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OUR MISSION: TO REDUCE THE BURDEN OF CARDIOVASCULAR DISEASE
Dr. Simon Gibbs,
While the outcomes of treating pulmonary arterial hypertension in expert centres have improved over the last decade, there remains unacceptable mortality and morbidity. There are two major therapeutic drives to improve the situation. Combination drug therapy is arguably the hottest topic in the clinic. Approved drug therapies target three distinct pathways: nitric oxide, prostacyclin and endothelin. Combination therapy creates the potential for synergistic effects but currently there is a lack of evidence about the best strategy to combine drugs that target these pathways. Getting patients into WHO functional classes I or II is ambitious but a much needed goal which many patients fail to achieve on traditional sequential combination therapy regimes. Starting patients on combination therapy from diagnosis is now being investigated in the AMBITION trial which will compare “up-front” combination therapy against monotherapy. A large number of novel agents which interfere with established signalling pathways have been tested successfully in animal models of pulmonary arterial hypertension and are now being investigated in clinical trials. Some of these are already in Phase III trials and include riociguat, a pulmonary vasodilator which increases the sensitivity of native soluble guanylate cyclase to nitric oxide as well as directly stimulating this enzyme; selexipag which stimulates the IP prostacyclin receptor and unlike prostacyclin itself is given orally; macitentan, an endothelin A and B receptor blocker which appears to have greater activity in basal tissue compared to other endothelin receptor antagonists; and imatinib which is a tyrosine kinase inhibitor and antiproliferative agent. Since animal models have a poor record of reliably predicting efficacy in human disease, the results of these trials must be awaited before these drugs find a use in clinical practice.
New approaches to the treatment of pulmonary hypertension
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