Could you give me a step-by-step illustration of how I would actually perform the analysis of the results?
The proposal's background section should provide enough information for you for you to make an informed decision about my experimental design.
New combination drug therapies for idiopathic pulmonary arterial hypertension
Background: Idiopathic pulmonary arterial hypertension, also known as primary pulmonary hypertension, is an extremely rare cardiopulmonary disease that afflicts less than .03% of the population. It results from malignant fibrosis of the vascular endothelium in the pulmonary arteries, causing vasoconstriction and pseudo-asthma (dyspnea, exercise intolerance, hypoxemia) due to the reduced lung perfusion, causing decreased gas exchange. Major complications include pulmonary edema, due to increased systolic pressure causing rupture of the pulmonary capillaries, and right heart failure, due to the right ventricular strain. It is defined as a resting mPAP of > 25 mmHg and PCWP of < 15 mmHg.
Chin and Rubin give a comprehensive picture of the state-of-the art treatments of IPAH (2008), the main ones of which are prostacyclin analogues, the first of which was epoprostenol, the current gold standard, which must be continually infused directly into the pulmonary trunk, and destroys the scar tissue in the pulmonary trunk. However, this treatment modality is cumbersome and expensive, requiring an expensive pump. Iloprost, a derivative of epoprostenol, is much more convenient than epoprostenol, being inhaled, rather then infused through a central catheter, thus avoiding the systemic side-effects of epoprostenol.
Beraprost is a revolutionary new prostacyclin analogue, which can be administered orally, rather then via frequent inhalations or a centrally-placed catheter. Nagaya et al., in the first major RCT on this drug’s efficacy in alleviating IPAH, performed their study on only those with mild IPAH (1999), so this new study will be performed in order to determine its effectiveness in those patients with more severe IPAH. Galie et al. found that treatment of patients with NYHA class III IPAH with beraprost resulted in increased exercise tolerance compared with placebo (2002).
Sildenafil, a popular vasodilator used to treat erectile dysfunction, was actually developed for the purpose of treating IPAH. Sildenafil works to alleviate the vasoconstriction component of IPAH by preventing cGMP from being degraded, resulting in vasodilation, which, according to the research done by Sastry et al., translates into an improved systolic pulmonary arterial pressure and exercise tolerance (2003). However, the Sastry RCT only compared sildenafil to a non-active placebo, not to an active control, so sildenafil would obviously be more effective than the alternative, which was nothing! This issue was addressed in Oudiz and Wasserman’s criticism of that study (2004). Also, they also took issue with the short length of the study, which did not allow for the analysis of the long-term effects. Sildenafil has also been shown to increase the effects of iloprost (Ghofrani et al. 2003), and a similar effect on the effect of beraprost can be inferred.
Bosentan is a potent inhibitor of endothelin (a potent vasoconstrictor), thereby decreasing mPAP. According to Ueno et al., combining a prostacyclin like beraprost together with an ERA like bosentan creates a synergy, which is a more effective treatment for IPAH than either alone (2002).
This study will compare the efficacy of beraprost in various dosages and iloprost in various dosages, plus adding either various dosages of sildenafil or various dosages of bosentan as an adjunct to the therapy, in alleviating the signs and symptoms of IPAH. We hope to present our findings at the 2010 Annual Scientific Session of the American College of Cardiology.
Objectives: To determine which prostacyclin forms the most effective synergy in alleviating the signs and symptoms of IPAH with which adjunct, and in what dosages.
Sample population: 2035 patients from age 13 on up recently diagnosed with NYHA class III to IV IPAH who are being attended to by MGH, JHMI, Cleveland Clinic, or Mayo Clinic Rochester.
Length: 18 months.
Study Methods: Types and dosages of prostacyclin analogue used in this RCT will be:
Iloprost: 2.5 mcg 9x/day, 5.0 mcg 9x/day, 7.5 mcg 9x/day
Beraprost: 60 mcg 4x/day, 90 mcg 4x/day, 120 mcg 4x/day
Types and dosages of adjunct medication will be:
Sildenafil: 20 mcg 3x/day, 30 mcg 3x/day, 45 mcg 3x/day
Bosentan: 125 mcg 2x/day, 187.5 mcg 2x/day, 281.25 mcg 2x/day
Study participants will be randomized to groups (n=55), which will receive one permutation consisting of a dosage of a prostacyclin analogue combined with a dosage of an adjunct medication e.g. iloprost 7.5 mcg 9x/day and sildenafil 45 mcg 3x/day, or beraprost 60 mcg 4x/day and bosentan 281.25 mcg 2x/day; one group of patients will receive continuous infusion of epoprostenol at 11.2 ng/kg/min, to act as an active control. The investigators will be blinded, as will the patients, pharmacists, and statisticians.
All patients will receive, at the commencement and conclusion of this study:
1. Exercise stress test, to evaluate exercise tolerance, as measured by minutes before reaching maximal heart rate or angina/dyspnea, whichever comes first.
2. Pulmonary artery catheterization, to evaluate resting mPAP and PCWP.
Patients will be encouraged to engage in mild-to-moderate exercise. Patients will be instructed to report any and all adverse effects.
Study Analysis Methods and Reporting Criteria: A 2x2x3x3 MANCOVA will be used to analyze the data. Factors will be the prostacyclin analogue, the adjunct medication, and dosage of each. Levels will be the choices of prostacyclin, the choices of adjunct, and the differing dosages for each. Dependant variables will be post-treatment resting mPAP, PCWP, and ET. Covariates will be age (continuous), body fat percentage (continuous), pre-treatment mPAP (continuous), pre-treatment PCWP (continuous), pre-treatment ET (continuous), and the presence of any and all other heart/lung conditions (true, false). Results will be considered statistically significant if p < .01. Confidence intervals will be reported along with p-values. Clinically significant results are:
1. Resting mPAP changes by >= 10%
2. PCWP changes by >= 10%
3. ET changes by >= 10%
Tables, charts, and graphs will be prepared for the convenience of colleagues.
1. Pulmonary Arterial Hypertension
Chin 2008 J. Am. Coll. Cardiol. 51:1527-1538
2. Effects of beraprost sodium, an oral prostacyclin analogue, in patients with pulmonary arterial hypertension: a randomized, double-blind, placebo-controlled trial
Galie 2002 J. Am. Coll. Cardiol. 39:1496-1502
3. Oral sildenafil as long-term adjunct therapy to inhaled iloprost in severe pulmonary arterial hypertension
Ghofrani 2003 J. Am. Coll. Cardiol. 42:158-164
4. Effect of orally active prostacyclin analogue on survival of outpatients with primary pulmonary hypertension
Nagaya 1999 J. Am. Coll. Cardiol. 34:1188-1192
5. Clinical efficacy of sildenafil in primary pulmonary hypertension
Oudiz 2004 J. Am. Coll. Cardiol. 44:2256
6. Clinical efficacy of sildenafil in primary pulmonary hypertension: A randomized, placebo-controlled, double-blind, crossover study
Sastry 2004 J. Am. Coll. Cardiol. 43:1149-1153
7. A combination of oral endothelin-a receptor antagonist and oral prostacyclin analogue is superior to each drug alone in ameliorating pulmonary hypertension in rats
Ueno 2002 J. Am. Coll. Cardiol. 40:175-181
1. IPAH: Idiopathic pulmonary arterial hypertension
2. cGMP: Cyclic guanosine monophosphate
3. RCT: Randomized controlled trial
4. mPAP: Mean pulmonary arterial pressure
5. PCWP; Pulmonary capillary wedge pressure
6. ERA: Endothelin receptor antagonist
7. NYHA: New York Heart Association
8. MGH: Massachusetts General Hospital
9. JHMI: Johns Hopkins Medical Institute
10. ET: Exercise Tolerance
11. MANCOVA: Multiple analysis of covariance