Open questions — ischemic heart disease¶
Last curated: 2026-09-02
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 is recruiting 10,000 post-MI participants (NCT06118281).
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).
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.
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). Pragmatic trials should measure referral, enrollment, completion, maintenance, events, and equity.
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).
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 | ORBITA symptom/physiology predictors | INOCA endotyping | A unified pre-catheterization symptom–physiology model that predicts benefit from PCI versus CMD/spasm care | OQ-3, OQ-10 |
| 2 | CANTOS/COLCOT inflammatory benefit | TET2 clonal hematopoiesis | Prospective evidence that clone-defined inflammation predicts treatment interaction | OQ-4, OQ-5, OQ-19 |
| 3 | Low-attenuation plaque on CCTA | PREVENT lesion PCI | A strategy trial randomizing imaging-triggered systemic intensification before mechanical sealing | OQ-9, OQ-20 |
| 4 | REVIVED viability failure | STICHES CABG benefit | Direct mapping of scar, completeness, and route in the same ischemic-LV population | OQ-2, OQ-17 |
| 5 | Polygenic risk | Early cumulative LDL exposure | A young-adult trial in which genetic risk changes treatment and lifetime apoB burden | OQ-16, OQ-22 |
| 6 | CR mortality benefit | Post-MI psychological distress/kinesiophobia | Integrated CR–mental-health intervention powered for completion and events | OQ-14, OQ-27 |
| 7 | SECURE polypill benefit | Guideline LDL/BP individualization | Modular fixed-dose therapy with protocolized add-on titration | OQ-13, OQ-15 |
| 8 | Women’s symptom/troponin differences | INOCA prevalence | A diagnostic pathway trial measuring missed ACS and CMD recognition together | OQ-10, OQ-24 |
| 9 | Dynamic bleeding risk | Rehabilitation/falls/frailty data | Post-discharge antithrombotic updates using functional recovery rather than baseline variables only | OQ-8, OQ-14 |
| 10 | Lp(a) outcomes trials | Global treatment-access gap | Cost-effective screening/treatment strategies for LMIC health systems if trials are positive | OQ-7, OQ-13 |
| 11 | CLEAR SYNERGY neutrality | COLOCT/LoDoCo2 imaging | Mechanistic mediator that explains trial heterogeneity rather than post-hoc subgrouping | OQ-4, OQ-21 |
| 12 | Type 2 MI heterogeneity | Coronary plaque/CMD imaging | Mechanism-specific acute injury classification linked to treatment trials | OQ-20, OQ-23, OQ-26 |
| 13 | AF-PCI aspirin-withdrawal trials | Dynamic frailty/renal-function trajectories | A sequential antithrombotic strategy that changes with recovery rather than baseline risk alone | OQ-8 |
| 14 | Global IHD quality gap | Trial-proven polypill and CR interventions | A health-system factorial that measures eligible-population coverage, not efficacy among people who reached specialty care | OQ-13, OQ-14, OQ-15 |
| 15 | Sex-specific troponin pathways | INOCA/MINOCA mechanism testing | One diagnostic pathway that counts both missed acute MI and chronic nonobstructive coronary endotypes | OQ-10, OQ-24, OQ-26 |
| 16 | Sex-specific troponin recognition | Guideline-treatment delivery | A pathway that converts added injury detection into equal adjudication, prevention and outcomes | OQ-24, OQ-29 |
| 17 | Neutral all-comer ECLS | Shock-stage heterogeneity | A prespecified physiological rule that identifies benefit before device harms accrue | OQ-28 |
| 18 | Total lipid-lowering events | Recurrent antithrombotic events | A common recurrent-event estimand weighting fatal, disabling and procedural outcomes transparently | OQ-8, OQ-30 |
| 19 | SCAD patient-initiated evidence | STEMI reperfusion networks | Pre-angiographic recognition and registry evidence for a rare substrate where routine lysis may misfit | OQ-31 |
| 20 | Cumulative young-adult LDL | Current threshold-based intensification | A validated exposure-history trigger tested for lifetime clinical benefit | OQ-16, OQ-32 |