Michael A. Weber

BACKGROUND: Dual antiplatelet therapy with clopidogrel plus low-dose aspirin has not been studied in a broad population of patients at high risk for atherothrombotic events. METHODS: We randomly assigned 15,603 patients with either clinically evident cardiovascular disease or multiple risk factors to receive clopidogrel (75 mg per day) plus low-dose aspirin (75 to 162 mg per day) or placebo plus low-dose aspirin and followed them for a median of 28 months. The primary efficacy end point was a composite of myocardial infarction, stroke, or death from cardiovascular causes. RESULTS: The rate of the primary efficacy end point was 6.8 percent with clopidogrel plus aspirin and 7.3 percent with placebo plus aspirin (relative risk, 0.93; 95 percent confidence interval, 0.83 to 1.05; P=0.22). The respective rate of the principal secondary efficacy end point, which included hospitalizations for ischemic events, was 16.7 percent and 17.9 percent (relative risk, 0.92; 95 percent confidence interval, 0.86 to 0.995; P=0.04), and the rate of severe bleeding was 1.7 percent and 1.3 percent (relative risk, 1.25; 95 percent confidence interval, 0.97 to 1.61 percent; P=0.09). The rate of the primary end point among patients with multiple risk factors was 6.6 percent with clopidogrel and 5.5 percent with placebo (relative risk, 1.2; 95 percent confidence interval, 0.91 to 1.59; P=0.20) and the rate of death from cardiovascular causes also was higher with clopidogrel (3.9 percent vs. 2.2 percent, P=0.01). In the subgroup with clinically evident atherothrombosis, the rate was 6.9 percent with clopidogrel and 7.9 percent with placebo (relative risk, 0.88; 95 percent confidence interval, 0.77 to 0.998; P=0.046). CONCLUSIONS: In this trial, there was a suggestion of benefit with clopidogrel treatment in patients with symptomatic atherothrombosis and a suggestion of harm in patients with multiple risk factors. Overall, clopidogrel plus aspirin was not significantly more effective than aspirin alone in reducing the rate of myocardial infarction, stroke, or death from cardiovascular causes. (ClinicalTrials.gov number, NCT00050817.).

BACKGROUND: We attempted to characterize age-related changes in blood pressure in both normotensive and untreated hypertensive subjects in a population-based cohort from the original Framingham Heart Study and to infer underlying hemodynamic mechanisms. METHODS AND RESULTS: A total of 2036 participants were divided into four groups according to their systolic blood pressure (SBP) at biennial examination 10, 11, or 12. After excluding subjects receiving antihypertensive drug therapy, up to 30 years of data on normotensive and untreated hypertensive subjects from biennial examinations 2 through 16 were used. Regressions of blood pressure versus age within individual subjects produced slope and curvature estimates that were compared with the use of ANOVA among the four SBP groups. There was a linear rise in SBP from age 30 through 84 years and concurrent increases in diastolic blood pressure (DBP) and mean arterial pressure (MAP); after age 50 to 60 years, DBP declined, pulse pressure (PP) rose steeply, and MAP reached an asymptote. Neither the fall in DBP nor the rise in PP was influenced significantly by removal of subsequent deaths and subjects with nonfatal myocardial infarction or heart failure. Age-related linear increases in SBP, PP, and MAP, as well as the early rise and late fall in DBP, were greatest for subjects with the highest baseline SBP; this represents a divergent rather than parallel tracking pattern. CONCLUSIONS: The late fall in DBP after age 60 years, associated with a continual rise in SBP, cannot be explained by "burned out" diastolic hypertension or by "selective survivorship" but is consistent with increased large artery stiffness. Higher SBP, left untreated, may accelerate large artery stiffness and thus perpetuate a vicious cycle.

BACKGROUND: The optimal combination drug therapy for hypertension is not established, although current U.S. guidelines recommend inclusion of a diuretic. We hypothesized that treatment with the combination of an angiotensin-converting-enzyme (ACE) inhibitor and a dihydropyridine calcium-channel blocker would be more effective in reducing the rate of cardiovascular events than treatment with an ACE inhibitor plus a thiazide diuretic. METHODS: In a randomized, double-blind trial, we assigned 11,506 patients with hypertension who were at high risk for cardiovascular events to receive treatment with either benazepril plus amlodipine or benazepril plus hydrochlorothiazide. The primary end point was the composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, hospitalization for angina, resuscitation after sudden cardiac arrest, and coronary revascularization. RESULTS: The baseline characteristics of the two groups were similar. The trial was terminated early after a mean follow-up of 36 months, when the boundary of the prespecified stopping rule was exceeded. Mean blood pressures after dose adjustment were 131.6/73.3 mm Hg in the benazepril-amlodipine group and 132.5/74.4 mm Hg in the benazepril-hydrochlorothiazide group. There were 552 primary-outcome events in the benazepril-amlodipine group (9.6%) and 679 in the benazepril-hydrochlorothiazide group (11.8%), representing an absolute risk reduction with benazepril-amlodipine therapy of 2.2% and a relative risk reduction of 19.6% (hazard ratio, 0.80, 95% confidence interval [CI], 0.72 to 0.90; P<0.001). For the secondary end point of death from cardiovascular causes, nonfatal myocardial infarction, and nonfatal stroke, the hazard ratio was 0.79 (95% CI, 0.67 to 0.92; P=0.002). Rates of adverse events were consistent with those observed from clinical experience with the study drugs. CONCLUSIONS: The benazepril-amlodipine combination was superior to the benazepril-hydrochlorothiazide combination in reducing cardiovascular events in patients with hypertension who were at high risk for such events. (ClinicalTrials.gov number, NCT00170950.)

These guidelines have been written to provide a straightforward approach to managing hypertension in the community. We have intended that this brief curriculum and set of recommendations be useful not only for primary care physicians and medical students, but for all professionals who work as hands-on practitioners. We are aware that there is great variability in access to medical care among communities. Even in so-called wealthy countries there are sizable communities in which economic, logistic, and geographic issues put constraints on medical care. And, at the same time, we are been reminded that even in countries with highly limited resources, medical leaders have assigned the highest priority to supporting their colleagues in confronting the growing toll of devastating strokes, cardiovascular events, and kidney failure caused by hypertension. Our goal has been to give sufficient information to enable health care practitioners, wherever they are located, to provide professional care for people with hypertension. All the same, we recognize that it will often not be possible to carry out all of our suggestions for clinical evaluation, tests, and therapies. Indeed, there are situations where the most simple and empirical care for hypertension—simply distributing whatever antihypertensive drugs might be available to people with high blood pressure—is better than doing nothing at all. We hope that we have allowed sufficient flexibility in this statement to enable responsible clinicians to devise workable plans for providing the best possible care for patients with hypertension in their communities. Note: This preferably should be a fasting sample so that a fasting blood glucose level and more accurate lipid profiles can be obtained. Several lifestyle interventions have been shown to reduce blood pressure. Apart from contributing to the treatment of hypertension, these strategies are beneficial in managing most of the other cardiovascular risk factors. In patients with hypertension that is no more severe than stage 1 and is not associated with evidence of abnormal cardiovascular findings or other cardiovascular risks, 6 to 12 months of lifestyle changes can be attempted in the hope that they may be sufficiently effective to make it unnecessary to use medicines. However, it may be prudent to start treatment with drugs sooner if it is clear that the blood pressure is not responding to the lifestyle methods or if other risk factors appear. Also, in practice settings where patients have logistical difficulties in making regular clinic visits, it might be most practical to start drug therapy early. In general, lifestyle changes should be regarded as a complement to drug therapy rather than an alternative. Starting treatment: (see the algorithm in the Figure). Treatment with drugs should be started in patients with blood pressures >140/90 mm Hg in whom lifestyle treatments have not been effective. (Note: As discussed earlier in Section 12 on Nonpharmacologic Treatment, drug treatment can be delayed for some months in patients with stage 1 hypertension who do not have evidence of abnormal cardiovascular findings or other risk factors. In settings where healthcare resources are highly limited, clinicians can consider extending the nondrug observation period in uncomplicated stage 1 hypertensive patients provided there is no evidence for an increase in blood pressure or the appearance of cardiovascular or renal findings). In patients with stage 2 hypertension (blood pressure ≥160/100 mm Hg), drug treatment should be started immediately after diagnosis, usually with a 2-drug combination, without waiting to see the effects of lifestyle changes. Drug treatment can also be started immediately in all hypertensive patients in whom, for logistical or other practical reasons, the practitioner believes it is necessary to achieve more rapid control of blood pressure. The presence of other cardiovascular risk factors should also accelerate the start of hypertension treatment. Note: There is an assumption, unless otherwise stated, that all drugs in a class are similar to each other. We only mention individual agents if they have an important property that is not shared by the others in its class. Table 2 provides a list of commonly used antihypertensive drugs and their doses. Note: Thiazides plus β-blockers are also an effective combination for reducing blood pressure, but since both classes can increase blood glucose concentrations this combination should be used with caution in patients at risk for developing diabetes. The authors of this statement acknowledge that there are insufficient published data from clinical trials in hypertension to create recommendations that are completely evidence-based, and so inevitably some of our recommendations reflect expert opinion and experience. We also should point out that because of the major differences in resources among points of care it is not possible to create a uniform set of guidelines. For this reason we have written a broad statement on the management of hypertension and have not presumed to anticipate the conditions or shortfalls that might exist in particular communities. We expect that experts who are familiar with local circumstances will feel free to use their own judgment in modifying our recommendations and to create practical instructions to help guide front-line practitioners in providing the best care possible. The authors of this statement would welcome comments and suggestions from colleagues. We recognize that in this initial version of the guidelines there will probably be omissions, redundancies, and inaccuracies. Please feel free to get in touch with us either by letters to the Journal or by personal communication. This statement was written under the sponsorship of the American Society of Hypertension and the International Society of Hypertension. In addition, the Asia Pacific Society of Hypertension has endorsed these guidelines. The statement was prepared without any external funding. The work and time of the authors was provided by them entirely on a volunteer basis. MAW: Research funding: Medtronics. Consulting: Boehringer-Ingelheim, Novartis, Daichi Sankyo, Takeda, Forest. Speaker: Daiichi Sankyo, Takeda, Forest. ELS: Research Funding: Canadian Institutes of Health Research, Canada Research Chairs program of CIHR/Government of Canada, Servier France. Consultant: Servier, Novartis. Speaker: Forest Canada, Pfizer Japan. WBW: Research Funding: National Institutes of Health. Consulting: Safety Committees (DSMB, CEC, Steering Committees); Ardea Biosciences, Inc.; AstraZeneca; Dendreon, Forest Research Institute, Inc.; Roche; St. Jude's Medical, Takeda Global Research, Teva Neuroscience. SM, LHL, JGK, BJM, DLC, JCC, RRJC, ST, AJR, AES, RMT: No conflicts of interest. JMF: Research Funding: Novartis, Medtronic. Consultant: Novartis, Medtronic, Back Beat Hypertension. BLC: Research Funding: NIH and VA. VSR: Consultant: Medtronic, Daiichi-Sankyo, Forest. DK: Research Funding: Medtronic. RT: Research Funding: NIH. Consultant: Medtronic, Janssen, Merck, GSK. JC: Research Funding and Speaker: Servier in relation to ADVANCE trial and Post-trial study. GLB: Research Funding: Takeda. Consultant: Takeda, AbbVie, Daiichi-Sankyo, Novartis, CVRx, Medtronic, Relypsa, Janssen, BMS. JW: Consultant and Speaker: Boehringer-Ingelheim, MSD, Novartis, Omron, Pfizer, Servier, and Takeda. JDB: Research and Consultant: CVRx. DS: Research: Medtronic, CVRx. Consultant: Takeda, UCB, Novartis, Medtronic, CVRx. Speaker: Takeda. SBH: Speaker: Novartis, Servier.