Pharmacotherapy vs medical devices for cardiovascular disorders Flashcards
Medicines:
- Pharmacological interventions involve the use of drugs to treat or manage conditions.
- They work through biochemical reactions that alter physiological processes at the cellular or molecular level.
- Drugs require absorption into the bloodstream to exert their effects.
- Often have systemic effects that can lead to side effects affecting multiple organs or systems.
Device-Based Therapies:
- Involve physical devices that are either implanted in the body or used externally to treat or manage conditions.
- Their primary mode of action is mechanical or electrical rather than biochemical.
- Devices provide targeted therapy, often localized to specific organs or tissues, potentially reducing systemic side effects.
- Examples include stents, pacemakers, and blood pressure monitors.
State the differences between medicines and device-based therapies
- Potential for procedural harm
- Still has side effects (sometimes severe)
- Not easily reversible (?)
- Potentially costly
- Relatively limited trial evidence
- Uncertain long-term effects
- Typically reserved for severe disease
- Different regulation!
Define Ischaemic heart disease
progressive build-up of atherosclerotic plaques in the coronary arteries resulting in its narrowing and reduced blood flow to the heart muscle.
What is the current ‘device’ treatment for Ischaemic heart disease
Coronary artery stenting
What is Coronary artery stenting
involves the insertion of a balloon angioplasty. The balloon pushes the plaque and narrowing aside.
Briefly explain the evolution of Coronary artery stenting
Initially, involved the insertion of a balloon angioplasty. The balloon pushes the plaque and narrowing aside. However, there is still risk of recurrence of stenosis.
Bare-metal stents:
Then stents were developed to act as a ‘scaffold’ to keep the blood vessel/artery open after balloon angioplasty has cleared the blockage.
The stent prevents the artery from collapsing or closing again (re-stenosis) in the short-term. (reduced the risk of recurrence of stenosis)
However, there is still the risk of restenosis with inflammation cellular proliferation.
To counter-act this, drug-eluting stents were developed. These stents are coated with anti-proliferative drugs including paclitaxel, sirolimus, tacrolimus and dexamethasone.
Describe Drug-eluting stents (DES)
stents coated with anti-proliferative drugs including paclitaxel, sirolimus, tacrolimus and dexamethasone. The medication is slowly released to the surrounding arterial tissue with the aim of reducing inflammation and limiting the proliferation of smooth muscle cells that can lead to restenosis.
What are the limitations of drug-eluting stents?
Despite their effectiveness in reducing restenosis, drug-eluting stents have a downside. They can increase the risk of thrombosis. This can lead to acute coronary syndrome or myocardial infarction.
Furthermore, The combination of foreign body reaction and the anti-proliferative drugs can delay the healing and re-endothelialisation of the artery, leading to exposed stent struts that can trigger clot formation.
Due to the increased risk of thrombosis with drug-eluting stents, there is a need for prolonged use of antiplatelet medications. Drugs, such as aspirin and clopidogrel, help prevent platelet aggregation and thrombus formation in the stented artery.
Studies comparing stent-types and its findings
Studies comparing stent-types have demonstrated that drug-eluting stents compared to bare-metal stents result in a lower risk of cardiac death, myocardial infarction and all-cause mortality.
While DES offers improved clinical outcomes, there is a trade-off due to the necessity for prolonged use of antiplatelet medications, which carry associated side effects.
Who do DES stents benefit (patient population)
DES stenting may have greater benefits in patients with more ‘severe; conditions such as left anterior descending (LAD) artery and/or left main disease. This subgroup typically faces a higher risk of adverse outcomes, and the enhanced efficacy of DES in these patients underscores its importance in managing complex coronary artery disease.
The decision to use DES should consider patient-specific factors, including the risk of bleeding (which might complicate prolonged antiplatelet therapy) and the specific coronary anatomy involved.
State the Current standard therapies for heart failure
Implantable cardiac defibrillation, Cardiac resynchronisation therapy
What is Implantable cardiac defibrillation
Implantable cardiac defibrillation (ICDs): continuously monitor heart rhythms and deliver electrical shocks when detecting life-threatening arrythmias, to restore normal heart rhythm. (prevents the need for a defibrillator). This is a mini defibrillator that can deliver a shock to the heart when appropriate.
Rationale for implantable cardiac defibrillators in heart failure
Sudden Cardiac Death is a Major Concern due to potentially fatal arrhythmias
Persistence of arrhythmias despite β-blocker
Supporting evidence for ICD: Large-scale trials such as SCD-HeFT (Sudden Cardiac Death in Heart Failure Trial) have demonstrated that ICDs significantly reduce the risk of death from arrhythmias in patients with non-ischemic and ischemic heart failure.
Pharmacological options of reducing severe arrythmias such as amiodarone was found to have no effect on death rate. This evidence supports the use of ICDs in heart failure patients, particularly those with reduced ejection fraction who are at higher risk.
Adverse effects of implantable cardiac defibrillators
inappropriate shocks
device infection
potential lead failure.
Cardiac resynchronisation therapy (CRT)
CRT devices work by coordinating the timing of the left and right ventricles’ contractions, improving the efficiency of the heart’s pumping ability in patients with dysynchrony (delayed ventricular contraction/not at the same time).
By placing pacing wires in both right and left ventricles, pacing can cause synchronous contractions and can help improve overall left systolic function.
Describe the criteria for implantation for cardiac resynchronisation therapy
- Reduced LV ejection fraction (<35%, severe HF), and
- Dyssynchronous left and right ventricular contractions (or left bundle branch block with QRS >120ms), and
- Above despite taking maximally tolerated doses of medications known to have prognostic effects
(It is intended for patients with more ‘severe’ heart failure)
Describe how Cardiac resynchronisation therapy is proposed to improve outcomes for patients with severe heart failure
CRT has been shown to Improve symptoms, Reduce hospitalizations and decrease mortality in patients with heart failure (particularly those who exhibit specific patterns of electrical delay (QRS prolongation).
Adverse events of Cardiac resynchronisation therapy
lead dislodgement, infection, and, in some cases, lack of response to therapy (non-responders).
Describe LVAD
Left ventricular assist device
Describe significant risks and complications of LVAD
infection (on the device, this is difficult to treat)
Bleeding - due to the implantation of the device
Risk of devices: ICD and CRT
Risks include:
* Infections, Bleeding,
stroke, infection (on the device, this is difficult to treat), and device malfunction.
* Unintended therapy – sometimes the detection of arrythmias is not accurate and a defibrillating shock is delivered
procedures are typically undertaken with local anaesthesia. It requires the introduction of wires via veins into the heart.
Left ventricular assist device (LVAD)
LVADs are mechanical pumps implanted to help the left ventricle pump blood to the aorta and the rest of the body. Supports heart function and blood flow in patients with severe heart failure.
Evidence for LVAD
LVADs have been shown to improve survival and quality of life in end-stage heart failure patients, both as a bridge to transplantation and as destination therapy.
LVAD adverse events
bleeding, stroke, infection (on the device, this is difficult to treat), and device malfunction.
* Significant need for re-operation
* Requires anticoagulation = bleeding risk
In what situations would LVAD most likely be used
reserved for patients with severe heart failure as a bridge to heart transplantation and ‘destination therapy’
Patient with heart failure have autonomic dysfunction, characterized by:
- Decrease sympathetic outflow
- Increase parasympathetic activity
Baroreflex activation therapy (BAT) theory
The carotid sinus baroreflex have reduced sensitivity in patients with HF, leading to decreased inhibitory effect on sympathetic excitation and therefore sustained sympathetic outflow. Electrical stimulation of the Baroreflex is proposed to increase parasympathetic activity, counteracting the sympathetic activity.
Describe how baroreflex activation therapy (BAT)
BAT involves electrical stimulation of the baroreceptors in the carotid artery to induce reflex adjustments that improve cardiac function, reduce sympathetic overactivity, and enhance renal function (the stimulation enhances the body’s natural baroreflex, leading to reduced sympathetic nerve activity and increased parasympathetic activity, which can help manage hypertension and heart failure).
BAT First Generation Device Issues:
o Procedural adverse events occurred in 30-40% of patients.
o About 5% experienced nerve injury with residual deficits.
o The battery life was relatively short, averaging around 1.5 years.
BAT Improvements in Second Generation
o The introduction of a smaller electrode has led to a lower rate of adverse events and a longer battery life.
o a significant reduction in complications over time between first and second-generation devices.
Factors contributing to hypertension
Genetics
Lifestyle factors: diet, physical activity, obesity
Age
Stress
Medical conditions: diabetes, kidney disease, and sleep apnea can contribute to hypertension.
Roles of the Nephron, Baroreceptors, and ANS in Hypertension
Nephron
The nephron, the functional unit of the kidney, regulates blood pressure through:
1. Filtration: Filtering blood to form urine, removing excess sodium and water.
2. Reabsorption: Adjusting reabsorption of sodium and water, influencing blood volume and pressure.
3. Renin-Angiotensin-Aldosterone System (RAAS): Secreting renin, which activates RAAS, leading to vasoconstriction and sodium retention, raising blood pressure.
What are baroreceptors
Baroreceptors are pressure-sensitive receptors in the aortic arch and carotid sinuses
They: Detect Blood Pressure Changes by sensing stretch in arterial walls.
Send signals to the brain to adjust heart rate and vascular tone.
Regulate autonomic responses to maintain blood pressure homeostasis.
The ANS regulates involuntary physiological functions and plays a crucial role in hypertension through:
- Sympathetic Nervous System (SNS): Increases heart rate, cardiac output, and vasoconstriction, raising blood pressure.
- Parasympathetic Nervous System (PNS): Decreases heart rate and promotes vasodilation, lowering blood pressure.
- Stress Response: Chronic activation of SNS due to stress can lead to sustained high blood pressure.
Current treatment for hypertension
o For adults under 55, start with an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB).
o For adults 55 and over or of African or Caribbean family origin, start with a calcium channel blocker (CCB).
Is there an unmet need for hypertension treatment?
Resistant hypertension is estimated at around 30%
renal denervation
denervate renal nerves, aiming to disrupt the neural communication (from the kidneys to the brain) that exacerbates hypertension using:
Radiofrequency: Uses heat to ablate renal nerves.
Ethanol Injection: Involves direct injection to destroy nerve pathways.
Intravascular Ultrasound: Uses ultrasound energy within blood vessels.
External Ultrasound: Applies ultrasound energy from outside the body.
What are the goals of Renal Denervation
Reduction of Renal Signals: These techniques aim to reduce afferent renal sympathetic activity, thereby decreasing efferent sympathetic effects that contribute to:
Vasoconstriction
Increased cardiac output
Enhanced renin secretion
Elevated salt-and-water retention
Central arterio-venous anastomosis
device-based therapy designed to reduce blood pressure in patients with resistant hypertension. This procedure involves the creation of a central iliac arterio-venous anastomosis (controlled connection between an artery and a vein of large vessels), which can physiologically alter systemic vascular resistance and cardiac output.
Procedure Description of Central arterio-venous anastomosis
- Formation of Anastomosis: The procedure involves creating a connection between the central iliac artery and vein, typically using a device that connects these large vessels (coupler device). This anastomosis is designed to allow some arterial blood to flow directly into the venous system.
- Reduction in Afterload: By shunting some arterial blood to the venous system, the therapy effectively reduces the volume of blood the heart needs to pump against, thereby lowering arterial pressure. This reduction in afterload can help in easing the workload on the heart.
This reduces blood pressure
What is the Main proposed mechanism of Central arterio-venous anastomosis
Central arterio-venous anastomosis
reduce effective arterial volume, systemic vascular resistance (SVR) and cardiac afterload, thus lowering blood pressure
Evidence for Central arterio-venous anastomosis
- Initial Studies: Showed significant reductions in office blood pressure measurements over 12 months, without changes to medication regimens.
- Long-Term Effects: Further studies noted consistent large reductions in both systolic and diastolic blood pressure after 6 and 12 months compared to control groups receiving only medication.
Study Design and Bias of Central arterio-venous anastomosis
- Open-Label Studies: Early studies were open-label, raising concerns about biases that could influence outcomes, including placebo effects.
- Sham-Controlled Trials: Subsequent studies included sham procedures to provide more reliable data, confirming the procedure’s effect on reducing SVR and blood pressure.
Challenges and complications of Central arterio-venous anastomosis
- Procedural Complications: Some patients experienced venous stenosis, a narrowing of the veins, which could lead to painful swelling of the leg and was not always reversible.
- Placebo Effect Challenges: The palpable “buzz” felt by patients from the anastomosis made it difficult to conduct effective sham-controlled studies, as this sensation could bias the patients’ perception of treatment efficacy.
Due to adverse effects, the clinical trials have almost completely stopped
Baroreflex activation therapy (BAT) for Hypertension
Involves electrically stimulating the baroreceptors in the carotid sinus to enhance the body’s natural baroreflex mechanisms, which help regulate blood pressure.
Baroreceptors
Baroreceptors are sensors located in the carotid arteries that detect changes in blood pressure. By stimulating these receptors, BAT aims to activate the baroreflex, which sends signals to the central nervous system to reduce sympathetic nerve activity and enhance parasympathetic output.
Baroreflex activation therapy (BAT) for Hypertension Mechanism of Action
By stimulating these receptors, BAT aims to activate the baroreflex, which sends signals to the central nervous system to reduce sympathetic nerve activity and enhance parasympathetic output.
* Decrease in Sympathetic Tone: This decrease in sympathetic tone leads to vasodilation (widening of blood vessels), reduced heart rate, and decreased cardiac output, collectively contributing to a decrease in blood pressure.
* Enhancement of Parasympathetic Activity: Increased parasympathetic activity promotes relaxation of the blood vessels and slowing of the heart rate, further aiding in blood pressure control.
Current Evidence and Clinical Use of BAT
- Resistant Hypertension: BAT has been most extensively studied in the context of resistant hypertension, where patients do not achieve blood pressure control despite using multiple antihypertensive medications. BAT was initially studied in the use of hypertension before branching too heart failure.
- Heart Failure: Some studies suggest that BAT may also benefit heart failure patients by improving autonomic balance and reducing the excess sympathetic activation that is often seen in heart failure.
Bat first generation and second generation
o First-Generation Devices: The initial devices had a higher rate of procedural adverse events (30-40%), including nerve injuries (with residual deficit) and issues related to device integrity, such as short battery life (average 1.5 years).
o Second-Generation Improvements: Newer devices with smaller electrodes and longer battery life have reduced the rate of adverse events, but it is still significant.
Current State of BAT for hypertension
o Data Limitations: Especially for the actual only available second-generation device. The first-generation devices are not used due to adverse events.
Current research is insufficient to establish BAT as a standard care, primarily due to previous device-related complications and the need for more robust clinical evidence.
o Recruitment for these trials are difficult. With 12 drugs for blood-pressure most people prefer medication over devices.
Endovascular baroreflex amplification (EBA)
Mechanism of Action:
EBA involves the insertion of a stent-like device in the carotid sinus. The device mechanically alters the shape and tension of the artery wall where baroreceptors are located.
* Baroreceptor Activation: The physical change in the artery wall increases the strain, which is sensed by the baroreceptors as an increase in blood pressure. In response, the baroreceptors stimulate pathways that reduce sympathetic nervous system output, thereby decreasing blood pressure.
Proposed Benefits of Endovascular baroreflex amplification (EBA)
Mechanism of Action:
- Minimally Invasive: Compared to traditional surgical approaches for activating the baroreflex, the endovascular approach is less invasive, potentially offering a safer profile and quicker recovery.
- Sustained Effects: Initial studies suggest that the blood pressure-lowering effects of EBA are sustained over time, providing long-term benefits without altering medication regimens.
Study Outcomes for Endovascular baroreflex amplification (EBA)
Early trials report significant reductions in blood pressure measurements post-implantation.
A blood pressure reduction persisting for 1 year was achieved in patients with severe uncontrolled hypertension. However, this single-arm trial raises questions about placebo effects
Safety and Adverse Effects of Endovascular baroreflex amplification (EBA)
- Vascular Access Complications: The most common adverse events are related to vascular access complications, (can include bleeding, infection, and damage to the blood vessels.
increased rick of TIA = patients are required to take antiplatelet medications to prevent thrombosis.
The requirement of aspirin defeats the initial intent/purpose of the device (to replace medication)
Median nerve stimulation (MNS)
involves the electrical stimulation of the median nerve at the wrist.
hypothesized that MNS works by triggering the release of endogenous opioids, which can modulate the autonomic nervous system, thereby reducing blood pressure.
Deep brain stimulation for hypertension
hypotensive effects of DBS were first noted incidentally in patients who were undergoing this treatment for chronic pain.
Deep brain stimulation considerations
- Complexity of Treatment: DBS involves invasive neurosurgery, where electrodes are implanted in specific areas of the brain. The procedure carries significant risks and is complex to administer.
The application of DBS for hypertension requires more substantial evidence through well-designed clinical trials to ascertain safety, efficacy, and long-term outcomes.
Explain the UK regulatory processes for device-based therapies
A medical device must carry a CE mark to be marketed in Europe. This means the device meets the relevant regulatory requirements and, when used as intended, works properly and is acceptably safe (poses minimal risk to patients and users).
This must be verified by an independent certification body, called a Notified Body. The MHRA is responsible for appointing UK Notified Bodies and regularly audits them.
Manufacturers should be able to support their claims for the device. In many cases, this will come from a clinical trial. Where a manufacturer plans to carry out a clinical trial in the UK, agreement must be obtained from the MHRA.
