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ENGLISH COURSE_ SYSTEMATIC REVIEW OF A META-ANALYSIS

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					 ENGLISH COURSE:
SYSTEMATIC REVIEW
OF A META-ANALYSIS.


              Resident Doctor: Jai K. Daryanani
         Health Care Centre: San Andrés Torcal
                                Zone II , Malaga
             Tutor: Dr Vicente Villatoro Jimenez
          SYSTEMATIC REVIEW
Effect of intensive control of glucose
                  on a
    meta-analysis of randomised
             controlled trials

Kausik K Ray, Sreenivasa Rao Kondapally Seshasai*, Shanelle Wijesuriya*,Rupa
   Sivakumaran*, Sarah Nethercott*, David Preiss, Sebhat Erqou,Naveed Sattar


Lancet 2009; 373: 1765–72
SYSTEMATIC REVIEW
             INTRODUCTION
• DM II         Risk factor for Cardiovascular.
• Observational studies: + correlation between measures
  of glycaemic control and cardiovascular outcomes
  independent of risk factors
• Randomised Control trials aimed to asses :

Intensive       Standard                 Clinical events
Glucose VS      Treatment
Treatment                               Lengthens life
               INTRODUCTION
 • Meta-Analysis : 5 controlled clinical trials
 • Aimed to asses :
                                 CARDIOVASCULAR
  Intensive     Standard         EVENTS
  Glucose VS    Treatment
  Treatment                      STROKE
                                 ALL CAUSE MORTALITY



Model of Meta- Analysis: RANDOM EFFECTS META-ANALYSIS
                METHODS
•  DATA SOURCES:
Medline                     January 1970
Cochrane Central           to
Embase                      January 2009


                          Cardiovascular
                            Diseases
Terms Related
                          DIABETES
                          VASCULAR
                          OUTCOMES
                Glucose                    Diabetes
                HbA1c                      Mellitus
                   METHODS
• DATA SOURCES:

• Search Provided 2439 ARTICLES!!!!
• Further screened from inclusion (Titles/Abstracts/Full
  text/ combination)
• Electronical search from Lists of Relevant articles
  including Meta-analysis and Reviews
                     METHODS
              STUDY SELECTION

CRITERIA INCLUSION:
1.   DMII patients allocated randomly Intensive Therapy/ Standard
     regimen with glycaemic control measured by HbA1c.
2.   Primary End-Point: CARDIOVASCULAR EVENTS:
•    Non fatal myocardial infarction
•    Coronary Heart Disease ( Fatal or Non Fatal)
•    Stroke
•    All cause of mortality
3.   Stable individuals ONLY!!
                  METHODS
                 STUDY SELECTION
EXCLUSION CRITERIA:
ADOPT & RECORD


   RECORD

    DREAM


    UGDP


   STENO 2


  KUMAMATO
                METHODS
             STUDY SELECTION
5 STUDYS fulfilled CRITERIA INCLUSION:
•  UKPDS: United Kingdom Prospective Diabetes
   Study
•  PROspective: Pioglitazone Clinical Trial In
   macrovascular events
•  ADVANCE: Action in Diabetes and Vascular
   Disease
•  VADT: Veterans Affairs Diabetes Trial
•  ACCORD: Action to Control Cardiovascular Risk in
   Diabetes Trial
PARTICIPANTES: 33.040
                     METHODS
    STUDYS                     INTENSIVE                     STANDARD
HbA1C at follow up
    UKPDS            Sulfonylurea, insulin, or Metformin     Standard Diet
                                    7.9 %                        7.0%

  PROactive           15-45mg oral Pioglitazone plus       Current Medication
                         current medication 7.6%                 7.0%
                        30-120mg glicazide, with or        Standard treatment
                                   without                       As per
  ADVANCE               metformin,thiazolidienedion,         Local guideline
                        glinide, acarbose or insulin.
                                                                 6.8%
                                    7.3%
                         Max dose Metformin with              Half Dose of
                         rosiglitazone(BMI>27) or              Intensive
     VADT                glimepiride&rosiglitazone             Treatment
                              (BMI>27)8.4%                       6.9%

   ACCORD             Metformin/Sulphonylurea/glinide/         Standard
                     Thiazlindinedione/acarbose/insulin        Treatment
                             /combination 7.5%                   6.4%
          DATA EXTRACTION
• NUMBER OF EVENTS


 3500
                                                2892
 3000
 2500                     2318

 2000
            1497                                          EVENTS
 1500                                 1127
 1000
  500
    0
        NON FATAL MI   CORONARY HD   STROKE   ALL CAUSE
       DATA EXTRACTION
1. Study investigators independently
   abstracted data in duplicate using a
   standard format from all relevant studies
2. Another investigator adjudged any
   discrepancies
     BASELINE CHARACTERISTICS
1.    Age
2.    HbA1c concentration
3.    Blood Pressure
4.    BMI
5.    Absolute Number of Events       PROactive
      (NFMI, Coronary Heart
                                        UKPDS
                                      ADVANCE
      disease, Stroke and all cause
      of Mortality)                     VADT
6.    Heart failure                   ACCORD
7.    Type of death                    UKPDS
8.    HbA1c during follow up
9.    Adverse events:
      Hypoglycaemia & Weight
      gain
BASELINE CHARACTERISTICS
       STATISTICAL ANALISIS
• UKPDS, ProAcive, ADVANCE                Hazard Ratios & CI
  95%
• VADT & Accord             provided absolute number
  events
• We examined the relationship between intensive glucose
  control and standard therapy on the outcomes of interest
• Statistical heterogeneity across trials was assessed with
  χ2 (p<0・1) and I2 statistics.
• Absolute rates of every end point was : Absolute Nº Events
                                       Nº Person Years-follow up

• Analyses were done with Stata V10.1
• RANDOM EFFECTS-MODEL META-ANALYSIS.
STATISTICAL ANALISIS
        FUNDING SOURCE
• No Funding Source
• The author had full access to data and
  final responsibility for decision to submit
  for publication.
       RESULTS

                 33040



<1 y
                     RESULTS
• 4 Studies       Macrovascular disease 32-100%
• Proactive, Macrovascular disease        Criteria eligibility
• Participants Age; 53-66 years; >50% were men
• LDL, Systolic BP, HbA1c concentration
• Participants with Intensive treatment had a 0.9% mean
  HbA1C compared to Standard
• There were 2.3 fewer events of myocardial infarction
  in the Intensive treatment and 2.9 fewer events of
  CHD for every 200 patients /5 years
• STROKE & All cause Mortality were not Statistically
  different
RESULTS
                             RESULTS




                                                             0.83(0.75-0.93




Probability of Events of Non Fatal Myocardial Infarction with intensive/standard
                           RESULTS




                                                           0.85(0.77-0.93




Probability of Events of Coronary Heart Disease with intensive/standard
                RESULTS




Probability of Events of Stroke with intensive/standard
                     RESULTS




Probability of Events of All cause Mortality with intensive/standard
                   RESULTS
• Data for cardiovascular mortality and Non cardiovascular
  mortality restricted to 4 STUDIES of 28420 participants
• UKPDS did not record data for Cardiovascular
  Mortality
• Intensive therapy did NOT affect the TYPE OF DEATH
• Patients with Intensive therapy had more
  hypoglycaemia episodes (2:1)
• Patients with intensive therapy were a mean of 2.5 Kg
  heavier than those on Standard Treatment
                  DISCUSSION
•    Meta-analysis shows cardiovascular benefit with
     the intensive treatments vs the standard.
•    Reduction of HbA1c of 0.9% resulted in:

1.     17% in events of Non fatal myocardial infarction
2.     15% in events of Coronary Heart Disease
3.   Non significant 7% reduction in events of Stroke

Did not affect all cause of Mortality
                    DISCUSSION
                        LIMITATIONS
1.   Retrospective Research affected by METHODOLOGICAL,
     comprehensiveness and possibility of publication bias.
2.   Due to different variety of studies, this meta-analysis can only
     report whether intensive treatment is safe and effective for
     reduction of macrovascular events
3.   The study cant provide superiority of a specific glucose
     lowering regimen
4.   Not Sufficient DATA available TO analyse the effects of
     Intensive treatment within various subgroups ( age, men vs
     women, duration diabetes, baseline HbA1c, comorbility)
5.   Used ODDS Ratios vs Hazard Ratios, to enable data of all 5
     studies .
6.   Sensitivity analysis              Random effects model
               DISCUSSION
• This meta-analysis provides the effectiveness of
  glycaemic control for cardiovascular risk reduction,
  but doesn’t prove a clear benefit to all cause
  mortality.
• LIPID treatment and BP reduction have strong
  evidence in reduction to all cause mortality in DM II
  patients.
• Optimum methods to achieve glycaemic control need to
  be established, and guidelines drawn up with specific
  recommendations for reduction of HbA1c concentration.

				
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