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Failure to uptitrate BB doses may be partly to blame. To explore other options for lowering HR and improving angina control, CONTROL-2 was initiated to compare the efficacy and tolerability of the combination of BBs with ivabradine versus uptitration of BBs to maximal tolerated dose, in patients with stable angina.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>This multicenter, open, randomized study included 1104 patients with Canadian Cardiovascular Society (CCS) class II or III stable angina, in sinus rhythm, and on background stable treatment with non-maximal recommended doses of BBs. Consecutive patients were allocated to ivabradine\u00a0+\u00a0BB or BB uptitration in a 4:1 ratio.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>At the end of the study (week 16), addition of ivabradine to BB treatment and BB uptitration resulted in reduction in HR (61\u00a0\u00b1\u00a06 vs. 63\u00a0\u00b1\u00a08\u00a0bpm; <jats:italic>p<\/jats:italic>\u00a0=\u00a00.001). At week 16, significantly more patients on ivabradine\u00a0+\u00a0BB were in CCS class I than with BB uptitration (37.1% vs. 28%; <jats:italic>p<\/jats:italic>\u00a0=\u00a00.017) and significantly more patients were angina-free (50.6% vs. 34.2%; <jats:italic>p<\/jats:italic>\u00a0&lt;\u00a00.001). Patient health status based on the visual analogue scale (VAS) was also better in the ivabradine\u00a0+\u00a0BB group. Adverse events (AEs) were significantly more common with BB uptitration than with the ivabradine\u00a0+\u00a0BB combination (18.4% vs. 9.4%, <jats:italic>p<\/jats:italic>\u00a0&lt;\u00a00.001).<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>In patients with stable angina, combination therapy with ivabradine\u00a0+\u00a0BB demonstrated good tolerability, safety, and more pronounced clinical improvement, compared to BB uptitration.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Trial Registration<\/jats:title>\n                <jats:p>ISRCTN30654443.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Funding<\/jats:title>\n                <jats:p>Servier.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s12325-018-0681-5","type":"journal-article","created":{"date-parts":[[2018,3,5]],"date-time":"2018-03-05T09:56:09Z","timestamp":1520243769000},"page":"341-352","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Efficacy of Ivabradine in Combination with Beta-Blockers Versus Uptitration of Beta-Blockers in Patients with Stable Angina (CONTROL-2 Study)"],"prefix":"10.1007","volume":"35","clinical-trial-number":[{"clinical-trial-number":"isrctn30654443","registry":"10.18810\/isrctn"}],"author":[{"given":"Maria","family":"Glezer","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuri","family":"Vasyuk","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuri","family":"Karpov","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2018,3,5]]},"reference":[{"key":"681_CR1","doi-asserted-by":"publisher","first-page":"1459","DOI":"10.1016\/S0140-6736(16)31012-1","volume":"388","author":"GBD 2015 Mortality and Causes of Death Collaborators","year":"2016","unstructured":"GBD 2015 Mortality and Causes of Death Collaborators. 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