Pioglitazone use and heart failure in patients with type 2 diabetes and preexisting cardiovascular disease: data from the PROactive study (PROactive 08).
OBJECTIVE
PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive) enrolled patients with type 2 diabetes and preexisting cardiovascular disease. These patients were at high risk for heart failure, so any therapeutic benefit could potentially be offset by risk of associated heart failure mortality. We analyzed the heart failure cases to assess the effects of treatment on morbidity and mortality after reports of serious heart failure.


METHODS
PROactive was an outcome study in 5,238 patients randomized to pioglitazone or placebo. Patients with New York Heart Association Class II-IV heart failure at screening were excluded. A serious adverse event of heart failure was defined as heart failure that required hospitalization or prolonged a hospitalization stay, was fatal or life threatening, or resulted in persistent significant disability or incapacity. Heart failure risk was evaluated by multivariate regression.


RESULTS
More pioglitazone (5.7%) than placebo patients (4.1%) had a serious heart failure event during the study (P = 0.007). However, mortality due to heart failure was similar (25 of 2,605 [0.96%] for pioglitazone vs. 22 of 2,633 [0.84%] for placebo; P = 0.639). Among patients with a serious heart failure event, subsequent all-cause mortality was proportionately lower with pioglitazone (40 of 149 [26.8%] vs. 37 of 108 [34.3%] with placebo; P = 0.1338). Proportionately fewer pioglitazone patients with serious heart failure went on to have an event in the primary (47.7% with pioglitazone vs. 57.4% with placebo; P = 0.0593) or main secondary end point (34.9% with pioglitazone vs. 47.2% with placebo; P = 0.025).


CONCLUSIONS
Although the incidence of serious heart failure was increased with pioglitazone versus placebo in the total PROactive population of patients with type 2 diabetes and macrovascular disease, subsequent mortality or morbidity was not increased in patients with serious heart failure.
Medizinische Klinik III der Universität zu Köln Kerpener Str. 62, D-50937 Köln, Germany. erland.erdmann@uni-koeln.de
Erland
E
Erdmann
Bernard
B
Charbonnel
Robert G
RG
Wilcox
Allan M
AM
Skene
Massimo
M
Massi-Benedetti
John
J
Yates
Meng
M
Tan
Robert
R
Spanheimer
Eberhard
E
Standl
John A
JA
Dormandy
D002318:Cardiovascular Diseases / Q000453:epidemiology*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D003925:Diabetic Angiopathies / Q000453:epidemiology*; D004311:Double-Blind Method; D006333:Heart Failure / Q000139:chemically induced* / Q000401:mortality; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects*; D015994:Incidence; D015999:Multivariate Analysis; D009203:Myocardial Infarction / Q000453:epidemiology; D000077205:Pioglitazone; D010919:Placebos; D018570:Risk Assessment; D016019:Survival Analysis; D045162:Thiazolidinediones / Q000009:adverse effects*; D013997:Time Factors
D007004:Hypoglycemic Agents; D010919:Placebos; D045162:Thiazolidinediones; D000077205:Pioglitazone