Faculty Bibliography

OPINION STATEMENT: Triglycerides are routinely obtained with standard lipid testing, but their role in cardiovascular risk is controversial. An excess of triglycerides is commonly encountered in patients with the metabolic syndrome or diabetes, and represents an excess burden of small, dense low-density lipoproteins (LDLs), which confers additive risk for cardiovascular disease. Current guidelines prioritize LDL targets first, but treatment of triglycerides once LDL targets are achieved bears consideration. Beyond lifestyle modification, potential pharmacologic therapies include statins, fibrates, niacin, omega-3 fatty acids and antidiabetic drugs. There are few trials to date comparing these agents directly in the management of hypertriglyceridemia, but available data seems to demonstrate that the greatest benefit of triglyceride lowering is experienced in a subgroup of patients with an atherogenic lipid profile (elevated triglycerides, low high-density lipoprotein (HDL), elevated small, dense LDL particles). Here, we discuss the current understanding of how triglyceride elevations impart cardiovascular risk, current therapies and the data supporting their use, and ongoing studies to elucidate the degree to which treatment of triglycerides modifies risk of future cardiovascular events.

Home blood pressure (BP) monitoring may enhance assessment of BP control. In this 16-week study, men and women 70 years or older with systolic BP between 150 and 200 mm Hg were randomized to receive valsartan/hydrochlorothiazide (V/HCTZ) 160/12.5 mg (n = 128), HCTZ 12.5 mg (n = 128), or V 160 mg (n = 128) for 4 weeks. Participants whose BP was 140/90 mm Hg or higher at weeks 4, 8, or 12 were uptitrated to a maximum of V/HCTZ 320/25 mg. Participants were evaluated by home BP monitoring using an automated device weekly before taking daily study medication (n = 301). Baseline BP +/- SD for clinic (165.5 +/- 11.8/85.1 +/- 9.5 mm Hg) was approximately 3/1 mm Hg greater than home readings (162.5 +/- 15.8/84.3 +/- 10.2 mm Hg). Reductions in BP +/- SEM at week 4 were similar for clinic (12.6 +/- 1.0/4.7 +/- 0.5 mm Hg) and home (10.9 +/- 1.1/3.8 +/- 0.5 mm Hg) readings (P = .25/P = .23; clinic versus home); differences between V/HCTZ and HCTZ or V were also similar for both home and clinic readings and results by either technique correlated significantly (P < .0001). Home BP measurements confirm that treatment initiated with V/HCTZ versus monotherapy resulted in greater antihypertensive efficacy. Home BP monitoring, if done with proper technique, provides a reliable indicator of BP control in elderly patients and may help guide drug dosing and titration.

PURPOSE: Renin profiling has been proposed as a method to guide antihypertensive drug selection. This prespecified post-hoc analysis examined the influence of baseline plasma renin activity (PRA) on blood pressure (BP) responses. METHODS: A 16-week, randomized, double-blind, prompted-titration trial evaluated initial valsartan (V)/hydrochlorothiazide (HCTZ) combination therapy versus initial HCTZ or V monotherapy in individuals aged >/=70 years with systolic hypertension. Sitting PRA was measured at baseline, Week 4, and Week 16. Subjects were stratified into 2 groups for analysis: low renin (baseline PRA <0.65 ng/mL/h) or normal-high renin (baseline PRA >/=0.65 ng/mL/h). RESULTS: PRA data were available in 322/384 subjects: 178 had low PRA and 144 had normal-high PRA. At Week 4, V/HCTZ was more effective than HCTZ or V at reducing mean sitting systolic BP (MSSBP), independent of baseline PRA, with reductions of -16.9, -12.6, and -9.5 mmHg, respectively, in low-renin subjects and -19.4, -11.5, and -8.6 mmHg in normal-high renin subjects. Baseline PRA was similar in responders (subjects not uptitrated at Week 4) and nonresponders (subjects uptitrated at Week 4). In responders, the reactive rise in PRA at Week 4 was related to change in MSSBP, with the greatest increases in PRA observed in the V/HCTZ group. Higher baseline PRA was associated with a greater reactive rise in PRA. CONCLUSIONS: Baseline PRA is not a useful guide to the BP responses of initial combination V/HCTZ in elderly individuals with systolic hypertension.

Almost one third of annual worldwide mortality is attributed to cardiovascular disease (CVD), making it the leading cause of global death. Dyslipidemia is a well-established risk factor for CVD and plays a pivotal role in the pathogenesis of atherosclerosis. Statins, which inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and lower low-density lipoprotein cholesterol, have emerged as the most effective therapy to date against atherothrombotic CVD. Although their role in secondary prevention of CVD is undisputed, it remains a topic for debate as to how widely they should be used for primary prevention. The Framingham Risk Score and the National Cholesterol Education Program Adult Treatment Panel III guidelines are the cornerstones for the current guidelines for primary prevention statin therapy. Although these guidelines serve as help to evaluate cardiovascular risk and effectively identify many patients who will benefit from statin therapy, there is a growing population of "intermediate-risk" patients who may be undertreated. Additional noninvasive tests may complement the traditional risk scores, potentially expanding the indications for statins.

Blood pressure (BP) control rates in the United States remain low despite the availability of a wide array of treatment options. High-risk populations, including women, black individuals, and obese patients are even less likely to achieve BP targets than the general population. Uncontrolled BP can lead to serious consequences. Therefore, additional effective and well-tolerated treatment strategies are necessary, particularly for these difficult-to-treat populations. The majority of patients require 2 or more pharmacologic agents to achieve BP control. In patients with stage 2 hypertension, current guidelines recommend rational antihypertensive combinations as initial therapy. The renin-angiotensin-aldosterone system (RAAS) plays an important role in development of hypertension and progression, and the use of RAAS inhibitors has shown BP-lowering effectiveness and excellent tolerability across a continuum of patient types. Agents that block the RAAS form a reasonable foundation for combination therapy. In this article, we review data from studies of valsartan-based antihypertensive combinations in stage 2 hypertension, with a focus on women, black individuals, and obese patients

J Clin Hypertens (Greenwich). 2011;13:722-730. (c)2011 Wiley Periodicals, Inc. This 16-week trial investigated the efficacy and safety of single-pill valsartan/hydrochlorothiazide (HCTZ) vs the individual components in patients 70 years and older with systolic hypertension. Patients were randomized to valsartan/HCTZ 160/12.5 mg (n=128), HCTZ 12.5 mg (n=128), or valsartan 160 mg (n=128) for 4 weeks. Patients whose blood pressure (BP) was >/=140/90 mm Hg at weeks 4, 8, or 12 were up-titrated to a maximum of valsartan/HCTZ 320/25 mg. Week 4 systolic BP reduction (primary efficacy outcome) was greater with valsartan/HCTZ than valsartan (-17.3 mm Hg vs -8.6 mm Hg, P <.0001) but only marginally greater than HCTZ (-13.6 mm Hg, P =.096). Median time to BP control was shorter with valsartan/HCTZ (4 weeks) vs HCTZ (8 weeks, P<.05) or valsartan (12 weeks, P<.0001). Thiazide monotherapy was more effective than angiotensin receptor blocker monotherapy (by about 5 mm Hg), but greater antihypertensive efficacy was achieved by initiating treatment with combination valsartan/HCTZ in the elderly

BACKGROUND: Stage 2 hypertension often requires combination antihypertensive therapy. Ambulatory blood pressure monitoring (ABPM) is a useful tool for studying antihypertensive drugs and their combinations. OBJECTIVE: This multicenter, double-blind, parallel-group, prompted-titration study of patients of at least 70 years of age with systolic hypertension compared the efficacy of valsartan, hydrochlorothiazide, and their combination on ambulatory blood pressure (ABP) reduction. METHODS: After a 3-14-day washout, patients with systolic blood pressure of 150-200 mmHg were randomized (1 : 1 : 1) to initially receive once-daily valsartan/hydrochlorothiazide 160/12.5 mg combination therapy, hydrochlorothiazide 12.5 mg monotherapy, or valsartan 160 mg monotherapy. Prompted uptitration of patients in whom BP was more than or equal to 140/90 mmHg was performed after 4, 8, and 12 weeks of treatment. ABPM was performed at baseline and weeks 4 and 16 (study end). RESULTS: In this ABPM substudy (n=108), initiation of treatment with valsartan/hydrochlorothiazide lowered ABP more effectively than either monotherapy throughout the daytime, night-time, and 24-h monitoring periods, as well as during the last 4 and 6-h dosing periods. Twenty-four-hour ABP was reduced from 141.1/76.5 mmHg at baseline to 125.8/69.2 mmHg at week 4 (primary time point) with valsartan/hydrochlorothiazide compared with reductions from 142.2/78.7 to 139.1/77.5 mmHg with hydrochlorothiazide and 142.2/78.3 to 136.4/75.1 mmHg with valsartan (all P<0.01 in favor of combination therapy). In the overall study, tolerability was similar among the three treatment groups. CONCLUSION: In elderly hypertensives, starting combination therapy with valsartan/hydrochlorothiazide provides more effective 24-h blood pressure control than the monotherapy components, with few therapy-related side-effects

OPINION STATEMENT: The pathogenesis of cardiovascular disease is a complex and dynamic process. The renin-angiotensin-aldosterone system (RAAS) is a potent and powerful mediator in the homeostasis of the cardiovascular and renal systems. RAAS blockade via angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) has been consistently proven to be an effective and safe strategy for the primary and secondary prevention of cardiovascular disease in patients across a wide spectrum of risk. Although the beneficial effects of RAAS blockade may be due to its effects on central and peripheral blood pressure, there are many additional mechanisms to consider that may contribute additional protection. While a combination of ACE inhibitors and ARBs has not yielded significantly positive results, the newer class of direct renin inhibitors (DRIs) may offer a novel and effective strategy for monotherapy as well as in combination

There is now clear evidence that reducing blood pressure (BP) with a broad range of agents, including angiotensin converting enzyme inhibitors and angiotensin receptor blockers, improves cardiovascular and renal outcomes. There is also evidence suggesting that these drugs have beneficial effects that are independent of BP lowering. Aliskiren is a direct renin inhibitor that interrupts the renin-angiotensin-aldosterone system (RAAS) at its rate-limiting step. Unlike angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, aliskiren produces a sustained reduction in plasma renin activity and reduces plasma levels of angiotensin II and aldosterone. Preclinical data and clinical trials in high-risk patients using surrogate markers increasingly suggest that aliskiren can reduce the progression of end-organ damage beyond that afforded by BP control. With its unique mechanism of action, combining aliskiren with another RAAS-blocking agent that has a different mechanism of action may provide more comprehensive blockade of the RAAS, potentially conferring additional clinical benefits. Evaluation of these end-organ effects in humans is underway in clinical trials designed to assess the effects of aliskiren alone and in combination with other antihypertensive agents on cardiovascular and renal outcomes