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Adverse Effects of Nonsteroidal Anti-inflammatory Drugs on the Cardiovascular System

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NSAIDs and Aspirin

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Abstract

Nonsteroidal anti-inflammatory drugs (NSAIDs) are very effective medications, but their use is associated with a broad spectrum of adverse reactions involving the liver, kidney, cardiovascular (CV) system, skin, and gut. As a consequence, this class of drugs represents a leading cause of drug-related morbidity, especially in the elderly and in patients with comorbidities. Most adverse effects are related to the inhibition of cyclooxygenase (COX) isoenzymes, which is systemic and neither site nor organ specific. Gastrointestinal (GI) undesirable effects are the most common, but—in the last decade—those concerning the CV system have been increasingly appreciated.

Patients with cardiovascular disease (CVD) and comorbidities for which NSAIDs may provide symptomatic relief (e.g., osteoarthritis, OA, rheumatoid arthritis, RA) tend to be older, which places them at greater risk of harm. For these reasons, the use of NSAIDs in patients with CVD is a significant public health concern. An understanding of the risks associated with NSAIDs is critical for clinicians across the different practice settings.

Meta-analyses of randomized clinical trials (RCTs) and observational studies have shown that COX-2 selective and nonselective NSAIDs are associated with an increased risk of atherothrombotic events (particularly acute myocardial infarction, AMI), with no significant difference in the incidence of vascular events between selective and nonselective agents (with the exception of naproxen). The risk of cardiotoxicity depends on dose, duration, and frequency of drug administration. Available data show that the risk of stroke conferred by NSAIDs is much smaller, if any, than the risk of AMI. Use of both subclasses of NSAIDs can lead to the development of congestive heart failure (CHF) in susceptible individuals and also increase the risk of dysrhythmia (atrial fibrillation, AF, and flutter), particularly in presence of CHF and chronic kidney disease.

Both COX-2 selective and nonselective compounds have been associated with renal and renovascular adverse events, a finding consistent with the important role of constitutively expressed COX-2 in sustaining the physiological production of vasodilator and natriuretic prostanoids in the kidney. NSAIDs elevate blood pressure (BP) in hypertensive population and antagonize the BP lowering effect of antihypertensive medications (with exception of calcium channel blockers). In addition, fluid and electrolyte disturbances are common, especially in patients with underlying renal disease, CHF, and hepatic insufficiency.

The risk of pharmacokinetic and pharmacodynamic drug interactions with NSAIDs is high. However, while nonselective compounds interfere with the anti-aggregant activity of low-dose aspirin (ASA), COX-2 selective agents do not.

It should be emphasized that the intrinsic patient’s CV risk factors are of paramount importance. Indeed, the lower the risk factors, the lower the propensity for NSAIDs to cause CV adverse events. Drugs are indeed only one of the several concomitant risk factors and are not likely the most important. Anti-inflammatory therapy should therefore be tailored to the individual patient after careful evaluation of his/her risk factors and, ultimately, of the benefit-to-risk ratio.

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Notes

  1. 1.

    SOS project = Safety Of non-Steroidal anti-inflammatory drugs project http://www.sos-nsaids-project.org.

  2. 2.

    REACH = REduction of Atherothrombosis for Continued Health

Abbreviations

ACCEPT:

Assessing the Cardiovascular Risk Between CElecoxib and Nonselective Nonsteroidal Antiinflammatory Drugs in Patients With Rheumatoid Arthritis and Osteoarthritis Trial

AF:

Atrial fibrillation

AHA:

American Heart Association

AKF:

Acute kidney failure

AMI:

Acute myocardial infarction

APC:

Adenoma prevention with celecoxib

APPROVe:

Adenomatous Polyp Prevention on Vioxx™

AS:

Ankylosing spondylitis

ASA:

Acetylsalicylic acid (aspirin)

BP:

Blood pressure

CIs:

Confidence intervals

CHD:

Coronary heart disease

CHF:

Congestive heart failure

CHF:

Congestive heart failure

CHMP:

Committee for medicinal products for human use

CLASS:

Celecoxib Long-term Arthritis Safety Study

CNT:

Coxib and Traditional NSAID Trialist

COX:

Cyclooxygenase

CV:

Cardiovascular

CVD:

Cardiovascular disease

EDGE:

Etoricoxib versus Diclofenac sodium Gastrointestinal tolerability and Effectiveness trial

EMA:

European Medicines Agency

FDA:

Food and Drug Administration

GCs:

Glucocorticoids

GI:

Gastrointestinal

MEDAL:

Multinational Etoricoxib versus Diclofenac Arthritis Long-Term

NSAID:

Nonsteroidal anti-inflammatory drugs

OA:

Osteoarthritis

OD:

Once daily

OR:

Odd ratio

OTC:

Over the counter

PG:

Prostaglandin

PPI:

Proton pump inhibitor

PRECISION:

Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen or Naproxen

PreSAP:

Prevention of colorectal Sporadic Adenomatous Polyps

PsA:

Psoriatic arthritis

RA:

Rheumatoid arthritis

RCT:

Randomized clinical trial

REACH:

REduction of Atherothrombosis for Continued Health

RR:

Relative risk

SCOT:

Standard Care versus Celecoxib Outcome Trial

VIGOR:

Vioxx™ Gastrointestinal Outcomes Research

WHO:

World Health Organization

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Acknowledgments

We would like to thank Dr. Anna Bertelé (Laboratory of GI Functional Investigations, Maggiore University Hospital, Parma, Italy) for her precious help during the preparation of this manuscript. We are also indebted to Professor Richard H Hunt (MacMaster University, ON, CA) for his critical reading of the chapter and his valuable suggestions.

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  1. Clinical Pharmacology and Digestive Pathophysiology Unit, Department of Clinical and Experimental Medicine, Maggiore University Hospital, University of Parma, Cattani Pavillon, Parma, 43125, Italy

    Carmelo Scarpignato M.D., D.Sc., Pharm.D., M.P.H.

  2. Division of Pharmacology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy

    Corrado Blandizzi M.D., Ph.D.

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  1. Carmelo Scarpignato M.D., D.Sc., Pharm.D., M.P.H.
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Correspondence to Carmelo Scarpignato M.D., D.Sc., Pharm.D., M.P.H. .

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  1. IIS Aragón, CIBER Enfermedades Hepáicas y Digestivas (CIBERehd), Universidad de Zaragoza, Zaragoza, Spain

    Angel Lanas

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Scarpignato, C., Blandizzi, C. (2016). Adverse Effects of Nonsteroidal Anti-inflammatory Drugs on the Cardiovascular System. In: Lanas, A. (eds) NSAIDs and Aspirin. Springer, Cham. https://doi.org/10.1007/978-3-319-33889-7_5

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