fuster.

delivering educational lectures organized by pharmaceutical and societal organizations, none of which were directly related to this publication. Dr. Norhammar has received funding from the Swedish Heart-Lung Foundation and the Swedish Diabetes Foundation for the present report; and has received honoraria for advisory boards and lectures from Eli Lilly, AstraZeneca, MSD, and Boehringer Ingelheim. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Manuscript received May 20, 2016; revised manuscript received June 17, 2016, accepted June 21, 2016.

Johansson et al.

JACC VOL. 68, NO. 13, 2016 SEPTEMBER 27, 2016:1404–16

D

iabetes mellitus, predominantly type 2

the

(T2DM), affects 390 million people globally,

(Uppsala, Sweden) and run monthly against

a number expected to increase to 600

the Swedish Population Registry.

million in 2030 (1). Cardiovascular disease is the most common complication and mortality cause related to T2DM. Recent evidence favors increasing life expectancy in patients with T2DM because of improved risk factor management and post– myocardial infarction (MI) survival (2,3). Unfortunately, these improvements are expected to increase the prevalence of chronic complications, including heart failure (HF) (4). Besides enhancing the risk of HF, T2DM has an adverse impact on the prognosis of HF (5). Consequently, an increasing proportion of patients with T2DM are expected to develop ischemic HF in the future. Diabetes is over-represented in HF populations, even in the absence of ischemic heart disease (IHD). The presence of a specific diabetesinduced cardiomyopathy unrelated to hypertension or IHD but rather caused by deranged myocardial metabolism has been proposed as an explanation (6). However, the actual prevalence and role of this condition in terms of morbidity and mortality remain to be fully understood (7–9). Moreover, existing evidence related to the true impact of T2DM on HF sur-

Uppsala

Clinical

Research

Center

ABBREVIATIONS AND ACRONYMS CABG = coronary artery

STUDY POPULATION AND DESIGN. Between

bypass surgery

January 2003 and September 2011, 36,595

CI = confidence interval

patients with HF managed in a specialist

CKD = chronic kidney disease

setting were included in SwedeHF. The pre-

eGFR = estimated glomerular

sent cohort of 35,163 patients (68% from

filtration rate

hospitals, 32% from outpatient clinics) was

HF = heart failure

established after the exclusion of patients

HR = hazard ratio

with no information on sex or glucometabolic

IHD = ischemic heart disease

state (n ¼ 123) or who had type 1 diabetes

LVEF = left ventricular

mellitus (n ¼ 198) or IHD (n ¼ 1,111). The date

ejection fraction

of the first registration was assigned as the

MI = myocardial infarction

index date, and all descriptive data in the

NYHA = New York Heart

present analysis were extracted from this

Association

single occasion. The primary endpoint was all-cause mortality, acquired by merging the SwedeHF database with the Swedish Population Registry using the unique 10-digit personal identification number of Swedish

PCI = percutaneous coronary intervention

SwedeHF = Swedish Heart Failure Registry

T2DM = type 2 diabetes mellitus

citizens. Follow-up ended on September 13, 2011. DEFINITIONS. Definitions are based on the pre-

vival, often based on subgroup analyses of either

defined

clinical trials or registry reports, is conflicting. Studies

Appendix). HF was diagnosed by the attending

definitions

used

in

SwedeHF

(Online

have indicated better (9), equal (7,8), and compro-

physician based on guideline recommendations at the

mised (9) survival in ischemic and nonischemic HF

time of inclusion. New York Heart Association (NYHA)

(10,11). These discrepant results probably reflect the

functional classes I to IV were used to define HF

recruitment of different and selected patient popula-

severity. An adapted definition was used for IHD,

tions and often vaguely defined glucometabolic

defined as present or absent based on the case history

states.

from patient records. Patients reported as without IHD but with a confirmed coronary revascularization SEE PAGE 1417

The aim of this study was to investigate the prevalence and impact of ischemic and nonischemic HF and the role of previous revascularization in patients with T2DM in a contemporary unselected HF population that reflects everyday clinical practice.

METHODS

1405

Diabetes, Heart Failure, and Ischemic Heart Disease

procedure (n ¼ 739) or a history of previous MI (n ¼ 218) were reclassified as having IHD (Figure 1). Revascularization was defined in SwedeHF as a history of coronary artery bypass surgery (CABG) or percutaneous coronary intervention (PCI). This procedure is freely available in Sweden, and patients are generally offered this treatment according to the current European guidelines (14). MI was based on information from patient records. T2DM was defined

DATA SOURCE. The Swedish Heart Failure Registry

as a confirmed history of this diagnosis or the pre-

(SwedeHF), introduced throughout Sweden in 2003,

scription of glucose-lowering drugs. Comorbidities

has been described in detail elsewhere (12). Registry

were defined as the presence of any or several of the

information is available on the SwedHF website (13).

following: hypertension, atrial fibrillation, pulmonary

Participating centers (65 hospitals, 113 outpatient

disease, valvular heart disease, or idiopathic dilated

clinics) report to the registry, which contained infor-

cardiomyopathy, all of which were classified as “yes”

mation on 47,000 patients in 2011. The primary in-

or “no” based on patient records. Left ventricular

clusion criterion is a physician-judged diagnosis of

ejection fraction (LVEF) was the most recently esti-

HF; 76 variables are recorded via an Internet-based

mated, grouped into 4 classes: $50%, 40% to 50%,

case report form at hospital discharge or outpatient

30% to 39% and <30%. Estimated glomerular filtration

visits. Data are entered into a database managed by

rate (eGFR) was calculated with the MDRD formula,

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JACC VOL. 68, NO. 13, 2016 SEPTEMBER 27, 2016:1404–16

Diabetes, Heart Failure, and Ischemic Heart Disease

F I G U R E 1 Redefinition of IHD

Total cohort n = 35 163 IHD Original

IHD, verified by corai n = 5 977

No IHD IHD, not verified by corai n = 10 957 No/missing IHD but revascularized n = 739

IHD n = 16 934

Modified IHD

No IHD n = 18 229

No IHD n = 17 490

IHD n = 17 673 No/missing IHD, no/missing revascularization but Previous MI n = 218

Final IHD variable

No IHD n = 17 272

IHD n = 17 891

To avoid misclassification, an adapted definition was used for ischemic heart disease (IHD), defined as present or absent based on the case history from hospital records. Patients reported as being without IHD but with a confirmed coronary revascularization procedure (n ¼ 739) or history of previous myocardial infarction (MI) (n ¼ 218) were reclassified as having IHD, which yielded 17,891 patients (51%) with IHD and 17,272 (49%) without. corai ¼ coronary angiography.

and an eGFR <60 ml/min1 /1.73 m 2 was considered the

Univariate and multivariate models were used to

cutoff for chronic kidney disease (CKD).

evaluate the predictive value of T2DM, as well as revascularization, in all-cause mortality. Adjustments

STATISTICAL ANALYSIS. Statistical comparisons of

for potentially important covariates were performed

differences between independent groups were per-

in 2 models. Model 1 included age, sex, HF duration,

formed with the Student t test for continuous vari-

level of care, weight, systolic and diastolic blood

ables. Quantitative normally distributed variables are

pressure, LVEF class, eGFR class, hemoglobin class,

presented as the mean (standard deviation) and 95%

T2DM, hypertension, atrial fibrillation, pulmonary

confidence intervals (CIs) or, when appropriate, me-

disease, and use of angiotensin-converting enzyme

dian, range, and 95% CI. Natriuretic peptides were

inhibitors, angiotensin receptor II blockers, beta

logarithmically transformed before Student t testing.

blockers,

Categorical variables were compared by chi-square

diuretic

tests and are presented as counts and proportions

antithrombotic agents. Model 2 included the same

(%). Analyses of differences between those with and

variables as model 1 plus 2 additional variables (heart

without T2DM were performed in subgroups by IHD

rate and NYHA functional class) that were excluded

status and further in the IHD population in those with

from model 1 because of a large number of missing

and without previous revascularization. Statistical

values. In addition, because of the observational

differences for all-cause mortality by T2DM, IHD

character of the investigation, a propensity score

status, and revascularization were estimated with

model was applied to avoid potential bias regarding

Cox proportional hazard regression and depicted as

the impact of previous revascularization on all-cause

crude and age-adjusted estimated survival curves.

mortality. The propensity score, which expressed the

mineralocorticoid agents,

digitalis,

receptor nitrates,

antagonists, statins,

and

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JACC VOL. 68, NO. 13, 2016 SEPTEMBER 27, 2016:1404–16

Diabetes, Heart Failure, and Ischemic Heart Disease

probability of an assigned treatment, in this case

dilated cardiomyopathy (7% vs. 12%), hypertension

revascularization, given a set of known baseline

(59% vs. 60%), and pulmonary disease (18% vs. 20%).

characteristics, was used to balance the study popu-

Eighty-eight percent of the patients with T2DM

lation with regard to a chosen dependent variable

without IHD had at least 1 comorbidity. This

(15). Logistic regression was used to estimate indi-

increased to 90% when idiopathic dilated cardiomy-

vidual propensity scores for the history of revascu-

opathy was added (Table 2). Patients with and

larization in patients with IHD and T2DM (n ¼ 5,182)

without IHD underwent similar pharmacological

with a good fit (Hosmer and Lemeshow test; p ¼ 0.27

treatment except for a more frequent use of statins

[p > 0.05 is considered a good fit] and c-statistic of

and acetylsalicylic acid among those with IHD.

0.7) based on 26 baseline variables (including demographics, medical history, and reported pharma-

PATIENTS WITH IHD IN RELATION TO REVASCULARIZATION.

cological treatment) (15). The selected variables were

Baseline data for patients with IHD according to pre-

those that affected all-cause mortality in univariate

vious revascularization and the presence or absence

logistic regression given they had a reasonably low

of T2DM are outlined in Table 3. When we focused on

amount of missing data. An individual propensity

patients with T2DM and compared those with and

score was estimated for 3,467 patients with complete

without previous revascularization, the latter were

information on all variables. The impact of previous

older (mean age 77 years vs. 73 years) and more often

revascularization on all-cause mortality was there-

women (43% vs. 26%). Comorbidities, such as atrial

after determined by means of Cox regression adjusted

fibrillation and pulmonary disease and preserved

for the propensity score.

LVEF (16% vs. 19%), were less common in T2DM

A 2-sided probability value of p < 0.05 was

patients who had been revascularized than in

considered significant and is reported with 95% CI.

those who had not. Patients without previous revas-

Analyses were performed with SAS statistical soft-

cularization were more often prescribed diuretic

ware (version 9.4).

agents and digitalis but less often given renin-

ETHICAL CONSIDERATIONS. The Swedish National

Board of Health and Welfare and the Swedish Data Inspection Board approved the establishment of SwedeHF and subsequent patient registration and data analyses. The registry and this study conform to the Declaration of Helsinki. Individual patient consent was not required or obtained, but patients were informed about registry entry with permission to opt out. The Regional Ethical Review Board at Linköping University approved the merging of SwedeHF with the Swedish Population Registry.

RESULTS Important clinical characteristics are presented in Table 1. Among 35,163 patients, IHD was reported in 51%. The proportion of IHD in the T2DM cohort was 62% compared with 47% in those without T2DM, of whom 53% and 48%, respectively, had undergone previous revascularization. PATIENTS WITH T2DM WITH AND WITHOUT IHD.

angiotensin-aldosterone

system

inhibitors,

beta

blockers, and statins. A corresponding comparison of baseline data between patients without T2DM revealed a similar pattern, although in slightly different proportions from the T2DM cohort. PATIENTS WITH AND WITHOUT T2DM. Among pa-

tients with IHD (Table 1), those with T2DM were younger (75 years vs. 77 years) and had a higher prevalence of hypertension (59% vs. 45%) and CKD (63% vs. 56%). The proportion with preserved LVEF ($50%) was similar in both groups (17% vs. 18%), but the IHD patients with T2DM were more symptomatic (NYHA functional class III or IV; 54% vs. 46%). In general, patients with T2DM had more extensive pharmacological treatment with reninangiotensin-aldosterone system inhibitors (84% vs. 79%), diuretic agents (88% vs. 79%), and statins (67 vs. 59%). About 50% of the IHD patients had a history of revascularization, which was more common in patients with T2DM than without (53% vs. 48%).

When we compared T2DM patients with and without

In patients without IHD (Table 1), the mean age was

IHD, the former were slightly older (75 years vs. 74

73 years regardless of T2DM state. The comorbidity

years), more often men (66% vs. 57%), and more

pattern between those with and without T2DM cor-

frequently had reduced LVEF (<50%: 83% vs. 69%)

responded with that in patients with IHD, except that

and CKD (63% vs. 55%). Smoking (current/former)

preserved LVEF ($50%) was more common in pa-

was more common in T2DM patients with IHD (62%

tients without IHD than among those with this dis-

vs. 53%), whereas associated comorbidities were less

ease and more common in those with T2DM than in

common: atrial fibrillation (40% vs. 51%), idiopathic

those without (31% vs. 26%).

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Diabetes, Heart Failure, and Ischemic Heart Disease

T A B L E 1 Baseline Characteristics by Presence of T2DM and by Reported History of Ischemic/Nonischemic Heart Disease

Nonischemic Heart Disease No T2DM (n ¼ 14,029; 81%)

T2DM (n ¼ 3,243; 19%)

73.4  14

73.7  11

Ischemic Heart Disease

p Value

No T2DM (n ¼ 12,574; 70%)

T2DM (n ¼ 5,317; 30%)

p Value

77.2  11

74.8  10

<0.0001

1,833 (15)

924 (17) 2,739 (52)

Demographics Age, yrs

0.10 <0.0001

Age group, yrs

<0.0001

#65

3,814 (27)

755 (23)

66–80

4,897 (35)

1,475 (45)

5,170 (41)

>80

5,318 (38)

1,013 (31)

5,571 (44)

1,654 (31)

7,787 (56)

1,852 (57)

0.10

8,173 (65)

3,509 (66)

0.20

65/32

73/27

<0.0001

68/32

74/26

<0.0001

Weight, kg

76  19

86  21

<0.0001

75  16

83  18

<0.0001

BMI, kg/m2

26  6

29  6

<0.0001

26  5

28  6

<0.0001

Smoking habit (never/former/current)

49/37/14

47/40/13

0.009

41/47/12

38/50/12

0.007

Alcohol consumption (never/ordinary/problematic)

11/77/12

13/74/12

0.01

11/82/7

14/78/9

59/41

51/49

<0.0001

46/54

39/61

I

1,440 (14)

211 (9)

977 (11)

284 (8)

II

5,049 (48)

1,010 (44)

3,939 (44)

1,478 (39)

III

3,603 (34)

963 (41)

3,563 (40)

1,725 (46)

IV

418 (4)

138 (6)

508 (6)

283 (8)

77  17

77  17

73  15

74  15

<0.0001 <0.0001

Male Level of care (hospital/outpatient visit)

Duration of heart failure (6 months)

<0.0001

NYHA functional class

Heart rate, beats/min

0.0002 <0.0001

0.13

<0.0001

Blood pressure, mm Hg Systolic

128  22

131  22

<0.0001

126  21

129  22

Diastolic

74.4  13

73.8  13

0.005

72  12

72  12

Pulse pressure, mm Hg

53  18

57  19

<0.0001

55  18

58  19

<0.0001

Mean arterial pressure, mm Hg

92  14

93  14

0.03

90  13

91  13

0.0003

Hypertension

5,587 (41)

1,929 (60)

<0.0001

5,508 (45)

3,022 (59)

Atrial fibrillation

7,635 (55)

1,652 (51)

0.0004

5,320 (43)

2,116 (40)

Pulmonary disease

2,336 (17)

640 (20)

<0.0001

2,206 (18)

939 (18)

0.52

Valvular heart disease

3,010 (22)

561 (18)

<0.0001

2,449 (21)

894 (18)

<0.0001

Idiopathic dilated cardiomyopathy

2,138 (16)

379 (12)

<0.0001

820 (7)

336 (7)

0.69

.

5,871 (48)

2,768 (53)

<0.0001

727 (6)

297 (6)

0.19

Previous or present disease <0.0001 0.003

Previous interventions Revascularization (CABG/PCI) Valvular surgery

.

.

737 (5)

140 (4)

0.03

0.64

<0.0001

Left ventricular function (echocardiography)

0.15

EF $50%

3,028 (26)

817 (31)

1,890 (18)

797 (17)

EF 40%–49%

2,373 (20)

516 (19)

2,438 (23)

1,006 (22)

EF 30%–39%

2,816 (24)

564 (21)

3,353 (31)

1,422 (31)

EF <30%

3,564 (30)

761 (29)

3,092 (29)

1,415 (31) Continued on the next page

MORTALITY. The time of follow-up ranged between

Hazard ratios (HRs) of mortality from univariate

0 and 8.7 years (median 1.9 years). By the end of

and multivariate analyses are presented in Table 4.

the study period, 14,144 patients (40%) had died,

T2DM predicted mortality regardless of the presence

3,950 (46%) with T2DM and 10,194 (38%) without.

or absence of IHD (unadjusted HR: 1.20 [95% CI: 1.14

Estimated survival curves among patients with and

to 1.25] and 1.21 [95% CI: 1.14 to 1.29], respectively)

without T2DM and with and without IHD, before

and remained a mortality predictor in patients with

and after age adjustment, are shown in Figure 2 and

and without IHD after adjustment (HR: 1.40 [95% CI:

Central Illustration (left), whereas crude and adjusted

1.33 to 1.46] and 1.30 [95% CI: 1.22 to 1.39], respec-

survival rates in patients with IHD by previous

tively). This pattern persisted in the different

revascularization are shown in Figure 3 and Central

adjustment models, with a slight weakening of the

Illustration (right). The most serious prognosis was

HRs when the number of covariates increased

seen in patients with IHD and T2DM (Figure 2),

(Table 4). T2DM remained an independent mortality

especially those without previous revascularization

predictor

(Figure 3).

(adjusted HR: 1.36; 95% CI: 1.24 to 1.48), as well as in

among

revascularized

IHD

patients

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Diabetes, Heart Failure, and Ischemic Heart Disease

T A B L E 1 Continued

Nonischemic Heart Disease No T2DM (n ¼ 14,029; 81%)

T2DM (n ¼ 3,243; 19%)

134  18 70/24/6

Creatinine, mmol/L

103  52

eGFR, ml/min/1.73 m2

65  40 926 (7)

30–59 60–89 >90

Ischemic Heart Disease

p Value

No T2DM (n ¼ 12,574; 70%)

T2DM (n ¼ 5,317; 30%)

129  18

<0.0001

130  17

127  17

<0.0001

59/31/9

<0.0001

60/32/8

53/35/12

<0.0001

115  66

<0.0001

115  61

128  74

<0.0001

60  28

<0.0001

59  26

55  27

<0.0001

388 (12)

1,238 (10)

829 (16)

5,375 (38)

1,402 (43)

5,784 (46)

2,491 (47)

5,953 (42)

1,067 (33)

4,442 (35)

1,579 (30)

1,775 (13)

386 (12)

1,110 (9)

418 (8)

Cholesterol, mmol/l

4.7  1.2

4.4  1.2

<0.0001

4.4  1.2

4.1  1.2

<0.0001

LDL, mmol/l

2.9  1.0

2.5  0.9

<0.0001

2.6  1.0

2.3  1.0

<0.0001

p Value

Laboratory analyses Hb, g/l Hb class (normal/mild anemia/severe anemia)

eGFR class, ml/min/1.73 m2

<0.0001

<30

<0.0001

41  9

59  18

<0.0001

42  9

59  16

<0.0001

982  1,322

769  926

0.41*

951  1,488

1,092  2,197

0.22*

4,906  6,927

4,892  6,826

0.43*

6,207  8,488

6,115  8,257

0.78*

ACEI

8,999 (65)

1,953 (61)

<0.0001

7,783 (62)

3,212 (61)

0.05

ARB

2,194 (16)

745 (23)

<0.0001

2,383 (19)

1,383 (26)

<0.0001

HbA1c, mmol/mol BNP, pg/ml NT-pro-BNP, pg/ml Pharmacological and device intervention RAA inhibition

ACEI or ARB

10,979 (78)

2,616 (81)

0.003

9,973 (79)

4,446 (84)

<0.0001

MRA

3,858 (28)

1,077 (33)

<0.0001

3,389 (27)

1,658 (32)

<0.0001

BB

11,359 (81)

2,656 (82)

0.19

10,815 (86)

4,640 (88)

0.02

ACEI/ARB þ BB

9,345 (67)

2,248 (69)

0.003

8,862 (70)

3,997 (75)

<0.0001

ACEI/ARB þ BB þ MRA

2,647 (19)

776 (24)

<0.0001

2,435 (19)

1,309 (25)

<0.0001

Diuretic agents (loop/thiazide)

11,082 (79)

2,871 (89)

<0.0001

9,878 (79)

4,676 (88)

<0.0001

Digitalis

3,107 (22)

672 (21)

0.07

1,749 (14)

761 (14)

0.49

Statins

2,663 (19)

1,318 (41)

<0.0001

7,303 (59)

3,523 (67)

<0.0001 <0.0001

Nitrates (long-lasting)

803 (6)

301 (9)

<0.0001

3,514 (28)

1,755 (33)

Antithrombotic agent

5,726 (41)

1,206 (37)

<0.0001

3,761 (30)

1,579 (30)

0.79

Aspirin

4,919 (35)

1,429 (44)

<0.0001

8,624 (69)

3,728 (71)

0.05

1,165 (8)

298 (9)

1,277 (10)

498 (9)

Cardiac resynchronization therapy

132 (1.0)

26 (0.8)

169 (1.4)

74 (1.4)

Implantable cardioverter-defibrillator

254 (1.8)

48 (1.5)

391 (3.1)

166 (3.2)

Device therapy

0.25

Pacemaker

0.15

Values are mean  SD, n (%), or %. Percentages were computed by group. Pearson chi-square test and Student t test were used for unpaired groups. *Logarithmically transformed before Student t test. ACEI ¼ angiotensin-converting enzyme inhibitor; ARB ¼ angiotensin receptor II blocker; BB ¼ beta blocker; BMI ¼ body mass index; BNP ¼ B-type natriuretic peptide; CABG ¼ coronary artery bypass grafting; EF ¼ ejection fraction; eGFR ¼ estimated glomerular filtration rate; Hb ¼ hemoglobin; HbA1c ¼ glycosylated hemoglobin A1c; LDL ¼ low-density lipoprotein; MRA ¼ mineralocorticoid receptor antagonist; NT-pro-BNP ¼ N-terminal fragment pro–B-type natriuretic peptide; NYHA ¼ New York Heart Association; PCI ¼ percutaneous coronary intervention; RAA ¼ renin-angiotensin-aldosterone; SD ¼ standard deviation; T2DM ¼ type 2 diabetes mellitus.

T A B L E 2 Comorbidity Pattern Stratified by T2DM

Nonischemic Heart Disease No T2DM (n ¼ 14,029; 81%) Variable Combinations

HTN/AF

Missing

n (%)

317

9,958 (73)

Ischemic Heart Disease

T2DM (n ¼ 3,243; 19%)

No T2DM (n ¼ 12,574; 70%)

n (%)

p Value

53

2,563 (80)

<0.0001

Missing

Missing

512

T2DM (n ¼ 5,317; 30%)

n (%)

Missing

n (%)

p Value

8,164 (68)

224

3,852 (76)

<0.0001

575

10,442 (78)

141

2,639 (85)

<0.0001

745

8,675 (73)

381

3,952 (80)

<0.0001

1,012

10,763 (83)

261

2,617 (88)

<0.0001

1,262

8,790 (78)

609

3,903 (83)

<0.0001

HTN/AF/COPD/VHD/iDCM

1,160

11,349 (88)

288

2,674 (90)

0.0004

1,418

8,836 (79)

670

3,897 (84)

<0.0001

HTN/AF/COPD/VHD/iDCM/CKD

1,160

11,911 (95)

288

2,817 (93)

<0.0001

1,418

9,825 (88)

670

4,294 (92)

<0.0001

HTN/AF/COPD HTN/AF/COPD/VHD

AF ¼ atrial fibrillation; CKD ¼ chronic kidney disease; COPD ¼ chronic obstructive pulmonary disease; HTN ¼ hypertension; iDCM ¼ idiopathic dilated cardiomyopathy; T2DM ¼ type 2 diabetes mellitus; VHD ¼ valvular heart disease.

Johansson et al.

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JACC VOL. 68, NO. 13, 2016 SEPTEMBER 27, 2016:1404–16

Diabetes, Heart Failure, and Ischemic Heart Disease

T A B L E 3 Baseline Characteristics in Patients With IHD Stratified by Revascularization and T2DM

IHD: Revascularization No T2DM (n ¼ 5,871; 68%)

T2DM (n ¼ 2,768; 32%)

73.7  10

72.6  10

IHD: No Revascularization

p Value

No T2DM (n ¼ 6,466; 73%)

T2DM (n ¼ 2,414; 27%)

<0.0001

80.2  10

77.3  10

p Value

Demographics Age, yrs

<0.0001

Age group, yrs

<0.0001 <0.0001

#65

1,251 (21)

609 (22)

560 (9)

301 (12)

66–80

2,871 (49)

1,566 (57)

2,226 (34)

1,106 (46)

>80

1,749 (30)

596 (21)

3,680 (57)

1,007 (42)

Male sex

4,467 (76)

2,046 (74)

0.03

3,570 (55)

1,384 (57)

60/40

69/31

<0.0001

76/24

79/21

0.004

Level of care (hospital/outpatient visit)

0.07

Weight, kg

78  16

85  17

<0.0001

72  16

81  19

<0.0001

BMI, kg/m2

26  4.5

29  5.4

<0.0001

25  4.7

28  6.0

<0.0001

Smoking habit (never/former/current)

36/52/12

35/54/11

0.52

46/41/13

42/45/13

0.02

Alcohol consumption (never/ordinary/problematic)

9/84/7

12/80/8

0.02

14/79/7

16/74/9

0.002

Duration of heart failure (6 months)

48/52

39/61

<0.0001

45/55

40/60

<0.0001

NYHA functional class

<0.0001 <0.0001

I

558 (13)

158 (8)

407 (9)

122 (7)

II

2,024 (46)

848 (42)

1,847 (42)

600 (36)

III

1,679 (38)

919 (45)

1,837 (42)

769 (46)

IV

177 (4)

112 (6)

313 (7)

163 (10)

71  15

73  14

<0.0001

74  16

75  15

Systolic

125  21

129  22

<0.0001

128  22

130  22

Diastolic

72  12

71  12

0.30

72  13

72  12

0.28

Pulse pressure, mm Hg

53  17

58  19

<0.0001

56  18

58  18

<0.0001

Mean arterial pressure, mm Hg

90  13

91  13

<0.0001

91  14

91  14

0.20

Hypertension

2,494 (44)

1,570 (59)

<0.0001

2,903 (46)

1,378 (59)

<0.0001

Atrial fibrillation

2,253 (39)

987 (36)

0.02

2,955 (46)

1,062 (44)

0.17

892 (15)

432 (16)

0.50

1,266 (20)

481 (21)

0.50

1,041 (18)

429 (16)

0.008

1,372 (22)

444 (20)

378 (7)

172 (7)

0.71

422 (7)

153 (7)

0.79

527 (9)

226 (8)

0.21

182 (3)

60 (2)

0.39

1,091 (21)

383 (19)

Heart rate, beats/min

0.01

Blood pressure, mm Hg 0.0002

Previous or present disease

Pulmonary disease Valvular heart disease Idiopathic dilated cardiomyopathy

0.008

Previous interventions Valvular surgery Left ventricular function (echocardiography)

0.04

EF $50%

774 (14)

0.046

396 (16)

EF 40%–49%

1,307 (25)

544 (22)

1,094 (21)

444 (22)

EF 30%–39%

1,762 (33)

840 (33)

1,546 (29)

560 (28)

EF <30%

1,502 (28)

732 (29)

1,536 (29)

643 (32) Continued on the next page

IHD patients without previous revascularization

DISCUSSION

(HR: 1.45; 95% CI: 1.33 to 1.56). Among patients with T2DM and IHD, previous

There are 3 findings of major importance in this study

revascularization was associated with a decreased

of a large, contemporary HF population representing

mortality

patients

patients receiving typical (“everyday”) clinical care.

without a history of any coronary intervention

First, T2DM is associated with higher all-cause mor-

(adjusted HR: 0.82; 95% CI: 0.75 to 0.91). This as-

tality, regardless of whether HF is of ischemic or

sociation remained after adjustment for the pro-

nonischemic origin. In addition, previous revascu-

pensity score of previous revascularization (HR:

larization was associated with improved survival,

0.87; 95% CI: 0.78 to 0.96). Likewise, previous

which highlights how important it is to always

revascularization was associated with better prog-

consider the possibility of a coronary intervention in

nosis within the non-T2DM cohort (adjusted HR:

patients with T2DM and IHD. Finally, the vast ma-

0.89; 95% CI: 0.83 to 0.96).

jority of patients with T2DM and HF of nonischemic

risk

compared

with

T2DM

1411

Johansson et al.

JACC VOL. 68, NO. 13, 2016 SEPTEMBER 27, 2016:1404–16

Diabetes, Heart Failure, and Ischemic Heart Disease

T A B L E 3 Continued

IHD: Revascularization No T2DM (n ¼ 5,871; 68%)

IHD: No Revascularization

T2DM (n ¼ 2,768; 32%)

p Value

No T2DM (n ¼ 6,466; 73%)

T2DM (n ¼ 2,414; 27%)

p Value

Laboratory analyses Hb, g/l

131  17

127  17

<0.0001

129  17

127  17

<0.0001

Creatinine, mmol/l

112  59

126  70

<0.0001

117  63

129  77

<0.0001

eGFR, ml/min/1.73 m2

62  27

56  24

<0.0001

56  24

53  29

eGFR class, ml/min/1.73 m2

<0.0001

<30

<0.0001 <0.0001

421 (7)

380 (14)

786 (12)

422 (17)

30–59

2,510 (43)

1,253 (45)

3,162 (49)

1,179 (49)

60–89

2,301 (39)

899 (32)

2,066 (32)

639 (26)

639 (11)

236 (9)

452 (7)

174 (7)

Cholesterol, mmol/l

4.3  1.1

4.0  1.1

<0.0001

4.5  1.2

4.3  1.3

0.008

LDL, mmol/l

2.5  1.0

2.2  0.9

<0.0001

2.7  1.0

2.4  1.1

<0.0001 <0.0001

>90

41  9

59  16

<0.0001

42  10

58  15

846  1313

982  2,562

0.92*

1,051  1,642

1,241  1,560

0.02*

5,213  7,454

5,552  7,550

0.32*

7,208  9,199

6,956  9,119

0.47*

ACEI

3,895 (67)

1,677 (61)

<0.0001

3,763 (59)

1,463 (61)

0.05

ARB

1,304 (23)

830 (30)

<0.0001

1,039 (16)

521 (22)

<0.0001

HbA1c, mmol/mol BNP, pg/ml NT-pro-BNP, pg/ml Pharmacological and device intervention RAA inhibition

ACEI or ARB

5,091 (87)

2,412 (87)

0.58

4,720 (73)

1,932 (80)

<0.0001

MRA

1,602 (27)

886 (32)

<0.0001

1,721 (27)

725 (30)

0.001

BB

5,244 (90)

2,484 (90)

0.69

5,378 (84)

2,049 (85)

0.04

ACEI/ARB þ BB

4,623 (79)

2,205 (80)

0.33

4,103 (63)

1,704 (71)

<0.0001

ACEI/ARB þ BB þ MRA

1,290 (22)

737 (27)

<0.0001

1,107 (17)

535 (22)

<0.0001

Diuretic agents (loop/thiazide)

4,287 (73)

2,391 (87)

<0.0001

5,390 (84)

2,162 (90)

<0.0001

Digitalis

694 (12)

344 (13)

0.44

1,020 (16)

391 (16)

0.62

Statins

4,431 (76)

2,151 (78)

0.03

2,772 (43)

1,302 (54)

<0.0001

<0.0001

<0.0001

Nitrates (long-lasting)

1,495 (26)

880 (32)

1,960 (31)

836 (35)

Antithrombotic agent

1,900 (33)

856 (31)

0.17

1,791 (28)

682 (29)

0.58

Aspirin

4,280 (73)

2,047 (74)

0.38

4,192 (65)

1,605 (67)

0.14

563 (10)

250 (9)

684 (11)

232 (10)

Device therapy

0.07

Pacemaker

0.25

Cardiac resynchronization therapy

110 (2)

41 (1.5)

57 (0.8)

31 (1.3)

Implantable cardioverter-defibrillator

291 (5)

120 (4.8)

97 (1.5)

42 (1.8)

Values are mean  SD, n (%),or %. Percentages were computed by group. Pearson chi-square test and Student t test were used for unpaired groups. *Logarithmically transformed before Student t test. IHD ¼ ischemic heart disease; other abbreviations as in Table 1.

origin have 1 or more manageable comorbidities

The BARI 2D (Bypass Angioplasty Revascularization

known to cause or influence HF.

Investigation 2 Diabetes) trial failed to show any

There are 2 reasonable explanations for the low

survival benefit through revascularization compared

use of revascularization in patients with T2DM. One

with optimal medical therapy in patients with T2DM

is that the risk of this intervention might have been

and coronary artery disease (16). These findings,

considered high because of the large comorbidity

however, should be interpreted bearing in mind

burden, and another is that T2DM often causes a

that all patients had undergone coronary angiog-

more diffuse atherosclerosis with challenging coro-

raphy before inclusion. Those who fulfilled pre-

nary artery stenoses, which lessens the opportunity

vailing criteria for immediate revascularization were

or even willingness to perform a PCI or CABG. Still,

excluded, which left only those with mild to mod-

it is unlikely that these conditions can explain a

erate disease eligible for BARI 2D. In addition, the

proportion as large as 50% of eligible patients, that

neutral results might have been driven by a 49%

is, patients with T2DM with HF of ischemic origin.

crossover

Some

revascularization

discrepancy

exists

in

the

evidence

that

frequency

from

during

medical the

therapy

study

to

period.

supports revascularization as a tool to improve

Convincing evidence favoring revascularization to

prognosis in T2DM and coronary artery disease.

improve prognosis in patients with T2DM and acute

1412

Johansson et al.

JACC VOL. 68, NO. 13, 2016 SEPTEMBER 27, 2016:1404–16

Diabetes, Heart Failure, and Ischemic Heart Disease

therapy alone or optimal medical therapy plus

F I G U R E 2 Crude Survival Curves Stratified By T2DM and IHD

CABG. Unexpectedly, there was no difference in allcause mortality (22), but as emphasized, there are

IHD yes/no & T2DM yes/no

several critical issues related to this trial (23). One

1.0

important limitation is the considerable proportion of medically treated patients who crossed over to

Survival Probability

0.8

revascularization during the 5 years of follow-up. That this undermined the power of the observa-

0.6

tions is highlighted by a renewed as-treated rather

0.4

No T2DM, No IHD

than intention-to-treat analysis of the STICH data-

T2DM, No IHD No T2DM, IHD

base, which showed that CABG reduced mortality compared with medical therapy alone (24). Indeed,

T2DM, IHD Class No T2DM, IHD No T2DM, No IHD T2DM, IHD T2DM, No IHD

0.2

0 0

Events n (%) 5 443 (43%) 4 751 (34%) 2 666 (50%) 1 284 (40%)

2

a recently published 10-year follow-up of the STICH study (STICHES [STICH Extension Study]) found CABG to be significantly superior to medical therapy

4

alone when analyzed according to intention to treat,

6

Follow-Up (Years) Number at risk No T2DM, IHD No T2DM, No IHD T2DM, IHD T2DM, No IHD

12574 14029 5317 3243

5791 6943 2391 1565

which provides a strong evidence base for the

2158 2535 845 499

benefits of such intervention in HF (25). In addition,

537 688 183 119

the results of 2 studies that applied propensity score analyses strengthened the benefit of CABG over medical therapy in patients with IHD and left

Long-term prognosis was evaluated with survival curves among patients with and without type 2 diabetes mellitus (T2DM) and with and without ischemic heart disease (IHD). The

ventricular dysfunction (26,27). Nonetheless, there is a gap in knowledge concerning demand for pro-

most serious prognosis was seen in patients with IHD and T2DM. T2DM independently predicted mortality regardless of the presence or absence of IHD (unadjusted hazard ratio

spective clinical trials to assess myocardial viability

[HR]: 1.20; 95% confidence interval [CI]: 1.14 to 1.25 and HR: 1.21; 95% CI: 1.14 to 1.29,

with cardiac magnetic resonance imaging or posi-

respectively) and remained a mortality predictor both in patients with and in those without

tron emission tomography and the actual impact of

IHD after adjustment for age (HR: 1.40; 95% CI: 1.33 to 1.46 and HR: 1.30; 95% CI: 1.22 to

revascularization

1.39, respectively).

in

patients

with

T2DM

and

ischemic HF (14,28). It is hoped that the ongoing REVIVED (Revascularization for Ischemic Ventricular Dysfunction) trial studying the efficacy and coronary syndromes and multivessel disease is

safety of PCI in systolic HF will provide further in-

provided by the FRISC II (Fragmin and Fast Revas-

sights in this field. Until results from this and

cularization During Instability in Coronary Artery

similar trials are available, even a cautious inter-

Disease) and FREEDOM (Future Revascularization

pretation of the present observational analysis of a

Evaluation

large

in

Patients

With

Diabetes

Mellitus:

HF

population

underscores

the

potential

Optional Management of Multivessel Disease) trials

benefit of revascularization and the need to at least

(17,18), although neither of these trials addressed

offer all patients a thorough investigation by means

the outcome of revascularization specifically in

of coronary angiography or computed tomography

relation to the presence of HF. With regard to HF in

angiography.

general, a meta-analysis of 3,088 patients with left

The finding that the vast majority (z90%) of

ventricular dysfunction and signs of preserved

patients with T2DM and HF of nonischemic origin

myocardial viability found a strong association be-

had at least 1 comorbidity known to cause HF has

tween revascularization and survival (19). Unfortu-

important clinical implications. These comorbidities

the

included hypertension, atrial fibrillation, pulmonary

proportion of patients with diabetes. On the basis of

disease, and valvular heart disease, all conditions

general knowledge of T2DM prevalence in a popu-

largely manageable with well-established therapeu-

lation with coronary artery disease, it can be

tic or preventive strategies. Taking into consider-

assumed that at least 20% to 30% of the studied

ation all T2DM patients in the present contemporary

population could have this disease (20,21). The

HF population leaves only 7% to 10% of them

concept of revascularization in patients with estab-

without a reasonable pathogenesis. This makes it

lished HF has been challenged by the results of the

tempting to question the existence of a pure dia-

STICH (Surgical Treatment for Ischemic Heart Fail-

betes cardiomyopathy that by definition requires

ure) trial, which randomized 1,212 patients with IHD

signs of left ventricular dysfunction in patients with

and left ventricular dysfunction to optimal medical

T2DM without any obvious cause of the condition,

nately,

this

analysis

did

not

report

on

Johansson et al.

JACC VOL. 68, NO. 13, 2016 SEPTEMBER 27, 2016:1404–16

Diabetes, Heart Failure, and Ischemic Heart Disease

C ENTR AL I LL U STRA T I O N Prognostic Implications of T2DM in IHD and Nonischemic HF and the Role of Previous Revascularization

Johansson, I. et al. J Am Coll Cardiol. 2016;68(13):1404–16.

Insights from the Swedish Heart Failure Registry (SwedeHF). In this study of a large heart failure (HF) population representing everyday clinical care, type 2 diabetes mellitus (T2DM) was associated with higher all-cause mortality, regardless of whether HF was of ischemic or nonischemic origin. The presence of ischemic heart disease (IHD) was associated with the worst prognosis (left). In ischemic HF, previous revascularization (RV) was associated with improved survival (right), which highlights the importance of always considering the possibility of a coronary intervention in patients with T2DM and IHD.

such as coronary artery disease, hypertension, or

ischemia is more common among patients with

valvular heart disease (29). Previous data reported

diabetes than among those without and that it has

on deranged myocardial metabolism in HF related

adverse prognostic implications (31,32). Further ev-

to T2DM with increased myocardial energy produc-

idence for these pathogenic conditions is not pro-

tion via beta oxidation of free fatty acids (6). More

vided by the present investigation, which is only

current studies, using modern imaging methods,

able to indicate opportunities for further studies.

have

the

These investigations need to apply advanced imag-

myocardial tissue of HF patients, with increased

ing methods to well-defined diabetes populations to

diffuse fibrosis enhancing myocardial stiffness and

further enhance potential mechanisms for prevent-

compromising

changes

ing or treating HF, thereby improving the dismal

might be more frequent in patients with diabetes as

prognosis in patients with the combination of T2DM

a consequence of high glucose and possibly also

and HF.

reported

on

structural

relaxation

changes

(6,30).

These

in

high insulin levels; however, they could also be

Lastly, to put our observations in the context of

explained by long-standing, poorly controlled hy-

large clinical trials, compared with the placebo-

pertension or merely a result of aging. Another

treated group in a recent outcome trial focused on

assumption behind the increased HF prevalence and

ischemic HF in patients with T2DM, the EMPA-REG

poor prognosis in patients with T2DM is that the

trial (Empagliflozin Cardiovascular Outcome Event

group judged clinically to have nonischemic HF

Trial in Type 2 Diabetes Mellitus Patients) (33), mor-

might have a compromised myocardial function

tality in patients with T2DM and ischemic HF

secondary to silent ischemia or atherosclerosis in

throughout the trial period and median follow-up of

small vessels, causing hibernation or stunning, as

almost 2 years was considerably higher in the present

well as scar tissue resulting from silent MIs. Some

study (50%) than in the EMPA-REG trial population

observational

(15%). Although such comparison must be made with

studies

report

that

undiagnosed

1413

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Johansson et al.

JACC VOL. 68, NO. 13, 2016 SEPTEMBER 27, 2016:1404–16

Diabetes, Heart Failure, and Ischemic Heart Disease

limitation with registry data is the possibility of

F I G U R E 3 Crude Survival Curves in HF Patients With IHD Stratified By

varying diagnostic criteria. The registry defines the

Revascularization History and T2DM

different variables, but they have not been validated in any detail. The proportion with T2DM is probably

Revascularization yes/no, T2DM yes/no 1.0

an underestimation, because undiagnosed diabetes is common in populations with cardiovascular diseases

Survival Probability

0.8

(20,34). With regard to IHD in SwedeHF, the definition was expanded in an attempt to cover as many patients as possible (Figure 1), but information on

0.6

patient history at the time of inclusion was sometimes

No T2DM, RV

incomplete. In addition, no information was available

0.4 Class No T2DM, RV No T2DM, No RV T2DM, RV T2DM, No RV

0.2

0 0

Events n (%) 2 064 (34%) 3 379 (52%) 1 267 (44%) 1 399 (58%)

2

T2DM, RV No T2DM, No RV

regarding silent angina, which raises the possibility of

T2DM, No RV

misclassification of IHD. This also applies to revascularization,

4

6

5871 2768 6466 2414

2995 1364 2710 977

because

it

was

retrospectively

regarding this treatment should be seen as hypothesis

Follow-Up (Years) Number at risk No T2DM, RV T2DM, RV No T2DM, No RV T2DM, No RV

and

collected and not randomized, the assumptions made generating rather than representing facts. However,

1183 505 937 329

the large database allowed for extensive adjustment

306 107 224 75

of clinically relevant confounders when evaluating the outcome. Further on the adjustment, the application of a propensity score for treatment bias (which

The prognostic impact of revascularization (RV) and type 2 diabetes mellitus (TD2M) in patients with ischemic heart disease (IHD) was estimated in survival curves. Patients with

to some degree mimics a randomization) strength-

T2DM without previous revascularization had the worst outlook. Previous revascularization

ened the assumptions of the benefits of revasculari-

was associated with a decreased mortality risk in T2DM patients compared with T2DM

zation.

patients without previous revascularization (hazard ratio [HR]: 0.82; 95% confidence in-

differences detected in the descriptive analyses be-

terval [CI]: 0.75 to 0.91) after adjustment for demographics, comorbidities, and pharmacological treatment. This association remained after the addition of the propensity score of previous revascularization as a covariate in the adjusted model (HR: 0.87; 95% CI: 0.78 to

It

should

be

acknowledged

that

small

tween different groups become statistically significant because of the large sample size. These statistical

0.96). Likewise, previous revascularization was associated with better prognosis within the

significances might not always be of clinical rele-

non-T2DM cohort (adjusted HR: 0.89; 95% CI: 0.83 to 0.96).

vance, and this necessitates a cautious interpretation of the data. Because of missing data on important diabetes variables, including hemoglobin A 1c, it was

great caution because of obvious selection biases in the trial participants (e.g., younger, fewer comorbidities), it underlines the serious prognosis in an everyday population with T2DM and ischemic HF.

not possible to extend prognostic analyses related to different levels of glucose control. Moreover, we did not have details about diabetes duration or classes of glucose-lowering therapy, factors with known prognostic implications. A median follow-up of 1.9 years

STUDY STRENGTHS AND LIMITATIONS. The major

might appear short, but it is mainly an effect of a

strength of the present report is the size and unse-

larger proportion being included during the most

lected nature of the population, which reflects

recent period and that the follow-up period was

contemporary,

generally fairly long.

everyday

clinical

practice.

One

T A B L E 4 Unadjusted and Adjusted HRs of Mortality by T2DM Status in Groups Stratified by History of IHD and Revascularization

No IHD Study Group: T2DM (Yes vs. No)

Unadjusted

IHD

IHD: Revascularization

IHD: No Revascularization

n

HR (95% CI)

n

HR (95% CI)

n

HR (95% CI)

n

HR (95% CI)

17,272

1.21 (1.14–1.29)

17,891

1.20 (1.14–1.25)

8,639

1.37 (1.28–1.47)

8,880

1.14 (1.07–1.21)

Adjusted for age

17,272

1.30 (1.22–1.39)

17,891

1.40 (1.33–1.46)

8,639

1.50 (1.39–1.61)

8,880

1.34 (1.26–1.43)

Adjusted model 1

12,562

1.30 (1.20–1.41)

13,007

1.41 (1.33–1.50)

6,755

1.36 (1.24–1.48)

6,252

1.45 (1.33–1.56)

Adjusted model 2

9,193

1.21 (1.09–1.34)

9,183

1.34 (1.24–1.44)

4,914

1.28 (1.15–1.43)

4,160

1.43 (1.29–1.59)

Model 1: Adjusted for T2DM, age, sex, level of care, weight, systolic and diastolic blood pressure, duration of HF, EF class, Hb class, eGFR class, hypertension, atrial fibrillation, pulmonary disease, ACEI, ARB, MRA, beta blockers, diuretics, statins, nitrates, aspirin, and anticoagulants. Model 2: Adjusted for model 1 plus heart rate and NYHA functional class. CI ¼ confidence interval; HR ¼ hazard ratio; other abbreviations as in Tables 1 to 3.

Johansson et al.

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Diabetes, Heart Failure, and Ischemic Heart Disease

CONCLUSIONS

PERSPECTIVES

In a contemporary setting, almost 90% of HF patients with T2DM have an accompanying risk factor that can contribute to HF development, among which IHD is the most common. The presence of IHD was associated with the worst prognosis, which was, however, less severe if revascularization had been performed previously.

COMPETENCY IN MEDICAL KNOWLEDGE: T2DM is associated with a higher risk of mortality in patients with HF, whether of ischemic or nonischemic origin. In patients with T2DM and ischemic HF, previous revascularization is associated with improved prognosis compared with patients without revascularization. Most patients with nonischemic HF have other comorbidities associated with HF.

REPRINT REQUESTS AND CORRESPONDENCE: Dr.

Isabelle Johansson, Cardiology Unit, Department of Medicine, N3:06, Karolinska University Hospital Solna, SE-171 76 Stockholm, Sweden. E-mail: isabelle.

TRANSLATIONAL OUTLOOK: Randomized trials are needed to validate these observational data and confirm the impact of revascularization in patients with T2DM and ischemic HF.

[email protected].

REFERENCES 1. International Diabetes Federation. IDF Diabetes

10. Cubbon RM, Adams B, Rajwani A, et al. Diabetes

patients with coronary artery disease and left

Atlas. Brussels, Belgium; 2013. Available at: http://www.idf.org/diabetesatlas. Accessed May 15, 2016.

mellitus is associated with adverse prognosis in chronic heart failure of ischaemic and non-ischaemic aetiology. Diab Vasc Dis Res 2013;10:330–6.

ventricular dysfunction: a meta-analysis. J Am Coll Cardiol 2002;39:1151–8.

2. Olafsdottir E, Aspelund T, Sigurdsson G, et al. Similar decline in mortality rate of older persons

11. Varela-Roman A, Shamagian LG, Caballero EB, et al. Influence of diabetes on the survival of patients hospitalized with heart failure: a 12-year study. Eur J Heart Fail 2005;7:859–64.

20. Norhammar A, Tenerz A, Nilsson G, et al. Glucose metabolism in patients with acute myocardial infarction and no previous diagnosis of diabetes mellitus: a prospective study. Lancet 2002;359:2140–4.

12. Jonsson A, Edner M, Alehagen U, Dahlström U. Heart failure registry: a valuable tool for improving the management of patients with heart

21. Gyberg V, De Bacquer D, Kotseva K, et al., EUROASPIRE IV Investigators. Screening for dysglycaemia in patients with coronary artery

failure. Eur J Heart Fail 2010;12:25–31.

disease as reflected by fasting glucose, oral glucose tolerance test, and HbA1c: a report from EUROASPIRE IV: a survey from the European Society of Cardiology. Eur Heart J 2015;36: 1171–7.

with and without type 2 diabetes between 1993 and 2004: the Icelandic population-based Reykjavik and AGES-Reykjavik cohort studies. BMC Public Health 2013;13:36. 3. Lipscombe LL, Hux JE. Trends in diabetes prevalence, incidence, and mortality in Ontario, Canada 1995-2005: a population-based study. Lancet 2007;369:750–6. 4. McMurray JJ, Gerstein HC, Holman RR, Pfeffer MA. Heart failure: a cardiovascular outcome in diabetes that can no longer be ignored. Lancet Diabetes Endocrinol 2014;2: 843–51. 5. Johansson I, Edner M, Dahlström U, Näsman P, Rydén L, Norhammar A. Is the prognosis in patients with diabetes and heart failure a matter of unsatisfactory management? An observational study from the Swedish Heart Failure Registry. Eur J Heart Fail 2014;16:409–18. 6. Bugger H, Abel ED. Molecular mechanisms of diabetic cardiomyopathy. Diabetologia 2014;57: 660–71. 7. Dries DL, Sweitzer NK, Drazner MH, Stevenson LW, Gersh BJ. Prognostic impact of diabetes mellitus in patients with heart failure according to the etiology of left ventricular systolic dysfunction. J Am Coll Cardiol 2001;38: 421–8. 8. Domanski M, Krause-Steinrauf H, Deedwania P, et al., BEST Investigators. The effect of diabetes on outcomes of patients with advanced heart failure in the BEST trial. J Am Coll Cardiol 2003; 42:914–22. 9. De Groote P, Lamblin N, Mouquet F, et al. Impact of diabetes mellitus on long-term survival in patients with congestive heart failure. Eur Heart J 2004;25:656–62.

13. Swedish Heart Failure Registry (RiksSvikt) website. Available at: http://www.ucr.uu.se/ rikssvikt-en/. Accessed January 11, 2016. 14. Kolh P, Windecker S, Alfonso F, et al. 2014 ESC/EACTS guidelines on myocardial revascularization: the Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS): developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur J Cardiothorac Surg 2014;46:517–92. 15. Rosenbaum PR, Rubin DB. The central role of the propensity score in observational studies for causal effects. Biometrika 1983;70:41–55. 16. Frye RL, August P, Brooks MM, et al., BARI 2D Study Group. A randomized trial of therapies for type 2 diabetes and coronary artery disease. N Engl J Med 2009;360:2503–15. 17. Norhammar A, Malmberg K, Diderholm E, et al. Diabetes mellitus: the major risk factor in unstable coronary artery disease even after consideration of the extent of coronary artery disease and benefits of revascularization. J Am Coll Cardiol 2004;43: 585–91.

22. Velazquez EJ, Lee KL, Deja MA, et al., STICH Investigators. Coronary-artery bypass surgery in patients with left ventricular dysfunction. N Engl J Med 2011;364:1607–16. 23. Gurunathan S, Ahmed A, Senior R. The benefits of revascularization in chronic heart failure. Curr Heart Fail Rep 2015;12:112–9. 24. Doenst T, Cleland JG, Rouleau JL, et al., STICH Investigators. Influence of crossover on mortality in a randomized study of revascularization in patients with systolic heart failure and coronary artery disease. Circ Heart Fail 2013;6:443–50. 25. Velazquez EJ, Lee KL, Jones RH, et al., STICHES Investigators. Coronary-artery bypass surgery in patients with ischemic cardiomyopathy. N Engl J Med 2016;374:1511–20. 26. Gheorghiade M, Flaherty JD, Fonarow GC, et al. Coronary artery disease, coronary revascularization, and outcomes in chronic advanced systolic heart failure. Int J Cardiol 2011;151:69–75.

18. Farkouh ME, Domanski M, Sleeper LA, et al. Strategies for multivessel revascularization in patients with diabetes. N Engl J Med 2012;367:

27. Velazquez EJ, Williams JB, Yow E, et al. Longterm survival of patients with ischemic cardiomyopathy treated by coronary artery bypass grafting versus medical therapy. Ann Thorac Surg 2012;93:

2375–84.

523–30.

19. Allman KC, Shaw LJ, Hachamovitch R, Udelson JE. Myocardial viability testing and impact of revascularization on prognosis in

28. Ryden L, Grant PJ, Anker SD, et al. ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with

1415

1416

Johansson et al.

JACC VOL. 68, NO. 13, 2016 SEPTEMBER 27, 2016:1404–16

Diabetes, Heart Failure, and Ischemic Heart Disease

the EASD: the Task Force on diabetes, prediabetes, and cardiovascular diseases of the European Society of Cardiology (ESC) and developed in collaboration with the European Association for

31. Schelbert EB, Cao JJ, Sigurdsson S, et al. Prevalence and prognosis of unrecognized myocardial infarction determined by cardiac magnetic resonance in older adults. JAMA 2012;

34. Bartnik M, Ryden L, Ferrari R, et al., Euro Heart Survey Investigators. The prevalence of abnormal glucose regulation in patients with coronary artery disease across Europe: the Euro Heart Survey on dia-

the Study of Diabetes (EASD) [published correction appears in Eur Heart J 2014;35:1824]. Eur Heart J 2013;34:3035–87.

308:890–6.

betes and the heart. Eur Heart J 2004;25:1880–90.

29. Schilling JD, Mann DL. Diabetic cardiomyopathy: bench to bedside. Heart Fail Clin 2012;8: 619–31.

32. Zethelius B, Johnston N, Venge P. Troponin I as a predictor of coronary heart disease and mortality in 70-year-old men: a community-based cohort study. Circulation 2006;113:1071–8.

30. Ugander M, Oki AJ, Hsu LY, et al. Extracellular volume imaging by magnetic resonance imaging provides insights into overt and sub-clinical myocardial pathology. Eur Heart J 2012;33:

33. Fitchett D, Zinman B, Wanner C, et al., EMPAREG OUTCOME Trial Investigators. Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: results of the EMPA-REG OUTCOME trial. Eur Heart J 2016;

1268–78.

37:1526–34.

KEY WORDS heart failure, ischemic heart disease, prognosis, revascularization, type 2 diabetes mellitus

A PPE NDI X For an expanded Methods section, please see the online version of this article.