Heart risks of pop­u­lar pain re­liev­ers are still un­clear

Daily Local News (West Chester, PA) - - BUSINESS -

NEW OR­LEANS >> A study doc­tors had hoped would pro­vide some clear answers about which of the most com­mon pain re­liev­ers was safest for peo­ple with or at high risk for car­dio­vas­cu­lar dis­ease has in­stead left ex­perts puz­zled about how to in­ter­pret the re­sults.

The con­clu­sion of the trial, called PRE­CI­SION, ap­pears im­pres­sive at face value. Among peo­ple with arthri­tis tak­ing ibupro­fen, naproxen or cele­coxib for pain re­lief, the COX-2 in­hibitor cele­coxib — known by the brand name Cele­brex — posed no greater risk for heart at­tacks, strokes or car­dio­vas­cu­lar-re­lated deaths.

But the study, pre­sented at the Amer­i­can Heart As­so­ci­a­tion’s Sci­en­tific Ses­sions, doesn’t solidly back that up, ex­perts said.

“The trial was so poorly de­signed that the con­clu­sions are un­sup­port­able,” said Dr. Gar­ret FitzGer­ald, di­rec­tor of the In­sti­tute for Trans­la­tional Medicine and Ther­a­peu­tics at the Univer­sity of Penn­syl­va­nia, who wrote about the study in an ed­i­to­rial pub­lished in Cir­cu­la­tion.

“The trial is called PRE­CI­SION, and that’s the last thing it de­liv­ers,” he said. “It pro­vides us no use­ful in­for­ma­tion to influence prac­tice.”

The study’s lead in­ves­ti­ga­tor, Dr. Steven Nis­sen, had a dif­fer­ent take­away.

“The thing that ev­ery­body feared was that cele­coxib would be like Vioxx. And we can say defini­tively that it is not,” said Nis­sen, chair­man of car­dio­vas­cu­lar medicine at the Cleve­land Clinic, who pre­sented the find­ings Sun­day.

The three drugs stud­ied are part of a class of painkillers called non-steroidal anti-in­flam­ma­tory drugs, or NSAIDs. They are among the most com­monly used drugs in the world, in­clud­ing more than 100 mil­lion U.S. pre­scrip­tions in 2013.

Well-known over-the-counter brands such as Advil, Motrin and Aleve are used to treat ev-

ery­thing from fevers, headaches and men­strual cramps to back pain, arthri­tis and other chronic con­di­tions. Some are avail­able over-the-counter at low doses while high­er­dose drugs re­quire a pre­scrip­tion. A spe­cific class of NSAIDs, the COX-2 in­hibitors, were de­vel­oped in an at­tempt to avoid gas­troin­testi­nal side ef­fects.

Cele­brex was the only COX-2 in­hibitor left, and the FDA al­lowed Pfizer, the maker of Cele­brex and Advil, to keep Cele­brex on the mar­ket but re­quired that they con­duct a safety trial.

The study, si­mul­ta­ne­ously pub­lished in the New Eng­land Jour­nal of Medicine, hoped to en­roll peo­ple at risk for heart at­tacks and strokes and who needed to take med­i­ca­tion for chronic pain. The Euro­pean Medicines Agency re­fused to al­low in­ves­ti­ga­tors to en­roll pa­tients in Europe, and the more than 24,000 who ul­ti­mately joined the study ended up be­ing at low car­dio­vas­cu­lar risk — only about 1 per­cent of pa­tients each year had a heart at­tack or stroke or died from car­dio­vas­cu­lar causes across all three groups.

“Doc­tors may have been ner­vous about giv­ing peo­ple with high car­dio­vas­cu­lar risk a COX-2 in­hibitor,

so they never en­rolled them in the trial,” said Dr. El­liott Ant­man, a car­di­ol­o­gist at Brigham and Women’s Hospi­tal in Bos­ton and as­so­ciate dean for clin­i­cal/ trans­la­tional re­search at Har­vard Med­i­cal School, who was not in­volved in the study.

In ad­di­tion, FitzGer­ald said, the study de­sign in­cluded bi­ases in fa­vor of Cele­brex, a drug with sales once top­ping $2 bil­lion a year that is now avail­able as a generic. Its pa­tent ex­pired in 2014, eight years af­ter the PRE­CI­SION trial started.

The dose of cele­coxib, which is only avail­able as a pre­scrip­tion, was capped at the FDA-ap­proved amount for pa­tients with os­teoarthri­tis arthri­tis, who made up most pa­tients in the trial. But doc­tors could in­crease the pre­scrip­tion­strength dose of ibupro­fen and naproxen to achieve bet­ter pain re­lief. The av­er­age daily dose of cele­coxib was 209 mil­ligrams.

“Less drug ex­po­sure means you’re go­ing to have fewer side ef­fects,” FitzGer­ald said.

The re­searchers also found no in­di­ca­tion that naproxen was safer, as many had thought.

As­pirin use dur­ing the study, which wasn’t re­ported in Sun­day’s re­sults, might have given another ad­van­tage to cele­coxib be­cause ibupro­fen and naproxen can un­der­mine the blood thin­ner’s

ef­fec­tive­ness in pre­vent­ing heart at­tacks and strokes.

Mak­ing the re­sults even harder to un­tan­gle, ex­perts said, is that pa­tients went on and off their as­signed drug, and more than twothirds stopped tak­ing their as­signed drug al­to­gether by the 10-year study’s end.

Guide­lines cur­rently say NSAIDs should in gen­eral be avoided in peo­ple with or at high risk for heart dis­ease and stroke. These latest find­ings won’t change that ad­vice, Ant­man said.

“Use NSAIDs pref­er­en­tially in the low­est-risk pa­tient, give them the low­est dose re­quired to man­age their symp­toms and for the short­est pe­riod of time needed,” said Ant­man, who helped write the AHA’s 2007 rec­om­men­da­tions on NSAID use.

What the find­ings do high­light, FitzGer­ald said, is the need for a per­son­al­ized medicine ap­proach to pre­dict which NSAIDs will work and which ones will cause prob­lems based on a per­son’s unique ge­netic makeup and how they re­spond to en­vi­ron­men­tal fac­tors.

“That’s what counts for a pa­tient. They don’t want to know the av­er­age ef­fect. They want to know what’s go­ing to be the ef­fect for me,” said FitzGer­ald, who is part of a re­search con­sor­tium work­ing to un­der­stand how dif­fer­ent NSAIDs work dif­fer­ently in dif­fer­ent peo­ple.


A bot­tle of Cele­brex is dis­played at a phar­macy in New York. A new study re­leased on Sun­day may re­as­sure mil­lions of arthri­tis suf­fer­ers who want pain re­lief with­out bad side ef­fects. It found that Cele­brex, a drug sim­i­lar to ones with­drawn 12 years ago for safety rea­sons, is no riskier for the heart than some other pre­scrip­tion pain pills that are tough on the stom­ach.

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