Masked Hypertension. Why Should We Care? Dr. Peter J. Lin Director Primary Care Initiatives - Canadian Heart Research Centre

Masked Hypertension Why Should We Care? Dr. Peter J. Lin Director Primary Care Initiatives - Canadian Heart Research Centre

PRESENTER DISCLOSURE Faculty: Dr. Peter Lin Relationships with commercial interests: Grants/Research Support: None Speakers Bureau/Honoraria: Astrazeneca, BMS, Takeda, Purdue Boeringher Ingelheim, Bayer, Eli Lilly, Amgen, Janssen, Forest Laboratories, J&J, Merck, Novartis, Pfizer, Servier, Sanofi, Abbott, Mylan Consulting Fees: Astrazeneca, Boeringher Ingelheim, Bayer, Eli Lilly, Merck, Sanofi, Amgen, MdBriefCase Other: None

MITIGATING POTENTIAL BIAS Potential bias was mitigated through the use of current Hypertension Canada guidelines as the primary literature source for recommendations in the slide deck.

1931 - Key Opinion Leaders : Please do not measure the blood pressure because you might want to treat it.

Cardiovascular Mortality Risk Doubles with each 20/10 mmhg Increase in Systolic/Diastolic BP* Cardiovascular mortality risk 8 6 8X risk 4 2 0 1X risk 2X risk 4X risk 115/75 135/85 155/95 175/105 Systolic BP/Diastolic BP (mmhg) *Individuals aged 40 69 years Lewington et al. Lancet 2002;360:1903 13

SBP Reduction and CV Mortality 1.50 MIDAS/NICS/VHAS UKPDS C vs A P = 0.003 Odds Ratio 1.25 1.00 0.75 0.50 0.25 NORDIL STOP ACEIs STOP CCBs CAPPP INSIGHT HOT L vs H HOT M vs H MRC1 MRC2 HOPE STONE SHEP HEP Syst-Eur UKPDS L vs H Syst-China PART 2/SCAT ATMH STOP-1 EWPHE RCT70-80 -5 Staessen JA, et al. Lancet. 2001;358:1305-15. 0 5 10 15 20 25 Difference in SBP (mm Hg)

SBP Reduction and CV Mortality 1.50 P = 0.003 Odds Ratio 1.25 1.00 0.75 0.50 0.25-5 Staessen JA, et al. Lancet. 2001;358:1305-15. 0 5 10 15 20 25 Difference in SBP (mm Hg)

Measuring Blood Pressure 140 Home or Daytime ABPM SBP mmhg 135 135 140 Office SBP mmhg 2009 Canadian Hypertension Education Program Recommendations Derived from Pickering et al. Hypertension 2002: 40: 795-796. 10

Measuring Blood Pressure 140 Home or Daytime ABPM SBP mmhg 135 True Normotensive True hypertensive White Coat HTN 135 140 Office SBP mmhg 2009 Canadian Hypertension Education Program Recommendations Derived from Pickering et al. Hypertension 2002: 40: 795-796. 11

Stroke: Normotensive vs WCH vs Hypertensive Verdecchia P et al. Hypertension 2005;45:203-208

Measuring Blood Pressure 140 Home or Daytime ABPM SBP mmhg 135 Masked HTN True Normotensive True hypertensive White Coat HTN 135 140 Office SBP mmhg 2009 Canadian Hypertension Education Program Recommendations Derived from Pickering et al. Hypertension 2002: 40: 795-796. 14

Measuring Blood Pressure 140 Home or Daytime ABPM SBP mmhg 135 Masked HTN True Normotensive True hypertensive White Coat HTN 135 140 150 Office SBP mmhg 2009 Canadian Hypertension Education Program Recommendations Derived from Pickering et al. Hypertension 2002: 40: 795-796. 15

Measuring Blood Pressure 140 Home or Daytime ABPM SBP mmhg 135 Masked HTN True Normotensive 130 140 True hypertensive White Coat HTN 135 Office SBP mmhg 2009 Canadian Hypertension Education Program Recommendations Derived from Pickering et al. Hypertension 2002: 40: 795-796. 16

Prevalence of Masked Hypertension Overall, the prevalence of masked hypertension is: about 10% in the general population about 30% in treated hypertensive patients higher in patients with diabetes and chronic kidney disease patients 18

ACCOMPLISH trial : ACEi CCB vs ACEi HCTZ ACEi + HCTZ ACEi + CCB Absolute risk reduction in primary outcome events (i.e., CV death, nonfatal MI, nonfatal stroke, hospitalization for angina, resuscitation after sudden cardiac arrest, coronary revascularization): 2.2% Absolute risk reduction in deaths from CV causes: 0.4% 1. Jamerson K, et al. N Engl J Med. 2008;359(23):2417-2428. 20

Non-persistence with AntihypertensiveTherapy Leads to Increased Risk of Myocardial Infarction or Stroke 2 1 Acute MI 1.15 (1.00 1.33) Stroke 1.28 (1.15 1.45) 0 Risk* of MI or stroke associated with nonpersistent use of antihypertensive therapy relative to 2-year persistent use *Adjusted for gender, age, prescriber, initial antihypertensive, number of antihypertensives and other CV drugs 21 Values in parentheses are the 95% confidence intervals Breekveldt-Postma NS, et al. 2008

Poor Compliance is Linked to Hospitalization Risk All-cause hospitalization risk (%) 50 * 44 * 39 * 40 36 30 * 30 27 20 10 0 1 19 20 39 40 59 60 79 80 100 (n=350) (n=344) (n=562) (n=921) (n=5804) Level of compliance (%) The probability of one or more hospitalizations during a 12-month period *p<0.05 vs 80 100% compliant group 22 Sokol MC, et al. 2005

ACCORD Blood Pressure 135 mmhg 120 mmhg The ACCORD Study Group. N Engl J Med 2010;10.1056/NEJMoa1001286

The ACCORD Study Group. N Engl J Med 2010;10.1056/NEJMoa1001286

mmhg 200 BP reductions achieved in recent trials HOPE PROGRESS CAPPP INSIGHT 190 NORDIL 180 170 SBP HOT STONE STOP-2 160 ALLHAT 1 LIFE 150 ALLHAT 2 ANBP2 140 INVEST 130 SCOPE ASCOT VALUE Mancia and Grassi J.Hypertension 2002 updated

Recommendations: Hypertension/ Blood Pressure Control (2) Systolic Targets: People with diabetes and hypertension should be treated to a systolic blood pressure goal of <140 mmhg. A American Diabetes Association Standards of Medical Care in Diabetes. Cardiovascular disease and risk management. Diabetes Care 2017; 40 (Suppl. 1): S75-S87

Stroke benefit The ACCORD Study Group. N Engl J Med 2010;10.1056/NEJMoa1001286

Recommendations: Hypertension/ Blood Pressure Control (2) Systolic Targets: People with diabetes and hypertension should be treated to a systolic blood pressure goal of <140 mmhg. A Lower systolic targets, such as <130 mmhg, may be appropriate for certain individuals at high risk of CVD, if they can be achieved without undue treatment burden. C American Diabetes Association Standards of Medical Care in Diabetes. Cardiovascular disease and risk management. Diabetes Care 2017; 40 (Suppl. 1): S75-S87

mmhg 200 BP reductions achieved in recent trials HOPE PROGRESS CAPPP INSIGHT mmhg 120 190 NORDIL HOT 110 180 170 SBP STONE STOP-2 100 DBP ALLHAT 1 160 LIFE 90 ALLHAT 2 150 ANBP2 80 140 INVEST 130 SCOPE ASCOT VALUE 70 Mancia and Grassi J.Hypertension 2002 updated

BP Control Reduces CV Events: HOT Trial Diabetes Subgroup 30 25 24.4 P<0.005 Goal of therapy: target diastolic BP MI, stroke, CV mortality/1000 pt-y 20 15 10 18.8 11.9 < 80 mmhg 90 mm Hg (n=501) 85 mm Hg (n=501) 80 mm Hg (n=499) 5 0 < 85 mmhg Hansson et al. Lancet. 1998;351:1755.

Blood Pressure Lowering Therapy Evidence: Effect of Intensive Blood Pressure Control Hypertension Optimal Treatment (HOT) Study 18,790 patients with a baseline diastolic BP of 100-115 mm Hg randomized to a target diastolic BP of <90 mm Hg, <85 mm Hg, or <80 mm Hg Major CV events per 1000 patient-years Patients with Diabetes Patients without Diabetes Diastolic BP goal Diastolic BP goal More intensive blood pressure control provides greater benefit in patients with diabetes BP=Blood pressure, CV=Cardiovascular Source: Hansson L et al. Lancet 1998;351:1755-1762

Recommendations: Hypertension/ Blood Pressure Control (3) Diastolic Targets: Patients with diabetes should be treated to a diastolic blood pressure <90 mmhg. A Lower diastolic targets, such as <80 mmhg, may be appropriate for certain individuals at high risk for CVD if they can be achieved without undue treatment burden. C American Diabetes Association Standards of Medical Care in Diabetes. Cardiovascular disease and risk management. Diabetes Care 2017; 40 (Suppl. 1): S75-S87

Pre SPRINT Targets Population SBP DBP High Risk (SPRINT) 120 NA Diabetes < 130 < 80 All others* < 140 < 90 *Target BP with Automated Office Blood Pressure (AOBP) threshold < 135/85 Leung AA. 2016 CHEP Guidelines. Hypertension Canada s 2016 Canadian Hypertension Education Program Guidelines for Blood Pressure Measurement, Diagnosis, Assessment of Risk, Prevention, and Treatment of Hypertension. Can Cardio Soc 2016;32:569-588.

SPRINT Trial ACCORD Trial Patients (n=9361) age 50 years SBP 130 mm Hg CV risk (but without diabetes) assigned to: o SBP target <120 mm Hg (intensive treatment), or o SBP target <140 mm Hg (standard treatment) Primary composite outcome: MI, other acute coronary syndromes, stroke, HF, or death from CV causes 1. SPRINT Research Group. N Engl J Med 2015.

Year 1 Mean SBP 136.2 mm Hg Standard Mean SBP 121.4 mm Hg Intensive

SPRINT Primary Outcome Hazard Ratio = 0.75 (95% CI: 0.64 to 0.89) Standard (319 events) Intensive (243 events) Mean Follow up = 3.26 years NNT=61 Number of Participants

All cause Mortality Hazard Ratio = 0.73 (95% CI: 0.60 to 0.90) NNT = 90 Median = 3.26 years Standard (210 deaths) Adapt from Figure 2B in the N Engl J Med manuscript Intensive (155 deaths) Include NNT

Primary Outcome Experience in the Six Pre specified Subgroups of Interest *Treatment by subgroup interaction

SPRINT Treatment Algorithm Intensive Treatment May begin with a single agent for Age >75 or Older with SBP < 140 on 0 1 med at study entry. Second drug Added at 1 month visit if asymptomatic and SBP > 130

Number (%) of Participants with a Monitored Clinical Measure During Follow up Number (%) of Participants Intensive Standard HR (P Value) Laboratory Measures 1 Sodium <130 mmol/l 180 (3.9) 100 (2.2) 1.76 (<0.001) Potassium <3.0 mmol/l 114 (2.5) 74 (1.6) 1.50 (0.006) Potassium >5.5 mmol/l 176 (3.8) 171 (3.7) 1.00 (0.97) Signs and Symptoms Orthostatic hypotension 2 777 (16.6) 857 (18.3) 0.88 (0.013) Orthostatic hypotension with dizziness 62 (1.3) 71 (1.5) 0.85 (0.35) 1. Detected on routine or PRN labs; routine labs drawn quarterly for first year, then q 6 months 2. Drop in SBP 20 mmhg or DBP 10 mmhg 1 minute after standing (measured at 1, 6, and 12 months and yearly thereafter)

Serious Adverse Events* (SAE) During Follow up Number (%) of Participants Intensive Standard HR (P Value) All SAE reports 1793 (38.3) 1736 (37.1) 1.04 (0.25) SAEs associated with Specific Conditions of Interest Hypotension 110 (2.4) 66 (1.4) 1.67 (0.001) Syncope 107 (2.3) 80 (1.7) 1.33 (0.05) Injurious fall 105 (2.2) 110 (2.3) 0.95 (0.71) Bradycardia 87 (1.9) 73 (1.6) 1.19 (0.28) Electrolyte abnormality 144 (3.1) 107 (2.3) 1.35 (0.020) Acute kidney injury or acute renal failure 193 (4.1) 117 (2.5) 1.66 (<0.001) *Fatal or life threatening event, resulting in significant or persistent disability, requiring or prolonging hospitalization, or judged important medical event.

Old BP Targets Population SBP DBP High Risk (SPRINT) 120 NA Diabetes < 130 < 80 All others* < 140 < 90 *Target BP with Automated Office Blood Pressure (AOBP) threshold < 135/85 Leung AA. 2016 CHEP Guidelines. Hypertension Canada s 2016 Canadian Hypertension Education Program Guidelines for Blood Pressure Measurement, Diagnosis, Assessment of Risk, Prevention, and Treatment of Hypertension. Can Cardio Soc 2016;32:569-588.

New BP Targets (Post SPRINT) Population SBP DBP High Risk (SPRINT) 120 NA Diabetes < 130 < 80 All others* < 140 < 90 *Target BP with Automated Office Blood Pressure (AOBP) threshold < 135/85 Leung AA. 2016 CHEP Guidelines. Hypertension Canada s 2016 Canadian Hypertension Education Program Guidelines for Blood Pressure Measurement, Diagnosis, Assessment of Risk, Prevention, and Treatment of Hypertension. Can Cardio Soc 2016;32:569-588.

Who is a High Risk (SPRINT) Patient? Someone with any of the following: Leung AA. 2016 CHEP Guidelines. Hypertension Canada s 2016 Canadian Hypertension Education Program Guidelines for Blood Pressure Measurement, Diagnosis, Assessment of Risk, Prevention, and Treatment of Hypertension. Can Cardio Soc 2016;32:569-588.

Who is a High Risk (SPRINT) Patient? Someone with any of the following: CVD - Clinical or sub-clinical CKD (non-diabetic nephropathy, proteinuria <1 g/d, * egfr 20-59 ml/min/1.73m 2 ) CV Risk - Estimated 10-year global CV risk 15% Age 75 years * Four variable MDRD equation Framingham Risk Score Leung AA. 2016 CHEP Guidelines. Hypertension Canada s 2016 Canadian Hypertension Education Program Guidelines for Blood Pressure Measurement, Diagnosis, Assessment of Risk, Prevention, and Treatment of Hypertension. Can Cardio Soc 2016;32:569-588.

How do you make it easy? Systolic 120 < 130/80 <140/90 Diabetes CVD CKD (egfr 20-59) CV Risk > 15% Age > 75 Nothing from list

SBP

DBP

INVEST International Verapamil SR Trandolapril study MI and Stroke based on Diastolic Blood Pressure Achieved DBP Ann Intern Med. 2006;144:884 893.

INVEST International Verapamil SR-Trandolapril study MI and Stroke based on Diastolic Blood Pressure Achieved DBP Ann Intern Med. 2006;144:884 893.

2009 by Radiological Society of North America Baumüller S et al. Radiology 2009;253:56-64

Ann Intern Med. 2006;144:884 893.

Variable Mean ± SD or% No. of diseased vessels 1 0.1% 2 16.6% 3 83.3% No. of Diseased Vessels 3-83.3% Location of disease LAD 98.9% LCX 92.6% RCA 91.7% Proximal LAD involvement (target lesion = LAD located in proximal) 13.8% No. of lesions per patient 5.7 ±2.2 (1888) No. of Lesions per Patient - 5.7 Extent of disease per patient (total length of lesions, mm) 77.6 ± 33.8 (1888) Duke jeopardy score 9.3 ± 3.1 (1874) LVEF (%) 66.2 ± 11.3 (1291) LVEF >50% 90.9% 35% 50% 8.0% <35% 1.1%

Measure BP Properly Outside BP Systolic 120 < 130/80 <140/90 Diabetes CVD CKD (egfr 20-59) CV Risk > 15% Age > 75 Nothing from list

ALLHAT Number of Pills Needed 100 1 Drug 2 Drugs 3 Drugs 1.7 2.0 2 Patients (%) 80 60 40 20 1.3 1.4 1.6 1.2 0.8 0.4 Average # of drugs 0 6 mos 1 yr 3 yr 5 yr 0 Blood pressure controlled <140/90 mmhg 49.8% 55.2% 62.3% 65.6% Cushman WC, et al. J Clin Hypertens. 2002;4:393-405. www.hypertensiononline.org

Single Pill Combo and adherence 1. Sherrill B, et al. J Clin Hypertens. 2011;13(12):898 909.

Combine or Double Up? Ratio of Incremental SBP Lowering Effect at Standard Dose Incremental SBP reduction ratio observed/expected (additive) CCB = calcium channel blocker 1. Wald DS, et al. Am J Med 2009;122:290

CV risk Initial combination therapy 1. Corrao G, et al. Hypertension. 2011;58(4):566 572.

What can you combine? A: ACEI inhibitors ARBs B: Beta-blockers C: CCB D: Diuretics E: Everything else DRI (Direct Renin Inhibitor) Alpha-blockers (doxazosin, terazosin) Vasodilators (hydralazine, minoxidil) Central sympatholytics (clonidine, methyldopa) 63

Amlodipine Dilates ACEi Dilates 64

Amlodipine Dilates ACEi Dilates

STITCH algorithm 1. Feldman RD, et al. Hypertension. 2009;53(4):646-653.

STITCH study: Results Absolute difference: 12.0% 95% CI 1.5-22.4% P = 0.026 1. Feldman RD, et al. Hypertension. 2009;53(4):646-653.

First Line Treatment of Adults with Systolic/Diastolic Hypertension Without Other Compelling Indications TARGET <135/85 mmhg (automated measurement method) INITIAL TREATMENT Health behaviour management Thiazide/ thiazide like* ACEI ARB Long acting CCB Betablocker Single pill combination ** * Longer acting (thiazide like) diuretics are preferred over shorter acting (thiazide) diuretics BBs are not indicated as first line therapy for age 60 and above Renin angiotensin system (RAS) inhibitors are contraindicated in pregnancy and caution is required in prescribing to women of child bearing potential **Recommended SPC choices are those in which an ACE I is combined with a CCB, an ARB with a CCB, or an ACE I or ARB with a diuretic