Hypertension and the SPRINT Trial: Is Lower Better

Hypertension and the SPRINT Trial: Is Lower Better 8th Annual Orange County Symposium on Cardiovascular Disease Prevention Saturday, October 8, 2016 Keith C. Norris, MD, PhD, FASN Professor of Medicine, Geffen School of Medicine, UCLA Co-Director, UCLA-CTSI Community Engagement and Research Program PI, NIH Diversity Program Consortium Coordination and Evaluation Center at UCLA

Potential Conflicts of Interest* # NIH 1 AbbVie 4 * Activities within the last year Grants: 1 Honoraria: 2 Consulting: 3 Advisory Boards: 4 Speaker Bureau: 5 Financial Ownership: 6 # None related to this talk

Patients in the SPRINT who were assigned to reach a SBP goal below 120 mmhg vs 140mmHg (and 150mmHg for people over 60) had their risk of heart attacks, heart failure and strokes reduced by a third and their risk of death reduced by nearly a quarter. Terminated early due to results of interim analyses NY Times - September 11, 2015

Hypertension Hypertension: key modifiable risk factor for MI, stroke, CHF In 2013 >400,000 deaths in US associated with HTN ~1/3 of US adults have high BP 80 Million in US and 1 Billion globally In 15 years projected to increase to >40% Many patients have not reached BP goals NHANES 2009-2012 shows improvement, but only 51% in US had BP controlled (SBP <140 mm Hg)

Cardiovascular Mortality Risk HTN: graded increased risk of death from stroke & CVD 9 8 7 6 5 4 3 2 1 0 2x 4x 120/80 140/90 160/100 180/110 Systolic BP / Diastolic BP (mmhg) CV mortality risk doubles for every 20 mmhg increase in SBP 8x Chobanian et al. Hypertension 2003;42:1206-1252; 2 Lancet 2002;360:1903-1913

Awareness, Treatment, and Control of High BP Extent of awareness, treatment, and control of high blood pressure by race/ethnicity (National Health and Nutrition Examination Survey: 2007 2012). Hypertension is defined as SBP 140 mm Hg or DBP 90 mm Hg, or if the subject said yes to taking antihypertensive medication. NH indicates non- Hispanic. Source: National Center for Health Statistics and National Heart, Lung, and Blood Institute.

2014 Evidence-Based Guideline for the Management of High Blood Pressure in Adults: Report From the Panel Members Appointed to the Eighth Joint National Committee (JNC 8) JAMA. Published online December 18, 2013. doi:10.1001/jama.2013.284427

Important to Note. Not endorsed by NHLBI/NIH, ACC/AHA, or any other Professional Society

In patients > 60 y goal SBP <150/DBP < 90 mmhg. Strong Recommendation Implications: 5.8 million US no longer classified as having HTN RX &13.5 million under treatment and not previously at goal but now considered at goal Impacts nearly 20 million adults (most high risk for CV and related events) JAMA. Published online December 18, 2013. doi:10.1001/jama.2013.284427 Navar-Boggan AM, et al. Proportion of US adults potentially affected by the 2014 hypertension guideline. JAMA. 2014 Apr 9;311(14):1424-9

JNC 8 Minority View There was almost unanimous agreement on most recommendations However, a minority of the panel disagreed with the recommendation to increase the target SBP from 140 to 150 mm Hg in persons aged >=60 yrs without DM or CKD. This has Major Clinical & Public Health Implications

JNC 8 Minority View The higher SBP goal would apply to some of the groups at highest CV risk, such as African Americans, those with multiple CVD risk factors other than DM or CKD, and those with clinical CVD. There is insufficient and inconsistent evidence supporting increasing the SBP target from 140 to 150 mm Hg in persons aged 60 years or older Wright JT Jr., et al. Evidence Supporting a Systolic Blood Pressure Goal of Less Than 150 mm Hg in Patients Aged 60 Years or Older: The Minority View. Ann Intern Med 160(7): 499-503.

JNC 8 Minority View Absence of definitive evidence defining the optimum SBP target Observational studies and RCT data that the panel did not review provided more support for the SBP goal of less than 140 mmhg, especially in high-risk individuals. Wright JT Jr., et al. Evidence Supporting a Systolic Blood Pressure Goal of Less Than 150 mm Hg in Patients Aged 60 Years or Older: The Minority View. Ann Intern Med 160(7): 499-503.

Among patients at high risk for CV events (including CKD) but without diabetes, does targeting a systolic BP < 120 mmhg, vs. < 140 mmhg, result in lower rates of fatal and nonfatal major CV events and death from any cause. A Randomized Trial of Intensive versus Standard Blood-Pressure Control: The SPRINT Research Group. N Engl J Med 2015. DOI: 10.1056/NEJMoa1511939 14

SPRINT: What and Why? SPRINT: Systolic Blood Pressure Intervention Trial was designed to provide critical evidence regarding feasibility and potential benefits/risks of more intensive BP control in persons with preexisting CVD or at high risk for CVD, including the elderly and a sizeable fraction of patients with mild to moderate CKD Ambrosius, W. T., et al. (2014). "The design and rationale of a multicenter clinical trial comparing two strategies for control of systolic blood pressure: the Systolic Blood Pressure Intervention Trial (SPRINT)." Clin Trials 11(5): 532-546.

Does More Intensive BP Control Improve CV Risk and Survival? 9361 adults 50 years old with SBP 130-180 mmhg at entry (treated or untreated) No heart failure or LVEF<35%, prior stroke, diabetes, PKD, proteinuria >1 g/d, egfr <20 ml/min/1.73 m 2 1 additional CVD risk factor (age 75 years, clinical/subclinical CVD, egfr 20-60 ml/min/1.73 m 2, Framingham 10-year CVD Risk Score 15%) Pre-specified subgroups: age, gender, race, CKD status, CVD status, baseline tertile of SBP

Does More Intensive BP Control Improve CV Risk and Survival? Target SBP <140 vs. <120 mmhg Primary outcome CVD composite of acute myocardial infarction, non-mi ACS, stroke, HF, CVD death Secondary outcomes All-cause death, combined CVD composite + death, renal events (incident or progressive CKD) Safety events

Baseline Characteristics By Treatment Group >90% already on treatment at study entry The SPRINT Research Group. N Engl J Med 2015;373:2103-2116

Separation of Systolic Blood Pressure Level in the Two Treatment Groups in SPRINT Year 1 Mean SBP 136.2 mmhg Average Study SBP 134.6 mm Hg Mean SBP 121.4 mmhg Average Study SBP 121.5 mm Hg A Randomized Trial of Intensive versus Standard Blood-Pressure Control: The SPRINT Research Group. N Engl J Med 2015. DOI: 10.1056/NEJMoa1511939

Primary Outcome Composite of MI, acute coronary syndrome, stroke, CHF, or death from CV causes 25% reduction in primary outcome! SBP < 120 vs. <140 mmhg led to ~25% reduction in Composite CV outcome A Randomized Trial of Intensive versus Standard Blood-Pressure Control: The SPRINT Research Group. N Engl J Med 2015. DOI: 10.1056/NEJMoa1511939

Challenge to Achieve lower BP Goals UKPDS (144 mm Hg) RENAAL (141 mm Hg) ALLHAT (138 mm Hg) IDNT HOT (138 mm Hg) (138 mm Hg) INVEST (133 mm Hg) ABCD MDRD AASK (132 mm Hg) (132 mm Hg) (128 mm Hg) Sprint (<120mm Hg) 1.8 for < 134; 2.8 for < 121 mmhg Trial (SBP Achieved) 1 2 3 4 # BP Agents Adapted from Bakris et al. Am J Kidney Dis. 2000;36:646 21

Primary Outcome Improved in Patient Subgroups A Randomized Trial of Intensive versus Standard Blood-Pressure Control: The SPRINT Research Group. N Engl J Med 2015. DOI: 10.1056/NEJMoa1511939

Among ambulatory adults >75 years, treating to an SBP target < 120mmHg compared with < 140mmHg resulted in significantly lower rates of fatal and nonfatal major CV events and death from any cause, with an acceptable safety profile SBP < 120 vs. <140 mmhg led to ~34% reduction in Composite CV outcome Williamson, J. D., et al. (2016). "Intensive vs Standard Blood Pressure Control and Cardiovascular Disease Outcomes in Adults Aged >/=75 Years: A Randomized Clinical Trial." JAMA 315(24): 2673-2682.

Primary outcome includes nonfatal MI, acute coronary syndrome, nonfatal stroke, nonfatal acute decompensated CHF, and death from CV causes Pooled Primary Outcome & All-Cause Mortality significant for less fit and frail Williamson, J. D., et al. (2016). "Intensive vs Standard Blood Pressure Control and Cardiovascular Disease Outcomes in Adults Aged >/=75 Years: A Randomized Clinical Trial." JAMA 315(24): 2673-2682.

Utilization of BP meds for SPRINT participants > 75 years > 50% of Intensive treated group required 3 or more medications Williamson, J. D., et al. (2016). "Intensive vs Standard Blood Pressure Control and Cardiovascular Disease Outcomes in Adults Aged >/=75 Years: A Randomized Clinical Trial." JAMA 315(24): 2673-2682. 25

Serious adverse events did not differ by treatment group in SPRINT participants > 75 years Even among frail older participants no difference in SAEs between groups Williamson, J. D., et al. (2016). "Intensive vs Standard Blood Pressure Control and Cardiovascular Disease Outcomes in Adults Aged >/=75 Years: A Randomized Clinical Trial." JAMA 315(24): 2673-2682. 26

SPRINT Summary Among patients at high risk for cardiovascular events but without diabetes, targeting a SBP of less than 120 mm Hg, as compared with less than 140 mm Hg, resulted in lower rates of fatal and nonfatal major cardiovascular events and death from any cause Patient > 75 yrs &/or with CKD at baseline also did better No overall difference in serious adverse events (SAEs) between treatment groups SAEs associated with hypotension, syncope, electrolyte abnormalities, and reports of acute kidney injury or acute renal failure more common in Intensive Group Overall, benefits of more intensive BP lowering exceeded the potential for harm

Recommendations - Until new national guidelines become available: While just one study SPRINT results suggest a more prudent approach is not to relax the BP target to <150 mmhg in any subgroups (as suggested by JNC 8 ) but to continue with the more longstanding recommendation of a BP target of <140 mmhg Treatment of hypertension should target SBP <140 mm Hg

Important Considerations in Measuring BP n Med. 2015;163:778-786. Office measurement of blood pressure is done with a manual or automated sphygmomanometer. Attention to proper BP measurement protocol is vital. Proper protocol is to use the mean of 2 measurements taken while the patient is seated, allow for 5 min between entry into the office and blood pressure measurement, use an appropriately sized arm cuff, and place the patient s arm at the level of the right atrium. Multiple measurements over time have better positive predictive value than a single measurement. Ambulatory and home blood pressure monitoring can be used to confirm a diagnosis of hypertension after initial screening.

Conclusions Nearly 80 million US adults have hypertension that is not adequately controlled - better BP control may prevent more CV & stroke events SPRINT results suggest treating to SBP target of <120 mm Hg is effective and safe - May influence future BP guidelines for high risk patients While just one study, at a minimum it suggests a more prudent approach is not to relax the SBP target to <150 mmhg ( JNC 8 ) but to continue with the more longstanding recommendation of a SBP target of <140 mmhg

Break from what you know, and you will know much more. Ip Man