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.

Impact of dyslipidemia on cardiovascular risk stratification of hypertensive patients and association of lipid profile with other cardiovascular risk factors: results from the ICEBERG study.

BACKGROUND: Hypertension, dyslipidemia, and other cardiovascular risk factors are linked epidemiologically, clinically, and metabolically. Intensive/Initial Cardiovascular Examination regarding Blood Pressure levels, Evaluation of Risk Groups (ICEBERG) study focuses on the effect of dyslipidemia on cardiovascular risk evaluation and association of lipid profile with other risk factors. PATIENTS AND METHODS: The ICEBERG study consisted of two sub-protocols: ICEBERG-1, conducted at 20 university hospitals (Referral Group) and ICEBERG-2, conducted at 197 primary healthcare centers (Primary Care Group). Sub-protocol had two patient profiles: patients previously diagnosed with essential hypertension and under medical treatment (Treated Group) and patients with systolic blood pressure ≥130 mmHg or diastolic blood pressure ≥85 mmHg, with no antihypertensive treatment for at least 3 months before inclusion (Untreated Group). Dyslipidemia was evaluated and cardiovascular risk stratification was performed according to ESC/ESH guidelines. RESULTS: More than half of the treated and untreated subjects were classified into high or very high cardiovascular risk groups. In a total of 1817 patients, the percentage of patients in "high" plus "very high" added risk groups increased to 55.2% in Treated Referral Group (p < 0.001), to 62.6% in Untreated Referral Group (p = 0.25) and to 60.7% in Untreated Primary Care Group (p < 0.001), by re-evaluation of patients' lipid values. CONCLUSIONS: Serum lipid levels are useful in stratifying hypertensive patients into cardiovascular risk groups more accurately, for appropriate antihypertensive treatment.

Aspirin-resistant platelet aggregation in a cohort of patients with coronary heart disease.

Aspirin resistance could be defined as thrombotic and embolic cardiovascular events despite regular aspirin therapy. The study aimed to determine the profile and prevalence of aspirin resistance in coronary artery disease patients. We evaluated the prevalence of aspirin resistance in a cohort of 505 patients with the diagnosis of coronary artery disease taking 80-300 mg regular aspirin daily. Platelet functions were analyzed by the Platelet Function Analyzer (PFA)-100 with collagen and epinephrine cartridges and collagen and ADP cartridges. A closure time of 186 s or less with the collagen and epinephrine cartridge was defined as aspirin resistance. Of the patients, 118 (23.4%) were aspirin resistant by the PFA-100. Aspirin-resistant patients were more likely to be older than aspirin-sensitive patients (P = 0.024). No statistically significant differences between the aspirin-resistant and aspirin-sensitive individuals were present in gender, major risk factors of coronary artery disease, number and localization of involved coronary vessels, serum lipid levels, and blood counts. According to the high prevalence of coronary heart disease, many people are affected by aspirin resistance, which may play a role in adverse cardiovascular events. Monitoring of platelet function in patients with coronary heart disease may support the optimization of antiplatelet therapy with additional and/or alternative agents.

Effects of intensive versus moderate lipid-lowering therapy on myocardial ischemia in older patients with coronary heart disease: results of the Study Assessing Goals in the Elderly (SAGE).

BACKGROUND: Clinical trials have demonstrated that, compared with placebo, intensive statin therapy reduces ischemia in patients with acute coronary syndromes and in patients with stable coronary artery disease. However, no studies to date have assessed intensive versus moderate statin therapy in older patients with stable coronary syndromes. METHODS AND RESULTS: A total of 893 ambulatory coronary artery disease patients (30% women) 65 to 85 years of age with > or = 1 episode of myocardial ischemia that lasted > or = 3 minutes during 48-hour ambulatory ECG at screening were randomized to atorvastatin 80 mg/d or pravastatin 40 mg/d and followed up for 12 months. The primary efficacy parameter (absolute change from baseline in total duration of ischemia at month 12) was significantly reduced in both groups at month 3 and month 12 (both P<0.001 for each treatment group) with no significant difference between the treatment groups. Atorvastatin-treated patients experienced greater low-density lipoprotein cholesterol reductions than did pravastatin-treated patients, a trend toward fewer major acute cardiovascular events (hazard ratio, 0.71; 95% confidence interval, 0.46, 1.09; P=0.114), and a significantly greater reduction in all-cause death (hazard ratio, 0.33; 95% confidence interval, 0.13, 0.83; P=0.014). CONCLUSIONS: Compared with moderate pravastatin therapy, intensive atorvastatin therapy was associated with reductions in cholesterol, major acute cardiovascular events, and death in addition to the reductions in ischemia observed with both therapies. The contrast between the therapies' differing efficacy for major acute cardiovascular events and death and their nonsignificant difference in efficacy for reduction of ischemia suggests that low-density lipoprotein cholesterol-lowering thresholds for ischemia and major acute cardiovascular events may differ. The Study Assessing Goals in the Elderly (SAGE) demonstrates that older men and women with coronary artery disease benefit from intensive statin therapy.

The Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) trial: outcomes in patients receiving monotherapy.

In the main Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) report, we investigated outcomes in 15 245 high-risk hypertensive subjects treated with valsartan- or amlodipine-based regimens. In this report, we analyzed outcomes in 7080 patients (46.4%) who, at the end of the initial drug adjustment period (6 months), remained on monotherapy. Baseline characteristics were similar in the valsartan (N=3263) and amlodipine (N=3817) groups. Time on monotherapy was 3.2 years (78% of treatment exposure time). The average in-trial blood pressure was similar in both groups. Event rates in the monotherapy group were 16% to 39% lower than in the main VALUE trial. In the first analysis, we censored patients when they discontinued monotherapy ("censored"); in the second, we counted events regardless of subsequent therapy (intention-to-treat principle). We also assessed the impact of duration of monotherapy on outcomes. No difference was found in primary composite cardiac end points, strokes, myocardial infarctions, and all-cause deaths with both analyses. Heart failure in the valsartan group was lower both in the censored and intention-to-treat analyses (hazard ratios: 0.63, P=0.004 and 0.78, P=0.045, respectively). Longer duration of monotherapy amplified between-group differences in heart failure. New-onset diabetes was lower in the valsartan group with both analyses (odds ratios: 0.78, P=0.012 and 0.82, P=0.034). Thus, despite lower absolute event rates in monotherapy patients, the relative risks of heart failure and new-onset diabetes favored valsartan. Moreover, these findings support the feasibility of comparative prospective trials in lower-risk hypertensive patients.

Endothelial function in patients with obstructive sleep apnea syndrome but without hypertension.

BACKGROUND: Obstructive sleep apnea syndrome (OSAS) influences endothelial function and causes hypertension. OBJECTIVES: Our aim was to evaluate the role of endothelial dysfunction in the pathogenesis of hypertension in OSAS. METHODS: Twenty-three patients with OSAS but without hypertension and 15 healthy normotensive subjects were investigated. The presence or absence of OSAS was evaluated with a sleep study. Endothelial function was investigated with brachial artery ultrasound examination. RESULTS: Baseline characteristics were equivalent between the two groups. Minimal oxygen saturation and apnea-hypopnea indexes in the OSAS and control groups were 62.9 +/- 16.5 versus 94.9 +/- 1.1% (p < 0.0001) and 53.1 +/- 20.3 versus 3.8 +/- 0.9 (p < 0.0001), respectively. There was not statistically significant difference between basal brachial artery diameters measured in the morning and in the evening in all groups. Flow-mediated dilation (FMD) values measured in the morning were lower than those measured in the evening in both OSAS patients and the control group: FMD of OSAS patients was 6.04 +/- 3.18% in the morning and 10.38 +/- 4.23% in the evening hours (p = 0.001), and FMD of control subjects was 10.9 +/- 2.6% in the morning and 13.9 +/- 2.32 in the evening hours (p = 0.002). Differences in FMD values measured both in the morning and evening hours in OSAS patients were lower compared with those in control subjects (p < 0.0001 in the morning hours and p = 0.003 in the evening hours). CONCLUSIONS: We detected a prominent diurnal deterioration in endothelial function in normotensive OSAS patients compared with healthy subjects. This deterioration may occur due to ongoing hypoxemia during the night and it may be a possible cause of hypertension and atherosclerotic cardiovascular diseases in patients with OSAS.

Intensive cardiovascular examination regarding blood pressure levels: evaluation of risk groups. ICEBERG study.

OBJECTIVE: Assessment of total cardiovascular risk level is crucial for approaching hypertensive patients. Therefore, the aim of the Intensive/Initial Cardiovascular Examination regarding Blood pressure levels: Evaluation of Risk Groups (ICEBERG) study is to determine cardiovascular risk evaluation and stratification of subjects with high normal and high blood pressure (BP > or = 130/85 mmHg), and to evaluate the impact of laboratory tests on this stratification. METHODS: ICEBERG was an epidemiological study conducted at 20 university hospitals and 197 primary healthcare centers. A total of 10,313 patients, who were diagnosed with high BP and under antihypertensive treatment or not antihypertensive under treatment at least for the last 3 months were selected. Besides routine clinical evaluation, microalbuminuria (MAU) and high sensitive C-reactive protein (hs-CRP) tests, echocardiography (Echo) and carotid ultrasonography (USG) were performed in selected arms. The patients were stratified into low, moderate, high and very high added risk groups as described by the European Society of Hypertension/European Society of Cardiology Guidelines Committee (2003). RESULTS: Upon routine evaluation, the percentage of "high and very high added cardiovascular risk" groups was between 51.2% and 60.7% in different study arms. This percentage increased to 62.9% by subsequent serum biochemistry assessment and to 76.2% by hs-CRP test results. Switching upwards to "high and very high added risk" groups was around 6% when MAU results were used, with a 4.9% upwards switch to "high and very high added risk" groups when Echo was performed; this proportion increased by 6.8%, when carotid USG was taken into account. CONCLUSION: Cardiovascular risk evaluation by intensive cardiovascular examination including Echo and carotid USG provided more accurate risk stratification. Furthermore, a simple test to demonstrate presence of MAU usable at primary healthcare level will also help to evaluate the patient's risk profile better than routine assessment methods alone.

The role of exercise on platelet aggregation in patients with stable coronary artery disease: exercise induces aspirin resistant platelet activation.

OBJECTIVES: The aim of our study was to determine the relation between exercise stress test and aspirin resistance in patients with stable coronary artery disease. BACKGROUND: Clinically aspirin resistance is defined as having thrombotic and embolic cardiovascular events despite regular aspirin therapy. METHODS: We studied platelet functions of 62 patients with stable coronary artery disease and 20 subjects with normal coronary arteries by Platelet Function Analyzer (PFA-100, Dade Behring, Germany) at rest and after exertion with collagen and/or epinephrine (Col/Epi) and collagen and/or ADP cartridges. Closure time (CT)<186 seconds was defined as aspirin resistance with Col/Epi cartridges of PFA-100. Symptom limited treadmill stress test (protocol of Bruce) was performed with Oxford Streslink TD-1 system. RESULTS: 8 (12.9%) patients were aspirin resistant by PFA-100 (CT<186s despite regular aspirin therapy) at rest. At the first minute of the recovery period of exercise stress test 14 (22.5%) patients were aspirin resistant by PFA-100. CTs with Col/ADP were respectively 89+/-6 s (83--100s) and 89+/-5 s (82--104s) at rest and after exercise (p=0.107). 20.3% (11/54) of patients known as in vitro aspirin sensitives at rest had shorter CTs and 11.1% (6/54) had aspirin resistance after exercise (p=0.004). There was no statistically significiant difference in platelet functions in the control group after exertion. CONCLUSION: We conclude that 11.1% of in vitro aspirin sensitive subjects at rest had aspirin resistance after exercise by PFA-100. In some individuals, exercise induced platelet activation is aspirin insensitive at usual antiplatelet doses. We need further clinical trials to optimize antiplatelet therapy in patients with coronary artery disease.

Effect of irbesartan monotherapy compared with ACE inhibitors and calcium-channel blockers on patient compliance in essential hypertension patients: a multicenter, open-labeled, three-armed study.

OBJECTIVES: This multicenter, three-armed, open-labeled study investigated patient compliance of patients receiving irbesartan, angiotensin-converting enzyme (ACE) inhibitors or calcium-channel blockers (CCB) for essential hypertension for a 6-month period. Patients were either newly diagnosed or switched from existing antihypertensive medication due to lack of efficacy or side-effects. METHODS: Patients were started monotherapy with irbesartan (n=377), ACE inhibitors (n=298) or CCB (n=308) and were reevaluated on 1st, 3rd, and 6th months of the treatment. The primary endpoint was patient compliance, assessed by proportion of patients who had taken their study medication every day. Efficacy was recorded as mean reductions in blood pressure and the proportion of patients whose blood pressure normalized. Tolerability was assessed by reported adverse events. RESULTS: Significantly more patients receiving irbesartan had complied with study medication after 3 and 6 months of treatment than ACE inhibitors or CCB. Significantly fewer patients receiving irbesartan needed to change their antihypertensive medication. All three study treatments exhibited similar efficacy profiles, but irbesartan had significantly less adverse events. CONCLUSIONS: This study demonstrated that patient compliance to irbesartan was significantly superior to other study treatments. Irbesartan is therefore a suitable first-line therapy for essential hypertension in everyday clinical practice.

Comparison of the effects of trimetazidine and diltiazem on exercise performance in patients with coronary heart disease. The Turkish trimetazidine study (TTS).

OBJECTIVE: A multicentre, double-blind comparative study was performed to compare the effects of trimetazidine with diltiazem on exercise performance in patients with stable angina pectoris. METHODS AND RESULTS: A total of 116 male patients with documented coronary artery disease at 11 centres were randomized into trimetazidine and diltiazem groups both including 58 men (mean age 55.1+/-8.6 years and 54.9+/-6.6 years, respectively) in a prospective, multicentre, double-blind active treatment trial. The study consisted of a two-week placebo washout period and a four-week active treatment phase. Clinical examinations and exercise tests were performed at the beginning (D0) and at the end (D28) of the active treatment. Laboratory investigations were also performed at the beginning of the washout period (D-14) and at D28. Holter recordings were done in the mid of the washout period (D-7) and D28. Both trimetazidine and diltiazem decreased the number of anginal attacks per week (p < 0.0001 for both drugs) and weekly nitrate consumption (p = 0.0008 and p < 0.0001, respectively). Both trimetazidine and diltiazem improved the recovery of anginal pain (p = 0.0188 and p = 0.0079, respectively) and maximal ST-segment depression (p = 0.0134 and p = 0.0214, respectively) but none of the drugs significantly changed the time to 1 mm ST-segment depression and ST recovery time on exercise test. Diltiazem caused a slight prolongation of PR and QRS durations (p = 0.039) on ambulatory ECG whereas trimetazidine did not change these parameters significantly. CONCLUSION: This study suggests that trimetazidine is an effective and safe alternative for diltiazem in the treatment of patients with stable angina pectoris. Although several other trials have shown that this drug can be used in combination with other antianginal drugs or instead of beta blockers or nifedipine in the symptomatic treatment of stable anginal syndromes, this study suggests that trimetazidine can be used instead of diltiazem, a well-known powerful antianginal drug.

Guideline implementation in a multicenter study with an estimated 44% relative cardiovascular event risk reduction.

BACKGROUND: The extent of cardiovascular risk reduction by implementing coronary prevention guidelines needs to be documented in various population samples. HYPOTHESIS: This is a multicenter study to assess the impact of risk reduction in cardiovascular events upon implementation of coronary prevention guidelines in patients with or at high risk for coronary heart disease (CHD) in the setting of clinical practice. METHODS: Enrolled volunteers numbered 2,021. Inclusion criteria postulated a minimum of 20-40% cardiovascular event risk in the subsequent 10 years as estimated from the risk table of the European Society of Cardiology (ESC) Guidelines. The estimated CHD risk reduction was assessed in terms of the Framingham risk scores at baseline and at 12 months, computed from the data of each individual. Data of the compliant group (making up half of the initial participants) at the end of the study, along with absolute and relative risk reductions in the compliant group, were analyzed. RESULTS: Mean global risk burden was 25.9% at baseline, reduced through multilateral preventive measures in absolute terms by 9.4% at 6 months and by 11.7% at 12 months; the latter represents a relative risk reduction of 44%. Independent variables determining the (enhanced) reduction in risk level at the end of 12 months included (high) level of baseline risk, (high) degree of compliance with treatment, younger age, female gender, smoking, and (high) baseline triglyceride/high-density lipoprotein cholesterol (TC/HDL-C) ratio. While the relative reduction in patients with CHD amounted to 43%, a reduction of 46% (p<0.001) was obtained in the setting of primary prevention. Diabetes emerged as a factor modestly limiting the extent of risk reduction. While subjects without hypertension revealed a decline of coronary risk by merely 8.7%, those with hypertension showed a decline by 12.7% (p<0.001). Risk reductions were accompanied by a decrease of mean low-density lipoprotein cholesterol (LDL-C) level of 25.4%, a rise in mean HDL-C level of 5 mg/dl, a decrease in mean systolic blood pressure of 26 mmHg. Forty-five percent of smokers succeeded in discontinuing the habit. CONCLUSION: By implementing standard prevention guidelines in the Turkish population among 1,000 compliant high-risk men and women and among 1,000 patients with CHD, prevention of cardiovascular events could be expected in 117 persons in the subsequent 10 years.