Dr. Luca R. Limite. Proge8o Formazione Avanzata in Cardiologia nel Web 2015 Scuola di Specializzazione in Mala/e dell Apparato Cardiovascolare

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1 Scuola di Specializzazione in Mala/e dell Apparato Cardiovascolare Dire8ore Prof. Massimo Volpe Facoltà di Medicina e Psicologia, Università di Roma Sapienza Anno Accademico Dr. Luca R. Limite Proge8o Formazione Avanzata in Cardiologia nel Web 2015 Scuola di Specializzazione in Mala/e dell Apparato Cardiovascolare Dire8ore: Prof. Massimo Volpe massimo.volpe@uniroma1.it Coordinatore: Dr. Giuliano Tocci giuliano.tocci@uniroma1.it

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3 BACKGROUND: Resistant hypertension SubopSmal blood pressure control despite treatment with maximal tolerated doses of 3 drugs ~10% of hypertensive pasents, equasng to ~100 million people globally The first 3 BP-lowering medicasons should usually be an ACE-inhibitor or ARB + CCB + Thiazide-like DiureSc, i.e. A + C + D Mya8 A, et al. BMJ 2012; NICE hypertension guidelines 2011

4 BACKGROUND: : NICE guidelines NICE hypertension guidelines; available at: h8p://pathways.nice.org.uk/ (accessed on 11/2/2015)

5 BACKGROUND: drug therapy Meta-analysis on 1204 pts 3 small RCTs (combined 134 pasents) as well as open / observasonal studies Spironolactone (mean dose ~25mg daily) versus placebo No RCTs directly comparing spironolactone with other BP-lowering drugs Dahal K, et al. Am J Hypertens, 2015

6 BACKGROUND: drug therapy Dahal K, et al. Am J Hypertens, 2015

7 Study design 436 pz 335 pz Williams B, et al. BMJ Open, 2015

8 Endpoints Hierarchical Primary End-point i. Difference in average home systolic BP (HSBP) between spironolactone and placebo followed, if significant by ii. HSBP difference between spironolactone and the average of the other two acsve drugs (bisoprolol and doxazosin) followed, if significant by iii. HSBP difference between spironolactone and each of the other two acsve drugs

9 Endpoints Secondary Outcome Measures Seated clinic BP responses to each treatment Blood pressure control rates with each treatment (average HSBP <135mmHg) Safety and adverse events Whether baseline plasma renin (whilst on treatment with A+C+D) predicted the best drug for individual pasents

10 BASELINE PATIENTS DEMOGRAPHICS (N=335) Mean (SD) or N (%) Age (yrs) 61.4 (9.6) Male 230 (68.7%) Weight (kg) 93.5 (18.1) Smoker 26 (7.8%) Home BP (mmhg) Systolic (13.2) Diastolic 84.2 (10.9) Clinic BP (mmhg) Systolic 157 (14.3) Diastolic 90.0 (11.5) Blood electrolytes Sodium (mmol/l) 140 (3.0) Potassium (mmol/l) 4.1 (0.47) egfr (ml/min) 91.1 (26.8) DiabeSc 46 (13.7%)

11 RESULTS: HSBP at the final visit of each cycle (12 weeks) Comparators (n=314) HSBP difference (mmhg) p value Spironolactone vs Placebo (-11.7 to -8.74) p< Spironolactone vs mean Bisoprolol/Doxazosin (-6.91 to -4.36) p< Spironolactone vs Doxazosin -5.3 (-6.77 to -3.83) p< Spironolactone vs Bisoprolol (-7.45 to -4.51) p< Treatments HSBP (mmhg) Change from baseline Spironolactone (132.3 to 134.8) (-15.6 to -13.1) Doxazosin (137.6 to 140.1) -9.1 (-10.3 to -7.8) Bisoprolol (138.2 to 140.8) -8.4 (-9.7 to -7.1) Placebo (142.5 to 145.0) -4.2 (-5.4 to -2.9)

12 RESULTS: Clinic systolic blood pressure Comparators (n=314) Clinic systolic blood pressure difference (mmhg) p value Spironolactone vs Placebo ( ) p< Spironolactone vs mean Bisoprolol/Doxazosin ( ) p< Spironolactone vs Doxazosin ( ) p< Spironolactone vs Bisoprolol ( ) p< Treatments HSBP (mmhg) Change from baseline Spironolactone ( ) (-22.9 to -18.6) Doxazisin ( ) (-18.5 to -14.2) Bisoprolol ( ) (-18.4 to -14.1) Placebo ( ) (-13.0 to -8.7)

13 RESULTS: dose response Higher vs Lower dose HSBP (mmhg) P value Spironolactone (-5.28 to -2.45) p<0.001 Doxazosin (-2.32 to 0.56) Bisoprolol (-2.94 to -0.04) Placebo (-2.1 to 0.75) Difference in mean HSBP aqer treatment with the lower dose (week 6) versus the higher doses (week 12) of each treatment

14 RESULTS: BP control rates Home systolic blood pressure (mmhg) PaSents Met target Least Squares essmates Odds raso P value Baseline Final n. n. (%) Spironolactone (57.8%) 58.0 ( ) <0.001 Doxazosina (41.7%) 41.5 ( ) 0.52 ( ) <0.001 Bisoprololo (43.6%) 43.3 ( ) 0.55 ( ) <0.001 Placebo (24.4%) 23.9 ( ) 0.23 ( ) <0.001

15 Adverse Events Bisoprolol Spironolactone Doxazosin Placebo p value Serious adverse events 8 (2.6%) 7 (2.3%) 5 (1,7%) 5 (1.7%) Any adverse event 68 (11.3%) 67 (10.4%) 58 (10.1%) 42 (9.1%) Withdrawal for adverse events 2 (2.9%) 3 (3.4%) 8 (10.0%) 2 (2.6%) 0.084

16 Baseline Follow up Change p value Sodium (mmol/l) Spironolactone <0 001 Doxazosin Bisoprolol Placebo Potassium (mmol/l) Spironolactone <0 001 Doxazosin Bisoprolol Placebo egfr (ml/min) Spironolactone Doxazosin Bisoprolol Placebo

17 Baseline Follow up Change p value Sodium (mmol/l) Spironolactone <0 001 Doxazosin Bisoprolol Placebo Potassium (mmol/l) Spironolactone <0 001 Doxazosin Bisoprolol Placebo egfr (ml/min) Spironolactone Doxazosin Bisoprolol Placebo

18 Baseline Follow up Change p value Sodium (mmol/l) Spironolactone <0 001 Doxazosin Bisoprolol Placebo Potassium (mmol/l) Spironolactone <0 001 Doxazosin Bisoprolol Placebo Only 6 of 285 pts exposed to egfr (ml/min) MRA developed a serum potassium > 6 mmol/l Spironolactone Doxazosin Bisoprolol Placebo

19 Renin Profile versus Drug Response

20 Renin Profile versus Drug Response

21 SUMMARY Spironolactone has been shown to be the most effecsve drug treatment for resistant hypertension, controlling BP in almost 60% of pasents Spironolactone was well tolerated The dose-dependent response to spironolactone was inversely related to plasma renin The superiority of spironolactone supports a primary role of sodium retenson in resistant hypertension

22 HYPOTHESIS: a sodium retaining state? Resistant hypertension is a sodium retaining state, characterized by an inappropriately low plasma renin level despite treatment with A + C + D Undetected aldosterone producing adenomas? Further diuresc therapy with spironolactone is more effecsve at lowering BP than alternasve treatments, targesng different mechanisms

23 CRITICISMS Only white caucasians Healthy pasents Too short treatment durason to assess the occurrence of side effects (i.e. gynecomassa ~6% in longer-term studies) Long-term cardiovascular and renal outcomes? No data on serum aldosterone or comparison with an increase in dose of the background diuresc Sternlicht H et al. Lancet 2015

24 Scuola di Specializzazione in Mala/e dell Apparato Cardiovascolare Dire8ore Prof. Massimo Volpe Facoltà di Medicina e Psicologia, Università di Roma Sapienza Anno Accademico Dr. Luca R. Limite Grazie per la Vostra A8enzione Proge8o Formazione Avanzata in Cardiologia nel Web 2014 Scuola di Specializzazione in Mala/e dell Apparato Cardiovascolare Dire8ore: Prof. Massimo Volpe massimo.volpe@uniroma1.it Coordinatore: Dr. Giuliano Tocci giuliano.tocci@uniroma1.it