https://orcid.org/0000-0002-6424-9687
-
PDF
- Split View
-
Views
-
Cite
Cite
Ricardo Caballero, Eva Delpón, Juan Tamargo, News in cardiovascular pharmacotherapy from the ACC.24 Meeting, European Heart Journal - Cardiovascular Pharmacotherapy, Volume 10, Issue 4, July 2024, Pages 272–277, https://doi.org/10.1093/ehjcvp/pvae034
Close - Share Icon Share
Several interesting advances in cardiovascular pharmacotherapy were presented at the American College of Cardiology Annual Scientific Session (ACC.24) recently in Atlanta. The aim of this article is to briefly review the clinical studies that, in the authors’ opinion, were most relevant in the field. To simplify the presentation, the studies were grouped in those that achieved (positive clinical trials) or not (negative trials) the primary endpoints, and those that even when did not reach the primary endpoints observed some promising results that can be the basis for future studies. The main characteristics and limitations of the trials are summarized in Table 1.
| Trial . | Population . | Treatment . | Primary endpoint . | Results/Limitations . |
|---|---|---|---|---|
| 1. Positive clinical trials | ||||
| New investigational drugs | ||||
| Bridge-TIMI 73a1 NCT05355402 | Phase 2b, R, DB, PC 154 with moderate HTG (TG levels 150 to <500, median 241.5 mg/dL) plus high CV risk or severe HTG (TG levels ≥500 mg/dL) FU: 49 weeks Female: 42% | Olezarsen (50 or 80 mg) or placebo for an s.c. injection every 4 weeks | Per cent change in TG levels from baseline to 6 months | Olezarsen reduced TG levels by 49.3% and 53.1% (7.8% with placebo; P < 0.001 for both) and 85.7% and 93.3% of patients achieved a TG level <150 mg/dL, respectively. It also reduced APOC3 (64.2% and 73.2%, respectively), APOB (18% with both doses), and non-HDL-C, but not LDL-C, levels. Effects were maintained for 12 months. |
| LIBerate-HR2 NCT04806893 | Phase 3, R, PC, PA 922 with established or at high risk for CVD. Baseline average LDL-C 116 mg/dL; 84% on statins, 17% on ezetimibe; 45% with DM; 10% with FHo FU: 52 weeks Female: 47% | Lerodalcibep 300 mg s.c. once-monthly vs. placebo | Change in LDL-C at 52 weeks and average of LDL-C levels at weeks 50 and 52 | At 52 weeks, lerodalcibep reduced LDL-C levels (56.3% vs. 0.14% with placebo); 94% of patients achieved ≥50% reduction in LDL-C. At week 52, it also reduced APOB (43%) and lipoprotein (a) (33%). Similar proportion of patients abandoned the trial due to adverse events in both arms. |
| SHASTA 23 NCT04720534 | Phase 2b, PC, dose-ranging trial 229 with baseline fasting TG ≥500 and ≤4000 mg/dL (mean 897 mg/dL) and APOC3 of 32 mg/dL FU: 36 weeks after the second dose | Two s.c. injections of plozasiran (ARO-APOC3, 10, 25, or 50 mg) or placebo. The first injection was given on day 1; the second at week 12. | Percentage of change in fasting TG levels after 24 weeks | At 24 weeks, plozasiran dose-dependently reduced TG levels by 49%, 53%, and 57% (all P < 0.001), driven by placebo-adjusted reductions in APOC3 of 68%, 72%, and 77% (all P < 0.001), and 90.6% of patients treated with 25 or 50 mg of plozasiran achieved TG levels <500 mg/dL. |
| KARDIA-24 NCT05103332 | Phase 2, R, DB, PC 672 with uncontrolled hypertension (untreated SBP 155–180 mm Hg; treated SBP 145–180 mm Hg); 23% with DM. FU: 6 months Female: 43% | Zilebesiran 600 mg s.c. vs. placebo, added to indapamide (2.5 mg/day), amlodipine (5 mg/day), or olmesartan (40 mg/day) | Change in average 24 h ambulatory SBP at 3 months | Zilebesiran reduced SBP by 4–12 mm Hg. The average SBP reduction in the indapamide, amlodipine, and olmesartan groups was 18.5, 10.2, and 7.0 mm Hg (all P < 0.001). At 6 months, this difference persisted in the indapamide and amlodipine groups. |
| 2. Drugs already approved | ||||
| VICTORION-INITIATE5 NCT04929249 | Phase 3b, R. OL, PG 450 with established ASCVD and LDL-C ≥70 mg/dL or non-HDL-C ≥100 mg/dL despite maximally tolerated statin therapy. Mean baseline LDL-C 97.4 mg/dL. FU: 330 days Female: 31% | Inclisiran 300 mg s.c. on days 0, 90, and 270 vs. usual care prescribed at the treating provider's judgement | Per cent change from baseline in LDL-C and discontinuation of statin therapy | Inclisiran was superior to usual care in reducing LDL-C levels (60.0% vs. 7.0%; P < 0.001); more patients achieved LDL-C levels < 70 and <55 mg/dL: 81.8% vs. 22.2% and 71.6% vs. 8.9% (both P < 0.001) in the inclisiran arm without new safety. Statin discontinuation rates were numerically lower with inclisiran than with usual care (6.0% vs. 16.7%). |
| STEP-HFpEF (NCT04788511) and STEP-HFpEF DM (NCT04916470) trials6 | Pooled analysis 1145 with HF with LVEF ≥45%, BMI ≥30 kg/m², NYHA Class II–IV symptoms, and KCCQ-CSS <90 points. FU: 52 weeks Female: 49.5% | Semaglutide (0.25 mg for the first 4 weeks, uptitrated to 2–4 mg) or placebo given s.c. once weekly | Dual primary endpoints were change from baseline to week 52 in KCCQ-CSS and body weight | At 52 weeks, semaglutide significantly improved KCCQ-CSS (7.5 points) and 6-min walk distance and reduced body weight (−8.4%) (all P < 0.0001). These effects were consistent across multiple patient subgroups. |
| ULTIMATE-DAPT7 NCT03971500 | R, DB, PC and PA 3400 with an ACS event who completed the IVUS-ACS trial; 70% had single-vessel disease. FU: 63 months Female: 26% | All patients received DAPT (ticagrelor 90 mg b.i.d. + aspirin 100 mg) for 30 days. Then, patients who had no major ischaemic or bleeding events were randomized to DAPT or ticagrelor + placebo for 11 months. | Superiority endpoint: bleeding (BARC types 2, 3, or 5). Non-inferiority endpoint: MACCE (cardiac death, MI, ischaemic stroke, definite stent thrombosis, or clinically driven target vessel revascularization) | Between 1 and 12 months after PCI, ticagrelor + placebo reduced relevant bleeding vs. DAPT (2.1% vs. 4.6%; HR = 0.45; 0.30–0.66; P < 0.0001) without increasing MACCE. Net adverse clinical events (MACCE or BARC types 1–5 bleeding) were lower in the ticagrelor monotherapy group vs. the DAPT group (5.7% vs. 8.2%; P = 0.007). SL: 98% of participants from China and Pakistan (only 1.3% patients from Europe); 40% were enrolled with a diagnosis of unstable angina. |
| 2. Negative trials | ||||
| DEPOSITION8 NCT03954314 | Phase 3, R, DD, blinded, controlled 3242 undergoing open cardiac surgery. FU: hospital discharge or 10 days, whichever occurred sooner Female: 22.3% | Intravenous TXA (5–10 g) through surgery or topical intraoperative TXA (treatment) | Seizure without new neurologic deficit or structural change | Topical TXA did not reduce seizure incidence (P = 0.07) but increased RBC transfusion use (35.1% vs. 26.8%; absolute risk difference, 8.3%; 5.2–11.5; P = 0.007). The DSMB recommended to stop the trial for safety concerns. SL: trial underpowered for detecting differences in seizures. |
| TACT2 trial10 NCT02733185 | Phase 3, R, DB, 2 × 2 factorial, PC 959 (mean age 67 years) with a history of MI and DM. FU: 48 months Female: 27% | 40 weekly infusions of EDTA (up to 3 g based on renal function) or placebo | Composite of time to all-cause death, MI, stroke, coronary revascularization, or hospitalization for unstable angina | EDTA decreased serum lead levels (61%) vs. placebo, but it did not reduce the risk of death or CV events vs. placebo (HR = 0.93; 0.76–1.16; P = 0.53). |
| PROACT11 NCT03265574 | Phase 3, R, PA. OL 111 with breast cancer (62%) or non-Hodgkin lymphoma (38%). Negative baseline troponin T levels. Females: 78% | Enalapril (mean dose 17.7 mg) vs. placebo. Patients received ≥300 mg/m2 doxorubicin equivalent | Cardiac troponin T release 1 month after the last dose of anthracycline | No significant between-group differences in cardiac troponin T release (P = 0.40) or troponin I levels. Outcomes were similar in the two groups for LVEF. |
| AEGIS-II12 NCT03473223 | Phase 3, R, DB, PC trial 18 219 patients with AMI, multi-vessel coronary artery disease, and additional CV risk factors. FU: 90 days | CSL112, human plasma-derived APO A-I, four weekly 6 g infusions vs. placebo | Composite of MI, stroke, or CV death through 90 days | CSL112 did not reduce the primary endpoint (4.8% vs. 5.2%; HR = 0.93; 0.81–1.05; P = 0.24). However, the incidence of CV death or any type of MI was numerically lower in the CSL112 group at 180 (6.9% vs. 7.6%) and 365 days (9.8% vs. 10.5%). More hypersensitivity events were reported in the CSL112 group. |
| 3. Negative trials with promising clinical results | ||||
| EMPACT-MI13,14 NCT04509674 | Phase 3, event-driven, R, DB 6522 hospitalized for AMI and at risk for HF; 78.4% with LVEF ≤45%, 57% with congestion. FU: 17.9 months Female: 25% | Empagliflozin 10 mg o.d. vs. placebo in addition to standard care within 14 days of admission | First hospitalization for HF and death from any cause | Empagliflozine did not reduce the primary endpoint vs. placebo (8.2% vs. 9.1%; P = 0.21). In patients with AMI and LV dysfunction or congestion, empagliflozin reduced first (3.6% vs. 4.7%; HR = 0.77; 0.60–0.98; P = 0.031) and total (0.67; 0.51–0.89; P = 0.006) HF hospitalizations. SL: endpoint events were not centrally adjudicated; outpatient HF events were not analysed as clinical end points. |
| IMPROVE-HCM15 NCT04826185 | Phase 2, DB 67, non-obstructive HCM. Baseline pVO2 <80%, peak LV outflow gradient <30 mm Hg, LVEF 65.4% (NYHA Class II 59%; 35% in NYHA Class II, and LVEF ≥50%). FU: 12 weeks Female: 55% | Ninerafaxstat (IMB-1018972) 200 mg b.i.d. or placebo | Safety and tolerability of ninerafaxstat | Serious adverse events: 11.8% (4/34) in the ninerafaxstat group and 6.1% (2/33) with placebo. No differences in LVEF, pVO2, BP, heart rate, or KCCQ-CSS were observed. Ninerafaxstat improved ventilatory efficiency (P = 0.006). A post hoc analysis reported an improvement in KCCQ-CCS in the 35 patients with a baseline KCCQ-CSS ≤80 (P = 0.04). |
| REDUCE-AMI16 NCT03278509 | Phase 4, OL, PG, R, registry-based 5020 within 1–7 days after an ST- (35%) or non-ST elevation MI and LVEF ≥50% FU: 3.5 years Female: 23% | Metoprolol (median ≥100 mg) or bisoprolol (median ≥5 mg) or no β-blocker (usual care). β-Blockers were initiated inpatient and continued after discharge. | Composite of all-cause death or MI. Secondary endpoints: all-cause death, CV death, MI, hospitalization for atrial fibrillation, and hospitalization for HF | No differences in primary (7.9% in the β-blocker group and 8.3% in the usual care group; HR = 0.96; 0.79–1.16; P = 0.64) and secondary endpoints. SL study design (OL, registry-based); no central adjudication of endpoints; only safety endpoints associated with hospitalization were assessed; significant crossover between arms at 1 year (14%); medication adherence not assessed; increased β-blocker use in the usual care arm. |
| ARISE-HF18 NCT04083339 | Phase 3, R, PA trial 691 patients with diabetic cardiomyopathy (stage B HF) Baseline pVO2 15.7 mL/kg/min, LVEF 62%, BMI 30.6 kg/m2, and HbA1c 6.98%; 76% with hypertension; 38% received SGLT2Is or GLP-1RA. FU: 15 months Female: 50.4% | AT-001 (caficrestat), 1 or 1.5 g b.i.d. vs. placebo | Proportional change in pVO2 at 15 months | By 15 months, there were no differences in pVO2 between the placebo and AT-001 groups (P = 0.19). However, in a pre-specified subgroup analysis of patients (62%) not treated with SGLT2I or GLP-1RA, AT-001 (1.5 g b.i.d.) improved pVO2 (P = 0.04) and reduced the number of patients who experienced a clinically significant worsening in cardiac functional capacity ≥6% (32.7% vs. 46%; P = 0.035). |
| Trial . | Population . | Treatment . | Primary endpoint . | Results/Limitations . |
|---|---|---|---|---|
| 1. Positive clinical trials | ||||
| New investigational drugs | ||||
| Bridge-TIMI 73a1 NCT05355402 | Phase 2b, R, DB, PC 154 with moderate HTG (TG levels 150 to <500, median 241.5 mg/dL) plus high CV risk or severe HTG (TG levels ≥500 mg/dL) FU: 49 weeks Female: 42% | Olezarsen (50 or 80 mg) or placebo for an s.c. injection every 4 weeks | Per cent change in TG levels from baseline to 6 months | Olezarsen reduced TG levels by 49.3% and 53.1% (7.8% with placebo; P < 0.001 for both) and 85.7% and 93.3% of patients achieved a TG level <150 mg/dL, respectively. It also reduced APOC3 (64.2% and 73.2%, respectively), APOB (18% with both doses), and non-HDL-C, but not LDL-C, levels. Effects were maintained for 12 months. |
| LIBerate-HR2 NCT04806893 | Phase 3, R, PC, PA 922 with established or at high risk for CVD. Baseline average LDL-C 116 mg/dL; 84% on statins, 17% on ezetimibe; 45% with DM; 10% with FHo FU: 52 weeks Female: 47% | Lerodalcibep 300 mg s.c. once-monthly vs. placebo | Change in LDL-C at 52 weeks and average of LDL-C levels at weeks 50 and 52 | At 52 weeks, lerodalcibep reduced LDL-C levels (56.3% vs. 0.14% with placebo); 94% of patients achieved ≥50% reduction in LDL-C. At week 52, it also reduced APOB (43%) and lipoprotein (a) (33%). Similar proportion of patients abandoned the trial due to adverse events in both arms. |
| SHASTA 23 NCT04720534 | Phase 2b, PC, dose-ranging trial 229 with baseline fasting TG ≥500 and ≤4000 mg/dL (mean 897 mg/dL) and APOC3 of 32 mg/dL FU: 36 weeks after the second dose | Two s.c. injections of plozasiran (ARO-APOC3, 10, 25, or 50 mg) or placebo. The first injection was given on day 1; the second at week 12. | Percentage of change in fasting TG levels after 24 weeks | At 24 weeks, plozasiran dose-dependently reduced TG levels by 49%, 53%, and 57% (all P < 0.001), driven by placebo-adjusted reductions in APOC3 of 68%, 72%, and 77% (all P < 0.001), and 90.6% of patients treated with 25 or 50 mg of plozasiran achieved TG levels <500 mg/dL. |
| KARDIA-24 NCT05103332 | Phase 2, R, DB, PC 672 with uncontrolled hypertension (untreated SBP 155–180 mm Hg; treated SBP 145–180 mm Hg); 23% with DM. FU: 6 months Female: 43% | Zilebesiran 600 mg s.c. vs. placebo, added to indapamide (2.5 mg/day), amlodipine (5 mg/day), or olmesartan (40 mg/day) | Change in average 24 h ambulatory SBP at 3 months | Zilebesiran reduced SBP by 4–12 mm Hg. The average SBP reduction in the indapamide, amlodipine, and olmesartan groups was 18.5, 10.2, and 7.0 mm Hg (all P < 0.001). At 6 months, this difference persisted in the indapamide and amlodipine groups. |
| 2. Drugs already approved | ||||
| VICTORION-INITIATE5 NCT04929249 | Phase 3b, R. OL, PG 450 with established ASCVD and LDL-C ≥70 mg/dL or non-HDL-C ≥100 mg/dL despite maximally tolerated statin therapy. Mean baseline LDL-C 97.4 mg/dL. FU: 330 days Female: 31% | Inclisiran 300 mg s.c. on days 0, 90, and 270 vs. usual care prescribed at the treating provider's judgement | Per cent change from baseline in LDL-C and discontinuation of statin therapy | Inclisiran was superior to usual care in reducing LDL-C levels (60.0% vs. 7.0%; P < 0.001); more patients achieved LDL-C levels < 70 and <55 mg/dL: 81.8% vs. 22.2% and 71.6% vs. 8.9% (both P < 0.001) in the inclisiran arm without new safety. Statin discontinuation rates were numerically lower with inclisiran than with usual care (6.0% vs. 16.7%). |
| STEP-HFpEF (NCT04788511) and STEP-HFpEF DM (NCT04916470) trials6 | Pooled analysis 1145 with HF with LVEF ≥45%, BMI ≥30 kg/m², NYHA Class II–IV symptoms, and KCCQ-CSS <90 points. FU: 52 weeks Female: 49.5% | Semaglutide (0.25 mg for the first 4 weeks, uptitrated to 2–4 mg) or placebo given s.c. once weekly | Dual primary endpoints were change from baseline to week 52 in KCCQ-CSS and body weight | At 52 weeks, semaglutide significantly improved KCCQ-CSS (7.5 points) and 6-min walk distance and reduced body weight (−8.4%) (all P < 0.0001). These effects were consistent across multiple patient subgroups. |
| ULTIMATE-DAPT7 NCT03971500 | R, DB, PC and PA 3400 with an ACS event who completed the IVUS-ACS trial; 70% had single-vessel disease. FU: 63 months Female: 26% | All patients received DAPT (ticagrelor 90 mg b.i.d. + aspirin 100 mg) for 30 days. Then, patients who had no major ischaemic or bleeding events were randomized to DAPT or ticagrelor + placebo for 11 months. | Superiority endpoint: bleeding (BARC types 2, 3, or 5). Non-inferiority endpoint: MACCE (cardiac death, MI, ischaemic stroke, definite stent thrombosis, or clinically driven target vessel revascularization) | Between 1 and 12 months after PCI, ticagrelor + placebo reduced relevant bleeding vs. DAPT (2.1% vs. 4.6%; HR = 0.45; 0.30–0.66; P < 0.0001) without increasing MACCE. Net adverse clinical events (MACCE or BARC types 1–5 bleeding) were lower in the ticagrelor monotherapy group vs. the DAPT group (5.7% vs. 8.2%; P = 0.007). SL: 98% of participants from China and Pakistan (only 1.3% patients from Europe); 40% were enrolled with a diagnosis of unstable angina. |
| 2. Negative trials | ||||
| DEPOSITION8 NCT03954314 | Phase 3, R, DD, blinded, controlled 3242 undergoing open cardiac surgery. FU: hospital discharge or 10 days, whichever occurred sooner Female: 22.3% | Intravenous TXA (5–10 g) through surgery or topical intraoperative TXA (treatment) | Seizure without new neurologic deficit or structural change | Topical TXA did not reduce seizure incidence (P = 0.07) but increased RBC transfusion use (35.1% vs. 26.8%; absolute risk difference, 8.3%; 5.2–11.5; P = 0.007). The DSMB recommended to stop the trial for safety concerns. SL: trial underpowered for detecting differences in seizures. |
| TACT2 trial10 NCT02733185 | Phase 3, R, DB, 2 × 2 factorial, PC 959 (mean age 67 years) with a history of MI and DM. FU: 48 months Female: 27% | 40 weekly infusions of EDTA (up to 3 g based on renal function) or placebo | Composite of time to all-cause death, MI, stroke, coronary revascularization, or hospitalization for unstable angina | EDTA decreased serum lead levels (61%) vs. placebo, but it did not reduce the risk of death or CV events vs. placebo (HR = 0.93; 0.76–1.16; P = 0.53). |
| PROACT11 NCT03265574 | Phase 3, R, PA. OL 111 with breast cancer (62%) or non-Hodgkin lymphoma (38%). Negative baseline troponin T levels. Females: 78% | Enalapril (mean dose 17.7 mg) vs. placebo. Patients received ≥300 mg/m2 doxorubicin equivalent | Cardiac troponin T release 1 month after the last dose of anthracycline | No significant between-group differences in cardiac troponin T release (P = 0.40) or troponin I levels. Outcomes were similar in the two groups for LVEF. |
| AEGIS-II12 NCT03473223 | Phase 3, R, DB, PC trial 18 219 patients with AMI, multi-vessel coronary artery disease, and additional CV risk factors. FU: 90 days | CSL112, human plasma-derived APO A-I, four weekly 6 g infusions vs. placebo | Composite of MI, stroke, or CV death through 90 days | CSL112 did not reduce the primary endpoint (4.8% vs. 5.2%; HR = 0.93; 0.81–1.05; P = 0.24). However, the incidence of CV death or any type of MI was numerically lower in the CSL112 group at 180 (6.9% vs. 7.6%) and 365 days (9.8% vs. 10.5%). More hypersensitivity events were reported in the CSL112 group. |
| 3. Negative trials with promising clinical results | ||||
| EMPACT-MI13,14 NCT04509674 | Phase 3, event-driven, R, DB 6522 hospitalized for AMI and at risk for HF; 78.4% with LVEF ≤45%, 57% with congestion. FU: 17.9 months Female: 25% | Empagliflozin 10 mg o.d. vs. placebo in addition to standard care within 14 days of admission | First hospitalization for HF and death from any cause | Empagliflozine did not reduce the primary endpoint vs. placebo (8.2% vs. 9.1%; P = 0.21). In patients with AMI and LV dysfunction or congestion, empagliflozin reduced first (3.6% vs. 4.7%; HR = 0.77; 0.60–0.98; P = 0.031) and total (0.67; 0.51–0.89; P = 0.006) HF hospitalizations. SL: endpoint events were not centrally adjudicated; outpatient HF events were not analysed as clinical end points. |
| IMPROVE-HCM15 NCT04826185 | Phase 2, DB 67, non-obstructive HCM. Baseline pVO2 <80%, peak LV outflow gradient <30 mm Hg, LVEF 65.4% (NYHA Class II 59%; 35% in NYHA Class II, and LVEF ≥50%). FU: 12 weeks Female: 55% | Ninerafaxstat (IMB-1018972) 200 mg b.i.d. or placebo | Safety and tolerability of ninerafaxstat | Serious adverse events: 11.8% (4/34) in the ninerafaxstat group and 6.1% (2/33) with placebo. No differences in LVEF, pVO2, BP, heart rate, or KCCQ-CSS were observed. Ninerafaxstat improved ventilatory efficiency (P = 0.006). A post hoc analysis reported an improvement in KCCQ-CCS in the 35 patients with a baseline KCCQ-CSS ≤80 (P = 0.04). |
| REDUCE-AMI16 NCT03278509 | Phase 4, OL, PG, R, registry-based 5020 within 1–7 days after an ST- (35%) or non-ST elevation MI and LVEF ≥50% FU: 3.5 years Female: 23% | Metoprolol (median ≥100 mg) or bisoprolol (median ≥5 mg) or no β-blocker (usual care). β-Blockers were initiated inpatient and continued after discharge. | Composite of all-cause death or MI. Secondary endpoints: all-cause death, CV death, MI, hospitalization for atrial fibrillation, and hospitalization for HF | No differences in primary (7.9% in the β-blocker group and 8.3% in the usual care group; HR = 0.96; 0.79–1.16; P = 0.64) and secondary endpoints. SL study design (OL, registry-based); no central adjudication of endpoints; only safety endpoints associated with hospitalization were assessed; significant crossover between arms at 1 year (14%); medication adherence not assessed; increased β-blocker use in the usual care arm. |
| ARISE-HF18 NCT04083339 | Phase 3, R, PA trial 691 patients with diabetic cardiomyopathy (stage B HF) Baseline pVO2 15.7 mL/kg/min, LVEF 62%, BMI 30.6 kg/m2, and HbA1c 6.98%; 76% with hypertension; 38% received SGLT2Is or GLP-1RA. FU: 15 months Female: 50.4% | AT-001 (caficrestat), 1 or 1.5 g b.i.d. vs. placebo | Proportional change in pVO2 at 15 months | By 15 months, there were no differences in pVO2 between the placebo and AT-001 groups (P = 0.19). However, in a pre-specified subgroup analysis of patients (62%) not treated with SGLT2I or GLP-1RA, AT-001 (1.5 g b.i.d.) improved pVO2 (P = 0.04) and reduced the number of patients who experienced a clinically significant worsening in cardiac functional capacity ≥6% (32.7% vs. 46%; P = 0.035). |
ACS, acute coronary syndrome; AMI, acute myocardial infarction; APO, apolipoprotein; APOC3: apolipoprotein C-III; ASCVD, atherosclerotic cardiovascular disease; BARC, Bleeding Academic Research Consortium; b.i.d., twice daily; BMI, body mass index; BP, blood pressure; CV, cardiovascular; CVD: cardiovascular disease; DAPT, dual antiplatelet therapy; DB, double blind; DD, double-dummy; DM, diabetes mellitus; DSMB, Data and Safety Monitoring Board; EDTA, ethylenediaminetetraacetic acid; FHo, familial hypercholesterolaemia; FU, follow-up; GLP-1RA, glucagon-like peptide-1 receptor agonist; HbA1c, glycated haemoglobin; HDL-C, high-density lipoprotein cholesterol; HR, hazard ratio; HF, heart failure; HTG, hypertriglyceridaemia; KCCQ-CSS, Kansas City Cardiomyopathy Questionnaire Clinical Summary Score; LDL-C, low-density lipoprotein cholesterol; LV, left ventricular; LVEF, left ventricular ejection fraction; MACCE, major adverse cardiovascular or cerebrovascular events; MI, myocardial infarction; NCT, ClinicalTrials.gov identifier; NYHA, New York Heart Association; OL, open label; PA, parallel assignment; PC, placebo-controlled; PCI, percutaneous coronary intervention; PG, parallel group; pVO2, peak oxygen uptake; R, randomized; RBC, red blood cells; SBP, systolic blood pressure; s.c., subcutaneous; SGLT2I, sodium-glucose cotransporter-2 inhibitors; SL, study limitations; TG, triglyceride; TXA, tranexamic acid; VO2, peak oxygen uptake.
| Trial . | Population . | Treatment . | Primary endpoint . | Results/Limitations . |
|---|---|---|---|---|
| 1. Positive clinical trials | ||||
| New investigational drugs | ||||
| Bridge-TIMI 73a1 NCT05355402 | Phase 2b, R, DB, PC 154 with moderate HTG (TG levels 150 to <500, median 241.5 mg/dL) plus high CV risk or severe HTG (TG levels ≥500 mg/dL) FU: 49 weeks Female: 42% | Olezarsen (50 or 80 mg) or placebo for an s.c. injection every 4 weeks | Per cent change in TG levels from baseline to 6 months | Olezarsen reduced TG levels by 49.3% and 53.1% (7.8% with placebo; P < 0.001 for both) and 85.7% and 93.3% of patients achieved a TG level <150 mg/dL, respectively. It also reduced APOC3 (64.2% and 73.2%, respectively), APOB (18% with both doses), and non-HDL-C, but not LDL-C, levels. Effects were maintained for 12 months. |
| LIBerate-HR2 NCT04806893 | Phase 3, R, PC, PA 922 with established or at high risk for CVD. Baseline average LDL-C 116 mg/dL; 84% on statins, 17% on ezetimibe; 45% with DM; 10% with FHo FU: 52 weeks Female: 47% | Lerodalcibep 300 mg s.c. once-monthly vs. placebo | Change in LDL-C at 52 weeks and average of LDL-C levels at weeks 50 and 52 | At 52 weeks, lerodalcibep reduced LDL-C levels (56.3% vs. 0.14% with placebo); 94% of patients achieved ≥50% reduction in LDL-C. At week 52, it also reduced APOB (43%) and lipoprotein (a) (33%). Similar proportion of patients abandoned the trial due to adverse events in both arms. |
| SHASTA 23 NCT04720534 | Phase 2b, PC, dose-ranging trial 229 with baseline fasting TG ≥500 and ≤4000 mg/dL (mean 897 mg/dL) and APOC3 of 32 mg/dL FU: 36 weeks after the second dose | Two s.c. injections of plozasiran (ARO-APOC3, 10, 25, or 50 mg) or placebo. The first injection was given on day 1; the second at week 12. | Percentage of change in fasting TG levels after 24 weeks | At 24 weeks, plozasiran dose-dependently reduced TG levels by 49%, 53%, and 57% (all P < 0.001), driven by placebo-adjusted reductions in APOC3 of 68%, 72%, and 77% (all P < 0.001), and 90.6% of patients treated with 25 or 50 mg of plozasiran achieved TG levels <500 mg/dL. |
| KARDIA-24 NCT05103332 | Phase 2, R, DB, PC 672 with uncontrolled hypertension (untreated SBP 155–180 mm Hg; treated SBP 145–180 mm Hg); 23% with DM. FU: 6 months Female: 43% | Zilebesiran 600 mg s.c. vs. placebo, added to indapamide (2.5 mg/day), amlodipine (5 mg/day), or olmesartan (40 mg/day) | Change in average 24 h ambulatory SBP at 3 months | Zilebesiran reduced SBP by 4–12 mm Hg. The average SBP reduction in the indapamide, amlodipine, and olmesartan groups was 18.5, 10.2, and 7.0 mm Hg (all P < 0.001). At 6 months, this difference persisted in the indapamide and amlodipine groups. |
| 2. Drugs already approved | ||||
| VICTORION-INITIATE5 NCT04929249 | Phase 3b, R. OL, PG 450 with established ASCVD and LDL-C ≥70 mg/dL or non-HDL-C ≥100 mg/dL despite maximally tolerated statin therapy. Mean baseline LDL-C 97.4 mg/dL. FU: 330 days Female: 31% | Inclisiran 300 mg s.c. on days 0, 90, and 270 vs. usual care prescribed at the treating provider's judgement | Per cent change from baseline in LDL-C and discontinuation of statin therapy | Inclisiran was superior to usual care in reducing LDL-C levels (60.0% vs. 7.0%; P < 0.001); more patients achieved LDL-C levels < 70 and <55 mg/dL: 81.8% vs. 22.2% and 71.6% vs. 8.9% (both P < 0.001) in the inclisiran arm without new safety. Statin discontinuation rates were numerically lower with inclisiran than with usual care (6.0% vs. 16.7%). |
| STEP-HFpEF (NCT04788511) and STEP-HFpEF DM (NCT04916470) trials6 | Pooled analysis 1145 with HF with LVEF ≥45%, BMI ≥30 kg/m², NYHA Class II–IV symptoms, and KCCQ-CSS <90 points. FU: 52 weeks Female: 49.5% | Semaglutide (0.25 mg for the first 4 weeks, uptitrated to 2–4 mg) or placebo given s.c. once weekly | Dual primary endpoints were change from baseline to week 52 in KCCQ-CSS and body weight | At 52 weeks, semaglutide significantly improved KCCQ-CSS (7.5 points) and 6-min walk distance and reduced body weight (−8.4%) (all P < 0.0001). These effects were consistent across multiple patient subgroups. |
| ULTIMATE-DAPT7 NCT03971500 | R, DB, PC and PA 3400 with an ACS event who completed the IVUS-ACS trial; 70% had single-vessel disease. FU: 63 months Female: 26% | All patients received DAPT (ticagrelor 90 mg b.i.d. + aspirin 100 mg) for 30 days. Then, patients who had no major ischaemic or bleeding events were randomized to DAPT or ticagrelor + placebo for 11 months. | Superiority endpoint: bleeding (BARC types 2, 3, or 5). Non-inferiority endpoint: MACCE (cardiac death, MI, ischaemic stroke, definite stent thrombosis, or clinically driven target vessel revascularization) | Between 1 and 12 months after PCI, ticagrelor + placebo reduced relevant bleeding vs. DAPT (2.1% vs. 4.6%; HR = 0.45; 0.30–0.66; P < 0.0001) without increasing MACCE. Net adverse clinical events (MACCE or BARC types 1–5 bleeding) were lower in the ticagrelor monotherapy group vs. the DAPT group (5.7% vs. 8.2%; P = 0.007). SL: 98% of participants from China and Pakistan (only 1.3% patients from Europe); 40% were enrolled with a diagnosis of unstable angina. |
| 2. Negative trials | ||||
| DEPOSITION8 NCT03954314 | Phase 3, R, DD, blinded, controlled 3242 undergoing open cardiac surgery. FU: hospital discharge or 10 days, whichever occurred sooner Female: 22.3% | Intravenous TXA (5–10 g) through surgery or topical intraoperative TXA (treatment) | Seizure without new neurologic deficit or structural change | Topical TXA did not reduce seizure incidence (P = 0.07) but increased RBC transfusion use (35.1% vs. 26.8%; absolute risk difference, 8.3%; 5.2–11.5; P = 0.007). The DSMB recommended to stop the trial for safety concerns. SL: trial underpowered for detecting differences in seizures. |
| TACT2 trial10 NCT02733185 | Phase 3, R, DB, 2 × 2 factorial, PC 959 (mean age 67 years) with a history of MI and DM. FU: 48 months Female: 27% | 40 weekly infusions of EDTA (up to 3 g based on renal function) or placebo | Composite of time to all-cause death, MI, stroke, coronary revascularization, or hospitalization for unstable angina | EDTA decreased serum lead levels (61%) vs. placebo, but it did not reduce the risk of death or CV events vs. placebo (HR = 0.93; 0.76–1.16; P = 0.53). |
| PROACT11 NCT03265574 | Phase 3, R, PA. OL 111 with breast cancer (62%) or non-Hodgkin lymphoma (38%). Negative baseline troponin T levels. Females: 78% | Enalapril (mean dose 17.7 mg) vs. placebo. Patients received ≥300 mg/m2 doxorubicin equivalent | Cardiac troponin T release 1 month after the last dose of anthracycline | No significant between-group differences in cardiac troponin T release (P = 0.40) or troponin I levels. Outcomes were similar in the two groups for LVEF. |
| AEGIS-II12 NCT03473223 | Phase 3, R, DB, PC trial 18 219 patients with AMI, multi-vessel coronary artery disease, and additional CV risk factors. FU: 90 days | CSL112, human plasma-derived APO A-I, four weekly 6 g infusions vs. placebo | Composite of MI, stroke, or CV death through 90 days | CSL112 did not reduce the primary endpoint (4.8% vs. 5.2%; HR = 0.93; 0.81–1.05; P = 0.24). However, the incidence of CV death or any type of MI was numerically lower in the CSL112 group at 180 (6.9% vs. 7.6%) and 365 days (9.8% vs. 10.5%). More hypersensitivity events were reported in the CSL112 group. |
| 3. Negative trials with promising clinical results | ||||
| EMPACT-MI13,14 NCT04509674 | Phase 3, event-driven, R, DB 6522 hospitalized for AMI and at risk for HF; 78.4% with LVEF ≤45%, 57% with congestion. FU: 17.9 months Female: 25% | Empagliflozin 10 mg o.d. vs. placebo in addition to standard care within 14 days of admission | First hospitalization for HF and death from any cause | Empagliflozine did not reduce the primary endpoint vs. placebo (8.2% vs. 9.1%; P = 0.21). In patients with AMI and LV dysfunction or congestion, empagliflozin reduced first (3.6% vs. 4.7%; HR = 0.77; 0.60–0.98; P = 0.031) and total (0.67; 0.51–0.89; P = 0.006) HF hospitalizations. SL: endpoint events were not centrally adjudicated; outpatient HF events were not analysed as clinical end points. |
| IMPROVE-HCM15 NCT04826185 | Phase 2, DB 67, non-obstructive HCM. Baseline pVO2 <80%, peak LV outflow gradient <30 mm Hg, LVEF 65.4% (NYHA Class II 59%; 35% in NYHA Class II, and LVEF ≥50%). FU: 12 weeks Female: 55% | Ninerafaxstat (IMB-1018972) 200 mg b.i.d. or placebo | Safety and tolerability of ninerafaxstat | Serious adverse events: 11.8% (4/34) in the ninerafaxstat group and 6.1% (2/33) with placebo. No differences in LVEF, pVO2, BP, heart rate, or KCCQ-CSS were observed. Ninerafaxstat improved ventilatory efficiency (P = 0.006). A post hoc analysis reported an improvement in KCCQ-CCS in the 35 patients with a baseline KCCQ-CSS ≤80 (P = 0.04). |
| REDUCE-AMI16 NCT03278509 | Phase 4, OL, PG, R, registry-based 5020 within 1–7 days after an ST- (35%) or non-ST elevation MI and LVEF ≥50% FU: 3.5 years Female: 23% | Metoprolol (median ≥100 mg) or bisoprolol (median ≥5 mg) or no β-blocker (usual care). β-Blockers were initiated inpatient and continued after discharge. | Composite of all-cause death or MI. Secondary endpoints: all-cause death, CV death, MI, hospitalization for atrial fibrillation, and hospitalization for HF | No differences in primary (7.9% in the β-blocker group and 8.3% in the usual care group; HR = 0.96; 0.79–1.16; P = 0.64) and secondary endpoints. SL study design (OL, registry-based); no central adjudication of endpoints; only safety endpoints associated with hospitalization were assessed; significant crossover between arms at 1 year (14%); medication adherence not assessed; increased β-blocker use in the usual care arm. |
| ARISE-HF18 NCT04083339 | Phase 3, R, PA trial 691 patients with diabetic cardiomyopathy (stage B HF) Baseline pVO2 15.7 mL/kg/min, LVEF 62%, BMI 30.6 kg/m2, and HbA1c 6.98%; 76% with hypertension; 38% received SGLT2Is or GLP-1RA. FU: 15 months Female: 50.4% | AT-001 (caficrestat), 1 or 1.5 g b.i.d. vs. placebo | Proportional change in pVO2 at 15 months | By 15 months, there were no differences in pVO2 between the placebo and AT-001 groups (P = 0.19). However, in a pre-specified subgroup analysis of patients (62%) not treated with SGLT2I or GLP-1RA, AT-001 (1.5 g b.i.d.) improved pVO2 (P = 0.04) and reduced the number of patients who experienced a clinically significant worsening in cardiac functional capacity ≥6% (32.7% vs. 46%; P = 0.035). |
| Trial . | Population . | Treatment . | Primary endpoint . | Results/Limitations . |
|---|---|---|---|---|
| 1. Positive clinical trials | ||||
| New investigational drugs | ||||
| Bridge-TIMI 73a1 NCT05355402 | Phase 2b, R, DB, PC 154 with moderate HTG (TG levels 150 to <500, median 241.5 mg/dL) plus high CV risk or severe HTG (TG levels ≥500 mg/dL) FU: 49 weeks Female: 42% | Olezarsen (50 or 80 mg) or placebo for an s.c. injection every 4 weeks | Per cent change in TG levels from baseline to 6 months | Olezarsen reduced TG levels by 49.3% and 53.1% (7.8% with placebo; P < 0.001 for both) and 85.7% and 93.3% of patients achieved a TG level <150 mg/dL, respectively. It also reduced APOC3 (64.2% and 73.2%, respectively), APOB (18% with both doses), and non-HDL-C, but not LDL-C, levels. Effects were maintained for 12 months. |
| LIBerate-HR2 NCT04806893 | Phase 3, R, PC, PA 922 with established or at high risk for CVD. Baseline average LDL-C 116 mg/dL; 84% on statins, 17% on ezetimibe; 45% with DM; 10% with FHo FU: 52 weeks Female: 47% | Lerodalcibep 300 mg s.c. once-monthly vs. placebo | Change in LDL-C at 52 weeks and average of LDL-C levels at weeks 50 and 52 | At 52 weeks, lerodalcibep reduced LDL-C levels (56.3% vs. 0.14% with placebo); 94% of patients achieved ≥50% reduction in LDL-C. At week 52, it also reduced APOB (43%) and lipoprotein (a) (33%). Similar proportion of patients abandoned the trial due to adverse events in both arms. |
| SHASTA 23 NCT04720534 | Phase 2b, PC, dose-ranging trial 229 with baseline fasting TG ≥500 and ≤4000 mg/dL (mean 897 mg/dL) and APOC3 of 32 mg/dL FU: 36 weeks after the second dose | Two s.c. injections of plozasiran (ARO-APOC3, 10, 25, or 50 mg) or placebo. The first injection was given on day 1; the second at week 12. | Percentage of change in fasting TG levels after 24 weeks | At 24 weeks, plozasiran dose-dependently reduced TG levels by 49%, 53%, and 57% (all P < 0.001), driven by placebo-adjusted reductions in APOC3 of 68%, 72%, and 77% (all P < 0.001), and 90.6% of patients treated with 25 or 50 mg of plozasiran achieved TG levels <500 mg/dL. |
| KARDIA-24 NCT05103332 | Phase 2, R, DB, PC 672 with uncontrolled hypertension (untreated SBP 155–180 mm Hg; treated SBP 145–180 mm Hg); 23% with DM. FU: 6 months Female: 43% | Zilebesiran 600 mg s.c. vs. placebo, added to indapamide (2.5 mg/day), amlodipine (5 mg/day), or olmesartan (40 mg/day) | Change in average 24 h ambulatory SBP at 3 months | Zilebesiran reduced SBP by 4–12 mm Hg. The average SBP reduction in the indapamide, amlodipine, and olmesartan groups was 18.5, 10.2, and 7.0 mm Hg (all P < 0.001). At 6 months, this difference persisted in the indapamide and amlodipine groups. |
| 2. Drugs already approved | ||||
| VICTORION-INITIATE5 NCT04929249 | Phase 3b, R. OL, PG 450 with established ASCVD and LDL-C ≥70 mg/dL or non-HDL-C ≥100 mg/dL despite maximally tolerated statin therapy. Mean baseline LDL-C 97.4 mg/dL. FU: 330 days Female: 31% | Inclisiran 300 mg s.c. on days 0, 90, and 270 vs. usual care prescribed at the treating provider's judgement | Per cent change from baseline in LDL-C and discontinuation of statin therapy | Inclisiran was superior to usual care in reducing LDL-C levels (60.0% vs. 7.0%; P < 0.001); more patients achieved LDL-C levels < 70 and <55 mg/dL: 81.8% vs. 22.2% and 71.6% vs. 8.9% (both P < 0.001) in the inclisiran arm without new safety. Statin discontinuation rates were numerically lower with inclisiran than with usual care (6.0% vs. 16.7%). |
| STEP-HFpEF (NCT04788511) and STEP-HFpEF DM (NCT04916470) trials6 | Pooled analysis 1145 with HF with LVEF ≥45%, BMI ≥30 kg/m², NYHA Class II–IV symptoms, and KCCQ-CSS <90 points. FU: 52 weeks Female: 49.5% | Semaglutide (0.25 mg for the first 4 weeks, uptitrated to 2–4 mg) or placebo given s.c. once weekly | Dual primary endpoints were change from baseline to week 52 in KCCQ-CSS and body weight | At 52 weeks, semaglutide significantly improved KCCQ-CSS (7.5 points) and 6-min walk distance and reduced body weight (−8.4%) (all P < 0.0001). These effects were consistent across multiple patient subgroups. |
| ULTIMATE-DAPT7 NCT03971500 | R, DB, PC and PA 3400 with an ACS event who completed the IVUS-ACS trial; 70% had single-vessel disease. FU: 63 months Female: 26% | All patients received DAPT (ticagrelor 90 mg b.i.d. + aspirin 100 mg) for 30 days. Then, patients who had no major ischaemic or bleeding events were randomized to DAPT or ticagrelor + placebo for 11 months. | Superiority endpoint: bleeding (BARC types 2, 3, or 5). Non-inferiority endpoint: MACCE (cardiac death, MI, ischaemic stroke, definite stent thrombosis, or clinically driven target vessel revascularization) | Between 1 and 12 months after PCI, ticagrelor + placebo reduced relevant bleeding vs. DAPT (2.1% vs. 4.6%; HR = 0.45; 0.30–0.66; P < 0.0001) without increasing MACCE. Net adverse clinical events (MACCE or BARC types 1–5 bleeding) were lower in the ticagrelor monotherapy group vs. the DAPT group (5.7% vs. 8.2%; P = 0.007). SL: 98% of participants from China and Pakistan (only 1.3% patients from Europe); 40% were enrolled with a diagnosis of unstable angina. |
| 2. Negative trials | ||||
| DEPOSITION8 NCT03954314 | Phase 3, R, DD, blinded, controlled 3242 undergoing open cardiac surgery. FU: hospital discharge or 10 days, whichever occurred sooner Female: 22.3% | Intravenous TXA (5–10 g) through surgery or topical intraoperative TXA (treatment) | Seizure without new neurologic deficit or structural change | Topical TXA did not reduce seizure incidence (P = 0.07) but increased RBC transfusion use (35.1% vs. 26.8%; absolute risk difference, 8.3%; 5.2–11.5; P = 0.007). The DSMB recommended to stop the trial for safety concerns. SL: trial underpowered for detecting differences in seizures. |
| TACT2 trial10 NCT02733185 | Phase 3, R, DB, 2 × 2 factorial, PC 959 (mean age 67 years) with a history of MI and DM. FU: 48 months Female: 27% | 40 weekly infusions of EDTA (up to 3 g based on renal function) or placebo | Composite of time to all-cause death, MI, stroke, coronary revascularization, or hospitalization for unstable angina | EDTA decreased serum lead levels (61%) vs. placebo, but it did not reduce the risk of death or CV events vs. placebo (HR = 0.93; 0.76–1.16; P = 0.53). |
| PROACT11 NCT03265574 | Phase 3, R, PA. OL 111 with breast cancer (62%) or non-Hodgkin lymphoma (38%). Negative baseline troponin T levels. Females: 78% | Enalapril (mean dose 17.7 mg) vs. placebo. Patients received ≥300 mg/m2 doxorubicin equivalent | Cardiac troponin T release 1 month after the last dose of anthracycline | No significant between-group differences in cardiac troponin T release (P = 0.40) or troponin I levels. Outcomes were similar in the two groups for LVEF. |
| AEGIS-II12 NCT03473223 | Phase 3, R, DB, PC trial 18 219 patients with AMI, multi-vessel coronary artery disease, and additional CV risk factors. FU: 90 days | CSL112, human plasma-derived APO A-I, four weekly 6 g infusions vs. placebo | Composite of MI, stroke, or CV death through 90 days | CSL112 did not reduce the primary endpoint (4.8% vs. 5.2%; HR = 0.93; 0.81–1.05; P = 0.24). However, the incidence of CV death or any type of MI was numerically lower in the CSL112 group at 180 (6.9% vs. 7.6%) and 365 days (9.8% vs. 10.5%). More hypersensitivity events were reported in the CSL112 group. |
| 3. Negative trials with promising clinical results | ||||
| EMPACT-MI13,14 NCT04509674 | Phase 3, event-driven, R, DB 6522 hospitalized for AMI and at risk for HF; 78.4% with LVEF ≤45%, 57% with congestion. FU: 17.9 months Female: 25% | Empagliflozin 10 mg o.d. vs. placebo in addition to standard care within 14 days of admission | First hospitalization for HF and death from any cause | Empagliflozine did not reduce the primary endpoint vs. placebo (8.2% vs. 9.1%; P = 0.21). In patients with AMI and LV dysfunction or congestion, empagliflozin reduced first (3.6% vs. 4.7%; HR = 0.77; 0.60–0.98; P = 0.031) and total (0.67; 0.51–0.89; P = 0.006) HF hospitalizations. SL: endpoint events were not centrally adjudicated; outpatient HF events were not analysed as clinical end points. |
| IMPROVE-HCM15 NCT04826185 | Phase 2, DB 67, non-obstructive HCM. Baseline pVO2 <80%, peak LV outflow gradient <30 mm Hg, LVEF 65.4% (NYHA Class II 59%; 35% in NYHA Class II, and LVEF ≥50%). FU: 12 weeks Female: 55% | Ninerafaxstat (IMB-1018972) 200 mg b.i.d. or placebo | Safety and tolerability of ninerafaxstat | Serious adverse events: 11.8% (4/34) in the ninerafaxstat group and 6.1% (2/33) with placebo. No differences in LVEF, pVO2, BP, heart rate, or KCCQ-CSS were observed. Ninerafaxstat improved ventilatory efficiency (P = 0.006). A post hoc analysis reported an improvement in KCCQ-CCS in the 35 patients with a baseline KCCQ-CSS ≤80 (P = 0.04). |
| REDUCE-AMI16 NCT03278509 | Phase 4, OL, PG, R, registry-based 5020 within 1–7 days after an ST- (35%) or non-ST elevation MI and LVEF ≥50% FU: 3.5 years Female: 23% | Metoprolol (median ≥100 mg) or bisoprolol (median ≥5 mg) or no β-blocker (usual care). β-Blockers were initiated inpatient and continued after discharge. | Composite of all-cause death or MI. Secondary endpoints: all-cause death, CV death, MI, hospitalization for atrial fibrillation, and hospitalization for HF | No differences in primary (7.9% in the β-blocker group and 8.3% in the usual care group; HR = 0.96; 0.79–1.16; P = 0.64) and secondary endpoints. SL study design (OL, registry-based); no central adjudication of endpoints; only safety endpoints associated with hospitalization were assessed; significant crossover between arms at 1 year (14%); medication adherence not assessed; increased β-blocker use in the usual care arm. |
| ARISE-HF18 NCT04083339 | Phase 3, R, PA trial 691 patients with diabetic cardiomyopathy (stage B HF) Baseline pVO2 15.7 mL/kg/min, LVEF 62%, BMI 30.6 kg/m2, and HbA1c 6.98%; 76% with hypertension; 38% received SGLT2Is or GLP-1RA. FU: 15 months Female: 50.4% | AT-001 (caficrestat), 1 or 1.5 g b.i.d. vs. placebo | Proportional change in pVO2 at 15 months | By 15 months, there were no differences in pVO2 between the placebo and AT-001 groups (P = 0.19). However, in a pre-specified subgroup analysis of patients (62%) not treated with SGLT2I or GLP-1RA, AT-001 (1.5 g b.i.d.) improved pVO2 (P = 0.04) and reduced the number of patients who experienced a clinically significant worsening in cardiac functional capacity ≥6% (32.7% vs. 46%; P = 0.035). |
ACS, acute coronary syndrome; AMI, acute myocardial infarction; APO, apolipoprotein; APOC3: apolipoprotein C-III; ASCVD, atherosclerotic cardiovascular disease; BARC, Bleeding Academic Research Consortium; b.i.d., twice daily; BMI, body mass index; BP, blood pressure; CV, cardiovascular; CVD: cardiovascular disease; DAPT, dual antiplatelet therapy; DB, double blind; DD, double-dummy; DM, diabetes mellitus; DSMB, Data and Safety Monitoring Board; EDTA, ethylenediaminetetraacetic acid; FHo, familial hypercholesterolaemia; FU, follow-up; GLP-1RA, glucagon-like peptide-1 receptor agonist; HbA1c, glycated haemoglobin; HDL-C, high-density lipoprotein cholesterol; HR, hazard ratio; HF, heart failure; HTG, hypertriglyceridaemia; KCCQ-CSS, Kansas City Cardiomyopathy Questionnaire Clinical Summary Score; LDL-C, low-density lipoprotein cholesterol; LV, left ventricular; LVEF, left ventricular ejection fraction; MACCE, major adverse cardiovascular or cerebrovascular events; MI, myocardial infarction; NCT, ClinicalTrials.gov identifier; NYHA, New York Heart Association; OL, open label; PA, parallel assignment; PC, placebo-controlled; PCI, percutaneous coronary intervention; PG, parallel group; pVO2, peak oxygen uptake; R, randomized; RBC, red blood cells; SBP, systolic blood pressure; s.c., subcutaneous; SGLT2I, sodium-glucose cotransporter-2 inhibitors; SL, study limitations; TG, triglyceride; TXA, tranexamic acid; VO2, peak oxygen uptake.
Positive clinical trials
Investigational drugs
Several new lipid-lowering drugs have shown promising results on both efficacy and safety when added to standard lipid-lowering therapy (LLT). (1) Olezarsen (ISIS 678354) is an N-acetyl-galactosamine-conjugated antisense oligonucleotide (ASO) that specifically binds hepatic APOC3 mRNA to inhibit apolipoprotein (APO) C3 (APOC3) production and decrease triglyceride (TG) levels. The Bridge-TIMI 73a [A Study of Olezarsen (Formerly Known as AKCEA-APOCIII-LRx) in Adults With Hypertriglyceridemia and Atherosclerotic Cardiovascular Disease (Established or at Increased Risk for), and/ or With Severe Hypertriglyceridemia] trial showed that in patients with moderate hypertriglyceridaemia and elevated cardiovascular risk or with severe hypertriglyceridaemia, olezarsen reduced TG, APOC3, APOB, and non-high-density lipoprotein cholesterol (non-HDL-C) levels compared with placebo.1 Clinically relevant adverse effects were similar in the trial groups. (2) Lerodalcibep (LIB003) is a novel small recombinant fusion protein of a proprotein convertase subtilisin/kexin type 9 gene-binding domain (adnectin) and human serum albumin. The LIBerate-HR (Study of Long-Term Efficacy and Safety of LIB003 in CVD or High Risk for CVD Patients Needing Further LDL-C Reduction) trial found that in patients with established or at high risk for myocardial infarction (MI) or stroke, lerodalcibep decreased low-density lipoprotein cholesterol (LDL-C) and 94% of patients achieved ≥50% reduction in LDL-C (19% with placebo).2 Lerodalcibep also reduced APO and lipoprotein (a) levels and was well tolerated. (3) The dose-ranging SHASTA 2 (Study to Evaluate ARO-APOC3 in Adults With Severe Hypertriglyceridemia) trial studied the efficacy and safety of plozasiran [an APOC3-targeted small interfering RNA (siRNA), ARO-APOC3] in patients with severe hypertriglyceridaemia. At 24 and 48 weeks, the average reduction in TG levels with the higher doses of plozasiran was 74% and 58% (17% and 7% with placebo), respectively, and 90% and 77% of patients achieved TG levels <500 mg/dL.3 Plozasiran also reduced APOC3 levels (78% and 48% vs. −1% and +4% with placebo).
Zilebesiran is a first-in-class siRNA targeting hepatic synthesis of angiotensinogen, the most upstream precursor to all angiotensin peptides. Among patients with inadequately controlled hypertension despite optimal adherence with their medication regimen, the KARDIA (Zilebesiran as Add-on Therapy in Patients With Hypertension Not Adequately Controlled by a Standard of Care Antihypertensive Medication) trial found that a single subcutaneous (s.c.) injection of zilebesiran significantly reduced 24 h mean ambulatory (and office) systolic blood pressure (SBP) compared with placebo when added to indapamide, amlodipine, and olmesartan by 18.5, 10.2, and 7.0 mm Hg, respectively; SBP differences persisted after 6 months only in the indapamide and amlodipine groups.4 Zilebesiran increased the risk of mild hyperkalaemia, hypotension, and estimated glomerular filtration rate (eGFR) decline by >30%.
The main limitations of these trials are the short follow-up that does not allow to analyse the drug effects on clinical outcomes and the long-term drug safety, including possible drug interactions. Future clinical trials are aimed at answering both questions.
Drugs already approved
The VICTORION-INITIATE (A Randomized Study to Evaluate the Effect of an “Inclisiran First” Implementation Strategy Compared to Usual Care in Patients With Atherosclerotic Cardiovascular Disease and Elevated LDL-C Despite Receiving Maximally Tolerated Statin Therapy) trial assessed the effectiveness of an ‘inclisiran-first’ implementation strategy (addition of inclisiran to maximally tolerated statin therapy immediately upon failure to achieve acceptable LDL-C levels) compared with usual care in patients with established atherosclerotic cardiovascular disease (ASCVD) and LDL-C ≥70 mg/dL or non-HDL-C ≥100 mg/dL.5 During the study, more ‘inclisiran-first’ patients achieved LDL-C levels <70 and <55 mg/dL than in the usual care group (both P < 0.001) without major safety concerns compared with usual care. Statin discontinuation rates were not inferior in the inclisiran and usual care arms.
In a pre-specified pooled analysis of the STEP-HFpEF (Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity) and STEP-HFpEF DM (Research Study to Look at How Well Semaglutide Works in People Living With Heart Failure, Obesity and Type 2 Diabetes) trials that recruited patients with obesity and heart failure (HF) with preserved ejection fraction (HFpEF) with and without type 2 diabetes and Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) <90 points, semaglutide significantly improved HF-related symptoms, physical limitations, and exercise function and reduced body weight (all P < 0.0001).6 These effects were consistent across patient subgroups.
Clinical guidelines recommend dual antiplatelet therapy (DAPT) with aspirin plus a P2Y12 receptor inhibitor for 12 months following percutaneous coronary intervention (PCI) for an acute coronary syndrome (ACS) event to prevent MI and stent thrombosis. The ULTIMATE-DAPT (1-month vs 12-month DAPT for ACS Patients Who Underwent PCI Stratified by IVUS: IVUS-ACS and ULTIMATE-DAPT Trials) trial showed that in this population, 1 month DAPT, followed by de-escalation to ticagrelor monotherapy, reduces clinically relevant bleeding events without an increase in major adverse cardiovascular or cerebrovascular events (MACCE) at 1 year.7 Indeed, net adverse clinical events [MACCE or BARC (Bleeding Academic Research Consortium) types 1–5 bleeding] were lower with ticagrelor monotherapy than those in the DAPT group (5.7% vs. 8.2%; P = 0.007). Thus, many patients undergoing PCI for an ACS event might benefit from aspirin discontinuation and maintenance on ticagrelor monotherapy after 1 month of DAPT. But before modifying clinical practice guidelines, it is necessary to confirm that the present results obtained mainly in an Asian population (only 1.2% were Europeans) can be extrapolated to Western populations. Whether the present results can be observed with prasugrel and clopidogrel merits further investigation.
Clinical trials with negative results
The DEPOSITION (Decreasing Postoperative Blood Loss by Topical vs. Intravenous Tranexamic Acid in Open Cardiac Surgery) trial studied whether topical tranexamic acid (TXA) administered directly to the surgical site reduces the risk of in-hospital seizure without increasing the risk of transfusion among patients undergoing cardiac surgery on cardiopulmonary bypass as compared with intravenous (i.v.) TXA.8 Topical TXA did not reduce in-hospital seizures but increased red blood cell transfusions compared with i.v. TXA. Thus, trial was stopped early for safety. The trial, however, was underpowered for detecting differences in seizures. These results do not support the use of topical TXA in cardiac surgery.
The TACT (Trial to Assess Chelation Therapy) trial reported that chelation therapy with an ethylenediaminetetraacetic acid (EDTA)-based infusion regimen significantly reduced the primary endpoint (death, re-infarction, stroke, coronary revascularization, or hospitalization for angina) in patients with diabetes and prior MI.9 However, these results were not confirmed in the TACT2 (Trial to Assess Chelation Therapy 2) trial, where EDTA disodium-based chelation did not improve clinical outcomes, possibly because the basal blood lead levels were lower and a greater proportion of patients were treated with new glucose-lowering drugs [i.e. glucagon-like peptide-1 receptor agonists (GLP-1RA), sodium-glucose cotransporter-2 inhibitors (SGLT2I)] that improve cardiovascular outcomes and were not available in the TACT trial.10 Thus, chelation therapy is not indicated in older adults with a history of MI and diabetes mellitus.
The PROACT (Can we Prevent Chemotherapy-related Heart Damage in Patients With Breast Cancer and Lymphoma?) trial found that in patients treated with high-dose anthracycline chemotherapy for breast cancer or lymphoma, enalapril did not modify troponin T release or troponin I levels, left ventricular (LV) ejection fraction (LVEF), or LV global longitudinal strain.11 These results suggest that angiotensin-converting enzyme inhibitors are unlikely to play a significant role in the prevention of anthracycline-induced cardiotoxicity.
Additionally, the AEGIS-II (Study to Investigate CSL112 in Subjects With Acute Coronary Syndrome) trial found that among patients with acute MI (AMI), multi-vessel coronary artery disease, and additional cardiovascular risk factors, four weekly infusions of CSL112 (a human APO A1 derived from plasma) did not result in a lower risk of MI, stroke, or death from cardiovascular causes than placebo through 90 days.12 A higher number of hypersensitivity events were reported in the CSL112 group.
Negative clinical trials with promising results
The EMPACT-MI (Effect of Empagliflozin on Hospitalization for Heart Failure and Mortality in Patients With Acute Myocardial Infarction) trial found that early initiation of empagliflozin (10 mg o.d.) in patients hospitalized for AMI at an increased risk for HF did not reduce the risk of a first hospitalization for HF or death from any cause compared with placebo.13 However, as expected from previous studies, in patients after AMI with LV dysfunction or congestion, empagliflozin significantly reduced the risk for first and total HF hospitalizations compared with placebo.14
The IMPROVE-HCM (A Study to Evaluate the Safety, Tolerability, and Efficacy of IMB-1018972 in Patients With Non-obstructive Hypertrophic Cardiomyopathy Trial) trial analysed the short-term safety of ninerafaxstat (IMB-1018972), a new mitotrope that increases myocardial metabolic efficiency, in patients with non-obstructive hypertrophic cardiomyopathy (HCM). At 12 weeks, more treatment emergent serious adverse events occurred in the ninerafaxstat group than in the placebo group.15 Interestingly, ninerafaxstat improved ventilatory efficiency (VE/VCO2 slope; P = 0.006) and in a post hoc analysis, it improved the KCCQ-CSS in patients with a baseline score ≤80 (P = 0.04). These results open a new therapeutic approach via improving abnormal myocardial energetics in patients with non-obstructive HCM.
Currently, AMI guidelines regarding β-blocker utilization for secondary prevention in patients with preserved LVEF are uncertain. The REDUCE-AMI (Randomized Evaluation of Decreased Usage of Beta-Blockers after Acute Myocardial Infarction) trial showed that in this population, long-term treatment with metoprolol or bisoprolol did not reduce all-cause death or new non-fatal MI among patients with AMI and preserved LVEF (≥50%) compared with usual care.16 There were also no differences in other secondary endpoints. These results suggested that patients with preserved LVEF following AMI may not benefit from β-blockers without another indication for their use. However, because of the limitation of this trial (Table 1) before quitting their use, it seems prudent to await the results of ongoing randomized trials evaluating the role of β-blockers in this population.
Aldose reductase (AR) catalyzes the first and rate-limiting step in the polyol pathway. Its activity is enhanced in hyperglycaemic conditions, leading to altered cardiac metabolism, increased oxidative stress, and adverse remodelling and its inhibition prevents diabetic cardiomyopathy (DbCM) in animal models.17 However, in the ARISE-HF (Safety and Efficacy of AT-001 in Patients With Diabetic Cardiomyopathy) trial the selective AR inhibitor AT-001 (caficrestat) did not improve exercise capacity compared with placebo in patients with DbCM at high risk of progression to overt HF. However, in a pre-specified subgroup analysis of patients not treated with SGLT2I or GLP-1RA, AT-001 (1.5 g b.i.d.) significantly improved peak VO2 and reduced the number of patients who experienced a clinically significant worsening in cardiac functional capacity ≥6%.18 Thus, further studies are needed to determine the impact of AT-001 in patients with DbCM.
The next challenge is to confirm some of the promising results observed with some of these drugs in future studies specifically designed for each purpose. Only in this way could we know their true role in the treatment of cardiovascular disease.
Funding
Ministerio de Ciencia e Innovación [PID2020-118694RB-I00], Comunidad de Madrid [P2022/BMD-7229], and Instituto de Salud Carlos III [CIBERCV: CB16/11/00303; CB16/11/00458].
Conflict of interest: The authors declare that there are no conflicts of interest.
Data availability
There are no new data associated with this article.
