Μη στεροειδή αντιφλεγμονώδη και αρτηριακή υπέρταση Ανδρέας Πιτταράς

Νόσοι και παθολογικές καταστάσεις αποδιδόμενες στην Υπέρταση Γάγγραινα κάτω άκρων Καρδιακήανεπάρκεια Υπερτροφία αριστεράς κοιλίας Έμφραγμαμυοκαρδίου Υπερτασικήεγκεφαλοπάθεια Στεφανιαίανόσος Εγκεφαλικήαιμορραγία Προεκλαμψία/Εκλαμψία Εγκεφαλικόεπεισόδιο Χρόνια νεφρική ανεπάρκεια Τύφλωση Ρήξηαρτηριακούανευρύσματος Προσαρμογή από Dustan HP et al. Arch Intern Med. 1996;156; ΥΠΕΡΤΑΣΗ

Η ΥΠΕΡΤΑΣΗ ΕΙΝΑΙ ΕΝΑΣ ΜΕΙΖΩΝ ΘΕΡΑΠΕΥΣΙΜΟΣ ΠΑΡΑΓΟΝΤΑΣ ΚΙΝΔΥΝΟΥ ΓΙΑ ΚΑΡΔΙΑΓΓΕΙΑΚΗ ΝΟΣΟ Ισχυρός και ανεξάρτητος παράγοντας κινδύνου για ΣΝ, ΑΕΕ, Περιφερική αρτηριοπάθεια, Καρδιακή ανεπάρκεια Η συσχέτιση με τον κίνδυνο είναι συνεχής και βαθμιαία Τα οφέλη από τη μείωση της ΑΠ με φαρμακολογική θεραπεία είναι βαθμιαία και συνεχή

Incidence of cardiovascular disease 120 ΤΟ ΘΕΡΑΠΕΥΤΙΚΟ ΑΠΟΤΕΛΕΣΜΑ ΣΤΗΝ ΥΠΕΡΤΑΣΗ ΑΝΤΙΚΑΤΟΠΤΡΙΖΕΙ ΤΑ ΔΕΔΟΜΕΝΑ ΤΩΝ ΠΑΡΑΤΗΡΗΣΕΩΝ ? ΔΕΔΟΜΕΝΑ ΠΑΡΑΤΗΡΗΣΕΩΝ ΘΕΡΑΠΕΥΤΙΚΟ ΑΠΟΤΕΛΕΣΜΑ Systolic blood pressure (mmHg)

Αντιυπερτασική αγωγή και καρδιαγγειακά επεισόδια Combined results from hypertension treatment trials* Decrease in events—treated compared to controls** *17 randomized, placebo-controlled treatment trials (48,000 subjects) —14 diuretic and 3 beta blocker based trials **All differences are statistically significant. Herbert P, Moser M, et al. Arch Intern Med. 1993;153: Moser M, Herbert PR. J Am Coll Cardiol. 1996;27(5): Percent

ΤΟ ΠΑΡΑΔΟΞΟ ΤΗΣ ΑΡΤΗΡΙΑΚΗΣ ΠΙΕΣΗΣ ΕΠΙΔΗΜΙΟΛΟΓΙΚΕΣ ΠΡΟΣΔΟΚΙΕΣ & ΠΡΑΚΤΙΚΗ ΕΜΠΕΙΡΙΑ % reduction in events for 6 mm Hg fall in diastolic BP CHD Strokes

ΠΑΡΑΓΟΝΤΕΣ ΓΙΑ ΤΟ ΜΙΚΡΟΤΕΡΟ ΟΦΕΛΟΣ ΜΕΙΩΣΗΣ ΣΤΕΦ. ΝΟΣΟΥ ΣΤΙΣ ΜΕΛΕΤΕΣ ΠΑΡΑΓΟΝΤΕΣ ΓΙΑ ΤΟ ΜΙΚΡΟΤΕΡΟ ΟΦΕΛΟΣ ΜΕΙΩΣΗΣ ΣΤΕΦ. ΝΟΣΟΥ ΣΤΙΣ ΜΕΛΕΤΕΣ Καθυστερημένη έναρξη – ανεπαρκής διάρκεια θεραπείας Μεταβολικές ανεπιθύμητες δράσεις φαρμάκων Επίδραση συνυπαρχουσών θεραπειών στην ΑΠ Σχετική θεραπευτική αποτυχία–Ανθιστάμενη υπέρταση Υποεκτίμηση του ΣΡΑΑ Επιμονή στη μονοθεραπεία, μη εξοικείωση σε συνδυασμό φαρμάκων Αποτυχία συνεκτίμησης πολλαπλών παραγόντων κινδύνου και βλαβών σε όργανα στόχους

Ο ΑΠΟΛΥΤΟΣ ΕΛΕΓΧΟΣ ΤΗΣ ΥΠΕΡΤΑΣΗΣ ΕΙΝΑΙ ΔΥΣΚΟΛΗ ΥΠΟΘΕΣΗ !!!!

Ποσοστά ενημέρωσης, θεραπείας και ρύθμισης υπερτασικών στις ΗΠΑ* 10% 31% 51% 29% 55% 73% 27% 54% 68% AwareTreated Controlled Controlled † Percentage of Population *Data represent percentage of adults 18 to 74 years of age who have systolic blood pressure  140 mm Hg, diastolic blood pressure  90 mm Hg, or are taking antihypertensive medication. † Systolic blood pressure <140 mm Hg and diastolic blood pressure <90 mm Hg. Adapted from JNC VI. Arch Intern Med. 1997;157:

ΑΙΤΙΕΣ ΑΝΘΙΣΤΑΜΕΝΗΣ ΗΤΝ ΣΧΕΤΙΖΟΜΕΝΕΣ ΚΑΤΑΣΤΑΣΕΙΣ - Αύξηση παχυσαρκίας - Αιθανόλη ( > 30 ml/d) - Κάπνισμα - Sleep Apnea - Αντίσταση ινσουλίνη/υπερινσουλιναιμία - Αγχώδης υπεραερισμός-Κρίσεις πανικού - Χρόνιος πόνος - Εντονη αγγειοσύσπαση (αρτηριίτις)

Αρθρίτιδα : κοινωνικά - ιατρικά Περίπου 43 εκατομμύρια (1 στους 6) αμερικανοί έχουν αρθρίτιδα (1 στους 4 υπέρταση) Υψηλού κινδύνου για καρδιαγγειακά συμβάντα Μεγαλύτερης ηλικίας Τρόπος ζωής Συνυπάρχουσες θεραπείες Συνυπάρχουσες κλινικές καταστάσεις Σε περίπτωση ρευματοειδούς αρθρίτιδας, επίδραση χρόνιας συστηματικής φλεγμονής στο αγγειακό ενδοθήλιο

ΑΙΤΙΕΣ ΑΝΘΙΣΤΑΜΕΝΗΣ ΗΤΝ ΦΑΡΜΑΚΑ - Κυκλοσπορίνη - Ερυθροποιητίνη - Κορτικοστεροειδή - Μη στεροειδή αντιφλεγμονώδη - Amitriptyline + Guanethidine, Methyldopa, Cloηidine.

Μηχανισμός δράσης ΜΣΑΦ Φωσφολιπίδια ιστων Αραχιδονικο οξύ COX-1 COX-2 NSAID (-) COXIBs Προσταγλανδίνες PGH2 Θρομβοξάνη Προσταγλανδίνες PGE 2 PGI 2 (Προστακυκλίνη) Γαστροπροστασία Φωσφολιπάσες (-)

Επίδραση των προσταγλανδινών στην ΑΠ : νεφρικοί & αγγειακοί μηχανισμοί Νεφροί Αγγεία Διατήρηση GFR (-) Μείωση σωληναριακής απορρόφησης Να (-) Αμεση αγγειοδιαστολή (-) Μείωση χυμικής σύσπασης (-) Αγγειοτασίνη ΙΙ Νορεπινεφρίνη +

Η Αγγειοτασίνη II Διαδραματίζει Πρωταρχικό Ρόλο στη Βλάβη των Οργάνων Adapted from Willenheimer R et al Eur Heart J 1999; 20(14): 997  1008, Dahlöf B J Hum Hypertens 1995; 9(suppl 5): S37  S44, Daugherty A et al J Clin Invest 2000; 105(11): 1605  1612, Fyhrquist F et al J Hum Hypertens 1995; 9(suppl 5): S19  S24, Booz GW, Baker KM Heart Fail Rev 1998; 3: 125  130, Beers MH, Berkow R, eds. The Merck Manual of Diagnosis and Therapy. 17th ed. Whitehouse Station, NJ: Merck Research Laboratories 1999: 1682  1704, Anderson S Exp Nephrol 1996; 4(suppl 1): 34  40, Fogo AB Am J Kidney Dis 2000; 35(2): 179  188 Αιι ΑΤ1 υποδοχέας Αθηροσκλήρυνση* Αγγειοσύσπαση Αγγειακή υπερτροφία Δυσλειτουργία ενδοθηλίου Υπερτροφία αριστεράς κοιλίας Ίνωση Αναδιαμόρφωση Απόπτωση Εγκεφαλικό Θάνατος Υπέρταση Καρδιακή ανεπάρκεια Έμφραγμα μυοκαρδίου Νεφρική ανεπάρκεια  Ρυθμός σπειραματικής διήθησης  Πρωτεϊνουρία  Απελευθέρωση αλδοστερόνης Σπειραματική σκλήρυνση *Προκλινικά δεδομένα

Υπέρταση και χρόνια νεφροπάθεια: Αιμοδυναμικές ανωμαλίες Mean BP Total Systemic Vascular Resistance = X Increased Cardiac Output Intravascular Volume  Σπειραματική διήθηση  Απέκκριση Νατρίου  Εξωκυττάρια υγρά  Δραστικότητα νεφρ. νεύρωση Myocardial Performance  Adrenergic Activity Increased Vasoconstriction  Adrenergic Stimuli  Angiotensin II  Endothelin  Endothelium-derived Contracting Factors  Thromboxane Cardiac Output Decreased Vasodilation  Prostacyclin  Nitric oxide  EDHF* Textor SC. Atlas of Diseases of the Kidney, *Endothelium-derived Hyperpolarizing Factors

Imbalance in Factors Affecting Vascular Tone and Structure Nephron destruction and renal failure Angiotensin II Catecholamines Endothelin-1 ROS Cytokines EDCF Nitric Oxide Prostacyclin Bradykinin EDHF Constrictors/ Growth Promoters Dilators/ Growth Inhibitors Vascular tone and structure EDHF= endothelium- derived hyperpolarizing factors ROS= reactive oxygen species EDCF= endothelium- derived constricting factors

Κατάταξη ΜΣΑΦ κατά ΠΟΥ Piroxicam (Feldene) Indomethacin Ibuprofen Tenoxicam (Tilcitin) Droxycam Lornoxicam (Xefo) Meloxicam (Movatec) Celecoxib (Celebrex) Refecoxib (Vioxx) Valdecoxib (Bextra) Parecoxib (Dynastat) ΟΞΙΚΑΜΕΣ (NS) ΚΟΞΙΜΠΕΣ

Επιδραση στην αύξηση ΑΠ (κατά σειρά αποτελέσματος) Piroxicam Indomethacin Ibuprofen Diclofenac Naproxen Flurbiprofen Sulindac Aspirin Μέση αύξηση ΑΠ ~ 5mmHg Ann Intern Med ; 121:

Eπίδραση στην ΑΠ (2 μεταναλύσεις) ΥπερτασικοίΝορμοτασικοί NSAIDs (pooled) Indomethacin Naproxen ND Piroxicam ND Sulindac(-) (-)1.6 Aspirin(-) COXIBs (SBP) Rofecoxib Celecoxib(-)0.44.3

Μείωση ΣΑΠ μειώνει τον κίνδυνο για ΣΝ και ΑΕΕ †SHEP. JAMA. 1991;265: ††Staessen JA, et al. Lancet. 1997;350: SHEP † Syst-Eur †† Baseline BP, mm Hg170/77184/85 Μείωση ΑΠ, mm Hg11/310/4-5

ΣΥΓΚΡΙΣΗ HOPE ΜΕ ΠΡΟΗΓΟΥΜΕΝΕΣ ΜΕΛΕΤΕΣ

Rofecoxib, but not Celecoxib and NSAID, is associated with an increased risk of edema and BP increase compared to nonusers of NSAID Rofecoxib OR 1.33 (οίδημα) Rofecoxib OR 2.08 (BP-ΝΤ) NSAID - Celecoxib NS Rofecoxib OR 1.55 (BP-HTN) NSAID – Celecoxib NS J-Rheumatology June 2004, N=8538 pts

COX-2 inhibitors vs non selective NSAIDs and CHF outcomes in elderly pts: a population-based cohort study NS NSAID (n=5.391pts) and Rofecoxib (n= pts) users had an increased risk of admission for CHF (RR:1.5 & 1.8 respectively). Celecoxib (n=18.908pts) users (RR:1.0). Non users control (n= ) Lancet, May 2004,

NSAIDs as a trigger of clinical heart failure Initiation of NSAID therapy may double the risk of developing heart failure in susceptible individuals. Pts with renal failure, diabetes or hypertension when taking NSAIDs might be at a greater risk of developing heart failure than pts without those conditions. Epidemiology, March 2003, 240-6

Στόχοι της αντιϋπερτασικής αγωγής στην κλινική πράξη  Αποτελεσματική ρύθμιση της ΑΠ  Δράση/εφαρμογή σ’όσο το δυνατόν μεγαλύτερο % ασθενών  Υψηλή ποιότητα ζωής : ανεπιθύμητες ενέργειες παρόμοιες με του εικονικού φαρμάκου (placebo)  Ασήμαντες ή ανύπαρκτες αλληλεπιδράσεις με συγχορηγούμενα φάρμακα  Ασήμαντες ή ανύπαρκτες δυσμενείς επιδράσεεις σε συνυπάρχοντα νοσήματα (πχ άσθμα, στεφ,νόσος, σ.διαβήτης, κ.ανεπάρκεια κλπ)  Ευνοϊκή δράση στα όργανα-στόχους (οργανοπροστασία)  Ευνοϊκή επίδραση στη καρδιαγγειακή (και γενική) νοσηρότητα και θνησιμότητα

Effects of Celecoxib and Rofecoxib on BP and edema in pts >65 yo with HTN and osteoarthritis Am J Cardiol Nov 2002, Significantly more pts in the Rofecoxib group (n=543) compared with Celecoxib group (n=549) developed increased SBP at any time point (14.9% vs 6.9% p<0.01). Rofecoxib caused the greatest increase in SBP in pts receiving ACEIs or BBs, whereas those on CCBs or Diuretic monotherapy receiving either Celecoxib or Rofecoxib showed no significant increases in BP. More edema in the Rofecoxib group

Επίδραση στην ΑΠ BB AMEA+ Diuretic * * *

NSAID Trials and the Choice of Comparators — Questions of Public Health Importance Bruce M. Psaty, M.D., Ph.D., and Noel S. Weiss, M.D., Dr.P.H. NEJM Volume 356: January 25, 2007January 25, 2007

Under ideal conditions, large clinical trials would be designed so that they satisfied the marketing needs of the pharmaceutical manufacturers that generally sponsor them and, at the same time, answered important clinical questions that may have a major influence on public health. In practice, however, alternative choices in trial design often favor one of these two goals. The choice of the reference treatment in active- comparator studies is an excellent example.

For nonsteroidal antiinflammatory drugs (NSAIDs), which all relieve arthritis pain, the question of greatest interest in randomized trials involves the incidence of adverse events. The more selective cyclooxygenase-2 (COX-2) inhibitors were developed in the hope that they would pose a lower risk of gastrointestinal bleeding than traditional NSAIDs. Although an early trial of the COX-2 inhibitor rofecoxib showed a relative gastrointestinal benefit, it also suggested that the risk of myocardial infarction was about five times as high with rofecoxib as with naproxen. Subsequently, placebo-controlled trials of rofecoxib, celecoxib, and valdecoxib documented an increased risk of cardiovascular disease.

In the recently reported Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) program, 24,913 subjects with osteoarthritis and 9787 with rheumatoid arthritis were randomly assigned to receive etoricoxib or diclofenac and were followed for an average of 18 months. 1 The pain-relief efficacy was similar for the two drugs. In the intention-to-treat analysis, etoricoxib was not associated with a significantly higher risk of thrombotic cardiovascular events than was diclofenac (hazard ratio, 1.05; 95% confidence interval [CI], 0.93 to 1.19). Complicated upper gastrointestinal events — which included perforation, obstruction, documented ulcer, and significant bleeding — did not differ between the two treatment groups (0.30 event per 100 person-years with etoricoxib vs per 100 person-years with diclofenac). The MEDAL report provides relatively precise estimates of the risk–benefit trade-off for the choice between diclofenac and etoricoxib. 1

Diclofenac, though not the most frequently used NSAID in the United States, was chosen as the comparator, according to the MEDAL report, because it is "the most widely prescribed NSAID in the world." 1 1 However, its relative COX-2 selectivity is similar to that of celecoxib. The potential for cardiovascular complications associated with COX-2 inhibition was recognized as early as So even before the MEDAL trial began, one might have hypothesized that diclofenac would increase the risk of cardiovascular events.

Recent observational data (see figure) and clinical- trial evidence support this hypothesis. In a meta- analysis of 121 placebo-controlled trials, the COX-2 inhibitors were associated with an increased risk of vascular events (relative risk, 1.42; 95% CI, 1.13 to 1.76). 3 In 26 trials that included diclofenac as the active comparison treatment, the risk was, if anything, slightly lower with the "new" COX-2 inhibitors (relative risk, 0.92; 95% CI, 0.81 to 1.05). In contrast, in the 42 trials that used naproxen as the comparison treatment, COX-2 inhibitors were associated with an increased risk (relative risk, 1.57; 95% CI, 1.21 to 2.03). 3 These data suggest that as compared with naproxen, diclofenac may increase the risk of vascular events by about 70%.figure 3

In other words, the comparison drug in the MEDAL trial appears to have cardiovascular toxicity similar to that of other COX-2 inhibitors. To address the most important clinical question, the comparison group should receive the best available active treatment. Indeed, in February 2005, the Arthritis and Drug Safety and Risk Management Advisory Committees of the Food and Drug Administration (FDA) recommended naproxen, not diclofenac, as the "preferred comparator" for large trials of COX-2 inhibitors. This public recommendation by an independent group not only helps to set the standard for future trials but also aids in the interpretation of completed trials.

The withdrawal from the market of two COX-2 inhibitors, rofecoxib and valdecoxib, because of cardiovascular toxicity has inspired greater scrutiny of this whole class of drugs. One side effect of these withdrawals may be the size and scope of the MEDAL program, which is more typical of post-marketing phase 4 trials than preapproval phase 3 trials. When the FDA reviews the evidence with regard to etoricoxib, it will have an unusual abundance of data available. But the question of etoricoxib's approvability, which will depend on a finding about whether it is "safe and effective for the intended use," is a narrow one.

This determination is distinct from the key clinical question: What is the gastrointestinal and cardiovascular safety of etoricoxib as compared with that of traditional NSAIDs? Etoricoxib is likely to be associated with a higher rate of cardiovascular events than naproxen, but the relative gastrointestinal safety of the two drugs remains unknown. Is the combination of naproxen and a proton- pump inhibitor as safe as or safer than etoricoxib for the gastrointestinal tract? The MEDAL program missed the opportunity to address these important clinical and public health questions.

In recent years, similar questions have remained unanswered after trials comparing some new cardiovascular drugs with other active treatments; in several trials of antihypertensive therapy, for instance, organizers selected the beta-blocker atenolol as the comparator, although low-dose diuretics are the most effective antihypertensive agents in preventing cardiovascular disease. 4 4

The Institute of Medicine's committee on drug safety recently proposed a public–private partnership to help define key public health questions that merit investment in large, long-term phase 4 trials. 5 5 This partnership would not only identify the studies of greatest public health importance but also recommend the best design features, including, when appropriate, the comparison treatment. Under this model, the public designation of a phase 4 trial as a key study through an independent and unbiased process might provide sponsors with an incentive to evaluate their drugs in a manner that highlights their potential clinical value and not their anticipated marketing potential. Such a designation might also engender in them a sense of responsibility for funding studies designed to answer pressing clinical questions.

Would industry support such trials? Some companies might well give priority to their social obligations. Others might not, especially if participation would conflict with their responsibility to shareholders to devote resources to studies that would be likely to show their products to the best advantage. In view of this tension between marketing needs and public health questions, some commentators have called for a national commitment to publicly supported studies of the risks and benefits of drugs. In the absence of such funding, perhaps Congress could provide the FDA with the authority to dictate the design and conduct of occasional phase 4 trials. 5 But funding is not the sole problem. In the United States, the long tradition of leaving to the pharmaceutical industry the task of evaluating the efficacy and safety of its products has permitted manufacturers to make study-design choices that largely determine the shape of the answers eventually provided by the trials. The identification, design, and prioritization of large phase 4 drug trials of potential public health importance represent a major medical, social, and scientific effort that currently lacks a champion in the United States. 5

But funding is not the sole problem. In the United States, the long tradition of leaving to the pharmaceutical industry the task of evaluating the efficacy and safety of its products has permitted manufacturers to make study-design choices that largely determine the shape of the answers eventually provided by the trials. The identification, design, and prioritization of large phase 4 drug trials of potential public health importance represent a major medical, social, and scientific effort that currently lacks a champion in the United States.

Τα ΜΣΑΦ μπορεί να προκαλέσουν αύξηση της ΑΠ (~5mmHg) και να επηρρεάσουν τη φαρμακευτική αγωγή Θεραπεία με ΜΣΑΦ μπορεί να αυξήσει 40% την πιθανότητα διάγνωσης υπέρτασης σε σύγκριση με μη χρήστες Μπορούν να επηρρεάσουν θεραπεία με ΑΜΕΑ, β-αποκλειστές και διουρητικά Δεν επηρρεάζουν CCB και κεντρικά δρώντα που δεν σχετίζονται με την παραγωγή προσταγλανδινών Σε ηλικιωμένους υπό διουρητικά μπορεί να προκαλέσουν υπονατριαιμία