Optimal Pharmacological Therapy After Valve Intervention

JEFFREY S. BORER, M.D.Professor of Medicine, Cell Biology, Radiology and Surgery

Director, The Howard Gilman Institute for Heart Valve Disease and

The Schiavone Cardiovascular Translational Research Institute

Former Chairman, Department of Medicine

and Former Chief, Division of Cardiovascular Medicine

State University of New York Downstate Medical Center

Disclosures

• Consulting fees, Committee fees with– Servier– Amgen– Novartis– Cardiorentis– Pfizer– ARMGO– Takeda USA– Celladon– BioMARIN (stock)

UNDERLYING PRINCIPLES/ISSUES• There is no established/evidence-based cardiovascular

pharmacological therapy for – any uncomplicated valve disease– post-procedural adjunctive benefit for any valve intervention

UNDERLYING PRINCIPLES/ISSUES• There is no established/evidence-based cardiovascular

pharmacological therapy for – any uncomplicated valve disease– post-procedural adjunctive benefit for any valve intervention

• Therefore, no specific drug regimen exists for post-intervention pts who had had low flow/low gradient AS

UNDERLYING PRINCIPLES/ISSUES• There is no established/evidence-based cardiovascular

pharmacological therapy for – any uncomplicated valve disease– post-procedural adjunctive benefit for any valve intervention

• Therefore, no specific drug regimen exists for post-intervention pts who had had low flow/low gradient AS

• BUT low flow/low gradient AS commonly is associated with many adversities common to other AS presentations (e.g., associated MR) and, after intervention, commonly is associated with additional adversities (e.g., paraprosthetic AR, etc.)

UNDERLYING PRINCIPLES/ISSUES• There is no established/evidence-based cardiovascular

pharmacological therapy for – any uncomplicated valve disease– post-procedural adjunctive benefit for any valve intervention

• Therefore, no specific drug regimen exists for post-intervention pts who had had low flow/low gradient AS

• BUT low flow/low gradient AS commonly is associated with many adversities common to other AS presentations (e.g., associated MR) and, after intervention, commonly is associated with additional adversities (e.g., paraprosthetic AR, etc.)

• Therefore, it is useful to discuss the general principles of selection of drug therapy after any valve intervention.

UNDERLYING PRINCIPLES/ISSUES• Use of drugs after a mechanical valve intervention primarily is a function of

– Type of procedure performed • Surgical

– Diuretics for removal of procedural fluid load – early: days to weeks– Other pre-op HF drugs if HF was present – early and as needed thereafter– Anticoagulant and antiplatelet agents

• Transcutaneous– pre-op HF drugs if HF was present – early and as needed thereafter– Anticoagulant and antiplatelet agents

• Repair– pre-op HF drugs if HF was present – early and as needed thereafter– Possibly anticoagulant and antiplatelet agents short-term

• Replacement– Pre-op HF drugs if HF was present – early and as needed thereafter– Bioprosthetic – possibly antiplatelet drugs, possibly short term anticoagulants– Mechanical – permanent anticoagulation (only warfarin at present – NOACs

contraindicated)

– Time after procedure at which drugs are to be given (<4 weeks post-op vs chronic)

UNDERLYING PRINCIPLES/ISSUES• Use of drugs after a mechanical valve intervention primarily is a function of

– Type of procedure performed • Surgical

– Diuretics for removal of procedural fluid load – early: days to weeks– Other pre-op HF drugs if HF was present – early and as needed thereafter– Anticoagulant and antiplatelet agents

• Transcutaneous– pre-op HF drugs if HF was present – early and as needed thereafter– Anticoagulant and antiplatelet agents

• Repair– pre-op HF drugs if HF was present – early and as needed thereafter– Possibly anticoagulant and antiplatelet agents short-term

• Replacement– Pre-op HF drugs if HF was present – early and as needed thereafter– Bioprosthetic – possibly antiplatelet drugs, possibly short term anticoagulants– Mechanical – permanent anticoagulation (only warfarin at present – NOACs

contraindicated)

– Time after procedure at which drugs are to be given (<4 weeks post-op vs chronic)

0

10

20

30

40

50

60

Pre-op <1 1-2 2-3 4-6

YEARS AFTER AVR

LV E

JEC

TIO

N F

RA

CTI

ON

(%)

0

NSNSNS

NSNS

p<.01p<.01

p<.05

NATURAL HISTORY OF LVEF AFTER AVR FOR AR:EFFECT OF DRUGS MAY VARY WITH CHANGING MYOCARDIUM

Borer et al, Circulation 1990

UNDERLYING PRINCIPLES/ISSUES

Use of drugs after a mechanical valve intervention primarily is a function of

– Hemodynamic success of the procedure (?residual stenosis or regurgitation?)

– Comorbidities that are likely to directly affect cardiac function (most important: hypertension; dysrhythmia)

– Residual symptom status (is there clinical heart failure?)

– Residual ventricular/myocardial function

Relative risk ratio for short-term mortality versus severity of valve prosthesis-patient mismatch

Claudia Blais et al. Circulation. 2003;108:983-988

Copyright © American Heart Association, Inc. All rights reserved.

LV Wall Volume vs AS Severity for Different Magnitudes of Hypertension

Garcia et al. Journal of Biomechanics 40 (2007) 972–980

BUT no evidence that residual obstruction can be beneficiallyovercome with drugs; better to mechanically relieve obstruction

Survival in Asymptomatic Patients as a Function of the Severity of Aortic Regurgitation

Detaint et al. JACC Img. 2008;1:1-11.

Copyright © The American College of Cardiology. All rights reserved.

Paravalvular Leak After Transcatheter Aortic Valve Replacement: Survival Over 36 months

Généreux et al . JACC 2013;61(11):1125-1136.

CHRONIC VASODILATOR DRUG (VDD) USE vs. CARDIAC EVENTS

0 2 4 6 8 10 12Years After Study Entry

100

0102030405060708090

% C

ardi

ac E

vent

Fre

e No VDD: Avg Annual Risk = 3.99%

VDD : Avg Annual Risk = 17.46%

p = .0005

Supino, Borer, Herrold et al, AJC 2005

Enriquez-Sarano, M. et al. N Engl J Med 2005;352:875-883

Asymptomatic Mitral Regurgitation: Cardiac Events vs Effective Regurgitant Orifice (ERO)

Study, year Pts Drug ResultHeck et al 1985 10 Captopril Neg/neutralWisenbaugh et al l994

12 Captopril Neg/neutral

Schon et al 1994 12 Quinapril Neg/neutralSampaio et al 2005 47 Enalapril Neg (reduction in

anaerobic threshold at 12 months)

MR: “LONG-TERM” PHARMACOLOGICAL AFTERLOAD REDUCTION, n=81

(=included some symptomatic pts)

UNDERLYING PRINCIPLES/ISSUES

– Hemodynamic success of the procedure (?residual stenosis or regurgitation?)

– Comorbidities that are likely to directly affect cardiac function (most important: hypertension; dysrhythmia)

– Residual symptom status (is there clinical heart failure?)

– Residual ventricular/myocardial function

Clinical Risk Markers for Aortic Stenosis

Stewart et al. J Am Coll Cardiol 1997;29:630–4

BUT – though eventually there should be no difference between the myocardiumof a pt with prior AS and a person with hypertension without prior AS, as yet no evidence that treatment of hypertension after AVR for AS impactsbeneficially on outcome – or of when after AVR the treatment works well, or ifthere is a difference among effects of different antihypertensives

LV Wall Volume vs AS Severity for Different Magnitudes of Hypertension

Garcia et al. Journal of Biomechanics 40 (2007) 972–980

CARDIAC EVENT-FREE SURVIVAL IN CHRONIC SEVERE AR: IMPACT OF HYPERTENSION

(N=73)

p<.005, age/gender adjusted Supino, Borer, et al. Am J Cardiol. 2005

NIFEDIPINE vs DIGOXIN IN ASx AR: EFFECT ON NATURAL HISTORY (n=143, BPs 154)

Scognamiglio et al NEJM 1994

NIFEDIPINE vs DIGOXIN IN ASx AR: EFFECT ON NATURAL HISTORY (n=143, BPs 154)

Scognamiglio et al NEJM 1994

NIFEDIPINE vs DIGOXIN IN ASx AR: EFFECT ON NATURAL HISTORY (n=143, BPs 154)

Scognamiglio et al NEJM 1994

NIFEDIPINE (n=32) OR ENALAPRIL (n=32) IN ASx AR: EFFECT ON NATURAL HISTORY

(no drug control n=31) (BPs 141)

Evangelista et al NEJM 2005

Evangelista et al NEJM 2005

NIFEDIPINE (n=32) OR ENALAPRIL (n=32) IN ASx AR: EFFECT ON NATURAL HISTORY

(no drug control n=31) (BPs 141)

Evangelista et al NEJM 2005

NIFEDIPINE (n=32) OR ENALAPRIL (n=32) IN ASx AR: EFFECT ON NATURAL HISTORY

(no drug control n=31) (BPs 141)

Mitral Regurgitation: Chronic Vasodilator Therapy Use at Entry

vs. Event-Free Survival: All patients (N=56)

Years After Study Entry

% F

ree

of C

ardi

ac D

eath

of S

urgi

cal I

ndic

atio

n

Supino, Borer, et al. Cardiology 2014; 129:262-266

Mitral Regurgitation:Hypertensive Patients (N=14)

% F

ree

of C

ardi

ac D

eath

of S

urgi

cal I

ndic

atio

n

Years After Study Entry

Supino, Borer, et al. Cardiology 2014; 129:262-266

UNDERLYING PRINCIPLES/ISSUES

– Hemodynamic success of the procedure (?residual stenosis or regurgitation?)

– Comorbidities that are likely to directly affect cardiac function (most important: hypertension; dysrhythmia)

– Residual symptom status (is there clinical heart failure?)

– Residual ventricular/myocardial function

RESIDUAL SYMPTOMS

• Treat empirically to relieve symptoms– If heart failure symptoms and systolic dysfunction is present,

follow systolic HF guidelines

UNDERLYING PRINCIPLES/ISSUES

– Hemodynamic success of the procedure (?residual stenosis or regurgitation?)

– Comorbidities that are likely to directly affect cardiac function (most important: hypertension; dysrhythmia)

– Residual symptom status (is there clinical heart failure)

– Residual ventricular/myocardial function

RESIDUAL VENTRICULAR DYSFUNCTION

• Follow guidelines for systolic heart failure– ACEI/ARB– Beta blockers– MRA– Ivabradine if LVEF ≤35% and heart rate ≥70 bpm in sinus rhythm– + diuretics if volume excessive

CONCLUSIONS• There is no established/evidence-based cardiovascular

pharmacological therapy for – any uncomplicated valve disease– post-procedural adjunctive benefit for any valve intervention

CONCLUSIONS• There is no established/evidence-based cardiovascular

pharmacological therapy for – any uncomplicated valve disease– post-procedural adjunctive benefit for any valve intervention

• Drug treatment after valve intervention is largely based on extrapolation from data from patients with unintervened valve disease

CONCLUSIONS• There is no established/evidence-based cardiovascular

pharmacological therapy for – any uncomplicated valve disease– post-procedural adjunctive benefit for any valve intervention

• Drug treatment after valve intervention is largely based on extrapolation from data from patients with unintervened valve disease

• Modified by judgment based on– Time after procedure at which drugs are to be given– Hemodynamic success of the procedure (?residual stenosis or

regurgitation?)– Comorbidities that are likely to directly affect cardiac function

(most important: hypertension; dysrhythmia)– Residual symptom status (is there clinical heart failure?)– Residual ventricular/myocardial function

CONCLUSIONS• There is no established/evidence-based cardiovascular

pharmacological therapy for – any uncomplicated valve disease– post-procedural adjunctive benefit for any valve intervention

• Drug treatment after valve intervention is largely based on extrapolation from data from patients with unintervened valve disease

• Modified by judgment based on– Time after procedure at which drugs are to be given– Hemodynamic success of the procedure (?residual stenosis or

regurgitation?)– Comorbidities that are likely to directly affect cardiac function

(most important: hypertension; dysrhythmia)– Residual symptom status (is there clinical heart failure?)– Residual ventricular/myocardial function

• The myocardium of valve-diseased hearts recovers slowly (years) after intervention– EFFECT OF DRUGS MAY VARY WITH THE CHANGES IN

MYOCARDIUM