Case 1: CVD Risk (hypertension & dyslipidaemia)

Question 1

Pathophysiology of hypertension

Answer 1

Hypertension:

• too much sympathetic activity + angiotensin II
• blood vessel walls are stretched = increases wall tension
• causes remodeling of heart = thicker, stiffer wall, smaller lumen
• poor supply to end organs - heart needs to work harder
• increase in afterload, arterial damage

Question 2

• optimal BP
• normal BP
• High-normal BP
• Grade 1 hypertension
• Grade 2 hypertension
• Grade 3 hypertension

Answer 2

optimal: <120/<80 mmHg
normal: 120-129/80-84 mmHg
High-normal: 130-139/85-89 mmHg
Grade 1: 140-159/90-99 mmHg
Grade 2: 160-179/100-109 mmHg
Grade 3: >180/>110 mmHg

Question 3

Treatment goals based on 5 yr CV risk (age under 75 years)

Answer 3

<5% - lifestyle modifications w BP > 130/80 mmHg, BP lowering meds NOT recommended

5-15% - discuss benefits + harms of initiating BP lowering meds for patients with BP persistently >140/90 mm HG

> 15% - BP lowering meds strongly recommended for patients w BP persistently > 130/80mmHg

> 160/100 mmHg w any level of CV risk - BP lowering meds generally recommended

Question 4

If BP lowering meds are initiated - what target BP is recommended?

Answer 4

< 130/80 mmHg

- approach w caution in older frail patients

Question 5

What are the underlying causes + contributing factors in development of hypertension?

Answer 5

• Increased cardiac output
  hypervolemia (liquid portion of blood - plasma is too high), stress (sympathetic activation), pheochromocytoma

-Increased systemic vascular resistance 
stress (sympathetic activation) 
Atherosclerosis 
Renal artery disease (increased ang II) 
Pheochromocytoma (increased catecholamines) 
thyroid dysfunction 
diabetes 
cerebral ischemia

Question 6

Pathophysiology of dyslipidaemia

Answer 6

• Abnormally elevated cholesterol or fats (lipids) in the blood
• Increases chance of getting clogged arteries (atherosclerosis) and heart attacks, stroke or other circulatory concerns
• Especially in smokers

Question 7

Statins: MOA

Answer 7

a) Lipid mediated effects
○ Specific, reversible inhibitors of the hepatic enzyme HMG-CoA reductase
○ Cause upregulation of synthesis of LDL receptor
○ LDL proteins bind to receptor and get internalised within hepatocytes = reduced plasma LDL-cholesterol levels
- More LDL proteins removed from blood
○ Inhibit hepatic cholesterol synthesis
○ Leads to compensatory changes leading to decreased plasma cholesterol (inhibit synthesis), decrease triglycerides, can promote HDL-C, lower LDL-C

b) Non-lipid mediated effects
- Anti-inflammatory
- Increase plaque stability
- Improves endothelial cell function
- Reduces platelet aggregability (less likely to form thrombi that cause stroke)

Question 8

Statins: effects on lipids + lipoproteins

Answer 8

Statins = decrease LDL-C –> reduce ASCVD morbidity + mortality

• lower triglycerides, reduce pancreatitis risk

Question 9

Statins: first line choice + dose

Answer 9

Atorvastatin - if not tolerate: lower dose or change to other statin

Dose: 5 year CVD risk 5-15%: 10-20mg atorvastatin (max 80mg daily)

5 year CVD risk >15% : 10-40 mg atorvastatin (max 80mg daily)

Question 10

Statins: monitoring

Answer 10

○ Check creatine kinase (CK) levels only in those with symptomatic muscle pain, tenderness or weakness.

○ Request liver function tests only if hepatotoxicity is suspected.

○ Reduce dose or discontinue the statin for muscle pain without a rise in CK. Reconsider statin once symptoms have subsided.

○ Monitor symptoms and CK weekly along with dose reduction or discontinuation with a CK rise three to ten times above normal

• Discontinue statin immediately with a rise in CK of more than ten times above normal with symptoms

Question 11

Statins: adverse effects

Answer 11

○ Mild side effects include:

- Myopathy (muscle pain or weakness with rise in creatinine kinase) 
- GI disturbance
- Raised liver enzyme levels in plasma 

○ Serious adverse effects are rare but include:

• Myositis (rhabdomyolysis)
• skeletal muscle damage - start breaking down
• Hepatotoxicity
• Angioedema - swelling in skin such as lips
• Incidence increases with risk factors and statin dose

○ Increased risk of development of type 2 diabetes

• Pravastatin: lowest potency statin - lowest risk of developing new onset of diabetes mellitus
• Atorvastatin: moderate risk
• Rosuvastatin (highest potency) - highest risk
• Statin treatment should NOT be withheld in people at risk of diabetes or if diabetes develops –> expected decrease in major vascular events is greater than increased CVD risk

○ Increase in haemorrhagic stroke (outweighed by decreased risk of ischaemic stroke)

Depending on conc of statin (influenced by co-morbidities) - rhabdomyolysis can occur –> rare but can lead to sig. kidney problems

Question 12

Statins: interactions

Answer 12

○ Statin metabolism: by CYP3A4 and 2A9 enzymes

○ Interact with CYP inhibitors (e.g. cyclosporin, ketoconazole, erythromycin, verapamil, protease inhibitors)

• Can cause elevated statin levels and toxicity
• Inhibit breakdown of statin

○ Grapefruit juice: also CYP3A4 inhibitor

○ Interact w: co-administration w other lipid lowering drugs
- E.g. fibrates, nicotinic acid
- Can cause myopathy
Fibrates: inhibit statin-acid glucuronidation

Question 13

Statins: potency

Answer 13

Rosuvastatin is the most potent statin available in NZ, followed by atorvastatin, simvastatin then pravastatin

Question 14

If patient intolerant to statins or if lipid targets not achieved w statin monotherapy–> what alternative/additional meds can you recommend? effectiveness?

Answer 14

Ezetimibe
○ MOA: inhibits absorption of dietary cholesterol in small intestine –> reduced LDL-C

○ Evidence shows when added to simvastatin: reduces CV events in patients w previous ACS
○ Benefits of combo treatment enhanced in diabetics + those high risk patients without diabetes
○ Reduces risk of myocardial infarction and stroke by 13.5% and 16%
○ Use recommended in combo with PCSK9 inhibitor (if max tolerated dose of statin not achieve LDL-C goals)
○ Treatment w ezetimibe and statin produce modest LDL-C reduction compared to statin alone
○ Atorvastatin + ezetimibe = best therapeutic effect

Alirocumab

○ PCSK9 inhibitor - enhances LDL-C uptake by increasing number of LDL receptors
○ Monoclonal antibody based treatment
○ Taken every other week - significantly reduces ischemic events
○ However: minimal evidence on safety or use in place of statin –> first recommend try other lipid lowering treatments

Fibrates
○ MOA: lower triglycerides, increase HDL-C
○ No longer routinely recommended for reducing CVD risk for either primary or secondary prevention –> lack of strong evidence in reducing cv morbidity, mortality and LDL-C
○ Bezafibrate: only fully funded fibrate available in NZ
○ May be used in conjunction with statin treatment in patients with a high CVD risk where lifestyle changes and a maximally tolerated dose of statin have not produced reasonable reductions in lipid levels.
- This combination increases the risk of myopathy; to minimise this risk it is suggested that the fibrate is taken in the morning and the statin in the evening

Question 15

Lifestyle modifications for CVD risk

Answer 15

○ Reducing salt intake
○ Healthy diet
- Adopt Mediterranean diet
- Replace saturated with unsaturated fats
- Choose more plant-based food pattern, rich in fibre: include–> whole grains, fruits, vegetables, pulses, nuts
- Eat fish preferably fatty at least once a week
- Restrict (processed) meat
- Restrict free sugar consumption - esp. sugar sweetened beverages to max 10% energy intake (soft drinks, fruit juices)
- More fruit and vegetable per day (> 200g)

○ Regular exercise of moderate intensity : e.g. walking for 30 minutes a day

○ Limit alcohol to 3 standard drinks per day and no more than 15 standard drinks per week

• At least 2 alcohol free days per week
• Max 100g per week

○ Smoking Cessation

• Offer follow up support
• Nicotine replacement therapy
• Varenicline
• Bupropion