• Share
  • Email
  • Embed
  • Like
  • Save
  • Private Content
HEART2D TRIAL
 

HEART2D TRIAL

on

  • 18,733 views

 

Statistics

Views

Total Views
18,733
Views on SlideShare
18,733
Embed Views
0

Actions

Likes
0
Downloads
9
Comments
0

0 Embeds 0

No embeds

Accessibility

Categories

Upload Details

Uploaded via as Microsoft PowerPoint

Usage Rights

© All Rights Reserved

Report content

Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
  • Full Name Full Name Comment goes here.
    Are you sure you want to
    Your message goes here
    Processing…
Post Comment
Edit your comment
  • GOOD MORNING,
  • DECODE: IGT increases mortality risk A number of studies have suggested that impaired glucose tolerance (IGT) is a strong risk factor for cardiovascular disease. One of the largest of these studies is a European study called the Diabetes Epidemiology: Collaborative analysis of Diagnostic criteria in Europe (DECODE) study which had over 25,000 subjects. Additionally in this study, IGT made a stronger risk factor for cardiovascular disease than impaired fasting glucose (IFG). These observations have suggested to some individuals that testing whether subjects have IGT may reduce the incidence of type 2 diabetes and may also be used to reduce the risk of cardiovascular disease. However, in diabetes prevention studies (such as the DPP study or the DREAM study), the rate of cardiovascular disease was in fact extremely low. Thus, this question has not been feasible to test so far. The reasons for the discrepancy between epidemiological studies such as the DECODE study and clinical trials such as the DPP and the DREAM study is not fully understood, but it may relate partially to the increased use of statins and blood pressure medications and healthy participant effect in the more current clinical trials rather than epidemiology studies. If IGT is a superior risk factor for the development of type 2 diabetes, why is it not used more commonly as a screening tool in the United States? The simple answer is that the diagnosis of IGT requires a 75 gm oral glucose load followed by a blood sample 2 hours later. References: Glucose tolerance and mortality: comparison of WHO and American Diabetes Association diagnostic criteria. The DECODE study group. European Diabetes Epidemiology Group. Diabetes Epidemiology: Collaborative analysis Of Diagnostic criteria in Europe. Lancet 1999;354:617-621. DREAM (Diabetes REduction Assessment with ramipril and rosiglitazone Medication) Trial Investigators; Gerstein HC, Yusuf S, Bosch J, Pogue J, Sheridan P, Dinccag N, Hanefeld M, Hoogwerf B, Laakso M, Mohan V, Shaw J, Zinman B, Holman RR. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial. Lancet 2006;368:1096-1105. Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346:393-403.
  • STOP-NIDDM Trial: Acarbose Prevents Type 2 Diabetes Mellitus and Cardiovascular Events in Subjects With Impaired Glucose Tolerance Examining the different events between the acarbose and placebo populations in the STOP-NIDDM trial showed that there were 15 events in the acarbose group and 32 events in the placebo groups, suggesting that a treatment focused on postprandial hyperglycemia could reduce the risk for cardiovascular events. These intriguing data await further confirmation and additional studies. Reference: Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, Laakso M, for the STOP-NIDDM Trial Research Group. Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance: the STOP-NIDDM trial. JAMA . 2003;290:486-494.
  • Diabetes Mellitus Insulin Glucose Infusion in Acute Myocardial Infarction (DIGAMI): Benefit of Tight Glycemic Control in No Insulin–Low Risk Cohort The Diabetes Mellitus Insulin Glucose Infusion in Acute Myocardial Infarction (DIGAMI) Study was performed in Scandinavia and randomized patients with diabetes mellitus with acute myocardial infarction to two different glycemic control strategies. One group was treated with “ad hoc” glycemic control and the other group was treated with intensive glycemic control with intravenous insulin therapy for at least 24 hours followed by 3 months of multidose daily insulin. The group randomized to tight glycemic control had a significant reduction in mortality evident at 3 years. Most of the benefit in the tightly controlled group was due to benefit in diabetic patients who were not on insulin therapy at the time of randomization. Tight glycemic control in a setting of acute myocardial infarction may reduce platelet aggregability, alter lipoprotein metabolism, reduce free fatty acid levels, restore fibrinolysis, change the sympathetic and parasympathetic balance, and improve myocardial energy metabolism. Reference: Malmberg K, for the DIGAMI (Diabetes Mellitus, Insulin Glucose Infusion in Acute Myocardial Infarction) Study Group. Prospective randomised study of intensive insulin treatment on long term survival after acute myocardial infarction in patients with diabetes mellitus. BMJ 1997;314:1512-1515.
  • ACCORD: Deaths in Intensive vs. Standard Glycemic Control Groups: Preliminary Results The ACCORD trial was stopped prematurely because of an excess overall mortality among the diabetic patients who were randomized to the intensive glycemic control treatment arm. These patients attained a hemoglobin A 1c concentration of 6.4% when compared to the standard glycemic control arm in which the target was to attain a concentration of hemoglobin A 1c between 7.0% and 7.9%. Even though there was a nonstatistically significant 10% reduction in the primary composite outcome of nonfatal myocardial infarction, stroke or cardiovascular death, the trial was stopped because of the increased overall mortality. The specific cause of the increased mortality with intensive glycemic control is not presently known but was apparently not due to any specific therapy (including rosiglitazone) or to hypoglycemia-related events. References: National Heart Lung and Blood Institute. ACCORD telebriefing prepared remarks. National Heart Lung and Blood Institute Web site. http://www.nhlbi.nih.gov/health/prof/heart/other/accord/remarks.pdf. Dated February 6, 2008. Accessed November 2008. National Heart Lung and Blood Institute. For safety, NHLBI changes intensive blood sugar treatment strategy in clinical trial of diabetes and cardiovascular disease. National Heart Lung and Blood Institute Web site. http://www.nih.gov/news/health/feb2008/nhlbi-06.htm. Dated February 6, 2008. Accessed November 2008.
  • ADVANCE: Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation The ADVANCE trial showed that lowering glucose with a target of <6.5% was no better than standard glycemic control with regard to the risk for macrovascular endpoints. The results of both the ACCORD and ADVANCE trials do not suggest that intensive glycemic control is associated with a reduction in cardiovascular events, at least with the treatments used in these studies and the length of the follow-up periods. An open question remains about whether continuation of these trials beyond the length of treatment might have produced a benefit as was seen within the DCCT-EDIC follow-up period. ACCORD = Action to Control Cardiovascular Risk in Diabetes DCCT-EDIC = Diabetes Control and Complications Trial-Epidemiology of Diabetes Interventions and Complications Reference: ADVANCE Management Committee. Study rationale and design of ADVANCE: action in diabetes and vascular disease – preterax and diamicron MR controlled evaluation. Diabetologia . 2001;44:1118-1120.

HEART2D TRIAL HEART2D TRIAL Presentation Transcript

  • Department of Family Medicine Perpetual Succour Hospital JOURNAL CLUB SERIES Vivian C. Barrera,MD 1 st year resident
  • Answerable question….. Which strategy is better…..?
    • Is post prandial hyperglycemia an independent risk factor for cardiovascular disease in diabetes ?
  • Effects of Prandial Versus Fasting Glycemia on Cardiovascular Outcomes in Type 2 Diabetes : The HEART2D TRIAL
    • Diabetes Care Vol 32, Num 3, March 2009
    • Itamar Raz, MD; et al..
    • Cardiovascular disease is the leading cause of M & M in diabetics
    • 65% attributable to Heart disease and stroke
    • Chronic hyperglycemia increases risk
    • Postprandial hyperglycemia associated with CVE
  • ↑ 0xidative stress inflammation Endothelial Dysfunction Decreased fibrinolysis Plaque instability Cardiac events
  • DECODE: IGT Increases Mortality Risk Collaborative Analysis of Diagnostic Criteria in Europe N = 25,364 aged > 30 years Cumulative Mortality Hazard (%) DECODE Study Group. Lancet 1999;354:617-21. Follow-up (years) Diagnosed diabetes (n = 1275) Undiagnosed diabetes (n = 3071) Impaired glucose tolerance (n = 2766)* Normal glucose tolerance (n = 18,252)* *2-hour oral glucose tolerance test (OGTT) IGT = impaired glucose tolerance 0 2 4 6 8 10
  • STOP-NIDDM Trial: Acarbose Prevents Type 2 Diabetes Mellitus and Cardiovascular Events in Subjects With Impaired Glucose Tolerance Study Population Favors Acarbose Favors Placebo Hazard Ratio Chiasson JL, et al. JAMA. 2003;290;486–494. Copyright © 2003 American Medical Association. All rights reserved. CI = confidence interval 0.03 0.51 0.63 0.18 0.13 0.02 P Value 0.51 (0.28–0.95) 0.56 (0.10–3.07) 0.55 (0.05–6.11) 0.61 (0.29–1.26) 0.45 (0.16–1.28) 0.09 (0.01–0.72) Hazard Ratio (95% CI) 32 4 2 2 20 12 12 Placebo n=888 15 2 0 1 11 5 1 Acarbose n=662 Congestive heart failure Cerebrovascular stroke Cardiovascular death Revascularization procedures Angina Myocardial infarction Any cardiovascular event 0 0.5 1.0 1.5
  • Diabetes Mellitus Insulin Glucose Infusion in Acute Myocardial Infarction (DIGAMI): Benefit of Tight Glycemic Control in No Insulin – Low Risk Cohort Malmberg K, et al. BMJ. 1997;314:1512-1515. 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 Mortality Mortality Total Cohort No Insulin – Low Risk Years in Study Years in Study Control Insulin-glucose Infusion Insulin-glucose Infusion Control p = .0111 p = .004 n=133 n=139 n=314 n=306 0 1 2 3 4 5 0 1 2 3 4 5
  • Primary objective
    • Hyperglycemia and its effects after acute myocardial infarction on cardiovascular outcomes in patients with type 2 diabetes
    • Demonstrate the difference
    vs
  • RESEARCH DESIGN AND METHODS
    • Prospective , open-label, randomized , two-arm parallel, clinical trial
    • Conducted at 105 study centers in 17 countries..
    • Treatment group assignments were blinded to the sponsor during the trial
    • October 25, 2002 - July 6, 2005
  • RESEARCH DESIGN AND METHODS
    • Patients (aged 30–75 years ) with type 2 diabetes , duration of ≥3 months
    • Entered within 18 days of an AMI
    • Within 21 days of hospital admission for the recent AMI, randomly assigned into one of two treatment groups
  • Determination of Sample Size and Statistical Methods To achieved 80% power, 490 patients must have experienced one of the primary outcomes to detect a difference between groups assuming the following difference of 2.5mmol/l between groups in postprandial glucose
  • 1355 patients were planned for random assignment with 678 patients in each group All comparisons were performed using 2 tailed tests with a nominal significance level 0.05
  • PRANDIAL STRATEGY 3x daily Insulin Lispro BASAL STRATEGY target AIC 7.0 % If >8.0 % Add NPH at bedtime NPH insulin BID or Lantus OD FBG <6.7mmol/L or < 121mg/dl Human insulin 30/70 BID Self monitor PPBG <7.5mmol / <135mg/dl Follow-up 7 years
  • Results 1227 enrolled in the study , 1,115 randomly assigned Prandial n 557 ( 338) Basal n 558 ( 346) Prandial 51 deaths, 38 discontinued Bsal 51 deaths, 44 discontinued
  • Table 1Baseline characteristics of the intent to treat study population by treatment group 0.829 50.97 ± 10.08 50.54 ± 10.05 LVEF (%) 0.428 434 ± 34 435 ± 33 QTc interval (ms) 0.171 163 ± 610 115 ± 430 Urinary albumin-to-creatinine ratio (mg/g) 0.556 2.71 ± 1.02 2.68 ± 1.02 LDL cholesterol (mmol/l) 0.607 0.96 ± 0.23 0.96 ± 0.25 HDL cholesterol (mmol/l) 0.871 4.45 ± 1.25 4.45 ± 1.25 Total cholesterol (mmol/l) 0.074 1.77 ± 0.95 1.89 ± 1.15 Triglycerides (mmol/l) 0.089 8.27 ± 1.52 8.42 ± 1.40 A1C (%) 0.807 160 (28.8) 160 (28.8) Intravenous insulin infusion (recent AMI) 0.970 98 (17.6) 97 (17.4) Thrombolysis (recent AMI) 0.858 101 (18.1) 99 (17.8) Prior myocardial infarction 0.542 76.87 ± 9.56 76.60 ± 9.06 Diastolic blood pressure (mmHg) 0.346 127.76 ± 17.75 126.88 ± 16.63 Systolic blood pressure (mmHg) 0.832 447 (80.3) 449 (80.8) Overweight (BMI ≥25 kg/m 2 ) 0.380 29.2 ± 5.0 29.0 ± 4.6 BMI (kg/m 2 ) 0.513 81.86 ± 15.86 81.12 ± 15.17 Weight (kg) 0.143 12.3 ± 15.4 13.7 ± 16.5 Past tobacco use (years) 0.316 81 (14.5) 93 (16.7) Current tobacco use 0.518 9.0 ± 7.3 9.3 ± 7.2 Duration of diabetes (years) >0.999 Country 11 (2.0) 11 (2.0) Other     6 (1.1) 1 (0.2) African descent     58 (10.4) 61 (11.0) Western Asian     483 (86.6) 484 (86.9) Caucasian     0.302 Origin 0.277 220 (39.4) 202 (36.3) Aged ≥65     0.724 60.9 ± 9.8 61.1 ± 9.7 Mean     Age (years) 350 (62.7) 356 (63.9) Male     208 (37.3) 201 (36.1) Female     0.680 Sex 558 557 n P value BASAL PRANDIAL Variable
  • Table 1—Diabetes therapy at baseline (p=0·740 between groups ) 7 (1.3%) 4 (0.7%) Other 4 (0.7%) 2 (0.4%) Any combination of oral agents and MDI 27 (4.9%) 38 (6.9%) Multiple daily insulin injection (MDI) [≥3 inj/day] 40 (7.3%) 41 (7.5%) Combination oral + basal/premixed insulin 124 (22.5%) 121 (22.0%) Basal/premixed insulin (once- or twice-daily) 13 (2.4%) 10 (1.8%) Other combination of oral agents 11 (2.0%) 16 (2.9%) Metformin and sulfonylurea, + any other oral 86 (15.6%) 83 (15.1%) Metformin and sulfonylureas 3 (0.5%) 6 (1.1%) Fast-acting insulin secretagogues 1 (0.2%) 3 (0.5%) Alpha-glucosidase inhibitors 147 (26.7%) 138 (25.1%) Sulfonylureas 33 ( 6 . 0%) 41 ( 7 . 5%) Biguanides 54 ( 9 . 8%) 46 ( 8 . 4%) Diet and exercise BASAL (n=550) PRANDIAL (n=549) Variable (n, %)
    • Primary and Secondary Cardiovascular Endpoint
    Mean # days : 963 ( 2.7 y) ( 1-1678 days)
  • Table 2—Summary and analysis of individual outcomes for time to first adjudicated event 0.471 0.89 (0.66, 1.22) 86 (15.4%) 75 (13.5%) Coronary angiography planned after randomization 0.800 1.13 (0.44, 2.93) 8 (1.4%) 9 (1.6%) Amputation for PVD 0.863 0.93 (0.41, 2.11) 12 (2.2%) 11 (2.0%) Revascularization for PVD 0.662 0.90 (0.56, 1.44) 37 (6.6%) 33 (5.9%) Congestive heart failure 0.647 1.09 (0.75, 1.58) 54 (9.7%) 58 (10.4%) Hospitalized acute coronary syndromes 0.525 0.91 (0.68, 1.22) 94 (16.8%) 84 (15.1%) Coronary revascularization planned after randomization 0.948 1.01 (0.71, 1.43) 63 (11.3%) 63 (11.3%) Any myocardial infarction 0.419 0.50 (0.09, 2.75) 4 (0.7%) 2 (0.4%) Silent myocardial infarction 0.716 1.07 (0.73, 1.58) 50 (9.0%) 53 (9.5%) Nonfatal clinical myocardial infarction 0.983 1.01 (0.45, 2.25) 12 (2.2%) 12 (2.2%) Fatal myocardial infarction 0.581 1.20 (0.63, 2.29) 17 (3.0%) 20 (3.6%) Any stroke 0.573 1.21 (0.62, 2.35) 16 (2.9%) 19 (3.4%) Nonfatal stroke 0.654 1.50 (0.25, 8.99) 2 (0.4%) 3 (0.5%) Fatal stroke 0.816 1.05 (0.69, 1.60) 42 (7.5%) 44 (7.9%) Cardiovascular death 0.982 1.00 (0.68, 1.48) 51 (9.1%) 51 (9.2%) All-cause death p-value Estimated Hazard Ratio (95% CI) BASAL (n=558) PRANDIAL (n=557) Individual Outcomes*
  • FIGURE 2— Glycemic measures. A : Mean ± SD A1C at each visit by treatment strategy (PRANDIAL versus BASAL). B : Seven-point mean self-monitored blood glucose profiles at baseline (dotted line) and throughout the study (postrandomization, solid line) by treatment strategy (PRANDIAL versus BASAL 28% 31%
  • PRIMARY & SECONDARY CARDIOVASCULAR ENDPOINTS prandial basal P value (0.952) 424.1 423.8 QT INT (0.257) 52.39 54.3 LVEF (0.817) 52.39 71.4 HEART RATE (0.978) 77.5 77.4 DIASTOLIC (0.782) 132.4 131.8 SYSTOLIC (0.719) 2.70 2.26 LDL (0.523) 1.11 1.14 HDL (0.997) 4.65 4.65 TCHOL (0.894) 2.18 2.21 TGL (0.233) 7.3 7.7 Premeal BG (p0.005) 7.0 8.1 FBG
  • prandial basal P value 0.038 0 5 sepsis >.999 2.3 2.2 Congestive HF .030 0.7 2.3 Cardiac failure .007 61.5 65.7 Nocturnal hypoglycemia 0.071 9.5 12.9 Severe hypoglycemia 0.367 55.2 55. Incidence of hypoglycemia 0.05 21 28 Regimen intensification, frequency <0.00 0.52 .60 Received greater insulin dose <.001 3.1 4.8 Gain more weight 0.046 78.9 83.7 Beta- blocker 0.478 95.9 95.0 Cardivascular drugs
  • CONCLUSIONS
    • No difference in prandial and basal with respect to risk for the first combined cardiovascular event
    • Similar overall glycemic control measures by AIC in both treatment groups
    • AIC values did not reach the goal of 7.0 %
  • PROactive Trial: Significant Reduction in Secondary Outcome Events, % 0 6 18 24 36 12 30 Time from randomization (months) *Excluding silent myocardial infarction (MI) All-cause mortality, nonfatal MI*, stroke Dormandy JA et al. Lancet 2005;366:1279–1289. Pioglitazone 301 events Placebo 358 events 16% RRR HR 0.84 (0.72–0.98) P = 0.027
    • In both glycemic control groups, the mortality rate was lower than that seen in similar populations in other studies. 1
    • In the intensive group, a 10% reduction in primary composite outcome (nonfatal myocardial infarction, stroke, or cardiovascular death) was observed. 1
    • Specific cause of increased mortality with intensive glycemic control is not known, but it is not due to specific therapy or hypoglycemia. 1,2
    • What would be the cardiovascular outcome with 10-year follow-up?
    ACCORD: Deaths in Intensive vs. Standard Glycemic Control Groups: Preliminary Results 1 NHLBI Web site. http://www.nhlbi.nih.gov/health/prof/heart/other/accord/remarks.pdf 2 NHLBI Web site. http://www.nih.gov/news/health/feb2008/nhlbi-06.htm . 3 14 11 Rate per 1,000 patients/year 54 257 203 Deaths, n Difference Intensive Glycemic Control (Hemoglobin A 1c , <6.0%) Standard Glycemic Control (Hemoglobin A 1c 7.0–7.9%) Average duration of treatment ~4 years. Intensive glycemic control arm stopped at 18 months by Data Safety Monitoring Board.
  • ADVANCE: Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation Primary objective: To determine the effect of blood pressure treatment (ACE-inhibitor + diuretic vs. placebo) and glycemic intervention (intensive vs. standard) on microvascular and macrovascular complications in patients with type 2 diabetes mellitus (2  2 factorial design) Patient population: Type 2 diabetes (hypertensive + nonhypertensive) (N = 11,140) Primary endpoint: Macrovascular : composite of nonfatal stroke, nonfatal myocardial infarction, cardiovascular death Microvascular : composite of new or worsening nephropathy or retinopathy Secondary endpoints: Cerebrovascular disease, cardiovascular disease, peripheral vascular disease, microalbuminuria, visual deterioration, neuropathy, heart failure, cognitive function and dementia, all-cause mortality Treatment duration: 4.5 years ADVANCE Management Committee. Diabetologia. 2001;44:1118–1120. Placebo Perindopril + Indapamide Standard ¶ Placebo Perindopril + Indapamide Intensive* (HbA 1c ≤6.5%) Blood Pressure Intervention *Gliclazide plus oral agents/insulin to achieve hemoglobin A 1c (HbA 1c ) target ¶ Based on standard guidelines Glycemic Control
  • THE NULL RESULTS……..
    • Retarding the progression of advanced atherosclerosis… very difficult
    • Risk factors were similar between the groups
    • The difference in glycemic control was modest
      • Greater separation of post prandial blood glucose may be needed to adequately test the hypothesis
      • Overall glycemic controll were not fully realized
  • thank you Lee min ho