MAJOR CARDIOLOGY TRIALS - MASTER COMPENDIUM

MASTER COMPENDIUM — MAJOR CARDIOLOGY TRIALS (Ischemia, ACS, PCI, CABG, Lipids, HTN, Valves, HF-adjacent, VTE, PAD, Diabetes CVOTs, Stroke,Cardiac Electrophysiology, CRT, ICD, Atrial Fibrillation, VT etc.)

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1. ACUTE CORONARY SYNDROME / MYOCARDIAL INFARCTION / FIBRINOLYSIS

ISIS-2

Conclusion: Aspirin + streptokinase after acute MI markedly reduced mortality vs neither therapy.

Key Points: Established aspirin as essential; demonstrated benefit of early reperfusion with fibrinolysis.

GISSI-1 / GISSI-2

Conclusion: Early fibrinolysis reduced mortality; later GISSI refined therapies and showed benefits of ACE inhibitors and other measures.

Key Points: Important early large trials shaping acute MI care pathways.

GUSTO-I

Conclusion: Accelerated tPA strategy reduced 30-day mortality versus streptokinase in STEMI.

Key Points: Emphasized speed of reperfusion; informed primary PCI era transition.

DANAMI / DANAMI-2

Conclusion: Primary PCI superior to fibrinolysis for STEMI where timely PCI available.

Key Points: Supported development of regional PCI networks.

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2. PRIMARY PERCUTANEOUS CORONARY INTERVENTION (PCI) & STENT TRIALS

STENT TRIALS – SIRIUS, TAXUS, CYPHER-era

Conclusion: Drug-eluting stents (DES) dramatically reduced restenosis vs bare-metal stents (BMS).

Key Points: Reduced repeat revascularization; safety concerns about late thrombosis prompted prolonged DAPT.

SPIRIT / COMPARE / PLATINUM series

Conclusion: Newer-generation DES improved efficacy and safety over first-generation DES.

Key Points: Lower stent thrombosis and improved outcomes with thinner struts and better polymers.

PRISON / ISAR-REACT / CHAMPION trials (Cangrelor)

Conclusion: Intravenous antiplatelet agents (cangrelor) reduced periprocedural ischemic events in selected PCI populations.

Key Points: Useful in patients unable to take oral P2Y12 or needing rapid platelet inhibition.

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3. ANTIPLATELET / P2Y12 / DURATION TRIALS

CURE

Conclusion: Clopidogrel + aspirin reduced ischemic events vs aspirin alone in non-STEMI.

Key Points: Established dual antiplatelet therapy (DAPT) as standard.

TRITON-TIMI 38

Conclusion: Prasugrel superior to clopidogrel for ischemic events in ACS but increased bleeding.

Key Points: Stronger platelet inhibition → better ischemic protection but bleeding tradeoff.

PLATO

Conclusion: Ticagrelor reduced CV death, MI, or stroke vs clopidogrel in ACS with similar overall major bleeding.

Key Points: Faster on/off effect; mortality benefit compared to clopidogrel.

DAPT Trial

Conclusion: Extended DAPT (30 months) reduced stent thrombosis and MI but increased bleeding and all-cause mortality signal.

Key Points: Individualize DAPT duration based on ischemic vs bleeding risk.

PEGASUS-TIMI 54

Conclusion: Long-term ticagrelor + aspirin reduced ischemic events in prior MI patients at increased ischemic risk, with more bleeding.

Key Points: Long-term antiplatelet therapy can benefit select high-risk patients.

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4. STABLE ISCHEMIC HEART DISEASE / REVASCULARIZATION STRATEGIES

COURAGE

Conclusion: In stable CAD, PCI + OMT did not reduce death or MI vs optimal medical therapy (OMT) alone.

Key Points: Revascularization primarily for symptom relief; reinforces OMT.

BARI / BARI 2D (surgical vs PCI in diabetics)

Conclusion: CABG superior to PCI for diabetics with multivessel disease in long-term survival and repeat revascularization.

Key Points: Diabetes strong factor favoring CABG for multivessel CAD.

SYNTAX

Conclusion: CABG superior to PCI in complex (high SYNTAX score) 3-vessel or left main disease; comparable in lower complexity.

Key Points: Anatomy-guided decision-making (SYNTAX score) crucial.

FREEDOM

Conclusion: In diabetics with multivessel CAD, CABG reduced death and MI vs PCI (drug-eluting stents).

Key Points: Reinforced CABG as preferred revascularization in diabetic multivessel disease.

ISCHEMIA

Conclusion: In stable ischemic heart disease with moderate–severe ischemia, an initial invasive strategy did not reduce major adverse CV events vs conservative strategy over median follow-up.

Key Points: Revascularization reserved for symptoms or refractory ischemia; emphasizes medical therapy first.

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5. THROMBOLYSIS & EARLY REPERFUSION TRIALS (historic; informed modern practice)

TIMI studies (thrombolysis era)

Conclusion: TIMI risk scores and reperfusion trials improved understanding of MI risk stratification and therapy effect.

Key Points: Foundation for risk-based therapy and trials design.

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6. ANTI-THROMBOTIC STRATEGIES AFTER ACS / PCI

ATLAS ACS 2-TIMI 51

Conclusion: Very low–dose rivaroxaban added to standard antiplatelets reduced CV events after ACS but increased bleeding.

Key Points: Antithrombotic intensification reduces ischemic events at bleeding cost.

WOEST

Conclusion: In patients requiring OAC undergoing PCI, omitting aspirin (OAC + clopidogrel) reduced bleeding without increasing thrombotic events.

Key Points: Informs triple therapy minimization strategies.

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7. CORONARY ARTERY BYPASS GRAFTING (CABG) TRIALS

CABG vs Medical Therapy (pre-DES era)

Conclusion: CABG improved survival in left main disease and multivessel disease with LV dysfunction vs medical therapy.

Key Points: Surgery remains standard in complex disease and reduced EF.

ART / EXCEL (left main trials)

Conclusion: EXCEL showed PCI noninferior to CABG in selected low-to-intermediate complexity left main disease for certain endpoints; ART and longer follow-up nuance comparisons.

Key Points: Heart-team selection essential; patient anatomy and comorbidity guide choice.

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8. LIPID LOWERING TRIALS

4S (Scandinavian Simvastatin Survival Study)

Conclusion: Simvastatin reduced mortality and major coronary events in patients with CHD.

Key Points: Landmark proving statin mortality benefit.

PROVE-IT TIMI 22

Conclusion: Intensive statin therapy (high-dose) superior to moderate-dose for ACS outcomes.

Key Points: "Lower LDL → better outcomes" paradigm reinforced.

IMPROVE-IT

Conclusion: Adding ezetimibe to statin provided incremental reduction in CV events after ACS.

Key Points: Proof that further LDL lowering beyond statin improves outcomes.

JUPITER

Conclusion: Rosuvastatin reduced vascular events in patients with elevated CRP and normal LDL.

Key Points: Inflammation marker role and primary prevention expansion.

FOURIER (evolocumab) & ODYSSEY OUTCOMES (alirocumab)

Conclusion: PCSK9 inhibitors significantly lowered LDL-C and reduced ischemic events when added to statins.

Key Points: Powerful LDL reduction with clinical event benefit in high-risk patients.

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9. HYPERTENSION TRIALS

ALLHAT

Conclusion: Thiazide-type diuretics were at least as effective as ACEi or CCB in preventing major CV events.

Key Points: Thiazides are excellent first-line agents for many patients.

SPRINT

Conclusion: Intensive systolic BP target (<120 mmHg) reduced CV events and mortality vs standard (<140 mmHg) in high-risk non-diabetic adults.

Key Points: Aggressive BP control beneficial but increases some adverse events; patient selection essential.

HOPE

Conclusion: Ramipril reduced CV events in high-risk patients, many without heart failure.

Key Points: ACE inhibitors have broad vascular protective effects.

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10. HEART FAILURE (adjacent — important crossover trials already covered earlier)

(You already have the HF master list; included here only if cross-referencing needed.)

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11. VALVE / STRUCTURAL INTERVENTION TRIALS

PARTNER (TAVR series)

Conclusion: TAVR noninferior (and later superior in selected cohorts) to SAVR in high, intermediate, and low surgical risk patients for severe aortic stenosis.

Key Points: TAVR rapidly expanded from inoperable/high-risk to low-risk populations.

SURTAVI / CoreValve Evolut trials

Conclusion: Self-expanding TAVR platforms showed noninferiority to surgery in intermediate-risk patients.

Key Points: Multiple device platforms validated; valve selection individualized.

COAPT (Mitral TEER / MitraClip in secondary MR)

Conclusion: In patients with secondary (functional) MR and HF, MitraClip plus GDMT reduced HF hospitalizations and mortality vs GDMT alone.

Key Points: Powerful positive trial but with strict selection criteria.

MITRA-FR

Conclusion: No benefit of MitraClip vs medical therapy in a different population with less severe MR or more dilated ventricles.

Key Points: Discrepancy with COAPT highlights importance of patient selection and proportionate vs disproportionate MR concept.

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12. PERIPHERAL ARTERIAL DISEASE (PAD) & LIMB ISCHEMIA

COMPASS

Conclusion: Low-dose rivaroxaban + aspirin reduced major CV events and limb events in stable atherosclerotic disease vs aspirin alone, at cost of increased major bleeding.

Key Points: Combined low-dose anticoagulation strategy benefits selected atherosclerotic patients.

EUCLID

Conclusion: Ticagrelor not superior to clopidogrel for prevention of CV events in symptomatic PAD.

Key Points: No clear P2Y12 advantage in PAD population.

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13. VENOUS THROMBOEMBOLISM (VTE) / PULMONARY EMBOLISM

EINSTEIN-PE

Conclusion: Rivaroxaban noninferior to standard therapy for PE with convenient oral once-daily dosing.

Key Points: Supported DOAC adoption for VTE.

AMPLIFY

Conclusion: Apixaban noninferior to conventional therapy with less bleeding.

Key Points: DOACs safe and effective alternatives to warfarin for VTE.

HOKUSAI-VTE

Conclusion: Edoxaban noninferior for recurrent VTE vs warfarin with reduced bleeding when given after initial heparin.

Key Points: Supports multiple DOAC options.

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14. DIABETES CARDIOVASCULAR OUTCOME TRIALS (CVOTs)

EMPA-REG OUTCOME

Conclusion: Empagliflozin reduced CV death and HF hospitalization in diabetics.

Key Points: SGLT2 inhibitors confer major CV & HF benefits beyond glucose lowering.

CANVAS / CANVAS-R

Conclusion: Canagliflozin reduced HF hospitalization but raised concerns about amputation risk in some analyses.

Key Points: SGLT2 class benefit with device-specific safety signals investigated.

DECLARE-TIMI 58

Conclusion: Dapagliflozin reduced HF hospitalization; neutral for MACE.

Key Points: Consistent HF benefits across SGLT2 trials.

LEADER

Conclusion: Liraglutide (GLP-1 RA) reduced major adverse CV events in type 2 diabetes.

Key Points: GLP-1 RAs provide CV risk reduction, particularly for atherosclerotic events.

SUSTAIN-6 / REWIND / PIONEER

Conclusion: Other GLP-1 RAs (semaglutide, dulaglutide, etc.) show reductions in MACE in diabetics.

Key Points: GLP-1 class benefits for atherosclerotic events; choose agent-specific data.

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15. STROKE / CEREBROVASCULAR TRIALS (relevant to cardiology teams)

NINDS tPA Trial

Conclusion: IV tPA within 3 hours of ischemic stroke improved functional outcomes.

Key Points: Time-critical reperfusion concept for stroke.

DAWN / DEFUSE-3

Conclusion: Selected patients benefit from thrombectomy up to 16–24 hours using perfusion imaging selection.

Key Points: Imaging-guided late-window intervention changed acute stroke workflow.

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16. CARDIOGENIC SHOCK / MECHANICAL SUPPORT

IABP-SHOCK II

Conclusion: In cardiogenic shock complicating STEMI, intra-aortic balloon pump (IABP) did not reduce mortality.

Key Points: Routine IABP no longer recommended; selective use only.

Impella / ECMO observational studies and trials

Conclusion: Mechanical circulatory support devices used as salvage or bridge therapy; randomized evidence evolving.

Key Points: Patient selection and timing remain crucial.

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17. PREVENTION / RISK-MODIFICATION TRIALS

TLC / Lifestyle Trials (varied)

Conclusion: Smoking cessation, exercise, weight loss, BP and lipid control reduce CV events.

Key Points: Lifestyle modification remains foundational prevention.

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18. MISCELLANEOUS PRACTICAL TRIALS

POISE (perioperative beta-blocker trial)

Conclusion: Perioperative beta blockers reduced MI but increased stroke and mortality in some settings.

Key Points: Perioperative beta blocker initiation requires careful risk–benefit consideration.

SGLT2 in HF (already in HF list)

Conclusion: Class benefit in HF regardless of diabetes.

Key Points: Now standard HF therapy.

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SUMMARY & PRACTICAL TAKEAWAYS

• Reperfusion (primary PCI when timely) is the cornerstone of STEMI care; fibrinolysis still valuable where PCI delayed.

• DAPT and contemporary P2Y12 choices (ticagrelor/prasugrel) are guided by ischemic vs bleeding risk.

• Revascularization for stable CAD should be individualized — symptom relief is the primary indication in many cases; ISCHEMIA and COURAGE support optimal medical therapy first for many patients.

• Statins and intensive LDL lowering (including ezetimibe/PCSK9) reduce events; LDL ≈ primary modifiable risk target.

• SGLT2 inhibitors and GLP-1 RAs changed CV risk management in diabetes and HF.

• TAVR and structural therapies revolutionized valve management — careful patient selection essential (COAPT vs MITRA-FR lessons).

• DOACs replaced warfarin for most VTE/PE indications and many NVAF scenarios; tailored in ACS/PCI when OAC needed.

• PAD and systemic atherosclerosis may benefit from low-dose anticoagulation strategies (COMPASS) but bleeding risk must be weighed.

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ELECTROPHYSIOLOGY TRIALS

1. CARDIAC RESYNCHRONIZATION THERAPY (CRT) TRIALS

COMPANION (2004)

Conclusion: CRT-P and CRT-D significantly reduced HF hospitalization and all-cause mortality in NYHA III–IV HF on optimal medical therapy.

Key Points:

• CRT-D produced the largest mortality reduction.

• Established CRT as standard therapy in advanced HF with wide QRS.

CARE-HF (2005)

Conclusion: CRT reduced all-cause mortality and HF hospitalization in patients with severe HF and QRS prolongation.

Key Points:

• Strong evidence for CRT without an ICD.

• Marked improvement in LV remodeling.

MADIT-CRT (2009)

Conclusion: CRT-D reduced HF events in NYHA I–II HF with LBBB and LVEF ≤30%.

Key Points:

• Benefit strongest in LBBB ≥150 ms.

• Shifted CRT earlier in HF progression.

RAFT (2010)

Conclusion: CRT-D reduced mortality and HF hospitalizations in NYHA II–III patients.

Key Points:

• Major support for CRT in mildly symptomatic HF.

• Mortality benefit comparable to advanced HF groups.

REVERSE (2008)

Conclusion: CRT improved LV remodeling and delayed HF progression in NYHA I–II patients.

Key Points:

• First trial to show structural benefits in mild HF.

• No early mortality difference, but strong remodeling effects.

Echo-CRT (2013)

Conclusion: CRT in narrow QRS (<130 ms) increased mortality → trial stopped early.

Key Points:

• Mechanical dyssynchrony without QRS widening = harmful.

• Reinforced QRS width as essential selection criterion.

BLOCK-HF (2013)

Conclusion: CRT pacing superior to RV pacing for AV block with reduced EF.

Key Points:

• Prevents pacing-induced cardiomyopathy.

• First evidence for CRT in pacing-dependent patients.

BIOPACE (2021)

Conclusion: No significant mortality benefit of CRT over RV pacing in AV block.

Key Points:

• Conflicts with BLOCK-HF.

• Benefits may be limited to reduced EF subgroups.

2. IMPLANTABLE CARDIOVERTER-DEFIBRILLATOR (ICD) TRIALS

MADIT I (1996)

Conclusion: ICD reduced mortality in post-MI patients with NSVT and inducible VT on EP testing.

Key Points:

• First clear ICD mortality benefit.

• EP-guided risk stratification validated.

MUSTT (1999)

Conclusion: EP-guided therapy (ICD in majority) reduced arrhythmic death in CAD with NSVT and low EF.

Key Points:

• Supported ICD use in ischemic cardiomyopathy.

• Strengthened the role of EP testing historically.

MADIT II (2002)

Conclusion: ICD reduced mortality in post-MI LVEF ≤30% patients without EP testing.

Key Points:

• Simplified ICD eligibility.

• Landmark trial for primary prevention.

SCD-HeFT (2005)

Conclusion: ICD significantly reduced mortality in HFrEF (ischemic + nonischemic).

Key Points:

• Amiodarone showed no mortality benefit.

• Strongest ICD evidence in broad HF population.

DINAMIT (2004)

Conclusion: Early ICD implantation post-MI (<40 days) reduced arrhythmic death but did NOT improve overall mortality.

Key Points:

• High nonarrhythmic death offsets benefit.

• Led to 40-day waiting period rule.

IRIS (2009)

Conclusion: Similar results to DINAMIT: early post-MI ICD no mortality benefit.

Key Points:

• DO NOT implant ICD early after MI unless secondary prevention.

DEFINITE (2004)

Conclusion: ICD reduced arrhythmic death in nonischemic cardiomyopathy.

Key Points:

• Mortality signal favorable but not statistically significant.

• Helped support NICM ICD use.

DANISH (2016)

Conclusion: ICD did not reduce all-cause mortality in NICM overall.

Key Points:

• Mortality benefit present in age <70 years.

• High CRT use reduced overall event differences.

AVID / CIDS / CASH

Conclusion: ICD therapy superior to antiarrhythmic drugs for survivors of VT/VF.

Key Points:

• Foundation for secondary-prevention ICD indication.

• Amiodarone inferior to ICD for survival.

3. ATRIAL FIBRILLATION TRIALS

AFFIRM (2002)

Conclusion: Rate control equal to rhythm control for mortality.

Key Points:

• Rhythm control linked with more hospitalizations.

• Rate control safer in older patients.

RACE (2002)

Conclusion: Rate control non-inferior to rhythm control for major CV outcomes.

Key Points:

• Corroborated AFFIRM.

• Simplified AF management.

RACE II (2010)

Conclusion: Lenient rate control (<110 bpm) equal to strict rate control for outcomes.

Key Points:

• Avoid overly aggressive rate control.

• Changed rate-control targets globally.

RE-LY (2009)

Conclusion: Dabigatran 150 mg superior to warfarin for stroke prevention.

Key Points:

• 110 mg safer with similar efficacy.

• First major DOAC success.

ROCKET-AF (2011)

Conclusion: Rivaroxaban non-inferior to warfarin.

Key Points:

• Lower intracranial bleed risk.

• High-risk AF population.

ARISTOTLE (2011)

Conclusion: Apixaban superior to warfarin in mortality, stroke, and bleeding.

Key Points:

• Best overall DOAC trial results.

• Consistent across subgroups.

ENGAGE AF (2013)

Conclusion: Edoxaban non-inferior with lower bleeding risk.

Key Points:

• Once-daily DOAC option.

CABANA (2018)

Conclusion: Intention-to-treat neutral but ablation improved QoL and per-protocol mortality/CV outcomes.

Key Points:

• Ablation superior for rhythm maintenance.

• QoL benefit very strong.

CASTLE-AF (2018)

Conclusion: Ablation reduced mortality + HF hospitalization in HFrEF.

Key Points:

• Major shift for AF in HF.

• One of the strongest ablation trials ever.

EAST-AFNET 4 (2020)

Conclusion: Early rhythm control reduced death, stroke, and HF events.

Key Points:

• Overturned “rate first” paradigm.

• Supports early rhythm strategy.

4. ANTIARRHYTHMIC DRUG TRIALS

CAST (1989–1991)

Conclusion: Class Ic drugs increased mortality in post-MI PVC suppression.

Key Points:

• PVC suppression ≠ improved outcome.

• Avoid flecainide/encainide in structural heart disease.

SWORD (1996)

Conclusion: D-sotalol increased mortality in LV dysfunction.

Key Points:

• Reverse-use dependence hazardous.

• Avoid pure potassium-channel blockers in HF.

EMIAT & CAMIAT

Conclusion: Amiodarone reduced arrhythmias, mortality effect modest.

Key Points:

• Amiodarone best for arrhythmia control, not mortality.

ATHENA (2009)

Conclusion: Dronedarone reduced CV hospitalization.

Key Points:

• Safer than amiodarone but less effective.

ANDROMEDA (2008)

Conclusion: Dronedarone increased mortality in HF.

Key Points:

• Contraindicated in HFrEF.

PALLAS (2011)

Conclusion: Increased rates of stroke and death in permanent AF.

Key Points:

• Dronedarone should NOT be used in permanent AF.

5. PACEMAKER TRIALS

MOST (2002)

Conclusion: DDD pacing reduced AF vs VVI but no mortality difference.

Key Points:

• Supports physiologic pacing.

• Symptom improvement.

CTOPP (2000)

Conclusion: Physiologic pacing reduced AF and stroke.

Key Points:

• Mortality unchanged.

• Strong evidence against chronic VVI.

UKPACE (2005)

Conclusion: No mortality difference between DDD and VVI in elderly AV block.

Key Points:

• Elderly less sensitive to pacing mode.

DANPACE (2011)

Conclusion: DDD superior to AAI due to fewer re-operations.

Key Points:

• AAI caused later AV block in many patients.

ASSERT (2012)

Conclusion: Subclinical device-detected AF predicts stroke.

Key Points:

• Changed OAC decision-making.

Micra Leadless Trials

Conclusion: Leadless pacemakers had fewer lead/pocket complications.

Key Points:

• Ideal for VVI pacing needs.

6. CONDUCTION SYSTEM PACING (CSP)

His-SYNC (2018)

Conclusion: HBP achieved similar resynchronization to CRT.

Key Points:

• High crossover rates due to high thresholds.

HOPE-HF (2020)

Conclusion: AV-optimized HBP improved exercise capacity in prolonged PR.

Key Points:

• Restoring physiologic timing matters.

LBBAP Trials (Multiple 2020–2024)

Conclusion: LBBAP preserved EF and reduced HF hospitalization vs RV pacing.

Key Points:

• Lower thresholds and more stable than His-bundle pacing.

His-Alternative

Conclusion: HBP non-inferior to CRT for LV function and symptoms.

Key Points:

• Useful when CS lead fails.

7. VT ABLATION TRIALS

VANISH (2016)

Conclusion: Ablation superior to escalating AAD therapy in ischemic VT.

Key Points:

• Fewer ICD shocks and VT storms.

SMASH-VT (2007)

Conclusion: Prophylactic substrate ablation reduced ICD therapies.

Key Points:

• Supports substrate modification even without inducible VT.

VTACH (2010)

Conclusion: Ablation before ICD reduced recurrence and prolonged time to VT.

Key Points:

• Earlier ablation = better outcomes.

PARTITA (2022)

Conclusion: Ablation soon after first appropriate ICD shock improved outcomes.

Key Points:

• Timing matters—early ablation beneficial.

SURVIVE-VT

Conclusion: Early ablation reduces VT recurrence and ICD shocks.

Key Points:

• Increasing evidence favors early rhythm control in VT.

8. SUPRAVENTRICULAR TACHYCARDIA (SVT)

WPW Ablation Trials

Conclusion: Catheter ablation far superior to drug therapy.

Key Points:

• Nearly curative.

• Eliminates risk of AF → VF in WPW.

Cryo vs RF for AVNRT

Conclusion: Cryo safer near AV node, RF more durable.

Key Points:

• Cryo preferred in young patients.

Slow-Pathway RF Studies

Conclusion: Slow-pathway RF produces durable AVNRT cure.

Key Points:

• Gold standard technique.

9. ATRIAL FLUTTER TRIALS

CTI Ablation Trials

Conclusion: Ablation superior to antiarrhythmic drugs for typical flutter.

Key Points:

• Highly effective and curative.

Early Ablation vs Drug Therapy

Conclusion: Ablation reduces hospitalizations and recurrence.

Key Points:

• Prevents progression to AF.

10. SYNCOPE TRIALS

ISSUE-2 & ISSUE-3

Conclusion: Pacing effective for ILR-proven asystolic syncope.

Key Points:

• Documentation essential before pacing.

SPRITELY

Conclusion: Pacing reduced serious syncope outcomes in elderly.

Key Points:

• Supports pacing in high-risk older adults.

VASIS Tilt Studies

Conclusion: Tilt testing useful for diagnosis, limited therapeutic role.

Key Points:

• Does not reliably guide therapy.

11. MONITORING & REMOTE SURVEILLANCE TRIALS

IN-TIME (2014)

Conclusion: Remote ICD monitoring improved HF outcomes.

Key Points:

• Strong evidence for remote follow-up.

CONNECT

Conclusion: Remote ICD management reduced clinic visits and detection-to-action time.

Key Points:

• Improves workflow and patient safety.

LOOP (2021)

Conclusion: More AF detected but no significant stroke reduction.

Key Points:

• Detection alone not enough—risk profile matters.

12. GENETIC ARRHYTHMIA TRIALS

LQT β-blocker Trials

Conclusion: Nadolol most effective at event reduction.

Key Points:

• First-line therapy for congenital LQT.

CPVT Flecainide Trials

Conclusion: Flecainide + beta-blocker reduces arrhythmias significantly.

Key Points:

• Standard of care now.

Brugada ICD Observational Trials

Conclusion: ICD prevents SCD in high-risk Brugada.

Key Points:

• Risk stratification essential (syncope, spontaneous type 1 ECG).

13. LEFT ATRIAL APPENDAGE OCCLUSION (LAAO)

PROTECT-AF (2009)

Conclusion: LAAO non-inferior to warfarin.

Key Points:

• First major proof LAA closure works.

PREVAIL (2014)

Conclusion: Improved procedural safety, consistent efficacy.

Key Points:

• Reinforced Watchman protocol refinements.

PRAGUE-17 (2020)

Conclusion: LAAO non-inferior to DOACs in high-risk AF.

Key Points:

• Alternative in patients unsuitable for long-term anticoagulation.

14. AF RISK FACTOR MODIFICATION

LEGACY

Conclusion: ≥10% weight loss massively reduces AF burden.

Key Points:

• Weight control is disease-modifying.

ARREST-AF

Conclusion: Risk-factor control improves ablation outcomes.

Key Points:

• Lifestyle is essential AF therapy.

CARDIO-FIT

Conclusion: Fitness improvement reduces AF recurrence.

Key Points:

• Cardiorespiratory fitness strongly protective.

15. ABLATION TECHNOLOGY TRIALS

ADVENT (2023)

Conclusion: PFA non-inferior to RF with fewer complications.

Key Points:

• Tissue-selective; minimal esophageal risk.

inspIRE

Conclusion: Extremely low PV reconnection with PFA.

Key Points:

• Durability excellent.

FIRE & ICE

Conclusion: Cryoballoon equal to RF for AF ablation.

Key Points:

• Faster and simpler workflow.

16. AUTONOMIC MODULATION

BAROSTIM Trials

Conclusion: Baroreceptor activation improves symptoms and NT-proBNP in HF.

Key Points:

• Neuromodulation emerging therapy.

Renal Denervation AF Trials

Conclusion: Reduced AF recurrence in hypertensive/high sympathetic patients.

Key Points:

• Adjunct therapy in select cases.

17. POSTOPERATIVE AF

Amiodarone Prophylaxis

Conclusion: Reduces postoperative AF significantly.

Key Points:

• One of the strongest POAF preventives.

Colchicine Trials

Conclusion: Lowers POAF via anti-inflammatory effect.

Key Points:

• GI intolerance limits use.

18. HIGH-POWER, SHORT-DURATION RF

QDOT-FAST

Conclusion: Shorter procedures with similar safety and effectiveness.

Key Points:

• Efficient lesion formation.

HPSD Protocols

Conclusion: High-power improves consistency of lesions.

Key Points:

• Increasingly used worldwide.

Here is a clean, expanded, copy-and-paste–ready section on AHRE (Atrial High-Rate Episodes) and Subclinical AF trials, in the same format as your master document.

ATRIAL HIGH-RATE EPISODE (AHRE) TRIALS – EXPANDED SUMMARY

1. ASSERT TRIAL (2012)

Conclusion: Device-detected AHRE (atrial rate >190 bpm for ≥6 minutes) were strongly associated with a 5-fold increased risk of clinical AF and 2.5-fold increased risk of stroke/systemic embolism.

Key Points:

• AHRE are not benign and carry significant thromboembolic risk.

• Even short AHRE episodes predict future overt AF.

2. TRENDS TRIAL (2009)

Conclusion: An atrial tachyarrhythmia burden ≥5.5 hours/day doubled the risk of thromboembolism compared to no AHRE.

Key Points:

• First major trial showing AHRE burden (not just presence) relates to stroke risk.

• Suggested threshold for anticoagulation consideration.

3. MOST Substudy (MOde Selection Trial – 2003)

Conclusion: AHRE >220 bpm lasting ≥10 minutes predicted a six-fold increase in the risk of developing clinical AF and a doubling of stroke risk.

Key Points:

• Early evidence linking device-detected atrial tachyarrhythmias to stroke.

• Provided foundation for ASSERT and later AHRE studies.

4. KP-RHYTHM Study (Kaiser Permanente, 2018)

Conclusion: AHRE episodes ≥5 minutes increased stroke risk, but risk rose substantially when AHRE lasted ≥24 hours.

Key Points:

• Confirms duration-dependent risk.

• Long AHRE episodes behave similar to clinical AF for stroke prediction.

5. LOOP TRIAL (2021)

Conclusion: Continuous monitoring with loop recorders detected far more AF/AHRE, but anticoagulation based solely on detection did NOT significantly reduce stroke.

Key Points:

• Detection alone is not enough — patient-level risk matters.

• Supports CHA₂DS₂-VASc–guided approach even in AHRE.

6. NOAH-AFNET 6 (2023, NEJM – Landmark AHRE RCT)

Conclusion: In patients with AHRE (median longest episode 2.8 hours), edoxaban did NOT reduce stroke or CV death but increased major bleeding.

Key Points:

• Anticoagulation for AHRE without ECG-confirmed AF is not beneficial.

• Supports a “wait until AF is documented” strategy unless AHRE burden is extreme.

7. ARTESiA Trial (2023, NEJM – Apixaban vs Aspirin for AHRE)

Conclusion: In AHRE patients (episodes ≥6 minutes), apixaban reduced stroke/systemic embolism but increased major bleeding.

Key Points:

• Lower ischemic stroke vs more bleeding → risk–benefit individualized.

• ARTESiA + NOAH form the modern evidence base for AHRE management.

8. ASSERT-II (2017)

Conclusion: AHRE detected by implantable monitors in high-risk older patients occurred frequently, but stroke risk remained modest unless AHRE burden increased significantly.

Key Points:

• Confirms many AHRE episodes are brief and low-risk.

• Duration and burden → key determinants of clinical importance.

9. SOS-AF Project (Meta-analysis, 2015)

Conclusion: AHRE >5–6 minutes increased stroke risk, with risk increasing sharply at >24 hours of cumulative AHRE.

Key Points:

• Duration threshold models validated across large datasets.

• Critical in shaping AHRE clinical guidelines.

10. IMPACT Trial (2014)

Conclusion: Anticoagulation guided by device-detected AHRE did not reduce stroke, partly because therapy delays were long, and AF episodes often short.

Key Points:

• Early attempt at “remote monitoring–guided OAC” was not effective.

• Highlighted difficulty of linking OAC directly to AHRE episodes.

11. CRYSTAL-AF (2014)

Conclusion: Implantable loop recorders dramatically increased detection of subclinical AF compared to standard monitoring.

Key Points:

• Many AF cases previously classified as “cryptogenic stroke” were actually undiagnosed AHRE/AF.

• Provided rationale for prolonged monitoring in stroke patients.

12. PER DIEM (2021)

Conclusion: Implantable monitoring detected more AF/AHRE than short-term external monitoring after ischemic stroke.

Key Points:

• Reinforces long-term rhythm monitoring in stroke evaluation.

• AHRE detection essential for secondary prevention.

13. ASSERT-III / Ongoing Studies

Conclusion: Evaluating thresholds for OAC initiation in AHRE patients.

Key Points:

• Future guidelines will likely refine AHRE duration cutoffs.

• High-burden AHRE (>24 hrs) increasingly treated as AF.

SUMMARY OF MODERN AHRE EVIDENCE

Proven High-Risk AHRE Features:

• AHRE ≥24 hours → stroke risk similar to AF

• AHRE 6 min – 24 hrs → elevated but modest risk

• AHRE presence → predicts future AF development

Anticoagulation Evidence:

• NOAH-AFNET 6: NO OAC benefit in AHRE → ↑ bleeding

• ARTESiA: Apixaban prevents stroke → ↑ bleeding

➡️ Therefore: OAC for AHRE must be individualized.