- Mipomersen treatment results in statistically significant reductions in LDL-C, but high withdrawal rates of 50-70% by 2 years due to intolerability limit its long-term benefits.
- Mipomersen causes liver enzyme elevations and hepatic steatosis in many patients, which may progress to steatohepatitis and fibrosis over years. It is difficult to identify patients at risk of long-term liver damage.
- The clinical trials were not prospectively designed or adjudicated to assess cardiovascular outcomes, so limited conclusions can be drawn about mipomersen's effects on cardiovascular risk. Uncertainties remain regarding its long-term benefits and risks.
Hypertension affects a large portion of the global population and is a major risk factor for cardiovascular disease. While treatment has improved, blood pressure remains difficult to control for many patients. Guidelines recommend treating with multiple-drug combinations to effectively lower blood pressure and reduce cardiovascular risk. Fixed-dose combinations can simplify treatment regimens and improve patient compliance compared to free-drug combinations, helping to better control blood pressure and reduce health risks.
Hepatic disease can significantly alter the pharmacokinetics and pharmacodynamics of drugs due to changes in drug metabolism and clearance in the liver. The degree of liver function impairment is commonly assessed using the Child-Pugh score, with higher scores indicating more severe impairment. For drugs that undergo significant hepatic metabolism or clearance, dosage reductions may be necessary in patients with liver disease to avoid drug accumulation, decreased formation of active metabolites, and increased risk of adverse effects. The need for dosage adjustment depends on the fraction of the drug metabolized by the liver and the severity of liver function impairment.
The document discusses several issues related to prescribing medications for elderly patients, noting that while the elderly population takes a significant amount of prescription and non-prescription drugs, they are also at higher risk for adverse drug reactions, drug-drug interactions, and under-prescribing of needed medications due to changes in pharmacokinetics and pharmacodynamics that occur with aging. It emphasizes the importance of considering an individual's overall health status and potential for drug interactions when determining the appropriate medication regimen for elderly patients.
This document discusses principles of drug therapy and pharmacology in heart disease. It covers topics such as variability in drug effects due to pharmacokinetic, pharmacodynamic, and pharmacogenomic factors. It discusses optimizing drug dosages starting at low levels and monitoring for adverse effects. Special considerations for drug therapy in the elderly population and issues with polypharmacy are also covered. The risks of non-adherence to drug regimens in elderly patients are described.
This document summarizes geriatric pharmacology and aging-related changes. It discusses theories of aging, how aging affects drug absorption, distribution, metabolism, and excretion. It also covers age-related changes in drug sensitivity and interactions, principles of prescribing for older adults, and common diseases in the elderly. Potential anti-aging therapies like calorie restriction, DHEA, and estrogen/progesterone are also mentioned.
Combination Therapy In Hypertension - Dr Vivek Baliga PresentationDr Vivek Baliga
Dr Vivek Baliga of Baliga Diagnostics, Bangalore, discusses the common combination therapies used in the management of hypertension in clinical practice.
Hypertension affects a large portion of the global population and is a major risk factor for cardiovascular disease. While treatment has improved, blood pressure remains difficult to control for many patients. Guidelines recommend treating with multiple-drug combinations to effectively lower blood pressure and reduce cardiovascular risk. Fixed-dose combinations can simplify treatment regimens and improve patient compliance compared to free-drug combinations, helping to better control blood pressure and reduce health risks.
Hepatic disease can significantly alter the pharmacokinetics and pharmacodynamics of drugs due to changes in drug metabolism and clearance in the liver. The degree of liver function impairment is commonly assessed using the Child-Pugh score, with higher scores indicating more severe impairment. For drugs that undergo significant hepatic metabolism or clearance, dosage reductions may be necessary in patients with liver disease to avoid drug accumulation, decreased formation of active metabolites, and increased risk of adverse effects. The need for dosage adjustment depends on the fraction of the drug metabolized by the liver and the severity of liver function impairment.
The document discusses several issues related to prescribing medications for elderly patients, noting that while the elderly population takes a significant amount of prescription and non-prescription drugs, they are also at higher risk for adverse drug reactions, drug-drug interactions, and under-prescribing of needed medications due to changes in pharmacokinetics and pharmacodynamics that occur with aging. It emphasizes the importance of considering an individual's overall health status and potential for drug interactions when determining the appropriate medication regimen for elderly patients.
This document discusses principles of drug therapy and pharmacology in heart disease. It covers topics such as variability in drug effects due to pharmacokinetic, pharmacodynamic, and pharmacogenomic factors. It discusses optimizing drug dosages starting at low levels and monitoring for adverse effects. Special considerations for drug therapy in the elderly population and issues with polypharmacy are also covered. The risks of non-adherence to drug regimens in elderly patients are described.
This document summarizes geriatric pharmacology and aging-related changes. It discusses theories of aging, how aging affects drug absorption, distribution, metabolism, and excretion. It also covers age-related changes in drug sensitivity and interactions, principles of prescribing for older adults, and common diseases in the elderly. Potential anti-aging therapies like calorie restriction, DHEA, and estrogen/progesterone are also mentioned.
Combination Therapy In Hypertension - Dr Vivek Baliga PresentationDr Vivek Baliga
Dr Vivek Baliga of Baliga Diagnostics, Bangalore, discusses the common combination therapies used in the management of hypertension in clinical practice.
This document discusses polypharmacy and aging. It covers several topics related to challenges of geriatric pharmacology including how aging affects pharmacokinetics and pharmacodynamics. Pharmacokinetics like absorption, distribution, metabolism and elimination can all be impacted by aging. Factors like reduced liver and kidney function, lower muscle mass and protein levels can influence how drugs are processed in older patients. Pharmacodynamics may also be altered, with some drugs having increased effects. Careful consideration of age-related changes is important for safe and effective prescribing in geriatric patients.
ABSTRACT- Diabetes mellitus is associated with hyperglycemia and patients are at an increased risk of cardiovascular disease. The present study
was carried out to evaluate the diagnostic value of Glycated hemoglobin (HbA1c) in predicting risk of development of diabetic dyslipidemia. 70 clinically
diagnosed cases of type 2 diabetes mellitus with the age range 30-75 years were included in the study group. Out of which 35 diabetic patients
with good glycemic control were included under Group A and 35 diabetic patients with poor glycemic control were included under Group B. 70 age
and sex matched healthy individuals served as controls. HbA1c demonstrated positive and significant correlation with total cholesterol (TC), low
density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C) and LDL/HDL-C, non-HDL-C and TC/HDL-C ratio. Patients
with HbA1c value > 7.0% had significantly higher value of TC, Triacylglycerol (TAG), LDL-C, LDL-C/HDL-C ratio, non-HDL-C and TC/HDL-C
ratio as compared to the patients with HbA1c ≤ 7.0%. However, there was no significant difference in value of HDL-C between two groups. Thus
HbA1c can be used as a potential dual marker of glycemic control and dyslipidemia in type 2 diabetes mellitus.
Keywords: - Type2 Diabetes Mellitus, Glycated hemoglobin, Dyslipidemia, Cardiovascular disease, Lipid Profile panel
1) The study examined the influence of continuing or withdrawing beta-blocker therapy on outcomes in patients hospitalized with heart failure.
2) It found that continuing beta-blocker therapy was associated with lower risks while withdrawing therapy was linked to excess mortality.
3) Continuing therapy was also generally well-tolerated according to the results.
Pharmacotherapy considerations in elderly adultsSafaa Ali
Pharmacotherapy considerations in elderly adults focuses on how aging affects the body's processing of drugs. Key changes include reduced absorption in the gastrointestinal tract, altered distribution in tissues due to changes in body composition, and decreased metabolism and excretion due to reduced liver and kidney function. These pharmacokinetic changes mean drugs for elderly patients often require dosage adjustments to avoid adverse drug reactions. Common issues include increased risk of drug interactions due to slower drug clearance and greater sensitivity to pharmacodynamic effects like sedation or hypotension.
Applications of pharmacokinetics parameters in disease statesUmair hanif
The document discusses how various disease states can impact pharmacokinetic parameters and drug responses. It summarizes how cardiac failure can impair drug absorption through the gastrointestinal tract and decrease distribution to tissues with low blood flow. Renal and hepatic diseases are also discussed as impacting drug clearance pathways. Specifically, cardiac and renal diseases can decrease drug clearance rates dependent on organ blood flow/function, while liver diseases impact metabolic clearance pathways. Overall, disease states can influence absorption, distribution, metabolism and excretion of drugs in complex ways that require careful titration and monitoring of drug therapy.
Hypertension remains difficult to treat effectively despite available drugs. Aggressive treatment of moderate and mild hypertension through combinations of drugs from different classes leads to better outcomes. Combination therapy is recommended to control blood pressure as it is more effective than monotherapy due to targeting multiple mechanisms. Fixed-dose combinations have advantages over individual drugs such as better blood pressure control, fewer side effects, and increased compliance.
The document discusses the rationale and history of using combination therapy to treat hypertension. It notes that combination therapy has been used since the 1950s and studies in the 1960s showed improved blood pressure control and reduced morbidity. Guidelines now recommend initial combination therapy using single pill combinations over stepwise monotherapy due to greater effectiveness in reducing blood pressure and heart disease risk. For patients still uncontrolled on dual therapy, guidelines recommend adding a third drug, often in a single pill combination, to help achieve target blood pressure goals.
This document provides guidelines for the comprehensive management of type 2 diabetes. It focuses on obesity and prediabetes as underlying risk factors. The guidelines address obesity treatment, prediabetes management, hyperglycemia treatment through lifestyle and medications, hypertension management, hyperlipidemia management, and other risk reduction strategies. The guidelines emphasize treating the whole patient and considering multiple risks and complications. Weight loss through various means is recommended for overweight patients with prediabetes or diabetes to improve health outcomes.
Combination therapy to achieve target blood pressure goalsDr Pradip Mate
The document discusses the history and rationale for using combination therapy in the management of hypertension. It notes that combination therapy has been used since the 1950s, starting with pills containing reserpine. Major developments included the addition of thiazide diuretics in the 1960s-1970s and ACE inhibitors/calcium channel blockers in the 1980s-1990s. The rationale for initial combination therapy includes more effective blood pressure control, multi-factorial causes of hypertension, counteracting regulatory mechanisms, and improved patient adherence compared to monotherapy. Current guidelines recommend starting with dual combination therapy or advancing to triple therapy if blood pressure remains uncontrolled.
The document discusses multidrug use in the elderly. It notes that the elderly population is growing and consuming more prescription drugs. Age-related changes to pharmacokinetics and pharmacodynamics can increase risks of adverse drug events from polypharmacy. Drugs are metabolized and cleared more slowly from the body due to reduced liver and kidney function. The elderly also experience increased drug sensitivity. Careful monitoring is needed to balance treatment benefits and risks.
This document provides information on antihypertensive drugs. It begins by listing the specific learning objectives, which include defining hypertension, discussing types and drugs for treatment, mechanisms of action, adverse effects, and considerations for use in various conditions. It then covers primary and secondary hypertension, urgency vs emergency, and mnemonics for drug classes. Individual drug classes are discussed in detail, including diuretics, ACE inhibitors, ARBs, calcium channel blockers, arteriolar vasodilators, and beta blockers. Mechanisms, advantages, disadvantages, and special considerations are provided for each class.
Evolocumab and its clinical outcomes in patients of cardiovascular diseasetarun kumar
This document summarizes a journal club presentation on a clinical trial investigating the PCSK9 inhibitor evolocumab. The trial found that adding evolocumab to statin therapy in patients with cardiovascular disease reduced LDL cholesterol by 59% on average and reduced the risk of the primary composite cardiovascular endpoint of death, heart attack, stroke or revascularization by 15% and the secondary composite of just death, heart attack or stroke by 20% over a median follow up of 26 months. Evolocumab demonstrated a safety profile similar to placebo with no significant differences in adverse events. This trial provides evidence that further lowering of LDL cholesterol beyond standard statin therapy provides cardiovascular benefit.
Warfarin is an anticoagulant drug used to prevent blood clots and treat existing clots. It works by inhibiting vitamin K dependent clotting factors. It was originally developed as a rodenticide but was found to be an effective anticoagulant in humans. Common adverse effects include bleeding risks, which are monitored through INR testing. Warfarin has many drug and food interactions that can increase bleeding risks. It requires careful dosing and monitoring to safely maintain therapeutic anticoagulation levels.
Ruxolitinib is an oral inhibitor of JAK1 and JAK2 that is effective for treating polycythemia vera in patients who have an inadequate response or intolerance to hydroxyurea. It reduces hematocrit and spleen size while improving symptoms. In clinical trials, ruxolitinib provided durable control of hematocrit without phlebotomy and significantly reduced spleen volume compared to best available therapies. The most common side effects were mild and included headache, diarrhea, and fatigue.
mono-therapy vs. combination therapy in hypertensionAhmed Taha
Initial combination therapy is superior to sequential mono-therapy for treating hypertension. Combination therapy controls blood pressure faster by acting on multiple mechanisms, reducing complications by 40-54%. Combinations have greater efficacy, improve adherence, and have protective effects beyond blood pressure lowering like anti-inflammatory and metabolic benefits. Clinical trials show combination therapy achieves better blood pressure control rates and lowers cardiovascular events compared to mono-therapy. Therefore, guidelines recommend starting treatment for hypertension with initial combination therapy.
The document discusses hypertension, including its definition, classification, epidemiology, etiology, pathophysiology, and treatment. Some key points:
- Hypertension is defined as persistent elevation of blood pressure above 140/90 mmHg. It becomes more prevalent with age.
- Risk factors for hypertension include genetics, obesity, sodium intake, activation of the renin-angiotensin-aldosterone system, and sympathetic overactivity.
- Treatment involves lifestyle modifications like weight loss, diet changes, and exercise, as well as pharmacological therapy including diuretics, ACE inhibitors, calcium channel blockers, and others. Combination therapy is often used for more severe cases.
This document discusses several key clinical pharmacological issues related to medication use in the elderly population. It notes that older adults on average take 5-8 medications daily and are more susceptible to adverse drug reactions due to multiple medical conditions and interactions. Several normal age-related physiological changes are also described, such as reduced liver and kidney function, that require dosing adjustments for many medications cleared by these organs. The document highlights specific high risk drug categories and medications that require special consideration or dosage modification in older adults.
1) Several cardiovascular outcome trials (CVOTs) have evaluated the cardiovascular safety of various anti-hyperglycemic medications used to treat type 2 diabetes since 2008 FDA guidelines requiring such trials.
2) The trials found that GLP-1 agonists liraglutide and semaglutide reduced cardiovascular events, while DPP-4 inhibitors and sulfonylureas showed cardiovascular neutral results. SGLT2 inhibitors empaglifozin and canaglifozin reduced cardiovascular death and hospitalization for heart failure.
3) However, CVOTs have limitations such as lack of generalizability, short follow-up periods, and placebo-controlled designs, indicating a need for more
This document discusses measures that can be taken to improve drug absorption, distribution, metabolism, and excretion in older adults in order to reduce adverse drug reactions. It notes that older adults are more susceptible to adverse drug reactions due to age-related changes in absorption, distribution, metabolism, and excretion of drugs. It provides recommendations such as maintaining normal circulation, liver and kidney function, hydration, and body temperature to enhance drug processing and clearance in older adults. It also stresses the importance of monitoring for potential adverse drug reactions even after a drug is discontinued.
This tutorial document provides instructions for creating a basic game with sprites, sounds, gravity, and moving objects using a game engine. It recommends starting by creating a sprite and sound for jumping, then adding gravity to an object and making it solid so it bounces off walls. Further instructions explain how to make objects move and optimize the game's frame rate. The goal is to help new users make their first game and provide a starting point to develop more professional designs.
Glasziou taking healthcare interventions from trial to practiceMarilyn Mann
The document discusses improving the reporting of healthcare interventions in clinical trials to facilitate moving findings from trials into practice. It notes that currently many trial reports do not adequately describe interventions, making it difficult or impossible for clinicians to replicate them. The document proposes that trial protocols and publications should provide detailed descriptions of intervention contents, delivery personnel, locations, doses, schedules, and the degree of flexibility allowed. This would help reduce waste from unusable findings and better support evidence synthesis, clinical practice, and health policy decisions.
This document discusses polypharmacy and aging. It covers several topics related to challenges of geriatric pharmacology including how aging affects pharmacokinetics and pharmacodynamics. Pharmacokinetics like absorption, distribution, metabolism and elimination can all be impacted by aging. Factors like reduced liver and kidney function, lower muscle mass and protein levels can influence how drugs are processed in older patients. Pharmacodynamics may also be altered, with some drugs having increased effects. Careful consideration of age-related changes is important for safe and effective prescribing in geriatric patients.
ABSTRACT- Diabetes mellitus is associated with hyperglycemia and patients are at an increased risk of cardiovascular disease. The present study
was carried out to evaluate the diagnostic value of Glycated hemoglobin (HbA1c) in predicting risk of development of diabetic dyslipidemia. 70 clinically
diagnosed cases of type 2 diabetes mellitus with the age range 30-75 years were included in the study group. Out of which 35 diabetic patients
with good glycemic control were included under Group A and 35 diabetic patients with poor glycemic control were included under Group B. 70 age
and sex matched healthy individuals served as controls. HbA1c demonstrated positive and significant correlation with total cholesterol (TC), low
density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C) and LDL/HDL-C, non-HDL-C and TC/HDL-C ratio. Patients
with HbA1c value > 7.0% had significantly higher value of TC, Triacylglycerol (TAG), LDL-C, LDL-C/HDL-C ratio, non-HDL-C and TC/HDL-C
ratio as compared to the patients with HbA1c ≤ 7.0%. However, there was no significant difference in value of HDL-C between two groups. Thus
HbA1c can be used as a potential dual marker of glycemic control and dyslipidemia in type 2 diabetes mellitus.
Keywords: - Type2 Diabetes Mellitus, Glycated hemoglobin, Dyslipidemia, Cardiovascular disease, Lipid Profile panel
1) The study examined the influence of continuing or withdrawing beta-blocker therapy on outcomes in patients hospitalized with heart failure.
2) It found that continuing beta-blocker therapy was associated with lower risks while withdrawing therapy was linked to excess mortality.
3) Continuing therapy was also generally well-tolerated according to the results.
Pharmacotherapy considerations in elderly adultsSafaa Ali
Pharmacotherapy considerations in elderly adults focuses on how aging affects the body's processing of drugs. Key changes include reduced absorption in the gastrointestinal tract, altered distribution in tissues due to changes in body composition, and decreased metabolism and excretion due to reduced liver and kidney function. These pharmacokinetic changes mean drugs for elderly patients often require dosage adjustments to avoid adverse drug reactions. Common issues include increased risk of drug interactions due to slower drug clearance and greater sensitivity to pharmacodynamic effects like sedation or hypotension.
Applications of pharmacokinetics parameters in disease statesUmair hanif
The document discusses how various disease states can impact pharmacokinetic parameters and drug responses. It summarizes how cardiac failure can impair drug absorption through the gastrointestinal tract and decrease distribution to tissues with low blood flow. Renal and hepatic diseases are also discussed as impacting drug clearance pathways. Specifically, cardiac and renal diseases can decrease drug clearance rates dependent on organ blood flow/function, while liver diseases impact metabolic clearance pathways. Overall, disease states can influence absorption, distribution, metabolism and excretion of drugs in complex ways that require careful titration and monitoring of drug therapy.
Hypertension remains difficult to treat effectively despite available drugs. Aggressive treatment of moderate and mild hypertension through combinations of drugs from different classes leads to better outcomes. Combination therapy is recommended to control blood pressure as it is more effective than monotherapy due to targeting multiple mechanisms. Fixed-dose combinations have advantages over individual drugs such as better blood pressure control, fewer side effects, and increased compliance.
The document discusses the rationale and history of using combination therapy to treat hypertension. It notes that combination therapy has been used since the 1950s and studies in the 1960s showed improved blood pressure control and reduced morbidity. Guidelines now recommend initial combination therapy using single pill combinations over stepwise monotherapy due to greater effectiveness in reducing blood pressure and heart disease risk. For patients still uncontrolled on dual therapy, guidelines recommend adding a third drug, often in a single pill combination, to help achieve target blood pressure goals.
This document provides guidelines for the comprehensive management of type 2 diabetes. It focuses on obesity and prediabetes as underlying risk factors. The guidelines address obesity treatment, prediabetes management, hyperglycemia treatment through lifestyle and medications, hypertension management, hyperlipidemia management, and other risk reduction strategies. The guidelines emphasize treating the whole patient and considering multiple risks and complications. Weight loss through various means is recommended for overweight patients with prediabetes or diabetes to improve health outcomes.
Combination therapy to achieve target blood pressure goalsDr Pradip Mate
The document discusses the history and rationale for using combination therapy in the management of hypertension. It notes that combination therapy has been used since the 1950s, starting with pills containing reserpine. Major developments included the addition of thiazide diuretics in the 1960s-1970s and ACE inhibitors/calcium channel blockers in the 1980s-1990s. The rationale for initial combination therapy includes more effective blood pressure control, multi-factorial causes of hypertension, counteracting regulatory mechanisms, and improved patient adherence compared to monotherapy. Current guidelines recommend starting with dual combination therapy or advancing to triple therapy if blood pressure remains uncontrolled.
The document discusses multidrug use in the elderly. It notes that the elderly population is growing and consuming more prescription drugs. Age-related changes to pharmacokinetics and pharmacodynamics can increase risks of adverse drug events from polypharmacy. Drugs are metabolized and cleared more slowly from the body due to reduced liver and kidney function. The elderly also experience increased drug sensitivity. Careful monitoring is needed to balance treatment benefits and risks.
This document provides information on antihypertensive drugs. It begins by listing the specific learning objectives, which include defining hypertension, discussing types and drugs for treatment, mechanisms of action, adverse effects, and considerations for use in various conditions. It then covers primary and secondary hypertension, urgency vs emergency, and mnemonics for drug classes. Individual drug classes are discussed in detail, including diuretics, ACE inhibitors, ARBs, calcium channel blockers, arteriolar vasodilators, and beta blockers. Mechanisms, advantages, disadvantages, and special considerations are provided for each class.
Evolocumab and its clinical outcomes in patients of cardiovascular diseasetarun kumar
This document summarizes a journal club presentation on a clinical trial investigating the PCSK9 inhibitor evolocumab. The trial found that adding evolocumab to statin therapy in patients with cardiovascular disease reduced LDL cholesterol by 59% on average and reduced the risk of the primary composite cardiovascular endpoint of death, heart attack, stroke or revascularization by 15% and the secondary composite of just death, heart attack or stroke by 20% over a median follow up of 26 months. Evolocumab demonstrated a safety profile similar to placebo with no significant differences in adverse events. This trial provides evidence that further lowering of LDL cholesterol beyond standard statin therapy provides cardiovascular benefit.
Warfarin is an anticoagulant drug used to prevent blood clots and treat existing clots. It works by inhibiting vitamin K dependent clotting factors. It was originally developed as a rodenticide but was found to be an effective anticoagulant in humans. Common adverse effects include bleeding risks, which are monitored through INR testing. Warfarin has many drug and food interactions that can increase bleeding risks. It requires careful dosing and monitoring to safely maintain therapeutic anticoagulation levels.
Ruxolitinib is an oral inhibitor of JAK1 and JAK2 that is effective for treating polycythemia vera in patients who have an inadequate response or intolerance to hydroxyurea. It reduces hematocrit and spleen size while improving symptoms. In clinical trials, ruxolitinib provided durable control of hematocrit without phlebotomy and significantly reduced spleen volume compared to best available therapies. The most common side effects were mild and included headache, diarrhea, and fatigue.
mono-therapy vs. combination therapy in hypertensionAhmed Taha
Initial combination therapy is superior to sequential mono-therapy for treating hypertension. Combination therapy controls blood pressure faster by acting on multiple mechanisms, reducing complications by 40-54%. Combinations have greater efficacy, improve adherence, and have protective effects beyond blood pressure lowering like anti-inflammatory and metabolic benefits. Clinical trials show combination therapy achieves better blood pressure control rates and lowers cardiovascular events compared to mono-therapy. Therefore, guidelines recommend starting treatment for hypertension with initial combination therapy.
The document discusses hypertension, including its definition, classification, epidemiology, etiology, pathophysiology, and treatment. Some key points:
- Hypertension is defined as persistent elevation of blood pressure above 140/90 mmHg. It becomes more prevalent with age.
- Risk factors for hypertension include genetics, obesity, sodium intake, activation of the renin-angiotensin-aldosterone system, and sympathetic overactivity.
- Treatment involves lifestyle modifications like weight loss, diet changes, and exercise, as well as pharmacological therapy including diuretics, ACE inhibitors, calcium channel blockers, and others. Combination therapy is often used for more severe cases.
This document discusses several key clinical pharmacological issues related to medication use in the elderly population. It notes that older adults on average take 5-8 medications daily and are more susceptible to adverse drug reactions due to multiple medical conditions and interactions. Several normal age-related physiological changes are also described, such as reduced liver and kidney function, that require dosing adjustments for many medications cleared by these organs. The document highlights specific high risk drug categories and medications that require special consideration or dosage modification in older adults.
1) Several cardiovascular outcome trials (CVOTs) have evaluated the cardiovascular safety of various anti-hyperglycemic medications used to treat type 2 diabetes since 2008 FDA guidelines requiring such trials.
2) The trials found that GLP-1 agonists liraglutide and semaglutide reduced cardiovascular events, while DPP-4 inhibitors and sulfonylureas showed cardiovascular neutral results. SGLT2 inhibitors empaglifozin and canaglifozin reduced cardiovascular death and hospitalization for heart failure.
3) However, CVOTs have limitations such as lack of generalizability, short follow-up periods, and placebo-controlled designs, indicating a need for more
This document discusses measures that can be taken to improve drug absorption, distribution, metabolism, and excretion in older adults in order to reduce adverse drug reactions. It notes that older adults are more susceptible to adverse drug reactions due to age-related changes in absorption, distribution, metabolism, and excretion of drugs. It provides recommendations such as maintaining normal circulation, liver and kidney function, hydration, and body temperature to enhance drug processing and clearance in older adults. It also stresses the importance of monitoring for potential adverse drug reactions even after a drug is discontinued.
This tutorial document provides instructions for creating a basic game with sprites, sounds, gravity, and moving objects using a game engine. It recommends starting by creating a sprite and sound for jumping, then adding gravity to an object and making it solid so it bounces off walls. Further instructions explain how to make objects move and optimize the game's frame rate. The goal is to help new users make their first game and provide a starting point to develop more professional designs.
Glasziou taking healthcare interventions from trial to practiceMarilyn Mann
The document discusses improving the reporting of healthcare interventions in clinical trials to facilitate moving findings from trials into practice. It notes that currently many trial reports do not adequately describe interventions, making it difficult or impossible for clinicians to replicate them. The document proposes that trial protocols and publications should provide detailed descriptions of intervention contents, delivery personnel, locations, doses, schedules, and the degree of flexibility allowed. This would help reduce waste from unusable findings and better support evidence synthesis, clinical practice, and health policy decisions.
Oxman et al a surrealistic mega analysis of redisorganization theoriesMarilyn Mann
This surrealistic review summarizes the lack of empirical evidence for organizational theories and repeated reorganizations in healthcare. The authors discovered that the most common reason for reorganizations is "no good reason" and that they perpetuate cycles of change. They identified indicators of successful reorganizations as activities that waste money, like large consulting fees for friends. The authors propose ethics committees to review future reorganization proposals to reduce uncontrolled experimentation on healthcare providers and users.
Involveconference2 121120053215-phpapp02Marilyn Mann
Iain Chalmers argues that a significant amount of medical research is wasted due to issues such as:
1) Low priority questions being addressed instead of what matters most to clinicians and patients.
2) Many studies being poorly designed and not learning from existing evidence.
3) Important results from studies often not being published or reported, leading to bias.
He advocates for greater public involvement in setting research agendas and priorities to better align research with patient and clinician needs and reduce waste estimated at over $85 billion per year. The James Lind Initiative seeks to address research waste and improve focus on shared uncertainties.
This document discusses how the media product represents humanity as a whole rather than specific social groups due to the lack of human characters. It aims to convey humanity's weakness and vulnerability through a zombie virus outbreak. The tone of the news reporters is calm yet apprehensive as they speak on behalf of and represent how the human race should be seen. Both male and female reporters are used to challenge dominant ideologies of male power. Ambulance sirens and other foley sounds were added to portray the despair and danger facing humanity. While a zombie virus is scientifically impossible, efforts were made to construct a realistic scenario, such as filming establishing shots early to avoid people.
This document summarizes the results of the HOPE-3 Trial, which evaluated the effects of blood pressure lowering and statin use on cognitive and functional outcomes in older adults. The trial found that while both interventions reduced cardiovascular events, they did not significantly prevent cognitive or functional decline over 5.6 years. However, there were trends toward benefit of blood pressure lowering in those with the highest baseline blood pressure and longer duration of treatment. Rosuvastatin also had no adverse effects on cognition. In conclusion, the interventions were generally not effective at preventing cognitive or functional decline, but some subgroups may benefit.
Sharing Clinical Research Data: an IOM WorkshopMarilyn Mann
This document provides an agenda for a workshop on sharing clinical research data. The workshop is organized by four IOM forums and will bring together participants from industry, academia, government agencies, disease advocacy groups, and other stakeholders.
The workshop objectives are to examine the benefits of sharing clinical trial data, identify barriers to sharing, and explore strategies to address barriers. The agenda includes sessions on benefits of data sharing, data sharing models and best practices, and issues of standardization and governance. Presentations will cover topics such as pooling data across trials, lessons from data sharing projects, overcoming challenges to sharing, and case studies of different standardization approaches. The goal is to identify priority actions and frameworks to guide new data sharing initiatives
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.
This study examined blood levels of homocysteine, vitamin B12, and folic acid in patients with metabolic syndrome compared to controls. The study found that patients with metabolic syndrome had significantly higher levels of homocysteine (2.6 times higher) and significantly lower levels of vitamin B12 (only 53% of controls) and folic acid (only 61% of controls). Lower levels of these vitamins were also associated with higher weight, BMI, blood sugar, and lipid levels. The study concludes that Indian patients with metabolic syndrome have a strong association with abnormal levels of these metabolites, suggesting they may play a greater role in Asians with metabolic syndrome than other populations.
The HOPE-3 trial found that combining treatment with rosuvastatin, candesartan, and hydrochlorothiazide reduced the risk of cardiovascular events by 29% compared to placebo in a population at intermediate cardiovascular risk. The combination therapy lowered LDL cholesterol by 33.7 mg/dL and systolic blood pressure by 6.2 mmHg on average over 5.6 years. It reduced the risk of the primary composite outcome of cardiovascular death, myocardial infarction, or stroke compared to placebo, with numbers needed to treat of 72 and 63 to prevent an event in the primary outcomes. Subgroup analyses suggested greater benefit for those with higher baseline blood pressure.
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.
This study analyzed data from over 21,000 Japanese patients to investigate the relationship between blood pressure measurements and cardiovascular outcomes. The results showed that morning home systolic blood pressure was a stronger predictor of coronary artery disease events than clinic blood pressure. There was a graded association between higher morning home systolic blood pressure and increased risk of coronary events. Neither home nor clinic blood pressure measurements showed a J-shaped curve relationship with stroke or coronary artery disease risk.
1) Hospitalization for coronary heart disease presents an opportunity to initiate lipid-lowering therapy to treat the underlying disease process and improve long-term outcomes. However, studies show many high-risk patients are discharged without receiving lipid-lowering medications.
2) Initiating lipid-lowering therapy during hospitalization through programs that incorporate order sets and reminders can significantly increase treatment rates compared to conventional outpatient initiation after discharge.
3) In-hospital initiation is associated with improved long-term compliance, lower LDL cholesterol levels, and reduced mortality and heart attack rates compared to delayed outpatient initiation after discharge.
Residual Inflammatory Risk inPatients With Low LDL CholesterolLevels Underg...Shadab Ahmad
Patients with coronary artery disease undergoing percutaneous coronary intervention (PCI) are at high risk of future adverse ischemic events.
Indeed, increased inflammatory status pre- and post-PCI has also been associated with poor prognosis, and control of the residual inflammatory risk (RIR) in the CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study) trial has recently opened new perspectives in the field of secondary prevention.
Management of Hyperglycemia in Type 2 Diabetes, 2015: A Patient- Centered App...Mgfamiliar Net
Update to a Position Statement of the American Diabetes Association and the European Association for the Study of Diabetes
Diabetes Care 2015;38:140–149 | DOI: 10.2337/dc14-2441
Intensive Glucose Control in Patients with Type 2 Diabetes — 15-Year Follow-upMohammed Shadman Shakib
VADT 15 year follow up NEJM article presentation
NEJM
June 6,2019
380:2215-2224
This article was presented in the morning session of MU-II, Dhaka Medical College Hospital.
This study investigated the safety of common type 2 diabetes drug combinations using real-world data from Denmark. It found:
1. Combinations including metformin plus an SGLT2 inhibitor, GLP-1 agonist, or both were associated with the lowest risks of major cardiovascular events, severe hypoglycemia, and death compared to other combinations.
2. Metformin plus a sulfonylurea had the highest risks, while metformin plus an SGLT2 inhibitor, GLP-1 agonist, or their combination showed the greatest reductions in risks.
3. Adding a GLP-1 agonist to metformin plus basal insulin significantly decreased the risks of all three outcomes compared to metformin plus basal
Gary H Lyman discusses chemotherapy-induced neutropenia and the use of colony-stimulating factors to manage it. Chemotherapy often causes neutropenia, which can lead to febrile neutropenia and complications that reduce chemotherapy dose intensity. Colony-stimulating factors like G-CSF have been shown in clinical trials to reduce the risk of febrile neutropenia and allow for full dose chemotherapy. Clinical practice guidelines from organizations like EORTC and ASCO recommend using colony-stimulating factors for patients with a high risk (over 20%) of febrile neutropenia or when dose-dense chemotherapy is associated with improved survival.
This document summarizes a study examining the effect of continuing or discontinuing metformin treatment for patients with diabetes and cirrhosis. The study found that of 250 diabetic patients on metformin at cirrhosis diagnosis, 172 (68.8%) continued metformin while 78 (31.2%) discontinued. Patients who continued metformin had a 57% reduced risk of death compared to those who discontinued. The study concludes that metformin should be continued for diabetic patients with cirrhosis without contraindications due to a survival benefit, especially for those with NASH-related cirrhosis. However, the study had limitations such as sample size and inability to assess dose/duration effects of metformin. Further research is needed to validate these results in a larger cohort
Contrast Simulation Study material 20150509.pptAIDA BORLAZA
This document provides guidelines for contrast reactions and their management from the American College of Radiology (ACR). It discusses various types of intravenous contrast media and their risks. Adverse reactions can range from mild to severe/life-threatening and include contrast-induced nephrotoxicity and nephrogenic systemic fibrosis. The document outlines Boston Medical Center's premedication regime using steroids and antihistamines to reduce reaction risk. It also provides guidance on assessing and treating acute contrast reactions according to their severity per ACR guidelines.
Ezzahti sijbrands mulder roeters van lennep familial hypercholesterolemia new...Marilyn Mann
This document summarizes new treatment options for familial hypercholesterolemia (FH), a genetic disorder associated with high cholesterol and increased risk of heart disease. It describes recent clinical trial results of monoclonal antibodies against PCSK9 (REGN727 and AMG145) that lowered LDL cholesterol by up to 68% with minimal side effects. It also discusses mipomersen, an inhibitor of apolipoprotein B synthesis that lowered LDL by 21-47% but was associated with elevated liver enzymes in 6-15% of patients, raising safety concerns. The new drugs show promise for improving cholesterol levels in FH patients but require further study of their long-term safety and impact on heart disease outcomes.
This document summarizes findings from a survey of 50 primary care physicians on their knowledge and perceptions related to treating type 2 diabetes. The survey found that many physicians were unfamiliar with current guidelines regarding appropriate A1c targets and misunderstood results from the ACCORD trial. Physicians were also more likely to recall claims made in marketing materials compared to evidence from clinical studies. Overall, the survey suggests that disseminating evidence-based practices to physicians remains challenging and that new strategies are needed to accelerate adoption of optimal treatment guidelines.
This randomized controlled trial evaluated the efficacy and safety of canagliflozin compared to placebo in patients with type 2 diabetes inadequately controlled with metformin and sulfonylurea. At 26 weeks, HbA1c and fasting plasma glucose were significantly reduced from baseline with canagliflozin 100mg and 300mg compared to placebo. Reductions were maintained at 52 weeks. Canagliflozin also reduced body weight and systolic blood pressure more than placebo. Overall adverse event rates were similar, but genital mycotic infections and osmotic diuresis events were more common with canagliflozin. Increased non-severe hypoglycemia was also seen with canagliflozin.
This document discusses treatment guidelines for diabetic patients experiencing acute coronary syndrome (ACS). It recommends starting insulin therapy to control hyperglycemia during the first 48 hours as high blood glucose is linked to higher mortality. For long-term treatment after discharge, it recommends metformin as first-line due to its cardiovascular benefits without hypoglycemia risk. Novel drugs like SGLT2 inhibitors and GLP-1 receptor agonists are also good options due to proven reductions in major adverse cardiovascular events and heart failure in patients with established cardiovascular disease. The document provides guidelines on initiating and optimizing treatment with these newer drugs for diabetic patients with ACS or at high cardiovascular risk.
This document discusses treatment guidelines for diabetic patients experiencing acute coronary syndrome (ACS). It recommends starting insulin therapy to control hyperglycemia during the first 48 hours as high blood glucose is linked to higher mortality. For long-term treatment after discharge, it recommends metformin as first-line due to its cardiovascular benefits without hypoglycemia risk. Novel drugs like SGLT2 inhibitors and GLP-1 receptor agonists are also good options due to proven reductions in major adverse cardiovascular events and heart failure in patients with established cardiovascular disease. The document provides guidelines on initiating and optimizing treatment with these newer drugs for diabetic patients with ACS or at high cardiovascular risk.
This budget impact analysis estimates the costs of treating heterozygous familial hypercholesterolemia (HeFH) patients with alirocumab over one year within a hypothetical commercial health plan. The analysis found that treating an estimated 1,120 HeFH patients with alirocumab would result in a total drug cost of $11.7 million for the health plan, or $0.976 per member per month. Sensitivity analysis showed that the model was most sensitive to changes in the wholesale acquisition cost of alirocumab. While alirocumab is more effective than other options, its high cost needs to be weighed against potential long-term outcomes benefits for formulary decision making.
This study compared the efficacy and toxicities of gemcitabine/cisplatin combination chemotherapy and paclitexal/carboplatin combination chemotherapy as first-line treatment for 53 patients with stage IIIB or IV non-small cell lung cancer. The study found that gemcitabine/cisplatin combination resulted in better response rates but not statistically significantly so. It also found that gemcitabine/cisplatin combination resulted in more hematological toxicities. Patient demographics were not significantly different between the two treatment arms. The study concluded that platinum-based combinations are effective for non-small cell lung cancer but require proper premedications.
The document summarizes evidence from several major studies on glycemic control targets in diabetes:
1. The DCCT found that intensive insulin therapy (HbA1c <6%) significantly reduced microvascular complications compared to standard therapy but was associated with higher risk of hypoglycemia.
2. The UKPDS found no glycemic threshold for reducing complications, and lower HbA1c was associated with lower risk, suggesting targeting normal levels if possible.
3. The ACCORD trial found that an HbA1c goal of <6% increased mortality risk compared to a goal of 7-7.9% without significantly reducing cardiovascular outcomes or microvascular complications.
Individualization of gly
This document contains summaries of several studies presented at the ACC24 conference around cardiovascular diseases like hypertension, angina, CAD, MI, AF, and HF. One study found that CSL112 infusions did not significantly reduce cardiovascular outcomes in AMI patients over 90 days compared to placebo. Another study found that a transcatheter inter-atrial shunt did not improve symptoms or prognosis in HF patients after 2 years regardless of LVEF. A third study found that Empagliflozin reduced HF hospitalization risk by 23-33% in post-MI patients but did not reduce all-cause mortality.
This summarizes the outcomes of a 6-month pharmacist-provided diabetes management program for employees of the City of Toledo. The program showed improvements in clinical outcomes like A1c and blood pressure. It also improved humanistic outcomes such as patient satisfaction, knowledge, and adherence. Economic outcomes like healthcare utilization and costs improved as well, with a 62.69% reduction in total costs. The study demonstrates positive short-term outcomes across clinical, humanistic and economic domains from a pharmacist-led diabetes management program.
Similar to Ema scientific conclusions and grounds for refusal of mipomersen (20)
Comparative effectiveness randomized trial to improve stroke care delivery c...Marilyn Mann
A Vanderbilt University Medical Center study comparing the current way stroke care is delivered with a redesigned model that better integrates rehabilitation and skilled nursing facilities as well as lay health educators who make home visits. A pilot project suggests this new model can decrease hospital length of stay and readmissions, recurrence rates, and lower cost.
1) A patient with familial hypercholesterolemia (FH) on PCSK9 inhibitors described facing step therapy requirements and high copays to access the drug, with an initial $1000 copay and $400 monthly copay.
2) A study found that only 30.9% of patients prescribed PCSK9 inhibitors ever received the therapy due to prior authorization denials and high copays, with prescription abandonment rates over 75% for copays over $350.
3) Medicare Part D plans have annual out-of-pocket costs for PCSK9 inhibitors and statins of nearly $5000 on average.
Pcsk9 loss of-function genetic variant is associated with pre-diabetes and di...Marilyn Mann
PCSK9 loss-of-function genetic variant is associated with pre-diabetes and diabetes. The study investigated the effect of PCSK9 loss-of-function variants on the incidence of pre-diabetes and diabetes in a cohort with familial hypercholesterolemia. It found that individuals carrying the PCSK9 loss-of-function variant had a lower risk of coronary events but a higher occurrence of pre-diabetes and diabetes. Further research is needed to understand the potential long-term metabolic effects of PCSK9-lowering therapies and risk of new-onset diabetes.
Alirocumab effect on new-onset or worsening diabetes, blood glucose, and HbA1c.Marilyn Mann
In 9 randomized clinical trials of alirocumab including 2482 patients, 3.4% of patients on alirocumab reported treatment-emergent diabetes or worsening of preexisting diabetes compared to 3.1% of patients on placebo. Laboratory tests found that at 52 weeks, patients on alirocumab on average saw a 0.16 mmol/L increase in fasting glucose levels and a 0.10% increase in hemoglobin A1c levels compared to placebo.
This document is a complaint filed by Health Diagnostic Laboratory, Inc. (HDL) against Robert Bradford Johnson and F. Calhoun Dent III seeking preliminary and permanent injunctive relief. HDL alleges that Johnson and Dent, as owners of BlueWave Healthcare Consultants, violated confidentiality, non-competition, and non-solicitation provisions of HDL's Shareholder Agreement by refusing to renegotiate potentially non-compliant provisions in their sales agreement and threatening to compete with HDL after HDL terminated the sales agreement. HDL seeks an injunction to prevent Johnson and Dent from using HDL's confidential information and damaging its business relationships and goodwill with healthcare providers.
This document discusses Alberto Gomez's experience receiving an LVAD (Left Ventricular Assist Device) to treat his advanced heart failure at MedStar Washington Hospital Center. It describes how Alberto had faith and hope even when diagnosed, and was determined to make his LVAD treatment work despite challenges. It highlights how LVADs have revolutionized heart failure treatment by providing an alternative to transplant. It also notes how Alberto now supports other heart failure patients by sharing his experience and offering prayer.
1) The IMPROVE-IT trial investigated whether adding ezetimibe to simvastatin therapy provides additional cardiovascular benefit compared to simvastatin monotherapy in 18,144 high-risk patients who recently had an acute coronary syndrome.
2) Patients receiving ezetimibe/simvastatin had a lower rate of major cardiovascular events (32.7% vs 34.7%) over a median follow-up of 6 years, demonstrating the additional clinical benefit of further lowering LDL-C with ezetimibe.
3) Ezetimibe/simvastatin also reduced the rate of the composite endpoint of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke compared to
Ph rma principlesforresponsibleclinicaltrialdatasharingMarilyn Mann
The document outlines commitments by biopharmaceutical companies to responsibly share clinical trial data with qualified researchers and the public. The key commitments are:
1) Sharing patient-level data, study-level data, and protocols with qualified researchers upon request to facilitate legitimate research. Requests will be reviewed by a scientific board.
2) Making clinical study report synopses publicly available after drug approval to help patients and doctors understand trial results. Full reports may also be shared with researchers.
3) Informing trial patients about results in a factual summary developed with regulators.
The CHMP refused marketing authorization for the drug Kynamro intended for treatment of patients with familial hypercholesterolemia. Kynamro works by blocking production of apolipoprotein B to reduce LDL cholesterol levels, but two clinical trials showed a high rate of patients stopping treatment due to side effects. The CHMP also had concerns about potential long-term liver damage and an increased risk of cardiovascular events. Upon re-examination, the CHMP's concerns remained unresolved and the refusal was confirmed. Patients currently receiving Kynamro through clinical trials or compassionate use programs will be able to continue treatment.
Ioannidis why science is not necessarily self correctingMarilyn Mann
This document summarizes a hypothetical scenario describing how science could deteriorate on the planet F345 in the year 3045268. In this scenario:
- Most research is conducted in "null fields" where there are few or no genuine effects to discover.
- The primary goal is making extravagant claims to obtain more funding, rather than replicating or questioning results.
- Critical thinking is discouraged, and the most advanced science occurs where free thought is restricted.
- Young scientists are taught to prioritize statistically significant results over replicating or questioning findings.
This document discusses designing comparative effectiveness research networks and agendas. It describes how networks can be defined as diverse pieces of data pertaining to related research questions. The geometry and structure of networks can provide insights into the relationships between different research questions and comparisons. Key aspects of network geometry include size, diversity, co-occurrence, and homophily. Prospectively designing networks can help maximize the informativeness of research by enhancing the network geometry and incorporating data continuously.
The Committee for Medicinal Products for Human Use (CHMP) adopted a negative opinion, recommending the refusal of the marketing authorisation for the medicinal product Kynamro, intended for the treatment of certain forms of familial hypercholesterolaemia. While Kynamro was effective at reducing LDL cholesterol levels, the CHMP was concerned about its safety profile. A high proportion of patients stopped taking Kynamro due to side effects and there were concerns about liver toxicity and an increased risk of cardiovascular events. Therefore, the CHMP determined that the risks of Kynamro did not outweigh its benefits and recommended refusing its marketing authorisation.
Workshop report ema 2012 nov 22, access to dataMarilyn Mann
The European Medicines Agency held a workshop on increasing transparency of clinical trial data.
The Agency's director stated their commitment to publishing clinical trial data after marketing authorization. Experts debated issues around data transparency from various perspectives. The Agency will form advisory groups to develop proposals on how to implement proactive clinical trial data publication by January 2014.
1) A clinical trial assessed whether chelation therapy improved quality of life outcomes in patients with stable coronary artery disease and a history of heart attack.
2) The trial found no consistent or sustained improvements in domains of health-related quality of life, including physical and mental functioning, with chelation therapy over 2 years of follow up.
3) A subgroup analysis found a potential benefit of chelation therapy for patients with angina symptoms at baseline, but no benefit was seen for patients with heart failure symptoms.
Trial to assess chelation therapy (tact) slidesMarilyn Mann
The Trial to Assess Chelation Therapy (TACT) was a randomized controlled trial that compared chelation therapy (disodium EDTA injections) to placebo injections in 1708 patients with prior heart attacks. The primary goal was to see if chelation therapy reduced cardiovascular events like death, heart attack, stroke, and hospitalization. The trial found that chelation therapy reduced the primary composite endpoint compared to placebo with a hazard ratio of 0.82 and p-value of 0.035. A pre-specified subgroup analysis found the benefit was greater in patients with diabetes, with a hazard ratio of 0.61 and p-value of 0.002 for chelation therapy versus placebo in reducing cardiovascular events. The trial provides evidence that che
This study assessed the effectiveness and safety of AMG145, a human monoclonal antibody to PCSK9, in patients with heterozygous familial hypercholesterolemia (HeFH) who were on intensive statin therapy but unable to reach LDL-C treatment goals. At 12 weeks, patients receiving 350 mg or 420 mg of AMG145 subcutaneously every 4 weeks saw LDL-C level reductions of 43% and 55% respectively, compared to a 1% increase in the placebo group. No serious adverse events occurred. AMG145 may provide an effective additional treatment to help more HeFH patients reach their LDL-C goals.
Godlee clinical trial data for all drugs in current useMarilyn Mann
1) The editorial argues that clinical trial data for all drugs currently in use should be made publicly available for independent scrutiny, as drug companies have systematically misreported and withheld data from clinical trials, endangering patients.
2) It highlights GSK's recent commitment to allow access to anonymized patient-level data from clinical trials as a positive step, but notes that independent researchers should be able to access all clinical trial data once regulatory approval is granted.
3) The editorial expresses frustration that Roche has withheld about 60% of clinical trial data on Tamiflu from the Cochrane review and regulators, costing taxpayers billions, and calls on Roche to release the full data to allow independent evaluation of Tamif
5-hydroxytryptamine or 5-HT or Serotonin is a neurotransmitter that serves a range of roles in the human body. It is sometimes referred to as the happy chemical since it promotes overall well-being and happiness.
It is mostly found in the brain, intestines, and blood platelets.
5-HT is utilised to transport messages between nerve cells, is known to be involved in smooth muscle contraction, and adds to overall well-being and pleasure, among other benefits. 5-HT regulates the body's sleep-wake cycles and internal clock by acting as a precursor to melatonin.
It is hypothesised to regulate hunger, emotions, motor, cognitive, and autonomic processes.
Kosmoderma Academy, a leading institution in the field of dermatology and aesthetics, offers comprehensive courses in cosmetology and trichology. Our specialized courses on PRP (Hair), DR+Growth Factor, GFC, and Qr678 are designed to equip practitioners with advanced skills and knowledge to excel in hair restoration and growth treatments.
Osteoporosis - Definition , Evaluation and Management .pdfJim Jacob Roy
Osteoporosis is an increasing cause of morbidity among the elderly.
In this document , a brief outline of osteoporosis is given , including the risk factors of osteoporosis fractures , the indications for testing bone mineral density and the management of osteoporosis
Histololgy of Female Reproductive System.pptxAyeshaZaid1
Dive into an in-depth exploration of the histological structure of female reproductive system with this comprehensive lecture. Presented by Dr. Ayesha Irfan, Assistant Professor of Anatomy, this presentation covers the Gross anatomy and functional histology of the female reproductive organs. Ideal for students, educators, and anyone interested in medical science, this lecture provides clear explanations, detailed diagrams, and valuable insights into female reproductive system. Enhance your knowledge and understanding of this essential aspect of human biology.
These lecture slides, by Dr Sidra Arshad, offer a simplified look into the mechanisms involved in the regulation of respiration:
Learning objectives:
1. Describe the organisation of respiratory center
2. Describe the nervous control of inspiration and respiratory rhythm
3. Describe the functions of the dorsal and respiratory groups of neurons
4. Describe the influences of the Pneumotaxic and Apneustic centers
5. Explain the role of Hering-Breur inflation reflex in regulation of inspiration
6. Explain the role of central chemoreceptors in regulation of respiration
7. Explain the role of peripheral chemoreceptors in regulation of respiration
8. Explain the regulation of respiration during exercise
9. Integrate the respiratory regulatory mechanisms
10. Describe the Cheyne-Stokes breathing
Study Resources:
1. Chapter 42, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 36, Ganong’s Review of Medical Physiology, 26th edition
3. Chapter 13, Human Physiology by Lauralee Sherwood, 9th edition
Cell Therapy Expansion and Challenges in Autoimmune DiseaseHealth Advances
There is increasing confidence that cell therapies will soon play a role in the treatment of autoimmune disorders, but the extent of this impact remains to be seen. Early readouts on autologous CAR-Ts in lupus are encouraging, but manufacturing and cost limitations are likely to restrict access to highly refractory patients. Allogeneic CAR-Ts have the potential to broaden access to earlier lines of treatment due to their inherent cost benefits, however they will need to demonstrate comparable or improved efficacy to established modalities.
In addition to infrastructure and capacity constraints, CAR-Ts face a very different risk-benefit dynamic in autoimmune compared to oncology, highlighting the need for tolerable therapies with low adverse event risk. CAR-NK and Treg-based therapies are also being developed in certain autoimmune disorders and may demonstrate favorable safety profiles. Several novel non-cell therapies such as bispecific antibodies, nanobodies, and RNAi drugs, may also offer future alternative competitive solutions with variable value propositions.
Widespread adoption of cell therapies will not only require strong efficacy and safety data, but also adapted pricing and access strategies. At oncology-based price points, CAR-Ts are unlikely to achieve broad market access in autoimmune disorders, with eligible patient populations that are potentially orders of magnitude greater than the number of currently addressable cancer patients. Developers have made strides towards reducing cell therapy COGS while improving manufacturing efficiency, but payors will inevitably restrict access until more sustainable pricing is achieved.
Despite these headwinds, industry leaders and investors remain confident that cell therapies are poised to address significant unmet need in patients suffering from autoimmune disorders. However, the extent of this impact on the treatment landscape remains to be seen, as the industry rapidly approaches an inflection point.
Mercurius is named after the roman god mercurius, the god of trade and science. The planet mercurius is named after the same god. Mercurius is sometimes called hydrargyrum, means ‘watery silver’. Its shine and colour are very similar to silver, but mercury is a fluid at room temperatures. The name quick silver is a translation of hydrargyrum, where the word quick describes its tendency to scatter away in all directions.
The droplets have a tendency to conglomerate to one big mass, but on being shaken they fall apart into countless little droplets again. It is used to ignite explosives, like mercury fulminate, the explosive character is one of its general themes.
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Promoting Wellbeing - Applied Social Psychology - Psychology SuperNotesPsychoTech Services
A proprietary approach developed by bringing together the best of learning theories from Psychology, design principles from the world of visualization, and pedagogical methods from over a decade of training experience, that enables you to: Learn better, faster!
2. Scientific conclusions and grounds for refusal presented by the European
Medicines Agency
Overall summary of the scientific evaluation of Kynamro
• Quality issues
The quality of this product is considered to be acceptable. Physicochemical and biological aspects
relevant to the uniform clinical performance of the product have been investigated and are controlled in
a satisfactory way. At the time of opinion, there are no outstanding issues on the quality of the active
substance or the medicinal product.
• Efficacy issues
Treatment with mipomersen results in a statistically significant decline of 24.7% and
35.9% in LDL-C levels at Primary Efficacy Time point (PET) versus baseline in
patients with homozygous familial hypercholesterolaemia (HoFH) and severe
heterozygous familial hypercholesterolaemia (HeFH) on top of statins, respectively.
This corresponds to a reduction by 21% and 48% with mipomersen when corrected
with placebo (for HoFH and HeFH, respectively). In absolute terms, it corresponds to
a placebo-corrected reduction with mipomersen by -100 and -114 mg/dl in LDL-C at
PET versus baseline, which may be considered of clinical relevance. Approximately
70% of patients in the mipomersen groups of pivotal trials had at least a 15%
decrease in LDL-C levels from baseline to PET in comparison with approximately 20%
of patients in the placebo groups. Statistically significant percent reductions with
mipomersen compared to placebo were also observed for apo B, TC, and non HDL-C
from baseline to PET. However, based on data from pivotal studies and OLE CS6
study, withdrawal rates may be as high as 50%-70% at two years and mainly due to
mipomersen treatment intolerability, thus, significantly decreasing the rate of
patients that may benefit from the lipid-lowering effect of the drug in the long-term,
which is considered a major concern. In the HoFH, the retention rate was only 8% at
3 years, with 63% withdrawing due to adverse events.
Uncertainties remain regarding effects of mipomersen on long-term cardiovascular
outcome. Potential negative effects on cardiovascular risk factors may counteract the
potential beneficial effect on CV outcome due to reduction in LDL-C.
• Safety issues
The mipomersen safety database from the conducted clinical programme is limited
considering the original target population that intends to include patients with HeFH,
even if it is limited to severe cases, and raises serious safety concerns for the both
patient groups. For a medicinal product that is intended to protect patients at high CV
risk, the data on Major Adverse Cardiac Event (MACE) during the phase 3 studies
raise a safety concern. Mipomersen reduces LDL level in a relevant manner, but in
long term use might induce other changes in CV risk factors that could counteract
such effect.
Mipomersen exhibits adverse effect on liver and other mechanisms of liver damage
beyond fat accumulation cannot be excluded. Importantly, steatosis is plausibly
correlated with the effect on cholesterol levels, which introduces an additional doubt
on the long-term sustainability of this therapy, particularly in those patients where
3. the beneficial effect in the lipid profile is more marked. There is no known threshold
at which hepatic steatosis or liver fat fraction results in inflammation and progressive
liver disease, which renders the monitoring of onset of liver related adverse events
difficult.
The numerically higher number of neoplasms and cancer raises an additional safety
concern. There is no proven relationship between mipomersen treatment and the
occurrence of neoplasm, mainly due to the low incidence rate, lack of systematic
evaluation during the studies, and the short timing after start of mipomersen, but
uncertainties about the clinical relevance of these findings remain. Mipomersen is
also associated with a high incidence of flu-like symptoms, effect on inflammatory
markers and decrease on complement component C3. Mipomersen may be
immunogenic and antibodies were detected in 65% of subjects taking the product. In
addition, complement activation was more pronounced in patients with antibody
formation. However, the consequences of these findings are unclear.
Therefore, the CHMP concluded on 13 December 2012 that the benefit/risk ratio of
mipomersen is negative.
Following the CHMP scientific conclusions adopted on 13 December 2012 that
Kynamro was not approvable for the treatment of
Kynamro is an apolipoprotein B (apo B) synthesis inhibitor indicated as an adjunct
to maximally tolerated lipid-lowering medicines and diet to reduce low density
lipoprotein-cholesterol (LDL-C) in adult patients with homozygous familial
hypercholesterolaemia (HoFH).
On the basis of the following grounds for the refusal of the Marketing Authorisation:
The long-term benefit/risk of mipomersen remains undetermined, even if the
indication is restricted to patients with HoFH.
• CHMP ground 1: The long-term consequences of mipomersen-induced liver
steatosis are of major concern and difficult to monitor in clinical practice through
non-invasive tests;
• CHMP ground 2: Uncertainties remain regarding effects of mipomersen on long-
term cardiovascular outcome. In particular, the numerical imbalance in overall CV
events, MACE and CV hospitalisations is of concern. Potential negative effects, in
particular inflammatory effects, immunological reactivity, increase in blood
pressure and renal toxicity (as shown by proteinuria) on other cardiovascular risk
factors may counteract the potential beneficial effect on CV outcome due to
reduction in LDL-C;
• CHMP ground 3: The high overall withdrawal rate with mipomersen after 2-3
years, even in the restricted HoFH population, remains a major concern, thus
severely limiting the number of patients that may obtain a potential benefit from
its lipid-lowering effect. Given that withdrawals are mainly due to intolerance, it is
unlikely that retention rates may be improved in a less selected population in
standard practice;
on 31 January 2013, the applicant submitted its detailed grounds for the request for
re-examination of the CHMP opinion recommending the refusal of the granting of the
marketing authorisation.
4. Summary of the applicant’s grounds for re-examination:
The applicant requested a re-examination of the CHMP’s opinion for mipomersen, to
re-assess the benefit/risk in the very rare Homozygous Familial
Hypercholesterolaemia (HoFH) population (estimated size in the European Union,
500 patients) with a high unmet medical need. The applicant addressed the CHMP’s
concerns of liver and cardiovascular safety, tolerability and patient retention, as well
as post-approval management plans, in light of the benefit/risk in the HoFH
population, which the applicant believes is positive.
The indication originally proposed in the mipomersen MAA included both HoFH and
severe HeFH. Following discussions at the Scientific Advisory Group (SAG) meeting
in September 2012, the applicant restricted the indication to HoFH patients only, in
which the lifetime exposure to extremely high low density lipoprotein cholesterol
(LDL-C) levels is responsible for CVS morbidity and early age mortality. The benefits
of mipomersen-induced reductions in LDL-C in this population, which is at great risk
of premature death, are anticipated to be large (potentially greater than 50% risk
reduction of CHD, based on meta-analysis of multiple clinical trials), in contrast to
the known and hypothetical risks of treatment with mipomersen.
The following issues were addressed by the applicant;
• A statistically significant mean reduction in LDL-C of approximately 25%
(absolute change -2.92mmol/L) in patients with HoFH already receiving maximally
tolerated lipid-lowering therapy is highly relevant for this small group of patients
with a high unmet medical need;
• Effects of mipomersen on the liver (including increases in hepatic
transaminases and hepatic fat) decrease or stabilize with continued treatment in
most patients and return towards baseline when patients discontinue mipomersen
treatment. The applicant presents a comprehensive approach to risk management
for liver effects, including hepatic transaminase monitoring, liver imaging to assess
hepatic fat, and observations of clinical signs/symptoms of possible liver damage.
• Within the context of the small number of patients tested, the 6-month
treatment time of placebo-controlled studies, and the 6-month follow-up time, final
conclusions regarding CVS adverse effects as demonstrated in the clinical studies
cannot be reached at this time; however, the results of analyses performed to date
do not provide support for a difference in the rate of MACE between treatment
groups. Additional data will be collected in on-going and proposed studies.
• The rates of discontinuation from mipomersen treatment (taking into account
the patient's consented length of treatment) are similar to those observed with
statins and other lipid-lowering therapies and with other approved SC injectable
therapies studied in similar long-term studies, although, due to a lack of placebo
control in the long-term extension study, the true adherence rate in this study is not
possible to assess. The applicant has proposed a Patient Support Programme (a
broad adherence support programme) to help address this concern. While some
patients might discontinue, patients remaining long-term are anticipated to receive
benefit from substantial reductions in LDL-C.
The applicant presented an updated proposed SmPC and RMP, and the post-
authorisation safety study (PASS) and believes that mipomersen would serve as an
important therapeutic option to help address the significant unmet medical need of
5. patients with HoFH.
The CHMP considered the following:
The CHMP assessed all the detailed grounds for re-examination and argumentations
presented by the applicant and considered the views of the PRAC (PRAC meeting 4-7
February 2013) and the advisory expert group held on 12 March 2013.
CHMP position on ground 1
In the clinical development programme increases in hepatic transaminases (ALT, AST)
and liver fat were observed frequently in patients who received mipomersen therapy.
Liver enzyme increase
With regard to ALT and AST elevations, results from the pooled phase 3 studies
(mipomersen n=261, placebo n=129, including patients with HoFH and HeFH) are
summarized. In the pooled phase 3 studies, thirty six (13.8%) mipomersen-treated
patients experienced increases in ALT and AST that met protocol-defined
monitoring/safety rules for liver chemistry. For 14 (5.4%) of these patients, dosing
with mipomersen was stopped (stopping rules were ≥8 x ULN for AST/ALT on one
occasion, ≥5 x ULN for AST/ALT over 7 days, or ≥3 x ULN for AST/ALT and elevated
bilirubin). Of the 22 patients in the mipomersen-group with ALT levels ≥ 3 x ULN, 19
experienced decreases in ALT levels below 3 x ULN during continued treatment. In
the Open-Label Extention study, patients showed ALT increases (18%), AST
increases (16%), hepatic enzyme increases (3%), abnormal liver function tests
(2%), and transaminases increases (0.7%). Twenty two (15.6%) patients
experienced increases in ALT and AST that met protocol-defined monitoring/safety
rules for liver chemistry; for 8 (5.7%) of these patients, dosing with mipomersen was
stopped.
The applicant claims that in the majority of patients ALT and AST levels stabilize or
decrease even with continued treatment or they return to (near) baseline following
discontinuation of mipomersen treatment. This may not be the case for all patients
and for patients with sustained increase of ALT or AST level the risk in terms of
hepatic damage still remains unclear. From the available data, it is also not clear
whether patients´ ALT or AST levels reached a maximal effect (plateau). In all phase
3 studies, patients were excluded for “significant hepatic disease”. In case of the
pivotal study in HoFH patients (ISIS 301012-CS5) patients with a documented
history of hepatic disease, liver cirrhosis, or liver steatosis were also excluded.
Exclusion criteria were also in place to ensure adequate hepatic function based on
laboratory values (ALT, ALT > 1.5 x ULN).
Steatosis
The CHMP noted that in two phase 3 studies (ISIS 301012-CS7 and ISIS 301012-
CS12) hepatic fat fraction was assessed with magnetic resonance imaging (MRI) at
baseline and Week 28 (or early termination):
- a median increase in hepatic fat fraction of 9.6% in mipomersen treated
patients versus 0.02% in placebo-treated patients was observed,
- 61.8% (63/102) of mipomersen treated patients with paired MRI studies
experienced a ≥5% increase from baseline in hepatic fat.
In the OLE study, the number of patients with available data at baseline and week
6. 26, week 52 and week 72 is too small to draw firm conclusions regarding long-term
effects on liver fat accumulation with mipomersen treatment. In the pivotal study in
HoFH patients (ISIS 301012-CS5), hepatic fat was not routinely measured post –
baseline, however, according to the applicant, there were 11 patients from CS5 with
liver fat content assessment at baseline and at 12 months or longer on mipomersen
treatment.
There was an association between the higher increases in hepatic fat content and
greater percent reductions in apo B consistent with the mipomersen mechanism of
action, suggesting a direct relationship between the degree of mipomersen lipid-
lowering effect and the degree of steatosis, which the CHMP considers to be a
concern still not adequately addressed.
According to literature (e.g. as summarised in the AWMF guideline on the
histopathology of non-alcoholic and alcoholic fatty liver disease; German Society of
Pathology, 2009), the natural course of hepatic steatosis/non-alcoholic fatty liver
disease (NAFLD) in individual patients is not predictable; it is indicated that steatosis
may progress to steatohepatitis/NASH in about 10-20% of cases, and of these less
than 5% ultimately develop cirrhosis. As liver biopsy was not performed on a regular
basis in the mipomersen study programme, it is not clear whether a small or a
significant proportion of patients with mipomersen-induced steatosis also had
inflammatory changes and fibrosis, i.e. might develop steatohepatitis, which may not
be reversible after stopping the treatment.
Thus, the CHMP concluded that with respect to mipomersen´s hepatotoxicity, no
aspects other than the ones already assessed in the initial procedure, which could
lead to different conclusions, were presented by the applicant. Mipomersen
treatment can cause liver enzyme elevations and hepatic steatosis and this may
induce steatohepatitis. There is a concern that this could progress to hepatic fibrosis
and ultimately cirrhosis, over the course of several years still remained. Considering
that liver fat accumulation correlates with its effects on LDL, this hepatic effect is
likely to appear in virtually all patients in whom the drug is exerting a significant
effect.
The crucial question is how to identify patients at particular risk of long term liver
damage and whether persistent hepatotoxicity can evolve for some patients whose
transaminases and increased liver fat fraction do not return to baseline after
discontinuation of mipomersen treatment and who are thus at risk to develop
progressive liver disease. Though such liver disease could develop after long-term
treatment, and thus patients could have experienced CVS benefit, hepatotoxicity could
also develop as sequel to liver enzyme elevations following only short term treatment,
even if patients are discontinued early. These patients would not have experienced
any CVS benefit. Mipomersen is a drug that is intended for life-long administration;
therefore further long-term data on hepatic safety in HoFH patients are essential
before marketing authorisation could be granted. The CHMP concluded that such data
has not been presented by the applicant at this time point.
CHMP position on ground 2:
Retrospectively analysed CVS risk
The pivotal studies with mipomersen have neither been prospectively planned nor
adjudicated for CVS safety outcome and thus, only limited conclusions can be drawn
7. from the presented data. This is regarded by the CHMP as a major deficiency, and
was also criticized by the expert advisory group.
The adopted Guideline on Clinical Investigation of Medicinal Products in the
Treatment of Lipid Disorders (CPMP/EWP/3020/03/2004), states on the matter that
the safety database should be large enough to reasonably rule out any suspicion of a
detrimental effect of the new drug on mortality and that this requirement acquires
special relevance in case of drugs belonging to a new therapeutic class. Furthermore,
the guideline also states that “a new lipid-modifying agent is only acceptable for
authorisation if there is no suggestion of a detrimental effect on morbidity and
mortality. Otherwise, additional studies to clarify the drug effect on these parameters
are mandatory.” The issue of prospective planning for CVS safety outcome is even
more specifically addressed in the recent Draft Guideline on Clinical Investigation of
Medicinal Products in the Treatment of Lipid Disorders (EMA/CHMP/718840/2012).
The CHMP acknowledged that in a small population like that of HoFH patients, the
collection of a large database is not likely; nevertheless the importance of monitoring
the CVS safety data as stressed in this guidance still applies. Therefore, the lack of
predefined adjudication of CVS events is clearly a deficiency and, if a marked
difference in CVS events is observed, this may raise a concern despite a small
database.
Numerical imbalance in CVS events
Despite the fact that CVS events analyses were performed post hoc, the imbalance
observed in the pivotal trials is worrisome. On the other hand, given the absence of
events in the placebo arms of the combined pivotal phase 3 studies in patients at
very high cardiovascular risk, the relatively small sample size and short study
duration, this finding might also be attributed to a chance. This is based on the
consideration that in a high risk population a larger proportion of events could be
expected also in the placebo group. Indeed, an annual event rate of 6% has been
described for a composite endpoint of non-fatal MI and cardiac death in a comparable
population (Scandinavian-Simvastatin Survival Study Group, 1995, Lancet). A similar
or even higher event rate might be expected for MACE (including acute myocardial
infarction, stroke or CVA, unstable angina, PCI, and CABG) in a patient population
such as the one enrolled in the pivotal phase 3 studies (HoFH and severe HeFH
patients). Furthermore, in the placebo arm of the pooled phase 2 and 3 trial
population including patients at somewhat lower CVS risk (as compared with the very
high CV risk in HoFH patients), a higher number of MACE was noted, again potentially
indicating that the absence of MACE in the placebo arms of the pivotal studies of
overall small size might be a chance finding. Nevertheless, the relevance of the direct
comparison to mipomersen within the two trials must not be disregarded.
Potential effect of LDL reduction
The applicant argues that the degree of LDL reduction observed with mipomersen
treatment is expected to result in a potential reduction in coronary heart disease risk
greater than 50%, which is based on meta-analyses of data from multiple studies
(Baigent, 2010, the Lancet). The CHMP felt that this assumption would imply that the
benefits of mipomersen treatment in HoFH patients would outweigh an unknown
detrimental effect of this new substance. However, while it is agreed that the LDL
reduction is predictive of a long-term CVS risk reduction, the implied magnitude of
reduction of CHD risk of 50% is speculative. It cannot be taken for granted that the
8. proposed extrapolations apply, i.e. whether the observed LDL reduction in HoFH
patients, starting from LDL levels at the upper end of the scale, will translate into
equally large CVS risk reductions as claimed for statin treated broad hyperlipidaemic
populations of different states of health. This view was also supported by the experts
who considered the extrapolation as only hypothetical.
In addition, it must also be considered that the estimates result from a small HoFH
patient set, and though a treatment effect on LDL reduction is shown, the magnitude
of this estimate is still prone to some variability. Finally, LDL reduction is only one
mechanism affecting cardiovascular risk and as discussed above, no detrimental
effect should be present that might counteract such improvements.
To conclude on ground 2, the discussion provided by the applicant for the re-
examination of Kynamro does not provide a new insight to the former CHMP
assessment on mipomersen treatment and CVS risk. Clinical studies have not been
prospectively planned nor adjudicated for CVS safety outcomes so that only limited
conclusions can be drawn from the presented data. Though considerable uncertainty
remains, overall the analyses suggest an unfavourable effect of mipomersen
treatment on several CVS risk factors. The CHMP also noted that the experts were
not reassured that mipomersen is not conclusively linked to renal and CVS harm, and
concluded that a >50% reduction in 5-year CHD risk as envisaged by the applicant
for mipomersen treatment is purely hypothetical. Furthermore, although the relevant
risks (apart from the off label use) are identified within the RMP, the PRAC considers
the RMP insufficient to adequately identify CVS risk. A detrimental effect of
mipomersen on CVS risk has not been shown but cannot be excluded since data are
too limited.
CHMP position on ground 3
Focusing on the targeted HoFH population, the CHMP noted that the withdrawal rate
for HoFH patients who had been enrolled in the pivotal 6 months DB study CS5 and
consented to further participate in the OL extension study CS6 (for one or two years,
including the time in CS5), was approximately 60% (23/38) within the first two
years. Withdrawal rate was similar in HoFH patients and in the full population of OLE
CS6 (56%). Within (maximal) 2 years of treatment almost 50% (18/38) of these
HoFH patients withdrew from treatment due to AEs, mainly due to injection site
reactions (ISRs), flu-like symptoms (FLS) and liver enzyme elevations.
The withdrawal rate - even if “similar to that observed with statins and other lipid-
lowering therapies and with other approved SC injectable therapies studied in similar
long-term studies” as claimed by the applicant - must be seen in the context of the
identified safety concerns and the limited population studied.
With respect to the Kynamro Patient Support programme, the CHMP considered that
its usefulness, suitability and applicability in different EU countries are difficult to
foresee.
With regard to ground 3, the CHMP concluded that the high withdrawal rate is not per
se regarded as a sufficient reason to withhold approval of an effective treatment
option in a population of very high CVS risk, but, on a population level, the low
tolerability resulting in low treatment adherence will have a negative impact on the
utility of a treatment intended for long-term/life-long use. For the individual patient,
the worst case scenario could be that they might not obtain the potential benefit of
9. mipomersen in terms of reduced CVS morbidity/mortality because they cannot
tolerate long-term treatment, but might be harmed by progressive liver disease
resulting from mipomersen-induced steatohepatitis. Furthermore, the CHMP
considered the input from the expert group meeting and noted that there was an
agreement amongst the experts that the tolerability of mipomersen treatment was
poor. The experts felt, however, that potentially a restricted prescription programme
in dedicated centres capable of providing support on individual patient basis might be
helpful.
As part of their discussions, the CHMP discussed whether a Marketing Authorisation
under exceptional circumstances for Kynamro in the restricted claimed indication as
presented by the applicant during the oral explanation could be considered. The
CHMP concluded that such type of Marketing Authorisation could not be
recommended in the present case as it does not fulfil the requirements of Article
14(8) of Regulation (EC) No 726/2004, in particular, as the applicant would be able
to provide comprehensive data on the efficacy and safety under normal condition of
use of Kynamro.
The CHMP also discussed whether a conditional Marketing Authorisation for the
claimed restricted indication could be considered. This was not considered applicable
either, even if possible within the scope of Article 2 of Commission Regulation (EC)
No. 507/2006, as the requirements as defined in Article 4 of the said Regulation were
not met, in particular the demonstration by the applicant of a positive risk-benefit
balance of the medicinal product and the likelihood to provide comprehensive clinical
data by way of specific obligations. Such conditional Marketing Authorisation could
therefore not be recommended.
Overall, based on the assessment of the detailed grounds for re-examination
submitted by the applicant, including the revised risk management proposals for
monitoring of liver lipids and liver toxicity, and the revised restricted indication, as
applied for by the applicant, the CHMP concluded that the benefit/risk of Kynamro
remains unfavourable.
Grounds for refusal
Whereas
The long-term benefit/risk of mipomersen remains undetermined, even if the
indication is restricted to patients with HoFH. Although most of the relevant risks are
identified within the risk management plan, the risk management system is
considered inadequate and the proposed risk minimization measures are deficient in
a number of important areas. The studies proposed are poorly defined and it is
questioned that these can solve the concerns of particular interest like CVS
events/hepatic toxicity.
1. Uncertainties remain regarding effects of mipomersen on long-term
cardiovascular outcome. In particular, the numerical imbalance in overall CVS
events, MACE and CVS hospitalizations is of concern. Potential negative
effects, in particular inflammatory effects, immunological and renal toxicity (as
shown by proteinuria) on other cardiovascular risk factors may counteract the
potential beneficial effect on CVS outcome due to reduction in LDL-C.
2. No conclusive evidence was provided to support the assumption that
mipomersen-induced liver steatosis, which is associated with its mechanism of
10. action, has a benign course. Concern remains about the potential progression
of fatty liver disease to steatohepatitis and fibrosis, for which monitoring of
patients at risk of developing inflammatory and fibrotic changes includes
repeated liver biopsy. Furthermore, there is a potential risk of irreversibility of
liver disease even if mipomersen-treatment is stopped.
3. The high overall withdrawal rate with mipomersen after 2-3 years, even in the
restricted HoFH population, remains a concern, thus severely limiting the
number of patients that may obtain a potential benefit from its lipid-lowering
effect. Given that withdrawals are mainly due to intolerance, it is unlikely that
retention rates may be improved in clinical practice.
The CHMP is of the opinion that the safety and efficacy of the above mentioned
medicinal product is not properly or sufficiently demonstrated.
Therefore, pursuant to Article 12 of Regulation (EC) No 726/2004, the CHMP has
recommended the refusal of the granting of the marketing authorisation for
Kynamro.