Scuola di Specializzazione in Mala/e dell Apparato Cardiovascolare Dire8ore Prof. Massimo Volpe Facoltà di Medicina e Psicologia, Università di Roma Sapienza Anno Accademico 2014-2015 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 E-mail: massimo.volpe@uniroma1.it Coordinatore: Dr. Giuliano Tocci E-mail: giuliano.tocci@uniroma1.it
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
BACKGROUND: : NICE guidelines NICE hypertension guidelines; available at: h8p://pathways.nice.org.uk/ (accessed on 11/2/2015)
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
BACKGROUND: drug therapy Dahal K, et al. Am J Hypertens, 2015
Study design 436 pz 335 pz Williams B, et al. BMJ Open, 2015
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
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
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 147.6 (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%)
RESULTS: HSBP at the final visit of each cycle (12 weeks) Comparators (n=314) HSBP difference (mmhg) p value Spironolactone vs Placebo -10.2 (-11.7 to -8.74) p<0.0001 Spironolactone vs mean Bisoprolol/Doxazosin -5.64 (-6.91 to -4.36) p<0.0001 Spironolactone vs Doxazosin -5.3 (-6.77 to -3.83) p<0.0001 Spironolactone vs Bisoprolol -5.98 (-7.45 to -4.51) p<0.0001 Treatments HSBP (mmhg) Change from baseline Spironolactone 133.5 (132.3 to 134.8) -14.4 (-15.6 to -13.1) Doxazosin 138.8 (137.6 to 140.1) -9.1 (-10.3 to -7.8) Bisoprolol 139.5 (138.2 to 140.8) -8.4 (-9.7 to -7.1) Placebo 143.7 (142.5 to 145.0) -4.2 (-5.4 to -2.9)
RESULTS: Clinic systolic blood pressure Comparators (n=314) Clinic systolic blood pressure difference (mmhg) p value Spironolactone vs Placebo -9.92 (-11.3-8.59) p<0.0001 Spironolactone vs mean Bisoprolol/Doxazosin -4.44 (-5.59-3.28) p<0.0001 Spironolactone vs Doxazosin -4.42 (-5.75-3.09) p<0.0001 Spironolactone vs Bisoprolol -4.45 (-5.80-3.11) p<0.0001 Treatments HSBP (mmhg) Change from baseline Spironolactone 136.5 (134.4 138.7) -20.7 (-22.9 to -18.6) Doxazisin 141.0 (138.8 143.1) -16.3 (-18.5 to -14.2) Bisoprolol 141.0 (138.8 143.2) -16.3 (-18.4 to -14.1) Placebo 146.5 (144.3 148.6) -10.8 (-13.0 to -8.7)
RESULTS: dose response Higher vs Lower dose HSBP (mmhg) P value Spironolactone -3.86 (-5.28 to -2.45) p<0.001 Doxazosin -0.88 (-2.32 to 0.56) 0.231 Bisoprolol -1.49 (-2.94 to -0.04) 0.043 Placebo -0.68 (-2.1 to 0.75) 0.350 Difference in mean HSBP aqer treatment with the lower dose (week 6) versus the higher doses (week 12) of each treatment
RESULTS: BP control rates Home systolic blood pressure (mmhg) PaSents Met target Least Squares essmates Odds raso P value Baseline Final n. n. (%) Spironolactone 148.3 133.9 282 163 (57.8%) 58.0 (52.0-63.7) <0.001 Doxazosina 147.8 138.9 276 115 (41.7%) 41.5 (35.8-46.5) 0.52 (0.37-0.73) <0.001 Bisoprololo 147.7 139.6 280 122 (43.6%) 43.3 (37.5-49.2) 0.55 (0.39-0.78) <0.001 Placebo 147.8 143.5 270 66 (24.4%) 23.9 (19.1-29.4) 0.23 (0.16-0.33) <0.001
Adverse Events Bisoprolol Spironolactone Doxazosin Placebo p value Serious adverse events 8 (2.6%) 7 (2.3%) 5 (1,7%) 5 (1.7%) 0.831 Any adverse event 68 (11.3%) 67 (10.4%) 58 (10.1%) 42 (9.1%) 0.711 Withdrawal for adverse events 2 (2.9%) 3 (3.4%) 8 (10.0%) 2 (2.6%) 0.084
Baseline Follow up Change p value Sodium (mmol/l) Spironolactone 139 74 137 84-1 91 <0 001 Doxazosin 139 37 139 30-0 07 0 840 Bisoprolol 139 96 139 78-0 17 0 608 Placebo 139 14 139 25 0 11 0 745 Potassium (mmol/l) Spironolactone 4 06 4 49 0 43 <0 001 Doxazosin 4 08 4 16 0 08 0 127 Bisoprolol 4 11 4 26 0 15 0 007 Placebo 4 05 4 09 0 03 0 410 egfr (ml/min) Spironolactone 93 20 83 18-10 02 0 004 Doxazosin 92 70 85 38-7 32 0 023 Bisoprolol 92 40 86 35-6 05 0 006 Placebo 92 52 92 67 0 15 0 923
Baseline Follow up Change p value Sodium (mmol/l) Spironolactone 139 74 137 84-1 91 <0 001 Doxazosin 139 37 139 30-0 07 0 840 Bisoprolol 139 96 139 78-0 17 0 608 Placebo 139 14 139 25 0 11 0 745 Potassium (mmol/l) Spironolactone 4 06 4 49 0 43 <0 001 Doxazosin 4 08 4 16 0 08 0 127 Bisoprolol 4 11 4 26 0 15 0 007 Placebo 4 05 4 09 0 03 0 410 egfr (ml/min) Spironolactone 93 20 83 18-10 02 0 004 Doxazosin 92 70 85 38-7 32 0 023 Bisoprolol 92 40 86 35-6 05 0 006 Placebo 92 52 92 67 0 15 0 923
Baseline Follow up Change p value Sodium (mmol/l) Spironolactone 139 74 137 84-1 91 <0 001 Doxazosin 139 37 139 30-0 07 0 840 Bisoprolol 139 96 139 78-0 17 0 608 Placebo 139 14 139 25 0 11 0 745 Potassium (mmol/l) Spironolactone 4 06 4 49 0 43 <0 001 Doxazosin 4 08 4 16 0 08 0 127 Bisoprolol 4 11 4 26 0 15 0 007 Placebo 4 05 4 09 0 03 0 410 Only 6 of 285 pts exposed to egfr (ml/min) MRA developed a serum potassium > 6 mmol/l Spironolactone 93 20 83 18-10 02 0 004 Doxazosin 92 70 85 38-7 32 0 023 Bisoprolol 92 40 86 35-6 05 0 006 Placebo 92 52 92 67 0 15 0 923
Renin Profile versus Drug Response
Renin Profile versus Drug Response
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
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
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
Scuola di Specializzazione in Mala/e dell Apparato Cardiovascolare Dire8ore Prof. Massimo Volpe Facoltà di Medicina e Psicologia, Università di Roma Sapienza Anno Accademico 2014-2015 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 E-mail: massimo.volpe@uniroma1.it Coordinatore: Dr. Giuliano Tocci E-mail: giuliano.tocci@uniroma1.it