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FAQs
The PROactive Executive has received many letters and e-mails about the PROactive study. These have been compiled into Frequently Asked Questions (FAQs).
Over the next few months more will be added.
Please click on the relevant question to reveal the answer.
Rationale/Study Design
1. How was standard of care defined and how optimal was
it?
2. Please clarify the endpoint definitions.
3. Why did you include silent MIs in the primary endpoint
and then exclude them from the main secondary endpoint?
4. Why did you exclude acute coronary syndrome from the
main secondary combined endpoint analysis?
5. Did the study end early?
6. Were any of the patients ever on a thiazolidinedione
prior to the study?
7. Why were patients on insulin monotherapy excluded from
the study?
8. How was the dose of pioglitazone titrated?
9. Could patients’ concomitant medication be changed?
10. What type of adjudication was used to assess endpoints
and by what criteria?
11. Where was the study conducted? Who designed the study?
12. If someone died of a non-related event, e.g., cancer, was that included?
Hypothesis
13. Why didn’t the study meet the primary endpoint?
14. If the study had continued longer, would the differences in outcome have become greater?
15. Why were there more peripheral vascular complications with pioglitazone?
16. What is the added benefit on top of guideline (IDF)-directed background medication?
18. Why were patients with NYHA Class II, III and IV Heart Failure excluded from the study?
Metabolic Results
19. Why did the active group have better glucose control?
20. Can effects on glucose alone explain the results?
21. Did you measure high-sensitivity C-reactive protein (hsCRP)?
22. Lipids were measured, but are there data for LDL particle size and number?
Safety
23. Almost half of the patients had serious side effects.
24. What about the increased risk of heart failure?
25. In patients with heart failure, how often was pioglitazone stopped?
26. How do you explain the high rate of oedema?
27. Why are hypoglycaemia rates much higher than reported previously?
General
28. Were the results of the PROactive study likely to be a class effect of TZDs?
29. Can we extrapolate these results to primary prevention of CVD in type 2 diabetes?
1. How was standard of care defined and how optimal
was it?
At baseline, patients were treated according to prevailing standard of care at
each investigator’s site. Several times throughout the study, investigators
were required to optimise all therapy according to the International Diabetes
Federation European Region 1999 guidelines (an oral glucose-lowering drug(s) if
HbA1c >6.5% [standardised using the Diabetes Control and Complications Trial;
DCCT] and/or fasting venous plasma glucose >6.0 mmol/L [=110 mg/dL]; insulin
if HbA1c >7.5%; a statin if LDL cholesterol =3.0 mmol/L [=115 mg/dL]; a fibrate
if triglyceride >2.2 mmol/L [>200 mg/dL]; lifestyle management followed
by a blood pressure lowering drug(s) if blood pressure >140/85 mmHg; European
Diabetes Policy Group, Diabet Med 1999). Back to the Top
2. Please clarify the endpoint definitions.
The analysis of the study focused on two key endpoints: a primary composite endpoint
of seven different macrovascular events, which used both disease- and procedural-specific
endpoints (disease-specific endpoints: all-cause mortality, non-fatal myocardial
infarction (MI) [including silent MI], stroke, major leg amputation, acute coronary
syndrome; and procedural-specific (cardiac intervention [coronary artery bypass
graft and percutaneous coronary intervention] and leg revascularisation), and
a pre-specified main secondary combined the disease-specific endpoints of heart
attacks, strokes, and deaths. The study was powered on the primary combined endpoint
not of the individual components. Back to the Top
3. Why did you include silent MIs in the primary
endpoint and then exclude them from the main secondary endpoint?
Silent MIs were included in the primary composite endpoint that was designed to
capture all cardiovascular events. Silent MIs were excluded from the main secondary
endpoint due to the objective impossibility to time the event precisely. Silent
myocardial infarction is very difficult to define with certainty. For instance,
it is impossible to define it in left bundle branch block (LBBB). Therefore, we
omitted silent MI in the hard endpoints, such as death, myocardial infarction
and stroke. The main secondary composite endpoint was designated to analyse only
disease-specific endpoints, which have been commonly used in many other outcomes
studies.
Back to the Top
4. Why did you exclude acute coronary syndrome
from the main secondary combined endpoint analysis?
Acute coronary syndrome, defined in the protocol as unstable angina excluding
patients with a definite MI, was included in the primary composite endpoint that
was designed to capture all cardiovascular events. The main secondary combined
endpoint was designed to evaluate more objective and life-threatening endpoints.
There were fewer acute coronary syndrome events seen in the pioglitazone group
(n=42) compared with the placebo group (n=63). Back to the Top
5. Did the study end early?
The study concluded according to the protocol when the pre-specified targets were
reached (1. Last patient recruited was followed for at least 30 months and 2.
the number of patients with one or more endpoint events was at least 760).During
the conduct of the study the Drug Safety Monitoring Board reviewed the events
and determined that there was no need to interrupt the study. Back to the Top
6. Were any of the patients ever on a thiazolidinedione
prior to the study?
Patients were excluded if they had current use of pioglitazone or other thiazolidinediones.
Use of a thiazolidinedione prior to study entry was not recorded. Back to the Top
7. Why were patients on insulin monotherapy excluded
from the study?
We wanted to make sure that patients with type 1 diabetes were excluded. Back to the Top
8. How was the dose of pioglitazone titrated?
PROactive was designed as a forced-titration study with the objective of maintaining
patients on the maximum tolerated dose of study medication. The pioglitazone dose
increased from 15 mg to 30 mg, then to 45 mg during the first 2 months of treatment.
At any time during this period and during the remainder of the study, the dose
could be increased or decreased within the range of 15 mg to 45 mg, based upon
tolerability. Over 90% of patients in the study were titrated to 45 mg. Back to the Top
9. Could patients’ concomitant medication be changed?
Throughout the study, investigators were encouraged to optimise all therapy according
to the International Diabetes Federation European Region 1999 guidelines (European
Diabetes Policy Group, Diabet Med 1999), with the only restriction being that
they could not prescribe a thiazolidinedione. Back to the Top
10. What type of adjudication was used to assess endpoints
and by what criteria?
Clinical events identified as possibly constituting a primary or secondary study
endpoint were passed through a central adjudication process, which was blinded
regarding study treatment allocation. For example, as they were not part of the
primary or secondary endpoints, but classified as adverse events, heart failure
events were reported by the local investigators and not centrally adjudicated.
No information on the criteria used was provided. Back to the Top
11. Where was the study conducted? Who designed the study?
The study was a European study conducted by 321 centres in 19 countries. An International Steering Committee (ISC) was responsible for the overall design and conduct of the trial. Back to the Top
12. If someone died of a non-related event, e.g. cancer, was that included?
Yes, that event would be included under all-cause mortality. Back to the Top
13. Why didn’t the study meet the primary endpoint?
The study did not reach its primary composite endpoint. This was possibly due to the mix of disease- and procedural-specific endpoints. Procedural endpoints (e.g. coronary artery bypass surgery [CABG]/percutaneous coronary intervention [PCI] n=101 events in each group, leg revascularisation n=71 events in the pioglitazone group and n=57 in the placebo group) are less specific and less sensitive than disease endpoints and bias treatment toward the null hypothesis of 1. In addition, the study was of relatively short duration (3 years) compared with other cardiovascular outcomes studies. Back to the Top
14. If the study had continued longer, would the differences in outcome have become greater?
We cannot say this for certain, but the Kaplan Meier curve for the primary endpoint appeared to continue diverging at the end of the study. Back to the Top
15. Why were there more peripheral vascular complications with pioglitazone?
We have not identified any obvious reason for the difference. However, the biology of peripheral vascular disease is likely to be different from coronary vascular disease, and therefore this subgroup will be analysed further. Back to the Top
16. What is the added benefit on top of guideline (IDF)-directed background medication?
The addition of pioglitazone to existing therapy was compared with current recommended therapy. The study demonstrated that pioglitazone protected against life-threatening cardiovascular outcomes (heart attacks, strokes, and deaths) while patients were being treated better than that achieved with usual standard of care in global communities. In the Steno-2 study, in which intensified multi-factorial intervention was compared with standard multi-factorial intervention, significantly fewer patients in the control group received statins, antihypertensives or antiplatelet therapy, whereas in PROactive, patients in both groups were receiving comparable multi-factorial interventions at baseline and at study end (statins, fibrates, anti-hypertensives, and anti-platelet therapy). Any effect of pioglitazone should therefore be considered as additional to these interventions. Use of anti-hypertensives and anti-platelet therapy was similar between PROactive and the intensive group in Steno-2.In PROactive, the baseline use was 92% for anti-hypertensives, 96% for glucose-lowering agents, 52% for lipid-altering medication, and 73% for aspirin. Back to the Top
17. If all of the patients were treated with statins, would there still be an effect of pioglitazone?
At baseline, statin use or non-use did not predict beneficial response to pioglitazone. Use of statins at baseline was not different between pioglitazone and placebo groups. The majority of patients in PROactive were treated with statins. The protocol specified that patients were to receive best standard of care treatment. The variability between the 25 predefined subgroups of baseline characteristics in terms of CV outcomes, including the use or non-use of statins at baseline, was not more than expected by chance alone. Therefore, the best estimate of treatment effect for any and all subgroups is the same as that for the entire PROactive cohort as a whole.
Back to the Top
18. Why were patients with NYHA Class II, III and IV Heart Failure excluded from the study?
Patients were excluded from the study if they had a NYHA score of II or above. European license requirements for thiazolidinedione use exclude NYHA Class I–IV, and an agreement with the European regulatory agency allowed inclusion of NYHA Class I in this study. Back to the Top
19. Why did the active group have better glucose control?
In this double-blind study, the protocol-specified target HbA1c was 6.5%, as per IDF guidelines. Glycaemic control was better in the pioglitazone group than in the placebo group, despite an increased use of metformin and insulin in the placebo group. Pioglitazone is a glucose-lowering drug and there is evidence to suggest that it has effects on β-cell preservation (from animal and in vitro studies) and improved insulin sensitivity. Therefore, it was fully expected that glycaemic control would be better in the group receiving pioglitazone.
20. Can effects on glucose alone explain the results?
This study was not designed to determine the mechanism by which pioglitazone impacted cardiovascular events.
Glucose effects alone are not likely since a 0.5% reduction in HbA1c has not been shown to have this effect on cardiovascular events in other studies.
Pioglitazone exerts pleiotropic metabolic and vascular effects (as demonstrated by improvements in diabetic dyslipidaemia, C-reactive protein, matrix metalloproteinase-9, interleukin-6, tumor necrosis factor-α, and macrophage chemoattractant protein 1, plasminogen activator inhibitor-1, tissue plasminogen activator, endothelin-1 and carotid intima-media thickness), which could have contributed to the results observed in PROactive. Some of these favourable effects are not shown by all thiazolidinediones and thus the results of PROactive cannot be generalised to apply to all members of this class. Back to the Top
21. Did you measure high-sensitivity C-reactive protein (hsCRP)?
No, unfortunately not. Although we know from other studies that pioglitazone reduces hsCRP and other cardiovascular risk markers, it is unlikely that this is the only explanation for its benefit. Back to the Top
22. Lipids were measured, but are there data for LDL particle size and number?
No. At the initiation of the study, LDL particle size and number were not routinely measured in clinical practice. Lipid parameters measured included triglycerides, HDL cholesterol, and direct LDL cholesterol. Back to the Top
23. Almost half of the patients had serious side effects.
Serious adverse events were included in the endpoint analysis and were defined as: fatal, life-threatening, required inpatient hospitalisation, or occurred while in hospital and prolonged hospital stay and resulted in persistent or significant disability or incapacity.
Overall, pioglitazone had numerically (but not significantly) fewer serious adverse events, endpoint events, and non-endpoint events than the placebo group. Back to the Top
24. What about the increased risk of heart failure?
An increase in signs of heart failure and serious heart failure were noted with pioglitazone versus placebo. There was, however, no difference between groups for death due to heart failure. Other ECG studies have shown that there is no evidence for direct damage of the cardiac muscle by pioglitazone. Back to the Top
25. In patients with heart failure, how often was pioglitazone stopped?
The number of patients who stopped study drug treatment, for all reasons, was the same in each group.
Only 34 patients (out of 149 [22.8%]) in the pioglitazone group and 17 (out of 108 [15.7%]) in the placebo group had a serious heart failure event that resulted in permanent discontinuation of the study medication. The proportion of patients with serious heart failure for whom the heart failure event resolved during follow-up was 77.9% (n=116) for pioglitazone and 74.1% (n=80) for placebo.
The number of patients who died from heart failure was the same in both groups, despite heart failure being reported more often in the pioglitazone group. Back to the Top
26. How do you explain the high rate of oedema?
Fluid retention is a known effect of PPAR-γ agonists. The relative incidence in the pioglitazone arm compared with the placebo arm seen over the 3-year duration of this study is similar to that observed in previous studies. The study protocol stated that physicians should determine the presence or absence of oedema at each visit and this would be expected to increase the reporting rate in both arms of the study. Back to the Top
27. Why are hypoglycaemia rates much higher than reported previously?
Pioglitazone was force dose-titrated in the first 3 months of the study in a double-blind manner. During any titration of glucose-lowering therapies, increased surveillance for hypoglycaemia is standard practice. The reported events happened primarily in the first 6 months of treatment initiation. This is consistent with aggressive treatment by investigators to reach IDF glycaemic targets. Back to the Top
28. Were the results of the PROactive study likely to be a class effect of TZDs?
It is unknown. This study is an outcomes trial that was not designed to describe mechanistic reasons for the outcomes seen. There are many biological effects seen with pioglitazone that may contribute to outcomes, including effects on glycaemia, lipids, inflammation, etc. These actions are ligand-specific, which implies that results obtained with one thiazolidinedione might not be applicable to others. Back to the Top
29. Can we extrapolate these results to primary prevention of CVD in type 2 diabetes?
In PROactive, a secondary prevention trial, pioglitazone reduced heart attacks, strokes, and deaths in high-risk patients with type 2 diabetes. These data cannot be extrapolated to a primary prevention population. Back to the Top
30. How does PROactive compare to other cardiovascular and diabetes trials, such as RECORD, VA-HIT, CARDS, HPS, CARE, 4S, TNT, and UKPDS?
Kaplan-Meier estimates indicate that allocation of 1000 patients to pioglitazone would avoid 21 first myocardial infarctions, strokes, or deaths over 3 years. In other words, 48 patients would need to be treated for 3 years to avoid one first major cardiovascular event.
Although several intervention trials using antihypertensive agents, lipid-modifying drugs (principally statins), glucose-lowering agents, or multifactorial intervention strategies have looked at macrovascular outcomes in patients with type 2 diabetes, much of the data pertaining to patients with diabetes are post-hoc or, in some instances, predefined subgroup analyses from larger cohorts. This makes direct comparisons difficult and, in most cases, inappropriate. Comparison between the results of PROactive and previous outcomes studies is also complicated by differences in predefined endpoints, study population, study duration, concomitant medication use, and a range of other methodological issues. Back to the Top