Table 2.
Clinical trials that did not reach the primary endpoint (negative trials) or provided neutral effectsa
| Trialb | Trial design/population | Treatment | Primary endpoint | Results |
|---|---|---|---|---|
| Clinical trials with negative results | ||||
| ARCADIA60 NCT03192215 | Phase 3, R, DB trial. 1015 with cryptogenic stroke and atrial cardiopathy Female: 54.3% FU: 1.8 years |
Apixaban, 2.5 or 5 mg b.i.d. vs. aspirin, 81 mg o.d. | Time-to-event analysis was recurrent stroke | The rate of recurrent stroke was similar with apixaban and placebo (4.4% and 4.4%). The trial was stopped for futility after a planned interim analysis |
| BICS58 ISRCTN10497306 | R, DB, PC trial. 515 with chronic obstructive pulmonary disease at high risk of exacerbation Female: 47% FU: 12 months |
Bisoprolol (1.25 mg o.d. up-titrated to 5 mg/day, using a standardized protocol) vs. placebo | Patient-reported chronic obstructive pulmonary disease exacerbations treated with oral corticosteroids and/or antibiotics during FU | Bisoprolol did not reduce the number of self-reported chronic obstructive pulmonary disease exacerbations requiring treatment with oral corticosteroids and/or antibiotics |
| CHANCE-368 NCT05439356 | Phase 3, DB, R, PC trial. 8343 with a minor-to-moderate IS or TIA and high-sensitivity C-reactive protein ≥2 mg/L Female: 37% FU: 90 days |
Colchicine (0.5 mg b.i.d. on days 1–3, followed by 0.5 mg daily thereafter) or placebo | Any new stroke (ischaemic or haemorrhagic) within 90 days after randomization | Low-dose colchicine initiated within 24 h of symptom did not reduce the risk of subsequent stroke (HR 0.98; 0.83–1.16; P = 0.79) or increase the risk of serious adverse events as compared with placebo within 90 days |
| CLEAR SYNERGY70 NCT03048825 | Phase 3, R, DD, 2-by-2 factorial design trial. 7062 with STEMI (95.2%) or NSTEMI (4.8%) who underwent PCI Female: 20% FU: 3 years |
Colchicine (0.5 mg o.d. if <70 kg; 0.5 mg b.i.d. if ≥70 kg; after 90 days, colchicine was given o.d.) vs. placebo | Time-to-event of the composite of CV death, recurrent MI, stroke, or unplanned ischaemia-driven coronary revascularization | Colchicine started soon after MI did not reduce the primary outcome (HR 0.99; 0.85–1.16; P = 0.93). The incidence of individual components of the primary outcome was similar in the two groups. Diarrhoea was more frequent with colchicine |
| CLEAR SYNERGY73 NCT03048825 | Spironolactone (25 mg o.d.) vs. placebo | Composite 1: CV death or new or worsening HF, evaluated as the total number of events Composite 2: first MI, stroke, new or worsening HF, or CV death |
Spironolactone did not reduce the first (aHR 0.91; 0.69–1.21; P = 0.51) or the second co-primary outcome (0.96; 0.81–1.13; P = 0.60) as compared with placebo. Hyperkalaemia and gynaecomastia were more frequent in the spironolactone group | |
| DAPA-MI64 NCT04564742 | Phase 3, PG, DB, PC, registry-based trial. 4017 without prior diabetes or chronic HF, presenting with AMI (STEMI/NSTEMI) and impaired LV systolic function Female: 20% FU: 1 year |
Dapagliflozin (10 mg o.d.) or placebo | Hierarchical composite of death, HF hospitalization, non-fatal MI, atrial fibrillation/flutter, T2D, NYHA functional class, and BW decrease ≥5% at the last visit | Dapagliflozin had no impact on the composite of CV death or HF hospitalization, but the analysis of the primary hierarchical composite outcome resulted in significantly more wins for dapagliflozin vs. placebo (win ratio, 1.34; 1.20–1.50; P < 0.001), mainly driven by the added cardiometabolic outcomes |
| DICTATE-AHF74 NCT04298229 | Phase 3, OL, P, R trial. 240 with or without T2D randomized within 24 h of hospitalization for hypervolemic AHF FU: day 5 or discharge |
Dapagliflozin 10 mg o.d. vs. usual care with protocolized diuretic titration | Diuretic efficiency expressed as cumulative weight change per cumulative loop diuretic dose, compared across treatment assignment | There were no differences in diuretic efficiency between dapagliflozin and usual care, but dapagliflozin reduced loop diuretic doses (P = 0.006) and i.v. diuretic up-titrations (P ≤ 0.05) to achieve equivalent weight loss as usual care and significantly improved median 24 h natriuresis and urine output |
| DEPOSITION62 NCT03954314 | Phase 3, R, DD, blinded trial. 3242 undergoing open cardiac surgery FU: hospital discharge or 10 days Female: 22.3% |
IV TXA (5 g) through surgery vs. topical intraoperative TXA (10 g) at the end of surgery | In-hospital seizure | Topical TXA did not reduce seizure incidence, but increased RBC transfusion use and severe haemorrhage requiring ≥4 RBC units. The DSMB stopped the trial for safety concerns |
| EMPACT-MI66 NCT04509674 | Phase 3, event-driven, R, DB, PC trial 6522 hospitalized for AMI and at risk for HF Female: 25% FU: 17.9 months |
Empagliflozin 10 mg o.d. vs. placebo in addition to standard care within 14 days of admission | Composite of HF hospitalization or all-cause mortality | Empagliflozin did not reduce the primary endpoint vs. placebo (P = 0.21), but reduced first (HR, 0.77; 0.60–0.98; P = 0.031) and total HF hospitalizations (0.67; 0.51–0.89; P = 0.006) across the spectrum of LVEF and congestion risk profiles. Serious AEs were similar in both groups |
| OCEANIC-AF61 NCT05643573 | Phase 3, DB, DD, R, PG trial. 14 810 high-risk patients with AF Mean CHA2DS2-VASc score 4.3 Female: 35% FU: 1 year |
Asundexian (50 mg o.d.) vs. standard-dose apixaban | Whether asundexian is at least non-inferior to apixaban for the prevention of stroke or systemic embolism | The trial was stopped prematurely because asundexian increased the risk of stroke or systemic embolism vs. apixaban (HR 3.79), but produced fewer major bleeding events (0.32; 0.18–0.55) |
| REDUCE-AMI56 NCT03278509 | Phase 4, OL, R, PG, trial. 5020 within 1–7 days post-MI and LVEF ≥50% obtained from the SWEDEHEART and Swedish Population Registries Female: 23% FU: 3.5 years |
Metoprolol (median ≥100 mg) or bisoprolol (median ≥5 mg) or no β-blocker (usual care) | Composite of all-cause mortality or MI | Among patients with AMI with HFpEF, long-term β-blocker treatment did not lower the risk of all-cause mortality or MI vs. usual care (7.9% vs.8.3%; HR 0.96; 0.79–1.16; P = 0.64) and the cumulative incidence of any of the secondary endpoints |
| RESPECT-EPA75 UMIN000012069 | P, R, OL, blinded endpoint trial. 3884 patients with stable CAD and a low EPA/AA ratio (median 0.243) treated with statins for at least 1 month Females: 17% FU: 5 years |
EPA (1800 of icosapent ethyl daily) or control group | Composite of CV death, non-fatal MI, non-fatal ischaemic stroke, unstable angina pectoris, and coronary revascularization | The primary endpoint occurred in fewer patients in the EPA group (HR 0.79; 0.62–1.00; P = 0.055). The secondary composite endpoint of coronary events was significantly lower in the EPA group (0.73; 0.55–0.97; P = 0.03). The rate of new-onset AF was higher in the EPA group (3.1% vs. 1.6%; P = 0.017) |
| Clinical trials with neutral results | ||||
| AβYSS57 NCT03498066 | Phase 4, OL, R, non-inferiority trial. 3698 with an MI, LVEF ≥40%, and no history of a CV event in the previous 6 months Female: 17% FU: 3 years |
Interruption or continuation of β-blocker treatment | Composite of death, non-fatal MI, non-fatal stroke, or CV hospitalization at the longest follow-up (minimum, 1 year) | Interruption of long-term β-blocker treatment was not found to be non-inferior to a strategy of β-blocker continuation (HR 1.16; P = 0.44 for non-inferiority). β-Blocker interruption did not improve patients’ quality of life |
| CONVINCE69 NCT02898610 | Phase 3, R, PG, OL trial. 3154 with non-severe, non-cardioembolic IS or high-risk TIA Female: 30% FU: 28 days |
Colchicine (0.5 mg orally per day) plus guideline-based usual care vs. usual care only | Composite of first fatal or non-fatal recurrent IS, MI, cardiac arrest, or hospitalization for unstable angina | There was no difference in the primary endpoint in patients on colchicine vs. placebo (HR 0.84; 0.68–1.05; P = 0.12) or the rates of serious adverse events in both groups |
| PARADISE-MI71 NCT02924727 | Phase 3, R, DB, PG trial. 5661 with STEMI/NSTEMI (76%/24%), LV dysfunction, pulmonary congestion, and ≥1 risk-enhancing factor Female: 24% FU: 23 months |
Sacubitril–valsartan (target dose 97/103 mg b.i.d.) vs. ramipril (target dose of 5 mg b.i.d.), in addition to standard treatment | Cardiovascular death or incident HF, whichever occurred first | The incidence of the primary outcome did not differ between the sacubitril/valsartan and the ramipril groups, irrespective of the type of AMI |
| STOP-or-NOT trial72 NCT03374449 | OL, R, pragmatic trial. 2222 treated with ACEIs and ARBs for ≥3 months before major non-cardiac surgery Female: 35% FU: 28 days |
Continuation vs. discontinuation of ACEIs/ARBs 48 h prior to surgery | Composite of all-cause mortality and major post-operative complications within 28 days after surgery | Discontinuation of ACEIs/ARBs did not increase the rate of all-cause mortality or major post-operative complications. Episodes of hypotension during surgery occurred were more frequent and longer in the continuation strategy |
ACEIs, angiotensin-converting enzyme inhibitors; AF, atrial fibrillation; AHF, acute heart failure; aHR, adjusted hazard ratio; AMI, acute myocardial infarction; ARBs, angiotensin receptor blockers; b.i.d., twice daily; CAD, coronary artery disease; CV, cardiovascular; DB; double-blind; DD, double-dummy; DSMB, Data and Safety Monitoring Board; FU, follow-up; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; HR, hazard ratio; IS, ischaemic stroke; ISRCTN, the UK's Clinical Study Registry; i.v., intravenous; LV, left ventricular; LVEF, left ventricular ejection fraction; MI, myocardial infarction; NCT, ClinicalTrials.gov identifier; NSTEMI, non-ST-elevation myocardial infarction; o.d., once daily; OL, open label; P, prospective; PC, placebo-controlled; PCI, percutaneous coronary intervention; PG, parallel group; R, randomized; RBC, red blood cells; STEMI, ST-elevation MI; TIA, transient ischaemic attack; TXA, tranexamic acid.
a
In alphabetic order.
b
Acronyms of the trials are summarized in Supplementary material online, Table S1.