ACE INHIBITOR-RELATED ANGIOEDEMA ACEI-RAE. MURAT BAS (Munich, Germany) & HENRIETTE FARKAS (Budapest, Hungary)

Transcription

1 ACE INHIBITOR-RELATED ANGIOEDEMA ACEI-RAE MURAT BAS (Munich, Germany) & HENRIETTE FARKAS (Budapest, Hungary)

2 OUTLINE ACEI Effects Adverse effects The pathophysiology of ACEI-RAE The clinical characteristics of ACEI-RAE The diagnosis of ACEI-RAE The treatment of ACEI-RAE

3 Raffaello: Adam and Eve in the Garden of Eden with the serpent, 1511.Stanza della Segnatura, Vatican

4 ACEI ACEIs were originally synthesized from compounds found in the venom of the Brazilian viper: Bothrops jararaca ACEI-s are used primarily for the treatment of hypertension and congestive heart failure. This is the fourth most commonly prescribed class of all medications.

5 ACEIs GROUPED BY THEIR STUCTURE Sulfhydrylcontaining agents Captopril Zofenopril Dicarboxylatecontaining agents Enalapril Ramipril Quinapril Perindopril Lisinopril Benazepril Imidapril Trandolapril Phosphonatecontaining agents Fosinopril (Smith RE. Nat Rev Drug Discov 2007)

6 ACEIs MODE OF ACTION ANGIOTENSIN I INACTIVE METABOLITES ACEI ACE ACE ACEI ACEI ACE ANGIOTENSIN II BRADYKININ SUBSTANCE P AT1R AT2R BR1 BR2 NK1R

7 ACEIs EFFECTS ON THE RAAS RENIN ALDOSTERONE ANGIOTENSINOGEN ANGIOTENSIN I ANGIOTENSIN II ACEI ARB NOREPINEPHRINE NO ACTIVITY PAI 1 cgmp ACE ANGIOTENSIN II RECEPTORS A 1 A 2 VASODILATION HYPOTENSION

8 ARBs MODE OF ACTION (Campbell DJ J. Cardiovasc Pharmacol. 1995) (Goodfriend Tl. N Engl J Med 1996) ANGIOTENSINOGEN RENIN ANGIOTENSIN I ACE ANGIOTENSIN II AT1RB AT1R AT2R Vasoconstriction Renal perfusion BP Kininogenase activation BK release Vasodilation

9 ACEIs MODE OF ACTION ANGIOTENSIN I INACTIVE METABOLITES ACEI ACE ACE ACEI ACEI ACE ANGIOTENSIN II BRADYKININ SUBSTANCE P AT1R AT2R BR1 BR2 NK1R

10 THE BREAKDOWN OF BRADYKININ ANGIOTENSIN-CONVERTING ENZYME (ACE) KININASE II NEUTRAL ENDOPEPTIDASE (NEP) ACEI H2N- Arg Pro Pro Gly Phe Ser Pro Phe Arg -COOH AMINOPEPTIDASE (APP) Dipeptidylpeptidase IV CARBOXIPEPTIDASE (CPN) KININASE I DES-ARG 9 -BRADYKININ ACE ACEI INACTIVE PEPTIDES APP

11 ACEIs MODE OF ACTION ANGIOTENSIN I INACTIVE METABOLITES ACEI ACE ACE ACEI ACEI ACE ANGIOTENSIN II BRADYKININ SUBSTANCE P AT1R AT2R BR1 BR2 NK1R

12 THE BREAKDOWN OF SUBSTANCE P HISTAMINE SEROTONIN NEURON ACE ACEI (Skidgel CF. Peptides 1984) MAST CELL SUBSTANCE P INACTIVE METABOLITE APP NEP DPPIV NK1 TARGET CELL NO EICOSANOID KININ BRADYKININ PLASMA EXTRAVASATION, VASODILATION, EDEMA (Campos MM. Neuropeptides 2000)

13 ACEIs ADVERSE EFFECTS Chronic cough Hypotension Hyperkalemia Bone marrow depression Hepatic failure Oligohydramnios, intrauterine fetal malformations ANGIOEDEMA

14 ACEI-RAE INCIDENCE Estimated incidence: % Meta-analysis of randomized trials of patients on ACEIs, ARBs, DRIs; the literature search was made by cardiologists. (Makani H. Am J Cardiol 2012) 26 trials ACEI, 19 ARB, 2 DRI, 7 head-to-head comparisons (ACEI-ARB) INCIDENCE OF ANGIOEDEMA ACEI 0.3% 95% CI 0.28 to 0.32 ARB 0.11% 95% CI 0.09 to 0.13 DRI 0.13% 95% CI 0.28 to 0.32 Placebo 0.07% 95% CI 0.05 to 0.09 The incidence of AEs with ARB and DRI was only half of that seen with ACEIs, and not significantly different from placebo. The risk of AE with ACEIs was 2.2 times higher than with ARBs. The incidence of AE was higher in patients with heart failure.

15 ACEI-RAE INCIDENCE Multicenter study with medical record review of ACEI-RAE in patients who presented at 5 EDs in the EMN between 2003 and (Banerji A. Ann Allergy Asthma Immunol 2008.) 586 patients experienced AEs 30% (95% CI, 26 34%) were found to have ACEI-RAE Annual rate of visits for ACEI-RAE was 0.7 per 10,000 ED visits 11% were admitted to the ICU (for facial and/or upper airway edema)

16 ACEI-RAE INCIDENCE Retrospective chart review of angioedema patients evaluated initially by the otolaryngology service, between 1999 and 2004: 182 patient with AEs 63% of patients with ACEI-RAE (Mahoney E. Otolaryngology Head and Neck Surgery 2008) Retrospective chart review of angioedema patients by ENTs between 1997 and 2008: 367 AE episodes in 337 patients 48% of episodes ACEI, 1,9% ARB, 1,4% ACEI and ARB (Tai S. Ann Otology, Rhinology and Laryngology 2010)

17 ACEI-RAE PATHOMECHANISM METABOLIC Bradykinin elevation Des-Arg 9 -bradykinin elevation Substance-P elevation CRP elevation GENOMIC ACE polymorphism APP polymorphism AR II polymorphism BR1 polymorphism BR2 polymorphism EPIDEMIOLOGIC Recurrence Demographics Environment Medications Co-morbidity

18 ACEI-RAE METABOLIC MECHANISMS Elevated serum BK without increased HMWK breakdown products (Agostoni A. Immunopharmacology 1999) Prolonged half-life of bradykinin (Byrd JB Hypertension 2008) The half-life of BK degradation is affected by ACE > APP > NEP, DPPIV (Fryer RM. Br J Pharmacol 2008) During ACEI therapy, BK degradation depends on APP The variation of APP levels is associated with an increased incidence of AEs (Kitamura S. Am J Physiol 1999)

19 ACEI-RAE METABOLIC MECHANISMS One-half of the patients with ACEI-RAE has a defective enzyme defect involved in Des-Arg 9 BK metabolism, leading to the accumulation of the latter (Molinaro G J. Pharmacol Exp Ther 2002) Prolonged half-life of Des-Arg 9 -BK (Byrd JB. Hypertension 2008) During ACEI therapy, Des-Arg 9 -BK degradation depends on APP (Adam A. Lancet 2002)

20 ACEI-RAE METABOLIC MECHANISMS DPPIV activity decreased in ACEI-RAE Decreased activity of DPPIV correlated to a prolonged half-life of substance P during ACEI therapy (Byrd JB. Hypertension 2008) Increased levels of DPPIV result in increased serum glucose diabetics have a lower risk of developing ACEI-RAE (Mannucci E. Diabetologia 2005) DPPIV activity is lower in smokers (Van D. Clin Exp Allergy 1999) DPPIV levels decrease with advancing age (Lefebvre J. Hypertension 2002)

21 ACEI-RAE METABOLIC MECHANISMS Patients with ACEI-RAE have elevated levels of CRP (Bas M. Br J Clin Pharmacol 2005) CRP-induced IL-6 could stimulate kininogen release, thereby induce bradykinin generation Chen HM. J Biol Chem 1993) Increased plasma levels Increased the vasodilator potency of bradykinin by 10-fold (Bas M. Journal of Allergy and Immunol 2008)

22 ACEI-RAE PATHOMECHANISM METABOLIC Bradykinin elevation Des-Arg9-bradykinin elevation Substance-P elevation CRP elevation GENOMIC ACE polymorphism APP polymorphism ATR polymorphism BR1 polymorphism BR2 polymorphism EPIDEMIOLOGIC Demographics Environment Medications Co-morbidity

23 ACEI-RAE GENOMIC FACTORS I/D polymorphism is not correlated with ACEI-RAE (n=65) (Bas M, Br J Clin Pharmacol, 2010) I/I genotype associated with low circulating ACE level (Kostis JB. Ann Intern Med 1992) XPNPEP2 is X-linked (Woodard-Grice AV, Pharmacogenet Genomics 2010) C-2399A for XPNPEP2 associated with reduction in APP activity, higher incidence of ACEI-RAE (Duan QL, Am J Hum Genet 2005)

24 ACEI-RAE GENOMIC FACTORS Polymorphism of the AT-II receptor could be related to ACEI-RAE (No relevant data) (Mukae S. J Hum Hypertens 2002) No associated polymorphism with ACEI-RAE. Up-regulated following inflammatory stimuli, and mediates kinininduced vasodilatation. (deblois D. Br J Pharmacol 2001) BR2R exon 1 polymorphism with +9/+9 genotype is associated with decreased vasodilatation and tpa production during ACE inhibition compared with -9 allele (Van Guilder GP, Hypertension 2008, Lung CC. J Allergy Clin Immunol 1997)

25 ACEI-RAE GENOMIC FACTORS BR2R (2/3 and C181T) receptor polymorphisms are not correlated with ACEI-RAE (n=65) (Bas M, Br J Clin Pharmacol, 2010)

26 ACEI-RAE PATHOMECHANISM METABOLIC Bradykinin elevation Des-Arg9-bradykinin elevation Substance-P elevation CRP elevation GENOMIC ACE polymorphism APP polymorphism AR II polymorphism BR1 polymorphism BR2 polymorphism EPIDEMIOLOGIC Demographics Environment Medications Co-morbidity

27 ACEI-RAE EPIDEMIOLOGY 10-fold increase in angioedema recurrence if patient remains on ACEI therapy (Brown NJ. JAMA 1997)

28 ACEI-RAE EPIDEMIOLOGY Relative risk of 3.3 for Blacks compared with Whites (differences in sensitivity to BK) (McDowell SE. BMJ 2006) African Americans had increased severity of ACEI-RAE with more ICU admissions. (Tai S. Ann Otology, Rhinology and Laryngology 2010) 1.45-fold higher rates of AE in women (Miller DR. Hypertension. 2008) Age over 65 years means a higher risk (OD: 1.6) (Kostis JB. Arch Intern Med 2005)

29 ACEI-RAE EPIDEMIOLOGY Aspirin, NSAID most frequent cause Banerji A. Ann All Asthma Immunol 2008) Immunosuppressive treatment (decreased DPPIV) (Sharpe S. Clin Chem 1990) Lidocaine, statins, mtor inhibitors, DPPIV inhibitors

30 ACEI-RAE EPIDEMIOLOGY Smoking increases the risk of angioedema (HR: 2.7; 95% CI: ) (Morimoto T. J Eval Clin Pract 2004 ) Trauma (upregulation of B1R) 58% of patients reported trauma within 48 hours. (Hoover T. Clin Experiment Allergy 2012)

31 ACEI-RAE EPIDEMIOLOGY C1-INH Deficiency increases the risk (Agostoni A. Immonopharmacology 1999) Allergic diseases increase /decrease the risk (Kostis Am J Hypertens 2004 / Banerji A. Ann All Asthma Immunol 2008) Lower occurence rates in diabetic patients (increased DPPIV activity) (Manucci E. Diabetologia 2005)

32 ACEI-RAE EPIDEMIOLOGY ACEI-induced cough is not a prognostic sign (Bas M et al. HNO 2004 / Bas M et al. Allergy 2007) History of ACE inhibitor-induced cough was a risk factor for angioedema (9.1; 95% CI: ) (Morimoto T. J Eval Clin Pract 2004 ) Greater risk of appendicitis (1.22; 95% ) (Mukamal KJ. Annals of Epidemiology 2012)

33 ACEI-RAE CLINICAL FEATURES Lack of wheals, itching (Hoover T. Clin Experimental Allergy 2012) Subcutaneous and submucosal angioedema (Cicardi M. Arch Intern Med 2004)

34 ACEI-RAE CLINICAL FEATURES B A C D Manifestations Face / lips / buccal Oropharynx (soft palate / uvula) Tongue / mouth base Base of the tongue hypopharynx / larynx Grade A B C D Frequency [n] Bas M. unpublished

35 ACEI-RAE CLINICAL FEATURES Courtesy of Dr. M. Bas, Technical University Munich (Bas M. unpublished) (Stojiljkovic L. Curr Opin Anaesthesiol 2012)

36 ACEI-RAE CLINICAL FEATURES Underestimated Acute abdominal pain is the reason for 5% to 10 % of all ED visits (Nayak AU. J Em Trauma Shock 2010) Patients undergo laparotomy, but the intra-abdominal findings are negative in 12,2% of cases (in 1 out of every 9 patients) (Laal M. Int J Collab Res Intern Med Public Health 2009) Abdominal ultrasound, CT, MRI may be helpful in establishing the diagnosis of ACEI-related intestinal angioedema (Quit GY. Gastroenterology 2000)

37 ACEI-RAE CLINICAL FEATURES One-third of cases with ACEI-RAE is severe, treated in ED Fatal outcome is rare (Banerji A. Ann Allergy Asthma Immunol 2008) Airway support was provided for 16% of patients ACEI-RA can occur any time during therapy on the 1 st day or after 8-10 years or longer (Agostoni A. Immunopharmacology 1999) Average latency period: 10.2 months Bas M. Br J Clin Pharmacol 2004) Some patients develop symptoms even after the discontinuation of ACEI (Cicardi M. Arch Intern Med 2004)

38 ACEI-RAE DIAGNOSIS Angioedema develops during treatment with ACEI Physical, radiological (UH, CT, MRI) findings AE resolves after discontinuation of the ACEI C1-INH deficiency should be ruled out

39 ACEI-RAE Treatment Current treatment

40 ACEI-RAE Treatment Current treatment Only a little publications with one or two cases are published. Sometimes opposite statements The modification of the standard treatment is ongoing, some results are new (not published)

41 ACEI-RAE Treatment Treatment options Intubation, conicotomy, tracheotomy Fresh frozen plasma Cortisone, antihistamines and epinephrine Anti-Bradykinin-Therapies C1 inhibitor concentrate Icatibant

42 ACEI-RAE Tracheotomy/ coniotomy/ Treatment early intubation Author Journal type Public ation year First onset of symptom relief Time of complette symtom resolution conclusion note Evidence Bramante R M Bas NEJM 1 case 2011 no improvement after methylprednisolone, and epinephrine. nasotracheal intubation was performed Ann Emerg Med. Original paper N= tracheotomy (3/47), intubated (2/47) Waldfahrer HNO 1 case 1995 Early intubation or tracheotomy because of ineffective antiallergic treatment Maier C. Anaesthesis t. 1 case 1995 Despite high-dose steroids, dyspnoea developed within 2 h Patient must be intubated Initially, all patients were treated with cortisone and antihistamines. Retrosp ective After no improvement was happen, the only option to save the airway was the intubation and the tracheotomy

43 ACEI-RAE Treatment Intubation Nasal, endoscopic intubation Oral intubation in sedation! Nasal endoscopic intubation in local anaesthesia is recommended in different published cases

44 ACEI-RAE Fresh frozen plasma Treatment Author Journal type Public ation year Stewart M Warrier MR Karim MY, BMJ Case Reports Ann Allergy Asthma Immunol J Allergy Clin Immunol First onset of symptom relief Time of complette symtom resolution 2 cases 2012 Successful treatment 1 case 2004 Rapid improvement Successful treatment conclusion note Evidence Start of treatment at 4. day after AE onset 1 case 2002 No abstract available The use of FFP in ACEI-RAE is comparable with HAE. There are a some published cases with a successful improvement.

45 ACEI-RAE Cortisone/ antihistamines/ Treatment epinephrine Author Journal type Public ation year First onset of symptom relief Time of complette symtom resolution conclusion note Evi den ce Bramante R M Bas M Westra SW Joseph R. Shiber Maier C. NEJM 1 case 2011 no improvement after methylprednisolone, and epinephrine. nasotracheal intubation was performed Ann Emerg Med. Original paper N= h tracheotomy (3/47), intubated (2/47), received a second dose of methylprednisolone (12/47).Cortisone is not effective NEJM 1 case h epinephrine, antihistamines, and corticosteroids NEJM 1 case h Successful treatment with diphenhydramine and methylprednisolone Anaesthe sist. 1 case 1995 Despite high-dose steroids, dyspnoea developed within 2 h Patient must be intubated The standard treatment in the past. The effectiveness of cortisone and antihistamines could not be confirmed in large case series. At the present nearly all patients were treated with this anti-allergic drugs. Retrosp ective

46 ACEI-RAE Anti-Bradykinin-Therapy Treatment Estrogen Hageman Factor (XIIa) Prekallikrein + B2 B2 B2 B2 B2 Berinert P Cinryze Ruconest C1 INH Kallikrein Ecallantide (Kalbitor) Bradykinin Bradykinin Icatibant Icatibant Icatibant Icatibant Icatibant Kininogen (high molecular weight) Kallidin Bradykinin Arg Pro Pro Phe Pro Arg Gly Ser Phe Amino- Kininase II Peptidase P (ACE) Dipeptidyl- Peptidase IV Kininase I Modified from : Bas M. (2009) Laryngorhinootologie

47 ACEI-RAE C 1 Inhibitor concentrate Treatment Author Journal type Public ation year Gelée B Rev Med Interne. First onset of symptom relief Time of complette symtom resolution 1 case min Successful treatment conclusion note Evidence 1000 IE Nielsen EW Acta Anaesthesio l Scand. 1 case min Successful treatment 1500 IE Treatment after 8 h AE onset Steinbach Anaesthesio l Reanim. 1 case 2001 Successful treatment C1 INH concentrates ( IE) are in published cases effective.

48 Unpublished data Bas et al.

49 ACEI-RAE C 1 Inhibitor concentrate Treatment Unpublished data Bas et al. mean time until complete resolution of symptoms [h] h 33 h 0 C1-INH N=8 standard therapy N=47 We have treated 8 patients with C1 INH concentrates ( IE). The mean time of complete symptom resolution was 10 h. A double blind randomized study is necessary to test the effectiveness. We will start in January next year with a double blind study with Berinert.

50 ACEI-RAE Icatibant Treatment Author Journal type Public ation year First onset of symptom relief Time of complette symtom resolution conclusion note Evidenc e Bas M Anaesthesist. 1 case min 4 h Icatibant is effective Treatment after 5 h AE onset Fast S Bas M Schmidt PW Ugeskr Laeger. Ann Emerg Med. J Am Acad Dermatol. 1 case 2011 Original paper N= min 4,4 h Icatibant is effective Open label, unblinded 1 case 2010?? Icatibant is effective Abstract not available Icatibant is in the published cases effective.

51 ACEI-RAE Icatibant Treatment 3h 4h 6h Icatibant Initial 1h 2h

52 ACEI-RAE Icatibant Treatment mean time until complete resolution of symptoms [h] h 33 h Icatibant N=18 standard therapy Icatibant: The mean time of complete symptom resolution was 5 h. Unpublished data Bas et al.

53 ACEI-RAE Treatment unpublished data Icatibant Arms AMelioration of Angiotensin Converting Enzyme Inhibitor Induced Angioedema Study Experimental: Arm A (n=15) Active Comparator: Arm B (n=15) Assigned Interventions Drug: Icatibant (subcutaneous) and plazebo (intravenous) Drug: Cortisone + Clemastin (intravenous) and plazebo (subcutaneous) Primary endpoint: Time of complete symptom resolution The primary endpoint was achieved (high significant). The difference between Cortisone and Icatibant is nearly the open label case series. First detail results next year.