Disease Modifying Medication for Chronic Ischaemic Heart Disease Notes

Disease Modifying Medication for Chronic Ischaemic Heart Disease

Aim of Disease Modifying Medication

The primary aim is to prevent the progression of atherosclerotic vascular disease, stabilise existing disease, and prevent future adverse events.

Cholesterol and Atherosclerosis

Cholesterol, particularly LDL cholesterol, plays a significant role in the pathogenesis of atherosclerosis.

  • LDL cholesterol becomes trapped within the extracellular matrix.
  • This triggers an inflammatory reaction.
  • Macrophages ingest cholesterol crystals, forming foam cells.
  • These processes contribute significantly to atherosclerosis.

Lipid-laden atherosclerotic plaques are particularly risky due to the increased risk of inflammation and plaque rupture. This can lead to adverse events like heart attacks. Conversely, plaques that are cholesterol-depleted and predominantly fibrous are more stable and less prone to rupture.

Therefore, a primary therapeutic goal is to remove cholesterol from atherosclerotic plaques. This can be achieved by lowering LDL cholesterol levels as much as possible for each patient.

  • Lowering LDL cholesterol can reduce disease progression.
  • It reduces the risk of adverse events.
  • It improves primary prevention.

While we cannot dissolve plaques, we can stabilize them, leading to major benefits for patients.

Diet

The initial strategy involves dietary modifications, including:

  • Avoiding saturated fats.
  • Limiting red meat consumption.
  • Increasing the intake of fruits and vegetables.

However, diet typically results in only a limited reduction in LDL cholesterol, around 10-15%. This is because LDL cholesterol levels are mainly determined by the recycling of LDLs through the circulation and the liver, as well as the synthesis of LDL cholesterol and the LDL receptor in the liver. These processes are largely genetically determined.

Statin Drugs

Mechanism and Benefits

Statins represent a major advance, inhibiting hepatic synthesis of cholesterol by inhibiting HMG CoA reductase. Statins are effective at lowering LDL cholesterol, limiting atheroma progression, and reducing the risk of future adverse events like myocardial infarction, death, stroke, and the need for revascularization.

Usage

Statins are used for:

  • Secondary prevention after an initial event.
  • Primary prevention in high-risk individuals.
Adverse Reactions

Myalgia (muscle pain) is a common initial symptom, which is rarely limiting and often responds to a reduction in statin dose or a change in the type of statin. A mild asymptomatic increase in serum creatine kinase is not a reason to stop statin use. Similarly, a mild increase in liver function tests (transaminases) does not necessitate stopping statin therapy, as there is no evidence of harm from these biochemical changes. However you may want to monitor this and see if it progresses.

Efficacy

The benefits of statins are well-documented in large-scale clinical trials. The reduction in risk is proportional to the patient's risk level. Patients who have already experienced a myocardial infarction benefit greatly from statin therapy due to their high short and long-term risk of future adverse events. High-risk patients who have not yet had an event, such as cigarette-smoking diabetic patients, also benefit significantly.

Potency and Tolerability

The benefit is present irrespective of the statin. Atorvastatin and rosuvastatin are more potent for LDL reduction compared to simvastatin and pravastatin. However, simvastatin and pravastatin are better tolerated in patients experiencing myalgia. The magnitude of benefit is directly related to the degree of LDL reduction achieved. Any degree of LDL lowering is worthwhile, and the more achieved, the greater the benefit.

Recommendations for high-risk patients or those who have had an event:

  • Use a statin, preferably a high-intensity statin like atorvastatin or rosuvastatin.
  • Administer the maximum tolerated dose, irrespective of their LDL cholesterol level.

Even patients with normal LDL cholesterol levels benefit from statin therapy due to the additional lowering of LDL.

Key points
  • High-intensity statins at maximum tolerated doses are crucial for protecting high-risk patients.
  • Statins are effective for secondary prevention in patients with known disease.
  • They prevent stroke and myocardial infarction.
  • They provide primary prevention of death and adverse events in high-risk patients.
  • Practitioners should choose the statin and titrate the dose accordingly.
Drug interactions
  • Fibrates (e.g., gemfibrozil) increase the risk of myalgia and CPK rises.
  • Amiodarone requires careful monitoring of the ECG for QTc prolongation.

Ezetimibe

For patients who cannot tolerate statins or for whom statins are insufficient to achieve satisfactory LDL cholesterol levels, ezetimibe can be added. Ezetimibe inhibits the circulation of LDL cholesterol between the gut and the circulation, providing additional benefit. Clinical trials support the use of a statin and ezetimibe combination in high-risk patients.

Titration of medication and selecting the best possible profile for each patient are important for lowering LDL cholesterol.

PCSK9 Inhibitors

Mechanism

PCSK9 inhibitors are a newer class of drugs. Familial hypercholesterolemia, often under-recognized, involves a defect in LDL receptor kinetics, impairing the uptake of LDL particles for recirculation. Increasing the number of LDL receptors is desirable.

PCSK9 is a zymogen enzyme that binds to the LDL receptor and triggers its degradation. PCSK9 inhibitors, such as evolocumab, are monoclonal humanized antibodies that prevent LDL receptor degradation, increasing the availability of LDL receptors and lowering serum LDL levels. These inhibitors can achieve up to a 60% reduction in mean LDL cholesterol, even in patients already taking a statin.

Use Cases

PCSK9 inhibitors are beneficial for:

  • High-risk patients.
  • Patients with familial hypercholesterolemia.
  • Patients unable to take statins.

They produce significant reductions in LDL cholesterol, with emerging clinical trial evidence of additional clinical benefits.

Safety

Lowering LDL cholesterol levels to very low levels is not detrimental to health. Studies on populations with genetic defects leading to very low LDL levels (e.g., Pima Indians with a hereditary defect in PCSK9) show no adverse effects. The benefits for cardiovascular disease are substantial.