Top Breakthrough Cardiovascular Clinical Trials to Watch in 2026

TL;DR

2026 is the year cardiology finally tests whether lowering lipoprotein(a) prevents heart attacks and strokes — with the Lp(a)HORIZON readout of pelacarsen due mid-year — and the year obesity drugs, finerenone, transcatheter tricuspid replacement and pulsed field ablation each move from "promising" to potentially standard of care.

For UK patients, the most consequential mid-2026 readouts to watch are Lp(a)HORIZON (pelacarsen), REDEFINE-HF (finerenone in hospitalised HFpEF), and the first phase 3 readouts of Eli Lilly's TRIUMPH programme for retatrutide.

Expect headline disappointments too: OCEAN(a)-Outcomes (olpasiran) has slipped to 2027, REDEFINE 4 already failed to show non-inferiority versus tirzepatide, and AVANT GUARD showed pulsed field ablation worked but with a stroke signal that complicates a clean victory lap.

Why 2026 matters

For most of the past two decades, cardiology's biggest breakthroughs have been refinements: a better stent, a safer anticoagulant, an SGLT2 inhibitor repurposed for heart failure. 2026 is different. Within a single calendar year, four parallel revolutions in cardiovascular medicine are converging on their pivotal readouts.

The first revolution is genetic. Lipoprotein(a), or Lp(a), is an inherited cholesterol-like particle that affects about one in five people worldwide and that no diet, statin or PCSK9 inhibitor meaningfully lowers (for related adjunct biomarkers, see Homocysteine and Heart Disease). By mid-2026, Novartis is expected to release results from Lp(a)HORIZON, the first cardiovascular outcomes trial of any Lp(a)-lowering therapy in history.

The second revolution is metabolic. SELECT showed semaglutide cut three-point MACE by 20% (HR 0.80, 95% CI 0.72–0.90) over 40 months in people with obesity and established cardiovascular disease. In 2026 the question shifts from "does this class work?" to "how far does it go, and which molecule is best?"

The third revolution is structural and electrical. Transcatheter tricuspid valve replacement, pulsed field ablation (PFA), early intervention in asymptomatic aortic stenosis and next-generation left atrial appendage occlusion are all generating phase 3 randomised data in 2026.

The fourth revolution is heart failure pharmacology. Finerenone's expansion from diabetic kidney disease into the entire HFmrEF/HFpEF spectrum — and now into the acutely decompensated, hospitalised population through REDEFINE-HF — is the most consequential addition to the heart failure armamentarium since SGLT2 inhibitors.

2026 trial readout timeline

Lipids and Lp(a): the year of the genetic risk factor

Lp(a)HORIZON — pelacarsen (Novartis/Ionis)

Pelacarsen is an antisense oligonucleotide that binds the messenger RNA encoding apolipoprotein(a) and, in phase 2, lowered Lp(a) by up to 80% on monthly subcutaneous dosing. Lp(a)HORIZON randomised 8,323 patients with established cardiovascular disease and Lp(a) ≥70 mg/dL to 80 mg pelacarsen monthly versus placebo on top of standard lipid-lowering therapy.

The primary endpoint is a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke and urgent coronary revascularisation. When the headline result lands, read the appendix with care — our guide on interpreting cardiovascular trial subgroup analyses explains how to tell signal from noise in the inevitable forest plots. Novartis announced, as part of its 2025 year-end earnings, that the phase 3 readout has slipped from 2025 to the first half of 2026, with regulatory submissions planned in the second half.

Why this readout matters: an estimated 1.4 billion people globally have Lp(a) ≥60 mg/dL, and no licensed pharmacological therapy lowers it. A positive Lp(a)HORIZON makes pelacarsen first-in-class and validates Lp(a) as a causal target for the whole biopharma sector. A negative result would force the field to rethink a 60-year-old hypothesis.

OCEAN(a)-Outcomes — olpasiran (Amgen) — now a 2027 story

Olpasiran is a small interfering RNA targeting the LPA gene in hepatocytes, dosed every 12 weeks. In OCEAN(a)-DOSE it cut Lp(a) by more than 95% at the top dose. OCEAN(a)-Outcomes enrolled approximately 7,297 patients with ASCVD and Lp(a) ≥200 nmol/L. On Amgen's Q1 2026 earnings call, R&D head Jay Bradner confirmed the trial has slipped past 2026. Pelacarsen will therefore have the field to itself for at least a year.

ACCLAIM-Lp(a) — lepodisiran (Eli Lilly)

Lepodisiran lowered Lp(a) by 94.8% from baseline at 360 days after two doses in the phase 2 ALPACA study. ACCLAIM-Lp(a) is enrolling roughly 12,500 patients in both primary and secondary prevention, with dosing every six months. Lilly has publicly guided to 2029 for the primary readout — but it is the only phase 3 Lp(a) trial enrolling true primary prevention patients.

CORALreef Outcomes — enlicitide (Merck): the oral PCSK9 story

Enlicitide decanoate (MK-0616) is an oral macrocyclic peptide PCSK9 inhibitor. The pivotal CORALreef Lipids phase 3 trial reported a 55.8 percentage-point placebo-corrected LDL-C reduction at week 24, declining modestly to 47.6 points at week 52, with safety comparable to placebo. The cardiovascular outcomes trial CORALreef Outcomes is now active and reads out after 2027. If approved, enlicitide would be the first oral PCSK9 inhibitor.

VERVE-102: one-and-done gene editing

VERVE-102 is an in vivo CRISPR base-editing therapy delivered by a GalNAc-LNP to inactivate the PCSK9 gene in hepatocytes — a single intravenous infusion designed to provide lifelong LDL-C lowering. The Heart-2 phase 1b trial reported in April 2025 that the highest dose (0.6 mg/kg) reduced LDL-C by a mean of 53% and PCSK9 protein by 60%, with no treatment-related serious adverse events across 14 dosed participants.

Mechanisms of lipid lowering being trialled in 2026

Heart failure, atrial fibrillation, valves and devices

REDEFINE-HF — finerenone in the hospitalised HFpEF patient

FINEARTS-HF (Solomon et al., NEJM 2024) established finerenone as the first MRA with class I evidence in HFmrEF/HFpEF, leading to FDA approval in July 2025. REDEFINE-HF randomises approximately 5,200 patients hospitalised with acute decompensated heart failure and LVEF ≥40% to finerenone versus placebo started in-hospital. Primary completion was scheduled for April 2026; AHA 2026 in New Orleans (7–10 November) is the most likely readout venue.

If positive, REDEFINE-HF would close the loop on finerenone's deployment from chronic outpatient through acute hospitalisation — the population at highest absolute event rate.

SUMMIT, SURMOUNT-MMO and the HFpEF/obesity convergence

The SUMMIT trial (Packer et al., NEJM 2025; N=731) showed tirzepatide reduced the composite of cardiovascular death and worsening heart failure events by 38% (HR 0.62, 95% CI 0.41–0.95) in patients with HFpEF and obesity. Sub-analyses presented through 2025–2026 showed reductions in left ventricular mass and pericardial/epicardial adipose tissue at 52 weeks, suggesting structural reverse remodelling.

SURMOUNT-MMO is an event-driven trial of approximately 15,000 adults with obesity (without diabetes) randomised to tirzepatide versus placebo. Primary completion is October 2027.

TRISCEND II 2-year — transcatheter tricuspid valve replacement

Severe tricuspid regurgitation has historically been the "forgotten valve." The Edwards EVOQUE TTVR system was FDA-approved in February 2024. At ACC 2026, Vinod Thourani presented the 2-year randomised TRISCEND II results: "I'm starting to feel a lot more comfortable saying that [TTVR] does help with mortality." The companion European Heart Journal publication (Lurz et al., 1 May 2026) showed the benefit was strongest in patients with the most severe baseline TR.

EARLY TAVR and Evolut Low Risk 6-year

EARLY TAVR (Généreux et al., NEJM 2024; N=901) showed that in asymptomatic patients with severe aortic stenosis, early TAVR halved the composite of death, stroke or unplanned cardiovascular hospitalisation versus clinical surveillance (HR 0.50, 95% CI 0.40–0.63).

The unresolved question is durability in younger patients. The Evolut Low Risk 6-year data (Forrest et al., JACC 2026) showed a higher reintervention risk with TAVI emerging between years 6 and 7 — exactly the horizon at which a 60-year-old patient implanted today would be considering a second valve.

CHAMPION-AF — Watchman FLX versus DOAC

CHAMPION-AF (Doshi, Kar et al., NEJM 2026) randomised 3,000 patients with non-valvular AF eligible for long-term anticoagulation to Watchman FLX LAAC versus a DOAC. At 3 years, the primary composite occurred in 81 device patients versus 65 DOAC patients (absolute difference 0.9%), meeting non-inferiority. Non-procedure-related bleeding occurred in 10.9% (device) versus 19% (DOAC). Ischaemic stroke was numerically slightly higher in the device arm.

AVANT GUARD and ADVENT-LTO — pulsed field ablation matures

AVANT GUARD (Wazni et al., NEJM 2026; N=310) randomised patients with persistent AF 2:1 to PFA-first versus antiarrhythmic drug therapy. PFA reduced the risk of treatment failure by 54% (HR 0.46, 95% CI 0.33–0.65). Device- or procedure-related serious adverse events occurred in 5.1% of the PFA group — but six strokes occurred in the PFA arm, prompting vigorous debate at Heart Rhythm 2026.

The 4-year ADVENT-LTO follow-up (Reddy et al., Nature Medicine 2026) confirmed durable effectiveness (72.8% PFA vs 64.3% thermal at four years).

Obesity and GLP-1 / GIP / glucagon: the cardiometabolic frontier

The 2026 obesity-cardiovascular story is best understood as four parallel races.

Lilly's tirzepatide (Mounjaro / Zepbound) holds the lead with SURPASS-CVOT (NEJM December 2025; HR 0.92 for MACE non-inferiority vs dulaglutide, with a prespecified secondary mortality reduction of HR 0.84) and SURMOUNT-MMO (Oct 2027) anchoring its cardiovascular evidence base.

Novo Nordisk's CagriSema has had a difficult 2026: REDEFINE 4 (reported 23 February 2026) showed CagriSema achieved 23.0% weight loss but failed non-inferiority versus tirzepatide 15 mg (25.5% weight loss). REDEFINE 3, the 7,101-patient CV outcomes trial, has a completion date of October 2027.

Lilly's retatrutide — a triple GLP-1/GIP/glucagon receptor agonist — is the most exciting metabolic asset of 2026. TRIUMPH-1 (reported 21 May 2026) showed 28.3% weight loss at 80 weeks on the 12 mg dose, the largest weight loss ever achieved by an injectable in a phase 3 trial. TRIUMPH-3, expected later in 2026, will provide the first prospective data in patients with established CVD.

Orforglipron, Lilly's once-daily small-molecule oral GLP-1, met its primary CV safety endpoint (MACE-4 non-inferiority versus insulin glargine) in ACHIEVE-4 in early 2026, with a hypothesis-generating 57% lower all-cause mortality signal (HR 0.43, 95% CI 0.25–0.75). If approved, orforglipron would be the first orally available GLP-1 receptor agonist that does not require food/water timing restrictions — a manufacturing and access game-changer.

Comprehensive 2026 trial summary

Where each trial fits in the patient pathway

What 2026 collectively means for the next decade

The cumulative effect of these readouts is that, by the end of 2026, six distinct cardiovascular populations will have either a new licensed therapy or near-imminent regulatory submission supporting one:

• People with high Lp(a) and prior cardiovascular events may have pelacarsen.
• People with statin-intolerance or who refuse injectable PCSK9 inhibitors may have oral enlicitide.
• People with HFmrEF/HFpEF hospitalised acutely may have finerenone evidence supporting in-hospital initiation.
• People with persistent atrial fibrillation may have PFA as first-line.
• People with severe tricuspid regurgitation may have TTVR as a guideline-recommended option.
• People with obesity and cardiovascular risk may have a credible choice between three to four incretin-based therapies, including the first orally bioavailable option.

The strategic shift is from "treat the consequences" to "treat the cause earlier." The 2010s were the decade of better treatment after a heart attack. The late 2020s are shaping up to be the decade of preventing the heart attack itself, in populations that statin-based prevention never adequately served.

Limitations and uncertainty

Readers should hold all of the above with appropriate epistemic humility. Pivotal trials get delayed: Lp(a)HORIZON was originally guided for 2025, now H1/mid-2026; OCEAN(a)-Outcomes was expected in 2026, now 2027. Trials miss their primary endpoints, as REDEFINE 4 demonstrated with CagriSema. Trials hit their primary endpoint with unsettling signals on secondary outcomes, as AVANT GUARD did with strokes despite a strong efficacy result.

Surrogate endpoints — LDL-C reduction, Lp(a) reduction, weight loss — do not automatically translate into mortality benefit; the field has been burned multiple times before (CETP inhibitors, niacin, fibrates added to statins) by drugs that moved biomarkers convincingly but failed to prevent events.

The ESC Congress 2026 Hot Line programme (Munich, 28–31 August) will not be public until late June 2026. Confirmed Munich anchors include the new 2026 ESC Heart Failure Guidelines and the 5th Universal Definition of Myocardial Infarction.

Recommendations

For clinicians, three actions are warranted now:

1. Prepare to integrate Lp(a) testing into routine cardiovascular risk assessment ahead of any pelacarsen approval.
2. Audit your HFpEF population for finerenone eligibility today — uptake remains below 30% in most UK secondary care settings even though FINEARTS-HF already provides class I evidence.
3. Develop a structured discussion for patients with obesity and cardiovascular risk: SELECT, SUMMIT and SURPASS-CVOT have already changed the answer to "should this patient be on an incretin?" from "maybe" to "almost certainly."

For policy and commissioning, NICE technology appraisal pathways and NHS England commissioning for the most likely 2026 approvals — pelacarsen, enlicitide, retatrutide for obesity, EVOQUE TTVR — need to be planned now rather than reactively.

For patients and informed lay readers, the most actionable thresholds are:

• An Lp(a) above approximately 70 mg/dL (or 150 nmol/L) identifies a population with up to four- to fivefold elevated cardiovascular risk and is the population in which pelacarsen would first be licensed.
• A BMI of 27 kg/m² with one cardiovascular risk factor, or 30 kg/m² regardless of risk factors, places a person in the population studied across SELECT, SUMMIT, SURMOUNT-MMO and the orforglipron and retatrutide programmes.
• Anyone with persistent atrial fibrillation who has been told to "live with it" deserves a fresh conversation about pulsed field ablation given AVANT GUARD.

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Caveats

This is a forward-looking article written on 22 May 2026, when several pivotal 2026 trials had not yet read out. Specific readout dates beyond what trial sponsors have publicly guided to are inferences based on enrolment, event-driven design, and conference calendars and should not be treated as firm. The list of trials covered is selective rather than exhaustive — important trials in pulmonary hypertension (ADVANCE OUTCOMES — ralinepag), hypertrophic cardiomyopathy (mavacamten SCOUT-HCM), antiplatelet therapy (HOST-EXAM 10-year), chronic total occlusion PCI (ORBITA-CTO), and resistant hypertension (renal denervation trials) all reported important 2026 data but fall outside the four categories specified by this brief. Treatment decisions must always be individualised in consultation with a cardiologist or general practitioner.