Impaired diurnal blood pressure variation and all-cause mortality.

BACKGROUND: Most healthy people exhibit a decrease in systolic blood pressure (SBP) at night. A drop of <10% from mean daytime values, "non-dipping," is associated with kidney disease and cardiovascular events. We hypothesized that non-dipping would predict all-cause mortality. METHODS: Consecutive patients referred for ambulatory blood pressure (BP) monitoring at the Cleveland Clinic between 1994 and 2004 were included. Mean daytime (6 AM-11 PM) and nighttime (11 PM-6 AM) SBP values were calculated. We examined diurnal BP variation as a continuous variable, ((Mean daytime SBP - Mean nighttime SBP)/(Mean daytime SBP)) x 100%, and also as a categorical variable, defining "non-dipping" as a nocturnal SBP drop of <10%; subjects who exhibited non-dipping were defined as "non-dippers" and the others as "dippers." All-cause mortality was ascertained from the Social Security Death Index. RESULTS: Of the 621 patients included in the study, 261 were dippers and 360 were non-dippers. Non-dippers were older (P < 0.0001), more likely to be non-white (P < 0.05), and had higher rates of smoking, diabetes, hypertension, coronary artery disease, congestive heart failure, and renal insufficiency (P < 0.01 for all). Over a mean follow-up of 6.3 years, 61 patients died, including 10 dippers (3.8%) and 51 non-dippers (14.2%). The unadjusted hazard ratio for death based upon a decrement in the dipping percentage from the 75th to 25th percentile was 2.22 (95% confidence interval 1.64-2.95; P < 0.0001). This was attenuated after adjustment for comorbid conditions, including mean 24-h SBP and renal function: adjusted hazard ratio 1.62 (1.14-2.24; P < 0.005). CONCLUSIONS: Blunted diurnal BP variation is a strong predictor of death, but this may be accounted for, in large part, by its association with other cardiovascular risk factors.

Blood pressure control by drug group in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).

Blood pressure (BP) control rates and number of antihypertensive medications were compared (average follow-up, 4.9 years) by randomized groups: chlorthalidone, 12.5-25 mg/d (n=15,255), amlodipine 2.5-10 mg/d (n=9048), or lisinopril 10-40 mg/d (n=9054) in a randomized double-blind hypertension trial. Participants were hypertensives aged 55 or older with additional cardiovascular risk factor(s), recruited from 623 centers. Additional agents from other classes were added as needed to achieve BP control. BP was reduced from 145/83 mm Hg (27% control) to 134/76 mm Hg (chlorthalidone, 68% control), 135/75 mm Hg (amlodipine, 66% control), and 136/76 mm Hg (lisinopril, 61% control) by 5 years; the mean number of drugs prescribed was 1.9, 2.0, and 2.1, respectively. Only 28% (chlorthalidone), 24% (amlodipine), and 24% (lisinopril) were controlled on monotherapy. BP control was achieved in the majority of each randomized group-a greater proportion with chlorthalidone. Over time, providers and patients should expect multidrug therapy to achieve BP <140/90 mm Hg in a majority of patients.

Safety of rosuvastatin: update on 16,876 rosuvastatin-treated patients in a multinational clinical trial program.

BACKGROUND: The safety and tolerability of rosuvastatin were assessed using data from 16,876 patients who received rosuvastatin 5-40 mg in a multinational phase II/III/IIIb/IV program, representing 25,670 patient-years of continuous exposure to rosuvastatin. METHODS: An integrated database, consisting of 33 trials whose databases were locked up to and including September 16, 2005, was used to examine adverse events and laboratory data. RESULTS: In placebo-controlled trials, adverse events irrespective of causality assessment occurred in 52.1% of patients receiving rosuvastatin 5-40 mg (n = 931) and 51.8% of patients receiving placebo (n = 483). In all controlled clinical trials with comparator statins, rosuvastatin 5-40 mg was associated with an adverse event profile similar to profiles for atorvastatin 10-80 mg, simvastatin 10-80 mg, and pravastatin 10-40 mg. Clinically significant elevations in alanine aminotransferase (> 3 times the upper limit of normal [ULN] on at least 2 consecutive occasions) were uncommon (< or = 0.2%) in the rosuvastatin and comparator statin groups. Elevated creatine kinase > 10 times ULN occurred in < or = 0.3% of patients receiving rosuvastatin or other statins. Myopathy (creatine kinase > 10 times ULN with muscle symptoms) possibly related to treatment occurred in 0.03% of patients taking rosuvastatin at doses < or = 40 mg. The frequency of dipstick-positive proteinuria at rosuvastatin doses < or = 20 mg was comparable to that seen with other statins, and the development of proteinuria was not predictive of acute or progressive renal disease. Both short- and long-term rosuvastatin treatment were associated with small increases in estimated glomerular filtration rate, with improvements appearing to be somewhat greater in those patients beginning treatment with greater renal impairment. In the phase II-IV program, no deaths were attributed to rosuvastatin; at doses of rosuvastatin < or = 40 mg, 1 case of rhabdomyolysis occurred in a patient who received rosuvastatin 20 mg and concomitant gemfibrozil treatment. CONCLUSION: In summary, rosuvastatin was well tolerated by a broad range of patients with dyslipidemia, and its safety profile was similar to those of comparator statins investigated in the clinical program. (Nota bene: The clinical development program for rosuvastatin initially evaluated rosuvastatin doses up to 80 mg. Following completion of the phase III/IIIb program, a decision was made not to pursue marketing approval for the 80-mg dose because the additional lipid-modifying benefits of this dose did not justify the potential risks for use in the general population of patients with dyslipidemia.)

Association of impaired diurnal blood pressure variation with a subsequent decline in glomerular filtration rate.

BACKGROUND: Most healthy people exhibit a decrease in systolic blood pressure (SBP) at night. A drop of less than 10% from mean daytime values (nondipping) is associated with chronic kidney disease, insulin resistance, and cardiovascular events. Whether nondipping precedes a decline in renal function remains unclear. We hypothesized that nondipping would predict a decline in the glomerular filtration rate (GFR) over time. METHODS: Consecutive patients referred for ambulatory blood pressure monitoring were included in our retrospective cohort if they had a serum creatinine level noted at the time of their ambulatory blood pressure recording and a follow-up creatinine level recorded at least 1 year later. Mean day and night SBPs were compared (nighttime SBP-daytime [corrected] SBP ratio). We defined nondipping as a nighttime [corrected] SBP-daytime [corrected] SBP ratio higher than 0.90. The GFR was calculated using the Modification of Diet in Renal Disease 4-variable equation. RESULTS: Of 322 patients included, 137 were dippers and 185 were nondippers; their mean baseline GFRs were 80.5 mL/min per 1.73 m(2) and 76.4 mL/min per 1.73 m(2), respectively. During a median follow-up of 3.2 years, the GFRs remained stable among dippers (mean change, 1.3%) but declined among nondippers (mean change, -15.9%) (P<.001). The creatinine levels increased by more than 50% in 2 dippers (1.5%) and in 32 nondippers (17.3%) (P<.001). These findings persisted after adjustment for other predictors of GFR decline. CONCLUSION: Blunted diurnal blood pressure variation is associated with a subsequent deterioration in renal function that is independent of SBP load and other risk factors for renal impairment.

Inflammation in renal disease.

Inflammation is a component of the major modifiable risk factors in renal disease. Elevated high-sensitivity C-reactive protein (hs-CRP) levels have been shown to predict all-cause and cardiovascular mortality in patients dependent on dialysis and to predict worsening renal function in subjects without overt renal disease. Levels of hs-CRP are also predictive of hypertension, a major risk factor for renal disease, across all levels of blood pressure in subjects without initial hypertension. Many of the treatments used in patients with renal disease exert anti-inflammatory activities that constitute or contribute to their therapeutic effects. A number of studies have indicated that statin therapy exerts a renoprotective effect that is possibly mediated by anti-inflammatory activities.

Effect of short-term rosuvastatin treatment on estimated glomerular filtration rate.

To define the effect of short-term rosuvastatin treatment on the estimated glomerular filtration rate (eGFR), the database of controlled clinical trials in the Rosuvastatin Clinical Development Program was reviewed. Thirteen studies comprising 3,956 rosuvastatin-treated patients were selected based on a serum creatinine measurement at 6 or 8 weeks after initiation of rosuvastatin treatment, randomization to approved and marketed rosuvastatin doses (5 to 40 mg), and unchanged rosuvastatin dose from treatment initiation (baseline) through 6 to 8 weeks of treatment. eGFR was determined with the Modification of Diet in Renal Disease formula. eGFR significantly increased for each dose of rosuvastatin individually and for all doses combined compared with baseline (range +0.9 to +3.2 ml/min/1.73 m2). Further analysis of 5 blinded, placebo-controlled trials comprising 525 patients showed an increase in eGFR of +0.8 ml/min/1.73 m2 (95% confidence interval +0.1 to +1.5) for all rosuvastatin-treated patients, which was significantly different from baseline (p <0.04) and from a change of -1.5 ml/min/1.73 m2 in the placebo-treated patients (95% confidence interval -2.5 to -0.5, p <0.001). The increase in eGFR for rosuvastatin-treated patients was consistent across all major demographic and clinical subgroups of interest, including patients with baseline proteinuria, baseline eGFR <60 ml/min/1.73 m2, and in patients with hypertension and/or diabetes. In conclusion, these results are consistent with previous rosuvastatin studies that showed an upward trend in eGFR with long-term treatment (> or =96 weeks) and with the hypothesis that statins may have pleiotropic mechanisms of action that include beneficial renal effects.

Relation of diurnal blood pressure variation and triglyceride-to-high-density lipoprotein cholesterol ratio in patients without diabetes mellitus.

A night-time decrease in systolic blood pressure that differs <10% from mean daytime values ("nondipping") is associated with increased rates of cardiovascular morbidity and mortality. We hypothesized that insulin resistance would be associated with nondipping in patients who did not have frank diabetes mellitus or hypertension. We included 106 consecutive outpatients who had been referred for 24-hour ambulatory monitoring of blood pressure. Our data suggest that insulin resistance, defined as a high ratio of triglyceride to high-density lipoprotein, is associated with blunted diurnal blood pressure variation (odds ratio 6.3, 95% confidence interval 2.6 to 16.4, p <0.0001) before the development of abnormal levels of fasting blood glucose.

Renal effects of atorvastatin and rosuvastatin in patients with diabetes who have progressive renal disease (PLANET I): a randomised clinical trial.

BACKGROUND: The role of lipid-lowering treatments in renoprotection for patients with diabetes is debated. We studied the renal effects of two statins in patients with diabetes who had proteinuria. METHODS: PLANET I was a randomised, double-blind, parallel-group trial done in 147 research centres in Argentina, Brazil, Bulgaria, Canada, Denmark, France, Hungary, Italy, Mexico, Romania, and the USA. We enrolled patients with type 1 or type 2 diabetes aged 18 years or older with proteinuria (urine protein:creatinine ratio [UPCR] 500-5000 mg/g) and taking stable angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or both. We randomly assigned participants to atorvastatin 80 mg, rosuvastatin 10 mg, or rosuvastatin 40 mg for 52 weeks. The primary endpoint was change from baseline to week 52 of mean UPCR in each treatment group. The study is registered with ClinicalTrials.gov, number NCT00296374. FINDINGS: We enrolled 353 patients: 118 were assigned to rosuvastatin 10 mg, 124 to rosuvastatin 40 mg, and 111 to atorvastatin 80 mg; of these, 325 were included in the intention-to-treat population. UPCR baseline:week 52 ratio was 0·87 (95% CI 0·77-0·99; p=0·033) with atorvastatin 80 mg, 1·02 (0·88-1·18; p=0·83) with rosuvastatin 10 mg, and 0·96 (0·83-1·11; p=0·53) with rosuvastatin 40 mg. In a post-hoc analysis to compare statins, we combined data from PLANET I with those from PLANET II (a similar randomised parallel study of 237 patients with proteinuria but without diabetes; registered with ClinicalTrials.gov, NCT00296400). In this analysis, atorvastatin 80 mg lowered UPCR significantly more than did rosuvastatin 10 mg (-15·6%, 95% CI -28·3 to -0·5; p=0·043) and rosuvastatin 40 mg (-18·2%, -30·2 to -4·2; p=0·013). Adverse events occurred in 69 (60%) of 116 patients in the rosuvastatin 10 mg group versus 79 (64%) of 123 patients in the rosuvastatin 40 mg group versus 63 (57%) of 110 patients in the atorvastatin 80 mg group; renal events occurred in nine (7·8%) versus 12 (9·8%) versus five (4·5%). INTERPRETATION: Despite high-dose rosuvastatin lowering plasma lipid concentrations to a greater extent than did high-dose atorvastatin, atorvastatin seems to have more renoprotective effects for the studied chronic kidney disease population. FUNDING: AstraZeneca.

ALLHAT says diuretics are better; ANBP2 says ACEs are better--can we resolve the differences?

The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) and the second Australian National Blood Pressure Study (ANBP2) came to different conclusions about which class of drug to try first for treating high blood pressure: a diuretic or an angiotensin-converting enzyme (ACE) inhibitor. But when examined closely, the results may not be all that different after all.

The ALLHAT Trial. Diuretics are still the preferred initial drugs for high blood pressure.

The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) compared four antihypertensive agents in patients 55 years and older: chlorthalidone, doxazosin, amlodipine, and lisinopril. The doxazosin arm was terminated early because of an excess of congestive heart failure. Chlorthalidone was at least equivalent to amlodipine and lisinopril in all of the outcomes measured, and was better in some, notably heart failure.

Microalbuminuria: is it a valid predictor of cardiovascular risk?

Microalbuminuria strongly predicts cardiovascular morbidity and mortality, clinical nephropathy, and progression of renal disease in high-risk populations. We recommend screening patients with type 2 diabetes, older patients with type 1 diabetes, and older patients with stage 2 hypertension or higher (ie, > or = 160/100 mm Hg).

Renal safety of intensive cholesterol-lowering treatment with rosuvastatin: a retrospective analysis of renal adverse events among 40,600 participants in the rosuvastatin clinical development program.

OBJECTIVE: Intensive lowering of low-density lipoprotein cholesterol (LDL-C) with statins reduces cardiovascular risk but can cause liver-, muscle-, and possibly renal-related adverse events (AEs). We assessed the effects of rosuvastatin on the risk of developing renal impairment or renal failure among participants in the rosuvastatin clinical development program. METHODS: The analysis was based on AE data reported by investigators from 36 studies that included 40,600 participants who did not have advanced, pre-existing renal disease. Rates of renal AEs were determined based on time to first occurrence of renal impairment or renal failure. RESULTS: Renal impairment or renal failure was reported in 536 study participants during 72,488 patient-years of follow-up. Renal event rates were higher in patients with history of heart failure (n = 5011), hypertension (n = 21,864), diabetes (n = 5165), or estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m(2) (n = 9507) at baseline but did not differ with rosuvastatin compared with placebo or with rosuvastatin 40 mg compared with rosuvastatin 10mg. Relative risk (RR) estimates obtained from pooled analysis of placebo-controlled trials were RR: 1.03 (95% CI: 0.86-1.23, p = 0.777) for any reported renal impairment or renal failure event, RR: 1.02 (95% CI: 0.76-1.37, p = 0.894) for serious renal AEs, and RR: 0.70 (95% CI: 0.36-1.35, p = 0.282) for renal AEs leading to death. CONCLUSION: These findings suggest that intensive LDL-C-lowering treatment with rosuvastatin does not affect the risk of developing renal insufficiency or renal failure in patients who do not have advanced, pre-existing renal disease.

Longitudinal assessment of estimated glomerular filtration rate in apparently healthy adults: a post hoc analysis from the JUPITER study (justification for the use of statins in prevention: an intervention trial evaluating rosuvastatin).

BACKGROUND: Serum creatinine-based estimates of glomerular filtration rate (eGFR) are frequently used to identify patients with chronic kidney disease and assess cardiovascular risk both in clinical trials and in clinical practice. Although change in eGFR may be useful to assess change in renal function in patients with chronic kidney disease, the utility of serum creatinine-based eGFR is uncertain, particularly among individuals with normal or only mildly impaired renal function. OBJECTIVE: The goal of this study was to examine the relationship between baseline serum creatinine and eGFR, as well as changes in these parameters, in apparently healthy adults in a post hoc analysis of data obtained in participants in the JUPITER study (Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin). METHODS: JUPITER was a randomized study of rosuvastatin 20 mg versus placebo in apparently healthy adults with high-sensitivity C-reactive protein levels ≥ 2.0 mg/L, LDL-C <130 mg/dL, and serum creatinine ≤ 2.0 mg/dL. Changes from baseline in serum creatinine and eGFR, based on the Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations, were assessed in the entire population and in subsets classified according to baseline eGFR status. RESULTS: Baseline characteristics of the 16,279 JUPITER study participants (mean age, 66 years; 62% men; 72% white; and 58% with a history of hypertension) who had both a baseline and ≥ 1 postbaseline serum creatinine measurement were similar to the entire population of 17,802 patients who entered the trial. The mean age of the study population was 66 years, 62% were men, 72% were white, and 58% had a history of hypertension. Mean (SD) serum creatinine increased from baseline by 0.08 (0.16) mg/dL and 0.09 (0.14) mg/dL in the rosuvastatin and placebo groups, respectively (P = 0.001) at year 1 and by 0.09 (0.18) and 0.10 (0.16) mg/dL (P = 0.0045) at the final visit. Reductions in MDRD and CKD-EPI eGFR were ∼ 0.5 mL/min/1.73 m(2) greater with placebo than with rosuvastatin (P < 0.004) at year 1 and the final visit. The magnitude of eGFR change was closely related to baseline eGFR, with greater reductions among subjects with eGFR ≥ 60 mL/min/1.73 m(2) in both the rosuvastatin and placebo groups. Among those with an eGFR ≥ 90 mL/min/1.73 m(2) , mean changes at year 1 and final visit ranged from -16 to -23 mL/min/1.73 m(2) with MDRD and CKD-EPI, respectively; in contrast, mean changes were <1 mL/min/1.73 m(2) in subjects with eGFR <60 mL/min/1.73 m(2) . CONCLUSIONS: In JUPITER, reductions in MDRD or CKD-EPI eGFR levels were greater in study participants with higher baseline eGFR levels but less in the rosuvastatin than in the placebo group. Future studies are required to assess the reliability of serum creatinine-based estimates of GFR to assess change in renal function, particularly among individuals with normal serum creatinine levels.

Taking blood pressure: too important to trust to humans?

The measurement of blood pressure in the physician's office is subject to a number of observer errors and also to the "white-coat effect." Automatic devices that measure blood pressure without a human observer in the room can eliminate many of these problems. We argue for greater use of these devices in the physician's office.