Christopher P Cannon’s research while affiliated with Brigham and Women's Hospital and other places

Background/Introduction Patients with peripheral artery disease (PAD) are at risk of developing progressive symptoms leading to revascularization as well as major adverse limb events such as critical limb ischemia and amputation. Recently, two trials of PCSK9 inhibitors, which lower both LDL-C and Lp(a) have demonstrated reductions in MALE and peripheral revascularization. Whether this benefit is present for other LDL-C lowering therapies has not been well described. Purpose To evaluate whether LDL-C lowering with ezetimibe reduces the risk of adverse limb events. Methods IMPROVE-IT randomized 18,144 patients with acute coronary syndrome (ACS), including 1,005 with PAD, to ezetimibe or placebo on top of statin and followed for a median of 6 years. Two vascular specialists blinded to treatment allocation independently reviewed all adverse events to categorize limb outcomes including critical limb ischemia (CLI), and related amputation as well as progressive symptoms leading to lower extremity revascularization (worsening PAD). Total limb outcomes over follow up were compared by treatment groups using negative binomial regression and relative risks (RR) are presented. Results A total of 397 patients had worsening symptoms (in 346 PAD patients) and 43 developed CLI (in 36 patients) during follow up. The risk of total PAD events (CLI or worsening symptoms) was lower with ezetimibe versus placebo (RR 0.77, 95% CI 0.62 – 0.96, p=0.018) with a consistent trend for both components (Figure Panel A). When evaluating the relationship of achieved LDL-C at 1-month post-randomization and the risk of first PAD event, there appeared to a linear relationship extending to an LDL-C less than 25 mg/dL (Figure Panel B). Conclusion Further lowering of LDL-C with ezetimibe on top of statin therapy in patients with ACS was associated with a lower risk of adverse limb events over long-term follow up including CLI and progressive disease leading to revascularization. These data support the importance of intensive lipid lowering therapies in improving limb outcomes in patients with atherosclerotic vascular disease. In addition, these data support LDL-C as a treatment target for optimizing outcomes in patients with peripheral artery disease.Figure Panel AFigure Panel B

Background Persistence to P2Y12 inhibitors after myocardial infarction (MI) remains low. Out‐of‐pocket cost is cited as a factor affecting medication compliance. We examined whether a copayment intervention affected 1‐year persistence to P2Y12 inhibitors and clinical outcomes. Methods and Results In an analysis of ARTEMIS (Affordability and Real‐World Antiplatelet Treatment Effectiveness After Myocardial Infarction Study), patients with MI discharged on a P2Y12 inhibitor were stratified by baseline out‐of‐pocket medication burden: low (0–49 per month), intermediate (50–149 per month), and high (≥$150 per month). The impact of the voucher intervention on 1‐year P2Y12 inhibitor persistence was examined using a logistic regression model with generalized estimating equations. We assessed the rates of major adverse cardiovascular events among the groups using a Kaplan–Meier estimator. Among 7351 MI‐treated patients at 282 hospitals, 54.2% patients were in the low copay group, 32.0% in the middle copay group, and 13.8% in the high copay group. Patients in higher copay groups were more likely to have a history of prior MI, heart failure, and diabetes compared with the low copay group (all P <0.0001). Voucher use was associated with a significantly higher likelihood of 1‐year P2Y12 inhibitor persistence regardless of copayment tier (low copay with versus without voucher: adjusted odds ratio [OR], 1.44 [95% CI, 1.25–1.66]; middle copay: adjusted OR, 1.63 [95% CI, 1.37–1.95]; high copay group: adjusted OR, 1.41 [95% CI, 1.05–1.87]; P interaction=0.42). Patients in the high copay group without a voucher had similar risk of 1‐year major adverse cardiovascular events compared with patients in the high copay group with a voucher (adjusted hazard ratio, 0.89 [95% CI, 0.66–1.21]). Conclusions Medication copayment vouchers were associated with higher medication persistence at 1 year following an MI, regardless of out‐of‐pocket medication burden. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02406677.

Individualised and patient-centric care is essential in the effective management of statin intolerance to enable the patient to initiate a therapy which they are willing to take, and which will allow them to reach (as far as possible) risk-reduction targets for CVD. This requires careful history taking, and careful selection from the ever-widening range of evidence-based lipid-lowering therapies to meet the patients’ needs. If we are successful, we may have most of the SI patients on LDL-C target.

Background The sodium‐glucose cotransporter 2 inhibitor canagliflozin reduced the risk of first cardiovascular composite events in the CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) trial. In this post hoc analysis, we evaluated the effect of canagliflozin on total (first and recurrent) cardiovascular events. Methods and Results The CREDENCE trial compared canagliflozin or matching placebo in 4401 patients with type 2 diabetes, albuminuria, and estimated glomerular filtration rate of 30 to <90 mL/min per 1.73 m ² , over a median of 2.6 years. The primary outcome was analyzed as a composite of any cardiovascular event including myocardial infarction, stroke, hospitalization for heart failure, hospitalization for unstable angina, and cardiovascular death. Negative binomial regression models were used to assess the effect of canagliflozin on the net burden of cardiovascular events. During the trial, 634 patients had 883 cardiovascular events, of whom 472 (74%) had just 1 cardiovascular event and 162 (26%) had multiple cardiovascular events. Canagliflozin reduced first cardiovascular events by 26% (hazard ratio, 0.74 [95% CI, 0.63–0.86]; P <0.001) and total cardiovascular events by 29% (incidence rate ratio, 0.71 [95% CI, 0.59–0.86]; P <0.001). The absolute risk difference per 1000 patients treated over 2.5 years was −44 (95% CI, −67 to −21) first cardiovascular events and −73 (95% CI, −114 to −33) total events. Conclusions Canagliflozin reduced cardiovascular events, with a larger absolute benefit for total cardiovascular than first cardiovascular events. These findings provide further support for the benefit of continuing canagliflozin therapy after an initial event to prevent recurrent cardiovascular events. Registration Information URL: https://www.clinicaltrials.gov ; Unique Identifier: NCT02065791.

Open in new tabDownload slide Goals and approach to patient-provider discussion for statin intolerance.

Aims: Patients with type 2 diabetes mellitus (T2D) and PAD have a markedly elevated risk of macrovascular events and death. The sodium glucose co-transporter 2 (SGLT2) inhibitor canagliflozin has well-established cardiorenal benefits but net effects in patients with PAD remain uncertain. We sought to define the proportional and absolute benefits of canagliflozin in those with and without peripheral arterial disease (PAD). Materials and methods: We pooled individual participant data from the CANVAS Program (n = 10 142) and CREDENCE trial (n = 4401). In this post hoc analysis, the main outcomes of interest were major adverse cardiovascular events (MACE: non-fatal MI, non-fatal stroke or CV death), kidney outcomes, and extended MALE (major adverse limb events). Cox proportional hazards models were used to assess canagliflozin treatment effects in those with and without PAD. Absolute risk reductions per 1000 patients treated for 2.5 years were estimated using Poisson regression. Results: Of 14 543 participants, 3159 (21.7%) had PAD at baseline. In patients with PAD, canagliflozin reduced MACE (hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.62-0.92), with similar relative benefits for other cardiovascular and kidney outcomes in participants with or without PAD at baseline (all Pinteraction > 0.268). There was no increase in the relative risk of extended MALE events with canagliflozin, irrespective of baseline PAD history (Pinteraction > 0.864). Absolute benefits of canagliflozin were greater in those with PAD. Conclusions: Patients with T2D and PAD derived similar relative cardiorenal benefits from canagliflozin treatment but higher absolute benefits compared to those without PAD, with no increase in MALE. This article is protected by copyright. All rights reserved.

Background The impact of including race in the CKD-Epi equation on screening, recruitment, and outcomes of clinical trials is unclear. Methods The inclusion and outcomes of participants in the CREDENCE trial which randomized individuals with type 2 diabetes and CKD to canagliflozin or placebo was evaluated after calculating eGFR using the 2009 CKD-Epi creatinine equation with and without a race-specific coefficient or the 2021 CKD-Epi creatinine equation. Treatment effects were estimated using proportional hazards models and piecewise linear mixed-effect models for eGFR slope. Results Of 4401 randomized participants 2931 (67%) were White, 224 (5%) Black, 877 (20%) Asian and 369 (8%) other race. Among randomized participants, recalculation of screening eGFR using the 2009 equation without a race specific coefficient had no impact on the likelihood of non-Black participants meeting inclusion criteria but would have excluded 22 (10%) of randomized Black participants for eGFR <30 mL/min/1.73 m ² . Recalculation with the 2021 equation would have excluded 8 (4%) of Black participants for low and 1 (0.4%) for eGFR ≥90 mL/min/1.73 m ² whereas 30 (0.7%) and 300 (7%) non-Black participants would have been excluded for low and high eGFR, respectively. A high proportion (8/22, 36.4%) of endpoints in Black participants occurred in individuals who would have been excluded following recalculation using the race-free 2009 but not when recalculated with the 2021 equation (1/8, 12.5%) Cardiovascular and kidney treatment effects remained consistent across eGFR categories following recalculation with either equation. Changes in estimated treatment effects on eGFR slope were modest but were qualitatively larger following recalculation using the 2021 equation. However, effect of canagliflozin on chronic change in eGFR was attenuated by 7% among Black participants and increased 6% in non-Black participants. Conclusion In CREDENCE, eGFR recalculation without the race-specific coefficient had small but potentially important effects on event rates and the relative proportion of Black participants, without substantially changing efficacy estimates.