Anticoagulation: The Latest on Blood Thinners from Aspirin to Xarelto Gail Pokorney, MD Dine & Discuss Central Peninsula Hospital August 20, 2015

Objectives Understand why blood thinners are used Atrial fibrillation Venous thromboembolism Mechanical heart valve Understand the pros and cons of different blood thinners Warfarin New Oral Anticoagulants (NOACs) Objectives

Polling the audience How many of you know someone… Who is on a blood thinner? Who has atrial fibrillation? Who has had a blood clot in the leg or the lung? Who goes regularly to an INR clinic to get a blood test? How many of you have seen TV advertisements for the new blood thinners? How many of you have seen lawsuit announcements about the new blood thinners? Polling the audience

A prescription medication that makes your blood less likely to clot “Anticoagulant” Anticoagulants prevent clots from forming and treat clots that have already formed What is a blood thinner? Anticoagulants do not dissolve clots that exist but prevent clots from growing in size and traveling to a new part of the body.

Atrial fibrillation (“A-fib”) = irregular heart rhythm that increases the risk of stroke from a blood clot in the brain 3 million people in the U.S. are affected Atrial flutter (“A-flutter”) = regular or irregular heart rhythm that has the same risks as A-fib and is managed the same way Why use a blood thinner?

Atrial fibrillation Lead-in to next slide: So does everyone with this problem need a blood thinner?

Age and other medical problems determine the risk of stroke and therefore the need for a blood thinner Most cases merit anticoagulation Anticoagulation should continue so long as the A-fib persists Atrial fibrillation So does everyone with A-fib need to worry about a stroke and need to be on blood thinners?

Venous thromboembolism (VTE) = blood clots in the legs (“deep vein thrombosis” or “DVT”) and lungs (“pulmonary embolism” or “PE”) 1-2 people out of every 1000 are affected Can form from immobility after surgery Can form without a trigger Why use a blood thinner?

VTE

All people with DVT or PE need to be on a blood thinner for at least 3 months Sometimes the decision is made to continue anticoagulation indefinitely VTE

Mechanical heart valve = a device used to replace a damaged heart valve Why use a blood thinner?

Mechanical Heart Valve

Mechanical Heart Valve All people with a mechanical valve need to be on a blood thinner indefinitely to prevent a blood clot from forming on the artificial valve Mechanical Heart Valve Transition: so now that we’ve talked about the reasons for using a blood thinner, let’s turn our attention to the blood thinner themselves.

Blood Thinners: Pros and Cons All blood thinners prevent and treat clotting All blood thinners increase the risk of bleeding Our greatest fear is bleeding in the brain Bleeding in the stomach/intestines is a major concern as well Any decision about anticoagulation needs to weigh the benefits of clot prevention against the risk of bleeding Blood Thinners: Pros and Cons Refer back to NOAC lawsuit commercials

Blood Thinner Options Warfarin (Coumadin) New Oral Anticoagulants Dabigatran (Pradaxa) Rivaroxaban (Xarelto) Apixaban (Eliquis) Edoxaban (Savaysa) Enoxaparin (Lovenox) Aspirin Blood Thinner Options

Clotting Cascade Warfarin Warfarin NOACs clot + + + + + + X X 12 Clotting Cascade Warfarin X 12a + 11 11a + 9 K 7 K 9a + 10 8a K X NOACs 7a + 10 10a + 2 5a K Clotting cascade: The penultimate step in the formation of fibrin is the conversion of prothrombin (factor II) to thrombin (factor IIa) by the enzyme activated factor X and the cofactor activated factor V. The enzyme thrombin then converts fibrinogen to fibrin in the final step of clot formation. Warfarin is a vitamin K antagonist. It acts as an anticoagulant by reducing the function of the vitamin K–dependent clotting proteins—factors II, VII, IX, and X—thereby attenuating the extrinsic, intrinsic, and common pathways of blood coagulation. Because of its indirect mechanism of action, the onset and offset of action with warfarin take several days. In contrast, the NOACs inhibit only a single target—either factor Xa or thrombin – and so have a rapid onset of action. Peak plasma levels are achieved 1 to 4 hours after oral administration. With half-lives of about 12 hours, the NOACs also have a rapid offset of action. 2a + 1 clot

The goal of warfarin is to decrease the clotting tendency of the blood but not prevent clotting completely The most commonly used test to measure the effect of warfarin is the prothrombin time (PT) INR is the standardized way to express PT The longer it takes the blood to clot, the higher the PT and INR Normal INR is 1 Target INR on warfarin is 2-3 If the INR is below the target range (“under- anticoagulated”), there is a risk of clotting If the INR is above the target range (“over- anticoagulated”), there is an increased risk of bleeding Warfarin Monitoring The most commonly used test to measure the effect of warfarin is the prothrombin time (called pro time, or PT). The PT is a laboratory test that measures the time it takes for the clotting mechanism to progress. It is particularly sensitive to the clotting factors affected by warfarin. The PT is also used to compute a value known as the INR (or International Normalized Ratio). The INR is a way of expressing the PT in a standardized way; this ensures that results obtained by different laboratories can be reliably compared. The target INR range depends upon the clinical situation. In most cases the target INR range will be 2 to 3, although other ranges may be chosen if there are special circumstances.

Warfarin: What’s Good It works! Inexpensive Familiar Effective at preventing stroke from A-fib and mechanical valves Effective at preventing recurrent blood clots in the legs and lungs Inexpensive Familiar We know if you’re taking your medicine Anticoagulant effect can be reversed with vit K Warfarin: What’s Good

Warfarin: What’s Bad Slow onset of action Dietary restrictions Interference from other medications INR results are variable Requires regular blood tests (“INR checks”) Antidote does not always work Bleeding is a major problem Warfarin: What’s Bad Many clinical trials find that INRs are in range only 55-65% of the time – and this under the controlled circumstances of a clinical trial. Risk of major bleeding in patients anticoagulated with warfarin ranges from 0.4% – 7.2% per year 65,000 patients treated annually in US emergency departments for warfarin-related hemorrhage

NOACs: What’s Good As good as warfarin at preventing stroke in A-fib As good as warfarin at preventing recurrent blood clots in the legs and lungs Start working right away Wear off quickly Fixed dose given once or twice daily No monitoring Minimal food and drug interactions Less major bleeding relative to warfarin NOACs: What’s Good NOACs were developed to work as well as warfarin and to address the shortcomings of warfarin.

NOACs: What’s Bad We can’t tell if you’re taking your medicine Missing a dose is a big deal Expensive No antidote Still a bleeding risk NOACs: What’s Bad

Some of the differences between the NOACs and warfarin are a matter of convenience, and some can be more serious Warfarin vs NOACs

More about bleeding Not all bleeding is created equal Intracranial hemorrhage is catastrophic Nosebleeds, bloody urine, and even GI tract bleeding are all treatable More about bleeding 3% rate of death or disability for bleeding outside the brain on warfarin vs 76% for bleeding inside the brain

Warfarin has an antidote in theory, but in practice it is often too little, too late It is better to avoid major bleeding in the first place More about bleeding Current strategies for reversing the effects of warfarin do not improve outcomes in patients with severe bleeding. Case-fatality rate after warfarin-associated major bleeding: 13.4% This is with vitamin K and FFP readily available!

NOACs reduce the risk of major bleeding relative to warfarin when used to treat DVT and PE NOACs reduce the risk of death and intracranial bleeding relative to warfarin when used to treat A- fib Apixaban reduces the risk of GI bleeding as well Remember: risk of bleeding with warfarin is closely linked to the consistency of the INR More about bleeding Major bleeding = fatal bleeding, bleeding in a critical area or organ, or bleeding causing a fall in hemoglobin of 2 mg/dL.

To switch or not to switch? Consider a switch Variable INRs Burdensome monitoring (“warfarin hate factor”) High risk of bleeding Do not switch Consistent INRs Cost/coverage issues Difficulty remembering to take medications To switch or not to switch?

Who should not use a NOAC? Mechanical heart valve Abnormal kidney or liver function Blood clot in the setting of active cancer History of gastric bypass surgery Weight extremes Pregnancy Who should not use a NOAC?

Tips for blood thinner use Know your dose Know why your doctor is prescribing it for you Take it exactly as prescribed; never miss a dose Do not use NSAID pain relievers, like ibuprofen or naproxen Ask your doctor before taking any new medications, including OTCs and supplements Tips for blood thinner use

What about those injections? Enoxaparin (Lovenox) is a blood thinner used in the following circumstances: Bridge to warfarin Bridge to dabigatran and edoxaban in the treatment of DVT and PE Primary treatment of DVT and PE in the setting of active cancer What about those injections?

Aspirin works differently from all the other blood thinners discussed in this talk Aspirin interferes with the function of platelets, which are small blood cells involved in the clotting process Aspirin is used in a wide variety of medical conditions, not just the ones discussed in this talk Ex: coronary artery disease What about Aspirin?

Aspirin is no longer recommended for stroke prevention in A-fib In people taking both aspirin AND warfarin or a NOAC, aspirin may increase the risk of bleeding without providing additional protection against clots Bottom Line: if you are taking aspirin for stable heart disease, as well as warfarin or a NOAC for A- fib, ask your doctor if you need to stay on aspirin What about Aspirin?

Summary of key points All blood thinners prevent and treat clotting All blood thinners increase the risk of bleeding Any decision about anticoagulation needs to weigh the benefits of clot prevention against the risk of bleeding Individualized decision Some of the differences between warfarin and the NOACs are a matter of convenience, and some are more serious Refer to your hand-out for a summary Summary of key points

Case #1 50-year-old man with a new diagnosis of PE No other medical problems Travels frequently for business Case #1

Case #2 80-year-old woman presenting to the ER with a stroke Heart monitor in the hospital shows atrial fibrillation Also has severe chronic kidney disease Case #2

Questions?