terbogrel and Hypertension--Pulmonary

Many targeted therapies have been approved for pulmonary arterial hypertension (PAH), most of which are in oral forms. However, the effects of these drugs on lifesaving are unclear. Our objective was to evaluate the effects of oral treatments on clinical outcomes especially all-cause mortality in patients with PAH.. MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched for relevant articles up to April 2014. Randomized, double-blind, parallel-group clinical trials that compared oral agents with placebo were selected. Data for populations, interventions, and outcomes were extracted independently by 2 investigators, and disagreements were resolved by consensus. Quality assessment was performed using the Cochrane risk-of-bias tool.. Twenty-one randomized, controlled, clinical trials involving 5105 patients were identified in the primary analysis. The overall estimated odds ratio (OR) of combined clinical worsening (CCW) events between active treatment groups and control groups was 0.55 (95% CI 0.47-0.64, P < .001). However, the effect of oral treatments on reducing all-cause mortality was not statistically significant (OR 0.82, 95% CI 0.61-1.10, P = .192), which was consistent for approved drugs (OR 0.84, 95% CI 0.61-1.18, P = .316) and drugs that were not approved (OR 0.72, 95% CI 0.36-1.44, P = .352). In the sensitivity analysis, a significant reduction was achieved in CCW events (P < .001) but not in all-cause mortality (P = .057).. This pooled analysis shows the benefits of oral treatments on CCW events in patients with PAH. However, these drugs seem to exhibit less favorable effects on life expectancy in the short-term follow-up, suggesting further evaluation is required.

Topics: Administration, Oral; Antihypertensive Agents; Benzamides; Endothelin Receptor Antagonists; Exercise Test; Humans; Hypertension, Pulmonary; Imatinib Mesylate; Phosphodiesterase 5 Inhibitors; Piperazines; Prostaglandins; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Pyrimidines; Treatment Outcome; Vasodilator Agents

Inhaled nitric oxide (INO) is a selective pulmonary vasodilator that has the ability to produce vasodilation in the pulmonary vascular bed without causing it in the systemic circulation. This property of INO has made it a useful therapy in the management of both adult and paediatric patients with a variety of conditions associated with pulmonary hypertension (PH), with or without hypoxia. Toxicity, cost and negative-outcome studies have prompted a search for alternative agents. These include inhaled prostacyclin and alternative prostaglandin preparations such as inhaled iloprost, treprostinol and beraprost. The phospodiesterase inhibitors show real potential in the management of both acute and chronic forms of PH, and antagonists of endogenous pulmonary vasoconstrictors, such as endothelin and thromboxane, are being evaluated for the long-term treatment of conditions such as primary pulmonary hypertension.

Topics: Administration, Inhalation; Adrenomedullin; Endothelins; Humans; Hypertension, Pulmonary; Nitric Oxide Donors; Peptides; Phosphodiesterase Inhibitors; Pyridines; Thromboxane-A Synthase; Vasodilator Agents

Past medical therapy for pulmonary arterial hypertension included the use of calcium-channel antagonists in acute vasoreactive subjects and oral anticoagulants and continuous intravenous administration of epoprostenol in the more severe cases. Recently, the thromboxane inhibitor terbogrel, the prostacyclin analogues treprostinil, beraprost and iloprost, and the endothelin receptor antagonist bosentan have been tested in clinical trials in >1,100 patients. Except for terbogrel, all compounds improved the mean exercise capacity by different degrees, as assessed by the 6-min walk test. In the evaluation of the clinical relevance of exercise capacity improvements, additional elements need to be considered, such as baseline functional class and concomitant favourable effects on combined clinical events (including hospitalisations, mortality and rescue therapies), quality of life and haemodynamics. No trials have shown effects on mortality, as the study protocols were not designed for assessing this end-point. Each new compound presents side-effects that are unpredictable in the individual patient and require appropriate attention upon treatment initiation and maintenance. These new therapeutic options will be available in the near future and will allow tailoring of the most appropriate treatment to the single patient, according to an individualised benefit-to-risk ratio.

Topics: Dose-Response Relationship, Drug; Drug Administration Schedule; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Iloprost; Male; Prognosis; Pyridines; Randomized Controlled Trials as Topic; Severity of Illness Index; Survival Rate; Treatment Outcome; Vasodilator Agents

Circulating mediators, including thromboxane A2, the vasoconstrictor, platelet aggregant, and smooth muscle mitogen, may contribute to the progression of vascular narrowing in primary pulmonary hypertension (PPH).. To further understand the contribution of thromboxane and to provide novel therapy for PPH, we administered the potent orally active thromboxane synthetase inhibitor and thromboxane receptor antagonist terbogrel for 12 weeks to patients with New York Heart Association functional classification II and III PPH. The study had a multicenter randomized placebo-controlled design. The primary endpoint was a change in the distance walked during 6 minutes. The pharmacologic effects of terbogrel on thromboxane and prostacyclin metabolism also were studied.. Although the planned enrollment was 135 patients, the study was halted after only 71 patients had been randomized because of the unforeseen side effect of leg pain, which occurred almost exclusively in patients with terbogrel treatment. Only 52 patients completed the 12-week study, and only 22 patients (31%) were fully compliant with the study medication. The leg pain confounded the primary endpoint of walking distance. On an intention-to-treat analysis, no improvements in 6-minute walk distance or in hemodynamics in patients with terbogrel treatment were seen. However, terbogrel was effective from a pharmacologic standpoint, reducing thromboxane metabolites by as much as 98% (P <.0001), with a modest but statistically insignificant (39%) rise in prostacyclin metabolites.. Inhibition of thromboxane with an orally active agent is feasible in PPH, but the incidence of severe leg pain with terbogrel precludes its use in this disorder. Similar therapeutic efforts, with other thromboxane inhibitors, should be considered.

Topics: Double-Blind Method; Enzyme Inhibitors; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Platelet Aggregation Inhibitors; Pyridines; Thromboxane-A Synthase; Walking

The pulmonary vasoconstrictor, thromboxane, may contribute to the development of pulmonary hypertension. Our objective was to determine whether a combined thromboxane synthase inhibitor-receptor antagonist, terbogrel, prevents pulmonary hypertension and the development of aberrant pulmonary arterial responses in newborn piglets exposed to 3 days of hypoxia. Piglets were maintained in room air (control) or 11% O(2) (hypoxic) for 3 days. Some hypoxic piglets received terbogrel (10 mg/kg po bid). Pulmonary arterial pressure, pulmonary wedge pressure, and cardiac output were measured in anesthetized animals. A cannulated artery technique was used to measure responses to acetylcholine. Pulmonary vascular resistance for terbogrel-treated hypoxic piglets was almost one-half the value of untreated hypoxic piglets but remained greater than values for control piglets. Dilation to acetylcholine in preconstricted pulmonary arteries was greater for terbogrel-treated hypoxic than for untreated hypoxic piglets, but it was less for pulmonary arteries from both groups of hypoxic piglets than for control piglets. Terbogrel may ameliorate pulmonary artery dysfunction and attenuate the development of chronic hypoxia-induced pulmonary hypertension in newborns.

Topics: Animals; Chronic Disease; Hypertension, Pulmonary; Hypoxia; Pulmonary Circulation; Pyridines; Swine; Thromboxanes