MELGAR O. MATULAC MD., LEORA FLOR MACAPUGAY MD., MICHAEL REYES MD., KRISTINE TUMABIENE MD., ALRIC MONDRAGON MD. SECTION OF CARDIOLOGY DEPARTMENT OF MEDICINE UNIVERSITY OF THE PHILIPPINES – PHILIPPINE GENERAL HOSPITAL S ildenafil I mproves Exercise C apacity in Heart Failure: A Meta-analysis S I C HEART Study

HEART FAILURE FACTS: - 1 in 3 develop HF at age > only 35% surviving 5 years after the first diagnosis. 1,2 1.Gyse`le S. BleuminkQuantifying the heart failure epidemic:prevalence, incidence rate, lifetime risk and prognosis of heart failure The Rotterdam Study. European Heart Journal (2004) 25, 1614– John J McMurrayHEART FAILURE Epidemiology, aetiology, and prognosis of heart failure. Heart 2000; 83:596–602 3.Behling A, Rohde L, Colombo F, et al. Effects of 5’ -Phosphodiesterase Four-Week Long Inhibition With Sildenafil in Patients With Chronic Heart Failure: A Double-Blind, Placebo-Controlled Clinical Trial. Journal of Cardiac Failure (3): As HEART FAILURE progresses: 68 – 78 % (w/ LV dysfunction) PULMONARY HYPERTENSION RV DYSFUNCTION MORTALITY 2X Despite advancement in Treatment: - Most HF patients are limited by their EXERCISE AND FUNCTIONAL CAPACITIES affecting their QUALITY OF LIFE OUR CHALLENGE ! DISCOVER NEW FORMS OF INTERVENTION TO IMPROVE OVERALL CARDIAC PERFORMANCE

Zhi You Fang.Mechanisms of exercise training in patients with heartfailure. AHJ 2002 ENDOTHELIAL DYSFUNCTION IN ASSOCIATION WITH HEART FAILURE AND MUSCULAR DYSFUNCTION CHF HALLMARK INCREASE IMPEDANCE TO THE RIGHT AND LEFT VENTRICULAR EJECTION DUE TO INCREASE IN PULMONARY AND SYSTEMIC VASCULAR RESISTANCE ENDOTHELIAL DYSFUNCTION THERAPEUTIC GOAL IN CHF IMPROVE THE OVERALL CARDIAC PERFORMANCE IS REDUCTION IN PULMONARY VASCULAR RESISTANCE

SILDENAFIL ( PHOSPHODIESTERASE 5 INHIBITOR) 1.ovebucketblog.com 2.Parnham. Milestone in Drug Therapy. Library of Congress 2004 Sildenafil citrate - selective PDE5 inhibitor, acts on NO/cGMP pathway - First synthesized in 1989, ANGINA as the particular indication – Clinical development indicated for Angina, similar to nitrates but w/o tachyphylaxis. - Penile erection as commonly reported side effect.

RESEARCH QUESTION Among patients with chronic heart failure and secondary pulmonary hypertension, will long-term treatment with PHOSPHODIESTERASE – 5 INHIBITOR (Sildenafil) improve exercise capacity?

METHODOLOGY LITERATURE SEARCH Search Strategy: Medline, Embase, Cochrane Library Search Terms: Sildenafil, Phosphodiesterase-5 inhibitor, Heart Failure Limited to: Humans subjects & RCT’s Secondary Search: Bibliographies of RCTs 49 citations Excluded: 24 studies 25 articles evaluated 4 RCTS satisfied the eligibility criteria Data extraction,Quality assesment & Synthesis of evidence Studies EXCLUDED: 17 6 RCTs: Acute use 2 RCTs: IV Sildenafil 1 RCT : Preserved EF 3 Trials: Cardiac Transplant 2 RCTs: (+) Lung Problem 4 RCTs: (+) other drugs 3 RCTs: Erectile Dysfunction ELIGIBILITY CRITERIA: - RCTs: Stable Heart Failure on standard HF Therapyrandomized to either placebo or Sildenafil - Chronic LV systolic dysfunction (EF <40% who underwent cardiopulmonary testing before and after Sildenafil treatment RESEARCH QUESTION

STUDYTITLE Guazzi 2007 et al Long-Term Use of Sildenafil in the Therapeutic Management of Heart Failure J. Am. Coll. Cardiol (22): Lewis 2007 et al Sildenafil Improves Exercise Capacity and Quality of Life in Patients With Systolic Heart Failure and Secondary Pulmonary Hypertension. Circulation : Behling 2008 et al Effects of 5’ -Phosphodiesterase Four-Week Long Inhibition With Sildenafil in Patients With Chronic Heart Failure: A Double-Blind, Placebo-Controlled Clinical Trial. Journal of Cardiac Failure (3): Guazzi 2010 et al Inhibition With Sildenafil Improves Left Ventricular Diastolic Function, Cardiac Geometry, and Clinical Status in Patients With Stable Systolic Heart Failure: Results of a 1-Year, Prospective, Randomized, Placebo-Controlled Study. Circ Heart Fail

OUTCOMES MEASURED PRIMARY OUTCOMES: CHANGES IN EXERCISE CAPACITY VO2 at Peak exercise VE/VCO2 Slope SECONDARY OUTCOMES: Pulmonary artery pressures Left ventricular ejection fraction SAFETY OUTCOMES: Headache Flushing PEAK VO 2 - measure of O 2 consumption during peak exercise - most widely used parameter to predict survival, re-hospitalization and risk stratification in patients with CHF 1 - Low peak VO 2 < 12.2ml/kg/min: 66% 1 yr cardiac mortality VE/VCO 2 Ratio ( Ventilation/ CO 2 production ratio) 2 - Excessive ventilatory response to exercise perceived as breathlessness - Measure of ventilatory efficiency: Increase ventilation – premature exhaustion of ventilatory reserve - Risk predictor in patients w/ CHF: Higher VE/VCO2 – higher mortality 1

TRIAL ID/YR POPULATIONINTERVENTION (versus Placebo) (Duration/Assesment) OUTCOMEMETHOD #Age (mean yrs) Males (%) NYHA FC/ EF % PASP (mhg) Guazzi et al %II-III 31.25% 32.8Sildenafil 50mgBID* 6 mos ( 3 & 6) Pulmonary Pressure Brachial artery FMD) Ergoreflex assessment; Peak exercise (VO2 uptake) & (VE/VCO2 slope ) QOL score. SC, RCT : DB Placebo Lewis et al %II-IV 19.5% 31.5Sildenafil 25mg TID* 3 mos (↑ Q 2 wks to 75mg TID) SV & SVR. (Restinq/exercise) MPAP, PWP, PVR Peak exercise VO2 & VE/VCO2 slope 6 min walk test; Hospitalization QOL score SC, RCT:DB, Placebo Behling et al II-III 28±6% 59±18Sildenafil 50mg TID 4 wks Pulmonary Pressure Peak exercise(VO2) & VE/VCO2 slope Endothelial function SC, RCT: DB, Placebo Guazzi et al II-III 30% 37.4Sildenafil 50mg TID 1 year ( 6 mo to 1 year) LV EF, diastolic function, geometry, Peak VO2, & VE/VCO2 slope QOL SC, RCT:DB, Placebo SC: Single center, RCT: Randomized controlled trials, DB: Double blind, FMD: Flow mediated dilatation, QOL: quality of life, SV: Stroke volume, SVR: Systemic vascular resistance, MPAP: Mean pulmonary artery pressure, PWP: Pulmonary wedge pressure, PVR: Pulmonary vascular resistance, LV EF: Left ventricular ejection fraction,

TRIAL ID INCLUSIONEXCLUSION Guazzi 2007 et al - Stable, NYHA FC II-III, CHF (ischemic or idiopathic cardiomyopathy) - (-) Exercise stress test prior to study initiation -FEV1s/ FVC ratio >70%, LVEF ≤45% by Echo -NOT involves in any physical training program & NOT receiving agents that could affect endothelial function (statins, antioxidant vitamins, xanthine oxidase inhibitors or ergoreflex (aspirin) -nonsmokers or were ex smokers of at least 8 mos. - Not able to complete a maximal exercise test or if they had SBP >140 and <110 mmhg, DM, Tx w/ nitrate, Sildenafil intolerance, Significant lung/valvular diseases, neuromuscular disorders, claudication or PVD. Lewis et al - ≥18 yo with LVSD (LVEF) 25mmhg. -Pts enrolled in previous study of the short term effects of 1 – time administration of sildenafil on exercise capacity. - Noncardiac limitation to exercise, provocable ischemia, hemodynamic instability or ongoing nitrate therapy. - Concentric LVH, critical AS or long term use of medications that inhibit CP450 3A4 Behling et al -Chronic LV systolic dysfunction(LVEF ≤40%) receiving standard medical therapy for CHF, independently on reports of ED. - Systolic arterial pressure less than 90mmhg, HR <50bpm, use of nitrates, oral anticoagulation, chronic AF & intolerance to sildenafil. Guazzi 2007 et al - <65yo, stable HF NYHA FC II-III ( ischemic or idiopathic CM) - Neg. exercise stress test prior to study initiation - FEV1s/ FVC ratio >70%, LVEF ≤45% by Echo - NOT involves in any physical training program and NOT receiving agents that could affect endothelial function (statins, antioxidant vitamins, xanthine oxidase inhibitors or ergoreflex (aspirin) - nonsmokers or were ex smokers of at least 8 mos. Not able to complete a maximal exercise test or if they had SBP >140 and <110 mmhg, DM, Tx w/ nitrate, Sildenafil intolerance, Significant lung/valvular diseases, neuromuscular disorders, claudication or PVD. NYHA FC: New York Heart Association Functional Class, FEV: Forced expiratory volume, FVC: Forced vital capacity, LVEF: Left ventricular ejection fraction, DM: Diabetes milletus, PVD: Peripheral vascular disease, AF: atrial fibrillation, HF: Heart Failure, PH: Pulmonary hypertension, AS: aortic stenosis, ED: Erectile dysfunction

VALIDITY OF INCLUDED STUDIES Study Randomized Allocation ConcealmentITT Patients blinded Physicians blinded Outcomes assessors blinded Guazzi 2007 et al YYYYYY Lewis 2007 et al YYYYYY Behling 2008 et al YYYYYY Guazzi 2010 et al YYYYYY

RESULTS AND DISCUSSION Sildenafil Improves Exercise Capacity in Heart Failure: A Meta-analysis (SIC Heart Study)

Mean Change in Peak VO2 at the END OF STUDY: SIGNIFICANT INCREASE TRIAL PLACEBO GROUPSILDENAFIL GROUP BaselineEnd of study Mean Change BaselineEnd of study Mean Change P value Behling17.2±216.5± ±318.5± * Guazzi ± ± ± ± <0.01 t Guazzi ± ± ± ± <0.01* Lewis10.2± ± ± * Change in Peak VO2 from baseline

Mean Change in Peak VO2 at 1 – 3 months Mean Change in Peak VO2 at 6 months SIGNIFICANT IMRPOVEMENT in PEAK VO 2 at 3 rd and 6 th month

Mean Change in VE/VCO 2 at the END OF STUDY: SIGNIFICANT DECREASE TRIAL PLACEBO GROUPSILDENAFIL GROUP BaselineEnd of study Mean Change BaselineEnd of study Mean Change P value Behling 39.1±640.6± ±634.1± * Guazzi ± ± ± ± <0.01 t Guazzi ± ± ± ± <0.01* Change in VE/VCO 2 from baseline

Mean Change in PAP at the END OF STUDY: SIGNIFICANT DECREASE TRIAL PLACEBO GROUPSILDENAFIL GROUP BaselineEnd of study Mean Change BaselineEnd of study Mean Change P value Behling 62±2365±20+356±1338± * Guazzi ± ± ± ± <0.01 t Guazzi ± ± ± ± <0.01* Lewis 33±331±3-230±228± * Change in Pulmonary Artery Pressure from baseline

TRIALPLACEBO GROUPSILDENAFIL GROUP BaselineEnd of study Mean Change BaselineEnd of study Mean Change P value Guazzi ± ± ± ± NS t Guazzi ± ± ± ± <0.01* Mean Change in LVEF at the END OF STUDY Change in LVEF from baseline

NO SIGNIFICANT DIFFERENCE in SAFETY OUTCOME WITH PLACEBO Occurrence of HEADACHE during Sildenafil Treatment Occurrence of FLUSHING during Sildenafil Treatment

CONCLUSION AND RECOMMENDATION Sildenafil Improves Exercise Capacity in Heart Failure: A Meta-analysis (SIC Heart Study) Sildenafil improves exercise capacity as evidenced by improvement in Oxygen uptake, Ventilatory efficiency and Pulmonary pressure reduction without significant adverse effects FUNCTIONAL CAPACITY CLINICAL STATUS QUALITY OF LIFE SILDENAFIL could be an ADJUNCT to standard medical therapy for chronic heart failure Warrants LARGER LONG TERM CLINICAL TRIALS

MELGAR O. MATULAC MD., LEORA FLOR MACAPUGAY MD., MICHAEL REYES MD., KRISTINE TUMABIENE MD., ALRIC MONDRAGON MD. SECTION OF CARDIOLOGY DEPARTMENT OF MEDICINE UNIVERSITY OF THE PHILIPPINES – PHILIPPINE GENERAL HOSPITAL S ildenafil I mproves Exercise C apacity in Heart Failure: A Meta-analysis S I C HEART Study