Contempo GIMSI Cosa cambia alla luce della letteratura in tema di terapia farmacologica

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1 Contempo GIMSI Cosa cambia alla luce della letteratura in tema di terapia farmacologica Dott.ssa Diana Solari Centro Aritmologico e Sincope Unit, Lavagna

2 POST 2 (Prevention of Syncope Trial) J Am Coll Cardiol Jul 5; 68 (1): 1-9.

3 BACKGROUND No pharmacological therapies have been proven effective for VVS prevention by randomized controlled trials Fludrocortisone is a synthetic adrenal corticosteroid that increases blood pressure through sodium and water retention, expanding plasma volume It is used for treatment of orthostatic hypotension due to autonomic failure (recommended dose 0.3 mgdaily) No clinical studies have tested the effectiveness of fludrocortisone to prevent syncope in adults with VVS SINCOPE

4 AIM OF THE STUDY To determine whether fludrocortisone reduces the proportion of patients with recurrent VVS by at least 40% SINCOPE

5 METHODS Multicenter, randomized, double-blind, placebo-controlled trial Between June 2005 and August 2010 Patients with recurrent VVS Fludrocortisone vs placebo at highest tolerated doses from 0.05 mg to 0.2 mg daily over a 1-year treatment period 2 week dose stabilization Followed for medians of 364 days (IQR days) Main outcome: first recurrence of syncope. SINCOPE

6 INCLUSION CRITERIA - 14 years of age - score >3 on the Calgary Syncope Symptom Score - 2 lifetime syncopal spells (> 40% risk of syncope in the next year) EXCLUSION CRITERIA - other causes of syncope - significant comorbidities, glaucoma, diabetes mellitus, hepatic disease - pacemaker - blood pressure > 130/85 mm Hg - clinical need for or contraindication to fludrocortisone SINCOPE

7 RESULTS Total analyzed patients: 210 (105 vs 105) 96 pts almost 1 syncopal recurrence 56 pts no syncopal recurrence SINCOPE 58 pts no study termination (32 vs 26) - 14 lost to FU (9 vs 5) - 16 side effects (11 vs 5) - 1 presumed treatment failure vs 1 physician preference - 26 other reason (11 vs 15) Followed in the study

8 RESULTS BASELINE CHARACTERSTICS SINCOPE

9 SINCOPE RESULTS 12-month syncope event rates lower in the fludrocortisone arm compared with placebo (44.0% vs. 60.5%) 31% reduction in the hazard of fainting Difference not statistically significant (p = 0.069). p = 0.069

10 SINCOPE RESULTS EXPLORATORY ANALYSIS 61.3% of pts reached the target dose ( 0.2 mg) 2 weeks after randomization (dose stabilization period) Analyzing only syncopal recurrence after the first 2 weeks, fludrocortisone significantly reduced the proportion of patients with syncope (HR: 0.62; 95% CI: 0.40 to 0.95; p = 0.029). p = 0.029

11 SINCOPE RESULTS EXPLORATORY ANALYSIS When further restricted to patients who achieved a stabilized dose of 0.2 mg there was a significant reduction in symptoms due to treatment with fludrocortisone (HR: 0.51; 95% CI: 0.28 to 0.89; p = 0.019). p = 0.019

12 CONCLUSIONS The study did notdemonstrate that fludrocortisone reduced the likelihood of VVS by the specified risk reduction of 40% Significant effects were noted after dose stabilization and in post hoc multivariable and on-treatment analyses Significant benefit in univariableanalysis: - baseline systolic BP <110 mm Hg (HR: 0.48; 95% CI: 0.25 to 0.92; p = 0.028) - body mass index 20 (HR: 0.59; 95% CI: 0.37 to 0.95; p = 0.030) - syncope frequency 8 episodes/year (HR: 0.46; 95% CI: 0.23 to 0.95; p = 0.036) Larger studies would be needed to determine the agent s utility in specific subgroups of patients.

13 Clin Auton Res. 2016; 26:

14 BACKGROUND DROXIDOPA synthetic amino acid precursor that is converted by dopa decarboxylase enzyme to norepinephrine, resulting in peripheral arterial and venous vasoconstriction approved by FDA for the treatment of NOH in 2014 SINCOPE

15 Clin Auton Res. 2016; 26: RCTs 485 patients parallel, randomized, controlled trials droxidopa vs placebo pts with symptomatic NOH 2 studies on pts with Parkinson s Disease only 2 studies on pts with Parkinson s disease (PD), pure autonomic failure (PAF), and multiple system atrophy (MSA) SINCOPE

16 RESULTS FROM BASELINE TO ENDPOINT ORTHOSTATIC HYPOTENSION QUESTIONNAIRE SYMPTOM COMPOSITE SCORE P=0.02 DIZZINES/ LIGHTHEAD- EDNESS SCORE P=0.004 SYMPTOM- IMPACT COMPOSITE SCORE P= P=0.008 STANDING SBP P=0.003

17 RESULTS MEAN DIFFERENCE OF CHANGE FROM BASELINE TO 1, 2 AND 8 WEEKS ORTHOSTATIC HYPOTENSION QUESTIONNAIRE DIZZINES/LIGHTHEADEDNESS SCORE WEEK 1 P=0.002 WEEK 1 P=0.005 WEEK 2 P=0.04 WEEK 2 P=0.009 WEEK 8 P=0.61 WEEK 8 P=0.011

18 CONCLUSIONS The efficacy of droxidopa decreased gradually after 2 weeks, and its statistical significance was lost after 8 weeks. Droxidopa is a safe and effective drug for the short-term management of NOH symptoms. However, current evidence is insufficient to confirm the efficacy of droxidopa for long-term use. SINCOPE

19 Neurology Sep 23; 83 (13):

20 BACKGROUND Midodrine hydrochloride: α1-adrenergic receptor agonist Currently recommended for treatment of Symptomatic Orthostatic Hypotension (SOH) and recurrent reflex syncope (RRS) in most of clinical practice guidelines Approved with FDA s accelerated-approval process based on surrogate endpoints (changes in blood pressure, heart rate, or tilt test) Lack of high-quality evidence supporting its utilization SINCOPE

21 Neurology Sep 23; 83 (13): RCTs 593 patients Randomized controlled parallel group trials and randomized crossover trials Midodrine vs control (placebo, no treatment, or supportive treatment) Patients of any age with a diagnosis of RRS or SOH Oral midodrine (daily doses from 2.5 to 30 mg) alone or associated with standard care or other drugs.

22 RESULTS HEALTH-RELATED QUALITY OF LIFE SYMPTOM IMPROVEMENT RRS #3 P= % SOH #5 P= RISK OF SYNCOPE RECURRENCE +30% RRS #2 P= RRS #5 P= %

23 CONCLUSIONS In both SOH or RRS midodrine might have a positive impact on clinical important outcomes Midodrine is not related to serious and life-threatening adverse effects, but it could be associated with some uncomfortable side effects (reported in 7/11 RCTs), such as urinary urgency or retention, pilomotor reactions, and supine hypertensionwhose clinical significance remains uncertain The quality of the evidence supporting the results is low/moderate Pharmacologic treatments such as midodrine should be considered in those who remain symptomatic after non pharmacologic measures are adequately instituted. SINCOPE

24 GRAZIE PER L ATTENZIONE

25

26 RESULTS PATIENT FLOW

27 BACKGROUND NEUROGENIC ORTHOSTATIC HYPOTENSION (NOH) Orthostatic hypotension (OH): sustained decrease in blood pressure by 20 mmhg systolic or 10 mmhg diastolic within 3 min after standing Neurogenic OH (NOH): rare subtype that occurs due to the failure of the autonomic nervous system to raise peripheral resistance in response to postural changes. NOH is associated with neurodegenerative diseases: Parkinson s disease (PD), pure autonomic failure (PAF), and multiple system atrophy (MSA). NOH becomes symptomatic when standing blood pressure (BP) fails to maintain adequate cerebral perfusion à dizziness, lightheadedness, syncope, visual disturbances, weakness, fatigue, and falls Management of NOH: controlling aggravating factors + physical countermeasures, lifestyle changes, volume expansion, acute drinking of water + fludrocortisone and midodrine

28 SUMMARY OF INCLUDED STUDIES

29 METHOD INCLUSION CRITERIA - parallel, randomized, controlled trials - studies that compared droxidopa with placebo - studies whose population included adult patients with symptomatic NOH - studies reporting mean change in Orthostatic Hypotension Questionnaire (OHQ) scores and standing systolic blood pressure (SBP) from baseline to the end of the follow-up.

30 CALGARY SYNCOPE SYMPTOM SCORE SINCOPE

31 TRIAL SELECTION 11 RCTs

32 SINCOPE CONCLUSIONS - 2 Nonpharmacologicmeasures (reassurance regarding the benign nature of the condition, maintaining an adequate fluid and salt intake, regular exercise, and the application of physical counter-pressure maneuvers) are recommended as the first step in the treatment of patients with RRS and SOH. These measures improve symptoms in a significant proportion of patients with the RRS, but are less effective in patients with SOH. Pharmacologic treatments such as midodrine should be considered in those who remain symptomatic after these measures are adequately instituted, but it must be aware of the uncertainty that exists related to the response rate among different subgroups of patients, and its longterm efficacy and safety.

33 METHODS - OUTCOME MEASURES Health-related quality of life (HRQL) assessed by any validated questionnaire Symptom improvement defined as any improvement reported by the patient in symptoms attributed to OH or recurrent syncope Syncope recurrence Drug-related adverse effects (goose bumps, tingling, chills, or any other pilomotor reactions, agitation, depression, anxiety, insomnia, gastrointestinal discomfort, palpitations, and urinary problems: urinary retention, hesitancy, or urgency) SINCOPE