Canagliflozin Cardiovascular Assessment Study - CANVAS

Nov 16, 2019
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Presenter/Author:
James L. Januzzi, Jr., MD, FACC
Author/Summarized by Author:
Anthony A. Bavry, MD, MPH, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
Janssen Research and Development
Date Presented:
11/16/2019
Date Published:
03/17/2019
Date Updated:
11/16/2019
Original Posted Date:
06/13/2017
References

Contribution To Literature:

The CANVAS trial showed that canagliflozin was superior to placebo at preventing cardiovascular events.

Description:

The goal of the trial was to evaluate the sodium-glucose cotransporter 2 inhibitor canagliflozin compared with placebo among patients with type 2 diabetes.

Study Design

  • Randomized
  • Parallel
  • Placebo
  • Blinded

Patients with type 2 diabetes were randomized to canagliflozin (n = 5,795) versus placebo (n = 4,347). Patients in the canagliflozin arm received 300 mg daily or 100 mg daily.

Inclusion criteria:

  • Patients with type 2 diabetes and high cardiovascular risk
  • ≥30 years of age and history of symptomatic atherosclerotic cardiovascular disease, or
  • ≥50 years of age and 2+ of the following: diabetes duration >10 years, systolic blood pressure >140 mm Hg on antihypertensive therapy, current smoking, albuminuria, or high-density lipoprotein cholesterol <38.7 mg/dl
  • Total number of enrollees: 10,142
  • Duration of follow-up: 188 weeks
  • Mean patient age: 63 years
  • Percentage female: 36%
  • Percentage with diabetes: 100%

Other salient features/characteristics:

  • Mean duration of diabetes: 13.5 years
  • 65.6% of participants had history of cardiovascular disease

Principal Findings:

The primary outcome, incidence of cardiovascular death, myocardial infarction, or stroke, occurred in 26.9 participants per 1,000 patient-years of the canagliflozin group versus 31.5 participants per 1,000 patient-years of the placebo group (p = 0.02 for superiority, p < 0.001 for noninferiority). The benefit for canagliflozin appeared to be similar for patients with heart failure with reduced ejection fraction (HFrEF) and those with heart failure with preserved ejection fraction (HFpEF).

Secondary outcomes:

  • Amputation: 6.3 participants per 1,000 patient-years versus 3.4 participants per 1,000 patient-years (p < 0.05)
  • Progression of albuminuria: 89.4 participants per 1,000 patient-years versus 128.7 participants per 1,000 patient-years (p < 0.05)

Primary versus secondary prevention: Approximately 34% of the cohort was enrolled for primary prevention (age ≥50 years, no known coronary artery disease/ cardiovascular disease/ peripheral artery disease, at least two risk factors). Event rates were higher in the secondary prevention subset. Compared with placebo, canagliflozin reduced the primary endpoint (p for interaction = 0.18), heart failure hospitalization (p for interaction = 0.91), and progression to albuminuria (p for interaction = 0.48) in both subgroups. It also increased lower extremity amputations (p for interaction = 0.63) in both subgroups.

Treatment effect according to heart failure: Reduction in cardiovascular death or hospitalization for heart failure appeared to be greater among those with a history of heart failure (hazard ratio [HR] 0.61, 95% confidence interval [CI] 0.46-0.80), compared to those with no history of heart failure (HR 0.87, 95% CI 0.72-1.06; p for interaction 0.021).

Treatment effect according to baseline renal function: Cardiovascular death, myocardial infarction, or stroke was similar among those with chronic kidney disease (estimated glomerular filtration rate [eGFR] ≥30 to <60 ml/min/1.73 m2) (HR 0.70, 95% CI 0.55-0.90), compared to those with normal renal function (eGFR ≥60 ml/min/1.73 m2) (HR 0.92, 95% CI 0.79-1.07; p for heterogeneity 0.08).

Association with N-terminal pro–B-type natriuretic peptide (NT-proBNP): NT-proBNP ≥125 pg/ml at baseline was substantially prognostic for subsequent heart failure hospitalization. At 1 year, canagliflozin was associated with a reduction in NT-proBNP, while placebo was associated with an increase in NT-proBNP.

Interpretation:

Among patients with type 2 diabetes, canagliflozin was beneficial. Canagliflozin compared with placebo was associated with a lower frequency of adverse cardiovascular events. Canagliflozin was also associated with a lower rate of progression of albuminuria; however, amputation occurred more frequently. Effects were similar among both primary and secondary prevention participants, with lower event rates among the primary prevention participants. The benefit of canagliflozin may be greater among those with a prior history of heart failure. The benefit of canagliflozin did not appear to be modified by baseline renal function.

References:

Presented by Dr. James L. Januzzi at the American Heart Association Annual Scientific Sessions (AHA 2019), Philadelphia, PA, November 16, 2019.

Figtree GA, Rådholm P, Barrett TB, et al. Effects of Canagliflozin on Heart Failure Outcomes Associated With Preserved and Reduced Ejection Fraction in Type 2 Diabetes: Results From the CANVAS Program. Circulation 2019;Mar 17:[Epub ahead of print].

Neuen BL, Ohkuma T, Neal B, et al. Cardiovascular and Renal Outcomes With Canagliflozin According to Baseline Kidney Function: Data From the CANVAS Program. Circulation 2018;138:1537-50.

Rådholm K, Figtree G, Perkovic V, et al. Canagliflozin and Heart Failure in Type 2 Diabetes: Results From the CANVAS Program (Canagliflozin Cardiovascular Assessment Study). Circulation 2018;138:458-68.

Presented by Dr. Gemma Figtree at the American College of Cardiology Annual Scientific Session (ACC 2018), Orlando, FL, March 11, 2018.

Mahaffey KW, Neal B, Perkovic V, et al., on behalf of the CANVAS Program Collaborative Group. Canagliflozin for Primary and Secondary Prevention of Cardiovascular Events: Results From the CANVAS Program (Canagliflozin Cardiovascular Assessment Study). Circulation 2018;137:323-34.

Presented by Dr. Kenneth W. Mahaffey at the American Heart Association Annual Scientific Sessions (AHA 2017), Anaheim, CA, November 13, 2017.

Neal B, Perkovic V, Mahaffey KW, et al., on behalf of the CANVAS Program Collaborative Group. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med 2017;377:644-57.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Heart Failure and Cardiomyopathies, Prevention, Lipid Metabolism, Nonstatins, Acute Heart Failure, Smoking

Keywords: AHA Annual Scientific Sessions, AHA19, ACC Annual Scientific Session, ACC19, ACC18, AHA17, Albuminuria, Amputation, Antihypertensive Agents, Atherosclerosis, Blood Pressure, Diabetes Mellitus, Type 2, Cardiovascular Diseases, Cholesterol, HDL, Glucose, Heart Failure, Lipoproteins, HDL, Metabolic Syndrome, Myocardial Infarction, Primary Prevention, Renal Insufficiency, Chronic, Risk Factors, Secondary Prevention, Smoking, Stroke


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