The following are summaries of the recent clinical trials published in the New England Journal of Medicine suggesting a cardiovascular risk associated with COX-2 specific inhibitors. The reports and editorial comments are as follows:
- APC trial of celecoxib versus placebo in the prevention of colonic adenomatous polyps;
- APPROVe trial of rofecoxib versus placebo in the prevention of colonic adenomatous polyps;
- Trial of parecoxib/valdecoxib in patients post coronary bypass grafting (CABG);
- Our editorial comments regarding these three studies
…see prior report and discussion of the lumiracoxib versus naproxen/ibuprofen trial in patients with osteoarthritis)
(reference: Solomon et al. NEJM 2005;352)
The APC trial randomized 2035 men and women (age 32-88 years) to receive placebo or celecoxib (400 or 800 mg per day in divided doses) after surgical resection of colorectal adenomas at 91 centers in the United States, Canada, and Australia between November 1999 and 2002. Subjects were followed for 3 years, with a primary outcome measure of colorectal polyp recurrence after 1 and 3 years of therapy. Of note, the primary analysis remains ongoing. Patients were not excluded based on prior cardiovascular disease (CVD) or risk factors for CVD (though randomization was stratified according to the use of aspirin).
Based on the recommendations of the study’s data and safety monitoring board (DSMB), an independent cardiovascular safety committee was organized near the conclusion of the ongoing trial to assess cardiovascular safety. At the time of the convened analysis, 77% of enrolled subjects had completed the trial, while the remaining 23% had all completed at least 2.8 years of follow-up. Although CVD endpoint definitions were not pre-defined before initiation of the study, they were established by the cardiovascular safety committee prior to blinded adjudication and analysis of the data.
Two-thirds of all enrolled subjects were males with a mean age of ~60 years. Baseline characteristics (assessed at enrollment visit via patient report) were balanced among the treatment groups and included subjects with prior MI (~4%), stroke (~2.5%), CHF (~2%), and angina (~7%). Approximately 40% of subjects were designated, as having hypertension, 9% with diabetes, and 17% were current smokers. In each treatment group, approximately 30% of subjects were receiving concomitant aspirin prophylaxis, and 28% were receiving concomitant lipid-lowering drugs.
Incidence of CVD endpoints according to treatment
|Total deaths (number)||6||6||9|
|CVD deaths (number)||1||3||6|
|CVD deaths/1000 pt-yrs||3.4||7.8||11.4|
Hazard Ratio for Composite Endpoint (celecoxib vs. placebo)
|Composite Endpoint||Celecoxib 400 mg/day||Celecoxib 800mg/day|
|HR||95% CI||HR||95% CI|
|Any CVD death||3.0||0.3-28.6||6.1||0.7-50.3|
|Any CVD death + non-fatal MI||3.0||1.0-9.3||3.8||1.3-11.5|
|Any CVD death + non-fatal MI + non-fatal stroke||2.5||1.0-6.4||3.4||1.4-8.5|
|Any CVD death + non-fatal MI + non-fatal stroke + non-fatal CHF||2.3||0.9-5.5||3.4||1.4-7.8|
As baseline characteristics were balanced between groups, neither concomitant use of aspirin or lipid lowering drugs significantly altered the associations calculated above.
Among patients at risk for recurrence of colorectal polyp, continuous celecoxib may be associated with a dose related increase in the composite endpoint of CVD death, non-fatal MI, stroke, and CHF. The measured effect is independent of concomitant use of aspirin or lipid-lowering medication.
(reference: Bresalier et al. NEJM 2005;352)
The APPROVe Trial randomized 2586 men and women (age > 40) to receive placebo or rofecoxib (25 mg per day) within 12 weeks of surgical resection of colorectal adenomas at 108 centers worldwide between February 2000 and November 2001. Subjects were followed for 3 years, with a primary outcome measure of colorectal polyp recurrence after 3 years of therapy. Patients were excluded based on prior CVD or risk factors for CVD (uncontrolled hypertension, angina, CHF, recent (within 1 year) MI, angioplasty, or coronary artery bypass, or recent (within 2 years) stroke or transient ischemic attack (TIA)). Initially, subjects taking low-dose aspirin were excluded. However, in May 2000 the enrollment of subjects receiving < 100 mg of aspirin per day were allowed (but capped at 20% of the total enrolled subjects).
Analysis of cardiovascular safety was planned prior to enrollment. Investigator-reported and adjudicated CVD events were analyzed according to two pre-specified outcomes: Thrombotic events (sudden cardiac death, fatal and non-fatal MI, unstable angina, fatal and non-fatal ischemic stroke, TIA, peripheral arterial and venous thromboses, and pulmonary embolism (PE)) and a composite endpoint (any CVD death + any unknown death + non-fatal MI + any non-fatal stroke). Neither CHF nor accelerated/malignant HTN was accounted for in either endpoint.
On September 30, 2004, based on the interim review of the study’s external safety monitoring board, the trial was terminated due to a disproportionate number of CVD events noted in the rofecoxib group. At termination, 1857 subjects (72%) of subjects had completed three years of treatment. To date, the primary analysis is ongoing and remains blinded.
62% of all enrolled subjects were males with a mean age of 59 years. 9% of subjects had a history of symptomatic atherosclerotic CVD. ~20% of subjects used low-dose aspirin at some point in the trial. Similar to the APC trial, approximately 35% of subjects were designated as having hypertension, 9% with diabetes, and 22% were current smokers. Approximately 28% of subjects were designated as having high cardiovascular risk at baseline based on history of CVD or combined risk factors for CVD. Baseline characteristics were balanced across active treatment and placebo groups. However, during the study a significantly higher proportion of subjects in the rofecoxib group required antihypertensives (44% vs. 36%, p<0.001) or anti-platelet agents (4% vs. 2%, p=0.003).
|HR (95% CI)|
|Mean duration of treatment||2.4 years||2.6 years||—|
|Patient-years of follow-up||3059||3327||—|
|Death from CVD (MI, stroke, or sudden death)||6||5||—|
|Total thrombotic events||46 (1.5/100 pt-yrs)||26 (0.78/100 pt-yrs||1.92 (1.19-3.11)|
|Any cardiac event (fatal/non-fatal MI, sudden death, or unstable angina)||31(1.01/100 pt-yrs)||12 (0.36/100 pt-yrs)||2.80 (1.44-5.45)|
|Any cerebrovascular event (fatal/non-fatal stroke or TIA)||15(0.49/100 pt-yrs)||7 (0.21/100 pt-yrs)||2.32 (0.89-6.74)|
|Peripheral arterial/venous thrombosis or PE||3 (0.10/100 pt-yrs)||7 (0.21/100 pt-yrs)||0.46 (0.08-2.03)|
Rofecoxib-treated patients had a statistically significant higher incidence of cardiac events and total thrombotic events compared to placebo treated patients. Proportional differences between the two treatment groups were not evident until the second 18 months of the trial. No significant interactions were detected in subgroup analysis according to baseline demographic and clinical parameters, including CVD risk factors, previous CVD, and use of low-dose aspirin (at baseline or during the trial).
In addition to the primary endpoints, higher incidences of new or worsening blood pressure and peripheral edema were also observed in the rofecoxib treated group compared to placebo. These differences temporally mirrored a disproportionate increase in incident CHF and pulmonary edema in the rofecoxib group. However, entering the relative changes in blood pressure for the two treatment groups into the statistical model only slightly altered the hazard ratio for total thrombotic events (HR 1.87; 95% CI 1.14-3.06).
Conclusions: Among patients at risk for colorectal polyp recurrence, continuous use of rofecoxib at a dose of 25mg per day is associated with an increased risk of thrombotic events. This increased risk was not reduced by concomitant low dose aspirin.
Parecoxib is a pro-drug form of valdecoxib that is given intravenously. It is not yet approved in the U.S. Its safety and efficacy were evaluated in a large randomized placebo controlled study in patients who underwent elective coronary artery bypass surgery. The safety data from this study were reported in New England journal of Medicine recently (Nussmeier et al. NEJM 2005;352).
1671 men and women age 18-80 years and undergoing elective primary coronary artery bypass grafting (CABG) without recent cardiovascular or GI events, and stable renal function without risk factors for renal complications were randomized to receive valdecoxib (Bextra) and its IV pro-drug parecoxib (Dynastat) in the following way:
|Group 3 (Placebo)
|Parecoxib 40mg IV on morning after CABG
Parecoxib 20mg IV every 12 hrs for 3 days
Valdecoxib 20mg every 12 hrs through day 10
|Placebo IV on morning after CABG
Placebo IV every 12 hrs for 3 days
Valdecoxib 20mg p.o. every 12 hrs through day 10
|Placebo IV on morning after CABG
-then- Placebo IV every 12 hrs for 3 days
Placebo p.o. every 12 hrs through day 10
Patients were allowed opiates for pain control. All patients received low-dose aspirin. Patients were followed for 30 days for the occurrence of any cardiovascular event (MI, unstable angina, sudden cardiac death, unexpected unidentified death, ischemic/hemorrhagic stoke, TIA, peripheral vascular occlusion, or pulmonary embolus), renal insufficiency (severe renal dysfunction or need for dialysis), complication of peptic ulcer (bleeding ulcer, perforation, or obstruction), or surgical wound complication.
Approximately 85% of enrolled patients were male with a mean age of 62 years. Baseline preoperative characteristics, including race/ethnicity, BMI, and comorbid diseases were balanced between treatment groups. The occurrence of pre-specified adverse events according to treatment group was as follows (only patients who received the assigned treatment were analyzed):
|Group 2 vs. placebo
|Group 1 vs.Placebo
|Group 1 + Group 2 vs. placebo
RR (95% CI)
|Any confirmed event||22||40||1.9 (1.1-3.2)||40||1.9 (1.1-3.2)||1.9 (1.1-3.2)|
|Cardiovascular events||3||6||2.0(0.5-8.1)||11||3.7 (1.0-13.5)||2.9 (0.8-9.9)|
|Renal events||3||4||1.3(0.3-6.0)||7||2.4 (0.6-9.2)||1.9 (0.5-6.7)|
|GI events||2||4||2.0(0.4-11.1)||7||3.0 (0.6-15.2)||2.5 0.6-11.6)|
|Surgical-wound events||16||27||1.7 (0.9-3.3)||20||1.3 (0.7-2.5)||1.5 (0.8-2.7)|
|Deaths||1||3||3.0 (0.3-29.3)||4||4.1 (0.5-36.4)||3.6 (0.4-29.1)|
The use of parecoxib and valdecoxib for post-surgical pain control following elective CABG is associated with an increase in cardiovascular events.
Prior attempts to ascertain the potential association of COX-2 inhibitors with CV events have compared treatment with COX-2 specific inhibitors to conventional NSAIDs in patients with RA and/or OA for < twelve months of treatment. The APC and APPROVe studies add an important new dimension in providing a placebo control and a much longer duration of treatment. Both of these studies show an increased risk for CV events in the COX-2 specific inhibitor group compared to placebo.
The celecoxib APC results are in sharp contrast, however, to those of the following studies in which the incidence of CV events was NOT statistically different between the celecoxib and comparator NSAID and/or placebo groups: a) the CLASS study (a 6 month trial in RA and OA patients comparing celecoxib to ibuprofen and diclofenac); b) the unpublished PreSAP trial (also a placebo-controlled adenoma prevention trial comparing celecoxib to placebo); and c) the unpublished ADAPT trial (an Alzheimer’s prevention trial comparing celecoxib, placebo and naproxen in elderly patients).
On the other hand, the results of the rofecoxib APPROVe study are consistent with those of the previously published VIGOR study in RA patients in which treatment with rofecoxib was associated with a higher incidence of CV events when compared with naproxen.
The parecoxib/valdecoxib study in patients undergoing CABG is very disturbing given the observed increase in CV events in the parecoxib/valdecoxib treated group within a very short treatment period. These results are also in sharp contrast, however, to those from prior valdecoxib studies in OA and RA patients in which a cardiovascular “signal” with valdecoxib was not observed. It could be argued, because post-CABG patients have extremely high risk for CV events and they received higher than FDA approved doses of valdecosib, that the results from these patients should not be applied to patient groups at lower risk. Having said that, however, it is important to note that none of the arthritis studies with valdecoxib were longer than 6 months and the overall number of patients treated is quite small (approximately, 3000). Thus, the true risk for CV events in arthritis populations is unknown and would require longer duration studies.
These studies, taken together, raise the likelihood that there is an increased risk of CV events with the class of COX-2 specific inhibitors, and that this risk appears to be higher for rofecoxib and valdecoxib than for celecoxib. Just how significant this risk is, particularly when considered in context of the potential benefits of the drugs, was the subject of the recent Food and Drug Administration meeting.
There are two other COX-2 specific inhibitors that are in development: 1) etoricoxib (Arcoxia; approved in Europe but not in the U.S.); and lumiracoxib. The lumiracoxib TARGET study was summarized earlier on this website. Data from the etoricoxib studies will be summarized in a review of the FDA meeting to be posted on this site very soon. Watch for it !! Review of the cumulative data of CV risk with all NSAIDs (conventional and COX-2 specific) raised the possibility that CV risk with conventional NSAIDs may not be negligible either. This topic will be discussed in the review of the FDA meeting.