Summaries of Late-breaking Science Presentations at the 2018 American Heart Association meeting in Chicago, IL

Summaries of Late-breaking Science Presentations at the 2018 American Heart Association meeting in Chicago, IL

Summaries of Late-breaking Science Presentations at the 2018 American Heart Association meeting in Chicago, IL

 By Heather Nelson Cortes, PhD and Kevin C Maki, PhD

 Dapagliflozin and Cardiovascular Events in the DECLARE-TIMI 58 Trial

The Dapagliflozin Effect on Cardiovascular Events—Thrombolysis in Myocardial Infarction 58 (DECLARE-TIMI 58) Trial was designed to assess the safety and efficacy of dapagliflozin (10 mg/d), a selective sodium-glucose cotransporter (SGLT)-2 inhibitor, in the reduction of cardiovascular events in patients with type 2 diabetes mellitus.  This was a phase 3b, randomized, double-blinded, placebo-controlled trial in 17,160 patients ≥40 y of age with type 2 diabetes and either cardiovascular disease (CVD) or multiple CVD risk factors.  The primary efficacy endpoints were major adverse cardiovascular events (MACE; defined as cardiovascular death, myocardial infarction or ischemic stroke) and a composite of heart failure hospitalization (HHF) or cardiovascular death.  Median follow-up was 4.5 y.  The results for the outcomes including the hazard ratios (HR) and 95% confidence intervals (CI) are shown in the table below.

 

Outcome

Dapagliflozin

(n = 8582)

Placebo

(n = 8578)

HR (95% CI)

p-value

 

Rate/1000 patient-y

 

 

MACE

22.6

24.2

0.93 (0.84 to 1.03)

0.17

CVD/HHF

12.2

14.7

0.83 (0.73 to 0.95)

0.005

HHF

6.2

8.5

0.73 (0.61 to 0.88)

Cardiovascular death

7.0

7.1

0.98 (0.82 to 1.17)

All-cause mortality

15.1

16.4

0.93 (0.82 to 1.04)

Renal composite1

10.8

14.1

0.76 (0.67 to 0.87)

1Renal outcome was described as a 40% decrease in estimated glomerular filtration rate to <60 mL/min/1.73 m2, end-stage renal disease or death from renal or cardiovascular cause.

 

Conclusion:  Compared to placebo, dapagliflozin was safe and reduced the composite of cardiovascular death or HHF, but did not significantly reduce the incidence of MACE.

 Reference:

Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2018; Epub ahead of print.

 

 

Ezetimibe and Cerebro- and Cardiovascular Events in the EWTOPIA Trial
The role of lipid-lowering therapy in elderly (≥75 y of age) Japanese men and women with elevated low-density lipoprotein cholesterol (LDL-C) levels, but no history of coronary artery disease had not been well studied previously.  The Ezetimibe Lipid Lowering Trial on Prevention of Atherosclerosis in 75 or Older (EWTOPIA 75) investigation was a prospective, multi-center, open-label, blinded endpoint, randomized controlled trial conducted between 2009-2016 in Japanese men and women whose LDL-C level was ≥140 mg/dL and who had one or more cardiovascular risk factors (diabetes, hypertension, smoking, low high-density lipoprotein cholesterol, high triglycerides, previous history of cerebral infarction or peripheral artery disease). 

The primary endpoint was MACE, defined as a composite of sudden cardiac death, myocardial infarction, coronary revascularization, and/or stroke.  Secondary outcomes included cardiac events, cerebrovascular events, and all-cause mortality.  Eligible patients were randomized to either an ezetimibe group (10 mg/d plus dietary counseling; n = 1716) or a control group (dietary counseling alone; n = 1695).  LDL-C levels were reduced significantly more among patients taking ezetimibe (from 161 to 120 mg/dL) compared to subjects in the control group (from 162 to 131 mg/dL) (p < 0.001 for interaction).  The results for the outcomes are shown in the table below.

 

Outcome

HR (95% CI)

p-value

MACE

0.66 (0.50 to 0.86)

0.002

Cardiac events

0.60 (0.37 to 0.98)

0.04

Cerebrovascular events

0.78 (0.55 to 1.11)

>0.05

All-cause mortality

1.09 (0.89 to 1.34)

 

Conclusions:  In an elderly (≥75 y) Japanese population, ezetimibe (10 mg/d) plus dietary counseling compared to dietary counseling alone for primary prevention (elevated LDL-C, no history of CVD), was shown to help prevent cerebro- and cardiovascular events. 

 References:

Kumbhani DJ.  Ezetimibe in prevention of cerebro- and cardiovascular events in middle- to high-risk, elderly (75 years old or over) patients with elevated LDL-cholesterol – EWTOPIA 75.   https://www.acc.org/latest-in-cardiology/clinical-trials/2018/11/08/22/56/ewtopia75#references-for-article.

Ouchi Y. Ezetimibe in prevention of cerebro- and cardiovascular events in middle-to high-risk, elderly (75 years old or over) patients with elevated LDL-cholesterol: a multicenter, randomized, controlled, open-label trial. Presented at AHA 2018. November 10, 2018. Chicago, IL.

 

 

The Cardiovascular Inflammation Reduction Trial (CIRT): Low Dose Methotrexate for the Prevention of Atherosclerotic Events
CIRT was a randomized, double-blind trial of low-dose methotrexate (LD-MTX; target dose 15-20 mg/week) or placebo in patients with a prior myocardial infarction or multi-vessel coronary disease who also had either type 2 diabetes or metabolic syndrome.  It was designed to investigate whether inhibiting inflammation with LD-MTX might provide a similar cardiovascular benefit to that shown previously by treatment with canakinumab, an anti-inflammatory agent.  At the outset of CIRT, the primary endpoint was a composite of nonfatal myocardial infarction, nonfatal stroke or cardiovascular death.  Towards the end of the trial, but before the trial was unblinded, hospitalization for unstable angina that led to urgent revascularization was added to the composite primary endpoint.

Eligible patients were randomly assigned to either LD-MTX (n = 2391) or placebo (n = 2395), and all patients also received 1 mg folate/day.  The trial was stopped after a median follow-up of 2.3 years (maximum 5.1 years) because it had crossed a pre-specified boundary for futility for both the original and final endpoints, and due to the lack of evidence for a reduction in C-reactive protein (CRP) with LD-MTX.  Median changes in inflammatory markers from enrollment to eight months in the LD-MTX and placebo groups, respectively, were 0.09 and 0.05 mg/L for CRP, -0.24 and -0.31 pg/mL for interleukin (IL)-1ß and 0.30 and 0.04 pg/mL for IL-6 (all p >0.05).  Results for the cardiovascular endpoints are shown below.

 

Outcome

LD-MTX

(n = 2391)

Placebo

(n = 2395)

HR (95% CI)

p-value

 

Rate/100 patient-y

 

 

Original MACE

3.46

3.43

1.01 (0.82 to 1.25)

0.91

Final MACE

4.13

4.31

0.96 (0.79 to 1.16)

0.67

Conclusions:  In patients with prior myocardial infarction or multivessel CVD with either type 2 diabetes or metabolic syndrome, LD-MTX did not reduce inflammatory markers or cardiovascular events when compared to placebo.

 Reference:

Ridker PM, Everett BM, Pradhan A, et al. Low-dose methotrexate for the prevention of atherosclerotic events. N Engl J Med. 2018; Epub ahead of print.

Photo by Aaron Bean