PDE5 inhibitors for HAPE

44b9d320267a3204e78af152243303c1?s=47 Kenrick Turner
July 03, 2013
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PDE5 inhibitors for HAPE

A literature review of whether PDE5 inhibitors have a role in the prophylaxis and treatment of High Altitude Pulmonary Oedema.

44b9d320267a3204e78af152243303c1?s=128

Kenrick Turner

July 03, 2013
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  1. PDE5 INHIBITORS for HAPE Do they have a role in

    prophylaxis & treatment?
  2. HELLO! EMAIL: kenrick@cantab.net SLIDES: http://kenners.org/talks Despite the obligatory smile, I’m

    not feeling so great... Kenrick Turner BASMU Medical Officer on OOPE from Core Surgical Training
  3. SO HAPE IS IMPORTANT, RIGHT?

  4. INCIDENCE EXTREME VERY HIGH HIGH 1500m 3500m 5500m 0.2% 4

    days1 6% 2 days1 2% 7 days1 15% 2 days1 1. Bärtsch P, et al. Pulmonary extravascular fluid accumulation in climbers. Lancet. 2002 Aug 17;360(9332):571 2. Sophocles AM. High-altitude pulmonary edema in Vail, Colorado. West. J. Med. 1986 May;144(5):569–73. 0.01% 1 day2
  5. 40MPEOPLE VISIT >2500M IN THE USA PER YEAR3 2. Sophocles

    AM. High-altitude pulmonary edema in Vail, Colorado. West. J. Med. 1986 May;144(5):569–73. 3. Hackett PH, Roach RC. High-Altitude Medicine and Physiology. Wilderness Medicine. Sixth Edition. Elsevier Inc; 2012. pp. 2–e11. 0.01% INCIDENCE OF HAPE2 4000 EXPECTED CASES OF HAPE
  6. MORTALITY THESE NUMBERS ARE A LITTLE SKETCHY... 4-11% 4. Menon

    ND. High Altitude Pulmonary Edema: A clinical study. N Engl J Med. 1965 Jul 8;273:66–73. 5. Lobenhoffer HP, Zink RA, Brendel W. High Altitude Pulmonary Edema: Analysis of 166 Cases. In: Brendel W, Zink R, editors. Topics in Environmental Physiology and Medicine. Springer New York; 1982. pp. 219–31. 44% Descent & oxygen4,5 Untreated5
  7. 1:250,000 Your chance of dying from HAPE if you go

    above >2500m MORTALITY
  8. SO HAPE IS IMPORTANT, RIGHT? Maybe.

  9. 1 2 3 Pathophysiology of HAPE PDE5 as a therapeutic

    target in HAPE Summary of the literature 4 Recommendations ROADMAP
  10. PATHOPHYSIOLOGY OF HAPE

  11. DEFINITION “NON-CARDIOGENIC PULMONARY OEDEMA ASSOCIATED WITH ALTITUDE” Excessive pulmonary hypertension

    High-protein permeability leak Normal left heart function Suggests a failure of pulmonary capillaries secondary to over-perfusion & hypertension
  12. HAPE ↓Alveolar Na+ clearance Capillary stress failure + leak Overperfusion

    + ↑Pcap ↑Ppa Uneven Hypoxic Pulmonary Vasoconstriction Hypoxia Intervene! Maggiorini M, Mélot C, Pierre S, Pfeiffer F, Greve I, Sartori C, et al. High-altitude pulmonary edema is initially caused by an increase in capillary pressure. Circulation. 2001 Apr 24;103(16):2078–83. STRESS-FAILURE MODEL OF HAPE
  13. PDE5 INHIBITORS AS A THERAPEUTIC TARGET

  14. Gualynate cyclase eNOS Protein kinase G PDE5 GTP cGMP GMP

    L-arginine NO ↓PA O2 ↓Ca2+ cytosol ↓K+ cytosol Vasodilation Archer SL, Michelakis ED. Phosphodiesterase type 5 inhibitors for pulmonary arterial hypertension. N Engl J Med. 2009 Nov 5;361(19):1864–71. NO/cGMP PATHWAY
  15. Gualynate cyclase eNOS Protein kinase G PDE5 GTP cGMP GMP

    L-arginine NO ↓PA O2 ↓Ca2+ cytosol ↓K+ cytosol Vasodilation PDE5i Archer SL, Michelakis ED. Phosphodiesterase type 5 inhibitors for pulmonary arterial hypertension. N Engl J Med. 2009 Nov 5;361(19):1864–71. NO/cGMP PATHWAY
  16. SUMMARY OF THE LITERATURE

  17. 10 RCTs in last decade 1 Meta-analysis EVIDENCE FOR PREVENTION

  18. 0 RCTs 0 Meta-analyses EVIDENCE FOR TREATMENT Only a few

    case reports and case-series, & usually used alongside Dexamethasone and Acetazolamide.
  19. 95% CI -0.70, 2.51; p = 0.27). Systolic Blood Pressure

    and Heart Rate The overall SBP analysis demonstrated that nonsignificant effects were observed in the PDE5 inhibitor treatment group at rest (WMD, -2.23; (WMD 1.42; 95% CI -1.75, 4.59; p = 0.38; figure 3) or during exercise (WMD 2.83; 95% CI -1.31, 6.96; p = 0.18) in the active treatment group compared with the control group. The results of a sensitivity analysis excluding the Aldashev et al.[7] study were consistent with those of an initial analysis for SBP and HR during rest conditions. Ghofrani et al.[6] Aldashev et al.[7] Ricart et al.[8] Richalet et al.[10] Maggiorini et al.[12] Faoro et al.[14] Reichenberger et al.[15] Total (95% CI) Test for heterogeneity: χ2 = 19.26, df = 6 (p = 0.004), I2 = 68.9% Test for overall effect: Z = 4.39 (p < 0.0001) 14 9 14 6 8 14 14 79 22.00 (4.90) 39.00 (10.00) 34.90 (3.00) 23.60 (3.40) 40.20 (1.80) 40.00 (7.50) 20.10 (3.70) Study n 14 8 14 6 9 14 14 79 n Treatment group SPAP [mean (SD)] 27.10 (5.20) 55.00 (18.00) 40.80 (2.10) 34.30 (7.90) 56.80 (8.80) 41.00 (7.50) 25.70 (10.10) 18.51 4.59 22.31 11.95 13.82 14.49 14.33 100.00 0 −50 Favours treatment Favours control −100 50 100 −5.10 −16.00 −5.90 −10.70 −16.60 −1.00 −5.60 −7.51 [−8.84, −1.36] [−30.08, −1.92] [−7.82, −3.98] [−17.58, −3.82] [−22.48, −10.72] [−6.56, 4.56] [−11.23, −0.03] [−10.87, −4.16] Control group SPAP [mean (SD)] WMD (random) [95% CI] Weight (%) WMD (random) [95% CI] Fig. 1. Forest plot of weighted mean difference (WMD) in systolic pulmonary artery pressure (SPAP) at rest in subjects taking phospho- diesterase type 5 inhibitors for the management of high-altitude pulmonary hypertension versus control subjects; data are from seven trials (WMD -7.51; 95% CI -10.87, -4.16; p < 0.0001). df = degrees of freedom; I2 = percentage of the total variation across studies due to hetero- geneity; Z = test of overall treatment effect. ª 2010 Adis Data Information BV. All rights reserved. Clin Drug Investig 2010; 30 (4) META-ANALYSIS Jin B, et al. Phosphodiesterase Type 5 Inhibitors for High-Altitude Pulmonary Hypertension. Clinical Drug Investigation. Springer International Publishing; 2010 Apr;30(4):259–65. PDE5 inhibitors reduce hypoxia-induced pulmonary hypertension
  20. THE RCTS AREN’T GREAT Small samples (n<20) Surrogate end points

    (PA pressure) Surrogate measures of surrogate endpoints (ΔpTR for PA) Surrogate conditions (normobaric hypoxia) Selected groups (HAPE susceptible) Wide variation in regimes of PDE5 inhibitors Poor randomization No intention to treat Conflicts of interest (funded by Pfizer)
  21. THINGS WE CAN SAY Reduces incidence of HAPE in HAPE-susceptible

    individuals6 Improves PaO2 at altitude & probably improve exercise capacity7 Reduces hypoxia-induced pulmonary hypertension8 6. Maggiorini M, et al. Both tadalafil and dexamethasone may reduce the incidence of high-altitude pulmonary edema a randomized trial. Ann. Intern. Med. 2006 Oct 3;145(7):497–506. 7. Ghofrani HA, et al. Sildenafil increased exercise capacity during hypoxia at low altitudes and at Mount Everest base camp. Ann. Intern. Med. 2004 Aug 3;141(3):169–77. 8. Zhao L, et al. Sildenafil inhibits hypoxia-induced pulmonary hypertension. Circulation. 2001 Jul 24;104(4):424–8.
  22. PITFALLS Risk of tachyphylaxis9 No role in treatment (yet) May

    exacerbate AMS9 9. Bates MGD, et al. Sildenafil Citrate for the Prevention of High Altitude Hypoxic Pulmonary Hypertension: Double Blind, Randomized, Placebo-Controlled Trial. High Altitude Medicine & Biology. 2011 Oct;12(3):207–14.
  23. ANOTHER MECHANISM?

  24. ANOTHER MECHANISM? HAPE ↓Alveolar Na+ clearance Capillary stress failure +

    leak Overperfusion + ↑Pcap ↑Ppa Uneven Hypoxic Pulmonary Vasoconstriction Hypoxia Intervene! Intervene!
  25. RECOMMENDATIONS

  26. 1 2 Descent, oxygen, and Nifedipine remain the treatment for

    HAPE. RECOMMENDATIONS PDE5 inhibitors should be considered for prophylaxis in HAPE-susceptible individuals.
  27. ? Thank you