New pharmacological agents and novel cardiovascular pharmacotherapy strategies in 2022

Abstract

Cardiovascular diseases (CVD) remain the leading cause of death worldwide, and pharmacotherapy of most of them is suboptimal. Thus, there is a clear unmet clinical need to develop new pharmacological strategies with greater efficacy and better safety profiles. In this review, we summarize the most relevant advances in cardiovascular pharmacology in 2022, including the approval of first-in-class drugs that open new avenues for the treatment of obstructive hypertrophic cardiomyopathy (mavacamten), type 2 diabetes mellitus (tirzepatide), and heart failure (HF) independent of left ventricular ejection fraction (sodium-glucose cotransporter 2 inhibitors). We also dealt with fixed dose combination therapies repurposing different formulations of ‘old’ drugs with well-known efficacy and safety for the treatment of patients with acute decompensated HF (acetazolamide plus loop diuretics), atherosclerotic cardiovascular disease (moderate-dose statin plus ezetimibe), Marfan syndrome (angiotensin receptor blockers plus β-blockers), and secondary cardiovascular prevention (i.e. low-dose aspirin, ramipril, and atorvastatin), thereby filling existing gaps in knowledge and opening new avenues for the treatment of CVD. Clinical trials confirming the role of dapagliflozin in patients with HF and mildly reduced or preserved ejection fraction, long-term evolocumab to reduce the risk of cardiovascular events, vitamin K antagonists for stroke prevention in patients with rheumatic heart disease-associated atrial fibrillation, antibiotic prophylaxis in patients at high risk for infective endocarditis before invasive dental procedures, and vutrisiran for the treatment of hereditary transthyretin-related amyloidosis with polyneuropathy were also reviewed. Finally, we briefly discuss recent clinical trials suggesting that FXIa inhibitors may have the potential to uncouple thrombosis from haemostasis and attenuate/prevent thromboembolic events with minimal disruption of haemostasis.

Introduction

Cardiovascular diseases (CVD) remain the leading cause of death worldwide, and pharmacotherapy of most CVD is suboptimal and often associated with potentially harmful effects. Thus, there is a clear unmet clinical need for novel pharmacological agents and therapeutic approaches to improve treatment efficacy and drug safety profiles.

The year 2022 was exciting because important ‘first-in-class’ cardiovascular drugs have been approved and many randomized clinical trials (RCTs) assessing the efficacy and safety of repurposing ‘old’ drugs in combination were published, thereby filling existing gaps in knowledge and opening new avenues for the management of CVD. In this review, we highlight the new pharmacological agents and the main advances in cardiovascular pharmacotherapy strategies (Figure 1) and discuss the most relevant RCTs (Table 1) that have taken place during 2022.

For the selection of the most relevant advances in cardiovascular pharmacology, we reviewed individual drugs or combinations of drugs approved by the European Medicines Agency (EMA) and the Food and Drug Administration (FDA) in 2022. We also searched for clinical trials in pre-specified fields published in 2022 using the PubMed and EMBASE databases. The drugs and clinical trials were selected for inclusion in this review mainly from a pharmacological point of view by consensus among the authors.

First-in-class drugs

This section includes drugs with ‘new mechanisms of action’, which constitute important advances in current pharmacotherapy options. A summary of their pharmacokinetic properties is provided in Table 2.

Mavacamten for treatment of obstructive hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is a complex cardiac disease often caused by mutations in genes encoding proteins responsible for cardiac sarcomere function.^1,2 Albeit phenotypically and clinically variable, it is often characterized by left ventricular (LV) hypertrophy, fibrosis, hypercontractility, and diastolic dysfunction.^2,3 HCM is predominantly an obstructive disease (oHCM), and ∼70% of patients present a dynamic LV outflow tract obstruction (LVOTO) at rest or during exercise, causing severe symptoms in many cases.³ Exercise intolerance and arrhythmogenic risk are hallmarks of HCM, partially due to specific alterations in cellular electro-mechanical properties.⁴

For almost 50 years, the pharmacological treatment of HCM was based on the off-label use of non-vasodilator β-blockers and/or non-dihydropyridine L-type Ca²⁺ channel blockers, and add-on therapy with antiarrhythmic drugs like disopyramide.^2,3 These drugs slow the heart rate and decrease cardiac contractility, alleviate symptoms, reduce LVOTO and myocardial stress during systole, improve LV diastolic filling, ventricular relaxation, and quality of life, and prevent cardiac arrhythmias. However, they do not specifically target the underlying cause of the disease or its pathophysiological mechanisms and, therefore, are unable to halt the natural progression of the disease and its complications.⁵

During the chemo-mechanical cycle, the globular head of the myosin molecule bends towards and binds to actin to form cross-bridges. The movement of the myosin head requires the hydrolysis of ATP to release energy, the so-called ‘power stroke’. During this process, the myosin heads can adopt three different conformations: (1) an open-headed state, available for actin cross-bridge formation; (2) a super-relaxed state of the myosin globular head (SRX), in which both myosin heads are folded back along the thick-filament backbone and cannot bind actin; and (3) a disordered state of the myosin globular head (DRX), in which one myosin head adopts a folded state while the other head is active and able to hydrolyse ATP and bind to actin.^6–8

HCM-associated sarcomere mutations shift the proportion of myosin heads from the SRX to the DRX state and increase the DRX/SRX ratio, leading to an excessive actin-myosin cross-bridge formation, hypercontractility, impaired relaxation, increased ATP consumption, abnormal Ca²⁺ sensitivity, altered Ca²⁺ handling, and cardiac hypertrophy.^6–8 Drugs decreasing the number of cross-bridges by shifting the overall myosin population towards an energy-sparing, recruitable SRX state may restore the physiological actin-myosin interactions, counteract the hypercontractile state, and improve myocardial efficiency in patients with oHCM.⁸ This was the rationale for the development of cardiac myosin adenosine triphosphatase (ATPase) inhibitors.

Mavacamten is a first-in-class, small-molecule, allosteric, and reversible myosin ATPase inhibitor specifically designed to target sarcomeric hypercontractility in patients with oHCM.^9,10 In animal models harbouring MYH7 and MYBPC3 mutations, mavacamten reduces the rate of phosphate release from myosin heads (the rate-limiting step in the electromechanical cycle), shifts overall myosin population towards the SRX state (Figure 2A), decreases the number of myosin heads available for cross-bridge formation, cardiac contractility, and impaired ventricular filling, and improves ATP consumption and relaxation, shortening the time to restore resting sarcomere length.^5,10,11 After 20–26 weeks of treatment, mavacamten reduces/prevents the development of LV hypertrophy, sarcomere hypercontractility, myocyte disarray, and cardiac fibrosis, improves active lusitropic function, and normalizes profibrotic and mitochondrial gene expression.¹⁰

In phase 2 (PIONEER-HCM, MAVERICK-HCM, PIONEER-OLE, and MAVERICK-LTE) and 3 (PIONEER-OLE, VALOR-HCM, MAVA-LTE, EXPLORER-HCM, and EXPLORER-CN) trials, mavacamten significantly improves exercise capacity, resting and post-exercise LV outflow tract gradient, functional NYHA class, serum N-terminal pro-B-type natriuretic peptide (NT-proBNP), and hs-cTroponin-I levels, suggesting an improvement in myocardial wall stress. Mavacamten also shows a favourable effect on cardiac remodelling and reduces LV mass index, maximum LV, and left atrial volume index in patients with oHCM.^5,12,13 Based on these results, mavacamten was approved by the FDA and EMA for the treatment of adults with symptomatic NYHA class II–III oHCM to improve functional capacity and symptoms.¹³ This new therapeutic option validates the potential of targeted molecular approaches for patients with HCM.

Recently, the VALOR-HCM trial demonstrated that in patients with severely symptomatic drug-refractory oHCM who met guideline criteria of eligibility for SRT, mavacamten significantly reduces the need for SRT by ∼77% after 16 months of treatment.¹⁴ Nevertheless, larger follow-up clinical trials are required to establish and validate the safety and efficacy of mavacamten as an alternative or add-on option to SRT or alcohol septal ablation in patients with symptomatic oHCM. However, as no direct comparative studies were performed, it remains unclear whether life-long pharmacotherapy using mavacamten, with potential side effects and very high costs, will be superior to SRT. Furthermore, there is no evidence that ‘a drug fits all’ strategy is equally effective in a disease with high-genotypic variability and phenotypic presentation, especially for mutations in the thin filament.

Pharmacologically, the use of mavacamten is challenging because of its long half-life time and extensive metabolism via major CYP2C19, CYP3A4, and CYP2C9 enzyme families (Table 2). Thus, mavacamten is contraindicated in patients treated with strong CYP2C19 or CYP3A4 inhibitors that increase drug exposure and the risk of heart failure (HF) or with moderate-strong CYP2C19 or CYP3A4 inducers that decrease mavacamten exposure and potentially reduce its clinical efficacy.^5,13,15 Conversely, since mavacamten is an inducer of CYP3A4, CYP2C9, and CYP2C19, its combination with CYP3A4, CYP2C19, or CYP2C9 substrates may reduce the exposure and activity of these drugs. In such cases, close monitoring of the patients is highly recommended.^5,13,15 Because mavacamten reduces cardiac contractility, its co-administration with negative inotropic drugs (e.g. disopyramide, verapamil, or diltiazem) may cause LV systolic dysfunction and HF symptoms in patients with oHCM and should be avoided. Mavacamten may decrease exposures to ethinyl estradiol and progestin, leading to contraceptive failure. Use of contraceptives not affected by CYP450 induction or the addition of non-hormonal contraception during treatment and for 4 months after the last dose is recommended.

The most frequent adverse reactions to mavacamten include dizziness (>10%), syncope, and a dose-dependent decrease in LV ejection fraction (LVEF) due to systolic dysfunction. Thus, regular LVEF and Valsalva left ventricular outflow tract (LVOT) gradient assessments are required. Algorithms for initiation and maintenance dosing, patient monitoring schedules, and guidance for treatment interruption or discontinuation are provided in the prescribing information.¹⁵ Drug initiation is not recommended in patients with LVEF <55% and treatment should be interrupted if LVEF drops <50% or if the patient experiences HF symptoms or worsening clinical status.¹⁵ In the USA, mavacamten is available only through a Risk Evaluation and Mitigation Strategy (REMS) called CAMZYOS REMS Program.

Several ongoing trials analyse the effects of mavacamten in patients with HCM [EXPLORER-LTE (NCT03470545), EXPLORER-CN (NCT05174416), PIONEER-OLE (NCT03496168), MAVA-LTE (NCT03723655), VALOR-HCM (NCT04349072)] and with HF with preserved ejection fraction (HFpEF) (EMBARK-HFpEF, NCT04766892).

Tirzepatide for therapy of diabetes and obesity

Tirzepatide (LY329817) is the first dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist for the treatment of type 2 diabetes mellitus (T2DM) approved as an adjunct to diet and exercise to improve glycaemic control in adults with T2DM, particularly associated with obesity/overweight.^16–18 Tirzepatide is a 39-aminoacid synthetic chimeric peptide based on the native GIP that contains 2 aminoisobutyric acid residues at positions 2 and 13, a C-terminal amide, and at position 20, the lysine residue is attached to a 1,20-eicosanedioic acid, which increases binding to albumin and prolongs its half-life, allowing for once-a-week administration.^17–19 Tirzepatide is an imbalanced dual GIP/GLP-1 receptor agonist binding to GIP receptors with the same affinity as native GIP, whereas its affinity to GLP-1 receptors (GLP-1R) is ∼five-fold weaker than native GLP-1.¹⁶ The main physiological effects of GIP and GLP-1 are summarized in Figure 2B and the pharmacokinetic properties of tirzepatide in Table 2.

GLP-1 and GIP receptors are expressed on pancreatic β-cells, and their activation stimulates insulin secretion and lowers blood glucose in T2DM. The binding of GLP-1 and GIP to their receptors activates the adenylate cyclase/cyclic adenosine monophosphate (cAMP)/protein kinase (PKA) and the exchange protein activated by cAMP2 (EPAC2)/cAMP-guanine nucleotide exchange factor (GEF) signalling pathways (Figure 2B). PKA inhibits both voltage-dependent and ATP-sensitive K⁺ channels, leading to membrane depolarization that activates Ca²⁺ influx through voltage-gated Ca²⁺ channels, along with Ca²⁺ release from intracellular stores.^16,20 The subsequent increase in intracellular [Ca²⁺] enhances the gene transcription of proinsulin, increases the density of insulin-containing granules near the plasma membrane, and promotes the fusion of insulin-vesicles with the plasma membrane, thereby increasing insulin secretion from pancreatic β-cells, preferentially in a glucose-dependent manner after food intake.^16,20

The effectiveness and safety of once-weekly administration of tirzepatide (5–15 mg given s.c.) compared with placebo and other glucose-lowering drugs to improve glycaemic control in adults with T2DM were established in the SURPASS clinical programme, which comprised 10 clinical trials recruiting >13 000 patients.¹⁷ Tirzepatide significantly reduces glycated haemoglobin (HbA1c) compared with placebo or glucose-lowering drugs, and in comparative trials, a dose of 15 mg produces a 0.5% and 1.0% greater reduction in HbA1c than semaglutide or insulin-analogues, respectively. Drug efficacy is not influenced by age, gender, race, ethnicity, baseline body mass index or HbA1c, diabetes duration, or renal function.

In patients with T2DM, tirzepatide decreases fasting and postprandial glucose levels more effectively than semaglutide, reduces food intake and body weight, enhances first- and second-phase insulin secretion, and improves insulin sensitivity after 28 weeks of treatment. It also reduces fasting and postprandial glucagon concentrations and delays gastric emptying.¹⁶

Most importantly, tirzepatide reduces body weight and systolic blood pressure (∼5–6 mmHg) in a dose-dependent manner and decreases inflammatory markers (e.g. high-sensitivity C-reactive protein), triglycerides, and very low-density lipoprotein levels. In a sub-study of the SURPASS-3 trial, using magnetic resonance imaging (MRI), tirzepatide significantly reduces liver fat content and the volume of visceral and abdominal subcutaneous adipose tissue.²¹ At high doses, tirzepatide significantly decreases biomarkers of non-alcoholic fatty liver disease (NAFLD) and increases adiponectin levels in patients with T2DM.^16,22

In a recent meta-analysis of seven RCTs (4887 participants treated with tirzepatide, 2328 controls), each with at least one MACE-4 event, treatment with once weekly tirzepatide (5, 10, and 15 mg daily) for up to 24 months does not increase the risk of four-component major adverse cardiac events [cardiovascular death, myocardial infarction (MI), stroke, and hospitalized unstable angina] across a spectrum of T2DM duration and cardiovascular risk levels.²³

Tirzepatide does not inhibit/induce CYP enzymes or block drug transporter proteins, but it delays gastric emptying and may affect the absorption of concomitantly administered oral drugs. Of note, hepatic or renal impairment does not impact the pharmacokinetics of tirzepatide. The most frequent adverse reactions (>10%) are nausea, vomiting, diarrhoea, and decreased appetite. Vomiting, constipation, dyspepsia, and abdominal pain are reported in 4–10% of patients and hypersensitivity reactions and injection site reactions (e.g. eczema and urticaria) in 3% of the individuals. Although hypoglycaemia is not an intrinsic adverse effect of tirzepatide monotherapy, tirzepatide might increase the risk of hypoglycaemia from 2 to 16% when combined with insulin secretagogues or insulin.²⁴ Like GLP-1R agonists, tirzepatide may cause acute gallbladder disease (0.5%) and acute pancreatitis and should be avoided in patients with a history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2.

Tirzepatide represents a promising drug for the treatment of metabolic disorders, including T2DM, obesity/overweight, and NAFLD.^17,18 Several ongoing clinical trials analyse its efficacy and safety in patients with T2DM [SURPASS-6 (NCT04537923), SURPASS-PEDS (NCT05260021), SURPASS-CVOT (NCT04255433)], T2DM and obesity/overweight [SURMOUNT-2–4 (NCT04184622, NCT04657003 NCT04657016, NCT04660643), SURMOUNT-CN (NCT05024032), SURMOUNT-J (NCT04844918), SURMOUNT-MM (NCT0555651)], non-alcoholic steato-hepatitis (SYNERGY-NASH, NCT04166773), overweight/obesity and chronic kidney disease with or without T2DM (TREASURE-CKD, NCT05536804), and HFpEF and obesity (SUMMIT, NCT04847557). The recent approval of tirzepatide will certainly foster the development of other dual agonists or tri-agonists, achieving a concurrent activation of GLP-1, GIP, and glucagon receptors, leading to the development of more efficient pharmacological approaches for cardiometabolic diseases.

Sodium-glucose cotransporter-2 inhibitors for heart failure treatment

The 2022 AHA/ACC/HFSA Guideline for the Management of HF recommends sodium-glucose cotransporter-2 inhibitors (SGLT2Is) in adults already on guideline-directed medical therapy with²⁵ (a) HF and T2DM for the management of hyperglycaemia and to reduce HF-related morbidity and mortality (I, A). (b) T2DM and either established cardiovascular disease or high cardiovascular risk to prevent HF hospitalizations (1, A). This benefit predominantly reflects primary prevention of symptomatic HF, because only 10–14% of participants had HF at baseline. (c) Symptomatic chronic HF with reduced ejection fraction (HFrEF, LVEF ≤40%, NYHA class II–IV, and elevated natriuretic peptides) to reduce HF hospitalizations and cardiovascular mortality, irrespective of the presence of T2DM (I, A). (d) Mildly reduced [HF with mildly reduced ejection fraction (HFmrEF)] or HFpEF to reduce HF hospitalizations and cardiovascular mortality (2a, B-R). In 2022, for the first time, the FDA approved an expanded indication of empagliflozin to reduce the risk of cardiovascular death and HF hospitalization in adults with HF, regardless of ejection fraction, which confirmed SGLT2 inhibitors as first-choice drugs for the treatment of HF. A similar statement was made Butler et al.²⁶ However, SGLT2Is have not been evaluated in patients with severe renal impairment [estimated glomerular filtration rate (eGFR) <25 mL/min/1.73 m²], T1DM, or systolic blood pressure <100 mm Hg.

Novel insights filling existing gaps in knowledge in cardiovascular pharmacotherapy

In this section, we briefly discuss clinical trials that provided novel insights that fill existing gaps in knowledge in cardiovascular pharmacotherapy.

Efficacy and safety of SGLT2Is among patients with HFmrEF or HFpEF

Although patients with HFmrEF or HFpEF represent about half of the HF population, current pharmacological options are very limited. SGLT2Is reduce the risk of HF hospitalization and cardiovascular death among patients with HFrEF, but their efficacy has been less frequently assessed in patients with LVEF ≥40%.

The DELIVER trial randomized patients with HF and a LVEF >40% to dapagliflozin or placebo in addition to usual therapy. The trial also included patients with a previously reduced LVEF that improved to >40% by the time of enrollment, a group that was usually excluded from prior trials.²⁷ Over a median of 2.3 years, dapagliflozin significantly reduced the composite primary outcome of worsening HF or cardiovascular death, total events, and symptom burden as compared with placebo. First statistical significance was reached for worsening HF by day 16 after randomization.²⁸ Effects on the primary endpoint were consistent among patients with LVEF ≥60% or ≤60%, with recent HF hospitalization (during or within 30 days), or with/without previous LVEF ≤40% that improved to >40% by the time of enrollment, and in other pre-specified subgroups, including patients with/without diabetes.^27,29 Serious adverse events and adverse events leading to discontinuation were similar in both groups.²⁹

Thus, among patients with HFmrEF or HFpEF, dapagliflozin reduces the risk of worsening HF, cardiovascular deaths, and symptom burden with no excess of adverse events. These data are complementary to the findings from the EMPEROR-Preserved trial³⁰ and strongly support the use of SGLT2Is in all patients with HF, irrespective of patient phenotype or care setting.

Long-term low-density lipoprotein-cholesterol lowering with evolocumab reduces the risk of cardiovascular events

Proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors lead to marked reductions in low-density lipoprotein-cholesterol (LDL-C) even in patients receiving high-intensity statin therapy, but median treatment durations in major trials were 2–3 years only. Therefore, large-scale, long-term data are lacking. Originally, the FOURIER (parent) trial, recruiting 27 564 patients with atherosclerotic cardiovascular disease (ASCVD) and LDL-C ≥70 mg/dL, showed that after a median of 2.2 years evolocumab reduced LDL-C and risk of cardiovascular events, but not cardiovascular mortality. A total of 6635 patients who completed the FOURIER trial (3355 originally randomized to evolocumab, 3280 to placebo) were eligible to receive evolocumab in 2 open-label extension studies (FOURIER-OLE) designed to assess drug safety during a median follow-up of 5.0 years (maximum exposure to evolocumab in parent plus FOURIER-OLE 8.4 years).³¹ The primary end point was the incidence of adverse events; lipid values and major adverse cardiovascular events were prospectively collected. After 12 weeks in FOURIER-OLE, the median LDL-C was 30 mg/dL, and 63.2% of patients achieved LDL-C levels <40 mg/d. The incidence of serious adverse events (injection-site reactions, allergic reactions, muscular events, new-onset diabetes, cataracts, haemorrhagic stroke, and neurocognitive events) did not exceed that observed in placebo-treated patients during the FOURIER study and did not increase over time. Importantly, patients originally randomized in the parent trial to evolocumab vs. placebo had a 15% lower risk of cardiovascular death, MI, stroke, or hospitalization for unstable angina or coronary revascularization, a 20% lower risk of cardiovascular death, MI, or stroke, and a 23% lower risk of cardiovascular death when compared with placebo-treated patients switched to evolocumab once the parent trial was completed. Thus, despite the open-label design, long-term LDL-C lowering with evolocumab for >8 years is safe and well tolerated and leads to further reductions in cardiovascular events compared with delayed treatment initiation. These findings support current guidelines recommendations, confirm that targeting LDL-C to lower levels for a longer time is likely to yield the best results, and suggest to start lipid-lowering therapy as early as possible to reduce the detrimental life-long impact of elevated LDL-C on vessel function and CVD burden.

Vitamin K antagonists for prevention of cardioembolic events in patients with RHD-AF

Patients with rheumatic heart disease-associated atrial fibrillation (RHD-AF) constitute a unique AF population because they are younger, more often female, present advanced valvular disease, and are at higher risk of stroke. Of note, these patients are usually excluded from trials using direct oral anticoagulants. The INVICTUS trial compared the efficacy and safety of rivaroxaban and dose-adjusted vitamin K antagonist (VKA) therapy in 4531 patients with RHD-AF (mean age 50.5 years; 72.3% women; ∼85% with moderate-severe mitral valve stenosis) and at least one of the following criteria: a CHA₂DS₂VASc score ≥2, mitral stenosis (mitral-valve area <2 cm²) or echocardiographic evidence of either left atrial spontaneous echo contrast or left atrial thrombus.³² The primary efficacy outcome (composite of stroke, systemic embolism, MI, or death from vascular or unknown causes) occurred in 560 patients in the rivaroxaban group and in 446 patients in the VKA group (35.0% vs. 26.6%, respectively). This significant difference was primarily driven by more deaths (552 vs. 442) and ischaemic strokes (74 vs. 48) in the rivaroxaban group. This difference in mortality was almost entirely due to higher rates of sudden cardiac death (141 vs. 94) and of death due to mechanical or pump failure (237 vs. 174) in the rivaroxaban group. Drug discontinuation was greater with rivaroxaban than with VKA (23% vs. 6%) at all visits, but there were no differences in major bleeding between treatment groups, although the rate of fatal bleeding was lower with rivaroxaban. The higher rates of sudden cardiac death and death from mechanical or pump failure with rivaroxaban were unexpected and unrelated to heart-valve deterioration or the higher incidence of drug discontinuation, because many patients who discontinued rivaroxaban then received a VKA. These results support current guidelines, which recommend VKA as the standard of care for stroke prevention in patients with RHD-AF.³³

Antibiotic prophylaxis of endocarditis before invasive dental procedures

The ESC guidelines recommend antibiotic prophylaxis before invasive dental procedures to prevent infective endocarditis in patients at high risk of endocarditis.³⁴ However, there are limited data directly supporting the efficacy of antibiotics in endocarditis prevention during invasive dental procedures. Using cohort and case-crossover methodologies in a population of almost 8 million people, Thornhill et al.³⁵ found a significant temporal association between invasive dental procedures and subsequent development of infective endocarditis in high-infective endocarditis-risk individuals and between antibiotic prophylaxis and reduced infective endocarditis incidence following invasive dental procedures. Time course studies and case-crossover analysis showed a significant temporal association between the occurrence of infective endocarditis and invasive dental procedures in the preceding 4 weeks, with this relationship being strongest for dental extractions and oral-surgical procedures. Prophylaxis with antibiotics was associated with a 51% reduction in infective endocarditis incidence following invasive dental procedures. The cohort study confirms the association between infective endocarditis and invasive dental procedures in patients and the efficacy of prophylaxis with antibiotics in reducing these associations. These data are consistent with guidelines recommendation that patients at high risk for infective endocarditis should receive antibiotic prophylaxis before invasive dental procedures.³⁴

Vutrisiran for treatment of hereditary transthyretin-mediated amyloidosis

Hereditary transthyretin (TTR)-related amyloidosis (hATTR) is a rare, rapidly progressive malignant disease caused by variants in the TTR gene.^36,37 Normal TTR is a tetramer composed of four identical subunits produced primarily in the liver that functions as a transporter for thyroxine and retinol (vitamin A). TTR mutations result in abnormal depolymerization, misfolding, and aggregation of TTR into amyloid fibrils that deposit in multiple organs and tissues, leading to a heterogeneous clinical presentation including sensory, motor, and autonomic polyneuropathy, along with cardiomyopathy.^37,38 Without treatment, median survival is 4.7 years following diagnosis,^37,39 while median survival for hATTR patients with cardiomyopathy is only 3.4 years.^37,39

Vutrisiran (ALN-TTRSC02) is a double-stranded small interfering RNA (siRNA) conjugated to a triantennary N-acetylgalactosamine ligand that binds to asialoglycoprotein receptors (ASGPR), which are almost exclusively expressed on hepatocytes, the primary site of TTR synthesis (Figure 3).⁴⁰

Based on the results of the HELIOS-A study, vutrisiran administered by subcutaneous injection once every 3 months (Q3M) was approved for the treatment of hATTR amyloidosis in adults with stage 1 or stage 2 polyneuropathy. This study compared vutrisiran with patisiran (another siRNA targeting TTR mRNA) and the placebo arm from the APOLLO phase 3 study of patisiran recruiting a comparable patient population of adults with hATTR and polyneuropathy.⁴¹ Vutrisiran produced a rapid (≤3 weeks) and sustained reduction in serum TTR levels over 18 months across all patient subgroups, like that observed in the patisiran group. Vutrisiran significantly improved signs and symptoms of polyneuropathy in the modified Neuropathy Impairment Score + 7 (mNIS + 7), Norfolk Quality of Life-Diabetic Neuropathy total score, 10-metre walk test, modified body mass index, and Rasch-built Overall Disability Scale at 9 and 18 months compared with placebo. Vutrisiran caused a 2.2-point mean decrease (improvement) in mNIS + 7 from baseline compared with a 14.8-point mean increase (worsening) in the external placebo group (P < 0.0001). After 9 months, 50% of patients treated with vutrisiran experienced improvement in neuropathy signs relative to baseline.

Of importance, no dose adjustment of the drug is required in patients with mild-moderate renal impairment (eGFR ≥30 to <90 mL/min/1.73 m²) or mild hepatic impairment.⁴⁰ Vutrisiran is not a substrate/inhibitor of CYP enzymes, which makes relevant drug-drug interactions less likely. The most common adverse reactions (≥4%) were arthralgia, dyspnea, and decreased vitamin A levels. Vitamin A supplementation is recommended, and patients who develop ocular symptoms suggestive of vitamin A deficiency (e.g. night blindness) should be referred to an ophthalmologist.

The pharmacokinetic properties of vutrisiran are shown in Table 2. A biannual 50 mg dosing regimen is currently being evaluated in the ongoing randomized treatment extension period in the HELIOS-A trial. The ongoing HELIOS-B phase 3 trial (NCT04153149) will assess both the efficacy and safety of vutrisiran in patients with ATTR amyloidosis with cardiomyopathy.

Factor XI inhibitors: an emerging new class of anticoagulants

Anticoagulants are the mainstream therapy for the prevention and treatment of venous thrombosis and cardioembolic complications, but their use is associated with an increased risk of bleeding despite the better safety profile of direct oral anticoagulants vs. VKA. Therefore, there has been great interest in developing new anticoagulants with a reduced risk of bleeding while maintaining similar efficacy in treating/preventing thrombosis.

In principle, the bleeding risk of anticoagulants can be avoided if they selectively target the coagulation factors that are more important for pathological thrombus formation than for physiological haemostasis. Selective inhibition of factor (F)XI or FXIa has been proposed as a possible target for the development of safer anticoagulants.^42,43 FXI is activated by FXIIa, a component of the contact system (so-called intrinsic pathway), and thrombin generated during the final phase of the coagulation (Figure 4), and contributes to clot formation, growth, and stabilization.^44,45 However, some evidence suggests that FXI contributes more to thrombosis with a minor role in physiological haemostasis. Indeed, in animal models, FXI inhibition protects against arterial and venous thrombosis without an increase in bleeding complications. Additionally, patients with congenital FXIa deficiency present a reduced risk of thrombosis and cardiovascular events and their risk of bleeding is lower compared with other coagulation factor deficiencies with a less clear dose-dependence for bleeding risk. Conversely, patients with elevated FXI levels show prothrombotic phenotypes.^42,46,47

Several FXI or FXIa inhibitors, including antisense oligonucleotides, monoclonal antibodies, and small molecules, are under clinical development (Table 3). They have been investigated in phase 2 studies for prevention of venous thromboembolism in patients undergoing total knee arthroplasty, major adverse vascular events in patients with end-stage kidney disease undergoing haemodialysis, or as an add-on to antiplatelet therapy for prevention of recurrent ischaemic events in patients with acute MI, AF, or non-cardioembolic stroke. Despite some promising results of these small trials, as all dose-finding phase II trials, they were underpowered to assess drug efficacy on clinical outcomes. Furthermore, for some of them, a clear dose-response in terms of bleeding or prolongation of laboratory tests for haemostasis could not be identified. Ongoing phase III trials will validate the hypothesis of FXI as being a clot factor less important for physiological haemostasis in humans and determine whether FXI inhibitors attenuate thrombosis with little or no disruption of homeostasis.

Novel insights regarding fixed dose combinations of cardiovascular drugs

Non-adherence to therapy remains a major obstacle in the primary and secondary prevention of CVD. Fixed dose combinations (FDC) of drugs with diverse and/or complementary mechanisms of action that may allow dose reduction of individual drugs and may lead to synergistic or additive clinical effects. Thus, FDC of drugs could achieve greater efficacy and may overcome potential adverse effects often associated with high doses of individual drugs by either countering biological compensatory mechanisms, sparing doses on each compound, or acting on multi-target mechanisms. FDC may also improve drug adherence among patients with multimorbidity receiving polypharmacy and reduce the total costs of treatment.

Combination of acetazolamide and loop diuretics in HF patients resistant to loop diuretics alone

Acute decompensated HF (ADHF), usually due to volume overload, is among the most common causes for hospitalization, morbidity, mortality, and health care expenditures.^25,48 Treating the clinical signs and symptoms of HF, while preserving or improving renal function, is a crucial therapeutic goal.

Due to their rapid onset of action and strong diuretic efficacy, intravenous loop diuretics have been, for decades now, the cornerstone of ADHF treatment to alleviate symptoms and signs of fluid overload and congestion, decrease ventricular filling pressures, improve exercise capacity, and reduce HF hospitalization.⁴⁸ However, selection of the appropriate drug, dosing schedule, and route of administration of diuretics remained uncertain, and >50% of patients admitted for ADHF are discharged on loop diuretics with residual pulmonary congestion, which is associated with re-hospitalization and death within 6 months after discharge.⁴⁹

Among patients with ADHF, there are no significant differences in patients’ global assessment of symptoms or in changes in renal function from baseline to 72 h when diuretic therapy is administered by means of boluses as compared with continuous infusion or with a low-dose strategy as compared with a high-dose strategy. Although differences in the patient's global assessment of symptoms do not reach statistical significance, the high-dose group has more favourable outcomes with regard to several pre-specified secondary measures, including relief of dyspnea, change in weight, and net fluid loss.⁵⁰ However, at high doses, both orally and intravenously applied loop diuretics may produce harmful effects, including neurohumoral activation, electrolyte disturbances, ototoxicity (especially in combination with aminoglycosides), and acute worsening of renal function.⁵¹ Additionally, intermittent bolus dosing may be associated with a higher rate of diuretic resistance due to prolonged periods of subtherapeutic drug levels in the kidney and a higher risk of ototoxicity. Continuous infusions result in lower peak plasma levels but more constant delivery of the drug to the tubule, leading to a greater diuresis and better safety profile, but restrict patient mobility.⁵¹

Since diuretics act at different regions in the nephron, conceptually, it would be expected that the combination of loop diuretics with other diuretic drugs acting at distinct nephron sites (sequential nephron blockade) will result in a synergistic diuretic effect, leading to faster and stronger decongestion in patients with ADHF treated with loop diuretics alone.

Acetazolamide is a carbonic anhydrase inhibitor that reduces sodium and bicarbonate resorption in the renal proximal tubules, but produces poor diuretic and natriuretic effects, with rapidly emergent diuretic resistance in the case of prolonged use.⁵² Therefore, acetazolamide was infrequently used in AHF. However, several recent small-size studies with a short follow-up (up to 72 h) suggest that the addition of acetazolamide increases the natriuretic response to loop diuretics compared with an increase in loop diuretic dose in ADHF at high risk for diuretic resistance.^53–55 The potential underlying mechanisms may include: (1) the blockade of sodium reabsorption produced by acetazolamide in the proximal tubules, so that more sodium reaches the Henle's loop, which increases the effect of loop diuretics; and (2) the direct renal vasodilator⁵⁶ and protective effects of acetazolamide against ischaemia—reperfusion via up-regulating hypoxia-inducible factor-1α (HIF-1α),⁵⁷ along with inhibition of pendrin expression in the distal nephron, which may potentiate furosemide-induced diuresis.⁵⁸

The ADVOR trial randomized 519 patients with ADHF, volume overload, and NT-proBNP >1000 pg/mL (or B-type natriuretic peptide levels >250 pg/mL) to either intravenous acetazolamide or placebo added to standardized intravenous loop diuretics (at a dose equivalent to twice the oral maintenance dose).⁵⁹ The combination of acetazolamide with loop diuretics increases cumulative urine output and natriuresis, improves the incidence of successful decongestion at day 3 from 30.5 to 42.2%, an effect consistent with a better diuretic efficiency, and shortens the length of hospital stay from 9.9 to 8.8 days. However, combination therapy has no significant effect on all-cause death or HF re-hospitalization rate during 3 months of follow-up. The incidence of worsening kidney function, hypokalaemia, hypotension, and other adverse events was similar in both groups.

Although these results suggest that the addition of acetazolamide to loop diuretics may increase the successful decongestion in ADHF patients, the study has several limitations. Patients with newly diagnosed HF and those being on SGLT2Is were excluded, and renin-angiotensin-aldosterone inhibitors were prescribed in only 52% of patients. It was also unclear how many participants with HFrEF were on goal-directed therapy at baseline. Although the acetazolamide group had a higher rate of successful decongestion, there were no differences in the risk of death or re-hospitalization between groups. Subgroup analysis suggested that acetazolamide was not superior among patients with a greater likelihood of diuretic resistance, including females, patients receiving >60 mg of furosemide, with ischaemic cardiomyopathy, or eGFR ≥39 mL/min/1.73 m². Finally, the trial does not prove the superiority of acetazolamide compared with other potential strategies, i.e. the combination of thiazide diuretics (metolazone or hydrochlorothiazide) with loop diuretics, or even a more aggressive loop diuretic therapy in patients with ADHF and refractory volume overload. Thus, further clinical trials are required to demonstrate and validate the therapeutic value of different combinations of diuretic drugs for the treatment of ADHF.

Combination of statins and ezetimibe in patients with atherosclerotic cardiovascular disease

In patients with ASCVD, the extent of LDL-C reduction is the strongest independent predictor of major vascular events (coronary death or non-fatal MI, coronary revascularization, and ischaemic strokes). In a meta-analysis of 26 RCTs (>170 000 patients), the use of high-intensity statin therapy produces an additional 15% reduction in major vascular events compared with less intense regimens.⁶⁰ Thus, clinical guidelines recommend monotherapy with the highest tolerated dose of statin before consideration of additional non-statin therapy to reach LDL-C goals in patients with ASCVD.^61,62 However, high-intensity statin therapy may increase the risk of adverse effects, drug-drug interactions, drug discontinuation, and non-adherence to therapy in the primary and secondary prevention of ASCVD.⁶³

A meta-analysis showed that low-intensity statin plus bile acid sequestrants or ezetimibe decreased LDL-C levels to an extent like that obtained with high-intensity statin monotherapy. Thus, such combinations may constitute an alternative to high-intensity statin monotherapy among high-risk patients who are statin-intolerant or who do not achieve lipid-lowering goals on statins alone.^64,65 However, the long-term clinical benefits/harms of a lower-intensity statin–ezetimibe therapy remained uncertain in patients with ASCVD.

The RACING trial compared the efficacy and safety of moderate-intensity statin with ezetimibe (rosuvastatin plus ezetimibe) to high-intensity statin monotherapy in patients with ASCVD who required high-intensity statin therapy to achieve LDL-C levels ≤70 mg/dL.⁶⁶ After 3 years, the primary outcome (composite of cardiovascular death, major cardiovascular events, or non-fatal stroke) occurred in 9.1% of patients in the combination therapy group and 9.9% in the monotherapy group. This result met the non-inferiority margin of 2.0%, indicating that the combination therapy was non-inferior to statin monotherapy. At 1, 2, and 3 years, LDL-C levels <70 mg/dL were observed in 72–75% of patients on combination therapy and in 55–60% of those treated with high-intensity statin monotherapy. Interestingly, discontinuation or dose reduction of the study drug due to intolerance occurred less frequently in the combination therapy group (4.8% vs. 8.2%). The secondary composite endpoint of all-cause mortality, major cardiovascular events, or nonfatal stroke was similar in both treatment groups.

Thus, combination of moderate-intensity statin therapy with ezetimibe is non-inferior to high-intensity statin monotherapy in patients with ASCVD but is associated with a lower incidence of drug discontinuation or dose reduction due to adverse effects and a higher proportion of patients reaches their LDL-C level target. Thus, combination therapy rather than doubling the statin dose might be considered for patients at high risk for adverse effects or intolerance to high-intensity statin therapy. However, because of the open-label design of the study, further clinical trials are required to validate the non-inferiority and improved tolerability of moderate-intensity statin therapy with ezetimibe compared with high-intensity statin monotherapy in patients with ASCVD.

Combination of angiotensin receptor blockers and β-blockers in patients with Marfan syndrome

The Marfan syndrome is a rare genetic disorder with autosomal dominant heritage caused by pathological variants in the fibrillin-1 gene (FBN1), which lead to increased levels of active transforming growth factor beta (TGF-β), along with abnormal microfibrils formation and connective tissue synthesis. This causes progressive enlargement of the aortic root and increases the risk of aortic complications, mainly aortic dissection, leading to premature death or disability.⁶⁷ Beta-blockers and angiotensin receptor blockers (ARBs) reduce TGF-β expression and circulating TGF-β levels and slow aortic root enlargement.⁶⁸ Because the effects of their combination remained uncertain, Pitcher et al.⁶⁹ performed a meta-analysis of 10 RCTs, including 1836 patients with no previous aortic surgery, that compared ARBs vs. control or ARBs vs. β-blockers, which followed a protocol that was agreed upon and published before study analyses. The primary endpoint was the annual rate of change of body surface area-adjusted aortic root dimension Z score, measured at the sinuses of Valsalva. During a median follow-up of 3 years, ARB therapy approximately halved the primary endpoint, and the benefits were significantly greater in patients with than in those without pathogenic FNB1 variants and persisted in those treated with β-blockers. Three trials compared ARBs with β-blockers in 766 patients and showed that during a median follow-up of 3 years, the annual change in the aortic root Z score was similar in the two groups. Assuming additivity, combination therapy with both ARBs and β-blockers from the time of diagnosis would provide even greater reductions in the rate of aortic enlargement than either treatment alone and, if maintained over a number of years, would be expected to delay the need for aortic surgery substantially.

This meta-analysis, however, has several limitations. For instance, not all trial datasets were available for individual data analysis. In addition, all RCTs analysed the effects of losartan or atenolol, and only 1 trial studied irbesartan or nebivolol. Why the individual studies used different angiotensin-converting enzyme inhibitors (ACEIs) and β-blockers, making an interstudy comparison difficult, is unclear and should be considered when interpreting the study outcomes. Furthermore, only 11% of the patients were older ≥40 years, so that the extrapolation of the present data to older adults with Marfan syndrome is uncertain. Finally, the number of patients who had major clinical outcomes was too small to provide sufficient statistical power to detect benefits from such outcomes over the relatively short duration of the trials.

Polypill strategy in secondary cardiovascular prevention revisited

Almost 20 years ago, Wald and Law⁷⁰ proposed a FDC of six drugs, so-called ‘polypill’, for the prevention of CVD, suggesting that administration of this polypill to all adults ≥55 years of age would reduce cardiovascular events by >80%. In recent years, different cardiovascular polypills have been developed to prevent the progressive increase in global CVD burden. These data were further confirmed by more recent trials and a large individual patient's data meta-analysis.^71,72 A FDC that includes drugs with established efficacy to improve cardiovascular outcomes (low-dose aspirin, ACEIs, and statins) was proposed for the secondary prevention of cardiovascular death and complications post-MI.⁷³ This polypill simplifies treatment, increases adherence and persistence to therapy, and has the potential to improve pharmacological treatment worldwide while reducing direct and indirect costs. However, its efficacy in preventing secondary cardiovascular events remained uncertain.^73,74

The SECURE trial compared a polypill-based strategy containing low-dose aspirin (100 mg), ramipril (2.5, 5, or 10 mg), and atorvastatin (20 or 40 mg) with usual care in patients with a MI within the previous 6 months.⁷⁵ After a follow-up of 3 years, the primary composite outcome (cardiovascular death, non-fatal type 1 MI, nonfatal ischaemic stroke, or urgent revascularization) decreases significantly by ∼25% (9.5% vs. 12.7%) in the polypill group. A key secondary composite outcome of cardiovascular death, non-fatal type 1 MI, or non-fatal ischaemic stroke is also reduced by ∼30% in the polypill group as compared with the usual-care group (8.2% vs. 11.7%). The lower risk of cardiovascular events in the absence of substantial differences in blood pressure and LDL-C levels may be related to the pleiotropic effects of statins and ACEIs^76,77 and the greater drug adherence.^78,79 Indeed, in patients with recent MI, cardiovascular risk was 27% lower among the patients with a high degree of adherence than among those with a low degree of adherence⁷⁸ and in secondary prevention patients, compared with control groups, those treated with a polypill containing aspirin, ramipril, and atorvastatin showed a 27% lower frequency of recurrent MACE, improved BP and LDL-C control rates, and increased medication persistence.⁷⁹

Future directions

Several new anticoagulants and platelet antiaggregants, cardiac myosin inhibitors, lipid-lowering drugs targeting LDL-C, triglycerides, and apolipoprotein (a), oral dual endothelin receptor antagonists, and drugs that may improve cardiac function in patients with HF or MI are under clinical development and are expected to offer new therapeutic opportunities in the near future. These potential advancements, along with the repurposing of approved drugs (i.e. SGLT2 is in the treatment of HF, glucagon-like peptide 1 receptor agonists in the treatment of obesity, or colchicine in the treatment of coronary artery disease) will create unique opportunities and open up new avenues in the treatment of CVD.

Conclusions

This review provides a summary of the most recent and relevant advances in cardiovascular pharmacology in 2022, including the approval of first-in-class drugs that open new avenues for pharmacotherapy of oHCM (mavacamten), T2DM (tirzepatide), and HF independent of LVEF (SGLT2Is). FDC therapy repurposing different formulations of ‘old’ drugs with well-known efficacy and safety offers new effective options for the treatment of patients with ADHF (acetazolamide plus loop diuretics), ASCVD (moderate-dose statin plus ezetimibe), Marfan syndrome (ARBs plus β-blockers), and secondary cardiovascular prevention (i.e. low-dose aspirin, ramipril and atorvastatin). In addition, some trials have confirmed the role of dapagliflozin in patients with HFmrEF or HFpEF, of long-term evolocumab to reduce the risk of cardiovascular events, of VKA for stroke prevention in patients with RHD-AF, the value of antibiotic prophylaxis in patients at high risk for infective endocarditis before invasive dental procedures, and of vutrisiran for the treatment of hATTR with polyneuropathy. Finally, the results from multiple phase 2 trials with FXIa inhibitors suggest that these drugs may have the potential to prevent thromboembolic events, which has to be confirmed in large ongoing phase III trials.

Funding

J.T. was supported by a grant from the Comunidad de Madrid (P2022/BMD-7229). P.F. was supported by the National Research, Development and Innovation Office of Hungary (Research Excellence Program TKP within the framework of the Therapeutic Development thematic programme of the Semmelweis University; National Heart Laboratory (RRF-2.3.1-21-2022-00003), by the EU Horizon 2020 project COVIRNA (Grant #101016072), and by COST CIG IG16225. The research of D.D. is supported by the National Institutes of Health (R01-HL131517, R01-HL136389, R01-HL089598, R01HL163277, and R01-HL160992) and the European Union (large-scale integrative project MAESTRIA, No. 965286).

Conflict of interest: J.T.: none.

S.A.: This MS is being edited by Prof. Gregory Lip as a Guest Editor, since Stefan Agewall is the Editor-in-Chief of the EHJ-CVP.

C.B. has received lecture fees from Menarini Corporate, Servier Pharma, Amarin, Novo Nordisk, Alfasigma, Berlinchemie, and Sanofi and is a member of advisory board of the same companies.

C.C.: none.

E.C.: none.

G.A.D.: none.

P.F. is the founder and CEO of Pharmahungary Group, a group of R&D companies.

E.G. has received speaker honoraria or consultancy fees from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Pfizer, MSD, Mundipharma, Organon, and Lundbeck Pharma. He is an investigator in clinical trials sponsored by AstraZeneca, Bayer, and Idorsia, and has received unrestricted research grants from Boehringer Ingelheim.

B.R.: none.

P.S. has received personal fees from Boehringer Ingelheim and AstraZeneca and grants from Boehringer Ingelheim, AstraZeneca, and Daiichi Sankyo.

A.G.S. has received lecture honoraria from AbbVie, Novartis, Bayer, Eli Lilly, Pfizer, and Sanofi.

S.S. has received speakers/consultancy honoraria from Boehringer Ingelheim Pharma GmbH and AstraZeneca.

A.N. has received speaker's/consultancy honoraria from Bayer, Boehringer Ingelheim, and AstraZeneca, and unrestricted grants from Boehringer Ingelheim and AstraZeneca.

J.C.K. has received speaker honoraria from Menarini Farmaceutica s.r.l and Servier.

D.D. has received honoraria for educational lectures from Novartis and Daiichi Sankyo and honoraria for consultancy services from Omeicos and AbbVie, unrelated to present manuscript.

Data availability statement

The data underlying this review were taken from the quoted references.

References