combination therapy and cardiovascular events: a

This is a transcript of an online program, which may be found at:

http://www.theheart.org/article/976601.do

Combination Therapy and Cardiovascular Events: A Neurologist’s Perspective

Combination Therapy and Cardiovascular Events:

A Neurologist’s Perspective

J. Donald Easton, MDProfessor of NeurologyDepartment of Clinical NeurosciencesRhode Island HospitalBrown Medical SchoolProvidence, Rhode Island

Mark J. Alberts, MDProfessor of NeurologyDirector of the Stroke ProgramNorthwestern University Medical SchoolNorthwestern Memorial Hospital Chicago, Illinois

Peter Rothwell, MD, PhD, FRCP, FMedSciProfessor of MedicineUniversity Department of Clinical NeurologyJohn Radcliffe InfirmaryOxford, United Kingdom

Slide 1 Peter Rothwell, MD: Hello. I'm Peter Rothwell, Professor of Neurology, Department of Clinical Neurology at the John Radcliffe Hospital in Oxford, United Kingdom. It's my pleasure to welcome you to our program entitled, "Combination Therapy and Cardiovascular Events: A Neurologist's Perspective." Joining me for the discussion are Don Easton, Professor of Neurology, Department of Clinical Neurosciences at Rhode Island Hospital Brown Medical School in Providence, Rhode Island, and Mark Alberts, Professor of Neurology, Director of the Stroke Program at Northwestern University Medical School, Northwestern Memorial Hospital in Chicago, Illinois. In this program, we'll discuss the current data on cardiovascular events, and specifically prevention of stroke and other cardiovascular events from a neurologist's perspective, both primary prevention and secondary prevention. As you know, stroke is a major clinical burden and a major cost to the economy. There are about 10 million stroke deaths worldwide each year, and stroke now in most developed countries is as common as acute coronary syndromes [ACS]. About one quarter of strokes are caused by atrial fibrillation [AF] and the remainder are caused by large artery atherosclerosis, small vessel disease, and a host of rare causes. So it's a more heterogeneous syndrome than acute coronary events.




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Risk for any Stroke, Myocardial Infarction, or Vascular Death After TIA

No. of pt remaining

Stroke 290 264 230 196 164 136

MI or CHD 290 265 230 200 173 137

Stroke, MI, or Vascular death

290 260 225 189 157 130

Slide 2 From a neurologist's point of view, we often see patients with TIA [transient ischemic attack] or stroke initially and we're thinking then about how we can prevent a recurrent event. And the risks in this population are particularly high. You can see on these data from patients with TIA back in the 1990s that if you combine the risk for stroke over 10 years with the risk for coronary events, then the risk for all vascular events or vascular death is about 50% at 10 years. So even with optimal medical therapy at that time, the risks were high.




Study Demented/ Prev 95%CI Age DxTotal (%)

Klimkowicz, et al (72) 33 / 49 67.3 54.2-80.5 66 DSM IVZhou, et al (70) 45 / 113 39.8 30.8-48.8 68 DSM IVPohjasvaara, et al (3) 30 / 100 30.0 21.0-39.0 71 DSM IIIGorelick, et al (43) 61 / 147 41.5 33.5-49.5 72 DSM III

Total 169 / 409 41.3 29.6-53.1 p(het.) < 0.001

5 10 15 20 25 30 35 40 45 50 55

Klimkowicz, et al (72) 69 / 220 31.4 25.2-37.5 66 DSM IVZhou, et al (70) 118 / 434 27.2 23.0-31.4 68 DSM IVBarba, et al (54) 75 / 251 29.9 24.2-35.5 69 DSM IIIRde Koning, et al (78,79) 71 / 300 23.7 18.9-28.5 70 DSM IIIRde Koning, et al (80) 35 / 121 28.9 20.8-37.0 70 DSM IVDesmond, et al (7) 119 / 453 26.3 22.2-30.3 71 DSM IIIRPohjasvaara, et al (3) 115 / 451 25.5 21.5-29.5 71 DSM IIITang, et al (76) 56 / 280 20.0 15.3-24.7 70 DSM IVHenon, et al (2) 44 / 142 31.0 23.4-38.6 72 ICD10

Total 702 / 2652 26.5 24.3-28.7 p(het.) = 0.07

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Systematic Review of Predictors of Post-Stroke DementiaHospital-based studies including prestroke dementia

Unpublished data

Recurrent stroke

Any stroke

Prevalence Slide 3 And of course, it's not just stroke; there are other sequelae which are a great problem for clinicians and patients, one of which is post-stroke dementia. About 40% of patients with a recurrent stroke have post-stroke dementia, as you can see in this systematic review. Even looking at all strokes, combining first and recurrent stroke, it's about one quarter of patients. So if we can prevent stroke, then we can prevent post-stroke dementia, which is another potential benefit of antiplatelet therapy and active prevention. And there's a temptation, therefore, to treat patients as aggressively as possible.




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Stroke risk after 90 days

Unpublished data. Slide 4 We have made some progress in recent years. This slide shows the risk for recurrent stroke in the same population in Oxfordshire, United Kingdom in all patients presenting with TIA or stroke. The upper line shows the 1980s and the yellow line shows the current position. So we've improved somewhat. We're about 40% better than we were 20 years ago, which is probably down to blood pressure lowering, statins, antiplatelet therapy. But there's still some way to go. The temptation, of course, to reduce the risk further is to try ever more intensive and aggressive antiplatelet therapy, which will have some benefits, as we'll discuss shortly. But there's also a downside, as I know both of my colleagues will emphasize. The big worry we have, particularly as neurologists, in the sense that we see a lot of the intracerebral hemorrhages, is this risk for bleeding on antithrombotic therapy.




Annual Bleeding Risks in Trial vs NontrialPopulations

Unpublished data.

Intracerebral Fatal/LT/majorESPRIT•A+D vs A 0.18% vs 0.35% 0.5% vs 0.7%

MATCH•A+C vs C 1.3% vs < 1% 1.5% vs 0.6%

CHARISMA•A+C vs A 0.13% vs 0.13% 1.7% vs 1.2%

PRoFESS•A+D vs C 0.6% vs 0.4% 1.7% vs 1.5%

OXVASC 0.70% (0.44-1.06) 2.8% (2.2-3.4)

Slide 5 Particularly the worry we have is that the risk might be higher in the real world than it is in randomized controlled trials with a selected group of patients in a relatively controlled follow-up environment. We've looked at this recently again in Oxfordshire and you can see the annual risks for intracerebral hemorrhage and fatal life-threatening or major bleeding in 4 trials compared with the risk in our general population cohort. And the risks are somewhat higher, even though these patients were predominantly on monotherapy. So we do worry about bleeding and it's the downside of more aggressive preventive treatment. And so from the clinical point of view, we're moving more towards thinking about stratifying our treatment decisions by risk and looking for those patients who have got a sufficiently high risk for ischemic events for it to be worth taking the risk for the bleeds.




Risk Model Stratification in the European Stroke Prevention Study 2 (ESPS2) Trial

Sacco RL, et al. Arch Neurol. 2005;62:403-408.

Risk Model Risk Groups Variables

Framingham10-year stroke probability•≤ 0.15 = Low•> 0.15 = High

AgeSystolic blood pressureAntihypertensive therapyDiabetes mellitusCigarette smokerCardiovascular diseaseAtrial fibrillationLeft ventricular hypertrophy

Stroke Prognostic Instrument II (SPI-2)

SPI-2 Score•0-3 = Low•4-7 = Middle•8-15 = High

Congestive heart failureDiabetes mellitusPrior strokeAge > 70 yearsStroke for entry eventSevere hypertensionCoronary artery disease

Slide 6 We're fortunate in stroke in many ways in that it's a relatively predictable condition. There are various risk scores and risk factors we can use to identify patients at particularly high risk for ischemic events. There are 2 well-known models here, the Framingham score and the stroke prognostic index. And these were used in a trial some years ago to stratify patients by their predicted risk for ischemic events and to look at the balance of risk and harm for a more intensive antiplatelet therapy.




Overall Stroke Efficacy ESPS2: 23% RHR for ASA/ER-DP vs ASA

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Slide 7 And you can see on this slide that dual antiplatelet therapy, aspirin plus dipyridamole, which are the white bars, was rather more effective in high-risk patients than low-risk patients, whichever prognostic score was used. So there are ways in which we can begin to target treatment and find the patients who are most likely to benefit and perhaps less likely to be harmed by aggressive antiplatelet treatment. And that brings us nicely to perhaps the group that's at highest risk for recurrent stroke or instant stroke in primary prevention, and that's the patients with AF, nonvalvular AF. And Don is going to update us on the current data on how we should best manage that particularly high-risk group. Don. J. Donald Easton, MD: Well, we've known for, of course, a number of years that patients with AF are at higher risk than the regular population. And I think Mark in a little bit is going to detail some of the ways that we can stratify those at the highest risk and the lowest risk. And then we've learned from a whole series of trials in primary prevention and a couple in secondary prevention that antithrombotic therapy is very effective. It turns out that warfarin anticoagulation or any of the anticoagulants are the most effective, but you pay a price in bleeding. We also know that aspirin is effective too, but substantially less so than is warfarin. Yet, there are patients who are unsuitable for oral anticoagulation because of bleeding risk. And so they're often treated with aspirin.




ACTIVE ProgramDocumented AF + ≥ 1 risk factor:

Age ≥ 75 yrs, hypertension, prior stroke/TIA, LVEF < 45, PAD, age 55-74 yrs + CAD or diabetes

ACTIVE W

Clopidogrel + ASA vs OAC

Contraindications to OAC or unwilling

ACTIVE A

Clopidogrel + ASA vs ASA

No exclusion criteria for ACTIVE I

ACTIVE I

Irbesartan vs placebo

Partial factorial design

Mean follow-up 3 yrs

Clopidogrel 75 mg QD

Aspirin 75 - 100 mg QD recommended

6706 patients 7563 patients

9024 patients

Adapted from: The ACTIVE Steering Committee. Am Heart J 2006;151:1187-93 Slide 8 And then now comes on the scene the ACTIVE A [Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events] trial looking at dual antiplatelet therapy to see if it would find its place between oral anticoagulation's effectiveness and aspirin alone's effectiveness. And it turns out that's what was seen in the ACTIVE A trial. I sort of begin with the background view that risk for major bleeding is somewhere in the neighborhood of 2.5% per year on oral anticoagulation and in the neighborhood of 1% per year on aspirin.




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HR=0.89 (0.81-0.98) p=0.014

3772 3456 3180 2522 11793782 3426 3103 2460 1156

No. at Risk

ASAC+A

Years

Primary Outcomes ACTIVE A

Reprinted with permission: Active A Investigators. N Engl J Med. 2009;360:2066-2078. Slide 9 So now the question, is what happens when you go on dual antiplatelet therapy with clopidogrel plus aspirin? It turns out that the bleed rate falls in between: 1.7% per year. But it also got a 28% relative risk reduction in ischemic events, most of which were strokes.




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3772 3491 3229 2570 12033782 3458 3155 2517 1186

No. at Risk

ASAC+A

Years

Stroke - ACTIVE A

Reprinted with permission: Active A Investigators. N Engl J Med. 2009;360:2066-2078. Slide 10 So clearly the benefit is there. There's a slightly higher price to pay. But we have to always remind people that, even though the bleed rate is 2.5% per year roughly on oral anticoagulation, we use it. And we use it because risks for ischemia are so high and the treatment is so effective. What we learned from ACTIVE A is that it's true that dual antiplatelet therapy is also more effective than aspirin alone, but not effective as warfarin as we learned in ACTIVE W [Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events]. So I think, as has already been alluded to by you, Peter, can we then identify the patients that are at particularly high risk and those that are most likely to get a benefit without the bleeding risk associated with it? And as I say, Mark will get into that in a moment.




Outcome

Clopidogrel + Aspirin Aspirin

Clopidogrel + Aspirin vsAspirin

# Rate/Year # Rate/Year RR 95% CI P value

Ischemic/Uncertain 268 2.1 388 3.2 0.68 0.59-0.80 < .001

Hemorrhagic 30 0.2 22 0.2 1.37 0.79-2.37 .27

Nondisabling(mod. rankin 0-2) 107 0.9 153 1.2 0.70 0.54-0.89 .004

Disabling or fatal (mod. rankin 3-6) 198 1.6 267 2.1 0.74 0.62-0.89 .001

Stroke Types and Severity

Slide 11 So I think now with that sort of background, the question would be, we have patients with AF most of whom should be treated with oral anticoagulation because it's the most effective therapy. But we know that half of the patients out there with AF are not treated with oral anticoagulation because they're deemed unsuitable in one way or another. Sometimes that's a doctor's choice. Sometimes it's a patient's choice. Sometimes it's a fear of falling and other issues associated with it. And so there's this large group of patients that are at risk for ischemic events who are not going to be treated with anticoagulation, but in whom we'd like to do more than treat them with just aspirin. And there's where the role is for the dual antiplatelet therapy. And so I think with that, we might move on then to the discussion of issues of who are these patients with AF at highest risk, and more about the bleeding side here. Dr. Rothwell: Mark, can you tell us about that? Mark J. Alberts, MD: Yes. Thanks, Peter.




CHADS2 Stroke Risk Stratification Scheme for Patients With Nonvalvular AF

Adapted from Hersi A, et al. Curr Probl Cardiol. 2005;30:175–234.

CHADS2 Score

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Relationship Between CHADS2Score and Annual Risk for

StrokeRisk factors Score

CRecent congestive heart failure

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H Hypertension 1A Age ≥ 75 yrs 1D Diabetes mellitus 1S2 History of stroke/TIA 2

CHADS2 Score

Slide 12 When we talk about risk factors for having ischemic stroke in patients with AF or even other conditions, I think we have a good example in terms of the CHADS2 score, where a group of clinical predictors have been used, as you can see in the slide, to nicely calculate the annual risk of having an ischemic stroke. And as patients get more of these risk factors, their risk of having an ischemic stroke goes up dramatically. As you can see, this is one very valuable tool that clinicians use every day to identify those at high risk vs low risk for having an ischemic event.




Risk Stratification in AF*

Singer DE, et al. Chest. 2004;126:429S-456S.Fuster V, et al. J Am Coll Cardiol. 2001;38:1231-1265.

Low Risk Moderate Risk High Risk• Aged < 65 yrs• No high-risk factors

• Aged 65-75 yrs• No high-risk factors

• Aged > 75 yrs• History of stroke/TIA• Hypertension• Poor LV systolic function• Mitral stenosis• Prosthetic heart valve• Diabetes

*Stroke risk, as ascertained by the SPAF investigators, is > 7%/yr in patients at high risk, 2.5%/yr in patients at moderate risk, and ~ 1%/yr in patients at low risk.

Slide 13 And another format that's been used is shown in this slide, this table that uses a combination of clinical factors to define groups of patients at low, moderate, or high risk for having an ischemic stroke as it applies to an AF population. Now the dirty little secret here is that, while these factors really define a group at high risk of having an ischemic event, these same factors define the same group of patients who are at risk for bleeding. So there is no easy answer to this, because if we identify a high-risk group for ischemic events, those patients are going to have the same risk factors for having a hemorrhagic event. So how do we square this and how do we come to terms with this? And does this have implications for treating ischemic stroke in general? In my opinion, I think the answer is yes. And let's talk about some recent studies of combination antiplatelet therapy for routine folks with ischemic stroke.




MATCH: Main Safety Outcomes

Types of Bleeding Events

ASA + Clopidogrel†

(n = 3759)

Placebo + Clopidogrel(n = 3781)

% AbsoluteDifference(95% CI) P value

Life-threatening*

bleeding events (%) 96 (3%) 49 (1%) 1.26 (0.64 to 1.88) < .0001

Fatal 16 (< 1%) 11 (< 1%) 0.13 (-0.14 to 0.40)

Nonfatal 81 (2%) 38 (1%) 1.15 (0.59 to 1.71)

Major bleeding† events(%) 73 (2%) 22 (1%) 1.36 (0.86 to1.86) < .0001

*Life-threatening: defined as any fatal bleeding event, or a drop in hemoglobin of ≥ 5 g/dL, or significant hypotension withthe need for inotropes (hemorrhagic shock), or symptomatic intracranial hemorrhage, or requiring transfusion of ≥ 4 units of red blood cells, or equivalent amount of whole blood.

†Major bleeding: defined as significant disabling (with persistent sequelea), or intraocular bleeding leading to significantvision loss, or requiring transfusion ≥ 3 units of red blood cells, or equivalent amount of whole blood.

Adapted from Diener HC, et al. Lancet. 2004;364:331-337.

From this study, it has been learned that in patients with recent TIA or stroke whoare at high risk for recurrent ischemic events, the combination of ASA and clopidogrel has not been shown to be more effective than clopidogrel alone, but the combination has been shown to increase major bleeding.

Slide 14 When we talk about using combination antiplatelet therapy for run of the mill stroke prevention, the first study to talk about is the MATCH [Management of Atherothrombosis With Clopidogrel in High-Risk Patients With Recent Transient Ischemic Attacks or Ischemic Stroke] study. So MATCH compared aspirin combined with clopidogrel vs clopidogrel monotherapy for the secondary prevention of stroke, MI [myocardial infarction], vascular death, and rehospitalization. Now keep in mind the MATCH population was also enriched for high-risk patients, in terms of selecting patients with hypertension, diabetes, and prior vascular events. What we found in MATCH is that the combination was no more effective than clopidogrel alone for stroke prevention in terms of efficacy. But in terms of bleeding complications, you can see from the data on this slide that the group that got combination therapy had much higher bleeding rates than the group that got clopidogrel monotherapy.




PRoFESS: Safety

Major hemorrhagic events and intracranial bleeds occurredmore frequently in the ER-DP plus ASA group comparedwith clopidogrel.

Aspirin, Extended-Release

Dipyridamole(ER-DP + ASA) Clopidogrel

Hazard Ratio (95% CI) P value

Major hemorrhagicevents 4.1% 3.6% 1.15 (1.00-1.32) .06

Intracranialhemorrhage* 1.4% 1.0% 1.42 (1.11-1.83) .006

*All intracranial hemorrhages, which include 128 of the 250 repeated ICH events, were also reported in the primary outcome.

Sacco R. European Stroke Conference Webcast. Available at http://eurostroke.org/Accessed May 15, 2008.

Slide 15 If we look at another contemporary study well, that's the PRoFESS [Prevention Regimen For Effectively Avoiding Second Strokes] trial, PRoFESS compared low-dose aspirin combined with extended-release dipyridamole as a combination therapy vs clopidogrel monotherapy. At the end of the day, what PRoFESS found, and again some of the PRoFESS population was also enriched for having other risk factors for stroke such as hypertension, diabetes, and prior events, was that there was no dramatic difference in efficacy in terms of preventing recurrent stroke looking at combination therapy vs clopidogrel monotherapy. But what we found is that, again, combination therapy was associated with a higher rate of major systemic bleeding events as well as all types of intracranial bleeds. So the theme sort of continues that combination therapy may be associated at least in a stroke population with a higher risk for bleeding events.




Bleeding in ACTIVE

Relative Risks for Hemorrhage, According to Treatment Group

Clopidigrel Plus Aspirin Aspirin

BleedingNo. of Events %/yr

No. of Events %/yr

Relative Risk(95% CI)

Major Bleeding 251 2.0 162 1.3 1.57 (1.29-1.92)Severe 190 1.5 122 1.0 1.57 (1.25-1.98)Fatal 42 0.3 27 0.2 1.56 (0.96-2.53)

Alberts J. European Society of Cardiology; 2009; Stockholm, Sweden. Slide 16 And then this brings us to the ACTIVE study, as Peter was talking about a few minutes ago, that looked at combination antiplatelet therapy for stroke prevention in a group of patients who have AF, who were unsuitable for treatment with warfarin. And again, here the story is a little bit different because the combination antiplatelet therapy did appear to be more effective, particularly for preventing major strokes. And the price that you paid was a little bit of increased risk in terms of bleeding events. But it's important to remember that most of the strokes that these patients with AF get are catastrophic strokes that don't respond to standard medical therapy, that don't respond to tPA [tissue plasminogen activator] or endovascular treatments, whereas some of the bleeding events such as subdural hematomas and GI [gastrointestinal] hemorrhages are relatively easy to treat and relatively straightforward in terms of transfusions and the like. So I think ACTIVE is a very good contemporary example of trying to weigh risks vs benefits of combination therapy.




Bleeding in REACH

ParameterOddsratio

95% confidence interval P value

AntiplateletsASA alone vs none 1.084 (.851-1.380) .51Other AP alone vs none 1.356 (.989-1.861) .06Dual AP therapy vs none 2.143 (1.601-2.867) < .001Anticoagulants 2.259 (1.797-2.840) < .001

Alberts J. European Society of Cardiology; 2009; Stockholm, Sweden. Slide 17 And this brings us to the last study I want to touch on, which is the REACH [Remote Evaluation of Acute Ischemic Stroke] registry. REACH is an international study of over 69,000 patients followed prospectively in primary practice, primary care, office-based nonspecialist type of settings. So I think it's a good real-world example of how patients are treated and how they're followed up not testing any particular medication. And as you can see here, what we found in the REACH registry when looking at serious bleeds as defined in REACH is that looking at aspirin as a monotherapy, there was this trend for more bleeding events. But when you talk about combination antiplatelet therapy, here we see a significant increase in terms of serious bleeding events that almost approached the degree of risk for serious bleeding events that was seen in patients who were taking anticoagulation. So I think that the general theme that we've tried to develop here is that risk stratification is very important. But while we can stratify patients for high risk for ischemic events, those same risk factors are going to put patients at higher risk for bleeding, particularly with anticoagulation and perhaps in some settings when we talk about combination antiplatelet therapy. So this leads us to some discussions. And let me ask Peter and Don how they approach their high-risk patients; let's say somebody in AF who needs to be on Coumadin [warfarin], but may be at an increased fall risk, how they would deal with a patient like that in a real-life setting. Dr. Rothwell: Well, I think that's a good question. I do think myself and I'd be interested to get your views on this, that sometimes we overestimate the risks of warfarin where in a sense we're more worried about doing harm than doing benefit. As you both know, the BAFTA




[Birmingham Atrial Fibrillation Treatment of the Aged] trial in the United Kingdom recently showed that even in very elderly frail patients in primary care, warfarin was more effective than aspirin in nonvalvular AF. And interestingly, the risks for bleeding on aspirin were as high as the risks on warfarin. So that's made me feel a little bit more secure about trying to persuade patients to think about warfarin even if they are at relatively high risk and obviously without a major contraindication. I wonder, Don, what do you feel these days? Dr. Easton: No, I agree with that, Peter. In fact, I think when you look at the CHADS score that Mark showed us earlier and you see how steeply the curve rises as you bring on additional risk factors, even though you will pay a higher price in bleeding, the number of ischemic events is so high that anticoagulation is still by far the treatment of choice. And so I too think that many physicians out there are frightened by anticoagulation not realizing that it's very frightening to have a stroke. And as Mark said, in the ACTIVE trial too, some three fourths of the strokes were serious; that is, they were Rankin 3 or higher. And for those who don't use Rankin scores every day, you would know that that means moderate disability, able to ambulate but needing help to ambulate and then worse. So we're talking about very serious strokes in this group of patients. And I'd rather have a 2-unit transfusion than a Rankin 3 stroke. Dr. Rothwell: Yeah. Dr. Easton: And so I too am pretty careful about not overemphasizing the dark side of antithrombotic therapy. Dr. Rothwell: Yeah. Mark, to explore on that further, can we think about, the very important point that you made that the predictors of high risk for ischemic events are similar to the predictors of high risk for bleeding? I mean from a purely statistical point of view, you could put the argument, well, if you take a high-risk group, you double the risk for ischemic events, you double the risk for bleeding, and you double the difference between them. So you double the benefit. Do you think it's as simple as that? Or do you think we need to put more work into developing risk scores for these different outcomes? Dr. Alberts: Well, we in fact are looking at a risk score based on the REACH registry, which is some of the data I showed a few minutes ago trying to parse out the high risk vs medium vs low risk. But I think at the end of the day, it's really a balancing act in terms of how much does a GI bleed or a subdural hematoma? What's the long-term disability from those events vs the long-term disability from having a big, large MCA [middle cerebral artery] territory stroke from AF?




As we touched on a few minutes ago, some of our standard treatments for ischemic stroke, such as just tPA, MERCI [Mechanical Embolus Removal in Cerebral Ischemia], penumbra, those other endovascular devices, they don't work particularly well for those large hemispheric MCA territory strokes from cardioembolic phenomena like you see in AF. So I think in general, in my opinion, the balance comes down to preventing the ischemic event while doing everything you can to reduce the risk of having a hemorrhage.

And so we were talking about before, what we oftentimes hear is, "The patient's at high risk of falling, and I don't want them to fall and bang their head." And someone recently published something saying that the risk of that happening is miniscule as opposed to the risk of them having a catastrophic stroke not being on warfarin or perhaps even combination antiplatelet therapy. So it's a balancing act. And if worse comes to worst, put them in a wheelchair. They'll have less way to fall. Dr. Rothwell: Yeah. I mean, Don, one of the interesting things I think from ACTIVE A was the fact that if you look at the combined endpoints of ischemic events or major bleeding, there was more or less no difference between the groups. Do you think that we'll get somewhere with health economic analyses in teasing apart which strategy is better? Dr. Easton: I do. And everything we've talked about so far is ischemia vs hemorrhage. It's not talking about quality of life. It's not talking about the fact of the length of stay inhospital; in the ACTIVE A trial, for example, hospital days were substantially greater for the patients that were not treated with combination therapy. So there are other prices to be taken into account that go with this. And certainly we're all used to the aphorism that old folks think there are fates worse than death and stroke is often one of them. And certainly a Rankin 3 or 4 stroke is one of them. Dr. Rothwell: Yeah. Dr. Easton: I would much prefer to have a bleed, most bleeds. Dr. Rothwell: Mark, I hate to land this on you, but what do you think the road of MR [magnetic resonance] imaging in microbleeds is likely to be over the next few years in trying to tease apart the risks and benefits in this patient group? Dr. Alberts: It's a very good question. And my understanding of the literature is that if you look at these microbleeds on gradient echo MRI, they really can be split into 2 categories. One category is patients who have small vessel disease from poorly treated hypertension, diabetes, smoking and their blood vessels are leaky and they have these micro-hemorrhages. Another big group is the group of people with amyloid angiopathy. Dr. Rothwell: Yeah.




Dr. Alberts: And it's important to understand what the causes of the microbleeds are. If it's an elderly person with a lot of cortical hemorrhages and they're a little bit demented, I would lean more towards perhaps amyloid angiopathy. And I think those people are at particularly high risk for warfarin or combination therapy. On the other hand, if it's microbleeds from poorly controlled vascular disease, then I think that emphasizes very aggressive risk factor control. Then once you get the risk factors under better control, then maybe that's a better population to use combination therapy on, like the AF folks who for one reason or another cannot use warfarin. Dr. Rothwell: Yeah. That's a key point I think, isn't it, Don? That if we want to reduce the risks for any of these treatment options, we need to treat the blood pressure and try and reduce the other risk factors for bleeding as much as possible. Dr. Easton: Yeah. I think it's interesting that we often get into the discussions about which antithrombotic to use under which circumstance and don't emphasize the fact that failure to treat hypertension moves events up by a decade in terms of when they'll occur in a person's lifetime. The same thing is true with cigarette smoking, the same thing with hypercholesterolemia, and so on. And so those are factors that have a huge impact on event rates. And we really must attend to those at the front end of everything we do and then talk about the best antithrombotic therapies. Dr. Rothwell: Yeah, absolutely. Well, perhaps we could finish by thinking about ourselves. Let's assume we've each got a low-chance score and we each find ourselves in AF. And we can't get ourselves out of it. What we would want for ourselves in terms of preventive treatment? Dr. Easton: You realize I'm in a higher CHADS score already than either of you two. Dr. Rothwell: I didn't want to suggest that, Don. Dr. Easton: Because age is one of those factors. Dr. Rothwell: Yeah. Dr. Easton: No. I think for me I simply believe that if you've got a CHADS score of 1 or 2 or higher, that there should be a good reason not to anticoagulate that patient. But having said that, there will be this large group of patients that are left behind. And then the whole issue is, are you going to treat them with aspirin or are you going to treat them with combination therapy? And that's where my view would be, again, go with the combination therapy unless there's a good reason not to. And that would be, again, in the area of bleeding risk and so forth. So I think we need the most potent antithrombotic therapy we can give, but we have to risk stratify




the safety of doing so. Dr. Rothwell: Yeah. And that's going to need more work along the lines that Mark is suggesting with the risk model from REACH. Dr. Easton: Right. Dr. Rothwell: Yeah. Dr. Alberts: And I'm a firm believer that the best way to treat stroke is to prevent stroke. So I think maximum prevention. We should also mention the fact that there are a number of novel agents in the pipeline that we may be hearing about in the next few months in terms of direct thrombin inhibitors and anti-Xa agents that may be very effective and may or may not be safer than warfarin and other therapies for preventing strokes in people with AF. So people should keep their ears tuned to late-breaking results coming out this summer. Dr. Rothwell: Absolutely. So I think our discussions may become redundant in a few months' time. It will be very interesting to see. Thank you very much, gentlemen. I think that was a very interesting discussion. Dr. Easton: It was a pleasure. Dr. Alberts: A pleasure.

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