Dott.ssa B. Bassi Dr. G. Bondi Dr. C. Camporesi Dott.ssa L. Gardelli Dr. F. Girelli Dr. V. Mazzeo

Premessa

• Il principale obiettivo di una terapia è quello di trarre il massimo beneficio e di ridurre al minimo i rischi • La terapia antiipertensiva, nel paziente diabetico e nefropatico ha in particolare come obiettivo “ in primis ” quello ridurre la mortalità e gli eventi CV, ma anche quello potenziale di ridurre l deterioramento della funzione renale ’ eventuale incidenza e/o evoluzione delle complicanze micro vascolari per il DM e prevenire e/o ritardare il

CHD and Stroke Mortality vs. Usual BP by Age

256 128 64 32 16 8 4 2 0 1 Systolic Blood Pressure Age at risk: 80-89 years 120 140 160 180 70-79 years 60-69 years 50-59 years 40-49 years 256 128 64 32 16 8 4 2 1 0 Age at risk: 80-89 years 70-79 years 60-69 years 50-59 years 120 140 160 180 Usual Systolic BP (mm Hg) Diastolic Blood Pressure Age at risk: 256 128 64 32 16 8 4 2 0 1 256 128 64 32 16 8 4 2 1 0 70 80 90 100 110 80-89 years 70-79 years 60-69 years 50-59 years 40-49 years Age at risk: 80-89 years 70-79 years 60-69 years 50-59 years 70 80 90 100 110 Usual Diastolic BP (mm Hg)

CHD Stroke

Prospective Studies Collaboration. Lancet. 2002;360:1903-1913.

Cumulative incidence of cv events in subjects without hypertension

Vasan RS et al, NEJM 2001

Age-adjusted 16-year Incidence of all cause end-stage renal disease by systolic and diastolic blood pressure in 300645 white men and 20 222 African-American men

MRFIT Study

Klag M.J.JAMA. 1997;277:1293-1298

Relative risk for kidney disease progression based on current level of systolic blood pressure and current urine protein excretion.

A Patient-Level Meta-Analysis

Jafar TH Ann Intern Med. 2003;139:244-252.

HOT Study: significant benefit from intensive treatment in the diabetic subgroup

25 20 15 10 5 p=0.005 for trend 0  90  85 Target Diastolic Blood Pressure  80 mm Hg Hansson L et al. Lancet. 1998

UKPDS study

-37% -24% -32% -21% -44%

Any clinical end point, fatal or non-fatal, related to diabetes. Less tight control: 154/87 mmHg Tight control: 144/82 mmHg Microvascular end points (mostly retinal photocoagulation), fatal or non-fatal myocardial infarction or sudden death, and fatal or non-fatal strokes . Mortality for disease related to diabetes (myocardial infarction, sudden death, stroke, peripheral vascular disease, and renal failure).

British Medical Journal Publishing Group et al. BMJ 1998;317:703-713

Blood pressure and cardiovascular death

10 8 6 4 2 0 Diabetics n=3,305 death rate - 5.3% Non-diabetics n=88,257 death rate - 2.2% <120 120-139 140-159 Systolic blood pressure (mmHg) >160 Asia-Pacific Cohort Studies Collaboration. Diabetes Care. 2004;27:2836-2842

I LIMITI DEGLI STUDI

✓

Uno studio osservazionale ci può dare interessanti informazioni, ma è suscettibile di possibili errori, come quello di selezione dei pazienti

✓

L

’

interpretazione dei risultati in studi

“

post hoc

”

al target PA raggiunto, tradisce il principio della randomizzazione e

“

intention to treat analysis

”

in base

✓ Comparare targets pressori raggiunti in diversi trials può non essere appropriato (terapia concomitante, diverso profilo di rischio cardiovascolare)

Estimated mean changes (SE) in glomerular filtration rate (GFR) (mL /min per 1.73 m2) from baseline through follow-up in the 2 blood pressure goal interventions

AASK Study

Usual BP goal: 141/85 mmHg Lower BP goal: 128/78 mmHg

P=0.24

1094 African Americans aged 18 to 70 years with hypertensive renal disease (GFR, 20-65 mL/min per 1.73m2

J.T. Wright et al. JAMA, November 20, 2002—Vol 288, No. 19

Estimated percentage changes in the urine protein/creatinine ratio from baseline throughout follow-up by blood pressure

AASK study

Usual BP goal: 141/85 mmHg Lower BP goal: 128/78 mmHg (P<0.001) 1094 African Americans aged 18 to 70 years with hypertensive renal disease (GFR, 20-65 mL/min per 1.73m2

J.T. Wright et al. JAMA, November 20, 2002—Vol 288, No. 19

Cumulative probability of kidney failure (top) and cumulative probability of the composite of kidney failure or all-cause mortality before kidney failure (bottom).

MDRD Study

p=0.00003

Usual BP :…….. <140/90 mmHg Low BP : <125/75 mmHg p= 0.0024

840 persons with predominantly nondiabetic kidney disease and a glomerular filtration rate of 13 to 55 mL/minper 1.73 m2.

Samak M.J. et al. Ann Intern Med. 2005;142:342-351.

Fenomeno della curva J

Cruickshank JM. Cardiovasc Drugs Ther 2000;14(4):373—9 .

Incidence of total MI and total stroke by DBP pressure strata in patients with HBP and CAD enrolled in the INVEST

Messerli FH et Al, Ann Intern Med 2006;144:884-893

Studio PROGRESS: curva J non evidente per l’ictus ischemico ed emorragico (p = 0,0005) (p < 0,0001) Arima H, et al. J Hypertens 2006;24(6):1201—8 .

Sintesi degli studi clinici favorevoli alla curva J

Dogma discusso: Un uso aggressivo degli agenti ipotensivanti nei pazienti ipertesi con malattia coronarica può essere pericoloso?

Messerli F, Mancia G, et al. Ann Intern Med 2006

JNC VII

< 140/90 mmHg < 130/80 mmHg nei diabetici < 130/80 mmHg nella insufficienza renale cronica

JAMA 2003; 289:2560-2572

ESH/ESC 2007

< 140/90 mmHg < 130/80 mmHg nei diabetici < 130/80 mmHg nella insufficienza renale cronica < 125/75 mmHg se proteinuria > 1 g/die

J Hypertens 2007; 25:1105-1187

Effects of blood pressure lowering on death and macrovascular and microvascular disease (coronary and renal) : the ADVANCE Trial Average BP during follow-up Placebo arm: 140.3/77 mmHg Perindopril-Indapamide arm: 134.7/74.8 mmHg Advance collaborative Group Lancet 2007; 370: 829–40

Mortality and morbidity associated with lower vs standard blood pressure targets (Review)

PAS 139.3 vs 143.2 Δ 3.9 mmHg PAD 81.7 vs 85.1 Δ 3.4 mmHg Seven trials (22,089 subjects) AASK, ABCD (H), ABCD (N), HOT, MDRD, REIN-2, TOTO Arguedas JA et al, Cochrane Database Syst Rev 2009: CD004349

Relative risk estimates of coronary heart disease events and stroke in blood pressure difference trials according to pre-treatment diastolic and systolic blood pressures

(taken as average in placebo group over course of trial). Law, M R et al. BMJ 2009;338:b1665

Effects of active treatment vs. placebo on recurrent stroke in patients with different baseline BP values in the PROGRESS trial

Arima H et al, J Hypertens 2006

Prognostic between changes in SBP from baseline to follow up of blood pressure in patients with high vascular risk ONTARGET STUDY

Quartile 1: baseline SBP  130 mmHg Quartile 2: baseline SBP 131-142 mmHg Quartile 3: baseline SBP 143-154 mmHg Quartile 4 baseline: SBP > 154 mmHg Sleight P. et al, Journal of Hypertension. 27(7):1360-1369, July 2009.

SBP Achieved (mmHg)

Blood Pressure Lowering and Cardiovascular Prevention in Diabetes

50 162 155 40 153 34 154 34 148 31 25 145 144 145 143 139 140 138 137 134 132 8 0 128 0 S. Eur DM SHEP DM UK PDS HOT DM HOPE ADV ABCD HT ABCD NT 40 30 20 % CV event reduction 10 0

Zanchetti et al. J Hypertens 2009; 27: 923-934

Achieved SBP in patients randomized to a more active or less active treatment in clinical trials in hypertension

Mancia G et al, J Hypertens 2009

ESH reappraisal 2009

< 140/90 mmHg in tutti i pazienti ipertesi 130-139/80-85 in tutti i pazienti ipertesi (possibilmente ai limiti bassi di questo range) < 130/80 mmHg nei diabetici e nei pazienti a rischio molto elevato (pregressi eventi cardiovascolari) (può essere una raccomandazione

‘

saggia

’

, sebbene

‘

non supportata in misura consistente dai trials

’

)

J Hypertens

2009; 27:2121-2158

ACCORD study N Engl J Med 2010;10.1056/NEJMoa1001286 Primary Outcome

Nonfatal MI, Nonfatal Stroke or CVD Death

Total Mortality

HR = 0.88

95% CI (0.73-1.06)

P 0.20

5 0 0 1 2

Y a

3 4 5 6

P s R o a

7 8 HR = 1.07

95% CI (0.85-1.35)

P 0.55

5 0 0 1 2

Y a

3 4 5 6

P s R d m a

7 8 PAS : 119.3 mmHg PAS: 133.5 mmHg HR = 1.06

95% CI (0.74-1.52)

P 0.74

5 0 0 1 2

e r

3 4 5 6 7

P s R o t n

8

CVD Deaths

Non Fatal MI ACCORD study N Engl J Med 2010;10.1056/NEJMoa1001286 Nonfatal Stroke

HR = 0.87

95% CI (0.68-1.10)

P 0.25

5 0 0 1 2

Y a

3 4 5 6

P s R o a

7 8 HR = 0.63

95% CI (0.41-0.96)

P 0.03

5 0 0 1 2

Y a

3 4 5 6

P s R n o a

7 8 HR = 0.59

95% CI (0.39-0.89)

P 0.01

PAS : 119.3 mmHg PAS: 133.5 mmHg

Total Stroke

5 0 0 1 2

Y a

3 4 5 6

P s R d m a

7 8

Serious AE Hypotension Syncope Bradycardia or Arrhythmia Hyperkalemia Renal Failure eGFR ever <30 mL/min/1.73m

2 Any Dialysis or ESRD Dizziness on Standing †

ADVERSE EVENTES ACCORD STUDY Intensive N (%)

77 (3.3) 17 (0.7) 12 (0.5)

Standard N (%)

30 (1.3) 1 (0.04) 5 (0.2) 12 (0.5) 9 (0.4) 5 (0.2) 3 (0.1) 1 (0.04) 1 (0.04)

P

<0.0001

<0.0001

0.10

0.02

0.01

0.12

99 (4.2) 52 (2.2) <0.001

59 (2.5) 217 (44) 58 (2.4) 188 (40) 0.93

0.36

† Symptom experienced over past 30 days from HRQL sample of N=969 participants assessed at 12, 36, and 48 months post-randomization

BP to intensive targets (< 130/80 mm Hg ) compared BP to standard targets (< 140-160/85-100 mmHg)

Arch Intern Med. 2012;172(17):1296-1303.

Intensive and Standard Blood Pressure Targets in Patients With Type 2 Diabetes Mellitus

Systematic Review and Meta-analysis

RR 0.76; 95% CI, 0.55-1.05

Mortality Myocardial infarction RR 0.93; 95%CI, 0.80-1.08) Stroke RR 0.65; 95% CI, 0.48-0.86) Arch Intern Med. 2012;172(17):1296-1303.

Effects of intensive blood pressure lowering on progressive kidney failure.

HR overall : 0.82 (0.68-0.98) HR overall : 0.79 (0.67-0.93)

Lv J et al. CMAJ 2013;185:949-957

©2013 by Canadian Medical Association

Subgroup analysis of the effect of intensive blood pressure lowering on kidney failure in patients with proteinuria compared with those without proteinuria.

Lv J et al. CMAJ 2013;185:949-957

©2013 by Canadian Medical Association

Occurrence of Microalbuminuria during the 48-Month Follow-up Period ROADMAP STUDY

Risk reduction in favour of Olmesartan: 23% (p=0.01) Risk reduction only in patients with baseline SBP> 135 mmHg (p=0.03) Haller H. et al. N Engl J Med 2011;364:907-17 .

ROADMAP Study

Haller H. N Engl J Med 2011;364:907-17 .

I LIMITI DEGLI STUDI

✓ Uno studio osservazionale ci può dare interessanti informazioni, ma è suscettibile di possibili errori, come quello di selezione dei pazienti ✓ L ’ interpretazione dei risultati in studi “ post hoc ” al target PA raggiunto, tradisce il principio della randomizzazione e “ intention to treat analysis ” in base ✓

Comparare targets pressori raggiunti in diversi trials può non essere appropriato (terapia concomitante, diverso profilo di rischio cardiovascolare)

Adjusted incidence RRs (95% CI) for stroke, myocardial infarction (MI), and other major cardiovascular (CV) events estimated based on mean level of blood pressure control in the year after hypertension onset.

15,665 adults with diabetes but no diagnosed coronary or cerebrovascular disease at baseline mean 38-month follow-up period.

O’Connor P J et al. Dia Care 2013;36:322-327

2007 2009 2013

2007 ESH/ESC Guidelines: Initiation of Antihypertensive Treatment Blood Pressure (mmHg) Other risk factors OD or disease No other risk factors 1-2 risk factors ≥ 3 Risk Factors, MS or OD Diabetes Established CV or renal disease or renal disease Normal SBP 120-129 or DBP 80-84 No BP intervention Lifestyle changes Lifestyle changes Lifestyle changes Lifestyle changes + Immediate drug treatment High Normal SBP 130-139 or DBP 85-89 No BP intervention Lifestyle changes Lifestyle changes and consider drug treatment Lifestyle changes + Drug treatment Lifestyle changes + Immediate drug treatment Grade 1 HT SBP 140-159 or DBP 90-99 Lifestyle changes for several months then drug treatment if BP uncontrolled Lifestyle changes for several weeks then drug treatment if BP uncontrolled Grade 2 HT SBP 160-179 or DBP 100-109 Lifestyle changes for several weeks then drug treatment if BP uncontrolled Lifestyle changes for several weeks then drug treatment if BP uncontrolled Lifestyle changes + Drug treatment Lifestyle changes + Immediate drug treatment Lifestyle changes + Drug treatment Lifestyle changes + Immediate drug treatment Grade 3 HT SBP ≥ 180 or DBP ≥ 110 Lifestyle changes + Immediate drug treatment Lifestyle changes + Immediate drug treatment Lifestyle changes + Immediate drug treatment Lifestyle changes + Immediate drug treatment

2013 ESH/ESC Guidelines for the managment of arterial hypertension

Summary of recommendations on initiation of antihypertensive drug treatment

BP = blood pressure; CKD = chronic kidney disease; CV = cardiovascular; CVD = cardiovascular disease; DBP = diastolic blood pressure; HT = hypertension; OD = organ damage; RF = risk factor; SBP = systolic blood pressure.

2013 ESH/ESC Guidelines for the management of arterial hypertension

Treatment strategies in patients with diabetes

2013 ESH/ESC Guidelines for the management of arterial hypertension

Therapeutic strategies in hypertensive patients with nephropathy

Obiettivo Generale Diabetici Nefropatici Nefropatici con franca proteinuria Anziani < 80 aa Anziani < 80 aa In buone condizioni Anziani > 80 aa In buone condizioni fisiche e mentali OBIETTIVI PRESSORI (LG ESH/ESC 2013) < 140/90 mmHg < 140/85 mmHg SBP < 140 mmHg SBP <130 mmHg SBP 150-140 mmHg SBP < 140 mmHg SBP 150-140 mmHg I A I A IIa B IIb B I A IIb C I B

 People with diabetes and hypertension should be treated to a systolic blood pressure (SBP) goal of < 140 mmHg . B  Lower systolic targets, such as <130 mmHg , may be appropriate for certain individuals, such as younger patients, if it can be achieved without undue treatment burden. C  Patients with diabetes should be treated to a diastolic blood pressure (DBP) < 80 mmHg . B

Clinical Practice Guidelines for the management of blood pressure in chronic kidney diseases

Nefropatia diabetica e non con albuminuria < 30 mg/24h ≤ 140/90 mmHg Nefropatia diabetica e non con albuminuria fra 30 e 300 mg/24h o proteinuria franca ≤ 130/80 mmHg Nefropatia diabetica e non con albuminuria fra 30 e 300 mg/24h o proteinuria franca ARB/ ACEi Kidney International supplements vol. 2, issue 5, Dec 2012

TAKE HOME MESSAGE

 Nel diabete mancano chiare evidenze di benefici nell ’ iniziare un trattamento antiipertensivo per valori di PAS < 140 mmHg o addirittura <130 mmHg ed anzi una riduzione troppo aggressiva e rapida potrebbe rivelarsi pericolosa  La riduzione della proteinuria è globalmente considerata come un target terapeutico (studi osservazionali da RCTs  variazioni della proteinuria sono predittori di eventi CV e renali) ✓ Mancano comunque solide evidenze in gruppi randomizzati di una relazione fra riduzione della proteinuria ed eventi CV e renali ✓ Malgrado ciò le ultime LG incoraggiano globalmente la riduzione della PAS < 130 mmHg nella nefropatia diabetica e non, in presenza di proteinuria franca.

✓ Obiettivi pressori più rigorosi potrebbero essere ricercati in pazienti selezionati (ad alto rischio di ictus, diabete di recente insorgenza, assenza di coronaropatia) ✓ La letteratura più recente sembra infatti suggerire di spostare l ’ attenzione dal “ target pressorio ” al “ momento temporale ” in cui questo obiettivo pressorio deve essere raggiunto (importanza di una diagnosi tempestiva di ipertensione)

TAKE HOME MESSAGE (2)

 I farmaci più indicati per ridurre la PA nei pazienti diabetici e/o nefropatici sono rappresentati dagli ACEi e sartani  il doppio blocco con ACEi e sartani non è praticamente mai indicato ✓ prudenza nell ’ associare ACEi e sartani con diuretici antialdosteronici

<140/90?

<130/90?