Module 3 Studies

Question 1

Anticoagulants: Warfarin (1)

Answer 1

Hylek & Singer in 1994: INR between 2-3 to prevent risk of haemorrhagic stroke

Question 2

Anticoagulants: Factor XI inhibition (1)

Answer 2

Buller et al, 2015: use of FXI-ASO prophylactically before surgery vs. LMWH – enoxaparin
300mg FXI-ASO significantly lower rates of VTE (30% LMWH, 4% FXI-ASO), without increasing the risk of bleeding

Question 3

Anticoagulants: DOACs (4)

Answer 3

• Dabigatran: RE-LY trial
• Rivaroxaban: ROCKET-AF
• Apixaban: ARISTOTLE
  The aforementioned trials demonstrated DOACs are better at reducing stroke rates in AF compared to warfarin, with lower bleeding risks
• Pollack et al, 2015: Monoclonal antibody against dabigatran is licensed – thrombin time decreased quickly

Question 4

VSMC (1)

Answer 4

• Hai & Murphy, 1998 – Kinetic model for latch phenomonen for VSMC. System is trapped in non-motile, tension generating state – maintains high amount of force with low energy expenditure

Question 5

Angiogenesis (2)

Answer 5

• Adams RH group, 2009: Proposes that fringe modification by glycosyltransferases reduces Notch signalling upon Jagged-1 binding – allowing Jagged-1 to act as antagonist. Also the idea that perhaps Jagged-1 stimulates non-canonical signalling – further work required
• Phng et al, 2009: Post natal mice treated with DAPT - more filopodia. Treated with Jagged-1 peptide - less filopodia

Question 6

Atherosclerosis (4)

Answer 6

• CANTOS trial: antibody against IL-1 in patients with previous MI reduced the rate of atherosclerotic cardiovascular events (independent of lipid lowering)
• Mason J group, 2018: Laminar shear stress found to increase amount of CD59 which is protective against complement
• Boyle JJ et al, 2011: M-hem macrophages. CD163 macrophages have high levels of haem and are protective from oxidative stress (paradox) – more IL-10 (anti-inflammatory). ATF-1 treatment reduces foam cell formation
• Wan et al, 2013: Metformin reduces AMPK dependent oxidative stress and foam cell formation – reduced lesion area

Question 7

Anti-platelets (3)

Answer 7

• CAPRIE trial – large RCT of clopidogrel vs aspirin in patients at risk of ischaemic events. Less GI side effects with equivocal efficacy
• PLATO trial – Ticagrelor vs clopidogrel in ACS patients. Fewer mortalities with ticagrelor
• TRITON-TIMI-38 trial – prasugrel vs clopidogrel in ACS patients. Reduced rates of ischaemic events, but with increased risk of major bleeding, but overall mortality rates did not differ

Question 8

RAAS Drugs: ACEi (1)

Answer 8

• CONSENSUS trial (1987) – use of enalapril vs placebo in CHF (NYHA class IV) – reduction in mortality and improvement in symptoms (regression of progressive HF – relegation of NYHA class)

Question 9

RAAS Drugs: ARBs (2) & ACEi + ARB (1)

Answer 9

• ELITE - losartan > captopril for HF
• LIFE - losartan > atenolol (improved mortality) in HT
• ON TARGET. No added event benefit of both ARB and ACEi together, but increased amounts of adverse events (hypotension, reduced renal function)

Question 10

RAAS Drugs: MRA (1)

Answer 10

• RALES trial – in severe HF, in addition to standard therapy, spironolactone reduced mortality

Question 11

RAAS Drugs: Future Drugs (1)

Answer 11

• Iwai et al, 2004: AT2 receptor stimulation attenuates effects of cerebral ischaemia in mice – potential for stroke therapy

Question 12

Lipid lowering: Statins (1)

Answer 12

• 4S – simvastatin in patients with existing CHD – more beneficial risk reduction in those high-risk vs low risk. Reduction in mortality, MI rates, compared to placebo

Question 13

Lipid lowering: Fibrates (1)

Answer 13

• HIT trial – reduces CV death, stroke, overall mortality. Good in patients with low HDL and normal LDL (doesn’t seem to reduce LDL levels)

Question 14

Lipid lowering: Ezetimibe (1)

Answer 14

• IMPROVE-IT - showed ezetimibe was beneficial as an add-on therapy to statins. Caused absolute risk reduction in primary endpoint (ACS) vs simvastatin alone

Question 15

Lipid lowering: PCSK9 inhibitors (1)

Answer 15

• Roth et al, 2012: When added to statins, there is greater reduction in LDL

Question 16

Leukocyte recruitment (2)

Answer 16

• Woollard et al 2010 – observed random movement of monocytes with unconventional migration
• Ginhoux et al, 2014 – patrolling monocytes, perhaps monitoring the integrity of the endothelium