Journal Club Julie Shah, MD Milton S Hershey Medical Center Penn State University

Lancet- June 25 th 2011 Effect of early intensive multi-factorial therapy on 5- year cardiovascular outcomes in individuals with type 2 diabetes detected by screening ( ADDITION – Europe): a cluster – randomized trial Simon Griffin, Knut Borch-Johnsen, Melanie Davies, Kamlesh Khunti, Guy Rutten, Annelli Sandbaek, Stephen Sharp, Rebecca Simmons, Maureen van den Donk, Nicholas Wareham, Torsten Lauritzen

Background ♥Intensive treatment of multiple cardiovascular risk factors can decrease mortality among people with established type 2 diabetes. ♥Many patients already have evidence of diabetic complications and modifiable cardiovascular risk factors at the time of diagnosis.

Background ♥There is no evidence from clinical trials that shows whether early intensive multifactorial treatment improves outcomes when started BETWEEN detection by screening and clinical diagnosis. ♥This study was performed to investigate the effect of early multi-factorial treatment after diagnosis by SCREENING

Methods ♥ADDITION- Europe combined data from four separate studies performed in Denmark, Netherlands and two sites in UK (Cambridge and Leicester) ♥Anglo- Danish- Dutch study of Intensive Treatment in people with screen detected diabetes in primary care

Study Design ♥Each study consisted of a screening phase and then a pragmatic, cluster- randomized parallel- group trial ♥All participating patients provided informed consent. ♥General practices in the four areas which were within 100 miles of the study center were invited to participate.

Study Design ♥Time period: April 2001 to Dec 2006 ♥Patients: All pts within the practice aged without known Diabetes were included. ♥Based on their records, their risk score was calculated. ♥Those at high risk were invited for further screening (fasting blood glucose or OGTT) ♥If positive, required confirmatory testing and then included in the study

Study Design Exclusion criteria: ♥Life expectancy less than 12 months ♥Unable to give informed consent ♥Pregnant/ lactating women

Study Design ♥Randomization Each PRACTICE was randomly assigned to provide routine care OR intensive multi- factorial treatment in a 1:1 ratio by statisticians at each center according to a computer- generated list

Intervention Participants were evaluated on an average every 2 months by GP or NP Same approach was used at all centers, although the choice of medication was made by the physician and patient

Outcomes ♥Primary endpoint: First cardiovascular event ♥Secondary endpoints: cardiovascular death, MI, stroke, revascularization, amputation, all cause mortality ♥Statistical analysis :  Intention to treat analysis  STATA ( version 11)

14538 met criteria 3233 detected by screening 3057 agreed to participate Routine care 1377 Intensive treatment 1678

RCIT Calculated requirement of 2700pt with 1350 in the IT group to detect 30% reduction in risk of primary endpoint. Total= 3055

Results ♥Baseline demographic, clinical, biochemical and treatment characteristics in the two treatment groups were well matched overall (refer to table 2 of article) ♥In Denmark however, more patients were assigned to IT group (910 vs 623) and more pts had ischemic heart disease ♥Mean follow- up period was 5.3+/- 1.6 years

Results 17%RR 30% RR

Difference between study groups for all components of primary end point favored IT group. Differences were greatest for MI and smallest for stroke

All cause mortality 196 patients died overall- 30.6% CV deaths, 49.5% cancer related and 19.9% other causes

At the end of 5 years, small but SIGNIFICANT differences were seen in change from baseline for HbA1c, BP and cholesterol; all favoring IT group. In both study groups, risk factors such as BP and cholesterol levels improved notably after diagnosis

Limitations ♥Non- random recruitment of general practices ♥Assessment of hypoglycemia was imprecise ♥Intervention could have influenced the type of patients recruited in the IT group – eg in Denmark ♥Lower than expected event rate suggests that 5 year f/u period is not sufficient

Discussion ♥The intervention was associated with significantly increased prescription of treatments and improvements in CV risk factors ♥There was a non- significant 17% relative reduction in the incidence of cardiovascular events at 5 years.

♥The incidence of CV events in the routine care group (8.5%) was lower than that seen in similarly newly diagnosed patients in UKPDS trial (12.1%) 12.1%

♥Several changes in the national guidelines during the time of the study ( such as treatment with statins and BP control) which improved delivery of ‘routine care’ in general practice. Thus the likelihood of achieving the target reduction between the two groups became unlikely

♥Secondly, the event rates were only half of what was expected while calculating the initial power of this study. This might have obscured the true benefit as suggested by the divergence in event rates at 4 yrs

♥Participating practices were financially motivated and thus they might have already improved their “routine care” which may not be representative of routine care available elsewhere.

Conclusion ♥Interesting to see the outcomes at 10 yrs of follow-up. ♥Interesting to note that the improvement in guidelines has led to decrease in CV events (e.g. as compared to UKPDS) ♥Substantial improvement in BP and cholesterol seen in both groups suggests that early dx and treatment by current guidelines is likely to be beneficial.