ORI G I N AL ARTI C L E
Blood Pressure and Cardiovascular Outcomes in Patients Taking Nonsteroidal Antiinflammatory Drugs Henry Krum,1 Gary Swergold,2 Arnold Gammaitoni,3 Paul M. Peloso,3 Steven S. Smugar,3 Sean P. Curtis,3 D. Craig Brater,4 Hongwei Wang,3 Amarjot Kaur,3 Loren Laine,5 Matthew R. Weir,6 & Christopher P. Cannon7 1 Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia 2 Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA 3 Merck Research Laboratories, Rahway, NJ, USA 4 Indiana University School of Medicine, Indianapolis, IN, USA 5 Department of Medicine, University of Southern California, Keck School of Medicine, Los Angeles, CA, USA 6 Division of Nephrology, University of Maryland School of Medicine, Baltimore, MD, USA 7 TIMI Study Group, Brigham and Women’s Hospital, Boston, MA, USA
Keywords Cardiovascular events; Cyclo-oxygenase-2 inhibitors; Hypertension; Nonsteroidal antiinflammatory drugs. Correspondence Professor Henry Krum, MBBS, PhD, FRACP Centre of Cardiovascular Research and Education in Therapeutics Department of Epidemiology and Preventive Medicine School of Public Health and Preventive Medicine Monash University/Alfred Hospital Melbourne, Vic. 3004, Australia. Tel.: +61 3 9903 0042 Fax: +61 3 9903 0556 E-mail:
[email protected]
doi: 10.1111/j.1755-5922.2011.00283.x
SUMMARY Introduction: The increased thrombotic cardiovascular (CV) risk in trials of cyclooxygenase-2 (COX-2) inhibitors versus placebo, and the apparent similar risk with nonsteroidal antiinflammatory drugs (NSAIDs), may be related to their potential to elevate blood pressure (BP). Aims: We evaluated the relationship between baseline BP and change in BP on CV events (CVEs) in patients receiving NSAIDs or COX-2 inhibitors in the prospective randomized, double-blind, Multinational Etoricoxib and Diclofenac Arthritis Long-term Program (N = 34,701) comparing etoricoxib 60 or 90 mg or diclofenac 150 mg daily for a mean duration of 18 months. The main outcome measure was confirmed thrombotic CVEs. The Antiplatelet Trialists’ Collaboration endpoint, all-cause mortality, CV/congestive heart failure (CHF) mortality, and CHF incidence were similarly evaluated. Results: We found that baseline systolic BP (SBP) was associated with significantly higher risk of all events (P < 0.001). Baseline diastolic BP (DBP) was inversely and significantly associated with risk of all events (P < 0.001 to P = 0.016) except CV/CHF mortality (P = 0.054). There was no significant differential effect between etoricoxib and diclofenac in relation to CVEs, except for confirmed CHF, for which the risk was significantly higher with etoricoxib (P = 0.019). Only CHF risk (P = 0.020 for both SBP and DBP change), but not thrombotic endpoints, was significantly associated with change in BP from months 0 to 4. These findings were not meaningfully altered after covariate adjustment for baseline CV risk. Conclusions: Baseline BP, but not change in BP, was significantly associated with risk of thrombotic CVEs through 18 months. The CV risk of COX-2s and NSAIDs did not appear to be related to the BPelevating effects of these agents, although such analyses, i.e., from randomized controlled trials, are unable to definitively exclude such a relationship.
Nonselective nonsteroidal antiinflammatory drugs (nsNSAIDs) and cyclo-oxygenase-2 (COX-2) selective inhibitors have been demonstrated to increase systemic blood pressure (BP) levels, predominantly systolic BP (SBP) [1–3] COX-2 inhibitors have also been associated with increases in cardiovascular (CV) events in some patients in comparison with patients receiving placebo and the nsNSAID naproxen in some clinical trials [4–9] and to matched subjects not receiving these agents in observational cohorts [10–12]. A number of hypotheses have been proposed to explain mechanisms underlying this increase in CV risk, including enhancement of thrombosis and development of hypertension [13–15].
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Cardiovascular Therapeutics 30 (2012) 342–350
The Multinational Etoricoxib and Diclofenac Arthritis Longterm (MEDAL) program is the largest ever prospective randomized clinical trial of these agents in patients with osteoarthritis (OA) and rheumatoid arthritis (RA) and the first to focus on CV events (CVEs) as primary outcome variables [16]. Despite an approximately 2 mm Hg greater increase in population mean SBP with etoricoxib compared with diclofenac, a difference typically considered clinically meaningful in CV outcomes studies [17–20], there were no significant differences in CV outcomes between etoricoxib and diclofenac over the mean observed follow-up period of 18 months. However, the relationship between BP changes induced by ns-NSAIDs and COX-2 inhibitors with subsequent CV
ª 2011 Blackwell Publishing Ltd
NSAIDs, Blood Pressure and CV Events
H. Krum et al.
outcomes has not been well examined, especially from prospective trial data. We therefore evaluated the effects of baseline BP and ontreatment change in BP on subsequent development of CVEs in the MEDAL program.
Methods Study Design The design of the MEDAL program has been described previously [16;21]. In brief, it was conducted from 2002 to 2006 at 1380 sites in 46 countries and comprised three separate randomized, doubleblind studies: the Etoricoxib versus Diclofenac in Gastrointestinal tolerability and Effectiveness (EDGE) study [22], the EDGE II study [23], and the MEDAL study [24]. Patients were randomized to etoricoxib 60 or 90 mg or diclofenac 150 mg once daily. The study primary endpoint was adjudication-confirmed thrombotic CV serious adverse experiences evaluated using a perprotocol approach for the noninferiority evaluation of etoricoxib versus diclofenac.
Patient Population Patients age ≥50 years with OA or RA were enrolled in the MEDAL program studies (N = 34,701). Patients with a history of myocardial infarction, coronary artery bypass grafting, or percutaneous coronary intervention >6 months preceding enrolment were allowed to participate. Low-dose aspirin ( 176.8 μmol/L [2.0 mg/dL]; or uncontrolled hypertension (sitting diastolic BP [DBP] >95 mm Hg or sitting SBP >165 mm Hg) at screening.
discontinued from the study were contacted every 6 months by telephone through the end of the study. All patients had a poststudy follow-up telephone contact 28 days after their last dose of study medication to assess for serious adverse experiences following discontinuation. All potential thrombotic CVEs from the three trials were identified through active surveillance of reported adverse events and were adjudicated by an independent blinded committee. Electrocardiograms performed on all patients at randomization, along with any during the trial, were compared to the electrocardiogram obtained at the end of the study to identify silent myocardial infarction; suspected cases were also adjudicated.
Relationship between BP and CVEs We evaluated the relationship between BP at baseline and at various on-treatment time points and subsequent major CVEs, as a post hoc analysis. The primary evaluation was the relationship of baseline BP and on-treatment change in BP at Month 4 to subsequent ontreatment confirmed thrombotic CVEs, comprising myocardial infarction (including silent infarction), unstable angina, intracardiac thrombus, resuscitated cardiac arrest, thrombotic stroke, cerebrovascular thrombosis, transient ischemic attack, peripheral venous thrombosis, pulmonary embolism, peripheral arterial thrombosis, and sudden and/or unexplained death. We chose Month 4 as the principal time interval from baseline because the BP effects of most NSAIDs and COX-2 selective inhibitors, including etoricoxib and diclofenac, would have reached steady-state pharmacodynamically by that point. Additional endpoints evaluated included antiplatelet trialists collaboration (APTC) events, all-cause mortality, CV and CHF mortality, and confirmed CHF. We also evaluated the effect of the degree of BP change from baseline (
