REVIEW

European Heart Journal - Cardiovascular Pharmacotherapy (2024) 10, 219–244

https://doi.org/10.1093/ehjcvp/pvae013

New pharmacological agents and novel

cardiovascular pharmacotherapy strategies
in 2023
Juan Tamargo 1 , ∗ , Stefan Agewall2 ,3 , Claudio Borghi 4 , Claudio Ceconi5 ,
Elisabetta Cerbai 6 , Gheorghe A. Dan7 , Péter Ferdinandy8 ,9 ,

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Erik Lerkevang Grove10 ,11 , Bianca Rocca6 ,12 , Emma Magavern13 ,
Patrick Sulzgruber 14 , Anne Grete Semb15 , Samuel Sossalla16 ,17 ,
Alexander Niessner 18 , Juan Carlos Kaski19 and Dobromir Dobrev 20 ,21 ,22
1
Department of Pharmacology and Toxicology, School of Medicine, Universidad Complutense, Instituto De Investigación Sanitaria Gregorio Marañón, 28040 Madrid, Spain.; 2 Institute
of Clinical Science, Oslo University, 0318 Oslo, Norway; 3 Institute of Clinical Sciences, Karolinska Institute, Danderyd Hospital, 171 77 Stockholm, Sweden; 4 Department of
Cardiovascular Medicine, University of Bologna-IRCCS AOU S. Orsola, 40138 Bologna, Italy; 5 Motusmed Clinic, 25122 Brescia, Italy; 6 Department Neurofarba, Section of
Pharmacology and Toxicology, University of Florence, 50139 Florence, Italy; 7 Carol Davila. University of Medicine, Colentina University Hospital, 0221 Bucharest, Romania;
8
Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, H-1089, Hungary; 9 Pharmahungary Group, Budapest, H-1031, Hungary; 10 Department of
Cardiology, Aarhus University Hospital, 8200 Aarhus N, Denmark; 11 Department of Clinical Medicine, Faculty of Health, Aarhus University, 8200 Aarhus N, Denmark; 12 Section of
Pharmacology, Department of Safety and Bioethics, Catholic University School of Medicine, 00168 Roma, Italy; 13 William Harvey Research Institute, Centre of Clinical Pharmacology
and Precision Medicine, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK; 14 Department of Medicine, Division of Cardiology, Medical University of
Vienna, 1090 Vienna, Austria; 15 Preventive Cario-Rheuma clinic, Division of Research and Innovation, REMEDY centre, Diakonhjemmet Hospital, 0370 Oslo, Norway; 16 Cardiology and
Angiology, Justus-Liebig-University, D-35392 Giessen, Germany; 17 Department of Cardiology, Kerckhoff-Clinic/DZHK, D-61234 Bad Nauheim, Germany; 18 Department of Internal
Medicine II, Division of Cardiology, Medical University of Vienna, 1090 Vienna, Austria; 19 Molecular and Clinical Sciences Research Institute, St. George’s, University of London,
Cranmer Terrace, London SW17 0RE, UK; 20 Institute of Pharmacology, West-German Heart and Vascular Centre, University Duisburg-Essen, DE-45122 Essen, Germany;
21
Department of Medicine, Montreal Heart Institute and Université de Montréal, H1Y 3N1 Montréal, Canada; and 22 Department of Integrative Physiology, Baylor College of Medicine,
77030 Houston, TX, USA

Received 20 December 2023; revised 1 February 2024; accepted 19 February 2024; online publish-ahead-of-print 20 February 2024

Although cardiovascular diseases (CVDs) are the leading cause of death worldwide, their pharmacotherapy remains
suboptimal. Thus, there is a clear unmet need to develop more effective and safer pharmacological strategies. In this
review, we summarize the most relevant advances in cardiovascular pharmacology in 2023, including the approval of
first-in-class drugs that open new avenues for the treatment of atherosclerotic CVD and heart failure (HF). The new
indications of drugs already marketed (repurposing) for the treatment of obstructive hypertrophic cardiomyopathy,
hypercholesterolaemia, type 2 diabetes, obesity, and HF; the impact of polypharmacy on guideline-directed drug use is
highlighted as well as results from negative clinical trials. Finally, we end with a summary of the most important phase 2
and 3 clinical trials assessing the efficacy and safety of cardiovascular drugs under development for the prevention and
treatment of CVDs.
............................................................................................................................................................................................
Keywords Cardiovascular drugs r New cardiovascular pharmacological agents r Cardiovascular
pharmacotherapy r Cardiovascular treatment strategies

Introduction
Cardiovascular disease (CVD) remains the leading cause of mortality
worldwide, but despite considerable progress, drug efficacy in most
CVDs is moderate and adverse effects and drug–drug interactions
(DDIs) preclude often their clinical use. There is a hope that identi-
fying novel drug targets and developing safer and more effective CV
drugs may slow CVD progression and improve symptoms, morbidity,
and mortality. In this context, the development of drugs for the
prevention and treatment of CV risk factors is critical. In 2023, two
‘first-in-class’ drugs with novel mechanisms of action, colchicine (first
described in the Ebers papyrus in 1550 BCE), and sotagliflozin, were
approved for the treatment of atherosclerotic CV disease (ASCVD)
and heart failure (HF), respectively. Several randomized clinical trials
(RCTs) evaluated new clinical applications of marketed drugs for
the treatment of hypercholesterolaemia, type 2 diabetes (T2D), and

∗
Corresponding author. Tel: +34-91-3941472, Email: jtamargo@med.ucm.es
© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.
All rights reserved. For permissions, please e-mail: journals.permissions@oup.com
220 J. Tamargo et al.

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Figure 1 Summary of new drugs and novel cardiovascular pharmacotherapy approaches in 2023. Abbreviations: AF, atrial fibrillation; CAD,
coronary artery disease; CKD, chronic kidney disease; CV, cardiovascular; CVD, cardiovascular disease; DM, diabetes mellitus; HF, heart failure; HFH,
hospitalizations for heart failure; HFpEF, heart failure with preserved ejection fraction; HFrEF, HF with reduced ejection fraction; LDL-C, low-density
lipoprotein cholesterol; MACE, major adverse cardiovascular events; MI, myocardial infarction; MINS, myocardial injury after non-cardiac surgery;
DOACs, non-vitamin K oral anticoagulants; NYHA, New York Heart Association; oHCM, obstructive hypertrophic cardiomyopathy; SE, systemic
embolism; SET, septal reduction therapy; T2D, type 2 diabetes mellitus; and VKAs: vitamin K antagonists.

obesity, compared the efficacy of drugs from the same class (diuretics,
anticoagulants) or analysed the possible impact of polypharmacy on
the use of guideline-recommended drugs. The results of these studies
provide new pharmacological options for the management of CVDs
and fill unmet needs. We also present results from clinical trials, which
failed to meet their primary end-points. To select the main advances
in CV pharmacology, we reviewed individual drugs or combinations of
drugs approved by the European Medicines Agency and the Food and
Drug Administration (FDA) in 2023 and searched for clinical trials in
pre-specified fields published this year using the PubMed and EMBASE
databases. Drugs and clinical trials were selected for inclusion in this
review by consensus of the authors.
The main drug developments during 2023 are summarized in
Figure 1. The most relevant phase 3 RCTs are shown in Table 1 and
the pharmacokinetic properties, safety profiles, DDIs, and contraindi-
cations of the most recently approved drugs were presented in Tables
2 and 3.
First-in-class drugs
Newly identified mechanisms of action have allowed the use of
colchicine and sotagliflozin for indications other than those tradition-
ally used for.
Colchicine, the first anti-inflammatory
drug approved for patients with ASCVD
Inflammation plays a key role in the development and progression of
ASCVD and patients with increased inflammatory biomarker levels
are known to be at a higher risk of recurrent CV events.1 , 2 Even
in statin-treated patients, inflammation is a powerful determinant
of CV death and all-cause mortality, even greater than low-density
lipoprotein cholesterol (LDL-C).3
Colchicine is an alkaloid derived from the Colchicum autum-
nale, which has anti-inflammatory properties and has been used
for many years for the treatment of gout, familial Mediterranean
fever, and pericarditis. Colchicine irreversibly binds to β-tubulin, im-
pedes tubulin polymerization and consequently (Figure 2A): (i) impairs
neutrophil chemotaxis, adhesion and mobilization, superoxide pro-
duction, and the expression of neutrophil extracellular traps (NETs);
(ii) suppresses NLRP3 inflammasome formation and the activation
of pro-inflammatory cytokines [IL-1β, IL-6, IL-18, and C-reactive
protein (CRP)]; (iii) inhibits oxidized LDL-C and cholesterol crystal-
induced foam cell formation, and the growth of vascular smooth
muscle cells and fibroblasts; and (iv) interferes with neutrophil-platelet
interaction.4
In 2021, the European Society of Cardiology guidelines for the
prevention of CVDs recommended low-dose colchicine (LoDoCo)
(0.5 mg po daily) for secondary prevention, particularly among individ-
uals with uncontrolled risk factors or recurrent events despite optimal
Table 1 Summary of selected phase 2, 3, and 4 clinical trials published in 2023

Trial (NCT) Trail characteristics Treatment Primary outcomes Main results (HR, 95% CI) Trial limitations
...................................................................................................................................................................................................................................................................................
ARTESIA43 Phase 4, P, R, DB, DD Apixaban (5 mg bid; 2.5 mg Stroke or systemic embolism, Apixaban resulted in a lower risk of Very small number of events
NCT01938248 4012 patients with subclinical bid when indicated) vs assessed in the stroke or systemic embolism
AF lasting 6 min to 24 h; aspirin (81 mg od) started intention-to-treat (0.78% vs 1.24% per patient-year;
mean CHA2 DS2 -VASc if subclinical AF lasted population. Primary safety HR 0.63; 0.45-0.88; P = 0.007), but
score 3.9 >24 h or clinical AF outcome was major increased the rate of major
FU: 3.5 years developed bleeding, assessed in the bleeding (1.71% vs. 0.94%
on-treatment population patient-year in the apixaban vs
aspirin groups, respectively (HR
1.80; 1.26–2.57; P = 0.001)

AZALEA-TIMI 7142 Phase 2b, OL, R, AC Abelacimab (90 mg and 150 Major or clinically relevant Net clinical outcomes were It was not powered for
NCT04755283 1287 patients with AF. mg s.c. monthly) vs non-major bleeding. Net significantly better with both doses ischaemic outcomes (no
Median CHA2 DS2 -VASc rivaroxaban 20 mg daily (15 clinical outcome: ischaemic of abelacimab as compared with differences were observed
score ≥4 [≥3 with at least mg if CrCl ≤50 ml/min) stroke, systemic embolism, rivaroxaban (both P < 0.001). between groups)
one of the following major or clinically relevant Major bleeding, GI bleeding and
factors: planned non-major bleeding and clinically relevant non-major
concomitant use of all-cause death bleeding (but not intracranial
antiplatelet drugs (26%) or haemorrhage) were also
New pharmacological agents and novel cardiovascular pharmacotherapy strategies

CrCl ≤50 ml/min (21%)] significantly reduced in the

FU: 1.8 years abelacimab groups compared with
the rivaroxaban group
China Tongxinluo Phase 4, R, DB, PC Tongxinluo or placebo orally 30-day major adverse cardiac Tongxinluo, as an adjuvant therapy to The active ingredient(s) and
(CTS-AMI) Study31 3777 patients with STEMI (a loading initial dose of and cerebrovascular events, STEMI guideline-directed the exact mechanism of
NCT03792035 within 24 h of symptom 2.08 g, followed by a a composite of cardiac treatments, significantly improved action remain unknown;
onset maintenance dose of 1.04 death, MI, emergent both 30-day [RR 0.64 (0.47–0.88)] poor prescription of
FU: 12 months g, 3 times a day), in coronary revascularization, and 1-year clinical outcomes (0.64; guideline-recommended
addition to STEMI and stroke. 0.49–0.82) medical therapy during and
guideline-directed after hospitalization. The
treatments. effects of Tongxinluo need
to be assessed in other
patient populations, with
better adherence to
guideline-directed therapy
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Table 1 Continued

Trial (NCT) Trail characteristics Treatment Primary outcomes Main results (HR, 95% CI) Trial limitations
...................................................................................................................................................................................................................................................................................
CLEAR Outcomes14 DB, R, PC Oral bempedoic acid (BA), 4-MACE: CV death, BA reduced the primary end-point The inclusion of only patients
NCT02993406 13,970 patients unable or 180 mg od or matching non-fatal MI, non-fatal (HR 0.87; 0.79–0.96; P = 0.004), who had reported that they
unwilling to take statins placebo stroke, or coronary the composite of CV mortality, were unable or unwilling to
due to unacceptable revascularization non-fatal stroke, or non-fatal MI take statins resulted in a higher
adverse effects which were (HR 0.85; 0.76–0.96; P = 0.006), mean LD-C level at baseline
at high risk for CVD fatal or non-fatal MI (0.77;
FU: 40.6 month 0.66–0.91; P = 0.002) and
coronary revascularization (0.81;
0.72–0.92; P = 0.001). No effect
on stroke or CV and all-cause
death

CLEAR Outcome15 Masked, R trial Oral bempedoic acid (BA), First occurrence of any BA reduced the primary endpoint This was a secondary analysis of a
NCT02993406 4206 primary prevention 180 mg daily or matching component of a (HR 0.70; 0.55-0.89; P = 0.002); larger RCT; the number of
patients. 66% with diabetes placebo composite of CV death, the composite of CV death, MI, or events was low, resulting in
FU: 39.9 months non-fatal MI, non-fatal stroke (0.64; 0.48–0.84; P < wider confidence intervals; the
stroke, or coronary 0.001); MI (0.61; 0.39–0.98); CV inclusion of patients who
revascularization death (0.61; 0.41–0.92); and reported inability to tolerate
all-cause mortality (0.73; statins resulted in higher mean
0.54–0.98). No effect on stroke or baseline LDL-C levels; the trial
coronary revascularization. BA also selected patients using specific
reduced LDL-C (30.2 mg/dL) and criteria for a high level of risk
hs-CRP levels (0.56 mg/L) of a first cardiac event

CLOROTIC trial35 P, DB, PC Oral HCTZ or placebo in Changes in BW and Patients on HCTZ showed greater Recruitment did not reach the
NCT01647932 230 patients with AHF, 96.5% addition to i.v. furosemide patient-reported 24 h diuresis and weight loss for needed sample size as per
in NYHA functional class (40 mg). HCTZ doses dyspnoea from baseline each 40 mg of furosemide (P < protocol; at baseline, gender,
II–IV, irrespective of were adjusted according to to 72 h after 0.001) and at 72 and 96 h were systolic blood pressure, BMI,
etiology and/or LVEF the eGFR randomization. more likely to lose weight than and ischaemic cause of HF
those assigned to placebo [−2.3 were unbalanced between
vs. −1.5 kg; P = 0.002], but groups; patients had a history
frequently presented impaired of HF and required
renal function. No differences in moderate-to-high doses of
patient-reported dyspnoea, loop diuretics before
mortality or rehospitalizations. admission; renal function or
electrolytes were not
monitored in the follow-up
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Table 1 Continued

Trial (NCT) Trail characteristics Treatment Primary outcomes Main results (HR, 95% CI) Trial limitations
...................................................................................................................................................................................................................................................................................
COP-AF trial48 Investigator-initiated, R, PC Oral colchicine (0.5 mg bid) Clinically important Colchicine did not reduce the Site variability in postoperative
NCT03310125 trial or placebo, starting within perioperative AF and MINS incidence of clinically important AF cardiac monitoring; <50% of
3209 patients scheduled for 4 h before surgery and during 14 days of or MINS, but increased the risk of patients underwent ECG on
non-cardiac thoracic continuing for 10 days follow-up. Main safety mostly benign non-infectious postoperative day 3; a trend of
surgery with general outcomes: a composite of diarrhoea fewer CV events found in
anaesthesia sepsis or infection, and post-hoc analyses should be
non-infectious diarrhoea confirmed in further RCTs

Danish Nationwide Register-based cohort study Treated with simvastatin or Statin response (percentage Patients ≥75 years had greater Use of administrative data only,
cohort study16 82,958 statin initiators. 10,388 atorvastatin between 2008 reduction in pre-statin LDL-C reductions than those <50 lack of information on BMI;
(13%) aged ≥75 years and 2018 LDL-C level) and years (adjusted PRD 2.62 mainly Caucasians which limits
percentage reduction percentage points). A smaller generalizability
differences (PRDs) effect was observed for initiators
according to age and of high-intensity statin therapy
simvastatin or atorvastatin
dose based on a
longitudinal model for
LDL-C

DAPA-MI28 Registry-based, R, DB trial Dapagliflozin (10 mg od) vs. Hierarchical composite of Dapagliflozin resulted in a significant Study was performed only in
New pharmacological agents and novel cardiovascular pharmacotherapy strategies

NCT04564742 4017 patients from the placebo death, HF hospitalization, improvement of cardiometabolic Sweden and United Kingdom;
SWEDEHEART and nonfatal MI, AF/Afl, T2D, outcomes vs. placebo, with 34% event rates for CV death and
NICOR Registries, with NYHA at the last visit, and more wins in the primary outcome HF hospitalization were
AMI and impaired LV a BW decrease of ≥5% at (win ratio, 1.34; 1.20- 1.50; P < substantially lower than
systolic function, without the last visit using the win 0.001). This benefit was driven by expected; many of the
prior diabetes or chronic ratio analysis method an improvement in outcomes considered in the
HF cardiometabolic components win ratio analysis were ones
FU: up to 29 months that could be perceived as
favouring dapagliflozin

FRAIL-AF41 Pragmatic, OL, R, controlled, 662 patients switched from a Major or clinically relevant Trial stopped for futility. Switching to Trial underpowered for early
EudraCT superiority trial VKA to a DOAC; 661 non-major (CRNM) DOACs increased the rate of interruption. The study
(2017-000393-11) 1330 patients (mean age 83 patients continued VKAs. bleeding complications major and/or CRNM bleeding included patients who were
y), with a GFI score ≥3; (whichever came first), complications (HR 1.69; 1.23-2.32; tolerant to VKA-therapy; the
mean CHA2DS2-VASc accounting for death as a P = 0.001). HR for choice of the DOAC was at
score of 4. competing risk thromboembolic events was 1.26 the discretion of the
FU: 12 months (0.60–2.61) prescriber; the trial was not
powered to show differences
in clinical outcomes in isolation
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Table 1 Continued

Trial (NCT) Trail characteristics Treatment Primary outcomes Main results (HR, 95% CI) Trial limitations
...................................................................................................................................................................................................................................................................................
GUIDE-IT57 Post hoc analysis of the Polypharmacy, defined as The association between Patients without polypharmacy at Secondary analysis of a RCT;
GUIDE-IT trial receiving ≥5 medications polypharma-cy and odds of baseline had increased odds of treatment assignment was not
891 patients with HFrEF (excluding HFrEF GDMT) receiving optimal GDMT achieving GDMT (OR 1.16; blinded.
FU: 12 months at baseline over time among patients 1.12-1.21 per 1-month increase;
with HFrEF P < 0.001) vs. patients with
polypharmacy

HEART-FID trial51 R, DB, PC, event-driven trial
NCT03037931 3065 ambulatory patients
with HFrEF, and iron
deficiency (ferritin <100
ng/mL or ferritin 100–300
ng/mL with a transferrin
saturation <20%), and
either HFH or elevated
NT-proBNP levels
FU: 12 months
Ferric carboxymaltose (2
doses of 15 mg/kg 7 days
apart repeated every 6
months as indicated by the
results of iron indices;
maximum combined dose
of 1500 mg) or placebo
A hierarchical composite of
death at 12 months, HF
hospitalization at 12
months, and the change in
the 6-min walk distance
from baseline to 6 months,
assessed as the unmatched
win ratio
No difference between ferric The effect of ferric
carboxymaltose and placebo with carboxymaltose on the 6-min
respect to the hierarchical walk distance was very small,
composite of death, and the lack of a long-term
hospitalizations for HF, or 6-min reduction in HF hospitalization
walk distance (overall unmatched unexpected. This may be due
win ratio 1.10; 0.99–1.23) to the lower-risk of the
recruited population; mean
transferrin saturation at
baseline was higher in this
study than in previous trials

LODESTAR trial18 Investigator initiated, P, OL A treat-to-target strategy Composite of death, MI, No differences in mean LDL-C levels OL trial in Asian patients; at the
NCT02579499 trial using 2 × 2 factorial (LDL-C level of 50–70 stroke, or coronary or in the primary end point time of the trial design, data
randomization mg/dL) or a high-intensity revascularization with a between both strategies (absolute were limited to provide
4400 Korean patients with statin treatment non-inferiority margin of difference −0.6 percentage points; evidence for the sample size
CAD; 33% had DM (rosuvastatin, 20 mg, or 3.0 percentage points upper boundary of the 1-sided estimation based on statin
FU: 36 months atorvastatin, 40 mg) 97.5% CI, 1.1 percentage points; P type; lower event rates than
< 0.001 for non-inferiority) anticipated (the trial may be
underpowered); only 60% in
the treat-to-target strategy
group achieved LDL-C levels
<70 mg/dL; follow-up may be
too short to reflect
longer-term effects of the 2
strategies; ophthalmological
examinations were not
specified in the protocol

LODESTAR trial19 Subanalysis of the LODESTAR Rosuvastatin (mean daily dose Three-year composite of At 3 years, rosuvastatin and
NCT02579499 trial 17.1 mg) vs. atorvastatin all-cause death, MI, stroke, atorvastatin showed comparable
(mean daily dose 36.0 mg) or any coronary efficacy (HR 1.06; 0.86–1.30;
revascularization P = 0.58). Patients on rosuvastatin
showed lower LDL-C levels
(P < 0.001)
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Table 1 Continued

Trial (NCT) Trail characteristics Treatment Primary outcomes Main results (HR, 95% CI) Trial limitations
...................................................................................................................................................................................................................................................................................
MK-0616-008 trial21 Phase 2b, R, DB, PC MK-0616 (6-30 mg od) vs. Percentage of change from All doses of MK-0616 showed Small number of patients and
NCT05261126 375 patients with placebo baseline in LDL-C) at week statistically superior reductions in short duration of treatment.
hypercholesterolaemia and a 8 and proportion of LDL_C vs. placebo, with up to Larger long-term studies are
wide range of ASCVD participants with AEs and 60.9% placebo-adjusted reduction needed to assess the efficacy
FU: 8 weeks study intervention from baselines values; no overall and safety of MK-0616 in the
discontinuations due to trends in AEs across treatment context of available treatments
AEs groups

NOAH-AFNET 650 Investigator-initiated, DB, DD, R
NCT02618577 trial
2536 patients (mean age 78
years) with AHREs lasting for
at least 6 min and at least one
additional risk factor for stroke
FU: 21 months
Edoxaban 60 mg od or
placebo.
Edoxaban 30 mg if BW ≤60
kg, creatinine clearance of
15–50 ml/min, or
concomitant use of strong
P-glycoprotein inhibitors
Composite of CV death,
stroke, or systemic
embolism, evaluated in a
time-to-event analysis.
Safety outcome: composite of
death from any cause or
major bleeding
Early termination due to safety
concerns. Edoxaban did not reduce
the primary composite endpoint
(HR 0.81; 0.60–1.08; P = 0.15).
Higher incidence of death or major
bleeding in the edoxaban group
(HR 1.31; 1.02–1.67; P = 0.03)

OASIS-123 R, DB, PC, superiority trial Oral semaglutide escalated to Percentage change in BW and At week 68, mean BW change from The trial population (Caucations
NCT05035095 667 with a BMI ≥30 kg/m2 , or at 50 mg od or matching whether participants baseline to week 68 was −15.1% 76%, women 26%) might not
least 27 kg/m2 with placebo, plus lifestyle reached a BW ≥5% at with semaglutide 50 mg (−2.4% reflect the general population
New pharmacological agents and novel cardiovascular pharmacotherapy strategies

BW-related complications and
comorbidities, without T2D
FU: 68 weeks
intervention week 68, regardless of with placebo; P < 0·0001). More with overweight/obesity in all
treatment discontinuation patients reached BW reductions countries; patients with T2D
or use of other ≥5, 10, 15, and 20% with were excluded; drug adherence
BW-lowering therapies semaglutide 50 mg vs. placebo (P was not formally assessed; the
< 0.0001) protocol allowed flexibility in
the implementation of lifestyle
interventions

OCEANIC-AF Phase 3, R, DB, DD Asundexian od vs. apixaban Time to first occurrence of The study was stopped early due to
NCT05643573 14,830 with AF and indication for (2.5 or 5 mg bid) composite of stroke or inferior efficacy of asundexian vs.
indefinite treatment with an systemic embolism. Time apixaban
oral anticoagulant. to first occurrence of ISTH
CHA2 DS2 -VASc score ≥3 if major bleeding
male (≥4 if female), or
CHA2 DS2 -VASc score of 2 if
male or 3 if female and
enrichment criteria
FU: 34 months
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Table 1 Continued

Trial (NCT) Trail characteristics Treatment Primary outcomes Main results (HR, 95% CI) Trial limitations
...................................................................................................................................................................................................................................................................................
SELECT22 R, DB, PG, event-driven Semaglutide (0.5 uptitrated Composite of CV death, Semaglutide was superior to placebo The effects of semaglutide on the
NCT03574597 superiority trial every 4 weeks up to 2.4 non-fatal MI, or non-fatal to reduce the primary endpoint prevention of CV events in
17,604 patients with mg) vs. matching placebo stroke in a (HR 0.80; 0.72–0.90; P < 0.001), persons with overweight/
preexisting CVD and time-to-first-event analysis but produced a higher rate of obesity but without previous
overweight or obesity, but adverse effects leading to CVD were not studied; limited
not history of T2D permanent drug discontinuation vs. inclusion of women (27.7%)
FU: 39.8 months placebo (16.6% vs. 8.2%; P < 0.001 and Blacks (3.8%). Although
patient did not have T2D,
66.4% met the HbA1c
criterion for prediabetes

STELLAR 33 Phase 3, DB, Sotatercept (0.3–0.7 mg/kg Change from baseline at week The median change from baseline at Only patients with pulmonary
NCT04576988 163 patients with pulmonary s.c) or placebo every 3 24 in the 6-min walk week 24 in the 6-min walk distance arterial hypertension WHO
hypertension (WHO weeks distance was 34.4 meter (33.0–35.5) in the class II–III and baseline
functional class II–III) sotatercept group and 1.0 m pulmonary vascular resistance
FU: 24 weeks (−0.3–3.5) in the placebo group values of at least 400 dyn sec
cm−5 (≥5 Wood units) were
eligible; potential for unblinding
due to side effects; the trial
was not designed to study the
drug effects on mortality

STEP-HFpEF24 R, DB, PC Semaglutide (2.4 mg s.c.) or Dual primary end points were Semaglutide significantly reduced Short follow-up; the trial was not
NCT04788511 529 patients with HFpEF and placebo administered s.c. the changes from baseline KCCQ-CSS and mean percentage powered to evaluate clinical
a BMI ≥30 kg/m2 once weekly in the KCCQ-CSS score change in BW, and increased 6-min outcomes (i.e. HF
FU: 52 weeks and in BW walk distance (all P < 0.001) hospitalization, urgent visits);
lack of data on HbA1c levels;
few patients were on SGLT2
inhibitors at baseline; exclusion
of diabetics; only 4% of Blacks

SURMOUNT-226 DB, R, PC Once-weekly tirzepatide (10 Coprimary endpoints: Tirzepatide, 10 or 15 mg, reduced The dose of 5 mg of tirzepatide
NCT04657003 938 patients with a BMI ≥27 or 15 mg s.c.) or placebo percent change in from mean BW by 12.8 and 14.7% (3.3% approved for T2D was not
kg/m2 and HbA1c of for 72 weeks baseline and BW reduction with placebo; P < 0.0001 for evaluated; >30% of screened
7–10% of ≥5% both). The percentage of patients individuals were excluded from
FU: 72 weeks with BW reduction ≥5%: 79 and the study; most patients (56%)
83% vs. 32% (both P < 0.0001); did not meet diabetes entry
BW reduction ≥15%: 39.7%, criteria; people treated with
48.0%, and 2.7%, respectively (P < insulin were excluded
0.0001 for both)
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Table 1 Continued

Trial (NCT) Trail characteristics
...................................................................................................................................................................................................................................................................................
SURMOUNT-327 DB, R, PC
NCT04657016 579 adults with BMI ≥30 or
≥27 kg/m2 and at least one
obesity-related
complication (excluding
diabetes), who achieved
≥5.0% weight reduction
after a 12-week intensive
lifestyle intervention
Treatment Primary outcomes Main results (HR, 95% CI) Trial limitations
Once-weekly tirzepatide (10 Co-primary endpoints: % Intensive lifestyle intervention Predominantly White population;
or 15 mg s.c.) or placebo change in BW and the followed by 72 weeks of exclusion of 17.5% of
for 72 weeks proportion of study tirzepatide led to a BW change of participants who did not lose
participants who achieved −24.3% (−4.5% with intensive ≥5% of baseline weight with
≥5% weight reduction lifestyle intervention followed by intensive lifestyle intervention
from randomization to placebo) More participants on
week 72 tirzepatide than placebo achieved
reductions in BW of ≥10, ≥15,
and ≥20% (P < 0.001)

TRANSFORM-HF39 Phase 3, OL, R, pragmatic trial Changes in dose and All-cause mortality in a Torsemide compared with Sample size was almost half that
New pharmacological agents and novel cardiovascular pharmacotherapy strategies

NCT03296813 2859 patients hospitalized
with HF regardless of LVEF
FU: 30 months for death, 12
months for hospitalizations
frequency of the time-to-event analysis. Five furosemide did not result in a originally planned; the OL and
randomized therapy after secondary outcomes; significant difference in all-cause pragmatic design; the primary
discharge were at the all-cause mortality or mortality (26.1% vs. 26.2%; HR outcome may not allow to
discretion of the patient’s all-cause hospitalization 1.02; 0.89–1.18), all-cause assess subtle differences
usual outpatient clinicians. and total hospitalizations mortality or all-cause between treatment groups;
Conversion guide: 1 mg of assessed over 12 months hospitalization (0.92; 0.83–1.02) or loop diuretic discontinuation
torsemide to 2–4 mg of being highest in the total hospitalization (0.94; and crossovers occurred during
oral furosemide hierarchy 0.84–1.07) follow-up; loop diuretic dose
was left to clinician discretion
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 228

Table 1 Continued

Trial (NCT) Trail characteristics Treatment Primary outcomes Main results (HR, 95% CI) Trial limitations
...................................................................................................................................................................................................................................................................................
VALOR-HCM11 Phase 3, R, DB, PC Mavacamten (5–15 mg) vs. Proportion of patients Mavacamten reduced the need for The efficacy end point was driven
NCT04349072 112 patients with obstructive placebo. undergoing SRT, remaining SRT at week 56, with sustained by reduction in guideline
HCM (NYHA class III/IV, Dose titrations were guideline eligible or improvements in LVOT gradients eligibility for SRT rather than
mean LVOT 84 mmHg) performed using unevaluable SRT status at and symptoms the decision of patients not to
referred for SRT echocardiographic LVOT week 56. proceed with SRT; the small
FU: 56 weeks gradient and LVEF sample size and short FU do
measurements not allow to determine
whether mavacamten can
provide the long-term clinical
benefits comparable with
those achieved with SRT; the
study was performed in
centres with established good
outcomes for SRT procedures.

Abbreviations: AC, active controlled; AEs, adverse events; AF, atrial fibrillation; AHREs, atrial high-rate episodes; bid. twice daily; ASCVD, atherosclerotic cardiovascular disease; BMI, body-mass index; BW, bodyweight; CrCl, creatinine
clearance; CVD, cardiovascular disease; DB, double blind; DD, double-dummy; DOACs, non-vitamin K oral anticoagulants; eGFR, estimated glomerular filtration rate; FU, follow-up; GDMT, guideline-directed medical therapy; GFI,
Groningen Frailty Indicator; GI, gastrointestinal; HbA1c, glycated haemoglobin; HCM, hypertrophic cardiomyopathy; HCTZ, hydrochlorothiazide; HF, heart failure; HFrEF, heart failure with reduced ejection fraction; HFpEF, heart failure
with preserved ejection fraction; HR, hazard ratio; hs-CRP, high-sensitivity C-reactive protein; ISTH, International Society on Thrombosis and Haemostasis; i.v., intravenously; KCCQ-CSS, Kansas City Cardiomyopathy Questionnaire clinical
summary score; LDL-C, low-density lipoprotein cholesterol; LVEF, left ventricular ejection fraction; LVOT, left ventricular outflow tract; MACE, major adverse cardiovascular events; MI, myocardial infarction; MINS, myocardial injury after
non-cardiac surgery; NCT, ClinicalTrials.gov identifier; NT-proBNP, N-terminal pro-brain natriuretic peptide; NYHA, New York Heart Association; od, once daily; OL, open label; P, prospective; PC, placebo-controlled; PG, parallel group;
R, randomized; s.c., subcutaneous; SGLT2Is, sodium-glucose cotransporter 2 inhibitors; SRT, septal reduction therapy; STEMI, ST-segment elevation myocardial infarction; VK A , vitamin K antagonists; WHO, World Health Organization.
Acronyms: CLEAR Outcomes, Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen—CLEAR Outcomes; COP-AF, Colchicine For The Prevention Of Perioperative Atrial Fibrillation in patients undergoing thoracic
surgery; CLOROTIC, Safety and Efficacy of the Combination of Loop With Thiazide-type Diuretics in Patients With Decompensated Heart Failure; DAPA-MI, Dapagliflozin Effects on Cardiometabolic Outcomes in Patients With an Acute
Heart Attack; FRAIL-AF, Switching anticoagulant management from a VKA to a NOAC-based treatment strategy in frail elderly patients with atrial fibrillation; GUIDE-IT, Guiding Evidence-Based Therapy Using Biomarker Intensified
Treatment; HEART-FID, Randomized Placebo-controlled Trial of FCM as Treatment for Heart Failure With Iron Deficiency; LODESTAR, Low-Density Lipoprotein Cholesterol-Targeting Statin Therapy Versus Intensity-Based Statin
Therapy in Patients With Coronar y Arter y Disease; NICOR, U.K.-based National Institute for Cardiovascular Research; NOAH-AFNET 6, Non-Vitamin K Antagonist Oral Anticoagulants in Patients with Atrial High Rate Episodes; OASIS,
Oral Semaglutide Treatment Effect in People with Obesity; SELECT, Semaglutide Effects on Heart Disease and Stroke in Patients With Overweight or Obesity; STEP-HFpEF, Research Study to Investigate How Well Semaglutide Works in
People Living With Heart Failure and Obesity; SURMOUNT, Tirzepatide for the treatment of obesity development program; SWEDEHEART, Swedish Web-system for Enhancement and Development of Evidence-based care in Heart
disease Evaluated According to Recommended Therapies; TRANSFORM-HF, Torsemide Comparison With Furosemide for Management of Heart Failure; VALOR-HCM (A Study to Evaluate Mavacamten in Adults With Symptomatic
Obstructive Hypertrophic Cardiomyopathy Who Are Eligible for Septal Reduction Therapy.
J. Tamargo et al.

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Table 2 Pharmacokinetic properties and doses of new drugs or drugs with new clinical indications

Protein
Drug (route of Bioavailability Tmax plasma Excretion route
administration) (%) (h) binding (%) Vd (L/kg) Half-life (h) Metabolism (renal/faeces, %) Dose (mg)
...................................................................................................................................................................................................................................................................................
Bempedoic acid (Oral) — 3.5 99 0.25 21 ± 11 Glucuronidation (UGT1A9; 62/25.5 180 mg od
minor CYP3A4) 5*

Colchicine (Oral) 45 1.5–2 39 18.5 19 Demethylation 40–60* 0.5 mg od

Semaglutide (s.c., oral,**) 89 1–3 days 99 0.17 1 week Proteolytic cleavage and 3* s.c.: 0.25–2.4 mg once-weekly
β-oxidation of the fatty acid Oral: 2–20 mg od co-formulated
side chain with SNAC
New pharmacological agents and novel cardiovascular pharmacotherapy strategies

Sotaglliflozin (oral)*** 25 2.5–4 98 128 21–35 Glucuronidation 62/35 200–400 mg

1.5–3.5*

Tirzepatide (s.c.) 80 8–72 99 0.14 5 days Proteolytic cleavage and 0* 2.5–15 mg once weekly
β-oxidation of the fatty acid
side chain

*Drug recovered unchanged in urine. **: Oral semaglutide should be administered at least 30 min before the first food, drink, or other oral medicines of the day with a sip of plain water only. ***: not more than one hour before the first
meal of the day
Abbreviations: CYP, cytochrome P450; h, hours; od, once daily; PO, oral administration; s.c., subcutaneous; SNAC, (sodium N-[8-(2-hydroxybenzoyl)amino] caprylate) that increases lipophilicity of the peptide molecule; Tmax , time to peak
plasma levels; UGT1A9, UDP glucuronosyltransferase 1 family polypeptide A9; Vd , volume of distribution.
229

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 230

Table 3 Adverse effects, drug–drug interactions, precautions, and contraindications of new drugs or drugs with new clinical indications

Drug Adverse effects Drug interactions Precautions Contraindications***

...................................................................................................................................................................................................................................................................................
Bempedoic acid (BA) Common**: hyperuricaemia, gout, BA inhibits OATP1B1 and 1B3 and may Monitor for signs and symptoms of Avoid in patients with a history of
cholelithiasis, anaemia, back pain, increase the exposure of substrates of hyperuricaemia and uric acid levels; tendon disorders or rupture, during
abdominal pain, bronchitis, pain in OATP1B1 or 1B3 (i.e. bosentan, initiate treatment with urate-lowering pregnancy and breast-feeding
extremity, and elevated liver enzymes. fimasartan, asunaprevir, glecaprevir, drugs as appropriate. Discontinue the Avoid doses of simvastatin >20 mg/day
Tendon rupture grazoprevir, voxilaprevir, and statins) drug at the first sign of tendon rupture. or of pravastatin >40 mg daily
BA increases 1.5-fold the exposure of
atorvastatin, pravastatin, and
rosuvastatin

Colchicine GI: diarrhoea, vomiting, abdominal Colchicine is a substrate of CYP3A4 and Monitor closely patients with renal or Patients with pre-existing blood
cramping/pain. P-gp hepatic impairment. dyscrasias, renal failure (creatinine
Haematological: leukopaenia, Strong P-gp inhibitors: clarithromycin, Use of colchicine and digoxin increase clearance <15 mL/min) or severe
thrombocytopaenia, pancytopaenia, cyclosporine, fluconazole, itraconazole, the exposure of both drugs; monitor hepatic impairment
aplastic anaemia voriconazole. serum digoxin levels. Coadministration with strong CYP3A4
Neuromuscular: myotoxicity, weakness, Strong CYP3A4 inhibitors: Discontinue colchicine for 1–2 weeks if or P-gp inhibitors because of the risk
numbness, paraesthesia, clarithromycin, fluconazole, HIV strong CYP3A4 or P-gp inhibitors are of life-threatening drug reactions.
rhabdomyolysis protease inhibitors (atazanavir, initiated as short-term therapy Avoid grapefruit juice
Rashes, alopecia darunavir, indinavir, lopinavir, nelfinavir, Colchicine is excreted into human breast
Acute renal impairment ritonavir), itraconazole, voriconazole milk
Increased risk of myotoxicity if combined
with statins or fibrates

Semaglutide Very common***: nausea, diarrhoea,
vomiting, abdominal pain, constipation,
fatigue, headache
Common**: hypoglycaemia (when used
with insulin or sulfonylureas), dizziness,
dyspepsia, flatulence, cholelithiasis;
injection site reactions
Uncommon*: increases in heart rate,
acute pancreatitis
Delays gastric emptying: potential to
impact the absorption of
concomitantly administered oral
medications. Caution in patients
receiving oral medicinal products that
require rapid gastrointestinal
absorption
Discontinue if pancreatitis is suspected; Personal or family history of medullary
do not restart if pancreatitis is thyroid carcinoma or in patients with
confirmed. If cholelithiasis is suspected, multiple endocrine neoplasia
gallbladder studies and clinical syndrome type 2
follow-up are indicated. Risk of
hypoglycaemia increases with an insulin
secretagogues or insulin (reduce the
doses if needed). Monitor: severe
gastrointestinal adverse reactions that
can cause dehydration; hypoglycaemia;
and diabetic retinopathy in patients
with T2D. Discontinue the drug if
depression or suicidal thoughts
develop. Not recommended in
patients with severe renal impairment
(eGFR <30 mL/min/1.73m2 )
J. Tamargo et al.

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Table 3 Continued

Drug Adverse effects Drug interactions Precautions Contraindications***

...................................................................................................................................................................................................................................................................................
Sotagliflozin Common**: urinary tract infection, Increase digoxin exposure: monitor Consider ketone monitoring in patients Not recommended during the second
volume depletion, diarrhoea, digoxin levels. Decrease serum lithium with type 1 diabetes or at risk for and third trimesters of pregnancy or
hypoglycaemia, dizziness, genital concentrations: monitor serum levels ketoacidosis. Correct volume breastfeeding, and in patients with
mycotic infections. Hypoglycaemia with concomitant use depletion if necessary. Assess renal moderate or severe hepatic
with insulin and insulin secretagogues function before initiating and then as impairment
clinically indicated. Monitor for signs
and symptoms of hypotension,
urosepsis, and pyelonephritis during
therapy. Monitor and treat genital
mycotic infections as appropriate.
New pharmacological agents and novel cardiovascular pharmacotherapy strategies

Tirzepatide Very common***: nausea, diarrhoea
Common**: anorexia, vomiting,
constipation, dyspepsia, flatulence,
abdominal pain, fatigue, and injection
site reactions
Delays gastric emptying: potential to
impact the absorption of
concomitantly administered oral
medications.
Hypoglycaemia in combination with
insulin or insulin secretagogues.
Discontinue if pancreatitis is suspected. Personal or family history of medullary
Monitor renal function in patients with thyroid carcinoma, or in patients with
renal impairment reporting severe GI multiple endocrine neoplasia
adverse reactions. Monitor patients syndrome type 2
with a history of diabetic retinopathy.
If cholelithiasis is suspected, gallbladder
studies and clinical follow-up are
indicated

*Uncommon: ≤1%. **Common: ≥1%–<10%. *** Very common: ≥10%. ***: Hypersensitivity to the active substance or to any of the excipients
Abbreviations: CYP, cytochrome P450; GI, gastrointestinal; OATP, organic anion transporting polypeptide family; and P-gp, P-glycoprotein.
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232 J. Tamargo et al.

(A)

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(B)

Figure 2 Mechanism of the anti-inflammatory effect of colchicine (A) and of the glucose-lowering effect of sotagliflozin (B). Abbreviations: CRP,
C-reactive protein; GLUT2, glucose transporter 2; IL, interleukin; LDL-C, low-density lipoprotein cholesterol; NETs, neutrophil extracellular traps;
NLRP3, NOD-like receptor pyrin domain-containing-3 inflammasome; and SGLT1/2, sodium-glucose linked transporter type 1 and 2.

medical therapy.5 In 2023, colchicine was the first anti-inflammatory
drug approved by the U.S. FDA to reduce the risk of myocardial
infarction (MI), stroke, coronary revascularization, and CV death in
adult patients with established ASCVD or with multiple CV risk
factors. This approval was based on the outcome of three trials.
The LoDoCo trial randomized 532 patients with stable coronary
artery disease (CAD) receiving aspirin and/or clopidogrel and statins
(95%) to colchicine or placebo. After 3 years, colchicine reduced
the risk of CV events, including acute coronary syndromes, out-
of-hospital cardiac arrest, and non-cardioembolic ischaemic stroke
(5.3% vs. 16%; hazard ratio (HR) 0.33, 0.18–0.59; P < 0.01).6 The
LoDoCo2 study randomized 5522 patients with stable CAD treated
with high-intensity statins and standard secondary prevention thera-
pies to LoDoCo or placebo. After 26.8 months, colchicine reduced
ASCVD events (CV death, MI, ischaemic stroke, and ischaemia-
driven coronary revascularization) (6.8% vs. 9.6%; HR 0.69; 0.57–0.83;
P < 0.001).7 In the COLCOT trial (4745 patients up to 30 days
post-MI), after a median follow-up of 23 months colchicine reduced
the composite of CV death, cardiac arrest, MI, stroke, or urgent
hospitalizations for angina (5.5% vs. 7.1%; HR 0.77, CI 0.61–0.96;
P < 0.02), the risk of stroke (26%), and the incidence of angina
requiring revascularization (50%).8 The effect size was greater than
New pharmacological agents and novel cardiovascular pharmacotherapy strategies
that observed in recent secondary prevention trials with lipid-lowering
drugs and was particularly evident with early initiation of therapy, i.e.
when colchicine was started within the first 3 days post-MI. Thus,
the combination of LoDoCo with intensive LDL-C lowering therapy
represents a new strategy to reduce inflammatory and residual risk
in patients with established ASCVD or with multiple CV risk factors.
However, colchicine is metabolized via CYP3A4 and P-gp, is renally
excreted and adverse effects can lead to drug discontinuation in >10%
of patients (Tables 2 and 3). Thus, its combination with strong CYP3A4
or P-glycoprotein inhibitors increase colchicine exposure and is con-
traindicated. Importantly, the reported increase in the incidence of
non-CV deaths, albeit not statistically significant, warrants further
research, and careful phase IV pharmacovigilance.
Sotagliflozin, the first SGLT1/2 inhibitor,
for the treatment of HF
Sotagliflozin is the first oral inhibitor of sodium-glucose cotransporter
(SGLT) types 1 and 2, responsible for gastrointestinal glucose absorp-
tion and glucose reabsorption at the renal proximal tubuli, respectively
(Figure 2B). Based on the SOLOIST-WHF9 and SCORED10 phase 3
cardiovascular outcomes trials, the FDA approved sotagliflozin as an
agent shown to reduce the risk of CV death, hospitalization for HF,
and urgent HF visits in adults with; (i) HF; or (ii) T2D, chronic kidney
disease (CKD) and other CV risk factors. The SOLOIST-WHF trial
recruited 1222 patients with T2D who were recently hospitalised
for worsening HF.9 After 9 months, as compared with placebo, so-
tagliflozin, initiated before or shortly after discharge, reduced CV
death and hospitalization rate and urgent visits for HF (51.0 vs. 76.3
events per 100 patient-years; HR 0.67; 0.52–0.85; P < 0.001) and
HF urgent visits and hospitalization rate vs. placebo (40.4 vs. 63.9
events per 100 person-years; 0.64; 0.49–0.83; P < 0.001), but not
CV mortality. The SCORED trial recruited 10,584 patients with T2D,
CKD [estimated glomerular filtration rate (eGFR) 25–60 mL/min/
1.73 m2 ], and risks for CVD.9 After 16 months, sotagliflozin reduced
the composite of the CV mortality, hospitalizations for HF, and urgent
visits for HF as compared with placebo (5.6 vs. 7.5 events per 100
patient-years; HR 0.74; 0.63–0.88; P < 0.001), but not CV death. In
both trials, 5.5% of patients discontinued sotagliflozin due to adverse
drug reactions (Table 3).
New indication of mavacamten in
patients with obstructive hypertrophic
cardiomyopathy
The approval of mavacamten for this indication in 2023 was based
on the cumulative longer-term results of the phase 3 VALOR-HCM
trial, which randomized 112 patients with symptomatic obstructive
hypertrophic cardiomyopathy (oHCM) (93% in NYHA HF class III–IV)
and mean post-exercise left ventricular outflow tract (LVOT) gradient
of 84 mmHg referred for septal reduction therapy (SRT) to mava-
camten (5–15 mg/day) or placebo.11 Patients assigned to mavacamten
at baseline continued the drug for 56 weeks; patients taking placebo
crossed over to mavacamten from week 16 to week 56 (40-week
exposure). At week 56, 5 of 56 patients (8.9%) in the mavacamten
group and 10 of 52 patients (19.2%) in the placebo crossover group
continued to meet the composite efficacy end-point. Only 3 of 56
patients (5.4%) from the original mavacamten group and 3 of 52
patients (5.8%) from the placebo crossover group chose to undergo
SRT. Thus, mavacamten reduced the need for SRT, with sustained
improvements in resting and Valsalva related LVOT gradients and
symptoms.
233
Recent clinical trials of
lipid-lowering drugs
Bempedoic acid reduces major adverse
cardiovascular events in statin-intolerant
patients
Statins are the first-line therapy in primary and secondary ASCVD
risk reduction,12 but nearly 10% of patients report statin intolerance.
Bempedoic acid (BA) is a prodrug that requires the conversion to an
active metabolite by the very-long-chain acyl-CoA synthetase 1, an
enzyme expressed abundantly in the liver but not present in skeletal
muscle. BA is an ATP citrate lyase inhibitor that inhibits cholesterol
synthesis in the liver and reduces LDL-C levels by 18–20% (up to 40%
in combination with ezetimibe),13 but its effects on CV outcomes
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remained uncertain.
The CLEAR Outcomes trial randomized 13,970 patients at high risk
for CV disease, who were unable or unwilling to take statins to BA
(180 mg daily) or placebo.14 Approximately 70% of patients required
secondary-prevention therapy and 30% required primary-prevention
therapy. After 6 months, BA reduced mean baseline LDL-C levels
(139.0 mg/dL) by 29.2 mg/dL. After 40.6 months, BA (vs. placebo)
reduced the four-component composite of major adverse CV events
(MACEs), defined as death from CV causes, non-fatal MI, non-fatal
stroke, or coronary revascularization [11.7% vs. 13.3%; HR 0.87;
0.79–0.96; P = 0.004], the incidence of a composite of CV death,
non-fatal stroke, or non-fatal MI (0.85; 0.76–0.96; P = 0.006), fatal
or non-fatal MI (0.77; 0.66–0.91; P = 0.002), and the incidence of
coronary revascularization (0.81; 0.72–0.92; P = 0.001). However,
BA had no significant effects on fatal or non-fatal stroke, CV, or all-
cause death. BA also led to a 22% reduction in high-sensitivity CRP
levels. Interestingly, a subgroup analysis identified that the benefit of
BA favoured the primary-prevention cohort (HR 0.68; 0.53–0.87), but
not the secondary-prevention cohort (HR 0.91; 0.82–1.01; P = 0.03).
In an analysis of 4206 patients from the CLEAR Outcomes trial with
elevated CV risk but no prior clinical event (primary prevention), after
a mean follow-up of 39.9 months, BA reduced significantly LDL-C
(by 30.2 mg/dL) and high-sensitivity CRP levels (by 0.56 mg/L) and
the time from randomization to the first occurrence of any compo-
nent of a composite of cardiovascular death, non-fatal MI, non-fatal
stroke, or coronary revascularization (HR 0.70; 0.55–0.89; P = 002).15
BA also reduced the composite of CV death, MI, or stroke (HR
0.64; 0.48–0.84; P < 0.001), MI (0.61; 0.39–0.98), CV death (0.61;
0.41–0.92), and all-cause mortality (0.73; 0.54–0.98), but not the
incidence of stroke or coronary revascularization. Thus, in patients
who were unable or unwilling to take recommended doses of statins,
BA significantly reduced MACE, although some side effects, including
hyperuricaemia, gout, elevated liver enzymes, and potential for tendon
rupture (Table 3) must be carefully monitored and the increased risk
of myopathy when combined with statins should be considered.13 A
major limitation of both trials is the inclusion of patients who were
unable or unwilling to take statins, which resulted in a high mean
baseline LDL-C levels. The effects of BA on CV events in patients
with lower LDL-C levels or treated with statins were not studied.
Age-dependent effects of statins
There is a large inter-individual variation in the reduction of LDL-C
in response to statins. One possible reason for such variability is age,
because older adults have been underrepresented in pivotal RCTs.
A Danish Nationwide register-based cohort study recruited 82,958
adults (13% ≥75 years; 16% <50 years) who started therapy with
either simvastatin or atorvastatin.16 Low- to moderate-intensity
statins were associated with a greater reduction in LDL-C levels in
234
older than in younger individuals (39.0% vs. 33.8% for simvastatin
20 mg; 44.2% vs. 40.2% for atorvastatin 20 mg). The adjusted per-
centage reduction differences (PRDs) for initiators aged ≥75 years or
<50 years was 2.62 percentage points, and the association was consis-
tent for primary and secondary prevention (2.54 vs. 2.32 percentage
points, respectively), but smaller for initiators of high-intensity statins
(atorvastatin, 40 mg: 1.36 percentage points; atorvastatin, 80 mg:
−0.58 percentage points). Thus, low- to moderate-intensity statins
may be a more appropriate initial treatment in older adults at higher
risk for adverse events.
Treat-to-target or high-intensity statin
in patients with CAD
In patients with CAD, guidelines recommend intensive reduction of
LDL-C levels with statins to reduce future adverse CV events.12 , 17
Two therapeutic strategies can be used: initial treatment with high-
intensity statins to achieve at least a 50% reduction in LDL-C or
initial treatment with moderate-intensity statins and titration to a
specific level of LDL-C. The first strategy raises concerns about
individual variability in drug response and appearance of adverse
effects, while the second strategy may allow a tailored approach,
facilitate patient-physician communication, and enhance adherence
to therapy. The LODESTAR trial assessed whether a treat-to-
target strategy, with an LDL-C level between 50 and 70 mg/dL
as target, is non-inferior to the use of high-intensity statin treat-
ment (rosuvastatin 20 mg, or atorvastatin 40 mg) in patients with
CAD.18 At 3-years follow-up, there were no differences in the LDL-
C levels and the treat-to-target LDL-C strategy was non-inferior
to a high-intensity statin therapy for the composite primary out-
come of all-cause death, MI, stroke, or coronary revascularization
(8.1% vs. 8.7%; P < 0.001 for non-inferiority). Thus, a treat-to-
target strategy may allow a tailored approach in response to statin
therapy.
In a subgroup analysis at 3 year follow-up, rosuvastatin (mean
dose 17.1 mg/day) and atorvastatin (mean 36 mg/day) showed
comparable efficacy for the composite primary outcome (2.6% vs.
2.3%; HR 1.06; 0.86–1.30; P = 0.58)19 despite a higher frequency
of subjects achieving LDL-C level <70 mg/dL in the rosuvastatin
than in the atorvastatin group. Interestingly, patients on rosuvastatin
had slightly lower mean LDL-C levels that those on atorvastatin
(1.8 vs. 1.9 mmol/L; P < 0.001), but were associated with a
higher incidence of new onset diabetes mellitus requiring antidia-
betic treatment (7.2% vs. 5.3%; HR 1.39; 1.03–1.87; P = 0.03) and
cataract surgery (2.5% vs. 1.5%; HR 1.66; 1.07–2.58; P = 0.02).
Given the known relationship between diabetes and cataract it
may be that the findings with regard to cataract are mediated by
diabetes.
A new step in the development of
proprotein convertase subtilisin/kexin
type 9 (PCSK9) inhibitors
Currently available PCSK9-targeting therapeutic options, including
monoclonal antibodies (evolocumab, alirocumab) and the small in-
terfering RNA (inclisiran), have demonstrated a 50–60% reduction in
LDL-C, when administered subcutaneously on top of statin therapy.20
MK-0616 is the first orally bioavailable, renally excreted, macrocyclic
peptide that binds to PCSK9. A recent phase 2b trial recruiting 375
patients with hypercholesterolaemia and a broad range of cardiovas-
cular risk factors reported that at 8 weeks MK-0616 (6–30 mg/day) led
to statistically significant reductions in LDL-C compared with placebo,
J. Tamargo et al.
with >55% placebo-adjusted reduction observed at doses ≥12 mg.21
Because of the small sample size and short follow-up, larger trials
are required to confirm the safety and efficacy of MK-0616 and its
potential as a valuable alternative to injectable PCSK9 inhibitors in
patients with hypercholesterolaemia.
Advances in the treatment of
overweight/obesity
Semaglutide in overweight or obese
patients without T2D
Semaglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist ap-
proved as an adjunct to reduced calories diets and increased physical
activity for chronic weight management in: (i) adults with obesity
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[body-mass index (BMI) ≥30 kg/m2 ] or overweight (≥27–29.9 kg/m2 )
and weight-related complications (e.g. T2D), hypertension, dyslipi-
daemia, obstructive sleep apnoea, or CV disease, (ii) adolescents from
12 years of age with a BMI at ≥95th percentile for their age and gender
(obesity) and who weigh more than 60 kg. Two recent trials compared
the efficacy and safety of semaglutide versus placebo in overweight or
obese adults without T2D.
Semaglutide reduces the risk of adverse CV events in patients with
T2D, but whether it can reduce CV risk associated with overweight
and obesity in patients without T2D have not been studied. The SE-
LECT CV outcome trial randomized 17,604 overweight patients with
preexisting CVD and BMI ≥27 kg/m2 , but without T2D, to semaglu-
tide (2.4 mg s.c., once-weekly) or matching placebo.22 Semaglutide
reduced the incidence of 3-point MACE (CV death, non-fatal MI,
and non-fatal stroke) by 20% (6.5 vs. 8.0%; HR 0.80; 0.72–0.90; P <
0.001), but semaglutide was more often discontinued than placebo
(16.6% vs. 8.2%; P < 0.001), particularly due to gastrointestinal
(10.0% vs. 2.0%; P < 0.001) and metabolic adverse events (1.2%
vs. 0.3%; P < 0.001) (Table 3). The OASIS trial randomized 667
adults with a BMI ≥30 kg/m2 , or at least 27 kg/m2 with bodyweight
(BW)-related complications and comorbidities to oral semaglutide
(50 mg od) or placebo.23 After 68 weeks, the reduction in mean
BW from baseline was −15·1% with semaglutide vs. −2.4% with
placebo (−12.7 percentage points; −14.2 to −11.3; P < 0.0001)
and more participants reached BW reductions of ≥5% (85 vs. 26%),
≥10% (69 vs. 12%), ≥15% (54 vs. 6%), and ≥20% (34 vs. 3%) with
semaglutide (all P < 0.0001). Gastrointestinal adverse events were
more frequent in patients treated with semaglutide (80 vs. 46% with
placebo). Thus, in overweight or obese adults without T2D, semaglu-
tide produced a clinically meaningful decrease in BW compared with
placebo.
HF with preserved ejection fraction (HFpEF) is increasing in preva-
lence, especially in obese patients, but the effects of BMI lowering
drugs have never been analysed in this population. The STEP-HFpEF
randomized 529 patients with HFpEF and a BMI ≥30 kg/m2 to
semaglutide (2.4 mg s.c. once-weekly) or placebo for 52 weeks.24
As compared with placebo, semaglutide reduced BW (13.3 vs. 2.6%;
P > 0.001), improved patient-oriented quality of life (QoL) out-
comes, including the Kansas City Cardiomyopathy Questionnaire
(16.6 vs. 8.7 points; P < 0.001) and 6-min walk distance (21.5
vs. 1.2 m; P < 0.001), reduced NT-proBNP (−20.9 vs. −5.3; P
< 0.05), and decreased CRP (49 vs. 9%; P < 0.001) levels. Thus,
in patients with HFpEF, semaglutide reduced BW and HF-related
symptoms, and improved exercise tolerance compared with placebo.
Whether the improvements in QoL were driven by weight loss is
uncertain. Although the trial was underpowered for major vascular
events, a reduction in HF hospitalization or urgent visit for HF was
detected (1 vs. 12 events; P < 0.05). These results support
New pharmacological agents and novel cardiovascular pharmacotherapy strategies
the need to perform further RCTs to study the effects of
new weight loss medications in patients with HFpEF, T2D, and
obesity.
Tirzepatide in patients with obesity and
T2D
Tirzepatide is a dual GLP-1 and glucose-dependent insulinotropic
peptide receptor (GIP) agonist indicated as an adjunct to diet and
exercise to improve glycaemic control in adults with T2D.25 In phase
2 studies in patients with T2D, tirzepatide produces clinically relevant
BW reduction, which justifies investigating its role in the treatment
of obesity. The SURMOUNT-2 dose-finding, phase 2 trial compared
the efficacy and safety of tirzepatide vs. placebo in 1514 adults
with overweight or obesity and T2D (mean BW, BMI, and glycated
haemoglobin: 100.7 kg, 36.1 kg/m2 and 8.02%, respectively).26 Patients
were randomized to once-weekly, subcutaneous tirzepatide (10 or 15
mg) or placebo. At week 72, tirzepatide reduced mean BW by 12.8%
(10 mg) and 14.7% (15 mg) vs. and placebo (3.2%), and decreased
HbA1c to <5.7% by 55.3% (15 mg) and 50.2% (10 mg) vs. placebo
(2.8%). BW reductions ≥15 and ≥20% were achieved in 51.8 and
34.0% of patients treated with 15 mg tirzepatide vs. 2.6 and 1.0% with
placebo. Compared with placebo, pooled doses of tirzepatide signifi-
cantly reduced systolic blood pressure (−7.2 vs. −1.0 mmHg), fasting
triglycerides (−28.6 vs. −5.8%), and non-HDL-cholesterol (−6.6 vs.
2.3%). Treatment discontinuation due to adverse events was 3.8%
in the 10 mg tirzepatide group and 7.4% in the 15 mg tirzepatide
group. Thus, once-weekly tirzepatide (10 and 15 mg) provided a
significant reduction in BW in adults with obesity and T2D, with a
safety profile that was similar to other incretin-based therapies for
BW management (Table 3).
In another RCT, 972 overweight or obese patients with at least one
obesity-related complication (excluding T2D), who achieved ≥5.0%
weight reduction after a 12-week intensive lifestyle intervention, were
randomized to tirzepatide or placebo.27 Mean BW reduction at week
72 was 18.4% with tirzepatide and 2.5% with placebo (P < 0.001).
More participants on tirzepatide than placebo achieved reductions
in BW of ≥10% (76.7% vs. 8.9%), ≥15% (65.4% vs 4.2%), and
≥20% (44.7% vs 2.2%), respectively (all P < 0.001). Thus, tirzepatide
caused a substantial additional BW reduction in patients with over-
weight/obesity following initial weight loss with intensive lifestyle
intervention.
SGLT2 inhibitors in patients with acute
MI without diabetes or chronic HF
There is an unmet need for new drugs that reduce the risk of MACE
and metabolic outcomes in patients with acute MI. The DAPA-MI
study randomized 4017 patients from two registries (SWEDEHEART
in Sweden and MINAP in the UK) with no T2D or chronic HF, with
acute MI and impaired left ventricular systolic function to dapagliflozin
(10 mg od) or placebo.28 The primary outcome was a hierarchical
composite using the win ratio analysis method. After 1 year of treat-
ment, the analysis of the primary hierarchical composite outcome
including all seven components resulted in significantly more wins
for dapagliflozin than for placebo (32.9% wins for dapagliflozin and
24.6% wins for placebo; win ratio, 1.34; 1.20–1.50; P < 0.001). This
benefit was mainly driven by the cardiometabolic components, adjudi-
cated hospitalization for HF, new diagnosis of T2D, NYHA functional
classification, and BW decrease ≥5% from baseline to the last trial
visit. However, the composite of time to CV death/hospitalization
for HF was similar in both treatment groups. However, because of
the exclusion of patients with T2D and chronic HF, the enrolled
235
population was at lower risk of CV events as compared with other
MI trials.
Chinese traditional medicine in
the treatment of acute MI
Tongxinluo capsule is a medicine consisting of 12 traditional Chinese
herbs and insects used for the treatment of CV diseases, particularly
CAD, combined with conventional western medicine. Although the
active ingredient(s) and the exact mechanism of action remain un-
clear, its cardioprotective effects have been related to the content in
peoniflorin, ginsenoside Rg1 and ginsenoside Rb19.29 , 30 The efficacy
and safety of Tongxinluo was studied in 3777 patients with recent
(wihin 24 h of symptom onset) ST-segment elevation myocardial
infarction (STEMI).29 , 30 Tongxinluo as an adjuvant therapy in addition
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to guideline-directed treatments reduced the primary end point of
30-day major adverse cardiac and cerebrovascular events (MACCEs),
a composite of cardiac death, myocardial reinfarction, emergent coro-
nary revascularization, and stroke (3.4 vs. 5.2%; HR 0.64; 0.47–0.88;
P = 0.001), as well as secondary outcomes of cardiac death, myocar-
dial reinfarction and severe STEMI complications, but there were no
differences in stroke.31 By 1 year, the Tongxinluo group continued to
have lower rates of MACCEs (0.64; 0.49–0.82), cardiac death (0.73;
0.55–0.97; P = 0.03), MI (0.26; 0.10–0.67; P = 0.005), and stroke (0.44;
0.21–0.92; P = 0.03), with no significant diffrences in major bleeding.
Thus, among Chinese patients with STEMI, the use of Tongxinluo, as
an adjuvant therapy to STEMI guideline-directed treatments, signifi-
cantly improved both 30-day and 1-year clinical outcomes. Overall, the
suboptimal use of guideline-directed medical therapy (GDMT) during
hospitalization (β-blockers, angiotensin-converting enzyme inhibitors
or angiotensin receptor blockers were prescribed only in 64 and 51%
of patients during hospitalization), which was lower at discharge, could
have affected the magnitude of the benefit of Tongxinluo. Thus, the ef-
fects of Tongxinluo should be further assessed in suitable populations
with better adherence to guideline-directed therapy.
Sotatercept, a new approach for the
treatment of pulmonary arterial
hypertension
Sotatercept is a first-in-class fusion protein consisting of the Fc do-
main of human IgG linked to the extracellular domain of human
activin receptor type IIA (ActRIIA), which acts as a ligand trap for
members of the transforming growth factor β superfamily members,
thus restoring the balance between the growth-promoting activin
growth differentiation factor and the growth-inhibiting bone mor-
phogenetic protein pathways.32 The STELLAR trial studied the effect
of sotatercept (0.3–0.7 mg/kg every 3 weeks) vs. placebo in 163
adult patients with pulmonary arterial hypertension [World Health
Organization (WHO) functional class II or III].33 The primary endpoint
was the change from baseline at week 24 in the 6-min walk distance.
Sotatercept, added to background therapy, significantly improved ex-
ercise capacity as assessed by 6-min walk distance (34.4 vs. 1.0 m in
the placebo group), pulmonary vascular resistances, WHO functional
class, NT-proBNP levels, risk of death assessed by means of the simpli-
fied French risk model, and the physical impacts and cardiopulmonary
symptoms domain scores of the PAH-SYMPACT quality-of-life tool.
Adverse events that occurred more frequently with sotatercept
than with placebo included bleeding events (mainly epistaxis and
gingival bleeding), dizziness, telangiectasia, increased haemoglobin lev-
els, thrombocytopaenia, and increased blood pressure. The main
limitations of the study include the enrolment of patients in WHO
functional class II or III patients with certain forms of pulmonary
236
arterial hypertension and with baseline pulmonary vascular resistance
values of at least 400 dyn s cm−5 (which is not reflective of the broader
haemodynamic definition of pulmonary arterial hypertension in clin-
ical guidelines);34 the short period of treatment does not allow to
establish the long-term durability of treatment response; and the trial
was neither designed nor powered to study the effects of sotatercept
on mortality.
New head-to-head studies in
different clinical settings
Combining loop with thiazide diuretics
for decompensated HF
Loop diuretics are the cornerstone of treatment aimed to reduce
volume overload and congestion in patients with acute HF (AHF),
but some patients exhibit fluid overload despite being treated with
high doses of loop diuretics. In these patients, the combination
of loop with thiazide diuretics (the so-called ‘sequential nephron
blockade’) significantly increases diuresis, but the safety and efficacy
of this approach in patients hospitalized with AHF is unknown. The
CLOROTIC trial randomized 230 patients with AHF to receive ei-
ther hydrochlorothiazide (HCTZ 25–100 mg) or placebo added to
background i.v. furosemide.35 Patients on HCTZ showed greater
24 h diuresis (1775 vs. 1400 mL; P < 0.05) and a stronger decrease
in BW at 72 and 96 h post-randomization compared with those
on placebo [2.3 vs. 1.5 kg; P < 0.002]. However there were no
differences in patient-reported dyspnoea between groups. Of note,
patients on HCTZ more frequently presented with impaired renal
function (increase in creatinine 26.5 μmoL/L or decrease in eGFR
>50%; 46.5% vs. 17.2% on placebo; P < 0.001). Unfortunately, neither
renal function nor electrolytes were monitored during the follow-up,
therefore it is unclear if renal function decline is only a transient event.
There were no differences in mortality, length of hospital stays or
rehospitalization between groups. Thus, further data on outcome and
safety are clearly warranted.36
Torsemide vs. furosemide after discharge
in patients hospitalized with HF
Furosemide is the most frequently used loop diuretic in patients
with HF, but torsemide has a higher bioavailability (80–100% vs. 10–
100%, which allows equivalency 1:1 between oral and i.v. doses, while
furosemide equivalence is 2:1) and it has a longer half-life (3–6 vs. 1.5–
3 h, respectively) than furosemide.37 Additionally, in preclinical studies
torsemide reduced myocardial fibrosis, aldosterone secretion, and
plasma NT-proBNP levels, and improved ventricular remodelling.38
The TRANSFORM-HF compared torsemide and furosemide on all-
cause mortality in 2859 patients hospitalized for HF regardless of
ejection fraction.39 Although the pre-specified primary hypothesis
was that torsemide would reduce all-cause mortality by 20% com-
pared with furosemide, 12 months post-randomization there were
no differences in all-cause mortality (26.1% vs. 26.2%; HR 1.02; 0.89–
1.18) or all-cause hospitalization (HR 0.94; 0.84–1.07) among patients
with reduced, mildly reduced, or preserved ejection fraction between
groups. However, this study has important limitations. The actual
sample size was 50% smaller than per protocol and accordingly the
subgroup analyses might be strongly biased. Also, patient withdrawals
were much higher than predicted. In addition, discontinuation of loop
diuretic and crossovers during follow-up often occurred. Finally, the
selection of loop diuretic dose was left to clinician’s discretion. Thus,
future head-to-head studies are required to establish and validate the
value of individual loop diuretics.
J. Tamargo et al.
Safety of switching from oral vitamin K
antagonists to direct non-vitamin K oral
antagonists in older, frail patients
Cardioembolic stroke prevention with vitamin K antagonists (VKAs)
or direct non-vitamin K oral antagonists (DOACs) is vital for manage-
ment of atrial fibrillation (AF). DOACs are currently preferred because
they significantly reduced systemic embolism/stroke and intracranial
haemorrhage compared with warfarin, with a similar risk of major
extracranial bleeding.40 However, many older AF patients diagnosed
with frailty are treated with VKAs, mainly because this population was
excluded or was underrepresented in the pivotal trials with DOACs.
To assess whether frail old patients with AF treated with VKAs should
be switched to a DOAC, 1330 older AF patients with frailty (mean
age 83 years, median Groningen Frailty Indicator 4, mean CHA2 DS2-
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VASc score of 4) were randomized to switch from INR-guided VKA
treatment to a DOAC or to continued VKA treatment.41 Patients
with an eGFR <30 mL/min/1.73 m2 or with valvular AF were ex-
cluded. Of importance, the trial was halted prematurely due to safety
concerns, because switching from INR-guided VKA-management to
a DOAC-based treatment was associated with an increased the risk
of major and/or clinically relevant non-major bleeding complications
(HR 1.69; 1.23–2.32; P = 0.001) without a reduction in thromboem-
bolic events (1.26; 0.60–2.61). The excess of bleeding occurred after
100 days and increased with time. The HR of switching from a VKA
to a DOAC for major bleeding was 1.52 (0.81–2.8), for the composite
outcome ischaemic and/or haemorrhagic stroke 1.30 (0.59–2.87), and
for all-cause mortality 0.96 (0.64–1.45). Nevertheless, it should be
mentioned that during the study the range of TTR (time in therapeutic
range) levels for older patients was between 65.3 and 74.0%. Thus, the
results of this study suggest that without a clear indication, switching a
patient, who is stable on INR-guided VKA management (TTR around
70%) to a NOAC should not be considered in older AF patients living
with frailty, because of the higher risk of major or clinically relevant
non-major bleedings. Nevertheless, and given the significant advances
of DOACs vs. warfarin, further studies are needed to assess whether
frail AF patients with a low TTR could benefit from switching from
VKA to a NOAC and establish the optimal anticoagulation strategy
for elderly and frail AF patients.
Abelacimab vs. rivaroxaban in patients
with AF
The AZALEA-TIMI-71 trial was a phase 2, dose-finding study com-
paring the effects two doses of abelacimab (once-monthly s.c.), a
novel factor XI/XIa inhibitor, with rivaroxaban in 1287 patients with
AF being at moderate risk for ischaemic stroke (median CHA2 DS2 –
VASc Score 5).42 The trial was terminated early due to greater than
anticipated reduction in major and clinically relevant non-major bleeds
in the abelacimab group compared to rivaroxaban. The combined rate
of major or clinically relevant non-major bleeding was 8.1% per 100
patient-year with rivaroxaban and 1.9% (HR 0.23; 0.13–0.42) and 2.7%
(0.33; 0.19–0.55) per 100 patient-year with 90 and 150 mg abelacimab,
respectively (P < 0.001 for both). The incidence rate of major bleeding
was 3.7% in the rivaroxaban group and 0.7% (0.19; 0.07–0.50; P <
0.001) and 1.0% (0.26; 0.11–0.61; P = 0.002) in the 90- and 150-mg
abelacimab groups. The corresponding incidence rates of gastroin-
testinal bleeding were 2.1, 0.1, and 0.1% (both P = 0.008) and those of
clinically relevant non-major bleeding were 4.6, 1.1 (0.25; 0.11–0.54; P
< 0.001), and 1.8% (0.39; 0.21–0.75; P = 0.004), respectively. The net
clinical outcome (composite of ischaemic stroke, systemic embolism,
major or clinically relevant non-major bleed, and all-cause death) was
11.1% for rivaroxaban and 5.6. (0.49; 0.34–0.73; P < 0.001) and
5.5% (0.49; 0.33–0.77; P < 0.001) for 90 and 150 mg of abelacimab.
However, the study was not powered for detecting differences in
New pharmacological agents and novel cardiovascular pharmacotherapy strategies
cardioembolic events. These results indicate that at the two doses
tested abelacimab rarely causes bleeding events among patients with
AF and a high CHA2 DS2 -VASc score compared to rivaroxaban. The
ongoing phase 3 trial (LILAC-TIMI 76, NCT05712200) assesses the
safety and efficacy of abelacimab 150 mg vs. placebo among patients
with AF deemed unsuitable for anticoagulation.
Apixaban vs. aspirin for stroke
prevention of subclinical AF
Subclinical AF is a short-lasting asymptomatic event that can be only
detected by long-term continuous electrocardiografic (ECG) moni-
toring with pacemakers or defibrillators. Although subclinical AF is
associated with a 2.5-fold increase in the risk of stroke, oral anticoag-
ulation is of uncertain benefit. The ARTESIA trial tested the efficacy
of apixaban (5 mg bid) vs. aspirin (81 mg od) in 4012 patients (31.6%
women) with a mean CHA2 DS2 -VASc score of ∼4 and subclinical
AF lasting 6 min–24 h.43 The trial medication was discontinued, and
anticoagulation started if subclinical AF persisted >24 h or clinical AF
developed. After 3.5 ± 1.8 years follow-up, the primary endpoint of
stroke or systemic embolism occurred in 55 patients in the apixaban
group (0.78% per patient-year) and in 86 patients in the aspirin group
(1.24% patient-year; HR 0.63; 0.45–0.88; P = 0.007; NNT 217). In the
on-treatment population, the rate of major bleeding was 1.71 and
0.94% per patient-year in the apixaban vs. aspirin groups, respectively
(HR 1.80; 1.26–2.57; P = 0.001, NNH 130). No differences between
the apixaban and aspirin groups were observed in terms of all-cause
death or CV death. Thus, among patients with subclinical AF, even
if apixaban resulted in a lower risk of stroke or systemic embolism
than aspirin, increased risk of major bleeding outweighed the benefit
as compared with aspirin.
Trials with negative outcome
Colchicine prevention of perioperative
AF and myocardial injury after
non-cardiac surgery
The activity of the components of the NLRP3 (NACHT-, LRR-
and pyrin domain-containing 3) inflammasome is enhanced in
atrial cardiomyocytes of AF patients44 , 45 and higher levels of pro-
inflammatory biomarkers are associated with an increased risk of
perioperative AF and myocardial injury after non-cardiac surgery
(MINS).46 , 47 After thoracic surgery, these two complications are
associated with worse postoperative outcomes. To test the hy-
pothesis that an anti-inflammatory drug might reduce the incidence
of AF and MINS in patients undergoing major thoracic surgery,
Conen et al.48 enrolled 3209 patients scheduled for non-cardiac
thoracic surgery with general anaesthesia, and were expected to
require at least one overnight hospital stay after surgery. Pa-
tients were randomized to colchicine (0.5 mg bid) or matching
placebo, starting within 4 h before surgery and continuing for
10 days. Clinically important AF occurred in 6.4% of patients assigned
to colchicine and 7.5% of patients assigned to placebo (HR.0.85;
0.65–1.10; P = 0.22) and MINS was present in 18.3% and 20.3% of
patients, respectively (HR 0.89; 0.76–1.05; P = 0.16). Non-infectious
diarrhoea was more common in the colchicine than the placebo group
(8.3 vs. 2.4%; HR 3.64, 2.54–5.22; P < 0.001). However, in a post-hoc
analysis colchicine reduced the risk of the composites of MINS and
clinically important AF (0.84; 0.73–0.97; P = 0.02) and of vascular
mortality, nonfatal MINS, non-fatal stroke, and clinically important
AF (0.83; 0.72–0.96; P = 0.01). Thus, given the major limitations of
post-hoc analyses and a negative RCT, further studies are required
to evaluate the benefit/risk profile of colchicine for the prevention of
perioperative AF and MINS.
237
Patients with atrial high-rate episodes
are better managed without
anticoagulation
Atrial high-rate episodes (AHREs) are atrial tachyarrhythmias with a
rather short duration detected by continuous rhythm monitoring by
pacemakers, defibrillators, or implantable cardiac monitors.49 They
occur in 10–30% of elderly patients without AF and increase the risk
of stroke, but whether the occurrence of AHREs in patients without
AF justifies the initiation of oral anticoagulant therapy (OAT), partic-
ularly in patients with risk factors for stroke or in those who have
AHREs that last longer than 24 h, is not known. The NOAH-AFNET
6 trial compared the efficacy and safety of edoxaban vs. no OAT in
2536 elderly patients with AHREs lasting for at least 6 min and with
risk factors for stroke, but without ECG-documented AF.50 The trial
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was terminated prematurely based on safety concerns, but with the
planned enrolment completed. Edoxaban did not significantly reduce
the composite of CV death, stroke, or systemic embolism vs. placebo
(3.2% vs. 4.0% per patient-year; HR 0.81; 0.60–1.08; P = 0.15) and the
incidence of stroke was 1% per patient-year in both groups. Edoxaban,
however, increased the incidence of a composite of all-cause death or
major bleeding (5.9% vs. 4.5% per patient-year; HR 1.31; 1.02–1.67;
P = 0.03) driven by an increase in major bleeding (2.1% vs. 1.0%;
HR 2.1; 1.30–3.38; P = 0.002). These results may suggest that elderly
patients with AHREs, but without ECG-documented AF, are better
managed without OAT until further ECG monitoring documents pres-
ence of AF. The outcome of NOAH-AFNET 6 contrasts the results
of the ARTESIA trial, which showed that in patients with subclinical
AF (AHRE shorter than 24 h) apixaban reduced the risk of stroke
or systemic embolism compared to aspirin, but at the expense of a
higher risk of major bleeding.43 Further randomized trials are required
to validate the efficacy of OAT for the prevention of both short (≤24
h) and long (≥24 h) AHREs and the related risk of stroke and systemic
embolism.
Ferric carboxymaltose in HF with iron
deficiency
The HEART-FID trial assessed the long-term safety and efficacy
of ferric carboxymaltose in 3014 ambulatory patients with heart
failure with reduced ejection fraction (HFrEF) on maximally toler-
ated background therapy for ≥2 weeks before randomization and
iron deficiency (defined as ferritin levels <100 ng/mL or a level of
100–300 ng/mL with a transferrin saturation of <20%), and either
hospitalization for HF within the previous 12 months or elevated
natriuretic peptide levels.51 Ferric carboxymaltose was administered
every 6 months based on haemoglobin and iron indexes. After
12 months, there was no apparent difference between ferric carboxy-
maltose and placebo with respect to the hierarchical composite of
death, hospitalization for HF, or 6-min walk distance. Ferric carboxy-
maltose appeared to be safe and the number of patients with serious
adverse events during the study was similar to placebo (27.0% vs.
26.2%). These negative results could be due to differences in study
design (including criteria for iron deficiency), enrolled population and
the dose and timing of administration of ferric carboxymaltose.51
Inferior efficacy of asundexian vs.
apixaban for prevention of stroke and
systemic embolism in AF patients
The phase III OCEANIC-AF trial compared asundexian and
apixaban in patients with AF at risk for stroke to determine
the efficacy of asundexian for prevention of stroke and
systemic embolism. However, based on the recommendations
of the studyʼs Independent Data Monitoring Committee,
238
this trial was recently stopped due to an inferior efficacy of
asundexian vs. apixaban (https://www.bayer.com/media/en-us/
oceanic-af-study-stopped-early-due-to-lack-of-efficacy/). Available
safety data are consistent with previously reported safety profiles of
asundexian.
New developments with fixed-dose
combination for the prevention and
treatment of CVDs
Fixed-dose combinations (polypill) that include key generic drugs that
improve CV clinical outcomes have been proposed as a simple prac-
tical approach in primary and secondary prevention. CV polypills are
also expected to facilitate the implementation of and adherence to
evidence-based treatments, especially in resource-limited settings.
The Polycap Study 3 (TIPS-3, NCT01646437) analysed whether
a polypill (containing multiple antihypertensive drugs and a statin),
aspirin, or their combination could reduce cognitive and functional
decline in 5713 individuals older than 65 years being at an inter-
mediate risk of CV diseases (86% had hypertension, and 32% had
glucose intolerance).52 Cognitive assessments included the Montreal
Cognitive Assessment, the Digit Symbol Substitution Test to assess
psychomotor speed, attention, and executive function, and the Trail
Making Test Part B to assess attention. Functional status was assessed
using the Standard Assessment of Global Everyday Activities. Dur-
ing a 5-year follow-up, a polypill with or without aspirin, was not
associated with reduced cognitive outcomes, but was associated with
reduced functional decline. The SMAART phase 2 open- label trial
(NCT03329599) performed in Ghana tested the efficacy of a CV
polypill containing 5 mg ramipril, 50 mg atenolol, 12.5 mg HCTZ,
20 mg simvastatin, and 100 mg aspirin administered as two cap-
sules once per day for 12 months as compared with usual care on
carotid intima-media thickness in 149 patients who had an ischaemic
stroke within the previous 2 months.53 The mean change in carotid
intima-media thickness at month 12 was −0.092 mm (−0.130 to
−0.051) in the usual care group vs. −0.017 mm (−0.067–0.034) in
the polypill group (P = 0.11). Thus, the polypill regimen resulted in
a similar regression in subclinical atherosclerosis compared with the
tailored drug regimen, but adverse events (including cough-induced
by angiotensin-converting enzyme inhibitors, blood pressure <90/60
mmHg and bradycardia) occurred more frequently in the polypill than
in the usual care group (11% vs. 3%: P = 0.049). However, individual
frequencies of serious adverse events (deaths, hospitalizations, and
seizures) were not significantly different between the two groups.
A systematic review and meta-analysis of 7 trials with a total of
1918 patients assessed the efficacy and safety of low-dose combi-
nation (LDC) antihypertensives (consisting of 3 or 4 blood pressure
lowering drugs) for the management of hypertension.54 The primary
outcome was mean reduction in systolic BP (SBP) between LDC
and monotherapy, usual care or placebo. At 4–12 weeks follow-up,
LDC was associated with a greater mean reduction in SBP than initial
monotherapy or usual care (mean reduction, 7.4 mm Hg; 4.3–10.5)
and placebo (mean reduction, 18.0 mm Hg; 15.1–20.8). LDC was
associated with a higher proportion of participants achieving BP
<140/90 mm Hg compared to both monotherapy or usual care (66%
vs. 46%; RR, 1.40; 1.27–1.52) and placebo (54% vs. 18%; RR, 3.03;
1.93–4.77). Thus, a LDC-containing 3 or 4 antihypertensive drugs was
an effective and well-tolerated BP-lowering treatment option for the
initial or early management of hypertension.
Finally, a meta-analysis explored whether the effects of fixed-dose
combination treatment on the risk of developing CV disease differ in
patents with normal (≥60 ml/min/1.73 m2 ) compared to low eGFR
(<60 ml/min/1.73 m2 ).55 Drug combination therapies consisted of
at least two BP-lowering drugs and a statin, with or without aspirin
J. Tamargo et al.
vs. placebo or minimal care. The primary composite outcome was
time to first occurrence of a combination of CV death, MI, stroke,
or arterial revascularization. During a median follow-up of 5 years,
in the normal eGFR group the primary outcome occurred in 3%
participants in the treatment group compared with 5% in the control
group (HR 0.68; 0.57–0.81; P < 0.001). Similarly, in the low eGFR
group the primary outcome occurred in 4% and 8% of patients,
respectively (0.49; 0.36–0.66; P < 0.001; P for interaction 0.047).
Thus, a fixed-dose combination treatment strategy is effective and
safe at preventing CV diseases, irrespective of eGFR, although the
risk reduction was stronger in individuals with low eGFR.
The negative impact of
polypharmacy
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Polypharmacy (commonly defined as concomitant use of ≥5
medications) is a common situation, particularly in elderly patients
with comorbidities. Of note, more than 40% of these patients are
taking drugs which may modify the use of GDMT, thereby increasing
the risk of adverse effects, DDIs, and non-adherence.56
Patients on polypharmacy are less likely
to receive GDMT for HF
To analyse the impact of polypharmacy, a post-hoc analysis of the
GUIDE-IT trial assessed the association between polypharmacy (≥5
medications excluding HFrEF GDMT) and odds of receiving opti-
mal GDMT over time in 891 patients with HFrEF.57 The outcome
was optimal triple therapy GDMT (concurrent administration of a
renin-angiotensin aldosterone blocker and beta-blocker at 50% of
the target dose and a mineralocorticoid receptor antagonist at any
dose). The median number of non-GDMT medications for other
indications at baseline was 4 [interquartile range (IQR): 3–6] and
46.5% of participants received polypharmacy. These patients were
older and had a higher burden of cardiac/non-cardiac comorbidities,
greater severity of HF and worse QoL. After 1 year, patients with-
out polypharmacy at baseline were more likely to achieve optimal
GDMT [OR 1.16 (1.12–1.21) per 1-month increase; P < 0.001] but
not patients with polypharmacy. Thus, patients with HFrEF who are
on non-GDMT polypharmacy have lower odds of achieving optimal
GDMT on follow-up. Implementation of multidisciplinary interven-
tions to lower non-GDMT polypharmacy burden are required to
improve optimal GDMT therapy in patients with HFrEF.
Effect of polypharmacy in AF patients
treated with OAT
A meta-analysis of RCTs and observational studies compared the risks
of stroke, all-cause death, and bleeding between DOACs and VKAs
in 767,544 AF patients with (53.3%) or without polypharmacy.58
Moderate and severe polypharmacy were defined as the use of 5–8
and ≥9 drugs, respectively. There were no differences in the rates
of stroke or systemic embolism between polypharmacy and no-
polypharmacy AF patients, but moderate and severe polypharmacy
increased the risk of all-cause death and major bleeding compared
with no-polypharmacy in AF patients. The use of DOACs as com-
pared with VKAs significantly reduced the risks of stroke or systemic
embolism in AF patients with moderate (HR 0.77; 0.69–0.86) and
severe polypharmacy (0.76; 0.69–0.82) but there was no significant
difference in the risk of major bleeding in patients with moderate
and severe polypharmacy between the two groups. DOACs were
associated with a reduction in any bleeding, but there were no sig-
nificant differences in the risk of ischaemic stroke, all-cause death,
and gastrointestinal bleeding compared with VKAs in AF patients
with moderate and severe polypharmacy. Compared with VKAs,
Table 4 New drugs in phase 2 and 3 of clinical development

Disease Drug Mechanism of action Clinical trials (Acronym, NCT)

...................................................................................................................................................................................................................................................................................
Hypertrophic cardiomyopathy Aficamten Cardiac myosin inhibitor Phase 2: HFpEF (EMBARK-HFpEF, NCT04766892)
Phase 3: HCM (FOREST-HCM, NCT04848506), non-obstructive HCM (ACACIA-HCM,
NCT06081894), obstructive HCM (SEQUOIA-HCM, NCT05186818; MAPLE-HCM,
NCT05767346)
Mavacamten Cardiac myosin inhibitor Phase 3: non-obstructive HCM (ODYSSEY-HCM, NCT05582395);
obstructive/non-obstructive HCM (NCT03723655)
Primary dilated Danicamtiv Selective allosteric cardiac myosin activator Phase 2: NCT04572893
cardiomyopathy
Transthyretin amyloidosis Acoramidis Selective kinetic stabilizer of WT and V122I-TTR Phase 3: ATTRibuteCM (NCT03860935; NCT04622046)
with cardiomyopathy Eplontersen ASO to inhibit the production of hepatic TTR Phase 3: CARDIOTTRansform (NCT04136171)
protein
Vutrisiran siRNA that causes degradation of mutant and Phase 3: HELIOS-B (NCT04153149)
wild-type TTR mRNA
Ar terial hyper tension Aprocitentan Dual endothelin receptor antagonist Phase 3: resistant hypertension (PRECISION, NCT03541174)
IONIS -AGT-LR X LICA to target to AGT mRNA Phase 2: controlled (NCT03714776) or uncontrolled hypertension (NCT04083222)
Baxdrostat Highly selective inhibitor of aldosterone synthase Phase 3: resistant hypertension (NCT06034743)
Zilebesiran siRNA to inhibit hepatic angiotensinogen Phase 2: mild to-moderate hypertension not adequately controlled (KARDIA-1,
synthesis NCT04936035; KARDIA-2, NCT05103332).
Pulmonary arterial Sotatercept Fusion protein of the extracellular domain of the Phase 3: PAH (SOTERIA, NCT04796337; ZENITH, NCT04896008; HYPERION,
New pharmacological agents and novel cardiovascular pharmacotherapy strategies

hypertension human activin receptor type IIA and the Fc NCT04811092), PAH and HFpEF (CADENCE, NCT04945460)
domain of IgG1
Antiinflammatory drugs Mitiperstat Selective, covalent myeloperoxidase inhibitor Phase 2: HFpEF (SATELLITE, NCT03756285)
Ziltivekimab Fully human mAb against the IL-6 ligand Phase 3: ASCVD and CKD (ZEUS trial, NCT05021835)
Dyslypidaemia ARO-ANG3 siRNA to target mRNA transcripts from the Phase 2: mixed dyslipidaemia (ARCHES-2, NCT04832971), HoFH (GATEWAY,
ANGPTL3 gene NCT05217667)
CSL112 Human plasma-derived apoA-I formulated with Phase 3: ACS (AEGIS-II, NCT03473223)
phosphatidylcholine
Lepodisiran GalNAc-conjugated siRNA targeting Lp(a) Phase 2: elevated Lp(a) (NCT05565742)
Lerodalcibep Small recombinant fusion protein of a Phase 3: high risk CVD patients (LIBerate-VI, NCT05004675; LIBerate-CVD, NCT04797247;
PCSK9-binding domain (adnectin) and human LIBerate-HR, NCT04806893, LIBerate-OLE, NCT04798430, LIBerate-FH, NCT04797104)
serum albumin
LY3819469 siRNA targeting Lp(a) Phase 2: elevated Lp(a) (NCT05565742)
MK-0616 Oral PCSK9 Inhibitor Phase 3: hipercolesterolaemia (CORALreef Lipids, NCT05952856), HeFH (CORALreef HeFH,
NCT05952869), and MACE (CORALreef Outcomes, NCT06008756)
Olezarsen LIgand Conjugated ASO (LICA) targeting Phase 3: (a) FCS (BALANCE, NCT04568434; NCT05185843, NCT05130450). (b) Severe
apoC-III hypertriglyceridaemia (NCT05079919, NCT05681351, NCT05610280, NCT05552326,
NCT05355402)
239

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 240

Table 4 Continued

Disease Drug Mechanism of action Clinical trials (Acronym, NCT)

...................................................................................................................................................................................................................................................................................
Olpasiran siRNA that prevents assembly of Lp(a) Phase 3: ASCVD (OCEAN(a) DOSE, NCT05581303)
Pelacarsen ASO targeting the mRNA transcribed from the Phase 3: CVD [Lp(a)HORIZON, NCT04023552; NCT05305664; OLE, NCT05900141).
LPA gene Phase 2: calcific aortic valve stenosis (NCT05646381)
Recaticimab Long-acting humanized IgG1 monoclonal Phase 3: non-familial hypercholesterolaemia and mixed hyperlipidaemia uncontrolled with
anti-PCSK9-antibody due to YTE mutation in statin therapy (REMAIN-2, NCT04885218)
Fc region
Solbinsiran N-GalNAc conjugated DsiRNA designed to Phase 2: mixed dyslipidaemia (MUIR study, NCT05089084; PROLONG-ANG3,
target ANGPTL3 NCT05256654; NCT05413135), severe hypertriglyceridaemia (SHASTA-2, NCT04720534)
Phase 3: FCS (PALISADE, NCT05089084; NCT05902598).
Tafolecimab Fully human IgG2 PCSK9 monoclonal antibody Acute coronary syndrome undergoing PCI (NCT06096909)
Zerlasiran siRNA against Apo-A Phase 2: at high risk of ASCVD events (NCT05537571)
Obesity Cagrilintide Long-acting amylin analogue Phase 3: T2D and increased body weight (REDEFINE 2, NCT05394519: REDEFINE 5,
NCT05996848)
Semaglutide GLP-1 agonist Phase 3: HF, obesity, and T2D (STEP HFpEF DM, NCT04916470)
Tirzepatide Dual GLP-1 agonist and GIP agonist Phase 3: overweight/obesity without DM (SURMOUNT-MMO, NCT05556512;
NCT06075667), MACE in patients with T2D (SURPASS-CVOT, NCT04255433), and
HFpEF and obesity (SUMMIT, NCT04847557).
Phase 2: T2D and obesity (NCT06037252), overweight/obesity and CKD ± T2D
(TREASURE-CKD, NCT05536804)
Factor XI inhibitors: Abelacimab Binds to the catalytic domain of FXI and Phase 2: AF vs. rivaroxaban (AZALEA-TIMI 71, NCT04755283)
Monoclonal antibodies prevents its activation Phase 3: (a) ischaemic stroke or systemic embolism in patients with AF (LILAC-TIMI 76,
NCT05712200). (b) CAT vs. apixaban (ASTER, NCT05171049), and vs. dalteparin
(MAGNOLIA, NCT05171075)
MK-2060 Anti-FXI IgG mAb Phase 2: ESRD on haemodialysis (MK-2060-007, NCT05027074)
Osocimab Binds to the catalytic domain of FXIa and inhibits Phase 2: ESKD on haemodialysis vs. placebo (CONVERT, NCT04523220)
its activation
REGN9933 Binds and inhibits FXIa Phase 2: TKA vs. enoxaparin and apixaban (NCT05618808)
Xisomab Recombinant antibody that binds to FXI and Phase 2: CAT prevention in patients on chemotherapy (NCT04465760); ESKD on
blocks its activation by FXIIa haemodialysis (NCT03612856)
REGN9933 Binds and inhibits FXIa Phase 2: TKA vs. enoxaparin and apixaban (NCT05618808)
Factor XI inhibitors: Small Asundexian Target the active site on FXIa Phase 3: stroke prevention (OCEANIC-STROKE, NCT05686070)
molecules Milvexian Binds and inhibits the FXIa catalytic active site Phase 3: stroke vs. placebo (LIBREXIA-STROKE, NCT05702034) or vs. apixaban in patients
with AF (LIBREXIA-AF, NCT05757869); post-MI (LIBREXIA-ACS, NCT05754957)
Phase 2: stroke in patients receiving aspirin and clopidogrel after acute ischaemic stroke or
TIA (AXIOMATIC-SSP,NCT03766581)

Abbreviations: AGT, angiotensinogen; AF, atrial fibrillation; ANGPTL3, angiopoietin-like protein 3; Apo(a), apolipoprotein(a); ApoA-I, apolipoprotein A-I; ASCVD, atherosclerotic cardiovascular disease; ASOs, antisense oligonucleotides;
ATTR-CM, transthyretin amyloidosis with cardiomyopathy; CAT, cancer-associated thromboembolism; CRT, catheter-related thrombosis in cancer patients; DsiRNA, Dicer-substrate small interfering RNA; FCS, familial chylomicronaemia
syndrome; ESKD, end-stage kidney disease; HeFH, hipercolesterolaemia familiar heterocigota; HFpEF, HF with preserved ejection fraction; HoFH, homozygous familial hypercholesterolaemia; LICA, LIgand-Conjugated Antisense; MI,
myocardial infarction; mRNA, messenger RNA; N-gal, N-acetyl galactosamine; PCI, percutaneous coronary intervention; PCSK9, proprotein convertase subtilisin/kexin type 9; and TK A , total knee arthroplasty.
J. Tamargo et al.

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New pharmacological agents and novel cardiovascular pharmacotherapy strategies
the risk of intracranial haemorrhage was lower in patients with
moderate polypharmacy, but not in patients with severe polyphar-
macy in DOACs users. Thus, in patients with AF and polypharmacy,
DOACs showed advantages over VKAs in terms of prevention of
stroke or systemic embolism and any bleeding, and were compara-
ble to VKAs for major bleeding, ischaemic stroke, all-cause death,
intracranial haemorrhage, and gastrointestinal bleeding.
New cardiovascular drugs under
clinical development
Multiple drugs with different mechanisms of action are currently
evaluated in phase 2 (dose-finding) and phase 3 RCTs that analyse
their efficacy and safety in the prophylaxis and treatment of CV
diseases (Table 4). There is a fast and progressive rise in the num-
ber of biological products, including oligonucleotide drugs [antisense
oligonucleotides (ASOs), small interfering RNAs (siRNAs)], and mon-
oclonal antibodies (mAb), compared with small molecules that show
important differences in: (i) potency (mAb are more potent than small
molecules); (ii) route of administration [ASOs and mAb: parenteral
(s.c. or i.v.); small molecules: orally or i.v.)]; (iii) onset (mAb: immediate
or rapid when given i.v. or s.c., respectively; slow/delayed with siRNA;
small molecules: within 2–4 h after oral intake); (iv) biotransformation
(mAb and ASOs are not metabolized in the liver, but undergo a pro-
teolytic metabolism in the reticuloendothelial system and phagocytic
cells; small molecules: via hepatic cytochrome P450 isoforms); and,
(v) half-life (small molecules: 11–24 h and should be administered
once-/twice-daily; mAb: weekly or monthly). The clinical relevance
of these differences for the pharmacodynamic and pharmacokinetic
behaviour and thus for the efficacy and safety of biologicals remains
uncertain and should be determined in carefully designed phase 3
trials. All drugs under development listed in Table 4 may represent new
therapeutic approaches and can open unprecedented opportunities
for better treatment of CV diseases.
Conclusions
We have provided a summary of the most recent and relevant ad-
vances in CV pharmacology in 2023, including the approval of two
first-in-class drugs (colchicine and sotagliflozin), and an updated label
for mavacamten to reduce the need/eligibility for SRT in patients with
oHCM. The promise of a new and effective anticoagulant blocking fac-
tor XI(a) with lower bleeding risk has provided inconsistent evidence
from a phase 2 and an early-terminated phase 3 trials. New evidence
has been obtained with drugs already marketed for the treatment
of patients with hypercholesterolaemia (bempedoic acid, statins),
high BMI with or without T2D (semaglutide, tirzepatide), acute HF
(loop and thiazide diuretics), HFrEF (ferric carboxymalthose), HFpEF
(semaglutide), acute MI (dapagliflozin), and AF (colchicine, edoxaban).
The negative impact of polypharmacy on the use of GDMT was
confirmed in patients with HFrEF treated with VKAs or DOACs.
Finally, the large number of CV drugs being on investigation in phase 2
and 3 clinical trials may lead to the development of novel drugs for the
prevention, treatment, and management of CV diseases in the coming
years.
Funding
EU Grant Horizon 2020 MAESTRIA Consortium (grant number 965286
to D.D.), National Institutes of Health (R01-HL131517, R01-HL136389,
R01-HL089598, R01HL163277, R01HL160992, and R01HL165704 to
D.D.), and S2022/BMD-7229.
Conflict of interest: J.T.: none.
241
S. A .: This MS is being edited independently by a Guest Editor, Prof.
Gregory Lip, since
S. A . is the Editor-in-Chief of the EHJ-CVP.
C.B.: Board of speakers in Servier, Novo-Nordisk, Menarini Cor-
porate, EGIS.
C .C .: none.
E.C.: none.
G. A .: Speaker-fees from Boehringer-Ingelheim, Novartis, Bayer,
Sanofi, KRK A .
P.F.: Founder & CEO of Pharmahungary Group, a Group of R&D
companiesE. Grove: Speaker honoraria or consultancy fees from As-
traZeneca, Bayer, Boehringer Ingelheim, Bristol–Myers Squibb, Pfizer,
Novo Nordisk, Lundbeck Pharma and Organon. Investigator in clinical
trials sponsored by AstraZeneca, Idorsia or Bayer and unrestricted
research grants from Boehringer Ingelheim.
Downloaded from https://academic.oup.com/ehjcvp/article/10/3/219/7611692 by guest on 25 May 2024
E.L.G.: Speaker honoraria or consultancy fees from AstraZeneca,
Bayer, Boehringer Ingelheim, Bristol–Myers Squibb, Pfizer, Novo
Nordisk, Lundbeck Pharma and Organon. Investigator in clinical trials
sponsored by AstraZeneca, Idorsia or Bayer and unrestricted research
grants from Boehringer Ingelheim.
E.M.: none.
B.R.: none.
P.S.: Grants from Bayer, Daiichi Sankyo and Astra Zeneca, and
grants personal fees from Boehringer-Ingelheim outside the submitted
work.
A.G.S.: Speaker’s/consultancy honoraria from Merck/Schering-
Plough, BMS, UCB, Pfizer/Wyeth, Novartis, Lilly and Women’s
College Hospital, Toronto, Canada.
S.S.: Speaker’s/consultancy honoraria from Boehringer Ingelheim
Pharma GmbH, Novartis, Bristol–Myers Squibb, and AstraZeneca.
A.N.: Speaker’s/consultancy honoraria from Boehringer Ingelheim
Pharma GmbH, Bristol–Myers Squibb, Chiesi, Daiichi Sankyo, Pfizer,
Galapagos, Novo Nordisk.
J.C.K.: Speaker fees honoraria from Menarini Farmaceutica srl.
D.D.: Speaker’s/consultancy honoraria from Daiichi Sankyo and
AbbVie.
Data availability
The data underlying this review were taken from the quoted
references.
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