HYVCTTSSS

Clinical Question

In patients with sepsis or septic shock, does combined treatment with intravenous hydrocortisone, vitamin C, and thiamine reduce mortality compared to placebo?

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

As of July 2020, no guidelines have been published that reflect the results of this trial.

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

• Meets diagnostic criteria for Sepsis-3
• Age ≥ 18 years
• Procalcitonin ≥ 2 ng/mL when entering the ICU

Exclusion Criteria

• Pregnancy
• Limitations of care (e.g., family discontinued treatment)
• Noninfectious factors that may lead to death (e.g., severe head injury, cardiogenic shock)
• Persistent infection sources that cannot be removed

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)