CVD & Stroke: Understanding the Relation and Impact on Risk - - PowerPoint PPT Presentation

▶
cvd stroke understanding the
SMART_READER_LITE
LIVE PREVIEW

CVD & Stroke: Understanding the Relation and Impact on Risk - - PowerPoint PPT Presentation

Feb 05, 2024 308 likes •786 views

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

slide-1
SLIDE 1

CVD & Stroke: Understanding the Relation and Impact on Risk Management CV Risk Management 2016 Moscow, Russia

David D. Waters, MD

October 15, 2016

slide-2
SLIDE 2

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

slide-3
SLIDE 3

Age-Standardized Stroke Incidence Per 100,000 Person-Years: 2010

Feigin VL et al, Lancet 2014;383:245

slide-4
SLIDE 4

Age-Standardized Stroke Mortality Per 100,000 Person-Years: 2010

Feigin VL et al, Lancet 2014;383:245

slide-5
SLIDE 5

The Lancet 2005 365, 2098-2104DOI: (10.1016/S0140-6736(05)66734-7)

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

slide-6
SLIDE 6

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

slide-7
SLIDE 7

The ACCORD Study Group. N Engl J Med 2010;362:1575

ACCORD BP Trial: Systolic BP During Follow-Up

slide-8
SLIDE 8

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 m2, p<0.001) in aggressively treated group

The ACCORD Study Group. N Engl J Med 2010;362:1575

slide-9
SLIDE 9

The ACCORD Study Group. N Engl J Med 2010;362:1575

ACCORD BP Trial: Primary Outcome and Components

p=0.03

slide-10
SLIDE 10

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

slide-11
SLIDE 11

SPRINT: Systolic Blood Pressure During Follow-Up

The SPRINT Research Group. N Engl J Med 2015;373:2103-2116

slide-12
SLIDE 12

SPRINT: Primary Outcome*

The SPRINT Research Group. N Engl J Med 2015;373:2103-2116

* Primary outcome was MI, other ACS, stroke, heart failure, or CV death

slide-13
SLIDE 13

SPRINT: Total Mortality

The SPRINT Research Group. N Engl J Med 2015;373:2103-2116

slide-14
SLIDE 14

SPRINT: Outcomes in Subgroups

The SPRINT Research Group. N Engl J Med 2015;373:2103-2116

slide-15
SLIDE 15

SPRINT: Primary, Secondary and Renal Outcomes

The SPRINT Research Group. N Engl J Med 2015;373:2103-2116

slide-16
SLIDE 16

SPRINT: Adverse Events

The SPRINT Research Group. N Engl J Med 2015;373:2103-2116

slide-17
SLIDE 17

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

slide-18
SLIDE 18

Perkovic V, Rodgers A. N Engl J Med 2015;373:2175-2178.

Combined SPRINT and ACCORD Trial Data

slide-19
SLIDE 19

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
slide-20
SLIDE 20

Reductions in Total and LDL Cholesterol

200 150 150 75 125 100 100 (mg/dL) (mg/dL)

Total cholesterol (mmol/L) LDL cholesterol (mmol/L) Years

1.3 mmol/L 1.1 mmol/L 1.2 mmol/L 1.0 mmol/L LLA Close-out 2 4 6 1 2 3 Atorvastatin 10 mg Placebo

1 2 3 4 1 2 3

slide-21
SLIDE 21

1 2 3 4 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Years Cumulative Incidence (%)

36% reduction

Primary End Point: Nonfatal MI and Fatal CHD

HR = 0.64 (0.50-0.83) Atorvastatin 10 mg Number of events 100 Placebo Number of events 154 p=0.0005

slide-22
SLIDE 22

1 2 3 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Years Cumulative Incidence (%)

Secondary End Point: Fatal and Nonfatal Stroke

27% reduction

HR = 0.73 (0.56-0.96) p=0.0236 Atorvastatin 10 mg Number of events 89 Placebo Number of events 121

slide-23
SLIDE 23

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

slide-24
SLIDE 24

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

slide-25
SLIDE 25

The HOPE-3 Trial

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

228 centers in 21 countries

slide-26
SLIDE 26

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 Latin American Chinese Other Asian Black African 20% 28% 29% 20% 2%

Baseline Characteristics

12,705 randomized

11

slide-27
SLIDE 27

BP Lowering vs. Placebo: SBP Changes

Years

Systolic Blood Pressure (mmHg)

1 2 3 4 5 6 7

120 125 130 135

140

6356 5907 5667 5446 5213 3862 1437 350 6347 5879 5623 5442 5186 3822 1424 334 Cand/HCTZ Placebo

Placebo Candesartan + HCTZ

Δ BP=6.0/3.0 mmHg

12

slide-28
SLIDE 28

Years Cumulative Hazard Rates

0.0 0.02 0.04 0.06 0.08 0.10 1 2 3 4 5 6 7

6356 6272 6200 6103 5968 4969 2076 522 6349 6270 6198 6096 5967 4970 2075 488

  • No. at Risk

Cand + HCTZ

Placebo

Placebo Candesartan + HCTZ HR (95% CI) = 0.95 (0.81-1.11) P-value = 0.51

CV Death, MI, Stroke, Cardiac Arrest, Revascularization, Heart Failure

14

slide-29
SLIDE 29

CV Death, MI, Stroke, Cardiac Arrest, Revasc, HF

0.5 1.0 2.0

Candesartan + HCTZ Better Placebo Better

3.5 4.6 7.5 1.25 (0.92-1.70) 1.02 (0.77-1.34) 0.76 (0.60-0.96) 0.009 HR (95% CI) P Trend

Prespecified Subgroups: By Thirds of SBP

SBP mmHg Mean ≤131.5 131.6-143.5 >143.5 Diff 6.1 5.8 5.6 Cutoffs 122 138 154 Placebo Event Rate% 15

slide-30
SLIDE 30

Cholesterol Lowering Arm: Change in LDL-C, Apo-B, and CRP

0 Year 1 Year 3 Study End 80 90 100 110 120 130

Placebo Rosuvastatin LDL-C (mg/dL)

0 Year 1 Year 3 Study End 0.7 0.8 0.9 1.0 1.1

APO B (g/L)

0 Year 1 Year 3 Study End 0.3 0.4 0.5 0.6 0.7 0.8

log hsCRP (g/L)

mean Δ 34.6 mg/dl* mean Δ 0.23 g/l* log mean Δ 0.19*

Placebo Rosuvastatin Placebo Rosuvastatin

* P< 0.001

19

slide-31
SLIDE 31

CV Death, MI, Stroke, Cardiac Arrest, Revasc, Heart Failure

Years

Cumulative Hazard Rates

0.0 0.02 0.04 0.06 0.08 0.10 1 2 3 4 5 6 7

Placebo Rosuvastatin

HR (95% CI) = 0.75 (0.64-0.88) P-value = 0.0004

6361 6241 6039 2122 6344 6192 5970 2073 Rosuva Placebo

21

slide-32
SLIDE 32

Years Cumulative Hazard Rates

0.0 0.01 0.02 0.03 0.04

1 2 3 4 5 6 7

Placebo Rosuvastatin HR (95% CI) = 0.74 (0.58-0.96) P-value = 0.0214

Years

0.0 0.005 0.010 0.015 0.020

1 2 3 4 5 6 7

Placebo Rosuvastatin HR (95% CI) = 0.70 (0.52-0.95) P-value = 0.0227

Coronary Heart Disease Stroke

Coronary Heart Disease: MI, Coronary revascularization 22

slide-33
SLIDE 33

Stroke Risk and LDL-C Lowering

Each 10% LDL-C Reduction Was Estimated to Reduce the Risk of Stroke by 15.6%

Amarenco P et al. Stroke. 2004;35:2902-2909.

Odds ratios, non log-scale Between group difference in LDL-cholesterol reduction (%)

Small Trials GREACE MIRACL CARE 4S ASCOT-LLA HPS LIPID ALLHAT-LLT GISSI Post-CABG PROSPER WOSCOPS AFCAPS/TexCAPS

  • 10
  • 15
  • 20
  • 25
  • 30
  • 35
  • 40
  • 45
  • 50
  • 55

1.2 0.2 0.4 0.6 0.8 1.0

LDL-C, low-density lipoprotein cholesterol.

slide-34
SLIDE 34

4,731 Patients

SPARCL: Study Design

Placebo Atorvastatin 80 mg/day

Double-Blind Period

The SPARCL Investigators. Cerebrovasc Dis. 2003;16:389-395. Amarenco P et al, N Engl J Med 2005;355:549

Primary End Point

Time to the First Occurrence of a Fatal or Nonfatal Stroke Patient Population  205 sites worldwide  Previously documented stroke or TIA within 6 months  No history of CHD  LDL-C levels ≥100 mg/dL and ≤190 mg/dL

TIA, transient ischemic attack; CHD, coronary heart disease; LDL-C, low-density lipoprotein cholesterol.

slide-35
SLIDE 35

20 40 60 80 100 120 140

Baseline Month 1 Month 3 Month 6 Year 1 Year 2 Year 3 Year 4 Year 5 Year 6 Last

Timepoint Mean LDL-C level (mg/dL)

LDL-C During Follow-Up

Mean on-treatment LDL-C:

Placebo=129 mg/dL Atorvastatin=73 mg/dL Baseline LDL-C: ~133 mg/dL

Amarenco P et al, N Engl J Med 2005;355:549 LDL-C, low-density lipoprotein cholesterol.

slide-36
SLIDE 36

Primary Endpoint: Time to Fatal or Non-Fatal Stroke

Adjusted HR*=0.84 (95% CI 0.71, 0.99), P=.03 16% RR

Years since randomization Fatal or non-fatal stroke (%)

1 2 3 4 5 6 0% 4% 8% 12% 16% Placebo Atorvastatin

* Treatment effect from Cox proportional hazards models with pre-specified adjustment for geographical region, entry event, time since entry event, gender, and baseline age. RR, risk reduction; HR, hazard ratio; CI, confidence interval. Amarenco P et al, N Engl J Med 2005;355:549

slide-37
SLIDE 37

Event Secondary Endpoint: Time to Major Coronary Event

Adjusted HR*=0.65 (95% CI 0.49, 0.87), P=.003

35% RR Years since randomization Major coronary event (%)

1 2 3 4 5 6 0% 2% 4% 6% 8% Placebo Atorvastatin

* Treatment effect from Cox proportional hazards models with pre-specified adjustment for geographical region, entry event, time since entry event, gender, and baseline age. Amarenco P et al, N Engl J Med 2005;355:549 RR, risk reduction; HR, hazard ratio; CI, confidence interval.

slide-38
SLIDE 38

Benefit/Risk of Atorvastatin in Patients With Prior Stroke

0% 4% 8% 12% 16% 20%

Atorvastatin n=2365 Placebo n=2366 Atorvastatin n=2365 Placebo n=2366

Incidence (%) Stroke and Major Coronary Events

Major Coronary Event Ischemic Stroke Hemorrhagic Stroke Unclassified Stroke

Stroke P=.03 11.2% 13.1% 14.1% 17.2% P=.002

Amarenco P et al, N Engl J Med 2005;355:549

slide-39
SLIDE 39

Combined Effect of Lipid and BP Control on Stroke and Major CV Events

Amarenco P et al, Stroke 2009;40:2486

Parameters are LDL-C <70 mg/dL, BP <120/80 mm Hg, Triglycerides <150 mg/dL, and HDL-C >50 mg/dL

slide-40
SLIDE 40

What Did We Learn From These Trials?

ACCORD

lowering BP aggressively in diabetics did not reduce CV events (except stroke) but increased serious adverse effects

SPRINT

lowering BP aggressively in non-diabetics reduced CV events by 25% and mortality by 27%

ASCOT-LLA

lowering LDL-C with atorvastatin in hypertensive patients with other RF’s reduced CV events by 36% and stroke by 27%

HOPE-3

lowering LDL-C with rosuvastatin reduced CV events in patients at intermediate risk; BP lowering only effective in highest BP tercile

SPARCL

lowering LDL-C with atorvastatin reduced cerebrovascular and coronary events in patients with stroke or TIA

slide-41
SLIDE 41
slide-42
SLIDE 42

Group 1 Clinical ASCVD

CHD, stroke, and peripheral arterial disease, all of presumed atherosclerotic origin

Group 3 Diabetes mellitus

+ age of 40–75 years + LDL-C 70–189 mg/dL (~1.8–5 mmol/L)

Group 4 ASCVD risk ≥7.5%

No diabetes + age of 40–75 years + LDL-C 70–189 mg/dL (~1.8–5 mmol/L)

Group 2 LDL-C ≥190 mg/dL (~5 mmol/L)

Who to Treat: US Guidelines

Stone NJ, et al. J Am Coll Cardiol 2013 Nov 7. Epub ahead of print

slide-43
SLIDE 43

JNC8 Summary Recommendations

  • In subjects aged ≥60 years, initiate pharmacologic Rx

to lower BP at SBP ≥150 mm Hg or DBP ≥90 mm Hg and treat to a goal SBP <150 and DBP <90 mm Hg (A)

  • In subjects <60 years, initiate pharmacologic Rx to

lower BP at SBP ≥140 or DBP ≥90 mm Hg and treat to a goal SBP <140 and DBP <90 mm Hg (E)

  • In adults with CKD, initiate pharmacologic Rx to lower

BP at SBP ≥140 or DBP ≥90 mm Hg and treat to goal SBP <140 and goal DBP <90 mm Hg (E)

  • In adults with diabetes, initiate pharmacologic Rx to

lower BP at SBP ≥140 or DBP ≥90 mm Hg and treat to a goal SBP <140 and goal DBP <90 mm Hg (E)

James PA et al, JAMA 2014;311:507

slide-44
SLIDE 44

JNC8 Summary Recommendations (2)

  • In nonblack subjects, including diabetics, initial Rx

should include a thiazide-type diuretic, CCB, ACEI, or ARB (B)

  • In black subjects, including diabetics, initial Rx should

include a thiazide-type diuretic or CCB (B,C)

  • In adults with CKD, initial or add-on Rx should include

an ACEI or ARB to improve kidney outcomes (B)

  • The main objective of BP Rx is to attain and maintain

goal BP. If goal BP is not reached within a month, increase the dose of the initial drug or add a 2nd drug. Continue to assess BP and adjust Rx until goal BP is reached (E)

James PA et al, JAMA 2014;311:507

slide-45
SLIDE 45

James PA et al, JAMA 2014;311:507

2014 Guideline for the Management of High Blood Pressure in Adults: Report From the Eighth Joint National Committee (JNC 8)

slide-46
SLIDE 46

Conclusions

  • Stroke is common worldwide, often devastating,

carries a poor prognosis, and is preventable

  • Hypertension is the #1 risk factor for stroke
  • The SPRINT trial suggests that lowering BP

more aggressively will improve outcomes

  • Following JNC8 and new lipid guidelines will

lead to a reduction in first and recurrent strokes

  • The JNC8 BP goal is <140/90 except for those ≥

60 years old where it is <150/90 mm Hg

  • High-intensity statin therapy is recommended

for all patients with ASCVD, including ischemic stroke