Advances in Heart Failure with Preserved Ejection Fraction Management - The role of Sacubitril-Valsartan, Pirfenidone, Spironolactone and Empagliflozin: Is Success a Series of Small Victories?

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is a syndrome characterized by marked heterogeneity in comorbidities and etiopathology substrates, leading to a diverse range of clinical manifestations and courses. Treatment options have been extremely limited and up to this day, there are virtually no pharmaceutical agents proven to reduce mortality in these patients. OBJECTIVE: The primary objective of this narrative review is to critically summarize existing evidence regarding the use of Angiotensin Receptor-Neprilysin Inhibitor (ARNI), spironolactone, pirfenidone and empagliflozin in HFpEF. METHODS: Medline (via PubMed) and Scopus were searched - from inception up to May 2022- using adequately selected keywords. Additional hand-search was also performed using the references of the articles identified as relevant (snowball strategy). RESULTS: Angiotensin Receptor-Neprilysin Inhibitor (ARNI) and spironolactone, despite being very successful in HFrEF, did not do well in clinical trials of HFpEF, although there appear to be certain subsets of patients who may derive benefit. Data regarding pirfenidone are limited and come from small trials; as a result, it would be premature to draw firm conclusions, although it seems improbable that this agent will ever become a mainstay in the general population of HPpEF patients, while there may be a niche for the drug in individuals with comorbidities associated with an intense fibrotic activity. Finally, empagliflozin, largely welcomed as the first agent to have a "positive" randomized clinical trial in HFpEF, does not seem to evade the general pattern of reduced hospitalizations for HF with no substantial effect on mortality, seen in ARNI and spironolactone HFpEF trials. CONCLUSION: Recent research in drug treatment for HFpEF has resulted in an overall mixed picture, with trials showing potential benefits from certain classes of drugs, such as sodium-glucose co-transporter 2 inhibitors, and no benefit from other drugs, which have shown to be effective in patient with reduced ejection fraction. However, small steps may be the way to go in HFpEF, and success is sometimes just a series of small victories.

A stand-alone structured educational programme after myocardial infarction: a randomised study.

BACKGROUND: Acute myocardial infarction (MI) is a major clinical manifestation of coronary artery disease. Post-MI morbidity and mortality can be reduced by lifestyle changes and aggressive risk factor modification. These changes can be applied more effectively if the patient is actively involved in the process. The hypothesis of this study was that an educational programme in post-MI patients could lead to reduced incidence of cardiovascular events. METHODS: Post-MI patients were prospectively randomised into two groups. Patients in the intervention arm were scheduled to attend an 8-week-long educational programme on top of usual treatment, while controls received optimal treatment. The primary endpoint was the composite of all-cause death, MI, cerebrovascular event and unscheduled hospitalisation for cardiovascular causes. Endpoint adjudication was blinded. RESULTS: 329 patients (238 men) were included, with a mean follow-up time of 17±4 months. In the primary analysis, mean primary end point-free survival time was 597 days (95% CI 571 to 624) in controls, compared with 663 days (95% CI 638 to 687) in the intervention group (p<0.001). The HR in the univariate Cox regression analysis was 0.48 (95% CI 0.32 to 0.73; p=0.001). The raw rates of the primary endpoint were 20.8% (6 deaths, 13 MIs, 2 strokes and 14 hospitalisations) vs 36.6% (8 deaths, 22 MIs, 7 strokes and 22 hospitalisations), respectively (OR 0.46, 95% CI 0.28 to 0.74; p=0.002). CONCLUSION: These results suggest that a relatively short adult education programme offered to post-MI patients has beneficial effects, resulting in reduced risk of cardiovascular events. TRIAL REGISTRATION NUMBER: NCT04007887.

Usefulness of a Structured Adult Education Program in Modifying Markers of Cardiovascular Risk After Acute Myocardial Infarction.

Patient involvement in therapeutic strategies leading to lifestyle changes and increasing adherence to beneficial treatment is important for high risk coronary artery disease patients. The hypothesis of the present substudy was that a program of education specifically structured to educate postmyocardial infarction patients would lead to measurable differences in specific indices of cardiovascular risk. Post-MI patients were randomly assigned to 2 groups. Patients in the intervention arm attended an 8-week long educational program in addition to usual treatment and controls received standard treatment. Low-density lipoprotein cholesterol, systolic blood pressure, body-mass index, and glycosylated hemoglobin were assessed at baseline and at 12 months (values are reported as median [interquartile range]). One hundred ninety-eight consecutively randomized patients were included in the present substudy. The median change in Low-density lipoprotein cholesterol was -54 (-45 to [-62]) mg/dl in the intervention group as compared with -35 (-28 to [-43]) mg/dl in controls (p <0.001). Systolic blood pressure change was -7.5 (-15.3 to 0.3) mm Hg and -3.0 (-11.8 to 2.8) mm Hg, respectively (p = 0.011). The median change in body-mass index was 0.0 (-3.0 to 3.0) kg/m2 as compared with 2.0 (-1.0 to 3.9) kg/m2, respectively (p = 0.002). The reduction in glycosylated hemoglobin was significant in both groups with a median absolute change of -0.29 (-1.11 to 0.09) % in the intervention group and -0.24 (-0.69 to 0.06) % in controls (p = 0.168). If only diabetic patients were considered, the change was -0.65 (-1.3 to [-0.23]) % in the intervention group versus -0.41 (-0.74 to [-0.07]) % in controls (p = 0.021). In conclusion, a relatively short patient education program may have long-lasting effects on established modifiable markers of cardiovascular risk.

Colchicine for prevention of atrial fibrillation recurrence after pulmonary vein isolation: mid-term efficacy and effect on quality of life.

BACKGROUND: Our group previously showed that colchicine treatment is associated with decreased early recurrence rate after ablation for atrial fibrillation (AF). OBJECTIVE: The purpose of this study was to test the mid-term efficacy of colchicine in reducing AF recurrences after a single procedure of pulmonary vein isolation in patients with paroxysmal AF. Assessment of quality-of-life (QOL) changes was a secondary objective. METHODS: Patients with paroxysmal AF who were scheduled for ablation were randomized to a 3-month course of colchicine 0.5 mg twice daily or placebo and were followed for a median of 15 months (with a 3-month blanking period). QOL was assessed with a general-purpose health-related QOL tool (26-item World Health Organization QOL questionnaire) at baseline and after 3 and 12 months. RESULTS: Two hundred twenty-three randomized patients underwent ablation, and 206 patients were available for analysis (144 male, age 62.2 ± 5.8 years). AF recurrence rate in the colchicine group was 31.1% (32/103) vs 49.5% (51/103) in the control group (P = .010), translated in a relative risk reduction of 37% (odds ratio 0.46, 95% confidence interval 0.26-0.81). The number needed to treat was 6 (95% confidence interval 3.2-19.8). Physical domain QOL scores at 12 months were 63.6 ± 13.8 in the colchicine group and 52.5 ± 18.1 in controls, whereas psychological domain scores were 56.1 ± 13.7 vs 44.7 ± 17.3, respectively (P <.001, for both). CONCLUSION: Colchicine treatment after pulmonary vein isolation for paroxysmal AF is associated with lower AF recurrence rates after a single procedure. This reduction is accompanied by corresponding improvements in physical and psychological health-related QOL scores.

Anti-inflammatory treatment with colchicine in stable chronic heart failure: a prospective, randomized study.

OBJECTIVES: The purpose of this study was to test the efficacy of a 6-month course of anti-inflammatory treatment with colchicine in improving functional status of patients with stable chronic heart failure (CHF). BACKGROUND: CHF has been shown to be associated with inflammatory activation. Inflammation has been designated as a therapeutic target in CHF. METHODS: Patients with stable CHF were randomly assigned to colchicine (0.5 mg twice daily) or placebo for 6 months. The primary endpoint was the proportion of patients achieving at least one-grade improvement in New York Heart Association class. RESULTS: Two hundred sixty-seven patients were available for final evaluation of the primary endpoint: its rate was 11% in the control group and 14% in the colchicine group (odds ratio: 1.40; 95% confidence interval: 0.67 to 2.93; p = 0.365). The rate of the composite of death or hospital stay for heart failure was 9.4% in the control group, compared with 10.1% in the colchicine group (p = 0.839). The changes in treadmill exercise time with treatment were insignificant and similar in the 2 groups (p = 0.938). C-reactive protein and interleukin-6 were both significantly reduced in the colchicine group (-5.1 mg/l and -4.8 pg/ml, respectively; p < 0.001 for both, compared with the control group). CONCLUSIONS: According to this prospective, randomized study, anti-inflammatory treatment with colchicine in patients with stable CHF, although effective in reducing inflammation biomarker levels, did not affect in any significant way patient functional status (in terms of New York Heart Association class and objective treadmill exercise tolerance) or the likelihood of death or hospital stay for heart failure.

Effectiveness of moxonidine to reduce atrial fibrillation burden in hypertensive patients.

There is substantial evidence that the autonomic system plays an important part in the pathogenesis of atrial fibrillation (AF). It appears that, although some patients have a preponderantly sympathetic or vagal overactivation leading to AF, a combined sympathovagal drive is most commonly responsible for AF triggering. The purpose of this hypothesis-generating study was to test whether moxonidine, a centrally acting sympathoinhibitory agent, on top of optimal antihypertensive treatment, can lead to a decrease in AF burden in hypertensive patients with paroxysmal AF. This was a prospective, double-blind, 1-group, crossover study. Hypertensive patients with paroxysmal AF sequentially received treatment with placebo and moxonidine for two 6-week periods, respectively. The change in AF burden (measured as minutes of AF per day in three 48-hour Holter recordings) between the 2 treatment periods was the primary outcome measure. Fifty-six patients (median age 63.5 years, 35 men) were included. During moxonidine treatment, AF burden was reduced from 28.0 min/day (interquartile range [IQR] 15.0 to 57.8) to 16.5 min/day (IQR 4.0 to 36.3; p <0.01). European Heart Rhythm Association symptom severity class decreased from a median of 2.0 (IQR 1.0 to 2.0) to 1.0 (IQR 1.0 to 2.0; p = 0.01). Systolic blood pressure levels were similar in the 2 treatment periods, whereas diastolic blood pressure was lower (p <0.01) during moxonidine treatment. The most frequent complaint was dry mouth (28.6%). No serious adverse events were recorded. In conclusion, treatment with moxonidine, a centrally acting sympathoinhibitory agent, results in reduction of AF burden and alleviation of AF-related symptoms in hypertensive patients with paroxysmal AF.

Renoprotective effect of remote ischemic post-conditioning by intermittent balloon inflations in patients undergoing percutaneous coronary intervention.

OBJECTIVES: The aim of the present study was to assess the efficacy of remote ischemic post-conditioning (RIPC) by repeated intermittent balloon inflations in preventing acute kidney injury (AKI) in patients with a non-ST-segment elevation myocardial infarction undergoing percutaneous coronary intervention (PCI). BACKGROUND: AKI complicating PCI is associated with increased morbidity and mortality. Remote ischemic preconditioning, using cycles of upper limb ischemia-reperfusion as a conditioning stimulus, has been recently shown to prevent AKI in patients undergoing elective coronary angiography. METHODS: Eligible patients were randomized to receive RIPC by cycles of inflation and deflation of the stent balloon during PCI or a sham procedure (control patients). The primary endpoint was AKI, defined as an increase of ≥ 0.5 mg/dl or ≥ 25% in serum creatinine within 96 h from PCI. The 30-day rate of death or re-hospitalization for any cause was one of the secondary endpoints. RESULTS: A total of 225 patients were included (median age, 68 years; 36% female). The AKI rate in the RIPC group was 12.4% versus 29.5% in the control group (p = 0.002; odds ratio: 0.34; 95% confidence interval: 0.16 to 0.71). The number needed to treat to avoid 1 case of AKI was 6 (95% confidence interval: 3.6 to 15.2). The 30-day rate of death or re-hospitalization for any cause was 22.3% in the control group versus 12.4% in RIPC patients (p = 0.05). CONCLUSIONS: RIPC by serial balloon inflations and deflations during PCI was found to confer protection against AKI in patients with a non-ST-segment elevation myocardial infarction undergoing PCI. The reduction in the rate of AKI translated into a clear trend (of borderline significance) toward better 30-day clinical outcome.