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Sophia is a 67 yo woman w/ aFib and diabetes who has also been treated for hypertension for 10 yrs. Three weeks ago, she experienced a TIA. What is her CHADS2 score and why?
What is the difference between a thrombotic stroke and an embolic stroke?
- Thrombotic: Occurs when an occlusion that blocks blood flow to the brain forms (due to atherosclerosis) in an artery supplying or within the brain.
- Embolic: Occurs when a thrombus fragmnet that has embolized from a site outside the brain lodges in an artery in the brain and blocks blood flow.
Describe the sequence of normal coagulation.
- Starts with Hemostasis: Vasular spasm (minutes to hours), Platelet plug formation, coagulation.
- Coagulation: Intrinsic or Extrinsic meets at Common Pathway.
- Instinsic: Slowly over several minutes, more steps than extrinsic, triggered by activators directly in blood.
- Extrinsic: rapid within seconds, fewer steps, triggered by outside tissue damage
Describe the differences between systemic circulation and pulmonary circulation.
- Systemic: structures on left side of heart send O2 blood to all other parts of the body (except the lungs) and bring deoygenated blood back to the right side of the heart.
- Pulmonary: structures on the right side of the heart pump deoxygenated blood to the lungs and oxygenated blood back to the left side of the heart.
Describe 3 of the 4 factors that are thought to be fueling the increasing prevalence of aFib.
increasing age, hypertension, heart failure, prior MI?
Define atrial fibrillation.
Abnormal and uncoordinated electical impulses cause disorganized, rapid, and irregular contractions in the atria that cause irregular contractions in the ventricles.
Decribe the reasons why a patient with aFib is at an increased risk for experiencing an ischemic stroke.
A thrombus may develop inappropriately due to the interaction of Virchow triad: Blood stasis, endothelial dysfunction, a hypercoagulable state. The most likely place for this to develop is the LAA resulting in a cardioembolic stroke.
Name the 4 agents that can be used for reducing the risk of stroke in patients with nonvalvular aFib.
Warfarin, Aspirin, Pradaxa, Xeralto
What is the difference between cardioablation and cardioversion?
- Cardioablation is performed with either radiofrequency engery or cryotherapy to ablate the source of extopic stimuli - usually the pulmonary veins.
- Cardioversion is an attempt to convert the AF to normal sinus rhythm by either direct electical current or pharmacologic therapy with AADs.
What is TEE? What is TTE? When would a physician choose to perform a TEE over a TTE in an aFib patient?
- TEE=Transesophageal echocardiogram is invasive and done on inpatient basis.
- TTE=Transthoracic echocardiogram is a noninvasive part of the standard workup of AF.
- The TTE has a low sensitivity to detect a left atrial thrombus so the TEE is used instead. The TEE is also used to guede cardioversion.
What do P waves and QRS waves on an ECG represent? What is different about the presentation of p waves and QRS waves in the aFib patient?
P waves represent the contraction of the atria in a normal heart and QRS complex represents contraction of the ventricle. In the aFib pt., the p-wave is usually absent and substituted with fibrillatory waves. The AF ECG shows irregulary timed QRS waves.
What characterizes Paroxysmal aFib, Persistent aFib and Permanent aFib?
- Paroxysmal: self-terminating
- Persistent: not self-terminating, lasts >7 days
- Permanent: long duration with no cardioversion or > 1 attempts have failed to restore NSR.
- All three are considered recurrent.
What are the 3 main goals of aFib treatment?
regaining NSR (normal sinus rhythm), controlling heart rate, preventing thromboembolism, thus reducing risk of stroke.
Explain what CHADS2 stands for, the values associated with int, and the implication of those scores on the assessment of patients with aFib.
Congestive heart failure, hypertension, age > 75, Diabetes, prior Stroke or TIA. All have a value of 1 except for prior Stroke or TIA. The higher the score = higher risk of stroke. The scores are used as the basis for therapy recommendations for specific antithrombotic agents.
What does INR stand for? What is the target INR range for nonvalvular aFib patient who is treated with a VKS/warfarin? What risks are associated with an INR score <2 or >4 in a VKS/warfarin patient?
International Normalized Ratio. Range of 2-3 with a target of 2.5. <2 risk of stroke, >4 risk of bleeding.
Explain the difference between a thrombus and an embolus.
A thrombus is a clot. An embolis is a clot that has traveled.
What is the indication for rivaroxaban (Xeralto) for patients with nonvalvular aFib?
To reduce the risk of stroke & systemic embolism in pts with nonvalvular AF.
What was the composite endpoint in Rocket AF and what efficacy results did Xarelto demonstrate?
Time to first occurrence of stroke or non-CNS systemic embolism. Rivaroxaban was demonstrated noninferior to warfarin.
What is the mechanism of action of Xarelto?
It is an oral factor Xa inhibitor that selectively blocks the active site of factor Xa and does not require a cofactor.
In ROCKET AF, how many patients were randomized, what was the mean CHADS2 score, and what was the comparator agent?
14,264, 3.5, warfarin
Name 3 issues that need to be considered in the clinical use of warfarin.
delayed peak effect, narrow therapeutic window, INR monitoring, genetic factors can affect its action, many drugs/foods/herbals can affect its action.
Describe the process of INR monitoring that is necessary during warfarin therapy, beginnning when a patient takes the initial dose of warfarin.
The INR should be determined daily after initial dose until it stabilizes in therapeutic range. Periodic INRs after that based on situation but usually at 1-4 week intervals. Additional tests should be performed when other warfarin products are interchanged and when other meds are changed.
Describe the overall results of the Coumadin clinical trials program in aFib (how many trials/study design/risk reduction and major bleeding range).
5 prospective, randomized, controlled trials with 3711 non-rheumatic AF. Risk reduction ranged 60-86% in all except CAFA(45%) which was stopped early due to published positive results on 2 other trials. Major bleeding range .6 - 2.7%.
Describe the mechanism of action of Pradaxa and how it affects the development of a thrombus.
Pradaxa is an oral pro-drug that is converted to dabigatran, a direct thrombin inhibitor. Thrombin plays a central role in the clotting process. Dabigatran binds to active site of thrombin - both free and clot-bound. This binding prevents: thrombin from converting fibrinogen to fibrin, activating factors V, VIII, and XI, and from stimulating platelets.
What is the recommended dose of Pradaxa for patients with CrCl>30 mL/min? What should a patient do if he/she misses a dose of Pradaxa?
150 mg bid. Missed dose should be taken as soon as possible on the same day. If it cannot be taken at least 6hrs before next dose, missed dose should be skipped. The dose should not be doubled to make up for missed dose.
In RE-LY, describe how the risk of major bleeding in the Pradaxa arm compared with the risk of major bleeding in the warfarin arm.
3.3% Pradaxa vs 3.6% Warfarin. No significant difference.
In RE-LY, how did the rate of major GI bleeds compare in the Pradaxa 150mg arm vs. the wafarin arm? How did the rate of GI adverse reactions compare with Pradaxa 150 mg. vs warfarin?
- Higher rate of GI bleeds in Pradaxa (150 mg) arm. 1.6% vs 1.1% Higher incidence of GI a/e 35% vs 24%.
- d/c due to GI symptons higher in Pradaxa arm: 2.1% vs .6%.
Describe the RE-LY study design including how many patients were enrolled, what doses were evaluated, and the mean CHADS2 score.
Multicenter, randomized parallel group trial comparing 2 blinded doses of Pradaxa (150 mg and 110 mg) with open-label warfarin in 18,113 pts with a mean CHADS2 of 2.1
Define the moa of aspirin.
ASA binds irreversibly to COX which stops the production of TXA2 in platelets and decreases platelet aggregation and thrombus formation.
What are the 2 key adverse events associated with aspirin?
major bleeding and dose-related GI toxicity.
True/False: Rivaroxaban is administered orally once daily with or without food.
False: Rivaroxaban is administered orally once daily with the evening meal.
How is Rivaroxaban metabolized?
Riveroxaban in a substrate of CYP3A4/5, CYP 2J2, and the P-gp and ATP-bindindg cassette G2 transporters.
How is Dabigatran metabolized?
It is not a substrate, inducer, or inhibitor of CYP450 enzymes. It is a substrate of P-gp.
What is the primary moa of warfarin?
Warfarin inhibits 2 of the enzymes in the vitamin K cycle: vitamin K epoxide reductase and vitamin K reductase.
AF is thought to increase the overall risk for stroke by how much?
4- to 5-fold
True/False: Cardioversion does not treat the underlying cause of AF, and thus, AF recurrence is expected in most patients.
What are calcium channel blockers used for in AF?
What happens to make AF "recurrent"?
After 2 or more episodes, the AF is termed recurrent.
In 2012, the prevalence of AF in the US is estimated to be what?
What are the most common symptoms of AF?
palpitations, dyspnea, dizziness.
Is fibrin soluble or insoluble?
What triggers the beginning of the intrinsic pathway?
Damage to endothelial cells cause the collagen fibers underneath the endothelium to become exposed.
Each step or conversion in the coagulation cascade requires what 3 things?
- an active coagulation factor (enzyme)
- an inactive coagulation factor (substrate)
- a cofactor (reaction accelerator)
What does the Virchow triad describe?
- The risk factors for forming a spontaneous thrombus.
- (damage, abnormal blood flow, hypercoagulability)
True/False: The coronary circulation is considered a subpathway of the pulmonary circulation.
False: The coronary circulation is considered a subpathway of the systemic circulation.