Prevention of reperfusion injury in STEMI - Contra Prof David Erlinge, MD, PhD Lund University, Skane University Hospital, Lund Sweden Disclosure statement: Received speakers fees from the Medicines company, AstraZeneca, Lilly, Philips and Boerhinger Ingelheim. Research grants from Lilly.
The final words of cardioprotection studies this treatment strategy looks promising and should be confirmed in a larger clinical trial Time to deliver?
Cardioprotection For how long time can you be promising? 40 years of futile efforts cost several hundred million dollars Lefer & Bolli, J Cardiovasc Pharm & Therap. 2011
Pharmacological therapies Pharmacological strategies have often worked well in animal studies, looked promising in small clinical phase I or II studies, but generally failed in larger randomized clinical trials. Some of the failed therapies include: Antioxidant therapy (superoxide dismutase, trimetazidine, allopurinol, edaravone), Calcium-channel antagonists (diltiazem, MCC-135) Sodium hydrogen exchange inhibitors (cariporide, eniporide) Anti-inflammatory agents (anti-cd18, anti-cd11, P-selectin antagonists, FX06; an inhibitor of vascular endothelial-cadherin and adenosine) Complement-inhibitors (pexelizumab) Protein kinase C-delta-inhibitors (delcasertib). Metabolic modulation (glucose, insulin, potassium) Magnesium Nicorandil, athorvastatin and erythropoietin. Some pharmaceutical agents are still promising after medium-sized clinical trials: Cyclosporine Atrial natriuretic peptide.
CATCH 22 Catch-22" is a rule with selfcontradictory circular logic He would be crazy to fly more missions and sane if he didn't, but if he were sane he had to fly them. If he didn't want to he was sane and had to.
CATCH 22 The drug cannot reach the area at risk before reperfusion Reperfusion injury happens during the first 5-10 minutes. Drug arriving only a few minutes after reperfusion has no effect.
Cardioprotective Mechanisms Reduced cardiac metabolism Preserve cardiomyocyte ATP and glycogen levels Reduce systemic metabolism (reduced cardiac output demand) mptp (Mitochondrial permeability transition pore) Reduce enzyme kinetics Apoptosis Endothelial swelling Reactive hyperemia Inflammation Complement Reactive oxygen species (ROS) release Reduced t-pa release Intracellular signalling in the cardiomyocyte PKC Akt NO Mitochondrial protein gene expression (HSP70, ANT1, beta-f1-atpase) Cardioprotective signalling (P53, HIF-1) Calcium and sodium overload sodium hydrogen exchange The problem with cardioprotective agents could be that they only affect one single mechanism per treatment.
The Mechanical approach A more mechanical approach is the conditioning therapies consisting of shorter ischemic periods triggering protective responses that are still not fully understood. Pre-conditioning: Highly effective, but not clinically feasible. Remote per-conditioning: The circulation to the arm is occluded repeatedly on STEMI patients in the ambulance on the way to the PCI-lab Postconditioning: Repeated occlusions directly after opening the vessel are performed with the angioplasty balloon.
Remote per-conditioning Remote per-conditioning, by which the circulation to the arm is occluded repeatedly on STEMI patients in the ambulance on the way to the PCI-lab, was recently shown to reduce infarct size in a trial with 142 patients (Botker, Lancet 2010). However, effect on ejection fraction disappeared after 30 days
Postconditioning Postconditioning has been tested in four clinical trials in which infarct size has been examined. 1. In a study from Ovize on 38 patients, infarct size was reduced by 39% 2. Yang found a 27% reduction with SPECT after one week (n=41). 3. Lonborg found a 19% reduction in infarct size by postconditioning after 3 months (n=86). 4. On the other hand, one of the larger studies (n=76), which used MRI for infarct size evaluation, did not see a difference in infarct size or troponin levels in the whole material (Sörensson 2010). Larger studies are therefore needed.
Primum Non Nocere Ovize et al, Cardiovasc Res, 2010 Sörensson et al, Heart, 2010 Post-conditioning increase infarct size when ischemia time is short in animal studies Post-conditioning was neutral in all patients. Patients with large areas at risk or LAD occlusion had reduced infarct size. = When small area at risk or non- LAD, infarct size is increased We must know ischemia time, location and area at risk before we decide on post-conditioning, and where the limit for benefit is.
Small and large clinical trials Trial n Primary endpoint Trial result TAMI 9 430 infarct size, EF negative (22% v 17%) ISIS-4, MAGIC 58,050 35d mortality negative (7.6 v 7.2%) CORE Pilot 114 infarct size positive (16 v 26%) CORE 2,607 death,shock,remi negative (14 v 12.6%) EMIP-FR 19,665 35d mortality negative (12.2 v 12.3%) Rhapsody 770 infarct size negative (no effect) AMISTAD 236 infarct size positive (20 v 13%) AMISTAD-2 2,118 6 mo death/chf negative (16 v 18%) HALT/LIMIT 400+ infarct size negative (no effect) Rupprecht 100 EF, infarct size positive (50 v 40%) ESCAMI 1,389 infarct size negative (no effect) CARDINAL 1,800 infarct size negative (no effect)* From C. Granger
Association between patient numbers and effect on infarct size n=180 Conclusion: A meaningful infarct size reduction can only be achieved in populations of less than 180 persons.
Graveyard of Failed Therapies Adapted from C. Granger
We have to play well to succeed
Stairway to heaven We have a long way to go
Cardioprotection for which patient? STEMI patients where cardioprotection does not work (based on post-hoc explanations): Short duration Long duration TIMI 1-3 Collaterals Non-LAD Small area at risk Previous MI Who are left? How big is this group?
Pubmed search Search on reperfusion injury and myocardial infarction Aug 14 2011 3115 630 0 Adapted from M. Bell
Why does cardioprotection work in animals but not man?
Does Reperfusion injury exist? He concludes that Although it is likely that the question of whether lethal reperfusion injury occurs in humans will remain unanswered for some time 18 years and counting (my comment) the concept of reperfusion injury should not dissuade the clinician from instituting reperfusion as soon as possible after the onset of acute myocardial infarction Luckily, we have followed his advice with tremendous progress the last 18 years
Does Reperfusion injury exist in man? Humans have collaterals Often preconditioned by stenosis or short occlusions Protection blunted by medications or comorbidities Animal models in 3-4 months mice equivalent to humans 7-10 years =
Publication bias Extremely difficult to publish negative results. If published, in low impact journals Positive results in mice = Circulation Research, IF 14 Negative results in pig = BMC Cardiovasc Disorders, IF 2
Single or multicenter During 40 years of futile research several hundred interventions evaluated in single center studies have claimed to limit infarct size. Only once evaluated in a blinded fashion in a multi-center animal trial, the result was negative. One center = significant effect Multicenter, blinded = no effect Evaluation of an Adenosine A1 agonist in a three center, blinded, randomized, controlled experimental study. Baxter et al.,cardiovascular drugs and Therapy, 2000.
The Hatter Workshop Inability to succesfully translate novel cardioprotective strategies discovered in the research laboratory into the clinical arena
The Hatter recommendations: Preclinical Lost intranslation In vitro including human tissue Small and large animals Resemble clinical setting Presence of confounders (diabetes, medication etc) Clinical study LAD only TIMI 0 or 1 No collaterals (excluded) Chest pain <12h Cardiac markers Infarct size EF Mortality, CHF
CEASAR 6 major methodological problems in previous preclinical studies: Lack of randomisation Non-blinded treatment allocation Non-blinded data analysis Lack of standardized animal models and protocols Lack of rigorous statistical methods Models that do not mimic the clinical situation Lefer & Bolli, J Cardiovasc Pharm & Therap. 2011
CEASAR An impressive attempt to improve pre-clinical evaluation is the CEASAR network. Autologous to a clinical trial network. Four independent laboratories and cores. Three animal models (mouse, concious rabbit, conscious pig). Comorbidities (diabetes, hypertension, dyslip, old age) Each model tested at minimum two sites. Adequately powered. Blinded, randomized. We expect the majority of agents tested by CEASAR will fail www.nihcaesar.org