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Pivot X, et al. "6 months versus 12 months of adjuvant trastuzumab in early breast cancer: final analysis of a multicentre,open-label, phase 3 randomised trial". The Lancet. 2019. :1979-1987.
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Clinical Question

In patients with Early Breast Cancer with HER2 overexpression, is 6-months adjuvant Trastuzumab non-inferior to the standard 12-months treatment ?

Bottom Line

Not only does targeting euglycemia (HbA1c <6%) not reduce cardiovascular risk, it is associated with increased mortality.

Major Points

Several small and large randomized trials in diabetics had previously suggested a sizable benefit of tight glycemic control in reducing cardiovascular risk. The ACCORD trial was the largest study of its kind and demonstrated that not only does euglycemia (ie, HbA1c <6%) not reduce cardiovascular risk, it also is associated with a trend towards increased mortality.

Guidelines

Design

  • Multicenter, double-blind, parallel-group, randomized, controlled trial
  • N=10,251
    • Intensive (n=5,128)
    • Standard (n=5,123)
  • Setting: 77 centers in Canada and the United States
  • Enrollment: January to June 2001, February 2003 to October 2005
  • Mean follow-up: 3.5 years
  • Analysis: Intention-to-treat
  • Primary outcome:

Population

Inclusion Criteria

  • Type 2 diabetes mellitus
  • Hemoglobin A1c ≥7.5%
  • Age 40-79 years with CAD or 55-79 years with
  • Anatomical evidence of significant atherosclerosis
  • Albuminuria
  • LVH
  • ≥2 cardiovascular risk factors (dyslipidemia, HTN, current smoking, obesity)

Exclusion Criteria

  • Frequent or recent serious hypoglycemic events
  • Unwillingness to perform home glucose monitoring or insulin injections
  • BMI >45
  • Cr >1.5mg/dl
  • Serious illness

Baseline Characteristics

  • Mean age: 72 years
  • Mean BMI: 28
  • Mean HbA1c: 8.8%
  • Units of insulin: 14 units/day

Interventions

  • Randomized to intensive (targeting HbA1c <6%) or standard (HbA1c 7-7.9%) glycemic therapy

    • Then 46% were randomized to intensive (SBP <120) vs. standard (SBP <140) blood pressure therapy
    • Remaining 54% randomized to fenofibrate vs. placebo; all received statin
  • Intensive glycemic control group attended monthly visits for 4 months, then every 2 months, with additional visits and telephone calls as needed
  • Standard therapy group had glycemic control visits every 4 months

Outcomes

Comparisons are intensive therapy vs. standard therapy.

Primary Outcomes

Annual rate of nonfatal MI or nonfatal stroke or cardiovascular death
2.11% vs. 2.29% (HR 0.90; 95% CI 0.78-1.04; P=0.16)

Secondary Outcomes

Annual rate of death from any cause
1.41% vs. 1.14% (HR 1.22; 95% CI 1.01-1.46; P=0.04)
Annual rate of cardiovascular death
0.79% vs. 0.56% (HR 1.35; 95% CI 1.04-1.76; P=0.02)

Subgroup Analysis

Adverse Events

Criticisms

Funding

Further Reading