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Risk Framing in Cardiovascular Medicine I

      To the Editor:
      We applaud the work of Drs Alkhouli and Rihal
      • Alkhouli M.
      • Rihal C.S.
      The odyssey of risk framing in cardiovascular medicine: a patient-centered perspective.
      in examining the important topic of risk/benefit framing in patient-centered decision making. However, we disagree with the choice of a sodium-glucose cotransporter 2 inhibitor (SGLT2i), canagliflozin, as an example in their arguments and that “the other 98% [of treated patients] would see no incremental benefit from the treatment.”(p.1316) First, to clarify, the primary outcome in Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation was not a composite major adverse cardiovascular event outcome as stated, but rather a composite of end-stage kidney disease, doubling of the serum creatinine level from baseline sustained for at least 30 days, or death from renal or cardiovascular disease. Patients who received canagliflozin 100 mg/d had a 30% relative risk reduction (4.3% absolute risk reduction) for this primary outcome.
      • Perkovic V.
      • Jardine M.J.
      • Neal B.
      • et al.
      CREDENCE Trial Investigators
      Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.
      Reduction of hospitalization for heart failure (a secondary end point) was profound, with a 39% relative risk reduction (2.4% absolute risk reduction) seen in patients receiving canagliflozin. This is in addition to the major adverse cardiovascular event outcome data quoted by the authors.
      • Mahaffey K.W.
      • Jardine M.J.
      • Bompoint S.
      • et al.
      Canagliflozin and cardiovascular and renal outcomes in type 2 diabetes mellitus and chronic kidney disease in primary and secondary cardiovascular prevention groups.
      Sodium-glucose cotransporter 2 inhibitors continue to show promise as one of the most important and pluripotent cardiovascular medications of a generation, recently exhibiting groundbreaking efficacy in heart failure with reduced ejection fraction with and without diabetes
      • McMurray J.J.V.
      • Solomon S.D.
      • Inzucchi S.E.
      • et al.
      DAPA-HF Trial Committees and Investigators
      Dapagliflozin in patients with heart failure and reduced ejection fraction.
      ,
      • Milton Packer M.
      • Anker S.D.
      • Butler J.
      • et al.
      Cardiovascular and renal outcomes with empagliflozin in heart failure.
      and dramatic renoprotective effects in patients with chronic kidney disease with and without diabetes, including markedly lowering mortality.
      • Heerspink H.J.L.
      • Stefánsson B.V.
      • Correa-Rotter R.
      Dapagliflozin in patients with chronic kidney disease.
      Many of these effects are thought to be classwide, and the use of these agents often targets multiple cardiovascular protective end points in an individual patient. Studies have also reported the cost-effectiveness of this class.
      • Hong D.
      • Si L.
      • Jiang M.
      • et al.
      Cost effectiveness of sodium-glucose cotransporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and dipeptidyl peptidase-4 (DPP-4) inhibitors: a systematic review [published correction appears in Pharmacoeconomics. 2019;37(12):1553].
      Therefore, although again we agree with the central message of the commentary, we disagree with the authors’ selection of an SGLT2i as an example and recommend against limiting SGLT2i benefit to a single end point.

      References

        • Alkhouli M.
        • Rihal C.S.
        The odyssey of risk framing in cardiovascular medicine: a patient-centered perspective.
        Mayo Clin Proc. 2020; 95: 1315-1317
        • Perkovic V.
        • Jardine M.J.
        • Neal B.
        • et al.
        • CREDENCE Trial Investigators
        Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.
        N Engl J Med. 2019; 380: 2295-2306
        • Mahaffey K.W.
        • Jardine M.J.
        • Bompoint S.
        • et al.
        Canagliflozin and cardiovascular and renal outcomes in type 2 diabetes mellitus and chronic kidney disease in primary and secondary cardiovascular prevention groups.
        Circulation. 2019; 140: 739-750
        • McMurray J.J.V.
        • Solomon S.D.
        • Inzucchi S.E.
        • et al.
        • DAPA-HF Trial Committees and Investigators
        Dapagliflozin in patients with heart failure and reduced ejection fraction.
        N Engl J Med. 2019; 381: 1995-2008
        • Milton Packer M.
        • Anker S.D.
        • Butler J.
        • et al.
        Cardiovascular and renal outcomes with empagliflozin in heart failure.
        N Engl J Med. 2020; 383: 1413-1424
        • Heerspink H.J.L.
        • Stefánsson B.V.
        • Correa-Rotter R.
        Dapagliflozin in patients with chronic kidney disease.
        N Engl J Med. 2020; 383: 1436-1446
        • Hong D.
        • Si L.
        • Jiang M.
        • et al.
        Cost effectiveness of sodium-glucose cotransporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and dipeptidyl peptidase-4 (DPP-4) inhibitors: a systematic review [published correction appears in Pharmacoeconomics. 2019;37(12):1553].
        Pharmacoeconomics. 2019; 37: 777-818

      Linked Article

      • In reply—Risk Framing in Cardiovascular Medicine I and II
        Mayo Clinic ProceedingsVol. 95Issue 11
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          We thank the authors for their insightful comments on our perspective published in the journal.1 We agree with Dr Modarressi1 that sodium-glucose cotransporter-2 inhibitors indeed represent an important new treatment for patients with heart failure. Although we used the trial definition of major adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction, or stroke) in the text and in the table’s footnote, we acknowledge that this was a secondary and not a primary end point.
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      • The Odyssey of Risk Framing in Cardiovascular Medicine: A Patient-Centered Perspective
        Mayo Clinic ProceedingsVol. 95Issue 7
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          “The best interest of the patient is the only interest to be considered.”1— William J. Mayo, MD
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      • Risk Framing in Cardiovascular Medicine II
        Mayo Clinic ProceedingsVol. 95Issue 11
        • Preview
          We read with interest the commentary by Alkhouli and Rihal.1 The authors accurately remark about the need of easily understood tools, available to clinicians and patients at point of care, that could simplify the assessment of individual patient risk benefit and harm of an intervention. In particular, they observed the paucity of intervention-specific, individualized risk/benefit scores that facilitate the identification of higher risk individuals that benefit the most from an intervention, with acceptable probability of harm.
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