Cutrell A, Hernandez J, Brothers C et al. 2008 Is abacavir (ABC)-containing combination antiretroviral therapy (CART) associated with myocardial infarction

Cutrell A, Hernandez J, Brothers C et al. 2008

Is abacavir (ABC)-containing combination antiretroviral therapy

(CART) associated with myocardial infarction (MI)? No association identified in pooled

summary of 54 clinical trials

A Cutrell, J Hernandez, C Brothers, J Yeo, W Burkle, W Spreen.

XVII International AIDS Conference, 3-8 August 2008, Mexico City


Background and Objective

• The D:A:D study group recently reported an unexpected increase in risk of MI with ABC and ddI in a large, prospective observational cohort (Lancet 2008; 371:1417-26).

• To determine whether there is an increase in cardiovascular events associated with ABC containing CART as compared to non-ABC containing CART using GSK-sponsored clinical trials contained in the GSK HIV Data Repository.


Methods (1)

• GSK-sponsored clinical trials with > 24 weeks of follow up with data from 1995-2006 were analyzed. – Data from 54 clinical trials analyzed:

• 12/54 adult trials were randomized for ABC vs control• 33/54 trials included ABC in background ART• 8/54 trials did not include ABC

• Includes data from 14683 subjects (14174 adults and 509 children)

• Descriptive statistics were summarized for naïve and experienced subjects treated with and without ABC.


Methods (2)• To capture events of interest (myocardial ischemia or

infarction) all data were queried for events coded as “Coronary Artery Disorders” and “Ischemic Coronary Artery Disorders”.– Specific preferred terms included: coronary artery

atherosclerosis, coronary artery disease, coronary artery occlusion, acute MI, angina pectoris, angina unstable, MI and myocardial ischemia.

• All fatal cases (any cause) in the HIV Data Repository were reviewed by an external cardiologist.

• Framingham risk not calculated at baseline – not all factors routinely collected.

• Rates per 1000 person/years were calculated, and Poisson regression models were used to calculate unadjusted relative rates and 95% confidence intervals using SAS.


Demographic and HIV-disease Characteristics at Baseline

ADULT NAIVE ADULT EXPERIENCED

ABCN=5859

No ABCN=2406

ABCN=3643

No ABCN=2266

Age at Screening, nMedian, year

(min-max)

585936 (17-78)

240635 (18-74)

363940 (18-78)

226339 (18-74)

Race, nWhiteBlack

572849%29%

231454%22%

359164%21%

226573%16%

Sex, nMale

585878%

240679%

364386%

226685%

Viral Load (log10), n Median (Min-Max)

57934.81 (1.28-

7.64)

23974.67 (1.28-6.6)

36264.25 (0.84-6.74)

22474.18 (1.38-7.05)

CD4 Count, n Median (Min-Max)

5819273 (0-1883)

2393337 (0-1729)

3629265 (0-2089)

2250295 (0-1799)


Baseline Lipids and Glucose (mmol/L)n

Median(Min-Max)

ADULT NAIVE ADULT EXPERIENCED

ABCN=5859

No ABCN=2406

ABCN=3643

No ABCN=2266

Cholesterol 5484 4.1

(1.0-10.1)

22724.2

(1.6-10.1)

22494.8

(0.05-15.0)

18084.6

(1.8-15.0)

LDL 21432.5

(0.1-6.3)

1662.7

(0.8-6.4)

393.2

(1.0-5.5)

233.7

(1.3-5.2)

HDL 22150.9

(0.05-3.1)

1720.9

(0.2-2.5)

481.0

(0.3-2.6)

241.1

(0.5-1.5)

Triglycerides 54821.4

(0.3-28.9)

22721.4

(0.2-15.4)

22342.1

(0.04-38.1)

18031.9

(0.4-35.3)

Glucose 49995.0

(1.3-27.2)

23535.0

(0.9-24.1)

22015.2

(2.2-26.0)

16625.2

(2.1-26.2)


CV Outcomes - Exposure to ABC Compared with No Exposure to ABC

Exposure to ABC

Events

/Patients

Frequency Events

/Person- Years

Rate

/1000 Person-Years

Relative rate

(95% CI)

Any Myocardial Infarction or Acute Myocardial Infarction:

None 7/5044 0.139% 11/4653 2.36

ABC CART 11/9639 0.114% 16/7845 2.04 0.863 (0.40,1.86)

Any ischemic Coronary Artery Disease or Disorder:

None 21/5044 0.416% 27/4642 5.82

ABC CART 24/9639 0.249% 27/7832 3.45 0.593 (0.35 ,1.01)


CV Outcomes - Exposure to ABC or No ABC (12 Adult Randomized Trials)

Exposure to ABC

Events

/Patients

Frequency Events

/Person-Years

Rate

/1000 Person-Years

Relative rate

(95% CI)

Any Myocardial Infarction or Acute Myocardial Infarction:

None 6/1692 0.355% 7/1706 4.10

ABC CART 2/1570 0.127% 4/1863 2.15 0.523

(0.15 – 1.79)

Any ischemic Coronary Artery Disease or Disorder:

None 13/1692 0.768% 13/1702 7.64

ABC CART 5/1570 0.318% 8/1860 4.30 0.563

(0.23-1.36)


Strengths and Limitations

• Prospective clinical trial data with large number of patients exposed to ABC, consistent data collection

• Standard and real-time monitoring and follow up of all reported AEs

• External expert review supportive

• Post-hoc analysis• Duration of exposure

on average 24-48 weeks • Studies not designed to

detect CV risk specifically

• Low event rate therefore less power


Conclusion• Overall, among pts in the GSK HIV Data

Repository:– the incidence rate of MI and Coronary Artery Disorders

was low – there was no difference in incidence of ischemic

coronary artery events or myocardial infarction in subjects who received abacavir-containing vs. non-ABC containing CART

• Further study is needed to fully evaluate the association of ABC and cardiovascular disease.


What’s Next to Further Address the Question?

Analysis of Internal Clinical Trial DataContinued vigilance of spontaneous event

data and published literature In all future studies, incorporate

cardiovascular risk factor and biomarker collection

Mechanism research Analyze inflammatory markers in current and

future studies Support additional cohort collaborations


HEAT Biomarker Analysis: Geometric Mean (95% CI) by Study Week (ITT-E)

n (obs)ABC/3TC = 243 248 230 256 251 232TDF/FTC = 249 235 216 252 236 216

0

0.5

1

1.5

2

2.5

3

0 48 96

Study Week

hsC

RP (

mg/L

)

Interleukin 6 (IL-6)

0

0.5

1

1.5

2

2.5

3

0 48 96

Study Week

IL-6

(pg/m

L)

High Sensitivity C-Reactive Protein (hsCRP)

Adapted from Smith K, et al. IAC 2008. Abstract LBPE1138.


Acknowledgments

The authors wish to thank…• Harry Staines, Suki Pabla, Dupe Bassey, Lee

Tombs and Pinal Patel at SRG Interesource Satellite Operations for statistical support

• Drs. Peter Kowey & Gary Koch for expert input

• Investigators who supported the clinical trials

• All of the patient volunteers.


Back up slides


Proportion of Subjects on ART +/- ABC Reporting MI or Acute MI among 14682 Subjects

ART Regimen

Subjects

0

0.5

1

1.5

2

2.5

3

3.5

Percent

High 95%CI

Low 95%CI

Percent

n/N= ABC12/9639

Non-ABC 7/5043

Total19/14682

0.125% 0.139% 0.129%



Proportion of ART-naïve Subjects on ART +/- ABC Reporting MI or Acute MI among 8265 Subjects

ART Regimen

Subjects

0

0.5

1

1.5

2

2.5

3

3.5

Percent

Low 95%CI

High 95%CI

Percent

n/N= ABC11/5859

Non-ABC3/2406

Total 14/8265

0.169% 0.125% 0.188%



Proportion of ART-experienced Subjects on ART +/-ABC Reporting MI or Acute MI among 5908 Subjects

ART Regimen

Patients

0

0.5

1

1.5

2

2.5

3

3.5

Percent

Low 95%CI

High 95%CI

Percent

n/N= ABC 1/3643

Non-ABC 4/2266

Total 5/5908

0.067% 0.177% 0.027%



Abacavir and Risk of MI:Evaluation of potential biologic mechanisms

• Review of preclinical, clinical pharmacology and clinical information does not indicate a clear contribution of abacavir therapy to enhanced risk of MI via plausible biologic mechanisms. Rather, the preponderance of data support a conclusion of a generally favorable cardiovascular safety profile.



Safety pharmacology

• Isolated cardiac muscle (rat, guinea-pig & cat):– No inotropic, chronotropic or dysrythmic effects.

• Concious normotensive rat:– No effect on Arterial BP or heart rate (100mg/Kg).

• Anesthetized dog:– Little effect on ABP or HR, no arrhythmia (50 mg/Kg IV)

• No effect on 19 receptor binding sites, including:– cholinergic, adrenergic, histaminergic and serotonergic.

• No effect in tissue responsiveness to arachidonic acid, bradykinin and angiotensin II



Incidence of Serious CV Events D:A:D Study, VA Study & GSK Data Repository

D:A:D1999-2006

VA1993-2003

GSK DR 1995-2007

Patient numbers 33,000 41,213 14,680

Total patient f/u, PY 156,667 168,213 12,498

Average patient f/u, yrs 4.7 4.1 0.72

Incidence of serious CV events/MI

1.6% 4.2% 0.31%0.129%

Incidence 1000/PY 3.3 10 4.39/1.92

Sabin C, et al. 15th CROI 2008: Abstract.Bozzette S, et al. J Acquir Immune Defic Syndr 2007;0:1-4.

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Cutrell A, Hernandez J, Brothers C et al. 2008 Is abacavir (ABC)-containing combination antiretroviral therapy (CART) associated with myocardial infarction