MELGAR O. MATULAC MD., LEORA FLOR MACAPUGAY MD., MICHAEL REYES MD., KRISTINE TUMABIENE MD., ALRIC MONDRAGON MD .

SECTION OF CARDIOLOGYDEPARTMENT OF MEDICINE

UNIVERSITY OF THE PHILIPPINES – PHILIPPINE GENERAL HOSPITAL

Sildenafil Improves Exercise Capacity in Heart Failure: A Meta-

analysis

S I C HEART Study

HEART FAILUREFACTS: - 1 in 3 develop HF at age >551

- 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, 1614–1619

2. John J McMurrayHEART FAILURE Epidemiology, aetiology, and prognosis of heart failure. Heart 2000;83:596–6023. 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. 2008. 14(3):189-97

As HEART FAILURE progresses:

68 – 78 % (w/ LV dysfunction) PULMONARYHYPERTENSION

RVDYSFUNCTIONMORTALITY

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

www.sciencedirect.comZhi 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.com2. 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. - 1991 – 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?

METHODOLOGYLITERATURE SEARCH

Search Strategy: Medline, Embase, Cochrane LibrarySearch Terms: Sildenafil, Phosphodiesterase-5 inhibitor, Heart FailureLimited to: Humans subjects & RCT’sSecondary 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

STUDY TITLEGuazzi 2007

et al Long-Term Use of Sildenafil in the Therapeutic Management of

Heart Failure J. Am. Coll. Cardiol. 2007. 50(22):2136-44.

Lewis 2007et al

Sildenafil Improves Exercise Capacity and Quality of Life in Patients With Systolic Heart Failure and Secondary Pulmonary

Hypertension. Circulation. 2007. 116: 1555-62.

Behling 2008et 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. 2008. 14(3):189-97

Guazzi 2010et 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. 2011. 8-1

OUTCOMES MEASUREDPRIMARY 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 VO2

- measure of O2 consumption during peak exercise- most widely used parameter to predict survival, re-hospitalization and risk stratification in patients with CHF1

- Low peak VO2 < 12.2ml/kg/min: 66% 1 yr cardiac mortality

VE/VCO2 Ratio ( Ventilation/ CO2 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 mortality1

TRIAL ID/YR

POPULATION INTERVENTION(versus Placebo)

(Duration/Assesment)

OUTCOME METHOD

# Age(mean yrs)

Males(%)

NYHA FC/ EF %

PASP(mhg)

Guazziet al2007

46 62.5 100% II-III31.25%

32.8 Sildenafil 50mgBID*6 mos ( 3 & 6)

Pulmonary PressureBrachial artery FMD)Ergoreflex assessment; Peak exercise (VO2 uptake) & (VE/VCO2 slope) QOL score.

SC, RCT : DBPlacebo

Lewis et al2007

34 58 85% II-IV19.5%

31.5 Sildenafil 25mg TID*3 mos

(↑ Q 2 wks to 75mg TID)

SV & SVR. (Restinq/exercise)

MPAP, PWP, PVRPeak exercise VO2 & VE/VCO2 slope6 min walk test; HospitalizationQOL score

SC, RCT:DB, Placebo

Behling et al2008

19 48 68 II-III28±6%

59±18 Sildenafil 50mg TID4 wks

Pulmonary PressurePeak exercise(VO2) & VE/VCO2 slope Endothelial function

SC,RCT: DB, Placebo

Guazzi et al2010

45 60.5 100 II-III30%

37.4 Sildenafil 50mg TID1 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

INCLUSION EXCLUSION

Guazzi 2007et 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) <40%, NYHA FC II-IV chronic HF despite standard HF therapies with secondary PH >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

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 GROUP SILDENAFIL GROUPBaseline End of

studyMean

ChangeBaseline End of

studyMean

ChangeP value

Behling 17.2±2 16.5±2 -0.7 16.4±3 18.5±3 +2.1 0.004*

Guazzi 2007 15.3±1.8 15.1±1.5 -0.2 14.8±1.5 18.7±1.7 +3.9 <0.01t

Guazzi 2010 12.7±5.0 13.0±5.0 +0.03 12.9±6.8 15.6±5.8 +2.7 <0.01*

Lewis 10.2±0.8 9.93 -0.27 12.2±0.7 13.9±1.0 +1.7 0.02*

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 VO2 at 3rd and 6th month

Mean Change in VE/VCO2 at the END OF STUDY: SIGNIFICANT DECREASE

TRIAL PLACEBO GROUP SILDENAFIL GROUP

Baseline End of study

Mean Change

Baseline End of study

Mean Change

P value

Behling 39.1±6 40.6±9 +1.5 44.7±6 34.1±5 -10.6 0.002*

Guazzi 2007 34.4±2.7 34.5±3.7 +0.1 35.5±4.7 29.8±2.7 -5.7 <0.01t

Guazzi 2010 35.5±3.7 35.9±4.2 +0.4 35.1±4.2 29.1±3.1 -6.0 <0.01*

Change in VE/VCO2 from baseline

Mean Change in PAP at the END OF STUDY: SIGNIFICANT DECREASE

TRIAL PLACEBO GROUP SILDENAFIL GROUPBaseline End of

studyMean

ChangeBaseline End of

studyMean

ChangeP value

Behling 62±23 65±20 +3 56±13 38±10 -18 0.004* Guazzi 2007 31.9±2.7 33.7±3.1 +1.8 33.7±3.1 23.9±3.1 -9.80 <0.01t

Guazzi 2010 37.7±3.9 37.9±4 +0.2 37.1±4.3 24.0±3.0 -13.10 <0.01* Lewis 33±3 31±3 -2 30±2 28±2 -2.0 0.16*

Change in Pulmonary Artery Pressure from baseline

TRIAL PLACEBO GROUP SILDENAFIL GROUP

Baseline End of study

Mean Change

Baseline End of study

Mean Change

P value

Guazzi 2007

31.9±3.3 30.4±3.6 -1.1 30.6±3.0 34.7±2.8 +4.1 NSt

Guazzi 2010

30.2±4.0 31.0±3.2 +0.8 29.5±3.0 36.3±3.0 +6.8 <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 effectsFUNCTIONAL CAPACITY

CLINICAL STATUS QUALITY OF LIFE

SILDENAFIL could be an ADJUNCT to standard medical therapy for chronic

heart failureWarrants LARGER LONG TERM

CLINICAL TRIALS

MELGAR O. MATULAC MD., LEORA FLOR MACAPUGAY MD., MICHAEL REYES MD., KRISTINE TUMABIENE MD., ALRIC MONDRAGON MD .

SECTION OF CARDIOLOGYDEPARTMENT OF MEDICINE

UNIVERSITY OF THE PHILIPPINES – PHILIPPINE GENERAL HOSPITAL

Sildenafil Improves Exercise Capacity in Heart Failure: A Meta-

analysis

S I C HEART Study