Treating To New Targets Research Articles

Aggressive Blood Pressure Lowering Is Dangerous: The J-Curve

Blood pressure (BP) is poorly controlled in the population, a phenomenon with adverse prognostic impact.1 However, a more aggressive approach toward BP lowering has been tempered over the last 2 to 3 decades by some reports suggesting a paradoxical increase in morbidity and mortality associated with an excessive reduction in BP, the so-called J-shaped curve hypothesis. Many investigations addressed this issue, and some excellent reviews discussed strengths and limitations of these studies in detail.2–5 We conducted an updated critical review of the most relevant studies and meta-analysis from our and other groups. We recognize that there is some evidence that a diastolic BP target <80 mm Hg,6 or an achieved diastolic BP <70 mm Hg,7 might be associated with an increased risk of myocardial infarction6 (MI) or total cardiovascular events7 in hypertensive patients with established coronary artery disease (CAD). However, with the possible exception of hypertensive patients with CAD, there are no convincing data behind the conclusion that an aggressive reduction of BP could be a direct cause of adverse outcome. Several studies that reported a J-shaped association between achieved BP and outcome have methodological limitations.2–5 In particular, several clinical conditions including, but not limited to, heart failure, previous MI, and cancer might have been the dominant and direct cause of adverse outcome in these patients, antihypertensive treatment being thus a sort of innocent bystander. As an implication of this line of thinking, dangerous would not be the excessive reduction in BP but rather the excessively low BP. The difference is not trivial. In subjects with or without risk factors, but free from overt cardiovascular disease, the log-linear relation between BP and rate of mortality from CAD or stroke appears to begin at values around 115/75 mm Hg, without …

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Lipid lowering in patients with treatment-resistant hypertension: an analysis from the Treating to New Targets (TNT) trial

Patients with resistant hypertension are at high risk for adverse cardiovascular events. Efforts have been focused on lowering the surrogate endpoint of blood pressure (BP) with scant focus on reduction of hard cardiovascular endpoints. However, whether or not intensive lipid lowering is beneficial for reducing the risk of cardiovascular events in this high-risk cohort is not known. We evaluated 10 001 patients with coronary artery disease and a low-density lipoprotein cholesterol level <130 mg/dL, randomized to atorvastatin 80 vs. 10 mg, enrolled in the Treating to New Targets trial. Treatment-resistant hypertension (TRH) was defined as BP ≥140 mmHg despite being on three antihypertensive agents or <140 mmHg on four or more agents. Subjects were followed up for a median duration of 4.9 years. The primary outcome was major cardiovascular events (composite of non-fatal myocardial infarction (MI), fatal coronary heart disease (CHD), resuscitated cardiac arrest, and stroke). Among the 10 001 patients in the trial, 1112 (11.1%) patients had TRH. Atorvastatin 80 mg, in patients with TRH, was associated with a significant reduction in the risk of the primary outcome (HR = 0.70; 95% CI 0.52-0.93; P = 0.01), driven largely by a significant reduction in CHD deaths (HR = 0.55; 95% CI 0.32-0.97; P = 0.04). In addition, atorvastatin 80 mg was associated with a reduction in major coronary events (HR = 0.67; 95% CI 0.49-0.93; P = 0.02), and any cardiovascular or coronary event and with a trend (P = 0.05) towards reduction in all-cause mortality (HR = 0.68; 95% CI 0.46-1.01) when compared with atorvastatin 10 mg. The results were similar when analysed for the two separate components of the TRH cohort. In subjects with TRH, intensive lipid lowering with atorvastatin 80 mg is associated with a significant reduction in cardiovascular events.

Clinical determinants of incident aortic valve stenosis in patients treated with atorvastatin: results from three large randomized clinical trials

Background: Aortic valve stenosis (AVS) is the most common valvular heart disease in the Western world, and may share some risk factors with coronary heart disease (CHD). Clinical trials have failed to show a benefit for statin therapy in delaying the progression of AVS among asymptomatic individuals with known AVS. Whether statin therapy may decrease the incidence of AVS in populations enriched with CHD risk factors is unknown. Our objective was to compare the incidence rates of AVS among patients treated with high- versus low-dose statin or placebo and to identify clinical risk factors associated with the risk of AVS. Methods and results: Results from three large-scale atorvastatin trials were included in this study, the Treating to New Targets (TNT) trial, in which 80 mg and 10 mg/day of atorvastatin were compared in patients with stable coronary disease, the Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) trial, in which atorvastatin 80 mg was compared to simvastatin 20 mg/day in post-myocardial infarction patients, and the Stroke Prevention by Aggressive Reduction in Cholesterol levels (SPARCL) trial, in which 80 mg/day of atorvastatin was compared to placebo in patients with a recent stroke or transient ischemic attack. All patients with known AVS at baseline were excluded from this analysis. During the follow-up (median=4.9 years), 45 patients developed AVS in TNT, 28 in IDEAL and 9 in SPARCL. Among the 82 patients who developed AVS, 39 (47.6%) patients were treated with atorvastatin 80 mg and 43 (52.4%) were treated with low-dose statin or placebo (hazard ratio [HR]=0.91 [95% CI, 0.59-1.41], p=0.67). Risk factors that showed a significant association in univariate regression analyses were entered into a multivariate model. These risk factors included age, height, weight, body mass index, diabetes, angina, previous coronary artery bypass grafting, peripheral vascular disease, warfarin and antiplatelets use, prior use of statins and calcium channel blockers use. In multivariate analyses forcing treatment, sex and race into the model, age (hazard ratio [HR]=2.24 [95% CI, 1.66-3.02], p<0.0001 per 1-SD increment), diabetes (HR=1.69 [1.00-2.82], p=0.05), warfarin and antiplatelets use (HR=2.89 [1.80-4.62], p<0.0001) and prior statin use (HR=2.56 [1.48-4.44], p=0.03) were significantly associated with the onset of AVS. Conclusions: In this study, high-dose statin therapy did not impact the incidence of AVS. We found that age, diabetes, warfarin and antiplatelets use and prior use of statins were significant predictors of incident AVS in these high-risk patients.

Retraction notice to “Plasma PCSK9 levels and clinical outcomes in the TNT (Treating to New Targets) Trial” [J Am Coll Cardiol 2012;59:1778–1784

Roeland Huijgen, MD,* S. Matthijs Boekholdt, MD, PhD,*† Benoit J. Arsenault, PhD,* Weihang Bao, PhD,‡ Jean-Michel Davaine, MD,§ Fatiha Tabet, PhD,‖ Francine Petrides, BSC,‖ Kerry-Anne Rye, PhD, ‖¶ David A. DeMicco, PharmD,‡ Philip J. Barter, MD, PhD,‖¶ John J. P. Kastelein, MD, PhD,* Gilles Lambert, PhD§‖From the *Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands; †Department of Cardiology, Academic Medical Center, Amsterdam, the Netherlands; ‡Pfizer Inc., New York, New York; §Laboratoire Inserm U957, Faculté de Médecine, Université de Nantes, Nantes, France; ‖The Heart Research Institute, Sydney, New South Wales, Australia; and the ¶Faculty of Medicine, University of Sydney, New South Wales, AustraliaThis article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy).This article has been retracted at the request of the author.The main findings of the TNT Trial were published in 2005 (1). Since that time, members of the Steering Committee and other investigators have published 32 papers based upon additional analyses of TNT. The data for these papers were derived from analyses of the TNT clinical database, managed by Pfizer. The clinical database has been crosschecked many times and the data in it is valid. During the trial, blood samples were drawn from the patients at regular intervals for subsequent analysis. We performed a nested case-control study that included 507 patients who experienced a CV event and 1,020 control patients in the main biomarker analysis, and 496 patients who experienced a CV event and 1,117 control patients in the PCSK9 analysis. The biomarker database was sesimple-parate from the clinical database. An anonymization code was run in 2007 to link patients from one database to the other.In late 2012, the TNT frozen blood samples were integrated into a large automated biobank that includes samples from other Pfizer trials. At that time discrepancies were noted among the samples, indicating that an error had occurred when the samples were anonymized in 2007. Further investigation revealed that the code created to manually anonymize the data was accidentally run twice. During the first run, anonymized subject identifiers were successfully assigned to both biosamples and clinical data. However, after this first run had passed quality control checks, the anonymization code was re-run inadvertently, replacing the first correct set of identifiers with a random and incorrect set. We do not understand how or why the code was re-run. The study team, who were blinded as to patient identity, thus reported on mismatched clinical and biomarker data. The investigators of the biomarkers study were puzzled that none of the 18 biomarkers were predictive of cardiovascular events. However we were reassured because on-treatment LDL-cholesterol, HDL-cholesterol and triglyceride levels were all strongly predictive of events, and we reported this in the paper. These lipid levels were part of the clinical database, and thus were not subject to the error that occurred with the biomarkers. In the PCSK9 analysis, PCSK9 levels were predictive of events in the atorvastatin 10-mg group (p 0.039) but not in the 80-mg group. This finding, which we now realize is totally spurious, was not unexpected and raised no red flags. Similarly, the failure of vitamin D levels to predict events, as reported in the AHJ paper, was not surprising.Since the error was discovered, we have created a new anonymized clinical and biomarker database by restoring the original set of anonymized identifiers. We are currently reanalyzing the data according to our original study plans. However, the nested case-control feature of the original study design has been lost because the patient selection for biomarker sampling was random. Only approximately one tenth of patients now had an event, compared to one third in the original study design. Thus, the power to detect a difference in the level of a biomarker between patients with and without events has been attenuated.All authors of these manuscripts are anguished to have made this mistake and publishing incorrect information.

Cardiovascular Event Reduction Versus New-Onset Diabetes During Atorvastatin Therapy

The purpose of this study was to compare the incidence of new-onset diabetes (NOD) with cardiovascular (CV) event reduction at different levels of NOD risk. Statins reduce the number of CV events but increase the incidence of NOD. We previously reported that 4 factors independently predicted NOD: fasting blood glucose >100 mg/dl, fasting triglycerides >150 mg/dl, body mass index >30 kg/m(2), and history of hypertension. We compared NOD incidence with CV event reduction among 15,056 patients with coronary disease but without diabetes at baseline in the TNT (Treating to New Targets) (n = 7,595) and IDEAL (Incremental Decrease in Endpoints Through Aggressive Lipid Lowering) (n = 7,461) trials. CV events included coronary heart disease death, myocardial infarction, stroke, and resuscitated cardiac arrest. Among 8,825 patients with 0 to 1 of the aforementioned NOD risk factors at baseline, NOD developed in 142 of 4,407 patients in the atorvastatin 80 mg group and in 148 of 4,418 in the atorvastatin 10 mg and simvastatin 20 to 40 mg groups (3.22% vs. 3.35%; hazard ratio [HR]: 0.97; 95% confidence intervals [CI]: 0.77 to 1.22). Among the remaining 6,231 patients with 2 to 4 NOD risk factors, NOD developed in 448 of 3,128 in the atorvastatin 80 mg group and in 368 of 3,103 in the lower-dose groups (14.3% vs. 11.9%; HR: 1.24; 95% CI: 1.08 to 1.42; p = 0.0027). The number of CV events was significantly reduced with atorvastatin 80 mg in both NOD risk groups. Compared with lower-dose statin therapy, atorvastatin 80 mg/day did not increase the incidence of NOD in patients with 0 to 1 NOD risk factors but did, by 24%, among patients with 2 to 4 NOD risk factors. The number of CV events was significantly reduced with atorvastatin 80 mg in both NOD risk groups.

RETRACTED: Plasma PCSK9 Levels and Clinical Outcomes in the TNT (Treating to New Targets) Trial: A Nested Case-Control Study

The purpose of this study was to investigate whether high levels of circulating proprotein convertase subtilisin kexin type 9 (PCSK9) would increase cardiovascular risk in statin-treated patients. Statins activate low-density lipoprotein (LDL) receptor gene expression, thus lowering plasma LDL levels. But statins also activate the expression of PCSK9, a secreted inhibitor of the LDL receptor, thereby limiting their beneficial effects. We have measured the plasma PCSK9 levels of 1,613 patients with stable coronary heart disease enrolled in the Treating to New Targets study, a randomized trial that compared the efficacy of high- versus low-dose atorvastatin. After a run-in period with atorvastatin 10 mg daily, patients were randomized to either continue with 10 mg or be up-titrated to 80 mg of atorvastatin, and followed during 5 years for major cardiovascular events (MCVEs). Circulating PCSK9 levels measured at randomization were predictive of clinical outcomes in the group randomized to remain on atorvastatin 10 mg (p = 0.039), but not in the group that intensified atorvastatin treatment to 80 mg (p = 0.24). Further, PCSK9 levels measured 1 year post-randomization did not change upon increase of the statin dose. PCSK9 levels predict cardiovascular events in patients treated with low-dose atorvastatin. (A Study to Determine the Degree of Additional Reduction in CV Risk in Lowering LDL Below Minimum Target Levels [TNT]; NCT00327691).

Determinants of Residual Risk in Secondary Prevention Patients Treated With High- Versus Low-Dose Statin Therapy

Background— Cardiovascular events occur among statin-treated patients, albeit at lower rates. Risk factors for this “residual risk” have not been studied comprehensively. We aimed to identify determinants of this risk above and beyond lipid-related risk factors. Methods and Results— A total of 9251 coronary patients with low-density lipoprotein cholesterol &lt;130 mg/dL randomized to double-blind atorvastatin 10 or 80 mg/d in the Treating to New Targets (TNT) study had complete on-treatment 1-year lipid data. Median follow-up was 4.9 years. The primary end point was major cardiovascular events (n=729): coronary death, nonfatal myocardial infarction, resuscitation after cardiac arrest, or fatal or nonfatal stroke. Multivariable determinants of increased risk were older age (adjusted hazard ratio [aHR], 1.13 per 1 SD [8.8 years]; 95% confidence interval [CI], 1.04–1.23), increased body mass index (aHR, 1.09; 95% CI, 1.02–1.17 per 4.5 kg/m 2 ), male sex (aHR, 1.33; 95% CI, 1.07–1.65), hypertension (aHR, 1.38; 95% CI, 1.17–1.63), diabetes mellitus (aHR, 1.33; 95% CI, 1.11–1.60), baseline apolipoprotein B (aHR, 1.19; 95% CI, 1.11–1.28 per 19 mg/dL), and blood urea nitrogen (aHR, 1.10; 95% CI, 1.03–1.17 per 4.9 mg/dL), in addition to current smoking, prior cardiovascular disease, and calcium channel blocker use. Determinants of decreased risk were high-dose statin (aHR, 0.82; 95% CI, 0.70–0.94), aspirin use (aHR, 0.67; 95% CI, 0.56–0.81), and baseline apolipoprotein A-I (aHR, 0.91; 95% CI, 0.84–0.99 per 25 mg/dL). On-treatment 1-year lipids or apolipoproteins were not additionally associated with risk in multivariable models. Known baseline variables performed moderately well in discriminating future cases from noncases (Harrell c index=0.679). Conclusions— Determinants of residual risk in statin-treated secondary prevention patients included lipid-related and nonlipid factors such as baseline apolipoproteins, increased body mass index, smoking, hypertension, and diabetes mellitus. A multifaceted prevention approach should be underscored to address this risk. Clinical Trial Registration— URL: http://clinicaltrials.gov . Unique identifier: NCT00327691.

Statin of Preference to Treat Dyslipidaemia in Patients with Renal Dysfunction : Cues from Saturn

Sir, The recent conclusion of SATURN (Study of Coronary Atheroma by InTravascular Ultrasound: Effect of Rosuvastatin versus AtorvastatiN) study,1 demonstrated that maximal suggested doses of both atorvastatin and rosuvastatin ameliorate atherosclerosis to a similar extent by facilitating the regression of percent atheroma volume. Both statins, however, caused renal proteinurea, albeit to different extents. The published results of the study ephemerally state that “proteinuria was commoner in the rosuvastatin group than in the atrovastatin group (3.8% versus 1.7%)”. Further, the treatment group pertaining to atrorvastatin had higher number of diabetics compared to the group on rosuvastatin (16.8% versus 13.8%). Diabetes augments kidney failure,2,3 accounting for nearly 44% of new cases in the United States, therefore it is plausible the atorvastatin treatment group had more patients with renal dysfunction than the rosuvastatin treatment group whereby the actual reported percentage of patients with proteinuria on rosuvastatin might not reflect the true value. The median age of the participants in SATURN-trial is ∼57 years. An individual of 57 years has an average glomerular filtration rate (GFR) of 93 ml/min/1.73m2 versus 116 ml/min/1.73m2 observed in individuals 20–29 years of age, indicating a decline in renal function with advancement with age. The intriguing issue of pivotal importance remaining unanswered is “Which statin should preferably be administered in patients who are elderly with declining renal function/chronic kidney disease (CKD) patients/patients with diabetic proteinuria?” Currently, with contradicting results from several trials, a conclusive answer to the above is unavailable. As a case in point, atorvastatin exhibited reno-protective effects in the Treating to New Targets (TNT) study, but decreased estimated (e)-GFR in PLANET-I and CARDS trials.4,5 Similarly, rosuvastatin exhibited reno-protective effects in mouse-model experiments, but in PLANET-I it exhibited reno-deleterious effects as it significantly decreased e-GFR.6 The results of the SHARP trial,7 show promise where simvastin plus ezetimibe could be prescribed for patients with renal dysfunction, without plausible detrimental effects on renal health, although the trial lacked a longer follow-up period.8 Future head-to-head trials with different statins or a statins plus non-statin-cholesterol lowering drug combination, conducted in a patient population with CKD and with a suitable follow up period, are essential to answer the question posed above. In the meantime, clinicians will have to choose the statin appropriate to the need of the patient.

Reducing Residual Risk in Secondary Prevention of Cardiovascular Disease

Prevention of cardiovascular disease (CVD) spans the human lifespan, including primordial, primary, and secondary prevention efforts. Extensive evidence from epidemiological, genetic, and animal studies confirms the central importance of elevated low-density lipoprotein (LDL) cholesterol (LDL-C) in atherosclerotic CVD events.1 The Cholesterol Treatment Trialists Collaboration provides per-person documentation from large-scale randomized clinical trials of the striking reduction in CVD events per 1 mmol (38.8 mg/dL) of LDL-C lowering with statins over a wide range of baseline LDL-C values.2,3 It is worth recalling that the major statin trials were not designed to determine the effectiveness of titration to LDL-C or even to non–high-density lipoprotein cholesterol goals by statins but were fixed-dose comparisons of various statins against placebo and then, more recently, large-dose statin therapy versus moderate-dose statin therapy. What is not so clear is whether we can intervene to reduce so-called residual risk further in secondary prevention patients optimally treated with statin therapy. A promising short list of proposed potential targets other than LDL includes efforts to promote smoking cessation and therapies to improve the prothrombotic and inflammatory state of the metabolic syndrome and to control elevated blood pressure.4 Article see p 1979 The article by Mora et al5 in this issue of Circulation is helpful in shedding light on this unresolved but important clinical problem. The investigators used data from a large-scale clinical trial of secondary prevention patients called Treating to New Targets (TNT). They evaluated risk factors for recurrent CVD events in those treated with intensive statin therapy (atorvastatin 80 mg/d) to address the challenges inherent in further risk reduction for those who had major cardiovascular events despite high-dose (atorvastatin 80 mg/d) statin therapy. The trial design of TNT included enrollment of participants with chronic coronary artery …

Relation of Improvement in Estimated Glomerular Filtration Rate With Atorvastatin to Reductions in Hospitalizations for Heart Failure (from the Treating to New Targets [TNT] Study)

Impaired kidney function often accompanies heart failure (HF) and is associated with a worse prognosis. This post hoc analysis of the Treating to New Targets (TNT) trial examined whether the observed decrease in HF hospitalizations with high- compared to low-dose atorvastatin could be related to improvements in kidney function. Of 10,001 TNT participants, 9,376 had estimated glomerular filtration rate (eGFR) measurements at baseline and 1 year and were included in this analysis. The association of change in year-1 eGFR and subsequent HF hospitalization was examined using Cox regression models. In total 218 participants developed subsequent HF hospitalization. Little change in eGFR occurred over 1 year in the atorvastatin 10-mg group, whereas eGFR improved in the 80-mg group by 1.48 ml/min/1.73 m(2) (95% confidence interval 1.29 to 1.67, p <0.0001). Subsequent HF was preceded by a decrease in eGFR over 1 year compared to modest improvement in those without subsequent HF (-0.09 ± 7.89 vs 0.81 ± 6.90 ml/min/1.73 m(2), p = 0.0015). After adjusting for baseline eGFR, each 5-ml/min/1.73 m(2) increase in eGFR at 1 year was associated with a lower risk of subsequent HF hospitalization (hazard ratio 0.85, 95% confidence interval 0.77 to 0.94, p = 0.002). This relation was independent of treatment effect or change in low-density lipoprotein cholesterol level at 1 year. In conclusion, treatment with high- compared to low-dose atorvastatin was associated with improvement in eGFR at 1 year, which was related to a decrease in subsequent HF hospitalization. This suggests that improvement in kidney function may be related to the beneficial effect of high-dose atorvastatin on HF hospitalization.

The 719Arg Variant of KIF6 and Cardiovascular Outcomes in Statin-Treated, Stable Coronary Patients of the Treating to New Targets and Incremental Decrease in End Points Through Aggressive Lipid-Lowering Prospective Studies

Carriers of the KIF6 719Arg variant may be at increased risk for CVD and may benefit more from statin therapy, in terms of CVD risk reduction, than noncarriers. Our objective was to investigate whether carriers of the KIF6 719Arg genetic variant (rs20455) are at increased cardiovascular risk and obtain more benefit from high-dose statin therapy than do noncarriers. We used an adjusted Cox proportional hazard model to assess the hazard ratio (HR) for the reduction of major cardiovascular events by 80 mg/d atorvastatin over 10 mg/d atorvastatin in 4599 patients of the Treating to New Targets (TNT) study and by 80 mg/d atorvastatin over 20-40 mg/d simvastatin in 6541 patients of the Incremental Decrease in End Points Through Aggressive Lipid-Lowering (IDEAL) study. A total of 381 and 648 patients had a cardiovascular event during follow-up in TNT and IDEAL, respectively. Heterozygotes and homozygotes for the minor allele were not at increased risk compared with noncarriers. In TNT, for noncarriers of the 719Arg allele, the HR for high- versus low-dose atorvastatin was 0.81 (95% confidence interval, 0.59-1.11). In carriers of 1 or 2 minor alleles, the HR was 0.85 (0.66-1.11) and carriers of 2 copies of the minor allele obtained a significant risk reduction (HR: 0.44, 95% confidence interval, 0.23-0.84). In IDEAL, the respective HRs were 0.85 (0.67-1.10), 0.88 (0.62-1.07) and 0.91 (0.58-1.43). The interaction term for carrier status by treatment was also nonsignificant (P=0.810 in TNT and P=0.909 in IDEAL). In these 2 large, randomized clinical trials, carriers of the KIF6 719Arg allele were not at increased cardiovascular risk and did not obtain consistent cardiovascular benefit from high-dose statin therapy compared with noncarriers.

The epidemiological concept of residual risk

Residual cardiovascular risk can be defined as the residual risk of incident vascular events or progression of established vascular damage persisting in patients treated with current evidence-based recommended care including the risk that established from risk factors, such as dyslipidemia, high blood pressure, and the risk related to emerging or newer risk factors. The concept clearly derives from intervention trials, mainly the statin trials, and there is a lot of debate about the residual risk conferred by other lipid components, in particular low levels of HDL cholesterol and high levels of triglycerides. A meta-analysis of 53 fibrates (16,802 subjects) and 30 niacin trials (4,749 subjects) revealed an average HDL-C increase of 10% with fibrates and 16% with niacin, a triglyceride decrease of 36% with fibrates and 20% with niacin, and a LDL-C decrease of 8% with fibrates and 14% with niacin. These lipid changes resulted in similar overall reductions in major coronary events evidenced by a 25% decrease with fibrates and 27% with niacin. However, recent analyses of the primary and secondary prevention trials like JUPITER, Treating to New Targets (TNT) and PROVE-IT TIMI 22 force to reconsider the issue. In these three trials, HDL-C was useful in the initial risk assessment but when LDL-C was aggressively lowered the residual risk predictive value of HDL-C was markedly attenuated. Also epidemiological studies evaluate the residual risk in treated hypertensives and dyslipidemic subjects within a general population. The PRIME study in Northern Ireland and France and the Progetto CUORE study in Italy, both with a 10-year follow-up were able to test the hypothesis of the residual cardiovascular risk in treated hypertensives, because the proportion of treated dyslipidemic subjects was too low at baseline. In both studies treatment with antihypertensive agents was associated with a sizeable residual cardiovascular risk with the hazard ratio of 1.5-1.7, suggesting that more efficient risk reduction strategies in hypertension should be developed as a priority. In conclusion residual cardiovascular risk should be better studied in cardiovascular epidemiology, refining the methods to evaluate it, to consider measures of exposure to the modifiable risk factors and indicators of treatment (both at pharmacological and lifestyle level) over the time. Repeated measures and cohortal follow-up are needed and also new statistical methods are necessary to evaluate the residual risk to understand how to reduce it.

Predictors of New-Onset Diabetes in Patients Treated With Atorvastatin: Results From 3 Large Randomized Clinical Trials

We sought to examine the incidence and clinical predictors of new-onset type 2 diabetes mellitus (T2DM) within 3 large randomized trials with atorvastatin.Statin therapy might modestly increase the risk of new-onset T2DM.We used a standard definition of diabetes and excluded patients with prevalent diabetes at baseline. We identified baseline predictors of new-onset T2DM and compared the event rates in patients with and without new-onset T2DM.In the TNT (Treating to New Targets) trial, 351 of 3,798 patients randomized to 80 mg of atorvastatin and 308 of 3,797 randomized to 10 mg developed new-onset T2DM (9.24% vs. 8.11%, adjusted hazard ratio [HR]: 1.10, 95% confidence interval [CI]: 0.94 to 1.29, p = 0.226). In the IDEAL (Incremental Decrease in End Points Through Aggressive Lipid Lowering) trial, 239 of 3,737 patients randomized to atorvastatin 80 mg/day and 208 of 3,724 patients randomized to simvastatin 20 mg/day developed new-onset T2DM (6.40% vs. 5.59%, adjusted HR: 1.19, 95% CI: 0.98 to 1.43, p = 0.072). In the SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) trial, new-onset T2DM developed in 166 of 1,905 patients randomized to atorvastatin 80 mg/day and in 115 of 1,898 patients in the placebo group (8.71% vs. 6.06%, adjusted HR: 1.37, 95% CI: 1.08 to 1.75, p = 0.011). In each of the 3 trials, baseline fasting blood glucose, body mass index, hypertension, and fasting triglycerides were independent predictors of new-onset T2DM. Across the 3 trials, major cardiovascular events occurred in 11.3% of patients with and 10.8% of patients without new-onset T2DM (adjusted HR: 1.02, 95% CI: 0.77 to 1.35, p = 0.69).High-dose atorvastatin treatment compared with placebo in the SPARCL trial is associated with a slightly increased risk of new-onset T2DM. Baseline fasting glucose level and features of the metabolic syndrome are predictive of new-onset T2DM across the 3 trials.

Impact of Smoking on Cardiovascular Events in Patients With Coronary Disease Receiving Contemporary Medical Therapy (from the Treating to New Targets [TNT] and the Incremental Decrease in End Points Through Aggressive Lipid Lowering [IDEAL] Trials)

To define the incremental risk of cigarette smoking in patients with coronary disease receiving contemporary medical therapy, we performed a post hoc analysis of 18,885 patients by combining data from the Treating to New Targets (TNT) and the Incremental Decrease in End Points through Aggressive Lipid Lowering (IDEAL) trials. These studies compared high-dose treatment (atorvastatin 80 mg/day) to moderate-dose treatment (atorvastatin 10 mg/day in TNT and simvastatin 20 to 40 mg/day in IDEAL) in patients with established coronary heart disease. The primary end point of this pooled analysis was major cardiovascular events, a composite of cardiac death, myocardial infarction, stroke, or resuscitated cardiac arrest. At baseline 4,196 patients had never smoked, 11,513 were ex-smokers, and 3,176 were current smokers. The adjusted hazard ratio for current smokers compared to never smokers was 1.68 (95% confidence interval 1.46 to 1.94) and that for current smokers compared to ex-smokers was 1.57 (95% confidence interval 1.41 to 1.76). Event rates for current smokers compared to ex-smokers were similarly increased in each treatment group. The difference in absolute event rates between current and ex-smokers in this pooled analysis was 4.5%, which is >2 times as large as the decrease in absolute event rates between high-dose and moderate-dose statin therapy found in the IDEAL (1.7%) and TNT (2.2%) trials, respectively. In conclusion, in patients with coronary disease receiving modern medical therapy, smoking cessation is of substantial benefit with a number needed to treat of 22 to prevent a major cardiovascular event over 5 years. Smoking cessation deserves greater emphasis in secondary prevention.

Blood pressure targets of antihypertensive treatment: up and down the J-shaped curve

This editorial refers to ‘Effects of a fixed combination of perindopril and indapamide in patients with type 2 diabetes and chronic kidney disease’[†][1], by H.J. Lambers Heerspink et al. , on page 2888 and ‘J-curve revisited: an analysis of blood pressure and cardiovascular events in the Treating to New Targets (TNT) Trial’[‡][2], by S. Bangalore et al. , on page 2897 The solid evidence (mostly from placebo-controlled trials) that lowering blood pressure (BP) in hypertensives is accompanied by reduced incidence of cardiovascular outcomes generated the opinion that the lower the BP achieved the greater the outcome reduction. It has also been inferred that the direct relationship between BP and incident outcomes, down to at least 115 mmHg systolic BP (SBP) and 75 mmHg diastolic BP (DBP), described in uncomplicated individuals,1 can also be observed in treated hypertensives, and high-risk individuals might benefit from further BP lowering even if initially normotensives. These opinions and recommendations have recently been reappraised by a Task Force document of the European Society of Hypertension (ESH) on the basis of a critical analysis of available evidence from trials.2 It has been concluded that there is no solid evidence in favour of the recommendation that high-risk patients should require a SBP target below 130 mmHg and should receive antihypertensive agents even when their BP is in the high-normal range.2 Furthermore, several groups of authors have recently revisited the hypothesis of a J-shaped relationship between BP achieved by treatment and incident cardiovascular events. This hypothesis continues to be widely popular for several reasons: (i) common sense indicates a threshold BP must exist below which survival is impaired (at 0 mmHg all would be dead); (ii) physiology has shown there is a low (as well as high) BP threshold for organ blood flow autoregulation, and this threshold can … *Corresponding author. Tel: +39 02 50320484, Fax: +39 02 50320480, Email: alberto.zanchetti{at}unimi.it or alberto.zanchetti{at}auxologico.it [1]: #fn-2 [2]: #fn-3

On-treatment lipoprotein components and risk of cerebrovascular events in the Treating to New Targets study

The Treating to New Targets (TNT) study has recently provided evidence that reduction in LDL-C levels below 2·6 mmol L⁻¹ lowers the risk of cerebrovascular events by an additional 20% to 25%, thereby confirming the value of statin therapy in preventing transient ischaemic attacks and stroke. Despite the protective effects of statin therapy, the epidemiological association between lipid components and cerebrovascular events is less clear. We therefore assessed the strength of association between in-trial lipoprotein components and cerebrovascular disease in patients receiving intensive lipid-lowering therapy. In 9247 patients (mean age 61·0 years, 81·2% males), the association between lipoprotein components and the risk of cerebrovascular events after the first year into the TNT trial was assessed after stratification of lipoprotein components into approximate quartiles. Cox proportional hazards models were used to explore the association between lipoprotein components and time to first cerebrovascular event after adjustment for potential confounding variables. All lipoprotein components, except LDL-C, showed a significant gradient for incidence of cerebrovascular events with increasing quartiles of the lipoprotein component. If the lipoprotein components were treated as continuous variables, the adjusted hazard ratios (95% CI) for cerebrovascular events for 1 SD difference in 1-year lipoprotein components were 1·13 (1·02-1·25) for LDL-C, 0·86 (0·76-0·97) for HDL-C, 1·17 (1·04-1·28) for apoB, 0·83 (0·74-0·94) for apoA-1, 1·22 (1·10-1·34) for TC/HDL-C and 1·24 (1·12-1·37) for apoB/apoA-1. In coronary heart disease patients receiving intensive lipid-lowering treatment, the on-treatment apoB/apoA-1 ratio provides the strongest association with incidence of cerebrovascular events followed by TC/HDL-C.

J-curve revisited: an analysis of blood pressure and cardiovascular events in the Treating to New Targets (TNT) Trial

In patients with coronary artery disease (CAD), a J-curve relationship has been reported between blood pressure (BP) and future cardiovascular events. However, this is controversial. The purpose of the study was to determine the relationship between on-treatment BP and cardiovascular outcomes in patients with CAD. We evaluated 10 001 patients with CAD and a low-density lipoprotein (LDL) cholesterol level <130 mg/dL, randomized to atorvastatin 80 vs. 10 mg, enrolled in the TNT trial. The post-baseline, time-dependent BPs [systolic blood pressure (SBP) and diastolic blood pressure (DBP)] were categorized into 10 mmHg increments. The primary outcome was a composite of death from coronary disease, non-fatal myocardial infarction (MI), resuscitated cardiac arrest, and fatal or non-fatal stroke. Among the 10 001 patients, 982 (9.82%) experienced a primary outcome at 4.9 years (median) of follow-up. The relationship between SBP or DBP and primary outcome followed a J-curve with increased event rates above and below the reference BP range, both unadjusted and adjusted (for baseline covariates, treatment effect, and LDL levels). A time-dependent, non-linear, multivariate Cox proportional hazard model identified a nadir of 146.3/81.4 mmHg where the event rate was lowest. A similar non-linear relationship with a higher risk of events at lower pressures was found for most of the secondary outcomes of all-cause mortality, cardiovascular mortality, non-fatal MI, or angina. However, for the outcome of stroke, lower was better for SBP. In patients with CAD, a low BP (<110-120/<60-70 mmHg) portends an increased risk of future cardiovascular events (except stroke).

Comparison of 80 versus 10 mg of Atorvastatin on Occurrence of Cardiovascular Events After the First Event (from the Treating to New Targets [TNT] Trial)

Analyses of randomized clinical trials are usually restricted to examination of time to first event. However, because many patients have multiple events, this approach precludes much potentially useful clinical and economic data. To assess the effect on overall disease burden in the Treating to New Targets (TNT) study, we evaluated the effect of treatment with atorvastatin 80 versus 10 mg in the period after the occurrence of a first cardiovascular event. In TNT, 10,001 patients with stable coronary heart disease received double-blind therapy with atorvastatin 80 or 10 mg and were followed for 4.9 years. Post hoc time-to-event analysis was used to estimate separate hazard ratios for time to any first, second, third, fourth, and fifth recurrent cardiovascular events. During TNT, 3,082 patients had a first recurrent cardiovascular event, with 1,516, 698, 345, and 197 developing second, third, fourth, and fifth recurrent events, respectively. In patients receiving atorvastatin 80 mg, the relative risk of a first recurrent event was significantly decreased compared to those receiving atorvastatin 10 mg. Significant benefit with the 80-mg dose was also observed for second, third, fourth, and fifth recurrent events. Similar findings were recorded in 5,854 patients with type 2 diabetes mellitus and/or metabolic syndrome and in 3,809 patients > or = 65 years of age compared to younger patients. In conclusion, treatment with atorvastatin 80 mg continued to significantly decrease the risk of any cardiovascular event over time compared to atorvastatin 10 mg in patients who had survived previous events. In TNT, analyses limited to the primary end point significantly underestimated the decrease in total cardiovascular disease burden achieved by intensive low-density lipoprotein cholesterol lowering.

Response to Letters Regarding Article, “Evidence for Statin Pleiotropy in Humans: Differential Effects of Statins and Ezetimibe on Rho-Associated Coiled-Coil Containing Protein Kinase Activity, Endothelial Function, and Inflammation”

We appreciate the comments by Settergren et al on differences in the patient population and response to lipid-lowering therapies between our 2 studies.1,2 We agree that our patient population had lower cardiovascular risks and higher on-treatment low-density lipoprotein cholesterol (LDL-C) levels. Thus, it is possible that LDL-C lowering alone may not be the overwhelming determinant of endothelial function as observed in our study. Furthermore, the lipid-lowering response to statin monotherapy and the combination of statin and ezetimibe may differ between white and Asian patients.3 Regardless of these ethnic and cardiovascular risk factor differences, the LDL reduction was similar between simvastatin 40 mg and simvastatin/ezetimibe 10 mg/10 mg in our study. However, endothelial function differed significantly between these 2 treatment groups (simvastatin 40 mg versus simvastatin/ezetimibe 10/10 mg: +32.1% versus −0.5%, P <0.01). Because of these contrasting results, we agree that there is a need for a larger-scale and perhaps multicenter study to further investigate whether changes in endothelial function with statin therapy are solely dependent on LDL-C lowering and, if so, whether they are affected by patient background and the degree of LDL-C lowering. From the results of the Pravastatin or Atorvastatin Evaluation and Infection Therapy/Thrombolysis in Myocardial Infarction 22 (PROVE-IT/TIMI 22) and the Treating to New Targets (TNT) trials, it is clear that a greater reduction in LDL-C with either a more potent statin, a higher dose of statin, or both leads to a greater reduction in cardiovascular events. …