Disclosure: Consultancy fees: Astra-Zeneca, Servier, Sanofi Lecture Honoraria: Sanofi, Boehringer-Ingelheim, Servier Travel grants: Sanofi, Novartis, Menarini, Pfizer, Servier Fellowship grants: Hellenic Cardiology Foundation, Hellenic Cardiological Society This presentation has no conflict of interest

Διαφέρουν τα αντι-υπερτασικά φάρμακα ως προς τα καρδιαγγειακά τους οφέλη και την ασφάλειά τους; Α. Ναι Β. Όχι

Benefits of BP lowering seminal analysis 14 RCTs in 37,000 hypertensive pts A reduction of 5-6 mmHg in diastolic BP was associated with: 35-40% less strokes 20-25% less CHD 15% less CV death

Updated BP lowering meta-analysis Selection of RCTs Thomopoulos, Parati, Zanchetti. J Hypertens 2014;32:2285

Relative and absolute risk reduction of outcomes in BP lowering trials 68 RCTs, almost 250,000 pts 54 57 36 55 38 58 66 Δ-BP -6.6/-3.5 -6.7/-3.4 -6.0/-2.9 -6.9/-3.4 -6.8/-3.4 -6.7/-3.5 Standardized* RR (95% CI) 0.64 (0.57-0.71) 0.82 (0.76-0.86) 0.62 (0.51-0.75) 0.74 (0.70-0.80) 0.73 (0.68-0.79) 0.84 (0.77-0.92) 0.90 (0.85-0.95) Standardized* RR (95% CI) Mean Absolute Risk Reduction Per 1000 pts treated for 5 years Stroke CHD HF Stroke+CHD Stroke+CHD+HF CV Death All-cause Death -19 -8 -19 -24 -39 -8 -9 0.4 0.7 1 1.3 -40 -30 -20 -10 10 Active Better Control Better Active Better Control Better *Stardardized measures for 10/5mmHg SBP/DBP reduction Thomopoulos, Parati, Zanchetti. J Hypertens 2014;32:2285

Outcome reduction to the extent of BP reduction log Scale Thomopoulos, Parati, Zanchetti. J Hypertens 2014;32:2285

Permanent discontinuations in BP lowering trials 44 RCTs reporting permanent discontinuations 6 RCTs reporting serious adverse events 50 RCTs on 180,000 pts followed-up for 4 years (almost 720,000 pts*years) Thomopoulos, Parati, Zanchetti. J Hypertens 2016;34:1451

Μεταβολές σχετικού και απόλυτου κινδύνου διαφορετικών εκβάσεων μαζί με τις αποσύρσεις από τη θεραπεία λόγω παρενεργειών Outcome N Trials 40 42 28 31 43 48 50 Standardized* RR (95% CI) 0.68 (0.60-0.76) 0.82 (0.76-0.85) 0.66 (0.54-0.81) 0.75 (0.70-0.81) 0.76 (0.70-0.81) 0.86 (0.76-0.95) 0.91 (0.87-0.96) 1.89 (1.51-2.39) Standardized* RR (95% CI) Mean Absolute Risk Reduction Per 1000 pts treated for 5 years Stroke CHD HF Stroke+CHD Stroke+CHD+HF CV Death All-cause Death AEs -16 -8 -16 -25 -33 -7 -12 -84 0.5 1 2 3 -50 50 100 150 Active Better Control Better Active Better Control Better *Standardized measures for 10/5mmHg SBP/DBP reduction Thomopoulos, Parati, Zanchetti. J Hypertens 2016;34:1451

Relationships of outcome reductions and increase in discontinuations for adverse events to the extent of SBP and DBP reductions Thomopoulos, Parati, Zanchetti. J Hypertens 2016;34:1451

Number of outcomes prevented και number of permanent treatment discontinuations in relation to BP lowering Thomopoulos, Parati, Zanchetti. J Hypertens 2016;34:1451

Which evidence makes sense? RCTs: 2 levels of evidence RCTs active drug vs placebo Head to Head Active drug vs all-other active

The extent of BP-lowering by different anti-hypertensive agents All different agents reduce BP almost at the same extent Law et al BMJ 2003;326:1427

Drug-class RCTs vs placebo providing data for permanent discontinuations or adverse events D vs placebo (n=6, 29,038 pts) BB vs placebo (n=4, 17,976 pts) CCB vs placebo (n=6, 11,479 pts) ACEi vs placebo (n=9, 31,499 pts) ARB vs placebo (n=12, 56,240 pts) Australian mild HEP ACTION AIPRI DIRECT-2 HYVET MRC mild CAMELOT BENEDICT GISSI-AF MRC old Fogari IDNT TEST DIABHYCAR I-PRESERVE OSLO NICOLE DREAM IRMA-2 SHEP REIN-2 NAVIGATOR HOPE ORIENT Lewis ProFess PEACE RENAAL ROADMAP SCOPE TRANSCEND Thomopoulos, Parati, Zanchetti. J Hypertens 2016;34:1921

Changes in relative and absolute risk of CV events and of treatment discontinuations Different drug class vs placebo or no treatment Drug Class D BB CCBs ACEi ARB Outcome N Trials 6 4 5 9 12 Standardized* RR (95% CI) 0.75 (0.68-0.82) 2.23 (1.32-3.76) 0.90 (0.82-0.98) 2.88 (1.58-5.28) 0.73 (0.55-1.07) 2.03 (1.17-3.56) 0.58 (0.43-0.78) 2.78 (1.37-5.47) 0.80 (0.70-0.93) 1.13 (0.78-1.62) Standardized* RR (95% CI) Mean Absolute Risk Reduction Per 1000 pts treated for 5 years Stroke+CHD+HF Adverse events Stroke+CHD -19 43 -7 55 -39 84 -42 258 -33 10 NS 0.5 1 2 3 -50 50 100 150 Active Better Control Better Active Better Control Better *Stardardized measures for 10/5mmHg SBP/DBP reduction Thomopoulos, Parati, Zanchetti. J Hypertens 2016;34:1921

Head to head RCTs comparisons of different drug classes providing information on permanent discontinuations attributed to adverse events (I) D vs BB (n=6, 26,294 pts) D vs CCBs (n=6, n=48568) D vs ACEi (n=2, 24878) D vs ARB (n=1, 2204) D vs all (n=15, 85595 pts) COPE ACCOMPLISH ALLHAT AIPRI All mentioned HAPPHY NESTOR IPPPSH COLM MRC mild MIDAS MRC old INSIGHT VA-COOP NICS-EH BB vs CCBs (n=4, 44,825 pts) BB vs ACEi (n=2, 1635 pts) BB vs ARBs (n=2, 11,362 pts) BB vs all (n=8, 82,616 pts) AASK ASCOT UKPDS-39 LIFE ELSA INVEST Thomopoulos, Parati, Zanchetti. J Hypertens 2016;34:1921

Head to head RCTs comparisons of different drug classes providing information on permanent discontinuations attributed to adverse events (II) CCB vs ACEi (n=9, 23,836) CCB vs ARB (n=4, 22,244) CCB vs all (n=15, 85595 pts) AASK CASE-J All mentioned ABCD-H IDNT +CONVINCE ALLHAT NAGOYA BENEDICT VALUE CAMELOT FACET Fogari JMIC B JMIND ACEi vs ARBs (n=3, 17,728 pts) ACEi vs all (n=8, 58,939 pts) DETAIL All mentioned+ ONTARGET REIN-str.1 ROAD REIN-str.2 ARB vs all (n=8, 58,939 pts +HIJ CREATE Thomopoulos, Parati, Zanchetti. J Hypertens 2016;34:1921

Summary table of benefits and burdens between different anti-HTN classes better worse equivalence Thomopoulos, Parati, Zanchetti. J Hypertens 2016;34:1921

Relationships of treatment discontinuations for adverse events with number (mean per patient) of antihypertensive drugs and all cardiovascular drugs given to placebo-treated patients in trials comparing different classes of antihypertensive drugs with placebo The role of background treatment Thomopoulos, Parati, Zanchetti. J Hypertens 2016;34:1921

Συμπεράσματα Τα οφέλη της αντιυπερτασικής αγωγής προέρχονται από την μείωση της ΑΠ αυτής καθ’ αυτής. Επίσης, το μέγεθος της μείωσης της ΑΠ συναρτάται με τον κίνδυνο διακοπής της αγωγής λόγω παρενεργειών. Όλες οι κατηγορίες των αντιυπερτασικών φαρμάκων έναντι του εικονικού φαρμάκου μειώνουν τα καρδιαγγειακά επεισόδια, αλλά αυξάνουν τον κίνδυνο διακοπής της θεραπείας λόγω παρενεργειών (εκτός των σαρτανών που δεν τον επηρεάζουν). Οι συγκρίσεις κάθε διαφορετικής κατηγορίας φαρμάκου με όλες τις υπόλοιπες κατηγορίες μαζί δείχνουν ότι ο κίνδυνος μείωσης των καρδιαγγειακών επεισοδίων και της αύξησης των παρενεργειών είναι παρόμοιος, εκτός των σαρτανών που έχουν μικρότερο κίνδυνο διακοπής της θεραπείας. Ο αριθμός των φαρμάκων που συνταγογραφείται για καρδιαγγειακή προστασία συσχετίζεται γραμμικά με τον κίνδυνο διακοπής της θεραπείας λόγω παρενεργειών. Χρειάζεται προσεκτική επιλογή καλώς ανεκτών φαρμάκων από κάθε ασθενή ξεχωριστά για τη μεγιστοποίηση του λόγου κόστους / οφέλους.