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Influence of Cardiovascular and Noncardiovascular Co-morbidities on Outcomes and Treatment Effect of Heart Rate Reduction With Ivabradine in Stable Heart Failure (from the SHIFT Trial)

Published:October 05, 2015DOI:https://doi.org/10.1016/j.amjcard.2015.09.029
      Incidence of chronic heart failure (HF) increases with age and cardiovascular (CV) morbidity. Co-morbidities increase hospitalization and mortality in HF, and non-CV co-morbidities may lead to preventable hospitalizations. We studied the impact of co-morbidities on mortality and morbidity in Systolic Heart Failure Treatment with the If Inhibitor Ivabradine Trial, and investigated whether the impact of ivabradine was affected by co-morbidities. We analyzed the Systolic Heart Failure Treatment with the If Inhibitor Ivabradine Trialpopulation, with moderate-to-severe HF and left ventricular dysfunction (in sinus rhythm with heart rate at rest ≥70 beats/min), according to co-morbidity: chronic obstructive pulmonary disease, diabetes mellitus, anemia, stroke, impaired renal function, myocardial infarction, hypertension, and peripheral artery disease. Co-morbidity load was classed as 0, 1, 2, 3, 4+ or 1 to 2 co-morbidities, or 3+ co-morbidities. Co-morbidities were evenly distributed between the placebo and ivabradine groups. Patients with more co-morbidities were likely to be older, women, had more advanced HF, were less likely to be on β blockers, with an even distribution on ivabradine 2.5, 5, or 7.5 mg bid and placebo at all co-morbidity loads. Number of co-morbidities was related to outcomes. Cardiovascular death or HF hospitalization events significantly increased (p <0.0001) with co-morbidity load, with the most events in patients with >3 co-morbidities for both, ivabradine and placebo. There was no interaction between co-morbidity load and the treatment effects of ivabradine. Hospitalization rate was lower at all co-morbidity loads for ivabradine. In conclusion, cardiac and noncardiac co-morbidities significantly affect CV outcomes, particularly if there are >3 co-morbidities. The effect of heart rate reduction with ivabradine is maintained at all co-morbidity loads.
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      References

        • Levy D.
        • Kenchaiah S.
        • Larson M.G.
        • Benjamin E.J.
        • Kupka M.J.
        • Ho K.K.
        • Murabito J.M.
        • Vasan R.S.
        Long-term trends in the incidence of and survival with heart failure.
        N Engl J Med. 2002; 347: 1397-1402
        • Wong C.Y.
        • Chaudhry S.I.
        • Desai M.M.
        • Krumholz H.M.
        Trends in comorbidity, disability, and polypharmacy in heart failure.
        Am J Med. 2011; 124: 136-143
        • Afilalo J.
        • Alexander K.P.
        • Mack M.J.
        • Maurer M.S.
        • Green P.
        • Allen L.A.
        • Popma J.J.
        • Ferrucci L.
        • Forman D.E.
        Frailty assessment in the cardiovascular care of older adults.
        J Am Coll Cardiol. 2014; 63: 747-762
        • Lakatta E.G.
        Cardiovascular regulatory mechanisms in advanced age.
        Physiol Rev. 1993; 73: 413-467
        • Briesacher B.A.
        • Gurwitz J.H.
        • Soumerai S.B.
        Patients at-risk for cost-related medication nonadherence: a review of the literature.
        J Gen Intern Med. 2007; 22: 864-871
        • Boyd C.M.
        • Darer J.
        • Boult C.
        • Fried L.P.
        • Boult L.
        • Wu A.W.
        Clinical practice guidelines and quality of care for older patients with multiple comorbid diseases: implications for pay for performance.
        JAMA. 2005; 294: 716-724
        • Braunstein J.B.
        • Anderson G.F.
        • Gerstenblith G.
        • Weller W.
        • Niefeld M.
        • Herbert R.
        • Wu A.W.
        Noncardiac comorbidity increases preventable hospitalizations and mortality among Medicare beneficiaries with chronic heart failure.
        J Am Coll Cardiol. 2003; 42: 1226-1233
        • Böhm M.
        • Pogue J.
        • Kindermann I.
        • Pöss J.
        • Koon T.
        • Yusuf S.
        Effect of comorbidities on outcomes and angiotensin converting enzyme inhibitor effects in patients with predominantly left ventricular dysfunction and heart failure.
        Eur J Heart Fail. 2014; 16: 325-333
        • Swedberg K.
        • Komajda M.
        • Böhm M.
        • Borer J.S.
        • Ford I.
        • Tavazzi L.
        Rationale and design of a randomized, double-blind, placebo-controlled outcome trial of ivabradine in chronic heart failure: the Systolic Heart Failure Treatment with the I(f) Inhibitor Ivabradine Trial (SHIFT).
        Eur J Heart Fail. 2010; 12: 75-81
        • Swedberg K.
        • Komajda M.
        • Böhm M.
        • Borer J.S.
        • Ford I.
        • Dubost-Brama A.
        • Lerebours G.
        • Tavazzi L.
        • SHIFT Investigators
        Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study.
        Lancet. 2010; 376: 875-885
        • Böhm M.
        • Swedberg K.
        • Komajda M.
        • Borer J.S.
        • Ford I.
        • Dubost-Brama A.
        • Lerebours G.
        • Tavazzi L.
        • SHIFT Investigators
        Heart rate as a risk factor in chronic heart failure (SHIFT): the association between heart rate and outcomes in a randomised placebo-controlled trial.
        Lancet. 2010; 376: 886-894
        • Lam C.S.
        • Lyass A.
        • Kraigher-Krainer E.
        • Massaro J.M.
        • Lee D.S.
        • Ho J.E.
        • Levy D.
        • Redfield M.M.
        • Pieske B.M.
        • Benjamin E.J.
        • Vasan R.S.
        Cardiac dysfunction and noncardiac dysfunction as precursors of heart failure with reduced and preserved ejection fraction in the community.
        Circulation. 2011; 124: 24-30
        • McMurray J.J.
        • Adamopoulos S.
        • Anker S.D.
        • Auricchio A.
        • Böhm M.
        • Dickstein K.
        • Falk V.
        • Filippatos G.
        • Fonseca C.
        • Gomez-Sanchez M.A.
        • Jaarsma T.
        • Køber L.
        • Lip G.Y.
        • Maggioni A.P.
        • Parkhomenko A.
        • Pieske B.M.
        • Popescu B.A.
        • Rønnevik P.K.
        • Rutten F.H.
        • Schwitter J.
        • Seferovic P.
        • Stepinska J.
        • Trindade P.T.
        • Voors A.A.
        • Zannad F.
        • Zeiher A.
        • ESC Committee for Practice Guidelines
        ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC.
        Eur J Heart Fail. 2012; 14: 803-869
        • Böhm M.
        • Borer J.
        • Ford I.
        • Gonzalez-Juanatey J.R.
        • Komajda M.
        • Lopez-Sendon J.
        • Reil J.C.
        • Swedberg K.
        • Tavazzi L.
        Heart rate at baseline influences the effect of ivabradine on cardiovascular outcomes in chronic heart failure: analysis from the SHIFT study.
        Clin Res Cardiol. 2013; 102: 11-22
        • Voors A.A.
        • van Veldhuisen D.J.
        • Robertson M.
        • Ford I.
        • Borer J.S.
        • Böhm M.
        • Komajda M.
        • Swedberg K.
        • Tavazzi L.
        • SHIFT investigators
        The effect of heart rate reduction with ivabradine on renal function in patients with chronic heart failure: an analysis from SHIFT.
        Eur J Heart Fail. 2014; 16: 426-434
        • Tavazzi L.
        • Swedberg K.
        • Komajda M.
        • Böhm M.
        • Borer J.S.
        • Lainscak M.
        • Robertson M.
        • Ford I.
        • SHIFT Investigators
        Clinical profiles and outcomes in patients with chronic heart failure and chronic obstructive pulmonary disease: an efficacy and safety analysis of SHIFT study.
        Int J Cardiol. 2013; 170: 182-188
        • Tavazzi L.
        • Swedberg K.
        • Komajda M.
        • Böhm M.
        • Borer J.S.
        • Lainscak M.
        • Ford I.
        • SHIFT Investigators
        Efficacy and safety of ivabradine in chronic heart failure across the age spectrum: insights from the SHIFT study.
        Eur J Heart Fail. 2013; 15: 1296-1303
        • Borer J.S.
        • Böhm M.
        • Ford I.
        • Robertson M.
        • Komajda M.
        • Tavazzi L.
        • Swedberg K.
        • SHIFT Investigators
        Efficacy and safety of ivabradine in patients with severe chronic systolic heart failure (from the SHIFT study).
        Am J Cardiol. 2014; 113: 497-503
        • Dunlay S.M.
        • Redfield M.M.
        • Weston S.A.
        • Therneau T.M.
        • Hall Long K.
        • Shah N.D.
        • Roger V.L.
        Hospitalizations after heart failure diagnosis: a community perspective.
        J Am Coll Cardiol. 2009; 54: 1695-1702
        • Mogensen U.M.
        • Ersbøll M.
        • Andersen M.
        • Andersson C.
        • Hassager C.
        • Torp-Pedersen C.
        • Gustafsson F.
        • Køber L.
        Clinical characteristics and major comorbidities in heart failure patients more than 85 years of age compared with younger age groups.
        Eur J Heart Fail. 2011; 13: 1216-1223
        • Barr R.G.
        • Bluemke D.A.
        • Ahmed F.S.
        • Carr J.J.
        • Enright P.L.
        • Hoffman E.A.
        • Jiang R.
        • Kawut S.M.
        • Kronmal R.A.
        • Lima J.A.
        • Shahar E.
        • Smith L.J.
        • Watson K.E.
        Percent emphysema, airflow obstruction, and impaired left ventricular filling.
        N Engl J Med. 2010; 362: 217-227
        • Smith G.L.
        • Shlipak M.G.
        • Havranek E.P.
        • Foody J.M.
        • Masoudi F.A.
        • Rathore S.S.
        • Krumholz H.M.
        Serum urea nitrogen, creatinine, and estimators of renal function: mortality in older patients with cardiovascular disease.
        Arch Intern Med. 2006; 166: 1134-1142
        • Groenveld H.F.
        • Januzzi J.L.
        • Damman K.
        • van Wijngaarden J.
        • Hillege H.L.
        • van Veldhuisen D.J.
        • van der Meer P.
        Anemia and mortality in heart failure patients: a systematic review and meta-analysis.
        J Am Coll Cardiol. 2008; 52: 818-827
        • Schirmer S.H.
        • Degen A.
        • Baumhäkel M.
        • Custodis F.
        • Schuh L.
        • Kohlhaas M.
        • Friedrich E.
        • Bahlmann F.
        • Kappl R.
        • Maack C.
        • Böhm M.
        • Laufs U.
        Heart-rate reduction by If-channel inhibition with ivabradine restores collateral artery growth in hypercholesterolemic atherosclerosis.
        Eur Heart J. 2012; 33: 1223-1231
        • Böhm M.
        • Cotton D.
        • Foster L.
        • Custodis F.
        • Laufs U.
        • Sacco R.
        • Bath P.M.
        • Yusuf S.
        • Diener H.C.
        Impact of resting heart rate on mortality, disability and cognitive decline in patients after ischaemic stroke.
        Eur Heart J. 2012; 33: 2804-2812
        • Böhm M.
        • Schumacher H.
        • Leong D.
        • Mancia G.
        • Unger T.
        • Schmieder R.
        • Custodis F.
        • Diener H.C.
        • Laufs U.
        • Lonn E.
        • Sliwa K.
        • Teo K.
        • Fagard R.
        • Redon J.
        • Sleight P.
        • Anderson C.
        • O'Donnell M.
        • Yusuf S.
        Systolic blood pressure variation and mean heart rate is associated with cognitive dysfunction in patients with high cardiovascular risk.
        Hypertension. 2015; 65: 651-661
        • Böhm M.
        • Schumacher H.
        • Schmieder R.E.
        • Mann J.F.
        • Teo K.
        • Lonn E.
        • Sleight P.
        • Mancia G.
        • Linz D.
        • Mahfoud F.
        • Ukena C.
        • Sliwa K.
        • Bakris G.
        • Yusuf S.
        Resting heart rate is associated with renal disease outcomes in patients with vascular disease: results of the ONTARGET and TRANSCEND studies.
        J Intern Med. 2015; 278: 38-49
        • Page 2nd, R.L.
        • Lindenfeld J.
        The comorbidity conundrum: a focus on the role of noncardiovascular chronic conditions in the heart failure patient.
        Curr Cardiol Rep. 2012; 14: 276-284
        • Wolff J.L.
        • Starfield B.
        • Anderson G.
        Prevalence, expenditures, and complications of multiple chronic conditions in the elderly.
        Arch Intern Med. 2002; 162: 2269-2276
        • Desai M.M.
        • Bruce M.L.
        • Desai R.A.
        • Druss B.G.
        Validity of self-reported cancer history: a comparison of health interview data and cancer registry records.
        Am J Epidemiol. 2001; 153: 299-306