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
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
Hypertension in type 2 diabetes Lancet 2007 Combined analysis in Diabetes Care 2009
SBP (mmhg) Summary of treatment effects in antihypertensive trials 160 Uncomplicated HT SBP (mmhg) 190 Elderly 150 148 150 149 180 180 186 170 160 150 140 130 140 130 120 110 100 SBP (mmhg) PL Active 155 148 145 145 154 144 130 143 139 162 153 140 130 143 134 140 134 146 138 132 137 138 128 144 140 142 137 OS HDFP AUS MRC FEV Diabetes 145 143 144 141 BP Benefit Partial benefit BP Benefit Partial benefit No benefit 170 160 150 140 130 120 160 150 140 130 120 PL Active 149 143 172 150 EW SBP (mmhg) PL Active 141 132 162 150 150 170 143 140 136 167 138 135 165 156 133 128 161 151 130 124 160 151 140 136 130 122 159 144 Previous CVD 136 130 148 145 SHEP MRC S. China SCOPE CW STOP S. Eur HYVET JATOS Stroke CHD 130 124 147 138 132 129 BP Benefit Partial benefit No benefit BP Benefit Partial benefit No benefit 120 110 110 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
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 130-150 mmhg. Sleight P, et al. J Hypertens 2009 Jul;27:1360-9.
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)
ONTARGET T v R: Pre-specified Subgroup Analysis No. of Patients Incidence of Primary Outcome in Ramipril Group Primary Composite 17118 16.4 Hx of CVD No Hx of CVD 15627 1486 16.7 13.1 SBP < 134 134-150 > 150 5704 6042 5352 16.2 14.9 18.3 Diabetes No Diabetes 6390 10723 20.6 14.0 HOPE Risk Score Low Medium High 5709 5664 5745 10.4 15.0 23.8 Age < 65 65-75 > 75 7319 7310 2489 13.0 17.2 24.1 Male Female 12537 4581 16.7 15.7 Telmisartan better Ramipril better 0.7 1.0 1.3 Relative Risk in Telmisartan Group (95% Confidence Interval)
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
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) 143.7 ± 16.9 Diastolic BP (mmhg) 81.8 ± 10.3 Pulse pressure (mmhg) 61.9 ± 13.8
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
Unadjusted Kaplan-Meier plots for outcomes in relation to baseline SBP quartiles p=0.01 p=0.15 p=0.58 P<0.0001 Q1 <132 mmhg; Q2 132-144 mmhg; Q3 144-155 mmhg; Q4 >155 mmhg
Relationship between outcome rates and hazard risk for in-trial SBP divided into deciles in diabetics 30 Primary outcome 3.0 CV mortality 3.0 25 2.5 2.5 20 2.0 2.0 15 10 1.5 1.0 1.5 1.0 5 0.5 0.5 0 0 0 30 25 MI 3.0 2.5 Stroke 6.0 5.0 20 2.0 4.0 15 1.5 3.0 10 5 0 115 124 129 133 136 139 142 146 151 163 In-trial SBP (mmhg) 1.0 0.5 0 115 124 129 133 136 139 142 146 151 163 In-trial SBP (mmhg) 2. 0 1.0 0
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
Mean # Meds Intensive: 3.2 3.4 3.5 3.4 Standard: 1.9 2.1 2.2 2.3 Average : 133.5 Standard vs. 119.3 Intensive, Delta = 14.2 mmhg Cushman W, et al. N Engl J Med 2010
Primary and secondary outcomes Intensive Events (%/yr) Standard Events (%/yr) HR (95% CI) P Primary 208 (1.87) 237 (2.09) 0.89 (0.73-1.07) 0.20 Total Mortality 150 (1.28) 144 (1.19) 1.07 (0.85-1.35) 0.55 Cardiovascular Deaths 60 (0.52) 58 (0.49) 1.06 (0.74-1.52) 0.74 Nonfatal MI 126 (1.13) 146 (1.28) 0.87 (0.68-1.10) 0.25 Nonfatal Stroke 34 (0.30) 55 (0.47) 0.63 (0.41-0.97) 0.03 Total Stroke 36 (0.32) 62 (0.53) 0.59 (0.39-0.89) 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
Patients with Events (%) Patients with Events (%) 20 Primary Outcome Non-fatal MI, Non-fatal Stroke or CVD Death 20 Total Stroke 15 HR = 0.89 95% CI (0.73-1.07) P = 0.20 15 HR = 0.59 95% CI (0.39-0.89) P = 0.01 10 10 NNT for 5 years = 89 5 5 0 0 1 2 3 4 5 6 7 8 Years Post-Randomization 0 0 1 2 3 4 5 6 7 8 Years Post-Randomization Cushman W, et al. N Engl J Med 2010
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. 2003:290:2805-2816
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.
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) < 0.0001 Nonfatal MI 29 (1.3) 33 (1.7) 67 (3.1) 0.008 Nonfatal Stroke 22 (1.0) 26 (1.3) 52 (2.4) 0.001 Total MI 108 (4.8) 100 (5.0) 185 (8.5) < 0.0001 Total Stroke 34 (1.5) 33 (1.7) 70 (3.2) 0.0001 All Cause Mortality 248 (11.0) 201 (10.2) 334 (15.4) < 0.0001 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) 0.01 1.15; 95% CI, 1.01-1.32; P = 0.04 (in JAMA 2010)
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
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
SWEDEN: 5-year rates of CHD by SBP across 110-180 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
ACCORD-BP INVEST NDR SBP SBP Regression P End-points Interval Mean analyses value HR (95% CI) ACCORD-BP Fatal/nonfatal CVD <120 119 0.88 (0.73-1.06) 0.2 N=4,733 <140 134 1.0 Previous CVD 34% Follow-up 4.7 yrs OR (95% CI) INVEST Total mortality + 111-129 ~125 1.08 (0.91-1.28) 0.4 N=6,400 nonfatal MI + 130-139 ~135 1.0 Previous CHD 100% nonfatal stroke >140 ~150 1.5 (1.2-1.7) <0.001 HR (95% CI) NDR Fatal/nonfatal CVD 110-129 123 0.90 (0.74-1.10) 0.3 N=12,677 130-139 135 1.0 Previous CVD 19% >140 153 1.30 (1.14-1.48) <0.001 Follow-up 4.8 yrs
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 110-129 Tertile 1 (decrease) 501 / 68 1.77 (1.23-2.56) 0.002 Tertiles 2-3 (increase) 1017 / 49 1.0 130-139 Tertile 1 654 / 31 0.63 (0.42-0.93) 0.02 Tertiles 2-3 1611 / 114 1.0 >140 Tertile 1 2943 / 200 0.68 (0.58-0.80) <0.001 Tertiles 2-3 5951 / 563 1.0 Stroke 110-129 Tertile 1 497 / 12 1.41 (0.70-2.85) 0.3 Tertiles 2-3 1021 / 21 1.0 130-139 Tertile 1 666 / 14 0.53 (0.29-0.95) 0.03 Tertiles 2-3 1599 / 60 1.0 >140 Tertile 1 2914 / 113 0.73 (0.59-0.91) 0.004 Tertiles 2-3 5980 / 296 1.0 * Fully adjusted Nilsson P, et al. ESH XX Meeting (abstract) J Hypertens 2010 (in press)
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
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