Top 5 (Topics) Papers In GIM Rocky Mountain ACP Internal Medicine Meeting Raj Padwal November 13, 2008

Transcription

1 Top 5 (Topics) Papers In GIM 2008 Rocky Mountain ACP Internal Medicine Meeting Raj Padwal November 13, 2008

2 Methods Searched ACPJC/EBM, TOC of top medical journals, MEDSCAPE Best Evidence, consultation with colleagues. Focus on common diseases and studies with potential to change practice. Excluded studies presented in-depth in this meeting

3 Bottom Line New Evidence Does Not Favour: 1. Intensive glucose control in DM2 2. Steroids for relative adrenal insufficiency in critically ill patients with septic shock 3. Intensive glucose control in the critically ill 4. Combinination ACE/ARB therapy for high CV risk New Evidence Favours: 1. Using ARBs in patients at high-cardiovascular risk 2. Prescribing statins in low-mod risk patients with no prior CVD or DM2 and elevted baseline CRP

4 Topic 1: Intensive Glucose Control in DM2

5 Intensive Glucose Control in DM2: Background Observational studies demonstrate a linear relationship between glucose control and mortality. A 1% increase in A1c = an 18% increase in CVD risk. Even extends into the normal range of glucose levels. UKPDS provided evidence for a reduction of A1c to around 7. Clear benefit on microvascular outcomes. Is there a benefit to tighter control, particularly for macrovascular outcomes?

6 Intensive Glucose Control in DM2: ACCORD and ADVANCE

7 Intensive Glucose Control in DM2: Studies ACCORD (NA) Dual funded ADVANCE (20 countries) Dual N (age) (62) (66) Population y with CVD or with EOD or 2 risk fact. A1c of 7.5% or 55 y with macro or micro dz or 1 other risk fact more. Baseline A1C Target A1C <6 <6.5 (achieved) (6.4 vs. 7.5) (6.5 vs. 7.3) Duration/FU 3.4 (stopped early)/98% 5.0/99%

8 Intensive Glucose Control in DM2: Treatments Treatment ACCORD ADVANCE (intensive vs. standard) Insulin 77 vs vs 24 Metformin 95 vs vs 67 Secretagogue 87 vs vs 62 (gliclazide) TZD 92 vs vs 11 Statin 88 vs vs 48

9 Intensive Glucose Control in DM2: Results Endpoint ACCORD ADVANCE Nonfatal MI, nonfatal stroke, CV death 6.9% vs. 7.2% 0.9 ( )* Non-fatal MI 0.76 ( ) Non-fatal Stroke 1.06 ( ) Death 1.22 ( ) 0.93 ( ) Micro or Macro 18% vs. 20%; HR 0.9 ( )* Micro alone 0.86 ( ) Macro alone 0.94 ( )

10 Intensive Glucose Control in DM2: Conclusions 1. Did not improve macrovascular outcomes and, when using aggressive, multidrug regimens associated with weight gain, hypoglycemia and increased mortality. 2. A1c should be individualized: a goal of 7.0 is reasonable for most patients. 3. Focus on bp, lipids, other CV risk factors to reduce macrovascular outcomes.

11 Topic 2: Steroids in Septic Shock

12 Steroids in Septic Shock: Background Septic shock: 2-20% of inpatients with up to 60% mortality rate. Relative adrenal insufficiency is common and correlated with increased mortality. Guidelines recommend the use of glucocorticoids largely based upon one small prior study of 300 patients demonstrating a significant reduction in 28d mortality from 61% to 55% (Annane et al).

13 Steroids in Septic Shock: CORTICUS study

14 CORTICUS Study: Methods DBPCT in patients (52 ICUs) with septic shock. Funded independent of pharma. Hydrocortisone 50 mg iv q6h (n=251) versus placebo (n=248) x 5d given w/in 72 h then tapered over 6 d. Primary outcome: death at 28 d Only 500/800 patients recruited.

15 CORTICUS: Results No relative adrenal insufficiency: 39.2% vs. 36%; HR 1.09 (0.77 to 1.42) Relative adrenal insufficiency: 28.8% vs. 28.9%; HR 1.00 (0.68 to 1.49)

16 CORTICUS: Results Shock reversed more quickly in hydrocortisone group. New sepsis or septic shock more common in hydrocortisone group: 33% vs. 26%; RR 1.3 ( )

17 Differences with Annane study Enrolment within 72 h vs. 8 h Tapered course rather than abrupt stop at day 8 No fludrocortisone given Lower degree of organ dysfunction Lower overall mortality rate (32% vs. 61%)

18 Steroids in Septic Shock: Conflicting data. Conclusion Potential for increased infection. Some suggest giving steroids if patients are sick and given early (w/in 8h). Others say should not be used pending further study.

19 Topic 3: Intensive Glucose Control in the Critically Ill

20 Intensive Glucose Control in the Critically Ill: Background Tight glucose control in the ICU has been advocated based largely upon one study in the surgical ICU setting (van den Berghe et al 2001). 12-month mortality significantly reduced in 1548 patients from 8.0% to 4.6%. Many guidelines have advocated maintaining the glucose concentration between mmol/l.

21 Intensive Glucose Control in the Critically Ill: Background Concern about the method of diagnosis of tight control. Study by van den Berghe et al used only mean am glucose. Controversy about the mechanism of benefit. Glucose control? Extra glucose in a controlled environment?

22 Intensive Glucose Control in the Critically Ill

23 Intensive Glucose Control in the Critically Ill: Methods Meta-analysis of randomized trials MEDLINE, Cochrane, registries, reference lists, abstracts from meetings No language restriction

24 Intensive Glucose Control in the Critically Ill: Results 29 studies involving 8432 patients and 1869 deaths Death 21.6% vs. 23.3%; RR 0.93 ( ) No difference in mortality when stratified by degree of glucose control or ICU setting.

25 Intensive Glucose Control in the Critically Ill: Results

26 Intensive Glucose Control in the Critically Ill: Results Increased risk of hypoglycemia: 13.7% vs. 2.5%; RR 5.13 ( ) Decreased risk of septicemia: 10.9% vs. 13.4%; RR 0.76 ( )

27 Intensive Glucose Control in the Critically Ill: Conclusions Tight control does not reduce mortality and may be harmful in terms of increased hypoglycemia Use should be reserved pending ongoing large RCTs (NICE SUGAR)

28 Topic 4: ARB and ACE/ARB Combination Therapy in Patients at High Risk for CVD

29 ARB and ACE/ARB Combination Therapy: Background Trials have demonstrated reductions in CV risk with ace inhibitor therapy in patients at high CV risk. The role of ARB and ACE/ARB combination therapy was unknown

30 ARB and ACE/ARB in High Risk: ONTARGET

31 ONTARGET: Methods DBRPCT of patients in 40 countries with CVD or DM2 and end-organ damage. Funded by Boehringer Ingelheim and HSF Ontario 80 mg telmisartan versus ramipril 10 mg versus placebo Primary outcome: CV death, MI, stroke or HF hospitalization.

32 ONTARGET: Results 74% CAD 38% DM2; 70% HTN Combo therapy reduced BP by 2.4/1.4 mm Hg compared to ramipril group. 60% Statin; 75% ASA Follow-up 100% over 56 months.

33 ONTARGET: Results 16.5% (ram) vs. 16.7% (tel) vs. 16.3% (combo) T vs. R: HR 1.01 ( ) Comb vs. R: HR 0.99 ( )

34 ONTARGET: Results Renal impairment higher with combo therapy vs. ramipril: 13.5% vs 10.2%; RR 1.33 ( ) Hypotension also higher with combo 4.8% vs. 1.7%; RR 2.75; p<0.001

35 ARB and ACE/ARB Combo Therapy: Conclusions In patients at high CV risk, ARB therapy is equivalent to ACE inhibitor therapy in reducing CV events. Combination therapy was not more beneficial and may cause harm.

36 Topic 5: Statins in Low Risk Patients

37 Statins in Low Risk Patients: Background Half of all CV events occur among healthy patients with LDL levels below current recommend treatment thresholds. CRP is an inflammatory biomarker that independently predicts risk of CV events. Question: Do patients with low LDL levels but elevated CRP levels benefit from statin therapy?

38 Statins in Low Risk Patients: JUPITER trial

39 JUPITER: Methods DBRPCT of Rosuvastatin 20 mg versus placebo in 26 countries funded by Astra-Zenica. Primary investigators: patents for CRP assay. Inclusion: men ( 50) or women ( 60) with no CVD and LDL less than 3.4, CRP of 2, trig less than 5.6. Exclusion: Diabetes/CAD, inflammatory disease, statin use, uncont HTN, renal dz, liver dz, cancer w/in 5 y, alcohol/drug abuse Outcome: Major CV event: non-fatal MI, non-fatal stroke, hospitalization for unstable angina, arterial revascularization or CV death. Terminated early after median follow-up of 1.9 years

40 JUPITER: Baseline Mean age 66 y Mean BP 134/80; 15% smokers 41% had metabolic syndrome; half had FH risk score < 10% Median LDL 2.8 Median CRP 4.2 mg/l Median HDL 1.3

41 JUPITER: Results Median LDL achieved was 1.4 mmol/l (50% drop) and median CRP was 2.2 (37% drop) mg/l. 4% rise in HDL not significant

42 JUPITER: Results 0.77% versus 1.36% (per year) ARR 0.59% HR 0.56; 95% CI 0.46 to 0.69 NNT 31 over 4 years NNT: 120 over 1.9 years for hard endpoints

43 JUPITER: Results

44 JUPITER: Conclusions Rosuvastatin reduces cardiovascular events in patients with elevated CRP and low LDL levels. Potential to change current practice. However, narrow inclusion criteria limits generalizability. Well tolerated: 1 rhabdo, 10 myopathy; Incidence of DM2 higher with statin: 3.0% vs. 2.4%; p=.001. This has been seen in previous studies. Cost-effectiveness is a major question.

45 Bottom Line New Evidence Does Not Favour: 1. Intensive glucose control in DM2 2. Steroids for relative adrenal insufficiency in critically ill patients with septic shock 3. Intensive glucose control in the critically ill 4. Combinination ACE/ARB therapy for high CV risk New Evidence Favours: 1. Using ARBs in patients at high-cardiovascular risk 2. Prescribing statins in low-mod risk patients with no prior CVD or DM2 and elevated baseline CRP

46 References 1. ADVANCE: NEJM 2008;358: ACCORD: NEJM 2008;358: CORTICUS: NEJM 2008;358: Intensive glucose ICU meta: JAMA 2008;300: ONTARGET: NEJM 2008;358: JUPITER: NEJM 2008;359: