Julho de 2010

Cholesterol Lowering, Cardiovascular Diseases, and the Rosuvastatin-JUPITER Controversy A Critical Reappraisal
Michel de Lorgeril, MD; Patricia Salen, BSc; John Abramson, MD; Sylvie Dodin, MD; Tomohito Hamazaki, PhD; Willy Kostucki, MD; Harumi Okuyama, PhD; Bruno Pavy, MD; Mikael Rabaeus, MD

Background: Among the recently reported cholesterol lowering drug trials, the JUPITER (Justification for the Use of Statins in Primary Prevention) trial is unique: it reports a substantial decrease in the risk of cardiovascular diseases among patients without coronary heart disease and with normal or low cholesterol levels.
Methods: Careful review of both results and methods used in the trial and comparison with expected data.
Results: The trial was flawed. It was discontinued (according to prespecified rules) after fewer than 2 years of follow-up, with no differences between the 2 groups on the most objective criteria. Clinical data showed a major discrepancy between significant reduction of nonfatal stroke and myocardial infarction but no effect on mortality from stroke and myocardial infarction. Cardiovascular mortality was surprisingly low compared with total mortality—between 5% and 18%—whereas the expected rate would have been close to 40%. Finally, there was a very low case-fatality rate of myocardial infarction, far from the expected number of close to 50%. The possibility that bias entered the trial is particularly concerning because of the strong commercial interest in the study.
Conclusion: The results of the trial do not support the use of statin treatment for primary prevention of cardiovascular diseases and raise troubling questions concerning the role of commercial sponsors.
Arch Intern Med. 2010;170(12):1032-1036


Statins and All-Cause Mortality in High-Risk Primary Prevention A Meta-analysis of 11 Randomized Controlled Trials Involving 65 229 Participants
Kausik K. Ray, MD, MPhil, FACC, FESC; Sreenivasa Rao Kondapally Seshasai, MD, MPhil; Sebhat Erqou, MD, MPhil, PhD; Peter Sever, PhD, FRCP, FESC; J. Wouter Jukema, MD, PhD; Ian Ford, PhD; Naveed Sattar, FRCPath

Background: Statins have been shown to reduce the risk of all-cause mortality among individuals with clinical history of coronary heart disease. However, it remains uncertain whether statins have similar mortality benefit in a high-risk primary prevention setting. Notably, all systematic reviews to date included trials that in part incorporated participants with prior cardiovascular disease (CVD) at baseline. Our objective was to reliably determine if statin therapy reduces all-cause mortality among intermediate to high-risk individuals without a history of CVD.
Data Sources: Trials were identified through computerized literature searches of MEDLINE and Cochrane databases (January 1970-May 2009) using terms related to statins, clinical trials, and cardiovascular end points and through bibliographies of retrieved studies.
Study Selection: Prospective, randomized controlled trials of statin therapy performed in individuals free from CVD at baseline and that reported details, or could supply data, on all-cause mortality.
Data Extraction: Relevant data including the number of patients randomized, mean duration of follow-up, and the number of incident deaths were obtained from the principal publicationorbycorrespondence with the investigators.
Data Synthesis: Data were combined from 11 studies and effect estimates were pooled using a random-effects model meta-analysis, with heterogeneity assessed with the I2 statistic. Data were available on 65 229 participants followed for approximately 244 000 person-years, during which 2793 deaths occurred. The use of statins in this high-risk primary prevention setting was not associated with a statistically significant reduction (risk ratio, 0.91; 95% confidence interval, 0.83-1.01) in the risk of all-cause mortality. There was no statistical evidence of heterogeneity among studies (I2=23%; 95% confidence interval, 0%-61% [P=.23]).
Conclusion: This literature-based meta-analysis did not find evidence for the benefit of statin therapy on all-cause mortality in a high-risk primary prevention set-up.
Arch Intern Med. 2010;170(12):1024-1031


Treatment of hypertension in patients 80 years and older: the lower the better? A meta-analysis of randomized controlled trials
Theodora Bejan-Angoulvanta,b,c, Mitra Saadatian-Elahia, James M. Wrightd, Eleanor B. Schrone, Lars H. Lindholmf, Robert Fagardg, Jan A. Staesseng and Franc¸ois Gueyffiera,b,c

Background Results of randomized controlled trials are consistent in showing reduced rates of stroke, heart failure and cardiovascular events in very old patients treated with antihypertensive drugs. However, inconsistencies exist with regard to the effect of these drugs on total mortality.
Methods We performed a meta-analysis of available data on hypertensive patients 80 years and older by selecting total mortality as the main outcome. Secondary outcomes were coronary events, stroke, cardiovascular events, heart failure and cause-specific mortality. The common relative risk (RR) of active treatment versus placebo or no treatment was assessed using a random-effect model. Linear metaregression was performed to explore the relationship between intensity of antihypertensive therapy and blood pressure (BP) reduction and the log-transformed value of total mortality odds ratios (ORs).
Results The overall RR for total mortality was 1.06 (95% confidence interval 0.89–1.25), with significant heterogeneity between hypertension in the very elderly trial (HYVET) and the other trials. This heterogeneity was not explained by differences in the follow-up duration between trials. The meta-regression suggested that a reduction in mortality was achieved in trials with the least BP reductions and the lowest intensity of therapy. Antihypertensive therapy significantly reduced (P<0.001) the risk of stroke (35%), cardiovascular events (27%) and heart failure (50%). Cause-specific mortality was not different between treated and untreated patients.
Conclusion Treating hypertension in very old patients reduces stroke and heart failure with no effect on total mortality. The most reasonable strategy is the one associated with significant mortality reduction; thiazides as first-line drugs with a maximum of two drugs.
J Hypertens 28:1366–1372 Q 2010


Blood pressure, cerebral blood flow, and brain volumes. The SMART-MR study
Majon Mullera, Yolanda van der Graafb, Frank L. Visserenc, Anne L.M. Vlekb, Willem P.Th.M. Malid Mirjam I. Geerlingsb, for the SMART Study Group

Background Low blood pressure (BP) has been related to increased risk of brain atrophy. As brain hypoperfusion might be a marker for impaired cerebral autoregulation, the risk of brain atrophy may be especially increased if BP is low in combination with brain hypoperfusion. We examined whether low BP was associated with brain atrophy and whether this association was stronger in patients with lower parenchymal cerebral blood flow (CBF), as an indicator of brain perfusion.
Methods Within the Second Manifestations of ARTerial disease-Magnetic Resonance study, a cohort study among 1309 patients with atherosclerotic disease, cross-sectional analyses were performed in 965 patients (mean age 58W10 years) with available BP and CBF measures. Parenchymal CBF was measured with magnetic resonance angiography and was expressed per 100 ml brain volume. Brain segmentation was used to quantify cortical gray matter volume and ventricular volume (% of intracranial volume).
Results Linear regression analyses, adjusted for age, sex, and vascular risk factors showed that the association of systolic BP and pulse pressure, but not diastolic BP, with cortical gray matter volume was modified by parenchymal CBF (P interaction <0.05). In patients with lower parenchymal CBF, but not in those with high arenchymal CBF, lower systolic BP and pulse pressure (per SD decrease) were associated with reduced cortical gray matter volume: b (95% confidence interval) S0.29% (S0.63; 0.00) and S0.34% (S0.69; S0.01).
Conclusion Our findings suggest that lower BP by itself is not sufficient to induce brain atrophy; however, lower SBP and lower pulse pressure in combination with lower parenchymal CBF increased the risk for cortical atrophy.
J Hypertens 28:1498–1505 Q 2010


Reduced discontinuation of antihypertensive treatment by two-drug combination as first step. Evidence from daily life practice
Giovanni Corraoa, Andrea Parodia, Antonella Zambona, Franca Heimanb, Alessandro Filippic,d, Claudio Cricellic,d, Luca Merlinoe and Giuseppe Manciaf

Objectives To measure persistence with antihypertensive drug therapy in patients initiating treatment with mono or combination therapy.
Methods Data analysis was based on two cohorts of patients, that is, a cohort derived from the registration of drug prescriptions in all residents of the Lombardy region receiving Public Health Service and a cohort of patients followed by general practitioners throughout the Italian territory. Data were limited to patients aged 40–80 years who received their first antihypertensive drug prescription (nU433680 and 41199, respectively) in whom persistency of treatment was examined over 9 months. A proportional hazards model was fitted to estimate the association between the pattern of initial antihypertensive drug therapy and risk of treatment discontinuation. Data were adjusted for available potential confounders.
Results Taking patients starting with diuretic monotherapy as reference, the adjusted risk of treatment discontinuation was progressively lower in patients starting with monotherapy other than a diuretic, a two-drug combination, including a diuretic and a two-drug combination without a diuretic. No significant difference in the risk of discontinuation was seen between extemporaneous and fixed dose combinations, including a diuretic, that is, the only combination reimbursable by Public Health Service and, thus, available in the database. Data were similar for the two cohorts.
Conclusion Initiating treatment with a combination of two drugs is associated with a reduced risk of treatment discontinuation.
J Hypertens 28:1584–1590 Q 2010


Prognostic impact of the ambulatory arterial stiffness index in resistant hypertension
Elizabeth S. Muxfeldt, Claudia R.L. Cardoso, Vinicius B. Dias, Ana C.M. Nascimento and Gil F. Salles

Objective The ambulatory arterial stiffness index (AASI), derived from ambulatory blood pressure (BP) monitoring recordings, is an indirect marker of arterial stiffness and a potential predictor of cardiovascular risk. Resistant hypertension is defined as uncontrolled office BP despite the use of at least three antihypertensive drugs. The aim of this prospective study was to investigate the AASI prognostic value in patients with resistant hypertension.
Methods At baseline, 547 patients underwent clinical– laboratory, and 24-h ambulatory BP monitoring examinations. AASI was defined as 1 minus the regression slope of DBP on SBP, and was calculated by standard and symmetric regression. Primary endpoints were a composite of fatal and nonfatal cardiovascular events and all-cause and cardiovascular mortalities. Multiple Cox regression was used to assess associations between AASI and subsequent endpoints.
Results After median follow-up of 4.8 years, 101 patients (18.4%) reached the primary endpoint, and 65 all-cause deaths (11.9%) occurred (45 from cardiovascular causes). 24-h AASI was the best independent predictor of composite endpoint (hazard ratio 1.46, 95% confidence interval 1.12– 1.92, for increments of 1-SDU0.14), whereas cardiovascular mortality was best predicted by night-time AASI (hazard ratio 1.73, 95% confidence interval 1.13–2.65), after adjustments for cardiovascular risk factors, including mean ambulatory BPs and nocturnal BP reduction. Symmetric AASI was not superior to standard AASI. In sensitivity analysis, 24-h AASI was a better predictor of cardiovascular outcomes in women, in younger individuals, and in nondiabetic individuals.
Conclusion AASI is a predictor of cardiovascular morbidity and mortality in resistant hypertension, over and beyond traditional risk factors and other ambulatory BP monitoring parameters.
J Hypertens 28:1547–1553 Q 2010


Influence of blood pressure reduction on composite cardiovascular endpoints in clinical trials
Paolo Verdecchiaa, Giorgio Gentileb, Fabio Angelia, Giovanni Mazzottaa, Giuseppe Manciac and Gianpaolo Reboldib

Background The use of a composite cardiovascular endpoint (CCEP) is frequent in clinical trials. However, the relation between the reduction in blood pressure (BP) and the risk of CCEP is poorly known.
Methods We conducted a meta-analysis of trials, which compared different BP-lowering agents with placebo or active treatments in patients with hypertension or composite features of high cardiovascular risk. The outcome measure was a triple (myocardial infarction, stroke and cardiovascular death) or quadruple (those mentioned above and congestive heart failure) CCEP.
Results Thirty trials fulfilled the inclusion criteria, for a total of 221 024 patients. Experimental treatments reduced the risk of CCEP by 9% (P< 0.0001). In a multivariable metaregression analysis, for each 5-mmHg reduction in SBP, there was a 13% less risk of CCEP (95% confidence interval 8–19, PU0.001) and, for each 2-mmHg reduction in DBP, there was a 12% less risk of CCEP (95% confidence interval 7–16, PU0.001). Use of triple or quadruple CCEP (PU0.150), its definition as primary or nonprimary endpoint (PU0.305) and use of placebo or active control as comparators (PU0.552) did not influence the estimates. A different BP reduction of at least 4.6mmHg in SBP or at least 2.2mmHg in DBP was required to achieve a 95% prediction interval entirely lying below the unity.
Conclusion BP reduction is important to reduce the risk of CCEP in clinical trials. A significant difference between two treatment groups in the risk of CCEP may be anticipated for a SBP/DBP reduction differing by 4.6/2.2mmHg or more.
J Hypertens 28:1356–1365 Q 2010


Effect of dosing time of angiotensin II receptor blockade titrated by self-measured blood pressure recordings on cardiorenal protection in hypertensives: the Japan Morning Surge-Target Organ Protection (J-TOP) study
Kazuomi Karioa, Satoshi Hoshidea, Motohiro Shimizua, Yuichiro Yanoa, Kazuo Eguchia, Joji Ishikawaa, Shizukiyo Ishikawab and Kazuyuki Shimadaa

Objectives To study the impact of the dosing time of an angiotensin II receptor blocker (ARB) titrated by selfmeasured home blood pressure (HBP) on cardiorenal damage in hypertensives.
Methods We conducted an open-label multicenter trial, the J-TOP study, that enrolled 450 hypertensives with selfmeasured systolic HBP more than 135mmHg. The study patients were stratified into three groups according to the difference between their morning and evening SBPs difference: a morning hypertension group (morning and evening difference at least 15mmHg; nU170), a morning and evening hypertension group (0mmHg<— morning and evening difference <15mmHg; nU198), and an evening hypertension group (morning and evening difference <0mmHg; nU82). Individuals were then randomly allocated to receive bedtime dosing or awakening dosing of candesartan (Wdiuretic as needed) titrated to achieve a target systolic HBP less than 135mmHg. The 6-month change in the urinary albumin/creatinine ratio (UACR) was assessed.
Results In total patients, the UACR was more markedly reduced in the bedtime-dosing group than in the awakening-dosing group (S45.7 vs. S34.5%, PU0.02), whereas there were no differences in the reduction of any of the HBPs including the sleep blood pressures (BPs) between the two groups. Among the three subgroups stratified by the morning and evening difference, the difference in the UACR reduction between the bedtimedosing and awakening-dosing groups was only significant in the morning hypertension group (S50.6 vs. S31.3%, PU0.02).
Conclusion In HBP-guided antihypertensive treatment in hypertensives, bedtime dosing of an ARB may be superior to awakening dosing for reducing microalbuminuria.
J Hypertens 28:1574–1583 Q 2010.
 

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