Open questions — ischemic heart disease¶
Last curated: 2026-10-29
Stable identifiers are retained when questions are revised. Tier 1 questions could change practice and are designable now; Tier 2 questions require methods, longer follow-up, or stronger preliminary evidence.
Tier 1 — practice-changing and designable now¶
OQ-1 — Does any stable-CAD subgroup gain survival from PCI?¶
COURAGE and ISCHEMIA found no overall death/MI benefit, while ISCHEMIA-EXTEND found lower cardiovascular but higher non-cardiovascular mortality and no net survival advantage (Boden 2007, PMID 17387127; Maron 2020, PMID 32227755; Hochman 2023, PMID 36335918). A prospectively defined trial or pooled strategy analysis should target excluded/high-risk anatomy and avoid post-hoc subgroup claims.
OQ-2 — CABG or PCI in ischemic LV dysfunction?¶
STICHES supports long-term CABG benefit; REVIVED shows no prognostic PCI benefit despite viability (Velazquez 2016, PMID 27040723; Perera 2022, PMID 36027563). STICH3C directly tests the routes (NCT05427370).
OQ-3 — Can placebo-controlled PCI response be predicted before the procedure?¶
Symptom phenotype, FFR/iFR, and dobutamine-stress ischemia each predict ORBITA-program response (Simader 2024, PMID 38759906; Foley 2025, PMID 39462291; Ahmed-Jushuf 2025, PMID 40335250). A locked multivariable score requires prospective sham-controlled validation.
OQ-4 — Who benefits from colchicine after conflicting trials?¶
COLCOT and LoDoCo2 reduced events; CLEAR SYNERGY was neutral in acute MI (Tardif 2019, PMID 31733140; Nidorf 2020, PMID 32865380; Jolly 2025, PMID 39555823). A biomarker/enrichment trial should test timing, adherence, hsCRP, CKD and clonal hematopoiesis interactions.
OQ-5 — Does hsCRP-guided anti-inflammatory care improve outcomes?¶
CANTOS used hsCRP enrichment, but live PubMed and ClinicalTrials.gov searches repeated on 2026-09-02 found no completed strategy trial that titrates colchicine or another therapy to an hsCRP target (Ridker 2017, PMID 28845751). RIGHT registered hsCRP-enriched colchicine randomization, but its record is stale and remains status unknown with no posted results (NCT06025071). A decisive test should randomize a biomarker-guided algorithm rather than drug versus placebo alone.
OQ-6 — Does IL-6 inhibition achieve net cardiovascular benefit?¶
Ziltivekimab lowers inflammatory biomarkers, but outcomes and infection/competing mortality determine value (Wada 2023, PMID 37211246). ARTEMIS (10,000 post-MI participants) closed recruitment and is active, not recruiting as of the 2026-09-09 registry update (NCT06118281). ZEUS completed in June 2026 with no primary publication in PubMed or Europe PMC on 2026-10-22 (NCT05021835). HERMES, in HFpEF/HFmrEF rather than atherosclerosis, was terminated on 2026-09-03 and is reported as stopped for futility (NCT05636176; Packer 2026, PMID 42833572). Sharpened 2026-10-22: ZEUS is now the first readout that can answer the question for atherosclerotic events.
OQ-7 — Does selective Lp(a) lowering prevent events?¶
PCSK9 trials support residual lipid-risk reduction but do not isolate Lp(a). Lp(a)HORIZON and OCEAN(a)-Outcomes are outcome-scale tests (NCT04023552; NCT05581303). Sharpened 2026-10-22: HORIZON's September 2026 topline reported that pelacarsen lowered Lp(a) but did not reduce the primary composite, with full data awaited (Sabouret 2026, PMID 42880684); no peer-reviewed primary report was found in PubMed or Europe PMC on 2026-10-22. The question is now narrower and harder: is the null a property of pelacarsen (magnitude/duration of suppression, ASO pharmacology), of the population (late treatment after decades of exposure, intensive background therapy), or of the hypothesis that lowering Lp(a) in adults with established disease reduces events? OCEAN(a)-Outcomes (olpasiran every 12 weeks; primary outcome CHD death, MI or urgent coronary revascularization; primary completion estimated 2028-03) is the next test, and the full HORIZON report's results in the higher-Lp(a) primary population will decide how much weight the topline carries.
Rechecked 2026-10-29: targeted PubMed and Europe PMC searches found no primary HORIZON outcome report; registry results remain unposted. OCEAN(a)-Outcomes was updated on 27 October and remains active without recruitment or posted results (NCT04023552; NCT05581303). This is a finding in those sources, not an exclusion of conference or inaccessible registry results.
OQ-8 — What is the safest effective DAPT duration for an individual patient?¶
TWILIGHT and MASTER DAPT support abbreviated/aspirin-withdrawal strategies in selected patients, while extended DAPT reduces MI/stent thrombosis at a bleeding cost (Mehran 2019, PMID 31556978; Valgimigli 2021, PMID 34449185; Mauri 2014, PMID 25399658). STOPDAPT-2 and SMART-CHOICE add short-DAPT evidence from East Asian populations, but agent, ACS mix, adherence, stent platform, and noninferiority margins constrain transportability (Watanabe 2019, PMID 31237644; Hahn 2019, PMID 31237645). A dynamic strategy should rerandomize or update treatment at 1, 3, 6, and 12 months and estimate CV death/spontaneous MI/stent thrombosis separately from intracranial/fatal and transfusion-requiring bleeding.
OQ-9 — Can vulnerable-plaque PCI add benefit to maximal systemic prevention?¶
PROSPECT identified high-risk morphology but low lesion-level positive predictive value; PREVENT then randomized prophylactic treatment of selected high-risk plaques and reported a lower 2-year target-vessel composite (0.4% versus 3.4%, absolute difference −3.0 points, 95% CI −4.4 to −1.8), with no significant difference in death or MI and event rates low in both arms (Stone 2011, PMID 21247313; Park 2024, PMID 38604213; NCT02316886). Longer-term target-lesion and patient-level events must be separated, and the composite's revascularization and unstable-angina components must be reported alongside hard events in an open-label design.
OQ-10 — Should coronary function testing become routine in persistent ANOCA/INOCA?¶
CorMicA improved symptoms and quality of life, while reduced CFR predicts events (Ford 2018, PMID 30266608; Kelshiker 2022, PMID 34849697). A strategy trial should test hospital use, repeated testing, function, and hard outcomes.
OQ-11 — Which post-MI patients with preserved EF benefit from beta-blockers?¶
REDUCE-AMI was neutral; ABYSS did not establish safe interruption (Yndigegn 2024, PMID 38587241; Silvain 2024, PMID 39213187). Trials should enrich for arrhythmia, residual ischemia, hypertension, or autonomic phenotypes.
OQ-12 — How should complete revascularization be timed after STEMI?¶
COMPLETE supports complete treatment; MULTISTARS AMI informs immediate versus staged timing (Mehta 2019, PMID 31475795; Stähli 2023, PMID 37634190). Anatomy, contrast load, renal function, and physiologic selection need a prespecified algorithm. Sharpened 2026-10-22: the selection half is partly answered — AIR-STEMI (n=1,823) found angiography-derived physiology guidance reduced the death/MI/stroke/ischemia-driven-revascularization composite versus angiography guidance (8.9% vs 13.7%; HR 0.62, 95% CI 0.47–0.83) and reduced contrast nephropathy or major bleeding (Biscaglia 2026, PMID 42670979). Component-level results were not read; timing and its interaction with the selection method remain open.
OQ-13 — Which implementation bundle closes the low-SDI mortality gap?¶
The IHD quality-of-care gradient persists despite effective generic therapies (Aminorroaya 2022, PMID 34041535). Cluster trials should compare integrated BP/LDL detection, reperfusion networks, polypills, and rehabilitation—not isolated educational interventions. The primary estimand should be population-level eligible-to-treated coverage and one-year CV death/recurrent MI, with time-to-reperfusion, LDL/BP attainment, CR completion, bleeding, catastrophic expenditure, and sex/rurality gradients as prespecified mediators.
OQ-14 — Can automatic hybrid rehabilitation eliminate access disparities?¶
CR reduces cardiovascular mortality; home and center models are broadly comparable in selected patients (Dibben 2023, PMID 36746187; McDonagh 2023, PMID 37888805). The 2026 Cochrane update (107 trials) places the clear 12-month gains in MI (RR 0.72) and hospitalization (RR 0.65), with the cardiovascular-mortality benefit accruing over longer follow-up (Dibben 2026, PMID 42754260). Uptake interventions raise enrolment (RR 1.19) and completion (RR 1.22) but with low-to-moderate certainty, and the review calls for trials in underserved populations (Long 2026, PMID 42823225). In Latin America and the Caribbean the 2025 ICCPR audit estimated median CR coverage of 2.9% per country, with systematic referral in 6.3% of programs (Ghisi 2026, PMID 42790273); SciELO/LILACS could not be searched (HTTP 403), so regional trial evidence on access interventions was not checked. Pragmatic trials should measure referral, enrollment, completion, maintenance, events, and equity.
Updated 2026-10-29: the dedicated ESC rehabilitation guideline is now catalogued (Bäck 2026, PMID 42661418). Recommendation strength does not answer the access-strategy question. SciELO and LILACS could not be searched (HTTP 403); this sweep cannot exclude additional regional implementation evidence.
OQ-15 — Can polypill and individualized titration coexist?¶
SECURE reduced MACE and improved adherence (Castellano 2022, PMID 36018037). A modular polypill strategy could test simplicity against dose flexibility and contraindication management.
Tier 2 — enabling science and longer-horizon questions¶
OQ-16 — Is there an LDL-C safety floor over decades?¶
FOURIER showed benefit and no major safety signal at median achieved LDL-C 30 mg/dL over median 2.2 years, not lifetime exposure (Sabatine 2017, PMID 28304224).
OQ-17 — Why did viability fail to select PCI benefit?¶
REVIVED found neither prognostic nor EF improvement despite mandated viability (Perera 2022, PMID 36027563). Scar topology, completeness, myocardial energetics, and route may outperform binary viability.
OQ-18 — What biological substrate explains plaque erosion?¶
Erosion differs from rupture and may support stent-sparing approaches in selected patients, but diagnostic certainty and recurrence risk remain unresolved (Braunwald 2013, PMID 23473110).
OQ-19 — Can clonal plaque immunity be targeted safely?¶
Human plaque T cells show clonal expansion and cross-reactivity, but antigen-specific therapy must avoid systemic immune harm (Chowdhury 2022, PMID 35430876).
OQ-20 — Can multimodal plaque prediction reach actionable positive predictive value?¶
CCTA low attenuation, plaque burden, physiology, AI features, inflammation, and thrombogenicity each carry signal; no prospective integrated strategy is validated (Williams 2020, PMID 32174130; Koo 2024, PMID 38752951).
OQ-21 — What is the causal mediator of colchicine benefit?¶
Clinical event reduction has not mapped consistently onto OCT plaque stability or pericoronary inflammation changes (Yu 2024, PMID 39166327; Fiolet 2025, PMID 40393691).
OQ-22 — Can polygenic risk scores be equitable and actionable?¶
Scores modestly improve prediction but ancestry transferability and strategy-level outcome benefit are incomplete (Marston 2023, PMID 36576811; Klarin 2022, PMID 34811547).
OQ-23 — Which INOCA endotypes are stable over time?¶
CFR, resistance, and provoked spasm can be discordant; longitudinal repeat-phenotyping data are limited (Kunadian 2020, PMID 32626906).
OQ-24 — How much IHD in women is misclassified as non-cardiac or non-obstructive benign disease?¶
Sex differences in symptom interpretation, thresholds, referral, and coronary phenotype make routine datasets vulnerable to ascertainment bias (Ferry 2019, PMID 31431112; Grant 2024, PMID 38548464). A diagnostic-pathway trial should use sex-specific assay thresholds but identical adjudication, mandate downstream mechanism testing after nonobstructive angiography, and count missed type 1 MI, diagnosed CMD/spasm/MINOCA substrate, repeat emergency visits, treatment, and patient-reported diagnostic invalidation.
OQ-25 — What patient-reported outcome set should anchor stable-CAD trials?¶
ORBITA shows that symptoms require blinded, frequent measurement; death/MI composites omit function, uncertainty, and medication burden (Al-Lamee 2018, PMID 29103656; Rajkumar 2023, PMID 38015442).
OQ-26 — How should type 2 MI be split for trials?¶
The diagnosis aggregates anemia, tachyarrhythmia, hypoxemia, hypotension and coronary mechanisms; one therapy is unlikely to fit all (White 2021, PMID 33372537).
Sharpened 2026-10-29: the Fifth Universal Definition already separates primary coronary pathology from secondary MI and procedure-related MI (Mills 2026, PMID 42666939, full text Table 1). The remaining question is how re-adjudication changes historical type 2 cohorts and treatment-effect estimates; it is no longer whether a more mechanistic taxonomy should be proposed. The EHJ correction still needs reconciliation (PMID 42905436).
OQ-27 — Can treatment of psychological distress improve cardiac as well as patient-reported outcomes?¶
Post-MI depression, anxiety and PTSD are common, but psychological interventions and cardiac endpoints remain heterogeneous (Chong 2025, PMID 40142595; Richards 2018, PMID 29212370).
OQ-28 — Which infarct-related shock phenotype benefits from mechanical circulatory support?¶
Routine early ECLS did not reduce 30-day mortality and increased moderate/severe bleeding and vascular complications, but a neutral all-comer strategy does not exclude benefit in a prospectively identifiable hemodynamic phenotype (Thiele 2023, PMID 37634145). A selection trial should define shock stage, LV/RV failure, arrest duration, lactate trajectory, timing relative to PCI, and device-related competing harms before randomization.
OQ-29 — How can added diagnostic sensitivity become equitable treatment benefit?¶
Sex-specific hs-troponin thresholds increased recognized myocardial injury by 42% in women but did not close treatment gaps or improve one-year outcomes (Lee 2019, PMID 31623760). A diagnostic-pathway trial must bundle assay thresholds with mechanism adjudication, explicit treatment protocols, and accountability for sex-stratified delivery.
OQ-30 — Should recurrent-event burden replace time-to-first event in secondary-prevention trials?¶
Bempedoic acid reduced total MACE-4 more than a first-event analysis alone reveals, while potent antiplatelet therapy also changes recurrent ischemic and bleeding events (Nicholls 2024, PMID 38231501; Murphy 2008, PMID 18682445). Trials should jointly report first events, recurrent events, death, and treatment discontinuation without allowing frequent revascularization to dominate fatal or disabling outcomes.
OQ-31 — What is the safest reperfusion strategy when STEMI is caused by suspected SCAD?¶
A small historical case-based review found only one complication among 19 thrombolysis-treated reports, whereas the AHA scientific statement emphasizes that SCAD is a distinct substrate requiring different evaluation and management (Jović 2015, PMID 26226727; Hayes 2018, PMID 29472380). Because randomized trials are improbable, a prospective international registry should record pre-angiographic probability, lytic exposure, dissection extension, rescue PCI/CABG, infarct size, and recurrence.
OQ-32 — Can cumulative LDL exposure improve treatment timing beyond a single measurement?¶
Cumulative and time-weighted LDL-C from young adulthood through midlife predicted CHD independently of the most recent midlife value (Zhang 2021, PMID 34550307). The unresolved question is whether a validated exposure-history measure changes treatment early enough to improve lifetime outcomes without unacceptable overtreatment.
Decision-ready specifications for highest-priority questions¶
| OQ | Minimum design | Primary estimand | Harms/competing events that cannot be hidden |
|---|---|---|---|
| OQ-2 | Pragmatic CABG-versus-PCI randomization in surgically eligible ischemic LV dysfunction, stratified by scar and coronary complexity | Restricted-mean survival free of HF hospitalization at 5 and 10 years | Periprocedural death/MI/stroke, AKI, bleeding, recovery time, repeat revascularization |
| OQ-4/5 | Biomarker-stratified colchicine or pathway-specific agent with a test-and-treat strategy arm | CV death/spontaneous MI/ischemic stroke by prespecified hsCRP/CHIP stratum | Serious/fatal infection, non-CV death, GI intolerance, discontinuation |
| OQ-8 | Sequential multiple-assignment trial updating antithrombotics after an event-free or event-containing landmark | Joint distribution of spontaneous MI/stent thrombosis and intracranial/fatal bleeding | Conditioning on survival/event-free adherence, transfusion, urgent surgery |
| OQ-10 | Function-testing care pathway versus symptom-matched empirical care | Angina/function plus unplanned cardiovascular-care days over 24 months | Procedural complications, false-positive labeling, drug adverse effects, missed noncoronary disease |
| OQ-13 | Health-system cluster factorial of reperfusion network, essential medicines/polypill, and automatic CR | One-year CV death/recurrent MI among all eligible residents, not only attendees | Catastrophic cost, treatment inequity, bleeding, displacement of other services |
| OQ-14/27 | Automatic hybrid CR with stepped psychological care versus automatic CR alone | CR completion and patient-reported function at 6 months, CV hospitalization at 24 months | Digital exclusion, falls/injury, worsening distress, unequal uptake |
| OQ-20 | Locked multimodal model followed by randomized model-guided care | Net clinical benefit of acting on the model, not C-statistic change | Incidental findings, invasive tests, contrast/radiation, unnecessary PCI |
These specifications prevent surrogate substitution. For example, ziltivekimab-induced hsCRP reduction is target engagement rather than an outcome (Ridker 2021, PMID 34015342); CCTA plaque discrimination is not proof that imaging-guided intervention helps (Williams 2020, PMID 32174130); and bleeding reductions in AF-PCI trials do not exclude small ischemic differences when those trials lack power for rare efficacy events (Lopes 2019, PMID 30883055; Cannon 2017, PMID 28844193).
Dots not yet connected¶
| # | Dot A | Dot B | The missing junction | Powers |
|---|---|---|---|---|
| 1 | In ORBITA-2, typical (Rose) angina (OR 1.9, 95% CrI 1.6–2.1), lower FFR (lower vs upper quartile OR 2.01, 95% CrI 1.79–2.26) and a higher dobutamine-stress score (OR 1.23, 95% CrI 1.13–1.35) each predicted placebo-controlled angina relief from PCI (Simader 2024, PMID 38759906; Foley 2025, PMID 39462291; Ahmed-Jushuf 2025, PMID 40335250). In ORBITA, among 131 patients, PCI increased exercise time by 48 s (95% CrI 6–92) at the 20th centile of computational microvascular resistance and by 16 s (95% CrI −29 to 61) at the 80th centile, with modest interaction evidence (Pr 83.1%) (Taylor 2026, PMID 42043369) | In patients without obstructive disease, invasive coronary function testing linked to stratified therapy improved the Seattle Angina Questionnaire summary score by 11.7 units at 6 months (95% CI 5.0–18.4) (CorMicA: Ford 2018, PMID 30266608). In isolated coronary microvascular dysfunction, abnormal coronary flow reserve predicts all-cause mortality (HR 5.44, 95% CI 3.78–7.83) and major adverse cardiovascular events (HR 3.56, 95% CI 2.14–5.90) (Kelshiker 2022, PMID 34849697). Across the same meta-analysis's mixed disease groups the all-cause mortality HR is 3.78 (95% CI 2.39–5.97) | ORBITA-program analyses suggest that microvascular dysfunction blunts PCI's symptomatic benefit, and CorMicA shows that endotype-directed therapy works when no stenosis is present. No trial has randomized patients who have both an obstructive stenosis and demonstrated microvascular dysfunction or vasospasm between PCI and endotype-directed medical therapy. Searched 2026-10-07: PubMed ("percutaneous coronary intervention"[tiab] OR PCI[tiab]) AND ("microvascular dysfunction"[tiab] OR "coronary microvascular"[tiab] OR vasospas*[tiab] OR "vasomotor"[tiab]) AND (angina[tiab]) AND randomized controlled trial[pt] returned 15 records, none such a trial; ClinicalTrials.gov interventional (microvascular dysfunction OR vasospasm OR INOCA) AND percutaneous coronary intervention AND stratified returned 0 |
OQ-3, OQ-10 |
| 2 | In 13,129 UK Biobank participants with established ASCVD, CHIP (prevalence 5.1%) predicted ASCVD events or death (adjusted HR 1.23, 95% CI 1.10–1.38), and large TET2 clones predicted them more strongly (HR 1.89, 95% CI 1.40–2.55) (Gumuser 2023, PMID 37197843) | The only clone-by-treatment data are exploratory. In CANTOS, the 103 TET2 carriers had a canakinumab MACE HR of 0.38 (95% CI 0.15–0.96; interaction P=0.14) (Svensson 2022, PMID 35385050). In LoDoCo2 (n=854), colchicine slowed the growth of TET2 clones (interaction P=0.04) but not the growth of all clones combined (P=0.13) (Mohammadnia 2025, PMID 40892620) | No trial has stratified randomization on CHIP status with clinical events as the powered outcome. The two registered anti-inflammatory trials enroll both TET2-CHIP and non-CHIP participants and use imaging endpoints, with 120 participants estimated and both recruiting: colchicine 0.5 mg versus standard care, primary percent change in total plaque volume at 12 months (NCT07362966, ages 40–85), and canakinumab 150 mg versus placebo, primary change in perivascular fat attenuation at 48 weeks (NCT06691217, ages 18 and older). A COLCOT sequencing analysis that did not stratify randomization on CHIP, and that added any coronary revascularization to the trial's primary endpoint, counted a composite event in 2 (4.2%) colchicine versus 4 (8.3%) placebo participants with TET2 CHIP at variant allele fraction ≥2% (HR 0.62, 95% CI 0.11–3.42; p=0.58), and in 58 (7.6%) versus 65 (8.7%) without TET2 CHIP (HR 0.85, 95% CI 0.60–1.21; p=0.36) (Tardif 2024, medRxiv doi:10.1101/2024.10.17.24315679, preprint, not peer reviewed). The canakinumab events interaction remains one post hoc subgroup (interaction P=0.14). Searched 2026-10-07: ClinicalTrials.gov clonal hematopoiesis AND (colchicine OR canakinumab OR ziltivekimab OR anti-inflammatory) returned 7 records, these 2 relevant; PubMed (canakinumab[tiab] OR colchicine[tiab]) AND ("clonal hematopoiesis"[tiab] OR "clonal haematopoiesis"[tiab] OR TET2[tiab]) returned 34 records, none an event-powered CHIP-stratified trial |
OQ-4, OQ-5, OQ-19 |
| 5 | CAD polygenic risk predicts MI most strongly before age 50 (HR per SD 1.72, 95% CI 1.56–1.89, versus 1.42 after age 60). Before age 50 it moves 20% of borderline-risk adults into statin-eligible risk (Marston 2023, PMID 36576811). In primary-prevention statin trials, high-PRS participants had a larger relative risk reduction (46% versus 26%; heterogeneity P=0.05) (Natarajan 2017, PMID 28223407) | Cumulative LDL-C exposure between ages 18 and 60 predicts CHD independently of the most recent midlife LDL-C. Comparing the top with the bottom quartile, the hazard ratio is 1.57 (95% CI 1.10–2.23; P for trend 0.01) in 18,288 participants. The same models found no association with ischemic stroke or heart failure (Zhang 2021, PMID 34550307) | In MI-GENES (ages 45–65), PRS disclosure raised statin initiation (39% versus 22%) and lowered LDL-C (96.5 versus 105.9 mg/dL) (Kullo 2016, PMID 26915630). A post hoc follow-up of completers (103 in the integrated-risk arm, 100 in the Framingham arm) counted 2 versus 9 MACE over a median 9.5 years (HR 0.20, 95% CI 0.04–0.94; P=0.042) (Naderian 2025, PMID 40151934). EE-PRS (NCT06820086) is active, not recruiting, with 2,714 participants enrolled: men aged 45–80 and women aged 55–80 on 1 January 2025, top 20% CAD polygenic risk, rosuvastatin 20 mg versus usual primary care (cholesterol-lowering treatment may still be started under ordinary guidelines), and time to major adverse cardiovascular events as the primary outcome. ClinicalTrials.gov API v2 on 2026-10-07, interventional studies for polygenic risk (statin OR lipid OR LDL OR cholesterol), returned 30 studies (pageSize 100, totalCount 30). NCT05603663 (status UNKNOWN, last updated 2022-10-28, 1,540 actual, ages 25–44) randomizes the timing of high-PRS disclosure; every arm may be treated for high cholesterol if appropriate, and the primary outcome is body-mass index at 12 months. NCT05850091 (active, not recruiting, last updated 2026-06-10, 200 estimated, ages 40–75, high CAD PRS and plaque causing less than 70% stenosis) factorially assigns rosuvastatin 20 mg with or without colchicine 0.6 mg versus placebo; the primary outcome is one-year change in non-calcified plaque volume, and ages 40–44 are eligible. NCT07087431 (recruiting, last updated 2026-03-19, 500 estimated, ages 30–75, not on an LDL-lowering medication) compares immediate with deferred CAD PRS disclosure; the primary outcome is 12-month change in LDL-C, and the trial does not assign a statin. NCT04291157 (status UNKNOWN, last updated 2020-02-27, 1,000 estimated, men 30–65 or women 40–70, high CVD PRS, no statin at entry) compares proactive SCORE-plus-PRS prevention with usual care; the primary outcome is the 10-year risk score at 12 months. No registered trial is powered for cardiovascular events from PRS-triggered lipid-lowering restricted to adults under 45. The PubMed query "polygenic"[tiab] AND ("young adult*"[tiab] OR "younger adults"[tiab] OR "aged 18"[tiab] OR "under 40"[tiab]) AND (statin*[tiab] OR "lipid-lowering"[tiab] OR LDL[tiab]) AND (trial[tiab] OR randomized[tiab] OR randomised[tiab]) returned 2 records on 2026-10-07 and cannot see registry-only trials. CENTRAL was not searched (HTTP 403) |
OQ-16, OQ-22, OQ-32 |
| 6 | Exercise-based CR reduces cardiovascular mortality (RR 0.74, 95% CI 0.64–0.86; 85 RCTs, 23,430 participants) (Dibben 2023, PMID 36746187) | Psychological interventions in CHD reduce cardiovascular mortality (RR 0.79, 95% CI 0.63–0.98) and depressive symptoms (SMD −0.27) (Richards 2018, PMID 29212370). Formally diagnosed depression affects 23.58% (95% CI 22.86–24.32) of patients after MI (Chong 2025, PMID 40142595) | The two mortality estimates come from separate trial populations. Trials that embed psychological treatment within CR are sized for symptoms or readmission, not cardiovascular death or MI. PATHWAY (n=332) reduced the Hospital Anxiety and Depression Scale total by 3.24 points (95% CI −4.67 to −1.81) at 4 months but "was not intended to assess cardiac outcomes" (Wells 2021, PMID 34148379). The event data that exist are readmission outcomes: null rehospitalization in Black 1998 (PMID 9584539), and fewer all-cause readmissions (12.0% versus 25.4%) and emergency visits (13.3% versus 35.6%) at one year in a 210-patient biofeedback trial whose participants were referred by cardiologists (Yu 2018, PMID 29297147). The report places that method in cardiac rehabilitation programs. Whether the two mortality effects add together when delivered in one programme is untested. Searched 2026-10-07: PubMed "cardiac rehabilitation"[tiab] AND (psycholog*[tiab] OR depress*[tiab] OR anxiety[tiab]) AND (mortality[tiab] OR "cardiovascular events"[tiab] OR "cardiac events"[tiab] OR MACE[tiab]) AND randomized controlled trial[pt] returned 60 records. The audit re-ran the same query on 2026-10-07 (count again 60) and read the abstracts of the nearest records. CBR-CARDIO (PMID 37189029) enrolls 410 patients and sets cardiac anxiety at 12 months as the primary outcome. A 200-patient trial of psychological support (PMID 41803954) set lipids and cardiac imaging as the primary outcomes and did not report event counts. None was a CR-embedded psychological trial powered for CV death or MI. CENTRAL was not searched (HTTP 403) |
OQ-14, OQ-27 |
| 11 | In recent MI, the two event trials disagree: COLCOT (≤30 days post-MI) HR 0.77 (95% CI 0.61–0.96) (Tardif 2019, PMID 31733140), and CLEAR SYNERGY HR 0.99 (95% CI 0.85–1.16), even though, in a 3-month subgroup, the least-squares mean CRP difference was −1.28 mg/L (95% CI −1.81 to −0.75) (Jolly 2025, PMID 39555823). A compatibility analysis finds CLEAR SYNERGY cannot be designated the outlier (Scheier 2026, PMID 42435998) | After ACS, the two OCT trials also disagree. In COLOCT (n=128), colchicine increased minimum fibrous-cap thickness by 34.2 µm (95% CI 9.7–58.6) (Yu 2024, PMID 39166327). In COCOMO-ACS (64 randomized; 57 with evaluable serial imaging, 29 placebo and 28 colchicine), minimum fibrous-cap thickness did not differ (P=0.18) but cap rupture was less frequent (placebo 27.6% versus colchicine 3.6%, P=0.03) (Psaltis 2025, PMID 39189611) | No colchicine study has measured serial plaque change and clinical events in the same participants, so plaque stabilization has never been tested as the mediator of event benefit. The only event-trial imaging substudy is cross-sectional, after a median 28.2 months of treatment (LoDoCo2 CT, n=151): pericoronary fat attenuation did not differ between arms (−79.5 versus −78.7 HU, p=0.236), and calcified-plaque volume was higher on colchicine (169.6 versus 113.1 mm³). It is a between-arm comparison, not a within-patient change, and it is not linked to events (Fiolet 2025, PMID 40393691). Searched 2026-10-07: PubMed ("COLCOT"[tiab] OR "CLEAR SYNERGY"[tiab] OR "LoDoCo2"[tiab]) AND ("optical coherence"[tiab] OR "intravascular"[tiab] OR "computed tomography"[tiab] OR "plaque"[tiab]) returned 14 records, and colchicine[tiab] AND ("myocardial infarction"[tiab] OR "acute coronary"[tiab]) AND ("optical coherence"[tiab] OR "intravascular ultrasound"[tiab] OR "computed tomography"[tiab] OR "plaque"[tiab]) AND (randomized[tiab] OR randomised[tiab]) returned 21 records; neither contained an event-linked imaging analysis |
OQ-4, OQ-21 |
| 15 | Sex-specific hs-troponin I thresholds increased myocardial-injury diagnoses by 42% in women versus 6% in men. Yet women's 1-year recurrent MI or CV death did not improve (adjusted HR 1.11, 95% CI 0.92–1.33), and women with injury remained less likely than men to undergo revascularization (15% versus 34%), receive dual antiplatelet therapy (26% versus 43%), or receive a statin (16% versus 26%) (High-STEACS: Lee 2019, PMID 31623760). The hs-assay with sex-specific thresholds identified 30% (27/90) of women with type 1 MI whom the older uniform-threshold assay had missed (Ferry 2019, PMID 31431112) | In women with MINOCA, OCT plus CMR identified a mechanism in 84.5% (98/116). Of those 98, 24.5% (24/98) were non-ischemic alternative diagnoses (myocarditis, takotsubo syndrome or cardiomyopathy), which is 20.7% (24/116) of all women imaged (Reynolds 2021, PMID 33191769) | High-STEACS changed the threshold alone. Multimodality mechanism imaging has been applied only to women already diagnosed with MI after angiography. No study has applied OCT/CMR mechanism testing to the patients newly reclassified by sex-specific thresholds, so it is unknown what share of the added 42% is type 1 MI, MINOCA substrate or non-ischemic injury. Searched 2026-10-07: PubMed ("sex-specific"[tiab]) AND troponin[tiab] AND (MINOCA[tiab] OR INOCA[tiab] OR "coronary function"[tiab] OR "microvascular"[tiab] OR "magnetic resonance"[tiab]) returned 12 records, none such a study; ClinicalTrials.gov sex-specific troponin AND (MINOCA OR cardiac magnetic resonance OR optical coherence tomography) returned 12 records, none relevant |
OQ-10, OQ-24, OQ-26 |