Effects of intensive versus mild lipid lowering by statins in patients with ischemic congestive heart failure: Korean Pitavastatin Heart Failure (SAPHIRE) study

Hae-Young Lee, Hyun-Jai Cho, Hee-Yul Kim, Hee-Kyung Jeon, Joon Han Shin, Suk-Min Kang, Sang Hong Baek, Hae-Young Lee, Hyun-Jai Cho, Hee-Yul Kim, Hee-Kyung Jeon, Joon Han Shin, Suk-Min Kang, Sang Hong Baek

Abstract

Background/aims: This study was designed to evaluate the dose-effect relationship of statins in patients with ischemic congestive heart failure (CHF), since the role of statins in CHF remains unclear.

Methods: The South koreAn Pitavastatin Heart FaIluRE (SAPHIRE) study was designed to randomize patients with ischemic CHF into daily treatments of 10 mg pravastatin or 4 mg pitavastatin.

Results: The low density lipoprotein cholesterol level decreased by 30% in the pitavastatin group compared with 12% in the pravastatin (p < 0.05) group. Left ventricular systolic dimensions decreased significantly by 9% in the pitavastatin group and by 5% in the pravastatin group. Left ventricular ejection fraction (EF) improved significantly from 37% to 42% in the pitavastatin group and from 35% to 39% in the pravastatin group. Although the extent of the EF change was greater in the pitavastatin group (16% vs. 11%) than that in the pravastatin group, no significant difference was observed between the groups (p = 0.386). Exercise capacity, evaluated by the 6-min walking test, improved significantly in the pravastatin group (p < 0.001), but no change was observed in the pitavastatin group (p = 0.371).

Conclusions: Very low dose/low potency pravastatin and high dose/high potency pitavastatin had a beneficial effect on cardiac reverse remodeling and improved systolic function in patients with ischemic CHF. However, only pravastatin significantly improved exercise capacity. These findings suggest that lowering cholesterol too much may not be beneficial for patients with CHF.

Trial registration: ClinicalTrials.gov NCT00701285.

Keywords: Exercise capacity; Heart failure; Hydroxymethylglutaryl-CoA reductase inhibitors; Pitavastatin.

Conflict of interest statement

This study was supported by a grant from JW Pharmaceutical Corp., Korea.

Figures

Figure 1
Figure 1
Study design.
Figure 2
Figure 2
Study patients.
Figure 3
Figure 3
Left ventricular remodeling following statin treatment. (A) Left ventricular end systolic dimension (LVESD) changes following statin treatment. (B) Left ventricular ejection fraction (LVEF) changes following statin treatment. (C) Left ventricular E/A ratio changes following statin treatment.
Figure 4
Figure 4
The 6-minute walk test before and 52 weeks after statin therapy.

References

    1. McMurray JJ. CONSENSUS to EMPHASIS: the overwhelming evidence which makes blockade of the renin-angiotensin-aldosterone system the cornerstone of therapy for systolic heart failure. Eur J Heart Fail. 2011;13:929–936.
    1. Zannad F, McMurray JJ, Krum H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med. 2011;364:11–21.
    1. Packer M, Coats AJ, Fowler MB, et al. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med. 2001;344:1651–1658.
    1. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med. 1998;339:1349–1357.
    1. Laufs U, Liao JK. Isoprenoid metabolism and the pleiotropic effects of statins. Curr Atheroscler Rep. 2003;5:372–378.
    1. Laufs U, Kilter H, Konkol C, Wassmann S, Bohm M, Nickenig G. Impact of HMG CoA reductase inhibition on small GTPases in the heart. Cardiovasc Res. 2002;53:911–920.
    1. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S) Lancet. 1994;344:1383–1389.
    1. Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels: Cholesterol and Recurrent Events Trial investigators. N Engl J Med. 1996;335:1001–1009.
    1. de Lemos JA, Blazing MA, Wiviott SD, et al. Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial. JAMA. 2004;292:1307–1316.
    1. Kjekshus J, Apetrei E, Barrios V, et al. Rosuvastatin in older patients with systolic heart failure. N Engl J Med. 2007;357:2248–2261.
    1. Gissi-HF Investigators. Tavazzi L, Maggioni AP, et al. Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet. 2008;372:1231–1239.
    1. Ramasubbu K, Estep J, White DL, Deswal A, Mann DL. Experimental and clinical basis for the use of statins in patients with ischemic and nonischemic cardiomyopathy. J Am Coll Cardiol. 2008;51:415–426.
    1. Bonsu KO, Kadirvelu A, Reidpath DD. Statins in heart failure: do we need another trial? Vasc Health Risk Manag. 2013;9:303–319.
    1. Krum H, McMurray JJ. Statins and chronic heart failure: do we need a large-scale outcome trial? J Am Coll Cardiol. 2002;39:1567–1573.
    1. Horwich TB, Hamilton MA, Maclellan WR, Fonarow GC. Low serum total cholesterol is associated with marked increase in mortality in advanced heart failure. J Card Fail. 2002;8:216–224.
    1. Mortensen SA, Leth A, Agner E, Rohde M. Dose-related decrease of serum coenzyme Q10 during treatment with HMG-CoA reductase inhibitors. Mol Aspects Med. 1997;18(Suppl):S137–S144.
    1. Krishnan GM, Thompson PD. The effects of statins on skeletal muscle strength and exercise performance. Curr Opin Lipidol. 2010;21:324–328.
    1. Saito Y, Yamada N, Teramoto T, et al. A randomized, double-blind trial comparing the efficacy and safety of pitavastatin versus pravastatin in patients with primary hypercholesterolemia. Atherosclerosis. 2002;162:373–379.
    1. Iglesias P, Diez JJ. New drugs for the treatment of hypercholesterolaemia. Expert Opin Investig Drugs. 2003;12:1777–1789.
    1. Kim MK, Kim B, Lee JY, et al. Tissue Doppler-derived E/e' ratio as a parameter for assessing diastolic heart failure and as a predictor of mortality in patients with chronic kidney disease. Korean J Intern Med. 2013;28:35–44.
    1. Yang JH, Choi JH, Ki YW, et al. Plasma N-terminal pro-B-type natriuretic peptide is predictive of perioperative cardiac events in patients undergoing vascular surgery. Korean J Intern Med. 2012;27:301–310.
    1. Takano H, Mizuma H, Kuwabara Y, et al. Effects of pitavastatin in Japanese patients with chronic heart failure: the Pitavastatin Heart Failure Study (PEARL Study) Circ J. 2013;77:917–925.
    1. Lipinski MJ, Cauthen CA, Biondi-Zoccai GG, et al. Meta-analysis of randomized controlled trials of statins versus placebo in patients with heart failure. Am J Cardiol. 2009;104:1708–1716.
    1. Ashton E, Windebank E, Skiba M, et al. Why did high-dose rosuvastatin not improve cardiac remodeling in chronic heart failure? Mechanistic insights from the UNIVERSE study. Int J Cardiol. 2011;146:404–407.
    1. Golomb BA, Evans MA, Dimsdale JE, White HL. Effects of statins on energy and fatigue with exertion: results from a randomized controlled trial. Arch Intern Med. 2012;172:1180–1182.
    1. Perez AC, Jhund P, Preiss D, Kjekshus J, McMurray JJ. Effect of rosuvastatin on fatigue in patients with heart failure. J Am Coll Cardiol. 2013;61:1121–1122.
    1. Kashani A, Phillips CO, Foody JM, et al. Risks associated with statin therapy: a systematic overview of randomized clinical trials. Circulation. 2006;114:2788–2797.
    1. Schachter M. Chemical, pharmacokinetic and pharmacodynamic properties of statins: an update. Fundam Clin Pharmacol. 2005;19:117–125.
    1. Kihara Y. Statin therapy in chronic heart failure: frog prince or bare frog? Circ J. 2013;77:895–897.
    1. Rauchhaus M, Clark AL, Doehner W, et al. The relationship between cholesterol and survival in patients with chronic heart failure. J Am Coll Cardiol. 2003;42:1933–1940.

Source: PubMed

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