Direct and indirect CV effects of current drugs and those in development Heribert Staudinger CSRC MARCH 201
Cardiac Manifestations of COPD Cardiovascular Disease is probably the most frequent and most important disease coexisting with COPD GOLD 2014 Ischemic Heart Disease Heart Failure Atrial Fibrillation and other arrhythmias Hypertension Right ventricular dysfunction Pulmonary hypertension Impact of respiratory changes on the heart: Intrathoracic pressure changes Dynamic hyperinflation Work of breathing may amount to 50% of the body s energy consumption Exercise limitations Hypoxia Hypercapnia
Direct and Indirect Cardiac Effects Net-effect of a COPD drug may not be obvious Direct effects on the heart ß 1, some ß 2 -effects, vagal tone Effects on the vascular system Direct, e.g. ß 2 -receptor mediated Indirect: ventilation changes may effect hypoxic vasoconstriction Effects on VQ-mismatching Indirect effects Metabolic effects, e,g, hypokalemia Effects on hypoxia/hypercapnia Effects on intrathoracic pressure Effects on systemic inflammation Biomarker effects on fibrinogen While it is important to understand individual elements, the integral clinical effect may not be obvious and needs focused attention In emergency room studies, the heart rate of patients with asthma usually decreases with improved ventilation, even on high doses of inhaled ß-agonists causing tachycardia in healthy volunteers
Direct and Indirect CV Effects of COPD Drugs Overview Drug Inhaled ß 2 -agonists Inhaled quaternary anticholinergics Inhaled corticosteroids Theophylline/Methylxanthines PDE4-inhibitors New drugs cardiac effects HR, BP-changes, hypokalemia, supraventricular and ventricular arrhythmias, subject to desensitization, may decrease PAP, slight and transient QTc-prolongation, hyopxia AEs: Angina, Arrhythmias, (including atrial fibrillation, extrasystoles, supraventricular tachycardia), ventricular tachycardia, hypertension, hypotension HR, paradoxical threshold effects, supraventricular and ventricular arrhythmias, minor QTc-prolongation, class tends to have ion channel effects AEs: Chest pain (non-specific), atrial fibrillation, supraventrivular tachycardia, No significant direct cardiovascular effects, some metabolic effects on potassium, no conclusive data on indirect effects e.g. on MACE/ischemic events via antiinflammatory mechanisms Primarily often serious pro-arrhythmic effects, narrow therapeutic window, clearance impacted by many other drugs, but also by caffeine and Heart Failure. PAP Selective PDE4-inhinbitors do not appear to have relevant direct CV-effects. A metaanalysis of placebo-controlled studies found lower MACE composite rate compare to placebo (Chest. 2013;144(3):758-765) Indirect effects such as changes in fibrinogen, CRP, lipids, neutrophils likely to be the major focus.
TIOSPIR Serious Adverse Events and Major Adverse Cardiovascular Events.
ERJ Ischemic Cardiac Events in TORCH and EUROSCOP Calverley PM et al. N Engl J Med 2007;356:775-789 Calverley PM et al. Thorax. 2010 Aug;65(8):719-725 Fig. 1 Distribution of ischaemic cardiac events among adult patients with chronic obstructive pulmonary disease randomised to receive budesonide 800 μg day 1 ( ) or placebo ( ) for up to 3 yrs. CAD: coronary artery disease. 1: Löfdahl CG, Postma DS, Pride NB, Boe J, Thorén A. Possible protection by inhaled budesonide against ischaemic cardiac events in mild COPD. Eur Respir J. 2007 Jun;29(6):1115-9.
Issues with Publications on Major COPD Outcome Studies Reporting of CV-outcomes Cardiac events not reported in a standardized way reported delayed and not in context with respiratory events/mortality Tiospir publication (N Engl J Med 2013; 369:1491-1501) reports MACE UPLIFT (N Engl J Med 2008; 359:1543-1554) reported RRs for serious AEs reported by > 1% of patients MACE not reported for TORCH (N Engl J Med 2007; 356:775-789), focuses on CV mortality Post-hoc analysis on ischemic events in Thorax (2010;65:719-725) MACE not reported in orginal EUROSCOP publication Post-hoc analysis of ischemic events published in 2007 (Eur Respir J. 2007 Jun;29(6):1115-9.) Adjudication handled inconsistently No baseline assessment of cardiac comorbidity Biomarkers (e.g. Fibrinogen, CRP) not included/analyzed/reported in a standardized way Patients with long-term oxygen therapy excluded Undertreatment with LTOT in clinical studies? In a recently published study LTOT prevented inclusion of 31% of patients (Respiration 2014;87(1):11-7)
Split More Accurately or Lump? Adjudication vs. Lumping Cardiorespiratory Events/Mortality COPD mortality is mostly respiratory and cardiovascular Torch: 62% out of 875 deaths were either pulmonary or cardiovascular (306 pulmonary deaths, 237 cardiovascular deaths) The remaining deaths were a more heterogeneous group The Clinical Endpoint Committee of TORCH focused on the probability of COPDrelatedness In UPLIFT (Am J Respir Crit Care Med 2009, 180:948-955), adjudicated incidence rates of death by organ class were much lower for cardiac events, behind neoplasms adjudication requiring objective evidence in support of an MI resulted in a reduction of MIs (from 36 to 17) compared to the investigator diagnosis It could be argued on clinical grounds that cardiorespiratory effects should be assessed jointly the separation based on clinical information may not be in many cases not very meaningful cardiorespiratory mortality may be a clinically more meaningful outcome than e.g. decline in lung function
Points for Future Consideration for clinical development and the design of outcome trials Should there be a standardized baseline assessment of cardiovascular comorbidities in all clinical COPD studies? E.g. ischemic heart disease, Heart Failure, Atrial Fibrillation, Hypertension, Right ventricular dysfunction, pulmonary hypertension Should MACE and ischemic events be reported in a standardized way across COPD-programs and be part of the main evaluation? For mortality assessments, should we look at a composite endpoint combining pulmonary and cardiovascular mortality? Should the key cardiovascular outcomes generally be adjudicated? Should biomarkers such as fibrinogen or CRP be included in studies of new drugs? Specific recommendations? Oxygen may have an impact on cardiorespiratory outcomes. Most clinical studies in COPD (even those including patients with low baseline FEV 1 ) do not permit long-term oxygen therapy (LTOT). In one recently published series 31% of potential study participants were excluded due to LTOT Should we include patients on LTOT and require per protocol that LTOT is used according to guideline recommendations?
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Cumulative incidence of (A) all cardiovascular adverse events and (B) ischaemic cardiovascular adverse events. Calverley P M A et al. Thorax 2010;65:719-725 Copyright BMJ Publishing Group Ltd & British Thoracic Society. All rights reserved.
Tashkin DP et al. N Engl J Med 2008;359:1543-1554. Incidence Rate of Serious Adverse Events per 100 Patient-Years.