in High Risk Cardiovascular Patients in the ONTARGET Trial M. Bhm, - - PowerPoint PPT Presentation

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Medication Adherence and Outcomes in High Risk Cardiovascular Patients in the ONTARGET Trial M. Bhm, H. Schumacher, U. Laufs, P. Sleight, R. Schmieder, T. Unger, K. Koon, S. Yusuf on behalf of the ONTARGET-Investigators Disclosures Authors

SLIDE 1

M. Böhm,
H. Schumacher, U. Laufs, P. Sleight,
R. Schmieder, T. Unger, K. Koon, S. Yusuf
n behalf of the ONTARGET-Investigators

Medication Adherence and Outcomes in High Risk Cardiovascular Patients in the ONTARGET Trial

SLIDE 2

Authors were members of the ONTARGET Steering Committee and received honoraria and research grants from Boehringer Ingelheim as well as fees from other major cardovascular pharmaceutical companies

Disclosures

SLIDE 3

Nonadherence to medications

is a problem in high risk patients
associated with multidrug treatment

Background

related to outcomes in several conditions
Hypertension
Hyperlipidemia
CAD
CHF
Associated with-health related

life style characteristics

(„healthy adherer phenomenom“)

SLIDE 4

Objectives of ONTARGET

Patients: CV high risk patients after MI, Stroke, PAD, or DM + 2RF Questions: 1.Is telmisartan “non-inferior” to ramipril? 2.Is the combination superior to ramipril? Outcome: 1.Primary: CV death, MI, stroke, CHF hosp 2.Key secondary: CV death, MI, stroke (HOPE trial outcome) 3.Single Components of the primary

ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial, Am Heart J 148: 52-61, 2004

SLIDE 5

Primary Outcome Telmisartan vs. Ramipril vs. Combination

1.0 RR (95% CI) 1.1 1.2 0.9 0.8 Ramipril better Telmisartan better Primary Composite CV Death / MI / Stroke (HOPE Composite) P=0.0045 P=0.001 Non-Inferiority Margin

0.0 0.05

Cumulative Hazard Ratio

500

Follow-up (days)

1000 1500 0.10 0.15 0.20 Telmisartan Ramipril Combination

ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial, N Engl J Med 358: 1547-1559, 2008

SLIDE 6

Objective of Current Analysis

Identification of patient characteristics

for nonadherence

Effect of nonadherence on outcomes
Effect of CV-outcomes on adherence

SLIDE 7

Definitions and Methods

Nonadherence: Complete and Permanent Discontinuation of All Study Medications Statistical Analysis:

differences tested by Chi-square (categorical) or

Student`s t-test (continuous)

Cox propotional hazard model
nonadherence as time-dependent covariate
multiple regression
p<0.01

SLIDE 8

0.00 0.05

Proportion of Patients

360

Days of follow-up

Permanent Stop of Study Medication Continuously Increased Over Time

0.10 0.15 0.20 0.25 720 1080 1440 1800 2160

4629 patients discontinued

20.991 adherent

SLIDE 9

Cox Regression on Time to Permanent Stop of Study Medication (Non-Adherence, adjusted)

<0.0001 <0.0001 0.0009 <0.0001 <0.0001 <0.0001 <0.0001 0.0005 0.0026 0.0013 <0.0001 <0.0001 1.035 1.200 1.302 0.569 0.645 0.863 0.806 1.193 1.113 1.128 1.223 1.111 (1.030 – 1.039) (1.117 – 1.289) (1.115 – 1.521) (0.511 – 0.639) (0.574 – 0.726) (0.804 – 0.927) (0.750 – 0.865) (1.080 – 1.316) (1.038 – 1.192)) (0.974 – 1.128) (0.927 – 1.104) (0.867 – 1.036) Age, linear Female vs Male Black vs White Asian vs White Other vs White Activity 2-6/week vs ≤ 1/week Every day vs ≤ 1/week Smoking Current vs Never Smoking Formerly vs Never Stroke / TIA History of diabetes Episodes of depression Variable Pr > ChiSq HR 95% CI

Age, Gender, Ethnics, Physical Activity, Smoking, Diabetes, neuro-psychiatric disorders

SLIDE 10

100.0 4629 13.7 635 ≥ 4 years 86.3 3994 13.2 613 3y - < 4 years 73.0 3381 17.0 785 2y - < 3 years 56.1 2596 22.4 1038 1y - < 2 years 33.7 1558 13.4 619 6m - < 1 year 20.3 939 12.6 585 6w - < 6 months 7.7 354 7.7 354 < 6 weeks Cumulative Percent Cumulative Frequency Percent Frequency Permanent discontinuation

Distribution of Premature Permanent Discontinuations of Study Medication - By Time

SLIDE 11

Nonadherence Increases Overall Event Rates

SLIDE 12

Rapid Increase of Events by Year After Permanent Discontinuation of Study Medication

SLIDE 13

Rapid Increase of Events by Year After Permanent Discontinuation of Study Medication

SLIDE 14

Cox Model with Time-Dependent Covariate

4-fold endpoint 3-fold endpoint CV death MI Stroke CHF Hospitalisation <.0001 <.0001 <.0001 0.6569 0.5171 <.0001 1.298 (1.181 – 1.427) 1.385 (1.255 – 1.528) 2.050 (1.824 – 2.303) 1.043 (0.866 – 1.256) 1.066 (0.879 – 1.293) 1.464 (1.228 – 1.745) p Hazard Ratio (CI) Time-dependent (HR for being off medication)

SLIDE 15

Rate of Rise of Event Rates after Stop of Study Medication is Similiar Between Years of Discontinuation

365

Days of follow-up

730 1095 1460 1825 2190

4-fold Endpoint

(CV-Death, MI, Stroke, CHF-Hospitalisation)

≥ 4 years 3 - <4 years 2 - <3 years 1 - <2 years <1 year No Discontinuation

0.00 0.05

Proportion of Patients

0.25 0.10 0.15 0.20

SLIDE 16

Risk for Discontinuation of Medication is Increased After Nonfatal Primary Event

SLIDE 17

Risk for Discontinuation of Medication is Increased After Nonfatal Other Events

SLIDE 18

Number of Events Increases Nonadherence

Events None 1 2 3 ≥ 4

20 30 40 50 60 70 80 90

Adherence No adherence

100

SLIDE 19

CHF Myocardial Infarction CV-Death Stroke 3-Fold Endpoint 4-Fold Endpoint

60 65

Rate of Adherence (%)

70 75 80 85 90

No Event ≥ 4 years 2 - <3 years 1 - <2 years <1 year 3 - <4 years

Patients with an Early Event Have Worse Mean Adherence Rates

SLIDE 20

Conclusions:

Ageing, females, ethnics, low physical activity,

smoking, diabetes, neuro-psychiatric disorders are predictors of nonadherence

becoming nonadherent rapidly increases events
the event itself reduces adherence

leading into a vicious cycle!

SLIDE 21

Age, Gender, Ethnics, Physical Activity, Smoking, Diabetes, neuro-psychiatric disorders