Larry Reis RPh CGP FASCP Prepared June 2014 for NADONA REIS RXCARE CONSULTING Reisrxcare@comcast.net 1 Program Objectives Discuss complications of current anticoagulant Rx Identify risks of using anticoagulants in the LTC Resident Discuss the goals of managing the resident requiring anticoagulation therapy Discuss how new anticoagulants should be administered and monitored in LTC Discuss the role of the IDT in using newer anticoagulants 2 Why Use Anticoagulants? The risk of stroke or systemic embolism is significant is certain clinical situations: Post surgical orthopedic w/o anticoagulant = 40 60% DVT. DVT may lead to PE (Pulmonary Embolism) 2,000,000 Americans have DVT annually and about 300,000 die from PE with most caused by DVT. More Americans die from DVT complications than from AIDS and breast cancer combined** All of us in LTC deal on a daily basis with the implications of stroke and embolism So the benefit of preventing stroke and embolism is clear and a definite goal is to: BENEFIT while minimizing the RISK **Gerotziafas Curr Opin Pulm Med 2004;10:356 365 3 1
With A. Fib Stroke Risk Increases Atrial Fibrillation chronic maintenance required Framingham study showed FIVE TIMES risk of stroke with atrial fibrillation verses none RATE OF STROKE with Atrial Fib untreated and concurrent: Prior CVA = 11.7% Diabetes = 8.6% Prior MI = 8.2% Heart Failure = 6.8% Hypertension = 5.6% Atrial Fibrilation Investigators Arch Intern Medicine 1994:154:1449 1457 4 Warfarin: The #1 Rx for Hospital Admission and Adverse Outcomes Important to know the MD goal for treatment. Generally is 2.0 to 3.0 for most diagnoses, including atrial fibrillation Lab Results: High PT is NOT a problem. If receiving effective anticoagulation the PT should be high. Focus on the INR results as your guide to proper range. Drug Interactions: Antibiotics are the #1 cause Warfarin is a VKA (Vitamin K Antagonist) Septra/Bactrim or Erythromycin Products are the worst but all antibiotics can influence 2
Case Study: Warfarin Diagnosis = atrial fibrillation Coumadin dose 5mg daily INR ordered monthly. 4/25 = 2.1 5/25 = 2.3 6/25 = 2.1 Antibiotic for UTI = Septra DS BID x 7 days 7/1 7/8 Lab is not normally drawn until 25 th of the month Pharmacy sends alert & suggests draw on 7/4 which actually gets pushed to 7/5 (holiday). INR = 4.4 MD orders hold Warfarin x 3 days then give 3mg daily No draw ordered until the scheduled draw on 7/25. What will the results be and where is the risk? Warfarin Case Study Slide 2 On 7/25 the INR was LOW = 1.4 This translates to higher risk as our target was 2.0 3.0 Why? the body has adapted back to baseline after antibiotic Key Points: Does your pharmacy have a system to notify you of drug interactions? Should also recommend INR check at 3 days into Rx and within 7 days post completion of antibiotic. A real positive would be to review original C/S & see if lower risk alternative to Septra existed **** If no options a dose reduction should be started Day 1. IF INR s still in range during Rx, then post Rx resume prior dose IF there is an interacting drug, or an abnormal INR then monthly INR is not enough, resume weekly until stable 9 3
Practical Risk Reduction with Warfarin Remember EVERY survey will now contain at least one warfarin resident *** DRUG INTERACTIONS Antibiotics most common 3 days post start of any antibiotic obtain INR Macrolide (azithromycin) and Sulfonamide (Bactrim/SXT) are the highest probability but potential is there DO NOT FORGET to evaluate and increase dose post antibiotic completion. Discuss the why behind this interaction NOTE: 6 of the top 10 drug interactions in long term care involve WARFARIN (ISMP) DOSE CHANGES: Whether up or down Obtain WEEKLY INR until stable in range 10 LAB RESULT COMMUNICATION Provide the drug, dose and frequency ON the lab slip If ALTRNATING DAY DOSING indicate what dose was given the day prior to the INR check REPORT ANY HELD or refused doses in the past 7 days MD may have held and ordered a repeat but may not remember this when you report a normal result after a 2 day hold and will continue same dose If you receive a new order for frequent lab monitoring, e.g. weekly make SURE the lab requisitions are complete, etc. to assure these will be done 11 Anticoagulant challenges UNDER TREATMENT: Increases the risk of clot and negative outcome OVER TREATMENT/DOSING: Increased bleed risk GI Bleed in general is more likely in newer anticoagulants than with warfarin Intracranial Hemorrhage (ICH) is more common with Warfarin than with the newer agents. TAKE your pick GI Bleed verses ICH = Benefit/Risk REMEMBER: Even with proper use and dose of ANY anticoagulant there is always a risk of bleed 12 4
Signs and Symptoms of Bleed Unusual bruising Unusual bleeding of gums Pink or brown urine Red or black tarry stools Coughing up blood Vomiting blood or coffee grounds emesis Protracted nose bleed Cuts that do not stop bleeding Unusual joint swelling 13 Warfarin Warfarin is the #1 medication causing emergency hospitalization. Over 33% of ER visits due to Rx are from Warfarin Four medication classes represent almost 70% of all medication related ER visits in the elderly Warfarin 33% Antiplatelet 13% (so bleeding events = 46%) Insulin 14% Oral Hypoglycemic 11% (so blood sugar risk 25%) Budnitz et al NEJM November 2011 Emergency Hospitilization for ADR in Older Americans 14 My resident had INR of 7 and was OK Could be but you were lucky What if had experienced a fall What if he/she was taking a GI irritant Rx such as a NSAID or Aspirin What if he or she had an accidental cut DO NOT TAKE ELEVATED INR FOR GRANTED 15 5
The Post Op Resident Highest risk are orthopedic: post hip or knee surgery During periods of reduced mobility the risk is highest Hint: Orders for LMWH (low molecular weight heparin) products such as Lovenox (enoxaparin), Arixtra, Fragmin should NOT be open ended for post surgical. For ACTIVE DVT or PE treatment duration is LONGER Once up and ambulatory and participating in therapy the risk of clot is greatly reduced. For PROPHYLAXIS there can be cost savings with dose management as well. Other than post knee 30mg BID Enoxaparin can be replaced with 40mg once daily 18 6
The Admit from Acute May Be High Risk for DVT/PE Risk of DVT is high for up to 2 weeks after surgery. Damage to vein can trigger Acute illness that will reduce mobility (which slows blood flow) also puts residents at increased risks: CHF Cancer Acute infection COPD Transition of Care: Make sure the acute has given you an order for DVT prophylaxis 19 PE Symptoms and Warnings Sharp chest pain on inhalation Unexplained cough perhaps with blood Shortness of breath Anxiety or nervousness Rapid pulse Very low blood pressure Sudden collapse Sweating THIS IS AN EMERGENCY SITUATION 21 7
Let s Talk About Rx: Heparins Heparin (UFH = unfractionated Heparin) Inhibits multiple points in the coagulations cascade Frequent lab monitors (aptt) May create heparin induced thrombocytopenia (reduced platelets) : May occur in up to 30% of patients. Platelets <100 = stop Has no impact on existing clots Low Molecular Weight Heparin (LMWH) such as Lovenox (Enoxaparin) Has more affinity for Xa than IIa Do not need lab monitoring With both may see increased liver enzymes 22 We Now Have Options to LMWH Initially only Xarelto had the indication to treat and prevent DVT/PE but as of March 2014 all three oral agents (Xarelto, Pradaxa, Eliquis) have some degree of indication. Pradaxa has a treatment limitation for active DVT PE that a parenteral anticoagulant must have been used first for 5 to 10 days For prophylaxis of DVT/PE Pradaxa is for patients who have been previously treated for such REALITY: Currently Xarelto is the oral agent of choice being prescribed as an alternative to Enoxaparin. 23 Duration of Treatment DVT Prevention Lovenox (Enoxaparin) Usual = 7 to 10 days with extended treatment if indicated for up to 3 weeks Oral agents (Dabigatran, Rivaroxaban, Apixaban) are slightly longer in duration: Recommended 10 to 14 days at minimum with extended treatment to 35 days (See specific product literature) 24 8
Rivaroxaban (Xarelto) vs. Lovenox (enoxaparin) Xarelto = oral while Lovenox = SQ administration Efficacy shows Xarelto superior to Lovenox in reducing incidence of any DVT, non fatal PE, and all cause mortality up to days 30 to 42 (RECORD Study) HIP Xarelto = 2% compared to Lovenox 9% Equivalent safety (major bleed) Xarelto 0.3% compared to Lovenox 0.2% RECORD study portion on knee surgery Efficacy (reduced DVT etc.): Xarelto = 9.6% incidence vs. Lovenox 19% Major bleed: Xarelto 0.6% vs. Lovenox 0.5% 25 Summary: Xarelto verses Lovenox Efficacy measure: incidence of DVT, PE, or death Xarelto = 2% Lovenox = 9.3% Safety Measure: Major Bleed Xarelto = 0.3% Lovenox = 0.2% Better efficacy against DVT verses Lovenox with similar safety profile Less impact on liver function or platelets than Lovenox. Duration of treatment may be slightly longer Oral verse subcutaneous is one advantage Data is from the RECORD Study 26 CONVERTING WARFARIN LMWH (e.g. Lovenox) to Warfarin Start warfarin and monitor until you get therapeutic INR (between 2.0 and 3.0) and then DC the Lovenox CONVERTING WARFARIN to Pradaxa (Dabigatran) or ELIQUIS (Apixaban) Due to rapid onset you should: Discontinue Warfarin When INR drops below 2.0 START Pradaxa or Eliquis WITH Xarelto the recommendation is start when below 3 This is official but for safety I would recommend to wait until below 2.5 27 9
Chronic Anticoagulant Use NEWER agents goal = equal or greater benefit in Atrial Fibrillation with reduced RISK PRADAXA (Dabigatran) FDA approved Oct 2010 NVAF and just approved for DVT/PE Prophylaxis XARELTO (Rivaroxaban) Approved July 2011 NVAF Prophylaxis or treatment of DVT and PE ELIQUIS (Apixaban) Approved December 2012 NVAF Prophylaxis of DVT which may cause PE in hip/knee ** New indication March 2014 28 Black Box Warnings With Warfarin: MAY CAUSE BLEEDING Can discuss legal actions and the concepts of benefit to risk With the newer three agents: May be increased risk of stroke and embolism if discontinued. And they do cause bleeding but this is not in the BBW. 29 30 10
Focus on Pradaxa (Dabigatran) Dosing Guidelines are simple: 150mg BID is standard Reduce to 75mg BID if Creatinine Clearance 30 to 50 If over 75 years of age there is an increased bleed risk so many will reduce to 75mg BID even with good RF ADMINISTRATION: A key factor is that it must be swallowed whole and should not be chewed, crushed or open capsules 31 Pradaxa Continued A Direct Thrombin Inhibitor (DTI) The ONLY oral agent with this mechanism so works further down the coagulation cascade so less influence by other medications. Thrombin Fibrinogen Fibrin 32 Pradaxa verses Warfarin PRADAXA WARFARIN MAJOR BLEED 3.30% 3.60% GI Bleed 1.60% 1.10% Total Bleed 16.60% 18.40% ICH 0.30% 0.80% Translation: Less major bleed but higher risk of GI bleeding but Significantly lower risk of ICH Study and FDA supported conclusions: more effective than Warfarin with A favorable risk profile 33 11
Focus on Xarelto (Rivaroxaban) Indications also include DVT PE Treatment & Prevention. Is a Factor Xa Inhibitor Dosing to prevent DVT in knee/hip surgery (ACCP) 10 to 15mg for minimum 10 14 days up to 35 days Dosing for treatment of DVT or PE 15mg BID x 21 days then to 20mg daily (with food) Dosing in atrial fibrillation 15mg once daily with the evening meal ADMINISTRATION: The 15 and 20mg can be crushed and mixed with applesauce or given via tube 34 Xarelto verses Warfarin XARELTO WARFARIN Major Bleed 5.60% 5.40% GI Bleed 3.10% 2% Fatal Bleed 0.40% 0.80% Translation: Similar in major bleed with significantly more GI bleed And yet significantly less fatal bleed (e.g. ICH) 35 Focus on Eliquis (Apixaban) Same as others: Non valvular Atrial Fibrillation (NVAF) Dosing = 5mg BID UNLESS Over 80 years of age AND have one of the following Weigh less than 60 kg Or have Cr >1.5 In this case dose is 2.5mg BID For prophylaxis post surgery dose is 2.5mg BID Hip = for 35 days and for Knee = 12 days ADMINISTRATION: May be crushed and mixed in 60ml of D5W and given via g tube. No study information on crushing and giving PO is available. 36 12
Eliquis verses Warfarin ELIQUIS WARFARIN Major Bleed 2.13% 3.09% Fatal Bleed 0.06% 0.24% ICH 0.33% 0.82% Hemr Stroke 0.24% 0.47% Translation: Has a significant safety profile verses Warfarin in Major bleed Including fatal bleed and ICH and reduce hemorrhagic stroke Data from the ARISTOTLE Study 37 Common Ground with Newer Rx NO Antidote exists With Warfarin (VKA) we can give Vitamin K Problem = we are often playing catch up yo yo No such antidote is currently available Only Pradaxa seems to be impacted by dialysis Some indications that perhaps PCC = Prothrombin Complex Concentrate may help. All have relatively short duration of effect Supportive care AND remember survivability and QOL are much better with a GI bleed than ICH 38 Common Ground with Newer Rx Even though we do not follow INR these ARE anticoagulants and do cause BLEED Should MONITOR CBC Hgb dropping = concern Watch for signs of bleeding or bruising as you would with Warfarin All should be stopped prior to elective surgical procedures and resumed afterwards once stable. 39 13
When do we drop Warfarin? A resident on maintenance Warfarin who has: good INR control no current ADR or bleed A stable medication regimen CAN certainly be continued HOWEVER with Warfarin: Slow onset of effect so adjustments may take time Susceptible to many drug interactions Individual genetic variability the same dose may have a remarkably different effect on 2 individuals with the same general age, weight, etc. 40 When do we drop Warfarin? If you have titrated dose up to 10mg + and still have low INR OR with doses in the 1mg range you at times have high INR = genetic impact. If you have to use frequent antibiotics such as in someone with recurrent UTI If on any of the many medications that interact with Warfarin and need adjustment, such as levothyroxine THEN One of the newer agents makes sense as an alternative choice 41 What About Combinations Aspirin, Plavix (Clopidogrel) may be used at times in combination with Warfarin or the newer agents. Risk of bleeding increases significantly as you combine one, and then two agents. APPRAISE 2 study of apixaban in residents treated with ASA or ASA and Clopidogrel was terminated early due to MUCH higher bleeding compared to placebo. Apixaban + 1 agent = 2.77% major bleed compared 0.62 Apixaban + 2 Rx = 5.90% major bleed vs. 2.5% with placebo A personal extrapolation: combinations are absolutely high risk with no EBM benefits noted and should not be used. 42 14
Quick Notes on Antiplatelet Rx Treatment goals to reduce recurrent MI, stroke Plavix (Clopidogrel) Interaction with PPI s primarily with Omeprazole Must be metabolized CYT P450 (CYP2C 19) Effient (prasugrel) is the new kid on the block: NOT indicated for 75 years+ unless very high risk such as history of MI Must swallow whole Higher risk in lower weight (below 60 kg) Aggrenox (ASA/Dipyridamole) does NOT have the same indications but is for stroke prevention with hx TIA or CVA and despite what Medicare D PDP may say is not a viable alternative. 43 Multiple IDT Members Critical Nursing: awareness of admitting diagnosis and review of orders Assessment of the resident Consultant Pharmacist Evaluates the appropriate Rx and Dose and Duration MD and Medical Director Director of Nurses : follow and screening of new admissions Patient/Family: awareness can help alert of any signs and symptoms of potential VTE 44 SUMMARY Prevention of DVT/PE and stroke has a major effect on mortality and quality of life for the high risk resident Oral options to LMWH exist for treatment and prevention of DVT New anticoagulants are available as options to Coumadin (Warfarin) that are: More effective in preventing stroke SAFER than warfarin BUT all are anticoagulants and RISK must be managed 45 15