Heterogeneity in Early Responses in ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial).

Randomized trials of hypertension have seldom examined heterogeneity in response to treatments over time and the implications for cardiovascular outcomes. Understanding this heterogeneity, however, is a necessary step toward personalizing antihypertensive therapy. We applied trajectory-based modeling to data on 39 763 study participants of the ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) to identify distinct patterns of systolic blood pressure (SBP) response to randomized medications during the first 6 months of the trial. Two trajectory patterns were identified: immediate responders (85.5%), on average, had a decreasing SBP, whereas nonimmediate responders (14.5%), on average, had an initially increasing SBP followed by a decrease. Compared with those randomized to chlorthalidone, participants randomized to amlodipine (odds ratio, 1.20; 95% confidence interval [CI], 1.10-1.31), lisinopril (odds ratio, 1.88; 95% CI, 1.73-2.03), and doxazosin (odds ratio, 1.65; 95% CI, 1.52-1.78) had higher adjusted odds ratios associated with being a nonimmediate responder (versus immediate responder). After multivariable adjustment, nonimmediate responders had a higher hazard ratio of stroke (hazard ratio, 1.49; 95% CI, 1.21-1.84), combined cardiovascular disease (hazard ratio, 1.21; 95% CI, 1.11-1.31), and heart failure (hazard ratio, 1.48; 95% CI, 1.24-1.78) during follow-up between 6 months and 2 years. The SBP response trajectories provided superior discrimination for predicting downstream adverse cardiovascular events than classification based on difference in SBP between the first 2 measurements, SBP at 6 months, and average SBP during the first 6 months. Our findings demonstrate heterogeneity in response to antihypertensive therapies and show that chlorthalidone is associated with more favorable initial response than the other medications.

Unsuccessfully Treated Hypertension: A Major Public Health Problem With a Potential Solution.

BACKGROUND: About one-half of all hypertensive adults do not have their blood pressure controlled. They are often prescribed medications that conform to national guidelines but they continue to have elevated blood pressure. This public health problem might be improved by applying plasma renin guided therapy. RESULTS: A contributor to the public health problem of unsuccessfully treated hypertension is that the circulating renin-angiotensin system (RAS) is not recognized in treatment guidelines as clinically relevant for the treatment of hypertension or as important as the body salt status for determining blood pressure levels. Another contributor to the problem is the lack of specificity in the package inserts for antihypertensive drugs. They do not specifically state under the heading "Indications" that RAS blockers are primarily most effective in hypertensive subjects with medium and high plasma renin levels; by contrast, natriuretic drugs are most effective in those with low plasma renin levels. METHODS: Literature review. CONCLUSIONS: To address the problem of unsuccessfully treated hypertension, we recommend that the "Indications" section of package inserts for antihypertensive drugs be more specific. The primary indication for RAS blockers ought to be hypertension with medium and high plasma renin levels, and natriuretic agents for those with low plasma renin levels. Similar language ought to be added to treatment guidelines. Additionally, 3 other reasons for lack of blood pressure control also need to be addressed-failure to prescribe antihypertensive drugs to hypertensive subjects, failure of patients to fill prescriptions, and low drug adherence.

Diabetes and Cognitive Decline in Older Adults: The Ginkgo Evaluation of Memory Study.

BACKGROUND: Previous studies have shown that individuals with diabetes exhibit accelerated cognitive decline. However, methodological limitations have limited the quality of this evidence. Heterogeneity in study design, cognitive test administration, and methods of analysis of cognitive data have made it difficult to synthesize and translate findings to practice. We analyzed longitudinal data from the Ginkgo Evaluation of Memory Study to test our hypothesis that older adults with diabetes have greater test-specific and domain-specific cognitive declines compared to older adults without diabetes. METHODS: Tests of memory, visuo-spatial construction, language, psychomotor speed, and executive function were administered. Test scores were standardized to z-scores and averaged to yield domain scores. Linear random effects models were used to compare baseline differences and changes over time in test and domain scores among individuals with and without diabetes. RESULTS: Among the 3,069 adults, aged 72-96 years, 9.3% reported diabetes. Over a median follow-up of 6.1 years, participants with diabetes exhibited greater baseline differences in a test of executive function (trail making test, Part B) and greater declines in a test of language (phonemic verbal fluency). For the composite cognitive domain scores, participants with diabetes exhibited lower baseline executive function and global cognition domain scores, but no significant differences in the rate of decline. CONCLUSIONS: Identifying cognitive domains most affected by diabetes can lead to targeted risk modification, possibly in the form of lifestyle interventions such as diet and physical activity, which we know to be beneficial for improving vascular risk factors, such as diabetes, and therefore may reduce the risk of executive dysfunction and possible dementia.

The Harms of Antipsychotic Drugs: Evidence from Key Studies.

This safety assessment provides a detailed analysis of key studies and focuses on the six most widely used antipsychotic drugs. Lines of evidence include mechanisms of action, short-term treatment of psychosis, relapse prevention, early intervention in schizophrenia, long-term comparisons between first- and second-generation agents, and flexible treatment algorithms. Despite the diversity of study settings, several common features were seen. All the agents obstruct normal signaling through widely dispersed dopamine D2 receptors. Treatment failure or psychosis relapse was the most frequent outcome in most key studies, ranging from 38 to 93%. High discontinuation rates caused most trials to fail to demonstrate a substantial treatment benefit, or difference from an active comparator. Assessment of harm to the extrapyramidal motor system was confounded because of extensive neurological impairment from previous antipsychotic drug treatment measured at baseline, abrupt discontinuation effects, and high rates of concomitant medications to manage drug adverse effects. Claims that second-generation antipsychotic drugs have safety advantages over classical neuroleptic drugs and prevent relapse were not supported in these key studies. The extent of injury to and impairment of multiple body systems caused by antipsychotic drugs shows the need for a scientific, clinical, and regulatory reappraisal of the appropriate use of these agents.

Age and Cardiovascular Risk Attributable to Apolipoprotein B, Low-Density Lipoprotein Cholesterol or Non-High-Density Lipoprotein Cholesterol.

BACKGROUND: Higher concentrations of the apolipoprotein B (apoB) lipoproteins increase the risk of cardiovascular disease. However, whether the risk associated with apoB lipoproteins varies with age has not been well examined. METHODS AND RESULTS: We determined the associations for total cholesterol, low-density lipoprotein (LDL)-cholesterol (LDL-C), non-high-density lipoprotein-cholesterol (non-HDL-C), apoB, apolipoprotein A-I (apoA-I), and HDL-cholesterol (HDL-C) with myocardial infarction at different ages in 11 760 controls and 8998 myocardial infarction cases of the INTERHEART Study. Logistic regression was used to compute the odds ratio of myocardial infarction for 1 SD change in each lipid marker by decade from <40 to >70 years of age. Except for those >70, plasma levels of total cholesterol, LDL-C, and non-HDL-C and apoB were greater in cases than controls. However, the average levels of these markers decreased significantly as age increased. By contrast, levels of apoA-I and HDL-C were significantly greater in controls than cases but increased significantly as age increased. The cardiovascular risk associated with the atherogenic lipid markers differed at different ages. Most notably, there was a significant decline in the odds ratio for total cholesterol, LDL-C, and non-HDL-C, and apoB with increases in age whereas the odds ratios associated with apoA-I and HDL-C were consistent across the age groups. CONCLUSIONS: These data indicate that the risk of cardiovascular events associated with apoB particles is greater in younger compared to older individuals. This finding is consistent with greater relative benefit from LDL-lowering therapy in younger compared to older individuals and so argues for therapy in younger individuals with elevated lipids.

An evidence-based analysis of the National Lipid Association recommendations concerning non-HDL-C and apoB.

BACKGROUND: The National Lipid Association (NLA) selected non-HDL-C as its prime index of the cardiovascular risk associated with the apoB lipoproteins. ApoB was recommended only as an optional secondary target after low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (HDL-C) targets were achieved. OBJECTIVE: The aims of this analysis were to determine whether (1) all relevant uses of apoB were considered by the NLA; (2) all the relevant evidence was considered by the NLA panel; and (3) all the evidence that was considered was interpreted correctly. RESULTS: (1) The utility of apoB in the diagnosis of the atherogenic dyslipoproteinemias was not considered. (2) All the relevant observational studies were not identified, and some that were cited were incorrectly interpreted. In particular, an equal hazard ratio for two markers in a group does not mean they will predict risk equally in individuals within the group in whom they are discordant. This matters because discordance analysis consistently demonstrates apoB and LDL particle number are more accurate measures of cardiovascular risk than LDL-C/non-HDL-C. (3) The target levels of apoB selected by the NLA are too high relative to the levels selected for LDL-C and non-HDL-C. CONCLUSIONS: The review of the evidence by the NLA was incomplete. More complete examination of the evidence indicates that apoB is a more accurate marker of cardiovascular risk than non-HDL-C and that the practice of lipidology would be improved by inclusion of apoB along with lipoprotein lipids in routine clinical care.

Completeness of serious adverse drug event reports received by the US Food and Drug Administration in 2014.

PURPOSE: Adverse drug event reports to the US Food and Drug Administration (FDA) remain the primary tool for identifying serious drug adverse effects without adequate existing warnings. We assessed the completeness of reports the FDA received in 2014. METHODS: Serious adverse drug event reports were evaluated for whether they included age, gender, event date, and at least one medical term describing the event in computer excerpts. Report sources were direct reports to the FDA, manufacturer expedited reports about events without adequate warnings, and manufacturer periodic reports about events with existing warnings. RESULTS: In 2014, the FDA received 528,192 new case reports indicating a serious or fatal outcome, 25,038 (4.7%) directly from health professionals and consumers, and 503,154 (95.3%) from drug manufacturers. Overall, 21,595 (86.2%) of serious reports submitted directly to the FDA provided data for all four completeness variables, compared with 271,022 (40.4%) of manufacturer expedited reports and 24,988 (51.3%) of periodic reports. Among manufacturer serious reports, 37.9% lacked age and 46.9% had no event date. Performance by 25 manufacturers submitting 5000 or more reports varied from 24.4% complete on all variables to 67% complete. Patient death cases had the lowest completeness scores in all categories. CONCLUSIONS: By these measures, report completeness from drug manufacturers was poor compared with direct submissions to the agency. The FDA needs to update reporting requirements and compliance policies to help industry capture better adverse event information from new forms of manufacturer interactions with health professionals and consumers. Copyright © 2016 John Wiley & Sons, Ltd.

Lipoprotein-Associated Phospholipase A2 and Incident Peripheral Arterial Disease in Older Adults: The Cardiovascular Health Study.

OBJECTIVE: Although prior studies report a relationship between elevated lipoprotein-associated phospholipase A2 (Lp-PLA2) and incident cardiovascular disease, the prospective association of Lp-PLA2 with incident peripheral arterial disease (PAD) has not been studied. We investigated the association between Lp-PLA2 mass and activity and the risk of developing clinical PAD and low ankle-brachial index (ABI). APPROACH AND RESULTS: Among Cardiovascular Health Study participants, a population-based cohort of 5888 adults aged ≥65 years enrolled in 1989 to 1990, Lp-PLA2 mass and activity were measured in 4537 individuals without baseline PAD. Clinical PAD, defined as leg artery revascularization or diagnosed claudication, was ascertained through 2011. Incident low ABI, defined as ABI <0.9 and decline of ≥0.15, was assessed among 3537 individuals who had an ABI >0.9 at baseline and a second ABI measurement 3 or 6 years later. Analyses were adjusted for demographics, cholesterol, smoking, comorbidities, and C-reactive protein. Each standard deviation increment in Lp-PLA2 mass (117 ng/mL) was associated with a higher risk of developing clinical PAD (hazard ratio 1.28; 95% confidence interval 1.13, 1.45) and incident low ABI (odds ratio 1.16; 95% confidence interval 1.00, 1.33). Results per standard deviation increment in Lp-PLA2 activity (13 nmol/min per mL) were similar for clinical PAD (hazard ratio 1.24; 95% confidence interval 1.07, 1.44) and low ABI (odds ratio 1.28; 95% confidence interval 1.09, 1.50). CONCLUSIONS: Higher Lp-PLA2 mass and activity were associated with development of both incident clinical PAD and low ABI. Future studies are needed to determine whether pharmacological inhibition of Lp-PLA2 reduces the incidence of PAD.

Electronic Health Data for Postmarket Surveillance: A Vision Not Realized.

What has been learned about electronic health data as a primary data source for regulatory decisions regarding the harms of drugs? Observational studies with electronic health data for postmarket risk assessment can now be conducted in Europe and the US in patient populations numbering in the tens of millions compared with a few hundred patients in a typical clinical trial. With standard protocols, results can be obtained in a few months; however, extensive research published by scores of investigators has illuminated the many obstacles that prevent obtaining robust, reproducible results that are reliable enough to be a primary source for drug safety decisions involving the health and safety of millions of patients. The most widely used terminology for coding patient interactions with medical providers for payment has proved ill-suited to identifying the adverse effects of drugs. Directly conflicting results were reported in otherwise similar patient health databases, even using identical event definitions and research methods. Evaluation of some accepted statistical methods revealed systematic bias, while others appeared to be unreliable. When electronic health data studies detected no drug risk, there were no robust and accepted standards to judge whether the drug was unlikely to cause the adverse effect or whether the study was incapable of detecting it. Substantial investment and careful thinking is needed to improve the reliability of risk assessments based on electronic health data, and current limitations need to be fully understood.

Is the Guideline Process Replicable and, if Not, What Does This Mean?

Increasingly, guidelines determine how medical care will be provided. However there has been limited study of the determinants of the reliability of the guideline process. Guidelines translate evidence into recommendations. If only the evidence determines the recommendations, given the same evidence, different panels of experts should make the same recommendations. That is, the process should be replicable, an essential characteristic of a valid scientific process. The multiple recent cholesterol guidelines, which have considered the same evidence, offer an opportunity to examine guidelines from this perspective. Considerable discordance among the guideline recommendations is evident pointing to an important role for the participants, in addition to the evidence, in the development of guideline recommendations. Guideline recommendations, therefore, appear to be based on both evidence and expert opinion.

Apolipoprotein B improves risk assessment of future coronary heart disease in the Framingham Heart Study beyond LDL-C and non-HDL-C.

AIMS: Analyses using conventional statistical methodologies have yielded conflicting results as to whether low-density lipoprotein cholesterol (LDL-C) or non-high-density lipoprotein cholesterol (non-HDL-C) or apolipoprotein B (apoB) is the best marker of the apoB-associated risk of coronary heart disease. The aim of this study was to determine the additional value of apoB beyond LDL-C or non-HDL-C as a predictor of coronary heart disease. METHODS AND RESULTS: For each patient from the Framingham Offspring Cohort aged 40-75 years (n = 2966), we calculated the extent to which the observed apoB differed from the expected apoB based on their LDL-C or non-HDL-C. We added this difference to a Cox model predicting new onset coronary heart disease over a maximum of 20 years adjusting for standard risk factors plus LDL-C or non-HDL. The difference between observed and expected apoB over LDL-C or non-HDL-C was highly prognostic of future coronary heart disease events: adjusted hazard ratios 1.26 (95% confidence interval: 1.15, 1.37) and 1.20 (1.11, 1.29), respectively, for each standard deviation increase beyond expected apoB levels. When this difference between observed and expected apoB was added to standard coronary heart disease prediction models including LDL-C or non-HDL-C, prediction improved significantly (likelihood ratio test p-values <0.0001) and discrimination c-statistics increased from 0.72 to 0.73. The corresponding relative integrated discrimination improvements were 11% and 8%, respectively. CONCLUSIONS: apoB improves risk assessment of future coronary heart disease events over and beyond LDL-C or non-HDL-C, which is consistent with coronary risk being more closely related to the number of atherogenic apoB particles than to the mass of cholesterol within them.

Plasma renin testing to guide antihypertensive therapy.

Plasma renin activity (PRA)-guided therapy has been proposed as a strategy for selecting antihypertensive medications matched to the patient's underlying pathophysiology. To date, there are only a few studies that have sought to compare a PRA-guided strategy to usual care. In one trial of 363 untreated patients, based on home blood pressure (BP) averages, PRA was predictive of responses to beta-blocker and thiazide diuretic as monotherapy and add-on therapy. In another trial of 77 treated but uncontrolled patients, a PRA-guided strategy was superior to clinical hypertension specialist care for guiding add-on or subtraction (stopping an agent that might cause a paradoxical pressor response) therapy. In the ValVET study, PRA-guided therapy was not superior to fixed-dose therapy consisting of an angiotensin receptor blocker and hydrochlorothiazide. One modeling study found a PRA-guided strategy may be cost-effective compared to standard care for younger patients and those with a greater number of cardiovascular risk factors. We conclude that additional, well-designed randomized trials with sufficient sample sizes comparing PRA-guided management to usual care are needed to clarify whether this strategy should be adopted broadly.

The Risk-Benefit Paradigm vs the Causal Exposure Paradigm: LDL as a primary cause of vascular disease.

All current guidelines use the 10-year risk of a cardiovascular event to select subjects for statin primary preventive therapy. Benefit from therapy is stated to be determined by risk with the result that statin primary preventive therapy is initiated only when the risk of a cardiovascular event over the next decade exceeds a specified level. Thus all current guidelines are based primarily on the Risk-Benefit paradigm of primary prevention. The recent American Heart Association/American College of Cardiology guidelines differ from others in basing selection for statin therapy virtually exclusively on risk except for those few subjects with markedly elevated levels of low-density lipoprotein cholesterol (LDL-C). The Causal Exposure paradigm differs from the Risk-Benefit paradigm in that the objective of therapy is to prevent the anatomic disease within arterial walls that produces cardiovascular risk. Moreover, the anatomic disease and, therefore, the cardiovascular risk, is a function of the injurious action of the causal factors of vascular disease, such as blood pressure and LDL, on the arterial wall over long periods. In this article, we explain the strengths and weaknesses of both paradigms to provide a more secure framework to compare the strengths and weaknesses in the different cholesterol guidelines with particular emphasis on the evidence that the cardiovascular risk and the benefit from statin therapy is related to the level of LDL.

A pilot test of a new tool for remote blood pressure monitoring.

We conducted a pilot trial of a remote blood pressure (BP) monitoring system, in which subjects measured their own BP at a primary healthcare centre. The data were wirelessly transmitted to the general practitioner. A total of 132 subjects with a new or prior diagnosis of hypertension were enrolled. Their mean age was 61 years and 77 were men (58%). They were followed for an average of 487 days (range 19-1110). The median number of BP measurements made was 6 per patient (range 2-49). The mean blood pressure decreased from 137/85 to 132/78 mmHg (P < 0.001) and the percentage of subjects with adequately controlled BP (defined as < 140/90 mmHg) increased from 47 to 66% (P < 0.01). Randomised trials are now required to confirm these findings.

Relations of change in plasma levels of LDL-C, non-HDL-C and apoB with risk reduction from statin therapy: a meta-analysis of randomized trials.

BACKGROUND: Identifying the best markers to judge the adequacy of lipid-lowering treatment is increasingly important for coronary heart disease (CHD) prevention given that several novel, potent lipid-lowering therapies are in development. Reductions in LDL-C, non-HDL-C, or apoB can all be used but which most closely relates to benefit, as defined by the reduction in events on statin treatment, is not established. METHODS AND RESULTS: We performed a random-effects frequentist and Bayesian meta-analysis of 7 placebo-controlled statin trials in which LDL-C, non-HDL-C, and apoB values were available at baseline and at 1-year follow-up. Summary level data for change in LDL-C, non-HDL-C, and apoB were related to the relative risk reduction from statin therapy in each trial. In frequentist meta-analyses, the mean CHD risk reduction (95% CI) per standard deviation decrease in each marker across these 7 trials were 20.1% (15.6%, 24.3%) for LDL-C; 20.0% (15.2%, 24.7%) for non-HDL-C; and 24.4% (19.2%, 29.2%) for apoB. Compared within each trial, risk reduction per change in apoB averaged 21.6% (12.0%, 31.2%) greater than changes in LDL-C (P<0.001) and 24.3% (22.4%, 26.2%) greater than changes in non-HDL-C (P<0.001). Similarly, in Bayesian meta-analyses using various prior distributions, Bayes factors (BFs) favored reduction in apoB as more closely related to risk reduction from statins compared with LDL-C or non-HDL-C (BFs ranging from 484 to 2380). CONCLUSIONS: Using both a frequentist and Bayesian approach, relative risk reduction across 7 major placebo-controlled statin trials was more closely related to reductions in apoB than to reductions in either non-HDL-C or LDL-C.