of macrovascular events in patients with type 2 diabetes in the PROactive Study effect on increasing the risk of MI and death in patients with diabetes. …
Evidence Based Medicine
Sidharth A Shah, MD
Secondary prevention of macrovascular events in patients with type 2
diabetes in the PROactive Study PROspective pioglitAzone Clinical Trial in
macroVascular Events: a randomised controlled trial John A Dormandy et
al The Lancet, Volume 366, Issue 9493, 8 October 2005-14 October
2005, Pages 1279-1289
HYPOTHETICAL CLINICAL SCENARIO: A 65 yo patient of yours with previous
history of MI approximately 2 years ago, type II DM on metformin and
pioglitazone HgbA1C 82 states that she has read about the hype
regarding rosiglitazone and its effect on increasing the risk of MI and
death in patients with diabetes She asks you whether she needs to be taken
off her pioglitazone given the recent bad press the media has brought
about rosiglitazone How will you respond to her concerns?
CLINICAL QUESTION: In patients with Type II DM and evidence of evidence of
macrovascular disease, does pioglitazone increase risk for all-cause
mortality and macrovascular complications compared to those patients on
alternate treatment regimens that dont include pioglitazone?
I BACKGROUND:
a Methodology:
i Inclusion criteria:
1 Primary-care practices and diabetic or cardiovascular
specialist departments in hospitals
2 HgA1C 65
3 Evidence of macrovascular disease:
a MI or CVA at least 6mos prior to entry into
trial
b PCI or CABG at least 6mos before recruitment
c ACS at least 3mos before recruitment
d Obstructive arterial disease in the leg
i Previous major amputation
ii Intermittent claudication with ABI 09
e Objective evidence of CAD
i Positive exercise test
ii Angiography at least one stenosis 50
iii Positive scintigraphy
ii Exclusion criteria:
1 Type I DM
2 Planned coronary or peripheral revascularization
3 Taking insulin only
4 HF Class II or above
5 HD
6 Serum ALT 25x normal
7
Ischemic ulcers
8 Gangrene
9 Pain at rest in the leg
iii Treatment vs Control:
1 Treatment: Any regimens that included pioglitazone
2 Control: Any regimen other than pioglitazone
PATIENTS
GROUP A GROUP B
Oral pioglitazone placebo
iv Outcome Measures
1 Primary endpoint:
a All-cause mortality
b Non-fatal MI including silent MI
c CVA
d ACS
e Endovascular or surgical intervention on the
coronary or leg arteries
f Amputation above the ankle
2 Pre-specified secondary endpoints:
a All-cause mortality
b Nonfatal MI
c CVA
II ARE THE RESULTS VALID?
a Were the patients randomized? Yes, 5238 patients were randomized
to either receive pioglitazone or placebo, in
addition to their
existing meds for hyperglycemia
b Was randomization concealed? Yes, all investigators and study
personnel were unaware of treatment assignment Only the data
and safety monitoring committee saw unblinded data
c Were patients analyzed in the groups to which they were
randomized? Yes, all patients were analyzed according to
intention-to-treat principles
d Were the patients in the treatment and control groups similar
with respect to known prognostic variables? Yes See table 1
e Were patients aware of group allocation? Were the outcome
assessors aware of group allocation? No
f Was follow-up complete? Yes All patients were accounted for
III WHAT ARE THE RESULTS?
How large was the treatment effect?
a Primary composite endpoint see above: Pioglitazone and placebo
did not differ for the primary composite endpoint The hazzard
ratio HR for type II diabetics randomized to pioglitazone vs
those patients randomized to placebo was 090 95 CI 080-102;
P0095, conferring a nonsignficant effect See Figure
1
b Pre-specified secondary endpoints all cause mortality, non-
fatal MI, and CVA: Fewer patients in the pioglitazone arm than
in the placebo group had at least one event with regards to the
secondary endpoint; ie, the HR for type II diabetics randomized
to pioglitazone vs those patients not randomized to pioglitazone
was 084 95 CI 072-098; P0027, thereby revealing a
signficant effect See Figure 3 and Table 3
c How precise was the estimate of the treatment effect? To answer
this, look at the 95 confidence intervals, which is a range of
values that includes the true RRR 95 of the time
IV HOW CAN I APPLY THE RESULTS TO PATIENT CARE?
a Were the study patients similar to the patients in my practice?
For the most part, a patient in my clinic would share many of
the baseline characteristics of patients in this study Table 1
b Were all clinically important outcomes considered? Yes, the
primary and secondary endpoints were a composite of those
outcomes we would be concerned with in a patient with diabetes-
ie,
CVA, MI, death, etc
c Are the likely treatment benefits worth the potential harm and
costs?
Source:bcbsok.com
