STEMI Stents What next? Arshad Khan - HNE Clinical Research Fellow. Supervisors: Prof Boyle and Attia.

STEMI Stents What next? Arshad Khan - HNE Clinical Research Fellow. Supervisors: Prof Boyle and Attia.

PART 1 Systems of care for STEMI.

STEMI Management Coronary angiogram +/- stenting. Prehospital thrombolysis followed by rescue or routine angiogram +/- stenting

Untreated STEMI Danchin N, et al. Long-Term Survival After Lysis or PCI in STEMI. Circulation. 2014.

Pre-hospital thrombolysis STEMI patients with significant delays to primary angioplasty.

HNE Health. Area: 130, 000 square Kilometres. One 24/7 cath. Lab. Distance of farthest hospital to JHH: Over 500 kilometres.

STEMI care team 24/7 on call. Supported by: -NSW ambulance. Emergency, Retrieval and ICU teams

STEMI - Systems of care. 2008 onwards Estimated first medical contact to cath. lab arrival time > 60 min. Fibrinolysis versus primary angioplasty.

Hunter AMI Registry Non-randomised PHT and Primary PCI experience. August 2008 to August 2013. Data was prospectively collected.

Aims In patients with STEMI: safety of pre-hospital thrombolysis Risk of death (nonrandomised) across Hunter New England

Outcomes All-cause mortality. Bleeding.

Results PHT (n=150) PPCI (n=334) P-value Age Mean ± S.D. 62±13 65±13 0.02 75 yr. no. (%) 27 (18) 88 (26) 0.01 Males no. (%) 114 (76) 251 (75) 0.8 S/blood pressure Mean ± S.D. 125±25 131±24 0.01

Results PHT (n=150) PPCI (n=334) P Value First medical contact to treatment (Range) min. 35 (6 95) 130 (45 300) 0.004 Distance to cath. lab. (Km) Median (Range) 120 (8-483) 20 (5 69) 0.001 Length of stay mean ± S.D. 4±3 4±3 1 Ejection Fraction (%) Mean ± S.D. 49±10 47±7 0.2 Peak Troponin Mean ± S.D. 44±28 50±35 0.06

Results PHT (n=150) Primary PCI (n=334) P-Value Coronary Angiography 92% 100% <0.001 Rescue PCI 27% NA - Median Time from symptom to angiography (Range) Hours. 28 (2-245) 3.5 (1 17) <0.001 Initial TIMI flow 2 45% 8% <0.001

1 year all-cause mortality

Results PHT PPCI Safety outcomes Total bleeding No. (%) 14 (9%) 17 (5%) TIMI major Bleeding - No. (%) 2 (1.4) 0 Intracranial Haemorrhage -No. (%) 1 (0.7) 0

Conclusions Our real-world experience shows that PHT followed by early transfer to a PCI-capable centre is a safe and effective reperfusion strategy.

PART 2 LVEDP as a treatment target in STEMI

LVEDP measurement.

LVEDP measurement.

Physiology Indicative of the hemodynamic health of the left ventricle. Preload Contractility Compliance and stiffness Myocardial Ischemia Afterload

LV Compliance

Law of Laplace: Wall stress increases the tension in the myocardium and thus reduces myocardial blood flow and counteracts myocardial shortening LV wall stress = (LV pressure X radius)/(2 X wall thickness) Gjesdal, O. et al. (2011) Cardiac remodeling at the population level risk factors, screening, and outcomes Nat. Rev. Cardiol. doi:10.1038/nrcardio.2011.154

Significance of LVEDP Adverse LV remodelling Heart failure. Mortality.

675 pts, (STEMI= 43%). LVEDP 26.5 mmhg LVEDP and MACE in STEMI In hospital mortality 4.9% vs 2.4% In hospital HF 37% vs 28% 3 months mortality 3 months MACE 1 year MACE 16% vs 11% 1 year mortality 13% (66% STEMI ) vs 5% 2 year MACE - - 2 year mortality 1909 (out of 5745) pts 22 mmhg - - 4% vs 2% 12% vs 7% - - - 2797 (out of 3602 pts) 18 mmhg 3.1% vs 1.5% 6.3% vs 3.7% - - 20% vs 17% 6% vs 4%

Brienesse S, Davies A, et al. Under review.

Aortic valvuloplasty and LVEDP - Severe AS undergoing BAV. -111 patients from MGH. -Inhospital MACE. -OR 1.08, for each mm Hg rise in pressure; 95% CI 1.02 1.14). -Independent of LVEF.

CABG and LVEDP Patients undergoing CABG. 602 pts had LVEF < 35%. Cut-off LVEDP = 18 mmhg. Increased mortality.

LVEDP as a treatment target

Reperfusion and LVEDP STEMI, N=29 LVEDP measured before and after PPCI. Dropped by 5.7 ± 2.9 mmhg. Changes in LVEDP post primary PCI. AM Heart Hosp J. 2010 Winter;8(2):E86-90

LVAD and LVEDP Seidel T, et al. Circulation. 2017;135:1632 1645. doi: 10.1161/CIRCULATIONAHA. 116.024470.

CRT and LVEDP N=17 Invasive haemodynami cs at baseline and 1 month post CRT (plus OMT). 30% reduction in LVEDP and PCWP

Research question Does reducing LVEDP after primary PCI prevent LV remodeling and improve outcomes?

JHH data 2015 152/236 patients (64%) Median LVEDP: 22 mmhg (IQR: 19 30) Median follow up: 13 months (IQR: 4 17 months) All-cause mortality: 5% (7 out of 152). 6.6% vs 2.6%, RR: 2.5, P=0.2, CI: 0.5004 to 12.4912, NNT (Harm): 25

P=0.2

How to reduce LVEDP Nitrates and frusemide by affecting preload and afterload.

Our proposed clinical trial program Phase 1 Dose finding/safety study. Phase 2 Randomised, doubleblind study with LV remodelling endpoint. Phase 3 Randomised, doubleblind multi-centre study with clinical endpoints

Phase 1 Acute haemodynamic, dose finding/safety study. Aim : Find the dose of nitrate, in conjunction with a single bolus of frusemide, which can be used to reduce LVEDP following Primary PCI?

Phase 1 Inclusion criteria STEMI with LVEDP 20 mmhg after intervention to infarct related artery.

Phase 1 Intervention Frusemide 40mg IV plus escalating GTN doses - 100mcg every minute (up to 1000 mcg over 10 minutes).

Phase 1 End points Dose of GTN needed to cause 20% reduction in LVEDP. Effect on systolic blood pressure?

Results - Phase 1 Recruitment N=10, Age 65±7, Males=5 (50%), Anterior=5 (50%) Variable response: Median=200 mcg (Range: 200 800), Mean 260±180 Systemic BP: 9% reduction (7 16%). No symptoms.

LVEDP (mmhg) 50 45 Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7 Patient 8 Patient 9 Patient 10 40 35 30 25 27±3 mmhg 20 15 16±4 mmhg 10 5 0 BASELINE POST GTN

Phase 1 - Conclusion Safe in STEMI. Reduce LVEDP. Effect of LVEDP reduction should be tested in prospective RCTs.

Phase 2 RCT. Research question? Do nitrates and frusemide affect remodelling and Infarct size in STEMI patients with raised LVEDP?

Phase 2 Inclusion criteria: STEMI with LVEDP 20 mmhg. Systolic BP 100 mmhg.

Phase 2 Exclusion criteria: Inability to informed consent. Patients presenting with cardiogenic shock Cardiopulmonary resuscitation. Any ventricular arrhythmias requiring treatment. Current life-threatening condition (other than vascular disease) with life expectancy < 1year. Severe infection, or any significant trauma (fractures, burns etc.) Pregnancy. Contraindications to cardiac magnetic resonance imaging. Renal impairment with known egfr < 30 ml/min or maintenance haemodialysis.

Phase 2 Intervention Primary PCI (All patients). Randomised to treatment or placebo arm. Treatment arm: Oral Lasix 40mg daily and Isosorbide mononitrate 30-60 mg daily for 3 months.

Phase 2 CMR and Echo Baseline and 3 months. Blood tests Troponin, BNP, UECs, Creatinine. Follow up 3 and 12 months.

Sample calculation N=50 (25 in each arm). Placebo arm adverse remodelling of 10% Intervention arm reverse remodelling of 5% P=0.05, Power = 80%.

Phase 2 End points Primary safety end point: Safety and tolerability of ISMN and frusemide. Primary efficacy endpoint: Change in left ventricular end diastolic volume index from post-mi to 3 months. Secondary endpoints: Death, MI, Stroke and HF.

Progress - Phase 2 Ethics Funding Heart Foundation.

Acknowledgements Prof Boyle and Fletcher. HNE Health Research and Translation Centre. NSW Ambulance. Dr Leitch and Bastian Interventional group Collins, Hatton, Bhagwandeen and Thambar. Dr Turner, Singham, Hackworthy and sonographers. ATs and Fellows- A Davies, M McGee, N Whitehead, D Baker, Al-Omary. Deb Bick and cath lab staff. Cardiac techs.

Thank you.