1. Pioglitazone after Ischemic Stroke or Transient Ischemic Attack
Lindsay Waddington
PGY-1 Pharmacy Resident
St. Vincent Hospital - Indianapolis

2. Ischemic Stroke and Transient Ischemic Attack
Almost 800,000 annual stroke diagnoses in the US
87% are ischemic stroke
25% in patients with a history of stroke
Risk Factors
Non-modifiable: age, sex, ethnicity
Modifiable: smoking status, sedentary lifestyle, hyperlipidemia, hypertension, diabetes/glucose control
Secondary Prophylaxis
Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics—2015 update: a report from the American Heart Association. Circulation. 2015 ;e

3. Insulin Resistance
Major component of Metabolic Syndrome
Contributor to atherosclerotic complications such as stroke and heart attack
Homeostasis model assessment of insulin resistance index (HOMA-IR)
(Fasting glucose mmolL x fasting insulin microunits/mL)/22.5
Insulin resistance is present in almost all patients with DMII but also in more than 50% of patients without DM who had an ischemic stroke or TIA
3.0 identifies the highest quartile among populations without diabetes
0.2 to 15
Treatment of insulin resistance could be a new approach to secondary stroke prophylaxis
Reaven GM. Banting Lecture 1988: Role of insulin resistance in human disease. Diabetes1988;37:

4. Pioglitazone Thiazolidinedione (TZD) Indication Dosing
Increases insulin sensitivity via PPAR-γ
Dependent upon endogenous insulin
Indication
Adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes
Dosing
pioglitazone 15mg or 30mg orally once daily
Maximum dose pioglitazone 45mg orally once daily
Actos [package insert]. Deerfield, IL: Takeda Pharmaceuticals America, Inc.; 1999.

5. Pioglitazone Contraindications Monitoring NYHA class III or IV
hypersensitivity
Monitoring
Signs and symptoms of heart failure
> Edema, weight gain, shortness of breath
Liver function
Fractures
Bladder Cancer
Actos [package insert]. Deerfield, IL: Takeda Pharmaceuticals America, Inc.; 1999.

6. PROactive and PERISCOPE Trials
PROactive (N=5,238)
Pioglitazone’s effect on the number of CVD events in high-risk patients with T2DM
Pioglitazone titrated to 45mg orally vs. placebo
No difference found in primary outcome
PERISCOPE (N=543)
Pioglitazone vs. glimepiride on the progression of coronary atherosclerosis in patients with T2DM
In favor of pioglitazone
Confounder of statins
Glimepiride 1 to 4 or pioglitazone 15 to 45
Wilcox R, Bousser M-G, Betteridge DJ, et al. Effects of pioglitazone in patients with type 2 diabetes with or without previous stroke: results from PROactive (PROspective pioglitAzone Clinical Trial In macroVascular Events 04). Stroke 2007;38:
Nissen SE, Nicholls SJ, Wolski K, et al. Comparison of pioglitazone vs glimepiride on progression of coronary atherosclerosis in patients with type 2 diabetes: the PERISCOPE randomized controlled trial. JAMA 2008;299:

7. Randomized International Multicenter (179 hospitals) Double-blind Placebo-controlled trial
Since pioglitazone improves insulin sensitivity (decreasing insulin resistance – risk factor for stroke/MI) initiating pioglitazone post event might have some benefit
Primary outcome: fatal or nonfatal stroke or MI
Kernan WN, Viscoli CM, Furie KL, et al. Pioglitazone after ischemic stroke or transient ischemic attack. N Engl J Med. Web published Feb 17, 2016.

8. Methods
3876 patients were randomized to a target dose of pioglitazone 45mg orally once daily OR placebo
Patients were contacted every 4 months with a questionnaire
Ended at 5 years or last scheduled contact before July 2015
Pts who did not have new or worsening edema, sob, myalgia, or excessive weight gain were increased to 30mg after 4 weeks and 45mg (3 tabs) at 8weeks at 12 weeks changed to 45mg single tab
Kernan WN, Viscoli CM, Furie KL, et al. Pioglitazone after ischemic stroke or transient ischemic attack. N Engl J Med. Web published Feb 17, 2016.

9. Patient Recruitment INCLUSION EXCLUSION Recent stroke or TIA
Diabetes Mellitus
Insulin resistance score of >3.0 (HOMA- IR) at least 14 days post event
NYHA Class 3 or 4
NYHA Class 2 with reduced ejection fraction
40yo
Active liver disease
Hgb <8.5g/dL
Moderate to severe pitting edema
Bladder cancer
Recent win 6mo
Active liver disease or elevated ALT
Kernan WN, Viscoli CM, Furie KL, et al. Pioglitazone after ischemic stroke or transient ischemic attack. N Engl J Med. Web published Feb 17, 2016.

10. Results Study groups had no significant differences at baseline
Mean age 63.5
88% in experimental group and 87% in placebo had a stroke as the index event
Time from event to randomization ~80 days
At exit 60% still taking pioglitazone
172 (9%) stopped pioglitazone due to edema/weight gain 51 (3%) placebo
Kernan WN, Viscoli CM, Furie KL, et al. Pioglitazone after ischemic stroke or transient ischemic attack. N Engl J Med. Web published Feb 17, 2016.

11. Results: Primary Outcome
Pioglitazone
n= 1939
Placebo
n= 1937
Hazard Ratio
P-value
Fatal or nonfatal stroke or MI
175 (9%)
228 (11.8%)
0.76 [95% CI; 0.62, 0.93]
P=0.007
Number Needed to Treat ~36
Kernan WN, Viscoli CM, Furie KL, et al. Pioglitazone after ischemic stroke or transient ischemic attack. N Engl J Med. Web published Feb 17, 2016.

12. Results: Secondary Outcomes
Diabetes
Stroke
Acute Coronary
Syndrome
Stroke, MI, Serious Heart Failure
All Cause Mortality
Pioglitazone
n= 1939
73 (3.8%)
127 (6.5%)
96 (5%)
206 (10.6%)
136 (7%)
Placebo
n= 1937
149 (7.7%)
154 (8.0%)
128 (6.6%)
249 (12.9%)
146 (7.5%)
Hazard Ratio
0.48 [95% CI; 0.33, 0.69]
0.82 [95% CI; 0.61, 1.10]
0.75 [95% CI; 0.52, 1.07]
0.82 [95% CI; 0.65, 1.05]
0.93 [95% CI; 0.73, 1.17]
P - value
<0.001
0.19
0.11
0.52
Stroke, acs, composite (st, mi, hf resulting in death), all cause, cognitive decline modified mini,
NNT25
Kernan WN, Viscoli CM, Furie KL, et al. Pioglitazone after ischemic stroke or transient ischemic attack. N Engl J Med. Web published Feb 17, 2016.

13. Pioglitazone: what comes to mind?
Actos [package insert]. Deerfield, IL: Takeda Pharmaceuticals America, Inc.; 1999.

14. Results: Safety profile
Shortness of breath
ALT >ULN
Weight gain
>4.5kg
>13.6kg
Edema
Bone fracture
Serious*
Non-serious
Pioglitazone
n= 1939
342 (17.6%)
26 (1.3%)
1013 (52.2%)
691 (35.6%)
91 (5.1%)
221 (11.4%)
133 (6.9%)
Placebo
n= 1937
292 (15.1%)
59 (3.0%)
653 (33.7%)
483 (24.9%)
62 (3.2%)
88 (4.5%)
94 (4.9%)
P-value
0.03
<0.001
0.003
0.008
NNH 39
n/a 5 9 67 15 50
*requiring surgery or hospitalization
Kernan WN, Viscoli CM, Furie KL, et al. Pioglitazone after ischemic stroke or transient ischemic attack. N Engl J Med. Web published Feb 17, 2016.

15. Conclusion
Authors: risk of stroke was lower among patients who received pioglitazone than among those who received placebo
lower risk of diabetes
higher risks of weight gain, edema, and fracture
Of 100 patients treated over 5 years, prevent 3 strokes and cause 2 serious bone fractures
Kernan WN, Viscoli CM, Furie KL, et al. Pioglitazone after ischemic stroke or transient ischemic attack. N Engl J Med. Web published Feb 17, 2016.

16. Article Critique Large trial idea for external validity
Statistical vs. clinical significance
Separated out serious vs. non-serious events
Duration of therapy/therapy onset
Subjective data collection
4 Interim analysis (O’Brien Flemming)
Extended trial after 2nd and 3rd analysis
Composite primary outcome
Large trials can also increase the ability to find statistical significance regardless of clinical significance
2nd & 3rd interim analysis recommended extension – slower recruitment and event rate
Is insulin resistance alone the risk factor or is it the associated HTN, HLD, hyperinsulinemia, dyslipidemia, endothelial dysfunction, hypercoagulability, inflammation,and increased platelet reactivity.

17. Application to Practice
Emphasize the importance of managing comorbidities post stroke/TIA
Would not look to start pioglitazone in patients post event
Would recommend diet, exercise, and optimization and compliance of current medications
Future studies looking at other options to manage blood glucose and insulin resistance
HTN, HLD, hyperinsulinemia, dyslipidemia, endothelial dysfunction, hypercoagulability, inflammation,and increased platelet reactivity.

18. Pioglitazone after Ischemic Stroke or Transient Ischemic Attack
Lindsay Waddington
PGY-1 Pharmacy Resident
St. Vincent Hospital - Indianapolis