KDIGO Guideline Debates:HYPERTENSION · Primary and Secondary Outcomes Patients with T2D and hypertension (N = 4733) Random assignment –Intensive therapy: target SBP < 120 mm Hg

KDIGO Guideline Debates:HYPERTENSION

Swapnil Hiremath, MD, MPH, FASN, ASH Specialist in HT University of Ottawa, Canada @hswapnil

Disclosures

▪ No relevant financial disclosures

▪ Member of Canadian Hypertension Education Program (CHEP) Guideline Task Force

At the end of this talk, the participant will…

▪ Appreciate why blood pressure should be lowered in CKD

▪ Get an overview of recent literature in this area, including SPRINT

▪ Decide which patients might be eligible for more intensive blood pressure lowering

Swapnil Hiremath, KDIGO Symposium, CBN 2016, Maceio

Blood pressure and Treatment: The High Risk strategy

Distribution of Blood Pressure

Risk of stroke


Blood pressure and Treatment: The population strategy

Geoffrey Rose: Sick individuals and sick populations. International Journal of Epidemiology 1985;14:32–38. Swapnil Hiremath, KDIGO Symposium, CBN 2016, Maceio

Example: Statins for primary prevention

Finegold et al; Open Heart, 2016 Swapnil Hiremath, KDIGO Symposium, CBN 2016, Maceio

BLOOD PRESSURE AND OUTCOMES: the reality

0

0.5

1

1.5

2

2.5

3

110 120 130 140 150 160 170 180 190 200 210

Stroke CV Dz

Incr

easi

ng

ris

k

Increasing blood pressure


Risk, Prevention and Outcomes

diabetes

CKD

Elderly

General population


CHEP 2015 Japan JNC 8 ESH/ESC 2013

KDIGO 2012

Non-proteinuric CKD

140/90 140/90 140/90 140/90 140/90

Proteinuric CKD 140/90 130/80 140/90 140/90 130/80

Diabetic, non proteinuric CKD

130/80 130/80 140/90 140/90 140/90

Diabetic, proteinuric CKD

130/80 130/80 140/90 140/90 130/80

Elderly 150/901 150/90 150/902 140/90 Individualized

The state of hypertension guidelines pre-SPRINT (numbers refer to blood pressure target in mm Hg)


SPRINT Research Question

Examine effect of more intensive high blood pressure treatment than is currently recommended, in high risk populations, excluding Diabetes

Randomized Controlled Trial Target Systolic BP

Intensive Treatment

Goal SBP < 120 mm Hg

Standard Treatment

Goal SBP < 140 mm Hg

SPRINT design details available at: ClinicalTrials.gov (NCT01206062)

Ambrosius WT et al. Clin. Trials. 2014;11:532-546. Swapnil Hiremath, KDIGO Symposium, CBN 2016, Maceio

Pre-specified Subgroups of Special Interest

▪ Age (<75 vs. ≥75 years)

▪ Gender (Men vs. Women)

▪ Race/ethnicity (African-American vs. Non African-American)

▪ CKD (eGFR <60 vs. ≥60 mL/min/1.73m2)

▪ CVD (CVD vs. no prior CVD)

▪ Level of BP (Baseline SBP tertiles: ≤132, 133 to 144, ≥145 mm Hg)

Wright JT Jr, et.al. N Engl J Med 2015;373:2103-2116. Swapnil Hiremath, KDIGO Symposium, CBN 2016, Maceio

SPRINT: Achieved BP

Wright JT Jr et.al.. N Engl J Med 2015;373:2103-2116. Swapnil Hiremath, KDIGO Symposium, CBN 2016, Maceio

Hazard Ratio = 0.75 (95% CI: 0.64 to 0.89)

Standard

Intensive (243 events)

During Trial (median follow-up = 3.26 years) Number Needed to Treat (NNT) to prevent a primary outcome = 61

Primary Outcome: Cumulative Hazard

(319 events)

Number of Participants


Include NNT

Hazard Ratio = 0.73 (95% CI: 0.60 to 0.90)

During Trial (median follow-up = 3.26 years)

Number Needed to Treat (NNT) to Prevent a death = 90

Standard (210 deaths)

Intensive (155 deaths)

Number of Participants

Wright JT Jr, et.al. N Engl J Med 2015;373:2103-2116.

All-Cause Mortality: Cumulative Hazard


All-cause Mortality in the Six Pre-specified Subgroups of Interest

*

*p=0.34, after Hommel adjustment for multiple comparisons

Wright JT Jr et.al.. N Engl J Med 2015;373:2103-2116.


SPRINT: Caveats and Criticisms

▪Method of BP measurement

▪Trial Stopped early

▪Lots of Adverse events in Intensive (Low BP, < 120 mm Hg) arm


BP Measurement in SPRINT

▪ 5 Minutes quiet rest

▪ 3 BP readings, average used

▪ Reduces white coat effect

▪ BP readings ~ 10 mm Hg lower than casual BP recordings


BP Measurement: Reality vs Clinical Trials

▪ BP measurement in clinical trials is done meticulously, after proper rest, correct technique

▪ Casual BP in routine practice : white coat effect, artifacts, non-resting BP

From Myers et al, CAMBO trial, BMJ 2011


BP Measurement: Practical Aspect

▪ A proper auscultatory BP is ideal, but rarely done outside trials, specialized clinics

▪ Ambulatory blood pressure monitoring: ideal, but cost, logistics, patient convenience

▪ Automated BP monitors are an alternative (eg OMRON HEM 907; BPTru): but cost, longer clinic visit

Difference of 5-15 mm Hg between automated BP and casual BP


Trial stopped early

Extremely unlikely to change overall benefit of intensive arm if trial continued

The precision of the outcome (eg NNT ~ 61) is a bit uncertain


Serious Adverse Events* (SAE) During Follow-up

All SAE reports

Number (%) of Participants

Intensive Standard HR (P Value)

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 (0.02)

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.


Adverse Events

▪ Overall adverse events similar

▪ Despite greater syncope, hypotension, injurious falls similar in 2 groups

▪ Despite increase in AKI (biochemical AKI) need for dialysis similar in both groups

▪ All-cause mortality is the most important adverse event!


SPRINT: (My Personal) take home message

▪ Strong Internal Validity

▪ Consider Intensive Lower BP (Aim SBP < 120) for – Patients with high risk (eg CKD)

– Not for patients who are at risk of adverse events

– Using SPRINT-like BP measurement strategy

– Using SPRINT-like BP lowering medications (eg chlorthalidone, longer acting RAS blockers, spironolactone)

– Frequent monitoring for electrolytes, symptoms


Post-SPRINT Meta-analysis

Ettehad et al. Lancet 2016


Risk of coronary events in people with CKD compared with diabetes: a population-level cohort study

Tonelli M et.al. The Lancet 2012;380:807-812; Polonsky& Bakris Lancet 2012;380:783-785

NHANES 2003-2006 48 month FU N=1,268,029


The Paradox of Blood Pressure and The Kidney

▪ Patients with CKD are at high risk of bad cardiovascular outcomes from high blood pressure

▪ Intensive treatment of high blood pressure in patients with CKD *may* not improve renal outcomes


diabetes

CKD

Elderly

General population

How about Diabetes?


ACCORD BP Study: Primary and Secondary Outcomes ▪ Patients with T2D and hypertension (N = 4733)

▪ Random assignment

– Intensive therapy: target SBP < 120 mm Hg

– Standard therapy: target SBP < 140 mm Hg

▪ 1° outcome: nonfatal MI, nonfatal stroke, death from CV causes

▪ Mean follow-up = 4.7 y

Outcome Intensive Standard HR P-value

SBP after 1 year (mmHg) 119.3 133.5 NR NR

1° outcome (annual rate) 1.87 2.09 0.88 .20

Death from any cause (annual rate) 1.28 1.19 1.07 .55

Stroke (annual rate) 0.32 0.53 0.59 .01

AEs (rate) 3.3 1.3 NR <.001

The ACCORD Study Group. N Engl J Med. 2010 March 14. [Epub ahead of print].


Perkovic V, Rodgers A. N Engl J Med 2015. DOI: 10.1056/NEJMe1513301

Outcomes from SPRINT and ACCORD Trials and Combined


Choice of Medications


Medication algorithm choice in SPRINT

Start with ACEi/ARB OR Diuretic (chlorthalidone preferred) OR Calcium channel blocker In 2 or 3 drug combination

Potent & Longer acting drugs: Lisinopril, Azilsartan, Chlorthalidone


New Wording in UpToDate

▪ For patients with one or more of the characteristics listed above, we recommend targeting a BP of 120 to 125 mmHg if AOBP measurements are used rather than a higher goal BP (Grade 1A).

▪ For these patients, we recommend targeting a BP of 125 to 130 mmHg if other methods of BP measurement are used.

▪ In patients with diabetes, we suggest a goal blood pressure of 120 to 125 mmHg (if AOBP is used to measure blood pressure), or a goal blood pressure of 125 to 130 mmHg (if manual ausculatory measurements are used), (Grade 2B).

Forman J, Bakris G and Kaplan N UpToDate 4/2016 Swapnil Hiremath, KDIGO Symposium, CBN 2016, Maceio

New recommendation: Canada

▪ For high-risk patients, aged ≥50 years, with systolic BP levels ≥ 130 mmHg, intensive management to target a systolic BP ≤ 120 mmHg should be considered. Intensive management should be guided by Automated BP. Patient selection for intensive management is recommended and caution should be taken in certain high-risk groups.

▪ What is considered high risk? At least one of: – Clinical or sub-clinical cardiovascular disease.

– Chronic kidney disease (non-diabetic nephropathy, proteinuria <1 g/d, or estimated glomerular filtration rate 20-59 mL/min/1.73m2).

– Estimated 10-year global cardiovascular risk >15%.

– Age ≥ 75 years.

Leung et al, Can J Cardiol, 2016 Swapnil Hiremath, KDIGO Symposium, CBN 2016, Maceio

▪ Limited or No Evidence – Heart failure (ejection fraction <35%) or recent myocardial infarction (within last 3

months). – Indication for, but not currently receiving, a beta-blocker. – Frail or institutionalized elderly.

▪ Inconclusive evidence – Diabetes mellitus. – Prior stroke. – eGFR < 20 mL/min/1.73 m2.

▪ Contraindications – Patient unwilling or unable to adhere to multiple medications. – Standing SBP <110 mmHg. – Inability to measure SBP accurately. – Known secondary cause(s) of hypertension.

New recommendation: Canada

Leung et al, Can J Cardiol, 2016 Swapnil Hiremath, KDIGO Symposium, CBN 2016, Maceio

New Recommendation: Australia

Gabb et al, Med J Australia, 2016


Blood Pressure Guideline Update

KDIGO has noted the publication of the Systolic

Blood Pressure Intervention Trial (SPRINT)

results and has launched a process to review

and update its Blood Pressure Guideline,

originally published in 2012.

The search for an independent Evidence Review

Team to perform a systematic literature review

support the Work Group in this update will

commence soon. This project is lead by Alfred

Cheung, USA, and Johannes Mann, Germany.


Blood Pressure Guideline Update Work Group

Guideline Co-Chairs

Alfred Cheung

USA

Work Group Members

Tara Chang USA

Bill Cushman

USA

Fan Fan Hou China

Joachim Ix USA

Roberto Pecoits-Filho

Brazil

Vlado Perkovic Australia

Mark Sarnak USA

Sheldon Tobe

Canada

Charles Tomson United Kingdom

Johannes Mann

Germany


Intensive Blood Pressure targets

diabetes CKD

Elderly

General population

For Whom? How?

Frail

The Right measurement method The correct medicines


Thank you!

Special thanks to KDIGO and CBN 2016 Organisers Email: [email protected] Twitter @hswapnil

mailto:[email protected]

Documents

KDIGO Guideline Debates:HYPERTENSION · Primary and Secondary Outcomes Patients with T2D and hypertension (N = 4733) Random assignment –Intensive therapy: target SBP < 120 mm Hg