Blood Pressure Targets in Diabetes

Transcription

1 Stockholm, 29 th August 2010 ESC Meeting Blood Pressure Targets in Diabetes Peter M Nilsson, MD, PhD Department of Clinical Sciences University Hospital, Malmö Sweden

2 Studies on BP in DM2 ADVANCE RCT (Lancet 2007) ONTARGET-DM Obs (ESH Milan 2009) ACCORD RCT (N Engl J Med 2010) INVEST Obs (JAMA 2010) NDR-Sweden Obs (J Hypertens 2010) RCT: randomized controlled trial; Obs: observational study

3 Hypertension in type 2 diabetes Lancet 2007 Combined analysis in Diabetes Care 2009

4 SBP (mmhg) Summary of treatment effects in antihypertensive trials 160 Uncomplicated HT SBP (mmhg) 190 Elderly SBP (mmhg) PL Active OS HDFP AUS MRC FEV Diabetes BP Benefit Partial benefit BP Benefit Partial benefit No benefit PL Active EW SBP (mmhg) PL Active Previous CVD SHEP MRC S. China SCOPE CW STOP S. Eur HYVET JATOS Stroke CHD BP Benefit Partial benefit No benefit BP Benefit Partial benefit No benefit HOT UKPDS ADV ABCD S. Eur SHEP HOPE PROG HT NT IDNT IDNT REN IR AM 100 PATS ACC PROG PROF HOPE CAM-AM PREV CAM-EN EU TR ACT PEA Mancia G, et al. J Hypertens 2009

5 Prognostic value of blood pressure in patients with high vascular risk in the ONTARGET study In high-risk patients, the benefits from SBP lowering below 130 mmhg are driven mostly by a reduction of stroke; myocardial infarction is unaffected and cardiovascular mortality is unchanged or increased. Future trials should be designed to test the value of SBP lowering in high-risk patients with SBP in the range of mmhg. Sleight P, et al. J Hypertens 2009 Jul;27:

6 Revised ESH guidelines 2009 Go for a flexible blood pressure goal in the individual DM patient, accept less than 140 mmhg SBP in most In newly detected patients with DM2 a tighter risk factor control is a goal, but in elderly patients with long diabetes duration and many co-morbidities the BP goal should be more flexible to avoid potential harm Avoid coronary hypoperfusion and orthostatic reactions in susceptible patients Mancia G, et al. J Hypertens 2009 (November)

7 ONTARGET T v R: Pre-specified Subgroup Analysis No. of Patients Incidence of Primary Outcome in Ramipril Group Primary Composite Hx of CVD No Hx of CVD SBP < > Diabetes No Diabetes HOPE Risk Score Low Medium High Age < > Male Female Telmisartan better Ramipril better Relative Risk in Telmisartan Group (95% Confidence Interval)

8 Late Breaker Session 1 Milan, 2009 Safety and Efficacy of Aggressive Blood Pressure Lowering Among Patients with Diabetes: Subgroup Analyses from the ONTARGET Trial J Redon, P Sleight, G Mancia, P Gao, P Verdecchia, R Fagard, H Schumacher, M Weber, M Boehm, B Williams, J Pogue, S Lewington, T Koon and S Yusuf on behalf of the ONTARGET investigators

9 General characteristics of the study population (n=9603) Mean age (yr) 66.1 ± 6.9 Gender (female) 3154 (32.8%) Body Mass index (kg/m2) 29.2 ± 4.9 Waist circumference (cm) 99.0 ± 13.7 Systolic BP (mmhg) ± 16.9 Diastolic BP (mmhg) 81.8 ± 10.3 Pulse pressure (mmhg) 61.9 ± 13.8

10 Number of events during the 4.6 yr of follow-up Event class Number Primary outcome 1938 Cardiovascular death 868 Myocardial infarction 563 Stroke 513 Hospitalization for Congestive Heart Failure 587

11 Unadjusted Kaplan-Meier plots for outcomes in relation to baseline SBP quartiles p=0.01 p=0.15 p=0.58 P< Q1 <132 mmhg; Q mmhg; Q mmhg; Q4 >155 mmhg

12 Relationship between outcome rates and hazard risk for in-trial SBP divided into deciles in diabetics 30 Primary outcome 3.0 CV mortality MI Stroke In-trial SBP (mmhg) In-trial SBP (mmhg)

13 Blood Pressure Trial (42% of ACCORD participants) 4,200 patients of different ethnic background Age-eligible, high-risk people with type 2 diabetes 2,100 to Intensive Group < 120 mmhg SBP (SBP Target < 120 mm Hg) 2,100 to Standard Group < 140 mmhg SBP (SBP Target < 140 mm Hg) Treated and followed for > 4 years (mean 5.5 yrs) MAJOR CVD EVENTS Results were presented during ACC in March 2010

14 Mean # Meds Intensive: Standard: Average : Standard vs Intensive, Delta = 14.2 mmhg Cushman W, et al. N Engl J Med 2010

15 Primary and secondary outcomes Intensive Events (%/yr) Standard Events (%/yr) HR (95% CI) P Primary 208 (1.87) 237 (2.09) 0.89 ( ) 0.20 Total Mortality 150 (1.28) 144 (1.19) 1.07 ( ) 0.55 Cardiovascular Deaths 60 (0.52) 58 (0.49) 1.06 ( ) 0.74 Nonfatal MI 126 (1.13) 146 (1.28) 0.87 ( ) 0.25 Nonfatal Stroke 34 (0.30) 55 (0.47) 0.63 ( ) 0.03 Total Stroke 36 (0.32) 62 (0.53) 0.59 ( ) 0.01 Also examined Fatal/Nonfatal HF (HR=0.94, p=0.67), a composite of fatal coronary events, nonfatal MI and unstable angina (HR=0.94, p=0.50) and a composite of the primary outcome, revascularization and unstable angina (HR=0.95, p=0.40) Cushman W, et al. N Engl J Med 2010

16 Patients with Events (%) Patients with Events (%) 20 Primary Outcome Non-fatal MI, Non-fatal Stroke or CVD Death 20 Total Stroke 15 HR = % CI ( ) P = HR = % CI ( ) P = NNT for 5 years = Years Post-Randomization Years Post-Randomization Cushman W, et al. N Engl J Med 2010

17 INVEST Trial Design International trial in 22,576 patients with CAD and hypertension Randomized to multi-drug treatment strategies verapamil SR + trandolapril + HCTZ atenolol + HCTZ + trandolapril Trandolapril recommended for all patients with diabetes Primary Outcome: First occurrence of allcause mortality, nonfatal MI or nonfatal stroke Secondary Outcomes: All-cause mortality, nonfatal MI, nonfatal stroke, total MI and total stroke Main finding: risk for CV adverse outcomes was equivalent comparing the strategies Pepine et al. JAMA. 2003:290:

18 INVEST: Methods Patients with diabetes at baseline grouped according to mean on-treatment SBP Tight Control Usual Control Not Controlled <130 mm Hg 130-<140 mm Hg 140 mm Hg Sep 97- Mar 03 Apr 03- Nov 08 Tight Control INVEST follow up Evaluated time to primary and secondary outcomes according to group Extended follow up (US Cohort) - National Death Index search to evaluate long term effect on mortality Further categorized on-treatment SBP in 5 mm Hg segments to evaluate effect of very low SBP Cooper-DeHoff RM, et al. Tight blood pressure control and cardiovascular outcomes among hypertensive patients with diabetes and coronary artery disease. JAMA 2010 Jul 7;304:61-8.

19 Results: Outcome Rates INVEST Follow Up n=6400 Tight Control n=2,255 Usual Control n=1,970 Not Controlled n=2,175 Outcome # of Events (Event Rate %) p value Primary Outcome 286 (12.7) 249 (12.6) 431 (19.8) < Nonfatal MI 29 (1.3) 33 (1.7) 67 (3.1) Nonfatal Stroke 22 (1.0) 26 (1.3) 52 (2.4) Total MI 108 (4.8) 100 (5.0) 185 (8.5) < Total Stroke 34 (1.5) 33 (1.7) 70 (3.2) All Cause Mortality 248 (11.0) 201 (10.2) 334 (15.4) < Extended Follow Up n=4370 Tight Control n=1,389 Usual Control n=1,423 Not Controlled n=1,558 Outcome # of Events (Event Rate %) p value All Cause Mortality 270 (19.4) 259 (18.2) 370 (23.7) ; 95% CI, ; P = 0.04 (in JAMA 2010)

20 Results: Outcomes Tight Control Group (n=2,255) Reference Other significant variables in Cox regression model: age, race, PAD, MI, CHF, US residency, renal impairment, LVH, TIA/stroke

21 Results: Outcomes During INVEST Nonfatal MI Nonfatal Stroke Tight Control vs Usual Control Log Rank p=0.49 Tight Control vs Usual Control Log Rank p=0.38 Tight control of systolic BP among patients with diabetes and CAD was not associated with improved cardiovascular outcomes compared with usual control

22 SWEDEN: 5-year rates of CHD by SBP across mmhg, fully adjusted in a Cox model based on data from 12,677 DM2 pat with treated HT Each spline represents event rates as a cubic function of SBP. Cederholm J, et al. J Hypertens 2010, online 14th July

23 ACCORD-BP INVEST NDR SBP SBP Regression P End-points Interval Mean analyses value HR (95% CI) ACCORD-BP Fatal/nonfatal CVD < ( ) 0.2 N=4,733 < Previous CVD 34% Follow-up 4.7 yrs OR (95% CI) INVEST Total mortality ~ ( ) 0.4 N=6,400 nonfatal MI ~ Previous CHD 100% nonfatal stroke >140 ~ ( ) <0.001 HR (95% CI) NDR Fatal/nonfatal CVD ( ) 0.3 N=12, Previous CVD 19% > ( ) <0.001 Follow-up 4.8 yrs

24 Hazard ratios by tertiles of change in systolic BP from baseline to follow-up Baseline SBP change during Patients / Hazard ratio * P Events SBP mmhg 5 years of follow-up Events (95% CI) value CHD Tertile 1 (decrease) 501 / ( ) Tertiles 2-3 (increase) 1017 / Tertile / ( ) 0.02 Tertiles / >140 Tertile / ( ) <0.001 Tertiles / Stroke Tertile / ( ) 0.3 Tertiles / Tertile / ( ) 0.03 Tertiles / >140 Tertile / ( ) Tertiles / * Fully adjusted Nilsson P, et al. ESH XX Meeting (abstract) J Hypertens 2010 (in press)

25 Summary Diabetes is associated with increased cardiovascular risk when a multiple-risk factor control approach is needed (Steno-2) Blood pressure control can prevent micro- and macrovascular events to a varying degree in diabetes (HOT, UKPDS, ADVANCE, ACCORD) A SBP goal of well below 140 mmhg is recommended by ESH and benefits were seen in ADVANCE for SBP less than 135 mmhg, but not below 120 mmhg (ACCORD). The benefits for less than 130 mmhg are confined to stroke reduction This strategy is supported by observational data (ONTARGET, INVEST, NDR-BP) PN 2010

26 Thank you!