Disclosure. Learning Objectives 1/17/2018. Pumping the Breaks in Pain Management: An Update on Cardiovascular Risk with NSAID Use

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1 Disclosure Pumping the Breaks in Pain Management: An Update on Cardiovascular Risk with Liz Van Dril, PharmD, BCPS PGY2 Ambulatory Care Resident January 17 th, 2018 Dr. Liz Van Dril has no actual or potential conflicts of interest in relation to this activity Learning Objectives 1. Explain the proposed mechanism for the increase in cardiovascular risk with NSAID use 2. Describe the historical context and findings of primary literature examining the cardiovascular risk associated with NSAID use Gastric mucosaderived COX 1 Prostaglandins E 2 &I 2 Mucus secre on Mucosal blood flow Mechanism: Why the Risk? Normal Physiologic Platelet derived COX 1 Thromboxane TxA 2 Platelet aggregation Vasoconstriction Vascular proliferation Arachidonic Acid Endotheliumderived COX 2 Prostacyclin PGI 2 Platelet aggregation Vasodilatation Vascular proliferation Tissue derived COX 2 Prostaglandins E 2 &I 2 Inflammation Pain Prothrombotic Antithrombotic N Engl J Med. 2004;351: Science. 2012;336: Mechanism: Why the Risk? NSAID induced CV Harm Mechanism: Why the Risk? Not Limited to COX 2 Selective Agents Platelet derived COX 1 Arachidonic Acid Endotheliumderived COX 2 All NSAIDs associated with COX 1 COX 2 imbalance Homeostatic mechanisms disrupted to varying degree with both selective and nonselective COX 2 inhibitors Thromboxane TxA 2 Prothrombotic Platelet aggregation Vasoconstriction Vascular proliferation COX 2 Selective Inhibition Prostacyclin PGI 2 Antithrombotic N Engl J Med. 2004;351: Science. 2012;336: COX 2 inhibition promotes sodium and water retention Blood pressure, a erload and adverse ventricular remodeling Exacerbates heart failure Risk for MI and stroke Inhibit cardioprotective effect of aspirin Antagonizes the irreversible platelet inhibition induced by aspirin Science. 2012;336: N Engl J Med. 1984;310: Arch Intern Med. 2002;162: Arch Intern Med. 2005;165: J Rheumatol. 2003;30: N Engl J Med. 2001;345: ICHP Champions LIVE Webinar 1

2 Timeline of NSAIDs and CV Risk Rofecoxib Withdrawal 2004 Rofecoxib Withdrawal FDA request to update product labeling 2005 APC and ADAPT Trials 2007 AHA Scientific ment 2016 PRECISION Trial FDA strengthens warning for risk of MI and stroke with NSAIDs 2017 BMJ Meta Analysis APPROVe Trial: Evaluated the efficacy of rofecoxib on the risk of recurrent neoplastic polyps in patients with a history of colorectal adenomas Composite of death from CV, hemorrhagic or unknown causes, nonfatal MI and stroke 2.7% for rofecoxib vs. 1.4% for placebo (HR 2.12 [95% CI, ]) Acute MI 1.7% for rofecoxib vs. 0.7% for placebo (HR 2.65 [95% CI, ]) FDA Safety Alert [9/30/2004]: Data safety and monitoring board recommended early discontinuation of APPROVe & Merck voluntarily withdraws rofecoxib N Engl J Med. 2005;352(11): Lancet. 2008;372(9651): Conflicting Evidence APC & ADAPT Adenoma Prevention with Celecoxib (APC) Trial Celecoxib (200 mg or 400 mg BID) vs. placebo for the prevention of colorectal adenomas Composite safety endpoint: CV death, nonfatal MI, nonfatal stroke or HF Risk with celecoxib 400 mg BID vs. placebo 3.4% vs. 1% (HR 3.4 [95 % CI, )] Safety steering committee stopped use of celecoxib in remaining patients Alzheimer's Disease Anti inflammatory Prevention Trial (ADAPT) Celecoxib (200 mg BID) or naproxen sodium (220 mg BID) vs. placebo for primary prevention of Alzheimer's dementia Steering committee suspended trial after CV risks observed in APC trial Composite safety endpoint: CV death, nonfatal MI, nonfatal stroke, HF or TIA Risk with naproxen vs. placebo, but no identified risk with celecoxib vs. placebo 8.25% vs. 5.68% (HR 1.63 [95% CI, ]) FDA Safety Alert [4/7/2005] Issued letters to all NSAIDs manufacturers requesting labeling revisions Contain a boxed warning that includes: Potential for increased risk of CV events Well described, serious, potential life threatening gastrointestinal (GI) bleeding N Engl J Med. 2005;352: PLoS Clin Trials. 2006;1(7): e33. Antman EM, Bennett JS, Daugherty A, et al. Use of nonsteroidal antiinflammatory drugs: an update for clinicians: a scientific statement from the American Heart Association. Circulation. 2007;115(12): AHA Scientific ment on the Use of NSAIDs Nonselective NSAIDs and CV Risk Versus Placebo or No Treatment Study Type Outcome RR 95% CI Naproxen Meta Analyses of RCTs Vascular events Meta Analyses of OSs CV events, mostly MI Ibuprofen Meta analysis of RCTs Vascular events Meta analysis of OSs CV events, mostly MI Registry Recurrent MI Registry Mortality Diclofenac Meta analysis of RCTs Vascular events Meta analysis of OSs CV events, mostly MI Registry Recurrent MI Registry Mortality Circulation. 2007;115(12): ICHP Champions LIVE Webinar 2

3 Nonselective NSAIDs and CV Risk Versus Selective COX 2 Inhibitor Study Type Outcome RR 95% CI Naproxen Meta Analyses of RCTs Vascular events Any non naproxen NSAID* Meta analysis of RCTs Vascular events *Primarily diclofenac or ibuprofen Circulation. 2007;115(12): AHA Scientific ment Stepped Care Approach to Pharmacologic Therapy for Musculoskeletal Symptoms with Known CVD or Risk Factors for Ischemic Heart Disease Acetaminophen, ASA, tramadol, narcotic analgesics Nonacetylated salicylates For select patients at low risk of thrombotic events Prescribe lowest dose required for symptom control Add ASA 81 mg daily and PPI to patients at increased risk of thrombotic events* Non COX 2 selective NSAIDs NSAIDs with some COX 2 activity COX 2 selective NSAIDs *Addition of ASA may not be sufficient protection against thrombotic events Regular monitoring for: Sustained HTN (or worsening of prior BP control) Edema Renal function Gastrointestinal bleeding Consider dose or discontinue offending if any of the above occur Adapted from: Circulation. 2007;115(12): Learning Assessment Which of the following statements is true regarding the proposed mechanism of cardiovascular harm observed with NSAID use? A. Inhibition of endothelium derived COX 2 results in unopposed increases in prostacyclin (PGI 2 ), which causes increased platelet aggregation and vasoconstriction B. Inhibition of COX 1 inhibits sodium and water retention which ultimately increases blood pressure, afterload and contributes to ventricular remodeling C. Inhibition of platelet derived COX 1 results in unopposed increases in thromboxane (TxA 2 ), which causes increased platelet aggregation and vasoconstriction D. Inhibition of COX 2 promotes sodium and water retention which ultimately increases blood pressure, afterload and contributes to ventricular remodeling More FDA Safety Alerts, the PRECISION Trial and Another Meta Analysis More Recent Developments FDA Safety Alert [7/9/2015] Strengthened warnings for CV or cerebrovascular events with NSAIDs Prescription labels revised to reflect the following information regarding NSAID use: Risk of heart attack or stroke within the first weeks of use Risk with higher doses and longer treatment durations Newer evidence makes it less clear if risk for MI or stroke is similar for all NSAIDs Risk of MI or stroke in patients with or without CAD or risk factors for CAD Risk for those with CAD or risk factors for CAD (vs. those without) due to a higher baseline risk Risk of death in the first year following first MI Risk of heart failure Nissen SE, Yeomans ND, Solomon DH, et al. Cardiovascular safety of celecoxib, naproxen or ibuprofen for arthritis. N Engl J Med. 2016; 375(26): Prospective Randomized Evaluation of Celecoxib Integrated Safety vs. Ibuprofen Or Naproxen: PRECISION trial ICHP Champions LIVE Webinar 3

4 Study Design Randomized, controlled noninferiority trial Results Celecoxib vs. Naproxen Celecoxib vs. Ibuprofen Naproxen vs. Ibuprofen Patient population: Rheumatoid arthritis (RA) or osteoarthritis with established or at high risk for CVD Primary composite outcome: CV death (including hemorrhagic) + Nonfatal MI + Nonfatal stroke Outcome Primary endpoint Major adverse CV events Adjusted Odds Ratio (95% CI) 0.93 ( ) 0.97 ( ) P value Adjusted Odds Ratio (95% CI) 0.85 ( ) 0.87 ( ) P value Adjusted Odds Ratio (95% CI) 1.08 ( ) 1.11 ( ) P value Primary outcome: composite of CV death (including hemorrhagic, nonfatal MI and nonfatal stroke Major adverse CV events: composite of primary endpoint, coronary revascularization, hospitalization for unstable angina, and TIA Mean daily doses (±SD): celecoxib 209±37 mg, naproxen 852±103mg, ibuprofen 2045±246mg Intervention: Celecoxib 100 mg BID vs. ibuprofen 600 mg TID vs. naproxen 375 mg BID Patients with RA could increase dose of study agent at subsequent visits: Celecoxib 200 mg BID vs. ibuprofen 800 mg TID vs. naproxen 500 mg BID Moderate doses of celecoxib (~200 mg/day) are noninferior to naproxen and ibuprofen for combined primary outcome of CV death, nonfatal MI and nonfatal stroke N Engl J Med. 2016;375(26): N Engl J Med. 2016;375(26): Study Design Bally M, Dendukuri N, Rich B et al. Risk of acute myocardial infarction with NSAIDs in real world use: bayesian meta analysis of individual patient data. Risk of Acute MI with NSAIDs: A Meta Analysis Systematic review one stage bayesian meta analysis Utilizing individual patient data Computerized drug prescriptions or medical databases from Canada and Europe Compared risk of acute MI for users versus non users Specific COX 2 selective or nonselective NSAID Daily NSAID dose Proximity of index event to NSAID use Duration of NSAID use Results Celecoxib Ended days PTID 1.03 (0.90 to 1.13) Ended 1 30 days PTID 1.15 (0.86 to 1.40) Any dose for 1 7 days 1.24 (0.91 to 1.82) 200 mg/day for 8 30 days 1.23 (1.00 to 1.62) >200 mg/day for 8 30 days 1.23 (0.78 to 1.80) 200 mg/day for >30 days 1.20 (1.01 to 1.47) >200 mg/day for >30 days 1.25 (0.94 to 1.66) Results Diclofenac Ended days PTID 1.11 (1.01 to 1.27) Ended 1 30 days PTID 1.08 (0.78 to 1.43) Any dose for 1 7 days 1.50 (1.06 to 2.04) 100 mg/day for 8 30 days 1.19 (0.94 to 1.48) >100 mg/day for 8 30 days 1.22 (0.92 to 1.62) 100 mg/day for >30 days 1.42 (1.18 to 1.68) >100 mg/day for >30 days 1.48 (1.08 to 1.95) ICHP Champions LIVE Webinar 4

5 Results Ibuprofen Results Naproxen Ended days PTID 1.06 (0.93 to 1.19) Ended 1 30 days PTID 1.15 (0.93 to 1.48) Any dose for 1 7 days 1.48 (1.00 to 2.26) 1,200 mg/day for 8 30 days 1.04 (0.72 to 1.35) >1,200 mg/day for 8 30 days 1.75 (1.00 to 2.93) 1,200 mg/day for >30 days 1.32 (1.02 to 1.74) >1,200 mg/day for >30 days 1.47 (1.04 to 2.04) Ended days PTID 1.07 (0.93 to 1.23) Ended 1 30 days PTID 1.30 (1.04 to 1.63) Any dose for 1 7 days 1.53 (1.07 to 2.33) 750 mg/day for 8 30 days 1.23 (0.90 to 1.61) >750 mg/day for 8 30 days 1.76 (1.14 to 2.65) 750 mg/day for >30 days 1.21 (0.95 to 1.52) >750 mg/day for >30 days 1.21 (0.91 to 1.57) Results Rofecoxib Ended days PTID 1.00 (0.87 to 1.12) Ended 1 30 days PTID 1.18 (0.95 to 1.50) Any dose for 1 7 days 1.58 (1.07 to 2.17) 25 mg/day for 8 30 days 1.27 (0.83 to 1.69) >25 mg/day for 8 30 days 2.65 (1.46 to 4.67) 25 mg/day for >30 days 1.35 (1.17 to 1.62) >25 mg/day for >30 days 1.56 (1.09 to 2.18) Use Characteristic Demonstrating Acute MI Risk Current use at any dose for 1 7 days Results Trends Agent (Adjust Odds Ratio [95% CrI]) Diclofenac (1.50 [1.06 to 2.04]) Ibuprofen (1.48 [1.00 to 2.26]) Naproxen (1.53 [1.07 to 2.33]) Rofecoxib (1.58 [1.07 to 2.17]) High dose for 8 30 days Ibuprofen >1,200 mg/day (1.75 [1.00 to 2.93]) Naproxen >750 mg/day (1.76 [1.14 to 2.65]) Rofecoxib >25 mg/day (2.65 [1.46 to 4.67]) High dose for >30 days Diclofenac >100 mg/day (1.48 [1.08 to 1.95]) Ibuprofen >1,200 mg/day (1.47 [1.04 to 2.04]) Rofecoxib >25 mg/day (1.56 [1.09 to 2.18]) Meta Analysis Conclusions All nonselective (including naproxen) and COX 2 selective NSAIDs risk of acute MI Onset of risk within the first week of use Greatest risk with short term use (8 30 days) at a high daily dose E.g. Ibuprofen >1200 mg, naproxen >750 mg, rofecoxib >25 mg No apparent further increases in risk beyond the first 30 days of use Strengths Critique Meta analysis of individual patient data Large patient population (>400,000 subjects) Studied general population and elderly (higher CVD risk) Limitations Exposure based on dispensed drug, not actual intake Use of OTC NSAIDs complicates true exposure ICHP Champions LIVE Webinar 5

6 Learning Assessment Which of the following statements is true regarding the findings of the most recent meta analysis using individual patient data comparing the risk of an acute MI for NSAID users versus nonusers? A. The risk for acute MI is increased within the first week of use for multiple nonselective NSAIDs B. COX 2 selective and all nonselective NSAIDs, except naproxen, increase the risk for acute MI C. The risk for acute MI is highest with lower doses used for extended durations for multiple nonselective NSAIDs D. COX 2 selective NSAIDs increase the risk for acute MI compared to all nonselective NSAIDs Clinical Considerations Recommend acetaminophen for mild to moderate pain Consider tramadol for moderate to severe pain Communicate the increased risk of acute MI to patients currently using NSAIDs Counsel patients using aspirin and NSAIDs to eliminate potential for drug drug interactions Immediate release aspirin 30 minutes before or 8 hours after ibuprofen Timing considerations for enteric coated aspirin and other NSAIDs unknown References FitzGerald GA. coxibs and cardiovascular disease. N Engl J Med. 2004; 351: Cannon CP, Cannon PJ. Physiology. Cox 2 inhibitors and cardiovascular risk. Science. 2012;336: Dzau VJ, Packer M, Lilly LS, et al. Prostaglandins in severe congestive heart failure. Relation to activation of the renin angiotensin system and hyponatremia. N Engl J Med. 1984;310: Feenstra J, Heerdink ER, Grobbee DE, Stricker BH. Association of nonsteroidal anti inflammatory drugs with first occurrence of heart failure and with relapsing heart failure: the Rotterdam Study. Arch Intern Med. 2002;162: Aw TJ, Haas SJ, Liew D, Krum H. Meta analysis of cyclooxygenase 2 inhibitors and their effects on blood pressure. Arch Intern Med. 2005;165: Singh G, Miller JD, Huse DM, et al. Consequences of increased systolic blood pressure in patients with osteoarthritis and rheumatoid arthritis. J Rheumatol. 2003;30: Catella Lawson F, Reilly MP, Kapoor SC, et al. Cyclooxygenase inhibitors and the antiplatelet effects of aspirin. N Engl J Med. 2001;345: U.S. Food and Drug Administration. FDA public health advisory: safety of Vioxx [9/30/2004]. (accessed 2017 Dec 15). Bresalier RS, Sandler RS, Quan H, et al. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med. 2005;352(11): Baron JA, Sandler RS, Bresalier RS, et al. Cardiovascular events associated with rofecoxib: final analysis of the APPROVe trial. Lancet. 2008;372(9651): Solomon SD, McMurray JJ, Pfeffer MA, et al. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med. 2005;352: ADAPT Research Group. Cardiovascular and cerebrovascular events in the randomized, controlled Alzheimer s disease anti inflammatory prevention trial (ADAPT). PLoS Clin Trials. 2006;1(7): e33. U.S. Food and Drug Administration. COX 2 selective (includes Bextra, Celebrex, and Vioxx) and non selective non steroidal anti inflammatory drugs (NSAIDs) [4/7/2005]. (accessed 2017 Dec 15). Antman EM, Bennett JS, Daugherty A, et al. Use of nonsteroidal antiinflammatory drugs: an update for clinicians: a scientific statement from the American Heart Association. Circulation. 2007;115(12): U.S. Food and Drug Administration. FDA strengthens warning that non aspirin nonsteroidal antiinflammatory drugs (NSAIDs) can cause heart attacks or strokes [7/9/2015]. (accessed 2017 Dec 17). Bally M, Dendukuri N, Rich B et al. Risk of acute myocardial infarction with NSAIDs in real world use: bayesian meta analysis of individual patient data. Nissen SE, Yeomans ND, Solomon DH, et al. Cardiovascular safety of celecoxib, naproxen or ibuprofen for arthritis. N Engl J Med. 2016;375(26): U.S. Food and Drug Administration. Information for healthcare professionals: concomitant use of ibuprofen and aspirin [9/2006]. (accessed 2017 Jul 20). ICHP Champions LIVE Webinar 6