Mark R. Goldstein

STATIN THERAPY IN THE ELDERLY: MISCONCEPTIONS

ACKNOWLEDGMENTS Conflict of Interest: The editor in chief has reviewed the conflict of interest checklist provided by the author and has determined that none of the authors have any financial or any other kind of personal conflicts with this letter. TSD is a speaker for Ortho Biotech and is an expert witness for vitamin B12 deficiency. All the authors took part in all aspects of this letter and there are no sponsors involved.

How Statins May Increase Prostate Cancer

To the Editors: We read Dr. Platzs excellent editorial on statins in the prevention of prostate cancer, and we agree with her conclusion that it is premature to recommend statins for the prevention of advanced prostate cancer ([1][1]). However, there are recent data suggesting that statins may

CorrespondenceStatin and exercise prescription

1622 www.thelancet.com Vol 381 May 11, 2013 We read with interest the article by Peter Kokkinos and colleagues. Although cardiorespiratory fi tness is developed by physical activity, they are diff erent, and they are linked diff erently to cardiovascular disease, with cardiorespiratory fi tness having a stronger protective association. Being inactive and being unfi t are independent risk factors, and inactivity might not be a cause of being unfi t. Thus, recommendation of physical activity basis of the cardiorespiratory fi tness status might not be entirely appropriate. Although cardiorespiratory fi tness and physical activity are generally believed to have benefi cial eff ects on longevity, the interactive eff ects of statins and cardiorespiratory fi tness cannot be reliably quantifi ed in an observational study, as confounding factors cannot be eliminated. The observation of an interaction between statins and cardiorespiratory fi tness, and a greater treatment eff ect of statins among high cardiorespiratory fi tness strata is at variance with randomised trials showing that statins substantially decrease cardiovascular diseases without any evidence of eff ect modifi cation across subgroups. Additionally, results of a metaanalysis of randomised trials reported a non-signifi cant eff ect of statins on all-cause mortality reduction in high-risk individuals without prior cardiovascular diseases, which is misinterpreted by the authors. Given the observational nature of the study, any diff erential benefi t is unlikely as suggested in table 3, in which the benefi ts of statins are similar across fi tness strata. Cardiorespiratory fi tness and physical activity should be encouraged as means to reduce incidence of cardiovascular diseases. When appropriate, based Authors’ reply We thank Thijs Eijsvoels and colleagues for their thoughtful comments on our study regarding physical activity and statin therapy. As they state, physically active individuals might be more vulnerable to the skeletal muscle side-eff ects of statins. A lipidlowering agent that will not adversely aff ect skeletal muscle will certainly be welcomed. We share Luca Mascitelli’s recommendation that physical activity should be regarded as the fi rst step in cardiovascular disease prevention, and that the addition of a statin should be considered only if it does not interfere with exercise. Most importantly, we concur with the eloquently stated and obvious truth that has been ignored by health-care professionals for many years: “improving of population health should not simply be made the work of drug companies.” We agree with Rajna Golubic and Kausik Ray regarding fi tness and physical activity, and their association with cardiovascular risk. However, Peter Kokkinos and colleagues report that, in dyslipidaemic individuals, combination of statin treatment and fi tness lowers mortality risk more than either alone. However, patients not prescribed statins but who were highly fi t still had a signifi cantly lower risk of mortality than those taking statins, but who were unfi t. These fi ndings might be important in clinical practice in which mounting evidence has established that fatigue and exertional intolerance are frequent adverse eff ects reported by patients receiving statins. In fact, in the study by Kokkinos and colleagues, peak exercise capacity is higher in individuals not taking statins. Evidence confi rmed unfavourable statin eff ects on energy and exertional fatigue. These data highlight that physical activity should be regarded as the fi rst step in cardiovascular disease prevention. Additionally, when clinical judgment suggests adding statins, use of the drug should be continued only if it does not interfere with exercise. This hierarchy might be considered in the primary prevention setting where the benefi cial eff ect of statin therapy is not so straightforward. Physical inactivity ahould be considered as a modifi able risk factor. Improving of population health should not simply be made the work of drug companies.

Hemorrhagic Stroke in the SPARCL Study

To the Editor: Goldstein et al1 reported a post hoc analysis of data from the Stroke Prevention with Aggressive Reductions in Cholesterol Levels (SPARCL) trial in order to determine the effects of high-dose atorvastatin in the secondary prevention of cerebrovascular events in men and women. However, they did not mention how statin therapy increased the risk of hemorrhagic stroke in men and women. In fact, in the SPARCL trial as compared …

Statins, leptin and regulatory T cells.

An interesting paper has suggested [1] that leptin signaling negatively modulates regulatory T cell (Treg) function. Although this intriguing finding may partially explain why obese individuals are predisposed to atherosclerosis, it may also shed light on why cholesterol lowering with high-dose statins may favor an increase in mortality, particularly among lean individuals [2,3]. A recent analysis of prospective randomized statin trials has shown a significantly increased risk of cancer associated with lowerachieved low-density lipoprotein (LDL) cholesterol levels [4]. Statins have been shown to increase the concentration ofTregs in vivo,by inducing the transcription factor, forkhead box P3 (FOXP3) [5]. Even though this may help to stabilize atherosclerotic plaque by reducing the effector T cell response in the atheroma [6], it may increase cancer risk by impairing host anti-tumor immune response [7]. Indeed, there was a significant increase in cancer incidence among elderly subjects randomized to pravastatin. The increase in cancer mortality in the Prospective Study of Pravastatin in the Elderly (PROSPER) trial, fully negated any benefit in cardiovascular disease reduction, leaving overall mortality unchanged [8]. Elderly subjects may be more likely to harbor cancer cells and, as a consequence, they may be at a greater risk for cancer propagation due to statin induced Treg increases. Since leptinnegativelymodulatesTregfunction[1], it isplausible that Treg function is increased in thin individuals, whom are relatively hypoleptinemic. Furthermore, this increase in Treg function may be amplified by statin therapy. Indeed, post hoc analysis of the Treating to New Targets (TNT) study [2] suggested a trend towards an increase in overall mortality among thinner subjects (half of the subjects in the trial without metabolic syndrome) randomized to high-dose atorvastatin [3]. Therefore, the implication that thin elderly individuals prescribed high-dose statins, may be at increased risk for the development of cancer, must not be taken lightly. Additionally, this needs further investigation, since high-dose statins are widely prescribed for adults of all ages and sizes [9].

Low Cholesterol, Delinquency, and Suicidality

Sir: It is well known that incarcerated adolescents are at high risk of suicide.1 We suggest that lower than normal cholesterol levels might be a biological marker of both a violent behavior leading to subsequent arrest and suicidality. Mounting evidence suggests a relation between low cholesterol and violence, aggression, and hostility.2,3 In particular, a statistically significant association has been shown between serum total cholesterol concentration below the 25th percentile (<145 mg/dL) and aggressive behaviors among non–African American children from a national sample of noninstitutionalized, school-aged children.4 Lower than median cholesterol levels have also been associated with the onset of conduct disorder during childhood among male criminals.5 On the other hand, lower than average cholesterol levels seem to indicate a population at risk for parasuicide or completed suicide,6 and follow-up studies have found that individuals with lower cholesterol levels have an increased risk of completing suicide.7 Indeed, the inheritance of defects leading to low cholesterol levels could predispose individuals to violent and suicidal behavior.8,9 Therefore, low cholesterol may be a risk factor for delinquency and suicidality or a risk marker for genotypes that predispose to such behaviors. Luca Mascitelli, M.D. Medical Service, “Julia” Alpine Brigade, HQ, Udine, Italy Francesca Pezzetta, M.D. Cardiology Department, Hospital of Tolmezzo, Tolmezzo, Italy Mark R. Goldstein, M.D. Private Practice, Bonita Springs, Florida

Cholesterol lowering in patients with CHD and metabolic syndrome

www.thelancet.com Vol 369 January 6, 2007 25 Development (DFID), should be requiring contractors to address this problem in a substantive way. But an external evaluation of DFID’s programmes found that gender violence was “not strategically addressed in practice”. Likewise, PEPFAR’s lack of transparency makes it impossible to verify its claims of bold action in this area or to assess its eff ectiveness. The Global Fund could also do much more to encourage proposals that include a substantial anti-violence component. We urgently need a multisectoral response to violence that can change entrenched social norms. The multibillion dollar international eff ort to address HIV/AIDS is certain to fail unless programmes that respond to violence are both appropriately designed and dramatically scaled-up to meet the need.

The PROSPER trial

Cancer incidence over the 3·2 years of the trial was 6·8% in the placebo group and 8·5% in those randomised to pravastatin (p=0·020). Cancer death during the trial was 3·1% in the placebo group and 4·0% in the pravastatin group. This exactly cancelled the mortality benefit of coronary heart disease death, which was 4·2% in the placebo group and 3·3% in the pravastatin group. All-cause death was unchanged, implying that pravastatin treatment changed how a patient died by increasing cancer death and decreasing death from coronary heart disease.

The Mediterranean Diet and Body Iron Stores

Abstract Adherence to a traditional Mediterranean diet has been shown to be associated with significantly lower risk of major degenerative diseases. Evidence suggests that the cumulative action of its multiple dietary components may be substantial. Lower body iron stores, induced by components of the Mediterranean diet, may be involved in its beneficial effects. Although iron is an essential nutrient, in excess it is a pro-oxidant that leads to degenerative diseases. Humans have no mechanism for excreting excess iron. Elevated iron stores can be prevented by diet or treated by phlebotomy or chelation; iron depletion has been shown to stabilize atherosclerotic plaque and decrease cancer mortality. The Mediterranean diet might be considered a low-iron available diet, that is, a diet containing a low amount of iron and one in which iron absorption inhibitors (polyphenols, phytates, and dairy products) prevail over enhancers (ascorbic acid and red meat). Over time, this dietary pattern leads to reduced iron stores.

Secondary prevention of stroke

was often not necessary and a stent could be directly implanted (“direct stenting”). In the conventional group, most patients needed predilatation. Patients randomised to aspiration had improved myocardial perfusion and clinical outcome compared with the conventional group. However, is there evidence to suggest that the higher rate of direct-stenting in the aspiration group has augmented these results? As shown by Loubeyre and colleagues, direct stenting can be safe and eff ect ive in sel ected patients undergoing pri mary per cutan eous coronary intervention (PCI). However, in unselected patients with ST-elevation myo cardial in farction (STEMI), direct stenting has never been shown to improve myocardial perfusion or clinical outcome compared with predilatation. Direct stenting in patients without adequate fl ow leads to the risk of undersized stenting, which is the most important predictor of restenosis. This problem is illustrated by a trial comparing direct stenting with predilatation in unselected STEMI patients: in-stent restenosis rate at 1-year angiographic follow-up was signifi cantly higher in the direct stenting group. Finally, the use of predilatation in TAPAS was not limited to patients randomised to conventional PCI. Predilatation was done in 207 of 502 (41·2%) of the patients randomly assigned aspiration. There were no diff erences between patients with and without predilatation in rates of cardiac death (7/207 [3·4%] vs 8/295 [2·7%], respectively; p=0·67), nor in cardiac death or non-fatal reinfarction (10/207 [4·8%] vs 16/295 [5·4%], respectively; p=0·77). This fi nding indicates that predilatation is not associated with impaired clinical outcome. Jaewon Oh and colleagues raise the important issue of the value of platelet inhibitors during primary PCI. In TAPAS, all patients were pretreated with clopidogrel, aspirin, and heparin. During the procedure, abciximab was given routinely to 469 of 502 (93·4%) in the thrombus-aspiration group and 452 of 503 (89·9%) in the conventional PCI group (p=0·12).