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DECLARE TIMI 58 Trial (2019): Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes

DECLARE TIMI 58 Trial Summary: Wiviott et al. randomized 17,160 patients with DMII (HbA1c 6.5-12%) who had multiple risk factors for or had established atherosclerotic CV disease to either dapagliflozin or a placebo. Their objective was to assess the cardiovascular safety profile of dapagliflozin, a selective inhibitor of SGLT2 in patients with type 2 diabetes. The results were promising and showed a significant decrease in CV death and HF hospitalizations (P=0.005). No difference was noted in the major adverse CV events. The authors of DECLARE TIMI 58 trial concluded that in patients with type 2 DM who had or were at risk for atherosclerotic CV disease, treatment with dapagliflozin did not result in a higher or lower rate of MACE but did result in a lower rate of CV death or hospitalization for heart failure.

Source: NEJM

CANTOS Trial (2017): Canakinumab for Atherosclerotic Disease

CANTOS trial explaining role of Canakinumab in coronary artery disease

2017, CANTOS Trial: Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease, NEJM

The CANTOS trial evaluated the inflammatory nature of coronary artery disease where hypothesis was that decreasing the inflammation marker such as interleukin 1B will result in lower incidence of cardiovascular events. For this purpose, canakinumab which is a monoclonal antibody against IL-1B was tested against a placebo. The only dose that achieved significance after multiplicity-adjusted threshold for statistical significance was the 150 mg group.

The patients that responded best were those who achieved on-treatment hsCRP concentrations less than 2 mg/L. The authors observed a 25% decrease in major cardiovascular events in these patients. This was in contrast to those who continued to elevated hsCRP levels despite treatment. Based on this observation, the CANTOS trial authors concluded, “the magnitude of hsCRP reduction following a single dose of canakinumab might provide a simple clinical method to identify individuals most likely to accrue the largest benefit from continued treatment.”

With CANTOS trial results, Dr. Paul Ridker et al. decided to take a step forward and tried to inhibit the chain of inflammatory markers including IL-1, IL6 and CRP. They utilized methotrexate for this purpose and described their results in the CIRT trial.

FOURIER Trial (2017): Evolocumab and Clinical Outcomes in Patients with CVD

evolocumab PCSK9 inhibitor role in atherosclerotic disease - FOURIER Trial

FOURIER Trial Key Points:

  1. FOURIER trial established the role of PCSK9 inihibitor therapy in reducing future cardiovascular events and mortality.
  2. Evolocumab showed benefit in terms of cardiovascular disease but didn’t show any mortality benefit.
  3. These agents were utilized in patients who were already on moderate to high intensity statin therapy.
  4. PCSK9 inhibition was well-tolerated without excess new-onset diabetes or neurocognitive effects despite dramatic LDL reduction.

Guidelines on PCSK9 inhibition – ACC 2017 Update for Non-Statin Therapy

  1. If patients with clinical ASCVD and comorbidities require >25% additional lowering of LDL-C, a PCSK9 inhibitor may be preferred as the initial non-statin agent.
  2. If patients with clinical ASCVD and baseline LDL-C ≥190 mg/dL require >25% additional lowering of LDL-C or have additional comorbidities as defined in the previous text, a PCSK9 inhibitor may be preferred as the initial non-statin agent.
  3. If high-risk patients with baseline LDL-C ≥190 mg/dL require additional LDL-C lowering (<50% reduction in LDL-C, may consider LDL-C ≥100 mg/dL or non–HDL-C ≥130 mg/dL) after the addition of a single non-statin agent (i.e., ezetimibe) to maximally tolerated statin therapy, it is reasonable to consider the addition of a second non-statin agent (i.e., ezetimibe plus PCSK9 inhibitor).
  4. Read full guidelines at ACC

Source: NEJM

EXCEL: Everolimus-Eluting Stents or Bypass Surgery for Left Main CAD

2016, Everolimus-Eluting Stents or Bypass Surgery for Left Main Coronary Artery Disease, NEJM

EXCEL Trial Summary

Summarized by Lina Ya’qoub, MD – Cardiovascular disease fellow at Louisiana State University

Methods

The Evaluation of XIENCE versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization (EXCEL) trial is an international, open-label, non-inferiority, multicenter randomized trial that compared everolimus-eluting stents with CABG in patients with left main coronary artery disease. Inclusion criteria were stenosis of the left main coronary artery of 70% or more, as estimated visually, or stenosis of 50-69% if determined by means of noninvasive or invasive testing to be hemodynamically significant, and a consensus among the members of the heart team regarding eligibility for revascularization with either PCI or CABG. In addition, participants were required to have low-to-intermediate anatomical complexity of coronary artery disease, as defined by a site-determined SYNTAX score, with low score being <=22 and intermediate score being 23-32.

Randomization

Among the 1905 patients who underwent randomization, 948 were assigned to the PCI group and 957 to the CABG group. Baseline clinical and angiographic characteristics were well balanced between the groups. Among the 948 patients assigned to the PCI group, 942 underwent revascularization; PCI was the first procedure in 935 patients. A mean of 2.4 stents with a mean total stent length of 49.1 mm were implanted per patient; 99.2% of the stents implanted were everolimus-eluting stents. Among the 957 patients assigned to the CABG group, 940 underwent revascularization; CABG was the first procedure in 923 patients. A mean of 2.6 grafts per patient were placed; an internal thoracic artery graft was used in 98.8% of the patients.

Follow-up/end-point events

The median duration of follow-up was 3.0 years (interquartile range, 2.4 to 3.0) in both groups. The primary composite end-point event of death, stroke, or myocardial infarction at 3 years occurred in 15.4% of the patients in the PCI group and in 14.7% of the patients in the CABG group (difference, 0.7 percentage points; upper 97.5% confidence limit, 4.0 percentage points; P=0.02 for noninferiority; hazard ratio, 1.00; 95% confidence interval [CI], 0.79 to 1.26; P=0.98 for superiority).

At 30 days, the composite end-point event of death, stroke, or myocardial infarction had occurred in 4.9% of the patients in the PCI group and in 7.9% of the patients in the CABG group (difference, −3.1 percentage points; upper 95.0% confidence limit, −1.2 percentage points; P<0.001 for noninferiority).At 3 years, the composite end-point event of death, stroke, myocardial infarction, or ischemia-driven revascularization had occurred in 23.1% of the patients in the PCI group and in 19.1% of the patients in the CABG group (difference, 4.0 percentage points; upper 95% confidence limit, 7.2 percentage points; P=0.01 for noninferiority).

Author Comments

Several studies have shown that outcome and safety of left main disease percutaneous coronary intervention (PCI) is similar to caronary artery bypass graft (CABG) in selected patients. The EXCEL trial aim was to assess major adverse cardiac events (death, stroke, MI) for PCI versus CABG over 3 years in patients with low-intermediate syntax scores. This randomized controlled trial proved that PCI was non-inferior to CABG in this population.

LIPID: Pravastatin in patients with coronary heart disease

1998, Pravastatin in patients with coronary heart disease, NEJM

POISE: Metoprolol succinate in patients undergoing non-cardiac surgery

 

 

2008, Extended-release metoprolol succinate in patients undergoing non-cardiac surgery, The Lancet 

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