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- Paul V. Nguyen, MD∗ ( and )
- Pierre Biron, MD
- ↵∗Centre Hospitalier Universitaire de Montréal, Department of Medicine, 3840 Rue Saint-Urbain, Montréal, Québec H2W1T8, Canada
We read with interest the paper by Rosenson et al. (1), who performed a retrospective analysis showing that only a “disappointing” 27% in a 5% random sample of Medicare patients 65 to 74 years of age hospitalized for acute myocardial infarction or revascularization from 2007 to 2009 had been prescribed high-intensity statins. Stricter adherence to the 2013 American Heart Association/American College of Cardiology (AHA/ACC) Guidelines was called for in the accompanying editorial comment. We would like to offer some words of caution.
Mounting evidence for harms (e.g., rhabdomyolysis, diabetes, acute renal failure) (2) associated with high-intensity statins published in the data and treatment at our institution of 3 recent consecutive cases of severe rhabdomyolysis (2 lethal and 1 severely debilitating, resulting in flaccid quadriplegia) in patients treated with high-intensity statins according to the new AHA/ACC guidelines prompted us to review the main evidence behind those recommendations, with respect to benefits on “hard” endpoints such as all-cause mortality or cardiovascular mortality.
In chronic stable coronary heart disease (CHD), 3 major secondary prevention trials were identified: TNT (Treat to New Targets), IDEAL (Incremental Decrease in End Points Through Aggressive Lipid Lowering), and SEARCH (Study of the Effectiveness of Additional Reduction in Cholesterol and Homocysteine). From these trials’ data, and using the latest Cochrane methodology and focusing on outcomes that are most relevant to patients, it was shown that high-intensity statins had no effect on total mortality as compared to standard dose statins (relative risk: 0.99; 95% confidence interval: 0.93 to 1.06). High-dose statins increased withdrawals due to adverse effects (relative risk: 1.45; 95% confidence interval: 1.34 to 1.58; absolute risk increase: 2.5%) as compared to standard dose statins (3).
In acute coronary syndromes, 2 major trials were identified:
1. The A-to-Z trial compared 80 mg with 20 mg of simvastatin in 4,497 patients with acute coronary syndromes. There was no significant benefit in total or cardiovascular mortality over the 2-year duration of the study. The National Institute for Clinical Excellence (NICE) 2014 reviewers labeled the trial as having a high risk of bias.
2. The PROVE IT–TIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis In Myocardial Infarction 22) trial investigators (4), compared 80 mg of atorvastatin to 40 mg of pravastatin in 4,162 patients in acute coronary syndromes. The PROVE IT–TIMI 22 trial was reported as strongly positive and considered to be the cornerstone trial leading to the “sea changing” era of intensive target-driven (“the lower, the better”) statin therapy. It is the only one of 5 blinded trials testing high intensity statin treatment to claim a benefit with respect to hard endpoints such as total mortality and CHD mortality, as there were statistically significant reductions in total and CHD mortality under the higher dose.
But a closer look at the PROVE IT–TIMI 22 trial shows negligible absolute benefits.
For the “hardest” endpoints (Table 1), such as death from all causes, at the 24-month mark, the absolute risk reduction was a mere 1% (3.2% on pravastatin 40 mg vs. 2.2% on atorvastatin 80 mg); for deaths from CHD, the absolute risk reduction was smaller, at 0.3% (about 6 patients), the difference between 1.4% (or about 28 patients) on pravastatin 40 mg versus 1.1% (or about 22 patients) on atorvastatin 80 mg. In the published paper, when expressed as relative risk reductions, the benefits look much more impressive: reductions of 28% for death and 30% for CHD death. Moreover, we do not know what to think about the erratum (4) published 2 years later, wherein the authors admitted to multiple inaccuracies (typo errors quite unlikely) in the reporting of the numbers of patients at risk at every time mark (6, 12, 18, 24, and 30 months) and in both groups.
The authors have neither redone the calculations of the Kaplan-Meier curves nor retracted the paper. Had they redone the calculations, would the small differences of 1% in absolute risk reduction in overall mortality—and the 0.3% absolute risk reduction in CHD mortality—in the high-intensity group have remained unaffected?
In conclusion, worthwhile benefits have not been clearly demonstrated with high-intensity statins, as compared to lower doses, with respect to “hard” endpoints such as total mortality or CV mortality.
It is doubtful that the small, if any, benefits of high-potency statins on soft and less patient-relevant outcomes, outcomes that are highly susceptible to biases (5), would outweigh the combined risks of acute kidney injury, rhabdomyolysis, diabetes, and severe muscular failure, not to mention dozens of other adverse reactions (2). Because the benefits do not bear scrutiny of the evidence, the harms caused may be substantial and the societal costs incurred by abiding to the new AHA/ACC guidelines would be enormous. We therefore suggest that until proven otherwise, a cause for concern is not with “underutilization of high-intensity statins” but rather may be with their “overutilization.”
Please note: Both authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- American College of Cardiology Foundation
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- Therapeutics Initiative
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- Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 Trial Investigators
- Nguyen P.V.