This document provides an outline and overview of transitioning patients from intravenous or inhaled treprostinil (Remodulin) therapy to oral treprostinil (Orenitram) therapy for pulmonary arterial hypertension. It describes a case series that rapidly transitioned 9 stable PAH patients from their current treprostinil treatment to oral Orenitram over 4 days. The results found that the transition was effective for most patients, though 2 required returning to their original therapy due to worsening symptoms.
The HOPE-3 trial evaluated the effects of rosuvastatin 10 mg daily alone or combined with candesartan/hydrochlorothiazide on cardiovascular outcomes in 12,705 participants without cardiovascular disease at intermediate risk, and found that the combination therapy reduced the primary composite outcome of cardiovascular death, myocardial infarction, or stroke by 29% compared to dual placebo. Significant reductions in LDL cholesterol and blood pressure were seen with combination therapy compared to dual placebo. Adverse events including muscle pain were increased but serious adverse events did not differ significantly between groups.
Naturopathic Treatmentfor the Prevention ofCardiovascular Disease: A Randomized Pragmatic TrialCCNM – Journal Club Sept 30th, 2010Dugald Seely, ND, MScDirector; Research & Clinical EpidemiologyThe Canadian College of Naturopathic Medicine
Presented by Murray Baron, MD at the Scleroderma Patient Education Conference, hosted by the Scleroderma Foundation Greater Chicago Chapter on Saturday, October 12, 2019 in Chicago, IL. For more about the foundation visit scleroderma.org/chicago.
The document summarizes guidelines for treating hypertension and their evidence basis. It discusses several major studies that informed guidelines recommending a target blood pressure of 130/80 mmHg or lower to slow kidney disease progression, including the MDRD trial which found a 32% reduction in kidney failure risk with intensive control to 125/75 mmHg compared to 140/90 mmHg. However, later trials like ACCORD and REIN-2 found no additional benefit from intensive control below 130/80 mmHg or additional medications to reach lower targets.
The study evaluated the efficacy and safety of combining LDL cholesterol lowering (rosuvastatin 10 mg) and blood pressure lowering (candesartan 16-12.5 mg and hydrochlorothiazide 12.5 mg) therapies versus placebo in 12,705 participants without cardiovascular disease but with risk factors. The combined therapy group experienced significantly fewer cardiovascular events (29% risk reduction) and fewer secondary outcomes (28% risk reduction) compared to the dual placebo group. The number needed to treat over 5.6 years was 72 to prevent one primary outcome and 63 to prevent one secondary outcome. While statistically significant differences were observed, the overall clinical benefit was modest given the event rates in both groups.
The DANISH trial investigated whether implanting an ICD in patients with non-ischemic heart failure reduced mortality. Over 67 months of follow-up:
1) ICD implantation did not provide an overall survival benefit compared to usual care.
2) The risk of sudden cardiac death was halved with an ICD.
3) Younger patients and those receiving CRT may benefit more from an ICD.
4) ICDs were associated with device-related complications but reduced inappropriate shocks compared to earlier studies. The trial adds to understanding ICD benefits in non-ischemic heart failure.
This document discusses the treatment of pulmonary arterial hypertension (PAH). It notes that PAH is characterized by vascular proliferation in the small pulmonary arteries, resulting in increased pulmonary vascular resistance and eventual right heart failure. While the pathogenesis is complex and diagnosis can be late, understanding of the disease has led to many new drug treatments. These include prostanoids, endothelin receptor antagonists, phosphodiesterase type 5 inhibitors, and inhaled nitric oxide, which work by different mechanisms. Combination drug therapy may be used for severe, unresponsive cases. Interventional procedures are an option when drug therapies fail. Guidelines recommend starting with calcium channel blockers or diuretics for early, low-risk cases and progressing to approved drugs for severe
This study investigated cardiovascular and gastrointestinal outcomes in clopidogrel users who were also taking proton pump inhibitors (PPIs) using a large cohort of patients in the Netherlands. The study found that clopidogrel users who were also taking PPIs had a 75% higher risk of cardiovascular events compared to clopidogrel-only users. However, the study had limitations such as channeling bias since PPI users had more risk factors, and residual confounding since important risk factors could not be adjusted for. While providing useful insights, the study's findings on the risks of PPI co-administration should be interpreted cautiously due to its limitations.
The HOPE-3 trial evaluated the effects of rosuvastatin 10 mg daily alone or combined with candesartan/hydrochlorothiazide on cardiovascular outcomes in 12,705 participants without cardiovascular disease at intermediate risk, and found that the combination therapy reduced the primary composite outcome of cardiovascular death, myocardial infarction, or stroke by 29% compared to dual placebo. Significant reductions in LDL cholesterol and blood pressure were seen with combination therapy compared to dual placebo. Adverse events including muscle pain were increased but serious adverse events did not differ significantly between groups.
Naturopathic Treatmentfor the Prevention ofCardiovascular Disease: A Randomized Pragmatic TrialCCNM – Journal Club Sept 30th, 2010Dugald Seely, ND, MScDirector; Research & Clinical EpidemiologyThe Canadian College of Naturopathic Medicine
Presented by Murray Baron, MD at the Scleroderma Patient Education Conference, hosted by the Scleroderma Foundation Greater Chicago Chapter on Saturday, October 12, 2019 in Chicago, IL. For more about the foundation visit scleroderma.org/chicago.
The document summarizes guidelines for treating hypertension and their evidence basis. It discusses several major studies that informed guidelines recommending a target blood pressure of 130/80 mmHg or lower to slow kidney disease progression, including the MDRD trial which found a 32% reduction in kidney failure risk with intensive control to 125/75 mmHg compared to 140/90 mmHg. However, later trials like ACCORD and REIN-2 found no additional benefit from intensive control below 130/80 mmHg or additional medications to reach lower targets.
The study evaluated the efficacy and safety of combining LDL cholesterol lowering (rosuvastatin 10 mg) and blood pressure lowering (candesartan 16-12.5 mg and hydrochlorothiazide 12.5 mg) therapies versus placebo in 12,705 participants without cardiovascular disease but with risk factors. The combined therapy group experienced significantly fewer cardiovascular events (29% risk reduction) and fewer secondary outcomes (28% risk reduction) compared to the dual placebo group. The number needed to treat over 5.6 years was 72 to prevent one primary outcome and 63 to prevent one secondary outcome. While statistically significant differences were observed, the overall clinical benefit was modest given the event rates in both groups.
The DANISH trial investigated whether implanting an ICD in patients with non-ischemic heart failure reduced mortality. Over 67 months of follow-up:
1) ICD implantation did not provide an overall survival benefit compared to usual care.
2) The risk of sudden cardiac death was halved with an ICD.
3) Younger patients and those receiving CRT may benefit more from an ICD.
4) ICDs were associated with device-related complications but reduced inappropriate shocks compared to earlier studies. The trial adds to understanding ICD benefits in non-ischemic heart failure.
This document discusses the treatment of pulmonary arterial hypertension (PAH). It notes that PAH is characterized by vascular proliferation in the small pulmonary arteries, resulting in increased pulmonary vascular resistance and eventual right heart failure. While the pathogenesis is complex and diagnosis can be late, understanding of the disease has led to many new drug treatments. These include prostanoids, endothelin receptor antagonists, phosphodiesterase type 5 inhibitors, and inhaled nitric oxide, which work by different mechanisms. Combination drug therapy may be used for severe, unresponsive cases. Interventional procedures are an option when drug therapies fail. Guidelines recommend starting with calcium channel blockers or diuretics for early, low-risk cases and progressing to approved drugs for severe
This study investigated cardiovascular and gastrointestinal outcomes in clopidogrel users who were also taking proton pump inhibitors (PPIs) using a large cohort of patients in the Netherlands. The study found that clopidogrel users who were also taking PPIs had a 75% higher risk of cardiovascular events compared to clopidogrel-only users. However, the study had limitations such as channeling bias since PPI users had more risk factors, and residual confounding since important risk factors could not be adjusted for. While providing useful insights, the study's findings on the risks of PPI co-administration should be interpreted cautiously due to its limitations.
Sydney Sexual Health Centre Journal Club presentation by Gwamaka E.M. on The Journal of Infectious Diseases Volume 214 Issue 10, published in November 2016.
The Journal of Infectious Diseases has been published continuously since 1904 and describes itself as "the premier global journal for original research on infectious diseases". Research published in the JID includes studies in microbiology, immunology, epidemiology, and related disciplines, on the pathogenesis, diagnosis, and treatment of infectious diseases; on the microbes that cause them; and on disorders of host immune responses. JID is an official publication of the Infectious Diseases Society of America.
The Sydney Sexual Health Centre Journal Club allows our team to stay up-to-date with what is being published in the field of sexual health. Staff members take turns to read, review and share the contents of an allocated journal. Journal Club encourages knowledge sharing and discussion about topics raised.
This study investigated whether treatment with the proton pump inhibitor lansoprazole could reduce the frequency of common colds and exacerbations in patients with chronic obstructive pulmonary disease (COPD). The study found that patients taking lansoprazole had significantly fewer COPD exacerbations and a lower risk of frequent common colds compared to the control group. The results suggest that lansoprazole may help reduce airway inflammation and inhibit rhinovirus infection in COPD patients. However, the study was limited by a small sample size, lack of placebo control, and population that was almost entirely male and of Japanese ethnicity.
1) Inhaled iloprost is a prostacyclin analog approved for treatment of pulmonary arterial hypertension. It works by selectively dilating pulmonary arteries and improving ventilation/perfusion matching in the lungs.
2) Clinical studies have shown inhaled iloprost improves exercise capacity and functional class when used alone or in combination with other PAH therapies like bosentan. It also delays time to clinical worsening.
3) When used with sildenafil, inhaled iloprost and oral sildenafil act synergistically to cause strong pulmonary vasodilation, further improving outcomes in patients with severe PAH.
Recent Developments in the Treatment of Hypertension Recent Developments in...MedicineAndFamily
This document summarizes recent evidence from clinical trials on the treatment of hypertension, with a focus on patients with type 2 diabetes. It discusses trials comparing different classes of antihypertensive drugs and levels of blood pressure control. The evidence suggests that ACE inhibitors may provide greater benefits for diabetic patients compared to other drugs, reducing cardiovascular events and slowing kidney and eye disease progression. Intensive blood pressure control is also supported, though some calcium channel blockers may increase cardiovascular risk in diabetes. Ongoing long-term safety documentation is still needed for many antihypertensive agents.
This document discusses chronic bronchitis and asthma. It provides information on the definition, epidemiology, risk factors, signs and symptoms, diagnosis, and treatment of each condition. For chronic bronchitis, key points include that it is progressive airflow obstruction, affects over 16 million Americans, and smoking is the primary risk factor. Asthma affects 7-10% of the population and prevalence has increased in recent decades. Diagnosis involves assessing severity, controlling triggers, and pharmacological management. Treatment focuses on minimizing symptoms and exacerbations through the use of bronchodilators and anti-inflammatory medications.
This document provides an overview of scleroderma and its pulmonary complications from the perspective of an expert in the field. It summarizes that interstitial lung disease is a common complication of scleroderma and may present in various ways. It also reviews treatment approaches for scleroderma-associated interstitial lung disease that have been supported by clinical trials, including cyclophosphamide, mycophenolate, and rituximab.
Nivolumab, a programmed death 1 (PD-1) checkpoint inhibitor, was associated with encouraging overall survival in uncontrolled studies involving previously treated patients with advanced renal-cell carcinoma. This randomized, open-label, phase 3 study compared nivolumab with everolimus in patients with renal-cell carcinoma who had received previous treatment.
Pulmonary Arterial Hypertension Overview
Michael J. Cuttica MD Assistant Professor of Medicine Northwestern Pulmonary Hypertension Program
Northwestern University
Vericiguat is a novel oral soluble guanylate cyclase stimulator being studied for the treatment of heart failure. The VICTORIA trial investigated vericiguat for reducing cardiovascular death or heart failure hospitalization in patients with recent worsening of chronic heart failure. The trial found that vericiguat reduced the primary composite outcome compared to placebo with an absolute risk reduction of 4.2 events per 100 patient-years. Vericiguat was well-tolerated overall but increased risks of hypotension and syncope compared to placebo. The results suggest vericiguat may be an effective additional treatment for reducing heart failure hospitalizations and cardiovascular death in patients with recent heart failure decompensation.
The AFFIRM trial compared rate control and rhythm control strategies for treating atrial fibrillation. Over 7,000 patients with recurrent atrial fibrillation aged 65 or older were randomized to either rate or rhythm control. The primary outcome was overall mortality, with secondary outcomes including death from cardiovascular causes, stroke, bleeding, and hospitalization. The trial found no significant difference in mortality between the two groups. However, rhythm control was associated with greater need for hospitalization and higher rates of crossover to rate control. The study concluded that rate control should be the primary treatment approach for atrial fibrillation.
The document discusses hypertension in several special situations. It describes how hypertension commonly co-exists with conditions like diabetes, cerebrovascular disease, renal disease, and congestive heart failure. It provides guidelines on evaluating and managing blood pressure in these situations. For example, it recommends that antihypertensive therapy aims to reduce stroke risk in cerebrovascular disease and slow renal disease progression when hypertension is present with renal problems. The document also examines hypertension among different demographic groups like women, pregnant women, and the elderly.
Nejm Effects of Aspirin for Primary Prevention in Persons with Diabetes MellitusBhargav Kiran
This document summarizes the results of the ASCEND trial, which investigated the effects of low-dose aspirin (100 mg daily) for primary prevention of cardiovascular events in 15,480 adults with diabetes but no history of cardiovascular disease. Over a mean follow-up of 7.4 years:
- Serious vascular events were lower in the aspirin group (8.5%) compared to placebo (9.6%), but major bleeding events were higher with aspirin (4.1% vs 3.2%).
- There was no significant difference in gastrointestinal cancer rates between groups.
- Aspirin prevented some vascular events but increased bleeding, largely offsetting the benefits. The absolute risks and benefits were closely balanced
The document summarizes a journal presentation comparing the efficacy and safety of new oral anticoagulants (NOACs) to warfarin for stroke prevention in atrial fibrillation patients. It provides background on atrial fibrillation and an overview of 4 large randomized controlled trials evaluating dabigatran, rivaroxaban, apixaban, and edoxaban. A meta-analysis of these trials found NOACs reduced the risk of stroke and systemic embolism by 19% and lowered mortality compared to warfarin, while increasing gastrointestinal bleeding but decreasing intracranial hemorrhage. NOACs showed consistent benefits across patient subgroups.
ROLE OF NON INVASIVE VENTILATION IN ACUTE CARDIOGENIC PULMONARY OEDEMA IN EDSrihari Cattamanchi
Non-invasive ventilation (NIV) was used to treat 49 patients with acute cardiogenic pulmonary edema in the emergency department. After 1 hour of NIV, patients' respiratory rate, heart rate, blood pressure, and oxygen saturation improved significantly. However, 14 patients (28.6%) still required intubation within 7 days and 10 patients (20.4%) died in the ICU within 10 days. The study concludes that NIV improves survival in acute cardiogenic pulmonary edema patients by reducing mortality and the need for intubation compared to conventional treatment.
New class of therapeutic agents called soluble guanylate cyclase (sGC) stimulators.
Impairment of NO synthesis and signaling through the NO-sGC–cGMP pathway is involved in the pathogenesis of pulmonary hypertension.
Dual mode of action,
Directly stimulating sGC independently of NO, and
Increasing the sensitivity of sGC to NO.
vasorelaxation , antiproliferative and antifibrotic effects
Based on the findings of the ACCORD BP trial and other studies such as SPRINT, the following guidelines would apply to this patient:
- For patients with diabetes and high cardiovascular risk like this patient, the blood pressure goal remains <140/90 mmHg.
- Given the patient's blood pressure of 132/88 on admission is only slightly elevated and he is not on any BP medications, starting antihypertensive medication in the acute setting would not be indicated.
- Close outpatient follow-up should be arranged to monitor the blood pressure over time and initiate lifestyle modifications and medications if the blood pressure remains elevated on subsequent readings to try to achieve the <140/90 mmHg goal.
- The risks of
1) A large clinical trial found no difference in 7-day or 30-day mortality between patients receiving noninvasive ventilation (CPAP or NIPPV) and standard oxygen therapy for acute cardiogenic pulmonary edema.
2) While noninvasive ventilation improved symptoms and physiological measures more than standard oxygen, these benefits did not translate to improved survival.
3) There were also no differences found between CPAP and NIPPV in terms of efficacy, safety, or effects on mortality.
This document summarizes guidelines from the Eighth Joint National Committee for the management of high blood pressure in adults. It provides evidence-based recommendations for treatment thresholds, goals, and medications. Treatment is recommended to reduce blood pressure below 150/90 mmHg for those aged 60+ and below 140/90 mmHg for others based on evidence from randomized controlled trials. Initial drug treatment should include an ACE inhibitor, ARB, calcium channel blocker, or thiazide diuretic depending on patient characteristics. Lifestyle modifications and medication are important to reduce hypertension and lower risks of health problems like heart attack, stroke, and death.
Community-acquired pneumonia (CAP) is a leading cause of death and hospitalization in the United States. Guidelines recommend using severity of illness scores like CURB-65 to determine appropriate site of care and empiric antibiotic therapy including β-lactams with macrolides or fluoroquinolones. Studies show guideline-concordant therapy improves outcomes. Procalcitonin levels may help determine duration of antibiotics, with lower levels associated with shorter treatment. Overall, clinicians should aim for 5-7 days of effective antibiotics guided by clinical and procalcitonin findings to optimize CAP treatment.
This document discusses proton pump inhibitors (PPIs) and their interaction with the blood thinner clopidogrel. It notes that PPIs and clopidogrel are among the most commonly prescribed medications. Studies have shown that the PPI omeprazole can reduce the effectiveness of clopidogrel by inhibiting the enzyme CYP2C19 needed to activate clopidogrel. Regulatory agencies now warn against combined use of clopidogrel and omeprazole. Alternative PPIs like pantoprazole may be safer options, and future research is still needed.
Dr. Nannika Pradhan presented on pulmonary hypertension (PH). The key points discussed include:
1. PH is defined as a mean pulmonary arterial pressure ≥25 mmHg at rest as assessed by right heart catheterization.
2. PH is classified clinically into 5 groups based on etiology.
3. Clinical features include dyspnea, chest pain, syncope, signs of right heart failure. Diagnosis involves echocardiogram, CT scan, ventilation-perfusion scan and right heart catheterization.
4. Treatment depends on disease severity and involves diuretics, oxygen supplementation, calcium channel blockers, endothelin receptor antagonists, phosphodiesterase-5 inhibitors, prostano
Pulmonary hypertension is defined as a mean pulmonary arterial pressure of at least 25 mm Hg. It can be caused by various conditions and is classified accordingly. Idiopathic pulmonary hypertension has no known cause. It presents with dyspnea and right heart failure. Diagnosis involves right heart catheterization showing elevated pulmonary pressures. Treatment includes diuretics, vasodilators like calcium channel blockers, endothelin receptor antagonists, phosphodiesterase inhibitors, prostanoids, and sometimes atrial septostomy or lung transplantation for severe cases refractory to medical therapy. Prognosis depends on factors like functional status, hemodynamics, and response to treatment.
Sydney Sexual Health Centre Journal Club presentation by Gwamaka E.M. on The Journal of Infectious Diseases Volume 214 Issue 10, published in November 2016.
The Journal of Infectious Diseases has been published continuously since 1904 and describes itself as "the premier global journal for original research on infectious diseases". Research published in the JID includes studies in microbiology, immunology, epidemiology, and related disciplines, on the pathogenesis, diagnosis, and treatment of infectious diseases; on the microbes that cause them; and on disorders of host immune responses. JID is an official publication of the Infectious Diseases Society of America.
The Sydney Sexual Health Centre Journal Club allows our team to stay up-to-date with what is being published in the field of sexual health. Staff members take turns to read, review and share the contents of an allocated journal. Journal Club encourages knowledge sharing and discussion about topics raised.
This study investigated whether treatment with the proton pump inhibitor lansoprazole could reduce the frequency of common colds and exacerbations in patients with chronic obstructive pulmonary disease (COPD). The study found that patients taking lansoprazole had significantly fewer COPD exacerbations and a lower risk of frequent common colds compared to the control group. The results suggest that lansoprazole may help reduce airway inflammation and inhibit rhinovirus infection in COPD patients. However, the study was limited by a small sample size, lack of placebo control, and population that was almost entirely male and of Japanese ethnicity.
1) Inhaled iloprost is a prostacyclin analog approved for treatment of pulmonary arterial hypertension. It works by selectively dilating pulmonary arteries and improving ventilation/perfusion matching in the lungs.
2) Clinical studies have shown inhaled iloprost improves exercise capacity and functional class when used alone or in combination with other PAH therapies like bosentan. It also delays time to clinical worsening.
3) When used with sildenafil, inhaled iloprost and oral sildenafil act synergistically to cause strong pulmonary vasodilation, further improving outcomes in patients with severe PAH.
Recent Developments in the Treatment of Hypertension Recent Developments in...MedicineAndFamily
This document summarizes recent evidence from clinical trials on the treatment of hypertension, with a focus on patients with type 2 diabetes. It discusses trials comparing different classes of antihypertensive drugs and levels of blood pressure control. The evidence suggests that ACE inhibitors may provide greater benefits for diabetic patients compared to other drugs, reducing cardiovascular events and slowing kidney and eye disease progression. Intensive blood pressure control is also supported, though some calcium channel blockers may increase cardiovascular risk in diabetes. Ongoing long-term safety documentation is still needed for many antihypertensive agents.
This document discusses chronic bronchitis and asthma. It provides information on the definition, epidemiology, risk factors, signs and symptoms, diagnosis, and treatment of each condition. For chronic bronchitis, key points include that it is progressive airflow obstruction, affects over 16 million Americans, and smoking is the primary risk factor. Asthma affects 7-10% of the population and prevalence has increased in recent decades. Diagnosis involves assessing severity, controlling triggers, and pharmacological management. Treatment focuses on minimizing symptoms and exacerbations through the use of bronchodilators and anti-inflammatory medications.
This document provides an overview of scleroderma and its pulmonary complications from the perspective of an expert in the field. It summarizes that interstitial lung disease is a common complication of scleroderma and may present in various ways. It also reviews treatment approaches for scleroderma-associated interstitial lung disease that have been supported by clinical trials, including cyclophosphamide, mycophenolate, and rituximab.
Nivolumab, a programmed death 1 (PD-1) checkpoint inhibitor, was associated with encouraging overall survival in uncontrolled studies involving previously treated patients with advanced renal-cell carcinoma. This randomized, open-label, phase 3 study compared nivolumab with everolimus in patients with renal-cell carcinoma who had received previous treatment.
Pulmonary Arterial Hypertension Overview
Michael J. Cuttica MD Assistant Professor of Medicine Northwestern Pulmonary Hypertension Program
Northwestern University
Vericiguat is a novel oral soluble guanylate cyclase stimulator being studied for the treatment of heart failure. The VICTORIA trial investigated vericiguat for reducing cardiovascular death or heart failure hospitalization in patients with recent worsening of chronic heart failure. The trial found that vericiguat reduced the primary composite outcome compared to placebo with an absolute risk reduction of 4.2 events per 100 patient-years. Vericiguat was well-tolerated overall but increased risks of hypotension and syncope compared to placebo. The results suggest vericiguat may be an effective additional treatment for reducing heart failure hospitalizations and cardiovascular death in patients with recent heart failure decompensation.
The AFFIRM trial compared rate control and rhythm control strategies for treating atrial fibrillation. Over 7,000 patients with recurrent atrial fibrillation aged 65 or older were randomized to either rate or rhythm control. The primary outcome was overall mortality, with secondary outcomes including death from cardiovascular causes, stroke, bleeding, and hospitalization. The trial found no significant difference in mortality between the two groups. However, rhythm control was associated with greater need for hospitalization and higher rates of crossover to rate control. The study concluded that rate control should be the primary treatment approach for atrial fibrillation.
The document discusses hypertension in several special situations. It describes how hypertension commonly co-exists with conditions like diabetes, cerebrovascular disease, renal disease, and congestive heart failure. It provides guidelines on evaluating and managing blood pressure in these situations. For example, it recommends that antihypertensive therapy aims to reduce stroke risk in cerebrovascular disease and slow renal disease progression when hypertension is present with renal problems. The document also examines hypertension among different demographic groups like women, pregnant women, and the elderly.
Nejm Effects of Aspirin for Primary Prevention in Persons with Diabetes MellitusBhargav Kiran
This document summarizes the results of the ASCEND trial, which investigated the effects of low-dose aspirin (100 mg daily) for primary prevention of cardiovascular events in 15,480 adults with diabetes but no history of cardiovascular disease. Over a mean follow-up of 7.4 years:
- Serious vascular events were lower in the aspirin group (8.5%) compared to placebo (9.6%), but major bleeding events were higher with aspirin (4.1% vs 3.2%).
- There was no significant difference in gastrointestinal cancer rates between groups.
- Aspirin prevented some vascular events but increased bleeding, largely offsetting the benefits. The absolute risks and benefits were closely balanced
The document summarizes a journal presentation comparing the efficacy and safety of new oral anticoagulants (NOACs) to warfarin for stroke prevention in atrial fibrillation patients. It provides background on atrial fibrillation and an overview of 4 large randomized controlled trials evaluating dabigatran, rivaroxaban, apixaban, and edoxaban. A meta-analysis of these trials found NOACs reduced the risk of stroke and systemic embolism by 19% and lowered mortality compared to warfarin, while increasing gastrointestinal bleeding but decreasing intracranial hemorrhage. NOACs showed consistent benefits across patient subgroups.
ROLE OF NON INVASIVE VENTILATION IN ACUTE CARDIOGENIC PULMONARY OEDEMA IN EDSrihari Cattamanchi
Non-invasive ventilation (NIV) was used to treat 49 patients with acute cardiogenic pulmonary edema in the emergency department. After 1 hour of NIV, patients' respiratory rate, heart rate, blood pressure, and oxygen saturation improved significantly. However, 14 patients (28.6%) still required intubation within 7 days and 10 patients (20.4%) died in the ICU within 10 days. The study concludes that NIV improves survival in acute cardiogenic pulmonary edema patients by reducing mortality and the need for intubation compared to conventional treatment.
New class of therapeutic agents called soluble guanylate cyclase (sGC) stimulators.
Impairment of NO synthesis and signaling through the NO-sGC–cGMP pathway is involved in the pathogenesis of pulmonary hypertension.
Dual mode of action,
Directly stimulating sGC independently of NO, and
Increasing the sensitivity of sGC to NO.
vasorelaxation , antiproliferative and antifibrotic effects
Based on the findings of the ACCORD BP trial and other studies such as SPRINT, the following guidelines would apply to this patient:
- For patients with diabetes and high cardiovascular risk like this patient, the blood pressure goal remains <140/90 mmHg.
- Given the patient's blood pressure of 132/88 on admission is only slightly elevated and he is not on any BP medications, starting antihypertensive medication in the acute setting would not be indicated.
- Close outpatient follow-up should be arranged to monitor the blood pressure over time and initiate lifestyle modifications and medications if the blood pressure remains elevated on subsequent readings to try to achieve the <140/90 mmHg goal.
- The risks of
1) A large clinical trial found no difference in 7-day or 30-day mortality between patients receiving noninvasive ventilation (CPAP or NIPPV) and standard oxygen therapy for acute cardiogenic pulmonary edema.
2) While noninvasive ventilation improved symptoms and physiological measures more than standard oxygen, these benefits did not translate to improved survival.
3) There were also no differences found between CPAP and NIPPV in terms of efficacy, safety, or effects on mortality.
This document summarizes guidelines from the Eighth Joint National Committee for the management of high blood pressure in adults. It provides evidence-based recommendations for treatment thresholds, goals, and medications. Treatment is recommended to reduce blood pressure below 150/90 mmHg for those aged 60+ and below 140/90 mmHg for others based on evidence from randomized controlled trials. Initial drug treatment should include an ACE inhibitor, ARB, calcium channel blocker, or thiazide diuretic depending on patient characteristics. Lifestyle modifications and medication are important to reduce hypertension and lower risks of health problems like heart attack, stroke, and death.
Community-acquired pneumonia (CAP) is a leading cause of death and hospitalization in the United States. Guidelines recommend using severity of illness scores like CURB-65 to determine appropriate site of care and empiric antibiotic therapy including β-lactams with macrolides or fluoroquinolones. Studies show guideline-concordant therapy improves outcomes. Procalcitonin levels may help determine duration of antibiotics, with lower levels associated with shorter treatment. Overall, clinicians should aim for 5-7 days of effective antibiotics guided by clinical and procalcitonin findings to optimize CAP treatment.
This document discusses proton pump inhibitors (PPIs) and their interaction with the blood thinner clopidogrel. It notes that PPIs and clopidogrel are among the most commonly prescribed medications. Studies have shown that the PPI omeprazole can reduce the effectiveness of clopidogrel by inhibiting the enzyme CYP2C19 needed to activate clopidogrel. Regulatory agencies now warn against combined use of clopidogrel and omeprazole. Alternative PPIs like pantoprazole may be safer options, and future research is still needed.
Dr. Nannika Pradhan presented on pulmonary hypertension (PH). The key points discussed include:
1. PH is defined as a mean pulmonary arterial pressure ≥25 mmHg at rest as assessed by right heart catheterization.
2. PH is classified clinically into 5 groups based on etiology.
3. Clinical features include dyspnea, chest pain, syncope, signs of right heart failure. Diagnosis involves echocardiogram, CT scan, ventilation-perfusion scan and right heart catheterization.
4. Treatment depends on disease severity and involves diuretics, oxygen supplementation, calcium channel blockers, endothelin receptor antagonists, phosphodiesterase-5 inhibitors, prostano
Pulmonary hypertension is defined as a mean pulmonary arterial pressure of at least 25 mm Hg. It can be caused by various conditions and is classified accordingly. Idiopathic pulmonary hypertension has no known cause. It presents with dyspnea and right heart failure. Diagnosis involves right heart catheterization showing elevated pulmonary pressures. Treatment includes diuretics, vasodilators like calcium channel blockers, endothelin receptor antagonists, phosphodiesterase inhibitors, prostanoids, and sometimes atrial septostomy or lung transplantation for severe cases refractory to medical therapy. Prognosis depends on factors like functional status, hemodynamics, and response to treatment.
Treatment strategies for pulmonary hypertensionSarfraz Saleemi
There is currently no cure for pulmonary hypertension (PAH). Treatment aims to alleviate symptoms, improve quality of life, and delay disease progression. Initial treatment involves lifestyle modifications and medications such as prostacyclins, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors. Combination therapy and newer treatments targeting cellular processes show promise. Ongoing monitoring assesses treatment response through physical exams, functional tests, labs, and imaging to optimize therapy.
Septic shock is a life-threatening condition that arises when sepsis leads to dangerously low blood pressure and problems in organ function. It results from an infection that causes changes throughout the body. Early recognition and treatment are important, including administering antibiotics within an hour, aggressive fluid resuscitation, and monitoring for organ dysfunction. Goals of management are restoring blood pressure, reversing signs of low perfusion, and treating the underlying infection while avoiding additional organ injury.
Update on the Management of Pulmonary HypertensionSarfraz Saleemi
This document provides an overview of treatment for pulmonary hypertension (PH), including:
- Currently there is no cure, but earlier treatment leads to better outcomes.
- Screening high-risk groups allows for earlier diagnosis.
- Initial treatment involves general measures, supportive therapy, and testing for vasoreactivity.
- Vasoreactive patients may be treated with calcium channel blockers, while others receive PH-specific drugs.
- Combination therapy provides greater improvements in symptoms and hemodynamics than monotherapy, though it also carries higher risk of side effects.
- Over time, treatment advances have significantly improved survival rates for PH patients.
Non ventilatory management apart from ventilatory stratetegies are important in management of ARDS. Various trials for and against are there. describing these aspects
This document summarizes advances in the management of pulmonary hypertension. It discusses the diagnostic approach and classification of pulmonary arterial hypertension. It then reviews the general measures, primary therapies including calcium channel blockers, and supportive therapies such as diuretics, digoxin, and anticoagulation. Recent advances in targeted therapies are discussed including prostanoids, endothelin receptor antagonists, phosphodiesterase-5 inhibitors, riociguat, macitentan, oral treprostinil, selexipag, and imatinib. Combination and sequential therapy are now recommended approaches. Balloon atrial septostomy is described as a palliative procedure to improve hemodynamics in advanced disease.
Pulmonary hypertension (PH) is defined as a mean pulmonary arterial pressure >20 mm Hg at rest. It can be caused by various conditions and is classified into 5 groups. Symptoms include dyspnea, fatigue, edema and syncope. Diagnosis involves ECG, echocardiogram, cardiac MRI and right heart catheterization. Treatment includes diuretics, oxygen therapy, calcium channel blockers, endothelin receptor antagonists, PDE5 inhibitors, prostacyclin analogs and lung transplantation in severe cases. Portopulmonary hypertension (POPH) occurs in 5% of cirrhosis patients and is treated similarly to PH but CCBs are generally avoided due to risk of worsening symptoms.
This document discusses asthma, including its definition, prevalence, risk factors, pathophysiology, diagnosis, classification, treatment goals, and management. Some key points:
- Asthma is a chronic inflammatory airway disorder affecting over 17 million people in the US. It is characterized by recurrent wheezing, coughing, and breathlessness.
- Risk factors for developing asthma include respiratory infections, allergens, environment, emotions, exercise, drugs/preservatives, and occupational stimuli.
- Diagnosis involves patient history, physical exam, pulmonary function tests, and trial of asthma medications. Severity is classified based on lung function and symptoms.
- Treatment goals are to control symptoms, prevent exacerbations,
Pulmonary arterial hypertension (PAH) is high blood pressure in the arteries connecting the heart and lungs. The document defines PAH and related types, and discusses risk factors, symptoms, diagnosis, classification, complications and treatments. PAH has no known cause in many cases, but can result from other conditions. Common symptoms include shortness of breath, chest pain and fatigue. Diagnosis involves medical tests and right heart catheterization. Treatment aims to improve symptoms and outcomes through medications, supplemental oxygen, diet changes and exercise.
1) The patient's platelet count decreased while receiving heparin therapy, with counts dropping to 78,000 on day 4 of treatment. Testing later revealed the presence of heparin-dependent platelet antibodies, consistent with type 2 heparin-induced thrombocytopenia (HIT).
2) Treatment options for this patient include argatroban or lepirudin due to her hepatic dysfunction and renal insufficiency. Her anticoagulation will need to be closely monitored and continued for several months.
The document discusses the management of acute severe asthma or status asthmaticus in children. It covers the pathophysiology, clinical assessment, pharmacologic therapies including inhaled beta-2 agonists, corticosteroids, magnesium sulfate, and ventilation. The goals of treatment are to improve oxygenation and bronchodilation while attenuating inflammation through aggressive use of nebulized bronchodilators and systemic corticosteroids. Children not responding require close monitoring, intravenous therapies, and may need intubation and mechanical ventilation to prevent respiratory failure.
This document discusses pulmonary hypertension (PH), including its definition, classification, pathophysiology, diagnosis, and management in intensive care patients. It defines PH as a mean pulmonary artery pressure >25 mmHg and outlines the various causes classified under five groups. The pathophysiology of PH involves vasoconstriction, vascular remodeling, thrombosis and endothelial dysfunction. Diagnosis involves history, physical exam, imaging like chest X-ray and ECG, as well as right heart catheterization. Management focuses on treating the underlying cause, using vasodilators, inotropes to support the right ventricle, diuretics, oxygen therapy and potentially surgery in refractory cases. PH increases mortality and deteriorations can be rapid
03.03 management of patients on antiretroviral drugs changiDavid Ngogoyo
This document discusses rational approaches to changing or stopping antiretroviral (ART) drug regimens. It describes three main reasons for altering a patient's regimen: drug toxicity/intolerance, drug interactions, and treatment failure. It provides examples of specific adverse drug reactions and interactions to watch for with different drug classes and combinations. It emphasizes managing side effects, avoiding interactions, confirming treatment failure before changing regimens, and involving experts in complicated cases.
03.03 management of patients on antiretroviral drugs changiDavid Ngogoyo
This document provides guidance on changing or stopping antiretroviral therapy (ART) in a rational manner. It describes the main reasons for altering a patient's ART regimen as drug toxicity, interactions, or treatment failure. It discusses how to diagnose and manage common adverse drug reactions and interactions. It emphasizes the importance of assessing adherence before changing a patient's failing regimen and consulting national treatment guidelines and experts when making decisions about second-line therapy.
Venous Thromboembolism (VTE): Recent Advances in Reducing the Disease BurdenNBCA
- Venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE), is a major cause of morbidity and mortality worldwide. It is estimated that there are 900,000 cases of VTE per year in the US.
- Recent clinical trials have found that the direct oral anticoagulants rivaroxaban, apixaban, edoxaban and dabigatran are non-inferior to standard therapy for treating VTE and reduce the risk of recurrence, while having a similar or lower risk of bleeding.
- The EINSTEIN DVT and EINSTEIN PE trials found that rivaroxaban was non-infer
Lec 16 management of high risk patients for mohsEhealthMoHS
This document provides guidelines for managing high-risk cardiac patients, including those with acute coronary syndrome (ACS) and infective endocarditis. It outlines tools for predicting cardiovascular risk, when to refer ACS patients for intervention, appropriate post-ACS medical management, and antibiotic regimens for infective endocarditis. The document also reviews criteria for referring arrhythmia cases for ablation and guidelines for implanting devices like ICDs and CRT systems.
This document summarizes recent advances in the treatment of pulmonary arterial hypertension (PAH). It discusses new drugs such as macitentan and riociguat that have been shown to improve outcomes in clinical trials. It also describes an experimental treatment called pulmonary artery denervation that aims to reduce pulmonary artery pressure by ablating nerve endings around the pulmonary arteries. The document reviews the clinical evidence from trials of these new treatments and identifies limitations and areas needing further study to improve outcomes for patients with PAH.
Pulmonary Hypertension for general physicians Sarfraz Saleemi
This patient, a 30-year-old woman, presented with progressive shortness of breath on exertion for two years. Tests revealed her pulmonary artery pressure was elevated at 55 mm Hg. Right heart catheterization confirmed a diagnosis of pulmonary arterial hypertension, showing a mean pulmonary artery pressure of 66 mm Hg and pulmonary vascular resistance of 15 wood units. As treatment for this non-vasoreactive pulmonary arterial hypertension, she will begin oral combination therapy based on her intermediate risk status.
1. Remodulin to Orenitram:
Transitioning from IV to Oral
Treprostinil Therapy
Libby Daugherty, Pharm.D. Candidate
APPE 1 – Critical Care – Piedmont Atlanta Hospital
June 17, 2016
3. Pulmonary Arterial Hypertension
Progressive disease caused by narrowing or
tightening of the pulmonary arteries
Right side of the heart becomes enlarged
due to the increased strain of pumping
blood through the lungs
Strain leads to symptoms of:
Breathlessness
Fatigue
Weakness
Angina
Syncope
4. Pulmonary Hypertension
Group 1: Pulmonary Arterial Hypertension
(PAH)
Idiopathic/Sporadic (IPAH)
Heritable (HPAH)
Drug- or Toxin-induced
Associated with (APAH)
Connective tissue diseases (PAH-CTD)
HIV infection (PAH-HIV)
Portal hypertention
Congenital heart disease (PAH-CHD)
Schistosomiasis
Sickle Cell Disease
Group 1’: Pulmonary Veno-Occlusive Disease
(PVOD) and/or Pulmonary Capillary
Hemangiomatosis (PCH)
Group 1’’: Persistent Pulmonary Hypertension of
the Newborn (PPHN)
Group 2: Pulmonary Hypertension (PH) due to
Left Heart Disease
Group 3: Pulmonary Hypertension (PH) due to
Lung Diseases and/or Hypoxemia
Group 4: Chronic Thromboembolic Pulmonary
Hypertension (CTEPH)
Group 4: Pulmonary Hypertension (PH) with
unclear multifactorial mechanisms
5. Pulmonary Hypertension
Group 1: Pulmonary Arterial Hypertension
(PAH)
Idiopathic/Sporadic (IPAH)
Heritable (HPAH)
Drug- or Toxin-induced
Associated with (APAH)
Connective tissue diseases (PAH-CTD)
HIV infection (PAH-HIV)
Portal hypertention
Congenital heart disease (PAH-CHD)
Schistosomiasis
Sickle Cell Disease
I II III IV
Limitation of usual
physical activity
None Mild Marked Inability
Activity level that
causes Dyspnea,
fatigue, chest pain,
presyncope
None
Normal
physical
activity
Less than
normal
physical
activity
Almost
any
physical
activity
Discomfort at rest None None None Present
Functional Classification
7. Pulmonary Arterial Hypertension
PAH is an Orphan Disease
Prevalence of 15-50 cases per million
Higher Prevalence among Certain Groups:
Female gender (2-4x more prevalent)
Systemic sclerosis (7-12%)
HIV (0.5%)
Sickle Cell Disease (2-3.75%)
Schistosomiasis (4.6%)
10. Transitioning to Oral Treprostinil
Rationale
IV and SQ administration require continuous
use of a CADD Cassette
IV administration carries the risk of blood
infections and sepsis
SQ administration van be very painful
INH administration is frequent and tedious
(up to 9 inhalations QID) and can cause
throat irritation/pain
Candidates
Clinically stable PAH patients
25-111ng/kg/min equivalent dose
11. Traditional Method for Transitioning from IV to PO
Treprostinil
Patient stabilized on IV treprostinil (Remodulin)
Total daily dose of oral treprostinil (Orenitram) is
calculated from the IV maintenance dose
PO total daily dose (mg) = IV dose (ng/kg/min) X
weight (kg) X 0.0072
Divide total daily dose by 3 for TID dosing
Decrease the dose of Remodulin while simultaneously
increasing the dose of Orenitram
Remodulin can be reduced by up to 30ng/kg/min
per day
Orenitram can be increased by up to 6mg (2mg TID)
per day
12. Titration and Transition
Titration
• Increased to goal (42ng/kg/min) over 96
hours
• Hemodynamic stability achieved
Transition
• Orenitram started at 2mg PO TID
• Increased by 2mg TID every day (every 3
doses)
• Remodulin decreased by 14 ng/kg/min every
3 doses of Orenitram
• Monitor for 24 hours, then discharge
13. Case Series
Oral treprostinil for the treatment of pulmonary arterial hypertension in patients transitioned
from parenteral or inhaled prostacyclins: case series and treatment protocol
Efforts to improve patient tolerability and reach optimal dosing have resulted in administration
requirements and titration schedules that can be relatively complex.
Data to guide the transition from parenteral/topical to oral prostacyclin therapy is limited.
14. Method
Inclusion Criteria
PAH Group 1
Stable patients with improved
symptoms/functional capacity
Maintained on treprostinil IV, SQ or INH
With or without background therapy
Who cannot tolerate IV administration due to
infection
Who cannot tolerate SQ administration due to
pain
Who have a preference for oral therapy based on
lifestyle factors
Procedure
Inpatient admission
Right Heart Catheterization to establish a pre-
transition baseline
Transition over 4 days
Orenitram titrated at 0.5 or 1mg TID per day
depending on the maintenance dose
Remodulin decreased by 10ng/kg/min per day
Tyvaso decreased by 3 breaths QID per day
Target dose = 10mg TID (equivalent to 40-
50ng/kg/min) upon discharge
15. Subjects
Variety of concomitant background therapy
with PDE-5i, ERA or combination
Stable on pre-transition maintenance dose
for at least 30 days
Median maintenance dose before transition
= 42 ng/kg/min
Total daily dose calculated for each patient
according to weight, maintenance dose and
bioavailability
Divided by 3 for TID dosing
Rounded to the nearest 0.5mg
Characteristic Value
No. patients (F/M) 9 (7/2)
Age (years) 50 (34-72)
Body weight (kg) 74.8 (50.9-115.7)
Type of PAH
IPAH 5
PAH-CTD 2
PAH-CHD 2
WHO Functional Class
2 7
3 2
Reason for transition
Intolerance of IV d/t infection 1
Intolerance of SQ d/t pain 4
Patient preference 4
Concomitant Therapy
PDE5i Monotherapy 5
ERA Monotherapy 1
PDE5i/ERA Combination 2
No background therapy 1
16. Patient Initial TRE
dose/route
Initiation
(mg)
Discharge
(mg)
Last clinic visit
(mg)
Clinical worsening Conversion failure
1 40 ng/kg/min
SQ
1 TID 10 TID 10.25 QID Yes, mild increase in sx, decline in
6MWD, increase in BNP level
No
2 12 breaths
QID INH
0.5 TID 2.5 TID 7 QID No No
3 24 ng/kg/min
SQ
0.5 TID 3.5 TID 2 BID No No
4 50 ng/kg/min
IV
1 TID 10 TID 10 QID No No
5 40 ng/kg/min
SQ
1 TID 8 TID 7 TID No No
6 70 ng/kg/min
SQ
1 TID 13 TID NA, discont. Yes, syncopal episode, decreased
energy and exercise tolerance
Yes, resumed SQ at higher dose
d/t clinical worsening and ADR
7 39 ng/kg/min
IV
1 TID 8.5 TID NA, discont. No Yes, resumed SQ at baseline
8 36 ng/kg/min
QS
0.5 TID 5 TID 8 TID No No
9 12 breaths
QID INH
1 TID 4 TID NA, discont.
d/t hospice
No No
17. Conclusion
Orenitram adds to the growing number of therapeutic options for patients with PAH
Precise application the treatment of PAH is not yet firmly established
Rapid transition over 4-day period appears reasonable and effective
Evidence suggests that it may serve an important role in prostacyclin transitions in carefully
selected, stable patients who are receiving background therapy.
Ongoing clinical trials will evaluate long-term effects, quality of life, disease progression and
survival.
Further study is needed regarding frequency of administration
18. References
Coons JC, Miller T, Simon MA, Ishizawar DC, Mathier MA. Oral treprostinil for the treatment of pulmonary arterial hypertension in patients transitioned from parenteral or
inhaled prostacyclins: case series and treatment protocol. Pulmonary Circulation. 2016;6(1):132–5.
Gleason JB, Dolan J, Piran P, Rahaghi FF. The Rapid Initiation, Titration, and Transition from Intravenous to Oral Treprostinil in a Patient with Severe Pulmonary Arterial
Hypertension. Case Reports in Pulmonology. 2015;2015:1–3.
Kumar P, Thudium E, Laliberte K, Zaccardelli D, Nelsen A. A Comprehensive Review of Treprostinil Pharmacokinetics via Four Routes of Administration. Clin Pharmacokinet
Clinical Pharmacokinetics. 2016;
Orenitram (treprostinil) [package insert]. Research Triangle Park, NC: United Therapeutics, 2014.
Pulmonary Arterial Hypertension (PAH) [Internet]. PAH-info.com. Actelion Pharmaceuticals Ltd; 2012 [cited 2016Jun16]. Available from: http://www.pah-info.com/home
Pulmonary Hypertension Fact Sheet [Internet]. Centers for Disease Control and Prevention. Centers for Disease Control and Prevention; 2014 [cited 2016Jun16]. Available from:
http://www.cdc.gov/dhdsp/data_statistics/fact_sheets/fs_pulmonary_hypertension.htm
Taichman DB, Ornelas J, Chung L, Klinger JR, Lewis S, Mandel J, et al. Pharmacologic Therapy for Pulmonary Arterial Hypertension in Adults. Chest. 2014;146(2):449–75.
Tonelli AR, Arelli V, Minai OA, Newman J, Bair N, Heresi GA, et al. Causes and Circumstances of Death in Pulmonary Arterial Hypertension. Am J Respir Crit Care Med
American Journal of Respiratory and Critical Care Medicine. 2013;188(3):365–9.
“2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the
European Society of Cardiology (ESC) and the European Respiratory Society (ERS).” Nazzareno Galiè, Marc Humbert, Jean-Luc Vachiery, Simon Gibbs, Irene Lang, Adam
Torbicki, Gérald Simonneau, Andrew Peacock, Anton Vonk Noordegraaf, Maurice Beghetti, Ardeschir Ghofrani, Miguel Angel Gomez Sanchez, Georg Hansmann, Walter
Klepetko, Patrizio Lancellotti, Marco Matucci, Theresa McDonagh, Luc A. Pierard, Pedro T. Trindade, Maurizio Zompatori and Marius Hoeper.Eur Respir J2015; 46: 903–975. Eur
Respir J European Respiratory Journal. 2015;46(6):1855–6.
Editor's Notes
Periwinkle Ribbon
Stomach cancer
Esophageal cancer
Eating disorders
Anorexia
Bulimia
EDNOS
Pulmonary hypertension
IPAH
Sporadic disease
No family history of PAH
No identified risk factor
HPAH
Various mutations (BMPR2 (Bone Morphogenetic Protein Receptor 2)= 80% of these)
APAH
Connective tissue diseases (PAH-CTD)
Systemic sclerosis (SSc)
Systemic lupus erythematosus (SLE)
HIV infection (PAH-HIV)
Rare but well documented
Portal hypertention
Complication of liver disease
Rare but well documented
Portopulmonary hypertension
Congenital heart disease (PAH-CHD)
Congenital shunts (especially Eisenmenger’s syndrome, right left shunt)
Can persist even after corrective surgery
Schistosomiasis
Parasitic disease caused by trematode flatworms
Chronic hemolytic anemia
Drug- or Toxin-Induced
Rare side effect of some appetite suppressants (anorexigenic agents)
Definite
Aminorex
Fenfluramine
Dexfenfluramine
Toxic rapeseed oil
Benfluorex
SSRIs
Likely
Amphetamines
Dasatinib
L-tryptophan
Methamphetamines
Possible
Cocaine
Phenylpropanolamine
St. John’s Wort
Interferon
Cyclophosphamide and similar
Groups 1’ and 1’’ have distinct etiologies from Group 1, but are still primary disease
Groups 2-5 are types of PH caused by another disease state (PH is secondary to something else)
PAH treatment usually not indicated in these groups (except for Group 4)
Underlying cause is treated instead
Any signs of right sided heart failure = FC IV
Diagnostic Gold Standard
PAH Characterized by:
Mean pulmonary arterial pressure (mPAP) ≥ 25mmHg at rest
Mean Pulmonary capillary wedge pressure (PCWP) ≤ 15mmHg
Population of USA = ~320 million
48,00 – 16,000 PAH patients in the US
Orphan Disease = affects < 200,000 nationwide
Population of Atlanta metro area = ~5.5 million
82.5 - 275 (<300 PAH patients in Atlanta)
2 PAH cases in 4 East ICU right now
Survival
Without therapy
1 year: 68%
3 years: 48%
5 years: 34%
With therapy
1 year: 83%
3 years: 58%
No cure for PAH
3 classifications of drugs to treat advanced PAH (Group II-IV)
Can slow progression, treat symptoms and improve quality of life
Prostacyclin pathway (Prosacyclin analogs)
Prostacyclin
low levels in patients with PAH
potent vasodilator
inhibitor of platelet activation
Activation of adenylate cyclase = increase in cAMP
therapy with prostacyclin or prostacyclin analogues can help to correct this deficiency
The only class that improves mortality
Nitric Oxide pathway (PDE-5 inhibitors)
Nitric oxide
potent vasodilator
possesses anti-proliferative properties
impaired production in PAH
vasodilatory effect is mediated by cGMP
rapidly degraded by phosphodiesterases (PDEs) into GMP
therapy with oral PDE-5 inhibitors reduces degradation
Endothelin pathway (ERAs)
Endothelin-1 (ET-1)
elevated levels are seen in PAH patients
levels correlate with disease severity
deleterious effects mediated through ETA receptors
Fibrosis
Hypertrophy and cell proliferation
Inflammation
Vasoconstriction
ETB receptors do the opposite, much weaker
Endothelin receptor antagonists can block these effects
Treprostinil is a prostacyclin analogue
Benefits
Multiple formulations
Long half life (4hr compared to 6min with Veletri)
48 hour stability at room temp (vs 24hr with Veletri)
Negatives
Takes longer to titrate than veletri
Rationale: Intolerance or Patient Preference
CADD Cassettes have to be changed every 48 hours and are cumbersome
Preliminary data from a study evaluating the safety, tolerability, pharmacokinetics, and logistics of transitioning clinically stable PAH patients from parenteral (25–111 ng/kg/min) to oral treprostinil indicates that the transition is feasible in the majority of subjects.
Orenitram (Treprostinil Diolamine) available in multiple strengths:
0.125
0.25
1
2.5
Current PAH guidelines (CHEST 2014, ESC/ERS 2015) offer no specific guidelines for transitioning from parenteral to oral treprostinil
Current method for transitioning is based on the Orenitram package insert
Oral daily dose based on the patient’s weight and the oral bioavailability of Orenitram
0.0072 is a correction factor for bioavailability and unit conversion
Before transition
May already be at goal
May require titration up to goal
TID dosing is preferred to BID dosing
From a case report: The Rapid Initiation, Titration, and Transition from Intravenous to Oral Treprostinil in a Patient with Severe Pulmonary Arterial Hypertension
Initial Titration
Started at 4ng/kg/min
Increased by 4ng/kg/min Q8H
Developed hypotension requiring PE around 36 hours (20ng/kg/min)
Unrelated to PAH
Infectious cause
Resolved with broad spectrum antibiotics
Increased to 42 ng/kg/min (goal) over 96 hours
Hemodynamic stability demonstrated
Transition
PO
Started at 2mg PO TID
Dose increased by 2mg TID every day (ever 3 doses, the dose was increased by 2mg) maximum suggested by package insert
IV
Started at baseline of 42 ng/kg/min
Dose decreased by 14 ng/kg min 1 hour after every PO dose increase
42 28 at HR1 (Day 0)
28 14 at HR25 (Day 1)
Stayed at 14 for HR 49 (Day 2)
14 0 at HR73 (Day 3)
Monitored for 24 hours (Day 4) after goal achieved, then discharged home
6/9 patients started on 1mg TID, 3/9 on 0.5mg TID
Median dose at discharge was 8mg TID (24mg total daily dose)
7/9 patients achieved a successful transition
1 patient discontinued d/t clinical worsening and significant ADRs
1 patient discontinued d/t ADRs
1 patient had clinical worsening, but was able to continue at a higher dose
6/9 patients had clinical follow-up at 47 weeks
1 D/C due to hospice, but had successfully transitioned
Median dose at follow-up was 28mg total daily
6MWD data for 4/6 follow-up patients
2 improved
403 412m @ 10 months
407 403m @ 6 months
2 declined
515 457m @ 10 months
311 256, @ 6 months
8/9 patients experienced ADRs, mostly GI-related
2 patients had to reduce their dose after discharge d/t ADR
Other 5 had increases in dose
No obvious correlation between concomitant background therapy and ADR
The 1 patient who did not have ADR was on combination PDE-5i/ERA
Dosing frequency adjusted to minimize ADR
Based on DLT
2 patients remained on TID
3 patients increased to QID
1 patient reduced to BID
Oral QID dosing has not been studied/reported, but in each case the patient was better able to tolerate the medication at a higher daily dose
PK and clinical outcomes need further investigation