Gastrointestinal Safety Profile of Selective COX-2 Inhibitors

16 May

The hypothesis that selective COX-2 inhibitors may provide an improved risk- benefit ratio in terms of gastrointestinal safety as compared with conventional NSAIDs was tested in three large phase III clinical trials on a total of 35,000 pa- tients. In the Gastrointestinal Outcomes Research (VIGOR) study (Bombardier et al. 2000) and in the Therapeutic  Arthritis  Research and Gastrointestinal Event Trial (TARGET) (Schnitzer et al. 2004) rofecoxib and lumiracoxib were found to decrease the risk of confirmed gastrointestinal  events (including ul- cerations, bleedings, and perforations) associated with traditional NSAIDs by more than 50%. In the Celecoxib Long-term Arthritis Safety Study (CLASS), however, a significant  beneficial effect of celecoxib was only evident when the definition  of upper  gastrointestinal  endpoints  was expanded  to include symptomatic  ulcers (Silverstein et al. 2000). Moreover, outcomes of the first

6 months were published instead of the complete 1-year data of this study. In addition, both the CLASS and TARGET studies have clearly shown that patients receiving low-dose aspirin for cardiovascular protection  do not benefit from the gastrointestinal safety of these drugs.

Another interesting finding of the past few years was the observation that COX-2 may influence ulcer healing and the associated angiogenesis. In accord with this concept, COX-2 has previously been shown to be induced in tissue

on the edges of ulcers (Mizuno et al. 1997). In animal studies selective COX-2 inhibitors have been demonstrated to retard ulcer healing (Schmassmann et al.

1998). Consequently, it is necessary to test whether effective ulcer healing oc-

curs in patients  with NSAID-associated ulcers switched to selective COX-2 inhibitors.

Cardiovascular Side Effects

Selective COX-2 inhibitors  have been associated with an increased incidence of cardiovascular  side effects. First data  supporting  a respective risk were published in the VIGOR study, where patients receiving rofecoxib had a sig- nificant fourfold increase in the incidence of myocardial infarctions, as com-

pared with patients randomized  to naproxen (Bombardier et al. 2000). There are  several reasons  for  the  fact that  these  results  have not  been  consid- ered  sufficiently. Accordingly, in the CLASS and  TARGET trials  no statis- tically significant  difference  was noted  in the  incidence  of cardiovascular events (cerebrovascular accident, myocardial infarction, angina) between cele- coxib/lumiracoxib and standard NSAIDs (Silverstein et al. 2000; Farkouh et al.

2004). However, in the latter trials patients with osteoarthritis were included. By contrast,  the VIGOR study was performed  on patients  with rheumatoid arthritis,  a condition  that  has  been  associated  with an  enhanced  rate  of cardiovascular  events. Moreover, about  a quarter  of the  patients  included in the CLASS and TARGET trials took aspirin  as a cardioprotective  agent, whereas the entry criteria for the VIGOR study precluded aspirin consump- tion.


Recently, long-term studies intended  to find out whether selective COX-2 inhibitors may be used to prevent the formation of adenomatous colon polyps (adenomatous polyposis prevention study with rofecoxib: APPROVe; adenoma prevention with celecoxib: APC) or Alzheimer’s disease (Alzheimer’s Disease anti-inflammatory Prevention  Trial: ADAPT) have shown that selective and nonselective  COX inhibitors  may increase  the incidence  of cardiac  infarc- tions  and  other  cardiovascular  reactions  (NIH 2004; Bresalier et al. 2005; Solomon et al. 2005). In these studies, the effect became fully evident only after treatment  for more than 1 1  years in otherwise healthy patients. More- over, in high-risk  patients  short-term treatment  with valdecoxib/parecoxib was associated with an increased rate of severe thromboembolic  events (Ott et al. 2003; Nussmeier et al. 2005). These observations had variable pharma- copolitical consequences including the withdrawal of rofecoxib (Vioxx) and valdecoxib (Bextra) from the market.  Moreover, the outcome  of these tri- als prompted  regulatory  bodies to request  changes in the labeling of both selective and nonselective COX inhibitors, including those available for over- the-counter  use (FDA 2005). Consequently, until proof of the opposite, all of these drugs are believed to go along with, at least in long-term  use, an in- creased cardiovascular risk. To minimize this risk, the respective substances should be taken at the lowest effective dose for the shortest  possible dura- tion of treatment  (European Agency for the Evaluation of Medicinal Products

2005a, b).

Scientifically these observations pose new questions: It has been assumed before that selective COX-2 inhibitors that do not inhibit platelet COX-1 might unfavorably alter the thromboxane/prostacyclin balance by inhibiting exclu- sively COX-2-dependent synthesis of vasoprotective prostacyclin in endothe- lial cells (Cheng et al. 2002). In fact, prostacyclin  is a potent  inhibitor  of platelet aggregation, activation, and adhesion  of leukocytes, and accumula- tion of cholesterol in vascular cells. Recent evidence, however, supports  the view that disturbance of the thromboxane/prostacyclin balance cannot be the sole mechanism conferring the cardiovascular risk of COX-2 inhibitors.  Ac-

cordingly, patients  with coronary artery bypass grafting experienced severe cardiovascular events by valdecoxib/parecoxib, albeit apparently protected by low-dose aspirin (Ott et al. 2003; Nussmeier et al. 2005). Likewise, a subgroup analysis from the APC trial has demonstrated that aspirin may not abrogate the potential cardiovascular harm of celecoxib (Solomon et al. 2005). More- over, given that in all long-term studies with coxibs and NSAIDs performed so far, an increased cardiovascular risk became evident after prolonged drug administration only, it appears  feasible that  a permanent  COX-2 blockade may play a crucial role in the development  of cardiovascular  events. In line with this concept, COX-2-derived prostaglandins  have been shown recently to upregulate  the expression of the thrombin  inhibitor  thrombomodulin in human smooth muscle cells, thus providing a molecular basis for a hitherto unknown platelet-independent mechanism underlying the prothrombotic ef- fects of both selective and nonselective COX-2 inhibitors (Rabausch et al. 2005). In this context it is also noteworthy  that the traditional  NSAID diclofenac, given as a retarded form, elicits a more pronounced inhibition of intravascular COX-2-dependent prostaglandin formation as compared to rofecoxib and cele- coxib (Hinz et al. 2006). Finally, a recently published population-based nested case-control  analysis has shown an increased  risk of myocardial  infarction associated with the current use of both selective (rofecoxib) and nonselective (diclofenac, ibuprofen) COX-2 inhibitors (Hippisley-Cox and Coupland 2005). Even though the methodology used in this study has been called in question, a potentially increased risk of traditional  NSAIDs in eliciting myocardial in- farctions warrants attention.  Consequently, the cardiovascular safety of both selective COX-2 inhibitors  and conventional NSAIDs should be reconsidered in future studies.

Although myocardial infarctions provide valuable data concerning cardio- vascular safety of drugs, the cardiorenal profiles of NSAIDs and selective COX-2 inhibitors  have also to be considered. As a matter of fact, the involvement of COX-2 in human renal function is supported by numerous clinical studies that showed that selective COX-2 inhibitors,  similar to other NSAIDs, may cause peripheral  edema, hypertension,  and exacerbation of pre-existing hyperten- sion by inhibiting  water and salt excretion by the kidneys (Catella-Lawson et al. 1999; Whelton et al. 2000; Schwarz et al. 2000). These observations are of immense importance given that relatively small changes in blood pressure could have a significant  impact  on cardiovascular  events. In patients  with osteoarthritis, increases in systolic blood pressure  of 1–5 mmHg have been associated  with 7,100–35,700 additional  ischemic heart  disease and  stroke events over 1 year (Singh et al. 2003). Likewise, the hypertension  optimal treatment  (HOT) study showed that diastolic blood pressure  differences of

+4 mmHg can lead to a 28% increase in myocardial  infarctions  (Hansson et al. 1998).

Future Developments

The available traditional antipyretic analgesics and selective COX-2 inhibitors still leave space for additional compounds. For acute pain a compound that is absorbed fast, fully bioavailable, and eliminated quickly (such as ibuprofen) might be of interest.

Inhibiting COX-1, COX-2, and 5-lipoxygenase (5-LOX) may be rewarding for the treatment  of osteoarthrosis.  The advantage of such compounds would

be that  they are not  associated  with alternative  processing  of arachidonic acid via the 5-LOX pathway. In fact, leukotrienes  generated  by 5-LOX may cause adhesion of neutrophils and vasoconstriction, resulting in ischemia and

consequently mucosal lesions. A compound claimed to be endowed with such dual COX-/LOX-inhibitory properties is licofelone (ML3000) (Tries et al. 2002). However, clinical data supporting  the claims are still scarce. Likewise, nitric

oxide (NO)-releasing NSAIDs are widely discussed. They are hoped to protect the gastrointestinal  tract by releasing vasodilatory NO and to produce the full therapeutic effects of, e.g., diclofenac or naproxen (Wallace 2002).

So far, hard  clinical data are missing despite many years of research.  It

is also unclear how patients  and physicians will solve the dosing problems of such compounds,  which release two active ingredients  (NO and NSAID) with different  pharmacokinetic and toxicological properties.  The microso- mal prostaglandin  E synthase I that is coexpressed with COX-2 under diverse inflammatory  conditions  may represent  a potential  target  for treatment  of inflammatory  pain (Jakobsson et al. 1999). From the pharmacological point of view an inhibition  of this enzyme would open the opportunity to inhibit the production  of COX-2-dependent proinflammatory PGE2 without a con- comitant  blockade of COX-2-dependent prostacyclin, which confers various protective actions in the cardiovascular  and renal system. Finally, targeting of individual PG receptor  subtypes may permit a separation  of desired and unwanted  effects of NSAIDs. Recently, blockade of the EP2 receptor  has at- tracted  attention  as a possible target  for centrally acting, antihyperalgesic agents (Reinold et al. 2005).


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