Pharmacotherapy vs medical devices for cardiovascular disorders

Question 1

Medicines:

Answer 1

• 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.

Question 2

Device-Based Therapies:

Answer 2

• 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.

Question 3

State the differences between medicines and device-based therapies

Answer 3

• 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!

Question 4

Define Ischaemic heart disease

Answer 4

progressive build-up of atherosclerotic plaques in the coronary arteries resulting in its narrowing and reduced blood flow to the heart muscle.

Question 5

What is the current ‘device’ treatment for Ischaemic heart disease

Answer 5

Coronary artery stenting

Question 6

What is Coronary artery stenting

Answer 6

involves the insertion of a balloon angioplasty. The balloon pushes the plaque and narrowing aside.

Question 7

Briefly explain the evolution of Coronary artery stenting

Answer 7

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.

Question 8

Describe Drug-eluting stents (DES)

Answer 8

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.

Question 9

What are the limitations of drug-eluting stents?

Answer 9

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.

Question 10

Studies comparing stent-types and its findings

Answer 10

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.

Question 11

Who do DES stents benefit (patient population)

Answer 11

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.

Question 12

State the Current standard therapies for heart failure

Answer 12

Implantable cardiac defibrillation, Cardiac resynchronisation therapy

Question 13

What is Implantable cardiac defibrillation

Answer 13

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.

Question 14

Rationale for implantable cardiac defibrillators in heart failure

Answer 14

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.

Question 15

Adverse effects of implantable cardiac defibrillators

Answer 15

inappropriate shocks
device infection
potential lead failure.

Question 16

Cardiac resynchronisation therapy (CRT)

Answer 16

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.

Question 17

Describe the criteria for implantation for cardiac resynchronisation therapy

Answer 17

• 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)

Question 18

Describe how Cardiac resynchronisation therapy is proposed to improve outcomes for patients with severe heart failure

Answer 18

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).

Question 19

Adverse events of Cardiac resynchronisation therapy

Answer 19

lead dislodgement, infection, and, in some cases, lack of response to therapy (non-responders).

Question 20

Describe LVAD

Answer 20

Left ventricular assist device

Question 21

Describe significant risks and complications of LVAD

Answer 21

infection (on the device, this is difficult to treat)

Bleeding - due to the implantation of the device

Question 22

Risk of devices: ICD and CRT

Answer 22

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.

Question 23

Left ventricular assist device (LVAD)

Answer 23

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.

Question 24

Evidence for LVAD

Answer 24

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.

Question 25

LVAD adverse events

Answer 25

bleeding, stroke, infection (on the device, this is difficult to treat), and device malfunction.
* Significant need for re-operation
* Requires anticoagulation = bleeding risk

Question 26

In what situations would LVAD most likely be used

Answer 26

reserved for patients with severe heart failure as a bridge to heart transplantation and ‘destination therapy’

Question 27

Patient with heart failure have autonomic dysfunction, characterized by:

Answer 27

• Decrease sympathetic outflow
• Increase parasympathetic activity

Question 28

Baroreflex activation therapy (BAT) theory

Answer 28

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.

Question 29

Describe how baroreflex activation therapy (BAT)

Answer 29

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).

Question 30

BAT First Generation Device Issues:

Answer 30

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.

Question 31

BAT Improvements in Second Generation

Answer 31

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.

Question 32

Factors contributing to hypertension

Answer 32

Genetics
Lifestyle factors: diet, physical activity, obesity
Age
Stress
Medical conditions: diabetes, kidney disease, and sleep apnea can contribute to hypertension.

Question 33

Roles of the Nephron, Baroreceptors, and ANS in Hypertension

Answer 33

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.

Question 34

What are baroreceptors

Answer 34

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.

Question 35

The ANS regulates involuntary physiological functions and plays a crucial role in hypertension through:

Answer 35

1. Sympathetic Nervous System (SNS): Increases heart rate, cardiac output, and vasoconstriction, raising blood pressure.
2. Parasympathetic Nervous System (PNS): Decreases heart rate and promotes vasodilation, lowering blood pressure.
3. Stress Response: Chronic activation of SNS due to stress can lead to sustained high blood pressure.

Question 36

Current treatment for hypertension

Answer 36

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).

Question 37

Is there an unmet need for hypertension treatment?

Answer 37

Resistant hypertension is estimated at around 30%

Question 38

renal denervation

Answer 38

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.

Question 39

What are the goals of Renal Denervation

Answer 39

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

Question 40

Central arterio-venous anastomosis

Answer 40

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.

Question 41

Procedure Description of Central arterio-venous anastomosis

Answer 41

• 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

Question 42

What is the Main proposed mechanism of Central arterio-venous anastomosis
Central arterio-venous anastomosis

Answer 42

reduce effective arterial volume, systemic vascular resistance (SVR) and cardiac afterload, thus lowering blood pressure

Question 43

Evidence for Central arterio-venous anastomosis

Answer 43

• 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.

Question 44

Study Design and Bias of Central arterio-venous anastomosis

Answer 44

• 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.

Question 45

Challenges and complications of Central arterio-venous anastomosis

Answer 45

• 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

Question 46

Baroreflex activation therapy (BAT) for Hypertension

Answer 46

Involves electrically stimulating the baroreceptors in the carotid sinus to enhance the body’s natural baroreflex mechanisms, which help regulate blood pressure.

Question 47

Baroreceptors

Answer 47

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.

Question 48

Baroreflex activation therapy (BAT) for Hypertension Mechanism of Action

Answer 48

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.

Question 49

Current Evidence and Clinical Use of BAT

Answer 49

• 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.

Question 50

Bat first generation and second generation

Answer 50

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.

Question 51

Current State of BAT for hypertension

Answer 51

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.

Question 52

Endovascular baroreflex amplification (EBA)
Mechanism of Action:

Answer 52

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.

Question 53

Proposed Benefits of Endovascular baroreflex amplification (EBA)
Mechanism of Action:

Answer 53

• 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.

Question 54

Study Outcomes for Endovascular baroreflex amplification (EBA)

Answer 54

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

Question 55

Safety and Adverse Effects of Endovascular baroreflex amplification (EBA)

Answer 55

• 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)

Question 56

Median nerve stimulation (MNS)

Answer 56

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.

Question 57

Deep brain stimulation for hypertension

Answer 57

hypotensive effects of DBS were first noted incidentally in patients who were undergoing this treatment for chronic pain.

Question 58

Deep brain stimulation considerations

Answer 58

• 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.

Question 59

Explain the UK regulatory processes for device-based therapies

Answer 59

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.