Canadian Cardiovascular Society Heart Failure Guidelines 2020 Ming Chang, Sandy Baptie, Shi-Yuan Yu LMPS Pharmacy Residents 2019-20
Evidence-based Drugs and Oral Doses From Trials *Limited evidence of short acting metoprolol tartrate in HF (succinate not available in Canada)
Therapeutic Approach to Patients with HFrEF
Updated Areas of Practice, 2020 1. Transcatheter mitral valve repair in HFrEF 2. Tafamidis for transthyretin amyloidosis 3. ARNI use in HFpEF 4. SGLT2 inhibitors for HF in patients with or without type 2 diabetes
Transcatheter Mitral Valve Repair 1. We recommend that maximally tolerated GDMT, including cardiac resynchronization therapy and revascularization where appropriate, be implemented before consideration of PMVR for patients with HFrEF and severe FMR (Strong Recommendation, High-Quality Evidence). 2. We suggest that patients with symptomatic HF (HFrEF) despite maximal GDMT and severe mitral regurgitation be evaluated for PMVR (Weak Recommendation, Moderate-Quality Evidence). 3. We recommend that a multidisciplinary dedicated heart team (including interventionalists, cardiac surgeons, imaging specialists, and HF specialists) perform the evaluation and care of potential candidates for PMVR (Strong Recommendation, Low-Quality Evidence).
Tafamidis for Transthyretin Amyloidosis ● This update has practical tips in the context of recent clinical trial evidence for the management of a subtype of cardiac amyloidosis known as ATTR (transthyretin amyloidosis) ● Transthyretin Amyloidosis Cardiomyopathy Trial (ATTR-ACT) using tafamidis vs placebo ○ Significantly lower all-cause mortality (HR, 0.70; 95% CI, 0.51-0.96) ○ Reduced cardiovascular hospitalizations (HR, 0.68; 95% CI, 0.56 to 0.81) ○ Reduced the rate of decline in functional capacity and quality of life (P < 0.001) ● Complexity in diagnosing CA and the potential for offering advanced or experimental treatment options, consideration should be given to referring patients with CA to experienced centres
ARNI (Sacubitril-Valsartan) LBQ657
ARNI in HFrEF PARADIGM-HF (2014) . D Randomized double blind Multicentre active comparator trial (2009-2012) P N=8399, mean age 64, 21% female, 66% White, EF= 30% (NYHA: I 4%, II 72%, III 23%, IV 0.8%) I Sacubitril/ Valsartan 97/103mg PO BID C Enalapril 10mg PO BID O Primary Outcome ● Composite of CV mortality or HF hospitalization: 21.8% vs. 26.5% (HR 0.80; 95% CI 0.73-0.87; P<0.001; NNT 21) ● CV Mortality 13.3% vs. 16.5% (HR 0.80; 95% CI 0.71-0.89; P<0.001; NNT 31) ● HF Hospitalization 12.8% vs. 15.6% (HR 0.79; 95% CI 0.71-0.89 P<0.001; NNT 36) Secondary Outcome ● All-Cause Mortality 17.0% vs. 19.8% (HR 0.84; 95% CI 0.76-0.93; P<0.001; NNT 36) ● Change in KCCQ at month 8: -2.99 vs. -4.63 (between group difference 1.64; 95% CI 0.63-2.65; P=0.001) ● New AFib: 3.1% vs. 3.1% (HR 0.97; 95% CI 0.72-1.31; P=0.83) ● Renal Function Decline: 2.2% vs. 2.6% (HR 0.86; 95% CI 0.65-1.13; P=0.28)
ARNI in HFrEF Recommendations An ARNI should be used in place of an ACEi or ARB, in patients with HFrEF, who remain symptomatic despite treatment with appropriate doses of GDMT to decrease cardiovascular death, HF hospitalizations, and symptoms (Strong Recommendation; High-Quality Evidence) When switching between an ARNI and an ACEi, a washout period of at least 36 hours is required to decrease the risk of angioedema (No washout ARB->ARNI)
ARNI in HFpEF PARAGON-HF (2019) D Randomized DB active comparator trial P N=4822, mean age 73, 52% female, 82% White, EF= 58% I Sacubitril/valsartan 97/103mg BID C Valsartan 160mg BID O Primary Outcome ● Composite of total (first and recurrent) HF hospitalizations and cardiovascular death 13% RRR in S/V arm; RR 0.87, (0.75-1.01; P= 0.06) ● First and recurrent HF exacerbations RR, 0.85 (0.72-1.00) ● Death from CV causes HR, 0.95 (0.79-1.16) Secondary Outcome ● Improvement in NYHA score at 8 months: OR, 1.45 (1.13-1.86) ● Change in KCCQ clinical summary score at 8 months: Difference 1.0 (0.0-2.1) ● Death from any cause: HR, 0.97 (0.84-1.13) ● Renal composite outcome: HR, 0.50 (0.33 -0.77)
ARNI in HFpEF Conclusions: ● No therapies have shown a mortality reduction in HFpEF ● ARNI does not lower risk of total HF hospitalizations/ cardiovascular death compared to valsartan in patients with HFpEF, may cause significant hypotension ● Hypothesis-generating findings: ○ Women had significant 27% reduction in 1 outcome ○ Patients EF ≤ 57% (trial median) had significant 22% reduction in 1 outcome
ARNI in HFpEF Recommendations: The statistically negative results of the PARAGON-HF primary end point analysis preclude any recommendation for the general use of sacubitril/valsartan in patients with HFpEF. The PARAGON-HF trial has provided a number of interesting insights; further analysis and investigation might inform future specific recommendations on the management of HFpEF.
Recommendations and Practical Tips for HFpEF
SGLT2 Inhibitors Why are we talking about a diabetes medication in a heart failure discussion?
SGLT2 Inhibitors in HFrEF 2020 CCS HF Update recommends SGLT2 inhibitors for: ● T2DM, age > 50, with additional CV risk factors, to reduce risk of Hospitalization due to HF (HHF) ● T2DM, age > 30, macroalbuminuria, to reduce HHF and renal disease progression ● Mild to moderate HFrEF and concomitant T2DM, to improve symptoms, QoL, and to reduce risk of hospitalization and CV mortality ● Mild to moderate HFrEF and without T2DM , to improve symptoms, QoL, and to reduce risk of hospitalization and CV mortality
SGLT2 Inhibitors ● Inhibits the sodium-glucose cotransporter 2 (SGLT2) protein to reduce glucose reabsorption → increased urinary glucose output (glucosuria) ● Mean A1C reduction: 0.5 to 0.7% ● SGLT2 inhibitors in Canada: canagliflozin, dapagliflozin, empagliflozin Zaccardi 2016
SGLT2 Inhibitors Rajasekeran 2016
SGLT2 Inhibitors ● In patients with T2DM, are SGLT2 inhibitors better than placebo in reducing CV risks when added to standard care? EMPA-REG DECLARE-TIMI 2017 2015 2019 CANVAS CV outcomes All-cause mortality HF hospitalization EMPA-REG NNT = 63 over 3.1 yrs NNT = 38 over 3.1 yrs NNT = 71 over 3.1 yrs (empagliflozin) CANVAS NNT = 200 over 3.6 yrs NSS NNT = 250 over 3.6 yrs (canagliflozin) DECLARE-TIMI NSS NSS NNT = 125 over 4.2 yrs (dapagliflozin)
SGLT2 Inhibitors TIMI Meta-Analysis reviewed the 3 trials ● Composite outcome (rate of CVD & HHF reduced by 23%) ○ HR 0.77; 95%CI 0.71-0.84, p < 0.001 ● HHF reduced by 31% ○ HR 0.69; 95%CI 0.61-0.7, p < 0.001 Zelniker 2019
SGLT2 Inhibitors in HFrEF DAPA-HF (NEJM 2019) D MC, DB, PC, RCT, ITT, International trial P Adult pts (with or without diabetes) with HFrEF, NYHA II-IV, receiving triple therapy (ACEI/ARB, BB, MRA) Key exclusion: current acute HF, MI/UA/stroke in past 12 weeks, eGFR < 30 ml/min I Dapagliflozin 10mg po once daily C Placebo O Primary: composite outcome (CV mortality + worsening HF) *worsening HF = hospitalization or urgent visit resulting in IV tx
DAPA-HF ● Well-balanced arms Average Pt 66yo, 77% male, 70% White NYHA Class II (67%), Class III (32%) Comorbidities DM (42%) Medications BB (96%), ACEI/ARB/ARNI (94%), MRA (71%), non-MRA diuretics (71%)
DAPA-HF
DAPA-HF
DAPA-HF
DAPA-HF Outcome HR (95% CI) p value NNT (1.5 years) Worsening HF or CV death 0.74 (0.65-0.85) < 0.001 21 Worsening HF 0.70 (0.59-0.83) N/A 27 HHF 0.70 (0.59-0.83) N/A 27 CV mortality 0.82 (0.69-0.98) N/A 53 All-cause mortality 0.83 (0.71-0.97) N/A 44 Safety profile NSS - -
DAPA-HF Strengths/Limitations ● Internal validity: ● External validity: ● Long term outcomes/benefits? DAPA-HF = 1.5 years ● In patients on ARNI? Only 11% in DAPA-HF ● In NYHA III-IV? Subgroup did not show benefit
Bottom Line and Future of SGLT2I ● In HFrEF, NYHA II, and maximally tolerated triple therapy (ACEI, BB, MRA), an SGLT2 inhibitor should be considered to reduce risk of worsening HF or CV mortality ● EMPEROR, EMPERIAL: empagliflozin in HFrEF + HFpEF ● DELIVER: dapagliflozin in HFpEF
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