Goals_and_Rationale_ASH_Presentation_2012
- 1. Systolic Blood Pressure Intervention Trial Goals and Rationale American Society of Hypertension May 20, 2012 Karen C. Johnson, MD, MPH University of Tennessee Health Science Center
- 2. American Society of Hypertension, Inc. (ASH) Disclosure of Relationships Over the past 12 months Karen C. Johnson MD, MPH has received grant funds from the National Heart Lung and Blood Institute (NHLBI) and the National Institute of Diabetes, Digestive, and Kidney Disease (NIDDK) of National Institutes of Health (NIH)
- 3. Systolic Blood Pressure Intervention Trial • SPRINT is a randomi zed controlled clinical trial examining the effect of a high blood pressure treatment strategy aimed at reducing systolic blood pressure (SBP) to a lower goal than is currently recommended.
- 4. SPRINT Important Goals SPRINT will test whether a treatment strategy aimed at reducing systolic blood pressure to: • lower goal (SBP < 120 mm Hg) compared with • currently recommended (SBP < 140 mm Hg) will reduce the occurrence of cardiovascular disease (CVD). N = 9250
- 5. SPRINT Primary Outcome • Composite of –MI – Stroke –Heart failure – Acute coronary syndrome – Cardiovascular death The primary hypothesis is that CVD event rates will be lower in the intensive intervention arm.
- 6. SPRINT Other Outcomes • Renal outcomes – For Chronic Kidney Disease (CKD), composite of: • ESRD or 50% decline in eGFR – For non-CKD, progression to CKD: • ESRD or 30% decrease in eGFR to a value of < 60 mL/min/1.73m2
- 7. SPRINT Other Outcomes SPRINT MIND will test whether the lower SBP goal influences the occurrence of dementia, change in cognition, and change in brain structure (on MRI).
- 8. Major Inclusion Criteria • At least 50 years old • Systolic blood pressure – SBP: 130 – 180 mm Hg on 0 or 1 medication – SBP: 130 – 170 mm Hg on up to 2 medications – SBP: 130 – 160 mm Hg on up to 3 medications – SBP: 130 – 150 mm Hg on up to 4 medications • Risk (one or more of the following) – Presence of clinical or subclinical CVD (not stroke) – Chronic Kidney Disease (CKD), defined as eGFR 20 – 59 ml/min/1.73m2 – Framingham Risk Score for 10-year CVD risk ≥ 15% – Not needed if eligible based on preexisting CVD or CKD – Age ≥ 75 years
- 9. Major Exclusion Criteria • Stroke • Diabetes • Congestive heart failure (symptoms or EF < 35%) • Proteinuria >1g/d • CKD with eGFR < 20 mL/min/1.73m2 (MDRD) • Adherence flags
- 10. SPRINT Intensive Intervention • Blood pressure medications are added and/or titrated at each study visit to achieve SBP <120 mm Hg • Intervention goal is to create a minimum mean difference between randomized groups of at least 10 mm Hg
- 11. SPRINT Standard Intervention • Intensify therapy if: – SBP ≥160 mm Hg @ 1 visit – ≥140 mm Hg @ 2 consecutive visits • Down-titration if: – SBP <130 mm Hg @ 1 visit – <135 mm Hg @ 2 consecutive visits
- 12. Medication Classes Provided by SPRINT • Angiotensin converting enzyme (ACE)-inhibitors • Angiotensin receptor blockers (ARBs) • Direct vasodilators • Thiazide-type diuretics • Loop diuretics • Potassium-sparing diuretics • Beta-blockers • Sustained-release calcium channel blockers (CCBs) • Alpha1-receptor blockers • Sympatholytics
- 13. Why is NIH Conducting SPRINT? • High blood pressure is one of the most common conditions among middle-aged and older adults, and is a leading risk factor for stroke, heart disease, chronic kidney disease, and other conditions. • Previous trials demonstrate effectiveness of treating SBP to about 140 mm Hg. • Observational studies suggest benefits of SBP lowering may extend to levels below 120 mm Hg. • SPRINT will provide critical evidence regarding feasibility and benefits and potential risks of more intensive BP control.
- 14. Why is NIH Conducting SPRINT? • High blood pressure is one of the most common conditions among middle-aged and older adults, and is a leading risk factor for stroke, heart disease, chronic kidney disease, and other conditions. • Previous trials demonstrate effectiveness of treating SBP to about 140 mm Hg. • Observational studies suggest benefits of SBP lowering may extend to levels below 120 mm Hg. • SPRINT will provide critical evidence regarding feasibility and benefits and potential risks of more intensive BP control.
- 15. Why is NIH Conducting SPRINT? • High blood pressure is one of the most common conditions among middle-aged and older adults, and is a leading risk factor for stroke, heart disease, chronic kidney disease, and other conditions. • Previous trials demonstrate effectiveness of treating SBP to about 140 mm Hg but treating to this goal is challenging • Observational studies suggest benefits of SBP lowering may extend to levels below 120 mm Hg. • SPRINT will provide critical evidence regarding feasibility and benefits and potential risks of more intensive BP control.
- 16. BP Lowering Treatment is Effective but Challenging Average Percent Reduction in previous trials targeting higher SBP goals – Stroke incidence: ~35-40% – Myocardial Infarction: ~20-25% – Heart Failure: ~50% Benefits relate to extent of SBP lowering Multiple medications often needed for control but significant side-effects may occur Lancet. 2000;356:1955-64.
- 17. Major Cardiovascular Events Systolic blood pressure difference between randomised groups (mmHg) 1.50 1.25 1.00 0.75 0.50 R e la tive r isk o f m a jo r C 0.25 -10 -8 -6 -4 -2 0 2 4 Lancet 2003; 362: 1527–35.
- 18. 18 Combination Therapy Is Often Needed to Achieve Target SBP Goals 1 2 3 4 BP Agents (number) Trial (SBP Achieved) UKPDS (144 mm Hg) RENAAL (141 mm Hg) ALLHAT (138 mm Hg) IDNT (138 mm Hg) HOT (138 mm Hg) INVEST (133 mm Hg) ABCD (132 mm Hg) MDRD (132 mm Hg) AASK (128 mm Hg) Am J Kidney Dis. 2000;36:646-661.
- 19. Why is NIH Conducting SPRINT? • High blood pressure is one of the most common conditions among middle-aged and older adults, and is a leading risk factor for stroke, heart disease, chronic kidney disease, and other conditions. • Previous trials demonstrate effectiveness of treating SBP to about 140 mm Hg. • Observational studies suggest benefits of SBP lowering may extend to levels below 120 mm Hg. • SPRINT will provide critical evidence regarding feasibility and benefits and potential risks of more intensive BP control.
- 20. IIsscchheemmiicc HHeeaarrtt DDiisseeaassee MMoorrttaalliittyy RRaattee IIHHDD mmoorrttaalliittyy ((aabbssoolluuttee rriisskk aanndd 9955%% CCII)) iinn EEaacchh DDeeccaaddee ooff AAggee 112200 114400 116600 118800 UUssuuaall SSBBPP ((mmmm HHgg)) LLaanncceett.. 22000022;;336600::11990033--11991133.. 225566 112288 6644 3322 1166 88 44 22 11 SSBBPP AAggee aatt rriisskk:: 8800--8899 yy 7700--7799 yy 6600--6699 yy 5500--5599 yy 4400--4499 yy 7700 8800 9900 110000 111100 UUssuuaall DDBBPP ((mmmm HHgg)) 225566 112288 6644 3322 1166 88 44 22 11 DDBBPP
- 21. Meta-Analysis: Treating to BP Goals Lower Than 140/90 mmHg Does Not Reduce Mortality or Morbidity OUTCOMES RELATIVE RISK 95 % CI Total mortality 0.92 0.86-1.15 MI 0.90 0.74-1.09 Stroke 0.99 0.79-1.25 CHF 0.88 0.59-1.32 Major CV events 0.94 0.83-1.07 End-Stage renal disease 1.01 0.81-1.27 (ESRD) n= 22,089 Arguedas JA, et al. Cochrane Database Syst. Rev. 2009:CD004349.
- 22. POTENTIAL COSTS / RISKS OF LOWER THAN INDICATED BP TARGETS • Increased cost of potentially unnecessary medications • Increased risk of medication side effects • Increased clinic visits if BP not at lower goal • Increased monitoring required • More complicated regimen that may jeopardize adherence to evidence-based treatment of other risk factors • Potential increased risk of lower BP goals
- 23. Why is NIH Conducting SPRINT? • High blood pressure is one of the most common conditions among middle-aged and older adults, and is a leading risk factor for stroke, heart disease, chronic kidney disease, and other conditions. • Previous trials demonstrate effectiveness of treating SBP to about 140 mm Hg. • Observational studies suggest benefits of SBP lowering may extend to levels below 120 mm Hg. • SPRINT will provide critical evidence regarding feasibility of lowering blood pressure to lower goals and benefits and potential risks of more intensive BP control.
- 24. Clinical Trial Evidence of Lower SBP Goals is Unclear • ACCORD – BP question: Does a strategy targeting systolic blood pressure (SBP) <120 mm Hg reduce CVD events compared to a strategy targeting SBP <140 mm Hg in 4,700 participants with type 2 diabetes at high risk for CVD events?
- 25. ACCORD Results are Mixed Outcome Intensive Events (%/yr) Standard Events (%/yr) HR (95% CI) P CVD (Primary) 208 (1.87) 237 (2.09) 0.88 (0.73-1.06) 0.20 Cardiovascular Deaths 60 (0.52) 58 (0.49) 1.06 (0.74-1.52) 0.74 Total Stroke 36 (0.32) 62 (0.53) 0.59 (0.39-0.89) 0.01
- 26. ACCORD Adverse Events Adverse Events Intensive N (%) Standard N (%) P value Serious AE 77 (3.3) 30 (1.3) <0.0001 Hypotension 17 (0.7) 1 (0.04) <0.0001 Syncope 12 (0.5) 5 (0.2) 0.10 Bradycardia or Arrhythmia 12 (0.5) 3 (0.1) 0.02 Hyperkalemia 9 (0.4) 1 (0.04) 0.01 Renal Failure 5 (0.2) 1 (0.04) 0.12 eGFR ever <30 mL/min/1.73m2 99 (4.2) 52 (2.2) <0.001 Any Dialysis or ESRD 59 (2.5) 58 (2.4) 0.93 Dizziness on Standing† 217 (44) 188 (40) 0.36 N Engl J Med. 2010;362:1575-85
- 27. Will the SPRINT Intervention produce an adequate difference in SBP?
- 28. ACCORD Systolic Pressures Average after 1st year: 133.5 Standard vs. 119.3 Intensive, Delta = 14.2 Mean # Meds Intensive: 3.2 3.4 3.5 3.4 Standard: 1.9 2.1 2.2 2.3 N Engl J Med. 2010;362:1575-85
- 29. Equipoise • The SPRINT hypothesis has never been tested in a randomized clinical trial setting in participants without diabetes or stroke • Epidemiologic data is suggestive of benefit • The ACCORD results, though negative overall, did not rule out substantial benefit, however there may be increased risk of certain adverse events with lower blood pressures
- 30. Summary • High blood pressure is a leading cause of death and disability in the US and world-wide. • Current treatment approaches are effective, but challenging, and may leave residual risk due to hypertension at levels of 140 mm Hg. • More intensive control of SBP might prevent strokes, CVD, dementia, and progression of chronic kidney disease. • SPRINT will provide critical evidence on these important questions.
- 31. For more information • Visit www.SPRINTTrial.org
- 32. SPRINT Symposia Speakers • SPRINT Design – Walter Ambrosius, PhD • SPRINT and Chronic Kidney Disease – Alfred Cheung, MD • SPRINT Mind – Jeff Williamson, MD
- 33. Take Home Message Evidence from previous studies suggests that the benefits to treating to a lower systolic blood pressure goal outweigh the risk but this has not been tested in a clinical trial setting in persons at high risk for CVD. SPRINT is designed to test this lower systolic blood pressure goal of < 120 mm Hg.
- 34. American Society of Hypertension, Inc. (ASH) Disclosure of Relationships Over the past 12 months Karen C. Johnson MD, MPH has received grant funds from the National Heart Lung and Blood Institute (NHLBI) and the National Institute of Diabetes, Digestive, and Kidney Disease (NIDDK) of National Institutes of Health (NIH)
- 35. Questions
Editor's Notes
- #19: Points of Emphasis / Key Messages This figure shows the number of antihypertensive medications required by patients in different clinical trials to achieve target SBP goals. The clinical trials are those that randomly assigned patients to different levels of BP reduction. On average, 3.2 different antihypertensive medications taken daily are required to achieve the recommended BP goal of &lt;130/80 mm Hg in patients with type 2 diabetes and &lt;130/85 mm Hg in patients with renal insufficiency. The achieved SBPs shown are for the low-pressure groups in these trials. This figure used data from ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial), MDRD (Modification of Dietary Protein in Renal Disease Trial), INVEST (International Verapamil SR-Trandolapril Study), AASK (African-American Study of Kidney Disease and Hypertension), UKPDS (United Kingdom Prospective Diabetes Study), RENAAL (Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan), ABCD (Appropriate Blood Pressure Control in Diabetes), HOT (Hypertension Optimal Treatment), and IDNT (Irbesartan in Diabetic Nephropathy Trial). Reference Updated from Bakris GL, Williams M, Dworkin L et al. Preserving renal function in adults with hypertension and diabetes: a consensus approach. National Kidney Foundation Hypertension and Diabetes Executive Committees Working Group. Am J Kidney Dis. 2000;36:646-661.
- #22: In 2009, a Cochrane systematic review of the evidence concluded that the evidence did not support a selecting a goal BP of &lt; 140/90