4. Prevention of HF and Asymp

4.1 Early detection of LVSD and prevention of HF

HF often progresses from asymptomatic LVSD to symptomatic HF.^[16] Early detection of LVSD might allow intervention on contributing risk factors and pharmacotherapy to delay or reverse the progression of adverse LV remodelling. Data on medications, including ACEs, ARBs, and β-blockers are summarized online in evidence reviews at www.ccs.ca. Conventional risk factors for cardiovascular disease (CVD) are often included in clinical assessment but a detailed family history might also uncover genetic causes or susceptibility to the development of LV dysfunction. The use of NPs might be useful to identify individuals who are at higher risk for the development of HF and in whom preventative strategies have been studied. The cut point used in the Saint Vincent Screening to Prevent Heart Failure (STOP-HF)^[17] trial of BNP > 50 pg/mL to undergo echocardiography and collaborative care resulted in a higher rate of use of renin-angiotensin-aldosterone system inhibition therapies, fewer HF events, and significant reduction in hospitalizations for major cardiovascular events over a follow-up on an average of 4.2 years. The NT-proBNP Selected Prevention of Cardiac Events in a Population of Diabetic Patients Without a History of Cardiac Disease (PONTIAC) study^[18] used a cut point of NT-proBNP > 125 pg/mL to apply further cardiology consultation and individualized β-blockade and renin-angiotensin-aldosterone system uptitration. Patients in the group randomized to intensified therapy had a 65% relative risk reduction (RRR) in the primary combined event rate of hospitalization or death due to cardiac disease at 2 years. Therapies used in these 2 trials are guideline-based, reinforcing the opportunity to enhance neurohormonal therapy in all individuals with cardiovascular risk factors, limited only by the availability of NP measurement to identify patients. Exercise as a strategy to prevent ischemic heart disease has supported guideline recommended minimum physical activity of at least 150 minutes per week of moderate intensity activity (approximately 500 metabolic equivalents of task minutes). A meta-analysis of 12 prospective cohort studies by Pandey et al.^[19] reported the risk of HF is reduced by 10%, 19%, and 35% in people who were participating in leisure activity of 500, 1000, and 2000 metabolic equivalents of task minutes per week, respectively, compared with individuals with no physical activity. This article noted an inverse dose-response relationship between physical activity and development of HF. The importance of prevention of HF is supported by evidence that preventing and treating cardiovascular risk factors and conditions that cause atherosclerotic disease leads to fewer patients developing HF. Many of these risk factors also contribute to the development of HF independently from atherosclerotic disease (Table 3). Previous HF guidelines have reviewed the substantial evidence supporting the screening and management of common risk factors for the development of HF such as hypertension, diabetes, smoking, dyslipidemia, obesity, alcohol use, and sedentary behaviour.^[20]–[27] Patients with established coronary artery disease (CAD) and/or previous acute coronary syndrome (ACS) should have these appropriately treated to prevent future HF events.

4.2 Preventing HF in patients with hypertension

Hypertension has been well documented as a risk factor for HF and the treatment of hypertension has been shown to reduce the risk of developing HF.^[28]–[30] In addition to the high-quality meta-analyses, more recent evidence from the Systolic Blood Pressure Intervention Trial (SPRINT) supports a more aggressive approach to hypertension management.^[31] This trial of 9361 participants deemed high risk for a cardiovascular event, randomized to intensive (systolic BP < 120 mm Hg) vs standard (systolic BP < 140 mm Hg) BP control showed there was a 25% risk reduction in the primary outcome of myocardial infarction (MI), ACS, stroke, HF, or death from cardiovascular causes after only a median of 3.26 years. There was a 33% reduction of future HF outcomes (patients with a history of symptomatic HF in the past 6 months or with LVEF < 35% were excluded). Readers are directed to Hypertension Canada’s 2017 Guidelines (http://www.onlinecjc.ca/article/S0828-282X(17)30110-1/fulltext) for additional information.

4.3 Preventing HF in patients with diabetes

Diabetes mellitus (DM) is an established risk factor for the development of HF.^{[29],[32],[33]} However, the relationship between glycemic control and the development of HF is inconsistent and complicated further by the long-term effects of diabetes on other organ systems (eg, kidneys) or development of CAD.^[34] It is recognized, however, that DM can produce HF independently of CAD by causing a diabetic cardiomyopathy.^[29] In several studies, the incidence of HF was two- and fourfold higher in patients with DM than in those without.^{[32],[33],[35]–[38]} Approximately 12% of DM patients have HF,^[35] and older than the age of 64 years, the prevalence increases to 22%.^[37] It is thought that diabetes promotes the development of myocardial fibrosis and diastolic dysfunction, autonomic dysfunction, and worsened renal and endothelial function. Moreover, there has been uncertainty regarding whether any glucose-lowering strategy, or specific therapeutic agent, is safe from a cardiovascular standpoint or can decrease cardiovascular risk. Older trials on the effects on cardiovascular outcomes of specific glucose-lowering strategies or medications either have been insufficiently powered or have shown no significant cardiovascular benefit or an increased risk of death or HF.

4.3.1 Glycemic control in diabetes to prevent HF

In the past, several diabetes guidelines have advocated for tight glycemic control (lower Hb A1c); however, there is no evidence that this approach improves cardiovascular outcomes and some studies suggest harm, including increased HF, not to mention increased risk for hypoglycemia. There are no specific studies targeting patients with HF. Data are largely extrapolated from the Diabetes Control and Complications Trial (DCCT) study of patients with type 1 diabetes,^[39] the UK Prospective Diabetes Study (UKPDS) study,^[40] the UKPDS Follow Up study,^[41] the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study,^[42],[43] the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR-Controlled Evaluation (ADVANCE) study,^[44] and the Veterans Affairs Diabetes Trial (VADT) study.^[45] With the available evidence, an intensive glycemic control strategy cannot be recommended for all patients with diabetes. Instead, each individual should be assessed for his or her optimal glycemic target for the prevention of macrovascular events or HF.

SGLT-2 inhibitors. The Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients-Removing Excess Glucose (EMPA-REG OUTCOME) trial,^[47] is an RCT to show cardiovascular benefit in the treatment of diabetes. A sodium-glucose co-transporter-2 (SGLT-2) inhibitor empagliflozin was compared with placebo in 7020 patients with type 2 diabetes and established CVD and eGFR ≥ 30 mL/min. The primary composite outcome was death from cardiovascular causes, nonfatal MI, or nonfatal stroke. The primary end point occurred less commonly in the patients treated with empagliflozin (10.5%) than in those who received placebo (hazard ratio [HR], 12.1%; 95% confidence interval [CI], 0.74-0.99). Moreover, empagliflozin had an RRR for cardiovascular mortality of 38%, all-cause mortality of 32%, and HF hospitalization of 35%. SGLT-2 inhibitors have not yet been studied in populations of patients with HF. Of note, only a subgroup of approximately 10% of patients in the EMPA-REG OUTCOME trial had a reported history of HF. There are ongoing trials of SGLT-2 inhibitors, and those might affect future recommendations, namely for patients with established HF.

DPP-4 inhibitors. The Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellituse Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) trial^[48] randomized 16,492 patients with type 2 diabetes who had a history of, or were at risk for, cardiovascular events to receive the dipeptidyl peptidase-4 (DPP-4) inhibitor saxagliptin or placebo and followed them for a median of 2.1 years. The primary end point was a composite of cardiovascular death, MI, or ischemic stroke. At a median follow-up of 2.1 years, rates of composite cardiovascular events were similar with saxagliptin and placebo, but hospitalization for HF was higher with saxagliptin (3.5% vs 2.8%; HR, 1.27; P = 0.007). In contrast, the Trial Evaluating Cardiovascular Outcomes With Sitagliptin (TECOS) study,^[49] an RCT of 14,671 patients comparing another DPP-4 inhibitor, sitagliptin, with placebo showed no increase in HF hospitalization (HR, 1.00; 95% CI, 0.83-1.20; P = 0.98). Studies involving other DPP-4 inhibitors alogliptin^[50] and linagliptin^[51] have not shown additional increases in the risk of HF events.

Glucagon-like peptide. Human glucagon-like peptide (GLP-1) agonists have been tested in patients with diabetes for the outcomes of cardiovascular events. One such agent, liraglutide, was tested in the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial, and 14% of the patients had a clinical history of HF. Overall, liraglutide was shown to be noninferior to placebo, and had fewer cardiovascular events overall. There was no statistically significant decrease or increase in the number of HF events. There are ongoing trials with other GLP-1 agonists that will inform a recommendation on this class of agents for the prevention of HF.^[52]

Thiazolidinediones. Two such drugs (pioglitazone and rosiglitazone) have each been shown to increase the risk of HF events.

Prospective Pioglitazone Clinical Trial in Macro Vascular Events (PROactive)^[53] was a randomized study of 5238 type 2 diabetic patients, comparing pioglitazone with placebo. More pioglitazone (5.7%) than placebo patients (4.1%) had a serious HF event during the study (P = 0.007). Of patients in the placebo group, 108 needed hospital admission for HF (153 admissions) compared with 149 (209 admissions) in the pioglitazone group (HR, 1.41; 95% CI, 1.10-1.80; P = 0.007).

Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes (RECORD)^[54] was an RCT of 4447 people with type 2 diabetes randomized to add-on rosiglitazone (n = 2220) or to a combination of metformin and sulfonylurea (n = 2227). Patients with any HF were excluded. Rosiglitazone-treated patients had a greater risk for at least 1 admission to hospital for HF compared with the placebo group (HR, 2.6; 95% CI, 1.1-4.1; P = 0.001). A meta-analysis of 42 trials of rosiglitazone^[55] showed a 43% increase in MI and a 64% increase in death from cardiovascular causes with use of rosiglitazone.