Cardiovascular and renal drugs pdf

Diabetes Care. Bromocriptine is a sympatholytic D2-dopamine agonist that has been approved for the treatment of type 2 diabetes. Based on animal and human studies, timed bromocriptine administration within 2 h of … Expand.

View 2 excerpts, references background. Dopamineagonist and heart failure in patients with Parkinson's disease: a nested case control study on multiple health care databases. Proceedings of the European Society of Cardiology Congress. The relative risk difference became significant 18 months after the start of drug administration [ 13 ].

The number of cardiovascular events across all arms was similar with no statistically significant differences. Several theories were formed in an effort to explain the conflicting results of large clinical trials with rofecoxib and celecoxib. According to the first published theory, the difference in the number of thrombotic events between the arms in VIGOR was not caused by a negative effect of rofecoxib, but by a cardioprotective effect of naproxen. Some studies have indeed shown a moderate protective effect with naproxen, but it appears that the difference between naproxen and rofecoxib in the VIGOR study was too large to be explained only by naproxen-mediated protection [ 15 ].

Baseline CV risk of patients appears to be an important predictor of risk of cardiovascular adverse effects of coxibs [ 16 ]. This seems unlikely though, because the difference in risk of CV events between celecoxib and traditional NSAID users was not found to be significant in a post-hoc analysis of subjects without aspirin use [ 14 ].

One of the most accepted theories explains the difference by the higher COX-2 selectivity of rofecoxib. In theory, this would cause a more pronounced disbalance between thrombogenic and anti-aggregatory prostanoids. On the other hand, the whole body of evidence gathered from all clinical studies ever conducted with various coxibs and NSAIDs show that increasing selectivity is not always linked to increasing CV risk. Apparently there must be other factors that come into play. Pharmacokinetic and pharmacodynamic characteristics of individual NSAIDs might be more important than initially expected.

Celecoxib has a shorter half-life than rofecoxib that theoretically might allow the regeneration of vascular prostacyclin at the end of the dosing interval. Also, the influence of blood pressure cannot be underestimated. The Framingham study showed it to be an important predictor of CV complications.

Celecoxib affects blood pressure less than rofecoxib and the exact mechanism leading to this difference is unknown. The reason might lie in the suppressive effect of high dose rofecoxib on degradation of aldosterone. Additionally, celecoxib seems to be a weak inhibitor of carbonic anhydrase [ 17 ]. The above described different effects on blood pressure could have far-reaching implications for long-term therapy, though the consequences of short-term treatment, lasting only weeks to a few months are questionable.

Solomon, et al. Based on the results, it appears that the risk of cardiovascular adverse events during treatment with celecoxib depends on two factors: a baseline cardiovascular risk of patients and b the dose of the drug used. Particularly important, is the interaction of these factors, which means enhancement of the effect of celecoxib dose in high-risk people. Compared with placebo, the relative risk for all doses combined was found to be 1. The study compared mg celecoxib two times a day with mg ibuprofen three times a day and mg naproxen two times a day.

The subjects suffered from osteoarthritis or rheumatoid arthritis and at the same time were at increased risk for CV events. Celecoxib was found to be non-inferior to ibuprofen and naproxen for the primary outcome of a composite of CV death, non-fatal myocardial infarction MI cor non-fatal stroke.

Clinical studies of newer coxibs also brought distressing results. In patients not on low dose ASA, cardiovascular events occurred more frequently in the selective COX-2 group, but the difference was not statistically significant 0. The study group consisted of patients with osteoarthritis [ 19 ]. In another study enrolling patients after coronary artery bypass grafting CABG , a series of events affecting the cardiovascular system emerged, ultimately leading to rejection of parecoxib prodrug of valdecoxib by the food and drug administration FDA [ 20 ].

An increased number of cardiovascular events compared with placebo and with traditional NSAIDs was also reported in the case of etoricoxib [ 22 ]. On the other hand, in the recently published retrospective analysis by de Souza Brito, et al. The study included a robust number of patients. On the other hand, all NSAIDs were grouped together without specifying the actual medications used, which poses a significant limitation. Therefore in recent years, the cardiovascular safety of NSAIDs has been addressed in many clinical trials and meta-analyses.

Trelle, et al. These conditions were met by 31 studies, involving a total of , patients with over , patient-years of follow-up. The primary outcome was acute myocardial infarction AMI. As secondary outcomes, stroke, CV death and death from any cause were studied. Results were statistically evaluated for three non-selective NSAIDs naproxen, ibuprofen, diclofenac and four coxibs rofecoxib, celecoxib, lumiracoxib, etoricoxib.

Another meta-analysis of randomized trials found RR of major coronary events to be 1. The increased risk of thrombotic events mediated by non-selective NSAIDs and selective COX-2 inhibitors has been also shown by large-scale epidemiological studies.

The results of 23 controlled observational studies six cohort and 17 case-control were summarized by McGettigan and Henry in their meta-analysis [ 26 ].

The case-control studies included 86, patients with cardiovascular events and , controls. Patients were followed for more than , patient-years. The RR of AMI and death from coronary causes during analgesic therapy lasting less than 90 days: naproxen- 0. The first theory trying to explain the risk of thrombotic events of selective COX-2 inhibitors was based on the assumption that COX-2 in the vessel wall was an important source of prostacyclin, whereas COX-1 was responsible for the production of thromboxane in platelets.

Selective COX-2 inhibition would in this situation decrease the production of PGI-2, which is a vasodilating and antithrombotic substance, without inhibiting the vasoconstricting and thrombogenic TXA The resulting imbalance between pro-thrombotic and antithrombotic factors could lead to thrombosis [ 28 ].

On the other hand, the greater risk of thrombotic events with highly selective COX-2 inhibitors when compared with non-selective NSAIDs apparently cannot be explained only by the concomitant inhibition of platelet function with the non-selective agents. This happens only with aspirin, and in certain situations with high dose naproxen [ 29 ]. The overall strength of COX-2 inhibition appears to be the most important determinant of cardiovascular risk [ 29 ]. Results of numerous experiments show the important role of COX-2 in production of prostacyclin in the vascular bed [ 30 ].

The inhibition of PGI-2 production causes an increase in vascular tone, blood pressure elevation, thrombogenic state and likely atherosclerosis. Cyclooxygenase-2 and PGI-2 also seem to play a key role in the resistance of the myocardium to ischemic-reperfusion injury observed after ischemic preconditioning or after administration of certain medications [ 31 - 32 ].

The potential importance of cardioprotective effects of COX-2 was also underscored in the position paper written by the working group for cardiovascular pharmacotherapy of the European Society of Cardiology [ 33 ]. Administration of statins before ischemia leads to reduction in the size of myocardial necrosis in animal models of ischemia-reperfusion injury.

Selective COX-2 inhibition attenuates this statin-induced cardioprotection [ 32 - 34 ]. In their study, Birnbaum, et al. In a study on healthy volunteers, it was demonstrated that administration of rosuvastatin before forearm ischemia results in a reduction of endothelial dysfunction induced by ischemia and reperfusion and that the beneficial effect of the statin disappears if celecoxib is co-administered [ 36 ].

Guidelines for the management of various forms of coronary artery disease recommend administration of statins to normocholesterolemic patients at high risk of coronary events [ 37 ]. The clinical benefit of statin therapy in this situation might at least partially be mediated by its pleiotropic effects. FDA is establishing a docket for public comment on this meeting. The docket number is FDAN The docket will close on December 15, Submit either electronic or written comments on this public meeting by December 15, Please note that late, untimely filed comments will not be considered.

Electronic comments must be submitted on or before December 15, Eastern Time at the end of December 15, Comments received on or before December 1, will be provided to the committee. Comments received after that date but by December 15, will be taken into consideration by FDA.

Background material and the link to the online teleconference meeting room will be available at: Meeting Materials, Cardiovascular and Renal Drugs Advisory Committee. Scroll down to the appropriate advisory committee meeting link. The meeting will include slide presentations with audio components to allow the presentation of materials in a manner that most closely resembles an in-person advisory committee meeting. Interested persons may present data, information, or views, orally or in writing, on issues pending before the committee.

FDA is establishing a docket for public comment on this meeting. The docket will close on December 7, Submit either electronic or written comments on this public meeting by December 7, Please note that late, untimely filed comments will not be considered.

Electronic comments must be submitted on or before December 7,