Antihypertensive Long-term Use Research Articles

Cardiovascular Outcomes in Hypertension-Treated Patients With Peripheral Artery Disease: The VALUE Trial.

Systolic blood pressure (BP) is a key predictor of cardiovascular events, but patients with peripheral artery disease (PAD) are rarely included in hypertension trials. The VALUE trial (Valsartan Antihypertensive Long-Term Use Evaluation) investigated the long-term effects of valsartan- or amlodipine-based treatments on cardiovascular outcomes in patients with hypertension with a high cardiovascular risk. The aim of this subanalysis was to clarify the relationship between achieved BP on treatment and cardiovascular outcomes in patients with hypertension with PAD. Patients were followed for 4 to 6 years, and BP was measured regularly. The primary end point was time to the first major adverse cardiovascular event, including myocardial infarction, stroke, cardiovascular death, and heart failure requiring hospitalization. Statistical analyses were performed using Cox regression, adjusting for various baseline covariates. Of the 13 803 participants, 1898 (13.8%) had PAD. During a median follow-up of 4.5 years, patients with PAD had a 23% increased risk of major adverse cardiovascular events compared with patients without PAD. Patients with an achieved systolic BP <130 mm Hg and 130 to 139 mm Hg, compared with those with systolic BP ≥140 mm Hg, were associated with a decreased risk of a major adverse cardiovascular event (hazard ratio, 0.65 [95% CI, 0.43-0.97]; P=0.037; 0.85 [95% CI, 0.74-0.97]; P=0.016, respectively). Additionally, systolic BP <130 mm Hg was associated with a decreased risk of cardiovascular death (hazard ratio, 0.33 [95% CI, 0.12-0.92]; P=0.034). The incidence of the primary outcome did not differ between antihypertensive treatment regimens (P=0.365). Our results indicate that more intensive BP control is associated with a reduction in cardiovascular morbidity and mortality in patients with hypertensive PAD.

RAG-AMERICAS-1: CLINICAL RESEARCH IN LATIN AMERICA: FROM SPONSORED TO INVESTIGATOR INITIATED RESEARCH

Latin American clinical researchers had participated in many controlled clinical trials in the 80 s and 90 s sponsored initiated that confirmed the place of calcium channel blockers and RAS blockade in hypertension treatment. Later, non-inferiority or superiority trials like ONTARGET, Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial and VALUE, Valsartan Antihypertensive Long-term Use Evaluation were performed worldwide including Latin-American countries. In the last decade, the absence of new drugs in the pipeline and sponsors portfolios at one side, and the recommendation of fixed-dose combination as initial treatment tool at the other could be supposed as main causes of a dramatic reduction in sponsored hypertension research. At the same time, a huge increase in investigator initiated research was observed. Scientific national and regional societies in many cases fueled this increase. In this scenario, the Cardiovascular Risk Factor Multiple Evaluation in Latin America, CARMELA study was the first large-scale population-based study that assessed cardiovascular risk factor prevalence in 7 Latin American cities and its relationship to hypertension mediated organ damage. CARMELA is an example of an epidemiological study investigator initiated supported by a sponsor in Latin America The FOCUS study, Fixed-Dose Combination Drug for Secondary Cardiovascular Prevention was another example of an investigator initiated research supported by a private company. FOCUS was funded by the 7th Framework Programme European Commission Consortium with the participation of the Centro Nacional de Investigaciones Cardiovasculares CNIC Madrid, Spain, World Heart Federation, Federación Argentina de Cardiología, and some European research organizations, supported by FERRER Internacional. FOCUS help to understand the reasons of treatment non-adherence in Latin American countries and also to recognize the potential benefits of fixed-dose combinations in secondary prevention. More recently, the Interamerican Society of Cardiology SIAC developed the CorCOVID Latam study which aim was to study changes in lifestyle habits, treatment adherence, and mental health status in patients with cardiometabolic disease, but no clinical evidence of COVID-19 during the pandemic. This study is a good example of the feasibility of non-sponsored research in Latam supported by a regional scientific society structure and members. Five publications related to gender differences in the impact of the pandemic in Latam, Influenza and Pneumococcal vaccination during the pandemic, and the psychological impact in more than 4 thousand patients were the fruit of this society research initiative.

CARDIOVASCULAR OUTCOMES AT RECOMMENDED BLOOD PRESSURE TARGETS IN MIDDLE AGED AND ELDERLY PATIENTS WITH TYPE 2 DIABETES MELLITUS AND HYPERTENSION

Objective: The optimal blood pressure (BP) target for patients with type-2 diabetes mellitus (DM) and hypertension has been set at &lt; 130/80 mmHg in guidelines. However, available data of event-based clinical outcomes trials show that little evidence supports these guideline recommendations. Design and method: We addressed this issue by post-hoc analyzing the risk of cardiovascular (CV) events in mostly elderly high-risk hypertensive patients with type-2 DM participating in the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial. Patients (n = 5250) were divided into 4 groups according to the proportion of on-treatment visits before the occurrence of an event (&lt; 25%, 25%-49%, 50–74%, 75% -100%) in which BP was reduced to &lt; 140/90 or &lt; 130/80 mmHg. Results: After adjustment for baseline demographic differences between groups, a reduction in the proportion of visits in which BP achieved &lt; 140/90 mmHg accompanied a progressive increase in the risk of CV mortality and morbidity as well as of cause-specific events such as stroke, myocardial infarction and heart failure (Figure, upper panel). A progressive reduction in the proportion of visits in which BP was reduced &lt; 130/80 mmHg did not have any effect on CV risks (Figure, lower panel). Conclusions: In mostly elderly high-risk hypertensive patients with type-2 diabetes mellitus participating in the VALUE trial, achieving more frequently BP &lt; 140/90 mmHg showed a marked protective effect on overall and all cause specific cardiovascular outcomes. This was not the case for a more frequent achievement of the more intensive BP target, i.e. &lt; 130/80 mmHg.

Cardiovascular outcomes at recommended blood pressure targets in middle-aged and elderly patients with type 2 diabetes mellitus compared to all middle-aged and elderly hypertensive study patients with high cardiovascular risk

Purpose Event-based clinical outcome trials have shown limited evidence to support guidelines recommendations to lower blood pressure (BP) to <130/80 mmHg in middle-aged and elderly hypertensive patients with diabetes mellitus or with general high cardiovascular (CV) risk. We addressed this issue by post-hoc analysing the risk of CV events in patients who participated in the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial and compared the hypertensive patients with type 2 diabetes mellitus with all high-risk hypertensive patients. Materials and methods Patients were divided into 4 groups according to the proportion of on-treatment visits before the occurrence of an event (<25% to ≥75%) in which BP was reduced to <140/90 or <130/80 mmHg. Patients with diabetes mellitus (n = 5250) were compared with the entire VALUE population with high CV risk (n = 15,245). Results After adjustments for baseline differences between groups, a reduction in the proportion of visits in which BP was reduced to <140/90 mmHg, but not to <130/80 mmHg, was accompanied by a progressive increase in the risk of CV morbidity and mortality as well as stroke, myocardial infarction and heart failure in both diabetes mellitus and in all high-risk patients. Target BP <130/80 mmHg reduced stroke risk in the main population but not in the diabetes mellitus patients. Patients with diabetes mellitus had higher event rates for the primary cardiac endpoint and all-cause mortality driven by a higher rate of heart failure. Conclusion In the high-risk hypertensive patients of the VALUE trial achieving more frequently BP <140/90 mmHg, but not <130/80 mmHg, showed principally the same protective effect on overall and cause-specific cardiovascular outcomes in patients with diabetes mellitus and in the general high-risk hypertensive population.

Cardiovascular outcomes at recommended blood pressure targets in middle-aged and elderly patients with type 2 diabetes mellitus and hypertension

Purpose Available data of event-based clinical outcomes trials show that little evidence supports the guidelines recommendations to lower blood pressure (BP) to <130/80 mmHg in middle-aged and elderly people with type 2 diabetes mellitus and hypertension. We addressed this issue by post-hoc analysing the risk of cardiovascular (CV) events in mostly elderly high-risk hypertensive patients with type 2 diabetes mellitus participating in the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial. Material and methods Patients (n = 5250) were divided into 4 groups according to the proportion of on-treatment visits before the occurrence of an event (<25% to ≥ 75%) in which BP was reduced to <140/90 or <130/80 mmHg. Results After adjustment for baseline demographic differences between groups, a reduction in the proportion of visits in which BP achieved <140/90 mmHg accompanied a progressive increase in the risk of CV mortality and morbidity as well as of cause-specific events such as stroke, myocardial infarction and heart failure. A progressive reduction in the proportion of visits in which BP was reduced <130/80 mmHg did not have any effect on CV risks. Conclusion In mostly elderly high-risk hypertensive patients with type 2 diabetes mellitus participating in the VALUE trial, achieving more frequently BP <140/90 mmHg showed a marked protective effect on overall and all cause-specific cardiovascular outcomes. This was not the case for a more frequent achievement of the more intensive BP target, i.e. <130/80 mmHg.

Blood Pressure-Lowering Profiles and Clinical Effects of Angiotensin Receptor Blockers Versus Calcium Channel Blockers.

Blood pressure-lowering drugs have different blood pressure-lowering profiles. We studied if differences in blood pressure mean and variability can explain the differences in risks of cardiovascular events and death among 15 245 high-risk hypertensive patients randomized to valsartan or amlodipine and followed for 4.2 years in the VALUE trial (Valsartan Antihypertensive Long-Term Use Evaluation). We selected patients with ≥3 visits and performed Cox regression analyses, defining mean blood pressure as a time-dependent covariate and visit-to-visit and within-visit blood pressure variability as the SD. Of 14 996 eligible patients, participants in the valsartan group had higher systolic mean blood pressure by 2.2 mm Hg, higher visit-to-visit systolic variability by 1.4 mm Hg, and higher within-visit systolic variability by 0.2 mm Hg (P values <0.0001). The higher risks of myocardial infarction and stroke in the valsartan group was attenuated after adjustment for mean and variability of systolic blood pressure, from HR 1.19 (95% CI, 1.02-1.39) to 1.11 (0.96-1.30) and from HR 1.13 (0.96-1.33) to 1.00 (0.85-1.18), respectively. The lower risk of congestive heart failure in the valsartan group was accentuated after adjustment, from HR 0.86 (0.74-1.00) to 0.76 (0.65-0.89). A smaller effect was seen on risk of death, from 1.01 (0.92-1.12) to 0.94 (0.85-1.04). In conclusion, the higher risks of myocardial infarction and stroke in patients randomized to valsartan versus amlodipine were related to the drugs' different blood pressure modulating profiles. The risk of congestive heart failure with valsartan was lower, independent of the less favorable blood pressure modulating profile.

Blood pressure variability in hypertensive patients with atrial fibrillation in the VALUE trial

Purpose: Blood pressure variability is associated with traditional cardiovascular risk factors, but little is known about the association with atrial fibrillation. We compared blood pressure variability in patients with and without atrial fibrillation using data from the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial.Materials and methods: The VALUE trial was a randomised-controlled trial of valsartan versus amlodipine in patients with hypertension and high cardiovascular risk, followed for 4.2 years (mean). For the present analysis we included patients with electrocardiogram at baseline and during follow-up, and ≥3 visits from 6 months onwards. We compared standard deviation (SD) of all blood pressures within each visit averaged across all visits (within-visit variability) and of mean blood pressure at each visit (visit-to-visit variability) in patients with and without atrial fibrillation at baseline. We similarly compared patients who developed non-persistent or persistent atrial fibrillation during follow-up with those who did not, using t-tests, ANOVA and linear regression.Results: Of 15,245 patients in the VALUE trial, 13,827 were eligible for analysis. SD of visit-to-visit systolic blood pressure was not significantly different between patients with and without atrial fibrillation at baseline (mean difference 0.3 mm Hg, p = 0.4), but significantly higher in patients with incident non-persistent or persistent atrial fibrillation during follow-up than in those who never developed atrial fibrillation (differences 1.2 and 1.8 mm Hg, respectively, p-values <0.0001). Associations with non-persistent and persistent atrial fibrillation were confirmed in linear regression models (p-values <0.0001). SD of within-visit systolic blood pressure was not significantly different between patients with and without atrial fibrillation at baseline (p = 0.4) but significantly higher in patients with persistent atrial fibrillation during follow-up (p = 0.04).Conclusion: In patients treated for hypertension, atrial fibrillation was not associated with increased blood pressure variability, but blood pressure variability was higher in those who developed atrial fibrillation during follow-up.

Blood pressure variability and risk of cardiovascular events and death in patients with hypertension and different baseline risks.

Blood pressure variability is associated with increased risk of cardiovascular events, particularly in high-risk patients. We assessed if variability was associated with increased risk of cardiovascular events and death in hypertensive patients at different risk levels. The Valsartan Antihypertensive Long-term Use Evaluation trial was a randomized controlled trial of valsartan vs. amlodipine in patients with hypertension and different risks of cardiovascular events, followed for a mean of 4.2 years. We calculated standard deviation (SD) of mean systolic blood pressure from visits from 6 months onward in patients with ≥3 visits and no events during the first 6 months. We compared the risk of cardiovascular events in the highest and lowest quintile of visit-to-visit blood pressure variability, using Cox regression. For analysis of death, variability was analysed as a continuous variable. Of 13803 patients included, 1557 (11.3%) had a cardiovascular event and 1089 (7.9%) died. Patients in the highest quintile of SD had an increased risk of cardiovascular events [hazard ratio (HR) 2.1, 95% confidence interval (95% CI) 1.7-2.4; P < 0.0001], and a 5 mmHg increase in SD of systolic blood pressure was associated with a 10% increase in the risk of death (HR 1.10, 95% CI 1.04-1.17; P = 0.002). Associations were stronger among younger patients and patients with lower systolic blood pressure, and similar between patients with different baseline risks, except for higher risk of death among patients with established cardiovascular disease. Higher visit-to-visit systolic blood pressure variability is associated with increased risk of cardiovascular events in patients with hypertension, irrespective of baseline risk of cardiovascular events. Associations were stronger in younger patients and in those with lower mean systolic blood pressure.

Angiotensin Receptor Blockers Reduce Cardiovascular Events, Including the Risk of Myocardial Infarction.

Opposing Viewpoint, see p 2088 More than a decade ago, the 15 245–patient VALUE trial (Valsartan Antihypertensive Long-Term Use Evaluation),1 designed to show “that for the same level of blood-pressure (BP) control, valsartan-based treatment would be superior to amlodipine-based treatment in reduction of cardiac morbidity and mortality,” unexpectedly fell short in that myocardial infarction (MI) was 19% more common in the valsartan arm than in the amlodipine arm. Because renin-angiotensin system inhibitors, specifically ACEIs, previously were documented to have cardioprotective properties, failure in doing so in VALUE was blamed on valsartan and the ARBs as a class. An accompanying editorial stating that ARBs “may increase MI—and patients may need to be told”2 caused a tempest in the teapot and led to extensive scrutiny of outcome data with this drug class. Subsequently, a number of investigators have proposed the concept of an “MI paradox” associated with ARBs. There was little question that at the time, in 2004, the editorialists had a point. However, many more solid randomized trials have been completed with results published since then that gradually but relentlessly challenged the above point of view.3 In the following, we analyze in aggregate the evidence of the comparative efficacy and safety of ACEIs and ARBs. When we look at experimental data and cardiac surrogate end points such as regression of left …

Predictors of cardiac morbidity in diabetic, new-onset diabetic and non-diabetic high-risk hypertensive patients: The Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial

Diabetic and new-onset diabetic patients with hypertension have higher cardiac morbidity than patients without diabetes. We aimed to investigate whether baseline predictors of cardiac morbidity, the major constituent of the primary endpoint in the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial, were different in patients with diabetes and new-onset diabetes compared to patients without diabetes. In total, 15,245 high-risk hypertensive patients in the VALUE trial were followed for an average of 4.2 years. At baseline, 5250 patients were diabetic by the 1999 World Health Organization criteria, 1298 patients developed new-onset diabetes and 8697 patients stayed non-diabetic during follow-up. Cardiac morbidity was defined as a composite of myocardial infarction and heart failure requiring hospitalization, and baseline predictors were identified by univariate and multivariate stepwise Cox regression analyses. History of coronary heart disease (CHD) and age were the most important predictors of cardiac morbidity in both diabetic and non-diabetic patients. History of CHD, history of stroke and age were the only significant predictors of cardiac morbidity in patients with new-onset diabetes. Predictors of cardiac morbidity, in particular history of CHD and age, were essentially the same in high-risk hypertensive patients with diabetes, new-onset diabetes and without diabetes who participated in the VALUE trial.

No evidence for a J-shaped curve in treated hypertensive patients with increased cardiovascular risk: The VALUE trial

Previous studies have debated the notion that low blood pressure (BP) during treatment, particularly diastolic (DBP), is associated with increased risk of cardiovascular disease. We evaluated the impact of low BP on cardiovascular outcomes in a high-risk population of 15,244 hypertensive patients, almost half of whom had a history of coronary artery disease (CAD). In the prospective Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial, patients were randomized to valsartan or amlodipine regimens and followed for 4.2 years (mean) with no difference in the primary cardiovascular endpoint. A Cox proportional hazards model was used to evaluate the relationship between average on-treatment BP and clinical outcomes. The relationship between BP and cardiovascular events was adjusted for age, gender and body mass index, and baseline qualifying risk factors and diseases (smoking, high total cholesterol, diabetes mellitus, proteinuria, CAD, previous stroke and left ventricular hypertrophy). DBP ≥ 90 mmHg, compared with < 90 mmHg, was associated with increased incidence of the primary cardiovascular endpoint (all cardiac events); however, DBP < 70 mmHg, compared with ≥ 70 mmHg, was not associated with increased incidence after covariate adjustment (no J-shaped curve). Similar results were observed for death, myocardial infarction (MI), heart failure and stroke, considered separately. Nadir for MI was at DBP of 76 mmHg and for stroke 60 mmHg. The ratio of MI to stroke increased with lower DBP. In CAD patients the MI to stroke ratio was more pronounced than in patients without CAD but there was no significant J-curve in either group. Systolic BP ≥ 150 but not < 130 mmHg, compared with 130–149 mmHg, similarly was associated with increased risk for primary outcome. In conclusion, patients in BP strata ≥ 150/90 mmHg, but not patients in BP strata < 130/70 mmHg, were at increased risk for adverse outcomes in this hypertensive, high-risk population. Although benefit in preventing MI in relation to preventing stroke levels off for the lowest BPs, these data provide no support for a J-curve in the treatment of high-risk hypertensive patients . The increase in the ratio of MI to stroke with lower DBP indicates target organ heterogeneity in that the optimal on-treatment DBP for cerebroprotection is below that for cardioprotection.

Heart Rate as a Predictor of Stroke in High-risk, Hypertensive Patients with Previous Stroke or Transient Ischemic Attack

Risk factors for first stroke are well established, but less is known about risk factors for recurrent stroke. In the present analysis, we aimed to assess the effect of heart rate and other possible predictors of stroke in a hypertensive population with previous stroke or transient ischemic attack (TIA). The Valsartan Antihypertensive Long-Term Use Evaluation trial was a multicentre, double-masked, randomized controlled, parallel group trial comparing the effects of an angiotensin receptor blocker (valsartan) and a calcium channel blocker (amlodipine) in patients with hypertension and high cardiovascular risk. We used Cox proportional hazard models to investigate the effect of baseline variables on the risk of stroke. Quadratic terms of the continuous variables were entered in the models to test for linearity. Of 15,245 patients included in the trial, 3014 had a previous stroke or TIA at baseline and were included in the present analysis. Stroke recurrence occurred in 239 patients (7.9%) during a median of 4.5 years of follow-up. Resting heart rate (per 10 beats per minute; hazard ratio [HR], 2.78; 95% confidence interval [CI], 1.18-6.58) and diabetes mellitus at baseline (HR, 1.47; 95% CI, 1.03-2.10) were significantly associated with an increased risk of stroke recurrence in the multivariable analysis. In high-risk, hypertensive patients with previous stroke or TIA, resting heart rate was the strongest predictor of recurrent stroke.

Is amlodipine more cardioprotective than other antihypertensive drug classes?

Is amlodipine more cardioprotective than other antihypertensive drug classes?

Analysis of Recent Papers in Hypertension Initial Combination Therapy Provides More Prompt Blood Pressure Control and Reduces Cardiovascular Events But Remains Underutilized

Analysis of Recent Papers in Hypertension Initial Combination Therapy Provides More Prompt Blood Pressure Control and Reduces Cardiovascular Events But Remains Underutilized

Cardiovascular outcomes in hypertensive patients

To determine whether blood pressure (BP) control in hypertensive patients achieved with combination drug therapy provides the same cardiovascular benefits as with single-agent therapy. Drug combinations, most often including hydrochlorothiazide (HCTZ), are now recommended for routine BP management, but their effects on cardiovascular event rates have not been compared with effective monotherapy. We conducted retrospective analyses of the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) data. VALUE compared cardiovascular event rates of valsartan and amlodipine. Patients with BPs not controlled (<140/90 mmHg) by the single agents had HCTZ and, if required, additional drugs of different classes, added. Using data pooled from the two treatment arms, we have now divided patients into those controlled on monotherapy and those controlled or not controlled by combination therapy. The primary study endpoint was first occurrence of cardiovascular death or nonfatal myocardial infarction or stroke. Comparisons between groups were by Cox regression, adjusted for on-treatment BP, age, prior cardiovascular events and left ventricular hypertrophy; the comparison between the monotherapy and combination therapy controlled groups was based on events occurring after 3 months by when the decision to use monotherapy or combination therapy was made. The primary endpoint occurred in 505 of 5924 (8.5%) monotherapy and 511 of 4621 (11.1%) combination therapy controlled patients: hazard ratio was 0.80 [95% confidence interval (CI) 0.70-0.90]. If these two groups were matched for baseline BPs and all events included from study baseline, the hazard ratio was 0.76 (95% CI 0.67-0.86). The difference between combination controlled and uncontrolled [434 of 3390 (12.8%)] groups was not significant [hazard ratio 0.90 (95% CI 0.80-1.03], nor when they were matched for baseline BPs [hazard ratio 0.95 (95% CI 0.81-1.11)]. Independent of prior cardiovascular history or baseline BP, hypertensive patients requiring combination therapy, which includes a thiazide diuretic for BP control, have a poorer cardiovascular prognosis than those controlled by monotherapy and only a nonsignificantly lower event rate than noncontrolled patients.

Do angiotensin receptor blockers prevent myocardial infarctions as well as other initial therapies?

As their introduction, angiotensin receptor blockers (ARBs) have been widely promulgated as an acceptable alternative to angiotensin-converting enzyme inhibitors (ACEIs). Beyond a simple antihypertensive effect, ACEIs have been shown to reduce the rates of myocardial infarction (MI), stroke, and new-onset heart failure, and appear to have a 'blood pressure independent' effect. Given the shared mechanism of preventing action of angiotensin II, the effects of ARB therapy on reduction in cardiovascular and renal outcomes were anticipated to be equal to that of ACEI. The role of ARBs in the prevention of MI has not only been disputed, but also has at times cast the class as a causative agent in increasing the risk of MI. This potentially deleterious effect was proposed after results from the Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) trial, in which the use of valsartan (ARB) was compared with amlodipine in patients at high cardiovascular disease risk, found an excess of MIs among patients in the valsartan arm. Subsequent clinical trials and meta-analyses have largely laid to rest the question of whether ARBs contribute to cardiovascular risk. The definitive answer of whether ARBs are effective, if at all, in preventing MI remains difficult to parse out. Current evidence from newer clinical trials and comprehensive meta-analyses suggests that ARBs, while effective antihypertensive agents that protect against risk of stroke, renal disease, diabetes, and heart failure, are likely to have a neutral effect upon reduction of MI when compared with other antihypertensive agents.

Usefulness of Heart Rate to Predict Cardiac Events in Treated Patients With High-Risk Systemic Hypertension

A high heart rate (HR) predicts future cardiovascular events. We explored the predictive value of HR in patients with high-risk hypertension and examined whether blood pressure reduction modifies this association. The participants were 15,193 patients with hypertension enrolled in the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial and followed up for 5 years. The HR was assessed from electrocardiographic recordings obtained annually throughout the study period. The primary end point was the interval to cardiac events. After adjustment for confounders, the hazard ratio of the composite cardiac primary end point for a 10-beats/min of the baseline HR increment was 1.16 (95% confidence interval 1.12 to 1.20). Compared to the lowest HR quintile, the adjusted hazard ratio in the highest quintile was 1.73 (95% confidence interval 1.46 to 2.04). Compared to the pooled lower quintiles of baseline HR, the annual incidence of primary end point in the top baseline quintile was greater in each of the 5 study years (all p <0.05). The adjusted hazard ratio for the primary end point in the highest in-trial HR heart rate quintile versus the lowest quintile was 1.53 (95% confidence interval 1.26 to 1.85). The incidence of primary end points in the highest in-trial HR group compared to the pooled 4 lower quintiles was 53% greater in patients with well-controlled blood pressure (p <0.001) and 34% greater in those with uncontrolled blood pressure (p = 0.002). In conclusion, an increased HR is a long-term predictor of cardiovascular events in patients with high-risk hypertension. This effect was not modified by good blood pressure control. It is not yet known whether a therapeutic reduction of HR would improve cardiovascular prognosis.

A current evaluation of the safety of angiotensin receptor blockers and direct renin inhibitors

The safety of angiotensin II receptor blockers (ARBs) for the treatment of hypertension and cardiovascular and renal diseases has been well documented in numerous randomized clinical trials involving thousands of patients. However, recent concerns have surfaced about possible links between ARBs and increased risks of myocardial infarction and cancer. Less is known about the safety of the direct renin inhibitor aliskiren, which was approved as an antihypertensive in 2007. This article provides a detailed review of the safety of ARBs and aliskiren, with an emphasis on the risks of cancer and myocardial infarction associated with ARBs. Safety data were identified by searching PubMed and Food and Drug Administration (FDA) Web sites through April 2011. ARBs are generally well tolerated, with no known class-specific adverse events. The possibility of an increased risk of myocardial infarction associated with ARBs was suggested predominantly because the Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) trial reported a statistically significant increase in the incidence of myocardial infarction with valsartan compared with amlodipine. However, no large-scale, randomized clinical trials published after the VALUE study have shown a statistically significant increase in the incidence of myocardial infarction associated with ARBs compared with placebo or non-ARBs. Meta-analyses examining the risk of cancer associated with ARBs have produced conflicting results, most likely due to the inherent limitations of analyzing heterogeneous data and a lack of published cancer data. An ongoing safety investigation by the FDA has not concluded that ARBs increase the risk of cancer. Pooled safety results from clinical trials indicate that aliskiren is well tolerated, with a safety profile similar to that of placebo. ARBs and aliskiren are well tolerated in patients with hypertension and certain cardiovascular and renal conditions; their benefits outweigh possible safety concerns.

Angiotensin-receptor blockade, cancer, and concerns

Ilke Sipahi and colleagues 1 Sipahi I Debanne SM Rowland DY Simon DI Fang JC Angiotensin-receptor blockade and risk of cancer: meta-analysis of randomised controlled trials. Lancet Oncol. 2010; 11: 627-636 Summary Full Text Full Text PDF PubMed Scopus (383) Google Scholar meta-analysis of angiotensin-receptor blockers (ARBs) and cancer risk is concerning. Although the increase in risk of new cancer occurrence over 4 years in patients randomly assigned to ARBs was modest (1·2%) compared with the control group, the public health implications are substantial; for example, this increased risk would result in a rise of 3000 new cancers for every 1 million individuals treated with these ARBs each year. Angiotensin-receptor blockade, cancer, and concerns – Authors' replySoon after publication of our article reporting an excess risk of cancer among patients treated with angiotensin-receptor blockers (ARBs),1 Stevo Julius and colleagues—on behalf of the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial—claimed that we did not contact them for their cancer data, and that the data “would have been provided” if requested.2 In their letter published here, they now state that VALUE has a policy of providing access to data only to its own investigators. Full-Text PDF

Angiotensin-receptor blockade, cancer, and concerns

As leaders of the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial, we feel obligated to point out a shortcoming in Ilke Sipahi and colleagues'1 meta-analysis of cancer rates in patients treated with angiotensin-receptor blockers (ARBs) published recently in this journal.