Should SPRINT change our practice? CRT 2017, Washington, DC, USA Should SPRINT change our practice? Thomas F. Lüscher, FESC, FRCP Professor and Chairman Cardiology University Heart Center and Director of Molecular Cardiology, University of Zürich, Switzerland www.tomluescher.ch

Disclosure Statement of Financial Interest I have no disclosures for this talk

Should SPRINT change our practice? Blood pressure, brain and Heart Is the relation between BP and events linear? What is a normal BP? Is there a BP that is too low? How low should BP ideally be?

Should SPRINT change our practice? Blood pressure, brain and Heart Is the relation between BP and events linear? What is a normal BP? Is there a BP that is too low? How low should BP ideally be?

FDR‘s Bood Pressure Chart 1935 - 1945

St. Louis Post-Dispatch April 13, 1945

Should SPRINT change our practice? Blood pressure, brain and Heart Is the relation between BP and events linear? What is a normal BP? Is there a BP that is too low? How low should BP ideally be?

Stroke, Age and Blood Pressure Systolic Blood Pressure Diastolic Blood Pressure Age at risk (years) Age at risk (years) 256 128 64 32 16 8 4 2 1 256 128 64 32 16 8 4 2 1 80–89 - 33% 80–89 - 37% 70–79 - 50% 70–79 - 52% 60–69 - 57% 60–69 - 60% 50–59 - 66% Stroke mortality (floating absolute risk and 95% CI) 50–59 - 62% It has long been known that increased blood pressure is a risk factor for cerebrovascular and cardiovascular (CV) mortality (Stamler J et al. Arch Intern Med 1993). This association is illustrated by the results of the Prospective Studies Collaboration meta-analysis (Lewington S et al. Lancet 2002). This large meta-analysis examined the records of one million adults who, at entry into one of 61 prospective observational studies, did not have pre-existing vascular disease. This slide shows the stroke mortality rate in each decade of age versus usual blood pressure at the start of that decade. The data demonstrate that there is a strong and direct relationship between increased blood pressure and stroke mortality at all ages. This relationship did not have a threshold for a systolic blood pressure (SBP) above 115mmHg or a diastolic blood pressure (DBP) above 75mmHg at any age. Lewington S, Clarke R, Qizilbash N, Peto R, Collins R. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 2002;360:1903–13. Stamler J, Stamler R, Neaton JD. Blood pressure, systolic and diastolic, and cardiovascular risks. US population data. Arch Intern Med 1993;153:598–615. 120 140 160 180 70 80 90 100 110 Usual systolic blood pressure (mmHg) Usual diastolic blood pressure (mmHg) Lewington S, et al. Lancet 2002

Blood Pressure, Stroke and CAD Hirnschlagsterblichkeit (n=1233) KHK Sterblichkeit (n=11,149) 32 16 16 8 Relatives Risiko für tödlichen Hirnschlag 8 4 Relatives Risiko für KHK Mortalität 4 2 2 1 Key Message: The strong positive relationship of SBP with the risks of stroke and CHD suggests that reduction of SBP has the potential to prevent stroke and CHD in both hypertensive and nonhypertensive patients. While much of the original research on the association between BP and CHD focused on DBP, more recent evidence shows that SBP is an even more powerful predictor of disease risk.1 The strong positive relationship of SBP with the risks of stroke and CHD suggests that reduction of SBP has the potential to prevent stroke and CHD in both hypertensive and nonhypertensive patients. The relative risks of death from stroke and CHD among men screened for the Multiple Risk Factor Intervention Trial (MRFIT) are shown.1 The relative risk of death from stroke was about 7 times greater in men with baseline SBP 151 mm Hg than in men with baseline SBP <112 mm Hg.1 Similarly, the relative risk of death from CHD for those with the higher SBP was about 4 times greater than for those with the lower SBP. The risks of stroke and CHD continue to decline as BP is lowered. The absence of any lower BP limit (SBP <120 mm Hg) suggests that larger reductions in BP are likely to produce greater reductions in risk. Reference 1. Neaton JD, Kuller L, Stamler J, et al. Impact of systolic and diastolic blood pressure on cardiovascular mortality. In: Laragh JH, Brenner BM, eds. Hypertension: Pathophysiology, Diagnosis, and Management. 2 ed. New York: Raven Press, 1995:127-144. <120 125 135 148 168 120 125 135 148 168 Approximativer mittlerer systolischer BD (mm Hg) Multiple Risk Factor Intervention Trial (MRFIT); n=347,978 men Neaton et al. In: Laragh et al (eds). Hypertension: Pathophysiology, Diagnosis, and Management. 2 ed. NY: Raven, 1995:127

Risk Factors and CV Events: Life Time Risk Berry et al. NEJM: 2012;366:321

Effect of Long-Term Antihypertensive Treatment on Mortality: The Framingham-Study 1950-1990 Männer Frauen Frauen + Männer 50 -23% 40 For optimal blood pressure control 2-3 antihypertensive drugs are required -24% 30 -25% Mortalitä (% über 10 Jahre) 20 -53% -54% 10 -55% Mortality Total Herz- Kreislauf Total Herz- Kreislauf Total Herz- Kreislauf Ohne Behandlung Mit Behandlung Circulation 1996

Should SPRINT change our practice? Blood pressure, brain and Heart Is the relation between BP and events linear? What is a normal BP? Is there a BP that is too low? How low should BP ideally be?

What is a normal blood pressure? Yanomani Indians Yanomani Indios: 95/61 mmHg

What is a normal blood pressure? Kuna Indians

Should SPRINT change our practice? Blood pressure, brain and Heart Is the relation between BP and events linear? What is a normal BP? Is there a BP that is too low? How low should BP ideally be?

Blood pressure lowering and clinical events Ettehad et al. Lancet 2016

Should SPRINT change our practice? Blood pressure, brain and Heart Is the relation between BP and events linear? What is a normal BP? Is there a BP that is too low? How low should BP ideally be?

Blood pressure lowering and clinical events The SPRINT Research Group. NEJM 2015

Blood pressure lowering and clinical events The SPRINT Research Group. NEJM 2015

Blood Pressure and Clinical Events Baseline Blood Pressure Subgroups of HOPE-3 Primary Outcomes: death, MI, stroke plus resuscitated SCD, CHF, revascularization

Blood Pressure and Clinical Events SPRINT versus HOPE-3 9361 hypertensives Increased CV risk, no diabe-tes Unattended BP measure-ment Baseline sBP 139.7 mmHg sBP difference 14.8 mmHg Final sBP 121.4 mmHg Event rate 1.65%/year ve. 2.19%/year (5.94% vs. 7.88%) Follow-up 3.6 years 12‘705 hypertensives No CV disease, intermedi-ate CV risk Standard BP measure-ment Baseline sBP 138.2 mmHg sBP difference 10.0 mmHg Final sBP 128.2 mmHg Events 260 (4.1%) vs 279 (4.4%) Follow-up 5.6 years

Blood Pressure Targets in Hypertensive Patients BP and MACE are linearly related In healthy individuals normal or optimal BP is 100/70mmHg There might be a J-curve in patients with a individual sweet spot sBP lowering beyond 140mmHg is protec-tive in those with higher base-line BP Hypotension and renal dysfunction must be watched when BP is lowered to 120-130 mmHg (this ma ba an opportunity for RNA) Guidelines have to rethink and individua-lize sBP target levels