ΕΙΝΑΙ ΟΛΑ ΤΑ ΔΙΟΥΡΗΤΙΚΑ ΤΑ ΙΔΙΑ ΚΑΙ ΣΕ ΠΟΙΕΣ ΔΟΣΕΙΣ;

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1 ΕΙΝΑΙ ΟΛΑ ΤΑ ΔΙΟΥΡΗΤΙΚΑ ΤΑ ΙΔΙΑ ΚΑΙ ΣΕ ΠΟΙΕΣ ΔΟΣΕΙΣ; Κωνσταντινίδης Δημήτρης Καρδιολόγος Επιστ. Συνεργάτης Μονάδας Υπέρτασης Ά Πανεπιστημιακή Καρδιολογική Κλινική ΓΝΑ Ιπποκράτειο

2 HISTORY OF DIURETICS TREATMENT OF ESSENTIAL HYPERTENSION WITH CHLOROTHIAZIDE (DIURIL)ITS USE ALONE AND COMBINED WITH OTHER ANTIHYPERTENSIVE AGENTS Edward D. Freis, M.D.; Annemarie Wanko, M.D.; Ilse M. Wilson, M.D.; Alvin E. Parrish, M.D. JAMA. 1958;166(2): Ten hypertensive patients were hospitalized on a constant intake of sodium chloride until their blood pressure levels had stabilized. Chlorothiazide in amounts of 1.5 Gm. per day reduced the systolic blood pressure in all. The average reduction was 18.7%, it took place within two or three days and was maintained to the end of a six-day period of medication. When it was withdrawn the blood pressure returned to its former level. Chlorothiazide (maintenance dose, 0.5 Gm. twice daily) added to the regimen of 73 ambulatory hypertensive patients who were receiving other antihypertensive drugs as well caused an additional reduction of blood pressure. In some patients it was possible to withdraw all other antihypertensive medication and to maintain the patient on chlorothiazide alone. Most of the patients noted a diuresis the first day or two after treatment with chlorothiazide. It exaggerated postural hypotension when that sign was already present, and reduction of the dosages of ganglion-blocking agents was necessary when chlorothiazide treatment was begun, in order to prevent postural collapse. Chlorothiazide also enhanced the antihypertensive activity of hydralazine, Veratrum, and reserpine. Side-effects were mild and infrequent and were promptly obviated by temporary withdrawal of the drug. John Baer Karl Beyer Frederick Novello James Sprague The renal team at MSD laboratories

3 ΔΡΑΣΗ ΤΩΝ ΘΕΙΑΖΙΔΙΚΩΝ ΔΙΟΥΡΗΤΙΚΩΝ 4-6 weeks RAAS activation Ernst M, Moser M. N Engl J Med 2009;361: Birkenhäger, WH. J. Hyperten. 1990, 8 (Suppl 2) S3-S7.

4 DIURETICS IN HYPERTENSION As with other antihypertensive drugs in monotherapy, only 40-60% of individuals treated with thiazide diuretics achieve an adequate BP control. Predictors of greater BP responses include higher baseline BP level, female gender, shorter duration of diagnosed or treated hypertension, lower plasma renin activity (elderly, blacks, diabetics) and urinary aldosterone excretion and greater decrease in urinary sodium excretion. Mancia G et al. Eur Heart J 2013;34:

5 Αγωγή με Διουρητικά Μονο- ή Συνδυασμένη Θεραπεία Φάρμακα 1 ης επιλογής JNC JNC Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure - Complete Report Σε άτομα > 55 ετών και μαύρης φυλής NICE 2011 NHS, National Institute for Health and Clinical Excellence: Hypertension Management of hypertension in adults in primary care Έναρξη με μία από τις 5 κατηγορίες - περιλαμβάνονται τα διουρητικά 2013 ESH/ESC European guidelines for the management of arterial hypertension Σε άτομα > 60 ετών και υπέρταση σταδίου ASH/ISH 2014 ASH/ISH Clinical practice guidelines for the management of hypertension in the community

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7 THE SYSTOLIC HYPERTENSION IN THE ELDERLY PROGRAM (SHEP): AN INTERVENTION TRIAL ON ISOLATED SYSTOLIC HYPERTENSION persons 60 years SBP mmhg and DBP <90 mmhg CTD mg/d (± atenolol) or placebo Average follow-up was 4.5 years Long-term All-Cause Mortality years -36% stroke -32% major cardiovascular events Each month of active treatment was therefore associated with approximately 1 day extension in life expectancy JAMA Jun 26;265(24): Kostis J, et al. JAMA. 2011;306(23):

8 A total of participants aged 55 years or older with hypertension and at least 1 other CHD risk factor. Participants were randomly assigned to receive chlorthalidone, 12.5 to 25 mg/d (n = ); amlodipine, 2.5 to 10 mg/d (n = 9048); or lisinopril, 10 to 40 mg/d (n = 9054) Mean follow-up was 4.9 years JAMA. 2002;288:

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10 MULTIPLE RISK FACTOR INTERVENTION TRIAL (MRFIT) It was the first study to hint that CTD may be superior to HCTZ (50 or 100 mg daily). Coronary heart disease (CHD) mortality of special intervention clinics using HCTZ was 44% higher than other clinics (P=0.23). -21% p= A retrospective observational cohort study from the MRFIT data Dorsch M, et al. Hypertension. 2011;57:

11 SECOND AUSTRALIAN NATIONAL BLOOD PRESSURE STUDY (ANBP2) 6083 subjects with hypertension who were 65 to 84 years Followed for a median of 4.1 years Enalapril vs hydrochlorothiazide N Engl J Med 2003;348:583-92

12 ΘΕΙΑΖΙΔΙΚΑ ΔΙΟΥΡΗΤΙΚΑ Roush GC et al. J Cardiovasc Pharmacol Ther Jan;19(1):5-13

13 Ernst M, et al. Hypertension. 2006;47: ABPM 30 patients, age HCTZ VS CTD Newly diagnosed hypertensive stage 1 or 2 4 weeks HCTZ 25mg or CTDN 12,5mg Up-titrated to HCTZ 50mg or CTDN 25mg for other 4 weeks OSBP ASBPM -7.1mmHg

14 FLAT DOSE-RESPONSE CURVE THEORY During the first 20 years: high doses of diuretics (HCTZ >100mg, CTD mg) much of electrolytic principally side effects. 1980s and 1990s: several studies confirmed that thiazide diuretics presented a flat dose-response curve, so that near-maximal Na + excretion was achieved at relatively low doses of HCTZ ( mg/day) and further increases in drug dose slightly increased Na + excretion but dose-dependently increased hydroelectrolytic and metabolic disorders. Lower doses less side effects. Materson BJ, et al. Clin Pharmacol Ther 1978;24:192-8 Jounela AJ, et al. Blood Press 1994;3:231-5 Materson BJ, et al. Hypertension 1990;15:348-60

15 DOSE EQUIVALENT HCTZ-CTD BP dropped 18/8 mm Hg with 25 mg CTD daily but only 28/11 mm Hg with 200 mg daily HCTZ = CTD/1,5-2 Although there was an 8-fold increase in dose (25 to 200 mg), serum concentration increased only 2-fold. Carter B, et al. Hypertension. 2004;43:4-9

16 DOSE OF HCTZ ABP Dose 12,5-25mg -6.5 mmhg after 17 weeks Messerli FH et al. J Am Coll Cardiol 2011;57:

17 EVENT REDUCTION WITH LOW DOSE OR HIGH DOSE DIURETIC OR B-BLOCKER

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19 COMBINATION WITH AT patients 306 patients On target 71.5% 62.3% The percentage of participants achieving target clinic blood pressure at week 6 was greater for the CTD versus HCTZ combination (64.1% vs 45.9%, P.001). The mean difference ASBPM at week 6 was 5.8 mmhg (95% CI, 8.4 to 3.2; P.001), favoring the azilsartan/ctd group. Hypokalemia was uncommon in both groups (1.7% vs 0.3%) Bakris GL, et al. Am J Med 2012; 12:1229e1 1229e10

20 PLEIOTROPIC EFFECTS OF INDAPAMIDE INDA vs HCTZ Senior R, et al. J Cardiovasc Pharmacol. 1993;22(suppl6):S Vinereanu D, et al. Am Heart J 2014;168:

21 HYVET 3845 patients over 80 years old Active treatment indapamide SR 1,5mg ± peridropil Target 150/80mmHg Median follow-up was 1.8 years Heart failure Similar serum potassium levels in the two Groups. 73.4% of patients in the active treatment group receiving both indapamide and perindopril at 2 years. N Engl J Med May 1, ;18

22 HCTZ VS INDAPAMIDE HCTZ INDAP Dose 1 12,5 1,5 (1,25) Dose (2,5) Dose ,5 (5) -4,7mmHg K + Roush G et al. Hypertension 2015;65:

23 ΑΝΕΠΙΘΥΜΗΤΕΣ ΕΝΕΡΓΕΙΕΣ ΔΙΟΥΡΗΤΙΚΩΝ Ηλεκτρολυτικές διαταραχές (υποκαλιαιμία, υπομαγνησιαιμία και υπονατριαιμία) με συνέπεια αύξηση του κινδύνου αρρυθμιών. Νεοεμφανιζόμενο διαβήτη (3-4%) χωρίς αύξηση των καρδιαγγειακών συμβαμάτων (μελέτη ALLHAT). Αύξηση ουρικού οξέος (εως 35%), σπάνια όμως ουρική αρθρίτιδα. Αύξηση της ολικής χοληστερόλης 5% και της LDL-C 7%. Η Ινδαπαμίδη προκαλεί αύξηση της γλυκόζης όχι όμως και του ουρικού οξέος, παρατείνει το QT διάστημα ανεξάρτητα από τα επίπεδα του K +.

24 HYPONATREMIA Η υπονατριαιμία πιο συχνή με την CTD σε ίσες δόσεις 12.5 mg/d AOR 2.09 (95% CI, ) 25 mg/d AOR 1.72 (95% CI, ) Δεν υπάρχει στατιστική διαφορά όταν χρησιμοποιούνται ισοδύναμες δόσεις CTDN 12.5 mg/d vs HCTZ 25 mg/d AOR 1.66 (95% CI, ) CTDN 25 mg/d vs HCTZ 50 mg/d AOR 0.85 (95% CI, ) Blijderveen J, et al. The American Journal of Medicine (2014) 127,

25 K + decrease with HCTZ and CTD HCTZ CTDN Chlorthalidone s effects on potassium are subject to more variability than can be explained primarily by dose Peterzan M, et al. Hypertension. 2012;59:

26 Effects of CTD vs HCTZ over time MRFIT CTD compared with HCTZ patients displayed: lower SBP (overall P<0.0001), TC (overall P<0.0001), LDL (overall P=0.0009), serum potassium (overall P=0.0003) higher uric acid (overall P<0.0001). Dorsch M, et al. Hypertension. 2011;57:

27 DIABETES LOW-DOSE THIAZIDEDIURETICS (DIME) STUDY 1130 patients were allocated to Diuretics (n=544) or No-diuretics group (n=586) 12.5 mg/day of hydrochlorothiazide, 1 mg/day of indapamide Median follow-up of 4.4 years Almost 80% of patients in the Diuretic Use group used inhibitors of RAS Diabetes K + levels were very slightly but significantly lower by 0.1 mmol/l in the Diuretics group Na + levels were also slightly but significantly lower by <1 mmol/l in the Diuretics group Serum uric acid levels were significantly higher in the Diuretic group- treatment with diuretics did not increase the incidence of gout Ueda S, et al. BMJ Open 2014;4:e004576

28 DIURETIC-INDUCED GLUCOSE CHANGES MAY UNDERLINE LESSER PROGNOSTIC SIGNIFICANCE (EXTENSION OF ALLHAT) CTD is associated with an increased risk of diabetes CTD (7.5%) amlodipine (5.6%) lisinopril (4.3%) Diabetes associated with CTD use has lower long-term cardiovascular disease risk than diabetes associated with angiotensin-converting enzyme inhibitor or calcium channel blocker use. Circ Cardiovasc Qual Outcomes. 2012;5:

29 ΠΟΙO ΔΙΟΥΡΗΤΙΚΟ; «If diuretic treatment is to be initiated or changed, offer a thiazide-like diuretic, such as chlortalidone ( mg once daily) or indapamide (1.5 mg modified-release once daily or 2.5 mg once daily) in preference to a conventional thiazide diuretic such as bendroflumethiazide or hydrochlorothiazide [new 2011]»

30 PATHWAY-3 2h Glucose Home SBP Office SBP p=0,039 p=0,0026 p=0,0068 p=0, patients 12 weeks of daily oral treatment with: 10mg amiloride or 25mg hydrochlorothiazide or 5mg amiloride + 12,5mg hydrochlorothiazide After 12 weeks all doses were doubled K + Uric Acid Brown MJ, et al. Lancet Diabetes Endocrinol Oct 16

31 OXI ΑΝ GFR<30ML/MIN/1.73M 2? JNC7 recommended changing from thiazide to loop diuretics when estimated GFR falls below 30 ml/min/1.73 m2, JNC8 recommendations do not take a position on the use of thiazide versus loop diuretics in CKD. KDIGO 2012: As the GFR falls below about ml/min/1.73 m2, the ability of thiazides to overcome fluid retention is diminished, although their antihypertensive benefit may be preserved Most clinicians switch to a loop diuretic in patients with CKD 4, particularly if the BP is becoming resistant to therapy or edema becomes a problem. Loop diuretics are particularly useful when treating edema and high BP in CKD 4 5 patients in addition or as an alternative to thiazide diuretics. Chlorthalidone 25mg daily was associated with a significant reduction in office BP, including in those subjects with GFR<30. Thiazides appear promising for treatment of both volume overload and hypertension in patients with advanced kidney disease, either as a lone diuretic or in combination with loop diuretics. Cirillo M, et al. Hypertension. 2014;63: Arjun D. Sinha, Rajiv Agarwal. Curr Hypertens Rep (2015) 17: 13

32 ΣΥΜΠΕΡΑΣΜΑΤΑ Τα διουρητικά παραμένουν ακρογωνιαίος λίθος στη θεραπεία της ΑΥ. Δεν υπάρχουν μεγάλες τυχαιοποιημένες μελέτες σύγκρισης των θειαζιδικών διουρητικών μεταξύ τους. Ισχυρό αποδεδειγμένο όφελος στην επιβίωση έχει κυρίως η χλωροθαλιδόνη και η ινδαπαμίδη. Ξεκινάμε από χαμηλές δόσεις και αυξάνουμε προοδευτικά και εξατομικευμένα.

33 Indapamide 1,5mg (PR), 2,5mg Chlortalidone 50mg? Hydrochlorothiazide 12,5mg-25mg

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