Pulmonary hypertension; does gender matter?

Transcription

1 Pulmonary hypertension; does gender matter? Nazzareno Galiè Istituto di Cardiologia Università di Bologna

2 Galiè N et al. European Heart Journal (2009) 30,

3 Pulmonary Hypertension mpap (mmhg) ± 3

4 Galiè. N et al Eur Heart J and Eur Respir J, 2009

5 Galiè.N et al Eur Heart J and Eur Respir J, 2009

6 Galiè N et al. European Heart Journal (2009) 30,

7 Pulmonary (arterial) hypertension; does gender matter? Yes Epidemiology Prognosis Treatment Pregnancy - Contraception

8 Epidemiology

9 Primary pulmonary hypertension. A national prospective study Rich S, et al. Ann Intern Med 1987;206: NIH registry started in 1981 (results published in 1987) 32 centers in US 187 PPH patients Mean age: 36 ± 15 y Time 1 st symptoms to diagnosis: 24 mo (mean) Female to male ratio: 1.7/1

10 N Engl J Med 1996;335: Case-controlled study Anorexigens as risk factor for ipah 35 centers in 4 European countries 95 ipah/pph vs 355 controls Female to male ratio: 2.3/1

11 Scottish National Registry Female to male ratio: 2.3/1 French National Registry Female to male ratio: 1.9/1 AJRCCM 2006;173:

12 Pulmonary Vascular Diseases Center Institute of Cardiology Bologna University Hospital As of 31 December 2009 Etiology of PAH (n= 792) CHD 22% CTD 18% Ch Anaemia 1% IPAH- HPAH- Drugs 41% Etiology Patients IPAH-HPAH-Drugs 324 HIV - PAH 68 Po- PAH 79 Po- PAH 10% HIV 8% CHD - PAH 175 CTD - PAH 140 Ch H Anaemia - PAH 6 Total 792

13 Pulmonary Vascular Diseases Center Institute of Cardiology Bologna University Hospital As of 31 December 2009 Gender distribution (PAH, n= 786) 63% 37% Male Female

14 Pulmonary Vascular Diseases Center Institute of Cardiology Bologna University Hospital As of 31 December 2009 Etiology and gender distribution of PAH (n= 792) Etiology Females IPAH-not responders 59 % IPAH-responders 77 % CHD PAH 60 % CTD PAH 88 % Po PAH 45 % HIV - PAH 44 %

15 Pediatric IPAH Female to male ratio: 1/1 Rosenzweig et al Pediatr Pulmon 2004;38:2-22.

16 Familial IPAH Autosomal dominant Reduced gene penetrance Sex bias Females > Males (2:1) Unaffected Obligate carrier Affected Family 04 45

17 Inheritance of sporadic PAH BMPR2 mutations Idiopathic PAH (n=50) Germline BMPR2 mutations (n=16) No mutation Mutation Paternally inherited: n= 3 994C T Spontaneous (de-novo): n=2 2386delG Female Male Adults > 20% Children <10% Thomson et al J Med Genet 2000 Morisaki H et al Hum Mut 2004 Grunig et al Paed Res 2004 Koehler et al J Med Genet 2004 Harrison et al Circulation 2005

18 Possible mechanisms Deleterious effect of female hormones on the pathobiology of distal pulmonary arteries Estrogens seems to impair BMPR-2 function Unknown mechanisms

19 Pulmonary Vascular Diseases Center Institute of Cardiology Bologna University Hospital Clinical Characteristics of 212 CTEPH Patients Mean Age: 65 ± 16 years (range 20 ± 85 ) MALES 41% FEMALES 59%

20 Prognosis

21 Survival in patients with primary pulmonary hypertension. Results from a national prospective registry P(t) = [H(t)] A(x, y, z) H(t) = [ t t 2 ] A(x,y,z) = e ( X y Z) x = mpap y = RAP z = CI D Alonzo GE Ann Intern Med 1991;115:5, 343-9

22 ESC Guidelines 2004

23 Galiè. N et al Eur Heart J and Eur Respir J, 2009

24 N= 190

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26 Pulmonary Vascular Diseases Center Institute of Cardiology Bologna University Hospital As of 31 December 2009 Etiology of PAH (n= 792) CHD 22% CTD 18% Ch Anaemia 1% IPAH- HPAH- Drugs 41% Etiology Patients IPAH-HPAH-Drugs 324 HIV - PAH 68 Po- PAH 79 Po- PAH 10% HIV 8% CHD - PAH 175 CTD - PAH 140 Ch H Anaemia - PAH 6 Total 792

27 Multivariate analysis IPAH nres p HR 95% - CI Age (years) Gender (male) MWD (m) RA Area I (cm 2 /m 2 ) CHD-PAH p HR 95% - CI 6MWD (m) RA Area I (cm 2 /m 2 ) CTD-PAH p HR 95% - CI 6MWD (m) LV ed-area (cm 2 )

28 Survival Survival stratification based on gender 70.8?% 63.8% F 47.5% 44.5?% M Log rank Test p=0.007 N Months F N M

29 Treatment

30 Medline search from January 1990 to October RCTs, 3199 patients

31 Study ID All Cause Mortality RR (95% CI) % Weight Rubin-1990 Barst-1996 Badesch-2000 Langleben-2002 Simmoneau-2002 Galiè-2002 Olschewski-2002 Rubin-2002 Barst-2003 Sastry-2004 Barst-2004 Galiè-2005 Galiè-2008 Galiè-2008 Simonneau-2008 Channick-2001 Singh-2006 Galiè-2006 Barst-2006 McLaughlin-2006 Hoeper-2006 Overall RR = - 43%, P = 0.023) 0.36 (0.04, 3.00) 0.06 (0.00, 0.96) 0.79 (0.22, 2.77) 1.66 (0.07, 39.30) 0.92 (0.38, 2.21) 1.00 (0.06, 15.65) 0.25 (0.03, 2.22) 0.24 (0.02, 2.60) 0.47 (0.04, 5.01) 0.39 (0.02, 8.73) 1.54 (0.06, 37.19) 1.01 (0.11, 9.55) 0.41 (0.11, 1.49) 0.99 (0.06, 15.58) 0.07 (0.00, 1.15) (Excluded) (Excluded) (Excluded) (Excluded) (Excluded) (Excluded) 0.57 (0.35, 0.93) Favors Treatments I Favors Controls Galiè N et al Eur Heart J 2009

32 Results - 3 Demographic and Clinical Characteristics N = 3199 Males 23% Females 77% Age 47.5 years Galiè N et al Eur Heart J 2009

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36 Pregnancy

37 Medline search from January 97 to September articles included, 73 parturients with PAH

38 Maternal mortality in parturients with PAH: Comparison between and Overall maternal mortality was significantly lower compared with previous era (25% vs. 38%, P = 0.047) Weiss BM et al., J Am Coll Cardiol 1998; 31(7): Berard et al.eur Heart J (2009) 30 (3):

39 Contraceptive strategies-1 There are no specific studies for birth control use in PAH The two safest methods of birth control are 1) the barrier method (condoms in men and/or a diaphragm with spermacide in women) 2) a vasectomy in the male partner for a woman with PAH in a monogamous (one partner) relationship Tubae ligation/occlusion may be considered in specific cases Galiè N et al. European Heart Journal (2009) 30, ACCF/AHA 2009 Expert Consensus Document on Pulmonary Hypertension

40 Contraceptive strategies-2 Oestrogen containing contraceptives may increase risk of venous thromboembolism and can aggravate PAH 1 Lower-dose oestrogen preparations with concurrent warfarin anticoagulation are a reasonable option 1;3 Progesteron only preparation (medroxiprogesteron acetate and etonogestrel) are effective approaches to contraception and avoid potential issue of oestrogens 2. The pills must be taken at the same time every day to be effective 1.ACCF/AHA 2009 Expert Consensus Document on Pulmonary Hypertension 2.Thorne S, J Fam Plann Reprod Health Care Apr;32(2): Galiè N et al. European Heart Journal (2009) 30,

41 Contraceptive strategies-3 Endothelin receptor antagonist (ERA) bosentan may reduce the efficacy of oral contraceptive agents The Mirena coil (hormone-releasing intra-uterin device) is effective (like sterilization) with reduced risk of vaginal bleeding but rarely leads to vasovagal reaction and infection when inserted 1 Concurrent use of 2 methods may be utilised 1.Thorne S, J Fam Plann Reprod Health Care Apr;32(2):75-81

42 Comments - 1 There is s clear influence of female gender on the development of all types of PAH The female prevalence is not present before the puberty Estrogens are likely linked to the predisposition of female gender to PAH Male gender is a predictor of increased mortality in PAH patients; the reason for this is unclear

43 Comments - 2 Pregnancy is a well known factor that aggravates PAH Despite lower death rates over the last decade compared to previous era, maternal mortality in parturients with PAH remains prohibitively high (25-38%) PAH is a contraindication for pregnancy

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