NSAIDs: The Truth About Cardiovascular Risk Adam Grunbaum DO FACOI FACR American College of Osteopathic Internists Annual Convention and Scientific Sessions October 3rd 2015

Disclosures • none

2

Objectives • Understand the risks associated with NSAID use in patients with and without history of cardiovascular disease

• Identify what patients are at highest risk for cardiovascular

complications with NSAID use and when alternate therapies should be considered

• Understand factors that limit risk of cardiovascular events associated with NSAIDs

3

Questions 1. Do NSAIDs increase cardiovascular risk in those with and without a history of known cardiovascular disease?

2. Are there any NSAIDs that confer less risk of cardiovascular events? 3. What settings should NSAID use be considered contra-indicated from a primarily cardiovascular standpoint?

4. Are there any other settings where NSAID use should be avoided from a cardioprotective standpoint? 4

History of NSAIDs • Aspirin has been on the market for greater than 115 years • The NSAIDs “class” constitute a chemically heterogenous group of compounds with drug specific selectivity that provide shared therapeutic effects •

Analgesic

•

Anti-inflammatory

•

Antipyretic

• Marketing of NSAIDs began ~1963 with indomethacin • Since then over 20 additional NSAIDs have been developed

• Estimated 70 million prescription NSAIDs written each year in the United States

• Combining over the counter use of NSAIDs 30 billion doses are consumed annually 5

History of NSAIDs • Approximately 15 years ago selective inhibitors of cyclooxygenase-2 developed • Showed promise based on anti-pyretic, anti-inflammatory and analgesics effects as a class • Variability of effects noted based on pharmacokinetics and pharmacodynamics

• Development continued with unique targets elucidated • i.e. chemoprevention of colorectal carcinoma

• As dosage limits pushed with newer drugs toxicity profiles became increasingly apparent •

Multiple NSAIDs demonstrated vascular toxicity represented by heart failure and new onset or worsening of hypertension*

• This culminated in newer agents suggesting increased risk of cardiovascular thrombotic effects • This was a surprise as aspirin had been shown to be cardioprotective to events in doses up to 1500mg a day** *Garcia Rodriguez LA, Hernandez-Diaz S. Nonsteroidal anti-inflammatory drugs as a trigger of clinical heart failure. Epidemiology. 2003; 14:240-246. **Patrono C, Garcia Rodriguez LA, Landolfi R, Baigent C. Low-dose aspirin for the prevention of atherothromosis. NEJM 2005;353:2373-2383.

6

NSAIDs and Cardiovascular Risk • September 2004 •

Merck voluntarily withdraws rofecoxib due to reports of increased heart attack and stroke

• December 2004 •

FDA announces a black box warning for valdecoxib adding a contra-indication in patients undergoing coronary artery bypass grafting surgery

•

One week after black box warning NIH suspends use of celecoxib in the Adenoma Prevention with Celecoxib trial due to increased cardiac events

•

Three days later NIH halts the Alzheimer's Disease Anti-inflammatory Prevention Trial as it showed an increased risk in cardiovascular events in those patients receiving naproxen in the trial but not in those given celecoxib

• December 23, 2004 •

FDA issues public health advisory for rofecoxib, valdecoxib, celecoxib and naproxen

7

US Food and Drug Administration Public Health Advisory • December 2004 Health Advisory •

“Physicians prescribing celecoxib or valdecoxib should consider the emerging information when weighing the benefits against risks for individual patients. Patients who are at a high risk of gastrointestinal (GI) bleeding, have a history of intolerance to nonselective NSAIDs, or are not doing well on nonselective NSAIDs may be appropriate candidates for COX-2 selective agents.”

•

“Individual patient risk for cardiovascular events and other risks commonly associated with NSAIDs should be taken into account for each prescribing situation.”

•

“Consumers are advised that all over-the-counter (OTC) pain medicines, including NSAIDs, should be used in strict accordance with the label directions. If use of an (OTC) NSAID is needed for longer than ten days, a physician should be consulted.”

• April 2005 News Release •

FDA asks valdecoxib sales and marketing to be suspended in the US

•

FDA requires celecoxib and all other prescription NSAIDs to have black box warning including CV eveents

•

FDA urges OTC NSAIDs to have more specific warnings of CV and GI events

http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2005/ucm108427.htm

8

NSAID Cardiovascular Controversy Begins…

9

Why are we here today??? •

FDA announcement July 2015 strengthens warnings for cardiovascular or cerebrovascular events

•

Based on the advisory committees’ recommendations, the prescription NSAID labels were revised to reflect the following information:

•

The risk of heart attack or stroke can occur as early as the first weeks of using an NSAID. The risk may increase with longer use of the NSAID.

•

The risk appears greater at higher doses.

•

It was previously thought that all NSAIDs may have a similar risk. Newer information makes it less clear that the risk for heart attack or stroke is similar for all NSAIDs; however, this newer information is not sufficient to determine that the risk of any particular NSAID is definitely higher or lower than that of any other particular NSAID.

•

NSAIDs can increase the risk of heart attack or stroke in patients with or without heart disease or risk factors for heart disease. A large number of studies support this finding, with varying estimates of how much the risk is increased, depending on the drugs and the doses studied.

•

In general, patients with heart disease or risk factors for it have a greater likelihood of heart attack or stroke following NSAID use than patients without these risk factors because they have a higher risk at baseline.

•

Patients treated with NSAIDs following a first heart attack were more likely to die in the first year after the heart attack compared to patients who were not treated with NSAIDs after their first heart attack.

•

There is an increased risk of heart failure with NSAID use.

FDA Drug Safety Communication 07-09-2015

10

NSAIDs and Cardiovascular Risk • NSAIDs differ many ways • • • •

Chemical class Chemical structures

Variability in the manner in which they inhibit COX-1 and COX-2 isoenzymes Causes varying effect on:

• Antipyretic effects • Analgesic effects • Anti-inflammatory effects 11

Elliott M. Antman et al. Circulation. 2005;112:759-770

Copyright © American Heart Association, Inc. All rights reserved.

NSAIDs and Cardiovascular Risk • How do aspirin derivatives increase risk of atherothrombosis??? • NSAIDs – selective and/or non-selective in inhibiting cyclooxygenase • COX-1: produces prostaglandins used for stimulation of typical body functions • i.e. stomach mucous production, regulation of gastric acid and kidney water excretion

• COX-2: produces prostaglandins used for signaling pain and inflammation

13

Figure 1. Molecular pathways for formation of eicosanoids and prostanoids.

Elliott M. Antman et al. Circulation. 2005;112:759-770

Copyright © American Heart Association, Inc. All rights reserved.

Prostanoid Hypothesis

Clinical Medicine & Research. Volume 5, Number 1: 19-34

15

NSAIDs and Cardiovascular Risk • Has been proposed that the major cardiovascular complications are COX-2 inhibition

mediated as blocking COX-2 shifts prothrombotic or antithrombotic balance on endothelial surfaces • Increases in sodium and water retention  edema  hypertension  HF • Loss of protective effects of COX-2 upregulation • May lead to myocardial ischemia and infarction • Can lead to larger infarct size, greater thinning ventricular wall in infarct zone and increased tendency for myocardial rupture*

• Imbalance of production of “prostanoids”, a subclass of eicosanoids containing: • Prostaglandins – mediate inflammatory and anaphylactic reactions • Thromboxanes – mediate vasoconstriction • Prostacyclins – an active part of the resolution phase of inflammation *Circulation 2007;115:288-291 and 326-332

16

Figure 4. Consequences of COX inhibition for prostacyclin and thromboxane A2 production in normal and atherosclerotic arteries.

Elliott M. Antman et al. Circulation. 2005;112:759-770

Copyright © American Heart Association, Inc. All rights reserved.

Considerations • What factors play a role in NSAIDs and potential adverse cardiovascular effects? • Does dose of NSAID matter? • How long can NSAIDs be used before risk unacceptable? • Are there any patient types more at risk? • Is risk the same for those for primary and secondary events? • Which agents, if any, confer the most risk? • Is there additive therapy that can diminish this risk? • What evidence is out there to answer any of these questions? • Most current knowledge from collections of post hoc analyses of subgroups of patients from studies designed to look at non-cardiovascular diseases

• Focus has primarily been on COX-2 inhibitors with nonselective NSAID risk estimated primarily from metaanalyses and observational studies

18

NSAIDs and Cardiovascular Risk • To date there are a number of large systematic reviews published covering randomized trials and non-randomized pharmaco-epidemiological studies • • •

NSAIDs and the risk of myocardial infarction in the general population. 2004 Circulation 109: 3000-3006

• • • • •

Do COX-2 inhibitors and traditional NSAIDs increase the risk of atherothrombosis? 2006 BMJ 332: 1302-1308

Relationship between COX-2 inhibitors and myocardial infarction in older adults. 2004 Circulation 109: 2068-2073 Cardiovascular Risk and inhibition of cyclooxygenase: a systematic review of observational studies of selective and non-selective COX inhibitors. 2006 JAMA 296: 1633-1644 Cardiovascular Safety of NSAIDs: network meta-analysis. 2011 BMJ 342: c7086 NSAID use selectively increases risk of non-fatal myocardial infarction. 2011 PLoS ONE 6: e16780 NSAIDs and the risk of myocardial infarction. 2006 Basic Clin Pharmacol 98: 266-274

Coxib and traditional NSAID Trialists' (CNT) Collaboration. The Lancet, Volume 382, Issue 9894, 2013, 769 - 779

• Many of these studies use the same data looking for different endpoints and to this point it is all that is available •

PRECISION is coming…..

19

Does Dose Matter??? • From a heart failure and ischemic cardiovascular event standpoint there is little data available to estimate risk but in the studies available there seems to be consensus that “low dose” NSAIDs (especially short term) do not confer as significant a risk • What is considered “high dose” of commonly used NSAIDs • Ibuprofen > 1200mg daily • Diclofenac > 100mg daily • Naproxen >500mg daily • Celecoxib > 200 mg daily • Rofecoxib > 25g daily (no longer on the market)

20

What Duration of Treatment Matters?? • Very few time to event analyses are available to answer this • Only a couple studies were randomized and designed specifically to look at this question but these were in the setting of the immediate post operative period with coronary artery bypass grafting (CABG) •

Findings here have been very consistent with COX-2 inhibitors leading to an absolute contra-indication in the immediate weeks post CABG

• These studies prompted some analyses of duration to treatment risk in patients with history of myocardial infarction

• Circulation. 2011; 123:2226-2235 • • •

83,677 patients ≥ 30 years old admitted for first time AMI from 1997-2006 Used registry data from Denmark for drug dispensing registries Strength: avoided selection bias Weakness: Observational

21

A through F, Incidence rates of death/recurrent myocardial infarction (Re-MI) per 1000 personyears during treatment with individual nonsteroidal anti-inflammatory drugs (NSAIDs).

Anne-Marie Schjerning Olsen et al. Circulation. 2011;123:2226-2235 Copyright © American Heart Association, Inc. All rights reserved.

Time-dependent Cox proportional-hazard analysis of risk of death/recurrent myocardial infarction (Re-MI) according to duration of nonsteroidal anti-inflammatory drug (NSAID) treatment in patients with prior myocardial infarction.

Anne-Marie Schjerning Olsen et al. Circulation. 2011;123:2226-2235 Copyright © American Heart Association, Inc. All rights reserved.

Hypertension Risks • Generally well accepted that most NSAIDs carry risk of elevating blood pressure • Effects seem dose-dependent and probably involves inhibition of cyclooxygenase-2 (COX-2) in the kidneys

• Presumably reducing sodium excretion and increasing intravascular volume

• Hard to generalize severity of effects on blood pressure as specific agents vary greatly on their effects • Indomethacin and Naproxen most consistently seem to cause greatest increases in mean arterial pressure (~34 mmHg)

•

Arch Intern Med. 1993;153(4):477.

• Some studies have shown potential of NSAIDs to antagonize most anti-hypertensive treatments with the exception of calcium channel blockers •

Hypertension. 2007;49(3):408

24

Heart Failure Risks • Also generally well accepted as a potential risk for developing heart failure and significant risk noted in NSAID users with history of heart failure

• ACC guidelines discourage use of all NSAIDs in patients with chronic heart failure for some years now • AHA has published prior scientific statements recommending against use of NSAIDs, particularly COX-2 inhibitors, in patients with established heart failure independent of severity of disease

• Arch Internal Medicine. 2009; 169(2): 141-149 • • • •

107,092 patients surviving initial hospitalization due to heart failure Aged 30 years or older Registry data collected from pharmacies concerning NSAID use Cox proportional hazard models adjusted for age, sex, comorbidity, medical treatment, case based severity.

25

From: Increased Mortality and Cardiovascular Morbidity Associated With Use of Nonsteroidal Anti-inflammatory Drugs in Chronic Heart Failure Arch Intern Med. 2009;169(2):141-149. doi:10.1001/archinternmed.2008.525

Table Title: Odds Ratios for Death, and Hospitalization Because of HF or AMIa

Copyright © 2015 American Medical Association. All rights reserved.

From: Increased Mortality and Cardiovascular Morbidity Associated With Use of Nonsteroidal Anti-inflammatory Drugs in Chronic Heart Failure Arch Intern Med. 2009;169(2):141-149. doi:10.1001/archinternmed.2008.525

Figure Legend: Hazard ratios for hospitalization because of heart failure associated with use of nonsteroidal anti-inflammatory drugs (NSAIDs) in patients with chronic heart failure. Cox proportional hazards regression analysis adjusted for age, sex, calendar year, comorbidity, concomitant pharmacotherapy, and severity of disease. Bars indicate 95% confidence intervals. Copyright © 2015 American Medical Association. All rights reserved.

From: Increased Mortality and Cardiovascular Morbidity Associated With Use of Nonsteroidal Anti-inflammatory Drugs in Chronic Heart Failure Arch Intern Med. 2009;169(2):141-149. doi:10.1001/archinternmed.2008.525

Figure Legend: Hazard ratios for death associated with use of nonsteroidal anti-inflammatory drugs (NSAIDs) in patients with chronic heart failure. Cox proportional hazards regression analysis adjusted for age, sex, calendar year, comorbidity, concomitant pharmacotherapy, and severity of disease. Bars indicate 95% confidence intervals. Copyright © 2015 American Medical Association. All rights reserved.

From: Increased Mortality and Cardiovascular Morbidity Associated With Use of Nonsteroidal Anti-inflammatory Drugs in Chronic Heart Failure Arch Intern Med. 2009;169(2):141-149. doi:10.1001/archinternmed.2008.525

Figure Legend: Hazard ratios for hospitalization because of acute myocardial infarction associated with use of nonsteroidal anti-inflammatory drugs (NSAIDs) in patients with chronic heart failure. Cox proportional hazards regression analysis adjusted for age, sex, calendar year, comorbidity, concomitant pharmacotherapy, and severity of disease. Bars indicate 95% confidence intervals. Copyright © 2015 American Medical Association. All rights reserved.

Cardiovascular Events: Myocardial Infarctions • As the rofecoxib studies for alternative indications and doses found increasing incidence of increased ischemic CV events…. • •

Concern about celecoxib safety as only valdecoxib and rofecoxib left market Need for cardiovascular data on nonselective NSAIDs arose

•

Concern as most countries allow non-prescription use

• JAMA. 2006: 296: 1633-1644 • • • •

Looked at eligible studies of case-control or cohort design on CV events Eligible studies had to report on cardiovascular risks associated with NSAID use Used nonuse/remote exposure as the reference point for risk calculation 7086 titles evaluated (from 1985-2006)  only 23 titles included in analysis

•

Totaled > 86,000 events and had > 1,000,000 controls 30

From: Cardiovascular Risk and Inhibition of Cyclooxygenase: A Systematic Review of the Observational Studies of Selective and Nonselective Inhibitors of Cyclooxygenase 2 JAMA. 2006;296(13):1633-1644. doi:10.1001/jama.296.13.jrv60011

Copyright © 2015 American Medical Association. All rights reserved.

From: Cardiovascular Risk and Inhibition of Cyclooxygenase: A Systematic Review of the Observational Studies of Selective and Nonselective Inhibitors of Cyclooxygenase 2 JAMA. 2006;296(13):1633-1644. doi:10.1001/jama.296.13.jrv60011

Copyright © 2015 American Medical Association. All rights reserved.

From: Cardiovascular Risk and Inhibition of Cyclooxygenase: A Systematic Review of the Observational Studies of Selective and Nonselective Inhibitors of Cyclooxygenase 2 JAMA. 2006;296(13):1633-1644. doi:10.1001/jama.296.13.jrv60011

Figure Legend: Reference exposure, nonuse or remote use of anti-inflammatory drugs (random effects model). CI indicates confidence interval.

Copyright © 2015 American Medical Association. All rights reserved.

From: Cardiovascular Risk and Inhibition of Cyclooxygenase: A Systematic Review of the Observational Studies of Selective and Nonselective Inhibitors of Cyclooxygenase 2 JAMA. 2006;296(13):1633-1644. doi:10.1001/jama.296.13.jrv60011

Figure Legend: Reference exposure, nonuse or remote use of anti-inflammatory drugs (random effects model). CI indicates confidence interval.

Copyright © 2015 American Medical Association. All rights reserved.

Coxib and traditional NSAID Trialists' (CNT) Collaboration – Lancet 2013 • Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials

• Meta-analyses of 280 trials of NSAIDs versus placebo •

124,513 participants - 68,342 person-years

• 474 trials of one NSAID versus another NSAID •

229,296 participants - 165 456 person-years

• Main outcomes • • • • •

Major vascular events (non-fatal myocardial infarction, non-fatal stroke, or vascular death) Major coronary events (non-fatal myocardial infarction or coronary death) Stroke Heart failure Upper gastrointestinal complications (perforation, obstruction, or bleed). 35

The Lancet, Volume 382, Issue 9894, 2013, 769 - 779

The Lancet, Volume 382, Issue 9894, 2013, 769 - 779

The Lancet, Volume 382, Issue 9894, 2013, 769 - 779

The Lancet, Volume 382, Issue 9894, 2013, 769 - 779

NSAIDs and Cardiovascular Risk • Through most studies average relative risks with gastrointestinal complications are estimated around 4 but cardiovascular complications seem to center in the range of 1 to 2 • Limits power of data statistically • Raises importance of risk variability estimates within study participants • Low vs High risk • Low vs High dose • Risk between similar drugs

• Data seem to suggest some traditional NSAIDs at higher doses seem to confer similar elevated risks to what was demonstrated with prior available COX-2 inhibitors

• But what about low dosing more consistently as with non-prescription use??? ly

40

Cardiovascular Risk with Non-steroidal AntiInflammatory Drugs: Systematic Review • Based on same protocol as earlier discussed JAMA article (same authors) • Confined analysis to non-randomised controlled observational designs • Prior placebo controlled trial had captured insignificant events but ongoing meta-analyses

and additional randomised data published now allowed for it • Period reviewed this time was January 1985 to November 2010 • Pair wise data was plentiful enough to be powered appropriately • As many of the values of pooled relative risk found to be close to 1 a sensitivity analysis was conducted to strength of association with cardiovascular events • Due to volume of analyses the sensitivity analysis was limited to pair-wise comparisons of drugs as this was most important measure of relative harm PLoS. Sept 2011; Vol 8 (9) e1001098

41

Table 1. Summary of the numbers of studies and overall results.

McGettigan P, Henry D (2011) Cardiovascular Risk with Non-Steroidal Anti-Inflammatory Drugs: Systematic Review of Population-Based Controlled Observational Studies. PLoS Med 8(9): e1001098. doi:10.1371/journal.pmed.1001098 http://127.0.0.1:8081/plosmedicine/article?id=info:doi/10.1371/journal.pmed.1001098

Table 2. Dose-response relationships for individual drugs included in the analyses.

McGettigan P, Henry D (2011) Cardiovascular Risk with Non-Steroidal Anti-Inflammatory Drugs: Systematic Review of Population-Based Controlled Observational Studies. PLoS Med 8(9): e1001098. doi:10.1371/journal.pmed.1001098 http://127.0.0.1:8081/plosmedicine/article?id=info:doi/10.1371/journal.pmed.1001098

Table 3. Estimated RRs of cardiovascular events according to risk of cardiovascular disease.

McGettigan P, Henry D (2011) Cardiovascular Risk with Non-Steroidal Anti-Inflammatory Drugs: Systematic Review of Population-Based Controlled Observational Studies. PLoS Med 8(9): e1001098. doi:10.1371/journal.pmed.1001098 http://127.0.0.1:8081/plosmedicine/article?id=info:doi/10.1371/journal.pmed.1001098

Table 4. Selected pair-wise comparisons of individual drugs.

McGettigan P, Henry D (2011) Cardiovascular Risk with Non-Steroidal Anti-Inflammatory Drugs: Systematic Review of Population-Based Controlled Observational Studies. PLoS Med 8(9): e1001098. doi:10.1371/journal.pmed.1001098 http://127.0.0.1:8081/plosmedicine/article?id=info:doi/10.1371/journal.pmed.1001098

Cardio-protection with aspirin & NSAIDs • Does NSAID induced COX inhibition affect the cardio-protective effects of aspirin therapy? •

Quick Answer: we don’t know definitively at this point (likely ibuprofen)

• Cardio-protective effect diminished •

Lancet. 2003;361: 573-574 •

•

Ibuprofen shown to inhibit irreversible platelet inhibition of aspirin

NEJM. 2001;345: 1809-1817 •

Ibuprofen shown to affect the pharmacodynamics of aspirin but rofecoxib, acetaminophen and diclofenac did not

• Cardio-protective effect unaffected •

J Clinical Pharmacology. 2002;42: 1027-1030 •

•

Celecoxib showed no effect on the pharmacodynamics of aspirin

Circulation. 2003;108: 1191-1195 •

Suggested that short term use of NSAIDs did not effect aspirin

• “Regular” use of NSAIDs (>60 days) did suggest an increased risk by loss of protective effects 46

Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen or Naproxen (PRECISION) • Patients 18 or older with a clinical diagnosis of Rheumatoid Arthritis or Osteoarthritis who require daily treatment with NSAIDs to maintain quality of life

• Will continue until 762 primary events are noted with at least 18 months follow-up • Currently ongoing with primary endpoints of cardiovascular death, nonfatal myocardial infarction or nonfatal stroke • Secondary endpoints include first occurrence of major adverse CV event including composite of CV death (including hemorrhagic), nonfatal MI, nonfatal stroke, hospitalization for USA or TIA or revascularization.

• Also includes clinically significant GI events • Multicenter, multinational study that is randomized, double-blind, triple dummy 3-arm parallel group design • • •

Celecoxib 100-200mg BID + Ibuprofen placebo + Naproxen placebo Ibuprofen 600-800mg TID + Celecoxib placebo + Naproxen placebo Naproxen 375-500mg BID + Celecoxib placebo + Ibuprofen placebo 47

Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen or Naproxen (PRECISION) • Key inclusion requirement is high risk for cardiovascular disease • Established Disease defined as: • • • • •

50% or greater occlusion of one or more coronary arteries by angiography 50% or greater occlusion of one or more carotid arteries by angiography or ultrasound History of stable angina Symptomatic peripheral arterial disease Prior: AMI, USA, PCI, CABG, TIA, Ischemic stroke, CEA or other arterial angioplasty

• Events must have occurred 3 months or more from randomization

• Diabetes Mellitus considered a cardiovascular disease equivalent • Inclusion as high risk requires 3 or more atherosclerotic risk factors 48

Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen or Naproxen (PRECISION) • Major inclusion criteria • Age >55 • Dyslipidemia (LDL > 160 mg/dL or HDL < 40 mg/dL in females and < 35 mg/dL in males or subjects currently undergoing lipid lowering therapy with statin drugs, fibrates or niacin)

• Family History of premature CV disease (MI, angina pectoris, heart failure, cardiac death, or coronary revascularization, stroke, carotid endarterectomy, or other arterial surgery or angioplasty in a parent, grandparent or sibling with symptom onset before age 55 for males and 65 for females)

• • • •

Current smoker LVH Documented ankle brachial index < 0.9 History of microalbuminuria, urine protein-creatinine ratio >2 49

Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen or Naproxen (PRECISION) •

Major exclusion criteria •

Unstable angina, MI, CVA, CABG 140 mmHg DBP >90 mmHg)

•

Uncontrolled arrhythmia 325mg daily

•

Oral corticosteroid equivalent of prednisone > 20mg daily

•

GI ulceration 2x the upper limit of normal

•

Creatinine level > 1.7mg/dL in men, 1.5 mg/dL in women

•

Malignancy