2 acc prevention antiplatelet and anticoagulant
Upcoming SlideShare
Loading in...5
×
 

2 acc prevention antiplatelet and anticoagulant

on

  • 495 views

 

Statistics

Views

Total Views
495
Views on SlideShare
495
Embed Views
0

Actions

Likes
0
Downloads
14
Comments
0

0 Embeds 0

No embeds

Accessibility

Upload Details

Uploaded via as Microsoft PowerPoint

Usage Rights

© All Rights Reserved

Report content

Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
  • Full Name Full Name Comment goes here.
    Are you sure you want to
    Your message goes here
    Processing…
Post Comment
Edit your comment
  • Platelet activation leads to platelet aggregation. As illustrated above, various classes of antiplatelet agents act by different mechanisms to reduce platelet activation and clot formation. <br /> Aspirin inhibits platelet aggregation by inhibiting the production of thromboxane A2. <br /> The P2Y12 receptor antagonists (clopidogrel, prasugrel and ticlopidine) bind and inhibit adenosine diphosphate (ADP) receptors on platelets, thereby, inhibiting glycoprotein IIb/IIIa-receptor activation and subsequent platelet aggregation. <br /> Dipyridamole interferes with platelet stimulating factors like collagen through various mechanisms including the inhibition of phosphodiesterase and inhibition of cellular uptake of adenosine. <br /> Glycoprotein IIb/IIa inhibitors directly interfere with platelet binding of fibrinogen, the final step in platelet aggregation. <br />
  • Numerous oral antiplatelet agents are approved for use in the prevention and/or treatment of CV disease. <br /> Among the P2Y12 receptor antagonists, clopidogrel has generally been given preference over ticlopidine because of a superior safety profile (unless an allergy is present). The newest FDA approved agent is prasugrel. The standard dose is 10 mg a day. It is approved for use in the setting of moderate to high risk ACS patients undergoing PCI as an adjunct to aspirin therapy. It should not be used in patients with a history of stroke or TIA, age >75 years (unless prior CHD or DM), or weight less than 60 kg. <br />
  • Aspirin inhibits the production of thromboxane A2, thereby inhibiting platelet aggregation. Thromboxane promotes platelet aggregation and vasoconstriction. During platelet activation, the hydrolysis of membrane phospholipids yields arachadonic acid, which is converted to prostaglandin H2 by the catalytic activity of the cyclooxygenase enzyme prostaglandin G/H synthase. <br /> By the selective and irreversible acetylation of a single serine residue within prostaglandin G/H synthase, aspirin causes the inactivation of cyclooxygenase activity. Aspirin also inhibits the production of endothelial-produced prostacyclin, a vasodilator and inhibitor of platelet aggregation. Unlike platelets, endothelial cells recover their ability to synthesize prostacyclin within a couple of hours. <br /> References: <br /> 1. Husain S, Andrews NP, Mulcahy D, Et al. Aspirin improves endothelial dysfunction in atherosclerosis. Circulation. 1998;97:716-20. <br /> 2. Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nature. 1971;231:235-5. <br /> 3. Patrono C. Aspirin as an antiplatelet drug. NEJM 1994;330:1287-94. <br />
  • The Physicians&apos; Health Study was a randomized, double-blind, placebo-controlled primary prevention trial designed to determine whether aspirin (325 mg every other day) was associated with a reduction in cardiovascular disease mortality. The trial included 22,071 participants, with an average follow-up of 60 months. <br /> Aspirin use was associated with a 44% reduction in the risk of MI; however, this effect was mainly present in men >50 years of age and no reduction in total cardiovascular mortality (RR 0.96; 95% CI 0.60 to 1.54) was observed. A slightly increased risk of stroke was observed among those taking aspirin (p=NS). This trend was noted primarily in the subgroup with hemorrhagic stroke (RR 2.14; 95% CI [0.96 to 4.77]; p=0.06). There was a non-significant increased risk of gastrointestinal ulcers in the aspirin group (RR 1.22, CI [0.98 to 1.53]; p=0.08). <br /> Overall: In men (especially >50 years of age), aspirin is associated with a reduced risk of a first MI. <br />
  • The Women&apos;s Health Study was a double-blind, placebo-controlled trial that randomized 39,876 healthy women >45 years of age to low dose aspirin (100 mg every other day) versus placebo for a mean follow up of 10 years. There was no reduction in the primary composite endpoint of nonfatal MI, nonfatal stroke, or death from a cardiovascular cause. Aspirin use was associated with a 17% reduction in the risk of stroke (RR 0.83; 0.69-0.99; P=0.04), a 24% reduction in the risk of ischemic stroke (RR 0.76; 0.63-0.93; P=0.009), and a non-significant increase in the risk of hemorrhagic stroke (RR 1.24; 0.82-1.87; P=0.31). Aspirin had no effect on the risk of fatal or nonfatal myocardial infarction (RR 1.02; 0.84-1.25; P=0.83). <br /> Among women >65 years of age, aspirin use was associated with a reduction of major cardiovascular events (RR 0.74; 0.59-0.92; P=0.008) and risk of ischemic stroke (RR 0.70; 0.49-1.00; P=0.05). GI bleeding requiring transfusion was more frequent in the aspirin group (RR 1.40; 1.07-1.83; P=0.02). <br /> Overall: The routine use of aspirin in low risk women (65 can reduce the risk of cardiovascular events. <br />
  • This slide demonstrates a reduction in the incidence of MI among men but not women and a reduction of CVA in women but not men in the major aspirin primary prevention trials. These differences may be due to a proportionally higher incidence of CVA versus MI in women as compared to men, as well as, differences in total CVD risk among the men and women in these trials. Ultimately, however, the reasons for these sex-based differences in the efficacy of aspirin for primary prevention of CVD are unclear and require further exploration. <br />
  • Data from six studies were included in this meta-analysis: The Physicians&apos; Health Study (1989), the Women&apos;s Health Study (2005), the Primary Prevention Project (2001), the Thrombosis Prevention Trial (1998), the Hypertension Optimal Treatment (HOT) trial (1998), and the British Doctor&apos;s Trial (1988). <br /> Among 51,342 women, there were 1285 major cardiovascular events: 625 strokes, 469 MIs, and 364 cardiovascular deaths. Aspirin therapy was associated with a significant 12% reduction in cardiovascular events (odds ratio [OR], 0.88; 95% confidence interval [CI], 0.79-0.99; P = .03) and a 17% reduction in stroke (OR, 0.83; 95% CI, 0.70-0.97; P = .02), predominantly resulting from reduced rates of ischemic stroke (OR, 0.76; 95% CI, 0.63-0.93; P = .008). There was no significant effect on MI or cardiovascular mortality. <br /> Among 44,114 men, there were 2047 major cardiovascular events: 597 strokes, 1023 MIs, and 776 cardiovascular deaths. Aspirin therapy was associated with a significant 14% reduction in cardiovascular events (OR, 0.86; 95% CI, 0.78-0.94; P = .01) and a 32% reduction in MI (OR, 0.68; 95% CI, 0.54-0.86; P = .001). There was no significant effect on stroke or cardiovascular mortality. <br /> Aspirin treatment increased the risk of bleeding in women (OR, 1.68; 95% CI, 1.13-2.52; P = .01) and men (OR, 1.72; 95% CI, 1.35-2.20; P&lt;.001) alike. <br />
  • The JPAD trial was a multicenter, prospective, randomized, open-label trial which enrolled 2539 patients in Japan with type 2 diabetes and no history of atherosclerotic disease. Patients were assigned to a low-dose aspirin group (81 or 100 mg per day) or a non-aspirin group for a median of 4.37 years. Primary end points were atherosclerotic events, including fatal or nonfatal ischemic heart disease, fatal or nonfatal stroke, and peripheral arterial disease. Secondary end points included each primary end point and combinations of primary end points as well as death from any cause. <br /> A total of 154 atherosclerotic events occurred: 68 in the aspirin group (13.6 per 1000 person-years) and 86 in the non-aspirin group (17.0 per 1000 person-years) (hazard ratio [HR], 0.80; 95% confidence interval [CI], 0.58-1.10; p = .16). The combined end point of fatal coronary events and fatal cerebrovascular events occurred in 1 patient (stroke) in the aspirin group and 10 patients (5 fatal myocardial infarctions and 5 fatal strokes) in the non-aspirin group (HR, 0.10; p = .0037). A total of 34 patients in the aspirin group and 38 patients in the non-aspirin group died from any cause (HR, 0.90; 95% CI, 0.57-1.14; P = .67). The composite of hemorrhagic stroke and significant gastrointestinal bleeding was not significantly different between the aspirin and non-aspirin groups. <br />
  • The Aspirin for Asymptomatic Atherosclerosis trial was an intention-to-treat, double-blind, randomized controlled trial conducted from April 1998 to October 2008, involving 28,980 men and women aged 50 to 75 years living in central Scotland. Eligible individuals were recruited from a community health registry, were free of clinical cardiovascular disease, and had an ABI screening test. A total of 3350 patients with a low ABI (0.95) were entered into the trial. Patients were randomized to once daily 100 mg aspirin (enteric coated) or placebo and were followed for a mean of 8.2 years. Treatment with aspirin was associated with no statistically significant reduction in the rate of fatal or nonfatal coronary events, stroke, or revascularization and no difference in all cause mortality. <br />
  • This data was taken from a meta-analysis of 6 randomized trials of antiplatelet therapy for prevention of death, MI, and stroke in low risk patients. In the primary prevention trials the absolute risk of a serious vascular event was an order of magnitude less than in the secondary prevention trials, and the absolute reduction in occlusive events only about twice as large as the absolute increase in bleeding. Moreover, these trials of aspirin were mainly in people who were not taking statin therapy, which would have reduced both MI and stroke rates with little hazard. <br /> Overall: Aspirin is of uncertain net value for the primary prevention of CVD. <br />
  • This data was taken from a meta-analysis of 6 randomized trials of antiplatelet therapy for prevention of death, MI, and stroke in low risk patients. In the primary prevention trials the absolute risk of a serious vascular event was an order of magnitude less than in the secondary prevention trials, and the absolute reduction in occlusive events only about twice as large as the absolute increase in bleeding. Moreover, these trials of aspirin were mainly in people who were not taking statin therapy, which would have reduced both MI and stroke rates with little hazard. <br />
  • This data was taken from a meta-analysis of randomized trials of antiplatelet therapy for prevention of death, MI, and stroke in high risk patients. Absolute reductions in the risk of having a serious vascular event were 36 ± 5 per 1,000 treated for 2 years among patients with previous MI; 38 ± 5 per 1,000 patients treated for 1 month among patients with acute MI; 36 ± 6 per 1000 treated for 2 years among those with previous stroke or TIA; 9 ± 3 per 1000 treated for 3 weeks among those with acute stroke; and 22 ± 3 per 1000 treated for 2 years among other high risk patients (with separately significant results for those with stable angina (P=0.0005), peripheral arterial disease (P=0.004), and atrial fibrillation (P=0.01). <br /> In each of these high risk categories, the absolute benefit substantially outweighed the absolute risk of major extra-cranial bleeding. <br /> Overall: Aspirin is recommended for the secondary prevention of CVD. <br />
  • This slide demonstrates that high doses of aspirin are no more effective than medium or low doses in reducing the odds of a vascular event. Because trials using very low doses (&lt;75 mg) are less conclusive, current data supports daily doses of aspirin in the 75-160 mg range. <br /> Several studies have demonstrated in both healthy volunteers and CHD patients that low dose enteric coated may have decreased bioavailability and may not sufficiently inhibit cyclooxygenase in a subset of patients. [Maree AO et al. J Am Coll Cardiol, 2005; 46:1258-1263 and Cox D et al. Stroke. 2006;37:2153-2158 ] <br /> Overall: For secondary prevention of CVD an aspirin dose of 75-325 mg/d is recommended. If 75-81 mg aspirin is used, consideration should be given towards a non-enteric coated preparation. <br />
  • The P2Y12 receptor antagonists (clopidogrel, ticlopidine, prasugrel, and ticagrelor) selectively bind P2Y12, one of the adenosine diphosphate (ADP) receptors on platelets. This binding inhibits ADP-induced activation of the platelet glycoprotein IIb/IIIa-receptor and prevents platelet aggregation. <br />
  • CAPRIE was a randomized, double blind trial designed to assess the relative efficacy of clopidogrel (75 mg daily) versus aspirin (325 mg daily) in reducing the risk of ischemic stroke, MI, or vascular death in patients with atherosclerotic vascular disease. An intention-to-treat analysis showed that patients treated with clopidogrel had an annual 5% risk of ischemic stroke, myocardial infarction, or vascular death compared to 6% with aspirin, resulting in a statistically significant relative risk reduction of 9% (95% Cl 0.3-16.5, P= 0.043). <br /> There were no major differences between the treatments with regard to the incidence of rash, diarrhea, upper gastrointestinal discomfort, intracranial hemorrhage, and gastrointestinal hemorrhage. <br /> Overall: Clopidogrel is slightly more efficacious than aspirin for the prevention of CVD events in patients with recent ischemic stroke, recent MI, or symptomatic peripheral arterial disease but its cost is much higher. <br />
  • The CURE trial evaluated the efficacy and safety of clopidogrel and aspirin in patients with a non-ST-segment elevation acute coronary syndrome. Patients that presented within 24 hours after the onset of symptoms were randomly assigned to receive clopidogrel (300 mg immediately, followed by 75 mg once daily) (6,259 patients) or placebo (6,303 patients), in addition to aspirin for 3 to 12 months. <br /> A composite of death from cardiovascular causes, nonfatal MI, or stroke, occurred in 9.3% of the patients in the clopidogrel + aspirin group and 11.4% in the aspirin alone group, corresponding to a significant 20% RR reduction. <br /> The co- primary outcome (a composite of the first primary outcome along with refractory ischemia) occurred in 16.5% of patients in the clopidogrel + aspirin group vs. 19% of patients in the aspirin alone group, resulting in a significant 14% RR reduction. The percentage of patients with in-hospital refractory or severe ischemia, heart failure, and revascularization procedures was also significantly lower in the clopidogrel + aspirin group. <br /> Patients on clopidogrel + aspirin had a significantly increased risk of major bleeding as compared to patients on aspirin alone (4% vs. 3%; relative risk, 1.38; P=0.001), but no greater incidence of life-threatening bleeding (2% vs. 2%, P=0.13) or hemorrhagic strokes. <br /> Overall: The combination of aspirin + clopidogrel (for 3-12 months) is more efficacious than aspirin alone for the prevention of subsequent CVD events in patients presenting with a non-ST-segment elevation acute coronary syndrome. <br />
  • In the Clopidogrel for the Reduction of Events during Observation (CREDO) trial, 2,116 patients scheduled to undergo percutaneous coronary intervention (PCI) or thought to be at high likelihood of undergoing PCI were randomized to a 300 mg loading dose of clopidogrel vs. placebo 3-24 hrs prior to PCI. Following PCI, all patients received clopidogrel (75mg daily) through day 28. From day 28 through 1 year, patients in the loading dose group received 75mg of clopidogrel daily. <br /> Clopidogrel reduced the 1-year risk of MI, CVA, or death by 27% (P=.02; absolute reduction 3%). No significant difference was seen in the 28 day combined risk of MI, death, or urgent target vessel revascularization (risk reduction 19%;p=0.23). <br />
  • The COMMIT (Clopidogrel and Metoprolol in Myocardial Infarction Trial)/CCS-2 (Second Chinese Cardiac Study), a collaboration between the UK Oxford Clinical Trials Unit and Chinese investigators, involved 45,852 patients with an MI (either ST-segment change or left bundle-branch block) within 24 hours of symptom onset. Patients undergoing primary percutaneous coronary intervention or at high risk of bleeding were excluded. <br /> The study randomized patients to treatment with clopidogrel (75 mg daily) for the duration of hospital stay (mean 16 days) or placebo. All patients received aspirin 162 mg daily. <br /> The two primary end points were the composite of death, reinfarction, or stroke and death from any cause at hospital discharge, both of which were significantly reduced. As shown in the figure on the left, allocation to clopidogrel produced a 9% reduction (P=.002) in death, reinfarction, or stroke. Predischarge deaths (shown in the figure on the right) were reduced by 7% (P=.03) in the clopidogrel group. <br /> The benefits of clopidogrel treatment were not associated with an increased risk of major bleeding or ICH. <br />
  • The CHARISMA trial randomized 15,603 patients with multiple CV risk factors or known CVD to aspirin (75-162 mg) or aspirin (75-162 mg) + clopidogrel (75 mg) for a mean of 30 months. The primary endpoint of stroke, myocardial infarction, or death from cardiovascular causes occurred in 6.8% of the clopidogrel + aspirin group and 7.3% of the placebo + aspirin group (RR 0.93; 95% CI, 0.83 to 1.05; P=0.22). There was a trend towards increased adverse events in the primary prevention group (RR 1.2; 95% CI, 0.91 to 1.59; P=0.20) and a modest trend towards benefit in those with a history of prior atherothrombotic disease (RR 0.88; 95% CI, 0.77 to 0.99; P=0.046). <br /> Overall: The combination of aspirin + clopidogrel provided no benefit over aspirin alone for the prevention of CVD events. <br />
  • This trial has not yet been published. <br /> The CURRENT-OASIS-7 trial randomized 25,087 ACS patients in a 2 x 2 factorial design to a high dose clopidogrel load and maintenance (600 mg LD, 150 mg MD x 1 week followed by 75 mg thereafter) versus a standard dose clopiodgrel load and maintenance (300 mg LD, followed by 75 mg thereafter), as well as, high dose aspirin (300-325 mg) versus low dose aspirin (75-100 mg). <br /> The primary endpoint of CV death, MI, or CVA at 30 days was not statistically different with the two clopidogrel regimens. However, in a pre-specified subgroup of patients undergoing PCI (70% of enrollees), the higher clopidogrel loading dose reduced the risk of the primary endpoint by 15% (HR 0.85, 95% CI 0.74 to 0.99). PCI patients in the high dose group had a 42% reduction in the risk of stent thrombosis (P&lt;0.001) compared with patients receiving the standard dose of clopidogrel. Treatment with high dose clopidogrel was also associated with a 25% increase in the CURRENT definition of major bleeding (p=0.01); however, there was no statistically significant increased risk of TIMI major, fatal, intracranial, and CABG-related bleeding. <br /> No difference in outcome was noted with the different doses of aspirin. There was also no increased bleeding with higher dose aspirin. <br />
  • The TRITON-TIMI 38 trial randomized 13,608 moderate- to high-risk ACS patients scheduled for PCI to receive prasugrel (60-mg loading dose and then 10-mg daily maintenance dose) or clopidogrel (300-mg/75-mg) for 6 to 15 months. <br /> Treatment with prasugrel resulted in a significant reduction in the primary efficacy end point (cardiovascular death/MI/stroke), as well as, MI, urgent target vessel revascularization (TVR), and stent thrombosis. However, this was at the expense of a significant increase in major bleeding (2.4% vs 1.8%, HR 1.32, p=0.03), life-threatening bleeding (1.4% vs 0.9%; P=0.01), and fatal bleeding (0.4% vs 0.1%; P=0.002). Subgroups that appeared to be particularly prone to serious bleeding include the elderly (age > 75) and the underweight (&lt; 60kg). In the small subgroup of patients in this study with a previous stroke or transient ischemic attack, prasugrel resulted in reduced efficacy in reducing the ischemic end point. <br /> In a substudy, among the 3,534 patients with a STEMI (Lancet, Feb 2009), the primary endpoint of CV death, non-fatal MI, or non-fatal CVA was reduced with prasugrel at 30 days (6.5% with prasugrel vs 9.5% with clopidogrel; p=0.0017) and 15 months (10·0% vs 12·4%; p=0·0221). The secondary endpoint of cardiovascular death, myocardial infarction, or urgent target vessel revascularization was also significantly reduced with prasugrel at 30 days (HR 0.75 p=0·0205) and 15 months (HR0.79; p=0·0250), as was stent thrombosis. <br /> As opposed to the initial study, TIMI life-threatening bleeding and TIMI major or minor bleeding were also similar with the two treatments in patients with a STEMI. Only TIMI major bleeding after CABG surgery was significantly increased with prasugrel (p=0·0033). <br /> *Patients in the clopidogrel arm only received a 300mg load (600mg is now standard of care for PCI) <br />
  • Ticagrelor is an oral, reversible, direct inhibitor of the adenosine diphosphate receptor, P2Y12. <br /> PLATO was a multicenter, double-blind, randomized trial of 18,624 ACS patients comparing ticagrelor (180-mg loading dose, 90 mg twice daily thereafter) and clopidogrel (300-to-600-mg loading dose, 75 mg daily thereafter). At 12 months, the primary end point of death from vascular causes, myocardial infarction, or stroke occurred in 9.8% of patients receiving ticagrelor as compared with 11.7% of those receiving clopidogrel (p&lt; 0.0003). <br /> Secondary endpoint analysis showed a decrease in the rate of MI alone (5.8% in the ticagrelor group vs. 6.9% in the clopidogrel group, P=0.005) and death from vascular causes (4.0% vs. 5.1%, P=0.001) but not stroke alone (1.5% vs. 1.3%, P=0.22). The rate of death from any cause was also reduced with ticagrelor (4.5%, vs. 5.9% with clopidogrel; P&lt;0.001). <br /> No significant difference in the rates of overall major bleeding was found between the ticagrelor and clopidogrel groups (11.6% and 11.2%, respectively; P=0.43), but ticagrelor was associated with a higher rate of major bleeding not related to coronary-artery bypass grafting (4.5% vs. 3.8%, P=0.03). <br />
  • Vitamin K is required for the carboxylation of clotting proteins II, VII, IX, and X. Without adequate levels of vitamin K, the liver produces partially carboxylated and decarboxylated clotting proteins, which have reduced procoagulant activity. Warfarin interferes with vitamin K dependent production of clotting proteins. Warfarin also decreases protein S levels, which initially creates a prothrombotic state. <br />
  • The Thrombosis Prevention Trial evaluated the effect of low dose oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischemic heart disease (IHD). <br /> The primary end point was an IHD composite, defined by the sum of coronary death and fatal and non-fatal myocardial infarction (MI). Warfarin reduced the primary end point by 21% (95% CI 4-35, P=0.02) due to a 39% reduction (95% CI 15-57, P=0.003) in fatal events and reduced all-cause mortality by 17% (95% CI 1-30, P=0.04). The main effect of aspirin was a reduction in the primary end point by 20% (95% CI 1-35, P=0.04), almost entirely due to a 32% reduction (95% CI 12-48, P=0.004) in non-fatal events. Absolute reductions in the primary end point due to warfarin or aspirin were 2.6 and 2.3 per 1,000 person years, respectively. Combination therapy with warfarin and aspirin reduced the primary end point by 34% (95% CI 11-51%, P=0.006) compared with placebo, but increased hemorrhagic and fatal strokes. <br /> Overall: Aspirin and warfarin to INR of 1.5 are equally efficacious in the reduction of first time MI, stoke and mortality. Warfarin + aspirin was more effective at reducing primary IHD events, but with a higher risk of hemorrhagic and ischemic strokes. <br />
  • This meta-analysis was designed to analyze the effects of long-term oral anticoagulation (OA), stratified by the intensity of anticoagulation and aspirin therapy, on outcomes in patients with CAD. <br /> Compared to placebo, high-intensity (INR 2.8-4.8) OA produced significant reductions in mortality, MI, and thromboembolic complications (including stroke), but with a 6-fold increased risk of major bleeding (including hemorrhagic stroke). Compared to placebo, moderate (INR 2-3) OA produced significant reductions in MI, stroke, but not death and had an 8-fold increased risk of major bleeding. <br /> Compared to aspirin therapy, moderate or high-intensity OA (INR>2) produced no reduction in death, MI, or stroke, and was associated with a 2.4 fold increased risk of major bleeding. Compared to aspirin therapy, low-intensity OA (INR, 2) + aspirin produced a 56% reduction in death, MI, or stroke, and was associated with a 1.6 fold increased risk of major bleeding that did not reach statistical significance. <br /> Overall: High intensity OA (INR 2.8-4.8) is an option for reducing CVD risk. In patients with an indication for moderate to high intensity OA (INR>2), the addition of aspirin is associated with fewer CVD events, but greater bleeding risk than OA alone. <br />
  • The WARIS II trial enrolled 3,630 patients under the age of 75 years hospitalized with an acute myocardial infarction* and randomized them to one of three groups: Warfarin (in a dose intended to achieve an INR of 2.8 to 4.2), aspirin (160 mg daily), or aspirin (75 mg daily) combined with warfarin (in a dose intended to achieve an INR of 2.0 to 2.5). Patients were excluded if they had malignant disease or poor compliance was anticipated. <br /> The primary outcome, a composite of death, nonfatal reinfarction, or thromboembolic cerebral stroke, occurred in 20.0% of patients receiving aspirin alone, 16.7% of patients receiving warfarin alone, and 15% of patients receiving warfarin and aspirin. The difference between the two groups receiving warfarin was not statistically significant. As compared with aspirin alone, the risk reduction in patients receiving warfarin plus aspirin was 29 percent (P=0.001) and in those receiving warfarin alone it was 19 percent (P=0.03). The reduction in the primary endpoint was driven by a decrease in non-fatal reinfarction and thromboembolic stroke. <br /> Episodes of major, nonfatal bleeding were observed in 0.62% of patients per treatment-year in both groups receiving warfarin and in 0.17% of patients receiving aspirin (P&lt;0.001). Major bleeding episodes** were not more frequent among patients receiving aspirin plus warfarin than among those receiving warfarin alone, but the incidence of minor bleeding episodes was higher in the combined-therapy group. <br /> *Acute myocardial infarction was defined by the 1979 WHO recommendation - two or more of the following: a history of typical chest pain, electrocardiographic changes typical of myocardial infarction, and a creatine kinase level greater than 250 U per liter, an aspartate aminotransferase level greater than 50 U per liter, or both, of probable cardiac origin. <br /> **Major bleeding episodes were defined as nonfatal cerebral hemorrhage or bleeding necessitating surgical intervention or blood transfusion. <br />
  • The CHAMP study was a randomized open-label study to compare the efficacy of warfarin (INR 1.5 to 2.5) plus aspirin (81 mg daily) with the efficacy of aspirin monotherapy (162 mg daily) in reducing the total mortality in 5,059 patients enrolled within 14 days of myocardial infarction and followed for a median of 2.7 years. Secondary end points included recurrent myocardial infarction, stroke, and major hemorrhage. Four hundred thirty-eight (17.3%) of 2537 patients assigned to the aspirin group and 444 (17.6%) of 2522 patients assigned to the combination group died (log-rank P=0.76). <br /> Recurrent myocardial infarction occurred in 333 patients (13.1%) taking aspirin and in 336 patients (13.3%) taking combination therapy (log-rank P=0.78). Stroke occurred in 89 patients (3.5%) taking aspirin and in 79 patients (3.1%) taking combination therapy (log-rank P=0.52). <br /> Major bleeding occurred more frequently in the combination therapy group than in the aspirin group (1.28 versus 0.72 events per 100 person years of follow-up, respectively; P&lt;0.001). There were 14 individuals with intracranial bleeds in both the aspirin and combination therapy groups. <br /> This trial failed to show a clinical benefit of adding warfarin to aspirin for secondary prevention. The results of this trial are in contrast to the WARIS II trial. Of note, the INR goal for the WARIS II trial was 2.0-2.5 and patients were followed for 4 years. <br />
  • In this meta-analysis of 24,542 secondary prevention patients, there was no difference in all cause mortality between patients receiving warfarin containing regimens with or without aspirin compared to non-warfarin containing regimens with or without aspirin. <br />
  • The Warfarin and Antiplatelet Therapy in Chronic Heart Failure (WATCH) trial prospectively randomized symptomatic heart failure patients in sinus rhythm with an ejection fraction &lt;35% to treatment with open-label warfarin (target INR 2.5-3.0) or double-blind antiplatelet therapy with aspirin (162 mg) or clopidogrel (75 mg). <br /> Although the trial was designed to enter 4,500 patients, it was terminated 18 months prematurely in June 2003 by the VA Cooperative Study Program because of poor enrollment, resulting in a reduction in power to achieve the original objective. Nonetheless, the results demonstrated no significant benefit to warfarin or clopidogrel over aspirin for the specified end points. <br /> Overall: Anti-platelet/anticoagulation recommendations are not impacted by left ventricular systolic dysfunction. <br />
  • This meta-analysis included 10 studies comparing Aspirin (A) + Warfarin at an INR of 2 to 3 versus Aspirin (A) alone and 3 studies comparing Aspirin (A) + Clopidogrel (C) versus Aspirin (A) alone. A+W versus A+C were studied using an adjusted indirect comparison. <br /> Each combined approach yielded a significantly lower risk of major adverse events, with albeit an increased risk of major bleeds, compared with aspirin alone. No significant difference was found for A + W versus A + C for risk of overall major adverse events, death, or acute MI. However, A + W (as compared to A + C) was associated with a significantly lower risk of thromboembolic stroke (OR 0.53, 95% CI 0.31 to 0.88, number needed to treat 60) and all types of stroke (OR 0.58, 95% CI 0.35 to 0.94, p = 0.038), with an increased risk of major bleeds (OR 1.9, 95% CI 1.2 to 2.8, number needed to harm 300). <br />
  • This analysis used a nationwide registry in Denmark that included 40,812 patients aged 30 years or older who had been admitted to hospital with a first-time myocardial infarction between 2000 and 2005. Claimed prescriptions starting at hospital discharge were used to determine the regimen prescribed according to the following groups: monotherapy with aspirin, clopidogrel, or vitamin K antagonist; dual therapy with aspirin plus clopidogrel, aspirin plus vitamin K antagonist, or clopidogrel plus vitamin K antagonist; or triple therapy including all three drugs. <br /> During a mean follow-up of 476.5 days (SD 142.0), 1,891 (4.6%) patients were admitted to the hospital with bleeding. The yearly incidence of bleeding was 2.6% for the aspirin group, 4.6% for clopidogrel, 4.3% for vitamin K antagonist, 3.7% for aspirin plus clopidogrel, 5.1% for aspirin plus vitamin K antagonist, 12.3% for clopidogrel plus vitamin K antagonist, and 12.0% for triple therapy. <br /> With aspirin as a reference, the adjusted hazard ratios for bleeding were 1.33 (95% CI 1.11-1.59) for clopidogrel, 1.23 (0.94-1.61) for vitamin K antagonist, 1.47 (1.28-1.69) for aspirin plus clopidogrel, 1.84 (1.51-2.23) for aspirin plus vitamin K antagonist, 3.52 (2.42-5.11) for clopidogrel plus vitamin K antagonist, and 4.05 (3.08-5.33) for triple therapy. Numbers needed to harm were 81.2 for aspirin plus clopidogrel, 45.4 for aspirin plus vitamin K antagonist, 15.2 for clopidogrel plus vitamin K antagonist, and 12.5 for triple therapy. <br /> A total of 702 (37.9%) of 1,852 patients with non-fatal bleeding had recurrent myocardial infarction or died during the study period compared with 7,178 (18.4%) of 38,960 patients without non-fatal bleeding (HR 3.00, 2.75-3.27, p&lt;0.0001). <br /> Treatment with triple therapy or dual therapy with clopidogrel plus vitamin K antagonist should be prescribed only after thorough individual risk assessment. <br />

2 acc prevention antiplatelet and anticoagulant 2 acc prevention antiplatelet and anticoagulant Presentation Transcript

  • The Evidence for Current Cardiovascular Disease Prevention Guidelines: Antiplatelet and American College of Cardiology Anticoagulation Subcommittee Best Practice Quality Initiative Therapy and Prevention Guidelines Evidence and Committee
  • Classification of Recommendations and Levels of Evidence *Data available from clinical trials or registries about the usefulness/efficacy in different subpopulations, such as gender, age, history of diabetes, history of prior myocardial infarction, history of heart failure, and prior aspirin use. A recommendation with Level of Evidence B or C does not imply that the recommendation is weak. Many important clinical questions addressed in the guidelines do not lend themselves to clinical trials. Even though randomized trials are not available, there may be a very clear clinical consensus that a particular test or therapy is useful or effective. †In 2003, the ACC/AHA Task Force on Practice Guidelines developed a list of suggested phrases to use when writing recommendations. All guideline recommendations have been written in full sentences that express a complete thought, such that a recommendation, even if separated and presented apart from the rest of the document (including headings above sets of recommendations), would still convey the full intent of the recommendation. It is hoped that this will increase readers’ comprehension of the guidelines and will allow queries at the individual recommendation level.
  • Icons Representing the Classification and Evidence Levels for Recommendations I IIa IIb III I IIa IIb III I IIa IIb III I IIa IIb III I IIa IIb III I IIa IIb III I IIa IIb III I IIa IIb III I IIa IIb III I IIa IIb III I IIa IIb III I IIa IIb III
  • Evidence for Current Cardiovascular Disease Prevention Guidelines Antiplatelet Therapy Evidence and Guidelines
  • Antiplatelet Therapy: Targets Clopidogrel bisulfate Ticlopidine hydrochloride Prasugrel hydrochloride Ticagrelor Dipyridamole Phosphodiesterase ADP ADP Gp 2b/3a Inhibitors Activation COX Collagen Thrombin TXA2 TXA2 Aspirin ADP=Adenosine diphosphate, COX=Cyclooxygenase, TXA2=Thromboxane A2 Source: Schafer AI. Antiplatelet Therapy. Am J Med 1996;101:199–209
  • Antiplatelet Therapy: Common Oral Agents Acetylsalicylic acid (ASA) Ticlopidine hydrochloride Clopidogrel bisulfate Prasugrel hydrochloride Ticagrelor Trade Name Aspirin1-3 Ticlid®4 Plavix®5 Effient®6 Brilinta®7 Class Salicylate P2Y12 Receptor P2Y12 Receptor P2Y12 Receptor P2Y12 Receptor Antagonist Antagonist Antagonist Antagonist Formulation Active Drug Active Drug Pro-Drug Pro-Drug Active Drug Maintenance Dose 75-325 mg daily* 250 mg BID 75 mg daily 10 mg daily 90 mg BID No No No No Yes Reversible *81 mg is the low dose aspirin option in the United States Sources: Pearson TA, et al. Circulation, 2002;106:388-391 2 Mosca L, et al. Circulation, 2007;115:1481-1501 3 Smith SC Jr. et al. JACC 2011;58:2432-2446 1 4http://www.accessdata.fda.gov/drugsatfda_docs/nda/2001/19-979S018_Ticlid_prntlbl.pdf 5http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020839s042lbl.pdf 6http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022307s001lbl.pdf http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Cardiova scularandRenalDrugsAdvisoryCommittee/UCM221383.pdf 7
  • Aspirin: Mechanism of Action Membrane Phospholipids Arachadonic Acid COX-1 Aspirin Prostaglandin H2 Thromboxane A2 ↑ Platelet Aggregation Vasoconstriction Prostacyclin ↓ Platelet Aggregation Vasodilation
  • Aspirin Evidence: Primary Prevention Physician’s Health Study (PHS) 22,071 male participants randomized to aspirin (325 mg every other day) followed for an average of 5 years Aspirin reduces the risk of myocardial Infarction among men CI=Confidence interval, CV=Cardiovascular Source: Steering Committee of the Physicians’ Health Study Research Group. NEJM 1989;321:129-135
  • Aspirin Evidence: Primary Prevention Womens’ Health Study (WHS) 39,876 women randomized to aspirin (100 mg every other day) or placebo for an average of 10 years Aspirin does not reduce cardiovascular events among women Source: Ridker P et al. NEJM 2005;352:1293-1304
  • Aspirin Evidence: Primary Prevention BDT, 1988 RR of MI in Men PHS, 1989 RR of CVA in Men TPT, 1998 HOT, 1998 PPP, 2001 RR = 0.68 (0.54-0.86) P=0.001 Combined 0.2 0.5 1.0 5.0 2.0 RR = 1.13 (0.961.33) P=0.15 0.2 0.5 1.0 2.0 RR of MI in Women HOT, 1998 5.0 RR of CVA in Women PPP, 2001 WHS, 2005 RR = 0.99 (0.83-1.19) P=0.95 Combined 0.2 0.5 Aspirin Better 1.0 2.0 Placebo Better 5.0 RR = 0.81 (0.69-0.96) P=0.01 0.2 0.5 Aspirin Better 1.0 2.0 5.0 Placebo Better CVA=Cerebrovascular accident, MI=Myocardial infarction, RR=Relative risk Source: Ridker P et al. NEJM 2005;352:1293-1304
  • Aspirin Evidence: Primary Prevention Sex-specific meta-analysis of 51,342 women and 44,114 men randomized to aspirin (doses ranging between 100 mg every other day to 500 mg daily) vs. placebo for 3.7-10 years Odds ratio * * p<0.05 Aspirin reduces the risk of stroke in women and MI in men AC=All cause, CV=Cardiovascular, MCE=Major cardiovascular events, MI=Myocardial infarction Source: Berger JS et al. JAMA. 2006;295:306-313
  • Aspirin Evidence: Primary Prevention Prevention of Progression of Arterial Disease and Diabetes (POPADAD) Study P=0.86 30 20 18.2 18.3 10 0 Aspirin No Aspirin Death from CHD or stroke (%) Composite primary end point* (%) 1,276 asymptomatic patients with DM and an ABI <0.99 randomized in a 2 x 2 design to aspirin (100 mg), antioxidants, aspirin plus antioxidants, or placebo 15 10 P=0.36 6.7 5.5 5 0 Aspirin No Aspirin Aspirin does not reduce the risk of adverse CV events in diabetics *Includes fatal CHD or stroke, non-fatal MI or stroke, or amputation above the ankle for critical limb ischemia ABI=Ankle brachial index, CHD=Coronary heart disease, CV=Cardiovascular, DM=Diabetes mellitus, MI=Myocardial infarction Source: Belch J et al. BMJ. 2008;337:a1840
  • Aspirin Evidence: Primary Prevention Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes (JPAD) Study Atherosclerotic Event (%) 2,539 diabetic patients without known coronary artery disease randomized to aspirin (81-100 mg) or placebo for a median of 4.7 years 9 Non-aspirin Group 6 Aspirin Group 3 HR (95% CI): 0.80 (0.58–1.10), P=0.16 0 0 1 2 Years 3 4 5 Aspirin does not reduce the risk of adverse CV events in diabetics CI=Confidence interval, CV=Cardiovascular, HR=Hazard ratio Source: Ogawa H et al. JAMA 2008;300:2134-2141
  • Aspirin Evidence: Primary Prevention Aspirin for Asymptomatic Atherosclerosis Trial Events/1000 patient-years 3,350 patients with an ABI <0.95 but no known cardiovascular disease randomized to aspirin (100 mg) or placebo for 8.2 years * * * ** Aspirin does not reduce the risk of CV events in those with an ABI <0.95 *Not statistically significant **Composite of initial fatal or nonfatal coronary event or stroke or revascularization ABI=Ankle brachial index, CV=Cardiovascular Source: Fowkes FGR et al. JAMA 2010;303:841-848
  • Aspirin Evidence: Primary Prevention Antithrombotic Trialists’ (ATT) Collaboration Rate Ratios for Vascular Events Non-fatal MI P-value P<0.0001 Any stroke P=0.40 Vascular Mortality P=0.70 Major extracranial bleed P<0.0001 Serious Vascular Events P=0.0001 0 0.5 1.0 1.5 2.0 Antiplatelet Better Antiplatelet Worse Aspirin reduces the risk of MI and vascular events at the expense of bleeding Source: Antithrombotic Trialists’ Collaboration. Lancet 2009;373:1849-1860
  • Aspirin Evidence: Primary Prevention Antithrombotic Trialists’ (ATT) Collaboration Meta-analysis of 95,456 low risk patients randomized to aspirin (100 mg every other day to 500 mg daily) vs. placebo for 3.7-10 years Major coronary event Non-fatal MI CHD mortality Stroke Hemorrhagic Ischemic Unknown cause Vascular death Any serious vascular event Major extracranial bleed Number of Events (Aspirin vs. Control) 934 vs. 1115 596 vs. 756 372 vs. 393 655 vs 682 116 vs. 89 317 vs. 367 222 vs. 226 619 vs. 637 1671 vs. 1883 335 vs. 219 Rate ratio (95% CI) (Aspirin vs. Control) 0.82 (0.75-0.90) 0.77 (0.69-0.86) 0.95 (0.82-1.10) 0.95 (0.85-1.06) 1.32 (1.00-1.75) 0.86 (0.74-1.00) 0.97 (0.80-1.18) 0.97 (0.87-1.09) 0.88 (0.82-0.94) 1.54 (1.30-1.82) Aspirin reduces the risk of ischemic events, but with a higher rate of bleeding Source: Antithrombotic Trialists’ Collaboration. Lancet 2009;373:1849-1860
  • Aspirin Evidence: Secondary Prevention Effect of antiplatelet treatment* on vascular events** Category Acute MI Acute CVA Prior MI Prior CVA/TIA Other high risk CVD (e.g. unstable angina, heart failure) PAD (e.g. intermittent claudication) High risk of embolism (e.g. Afib) Other (e.g. DM) All trials % Odds Reduction 2.0 0.0 0.5 1.0 1.5 Antiplatelet better Control better Aspirin reduces the risk of adverse cardiovascular events *Aspirin was the predominant antiplatelet agent studied **Include MI, stroke, or death Source: Antithrombotic Trialists’ Collaboration. BMJ 2002;324:71–86
  • Aspirin Evidence: Dose and Efficacy Effect of aspirin doses on vascular events in high-risk patients (excluding those with acute stroke) Aspirin Dose No. of Trials % Odds Reduction 500-1500 mg 34 19 160-325 mg 19 26 75-150 mg 12 32 <75 mg 3 13 65 23 Odds Ratio for Vascular Events Any aspirin P<0.0001 0 0.5 1.0 1.5 2.0 Antiplatelet Better Antiplatelet Worse High dose aspirin does not provide improved efficacy Source: Antithrombotic Trialists’ Collaboration. BMJ 2002;324:71-86
  • Aspirin Evidence: Dose and Efficacy Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent Events (CURRENT)-OASIS 7 Trial 0.04 0.0 0.01 0.02 0.0 3 Death, MI, or Stroke (%) 25,087 patients with an ACS randomized in a 2 x 2 factorial trial to double dose clopidogrel (600 mg LD, 150 mg x 7 days, then 75 mg MD) vs. standard dose clopidogrel (300 mg LD and 75 mg MD) and high dose aspirin (300-325 mg) vs. low dose aspirin (75-100 mg) 0 Aspirin 81-100 mg Aspirin 300-325 mg HR=0.97, P=0.61 3 6 9 12 15 Days 18 21 24 27 30 Higher dose aspirin does not provide benefit in ACS ACS=Acute coronary syndrome, MI=Myocardial infarction, LD=Loading dose, MD=Maintenance dose Source: CURRENT-OASIS 7 Investigators. NEJM 2010;363:930-942
  • Aspirin Recommendations I IIa IIb III Primary Prevention Aspirin (81 mg daily or 100 mg every other day) in at risk women >65 years of age I IIa IIb III Aspirin in at risk women <65 years of age for ischemic stroke prevention I IIa IIb III Aspirin in optimal risk women <65 years of age Source: Mosca L et al. Circulation 2007;115:1481-1501
  • Aspirin Recommendations (Continued) I IIa IIb III Primary Prevention Aspirin (75-162 mg daily) in [men]* at intermediate risk (10-year risk of CHD >10%) *Specific guideline recommendations for men do not exist, but these guidelines are based on previous general (not gender specific) primary prevention guidelines CHD=Coronary heart disease Source: Pearson TA et al. Circulation 2002;106:388-391
  • ADA/AHA/ACCF Primary Prevention of CV Disease Antiplatelet Agent Recommendations Primary Prevention I IIa IIb III Low-dose aspirin therapy (75-162 mg/day) is reasonable for adults with DM and no previous history of vascular disease who are at increased CVD risk (10-year risk >10%) and who are not at increased risk for bleeding (based on a history of previous GI bleeding or peptic ulcer disease or concurrent use of other medications that increase bleeding risk such as NSAIDs or warfarin). Those adults with DM at increased CVD risk include most men >50 years of age or women >60 years of age who have at least one additional major risk factor.*† ADA Level C Includes those with family history of premature CVD, hypertension, smoking, dyslipidemia, or albuminuria * † ACCF=American College of Cardiology Foundation, ADA=American Diabetes Association, AHA=American Heart Association, CV=Cardiovascular, CVD=Cardiovascular disease, DM=Diabetes mellitus, GI=Gastrointestinal, NSAIDs=Non-steroidal anti-inflammatory drugs Source: Pignone M et al. Circulation 2010;121:2694-2701
  • ADA/AHA/ACCF Primary Prevention of CV Disease Antiplatelet Agent Recommendations Primary Prevention (Continued) I IIa IIb III I IIa IIb III Aspirin should not be recommended for CV prevention for adults with DM at low CVD risk (men <50 years of age and women <60 years of age with no major additional CVD risk factors* [10-year risk <5%], as the potential adverse effects from bleeding offset the potential benefits.† Low-dose aspirin (75-162 mg/day) may be considered for those with DM at intermediate CVD risk (younger patients with >1 risk factors* or older patients with no risk factors*, or patients with a 10-year risk of 5-10% until further research is available.‡ *Includes those with family history of premature CVD, hypertension, smoking, dyslipidemia, or albuminuria † ADA Level C, ‡ADA Level E ACCF=American College of Cardiology Foundation, ADA=American Diabetes Association, AHA=American Heart Association, CV=Cardiovascular, CVD=Cardiovascular disease, DM=Diabetes mellitus Source: Pignone M et al. Circulation 2010;121:2694-2701
  • Aspirin Recommendations (Continued) I IIa IIb III Secondary Prevention Aspirin (75-162 mg daily) if known CAD† or NSTE-ACS‡ I IIa IIb III Aspirin (81-325 mg daily) following PCI or fibrinolytic therapy for a STEMI* I IIa IIb III Aspirin (preferentially at 81 mg daily) following PCI for a NSTE-ACS# or a STEMI* or fibrinolytic therapy for a STEMI* NSTEASVD=Atherosclerotic vascular disease, CAD=Coronary artery disease, ACS=Non-ST segment elevation acute coronary syndrome, PCI=Percutaneous coronary intervention, STEMI=ST-segment elevation myocardial infarction Sources: Smith SC Jr. et al. JACC 2011;58:2432-2446 ‡ Wright RS et al. JACC 2011;57:e215-367 * O’Gara PT et al. JACC 2013;61:e78-e140 # Jneid H et al. JACC 2012;60:645-681 †
  • Aspirin Recommendations (Continued) Secondary Prevention I IIa IIb III I IIa IIb III Aspirin (162-325 mg daily) for at least 1 month after bare metal stent implantation (Class I, Level B), at least 3 months after sirolimus-eluting stent implantation (Class I, Level B), and at least 6 months after paclitaxeleluting stent implantation (Class I, Level B) after which aspirin (75-162 mg daily) should be continued indefinitely (Class I, Level A for a bare metal stent and Class I, Level B for a drug eluting stent) I IIa IIb III Aspirin (75-162 mg daily) as the initial dose after stent implantation in those at higher bleeding risk Source: King SB 3rd et al. JACC 2008;51:172-209
  • Aspirin Recommendations (Continued) I IIa IIb III Secondary Prevention Aspirin (100-325 mg daily) following CABG surgery* *To be initiated within 6 hours of surgery CABG=Coronary artery bypass graft Source: Hillis LD et al. JACC 2011;58:e123-210
  • P2Y 12 Receptor Antagonist: Mechanism of Action ADP / ATP P2Y12 Receptor Antagonist P2X1 P2Y1 P2Y12 Gq coupled Cation influx Ca2+ No effect on fibrinogen receptor Calcium mobilization Ca2+ Gi2 coupled cAMP Platelet shape change Transient aggregation Fibrinogen receptor activation Thromboxane A2 generation Sustained Aggregation Response Sources: Savi P et al. Biochem Biophys Res Commun 2001; 283:379–383 Ferguson JJ. The Physiology of Normal Platelet Function. In: Ferguson JJ, Chronos N, Harrington RA (Eds). Antiplatelet Therapy in Clinical Practice. London: Martin Dunitz; 2000: pp.15–35
  • Clopidogrel Evidence: Secondary Prevention Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) Trial Cumulative risk* (%) 19,185 patients with ischemic CVA, MI, or PAD randomized to daily aspirin (325 mg) or clopidogrel (75 mg) for 2 years Aspirin 6 Clopidogrel 3 8.7% RRR, p=0.043 0 0 3 6 9 12 15 18 21 24 Months of follow-up 27 30 33 36 Clopidogrel provides slightly greater risk reduction than aspirin *Composite of myocardial infarction, ischemic stroke, or vascular death CVA=Cerebrovascular accident, MI=Myocardial infarction, PAD=Peripheral arterial disease Source: CAPRIE Steering Committee. Lancet 1996;348:1329-1339
  • Clopidogrel Evidence: Secondary Prevention Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) Trial Rate of CV death, myocardial infarction, or stroke 12,562 patients with a NSTE-ACS randomized to daily aspirin (75-325 mg) or clopidogrel (300 mg load, 75 mg thereafter) plus aspirin (75-325 mg) for 9 months Aspirin + Placebo Aspirin + Clopidogrel P<0.001 0 3 6 9 12 Months of Follow Up Dual antiplatelet therapy is more efficacious in a NSTE-ACS NSTE-ACS=Non ST-segment elevation acute coronary syndrome Source: Adapted from Figure 1 in The CURE Trial Investigators. NEJM 2001;345:494-502
  • Clopidogrel Evidence: Secondary Prevention Clopidogrel for the Reduction of Events during Observation (CREDO) Trial Risk of MI, stroke, or death (%) 2,116 patients undergoing PCI randomized to 4 weeks of DAP* followed by aspirin (75-325 mg) monotherapy vs. persistent DAP* for 1 year 15 4 weeks of DAP* 10 1 year of DAP* 5 27% RRR, P=0.02 00 3 6 Months from Randomization 9 12 DAP therapy produces greater benefit when used for 1 year *Dual antiplatelet therapy=Aspirin (75-325 mg daily) plus clopidogrel (300 mg load followed by 75 mg daily) DAP=Dual antiplatelet, PCI=Percutaneous coronary intervention, RRR=Relative risk reduction Source: Steinhubl S et al. JAMA 2002;288:2411-2420
  • Clopidogrel Evidence: Secondary Prevention Clopidogrel and Metoprolol in Myocardial Infarction Trial (COMMIT) 45,852 patients presenting within 24 hours of a STEMI treated medically and randomized to clopidogrel (75 mg daily) vs. placebo Death, MI, or Stroke, % 9 8 7 6 5 4 9% relative risk reduction (P=.002) 3 0 0 7 14 21 28 Days Since Randomization (up to 28 days) (8.1%) (7.5%) 8 In-Hospital Mortality, % (10.1%) (9.2%) 10 7 6 5 4 3 2 7% relative risk reduction (P=.03) 1 0 0 7 14 21 28 Days Since Randomization (up to 28 days) DAP therapy produces greater benefit in medically managed STEMI patients DAP=Dual antiplatelet, MI=Myocardial infarction, STEMI=ST-segment elevation myocardial infarction Source: COMMIT Collaborative Group. Lancet 2005;366:1607-1621
  • Clopidogrel Evidence: Secondary Prevention Clopidogrel as Adjunctive Reperfusion Therapy in Thrombolysis in Myocardial Infarction (CLARITY) Trial 3,491 patients (<75 years of age) presenting within 12 hours of a STEMI treated with fibrinolytic, aspirin, and heparin and randomized to clopidogrel (300 mg load followed by 75 mg daily) vs. placebo End Point (%)* 15 20% RRR 10 Aspirin + Clopidogrel Aspirin + Placebo 5 P=0.03 0 0 5 10 15 Days 20 25 30 DAP therapy benefits STEMI patients treated with fibrinolytic therapy *Composite of cardiovascular death, myocardial infarction, and need for urgent revascularization STEMI=ST-segment elevation myocardial infarction Source: Sabatine MS et al. NEJM 2005; 352:1179-1189
  • Clopidogrel Evidence: Secondary Prevention Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) Trial Incidence of CV death, MI, or CVA (%) 15,603 patients with multiple CV risk factors or known CVD randomized to aspirin (75-162 mg) or aspirin (75-162 mg) & clopidogrel (75 mg) for a mean of 30 months 8 Placebo 6 Clopidogrel 4 2 0 P = 0.22 0 6 12 Months 18 24 30 Routine DAP therapy offers little long-term benefit CV=Cardiovascular, CVA=Cerebrovascular accident, CVD=Cardiovascular disease, DAP=Dual antiplatelet, MI=Myocardial infarction Source: Adapted from Figure 4 in Bhatt DL et al. NEJM 2006;354:1706-1717
  • Clopidogrel Evidence: Secondary Prevention Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent Events (CURRENT)-OASIS 7 Trial Type of Bleeding 0.04 0.02 0 3 6 9 12 15 Days 18 21 24 27 30 1.7 1.3 2.5 2.0 Fatal HR 0.95, P=0.370 S (%) CURRENT Major* Clopidogrel Double D (%) TIMI Major Clopidogrel Standard 0.0 CV death, MI, or stroke 25,087 patients with an ACS randomized in a 2 x 2 factorial trial to double dose clopidogrel (600 mg LD, 150 mg x 7 days, then 75 mg MD) vs. standard dose clopidogrel (300 mg LD and 75 mg MD) and high dose aspirin (300-325 mg) vs. low dose aspirin (75-100 mg) 0.13 0.11 ICH 0.03 0.05 CABGrelated 1.0 0.9 High dose clopidogrel does not provide benefit in ACS *p=0.01 ACS=Acute coronary syndrome, CABG=Coronary artery bypass graft, ICH=Intracranial hemorrhage, LD=Loading dose, MD=Maintenance dose Source: CURRENT-OASIS 7 Investigators. NEJM 2010;363:930-942
  • Prasugrel Evidence: Secondary Prevention Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel (TRITON-TIMI 38) 13,608 patients with high-risk ACS scheduled for PCI randomized to clopidogrel (300 mg LD and 75 mg MD) or prasugrel (60 mg LD and 10 mg MD) for a median of 12 months CV death, MI, or stroke % 12.1 11 Clopidogrel 9.9 Bleeding Events C (%) P (%) P-value 1.8 2.4 .03 0.9 1.4 .01 0.9 1.1 .23 0.1 0.4 .002 0.3 0.3 .74 9 TIMI major Life threatening Nonfatal Fatal ICH Prasugrel 7 HR 0.77 HR 0.80 P=.001 P=.001 5 0 0 30 60 90 180 HR 0.81, P=0.0004 Days 270 360 450 Prasugrel reduces ischemic events with a higher rate of bleeding ACS=Acute coronary syndrome, ICH=Intracranial hemorrhage, LD=Loading dose, MD=Maintenance dose Source: Wiviott SD et al. NEJM 2007;357:2001-2015
  • Prasugrel Evidence: Secondary Prevention Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes (TRILOGY-ACS) CV Death, Nonfatal MI, and Nonfatal Stroke (%) 7243 patients with a medically managed NSTE-ACS randomized to prasugrel (10 mg) or clopidogrel for up to 30 months 20 16.0% Clopidogrel 10 13.9% Prasugrel HR=0.91, P=0.21 0 0 360 720 Time (Days) Prasugrel does not provide benefit in medically managed NSTE-ACS CV=Cardiovascular, MI=Myocardial infarction, NSTEACS=Non-ST-segment elevation acute coronary syndrome Source: Roe, MT et al. NEJM 2012;367:1297-1309
  • Ticagrelor Evidence: Secondary Prevention Platelet Inhibition and Patient Outcomes (PLATO) Study 18,624 patients with a moderate to high risk ACS randomized to clopidogrel (300-600 mg LD and 75 mg MD) or ticagrelor (180 mg LD and 90 mg twice daily MD) for 12 months CV Death, MI, or Stroke (%) 12 11.7 HR 0.84, p=0.001 9.8 Clopidogrel 10 8 Bleeding Events* C (%) T (%) TIMI major/year 7.9 7.7 PLATO major/year 11.6 11.2 Life threatening/year 5.8 5.8 Fatal/year 0.3 0.3 Ticagrelor 6 4 2 0 0 60 120 180 240 300 360 Days after randomization Ticagrelor reduces ischemic events with no higher rate of bleeding overall *No statistically significant differences were observed in bleeding rates overall ACS=Acute coronary syndrome, CV=Cardiovascular, LD=Loading dose, MD=Maintenance dose Source: Wallentin L et al. NEJM 2009;361:1045-1057
  • P2Y 12 Receptor Antagonist Recommendations Secondary Prevention I IIa IIb III I IIa IIb III I IIa IIb III Clopidogrel (75 mg daily; Class I, Level B), prasugrel* (10 mg daily; Class I, Level C), or ticagrelor (90 mg twice daily; Class I, Level C) if aspirin intolerance or a true aspirin allergy following a NSTE-ACS Clopidogrel (75 mg daily) or ticagrelor (90 mg twice daily) in addition to aspirin for up to 1 year following a NSTE-ACS managed conservatively *In PCI treated patients NSTE-ACS=Non ST-segment elevation acute coronary syndrome; PCI=Percutaneous coronary intervention, STEMI=ST-segment elevation myocardial infarction Source: Jneid H et al. JACC 2012;60:645-681
  • P2Y 12 Receptor Antagonist Recommendations Secondary Prevention I IIa IIb III Clopidogrel (75 mg daily), prasugrel (10 mg daily), or ticagrelor (90 mg twice daily) in addition to aspirin for 1 year following PCI for a NSTE-ACS† or a STEMI‡ I IIa IIb III I IIa IIb III Clopidogrel (75 mg daily) in addition to aspirin for a minimum of 14 days (Class I, Level A) and up to 1 year (Class I, Level C) following fibrinolytic therapy for a STEMI‡ NSTE-ACS=Non ST-segment elevation acute coronary syndrome; PCI=Percutaneous coronary intervention, STEMI=ST-segment elevation myocardial infarction Sources: Jneid H et al. JACC 2012;60:645-681 ‡ O’Gara PT et al. JACC 2013;61:e78-e140 †
  • P2Y 12 Receptor Antagonist Recommendations (Continued) Secondary Prevention I IIa IIb III I IIa IIb III If the risk of morbidity because of bleeding outweighs the anticipated benefit afforded by a P2Y12 receptor antagonist, earlier discontinuation should be considered Continuation of a P2Y12 receptor antagonist beyond 1 year may be considered in patients undergoing drug eluting stent placement Sources: Kushner F et al. JACC 2009;54:2205-2241 Jneid H et al. JACC 2012;60:645-681 O’Gara PT et al. JACC 2013;61:e78-e140
  • Evidence for Current Cardiovascular Disease Prevention Guidelines Anticoagulant Therapy Evidence and Guidelines
  • Warfarin: Mechanism of Action Vitamin K Antagonism of Vitamin K VII Synthesis of NonIX Functional X Coagulation Factors II Warfarin Source: Ansell J et al., Council on Clinical Cardiology. American Heart Association, Management of Oral Anticoagulant Therapy, www.americanheart.org/downloadable/heart/3491_Mgt.ppt
  • Warfarin Evidence: Primary Prevention Thrombosis Prevention Trial (TPT) 5,499 men at high risk for CHD randomized to aspirin (75 mg), warfarin (mean INR=1.5), warfarin and aspirin, or placebo for 6.4 years WA N=1277 W N=1268 A N=1268 P N=1272 MI and coronary death (primary end point) 71 (0.87%) 83 (1.03%) 83 (1.02%) 107 (1.33%) Stroke 29 (0.36%) 22 (0.27%) 18 (0.22%) 26 (0.32%) All cause mortality 103 (1.24%) 95 (1.14%) 113 (1.36%) 110 (13.1%) 34% (p=0.006) 21% (p=0.02) 20% (p=0.04) N/A RRR of ischemic heart disease events compared to placebo Warfarin provides similar efficacy to aspirin A=Aspirin, CHD=Coronary heart disease, P=Placebo, W=Warfarin, WA=Warfarin and aspirin Source: The Medical Research Council’s General Practice Research Framework. Lancet 1998;351:233-241
  • Warfarin Evidence: Secondary Prevention Meta-analysis of 31 trials comparing the effects of oral anticoagulation with and without aspirin on CV outcomes Events prevented per 1000 patients treated (95% CI) Major bleeds per 1000 patients treated (95% CI) High intensity OA control vs. 98 (73-123) 39 (35-43) Moderate intensity OA control vs. 24 (22-26) 35 (21-49) Moderate to high intensity OA and ASA vs. ASA 54 (43-65) 16 (10-22) Moderate to high intensity OA vs. ASA 13 (11-14) 14 (12-16) 7 (6-8) 5 (4-6) Low intensity OA and ASA ASA vs. Warfarin plus aspirin reduces the rate of adverse events with a higher rate of major bleeding ASA=Aspirin, CI=Confidence interval, CV=Cardiovascular, OA=Oral anticoagulation Source: Anand SS et al. JAMA 1999;282:2058-2067
  • Warfarin Evidence: Secondary Prevention Warfarin, Aspirin, or Both After Myocardial Infarction (WARIS II) Trial 3,630 patients following a myocardial infarction randomized to warfarin (INR 2.8-4.2), aspirin (160 mg daily) or warfarin (INR 2.0-2.5) plus aspirin (75 mg daily) for a mean of 4 years A (n) W (n) W+A (n) Cerebral 1 5 3 GI 6 18 21 Other 1 7 4 Total 8 33 28 Rate** * Type of Bleeding 0.62% 0.62% 0.17% Warfarin plus aspirin reduces the rate of adverse events with a higher rate of major bleeding *Composite of death, reinfarction, and stroke **p<0.001 A=Aspirin, W=Warfarin Source: Hurlen M et al. NEJM 2002;347:969-974
  • Warfarin Evidence: Secondary Prevention Clinical Trial Comparing Combined Warfarin and Aspirin With Aspirin Alone in Survivors of Acute Myocardial Infarction (CHAMP) 5059 patients within 14 days of a myocardial infarction randomized to aspirin (162 mg daily) or warfarin (INR 1.5-2.5) plus aspirin (81 mg daily) for 2.7 years W+A A W+A A W+A A W+A A Warfarin plus aspirin provides no greater benefit compared to treatment with aspirin alone A=Aspirin, CVD=Cardiovascular disease, INR=International normalized ratio, MI=Myocardial infarction, W=Warfarin Source: Fiore LD et al. Circulation 2002;105:557-563
  • Warfarin Evidence: Secondary Prevention Meta-analysis of 24,542 patients with recent MI comparing warfarin-containing regimens (OAC) with or without aspirin to non-warfarin-containing regimens with or without aspirin (No OAC) All-case Mortality Routine use of warfarin after MI does not reduce all-cause mortality CI=Confidence interval, MI=Myocardial infarction OAC=Oral anticoagulant Source: Figure 2 in Haq SA et al. Am J Med; 2010;123:250-258
  • Warfarin Evidence: Secondary Prevention Warfarin and Antiplatelet Therapy in Heart Failure (WATCH) Trial 1,587 patients with HF and LVSD (EF <0.35) randomized to aspirin (162 mg), clopidogrel (75 mg), or warfarin (mean INR=2.6) for 23 months Aspirin (n=523) Warfarin (n=540) Clopidogrel (n=524) Death, MI, or stroke (%) 20.5 19.8 21.8 HF hospitalizations (%) 22.2 16.1 18.3 19 30 13* Outcome Major bleeding (number of episodes) Clopidogrel and warfarin provide no greater benefit than aspirin in LVSD *p=0.012 vs warfarin EF=Ejection fraction, HF=Heart failure, LVSD=Left ventricular systolic dysfunction, MI=Myocardial infarction Source: Massie BM, et al. Circulation 2009;119:1616-1624
  • Warfarin Evidence: Secondary Prevention Meta-analysis of 61,905 patients with CV disease comparing treatment regimens with aspirin plus warfarin, aspirin plus clopidogrel, or aspirin alone * Odds Ratio** * * * * * * * A + W provide comparable benefit to A + C but with greater bleeding *p<0.05 **Include all-cause mortality, acute MI, thromboembolic stroke, major bleeds, and other types of stroke A=Aspirin, C=Clopidogrel, P=Placebo, W=Warfarin Source: Testa L et al. Am J Cardiol. 2007;99(12):1637-1642
  • Warfarin Evidence: Secondary Prevention Warfarin Versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) Trial 2305 patients with LV systolic dysfunction (mean LV EF of 25%) and sinus rhythm randomized to warfarin or aspirin Events*/100 PatientYears 10 7.47 7.93 Warfarin 5 0 Aspirin P=0.4 Warfarin provides no greater benefit than aspirin in LVSD *Composite of death, ischemic stroke, or intracerebral hemorrhage LVSD=Left ventricular systolic dysfunction Homma S et al. NEJM 2012;366:1859-1869
  • Triple Antithrombotic Therapy Evidence: Secondary Prevention Retrospective analysis of 40,812 patients admitted with a first myocardial infarction in a national registry in Denmark Triple antithrombotic therapy significantly increases the rate of bleeding Source: Sorensen R et al. Lancet 2009;374:1967-1974
  • Warfarin Evidence: Secondary Prevention What is the Optimal Antiplatelet and Anticoagulant Therapy in Patients with Oral Anticoagulation and Coronary Stenting (WOEST) Trial TIMI bleeding (%) 50% 40% Triple therapy Double therapy 44.9% 30% 19.5% 20% 10% Days 0% 0 3 6 9 1 0 0 0 2 0 1 8 0 2 7 0 3 6 5 Cumulative incidence of death, myocardial infarction, target vessel revascularizaton , stroke and stent trhombosis 573 patients undergoing PCI with an indication for oral anticoagulation randomized to double versus triple antithrombotic therapy* 20% Triple therapy Double therapy 17.7% 15% 11.3% 10% 5% Days 0% 0 3 6 9 1 0 0 0 2 0 1 8 0 2 7 0 3 6 5 Dual antithrombotic therapy significantly reduces CV risk and bleeding *Triple therapy=Aspirin (80 mg/day), clopidogrel, and OAC, Double therapy=Clopidogrel and OAC OAC=Oral anticoagulant Source: Presented at the Eurospean Society of Cardiology Congress, August 2012
  • Warfarin Recommendations Secondary Prevention I IIa IIb III I IIa IIb III Use of warfarin in conjunction with aspirin and/or a P2Y12 receptor antagonist is associated with an increased risk of bleeding, and patients and clinicians should watch for bleeding, especially GI, and seek medical evaluation for evidence of bleeding Warfarin either without (INR 2.5-3.5) or with low-dose aspirin (81 mg daily, INR 2.0-2.5) may be reasonable for patients at high CAD risk and low bleeding risk who do not require or are intolerant of a P2Y12 receptor antagonist CAD=Coronary artery disease, INR=International normalized ratio Source: Jneid H et al. JACC 2012;60:645-681
  • Warfarin Recommendations (Continued) Secondary Prevention I IIa IIb III I IIa IIb III The addition of warfarin (INR 2.0-3.0) may be reasonable for patients with a NSTE-ACS who have an indication for anticoagulation* Targeting oral anticoagulant therapy to a lower INR (2.0-2.5) might be reasonable in patients with a NSTE-ACS or STEMI managed with aspirin and a P2Y12 receptor antagonist *Indications for anticoagulation include: atrial fibrillation; left ventricular thrombus; or central, venous, or pulmonary emboli INR=International normalized ratio, NSTE-ACS=Non ST-segment elevation acute coronary syndrome, STEMI=ST-segment elevation myocardial infarction Sources: Jneid H et al. JACC 2012;60:645-681 O’Gara PT et al. JACC 2013;61:e78-e140
  • Warfarin Recommendations (Continued) Secondary Prevention I IIa IIb III Anticoagulation therapy with a Vitamin K antagonist should be provided to patients with STEMI and atrial fibrillation with CHADS2 score >2, mechanical heart valves, venous thromboembolism, or hypercoagulable disorder I IIa IIb III I IIa IIb III Anticoagulant therapy with a Vitamin K antagonist is reasonable for patients with STEMI and asymptomatic LV mural thrombi (Class IIa, Level C) and may be considered for patients with STEMI and anterior-apical akinesis or dyskinesis (Class IIb, Level C) LV=Left ventricular, STEMI=ST-segment elevation myocardial infarction Source: O’Gara PT et al. JACC 2013;61:e78-e140
  • Warfarin Recommendations (Continued) Secondary Prevention I IIa IIb III The duration of triple antithrombotic therapy with a Vitamin K antagonist, aspirin, and a P2Y12 receptor antagonist should be minimized to the extent possible to limit the risk of bleeding. Source: O’Gara PT et al. JACC 2013;61:e78-e140