Cardiovascular New Drug Update

Cardiovascular New Drug Update
C. Wayne Weart, Pharm D, FASHP, FAPhA, BCPS Professor of Clinical Pharmacy and Outcome Sciences South Carolina College of Pharmacy Professor of Family Medicine Medical University of South Carolina Charleston, South Carolina

Disclosure I am a consultant for Merck in the area of outcomes research. I served on a formulary advisory board for BMS and Pfizer for apixaban – Eliquis FDA approved on

FDA Safety Update on Statins
March 2, 2012 Monitoring Liver Enzymes Labels have been revised to remove the need for routine periodic monitoring of liver enzymes in patients taking statins. The labels now recommend that liver enzyme tests should be performed before starting statin therapy and as clinically indicated thereafter. FDA has concluded that serious liver injury with statins is rare.

March 2, 2012 Adverse Event Information: Rare post-marketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These reported symptoms are generally not serious and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).

March 2, 2012 Increases in glycosylated hemoglobin (HbA1c) and fasting plasma glucose FDA’s review of the results from the Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) reported a 27% increase in investigator-reported diabetes mellitus in rosuvastatin-treated patients compared to placebo-treated patients. High-dose atorvastatin had also been associated with worsening glycemic control in the Pravastatin or Atorvastatin Evaluation and Infection Therapy – Thrombolysis In Myocardial Infarction 22 (PROVE-IT TIMI 22) sub study. FDA also reviewed the published medical literature. A meta-analysis by Sattar et al. which included 13 statin trials with 91,140 participants, reported that statin therapy was associated with a 9% increased risk for incident diabetes (Absolute risk is about 1 in patients) FDA continues to believe that the cardiovascular benefits of statins outweigh these small increased risks. Cause and effect has not been established

Citalopram hydrobromide (Celexa) Safety Alert
August 24, 2011 FDA Drug Safety Communication: Abnormal heart rhythms associated with high doses of citalopram. Previously doses up to 60 mg per day were FDA approved but based upon new data and case reports of dose related QT interval prolongation, leading to an abnormal heart rhythm (including Torsade de Pointes), citalopram should no longer be used at doses greater than 40 mg per day.

Citalopram hydrobromide (Celexa) FDA Safety Alert
Patients at particular risk for developing prolongation of the QT interval include those with underlying heart conditions and those who are predisposed to low levels of potassium and magnesium in the blood. Studies have not shown a benefit in the treatment of depression at doses higher than 40 mg per day. Citalopram and sertraline are the recommended agents of choice for patients with depression and CVD according to the AHA/APA Circulation 2008;118:

Citalopram hydrobromide (Celexa) FDA Safety Alert
Additional Recommendations: Citalopram is not recommended for use in patients with congenital long QT syndrome, bradycardia, hypokalemia, or hypomagnesaemia, recent acute myocardial infarction, or uncompensated heart failure. Citalopram use is also not recommended in patients who are taking other drugs that prolong the QT interval. The maximum recommended dose of citalopram is 20 mg per day for patients with hepatic impairment, patients who are older than 60 years of age, patients who are CYP 2C19 poor metabolizers, or patients who are taking concomitant cimetidine (Tagamet) or another CYP2C19 inhibitor, because these factors lead to increased blood levels of citalopram, increasing the risk of QT interval prolongation and Torsade de Pointes.

FDA Statement regarding azithromycin (Zithromax) and the risk of cardiovascular death
A study published in the New England Journal of Medicine, on May 17, 2012, compared the risks of cardiovascular death in patients treated with azithromycin (Zithromax), amoxicillin, ciprofloxacin (Cipro), levofloxacin (Levaquin), and no antibacterial drug. The study reported a small increase in cardiovascular deaths, and in the risk of death from any cause, in persons treated with a 5-day course of azithromycin (Zithromax) compared to persons treated with amoxicillin, ciprofloxacin, or no drug. The risks of cardiovascular death associated with levofloxacin treatment were similar to those associated with azithromycin treatment The labels of all macrolides including azithromycin include a warning about prolongation of the QT interval. Prolongation of the QT interval can lead to torsades de pointes (TdP), an abnormal heart rhythm, which can be fatal. FDA will communicate any new information on azithromycin and this study or the potential risk of QT interval prolongation after the agency has completed its review.

Aliskiren (Tekturna) Safety Update
December 20, Novartis announced that following the seventh interim review of data from the ALTITUDE study with Rasilez®/Tekturna® (aliskiren), a decision to terminate the trial has been taken on the recommendation of the independent Data Monitoring Committee (DMC) overseeing the trial. The trial involved 8606 patients with type 2 diabetes and renal impairment who are at high risk of cardiovascular and renal events The DMC concluded that patients were unlikely to benefit from treatment added on top of standard anti-hypertensives (ACEI or ARB), and identified higher adverse events in patients receiving Rasilez/Tekturna in addition to standard of care in the trial. Specifically, in the trial arm in which Rasilez/Tekturna was added to the standard of care there was an increased incidence after months of non-fatal stroke, renal complications, hyperkalemia and hypotension in this high-risk study population.

Aliskiren (Tekturna) Safety Update Continued…
As a precautionary measure, Novartis will no longer promote Rasilez / Tekturna-based medicines for use in combination with a therapy in the ACE or ARB classes. Novartis is having discussions with the FDA about these findings and the FDA has not taken any specific action to date.

Aliskiren-containing Medications: Drug Safety Communication - New Warning and Contraindication
4/20/2012 RECOMMENDATION: Concomitant use of aliskiren with ARBs or ACEIs in patients with diabetes is contraindicated because of the risk of renal impairment, hypotension, and hyperkalemia. Avoid use of aliskiren with ARBs or ACEIs in patients with renal impairment where GFR < 60 mL/min. Patients should not stop taking aliskiren without talking to your healthcare professional. Stopping aliskiren suddenly can cause problems if your high blood pressure (hypertension) is not treated.

Generic Clopidogrel is here
FDA Approvals May 17, 2012 clopidogrel bisulfate Apotex Inc Aurobindo Pharma Ltd Dr Reddys Labs Ltd Gate Pharma Mylan Pharma Inc Roxane Sun Pharma Global Teva Torrent Pharma Ltd Brand Plavix $185.49/30 Generic wholesale cost $ $6.00/30 WAC as of 10/16/2012

Generic Atorvastatin– The price is falling!
May we now have 5 new manufacturers with FDA approval joining Dr Reddy’s and Watson with more to come: Apotex, Mylan, Ranbaxy, Sandoz, Teva Atorvastatin (Lipitor) Brand Generic 10mg % LDL $ $ 20mg % $ $6-7.66 40mg % $ $6-7.66 80mg % $ $6-7.66 Cost is per 30 day supply WAC

Dabigatran - Pradaxa A direct thrombin inhibitor indicated to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation 75 mg and 150 mg capsules BID $253.00/60 No need to monitor INR Not reversible with vitamin K or FFP (consider factor concentrates or dialysis)

Dabigatran- Pradaxa RE-LY (Randomized Evaluation of Long-term Anticoagulant Therapy), a randomized trial comparing two blinded doses of dabigatran (110 mg twice daily and 150 mg twice daily) with open-label warfarin (dosed to target INR of 2 to 3) in 18,113 patients with non-valvular, persistent, paroxysmal, or permanent atrial fibrillation and one or more of the following additional risk factors: (Mean CHADS2 Score 2.1) • Previous stroke, transient ischemic attack (TIA), or systemic embolism • Left ventricular ejection fraction <40% • Symptomatic heart failure, ≥ New York Heart Association Class 2 • Age ≥75 years • Age ≥65 years and one of the following: diabetes mellitus, coronary artery disease (CAD), or HBP The primary objective of this study was to determine if dabigatran was non-inferior to warfarin in reducing the occurrence of the composite endpoint, stroke (ischemic and hemorrhagic) and systemic embolism.

Table 1: Event rates by INR time in range vs dabigatran 110 BID
Dabigatran- Pradaxa Table 1: Event rates by INR time in range vs dabigatran 110 BID and 150 mg BID Event %/yr Warf n=6022 Warf Q 4 TTR < 53% Warf Q 1-2 TTR > 67% Dabig 110 n=6015 Dabig 150 n=6076 Stroke* + SEE 1.69 2.2 1.3 1.53 1.11** NNT 173 Maj Bld 3.36 4.6 2.7 2.71** 3.11 MI 0.53 Na 0.72 0.74** NNH 476 Comp. 7.64 11.9 5.3 7.09 6.91 *"Stroke" includes hemorrhagic stroke, **stat. sig. vs warfarin in original report. Comp = Stroke, systemic embolism, MI, PE, death, major bleeding. Warf 4th quartile = ITTR < 53.4%, 1st & 2nd quartile = ITTR > 67.1%. N Engl J Med 2009; 361:

Dabigatran- Pradaxa June 6, 2012 Pradaxa ® (dabigatran etexilate mesylate) capsules prescribing information has been updated to affirm that “PRADAXA 150mg twice daily was superior in reducing ischemic and hemorrhagic strokes relative to warfarin.” The update to the “Clinical Studies” section is based on the results of the pivotal RE-LY ® trial conducted in 18,000 patients with non-valvular atrial fibrillation (NVAF).

Dabigatran- Pradaxa Risk of extracranial and intracranial bleeding (% per year) by age End point Warfarin (%) Dabigatran 110 mg (%) Dabigatran 150 mg (%) P Extracranial bleeding (Mainly GI) Age <75 2.44 1.76 1.91 — Age >75 3.44 4.10 4.68 0.001 NNH 81 Intracranial bleeding 0.61 0.14 0.26 1.00 0.37 0.41 0.28 Circulation 2011;123:

Dabigatran- Pradaxa Compared to warfarin, both doses of dabigatran were associated with a significantly lower rate of haemorrhagic stroke, life-threatening bleeds, and intracranial haemorrhage (ICH) with and without haemorrhagic stroke; dabigatran 110 mg also showed a significant reduction in major bleeding compared to warfarin Warfarin has statistically significantly fewer GI bleeds compared to both doses of dabigatran, and significantly fewer major GI bleeds and life-threatening GI bleeds than dabigatran 150 mg

Dabigatran- Pradaxa The rates of adverse reactions leading to treatment discontinuation in RE-LY were 21% for dabigatran 150 mg and 16% for warfarin. The most frequent adverse reactions leading to discontinuation of dabigatran were bleeding and gastrointestinal events (i.e., dyspepsia, nausea, upper abdominal pain, gastrointestinal hemorrhage, and diarrhea). NNH 20 patients Drug Interactions The concomitant use of dabigatran with P-gp inducers (e.g., rifampin) reduces exposure to dabigatran and should generally be avoided P-gp inhibitors ketoconazole, verapamil, amiodarone, quinidine, and clarithromycin do not require dose adjustments

Dabigatran- Pradaxa ACCF/AHA/HRS 2011 Focused Update Recommendation Class I “Dabigatran is useful as an alternative to warfarin for the prevention of stroke and systemic thromboembolism in patients with paroxysmal to permanent AF and risk factors for stroke or systemic embolization who do not have a prosthetic heart valve or hemodynamically significant valve disease, severe renal failure (creatinine clearance <15 mL/min), or advanced liver disease.” (Level of Evidence: B) (Circulation. 2011;123:00-00 – on-line but in print )

AT-9 Chest Guidelines For patients with AF, including those with paroxysmal AF, who are at high risk of stroke (e.g., CHADS 2 score >/= 2), we recommend: oral anticoagulation rather than no therapy (Grade 1A) , aspirin (75 mg to 325 mg once daily) (Grade 1B) , or combination therapy with aspirin and clopidogrel (Grade 1B). we suggest dabigatran 150 mg twice daily rather than adjusted-dose VKA therapy (target INR range, ) (Grade 2B) Chest AT-9 (2/2012)

Dabigatran- Pradaxa AHA/ASA advisory on stroke prevention in atrial fibrillation (Stroke 2012; DOI: /STR.0b013e a. Available at: Warfarin, dabigatran, apixaban, and rivaroxaban are all indicated for the prevention of first and recurrent stroke in patients with non valvular AF. "The selection of an agent should be individualized on the basis of risk factors, cost, tolerability, patient preference, potential for drug interactions, and other clinical characteristics, including time in INR therapeutic range if the patient has been taking warfarin."

Dabigatran- Pradaxa AHA/ASA advisory on stroke prevention in atrial fibrillation (Stroke 2012) Dabigatran 150 mg twice daily is an "efficacious alternative" to warfarin for the prevention of first and recurrent stroke in patients with non valvular AF and at least one additional risk factor who have creatinine clearance (CrCl) >30 mL/min. Use of dabigatran 75 mg twice daily may be considered in patients with AF and at least one additional risk factor who have a low CrCl, in the range of 15 to 30 mL/min. Dabigatran is not recommended in patients with more severe renal failure (CrCl <15 mL/min).

Dabigatran- Pradaxa Converting from warfarin
When converting patients from warfarin therapy to dabigatran, discontinue warfarin and start dabigatran when the international normalized ratio (INR) is below 2.0. Converting from dabigatran to warfarin, adjust the starting time of warfarin based on creatinine clearance as follows: For CrCl >50 mL/min, start warfarin 3 days before discontinuing dabigatran. For CrCl mL/min, start warfarin 2 days before discontinuing dabigatran. For CrCl mL/min, start warfarin 1 day before discontinuing dabigatran.

Dabigatran- Pradaxa Management prior to surgery:
CrCl ≥ 50 mL/min: Discontinue dabigatran 1 to 2 days before procedure CrCl < 50 mL/min: Discontinue dabigatran 3 to 5 days before procedure. Major procedures, spinal puncture, spinal or epidural catheter placement may require discontinuation for a longer period of time.

Dabigatran- Pradaxa DOSING: Recommended Dose for patients with creatinine clearance (CrCl) >30 mL/min, the recommended dose of dabigatran is 150 mg taken orally, twice daily, with or without food. For patients with CrCl mL/min, or patients 75 years of age or older the recommended dose is 75 mg twice daily Instruct patients to swallow the capsules whole. Breaking, chewing, or emptying the contents of the capsule can result in increased exposure. Pradaxa capsules will hydrolyze over time when exposed to humidity, causing a breakdown of active ingredient, and rendering the medication less effective. Pradaxa is packaged in a 30-day supply bottle with a desiccant cap or in unit-of-use blister packaging to minimize product breakdown from moisture. (Use within 4 months of opening and keep in original container)

Don't use dabigatran off-label with mechanical valves
Primary-care practitioners may be putting the lives of patients with prosthetic heart valves at risk by switching their anticoagulation from warfarin to newer agents such as dabigatran (Pradaxa, Boehringer Ingelheim), say Canadian researchers. Dr Joel Price (University of Ottawa Heart Institute, ON) and colleagues report the cases of two women who had undergone valve replacement some years before and had been faring well on warfarin; they were switched to dabigatran and subsequently suffered valve thromboses. RE-ALIGN—a phase 2 dose-finding trial with dabigatran in patients with mechanical valves—is now under way, employing doses ranging from 150 to 330 mg twice daily, adjusted based on renal function and the results of the Hemoclot (Aniara, West Chester, OH) assay.

Rivaroxaban – Xarelto by Bayer HealthCare AG and Janssen Pharmaceuticals
Rivaroxaban exhibits a linear pharmacokinetic relationship with a rapid onset of action, resulting in maximal factor Xa inhibition in approximately 3 hours. Maintenance of the anti–factor Xa effect lasted 8 to 12 hours, depending on the dose of rivaroxaban. Terminal half-life of rivaroxaban is approximately 9 hours in adults and 12 hours in elderly patients (older than 65 years of age). Elimination of rivaroxaban occurs by multiple routes: renal (one-third is excreted unchanged), biliary/fecal, and hepatic (through CYP-450 3A4). Renal function impairment may influence elevated plasma concentrations and increased anti-Xa activity; therefore, dose adjustments may be required

Rivaroxaban - Xarelto July 5, 2011 The FDA approved rivaroxaban a factor Xa inhibitor indicated for the prophylaxis of deep vein thrombosis (DVT) which may lead to pulmonary embolism (PE) in patients undergoing knee or hip replacement. The recommended dose of is 10 mg taken orally once daily with or without food. The initial dose should be taken at least 6 to 10 hours after surgery once hemostasis has been established. For patients undergoing hip replacement surgery, treatment duration of 35 days is recommended. For patients undergoing knee replacement surgery, treatment duration of 12 days is recommended.

Dosage of Enoxaparin? Most of the trials (RECORD 1,2 and 3) used the European approved dose of enoxaparin 40 mg/d. Enoxaparin was usually started the evening before surgery and continued 6 to 8 h postoperatively. RECORD 4 used the US FDA approved dose of enoxaparin: 30 mg bid dosing rather than 40 mg once daily and started 12 h post operation.

Rivaroxaban - Xarelto RECORD 1 (Hip) R=1.1% vs. E=3.9%, RRR 71%, ARR 2.8%, NNT=36 RECORD 2 (Hip) R=2.0% vs. E=8.4%, RRR 76%, ARR 6.4%, NNT=16 RECORD 3 (Knee) R=9.7% vs. E=18.8%, RRR 48%, ARR 9.1%, NNT=11 RECORD 4 (Knee) US approved dosing R=6.9% vs. E=10.1%, RRR 31%, ARR 3.19%, NNT=32

AT-9 Chest Guidelines In patients undergoing THA or TKA, irrespective of the concomitant use of an IPCD or length of treatment, we suggest the use of LMWH in preference to the other agents we have recommended as alternatives: fondaparinux, apixaban, dabigatran, rivaroxaban, LDUH (all Grade 2B), adjusted-dose VKA, or aspirin (all Grade 2C). AT-9 Chest Guidelines

AT-9 Chest Guidelines “The best estimates suggest that five fewer symptomatic DVT per 1,000 achieved with rivaroxaban over LMWH will be offset by nine more major bleeding events. In summary, based on moderate-quality evidence, both the possibility of increased major bleeding events and the availability of long-term safety data for LMWH makes LMWH more appealing than rivaroxaban in spite of the inconvenience of subcutaneous administration.” AT-9 Chest Guidelines

AT-9 Chest Guidelines For patients undergoing major orthopedic surgery (THA, TKA, HFS) and receiving LMWH as thromboprophylaxis, we recommend starting either 12 h or more preoperatively or 12 h or more postoperatively rather than within 4 h or less preoperatively or 4 h or less postoperatively (Grade 1B). AT-9 Chest Guidelines

Rivaroxaban - Xarelto Avoid concomitant administration of rivaroxaban with combined P-gp and strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, lopinavir/ritonavir, ritonavir, indinavir/ritonavir, and conivaptan) which cause significant increases in rivaroxaban exposure that may increase bleeding risk. When clinical data suggest a change in exposure is unlikely to affect bleeding risk (e.g., clarithromycin, erythromycin), no precautions are necessary during co administration with drugs that are combined P-gp and CYP3A4 inhibitors.

Rivaroxaban - Xarelto Avoid the use of rivaroxaban in patients with severe renal impairment (CrCl <30 mL/min) Avoid the use of rivaroxaban in patients with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy. Overdose of rivaroxaban may lead to hemorrhage. A specific antidote of rivaroxaban is not available. Due to the high plasma protein binding, rivaroxaban is not expected to be dialyzable.

ROCKET-AF Trial The ROCKET AF study was a multicenter, double-blind, randomized trial of once-daily oral rivaroxaban 20 mg or 15 mg daily in patients with a creatinine clearance of 30 to 49 ml per minute) compared with dose-adjusted warfarin (INR 2-3) in moderate-to-high-risk patients with non valvular AF. The authors hypothesized that rivaroxaban is non inferior to warfarin at preventing the composite of stroke (ischemic and hemorrhagic) and systemic embolism. The 14,264 enrolled patients (median age, 73; 40% women) had a mean CHADS2 score of 3.5; about half had a CHADS2 score of 4. N Engl J Med 2011;365:

ROCKET-AF Trial Median follow-up was 707 days.
In the warfarin group, the overall mean proportion of time in therapeutic international normalized ratio range was 55%. -N Engl J Med 2011;365: On Sept 9, 2011 the FDA Cardiovascular and Renal Drugs Advisory Committee recommended approval of rivaroxaban for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (AF) by a 9-2 vote. The FDA had expressed concern over the low rate of desired INR’s)

ROCKET-AF Trial N Egl J Med 2011;365:883-91. Outcome Rivaroxaban
Warfarin (n=7090) Hazard ratio (95% CI) p Primary end point, non inferiority 1.71 2.16 0.79 ( ) NNT 222 <0.001 Primary end point, on treatment superiority 1.70 2.15 0.79 ( ) 0.015 intention-to-treat superiority 2.12 2.42 0.88 ( ) 0.117 Vascular death, stroke, embolism 3.11 3.63 0.86 ( ) NNT 193 0.034 Hemorrhagic stroke 0.26 0.44 0.59 ( ) NNT 556 0.024 Ischemic stroke 1.34 1.42 0.94 ( ) 0.581 Unknown stroke 0.06 0.10 0.65 ( ) 0.366

ROCKET-AF Trial N Engl J Med 2011;365:883-91. 14.91 14.52
Outcome Rivaroxaban (n=7081) Warfarin (n=7090) Hazard ratio (95% CI) p Major and non major bleeding 14.91 14.52 1.03 ( ) 0.442 Major bleeding 3.60 3.45 1.04 ( ) 0.576 >2 g/dL hemoglobin drop 2.77 2.26 1.22 ( ) NNH 197 0.019 Transfusion 1.65 1.32 1.25 ( ) NNH 304 0.044 Critical organ 0.82 1.18 0.69 ( ) NNT 278 0.007 Bleeding causing death 0.24 0.48 0.50 ( ) NNT 455 0.003 Intracranial hemorrhage 0.49 0.74 0.67 ( ) NNT 400

Rivaroxaban - Xarelto Nonvalvular Atrial Fibrillation:
For patients with CrCl >50 mL/min: 20 mg orally, once daily with the evening meal For patients with CrCl mL/min: 15 mg orally, once daily with the evening meal Avoid use in patients with CrCl <15 mL/min The absolute bioavailability of rivaroxaban at a dose of 20 mg in the fasted state is approximately 66%. Co administration of XARELTO with food increases the bioavailability of the 20 mg dose (mean AUC and Cmax increasing by 39% and 76% respectively with food). XARELTO 15 mg and 20 mg tablets should be taken with the evening meal

Rivaroxaban - Xarelto Box Warning: “Discontinuing XARELTO places patients at an increased risk of thrombotic events. An increased rate of stroke was observed following XARELTO discontinuation in clinical trials in atrial fibrillation patients. If anticoagulation with XARELTO must be discontinued for a reason other than pathological bleeding, consider administering another anticoagulant” Rocket AF did not have a protocol for what to do after the trial ended and the results were not good

Switching Anticoagulants?
Switching to XARELTO® from warfarin Discontinue warfarin and start XARELTO® as soon as the INR is below 3.0 to avoid periods of inadequate anticoagulation Switching from XARELTO® to warfarin No clinical trial data are available to guide converting patients from XARELTO® to warfarin. XARELTO® affects INR, so INR measurements made during co administration with warfarin may not be useful for determining the appropriate dose of warfarin. One approach is to discontinue XARELTO® and begin both a parenteral anticoagulant and warfarin at the time the next dose of XARELTO® would have been taken

Rivaroxaban - Xarelto Management prior to surgery
Discontinue rivaroxaban at least 24 hours before surgery.

Rivaroxaban for Atrial Fib and the Chest Guidelines
“Our guideline panel elected to make recommendations only for those drugs that have received regulatory approval for use in AF (i.e., dabigatran).” AT-9 Chest Guidelines

Canadian Cardiovascular Society Atrial Fibrillation Guidelines
We recommend that all patients with AF or AFL (paroxysmal, persistent, or permanent), should be stratified using a predictive index for stroke risk (e.g., CHADS2) and for the risk of bleeding (e.g., HAS-BLED), and that most patients should receive either an OAC or ASA (Strong Recommendation, High-Quality Evidence). We suggest, that when OAC therapy is indicated, most patients should receive dabigatran, rivaroxaban, or apixaban in preference to warfarin (Conditional Recommendation, High-Quality Evidence). Practical tip. Among patients > 75 years and certainly those > 80 years, dose reduction of the new OACs, especially dabigatran, should be considered. Canadian Journal of Cardiology 28 (2012) 125–136

For antithrombotic therapy of CKD patients, therapy should relate to eGFR as follows: eGFR > 30 mL per minute: We recommend that such patients receive antithrombotic therapy according to their CHADS2 score as detailed in recommendations for patients for patients with normal renal function (Strong Recommendation, High-Quality Evidence). eGFR mL per minute and not on dialysis: We suggest that such patients receive antithrombotic therapy according to their CHADS2 score as for patients with normal renal function. The preferred agent for these patients is warfarin (Conditional Recommendation, Low- Quality Evidence). -Canadian Journal of Cardiology 28 (2012) 125–136

Rivaroxaban - Xarelto AHA/ASA advisory on stroke prevention in atrial fibrillation (Stroke 2012; DOI: /STR.0b013e a. Available at: In patients with non valvular AF who are at moderate to high risk of stroke (prior history of transient ischemic attack [TIA], stroke, or systemic embolization or more than two additional risk factors), rivaroxaban 20 mg/day "is reasonable" as an alternative to warfarin. In patients with renal impairment and non valvular AF who are at moderate to high risk of stroke (prior history of TIA, stroke, or systemic embolization or more than two additional risk factors), with a CrCl of 15 to 50 mL/min, 15 mg of rivaroxaban daily may be considered, but its safety and efficacy have not been established. Rivaroxaban should not be used if the CrCl is <15 mL/min.

Rivaroxaban for Symptomatic Venous Thromboembolism: Einstein DVT
Open-label, randomized, event-driven, non inferiority study that compared oral rivaroxaban alone (15 mg twice daily for 3 weeks, followed by 20 mg once daily) with subcutaneous enoxaparin followed by a vitamin K antagonist (either warfarin or acenocoumarol) for 3 (12%), 6 (63%), or 12 (25%) months in patients with acute, symptomatic DVT. Patients randomized to VKA had an unadjusted mean percentage of time in the INR target range of 2.0 to 3.0 of 58% in EINSTEIN DVT study In parallel, we carried out a double-blind, randomized, event-driven superiority study that compared rivaroxaban alone (20 mg once daily) with placebo for an additional 6 or 12 months in patients who had completed 6 to 12 months of treatment for venous thromboembolism. N Engl J Med 2010;363:

* Intent to treat population
N Engl J Med 2010;363:

EINSTEIN DVT Trial Endpoint Xarelto N=1731 (%) Enox + Warf N=1718 (%)
HR (95% CI) Primary composite (DVT or nonfatal or fatal pulmonary embolism 36 (2.1%) 51 (3.0%) 0.68 ( ) Death (PE) 1 (<0.1%) 0 (0%) Death (PE can not be excluded) 3 (0.2%) 6 (0.3%) Symptomatic recurrent PE + DVT Symptomatic recurrent PE only 20 (1.2%) 18 (1.0%) Symptomatic recurrent DVT only 14 (0.8%) 28 (1.6%) Intent to treat population N Engl J Med 2010;363:

In parallel, we carried out a double-blind, randomized, event-driven superiority study that compared rivaroxaban alone (20 mg once daily) with placebo for an additional 6 or 12 months in patients who had completed 6 to 12 months of treatment for venous thromboembolism. In the continued-treatment study, which included 602 patients in the rivaroxaban group and 594 in the placebo group, rivaroxaban had superior efficacy (8 events [1.3%], vs. 42 with placebo [7.1%]; hazard ratio, 0.18; 95% CI, 0.09 to 0.39; P<0.001). N Engl J Med 2010;363:

The principal safety outcome was major bleeding or clinically relevant non major bleeding in the initial-treatment study The principal safety outcome occurred in 8.1% of the patients in each group. In the long term follow=up period, Four patients in the rivaroxaban group had nonfatal major bleeding (0.7%), versus none in the placebo group (P = 0.11). N Engl J Med 2010;363:

Rivaroxaban for the Treatment of Symptomatic Pulmonary Embolism
A randomized, open-label, event-driven, non inferiority trial involving 4832 patients who had acute symptomatic pulmonary embolism with or without deep-vein thrombosis, we compared rivaroxaban (15 mg twice daily for 3 weeks, followed by 20 mg once daily) with standard therapy with enoxaparin followed by an adjusted-dose vitamin K antagonist for 3 (5%), 6 (57%), or 12 (37%) months. Patients randomized to VKA had an unadjusted mean percentage of time in the INR target range of 2.0 to 3.0 of 60% in EINSTEIN PE study. N Engl J Med 2012; 366:

EINSTEIN PE Trial Endpoint Xarelto N=2419 (%) Enox + Warf N=2413 (%)
HR (95% CI) Primary composite endpoint 50 (2.1%) 44 (1.8%) 1.12 ( ) Death (PE) 3 (0.1%) 1 (<0.1%) Death (PE cannot be excluded) 8 (0.3%) 6 (0.2%) Symptomatic recurrent PE + DVT 0 (0%) 2 (<0.1%) Symptomatic recurrent PE only 23 (1.0%) 20 (0.8%) Symptomatic recurrent DVT only 18 (0.7%) 17 (0.7%) Intent to treat population N Engl J Med 2012; 366:

N Engl J Med 2012; 366:

Rivaroxaban for the Treatment of Symptomatic Pulmonary Embolism
The principal safety outcome occurred in 10.3% of patients in the rivaroxaban group and 11.4% of those in the standard therapy group (hazard ratio, 0.90; 95% CI, 0.76 to 1.07; P = 0.23). Major bleeding was observed in 26 patients (1.1%) in the rivaroxaban group and 52 patients (2.2%) in the standard-therapy group (hazard ratio, 0.49; 95% CI, 0.31 to 0.79; P = 0.003). Rates of other adverse events were similar in the two groups. N Engl J Med 2012; 366:

Rivaroxaban - Xarelto Nov 2, 2012 FDA approval for treatment of DVT and PE based upon EINSTIEN Trials non-inferior to warfarin (INR 2-3) and no difference in bleeding rates Treatment of DVT, PE, and Reduction in the Risk of Recurrence of DVT and of PE: 15 mg orally twice daily with food for the first 21 days for the initial treatment of acute DVT or PE. After the initial treatment period, 20 mg orally once daily with food for the remaining treatment and the long-term reduction in the risk of recurrence of DVT and of PE

Apixaban – Eliquis by BMS/Pfizer
Apixaban is a factor Xa inhibitor anticoagulant indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. 1-P priority FDA approval Available as a 2.5 and 5 mg tablet The recommended dose is 5 mg orally twice daily. In patients with at least 2 of the following characteristics: age > 80 years, body weight <60 kg, or serum creatinine >1.5 mg/dL, the recommended dose is 2.5 mg orally twice daily

Apixaban-Eliquis Apixaban is a direct-acting, reversible oral inhibitor of factor Xa, which is responsible for the conversion of prothrombin (factor II) to thrombin (factor IIa), ultimately leading to thrombus formation and clotting High affinity and high degree of selectivity for factor Xa Produces concentration-dependent anticoagulation No formation of reactive intermediates No organ toxicity or LFT abnormalities in chronic toxicology studies Low likelihood of drug interactions or QTc prolongation Good oral bioavailability No food effect Balanced elimination (~25% renal) Apixaban produces several metabolites via CYP3A4-dependent mechanisms. O-demethyl apixaban sulfate, a nonreactive metabolite, is the primary metabolite produced; therefore, the potential for apixaban to form reactive metabolites is expected to be minimal Half-life ~12 hrs

Apixaban – Eliquis Apixaban should be discontinued at least 48 hours prior to elective surgery or invasive procedures with a moderate or high risk of unacceptable or clinically significant bleeding. Apixaban should be discontinued at least 24 hours prior to elective surgery or invasive procedures with a low risk of bleeding or where the bleeding would be non-critical in location and easily controlled.

Apixaban - Eliquis Switching from warfarin to Apixaban: Warfarin should be discontinued and apixaban started when the international normalized ratio (INR) is below 2.0. Switching from Apixaban to warfarin: Apixaban affects INR, so that INR measurements during coadministration with warfarin may not be useful for determining the appropriate dose of warfarin. If continuous anticoagulation is necessary, discontinue apixaban and begin both a parenteral anticoagulant and warfarin at the time the next dose of apixaban would have been taken, discontinuing the parenteral anticoagulant when INR reaches an acceptable range.

Apixaban-Eliquis Box Warning:”DISCONTINUING ELIQUIS IN PATIENTS WITHOUT ADEQUATE CONTINUOUS ANTICOAGULATION INCREASES RISK OF STROKE” Drug Interactions Strong dual inhibitors of CYP3A4 and P-gp increase blood levels of apixaban: Reduce apixaban dose to 2.5 mg or avoid concomitant use Simultaneous use of strong inducers of CYP3A4 and P-gp reduces blood levels of apixaban: Avoid concomitant use

Apixaban - Eliquis In healthy subjects, administration of activated charcoal 2 and 6 hours after ingestion of a 20-mg dose of apixaban reduced mean apixaban AUC by 50% and 27%, respectively. Mean apparent half-life of apixaban decreased from 13.4 hours when apixaban was administered alone to 5.3 hours and 4.9 hours, respectively, when activated charcoal was administered 2 and 6 hours after apixaban, indicating that charcoal blocked the continued absorption of apixaban from the gut

AVERROES Trial 5599 patients with atrial fibrillation who were at increased risk for stroke and for whom vitamin K antagonist therapy was unsuitable to receive apixaban (at a dose of 5 mg twice daily) or aspirin (81 to 324 mg per day), to determine whether apixaban was superior. The trial was stopped early with a mean follow up period of 1.1 years. because of a clear benefit in favor of apixaban. The primary outcome was the occurrence of stroke or systemic embolism. N Engl J Med 2011;364:

AVERROES: Primary and secondary end points
Outcomes Apixaban (n=2809) Aspirin (n=2791) Relative risk (95% CI) Stroke or systemic embolic event 1.6 3.6 0.46 (0.33–0.64) ARR 2.0/NNT 50 Stroke, embolic event, MI, or vascular death 4.1 6.2 0.66 (0.53–0.83) ARR 2.1/NNT 48 MI 0.7 0.8 0.85 (0.48–1.50) Vascular death 2.5 2.9 0.86 (0.64–1.16) Cardiovascular hospitalizations 11.8 14.9 0.79 (0.68–0.91) ARR 3.1/NNT 33 Total death 3.4 4.4 0.79 (0.62–1.02) Connolly S. European Society of Cardiology 2010 Congress; August 31, 2010; Stockholm, Sweden.

AVERROES: Bleeding events
Outcomes Apixaban (n=2809) Aspirin (n=2791) Relative risk (95% CI) Major bleeding 1.4 1.2 1.14 (0.74–1.75) Clinical relevant nonmajor bleeding 3.0 2.6 1.18 (0.88–1.58) Minor bleeding 5.2 4.1 1.27 (1.01–1.61) Fatal bleeding 0.1 0.84 (0.26–2.75) Intracranial 0.4 0.3 1.09 (0.50–2.39) Connolly S. European Society of Cardiology 2010 Congress; August 31, 2010; Stockholm, Sweden.

Atrial Fibrillation with at Least One Additional Risk Factor for Stroke
Inclusion risk factors Age ≥ 75 years Prior stroke, TIA or SE HF or LVEF ≤ 40% Diabetes mellitus Hypertension Mean CHADS 2 Score 2.1 Randomize double blind, double dummy (n = 18,201) Exclusion Mechanical prosthetic valve Severe renal insufficiency Need for aspirin plus thienopyridine Apixaban 5 mg oral twice daily (2.5 mg BID in selected patients IE. ≥ 80 years, body weight ≤ 60 kg, serum creatinine ≥ 1.5 mg/dL ) Warfarin (target INR 2-3) Warfarin/warfarin placebo adjusted by INR/sham INR based on encrypted point-of-care testing device Primary outcome: stroke or systemic embolism Hierarchical testing: non-inferiority for primary outcome, superiority for primary outcome, major bleeding, death N Engl J Med 2011;365:

Apixaban and Warfarin Dosing
Apixaban (or matching placebo) was dosed at 5 mg twice daily, or 2.5 mg twice daily for a subset of patients with 2 or more of the following criteria: age ≥ 80 years, body weight ≤ 60 kg, serum creatinine ≥ 1.5 mg/dL (133 µmol/L). Warfarin (or matching placebo) was dosed guided by blinded encrypted INR point-of-care device, with target INR of 2.0–3.0. N Engl J Med 2011;365:981-92

ARISTOTLE Main Trial Results (Mean 1.8 yrs)
Stroke or systemic embolism ISTH major bleeding International Society of Thrombosis and Hemostasis 21% RRR 31% RRR Apixaban 212 patients, 1.27% per year Warfarin 265 patients, 1.60% per year HR 0.79 (95% CI, 0.66–0.95); P=0.011 ARR 0.33% NNT 303 Apixaban 327 patients, 2.13% per year Warfarin 462 patients, 3.09% per year HR 0.69 (95% CI, 0.60–0.80); P<0.001 ARR 0.96% NNT 105 Median TTR 66% N Engl J Med 2011;365:

Reduces stroke and systemic embolism by 21% (p=0.01) ARR 0.33%/NNT 303
Summary Treatment with apixaban as compared to warfarin in patients with AF and at least one additional risk factor for stroke: Reduces stroke and systemic embolism by 21% (p=0.01) ARR 0.33%/NNT 303 Reduces major bleeding by 31% (p<0.001) ARR 0.96%/NNT 105 Reduces mortality by 11% (p=0.047) ARR 0.42%/NNT 238 with consistent effects across all major subgroups and with fewer study drug discontinuations on apixaban than on warfarin, consistent with good tolerability. N Engl J Med 2011;365:981-92

Apixaban-Eliquis . Available at: AHA/ASA advisory on stroke prevention in atrial fibrillation (Stroke 2012; DOI: /STR.0b013e a Apixaban 5 mg twice daily is an "efficacious alternative" to aspirin in patients with nonvalvular AF deemed unsuitable for vitamin-K-antagonist therapy who have at least one additional risk factor and no more than one of the following characteristics: age >80 years, weight <60 kg, or serum creatinine >1.5 mg/dL. Apixaban 2.5 mg twice daily may be considered as an alternative to aspirin in patients with nonvalvular AF deemed unsuitable for vitamin-K-antagonist therapy who have at least one additional risk factor and more than two of the following criteria: age >80 years, weight <60 kg, or serum creatinine >1.5 mg/dL.

Is the patient a good candidate for a new anticoagulant? (CRABI)
C => Good prescription coverage? R => Normal renal function? A => Are you an early adopter willing to take a new drug with one large trial in AF? B => No history of GI bleeding? I => For patients on warfarin, has there been INR instability requiring frequent dose changes? Seth D Bilazarian MD, Private practice blog on theheart.org (9/2012)

Ticagrelor – Brilinta by Astra Zeneca
Indicated to reduce the rate of thrombotic cardiovascular events in patients with acute coronary syndrome (ACS) (unstable angina, non-ST elevation myocardial infarction, or ST elevation myocardial infarction). Shown to reduce the rate of a combined endpoint of cardiovascular death, myocardial infarction, or stroke compared to clopidogrel. The difference between treatments was driven by CV death and MI with no difference in stroke. In patients treated with PCI, it also reduces the rate of stent thrombosis.

Ticagrelor – Brilinta by Astra Zeneca
90 mg tablets Loading dose 180 mg, then 90 mg BID $ per month WAC

Ticagrelor - Brilinta Ticagrelor and its major metabolite reversibly interact with the platelet P2Y12 ADP-receptor to prevent signal transduction and platelet activation. Ticagrelor and its active metabolite are approximately equipotent. Transitioning from clopidogrel to ticagrelor resulted in an absolute inhibition of platelet inhibition (IPA) increase of 26.4% and from ticagrelor to clopidogrel resulted in an absolute IPA decrease of 24.5%. Patients can be transitioned from clopidogrel to ticagrelor without interruption of antiplatelet effect.

Mean inhibition of platelet aggregation (±SE) following single oral doses of placebo, 180 mg ticagrelor, or 600 mg clopidogrel

Ticagrelor - Brilinta Effects of Other Drugs on Ticagrelor
CYP3A4 is the major enzyme responsible for ticagrelor metabolism and the formation of its major active metabolite. Strong CYP3A inhibitors (e.g., atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin and voriconazole) substantially increase ticagrelor exposure and are not recommended Moderate CYP3A inhibitors have lesser effects (e.g., diltiazem and verapamil) and do not require a dosage adjustment CYP3A inducers (e.g., rifampin, dexamethasone, phenytoin, carbamazepine, and phenobarbital) substantially reduce ticagrelor blood levels and are not recommended

Ticagrelor - Brilinta Effects of Ticagrelor on Other Medications:
Patients receiving more than 40 mg per day of simvastatin or lovastatin may be at increased risk of statin-related adverse effects. Monitor digoxin levels with initiation of or any change in ticagrelor because of P-glycoprotein transporter inhibition Concomitant Aspirin Maintenance Dose: In PLATO, use of ticagrelor with maintenance doses of aspirin above 100 mg decreased the effectiveness of ticagrelor. Therefore, after the initial loading dose of aspirin (usually 325 mg), use ticagrelor with a maintenance dose of aspirin of mg

Ticagrelor – Brilinta N Engl J Med 2009;361:1045-57
PLATO Trial, a randomized double-blind study comparing ticagrelor (180 mg LD then 90 mg BID)(N=9333) to clopidogrel (300mg LD then 75 mg QD) (N=9291), both given in combination with aspirin ( mg QD but higher doses were allowed per investigator) and other standard therapy, in patients with acute coronary syndromes (ACS). Patients were treated for at least 6 months and for up to 12 months. Patients were predominantly male (72%) and Caucasian (92%). About 43% of patients were >65 years and 15% were >75 years. Primary endpoint was the composite of first occurrence of cardiovascular death, non-fatal MI (excluding silent MI), or non-fatal stroke. The components were assessed as secondary endpoints Median exposure to study drug was 277 days

Endpoint Ticagrelor N=9333 Clopidogrel N=9291 Hazard Ratio (95% CI) P-value ARR/NNT Primary Composite (CV death, MI, CVA) 9.8% 11.7% 0.84 ( ) 0.0003 1.9%/53 Secondary Endpoints CV death 4.0% 5.1% 0.79 ( ) 0.0013 1.1%/91 MI 5.8% 6.9% ( ) 0.0045 Stroke 1.5% 1.3% 1.17 ( ) 0.22 All cause mortality 4.5% 5.9% 0.78 ( ) 1.4%/72 In-stent thrombosis (11,289 pts with PCI/stenting) 1.9% 0.67 ( ) 0.0091 0.6%/167

Ticagrelor – Brilinta N Engl J Med 2009;361:1045-57.
No significant difference in the rates of major bleeding was found between the ticagrelor and clopidogrel groups (11.6% and 11.2%, respectively; P = 0.43) 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, ARI = 0.7%, NNH = 143) including more instances of fatal intracranial bleeding and fewer of fatal bleeding of other types. In a genetic sub study of PLATO (n=10,285), the effects of ticagrelor compared to clopidogrel on thrombotic events and bleeding were not significantly affected by CYP2C19 genotype.

PLATO: CV Death, MI, Stroke by maintenance aspirin dose in the US and outside the US

PLATO Trial: ticagrelor compared with clopidogrel and who underwent CABG
In a sub-group of 1,261 patients with CABG performed within 7 days after stopping study drug, reviewers blinded to treatment assignment classified causes of death. Numerically more vascular deaths occurred in the clopidogrel versus the ticagrelor group related to myocardial infarction (14 vs. 10), heart failure (9 vs. 6), arrhythmia or sudden death (9 vs. 3), and bleeding, including hemorrhagic stroke (7 vs. 2). Clopidogrel was also associated with an excess of nonvascular deaths related to infection (8 vs. 2). Among factors directly causing or contributing to death, bleeding and infections were more common in the clopidogrel group compared with the ticagrelor group (infections: 16 vs. 6, p <0.05, and bleeding: 27 vs. 9, p <0.01, for clopidogrel and ticagrelor, respectively).

Ticagrelor – Brilinta Dyspnea was usually mild to moderate in intensity and often resolved during continued treatment. If a patient develops new, prolonged, or worsened dyspnea during treatment with ticagrelor, exclude underlying diseases that may require treatment. If dyspnea is determined to be related to ticagrelor, no specific treatment is required; continue ticagrelor without interruption. Although the mechanism of dyspnea remains unknown, it appears to be related to adenosine-mediated stimulation of pulmonary C fibers. We do know that ticagrelor inhibits adenosine uptake by erythrocytes. Given the frequency of dyspnea as a side effect, with reports ranging from 6% to 38.6%, it may affect long-term compliance if the agent is to be used routinely. For clinicians, it could be problematic during the recovery phase of ACS, because the presence of dyspnea could be confused with an angina equivalent, leading to further testing to exclude ischemia only to ascertain that it is produced by the administration of ticagrelor.

Ticagrelor – Brilinta Serum Uric Acid: Serum uric acid levels increased approximately 0.6 mg/dL from baseline on ticagrelor and approximately 0.2 mg/dL on clopidogrel in PLATO. The difference disappeared within 30 days of discontinuing treatment. Reports of gout did not differ between treatment groups in PLATO (0.6% in each group). Serum Creatinine: In PLATO, a >50% increase in serum creatinine levels was observed in 7.4% of patients receiving ticagrelor compared to 5.9% of patients receiving clopidogrel. The increases typically did not progress with ongoing treatment and often decreased with continued therapy.

Ticagrelor – Brilinta BOX WARNING: BLEEDING RISK
BRILINTA, like other antiplatelet agents, can cause significant, sometimes fatal, bleeding . Do not use BRILINTA in patients with active pathological bleeding or a history of intracranial hemorrhage. Do not start BRILINTA in patients planned to undergo urgent coronary artery bypass graft surgery (CABG). When possible, discontinue BRILINTA at least 5 days prior to any surgery. Suspect bleeding in any patient who is hypotensive and has recently undergone coronary angiography, percutaneous coronary intervention (PCI), CABG, or other surgical procedures in the setting of BRILINTA. If possible, manage bleeding without discontinuing BRILINTA. Stopping BRILINTA increases the risk of subsequent cardiovascular events. WARNING: ASPIRIN DOSE AND BRILINTA EFFECTIVENESS Maintenance doses of aspirin above 100 mg reduce the effectiveness of BRILINTA and should be avoided. After any initial dose, use with aspirin mg per day

Ticagrelor – Brilinta DOSAGE AND ADMINISTRATION:
Initiate ticagrelor treatment with a 180 mg (two 90 mg tablets) loading dose and continue treatment with 90 mg twice daily with or without food After the initial loading dose of aspirin (usually 325 mg), use ticagrelor with a daily maintenance dose of aspirin of mg (typically 81mg) COST: $7.24 per day or $ per month WAC

Switching from Clopidogrel?
According to the London New Drugs Group APC/DTC Briefing May 2011: Patients treated with clopidogrel can be directly switched to ticagrelor if needed

AT-9 Chest Guidelines For patients in the first year after an ACS who have not undergone percutaneous coronary intervention (PCI): We recommend dual antiplatelet therapy (ticagrelor 90 mg twice daily plus low-dose aspirin mg daily or clopidogrel 75 mg daily plus low-dose aspirin mg daily) over single antiplatelet therapy (Grade 1B). We suggest ticagrelor 90 mg daily plus low dose aspirin over clopidogrel 75 mg daily plus low-dose aspirin (Grade 2B) . Chest AT-9 Feb 2012

AT-9 Chest Guidelines For patients in the first year after an ACS who have undergone PCI with stent placement: We recommend dual antiplatelet therapy (ticagrelor 90 mg twice daily plus low-dose aspirin mg daily, clopidogrel 75 mg daily plus low-dose aspirin, or prasugrel 10 mg daily plus low-dose aspirin over single antiplatelet therapy) (Grade 1B). We suggest ticagrelor 90 mg twice daily plus low-dose aspirin over clopidogrel 75 mg daily plus low-dose aspirin (Grade 2B). Evidence suggests that prasugrel results in no benefit or net harm in patients with a body weight of , <60 kg, age . >75 years, or with a previous stroke/transient ischemic attack. Chest AT-9 Feb 2012

ADA 2012 Clinical Practice Recommendations (Diabetes Care 2012;35: S11-S63)
“Growing evidence suggests that there is an association between increase in sleep-time blood pressure and incidence of CVD events. A recent RCT of 448 participants with type 2 diabetes and hypertension demonstrated reduced cardiovascular events and mortality with median follow-up of 5.4 years if at least one antihypertensive medication was given at bedtime.” “Administer one or more antihypertensive medications at bedtime. (A)”

Influence of Time of Day of Blood Pressure–Lowering Treatment on Cardiovascular Risk in Hypertensive Patients with Type 2 Diabetes Diabetes Care 2011; 34: A prospective, randomized, single study center in Spain, open-label, blinded end point trial on 448 hypertensive patients with type 2 diabetes, 255 men/193 women, mean age 62.5 years, randomized to ingest all their prescribed hypertension medications upon awakening or 1 or more of them at bedtime. Ambulatory blood pressure was measured for 48 hrs at baseline and again annually or even more frequently (quarterly) after adjustments in treatment. The mean follow-up was 5.4 years. This was a subset of the original MAPEC Trial in 2156 hypertensive subjects from Spain (Chronobiology International 2010; 27(8): 1629–1651)

Influence of Time of Day of Blood Pressure–Lowering Treatment on Cardiovascular Risk in Hypertensive Patients with Type 2 Diabetes (Diabetes Care 2011; 34: ) Results: patients ingesting one or more hypertension medications at bedtime showed a significantly lower cardiovascular risk (adjusted by age and sex) than subjects ingesting all medications upon awakening (hazard ratio 0.33 [95% CI 0.21–0.54]; P , 0.001). The difference between groups in the adjusted risk of major events (cardiovascular death, myocardial infarction, and stroke) was also statistically significant (0.25 [0.10–0.61]; P = 0.003). There was a significant 12% cardiovascular risk reduction per each 5 mmHg decrease in asleep systolic blood pressure during follow-up (P , 0.001).

Dronedarone – Multaq by Sanofi Aventis
Indicated to reduce the risk of cardiovascular hospitalization in patients with paroxysmal or persistent atrial fibrillation (AF) or atrial flutter (AFL), with a recent episode of AF/AFL and associated cardiovascular risk factors. Dose 400 mg tablets BID with food $297.00/60

Dronedarone - Multaq ATHENA was a double blind, and randomized placebo-controlled study of dronedarone in 4628 patients with a recent history of AF/AFL who were in sinus rhythm or who were to be converted to sinus rhythm. The objective of the study was to determine whether dronedarone could delay death from any cause or hospitalization for cardiovascular reasons. Subjects were randomized and treated for up to 30 months (median follow-up: 22 months) with either MULTAQ 400 mg twice daily (2301 patients) or placebo (2327 patients), in addition to conventional therapy for cardiovascular diseases that included beta-blockers (71%), ACE inhibitors or angiotensin II receptor blockers (ARBs)(69%), digoxin (14%), calcium antagonists (14%), statins (39%), oral anticoagulants (60%), aspirin (44%), other chronic antiplatelet therapy (6%) and diuretics (54%).

Dronedarone - Multaq ATHENA Results:
Primary endpoint (median follow up 22 months) Cardiovascular hospitalization or death from any cause 913 (39.2%) placebo vs (31.6%) dronedarone HR 0.76 or 24% RRR, 7.6% ARR, NNT=14, p<0.0001 Components of the endpoint (as first event) Cardiovascular hospitalization 856 (36.8%) placebo vs. 669 (29.1%) dronedarone Death from any cause 57 (2.4%) placebo vs. 58 (2.5%) dronedarone

Dronedarone - Multaq ANDROMEDA Study (Increased Mortality in Patients with Severe Heart Failure) Patients recently hospitalized with symptomatic heart failure and severe left ventricular systolic dysfunction were randomized to either MULTAQ 400 mg twice daily or matching placebo, with a primary composite end point of all-cause mortality or hospitalization for heart failure. After enrollment of 627 of 1000 planned patients (310 and 317 in the dronedarone and placebo groups, respectively), and a median follow-up of 63 days, the trial was terminated because of excess mortality in the dronedarone group. Twenty-five (25) patients in the dronedarone group (8.1%) versus 12 patients in the placebo group (3.8%) had died, hazard ratio 2.13; 95% CI: 1.07 to 4.25; p= ARI 4.3%, NNH = 26.

Dronedarone - Multaq BOX WARNING: HEART FAILURE
MULTAQ is contraindicated in patients with NYHA Class IV heart failure, or NYHA Class II - III heart failure with a recent decompensation requiring hospitalization or referral to a specialized heart failure clinic Contraindications: Second- or third-degree atrioventricular (AV) block or sick sinus syndrome (except when used in conjunction with a functioning pacemaker) Bradycardia less than 50 bpm Concomitant use of strong CYP 3A inhibitors, such as ketoconazole, itraconazole, voriconazole, cyclosporine, telithromycin, clarithromycin, nefazodone, and ritonavir Concomitant use of drugs or herbal products that prolong the QT interval and might increase the risk of Torsade de Pointes, such as phenothiazine anti-psychotics, tricyclic antidepressants, certain oral macrolide antibiotics, and Class I and III antiarrhythmics

Dronedarone - Multaq DIONYSOS Trial evaluating the efficacy and safety of dronedarone versus amiodarone for the maintenance of sinus rhythm in 504 patients with persistent Atrial Fibrillation (AF) for a short treatment duration (mean follow up of 7 months). AF recurrence or premature drug discontinuation for intolerance or lack of efficacy). There were 184 patients (73.9%) who reached the primary endpoint in the dronedarone arm as compared to 141 (55.3%) in the amiodarone arm (p<0.001). In the primary endpoint, atrial fibrillation after electrical cardioversion occurred in 36.5% of patients in the dronedarone arm vs % of patients in the amiodarone arm. Less thyroid and neurological adverse effects with dronedarone but more diarrhea, nausea, and vomiting

Dronedarone - Multaq January 14, 2011 Multaq (dronedarone) – FDA Drug Safety Communication: Risk of Severe Liver Injury The FDA has received several case reports of hepatocellular liver injury and hepatic failure in patients treated with dronedarone, including two post-marketing reports of acute hepatic failure requiring transplantation. February 8, 2011 FDA Drug Watch List - Dronedarone hydrochloride (Multaq, Sanofi-Aventis) Drug interaction with warfarin (increased anticoagulant effect) Drug Interactions: Dronedarone is metabolized primarily by CYP 3A and is a moderate inhibitor of CYP 3A and CYP 2D6. Dronedarone's blood levels can therefore be affected by inhibitors and inducers of CYP 3A, and dronedarone can interact with drugs that are substrates of CYP 3A and CYP 2D6.

Dronedarone - Multaq Recommendation for Rate Control During Atrial Fibrillation 2011 Focused Update Recommendation Comments Class III–No Benefit Treatment to achieve strict rate control of heart rate (<80 bpm at rest or <110 bpm during a 6-minute walk) is not beneficial compared to achieving a resting heart rate <110 bpm in patients with persistent AF who have stable ventricular function (left ventricular ejection fraction <0.40) and no or acceptable symptoms related to the arrhythmia, though uncontrolled tachycardia may over time be associated with a reversible decline in ventricular performance.3 (Level of Evidence: B)- New recommendation (The RACE II study shows that lenient-rate control <110 bpm is not inferior to strict-rate control <80 bpm. As lenient-rate control is generally more convenient, requiring fewer outpatient visits and examinations, lenient-rate control may be adopted as a reasonable strategy in patients with permanent AF – (N Engl J Med. 2010;362:1363–73). 2011 ACCF/AHA/HRS Focused Update on the Management of Patients With Atrial Fibrillation (Updating the 2006 Guideline) Circulation. 2011;123:

Dronedarone - Multaq Recommendations for Use of Dronedarone in Atrial Fibrillation 2011 Focused Update Recommendations Comments Class IIA 1. Dronedarone is reasonable to decrease the need for hospitalization for cardiovascular events in patients with paroxysmal AF or after conversion of persistent AF. Dronedarone can be initiated during outpatient therapy. (Level of Evidence: B) – New recommendation Class III–Harm 2. Dronedarone should not be administered to patients with class IV heart failure or patients who have had an episode of decompensated heart failure in the past 4 weeks, especially if they have depressed left ventricular function (left ventricular ejection fraction <35%).30 (Level of Evidence: B)- New recommendation

Dronedarone - Multaq New Safety Concern July 7, 2011 Paris, France Sanofi, maker of dronedarone (Multaq), has suspended its phase 3b trial of its antiarrhythmic drug due to a significant increase in cardiovascular events seen in patients randomized to dronedarone. The PALLAS trial (begun ) was testing the drug in ~10,000 patients with permanent atrial fibrillation and at least one other cardiovascular disease risk factor; at present, dronedarone is approved in patients with nonpermanent AF.

Events during the PALLAS study as of June 30, 2011
Events during the PALLAS study as of June 30, (FDA MedWatch ) Multaq N=1572 n (%) Placebo N=1577 n (%) Hazard Ratio/NNH p-value CV Death, Myocardial Infarction, Stroke, Systemic Embolism* 32 (2) 14 (0.9) 2.3/91 0.009 Death, Unplanned CV Hospitalization* 118 (7.5) 81 (5.1) 1.5/42 0.006 Death 16 (1) 7 (0.4) 2.3 0.065 Myocardial Infarction 3 (0.2) 1.0 1 Stroke 17 (1.1) 2.4/143 0.047 Heart Failure Hospitalization 34 (2.2) 15 (1) 2.3/84 0.008 *co primary endpoints

FDA Drug Safety Communication: Multaq (dronedarone) and increased risk of death and serious cardiovascular adverse events Healthcare professionals should not prescribe Multaq to patients with AF who cannot or will not be converted into normal sinus rhythm (permanent AF), because Multaq doubles the rate of cardiovascular death, stroke, and heart failure in such patients. Healthcare professionals should monitor heart (cardiac) rhythm by electrocardiogram (ECG) at least once every 3 months. If the patient is in AF, Multaq should be stopped or, if clinically indicated, the patient should be cardioverted. Multaq is indicated to reduce hospitalization for AF in patients in sinus rhythm with a history of non-permanent AF (known as paroxysmal or persistent AF) Patients prescribed Multaq should receive appropriate antithrombotic therapy.

We recommend that dronedarone not be used in patients with permanent AF nor for the sole purpose of rate control(Strong Recommendation, High-Quality Evidence). We recommend dronedarone not be used in patients with a history of heart failure or a left ventricular ejection fraction < 0.40 (Strong Recommendation, Moderate- Quality Evidence). We suggest dronedarone be used with caution in patients taking digoxin (Conditional Recommendation, Moderate- Quality Evidence). Canadian Journal of Cardiology 28 (2012) 125–136

Azilsartan medoxomil - Edarbi by Takeda
Approved for the treatment of hypertension, alone or in combination with other antihypertensive agents. No outcome data A pro drug that is structurally related to candesartan. Azilsartan medoxomil is rapidly hydrolyzed to azilsartan in the GI tract. T ½ ~ 11 hours Cost $86.00 per 30 tablets drugstore.com Usual dose 80 mg QD with or without food

Azilsartan medoxomil - Edarbi

Azilsartan medoxomil/chlorthalidone - Edarbyclor
First ARB in combination with chlorthalidone (40 mg with either 12.5 or 25 mg of chlorthalidone) Change in systolic blood pressure: End point Azilsartan Chlorthalidone 40/25 (n=355) 80/25 (n=352) Olmesartan HCTZ 40/25 (n=364) P Clinic SBP (change from baseline, mm Hg) - 42.5 - 44.0 - 37.1 <0.001* Change in 24-h mean SBP (change from baseline, mm Hg) - 33.9 - 36.3 - 27.5 *p<0.001 for azilsartan/chlorthalidone 40/25 mg vs olmesartan/HCTZ and azilsartan/chlorthalidone 80/25 mg vs olmesartan/HCTZ Presented during American Society of Hypertension (ASH) 2011 Scientific Meeting 5/24/2011

Implementing NICE guidance
Hypertension Implementing NICE guidance ABOUT THIS PRESENTATION: This presentation has been written to help you raise awareness of the NICE clinical guideline on hypertension. This guideline has been written for healthcare professionals caring for adults with hypertension in secondary care (excluding emergency care) and community settings in which NHS care is received. The guideline is available in a number of formats, including a quick reference guide. You may want to hand out copies of the quick reference guide at your presentation so that your audience can refer to it. See the end of the presentation for ordering details. You can add your own organisation’s logo alongside the NICE logo. We have included notes for presenters, broken down into ‘key points to raise’, which you can highlight in your presentation, and ‘additional information’ that you may want to draw on, such as a rationale or an explanation of the evidence for a recommendation. Where necessary, the recommendation will be given in full. DISCLAIMER This slide set is an implementation tool and should be used alongside the published guidance. This information does not supersede or replace the guidance itself. PROMOTING EQUALITY Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. August 2011 NICE clinical guideline 127

Summary of antihypertensive drug treatment
Aged over 55 years or black person of African or Caribbean family origin of any age Aged under 55 years Summary of antihypertensive drug treatment A C1 Step 1 Key A – ACE inhibitor or low-cost angiotensin II receptor blocker (ARB) C – Calcium-channel blocker (CCB) D – Thiazide-like diuretic (chlorthalidone mg or indapamide 2.5 mg) A + C1 Step 2 A + C + D Step 3 NOTES FOR PRESENTERS. Key priority recommendations are identified with [KPI] in these notes. Step 3 treatment Before considering step 3 treatment, review medication to ensure step 2 treatment is at optimal or best tolerated doses. [new 2011] [1.6.16] If treatment with three drugs is required, the combination of ACE inhibitor (or angiotensin-II receptor blocker), calcium-channel blocker and thiazide-like diuretic should be used. [2006] [1.6.17] Step 4 treatment Regard clinic blood pressure that remains higher than 140/90 mmHg after treatment with the optimal or best tolerated doses of an ACE inhibitor or an ARB plus a CCB plus a diuretic as resistant hypertension, and consider adding a fourth antihypertensive drug and/or seeking expert advice. [new 2011] [1.6.18] For treatment of resistant hypertension at step 4: Consider further diuretic therapy with low-dose spironolactone4 (25 mg once daily) if the blood potassium level is 4.5 mmol/l or lower. Use particular caution in people with a reduced estimated glomerular filtration rate because they have an increased risk of hyperkalaemia. Consider higher-dose thiazide-like diuretic treatment if the blood potassium level is higher than 4.5 mmol/l. [new 2011] [1.6.19] [KPI] When using further diuretic therapy for resistant hypertension at step 4, monitor blood sodium and potassium and renal function within 1 month and repeat as required thereafter. [new 2011] [1.6.20] If further diuretic therapy for resistant hypertension at step 4 is not tolerated, or is contraindicated or ineffective, consider an alpha- or beta-blocker. [new 2011] [1.6.21] If blood pressure remains uncontrolled with the optimal or maximum tolerated doses of four drugs, seek expert advice if it has not yet been obtained. [new 2011] [1.6.22] Footnotes (1) Choose a low-cost ARB. (2) A CCB is preferred but consider a thiazide-like diuretic if a CCB is not tolerated or the person has oedema, evidence of heart failure or a high risk of heart failure. (3) Consider a low dose of spironolactone4 or higher doses of a thiazide-like diuretic. (4) At the time of publication (August 2011), spironolactone did not have a UK marketing authorisation for this indication. Informed consent should be obtained and documented. (5) Consider an alpha- or beta-blocker if further diuretic therapy is not tolerated, or is contraindicated or ineffective. Resistant hypertension A + C + D + consider further diuretic (low dose spironolactone 25 mg or alpha- or beta-blocker Consider seeking expert advice Step 4 (1) - A CCB is preferred but consider a thiazide-like diuretic if a CCB is not tolerated or the person has oedema, evidence of heart failure or a high risk of heart failure.

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