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Ιωάννης Α. Παπαδάκης Παθολόγος – Κλινικός Υπερτασιολόγος (ESH) Διευθυντής Παθολογικής Κλινικής Παν/κου Νοσοκομείου Ηρακλείου (ΠαΓΝΗ) Υπεύθυνος Αντιϋπερτασικού Ιατρείου

Προϋπέρταση Καρδιαγγειακή προστασία Αντιϋπερτασική αγωγή και Σακχαρώδης Διαβήτης Θεραπεία υπέρτασης σε υπερήλικες Πρόληψη αγγειακών εγκεφαλικών επεισοδίων – Άνοιας Νεφροπροστασία Επίδραση των αναστολέων του άξονα ρενίνηςαγγειοτενσίνης (RAS) στη πρόληψη της κολπικής μαρμαρυγής ¾ Πόσο πρέπει να μειώσουμε την αρτηριακή πίεση ¾ ¾ ¾ ¾ ¾ ¾ ¾

¾ Δεν υπάρχει απλή διαχωριστική γραμμή μεταξύ φυσιολογικής και αυξημένης ΑΠ (G.Pickering, 50 χρόνια πρίν)

Η σχέση ΑΠ και Καρδιαγγειακού κινδύνου είναι συνεχής, σταθερή και ανεξάρτητη από την παρουσία άλλων παραγόντων κινδύνου N Engl J Med 2001

Ευρωπαϊκές Οδηγίες

ΣΑΠ mmHg

ΔΑΠ mmHg

JNC VII

Βέλτιστη

<120

<80

Φυσιολογική

120–129

80–84

Ανώτερη φυσιολογική

130–139

85–89

Υπέρταση βαθμού 1(ήπια)

140–159

90–99

Υπέρταση βαθμού 2 (μέτρια)

160–179

100–109

Υπέρταση βαθμού 3 (σοβαρή)

≥180

≥110

Προ-υπέρταση Υπέρταση σταδίου 1

Υπέρταση σταδίου 2

TROPHY Study

Feasibility of Treating Prehypertension with an Angiotensin-Receptor Blocker

Stevo Julius, M.D., Sc.D., Shawna D. Nesbitt, M.D., Brent M. Egan, M.D., Michael A. Weber, M.D., Eric L. Michelson, M.D., Niko Kaciroti, Ph.D., Henry R. Black, M.D., Richard H. Grimm Jr., M.D., Ph.D., Franz H. Messerli, M.D., Suzanne Oparil, M.D. and M. Anthony Schork, Ph.D.

N Engl J Med Volume 354;16:1685-1697 April 20, 2006

TROPHY Study

Study Design

809 persons with prehypertension (SBP 130-139 and/or DBP 8589mmHg) were randomly assigned in a blinded fashion to receive two years of candesartan or placebo, followed by two years of placebo for all

Julius, S. et al. N Engl J Med 2006;354:1685-1697

Kaplan-Meier Analysis of New-Onset Clinical Hypertension

16% 64%

P=0.007

P<0.001

Julius, S. et al. N Engl J Med 2006;354:1685-1697

Incidence of Serious Adverse Events

Incidence of New-onset Hypertension

Conclusion 他 Over a period of four years, stage 1 hypertension developed in nearly two thirds of patients (63%) with untreated prehypertension (the placebo group) 他 Treatment of prehypertension with candesartan appeared to be well tolerated and reduced the risk of incident hypertension during the study period 他 Thus, treatment of prehypertension appears to be feasible 他 Further research is needed to evaluate the clinical usefulness and ultimate safety of antihypertensive treatment for prehypertension

Προϋπέρταση Καρδιαγγειακή προστασία Αντιϋπερτασική αγωγή και Σακχαρώδης Διαβήτης Θεραπεία υπέρτασης υπερήλικες Τελικό καταληκτικόσε σημείο Πρόληψη αγγειακών εγκεφαλικών επεισοδίων – Άνοιας ¾Έμφραγμα μυοκαρδίου Νεφροπροστασία ¾Αγγειακό εγκεφαλικό επεισόδιο Επίδραση των αναστολέων του άξονα ρενίνης¾Θάνατος από(RAS) καρδιαγγειακό αίτιο αγγειοτενσίνης στη πρόληψη της κολπικής μαρμαρυγής ¾ Πόσο πρέπει να μειώσουμε την αρτηριακή πίεση ¾ ¾ ¾ ¾ ¾ ¾ ¾

Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA) B.Dahlof (Co-chair), P.Sever (Co-chair), N. Poulter (Secretary) H. Wedel (Statistician), G. Beevers, M. Caulfield, R. Collins S. Kjeldsen, A. Kristinsson, J. Mehlsen, G. McInnes, M. Nieminen E. O’Brien, J. Östergren, on behalf of the ASCOT Investigators

ASCOTASCOT-BPLA, Lancet 2005;366:8952005;366:895-906

ASCOT-BPLA: Treatment algorithm for BP targets BP medication titrated to achieve target: No diabetes: <140/90 mm Hg Diabetes: <130/80 mm Hg

19,342 patients 40–79 y with UNTREATED SBP ≥160 mmHg and/or DBP ≥100 mmHg OR TREATED SBP ≥140 mmHg and/or DBP ≥90 mmHg

RANDOMIZATION

N = 19,257 with hypertension and ≥3 other CV risk factors In each arm, pts with total cholesterol ≤6.5 mmol/L randomized to atorvastatin (10 mg) or placebo daily (n = 10,297)

Amlo 5 mg

Atenolol 50 mg

Amlo = amlodipine; Peri = perindopril; Doxa = doxazosin GITS (Gastrointestinal Transport System); BFZ = bendroflumethiazide

Amlo 10 mg

Atenolol 100 mg

VBWG

Amlo 10 mg + Amlo 10 mg peri 8 mg + Amlo 10 mg peri 8 mg (2 x 4 mg) + (2 x 4 mg) + doxa 8 mg + Amlo 10 mg peri 8 mg doxa 4 mg + (2 x 4 mg) peri 4 mg

Atenolol 100 mg + BFZ 1.25 mg + K+

Atenolol 100 mg + BFZ 2.5 mg + K+

Atenolol 100 mg + BFZ 2.5 mg + K+ + doxa 4 mg

5 Years or 1150 primary events

Atenolol 100 mg + BFZ 2.5 mg + K+ + doxa 8 mg

Πρόωρη διακοπή της μελέτης • Νοέμβριος 2004: διακοπή μελέτης λόγω σαφούς οφέλους στους ασθενείς της ομάδας ανταγ. ασβεστίου / περινδοπρίλης (4-8 mg)

Mean follow-up period 5.5 yrs

– Συμβάματα πρωτεύοντος τελικού σημείου 869*

*σε 803 ασθενείς (Η μελέτη είχε σχεδιασθεί για 1.150 ασθενείς με συμβάματα) συμβάματα)

Θνησιμότητα κάθε αιτίας λόγος πρόωρης διακοπής της μελέτης

ASCOTASCOT-BPLA, Lancet 2005;366:8952005;366:895-906

10.0

11% μείωση κινδύνου

8.0

Atenolol ± thiazide (No. of events 820)

6.0

4.0

Amlodipine ± perindopril (No. of events 738)

2.0

0.0 0.0

1.0

2.0

3.0

4.0

5.0

Έτη

p = 0.0247 ASCOTASCOT-BPLA, Lancet 2005;366:8952005;366:895-906

VBWG

ASCOT-BPLA: Reductions in BP over time 180 Systolic BP

160

140 Mean difference = 2.7, P < 0.0001

Blood 120 pressure (mm Hg) 100

137.7 136.1

Diastolic BP

80 Mean difference = 1.9, P < 0.0001

79.2 77.4

60 0 0

0.5

1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 Final visit

Time (years) Atenolol-based regimen*

(mean 5.7 [SD 0.6], range 4.6–7.3)

Amlodipine-based regimen†

*Atenolol 50–100 mg ± bendroflumethiazide 1.25–2.5 mg/potassium prn †Amlodipine 5–10 mg ± perindopril 4–8 mg prn Dahlöf B et al; ASCOT Investigators. Lancet. 2005;366:895-906.

VBWG

ASCOT-BPLA: Reduction in primary outcome (nonfatal MI and fatal CHD) 10 8 Proportion of events (%)

HR = 0.90 (95% CI, 0.79–1.02) RRR = 10% P = 0.1052

6 4

Atenolol-based regimen*

Amlodipine-based regimen†

0 0 Number at risk Amlodipine-based regimen (429 events) Atenolol-based regimen (474 events)

Time since randomization (years) 9639

9475

9337

9168

8966

7863

9618

9470

9290

9083

8858

7743

*Atenolol 50–100 mg ± bendroflumethiazide 1.25–2.5 mg/potassium prn †Amlodipine 5–10 mg ± perindopril 4–8 mg prn Dahlöf B et al; ASCOT Investigators. Lancet. 2005;366:895-906.

Καρδιαγγειακή θνησιμότητα %

Συνολικά στεφανιαία επεισόδια %

3.5 3.0

24%

2.5

μείωση κινδύνου

13%

10.0

Atenolol ± thiazide (No. of events 342)

8.0

2.0

μείωση κινδύνου

Atenolol ± thiazide (No. of events 852)

Amlodipine ± perindopril (No. of events 753)

6.0

Amlodipine ± perindopril (No. of events 263)

1.5

4.0

1.0

p = 0.0010

0.5

p = 0.0070

2.0

Έτη

0.0

0.0 0.0

1.0

2.0

3.0

4.0

5.0

Έτη

ASCOTASCOT-BPLA, Lancet 2005;366:8952005;366:895-906

16% μείωση κινδύνου

0.0

1.0

2.0

3.0

4.0

5.0

ASCOTASCOT-BPLA, Lancet 2005;366:8952005;366:895-906

Θανατηφόρο / μη θανατηφόρο ΑΕΕ %

23%

5.0

4.0

Atenolol ± thiazide (No. of events 422)

μείωση κινδύνου

3.0 Amlodipine ± perindopril (No. of events 327) 2.0

p = 0.0003

1.0

Έτη

0.0 0.0

1.0

2.0

3.0

4.0

5.0

ASCOTASCOT-BPLA, Lancet 2005;366:8952005;366:895-906

30% μείωση κινδύνου

Συμπεράσματα

¾ Ο συνδυασμός Amlodipine ± perindopril απέτρεψε περισσότερα καρδιαγγειακά επεισόδια και ανέπτυξε λιγότερα περιστατικά σακχαρώδη διαβήτη από ότι η κλασσική θεραπεία που βασίζεται στον συνδυασμό βαναστολέα ± διουρητικού. ¾ Τα αποτελέσματα αυτά δεν εξηγούνται μόνο από την καλύτερη ρύθμιση της πίεσης* που πέτυχε αυτή η θεραπεία. *μέση διαφορά ΣΑΠ 2,7mm Hg

HOPE study results â&#x20AC;&#x201C; primary endpoints Combined cardiovascular endpoint Cardiovascular mortality, myocardial infarction, stroke

Cardiovascular mortality

Myocardial infarction

Stroke

-20%

-22%

p<0.001

-26% p<0.001

-32% Ramipril n=4645, Placebo n=4652 The HOPE Study Investigators, 2000

p<0.001

ONTARGET Questions: 1.Is

telmisartan “non-inferior” to ramipril? 2.Is the combination superior to ramipril?

Outcome: 1.Primary:

CV death, MI, stroke, CHF hosp 2.Key secondary: CV death, MI, stroke (HOPE trial outcome)

Patient profile ≥55

years of age At high risk of cardiovascular disease: Coronary artery disease Peripheral arterial occlusive disease (PAD) Cerebrovascular event Diabetes mellitus with end-organ damage No patients with congestive heart failure

Design: Randomized, double blind, double dummy study conducted in 733 centers in 40 countries (n=25,620) 56 months follow-up with 99.8% outcome ascertainment The ONTARGET Investigators. Investigators. N Engl J Med 2008; 358: 15471547-1559

# at Risk Yr 1 T 8542 8176 R 8576 8214

Yr 2 7778 7832

Yr 3 7420 7473

Yr 4 7051 7095

0.15 0.10

Telmisartan Ramipril

0.05

Ramipril

Telmisartan

Systolic

135.8

134.8

Diastolic

77.5

76.9

0.0

Cumulative Hazard Rates

0.20

0.25

Time to Primary Outcome

2 Years of Follow-up

Primary Outcome & HOPE Primary Outcome N

Ram

Tel

N (%)

8576

8542

1412 (16.46%)

1423 (16.66%)

Tel vs Ram RR (95% CI)

P (non-inf)

1.01 (0.94-1.09)

0.0038

1.02 (0.95-1.10)

0.0055

0.99 (0.91-1.07)

0.0009

0.99 (0.91-1.07)

0.0012

Primary Outcome CV Death, MI, Stroke, CHF Hosp (Adjusted for SBP) HOPE Primary Outcome CV Death, MI, Stroke (Adjusted for SBP)

1210 (14.11%)

1190 (13.93%)

Reasons for Permanently Stopping Study Medications Ram N=8576 149

Tel N=8542 229

Syncope

1.27

0.4850

Cough

360

0.26

<0.0001

Diarrhea

1.59

0.20

Angioedema

0.40

0.0115

Renal Impairment Any Discontinuation

1.14

0.46

2099

1962

0.94

0.02

Hypotension

Tel vs. Ram RR P 1.54 0.0001

Time to Primary Outcome # at Risk Yr 1 8576 T&R 8502

8214 8134

Yr 3

Yr 4

7832 7740

7473 7377

7095 7023

0.15 0.10

Ramipril Tel. & Ram.

0.05

Ramipril

R+T

Systolic

135.8

133.5

Diastolic

77.5

76.1

0.0

Cumulative Hazard Rates

0.20

0.25

Yr 2

2 Years of Follow-up

ONTARGET

Reasons for Permanently Stopping Study Medications Ram N=8576

Ram + Tel N=8502

Hypotension

149

406

2.75

<0.0001

Syncope

1.95

0.032

Cough

360

392

1.10

0.1885

Diarrhea

3.28

0.0001

Angioedema

0.73

0.30

Renal Impairment

1.58

0.0050

2099

2495

1.20

<0.0001

Any Discontinuation

Ram + Tel vs. Ram RR P

ONTARGET: Effect on Albuminuria increase in log urine albumin:creatinine ratio Ramipril Telmisartan Ramipril+Telmisartan Mean 95% CI p v ramipril

31% 26–35%

24% 20–28% 0·027

21% 17–25% 0·0009

new onset micro/macro albuminuria Rv T

11.7 v 11.1%

HR=0.94 (0.86-1.02)

p=0.119

R v R+T

11.7 v 10.4%

HR=0.88 (0.81-0.96)

p=0.003

Mann et al 2008

Conclusions ¾

Telmisartan was clearly not inferior to ramipril for both the prespecified primary outcome of death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for heart failure and for the primary outcome in the HOPE trial (death from cardiovascular causes, myocardial infarction, or stroke).

Telmisartan exhibits superior overall tolerability: Less cough and angioneurotic edema More mild hypotensive symptoms, but no difference in severe hypotensive symptoms, such as syncope

There is no additional advantage (and there is some harm) from the combination of telmisartan and ramipril used in full doses in this population, as compared with ramipril alone.

The ONTARGET Investigators. Investigators. N Engl J Med 2008; 358: 15471547-1559

ACCOMPLISH – Trial Objectives Primary Endpoint: Time to first event of composite cardiovascular morbidity and mortality Cardiovascular morbidity: • Nonfatal, clinically evident acute myocardial infarction • Nonfatal stroke • Hospitalisation for unstable angina • Resuscitated sudden cardiac death • Coronary revascularisation procedures Cardiovascular mortality: • Fatal myocardial infarction • Fatal stroke • Coronary intervention • Congestive heart failure • Other cardiovascular causes including sudden cardiac death

Secondary Objectives: To evaluate the effect of the two fixed dose combination therapies on: • Composite cardiovascular morbidity • New onset diabetes • Renal disease progression • Hospitalisation for congestive cardiac failure

Jamerson K., et al. for the ACCOMPLISH trial investigators. N Engl J Med 2008; 359: 2417-2428

ACCOMPLISH â&#x20AC;&#x201C; Trial Design Prospective, randomized, double-blind, event-driven trial

Screening

Randomisation

Target BP <140/90 mmHg; <130/80 mmHg in patients with diabetes or renal insufficiency

Forced Titration

Free add-on* Benazepril 40 mg + Amlodipine 10 mg

Benazepril 40 mg + Amlodipine 5 mg Benazepril 20 mg + Amlodipine 5 mg

Benazepril 20 mg + HCT 12.5 mg

11,500 patients

Benazepril 40 mg + HCT 12.5 mg Benazepril 40 mg + HCT 25 mg Free add-on*

-2 Weeks

Day 1

*Beta blockers; alpha blockers; clonidine; loop diuretics HCT = Hydrochlorothiazide

Month 1

Month 2

Month 3 Follow up at 6 months and every 6 months thereafter

Jamerson K., et al. for the ACCOMPLISH trial investigators. N Engl J Med 2008; 359: 2417-2428

Year 5

Early termination in October 2007, after a mean of 30 months treatment exposure

20% risk reduction

Conclusions

他

The benazepril-amlodipine combination was superior to the benazepril-HCTZ combination in reducing CV events in patients with hypertension who were at high risk for such events.

Jamerson K., et al. for the ACCOMPLISH trial investigators N Engl J Med 2008; 359: 2417-2428

JIKEI Heart

Valsartan in a Japanese population with hypertension and other cardiovascular disease (Jikei Heart Study): a randomised, open-label, blinded endpoint morbidity-mortality study

Mochizuki S., et al. for the Jikei Heart Study group Lancet 2007; 369: 14311439

39% p=0.0002

Το σύνθετο καταληκτικό σημείο περιλαμβάνει: εγκεφαλικό επεισόδιο, ΤΙΑ, νοσηλεία για καρδιακή ανεπάρκεια ή στηθάγχη, ανεύρυσμα της αορτής, περιφερική αρτηριακή νόσο των κάτω άκρων, διπλασιασμό της κρεατινίνης και ανάγκη για αιμοκάθαρση.

JIKEI HEART: Καταληκτικά σημεία προσθήκης Βαλσαρτάνης στη συμβατική θεραπεία υπερτασικών με στεφανιαία νόσο και/ή συμφορητική καρδιακή ανεπάρκεια Βαλσαρτάνη Difference %

Καταληκτικά σημεία

Hazard ratio (95% CI)

Πρωτεύον καταληκτικό σημείο

0.61 (0.47-0.79)

0.0002

39%

Νέο ή υποτροπιάζον εγκεφαλικό

0.60 (0.38-0.95)

0.028

40%

Νοσηλεία λόγω καρδιακής ανεπάρκειας

0.54 (0.31-0.94)

0.029

46%

Νοσηλεία για στηθάγχη

0.35 (0.20-0.58)

<0.0001

65%

Mochizuki S., et al. for the Jikei Heart Study group Lancet 2007; 369: 1431-1439

Conclusions 他

The addition of valsartan to conventional treatment prevented more cardiovascular events than supplementary conventional treatment. These benefits cannot be entirely explained by a difference in blood pressure control.

Mochizuki S., et al. for the Jikei Heart Study group Lancet 2007; 369: 1431-1439

ADVANCE: a factorial randomised trial of blood pressure lowering and intensive glucose control in 11,140 patients with type 2 diabetes Effects of a fixed combination of the ACE inhibitor, perindopril, and the diuretic, indapamide on major vascular events

Lancet 2007 Sept 8;370:829-40

Randomised study treatments Blood pressure lowering Double-blind perindopril-indapamide versus matching placebo * 2.0 / 0.625mg or placebo for first 3 months 4.0 / 1.25mg or placebo thereafter

Blood glucose lowering (ongoing) Open-label gliclazide MR-based intensive therapy targeting an HbA1c of 6.5% versus usual guideline-based care * 50% of active group and 60% of placebo group also had open-label ACE inhibitor added by end of trial Lancet 2007;370:829-40

Primary study outcomes Macrovascular Non-fatal stroke, non-fatal myocardial infarction or death from any cardiovascular cause (including sudden death)

Microvascular New of worsening nephropathy or diabetic eye disease

Prespecified analyses: Macrovascular and microvascular jointly Macrovascular and microvascular separately

Lancet 2007;370:829-40

Blood pressure reduction BP = 145/81 mm Hg @ baseline 165

Placebo Perindopril-Indapamide

Mean Blood Pressure (mmHg)

155

Average BP during follow-up Systolic

145 135

140.3 mmHg 134.7 mmHg

Δ 5.6 mmHg (95% CI 5.2-6.0); p<0.001

125 115 105 95 85

Diastolic

Δ 2.2 mmHg (95% CI 2.0-2.4); p<0.001

65 R

77.0 mmHg 74.8 mmHg

Follow-up (Months)

Lancet 2007;370:829-40

Primary outcomes Major macro or microvascular event Number of events Per-Ind Placebo (n=5,569) (n=5,571)

Favours Favours Per-Ind Placebo

Relative risk reduction (95% CI)

Combined macro+micro 861

938

9% (0 to 17)*

Macrovascular

480

520

8% (-4 to 19)

Microvascular

439

477

9% (-4 to 20) 0.5

1.0

2.0

Hazard ratio

*p=0.04 Mean follow-up period 4.3 yrs Lancet 2007;370:829-40

All-cause mortality Cumulative incidence (%)

Placebo Perindopril-Indapamide

Relative risk reduction 14%: 95% CI 2-25% p=0.025 0 0

Follow-up (months)

Lancet 2007;370:829-40

Cardiovascular mortality Cumulative incidence (%)

Placebo Perindopril-Indapamide

Relative risk reduction 18%: 95% CI 2-32% p=0.03 0 0

Follow-up (months)

Lancet 2007;370:829-40

Conclusions 他 Routine administration of a fixed combination of

perindopril and indapamide to patients with type 2 diabetes was well tolerated and reduced the risks of major vascular events, including death.

他 Although the confidence limits were wide, the results

suggest that over 5 years, one death due to any cause would be averted among every 79 patients assigned active therapy.

Lancet 2007;370:829-40

United Kingdom Prospective Diabetes Study (UKPDS) (n=1148) • Αρτηριακή Πίεση ομάδας καλής ρύθμισης 144/82mmHg (vs 154/87mmHg)

(P<0.0001)

• τελικοί στόχοι σχετιζόμενοι με το διαβήτη: -24%

(P=0.0046)

• θάνατοι σχετιζόμενοι με το διαβήτη: -32%

(P=0.019)

• αγγειακά εγκεφαλικά επεισόδια: -44%

(P=0.013)

• τελικοί στόχοι μικροαγγειοπάθειας: -37%

(P=0.0092)

UKPDS HYPERTENSION SUBSTUDY

Diabetes-Related Deaths

Risk-Reduction of Stroke

Risk-Reduction 32%

Risk-Reduction 44%

P=0.019 Patients With Events (%)

Less Tight Control Tight Control

30 Mortality (%)

P=0.013

Less Tight Control Tight Control 10

0 0

3 4 5 6 Years from Randomization

UK Prospective Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 1998;317:703-13.

3 4 5 6 Years from Randomization

UK Prospective Study Group. Tight bl ood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 1998;317:703-13.

UKPDS. BMJ 1998;317:703-713.

N Engl J Med 2008;359:1565-1576.

Συμπεράσματα ¾ Τα οφέλη που είχαν παρατηρηθεί στην μελέτη UKPDS

από την καλή ρύθμιση της ΑΠ χάνονται όταν η διαφορά στην ΑΠ εξαφανισθεί. ¾ Η όσο το δυνατό πρωϊμότερη καλή ρύθμιση της ΑΠ

στους ασθενείς με σακχαρώδη διαβήτη τύπου 2 συνοδεύεται από ελάττωση του κινδύνου τόσο για τις μάκρο- όσο και τις μικροαγγειακές επιπλοκές, αλλά φαίνεται ότι αυτή η καλή ρύθμιση της ΑΠ πρέπει να συνεχίζεται για να παραμείνουν και τα οφέλη.

N Engl J Med 2008;359:1565-1576.

Differences in Glucose Tolerance Between Fixed-Dose Antihypertensive Drug STAR Trial Combinations in People With Metabolic Syndrome ¾

Patients with IGT and hypertension (n=240)

Fixed-dose combination of: ¾ ¾

trandolapril/verapamil-SR (T/V) or losartan/hydrochlorothiazide (L/H)

¾ Followed for up to 1 year ¾ Doses were titrated to a systolic blood pressure <130 mmHg ¾

Primary outcome was change from baseline in a 2-h glucose on oral glucose tolerance test (OGTT) at study end

Secondary outcomes included: ¾ ¾ ¾ ¾

changes in insulin sensitivity office and 24-h ambulatory blood pressure incidence of new-onset diabetes lipids, and inflammatory markers. Diabetes Care 2006; 29: 2592-2597

STAR Trial

OGTT results at baseline and study end

P=0.016

Diabetes Care 2006; 29: 2592-2597

STAR Trial

Secondary outcomes

L/H group had higher incidence of: ¾New-onset diabetes (L/H 26.6% vs. T/V 11.0 ; P = 0.002) ¾HbA1c > 7% (9.6% vs. 2.6%, respectively; P = 0.05) No differences were noted between groups at study end for: ¾mean office SBP (130.6+15.7 vs. 128.8+14.0 mmHg; P = 0.179) ¾DBP (78.7+10.0 vs.78.8+8.8 mmHg; P = 0.605) ¾total cholesterol (P = 0.20) ¾triglycerides (P = 0.36) ¾LDL cholesterol (P = 0.24) ¾HDL cholesterol (P = 0.13) ¾high-sensitivity C-reactive protein (P = 0.76) Diabetes Care 2006; 29: 2592-2597

STAR Trial

Conclusions

In patients with IGT, normal kidney function, and hypertension, the fixed-dose combination of trandolapril / verapamil-SR compared with an losartan / hydrochlorothiazide based therapy: 他improve glycemic control and 他reduces the risk of new-onset diabetes

Diabetes Care 2006; 29: 2592-2597

9306 patients with impaired glucose tolerance and established cardiovascular disease or cardiovascular risk factors to receive valsartan (up to 160 mg daily) or placebo in addition to lifestyle modification. Median follow-up 5.0 years Outcomes: 他The development of diabetes 他An extended composite outcome of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, hospitalization for heart failure, arterial revascularization, or hospitalization for unstable angina; and 他a core composite outcome that excluded unstable angina and revascularization. N Engl J Med 2010; 362(16):1477-1490.

N Engl J Med 2010; 362(16):1477-1490.

Incidence of Diabetes Mellitus Diabetes mellitus developed in: 他1532 patients (33.1%) in the valsartan group 他1722 patients (36.8%) in the placebo group HR 0.86 (95% CI, 0.80 to 0.92; P<0.001)

N Engl J Med 2010; 362(16):1477-1490.

Conclusions When added to a lifestyle intervention, valsartan at a daily dose of 160 mg, in patients with impaired glucose tolerance: 他 Reduced the risk of diabetes, but 他 Did not affect cardiovascular outcomes 他 No safety concerns were identified.

N Engl J Med 2010; 362(16):1477-1490.

Προϋπέρταση Καρδιαγγειακή προστασία Αντιϋπερτασική αγωγή και Σακχαρώδης Διαβήτης Θεραπεία υπέρτασης σε υπερήλικες Πρόληψη αγγειακών εγκεφαλικών επεισοδίων – Άνοιας Επιδημιολογικές μελέτες έχουν δείξει ότι η θεραπεία Νεφροπροστασία της Υπέρτασης σε άτομα > 80 ετών: Επίδραση αναστολέων του άξονα ρενίνης¾Μειώνει των τον κίνδυνο για ΑΕΕ, αλλά πιθανώς ¾Αυξάνει την θνητότητα. αγγειοτενσίνης (RAS) στη πρόληψη της κολπικής μαρμαρυγής ¾ Πόσο πρέπει να μειώσουμε την αρτηριακή πίεση ¾ ¾ ¾ ¾ ¾ ¾ ¾

Treatment of Hypertension in patients 80 Years of Age or Older The Trial: International, multi-centre, randomised double-blind placebo controlled Inclusion Criteria: Aged 80 or more, Systolic BP; 160 -199mmHg + diastolic BP; <110 mmHg, Informed consent

Exclusion Criteria: Standing SBP < 140mmHg Stroke in last 6 months Dementia Need daily nursing care

Primary Endpoint: All strokes (fatal and non-fatal)

+ Perindopril 4 mg

3845 patients 80 years or older with persistent hypertension

+ Perindopril 2 mg Indapamide SR 1.5 mg

Target blood pressure

Placebo

< 150/80 mmHg Placebo + Placebo + Placebo

M-2

M-1

M12

M18

M24

M60

Beckett N et al. N Engl J Med 2008;358:1887-98

Blood pressure separation Mean BP baseline: 173/91 mmHg

180

BP decrease: placebo: 14.5/ 6.8 mmHg active: 29.5/ 12.9 mmHg

15 mmHg

170 160 Blood Pressure (mmHg)

150 140

Placebo

130 120

Indapamide SR +/perindopril

I Median follow-up 1.8 years

110 100

6 mmHg

90 80 70

Follow-up (years)

Beckett N et al. N Engl J Med 2008;358:1887-98

All stroke (30% reduction)

P=0.055

Beckett N et al. N Engl J Med 2008;358:1887-98

Fatal Stroke (39% reduction)

P=0.046

Beckett N et al. N Engl J Med 2008;358:1887-98

Total Mortality (21% reduction)

P=0.019

Beckett N et al. N Engl J Med 2008;358:1887-98

Heart Failure (64% reduction)

P<0.0001

Beckett N et al. N Engl J Med 2008;358:1887-98

Biochemical Changes from Baseline ¾In 2 year cohort there were no significant differences between the

groups with regard to change in serum…. Potassium Uric acid Glucose Creatinine

Safety Reported serious adverse events (after randomisation) ¾448 in the placebo group vs 358 in active (p=0.001)

Only 5 categorised by the local investigator possible SADRs (3 in placebo group, 2 being in active) Beckett N et al. N Engl J Med 2008;358:1887-98

Conclusions ¾ Antihypertensive treatment based on indapamide (SR) 1.5mg (±

perindopril) reduced not only stroke (fatal and non-fatal) but also total mortality in a very elderly cohort.

¾ NNT (2 years) = 94 for stroke and 40 for mortality ¾ Large and significant benefit in reduction of heart failure events

and for combined endpoint of cardiovascular events

¾ Benefits seen early (1st year) ¾ Treatment regime employed was safe

Cautions ¾ Benefit from treating systolic pressures less than 160mmHg

requires further research

¾ Target blood pressure was 150/80 mmHg

Benefit from lower targets still needs to be established Beckett N et al. N Engl J Med 2008;358:1887-98

Morbidity and mortality after stroke, eprosartan compared with nitrendipine for secondary prevention. ¾Τυχαιοποιήθηκαν 1.405 υπερτασικοί που είχαν υποστεί ένα ΑΕΕ τους τελευταίους 24 μήνες να λάβουν επροσαρτάνη ή νιτρεδιπίνη. ¾Αποκλείσθηκαν ασθενείς με: Στένωση καρωτίδας > 70% Καρδιακή ανεπάρκεια (NYHA III-IV) Ηλικία > 85 Θεραπεία με αντιπηκτικά

¾Μέση περίοδο παρακολούθησης 2,5 ετών.

Schrader J., et al. for the MOSES Study Group. Stroke 2005; 36: 1218-1226

Πρωτεύον τελικό σημείο (νοσηρότητα και θνησιμότητα για την ίδια μείωση της ΑΠ) 300

Nιτρενδιπίνη

Eπροσαρτάνη

-21%

Επεισόδια (n)

250

p=0.014

200 150 100 50 0

Μείωση κινδύνου με την Επροσαρτάνη κατά 21% (p=0.014) 200

400

600

800

1000

1200

1400

1600

Ημέρες Stroke 2005; 36;1218-1226

Δευτερεύον τελικό σημείο (αγγειακά εγκεφαλικά επεισόδια) 150

Nιτρενδιπίνη

Eπροσαρτάνη

-25%

125

Επεισόδια (n)

p=0.026

100 75 50 25

Μείωση κινδύνου με την Επροσαρτάνη κατά 25% (p=0.026)

0 200

400

600

800

Ημέρες

1000

1200

1400

1600

Stroke 2005; 36;1218-1226

Δευτερεύον τελικό σημείο (καρδιαγγειακά επεισόδια) 150

Nιτρενδιπίνη

Eπροσαρτάνη

-25%

125

Επεισόδια (n)

p=0.06

100 75 50 25 0 200

400

600

800

Ημέρες

1000

1200

1400

1600

Stroke 2005; 36;1218-1226

New Engl J of Med 2008; 359: 1225-38

PRoFESS inclusion ¾ Age > 55yrs ¾ Ischemic stroke < 90 days ¾ 10.146 telmisartan vs. 10.186 placebo ¾ Median 15 days after stroke ¾ Primary outcome: stroke ¾ FU mean 2.5 years

New Engl J of Med 2008; 359: 1225-38

RRR 5% P=0.23

New Engl J of Med 2008; 359: 1225-38

RRR=6% p=0.11

RRR=18% p=0.1

RR 3.7%

ProGRESS

HOPE

RRR 22%

RR 1.8% RRR 20%

0.00

Mean FU 4.5 years + 1,5 years

Mean FU 4.2 years

Mean FU 4 years RR 1.8%

+ 1 years

ProFESS RR 0.9% RRR 7%

RRR 14%

P= 0.067

P= 0.045

ONTARGET

Mean FU 2.5 years

Conclusions 他 Therapy with telmisartan initiated soon after an ischemic stroke and continued for 2.5 years did not significantly lower the rate of recurrent stroke, major cardiovascular events, or newonset diabetes.

New Engl J of Med 2008; 359: 1225-38

OSCAR Effects of hypertension therapy based on eprosartan on systolic arterial blood pressure and cognitive function: primary results of the Observational Study on Cognitive function And Systolic Blood Pressure Reduction open-label study

J Hypertens. 2008;26(8):1642-1650.

OSCAR ¾ 25.745 Υπερτασικοί > 50 ετών. ¾ Eprosartan 600mg μονοθεραπεία ή σε συνδυασμό. ¾ 6 μήνες. ¾ Μείωση ΑΠ κατά 25 / 12 mmHg. ¾ Βελτίωση του Mini-Mental State Examination score (27,9+2,9 σε σχέση με 27,1+3,4, p<0,0001). ¾ Ασθενείς που στο τέλος της μελέτης είχαν ΣΑΠ<140mmHg είχαν μεγαλύτερη βελτίωση του Mini-Mental score. ¾ Τα αποτελέσματα της μελέτης αυτής ενισχύουν την τρέχουσα αντίληψη ότι η θεραπεία της υπέρτασης με φάρμακα που αναστέλλουν τον άξονα ρενίνης-αγγειοτενσίνης βελτιώνει την γνωσιακή λειτουργία.

J Hypertens. 2008;26(8):1642-1650.

Combination therapy with an ACE inhibitor and an angiotensin receptor blocker for diabetic nephropathy: a meta-analysis

Proteinuria was reduced with ACEI + ARB (p = 0.01)

Jennings D. L. et al. Diabetic Medicine 2007; 24: 486-493

Change

95% CI

p Value

SBP (mmHg)

- 5.2

- 8.4 to - 2.1

< 0.01

DBP (mmHg)

- 5.3

- 8.4 to - 2.2

< 0.01

GFR § (ml/min)

- 3.87

7.32 to 0.42

0.03

Serum creatinine $ (µmol/L)

6.86

- 0.76 to 13.73

0.09

Serum potassium & (mmol/L)

0.2

0.08 to 0.32

< 0.01

Blood pressure *

Prevention of Atrial Fibrillation by Renin-Angiotensin System Inhibition A Meta-Analysis 他 A total of 23 randomized controlled trials with 87.048 patients were analyzed. 他 Overall, RAS inhibition reduced the odds ratio for AF by 33% (p < 0.00001). 他 But there was substantial heterogeneity among trials.

Schneider M, et al., Am Heart J 2010; 55: 2299-2307

Prevention of Atrial Fibrillation by Renin-Angiotensin System Inhibition A Meta-Analysis In primary prevention: RAS inhibition was effective in patients with: ¾ heart failure and ¾ those with hypertension and left ventricular hypertrophy ¾ but not in post-myocardial infarction patients overall.

In secondary prevention: RAS inhibition was often administered in addition to antiarrhythmic drugs, including amiodarone, further reducing the odds for AF recurrence: ¾ after cardioversion by 45% (p = 0.01) and ¾ in patients on medical therapy by 63% (p < 0.00001). Schneider M, et al., Am Heart J 2010; 55: 2299-2307

ΠΙΕΣΗ - ΣΤΟΧΟΣ ESH-ESC 2007

r e t t e

B e Σε όλους τους υπερτασικούς h T r Χαμηλότερες τιμές αν είναι καλά ανεκτές e w o L <130/80 mmHg e h T Διαβήτης – Νεφρική νόσος Σ. <140/90 mmHg

Μεγάλος καρδιαγγειακό κίνδυνος

J - CURVE

30 20 10 0

(high risk pts, mainly with CAD) 30 3

INVEST (CAD pts) CV events (%)

CV events (%)

110 >110 >120 >130 >140 >150 >160 to 120 to 130 to 140 to 150 to 160

On-treatment SBP (mmHg) 35

TNT (CAD pts)

CV events (%)

Cardiac events (%)

VALUE (High risk pts)

0 112 121 126 130 133 136 140 144 149 160

On-treatment SBP (mmHg)

ONTARGET

< 120 >120 >130 >140 >150 >160 >170 ≥ 180 to 130 to 140 to 150 to 160 to 170 to 180

On-treatment SBP (mmHg)

5 4

10 1

5 0

Adjusted HR

≤ 60

6161-70 7171-80 8181-90 9191-100 > 100

On-treatment DBP (mmHg)

Adjusted HR

¾ ¾ ¾

A randomized open-label trial undertaken in 44 centres in Italy. 1111 non-diabetic patients with SBP > 150 mmHg and at least one additional risk factor. They were randomly assigned to a target SBP : ¾ ¾

< 140 mm Hg (usual control; n=553) or < 130 mm Hg (tight control; n=558)

The primary study outcome was the prevalence of electrocardiographic left ventricular hypertrophy at the final 2-year visit.

Secondary outcome was a composite of all-cause mortality, fatal or non-fatal MI, fatal or non-fatal stroke, TIA, congestive heart failure of NYHA III or IV requiring admission to hospital, angina pectoris with objective evidence of myocardial ischaemia, new-onset atrial fibrillation, coronary revascularisation, aortic dissection, PAD, and renal failure requiring dialysis. Lancet 2009; 374(9689): 525-533.

Rate of left ventricular hypertrophy by randomisation groups at baseline and follow-up At the end of the study BP was 135.6/78.7mmHg in the usual-control group and 131.9/77.4 mm Hg in the tight-control group. Between-group difference 3.8 mm Hg systolic (p<0.0001) and 1.5mmHg diastolic (p=0.041). SBP<130mmHg at 2 years: 27.3% in the usual-control group The likelihood of LVH compared with baseline decreased: 72.2% in the tight-control 69% in tight-control (p<0.0001) group (p<0.0001). 32% in usual-control (p=0.13) Lancet 2009; 374(9689): 525-533.

Secondary outcome

Lancet 2009; 374(9689): 525-533.

Conclusions 他 Tight control of systolic blood pressure to less than 130 mm Hg in non-diabetic patients with at least one additional risk factor decreased the likelihood of electrocardiographic left ventricular hypertrophy and clinical events, compared with usual control to less than 140 mm Hg systolic.

他 Adverse reactions were rare, generally mild, and occurred at a similar rate in the two treatment groups.

Lancet 2009; 374(9689): 525-533.

Published online March 14, 2010

ACCORD Study Design • Randomized multi-center clinical trial • Conducted in 77 clinical sites in North America (U.S. & Canada) • A total of 4.733 participants • Designed to independently test three medical strategies to reduce CVD in diabetic patients • BP question: does a therapeutic strategy targeting systolic blood pressure (SBP) <120 mmHg reduce CVD events compared to a strategy targeting SBP <140 mmHg in patients with type 2 diabetes at high risk for CVD events?

ACCORD BP Trial Eligibility & Outcomes • •

Stable Type 2 Diabetes >3m (HbA1c 7.5% to 11%) High CVD risk = clinical or subclinical disease or ≥2 risk factors

•

Age (limited to <80 years after Vanguard) • •

• • •

≥ 40 yrs with history of clinical CVD (secondary prevention) ≥ 55 yrs otherwise Systolic blood pressure: 130 to 180 mm Hg (if on 0-3 meds)

Urine protein <1.0 gm/24 hours or equivalent Serum Creatinine ≤1.5 mg/dl

•

The primary outcome was the first occurrence of a major cardiovascular event, which was defined as the composite of ¾ Nonfatal myocardial infarction, ¾ Nonfatal stroke, or ¾ Cardiovascular death

•

Prespecified secondary outcomes included the combination of the primary outcome plus revascularization or hospitalization for congestive heart failure

Mean # Meds Intensive: Standard:

3.2 1.9

3.4 2.1

3.5 2.2

3.4 2.3

Average after 1st year: 133.5 Standard vs. 119.3 Intensive, Delta = 14.2

Primary Outcome

Total Mortality

Nonfatal MI, Nonfatal Stroke or CVD Death 20

HR = 0.88 95% CI (0.73-1.06) P=0.20

Patients with Events (%)

HR = 1.07 95% CI (0.85-1.35) P=0.55

0 0

Years Post-Randomization

Mean follow-up period 4.7 yrs

Non Fatal MI

CVD Deaths 20

HR = 0.87 95% CI (0.68-1.10) P=0.25

Patients with Events (%)

HR = 1.06 95% CI (0.74-1.52) P=0.74

0 0

Years Post-Randomization

Nonfatal Stroke

Total Stroke 20

HR = 0.63 95% CI (0.41-0.96) P=0.03

Patients with Events (%)

HR = 0.59 95% CI (0.39-0.89) P=0.01

NNT for 5 years = 89

Years Post-Randomization

Intensive N (%) 77 (3.3)

Standard N (%) 30 (1.3)

<0.0001

Hypotension

17 (0.7)

1 (0.04)

<0.0001

Syncope Bradycardia or Arrhythmia Hyperkalemia

12 (0.5)

5 (0.2)

0.10

12 (0.5)

3 (0.1)

0.02

9 (0.4)

1 (0.04)

0.01

Renal Failure eGFR ever <30 mL/min/1.73m2 Any Dialysis or ESRD

5 (0.2)

1 (0.04)

0.12

99 (4.2)

52 (2.2)

<0.001

59 (2.5)

58 (2.4)

0.93

Dizziness on Standingâ&#x20AC;

217 (44)

188 (40)

0.36

Serious AE

â&#x20AC; Symptom experienced over past 30 days from HRQL sample of N=969 participants assessed at 12, 36, and 48 months post-randomization

Conclusions 他The ACCORD BP trial provide no conclusive evidence that the intensive BP control strategy reduces the rate of a composite of major CVD events in patients with type 2 diabetes at increased cardiovascular risk. 他 It is possible that lowering systolic blood pressure from the mid-130s to approximately 120 mm Hg does not further reduce most cardiovascular events or the rate of death, and most of the benefit from lowering blood pressure is achieved by targeting a goal of less than 140 mmHg. 他 Alternatively, it is possible that 5 years is not long enough to see significant cardiac benefits from the normalization of SBP among persons with diabetes who have good control of glycemia, especially when other effective treatments, such as statins and aspirin, are used frequently

Conclusions: Intensive glycemic control and intensive combination treatment of dyslipidemia, but not intensive blood-pressure control, reduced the rate of progression of diabetic retinopathy.

Principal results of the Japanese trial to assess optimal systolic blood pressure in elderly hypertensive patients (JATOS) ¾

4.418 patients (65-85 years old) with SBP > 160 mmHg

SBP target: ¾ ¾

< 140 mmHg strict treatment < 160 mmHg mild treatment

The primary endpoint was the combined incidence of cardiovascular disease and renal failure. The secondary endpoints were total deaths and any safety problems.

Follow-up 2-year

Results: ¾ The incidence of the primary endpoint was similar in the two groups (86 patients in each group; p=0.99). ¾ Total deaths were 54 in the strict-treatment group vs. 42 in the mildtreatment group (p=0.22), and ¾ Treatment was withdrawn because of adverse events in 36 patients in each group (p=0.99). Hypertens Res 2008 Dec;31(12):2115-27.

Συμπεράσματα I ¾ Τα υπάρχοντα δεδομένα δεν υποστηρίζουν την ανάγκη χορήγησης φαρμακευτικής αγωγής στα άτομα με προϋπέρταση. Πρέπει όμως αυτά να είναι σε παρακολούθηση και να καταβάλλεται προσπάθεια αλλαγής τρόπου ζωής καθώς η πλειοψηφία αυτών πολύ σύντομα θα αναπτύξει υπέρταση. ¾ Υπάρχει υπεροχή όσον αφορά την καρδιαγγειακή προστασία του συνδυασμού φαρμάκων που αναστέλλουν τον RAS και των αναστολέων διαύλων ασβεστίου έναντι του συνδυασμού βαποκλειστών και διουρητικών. ¾ Ειδικά στους διαβητικούς, η αντικατάσταση του διουρητικού από ένα αναστολέα των διαύλων ασβεστίου, στο συνδυασμό με φάρμακο που αναστέλλει τον RAS, μειώνει τα καρδιαγγειακά επεισόδια, ενώ στα άτομα με μεταβολικό σύνδρομο μειώνει τον κίνδυνο εμφάνισης διαβήτη.

Συμπεράσματα II ¾ Στους διαβητικούς τα πλεονεκτήματα που προκύπτουν από την καλή ρύθμιση της ΑΠ εξαφανίζονται όταν η ρύθμιση αυτή χαθεί. ¾ Τα οφέλη από τη ρύθμιση της ΑΠ ειδικά στην μείωση των ΑΕΕ, αλλά και της καρδιακής ανεπάρκειας επεκτείνονται ακόμα και στους υπερήλικες άνω των 80 ετών. ¾ Η χορήγηση αναστολέα του RAS είναι επωφελής στην δευτερογενή πρόληψη των ΑΕΕ, αλλά και βελτιώνει την γνωσιακή λειτουργία στους ηλικιωμένους.

Συμπεράσματα III ¾ Ο συνδυασμός ACEIs & ARBs δεν προσφέρει κανένα πλεονέκτημα (έναντι της μονοθεραπείας) ούτε στην καρδιαγγειακή προστασία, ούτε στην επιβράδυνση της εξέλιξης της διαβητικής νεφροπάθειας. ¾ Οι αναστολείς του RAS είναι επωφελείς στην πρόληψη (πρωτογενή και δευτερογενή) της κολπικής μαρμαρυγής. ¾ Από τις υπάρχουσες μελέτες δεν προκύπτει όφελος από την επιθετική μείωση της ΣΑΠ κάτω από 120mmHg τόσο για τον γενικό πληθυσμό των υπερτασικών, όσο και για τους διαβητικούς. ¾ SPRINT Trial (NIH) [SBP <140mmHg vs. <120mmHg]

Angiotensin-receptor blockade and risk of cancer: meta-analysis of randomised controlled trials ¾ New-cancer data were available for 61.590 patients from five trials. ¾ Patients randomly assigned to receive ARBs had a significantly increased risk of new cancer occurrence compared with patients in control groups (7.2% vs 6.0%, risk ratio [RR] 1.08, 95% CI 1.011.15; p=0.016). ¾ Among specific solid organ cancers examined, only new lungcancer occurrence was significantly higher in patients randomly assigned to receive ARBs than in those assigned to receive control (0.9% vs 0.7%, RR 1.25, 1.05-1.49; p=0.01). ¾ No statistically significant difference in cancer deaths was observed (1.8% vs 1.6%, RR 1.07, 0.97-1.18; p=0·183).

The Lancet Oncology, Early Online Publication, 14 June 2010