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

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 ;e29-322.

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;37:1595-1607

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.

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.

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;38:865-873 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;299:1561-1573

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.

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.

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.

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.

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.

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.

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

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.

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.

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.

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.

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