adt and cardiovascular risk: should antagonists be the ... · • higher risk for gnrh-agonists...

Urologische Klinik und Poliklinik

University Medicine Mainz

ADT AND CARDIOVASCULAR RISK:

should Antagonists be

the primary choice for ADT?

Igor Tsaur


Off-label use of drugs, devices, or other agents: none

Data from IRB-approved human research is presented: is not

2

I have the following financial interests or

relationships to disclose: Disclosure code

Sanofi L

Janssen C, L

Ferring L

Bayer C

COI


3

Rubens, 1616

GOLIATH

DAVID


4

Rubens, 1616

ANTAGONISTS

AGONISTS


Keating NL et al, J Clin Oncol, 2006

Diabetes CHD MI Sudden death

No treatment

REF

REF

REF

REF

GnRH-Agonists

1,44

<0,001

1,16

<0,001

1,11

0,03

1,16

0,004

OT

1,34

<0,001

0,99

0,74

0,94

0,44

1,01

0,85

73.196 patients, 34,6% GnRH-Agonists, 6,9 % OT Follow-up 2-9 a.

5

Different forms of ADT –

different CVE risks?


Everyday Urology – Oncology Insights, Vol. 2 (1) 6

Agonists vs. antagonists


ADT associated with CVE

• Higher risk for GnRH-Agonists than OT1

• Highest risk for pts. with CVE in the past2,3

Different function of GnRH-Antagonists compared to GnRH-Agonists

• Different CVE risk?

• Less arterial plaque rupture by GnRH-Antagonists blocking GnRH receptors

on lymphocytes?

• FSH-drop related protective effects on CVE?

1. Taylor LG et al, Cancer, 2009 2. Nanda AN et al, JAMA, 2009 3. Hedlund PO et al, Scand J Urol Nephrol, 2011

7




8



Crawford ED et al, Urol Oncol, 2017


9




Data on pre-existing comorbid diseases reported by pts. and classified by

study investigators according to MedDRA before analysis 10

Study Duration (mo.) Comparator Publication

CS21 T≤0.5 ng/ml

12 Leuprolide Klotz et al. BJU Int 2008

CS35 IPSS/QoL/PSA/T

12 Goserelin Shore et al. SUO 2012

CS37 PSA/QoL

7-12 Leuprolide unpublished in complete

design

CS28 LUTS improvement

3 Goserelinb Anderson et al. Urol Int 2012

CS30 prostate size reduction

3 Goserelinb Mason et al. Clin Oncol 2013

CS31 prostate size reduction

3 Goserelinb Axcrona et al. BJU Int 2012

Pooled data analysis of 6 RCTs


11

2328 pts.

1491 Degarelix

837

GnRH Agonist

463 (31%) Preexisting CV

conditions

458

Goserelin

379

Leuprolide

245 (29 %)

CVE defined as arterial embolic and thrombotic events, hemorrhagic and

ischemic CV conditions, MI or other ischemic heart disease

Primary end point: CVE or death

Design


12

Results: pts. with preexisting CVE

HR=0,44 (95 % CI 0,26–0,74)

p=0,002

No differences in men without preexisting CV conditions!


13

Results: all pts.

HR=0,60 (95 % CI 0,41–0,87)

p=0,008

Total significance achieved by pts. with preexisting CV conditions!


14

Results: all pts.

Powered by CS37 – unpublished at the time of the analysis


15

significant

Significance overall vs. subgroups

nonsignificant

CV conditions No preexisting CV conditions

Practice changing for all?


16

Hypothesis generating ≠ Practice changing

Retrospective post hoc analysis

CVE reportes as AE, not as independent end point

Uncontrolled bias in not monitored risk factors for CVE (e.g. lipide profiles)

Open-label studies – prone for bias due to underreporting of AEs

Hemorrhagic vs. ischemic – different pathophysiology

Short-term data, small number of events

Benefit only for pts. with preexisting CV conditions (1/3 of the cohort,

n=463 vs. 245), not for the majority of the cohort!


17


https://maismaismedicina.wordpress.com

Not only HTN, but also AV-malformation, aneurysms


18


Retrospective post hoc analysis

CVE reportes as AE, not as independent end point

Uncontrolled bias in not monitored risk factors for CVE (e.g. lipide profiles)

Open-label studies – prone for bias due to underreporting of AEs

Hemorrhagic vs. ischemic – different pathophysiology

Short-term data, small number of events

Benefit only for pts. with preexisting CV conditions (1/3 of the cohort,

n=463 vs. 245), not for the majority of the cohort!

Convincing?


19

Population-based data


20


Primary end point: HR for MI or ischemic stroke requiring hospitalization

more focussed on the issue of arterial plaques stability !!!!!!


21


Median time to ischemic event: 478 d.!!! Pooled data (3-12 mo.

trials) representative enough?

CVE profile of GnRH-Antagonists not better than that of –Agonists


22

Comparison of covariates

Statin

Alcohol

Hypertension

Smoker

Cholesterol

Type 2 diabetes

treated

Hypertension

treated

Age

Testosterone

BMI

Age Dyslipidamia

CAD Anticoagulant

drugs

Diabetes CKD

Heart failure Smoker

Arterial

thrombosis Statin

Hypertension Hemorrhagic

stroke

Obesity Ischemic

stroke

Alcohol COPD

Atrial

fibrillation

Anti-platelet

agents


23

Arch of Titus, Rome


24

Meta-analysis

CS 37 not included because not published!!!

Study quality cannot be assessed!!!


25

Meta-analysis

Severe CVE defined as QT-interval increase, angina pectoris, atrial fibrillation,

cardiac failure and myocardial ischemia

No significant difference Agonists ↔ Antagonists!!!


26

Recommendations

EAU Guideline Prostate Cancer 2018


27

Conclusions

Antagonists are not the primary choice for ADT in all patients!

Poor evidence to favour Antagonists over Agonists for CV safety

Antagonists MIGHT be considered in pts. with preexisting CV

Antagonists SHOULD be considered in pts. requiring rapid remission

PRONOUNCE trial ongoing, lets wait……


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