John Dodson, MD Brigham and Women’s Hospital Harvard Medical School Does the Convenience of Newer Antithrombotic Agents Outweigh the Risks in Older NVAF Patients? John Dodson, MD Brigham and Women’s Hospital Harvard Medical School Good morning and thank you. My talk is entitled, does the convenience of newer antithrombotic agents outweigh the risks in older non-valvular a-fib patients? Disclosures: None

DISCLAIMER: I DON’T KNOW I just wanted to put in a disclaimer here before I begin…

Outline “Good old” (“bad old?”) warfarin Novel anticoagulants Dabigatran - direct thrombin inhibitor Rivaroxaban - factor Xa inhibitor Apixaban - factor Xa inhibitor Benefits/harms tradeoff How I practice Please don’t leave the room just yet. I’m going to try and do the best I can with the available evidence. This is a really tricky subject, which is what makes it interesting. We’ll start with a brief overview of warfarin, and then discuss the three novel anticoagulants currently on the U.S. market. I’ll talk about some of the benefits and harms of these new drugs, and then finally, how I practice as a cardiologist who sees a fair number of frail elderly patients.

Warfarin Rivaroxaban Apixaban Dabigatran [Slide 4] Here’s a brief overview of how these drugs work. Warfarin acts on the vitamin K dependent clotting factors – [arrow] 2, 7, 9, and 10. Rivaroxaban and Apixaban are factor 10a inhibitors [arrow] – so they act downstream of warfarin. And dabigatran acts even further downstream [arrow], by directly inhibiting thrombin. Dabigatran

Warfarin “Old faithful” Warfarin has been used for decades, and there’s good evidence behind its effectiveness in preventing stroke in atrial fibrillation.

RRR = 62% Hart RG et al. Ann Intern Med 1999;131:492-501. This was a meta-analysis of six randomized trials for stroke prevention in atrial fibrillation that was published nearly 15 years ago, and the results were convincing. Warfarin versus placebo had a relative risk reduction of 62% for stroke [arrow]. [The risk of intracranial hemorrhage was double with warfarin what it was with placebo, although the absolute number of events was small: 0.3% per year with warfarin and 0.1% per year with placebo]. [Of note, these were clinical trial patients, and only and only 20% were over 75.] [2900 patients with 186 strokes] RRR = 62% Hart RG et al. Ann Intern Med 1999;131:492-501.

Warfarin “Maybe not that faithful” This trial evidence is convincing – but as we know in practice, there are many issues with warfarin that limit its use.

Warfarin - Problems Monitoring Labile INR Dietary restrictions Medication interactions Bleeding risk 50% of patients ≥75 with AF are untreated* Problems include the need for frequent monitoring, and even with this patients can have labile INR’s. There are dietary restrictions and medication interactions. And, what we’re probably most concerned about, there is a significant risk of bleeding. Because of all of these issues, it is estimated that up to 50% of patients over the age of 75 with atrial fibrillation are not treated with oral anticoagulants. *Hohnloser SH, J Am Coll Cardiol 2011;57:181-183.

Novel Oral Anticoagulants Dabigatran Rivaroxaban Apixaban So in the setting of these limitations, there has been a tremendous amount of research into new agents. And in the past several years three novel oral anticoagulants have entered into the U.S. market. I’m going to go through the pivotal trials for each of these agents because I think it’s important to know their comparative effectiveness versus warfarin.

Dabigatran Direct thrombin inhibitor Excretion: renal (80%), hepatic (20%) Dosing: 150 BID* Randomized trial: RE-LY (NEJM 2009) The first agent to be approved was dabigatran, which is a direct thrombin inhibitor. It is mainly excreted renally, and the pivotal randomized trial was called RE-LY. *75 BID with CrCl 15-30

RE-LY (Dabigatran) 18,113 AF patients Three arms (1:1:1 randomization) Dabigatran 150 BID Dabigatran 110 BID Warfarin Re-Ly enrolled over 18,000 patients with nonvalvular atrial fibrillation in 44 countries who were randomized to three arms: dabigatran 150 twice a day, 110 twice a day, and warfarin. The primary efficacy endpoint was stroke or systemic embolism, and there was a safety endpoint of major bleeding. Connolly SJ et al. N Engl J Med 2009;361:1139-1151

RE-LY (Dabigatran) Exclusions: Renal impairment (CrCl <30) Prosthetic heart valve History of intracranial bleeding GI bleed within past year Liver disease Anemia (Hb <10) Expected survival <3 years These were the exclusion criteria listed in the methods paper. It’s not uncommon for a randomized trial to have extensive criteria like this, but many of these are issues in our elderly patients which is why I am highlighting them. Of note, because the drug is renally cleared, patients with a creatinine clearance less than 30 were excluded from enrollment. Ezekowitz MD et al. Am Heart J 2009;157:805-810

These are some of the population characteristics These are some of the population characteristics. [arrow] Mean age was 72 years of age, and the mean CHADS score for stroke risk was 2.

RE-LY (Dabigatran) Primary event rate (stroke/embolism) Dabigatran 150: 1.11%/year* Dabigatran 110: 1.53%/year† Warfarin: 1.69%/year Safety event rate (major bleeding) Dabigatran 150: 3.11%/year§ Dabigatran 110: 2.71%/year‡ Warfarin: 3.36%/year For the primary endpoint, which was a composite of stroke or embolism, dabigatran 150 was superior to warfarin in reducing this risk, and dabigatran 110 was noninferior to warfarin. *Superior to warfarin; †Noninferior to warfarin

Dabigatran 150 (vs. warfarin): RR = 0.66, 95% CI 0.53-0.82 (P<0.001) We can see these results visually in the survival curves for the three drugs, with the Y axis being the rate of stroke or embolism. Patients who received dabigatran 150 were about one third less likely to experience stroke compared with warfarin.

RE-LY (Dabigatran) Primary event rate (stroke/embolism) Dabigatran 150: 1.11%/year* Dabigatran 110: 1.53%/year† Warfarin: 1.69%/year Safety event rate (major bleeding) Dabigatran 150: 3.11%/year§ Dabigatran 110: 2.71%/year‡ Warfarin: 3.36%/year For the safety endpoint of major bleeding, dabigatran 150 was noninferior to warfarin, and dabigatran 110 was superior to warfarin in terms of having a lower bleeding risk. The 150 dose was ultimately the one that was approved by the FDA, based on its significant reduction in stroke risk compared with warfarin. §Noninferior to warfarin; ‡Superior to warfarin

Rivaroxaban Factor Xa inhibitor Excretion: renal (65%), hepatic (35%) Dosing: 20mg daily (15mg with CrCl 30-49) Randomized trial: ROCKET-AF (NEJM 2010) The next drug to be approved was rivaroxaban, which is a factor Xa inhibitor. Its excretion is manly renal, and dosage is once daily. The major randomized trial was ROCKET-AF.

ROCKET-AF (Rivaroxaban) 14,264 AF patients 1:1 randomization (rivaroxaban vs. warfarin) Inclusion required CHADS2 ≥2 Rivaroxaban dose depended on Cr 20mg daily (CrCl ≥50) 15mg daily (CrCl 30-49) Rocket-AF recruited over 14,000 patients with nonvalvular AF in 45 countries and randomized them to rivaroxaban vs. INR-adjusted warfarin. They explicitly enrolled patients at increased risk for stroke – CHADS2 score of 2 or greater was required for study inclusion. The dose of rivaroxaban depended on creatinine, and it was reduced to 15mg daily for a creatinine clearance of 30-49. Primary endpoint: composite of stroke and systemic embolism Safety endpoint: major and nonmajor clinically relevant bleeding It was designed as a noninferiority trial [note: hemorrhagic stroke was included in both primary and safety endpoints] Patel MR et al. N Engl J Med 2011;365:883-891

ROCKET-AF (Rivaroxaban) Exclusions Mitral stenosis Prosthetic heart valve Gastrointestinal bleeding within 6 months Prior intracranial bleeding Currently receiving ASA plus clopidogrel Hemoglobin <10 Creatinine clearance <30 These were the exclusions for the ROCKET-AF study. Similar to RE-LY, there were many exclusion criteria that are common in our elderly patients. ROCKET AF Investigators. Am Heart J 2010;159:340-347.

These are the characteristics of the study patients These are the characteristics of the study patients. [arrow] Mean age here was 73, and as we can see their risk of stroke based on CHADS score was higher than with RE-LY. Over half had congestive heart failure which I’ve highlighted here.

ROCKET-AF (Rivaroxaban) Primary event rate (stroke/embolism) Rivaroxaban: 1.7%/year Warfarin: 2.2%/year HR 0.79 (95% CI 0.66-0.96), P<0.001 Safety event rate (major bleeding) Rivaroxaban: 14.9%/year Warfarin: 14.5%/year HR 1.03 (95% CI 0.96-1.11), P=0.44 At study follow-up the rate of stroke or embolism was 1.7% per year with rivaroxaban, which was significantly less compared with 2.2%for warfarin.

Patel MR et al. N Engl J Med 2011;365:883-891 Here are the survival curves for the primary endpoint, and we can see that they diverge fairly early. Patel MR et al. N Engl J Med 2011;365:883-891

ROCKET-AF (Rivaroxaban) Primary event rate (stroke/embolism) Rivaroxaban: 1.7%/year Warfarin: 2.2%/year HR 0.79 (95% CI 0.66-0.96), P<0.001 Safety event rate (major bleeding) Rivaroxaban: 14.9%/year Warfarin: 14.5%/year HR 1.03 (95% CI 0.96-1.11), P=0.44 For major bleeding, there was no significant difference between rivaroxaban and warfarin.

Apixaban Factor Xa inhibitor Excretion: renal (25%), hepatic (75%) Dosing: 5mg BID Randomized trial: ARISTOTLE (NEJM 2011) The third and newest novel anticoagulant to be approved is apixaban. Like rivaroxaban, it is a factor Xa inhibitor, however unlike rivaroxaban and dabigatran its main mechanism of excretion is hepatic rather than renal. The pivotal trial for apixaban was called Aristotle.

ARISTOTLE (Apixaban) 18,201 AF patients 1:1 randomization (apixaban vs. warfarin) Apixaban dose adjusted 5mg BID (standard) 2.5mg BID (age ≥80, wt <60kg, Cr 1.5-2.5) This trial enrolled over 18,000 patients with nonvalvular a-fib and randomized them to apixaban versus warfarin. Apixaban was dose-adjusted; most patients received a 5mg twice daily dose, but in those who were very elderly, low weight, or had significant renal impairment were given half that dose. Granger CB et al. N Engl J Med 2011;365:981-992

ARISTOTLE (Apixaban) Exclusions Mitral stenosis Previous intracranial hemorrhage Mechanical heart valve Currently receiving ASA plus clopidogrel CrCl <25 or Cr >2.5 Life expectancy < 1 year Hemoglobin <9 or platelet count <100,000 Here are the exclusion criteria, similar to the other trials. Although the drug is mainly cleared by the hepatic route, they still excluded patients with a creatinine clearance of less than 25 or a creatinine of greater than 2.5. Lopes RD et al. Am Heart J 2010;159:331-339.

These are the characteristics of the study patients These are the characteristics of the study patients. [arrow] The mean age was 70 years, approximately one-third had heart failure, and mean CHADS score was 2. So they were much more like RE-LY with dabigatran than like ROCKET-AF with rivaroxaban.

ARISTOTLE (Apixaban) Primary event rate (stroke/embolism) Apixaban: 1.3%/year Warfarin: 1.6%/year HR 0.79 (95% CI 0.66-0.95), P<0.001 Safety event rate (major bleeding) Apixaban: 2.1%/year Warfarin: 3.1%/year HR 0.69 (95% CI 0.60-0.80), P<0.001 Apixaban was found to significantly lower the risk of stroke or embolism; rates were 1.3% per year with apixaban and 1.6% per year with warfarin.

ARISTOTLE (Apixaban) Primary event rate (stroke/embolism) Apixaban: 1.3%/year Warfarin: 1.6%/year HR 0.79 (95% CI 0.66-0.95), P<0.001 Safety event rate (major bleeding) Apixaban: 2.1%/year Warfarin: 3.1%/year HR 0.69 (95% CI 0.60-0.80), P<0.001 In addition, patients receiving apixaban had a bleeding rate of 2.1% per year, compared with 3.1% per year with warfarin, which was a statistically significant difference.

Stroke or systemic embolism Major bleeding These are the survival curves just to show visually the lower rates of stroke or embolism, as well as the lower rates of major bleeding, with apixaban. One interesting thing worth noting is for all three trials the New England journal published the survival curves with a Y axis of 100 [arrow], as well as the much smaller Y axis in the inset figure. I’ve just highlighted that here – the absolute event rates are very low in these populations. Granger CB et al. N Engl J Med 2011;365:981-992

ARISTOTLE (Apixaban) All-cause mortality rate Apixaban: 3.52% Warfarin: 3.94% HR 0.89 (95% CI 0.88-0.99, P=0.047) Also worth mentioning, there was a significant reduction in all-cause mortality with apixaban which was a secondary endpoint. This was not seen in trials of the other two drugs.

Novel anticoagulants They work!* *In trials So, in a word, they work. According to the clinical trials we’ve seen they actually work quite well. *In trials

Benefits Convenience Rapid onset of action (3 hours) At least similar efficacy to warfarin There are several major benefits to these drugs. The first is convenience: patients don’t need to come to coumadin clinic, and they don’t need their INR checked. There are no dietary restrictions or dose adjustments necessary. In addition, they have a rapid onset of action – about three hours to peak drug levels with each medication. And as we’ve seen, there is at least similar efficacy to warfarin, and possibly even greater efficacy. Apixaban also showed a lower rate of bleeding; for dabigatran and rivaroxaban at standard dosing, bleeding was the same as with warfarin.

Harper P, Young L, Merriman E. N Engl J Med 2012;366:864-866. However our story’s not over yet: in 2012 this letter appeared in the New England Journal of Medicine in response to the use of dabigatran in clinical practice. The authors, who were from New Zealand, presented a case series of 44 patients who experienced major bleeding episodes over a two-month period after being prescribed dabigatran for atrial fibrillation. There were multiple types of bleeding including rectal, intracranial, genitourinary, and hemarthrosis. Of note, the majority of patients had some degree of renal impairment, even though this is a relative contraindication to dabigatran, and six patients actually had a creatinine clearance of less than 30. [7000 patients prescribed dabigatran] Harper P, Young L, Merriman E. N Engl J Med 2012;366:864-866.

“We are concerned that the potential risks of this medication [dabigatran] are not generally appreciated.” “The serious consequences of the lack of an effective reversal agent should not be underestimated. Prolonged bleeding increased morbidity and possibly contributed to the death of 1 patient.” [Arrow] In their commentary the authors stated the following: “we are concerned that the potential risks of this medication [dabigatran] are not generally appreciated”. [Arrow] In addition, “the serious consequences of the lack of an effective reversal agent should not be underestimated. Prolonged bleeding increased morbidity and possibly contributed to the death of 1 patient” who had experienced uncontrollable bleeding. Harper P, Young L, Merriman E. N Engl J Med 2012;366:864-866.

External Validity Typical clinical trial patient Typical patient we are treating And I think these authors are raising key point in discussing these trials, which is external validity [Arrow]. These drugs work well in clinical trial patients – here is a typical one – but then we are in our own clinic, and a typical patient we are treating looks more like this [Arrow]. I think there are still a lot of unanswered questions about use of these drugs in our elderly patients. Remember, the age in all three trials was less than 75 years – and we are routinely seeing patients in our practices who are in their 80’s and 90’s.

Issues Contraindications Less frequent monitoring Cost Not reversible Some of the specific issues we may run into in clinical practice include the following. The first is contraindications – for example renal impairment – that preclude the use of these drugs. The second issue is less frequent monitoring; while in one respect it is a benefit for the sake of convenience, lack of regular follow-up for anticoagulation may be a concern in elderly patients. There are then issues around cost, and then finally there are no standard agents available for reversal.

Issues: Contraindications Renal dysfunction Valvular AF (mitral stenosis) Mechanical valves Here are some of the contra-indications that we should be aware of. The big one is renal dysfunction, and none of these drugs have been studied in patients with a creatinine clearance of less than 25. They are not indicated for patients with valvular atrial fibrillation, and have not been studied in patients with mechanical valves. So any patient with these issues should receive warfarin, if indicated.

Issues: Contraindications Typical patient 90-year old female 5 feet tall, 50 kg Cr 1.1 Creatinine Clearance = 24 Rivaroxaban – generally contraindicated Dabigatran – half dose? (75 BID) Apixaban – generally contraindicated So we have a typical 90-year old patient that we are taking care of, who is 5 feet tall and weighs 50kg. Her creatinine is 1.1. If we calculate her creatinine clearance [arrow], it’s only 24. And many of us may not realize the degree of impairment on first-glance. In this setting [arrow], based on trial data, rivaroxaban is contraindicated. Dabigatran has an indication for 75 twice a day in patients with impaired renal function, but this was based on pharmacokinetic modeling and never studied in randomized trials. Patients with a creatinine clearance of less than 25 were excluded from the apixaban trial. So none of these agents would really be optimal.

Issues: Monitoring Coumadin clinic: is everything OK? Patients are monitored less frequently. While this is a potential benefit in terms of convenience, coumadin clinic also provides a framework for our patients to “check in” with someone more frequently than they would compared with regular physician visits, and thus any potential issues (such as bleeding) may be addressed before they lead to hospitalization. I routinely get messages from our coumadin nurses who are really on top of this. We also know whether they’re taking the medication since we have an objective measure in the INR.

Issues: Cost Variable insurance coverage There drugs can be more costly for patients than warfarin. I’ve found that the out-of-pocket costs are variable – I had a patient pay three hundred dollars for a prescription last month – he didn’t call our office before filling it; he just figured it was something he needed. So I now tell all my patients, if what I prescribe isn’t covered, to call the office – and I can possibly switch them to another novel anticoagulant, or else warfarin.

Issues: Not Reversible But I think the Achilles heel of these new agents right now is the fact that they’re not reversible [arrow]. Patients who come in on warfarin can be given fresh frozen plasma and vitamin K. The FDA also just approved a new prothrombin-complex concentrate that can be given without blood typing – so it can be administered as soon as a patient comes into the emergency department. With novel anticoagulants, there are no standard agents that are approved to reverse their effects.

Issues: Not Reversible 89 year-old female with atrial fibrillation On novel AC for anticoagulation Admitted after syncopal episode (LOC ~1 min) with head trauma I just wanted to give an example of one case, this is from Yale where I trained as a cardiology fellow. The patient was an 89 year-old female with a history of atrial fibrillation. She had recently been placed on a novel oral oral anticoagulant, and was admitted after a syncopal episode with head trauma.

Her head CT in the Emergency Department demonstrated a large scalp hematoma seen here on the right as well as small a right frontal subarrachnoid hemorrhage

Issues: Not Reversible Emergent hemodialysis is initiated for removal of drug from circulation Factor VII, prothrombin complex are given Three days later, patient is cleared by neurology for discharge home She required emergent hemodialysis for removal of the drug from her circulation, and at the recommendation of the hematologist she received factor VII and prothrombin complex. As we know, hemodialysis carries its own risks – not the least of which involves the placement of a large-bore dialysis catheter in the setting of anticoagulation. Nonetheless, she did reasonably well, and three days later was cleared by neurology for discharge home. Other patients may have much less benign outcomes, and I think that uncontrollable bleeding is an something we fear in all of our elderly patients.

How I practice Young, active patient (<75 years) Novel oral anticoagulant Older patient (≥75 years) Warfarin Older patient very high-risk for bleeding ASA alone, ?ASA/clopidogrel LAA closure device? I wanted to conclude with a general outline of how I practice. In a younger patient with an active lifestyle, who doesn’t want to be bothered with coumadin clinic visits and the inconvenience of medication adjustments, I’ll prescribe a novel anticoagulant. They all have proven benefit as we’ve seen. I’ll see the patient within a month after starting to make sure there are no issues with bleeding or other side effects such as gastrointestinal discomfort. And after that I’ll seem them once every six months or so. For an older patient who has a generally higher risk of bleeding, and is coming to a lot of doctor’s appointments anyway, I’ll prescribe warfarin. A couple reasons here: (1) we know they’re taking it, which is important given the number of medications they’re on; (2) it’s inexpensive; and (3) if they fall and have an intracranial bleed, it can be reversed. In an older patient that is at very high bleeding risk, or has had multiple falls, I’ll use aspirin alone, or possibly aspirin plus clopidogrel. There is a new left atrial appendage closure device that Tracy will discuss in her talk, and this may be a consideration down the road as well.

Support NIH/NIA T32 AG000158 (Training Program in Epidemiologic Research on Aging) NIH/NHLBI Clinical Research Loan Repayment Program Finally, I would like to thank the NIH which has supported me in my early career, and I’d like to answer any questions.

Questions

Extra slides

Chest 2012;141:e531s-e575s

American College of Chest Physicians “Where we recommend or suggest in favor of oral anticoagulation, we suggest dabigatran 150 mg bid rather than adjusted-dose vitamin K antagonist therapy” Chest 2012;141:e531s-e575s

American Geriatrics Society “Quote from guidelines”

RE-LY EXCLUSION CRITERIA

We knew from older studies that the benefit from warfarin was significantly greater than aspirin, and more recently this was replicated in elderly patients in the BAFTA trial. Mant J et al. Lancet 2006;370:493-503.

BAFTA (Warfarin) 973 patients age ≥75 (mean 81.5) with AF Warfarin vs. ASA Annual stroke: 1.8% (warfarin) vs. 3.8% (ASA)* Annual bleeding: 1.4% (warfarin) vs. 1.6% (ASA) BAFTA took 973 patients age ≥75 with AF and randomized them to oral anticoagulation with warfarin vs. aspirin 75mg daily. I won’t go into this study in detail but to summarize, the annual stroke rate was significantly lower with warfarin, and annual bleeding was similar between groups. There are several caveats to this study: patients were excluded if they had a major hemorrhage within the past 5 years, peptic ulcer disease, or judgment by their clinician that they either should or should not be on anticoagulation. Nonetheless, it extended findings of prior studies to older adults. *Statistically significant, RR 0.48, 95% CI 0.28 – 0.80, P=0.003

Other issues Dyspepsia – RE-LY 11% with dabigatran 6% with warfarin Dabigatran – dialyzable because of low plasma binding (35%) Rivaroxaban/apixaban: higher plasma binding (90%)