Prothrombotic effects of coxibs not convincingly demonstrated

[Guest guest]

Dec 6, 2002

Prothrombotic effects of coxibs " not convincingly demonstrated "

Two leading rheumatologists have reviewed the clinical data that has given

rise to the concern over cardiovascular (CV) events with the selective COX-2

inhibitors and conclude that prothrombotic effects " have not been

convincingly demonstrated. " Dr Vibeke Strand (Stanford University, CA) and

Dr Marc Hochberg (University of land, Baltimore) discuss the issue in

some detail in an editorial in Arthritis & Rheumatism-Arthritis Care &

Research [1].

Strand and Hochberg confine their discussion to the 2 original drugs in this

classcelecoxib (Celebrex®, Pharmacia & Pfizer) and rofecoxib (Vioxx®, Merck

& Co). They dissect the clinical data that has given rise to the CV

concerns, discussing in detail findings from both the VIGOR and CLASS

trials, and they also report comments made at the FDA advisory committee

meetings that reviewed these data in early 2001. This includes a remark from

Dr J Faich that neither the CLASS nor VIGOR trial (both involving around

8000 patients each) were designed or powered to demonstrate prothrombotic

effects of selective COX-2 agents and that such a trial would require

treatment groups of around 20 000 patients. The editorialists conclude that:

" The observed differences in thromboembolic CV events between the treatment

groups on VIGOR require confirmation in another large, adequately powered

randomized clinical trial before the findings can be accepted. "

Although these data were already in the public domain, Strand and Hochberg

comment that " broad recognition and discussion of these potential CV safety

issues did not occur " until a group of cardiologists highlighted the issue

in a Journal of the American Medical Society paper in the summer of 2001

[2]. In that paper, Dr Debabrata Murkherjee (University of Michigan, Ann

Arbor), Dr Nissen, and Dr Topol (both at the Cleveland Clinic

Foundation, OH) concluded, based on a meta-analysis of data from placebo

groups in primary prevention clinical trials, that patients who received

selective COX-2 agents in the CLASS and VIGOR trials appeared to be

associated with an increased risk for CV events. The issue received wide

coverage in US newspapers, some of it of a rather alarmist nature, as

reported by rheumawire at the time. But the meta-analysis on which the

conclusions were based was severely criticized, both at the time and

subsequently. In their editorial, Strand and Hochberg pull it to pieces and

say the comparisons made by Murkherjee and colleagues are " fraught with

methodologic limitations " and are of " dubious validity. "

As reported on rheumawire last week, the same cardiologists recently

reiterated their concerns over the CV effects of selective COX-2 inhibitors,

throwing into the debate recent findings with a new drug in this class,

etorixib (ArcoxiaTM, Merck & Co) and new preclinical data [3]. But at the

same time, a UK group of researchers has queried the evidence on which the

widespread concern over CV events is based [4].

As debate rumbles on, what's a clinician to do?

The issue of CV events with selective COX-2 inhibitors will no doubt rumble

on and on, but in the meantime, what is a clinician to do? As Strand and

Hochberg point out, guidance is needed for the practitioner prescribing

these agents to patients with arthritis. In their editorial, they set out

several pointers, and Hochberg elaborated on these in an interview with

rheumawire:

* Patients who have had a major cardiovascular thrombotic event or those

who are in need of secondary prophylaxis for cardiovascular thrombotic

eventseg, patients with angina or transient ischemic attacksshould be

treated with low-dose aspirin; it appears that the preferential

gastrointestinal safety of the selective COX-2 inhibitors over traditional

NSAIDs is preserved, even when low-dose aspirin is used concomitantly,

although this point is controversial.

* In patients who have identified risk factors for gastrointestinal

adverse events and are taking low-dose aspirin, concomitant administration

of proton pump inhibitors should be seriously considered even when

administering a selective COX-2 inhibitor.

* For patients who have not had a major cardiovascular event, physicians

must use their own clinical judgment to decide whether or not to prescribe

low-dose aspirin for primary prophylaxis, based on the patients' risk factor

profiles.