CVD & Stroke: Understanding the Relation and Impact on Risk Management CV Risk Management 2016 Moscow, Russia David D. Waters, MD October 15, 2016
Global and Regional Burden of Stroke: 1990 – 2010 • 119 studies published from 1990-2012 • From 1990 to 2010, the age-standardized incidence of stroke decreased 12% and stroke mortality decreased by 37% in high-income countries • In low/middle income countries, stroke incidence increased by 12% ( p =NS) and stroke mortality decreased by 20% • In 2010, first stroke (17 million), stroke survivors (33 million), stroke-related deaths (6 million), and DALYs lost (102 million) were high and had significantly increased since 1990 (68%, 84%, 26%, and 12% respectively) • most of the burden (69% incident strokes, 52% prevalent strokes, 71% stroke deaths, and 78% DALYs lost) was in low/middle-income countries Feigin VL et al, Lancet 2014;383:245
Age-Standardized Stroke Incidence Per 100,000 Person-Years: 2010 Feigin VL et al, Lancet 2014;383:245
Age-Standardized Stroke Mortality Per 100,000 Person-Years: 2010 Feigin VL et al, Lancet 2014;383:245
Long-Term Outcome After TIA or Minor Stroke • 2,473 Dutch patients with TIA or minor ischemic stroke followed for a mean of 10.1 years • 1489 (60%) patients died and 1336 (54%) had at least one vascular event • 10-year risk of death was 42·7% (95% CI 40·8 – 44·7) Van Wijk I et al, Lancet 2005;365:2098 The Lancet 2005 365, 2098-2104DOI: (10.1016/S0140-6736(05)66734-7)
ACCORD BP Trial • 4,733 patients with type 2 diabetes randomized to intensive (<120 mmHg) or standard (<140 mmHg) BP therapy and followed for 4.7 years • Any antihypertensive therapy permitted • Primary outcome: nonfatal MI, nonfatal stroke, CV death The ACCORD Study Group. N Engl J Med 2010;362:1575
ACCORD BP Trial: Systolic BP During Follow-Up The ACCORD Study Group. N Engl J Med 2010;362:1575
ACCORD BP Trial • 4,733 patients with type 2 diabetes randomized to intensive (<120 mmHg) or standard (<140 mmHg) BP therapy and followed for 4.7 years • Any antihypertensive therapy permitted • Primary outcome: nonfatal MI, nonfatal stroke, CV death • More adverse events attributed to BP therapy in aggressively treated group (dizziness, syncope, K + , K + ) • lower eGFR at end of study (74.8 ± 25.0 vs 80.6 ± 24.8 ml/ min/1.73 m 2 , p <0.001) in aggressively treated group The ACCORD Study Group. N Engl J Med 2010;362:1575
ACCORD BP Trial: Primary Outcome and Components p=0.03 The ACCORD Study Group. N Engl J Med 2010;362:1575
SPRINT (Systolic BP Intervention Trial) • 9,361 patients with systolic BP ≥130 mm Hg at increased CV risk without diabetes were randomized to intensive treatment of systolic BP (target <120 mm Hg) or standard treatment (target <140 mm Hg) • mean age 67.9 years, 36% women, 32% African American, 20% with CVD, 28% with CKD, 13% current smokers, no BP meds 9%, mean BP meds/pt 1.8 • mean BP at baseline: 139.7/78.2 mm Hg • primary composite outcome was MI, other ACS, stroke, heart failure, or CV death • trial stopped early after 3.26 years due to benefit in the intensive treatment group The SPRINT Research Group. N Engl J Med 2015;373:2103-2116
SPRINT: Systolic Blood Pressure During Follow-Up The SPRINT Research Group. N Engl J Med 2015;373:2103-2116
SPRINT: Primary Outcome* * Primary outcome was MI, other ACS, stroke, heart failure, or CV death The SPRINT Research Group. N Engl J Med 2015;373:2103-2116
SPRINT: Total Mortality The SPRINT Research Group. N Engl J Med 2015;373:2103-2116
SPRINT: Outcomes in Subgroups The SPRINT Research Group. N Engl J Med 2015;373:2103-2116
SPRINT: Primary, Secondary and Renal Outcomes The SPRINT Research Group. N Engl J Med 2015;373:2103-2116
SPRINT: Adverse Events The SPRINT Research Group. N Engl J Med 2015;373:2103-2116
SPRINT: Conclusions • Among patients at high risk for CV events but without diabetes, targeting a systolic BP <120 mm Hg, as compared with <140 mm Hg, resulted in lower rates of fatal and nonfatal major CV events and death from any cause, although significantly higher rates of some adverse events were observed in the intensive-treatment group The SPRINT Research Group. N Engl J Med 2015;373:2103-2116
Combined SPRINT and ACCORD Trial Data Perkovic V, Rodgers A. N Engl J Med 2015;373:2175-2178.
Patient Population: LLA Eligibility criteria • SBP 160 mm Hg and/or DBP 100 mm Hg (untreated) or SBP 140 mm Hg and/or DBP 90 mm Hg (treated) • TC 6.5 mmol/L (250 mg/dL) and TGs 4.5 mmol/L (400 mg/dL) • 40-79 years of age • 3+ CVD risk factors • No history of CHD
Reductions in Total and LDL Cholesterol Atorvastatin 10 mg Placebo 6 Total cholesterol 200 (mmol/L) 1.3 mmol/L 1.1 mmol/L (mg/dL) 4 150 100 2 0 1 2 3 4 150 LDL cholesterol 125 (mg/dL) (mmol/L) 3 1.2 mmol/L 1.0 mmol/L 100 2 75 1 LLA Close-out 0 1 2 3 Years
Primary End Point: Nonfatal MI and Fatal CHD Atorvastatin 10 mg Number of events 100 4 Placebo Number of events 154 Cumulative Incidence (%) 36% 3 reduction 2 1 HR = 0.64 (0.50-0.83) p=0.0005 0 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Years
Secondary End Point: Fatal and Nonfatal Stroke Atorvastatin 10 mg Number of events 89 3 Placebo Number of events 121 Cumulative Incidence (%) 27% reduction 2 1 HR = 0.73 (0.56-0.96) p=0.0236 0 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Years
Objectives In an intermediate-risk population without CVD, to evaluate the effects on CV events of: 1. BP lowering with a fixed dose combination of Candesartan 16 mg and HCTZ 12.5 mg daily 2. Cholesterol lowering with Rosuvastatin 10 mg daily 3. Combined BP and cholesterol lowering Participants received lifestyle advice and necessary therapies
Intermediate-Risk Population Inclusion Criteria (Target Risk 1.0%/yr) Women ≥ 60 yrs , men ≥ 55 yrs with at least one additional Risk Factor • • Increased WHR Dysglycemia • • Smoking Mild renal dysfunction • • Low HDL-C Family history of CHD Exclusion Criteria: CVD or indication(s) or contraindication(s) to study drugs No strict BP or LDL-C criteria for entry Uncertainty principle 5
The HOPE-3 Trial 228 centers in 21 countries Argentina, Australia, Brazil, Canada, China, Colombia, Czech Republic, Ecuador, Hungary, India, Israel, Korea, Malaysia, Netherlands, Philippines, Russia, Slovakia, South Africa, Sweden, United Kingdom, Ukraine 25
Baseline Characteristics 12,705 randomized Age (yrs) 66 Female 46% Blood Pressure (mmHg) 138/82 LDL-Cholesterol (mg/dL) 128 LDL-Cholesterol (mmol/L) 3.3 Elevated waist-to-hip ratio 87% hsCRP (g/L) median 2.0 Ethnicity White Caucasian 20% Latin American 28% Chinese 29% Other Asian 20% Black African 2% 11
BP Lowering vs. Placebo: SBP Changes 140 Systolic Blood Pressure (mmHg) Placebo 135 130 Candesartan + HCTZ 125 Δ BP=6.0/3.0 mmHg 120 0 1 2 3 4 5 6 7 Years Cand/HCTZ 6356 5907 5667 5446 5213 3862 1437 350 Placebo 6347 5879 5623 5442 5186 3822 1424 334 12
CV Death, MI, Stroke, Cardiac Arrest, Revascularization, Heart Failure 0.10 HR (95% CI) = 0.95 (0.81-1.11) 0.08 Cumulative Hazard Rates P-value = 0.51 0.06 Placebo 0.04 Candesartan + HCTZ 0.02 0.0 0 1 2 3 4 5 6 7 No. at Risk Years Cand + HCTZ 6356 6272 6200 6103 5968 4969 2076 522 Placebo 6349 6270 6198 6096 5967 4970 2075 488 14
Prespecified Subgroups: By Thirds of SBP CV Death, MI, Stroke, Cardiac Arrest, Revasc, HF SBP mmHg Placebo HR (95% CI) P Trend Cutoffs Mean Diff Event Rate% ≤ 131.5 122 6.1 3.5 1.25 (0.92-1.70) 0.009 131.6-143.5 138 5.6 4.6 1.02 (0.77-1.34) >143.5 154 5.8 7.5 0.76 (0.60-0.96) 0.5 1.0 2.0 Candesartan + HCTZ Better Placebo Better 15
Cholesterol Lowering Arm: Change in LDL-C, Apo-B, and CRP LDL-C (mg/dL) APO B (g/L) log hsCRP (g/L) 0.8 130 Placebo Placebo Placebo 1.1 0.7 120 1.0 0.6 110 mean Δ 34.6 mg/dl* mean Δ 0.23 g/l* log mean Δ 0.19* 0.9 0.5 100 0.4 0.8 90 Rosuvastatin Rosuvastatin Rosuvastatin 0.3 0.7 80 0 Year 1 Year 3 Study End 0 Year 1 Year 3 Study End 0 Year 1 Year 3 Study End * P< 0.001 19
CV Death, MI, Stroke, Cardiac Arrest, Revasc, Heart Failure 0.10 HR (95% CI) = 0.75 (0.64-0.88 ) Cumulative Hazard Rates 0.08 P-value = 0.0004 0.06 Placebo 0.04 Rosuvastatin 0.02 0.0 0 1 2 3 4 5 6 7 Years Rosuva 6361 6241 6039 2122 Placebo 6344 6192 5970 2073 21
Stroke Coronary Heart Disease 0.020 0.04 HR (95% CI) = 0.70 (0.52-0.95) HR (95% CI) = 0.74 (0.58-0.96) P-value = 0.0227 P-value = 0.0214 0.015 0.03 Cumulative Hazard Rates Placebo Placebo 0.010 0.02 Rosuvastatin Rosuvastatin 0.005 0.01 0.0 0.0 0 1 2 3 4 5 6 7 0 1 2 3 4 5 6 7 Years Years Coronary Heart Disease: MI, Coronary revascularization 22
Stroke Risk and LDL-C Lowering Each 10% LDL-C Reduction Was Estimated to Reduce the Risk of Stroke by 15.6% 1.2 Post-CABG GISSI Odds ratios, non log-scale PROSPER 1.0 WOSCOPS ALLHAT-LLT AFCAPS/TexCAPS 0.8 LIPID ASCOT-LLA 4S HPS CARE 0.6 GREACE MIRACL 0.4 Small Trials 0.2 -10 -15 -20 -25 -30 -35 -40 -45 -50 -55 Between group difference in LDL-cholesterol reduction (%) LDL-C, low-density lipoprotein cholesterol. Amarenco P et al. Stroke . 2004;35:2902-2909.
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